EP1192142A1 - Cyclo-iminodepsipeptides et leur utilisation pour lutter contre les endoparasites - Google Patents

Cyclo-iminodepsipeptides et leur utilisation pour lutter contre les endoparasites

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Publication number
EP1192142A1
EP1192142A1 EP00936833A EP00936833A EP1192142A1 EP 1192142 A1 EP1192142 A1 EP 1192142A1 EP 00936833 A EP00936833 A EP 00936833A EP 00936833 A EP00936833 A EP 00936833A EP 1192142 A1 EP1192142 A1 EP 1192142A1
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EP
European Patent Office
Prior art keywords
alkyl
optionally substituted
methyl
hetaryl
aryl
Prior art date
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Application number
EP00936833A
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German (de)
English (en)
Inventor
Peter Jeschke
Achim Harder
Georg Von Samson-Himmelstjerna
Gerhard Bonse
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Bayer AG
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Bayer AG
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Publication of EP1192142A1 publication Critical patent/EP1192142A1/fr
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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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to cycloiminodepsipeptides, in particular 24-membered cycloiminodepsipeptides, processes for their preparation and their use for combating endoparasites.
  • Naturally occurring peptides with an iminopeptide bond or an amidine group in the molecule are extremely rare. Examples include bottromycin, a peptide antibiotic from Streptomyces bottropensis, amidinomycin or netropsin (JM Waiswisz et al., J. Am. Chem. Soc. 79, 1957, p. 4520; S. Nakamura Chem. Phar. Bull 9, 1961, p. 641; S. Nakamura et al, J. Antibiot. 17A, 1964, p. 220).
  • Chemotactic peptides of the type N-Fon ⁇ yl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe-OR) are interesting as prototype bioregulators of immune cells - for example, they induce the release of lysozyme from human neutrophils (SV Rao et al, Spectroscopy (Ottawa) 4 (3), 1985, p. 153; B. Belleau et al., Int. J. Immunopharmacol. 11 (5), 1989, p. 467; E. Schiffmann et al., Proc. Natl Acad. Sci. USA 72, 1975, p.
  • cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring building blocks and 24 ring atoms, from corresponding cyclothiodepsipeptides.
  • Cyclic depsipeptides and their preparation and use as endoparasiticides have already been the subject of numerous publications.
  • PF 1022A cyclodepsipeptide
  • Cyclotetradepsipeptides EP-OS 664 297; Dioxomorpholines: WO 96/38 165; JP 08 225 552) and open-chain depsipeptides (EP-OS 657 171; EP-OS 657 172; EP-OS 657 173; WO 97/07 093) and their endoparasiticidal activity are described.
  • Cyclothiodepsipeptides consisting of amino acids, hydroxythiocarboxylic acids and optionally hydroxycarboxylic acids as ring building blocks and 24 ring atoms, their preparation and their use for controlling endoparasites is the subject of a previous patent application (WO 98/43 965) by the applicant.
  • the present invention also relates to a process for the preparation of cycloiminodepsipeptides, in particular cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring components and 24 ring atoms.
  • cycloiminodepsipeptides in particular cycloiminodepsipeptides, consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring building blocks and 24 ring atoms, for the preparation of agents for controlling endoparasites.
  • the present invention relates in particular to:
  • R 1 , R 4 , R 7 and R 10 independently of one another represent hydrogen, straight-chain or branched alkyl
  • R 2 , R 5 , R 8 and R n independently of one another represent hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl and aryl or hetaryl,
  • R 10 and R u together with the atoms to which they are attached represent an optionally substituted 5- or 6-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxy or sulfonyl,
  • R 6 and R 12 independently of one another represent hydrogen, optionally substituted alkyl or arylalkyl, and optionally substituted cycloalkylalkyl,
  • R 3 and R 9 independently of one another represent hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, cycloalkyl, alkoxycarbonylalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl, aryl or hetaryl, and
  • a for hydrogen optionally substituted alkyl, alkenyl, alkynyl,
  • Alkylcarbonyl, alkylsulfonyl, and cyano, nitro, carbamoyl, alkoxycarbonyl, formyl, - (C NH) -NH 2 , -P (0) -0-alkyl, -P (S) -0- alkyl or optionally for a radical A. 1
  • Y represents oxygen, sulfur or -NR 14 ,
  • R 13 and R 14 independently of one another for hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl, aryl or hetaryl as well as for formyl, alkoxydicarbonyl, alkylsulfonyl, haloalkoxyalkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbony
  • R 15 for hydrogen, hydroxy, alkoxy, alkylcarbonyl, alkoxycarbonyl,
  • R 16 represents hydrogen or alkyl
  • n 0, 1 or 2
  • Y 1 represents oxygen, sulfur or -NR 17 , R 18 , when Y 1 is nitrogen, can mean a cyclic amino group linked via this nitrogen atom,
  • R 17 and R 18 independently of one another represent hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, aryl, arylalkyl, hetaryl or hetarylalkyl, or
  • R 19 and R 20 independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl and optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl, or
  • R 19 and R 20 together represent an optionally substituted spirocyclic ring
  • R 20 and R 21 together with the atoms to which they are attached represent an optionally substituted 5-, 6- or 7-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl,
  • R 21 represents hydrogen, optionally substituted, straight-chain or branched alkyl, cycloalkyl, arylalkyl, hetarylalkyl, and aryl or hetaryl
  • R 22 represents hydrogen, optionally substituted straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cyano, arylalkyl, hetarylalkyl, and aryl or hetaryl,
  • R 13 can also stand for a selectively cleavable protective group, or a polymeric carrier which is connected to Y via a selectively cleavable anchor group,
  • the compounds of the general formula (I) can occur as geometric and / or optical isomer mixtures and also regioisomer mixtures of different compositions.
  • the invention relates to both the pure isomers and the isomer mixtures.
  • cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring units and 24 ring atoms, of the general formula (I) are preferred
  • R 1 , R 4 , R 7 and R 10 are straight-chain or branched C 4 alkyl, in particular methyl,
  • R 2 , R 5 , R 8 and R 11 independently of one another are C - alkyl, in particular isobutyl,
  • R 6 and R 12 independently of one another for optionally substituted d 4 -alkyl or aryl-C 1 -C 2 -alkyl, in particular optionally substituted
  • R 3 and R 9 independently of one another for optionally Hetaryl -C 2 alkyl, C 4 alkoxycarbonylmethyl, aryl C 2 alkyl, in particular optionally substituted benzyl,
  • R 23 and R 24 independently of one another each represent hydrogen, Ci -Cg-
  • R 23 and R 24 together with the nitrogen atom to which they are attached for hetaryl or heterocycloalkyl, in particular N-
  • a for hydrogen, optionally substituted C ⁇ - alkyl, 0 2 ⁇ - alkenyl, C 2- alkynyl, C 1 -C 4 alkylcarbonyl, C ⁇ . 6 - alkylsulfonyl and cyano, nitro, carbamoyl, C 2 - 6 alkoxycarbonyl, formyl, - (C NH) -NH 2 , -P (0) -0-C ⁇ -3 -alkyl, -P (S) -0 -C ⁇ -3 -
  • Y represents oxygen or -NR 14 ,
  • R 13 and R 14 independently of one another for hydrogen, optionally substituted, straight-chain or branched C 8 alkyl, C 2 8 alkenyl, C 2 8 alkynyl, C 3-7 cycloalkyl, C 3 . 7- cycloalkyl-C 1 . 2 -alkyl,
  • G ⁇ stands for thiocarboxy or carboxy
  • R 15 represents hydrogen, hydroxyl, C M - alkoxy, C M - alkylcarbonyl, C ⁇ - alkoxycarbonyl, halogen -CC-4-alkylcarbonyl, C M - alkylsulfonyl, nitro or cyano,
  • R 16 represents hydrogen or C M - alkyl
  • n 0, 1 or 2
  • Y 1 represents oxygen, sulfur or -NR 17 ,
  • R 18 when Y 1 is nitrogen, can mean a cyclic amino group linked via this nitrogen atom,
  • R 17 and R 18 independently of one another for hydrogen, optionally substituted, straight-chain or branched Ci -6- alkyl, C2-6-alkenyl, C2-6-alkynyl, C 3 . 7 -
  • Cycloalkyl C 3 . -Cycloalkyl-C ⁇ - 6 alkyl, -C ⁇ -6 - alkoxycarbonyl, aryl, aryl-C ⁇ - 2 - alkyl, hetaryl, hetaryl-C ⁇ _ 2 -alkyl, or
  • R 19 and R 20 independently of one another for hydrogen, optionally substituted straight-chain or branched C 6 alkyl, C2 6 alkenyl, C 3 7 cycloalkyl and optionally substituted aryl, aryl C 2 alkyl, hetaryl, hetaryl C ⁇ - 2 alkyl, or
  • R 19 and R 20 together represent an optionally substituted spirocyclic ring
  • R 20 and R 21 together with the atoms to which they are attached represent an optionally substituted 5-6- or 7-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl,
  • R 21 represents hydrogen, optionally substituted, straight-chain or branched C 6 alkyl, C 3 .7 cycloalkyl, aryl C 2 alkyl, hetaryl C 2 alkyl, and aryl or hetaryl,
  • R 22 is hydrogen, optionally substituted, straight or branched C ⁇ -, 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C. 3 7- Cycloalkyl, C 3- - Cycloalkyl-C ⁇ -6 -alkyl, C ⁇ . 6 - alkoxycarbonyl, C ⁇ _ 6 - alkylcarbonyl, C 3-7 -
  • R 13 also for a selectively removable protective group, for example allyl, allyloxycarbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl (Z), tert.-
  • Butyloxycarbonyl (Boc), tetrahydropyran-2-yl (THP) or fluorenyl methoxycarbonyl (Fmoc) and stands for a polymeric carrier which is bonded to Y by means of a selectively cleavable anchor group,
  • cycloiminodepsipeptides according to the invention and their salts are generally defined by the general formula (I).
  • cycloiminodepsipeptides according to the invention and their acid addition salts and metal salt complexes have good endoparasiticides, in particular anthelmintic ones
  • R to R have the meanings given under point 1, and
  • the process according to the invention relates in particular and preferably to the preparation of the new cycloiminodepsipeptides of the general formula (Ia)
  • metal salts or metal oxides in particular mercury (I ⁇ ) acetate, mercury (I ⁇ ) chloride or mercury (II) oxide, and in the presence of a basic reaction auxiliary and in the presence of a suitable diluent, or
  • A stands for a residue -YR 13 (A 1 ), in which
  • R 13 stands for residues from group B 1 to B 3 .
  • W stands for a suitable leaving group, such as halogen
  • R 13 represents radicals from the groups B 1 and B 3 ,
  • n 0,
  • the invention further relates to:
  • A stands for a residue -YR 13 (A 1 ),
  • Y represents oxygen or -N-H
  • R 13 for a selectively removable protective group for example allyl, allyloxycarbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl (Z), tert-
  • R 1 to R 12 have the meanings given under point 1,
  • Y is oxygen or -N-H
  • R 13 represents a selectively cleavable anchor group on a polymeric support
  • the cycloiminodepsipeptides according to the invention and their salts are generally defined by the general formula (I).
  • the cycloiminodepsipeptides according to the invention and their acid addition salts and metal complexes have good endoparasiticidal, in particular anthelmintic, effects and can preferably be used in the field of veterinary medicine.
  • Optionally substituted alkyl alone or as part of a radical in the general formulas means straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples include optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1, 1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3- Dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-
  • Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl may preferably be mentioned.
  • Optionally substituted alkenyl alone or as part of a radical in the general formulas means straight-chain or branched alkenyl with preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples include optionally substituted vinyl, 2-propenyl, 2-butenyl, 3-butenyl, l-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, l-methyl- 2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, l-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, l, l-dimethyl 2-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, l-methyl-2-pentenyl, 2-methyl-
  • Methyl-3-pentenyl 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, l, l-dimethyl-2-butenyl, l, l-dimethyl-3-butenyl, l, 2-dimethyl-2-butenyl, l, 2- Dimethyl-3-butenyl, l, 3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, l-ethyl- 2-butenyl, l-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 1, 2-trimethyl-2-propenyl, 1-ethyl-l-methyl-2- called propenyl and l-ethyl
  • Optionally substituted ethenyl, 2-propenyl, 2-butenyl or 1-methyl-2-propenyl may preferably be mentioned.
  • Optionally substituted alkynyl alone or as part of a radical in the general formulas means straight-chain or branched alkynyl with preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples include optionally substituted ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, l-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-methyl-3-butynyl, 2-methyl- 3-butynyl, l-methyl-2-butynyl, l, l-dimethyl-2-propynyl, l-ethyl-2-propynyl, 2-hexynyl, 3-
  • Optionally substituted cycloalkyl alone or as part of a radical in the general formulas means mono-, bi- and tricyclic cycloalkyl, preferably having 3 to 10, in particular 3, 5 or 7, carbon atoms.
  • Examples of optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and adamantyl may be mentioned.
  • Haloalkyl alone or as a constituent of a radical in the general formulas contains 1 to 4, in particular 1 or 2, carbon atoms with preferably 1 to 9, in particular 1 to 5 identical or different halogen atoms, preferably fluorine, chlorine or bromine, in particular fluorine or chlorine.
  • Examples include trifluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, chloromethyl, bromomethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2, 2-difluoroethyl, pentafluoroethyl and pentafluoro-tert-butyl called.
  • Optionally substituted alkoxy alone or as part of a radical in the general formulas means straight-chain or branched alkoxy with preferably 1 to 6, in particular 1 to 4, carbon atoms. Substituted methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy may be mentioned as examples.
  • Optionally substituted alkoxyalkoxy alone or as a constituent of a radical in the general formulas means 2 C-O-linked alkoxy radicals as mentioned above. Substituted methoxymethoxy, methoxyethoxy, methoxy-n-propoxy and ethoxyisopropoxy may be mentioned as examples.
  • Optionally substituted alkoxyalkoxyalkoxy, alone or as part of a radical in the general formulas, 3 each means C-O-linked alkoxy radicals as mentioned above. Substituted methoxymethoxyethoxy, methoxyethoxyethoxy and methoxyethoxy-n-propoxy may be mentioned as examples.
  • Optionally substituted haloalkoxy alone or as part of a radical in the general formulas means straight-chain or branched haloalkoxy with preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples include optionally substituted difluoromethoxy, trifluoromethoxy, trichloromethoxy, Chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy and 2-chloro-l, l, 2-trifluoroethoxy.
  • Optionally substituted alkylthio alone or as part of a radical in the general formulas means straight-chain or branched alkylthio with preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples of optionally substituted methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio and tert-butylthio may be mentioned.
  • the rest in the general formulas mean straight-chain or branched haloalkylthio having preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples include optionally substituted difluoromethylthio, trifluoromethylthio, trichloromethylthio, chlorodifluoromethylthio, 1-fluoroethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio, 1,1,2,2-tetrafluoroethylthio, 2,2,2-trifluoroethylthio and 2- Chlorine-l, l, 2-trifluoroethylthio called.
  • Optionally substituted alkylcarbonyl alone or as part of a radical in the general formulas means straight-chain or branched alkylcarbonyl having preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples of optionally substituted methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, sec-butylcarbonyl and tert-butylcarbonyl may be mentioned.
  • Optionally substituted cycloalkylcarbonyl alone or as part of a radical in the general formulas means mono-, bi- and tricyclic cycloalkylcarbonyl, preferably having 3 to 10, in particular 3, 5 or 7, carbon atoms.
  • optionally substituted cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, bicyclo [2.2.1] heptylcarbonyl, bicyclo [2.2.2] octylcarbonyl and adamantylcarbonyl may be mentioned.
  • Optionally substituted alkoxycarbonyl alone or as part of a radical in the general formulas means straight-chain or branched alkoxycarbonyl with preferably 2 to 7, in particular 2 to 5, carbon atoms.
  • Examples of optionally substituted methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl may be mentioned.
  • Aryl is, for example, a mononuclear, polynuclear or polynuclear aromatic radical such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl and the like, but preferably phenyl or naphthyl.
  • Optionally substituted aryl in the general formulas preferably means optionally substituted phenyl or naphthyl, especially phenyl.
  • Optionally substituted arylalkyl in the general formulas preferably means optionally substituted arylalkyl in the aryl part and / or alkyl having preferably 6 or 10, in particular 6 carbon atoms in the aryl part (preferably phenyl or naphthyl, in particular phenyl) and preferably 1 to 4, in particular 1 or 2 carbon atoms in the Alkyl part, where the alkyl part can be straight-chain or branched.
  • Exemplified and preferred are optionally substituted benzyl and 1-phenyl ethyl.
  • the optionally substituted radicals of the general formulas can carry one or more, preferably 1 to 3, in particular 1 to 2 identical or different substituents.
  • Examples of preferred substituents are:
  • Methoxycarbonyl and ethoxycarbonyl Alkylsulfmyl having 1 to 4, in particular 1 to 2, carbon atoms; Haloalkylsulfinyl with 1 to 4, in particular 1 to 2, carbon atoms and 1 to 5 halogen atoms, such as trifluoromethylsulfinyl; Haloalkylsulfonyl with 1 to 4, in particular 1 to 2, carbon atoms and 1 to 5 halogen atoms, such as trifluoromethylsulfonyl, perfluoro-n-butylsulfonyl, perfluoroisobutylsulfonyl; Arylsulfonyl preferably having 6 or 10 aryl carbon atoms such as phenylsulfonyl; Acyl, aryl, aryloxy, which in turn is one of the above
  • the number of these substituents is not limited, it is preferably one to four identical or different substituents.
  • the presence of two identical or different substituents on the same atom or on atoms of cyclic amino groups is also conceivable.
  • Optionally substituted mono- or dialkylamino groups alone or as part of a radical in the general formulas means straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • Examples of substituted mono- or dialkylamino groups are methylamino, ethylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino or dibutylamino.
  • Optionally substituted mono- or dialkoxyalkylamino groups alone or as part of a radical in the general formulas means straight-chain or branched alkoxyalkyl with preferably 1 to 6, in particular 1 to 4, carbon atoms.
  • substituted mono- or dialkoxyalkylamino groups are methoxymethylammo, methoxyethylamino, di- (methoxymethyl) -amino or di- (methoxyethyl) -amino.
  • Suitable cyclic amino groups are heteroaromatic or aliphatic ring systems with one or more nitrogen atoms as the heteroatom
  • heterocycles can be saturated or unsaturated, one ring system or several condensed ring systems, and optionally contain further heteroatoms such as one or two nitrogen, oxygen and sulfur, etc.
  • cyclic amino groups can also mean a spiro ring or a bridged ring system. The number of atoms, the cyclic
  • Forming amino groups is not limited, for example they consist of 3 to 8 atoms in the case of a single-ring system and 7 to 11 atoms in the case of a three-ring system.
  • cyclic amino groups with saturated and unsaturated monocyclic groups with a nitrogen atom as heteroatom are 1-azetidinyl, pyrrolidino, 2-pyrrolin-l-yl, 1-pyrrolyl, piperidino, 1,4-dihydropyrazin-l-yl, 1, 2,5,6-tetrahydropyrazine-1-yl, 1,4-dihydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-l-yl, called homopiperidinyl; exemplary of cyclic amino groups with saturated and unsaturated monocyclic groups with two or more
  • Nitrogen atoms as heteroatoms are 1-imidazolidinyl, 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 1-tetrazolyl, 1-piperazinyl, 1-homopiperazinyl, 1,2-dihydro-pyridazin-1-yl, 1,2-dihydro- called pyrimidin-l-yl, perhydropyrimidin-1-yl, 1,4-diazacyclo-heptan-l-yl; exemplary of cyclic amino groups with saturated and unsaturated monocyclic groups with one or two oxygen atoms and one to 3 nitrogen atoms as heteroatoms, such as oxazolidin-3-yl, 2,3-dihydroisoxazol-2-yl, isoxazol-2-yl, l, 2,3-oxadiazin-2-yl, morpholino, for example for cyclic amino groups with saturated and unsaturated monocyclic groups with one to three nitrogen atoms and one or
  • Suitable monovalent amino protecting groups are acyl groups, preferably having 1 to 6, in particular 1 to 4, carbon atoms, such as, for example, formyl, acetyl, propionyl, pivaloyl, hexanoyl or mono- (or di- or tri-)
  • Halogen-containing acyl groups such as 2-chloro, 2-bromo, 2-iodo, 2,2-dichloroacetyl, 2,2,2-trifluoroacetyl or 2,2,2-trichloroacetyl, alkoxycarbonyl- g ppen with preferably 1 to 14, in particular 1 to 4 carbon atoms, such as, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl (Boc), tert-amyloxycarbonyl (Aoc), hexyloxycarbonyl, methylsulfonylethoxycarbonyl, adamantyloxycarbonyl (Adoc) and l- [l-adamantyl] -l-methylethoxycarbonyl (Adpoc), carbamoyl groups, aroyl groups, such as, for example, phenylacetyl and phenylpropionyl, aryloxycarbon
  • Phenylglyoxyloyl and naphthylglyoxyloyl, alkoxycarbonyl groups with common substituents such as, for example, benzyloxycarbonyl (Cbo- or Cbz, Z), 4-methoxybenzyloxycarbonyl, 3,5-dimethoxy-benzyloxycarbonyl, 4-phenylazo-benzyl-oxycarbonyl, phenethyloxycarbonylcarbonyl, nitro-chlorobenzyl benzyl-oxycar-bonyl, ⁇ , ⁇ -dimethyl-3,5-dimethoxy-benzyloxycarbonyl, 2-nitro-4,5-dimethoxy-benzyl-oxycarbonyl (Nvoc), fluorenyl-9-methoxycarbonyl (Fmoc), Substituted or unsubstituted alkyl groups, such as, for example, benzylidene, hydroxybenzylidene, mono- (or di- or tri-
  • 1-lower alkoxy for example methoxy or ethoxy
  • lower alkylidene for example ethylidene or 1-n-butylidene
  • bisacyl radicals e.g. B. the phthalyl radical, which
  • Suitable hydroxy protective groups are optionally substituted alkyl groups having preferably 1 to 6, in particular 1 to 4, carbon atoms, such as, for example, tert-butyl, methylthiomethyl and trimethylsilyl, phenylalkyl-containing alkyl groups, such as, for example, benzyl or diphenylmethyl, heterocyclic groups such as tetrahydropyranyl and the like .
  • Suitable thiol protecting groups are optionally substituted alkyl groups having preferably 1 to 6, in particular 1 to 4, carbon atoms, such as, for example, acetamidomethyl and chloroacetamidomethyl, arylalkyl-containing alkyl groups, such as, for example, benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylrnethyl and pyridyldiphenylmethyl and the like.
  • the protective groups mentioned above have the function known in peptide chemistry of temporarily protecting amino, hydroxyl or thiol groups of compounds.
  • Suitable synthetic resins for use as polymeric supports for the solid-phase synthesis of the cyclodepsipeptides according to the invention are appropriately functionalized basic polymers (in the most widespread form on a chloromethylated polystyrene), such as amino-oxy- or hydrazino-functionalized resins of the Merrifield type .
  • the commercially available DHP HM resin from Novabiochem is particularly suitable here, it allows simple anchoring with a hydroxylamino or hydrazo function and thus enables the cyclodepsipeptides according to the invention to be provided.
  • R 1 , R 4 , R 7 and R 10 represent methyl
  • R 2 , R 5 , R 8 and R 1 * represent isobutyl
  • R 6 and R 12 represent methyl
  • R 3 and R 9 independently of one another represent optionally substituted benzyl, may be mentioned being the substituents hydrogen, halogen, in particular bromine, fluorine, chlorine or iodine, cyano, carbamoyl, carries a protective group hydroxy or unprotected hydroxy, C ⁇ -8 - alkoxy, especially methoxy , tert-butyloxy, C M alkoxy-C M alkoxy, especially methoxymethoxy, 2- Methoxyethoxy, C2- alkenyloxy, especially allyloxy, hetaryl-C M - alkoxy, especially fur-2-yl-methoxy, tetrahydrofur-2-yl-methoxy, N-Boc-pyrrolidin-2-yl-methoxy, pyrrolidin-2- yl-methoxy, 5-sec-butyl-l, 2,4-oxadiazol-3-yl-methoxy, 5-cyclopropyl-l, 2,4
  • R 23 and R 24 independently of one another each represent hydrogen, C M -alkyl, in particular methyl, ethyl, hetaryl-CM-alkyl, in particular fur-2-yl-methyl, tetrahydrofur-2-yl-methyl, pyrrolidin-2-yl- , stands,
  • R 23 and R 24 together with the nitrogen atom to which they are attached for hetaryl, in particular N-pyrrolidino, N-piperazino, N-morpholino, N-thiomorpholino, N-piperidino, N-imidazolo, 2-oxopyrrolidino, phthalimino or tetrahydrophthalimino, stand,
  • Y represents oxygen or -NR 14 ,
  • R 13 and R 14 independently of one another are hydrogen, straight-chain or branched C M -alkyl, in particular methyl, ethyl, propyl,
  • 2- alkylsuffonyl in particular 1,1,1-Trifluorethoxyethylsulfonyl, straight or branched C M alkyloxy-carbonyl, in particular methoxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, tert-butyloxycarbonyl, straight or branched C M alkylaminocarbonyl, especially methylaminocarbonyl , Ethylaminocarbonyl, 0 2 ⁇ - alkenyl, especially vinyl, 2-propenyl, 2-butenyl, Alkenyloxycarbonyl, in particular vinyloxycarbonyl, 2-propenyloxycarbonyl, 2-butenyloxycarbonyl, C I - A - haloalkenyloxycarbonyl, in particular l, l, 2-trifluorobut-l-
  • I I stands for a selectively removable protective group, for example acetyl (Ac), allyloxycarbonyl (Alloc), benzyloxycarbonyl (Z) or tert-butyloxycarbonyl (Boc),
  • R 19 is hydrogen
  • R 20 for hydrogen, propyl, isopropyl, isobutyl, benzyl, 4-
  • R 21 represents hydrogen or C r C 4 alkyl
  • R 1 , R 4 , R 7 and R 10 represent methyl
  • R 2 , R 5 , R 8 and R 1 ' represent isobutyl
  • R 6 and R 12 represent methyl
  • R 3 and R 9 represent benzyl
  • R 13 for hydrogen, straight-chain or branched C M - alkyl, in particular methyl, ethyl, propyl, tert-butyl, C M - alkylsulfonyl, in particular methylsulfonyl, C1-C 4 - alkylcarbonyl, in particular methylcarbonyl, cyano -CC 4 -alkyl , Hydroxy- C r C -alkyl, amino -CC-C 4 alkyl, C1.2-haloalkoxy-C 1 .
  • alkylsulfonyl in particular 1,1,1-trifluoroethoxyethylsulfonyl, straight-chain or branched C M alkyloxycarbonyl, in particular methoxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, sec-butyl
  • 25 is a radical from group B 4 ,
  • I I stands for a selectively removable protective group, for example acetyl (Ac), allyloxycarbonyl Alloc), benzyloxycarbonyl (Z) or tert-butyloxycarbonyl (Boc),
  • R 19 represents hydrogen
  • R 20 represents hydrogen, methyl, propyl, isopropyl, isobutyl,
  • R 21 represents hydrogen or methyl
  • Residual definitions or explanations can be combined with one another, i.e. also between the respective areas and preferred areas. They apply accordingly to the end products as well as to the preliminary and intermediate products.
  • Formula (I) and its salts also contain one or more centers of chirality and can thus be present as pure stereoisomers or in the form of various enantiomer and diastereomer mixtures which, if necessary, can be separated in a manner known per se or also by stereoselective reactions in combination with the use of stereochemically pure starting materials can be produced.
  • optically active, stereoisomeric forms of the compounds of the general formula (I) and their salts are preferably used according to the invention.
  • the invention therefore relates both to the pure enantiomers and diastereomers and to their mixtures for combating endoparasites, particularly on the
  • Suitable suitable salts of the cycloiminodepsipeptides of the general formula (I) are customary non-toxic salts, i. H. Salts with different bases and salts with added acids. Salts with inorganic are preferred
  • alkali metal salts for example sodium, potassium or cesium salts
  • alkaline earth metal salts for example calcium or magnesium salts
  • ammonium salts salts with organic bases and with inorganic amines, for example triethylammonium, dicyclohexylammonium, N, N'-dammonylethylendiumbenzene Pyridinium, picolinium or ethanolammonium salts, salts with inorganic
  • Acids for example hydrochlorides, hydrobromides, dihydrosulfates, trihydrosulfates, or phosphates, salts with organic carboxylic acids or organic sulfonic acids, for example for iates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates or para-toluenesulfonates, salts with basic amino acids, for example arginates, aspartates or glutamates and the like.
  • endothiopeptides or heterocyclic thiolactams can preferably be used as suitable starting components.
  • the syntheses of amidoxime, cyanamidine and amidrazone analogues of chemotactic peptides from endothiopeptides may be mentioned as examples (G. Sauve et al., Can. J.
  • the new cyclic iminodepsipeptides of the general formula (I) according to the invention can also be obtained from the corresponding cyclic thiodepsipeptides with amino compounds of the general formula (II) by reaction of one or more thioamide groups.
  • the reaction of a thioamide group is particularly preferred.
  • the compounds of the general formula (I) are new, they can be prepared, for example, by the processes given under 2 and 3 above.
  • the process 2a according to the invention for the preparation of the new cycloiminodepsipeptides of the general formula (Ia) the cyclic thiodepsipeptide cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L- leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) as amino compounds of the general formula (II) the O-methyl-hydroxylamine (A: -O-Me; see route A) or N-methylhydrazine (A: -NH-Me; see route B), the process can be represented by the following reaction scheme, Scheme I:
  • the compounds of the general formula (I) can be formed as a mixture of syn and ⁇ «tt isomers.
  • Formula (Ib) provides a general definition of the cyclothiodepsipeptides required as starting materials for carrying out process 2a according to the invention.
  • R 1 to R 12 preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the substances of the general formula (I) according to the invention.
  • cyclic thiodepsipeptides used as starting materials are known from a previous patent application and can accordingly be obtained via thionation of cyclic depsipeptides using suitable sulfurizing reagents (cf. WO 98/43965, see also preparation examples).
  • suitable sulfurizing reagents cf. WO 98/43965, see also preparation examples.
  • the amino compounds also to be used as starting materials for carrying out process 2a according to the invention are defined by the general formula (II).
  • amino compounds of formula (II) are e.g. T. commercially available, some are known and can be prepared by known methods (see, for example, hetaryl methoxamine: US Pat.
  • R 13 - E 13 has the same meaning as above and E represents a nucleofugic leaving group, for example aliphatic or aromatic substituted sulfonyloxy, e.g.
  • the compounds of the formula (II) can advantageously be released in the following manner:
  • the hydrazinolysis can preferably be carried out in one
  • Diluents for example alcohol are carried out at boiling temperature.
  • the hydrolysis can preferably be carried out in an aqueous, aqueous-alcoholic or alcoholic solution by heating for several hours.
  • R 'and R together represent an isopropylidene group
  • acid hydrolysis and, in the event that R' and R" together represent an ⁇ -hydroxy-benzylidene
  • R represents a carbethoxy group
  • use can be made of both alkaline and acid hydrolysis cf. DE-OS 2119012; D. Favara et al. Farmaco, Ed. Sci. 42 (10), (1987 ) P. 697).
  • Inorganic salts such as hydrochloric acid or sulfuric acid, in ethanolic or isopropanolic solution are preferably used to prepare the salts.
  • the reaction of the thiodepsipeptides of the general formula (Ib) with the amino compounds of the general formula (II) is preferably carried out in the presence of a metal salt or metal oxide and, if appropriate, in the presence of a basic reaction auxiliary using diluents.
  • Suitable metal salts or metal oxides for carrying out the process according to the invention are all metal salts with elements of subgroups I and II of the periodic table. Examples include the acetates, chlorides, bromides, iodides, fluorides, nitrates, sulfates, carbonates, trifluoroborates, trifluoromethanesulfonates of copper, silver, gold, zinc, cadmium or mercury.
  • acid binders such as amines, in particular tertiary amines, and alkali and alkaline earth compounds can be used as basic reaction auxiliaries for carrying out process 2a according to the invention.
  • Examples include the hydroxides, oxides and carbonates of lithium, sodium, potassium, magnesium, calcium and barium, further basic compounds such as amidine bases or guanidine bases such as 7-methyl-l, 5,7-triazabicyclo (4.4.0) dec-5-en (MTBD); Diazabicyclo (4.3.0) nonen (DBN), diazabicyclo-
  • octane (2.2.2) octane (DABCO), l, 8-diaza-bicyclo (5.4.0) undecene (DBU), cyclohexyl-tetra-butylguanidine (CyTBG), cyclohexyltetramethylguanidine (CyTMG), N, N, N, N-tetramethyl-1,8-naphthalenediarnine, pentamethylpiperidine, tertiary amines such as triethylamine, trimethylamine, tribenzylamine, triisopropylamine, tributylamine, tribenzylamine, tricyclohexylamine, triamylamine, trihexylamine, N, N-dimethylaniline, toluene, N, N-toluene , N-dimethyl-p-aminopyridine, N-methyl-pyrrolidine, N-methyl-piperidine, N-methyl-imi
  • Tertiary amines in particular trialkylamines such as triethylamine, N, N-diisopropylethylamine, N-propyldiisopropylamine, N, N'-dimethylcyclohexylamine or N-methylmorpholine, are preferably used.
  • diluents are advantageously used in an amount such that the reaction mixture remains readily stirrable throughout the process.
  • Suitable diluents for carrying out process 2a according to the invention are all inert organic solvents.
  • halogenated hydrocarbons in particular chlorinated hydrocarbons, such as tetrachlorethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroefhan, trichloroethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethene, chlorobenzene, chlorobenzene, chlorobenzene, chlorobenzene Chlorotoluene, trichlorobenzene; Alcohols such as methanol, ethanol, isopropanol, butanol; Ethers such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenetol, cyclohexyl methyl ether, dimethyl ether, diethyl ether,
  • Pentamethylene sulfone aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane and technical hydrocarbons, for example so-called white spirits with components with boiling points in the range from 40 ° C to 250 ° C, cymol, gasoline fractions within a boiling point interval of 70 ° C up to 190 ° C, cyclohexane,
  • Methylcyclohexane petroleum ether, ligroin, octane, benzene, toluene, chlorobenzene, bromobenzene, nitrobenzene, xylene;
  • Esters such as methyl, ethyl, butyl, isobutyl acetate and dimethyl, dibutyl, ethylene carbonate;
  • Amides such as hexamethylenephosphoric triamide, formamide, N-methylformamide, N, N-dimethylformamide, N, N-dipropylformamide, N, N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl 3,4,5,6-tetrahydro-2 (1H) pyrimidine, octyl pyrrolidone, octyl caprolactam, 1,3-dimethyl-2-imidazolinedione, N-formyl-piperidine, N,
  • mixtures of the solvents and diluents mentioned can also be used in the process according to the invention.
  • preferred diluents for carrying out the process according to the invention are nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile,
  • Benzonitrile or m-chlorobenzonitrile in particular acetonitrile, propionitrile or butyronitrile, ethers such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, cyclohexyl methyl, dimethyl ether, diethyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether , Tetrahydrofuran or dioxane, in particular tetrahydrofuran or dioxane,
  • Halogenated hydrocarbons especially chlorinated hydrocarbons, such as tetrahedral chlorethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichlorethylene or pentachloroethane, in particular methylene chloride, chloroform or carbon tetrachloride.
  • reaction of amino compounds of the general formula (II) according to method 2a is carried out by the cyclothiodepsipeptides of the general formula (Ib) in the presence of an amino compound of the general formula (II), in the presence of a specified metal salt or metal oxide with elements of I. and II. Side group of the periodic table and optionally in the presence of a specified basic reaction auxiliary in one of the specified diluents.
  • the reaction time is 10 minutes to 48 hours.
  • the reaction takes place at temperatures between -10 ° C and +200 ° C, preferably between +10 ° C and + 180 ° C, particularly preferably at room temperature. It can basically be under
  • Normal pressure can be worked.
  • the process is preferably carried out at normal pressure or at pressures of up to 15 bar and, if appropriate, under a protective gas atmosphere (nitrogen or helium).
  • Thioamide group in the cyclothiodepsipeptides of the general formulas (Ib) generally 0.5 to 7.0 mol, preferably 1.0 to 5.0 mol, particularly preferably 2.0 to 3.0 mol of an amino compound of the general formula (II) .
  • Formula (Ic) for example, the cyclic iminodepsipeptide cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leu - Cinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) and as compounds of the general formula (III) chloroformic acid vinyl ester (cf. path C) and as compounds of the general formula (IV) acetic anhydride (cf. path D), the processes can be represented by the following reaction scheme III.
  • Formula (Ic) generally defines the cycloiminodepsipeptides and their salts which are required as starting materials for carrying out processes 2b and 2c according to the invention. 1 19
  • Y and R to R preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the substances of the general formula (I) according to the invention.
  • cycloiminodepsipeptides of the general formula (Ic) (Y: -0-) used as starting materials are new and can be obtained either by process 2a described above or by process 3 described below.
  • the cycloiminodepsipeptides of the general formula (Ic) (Y: -OH) can be prepared from the cyclothiodepsipeptides of the general formula (Ib) and hydroxylamine as a compound of the general formula (II) (cf. Scheme IV).
  • the compounds of formula (III) are generally known compounds of organic chemistry or can, for. T. can be obtained commercially or by methods known from the literature (e.g. Houben Weyl, Methods of Organic Chemistry, Volume E 4).
  • Formula (III) is preferably carried out in the presence of basic reaction auxiliaries using diluents.
  • All the acid binders mentioned in process 2a such as amines, in particular tertiary amines, can be used as basic reaction auxiliaries for carrying out process 2b according to the invention.
  • Process 2b preferably uses the tertiary amines, in particular tri-alkylamines such as triethylamine, N, N-diisopropylethylamine, n-propyldiisopropylamine, N, N'-dimethylcyclohexylamine or N-methylmorpholine and pyridine derivatives, in particular pyridine.
  • tri-alkylamines such as triethylamine, N, N-diisopropylethylamine, n-propyldiisopropylamine, N, N'-dimethylcyclohexylamine or N-methylmorpholine and pyridine derivatives, in particular pyridine.
  • Process 2b is carried out by reacting compounds of the general formula (Ic) in the presence of basic reaction auxiliaries with compounds of the general formula (III), if appropriate, in one of the diluents indicated.
  • method 2b can also be carried out directly in a suitable basic reaction auxiliary without a diluent.
  • the carboxylic acid anhydrides to be used as starting materials for carrying out process 2c according to the invention are generally defined by the formula (IV).
  • the reaction time is 4 to 72 hours.
  • the reaction takes place at temperatures between -10 ° C and + 150 ° C, preferably between -5 ° C and +80 ° C, particularly preferably at 0 ° C to room temperature. It is operated under normal pressure.
  • process 2c can also be carried out with excess carboxylic anhydride of the formula (IV) without a diluent, provided the reaction mixture remains readily stirrable.
  • Formula (Ic) for example, the cyclic iminodepsipeptide cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leu cinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) as compounds of the general formula (V) (S) -N-tert-butyloxycarbonyl-N-methylalanine ((S) -Boc-MeAla- OH; see route E) and as compounds of the general formula (VI) allyl isocyanate
  • Y and R to R preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the substances of the general formula (I) according to the invention.
  • the compounds to be used as starting materials in particular for carrying out process 2d ⁇ ) according to the invention are generally of the formula
  • the natural or synthetic amino acids used as starting materials can be in the (S) or (R) form (or L or D form).
  • Examples include:
  • reaction of the cycloiminodepsipeptides of the general formula (Ic) with amino acid derivatives of the formula (V) is preferably carried out in the presence of
  • Coupling reagents for carrying out process 2d ⁇ are all which are suitable for producing an amide bond [cf. eg: Houben-Weyl, Methods of Organic Chemistry, Volume 15/2; Bodanszky et al., Peptide Synthesis 2nd ed. (Wiley & Sons, New York 1976) or Gross, Meienhofer, The Peptides: Analysis Synthesis, Biology (Academic Press, New York 1979)].
  • active ester method with pentachloro- (Pcp) and pentafluorophenol (Pfp), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboxamide (HONB), 1-hydroxy-benzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-l, 2,3-benzotriazine as alcohol component, coupling with carbodiimides such as dicyclohexylcarbodiimide (DCCI) according to the DCC additive method, or with n- Propanephosphonic anhydride (PPA) and mixed anhydride method with pivaloyl chloride, ethyl (EEDQ) and isobutyl chloroformate (IIDQ) or coupling with phosphonium reagents such as benzotriazol-l-yl-oxy-tris (dimethylamino-phosphonophonium) - he
  • phosphonium reagents such as bis (2-oxo-3-oxazolidinyl) phosphonium acid chloride (BOP-Cl), benzotriazol-1-yl-oxy-tris (dimethylamino-phosphonium) hexafluorophosphate (BOP), benzotriazole is preferred - 1 -yl-tris-pyrrolidinophosphonium hexafluorophosphate (Py BOB ® ), bromotris-pyrrolidinophosphonium hexa-fluorophosphate (PyBroP ® ) and phosphonic acid ester reagents, such as diethyl cyanophosphate (DEPC) or Diphenylphosphoryl azide (DPPA).
  • BOP-Cl bis (2-oxo-3-oxazolidinyl) phosphonium acid chloride
  • benzotriazol-1-yl-oxy-tris dimethylamino-phosphonium hexa
  • Tertiary amines in particular trialkylamines such as triethylamine, N, N-diisopropylamine, N-propyldiisopropylamine, N, N'-dimethylcyclohexylamine or N-methylmorpholine, are preferably suitable.
  • the solvents mentioned in process 2a such as, for. B. halogenated hydrocarbons, especially chlorinated hydrocarbons, such as methylene chloride, chloroform or 1,2-dichloroethane and mixtures of these with others mentioned
  • the process is generally carried out in such a way that compounds of the general formula (Ic) are reacted with compounds of the general formulas (V) in one of the specified diluents in the presence of one of the basic reaction auxiliaries specified.
  • the reaction time is 4 to 72 hours.
  • the reaction takes place at temperatures between -10 ° C and +120 ° C, preferably between -5 ° C and +50 ° C, particularly preferably at 0 ° C to room temperature. It is worked under normal pressure.
  • the compounds to be used as starting materials in particular for carrying out process 2d ⁇ ) according to the invention are generally defined by the formula (VI) or (VII).
  • the compounds of general formulas (VI) or (VII) can, for. T. can be obtained commercially or by methods known from the literature (cf., for example, Houben-Weyl, Methods of Organic Chemistry, Volume E 4).
  • reaction of the cycloiminodepsipeptides of the general formula (Ic) with compounds of the general formulas (VI) or (VII) is preferably carried out in the presence of diluents, if appropriate in the presence of a basic reaction auxiliary.
  • the solvents mentioned in process 2a such as B. halogenated hydrocarbons, especially chlorinated hydrocarbons, such as methylene chloride, chloroform or 1,2-dichloroethane, nitriles such as acetonitrile, propionitrile, butyronitrile, in particular acetonitrile, ethers such as ethyl propyl ether, n-buryl ether, diethyl ether, dipropyl ether, diisopropyl ether, tetrahydrofuran or dioxane, in particular tetrahydrofuran or dioxane, aliphatic or aromatic hydrocarbons such as n-hexane, n-heptane, benzene, toluene or xylene and mixtures of these with others mentioned diluents, use.
  • halogenated hydrocarbons especially chlorinated hydrocarbons, such as methylene chloride, chloroform or 1,2-d
  • Process 2d ⁇ ) can also be carried out in the presence of basic reaction auxiliaries. All such acid binders mentioned above, but preferably tertiary amines, in particular trialkylamines such as
  • Triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, and amidine bases or guanidine bases such as diazabicyclo (4.3.0) nonen (DBN), diazabicyclo (2.2.2) octane (DABCO), 1,8-diazabicyclo (5.4 .0) undecene (DBU), in particular 1,8-diazabicyclo (5.4.0) undecene (DBU), use.
  • Process 2d ⁇ ) is generally carried out by reacting compounds of the general formula (Ic) with compounds of the general formulas (VI) or (VII), optionally in the presence of one of the basic reaction auxiliaries specified in one of the diluents specified.
  • the reaction time is 4 to 72 hours.
  • the reaction takes place at temperatures between -10 ° C and +180 ° C, preferably between -5 ° C and +120 ° C, particularly preferably at 0 ° C to the boiling point of the diluent used.
  • it is possible to work under normal pressure, but it is also possible to work with increased or reduced pressure. It is preferable to work at
  • cycloiminodepsipeptides of the general formula (Ic) (Y: -0-) are either directly according to method 2a from the thiodepsipeptides of the general formula (Ib) and
  • Hydroxylamine can be prepared as a compound of the general formula (II) or can be obtained according to process 3 from suitable cycloiminodepsipeptides of the general formula (Ia).
  • Formula (Ia) generally defines the cycloiminodepsipeptides required as starting materials for carrying out process 3a according to the invention.
  • A, R 1 to R 12 preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the substances of the general formula (I) according to the invention.
  • the cycloiminodepsipeptides of the general formula (Ia) are, according to process 2a mentioned above, from the thiodepsipeptides of the general formula (Ib) and compounds of the general formula (LT), in which A is a residue - YR 13 (A 1 ) with selectively removable O
  • Protective group R 13 is, for example benzyl, benzyloxycarbonyl. Allyl, tert-butyloxycarbonyl, tetrahydropyranyl hydroxylamine, can be prepared. Depending on the protective group R 13 , this can be selectively removed in compounds of the general formula (Ia) either by means of hydrogenolysis in the presence of a suitable hydrogenation catalyst or by means of acidolysis in the presence of a protonic acid.
  • the hydrogenolysis of cycloiminodepsipeptides of the general formula (Ia) in accordance with the invention is particularly preferred in the presence of a hydrogenation catalyst, in the presence of a diluent and, if appropriate, in the presence of an acidic reaction auxiliary (cf. Scheme VI, route G, H, I).
  • Suitable catalysts for carrying out the catalytic hydrogenation are all customary hydrogenation catalysts, such as platinum catalysts (platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (for example palladium sponge, Palladium black, palladium oxide, palladium-carbon, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, palladium hydroxide, etc.), nickel catalysts, for example reduced nickel, nickel oxide, Raney nickel, etc.), ruthenium catalysts , Cobalt catalysts (for example reduced cobalt, Raney cobalt etc.), iron catalysts (for example reduced iron, Raney
  • copper catalysts e.g. reduced copper, Raney copper, Ullman copper, etc.
  • noble metal catalysts such as, for example, platinum and palladium or ruthenium catalysts, are preferably used, if appropriate on a suitable support, for example on carbon or silicon.
  • the inert organic solvents mentioned in process 2a such as, for. B. alcohols, especially methanol or ethanol, use.
  • Mineral acids may be mentioned, for example, as acidic reaction auxiliaries.
  • the mineral acids preferably include hydrohalic acids such as hydrofluoric acid, hydrobromic acid, hydrochloric acid or hydroiodic acid as well as sulfuric acid, phosphoric acid, phosphorous acid and nitric acid.
  • an alcoholic solution of the cyclic benzyloxyiminodepsipeptides of the formula (Ia) is reacted in the presence of a suitable hydrogenation catalyst and, if appropriate, in the presence of an acidic reaction auxiliary.
  • Palladium catalysts in particular palladium or palladium hydroxide carbon, are preferably used as hydrogenation catalysts.
  • Mineral acids in particular hydrohalic acids such as hydrochloric acid, are preferably used as acidic reaction auxiliaries.
  • the reaction time is 5 minutes to 20 hours.
  • the hydrogenation is carried out at temperatures between -5 ° C and +100 ° C, preferably between 0 ° C and +30 ° C.
  • the polymer-bound cycloiminodepsipeptide cyclo [-N-methyl-L-leucinyl-D- (po / ymer-THP-oxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl is used -lactyl-N-methyl-L-leucinyl-
  • Formula (Ia) generally defines the cycloiminodepsipeptides required as starting materials for carrying out process 3b according to the invention. 1 1 ")
  • a and R to R preferably represent those radicals which have already been mentioned for these substituents in connection with the description of the substances of the general formula (I) according to the invention.
  • cyclic hydroxy-iminodepsipeptides formed in this way are worked up in a conventional manner, for example by chromatographic purification (cf. also preparation examples). However, they can also be implemented directly (without further purification) in accordance with method 2b.
  • the iminodepsipeptides of the general formula (I) obtainable by process 2 according to the invention can be present as syn and ⁇ «tt isomers, but a mixture of both isomer forms is preferably formed under the reaction conditions of process 2 specified.
  • inert solvents mean in each case solvents which are included under the respective reaction conditions. conditions are inert, but need not be inert under any reaction conditions.
  • the active ingredients are suitable for combating pathogenic endoparasites, which occur in humans and in animal husbandry and animal breeding in useful, breeding, zoo, laboratory, experimental and hobby animals, with favorable warm-blooded toxicity. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive species. By combating the pathogenic endoparasites, illness, deaths and reduced performance (e.g. in the production of meat, milk, wool, hides, eggs, honey, etc.) are to be reduced, so that the use of the active ingredients enables more economical and easier animal husbandry.
  • Pathogenic endoparasites include cestodes, trematodes, nematodes, in particular:
  • Schistocephalus spp. Ligula spp., Bothridium spp., Diplogonorus spp ..
  • Cyclophyllidea for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosma spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyella spp., Berti , Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium
  • Plagiorchis spp. Prosthogonismus spp., Dicrocoelium spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp ..
  • Stronylus spp. Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylmdropharynx spp., Poteriostromum spp., Cyclococercus spp., Cyhcostephanus sppum., Opp.
  • Stephanurus spp. Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostomum spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., , Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Pararoafylo spp., Filaroidesylpp spp., Ostertagia spp., Marshallagia spp., Cooper
  • 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 ..
  • 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, fresh and salt water fish such as Trout, carp, eels, reptiles,
  • Insects such as Honey bee and silkworm.
  • Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
  • the pets include dogs and cats.
  • the application can be prophylactic as well as therapeutic.
  • the active ingredients are used directly or in the form of suitable preparations enterally, parenterally, dermally, nasally, by treating the environment or with the aid of shaped articles containing active ingredients, e.g. Strips, plates, ribbons, collars, ear tags, limb straps, marking devices.
  • enteral application of the active ingredients takes place e.g. orally in the form of powder
  • Suppositories tablets, capsules, fasting, watering, granules, drenches, boluses, medicinal feed or drinking water.
  • the dermal application takes place, for example, in the form of dipping (dipping), spraying (spraying), bathing, washing, pouring on (pour-on and spot-on) and applying the powder.
  • Parenteral use is for example 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,
  • Solutions for injection are administered intravenously, intramuscularly and subcutaneously.
  • Injection solutions are made by adding the active ingredient in a suitable solvent
  • Solvent is dissolved and additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives may be added.
  • additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives may be added.
  • the solutions are sterile filtered and filled.
  • 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. 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 diving (dipping, bathing or washing). These solutions are prepared as described above for the injection solutions.
  • Thickeners are: inorganic thickeners such as bentonites, colloidal
  • Silicic acid aluminum monostearate
  • organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.
  • 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. Pour-on formulations are poured onto 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 skin-compatible solvents or solvent mixtures. If necessary, other auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers and adhesives are added.
  • solvents water, alkanols, glycols, polyethylene glycols,
  • Polypropylene glycols 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, hydrocarbon or alkenyl, aromatic and aromatic substances synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1, 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 monomethyl ether, diethylene glycol monobutyl
  • 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. Emulsions can be used orally, dermally or as an injection.
  • Emulsions are either water in oil or oil in water.
  • emulsifiers are produced by dissolving the active ingredient either in the hydrophobic or in the hydrophilic phase and then using the solvent with the aid of suitable emulsifiers and possibly other auxiliary substances such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers, viscosity-increasing substances homogenized the other phase.
  • Hydrophobic phases may be mentioned are: paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / - capric acid triglyceride mixture with vegetable fatty acid of chain length Cg_j2 ° he d other natural fatty acids, specifically selected, Partialglycerid- mixtures saturated or unsaturated, possibly also hydroxyl-containing fatty acids, mono- and diglycerides of Cg / Cio 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 Cig-Ci g, isopropyl myristate, isopropyl palmitate, cypryl / capric alcohol esters of saturated fatty acid length Ci2-C ⁇ g, isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duck pancreas fat, dibutyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures, etc.
  • Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.
  • Fatty acids such as oleic acid and their mixtures.
  • the following can be mentioned as the hydrophilic phase:
  • 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 prepared by placing the active ingredient in a carrier liquid, if necessary
  • auxiliaries such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers suspended.
  • the surfactants specified above may be mentioned as wetting agents (dispersants).
  • the additives given above may be mentioned as further auxiliaries.
  • Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only in their higher viscosity.
  • the active ingredient is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and brought into the desired shape.
  • Inorganic and organic substances serve as such.
  • Inorganic substances are 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, decaying substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.
  • lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decaying substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.
  • the active substance according to the invention can be present in its preparations and in the use forms prepared from these preparations in a mixture with other active substances, such as insecticides, sterilants, bactericides, acaricides, nematicides or fungicides.
  • Insecticides include, for example, phosphoric acid esters, carbamates, carboxylic acid esters, chlorinated hydrocarbons, Phenylureas, nicotinyls, neonicotinyls, substances produced by microorganisms and others
  • Diethofencarb Difenoconazol, Dimethirimol, Dimethomorph, Diniconazol, Diniconazol-M, Dinocap, Diphenylamine, Dipyrithione, Ditalimfos, Dithianon, Dodemorph, Dodine, Drazoxolon, Ediphenphos, Epoxiconazol, Etaconazam, Fenirazolol, Ethiriazolol, Ethiriazolol, Ethiradololox, Fenitropan, fenpiclonil,
  • Mancopper Mancozeb, Maneb, Meferimzone, Mepanipyrirn, Mepronil, Metalaxyl, Metconazol, Methasulfocarb, Methfuroxam, Metiram, Metomeclam, Metsulfovax,
  • Oxadixyl Oxamocarb, Oxolinicacid, Oxycarboxim, Oxyfenthiin,
  • Paclobutrazole pefurazoate, penconazole, pencycuron, phosdiphen, pimaricin, piperalin, polyoxin, polyoxorim, probenazole, prochloraz, procymidon, propamocarb,
  • Thicyofen Thifluzamide, Thiophanate-methyl, Thiram, Tioxymid, Tolclofos-methyl,
  • Tridemorph triflumizole, triforin, triticonazole
  • Methane tetrathiol sodium salt methyl l- (2,3-dihydro-2,2-dimethyl-lH-inden-l-yl) -lH-imidazole-5-carboxylate,
  • Bactericides bronopol, dichlorophene, nitrapyrin, nickel-dimethyldithiocarbamate, kasugamycin,
  • Octhilinone furan carboxylic acid, oxytetracycline, probenazole, streptomycin, teclofta lam, copper sulfate and other copper preparations, quinolones such as ciprofloxacin, danofloxacin, difloxacin, enrofloxacin, flumequine, ibafloxacin, marbofloxacin, norfloxacin, ofloxacin, orbifloxacin, premafloxacin, sarafloxacin
  • Chlormephos Chlorpyrifos, Chlorpyrifos M, Chlovaporthrin, Cis-Resmethrin, Cispermethrin, Clocythrin, Cloethocarb, Clofentezine, Coumafos, Cyanophos, Cycloprene, Cycloprothrin, Cyfluthrin, Chhalophrin, Cythermethrin, Cythermethrin, Cythermethrin, Cythermethrin, Cypermin , Demeton-S-methyl, diafenthiuron, diazinon,
  • Fenoxycarb Fenpropathrin, Fenpyrad, Fenpyrithrin, Fenpyroximate, Fenthion, Fenvalerate, Fipronil, Fluazinam, Fluazuron, Flubrocythrinate, Flucycloxuron, Flucythrinate, Flufenoxuron, Flumethrin, Flutenzine, Fluvalinatexofosulfonos, Granofinosulfonate, Fonvalosfonosulfonate, Fungronosulfonate, Fungronosulfonate, Fifronosilane, Fungronosolate, Fifronosulfate, Fungronosolate, Fifronosulfate, Fungate, Fungus
  • Halofenozide HCH, Heptenophos, Hexaflumuron, Hexythiazox, Hydroprene, Imidacloprid, indoxacarb, isazofos, isofenphos, isoxathion, ivermectin,
  • Pirimiphos M Profenofos, Promecarb, Propoxur, Prothiofos, Prothoat, Pymetrozine,
  • Tefluthrin Temephos, Temivinphos, Terbufos, Tetrachlorvinphos, Thetacypermethrin, Thiamethoxam, Thiapronil, Thiatriphos, Thiocyclam hydrogen oxalate, Thiodicarb, Thiofanox, Thuringiensin, Tralocythrin, Tralomethrin
  • Triarathenes triazamates, triazophos, triazuron, trichlophenidines, trichlorfon,
  • the active compounds according to the invention can furthermore be present in their commercially available formulations and in the use forms prepared from these mold inhibitors in a mixture with synergists.
  • Synergists are compounds through which the action of the active ingredients is increased without the added synergist itself having to be active. 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 that are diluted before use contain the active ingredient in
  • the entire reaction mixture is then stirred in about 20 ml of aqueous NH C1 solution and extracted four times with 15 ml of chloroform.
  • the remaining crude product is chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane: acetone (4: 1).
  • a mixture of 100 mg of polystyrene resin containing cyclodepsipeptide, 3.0 ml of n-butanol and 3.0 ml of 1,2-dichloroethane is mixed with 8.5 mg of pyridine-p ⁇ r ⁇ -toluenesulfonic acid and stirred at 60 ° C. for one hour.
  • the polystyrene resin is then filtered off and washed five times with methylene chloride. After concentration in vacuo, 9.4 mg of crude product remain, in which example 1 could be detected by means of APCI-MS.
  • the remaining crude product is first passed through a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane:
  • the remaining crude product is first passed through a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane:
  • the 6- (amino-oxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene resin is first stirred in dichloromethane at room temperature for 30 minutes and then with the cyclothiodepsipeptide and mercury (II) acetate added.
  • the separated polystyrene resin is then washed three times in succession with dichloromethane, dimethylformamide / water (1: 1), dimethylformamide and dried in a high vacuum.
  • N-tert-butyloxycarbonylamino-oxyacetic acid (Novabiochem: 01-63-0060) are stirred in 75 ml of methylene chloride and at 0 ° C. with 3.1 g (24.0 mmol) N, N-diisipropylethylamine (Hünig's base), 3.1 g (12.0 mmol) of bis (2-oxo-3-oxazolidinyl) -phosphonium chloride (BOP-Cl) were added and the mixture was stirred for 30 minutes. Then 1.05 g (12.0 mmol) of morpholine are added and the mixture is stirred at 0 ° C. for a further 6 hours.
  • BOP-Cl bis (2-oxo-3-oxazolidinyl) -phosphonium chloride
  • Dry hydrochloric acid gas is passed into 220 ml of absolute methylene chloride in a solution of 0.65 g (2.5 mmol) of N-tert-butyloxycarbonylamino-oxyacetic acid morpholide cooled to 0 ° C. for 30 minutes. The mixture is then stirred for about 16 hours at room temperature and the entire reaction mixture is concentrated in vacuo. 380 mg (77% of theory) of hydrochloride of amino-oxyacetic acid morpholide are obtained.
  • the purified 6- (N-succinimidyl-oxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene resin is dried under high vacuum and can be used for the subsequent reaction step.
  • mice are experimentally infected with nematodes of the species Heterakis spumosa.
  • Heterakis spumosa is administered orally to the mice as 90 embryonated eggs.
  • the suspended active substances are administered intraperitoneally on the 46th day after the infection.
  • mice are selected on the 54th day after infection.
  • the adult parasites in the colon and caecum are counted microscopically.
  • the success of treatment in the dose group is related to the untreated control group.
  • mice are experimentally infected with nematodes of the species Nematospiroides dubius.
  • the mice Nematospiroides dubius are administered orally as 90 embryonic eggs.
  • the suspended active substances are administered intraperitoneally on the 46th day after the infection.
  • mice are selected on the 54th day after infection.
  • the adult parasites in the colon and caecum are counted microscopically.
  • the success of treatment in the dose group is related to the untreated control group.
  • the efficiency is determined by quantitatively counting the worm eggs excreted in the faeces before and after the treatment.
  • a complete suspension of egg excretion after treatment means that the worms have been aborted or are so damaged that they no longer produce eggs (effective dose).
  • MeLeu N-methyl-L-leucine
  • D-Lac D-lactic acid
  • D-PhLac D-phenyllactic acid

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
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Abstract

L'invention concerne des cyclo-iminodepsipeptides de formule (I), notamment des cyclo-iminodepsipeptides à 24 chaînons. Elle concerne également des procédés pour leur préparation et leur utilisation pour lutter contre les endoparasites.
EP00936833A 1999-06-11 2000-05-30 Cyclo-iminodepsipeptides et leur utilisation pour lutter contre les endoparasites Withdrawn EP1192142A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19926620 1999-06-11
DE19926620A DE19926620A1 (de) 1999-06-11 1999-06-11 Neue Cycloiminodepsipeptide, Verfahren zu ihrer Herstellung und ihre Verwendung zur Bekämpfung von Endoparasiten
PCT/EP2000/004935 WO2000076985A1 (fr) 1999-06-11 2000-05-30 Cyclo-iminodepsipeptides et leur utilisation pour lutter contre les endoparasites

Publications (1)

Publication Number Publication Date
EP1192142A1 true EP1192142A1 (fr) 2002-04-03

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EP (1) EP1192142A1 (fr)
JP (1) JP2003502318A (fr)
CN (1) CN1355794A (fr)
AU (1) AU768501B2 (fr)
BR (1) BR0011498A (fr)
CA (1) CA2374632A1 (fr)
DE (1) DE19926620A1 (fr)
HK (1) HK1047589A1 (fr)
HU (1) HUP0201592A2 (fr)
WO (1) WO2000076985A1 (fr)
ZA (1) ZA200109179B (fr)

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JP4902519B2 (ja) * 2007-12-21 2012-03-21 大塚化学株式会社 固定化触媒
TWI749509B (zh) * 2015-05-20 2021-12-11 美商百靈佳殷格翰動物保健美國有限公司 驅蟲酯肽化合物

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DE4317457A1 (de) * 1993-05-26 1994-12-01 Bayer Ag Octacyclodepsipeptide mit endoparasitizider Wirkung
DE4317432A1 (de) * 1993-05-26 1994-12-01 Bayer Ag Octacyclodepsipeptide mit endoparasitizider Wirkung
DE19713626A1 (de) * 1997-04-02 1998-10-08 Bayer Ag Neue Thiodepsipeptide zur Bekämpfung von Endoparasiten und ein einfaches Verfahren zu ihrer Herstellung

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See references of WO0076985A1 *

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AU5218000A (en) 2001-01-02
AU768501B2 (en) 2003-12-11
CN1355794A (zh) 2002-06-26
HK1047589A1 (zh) 2003-02-28
CA2374632A1 (fr) 2000-12-21
ZA200109179B (en) 2003-01-29
BR0011498A (pt) 2002-04-02
DE19926620A1 (de) 2000-12-14
JP2003502318A (ja) 2003-01-21
WO2000076985A1 (fr) 2000-12-21
HUP0201592A2 (en) 2002-08-28

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