HK1127299A - Use of triazinetrione sulphone for controlling coccidioses - Google Patents

Description

Use of triazinetrione sulfones for controlling coccidiosis

The application is a divisional application of an invention patent application with the application date of 2001, 8/6/8, the application number of 01817502.3 and the name of application of triazinetrione sulfone in controlling coccidiosis.

The present invention relates to the use of specific derivatives of triazinetriones for the control of coccidiosis in animals.

Coccidiosis is an infection that often occurs in animals, and thus asymptomatic infections caused in pigs by, for example, coccidia, Sarcocystis and Toxoplasma protozoa are prevalent worldwide. However, infection with, for example, pig Isospora (Isospora suis) has only been recognized in recent years as a cause of diarrhea in piglets, and has been studied very well. Infection is usually transmitted from sow to piglet or from piglet to piglet via oocysts, each containing two sporangia with two sporozoites respectively. The parasitic stage is propagated in the epithelial cells of the small intestine villi, but extra-intestinal stages have also been detected in the liver, spleen and lymph nodes. The clinical manifestations of the disease include necrotic, inflammatory destruction of intestinal epithelial cells, and thus severe interference with digestion and absorption. One acute condition is characterized by serous, whitish or yellowish, foul-smelling diarrhea, which usually occurs 2-3 weeks after birth. Weight loss in infected piglets. The treatment of this disease has not been adequately addressed to date. Antibiotics are ineffective; although the use of sulfa drugs is recommended, treatment is often too late. Other possibilities of treatment are contradictory: for experimentally infected piglets, the disease cannot be prevented by administering monensin, ampeloammonium or furazolidone. In recent studies, some units have found that despite good hygiene measures, pig isosporean (Isospora suis) is up to 92% of all litters.

From various publications, in particular DE-OS2718799, 2509037, 2532363, 2413722, WO 99/62519, it is known that various triazinetrione derivatives are suitable for controlling coccidiosis in animals.

Furthermore, the methods described herein are described in various publications, such as Driesen et al, Australian Vet.J., 72(4)139-141, 1995; rommel et al, int.j.of parasit, 17, 639-; from Haberkorn and Mundt, Prakt. Tierarzt, 69(4), 46, 49-51, 1988, Toltrazuril, in particular triazinetrione derivatives, are known to be suitable for the treatment of coccidiosis in pigs (pig isosporeas).

Since there are a number of requirements which need to be met by modern pharmaceuticals, for example in terms of level of activity, duration of action, spectrum of action, range of administration, toxicity, use in combination with other active ingredients, use with formulation aids or related syntheses, and since resistance may occur, the development of such substances cannot be regarded as complete, and there is a continuing great need for new compounds which have advantages over the known compounds in at least some respects.

It has now been found that triazinetrione sulfones of the formula (I) and their physiologically tolerable salts have a very good coccidiostatic action with very low toxicity to mammals,

wherein

R¹Represents a halogenated alkyl group,

R²represents alkyl, alkoxy, halogen or SO₂N(CH₃)₂。

The compounds of the formula (I) can be prepared by the processes disclosed in DE-OS2718799, 2509037, 2532363, 2413722, WO 99/62519.

When used in accordance with the invention for the treatment of coccidia in animals, the compounds of formula (I) exhibit surprisingly low mammalian toxicity compared to the known compounds of the prior art and are therefore clearly superior to the known compounds in this application.

The compounds of formula (I) for controlling coccidia in animals are preferably those defined below,

wherein

R¹Represents C having 1 to 5 halogen atoms₁-C₄-a halogenated alkyl group,

R²represents C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen or SO₂N(CH₃)₂，

And their physiologically tolerable salts.

Particularly preferred compounds of the formula (I) for use according to the invention are those defined below,

wherein

R¹Represents C having 1 to 5 halogen atoms₁-C₄-a halogenated alkyl group,

R²represents C₁-C₄-an alkyl group,

and their physiologically tolerable salts.

Very particularly preferred compounds of the formula (I) for use according to the invention are those defined below,

wherein

R¹Represents C₁-C₄A perhalogenated alkyl group, a halogen atom,

R²represents a methyl group or an ethyl group,

and their physiologically tolerable salts.

In particular, a compound of the formula named Ponazuril

The use of (b) is particularly preferred.

The compounds of the formula (I) may, if appropriate, be in the form of geometric and/or optical isomers or regioisomers or mixtures of such isomers of different composition, depending on the nature and number of the substituents. Both the pure isomers and the use of mixtures of isomers are claimed according to the invention.

Preferred, particularly preferred or very particularly preferred isocompounds are those which have the preferred, particularly preferred or very particularly preferred isosubstituents mentioned below.

For in R¹The haloalkyl groups mentioned in the definition of (1) include the preferred, particularly preferred and very particularly preferred haloalkyl groups mentioned, which are in turn fluoroalkyl groups, respectively.

However, the radical definitions and explanations generally described above or described in preferred ranges can also be combined with one another, that is to say arbitrarily between the respective ranges and preferred ranges.

The compounds according to the invention against coccidiosis can be converted into all customary formulations and can be administered in different administration forms. In this connection, oral administration, in particular as an aqueous oral suspension, is preferred.

A preferred dose is from 1 to 500mg of active ingredient per kg of body weight of the animal to be treated, a particularly preferred dose is from 10 to 200mg/kg, and a very particularly preferred dose is from 20 to 100 mg/kg.

Formulations suitable for use in animals are:

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

emulsions and semisolid formulations for use on the oral or skin and for injection; examples of semisolid formulations are suspensions, pastes;

formulations wherein the active ingredient is processed in an ointment base or in an oil-in-water or water-in-oil emulsion base;

solid formulations such as powders, premixes or concentrates, granules, pills, tablets, boluses, capsules; aerosols and inhalants.

Injection solutions are administered by intravenous, intramuscular and subcutaneous routes.

Injection solutions were prepared as follows: the active ingredient is dissolved in a suitable solvent and additives such as co-solvents, acids, bases, buffer salts, antioxidants, preservatives can be added. The solution is sterilized by filtration or, if necessary, prepared under aseptic conditions and filled.

Solvents which may be mentioned are: physiologically tolerable solvents, such as water, alcohols, such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, N-methylpyrrolidone, glycerol formal, solketal, dimethylacetamide, 2-pyrrolidone, tetraethylene glycol (polyethylene glycol ether of tetrahydrofurfuryl alcohol) and mixtures thereof.

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

Co-solvents which may be mentioned are: a solvent that promotes dissolution of the active ingredient in the primary solvent or prevents precipitation thereof. Examples are polyvinylpyrrolidone, polyethoxylated castor oil, polyethoxylated sorbitan esters.

Examples of preservatives are: benzyl alcohol, chlorobutanol, parabens, n-butanol, and organic acids with preservative characteristics, such as benzoic, propionic, or sorbic acid and its salts. Preservatives can also be used as a combination of two or more preservatives, if appropriate.

The oral solution is used directly. The concentrate is orally administered after being pre-diluted to a use concentration. Oral solutions and concentrates are prepared as described above in the case of injectable solutions, wherein sterile handling may be omitted.

Solutions for use in the skin or body cavity are applied by pouring, spreading, rubbing, spray soaking. These solutions were prepared as described above for the injection solutions. The addition of thickeners during the preparation is particularly advantageous.

The thickening agent comprises: inorganic thickeners such as bentonite, colloidal silica, aluminium monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohol and copolymers thereof, acrylates and methacrylates, xanthan gum.

Gels are applied or spread on the skin or introduced into body cavities. The gel was prepared as follows: the solution prepared as described above in the case of the injectable solution is mixed with a sufficient amount of a thickening agent to form a clear composition having an ointment-like consistency. The thickeners used are the thickeners described above.

Pour-on formulations are poured or sprayed onto a limited area of the skin, in which case the active ingredient either penetrates into the skin and has a systemic effect or is distributed on the body surface.

Pour-on formulations are prepared by dissolving, suspending or emulsifying the active ingredient in a suitable solvent or solvent mixture which is compatible with the skin. If appropriate, further auxiliaries, such as colorants, resorption-promoting substances, antioxidants, photoprotective agents, binders, are added.

Solvents which may be mentioned are: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols, such as benzyl alcohol, phenethyl alcohol, phenoxyethanol, esters, such as ethyl acetate, butyl acetate, benzyl benzoate;

ethers, for example alkylene glycol alkyl ethers, for example dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones, for example acetone, methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2, 2-dimethyl-4-hydroxy-methyl-1, 3-dioxolane.

Colorants are all colorants that are allowed to be applied to an animal and are soluble or suspendable.

The resorption promoting substance is DMSO, coating oil such as isopropyl myristate, dipropylene glycol pelargonate, silicone oil, fatty acid ester, triglyceride, and fatty alcohol.

The antioxidant is sulfite or metabisulfite, such as potassium metabisulfite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.

Examples of photo-protecting agents are benzophenones orAnd (e) a substance.

Examples of binders are cellulose derivatives, starch derivatives, polyacrylates, natural polymers, such as alginates, gelatin.

The emulsion can be used orally, transdermally or by injection.

They are prepared by: the active ingredient is dissolved in one phase and homogenized with the aid of suitable emulsifiers and, if appropriate, further auxiliaries, such as colorants, resorption-promoting substances, preservatives, antioxidants, photoprotective agents, viscosity-increasing substances.

Hydrophobic phases (oils) which may be mentioned are the following: the paraffin oil is used as a main component,silicone oils, natural vegetable oils, e.g. sesame oil, almond oil, castor oil, synthetic triglycerides, e.g. caprylic/capric acid diglycerides, having a chain length C_8-12Of vegetable fatty acids or of other specifically selected natural fatty acids, of partial glycerides of saturated or unsaturated fatty acids which may also contain hydroxyl groups, C₈/C₁₀Mono-and diglycerides of fatty acids.

Fatty acid esters, e.g. ethyl stearate, di-n-butyl adipate, hexyl laurate, dipropylene glycol pelargonate, medium chain branched fatty acids and chain lengths C₁₆-C₁₈Esters of saturated fatty alcohols, isopropyl myristate, isopropyl palmitate, chain length C₁₂-C₁₈Octanoic/decanoic acid esters, isopropyl stearate, oleyl oleate, decyl oleate, ethyl lactate, waxy fatty acid esters, such as artificial duck tail feather oil, dibutyl phthalate, diisopropyl adipate, in particular ester mixtures of the latter.

Fatty alcohols, for example isotridecanol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids, such as oleic acid and mixtures thereof.

Hydrophilic phases which may be mentioned are the following: water, alcohols such as propylene glycol, glycerin, sorbitol and mixtures thereof.

Emulsifiers which may be mentioned are the following: surfactants (including emulsifiers and wetting agents), e.g. surfactants

1. Nonionic surfactants, for example polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, ethanol, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ethers,

2. amphoteric surfactants, such as disodium N-lauryl-beta-iminodipropionate or lecithin,

3. anionic surfactants, such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono/dialkyl polyglycol ether orthophosphate monoethanolamine salts,

4. cationic surfactants, such as cetyl trimethylammonium chloride.

Other suitable auxiliaries are:

substances which increase the viscosity and stabilize the emulsion, for example carboxymethylcellulose, methylcellulose and other cellulose-and starch-derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silica or mixtures of the stated substances.

The suspension can be used orally, transdermally or by injection. They can be prepared by suspending the active ingredient in a liquid carrier, if appropriate with the addition of further auxiliaries, such as wetting agents, antifoams, colorants, resorption-promoting substances, suspension stabilizers, preservatives, antioxidants, photoprotectors, humectants (humectant).

Mention may preferably be made of an orally administrable suspension containing:

A) a concentration of from 0.1 to 30% by weight, particularly preferably from 1 to 10% by weight, of a compound of the formula (I),

B) suspension stabilizers, for example bentonite and/or xanthan gum,

C) if appropriate, ionic or nonionic wetting agents in concentrations of from 0.01 to 5% by weight, particularly preferably from 0.1 to 0.5% by weight,

D) if appropriate, from 0.01 to 5% by weight, particularly preferably from 0.05 to 0.5% by weight, of antifoams based, for example, on siloxanes,

E) if appropriate, a humectant in a concentration of from 1 to 30% by weight, particularly preferably from 5 to 20% by weight,

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

G) if appropriate, acidic or basic substances in the concentration required for adjusting the pH.

Liquid carriers which may be mentioned are the abovementioned solvents and homogeneous mixtures of solvents, provided that they are pharmaceutically acceptable and in which the active ingredient is not or only sparingly soluble. Preferably, water is used.

For suspensions which can be administered orally, wetting agents (dispersants) which may be mentioned are surfactants, for example

1. Anionic surfactants, for example sodium lauryl sulfate, fatty alcohol ether sulfates, mono/dialkyl polyglycol ether orthophosphate monoethanol amine salts, lignosulfonates or dioctyl sulfosuccinates,

2. cationic surfactants, such as cetyl trimethylammonium chloride,

3. amphoteric surfactants, such as disodium N-lauryl-beta-iminodipropionate or lecithin,

4. nonionic surfactants, for example polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, ethanol, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, sodium lauryl sulfate, sodium,

Suitable antifoams are those based on silicones, for example dimethicone or antifoam.

Suspension stabilizers which can be used are, for example, the viscosity-increasing substances mentioned above.

Conventional humectants can be used, and examples which may be mentioned are: propylene glycol, glycerol, sugar alcohols such as sorbitol, sugars such as sucrose.

Suitable preservatives are known to those skilled in the art; examples of which have been mentioned above. Organic acids having preservative properties, such as benzoic, propionic or sorbic acid and salts thereof, are preferably used. Preservatives can also be used as a combination of two or more preservatives, a preferred example which may be mentioned being the combination of sodium propionate with sodium benzoate.

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

Acids which may be mentioned are, for example: 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 metal and alkaline earth metal carbonates, for example sodium carbonate, and amines, for example monoethanolamine, diethanolamine or triethanolamine.

Suitable buffer systems are for example phosphate-based buffer systems.

The pH is preferably from 2 to 10, in particular from 3 to 7.

The active ingredient is preferably used in the suspension in micronized form, more particularly with a particle size distribution of generally 0.1 to 100 μm, preferably 1 to 50 μm.

Further auxiliaries which may be mentioned are those mentioned above.

The paste can be administered orally or transdermally. They differ from the liquid to thick liquid suspensions and emulsions described above in that they have a higher viscosity. Pastes containing Ponazuril (═ Toltrazuril sulfone) have been described in WO 99/62519.

Preferred pastes which may be mentioned are those which can be administered orally and which contain a compound of the formula (I), characterized in that

a) The active component has a particle size of 1 × 10^-6m, maximum particle size 50X 10^-6m, at a concentration of 0.1 to 20% by weight,

b) polyacrylic acid having an acrylic acid content of 56-68% by weight and a molecular weight of about 3X 10⁶In alkali metal or alkaline earth metal basesAnd, and is present in a concentration of 0.1 to 5% by weight,

c) if appropriate, a humectant in a concentration of from 5 to 30% by weight,

d) if appropriate, preservatives in a concentration of from 0.01 to 0.5% by weight,

e) and water to make up to 100% by weight.

The concentration by weight of active ingredient in the paste is preferably from 5% by weight to 20% by weight, particularly preferably from 10% by weight to 15% by weight.

The polyacrylic acid used in the paste is preferably neutralized with an alkali metal hydroxide or carbonate. Polyacrylic acids are present in the formulations of the invention in concentrations of 0.2% to 1%, preferably 0.5% by weight, they are commercially available and are described in pharmacopoeia, for example under the trade name Carbomer 934P.

In the paste, a preferred preservative is a paraben (paraben), such as methyl 4-hydroxybenzoate, ethyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate. Preservatives may be used alone or in combination to achieve sufficient preservative effect. Their concentration is generally from 0.01 to 0.5% by weight.

Humectants, such as glycerol or 1, 2-propylene glycol, are also optionally included in the pastes. The humectant is used at a concentration of 5% to 30%, preferably 10% to 20% by weight.

The active component is 1-10 × 10^-6m, preferably 1-5X 10^-6m is present in the paste. Maximum particle size of 50X 10^-6m, preferably 30X 10^-6And m is selected. Particle size is determined by laser light scattering measurements (e.g., using a Malvern Mastersizer). Pastes are obtained by mixing the individual components. Its consistency can be changed by increasing or decreasing the moisture content. A paste-like consistency is desirable. This enables the composition to be administered orally with a suitable applicator, such as a syringe, tube, spoon, or the like.

To prepare solid preparations, the active ingredient is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and converted into the desired form.

Carriers which may be mentioned are all physiologically tolerable solid inert substances. Inorganic and organic substances are used as such substances. Examples of inorganic substances are sodium chloride, carbonates, such as calcium carbonate, hydrogen carbonate, aluminum oxide, silicon dioxide, alumina, precipitated or colloidal silicon dioxide, phosphates.

Examples of organic substances are sugars, cellulose, food and feed, such as milk powder, animal meal, cereal flour and ground cereals (getriedemehle und-schroet), starch.

The auxiliary agent is the preservative, antioxidant and colorant.

Other suitable auxiliaries are lubricants and glidants, for example magnesium stearate, stearic acid, talc, bentonite, decomposition-promoting substances, for example starch or crosslinked polyvinylpyrrolidone, binders, for example starch, gelatin or linear polyvinylpyrrolidone, and dry binders, for example microcrystalline cellulose.

The active ingredient may also be in the form of a solid or liquid formulation as described above in which it is encapsulated.

The active ingredient may also be used in the form of an aerosol. For this purpose, the active ingredient is finely distributed under pressure in suitable formulations.

It is also advantageous to use the active ingredient in a formulation that releases the active ingredient in a delayed manner.

The active ingredient is preferably administered with feed and/or drinking water.

The feed includes feed components of plant origin, such as hay, beets, cereals, cereal by-products, feed components of animal origin, such as meat, fat, dairy products, bone meal, fish products, and feed components, such as vitamins, proteins, amino acids, such as DL-methionine, salts, such as calcium carbonate and sodium chloride. The feed also comprises supplementary feed, prepared feed and compound feed. They contain feed components in the composition, which ensure a balanced diet in terms of energy and protein supply and vitamin, inorganic salt and trace element supply.

The concentration of the active ingredient in the feed is generally about 0.01-500ppm, preferably 0.1-50 ppm.

The active ingredient may be added to the feed as such or in the form of a premix or feed concentrate.

Premixes and feed concentrates are mixtures of the active ingredients with suitable carriers.

The carrier comprises a feed ingredient or a mixture thereof.

They may also contain additional auxiliaries, for example substances which control the flowability and miscibility, for example silica, bentonite, lignosulphonates. Antioxidants such as BHT or preservatives such as sorbic acid or calcium propionate may also be added.

Concentrates for administration via drinking water must be formulated so that when mixed with drinking water a clear solution or stable homogeneous suspension results.

Suitable carriers are water-soluble substances (feed additives), such as sugars or salts (e.g. citrate, phosphate, sodium chloride, sodium carbonate).

They may likewise contain antioxidants and preservatives.

The active ingredient is suitable for controlling parasitic protozoa according to the invention, which occur in farm and breeding animals in animal breeding and animal breeding, zoos, laboratories and laboratory animals and pets, while the toxicity to warm-blooded animals is surprisingly low. They are also effective against pests in all or individual stages of development, as well as against resistant and generally sensitive pests. Parasitic protozoa are controlled in order to alleviate diseases, deaths and yield losses (e.g. reduction in the production of meat, milk, wool, hides, eggs, honey, etc.), so that the animals can be raised more economically and more easily by using active ingredients.

Parasitic protozoa include:

the class flagellates (Flagellata), for example Trypanosomatidae (trypanosomatida) such as Trypanosomatidae (Trypanosomatidae) such as Trypanosoma brucei (Trypanosoma brucei), Trypanosoma gambiae (t.gamniense), Trypanosoma nodosum (t.rhododendron), Trypanosoma congolense (t.congolense), Trypanosoma cruzi (t.cruzi), Trypanosoma evanesis (t.evansi), Trypanosoma matsudanum (t.equinum), Trypanosoma lewisi (t.lewisi), Trypanosoma pisi (t.percae), Trypanosoma canecium, Trypanosoma mobilis (t.vivax), leishmania brasiliensis (leishmaniasis), leishmania donii (l.donovani), leishmania tropicalis (l.troma), for example trichomonas (Giardia), Giardia (Giardia).

The subphylum Hypopharia (Sarcomastigophora) (Rhizopoda), for example, Entamoebaceae (Entamoebaceae) such as Entamoeba histolytica, Hartmanellae such as Acanthamoeba sp.

Apicomplexa (sporozoea), for example Eimeridae (Eimeridae) such as Eimeria acervulina, Eimeria adenoids (e.adenoides), Eimeria arabica (e.albahmensis), Eimeria ducks (e.anatis), Eimeria geestera (e.anseris), Eimeria assamica (e.arloingii), e.ashata, Eimeria arborescens (e.alburnis), Eimeria boviensis (e.brunetti), Eimeria canis (e.canis), Eimeria chinchiana, Eimeria pis (e.clausii), Eimeria columba, Eimeria conoides, Eimeria reticulata (e.crnei), Eimeria nilla (e.delbrunetti), Eimeria sp), Eimeria sp.eimeria sp), Eimeria sp (e.alhagoides), Eimeria maxima (e.alhagoides), Eimeria splenius, Eimeria maxima (e.nilla), Eimeria maxima (e.artemia, Eimeria maxima (e.artemia) Such as guinea fowl eimeria (e.g. meleagris), e.meleagris, and eimeria mitis (e.mitis), eimeria nilotiensis (e.necatrix), eimeria nilapaensis (e.g. ninakohlyyakimovae), e.ovis, eimeria smallii (e.para), eimeria malachita (e.pavonis), e.perforans, e.phasani, eimeria pyriformis (e.piriformis), eimeria predata (e.praecox), e.resiidula, eimeria roughi (e.scabra), e.speec, eimeria nilotica (e.stieda), eimeria suis (e.sui), eimeria avium (e.tenuiella), eimeria treemata (e.monocatala), e.e.e., "treecia", e, euteria trvatica (e.cukuporius), sai.e.g. Plasmodium, and the like), e.g. sporotrichia, e.e.g. sporotrichia, Plasmodium, e.g. sporotrichia, Plasmodium, and the like, such as Plasmodium falciparum (p.falciparum), plasmodium malariae (p.malariae), plasmodium ovale (p.ovale), plasmodium vivax (p.vivax), p.spec., e.g., Piroplasmea such as Babesia argentata, Babesia bovis (b.bovis), Babesia canis (b.canis), b.spec, pirillum peterii (Theileria parva), pirillum tireri (Theileria spec), e.g., adeleia such as clusteria canis (hepazoonas), h.spec.

Myxosporeae (Myxospora) and Microspora (Microspora), e.g. gracilaria (glugae spec), microsporidia (Nosema spec).

Pneumocystis carinii (Pneumocystis carinii), and Ciliata (Ciliata) such as, for example, Balantidium coli (Balantidium coli), ichthyophhritus spec, Trichodina spec, and rectomy spec.

The compounds of the invention are also effective against protozoa present as parasites on insects. Mention may be made of parasites of the order microsporidia, in particular of the genus microsporidia. Mention may in particular be made of nosema apis in bees.

Protozoa that should be very particularly emphasized are those of genera and species that cause asymptomatic infections in pigs, in particular: trypanosoma congolense simae, active trypanosome (t.vivax vivax), t.congolense congolense, t.brucei evansi, tritichomonas suis, trichomonas rotunda, tetratrichomonas butteri, eimeria de, eimeria suis, eimeria roughs, eimeria mimicus (e.perminua), eimeria echinacea (e.spinosa), e.polita, e.porci, e.neodellidiki, isosporozoon of swine, cryptosporidae, toxoplasma gondii, sarcocystis suis (sarcocystis. scheriana), sarcocystis hominis, babassu (babeatramani), babassu, cuckoo pouch.

Agricultural and breeding animals include mammals, such as cattle, horses, sheep, pigs, goats, camels, buffalo, donkeys, rabbits, light brown deer, reindeer, fur-bearing animals, such as mink, chinchilla, racoon, avian animals, such as chickens, geese, turkeys, ducks, pigeons, avian animals in the home or zoo. They also include useful and ornamental fish. All breeds, subspecies and species of pigs should be particularly emphasized.

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

Pets include dogs and cats.

The fish includes useful fish, breeding fish, aquarium fish and ornamental fish of all ages living in fresh water and salt water. Beneficial and breeding fish include, for example, carp, eel, salmon, whitefish, salmon, snapper, bream, redeye, Atlantic Pacific, plaice, verasper, Japanese smelt (Seriola quinqueradiata), Japanese eel (Anguilla japonica), yellow sea bream (Pagurus major), Seabass (Dicentra labrachu labrax), Gray rouge (Mugilus cephalus), Pompano, Gilthreid sebarecam (Sparus auratus), Tilapia, and chia species such as Plagioscion, Parasilurus. The composition of the invention is particularly suitable for the treatment of fish fry, such as carp with a body length of 2-4 cm. The composition of the invention is also very suitable for eel growth.

The following examples are intended to illustrate the invention, but not to limit it:

potency assay for Ponazuril compared to Toltrazuril:

efficacy of ponazuril on infection of chicks artificially induced with eimeria avium, e.maxima and e.acervulina:

the purpose of this experiment was to test the efficacy of Ponazuril on artificial mixed infections (avian eimeria, e.maxima and e.acervulina) in chicks under cage feeding conditions.

Groups of 44 chicks each were formed (4 replicates of 11 chicks each treated) and infected with sporulated oocysts on day 14. Ponazuril is administered on each of days 10-24 or 17-24. 3 doses were used in the feed in two treatment sessions: 5ppm, 10ppm and 20 ppm. The outcome of the treatment was determined by different clinical and parasitological parameters, including mortality due to coccidiosis and oocyst secretion in feces.

The infection is moderate to intense. Mortality due to coccidiosis was 20% of untreated controls. Infection can be controlled with all dosages and treatment regimens. The degree of control here depends directly on the dosage and the start of the treatment. Early treatment initiation significantly reduced the findings on parasitology (number of oocyst secretions and lesions) and improved the technical parameters (weight gain and feed conversion). The highest dose (20 mg Ponazuril in the feed) showed the best results. This dose corresponds to a dose of about 3.5mg/kg body weight per day.

B. Field trial of therapeutic efficacy of ponazuril in treating naturally infected herd lambs with coccidiosis compared to Toltrazril

The purpose of this experiment was to compare the efficacy of Toltrazuril and ponazuril on natural infection by an eimeria pathogen.

The active components were compared in three consecutive experiments:

experiment 1: untreated control-Toltrazril 20mg/kg-Ponazuril 20mg/kg

Experiment 2: untreated control-Ponazuril 20mg/kg

Experiment 3: untreated control-Toltrazril 20mg/kg-Ponazuril 10 mg/kg.

Oocyst secretion and fecal consistency were used as the main parameters. Occasionally, the animals were checked for body weight.

During the experiment, the infection pressure was low. Both Toltrazuril and Ponazuril were fully effective under the conditions tested.

C: efficacy of Toltrazuril and Ponazuril in the treatment of piglets experimentally infected with pig Isosporidium (Isosporiuis) (Ferkeln)

The purpose of this trial was to evaluate the efficacy of different doses of Toltrazuril and Ponazuril against coccidiosis in piglets.

On day 0, by administration via gastric tube 5X 10³Individual porcine isospora oocysts infected 2 groups (a and B) of 3 week-sized piglets. Group C is an untreated control group of infections.

On day 3 post-infection, all groups received Toltrazuril or Ponazuril as a single dose, depending on their respective body weights.

Group A. Toltrazuril 10mg/kg body weight

Toltrazril 20mg/kg body weight

Group B I.Ponazuril 10mg/kg body weight

Ponazuril 20mg/kg body weight

Group C was not administered

Comparison of the toxicity of the sulfides (Toltrazril) with the corresponding sulfones (Ponazril)

The following toxicity data were performed according to OECD/GLP guidelines, in particular OECD 414, 401 and 408. The teratogenicity of compounds is determined according to the US-guidance criteria "teratogenicity experiments", Guidelines for Registering Pesticides in the u.s.a., u.s.environmental Protection Agency, Hazard evaluation: human and medical animals U.S. Federal Register, Vol.43, paragraph163.83-3, adapted November 1982.

Preparation examples

General preparation method

The following suspensions can be prepared by the following method:

the materials were stirred together separately until a homogeneous suspension was prepared, and the pH was adjusted to the desired range. Here, the bentonite or sodium alginate suspension stabilizer is impregnated, if appropriate at about 80 ℃ or about 40 ℃. After the suspension is prepared, it can be dispensed into a suitable container.

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

Example 1 (suspension)

Ponazuril micro powder 10.0

Polyoxyyl-35-Castor oil 5.0

0.075 of methylparaben

Propyl p-hydroxybenzoate 0.025

Sodium carboxymethylcellulose 1.0

Adding softened water to 100.0g

Example 1 (suspension)

Ponazuril micro powder 1.0

0.075 of methylparaben

Propyl p-hydroxybenzoate 0.025

Sodium alginate 1.0

Adding softened water to 100.0g

Dipping at 40 deg.C

Example 3 (suspension)

Ponazuril micro powder 50.0

3.5 of bentonite

Xanthan gum 3.0

Dioctyl sodium sulfosuccinate

(Dioctylnatriumsulfosuccinat) 2.5

Defoaming detergent emulsion 1.0

Sodium benzoate 2.0

Sodium propionate 2.0

Citric acid powder 4.0-10.0

105.0 parts of 1, 2-propanediol

Adding softened water to 1030.0g

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

According to the manufacturer's recommendations, the bentonite is preferably first heated to 80 ℃ in an aqueous suspension, expanded and then processed with the other components to form a suspension.

Claims (2)

1. Use of a compound of formula (I) and its physiologically tolerable salts for the production of a composition for controlling diseases in animals caused by porcine isosporites

Wherein

R¹Represents C having 1 to 5 halogen atoms₁-C₄A halogenated alkyl group,

R²represents C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen or SO₂N(CH₃)₂。

2. Use according to claim 1, characterized in that the compound of formula (I) according to claim 1 is administered in the form of an oral aqueous suspension.