EP1109794A1 - Aza-cyclodepsipeptides and their use as antiparasitics - Google Patents

Aza-cyclodepsipeptides and their use as antiparasitics

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Publication number
EP1109794A1
EP1109794A1 EP99942898A EP99942898A EP1109794A1 EP 1109794 A1 EP1109794 A1 EP 1109794A1 EP 99942898 A EP99942898 A EP 99942898A EP 99942898 A EP99942898 A EP 99942898A EP 1109794 A1 EP1109794 A1 EP 1109794A1
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EP
European Patent Office
Prior art keywords
alkyl
formula
independently
spp
radical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP99942898A
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German (de)
French (fr)
Inventor
Hubert Dyker
Jürgen Scherkenbeck
Achim Harder
Norbert Mencke
Georg Von Samson-Himmelstjerna
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Bayer AG
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Bayer AG
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Publication of EP1109794A1 publication Critical patent/EP1109794A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

Definitions

  • the invention relates to new aza-cyclodepsipeptides, processes for their preparation and their use for controlling parasites, in particular helminths in veterinary and human medicine.
  • the invention relates to new 24-membered heterocycles which are composed of ⁇ -hydroxycarboxylic acids on the one hand and ⁇ -amino acids or ⁇ -aza-amino acids on the other hand, with at least one aza-amino acid being contained. So far, nothing has been known about such aza-cyclodepsipeptides.
  • X 1 , X 2 , X 3 and X 4 each independently represent N or CH, where at least one of these variables X represents nitrogen,
  • R 1 , R 2 , R 3 and R 4 independently of one another each represent hydrogen, in each case optionally substituted by halogen, alkyl, alkenyl, hydroxyalkyl, Alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or, in each case, optionally substituted cycloalkyl, cycloalkylalkyl, aryl, aryl or alkyl, harylaryl
  • he grouping -NR 9 -X'R 5 - represents a radical of the formula -NR 9 1 -CHR 5 1 - or a radical of the formula -NR 9 "2 -NR 5" 2 -,
  • R 5 "1 , R 6" 1 , R 7 "1 and R 8" 1 independently of one another each for hydrogen, optionally alkyl or amino-substituted alkyl, for mercaptomethyl,
  • R 9 "1 , R 10" 1 , R 11 "1 and R 12" 1 are each independently of one another hydrogen or
  • R 5 "2 to R 12" 2 independently of one another each represent hydrogen, in each case optionally substituted by halogen, alkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkyl Alkoxycarbonylaminoalkyl or for optionally substituted cycloalkyl,
  • the configuration on the chiral carbons is arbitrary, ie the compounds of the formula (I) according to the invention are composed of D- and / or L-configured amino acids and hydroxycarboxylic acids.
  • the invention relates to the pure stereoisomers and mixtures thereof.
  • the compounds are preferably composed of D-hydroxycarboxylic acids and L-amino acids.
  • the following always refers to compounds of the formula (I), although both the pure compounds and, if appropriate, mixtures with different proportions of isomeric compounds are meant.
  • the new compounds of the formula (I) can be obtained by one of the processes described below.
  • X 1 , X 2 , X 3 , X 4 and R 1 to R 12 have the meanings given above,
  • X 2 , X 3 , X 4 each independently represent N or CH and
  • R 1 to R 12 have the meanings given above,
  • X 2 , X 3 , X 4 each independently represent N or CH and
  • R 1 to R 12 have the meanings given above,
  • Y 1 represents chlorine, trichloromethoxy, C r C 4 alkoxy, optionally substituted phenoxy, 1-imidazolyl or 1, 2,4-triazolyl and
  • Y 2 represents chlorine, trichloromethoxy, 1-imidazolyl or 1, 2,4-triazolyl
  • Azacyclodepsipeptides of the above formula (Ia) can be prepared by using azadepsipeptides of the formula (V)
  • X 2 , X 3 , X 4 each independently represent N or CH and
  • R 1 to R 12 and Y 1 have the meanings given above,
  • the new compounds are generally defined by the formula (I).
  • Preferred compounds of the formula (I) are those in which the substituents or the areas have the following meanings:
  • R 1 , R 2 , R 3 and R 4 independently of one another each preferably represent hydrogen, C, -C, 6 alkyl, each optionally by fluorine, chlorine or bromine substituted C, -C 6 alkyl, C 2 -C 8 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C, -C 4 alkyl, C, -C 6 hydroxyalkyl , C, -C 4 -alkanoyloxy-C r C 6 -alkyl in particular acetoxymethyl or 1-acetoxyethyl, C, -C 4 -alkoxy-C r C 6 -alkyl in particular methoxymethyl or 1-methoxyethyl, aryl-C, -C 4 -alkoxy-C 1 -C 6 -alkyl, C r C 6 -ercaptoalkyl, in particular mercaptomethyl, C, -C 4
  • R 5 "1 , R 6" 1 , R 7 “1 and R 8" 1 each independently of one another preferably represent hydrogen, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, Mercaptomethyl, 2-methylthioethyl, 3-aminopropyl, 4-aminobutyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 3-guanidinopropyl, phenyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 2-
  • R 9 " ', R 10" 1 , R “ “ 1 and R 12 "1 each independently represent preferably
  • the pairs of radicals R ⁇ '/ R 9 "1 , R ⁇ ' / R 10" 1 , R '-' / R 11 "1 and R '-' / R 12" 1 also preferably each independently stand for the radicals - (CH 2 ) 3 - and - (CH 2 ) 4 -.
  • R 5 "2 to R 12" 2 independently of one another preferably represent hydrogen, C r C 15 -
  • Alkyl in particular 3,7,11-trimethyldodecyl, for C r C 8 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C, - which are each optionally substituted by fluorine, chlorine or bromine, - C 4 -alkyl, C, -C 6 -hydroxyalkyl, C, -C 4 -alkanoyloxy-C, -C 6 -alkyl, C 1 -C 4 -alkoxy-C, -C 6 -alkyl, aryl-C r C 4 -alkoxy-C r C 6 -alkyl, C, -C 6 -ercaptoalkyl, in particular mercaptomethyl, C r C 4 -alkylthio-C r C 6 -alkyl, in particular methylthioethyl, C r C 4 -alkylsulfmyl-
  • the pairs of residues R 5 "2 / R 9 - 2 , R 6 - 2 / R 10" 2 , R '-' / R 11 "2 and R 8 - 2 / R 12" 2 also together, independently of one another, preferably represent optionally mono- to tetrasubstituted by C, -C 4 -alkyl radicals - (CH 2 ) 3 - and - (CH 2 ) 4 -.
  • R 1 , R 2 , R 3 and R 4 independently of one another, each particularly preferably represent hydrogen, C, -C 12 alkyl, each optionally substituted by fluorine, chlorine or bromine, C, -C 4 alkyl, C 2 -C 6- alkenyl, C 3 -C 7 -cycloalkyl, in particular cyclopentyl, cyclohexyl or cycloheptyl, C 3 -C 7 -cycloalkyl-C, -C 4 - alkyl, C, -C 6 -hydroxyalkyl, phenyl-C, -C 4 -alkoxy-C r C 6 -alkyl, in particular
  • Phenyl is trisubstituted, substituted phenyl, phenyl-C r C 4 -alkyl, naphthylmethyl, 5- or 6-membered hetaryl, especially thienyl, thiazolyl or pyridyl, indolyl, benzo-l, 3-dioxolyl, 5- or 6- membered hetaryl-C, -C 4 -alkyl in particular thienylmethyl, thiazolylmethyl, imidazolylmethyl or pyridylmethyl or indolyl-C, -C 4 -alkyl.
  • R 5 "1 , R 6" ', R 7 “1 and R 8" 1 each independently, particularly preferably, represent methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, benzyl, 4-hydroxybenzyl, where Hydroxy groups can optionally be protected.
  • R 9 "1 , R 10 1 , R 1 and R 12" 1 each independently of one another are particularly preferably hydrogen or methyl.
  • radical pairs R ⁇ / R 9 1 , R 6 1 / R 10 1 , R 'VR 11'1 and R 8 1 / R 12 -' are also particularly preferably and in each case together independently of one another for the radicals - (CH 2 ) 3 - and - (CH 2 ) 4 -.
  • R 5 "2 to R 12" 2 independently of one another particularly preferably represent hydrogen, C r C 10 alkyl, in each case C r C 4 alkyl optionally substituted by fluorine, chlorine or bromine, C 3 -C 7 cycloalkyl, in particular Cyclopentyl, cyclohexyl or cycloheptyl, C 3 -C 7 cycloalkyl-C, -C 4 -alkyl, C, -C 6 -hydroxy-alkyl, especially hydroxymethyl or 1-hydroxyethyl, C, -C 4 -alkanoyl-oxy-C , -C 6 -alkyl, especially acetoxymethyl or 1-acetoxyethyl, C r C 4 - alkoxy-C C 6 -alkyl, especially methoxymethyl or 1-methoxyethyl,
  • Phenyl-C, -C 4 -alkoxy-C ) -C 6 -alkyl in particular benzyloxymethyl or 1-benzyloxyethyl, -CC 4 -alkoxycarbonylamino-C r C 6 -alkyl, in particular tert-butoxycarbonylaminopropyl or tert-butoxycarbonylaminobutyl, or for each optionally by fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino, C, -C 4 -alkylamino, di- (C, -C 4 ) -alkylamino, benzylamino,
  • Dibenzylamino protected amino such as acetyl, t-butoxycarbonyl, benzyloxy carbonyl or FMOC amino, C, -C 4 alkyl, C, -C 4 haloalkyl, C r C 4 alkoxy or C, -C 2 Haloalkoxy-substituted phenyl, phenyl-C, -C 4 -alkyl, 5- or 6-membered hetaryl, in particular thienyl, thiazolyl or pyridyl, 5- or 6-membered hetaryl-C, -C 4 -alkyl or indolyl-C, -C 4 alkyl.
  • the pairs of residues R 5 "2 / R 9" 2 , R 6 - 2 / R 10 - 2 , R 7 "2 / R u - 2 and R 8 - 2 / R 12" 2 are each also particularly preferred independently the optionally mono- to tetrasubstituted by methyl radicals - (CH 2 ) 3 - and - (CH 2 ) 4 -.
  • R 1 , R 2 , R 3 and R 4 each independently of the other very particularly preferably represent hydrogen, C, -C 12 alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, sec.-hexyl, n-heptyl, isoheptyl, sec-
  • R 5 "1 , R 6" 1 , R 7 "1 and R 8" 1 each independently of the other very particularly preferably represent methyl, isopropyl, isobutyl or sec-butyl.
  • R 9 "1 , R 10" 1 , R 11 "1 and R 12" 1 each very particularly preferably represent hydrogen or methyl.
  • radical pairs R ⁇ / R 9 "1 , R ⁇ / R 10" 1 , R ⁇ / R “ “ 1 and R ⁇ '/ R 12 "1 are also very particularly preferred and in each case together independently of one another for the radicals
  • R 5 "2 to R 12" 2 independently of one another very particularly preferably represent
  • Hydrogen, C, -C I0 alkyl especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec.-Pentyl, tert-pentyl, n-hexyl, isohexyl, sec.-hexyl, n-heptyl, isoheptyl, sec.-heptyl, octyl, isooctyl, sec.-octyl or 3,7-dimethyloctyl, for C 3 -C 7 cycloalkyl -C, - C 4 -alkyl in particular cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl, for each optionally by fluorine, chlorine, bromine, hydroxy, cyano, methyl,
  • pairs of radicals R 5 - 2 / R 9 - 2, R 6 - 2 / R 10-2, R 7 - 2 / R N'2 and R 8 - 2 / R 12 "2 are also very particularly preferably in each case together and independently from each other for the optionally mono- or disubstituted by methyl radical - (CH 2 ) 4 -.
  • R 1 , R 2 , R 3 and R 4 independently of one another represent methyl, which is optionally substituted by phenyl, which in turn can be substituted by halogen, cyano, nitro, amino, dialkylamino, morpholino,
  • R 5 , R 6 , R 7 and R 8 independently of one another are C 1 -C 4 -alkyl, in particular branched C 4 -alkyl, very particularly i-butyl, where
  • At least one of the radicals X ', X 2 , X 3 and X 4 represents ⁇ _ ;
  • R 9 , R 10 , R 11 and R 12 independently of one another represent C 1 -C 4 -alkyl, in particular methyl.
  • Saturated or unsaturated hydrocarbon radicals such as alkyl or alkenyl can also be used in connection with heteroatoms, e.g. in alkoxy, where possible, be straight-chain or branched.
  • Optionally substituted radicals can be mono- or polysubstituted, whereby in the case of multiple substitutions the substituents can be the same or different.
  • substituents can be the same or different.
  • the following abbreviations are used in the present text:
  • PhLac 2-hydroxy-3-phenylpropionic acid (ß-phenyllactic acid)
  • AzaAla 2-azaalanine (N-methyl-N-aminocarbamic acid)
  • reaction can proceed of process (B) according to the invention can be represented by the following formula:
  • Formula (II) provides a general definition of the azadepsipeptides required to carry out process (A) according to the invention.
  • X 1 , X 2 , X 3 , X 4 and R 1 to R 12 preferably represent those radicals which have already been mentioned as preferred substituents in connection with the description of the aza-cyclodepsipeptides of the formula (I).
  • the azadepsipeptides of formula (II) are new.
  • Azadepsipeptides of the formula (II) can be prepared, for example, by removing the protective group of C-terminally protected azadepsipeptides of the formula (VI) in a process (Aa) according to the following reaction scheme:
  • a 4 represents a C-terminal protective group such as, for example, tert.-
  • Butyl or benzyl See, e.g., T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley & Sons, New York 1991).
  • reaction can be carried out using customary methods of C-terminal deblocking, such as acidolysis, for example in the case of a tert-butyl ester, or catalytic hydrogenation, for example in the case of a benzyl ester.
  • acidolysis for example in the case of a tert-butyl ester
  • catalytic hydrogenation for example in the case of a benzyl ester.
  • Azadepsipeptides of the formula (II) can also be prepared, for example, by splitting off the protective group of N-terminally protected azadepsipeptides of the formula (VII) in one process (Ab) according to the following reaction scheme:
  • a 1 represents an N-terminal protective group such as, for example,
  • Butoxycarbonyl (BOC), Benzyloxycarbonyl (Cbz) or Benzyl (Bn) See, e.g., T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley & Sons, New York 1991).
  • the reaction can be carried out using conventional N-terminal deblocking methods such as
  • the C-terminally protected azadepsipeptides of the formula (VI) required for carrying out the process (Aa) or the N-terminally protected azadepsipeptides of the formula (VII) required for carrying out the process (Ab) can be prepared by and C-terminally protected azadepsipeptides of the formula (VIII)
  • both protective groups can also be split off in one step and compounds of formula (VIII) can be passed directly to compounds of formula (II) (process A.a / b).
  • Aza-octadepsipeptides of formula (VIII) can be e.g. manufacture by
  • reaction auxiliaries are those listed below in process (A).
  • N-terminally protected azadepsipeptides of the formula (IX) can be prepared, for example, by the O-protecting group A 3 bilaterally protected azadepsipeptides of the formula (XI), C-terminally protected azadepsipeptides of the formula (X) by the N-protecting group A 2 bilaterally protected azadepsipeptides of the formula (XII) are split off analogously to the generally known methods given above.
  • a 3 represents a C-terminal protective group as indicated for A 4 .
  • a 2 represents an N-terminal protecting group as indicated for A '.
  • the bilaterally protected (aza) tetradepsipeptides could in principle be combined into a single general formula because the odd-numbered residues in formula (XI) and the next higher even-numbered residues in formula (XII) stand for the same lists of residues. It should be expressed that in each synthesis of an individual compound of formula (I), the radicals can be selected independently of one another, ie the building blocks (XI) and (XII) are the same or different could be. The synthesis of the compound of the formula (XI) is to be explained as a representative here because the same also applies to the preparation of (XII).
  • the compounds of the formula (XI) can be prepared, for example, by building blocks of the formula (XIII) with building blocks of the formula (XIV) in the presence of a reaction auxiliary such as BOP-Cl or HATU and a base such as Hünig base and optionally in the presence of a diluent how to link dichloromethane according to the following reaction scheme:
  • Suitable reaction auxiliaries, bases and solvents are those listed in process (A).
  • Formula (III) provides a general definition of the compounds required for carrying out process (B) according to the invention.
  • X 2 to X 4 and R 1 to R 12 preferably represent those radicals which are preferred in connection with the description of the aza-cyclodepsipeptides of the formula (I)
  • A represents an N-terminal protective group as indicated for A.
  • R 13 represents optionally substituted alkyl or aryl.
  • (Aza) - Depsipeptide esters of the formula (XVI) can be prepared, for example, analogously to the synthesis of the compound (VII) by the peptide chemical methods used or described there.
  • Hydrazines of the formula (XVII) are known in some cases or can be obtained by known methods (cf. e.g. J. Chem. Soc. Perkin Trans. I 1975, 1712).
  • Y 1 preferably represents chlorine, trichloromethoxy, methoxy, ethoxy, 1-imidazolyl, 1,2,4-triazolyl or Z-substituted aryloxy, in particular pentafluorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl, Y 2 preferably for chlorine, trichloromethoxy, methoxy, ethoxy, 1-imidazolyl or 1,2,4-triazolyl.
  • the compounds of formula (IV) are generally known as phosgene or phosgene equivalents (see e.g. Org.Synthes Coll. Vol. 5, 201 (1973)).
  • Formula (V) provides a general definition of the compounds required for carrying out process (C) according to the invention.
  • X 2 X 3 , X 4 , R 1 to R 12 preferably for those radicals which have already been mentioned as preferred substituents in connection with the description of the aza-cyclodepsipeptides of the formula (I).
  • Y 1 preferably represents chlorine, trichloromethoxy, 1-imidazolyl, 1, 2,4-triazolyl or Z-substituted aryloxy, in particular pentafluorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl.
  • Compounds of the formula (V) can be prepared, for example, by splitting off the N-terminal protective group A 5 from compounds of the formula (XVIII) using the methods given above.
  • Compounds of the formula (XVIII) can be prepared, for example, by reacting the compounds of the formula (XV) described above with one of the phosgenating reagents of the formula (IV) described in process B) and, if desired, the product of the formula (XVIII) obtained, in the Y 1 does not represent Z-substituted aryloxy, with a corresponding phenol or phenolate such as, for example, 2,4-dinitrophenol.
  • Suitable reaction auxiliaries for carrying out process (A) according to the invention are all compounds which are suitable for forming an amide bond (cf., for example, Houben-Weyl, Methods of Organic Chemistry, Volume 15/2; Bodensky et al .; Peptide Synthesis 2nd ed., Wiley & Sons, New York 1976).
  • active ester method with pentafluorophenol PfP
  • N-hydroxysuccinimide N-hydroxybenzotriazole
  • HOBt 1-hydroxybenzotriazole
  • carbodimides such as dicyclohexylcarbodiimide or N '- (3-dimethylaminopropyl) -N-ethyl carbodiimide (EDC)
  • EDC N '- (3-dimethylaminopropyl) -N-ethyl carbodiimide
  • phosphorus reagents such as 1-benzotriazolyloxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP), O- (7-azabenzotrial-1 -yl) - 1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU), bis (2-oxo-3-oxazolidinyl) phosphoryl chloride (BOP-Cl), diphenyl
  • Organic solvents and any mixtures thereof can be used as solvents for carrying out process (A) according to the invention.
  • Examples include: aliphatic, alicyclic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, methylene chloride, chloroform, tetrachloromethane, dichloro-, trichloroethane or tetrachlorethylene; Ethers, such as diethyl,
  • the cyclization is preferably carried out in the presence of a base.
  • Inorganic or organic bases are suitable as such. These preferably include alkaline earth metal or alkali metal hydroxides, alcoholates, acetates, carbonates or hydrogen carbonates, such as, for example, sodium, potassium or ammonium hydroxide, sodium methylate, sodium ethylate, potassium tert-butoxide, sodium, Potassium, calcium or ammonium acetate, sodium, potassium or ammonium carbonate, sodium hydrogen or potassium hydrogen carbonate and tertiary amines, such as trimethylamine, triethylamine, tributylamine, ethyldiisopropylamine, N, N-dimethylaniline, N, N-dimethyl -benzylamine, pyridine, picoline, N-methylpiperidine, N-methylmorpholine, N, N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazab
  • reaction temperature in process (A) according to the invention can be varied within a substantial range.
  • the cyclization is carried out at temperatures between -40 ° C and + 150 ° C, preferably at -20 ° C to
  • the compound of the formula (II) and the base are generally used in a molar ratio of 1: 1 to 1: 3, preferably 1: 2. It is advantageous to work with high dilution, i.e. in general, 50 to 5000 ml of solvent are used per mole of compound of the formula (II).
  • Process (B) according to the invention can be carried out in the presence of a diluent. As such, those listed in process (A) are preferably used.
  • Process (B) according to the invention can be carried out in the presence of a suitable reaction auxiliary.
  • a suitable reaction auxiliary As such, all bases listed in process (A) are suitable.
  • the reaction temperature can be varied within a substantial range in process (B) according to the invention.
  • temperatures between -20 ° C and + 150 ° C, preferably between + 20 ° C and 120 ° C, where appropriate, the cyclization is initiated only after the reaction of the two reactants by increasing the temperature.
  • Process (C) according to the invention can be carried out in the presence of a diluent. As such, those listed in process (A) are preferably used.
  • Process (C) according to the invention can be carried out in the presence of a suitable reaction auxiliary.
  • a suitable reaction auxiliary As such, all bases listed in process (A) are suitable.
  • reaction temperature can be varied within a substantial range in process (C) according to the invention. In general, temperatures between -20 ° C and + 150 ° C, preferably between + 20 ° C and 120 ° C.
  • the compound of the formula (IX) and the base are generally used in a molar ratio of 1: 1 to 1: 3, preferably equimolar, if appropriate.
  • the implementations of the methods according to the invention can be carried out under normal pressure or under elevated pressure. Is preferably carried out at normal pressure.
  • the reaction is carried out, worked up and isolated by generally customary, known methods.
  • the end products are preferably by crystallization, chromatographic separation or by Removal of the volatile constituents, if necessary in a vacuum, cleaned (see also the preparation examples).
  • 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, skins, etc.) are to be reduced, so that the use of the active ingredients enables more economical and simple animal husbandry.
  • Pathogenic endoparasites include cestodes, trematodes, nematodes, in particular:
  • Schistocephalus spp. Ligula spp., Bothridium spp., Diphlogonoorus spp ..
  • Cyclophyllidea for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosmsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyella spp.
  • Taenia spp. Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium
  • 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., Typhloccelum spp., Paramphistomum spp., Calicophoron spp., Cotylopantoc.
  • Nanophyetus spp. Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp ..
  • Stronylus spp. Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx 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., Happertagagia spp., Ostemonchusagia.
  • 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 ..
  • the active compounds according to the invention show outstanding activity against larvae of Trichinella spiralis and worms such as Nippostrongylus brasiliensis.
  • 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.
  • 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.
  • the enteral application of the active ingredients takes place, for example, orally in the form of powder, suppositories, tablets, capsules, fasting, watering, granules, drenches, boluses, medicated 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 powdering.
  • 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, tablets, boluses, capsules; Aerosols and inhalants, molded articles containing active ingredients.
  • Solutions for injection are administered intravenously, intramuscularly and subcutaneously.
  • Injection solutions are prepared by dissolving the active ingredient in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives.
  • the solutions are sterile filtered and filled.
  • solvents physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof.
  • the active compounds can also be dissolved in physiologically tolerable vegetable or synthetic oils which are suitable for injection.
  • solubilizers solvents which promote the dissolution of the active ingredient in the main solvent or prevent its precipitation.
  • solvents which promote the dissolution of the active ingredient in the main solvent or prevent its precipitation.
  • examples are polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.
  • Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol.
  • Oral solutions are applied directly. Concentrates are used orally after previous dilution to the application concentration. Oral solutions and concentrates are prepared as described above for the injection solutions, whereby sterile work can be dispensed with.
  • Solutions for use on the skin are dripped on, spread on, rubbed in, sprayed on, sprayed on or applied by dipping (dipping, bathing or washing). These solutions are produced as described above for the injection solutions.
  • Thickeners are: inorganic thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates. Gels are applied to or spread on the skin or placed in body cavities. Gels are produced by adding solutions, which have been prepared as described for the injection solutions, with enough thickening agent to produce a clear mass with an ointment-like consistency. As
  • Thickeners the thickeners specified above are used.
  • Pour-on formulations are poured or sprayed onto limited areas of the skin, the active ingredient either penetrating the skin and acting systemically or being distributed over the surface of the body.
  • pour-on formulations are prepared by dissolving, suspending or emulsifying the active ingredient in suitable solvents or solvent mixtures that are compatible with the skin. If necessary, other auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers and adhesives are added.
  • solvents water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as
  • Alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1, 3-dioxolane.
  • Dyes are all dyes approved for use on animals, which can be dissolved or suspended.
  • Resorption-promoting substances are, for example, DMSO, 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 e.g. 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.
  • hydrophobic phase paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid biglyceride, triglyceride mixture with vegetable fatty acid of chain length C 8 -C 12 or other specially selected natural fatty acids, partial glyceride - Mixtures of saturated or unsaturated, possibly also containing hydroxyl groups
  • 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 C 16 -C lg , isopropyl myristate, isopropyl palmitate, caprylic / capric acid esters of saturated fatty alcohols of chain length C 12 - C 18 , isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, wax-like fatty acid esters such as artificial duckling glandular fat, di-butyl phthalate, adipate ester demiopropyl amide.
  • Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.
  • Fatty acids such as Oleic acid and its mixtures.
  • hydrophilic phase The following can be mentioned as the hydrophilic phase:
  • Alcohols such as e.g. Propylene glycol, glycerin, sorbitol and their mixtures.
  • nonionic surfactants e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;
  • ampholytic surfactants such as di-Na-N-lauryl- ⁇ -iminodipropionate or lecithin;
  • anionic surfactants such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt;
  • cationic surfactants such as cetyltrimethylammonium chloride.
  • auxiliaries substances which increase viscosity and stabilize the emulsion, such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes , colloidal silica or mixtures of the listed substances.
  • Suspensions can be used orally, dermally or as an injection. They are produced by suspending the active ingredient in a carrier liquid, optionally with the addition of other auxiliaries such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers.
  • the surfactants specified above may be mentioned as wetting agents (dispersants).
  • Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only in their higher viscosity.
  • the active ingredient is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and brought into the desired shape.
  • Inorganic 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, for example, sugar, cellulose, food and feed such as milk powder, animal meal, cereal meal and meal, starches. Excipients are preservatives, antioxidants, dyes, which have already been listed above.
  • auxiliaries are lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinyl pyrrolidone as well as dry binders such as microcrystalline cellulose.
  • lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinyl pyrrolidone as well as dry binders such as microcrystalline cellulose.
  • the active substances can also be present in the preparations in a mixture with synergists or with other active substances which act against pathogenic endoparasites.
  • Such agents are e.g. L-2,3,5,6-tetrahydro-6-phenyl-imidazolethiazole, benzimidazole carbamate, praziquantel, pyrantel, febantel.
  • Ready-to-use preparations contain the active substance in concentrations of
  • Preparations which are diluted before use contain the active ingredient in concentrations of 0.5 to 90% by weight, preferably 5 to 50% by weight.
  • H-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-OH e.g. from Example II-1
  • 266 mg (2.06 mmol) of ethyldiisopropylamine and 252 mg (0.99 mmol) of BOP-Cl were added to the solution.
  • the mixture was then allowed to warm to room temperature and stirred for a further 24 h.
  • the reaction solution was then washed with sat.
  • H-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn (e.g. from Ex. VII-1) were mixed in approx. Dissolved 30 ml of ethyl acetate and hydrogenated at normal pressure with hydrogen in the presence of Pd / C (10%). When the reaction was complete, the catalyst was filtered off and the solvent was removed in vacuo.
  • Example XII-1 were placed under argon in 60 ml of dry dichloromethane. At 0 ° C slowly 5J4 g (45 mmol) trifluoroacetic acid to the solution dripped. The mixture was allowed to warm to RT and stirred for about 15 h. The solution was then concentrated, the residue was taken up in dichloromethane and washed with sat. Sodium bicarbonate solution and sat. Washed sodium chloride solution. After drying over sodium sulfate, the solvent was removed in vacuo.
  • Butoxycarbonyl-l-isobutyl-2-methylhydrazyl) -carbonyloxy3-phenylacetic acid (e.g. from Example XIII-1) were placed under argon in 120 ml of dry dichloromethane. At 0 ° C., 9.69 g (75 mmol) of ethyldiisopropylamine and then 9J6 g (36 mmol) of BOP-Cl were slowly added to the solution. After stirring at 0 ° C. for 2 h, the mixture was allowed to warm to RT and stirred for a further 12 h.
  • Trichinella spiralis larvae were isolated from skeletal muscles and diaphragms of SPF / CFW1 mice and stored in 0.9% NaCl solution which had been supplemented with 20 ⁇ g ml "1 clotrimazole. The incubation of 20 larvae per determination was carried out in 2 ml of a solution carried out per 500 ml of 10 g of Bacto Casitone, 5 g
  • Yeast extract 2.5 g glucose, 0.4 g KH 2 PO 4 and 0.4 g K 2 HPO 4 (pH 7.2) supplemented by 10 ⁇ g ml "1 sisomicin and 1 ⁇ g ml " 1 clotrimazole contained.
  • 10 mg of the active ingredient to be tested were dissolved in 0.5 ml of dimethyl sulfoxide and added to the incubation medium in such a way that final concentrations of 100, 10, 1, 0J or 0.01 ⁇ g ml "1 were obtained. After 5 days of incubation at 19 The test was stopped at ° C.
  • the compound according to the invention from preparation example I-1 showed an effect of stage 3 at an exemplary active compound concentration of 100 ⁇ g / ml.

Abstract

The invention relates to new aza-cyclodepsipeptides of formula (I) in which X?1, X2, X3 and X4¿ independently of each other are N or C-H and at least one of these variables X represents nitrogen. The invention also relates to a method for their production and to their use for combating parasites, notably helminthes.

Description

AZA-CYCLODEPSIPEPTIDE UND IHRE VERWENDUNG ALS PARASITIZIDE AZA CYCLODEPSIPEPTIDES AND THEIR USE AS PARASITICIDES
Die Erfindung betrifft neue Aza-Cyclodepsipeptide, Verfahren zu ihrer Herstellung und ihre Verwendung zur Bekämpfung von Parasiten, insbesondere Helminthen in der Tier- und Humanmedizin.The invention relates to new aza-cyclodepsipeptides, processes for their preparation and their use for controlling parasites, in particular helminths in veterinary and human medicine.
Die Erfindung betrifft neue 24-gliedrige Heterocyclen, die aus α-Hydroxycarbon- säuren einerseits und α-Aminosäuren oder α-Aza-Aminosäuren andererseits alter- nierend aufgebaut sind, wobei mindestens eine Aza-Aminosäure enthalten ist. Über derartige Aza-Cyclodepsipeptide ist bisher nichts bekannt geworden.The invention relates to new 24-membered heterocycles which are composed of α-hydroxycarboxylic acids on the one hand and α-amino acids or α-aza-amino acids on the other hand, with at least one aza-amino acid being contained. So far, nothing has been known about such aza-cyclodepsipeptides.
Es wurden neue Aza-Cyclodepsipeptide der Formel (I)New aza-cyclodepsipeptides of the formula (I)
gefunden, in welcherfound in which
X1, X2, X3 und X4 unabhängig voneinander jeweils für N oder C-H stehen, wobei mindestens eine dieser Variablen X für Stickstoff steht,X 1 , X 2 , X 3 and X 4 each independently represent N or CH, where at least one of these variables X represents nitrogen,
R1, R2, R3 und R4 unabhängig voneinander jeweils für Wasserstoff, jeweils gegebenenfalls durch Halogen substituiertes Alkyl, Alkenyl, Hydroxyalkyl, Alkanoyloxyalkyl, Alkoxyalkyl, Arylalkoxyalkyl, Mercaptoalkyl, Alkylthio- alkyl, Alkoxycarbonylalkyl, Aryloxycarbonylalkyl, Arylalkyloxycarbonyl- alkyl, Carbamoylalkyl, Aminoalkyl, Alkylaminoalkyl, Dialkylaminoalkyl oder für jeweils gegebenenfalls substituiertes Cycloalkyl, Cycloalkylalkyl, Aryl, Arylalkyl, Hetaryl oder Hetarylalkyl stehen, undR 1 , R 2 , R 3 and R 4 independently of one another each represent hydrogen, in each case optionally substituted by halogen, alkyl, alkenyl, hydroxyalkyl, Alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or, in each case, optionally substituted cycloalkyl, cycloalkylalkyl, aryl, aryl or alkyl, harylaryl
ie Gruppierung -NR9-X'R5- für einen Rest der Formel -NR9 1 -CHR5 1- oder einen Rest der Formel -NR9"2-NR5"2- steht,he grouping -NR 9 -X'R 5 - represents a radical of the formula -NR 9 1 -CHR 5 1 - or a radical of the formula -NR 9 "2 -NR 5" 2 -,
die Gruppierung -NR10-X2R6-für einen Rest der Formel -NR10 1-CHR6 1- oder einenthe grouping -NR 10 -X 2 R 6 -for a radical of the formula -NR 10 1 -CHR 6 1 - or one
Rest der Formel -NR10"2-NR6"2- steht,Rest of the formula -NR 10 "2 -NR 6" 2 - stands,
die Gruppierung -NR1 '-X^-für einen Rest der Formel -NR11 "'-CHR7"1- oder einenthe grouping -NR 1 '-X ^ - for a radical of the formula -NR 11 " ' -CHR 7" 1 - or one
Rest der Formel -NRH"2-NR7"2- steht,Radical of the formula -NR H "2 -NR 7" 2 - stands,
die Gruppierung -NR12-X4R8-für einen Rest der Formel -NR12 1-CHR8 1- oder einenthe grouping -NR 12 -X 4 R 8 -for a radical of the formula -NR 12 1 -CHR 8 1 - or one
Rest der Formel -NR12"2-NR8"2- steht,Rest of the formula -NR 12 "2 -NR 8" 2 - stands,
R5"1, R6"1, R7"1 und R8"1 unabhängig voneinander jeweils für Wasserstoff, gegebenen- falls durch Amino oder Hydroxy substituiertes Alkyl, für Mercaptomethyl,R 5 "1 , R 6" 1 , R 7 "1 and R 8" 1 independently of one another each for hydrogen, optionally alkyl or amino-substituted alkyl, for mercaptomethyl,
Methylthioethyl, Carboxymethyl, Carboxyethyl, Carbamoylmethyl, Carbamoylethyl, Guanidinopropyl, für gegebenenfalls durch Amino, Nitro, Halogen, Hydroxy oder Alkoxy substituiertes Phenyl oder Benzyl, für Naphthylmethyl, Indolylmethyl, Imidazolylmethyl, Triazolylmethyl, Thienyl- methyl, Benzothienylmethyl oder Pyridylmethyl stehen, wobei funktionelleMethylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl, for phenyl or benzyl optionally substituted by amino, nitro, halogen, hydroxy or alkoxy, for naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl, thienylmethyl or benzothidylmethylmethyl, benzothidylmethyl
Gruppen gegebenenfalls geschützt vorliegen können,Groups may be protected,
R9"1, R10"1, R11"1 und R12"1 unabhängig voneinander jeweils für Wasserstoff oderR 9 "1 , R 10" 1 , R 11 "1 and R 12" 1 are each independently of one another hydrogen or
CrC4-Alkyl stehen, wobei die Restepaare R^' R9"1, R^'/R10"1, R' VR11"1 und R^/R12"1 auch jeweils gemeinsam unabhängig voneinander für die Reste -(CH2)3- und -(CH2)4- stehen, undC r C 4 alkyl, wherein the pairs of residues R ^ 'R 9 "1 , R ^' / R 10" 1 , R 'VR 11 "1 and R ^ / R 12" 1 each also independently of one another for the residues - (CH 2 ) 3 - and - (CH 2 ) 4 - stand, and
R5"2 bis R12"2 unabhängig voneinander jeweils für Wasserstoff, jeweils gegebenenfalls durch Halogen substituiertes Alkyl, Hydroxyalkyl, Alkanoyloxyalkyl, Alkoxyalkyl, Arylalkoxyalkyl, Mercaptoalkyl, Alkylthioalkyl, Carboxyalkyl, Alkoxycarbonylalkyl, Aryloxycarbonylalkyl, Arylalkyloxycarbonylalkyl, Carbamoylalkyl, Aminoalkyl, Alkylaminoalkyl, Dialkylaminoalkyl, Alkoxy- carbonylaminoalkyl oder für jeweils gegebenenfalls substituiertes Cycloalkyl,R 5 "2 to R 12" 2 independently of one another each represent hydrogen, in each case optionally substituted by halogen, alkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkyl Alkoxycarbonylaminoalkyl or for optionally substituted cycloalkyl,
Cycloalkylalkyl, Aryl, Arylalkyl, Hetaryl oder Hetarylalkyl stehen,Cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl,
wobei die Restepaare R5"2/R9"2, R6"2/R10"2, R^/R11"2 und R8"2/R12"2 auch jeweils gemeinsam unabhängig voneinander für die gegebenenfalls durch C,-C4-Alkyl substituierten Reste -(CH2)3- und -(CH2)4- stehen.where the pairs of residues R 5 "2 / R 9" 2 , R 6 "2 / R 10" 2 , R ^ / R 11 "2 and R 8" 2 / R 12 "2 are also together, independently of one another, for those optionally represented by C , -C 4 alkyl substituted radicals - (CH 2 ) 3 - and - (CH 2 ) 4 - are.
Funktionelle Gruppen sind geschützt z.B. durch aus der Peptidchemie bekannte Schutzgruppen (z.B. aufgeführt in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley & Sons, New York 1991).Functional groups are protected, for example, by protective groups known from peptide chemistry (for example listed in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 2 nd Ed., John Wiley & Sons, New York 1991).
Die Konfiguration an den chiralen Kohlenstoffen ist beliebig, d.h. die erfindungsgemäßen Verbindungen der Formel (I) sind aus D- und/oder L-konfigurierten Aminosäuren und Hydroxycarbonsäuren aufgebaut. Die Erfindung betrifft die reinen Stereoisomere und Gemische daraus. Bevorzugt sind die Verbindungen aus D- Hydroxycarbonsäuren und L-Aminosäuren aufgebaut. Im folgenden wird der Einfachheit halber jedoch stets von Verbindungen der Formel (I) gesprochen, obwohl sowohl die reinen Verbindungen als gegebenenfalls auch Gemische mit unterschiedlichen Anteilen an isomeren Verbindungen gemeint sind. Weiterhin wurde gefunden, daß man die neuen Verbindungen der Formel (I) nach einem der im folgenden beschriebenen Verfahren erhält.The configuration on the chiral carbons is arbitrary, ie the compounds of the formula (I) according to the invention are composed of D- and / or L-configured amino acids and hydroxycarboxylic acids. The invention relates to the pure stereoisomers and mixtures thereof. The compounds are preferably composed of D-hydroxycarboxylic acids and L-amino acids. For the sake of simplicity, however, the following always refers to compounds of the formula (I), although both the pure compounds and, if appropriate, mixtures with different proportions of isomeric compounds are meant. Furthermore, it was found that the new compounds of the formula (I) can be obtained by one of the processes described below.
A) Aza-Cyclodepsipeptide der Formel (I)A) aza-cyclodepsipeptides of the formula (I)
in welcherin which
X1, X2, X3, X4 und R1 bis R12 die oben angegebenen Bedeutungen haben,X 1 , X 2 , X 3 , X 4 and R 1 to R 12 have the meanings given above,
lassen sich herstellen, indem man Azadepsipeptide der Formel (II)can be prepared by using azadepsipeptides of the formula (II)
in welcher X , X , X , X und R bis R die oben angegebenen Bedeutungen haben,in which X, X, X, X and R to R have the meanings given above,
in Gegenwart eines Reaktionshilfsmittels und eines Lösungsmittels und gegebenenfalls in Gegenwart einer Base cyclisiert.cyclized in the presence of a reaction auxiliary and a solvent and optionally in the presence of a base.
Azacyclodepsipeptide der Formel (I-a)Azacyclodepsipeptides of the formula (I-a)
in welcherin which
X2, X3, X4 unabhängig voneinander jeweils für N oder C-H stehen undX 2 , X 3 , X 4 each independently represent N or CH and
R1 bis R12 die oben angegebenen Bedeutungen haben,R 1 to R 12 have the meanings given above,
lassen sich herstellen, indem man Azadepsipeptide der Formel (III) can be prepared by using azadepsipeptides of the formula (III)
in welcherin which
X2, X3, X4 unabhängig voneinander jeweils für N oder C-H stehen undX 2 , X 3 , X 4 each independently represent N or CH and
R1 bis R12 die oben angegebenen Bedeutungen haben,R 1 to R 12 have the meanings given above,
mit Verbindungen der Formel (IV)with compounds of formula (IV)
in welcherin which
Y1 für Chlor, Trichlormethoxy, CrC4-Alkoxy, gegebenenfalls substituiertes Phenoxy, 1-Imidazolyl oder 1 ,2,4-Triazolyl steht undY 1 represents chlorine, trichloromethoxy, C r C 4 alkoxy, optionally substituted phenoxy, 1-imidazolyl or 1, 2,4-triazolyl and
Y2 für Chlor, Trichlormethoxy, 1-Imidazolyl oder 1 ,2,4-Triazolyl steht,Y 2 represents chlorine, trichloromethoxy, 1-imidazolyl or 1, 2,4-triazolyl,
gegebenenfalls in Gegenwart eines Verdünnungsmittels und gegebenenfalls inoptionally in the presence of a diluent and optionally in
Gegenwart eines Reaktionshilfsmittels umsetzt und cyclokondensiert. C) Azacyclodepsipeptide der oben angegebenen Formel (I-a) lassen sich herstellen, indem man Azadepsipeptide der Formel (V)In the presence of a reaction auxiliary and cyclocondensed. C) Azacyclodepsipeptides of the above formula (Ia) can be prepared by using azadepsipeptides of the formula (V)
in welcherin which
X2, X3, X4 unabhängig voneinander jeweils für N oder C-H stehen undX 2 , X 3 , X 4 each independently represent N or CH and
R1 bis R12 und Y1 die oben angegebenen Bedeutungen haben,R 1 to R 12 and Y 1 have the meanings given above,
gegebenenfalls in Gegenwart eines Verdünnungsmittels und gegebenenfalls in Gegenwart eines Reaktionshilfsmittels cyclokondensiert.optionally cyclocondensed in the presence of a diluent and optionally in the presence of a reaction auxiliary.
Weiter wurde gefunden, daß die erfindungsgemäßen Verbindungen geeignet sind zurIt has also been found that the compounds according to the invention are suitable for
Bekämpfung von Helminthen in der Tier- und Humanmedizin.Combating helminths in veterinary and human medicine.
Die neuen Verbindungen sind durch die Formel (I) allgemein definiert. Bevorzugt sind Verbindungen der Formel (I), in welcher die Substituenten, beziehungsweise die Bereiche die folgenden Bedeutungen haben:The new compounds are generally defined by the formula (I). Preferred compounds of the formula (I) are those in which the substituents or the areas have the following meanings:
R1, R2, R3 und R4 stehen unabhängig voneinander jeweils bevorzugt für Wasserstoff, C,-C,6-Alkyl, für jeweils gegebenenfalls durch Fluor, Chlor oder Brom substituiertes C,-C6-Alkyl, C2-C8-Alkenyl, C3-C7-Cycloalkyl, C3-C7-Cyclo- alkyl-C,-C4-alkyl, C,-C6-Hydroxyalkyl, C,-C4-Alkanoyloxy-CrC6-alkyl insbesondere Acetoxymethyl oder 1-Acetoxyethyl, C,-C4-Alkoxy-CrC6-alkyl insbesondere Methoxymethyl oder 1-Methoxyethyl, Aryl-C,-C4-alkoxy-C1- C6-alkyl, CrC6-Mercaptoalkyl, insbesondere Mercaptomethyl, C,-C4-Alkyl- thio-C,-C6-alkyl, insbesondere Methylthioethyl, CrC4-Alkoxycarbonyl-C,- C6-alkyl, Aryloxycarbonyl-C]-C6-alkyl, insbesondere Phenoxycarbonyl- methyl, Aryl-C,-C4-alkyloxycarbonyl-C,-C6-alkyl, Carbamoyl-C,-C6-alkyl, insbesondere Carbamoylmethyl oder Carbamoylethyl, Amino-C,-C6-alkyl, C,-C4-Alkylamino-C1-C6-alkyl, Di-CrC4-alkylamino-C,-C6-alkyl oder für jeweils gegebenenfalls durch Halogen, Hydroxy, Cyano, C,-C6-Alkyl, C,-C4- Halogenalkyl, C,-C4-Alkoxy, C,-C4-Halogenalkoxy, Benzyloxy oder Silyl- oxy, das durch C,-C4-Alkyl und/oder Phenyl trisubstituiert ist, substituiertes Aryl, Aryl-CrC4-alkyl, Hetaryl oder Hetaryl-CrC4-alkyl.R 1 , R 2 , R 3 and R 4 independently of one another each preferably represent hydrogen, C, -C, 6 alkyl, each optionally by fluorine, chlorine or bromine substituted C, -C 6 alkyl, C 2 -C 8 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C, -C 4 alkyl, C, -C 6 hydroxyalkyl , C, -C 4 -alkanoyloxy-C r C 6 -alkyl in particular acetoxymethyl or 1-acetoxyethyl, C, -C 4 -alkoxy-C r C 6 -alkyl in particular methoxymethyl or 1-methoxyethyl, aryl-C, -C 4 -alkoxy-C 1 -C 6 -alkyl, C r C 6 -ercaptoalkyl, in particular mercaptomethyl, C, -C 4 -alkylthio-C, -C 6 -alkyl, in particular methylthioethyl, C r C 4 -alkoxycarbonyl-C , - C 6 -alkyl, aryloxycarbonyl-C ] -C 6 -alkyl, in particular phenoxycarbonyl-methyl, aryl-C, -C 4 -alkyloxycarbonyl-C, -C 6 -alkyl, carbamoyl-C, -C 6 -alkyl, in particular carbamoylmethyl or carbamoylethyl, amino-C, -C 6 -alkyl, C, -C 4 -alkylamino-C 1 -C 6 -alkyl, di-C r C 4 -alkylamino-C, -C 6 -alkyl or for each optionally substituted by halogen, hydroxy, cyano, C, -C6 alkyl, C, -C 4 - haloalkyl, C, -C 4 alkoxy, C, -C 4 -haloalkoxy, benzyloxy or silyl oxy, which, by C -C 4 alkyl and / or phenyl is trisubstituted , substituted aryl, aryl-C r C 4 alkyl, hetaryl or hetaryl-C r C 4 alkyl.
R5"1, R6"1, R7"1 und R8"1 stehen unabhängig voneinander jeweils bevorzugt für Wasserstoff, Methyl, iso-Propyl, iso-Butyl, sec.-Butyl, Hydroxymethyl, 1-Hydroxy- ethyl, Mercaptomethyl, 2-Methylthioethyl, 3-Aminopropyl, 4-Aminobutyl, Carboxymethyl, 2-Carboxyethyl, Carbamoylmethyl, 2-Carbamoylethyl, 3- Guanidinopropyl, Phenyl, Benzyl, 4-Hydroxybenzyl, 4-Methoxybenzyl, 2-R 5 "1 , R 6" 1 , R 7 "1 and R 8" 1 each independently of one another preferably represent hydrogen, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, Mercaptomethyl, 2-methylthioethyl, 3-aminopropyl, 4-aminobutyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 3-guanidinopropyl, phenyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 2-
Nitrobenzyl, 3 -Nitrobenzyl, 4-Nitrobenzyl, 2-Aminobenzyl, 3-Aminobenzyl, 4-Aminobenzyl, 3,4-Dichlorbenzyl, 4-Iodbenzyl, α-Naphthylmethyl, ß- Naphthylmethyl 3-Indolylmethyl, 4-Imidazolylmethyl, 1,2,3-Triazol-l-yl- methyl, 1,2,4-Triazol-l-yl-methyl, 3-Thienylmethyl, 3-Benzothienylmethyl, 2-Pyridylmethyl oder 3-Pyridylmethyl, wobei funktioneile Gruppen gegebenenfalls geschützt vorliegen können.Nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 3,4-dichlorobenzyl, 4-iodobenzyl, α-naphthylmethyl, β-naphthylmethyl 3-indolylmethyl, 4-imidazolylmethyl, 1,2-imidazolylmethyl , 3-triazol-l-yl-methyl, 1,2,4-triazol-l-yl-methyl, 3-thienylmethyl, 3-benzothienylmethyl, 2-pyridylmethyl or 3-pyridylmethyl, where functional groups can optionally be protected.
R9"', R10"1, R""1 und R12"1 stehen unabhängig voneinander jeweils bevorzugt fürR 9 " ', R 10" 1 , R "" 1 and R 12 "1 each independently represent preferably
Wasserstoff, Methyl oder Ethyl. die Restepaare R^'/R9"1, R^'/R10"1, R'-'/R11"1 und R'-'/R12"1 stehen auch bevorzugt jeweils gemeinsam unabhängig voneinander für die Reste -(CH2)3- und -(CH2)4-.Hydrogen, methyl or ethyl. the pairs of radicals R ^ '/ R 9 "1 , R ^' / R 10" 1 , R '-' / R 11 "1 and R '-' / R 12" 1 also preferably each independently stand for the radicals - (CH 2 ) 3 - and - (CH 2 ) 4 -.
R5"2 bis R12"2 stehen unabhängig voneinander bevorzugt für Wasserstoff, CrC15-R 5 "2 to R 12" 2 independently of one another preferably represent hydrogen, C r C 15 -
Alkyl, insbesondere auch 3,7,11-Trimethyldodecyl, für jeweils gegebenenfalls durch Fluor, Chlor oder Brom substituiertes CrC8-Alkyl, C3-C7-Cyclo- alkyl, C3-C7-Cycloalkyl-C,-C4-alkyl, C,-C6-Hydroxyalkyl, C,-C4-Alkanoyl- oxy-C,-C6-alkyl, C1-C4-Alkoxy-C,-C6-alkyl, Aryl-CrC4-alkoxy-CrC6-alkyl, C,-C6-Mercaptoalkyl, insbesondere Mercaptomethyl, CrC4-Alkylthio-CrC6- alkyl, insbesondere Methylthioethyl, CrC4-Alkylsulfmyl-CrC6-alkyl, insbesondere Methylsulfinylethyl, C,-C4-Alkylsulfonyl-C,-C6-alkyl, insbesondere Methylsulfonylethyl, Carboxy-C,-C6-alkyl, insbesondere Carboxymethyl, Carboxyethyl oder Carboxy-tert.-butyl, C,-C4-Alkoxycarbonyl-C,-C6-alkyl, insbesondere Methoxycarbonylmethyl oder Ethoxycarbonylethyl, Aryloxy- carbonyl-C,-C6-alkyl, insbesondere Phenoxycarbonylmethyl, Aryl-C,-C4- alkyloxycarbonyl-CrC6-alkyl, insbesondere Benzyloxycarbonylmethyl, Carb- amoyl-C,-C6-alkyl, insbesondere Carbamoylmethyl oder Carbamoylethyl, Amino-C,-C6-alkyl, insbesondere Aminopropyl oder Aminobutyl, C,-C4- Alkylamino-CrC6-alkyl insbesondere Methylaminopropyl oder Methyl- amino, Di-(CrC4)-alkylamino-C,-C6-alkyl insbesondere Dimethylamino- propyl oder Dimethylaminobutyl, CrC4-Alkoxycarbonylamino-C,-C6-alkyl, oder für jeweils gegebenenfalls durch Halogen, Hydroxy, Nitro, Cyano, Amino, C,-C4-Alkylamino, Di-(C,-C4)-alkylamino, Benzylamino, Dibenzyl- amino, geschütztes Amino wie z.B. Acetyl-, t-Butoxycarbonyl-, Benzyl- oxycarbonyl- oder FMOC-amino, CrC6-Alkyl, C,-C4-Halogenalkyl, CrC4- Alkoxy oder CrC4-Halogenalkoxy substituiertes Aryl, Aryl-C,-C4-alkyl, Hetaryl oder Hetaryl-CrC4-alkyl, wobei gegebenenfalls eine NH-Funktion im heterocyclischen Ring durch eine Aminoschutzgruppe, wie beispielhaft o.a., derivatisiert sein kann. Die Restepaare R5"2/R9-2, R6-2/R10"2, R'-'/R11"2 und R8-2/R12"2 stehen auch jeweils gemeinsam unabhängig voneinander bevorzugt für die gegebenenfalls einfach bis vierfach durch C,-C4-Alkyl substituierten Reste -(CH2)3- und -(CH2)4-.Alkyl, in particular 3,7,11-trimethyldodecyl, for C r C 8 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C, - which are each optionally substituted by fluorine, chlorine or bromine, - C 4 -alkyl, C, -C 6 -hydroxyalkyl, C, -C 4 -alkanoyloxy-C, -C 6 -alkyl, C 1 -C 4 -alkoxy-C, -C 6 -alkyl, aryl-C r C 4 -alkoxy-C r C 6 -alkyl, C, -C 6 -ercaptoalkyl, in particular mercaptomethyl, C r C 4 -alkylthio-C r C 6 -alkyl, in particular methylthioethyl, C r C 4 -alkylsulfmyl-C r C 6 -alkyl, in particular methylsulfinylethyl, C, -C 4 -alkylsulfonyl-C, -C 6 -alkyl, in particular methylsulfonylethyl, carboxy-C, -C 6 -alkyl, in particular carboxymethyl, carboxyethyl or carboxy-tert.-butyl, C , -C 4 -alkoxycarbonyl-C, -C 6 -alkyl, especially methoxycarbonylmethyl or ethoxycarbonylethyl, aryloxycarbonyl-C, -C 6 -alkyl, especially phenoxycarbonylmethyl, aryl-C, -C 4 - alkyloxycarbonyl-C r C 6 - alkyl, especially benzyloxycarbonylmethyl, carbamoyl-C, -C 6 -alkyl, especially carbamoylmethyl or carbamoyl ethyl, amino-C, -C 6 -alkyl, especially aminopropyl or aminobutyl, C, -C 4 - alkylamino-C r C 6 -alkyl, especially methylaminopropyl or methylamino, di- (C r C 4 ) -alkylamino-C , -C 6 -alkyl in particular dimethylamino-propyl or dimethylaminobutyl, C r C 4 -alkoxycarbonylamino-C, -C 6 -alkyl, or for each optionally by halogen, hydroxy, nitro, cyano, amino, C, -C 4 -alkylamino , Di- (C, -C 4 ) -alkylamino, benzylamino, dibenzylamino, protected amino such as acetyl-, t-butoxycarbonyl-, benzyl-oxycarbonyl- or FMOC-amino, C r C 6 -alkyl, C, - C 4 -haloalkyl, C r C 4 -alkoxy or C r C 4 -haloalkoxy substituted aryl, aryl-C, -C 4 -alkyl, hetaryl or hetaryl-C r C 4 -alkyl, where appropriate an NH function in the heterocyclic Ring can be derivatized by an amino protecting group, as exemplified above. The pairs of residues R 5 "2 / R 9 - 2 , R 6 - 2 / R 10" 2 , R '-' / R 11 "2 and R 8 - 2 / R 12" 2 also together, independently of one another, preferably represent optionally mono- to tetrasubstituted by C, -C 4 -alkyl radicals - (CH 2 ) 3 - and - (CH 2 ) 4 -.
R1, R2, R3 und R4 stehen unabhängig voneinander jeweils besonders bevorzugt für Wasserstoff, C,-C12-Alkyl, für jeweils gegebenenfalls durch Fluor, Chlor oder Brom substituiertes C,-C4-Alkyl, C2-C6-Alkenyl, C3-C7-Cycloalkyl, insbesondere Cyclopentyl, Cyclohexyl oder Cycloheptyl, C3-C7-Cycloalkyl-C,-C4- alkyl, C,-C6-Hydroxyalkyl, Phenyl-C,-C4-alkoxy-CrC6-alkyl, insbesondereR 1 , R 2 , R 3 and R 4 , independently of one another, each particularly preferably represent hydrogen, C, -C 12 alkyl, each optionally substituted by fluorine, chlorine or bromine, C, -C 4 alkyl, C 2 -C 6- alkenyl, C 3 -C 7 -cycloalkyl, in particular cyclopentyl, cyclohexyl or cycloheptyl, C 3 -C 7 -cycloalkyl-C, -C 4 - alkyl, C, -C 6 -hydroxyalkyl, phenyl-C, -C 4 -alkoxy-C r C 6 -alkyl, in particular
Benzyloxymethyl oder 1-Benzyloxyethyl, CrC4-Alkylthio-CrC6-alkyl, insbesondere Methylthioethyl, C,-C4-Alkoxycarbonyl-C1-C6-alkyl, insbesondere Methoxycarbonylmethyl oder Ethoxycarbonylethyl, Phenyl-C,-C4-alkyloxy- carbonyl-C]-C6-alkyl, insbesondere Benzyloxycarbonylmethyl, Amino-CrC6- alkyl, insbesondere Aminopropyl oder Aminobutyl, C,-C4-Alkylamino-CrC6- alkyl insbesondere Methylaminopropyl oder Methylamino, Di-(C,-C4)-alkyl- insbesondere Dimethylaminopropyl oder Dimethyl- aminobutyl oder für jeweils gegebenenfalls durch Fluor, Chlor, Brom, Iod, Hydroxy, Cyano, C,-C6-Alkyl, C,-C4-Halogenalkyl, C,-C4-Alkoxy, C,-C4- Halogenalkoxy, Benzyloxy oder Silyloxy, das durch C,-C4-Alkyl und/oderBenzyloxymethyl or 1-benzyloxyethyl, C r C 4 -alkylthio-C r C 6 -alkyl, in particular methylthioethyl, C, -C 4 -alkoxycarbonyl-C 1 -C 6 -alkyl, in particular methoxycarbonylmethyl or ethoxycarbonylethyl, phenyl-C, -C 4 alkyloxy carbonyl-C] -C6 alkyl, in particular benzyloxycarbonylmethyl, amino-C r C 6 - alkyl, in particular aminopropyl or aminobutyl, C, -C 4 alkylamino-C r C 6 - alkyl, in particular methylaminopropyl or methylamino, Di- (C, -C 4 ) alkyl- in particular dimethylaminopropyl or dimethylaminobutyl or for each optionally by fluorine, chlorine, bromine, iodine, hydroxy, cyano, C, -C 6 -alkyl, C, -C 4 -haloalkyl, C, -C 4 -alkoxy, C, - C 4 - haloalkoxy, benzyloxy or silyloxy, which is substituted by C, -C 4 alkyl and / or
Phenyl trisubstituiert ist, substituiertes Phenyl, Phenyl-CrC4-alkyl, Naph- thylmethyl, 5- oder 6-gliedriges Hetaryl, insbesondere Thienyl, Thiazolyl oder Pyridyl, Indolyl, Benzo-l,3-dioxolyl, 5- oder 6-gliedriges Hetaryl-C,-C4- alkyl insbesondere Thienylmethyl, Thiazolylmethyl, Imidazolylmethyl oder Pyridylmethyl oder Indolyl-C,-C4-alkyl.Phenyl is trisubstituted, substituted phenyl, phenyl-C r C 4 -alkyl, naphthylmethyl, 5- or 6-membered hetaryl, especially thienyl, thiazolyl or pyridyl, indolyl, benzo-l, 3-dioxolyl, 5- or 6- membered hetaryl-C, -C 4 -alkyl in particular thienylmethyl, thiazolylmethyl, imidazolylmethyl or pyridylmethyl or indolyl-C, -C 4 -alkyl.
R5"1, R6"', R7"1 und R8"1 stehen unabhängig voneinander jeweils besonders bevorzugt für Methyl, iso-Propyl, iso-Butyl, sec.-Butyl, Hydroxymethyl, Benzyl, 4- Hydroxybenzyl, wobei Hydroxygruppen gegebenenfalls geschützt vorliegen können. R9"1, R10 1, R1 und R12"1 stehen unabhängig voneinander jeweils besonders bevorzugt für Wasserstoff oder Methyl.R 5 "1 , R 6" ', R 7 "1 and R 8" 1 each independently, particularly preferably, represent methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, benzyl, 4-hydroxybenzyl, where Hydroxy groups can optionally be protected. R 9 "1 , R 10 1 , R 1 and R 12" 1 each independently of one another are particularly preferably hydrogen or methyl.
Die Restepaare R^/R9 1, R6 1/R10 1, R' VR11'1 und R8 1/R12-' stehen auch besonders bevorzugt und jeweils gemeinsam unabhängig voneinander für die Reste -(CH2)3- und -(CH2)4-.The radical pairs R ^ / R 9 1 , R 6 1 / R 10 1 , R 'VR 11'1 and R 8 1 / R 12 -' are also particularly preferably and in each case together independently of one another for the radicals - (CH 2 ) 3 - and - (CH 2 ) 4 -.
R5"2 bis R12"2 stehen unabhängig voneinander besonders bevorzugt für Wasserstoff, CrC10-Alkyl, für jeweils gegebenenfalls durch Fluor, Chlor oder Brom substituiertes CrC4-Alkyl, C3-C7-Cycloalkyl, insbesondere Cyclopentyl, Cyclohexyl oder Cycloheptyl, C3-C7-Cycloalkyl-C,-C4-alkyl, C,-C6-Hydroxy- alkyl, insbesondere Hydroxymethyl oder 1-Hydroxyethyl, C,-C4-Alkanoyl- oxy-C,-C6-alkyl, insbesondere Acetoxymethyl oder 1-Acetoxyethyl, CrC4- Alkoxy-C C6-alkyl, insbesondere Methoxymethyl oder 1-Methoxyethyl,R 5 "2 to R 12" 2 independently of one another particularly preferably represent hydrogen, C r C 10 alkyl, in each case C r C 4 alkyl optionally substituted by fluorine, chlorine or bromine, C 3 -C 7 cycloalkyl, in particular Cyclopentyl, cyclohexyl or cycloheptyl, C 3 -C 7 cycloalkyl-C, -C 4 -alkyl, C, -C 6 -hydroxy-alkyl, especially hydroxymethyl or 1-hydroxyethyl, C, -C 4 -alkanoyl-oxy-C , -C 6 -alkyl, especially acetoxymethyl or 1-acetoxyethyl, C r C 4 - alkoxy-C C 6 -alkyl, especially methoxymethyl or 1-methoxyethyl,
Phenyl-C,-C4-alkoxy-C)-C6-alkyl, insbesondere Benzyloxymethyl oder 1- Benzyloxyethyl, Cι-C4-Alkoxycarbonylamino-CrC6-alkyl, insbesondere tert- Butoxycarbonylaminopropyl oder tert.-Butoxycarbonylaminobutyl, oder für jeweils gegebenenfalls durch Fluor, Chlor, Brom, Iod, Hydroxy, Nitro, Cyano, Amino, C,-C4-Alkylamino, Di-(C,-C4)-alkylamino, Benzylamino,Phenyl-C, -C 4 -alkoxy-C ) -C 6 -alkyl, in particular benzyloxymethyl or 1-benzyloxyethyl, -CC 4 -alkoxycarbonylamino-C r C 6 -alkyl, in particular tert-butoxycarbonylaminopropyl or tert-butoxycarbonylaminobutyl, or for each optionally by fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino, C, -C 4 -alkylamino, di- (C, -C 4 ) -alkylamino, benzylamino,
Dibenzylamino, geschütztes Amino wie z.B. Acetyl-, t-Butoxycarbonyl-, Benzyloxy carbonyl- oder FMOC-amino, C,-C4-Alkyl, C,-C4-Halogenalkyl, CrC4-Alkoxy oder C,-C2-Halogenalkoxy substituiertes Phenyl, Phenyl-C,-C4- alkyl, 5- oder 6-gliedriges Hetaryl, insbesondere Thienyl, Thiazolyl oder Pyridyl, 5- oder 6-gliedriges Hetaryl-C,-C4-alkyl oder Indolyl-C,-C4-alkyl.Dibenzylamino, protected amino such as acetyl, t-butoxycarbonyl, benzyloxy carbonyl or FMOC amino, C, -C 4 alkyl, C, -C 4 haloalkyl, C r C 4 alkoxy or C, -C 2 Haloalkoxy-substituted phenyl, phenyl-C, -C 4 -alkyl, 5- or 6-membered hetaryl, in particular thienyl, thiazolyl or pyridyl, 5- or 6-membered hetaryl-C, -C 4 -alkyl or indolyl-C, -C 4 alkyl.
Die Restepaare R5"2/R9"2, R6-2/R10-2, R7"2/Ru-2 und R8-2/R12"2 stehen auch jeweils gemeinsam unabhängig voneinander besonders bevorzugt für die gegebenenfalls einfach bis vierfach durch Methyl substituierten Reste -(CH2)3- und -(CH2)4-. R1, R2, R3 und R4 stehen unabhängig voneinander jeweils ganz besonders bevorzugt für Wasserstoff, C,-C12-Alkyl, insbesondere Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, sec.-Butyl, tert.-Butyl, n-Pentyl, Isopentyl, sec- Pentyl, tert.-Pentyl, n-Hexyl, Isohexyl, sec.-Hexyl, n-Heptyl, Isoheptyl, sec-The pairs of residues R 5 "2 / R 9" 2 , R 6 - 2 / R 10 - 2 , R 7 "2 / R u - 2 and R 8 - 2 / R 12" 2 are each also particularly preferred independently the optionally mono- to tetrasubstituted by methyl radicals - (CH 2 ) 3 - and - (CH 2 ) 4 -. R 1 , R 2 , R 3 and R 4 each independently of the other very particularly preferably represent hydrogen, C, -C 12 alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, sec.-hexyl, n-heptyl, isoheptyl, sec-
Heptyl, Oktyl, Isooctyl, sec.-Octyl, n-Decyl oder n-Dodecyl, für jeweils gegebenenfalls durch Fluor oder Chlor substituiertes C,-C4- Alkyl, insbesondere Fluormethyl, Trifluormethyl oder Trichlormethyl, für C2-C6-Alkenyl, insbesondere Vinyl oder Allyl, für Cyclopentyl oder Cyclohexyl, für C3-C7- Cycloalkyl-C,-C4-alkyl, insbesondere Cyclopropylmethyl, für Methylthio- ethyl oder für jeweils gegebenenfalls durch Fluor, Chlor, Brom, Iod, Hydroxy, Cyano, Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, sec.- Butyl, tert.-Butyl, Trifluormethyl, Trichlormethyl, Methoxy, Difluormethoxy, Trifluormethoxy oder Benzyloxy substituiertes Phenyl, Phenyl-C,-C4-alkyl, insbesondere Benzyl, 3-Naphthylmethyl, Benzo-l,3-dioxol-5-yl, Thienyl- methyl, Imidazolylmethyl oder Indolylmethyl.Heptyl, octyl, isooctyl, sec.-octyl, n-decyl or n-dodecyl, for C, -C 4 -alkyl, in each case optionally substituted by fluorine or chlorine, in particular fluoromethyl, trifluoromethyl or trichloromethyl, for C 2 -C 6 -alkenyl , in particular vinyl or allyl, for cyclopentyl or cyclohexyl, for C 3 -C 7 -cycloalkyl-C, -C 4 -alkyl, in particular cyclopropylmethyl, for methylthioethyl or for each optionally by fluorine, chlorine, bromine, iodine, hydroxyl, Cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, trifluoromethyl, trichloromethyl, methoxy, difluoromethoxy, trifluoromethoxy or benzyloxy substituted phenyl, phenyl-C, -C 4 - alkyl, especially benzyl, 3-naphthylmethyl, benzo-l, 3-dioxol-5-yl, thienylmethyl, imidazolylmethyl or indolylmethyl.
R5"1 , R6"1 , R7"1 und R8"1 stehen unabhängig voneinander jeweils ganz besonders bevorzugt für Methyl, iso-Propyl, iso-Butyl oder sec.-Butyl.R 5 "1 , R 6" 1 , R 7 "1 and R 8" 1 each independently of the other very particularly preferably represent methyl, isopropyl, isobutyl or sec-butyl.
R9"1, R10"1, R11"1 und R12"1 stehen jeweils ganz besonders bevorzugt für Wasserstoff oder Methyl.R 9 "1 , R 10" 1 , R 11 "1 and R 12" 1 each very particularly preferably represent hydrogen or methyl.
Die Restepaare R^/R9"1, R^/R10"1, R^/R""1 und R^'/R12"1 stehen auch ganz beson- ders bevorzugt und jeweils gemeinsam unabhängig voneinander für die ResteThe radical pairs R ^ / R 9 "1 , R ^ / R 10" 1 , R ^ / R "" 1 and R ^ '/ R 12 "1 are also very particularly preferred and in each case together independently of one another for the radicals
-(CH2)3- und -(CH2)4-.- (CH 2 ) 3 - and - (CH 2 ) 4 -.
R5"2 bis R12"2 stehen unabhängig voneinander ganz besonders bevorzugt fürR 5 "2 to R 12" 2 independently of one another very particularly preferably represent
Wasserstoff, C,-CI0-Alkyl, insbesondere Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, sec.-Butyl, tert.-Butyl, n-Pentyl, Isopentyl, sec. -Pentyl, tert.-Pentyl, n-Hexyl, Isohexyl, sec.-Hexyl, n-Heptyl, Isoheptyl, sec.-Heptyl, Oktyl, Isooctyl, sec.-Octyl oder 3,7-Dimethyloctyl, für C3-C7-Cycloalkyl-C,- C4-alkyl inbesondere Cyclopentylmethyl, Cyclohexylmethyl oder Cyclo- heptylmethyl, für jeweils gegebenenfalls durch Fluor, Chlor, Brom, Hydroxy, Cyano, Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, sec.-Butyl, tert.-Butyl, Trifluormethyl, Trichlormethyl, Methoxy, Difluormethoxy, Tri- fluormethoxy oder Benzyloxy substituiertes Phenyl, Benzyl, Phenylethyl, 5- oder 6-gliedriges Hetarylmethyl, insbesondere Thienylmethyl, Thiazolyl- methyl, Furylmethyl oder Pyridylmethyl oder für Indolylmethyl.Hydrogen, C, -C I0 alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec.-Pentyl, tert-pentyl, n-hexyl, isohexyl, sec.-hexyl, n-heptyl, isoheptyl, sec.-heptyl, octyl, isooctyl, sec.-octyl or 3,7-dimethyloctyl, for C 3 -C 7 cycloalkyl -C, - C 4 -alkyl in particular cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl, for each optionally by fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.- Butyl, tert-butyl, trifluoromethyl, trichloromethyl, methoxy, difluoromethoxy, trifluoromethoxy or benzyloxy substituted phenyl, benzyl, phenylethyl, 5- or 6-membered hetarylmethyl, especially thienylmethyl, thiazolylmethyl, furylmethyl or pyridylmethyl or for indolylmethyl.
Die Restepaare R5-2/R9-2, R6-2/R10-2, R7-2/Rn'2 und R8-2/R12"2 stehen auch ganz besonders bevorzugt und jeweils gemeinsam unabhängig voneinander für den gegebenenfalls einfach oder zweifach durch Methyl substituierten Rest -(CH2)4-.The pairs of radicals R 5 - 2 / R 9 - 2, R 6 - 2 / R 10-2, R 7 - 2 / R N'2 and R 8 - 2 / R 12 "2 are also very particularly preferably in each case together and independently from each other for the optionally mono- or disubstituted by methyl radical - (CH 2 ) 4 -.
Die oben aufgeführten allgemeinen oder in Vorzugsbereichen aufgeführten Restedefinitionen bzw. Erläuterungen können untereinander, also auch zwischen den jeweiligen Bereichen und Vorzugsbereichen beliebig kombiniert werden. Sie gelten für die Endprodukte sowie für die Vor- und Zwischenprodukte entsprechend.The general definitions or explanations of residues or explanations listed above or in preferred areas can be combined with one another, that is to say also between the respective areas and preferred areas. They apply accordingly to the end products as well as to the preliminary and intermediate products.
Bevorzugt sind Verbindungen der Formel (I), in welcherCompounds of the formula (I) in which
R1, R2, R3 und R4 unabhängig voneinander für Methyl stehen, das gegebenenfalls durch Phenyl substituiert ist, das seinerseits durch Halogen, Cyano, Nitro, Amino, Dialkylamino, Morpholino substituiert sein kann,R 1 , R 2 , R 3 and R 4 independently of one another represent methyl, which is optionally substituted by phenyl, which in turn can be substituted by halogen, cyano, nitro, amino, dialkylamino, morpholino,
die Gruppen X'-R5, X2-R6, X3-R7, X4-R8 unabhängig voneinander für die Restethe groups X'-R 5 , X 2 -R 6 , X 3 -R 7 , X 4 -R 8 independently of one another for the radicals
-CH-R5 -CH-R6 -CH-R7 -CH-R8 oder-CH-R 5 -CH-R 6 -CH-R 7 -CH-R 8 or
N — R -N— RD -N — R -N— R°N - R -N - R D -N - R -N - R °
stehen, in welchenstand in which
R5, R6, R7 und R8 unabhängig voneinander für C,-C4- Alkyl, insbesondere für verzweigtes C4- Alkyl, ganz besonders für i-Butyl stehen, wobeiR 5 , R 6 , R 7 and R 8 independently of one another are C 1 -C 4 -alkyl, in particular branched C 4 -alkyl, very particularly i-butyl, where
mindestens einer der Reste X', X2, X3 und X4 für γ_ steht;at least one of the radicals X ', X 2 , X 3 and X 4 represents γ _ ;
R9, R10, R11 und R12 unabhängig voneinander für CrC4- Alkyl, insbesondere Methyl stehen.R 9 , R 10 , R 11 and R 12 independently of one another represent C 1 -C 4 -alkyl, in particular methyl.
Erfindungsgemäß bevorzugt werden die Verbindungen der Formel (I), in welchen einer der Reste X1, X2, X3 und X4 für N steht.According to the invention, preference is given to the compounds of the formula (I) in which one of the radicals X 1 , X 2 , X 3 and X 4 represents N.
Erfmdungsgemäß ebenfalls bevorzugt werden die Verbindungen der Formel (I), in welchen zwei der Reste X1, X2, X3 und X4 für N stehen.According to the invention, preference is likewise given to the compounds of the formula (I) in which two of the radicals X 1 , X 2 , X 3 and X 4 are N.
Gesättigte oder ungesättigte Kohlenwasserstoffreste wie Alkyl oder Alkenyl können, auch in Verbindung mit Heteroatomen, wie z.B. in Alkoxy, soweit möglich, jeweils geradkettig oder verzweigt sein.Saturated or unsaturated hydrocarbon radicals such as alkyl or alkenyl can also be used in connection with heteroatoms, e.g. in alkoxy, where possible, be straight-chain or branched.
Gegebenenfalls substituierte Reste können einfach oder mehrfach substituiert sein, wobei bei Mehrfachsubstitutionen die Substituenten gleich oder verschieden sein können. Im vorliegenden Text werden neben den allgemeinen bekannten Dreibuchstabencodes für Aminosäuren und den Abkürzungen für Alkylgruppen folgende Abkürzungen verwendet:Optionally substituted radicals can be mono- or polysubstituted, whereby in the case of multiple substitutions the substituents can be the same or different. In addition to the generally known three-letter codes for amino acids and the abbreviations for alkyl groups, the following abbreviations are used in the present text:
Lac: 2-Hydroxypropionsäure (Milchsäure)Lac: 2-hydroxypropionic acid (lactic acid)
Ph: PhenylPh: phenyl
Bn: BenzylBn: benzyl
Boc tert.-ButoxycarbonylBoc tert-butoxycarbonyl
PhLac: 2-Hydroxy-3-phenylpropionsäure (ß-Phenylmilchsäure)PhLac: 2-hydroxy-3-phenylpropionic acid (ß-phenyllactic acid)
AzaAla: 2-Azaalanin (N-Methyl-N-Aminocarbaminsäure)AzaAla: 2-azaalanine (N-methyl-N-aminocarbamic acid)
Azaxyz: 2-azaanaloge Aminosäure „xyz"Azaxyz: 2-aza analog amino acid "xyz"
Verwendet man beispielsweise H-MeLeu-D-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac- MeAzaAla-D-Lac-OH als Ausgangsstoff sowie Bis-(2-oxo-3-oxazolidinyl)-phos- phorylchlorid (BOP-Cl) als Reaktionshilfsmittel und Ethyldiisopropylamin als Base so kann der Reaktionsablauf des erfindungsgemäßen Verfahrens (A) durch das folgende Formelschema wiedergegeben werden:If, for example, H-MeLeu-D-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac-MeAzaAla-D-Lac-OH is used as the starting material and bis- (2-oxo-3-oxazolidinyl) -phosphoryl chloride (BOP -Cl) as a reaction aid and ethyldiisopropylamine as a base, the course of the reaction of process (A) according to the invention can be represented by the following formula:
Verwendet man beispielsweise H-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac-MeLeu-D- Lac-N(CH3)-N(s-Bu)H und Diphosgen als Ausgangsstoffe sowie Triethylamin als Reaktionshilfsmittel so kann der Reaktionsablauf des erfindungsgemäßen Verfahrens (B) durch das folgende Formelschema wiedergegeben werden:If, for example, H-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac-MeLeu-D-Lac-N (CH 3 ) -N (s-Bu) H and diphosgene as starting materials and triethylamine as reaction auxiliaries are used, the reaction can proceed of process (B) according to the invention can be represented by the following formula:
Verwendet man beispielsweise F5Ph-CO-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac- MeLeu-D-Lac-N(CH3)-N(s-Bu)H als Ausgangsstoff sowie Pyridin als Reaktionshilfsmittel, so kann der Reaktionsablauf des erfindungsgemäßen Verfahrens (C) durch das folgende Formelschema wiedergegeben werden: If, for example, F 5 Ph-CO-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac-MeLeu-D-Lac-N (CH 3 ) -N (s-Bu) H is used as the starting material and pyridine is used as reaction aid, for example the course of the reaction of process (C) according to the invention can be represented by the following formula:
Die zur Durchführung des erfindungsgemäßen Verfahrens (A) benötigten Azadepsipeptide sind durch die Formel (II) allgemein definiert. In dieser Formel stehen X1, X2, X3, X4 und R1 bis R12 vorzugsweise für diejenigen Reste, die bereits im Zusammenhang mit der Beschreibung der Aza-Cyclodepsipeptide der Formel (I) als bevorzugte Substituenten genannt wurden. Die Azadepsipeptide der Formel (II) sind neu.Formula (II) provides a general definition of the azadepsipeptides required to carry out process (A) according to the invention. In this formula, X 1 , X 2 , X 3 , X 4 and R 1 to R 12 preferably represent those radicals which have already been mentioned as preferred substituents in connection with the description of the aza-cyclodepsipeptides of the formula (I). The azadepsipeptides of formula (II) are new.
Azadepsipeptide der Formel (II) lassen sich z.B. herstellen, indem man in einem Verfahren (A.a) die Schutzgruppe C-terminal geschützter Azadepsipeptide der Formel (VI) gemäß dem folgenden Reaktionsschema abspaltet: Azadepsipeptides of the formula (II) can be prepared, for example, by removing the protective group of C-terminally protected azadepsipeptides of the formula (VI) in a process (Aa) according to the following reaction scheme:
(VI) (II)(VI) (II)
In Formel (VI) steht A4 für eine C-terminale Schutzgruppe wie beispielsweise tert.-In formula (VI) A 4 represents a C-terminal protective group such as, for example, tert.-
Butyl oder Benzyl (Vgl. z.B. T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2. Ed., John Wiley & Sons, New York 1991).Butyl or benzyl (See, e.g., T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley & Sons, New York 1991).
Die Reaktion läßt sich mittels üblicher Methoden C-terminaler Deblockierung wie Acidolyse, beispielsweise im Falle eines tert.-Butylesters, oder katalytischer Hydrierung, beispielsweise im Falle eines Benzylesters, durchführen.The reaction can be carried out using customary methods of C-terminal deblocking, such as acidolysis, for example in the case of a tert-butyl ester, or catalytic hydrogenation, for example in the case of a benzyl ester.
Azadepsipeptide der Formel (II) lassen sich z.B. auch herstellen, indem man in einem Verfahren (A.b) die Schutzgruppe N-terminal geschützter Azadepsipeptide der Formel (VII) gemäß dem folgenden Reaktionsschema abspaltet: Azadepsipeptides of the formula (II) can also be prepared, for example, by splitting off the protective group of N-terminally protected azadepsipeptides of the formula (VII) in one process (Ab) according to the following reaction scheme:
(VII) (II)(VII) (II)
In Formel (VII) steht A1 für eine N-terminale Schutzgruppe wie beispielsweise tert-In formula (VII) A 1 represents an N-terminal protective group such as, for example,
Butoxycarbonyl (BOC), Benzyloxycarbonyl (Cbz) oder Benzyl (Bn) (Vgl. z.B. T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2. Ed., John Wiley & Sons, New York 1991).Butoxycarbonyl (BOC), Benzyloxycarbonyl (Cbz) or Benzyl (Bn) (See, e.g., T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley & Sons, New York 1991).
Die Reaktion läßt sich mittels üblicher Methoden N-terminaler Deblockierung wieThe reaction can be carried out using conventional N-terminal deblocking methods such as
Acidolyse, beispielsweise im Falle der BOC-Gruppe, oder katalytischer Hydrierung, beispielsweise im Falle einer Benzylgruppe, durchführen.Perform acidolysis, for example in the case of the BOC group, or catalytic hydrogenation, for example in the case of a benzyl group.
Die für die Durchführung des Verfahrens (A.a) benötigten C-terminal geschützten Azadepsipeptide der Formel (VI) bzw. die zur Durchführung des Verfahrens (A.b) benötigten N-terminal geschützten Azadepsipeptide der Formel (VII) lassen sich herstellen, indem man von N- und C-terminal geschützten Azadepsipeptiden der Formel (VIII) The C-terminally protected azadepsipeptides of the formula (VI) required for carrying out the process (Aa) or the N-terminally protected azadepsipeptides of the formula (VII) required for carrying out the process (Ab) can be prepared by and C-terminally protected azadepsipeptides of the formula (VIII)
ausgeht und entweder in einem Verfahren (A.a.b) analog zu (A.b) die N-terminale Schutzgruppe abspaltet oder in einem Verfahren (A.b.a) analog zu (A.a) die C- terminale Schutzgruppe abspaltet. Je nach Art der Schutzgruppe kann man in einer besonderen Ausfuhrungsform des Verfahrens auch in einem Schritt beide Schutzgruppen abspalten und von Verbindungen der Formel (VIII) direkt zu Verbindungen der Formel (II) gelangen (Verfahren A.a/b).proceeds and either cleaves off the N-terminal protective group in a process (A.a.b) analogous to (A.b) or cleaves off the C-terminal protective group in a process (A.b.a) analogous to (A.a). Depending on the type of protective group, in a particular embodiment of the process, both protective groups can also be split off in one step and compounds of formula (VIII) can be passed directly to compounds of formula (II) (process A.a / b).
Aza-Octadepsipeptide der Formel (VIII) lassen sich z.B. herstellen, indem manAza-octadepsipeptides of formula (VIII) can be e.g. manufacture by
Verbindungen der Formel (IX) mit Verbindungen der Formel (X) in Gegenwart eines Reaktionshilfsmittels wie BOP-Cl oder HATU (u.a.) und einer Base wie Hünig-Base und gegebenenfalls in Gegenwart eines Verdünnungsmittels wie Dichlormethan gemäß dem folgendem Reaktionsschema umsetzt:Reacting compounds of formula (IX) with compounds of formula (X) in the presence of a reaction auxiliary such as BOP-Cl or HATU (among others) and a base such as Hünig base and optionally in the presence of a diluent such as dichloromethane according to the following reaction scheme:
O R8 O R6 O R7 O R5 OR 8 OR 6 OR 7 OR 5
AV X O X .0. \.... + .. X .0. i' X .0. l.AV X O X .0. \ .... + .. X .0. i 'X .0. l.
° X R4 O X R X R X O X R H0 X R3 Y O X R R Y O R,° XR 4 OXRXRXOXR H0 XR 3 YOXRRYOR,
(X) (IX) (X) (IX)
(VIII)(VIII)
Als Reaktionshilfsmittel, Basen und Lösungsmittel sind die weiter unten bei Verfahren (A) aufgelisteten geeignet.Suitable reaction auxiliaries, bases and solvents are those listed below in process (A).
N-terminal geschützte Azadepsipeptide der Formel (IX) lassen sich z.B. herstellen, indem man die O-Schutzgruppe A3 beidseitig geschützter Azadepsipeptide der Formel (XI), C-terminal geschützte Azadepsipeptide der Formel (X), indem man die N-Schutzgruppe A2 beidseitig geschützter Azadepsipeptide der Formel (XII) analog den oben angegebenen allgemein bekannten Methoden abspaltet.N-terminally protected azadepsipeptides of the formula (IX) can be prepared, for example, by the O-protecting group A 3 bilaterally protected azadepsipeptides of the formula (XI), C-terminally protected azadepsipeptides of the formula (X) by the N-protecting group A 2 bilaterally protected azadepsipeptides of the formula (XII) are split off analogously to the generally known methods given above.
In Formel (XI) steht A3 für eine C-terminale Schutzgruppe wie für A4 angegeben. In Formel (XII) steht A2 für eine N-terminale Schutzgruppe wie für A' angegeben. Die beidseitig geschützten (Aza)-Tetradepsipeptide könnte man prinzipiell zu einer ein- zigen allgemeinen Formel zusammenfassen, weil die ungeradzahlig indizierten Reste in Formel (XI) und die nächst höher geradzahlig indizierten Reste in Formel (XII) für diesselben Listen von Resten stehen. Es soll zum Ausdruck kommen, daß bei jeder Synthese einer individuellen Verbindung der Formel (I), die Reste voneinander unabhängig wählbar sind, d.h. die Bausteine (XI) und (XII) gleich oder verschieden sein können. Im weiteren soll hier stellvertretend die Synthese der Verbindung der Formel (XI) erläutert werden, weil dasselbe auch für die Darstellung von (XII) gilt.In formula (XI), A 3 represents a C-terminal protective group as indicated for A 4 . In formula (XII) A 2 represents an N-terminal protecting group as indicated for A '. The bilaterally protected (aza) tetradepsipeptides could in principle be combined into a single general formula because the odd-numbered residues in formula (XI) and the next higher even-numbered residues in formula (XII) stand for the same lists of residues. It should be expressed that in each synthesis of an individual compound of formula (I), the radicals can be selected independently of one another, ie the building blocks (XI) and (XII) are the same or different could be. The synthesis of the compound of the formula (XI) is to be explained as a representative here because the same also applies to the preparation of (XII).
Reine Tetradepsipeptide der Formel (XI) (X1, X2 = CH) sind aus Annu. Rep. Sankyo Res. Lab. 46, 67-75 (1994) und J. Antibiot. 47, 1322-1327 (1994) bekannt oder können nach analogen Methoden hergestellt werden. Die Verbindungen der Formel (XI) können z.B. hergestellt werden, indem man Bausteine der Formel (XIII) mit Bausteinen der Formel (XIV) in Gegenwart eines Reaktionshilfsmittels wie BOP-Cl oder HATU und einer Base wie Hünig-Base und gegebenenfalls in Gegenwart eines Verdünnungsmittels wie Dichlormethan gemäß dem folgenden Reaktionsschema verknüpft:Pure tetradepsipeptides of the formula (XI) (X 1 , X 2 = CH) are from Annu. Rep. Sankyo Res. Lab. 46, 67-75 (1994) and J. Antibiot. 47, 1322-1327 (1994) or can be prepared by analogous methods. The compounds of the formula (XI) can be prepared, for example, by building blocks of the formula (XIII) with building blocks of the formula (XIV) in the presence of a reaction auxiliary such as BOP-Cl or HATU and a base such as Hünig base and optionally in the presence of a diluent how to link dichloromethane according to the following reaction scheme:
(XIV) (XIII)(XIV) (XIII)
(XI)(XI)
Als Reaktionshilfsmittel, Basen und Lösungsmittel sind die bei Verfahren (A) Aufgelisteten geeignet.Suitable reaction auxiliaries, bases and solvents are those listed in process (A).
Einfach geschützte Didepsipeptide der Formeln (XIII) und (XIV) sind aus der o.a. Literatur bekannt oder können z.B. analog dort angegebener Methoden hergestellt werden. Einfach geschützte Aza-Didepsipeptide der Formeln (XIII) und (XIV) sind aus DE- AI 19612644 bekannt oder können z.B. analog zu den dort angegebenenSimply protected didepsipeptides of the formulas (XIII) and (XIV) are from the above. Known literature or can e.g. be prepared analogously to the methods specified there. Simply protected aza didepsipeptides of the formulas (XIII) and (XIV) are known from DE-A1 19612644 or can e.g. analogous to those specified there
Methoden hergestellt werden. Die zur Durchführung des erfindungsgemäßen Verfahrens (B) benötigten Verbindungen sind durch die Formel (III) allgemein definiert. In dieser Formel stehen X2 bis X4 und R1 bis R12 vorzugsweise für diejenigen Reste, die bereits im Zusammen- hang mit der Beschreibung der Aza-Cyclodepsipeptide der Formel (I) als bevorzugteMethods are made. Formula (III) provides a general definition of the compounds required for carrying out process (B) according to the invention. In this formula, X 2 to X 4 and R 1 to R 12 preferably represent those radicals which are preferred in connection with the description of the aza-cyclodepsipeptides of the formula (I)
Substituenten genannt wurden.Substituents were called.
Verbindungen der Formel (III) lassen sich z.B. herstellen, indem man die N- terminale Schutzgruppe A5 von Verbindungen der Formel (XV) nach weiter oben angegebenen üblichen Methoden abspaltetCompounds of the formula (III) can be prepared, for example, by splitting off the N-terminal protective group A 5 from compounds of the formula (XV) by the customary methods given above
In Formel (XV) steht A für eine N-terminale Schutzgruppe wie für A angegeben.In formula (XV), A represents an N-terminal protective group as indicated for A.
Verbindungen der Formel (XV) lassen sich z.B. herstellen, indem man (Aza)- Depsipeptidester der Formel (XVI) mit Hydrazinen der Formel (XVII) gemäß dem folgenden Reaktionsschema umsetzt: Compounds of the formula (XV) can be prepared, for example, by reacting (aza) - depsipeptide esters of the formula (XVI) with hydrazines of the formula (XVII) according to the following reaction scheme:
(XVI) (XVII)(XVI) (XVII)
(XV)(XV)
In Formel (XVI) steht R13 für gegebenenfalls substituiertes Alkyl oder Aryl. (Aza)- Depsipeptidester der Formel (XVI) lassen sich z.B. analog der Synthese der Verbindung (VII) durch die dort angewandten oder beschriebenen peptidchemischen Methoden herstellen.In formula (XVI), R 13 represents optionally substituted alkyl or aryl. (Aza) - Depsipeptide esters of the formula (XVI) can be prepared, for example, analogously to the synthesis of the compound (VII) by the peptide chemical methods used or described there.
Hydrazine der Formel (XVII) sind zum Teil bekannt oder können nach bekannten Methoden erhalten werden (vgl. z.B. J. Chem. Soc. Perkin Trans. I 1975, 1712).Hydrazines of the formula (XVII) are known in some cases or can be obtained by known methods (cf. e.g. J. Chem. Soc. Perkin Trans. I 1975, 1712).
Die weiterhin zur Durchführung des erfindungsgemäßen Verfahrens (B) benötigtenThose still required to carry out process (B) according to the invention
Verbindungen sind durch die Formel (IV) allgemein definiert. In dieser Formel steht Y1 vorzugsweise für Chlor, Trichlormethoxy, Methoxy, Ethoxy, 1-Imidazolyl, 1,2,4- Triazolyl oder Z-substituiertes Aryloxy, insbesondere Pentafluorphenyl, 4-Nitro- phenyl oder 2,4-Dinitrophenyl, Y2 vorzugsweise für Chlor, Trichlormethoxy, Meth- oxy, Ethoxy, 1-Imidazolyl oder 1,2,4-Triazolyl.Compounds are generally defined by formula (IV). In this formula, Y 1 preferably represents chlorine, trichloromethoxy, methoxy, ethoxy, 1-imidazolyl, 1,2,4-triazolyl or Z-substituted aryloxy, in particular pentafluorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl, Y 2 preferably for chlorine, trichloromethoxy, methoxy, ethoxy, 1-imidazolyl or 1,2,4-triazolyl.
Die Verbindungen der Formel (IV) sind als Phosgen bzw. Phosgenäquivalente allgemein bekannt (vgl. z.B. Org. Syntheses Coll. Vol. 5, 201 (1973)).The compounds of formula (IV) are generally known as phosgene or phosgene equivalents (see e.g. Org.Synthes Coll. Vol. 5, 201 (1973)).
Die zur Durchführung des erfindungsgemäßen Verfahrens (C) benötigten Verbindungen sind durch die Formel (V) allgemein definiert. In dieser Formel stehen X2, X3, X4, R1 bis R12 vorzugsweise für diejenigen Reste, die bereits im Zusammenhang mit der Beschreibung der Aza-Cyclodepsipeptide der Formel (I) als bevorzugte Substituenten genannt wurden. Y1 steht bevorzugt für Chlor, Trichlormethoxy, 1- Imidazolyl, 1 ,2,4-Triazolyl oder Z-substituiertes Aryloxy, insbesondere Pentafluor- phenyl, 4-Nitrophenyl oder 2,4-Dinitrophenyl.Formula (V) provides a general definition of the compounds required for carrying out process (C) according to the invention. In this formula, X 2 X 3 , X 4 , R 1 to R 12 preferably for those radicals which have already been mentioned as preferred substituents in connection with the description of the aza-cyclodepsipeptides of the formula (I). Y 1 preferably represents chlorine, trichloromethoxy, 1-imidazolyl, 1, 2,4-triazolyl or Z-substituted aryloxy, in particular pentafluorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl.
Verbindungen der Formel (V) lassen sich z.B. herstellen, indem man die N-terminale Schutzgruppe A5 von Verbindungen der Formel (XVIII) nach weiter oben angegebenen Methoden abspaltet.Compounds of the formula (V) can be prepared, for example, by splitting off the N-terminal protective group A 5 from compounds of the formula (XVIII) using the methods given above.
(XVIII)(XVIII)
Verbindungen der Formel (XVIII) lassen sich z.B. herstellen, indem man oben beschriebene Verbindungen der Formel (XV) mit einem der bei Verfahren B) beschriebenen Phosgenierungsreagenzien der Formel (IV) umsetzt und falls gewünscht, das erhaltene Produkt der Formel (XVIII), in der Y1 nicht für Z-substituiertes Aryloxy steht, mit einem entsprechenden Phenol oder Phenolat wie beispiels- weise 2,4-Dinitrophenol umsetzt.Compounds of the formula (XVIII) can be prepared, for example, by reacting the compounds of the formula (XV) described above with one of the phosgenating reagents of the formula (IV) described in process B) and, if desired, the product of the formula (XVIII) obtained, in the Y 1 does not represent Z-substituted aryloxy, with a corresponding phenol or phenolate such as, for example, 2,4-dinitrophenol.
Als Reaktionshilfsmittel zur Durchführung des erfindungsgemäßen Verfahrens (A) eignen sich alle Verbindungen die zur Knüpfung einer Amidbindung geeignet sind (vgl. z.B. Houben-Weyl, Methoden der Organischen Chemie, Band 15/2; Bodensky et al.; Peptide Synthesis 2nd ed., Wiley & Sons, New York 1976). Vorzugsweise kommen folgende Methoden in Frage: Aktivestermethode mit Pentafluorphenol (PfP), N-Hydroxysuccinimid, 1-Hydroxybenzotriazol (HOBt), Kopplung mit Carbo- diimiden wie Dicyclohexylcarbodiimid oder N'-(3-Dimethylaminopropyl)-N-ethyl- carbodiimid (EDC) sowie die Gemischte-Anhydrid-Methode oder die Kopplung mit Phosphorreagenzien wie 1 -Benzotriazolyloxy-tris-(dimethylamino)-phosphonium- hexafluorophosphat (BOP), O-(7-Azabenzotrial- 1 -yl)- 1 , 1 ,3 ,3-tetramethyluronium- hexafluorophosphat (HATU), Bis-(2-oxo-3-oxazolidinyl)-phosphorylchlorid (BOP- Cl), Diphenylphosphorylazid (DPPA) oder Cyanphosphonsäurediethylester (DEPC).Suitable reaction auxiliaries for carrying out process (A) according to the invention are all compounds which are suitable for forming an amide bond (cf., for example, Houben-Weyl, Methods of Organic Chemistry, Volume 15/2; Bodensky et al .; Peptide Synthesis 2nd ed., Wiley & Sons, New York 1976). The following methods are preferred: active ester method with pentafluorophenol (PfP), N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBt), coupling with carbodimides such as dicyclohexylcarbodiimide or N '- (3-dimethylaminopropyl) -N-ethyl carbodiimide (EDC) as well as the mixed anhydride method or the coupling with phosphorus reagents such as 1-benzotriazolyloxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP), O- (7-azabenzotrial-1 -yl) - 1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU), bis (2-oxo-3-oxazolidinyl) phosphoryl chloride (BOP-Cl), diphenylphosphoryl azide (DPPA) or cyanophosphonic acid diethyl ester (DEPC).
Besonders bevorzugt ist die Kopplung mit BOP-Cl, HATU oder EDC in Gegenwart von HOBt.Coupling with BOP-Cl, HATU or EDC in the presence of HOBt is particularly preferred.
Als Lösungsmittel zur Durchführung des erfindungsgemäßen Verfahrens (A) kom- men organische Lösungsmittel und beliebige Mischungen davon in Betracht. Beispielhaft seien genannt: aliphatische, alicyclische oder aromatische Kohlenwasserstoffe, wie beispielsweise Petrolether, Hexan, Heptan, Cyclohexan, Methylcyclo- hexan, Benzol, Toluol, Xylol oder Decalin; halogenierte Kohlenwasserstoffe, wie beispielsweise Chlorbenzol, Dichlorbenzol, Methylenchlorid, Chloroform, Tetra- chlormethan, Dichlor-, Trichlorethan oder Tetrachlorethylen; Ether, wie Diethyl-,Organic solvents and any mixtures thereof can be used as solvents for carrying out process (A) according to the invention. Examples include: aliphatic, alicyclic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, methylene chloride, chloroform, tetrachloromethane, dichloro-, trichloroethane or tetrachlorethylene; Ethers, such as diethyl,
Diisopropyl-, Methyl-t-butyl-, Methyl-t-Amylether, Dioxan, Tetrahydrofuran, 1,2- Dimethoxyethan, 1,2-Diethoxyethan, Diethylenglykoldimethylether oder Anisol; Ketone, wie Aceton, Butanon, Methyl-isobutylketon oder Cyclohexanon; Nitrile, wie Acetonitril, Propionitril, n- oder i-Butyronitril oder Benzonitril; Amide, wie Form- amid, N,N-Dimethylformamid, N,N-Dimethylacetamid, N-Methylformanilid, N-Me- thylpyrrolidon, l,3-Dimethyl-tetrahydro-2-pyrimidinon (DMPU), l,3-Dimethyl-2- imidazolidinon, Tetramethylharnstoff oder Hexamethylphosphorsäuretriamid; N- Oxide wie N-Methylmorpholin-N-oxid; Ester wie Methyl-, Ethyl- oder Butylacetat; Sulfoxide, wie Dimethylsulfoxid; Sulfone, wie Sulfolan.Diisopropyl, methyl t-butyl, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl ether or anisole; Ketones such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; Nitriles, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; Amides, such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, 1,3-dimethyl-tetrahydro-2-pyrimidinone (DMPU), 1,3-dimethyl 2-imidazolidinone, tetramethylurea or hexamethylphosphoric triamide; N-oxides such as N-methylmorpholine-N-oxide; Esters such as methyl, ethyl or butyl acetate; Sulfoxides such as dimethyl sulfoxide; Sulfones such as sulfolane.
Die Cyclisierung wird vorzugsweise in Gegenwart einer Base durchgeführt. Als solche kommen anorganische oder organische Basen in Frage. Hierzu gehören vorzugsweise Erdalkalimetall- oder Alkalimetallhydroxide, -alkoholate, -acetate, -carbonate oder -hydrogencarbonate, wie beispielsweise Natrium-, Kalium- oder Ammonium- hydroxid, Natrium-methylat, Natrium-ethylat, Kalium-tert.-butylat, Natrium-, Kalium-, Calcium- oder Ammoniumacetat, Natrium-, Kalium- oder Ammoniumcar- bonat, Natriumhydrogen- oder Kaliumhydrogencarbonat sowie tertiäre Amine, wie Trimethylamin, Triethylamin, Tributylamin, Ethyl-diisopropylamin, N,N-Dimethyl- anilin, N,N-Dimethyl-benzylamin, Pyridin, Picolin, N-Methylpiperidin, N-Methyl- morpholin, N,N-Dimethylaminopyridin, Diazabicyclooctan (DABCO), Diazabicyc- lononen (DBN) oder Diazabicycloundecen (DBU).The cyclization is preferably carried out in the presence of a base. Inorganic or organic bases are suitable as such. These preferably include alkaline earth metal or alkali metal hydroxides, alcoholates, acetates, carbonates or hydrogen carbonates, such as, for example, sodium, potassium or ammonium hydroxide, sodium methylate, sodium ethylate, potassium tert-butoxide, sodium, Potassium, calcium or ammonium acetate, sodium, potassium or ammonium carbonate, sodium hydrogen or potassium hydrogen carbonate and tertiary amines, such as trimethylamine, triethylamine, tributylamine, ethyldiisopropylamine, N, N-dimethylaniline, N, N-dimethyl -benzylamine, pyridine, picoline, N-methylpiperidine, N-methylmorpholine, N, N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclonones (DBN) or diazabicycloundecene (DBU).
Die Reaktionstemperatur kann bei dem erfindungsgemäßen Verfahren (A) innerhalb eines größeren Bereiches variiert werden. Im allgemeinen arbeitet man bei der Cyclisierung bei Temperaturen zwischen -40°C und +150°C, bevorzugt bei -20°C bisThe reaction temperature in process (A) according to the invention can be varied within a substantial range. In general, the cyclization is carried out at temperatures between -40 ° C and + 150 ° C, preferably at -20 ° C to
100°C, besonders bevorzugt bei 0°C bis Raumtemperatur.100 ° C, particularly preferably at 0 ° C to room temperature.
Bei der Durchführung des erfindungsgemäßen Verfahrens (A) werden die Verbindung der Formel (II) und die Base im allgemeinen im molaren Verhältnis von 1 :1 bis 1 :3, vorzugsweise 1:2, eingesetzt. Man arbeitet dabei vorteilhaft bei hoher Verdünnung, d.h. im allgemeinen setzt man pro Mol Verbindung der Formel (II) 50 bis 5000 ml Lösungsmittel ein.When carrying out process (A) according to the invention, the compound of the formula (II) and the base are generally used in a molar ratio of 1: 1 to 1: 3, preferably 1: 2. It is advantageous to work with high dilution, i.e. in general, 50 to 5000 ml of solvent are used per mole of compound of the formula (II).
Das erfindungsgemäße Verfahren (B) kann in Gegenwart eines Verdünnungsmittels durchgeführt werden. Als solches werden vorzugsweise die beim Verfahren (A) aufgelisteten eingesetzt.Process (B) according to the invention can be carried out in the presence of a diluent. As such, those listed in process (A) are preferably used.
Das erfindungsgemäße Verfahren (B) kann in Gegenwart eines geeigneten Reaktionshilfsmittels durchgeführt werden. Als solches kommen alle beim Verfahren (A) aufgelisteten Basen in Frage.Process (B) according to the invention can be carried out in the presence of a suitable reaction auxiliary. As such, all bases listed in process (A) are suitable.
Die Reaktionstemperatur kann bei dem erfindungsgemäßen Verfahren (B) innerhalb eines größeren Bereiches variiert werden. Im allgemeinen arbeitet man bei Temperaturen zwischen -20°C und +150°C, vorzugsweise zwischen +20°C und 120°C, wobei man gegebenenfalls die Cyclisierung erst nach der Umsetzung der beiden Reaktionspartner durch Temperaturerhöhung einleitet.The reaction temperature can be varied within a substantial range in process (B) according to the invention. In general, temperatures between -20 ° C and + 150 ° C, preferably between + 20 ° C and 120 ° C, where appropriate, the cyclization is initiated only after the reaction of the two reactants by increasing the temperature.
Bei der Durchführung des erfmdungsgemäßen Verfahrens (B) setzt man pro Mol der Verbindung der Formel (III) 1,0 bis 2,0 Mol, vorzugsweise 1,0 bis 1,2 Mol Verbindung (IV) und gegebenenfalls 1 ,0 bis 5 Mol Reaktionshilfsmittel ein.When carrying out process (B) according to the invention, 1.0 to 2.0 mol, preferably 1.0 to 1.2 mol, of compound (IV) and, if appropriate, 1.0 to 5 mol, are used per mol of the compound of the formula (III) Reaction aids.
Das erfindungsgemäße Verfahren (C) kann in Gegenwart eines Verdünnungsmittels durchgeführt werden. Als solches werden vorzugsweise die beim Verfahren (A) Aufgelisteten eingesetzt.Process (C) according to the invention can be carried out in the presence of a diluent. As such, those listed in process (A) are preferably used.
Das erfindungsgemäße Verfahren (C) kann in Gegenwart eines geeigneten Reaktionshilfsmittels durchgeführt werden. Als solches kommen alle beim Verfahren (A) aufgelisteten Basen in Frage.Process (C) according to the invention can be carried out in the presence of a suitable reaction auxiliary. As such, all bases listed in process (A) are suitable.
Die Reaktionstemperatur kann bei dem erfindungsgemäßen Verfahren (C) innerhalb eines größeren Bereiches variiert werden. Im allgemeinen arbeitet man bei Temperaturen zwischen -20°C und +150°C, vorzugsweise zwischen +20°C und 120°C.The reaction temperature can be varied within a substantial range in process (C) according to the invention. In general, temperatures between -20 ° C and + 150 ° C, preferably between + 20 ° C and 120 ° C.
Bei der Durchführung des erfindungsgemäßen Verfahrens (C) werden gegebenenfalls die Verbindung der Formel (IX) und die Base im allgemeinen im molaren Verhältnis von 1:1 bis 1:3, vorzugsweise äquimolar eingesetzt.When carrying out process (C) according to the invention, the compound of the formula (IX) and the base are generally used in a molar ratio of 1: 1 to 1: 3, preferably equimolar, if appropriate.
Die Umsetzungen der erfmdungsgemäßen Verfahren können bei Normaldruck oder unter erhöhtem Druck durchgeführt werden. Vorzugsweise wird bei Normaldruck gearbeitet. Die Reaktionsdurchführung, Aufarbeitung und Isolierung der Reaktionsprodukte erfolgt nach allgemein üblichen, bekannten Methoden. Die Endprodukte werden vorzugsweise durch Kristallisation, chromatographische Trennung oder durch Entfernung der flüchtigen Bestandteile, gegebenenfalls im Vakuum, gereinigt (vergl. auch die Herstellungsbeispiele).The implementations of the methods according to the invention can be carried out under normal pressure or under elevated pressure. Is preferably carried out at normal pressure. The reaction is carried out, worked up and isolated by generally customary, known methods. The end products are preferably by crystallization, chromatographic separation or by Removal of the volatile constituents, if necessary in a vacuum, cleaned (see also the preparation examples).
Die Wirkstoffe eignen sich bei günstiger Warmblütertoxizität zur Bekämpfung von pathogenen Endoparasiten, die bei Menschen und in der Tierhaltung und Tierzucht bei Nutz-, Zucht-, Zoo-, Labor-, Versuchs- und Hobbytieren vorkommen. Sie sind dabei gegen alle oder einzelne Entwicklungsstadien der Schädlinge sowie gegen resistente und normal sensible Arten wirksam. Durch die Bekämpfung der pathogenen Endoparasiten sollen Krankheit, Todesfälle und Leistungsminderungen (z.B. bei der Produktion von Fleisch, Milch, Wolle, Häuten usw.) vermindert werden, so daß durch den Einsatz der Wirkstoffe eine wirtschaftlichere und einfachere Tierhaltung möglich ist. Zu den pathogenen Endoparasiten zählen Cestoden, Trematoden, Nematoden, insbesondere:The active ingredients are suitable for combating pathogenic endoparasites, which occur in humans and in animal husbandry and animal breeding in useful, breeding, zoo, laboratory, experimental and hobby animals, with favorable warm-blooded toxicity. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive species. By combating the pathogenic endoparasites, illness, deaths and reduced performance (e.g. in the production of meat, milk, wool, skins, etc.) are to be reduced, so that the use of the active ingredients enables more economical and simple animal husbandry. Pathogenic endoparasites include cestodes, trematodes, nematodes, in particular:
Aus der Ordnung der Pseudophyllidea z.B.: Diphyllobothrium spp., Spirometra spp.,From the order of the Pseudophyllidea, for example: Diphyllobothrium spp., Spirometra spp.,
Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoorus spp..Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoorus spp ..
Aus der Ordnung der Cyclophyllidea z.B.: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosmsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp..From the order of the Cyclophyllidea, for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosmsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyella spp. , Taenia spp., Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium
Aus der Unterklasse der Monogenea z.B.: Cyrodactylus spp., Dactylogyrus spp.,From the subclass of Monogenea e.g. Cyrodactylus spp., Dactylogyrus spp.,
Polystoma spp..Polystoma spp ..
Aus der Unterklasse der Digenea z.B.: Diplostomum spp., Posthodiplostomum spp.,From the subclass of Digenea e.g .: 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., Typhloccelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonismus spp., Dicrocoelium spp., Collyriclum 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., Typhloccelum spp., Paramphistomum spp., Calicophoron spp., Cotylopantoc. Spp., Cotylopantoc. Spp ., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonismus spp., Dicrocoelium spp., Collyriclum spp.,
Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp..Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp ..
Aus der Ordnung der Enoplida z.B.: Trichuris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp..From the order of the Enoplida, for example: Trichuris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp ..
Aus der Ordnung des Rhabditia z.B.: Micronema spp., Strongyloides spp..From the order of the Rhabditia e.g .: Micronema spp., Strongyloides spp ..
Aus der Ordnung der Strongylida z.B.: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp.,From the order of the Strongylida, for example: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp.,
Poteriostomum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp.,Poteriostomum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp.,
Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostomum 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.,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.,Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Happertagagia spp., Ostemonchusagia.
Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amido- stomum spp., Ollulanus spp., Cylicocyclus spp.; Cylicodontophorus spp..Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp., Cylicocyclus spp .; Cylicodontophorus spp ..
Aus der Ordnung der Oxyurida z.B.: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.. Aus der Ordnung der Ascaridia z.B.: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp..From the order of the Oxyurida, for example: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp .. From the order of Ascaridia, for example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp ..
Aus der Ordnung der Spirurida z.B.: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp.,From the order of the Spirurida, for example: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp.,
Dracunculus spp..Dracunculus spp ..
Aus der Ordnung der Filariida z.B.: Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp..From the order of the Filariida, for example: Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp ..
Aus der Gruppe der Gigantohynchida z.B.: Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp..From the group of the Gigantohynchida, for example: Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp ..
Beispielsweise zeigen die erfindungsgemäßen Wirkstoffe hervorragende Wirkung gegen Larven von Trichinella spiralis und Würmer wie Nippostrongylus brasiliensis.For example, the active compounds according to the invention show outstanding activity against larvae of Trichinella spiralis and worms such as Nippostrongylus brasiliensis.
Zu den Nutz- und Zuchttieren gehören Säugetiere wie z.B. Rinder, Pferde, Schafe, Schweine, Ziegen, Kamele, Wasserbüffel, Esel, Kaninchen, Damwild, Rentiere, Pelztiere wie z.B. Nerze, Chinchilla, Waschbär.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.
Zu Labor- und Versuchstieren gehören Mäuse, Ratten, Meerschweinchen, Goldhamster, Hunde und Katzen.Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
Zu den Hobbytieren gehören Hunde und Katzen.The pets include dogs and cats.
Die Anwendung kann sowohl prophylaktisch als auch therapeutisch erfolgen.The application can be prophylactic as well as therapeutic.
Die Anwendung der Wirkstoffe erfolgt direkt oder in Form von geeigneten Zube- reitungen enteral, parenteral, dermal. Die enterale Anwendung der Wirkstoffe geschieht z.B. oral in Form von Pulver, Zäpfchen, Tabletten, Kapseln, Fasten, Tränken, Granulaten, Drenchen, Boli, medi- kiertem Futter oder Trinkwasser. Die dermale Anwendung geschieht z.B. in Form des Tauchens (Dippen), Sprühens (Sprayen), Badens, Waschens, Aufgießens (pour- on and spot-on) und des Einpuderns. Die parenterale Anwendung geschieht z.B. in Form der Injektion (intramusculär, subcutan, intravenös, intraperitoneal) oder durch Implantate.The active ingredients are used directly or in the form of suitable preparations enterally, parenterally, dermally. The enteral application of the active ingredients takes place, for example, orally in the form of powder, suppositories, tablets, capsules, fasting, watering, granules, drenches, boluses, medicated 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 powdering. Parenteral use is for example in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants.
Geeignete Zubereitungen sind:Suitable preparations are:
Lösungen wie Injektionslösungen, orale Lösungen, Konzentrate zur oralen Verabreichung nach Verdünnung, Lösungen zum Gebrauch auf der Haut oder in Körperhöhlen, Aufgußformulierungen, Gele;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;
Emulsionen und Suspensionen zur oralen oder dermalen Anwendung sowie zur Injektion; halbfeste Zubereitungen;Emulsions and suspensions for oral or dermal use and for injection; semi-solid preparations;
Formulierungen bei denen der Wirkstoff in einer Salbengrundlage oder in einer Öl in Wasser oder Wasser in Öl Emulsionsgrundlage verarbeitet ist;Formulations in which the active ingredient is processed in an ointment base or in an oil in water or water in oil emulsion base;
feste Zubereitungen wie Pulver, Premixe oder Konzentrate, Granulate, Pellets, Tabletten, Boli, Kapseln; Aerosole und Inhalate, wirkstoffhaltige Formkörper.solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; Aerosols and inhalants, molded articles containing active ingredients.
Injektionslösungen werden intravenös, intramusculär und subcutan verabreicht.Solutions for injection are administered intravenously, intramuscularly and subcutaneously.
Injektionslösungen werden hergestellt, indem der Wirkstoff in einem geeigneten Lösungsmittel gelöst wird und eventuell Zusätze wie Lösungsvermittler, Säuren, Basen, Puffersalze, Antioxidantien, Konservierungsmittel zugefügt werden. Die Lösungen werden steril filtriert und abgefüllt. Als Lösungsmittel seien genannt: Physiologisch verträgliche Lösungsmittel wie Wasser, Alkohole wie Ethanol, Butanol, Benzylalkohol, Glycerin, Kohlenwasserstoffe, Propylenglykol, Polyethylenglykole, N-Methylpyrrolidon, sowie Gemische derselben.Injection solutions are prepared by dissolving the active ingredient in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives. The solutions are sterile filtered and filled. The following may be mentioned as solvents: physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof.
Die Wirkstoffe lassen sich gegebenenfalls auch in physiologisch verträglichen pflanzlichen oder synthetischen Ölen, die zu Injektion geeignet sind, lösen.If appropriate, the active compounds can also be dissolved in physiologically tolerable vegetable or synthetic oils which are suitable for injection.
Als Lösungsvermittler seien genannt: Lösungsmittel, die die Lösung des Wirkstoffs im Hauptlösungsmittel fördern oder sein Ausfallen verhindern. Beispiele sind Polyvinylpyrrolidon, polyoxyethyliertes Rhizinusöl, polyoxyethylierte Sorbitanester.The following may be mentioned as 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.
Konservierungsmittel sind: Benzylalkohol, Trichlorbutanol, p-Hydroxybenzoesäure- ester, n-Butanol.Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol.
Orale Lösungen werden direkt angewendet. Konzentrate werden nach vorheriger Verdünnung auf die Anwendungskonzentration oral angewendet. Orale Lösungen und Konzentrate werden wie oben bei den Injektionslösungen beschrieben herge- stellt, wobei auf steriles Arbeiten verzichtet werden kann.Oral solutions are applied directly. Concentrates are used orally after previous dilution to the application concentration. Oral solutions and concentrates are prepared as described above for the injection solutions, whereby sterile work can be dispensed with.
Lösungen zum Gebrauch auf der Haut werden aufgeträufelt, aufgestrichen, eingerieben, aufgespritzt, aufgesprüht oder durch Tauchen (Dippen, Baden oder Waschen) aufgebracht. Diese Lösungen werden wie oben bei den Injektionslösungen be- schrieben hergestellt.Solutions for use on the skin are dripped on, spread on, rubbed in, sprayed on, sprayed on or applied by dipping (dipping, bathing or washing). These solutions are produced as described above for the injection solutions.
Es kann vorteilhaft sein, bei der Herstellung Verdickungsmittel zuzufügen. Verdickungsmittel sind: Anorganische Verdickungsmittel wie Bentonite, kolloidale Kieselsäure, Aluminiummonostearat, organische Verdickungsmittel wie Cellulose- derivate, Polyvinylalkohole und deren Copolymere, Acrylate und Metacrylate. Gele werden auf die Haut aufgetragen oder aufgestrichen oder in Körperhöhlen eingebracht. Gele werden hergestellt, indem Lösungen, die wie bei den Injektionslösungen beschrieben hergestellt worden sind, mit soviel Verdickungsmittel ver- setzt werden, daß eine klare Masse mit salbenartiger Konsistenz entsteht. AlsIt may be advantageous to add thickeners during manufacture. Thickeners are: inorganic thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates. Gels are applied to or spread on the skin or placed in body cavities. Gels are produced by adding solutions, which have been prepared as described for the injection solutions, with enough thickening agent to produce a clear mass with an ointment-like consistency. As
Verdickungsmittel werden die weiter oben angegebenen Verdickungsmittel eingesetzt.Thickeners, the thickeners specified above are used.
Aufgieß-Formulierungen werden auf begrenzte Bereiche der Haut aufgegossen oder aufgespritzt, wobei der Wirkstoff entweder die Haut durchdringt und systemisch wirkt oder sich auf der Körperoberfläche verteilt.Pour-on formulations are poured or sprayed onto limited areas of the skin, the active ingredient either penetrating the skin and acting systemically or being distributed over the surface of the body.
Aufgieß-Formulierungen werden hergestellt, indem der Wirkstoff in geeigneten hautverträglichen Lösungsmitteln oder Lösungsmittelgemischen gelöst, suspendiert oder emulgiert wird. Gegebenenfalls werden weitere Hilfsstoffe wie Farbstoffe, resorptionsfördernde Stoffe, Antioxidantien, Lichtschutzmittel, Haftmittel zugefügt.Pour-on formulations are prepared by dissolving, suspending or emulsifying the active ingredient in suitable solvents or solvent mixtures that are compatible with the skin. If necessary, other auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers and adhesives are added.
Als Lösungsmittel seien genannt: Wasser, Alkanole, Glycole, Polyethylenglykole, Polypropylenglycole, Glycerin, aromatische Alkohole wie Benzylalkohol, Phenyl- ethanol, Phenoxyethanol, Ester wie Essigester, Butylacetat, Benzylbenzoat, Ether wieThe following may be mentioned as solvents: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as
Alkylenglykolalkylether wie Dipropylenglycolmonomethylether, Diethylenglykol- mono-butylether, Ketone wie Aceton, Methylethylketon, aromatische und/oder aliphatische Kohlenwasserstoffe, pflanzliche oder synthetische Öle, DMF, Di- methylacetamid, N-Methylpyrrolidon, 2-Dimethyl-4-oxy-methylen- 1 ,3-dioxolan.Alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1, 3-dioxolane.
Farbstoffe sind alle zur Anwendung am Tier zugelassenen Farbstoffe, die gelöst oder suspendiert sein können.Dyes are all dyes approved for use on animals, which can be dissolved or suspended.
Resorptionsfördernde Stoffe sind z.B. DMSO, spreitende Öle wie Isopropylmyristat, Dipropylenglykolpelargonat, Silikonöle, Fettsäureester, Triglyceride, Fettalkohole. Antioxidantien sind Sulfite oder Metabisulfite wie Kaliummetabisulfat, Ascorbin- säure, Butylhydroxytoluol, Butylhydroxyanisol, Tocopherol.Resorption-promoting substances are, for example, DMSO, 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.
Lichtschutzmittel sind z.B. Stoffe aus der Klasse der Benzophenone oder Novan- tisolsäure.Light stabilizers are e.g. Substances from the class of benzophenones or novantisolic acid.
Haftmittel sind z.B. Cellulosederivate, Stärkederivate, Polyacrylate, natürliche Polymere wie Alginate, Gelatine.Adhesives are e.g. Cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.
Emulsionen können oral, dermal oder als Injektion angewendet werden.Emulsions can be used orally, dermally or as an injection.
Emulsionen sind entweder vom Typ Wasser in Öl oder vom Typ Öl in Wasser.Emulsions are either water in oil or oil in water.
Sie werden hergestellt, indem man den Wirkstoff entweder in der hydrophoben oder in der hydrophilen Phase löst und diese unter Zuhilfenahme geeigneter Emulgatoren und gegebenenfalls weiterer Hilfsstoffe wie Farbstoffe, resorptionsfördernde Stoffe, Konservierungsstoffe, Antioxidantien, Lichtschutzmittel, viskositätserhöhende Stoffe, mit dem Lösungsmittel der anderen Phase homogenisiert.They are produced by dissolving the active ingredient either in the hydrophobic or in the hydrophilic phase and homogenizing it with the solvent of the other phase with the aid of suitable emulsifiers and, if necessary, other auxiliary substances such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers, viscosity-increasing substances .
Als hydrophobe Phase (Öle) seien genannt: Paraffinöle, Silikonöle, natürliche Pflanzenöle wie Sesamöl, Mandelöl, Rizinusöl, synthetische Triglyceride wie Capryl/- Caprinsäure-biglycerid, Triglyceridgemisch mit Pflanzenfettsäure der Kettenlänge C8-C12 oder anderen speziell ausgewählten natürlichen Fettsäuren, Partialglycerid- gemische gesättigter oder ungesättigter eventuell auch hydroxylgruppenhaltigerThe following may be mentioned as hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid biglyceride, triglyceride mixture with vegetable fatty acid of chain length C 8 -C 12 or other specially selected natural fatty acids, partial glyceride - Mixtures of saturated or unsaturated, possibly also containing hydroxyl groups
Fettsäuren, Mono- und Diglyceride der C8/CI0-Fettsäuren.Fatty acids, mono- and diglycerides of C 8 / C I0 fatty acids.
Fettsäureester wie Ethylstearat, Di-n-butyryl-adipat, Laurinsäurehexylester, Dipropy- lenglykol-pelargonat, Ester einer verzweigten Fettsäure mittlerer Kettenlänge mit gesättigten Fettalkoholen der Kettenlänge C16-Clg, Isopropylmyristat, Isopropyl- palmitat, Capryl/Caprinsäureester von gesättigten Fettalkoholen der Kettenlänge C12- C18, Isopropylstearat, Ölsäureoleylester, Ölsäuredecylester, Ethyloleat, Milchsäure- ethylester, wachsartige Fettsäureester wie künstliches Entenbürzeldrüsenfett, Di- butylphthalat, Adipinsäurediisopropylester, letzterem verwandte Estergemische u.a..Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length C 16 -C lg , isopropyl myristate, isopropyl palmitate, caprylic / capric acid esters of saturated fatty alcohols of chain length C 12 - C 18 , isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, wax-like fatty acid esters such as artificial duckling glandular fat, di-butyl phthalate, adipate ester demiopropyl amide.
Fettalkohole wie Isotridecylalkohol, 2-Octyldodecanol, Cetylstearyl-alkohol, Oleyl- alkohol.Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.
Fettsäuren wie z.B. Ölsäure und ihre Gemische.Fatty acids such as Oleic acid and its mixtures.
Als hydrophile Phase seien genannt:The following can be mentioned as the hydrophilic phase:
Wasser, Alkohole wie z.B. Propylenglykol, Glycerin, Sorbitol und ihre Gemische.Water, alcohols such as e.g. Propylene glycol, glycerin, sorbitol and their mixtures.
Als Emulgatoren seien genannt: nichtionogene Tenside, z.B. polyoxyethyliertes Rizinusöl, polyoxyethyliertes Sorbitan-monooleat, Sorbitanmonostearat, Glycerin- monostearat, Polyoxyethylstearat, Alkylphenolpolyglykolether;The following may be mentioned as emulsifiers: nonionic surfactants, e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;
ampholytische Tenside wie Di-Na-N-lauryl-ß-iminodipropionat oder Lecithin;ampholytic surfactants such as di-Na-N-lauryl-β-iminodipropionate or lecithin;
anionaktive Tenside, wie Na-Laurylsulfat, Fettalkoholethersulfate, Mono/Dialkyl- polyglykoletherorthophosphorsäureester-monoethanolaminsalz;anionic surfactants, such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt;
kationaktive Tenside wie Cetyltrimethylammoniumchlorid.cationic surfactants such as cetyltrimethylammonium chloride.
Als weitere Hilfsstoffe seien genannt: Viskositätserhöhende und die Emulsion stabilisierende Stoffe wie Carboxymethylcellulose, Methylcellulose und andere Cellulose- und Stärke-Derivate, Polyacrylate, Alginate, Gelatine, Gummi-arabicum, Polyvinyl- pyrrolidon, Polyvinylalkohol, Copolymere aus Methylvinylether und Maleinsäureanhydrid, Polyethylenglykole, Wachse, kolloidale Kieselsäure oder Gemische der aufgeführten Stoffe. Suspensionen können oral, dermal oder als Injektion angewendet werden. Sie werden hergestellt, indem man den Wirkstoff in einer Trägerflüssigkeit gegebenenfalls unter Zusatz weiterer Hilfsstoffe wie Netzmittel, Farbstoffe, resorptionsfördernde Stoffe, Konservierungsstoffe, Antioxidantien Lichtschutzmittel suspendiert.The following may be mentioned as further auxiliaries: substances which increase viscosity and stabilize the emulsion, such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes , colloidal silica or mixtures of the listed substances. Suspensions can be used orally, dermally or as an injection. They are produced by suspending the active ingredient in a carrier liquid, optionally with the addition of other auxiliaries such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers.
Als Trägerflüssigkeiten seien alle homogenen Lösungsmittel und Lösungsmittelgemische genannt.All homogeneous solvents and solvent mixtures may be mentioned as carrier liquids.
Als Netzmittel (Dispergiermittel) seien die weiter oben angegebenen Tenside genannt.The surfactants specified above may be mentioned as wetting agents (dispersants).
Als weitere Hilfsstoffe seien die weiter oben Angegebenen genannt.The additives given above may be mentioned as further auxiliaries.
Halbfeste Zubereitungen können oral oder dermal verabreicht werden. Sie unterscheiden sich von den oben beschriebenen Suspensionen und Emulsionen nur durch ihre höhere Viskosität.Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only in their higher viscosity.
Zur Herstellung fester Zubereitungen wird der Wirkstoff mit geeigneten Träger- Stoffen gegebenenfalls unter Zusatz von Hilfsstoffen vermischt und in die gewünschte Form gebracht.To prepare solid preparations, the active ingredient is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and brought into the desired shape.
Als Trägerstoffe seien genannt alle physiologisch verträglichen festen Inertstoffe. Alle solche dienen anorganische und organische Stoffe. Anorganische Stoffe sind z.B. Kochsalz, Carbonate wie Calciumcarbonat, Hydrogencarbonate, Aluminiumoxide, Kieselsäuren, Tonerden, gefälltes oder kolloidales Siliciumdioxid, Phosphate.All physiologically compatible solid inert substances may be mentioned as carriers. All of these serve inorganic and organic substances. Inorganic substances are e.g. Table salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, phosphates.
Organische Stoffe sind z.B. Zucker-, Zellulose, Nahrungs- und Futtermittel wie Milchpulver, Tiermehle, Getreidemehle und -schrote, Stärken. Hilfsstoffe sind Konservierungsstoffe, Antioxidantien, Farbstoffe, die bereits weiter oben aufgeführt worden sind.Organic substances are, for example, sugar, cellulose, food and feed such as milk powder, animal meal, cereal meal and meal, starches. Excipients are preservatives, antioxidants, dyes, which have already been listed above.
Weitere geeignete Hilfsstoffe sind Schmier- und Gleitmittel wie z.B. Magnesium- stearat, Stearinsäure, Talkum, Bentonite, zerfallsfördernde Substanzen wie Stärke oder quervernetztes Polyvinylpyrrolidon, Bindemittel wie z.B. Stärke, Gelatine oder lineares Polyvinylpyrrolidon sowie Trockenbindemittel wie mikrokristalline Cellu- lose.Other suitable auxiliaries are lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinyl pyrrolidone as well as dry binders such as microcrystalline cellulose.
Die Wirkstoffe können in den Zubereitungen auch in Mischung mit Synergisten oder mit anderen Wirkstoffen, die gegen pathogene Endoparasiten wirken, vorliegen. Solche Wirkstoffe sind z.B. L-2,3,5,6-Tetrahydro-6-phenyl-imidazolthiazol, Benz- imidazolcarbamate, Praziquantel, Pyrantel, Febantel.The active substances can also be present in the preparations in a mixture with synergists or with other active substances which act against pathogenic endoparasites. Such agents are e.g. L-2,3,5,6-tetrahydro-6-phenyl-imidazolethiazole, benzimidazole carbamate, praziquantel, pyrantel, febantel.
Anwendungsfertige Zubereitungen enthalten den Wirkstoff in Konzentrationen vonReady-to-use preparations contain the active substance in concentrations of
10 ppm bis 20 Gew.-%, bevorzugt von 0J bis 10 Gew.-%.10 ppm to 20% by weight, preferably from 0J to 10% by weight.
Zubereitungen die vor Anwendung verdünnt werden, enthalten den Wirkstoff in Konzentrationen von 0,5 bis 90 Gew.-%, bevorzugt von 5 bis 50 Gew.-%.Preparations which are diluted before use contain the active ingredient in concentrations of 0.5 to 90% by weight, preferably 5 to 50% by weight.
Im allgemeinen hat es sich als vorteilhaft erwiesen, Mengen von etwa 1 bis 100 mg Wirkstoff je kg Körpergewicht pro Tag zur Erzielung wirksamer Ergebnisse zu verabreichen.In general, it has proven advantageous to administer amounts of approximately 1 to 100 mg of active ingredient per kg of body weight per day in order to achieve effective results.
Die Herstellung und die Verwendung der erfindungsgemäßen Wirkstoffe bzw.The production and use of the active compounds according to the invention or
Zwischenprodukte gehen aus den nachfolgenden Beispielen hervor. HerstellbeispieleIntermediates are shown in the examples below. Manufacturing examples
Beispiel 1-1Example 1-1
(Verfahren A)(Method A)
800 mg (0,825 mmol) H-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac- MeAzaLeu-D-Lac-OH (z.B. aus Beispiel II-l) wurden unter Argonatmosphäre in 1000 ml Dichlormethan vorgelegt. Bei 0°C wurden zu der Lösung 266 mg (2,06 mmol) Ethyldiisopropylamin und 252 mg (0,99 mmol) BOP-Cl zugegeben. Anschließend wurde auf Raumtemperatur erwärmen gelassen und 24 h nachgerührt. Die Reaktionslösung wurde danach mit ges. Natriumhydrogencarbonat-Lösung und Wasser gewaschen, über Natriumsulfat getrocknet und eingeengt. Nach Säulenchromatographie (Kieselgel, 0=4,5 cm, 1=25 cm; Cyclohexan : Ethylacetat 1 :1) wurden 247 mg 6J8-Dibenzyl-3,9J5,21-tetraisobutyl-4J0J2J6,22,24-hexamethyl- 1,7,13,19-tetraoxa-3 ,4,9,10J 6,22-hexaaza-cyclotetracosan-2,5 ,8 , 11 , 14, 17,20,23 -oc- taon (cyclo-[MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac]) als gelblicher, bei 90-91°C schmelzender Feststoff erhalten.800 mg (0.825 mmol) of H-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-OH (e.g. from Example II-1) were placed under an argon atmosphere in 1000 ml of dichloromethane. At 0 ° C, 266 mg (2.06 mmol) of ethyldiisopropylamine and 252 mg (0.99 mmol) of BOP-Cl were added to the solution. The mixture was then allowed to warm to room temperature and stirred for a further 24 h. The reaction solution was then washed with sat. Washed sodium bicarbonate solution and water, dried over sodium sulfate and concentrated. After column chromatography (silica gel, 0 = 4.5 cm, 1 = 25 cm; cyclohexane: ethyl acetate 1: 1), 247 mg of 6J8-dibenzyl-3,9J5,21-tetraisobutyl-4J0J2J6,22,24-hexamethyl-1,7 , 13,19-tetraoxa-3, 4,9,10J 6,22-hexaaza-cyclotetracosane-2,5, 8, 11, 14, 17,20,23 -oc-taon (cyclo- [MeLeu-D-PhLac -MeLeu-D-Lac-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac]) as a yellowish solid melting at 90-91 ° C.
Zusätzliche Reinigung durch HPLC (Reversed Phase RP18, 5 μm, Acetonitril/- Wasser-Gradient) ergab nach Gefriertrocknung 121 mg analytisch reine Substanz. HR-MS: m/z ber. für C50H74N6O12 Na 973,5262 gef. 973,5265Additional purification by HPLC (reversed phase RP18, 5 μm, acetonitrile / - water gradient) gave 121 mg of analytically pure substance after freeze-drying. HR-MS: m / z calc. For C 50 H 74 N 6 O 12 Na 973.5262 found 973.5265
Herstellung der VorprodukteManufacture of intermediate products
Beispiel II- 1Example II-1
850 mg (0,80 mmol) H-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac- MeAzaLeu-D-Lac-O-Bn (z.B. aus Bsp. VII-1) wurden in ca. 30 ml Ethylacetat gelöst und bei Normaldruck mit Wasserstoff in Gegenwart von Pd/C (10%-ig) hydriert. Nach beendeter Reaktion wurde vom Katalysator abfiltriert und das Lösungsmittel im Vakuum entfernt. Es wurden 806 mg H-MeLeu-D-PhLac-MeLeu-D-Lac- MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-OH als leicht gefärbter Schaum erhalten. 850 mg (0.80 mmol) H-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn (e.g. from Ex. VII-1) were mixed in approx. Dissolved 30 ml of ethyl acetate and hydrogenated at normal pressure with hydrogen in the presence of Pd / C (10%). When the reaction was complete, the catalyst was filtered off and the solvent was removed in vacuo. 806 mg of H-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-OH were obtained as a slightly colored foam.
Beispiel VII- 1Example VII-1
1,36 g (1J73 mmol) Boc-MeLeu-D-PhLac-MeLeu-D-Lac-Me AzaLeu-D-PhLac- MeAzaLeu-D-Lac-O-Bn (z.B. aus Bsp. VII- 1) wurden unter Argon in 10 ml Dichlormethan vorgelegt. Bei 0°C wurden zu der Lösung langsam 1,34 g (11,73 mmol) Trifluoressigsäure getropft und bei dieser Temperatur über Nacht nachgerührt. Anschließend wurde im Vakuum eingeengt, der Rückstand in Ethylacetat aufgenommen und mit ges. Natriumhydrogencarbonat-Lösung sowie ges. Natriumchlorid-Lösung gewaschen. Nach Trocknung und Entfernung des Lösungsmittels im Vakuum wurden 0,95 g (76% d.Th.) H-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac- MeAzaLeu-D-Lac-O-Bn als dunkel gefärbtes hochviskoses Öl erhalten.1.36 g (1J73 mmol) Boc-MeLeu-D-PhLac-MeLeu-D-Lac-Me AzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn (e.g. from Ex. VII-1) were under argon submitted in 10 ml of dichloromethane. At 0 ° C., 1.34 g (11.73 mmol) of trifluoroacetic acid were slowly added dropwise to the solution and the mixture was stirred at this temperature overnight. The mixture was then concentrated in vacuo, the residue was taken up in ethyl acetate and washed with sat. Sodium bicarbonate solution and sat. Washed sodium chloride solution. After drying and removal of the solvent in vacuo, 0.95 g (76% of theory) of H-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn obtained as a dark colored, highly viscous oil.
Beispiel VIII- 1Example VIII-1
2,67 g (4,5 mmol) Carbonsäure Boc-MeLeu-D-PhLac-MeLeu-D-Lac-OH (Annu. Rep. Sankyo Res. Lab. 46, 67-75 (1994) und J. Antibiot. 47, 1322-1327 (1994)) wurden unter Argon in 45 ml trockenem Dichlormethan vorgelegt. Bei 0°C wurden nacheinander 1,40 g (5,5 mmol) BOP-Cl und 0,59 g (5,8 mmol) N-Methylmorpholin langsam zugegeben. Nach ca. 1 h wurden 2,62 g (4,5 mmol) Hydrazin H-MeAzaLeu- 2.67 g (4.5 mmol) carboxylic acid Boc-MeLeu-D-PhLac-MeLeu-D-Lac-OH (Annu. Rep. Sankyo Res. Lab. 46, 67-75 (1994) and J. Antibiot. 47 , 1322-1327 (1994)) were placed under argon in 45 ml of dry dichloromethane. At 0 ° C, 1.40 g (5.5 mmol) BOP-Cl and 0.59 g (5.8 mmol) N-methylmorpholine were slowly added in succession. After approx. 1 h, 2.62 g (4.5 mmol) of hydrazine H-MeAzaLeu-
D-PhLac-MeAzaLeu-D-Lac-O-Bn (z.B. aus Beispiel X-l) gelöst in wenig Dichlormethan langsam hinzugegeben. Anschließend wurden weitere 0,59 g N-Methylmorpholin zugegeben. Es wurde auf RT erwärmen gelassen und 12 h nachgerührt. Anschließend wurde eingeengt, der Rückstand in Ethylacetat aufgenommen, mit ges. Νatriumchlorid-Lösung gewaschen, über Νatriumsulfat getrocknet und das Lösungsmittel im Vakuum entfernt. Nach Säulenchromatographie (Kieselgel, 0=4,5 cm, 1=25 cm; Cyclohexan : Ethylacetat 3:1) wurden 2,40 g (46% d.Th.) Boc-MeLeu-D- PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn als gelbes hochviskoses Öl erhalten. HR-MS: m/z ber. für C62H90N6O15 Na 1181,6362 gef. 1181,6349D-PhLac-MeAzaLeu-D-Lac-O-Bn (eg from Example Xl) dissolved in a little dichloromethane is slowly added. A further 0.59 g of N-methylmorpholine was then added. The mixture was allowed to warm to RT and stirred for a further 12 h. The mixture was then concentrated, the residue was taken up in ethyl acetate, washed with sat. Washed sodium chloride solution, dried over sodium sulfate and removed the solvent in vacuo. After column chromatography (silica gel, 0 = 4.5 cm, 1 = 25 cm; cyclohexane: ethyl acetate 3: 1), 2.40 g (46% of theory) of Boc-MeLeu-D-PhLac-MeLeu-D-Lac -MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn obtained as a yellow, highly viscous oil. HR-MS: m / z calc. For C 62 H 90 N 6 O 15 Na 1181.6362 found. 1181.6349
Beispiel X-lExample X-1
3,08 g (4,5 mmol) Boc-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn (z.B. aus3.08 g (4.5 mmol) Boc-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn (e.g. from
Beispiel XII- 1) wurden unter Argon in 60 ml trockenem Dichlormethan vorgelegt. Bei 0°C wurden zu der Lösung langsam 5J4 g (45 mmol) Trifluoressigsäure getropft. Es wurde auf RT erwärmen gelassen und ca. 15 h nachgerührt. Anschließend wurde die Lösung eingeengt, der Rückstand in Dichlormethan aufgenommen und mit ges. Natriumhydrogencarbonat-Lösung sowie ges. Natriumchlorid-Lösung gewaschen. Nach Trocknung über Natriumsulfat wurde das Lösungsmittel im Vakuum entfernt. Es wurden 2,67 g (quantitativ) H-MeAzaLeu-D-PhLac- MeAzaLeu-D-Lac-O-Bn als leicht dunkel gefärbtes viskoses Öl erhalten. MS (FAB): m/z (rel. Int.): 585 (M+H+, 35), 584 (M+, 20)Example XII-1) were placed under argon in 60 ml of dry dichloromethane. At 0 ° C slowly 5J4 g (45 mmol) trifluoroacetic acid to the solution dripped. The mixture was allowed to warm to RT and stirred for about 15 h. The solution was then concentrated, the residue was taken up in dichloromethane and washed with sat. Sodium bicarbonate solution and sat. Washed sodium chloride solution. After drying over sodium sulfate, the solvent was removed in vacuo. 2.67 g (quantitative) of H-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn were obtained as a slightly dark colored viscous oil. MS (FAB): m / z (rel. Int.): 585 (M + H + , 35), 584 (M + , 20)
Beispiel XI- 1Example XI-1
11,9 g (30 mmol) 2-(l-Isobutyl-2-methylhydrazyl)-carbonyloxypropionsäure-benzyl- ester (z.B. aus Beispiel XIV-1 oder WO 9736883) und 9,22 g (30 mmol) 2-(2-teτt.-11.9 g (30 mmol) benzyl ester of 2- (l-isobutyl-2-methylhydrazyl) -carbonyloxypropionate (for example from example XIV-1 or WO 9736883) and 9.22 g (30 mmol) of 2- (2- teτt.-
Butoxycarbonyl-l-isobutyl-2-methylhydrazyl)-carbonyloxy3-phenylessigsäure (z.B. aus Beispiel XIII- 1) wurden unter Argon in 120 ml trockenem Dichlormethan vorgelegt. Bei 0°C wurden zu der Lösung langsam 9,69 g (75 mmol) Ethyldiisopropylamin und anschließend 9J6 g (36 mmol) BOP-Cl zugegeben. Nach 2 h Rühren bei 0°C wurde auf RT erwärmen gelassen und weitere 12 h nachgerührt.Butoxycarbonyl-l-isobutyl-2-methylhydrazyl) -carbonyloxy3-phenylacetic acid (e.g. from Example XIII-1) were placed under argon in 120 ml of dry dichloromethane. At 0 ° C., 9.69 g (75 mmol) of ethyldiisopropylamine and then 9J6 g (36 mmol) of BOP-Cl were slowly added to the solution. After stirring at 0 ° C. for 2 h, the mixture was allowed to warm to RT and stirred for a further 12 h.
Nach Säulenchromatographie (Kieselgel, 0=6 cm, 1=30 cm; Cyclohexan : Ethylacetat 6:1) wurden 9,25 g (45% d.Th.) Boc-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac- O-Bn als gelbes viskoses Öl erhalten. HR-MS: m/z ber. für C36H52N4O9 Na 707,3632 gef. 707,3634After column chromatography (silica gel, 0 = 6 cm, 1 = 30 cm; cyclohexane: ethyl acetate 6: 1), 9.25 g (45% of theory) of Boc-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O -Bn obtained as a yellow viscous oil. HR-MS: calculated m / z for C 36 H 52 N 4 O 9 Na 707.3632. 707.3634
Beispiel XIII- 1Example XIII-1
15,54 g (30 mmol) 2-(2-tert.-Butoxycarbonyl-l-isobutyl-2-methylhydrazyl)-car- bonyloxy-3-phenylessigsäure-benzylester (z.B. aus WO 9736883) wurden in 150 ml15.54 g (30 mmol) of 2- (2-tert-butoxycarbonyl-l-isobutyl-2-methylhydrazyl) carbonyloxy-3-phenylacetic acid (e.g. from WO 9736883) were added in 150 ml
Ethylacetat gelöst und unter bei Normaldruck mit Wasserstoff in Gegenwart von Pd/C (10%-ig) hydriert. Nach beendeter Reaktion wurde vom Katalysator abfiltriert und das Lösungsmittel im Vakuum entfernt. Es wurden 11,9 g (quantitativ) 2-(2-tert- Butoxycarbonyl- 1 -isobutyl-2-methylhydrazyl)-carbonyloxy3 -phenylessigsäure als gelbbraunes Öl erhalten.Dissolved ethyl acetate and hydrogenated under normal pressure with hydrogen in the presence of Pd / C (10%). When the reaction was complete, the catalyst was filtered off and the solvent was removed in vacuo. 11.9 g (quantitative) of 2- (2-tert-butoxycarbonyl-1-isobutyl-2-methylhydrazyl) carbonyloxy3-phenylacetic acid were obtained as a tan oil.
MS: m/z (rel. Int.): 417 (M+Na+, 20); 395 (M+H+, 10); 394 (M+, 5); 393 (M-H+,MS: m / z (rel. Int.): 417 (M + Na + , 20); 395 (M + H + , 10); 394 (M + , 5); 393 (MH + ,
10); 339 (70); 321 (40); 295 (100); 173 (60); 148 (50); 131 (35); 101 (35) Η-NMR (500 Mhz, CDC13): δ (ppm) 0,95 (kompl. Ber., 6H, CH(CH3)2); 1,35-1,55 (kompl. Ber., 10H, C(CH3)3, CH(CH3)2); 2,6-3,45 (kompl. Ber., 8H, CH2Ph, OCH, NCH2, NCH3); 7,35 (m, 5H, C6H5) Beispiel XIV- 110); 339 (70); 321 (40); 295 (100); 173 (60); 148 (50); 131 (35); 101 (35) Η NMR (500 MHz, CDC1 3 ): δ (ppm) 0.95 (complete range, 6H, CH (CH 3 ) 2 ); 1.35-1.55 (complete range, 10H, C (CH 3 ) 3 , CH (CH 3 ) 2 ); 2.6-3.45 (complete range, 8H, CH 2 Ph, OCH, NCH 2 , NCH 3 ); 7.35 (m, 5H, C 6 H 5 ) Example XIV-1
12,25 g (30 mmol) 2-(2-tert.-Butoxycarbonyl-l-isobutyl-2-methylhydrazyl)-carbo- nyloxy-propionsäure-benzylester (z.B. aus WO 9736883) wurden unter Argon in 100 ml trockenem Dichlormethan vorgelegt. Bei 0°C wurden zu der Lösung langsam 27,36 g (240 mmol) Trifluoressigsäure getropft. Es wurde auf RT erwärmen gelassen und 24 h nachgerührt. Anschließend wurde die Lösung im Vakuum eingeengt, der Rückstand in Ethylacetat aufgenommen und mit ges. Natriumhydrogencarbonat-12.25 g (30 mmol) of benzyl 2- (2-tert-butoxycarbonyl-l-isobutyl-2-methylhydrazyl) -carbonyloxy-propionate (e.g. from WO 9736883) were placed under argon in 100 ml of dry dichloromethane. At 0 ° C., 27.36 g (240 mmol) of trifluoroacetic acid were slowly added dropwise to the solution. The mixture was allowed to warm to RT and stirred for a further 24 h. The solution was then concentrated in vacuo, the residue was taken up in ethyl acetate and washed with sat. Sodium hydrogen carbonate
Lösung sowie ges. Natriumchlorid-Lösung gewaschen. Nach Trocknung über Natriumsulfat und Enfernung des Lösungsmittels im Vakuum wurden 7,21 g (78% d.Th.) 2-(l -Isobutyl-2-methylhydrazyl)-carbonyloxy-propionsäure-benzylester als hellgelbes viskoses Öl erhalten. MS: m/z (rel. Int.): 309 (M+H+, 100); 308 (M+, 89); 101 (28); 91 (PhCHJ, 100)Solution and sat. Washed sodium chloride solution. After drying over sodium sulfate and removal of the solvent in vacuo, 7.21 g (78% of theory) of benzyl 2- (l-isobutyl-2-methylhydrazyl) -carbonyloxy-propionate were obtained as a light yellow viscous oil. MS: m / z (rel. Int.): 309 (M + H + , 100); 308 (M + , 89); 101 (28); 91 (PhCHJ, 100)
'H-NMR (500 Mhz, CDC13): δ (ppm) 0,90 (2d, 6H, CH(CH3)2); 1,53 (d, 3H, CHCH3); 2,70 (br. s, 3H, NCH3); 3,27 (m, 2H, NCH2); 5J8 (m, 3H, CH2Ph, OCH); 7,35 (m, 5H, C6H5) 'H NMR (500 MHz, CDC1 3 ): δ (ppm) 0.90 (2d, 6H, CH (CH 3 ) 2 ); 1.53 (d, 3H, CHCH 3); 2.70 (br. S, 3H, NCH 3 ); 3.27 (m, 2H, NCH 2); 5J8 (m, 3H, CH 2 Ph, OCH); 7.35 (m, 5H, C 6 H 5 )
An endungsbeispieleWith examples
Beispiel AExample A
Trichinen-Test (in- vitro Experiment)Trichinen test (in vitro experiment)
Man isolierte Trichinella spiralis Larven aus Skelettmuskeln und Diaphragmen von SPF/CFW1 Mäusen und bewahrte sie in 0,9%-iger NaCl-Lösung auf, die man mit 20 μg ml"1 Clotrimazol ergänzt hatte. Die Inkubation von 20 Larven pro Bestimmung wurde in 2 ml einer Lösung durchgeführt, die pro 500 ml 10 g Bacto Casitone, 5 gTrichinella spiralis larvae were isolated from skeletal muscles and diaphragms of SPF / CFW1 mice and stored in 0.9% NaCl solution which had been supplemented with 20 μg ml "1 clotrimazole. The incubation of 20 larvae per determination was carried out in 2 ml of a solution carried out per 500 ml of 10 g of Bacto Casitone, 5 g
Hefeextrakt, 2,5 g Glukose, 0,4 g KH2PO4 und 0,4 g K2HPO4 (pH 7,2) ergänzt durch 10 μg ml"1 Sisomicin und 1 μg ml"1 Clotrimazol enthielt. 10 mg des zu testenden Wirkstoffes wurden in 0,5 ml Dimethylsulfoxid gelöst und in der Menge zu dem Inkubationsmedium gegeben, daß Endkonzentrationen von 100, 10, 1, 0J oder 0,01 μg ml"1 erhalten wurden. Nach 5 Tagen Inkubation bei 19 °C wurde der Versuch gestoppt. Die Wirkung der getesteten Verbindungen wurde wie folgt quantifiziert: 3 = volle Wirkung (alle Larven sind tot); 2 = gute Wirkung (nicht alle, aber mehr als die Hälfte der Larven sind tot); 1 = schwache Wirkung (nicht alle, aber mehr als die Hälfte der Larven leben); 0 = keine Wirkung (Zahl der lebenden Larven gleicht der in unbehandelter Kontrolle). (Vgl. Tropenmed. Parasitol. 32, 31-34 (1981).Yeast extract, 2.5 g glucose, 0.4 g KH 2 PO 4 and 0.4 g K 2 HPO 4 (pH 7.2) supplemented by 10 μg ml "1 sisomicin and 1 μg ml " 1 clotrimazole contained. 10 mg of the active ingredient to be tested were dissolved in 0.5 ml of dimethyl sulfoxide and added to the incubation medium in such a way that final concentrations of 100, 10, 1, 0J or 0.01 μg ml "1 were obtained. After 5 days of incubation at 19 The test was stopped at ° C. The activity of the tested compounds was quantified as follows: 3 = full activity (all larvae are dead), 2 = good activity (not all, but more than half of the larvae are dead), 1 = weak Effect (not all, but more than half of the larvae live); 0 = no effect (number of live larvae is the same as in the untreated control) (see Tropenmed. Parasitol. 32, 31-34 (1981).
In diesem Test zeigte beispielsweise die erfindungsgemäße Verbindung gemäß Herstellbeispiel I-l bei einer beispielhaften Wirkstoffkonzentration von 100 μg/ml eine Wirkung der Stufe 3. Beispiel BIn this test, for example, the compound according to the invention from preparation example II showed an effect of stage 3 at an exemplary active ingredient concentration of 100 μg / ml. Example B
Nippostrongylus-Test (in-vitro Experiment)Nippostrongyl test (in vitro experiment)
Man isolierte erwachsene Nippostrongylus brasiliensis aus dem Dünndarm weiblicher Wistar-Ratten und bewahrte sie in 0,9%-iger NaCl-Lösung auf, die man mit 20 μg ml"1 Sisomicin und 2 μg ml"1 Clotrimazol ergänzt hatte. Die Inkubation jeder Gruppe männlicher oder weiblicher Würmer ohne (Kontrolle) oder mit dem in Dimethylsulfoxid gelösten, zu testenden Wirkstoff wurde in 1,0 ml Nährmedium durchgeführt. Zur Bestimmung der Aktivität der Acetylcholinesterase als Indikator für den Lebenszustand der Würmer wurde das Medium entnommen. Die Inkubation und Bestimmung der Enzymaktivität als Test für anthelmintische Wirkung ist in Z. Parasitenkd. 73 190-191 (1987) beschrieben. Das Niveau der Wirkung der Testverbindung wurde wie folgt quantifiziert: 3 = volle Wirkung (95% - 100%> Inhibierung des Enzyms); 2 = gute Wirkung (75% - 95% Inhibierung); 1 = schwache WirkungAdult Nippostrongylus brasiliensis was isolated from the small intestine of female Wistar rats and stored in 0.9% NaCl solution, which had been supplemented with 20 μg ml "1 sisomicin and 2 μg ml " 1 clotrimazole. The incubation of each group of male or female worms without (control) or with the active ingredient to be tested dissolved in dimethyl sulfoxide was carried out in 1.0 ml of nutrient medium. The medium was removed to determine the activity of acetylcholinesterase as an indicator of the life status of the worms. The incubation and determination of enzyme activity as a test for anthelmintic effects is described in Z. Parasitenkd. 73 190-191 (1987). The level of activity of the test compound was quantified as follows: 3 = full activity (95% - 100%> inhibition of the enzyme); 2 = good effect (75% - 95% inhibition); 1 = weak effect
(50% - 75%) Inhibierung); 0 = vernachlässigbare Wirkung (weniger als 50%o Inhibierung).(50% - 75%) inhibition); 0 = negligible effect (less than 50% o inhibition).
In diesem Test zeigte beispielsweise die erfindungsgemäße Verbindung gemäß Herstellbeispiel I-l bei einer beispielhaften Wirkstoffkonzentration von 100 μg/ml eine Wirkung der Stufe 3. In this test, for example, the compound according to the invention from preparation example I-1 showed an effect of stage 3 at an exemplary active compound concentration of 100 μg / ml.

Claims

Patentansprüche claims
1. Aza-Cyclodepsipeptide der Formel (I)1. Aza-cyclodepsipeptides of the formula (I)
in welcherin which
X1, X2, X3 und X4 unabhängig voneinander jeweils für N oder C-H stehen, wobei mindestens eine dieser Variablen X für Stickstoff steht,X 1 , X 2 , X 3 and X 4 each independently represent N or CH, where at least one of these variables X represents nitrogen,
R1, R2, R3 und R4 unabhängig voneinander jeweils für Wasserstoff, jeweils gegebenenfalls durch Halogen substituiertes Alkyl, Alkenyl,R 1 , R 2 , R 3 and R 4 independently of one another each represent hydrogen, in each case optionally substituted by halogen, alkyl, alkenyl,
Hydroxyalkyl, Alkanoyloxyalkyl, Alkoxyalkyl, Arylalkoxyalkyl, Mercaptoalkyl, Alkylthioalkyl, Alkoxycarbonylalkyl, Aryloxycar- bonylalkyl, Arylalkyloxycarbonylalkyl, Carbamoylalkyl, Aminoalkyl, Alkylaminoalkyl, Dialkylaminoalkyl oder für jeweils gegebenenfalls substituiertes Cycloalkyl, Cycloalkylalkyl, Aryl, Arylalkyl, Hetaryl oder Hetarylalkyl stehen, undHydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, Aryloxycar- bonylalkyl, dialkylaminoalkyl are Arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl or represents in each case optionally substituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl and
die Gruppierung -NR9-X'R5- für einen Rest der Formel -NR9"'-CHR5 1- oder einen Rest der Formel -NR9"2-NR5"2- steht, die Gruppierung -NR10-X2R6- für einen Rest der Formel -NR^'-CHR6"1- oder einen Rest der Formel -NR10"2-NR6"2- steht,the grouping -NR 9 -X'R 5 - represents a radical of the formula -NR 9 " '-CHR 5 1 - or a radical of the formula -NR 9" 2 -NR 5 "2 -, the grouping -NR 10 -X 2 R 6 - represents a radical of the formula -NR ^ '- CHR 6 "1 - or a radical of the formula -NR 10" 2 -NR 6 "2 -,
die Gruppierung -NRπ-X3R7- für einen Rest der Formel -NR'^'-CHR7"1- oder einen Rest der Formel -NR1 '"2-NR7"2- steht,the grouping -NR π -X 3 R 7 - represents a radical of the formula -NR '^' - CHR 7 "1 - or a radical of the formula -NR 1 '" 2 -NR 7 "2 -,
die Gruppierung -NR12-X4R8- für einen Rest der Formel -NR12 1-CHR8 1- oder einen Rest der Formel -NR12"2-NR8"2- steht,the grouping -NR 12 -X 4 R 8 - represents a radical of the formula -NR 12 1 -CHR 8 1 - or a radical of the formula -NR 12 "2 -NR 8" 2 -,
R5"1, R6"1, R7"1 und R8"1 unabhängig voneinander jeweils für Wasserstoff, gegebenenfalls durch Amino oder Hydroxy substituiertes Alkyl, für Mercaptomethyl, Methylthioethyl, Carboxymethyl, Carboxyethyl, Carbamoylmethyl, Carbamoylethyl, Guanidinopropyl, für gegebenenfalls durch Amino, Nitro, Halogen, Hydroxy oder Alkoxy substituier- tes Phenyl oder Benzyl, für Naphthylmethyl, Indolylmethyl,R 5 "1 , R 6" 1 , R 7 "1 and R 8" 1 independently of one another each for hydrogen, optionally substituted by amino or hydroxy-substituted alkyl, for mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl, for optionally phenyl or benzyl substituted by amino, nitro, halogen, hydroxy or alkoxy, for naphthylmethyl, indolylmethyl,
Imidazolylmethyl, Triazolylmethyl, Thienylmethyl,Imidazolylmethyl, triazolylmethyl, thienylmethyl,
Benzothienylmethyl oder Pyridylmethyl stehen, wobei funktioneile Gruppen gegebenenfalls geschützt vorliegen können,Benzothienylmethyl or pyridylmethyl, where functional groups may optionally be protected,
R9"1, R10"1, R11"1 und R12"1 unabhängig voneinander jeweils für Wasserstoff oder C,-C4- Alkyl stehen,R 9 "1 , R 10" 1 , R 11 "1 and R 12" 1 each independently represent hydrogen or C, -C 4 alkyl,
wobei die Restepaare R^/R9"1, R^/R10"1, R'-'/R11"1 und R' VR12"1 auch jeweils gemeinsam unabhängig voneinander für die Reste -(CH2)3- und -(CH2)4- stehen,where the pairs of radicals R ^ / R 9 "1 , R ^ / R 10" 1 , R '-' / R 11 "1 and R 'VR 12" 1 are each also independently of one another for the radicals - (CH 2 ) 3 - and - (CH 2 ) 4 - stand,
R5"2 bis R12"2 unabhängig voneinander jeweils für Wasserstoff, jeweils gegebenenfalls durch Halogen substituiertes Alkyl, Hydroxyalkyl, Alkanoyloxyalkyl, Alkoxyalkyl, Arylalkoxyalkyl, Mercaptoalkyl, Alkylthioalkyl, Carboxyalkyl, Alkoxy carbonylalkyl, Aryloxy- carbonylalkyl, Arylalkyloxycarbonylalkyl, Carbamoylalkyl, Amino- alkyl, Alkylaminoalkyl, Dialkylaminoalkyl, Alkoxycarbonylamino- alkyl oder für jeweils gegebenenfalls substituiertes Cycloalkyl, Cycloalkylalkyl, Aryl, Arylalkyl, Hetaryl oder Hetarylalkyl stehen undR 5 "2 to R 12" 2 independently of one another each represent hydrogen, in each case optionally substituted by halogen alkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxy- carbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl or for optionally substituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl and
wobei die Restepaare R5"2/R9"2, R6"2/R10"2, R7-2/Rπ"2 und R8"2/R12"2 auch jeweils gemeinsam unabhängig voneinander für die gegebenenfalls durch C,- C4-Alkyl substituierten Reste -(CH2)3- und -(CH2)4- stehen.wherein the pairs of residues R 5 "2 / R 9" 2 , R 6 "2 / R 10" 2 , R 7 - 2 / R π "2 and R 8" 2 / R 12 "2 are each also independently of one another for the, if appropriate by C, - C 4 alkyl substituted radicals - (CH 2 ) 3 - and - (CH 2 ) 4 - are.
2. Verfahren zur Herstellung der Aza-Cyclodepsipeptide der Formel (I)2. Process for the preparation of the aza-cyclodepsipeptides of the formula (I)
in welcherin which
X1, X2, X3 und X4 unabhängig voneinander jeweils für N oder C-H stehen, wobei mindestens eine dieser Variablen X für Stickstoff steht,X 1 , X 2 , X 3 and X 4 each independently represent N or CH, where at least one of these variables X represents nitrogen,
R1, R2, R3 und R4 unabhängig voneinander jeweils für Wasserstoff, jeweils gegebenenfalls durch Halogen substituiertes Alkyl, Alkenyl, Hydroxyalkyl, Alkanoyloxyalkyl, Alkoxyalkyl, Arylalkoxyalkyl, Mercaptoalkyl, Alkylthioalkyl, Alkoxycarbonylalkyl, Aryloxy- carbonylalkyl, Arylalkyloxycarbonylalkyl, Carbamoylalkyl,R 1 , R 2 , R 3 and R 4 are each independently of one another hydrogen, in each case optionally substituted by halogen, alkyl, alkenyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, aryloxy- carbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl,
Aminoalkyl, Alkylaminoalkyl, Dialkylaminoalkyl oder für jeweils gegebenenfalls substituiertes Cycloalkyl, Cycloalkylalkyl, Aryl, Arylalkyl, Hetaryl oder Hetarylalkyl stehen, undAminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or for optionally substituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl, and
ie Gruppierung -NR9-X'R5- für einen Rest der Formel -NR9"1 -CHR5"1- oder einen Rest der Formel -NR9"2-NR5"2- steht,he grouping -NR 9 -X'R 5 - represents a radical of the formula -NR 9 "1 -CHR 5" 1 - or a radical of the formula -NR 9 "2 -NR 5" 2 -,
ie Gruppierung -NR10-X2R6- für einen Rest der Formel -NR10"1 -CHR6"1- oder einen Rest der Formel -NR10"2-NR6"2- steht,he grouping -NR 10 -X 2 R 6 - represents a radical of the formula -NR 10 "1 -CHR 6" 1 - or a radical of the formula -NR 10 "2 -NR 6" 2 -,
ie Gruppierung -NRU-X3R7- für einen Rest der Formel -NR'ΑHR7"1- oder einen Rest der Formel -NRn"2-NR7"2- steht,he grouping -NR U -X 3 R 7 - represents a radical of the formula -NR'ΑHR 7 "1 - or a radical of the formula -NR n" 2 -NR 7 "2 -,
die Gruppierung -NR12-X4R8- für einen Rest der Formel -NR12 1-CHR8 1- oder einen Rest der Formel -NR12"2-NR8"2- steht,the grouping -NR 12 -X 4 R 8 - represents a radical of the formula -NR 12 1 -CHR 8 1 - or a radical of the formula -NR 12 "2 -NR 8" 2 -,
R5"1, R6"1, R7"1 und R8"1 unabhängig voneinander jeweils für Wasserstoff, gegebenenfalls durch Amino oder Hydroxy substituiertes Alkyl, für Mercaptomethyl, Methylthioethyl, Carboxymethyl, Carboxyethyl,R 5 "1 , R 6" 1 , R 7 "1 and R 8" 1 are each independently of one another hydrogen, optionally alkyl or amino-substituted alkyl, mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl,
Carbamoylmethyl, Carbamoylethyl, Guanidinopropyl, für gegebenenfalls durch Amino, Nitro, Halogen, Hydroxy oder Alkoxy substituiertes Phenyl oder Benzyl, für Naphthylmethyl, Indolylmethyl, Imidazolylmethyl, Triazolylmethyl, Thienylmethyl, Benzothienylmethyl oder Pyridylmethyl stehen, wobei funktioneileCarbamoylmethyl, carbamoylethyl, guanidinopropyl, for phenyl or benzyl optionally substituted by amino, nitro, halogen, hydroxy or alkoxy, for naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl, thienylmethyl, benzothienylmethyl or pyridylmethyl, functional parts
Gruppen gegebenenfalls geschützt vorliegen können,Groups may be protected,
R9"1, R10"1, R11"1 und R12"1 unabhängig voneinander jeweils für Wasserstoff oder C,-C4- Alkyl stehen, wobei die Restepaare R^/R9"1, R^'/R10 1, R'-'/R11"1 und R^/R12"1 auch jeweils gemeinsam unabhängig voneinander für die Reste -(CH2)3- und -(CH2)4- stehen,R 9 "1 , R 10" 1 , R 11 "1 and R 12" 1 each independently represent hydrogen or C, -C 4 alkyl, wherein the pairs of radicals R ^ / R 9 "1 , R ^ '/ R 10 1 , R' - '/ R 11" 1 and R ^ / R 12 "1 each also independently of one another for the radicals - (CH 2 ) 3 - and - (CH 2 ) 4 - stand,
R5"2 bis R12"2 unabhängig voneinander jeweils für Wasserstoff, jeweils gegebenenfalls durch Halogen substituiertes Alkyl, Hydroxyalkyl, Alkanoyloxyalkyl, Alkoxyalkyl, Arylalkoxyalkyl, Mercaptoalkyl, Alkylthioalkyl, Carboxyalkyl, Alkoxycarbonylalkyl, Aryloxy- carbonylalkyl, Arylalkyloxycarbonylalkyl, Carbamoylalkyl, Amino- alkyl, Alkylaminoalkyl, Dialkylaminoalkyl, Alkoxycarbonylamino- alkyl oder für jeweils gegebenenfalls substituiertes Cycloalkyl, Cycloalkylalkyl, Aryl, Arylalkyl, Hetaryl oder Hetarylalkyl stehen undR 5 "2 to R 12" 2 independently of one another each represent hydrogen, in each case optionally substituted by halogen, alkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, Alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl or for optionally substituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl and
wobei die Restepaare R5"2 R9"2, R6"2/R10"2, R7"2/Rπ"2 und R8"2/R12"2 auch jeweils gemeinsam unabhängig voneinander für die gegebenenfalls durch C,- C4-Alkyl substituierten Reste -(CH2)3- und -(CH2)4- stehen,wherein the pairs of residues R 5 "2 R 9" 2 , R 6 "2 / R 10" 2 , R 7 "2 / R π" 2 and R 8 "2 / R 12" 2 are each also independently of one another for those which may be C, - C 4 alkyl-substituted radicals - (CH 2 ) 3 - and - (CH 2 ) 4 -,
dadurch gekennzeichnet, daß mancharacterized in that one
A) Azadepsipeptide der Formel (II)A) Azadepsipeptides of the formula (II)
in welcher in which
X1, X2, X3, X4 und R1 bis R12 die oben angegebenen Bedeutungen haben,X 1 , X 2 , X 3 , X 4 and R 1 to R 12 have the meanings given above,
in Gegenwart eines Reaktionshilfsmittels und eines Lösungsmittels und gegebenenfalls in Gegenwart einer Base cyclisiert odercyclized in the presence of a reaction auxiliary and a solvent and optionally in the presence of a base or
für den Fall, daß Azacyclodepsipeptide der Formel (I-a) hergestellt werdenin the event that azacyclodepsipeptides of the formula (I-a) are prepared
in welcherin which
X2, X3, X4 unabhängig voneinander jeweils für N oder C-H stehen undX 2 , X 3 , X 4 each independently represent N or CH and
R1 bis R12 die oben angegebenen Bedeutungen haben,R 1 to R 12 have the meanings given above,
man Azadepsipeptide der Formel (III) azadepsipeptides of the formula (III)
in welcherin which
X2, X3, X4 unabhängig voneinander jeweils für N oder C-H stehen undX 2 , X 3 , X 4 each independently represent N or CH and
R1 bis R12 die oben angegebenen Bedeutungen haben,R 1 to R 12 have the meanings given above,
mit Verbindungen der Formel (IV)with compounds of formula (IV)
Y Y-Y Y-
(IV),(IV),
in welcherin which
Y1 für Chlor, Trichlormethoxy, C,-C4- Alkoxy, gegebenenfalls substituiertes Phenoxy, 1-Imidazolyl oder 1,2,4-Triazolyl steht undY 1 represents chlorine, trichloromethoxy, C 1 -C 4 -alkoxy, optionally substituted phenoxy, 1-imidazolyl or 1,2,4-triazolyl and
Y2 für Chlor, Trichlormethoxy, 1-Imidazolyl oder 1,2,4-Triazolyl steht, gegebenenfalls in Gegenwart eines Verdünnungsmittels und gegebenenfalls in Gegenwart eines Reaktionshilfsmittels umsetzt und cyclokondensiert oderY 2 represents chlorine, trichloromethoxy, 1-imidazolyl or 1,2,4-triazolyl, optionally in the presence of a diluent and optionally in the presence of a reaction auxiliary and cyclocondensed or
C) indem man Azadepsipeptide der Formel (V)C) by using azadepsipeptides of the formula (V)
in welcherin which
X2, X3, X4 unabhängig voneinander jeweils für N oder C-H stehen undX 2 , X 3 , X 4 each independently represent N or CH and
R1 bis R12 und Y1 die oben angegebenen Bedeutungen haben,R 1 to R 12 and Y 1 have the meanings given above,
gegebenenfalls in Gegenwart eines Verdünnungsmittels und gegebenenfalls in Gegenwart eines Reaktionshilfsmittels cyclokondensiert.optionally cyclocondensed in the presence of a diluent and optionally in the presence of a reaction auxiliary.
Azacyclodepsipeptide der Formel (I) gemäß Anspruch 1, in welcher dieAzacyclodepsipeptides of formula (I) according to claim 1, in which the
Substituenten die folgenden Bedeutungen haben: R1, R2, R3 und R4 stehen unabhängig voneinander für Wasserstoff, C,-C16- Alkyl, für jeweils gegebenenfalls durch Fluor, Chlor oder Brom substituiertes C,-C6-Alkyl, C2-C8-Alkenyl, C3-C7-Cycloalkyl, C3-C7- Cycloalkyl-C,-C4-alkyl, C,-C6-Hydroxyalkyl, C,-C4-Alkanoyloxy-CI- C6-alkyl, C1-C4-Alkoxy-C,-C6-alkyl, Aryl-CrC4-alkoxy-C,-C6-alkyl,Substituents have the following meanings: R 1 , R 2 , R 3 and R 4 independently of one another stand for hydrogen, C, -C 16 alkyl, for C, -C 6 alkyl, C 2 -C 8 alkenyl which are each optionally substituted by fluorine, chlorine or bromine , C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C, -C 4 -alkyl, C, -C 6 -hydroxyalkyl, C, -C 4 -alkanoyloxy-C I - C 6 -alkyl, C 1 -C 4 alkoxy-C, -C 6 -alkyl, aryl-C r C 4 -alkoxy-C, -C 6 -alkyl,
C,-C6-Mercaptoalkyl, CrC4-Alkylthio-CrC6-alkyl, C,-C4-Alkoxy- carbonyl-C,-C6-alkyl, Aryloxycarbonyl-C,-C6-alkyl, Aryl-C,-C4-alkyl- oxycarbonyl-C,-C6-alkyl, Carbamoyl-C,-C6-alkyl, Amino-CrC6-alkyl, C,-C4-Alkylamino-C,-C6-alkyl, Di-C,-C4-alkylamino-C,-C6-alkyl oder für jeweils gegebenenfalls durch Halogen, Hydroxy, Cyano, C,-C6-C, -C 6 mercaptoalkyl, C r C 4 alkylthio-C r C 6 alkyl, C, -C 4 alkoxycarbonyl-C, -C 6 alkyl, aryloxycarbonyl-C, -C 6 alkyl, Aryl-C, -C 4 -alkyl-oxycarbonyl-C, -C 6 -alkyl, carbamoyl-C, -C 6 -alkyl, amino-C r C 6 -alkyl, C, -C 4 -alkylamino-C, - C 6 -alkyl, di-C, -C 4 -alkylamino-C, -C 6 -alkyl or for each optionally by halogen, hydroxy, cyano, C, -C 6 -
Alkyl, C,-C4-Halogenalkyl, CrC4-Alkoxy, C,-C4-Halogenalkoxy, Benzyloxy oder Silyloxy, das durch C,-C4-Alkyl und/oder Phenyl trisubstituiert ist, substituiertes Aryl, Aryl-C,-C4-alkyl, Hetaryl oder Hetaryl-C,-C4-alkyl.Alkyl, C, -C 4 haloalkyl, C r C 4 alkoxy, C, -C 4 haloalkoxy, benzyloxy or silyloxy which is trisubstituted by C, -C 4 alkyl and / or phenyl, substituted aryl, aryl- C, -C 4 alkyl, hetaryl or hetaryl C, -C 4 alkyl.
R5"1, R6"1, R7"1 und R8"1 stehen unabhängig für Wasserstoff, Methyl, iso-Propyl, iso-Butyl, sec.-Butyl, Hydroxymethyl, 1 -Hydroxyethyl, Mercaptomethyl, 2-Methylthioethyl, 3-Aminopropyl, 4-Aminobutyl, Carb- oxymethyl, 2-Carboxy ethyl, Carbamoylmethyl, 2-Carbamoylethyl, 3- Guanidinopropyl, Phenyl, Benzyl, 4-Hydroxybenzyl, 4-Methoxy- benzyl, 2-Nitrobenzyl, 3 -Nitrobenzyl, 4-Nitrobenzyl, 2-Aminobenzyl, 3-Aminobenzyl, 4-Aminobenzyl, 3,4-Dichlorbenzyl, 4-Iodbenzyl, α- Naphthylmethyl, ß-Naphthylmethyl 3-Indolylmethyl, 4-Imida- zolylmethyl, 1,2,R 5 "1 , R 6" 1 , R 7 "1 and R 8" 1 independently represent hydrogen, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl , 3-aminopropyl, 4-aminobutyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 3-guanidinopropyl, phenyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 3,4-dichlorobenzyl, 4-iodobenzyl, α-naphthylmethyl, ß-naphthylmethyl 3-indolylmethyl, 4-imidazolylmethyl, 1,2,
3-Triazol-l-yl-methyl, 1,2,3-triazol-l-yl-methyl, 1,2,
4-Triazol-l-yl-methyl, 3- Thienylmethyl, 3-Benzothienylmethyl, 2-Pyridylmethyl oder 3-4-triazol-l-yl-methyl, 3-thienylmethyl, 3-benzothienylmethyl, 2-pyridylmethyl or 3-
Pyridylmethyl, wobei funktionelle Gruppen gegebenenfalls geschützt vorliegen können.Pyridylmethyl, where functional groups can optionally be protected.
R9"1, R10"1, R11"1 und R12"1 stehen unabhängig voneinander für Wasserstoff, Methyl oder Ethyl. Die Restepaare R^'/R9"1, R^'/R10"1, R7"'/R1 und R'-'/R12"1 stehen auch jeweils gemeinsam unabhängig voneinander für die Reste -(CH2)3- und -(CH2)4-.R 9 "1 , R 10" 1 , R 11 "1 and R 12" 1 are independently hydrogen, methyl or ethyl. The pairs of radicals R ^ '/ R 9 "1 , R ^' / R 10" 1 , R 7 " '/ R 1 and R' - '/ R 12" 1 also each independently stand for the radicals - (CH 2 ) 3 - and - (CH 2 ) 4 -.
R5"2 bis R12"2 stehen unabhängig voneinander für Wasserstoff, C,-C15-Alkyl, für jeweils gegebenenfalls durch Fluor, Chlor oder Brom substituiertes CrC8-Alkyl, C3-C7-Cycloalkyl, C3-C7-Cycloalkyl-C,-C4-alkyl, C,-C6- Hydroxyalkyl, C,-C4-Alkanoyloxy-CrC6-alkyl, CrC4-Alkoxy-CrC6- alkyl, Aryl-CrC4-alkoxy-CrC6-alkyl, CrC6-Mercaptoalkyl, C,-C4-R 5 "2 to R 12" 2 stand independently of one another for hydrogen, C, -C 15 alkyl, for C r C 8 alkyl optionally substituted by fluorine, chlorine or bromine, C 3 -C 7 cycloalkyl, C 3 -C 7 -cycloalkyl-C, -C 4 -alkyl, C, -C 6 - hydroxyalkyl, C, -C 4 -alkanoyloxy-C r C 6 -alkyl, C r C 4 -alkoxy-C r C 6 - alkyl , Aryl-C r C 4 -alkoxy-C r C 6 -alkyl, C r C 6 -ercaptoalkyl, C, -C 4 -
Alkylthio-C,-C6-alkyl, C -Alkylsulfinyl- - -alkyl, C,-C4-Alkyl- sulfonyl-CrC6-alkyl, Carboxy-C,-C6-alkyl, Carboxyethyl oder Carboxy-tert.-butyl, C,-C4-Alkoxycarbonyl-C,-C6-alkyl, Aryloxy- carbonyl-C , -C6-alkyl, Aryl-C -C4-alkyloxycarbony 1-C [ -C6-alky 1 , Carbamoyl-C,-C6-alkyl, Amino-C,-C6-alkyl, C,-C4-Alkylamino-CrC6- alkyl, Di-(CrC4)-alkylamino-CrC6-alkyl, C,-C4-Alkoxycarbonyl- amino-C,-C6-alkyl, oder für jeweils gegebenenfalls durch Halogen, Hydroxy, Nitro, Cyano, Amino, C,-C4-Alkylamino, Di-(C,-C4)-alkyl- amino, Benzylamino, Dibenzylamino, geschütztes Amino, C,-C6- Alkyl, C,-C4-Halogenalkyl, C,-C4-Alkoxy oder C,-C4-Halogenalkoxy substituiertes Aryl, Aryl-C1-C4-alkyl, Hetaryl oder Hetaryl-CrC4- alkyl, wobei gegebenenfalls eine NH-Funktion im heterocyclischen Ring durch eine Aminoschutzgruppe, wie beispielhaft o.a., derivatisiert sein kann.Alkylthio-C, -C 6 -alkyl, C -alkylsulfinyl- - -alkyl, C, -C 4 -alkyl-sulfonyl-C r C 6 -alkyl, carboxy-C, -C 6 -alkyl, carboxyethyl or carboxy-tert .-Butyl, C, -C 4 -alkoxycarbonyl-C, -C 6 -alkyl, aryloxycarbonyl-C, -C 6 -alkyl, aryl-C -C 4 -alkyloxycarbony 1-C [ -C 6 -alkyl 1 , Carbamoyl-C, -C 6 -alkyl, amino-C, -C 6 -alkyl, C, -C 4 -alkylamino-C r C 6 -alkyl, di- (C r C 4 ) -alkylamino-C r C 6- alkyl, C, -C 4 -alkoxycarbonylamino-C, -C 6 -alkyl, or for each optionally by halogen, hydroxy, nitro, cyano, amino, C, -C 4 -alkylamino, di- (C, -C 4 ) alkylamino, benzylamino, dibenzylamino, protected amino, C, -C 6 alkyl, C, -C 4 haloalkyl, C, -C 4 alkoxy or C, -C 4 haloalkoxy substituted aryl, Aryl-C 1 -C 4 -alkyl, hetaryl or hetaryl-C r C 4 -alkyl, where, if appropriate, an NH function in the heterocyclic ring can be derivatized by an amino protecting group, such as the above.
Die Restepaare R5"2/R9"2, R6"2/R10"2, R7"2/RH-2 und R8" /R12"2 stehen auch jeweils gemeinsam unabhängig voneinander für die gegebenenfalls einfach bis vierfach durch C,-C4-Alkyl substituierten Reste -(CH2)3- und -(CH2)4-. in welcherThe pairs of residues R 5 "2 / R 9" 2 , R 6 "2 / R 10" 2 , R 7 "2 / R H - 2 and R 8" / R 12 "2 are each also independently of one another for the optionally simple to C, -C 4 -alkyl-substituted radicals - (CH 2 ) 3 - and - (CH 2 ) 4 -. in which
R1, R2, R3 und R4 unabhängig voneinander für Methyl stehen, das gegebenenfalls durch Phenyl substituiert ist, das seinerseits durch Halogen, Cyano, Nitro, Amino, Dialkylamino, Morpholino substituiert sein kann,R 1 , R 2 , R 3 and R 4 independently of one another represent methyl, which is optionally substituted by phenyl, which in turn can be substituted by halogen, cyano, nitro, amino, dialkylamino, morpholino,
die Gruppen X^R5, X2-R6, X3-R7, X4-R8 unabhängig voneinander für die Restethe groups X ^ R 5 , X 2 -R 6 , X 3 -R 7 , X 4 -R 8 independently of one another for the radicals
-CH-R5 -CH-R6 -CH-R7 -CH-R8 -CH-R 5 -CH-R 6 -CH-R 7 -CH-R 8
oderor
-N — R -N— R° -N- -N— R°-N - R -N— R ° -N- -N— R °
stehen, in welchenstand in which
R5, R6, R7 und R8 unabhängig voneinander für C,-C4-Alkyl, insbesondere für verzweigtes C4-Alkyl, ganz besonders für i-Butyl stehen,R 5 , R 6 , R 7 and R 8 independently of one another are C 1 -C 4 -alkyl, in particular branched C 4 -alkyl, very particularly i-butyl,
R9, R10, Rn und R12 unabhängig voneinander für C,-C4-Alkyl, insbesondere Methyl stehen.R 9 , R 10 , R n and R 12 independently of one another are C, -C 4 -alkyl, in particular methyl.
5. Verwendung von Aza-Cyclodepsipeptiden der Formel (I) gemäß Anspruch 1 zur Bekämpfung von Endoparasiten. 5. Use of aza-cyclodepsipeptides of the formula (I) according to Claim 1 for combating endoparasites.
6. Verwendung von Aza-Cyclodepsipeptiden der Formel gemäß Anspruch 1 zur Herstellung von endoparasitiziden Mitteln.6. Use of aza-cyclodepsipeptides of the formula according to claim 1 for the preparation of endoparasiticidal agents.
7. Endoparasitizide Mittel gekennzeichnet durch einen Gehalt an Aza- Cyclodepsipeptiden der Formel (I) gemäß Anspruch 1 gegebenenfalls in Mischung mit üblichen Verdünnungs- und Zusatzstoffen. 7. Endoparasiticidal agents characterized by a content of aza-cyclodepsipeptides of the formula (I) according to claim 1, optionally in a mixture with customary diluents and additives.
EP99942898A 1998-09-04 1999-08-23 Aza-cyclodepsipeptides and their use as antiparasitics Withdrawn EP1109794A1 (en)

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