EP1311271A1 - Use of triazinetrione sulfoxides for controlling coccidioses - Google Patents

Abstract

The invention relates to the use of special derivatives of triazinetriones for controlling coccidioses in animals, especially in pigs.

Description

Use of triazinetrione sulfoxides to control coccidiosis

The present invention relates to the use of special derivatives of triazinetrions for combating coccidiosis in animals.

Coccidiosis are common infections in animals, e.g. Subclinical infections in pigs caused by protozoa of the genera Coccidia, Sarcosporidia and Toxoplasmas are common worldwide. However, Isospora suis infections, for example, have only been recognized as the cause of piglet diarrhea in recent years and have been intensively researched. As a rule, infection occurs from the mother sow to the piglet or from piglet to piglet via oocysts, which each contain two sporocysts with two sporozoites each. The multiplication of the parasite stages takes place in the epithelial cells of the small intestine villi, but extraintestinal stages in the liver, spleen and lymph nodes are also detected. The clinical manifestation of the disease includes necrotic, inflammatory destruction of the intestinal epithelial cells and, as a result, massive digestion and absorption disorders. An acute illness is characterized by watery, whitish to yellow foul-smelling diarrhea, which usually occurs in the 2nd to 3rd week of life. Infected piglets have a reduced weight gain. The treatment and therapy of the disease have so far been insufficiently resolved. Antibiotics are ineffective, sulfonamides are recommended, but therapy is usually too late. Other treatment options are contradictory: the administration of monensin, amprolium or furazolidone could not prevent disease in experimentally infected piglets. In recent farms, despite good hygiene, up to 92% of all litters identified Isospora suis in individual farms.

It is known from a number of publications, including DE-OS 27 18 799, 25 090 37, 25 323 63, 24 137 22, WO 99/62519, that various derivatives of triazintrione are suitable for combating coccidiosis in animals. Furthermore, a number of publications, for example Driesen et al., Australian Vet. J., 72 (4) 139-141, 1995; Rommel et al., IntJ. of Parasit., 17, 639-647, 1987; Haberkorn and Mundt, Prakt. Tierarzt, 69 (4), 46, 49-51, 1988 that toltrazuril, a certain triazinetrione derivative, is suitable for the treatment of coccidiosis (Isospora suis) in pigs.

Because of the diverse requirements placed on modern medicinal products, for example what the active level, duration of action, active spectrum, application spectrum, toxicity, combination with other active ingredients, combination with formulation aids or the

Synthesis is concerned, and because of the possible occurrence of resistance, the development of such substances can never be regarded as complete, and there is a constant high demand for new compounds which bring advantages, at least in part, over the known compounds.

It has now been found that triazinetrione sulfoxides of the formula (I)

in which

R ^{1 represents} haloalkyl,

R ^{2 represents} alkyl, alkoxy, halogen or SO ₂ N (CH ₃ ) ₂ , As well as their physiologically tolerable salts have a very good coccidiocidal effect with surprisingly low mammalian toxicity.

The compounds of formula (I) can be obtained by the processes known from DE-OS 27 18 799, 25 090 37, 25 323 63, 24 13722, WO 99/62519.

When used according to the invention for the treatment of coccidiosis in animals, the compounds of the formula (I) have a surprisingly low mammalian toxicity in comparison with the compounds known from the prior art and are therefore clearly superior to the known compounds in this use.

For use in combating coccidiosis in animals, preference is given to using compounds of the formula (I)

in which

R ^{1 represents} C * -C ₄ haloalkyl having 1 to 5 halogen atoms,

R ^{2 stands} for C ₁ -C ₄ alkyl, C ^ alkoxy, halogen or SO ₂ N (CH ₃ ) ₂ , and their physiologically tolerable salts.

According to the invention, particular preference is given to using compounds of the formula (I) in which

R ¹ represents C ¹ -C ₄ -haloalkyl having 1 to 5 halogen atoms,

R ^{2 represents} C ₁ -C ₄ alkyl, and their physiologically tolerable salts.

According to the invention, very particular preference is given to using compounds of the formula (I) in which R ^{1 represents} C _r C ₄ perhaloalkyl,

R ^{2 represents} methyl or ethyl, and their physiologically tolerable salts. The use of the compound of the formula is particularly preferred

also referred to as toltrazuril sulfoxide.

Depending on the type and number of the substituents, the compounds of the formula (I) can optionally be present as geometric and / or optical isomers or regioisomers or their isomer mixtures in different compositions. Both the use of the pure isomers and the isomer mixtures are claimed according to the invention.

Preferred, particularly preferred or very particularly preferred, etc. are compounds which carry the substituents mentioned under preferred, particularly preferred or very particularly preferred, etc.

Among the haloalkyl radicals given in the definition for R ¹ , including those which are preferred, particularly preferred, very particularly preferred, the fluoroalkyl radicals are in turn preferred. The general definitions or explanations of residues or explanations listed above or in preferred areas can, however, also be combined as desired, that is to say between the respective areas and preferred areas.

For use against coccidiosis according to the invention, the compounds according to the invention can be brought into all customary formulations and administered in various application forms. Oral applications are preferred, in particular application as an oral aqueous suspension.

Preferred dosages are 1-500 mg of active ingredient per kg of body weight of the animal to be treated, doses of 10 to 200 mg / kg are particularly preferred and doses of 20-100 mg / kg are very particularly preferred.

Preparations suitable for animals are:

Solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on formulations, gels;

Emulsions and semi-solid preparations for oral or cutaneous use and for injection; Semi-solid preparations are, for example, suspensions, pastes.

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

solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; Aerosols and inhalants.

Solutions for injection 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 filtered sterile or, if necessary, prepared aseptically and filled.

The following may be mentioned as solvents: physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone, glycerol formal, solketal ( ^■ = ^■ isopropylidene glycerol), dimethylacetamide, 2-pyrrolidone, tetraglycol (= Polyethylene glycol ether of tetrahydrofurfuryl alcohol) and mixtures thereof.

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

The following may be mentioned as solubilizers: solvents which require the active ingredient to be dissolved in the main solvent or prevent it from precipitating. Examples are polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

Preservatives are, for example: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol, and organic acids with preserving properties such as benzoic acid, propionic acid or sorbic acid and their salts. The preservatives can optionally also be used as a combination of two or more agents.

Oral solutions are applied directly. Concentrates are used orally after previous dilution to the application concentration. Oral solutions and concentrates are prepared as described above for the injection solutions, whereby sterile work can be dispensed with. Solutions for use on the skin or in body cavities are dripped on, spread on, rubbed in, sprayed on, bathed. These solutions are prepared as described above for the injection solutions. It is particularly advantageous to add thickeners during production.

Thickeners are: inorganic thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates, xanthans.

Gels are applied to or spread on the skin or placed in body cavities. Gels are made by adding enough thickening agent to solutions that have been prepared as described for the injection solutions to form a clear mass with an ointment-like consistency. The thickeners specified above are used as thickeners.

Pour-on formulations are poured or sprayed onto limited areas of the skin, the active ingredient either penetrating the skin and acting systemically or being distributed over the surface of the body.

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

The following may be mentioned as solvents: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, 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 monobutyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane.

Dyes are all dyes approved for use on animals, which can be dissolved or suspended.

Absorbing substances are DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.

Antioxidants are sulfites or metabisulfites such as potassium metabisulfite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.

Light stabilizers are e.g. Substances from the class of benzophenones or novantisol acid.

Adhesives are e.g. Cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.

Emulsions can be used orally, cutaneously or as an injection.

Emulsions are either water in oil or oil in water.

They are produced by dissolving the active ingredient in one phase and this with the aid of suitable emulsifiers and optionally other auxiliaries such as

Dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers, viscosity-increasing substances, homogenized.

The following may be mentioned as the hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as

Capryl / capric acid biglyceride, triglyceride mixture with vegetable fatty acids Chain length Cg_i2 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated, possibly also hydroxyl-containing fatty acids, mono- and diglycerides of C / Cio fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length Ciss-Cig, isopropyl myristate, isopropyl palmitate, caprylic / capric alcohol ester of the saturated fatty acid length "Cl8 * _> isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial ducklings glandular fat,

Dibutyl phthalate, adipic acid diisopropyl ester, ester mixtures related to the latter, etc.

Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids such as Oleic acid and its mixtures.

The following can be mentioned as the hydrophilic phase: water, alcohols, e.g. Propylene glycol, glycerin, sorbitol and their mixtures.

The following may be mentioned as emulsifiers: surfactants (contains emulsifiers and wetting agents), such as

1. non-ionic, e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate, polyoxyethyl stearate, alkylphenol polylglycol ether,

2. ampholytic, such as di-Na-N-lauryl-β-iminodipropionate or lecithin, 3. anionic, such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt,

4. cationic such as cetyltrimethylammonium chloride.

The following are also suitable as auxiliary substances:

Viscosity-increasing and emulsion-stabilizing substances such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes or colloidal silica Mixtures of the listed substances.

Suspensions can be administered orally, cutaneously or as an injection. They are prepared by placing the active ingredient in a carrier liquid, if necessary

Addition of other auxiliaries such as wetting agents, defoamers, dyes, absorption-promoting substances, suspension stabilizers, preservatives, antioxidants, light stabilizers, humectants suspended.

Oral suspensions containing:

A) Compounds of formula (I) in concentrations of 0.1 to 30 wt .-%, particularly preferably from 1 to 10 wt .-%.

B) suspension stabilizers such as e.g. Bentonites and / or xanthans in concentrations of from 0.01 to 5% by weight, particularly preferably from 0.05 to 1

Wt .-%.

C) optionally wetting agents of ionic or nonionic type in concentrations of 0.01 to 5% by weight, particularly preferably of 0.1 to 0.5% by weight. D) optionally defoamer based on silicone, for example, in concentrations of 0.01 to 5% by weight, particularly preferably 0.05 to 0.5% by weight.

E) optionally humectants in concentrations of 1 to 30% by weight, particularly preferably 5 to 20% by weight.

F) optionally preservatives or combinations thereof in concentrations of 0.001 to 5% by weight, particularly preferably 0.1 to 0.5% by weight.

G) optionally acidic or basic substances in the concentrations required to adjust the pH.

The solvents and homogeneous solvent mixtures listed further above may be mentioned as carrier liquids, provided that they are pharmaceutically acceptable and the active substance or substances do not dissolve therein or only to a small extent. Water is preferably used.

Wetting agents (dispersants) for the orally administrable suspensions may be mentioned as

1. anionic, such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphate monoethanolamine salt, lignin sulfonates or dioctyl sulfosuccinate,

cationic such as cetytrimethylammonium chloride,

ampholytic such as di-Na-N-lauryl-β-iminodipropionate or lecithin, 4. nonionic, for example polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, ethyl alcohol, glycerol, polyoxyethylene stearate, alkylphenol Pluronic ^®.

Defoamers are those based on silicone, for example

Dimethicon or Simethicon.

The viscosity-increasing substances listed above can be used, for example, as suspension stabilizers.

The usual humectants can be used, examples include: propylene glycol, glycerol, sugar alcohols such as sorbitol, sugars such as cane sugar.

Suitable preservatives are known to the person skilled in the art; Examples have already been mentioned above. Organic acids with preserving properties are preferably used, such as. B. benzoic acid, propionic acid or sorbic acid and its salts. The preservatives can also be used as a combination of two or more agents, a preferred example being a combination of sodium propionate and sodium benzoate.

The customary pharmaceutically acceptable acids, bases and buffers are suitable as acidic or basic substances for adjusting the pH.

Examples of acids which may be mentioned are: hydrochloric acid, citric acid and tartaric acid. As

Bases may be mentioned, for example: alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali and alkaline earth carbonates such as sodium carbonate and amines, for example mono-, di- or triethanolamine.

Examples of buffer systems which can be used are those based on phosphate. The pH is preferably in the range from 2 to 10, in particular 3 to 7.

The active ingredient is preferably used in the suspensions in micronized form, usually in particle size distributions of 0.1 to 100 μm, preferably 1 to 50 μm.

Further additives mentioned are those mentioned above.

Pastes can be administered orally or cutaneously. They differ from the liquid to viscous suspensions and emulsions described above by their higher viscosity. Pastes containing ponazuril ( ^■ * = toltrazuril sulfone) have already been described in WO 99/62519.

Oral administrable pastes containing compounds of the formula (I) which are characterized in that

a) the active ingredient is present in a grain size of 1 • 10 ~ ⁶ m and a maximum grain size of 50 • 10 " ⁶ m in a concentration of 0.1-20% by weight,

b) polyacrylic acids with an acrylic acid content of 56 to 68% by weight and a molecular weight of approx. 3 • 10 ⁶ , which are neutralized with alkali or alkaline earth bases, are present in a concentration of 0.1-5% by weight,

c) if appropriate, humectants are present in a concentration of 5 to 30% by weight,

d) optionally preservatives are present in a concentration of 0.01 to 0.5% by weight,

e) and the rest is filled with water in 100% by weight. The active ingredient is present in the pastes mentioned in weight concentrations from 5% by weight to 20% by weight, particularly preferably from 10% by weight to 15% by weight.

The polyacrylic acids used in the pastes mentioned are preferably neutralized with alkali hydroxide or carbonate. Polyacrylic acids are contained in the formulation according to the invention in weight concentrations of 0.2% to 1%, preferably of 0.5%. These are commercially available and in pharmacopoeias e.g. known under the trade name Carbomer 934 P.

Para-hydroxybenzoic acid esters (parabens) such as methyl 4-hydroxybenzoate, ethyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate are preferred as preservatives in the pastes mentioned. The preservatives can be used individually or in combination for adequate preservation. They are usually contained in concentrations of 0.01-0.5% by weight.

Optionally, the pastes mentioned can also contain humectants, e.g. Glycerin or 1,2-propylene glycol. Humectants are used in weight concentrations of 5% to 30%, preferably from 10% to 20%.

The active ingredient in the pastes mentioned has a particle size of 1 to

10 • 10 " ⁶ m, preferably from 1 to 5 • 10 ^-6 m. The maximum grain size is 50 • 10 ^_6 m, preferably 30 • 10" ⁶ m. The grain sizes are determined by laser scattered light measurement (eg with a Malvern Mastersizer). The paste is obtained by mixing the individual components together. It can be changed in consistency by increasing or decreasing the water content. A pasty consistency is desired. This allows the agent to be administered orally using suitable applicators such as syringes, tubes, spatulas, etc. To prepare solid preparations, the active ingredient is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and brought into the desired shape.

All physiologically compatible solid inert substances may be mentioned as carriers. Inorganic and organic substances serve as such. Inorganic substances are e.g. Table salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, phosphates.

Organic substances are e.g. Sugar, cellulose, food and feed such as

Milk powder, animal meal, cereal flour and meal, starches.

Excipients are preservatives, antioxidants, dyes, which have already been listed above.

Other suitable auxiliaries are lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decomposition substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinyl pyrrolidone as well as dry binders such as microcrystalline cellulose.

The active compounds can also be encapsulated in the form of their solid or liquid formulations mentioned above.

The active ingredients can also be used in the form of an aerosol. For this purpose, the active ingredient in a suitable formulation is finely distributed under pressure.

It may also be advantageous to use the active substances in formulations which release the active substance with a delay. The active ingredients are preferably administered together with the feed and / or the drinking water.

The feed includes single feed of vegetable origin such as hay, beets, cereals, grain by-products, single feed of animal origin such as meat,

Fats, milk products, bone meal, fish products, furthermore the feed materials such as vitamins, proteins, amino acids, e.g. DL-methionine, salts such as lime and table salt. The feed also includes supplementary, finished and compound feed. These contain feed materials in a composition that ensures a balanced diet with regard to energy and protein supply as well as the supply of vitamins,

Ensures mineral salts and trace elements.

The concentration of the active substances in the feed is normally about 0.01 to 500 ppm, preferably 0.1 to 50 ppm.

The active ingredients can be added to the feed as such or in the form of premixes or feed concentrates.

Premixes and feed concentrates are mixtures of the active ingredient with a suitable carrier.

The carrier substances include feed materials or mixtures thereof.

They can also contain other tools, such as - Substances that regulate fluidity and miscibility, e.g. Silicas, bentonites,

Lignosulfonates. In addition, antioxidants such as BHT or preservatives such as sorbic acid or calcium propionate can be added.

Concentrates for application via drinking water must be formulated in such a way that a clear solution or a stable, homogeneous suspension results when mixed with the drinking water. Water-soluble substances (feed additives) such as sugar or salts (for example citrates, phosphates, sodium chloride, sodium carbonate) are therefore suitable as carriers.

They can also contain antioxidants and preservatives.

The active substances are suitable for the control of parasitic protozoa according to the invention which are found in animal husbandry and animal breeding in farm animals, breeding, zoo, laboratory, experimental and hobby animals. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive strains. By combating the parasitic protozoa, illness, deaths and reduced performance (e.g. in the production of meat, milk, wool, skins, eggs, honey, etc.) are to be reduced, so that the use of the active ingredients enables more economical and easier animal husbandry.

The parasitic protozoa include:

Mastigophora (Flagellata) such as Trypanosomatidae e.g. Trypanosoma bracei, T. gambiense, T. rhodesiense, T. congolense, T. cruzi, T. evansi, T. equinum, T. lewisi,

T. percae, T. simiae, T. vivax, Leishmania brasiliensis, L. donovani, L. tropica, e.g. Trichomonadidae e.g. Giardia lamblia, G. canis.

Sarcomastigophora (Rhizopoda) such as Entamoebidae e.g. Entamoeba histolytica, Hartmanellidae e.g. Acanthamoeba sp., Hartmanella sp.

Apicomplexa (Sporozoa) such as Eimeridae, for example Eimeria acervulina, E. adenoides, E. alabahmensis, E. anatis, E. anseris, E. arloingi, E. ashata, E. auburnensis, E. bovis, E. brunetti, E. canis, E. chinchillae, E. clupearum, E. columbae, E. contorta, E. cran- daüs, E. debliecki, E. dispersa, E. ellipsoidales, E. falciformis, E. faurei, E. flavescenses, E. gallopavonis, E. hagani, E. intestinalis, E. iroquoina, E. irresidua, E. labbeana, E. leucarti, E. magna, E. maxima, E. media, E. meleagridis, E. meleagrimisis, 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, Isospora belli, I. canis, I. felis, I. ohioensis, I. rivolta, I. spec, I. suis, Neospora cani- num, N. hugesi, Cystisospora spec, Cryptosporidium spec such as Toxoplasmadidae eg Toxoplasma gondii, such as Sarcocystidae, for example Sarcocystis bovicanis, S. bovihomis, S. neurona, S. ovicanis, S. ovifelis, S. spec, S. suihominis such as Leucozoidae such as Leucozytozoon simondi, such as Plasmodiidae such as Plasmodium berghei, P. falcipa - Now, P. malariae, P. ovale, P. vivax, P. spec, such as Piroplasmea, for example Babesia argentina, B. bovis, B. canis, B. spec, Theileria parva, Theileria spec, such as Adeleina, for example Hepatozoon canis , H. spec.

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

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

The compounds of the invention are also active against protozoa, which occur as parasites in insects. Parasites of the tribe should be mentioned as such

Microsporida, especially the genus Nosema. Nosema apis is particularly worth mentioning for the honeybee.

Particularly noteworthy are the protozoan genera and species which lead to subclinical infections in pigs, in particular: Trypanosoma congolense simae, T. vivax vivax, T. congolense congolense, T. brucei evansi, Tritrichomonas suis, Trichomitus rotunda, Tetratrichomonas buttreyi, Eimeria debliecki, E. suis, E. scabra, E. perminuta, E. spinosa, E. polita, E. porci, E. neodebliecki, Isospora suis, Cryptosporidium, Toxoplasma gondii, Sarcocystis miescheriana, S. suihominis, Babesia trautmanni , B. penoncitoi, Balantidium coli. The livestock and breeding animals include mammals such as cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as mink, chinchilla, raccoon, birds such as chickens, geese, turkeys, Ducks, pigeons, bird species for home and zoo keeping. It also includes farm and ornamental fish. Of particular note are pigs of all types,

Subspecies and breeds.

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

The pets include dogs and cats.

The fish include utility, breeding, aquarium and ornamental fish of all ages that live in fresh and salt water. Useful and farmed fish include e.g. Carp, eel, trout, white fish, salmon, bream, roach, rudd, chub, sole, plaice, halibut, Japanese yellowtail (Seriola quinqueradiata), Japanaal (Anguilla japonica), red seabream (Pagurus major), seabass (Dicentrarchus labrax), Gray mullet (Mugilus cephalus), Pompano, Gilthead seabream (Sparus aurata), Tilapia spp., Chichlid species such as Plagioscion, Channel catfish. The agents according to the invention are particularly suitable for the treatment of fish fry, e.g.

Carp 2 to 4 cm in length. The agents are also very suitable for eel fattening.

The following examples are intended to explain the invention without restricting it: PREPARATION

General manufacturing process

The suspensions specified below can be prepared by the following methods:

The substances are stirred together until a homogeneous suspension is formed and the pH is adjusted to a desired range. The bentonite or sodium alginate suspension stabilizer is optionally used at approx.

80 or approx. 40 ° C open. After production, the suspension can be filled into suitable containers.

The amounts in the formulations are given in grams [g].

Example 1 (suspension)

Toltrazuril sulfoxide microfine 10.0

Polyoxyl 35 castor oil 5.0 p-hydroxybenzoic acid methyl ester 0.075 p-hydroxybenzoic acid propyl ester 0.025

Sodium carboxymethyl cellulose 1.0

Demineralize water ad 100.0 g

Example 2 (suspension)

Toltrazuril sulfoxide microfine 1.0 p-hydroxybenzoic acid methyl ester 0.075 p-hydroxybenzoic acid propyl ester 0.025 sodium alginate * 1.0

Demineralize water ad 100.0 g * Open-minded at 40 ° C

Example 3 (suspension)

Toltrazuril sulfoxide microfine 50.0

Bentonite ** 3.5

Xanthan 3.0

Dioctyl sodium sulfosuccinate 2.5 simethicone emulsion 1.0

Sodium benzoate 2.0

Sodium propionate 2.0

Citric acid powder 4.0-10.0

1,2-propylene glycol 105.0 demineralized water. ad 1030.0 g

The pH is adjusted to 3.4 to 4.2 by appropriate dosing of citric acid.

** As recommended by the manufacturer, the bentonite is preferably first heated to 80 ° C in an aqueous suspension and, after swelling, processed into a suspension with the other ingredients.

Claims

Patentansprtiche

1. Use of compounds of the formula (I)

in which

R ^{1 represents} haloalkyl,

R ^{2 represents} alkyl, alkoxy, halogen or SO ₂ N (CH ₃ ) ₂ ,

as well as their physiologically tolerable salts for combating coccidiosis in animals.

2. Use of compounds of formula (I) according to claim 1 for the preparation of agents against coccidiosis.

3. Use according to claim 1, characterized in that the compounds of formula (I) according to claim 1 are applied in the form of an aqueous oral suspension.

4. Means for use according to claim 1, characterized in that it is an orally administrable suspension of compounds of the formula (!) According to claim 1.

5. Composition according spoke 4, characterized in that it is an aqueous suspension.

6. Containing agents according to speech 4

A) Compounds of formula (I) in concentrations of 0.1 to 30 wt .-%, particularly preferably from 1 to 10 wt .-%.

B) suspension stabilizers such as e.g. Bentonites and / or xanthans in concentrations of from 0.01 to 5% by weight, particularly preferably from 0.05 to 1% by weight.

C) optionally wetting agents of ionic or nonionic type in concentrations of 0.01 to 5% by weight, particularly preferably of 0.1 to 0.5% by weight.

D) optionally defoamer on e.g. Silicone base in concentrations of 0.01 to 5% by weight, particularly preferably 0.05 to 0.5% by weight.

E) if appropriate, moisturizer in concentrations of 1 to 30% by weight, particularly preferably 5 to 20% by weight.

F) optionally preservatives or combinations thereof in concentrations of 0.001 to 5% by weight, particularly preferably of

0.1 to 0.5% by weight.

G) optionally acidic or basic substances in the concentrations required to adjust the pH.

7. A method for controlling coccidiosis in animals, characterized in that the animal in question is administered an agent comprising a compound of the formula (I) as defined in claim 1.