MXPA00011972A - Substituted cyclooctadepsipeptides - Google Patents

Abstract

The invention relates to new substituted cyclooctadepsipeptides of formula (I) wherein R1, R2, m and n are as defined in the description, a method for their preparation and their use for fighting endoparasites, as well as drugs containing them as active ingredients.

Description

CIC OOCTADEPSIPEPTIDOS SUBSTITUIDOS Field of the Invention The invention relates to novel cyclooctadepsipeptides, to the process for their preparation and to their use for controlling parasites, in particular helminths, in human and veterinary medicine, and to intermediates for their preparation.

Background of the Invention Several cyclodepsipeptides that have an antiparasitic action are described in the literature. EP 382 173 A2 discloses a cyclooctadepsetide with the name PF1 022. Cyclodepsipeptides of 24 additional members are known from EP 626 376 Al, EP 634 408 Al and EP 718 293 Al. Its antelimitic action is not satisfactory in all cases. WO 96/11 945 describes a process for sulfonylated depsipeptides. However, none of the uniform compounds are described.

Ref. 125353 Description of the Invention 1. New cyclooctadepsipeptides of the formula (I) have been found in which R1 in the ortho position and / or to represent sulfonyl radicals of the formula -SO2-A, R2 in the ortho and / or para position represent sulfonyl radicals of the formula where A represents the following radicals amino, mono-, or dialkylamino having up to 4 carbon atoms per alkyl, bis (hydroxyalkyl) amino moiety having from 1-4 carbon atoms in the alkyl, bis (alkoxyalkyl) amino moiety having from 1 to 4 C atoms per alkoxy or alkyl, mono- or di-C? -4-alkylamino portion which is substituted by phenyl, furyl, morpholinyl or pyridyl; they also represent saturated heterocyclics of 5 or 6 members, adhered by means of nitrogen, which, in addition to N, can contain 1 or 2 additional heteroatoms of the group consisting of O and N and which is optionally substituted; they also represent unsaturated heterocyclics, adhered by nitrogen, of the group consisting of pyrazolo, imidazole, pyrrolo, 1, 2, 4-t riazolo, 1, 2, 3-triazolo, which can optionally be substituted, n represents O, 1 or 2, m represents 1 or 2.

Substituents for the optionally substituted radicals which may be mentioned are C alquilo _ alkyl, acyl, such as C? _4 alkylcarbonyl, benzoyl, C alco alkoxycarbonyl 2. Additionally, a process for preparing compounds of the formula (I) has been found wherein R1, R2 and m and n are as defined above, characterized in that the compound PF 1022 of the formula it is reacted with a halogensulfonic acid or sulfuryl chloride or sulfur dioxide / chloride and the resulting halogensulfonylated compounds are additionally converted by reaction with compounds of the formula HE HAS, in which A is as defined above.

The compounds of the formula (I) according to the invention are highly suitable for controlling helminths in human or veterinary medicine.

Preference is given to the compounds of the formula (I) in which R1 represents -S02-A, n and m represents 1, R represents hydrogen -S02-A, and the radicals R1 and / or R2 are located in the para position.

A preferably represents amino, mono- or dimethyl-, diethyl-, diisopropylamino, 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 (pyridylethyl) amino, mono- or bis (pyridylmethyl) amino, mono- or bis (morpholinylethyl) amino, furfurylamino, N-furfuryl-N-methylamino, morpholino-, 1-piperazinyl-, 1-pyrazolyl-, 1-pyrrolidinyl, 1-piperidinyl, which are optionally substituted by methyl, ethyl, acyl, such as acetyl, benzoyl, ethoxycarbonyl or methoxycarbonyl.

Preference is also given to the compounds of the formula (I), in which R1 and R2 represent the radical -SO-2-A in the para position, where A represents 1-piperazinyl which is optionally monosubstituted by C? -4 alqualkylcarbonyl or C? _4alkoxycarbonyl, further represents amino, monoalkylamino C? _2 whose alkyl portion is optionally substituted by morpholino, furyl, or pyridyl, di-C1-4-alkylamino, further represents 1-pyrrolidinyl or 1-piperidinyl.

The new substituted cyclic depsipeptides of the formula (I) and their acid addition salts and metal salt complexes have very good anthelmintic properties and can preferably be used in the field of veterinary medicine. Surprisingly, in the control of disease worms, they exhibit a better activity than the prior art compounds of a similar constitution and the same direction of action.

For its preparation, initially the known compound PF 1022 of the formula below it is reacted with halogensulfonic acids (HalS03H), in particular chlorosulfonic acid, or with sulfuryl chloride or sulfur dioxide / chloride, if appropriate in a diluent which is inert to the reactants, and is suitable in the presence of Lewis acids.

The reaction is carried out at temperatures from 0 to 150 ° C, preferably from 0 to 80 ° C, particularly preferably from 0 to 60 ° C.

Suitable diluents are all organic solvents that are inert toward the reactants. These include, in particular, optionally halogenated, aliphatic and aromatic hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum, ether, benzine, ligroino, benzene, toluene, methylene, chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene. and o-dichlorobenzene, furthermore ethers such as diethyl ether, and dibutyl ether, dimethyl glycol ether, dimethyl diglycol ether, tetrahydrofuran and dioxane, furthermore ketones, such as acetone, methyl ether ketone, isopropyl methyl ketone and ketone. of isobutyl methyl, further esters, such as methyl acetate and ethyl acetate, in addition nitriles, such as for example, acetonitrile and propionitrile, benzonitrile, glutaronitrile, additionally amides, such as, for example, dimethylformamide, dimethylacetamide and N-methylpyrrolidone , and also dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric triamide.

The depsipeptides are reacted with an excess of reagent of (5 to 10 equivalents) and an excess of Lewis acid (15 to 20 equivalents).

The halogensulfones, in particular chlorosulfones, which are obtained in this step are compounds of the formula (I) in which the radicals R1 and / or R2 represent the radical -S02-halogen, in particular -S02-C1.

These compounds are then reacted with amines of the formula A-H, if appropriate in the presence of a diluent and if appropriate in the presence of the bases.

The diluents suitable for the reaction of the halogensulfones are the additional diluents mentioned above. The base used is either in excess of the amine of formula A-H, or alkali metal hydroxides, alkali metal or alkaline earth metal or tertiary metal carbonates, aliphatic or aromatic amines are used.

The second step of the reaction is carried out either after the product of the first step was isolated and purified, or immediately after the first step. This was carried out at temperatures from -10 to + 150 ° C, preferably between -5 ° C and + 20 ° C. This was carried out at atmospheric pressure.

It is also possible to react the compound PF 1022 with sulfuric acid (fuming) to give the corresponding compound -S02OH-substituted. This compound can then be converted to the corresponding halogensulfone using a halogenating agent. The halogenosilphone is then reacted, as described above, with amines to give the corresponding sulfonamides.

After the reaction was carried out, the diluent was completely distilled and the compounds of the formula (I) were purified in a customary manner, for example chromatographically.

The active compounds are suitable for controlling pathogenic endoparasites found in humans and in animals and in a variety of livestock, in productive livestock, a variety of materials, zoo animals, laboratory animals, animals used in experiments, and pets, and have a low toxicity to warm-blooded animals. These are active against resistant and normally sensitive species and against all or some of the stages of the development of pests. Controlling the pathogenic endoparasites, we try to reduce the disease, mortality and reduced performance (for example in the production of meat, milk, wool, leather, eggs, honey, etc.), so that it is possible to raise more economic and simple animals using the active compounds. Pathogenic endoparasites include, in particular, Cestodes, Trematodes, Nematodes, Acanthocephalides.

From the order of the Pseudophyllidea, for example: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoporus spp., From the order of Cyclophyllidea, for example: Mesocestoldes spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia., Cittotaenia spp., Andyra spp., Bertiella spp. ., Taenia spp., Echinococcus spp., Hydratigera spp., Davainea spp., Raillieetina spp., Hymenolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopilidium spp.

From the Monogenea subclass, for example: Gyrodactylus spp., Dactylogyrus spp., Polystoma spp.

From the subclass of Digenea, for example: Diplostomum spp., Pos thodiplos tomum spp., Schistosomaspp. , Trichobilharzia spp. , Ornithobilharzia spp., Austrobilhar zia spp. , Gigantobilharzia spp., Leucochloridium spp. , Brachylaima spp., Echinostoma spp. , Echinoparyphium spp., Echinochasmus spp. , Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp., Paramphistomum spp., Calicorphoron spp. Cotylophoron spp., Gigant ocotyle spp., Fischoederius spp., Gast rothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonismus spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp. ., Heterophyes spp., Metagonimus spp.

From the order of Enoplida, for example: Trichuris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp.

From the order of the Rhabditia, for example: Micronema spp., St rongyloides spp.

From the order of Strongylida, for example: Stronylus spp., Triodontophorus spp Oesophagodontus spp., Trichonema spp. Gyalocephalus spp., Cylindropharynx spp Posteriostromum spp., Cyclococercus spp Cylicostephanus spp., Oesophagostomum spp Chabertia spp., Stephanurus spp., Ancylostoma spp. , Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Mat astrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp. , Angiostrongylus spp., Aelurost rongylus spp. , Filaroides spp., Parafilaroides spp. , Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., Hyost rongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp.

From the order of Oxyurida, for example: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.

From the order of Ascaridia, for example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.

From the order of Spirurida, for example: Gnathqstoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.

From the order of Filariida, for example: Stephanofilaria spp., Spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp.

From the order of the Gigantorhynchida, for example: Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Pros thenorchis spp.

Productive livestock and breeding animals include mammals, such as, for example, livestock, horses, sheep, pigs, goats, camels, bison, donkeys, rabbits, fallow deers, reindeer, hair animals, such as, for example, mink, chinchilla , raccoon, birds, such as, for example chickens, geese, turkeys, or ducks, freshwater fish and marine fish, such as, for example, trout, carp, eels, reptiles and insects, such as, for example, bees and silkworm.

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

Pets include dogs and cats The administration can be effected prophylactically as well as therapeutically.

The active substances are administered, either directly or in the form of appropriate preparations, enterally, parenterally, dermally, nasally, for treatment of the habitat or with the aid of shaped articles containing the active compound, such as, for example, strips, plates , ribbons, necklaces, ear tags, leg bands, or branded devices.

The enteral administration of the active compounds is effected, for example, orally, in the form of powders, tablets, capsules, pastes, beverages, granules, solutions, suspensions and emulsions which can be applied orally, boluses, medicated foods or drinking water. . The dermal application is effected, for example, in the form of drip, atomized or emptying and distributing. Parenteral administration is effected, for example, in the form of injection (intramuscular, subcutaneous, intravenous or intraperitoneal) or by implants.

Appropriate preparations include: solutions, such as, solutions for injection, oral solutions, concentrates, by oral administration after dilution, solutions for use in body or skin cavities, emptying formulations, gels; emulsions and suspensions for oral or dermal administration and for injection; semi-solid preparations; formulations in which the active compound is incorporated in a cream base or in an oil-in-water or water-in-oil emulsion base; solid preparations, such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules, aerosols and inhalants, shaped articles containing the active compound.

The solutions for injection are administered intravenously, intramuscularly, and subcutaneously.

Solutions for injection were prepared by dissolving the active compound in an appropriate solvent and, if desired, adding additives, such as solubilizers, acids, bases, buffer salts, antioxidants, or preservatives. The solution was sterile filtered and emptied into the containers.

Suitable solvents include: physiologically acceptable solvents, such as water, alcohols, such as ethanol, but.anol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycols and N-met ilpyrrolidone, and mixtures thereof.

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

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

The following are preservatives: benzyl alcohol, riclorobutanol t, esters of p-hydroxybenzoic or n-butanol.

The oral solutions were administered directly. The concentrates are first diluted for concentrated administration and then administered orally. The oral and concentrated solutions were prepared as described above in the case of solutions for injection, the sterile procedure is not necessary.

The solutions for use on the skin were applied drop by drop, softened, massaged, splashed or sprayed. These solutions were prepared as described above in the case of solutions for injection.

It may be advantageous to add thickeners in the preparation process. The following are thickeners: inorganic thickeners, such as bentonites, colloidal silica, aluminum monostearate, or organic thickeners, such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

The gels were applied to the skin or softened in it or introduced into the body cavities. The gels were prepared by adding a quantity of thickener to the solutions which were prepared as described for the solutions for injection in which a clear composition was formed which has a consistency similar to the ointment. The thickeners used are the additional esters indicated above.

The formulations emptied and distributed were emptied into or splashed into limited areas of the skin, the active compound penetrated the skin and acted systematically.

The emptied and distributed formulations are prepared by dissolving, suspending or emulsifying the active compound in appropriate solvents or solvent mixtures that are tolerated by the skin. If appropriate, other auxiliaries are added, such as dyes, biological absorption promoters, antioxidants, photostabilizers or thickeners.

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

Colorants are all dyes that can be dissolved or suspended and approved for use in animals.

Examples of biological absorption promoters are DMSO, extender oils, such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid ethers, triglycerides or fatty alcohols.

The antioxidants are sulphites or metabisulfites, such as potassium metabisulfite, ascorbic acid, butyrohydroxy toluene, butylhydroxyanisole or tocopherol.

Tabuizer photos are, for example, novantisolic acid.

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

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

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

These were prepared by dissolving the active compound either in the hydrophobic or hydrophilic phase and homogenizing this phase with the solvent of the other phase, with the help of appropriate emulsifiers and, if appropriate, other auxiliaries, such as dyes, biological absorption promoters, preservatives, antioxidants, photostabilizers, and substances that increase viscosity.

Suitable hydrophobic phases (oils) include: paraffin oils, silicone oils, natural vegetable oils such as sesame seed oil, almond oil or castor oil, synthetic glycerides, such as caprylic / capric acid bigliceride , a mixture of triglyceride with long-chain vegetable fatty acids CB-i2 or others specially selected from natural fatty acids, partial mixtures of glycerides of saturated or unsaturated fatty acids which may also contain hydroxyl groups, and mono- and diglycerides of the C8 / C fatty acids 0-.

Fatty acid esters, such as ethyl stearate, di-n-butyl iripal adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid having a long chain medium with long chain saturated fatty alcohols C? 6-C18, isopropyl myristate, isopropyl palmitate, caprylic / capric esters of C? 2-C? 8 long chain saturated fatty alcohols, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, lactate of ethyl, esters of waxy fatty acid such as uropigial fat of artificial duck, dibutyl phthalate, diisopropyl adipate, mixtures of ether related to the latter, etc.

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

Fatty acids, such as, for example, oleic acid and their mixtures.

Appropriate hydrophilic phases include: water, alcohols, such as, for example, propylene glycol, glycerol, sorbitol and their mixtures.

Suitable emulsifiers include: nonionic surfactants, for example polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate or polyglycol aliphenol esters; ampholytic surfactants, such as disodium N-lauryl-β-iminodipropyanate or lecithin; anionic surfactants, such as Na lauryl sulfate, fatty alcohol ether sulfates, and the monoethanolamine salt of mono / dialkyl polyglycol ether orthophosphoric ester; cationic surfactants, such as cetyltrimethylammonium chloride.

Other suitable auxiliaries include: substances which increase the viscosity and stabilize the emulsion, such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, methylvinyl ether / anhydride copolymers maleic, polyethylene glycols, waxes, colloidal silica, or mixtures of listed substances.

The suspensions can be administered orally, dermally or as an injection. These are prepared by suspending the active compound in a liquid excipient, if appropriate with the addition of other auxiliaries, such as wetting agents, colorants, biological absorption promoters, preservatives, antioxidant photostabilizers.

Suitable liquid excipients include all homogeneous solvents and solvent mixtures.

Suitable wetting agents (dispersants) include the additional surfactants indicated above.

Other suitable auxiliaries include those additional indicated above.

The semi-solid preparations can be administered orally or dermally. These are only distinguished from the suspensions and emulsion-es described above for their high viscosity.

To prepare solid preparations, the active compound is mixed with suitable excipients, if appropriate with the addition of auxiliaries, and the mixture is formulated as desired.

Suitable excipients include all physiologically acceptable inert solid substances. Appropriate for this purpose are inorganic and organic substances. Inorganic substances are, for example, common salt, carbonates, such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, colloidal silica or precipitate, and phosphates.

The organic substances are, for example, sugars, cellulose, foodstuffs and animal seeds, such as milk powder, animal feed, cereal feed, coarse grain feed and starch.

The auxiliaries are preservatives, antioxidants and additional dyes that have already been mentioned above.

Other suitable auxiliaries are lubricants and glidants, such as, for example, magnesium stearate, stearic acid, talc, bentonites, disintegrants, such as crosslinked starch or polyvinylpyrrolidone, binders, such as, for example, starch, gelatin or linear polyvinylpyrrolidone, and dry binders, such as microcrystalline cellulose.

In the preparations, the active compounds can also be presented in mixtures with synergists or other active compounds that are active against pathogenic endoparasites. Examples of such active compounds are L-2,3,5,6-tetrahydro-6-phenyl-imidazolethiazole, benzimidazole carbamates, praziquantel, pyrantel or febantel.

The ready-to-use preparations contain the active compound in concentrations of 10 ppm to 20% by weight, preferably from 0.1 to 10% by weight.

Preparations that are diluted before use contain the active compound in concentrations of 0.5 to 90% by weight, preferably from 5 to 50% by weight.

In general, it is advantageous to administer amounts of from about 1 to about 100 mg of active compound per kg of body weight per day to obtain effective results.

Preparation Examples Example to Clorosulfonation of PF 1022 At 0 ° C, a solution of the PF 1022 depsipeptide (0.523 mmol) in dichloromethane, mixed with chlorosulfonic acid (37.3 mmol), and the mixture was stirred at 0 ° C for 2 hours and at room temperature for 2 hours. The reaction mixture was also directly reacted without further work.

Example b General procedure for preparing the sulfonamide.

At 0 ° C, the reaction mixture from Example 1 was added dropwise to acetone (50 ml). At 0 ° C, the mixture was then mixed with the appropriate amine (79.4 mmol) and stirred at 60 ° C for 12 hours. After this period of time, the mixture was concentrated, taken up in water and extracted with dichloromethane (3 x). The combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by column chromatography. This gave the depsipeptides of the formula (I) in which the substituents R1 and R2 in the para position have the contents given in the following table.

Table 1 Example A Anthelmintic activity in sheep Merino or mud bivalve, of a body weight of 25-35 kg, were experimentally infected with 5000 larvae of Haemonchus contorus L3 and, after the parasite's preparatory period expired (3-4 weeks), it was treated with the test substances. The test substances were administered orally using gelatin capsules. In the case of Trichostrongylus colubriformis, the infection was carried out using 12,000 L3 larvae. The anthelmintic activity was measured by the reduction of the eggs excreted with the feces. To this end, freshly obtained faeces were prepared according to the usual McMaster method, and the number of eggs per gram of faeces was determined. Egg numbers were determined at regular intervals (3-4 days) before and after treatment for a period of 6-8 weeks. A reduction of eggs of more than 95% in the test was designated as 3.

In this test, for example, the following compounds have the established activity: p. or orally 3 = completely effective (> 95% reduction) n.d. it was not determined.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (5)

Claims

1. Substituted cyclooctadepsipeptides of the formula (I) characterized because n represents 0, 1 or 2, m represents 1 or 2, RJ in the ortho position and / or to represent sulfonyl radicals of the formula -S02-A, R2 in the ortho position and / or to represent sulfonyl radicals of the formula -S02-A, where A represents the following radicals amino, mono-, or dialkylamino having up to 4 carbon atoms per alkyl, bis (hydroxyalkyl) amino moiety having from 1-4 carbon atoms in the alkyl, bis (alkoxyalkyl) amino moiety having from 1 to 4 C atoms per alkoxy or alkyl, mono- or di-C? -4-alkylamino portion which is substituted by phenyl, furyl, morpholinyl or pyridyl; they also represent saturated heterocyclics of 5 or 6 members, adhered by means of nitrogen, which, in addition to N, can contain 1 or 2 additional heteroatoms of the group consisting of O and N and which is optionally substituted; they also represent unsaturated heterocyclics, adhered by nitrogen, of the group consisting of pyrazolo, imidazole, pyrrolo, 1,2,4-t riazolo, 1, 2, 3-triazolo, which can optionally be substituted. Substituents for the optionally substituted radicals which may be mentioned are C? -4 alquiloalkyl, acyl, such as C? _4alkylcarbonyl, benzoyl, C? -4 alcoalkoxycarbonyl.

2. Processes for preparing substituted cyclooctadepsipeptides of the formula (I) in which n Representatives 0.1 or 2, represents 1 or 2, R1 in the ortho and / or para position represents one or two sulfonyl radicals of the formula -S02-A, R2 in the ortho and / or para position represents one or two sulfonyl radicals of the formula -S02-A, where A represents the following radicals: amino, mono-, or dialkylamino having from 1 to 4 carbon atoms per alkyl, bis (hydroxyalkyl) amino portion having from 1-4 carbon atoms in the alkyl, mono- or bis (alkoxyalkyl) amino moiety has from 1 to 4 carbon atoms per moiety of alkoxy or alkyl, mono- or di-C? -4-alkylamino which is substituted by phenyl, furyl, morpholinyl or pyridyl; further represents heterocyclics of saturated 5 or 6 members, adhered by nitrogen, which in addition to N, may contain 1 or 2 additional heteroatoms of the group consisting of O and N and which are optionally substituted; it also represents unsaturated heterocyclics, adhered by nitrogen, of the group consisting of pyrazolo, imidazolo, pyrrolo, 1, 2, 4-triazolo, 1, 2, 3-t riazolo, which can optionally be substituted, characterized in that the compound PF 1022 of the formula it is reacted with a halogensulfonic acid or sulfuryl chloride or sulfur dioxide / chloride and the resulting halogensulfonylated compounds are additionally converted by reaction with compounds of the formula HE HAS, in which, A is as defined above.

3. The use of the cyclooctadepsipeptides of the formula (I) according to claim 1 for controlling helminths in humans and veterinary medicine.

4. The use of the cyclooctadepsipeptides of the formula (I) according to claim 1 for preparing compositions for controlling endoparasites in humans and veterinary medicine.

5. Compositions for controlling endoparasites, characterized in that they comprise an amount of cyclooctadepsipeptides of the formula (I) according to claim 1, in addition to the extenders and diluents and, if applicable, customary additives.