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EP1109794A1 - Aza-cyclodepsipeptides et leur utilisation comme antiparasitaires - Google Patents

Aza-cyclodepsipeptides et leur utilisation comme antiparasitaires

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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
Authority
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.)
Withdrawn
Application number
EP99942898A
Other languages
German (de)
English (en)
Inventor
Hubert Dyker
Jürgen Scherkenbeck
Achim Harder
Norbert Mencke
Georg Von Samson-Himmelstjerna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
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Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP1109794A1 publication Critical patent/EP1109794A1/fr
Withdrawn legal-status Critical Current

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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.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne de nouveaux aza-cyclodepsipeptides de formule (I), dans laquelle X?1, X2, X3 et X4¿ représentent indépendamment N ou C-H, au moins une de ces variables représentant l'azote; leur procédé de fabrication et leur utilisation dans lutte contre les parasites, notamment les helminthes.
EP99942898A 1998-09-04 1999-08-23 Aza-cyclodepsipeptides et leur utilisation comme antiparasitaires Withdrawn EP1109794A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19840320A DE19840320A1 (de) 1998-09-04 1998-09-04 Aza-Cyclodepsipeptide
DE19840320 1998-09-04
PCT/EP1999/006145 WO2000014079A1 (fr) 1998-09-04 1999-08-23 Aza-cyclodepsipeptides et leur utilisation comme antiparasitaires

Publications (1)

Publication Number Publication Date
EP1109794A1 true EP1109794A1 (fr) 2001-06-27

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Country Status (7)

Country Link
EP (1) EP1109794A1 (fr)
JP (1) JP2002524453A (fr)
CN (1) CN1325388A (fr)
AU (1) AU5623599A (fr)
DE (1) DE19840320A1 (fr)
HK (1) HK1042089A1 (fr)
WO (1) WO2000014079A1 (fr)

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DE102008030764A1 (de) 2008-06-28 2009-12-31 Bayer Animal Health Gmbh Kombination von Amidin-Derivaten mit cyclischen Depsipeptiden
DE102009012423A1 (de) 2009-03-10 2010-09-16 Bayer Animal Health Gmbh Zubereitung auf Ölbasis
DE102010064245A1 (de) 2010-12-28 2012-06-28 Bayer Animal Health Gmbh Makrocylischen Lactone und deren Verwendung und deren Kombinationen mit anderen Wirkstoffen
WO2012028556A1 (fr) 2010-08-31 2012-03-08 Bayer Animal Health Gmbh Lactones macrocycliques et leur utilisation et leurs combinaisons avec d'autres substances actives
WO2013187480A1 (fr) * 2012-06-13 2013-12-19 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 Nouveau dérivé depsipeptidique cyclique et agent de lutte contre les organismes nuisibles comprenant ledit dérivé

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DE19612644A1 (de) * 1996-03-29 1997-10-02 Bayer Ag Oxadiazin-Derivate

Non-Patent Citations (1)

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Title
See references of WO0014079A1 *

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WO2000014079A1 (fr) 2000-03-16
HK1042089A1 (zh) 2002-08-02
JP2002524453A (ja) 2002-08-06
DE19840320A1 (de) 2000-03-09
CN1325388A (zh) 2001-12-05
AU5623599A (en) 2000-03-27

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