EP0986549A1 - Desoxycyclodepsipeptides et leur utilisation pour la lutte contre les endoparasites - Google Patents

Desoxycyclodepsipeptides et leur utilisation pour la lutte contre les endoparasites

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Publication number
EP0986549A1
EP0986549A1 EP98930724A EP98930724A EP0986549A1 EP 0986549 A1 EP0986549 A1 EP 0986549A1 EP 98930724 A EP98930724 A EP 98930724A EP 98930724 A EP98930724 A EP 98930724A EP 0986549 A1 EP0986549 A1 EP 0986549A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
optionally
benzyl
represents hydrogen
particularly preferably
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Withdrawn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
EP98930724A
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
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE19810017A external-priority patent/DE19810017A1/de
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP0986549A1 publication Critical patent/EP0986549A1/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Withdrawn legal-status Critical Current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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to new deoxycyclodepsipeptides, processes for their preparation and their use for controlling parasites, in particular helminths in the
  • cyclodepsipeptides with antiparasitic activity have been described in the literature.
  • a cyclooctadepsipeptide with the designation PF 1022 is known from EP-A 382 173.
  • 24-membered cyclodepsipeptides are known from EP-A 626 376, EP-A 634 408 and EP-A 718 293. Their anthelmintic effect is not satisfactory in all cases.
  • the invention relates to new deoxycyclodepsipeptides which, through complete or partial chemoselective reduction of the carbonyl groups, increase the amide function
  • the cyclodepsipeptides serving as starting products are alternately composed of 4 ⁇ -
  • ⁇ -Aminocarboxylic acids are natural or synthetic amino acids that can be the same or different. They can be N-alkylated, ie substituted by a straight-chain or branched CC 4 alkyl group, preferably a methyl group, which in turn can be substituted.
  • ⁇ -Hydroxycarboxylic acids are natural and synthetic 2-hydroxycarboxylic acids that can be the same or different.
  • the reduction takes place either directly or in a multi-stage process depending on the reducing agent chosen.
  • Complete or partial reduction means that e.g. in the case of an octadepsipeptide with a number of 4 amidic carbonyl groups, all 4 carbonyl groups concerned or 1 to 3 of these carbonyl groups are reduced.
  • the reduction generally gives mixtures of the deoxydepsipeptides with different degrees of reduction.
  • the individual components are available in different proportions, depending on the stoichiometry and type of reduction process.
  • Uniform deoxydepsipeptides are obtained from the mixtures by using the usual physical or chemical separation processes.
  • the products obtained in the reduction reaction can be converted chemically to further derivatives.
  • deoxycyclodepsipeptides according to the invention can be characterized by formula (I):
  • R 1 and R 2 each independently represent hydrogen, alkyl, hydroxymethyl or alkoxymethyl
  • R 3 and R 4 independently of one another each represent alkyl or phenyl or benzyl which is optionally mono- or polysubstituted by radicals W, where
  • W for halogen, nitro, cyano, carbonyl, alkoxycarbonyl, alkyl,
  • R 13 represents hydrogen or carboxy
  • R 14 represents hydrogen, alkyl, optionally substituted by halogen alkylcarbonyl or benzoyl or
  • R 15 represents hydrogen, alkyl, alkylcarbonyl or benzoyl optionally substituted by halogen or
  • R 16 represents hydrogen, optionally substituted by halogen, hydroxy or alkoxy alkyl, heterocyclylmethyl, formyl, alkylcarbonyl or optionally substituted arylmethyl or benzoyl or the radical -CO-CR 19 R 20 -NR 21 R 22 and
  • R 17 represents hydrogen, optionally alkyl substituted by halogen, hydroxy or alkoxy, heterocyclylmethyl, alkylcarbonyl or optionally substituted arylmethyl or benzoyl,
  • R 16 and R 17 together represent optionally substituted phthaloyl or together with the nitrogen atom to which they are attached represent an optionally substituted mono- or polycyclic, optionally bridged and / or spirocyclic, saturated or unsaturated heterocycle, which is one to 3 more Can contain heteroatoms from the series nitrogen, oxygen and sulfur,
  • Rl 8 represents alkyl or optionally substituted phenyl or benzyl
  • R 19 stands for one of the residues of a natural or synthetic ⁇ -amino acid, functional groups being optionally protected,
  • R 20 represents hydrogen, alkyl or phenyl
  • R 23 represents alkyl, phenyl or benzyl
  • R 21 represents hydrogen or alkyl
  • R 19 and R 21 together represent - (CH 2 ) 3 - and - (CH 2 ) - and R 22 represents hydrogen or a protective group known from peptide chemistry, such as acetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or benzyl (Bzl),
  • R 5 , R 6 , R 7 and R 8 each independently of one another for hydrogen, optionally substituted by amino or hydroxy-substituted alkyl, for mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl, for optionally by amino, nitro, halogen , Hydroxy or methoxy substituted phenyl or benzyl, stand for naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl or pyridylmethyl, where functional groups can optionally be protected and
  • R 9 , R 10 , R 11 and R 12 each independently represent hydrogen or optionally substituted C 1 -C 4 -alkyl.
  • the configuration on the chiral carbons is arbitrary, i.e. the compounds of 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 built up alternately from D-hydroxycarboxylic acids and L-amino acids.
  • the invention further relates to processes for the preparation of the compounds according to the invention, characterized in that cyclodepsipeptides with 24 ring members are produced by fermentation or synthetics
  • the compounds according to the invention are outstandingly suitable for controlling helminths in human and veterinary medicine.
  • R 1 and R 2 independently of one another each preferably represent hydrogen, -CC 6 - alkyl, hydroxymethyl or Ci-C ⁇ -alkoxymethyl.
  • R 3 and R 4 independently of one another each preferably represent CrC 6 alkyl or optionally phenyl or benzyl substituted once or twice by a radical W.
  • R 5 , R 6 , R 7 and R 8 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-guanidino-propyl, phenyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2- Aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 3,4-dichlorobenzyl, 4-iodobenzyl, ⁇ -naphthylmethyl, ⁇ -naphthylmethyl 3-indolylmethyl, 4-imidazolylmethyl, 1,2,
  • W preferably represents halogen, nitro, cyano, carbonyl, -CC 6 alkoxycarbonyl,
  • R 13 preferably represents hydrogen or carboxy.
  • R 14 preferably represents hydrogen, CC 6 alkyl, optionally by fluorine or
  • Chlorine substituted Ci-C ⁇ -alkylcarbonyl or benzoyl Chlorine substituted Ci-C ⁇ -alkylcarbonyl or benzoyl.
  • R 15 preferably represents hydrogen, -CC 6 alkyl, CC 6 - alkylcarbonyl or benzoyl.
  • R 16 preferably represents hydrogen, optionally substituted by halogen, hydroxy or C ö alkoxy-substituted Ci-C ⁇ -alkyl, represents heterocyclylmethyl with a 5- to 6-membered monocyclic or 8- to 10-membered bicycle containing 1 to four hetero atoms with 1 up to 4 nitrogen atoms, 1 to 2 oxygen or 1 to 2 sulfur atoms, for formyl, -C-C 6 alkylcarbonyl or in each case optionally substituted one to three times independently of one another by halogen, nitro, cyano, Ci-C 4 -alkyl or dC -alkoxy Benzyl or benzoyl or for the rest -CO-R 19 R 20 -NR 21 R 22 .
  • R 17 preferably represents hydrogen, optionally by halogen, hydroxy or
  • Ci-C ö -alkoxy-substituted Ci-C ⁇ -alkyl for heterocyclylmethyl with a 5- to 6-membered monocycle or 8 to 10-membered bicyclus with 1 to four heteroatoms with 1 to 4 nitrogen atoms, 1 to 2 oxygen or 1 to 2 sulfur atoms, Ci-C ö alkylcarbonyl or in each case optionally mono- to trisubstituted independently of one another by halogen, nitro, cyano, C -Al- alkyl or C ⁇ -C -alkoxy-substituted benzyl or benzoyl.
  • R 16 and R 17 also preferably together represent phthaloyl substituted by halogen, nitro, cyano, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy or together with the nitrogen atom to which they are attached, optionally for a
  • R 18 preferably represents methyl, ethyl or optionally mono- or disubstituted independently of one another by fluorine, chlorine, nitro, methyl, trifluoromethyl or methoxy or phenyl or benzyl.
  • R 19 preferably represents hydrogen, optionally substituted by amino or hydroxy -CC 4 alkyl or mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl or phenyl optionally substituted by amino, nitro, halogen, hydroxy or methoxy or Benzyl or for naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl or pyridylmethyl, where functional groups can optionally be protected.
  • R 20 preferably represents hydrogen, CC 4 alkyl or phenyl.
  • R 21 preferably represents hydrogen or -CC alkyl.
  • R 19 and R 21 together also preferably represent - (CH 2 ) 3 - and - (CH 2 ) 4 -.
  • R 22 preferably represents hydrogen or a protective group known from peptide chemistry, such as acetyl, tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
  • R 1 and R 2 independently of one another each particularly preferably represent hydrogen, C 1 -C 4 -alkyl, hydroxymethyl or C 1 -C 4 alkoxymethyl.
  • R 3 and R 4 independently of one another each particularly preferably represent phenyl or benzyl optionally substituted by a radical W.
  • R 5 , R 6 , R 7 and R 8 each independently of one another are particularly preferably methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, benzyl, 4-hydroxybenzyl, where hydroxyl groups can optionally be present in a protected manner.
  • R 9 , R 10 , R u and R 12 each independently of one another are particularly preferably
  • W particularly preferably represents fluorine, chlorine, bromine, iodine, nitro, cyano, carbonyl, CC 4 -alkoxycarbonyl, CC 4 -alkyl, -CH (R 13 ) NR 14 R 15 , C 2 -C 6 -alkenyl, CC 4 -alkoxycarbonyl-C 2 -C 4 -alkenyl, C 2 -C 4 -alkenyl, C 1 -C 4 -alkoxycarbonyl-
  • C -C 4 -alkynyl hydroxy, CC 4 -alkoxy, -C-C 4 -alkoxy-C ⁇ -C -alkoxy, C ⁇ -C - alkoxy-C ⁇ -C 4 -alkoxy-C ⁇ -C 4 -alkoxy, di- ( CC 4 -alkyl) -amino-C 2 -C -alkoxy, in each case, if appropriate, once or twice independently of one another by fluorine, bromine, nitro, cyano, CC 4 -alkyl, methyl or ethyl substituted by fluorine and / or chlorine, -C -C 4 alkoxy, trifluoromethoxy, hydroxy or
  • R 13 particularly preferably represents hydrogen or carboxy.
  • R 14 particularly preferably represents hydrogen, -CC alkyl, optionally mono- to trisubstituted by fluorine or chlorine -CC 4 alkylcarbonyl or benzoyl.
  • R 15 particularly preferably represents hydrogen or methyl, ethyl, n-propyl,
  • R 16 particularly preferably represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, simply methyl, ethyl or substituted by chlorine, bromine, hydroxyl, methoxy or ethoxy n-propyl, for furylmethyl, benzofurylmethyl, thienylmethyl, pyrrolylmethyl, indolylmethyl, imidazolylmethyl, pyridylmethyl, for formyl, Cj-Cr alkylcarbonyl or in each case optionally once or twice independently of one another by fluorine, chlorine, bromine, iodine, nitro, cyano, C ⁇ -C -Alkyl or -CC 4 -alkoxy substituted benzyl or benzoyl or for the rest -CO-CR19R20_R21R22
  • R 17 particularly preferably represents hydrogen or, depending on R 16 , the same radical from the series: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, simply by Chlorine, bromine, hydroxyl, methoxy or ethoxy substituted methyl, ethyl or n-propyl, for furylmethyl, benzofurylmethyl, thienylmethyl, pyrrolylmethyl, indolylmethyl, imidazolylmethyl, pyridylmethyl or in each case, if appropriate, once or twice independently of one another by fluorine, chlorine, bromine, iodine, nitro , Cyano, -CC 4 alkyl or CrC 4 alkoxy substituted benzyl.
  • R 16 and R 17 together also particularly preferably represent phthaloyl which is optionally monosubstituted to tetrasubstituted by fluorine, chlorine or methyl and / or monosubstituted or disubstituted by bromine, nitro, cyano, C 2 -C 4 -alkyl or methoxy or together with the nitrogen atom, to which they are bound, for an optionally substituted by fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, methoxy or ethoxy and optionally by C ⁇ - C4-alkylcarbonyl N-acylated, monocyclic with 3 to 8 ring members or bicyclic with 7 to 11 ring members, optionally bridged and / or spirocyclic, optionally condensed with one or two carbocyclic ring systems, saturated or unsaturated heterocycle, the 1 to 3 can contain further heteroatoms from the series 1 to 3 nitrogen atoms, 1 oxygen
  • R 19 particularly preferably represents hydrogen, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, 3-
  • R 20 particularly preferably represents hydrogen, -CC alkyl or phenyl.
  • R 21 particularly preferably represents hydrogen or -CC alkyl.
  • R 19 and R 21 together also particularly preferably represent - (CH 2 ) 3 - and - (CH 2 ) 4 -.
  • R 22 particularly preferably represents hydrogen or a protective group known from peptide chemistry, such as acetyl, tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
  • R 1 and R 2 independently of one another very particularly preferably represent methyl, hydroxymethyl or methoxymethyl.
  • R 3 and R 4 independently of one another each very particularly preferably represent benzyl optionally substituted by a radical W.
  • R 5 , R 6 , R 7 and R 8 each independently of the other are very particularly preferably isopropyl, isobutyl or sec-butyl.
  • R 9 , R 10 , R 11 and R 12 each very particularly preferably represent methyl.
  • W very particularly preferably represents bromine, iodine, nitro, cyano, carbonyl, methoxycarbonyl, ethoxycarbonyl, -CH (R 13 ) NR 14 R 15 , 2-oxopyrrolidin-5-yl, 2-oxopiperidine-6 -yl, 2-methoxycarbonyl-vinyl, 2-methoxycarbonyl-ethynyl, hydroxy, methoxy, 2-methoxy-ethoxy, 2-dimethylamino-ethoxy, in each case, if appropriate, once or twice independently of one another by fluorine, bromine, nitro, cyano, methyl, ethyl , Trifluoromethyl, difluoromethyl, chlorodifluoromethyl, trichloromethyl, methoxy, ethoxy, trifluoromethoxy, hydroxy or amino substituted phenyl, benzyl, phenoxy or benzylmethoxy, for 2-furylme
  • R 13 very particularly preferably represents hydrogen or carboxy.
  • R 14 very particularly preferably represents hydrogen, acetyl, chloroacetyl or
  • R 15 very particularly preferably represents hydrogen.
  • R 14 and R 15 together with the nitrogen atom to which they are attached, very particularly preferably represent 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxo-azepan-1 -yl, succinimino, maleinimino, dimethylmaleinimino, Glutarimino, phthalimino, tetrafluorophthalimino, 4,5-dichlorophthalimino or tetrachlorophthalimino.
  • R 16 very particularly preferably represents hydrogen, methyl, ethyl, n-propyl, isopropyl, 2-chloroethyl, 2-bromoethyl, 2-chloro-l-propyl, 2-hydroxyethyl, 2-methoxyethyl, 2-furylmethyl, 2-thienylmethyl , 2-pyrrolylmethyl, 2-imidazolylmethyl, formyl, acetyl, propionyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, benzoyl, 2-chlorobenzoyl, 4-chlorobenzoyl or 4-nitrobenzoyl or for the residues (a) to (1 ):
  • R 17 very particularly preferably represents hydrogen or a radical from the series which is the same depending on R 16 : methyl, ethyl, n-propyl, Isopropyl, 2-chloroethyl, 2-bromoethyl, 2-chloro-l-propyl, 2-hydroxyethyl, 2-methoxyethyl, 2-furylmethyl, 2-thienylmethyl, 2-pyrrolylmethyl, 2-imidazolylmethyl, benzyl, 2-chlorobenzyl or 4-chlorobenzyl.
  • R 16 and R 17 together also very particularly preferably represent phthaloyl, 3-
  • Heteroatoms from the series can contain 1 or 2 nitrogen atoms, 1 oxygen atom and 1 sulfur atom, such as in particular morpholinyl, pyrrolyl or piperazinyl.
  • R 19 very particularly preferably represents 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.
  • R 21 very particularly preferably represents hydrogen or methyl.
  • R 22 very particularly preferably represents hydrogen or a protective group known from peptide chemistry, such as acetyl, tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
  • Preferred groups of the compounds of the formula (I) according to the invention are the compounds of the formulas (Ia) to (1-d)
  • W 1 and W 2 each independently represent hydrogen or one of the radicals W.
  • Groups of the compounds of the formula (I) which are very particularly preferred according to the invention are the compounds of the formulas (I-1-1), (I-1-2) and (1-4)
  • W 1 and W 2 each independently represent hydrogen or one of the radicals W.
  • W 1 and W 2 are preferably the same radical.
  • Areas and preferred areas can be combined as desired. They apply accordingly to the end products as well as to the preliminary and intermediate products.
  • Saturated or unsaturated hydrocarbon radicals such as alkyl or alkenyl
  • Optionally substituted radicals can be mono- or polysubstituted, whereby in the case of multiple substitutions the substituents can be the same or different.
  • heterocyclyl or hetaryl are used in addition to purely heterocyclic
  • Ring systems also understood those that are condensed with carbocyclic ring systems.
  • cyclodepsipeptides required to carry out processes (a) and (b) according to the invention are known or can be fermented by known methods and / or synthetically produced (cf. for example EP 382 173 A2, JP 05 229997 A (cited in Derwent AN: 93-317424 / 40), EP 626 376 AI, EP 634 408 AI, EP 718 293 AI).
  • the borane further required for carrying out process (a) can be used as a diborane or borane complex such as, for example, borane-tetrahydrofuran or borane-dimethyl sulfide (cf. J. Org. Chem. 38, 912 (1973)).
  • the sulfurization reagent that may be required to carry out process (b) is a thionylation reagent, such as, for example, phosphorus pentasulfide or
  • the complex hydrides which may also be required for carrying out process (b) are, for example, sodium boranates such as sodium borohydride or sodium cyanoboranate or lithium alanates such as lithium aluminum hydride.
  • the further derivatization of the compounds according to the invention is carried out, for example, by the following reactions: alkylation on one or more of the 4 ring nitrogen atoms, nucleophilic or electrophilic aromatic substitution on aromatic radicals, derivatization of substituents on the aromatic radicals.
  • Aromatic radicals are preferably understood in the formula (I) to represent R 3 and R 4 phenyl or benzyl.
  • the introduction, substitution or derivatization of at least one radical W 1 and W 2 other than hydrogen in compounds of the formula (II) is particularly preferably meant.
  • the alkylating agents used are the alkylating agents customary in organic synthesis, such as dialkyl sulfate, in particular C 4 -dialkyl sulfate, optionally substituted alkyl halide, in particular C 4 alkyl halide, alkyl tosylate, in particular C 4 alkyl tosylate, alkyl mesylate, in particular C 4 alkyl mesylate.
  • the alkylation is carried out under the conditions customary in organic synthesis (see also the processes described in EP-A 634 408).
  • amino acids that are optionally activated as amino acid fluorides or by coupling with coupling reagents that are known from peptide chemistry. In these cases, the amino group is protected by protective groups such as e.g. Acetyl, t-butyloxycarbonyl or benzyloxycarbonyl protected.
  • the amino acids can be used in the form of their racemates or their pure enantiomers (D or L form). The L-form of the natural amino acids is preferred.
  • amino acids are e.g. Amino acids of the formula
  • P stands for H or the rest of common protective groups (eg acetyl, Boc, Cb z ), and
  • R ⁇ represents one of the following residues:
  • Nucleophilic aromatic substitution is preferably understood to mean the substitution of fluorine, chlorine, bromine, iodine, nitro by halides, alkanolates or primary or secondary amines or their metal amides.
  • the term encompasses, depending on the reaction conditions and nucleophile, also radical substitution of diazo groups. Examples include diazotization and subsequent hydrolysis in aqueous acid to the phenol derivative or with sulfur nucleophiles to the thiophenol derivative or sulfide, in bulk in the presence of fluoride or tetrafluoroborate as the nucleophile (Balz-Schiemann reaction), and under Sandmeyer conditions, for example with copper (I) halides or cyanide.
  • phenyl or benzyl residues are substituted by fluorine, chlorine, bromine, iodine or nitro. They are preferably reacted with optionally substituted C4 alkanolates or primary or secondary amines of the formula HNRl ⁇ R-V " m which R ⁇ and R ⁇ , which have the meaning given above, or with metal amides.
  • the reaction takes place according to generally known methods of organic chemistry.
  • Electrophilic aromatic substitution is preferably to be understood as meaning nitration, amidoalkylation, sulfation, sulfochlorination, sulfonylation, bromination, iodination, Friedel-Crafts acylation and alkylation.
  • the further derivatization of substituents of the aromatic radicals is carried out by reactions and under reaction conditions which are known from organic chemistry. Examples include: palladium-catalyzed alkynation and alkynylation, reduction of a nitro to the amino group, alkylation of an amino group, in particular monoalkylation with a bifunctional alkylation reagent followed by intramolecular alkylation to a heterocyclic radical of the formula -NR 16 R 17 , alkylation of a Hydroxy group, oxidation of an alkylthio group to the sulfoxide or sulfone.
  • 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 endo-parasites, illness, deaths and reduced performance (for example in the production of meat, milk, wool, hides, eggs, honey, etc.) are to be reduced, so that the use of the active compounds enables more economical and simple animal husbandry is.
  • Pathogenic endoparasites include cestodes, trematodes, nematodes, in particular:
  • 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.,
  • Echinochasmus spp. Hypoderaeum spp., Fasciola spp., Fas- ciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocoe - derius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonismus spp., Dicrocoelium spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchiseter spp., spp., Metagonimus spp ..
  • Stronylus spp. Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus sppum, spp., Oesophag.
  • Stephanurus spp. Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylrong spp., Neost.
  • 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., Cooperemato- spp., Marshallemat dirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp ..
  • 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 have excellent activity against worms such as Haemonchus contortus.
  • Livestock and breeding animals include mammals such as Cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon, birds such as Chickens, geese, turkeys, ducks, fresh and salt water fish such as Trout, carp, eels, reptiles, insects such as Honey bee and silkworm.
  • mammals such as Cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon, birds such as Chickens, geese, turkeys, ducks, fresh and salt water fish such as Trout, carp, eels, reptiles, insects such as Honey bee and silkworm.
  • Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
  • the pets include dogs and cats.
  • the application can be prophylactic as well as therapeutic.
  • the active ingredients are used directly or in the form of suitable preparations enterally, parenterally, dermally, nasally, by treating the environment or with the aid of shaped articles containing active ingredients, e.g. Strips, plates, ribbons, collars, ear tags, limb straps, marking devices.
  • the enteral application of the active ingredients takes place e.g. orally in the form of powder, suppositories, tablets, capsules, fasting, watering, granules, drenches, boluses, medicated feed or drinking water.
  • the dermal application happens e.g. in the form of diving (dipping), spraying (spraying), bathing, washing, pouring (pour-on and spot-on) and powdering.
  • Parenteral use happens e.g. in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants.
  • Suitable preparations are:
  • Solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on formulations, gels;
  • Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; Aerosols and inhalants, molded articles with active ingredients. Solutions for injection are administered intravenously, intramuscularly and subcutaneously.
  • Injection solutions are prepared by dissolving the active ingredient in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives.
  • additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives.
  • the solutions are sterile filtered and filled.
  • solvents physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof.
  • 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 diving (dipping, bathing or washing). These solutions are prepared as described above for the injection solutions.
  • Thickeners are: inorganic thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.
  • Gels are applied to or spread on the skin or placed in body cavities. Gels are produced by adding enough thickening agent to solutions which have been prepared as described for the injection solutions to form a clear mass with an ointment-like consistency.
  • the thickeners specified above are used as thickeners.
  • Pour-on formulations are poured or sprayed onto limited areas of the skin, the active ingredient either penetrating the skin and acting systemically or being distributed over the surface of the body.
  • pour-on formulations are prepared by dissolving, suspending or emulsifying the active ingredient in suitable skin-compatible solvents or solvent mixtures. If necessary, other auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers and adhesives are added.
  • solvents water, alkanols, glycols, polyethylene glycols,
  • Polypropylene glycols glycerin, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones such as acetone, methyl ethyl or ketone, aromatic and / aromatic and / vegetable or synthetic oils, DMF, dimethyl acetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-l, 3-dioxolane.
  • aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol
  • esters such as ethyl acetate, butyl acetate
  • benzyl benzoate ethers
  • alkylene glycol alkyl ethers such as dipropylene glycol mono
  • Dyes are all dyes approved for use on animals, which can be dissolved or suspended.
  • 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 2 -C 2 or other specially selected natural fatty acids, partial glyceride Mix saturated or unsaturated fatty acids which may also contain hydroxyl groups, mono- and diglycerides of C 8 / C 0 fatty acids.
  • Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length C 6 -C 8 , isopropyl myristate, isopropyl palmitate, caprylic / capric alcohol ester of the saturated chain length 2 -C ⁇ 8 , iso-propyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duck pancreas fat, dibutyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures, etc.
  • Fatty alcohols such as isotridecyl alcohol, 2-octyl
  • 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.
  • viscosity-increasing substances and substances that 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, substances which promote absorption, preservatives, antioxidants and light stabilizers.
  • solvents and solvent mixtures may be mentioned as carrier liquids.
  • 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. Common salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides,
  • Organic substances are e.g. Sugar, cellulose, food and animal feed such as milk powder, animal meal, cereal flour and meal, starches.
  • Excipients are preservatives, antioxidants, dyes, which have already been listed above.
  • auxiliaries are lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.
  • lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.
  • the active substances can also be present in the preparations in a mixture with synergists or with other active substances which act against pathogenic endoparasites.
  • Such active ingredients are, for example, L-2,3,5,6-tetrahydro-6-phenyl-imidazolethiazole, benzimidazole carbamates, praziquantel, pyrantel, febantel.
  • Ready-to-use preparations contain the active ingredient in concentrations of 10 ppm to 20% by weight, preferably 0.1 to 10% by weight.
  • Preparations which are diluted before use contain the active ingredient in concentrations of 0.5 to 90% by weight, preferably 5 to 50% by weight.
  • reaction solution was taken up in methyl tert-butyl ether and washed with saturated sodium chloride solution. After the solution had been dried over sodium sulfate and concentrated, the crude product was filtered through a little silica gel (cyclohexane: ethyl acetate 1: 1 to 1: 3). The reduction products were isolated using preparative HPLC.
  • the mixture was then poured onto ice, neutralized by adding solid sodium bicarbonate and then extracted with dichloromethane. The combined extracts were washed with a little water, dried and evaporated.
  • the 26 g of crude product obtained were separated by MPLC.
  • the first main fraction was 1.22 g of simply amidoalkylated compound 20-benzyl-8- [4- (2-oxoazepan-1-methyl) benzyl] -5, 11,17,23-tetraisobutyl-2,4,10 , 14, 16,22-hexamethyl-1, 7, 13, 19-tetraoxa-4, 10, 16,22-tetraaza-cyclotetra-cosan-6,9, 12,18,21,24-hexaone (20-a ), receive.
  • the active ingredients were administered orally as a pure active ingredient in gelatin capsules.
  • the efficiency is determined by quantitatively counting the worm eggs excreted in the faeces before and after the treatment.
  • a complete suspension of egg excretion after treatment means that the worms have been aborted or are so damaged that they no longer produce eggs (effective dose).

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

Abstract

L'invention concerne de nouveaux désoxycyclodepsipeptides de formule (I) dans laquelle C=X<1>, C=X<2>, C=X<3> et C=X<4> représentent indépendamment les uns des autres un des groupes CO, CS ou CH2, l'un au moins de ces groupes représentant CH2, ainsi que leurs mélanges et leurs dérivés. Ces composés sont produits à partir de cyclodepsipeptides ayant 24 chaînons cycliques formés en alternance par des acides alpha -aminocarboxyliques et des acides alpha -hydroxycarboxyliques, par réduction complète ou partiellement chimiosélective des groupes carbonyle de la fonction amide en groupes méthyle par des procédés de réduction appropriés. Les désoxycyclodepsipeptides selon l'invention sont utilisés comme anthelmintiques.
EP98930724A 1997-06-04 1998-05-25 Desoxycyclodepsipeptides et leur utilisation pour la lutte contre les endoparasites Withdrawn EP0986549A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE19723320 1997-06-04
DE19723320 1997-06-04
DE19810017A DE19810017A1 (de) 1997-06-04 1998-03-09 Desoxycyclodepsipetide
DE19810017 1998-03-09
PCT/EP1998/003059 WO1998055469A1 (fr) 1997-06-04 1998-05-25 Desoxycyclodepsipeptides et leur utilisation pour la lutte contre les endoparasites

Publications (1)

Publication Number Publication Date
EP0986549A1 true EP0986549A1 (fr) 2000-03-22

Family

ID=26037114

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Application Number Title Priority Date Filing Date
EP98930724A Withdrawn EP0986549A1 (fr) 1997-06-04 1998-05-25 Desoxycyclodepsipeptides et leur utilisation pour la lutte contre les endoparasites

Country Status (10)

Country Link
US (1) US6355615B1 (fr)
EP (1) EP0986549A1 (fr)
JP (1) JP2002502398A (fr)
CN (1) CN1076349C (fr)
AU (1) AU735424B2 (fr)
BR (1) BR9810412A (fr)
CA (1) CA2292698A1 (fr)
HK (1) HK1028605A1 (fr)
NZ (1) NZ501478A (fr)
WO (1) WO1998055469A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19921887A1 (de) * 1999-05-12 2000-11-16 Bayer Ag Endoparasitizide Mittel
DE19962147A1 (de) * 1999-12-22 2001-06-28 Bayer Ag Schädlingsbekämpfungsmittel / PF 1022-221
DE19962145A1 (de) * 1999-12-22 2001-06-28 Bayer Ag Schädlingsbekämpfungsmittel/Depsipeptide
DE10359798A1 (de) * 2003-12-19 2005-07-21 Bayer Healthcare Ag Cyclohexadepsipeptide zur Bekämpfung von Endoparasiten und ein Verfahren zu ihrer Herstellung
CN101919701B (zh) * 2006-07-14 2012-05-30 Ge医疗系统环球技术有限公司 X射线混合诊断系统
DE102008030764A1 (de) 2008-06-28 2009-12-31 Bayer Animal Health Gmbh Kombination von Amidin-Derivaten mit cyclischen Depsipeptiden
DE102009012423A1 (de) 2009-03-10 2010-09-16 Bayer Animal Health Gmbh Zubereitung auf Ölbasis
WO2012028556A1 (fr) 2010-08-31 2012-03-08 Bayer Animal Health Gmbh Lactones macrocycliques et leur utilisation et leurs combinaisons avec d'autres substances actives
DE102010064245A1 (de) 2010-12-28 2012-06-28 Bayer Animal Health Gmbh Makrocylischen Lactone und deren Verwendung und deren Kombinationen mit anderen Wirkstoffen
PT3298027T (pt) 2015-05-20 2022-01-26 Boehringer Ingelheim Animal Health Usa Inc Compostos depsipéptidos antelmínticos
WO2017116702A1 (fr) 2015-12-28 2017-07-06 Merial, Inc. Composés depsipeptidiques anthelminthiques
BR112019009977A2 (pt) * 2016-11-16 2019-08-27 Boehringer Ingelheim Animal Health Usa Inc compostos depsipeptídicos anti-helmínticos
US11331369B2 (en) * 2017-11-29 2022-05-17 Zoetis Services Llc Endoparasitic depsipeptides
AU2019266197B2 (en) * 2018-05-10 2023-03-02 Zoetis Services Llc Endoparasitic depsipeptides

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO176766C (no) * 1989-02-07 1995-05-24 Meiji Seika Kaisha Fremgangsmåte for fremstilling av en forbindelse med anthelmintaktivitet
JP2874342B2 (ja) * 1992-03-17 1999-03-24 藤沢薬品工業株式会社 デプシペプチド誘導体，その製法およびその用途
DE4317432A1 (de) * 1993-05-26 1994-12-01 Bayer Ag Octacyclodepsipeptide mit endoparasitizider Wirkung
PT718293E (pt) * 1993-09-06 2002-08-30 Fujisawa Pharmaceutical Co Composto ciclodepsipeptidico

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9855469A1 *

Also Published As

Publication number Publication date
CN1259129A (zh) 2000-07-05
JP2002502398A (ja) 2002-01-22
US6355615B1 (en) 2002-03-12
AU8105998A (en) 1998-12-21
WO1998055469A1 (fr) 1998-12-10
NZ501478A (en) 2001-05-25
HK1028605A1 (en) 2001-02-23
AU735424B2 (en) 2001-07-05
BR9810412A (pt) 2000-08-22
CA2292698A1 (fr) 1998-12-10
CN1076349C (zh) 2001-12-19

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