JP2002518520A - Substituted cyclooctadepsipeptides - Google Patents

Abstract

(57) The present invention provides novel substituted cyclooctadepsipeptides of formula (I) wherein R ¹ , R ² , m and n are as defined in the specification, their preparation The invention relates to methods and to the control of endoparasites and their use for medicaments containing them as active ingredients. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to novel substituted cyclooctadepsipeptides, processes for their preparation and their use in livestock and veterinary and human medicine for controlling parasites, especially helminths, and Intermediates for the production of

[0002] Various cyclodepsipeptides with antiparasitic activity have been described in the literature.
EP-A-382 173 discloses a cyclooctadepsipeptide with the name PF1022. In addition, 24-membered cyclodepsipeptides have been disclosed in EP-A-626 376, EP-A-634 408 and EP-A-718.
No. 293. Their anthelmintic action is not always satisfactory in every case. WO 96/11 945 discloses a method for sulfonylating depsipeptides. However, it does not disclose any homogeneous compounds.

[0003] 1. Formula (I)

[0004]

Embedded image

[0005] [In the formula, R ^1, in the ortho and / or para position, represents a sulfonyl group of the formula -SO ₂ -A, R ² is in ortho and / or para position, of the formula -SO ₂ -A Represents a sulfonyl group, wherein A is the following group: amino, mono- or dialkylamino having 1-4 C atoms in the alkyl portion, bis (hydroxyalkyl) amino having 1-4 C atoms in the alkyl portion A mono- or di-C _1-4 -alkylamino substituted by bis (alkoxyalkyl) amino, phenyl, furyl, morpholinyl or pyridyl having 1 to 4 C atoms for the alkoxy or alkyl moiety; Represents a saturated 5- or 6-membered heterocyclic ring attached via the nitrogen,
They may contain, in addition to N, one or two further heteroatoms from the group consisting of O and N, and may be optionally substituted; furthermore, pyrazole, imidazole, pyrrole, Represents an unsaturated heterocycle, attached through a nitrogen, from the group consisting of 1,2,4-triazole, 1,2,3-triazole, which may be optionally substituted; n represents 0, 1 or 2 and m represents 1 or 2], a novel cyclooctadepsipeptide has been found.

The substituents on the optionally substituted groups that may be mentioned are C _1-4-
Alkyl, acyl, for example C _1-4 -alkylcarbonyl, benzoyl, C _1-4 -alkoxycarbonyl.

[0007] 2. Furthermore, the expression

[0008]

Embedded image

Is reacted with halogenosulfonic acid, or sulfuryl chloride or sulfur dioxide / chlorine, and the resulting halogenosulfonylated compound is represented by the formula HA, wherein A is as defined above. Which is further converted by reaction with a compound of formula (I)

[0010]

Embedded image

Wherein R ¹ , R ² and m and n are as defined above, have been found.

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

Preferred compounds are those in which R ¹ represents —SO ₂ —A, n and m represent 1, R ² represents hydrogen or —SO ₂ —A, and the radicals R ¹ and / or R ² A compound of formula (I) located in the para position.

A is preferably 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 (pyridylmethyl) amino, mono or bis (pyridylethyl) Amino, mono- or bis (morpholinylethyl) amino, furfurylamino, N-furfuryl-N-methylamino, morpholino-, 1-piperazinyl-, 1-pyrazolyl-, 1-pyrrolidinyl, and 1-piperidinyl; May be optionally substituted by methyl, ethyl, acyl, such as acetyl, benzoyl, ethoxycarbonyl or methoxycarbonyl.

Also preferred compounds are those wherein R ¹ and R ² represent the group —SO ₂ —A in the para position, wherein A is C _1-4 -alkylcarbonyl or C _1-4 -alkoxycarbonyl Mono-C _1-2 -alkylamino, di-C ₁ , which is optionally monosubstituted 1-piperazinyl, and further wherein the amino, alkyl moiety is optionally substituted by morpholino, furyl or pyridyl. A compound of formula (I) which represents _-4 -alkylamino and also 1-pyrrolidinyl or 1-piperidinyl.

The novel 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 veterinary field. Surprisingly, they show better activity in controlling helminthic diseases than prior art compounds having similar structures and the same range of action.

For their production, first, the following formula

[0018]

Embedded image

The known compound PF1022 is prepared by reacting halogenosulfonic acid (HalSO ₃ H), in particular chlorosulfonic acid, or sulfuryl chloride or sulfur dioxide / chlorine in a diluent which is inert towards the reagent, if appropriate, and If appropriate, the reaction is carried out in the presence of a Lewis acid.

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

[0021] Suitable diluents are all organic solvents which are inert towards the reagents. These are, in particular, aliphatic, cycloaliphatic and aromatic, optionally halogenated hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzene, ligroin, benzene, toluene, methylene chloride, chloride. ethylene,
Chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, also ethers such as diethyl ether and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, and also ketones such as acetone, methyl ether ether ketone Methyl isopropyl ketone and methyl isobutyl ketone, furthermore esters such as methyl acetate and ethyl acetate, and also nitriles such as acetonitrile and propionitrile, benzonitrile, glutaronitrile, and additionally amides such as dimethylformamide, Dimethylacetamide and N-methylpyrrolidone, and also dimethylsulfoxide, tetramethylenesulfone and Including hexamethylphosphoric triamide.

The depsipeptide is prepared by using an excess of reagent (5-10 equivalents) and an excess of Lewis acid (15
~ 20 equivalents).

The halogenosulfone, in particular chlorosulfone, obtained at this stage is a compound of the formula (I) in which the radicals R ¹ and / or R ² represent the radical —SO ₂ -halogen, in particular —SO ₂ —Cl.

The compounds are then reacted with an amine of the formula HA, if appropriate in the presence of a diluent and, if appropriate, in the presence of a base.

Suitable diluents for the reaction of halogenosulfones are the further diluents mentioned above. The base used is either an excess of an amine of the formula AH or an alkali metal hydroxide, alkali metal or alkaline earth metal carbonate or tertiary aliphatic or aromatic amine. Is done.

The second stage of the reaction is carried out either after the product of the first stage has been isolated and purified or directly after the first stage. It is carried out at a temperature between -10 and + 150C, preferably between -5C and + 20C. It is performed at atmospheric pressure.

Further, the compound PF1022 is reacted with sulfuric acid (fuming sulfuric acid) to react with the corresponding —SO ₂
It is also possible to obtain OH-substituted compounds. This compound can then be converted to the corresponding halogenosulfone using a halogenating agent. Then
The halogenosulfone is reacted with an amine as described above to produce the corresponding sulfonamide.

After the reaction has been carried out, the diluent is distilled off and the compound of formula (I) is purified in a customary manner, for example by chromatography.

The active compounds control the pathogenic endoparasites encountered in humans and in animal cultivation and livestock raising in livestock, breeding animals, zoo animals, research animals, laboratory animals and pets. And has low toxicity to warm-blooded animals. They are active against pest resistant and normally susceptible species and against all or some stages of pest development. By controlling pathogenic endoparasites, disease, evil and reduced production (eg, meat, milk,
In the production of hair, hides, eggs, honey, etc.)
The use of active compounds allows for more economical and simple animal breeding. Pathogenic endoparasites include, in particular, tapeworms, flukes, nematodes, hookworms, such as: From the order of the Pseudophyllidea, for example: Diphylloborium species ( Diphyllobothrium spp.), Spirometra species (
Spirometra spp. ), Cystocephalus species (Schistose)
phalus spp. ), Ligula spp., Bothridium spp., Diphlogonoporus sp.
gonoporus spp. ).

From the order of the Cyclophyllidea, for example: Mesocestoides spp., Anoprocephala (Ano)
placephala spp. ), Paranoprocephala species (Paranopl
ocephala spp. ), Moniesia spp.
, Thysanosoma spp., Tisaniesia sp.
Thysaniezia spp. ), Avitellina species (Avitellina)
spp. ), Stilesia species (Stilesia spp.), Sittaeneia species (Cittotaenia spp.), Andira species (Andyra spp.)
. ), Bertiella spp., Taenia sp.
ia spp. ), Echinococcus spp.
, Hydratigera spp., Dabynea sp. (Da
Vinea spp. ), Railietina spp.
. ), Hymenolepis spp., Echinolepis spp., Echinococci (Echinocot)
yl spp. ), Diorchis spp., Dipyridium spp., Joyeuella sp.
xiella spp. ), Dipropylidium species
spp. ).

From the subgenus Monogenea, for example: Dirodactylus species (Gy
rodactylus spp. ), Dactylogyrus species
us spp. ), Polystoma spp.

From the subfamily Digenea, for example: ヂ Prostomam species (Dipl
ostumum spp. ), Post @ prostomam (Posthodipl)
ostumum spp. ), Cystosoma spp.
. ), Trichobirharzia spp.,
Ornithobilharzia spp., Austrobilharzia spp., Gigantobillharzia spp., Leucochrysippium sp. spp.), Echinostoma species (Echinostoma)
oma spp. ), Echinopariphyium species
spp. ), Echinochasmus spp.,
Hypoderaeum spp., Faciora sp.
asciola spp. ), Fasciolides s
pp. ), Fasciolopsis spp., Cyclocoelum spp., Tifurcoelm sp. (Ty)
phlocoelum spp. ), Paramfistomamu species (Paramphi)
stoum spp. ), Calicophoron sp.
p. ), Cotylophoron spp., Gigantocotyle spp., Fiscodelius sp.
choederius spp. ), Gastrotrophy species
lacus spp. ), Notocotylus spp.
), Catatropis spp., Pladialkis sp.
Plagiorchis spp. ), Prostgonimus species (Prosthog)
onimus spp. ) 、 ヂ Crocoelium species (Microcoelium)
spp. ), Eurytrema spp., Troglotrema spp., Paragonimus species (Paragon)
imus spp. ), Colliriculum spp.)
, Nanophytus spp., Opisthorchis spp., Clonorch sp.
is spp. ), Metorchis spp., Heterophies spp., Metagonimus sp.
onimus spp. ).

From the order of the Enoplida, for example: Triculis species (Trich)
uris spp. ), Capillaria spp., Trichromosoides spp., Trichinella spp.

From the order of the Rhabditis, for example: Micronema species (Micr)
onema spp. ), Strongyloides species
spp. ).

From the order of the Strongylidae, for example: Stronylus species (St
ronylus spp. ), Triodontophora species
orus spp. ), Esophagodontus species (Oesophagodontu)
s spp. ), Triconema spp., Gialocephalus spp., Cylindropharynx spp., Poteriostomum sp.
oteriostomum spp. ), Cyclococercas species (Cycloco
cercus spp. ), Silicostephas species
nus spp. ), Oesophagostomum species
spp. ), Chabertia spp., Stefanurus spp., Ansilostoma sp. (Ancyl)
ostoma spp. ), Ancinaria species (Uncinaria spp.)
, Bunostomum spp., Globocephalus species (
Globocephalus spp. ), Singhamus species (Syngamus)
spp. ), Cyatostoma spp., Metastrongilus spp., Dictiocaulus spp., Muellerius sp.
ius spp. ), Protostrongillus species
s spp. ), Neostrongilus spp.
. ), Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostronus spp. (Elap)
hostylylus spp. ), Parella host Longsilus species (Pare
laphostrongylus spp. ), Clenosoma species (Crenoso
ma spp. ), Paracrenosomal spp.
), Angiostrongillus spp.
, Elurostrongillus spp.,
Philaroides sp., Parafilaroides spp., Tricholonids sp.
ichostrongylus spp. ), Haemoncus species (Haemonc)
hus spp. ), Ostertagia spp.,
Marshallagia spp., Cooperia spp. (C
ooperia spp. ), Nematodirus sp.
p. ), Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollanus sp.
spp. ).

From the order of the Oxyurida, for example: Oxyurys sp.
is spp. ), Enterobius spp., Passalurus spp., Sifasia sp.
ia spp. ), Aspiculuris spp.),
Heterakis spp.

From the order of the Ascaridida, for example: Ascaris sp.
ris spp. ), Toxascaris spp.,
Toxokara spp., Parascaris sp.
aris spp. ), Anisakis spp., Ascaridia spp.

From the order of the Spirurida, for example: Gnatostoma species (Gn
atostoma spp. ), Physaloptera species
a spp. ), Thelazia spp., Gongylonema spp., Habronema sp.
spp. ), Parabronema spp., Dracia spp., Dracanculus spp.
us spp. ).

From the order of the Filariada, for example: Stefanophilaria spp., Parafilaria sp.
fiaria spp. ), Setaria spp. (Setaria spp.), Lore sp. (Loa spp.), Dirofilaria spp.
. ), Litomosoides spp., Brugia spp., Bucereria spp.
), Onchocerca species (Onchocerca spp.).

From the order of the Gigantorhynchida, for example: Filicollis spp., Moniliformis sp. (Monili)
formis spp. ), Macracanthrincus species (Macracantho)
rhynchus spp. ), Protenorchis species
s spp. ).

Producing livestock and breeding animals include mammals such as cows, horses, sheep, pigs, goats, camels, buffaloes, donkeys, rabbits, yellow deer, reindeer, fur animals such as mink, chinchilla, raccoon, birds Including, for example, chickens, geese, turkeys or ducks, freshwater and saltwater fish, such as trout, carps and eels, reptiles and insects, such as honeybees and silkworms.

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

Pets include dogs and cats.

Dosing can be performed prophylactically as well as therapeutically.

The active substance, either directly or in the form of suitable preparations, can be administered in the intestine, parenterally, on the skin, intranasally, by treating the habitat, or by molding containing the active compound. It is administered with the aid of an article, for example, a band, plate, tape, collar, ear tag, foot band, or marking device.

Enteral administration of the active substance includes, for example, powders, suppositories, tablets, capsules, pastes, drinks, granules, solutions, orally applicable suspensions and emulsions, large pills It is carried out orally in the form of an agent, a drug-added feed or drinking water.
Skin application is carried out, for example, in the form of dipping, spraying or sprinkling and spot-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: solutions, such as solutions for injection, oral solutions, concentrated solutions to be administered orally after dilution, solutions for dermal or intracavitary use, sprinkle formulations, gels. Emulsions and suspensions for oral or dermal administration and injection; semi-solid preparations; preparations in which the active compounds are incorporated into an ointment base or an oil-in-water or water-in-oil emulsion base; solid preparations such as powders, Premix or concentrate, granule, pellet,
Tablets, large pills, capsules; aerosols and inhalants, molded products containing active substances.

Solutions for injection are administered intravenously, intramuscularly and subcutaneously.

Injectable solutions may be prepared by dissolving the active compound in a suitable solvent and adding, if desired, additives such as solubilizers, acids, bases, buffer salts, antioxidants or preservatives. Prepared by The solution is sterile filtered and poured into a container.

Suitable solvents are: physiologically acceptable solvents such as water, alcohols, for example ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol and N-methylpyrrolidone, and mixtures thereof. Include.

Where appropriate, the active compounds may also be dissolved in physiologically acceptable vegetable or synthetic oils suitable for injection.

Suitable solubilizing agents include: solvents that enhance the dissolution of the active compound in the primary solvent or that prevent precipitation of the active compound. Examples are polyvinylpyrrolidone, polyethoxylated castor oil and polyethoxylated sorbitan esters.

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

The oral solution is administered directly. Concentrated solutions are first diluted to a dosage concentration and then administered orally. Oral solutions and concentrates are prepared as described above in the case of injectable solutions, but no sterilization steps are required.

The solution to be used on the skin is applied by dripping, applying, rubbing, sprinkling or spraying. These solutions are prepared as described above in the case of the solutions for injection.

It may be advisable to add thickeners during the manufacturing process. The following are thickeners: inorganic thickeners such as bentonite, colloidal silica, aluminum monostearate, or organic thickeners such as cellulose derivatives, polyvinyl alcohol and their copolymers, acrylates and methacrylates. .

The gel is applied or applied to the skin or introduced into a body cavity. Gels are prepared by adding an amount of a thickening agent to a solution prepared as described for the solvent for injection, such that a clear composition having an ointment-like consistency is formed. The thickeners used are the thickeners indicated further above.

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

[0062] Sprinkle and spot-on formulations are prepared by dissolving, suspending or emulsifying the active compound in a suitable solvent or solvent mixture that is acceptable to the skin. If appropriate, other auxiliaries such as coloring agents, bioabsorption enhancers, antioxidants, light stabilizers or adhesives are added.

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 alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether or diethylene glycol monobutyl ether, ketones such as acetone or methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable oils or synthetic Oils, DMF, dimethylacetamide, N-methylpyrrolidone, or 2,2-dimethyl-4-oxy-methylene-1, 3-dioxolan.

Coloring agents are all coloring agents that can be dissolved or suspended and that are approved for use in animals.

Examples of bioabsorption enhancing substances are DMSO, spreadable oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oil, fatty acid esters, triglycerides or higher alcohols.

The antioxidant is a sulfite or metabisulfite, for example potassium metabisulfite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or tocopherol.

Light stabilizers include, for example, novantisolic acid
d).

The adhesive is, for example, a cellulose derivative, a starch derivative, a polyacrylate, or a natural polymer such as alginate and gelatin.

Emulsions can be administered orally, dermally or as injections.

Emulsions are either water-in-oil or oil-in-water.

They dissolve the active compound in either the hydrophobic or hydrophilic phase, and dissolve this phase together with the other phase's solvents, as well as suitable emulsifiers and, if appropriate, colorants, bioabsorption enhancing agents. It is prepared by homogenization with the aid of other auxiliaries such as substances, preservatives, antioxidants, light stabilizers and thickeners.

Suitable hydrophobic phases (oils) are: paraffin oil, silicone oil, natural vegetable oils such as sesame oil, almond oil or castor oil, synthetic triglycerides such as caprylic / capric diglyceride, chain length C _8-12. Mixtures of triglycerides with vegetable fatty acids or other selected natural fatty acids of the invention, and also mixtures of partial glycerides of saturated or unsaturated fatty acids which may contain hydroxyl groups, and C ₈ /
Encompasses and diglycerides - C ₁₀ fatty acid mono.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, saturated fatty alcohols with a chain length of C _{16 to} C ₁₈ and branched fatty acids with a medium chain length esters, caprylic / capric acid esters of saturated fatty alcohols of isopropyl myristate, isopropyl palmitate, chain length C ₁₂ -C _18, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate Waxy fatty acid esters such as artificial duck tail buttocks, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter, and the like.

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

Fatty acids, such as oleic acid, and mixtures thereof.

[0073] Suitable hydrophilic phases include: water, alcohols such as propylene glycol, glycerol, sorbitol, and mixtures thereof.

Suitable emulsifiers are: nonionic surfactants, such as polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate or alkylphenols Polyglycol ethers; amphoteric surfactants such as disodium N-lauryl-β-iminodipropionate or lecithin; anionic surfactants such as sodium lauryl sulfate, fatty alcohol ether sulfate, and mono / dialkyl polyglycol ethers Monoethanolamine salts of orthophosphate esters; including cationic surfactants such as cetyltrimethylammonium chloride.

Other suitable auxiliaries are: substances which increase the viscosity and stabilize the emulsion, such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatine, gum arabic, polyvinylpyrrolidone, Includes polyvinyl alcohol, methyl vinyl ether / maleic anhydride copolymer, polyethylene glycol, wax, colloidal silica, or mixtures of the above.

The suspension can be administered orally, transdermally, or as an injection. They suspend the active compound in liquid additives, if appropriate with the addition of other auxiliaries, such as wetting agents, coloring agents, bioabsorption enhancers, preservatives, antioxidants and light stabilizers. Prepared.

[0077] Suitable liquid additives are all homogeneous solvents and solvent mixtures.

Suitable wetting agents (dispersing agents) further include the surfactants indicated above.

[0079] Other suitable auxiliaries include those further indicated above.

Semi-solid preparations can be administered orally or dermally. They differ from the aforementioned suspensions and emulsions only by their relatively high viscosity.

For preparing solid formulations, the active compounds are mixed with suitable additives and, if appropriate, auxiliaries, and the mixture is formulated as desired.

[0082] Suitable additives include all physiologically acceptable solid inert substances. Suitable for this purpose are inorganic and organic substances. Inorganic substances, for example,
Ordinary salts, carbonates such as calcium carbonate, bicarbonate, aluminum oxide,
Silica, clay, precipitated or colloidal silica, and phosphate.

Organic substances are, for example, sugars, cellulose, food and feed, for example milk powder, animal powder, cereal powder, coarse cereal powder, and starch.

Auxiliaries are furthermore preservatives, antioxidants and coloring agents which have already been mentioned above.

Other suitable auxiliaries are lubricants and lubricants such as magnesium stearate, stearic acid, talc, bentonite, disintegrants such as starch or cross-linked polyvinylpyrrolidone, binders such as starch, gelatin or starch. Chain polyvinylpyrrolidone, and a dry binder such as microcrystalline cellulose.

In the formulations, the active compounds can also be present in a mixture with a synergist or other active compounds which are active against pathogenic endoparasites. Examples of such active compounds are L-2,3,5,6-tetrahydro-6-phenyl-imidazothiazole, benzimidazole carbamate, praziquantel, pyrantel or fevantel.

The preparation to be used as it is has a concentration of 10 ppm to 20% by weight, preferably 0.1% by weight.
Contains from 10 to 10% by weight of active compound.

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

In general, it has been found to be advantageous to administer from about 1 to about 100 mg of active compound per kg of body weight per day for effective results.

[0090] In chlorosulfonated 0 ℃ of Example Example a PF1022, depsipeptide dichloromethane PF1022

[0091]

Embedded image

The (0.523 mmol) solution is mixed with chlorosulfonic acid (37.3 mmol) and the mixture is stirred at 0 ° C. for 2 hours and at room temperature for 2 hours. The reaction mixture is reacted further directly without further purification.

Example b General procedure for preparing sulfonamides.

At 0 ° C., the reaction mixture from Example 1 is added dropwise to acetone (50 ml).
Then, at 0 ° C., the mixture is mixed with the appropriate amine (79.4 mmol) and stirred at 60 ° C. for 12 hours. After this the mixture is concentrated, taken up in water and extracted with dichloromethane (3x). The combined organic extracts were washed with Na ₂ S
Dry over O ₄ and concentrate. The residue is purified by chromatography.
This gives a depsipeptide of formula (I) in which the substituents R ¹ and R ² in the para position have the meaning shown in the table below.

[0095]

[Table 1]

[0096]

[Table 2]

Example A Anthelmintic Activity in Sheep Merino or Blackhead sheep, weighing 25-35 kg, were treated with Haemonchus contortus L
5000 larvae of three larvae were experimentally infected and treated with test substances after a period of apparent pre-parasites (3-4 weeks). The test substance was orally administered using a gelatin capsule. Trichos Longilas Colaboliformis (Trichos)
In the case of C. longylus coloniformis, the infection is reduced to L3
The test was performed using 12,000 larvae. Anthelmintic activity was measured by the decrease in eggs excreted with feces. By the end of this, newly obtained feces are
prepared according to the er method and the number of eggs per gram of feces was determined. Egg numbers were determined at regular intervals before and after treatment (3-4 days) over a period of 6-8 weeks. In this test, a reduction of more than 95% of the eggs was designated as 3.

In this test, for example, the following compounds had the indicated activities:

[0099]

[Table 3]

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (71) Applicant Bayerwrk, Leverkusen, BRD ( 72) Inventor Plant, Andréu Deutsche D. 51373 Lehuel-Erkusen Balter-Freks-Schütlerase 20 (72) Inventor Halder, Achim Deutsche D.-51109 Cologne Europaring 54 (72) Inventor Huon Zamson Himmels Toyuelna, Georg Deutschland-42657 Solingen Neu Encamphusstraße 21

Claims (5)

[Claims] 1. A substituted cyclooctadepsipeptide of formula (I): Wherein, n stands for 0, 1 or 2, m represents 1 or 2, R ¹ is in the ortho and / or para position, represents a sulfonyl group of the formula -SO ₂ -A, R ² is Represents a sulfonyl group of the formula —SO ₂ —A in the ortho and / or para position, wherein A is the following group: amino, mono- or dialkylamino having 1-4 C atoms for the alkyl moiety, alkyl Bis (hydroxyalkyl) amino, having 1 to 4 C atoms in the moiety, substituted by mono- or bis (alkoxyalkyl) amino, phenyl, furyl, morpholinyl or pyridyl having 1 to 4 C atoms for the alkoxy or alkyl moiety Mono- or di-C _1-4 -alkylamino,
Also represents a saturated 5- or 6-membered heterocycle attached via a nitrogen,
They may contain, in addition to N, one or two further heteroatoms from the group consisting of O and N, and may be optionally substituted; furthermore, pyrazole, imidazole, pyrrole, Represents an unsaturated heterocycle attached via a nitrogen, from the group consisting of 1,2,4-triazole, 1,2,3-triazole, which may be optionally substituted. Substituents for optionally substituted groups that may be mentioned are C _1-4
-Alkyl, acyl, for example C _1-4 -alkylcarbonyl, benzoyl, C _1-4-
Alkoxycarbonyl. 2. The compound of formula (I) Wherein n represents 0, 1 or 2; m represents 1 or 2; R ¹ represents one or two sulfonyl groups of the formula —SO ₂ —A in the ortho and / or para position. Wherein R ² represents one or two sulfonyl groups of the formula —SO ₂ —A in the ortho and / or para position, wherein A represents the following groups: C-atoms 1-4 for amino, alkyl moieties Mono or dialkylamino having 1 to 4 carbon atoms, bis (hydroxyalkyl) amino having 1 to 4 C atoms in the alkyl portion, mono- or bis (alkoxyalkyl) amino having 1 to 4 C atoms in the alkoxy or alkyl portion, phenyl Mono- or di-C _1-4 -alkylamino substituted by furyl, morpholinyl or pyridyl,
Also represents a saturated 5- or 6-membered heterocycle attached via a nitrogen,
They may contain, in addition to N, one or two further heteroatoms from the group consisting of O and N, and may be optionally substituted; furthermore, pyrazole, imidazole, pyrrole, Represents an unsaturated heterocyclic ring attached via a nitrogen from the group consisting of 1,2,4-triazole, 1,2,3-triazole, which may be optionally substituted. A method for producing a substituted cyclooctadepsipeptide of the formula: Is reacted with halogenosulfonic acid, or sulfuryl chloride or sulfur dioxide / chlorine, and the resulting halogenosulfonylated compound is converted to a compound of the formula HA wherein A is as defined above. Wherein the compound is further converted by reaction with the compound of formula (I). 3. Use of a substituted cyclooctadepsipeptide of formula (I) according to claim 1 for controlling helminths in human and veterinary medicine. 4. Use of a substituted cyclooctadepsipeptide of formula (I) according to claim 1 for preparing a composition for controlling endoparasites in human and veterinary medicine. 5. The composition according to claim 1, which comprises, in addition to fillers and diluents and, if appropriate, customary additives, an amount of the substituted cyclooctadepsipeptide of the formula (I) according to claim 1. An endoparasite control composition.