WO2012028556A1 - Macrocyclic lactones and their use and their combinations with other active substances - Google Patents

Macrocyclic lactones and their use and their combinations with other active substances Download PDF

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Publication number
WO2012028556A1
WO2012028556A1 PCT/EP2011/064761 EP2011064761W WO2012028556A1 WO 2012028556 A1 WO2012028556 A1 WO 2012028556A1 EP 2011064761 W EP2011064761 W EP 2011064761W WO 2012028556 A1 WO2012028556 A1 WO 2012028556A1
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alkyl
compounds
active substances
thio
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PCT/EP2011/064761
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French (fr)
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Achim Harder
Wolfgang Roy
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Bayer Animal Health Gmbh
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Priority claimed from DE102010064245A external-priority patent/DE102010064245A1/en
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Publication of WO2012028556A1 publication Critical patent/WO2012028556A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/15—Depsipeptides; 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to novel uses of the macrocyclic lactones described hereinbelow, and to their combinations with other active substances.
  • CN 101619067A discloses the macrocyclic lactones compound I and compound II described hereinbelow, and their preparation.
  • the invention relates to the use of the compounds
  • compositions for controlling them for controlling endoparasitic filariae and gastrointestinal nematodes and for the preparation of compositions for controlling them.
  • Preferred is the use for controlling heartworm (Dirofilaria immitis).
  • the invention furthermore relates to derivatives of the compounds I and II.
  • the invention furthermore relates to the use for the preparation of compositions for controlling ectoparasitic arthropods.
  • the invention furthermore relates to combinations of the compounds I and II with further anthelmintics, in particular with
  • cyclic depsipeptides such as, for example, emodepside or PF1022
  • - benzimidazoles such as, for example , albendazole, fenbendazole, mebendazole, oxfendazole
  • salicylanilides such as, for example, niclosamide, rafoxanide, oxyclozanide, closantel etc. - by way of example, but not by limitation, other macrocyclic lactones (such as, for example, ivermectin, avermectin; abamectin; eprinomectin, nemamectin, moxidectin; milbemycin, selamectin).
  • macrocyclic lactones such as, for example, ivermectin, avermectin; abamectin; eprinomectin, nemamectin, moxidectin; milbemycin, selamectin).
  • the invention furthermore relates to derivatives of the compounds I and II.
  • Derivatives are, for example, those with substitutions in position 13 or 23 or else at both these positions simultaneously.
  • Suitable substances by way of example, but not by limitation, are oximes or oxime methyl ether, oxime carbamates (preferably in position 23), carbohydrate derivatives, in particular with oleandrose; esters and dicarboxylic acid esters; sulphonic acids, sulphinic acids, (thio)ethers; azoles; (thio)carbamates; hydrazones, (thio)semicarbazones; halogens; (thio)carbonates and amino acid esters.
  • derivatives in which the carbon atom in position 23 is geminally substituted by two independent hydroxyl, halogen, alkyl, alkenyl, aryl or aralkyl substituents.
  • Also furthermore in accordance with the invention are derivatives of the compound II in which the 23-hydroxyl group can be oxidized by standard methods of organic chemistry to give a 23-keto compound.
  • the compounds according to the invention can be used as intermediates for the preparation of further active compounds. If the compounds according to the invention are used as intermediates, the hydroxyl groups may be protected by suitable protecting groups. Examples of protected hydroxyl groups are known and some of them are described in "Protective Groups in Organic Synthesis” by Theodora W. Greene (Wiley-Interscience, New York 1981) and “Protective Groups in Organic Chemistry” by JFW McOmie (Plenum Press, London, 1973). These derivatives are also suitable for the preparation of compositions for controlling endo- and ectoparasites such as, for example, intestinal worms in dogs, cats, horses, cattle, goats, and for controlling all filariae. The compositions are particularly suitable for controlling heartworm. The derivatives can also be employed in combination, in particular with
  • cyclic depsipeptides such as, for example, emodepside or PF1022
  • benzimidazoles s u c h a s fo r example, albendazole, fenbendazole, mebendazole, oxfendazole
  • anthelmintically active imidazothiazoles such as, for example, tetramisole or in particular levamisole
  • liver fluke such as, for example, triclabendazole or clorsulon
  • salicylanilides such as, for example, niclosamide, rafoxanide, oxyclozanide or closantel other macrocyclic lactones (such as, for example, ivermectin, avermectin, abamectin, moxidectin, milbemycin, selamectin).
  • Cyclic depsipeptides and their endoparasiticidal activity are known: enniatins and other 18- membered cyclic depsipeptides (EP-A 644 883, EP-A 658 551, EP-A 669 343, WO 95/27498), 24-membered cyclic depsipeptides (EP-A 626 376, EP-A 626 375, EP 787 141, EP-A 903 347, EP-A 973 756, WO 98/55469, WO 99/47506, WO 00/14079, WO 98/37088, WO 99/67281), cyclic depsipeptides having 12 ring atoms (EP-A 664 297).
  • Cyclic octadepsipeptides such as PF1022 and emodepside and their activity against endoparasites (for example against intestinal nematodes and tissue nematodes) have likewise already been described, see, for example, EP-A 382 173, EP-A 634 408.
  • Depsipeptides resemble the peptides and differ from the latter in that one or more a-amino acid units are replaced by a-hydroxycarboxylic acid units.
  • Cyclic depsipeptides which are preferably employed in accordance with the invention are those having 18 to 24 ring atoms, in particular 24 ring atoms (octadepsipeptides) .
  • depsipeptides having 18 ring atoms include compounds of the general formula (II): in which
  • R 1 , R 3 and R 5 independently of one another represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, guanidinoalkyl which can optionally be substituted by one or two benzyloxycarbonyl radicals or by one, two, three or four alkyl radicals, alkoxycarbonylaminoalkyl, 9-fluorenylmethoxycarbonyl(Fmoc)aminoalkyl, alkenyl
  • R 2 , R 4 and R 6 independently of one another represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, mercaptoalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl or arylalkyl, substituents which may be mentioned being halogen, hydroxyl, alkyl, alkoxy, and their optical isomers and racemates.
  • Preferred compounds of the formula (II) are those in which R 1 , R 3 and R 5 independently of one another represent straight-chain or branched Ci-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C 6 -alkyl, in particular hydroxymethyl, 1-hydroxyethyl, Ci-C -alkanoyloxy-Ci-C 6 -alkyl, in particular acetoxymethyl, 1-acetoxyethyl, Ci-C -alkoxy
  • R 2 , R 4 and R 6 independently of one another represent straight-chain or branched Ci-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec- pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C 6 -alkyl, in particular hydroxymethyl, 1-hydroxyethyl, Ci-C -alkanoyloxy-Ci-C 6 -alkyl, in particular acetoxymethyl, 1-acetoxyethyl, Ci-C -alkoxy-Ci-C 6 -alkyl, in particular
  • Especially preferred compounds of the formula (II) are those in which R 1 , R 3 and R 5 independently of one another represent straight-chain or branched Ci-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C 6 -alkyl, in particular hydroxymethyl, 1-hydroxyethyl, Ci-C -alkanoyloxy-Ci-C 6 -alkyl, in particular acetoxymethyl, 1-acetoxyethyl, Ci-C - alkoxy-Ci-C 6 -alkyl, in particular meth
  • R 2 , R 4 and R 6 independently of one another represent straight-chain or branched Ci-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec- pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C 6 -alkyl, in particular hydroxymethyl, aryl-Ci-C -alkyloxy-Ci-C 6 -alkyl, in particular benzyloxymethyl, 1-benzyloxyethyl, carboxy-Ci-C 6 -alkyl, in particular carboxymethyl, carboxyeth
  • R 1 , R 3 and R 5 independently of one another represent straight-chain or branched Ci-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec- hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, C 2 -C 8 -alkenyl, in particular allyl, C 3 -C 7 - cycloalkyl-Ci-C -alkyl, in particular cyclohexylmethyl, phenyl-Ci-C -alkyl, in particular phenylmethyl,
  • R 2 , R 4 and R 6 independently of one another represent straight-chain or branched Ci-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, C 2 -C 8 -alkenyl, in particular vinyl, allyl, C 3 -C7-cycloalkyl-Ci-C 4 -alkyl, in particular cyclohexylmethyl, phenyl-Ci-C 4 - alkyl, in particular phenylmethyl, which can optionally be substituted by one or more identical or different radicals from among those specified hereinabove, and
  • depsipeptides are those known from the PCT application WO 93/19053.
  • Z represents N-morpholinyl, amino, mono- or dimethylamino.
  • R 1 , R 2 , R 3 , R 4 independently of one another represent hydrogen, Ci-Cio-alkyl or aryl, in particular phenyl, and which are optionally substituted by hydroxyl, Ci-Ci 0 -alkoxy or halogen.
  • the compounds of the general formula (II) are known and can be obtained by the processes described in EP-A-382 173, DE-A 4 317 432, DE-A 4 317 457, DE-A 4 317 458, EP-A-634 408, EP-A-718 293, EP-A-872 48 1 , EP-A-685 469, EP-A-626 375, EP-A-664 297, EP-A-669 343, EP-A-787 141, EP-A-865 498, EP-A-903 347.
  • the cyclic depsipeptides having 24 ring atoms also include compounds of the general formula (Hid)
  • R la , R 2a , R lla and R 12a independently of one another represent Ci-g-alkyl, Ci-g-haloalkyl, C 3 - 6 -cycloalkyl, aralkyl, aryl, R 3 a , R 5a , R 7a , R 9a independently of one another represent hydrogen or straight-chain or branched Ci_ 8 -alkyl which can optionally be substituted by hydroxyl, C 1 _ 4 -alkoxy, carboxyl,
  • carboxamide , imidazolyl, indolyl, guanidino, -SH or C 1 _ 4 -alkylthio, and furthermore
  • R 4a , R 6a , R 8a , R 10a independently of one another represent hydrogen, or represent straight-chain
  • R 1a , R 2a , R 11a and R 12a independently of one another represent methyl, ethyl, propyl, isopropyl, n-, s-, t-butyl or phenyl which is optionally substituted by halogen, C 1 _ 4 -alkyl, OH, C 1 _ 4 -alkoxy, and represent benzyl or phenylethyl, both of which can optionally be substituted by the radicals specified for phenyl; R 3a to R 10a have the abovementioned meanings.
  • R 1a , R 2a , R 11a and R 12a independently of one another represent methyl, ethyl, propyl, isopropyl or n-, s-, t-butyl,
  • R 3a , R 5a , R 7a , R 9a represent hydrogen, or represent straight-chain or branched C 1 _ 8 -alkyl, in particular methyl, ethyl, propyl, i-propyl, n-, s-, t-butyl, all of which can optionally be substituted by C 1 4 -alkoxy, in particular methoxy, ethoxy, imidazolyl, indolyl or C 1 _ 4 -alkylthio, in particular methylthio, ethylthio, and furthermore represent phenyl, benzyl or phenethyl, all of which can optionally be substituted by halogen, in particular chlorine.
  • R 4a , R 6a , R 8a , R 10a independently of one another represent hydrogen, or represent methyl, ethyl, n-propyl, n-butyl, vinyl, cyclohexyl, all of which can optionally be substituted by methoxy, ethoxy, imidazolyl, indolyl, methylthio, ethylthio, and also represent isopropyl, s-butyl, furthermore optionally halogen-substituted phenyl, benzyl or phenylethyl.
  • the compounds of the formula (Hid) can likewise be obtained by the methods described in EP-A-382 173, DE-A 4 317 432, DE-A 4 317 457, DE-A 4 317 458, EP-A-634 408, EP-A-718 293, EP-A-872 48 1 , EP-A-685 469, EP-A-626 375, EP-A-664 297, EP-A-669 343, EP-A-787 141, EP-A-865 498, EP-A-903 347.
  • Depsipeptides which are very especially preferred in accordance with the invention are PF 1022 A (see formula (Ilia)) and emodepside (PF 1022-221, compound of the formula (Illb) in which both radicals Z represent the morpholinyl radical).
  • the INN emodepside represents the compound with the systematic name: cyclo[( ?)-lactoyl-N-methyl-L-leucyl-( ?)-3-(p-mo ⁇ holinophenyl)lactoyl-N-methyl- L-leucyl-( ?)lactoyl-N-memyl-L-leucyl-( ?)-3-(p-mo ⁇ holinophenyl)lactoyl-N-methyl-L-leucyl.
  • Anthelmintically active imidazothiazoles are, in particular, tetramisole or, preferably, levamisole. They are frequently employed with one of the salts, for example in the form of the hydrochloride.
  • the broad-spectrum antinematode agents benzimidazoles; levamisole; morantel; pyrantel; monepantel, paraherquamide, piperazine
  • broad-spectrum anti-tapeworm agents praziquantel, epsiprantel, niclosamide
  • agents against liver fluke salicylanilides, clorsulon; triclabendazole, diamphenetide
  • macrocyclic lactones such as, for example, ivermectin, avermectin, abamectin, moxidectin, milbemycin, selamectin.
  • active substances may be present in stereoisomeric forms or as stereoisomer mixtures, for example as enantiomers or racemates. Not only the stereoisomer mixtures, but also the pure stereoisomers, may be used in accordance with the invention.
  • the active substances used in accordance with the invention may exist in stereoisomeric forms (enantiomers, diastereomers). According to the invention, the enantiomers or diastereomers and their respective mixtures may be employed. In the event that the active substances can exist in tautomeric forms, the present invention also comprises the use of the tautomeric forms.
  • the active substances can also be employed in the form of their salts, solvates and solvates of the salts.
  • physiologically acceptable salts of the active substances comprise acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • physiologically acceptable salts of the active substances also comprise salts of conventional bases such as by way of example and by preference alkali metal salts (for example sodium and potassium salts), alkaline-earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as by way of example and by preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.
  • alkali metal salts for example sodium and potassium salts
  • alkaline-earth metal salts for example calcium and magnesium salts
  • solvates refer to those forms of the active substances which, in the solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a specific form of the solvates, where the coordination takes place with water.
  • the present invention also comprises prodrugs of the active substances.
  • prodrugs comprises compounds which themselves may be biologically active or inactive, but which, during their residence time in the body, are converted into the actual active substance (for example metabolically or hydrolytically).
  • compositions, or active substances or combinations, used in accordance with the invention have an advantageous toxicity for warm-blooded species and are suitable for controlling pathogenic endoparasites which occur in humans and in animal keeping or animal breeding in productive livestock, breeding stock, zoo animals, laboratory animals, test animals and pets. In this context, they are active against all or individual developmental stages of the pests, and against resistant and normally-sensitive species.
  • pathogenic endoparasites it is intended to reduce disease, deaths and reduced productivity (for example in the production of meat, milk, wool, hides, eggs, honey and the like), so that more economical and simpler animal keeping is possible by employing the active substances.
  • the pathogenic endoparasites include Cestodes, Trematodes, Nematodes, Acanthocephala, in particular:
  • Cyclophyllidea for example Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp..
  • Strongylida for example Strongylus spp., Triodontophorus spp., Oesophagodontus spp . , Trichonema spp . , Gyalocephalus spp . , Cylindropharynx spp . , Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp . , Uncinaria spp ., Bunostomum spp .
  • Globocephalus spp. Syngamus spp., Cyathostomum 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.
  • Oxyurida From the order of the Oxyurida, for example 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..
  • Spirurida for example Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp..
  • Filariida for example Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp..
  • tapeworms for example Taenia spp.
  • nematodes such as, for example,
  • Strongylida in particular Haemonchus spp., Trichostrongylus spp., Cooperia spp. and Ostertagia spp., and Ascaridida such as, for example, Parascaris spp.
  • Ectoparasites are typically and preferably arthropods, in particular insects such as flies (biting and licking), parasitic fly larvae (blowflies, flesh flies, warble flies, botflies), midges, black flies, sand flies, gnats, horse flies, bugs, lice, hair lice, bird lice, fleas, keds and the like; or acarids such as ticks, for example hard ticks or soft ticks, or mites such as scab mites, harvest mites, bird mites and the like.
  • insects such as flies (biting and licking), parasitic fly larvae (blowflies, flesh flies, warble flies, botflies), midges, black flies, sand flies, gnats, horse flies, bugs, lice, hair lice, bird lice, fleas, keds and the like; or acarids such as ticks, for example hard ticks
  • Anoplurida for example Haematopinus spp., Linognathus spp., Pediculus spp., Phtirus spp., Solenopotes spp.; specific examples are: Linognathus setosus, Linognathus vituli, Linognathus ovillus, Linognathus oviformis, Linognathus pedalis, Linognathus stenopsis, Haematopinus asini macrocephalus, Haematopinus eurysternus, Haematopinus suis, Pediculus humanus capitis, Pediculus humanus corporis, Phylloera vastatrix, Phthirus pubis, Solenopotes capillatus;
  • Rhipicephalus (Boophilus) spp. Dermacentor spp., Haemophysalis spp., Hyalomma spp., Dermanyssus spp. , Rhipicephalus spp .
  • Ornithonyssus spp. Pneumonyssus spp., Raillietia spp., Pneumonyssus spp., Sternostoma spp., Varroa spp., Acarapis spp.; specific examples are: Argas persicus, Argas reflexus, Ornithodorus moubata, Otobius megnini, Rhipicephalus (Boophilus) microplus, Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) annulatus, Rhipicephalus (Boophilus) calceratus, Hyalomma anatolicum, Hyalomma aegypticum, Hyalomma marginatum, Hyalomma transiens, Rhipicephalus evertsi, Ixodes ricinus, Ixodes hexagonus, Ixo
  • Controlling the parasites can additionally contribute to preventing the transmission of infectious substances.
  • control means that the active substances act by reducing the occurrence of the parasite in question, in an animal infested with such parasites, to harmless levels. More precisely, the "control” as used in the present context means that the active substance kills the parasite in question, inhibits its growth or inhibits its proliferation.
  • the productive livestock include, in particular, mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, furbearers such as, for example, mink, chinchilla, raccoon.
  • mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, furbearers such as, for example, mink, chinchilla, raccoon.
  • mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, furbearers such as, for example, mink, chinchilla, raccoon.
  • furbearers such as, for example, mink, chinchilla, raccoon.
  • preferred among the mammalian productive livestock are
  • animal species which are not mammals, but which also belong to the productive livestock: birds such as, for example, chickens, geese, turkeys, ducks; freshwater and salt-water fish such as, for example, trout, carp, eels; reptiles; insects such as, for example, honeybees and silkworm.
  • the pets preferably include dogs and cats.
  • Toxoscaris spp. Toxocara spp., Trichuris spp., Trichinella spp. and the hookworms Ancylostoma spp. and Uncinaria spp.
  • the products may also be employed in humans. In humans, it is preferred to control Ascaris spp., Ancylostoma spp., Necator spp., Trichuris spp., Strongyloides spp. and Enterobius spp..
  • the herbivores plant eaters
  • animals which feed mainly on plants.
  • the treatment of ruminants such as, for example, sheep, goats, cattle is particularly preferred.
  • Nonruminant herbivores which are mammals and which may be mentioned as a preferred example are horses.
  • horses the abovementioned combinations can be employed preferably for example for controlling Strongylida or in particular roundworms (Ascaridia), such as, for example, Parascaris equorum.
  • the ruminants it is preferably Strongylida, in particular Haemonchus spp., Trichostrongylus spp., Cooperia spp. and Ostertagia spp., which can be controlled.
  • sheep are treated with particular preference.
  • cattle are also treated with particular preference.
  • the application can be effected both prophylactically and therapeutically.
  • the active substance is applied directly or in the form of suitable preparations, enterally, parenterally, dermally, nasally, by treating the environment, or with the aid of active-substance- containing shaped articles such as, for example, strips, discs, tapes, collars, ear tags, limb bands, marking devices.
  • the enteral application of the active substance is effected orally for example in the form of powders, suppositories, tablets, capsules, pastes, drinks, granules, drenches, boluses, medicated feed or drinking water. It is applied dermally for example in the form of dipping, spraying, bathing, washing, pouring-on and spotting-on and dusting. It is administered parenterally for example in the form of an 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 and spot-on formulations, gels;
  • Emulsions and suspensions for oral or dermal administration and for injection for injection; semi-solid preparations; Formulations in which the active substance is incorporated into an ointment base or into an oil-in- water or water-in-oil emulsion base;
  • Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules, aerosols and inhalants, active-substance-containing shaped articles.
  • Solutions for injection are administered intravenously, intramuscularly and subcutaneously.
  • Concentrates are used orally after previously having been diluted to the use concentration.
  • Solutions for use on the skin are trickled on, painted on, rubbed in, sprinkled on, sprayed on or applied by dipping, bathing or washing.
  • Gels are applied to or painted on to the skin or introduced into body cavities.
  • Pour-on and spot-on formulations are poured or sprinkled on to limited areas of the skin, the active substance either penetrating the skin and acting systemically or spreading over the body surface.
  • Emulsions can be employed orally, dermally or in the form of an injection. Emulsions are either of the water-in-oil type or of the oil-in-water type.
  • Suspensions can be employed orally, dermally or in the form of an injection.
  • Semi-solid preparations can be administered orally or dermally.
  • the active substance is mixed with suitable carriers, if appropriate with the addition of adjuvants, and shaped as desired. If appropriate, the products according to the invention may contain further active substances.
  • the use in combination means that either the anthelmintically active macrocyclic lactones and the active substances which act as combination partners are formulated in a combined preparation and, accordingly, applied jointly.
  • the products can also comprise separate preparations for each active substance.
  • all active substances can, correspondingly, be formulated in combined preparations, all active substances can be formulated in separate formulations, and also feasible are mixed forms, where some of the active substances are formulated together and some of the active substances are formulated separately.
  • compositions contain the active substances in each case in concentrations of from 0.1 ppm to 90% by weight, preferably from 0.1 to 50% by weight.
  • Ready-to-use preparations usually contain the active substances in concentrations of from in each case 0.1 ppm to 20% by weight, preferably from 0.1 to 10% by weight.
  • Preparations which are diluted prior to administration contain the active substances in concentrations of from 0.5-90% by weight, preferably from 5 to 50% by weight.
  • Customary dosages of the macrocyclic lactones per day are from 0.1 to 100 mg/kg bodyweight, preferably from 2 to 60 mg/kg bodyweight.
  • Customary dosages of the depsipeptides per day are from 0.1 to 100 mg/kg, preferably from 0.5 to 50 mg/kg, especially preferably from 1 to 50 mg/kg bodyweight per day.

Abstract

The invention relates to the use of the compounds Compound (I) Compound (II) for controlling endoparasitic filariae and gastrointestinal nematodes. Preferred is the use for controlling heartworm(Dirofilaria immitis).The invention furthermore relates to novel derivatives of the compounds (I) and (II).

Description

Macrocyclic lactones and their use and their combinations with other active substances
The present invention relates to novel uses of the macrocyclic lactones described hereinbelow, and to their combinations with other active substances.
CN 101619067A discloses the macrocyclic lactones compound I and compound II described hereinbelow, and their preparation.
The invention relates to the use of the compounds
Figure imgf000002_0001
for controlling endoparasitic filariae and gastrointestinal nematodes and for the preparation of compositions for controlling them. Preferred is the use for controlling heartworm (Dirofilaria immitis).
The invention furthermore relates to derivatives of the compounds I and II.
The invention furthermore relates to the use for the preparation of compositions for controlling ectoparasitic arthropods.
The invention furthermore relates to combinations of the compounds I and II with further anthelmintics, in particular with
cyclic depsipeptides, such as, for example, emodepside or PF1022
- benzimidazoles such as, for example , albendazole, fenbendazole, mebendazole, oxfendazole
levamisole, tetramisole
pyrantel, morantel; monepantel paraherquamide
praziquantel, epsiprantel
triclabendazole; clorsulon
salicylanilides such as, for example, niclosamide, rafoxanide, oxyclozanide, closantel etc. - by way of example, but not by limitation, other macrocyclic lactones (such as, for example, ivermectin, avermectin; abamectin; eprinomectin, nemamectin, moxidectin; milbemycin, selamectin).
The invention furthermore relates to derivatives of the compounds I and II. Derivatives are, for example, those with substitutions in position 13 or 23 or else at both these positions simultaneously.
Suitable substances by way of example, but not by limitation, are oximes or oxime methyl ether, oxime carbamates (preferably in position 23), carbohydrate derivatives, in particular with oleandrose; esters and dicarboxylic acid esters; sulphonic acids, sulphinic acids, (thio)ethers; azoles; (thio)carbamates; hydrazones, (thio)semicarbazones; halogens; (thio)carbonates and amino acid esters.
Also in accordance with the invention are derivatives in which the carbon atom in position 23 is geminally substituted by two independent hydroxyl, halogen, alkyl, alkenyl, aryl or aralkyl substituents.
Also furthermore in accordance with the invention are derivatives of the compound II in which the 23-hydroxyl group can be oxidized by standard methods of organic chemistry to give a 23-keto compound.
The abovementioned derivatives can be prepared analogously to methods known per se as are described for example in EP 259 779, EP 260 537, EP 307 225, US 4 916 154, EP 238 259, DE 3 614 549, EP 102 721, EP 142 969, US 4 760 054, EP 185 623, EP 307 219, EP 638 078, EP 241 145, BiosciBiotech, 61(2), 304-311, (1997).
The compounds according to the invention can be used as intermediates for the preparation of further active compounds. If the compounds according to the invention are used as intermediates, the hydroxyl groups may be protected by suitable protecting groups. Examples of protected hydroxyl groups are known and some of them are described in "Protective Groups in Organic Synthesis" by Theodora W. Greene (Wiley-Interscience, New York 1981) and "Protective Groups in Organic Chemistry" by JFW McOmie (Plenum Press, London, 1973). These derivatives are also suitable for the preparation of compositions for controlling endo- and ectoparasites such as, for example, intestinal worms in dogs, cats, horses, cattle, goats, and for controlling all filariae. The compositions are particularly suitable for controlling heartworm. The derivatives can also be employed in combination, in particular with
cyclic depsipeptides, such as, for example, emodepside or PF1022
benzimidazoles s u c h a s , fo r example, albendazole, fenbendazole, mebendazole, oxfendazole
anthelmintically active imidazothiazoles such as, for example, tetramisole or in particular levamisole
pyrantel, morantel, monepantel
paraherquamide
praziquantel, epsiprantel
niclosamide
- agents against liver fluke such as, for example, triclabendazole or clorsulon
salicylanilides such as, for example, niclosamide, rafoxanide, oxyclozanide or closantel other macrocyclic lactones (such as, for example, ivermectin, avermectin, abamectin, moxidectin, milbemycin, selamectin). Cyclic depsipeptides and their endoparasiticidal activity are known: enniatins and other 18- membered cyclic depsipeptides (EP-A 644 883, EP-A 658 551, EP-A 669 343, WO 95/27498), 24-membered cyclic depsipeptides (EP-A 626 376, EP-A 626 375, EP 787 141, EP-A 903 347, EP-A 973 756, WO 98/55469, WO 99/47506, WO 00/14079, WO 98/37088, WO 99/67281), cyclic depsipeptides having 12 ring atoms (EP-A 664 297). Cyclic octadepsipeptides such as PF1022 and emodepside and their activity against endoparasites (for example against intestinal nematodes and tissue nematodes) have likewise already been described, see, for example, EP-A 382 173, EP-A 634 408.
Depsipeptides resemble the peptides and differ from the latter in that one or more a-amino acid units are replaced by a-hydroxycarboxylic acid units. Cyclic depsipeptides which are preferably employed in accordance with the invention are those having 18 to 24 ring atoms, in particular 24 ring atoms (octadepsipeptides) .
The depsipeptides having 18 ring atoms include compounds of the general formula (II): in which
Figure imgf000005_0001
R1, R3 and R5 independently of one another represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, guanidinoalkyl which can optionally be substituted by one or two benzyloxycarbonyl radicals or by one, two, three or four alkyl radicals, alkoxycarbonylaminoalkyl, 9-fluorenylmethoxycarbonyl(Fmoc)aminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl and, if appropriate, substituted arylalkyl, substituents which may be mentioned being halogen, hydroxyl, alkyl and alkoxy,
R2, R4 and R6 independently of one another represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, mercaptoalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl or arylalkyl, substituents which may be mentioned being halogen, hydroxyl, alkyl, alkoxy, and their optical isomers and racemates.
Preferred compounds of the formula (II) are those in which R1, R3 and R5 independently of one another represent straight-chain or branched Ci-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C6-alkyl, in particular hydroxymethyl, 1-hydroxyethyl, Ci-C -alkanoyloxy-Ci-C6-alkyl, in particular acetoxymethyl, 1-acetoxyethyl, Ci-C -alkoxy-Ci-C6-alkyl, in particular methoxymethyl, 1-methoxyethyl, aryl-Ci-C - alkyloxy-Ci-C6-alkyl, in particular benzyloxymethyl, 1-benzyloxy-ethyl, mercapto-Ci-C6-alkyl, in particular mercaptomethyl, Ci-C -alkylthio-Ci-C6-alkyl, in particular methylthioethyl, Ci-C - alkylsulphinyl-Ci-C6-alkyl, in particular methylsulphinylethyl, Ci-C -alkylsulphonyl-Ci-C6-alkyl, in particular methylsulphonylethyl, carboxy-Ci-C6-alkyl, in particular carboxymethyl, carboxyethyl, Ci-C4-alkoxycarbonyl-Ci-C6-alkyl, in particular methoxycarbonylmethyl, ethoxycarbonylethyl, Ci-C - arylalkoxycarbonyl-Ci-C6-alkyl, in particular benzyloxycarbonylmethyl, carbamoyl-Ci-C6-alkyl, in particular carbamoylmethyl, carbamoylethyl, amino-Ci-Cg-alkyl, in particular aminopropyl, aminobutyl, Ci-C -alkylamino-Ci-C6-alkyl, in particular methylaminopropyl, methylaminobutyl, Ci-C4-dialkylamino-Ci-C6-alkyl, in particular dimethylaminopropyl, dimethylaminobutyl, guanido-Ci- C6-alkyl, in particular guanidopropyl, Ci-C -alkoxycarbonylamino-Ci-C6-alkyl, in particular tert- butoxycarbonylaminopropyl, tert-butoxycarbonylaminobutyl, 9-fluorenylmethoxy- carbonyl(Fmoc)amino-Ci-C6-alkyl, in particular 9-fluorenyl-methoxycarbonyl(Fmoc)aminopropyl, 9-fluorenylmethoxycarbonyl(Fmoc)aminobutyl, C2-C8-alkenyl, in particular vinyl, allyl, butenyl, C3-C7-cycloalkyl, in particular cyclopentyl, cyclohexyl, cycloheptyl, C3-C7-cycloalkyl-Ci-C -alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-Ci-C -alkyl, in particular phenylmethyl, which can optionally be substituted by radicals from the series consisting of halogen, in particular fluorine, chlorine, bromine or iodine, hydroxyl, Ci-C -alkoxy, in particular methoxy or ethoxy, Ci-C -alkyl, in particular methyl,
R2, R4 and R6 independently of one another represent straight-chain or branched Ci-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec- pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C6-alkyl, in particular hydroxymethyl, 1-hydroxyethyl, Ci-C -alkanoyloxy-Ci-C6-alkyl, in particular acetoxymethyl, 1-acetoxyethyl, Ci-C -alkoxy-Ci-C6-alkyl, in particular methoxymethyl, 1-methoxyethyl, aryl-Ci-C -alkyloxy-Ci-C6-alkyl, in particular benzyloxymethyl, 1-benzyloxy-ethyl, mercapto-Ci-C6-alkyl, in particular mercaptomethyl, Ci-C -alkylthio-Ci-C6-alkyl, in particular methylthioethyl, Ci-C -alkylsulphinyl-Ci-C6-alkyl, in particular methylsulphinylethyl, Ci-C - alkylsulphonyl-Ci-C6-alkyl, in particular methylsulphonylethyl, carboxy-Ci-C6-alkyl, in particular carboxymethyl, carboxyethyl, Ci-C -alkoxycarbonyl-Ci-C6-alkyl, in particular methoxycarbonylmethyl, ethoxycarbonylethyl, Ci-C -arylalkoxycarbonyl-Ci-C6-alkyl, in particular benzyloxycarbonylmethyl, carbamoyl-Ci-C6-alkyl, in particular carbamoylmethyl, carbamoylethyl, amino-Ci-C6-alkyl, in particular aminopropyl, aminobutyl, Ci-C -alkylamino-Ci-C6-alkyl, in particular methylaminopropyl, methylaminobutyl, Ci-C -dialkylamino-Ci-C6-alkyl, in particular dimethylaminopropyl, dimethylaminobutyl, C2-C8-alkenyl, in particular vinyl, allyl, butenyl, C3-C7- cycloalkyl, in particular cyclopentyl, cyclohexyl, cycloheptyl, C3-C7-cycloalkyl-Ci-C -alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl, phenyl-Ci-C -alkyl, in particular phenylmethyl, which can optionally be substituted by radicals from the series consisting of halogen, in particular fluorine, chlorine, bromine or iodine, hydroxyl, Ci-C -alkoxy, in particular methoxy or ethoxy, Ci-C -alkyl, in particular methyl, and their optical isomers and racemates. Especially preferred compounds of the formula (II) are those in which R1, R3 and R5 independently of one another represent straight-chain or branched Ci-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C6-alkyl, in particular hydroxymethyl, 1-hydroxyethyl, Ci-C -alkanoyloxy-Ci-C6-alkyl, in particular acetoxymethyl, 1-acetoxyethyl, Ci-C - alkoxy-Ci-C6-alkyl, in particular methoxymethyl, 1-methoxyethyl, aryl-Ci-C -alkyloxy-Ci-C6-alkyl, in particular benzyloxymethyl, 1-benzyloxyethyl, Ci-C -alkoxycarbonylamino-Ci-C6-alkyl, in particular tert-butoxycarbonylaminopropyl, tert-butoxycarbonylaminobutyl, C2-C8-alkenyl, in particular vinyl, allyl, C3-C7-cycloalkyl, in particular cyclopentyl, cyclohexyl, cycloheptyl, C3-C7-cycloalkyl-Ci-C - alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-Ci-C -alkyl, in particular phenylmethyl, which can optionally be substituted by one or more identical or different radicals from among those specified hereinabove,
R2, R4 and R6 independently of one another represent straight-chain or branched Ci-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec- pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C6-alkyl, in particular hydroxymethyl, aryl-Ci-C -alkyloxy-Ci-C6-alkyl, in particular benzyloxymethyl, 1-benzyloxyethyl, carboxy-Ci-C6-alkyl, in particular carboxymethyl, carboxyethyl, Ci-C -alkoxycarbonyl-Ci-C6-alkyl, in particular methoxycarbonylmethyl, ethoxycarbonylethyl, Ci-C - aryl-alkoxycarbonyl-Ci-C6-alkyl, in particular benzyloxycarbonylmethyl, Ci-C -alkylamino-Ci-C6- alkyl, in particular methylaminopropyl, methylaminobutyl, Ci-C -dialkylamino-Ci-C6-alkyl, in particular dimethylaminopropyl, dimethylaminobutyl, C2-C8-alkenyl, in particular vinyl, allyl, butenyl, C3-C7-cycloalkyl, in particular cyclopentyl, cyclohexyl, cycloheptyl, C3-C7-cycloalkyl-Ci-C -alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptyl-methyl, phenyl, phenyl-Ci-C -alkyl, in particular phenylmethyl, which can optionally be substituted by one or more identical or different radicals from among those specified hereinabove, and their optical isomers and racemates.
Very especially preferred compounds of the formula (II) are those in which R1, R3 and R5 independently of one another represent straight-chain or branched Ci-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec- hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, C2-C8-alkenyl, in particular allyl, C3-C7- cycloalkyl-Ci-C -alkyl, in particular cyclohexylmethyl, phenyl-Ci-C -alkyl, in particular phenylmethyl,
R2, R4 and R6 independently of one another represent straight-chain or branched Ci-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, C2-C8-alkenyl, in particular vinyl, allyl, C3-C7-cycloalkyl-Ci-C4-alkyl, in particular cyclohexylmethyl, phenyl-Ci-C4- alkyl, in particular phenylmethyl, which can optionally be substituted by one or more identical or different radicals from among those specified hereinabove, and their optical isomers and racemates. The following compounds of the general formula (II), in which the radicals R1 to R6 have the following meanings, may be mentioned individually:
Figure imgf000008_0001
Figure imgf000009_0003
A further depsipeptide which may be mentioned is the compound PF 1022 of the formula (Ilia) hereinbelow, which is known from EP-OS 382 173:
Figure imgf000009_0001
Further compounds which may be mentioned as depsipeptides are those known from the PCT application WO 93/19053.
Compounds from WO 93/19053 which may be mentioned in particular are those of the following formula (Illb):
Figure imgf000009_0002
in which Z represents N-morpholinyl, amino, mono- or dimethylamino.
Compounds of the following formula (IIIc) may furthermore be mentioned:
Figure imgf000010_0001
in which R1, R2, R3, R4 independently of one another represent hydrogen, Ci-Cio-alkyl or aryl, in particular phenyl, and which are optionally substituted by hydroxyl, Ci-Ci0-alkoxy or halogen.
The compounds of the general formula (II) are known and can be obtained by the processes described in EP-A-382 173, DE-A 4 317 432, DE-A 4 317 457, DE-A 4 317 458, EP-A-634 408, EP-A-718 293, EP-A-872 48 1 , EP-A-685 469, EP-A-626 375, EP-A-664 297, EP-A-669 343, EP-A-787 141, EP-A-865 498, EP-A-903 347.
The cyclic depsipeptides having 24 ring atoms also include compounds of the general formula (Hid)
in which
Figure imgf000010_0002
Rla, R2a, Rlla and R12a independently of one another represent Ci-g-alkyl, Ci-g-haloalkyl, C3-6-cycloalkyl, aralkyl, aryl, R3 a, R5a, R7a, R9a independently of one another represent hydrogen or straight-chain or branched Ci_8-alkyl which can optionally be substituted by hydroxyl, C1_4-alkoxy, carboxyl,
Figure imgf000011_0002
carboxamide, , imidazolyl, indolyl, guanidino, -SH or C1_4-alkylthio, and furthermore
Figure imgf000011_0001
represent aryl or aralkyl, both of which can be substituted by halogen, hydroxyl, C1_4-alkyl, C1_4- alkoxy,
R4a, R6a, R8a, R10a independently of one another represent hydrogen, or represent straight-chain
C1-5-alkyl, C2-6-alkenyl, C3_7-cycloalkyl, all of which can optionally be substituted by hydroxyl, C1_4-alkoxy, carboxyl, carboxamide, imidazolyl, indolyl, guanidino, SH or C1_4-alkylthio, and also represent aryl or aralkyl, both of which can be substituted by halogen, hydroxyl, C1_4-alkyl, C1_4- alkoxy, and their optical isomers and racemates.
It is preferred to employ compounds of the formula (Hid) in which R1a, R2a, R11a and R12a independently of one another represent methyl, ethyl, propyl, isopropyl, n-, s-, t-butyl or phenyl which is optionally substituted by halogen, C1_4-alkyl, OH, C1_4-alkoxy, and represent benzyl or phenylethyl, both of which can optionally be substituted by the radicals specified for phenyl; R3a to R10a have the abovementioned meanings.
Especially preferred compounds of the formula (Hid) are those in which
R1a, R2a, R11a and R12a independently of one another represent methyl, ethyl, propyl, isopropyl or n-, s-, t-butyl,
R3a, R5a, R7a, R9a represent hydrogen, or represent straight-chain or branched C1_8-alkyl, in particular methyl, ethyl, propyl, i-propyl, n-, s-, t-butyl, all of which can optionally be substituted by C1 4-alkoxy, in particular methoxy, ethoxy, imidazolyl, indolyl or C1_4-alkylthio, in particular methylthio, ethylthio, and furthermore represent phenyl, benzyl or phenethyl, all of which can optionally be substituted by halogen, in particular chlorine.
R4a, R6a, R8a, R10a independently of one another represent hydrogen, or represent methyl, ethyl, n-propyl, n-butyl, vinyl, cyclohexyl, all of which can optionally be substituted by methoxy, ethoxy, imidazolyl, indolyl, methylthio, ethylthio, and also represent isopropyl, s-butyl, furthermore optionally halogen-substituted phenyl, benzyl or phenylethyl.
The compounds of the formula (Hid) can likewise be obtained by the methods described in EP-A-382 173, DE-A 4 317 432, DE-A 4 317 457, DE-A 4 317 458, EP-A-634 408, EP-A-718 293, EP-A-872 48 1 , EP-A-685 469, EP-A-626 375, EP-A-664 297, EP-A-669 343, EP-A-787 141, EP-A-865 498, EP-A-903 347.
Depsipeptides which are very especially preferred in accordance with the invention are PF 1022 A (see formula (Ilia)) and emodepside (PF 1022-221, compound of the formula (Illb) in which both radicals Z represent the morpholinyl radical). The INN emodepside represents the compound with the systematic name: cyclo[( ?)-lactoyl-N-methyl-L-leucyl-( ?)-3-(p-moφholinophenyl)lactoyl-N-methyl- L-leucyl-( ?)lactoyl-N-memyl-L-leucyl-( ?)-3-(p-moφholinophenyl)lactoyl-N-methyl-L-leucyl. Anthelmintically active imidazothiazoles are, in particular, tetramisole or, preferably, levamisole. They are frequently employed with one of the salts, for example in the form of the hydrochloride.
Among the partners in combinations the following must be mentioned: the broad-spectrum antinematode agents (benzimidazoles; levamisole; morantel; pyrantel; monepantel, paraherquamide, piperazine), broad-spectrum anti-tapeworm agents (praziquantel, epsiprantel, niclosamide), agents against liver fluke (salicylanilides, clorsulon; triclabendazole, diamphenetide).
Other macrocyclic lactones (such as, for example, ivermectin, avermectin, abamectin, moxidectin, milbemycin, selamectin). Depending on the structure, active substances may be present in stereoisomeric forms or as stereoisomer mixtures, for example as enantiomers or racemates. Not only the stereoisomer mixtures, but also the pure stereoisomers, may be used in accordance with the invention.
Others which can be used, if appropriate, are: salts of the active substances with pharmaceutically acceptable acids or bases, and also solvates, in particular hydrates, of the active substances or of their salts.
Depending on their structure, the active substances used in accordance with the invention may exist in stereoisomeric forms (enantiomers, diastereomers). According to the invention, the enantiomers or diastereomers and their respective mixtures may be employed. In the event that the active substances can exist in tautomeric forms, the present invention also comprises the use of the tautomeric forms.
If appropriate, the active substances can also be employed in the form of their salts, solvates and solvates of the salts.
Salts which are preferred within the scope of the present invention are physiologically acceptable salts of the active substances. Depending on the structure of the active substance, physiologically acceptable salts of the active substances comprise acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
If appropriate, physiologically acceptable salts of the active substances also comprise salts of conventional bases such as by way of example and by preference alkali metal salts (for example sodium and potassium salts), alkaline-earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as by way of example and by preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.
Within the scope of the invention, solvates refer to those forms of the active substances which, in the solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a specific form of the solvates, where the coordination takes place with water. Moreover, the present invention also comprises prodrugs of the active substances. The term "prodrugs" comprises compounds which themselves may be biologically active or inactive, but which, during their residence time in the body, are converted into the actual active substance (for example metabolically or hydrolytically). The compositions, or active substances or combinations, used in accordance with the invention have an advantageous toxicity for warm-blooded species and are suitable for controlling pathogenic endoparasites which occur in humans and in animal keeping or animal breeding in productive livestock, breeding stock, zoo animals, laboratory animals, test animals and pets. In this context, they are active against all or individual developmental stages of the pests, and against resistant and normally-sensitive species. By controlling the pathogenic endoparasites, it is intended to reduce disease, deaths and reduced productivity (for example in the production of meat, milk, wool, hides, eggs, honey and the like), so that more economical and simpler animal keeping is possible by employing the active substances. The pathogenic endoparasites include Cestodes, Trematodes, Nematodes, Acanthocephala, in particular:
From the order of the Pseudophyllidea, for example Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoporus spp..
From the order of the Cyclophyllidea, for example Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp..
From the subclass of the Monogenea, for example Gyrodactylus spp., Dactylogyrus spp., Poly stoma spp..
From the subclass of the Digenea, for example Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium spp., Echinochasmus 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., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp..
From the order of the Enoplida, for example Trichuris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp..
From the order of the Rhabditia, for example Micronema spp., Strongyloides spp..
From the order of the Strongylida, for example Strongylus spp., Triodontophorus spp., Oesophagodontus spp . , Trichonema spp . , Gyalocephalus spp . , Cylindropharynx spp . , Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp . , Uncinaria spp ., Bunostomum spp . , Globocephalus spp., Syngamus spp., Cyathostomum 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., Cylicocyclus spp., Cylicodontophorus spp..
From the order of the Oxyurida, for example Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp..
From the order of the Ascaridia, for example Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp..
From the order of the Spirurida, for example Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.. From the order of the Filariida, for example Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp..
From the group of the Gigantohynchida, for example Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp..
Preferred is the control of tapeworms, for example Taenia spp. Equally preferred is the control of nematodes such as, for example,
From the order of the Spirurida, for example Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp..
Especially preferred is the use of the products according to the invention for controlling Strongylida, in particular Haemonchus spp., Trichostrongylus spp., Cooperia spp. and Ostertagia spp., and Ascaridida such as, for example, Parascaris spp.
Ectoparasites are typically and preferably arthropods, in particular insects such as flies (biting and licking), parasitic fly larvae (blowflies, flesh flies, warble flies, botflies), midges, black flies, sand flies, gnats, horse flies, bugs, lice, hair lice, bird lice, fleas, keds and the like; or acarids such as ticks, for example hard ticks or soft ticks, or mites such as scab mites, harvest mites, bird mites and the like. These ectoparasitic arthropods include:
From the order of the Anoplurida, for example Haematopinus spp., Linognathus spp., Pediculus spp., Phtirus spp., Solenopotes spp.; specific examples are: Linognathus setosus, Linognathus vituli, Linognathus ovillus, Linognathus oviformis, Linognathus pedalis, Linognathus stenopsis, Haematopinus asini macrocephalus, Haematopinus eurysternus, Haematopinus suis, Pediculus humanus capitis, Pediculus humanus corporis, Phylloera vastatrix, Phthirus pubis, Solenopotes capillatus;
From the order of the Mallophagida and the suborders Amblycerina and Ischnocerina, for example Trimenopon spp., Menopon spp., Trinoton spp., Bovicola spp., Wemeckiella spp., Lepikentron spp., Damalina spp., Trichodectes spp., Felicola spp.; specific examples are: Bovicola bovis, Bovicola ovis, Bovicola limbata, Damalina bovis, Trichodectes canis, Felicola subrostratus, Bovicola caprae, Lepikentron ovis, Wemeckiella equi; From the order of the Diptera and the suborders Nematocerina and Brachycerina, for example Aedes spp., Anopheles spp., Culex spp., Simulium spp., Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culicoides spp., Chrysops spp., Odagmia spp., Wilhelmia spp., Hybomitra spp., Atylotus spp., Tabanus spp., Haematopota spp., Philipomyia spp., Braula spp., Musca spp., Hydrotaea spp., Stomoxys spp., Haematobia spp., Morellia spp., Fannia spp., Glossina spp., Calliphora spp., Lucilia spp., Chrysomyia spp., Wohlfahrtia spp., Sarcophaga spp., Oestrus spp., Hypoderma spp., Gasterophilus spp., Hippobosca spp., Lipoptena spp., Melophagus spp., Pvhinoestrus spp., Tipula spp.; specific examples are: Aedes aegypti, Aedes albopictus, Aedes taeniorhynchus, Anopheles gambiae, Anopheles maculipennis, Calliphora erythrocephala, Chrysozona pluvialis, Culex quinquefasciatus, Culex pipiens, Culex tarsalis, Fannia canicularis, Sarcophaga carnaria, Stomoxys calcitrans, Tipula paludosa, Lucilia cuprina, Lucilia sericata, Simulium reptans, Phlebotomus papatasi, Phlebotomus longipalpis, Odagmia omata, Wilhelmia equina, Boophthora erythrocephala, Tabanus bromius, Tabanus spodopterus, Tabanus atratus, Tabanus sudeticus, Hybomitra ciurea, Chrysops caecutiens, Chrysops relictus, Haematopota pluvialis, Haematopota italica, Musca autumnalis, Musca domestica, Haematobia irritans irritans, Haematobia irritans exigua, Haematobia stimulans, Hydrotaea irritans, Hydrotaea albipuncta, Chrysomya chloropyga, Chrysomya bezziana, Oestrus ovis, Hypoderma bovis, Hypoderma lineatum, Przhevalskiana silenus, Dermatobia hominis, Melophagus ovinus, Lipoptena capreoli, Lipoptena cervi, Hippobosca variegata, Hippobosca equina, Gasterophilus intestinalis, Gasterophilus haemorroidalis, Gasterophilus inermis, Gasterophilus nasalis, Gasterophilus nigricornis, Gasterophilus pecorum, Braula coeca; From the order of the Siphonapterida, for example Pulex spp., Ctenocephalides spp., Tunga spp., Xenopsylla spp ., Ceratophyllus spp.; specific examples are : Ctenocephalides canis, Ctenocephalides felis, Pulex irritans, Tunga penetrans, Xenopsylla cheopis;
From the order of the Heteropterida, for example Cimex spp., Triatoma spp., Rhodnius spp., Panstrongylus spp.
From the order of the Blattarida, for example Blatta orientalis, Periplaneta americana, Blattela germanica, Supella spp. (for example Suppella longipalpa); From the subclass of the Acari (Acarina) and the orders of the Meta- and Mesostigmata, for example Argas spp ., Ornithodorus spp . , Otobius spp . , Ixodes spp ., Amblyomma spp . , Rhipicephalus (Boophilus) spp., Dermacentor spp., Haemophysalis spp., Hyalomma spp., Dermanyssus spp. , Rhipicephalus spp . (the original genus of the multiple-host ticks), Ornithonyssus spp., Pneumonyssus spp., Raillietia spp., Pneumonyssus spp., Sternostoma spp., Varroa spp., Acarapis spp.; specific examples are: Argas persicus, Argas reflexus, Ornithodorus moubata, Otobius megnini, Rhipicephalus (Boophilus) microplus, Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) annulatus, Rhipicephalus (Boophilus) calceratus, Hyalomma anatolicum, Hyalomma aegypticum, Hyalomma marginatum, Hyalomma transiens, Rhipicephalus evertsi, Ixodes ricinus, Ixodes hexagonus, Ixodes canisuga, Ixodes pilosus, Ixodes rubicundus, Ixodes scapularis, Ixodes holocyclus, Haemaphysalis concinna, Haemaphysalis punctata, Haemaphysalis cinnabarina, Haemaphysalis otophila, Haemaphysalis leachi, Haemaphysalis longicorni, Dermacentor marginatus, Dermacentor reticulatus, Dermacentor pictus, Dermacentor albipictus, Dermacentor andersoni, Dermacentor variabilis, Hyalomma mauritanicum, Rhipicephalus sanguineus, Rhipicephalus bursa, Rhipicephalus appendiculatus, Rhipicephalus capensis, Rhipicephalus turanicus, Rhipicephalus zambeziensis, Amblyomma americanum, Amblyomma variegatum, Amblyomma maculatum, Amblyomma hebraeum, Amblyomma cajennense, Dermanyssus gallinae, Ornithonyssus bursa, Ornithonyssus sylviarum, Varroa jacobsoni; From the order of the Actinedida (Prostigmata) and Acaridida (Astigmata), for example Acarapis spp., Cheyletiella spp., Ornithocheyletia spp., Myobia spp., Psorergates spp., Demodex spp., Trombicula spp., Listrophorus spp., Acarus spp., Tyrophagus spp., Caloglyphus spp., Hypodectes spp., Pterolichus spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Cytodites spp., Laminosioptes spp.; specific examples are: Cheyletiella yasguri, Cheyletiella blakei, Demodex canis, Demodex bovis, Demodex ovis, Demodex caprae, Demodex equi, Demodex caballi, Demodex suis, Neotrombicula autumnalis, Neotrombicula desaleri, Neoschongastia xerothermobia, Trombicula akamushi, Otodectes cynotis, Notoedres cati, Sarcoptis canis, Sarcoptes bovis, Sarcoptes ovis, Sarcoptes rupicaprae (=S. caprae), Sarcoptes equi, Sarcoptes suis, Psoroptes ovis, Psoroptes cuniculi, Psoroptes equi, Chorioptes bovis, Psoergates ovis, Pneumonyssoidic mange, Pneumonyssoides caninum, Acarapis woodi. The abovementioned active substances can be employed for controlling arthropods which attack animals.
By controlling these arthropods and/or endoparasites, it is intended to reduce deaths and to improve the productivity (in respect of meat, milk, wool, hides, eggs, honey and the like) and the health of the host animal, so that more economical and simpler animal keeping is possible by employing the active substances according to the invention.
Thus, for example, it is desirable to prevent or to interrupt the uptake of host blood by the parasites. Controlling the parasites can additionally contribute to preventing the transmission of infectious substances.
The expression "control", as it is used in the present context in the field of animal health, means that the active substances act by reducing the occurrence of the parasite in question, in an animal infested with such parasites, to harmless levels. More precisely, the "control" as used in the present context means that the active substance kills the parasite in question, inhibits its growth or inhibits its proliferation.
The productive livestock include, in particular, mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, furbearers such as, for example, mink, chinchilla, raccoon. Preferred among the mammalian productive livestock are cattle, sheep and pigs.
Also included for the use according to the invention are the following animal species, which are not mammals, but which also belong to the productive livestock: birds such as, for example, chickens, geese, turkeys, ducks; freshwater and salt-water fish such as, for example, trout, carp, eels; reptiles; insects such as, for example, honeybees and silkworm. The pets preferably include dogs and cats. In these, it is preferred to control Toxoscaris spp., Toxocara spp., Trichuris spp., Trichinella spp. and the hookworms Ancylostoma spp. and Uncinaria spp.. In accordance with a further embodiment, the products may also be employed in humans. In humans, it is preferred to control Ascaris spp., Ancylostoma spp., Necator spp., Trichuris spp., Strongyloides spp. and Enterobius spp..
Among the mammals, it is the herbivores (plant eaters) which are preferred for the use of the abovementioned combinations in accordance with one embodiment, in other words, animals which feed mainly on plants. The treatment of ruminants (such as, for example, sheep, goats, cattle) is particularly preferred.
Nonruminant herbivores which are mammals and which may be mentioned as a preferred example are horses. In horses, the abovementioned combinations can be employed preferably for example for controlling Strongylida or in particular roundworms (Ascaridia), such as, for example, Parascaris equorum.
Among the ruminants, it is preferably Strongylida, in particular Haemonchus spp., Trichostrongylus spp., Cooperia spp. and Ostertagia spp., which can be controlled.
In accordance with the invention, sheep are treated with particular preference.
In accordance with the invention, cattle are also treated with particular preference.
The application can be effected both prophylactically and therapeutically.
The active substance is applied directly or in the form of suitable preparations, enterally, parenterally, dermally, nasally, by treating the environment, or with the aid of active-substance- containing shaped articles such as, for example, strips, discs, tapes, collars, ear tags, limb bands, marking devices.
The enteral application of the active substance is effected orally for example in the form of powders, suppositories, tablets, capsules, pastes, drinks, granules, drenches, boluses, medicated feed or drinking water. It is applied dermally for example in the form of dipping, spraying, bathing, washing, pouring-on and spotting-on and dusting. It is administered parenterally for example in the form of an 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 and spot-on formulations, gels;
Emulsions and suspensions for oral or dermal administration and for injection; semi-solid preparations; Formulations in which the active substance is incorporated into an ointment base or into an oil-in- water or water-in-oil emulsion base;
Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules, aerosols and inhalants, active-substance-containing shaped articles.
Solutions for injection are administered intravenously, intramuscularly and subcutaneously.
Oral solutions are employed directly. Concentrates are used orally after previously having been diluted to the use concentration.
Solutions for use on the skin are trickled on, painted on, rubbed in, sprinkled on, sprayed on or applied by dipping, bathing or washing.
Gels are applied to or painted on to the skin or introduced into body cavities.
Pour-on and spot-on formulations are poured or sprinkled on to limited areas of the skin, the active substance either penetrating the skin and acting systemically or spreading over the body surface.
Emulsions can be employed orally, dermally or in the form of an injection. Emulsions are either of the water-in-oil type or of the oil-in-water type.
Suspensions can be employed orally, dermally or in the form of an injection.
Semi-solid preparations can be administered orally or dermally.
To prepare solid preparations, the active substance is mixed with suitable carriers, if appropriate with the addition of adjuvants, and shaped as desired. If appropriate, the products according to the invention may contain further active substances.
The use in combination means that either the anthelmintically active macrocyclic lactones and the active substances which act as combination partners are formulated in a combined preparation and, accordingly, applied jointly. However, the products can also comprise separate preparations for each active substance. In the event that it is intended to employ more than two active substances, all active substances can, correspondingly, be formulated in combined preparations, all active substances can be formulated in separate formulations, and also feasible are mixed forms, where some of the active substances are formulated together and some of the active substances are formulated separately.
Separate formulations permit the separate or staggered application of the active substances in question.
The compositions contain the active substances in each case in concentrations of from 0.1 ppm to 90% by weight, preferably from 0.1 to 50% by weight.
Ready-to-use preparations usually contain the active substances in concentrations of from in each case 0.1 ppm to 20% by weight, preferably from 0.1 to 10% by weight.
Preparations which are diluted prior to administration contain the active substances in concentrations of from 0.5-90% by weight, preferably from 5 to 50% by weight. Customary dosages of the macrocyclic lactones per day are from 0.1 to 100 mg/kg bodyweight, preferably from 2 to 60 mg/kg bodyweight.
Customary dosages of the depsipeptides per day are from 0.1 to 100 mg/kg, preferably from 0.5 to 50 mg/kg, especially preferably from 1 to 50 mg/kg bodyweight per day.

Claims

Patent claims
1. Compounds
Figure imgf000022_0001
for controlling endoparasitic filariae and gastrointestinal nematodes.
2. Use according to Claim 1 for the preparation of compositions for controlling heartworm (Dirofilaria immitis).
3. Derivatives of the compounds I and II selected from the group
oximes or oxime methyl ether oxime carbamates (preferably in position 23),
carbohydrate derivatives.
- esters and dicarboxylic acid esters,
sulphonic acids,
sulphinic acids,
(thio)ethers;
azoles;
- (thio)carbamates;
hydrazones,
(thio)semicarbazones;
halogens;
(thio)carbonates,
- amino acid esters,
hydroxyl.
halogen,
- alkyl, alkenyl,
aryl and
aralkyl.
Derivatives according to Claim 3 for controlling endoparasitic filariae and nematodes which occur in the stomach and/or the gut of the host animals (so-called gastrointestinal nematodes).
Derivatives according to Claim 3 for controlling heartworm (Dirofilaria immitis).
Composition, containing one or more compounds according to Claims 1 to 3.
Composition according to Claim 6, additionally containing active substances selected from the group
cyclic depsipeptides, such as, for example, emodepside or PF1022
benzimidazoles su ch as , fo r e xamp l e , albendazole, fenbendazole, mebendazole, oxfendazole
levamisole, tetramisole
pyrantel, morantel; monepantel
paraherquamide
praziquantel, epsiprantel
triclabendazole; clorsulon
salicylanilides such as, for example, niclosamide, rafoxanide, oxyclozanide, closantel etc. by way of example, but not by limitation, other macrocyclic lactones (such as, for example, ivermectin, avermectin; abamectin; eprinomectin, nemamectin, moxidectin; milbemycin, selamectin).
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