EP1311491A1 - Use of triazinetrione sulfones for combating coccidiosis - Google Patents

Abstract

The invention relates to the use of a special derivative of triazinetriones for combating coccidiosis in animals, particularly pigs.

Description

End of triazinetrione sulfones to combat 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 piglets or from piglet to piglet via oocysts, each containing 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 disorders of the indigestion and absorption. An acute illness is characterized by watery, whitish to yellow foul-smelling diarrhea, which usually occurs in the 2-3 week of life. Infected piglets have a reduced weight gain. The treatment and therapy of the underlying 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 an explanation 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 for modern pharmaceuticals, for example in terms of potency, potency, potency, spectrum of use, toxicity, combination with other drugs, combination with formulation aids or synthesis, and because of the possible occurrence of resistance, the

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

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

in which

R ^{1 represents} haloalkyl,

R ^{2 represents} alkyl, alkoxy, halogen or SO ₂ N (CH ₃ ) ₂ , and their physiologically tolerable salts have a very good coccidiocidal activity 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, 24 137 22, WO 99/62519.

In the use according to the invention for the treatment of coccidiosis in animals, the compounds of the formula (I) show a comparison with those from the prior art

Compounds known in the art have surprisingly low mammalian toxicity 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 ¹ -C 5 -haloalkyl having 1 to 5 halogen atoms,

R ² represents C 1 -C ₄ alkyl, C 1 -C ₄ 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 5 -alkyl with 1 to 5 halogen atoms,

R ^{2 represents} -C-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} Ci-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

called Ponazunl.

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 and very particularly preferred, the fluoroalkyl radicals are again 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 sterile filtered or if necessary prepared and filled aseptically. The following may be mentioned as solvents: physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerin, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone, glycerol formal, solketal (= isopropylidene glycerol), dimethylacetamide, 2-pyrrolidone, tetraglycol (= poly- ethylene 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 esters, 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, Alumim ^{'ummonostearat,} 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 onto or sprayed onto limited areas of the skin, the active ingredient either penetrating the skin and acting systemically or being distributed over the surface of the body.

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

The following may be mentioned as solvents: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, 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 kononobutyl 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-hydroxy-methyl-l 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 novantisolic 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 made by dissolving the active ingredient in one phase and submerging it

With the help of suitable emulsifiers and, if necessary, other auxiliary substances 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 caprylic / capric acid biglyceride, triglyceride mixture with vegetable fatty acids of chain length C ₈ . ₁₂ 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 ₈ / C ₁₀ 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 C; [6-Cιg, isopropyl myristate, isopropyl pahnitat, caprylic / capric alcoholic esters the chain length C ₁₂ - C ₁₈ , isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duckling gland fat, dibutyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures and others

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, polyoxyethylene 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 Cetylljrimemylammoniumchlorid.

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 produced by adding the active ingredient in a carrier liquid, optionally with the 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% 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 wt .-%, particularly preferably from 0.05 to 0.5 wt .-%.

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 are not or only to a small extent therein

Loosen dimensions. Water is preferably used.

Surfactants such as. Can be mentioned as wetting agents (dispersants) for the orally administrable suspensions

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

2. cationic such as cetytrimethylammonium chloride,

3. ampholytic such as di-Na-N-lauryl-β-iminodipropionate or lecithin,

4. non-ionic, e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate,

Polyoxyethylene stearate, alkylphenol polyglycol ether, Pluronic®.

Defoamers are those based on silicone, for example dimethicone or simethicone. 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. Examples of bases which may be mentioned are: 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 10-10 mm and a maximum grain size of 50-10 μm 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-l06, 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 in a concentration of 0.01 to

0.5% by weight are present,

e) and the rest is filled with water in 100% by weight.

The active ingredient is present in the pastes mentioned preferably in weight concentrations of 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 preferred in the formulation according to the invention in weight concentrations of 0.2% to 1% of 0.5% included. These are commercially available and are known in pharmacopoeias, for example under the trade name Carbomer 934 P.

The preservatives used in the pastes mentioned are preferably para-hydroxybenzoic acid esters (parabens) such as methyl 4-hydroxybenzoate, ethyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate. 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 moisture-retaining agents, e.g. Glycerin or 1,2-propylene glycol. Moisture-retaining agents are used in weight concentrations of 5% to 30%, preferably from 10% to 20%.

The active ingredient is present in the pastes mentioned in a grain size of 1 to 10-10 "6 m, preferably from 1 to 5-10" ^ m. The maximum grain size is'

50-10 "6 m, preferably at 30-10 ^_ 6 m. The grain sizes are determined by laser scattered light measurement (for example with a Malvern Mastersizer). The paste is obtained by mixing the individual components together. The consistency of the paste can be increased or decreased A pasty consistency is desired, which 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. Common salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides,

Silicas, clays, precipitated or colloidal silicon dioxide, phosphates. Organic substances are, for example, sugar, cellulose, food and feed such as milk powder, animal meal, cereal meal 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 polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.

The active compounds can also be encapsulated in the form of their solid or liquid formulation ranges 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 ingredients in formulations which

Release active ingredient 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, as well as the single feed 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 visibly ensures the energy and protein supply as well as the supply of vitamins, 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, lignin sulfonates. 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 (e.g. citrates, phosphates, common salt, sodium carbonate) are therefore suitable as carriers.

They can also contain antioxidants and preservatives.

With surprisingly low warm-blood toxicity, the active substances are suitable for combating parasitic protozoa according to the invention which are used in animal husbandry and

Animal husbandry occurs in farm, 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 (eg in the production of meat, milk, wool, hides, eggs, honey, etc.) are to be reduced, so that the use of the active ingredients enables more economical and easier animal husbandry is.

The parasitic protozoa include:

Mastigophora (Flagellata) such as Trypanosomatidae e.g. Trypanosoma brucei, T. .. gambiense, T. rhodesiense, T. congolense, T. cruzi, T. evansi, T. equinum, T. lewisi, T. percae, T. si iae, 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 e.g. Eimeria acervulina, E. adenoides, E. alabahmensis, E. anatis, E. anseris, E. arloingi, E. ashata, E. auburnensis, E. bovis, E. brunetti, E. canis, E. chinchillae, E. clupearum , E. columbae, E. contorta, E. crandalis, E. debliecki, E. dispersa, E. ellipsoidales, E. 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, Isospora belli, I. canis, I. felis, I. ohioensis, I. rivolta, I. spec, I. suis, Neospora caninum, N hugesi, Cystisospora spec., Cryptosporidium spec. such as Toxoplasmadidae, for example Toxoplasma gondii, such as Sarcocystidae, for example Sarcocystis bovicanis, S. bovihominis, S. neurona, S. ovica- nis, S. ovifelis, S. spec, S. suihominis such as Leucozoidae such as Leucozytozoon simondi, such as Plasmodiidae such as Pasmodium berghe falciparum, 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 according to the invention are also active against protozoa which act as

Parasites occur in insects. Parasites of the Microsporida strain, in particular of the genus Nosema, may be mentioned as such. Nosema apis is particularly worth mentioning for the honeybee.

Particularly noteworthy are the protozoan genera and species that lead to subclinical infections in pigs, in particular: Trypanosoma congolense simae, T. vivax vivax, T. congolense congolense, T. bracei 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. perroncitoi, Balantidium coli.

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. Pigs of all types, subspecies and breeds are particularly emphasized.

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), Japanese eel (Anguilla japonica), red seabream (Paguras 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 illustrate the invention without, however, restricting it:

Effectiveness studies of ponazuril compared to toltrazuril:

A. Effectiveness of Ponazuril against artificially caused infections of

Chickens with Eimeria tenella, E. maxima and E. acervulina:

The aim of this study was to test Ponazuril for efficacy against an artificial mixed infection (Eimeria tenella, E. maxima and E. acervulina) in chickens under cage conditions.

Groups of 44 birds each (4 repetitions per treatment of 11 animals each) were formed and infected with sporulated oocysts on day 14. Ponazuril was applied daily from day 10-24 or 17-24. Three doses in the feed were used in both treatment periods: 5 ppm, 10 ppm and 20 ppm.

The success of the treatment has been characterized by different clinical and parasitological ones Parameters determined including coccidiosis-related mortality and oocyst excretion in the faeces.

The infection was moderate to massive. The mortality from coccidiosis was 20% of the control treated with urine. The infection was controlled with all doses and treatment schedules. The degree of control was directly dependent on the dosage and the start of treatment. Starting treatment early reduced the parasitological findings significantly (oocyst excretion and number of lesions) and improved the technical parameters (body weight gain and feed turnover). The highest dose (20 mg ponazuril in the feed) showed the best results. This dose corresponded approximately to a dose of 3.5 mg / kg body weight and day.

B. Field trial on the effectiveness of ponazuril compared to toltrazuril for the treatment of natural infections of pasture lambs with coccidiosis:

The aim of the experiments was to compare the effectiveness of toltrazuril and ponazuril against natural infections with pathogens of the Eimeria family.

The active ingredients were compared in three successive experiments: Experiment 1: untreated control - toltrazuril 20 mg / kg - ponazuril 20 mg / kg Experiment 2: untreated control - ponazuril 20 mg / kg Experiment 3: untreated control - toltrazuril 20 mg / kg - ponazuril 10 mg / kg.

The main parameters used were oocyst excretion and the consistency of the excrement. The weight of the animals was also checked on occasion.

The infection pressure was low during the period of the examination. Both toltrazuril and ponazuril were fully effective under the test conditions.

C: Effectiveness of toltrazuril and ponazuril for the treatment of experimental infections of piglets with Isospora suis.

The aim of this experiment was to study the effectiveness of different

Dosages of toltrazuril and ponazuril against piglet coccidiosis.

2 groups (A and B) 3 weeks old piglets were infected on day 0 via gastric tube with 5 * 10 ³ oocysts from Isospora suis. Grappe C was kept as an infected, untreated control group.

All groups received toltrazuril or ponazuril as a single dose according to their individual body weight on day 3 after the infection.

Group A I. Toltrazuril 10 mg / kg body weight

II. Toltrazuril 20 mg / kg body weight

Group B I. Ponazuril 10 mg / kg body weight II. Ponazuril 20 mg / kg body weight

Group C no dose Day Coprological examination MacMaster

-3 0 3 4 5 6 7 9 11 13 15 17 19 21

group

A

II.

Group B

II.

Group 0.2 0.3 4.8 38 72 74 78 48.8 12 C 0.3 0.3 1.1 46 98 84.6 86 62.4 10

0.2 1.8 57.5 102 98 88 46.8 9.6

0.1 0.4 5.6 61 144 116 82.4 38.8 7.2

Comparison of the toxicity of a sulfide (toltrazuril) with the corresponding sulfone (ponazuril):

The following toxicity data were determined according to the OECD / GLP guidelines, in particular OECD 414, 401 and 408. The tests on the teratogenicity of the compounds were carried out in accordance with the US guidelines - "Teratogenicity study", Guidelines for Registering Pesticides in the USA, US Environmental Protection Agency, Hazard Evaluation: Human and Domestic Animals. US Federal Register, Vol. 43, paragraph 163.83-3, adopted November 1982.

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 suspension stabilizer bentonite or sodium alginate 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)

Ponazuril 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)

Ponazuril 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)

Ponazuril 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 aqueous suspension and after swelling with the others

Ingredients processed into a suspension.

Claims

claims: 1. Use of compounds of the formula (I) in which R represents haloalkyl, R ^{2 stands} for alkyl, alkoxy, halogen or SO N (CH ₃ ), and their physiologically tolerable salts for combating coccidiosis in Animals. Use of compounds of formula (I) according to claim 1 for the preparation of agents against coccidiosis. 3. Use according spoke 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 aqueous suspension of compounds of formula (I) according to spoke 1. 5. Composition according spoke 4, characterized in that it is an aqueous suspension. 6. Composition according to claim 4, comprising: 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 from 0.01 to 5 wt .-%, particularly preferably from 0.05 to 0.5 wt .-%. 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. 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.