CA2332122A1

CA2332122A1 - Substituted cyclooctadepsipeptides

Info

Publication number: CA2332122A1
Application number: CA002332122A
Authority: CA
Inventors: Jurgen Scherkenbeck; Hubert Dyker; Andrew Plant; Achim Harder; Georg Von Samson-Himmelstjerna
Original assignee: Individual
Current assignee: Bayer AG
Priority date: 1998-06-24
Filing date: 1999-06-11
Publication date: 1999-12-29
Also published as: HUP0102476A3; JP2002518520A; EP1090031A1; KR20010043957A; WO1999067281A1; BR9911574A; CN1307586A; DE19828047A1; AU4511499A; HUP0102476A2; PL345866A1

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

Le A 33 001-Forei n Countries Rtlwa/NZ' Substituted cyclooctade~psipeptides The invention relates to novel substituted cyclooctadepsipeptides, to processes for their preparation and to their use for controlling parasites, in particular helminths, in veterinary and human medicine, and to intermediates for their preparation.
Various cyclodepsipeptides having antiparasitic action are described in the literature.
EP 382 173 A2 discloses a cyclooctadepsipeptide with the name PF1022. Further 24-membered cyclodepsiipeptides are known from EP 626 376 A1, EP 6:34 408 A1 and EP 718 293 A1. Their anthelmintic action is not in all cases satisfactory.
WO 96/11 945 discloses a process for sulphonylating depsipeptides. However, it does not disclose any uniform compounds.
1. Novel cyclooctadepsipeptides of the formula (I) HsC N
H ~ O H O H~~~ O

HsC__N H O O H ~Ry m ~R2)n O O
H p O H N-CH3 (I), O ,~~H O H CH3 _ O
N CHs CH3 ~H3 H~,C CH3 have been found in which R1 in the orthc> and/or para position represents sulphonyl radicals of the formula -SO~-A, R2 in the ortho and/or para position represents sulphonyl radicals of the formula -SO-,-A, CA 02332122 2000-12-21.

Le A 33 001-Forei n~Coimtries where A represents the following radicals:
amino, mono- or dialkylamino having 1 to 4 C atoms per alkyl moiety, bis(hydroxyalkyl)amino having 1-4 C atoms in the alkyl moiety, bis(alkoxy-alkyl)amino having 1 to 4 C atoms per alkoxy or alkyl moiety, mono- or di-C1_4-alkylamino which is substituted by phenyl, furyl, morpholinyl or pyridyl;
furthermore represents saturated 5- or 6-membered heterocycles, attached via nitrogen, which, in addition to N, may contain 1 or 2 further heteroatoms from the group consisting of O and N and which are optionally substituted;
furthermore represents unsaturated heterocycles, attached via nitrogen, from the group consisting of pyrazole, imidazole, pymole, 1,2;4-triazole, 1,2,3-triazole, whi~.ch may optionally be substituted, n represents 0, I a~r 2, m represents 1 or 2.
Substituents for the optionally substituted radicals which may be mentioned are Cl_4-alkyl, acyl, such as C1_,~-alkylcarbonyl, benzoyl, CI_4-alkoxycarbonyl.
2. Furthermore, a process for preparing compounds of the formula (I;>

HsC N
H ~ , H O H~~~ O

HsC__N :H w0 O H ~Ry m (R2)n O O
H O O H N-CH3 (I), O ,,.H O H CH3 _ O
N CHs 3~ 3 in which RI, R? and m and n are as defined above, CA 02332122 2000-12-21.

Le A 33 001-Foreign Countries has been found which is characterized in that the compound PF 1022 of the formula H3C H3~3C CH3 HsC N
H ~ O H O H~~~ O

HsC_.N H O O H
O O

,,,H H
N CHs CH3 ~H3 H3(~ CH3 is reacted with a halogenosulphonic acid or with sulphuryl chloride or sulphur dioxide/chlorine ;end the resulting halogenosulphonylated compounds are converted further by reaction with compounds of the formula H-A, in which A is as defined above.
The compounds of the formula (I) according to the invention are highly suitable for controlling helminths in veterinary and human medicine.
Preference is given to compounds of the formula (I) in which R t represents -SO~-A, n and m represent l, R'- represent, hydrogen or -SO~-A, Le A 33 001-Foreign Countries 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(phenyleth:yl)amino, mono- or bis(pyridylmethyl)amino, mono- or bis(pyridylethyl)amino, mono- or bis(morpholinylethyl)amino, furfurylamino, N-furfuryl-N-methylamino, morpholino-, 1-piperazinyl-, I-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 compounds of the formula (I), in which R1 and R2 represent the radical -SO~-A in para position, where A represents 1-piperazinyl which is optionally monosubstituted by C1_4-alkylcarbonyl or C1_4-alkoxycarbonyl, furthermore represents amino, mono- Ci_~-alkylamino whose alkyl moiety is optionally substituted by morpholino, furyl or pyridyl, di-C1_4-alkylamino, furthermore represents 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 field of veterinary medicine. Surprisingly, in the control of worm diseases, they exhibit better activity than prior-art compounds of a similar constitution and the same: direction of action.
For their preparation, initially the known compound PF 1022 of the formula below Le A 33 001-Forei ng-Cormtries _5_ H3C H3~3C CH3 HsC N
v.~
HsC O; H O H O
H3C-N H ' O O H

O ,,~H O H CHs ~~H ~v is reacted with halogeno~sulphonic acids (HaIS03H), in particular chlorosulphonic acid, or with sulphuryl chloride or sulphur dioxide/chlor-ine, if appropriate in a diluent which is inert towards the reagents, and if appropriate in the presence of Lewis acids.
The reaction is carried out at temperatures of from 0 to 150°C, preferably at from 0 to 80°C, particularly preferably at from 0 to 60°C.
Suitable diluents are all organic solvents which are inert towards the reagents. These include, in particular aliphatic and aromatic, optionally halogenated hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, furthermore ethers, such as diethyl ether and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, furthermore ketones, such as acetone, methyl ether ketone, methyl isopropyl ketone and methyl isobutyl ketone, moreover esters, such as methyl acetate and ethyl acetate, furthermore nitriles, such as, for example, acetonitrile and propionitrile, benzonitrile, glutaronitrile, additionally amides, such as, for example, dimethylfonnamide, dimethylacetamide and N-methylpyrrolidone, and also dimethyl sulphoxide, tetramethylene sulphone and hexamethylphosphoric triamide.
The depsipeptides are reacted with an excess of reagent (5 to 10 equivalents) and an excess of Lewis acid (1~ to 20 equivalents).

Le A 33 001-Foreign Countries The halogenosulphones, in particular chlorosulphones, obtainable in this step are compounds of the formula (n in which the radicals R1 and/or R2 represent the radical -SOZ-halogen, in particular -SOZ-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 bases.
Suitable diluents for the reaction of the halogenosulphones are the diluents mentioned further above. The base used is either an excess of the amine of the formula A-H, or alkali metal hydroxides, alkali metal or alkaline earth metal carbonates or tertiary, aliphatic or aromatic amines are used.
The second step of the reaction is earned out either after the product of the first step has been isolated and purified, or immediately after the first step. It is carried out at temperatures of from -:l0 to +150°C, preferably between -5°C and +20°C. It is earned out at atmospheric pressure.
It is also possible to react the compound PF 1022 with sulphuric acid (oleum) to give the corresponding -SO~~OH-substituted compound. This compound can then be converted into the corresponding halogenosulphone using a halogenating agent.
The halogenosulphone is then reacted, as described above, with amines to give the corresponding sulphonamides.
After the reaction has been carried out, the diluent is distilled off and the compounds of the formula (I) are purified in a customary manner, for example chromatographically.
The active compounds, are suitable for controlling pathogenic endoparasites encountered in humans and in animal husbandry and livestock breeding, in productive livestock, breeding stock, zoo animals, laboratory animals, animals used in experiments, and pets, and have low toxicity toward warm-blooded animals. They are active against resistant and normally sensitive species and against all or some stages of development of the pests.. By controlling the pathogenic endoparasites, it is intended to CA 02332122 2000-12-21.

Le A 33 001-Foreign Cocmtries reduce disease, mortality <~nd decreasing performance (for example in the production of meat, milk, wool, hides, eggs, honey, etc.), so that more economical and simpler animal husbandry is possible by using the active compounds. The pathogenic endoparasites include Cestodes, Trematodes, Nematodes, Acantocephalides, in particular:
From the order of the: Pseudophyllidea, for example: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoporus spp.
From the order of the Cyclophyllidea, for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Ec:hinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.
From the subclass of the Monogenea, for example: Gyrodactylus spp., Dactylogyrus spp., Polystoma spp.
From the subclass of the Digenea, for example: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., >=?chinostoma spp., Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp., Paramphistomum spp., Calicophoron spp-Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonimus sp~~., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonismus spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., C:lonorchis spp. Metorchis spp., Heterophyes spp., Metagonimus spp.
From the order of the Enoplida, for example: Trichuris spp., Capillaria spp., 'Trichlom-osoides spp., Trichinella spp.
From the order of the Rhabditia, for example: Micronema spp., Strongyloides spp.

Le A 33 001-Foreign Countries _g_ From the order of the Strongylida, for example: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., T'richonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp., l3unostom-um spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneurrrostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp.
From the order of the Oxvurida, for example: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspic:uluris spp., Heterakis spp.
From the order of the Ascaridia, for example: Ascar-is spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anis~akis spp., Ascaridia spp.
From the order of the Spirurida, for example: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.
From the order of the F'ilariida, for example: Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Frirofilaria spp., Litomosoides spp., Brugia spp., ''Vuchereria spp., Onchocerca spp.
From the group of the C~igantorhynchida, for example: Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.
The productive livestock and breeding stock include mammals, such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur-bearing anirnals, such as, for example, minks, chinchilla, racoon, birds, such as, for example chickens, geese, turkeys or ducks, freshwater fish and sea fish, such as, for example, trout, carp, eels, reptiles and insects, such as, for example, 3_5 honeybee and silkworm.
CA 02332122 2000-12-21.

L.e A 33 001-Fore~rr Countries The laboratory and test animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
The pets include dogs and eats.
Administration can be effected prophylactically as well as therapeutically.
The active substances ane administered, either directly or in the form of suitable preparations, enterally, pau-enterally, dermally, nasally, by treating the habitat or with the aid of shaped articles containing the active compound, such as, for example, strips, plates, tapes, collars, ear tags, limb bands or marking devices.
Enteral administration of the active compounds is effected for example orally in the form of powders, tablets, capsules, pastes, drinks, granules, solutions, suspensions and emulsions which can be applied orally, boluses, medicated feed or drinking water.
Dermal application is effected, for example, in the form of dipping, spraying or pouring on and spotting-on. Parenteral administration is effected, for example, in the form of injection (intramuscular, subcutaneous, intravenous or intraperitoneal) or by implants.
Suitable preparations include:
solutions, such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on 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 ennulsion base;
solid preparations, such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; aerosols and inhalants, shaped articles containing t:he active compound.

Le A 33 001-Foreign Countries Solutions for injection are administered intravenously, intramuscularly and subcutaneously.
Solutions for injection are prepared by dissolving the active compound in a suitable solvent and, if desired, adding additives, such as solubilizers, acids, bases, buffer salts, antioxidants, or preservatives. The solutions are sterile-filtered and decanted into con-tamers.
Suitable solvents include: physiologically acceptable solvents, such as water., alcohols, such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycols and N-methylpynolidone, and their mixtures.
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 polyet:hoxylated sorbitan esters.
The following are preservatives: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic esters or n-butanol.
Oral solutions are administered directly. Concentrates are first diluted to the administration concentration and then administered orally. Oral solutions and concentrates are prepared as described above in the case of the solutions for injection, sterile procedure not being necessary.
Solutions for use on the skin are applied drop by drop, smoothed on, rubbed in, splashed on or sprayed on. These solutions are prepared as described above in the case of the 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, aluminium 3_5 monostearate, or organic thickeners, such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates.
CA 02332122 2000-12-21.

Le A 33 001-Forei ng~Cotmtries Gels are applied to the skin or smoothed on or introduced into body cavities.
Gels are prepared by adding such am amount of thickener to solutions which have been prepared as described for the solutions for injection that a clear composition is formed which has an ointment-like consistency. The thickeners used are the thickeners indicated further above.
Pour-on and spot-on formulations are poured onto or splashed onto limited areas of the skin, the active compound. penetrating the skin and acting systemically.
Pour-on and spot-on formulations are prepared by dissolving, suspending or emulsifying the active compound in suitable solvents or solvent mixtures which are tolerated by the skin. If appropriate, other auxiliaries, such as colorants, bioabsorption promoters, antioxidants, photostabilizers or tackifiers 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 mono-butyl ether, ketones, such as acetone or methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF., dimethyl acetamide, N-methylpymolidone, or 2,2-dimethyl-4-oxy-methylene-1,3-dioxolane.
Colorants are all colorants which can be dissolved or suspended and which are approved for use in animals.
Examples of bioabsorption promoters are DMSO, spreading oils, such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides or fatty alcohols.
Antioxidants are sulfites or metabisulfites, such as potassium metabisulfite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or tocopherol.
Photostabilizers are, for example, novantisolic acid.
CA 02332122 2000-12-21.

Le A 33 001-Forei n~Countries Tackifiers are, for example, cellulose derivatives, starch derivatives, polyacrylates or natural polymers such as alginates or gelatin.
Emulsions can be administered orally, dermally or as injections.
Emulsions are either the water-in-oil type or the oil-in-water type.
They are prepared by dissolving the active compound either in the hydrophobic or in the hydrophilic phase and by homogenizing this phase with the solvent of the other phase, with the aid of suitable emulsifiers and, if appropriate, other auxiliaries, such as colorants, bioabsorption promoters, preservatives, antioxidants, photostabilizers, and viscosity-increasing substances.
Suitable hydrophobic phases (oils) include: paraffin oils, silicone oils, natural vegetable oils such as sesame seed oil, almond oil or castor oil, synthetic triglycerides, such as caprylic/capric acid biglyceride, a triglyceride mixture with vegetable fatty acids of chain length Cg_,~ or other specifically selected natural fatty acids, mixtures of partial glycerides of saturated o:r unsaturated fatty acids which may also contain hydroxyl groups, and mono- and dii;lycerides of the Cs/C,o-fatty acids.
Fatty acid esters, such as cahyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid having a medium chain length with saturated fatty alcohols of chain length C,~,-C,s, isopropyl myristate, isopropyl palmitate, caprylic/capric esters of saturated fatty alcohols of chain length C,2-C,g, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid esters such as artificial duck uropygial fat, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter, etc.
Fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol.
Fatty acids, such as, for example, oleic acid and its mixtures.
Suitable hydrophilic phases include:
water, alcohols, such as, for example, propylene glycol, glycerol, sorbitol and their mixtures.
CA 02332122 2000-12-21.

Le A 33 001-Forei;~n Cotmtries Suitable emulsifiers include: nonionic surfactants, for example polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyeth;yl stearate or alkylphenol polyglycol ethers;
ampholytic surfactants, such as disodium N-lauryl-(3-iminodipropionate or lecithin;
anionic surfactants, such as Na lauryl sulfate, fatty alcohol ether sulfates, and the monoethanolamine salt of mono/dialkylpolyglycol 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/maleic anhydride copolymers, polyethylene glycols, waxes, colloidal silica, or mixtures of the listed substances.
Suspensions can be administered orally, dermally or as an injection. They are prepared by suspending the active: compound in a liquid excipient, if appropriate. with the addition of other auxiliaries, such as wetting agents, colorants, bioabsorption promoters; preservatives, .antioxidants photostabilizers.
Suitable liquid excipients include all homogeneous solvents and solvent mixtures.
Suitable wetting agents (dispersants) include the surfactants indicated further above.
Other suitable auxiliaries :include those indicated further above.
Semi-solid preparations can be administered orally or dermally. They are only distinguished from the above-described suspensions and emulsions by their higher mscosity.
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.

Le A 33 001-Forei ng~Countries Suitable excipients include all physiologically acceptable solid inert substances.
Suitable for this purpose are inorganic and organic substances. Inorganic substances are, for example, common salt, carbonates, such as calcium carbonate, hydrof;en carbo-nates, aluminum oxides, siilicas, clays, precipitated or colloidal silica, and phosphates.
Organic substances are, for example, sugars, cellulose, foodstuffs and animal feeds, such as powdered milk, animal meals, cereal meals, coarse cereal meals and starches.
Auxiliaries are preservatives, antioxidants and colorants which have already been mentioned further above.
Other suitable auxiliaries are lubricants and glidants, such as, for example, magnesium stearate, stearic acid, talc, bentonites, disintegrants, such as starch or crosslinked 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 present in mixtures with synergists or other active compounds which are active against pathogenic endoparasites. Examples of such active compounds are L-2,3,5,6-tetrahydro-6-phenyl-imidazolethiazole, benzirr~idazole carbamates, praziquantel, pyrantel or febantel.
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 which are diluted before use contain the active compound in concen-trations of 0.5 to 90% by weight, preferably from 5 to 50% by weight.
In general, it has been found to be advantageous to administer amounts of about 1 to about 100 mg of active compound per kg of body weight per day to obtain effective results.
CA 02332122 2000-12-21~

Le A 33 001-Forei n~Countries Preparation Examples Example a Chlorosulphonation of Ph 1022 At 0°C, a solution of the depsipeptide PF 1022 H3C H3~3C CH3 HsC N
v.

HsC_N :1-i w0 O H
O O
H O p H N-CH3 O .,,H O H CHs _ O
N CHs (0.523 mmol) in dichloromethane is admixed with chlorosulphonic acid (3 ~'.3 mmol), and the mixture is stirred at 0°C for 2 hours and at room temperature for 2 hours. The reaction mixture is directly reacted further without further work-up.
Example b General procedure for preparing the sulphonamide.
At 0°C, the reaction mixture from Example 1 is added dropwise to acetone (50 ml).
At 0°C, the mixture is then admixed with the appropriate amine (79.4 rnmol) and stirred at 60°C for 12 hours. After this period of time, the mixture is concentrated, taken up in water and extracted with dichloromethane (3 x). The combined organic extracts are dried over l~fa~S04 and concentrated. The residue is purified by column chromatography. This gives depsipeptides of the formula (I) in which the substituents R1 and R'- in the para position have the meanings Given in the table below.

Le A 33 001-Foreign Coc~ntries Table 1 No. R1 R2 h sical data:

1 O p FAB-MS (%):

SO SO

~ ~ 124 i' ( 100, M+) 2 ~OH ~OH FAB-MS (%):

S02 N~OH S02 N~OH 1282 (80, M.+) 3 ~OMe ~OMe FAB-MS (%):

S02 N~OMe S02 N~OMe 1361 (90, M+ Na+) 4 ~CH3 /---CH3 FAB-MS (%):

SO N SO N
~CH 2 ~CH 1219, (95, 3 3 M+~I+) S02 ~NH S02 ~ H

6 ~ ~ FAB~-MS
(%):

S02 N N-Me S02 N N-Me U ~/ 127 3 (90, M+~+) 7 ESI-MS (%):

S02 N-CH2 N ~ S02 N-CHz N~ 1200 (100, I N I N

H H M+~I+) I I

S02 N-CH~~ S02 N-CH2 I O I O

Me Me 9 ~ ~ FAB-MS (%):

-S02 ~ -COOC2H5 -S02 ~N-COOC2H5 1390 (100, M+H+) ~ ~ FA>=~-MS
(%):

-S02 ~N-COCH3 -S02 ~N-COCH3 132c~ ( 100, M+H+) 11 -SO N -SO N~ FAB-MS (%):

121p (100, M+H+) CA 02332122 2000-12-21.

Le A 33 001-Forei n~Countries No. R1 R2 h sical data:

12 -SO N' , -SO N FAB-MS (%):

( , M+H+) 13 O ~ FAB-MS (%):

_SO NHCH CH N -S02NHCH2 CH2 ~ + +
2 z z ~

1355 (M
H ) 14 \ \ FAB-MS (%):

I -Sp2NHCH2 CH2 ( 1317 (100, N M+Fi+) CA 02332122 2000-12-21' Le A 33 001-Foreign Countries Example A
Anthelmintic activity in sheep Merino or Blackhead sheep, of a body weight of 25-35 kg, were infected experimentally with 5000 Haemonchus contortus L3 larvae and, after the prepatency period of the parasites had expired (3-4 weeks), treated with the test substances. The test substances were administered orally using gelatin capsules. In the: case of Trichostrongylus colubriformis, the infection was earned out using 12,000 L3 larvae.
The anthelmintic activity was measured by reduction of the eggs excreted with the faeces. To this end, freshly obtained faeces were prepared in accordance with the customary McMaster meahod, and the number of eggs per gram of faeces was determined. The egg numbers were determined at regular intervals (3-4 days) before and after the treatment over a period of 6-8 weeks. A reduction of eggs of more than 95°70 in the test is designated 3.
In this test, for example, the following compounds had the activity stated:
Active compound Haemonchus contortusTrichostrongylus Preparation Example0.05 mg/kg p.o. colubriforrr~is No. 0.25 ma ka ~.o.

3 3 n.d.

6 3 n.d.

I

13 3 n.d.

14 3 n.d.

p.o. orally 3 = fully effective (>9_S°7o reduction) n.d. not determined

Claims

1. Substituted cyclooctadepsipeptides of the formula (I) in which n represents 0, 1 or 2, m represents 1 or 2, R1 in the ortho and/or para position represents sulphonyl radicals of the formula -SO2-A, R2 in the ortho and/or para position represents sulphonyl radicals of the formula -SO2-A, where A represents the following radicals:
amino, mono- or dialkylamino having 1 to 4 C atoms per alkyl moiety, bis(hydroxyalkyl)amino having 1-4 C atoms in the alkyl moiety, mono- or bis(alkoxyalkyl)amino having 1 to 4 C, atoms per alkoxy or alkyl moiety, mono- or di-C1-4-alkylamino which is substituted by phenyl, furyl, morpholinyl or pyridyl;

furthermore represents saturated 5- or 6-membered heterocycles, attached via nitrogen, which, in addition to N, may contain 1 or 2 further heteroatoms from the group consisting of O and N and which are optionally substituted;
furthermore represents unsaturated heterocycles, attached via nitrogen, from the group consisting of pyrazole, imidazole, pyrrole, 1,2,4-triazole, 1,2,3-triazole, which may optionally be substituted.
Substituents for the optionally substituted radicals which may be mentioned are C1-4-alkyl, aryl, such as C1-4-alkylcarbonyl, benzoyl, C1-4-alkoxycarbonyl.

2. Process for preparing substituted cyclooctadepsipeptides of the formula (I) in which n represents 0, 1 or 2, m represents 1 or 2, R1 in the ortho and/or para position represents one or two sulphonyl radicals of the formula -SO2-A, R2 in the ortho and/or para position represents one or two sulphonyl radicals of the formula -SO2-A, where A represents the following radicals:
amino, mono- or dialkylamino having 1 to 4 C atoms per alkyl moiety, bis(hydroxyalkyl)amino having 1-4 C atoms in alkyl moiety, mono- or bis(alkoxyalkyl)amino having 1 to 4 C atoms per alkoxy or alkyl moiety, mono- or di-C1-4-alkylamino, which is substituted by phenyl, furyl, morpholinyl or pyridyl;
furthermore represents saturated 5- or 6-membered heterocycles, attached via nitrogen, which in addition to N, may contain 1 or 2 further heteroatoms from the group consisting of O and N and which are optionally substituted;
furthermore represents unsaturated heterocycles, attached via nitrogen, from the group consisting of pyrazole, imidazole, pyrrole, 1,2,4-triazole, 1,2,3-triazole, which may optionally be substituted, characterized in that the compound PF 1022 of the formula is reacted with a halogenosulphonic acid or with sulphuryl chloride or sulphur dioxide/chlorine and the resulting halogenosulphonylated compounds are converted further by reaction with compounds of the formula H-A, in which A is as defined above.

3. Use of substituted cyclooctadepsipeptides of the formula (I) according to Claim 1 for controlling helminths in human and veterinary medicine.

4. Use of substituted cyclooctadepsipeptides of the formula (I) according to Claim 1 for preparing compositions for controlling endoparasites in human and veterinary medicine.

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