SK285494B6 - Endoparasiticidal composition - Google Patents

Abstract

Endoparasiticidal composition comprises piperazines together with cyclic depsipeptides consisting of amino acids and hydroxycarboxylic acids as ring units and having 24 ring atoms. The use of piperazines together with cyclic depsipeptides consisting of amino acids and hydroxycarboxylic acids as ring units and having 24 ring atoms for the production of endoparasiticidal compositions is also described.

Description

Technical field

The invention relates to the use of piperazines for enhancing the endoparasiticidal effect of cyclic depsipeptides in endoparasiticidal compositions.

BACKGROUND OF THE INVENTION

Piperazines and their action against endoparasites are well known (Melh et al., Diagnostic and Therapy of Parasitosen des Menschen, 2nd Ed., Gustav Fischer Verlag (1995), Melh et al., Diagnosis and Therapy of Parasitosen von Hus-, Nutz - und Heimtieren, 2nd ed., Gustav Fischer Verlag, (1993).

The cyclic depsipeptide PF 1022 and its action against endoparasites are known from EP-OS 382 173.

Further cyclic depsipeptides and their endoparasiticidal effects are the subject of EP-OS 0 626 375, EP-OS 0 626 376 and WO 93/25543.

SUMMARY OF THE INVENTION

It is an object of the present invention to use piperazines to enhance the endoparasiticidal effect of cyclic depsipeptides consisting of amino acids and hydroxycarboxylic acids as ring building blocks and 24 ring atoms.

Further, the present invention provides endoparasiticidal compositions comprising piperazines together with cyclic depsipeptides consisting of amino acids and hydroxycarboxylic acids as ring building blocks and 24 ring atoms.

It is also an object of the present invention to use piperazines together with cyclic depsipeptides consisting of amino acids and hydroxycarboxylic acids as ring building blocks and 24 ring atoms for the production of endoparasiticidal agents.

The cyclic depsipeptides having 24 ring atoms include compounds of formula (I)

in which

R ¹ , R ² , R ¹¹ and R ¹² are each independently C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 6 cycloalkyl, arylalkyl or aryl which are: optionally substituted with halogen, (C 1 -C 4) alkyl, hydroxy or (C 1 -C 4) alkoxy,

R ³ , R ⁵ , R ⁷ and R ⁹ independently represent a hydrogen atom or a straight or branched alkyl group having 1 to 8 carbon atoms, which may be optionally substituted by hydroxy, alkoxy having 1 to 4 carbon atoms, carboxy, carboxamide imidazolyl, indolyl, guanidino, mercapto or (C 1 -C 4) alkylthio and further aryl or arylalkyl which may be substituted by halogen, hydroxy, (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy atoms and

R ⁴ , R ⁶ , R ⁸ and R ¹⁰ are each independently hydrogen, straight C 1 -C 5 alkyl, C 2 -C 6 alkenyl and C 3 -C 7 cycloalkyl, which may optionally be substituted by hydroxy, C1-C4alkoxy, carboxy, carboxamide, imidazolyl, indolyl, guanidino, mercapto or alkylthio, and aryl or aralkyl which may be substituted by halogen, hydroxy, C1-4alkyl, (C1-C4) -alkoxy or alkoxy;

R ³ and / or R ⁷ represents a 4-morpholinobenzyl group as well as their optical isomers and racemates.

Preference is given to compounds of the general formula (I) in which

R ^{@ 1} , R ^{@ 2} , R @ ¹¹ and R @ ¹² are each independently methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl or phenyl optionally substituted by halogen, C1-alkyl; up to 4 carbon atoms, hydroxy or alkoxy of 1 to 4 carbon atoms, or a benzyl or phenylethyl group, which may optionally be substituted by the radicals mentioned for the phenyl group; and

R ³ to R ¹⁰ are as defined above.

Particularly preferred are compounds of formula (I) wherein:

R ^{@ 1} , R ^{@ 2} , R @ ¹¹ and R @ ¹² are each independently methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl or t-butyl,

R ³ , R ⁵ , R ⁷ and R ⁹ represent a hydrogen atom, a straight or branched alkyl group having 1 to 8 carbon atoms, in particular a methyl, ethyl, propyl, i-propyl, n-butyl, s-butyl and t-butyl group which may optionally be substituted by C 1 -C 4 alkoxy, in particular methoxy or ethoxy, imidazolyl, indolyl or C 1 -C 4 alkylthio, especially methylthio and ethylthio, and furthermore phenyl, benzyl or phenylethyl, which may optionally be substituted by halogen, especially chlorine, and R ^4, R ^6, R ⁸ and R ¹⁰ are independently hydrogen, methyl, ethyl, n-propyl, n-butyl, vinyl or cyclohexyl, which optionally may be substituted by methoxy, ethoxy , imidazolyl, indolyl, methylthio or ethylthio, as well as isopropyl and a s-butyl group, and further optionally a halogen-substituted phenyl, benzyl or phenylethyl group.

Further, as a 24-ring depsipeptide, the compound PF 1022, known from EP-OS 382 173, of the following formula:

In addition, compounds known from PCT application WO 93/19053 may also be mentioned as depsipeptides.

In particular, compounds of the general formula can be mentioned from this PCT application WO 93/19053

in which

Z is N-merpholinyl, nitro, amino, methylamino or dimethylamino, particularly preferably morpholinyl.

In addition, compounds of the following formula may be mentioned

in which

R ^1a , R ^2a , R ^3a and R ^4a independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or an aryl group, especially a phenyl group, which are optionally substituted by hydroxy, alkoxy having 1 to 10 carbon atoms or halogen.

Compounds of formula (I) may be prepared by the use of open-chain octadepsipeptides of formula (II)

R ¹ OR ¹ R ³ OR ^! RO R '? "OR ¹ R · * or OR * or a (II) in which R ¹ to R ¹² above, cyclizing in the presence of a diluent and in the presence of a coupling agent.

All compounds useful for coupling amide bonds find use as coupling reagents (see, for example, Houben Weyl, Methoden der organischen Chemie, vol. 15/2; Bodanszky et al., Peptide Synthesis (Willey & Sons, New York 1976)).

Advantageously, the following reagents and methods may be mentioned: Method of active esters with pentafluorophenol (Pfp), N-hydroxysuccinimide, 1-hydroxybenzotriazole, coupling with carbodiimides such as dicyclohexylcarbodiimide (DCC) or N '- (3-dimethylaminopropyl) -N- ethyl carbodiimide (Ebc) and mixed anhydride method, or by coupling with phosphonium reagents such as benzotriazol-1-yl-oxytris (dimethylaminophosphonium) hexafluorophosphate (BOP) or bis- (2-oxo-3-oxazolidinyl) phosphonium chloride (ΒΟΡ) -Cl) or phosphonic ester reagents such as cyanophosphonic acid diethyl ester (DEPC) and diphenylphosphoryl azide (DPPA).

Coupling with bis- (2-oxo-3-oxazolidinyl) phosphonium chloride (ΒΟΡ-Cl) and N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDC) in the presence of 1-hydroxybenzotriazole (HOBt) is particularly preferred.

The reaction is carried out at a temperature of 0 to 150 ° C, preferably 20 to 100 ° C, particularly preferably at room temperature.

Suitable diluents are all inert organic solvents. These include, in particular, aliphatic and aromatic or halogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, ligroin, benzene, toluene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, such as diethyl ether, dibutyl ether, glycol dimethyl ether, diglycol dimethyl ether, tetrahydrofuran and dioxane, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, esters such as methyl ester and ethyl acetate, nitrile such as nitrile such as acetonitrile such as glutaric acids, in addition amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, as well as dimethylsulfoxide, tetramethylenesulfone and hexymethylphosphoric triamide.

The compounds of formula (II) and the coupling agents are used in a ratio of 1: 1 to 1: 1.5 to each other, preferably your equimolar ratio.

After the reaction is complete, the diluent is distilled off and the compounds of formula (I) are purified by conventional means, for example by chromatography.

Open-chain octadepsipeptides of formula (II)

R 'O R' R ³ OR ^! r O r 'R' o R 'tuiinitnih?

in which the radicals are as defined above, are obtained by hydrogenolyzing compounds of formula (III)

R OR OR OR o (ΙΠ) in which

A represents a benzyl group and

R ¹ to R ¹² are as defined herein, in the presence of a diluent and a catalyst.

Compounds of formula (III)

in which the radicals are as defined above, are obtained by hydrolyzing the compounds of formula (IV)

in which the general radicals are as defined above, and

B is t-butoxy.

The compounds of formula (IV), as well as their stereoisomers, is obtained by the tetradepsipeptides of formula (V) R ¹ or R ² or R ^a 's or ⁴ wherein

A represents a benzyl group,

Z is hydroxy and the other substituents are as defined above, and tetradepsipeptides of formula (VI) R ⁷ ro r 'O R'

R ⁵ OR O in which

D is a hydrogen atom,

B is tert-butoxy and the other substituents are as defined above, condensed in the presence of a diluent and a coupling reagent.

The tetradepsipeptides of formula (V) are obtained by substituting tetradepsipeptides of formula (VB)

R ¹ OR ³ R ² OR ³

R ° OR ⁴ O in which

A represents a benzyl group,

B is a tert-butoxy group and the other substituents are as defined above, saponified in the presence of a diluent and a protonic acid.

Tetradepsipeptides of Formula (VI)

in which

D is a hydrogen atom,

B is a tert-butoxy group, and the other substituents are as defined above, obtained by substituting tetradepsipeptides of the general formula (Vil) r 'or ² r ² or ³

R ° OR O

in which

A represents a benzyl group,

B is n-butoxy and the other substituents are as defined herein, hydrogenolyzed in the presence of a diluent and a catalyst.

The tetradepsipeptides of formula (VII) are obtained by condensing the didepsipeptides of formula (VIII)

R ³ OR ³

in which

A represents a benzyl group,

Z is hydroxy and the other substituents are as defined above, and didepsipeptides of formula (IX) r ² or ³

in which

D is a hydrogen atom,

B is a tert-butoxy group and the other substituents are as defined herein, in the diluent and in the presence of a coupling agent.

Depsipeptides known from WO 93/1905 or EPOS 382 173 can be obtained by the methods described therein.

Piperazines include all compounds of formula (X)

R ' ²

I

R ' ⁴ (X) wherein

R ¹³ and R ¹⁴ are independently the same or different substituents from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, aryl and heteroaryl, as well as -CONR ¹⁵ R ¹⁶ or -CSNR ¹⁵ R ¹⁶ , wherein:

R ¹⁵ and R ¹⁶ are independently the same or different substituents from the group consisting of a hydrogen atom or an optionally substituted alkyl or cycloalkyl group.

Preferred are compounds of formula (X) in which

R ¹³ and R ¹⁴ are independently the same or different substituents from the group consisting of hydrogen, in each case optionally substituted alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 8 carbon atoms, as well as -CONR ^11; R ¹⁶ or -CSNR ¹⁵ R ¹⁶ , wherein

R ¹⁵ and R ¹⁶ are independently the same or different substituents from the group consisting of hydrogen or optionally substituted alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms.

Particularly preferred are compounds of formula (X) wherein:

R ¹³ and R ¹⁴ are independently the same or different substituents from the group consisting of hydrogen, in each case optionally substituted alkyl of 1 to 4 carbon atoms and cycloalkyl of 6 carbon atoms, as well as -CONR ¹⁵ R ¹⁶ or -CSNR ¹⁵ R ¹⁶ , where

R ¹⁵ and R ¹⁶ are independently the same or different substituents from the group consisting of hydrogen or optionally substituted alkyl of 1 to 4 carbon atoms or cycloalkyl of 6 carbon atoms.

Very particularly preferred are compounds of formula (X) wherein:

R ¹³ and R ¹⁴ are each independently the same or different substituents from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 9 same or different halogen, fluoro, chloro and bromo, a cycloalkyl radical having 6 carbon atoms such as the group of -CONR ¹¹⁵ R ^I5 or -CSNR ^ls R ^16, wherein

R ¹⁵ and R ¹⁶ are independently the same or different substituents from the group consisting of hydrogen or C 1 -C 4 alkyl or C 6 cycloalkyl.

Non-limiting examples include the following compounds:

piperazine, diethylcarbamazine, Ν, Ν'-dimethylpiperazine, N-methylpiperazine, Ν, Ν'-diethylpiperazine, N-ethylpiperazine, N-ethyl-N'-methylpiperazine, Ν, Ν'-dipropylpiperazine, N-propylpiperazine, N-propylpiperazine, N'-propylpiperazine, N-methyl-N'-propylpiperazine, N-cyclohexylpiperazine, N, N'-dicyclohexylpiperazine, fH, C ₂ H ₅

OÔO oO (N ^CH a), O ^N (CH _a ) _with O ^N (iC _and H,) _and (pH, i-CÄ jC, H ₇₎

O Ô O Ô

ΟΟΝΓΛΝΓΛ, ^Η), O ^ ^N OCH),, with piperazine and diethylcarbamazine being particularly preferred.

Piperazines are generally known organic compounds and are commercially available or can be obtained by known methods (Mehlh et al., Diagnostic and Therapy der Parasitosen des Menschen, 2nd ed., Gustav Fischer (1995), Mehlh et al., Diagnostic and Therapy der Parasitosen von Haus-, Nutz- und Heimtieren, 2nd ed., Gustav Fischer (1993)).

The compositions of the present invention are useful for good toxicity to the warm-blooded endoparasite killing that occurs in humans and in animal husbandry, such as breeding animals, livestock, zoo animals, laboratory and experimental animals, and animals raised for pleasure. They are effective against all or individual developmental stages of pests, as well as against resistant and normally sensitive species. The destruction of pathogenic endoparasites is intended to suppress diseases, deaths and performance degradation (for example, in the production of meat, milk, wool, skin, eggs, honey and the like), so that the use of the active substances makes animal use more economical and easier. The pathogenic endoparasites include Cestodes, Trematodes, Nematodes and Acantocephaly, in particular:

From the Pseudophylidea class, for example:

Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp. and Diphlogonoporus spp ..

From the class Cyclophyllidea, for example:

Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa sp., Thysaniezia spp., Stitia spp., Cittotaenia spp., Andyra spp., Bertiella sp., Taenia spp., Echococ. Hydatigera spp., Davainea spp., Raillietina spp., Hymonolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium sp., Joyeuxiella spp. and Diplopylidium spp.

From the subclass Monogenea, for example:

Gyrodactylus spp., Dactylogyrus spp. and Polystoma spp ..

From the Digenea subclass, for example:

Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Omithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium sp., Echinoparyphium sp. , Fasciola spp., Faciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp., Paramphistomum spp., Calicophoron spp., Gigantocotyle spp., Fischoederius spp. spp., Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimus spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp. and Metagonimus spp ..

From the Enoplida class, for example:

Trichuris spp., Capillaria spp., Trichomosoides spp. and Trichinella spp ..

From the Rhabditia class, for example:

Micronema spp. and Strongyloides spp ..

From the Strongylida class, for example:

Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostomum spp., Cyclococercus spp., Cylicostephanus spp. Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Mctastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp. Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Gilaroides spp., Paraftlaroides spp., Trichostrongylus spp. Cooperatum spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp. and Ollulanus spp ..

From the class Oxyurida, for example:

Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp. and Heterakis spp ..

From the Ascaridia class, for example:

Ascaris spp., Toxascaris spp., Toxocara spp., Tarascaris spp., Anisakis spp. and Ascaridia spp ..

From the Spirurida class, for example:

Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabroncma spp., Draschia spp. and Dracunculus spp ..

From the class Filariida for example:

Stephanofilaria spp., Parafilaria spp., Tetaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp. and Onchocerca spp ..

From the Gigantorhynchida class, for example:

Filicollis spp., Moniliformis spp., Macracanthorhynchás spp. and Prosthcnorchis spp ..

Breeding and productive animals include mammals such as cows, horses, sheep, pigs, goats, camels, hippos, donkeys, rabbits, fallow deer, reindeer and fur animals such as mink, chinchilla and raccoon, as well as birds such as chickens, geese, turkeys and ducks, freshwater and saltwater fish such as trout, carp and eels, as well as reptiles and insects such as bees and silkworms.

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

The animals kept for pleasure include dogs and cats.

The administration of the active compounds can be carried out both prophylactically and therapeutically.

The application of the active substances is carried out directly or in the form of suitable preparations by enteral, parenteral, dermal, nasal, environmental treatment or by means of shaped bodies containing the active substance, such as strips, pads, belts, collars, ear tags, limb belts and marking devices .

Enteral administration of the active ingredient is carried out, for example, orally in the form of powders, tablets, capsules, pastes, beverages, granules, orally administrable solutions, suspensions or emulsions, medicated feed or drinking water. The dermal application is carried out, for example, by dipping, spraying or pour-on and spot-on. Parenteral administration is by injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or via implants.

Suitable preparations include:

solutions such as injectable solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, glazing preparations and jellies;

emulsions and suspensions for oral or dermal administration as well as for injection, semi-solid preparations;

preparations in which the active substance is incorporated into an ointment base or oil-in-water emulsion base or water-in-oil base;

solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, capsules; aerosols and inhalants and shaped bodies containing mixtures of active substances.

Injectable solutions are administered intravenously, intramuscularly and subcutaneously.

Injectable solutions are prepared by dissolving the active ingredient in a suitable solvent and adding optional ingredients such as solubilizers, acids, bases, buffer salts, antioxidants and preservatives. The solutions obtained are then sterile filtered and filled.

Solvents include physiologically acceptable solvents such as water, alcohols such as ethyl alcohol, butyl alcohol, benzyl alcohol, glycerol, propylene glycol, and polyethylene glycols, N-methylpyrrolidone and mixtures thereof.

Alternatively, the active ingredients may also be dissolved in physiologically acceptable vegetable or synthetic oils which are suitable for injection.

Diluents which may be mentioned are solvents which promote the dissolution of the active substance in the main solvent or prevent its precipitation. Examples include polyvinylpyrrolidone, polyoxyethylated castor oil and polyoxyethylated sorbitan ester.

Preservatives are, for example, benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid esters and n-butyl alcohol.

Oral solutions are used directly. Concentrates are orally applied after prior dilution to the desired concentration. Oral solutions and concentrates are prepared as described for injectable solutions, but sterile work may be omitted.

Solutions for application to the skin are dripped, coated, sprayed, sprayed or sprayed. These solutions are prepared as described for injectable solutions.

It may be advantageous to add thickening agents during manufacture. Thickening agents include inorganic thickeners, such as bentonites, colloidal silicic acid or aluminum monostearate, or organic thickeners, such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

The gels are applied to or coated on the skin, or introduced into body cavities. These gels are prepared by preparing solutions as described for injectable solutions, and mixed with an amount of thickening agent to produce a clear mass with a consistency-like ointment. The thickeners used are those mentioned above.

The pouring means is poured or sprayed onto the delimited areas of the skin, the active substance penetrating the skin and acting systemically.

The pouring compositions are prepared by dissolving, suspending or emulsifying the active ingredient in a suitable skin-acceptable solvent or solvent mixture. Optionally, additional excipients such as colorants, resorption-promoting substances, antioxidants, light preservatives and adhesion promoters may be added.

Solvents include water, alkanols, glycols, polyethylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethyl alcohol or phenoxyethyl alcohol, esters such as ethyl acetate, butyl acetate and benzoic acid benzoate, ethers such as alkylene ethers such as dipropylene glycol monomethyl ether and diethylene glycol monobutyl ether, ketones such as acetone and methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, dimethylformamide, dimethylacetamide, N-methylpyrrolidone and 2,2-dimethyl-4-methoxy-4-methoxy-4-methoxy-4-methoxy 3-dioxolane.

Colorants are all colorants acceptable for use in animals which can be dissolved or suspended.

Examples of resorption enhancers include dimethylsulfoxide, oils such as isopropyl myristate and dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides and fatty alcohols.

Antioxidants are sulfites or meta-bisulfites such as potassium meta-bisulfite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or tocopherol.

For example, novantisolic acid may be mentioned as a light-protective agent.

Adhesion agents are, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, or gelatin.

The emulsions may be administered orally, dermally or as injections.

The emulsions are either water-in-oil or oil-in-water.

Said emulsions are prepared by dissolving the active ingredient either in the hydrophobic or hydrophilic phase and homogenizing it with suitable emulsifiers and optionally other excipients such as colorants, resorptive agents, preservatives, antioxidants, light-protective agents and a viscosity enhancing agent, with a second phase solvent.

Hydrophobic phases (oils) include paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil and castor oil, synthetic glycerides such as caprylic and capric biglyceride, mixtures of triglycerides with vegetable fatty acids of length and mixtures of partial glycerides saturated or unsaturated, and optionally also hydroxyl groups containing fatty acids or monoglycerides and diglycerides of fatty acids having 8 to 10 carbon atoms.

Also mentioned are fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycolpelargonate, mid-chain branched fatty acid esters of saturated fatty alcohols of 16 to 18 carbon atoms, isopropyl myristate, caprylic / capric with saturated fatty alcohols with a chain length of 12 to 18 carbon atoms, oleic acid oleic acid, oleic acid decyl ester, ethyl oleate, ethyl lactic acid ester, waxy fatty acid esters such as duck fatty gland fat, dibutyl folate, diisopropyl ester, diisopropyl ester, diisopropyl ester mixtures of said esters and the like.

Also mentioned are fatty alcohols such as isotridecyl alcohol, 2-octyldodecyl alcohol, cetyl stearyl alcohol or oleyl alcohol and fatty acids such as oleic acid or mixtures thereof.

The hydrophilic phase includes: water and alcohols such as propylene glycol, glycerol, sorbitol and mixtures thereof.

The following emulsifiers are used: non-ionic surfactants, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate or alkylphenol polyglycol ether;

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

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

cationic surfactants such as cetyltrimethylammonium chloride.

Viscosity-enhancing and emulsion-stabilizing agents such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, acacia, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, poly (maleic anhydride), polyvinyl alcohol, maleic anhydride, waxes, colloidal silicic acid or mixtures thereof.

Suspensions may be administered orally, dermally or as injections. They are prepared by suspending the active ingredient in a carrier liquid, optionally with the addition of additional excipients such as wetting agents, colorants, resorption-promoting agents, preservatives, antioxidants, light preservatives and the like.

All homogeneous solvents and solvent mixtures can be used as carrier liquids.

Wetting agents (dispersing agents) which may be mentioned are the surfactants mentioned above.

Substances already mentioned may be used as further excipients.

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

For the preparation of solid preparations, the active compound is mixed with a suitable carrier, if appropriate with the addition of excipients, and converted into the desired form.

Carriers which may be mentioned are all physiologically acceptable solid inert substances. Inorganic and organic substances serve as such. Inorganic substances are, for example, sodium chloride, carbonates such as calcium carbonate, bicarbonates, alumina, silicic acid, clay soils, precipitated or colloidal silicon dioxide or also phosphates.

Organic substances are, for example, sugar, cellulose, nutrients and feedingstuffs such as milk powder, animal meal and cereal flour or scrap, or starches.

Excipients are preservatives, antioxidants, colorants and the like, which have already been mentioned.

Other excipients are lubricants such as magnesium stearate, stearic acid, talc and bentonite, disintegrating agents such as starches or cross-linked polyvinylpyrrolidone, binders such as starch, gelatin or linear polyvinylpyrrolidone, as well as dry binders such as microcrystalline cellulose.

The active compounds may also be present in the formulations in admixture with synergists or other active substances acting against pathogenic endoparasites. Such active ingredients are, for example, L-2,3,5,6-tetrahydro-6-phenylimidazothiazole, benzimidazole carbamate or pyrantel.

Formulations suitable for application contain the active compound in concentrations of 10 ppm to 20% by weight, preferably 0.1 to 10% by weight.

The preparations which are diluted before use contain the active compound in a concentration of 0.5 to 90% by weight, preferably 5 to 50% by weight.

In general, it has been found advantageous to use about 10 to 100 mg of active ingredient per kilogram of body weight per day, preferably 10 to 50 mg of active ingredient mixture, to achieve effective results.

The compositions generally comprise piperazine and depsipeptide in a weight ratio of 50: 1 to 1000: 1, preferably 100: 1 to 1000: 1, very particularly preferably 250: 1 to 1000: 1 and particularly 250: 1 to 1000: 1.

In the biological examples, "depsipeptide 1" is a compound of the formula

The bioassays are carried out according to known methods (Plánt et al., Pesticide Science,

1996, 48, p. 351 et seq.).

DETAILED DESCRIPTION OF THE INVENTION

Biological examples

Table 1 - Synergistic effect of piperazine and depsipeptide I against Trichinella spiralis in vitro

concentration (pg / ml) effect piperazine 1000 500 0-1 0 Depsipeptide I 0.01 0,001 0-1 0 Piperazine / Depsipeptide I 1000 / 0,01 1-2 Piperazine / Depsipeptide I 500 / 0.01 1-2

= no effect; 1 = weak effect; 2 = good effect

Table 2 - Synergistic effect of piperazine and depsipeptide I against nematode mice

Heterakis spumoza dose (mg / kg) effect Nematospi-roides dibius doses (mg / kg) effect piperazine 4x250 4 x 100 1 0 piperazine 2 x 2000 4 x 1000 2 1 Depsipeptide I 4x1 4x0.5 1 1 PF 1022-221 4x1 4x0.5 2 0-2 Piperazine / Depsipeptide I 4 x 250 / 4x1 3 piperazine / PF 1022-221 2 x 2000 / 4 x 1 2-3 Piperazine / Depsipeptide I 4 x 100 / 4x1 2 Piperazine / PF 1022-221 4 x 1000 / 4x1 2-3

= worm reduction <50N%; 1 = worm reduction 50-75%; 2 = worm reduction of 75 to 90%; 3 = full effect, worm reduction> 90%.

Production examples

Examples for the preparation of cyclic depsipeptides with 24 ring atoms.

Production of compounds of formula (I)

To a solution of the compound of formula (II) (0.104 mmol) and Hunnig base (0.258 mmol) in dichloromethane (100 mL) at 0 ° C was added BOP-Cl (0.124 mmol) and stirred for 24 hours at room temperature. Then an equal amount of ΒΟΡ-Cl and base were added and stirred for an additional 24 hours. The solution obtained is washed twice with saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated. The residue obtained is purified by column chromatography using a cyclohexane / ethyl acetate mixture as the mobile phase.

Compounds of formula (I) are obtained in which the substituents have the meanings given in Table 3 below.

Table 3

Pr. R ^1a R ^ľa R ^3S R ^{, a} R ' R ^ea R ^{/ a} -reč- R " ^- R ^1ua  'Ŕ ™ _R ua FAB-MS m / z (%). et et Me s-Bu Bn S-Bu Me s-Bu Bn s-Bu et et 2 propyl propyl - ' - « propyl propyl 3 i-propyl i-propyl - - - i-propyl i-propyl 4 Me Me » s-Bu · · s-Bu » s-Bu - s-Bu Me M e 948 (82, (+H) +) 5 Me Me iPr iPr iPr iPr Me Me 915 (100, (M + Na) &lt; + &gt;) 893 (55, (M + H) +) 6 Me Me Bn Bn Bn Bn Me Me 1107 (100, (M + Na) +) 1085 (8, (M + H) +) 7 Me Me - s-Bu 2-Cl-Bn s-Bu » s-Bu 2-Cl-Bn s-Bu Me Me 8 Me ME - 2-Cl-Bn - 3-Cl-Bn Me Me 9 Me Me 4-Cl-Bn 4-Cl-Bn Me Me 10 propyl i-propyl Bn · - Bn propyl i-propyl

Me = Methyl Et = Ethyl

Bu = Butyl Bn = Benzyl Pr = Propyl

Examples of preparation of compounds of formula (III)

A solution of the open-chain octadepsipeptide of formula (III) (1.222 mmol) in ethyl alcohol (50 mL) is hydrogenated in the presence of Pd (OH) ₂ / C (20%; 200 mg) until complete uptake of hydrogen (about 2 hours). After filtering off the catalyst, a pure compound of formula (II) is obtained which can be reacted further without further purification.

According to this protocol, compounds of formula (II) are obtained in which the substituents have the meanings given in Table 4 below.

Table 4

Pr. R ' Ŕ ³ ' R ' "R" ^- R ^{55- -} R ^ R · R " ^- À " R ™ _R n. R ' ^3- 11 et et Me s-Bu Bn s-Bu Me s-Bu Bn s-Bu et et 12 propyl propyl • • • propyl propyl 13 i-propyl i-propyl • • • i-propyl i-propyl 14 Me Me - - • - Me Me 15 Me Me iPr iPr iPr - iPr Me Me 16 Me Me Bn Bn Bn Bu Me Me 17 Me Me s-Bu 2-Cl-Bn s-Bu s-Bu 2-Cl-Bn s-Bu Me Me 18 Me Me - 3-Cl-Bn - 3-Cl-Bn Me Me 19 Me Me 4-Cl-Bn 4-Cl-Bn • Me Me 20 propyl i-propyl » Bn - • Bn propyl i-propyl

Me = Methyl s-Bu = s-Butyl Et = Ethyl Bn = Benzyl

Production of compounds of formula (III)

To a solution of tert-butyl ester of formula (IV) (1.609 mmol) in dichloromethane (40 mL) at 0 ° C was bubbled hydrogen chloride gas over 1.5 hours. Then the mixture was warmed to room temperature and stirred for 12 hours. The solution was then rotary evaporated and dried under high vacuum. The residue obtained can be further reacted without further purification.

Analogously, compounds of formula (III) in which the substituents have the meanings given in Table 5 are obtained.

Table 5

Pr. R ^la R ^2a R ^ja R ' R ' R ' R R ⁴ R ' R ^IJa R ¹¹¹ -rW- A 21 et et Me s-Bu Bn s-Bu Me s-B u Bn s-Bu et et Bn 22 propyl propyl - propyl propyl 23 i-propyl i-propyl · i-propyl i-propyl 24 Me Me Me Me .. 25 Me Me · · iPr · iPr iPr iPr Me Me n 26 M4 Me Bn Bn Bn Bn Me Me at 27 Me Me s-Bu 2-Cl-Bn s-Bu s-Bu 2-Cl-Bn s-Bu Me Me 28 Me Me 2-Cl-Bn - 3-Cl-Bn Me Me 29 Me Me - 4-Cl-Bn 4-Cl-Bn Me Me 30 propyl i-propyl · Bn Bn - propyl i-propyl

Me = Methyl

Et = Ethyl s-Bu = s-Butyl

Bn = Benzyl

Production of compounds of formula (IV)

To a solution of the tetradepsipeptides of formula (VI) and (V) (2.52 mmol each) in dichloromethane (15 mL) at 0 ° C was added a solution of ethyldiisopropylamine (0.912 mmol) and BOP-C1 (0.438 mmol). The reaction mixture is stirred for 1 hour at 0 ° C and for 1.5 hours at room temperature, diluted with 20 ml of dichloromethane, washed twice with a little water, dried over anhydrous sodium sulfate and concentrated. The residue obtained is purified on silica gel using cyclohexane / t-BuOMe 2: 1 as the mobile phase.

Production of compounds of formula (V)

To a solution of the tetradepsipeptide of formula (VII) (2.848 mmol) in dichloromethane (50 mL) at 0 ° C was bubbled hydrogen chloride gas over 2 hours. The reaction mixture was stirred at room temperature for 8 hours, concentrated and dried under high vacuum. The residue obtained can be used without further purification.

Production of compounds of formula (VI)

A solution of the tetradepsipeptide of formula (VII) (9.53 mmol) in ethyl alcohol (37 mL) was treated with Pd (OH) ₂ / C (20%) (0.6 g) and hydrogenated for about 3 hours at room temperature and at room temperature. normal pressure. The reaction mixture is then filtered, concentrated and the residue is separated on silica gel using t-BuOMe, cyclohexane and ethyl alcohol 1: 1: 0.5.

Production of compounds of formula (VII)

A solution of didepsipeptide of formula (IV) (22.9 mmol) and didepsipeptide of formula (VIIIa) (27.5 mmol) in dichloromethane (80 mL), cooled to 0 ° C, was mixed with diisopropylethylamine (57.3 mmol) and BOP -C1 (29.8 mmol) and stirred for 1 hour at 0 ° C and for 1 hour at room temperature. After the precipitate was filtered off, the solution was diluted with dichloromethane, washed three times with a little water, dried over anhydrous sodium sulfate and concentrated. The residue is separated on silica gel using cyclohexane / ethyl acetate 15: 1.

Claims (11)

PATENT CLAIMS Endoparasiticidal compositions comprising piperazines together with cyclic depsipeptides consisting of amino acids and hydroxycarboxylic acids as ring building elements and with 24 ring atoms. Use of piperazines together with cyclic depsipeptides consisting of amino acids and hydroxycarboxylic acids as ring building elements and with 24 ring atoms for the production of endoparasiticidal agents. Use of piperazines according to claim 2, characterized in that the cyclic depsipeptides correspond to the formula (I) R ^with R 'O in which R ¹ , R ² , R ¹¹ and R ¹² are each independently C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 6 cycloalkyl, arylalkyl or aryl which are: optionally substituted with halogen, C 1 -C 4 alkyl, hydroxy or C 1 -C 4 alkoxy, R ³ , R ⁵ , R ⁷ and R ⁹ independently represent a hydrogen atom or a straight or branched alkyl group having 1 to 8 carbon atoms, which may optionally be substituted by hydroxy, alkoxy having 1 to 4 carbon atoms, carboxy, carboxamide , imidazolyl, indolyl, guanidino, mercapto or (C 1 -C 4) alkylthio and further aryl or arylalkyl which may be substituted by halogen, hydroxy, (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy and R ^4, R ^6, R ^p and R ¹⁰ are independently hydrogen, straight alkyl of 1 to 5 carbon atoms, alkenyl having 2 to 6 carbon atoms and cycloalkyl having 3 to 7 carbon atoms, which optionally can be substituted by hydroxy, C1-C4alkoxy, carboxy, carboxamide, imidazolyl, indolyl, guanidino, mercapto or alkylthio and further optionally aryl or aralkyl which may be substituted by halo, hydroxy-1, alkyl, carbon atoms or (C 1 -C 4) alkoxy; or R ³ , and / or R ⁷ represents a 4-morpholinobenzyl group as well as their optical isomer and racemate. Use according to claim 3, characterized in that the cyclic depsipeptides correspond to the formula (1) in which: R ^{@ 1} , R ^{@ 2} , R @ ¹¹ and R @ ¹² are each independently methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl or phenyl optionally substituted by halogen, C1-alkyl; up to 4 carbon atoms, hydroxy or alkoxy having 1 to 4 carbon atoms, or benzyl or phenylethyl, which may optionally be substituted by the radicals mentioned for the phenyl group; and R ³ to R ¹⁰ are as defined in claim 3. Use according to claim 3, characterized in that the cyclic depsipeptides correspond to the formula (I) in which R ^{@ 1} , R ^{@ 2} , R @ ¹¹ and R @ ¹² are each independently methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl or t-butyl, R ³ , R ⁵ , R ⁷ and R ⁹ represent a hydrogen atom, a straight or branched alkyl group having 1 to 8 carbon atoms, in particular a methyl, ethyl, propyl, i-propyl, n-butyl, s-butyl and t-butyl group which may optionally be substituted by C 1 -C 4 alkoxy, in particular methoxy or ethoxy, imidazolyl, indolyl or C 1 -C 4 alkylthio, especially methylthio and ethylthio, and furthermore phenyl, benzyl or phenylethyl, which may optionally be substituted with a halogen atom, especially chlorine and R ⁴ , R ⁶ , R ⁸ and R ¹⁰ are each independently hydrogen, methyl, ethyl, n-propyl, n-butyl, vinyl and cyclohexyl, which may optionally be substituted by methoxy, ethoxy, imidazolyl, indolyl, methylthio or ethylthio as well as isopropyl and s-butyl and further optionally halogen-substituted phenyl, benzyl or phenylethyl. Use according to claims 2 to 5, characterized in that the piperazines correspond to the formula (X) R ' ⁴ (X) wherein R ¹³ and R ¹⁴ are independently the same or different substituents from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, aryl and heteroaryl, as well as -CONR ¹⁵ R ¹⁶ or -CSNR ¹⁵ R ¹⁶ , wherein: R ¹⁵ and R ¹⁶ are independently the same or different substituents from the group consisting of a hydrogen atom or an optionally substituted alkyl or cycloalkyl group. Use according to claims 2 to 5, characterized in that the piperazines correspond to the formula (X) in which R ¹³ and R ¹⁴ are independently the same or different substituents from the group consisting of hydrogen, in each case optionally substituted alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 8 carbon atoms, as well as -CONR ¹⁵ R ¹⁶ or - CSNR ^I5 R ¹⁶ , where R ( ¹⁵⁾ and R ( ¹⁶⁾ independently of one another are the same or different substituents from the group consisting of hydrogen or in each case optionally substituted alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms. Use according to claims 2 to 5, characterized in that the piperazines correspond to the formula (X) in which R ¹³ and R ¹⁴ are independently the same or different substituents from the group consisting of hydrogen, in each case optionally substituted alkyl of 1 to 4 carbon atoms and cycloalkyl of 6 carbon atoms, as well as -CONR ¹⁵ R ¹⁶ or -CSNR ¹⁵ R ¹⁶ , where R ( ¹⁵⁾ and R ( ¹⁶⁾ independently of one another are the same or different substituents from the group consisting of hydrogen or in each case optionally substituted alkyl of 1 to 4 carbon atoms or cycloalkyl of 6 carbon atoms. Use according to claim 3, characterized in that the cyclic depsipeptides correspond to the formula Composition according to claim 1, characterized in that the cyclic depsipeptides correspond to any of the definitions set forth in claims 3 to 5 and 9 to 11 and / or piperazines correspond to any of the definitions set forth in claims 6 to 8. End of document in which Z is N-morpholinyl, nitro, amino, methylamino or dimethylamino, particularly preferably morpholinyl. Use according to claim 3, characterized in that the cyclic depsipeptides correspond to the formula Use according to claim 3, characterized in that the cyclic depsipeptides correspond to the formula