EP1064272A1 - Cyclooctadepsipeptide und ihre verwendung zur bekämpfung von endoparasiten - Google Patents
Cyclooctadepsipeptide und ihre verwendung zur bekämpfung von endoparasitenInfo
- Publication number
- EP1064272A1 EP1064272A1 EP99913226A EP99913226A EP1064272A1 EP 1064272 A1 EP1064272 A1 EP 1064272A1 EP 99913226 A EP99913226 A EP 99913226A EP 99913226 A EP99913226 A EP 99913226A EP 1064272 A1 EP1064272 A1 EP 1064272A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- spp
- cyclooctadepsipeptides
- alkyl
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
Definitions
- the invention relates to new cyclooctadepsipeptides, processes for their preparation and their use for controlling parasites, in particular helminths in veterinary and human medicine, and intermediates for their production.
- Pv.1 represents cyano, C-C-linked heterocyclyl or optionally substituted alkenyl, alkynyl or aryl and
- R.2 represents hydrogen or the same radical as R 1 . 2.
- X 1 represents bromine, iodine, -O-S ⁇ 2-R f , amino or -N2 + (X 3 ) " , in which - 3 -
- R f represents fluorinated Cj-C4-alkyl
- X 3 represents a diazonium salt stabilizing anion such as, for example, tetrafluoroborate and
- X ⁇ represents hydrogen or the same radical as X 1 ,
- X ⁇ - represents hydrogen or bromine
- ⁇ 2A represents hydrogen or iodine, - 5 -
- iodines the cyclooctadepsipeptide designated PF 1022 or
- R f represents fluorinated C 4 -C 4 -alkyl 1 and
- X 2 "3 stands for hydrogen or for -O-SÜ2-R f ,
- X 3 represents hydroxy or hydrogen
- Y represents -O-SO -R f , F or chlorine
- X 4 represents -N 2 + (X 3 ) "or hydrogen
- X 3 represents a diazominium salt stabilizing anion
- the new cyclooctadepsipeptides are generally defined by the formulas (I) and (II). - 8th -
- the substituents ⁇ l and X ⁇ or R and R ⁇ are preferably in the para or ortho position.
- the /? ⁇ r ⁇ position is particularly preferred.
- Preferred compounds of the formula (I) are those in which:
- -CH C (R 6 ) CO 2 R 7 or -C ⁇ CR 8 or for optionally single or multiple independently of one another by nitro, halogen.
- Benzyloxycarbonylamino, carboxy, -C -C-alkoxy carbonyl or phenyl substituted phenyl or naphthyl is, wherein
- R 3 represents C 1 -C 4 alkoxy or C 4 -C 4 alkylcarbonyloxy
- R 4 represents cyano or -CC-alkyl
- R ⁇ and R6 each represent hydrogen or methyl
- R? for C 1 -C 2 -alkyl, one or more times by halogen or simply by cyano, hydroxy, Cj-C4-alkoxy, C ⁇ -C4-dialkylamino or three- to eight-membered cyclic amino ( C2-C7-alkylene amino, with a methylene group by an oxygen, sulfur or nitrogen atom can be replaced) substituted C2-Ci 2-alkyl, represents (tetrahydro) furfuryl, C3-Cg-2-alkenyl, C3-Cg-cycloalkyl, optionally substituted by halogen-substituted phenyl or benzyl and - 9 -
- R 2 represents hydrogen or one of the radicals specified for R 1 .
- R 3 represents C 4 -C 4 -alkoxy or C 1 -C 4 -alkylcarbonyloxy
- R 4 represents cyano or C 1 -C 4 alkyl, - 10 -
- R5 and R6 each represent hydrogen or methyl
- R 8 for C 1 -C 4 alkyl, nC 5 -C ⁇ 2 alkyl, C 5 -C 6 cycloalkyl, -hydroxy-C ⁇ - Cg-alkyl, ⁇ -hydroxy-n-C2-C8-alkyl, ⁇ -C ⁇ -C4-alkoxy-C ⁇ -C 8 -alkyl, ⁇ -tetrahydropyranyloxy-nC ⁇ -C4-alkyl, 1-hydroxy ⁇ -Cß-cycloalkyl, ⁇ -amino-C j -Cg-alkyl, ⁇ -C ⁇ -C4-Alkylaminocarbonylamino- -C-C3-alkyl, ⁇ -carboxy-n-Ci -Cu -alkyl, C ⁇ -C4-alkoxycarbonyl-n- 1 -C 11 alkyl, phenoxycarbonyl-C ⁇ -C ⁇ ⁇ -
- R 2 represents hydrogen or one of the radicals specified for R 1 .
- Trifluoromethyl trifluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, amino, morpholino, piperidino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, acetylamino, propionylamino, methoxycarbonylamino, ethoxycarbonylamino, carbyloxycarbonoxy methoxycarbonoxy n-Butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxy or phenyl substituted phenyl, where
- R 3 represents methoxy, ethoxy, n-propoxy, isopropoxy, acetyloxy or propionyloxy,
- R 4 represents cyano or C 1 -C 4 alkyl
- R5 and R6 each represent hydrogen or methyl
- R 7 for methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert-butyl, neo-pentyl, n-pentyl, 2-ethylbutyl, n-hexyl, n-heptyl, 2- Ethylhexyl, n-octyl, n-nonyl, n-decyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1,1,3,3,3-hexafluoroisopropyl, heptafluoroisopropyl, 2,2,3, 3, 4,4-hexafluorobutyl, 2-chloroethyl, 2-bromoethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-methoxymethyl, 2-ethoxymethyl, 2-NN-dimethylaminomethyl
- R 8 for methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n -Decyl, cyclopentyl, cyclohexyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxypropyl, 1 -hydroxy-1-methylpropyl, 1-hydroxy-2-methylpropyl, 1-hydroxybutyl, 1-hydroxy - 1,2-dimethylpropyl, l-hydroxy-3-methylbutyl, 1-hydroxypentyl, 2-ethyl-l-hydroxybuty 1, 1 -hydroxy-1, 3 -dimethylbuty 1, 1 -hydroxy-1, 2.2 -trimethylpropyl, 1 -hydroxyhexyl
- R 2 represents hydrogen or one of the radicals specified for R 1 .
- ⁇ l is bromine, iodine, trifluoromethylsulfonyloxy, nonafluorobutylsulfonyloxy, amino or -N2 + (X 3 ) " , where X 3 is tetrafluoroborate;
- X ⁇ represents the radicals indicated at ⁇ l or hydrogen.
- reaction sequence of the invention can Process (2) can be represented by the following formula:
- reaction sequence of process (4b) according to the invention can be represented by the following formula: - 15 -
- reaction sequence of process (4c) according to the invention can be represented by the following formula:
- EP-A 634 408 describes the preparation of compounds of the present formula (I), in which R 1 and / or R 2 represent amino, by catalytic reduction of the corresponding nitro-substituted compounds.
- R 1 and / or R 2 represent amino
- EP-A 634 408 the conversion of the amino group into an OH residue by so-called
- the cyclooctadepsipeptide PF1022 required to carry out processes (4a) and (4b) according to the invention is known from EP 382 173 AI and can be used e.g. be produced by fermentation.
- cyclooctadepsipeptides of the formula (III) required for carrying out the process (4c) according to the invention are, for example, as PF1022E and PF1022H from JP 06184126 (cited in CA 122: 104043) or WO 97/11064 (cited in CA) - 17 -
- the diazotized cyclooctadepsipeptides of the formula (V) required for carrying out the process (4d) according to the invention can be prepared according to generally known methods
- alkyl nitric acid such as e.g. Isoamyl nitrite or butyl nitrite in anhydrous media such as acetic acid containing hydrogen chloride.
- Reagents for carrying out process (2) according to the invention are, for example, compounds of the formula (VII)
- R! "2 stands for one of the CC-linked heterocyclyl, optionally substituted alkyl, alkenyl or aryl radicals given there for R 1 ,
- R ⁇ and Rio each for hydrogen, isopropyl or together for propylene
- Rl I represents methyl, butyl or phenyl
- the compounds of formula (VII) are generally known compounds of organic chemistry.
- the boron compounds of the formula (VIII), in particular the boronic acids, are known and some are commercially available, or they can be prepared by known methods [cf. e.g. Chem. Rev. 45, 2457 (1995); Pure appl. Chem. 66, 213 (1994); Synlett 1990, 221].
- the tin compounds of the formula (IX) are known or can be prepared by known methods [cf. e.g. M. Pereyre, J.-P.
- a catalyst for carrying out process (2) according to the invention use is made, for example, of compounds, in particular complex compounds, of metals from subgroup VIII of the periodic table, such as of palladium or nickel. - 19 -
- Examples include: bis (1,5-cyclooctadiene) nickel (O), nickel (II) chloride, dichlorobis (triphenylphosphine) nickel, nickel (II) acetylacetonate, palladium (II) acetate, chloride , Dichloro-bis (triphenylphosphine) palladium, dichloro-bis [tri (2-methylphenyl) phosphine] palladium, diacetonitriiodichloropalladium, bis [ ⁇ - (acetato- ⁇ O: ⁇ O ')] to [[2- [bis ( 2-methylphenyl) phosphino- ⁇ P] phenyl] methyl- ⁇ C] dipalladium, tris (dibenzylidene acetone) dipalladium, di (dibenzylidene acetone) palladium, tetrakis (triphenylphosphine) palladium or one of
- Nickel (O) or nickel (II) compounds can be used as nickel catalysts.
- the nickel (II) compounds can be reduced in situ to suitable nickel (O) compounds in the presence of suitable ligands, e.g. through zinc powder.
- Couplings with alkynes use copper iodide as the cocatalyst, which can also be useful in reactions with tin compounds.
- Process (2) according to the invention is optionally carried out in the presence of a reaction auxiliary.
- alkali metal halides such as lithium chloride, lithium bromide, cesium fluoride or acid binders.
- Alkaline earth metal or alkali metal hydroxides, acetates, carbonates or hydrogen carbonates, such as, for example, sodium, potassium, barium or ammonium hydroxide, sodium, potassium, calcium, are preferably used as acid binders in the reaction with boron compounds of the formula (VIII) - or ammonium acetate, sodium, potassium or ammonium carbonate, sodium hydrogen or potassium hydrogen carbonate, silver carbonate, phosphates such as trisodium or tripotassium phosphate, alkali fluorides such as cesium fluoride, and tertiary amines such as trimethylamine, triethylamine, tributylamine, ethyldiisopropylamine, N, N-dimethylaniline, N
- Diazabicycloundecene (DBU). in the implementation of compounds of formula (II), the - 20 -
- alkali metal nitrites such as sodium nitrite are used for diazotization.
- Process (2) according to the invention is preferably carried out in the presence of a diluent.
- Water, organic solvents and any mixtures thereof can be used in the reaction with boron compounds of the formula (VIII).
- Examples include: aliphatic, alicyclic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, methylene chloride,
- Ethers such as diethyl, diisopropyl, methyl t-butyl, methyl t-amyl ether
- aqueous acids such as hydrochloric acid, trifluoroacetic acid or tetrafluoroboric acid
- a solubilizer such as alcohols such as methanol
- dipolar aprotic solvents are advantageous as diluents.
- ethers such as diethyl, diisopropyl, methyl t-butyl, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl ether or anisole;
- Ketones such as acetone, butanone, methyl isobutyl ketone or cyclohexanone;
- Nitriles such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile;
- Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; Sulfoxides such as dimethyl sulfoxide. Amines specified above as acid binders can also serve as diluents when used in a large excess. - 21 -
- Process (2) according to the invention can also be carried out in a two-phase system such as, for example, methylene chloride / water, preferably using a suitable phase transfer catalyst.
- suitable phase transfer catalysts are: tetrabutylammonium iodide, bromide or chloride, tri-butylmethylphosphonium bromide, trimethyl-C 1-4 alkyl alkyl ammonium chloride or
- reaction temperatures can be carried out when carrying out the process according to the invention.
- Process (2) can be varied over a wide range. In general, temperatures between 20 ° C and 200 ° C, preferably between 50 ° C and 150 ° C. In the case of an upstream diazotization, if appropriate, the process is initially carried out at from -20 ° C. to + 30 ° C.
- a bromination reagent is required to carry out process (4a) according to the invention. Bromine in the presence of 1,1-bis (trifluoroacetoxy) iodobenzene is suitable for this.
- Process (4a) according to the invention is preferably carried out in the presence of a diluent.
- a diluent Water, organic solvents and any mixtures thereof can be considered. Examples include: aliphatic, alicyclic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloro, trichloroethane or carbon tetrachloride; Ethers, such as diethyl, diisopropyl, methyl t-butyl, methyl t-amyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxye
- N-oxides such as N-methylmorpholine-N-oxide
- Esters such as methyl, ethyl or butyl acetate
- Sulfoxides such as dimethyl sulfoxide
- Sulfones such as sulfolane
- Alcohols such as methanol, ethanol, n- or i-propanol, n-, i-, s- or t-butanol, ethanediol, propan-l, 2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether; Water.
- reaction temperatures can be varied within a substantial range when carrying out process (4a) according to the invention. In general, temperatures between -50 ° C and + 50 ° C, preferably between -20 ° C and + 30 ° C.
- 0.5 to 5 moles of bromine are generally used per mole of PF 1022.
- 1.0 to 1.2 mol / ) / bis (trifluoroacetoxy) iodobenzene are used per mol of bromine.
- An iodination reagent is required to carry out process (4b) according to the invention.
- Process (4b) according to the invention is preferably carried out in the presence of a diluent.
- a diluent for this purpose, for the reaction with 7, / - bis (trifluoroacetoxy) iodobenzene, for example, all solvents listed in process (4a) are considered, for those with iodate, for example acetic acid and sulfuric acid.
- reaction temperatures can be varied within a substantial range when carrying out process (4b) according to the invention.
- /, / - bis (trifluoroacetoxy) iodobenzene at temperatures between -50 ° C and + 50 ° C, preferably between -20 ° C and + 30 ° C
- iodate at temperatures between 0 ° C and + 100 ° C, preferably between 20 ° C and + 80 ° C.
- Organic bases are primarily suitable as acid binders for carrying out process (4c) according to the invention.
- Examples include: Tertiary amines such as trimethylamine, triethylamine, tributylamine, N, N-dimethylaniline, N, N-dimethylbenzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N, N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclonones (DBN) or diazabicycloundecene (DBU).
- Tertiary amines such as trimethylamine, triethylamine, tributylamine, N, N-dimethylaniline, N, N-dimethylbenzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N, N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclonone
- Process (4c) is optionally carried out in the presence of a diluent.
- Organic solvents and any mixtures thereof can be used for this. Examples include: aliphatic, alicyclic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloro, trichloroethane or carbon tetrachloride; Ethers such as diethyl, diisopropyl, methyl t-butyl, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl ether or
- reaction temperatures can be varied within a substantial range when carrying out process (4c) according to the invention. In general, temperatures between -50 ° C and + 50 ° C, preferably between -20 ° C and + 30 ° C.
- 1 to 10 mol, preferably 1.2 to 5 mol, of sulfonic acid derivative (IV) and 1 to 10 mol, preferably 1 to 5, are generally employed per equivalent of hydroxy-substituted cyclooctadepsipeptide of the formula (III) Mole of acid binder.
- reaction temperatures can be varied within a substantial range when carrying out process (4d) according to the invention. In general, temperatures between 50 ° C and 180 ° C, preferably between 60 ° C and 140 ° C. Otherwise, one still irradiates with a light source that emits UV radiation.
- the fluorinated sulfonic acid of formula (VI) is generally used in a larger excess.
- the reactions of the processes according to the invention can be carried out under normal pressure or under elevated pressure. Is preferably carried out at normal pressure.
- the reaction is carried out, worked up and isolated by generally customary, known methods.
- the end products are preferably by crystallization, chromatographic separation or
- the active substances are suitable for combating pathogenic endoparasites in humans and in animal husbandry and animal breeding if the warm-blooded animal toxicity is favorable - 25 -
- Pathogenic endoparasites include cestodes, trematodes, nematodes, in particular:
- Schistocephalus spp. Ligula spp., Bothridium spp., Diphlogonoorus spp ..
- Cyclophyllidea for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosmsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyella spp.
- Taenia spp. Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium
- 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., Catatropispp., Catatropispp. Dicrocoelium spp., Collyriclum spp - 26 -
- Nanophyetus spp. Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp ..
- Stronylus spp. Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum 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., Haemonertusiapp., Ostemonchusagia ., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp ..
- Oxyuris spp. Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp ..
- Ascaris spp. Ascaris spp., Toxascaris spp., Toxocara spp.,
- Macracanthorhynchus spp. Prosthenorchis spp ..
- the active compounds according to the invention show outstanding activity against worms such as Haemonchus contortus, Trichostrongylus colubriformis, Nematospiroides dubius and Heterakis spumosa.
- 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.
- 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, tapes.
- enteral application of the active ingredients takes place e.g. orally in the form of powder
- Suppositories tablets, capsules, pastes, drinkers, granules, drenches, boluses, medicated feed or drinking water.
- the dermal application takes place, for example, in the form of diving (dipping), spraying (spraying), bathing, washing, pouring on (pouring) - 28 -
- 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, pour-on formulations, gels;
- Emulsions and suspensions for oral or dermal use and for injection are Emulsions and suspensions for oral or dermal use and for injection; semi-solid preparations;
- 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.
- the solutions are sterile filtered and filled.
- solvents physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof.
- solvents physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof.
- the active compounds can also be dissolved in physiologically tolerable vegetable or synthetic oils which are suitable for injection.
- solubilizers 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, sprayed on or applied by dipping (dipping, bathing or washing). 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 enough thickening agent to solutions which have been prepared as described for the injection solutions to form a clear mass with an ointment-like consistency.
- the thickeners specified above are used as thickeners. - 30 -
- Pour-on formulations are poured or sprayed onto limited areas of the skin, the active ingredient either penetrating the skin and acting systemically or being distributed over the surface of the body.
- 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, further auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers and adhesives are added.
- solvents water, alkanols, glycols, polyethylene glycols,
- Polypropylene glycols glycerin, 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 or ketone, aromatic and / aromatic and / vegetable or synthetic oils, DMF, dimethyl acetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-l, 3-dioxolane.
- aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol
- esters such as ethyl acetate, butyl acetate
- benzyl benzoate ethers
- alkylene glycol alkyl ethers such as dipropylene glycol mono
- 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 metabisulfate, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.
- Light stabilizers are e.g. Substances from the class of benzophenones or novantisolic acid.
- Adhesives are, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin. - 31 -
- Emulsions can be used orally, dermally or as an injection.
- Emulsions are either water in oil or oil in water.
- hydrophobic phase paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid biglyceride, triglyceride mixture with vegetable fatty acid of chain length Cg-Ci 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 Cjg-Cig, isopropyl myristate, isopropyl palmitate, caprylic / capric alcoholic acid esters of fatty acid esters ⁇ l8 > isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duckling gland fat, dibutyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures, etc.
- Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.
- Fatty acids such as oleic acid and their mixtures. - 32 -
- 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 sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt;
- cationic surfactants such as cetyltrimethylammonium chloride.
- 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, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols , Waxes, colloidal silica or mixtures of the listed substances.
- Suspensions can be used orally, dermally or as an injection. They are produced by adding the active ingredient in a carrier liquid, if necessary with the addition of other auxiliary substances such as wetting agents, dyes, substances that require absorption,
- surfactants specified above may be mentioned as wetting agents (dispersants). - 33 -
- 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 excipients, if appropriate with the addition of auxiliaries, and brought into the desired form.
- Inorganic substances are e.g. 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, decomposition substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinyl pyrrolidone as well as dry binders such as microcrystalline cellulose.
- lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decomposition substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinyl pyrrolidone as well as dry binders such as microcrystalline cellulose.
- the active substances can also be present in the preparations in a mixture with synergists or with other active substances which act against pathogenic endoparasites.
- Che active ingredients are e.g. L-2,3,5,6-tetrahydro-6-phenyl-imidazolethiazole, benzimide azole carbamates, praziquantel, pyrantel, febantel.
- Ready-to-use preparations contain the active ingredient in concentrations of 10 ppm to 20% by weight, preferably 0.1 to 10% by weight.
- Preparations which are diluted before use contain the active ingredient in concentrations of 0.5 to 90% by weight, preferably 5 to 50% by weight.
- PF 1022 (0.95 g; 1 mmol) was suspended in glacial acetic acid (4 ml) under argon. After adding sulfuric acid (conc .; 0.44 ml) sodium iodate (166 mg; 0.84 mmol) and iodine (406 mg; 1.60 mmol) were added. With vigorous stirring
- PhIL2 i-bis (trifluoroacetoxy) iodobenzene
- PF1022 (1.9 g; 2 mmol) was dissolved in chloroform (30 ml) under argon.
- P L2 (3.6 g; 8.4 mmol) was metered in at 0 ° C. and then bromine (1.28 g; 8 mmol) was added dropwise.
- the mixture was allowed to warm to room temperature. After five days at room temperature, the reaction mixture was poured into sodium sulfite solution (30% aq.). The phases were separated. The aqueous phase was extracted with chloroform. to
- Trifluoromethanesulfonic anhydride (79.1 ⁇ l; 135.4 mg; 0.22 mmol) was added dropwise to a solution of the monohydroxy compound PF1022E (386 mg; 0.40 mmol) in dry pyridine (2 ml) at -20 ° C. The mixture was allowed to warm to 0 ° C. and stirred at this temperature for 24 h. After checking by TLC, the mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with 10% hydrochloric acid, water and saturated sodium chloride solution, dried over magnesium sulfate and then concentrated.
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Tropical Medicine & Parasitology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19811559 | 1998-03-17 | ||
DE19811559A DE19811559A1 (de) | 1998-03-17 | 1998-03-17 | Cyclooctadepsipeptide |
PCT/EP1999/001407 WO1999047506A1 (de) | 1998-03-17 | 1999-03-04 | Cyclooctadepsipeptide und ihre verwendung zur bekämpfung von endoparasiten |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1064272A1 true EP1064272A1 (de) | 2001-01-03 |
Family
ID=7861200
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99913226A Withdrawn EP1064272A1 (de) | 1998-03-17 | 1999-03-04 | Cyclooctadepsipeptide und ihre verwendung zur bekämpfung von endoparasiten |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP1064272A1 (pt) |
JP (1) | JP2002506857A (pt) |
KR (1) | KR20010041450A (pt) |
CN (1) | CN1293664A (pt) |
AU (1) | AU3143899A (pt) |
BR (1) | BR9908861A (pt) |
CA (1) | CA2323628A1 (pt) |
DE (1) | DE19811559A1 (pt) |
PL (1) | PL342948A1 (pt) |
WO (1) | WO1999047506A1 (pt) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102008030764A1 (de) | 2008-06-28 | 2009-12-31 | Bayer Animal Health Gmbh | Kombination von Amidin-Derivaten mit cyclischen Depsipeptiden |
DE102009012423A1 (de) | 2009-03-10 | 2010-09-16 | Bayer Animal Health Gmbh | Zubereitung auf Ölbasis |
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 (de) | 2010-12-28 | 2012-06-28 | Bayer Animal Health Gmbh | Makrocylischen Lactone und deren Verwendung und deren Kombinationen mit anderen Wirkstoffen |
SG10202103403SA (en) * | 2015-05-20 | 2021-05-28 | Boehringer Ingelheim Animal Health Usa Inc | Anthelmintic depsipeptide compounds |
SG11201805368YA (en) | 2015-12-28 | 2018-07-30 | Merial Inc | Anthelmintic depsipeptide compounds |
EP3541789A1 (en) | 2016-11-16 | 2019-09-25 | Boehringer Ingelheim Animal Health USA Inc. | Anthelmintic depsipeptide compounds |
NZ769696A (en) * | 2018-05-10 | 2023-12-22 | Zoetis Services Llc | Endoparasitic depsipeptides |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK0634408T3 (da) * | 1992-03-17 | 2002-04-22 | Fujisawa Pharmaceutical Co | Depsipeptidderivater, fremstilling og anvendelse deraf |
WO1994019334A1 (en) * | 1993-02-19 | 1994-09-01 | Meiji Seika Kaisha, Ltd. | Pf1022 derivative, cyclic depsipeptide |
DE4317457A1 (de) * | 1993-05-26 | 1994-12-01 | Bayer Ag | Octacyclodepsipeptide mit endoparasitizider Wirkung |
WO1997011064A1 (fr) * | 1995-09-22 | 1997-03-27 | Meiji Seika Kaisha, Ltd. | Nouveaux derives depsipeptides cycliques de pf1022 |
DE19545639A1 (de) * | 1995-12-07 | 1997-06-12 | Bayer Ag | Verfahren zur Herstellung von substituierten Arylmilchsäure-haltigen Cyclodepsipeptiden mit 24 Ringatomen |
-
1998
- 1998-03-17 DE DE19811559A patent/DE19811559A1/de not_active Withdrawn
-
1999
- 1999-03-04 CA CA002323628A patent/CA2323628A1/en not_active Abandoned
- 1999-03-04 CN CN99804115A patent/CN1293664A/zh active Pending
- 1999-03-04 AU AU31438/99A patent/AU3143899A/en not_active Abandoned
- 1999-03-04 BR BR9908861-4A patent/BR9908861A/pt not_active IP Right Cessation
- 1999-03-04 EP EP99913226A patent/EP1064272A1/de not_active Withdrawn
- 1999-03-04 PL PL99342948A patent/PL342948A1/xx unknown
- 1999-03-04 JP JP2000536703A patent/JP2002506857A/ja active Pending
- 1999-03-04 WO PCT/EP1999/001407 patent/WO1999047506A1/de not_active Application Discontinuation
- 1999-03-04 KR KR1020007009600A patent/KR20010041450A/ko not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9947506A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU3143899A (en) | 1999-10-11 |
CN1293664A (zh) | 2001-05-02 |
DE19811559A1 (de) | 1999-09-23 |
WO1999047506A1 (de) | 1999-09-23 |
PL342948A1 (en) | 2001-07-16 |
KR20010041450A (ko) | 2001-05-25 |
BR9908861A (pt) | 2000-11-21 |
JP2002506857A (ja) | 2002-03-05 |
CA2323628A1 (en) | 1999-09-23 |
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