DE102009038950A1 - New antiparasitic combination of drugs - Google Patents

Abstract

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

Description

The present invention relates to the combined use of substituted benzimidazoles and 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 nitro-substituted benzimidazoles and polyether antibiotics have become known as coccidiosis agents ( US 5,331,003 ). Mixtures of substituted benzimidazoles with polyether antibiotics or synthetic coccidiosis agents as agents for controlling parasitic protozoa are out WO 96/38140 known.

Diseases caused by parasitic protozoa, such as coccidioses, are common infections in animals; so are z. B. subcutaneous infections caused by protozoa of the genera Coccidia, sarcosporidium and toxoplasma in the pig worldwide. 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 useful in controlling coccidia is disclosed in U.S. Pat EP 0 330 041 A2 described. Other applications of these compounds are in EP 0 353 526 A2 and EP 0 377 904 A2 disclosed.

Out WO 2006/024428 For example, combinations of diclazuril and similar 1,2,4-triazinediones with substituted benzimidazoles active against parasitic protozoa are known. Of the 1,2,4-triazinediones described therein, 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 development of resistance to the known means of use leads to serious problems shortly after the introduction of the funds. 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.

in welcher
R¹ für über Kohlenstoff gebundene heteroaromatische Reste steht, die gegebenenfalls substituiert sind,
X für O, S, SO oder SO₂ steht,
R² für einen oder mehrere, gleiche oder verschiedene Reste der Gruppe Wasserstoff, Halogen, Nitro, Alkyl, Alkoxy, Alkylthio, Halogenalkyl, Halogenalkoxy und Halogenalkylthio steht,
R³ für Wasserstoff, gegebenenfalls substituiertes Alkyl, Alkenyl, Alkinyl, Aralkyl steht,
oder dessen physiologisch verträgliches Salz.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 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.

in welcher
Z für Wasserstoff oder den Rest -CHR²R³ steht,
R¹ für Fluoralkyl steht,
R² für Wasserstoff oder Alkyl steht,
R³ für einen Rest der Formel

oder für einen Rest der Formel

R⁴ für Alkyl steht,
R⁵ für Alkyl oder substituiertes Phenyl steht,
R⁶ für Alkyl steht,
X¹, X², X³ und X⁴ unabhängig voneinander für Wasserstoff, Halogen, Halogenalkyl, Halogenalkoxy, Halogenalkylthio oder Halogenalkylsulfonyl stehen, oder auch
X² und X³ oder X³ und X⁴ gemeinsam für einen Dioxyhaloalkylen-Rest stehen.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 ^{4 is} alkyl,
R ^{5 is} alkyl or substituted phenyl,
R ^{6 is} alkyl,
X ¹ , X ² , X ³ and X ⁴ are each independently hydrogen, halogen, haloalkyl, haloalkoxy, haloalkylthio or haloalkylsulfonyl, or also
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:
R ¹ 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 ⁵ is preferably C _1-6 -alkyl or phenyl which is optionally mono- or polysubstituted by C _1-4 -alkyl, C _1-4 -haloalkyl, halogen, nitro, C _1-4 -alkoxy, C _{1 -4} haloalkoxy or optionally substituted one or more times with halogen methylene or ethylenedioxy.
R ⁶ is preferably C _1-4 -alkyl
X ¹ , X ² , X ³ and X ⁴ 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 haloalkylsulfonyl, or
X ² and X ³ or X ³ and X ⁴ according to another preferred embodiment together represent a dioxyhalo-C ₁ -C ₄ -alkylene radical.
R ¹ particularly preferably represents CF ₃ , CHF ₂ or CHF.
R ² particularly preferably represents hydrogen, methyl, ethyl, n-propyl or isopropyl.
R ⁴ particularly preferably represents methyl, ethyl, n-propyl or isopropyl.
R ⁵ particularly preferably represents C _1-6 -alkyl.
R ⁶ particularly preferably represents methyl or ethyl.
X ¹ , X ² , X ³ and X ⁴ are particularly preferably each independently 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 ² and X ³ or X ³ and X ⁴ are according to a further embodiment particularly preferably also together 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 -CClF-O-.

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

R¹ steht ganz besonders bevorzugt für -CF₃.
R² steht ganz besonders bevorzugt für Wasserstoff.
R⁴ steht ganz besonders bevorzugt für Methyl.
X¹ steht ganz besonders bevorzugt für Cl oder Br.
X² steht ganz besonders bevorzugt für Wasserstoff.
X³ und X⁴ stehen ganz besonders bevorzugt gemeinsam für -OCF₂-CF₂-O-.According to a further very particularly preferred embodiment, R ^{3 is} a radical of the formula

R ¹ very particularly preferably represents -CF ₃ .
R ² very particularly preferably represents hydrogen.
R ⁴ is very particularly preferably methyl.
X ¹ is very particularly preferably Cl or Br.
X ² is very particularly preferably hydrogen.
X ³ and X ⁴ most preferably together represent -OCF ₂ -CF 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 especially 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, for. B. WO 00/04022 . WO 00/68225 and EP 597 304 A1 and the literature cited therein.

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

According to a preferred further embodiment, Z in formula (II) is the radical -CHR ² R ³ and the other substituents may have the meanings given above, including the preferred and particularly preferred meanings. As preferred examples of this embodiment be the compound of formula (II-B) (see WO00 / 04022 ) and in particular the compound of formula (II-C) (see WO00 / 68225 ) called:

in welcher
R¹ für über Kohlenstoff gebundene heteroaromatische Reste steht, die gegebenenfalls substituiert sind,
X für O, S, SO oder SO₂ steht,
R² für einen oder mehrere, gleiche oder verschiedene Reste der Gruppe Wasserstoff, Halogen, Nitro, Alkyl, Alkoxy, Alkylthio, Halogenalkyl, Halogenalkoxy und Halogenalkylthio steht,
R³ für Wasserstoff, gegebenenfalls substituiertes Alkyl, Alkenyl, Alkinyl, Aralkyl steht,
gegebenenfalls in Form ihrer physiologisch verträglichen Salze.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 stands for O,
R ^{1 is} thiazolyl, benzthiazolyl or benzoxazolyl which is optionally substituted by C _1-4 -alkyl, in particular methyl; C _1-4 haloalkyl, in particular trifluoromethyl; Halogen, in particular chlorine, bromine, fluorine; Nitro, CN, amino, C _1-4 -alkylamino, C _1-4 -haloalkylamino, acylamino, C _1-4 -alkoxy, especially methoxy; C _1-4 haloalkoxy, especially trifluoromethoxy; C _1-4 alkylthio, in particular methylthio; C _1-4 -haloalkylthio, in particular trifluoromethylthio, C _1-4 -alkylsulfonyl, in particular methylsulfonyl and C _1-4 -haloalkylsulfonyl, in particular trifluoromethylsulfonyl,
R 2 is one or more radicals of the group hydrogen or halogen, in particular chlorine, bromine, C _1-4 -alkyl, in particular methyl,
R3 is hydrogen.

Very particular preference is given to compounds of the formula (I) in which
X stands for 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 most preferred compounds of formula (I), the following substituent meanings are emphasized:
R ¹ is optionally substituted by chlorine, methyl or trifluoromethyl-substituted benzothiazolyl,
R ² is a methyl radical.

As a preferred single compound, the following compound (IA) may be mentioned:

The compounds of formula (I) are in EP 330 041 A2 and can be prepared according to the methods 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, more 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, z. 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; z. B. -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 ; z. B. 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, particularly preferably 2 to 4 carbon atoms and one or more double bonds, completely particularly preferably having 2 to 3 carbon atoms and one double bond. Examples which may be mentioned are: 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, particularly 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 ingredients include, depending on the structure of the active ingredient acid addition salts of mineral acids, carboxylic acids and sulfonic acids, eg. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids, 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 with 1 to 16 C atoms, such as, by way of example and by way of preference, 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" includes compounds which may themselves be biologically active or inactive, however be converted during their residence time in the body to the actual active ingredient (for example, metabolically or hydrolytically).

The products according to the invention are suitable for controlling the toxicity of warm-blooded animals for controlling parasitic protozoa which occur in livestock and livestock breeding in livestock, 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 strains. By combating parasitic protozoa diseases, deaths and reductions in performance (eg in the 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 is possible.

The parasitic protozoa include:
Mastigophora (flagellata) such. B. Trypanosomatidae z. B. Trypanosoma b. Brucei, T. b. gambiense, T. b. 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 z. B. Trichomonadidae z. BT fetus, Tritrichomonas suis, Trichomitus rotunda, Tetratrichomonas buttreyi, Giardia duodenalis (syn. Intestinalis, G. lamblia, G. bovis, G. caprae), G. canis.
Sarcomastigophora (Rhizopoda) as Entamoebidae such. B. Entamoeba histolytica, E. bovis, E. ovis, E. dilimani, Hartmanellidae z. Acanthamoeba sp., Hartmanella sp.
Apicomplexa (Sporozoa) as Eimeridae z. E., A. anatis, 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. 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.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., E.stiedai, E.south, 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. as Toxoplasmadidae z. B. Toxoplasma gondii, such as Sarcocystidae z. B. 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 z. B. Leucozytozoon simondi, such as Plasmodiidae z. Plasmodium berghei, P. falciparum, P. malariae, P. ovale, P. vivax, P. spec., Such as Piroplasmea z. Babesia argentina, B. bovis, B. canis, B. divergens, B. bigemina, B. trautmanni, B. perroncitoi, B. spec., Theileria parva, T. annulata, T. lawrencei, Theileria spec Adeleina z. B. Hepatozoon canis, H. spec. Besnoitia besnoiti, B. tarandi, B. caprae.
Furthermore, Myxospora and Microspora z. Glugea spec. Nosema spec.
Furthermore, Pneumocystis carinii, and Ciliophora (Ciliata) such. B. Balantidium coli, Ichthiophthirius spec., Trichodina spec., 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.

For the breeding and breeding animals include mammals such. B. cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur animals such. As mink, chinchilla, raccoon, birds such. As chickens, geese, turkeys, ducks, pigeons, bird species for home and zookeeping. 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 z. 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., Chichlidae species such. Plagioscion, Channel catfish. Particularly suitable are the agents according to the invention for the treatment of fish fry, z. B. 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. As an example of a particularly important pathogen in pig Isospora suis is called.

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.

The enteral application of the active ingredients happens z. As orally in the form of powders, suppositories, tablets, capsules, pastes, infusions, granules, drenches, boluses, medicated feed or drinking water. The dermal application happens z. In the form of dipping, spraying, bathing, washing, pour-on and spot-on and powdering. The parenteral application happens z. 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, boluses, 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 optionally 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 prepared by adding solutions prepared as described for the injection solutions with sufficient thickening agent to give a clear mass with an ointment-like consistency.

Pour-on formulations are infused or sprayed onto limited areas of the skin, whereby the active ingredient either penetrates the skin and acts systemically or spreads 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. 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 homogenized with the aid of suitable emulsifiers and other excipients such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers, viscosity-regulating substances with the solvent of the other 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. Extrusions can be prepared by mixing the active ingredient with suitable excipients and then extruding the mixture under pressure, usually at elevated temperature, through dies. 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 ingredients can be formulated in a common preparation or all active substances can be formulated in separate formulations; mixed forms are also conceivable in which part of the active ingredients are formulated together and part of the active ingredients separately.

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

Ready-to-use preparations contain the active compounds 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 containing 0.05 to 15% m / V (or m / m in the case of solid preparation forms) of the active compounds. 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 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 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 z. Cornmeal or corn and soybean meal or mineral salts, preferably a small amount an edible anti-dusting oil, e.g. As 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, especially chickens, ducks, geese and turkeys, 0.005 to 100 ppm, preferably 0.05 to 100 ppm of an active ingredient with a suitable edible material, e.g. As 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, z. For example, in the case of treating mammalian coccidiosis or toxoplasmosis, it is preferable to administer drug levels of 0.05 to 100 mg / kg of body weight daily to achieve the desired results. Nevertheless, it may sometimes be necessary to deviate from the stated amounts, 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 distance, to which he 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 effectiveness of the compounds of the invention can be z. B. in cage experiments with the following experimental design, 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 with a nutritionally balanced animal feed, z. B. with the chick chick specified under, 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 , z. Corn and soy flour or mineral salts containing a small amount of an edible de-oiling oil, e.g. As corn oil or soybean oil mixed. The premix thus obtained may 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% Feed grain meal: 40% corn, 12% wheat 17.00% Soybean meal extr. 5.00% Corn gluten feed 5.00% Wheat middlings 3.00% fishmeal 3.00% Mineral blend 3.00% Luzernegrasgrünmehl 2.50% vitamin premix 2.00% Wheat germ, minced 2.00% soybean oil 2.00% Meat and bone meal 1.50% whey powder 1.00% molasses 1.00% Brewer's yeast, tied to brewer's grains 100.00%

Such a feed contains 18% crude protein, 5% crude fiber, 1% Ca, 0.7% P and per 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

• Anwendung mg/kg erfolgte p. o. and den Studientagen 1–3 & 7–8 p. i.
• * K0 = nicht infizierte Kontrollgruppe
• ** Ki = infizierte Kontrollgruppe

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 infectionem (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 Models of Coccidial Infection Chapter 99: 821-838, In: Handbook of Animal Models of Infection, Academic Press , The results are summarized in Table 1. Tab. 1: Efficacy of combinations of the compounds of the formulas (II-C) and (IA) against E. falciformis (synergism) treatment mg / kg death rate % By weight of uninfected control Review Faeces Review intestine Review Oocysts Overall effect% % n K0 * 0 0 0/3 2.7 g 0 0 0 Ki ** 0 0 0/3 -263 6 6 6 Vbdg. (II-C) 10 0 0/3 -250 6 6 6 0 Vbdg. (II-C) 25 0 0/3 -238 6 2 6 17 Vbdg. (II-C) 50 0 0/3 -238 6 6 6 0 Vbdg. (IA) 50 0 0/3 13 0 4 5 6 Vbdg. (IA) 100 0 0/3 38 0 3.3 1 44 Vbdg. (IA) 250 0 0/3 38 0 0 0 78 Vbdg. (II-C) 10 0 0/3 -13 0 3.3 1 44 Vbdg. (IA) 50 Vbdg. (II-C) 10 0 0/3 63 0 2 0 72 Vbdg. (IA) 100 Vbdg. (II-C) 25 0 0/3 38 0 3.3 0 67 Vbdg. (IA) 50 Vbdg. (II-C) 25 0 0/3 13 0 1.3 0 67 Vbdg. (IA) 250 Vbdg. (II-C) 50 0 0/3 63 0 0 0 83 Vbdg. (IA) 250

• Use mg / kg on study days 1-3 & 7-8 pi
• * K0 = 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) in the concentration specified 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 field isolate 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 evaluation of the efficacy the following criteria are taken into account: weight increase from the beginning of the experiment 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 evaluation of the intestinal mucosa, especially of the caeca (Rating 0 to 6) and the oocyst excretion as well as the percentage (in%) of the oocysts sporulating within 24 hours. The number of oocysts in the faeces was determined using the McMaster counting chamber (see Engelbrecht and co-workers "Parasitological Working 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 (vgtl. Haberkorn and G. Greif (1999): Animal Models 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 ranking is scored; 0% means no effect, 100% means full effect. Tab. 2: Effectiveness of combinations of the compounds of the formulas (II-C) and (IA) against the toltrazuril-resistant field strain RIJ 070320-1 treatment Can [ppm] mortality weight in% of not inf. control Dropping score lesion score oocysts in% of inf. control % efficacy % n not infected control 0 0 0/6 97.6 g 0 0 0 infected control 0 0 0/6 88 0 0 100 0 Vbdg. (II-C) 5 0 0/3 86 0 0 267 0 Vbdg. (II-C) 7.5 0 0/3 87 0 0 270 0 Vbdg. (II-C) 5 0 0/3 83 0 0 0.4 86 monensin 50 Vbdg. (II-C) 5 0 0/3 91 0 0 16 57 salinomycin 30 Vbdg. (II-C) 5 0 0/3 85 0 0 19 43 maduramycin 2 Vbdg. (II-C) 5 0 0/3 95 0 0 111 14 diclazuril 0.5 Vbdg. (II-C) 5 0 0/3 96 0 0 0 100 LDW 1748 3 Vbdg. (II-C) 7.5 0 0/3 82 0 0 0.7 86 monensin 50 Vbdg. (II-C) 7.5 0 0/3 87 0 0 0 86 salinomycin 30 Vbdg. (II-C) 7.5 0 0/3 84 0 0 1.5 71 maduramycin 2 Vbdg. (II-C) 7.5 0 0/3 98 0 0 12 57 diclazuril 0.5 Vbdg. (II-C) 7.5 0 0/3 93 0 0 0 100 Vbdg. (IA) 3 monensin 50 0 0/3 105 0 0 470 14 salinomycin 30 0 0/3 102 0 0 176 14 maduramycin 2 0 0/3 98 0 0 293 14 diclazuril 0.5 0 0/3 95 0 0 233 14

C. Ground keeping Coccidiosis / turkey

Coccidium-free 8 to 11-day-old male turkey chicks (eg BIG 6 / Moorgut Karzfehn) received 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. In each keeping device of the floor keeping 5-10 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 goiter with about 65,000 sporulated oocysts of each field isolate. These are highly virulent, toltrazuril-resistant strains. The following criteria are considered for the evaluation of the efficacy: weight increase from the beginning of the experiment to the end of the experiment, infection-related mortality, macroscopic evaluation of the faeces with regard to diarrhea and blood excretion on day 7 pi (evaluation 0 to 4), macroscopic evaluation of the intestinal mucosa, especially the caeca and the 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 Working 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 assessment is calculated (cf. A. Haberkorn and G. Greif (1999): Animal Models 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 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

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 ranking is scored; 0% means no effect, 100% means full effect. Tab. 3: Efficacy of combinations of the compounds of the formulas (II-C) and (IA) against the Toltrazuril-resistant field strain BAL 060810 D treatment Can [ppm] mortality weight in% of not inf. control dropping score lesion score oocysts in% of inf. control % efficacy % n ileum not infected control 0 0 0/10 313.3 g 0 0 0 100 infected control 0 0 0/10 44 1.5 1.8 100 0 Vbdg. (II-C) 5 20 1.5 57 2 1.5 1 23 Vbdg. (II-C) 5 0 0/5 92 1 0 75 46 monensin 50 Vbdg. (II-C) 5 0 0/5 109 0 0.2 7 77 salinomycin 30 Vbdg. (II-C) 5 20 1.5 78 1 0.5 26 23 maduramycin 2 Vbdg. (II-C) 5 20 1.5 63 1 1.5 4 38 diclazuril 0.5 Vbdg. (II-C) 5 0 0/5 101 0 0.6 4 85 Vbdg. (IA) 3 Vbdg. (II-C) 7.5 0 0/5 92 1 0.8 0 85 Vbdg. (IA) 3 monensin 50 0 0/5 67 1 2 9 54 salinomycin 30 0 0/5 111 1 1 7 69 maduramycin 2 0 0/5 49 1 2 30 35 diclazuril 0.5 0 0/5 64 2 2 6 54 Tab. 4: Effectiveness of combinations of the compounds of the formulas (II-C) and (IA) against the toltrazuril-resistant field strain LVL 080918 D treatment Can [ppm] mortality weight in% of not inf. control dropping score lesion score oocysts in% of inf. control % efficacy % n duodenum not infected control 0 0 0/5 318 g 0 0 0 100 infected control 0 11 1.9 49 0.5 1.9 100 0 Baycox 25 0 0/5 64 1 1.8 16 50 Baycox 25 0 0/5 63 1 1.8 114 29 Baycox 50 0 0/5 84 0 1.6 80 43 Baycox 50 0 0/4 95 0 0.75 74 50 Vbdg. (II-C) 5 0 0/5 98 0 0.2 0 93 Vbdg. (IA) 5 Vbdg. (II-C) 5 0 0/5 90 0 0 0 100 Vbdg. (IA) 5 Vbdg. (II-C) 3 0 0/5 91 0 0 0 100 Vbdg. (IA) 5 Vbdg. (II-C) 3 0 0/5 98 0 0 0 100 Vbdg. (IA) 5

Example of an application: Cremophor suspension

The active ingredient or active ingredients are mixed with 200 .mu.l Cremophor EL ^® (polyethoxylated castor oil, a, BASF,) are mixed, 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)

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• EP 0087375 [0002]
• EP 0152360 [0002]
• EP 0181826 [0002]
• EP 0239508 [0002]
• EP 0260744 [0002]
• EP 0266984 [0002]
• US 3,418,318 [0002]
• US 3472865 [0002]
• US 3576818 [0002]
• US 3728994 [0002]
• DE 2047369 [0002]
• EP 0597304 A1 [0002]
• WO 00/04022 [0002, 0014, 0015, 0016]
• WO 00/68225 [0002, 0014, 0016]
• US 5331003 [0003]
• WO 96/38140 [0003]
• EP 0330041 A2 [0005]
• EP 0353526 A2 [0005]
• EP 0377904 A2 [0005]
• WO 2006/024428 [0006]
• EP 597304 A1 [0014]
• EP 330041 A2 [0023]

Cited non-patent literature

• Haberkorn and G. Greif (1999): Animal Models of Coccidial Infection Chapter 99: 821-838, In: Handbook of Animal Models of Infection, Academic Press [0092]
• Engelbrecht and co-workers "Parasitological Working Methods in Medicine and Veterinary Medicine, Akademie-Verlag, Berlin (1965) [0093]
• Haberkorn and G. Greif (1999): Animal Models of Coccidial Infection, Chapter 99: 821-838, In: Handbook of Animal Models of Infection, Academic Press. [0093]
• Engelbrecht and co-workers "Parasitological working methods in medicine and veterinary medicine, academy publishing house, Berlin (1965) [0101]
• A. Haberkorn and G. Greif (1999): Animal Models of Coccidial Infection Chapter 99: 821-838, In: Handbook of Animal Models of Infection, Academic Press. [0101]

Claims (9)

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

in which R ^{1 represents} carbon-bonded 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. Products according to claim 1 for simultaneous, separate or sequential use against parasitic protozoa in humans or animals. A product according to any one of the preceding claims, wherein said 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 ^{3 is} a radical of the formula

or for a remainder of the formula

R ^{4 is} alkyl, R ^{5 is} alkyl or substituted phenyl, R ^{6 is} 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 a dioxyhaloalkylene radical. Products according to claim 3, characterized in that Z represents the radical -CHR ² R ³ . Products according to any one of the preceding claims, wherein the substituted benzimidazole, which is active against parasitic protozoa, is the compound of formula (IIa)

or their physiologically acceptable salt. Products according to any of the preceding claims, wherein the 1,2,4-triazine derivative is a compound of formula (Ia)

or their salt is. 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)

in which R ^{1 represents} carbon-bonded 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 their physiologically acceptable salts for the preparation of products for controlling parasitic protozoa. 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) are administered to the human or animal

in which R ^{1 represents} carbon-bonded 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 applied its physiologically acceptable salt in combination in an effective amount. Use of a product according to the preceding claims for the manufacture of a medicament for combating parasitic protozoan diseases in animals.