WO1999067281A1 - Substituted cyclooctadepsipeptides - Google Patents

Substituted cyclooctadepsipeptides Download PDF

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Publication number
WO1999067281A1
WO1999067281A1 PCT/EP1999/004028 EP9904028W WO9967281A1 WO 1999067281 A1 WO1999067281 A1 WO 1999067281A1 EP 9904028 W EP9904028 W EP 9904028W WO 9967281 A1 WO9967281 A1 WO 9967281A1
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spp
formula
substituted
stands
amino
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PCT/EP1999/004028
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German (de)
French (fr)
Inventor
Jürgen Scherkenbeck
Hubert Dyker
Andrew Plant
Achim Harder
Georg Von Samson Himmelstjerna
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Bayer Aktiengesellschaft
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Priority to KR1020007013553A priority Critical patent/KR20010043957A/en
Priority to PL99345866A priority patent/PL345866A1/en
Priority to CA002332122A priority patent/CA2332122A1/en
Priority to BR9911574-3A priority patent/BR9911574A/en
Priority to HU0102476A priority patent/HUP0102476A3/en
Priority to JP2000555932A priority patent/JP2002518520A/en
Priority to AU45114/99A priority patent/AU4511499A/en
Priority to EP99927953A priority patent/EP1090031A1/en
Publication of WO1999067281A1 publication Critical patent/WO1999067281A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to new substituted cyclooctadepsipeptides, processes for their preparation and their use for controlling parasites, in particular helminths in veterinary and human medicine, and intermediates for their preparation.
  • a cyclooctadepsipeptide with the name PF1022 is known from EP 382 173 A2. From EP 626 376 AI, EP 634 408 AI and EP 718 293 AI further 24-membered cyclodepsipeptides are known. Their anthelmintic effect is not satisfactory in all cases.
  • a method for sulfonylating depsipeptides is known from WO 96/11 945. However, no unified connections are known from this.
  • Amino, mono- or dialkylamino with 1 to 4 carbon atoms per alkyl part Bis (hydroxyalkyl) amino with 1-4 C-atoms in the alkyl part, bis (alkoxyalkyl) - amino with 1 to 4 C-atoms per alkoxy or alkyl part, mono- or di-C ⁇ _4-alkylamino by phenyl, furyl, morpholinyl or pyridyl is substituted;
  • n 0, 1 or 2
  • m stands for 1 or 2.
  • C 1 -C 4 -alkyl may be mentioned as substituents for the optionally substituted radicals.
  • Acyl such as Cj. 4- alkylcarbonyl, benzoyl, C ] _ 4 -alkoxycarbonyl.
  • the compounds of the formula (I) according to the invention are outstandingly suitable for controlling helminths in veterinary and human medicine.
  • R 1 represents -SO 2 -A
  • n and m stand for 1,
  • R 2 represents hydrogen or - SO 2 -A
  • A preferably represents amino, mono- or dimethyl-, diethyl-, diisopropyl-amino, N-mono- or N, N-bis (ethoxymethyl) amino, - (hydroxyethyl) amino, - (ethoxyethyl) amino, - (methoxyethyl) amino, mono- or dibenzylamino.
  • R 1 and R 2 stand for the radical -SO 2 -A in the para position, where A stands for 1-piperazinyl, which is optionally simply substituted by C j ⁇ alkylcarbonyl or C j " 4 alkoxycarbonyl, furthermore amino, Mono- C ⁇ _ alkyl amino, the alkyl part is optionally simply substituted by morpholino, furyl or pyridyl, Di-Cj. 4 -alkylamino, furthermore 1-pyrrolidinyl or 1-piperidinyl.
  • A stands for 1-piperazinyl, which is optionally simply substituted by C j ⁇ alkylcarbonyl or C j " 4 alkoxycarbonyl, furthermore amino, Mono- C ⁇ _ alkyl amino, the alkyl part is optionally simply substituted by morpholino, furyl or pyridyl, Di-Cj. 4 -alkylamino, furthermore 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, they are more effective in combating worm diseases than constitutionally similar, known compounds of the same type
  • halosulfonic acids HalS0 3 H
  • chlorosulfonic acid or with sulfuryl chloride or sulfur dioxide / chlorine
  • Lewis acids optionally in one against the reaction genetically inert diluent and optionally in the presence of Lewis acids.
  • the reaction takes place at temperatures from 0 to 150 ° C., preferably at 0 to 80 ° C., particularly preferably at 0 to 60 ° C.
  • Suitable diluents are all organic solvents which are inert to the reagents. These include in particular aliphatic and aromatic, optionally halogenated hydrocarbons, such as pentane, hexane, heptane, cyclohexane. Petroleum ether, gasoline, ligroin, benzene, toluene, methylene chloride, ethylene chloride. Chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, furthermore ethers such as diethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether.
  • ketones such as acetone, methyl ether, methyl isopropyl and methyl isobutyl ketone, also esters, such as methyl acetate and ethyl acetate, and also nitriles, e.g. Acetonitrile and propionitrile,
  • Benzonitrile e.g. Dimethylformamide, dimethylacetamide and N-methylpyrrolidone, as well as dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric acid triamide.
  • amides e.g. Dimethylformamide, dimethylacetamide and N-methylpyrrolidone, as well as dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric acid triamide.
  • the depsipeptides are reacted with an excess of reagent (5 to 10 equivalents) and an excess of Lewis acid (15 to 20 equivalents).
  • halogen sulfones in particular chlorosulfones, obtainable in this stage are compounds of the formula (I) in which the radicals R 1 and / or R 2 represent the radical -S0 2 -halogen, in particular -SO 2 -Cl.
  • diluents mentioned above are suitable as diluents for the implementation of the halogen sulfones. Either the amine is used as the base
  • Forml A-H is used in excess or alkali metal hydroxides, alkali metal or alkaline earth metal carbonates or tertiary, aliphatic or aromatic amines are used.
  • the second stage of the reaction takes place either after the product of the first stage has been isolated and purified, or immediately after the first stage. It is carried out at temperatures from -10 to + 150 ° C, preferably between -5 ° C and + 20 ° C. It is operated at normal pressure.
  • the compound PF 1022 can also be reacted with sulfuric acid (oleum) to give the corresponding -SO OH substituted compound. This compound can then be reacted with a halogenating agent to give the corresponding halogen sulfone. The halogen sulfone is then reacted with amines to the corresponding sulfonamides as described above.
  • the diluent is distilled off and the compounds of the formula (I) are reacted in the customary manner, e.g. chromatographically, cleaned.
  • the active ingredients are suitable for combating pathogenic endoparasites, which occur in humans and in animal husbandry and animal breeding in useful, breeding, zoo, laboratory, experimental and hobby animals, with favorable warm-blooded toxicity. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive species. By fighting the pathogenic endoparasites, disease. Deaths and reduced performance (for example in the production of meat, milk, wool, skins, eggs, honey, etc.) are reduced, so that the use of the active ingredients results in a more economical and more specialized animal husbandry is possible.
  • Pathogenic endoparsites include cesthodes, trematodes, nematodes, acantocephals in particular:
  • Cyclophyllidea for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitelellina spp., Stilesia spp., Cittotaenia spp., Andyella spp., Bertella spp spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplop. .
  • Opisthorchis spp. Clonorchis spp. Metorchis spp., Heterophyes spp., Metagonimus spp ..
  • Stronylus spp. Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostomum spp., Cyclococercus spp., Cylicostephanus sppum, spp., Oesophag.
  • Stephanurus spp. Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostr spp., Pneumostrongylus 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., Cooperemat. Spp., Marshallemat ., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp ..
  • Oxyuris spp. Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp ..
  • Ascaridia for example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp ..
  • the livestock and breeding animals include mammals such as cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as mink, chinchilla, raccoon, birds such as chickens, geese, turkeys, Ducks, freshwater and saltwater fish such as trout, carp, eels, reptiles.
  • Insects such as Honey bee and silkworm.
  • Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters. Dogs and cats.
  • the pets include dogs and cats.
  • the application can be prophylactic as well as therapeutic.
  • the active ingredients are used directly or in the form of suitable preparations enterally, parenterally, dermally, nasally, by treating the environment or with the aid of shaped articles containing the active ingredient, e.g. Strips, plates, ribbons, collars. Ear tags, limb straps, marking devices.
  • enteral application of the active ingredients takes place e.g. orally in the form of powder. Tablets, capsules, pastes, drinkers, granules, orally applicable solutions.
  • Suspensions and emulsions, boluses, medicated feed or drinking water happens e.g. in the form of diving (dipping), spraying (spraying) or pouring on (pour-on and spot-on).
  • Parenteral use happens e.g. in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants.
  • Suitable preparations are:
  • Solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities.
  • Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; Aerosols and inhalants, molded articles containing active ingredients.
  • Solutions for injection are administered intravenously, intramuscularly and subcutaneously.
  • Injection solutions are prepared by dissolving the active ingredient in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives.
  • additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives.
  • Solutions are sterile filtered and filled.
  • solvents physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone, and mixtures thereof.
  • the active compounds can also be dissolved in physiologically tolerable vegetable or synthetic oils which are suitable for injection.
  • solution mediators solvents which promote the dissolution of the active ingredient in the main solvent or prevent its precipitation.
  • solvents which promote the dissolution of the active ingredient in the main solvent or prevent its precipitation. Examples are polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.
  • Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester. n-butanol.
  • Oral solutions are applied directly. Concentrates are used orally after previous dilution to the application concentration. Oral solutions and concentrates are prepared as described above for the injection solutions, whereby sterile work can be dispensed with.
  • Solutions for use on the skin are dripped on, spread on, rubbed in, sprayed on or sprayed on. These solutions are prepared as described above for the injection solutions.
  • Thickeners are: inorganic thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates.
  • Gels are applied to or spread on the skin or placed in body cavities. Gels are produced by adding sufficient thickening agent to solutions which have been prepared as described for the injection solutions to produce a clear mass with an ointment-like consistency.
  • the thickeners specified above are used as thickeners.
  • Pour-on formulations are poured or sprayed onto limited areas of the skin, the active ingredient penetrating the skin and acting systemically.
  • pour-on formulations are prepared by dissolving, suspending or emulsifying the active ingredient in suitable solvents or solvent mixtures that are compatible with the skin. If necessary, other auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers and adhesives are added.
  • solvents water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol. Phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as Alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethyl acetamide, N-methyl pyrrolidone, 2,2-dimethyl-4-oxy-methylene 1,3-dioxolane.
  • solvents water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol
  • Dyes are all dyes approved for use on animals, which can be dissolved or suspended.
  • Absorbing substances are e.g. DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.
  • spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.
  • Antioxidants are sulfites or metabisulfites such as potassium metabisulfite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.
  • Light stabilizers are e.g. Novantisol acid.
  • Adhesives are e.g. Cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.
  • Emulsions can be used orally, dermally or as injections.
  • Emulsions are either water in oil or oil in water.
  • hydrophobic phase paraffin oils, silicone oils, natural ones
  • Vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as Capryl capric acid bigylceride, triglyceride mixture with vegetable fatty acids of chain length Cg_i 2 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids, which may also contain hydroxyl groups, mono- and diglycerides of Cg / Ci Q fatty acids.
  • Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length Ci ö-Cj, isopropyl myristate, isopropyl palmitate, caprylic / capric alcohol esters of the saturated fatty length C12-C18, isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duck pancreas fat, dibutyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures and others
  • Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.
  • Fatty acids such as Oleic acid and its mixtures.
  • hydrophilic phase The following can be mentioned as the hydrophilic phase:
  • Alcohols such as e.g. Propylene glycol, glycerin, sorbitol and their mixtures.
  • nonionic surfactants e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;
  • ampholytic surfactants such as di-Na-N-lauryl- ⁇ -iminodipropionate or lecithin;
  • anionic surfactants such as Na lauryl sulfate.
  • auxiliaries substances which increase viscosity and stabilize the emulsion, such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic,
  • Polyvinylpyrrolidone polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silica or mixtures of the substances listed.
  • Suspensions can be used orally, dermally or as an injection. They are produced by suspending the active ingredient in a carrier liquid, optionally with the addition of further auxiliaries such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants, and light stabilizers.
  • the surfactants specified above may be mentioned as wetting agents (dispersants).
  • Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only in their higher viscosity.
  • the active ingredient is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and brought into the desired shape.
  • Inorganic and organic substances serve as such.
  • Inorganic substances are, for example Table salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, phosphates.
  • Organic substances are e.g. Sugar, cellulose, food and animal feed such as milk powder, animal meal, cereal flour and meal, starches.
  • Excipients are preservatives, antioxidants, dyes, which have already been listed above.
  • auxiliaries are lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinylpyrrolidone as well as dry binders such as microcrystalline cellulose.
  • lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinylpyrrolidone as well as dry binders such as microcrystalline cellulose.
  • the active substances can also be present in the preparations as a mixture with synergists or with other active substances which act against pathogenic endoparasites.
  • Such agents are e.g. L-2,3,5,6-tetrahydro-6-phenyl-imidazothiazole, benzimidazole carbamate, praziquantel, pyrantel, febantel.
  • Ready-to-use preparations contain the active ingredient in concentrations of 10 ppm - 20 percent by weight, preferably 0.1-10 percent by weight.
  • Preparations which are diluted before use contain the active ingredient in concentrations of 0.5-90% by weight, preferably 5 to 50% by weight.

Abstract

The invention relates to new substituted cyclooctadepsipeptides of formula (I) wherein R<1>, R<2>, 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

Substituierte CyclooctadepsipeptideSubstituted cyclooctadepsipeptides
Die Erfindung betrifft neue substituierte Cyclooctadepsipeptide, Verfahren zu ihrer Herstellung und ihre Verwendung zur Bekämpfung von Parasiten, insbesondere Helminthen in der Tier- und Humanmedizin und Zwischenprodukte zu ihrer Herstellung.The invention relates to new substituted cyclooctadepsipeptides, processes for their preparation and their use for controlling parasites, in particular helminths in veterinary and human medicine, and intermediates for their preparation.
In der Literatur sind verschiedene Cyclodepsipeptide mit antiparasitärer Wirkung beschrieben. Aus der EP 382 173 A2 ist ein Cyclooctadepsipeptid mit der Bezeichnung PF1022 bekannt. Aus den EP 626 376 AI, EP 634 408 AI und EP 718 293 AI sind weitere 24-gliedrige Cyclodepsipeptide bekannt. Deren anthelmintische Wirkung ist nicht in allen Fällen befriedigend. Aus WO 96/11 945 ist ein Verfahren zur Sulfonylierung von Depsipeptiden bekannt. Es sind daraus jedoch keine einheitlichen Verbindungen bekannt.Various cyclodepsipeptides with antiparasitic activity have been described in the literature. A cyclooctadepsipeptide with the name PF1022 is known from EP 382 173 A2. From EP 626 376 AI, EP 634 408 AI and EP 718 293 AI further 24-membered cyclodepsipeptides are known. Their anthelmintic effect is not satisfactory in all cases. A method for sulfonylating depsipeptides is known from WO 96/11 945. However, no unified connections are known from this.
1. Es wurden neue Cyclooctadepsipeptide der Formel (I)1. New cyclooctadepsipeptides of the formula (I)
Figure imgf000003_0001
Figure imgf000003_0001
εefunden. in welcherfound. in which
R.1 in ortho- oder para-Stellung für Sulfonylreste der FormelR.1 in the ortho or para position for sulfonyl radicals of the formula
-SO -A steht,-SO -A stands,
R2 in ortho- oder para-Stellung für Sulfonylreste der FormelR2 in the ortho or para position for sulfonyl radicals of the formula
-SO2-A steht,-SO 2 -A stands,
wobei A für folgende Reste steht:where A stands for the following residues:
Amino, Mono- oder Dialkylamino mit 1 bis 4 C-Atomen pro Alkylteil. Bis(hydroxyalkyl)amino mit 1-4 C-Atomen in Alkylteil, Bis(alkoxyalkyl)- amino mit 1 bis 4 C-Atomen pro Alkoxy- oder Alkylteil, Mono- oder Di-Cι_4-alkylamino, das durch Phenyl, Furyl, Morpholinyl oder Pyridyl substituiert ist;Amino, mono- or dialkylamino with 1 to 4 carbon atoms per alkyl part. Bis (hydroxyalkyl) amino with 1-4 C-atoms in the alkyl part, bis (alkoxyalkyl) - amino with 1 to 4 C-atoms per alkoxy or alkyl part, mono- or di-Cι_4-alkylamino by phenyl, furyl, morpholinyl or pyridyl is substituted;
ferner für über Stickstoff gebundene gesättigte 5- oder 6-gliedrige Hetero- cyclen, die neben N 1 oder 2 weitere Heteroatome der Reihe O oder N enthalten können und die gegebenenfalls substituiert sind;furthermore for saturated 5- or 6-membered heterocycles bonded via nitrogen, which may contain, in addition to N 1 or 2, further heteroatoms of the O or N series and which are optionally substituted;
ferner für über Stickstoff gebundene ungesättigte Heterocyclen aus der Reihe Pyrazol, Imidazol, Pyrrol, 1 ,2,4-Triazol, 1,2,3-Triazol, die gegebenenfalls substituiert sein können,also for nitrogen-bound unsaturated heterocycles from the series pyrazole, imidazole, pyrrole, 1, 2,4-triazole, 1,2,3-triazole, which may optionally be substituted,
n für 0, 1 oder 2, m für 1 oder 2 steht.n stands for 0, 1 or 2, m stands for 1 or 2.
Als Substituenten für die gegebenenfalls substituierten Reste seien genannt Cj_4- Alkyl. Acyl wie Cj.4-Alkylcarbonyl, Benzoyl, C]_4-Alkoxycarbonyl. Es wurde auch ein Verfahren zur Herstellung der Verbindungen der Formel (I)C 1 -C 4 -alkyl may be mentioned as substituents for the optionally substituted radicals. Acyl such as Cj. 4- alkylcarbonyl, benzoyl, C ] _ 4 -alkoxycarbonyl. A process for the preparation of the compounds of formula (I)
Figure imgf000005_0001
in welcher R^ , R^ und m und n die oben angegebenen Bedeutungen haben,
Figure imgf000005_0001
in which R ^, R ^ and m and n have the meanings given above,
gefunden, dadurch gekennzeichnet, daß man die Verbindung PF 1022 der Formelfound, characterized in that the compound PF 1022 of the formula
Figure imgf000005_0002
mit einer Halogensulfonsäure oder mit Sulfurylchlorid oder Schwefeldioxid/Chlor umsetzt und die dabei erhältlichen halogensulfonylierten Verbindungen durch Umsetzung mit Verbindungen der Formel
Figure imgf000005_0002
with a halogen sulfonic acid or with sulfuryl chloride or sulfur dioxide / chlorine and the halogen sulfonylated compounds obtainable by reaction with compounds of the formula
H - A, in welcherH - A, in which
A die oben angegebene Bedeutung hat,A has the meaning given above,
weiter umsetzt.continues to implement.
Die erfindungsgemäßen Verbindungen der Formel (I) sind hervorragend zur Bekämpfung von Helminthen in der Tier- und Humanmedizin geeignet.The compounds of the formula (I) according to the invention are outstandingly suitable for controlling helminths in veterinary and human medicine.
Bevorzugt sind Verbindungen der Formel (I),Compounds of the formula (I) are preferred
in welcherin which
R1 für -SO2-A steht,R 1 represents -SO 2 -A,
n und m für 1 stehen,n and m stand for 1,
R2 für Wasserstoff oder - SO2-A steht,R 2 represents hydrogen or - SO 2 -A,
und die Reste R1 und/oder R2 in para-Stellung stehen.and the radicals R 1 and / or R 2 are in the para position.
A steht bevorzugt für Amino, Mono- oder Dimethyl-, Diethyl-, Diisopropyl- amino, N-Mono- oder N,N-Bis(ethoxymethyl)amino, -(hydroxyethyl)amino, -(ethoxyethyl)amino, -(methoxyethyl)amino, Mono- oder Dibenzylamino.A preferably represents amino, mono- or dimethyl-, diethyl-, diisopropyl-amino, N-mono- or N, N-bis (ethoxymethyl) amino, - (hydroxyethyl) amino, - (ethoxyethyl) amino, - (methoxyethyl) amino, mono- or dibenzylamino.
Mono- oder Bis(phenylethyl)amino, Mono- oder Bis(pyridylmethyl)amino, Mono- oder Bis(pyridylethyl)amino, Mono- oder Bis(morpholinylethyl)- amino, Furfurylamino, N-Furfuryl-N-methylamino, Morpholino-, 1-Pipera- zinyl-, 1-Pyrazolyl-, 1 -Pyrrolidinyl, 1-Piperidinyl, die gegebenenfalls durch Methyl. Ethyl, Acyl wie Acetyl, Benzoyl, Ethoxycarbonyl oder Methoxy- carbonvl substituiert sind. Bevorzugt sind auch Verbindungen der Formel (I), in welcherMono- 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, 1-piperidinyl, optionally substituted by methyl. Ethyl, acyl such as acetyl, benzoyl, ethoxycarbonyl or methoxycarbonvl are substituted. Preference is also given to compounds of the formula (I) in which
R1 und R2 für den Rest -SO2-A in para-Stellung stehen, wobei A für 1-Piperazinyl steht, das gegebenenfalls einfach durch Cj^-Alkylcarbonyl oder Cj„4-Alkoxycarbonyl substituiert ist, ferner für Amino, Mono- Cι_ -Alkyl- amino, dessen Alkylteil gegebenenfalls einfach durch Morpholino, Furyl oder Pyridyl substituiert ist, Di-Cj.4-Alkylamino, ferner für 1 -Pyrrolidinyl oder 1- Piperidinyl steht.R 1 and R 2 stand for the radical -SO 2 -A in the para position, where A stands for 1-piperazinyl, which is optionally simply substituted by C j ^ alkylcarbonyl or C j " 4 alkoxycarbonyl, furthermore amino, Mono- Cι_ alkyl amino, the alkyl part is optionally simply substituted by morpholino, furyl or pyridyl, Di-Cj. 4 -alkylamino, furthermore 1-pyrrolidinyl or 1-piperidinyl.
Die neuen substituierten cyclischen Depsipeptide der Formel (I) sowie deren Säure- additions-Salze und Metallsalz-Komplexe besitzen sehr gute anthelminthische Eigenschaften und können bevorzugt im Bereich der Veterinärmedizin eingesetzt werden. Überraschenderweise zeigen sie bei der Bekämpfung von Wurmerkrankungen eine bessere Wirksamkeit als konstitutionell ähnliche, vorbekannte Verbindungen gleicherThe 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, they are more effective in combating worm diseases than constitutionally similar, known compounds of the same type
Wirkungsrichtung.Direction of action.
Zu ihrer Herstellung wird zunächst die bekannte Verbindung PF 1022 der folgenden FormelThe known compound PF 1022 of the following formula is first used for its preparation
Figure imgf000007_0001
mit Halogensulfonsäuren (HalS03H), insbesondere Chlorsulfonsäure oder mit Sulfurylchlorid oder Schwefeldioxid/Chlor gegebenenfalls in einem gegen die Rea- genzien inerten Verdünnungsmittel sowie gegebenenfalls in Gegenwart von Lewis-Säuren umgesetzt.
Figure imgf000007_0001
with halosulfonic acids (HalS0 3 H), in particular chlorosulfonic acid or with sulfuryl chloride or sulfur dioxide / chlorine, optionally in one against the reaction genetically inert diluent and optionally in the presence of Lewis acids.
Die Umsetzung erfolgt bei Temperaturen von 0 bis 150°C, bevorzugt bei 0 bis 80°C, besonders bevorzugt bei 0 bis 60°C.The reaction takes place at temperatures from 0 to 150 ° C., preferably at 0 to 80 ° C., particularly preferably at 0 to 60 ° C.
Als Verdünnungsmittel kommen alle gegenüber den Reagenzien inerten organischen Lösungsmittel in Frage. Hierzu gehören insbesondere aliphatische und aromatische, gegebenenfalls halogenierte Kohlenwasserstoffe, wie Pentan, Hexan, Heptan, Cyclo- hexan. Petrolether, Benzin, Ligroin, Benzol, Toluol, Methylenchlorid, Ethylen- chlorid. Chloroform, Tetrachlorkohlenstoff, Chlorbenzol und o-Dichlorbenzol, ferner Ether wie Diethyl- und Dibutylether, Glykoldimethylether und Diglykoldimethyl- ether. Tetrahydrofuran und Dioxan, weiterhin Ketone, wie Aceton, Methylether-, Methylisopropyl- und Methylisobutylketon, außerdem Ester, wie Essigsäure- methylester und -ethylester, ferner Nitrile, wie z.B. Acetonitril und Propionitril,Suitable diluents are all organic solvents which are inert to the reagents. These include in particular aliphatic and aromatic, optionally halogenated hydrocarbons, such as pentane, hexane, heptane, cyclohexane. Petroleum ether, gasoline, ligroin, benzene, toluene, methylene chloride, ethylene chloride. Chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, furthermore ethers such as diethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether. Tetrahydrofuran and dioxane, furthermore ketones, such as acetone, methyl ether, methyl isopropyl and methyl isobutyl ketone, also esters, such as methyl acetate and ethyl acetate, and also nitriles, e.g. Acetonitrile and propionitrile,
Benzonitril, Glutarsäuredinitril, darüberhinaus Amide, wie z.B. Dimethylformamid, Dimethylacetamid und N-Methylpyrrolidon, sowie Dimethylsulfoxid, Tetra- methylensulfon und Hexamethylphosphorsäuretriamid.Benzonitrile, glutaronitrile, and also amides, e.g. Dimethylformamide, dimethylacetamide and N-methylpyrrolidone, as well as dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric acid triamide.
Die Depsipeptide werden mit einem Überschuß Reagenz (5 bis 10 Äquivalente) und einem Überschuß Lewis-Säure (15 bis 20 Äquivalente) umgesetzt.The depsipeptides are reacted with an excess of reagent (5 to 10 equivalents) and an excess of Lewis acid (15 to 20 equivalents).
Die in dieser Stufe erhältlichen Halogensulfone, insbesondere Chlorsulfone, sind Verbindungen der Formel (I), in welcher die Reste R1 und/oder R2 für den Rest -S02-Halogen, insbesondere -SO2-Cl stehen.The halogen sulfones, in particular chlorosulfones, obtainable in this stage are compounds of the formula (I) in which the radicals R 1 and / or R 2 represent the radical -S0 2 -halogen, in particular -SO 2 -Cl.
Diese Verbindungen werden anschließend mit Aminen der FormelThese compounds are then with amines of the formula
A - H gegebenenfalls in Gegenwart eines Verdünnungsmittels sowie gegebenenfalls in Gegenwart von Basen umgesetzt.A - H if appropriate in the presence of a diluent and if appropriate in the presence of bases.
Als Verdünnungsmittel für die Umsetzung der Halogensulfone kommen die weiter oben genannten Verdünnungsmittel in Frage. Als Basen wird entweder das Amin derThe diluents mentioned above are suitable as diluents for the implementation of the halogen sulfones. Either the amine is used as the base
Forml A-H im Überschuß eingesetzt oder es werden Alkalihydroxide, Alkali- oder Erdalkalicarbonate oder tertiäre, aliphatische oder aromatische Amine eingesetzt.Forml A-H is used in excess or alkali metal hydroxides, alkali metal or alkaline earth metal carbonates or tertiary, aliphatic or aromatic amines are used.
Die zweite Stufe der Umsetzung erfolgt entweder nachdem das Produkt der ersten Stufe isoliert und gereinigt wurde oder sofort im Anschluß an die erste Stufe. Es wird bei Temperaturen von -10 bis +150°C, bevorzugt zwischen -5°C und +20°C, gearbeitet. Es wird bei Normaldruck gearbeitet.The second stage of the reaction takes place either after the product of the first stage has been isolated and purified, or immediately after the first stage. It is carried out at temperatures from -10 to + 150 ° C, preferably between -5 ° C and + 20 ° C. It is operated at normal pressure.
Die Verbindung PF 1022 kann auch mit Schwefelsäure (Oleum) zur entsprechend -SO OH substituierten Verbindung umgesetzt werden. Diese Verbindung kann anschließend mit einem Halogenierungsmittel zum entsprechenden Halogensulfon umgesetzt werden. Das Halogensulfon wird dann, wie oben beschrieben, mit Aminen zu den entsprechenden Sulfonamiden umgesetzt.The compound PF 1022 can also be reacted with sulfuric acid (oleum) to give the corresponding -SO OH substituted compound. This compound can then be reacted with a halogenating agent to give the corresponding halogen sulfone. The halogen sulfone is then reacted with amines to the corresponding sulfonamides as described above.
Nach erfolgter Umsetzung wird das Verdünnungsmittel abdestilliert und die Verbindungen der Formel (I) in üblicher Weise, z.B. chromatographisch, gereinigt.After the reaction has taken place, the diluent is distilled off and the compounds of the formula (I) are reacted in the customary manner, e.g. chromatographically, cleaned.
Die Wirkstoffe eignen sich bei günstiger Warmblütertoxizität zur Bekämpfung von pathogenen Endoparasiten, die bei Menschen und in der Tierhaltung und Tierzucht bei Nutz-, Zucht-, Zoo-, Labor-, Versuchs- und Hobbytieren vorkommen. Sie sind dabei gegen alle oder einzelne Entwicklungsstadien der Schädlinge sowie gegen resistente und normal sensible Arten wirksam. Durch die Bekämpfung der pathogenen Endoparasiten sollen Krankheit. Todefälle und Leistungsminderungen (z.B. bei der Produktion von Fleisch, Milch. Wolle, Häuten, Eiern, Honig usw.) vermin- dert werden, so daß durch den Einsatz der Wirkstoffe eine wirtschaftlichere und ein- fächere Tierhaltung möglich ist. Zu den pathogenen Endoparsiten zählen Cesthoden, Trematoden, Nematoden, Acantocephalen insbesondere:The active ingredients are suitable for combating pathogenic endoparasites, which occur in humans and in animal husbandry and animal breeding in useful, breeding, zoo, laboratory, experimental and hobby animals, with favorable warm-blooded toxicity. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive species. By fighting the pathogenic endoparasites, disease. Deaths and reduced performance (for example in the production of meat, milk, wool, skins, eggs, honey, etc.) are reduced, so that the use of the active ingredients results in a more economical and more specialized animal husbandry is possible. Pathogenic endoparsites include cesthodes, trematodes, nematodes, acantocephals in particular:
Aus der Ordnung der Pseudophyllidea z.B.: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoporus spp..From the order of the Pseudophyllidea, for example: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoporus spp ..
Aus der Ordnung der Cyclophyllidea z.B.: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitel- lina spp., Stilesia spp., Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp..From the order of the Cyclophyllidea, for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitelellina spp., Stilesia spp., Cittotaenia spp., Andyella spp., Bertella spp spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplop. .
Aus der Unterklasse der Monogenea z.B.: Gyrodactylus spp., Dactylogyrus spp., Polystoma spp..From the subclass of Monogenea e.g. Gyrodactylus spp., Dactylogyrus spp., Polystoma spp ..
Aus der Unterklasse der Digenea z.B.: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciola sppFrom the subclass of Digenea, for example: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinopin spp., Echinopin spp., Hypoderaeum spp., Fasciola spp
Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp Paramphistomum spp., Calicophoron spp-, Cotylophoron spp., Gigantocotyle spp Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., Eurytrema spp Troglotrema spp., Paragonimus spp., Collyriclum spp., Nanophyetus spp.,Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp Paramphistomum spp., Calicophoron spp-, Cotylophoron spp., Gigantocotyle spp Fischoederius spp., Gastrothylacus spp., Notocotatropus spp., Cat. Spp., Cat. Dicrocoelium spp., Eurytrema spp. Troglotrema spp., Paragonimus spp., Collyriclum spp., Nanophyetus spp.,
Opisthorchis spp., Clonorchis spp. Metorchis spp., Heterophyes spp., Metagonimus spp..Opisthorchis spp., Clonorchis spp. Metorchis spp., Heterophyes spp., Metagonimus spp ..
Aus der Ordnung der Enoplida z.B.: Trichuris spp., CapiUaria spp., Trichomosoides spp., Trichinella spp.. Aus der Ordnung der Rhabditia z.B.: Micronema spp., Strongyloides spp..From the order of the Enoplida, for example: Trichuris spp., CapiUaria spp., Trichomosoides spp., Trichinella spp .. From the order of the Rhabditia, for example: Micronema spp., Strongyloides spp ..
Aus der Ordnung der Strongylida z.B.: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostomum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus 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., 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 Strongylida, for example: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostomum spp., Cyclococercus spp., Cylicostephanus sppum, spp., Oesophag. , Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostr spp., Pneumostrongylus 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., Cooperemat. Spp., Marshallemat ., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp ..
Aus der Ordnung der Oxyurida z.B.: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp..From the order of the Oxyurida, for example: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp ..
Aus der Ordnung der Ascaridia z.B.: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp..From the order of Ascaridia, for example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp ..
Aus der Ordnung der Spirurida z.B.: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracun- culus 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 ..
Aus der Ordnung der Filariida z.B.: Stephanofilaria spp., Parafilaria spp., Setaria spp.. Loa spp.. Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp.. Onchocerca spp..From the order of the Filariida, for example: Stephanofilaria spp., Parafilaria spp., Setaria spp .. Loa spp .. Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp .. Onchocerca spp ..
Aus der Ordnung der Gigantorhynchida z.B.: Filicollis spp., Moniliformis spp.. Macracanthorhynchus spp., Prosthenorchis spp.. Zu den Nutz- und Zuchttieren gehören Säugetiere wie z.B. Rinder, Pferde, Schafe, Schweine, Ziegen, Kamele, Wasserbüffel, Esel, Kaninchen, Damwild, Rentiere, Pelztiere wie z.B. Nerze, Chinchilla, Waschbär, Vögel wie z.B. Hühner, Gänse, Puten, Enten, Süß- und Salzwasserfische wie z.B. Forellen, Karpfen, Aale, Reptilien.From the order of the Gigantorhynchida, for example: Filicollis spp., Moniliformis spp. Macracanthorhynchus spp., Prosthenorchis spp .. The livestock and breeding animals include mammals such as cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as mink, chinchilla, raccoon, birds such as chickens, geese, turkeys, Ducks, freshwater and saltwater fish such as trout, carp, eels, reptiles.
Insekten wie z.B. Honigbiene und Seidenraupe.Insects such as Honey bee and silkworm.
Zu Labor- und Versuchstieren gehören Mäuse, Ratten, Meerschweinchen, Goldhamster. Hunde und Katzen.Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters. Dogs and cats.
Zu den Hobbytieren gehören Hunde und Katzen.The pets include dogs and cats.
Die Anwendung kann sowohl prophylaktisch als auch therapeutisch erfolgen.The application can be prophylactic as well as therapeutic.
Die Anwendung der Wirkstoffe erfolgt direkt oder in Form von geeigneten Zube- reitungen enteral, parenteral, dermal, nasal, durch Behandlung der Umgebung oder mit Hilfe wirkstoffhaltiger Formkörper wie z.B. Streifen, Platten, Bänder, Halsbänder. Ohrmarken, Gliedmaßenbänder, Markierungsvorrichtungen.The active ingredients are used directly or in the form of suitable preparations enterally, parenterally, dermally, nasally, by treating the environment or with the aid of shaped articles containing the active ingredient, e.g. Strips, plates, ribbons, collars. Ear tags, limb straps, marking devices.
Die enterale Anwendung der Wirkstoffe geschieht z.B. oral in Form von Pulver. Tabletten, Kapseln, Pasten, Tränken, Granulaten, oral applizierbaren Lösungen.The enteral application of the active ingredients takes place e.g. orally in the form of powder. Tablets, capsules, pastes, drinkers, granules, orally applicable solutions.
Suspensionen und Emulsionen, Boli, medikiertem Futter oder Trinkwasser. Die dermale Anwendung geschieht z.B. in Form des Tauchens (Dippen), Sprühens (Sprayen) oder Aufgießens (pour-on and spot-on). Die parenterale Anwendung geschieht z.B. in Form der Injektion (intramusculär, subcutan, intravenös, intra- peritoneal) oder durch Implantate.Suspensions and emulsions, boluses, medicated feed or drinking water. The dermal application happens e.g. in the form of diving (dipping), spraying (spraying) or pouring on (pour-on and spot-on). Parenteral use happens e.g. in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants.
Geeignete Zubereitungen sind:Suitable preparations are:
Lösungen wie Injektionslösungen, orale Lösungen, Konzentrate zur oralen Verab- reichung nach Verdünnung, Lösungen zum Gebrauch auf der Haut oder in Körperhöhlen. Aufguß formulierungen, Gele; Emulsionen und Suspension zur oralen oder dermalen Anwendung sowie zur Injektion; Halbfeste Zubereitungen;Solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities. Infusion formulations, gels; Emulsions and suspensions for oral or dermal use and for injection; Semi-solid preparations;
Formulierungen bei denen der Wirkstoff in einer Salbengrundlage oder in einer Öl inFormulations in which the active ingredient in an ointment base or in an oil in
Wasser oder Wasser in Öl Emulsionsgrundlage verarbeitet ist;Water or water in oil emulsion base is processed;
Feste Zubereitungen wie Pulver, Premixe oder Konzentrate, Granulate, Pellets, Tabletten, Boli, Kapseln; Aerosole und Inhalate, wirkstoffhaltige Formkörper.Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; Aerosols and inhalants, molded articles containing active ingredients.
Injektionslösungen werden intravenös, intramuskulär und subcutan verabreicht.Solutions for injection are administered intravenously, intramuscularly and subcutaneously.
Injektionslösungen werden hergestellt, indem der Wirkstoff in einem geeigneten Lösungsmittel gelöst wird und eventuell Zusätze wie Lösungsvermittler, Säuren, Basen, Puffersalze, Antioxidantien, Konservierungsmittel zugefügt werden. DieInjection solutions are prepared by dissolving the active ingredient in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives. The
Lösungen werden steril filtriert und abgefüllt.Solutions are sterile filtered and filled.
Als Lösungsmittel seien genannt: Physiologisch verträgliche Lösungsmittel wie Wasser, Alkohole wie Ethanol, Butanol, Benzylakohol, Glycerin, Propylenglykol, Polyethylenglykole, N-Methyl-pyrrolidon, sowie Gemische derselben.The following may be mentioned as solvents: physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone, and mixtures thereof.
Die Wirkstoffe lassen sich gegebenenfalls auch in physiologisch verträglichen pflanzlichen oder synthetischen Ölen, die zur Injektion geeignet sind, lösen.If appropriate, the active compounds can also be dissolved in physiologically tolerable vegetable or synthetic oils which are suitable for injection.
Als Lösungs Vermittler seien genannt: Lösungsmittel, die die Lösung des Wirkstoffs im Hauptlösungsmittel fördern oder sein Ausfallen verhindern. Beispiele sind Polyvi- nylpyrrolidon, polyoxyethyliertes Rhizinusöl, polyoxyethylierte Sorbitanester.The following may be mentioned as solution mediators: solvents which promote the dissolution of the active ingredient in the main solvent or prevent its precipitation. Examples are polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.
Konservierungsmittel sind: Benzylalkohol, Trichlorbutanol, p-Hydroxybenzoesäure- ester. n-Butanol. Orale Lösungen werden direkt angewendet. Konzentrate werden nach vorheriger Verdünnung auf die Anwendungskonzentration oral angewendet. Orale Lösungen und Konzentrate werden wie oben bei den Injektionslösungen beschrieben hergestellt, wobei auf steriles Arbeiten verzichtet werden kann.Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester. n-butanol. Oral solutions are applied directly. Concentrates are used orally after previous dilution to the application concentration. Oral solutions and concentrates are prepared as described above for the injection solutions, whereby sterile work can be dispensed with.
Lösungen zum Gebrauch auf der Haut werden aufgeträufelt, aufgestrichen, eingerieben, aufgespritzt oder aufgesprüht. Diese Lösungen werden wie oben bei den Injektionslösungen beschrieben hergestellt.Solutions for use on the skin are dripped on, spread on, rubbed in, sprayed on or sprayed on. These solutions are prepared as described above for the injection solutions.
Es kann vorteilhaft sein, bei der Herstellung Verdickungsmittel zuzufügen. Ver- dickungsmittel sind: Anorganische Verdickungsmittel wie Bentonite, kolloidale Kieselsäure, Aluminiummonostearat, organische Verdikkungsmittel wie Cellulose- derivate, Polyvinylalkohole und deren Copolymere, Acrylate und Metacrylate.It may be advantageous to add thickeners during manufacture. Thickeners are: inorganic thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates.
Gele werden auf die Haut aufgetragen oder aufgestrichen oder in Körperhöhlen eingebracht. Gele werden hergestellt indem Lösungen, die wie bei den Injektionslösungen beschrieben hergestellt worden sind, mit soviel Verdickungsmittel versetzt werden, daß eine klare Masse mit salbenartiger Konsistenz entsteht. Als Verdickungsmittel werden die weiter oben angegebenen Verdickungsmittel eingesetzt.Gels are applied to or spread on the skin or placed in body cavities. Gels are produced by adding sufficient thickening agent to solutions which have been prepared as described for the injection solutions to produce a clear mass with an ointment-like consistency. The thickeners specified above are used as thickeners.
Aufgieß-Formulierungen werden auf begrenzte Bereiche der Haut aufgegossen oder aufgespritzt, wobei der Wirkstoff die Haut durchdringt und systemisch wirkt.Pour-on formulations are poured or sprayed onto limited areas of the skin, the active ingredient penetrating the skin and acting systemically.
Aufgieß-Formulierungen werden hergestellt, indem der Wirkstoff in geeigneten haut- verträglichen Lösungsmitteln oder Lösungsmittelgemischen gelöst, suspendiert oder emulgiert wird. Gegebenenfalls werden weitere Hilfsstoffe wie Farbstoffe, resorp- tionsfördernde Stoffe, Antioxidantien, Lichtschutzmittel, Haftmittel zugefügt.Pour-on formulations are prepared by dissolving, suspending or emulsifying the active ingredient in suitable solvents or solvent mixtures that are compatible with the skin. If necessary, other auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers and adhesives are added.
Als Lösungsmittel seien genannt: Wasser, Alkanole, Glycole, Polyethylenglycole, Polypropylenglycole, Glycerin, aromatische Alkohole wie Benzylalkohol, Phenyl- ethanol. Phenoxyethanol, Ester wie Essigester, Butylacetat, Benzylbenzoat, Ether wie Alkylenglykolalkylether wie Dipropylenglykolmonomethylether, Diethylenglykol- mono-butylether, Ketone wie Aceton, Methylethylketon, aromatische und/oder aliphatische Kohlenwasserstoffe, pflanzliche oder synthetische Öle, DMF, Dimethyl- acetamid, N-Methylpyrrolidon, 2,2-Dimethyl-4-oxy-methylen- 1 ,3-dioxolan.The following may be mentioned as solvents: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol. Phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as Alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethyl acetamide, N-methyl pyrrolidone, 2,2-dimethyl-4-oxy-methylene 1,3-dioxolane.
Farbstoffe sind alle zur Anwendung am Tier zugelassenen Farbstoffe, die gelöst oder suspendiert sein können.Dyes are all dyes approved for use on animals, which can be dissolved or suspended.
Resorptionsfördernde Stoffe sind z.B. DMSO, spreitende Öle wie Isopropylmyristat, Dipropylenglykolpelargonat, Silikonöle, Fettsäureester, Triglyceride, Fettalkohole.Absorbing substances are e.g. DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.
Antioxidantien sind Sulfite oder Metabisulfite wie Kaliummetabisulfit, Ascorbin- säure, Butylhydroxytoluol, Butylhydroxyanisol, Tocopherol.Antioxidants are sulfites or metabisulfites such as potassium metabisulfite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.
Lichtschutzmittel sind z.B. Novantisolsäure.Light stabilizers are e.g. Novantisol acid.
Haftmittel sind z.B. Cellulosederivate, Stärkederivate, Polyacrylate, natürliche Polymere wie Alginate, Gelatine.Adhesives are e.g. Cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.
Emulsionen können oral, dermal oder als Injektionen angewendet werden.Emulsions can be used orally, dermally or as injections.
Emulsionen sind entweder vom Typ Wasser in Öl oder vom Typ Öl in Wasser.Emulsions are either water in oil or oil in water.
Sie werden hergestellt, indem man den Wirkstoff entweder in der hydrophoben oder in der hydrophilen Phase löst und diese unter Zuhilfenahme geeigneter Emulgatoren und gegebenenfalls weiterer Hilfsstoffe wie Farbstoffe, resorptionsfördernde Stoffe, Konservierungsstoffe, Antioxidantien, Lichtschutzmittel, viskositätserhöhende Stoffe, mit dem Lösungsmittel der anderen Phase homogenisiert.They are produced by dissolving the active ingredient either in the hydrophobic or in the hydrophilic phase and homogenizing it with the solvent of the other phase with the aid of suitable emulsifiers and, if necessary, other auxiliary substances such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers, viscosity-increasing substances .
Als hydrophobe Phase (Öle) seien genannt: Paraffinöle, Silikonöle, natürlicheThe following may be mentioned as the hydrophobic phase (oils): paraffin oils, silicone oils, natural ones
Pflanzenöle wie Sesamöl, Mandelöl, Rizinusöl, synthetische Triglyceride wie Capryl Caprinsäure-bigylcerid, Triglyceridgemisch mit Pflanzenfettsäuren der Kettenlänge Cg_i 2 oder anderen speziell ausgewählten natürlichen Fettsäuren, Par- tialglyceridgemische gesättigter oder ungesättigter eventuell auch hydroxylgrup- penhaltiger Fettsäuren, Mono- und Diglyceride der Cg/Ci Q-Fettsäuren.Vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as Capryl capric acid bigylceride, triglyceride mixture with vegetable fatty acids of chain length Cg_i 2 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids, which may also contain hydroxyl groups, mono- and diglycerides of Cg / Ci Q fatty acids.
Fettsäureester wie Ethylstearat, Di-n-butyryl-adipat, Laurinsäurehexylester, Dipro- pylen-glykolpelargonat, Ester einer verzweigten Fettsäure mittlerer Kettenlänge mit gesättigten Fettalkoholen der Kettenlänge Ci ö-Cj , Isopropylmyristat, Isopropyl- palmitat, Capryl/Caprinsäureester von gesättigten Fettalkoholen der Kettenlänge C12-C18, Isopropylstearat, Ölsäureoleylester, Ölsäuredecylester, Ethyloleat, Milch- säureethylester, wachsartige Fettsäureester wie künstliches Entenbürzeldrüsenfett, Dibutylphthalat, Adipinsäurediisopropylester, letzterem verwandte Estergemische u.a.Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length Ci ö-Cj, isopropyl myristate, isopropyl palmitate, caprylic / capric alcohol esters of the saturated fatty length C12-C18, isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duck pancreas fat, dibutyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures and others
Fettalkohole wie Isotridecylalkohol, 2-Octyldodecanol, Cetylstearyl-alkohol, Oleyl- alkohol.Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.
Fettsäuren wie z.B. Ölsäure und ihre Gemische.Fatty acids such as Oleic acid and its mixtures.
Als hydrophile Phase seien genannt:The following can be mentioned as the hydrophilic phase:
Wasser, Alkohole wie z.B. Propylenglycol, Glycerin, Sorbitol und ihre Gemische.Water, alcohols such as e.g. Propylene glycol, glycerin, sorbitol and their mixtures.
Als Emulgatoren seien genannt: nichtionogene Tenside, z.B. polyoxyethyliertes Rizinusöl, polyoxyethyliertes Sorbitan-monooleat, Sorbitanmonostearat, Glycerin- monostearat, Polyoxyethylstearat, Alkylphenolpolyglykolether;The following may be mentioned as emulsifiers: nonionic surfactants, e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;
ampholytische Tenside wie Di-Na-N-lauryl-ß-iminodipropionat oder Lecithin;ampholytic surfactants such as di-Na-N-lauryl-β-iminodipropionate or lecithin;
anionaktive Tenside, wie Na-Laurylsulfat. Fettalkoholethersulfate, Mono/Dialkyl- polyglykoletherorthophosphorsäureester-monoethanolaminsalz; kationaktive Tenside wie Cetyltrimethylammoniumchlorid.anionic surfactants such as Na lauryl sulfate. Fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt; cationic surfactants such as cetyltrimethylammonium chloride.
Als weitere Hilfsstoffe seien genannt: Viskositätserhöhende und die Emulsion stabilisierende Stoffe wie Carboxymethylcellulose, Methylcellulose und andere Cellulose- und Stärke-Derivate, Polyacrylate, Alginate, Gelatine, Gummi-arabicum,The following may be mentioned as further auxiliaries: substances which increase viscosity and stabilize the emulsion, such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic,
Polyvinylpyrrolidon, Polyvinylalkohol, Copolymere aus Methylvinylether und Maleinsäureanhydrid, Polyethylenglykole, Wachse, kolloidale Kieselsäure oder Gemische der aufgeführten Stoffe.Polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silica or mixtures of the substances listed.
Suspensionen können oral, dermal oder als Injektion angewendet werden. Sie werden hergestellt, indem man den Wirkstoff in einer Trägerflüssigkeit gegebenenfalls unter Zusatz weiterer Hilfsstoffe wie Netzmittel, Farbstoffe, resorptionsfördernde Stoffe, Konservierungsstoffe, Antioxidantien Lichtschutzmittel suspendiert.Suspensions can be used orally, dermally or as an injection. They are produced by suspending the active ingredient in a carrier liquid, optionally with the addition of further auxiliaries such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants, and light stabilizers.
Als Trägerflüssigkeiten seien alle homogenen Lösungsmittel und Lösungsmittelgemische genannt.All homogeneous solvents and solvent mixtures may be mentioned as carrier liquids.
Als Netzmittel (Dispergiermittel) seien die weiter oben angegebene Tenside genannt.The surfactants specified above may be mentioned as wetting agents (dispersants).
Als weitere Hilfsstoffe seien die weiter oben angegebenen genannt.Further additives mentioned are those mentioned above.
Halbfeste Zubereitungen können oral oder dermal verabreicht werden. Sie unterscheiden sich von den oben beschriebenen Suspensionen und Emulsionen nur durch ihre höhere Viskosität.Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only in their higher viscosity.
Zur Herstellung fester Zubereitungen wird der Wirkstoff mit geeigneten Trägerstoffen gegebenenfalls unter Zusatz von Hilfsstoffen vermischt und in die gewünschte Form gebracht.To prepare solid preparations, the active ingredient is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and brought into the desired shape.
Als Trägerstoffe seien genannt alle physiologisch verträglichen festen Inertstoffe. Als solche dienen anorganische und organische Stoffe. Anorganische Stoffe sind z.B. Kochsalz, Carbonate wie Calciumcarbonat, Hydrogencarbonate, Aluminiumoxide, Kieselsäuren, Tonerden, gefälltes oder kolloidales Siliciumdioxid, Phosphate.All physiologically compatible solid inert substances may be mentioned as carriers. Inorganic and organic substances serve as such. Inorganic substances are, for example Table salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, phosphates.
Organische Stoffe sind z.B. Zucker, Zellulose, Nahrungs-und Futtermittel wie Milchpulver, Tiermehle, Getreidemehle und -schrote, Stärken.Organic substances are e.g. Sugar, cellulose, food and animal feed such as milk powder, animal meal, cereal flour and meal, starches.
Hilfsstoffe sind Konservierungsstoffe, Antioxidantien, Farbstoffe, die bereits weiter oben aufgeführt worden sind.Excipients are preservatives, antioxidants, dyes, which have already been listed above.
Weitere geeignete Hilfsstoffe sind Schmier- und Gleitmittel wie z.B. Magnesium- stearat, Stearinsäure, Talkum, Bentonite, zerfallsfördernde Substanzen wie Stärke oder quervernetztes Polyvinylpyrrolidon, Bindemittel wie z.B. Stärke, Gelatine oder linerares Polyvinylpyrrolidon sowie Trockenbindemittel wie mikrokristalline Cellu- lose.Other suitable auxiliaries are lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinylpyrrolidone as well as dry binders such as microcrystalline cellulose.
Die Wirkstoffe können in den Zubereitungen auch in Mischung mit Synergisten oder mit anderen Wirkstoffe, die gegen pathogene Endoparasiten wirken, vorliegen. Solche Wirkstoffe sind z.B. L-2,3,5,6-Tetrahydro-6-phenyl-imidazothiazol, Benz- imidazolcarbamate, Praziquantel, Pyrantel, Febantel.The active substances can also be present in the preparations as a mixture with synergists or with other active substances which act against pathogenic endoparasites. Such agents are e.g. L-2,3,5,6-tetrahydro-6-phenyl-imidazothiazole, benzimidazole carbamate, praziquantel, pyrantel, febantel.
Anwendungsfertige Zubereitungen enthalten den Wirkstoff in Konzentrationen von 10 ppm - 20 Gewichtsprozent, bevorzugt von 0,1-10 Gewichtsprozent.Ready-to-use preparations contain the active ingredient in concentrations of 10 ppm - 20 percent by weight, preferably 0.1-10 percent by weight.
Zubereitungen die vor Anwendung verdünnt werden, enthalten den Wirkstoff in Konzentrationen von 0,5-90 Gew.-%, bevorzugt von 5 bis 50 Gewichtsprozent.Preparations which are diluted before use contain the active ingredient in concentrations of 0.5-90% by weight, preferably 5 to 50% by weight.
Im allgemeinen hat es sich als vorteilhaft erwiesen, Mengen von etwa 1 bis etwa 100 mg Wirkstoff je kg Körpergewicht pro Tag zur Erzielung wirksamer Ergebnisse zu verabreichen. HerstellbeispieleIn general, it has proven advantageous to administer amounts of about 1 to about 100 mg of active ingredient per kg of body weight per day in order to achieve effective results. Manufacturing examples
Beispiel aExample a
Chlorsulf onierung von PF 1022Chlorination of PF 1022
Eine Lösung des Depsipeptids PF 1022A solution of the depsipeptide PF 1022
Figure imgf000019_0001
(0,523 mmol) in Dichlormethan wird bei 0°C mit Chlorsulfonsäure (37,3 mmol) versetzt und 2 Stunden bei 0°C und 2 Stunden bei Raumtemperatur gerührt. Das Reaktionsgemisch wird ohne weitere Aufarbeitung direkt weiter umgesetzt.
Figure imgf000019_0001
(0.523 mmol) in dichloromethane is added at 0 ° C with chlorosulfonic acid (37.3 mmol) and stirred for 2 hours at 0 ° C and 2 hours at room temperature. The reaction mixture is directly reacted without further working up.
Beispiel bExample b
Allgemeine Verfahrensvorschrift zur Herstellung des Sulfonamids.General procedure for the preparation of the sulfonamide.
Das Reaktionsgemisch aus Beispiel 1 wird bei 0°C in Aceton (50 ml) eingetropft. Anschließend wird bei 0°C mit dem entsprechenden Amin (79,4 mmol) versetzt und 12 Stunden bei 60°C nachgerührt. Nach dieser Zeit wird eingeengt, in Wasser aufgenommen und mit Dichlormethan extrahiert (3 x). Die vereinigten organischen Extrakte werden über Na2SO4 getrocknet und eingeengt. Der Rückstand wird säulenchromatographisch gereinigt. Es werden Depsipeptide der Formel (I) erhalten. in welcher die Substituenten R1 und R2 in para-Stellung die in der folgenden Tabelle angegebenen Bedeutungen haben.The reaction mixture from Example 1 is added dropwise at 0 ° C. in acetone (50 ml). The corresponding amine (79.4 mmol) is then added at 0 ° C. and the mixture is stirred at 60 ° C. for 12 hours. After this time, the mixture is concentrated, taken up in water and extracted with dichloromethane (3 ×). The combined organic extracts are dried over Na 2 SO 4 and concentrated. The residue is purified by column chromatography. Depsipeptides of the formula (I) are obtained. in which the substituents R 1 and R 2 in the para position have the meanings given in the table below.
Tabelle 1Table 1
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000020_0001
Figure imgf000021_0001
Beispiel AExample A
Anthelmintische Wirksamkeit im SchafAnthelmintic effectiveness in sheep
Merino oder Schwarzkopf-Schafe, 25-35 kg Körpergewicht, wurden experimentell infiziert mit 5000 Haemonchus contortus L3-Larven und mit den Testsubstanzen behandelt am Ende der Präpatenzzeit der Parasiten (3-4 Wochen). Die Testsubstanzen wurden oral appliziert mit Hilfe von Gelatine-Kapseln. Im Fall von Trichostrongylus colubriformis wurde mit 12000 L3 -Larven infiziert. Die anthelmintische Wirksamkeit wurde gemessen anhand der Reduktion der mit Kot ausgeschiedenenMerino or Schwarzkopf sheep, 25-35 kg body weight, were experimentally infected with 5000 Haemonchus contortus L3 larvae and treated with the test substances at the end of the prepatent period of the parasites (3-4 weeks). The test substances were administered orally using gelatin capsules. In the case of Trichostrongylus colubriformis, 12000 L3 larvae were infected. The anthelmintic effectiveness was measured by the reduction of those excreted with feces
Eier. Zu diesem Zweck wurde frisch erhaltener Kot entsprechend der gängigen McMaster-Methode aufbereitet und die Eizahl wurde pro Gramm Kot bestimmt. Die Eizahlen wurden in regelmäßigen Intervallen (3-4 Tage) vor und nach der Behandlung über 6-8 Wochen bestimmt. Eine über 95%-ige Eireduktion wird im Test als 3 bezeichnet.Eggs. For this purpose, freshly obtained faeces were processed according to the usual McMaster method and the number of eggs was determined per gram of faeces. The egg numbers were determined at regular intervals (3-4 days) before and after the treatment over 6-8 weeks. Over 95% egg reduction is referred to as 3 in the test.
Bei diesem Test zeigten z.B. die folgenden Verbindungen die angegebene Wirkung:In this test, e.g. the following compounds have the stated effect:
Figure imgf000022_0001
Figure imgf000022_0001
p.o. oralp.o. orally
3 = volle Wirkung (>95% Reduktion) n.b. nicht bestimmt 3 = full effect (> 95% reduction) n.a. not determined

Claims

Patentansprüche claims
1. Substituierte Cyclooctadepsipeptide der Formel (I)1. Substituted cyclooctadepsipeptides of the formula (I)
Figure imgf000023_0001
Figure imgf000023_0001
in welcherin which
n für 0, 1 oder 2 steht, m für 1 oder 2 steht,n stands for 0, 1 or 2, m stands for 1 or 2,
Rl in ortho- und/oder para-Stellung für Sulfonylreste der FormelRl in the ortho and / or para position for sulfonyl radicals of the formula
-SO2-A-SO 2 -A
steht,stands,
R^ in ortho- und/oder para-Stellung für Sulfonylreste der FormelR ^ in the ortho and / or para position for sulfonyl radicals of the formula
-SO2-A steht,-SO 2 -A stands,
wobei A für folgende Reste steht: Amino, Mono- oder Dialkylamino mit 1 bis 4 C-Atomen pro Alkylteil, Bis- (hydroxyalkyl)amino mit 1-4 C-Atomen im Alkylteil, Mono- oder Bis- (alkoxyalkyl)amino mit 1 bis 4 C-Atomen pro Alkoxy- oder Alkylteil, Mono- oder Di-Cι_4-Alkylamino, das durch Phenyl, Furyl, Morpholinyl oder Pyridyl substituiert ist;where A stands for the following residues: Amino, mono- or dialkylamino with 1 to 4 carbon atoms per alkyl part, bis- (hydroxyalkyl) amino with 1-4 carbon atoms in the alkyl part, mono- or bis- (alkoxyalkyl) amino with 1 to 4 carbon atoms per alkoxy - Or alkyl part, mono- or Di-Cι_4-alkylamino, which is substituted by phenyl, furyl, morpholinyl or pyridyl;
ferner für über Stickstoff gebundene gesättigte 5- oder 6-gliedrige Heterocyclen, die neben N 1 oder 2 weitere Heteroatome der Reihe O oder N enthalten können und die gegebenenfalls substituiert sind;furthermore for saturated 5- or 6-membered heterocycles which are bonded via nitrogen and which, in addition to N 1 or 2, can contain further heteroatoms of the O or N series and which are optionally substituted;
ferner für über Stickstoff gebundene ungesättigte Heterocyclen aus der Reihe Pyrazol, Imidazol, Pyrrol, 1,2,4-Triazol, 1,2,3-Triazol, die gegebenenfalls substituiert sein können.also for nitrogen-bonded unsaturated heterocycles from the series pyrazole, imidazole, pyrrole, 1,2,4-triazole, 1,2,3-triazole, which may optionally be substituted.
Als Substituenten für die gegebenenfalls substituierten Reste seien genanntMention may be made of substituents for the optionally substituted radicals
Cj.4-Alkyl, Aryl wie Cj.4-Alkylcarbonyl, Benzoyl, Cι_4- Alkoxy carbonyl.C j . 4 alkyl, aryl such as Cj. 4 -Alkylcarbonyl, benzoyl, Cι_ 4 - alkoxy carbonyl.
2. Verfahren zur Herstellung substituierter Cyclooctadepsipeptide der Formel (I)2. Process for the preparation of substituted cyclooctadepsipeptides of the formula (I)
Figure imgf000024_0001
Figure imgf000024_0001
in welcher n für 0, 1 oder 2 steht, m für 1 oder 2 steht, Rl in ortho- und/oder para-Stellung für einen oder zwei Sulfonylreste der Formelin which n stands for 0, 1 or 2, m stands for 1 or 2, Rl in the ortho and / or para position for one or two sulfonyl radicals of the formula
-SOo-A-SOo-A
steht,stands,
R2 in ortho- und/oder para-Stellung für einen oder zwei Sulfonylreste der FormelR2 in the ortho and / or para position for one or two sulfonyl radicals of the formula
-SO2-A steht.-SO 2 -A stands.
wobei A für folgende Reste steht:where A stands for the following residues:
Amino, Mono- oder Dialkylamino mit 1 bis 4 C-Atomen pro Alkylteil, Bis(hydroxyalkyl)amino mit 1-4 C-Atomen in Alkylteil, Mono- oder Bis- (alkoxyalkyl)amino mit 1 bis 4 C-Atomen pro Alkoxy- oder Alkylteil, Mono- oder Di-Cj.4-Alkylamino, das durch Phenyl, Furyl, Moφholinyl oder Pyridyl substituiert ist;Amino, mono- or dialkylamino with 1 to 4 carbon atoms per alkyl part, bis (hydroxyalkyl) amino with 1-4 carbon atoms in alkyl part, mono- or bis- (alkoxyalkyl) amino with 1 to 4 carbon atoms per alkoxy- or alkyl part, mono- or di-C j . 4 -alkylamino which is substituted by phenyl, furyl, Moφholinyl or pyridyl;
ferner für über Stickstoff gebundene gesättigte 5- oder 6-gliedrige Heterocyclen, die neben N 1 oder 2 weitere Heteroatome der Reihe O oder N enthalten können und die gegebenenfalls substituiert sind;furthermore for saturated 5- or 6-membered heterocycles which are bonded via nitrogen and may contain, in addition to N 1 or 2, further heteroatoms of the O or N series and which are optionally substituted;
ferner für über Stickstoff gebundene ungesättigte Heterocyclen aus der Reihe Pyrazol, Imidazol, Pyrrol, 1 ,2,4-Triazol, 1,2,3-Triazol, die gegebenenfalls substituiert sein können,also for nitrogen-bound unsaturated heterocycles from the series pyrazole, imidazole, pyrrole, 1, 2,4-triazole, 1,2,3-triazole, which may optionally be substituted,
dadurch gekennzeichnet, daß man die Verbindung PF 1022 der Formel
Figure imgf000026_0001
mit einer Halogensulfonsäure oder mit Sulfurylchlorid oder Schwefeldioxid/Chlor umsetzt und die dabei erhältlichen halogensulfonylierten Verbindungen durch Umsetzung mit Verbindungen der Formelcharacterized in that the compound PF 1022 of the formula
Figure imgf000026_0001
with a halogen sulfonic acid or with sulfuryl chloride or sulfur dioxide / chlorine and the halogen sulfonylated compounds obtainable by reaction with compounds of the formula
H - A,H - A,
in welcherin which
A die oben angegebene Bedeutung hat,A has the meaning given above,
weiter umsetzt.continues to implement.
3. Verwendung von substituierten Cyclooctadepsipeptiden der Formel (I) gemäß Anspruch 1 zur Bekämpfung von Helminthen in der Human- und Veterinärmedizin.3. Use of substituted cyclooctadepsipeptides of the formula (I) according to Claim 1 for combating helminths in human and veterinary medicine.
4. Verwendung von substituierten Cyclooctadepsipeptiden der Formel (I) gemäß Anspruch 1 zur Herstellung von Mitteln zur Bekämpfung von Endoparasiten in der Human- und Veterinärmedizin. Mittel zur Bekämpfung von Endoparasiten gekennzeichnet durch einen Gehalt an substituierten Cyclooctadepsipeptiden der Formel (I) gemäß Anspruch 1 neben Streck- und Verdünnungsmitteln sowie gegebenenfalls üblichen Zusätzen. 4. Use of substituted cyclooctadepsipeptides of formula (I) according to claim 1 for the preparation of agents for controlling endoparasites in human and veterinary medicine. Agents for combating endoparasites characterized by a content of substituted cyclooctadepsipeptides of the formula (I) according to claim 1 in addition to extenders and diluents and, if appropriate, customary additives.
PCT/EP1999/004028 1998-06-24 1999-06-11 Substituted cyclooctadepsipeptides WO1999067281A1 (en)

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Publication number Priority date Publication date Assignee Title
DE102008030764A1 (en) 2008-06-28 2009-12-31 Bayer Animal Health Gmbh Combination of amidine derivatives with cyclic depsipeptides
WO2010102762A1 (en) 2009-03-10 2010-09-16 Bayer Animal Health Gmbh Oil-based preparation containing antiprotozoal triazines and anthelmintic cyclodepsipeptides
WO2012028556A1 (en) 2010-08-31 2012-03-08 Bayer Animal Health Gmbh Macrocyclic lactones and their use and their combinations with other active substances
DE102010064245A1 (en) 2010-12-28 2012-06-28 Bayer Animal Health Gmbh Use of macrocyclic lactones used in controlling endoparasitic filariae and gastrointestinal nematodes, particularly used in controlling heartworm

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WO1998043965A1 (en) * 1997-04-02 1998-10-08 Bayer Aktiengesellschaft Thiodepsipeptides for combating endoparasites and a method for producing the same

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102008030764A1 (en) 2008-06-28 2009-12-31 Bayer Animal Health Gmbh Combination of amidine derivatives with cyclic depsipeptides
WO2010102762A1 (en) 2009-03-10 2010-09-16 Bayer Animal Health Gmbh Oil-based preparation containing antiprotozoal triazines and anthelmintic cyclodepsipeptides
DE102009012423A1 (en) 2009-03-10 2010-09-16 Bayer Animal Health Gmbh Preparation based on oil
WO2012028556A1 (en) 2010-08-31 2012-03-08 Bayer Animal Health Gmbh Macrocyclic lactones and their use and their combinations with other active substances
DE102010064245A1 (en) 2010-12-28 2012-06-28 Bayer Animal Health Gmbh Use of macrocyclic lactones used in controlling endoparasitic filariae and gastrointestinal nematodes, particularly used in controlling heartworm

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PL345866A1 (en) 2002-01-14
EP1090031A1 (en) 2001-04-11
HUP0102476A2 (en) 2001-10-28
BR9911574A (en) 2001-03-20
HUP0102476A3 (en) 2003-08-28
CN1307586A (en) 2001-08-08
JP2002518520A (en) 2002-06-25

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