KR20010043957A - Substituted Cyclooctadepsipeptides - Google Patents

Abstract

The present invention relates to a novel, substituted cyclooctadepsipeptide represented by formula (I), a method for preparing the same, its use for controlling internal parasites, and a composition comprising these active compounds.

Wherein R ¹ , R ² , m, n are as defined in the specification.

Description

Substituted Cyclooctadepsipeptides

Various cyclodeptipeptides with parasite control have been disclosed in the literature. EP 382 173 A2 discloses a cyclooctadepsipeptide named PF1022. In addition, 24-membered cyclodeptipeptides are known from EP 626 376 A1, EP 634 408 A1, EP 718 293 A1 and the like. Their antiparasitic action is not always satisfactory. WO 96/11 945 discloses a process for the preparation of sulfonylating depsipeptides. However, the method does not disclose any uniform compound.

The present invention relates to novel substituted cyclooctadepsipeptides, methods for their preparation and their use to control parasites, in particular helminth, in the field of veterinary and human medicine, and intermediates for their preparation.

1. A novel cyclooctadepsipeptide represented by formula (I) has been found;

R ¹ in the ortho and / or para position represents a sulfonyl radical represented by the formula:

-SO ₂ -A,

R ² in the ortho and / or para position represents a sulfonyl radical represented by the formula:

-SO ₂ -A,

Where A represents the following radical:

Amino, mono- or dialkylamino having 1 to 4 carbon atoms in the alkyl moiety, bis (hydroxyalkyl) amino having 1 to 4 carbon atoms in the alkyl moiety, mono having 1 to 4 carbon atoms in the alkyl moiety Or bis (alkoxyalkyl) amino, or mono- or di-C _1-4 -alkylamino substituted by phenyl, furyl, morpholinyl or pyridyl;

Or a saturated 5- or 6-membered heterocycle which, in addition to N, may contain one or two heteroatoms selected from the group consisting of oxygen or nitrogen atoms, is substituted or unsubstituted and attached via nitrogen ;

Or pyrazole, imidazole, pyrrole, 1,2,4-triazole, 1,2,3-triazole, attached via nitrogen, substituted or unsubstituted, unsaturated heterocycle ;

n represents 0, 1 or 2,

m represents 1 or 2.

Here, optionally with substituents for the substituted radicals C _1-4 - may be mentioned acyl such as alkoxycarbonyl-alkyl, C _1-4 - alkylcarbonyl, benzoyl, C _1-4.

2. Also, a method for preparing a compound represented by formula (I) has been found.

Wherein R ¹ , R ² and m and n are as defined above,

The preparation method is a reaction of PF 1022 compound represented by the following formula with halogenosulphonic acid or sulfuryl chloride or sulfur dioxide / chlorine

The reaction product, the halogenosulfonylated compound is characterized in that the additional reaction with the compound of the formula

H-A,

here,

A is as defined above.

The compound represented by the formula (I) according to the present invention is very suitable for controlling enteroparasites in the field of veterinary medicine and human medicine.

R ¹ represents -SO ₂ -A,

n and m represent 1,

R ² represents hydrogen or -SO ₂ -A,

Preference is given to compounds represented by the formula (I) in which the radicals R ¹ and / or R ² are present in the para position.

A is preferably amino, mono- or dimethyl-, diethyl-, diisopropylamino, unsubstituted or substituted by methyl, ethyl, acetyl, such as acetyl, benzoyl, ethoxycarbonyl or methoxycarbonyl , N-mono- or N, N-bis (ethoxymethyl) amino,-(hydroxyethyl) amino,-(ethoxyethyl) amino,-(methoxyethyl) amino, mono- or dibenzylamino, mono Or bis (phenylethyl) amino, mono- or bis (pyridylmethyl) amino, mono- or bis (pyridylethyl) amino, mono- or bis (morpholinylethyl) amino, perarylamino, N-perferyl -N-methylamino, morpholino-, 1-piperazinyl-, 1-pyrazolyl-, 1-pyrrolidinyl, 1-piperidinyl and the like.

In addition, R ¹ and R ² represent an —SO ₂ A radical in the para position, wherein A is ₁ -monosubstituted or unsubstituted by C _1-4 -alkylcarbonyl or C _1-4 -alkoxycarbonyl Piperazinyl, and the alkyl moiety represents amino, mono-C _1-2 -alkylamino unsubstituted or substituted by morpholino, peryl or pyridyl, di-C _1-4 -alkylamino, and also Preference is given to compounds represented by the formula (I) which represent 1-pyrrolidinyl or 1-piperidinyl.

The novel substituted cyclic depsipeptides represented by the formula (I) and acid addition salts and metal salt complexes thereof have very good enteroparasitic control and may be preferably used in veterinary medicine. Surprisingly, in the control of parasitic diseases, they show superior activity compared to conventional compounds having similar structure and action.

For the preparation thereof, the following known compound PF 1022 is

Suitably in a diluent that is inert to the reagent and suitably in the presence of Lewis acid, in particular with a halogenosulphonic acid (HalSO ₃ H), such as chlorosulphonic acid, or sulfuryl chloride or sulfur dioxide / chlorine.

The reaction is carried out at a temperature of 0 to 150 ° C, preferably 0 to 80 ° C, more preferably 0 to 60 ° C.

Suitable diluents are all organic solvents which are inert to the reagents. These include, in particular, aliphatic, such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene And aromatic, halogenated or nonhalogenated hydrocarbons, also ethers such as diethyl ether and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, also acetone, methyl ether ketone, methyl isopropyl ketone and Ketones such as methyl isobutyl ketone, moreover esters such as methyl acetate and ethyl acetate, also nitriles such as acetonitrile and propionitrile, benzonitrile, glutaronitrile, and also dimethylformamide, dimethylacetamide and N-methylpyrroli Don and dimethyl sulfoxide, tetramethylene sulfide And it can be given, such as hexamethylphosphoric amide triamide.

The depsipeptide reacts with excess reagent (5-10 equivalents) and excess Lewis acid (15-20 equivalents).

Halogenosulfones, in particular chlorosulfones, obtainable at this stage are compounds represented by the formula (I) in which the radicals R ¹ and R ² represent the radicals —SO ₂ —halogen, in particular —SO ₂ —Cl.

These compounds are then reacted with an amine represented by the formula below, suitably in the presence of a diluent and suitably in the presence of a base.

A-H

Suitable diluents for the reaction of halogenogensulfone are the diluents mentioned above. The base used is an excess of the amine or alkali metal hydroxide represented by the formula A-H, and alkali metal or alkaline earth metal carbonates or tertiary, aliphatic or aromatic amines are used.

The second stage of the reaction is carried out after the product of the first stage has been separated off and purified or immediately after the first stage. The second step is carried out at a temperature of -10 to + 150 ° C, preferably -5 to + 20 ° C. The second step is carried out at atmospheric pressure.

It is also possible to react compound PF 1022 with sulfuric acid (oleum) to afford the corresponding —SO ₂ OH-substituted compounds. This compound can then be converted to the corresponding halogenosulphone using a halogenation reagent. The halogenosulphone is then reacted with an amine to produce the corresponding sulfonamide, as mentioned above.

After the reaction is carried out, the diluent is distilled off and the compound represented by compound (I) is purified by a conventional method, for example, by chromatography.

The active compounds are suitable for controlling pathogenic internal parasites in humans and in animal and livestock breeding, dairy cattle, breeding livestock, zoo animals, laboratory animals, animals and pets used in experiments, and also warm blood Low toxicity to animals. The active compound is active against all or some stages of growth of species and pests that are resistant and of moderate sensitivity. These active compounds are more economical and easier to use because they can reduce disease, mortality and performance (eg, in meat, milk, wool, leather, eggs, honey, etc.) by controlling pathogenic internal parasites. You can raise animals. Pathogenic internal parasites include Cestodes, Trematodes, Nematodes, and Acantocephalides, among others:

From Pseudophyllidea, for example:

Diphyllobothrium species, Spirometra species, Schistocephalus species, Ligula species, Bothridium species, Diphlogonoporus species Can be.

From the group Cyclophyllidea, for example:

Mesocestoides species, Anoplocephala species, Paranoplocephala species, Moniezia species, Thysanosomsa species, Thysaniezia species ), Avitellina, Stilesia, Cittotaenia, Andyra, Bertiella, Taenia, Echinococcus species, Hydratigera species, Davainea species, Rileylietina species, Hymenolepis species, Echinolepis species, Echinolepis species Echinocotyle species, Diorchis species, Dipylidium species, Joyyeuxiella species, Diplopylidium species.

From the Monogenea subclass, for example:

Gyrodactylus species, Dactylogyrus species, Polystoma species.

From Digenea subclasses, for example: Diplostomum species, Posthodiplostomum species, Schistosoma species, Trichobilharzia species, Ornitobilha Ornithobilharzia species, Austrobilharzia species, Gigantobilharzia species, Leucochloridium species, Brachylaima species, Echinostoma species, Echinostoma species Echinoparyphium species, Echinochasmus species, Hypoderaeum species, Fascioola species, Fasciolides species, Fasciolopsis species, and cyclocoelum (Cyclocoelum) species, Typhloccelum species, Paramphistomum species, Calicophoron species-Cotylophoron species, Gigantocotyle species, Pychoederius species Fischoederius species, Gastrothylacus species, furnace Notocotylus species, Catatropis species, Plagiorchis species, Prosthogonimus species, Dicrocoelium species, Eurytrema species , Troglotrema species, Paragonismus species, Collyriclum species, Nanophyetus species, Officepisthorchis species, Clonorchis species , Metorchis species, Heterophyes species, and Metagonimus species.

From the tree Enoplida, for example: Trichoris species, Capillaria species, Tricholomosoides species, Trichinella species.

From the tree of Rhabditia, for example: Micronema species, Stronxyoides species.

From the Strongylida neck, for example:

Stronylus species, Triodontophorus species, Oesophagodontus species, Trichonema species, Gyalocephalus species, Cylindropharynx species, Poteriostromum species, Cyclococercus species, Cylicostephanus species, Oesophagostonum species, Chabertia species, Stephanurus Species, Ancylostoma species, Uncinaria species, Bunostomum species, Globocephalus species, Syngamus species, Cyathostoma species, meta Metastrongylus species, Dictyocaulus species, Muellerius species, Protostrongylus species, Neostrongylus species, Cystocaulus species Species, Pneumostrils (Pneumostrongylus species, Spicocaulus species, Ellaphostrongylus species, Parelaphostrongylus species, Crenosoma species, Paracrenosoma species, Angiostrongylus species, Aelurostrongylus species, Filaroides species, Parafilaroides species, Trichostrongylus species, Haemonchus species , Ostertagia species, Marshallagia species, Couperia species, Nematotorus species, Hyostrongylus species, Obeliscoides species, Amidostomum species and Olulanus species are mentioned.

From the Oxyurida tree, for example: Oxyuris species, Enterobius species, Pasalurus species, Syphacia species, Aspiculuris ) And Heterakis species.

From the order of Ascariadia, for example: Ascaris species, Toxascaris species, Toxocara species, Parascaris species, Anisakis species, Ascariadia (Ascaridia) species.

From the Spirurida neck, for example: Gnathostoma species, Physaloptera species, Thelazia species, Gongylonema species, Habronema ), Parabronema species, Draschia species, and Dracunculus species.

From the Filariida neck, for example:

Stephanofilaria species, Parafilaria species, Setaria species, Loa species, Dirofilaria species, Litomosoides species, Brugia Species, Wuchereria species, and Onchocerca species.

From the Gigantorhynchida group, the species Filicollis, Moniliformis, Macracanthorhynchus and Prosthenorchis have.

Dairy and breeding livestock include, for example, cattle such as cattle, horses, sheep, pigs, goats, camels, buffaloes, donkeys, rabbits, fallow deer, reindeer, for example fur such as mink, chinchillas, raccoons- Carrying animals include, for example, birds such as chickens, geese, turkeys or ducks, freshwater fish such as mullet, carp, eel and sea fish, reptiles and insects such as bees and silkworms, for example.

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

Pets include dogs and cats.

Administration can be effected prophylactically and administrationally.

By treating the habitat or with the aid of shaped objects containing active compounds, such as strips, plates, tapes, collars, ear tags, limb bands or markers, The active substances are administered directly or in the form of suitable formulations, enterally, parenterally, percutaneously, nasally.

Enteric administration of the active compounds can be, for example, orally in the form of powders, tablets, capsules, drinks, granules, solutions, suspensions and emulsions, pills, medicated feeds or beverages, which can be applied orally. Administered. Transdermal administration is carried out, for example, in the form of dipping, spraying or pouring-on and spotting-on. Parenteral administration is carried out, for example, in the form of injections (intramuscular, subcutaneous, intravenous or intraperitoneal) or by implantation.

Suitable formulations include the following:

Injection solutions, oral solutions, concentrates for oral administration after dilution, solutions for use in skin or body cavities, pour-on preparations, gels;

Emulsions and suspensions for oral or transdermal administration and injection; Semi-solid formulations;

Preparations in which the active compound is incorporated into a cream base or a water-in-oil or oil-in-water emulsion base;

Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, pills, capsules; Aerosols and inhalants, objects in the form of active compounds.

Injection solutions are administered intravenously, intramuscularly and subcutaneously.

Injection solutions are prepared by dissolving the active compound in a suitable solvent, and preferably, additives such as solubilizers, acids, bases, buffer bases, antioxidants or preservatives can be added. The solution is sterile-filtered and transferred into the vessel.

Suitable solvents include the following: Alcohols such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol and N-methylpyrrolidone and mixtures thereof, physiologically acceptable solvents such as water.

Suitably, the active compound may be dissolved in a physiologically acceptable vegetable or synthetic oil suitable for injection.

Suitable solubilizers include: solvents which promote dissolution of the active compound in the main solvent or prevent precipitation of the active compound. For example, polyvinylpyrrolidone, polyethoxylated castor oil and polyethoxylated sorbitan esters.

The following are preservatives: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic ester or n-butanol.

Oral solutions are administered directly. The concentrate is first concentrated into the dosing concentrate and then orally administered. Oral solutions and concentrates are prepared as mentioned above for injection solutions and no bacterial process is required.

The solution used on the skin is applied drop by drop, gently, rubbed, splashed or sprayed. These solutions are prepared as mentioned above for injection solutions.

It may be advantageous to add thickeners to the manufacturing process. Thickeners include: inorganic thickeners such as bentonite, colloidal silica, aluminum monostearate or cellulose derivatives, organic vinyl thickeners such as polyvinyl alcohol and their copolymers, acrylates and methacrylates.

The gel is applied to the skin or gently or introduced into the body cavity. Gels are prepared by adding this amount of thickening agent to a solution prepared as an injection solution, thereby forming a clean composition having an persistence, such as an ointment. The thickener used is the thickener mentioned above.

Pour-on and spot-on formulations are poured or splattered over a limited area of the skin and the active compound penetrates the skin and acts systemically.

Pour-on and spot-on formulations are prepared by dissolving, suspending or emulsifying the active compound in a suitable solvent or mixture of solvents that is resistant to skin. Suitably, other adjuvants such as colorants, bioabsorption promoters, antioxidants, light stabilizers or tackifiers are added.

Suitable solvents include: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol and aromatic alcohols such as benzyl alcohol, phenylethanol or phenoxyethanol, ethyl acetate, butyl acetate or benzyl benzoate Esters such as, alkylene glycol alkyl ethers, ethers such as dipropylene glycol monomethyl ether or diethylene glycol mono-butyl ether, ketones such as acetone or methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF , Dimethyl acetamide, N-methylpyrrolidone, or 2,2-dimethyl-4-oxy-methylene-1,3-dioxolane.

The colorant can be dissolved or suspended and is also possible if the colorant is approved for use in animals.

Examples of bioabsorption accelerators include DMSO and spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides or fatty alcohols.

Antioxidants are metabisulfites or sulfites such as potassium metabisulfite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or tocopherol.

An example of the light stabilizer is novantisolic acid.

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

Emulsions can be administered orally, transdermally or in the form of injections.

The emulsion is either oil-in-water type or water-in-oil type.

The emulsion dissolves the active compound in either a hydrophobic or hydrophilic phase and is suitable emulsifiers, suitably, such as colorants, bioabsorption accelerators, preservatives, antioxidants, light stabilizers and other such as viscosity-enhancing substances. It is prepared by homogenizing this phase with the solvent of another phase, using the adjuvant of.

Suitable hydrophobic phases (oils) include: natural vegetable oils such as paraffin oil, silicone oil, sesame oil, almond oil or castor oil, caprylic / capric acid biglycerides Synthetic triglycerides such as lides, triglyceride mixtures with vegetable fatty acids having a chain length of C _8-12 or other specifically selected natural fatty acids, partial glycerides of saturated or unsaturated fatty acids which may contain hydroxyl groups together Ride mixtures and mono- and diglycerides of C ₈ / C ₁₀ -fatty acids.

Of fatty acid esters such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelaronate, and branched fatty acids of medium chain length with saturated fatty alcohols having a chain length of C _16-18 Esters, isopropyl myristate, isopropyl palmitate, caprylic / capric esters of saturated fatty alcohols with a chain length of C _12-18 , isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleic Waxy fatty acid esters such as ate, ethyl lactate, artificial duck uropygial fat, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the following, and the like.

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

Fatty acids such as oleic acid and mixtures thereof.

Suitable hydrophilic phases include:

Water, and alcohols such as propylene glycol, glycerol, sorbitol and mixtures thereof.

Suitable emulsifiers include the following: polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate or alkylphenol poly Nonionic surfactants such as glycol ethers;

Amphoteric surfactants such as disodium N-lauryl-β-iminodipropionate or lecithin;

Anionic surfactants such as Na lauryl sulfate, fatty alcohol ether sulfate, and monoethanolamine salts of mono / dialkylpolyglycol ether orthophosphoric esters;

Cationic surfactants such as cetyltrimethylammonium chloride.

Other suitable auxiliaries include: carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, poly Substances that increase viscosity and stabilize emulsions, such as vinyl alcohol, methylvinyl ether / maleic anhydride copolymer, polyethylene glycol, waxes, colloidal silica and mixtures of these materials.

Suspensions can be administered orally, transdermally or as injections. Suspensions are prepared by suspending the active compound in a liquid excipient and suitably adding other auxiliaries such as wetting agents, colorants, bioabsorption accelerators, preservatives, antioxidants, light stabilizers and the like.

Suitable liquid excipients include all homogeneous solvents and mixtures thereof.

Suitable wetting agents (dispersants) include the surfactants mentioned above.

Other suitable adjuvants include those mentioned above.

Semi-solid formulations may be administered orally or transdermally. They differ only in that they have a higher viscosity compared to the suspensions and emulsions mentioned above.

The solid formulation is prepared by mixing the active compound with a suitable excipient, suitably by adding an adjuvant and preferably formulating the mixture.

Suitable excipients include all physiologically acceptable inert solids. Suitable for this purpose are inorganic and organic materials. Inorganic materials include, for example, salts, calcium carbonates, carbonates such as hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicas, and phosphates.

Organic materials include, for example, food and animal feedstocks such as sugars, cellulose, powdered milk, animal meals, cereal meals, coarse cereal meals and starch.

Auxiliaries include the preservatives, antioxidants and coloring agents already mentioned above.

Other suitable auxiliaries include, for example, lubricants such as magnesium stearate, stearic acid, talc, bentonite and disintegrants such as glidant, starch or crosslinked polyvinylpyrrolidone, for example starch. , Binders such as gelatin or linear polyvinylpyrrolidone, and dry providers such as microcrystalline cellulose.

In preparation, the active compound may be present in a mixture with other active compounds or synergists that are active against pathogenic internal parasites. Examples of such active compounds are L-2,3,5,6-tetrahydro-6-phenyl-imidazolethiazole, benzimidazole carbamate, praziquantel, pyrantel or febantel ).

Immediate-use preparations contain the active compound at a concentration of 10 ppm to 20% by weight, preferably 0.1 to 10% by weight.

Formulations diluted prior to use contain the active compound in a concentration of 0.5 to 90% by weight, preferably 5 to 50% by weight.

In general, it is known that it is effective to administer active compounds in an amount of 1 to 100 kg per kg of body per day.

Preparation Example

Example a

Chlorosulfonation of PF 1022

At 0 ° C., a solution (0.523 mmol) of PF 1022 depsipeptide of structural formula

Mix with chlorosulphonic acid (373.3 mmol) and stir the mixture at 0 ° C. for 2 hours and at room temperature for 2 hours. The reaction mixture is further reacted directly without further work-up.

Example b

General process for preparing sulfonamides.

At 0 ° C., the reaction mixture from Example 1 is added dropwise to acetone (50 ml). Next, at 0 ° C., the mixture was mixed with a suitable amine (79.4 mmol) and stirred at 60 ° C. for 12 h. After this time, the mixture is concentrated, taken up in water and extracted with dichloromethane (3 x). The combined organic extracts are dried over Na ₂ SO ₄ and concentrated. The residue is purified by column chromatography. By doing so, a depsipeptide is obtained in which the substituents R ¹ and R ² in the para position are represented by the formula (I) in which the meanings mentioned below the table are obtained.

Table 1

Example A

Insecticidal activity on sheep

An amount of Merino or Blackhead, weighing 23-35 kg, was experimentally infected with 5000 Haemonchus contortus L3 larvae, and the parasite prepatency period had elapsed. Afterwards (3-4 weeks) it was treated with test substance. Test substances were administered orally using gelatin capsules. In the case of Trichostrongylus colubriformis, infection was performed using 12,000 L3 larvae. Insecticidal activity was measured by reduction of eggs with excreta. For this purpose, the feces obtained for the first time were prepared according to the usual McMaster Method, and the number of eggs per 1 gram of feces was measured. The number of eggs was measured at regular intervals (3-4 days) after and prior to treatment over a period of 6-8 weeks. In the test, the loss of eggs by more than 95% is represented by 3.

In this test, the activities for the following compounds are as follows:

p.o. Oral administration

3 = fully effective (> 95% reduction)

n.d. Measurement

Claims (5)

Substituted cyclooctadepsipeptides represented by Formula (I): here, n represents 0,1 or 2, m represents 1 or 2, R ¹ in the ortho and / or para position represents a sulfonyl radical represented by the formula: -SO ₂ -A, R ² in the ortho and / or para position represents a sulfonyl radical represented by the formula: -SO ₂ -A, Where A represents the following radical: Amino, mono- or dialkylamino having 1 to 4 carbon atoms in the alkyl moiety, bis (hydroxyalkyl) amino having 1 to 4 carbon atoms in the alkyl moiety, mono having 1 to 4 carbon atoms in the alkyl moiety Or bis (alkoxyalkyl) amino, or mono- or di-C _1-4 -alkylamino substituted by phenyl, furyl, morpholinyl or pyridyl; Or a saturated 5- or 6-membered heterocycle which, in addition to N, may contain one or two heteroatoms selected from the group consisting of oxygen or nitrogen atoms, is substituted or unsubstituted and attached via nitrogen ; Or pyrazole, imidazole, pyrrole, 1,2,4-triazole, 1,2,3-triazole, attached via nitrogen, substituted or unsubstituted, unsaturated heterocycle ; Here, optionally with substituents for the substituted radicals C _1-4 - may be mentioned acyl such as alkoxycarbonyl-alkyl, or C _1-4 -alkyl-carbonyl, benzoyl, C _1-4. Compound PF 1022 of Formula: Is reacted with halogenosulphonic acid or sulfuryl chloride or sulfur dioxide / chlorine and the resulting halogenosulfonylated compound is further added as H-A By reacting with a compound of Method for preparing a substituted cyclooctadepsipeptide represented by Formula (I): here, n represents 0,1 or 2, m represents 1 or 2, R ¹ in the ortho and / or para position represents a sulfonyl radical represented by one or two of the formulas -SO ₂ -A, R ² in the ortho and / or para position represents a sulfonyl radical represented by one or two of the formulas -SO ₂ -A, Where A represents the following radical: Amino, mono- or dialkylamino having 1 to 4 carbon atoms in the alkyl moiety, bis (hydroxyalkyl) amino having 1 to 4 carbon atoms in the alkyl moiety, mono having 1 to 4 carbon atoms in the alkyl moiety Or bis (alkoxyalkyl) amino, or mono- or di-C _1-4 -alkylamino substituted by phenyl, furyl, morpholinyl or pyridyl; Or a saturated 5- or 6-membered heterocycle which, in addition to N, may contain one or two heteroatoms selected from the group consisting of oxygen or nitrogen atoms, is substituted or unsubstituted and attached via nitrogen ; Or pyrazole, imidazole, pyrrole, 1,2,4-triazole, 1,2,3-triazole, attached via nitrogen, substituted or unsubstituted, unsaturated heterocycle . Use of a substituted cyclooctadepsipeptide represented by formula (I) according to claim 1 for controlling intestinal parasites in human medicine and veterinary medicine. Use of a substituted cyclooctadepsipeptide represented by formula (I) according to claim 1 for preparing a composition for controlling internal parasites in human medicine and veterinary medicine. For internal parasite control, characterized in that it comprises a certain amount of the substituted cyclooctapsipeptide represented by formula (I) according to claim 1 together with an extender and diluent, and optionally conventional additives. Composition.