DE19810017A1 - Deoxycyclodepsipetides - Google Patents

Abstract

The invention relates to novel desoxycyclodepsipeptides of formula (I) in which C=X<1>, C=X<2>, C=X<3> and C=X<4> independently of each other respectively represent one of the CO, CS or CH2 groups, with at least one of these groups representing CH2. The invention also relates to their mixtures and derivatives. Said compounds are produced from cyclodepsipeptides having 24 ring members formed by alternating alpha -amino carboxylic acids and alpha -hydroxy carboxylic acids by complete or partial chemoselective reduction of the carbonyl groups of the amide function into methylene groups, using suitable reduction methods. The desoxycyclodepsipeptides produced according to the invention have an anthelmintic effect.

Description

The invention relates to new deoxycyclodepsipeptides, processes for their preparation and their use for controlling parasites, especially helminths in the Veterinary and human medicine.

Various cyclodepsipeptides with antiparasitic activity are known in the literature wrote. EP-A 382 173 describes a cyclooctadepsipeptide PF 1022 known. From EP-A 626 376, EP-A 634 408 and EP-A 718 293 further 24-membered cyclodepsipeptides known. The anthelmintic effect of which is not satisfactory in all cases.

The invention relates to new deoxycyclodepsipeptides, which are complete or partially chemoselective reduction of the carbonyl groups of the amide function Methylene groups with suitable reduction methods from cyclodepsipeptides with 24 Ring members that alternate from α-aminocarboxylic acids and α-hydroxycarboxylic acids are built up, produced, as well as mixtures and derivatives thereof.

The cyclodepsipeptides serving as starting products are alternately from 4 α-Aminocarboxylic acids and 4 α-hydroxycarboxylic acid units.

α-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 C ₁ -C ₄ alkyl group, preferably a methyl group, which in turn can be substituted.

α-Hydroxycarboxylic acids are natural and synthetic 2-hydroxycarboxylic acids can be the same or different.

Complete or partial chemoselective reduction means that one or more rere amidic carbonyl groups (C = O next to N) can be reduced without the  Ester carbonyl groups (C = O next to O) attacked in the cyclodepsipeptide backbone will.

The reduction takes place either directly or in a multi-stage process in Dependence on the chosen reducing agent.

Complete or partial reduction means that e.g. B. with an octadepsipeptide with a number of 4 amidic carbonyl groups all 4 carbonyl concerned groups or 1 to 3 of these carbonyl groups can be reduced.

Mixtures of deoxydepsipeptides are generally used in the reduction different degrees of reduction. The individual components are in different proportions, depending on the stoichiometry and the type of reduction procedure. Uniform deoxydepsipeptides are obtained from the mixtures Use of the usual physical or chemical separation processes.

The products obtained in the reduction reaction can be added chemically Derivatives are implemented.

The deoxycyclodepsipeptides according to the invention can be characterized by formula (I):

in which
C = X ¹ , C = X ² , C = X ³ and C = X ⁴ each independently represent one of the groups CO, CS or CH ₂ , at least one of these groups representing CH ₂ ,
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, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , alkenyl, alkoxycarbonylalkenyl, alkynyl, alkoxy carbonylalkynyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkoxy alkoxy, dialkylaminoalkoxy, each optionally substituted alyl, Arylalkyl, aryloxy or arylmethoxy, represents heterocyclylmethoxy, -NR ¹⁶ R ¹⁷ , -SO ₂ -NR ¹⁶ R ¹⁷ , -SO ¹⁸ , -S (O) R ¹⁸ or -S (O) ₂ R ¹⁸ ,
R ^{13 represents} hydrogen or carboxy,
R ^{14 represents} hydrogen, alkyl, alkyl carbonyl or benzoyl optionally substituted by halogen or
R ¹³ and R ¹⁴ together represent a radical - (CH ₂ ) _n -CO-, in which n = 2, 3 or 4,
R ^{15 represents} hydrogen, alkyl, alkyl carbonyl or benzoyl optionally substituted by halogen or
R ¹⁴ and R ¹⁵ together represent a radical - (CH ₂ ) _o -CO-, in which o = 3, 4 or 5, a diacyl radical of a C ₄ -C ₆ dicarboxylic acid or, if appropriate, halogen-substituted phthaloyl,
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 substituted by halogen, hydroxyl or alkoxy alkyl, 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 Can contain 3 further heteroatoms from the series nitrogen, oxygen and sulfur,
R ^{18 represents} alkyl or optionally substituted phenyl or benzyl,
R ^{19 represents} one of the residues of a natural or synthetic α-amino acid, functional groups being optionally protected,
R ^{20 represents} hydrogen alkyl or phenyl,
R ¹⁹ and R ²⁰ together for - (CH ₂ ) _p -, where p = 2, 3, 4 or 5, or for - (CH ₂ ) ₂ -NR ²³ - (CH ₂ ) ₂ - wherein R ^{23 is} alkyl , Phenyl or benzyl,
R ^{21 represents} hydrogen or alkyl,
R ¹⁹ and R ²¹ together represent - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ - 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 represent hydrogen, optionally substituted by amino or hydroxy-substituted alkyl, mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl, optionally by amino, nitro, halo , Hydroxy or methoxy substituted phenyl or benzyl, stand for naphthyl methyl, indolylmethyl, imidazolylmethyl, triazolylmethyl or pyridylmethyl, where functional groups may 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 protective groups known from peptide chemistry are e.g. As listed in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 2 ^nd Ed., John Wiley & Sons, New York 1,991th

The configuration on the chiral carbons is arbitrary, i. H. the fiction Compounds of formula (I) are from D- and / or L-configured amino acids and hydroxycarboxylic acids built. The invention relates to pure stereo isomers and mixtures thereof. The connections are preferably made alternately D-hydroxy carboxylic acids and L-amino acids built.

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

• a) with borane (hydrogen boron) or complex hydrides in the presence of Metal salts reduced, or  
• b) reacted with a sulfurization reagent and then with complex Hydrides reduced in the presence of metal salts and the ver obtained according to one of the methods a) or b) Bonds further derivatized if necessary.

It was also found that the compounds of the invention are outstanding are suitable for combating helminths in human and veterinary medicine.

Compounds preferred according to the invention are given by the above-mentioned. Formula (I) defined.

C = X ¹ , C = X ² , C = X ³ and C = X ⁴ each independently of one another preferably represent one of the groups CO, CS or CH ₂ , at least one of these groups representing CH ₂ .

R ¹ and R ² independently of one another each preferably represent hydrogen, C ₁ -C ₆ alkyl, hydroxymethyl or C ₁ -C ₆ alkoxymethyl.

R ³ and R ⁴ independently of one another each preferably represent C ₁ -C ₆ alkyl or optionally phenyl or benzyl which is mono- or disubstituted by a radical W.

R ⁵ , R ⁶ , R ⁷ and RS independently of one another each preferably represent hydrogen, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, 3-aminopropyl, 4 -Aminobutyl, carboxy methyl, 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, α-naphthylmethyl, β-naphthylmethyl 3-indolylmethyl, 4-imidazolylmethyl, 1,2,3-triazol-1-yl-methyl, 1,2 , 4-triazol-1-yl methyl, 2-pyridylmethyl or 4-pyridylmethyl, where functional groups may optionally be protected.

R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each independently preferably represent hydrogen, methyl or ethyl.

W preferably represents halogen, nitro, cyano, carbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkyl, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , C ₂ -C ₆ alkenyl, C ₁ - C ₆ -alkoxycarbonyl-C ₂ -C ₄ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkoxycarbonyl-C ₂ -C ₄ -alkynyl, hydroxy, C ₁ -C ₆ -alkoxy, C ₁ - C ₆ -alkoxy-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alk oxy, di- (C ₁ -C ₆ -alkyl) - amino-C ₂ -C ₆ -alkoxy, each optionally single to triple independently of one another by halogen, nitro, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, hydroxy or Amino substituted phenyl, benzyl, phenoxy or benzylmethoxy, for heterocyclylmethoxy 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 to 2 sulfur atoms , for -NR ¹⁶ R ¹⁷ , -SO ₂ -NR ¹⁶ R ¹⁷ , -SR ¹⁸ , -S (O) R ¹⁸ or -S (O) ₂ R ¹⁸ .

R ¹³ preferably represents hydrogen or carboxy.

R ¹⁴ preferably represents hydrogen C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylcarbonyl or benzoyl optionally substituted by fluorine or chlorine.

R ¹³ and R ¹⁴ together also preferably represent a radical - (CH ₂ ) _n -CO-, where n = 2, 3 or 4.

R ¹⁵ preferably represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl or benzoyl.

R ¹⁴ and R ¹⁵ also preferably together represent a radical - (CH ₂ ) _o -CO-, where o = 3, 4 or 5, a diacyl radical of a C ₄ -C ₆ dicarboxylic acid or optionally substituted by halogen Phthaloyl.

R ¹⁶ preferably represents hydrogen, optionally substituted by halogen, hydroxy or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, for heterocyclylmethyl with a 5- to 6-membered monocyclic or 8- to 10-membered bicycle containing 1 up to four heteroatoms with 1 to 4 nitrogen atoms, 1 to 2 oxygen or 1 to 2 sulfur atoms, for formyl, C ₁ -C ₆ -alkylcarbonyl or in each case optionally up to three times independently of one another by halogen, nitro, cyano, C ₁ -C ₄ -Alkyl or C ₁ -C ₄ -alkoxy-substituted benzyl or benzoyl or for the radical -CO-R ¹⁹ R ²⁰ -NR ²¹ R ²² .

R ¹⁷ preferably represents hydrogen, C ₁ -C ₆ -alkyl optionally substituted by halogen, hydroxy or C ₁ -C ₆ -alkoxy; 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, for C ₁ -C ₆ alkylcarbonyl or in each case optionally up to three times independently of one another by halogen, nitro, cyano, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy-substituted benzyl or benzoyl.

R ¹⁶ and R ¹⁷ also preferably together represent phthaloyl which is 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 bound, optionally by a Halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy substituted and optionally N-acylated monocyclic with 3 to 8 ring members or bicyclic with 7 to 11 ring members, optionally bridged and / or spirocyclic, optionally with one or two carbocyclic ring system condensed, saturated or unsaturated heterocycle, which may contain 1 to 3 further heteroatoms from the series 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom.

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-substituted C ₁ -C ₄ -alkyl or mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl or, if appropriate, by amino, nitro, halogen, hydroxy or methoxy substituted phenyl or benzyl or for naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl or pyridylmethyl, where functional groups can optionally be protected.

R ²⁰ preferably represents hydrogen C ₁ -C ₄ alkyl or phenyl.

R ¹⁹ and R ²⁰ also preferably together represent - (CH ₂ ) _p -, where p = 2, 3, 4 or 5, or - (CH ₂ ) ₂ -NR ²³ - (CH ₂ ) ₂ -, wherein R ^{23 represents} C ₁ -C ₄ alkyl, phenyl or benzyl.

R ²¹ preferably represents hydrogen or C ₁ -C ₄ 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.

C = X ¹ , C = X ² , C = X ³ and C = X ⁴ independently of one another each particularly preferably represent one of the groups CO, CS or CH ₂ , at least one of these groups representing CH ₂ .

R ¹ and R ² independently of one another are each particularly preferably 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 , independently of one another, are each particularly preferably methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, benzyl, 4-hydroxybenzyl, where hydroxyl groups may optionally be protected.

R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each independently of one another are particularly preferably hydrogen methyl.

W particularly preferably represents fluorine, chlorine, bromine, iodine, nitro, cyano, carbonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -alkyl, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , C ₂ - C ₆ -alkenyl, C ₁ -C ₄ -alkoxycarbonyl-C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkenyl, C ₁ -C ₄ -alkoxycarbonyl-C ₂ -C ₄ -alkynyl, hydroxy, C ₁ - C ₄ -alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkoxy, di- (C ₁ -C ₄ -alkyl) -amino-C ₂ -C ₄ -alkoxy, in each case optionally singly or twice independently of one another by fluorine, bromine, nitro, cyano, C ₁ -C ₄ -alkyl, methyl substituted by fluorine and / or chlorine or ethyl, C ₁ -C ₄ alkoxy, trifluoromethoxy, hydroxy or amino substituted phenyl, benzyl, phenoxy or benzylmethoxy, for furylmethoxy, benzofurylmethoxy, thienylmethoxy, pyrrolylmethoxy, indolylmethoxy, imidazolylmethoxy, pyridylmethoxy, -NR ¹⁶ R ¹⁷ or -SO ₂ - NR ¹⁶ R ¹⁷ .

R ¹³ particularly preferably represents hydrogen or carboxy.

R ¹⁴ particularly preferably represents hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylcarbonyl or benzoyl which is optionally mono- to trisubstituted by fluorine or chlorine.

R ¹³ and R ¹⁴ together also particularly preferably represent a radical - (CH ₂ ) _n -CO-, where n = 2, 3 or 4.

R ¹⁵ particularly preferably represents hydrogen or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

R ¹⁴ and R ¹⁵ together also particularly preferably represent a radical - (CH ₂ ) _o -CO-, where o = 3, 4 or 5, a diacyl radical of a C ₄ -C ₆ -di carboxylic acid or optionally by fluorine or chlorine mono- or polysubstituted phthaloyl.

R ¹⁶ particularly preferably represents hydrogen methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, simply methyl, ethyl or n substituted by chlorine, bromine, hydroxyl, methoxy or ethoxy Propyl, for furylmethyl, benzofurylmethyl, thienylmethyl, pyrrolylmethyl, indolylmethyl, imidazolylmethyl, pyridylmethyl, for formyl, C ₁ -C ₄ -alkylcarbonyl or in each case optionally once or twice independently of one another by fluorine, chlorine, bromine, iodine, nitro, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy substituted benzyl or benzoyl or for the radical -CO-CR ¹⁹ R ²⁰ -R ²¹ R ²² .

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, hydroxy, methoxy or ethoxy substituted methyl, ethyl or n-propyl, for furylmethyl, benzofurylmethyl, thienylmethyl, pyrrolylmethyl, indolylmethyl, imidazolylmethyl, pyridylmethyl or in each case, if necessary, once or twice independently of one another by fluorine, chlorine, bromine, iodine Nitro, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy substituted benzyl.

R ¹⁶ and R ¹⁷ together also particularly preferably represent phthaloyl which is optionally mono- to tetrasubstituted by fluorine, chlorine or methyl and / or mono- 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 ₁ -C ₄ -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, which contain 1 to 3 further heteroatoms from the series 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom can.

R ¹⁹ 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, 4-methoxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 3,4-dichlorobenzyl, 4-iodobenzyl, α-naphthylmethyl, β-naphthylmethyl 3-indolylmethyl, 4-imidazolylmethyl, 1,2,3-triazol-1-yl-methyl, 1,2,4-triazol-1-yl-methyl, 2-pyridylmethyl or 4-pyridylmethyl, functional groups being optionally protected.

R ²⁰ particularly preferably represents hydrogen, C ₁ -C ₄ alkyl or phenyl.

R ¹⁹ and R ²⁰ together also particularly preferably represent - (CH ₂ ) _p -, in which p = 2, 3, 4 or 5, or - (CH ₂ ) ₂ -NR ²³ - (CH ₂ ) ₂ -, wherein R ^{23 is} C ₁ -C ₄ alkyl, phenyl or benzyl.

R ²¹ particularly preferably represents hydrogen or C ₁ -C ₄ 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.

C = X ¹ , C = X ² , C = X ³ and C = X ⁴ each independently of the other very particularly preferably represent one of the groups CO or CH ₂ , at least one of these groups representing CH ₂ .

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, meth oxycarbonyl, 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, singly or twice independently of one another by fluorine, bromine, nitro, cyano, methyl, ethyl , Trifluoromethyl, difluoromethyl, chlorodi fluoromethyl, trichloromethyl, methoxy, ethoxy, trifluoromethoxy, hydroxy or amino substituted phenyl, benzyl, phenoxy or benzylmethoxy, for 2-furylmethoxy, 2-thienylmethoxy, 2-pyrrolylmethoxy, -NR ¹⁶ R ¹⁷ or -SO ₂ -NR ¹⁶ R ¹⁷ .

R ¹³ very particularly preferably represents hydrogen or carboxy.

R ¹⁴ very particularly preferably represents hydrogen acetyl, chloroacetyl or benzoyl.

R ¹⁵ very particularly preferably represents hydrogen.

R ¹⁴ and R ¹⁵ , together with the nitrogen atom to which they are attached, also 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-1-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 (l) :

R ¹⁷ very particularly preferably represents hydrogen or one of the same radical from the series, depending on R ¹⁶ : methyl, ethyl, n-propyl, isopropyl, 2-chloroethyl, 2-bromoethyl, 2-chloro-1-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-fluorophthaloyl, 3,4-difluorophthaloyl, 4,5-difluorophthaloyl, 3,6-difluorophthaloyl, tetrafluorophthaloyl, 3-chlorophthaloyl, 4,5-dichlorophthaloyl, tetra chlorophthaloyl, 4-nitrophthaloyl, 3-methylphthaloyl, 4-methylphthaloyl, tetramethylphthaloyl, 4-tert-butylphthaloyl or together with the nitrogen atom to which they are bound, for a fluorine, chlorine, methyl, ethyl, n-propyl, if appropriate , Isopropyl, methoxy or ethoxy substituted and optionally N-acetylated monocyclic with 5 to 8 ring members or bicyclic with 7 to 11 ring members, optionally bridged, optionally with one or two carbocyclic ring system condensed, saturated or unsaturated heterocycle, the 1 to 2 further 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.

Groups of the compounds of the formula (I) which are preferred according to the invention are the compounds of the formulas (Ia) to (1-d)

Groups of the compounds of the formula (I) which are also preferred according to the invention are the compounds of the formula (I-1)

in which
C = X ¹ , C = X ² , C = X ³ and C = X ⁴ each independently have the meanings given above and
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 (I-1-4)

in which
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.

The general or priority ranges listed above nitions or explanations can be among each other, that is, between the respective Areas and preferred areas can be combined as desired. They apply to the end products as well as for the preliminary and intermediate products accordingly.

According to the invention, preference is given to the compounds of the formula (I) in which one Combination of the meanings listed above as preferred (preferred) is present.

According to the invention, particular preference is given to the compounds of the formula (I), in which a combination of the Be listed as particularly preferred above interpretations are available.

According to the invention, very particular preference is given to the compounds of the formula (I) in which a combination of the above as very particularly preferred meanings.  

Saturated or unsaturated hydrocarbon radicals such as alkyl or alkenyl can also in connection with heteroatoms such as e.g. B. in alkoxy, where possible, each straight chain or branched.

Optionally substituted radicals can be mono- or polysubstituted, in the case of multiple substitutions, the substituents are the same or different can.

The terms heterocyclyl or hetaryl are used in addition to purely heterocyclic Ring systems are also understood to mean those that can be used with carbocyclic ring systems are based.

If, for example, PF 1022A [cf. e.g. BJ antibiotic. 45, 692 (1992)] with borohydride / tetrahydrofuran complex, the course of the reaction of process (a) according to the invention can be represented by the following formula:

If, for example, PF 1022A and [2,4-bis (4-methoxyphenyl)] - 1,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson's reagent) are used as starting materials, and in a second reaction step, sodium borohydride is used In the presence of nickel chloride, the course of the reaction of process (b) according to the invention can be represented by the following formula:

For a further derivatization of the compounds according to the invention, for example four-fold reduced PF 1022A is reacted with fuming nitric acid. The course of the reaction can be represented by the following formula:

Those required to carry out processes (a) and (b) according to the invention Cyclodepsipeptides are known or can be fermented by known methods  and / or synthetically produced (cf. e.g. EP 382 173 A2, JP 05 229997 A (cited in Derwent AN: 93-317424 / 40), EP 626 376 A1, EP 634 408 A1, EP 718 293 A1).

The borane further required for carrying out process (a) can be used as diborane or borane complex such as borane tetrahydrofuran or borane di methyl sulfide can be used (see J. Org. Chem 38, 912 (1973)).

Any sulfurization required to carry out process (b) reagent is a thionylation reagent, such as phosphorus pentasulfide or [2,4-bis (4-methoxyphenyl)] - 1,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson-Re agent).

The com, which may also be required to carry out method (b) complex hydrides are, for example, sodium boranates such as sodium borohydride or Na triumcyanoboranate 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 residues, derivatization of substituents on the aromatic residues. 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 (I-1) is particularly preferred.

For the alkylation, compounds of the formula (I) according to the invention are used in which at least one of the radicals R ⁹ , R ¹¹ , R ¹⁰ , R ^{12 is} hydrogen and the other radicals and groups have the meanings and preferred meanings given above.

For the alkylation, preference is also given to using compounds of the formula (I) in which at least one of the radicals R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^{8 represents} optionally substituted phenyl or benzyl. These phenyl or benzyl radicals are substituted for the alkylation by at least one OH, NH ₂ , NHR ¹⁶ or SH group.

The alkylating agents which are customary in organic synthesis are alkylating agents, such as dialkyl sulfate, in particular C _1-4 dialkyl sulfate, optionally substituted alkyl halide, in particular C _1-4 alkyl halide, alkyl tosylate, in particular C _1-4 alkyl tosylate, alkyl mesylate, in particular C _1-4 - Alkyl mesylate used.

The alkylation is carried out under the conditions customary in organic synthesis carried out (see also the methods described in EP-A 634 408).

Acylations of the OH, NH ₂ , NHR ¹⁶ or SH group can be carried out in the customary manner

• 1. Acid chlorides or acid anhydrides, if appropriate in the presence of bases and solvents
• 2. Amino acids which are optionally activated as amino acid fluorides or by coupling with coupling reagents known from peptide chemistry are. In these cases, the amino group is protected in the usual way groups such as B. acetyl, t-butyloxycarbonyl or benzyloxycarbonyl ge protects. The amino acids can be in the form of their racemates or their pure Enantiomers (D or L form) can be used. The L shape is preferred of natural amino acids.

Such amino acids are e.g. B. amino acids of the formula

in which
P stands for H or the rest of common protective groups (e.g. acetyl, Boc, Cb _z ), and
R ^{19 represents} one of the following radicals:
-CH ₃ ,
-CH ₂ CH (CH ₃ ) ₂ ,
- (CH ₂ ) ₄ CH ₃ ,
-CH (CH ₃ ) ₂ ,
- (CH ₂ ) ₂ CH ₃ ,
-C (CH ₃ ) ₃ ,
-CH ₂ Ph,
-Ph,
- (CH ₂ ) ₂ -OH,
-CH (OH) CH ₃ ,
- (CH ₂ ) ₂ SCH ₃ ,
- (CH ₂ ) ₂ CONH ₂ ,
-CH ₂ -CO ₂ H,

In the above formula for amino acids, P and R _{19 can} together for one of the following divalent residues
- (CH ₂ ) ₃ -
- (CH ₂ ) ₄ -
stand.

The nucleophilic aromatic substitution is preferably the substitution of fluorine, chlorine, bromine, iodine, nitro by halides, alkanolates or primary or understood secondary amines or their metal amides. The term also includes the depending on reaction conditions and nucleophile also radical, substitution of Diazo groups. Examples include diazotization and subsequent hydro lysis in aqueous acid to the phenol derivative or with sulfur nucleophiles to the thio phenol derivative or sulfide, in bulk in the presence of fluoride or tetrafluoro borate as a nucleophile (Balz-Schiemann reaction), and under Sandmeyer conditions for example with copper (I) halides or cyanide.

For nucleophilic aromatic substitution, compounds of the formula (I) according to the invention are preferably used, in which at least one of the radicals R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^{8 is} substituted phenyl or benzyl.

For the nucleophilic substitution these phenyl or benzyl residues are substituted by fluorine, chlorine, bromine, iodine or nitro. They are preferably reacted with optionally substituted C _1-4 alkanolates or primary or secondary amines of the formula HNR ¹⁶ R ¹⁷ in which R ¹⁶ and R ¹⁷ have the meaning given above, or with metal amides.

The reaction takes place according to generally known methods of organic chemistry.

For the diazotization and subsequent hydrolysis to the corresponding phenols, thiophenols or sulfides and for reactions of the Balz-Schiemann or Sandmeyer reaction type, compounds of the formula (I) are used in which at least one of the radicals R ³ to R ^{8 is} optionally substituted phenyl or benzyl, at least one of these phenyl or benzyl radicals being substituted by amino. Such connections are according to the z. B. in EP-A 634 408 be described process obtained by nitration of the unsubstituted compounds and subsequent reduction of the nitro group to the amino group.

Under electrophilic aromatic substitution are preferably nitration, amido alkylation, sulfation, sulfochlorination, sulfonylation, bromination, iodination, Understanding Friedel-Crafts acylation and alkylation.

For the electrophilic aromatic substitution, compounds of the formula (I) are used in which at least one of the radicals R ³ to R ^{8 is} phenyl or benzyl. The implementation of these substitutions is e.g. B. in EP-A 634 408 and WO 95/3926. Reference is expressly made to the information given there on starting products, reactions and reaction conditions.

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, especially monoalkylation with a bifunctional alkylation reagent followed by intramolecular alkylation to a heterocyclic radical of the formula -NR ¹⁶ R ¹⁷ , alkylation of a hydroxyl group, Oxidation of an alkyl thio group to the sulfoxide or sulfone.

The active substances 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, disease, deaths and reduced performance (e.g. in the production of meat, milk, wool, skins, eggs, honey, etc.) are to be reduced, so that the use of the active compounds makes them more economical and easier animal husbandry is possible. Pathogenic endoparasites include cestodes, trematodes, nematodes, in particular:
From the order of the Pseudophyllidea z. E.g .: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoorus spp. .
From the order of the Cyclophyllidea z. For example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosmsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyra spp., Bertiella spp., Taenia spp. , Echino coccus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp. .
From the subclass of Monogenea z. For example: Cyrodactylus spp., Dactylogyrus spp., Polystoma spp. .
From the subclass of Digenea z. For example: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma sppium, Echinopary, Echinopary. , Hypoderaeum spp., Fasciola spp., Fas ciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp., Param phistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocotyle spp., Fischpp derothy spp ., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonismus spp., Dicrocoelium spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Heterophyes spp. .
From the order of the Enoplida z. For example: Trichuris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp. .
From the order of the Rhabditia z. E.g. Micronema spp., Strongyloides spp. .
From the order of Strongylida z. E.g .: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp.,. , Ancylostoma spp., Uncinaria spp., Buno stomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Neostrongylus spp. Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroidpp ., Marshallagia spp., Cooperia spp., Nemato dirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp. .
From the order of the Oxyurida z. For example: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp. .
From the order of Ascaridia z. For example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp. .
From the order of the Spirurida z. E.g .: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracun culus spp. .
From the order of the Filariida z. E.g .: Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Oncho cerca spp. .
From the group of the Gigantohynchida z. For example: Filicollis spp., Moniliformis spp., Macra canthorhynchus spp., Prosthenorchis spp.

For example, the active compounds according to the invention show excellent activity against worms like Haemonchus contortus.

The livestock and breeding animals include mammals such as B. cattle, horses, sheep, Pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as B. mink, chinchilla, raccoon, birds such. B. chickens, geese, turkeys, Ducks, freshwater and saltwater fish such as B. trout, carp, eels, reptiles, insects ten such as B. honey bee and silkworm.

Laboratory and experimental animals include mice, rats, guinea pigs, gold 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 accessories riding enterally, parenterally, dermally, nasally, by treating the environment or with the help of active ingredient-containing shaped bodies such. B. strips, plates, ribbons, collars, Ear tags, limb straps, marking devices.

The enteral application of the active ingredients happens, for. B. orally in the form of powder, Suppositories, tablets, capsules, fasting, watering, granules, drenches, boluses, medi feed or drinking water. The dermal application happens for. B. in the form of Diving (dipping), spraying (spraying), bathing, washing, pouring (pour-on and spot-on) and powdering. Parenteral use happens e.g. B. in the form injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implant tate.

Suitable preparations are:
Solutions such as injection solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, infusion formulations, gels;
Emulsions and suspensions for oral or dermal use and for injection; Semi-solid preparations;
Formulations in which the active ingredient is processed in an ointment base or in an oil in water or water in oil emulsion base;
Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; Aerosols and inhalants, molded articles containing active ingredients.

Solutions for injection are administered intravenously, intramuscularly and subcutaneously.

Injection solutions are made by mixing the active ingredient in a suitable solvent solvent is dissolved and possibly additives such as solubilizers, acids, bases, Buffer salts, antioxidants, preservatives can be added. 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, glycerin, hydrocarbons substances, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures of the same.

The active ingredients can optionally also be found in physiologically compatible plants Dissolve common or synthetic oils that are suitable for injection.

The following may be mentioned as solubilizers: solvents which dissolve the active ingredient in the Promote major solvents or prevent them from failing. 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 made according to previous Ver applied orally to the application concentration. Oral solutions and Concentrates are prepared as described above for the injection solutions, where when sterile work can be dispensed with.

Solutions for use on the skin are dripped on, spread on, on rubbed, sprayed on, sprayed on or by diving (dipping, bathing or washing ) applied. These solutions are the same as for the injection solutions wrote manufactured.

It may be advantageous to add thickeners during manufacture.  

Thickeners are: inorganic thickeners such as bentonites, colloidal Silicic acid, aluminum monostearate, organic thickeners such as cellulose deri vate, polyvinyl alcohols and their copolymers, acrylates and metacrylates.

Gels are applied or spread onto the skin or into body cavities brings. Gels are made by using solutions similar to those used for injection described have been prepared with so much thickener added, that a clear mass with ointment-like consistency is created. As a thickener the thickeners specified above are used.

Pour-on formulations are poured onto limited areas of the skin or sprayed on, the active ingredient either penetrating the skin and acting systemically or spread over the surface of the body.

Infusion formulations are made by placing the active ingredient in suitable skin compatible solvents or solvent mixtures dissolved, suspended or is emulsified. If necessary, other auxiliaries such as dyes are resorbed Promotional substances, antioxidants, light stabilizers, adhesives added.

The following may be mentioned as solvents: water, alkanols, glycols, polyethylene glycols, Polypropylene glycols, glycerin, aromatic alcohols such as benzyl alcohol, phenyl ethanol, 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 mono-butyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and / or ali phatic hydrocarbons, vegetable or synthetic oils, DMF, dimethyl acetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1,3-dioxolane.

Dyes are all dyes approved for use on animals that are dissolved or can be suspended.

Resorption promoting substances are e.g. B. 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. B. substances from the class of benzophenones or novantisole acid.

Adhesives are e.g. B. cellulose derivatives, starch derivatives, polyacrylates, natural poly mers like alginates, gelatin.

Emulsions can be used orally, dermally or as an injection.

Emulsions are either water in oil or oil in water.

They are made by either the active ingredient in the hydrophobic or dissolved in the hydrophilic phase and this with the help of suitable emulsifiers and optionally other auxiliaries such as dyes, absorption-promoting substances, Preservatives, antioxidants, light stabilizers, viscosity-increasing substances, homogenized with the solvent of the other phase.

The 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 mix saturated or unsaturated fatty acids, possibly also hydroxyl groups, mono- and diglycerides of C ₈ / C ₁₀ 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 ₁₆ -C ₁₈ , isopropyl myristate, isopropyl palmitate, caprylic / capric alcohol esters of saturated fatty acid length ₁₂ -C ₁₈ , 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 and others
Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids such as B. oleic acid and its mixtures.

The following can be mentioned as the hydrophilic phase:
Water, alcohols such as B. propylene glycol, glycerin, sorbitol and their mixtures.

The following may be mentioned as emulsifiers:
non-ionic surfactants, e.g. B. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkyl phenol polyglycol ether;
ampholytic surfactants such as di-Na-N-lauryl-β-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.

The following may be mentioned as further auxiliaries: viscosity-increasing agents and the emulsion stabi lizing substances 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 acid drid, polyethylene glycols, waxes, colloidal silica or mixtures of the above led fabrics.

Suspensions can be used orally, dermally or as an injection. you will be prepared by optionally taking the active ingredient in a carrier liquid Addition of other auxiliary substances such as wetting agents, dyes, absorption-promoting substances, Preservatives, antioxidants, sunscreen suspended.

Carrier liquids are all homogeneous solvents and solvents called mix.  

The surfactants specified above may be mentioned as wetting agents (dispersants).

Further additives mentioned are those mentioned above.

Semi-solid preparations can be administered orally or dermally. You under differ only from the suspensions and emulsions described above their higher viscosity.

The active ingredient is used with suitable carriers to produce solid preparations optionally mixed with additives and in the desired shape brought.

All physiologically compatible solid inert substances may be mentioned as carriers. All such serve inorganic and organic substances. Inorganic substances are e.g. B. Common salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, Silicas, clays, precipitated or colloidal silicon dioxide, phosphates.

Organic substances are e.g. B. sugar, cellulose, food and feed such as Milk powder, animal meal, cereal flour and meal, starches.

Excipients are preservatives, antioxidants, dyes that are already on have been listed above.

Other suitable auxiliaries are lubricants and lubricants such as. B. Magnesium stearate, stearic acid, talc, bentonite, decay promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such. B. starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.

The active substances can also be mixed with synergists or with other active substances that act against pathogenic endoparasites. Such active ingredients are e.g. B. L-2,3,5,6-tetrahydro-6-phenyl-imidazolothiazole, Benz imidazole carbamates, praziquantel, pyrantel, febantel.  

Ready-to-use preparations contain the active substance in concentrations of 10 ppm to 20% by weight, preferably from 0.1 to 10% by weight.

Preparations that are diluted before use contain the active ingredient in Kon concentrations of 0.5 to 90 wt .-%, preferably from 5 to 50 wt .-%.

In general, it has proven advantageous to use amounts of about 1 to 100 mg Active ingredient per kg body weight per day to achieve effective results submit.

The manufacture and use of the active compounds according to the invention start out the following examples.  

Manufacturing examples example 1 (Method a)

To a solution of 14.25 g (15 mmol) of 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19- tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-3,6,9,12,15,18,21,24-octaone (PF 1022) in 150 ml of dry tetrahydrofuran (THF) became 51 ml of a 1 molar Solution of borane-THF complex in THF quickly dripped. The solution was refluxed for 1 hour. The mixture was then cooled in an ice bath and hydrolyzed by adding 13.35 g (150 mmol) of 2-amino-2-methylpropanol. It was stirred for 30 min, then semi-saturated saline was added and extracted with ethyl acetate. After drying over sodium sulfate and concentrating, the product was purified by column chromatography (silica gel; cyclohexane: ethyl acetate = 10: 1) and crystallization from n-hexane / ethyl acetate. 4.97 to 6.08 g (34 to 41% of theory) of direct reduction product 8.20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl were obtained -1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cy clotetracosan-6,9,12,18,21,24-hexaone (1-b) as a colorless solid with melting point 149 to 150 ° C.
MS (FAB): m / z (nominal mass): 921 (M + H⁺)
HR-MS:
calcd for C ₅₂ H ₈₀ N ₄ O ₁₀ Na 943.5772
found 943.5776.

From the secondary fractions and the mother liquor from the crystallization, the mono-, tri- and tetra-reduction products were isolated by means of further column chromatography and crystallization.
Monoreduction product (1-a):
Mp: 130 to 132 ° C
MS (FAB): m / z (nominal mass): 935 (M + H⁺), 957 (M + Na⁺)
HR-MS: calcd for C ₅₂ H ₇₈ N ₄ O ₁₁ Na 957.5565
found 957.5565
Trireduction product (1-c):
MS (FAB): m / z (nominal mass): 907 (M + H⁺), 929 (M + Na⁺)
Tetrareduction product (1-d) = (Ex. 2):
MS (FAB): m / z (nominal mass): 893 (M + H⁺); 915 (M + Na⁺)

Example 2 (Method a)

4.75 g (5 mmol) of PF 1022 were reacted in 10 ml of THF with 100 ml of a 1-molar solution of borane as in Example 1 and worked up. After chromatography, 0.75 g (17% of theory) of tetrar reduction product 8,20-dibenzyl-5,11,17,23-tetra-isobutyl-2,4,10,14,16, 22-hexamethyl-1,7 , 13,19-tetraoxa-4,10,16, 22-tetraaza-cyclote tracosan-6,12,18,24-tetraone as a light yellow viscous oil.
MS (FAB): m / z (nominal mass): 893 (M + H⁺); 915 (M + Na⁺)

Example 3

2.68 g (2.91 mmol) 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexa methyl-1,7,13,19-tetraoxa- 4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone (e.g. according to example 1) were carried into smoking nitric acid at -10 ° C. The mixture was stirred at 0 ° C. for 2 h, poured onto ice and made basic with sodium carbonate. After extraction of the aqueous phase three times with dichloromethane, drying over sodium sulfate and evaporation of the solvent, 2.97 g (100% of theory) of a mixture of the regioisomeric 5,11,17,23-tetraisobutyl-2,4,10,14 , 16,22-hexamethyl-8,20-bis- (nitrobenzyl) -1,7,13,19-tetraoxa-4,10,16,22-te traaza-cyclotetracosane-6,9,12,18,21, Obtained 24-hexaone. The individual isomers can be separated chromatographically on the next reaction stage (hydrogenation, Ex. 4).
MS (MALDI): m / z (nominal mass): 1011 (M + H⁺).

Example 4

2.97 g (2.91 mmol) 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-8,20-di- (4-nitrobenzyl) -1,7, 13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone (e.g. according to example 3) were in a mixture of 40 ml of ethyl acetate and 8 ml of ethanol dissolved, mixed with 297 mg of palladium hydroxide on carbon (20% Pd) and hydrogenated for 6 h at room temperature and normal pressure. The catalyst is filtered off and washed with ethyl acetate. The filtrate was concentrated and chromatographed on silica gel using the mobile phase cyclohexane / ethyl acetate (2.5: 1). 1.52 g (54% of theory) of the isomeric 8,20-bis (aminobenzyl) -5,11,17,23-tetraisobutyl-2,4,1O, 14,16,22-hexamethyl 1,7,13,19-tetraoxa-4,10,16,22-tetraazatetracosan-6,9, 12,18,21,24-hexaone.
MS (MALDI): m / z (nominal mass): 951 (M + H⁺).

Preparative HPLC of the isomer mixture (mobile phase: acetonitrile / water = 40:60 + 1 trifluoroacetic acid) gave 639 mg (23% of theory) of the bis-para product 8.20-bis- (4-aminobenzyl) -5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-th traoxa-4,10,16,22-tetraazatetracosane-6,9,12,18,21,24-hexaone (4-a), 307 mg (11%) of the ortho-para isomer (4-b) and 27 mg (1%) of the bis-ortho isomer.  

Example 5

607 mg (0.638 mmol) 8,20-bis- (4-aminobenzyl) -5,11,17,23-tetraisobutyl-2,4,10,14, 16,22-hexamethyl-1,7,13,19- tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18, 21,24-hexaone (e.g. according to example 4, compound 4-a), 529 mg (3.83 mmol) Potassium carbonate and 952 mg (6.38 mmol) sodium iodide are placed in 10 ml dimethylformamide (DMF), mixed with 621.8 mg (2.68 mmol) bis (2-bromethyl) ether at room temperature and 20 h at 30 ° C stirred. The reaction mixture was concentrated in vacuo. The residue was taken up in water and extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel; cyclohexane: ethyl acetate = 2: 1) gave 453 mg (65% of theory) of 5,11,17,23-tetraisobutyl-2,4,10,14, 16,22-hexamethyl-8 , 20-bis- [4- (N-morpholinyl) benzyl] -1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24- hexaon.
MS (MALDI): m / z (nominal mass): 1091 (M + H⁺).

Example 6

Analogously to Example 5, 227.8 mg of 8- (4-aminobenzyl) -20- (2-aminobenzyl) - 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl- 1,7,13,19-tetraoxa-4,10,16,22-tetraazatetracosane-6,9,12,18,21,24-hexaone (e.g. according to example 4, compound 4-b) 196 mg ( 75% of theory) 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-8- [4- (N-morpholinyl) benzyl] -20- [2- ( N-morpholinyl) benzyl] -1,7,13,19-tetraoxa-4,10,16,22-th traaza-cyclotetracosane-6,9,12,18,21,24-hexaone.
MS (MALDI): m / z (nominal mass): 1091 (M + H⁺)

Example 7 (Method a)

223 mg (0.2 mmol) 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-8,20-bis- [4- (N-morpholinyi) benzyl] -1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane 3,6,9,12,15,18,21,24-octaon (cf. EP 634 408 A1) were in 2 ml of dry THF solved. At room temperature, 2.16 ml of a 1M solution of borane-THF complex added in THF. The solution was refluxed for 1.5 hours. Man cooled to 0 ° C, gave 249 mg (2.8 mmol) 2-amino-2-methyl-1-propanol in 2 ml dry nem THF and stirred for about 1 h. The reaction solution was in methyl tert-butyl ether added and washed with saturated saline. After drying NEN the solution over sodium sulfate and the concentration was the crude product a little silica gel filtered (cyclohexane: ethyl acetate 1: 1 to 1: 3). The reduction pro Products were isolated using preparative HPLC.

Direct reduction product 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-8,20-bis- [4- (N-morpholinyl) benzyl] -1,7,13,19- tetraoxa-4,10,16,22-tetraaza-cyclotetra cosan-6,9,12,18,21,24-hexaone (7-b) = (Ex. 5): 37 mg
MS (MALDI): m / z (nominal mass): 1091 (M + H⁺), 1113 (M + Na⁺)

Trireduction product 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-8,20-bis- [4- (N-morpholinyl) benzyl] -1,7,13,19- tetraoxa-4,10,16,22-tetraaza-cyclotetra cosan-6,9,12,18,24-pentaon (7-c): 10 mg
MS (MALDI): m / z (nominal mass): 1077 (M + H⁺)

Tetrar Reduction Product 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-8,20- bis- [4- (N-morpholinyl) benzyl] -1,7,13,19- tetraoxa-4,10,16,22-tetraaza-cyclo-tetracosane-6,12,18,24-tetraone (7-d): 22 mg
MS (MALDI): m / z (nominal mass): 1063 (M + H⁺); 1085 (M + Na⁺)

Example 8 (Method a)

0.57 g (0.5 mmol) 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-8,20-bis- [4- (2-furylmethoxy) benzyl] -1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-3,6, 9,12,15,18,21,24-octaone were reacted and worked up analogously to Example 1. 245 mg (44% of theory) of direct reduction product 5,11,17,23-tetraisobutyl-2,4,10, 14,16,22-hexamethyl-8,20-bis- [4- (2-furylmethoxy ) benzyl] -1,7,13,19-tetraoxa-4,10, 16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone (8-b) from melting point 116 to 119 ° C received.
MS (ESI): m / z (nominal mass): 1113 (M + H⁺), 1135 (M + Na⁺).

Furthermore, 76 mg monoreduction product and 32 mg tetrareduction product receive.  

Example 9 (Method a)

37.5 ml were added to a solution of 30.88 g (31.5 mmol) of PF 1022 in 190 ml of THF (37.5 mmol) of a 1 molar solution of borane-THF complex in THF quickly dripped. The solution was refluxed for 2 hours. Then to 0 ° C cooled and hydrolyzed by adding 30 ml of 2-amino-2-methylpropanol. It were stirred for 45 min at room temperature, then semi-saturated sodium chloride added solution and extracted 3 × with ethyl acetate. After drying over magnesium The crude product was sulfate and evaporated over a glass filled with silica gel frit (∅ = 10 cm) filtered with cyclohexane / ethyl acetate (15: 1 to 7: 1). There were 9.11 g (31% of theory) 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl- 1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracoan-6,9,12,15,18,21,24-heptaon (1-a) (see Ex. 1).  

Example 10 (Method a)

2.99 g (3.25 mmol) of 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexa methyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexa on (1-b) (e.g. from Ex. 1) became 1 molar in 20 ml THF with 9.75 ml (9.75 mmol) Borane solution implemented analogously to Example 1. After column chromatography (silica gel, ∅ = 4.5 cm, 1 = 25 cm; Cyclohexane: ethyl acetate 50: 1 to 5: 1) 0.72 g of tetra reduction product 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexame thyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,12,18,24-tetraone (2) (see Example 2), 0.22 g trireduction product (1-c) and 0.91 g unreacted Get raw material.  

Example 11

1.34 g (3.6 mmol) of O-benzyl-Nt-butoxycarbonyl-L-tyrosine were placed in 15 ml of aceto nitrile and 485.7 mg (4.8 mmol) of triethylamine and 520.9 mg (4.8 mmol) ethyl chloroformate added. After stirring for 2 minutes at room temperature, a solution of 1.43 g (1.5 mmol) of 8.20-bis (4-aminobenzyl) - 5,11,17,23-tetraisobutyl-2,4,10,14 , 16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone (e.g. from example 4 ) in 3 ml of aceto nitrile and stirred for 3-4 h at room temperature. The reaction mixture was taken up in ethyl acetate, washed with half-concentrated brine, dried and evaporated in vacuo. Column chromatography 16269 00070 552 001000280000000200012000285911615800040 0002019810017 00004 16150tography (∅ = 4.5 cm, 1 = 20 cm; cyclohexane: ethyl acetate 2: 1) gave 1.81 g (73% of theory) 8.20- bis- [4 -β- (4-benzyloxyphenyl) -α-tert-butoxycarbonylamino-propionylaminobenzyl] - 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19 -tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone obtained.
MS (ESI): m / z (nominal mass): 1657 (M + H⁺).

Example 12

829.0 mg (0.50 mmol) of double-protected tyrosine derivative from Example 12 and 83 mg of 10% palladium / carbon catalyst were placed in 5 ml of ethyl acetate. It was stirred with hydrogen under normal pressure at room temperature. After TLC control, additional catalyst and glacial acetic acid were added to complete the hydrogenolysis. After another conversion check, the catalyst was filtered through a filter aid (Cellite®, the filtrate was evaporated and purified by column chromatography (∅ = 4.5 cm, 1 = 10 cm; cyclohexane: ethyl acetate 2: 1). 0.52 g ( 70% of theory) 8,20-bis- [4-α-tert-butoxycarbonylamino-β- (4-hydroxyphenyl) propionylaminobenzyl] -5,11,17,23-tetraisobutyl-2,4,10 , 14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone.
MS (ESI): m / z (nominal mass): 1477 (M + H⁺), 739 (M + 2H ²⁺ ).

Example 13

475.6 mg (0.50 mmol) 8.20-bis- (4-aminobenzyl) -5,11,17,23-tetraisobutyl-2,4,10, 14,16,22-hexamethyl-1,7, 13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12, 18,21,24-hexaone (e.g. from example 4) were placed in 1.5 ml of glacial acetic acid and mixed with 162.9 mg (1.1 mmol) of phthalic anhydride boiled under reflux for 5 h. It was evaporated, the residue was taken up in tert-butyl methyl ether (MTBE) and washed with sodium hydrogen carbonate and saturated sodium chloride solution. After drying with sodium sulfate, the mixture was again evaporated and then filtered through a short silica gel column (∅ = 3 cm, 1 = 5 cm) with cyclohexane / ethyl acetate 2: 1. Evaporation of the filtrate gave 0.55 g of slightly contaminated 8,20-bis (4-phthalimidobenzyl) - 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7, 13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone as a yellow foam.
MS (ESI): m / z (nominal mass): 1211 (M + H⁺), 1233 (M + Na⁺)

Example 14

1.427 g (1.50 mmol) 8.20-bis (4-aminobenzyl) -5,11,17,23-tetraisobutyl-2,4,10, 14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12, 18,21,24-hexaone (e.g. from Example 4) were placed in 7.5 ml of dry toluene and 594.6 mg (582 µl; 4.5 mmol) 2,5-dimethoxytetrahydrofuran added, at 0 ° C 851.7 mg (3.0 mmol) of phosphorus pentoxide were added, initially with this Temperature, then stirred at room temperature. Because sales are incomplete was (TLC control) was again cooled to 0 ° C and again the same amounts 2,5-Dimethoxytetrayhydrofuran and phosphorus pentoxide added and react ge to let. For working up, water was added and the mixture was extracted with ethyl acetate combined extracts dried and evaporated. To complete the Extrak tion, the aqueous phase was then again poured out with dichloromethane shakes. Then the combined residues of the organic extracts by column chromatography (∅ = 4 cm, 1 = 28 cm; cyclohexane: ethyl acetate 3: 1) cleans. 353.9 mg (22% of theory) of 8.20-bis- [4- (1-pyrrolyl) benzyl] - 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22- tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone obtained.

MS (ESI); m / z (nominal mass): 1051 (M + H⁺), 1073 (M + Na⁺).  

Example 15

100 mg (0.1048 mmol) 8.20-bis- (4-aminobenzyl) -5,11,17,23-tetraisobutyl-2,4,10, 14,16,22-hexamethyl-1,7,13, 19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6, 9,12, 18,21,24-hexaone (e.g. from example 4) were dissolved in 1 ml trifluoroacetic acid and with 16.6 mg (0.24 mmol) sodium nitrite added. The mixture was warmed to 60 ° C. and stirred for 1 h. The mixture was then concentrated in vacuo and, to remove the acid residues, evaporated 3 × in each case after the addition of dry toluene in vacuo. The residue was taken up in 5 ml of dioxane, 1 ml of water and 175 mg of sodium carbonate were added and the mixture was stirred overnight. After adding more water, the mixture was extracted with ethyl acetate. The combined extracts were dried, concentrated and filtered with cycloexane / ethyl acetate mixture (3: 1) through a Pasteur pipette filled with silica gel. The crude product was purified on a semi-preparative HPLC column (RP phase; acetonitrile / water). 27.2 mg of 8.20-bis (4-hydroxybenzyl) - 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19- tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone, which was identified by mass and NMR spectroscopy ( ¹ H, 500 MHz).
MS (MALDI): m / z (nominal mass): 953 (M + H⁺), 975 (M + Na⁺)

Example 16

871.9 mg (6.309 mmol) of potassium carbonate, 1.568 g (10.52 mmol) of sodium iodide were placed in 20 ml of DMF. For this purpose, 613 mg (415 μl; 4.41 mmol) of 1-bromo-2-methoxyethane and a solution of 1.00 g (1.052 mmol) of 8.20-bis (4-aminobenzyl) - 5.11.17, 23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21, 24-hexaone (e.g. from example 4) added to 5 ml of DMF, warmed to 80 ° C. and stirred for a further 20 h. A further 306 mg (2.20 mmol) of 1-bromo-2-methoxyethane were then added and the mixture was left to react at 100 ° C. for 3 h. After cooling, it was taken up in water and extracted with dichloromethane. The combined filtrates were concentrated, dried and then separated by "flash chromatography" (column: Säule = 4.5 cm, 1 = 25 cm; silica gel; cyclohexane: ethyl acetate = 2: 1). The 462.5 mg residue of 497 mg evaporation residue of the middle main fraction was further separated after several analyzes by mass and NMR spectroscopy on a semi-preparative HPLC column (RP phase; acetonitrile / water). In the order of elution, 204.9 mg of double alkylated compound 8,20-bis (4-β-methoxyethylaminobenzyl) -5,11,17,23-tetraisobutyl-2,4,10,14,16,22- hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza cyclotetracosane-6,9,12,18,21,24-hexaone (16-a), 151.2 mg triple alkylated compound 8- [4-Bis- (β-methoxyethyl) aminobenzyl] -20- (4-β-methoxyethylaminobenzyl) - 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1 , 7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone (16-b) and 24.8 mg quadruple alkylated compound 8, 20-bis- [4-bis- (β-methoxyethyl) aminobenzyl) -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 (16-c). The last fraction from preparative chromatography (118 mg) contained predominantly triple alkylated compound (16-b).
MS (MALDI): m / z (nominal masses):
Bisalkylation product (16-a): 1067 (M + H⁺), 1089 (M + Na⁺)
Trisalkylation product (16-a): 1125 (M + H⁺), 1147 (M + Na⁺)
Tetrakis alkylation product (16-a): 1183 (M + H⁺)

Example 17

Analogously to Example 16, a solution of 1.00 g (1.052 mmol) of 8.20-bis (4-amino-benzyl) -5.11.17.23-tetraisobutyl-2,4,10,14,16,22- hexamethyl-1,7,13, 19-tetraoxa-4, 10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone in 3 ml DMF with 613 mg (415 µl; 4, 41 mmol) of 1-bromo-2-methoxyethane in the presence of 435.9 mg (3.15 mmol) of potassium carbonate, 784.5 mg (5.26 mmol) of sodium iodide in 10 ml of DMF were allowed to react at 100 ° C. for 22 h. The same amount of fresh 1-bromo-2-methoxyethane was then added again and the mixture was allowed to react at 100 ° C. for a further 6 h. After analogous working up and "flash chromatography", after a preliminary run of approx. 30 mg, 104 mg of 8 (or 20) - [4-bis- (β-methoxyethyl) aminobenzyl] - 20 (or 8) - (4- β-methoxyethylaminobenzyl) -5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane -6.9.12, - 15.18.21.24-heptaon (17-a), 59.5 mg intermediate fraction and 213.8 mg (34% of theory) 8.20-bis- [4- bis- (β-methoxyethyl) aminobenzyl) -5,11,17,23-tetraisobutyl-2,4,10,14, 16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16, 22-tetraaza-cyclotetracosane-6,9,12,18, 21,24-hexaone (17-b) ∼ (16-c). The formation of the tetraon (17-a) is based on the contamination of the starting material by (compared to PF 1022) simply reduced diaminobenzyl derivative, which could be isolated. It was created in the preceding synthesis sequence due to non-separation when re-creating Example 1).
MS (MALDI): m / z (nominal mass):
Compound (17-a): 1139 (M + H⁺), 1161 (M + Na⁺, 1177 (M + K⁺)

Example 18

Analogously to Example 16, a solution of 84 mg (0.0881 mmol) of 8.20-bis (4-hydroxybenzyl) -5,11,17,23-tetraisobutyl-2,4,10,14,16,22- hexamethyl-1,7,13,19-tetraoxa- 4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone (e.g. from example 15) in 2 ml DMF with 146, 9 mg (99.4 µl; 1.057 mmol) 1-bromo-2-methoxyethane in the presence of 73.05 mg (0.529 mmol) potassium carbonate, 131.5 mg (0.811 mmol) sodium iodide in 5 ml DMF 18 h at 100 ° C reacted. After cooling, the mixture was concentrated in vacuo, taken up in water, extracted with dichloromethane and the combined extracts were dried and concentrated. 77.6 mg of crude product were obtained. 106.6 mg of crude product from two batches were freed from portions insoluble in acetonitrile. The 84.4 mg obtained were then further purified by semipreparative HPLC (RP phase; acetonitrile / water). As one of the last fractions, 13.5 mg of 5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-8,20-bis- [4- (2-methoxyethoxy) - benzyl] -1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclo-tetracosane-6,9,12,18,21,24-hexaone.
MS (MALDI): m / z (nominal mass): 1069 (M + H⁺, 1091 (M + Na⁺)

Example 19

500 mg (0.526 mmol) 8.20-bis- (4-aminobenzyl) -5,11,17,23-tetraisobutyl-2,4,10, 14,16,22-hexamethyl-1,7,13,19- tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12, 18,21,24-hexaone (e.g. from example 4) and 59.3 mg (0.957 mmol) sodium cyanoboronate were at 0 ° C dissolved in 5 ml of methanol, 141.4 mg (1.471 mmol) of furfural added and then stirred for 3 h at room temperature. The same amounts of reagents were then added again and the mixture was stirred for a further 17 h. The reaction mixture was concentrated and then separated by "flash chromatography" (column: ∅ = 4.5 cm, 1 = 15 cm; silica gel; cyclohexane: ethyl acetate = 5: 1). 407.3 mg (70% of theory) of 8.20-bis-N- [4- (2-furylmethylamino) benzyl] -5.11, 17,23-tetraisobutyl-2,4,10,14 , 16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra aza-cyclotetracosane-6,9,12,18,21,24-hexaone.
MS (MALDI): m / z (nominal mass): 1110 (M + H⁺)

Example 20

200 ml of trifluoromethanesulfonic acid were initially introduced at 0 ° C., and 20 g (0.0217 mol) of 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1 , 7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone (1-b) (e.g. from Ex. 1) as well 6.2 g (0.0434 mmol) of N-hydroxymethyl-ε-caprolactam are added and the mixture is stirred at room temperature for 20 h. 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-ylmethyl) 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-hexaon (20-a), receive. After intermediate fractions totaling 4.21 g, 5.59 g of double amidoalkylated compound 8.20-bis- [4- (2-oxo azepan-1-ylmethyl) benzyl] -5,11,17,23-tetraisobutyl-2 , 4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone (20th -b) received.
MS (ESI): m / z (nominal masses):
Monoalkylation product (16-a): 1045 (M + H⁺)
Bisalkylation product (16-b): 1170 (M + H⁺)

Example 21

At 0 ° C 1.00 g (1.085 mmol) of 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16, 22-hexamethyl-1,7,13,19 -tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone (1-b) (e.g. from Ex. 1) in 15 ml dichloromethane, for this purpose 8.85 g (5.06 ml; 75.98 mol) of chlorosulfonic acid were added dropwise with cooling and the mixture was stirred at room temperature for 2 h. It was then poured onto ice and extracted with ethyl acetate and dichloromethane. The combined extracts were dried and evaporated. The residue was dissolved in 20 ml of dichloromethane and a solution of 0.370 mg (0.494 ml; 2.87 mmol) of ethyl diisopropylamine, 69.1 mg (0.564 mmol) of 4-dimethylaminopyridine and 612.2 mg (4.77 mmol ) N-acetylpiperazine in 10 ml of dichloromethane was added dropwise and the mixture was subsequently stirred overnight. The reaction mixture was diluted with further dichloromethane, washed with water, dried and concentrated. The residue was separated by "flash chromatography" (column: ∅ = 4.5 cm, 1 = 20 cm; silica gel; ethyl acetate: methanol = 9: 1). 379.3 mg (25% of theory) of 8.20-bis- [4- (4-acetylpiperazin-1-yl) sulfonylbenzyl] -5,11,17,23-tetraisobutyl-2,4, 10,14,16,22-hexa methyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexa on (21- a) and then 226.4 mg of 8- [4- (4-acetylpiperazin-1-yl) sulfonyl benzyl] - 20- (4-sulfobenzyl) -5,11,17,23-tetraisobutyl-2,4, 10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone (21-b) receive.
MS (ESI): m / z (nominal masses):
Connection (21-a): 1300 (M + H⁺)
Connection (21-b): 1190 (M + H⁺)

Examples 22 to 39

Analogous to Examples 1 to 21 or according to the general information about the manufacturer tion, the compounds of For mel (I-1-a) obtained.

Table 1

Application example Example A Haemonchus contortus / sheep

Sheep experimentally infected with Haemonchus contortus were identified after the expiration of the Prepatency of the parasite treated.

The active ingredients were administered orally as a pure active ingredient in gelatin capsules.

The efficiency is determined by having those excreted with the feces Quantify worm eggs before and after 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 decorate (dose effectiva).

The following results were obtained:

Claims (11)

1. Deoxycyclodepsipeptides of the formula (I)
in which
C = X ¹ , C = X ² , C = X ³ and C = X ⁴ each independently represent one of the groups CO, CS or CH ₂ , at least one of these groups representing CH ₂ ,
R ¹ and R ² each independently represent hydrogen, alkyl, hydroxy methyl or alkoxymethyl,
R ³ and R ⁴ are each, independently of one another, alkyl or phenyl or Ben zyl which is optionally mono- or polysubstituted by W radicals, where
W for halogen, nitro, cyano, carbonyl, alkoxycarbonyl, alkyl, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , alkenyl, alkoxycarbonylalkenyl, alkynyl, alkoxycarbonylalkynyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, dialkylaminoalkoxy, each optionally substituted aryl, arylalkyl , Aryloxy or arylmethoxy, represents heterocyclylmethoxy, -NR ¹⁶ R ¹⁷ , -SO ₂ -NR ¹⁶ R ¹⁷ , -SR ¹⁸ , -S (O) R ¹⁸ or -S (O) ₂ R ¹⁸ ,
R ^{13 represents} hydrogen or carboxy,
R ^{14 represents} hydrogen, alkyl, optionally substituted by halogen alkylcarbonyl or benzoyl or
R ¹³ and R ¹⁴ together represent a radical - (CH ₂ ) _n -CO-, in which n = 2, 3 or 4,
R ^{15 represents} hydrogen, alkyl, optionally substituted by halogen alkylcarbonyl or benzoyl or
R ¹⁴ and R ¹⁵ together represent a radical - (CH ₂ ) _o -CO-, where o = 3, 4 or 5, a diacyl radical of a C ₄ -C ₆ dicarboxylic acid or phthaloyl which is optionally substituted by halogen,
R ^{16 represents} hydrogen optionally substituted by halogen, hydroxyl or alkoxy, represents 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 substituted by halogen, hydroxyl or alkoxy alkyl, heterocyclylmethyl, alkyl carbonyl 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 bound, represent an optionally substituted mono- or polycyclic, optionally bridged and / or spiro-cyclic, saturated or unsaturated heterocycle which is one to Can contain 3 further heteroatoms from the series nitrogen, oxygen and sulfur,
R ^{18 represents} alkyl or optionally substituted phenyl or benzyl,
R ^{19 represents} one of the residues of a natural or synthetic α-amino acid, functional groups being optionally protected,
R ^{20 represents} hydrogen alkyl or phenyl,
R ¹⁹ and R ²⁰ together for - (CH ₂ ) _p -, where p = 2, 3, 4 or 5, or for - (CH ₂ ) ₂ -NR ²³ - (CH ₂ ) ₂ -, where R ^{23 is} Is alkyl, phenyl or benzyl,
R ^{21 represents} hydrogen or alkyl,
R ¹⁹ and R ²¹ together represent - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ - and
R ^{22 represents} hydrogen or a protective group known from peptide chemistry, such as acetyl, tert-butoxycarbonyl (Boc), benzyl oxycarbonyl (Cbz) or benzyl (Bzl),
R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently of one another hydrogen, optionally substituted by amino or hydroxy, for mercapto methyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoyl methyl, carbamoylethyl, guanidinopropyl, for optionally by amino, nitro, halogen , Hydroxy or methoxy substituted phenyl or benzyl, stand for naphthylmethyl, indolylmethyl, imidazolylmethyl, tri azolylmethyl 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. 2. A process for the preparation of the deoxycyclodepsipeptides of the formula (I) according to claim 1
in which
C = X ¹ , C = X ² , C = X ³ and C = X ⁴ each independently represent one of the groups CO, CS or CH ₂ , at least one of these groups representing CH ₂ ,
R ¹ and R ² each independently represent hydrogen, alkyl, hydroxy methyl or alkoxymethyl,
R ³ and R ⁴ are each, independently of one another, alkyl or phenyl or Ben zyl which is optionally mono- or polysubstituted by W radicals, where
W for halogen, nitro, cyano, carbonyl, alkoxycarbonyl, alkyl, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , alkenyl, alkoxycarbonylalkenyl, alkynyl, alkoxycarbonylalkynyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, dialkylaminoalkoxy, each optionally substituted aryl, arylalkyl , Aryloxy or arylmethoxy, represents heterocyclylmethoxy, -NR ¹⁶ R ¹⁷ , -SO ₂ -NR ¹⁶ R ¹⁷ , -SR ¹⁸ , -S (O) R ¹⁸ or -S (O) ₂ R ¹⁸ ,
R ^{13 represents} hydrogen or carboxy,
R ^{14 represents} hydrogen alkyl, optionally substituted by halogen-substituted alkylcarbonyl or benzoyl or
R ¹³ and R ¹⁴ together represent a radical - (CH ₂ ) _n -CO-, in which n = 2, 3 or 4,
R ^{15 represents} hydrogen, alkyl, alkyl carbonyl or benzoyl optionally substituted by halogen or
R ¹⁴ and R ¹⁵ together represent a radical - (CH ₂ ) _o -CO-, where o = 3, 4 or 5, a diacyl radical of a C ₄ -C ₆ dicarboxylic acid or phthaloyl which is optionally substituted by halogen,
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 substituted by halogen, hydroxyl or alkoxy alkyl, heterocyclylmethyl, alkyl carbonyl 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 Heteroatoms from the series nitrogen, oxygen and sulfur can contain
R ^{18 represents} alkyl or optionally substituted phenyl or benzyl,
R ^{19 stands} for one of the residues of a natural or synthetic α-amino acid, functional groups being optionally protected,
R ^{20 represents} hydrogen, alkyl or phenyl,
R ¹⁹ and R ²⁰ together for - (CH ₂ ) _p -, where p = 2, 3, 4 or 5, or for - (CH ₂ ) ₂ -NR ²³ - (CH ₂ ) ₂ - wherein R ^{23 is} alkyl , Phenyl or benzyl,
R ^{21 represents} hydrogen or alkyl,
R ¹⁹ and R ²¹ together represent - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ - and
R ^{22 represents} hydrogen or a protective group known from peptide chemistry, such as acetyl, tert-butoxycarbonyl (Boc), benzyl oxycarbonyl (Cbz) or benzyl (Bzl),
R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently of one another hydrogen, optionally alkyl substituted by amino or hydroxy, mercapto methyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoyl methyl, carbamoylethyl, guanidinopropyl, optionally by amino, nitro, Halogen, hydroxyl or methoxy substituted phenyl or benzyl, stand for naphthylmethyl, indolylmethyl, imidazolylmethyl, tri azolylmethyl 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
characterized in that one produces fermentatively or synthetically produced cyclodepsipeptides with 24 ring members

• a) reduced with borane (hydrogen boron) or complex hydrides in the presence of metal salts, or
• b) reacted with a sulfurization reagent and then reduced with complex hydrides in the presence of metal salts and, if appropriate, further derivatized the compounds according to the invention obtained by one of the processes a) or b).

3. deoxycyclodepsipeptides of formula (I) according to claim 1 in which
C = X ¹ , C = X ² , C = X ³ and C = X ⁴ each independently of one another preferably represent one of the groups CO, CS or CH ₂ , at least one of these groups representing CH ₂ .
R ¹ and R ² independently of one another each preferably represent hydrogen, C ₁ -C ₆ -alkyl, hydroxymethyl or C ₁ -C ₆ -alkoxymethyl.
R ³ and R ⁴ independently of one another each preferably represent C ₁ -C 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-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, β-naphthylmethyl, 3-indolylmethyl, 4-imidazolyimethyl, 1,2,3-triazol-1-yl-methyl, 1,2, 4-triazol-1-yl-methyl, 2-pyridyimethyl or 4-pyridylmethyl, where functional groups may optionally be protected.
R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each independently of one another preferably represent hydrogen, methyl or ethyl.
W preferably represents halogen, nitro, cyano, carbonyl, C ₁ -C ₆ alkoxy carbonyl, C ₁ -C ₆ alkyl, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , C ₂ -C ₆ alkenyl, C ₁ -C ₆ -alk oxycarbonyl-C ₂ -C ₄ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkoxycarbonyl-C ₂ - C ₄ -alkynyl, hydroxy, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkoxy, di- (C ₁ -C ₆ alkyl) -amino-C ₂ - C ₆ -alkoxy, each optionally single to triple independently of one another by halogen, nitro, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, hydroxy or amino-substituted phenyl, benzyl, phenoxy or benzylmethoxy, for heterocyclylmethoxy with a 5- to 6-membered monocycle or 8 to 10-membered bi-cycle with 1 to four heteroatoms with 1 to 4 nitrogen atoms, 1 to 2 oxygen or 1 to 2 sulfur atoms, for -NR ¹⁶ R ¹⁷ , -SO ₂ -NR ¹⁶ R ¹⁷ , -SR ¹⁸ , -S (O) R ¹⁸ or -S (O) ₂ R ¹⁸ .
R ¹³ preferably represents hydrogen or carboxy.
R ¹⁴ is preferably hydrogen, C ₁ -C ₆ alkyl, optionally substituted by fluorine or chlorine, C ₁ -C ₆ alkylcarbonyl or benzoyl.
R ¹³ and R ¹⁴ together also preferably represent a radical - (CH ₂ ) _n -CO-, where n = 2, 3 or 4.
R ¹⁵ preferably represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl or benzoyl.
R ¹⁴ and R ¹⁵ together also preferably represent a radical - (CH ₂ ) _o -CO-, where o = 3, 4 or 5, a diacyl radical of a C ₄ -C ₆ -di carboxylic acid or optionally substituted by halogen Phthaloyl.
R ¹⁶ preferably represents hydrogen, optionally substituted by halogen, hydroxy or C ₁ -C ₆ alkoxy-substituted C ₁ -C ₆ alkyl, heterocyclic methyl with a 5- to 6-membered monocycle or 8 to 10-membered bicyclic with 1 to four heteroatoms with 1 to 4 nitrogen atoms, 1 to 2 oxygen or 1 to 2 sulfur atoms, for formyl, C ₁ -C ₆ -alkylcarbonyl or in each case optionally up to three times independently of one another by halogen, nitro, cyano, C ₁ - C ₄ - alkyl or C ₁ -C ₄ alkoxy-substituted benzyl or benzoyl or for the radical -CO-R ¹⁹ R ²⁰ -NR ²¹ R ²² .
R ¹⁷ preferably represents hydrogen, optionally substituted by halogen, hydroxy or C ₁ -C ₆ alkoxy-substituted C ₁ -C ₆ alkyl, heterocyclic methyl with a 5- to 6-membered monocycle or 8 to 10-membered bicyclic with 1 to four heteroatoms with 1 to 4 nitrogen atoms, 1 to 2 oxygen or 1 to 2 sulfur atoms, for C ₁ -C ₆ alkylcarbonyl or in each case, if appropriate, single to triple, independently of one another, by halogen, nitro, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy substituted benzyl or benzoyl.
R ¹⁶ and R ¹⁷ also preferably together represent phthaloyl which is 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 bound, optionally by a Halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy substituted and optionally N-acylated monocyclic with 3 to 8 ring members or bicyclic with 7 to 11 ring members, optionally bridged and / or spirocyclic, optionally with one or two carbocyclic ring system condensed, saturated or unsaturated heterocycle, which may contain 1 to 3 further heteroatoms from the series 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom.
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, C ₁ -C ₄ -alkyl optionally substituted by amino or hydroxy, 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 may optionally be protected.
R ²⁰ preferably represents hydrogen, C ₁ -C ₄ alkyl or phenyl.
R ¹⁹ and R ²⁰ also preferably together represent - (CH ₂ ) _p -, where p = 2, 3, 4 or 5, or - (CH ₂ ) ₂ -NR ²³ - (CH ₂ ) ₂ -, wherein R ^{23 represents} C ₁ -C ₄ alkyl, phenyl or benzyl.
R ²¹ preferably represents hydrogen or C ₁ -C ₄ 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, benzyloxy carbonyl or benzyl. 4. deoxycyclodepsipeptides of formula (I) according to claim 1 in which
C = X ¹ , C = X ² , C = X ³ and C = X ⁴ independently of one another are each particularly preferably one of the groups CO, CS or CH ₂ , at least one of these groups being CH ₂ .
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 independently of one another each particularly preferably represent 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 ¹¹ and R ¹² each independently of one another are particularly preferably hydrogen methyl.
W particularly preferably represents fluorine, chlorine, bromine, iodine, nitro, cyano, carbonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -alkyl, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , C ₂ -C _6- alkenyl, C ₁ -C ₄ -alkoxycarbonyl-C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkenyl, C ₁ -C ₄ -alkoxycarbonyl-C ₂ -C ₄ -alkynyl, hydroxy, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkoxy, di- (C ₁ - C ₄ -alkyl) -amino-C ₂ -C ₄ -alkoxy, each optionally mono- or discrete independently of one another by fluorine, bromine, nitro, cyano, C ₁ -C ₄ -alkyl, methyl or fluorine and / or chlorine Ethyl, C ₁ -C ₄ alkoxy, trifluoromethoxy, hydroxy or amino substituted phenyl, benzyl, phenoxy or benzylmethoxy, for furyl methoxy, benzofurylmethoxy, thienylmethoxy, pyrrolylmethoxy, indolylmethoxy, imidazolylmethoxy, pyridylmethoxy, -NR ¹⁶ R ¹⁷ or -SO ₂ -NR ¹⁶ R ¹⁷ .
R ¹³ particularly preferably represents hydrogen or carboxy.
R ¹⁴ particularly preferably represents hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyl carbonyl or benzoyl which is optionally mono- to trisubstituted by fluorine or chlorine.
R ¹³ and R ¹⁴ together also particularly preferably represent a radical - (CH ₂ ) _n -CO-, where n = 2, 3 or 4.
R ¹⁵ particularly preferably represents hydrogen or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
R ¹⁴ and R ¹⁵ together also particularly preferably represent a radical - (CH ₂ ) _o -CO-, where o = 3, 4 or 5, a diacyl radical of a C ₄ -C ₆ dicarboxylic acid or optionally by fluorine or Chlorine mono- or polysubstituted phthaloyl.
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, C ₁ -C ₄ -alkylcarbonyl or in each case optionally once or twice independently of one another by fluorine, chlorine, bromine, iodine, nitro, Cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy substituted benzyl or benzoyl or for the rest -CO-CR ¹⁹ R ²⁰ -R ²¹ R ²² .
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, hydroxy, methoxy or ethoxy-substituted methyl, ethyl or n-propyl, for furylmethyl, benzofurylmethyl, thienylmethyl, pyrrolylmethyl, indolylmethyl, imidazolylmethyl, pyridylmethyl or in each case, if necessary, single or double independently of one another by fluorine, chlorine, bromine, iodine , Nitro, Cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy substituted benzyl.
R ¹⁶ and R ¹⁷ together also particularly preferably represent phthaloyl which is optionally mono- to tetrasubstituted by fluorine, chlorine or methyl and / or mono- 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 a substituted by fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, methoxy or ethoxy and optionally by C ₁ -C ₄ alkylcarbonyl N-acylated, monocyclic with 3 to 8 ring members or bicyclic with 7 to 11 ring members, optionally bridged and / or spirocyclic, optionally with one or two carbocyclic ring system condensed, saturated or unsaturated heterocycle, the 1 to 3 further heteroatoms from the series 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom may contain.
R ¹⁹ 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, 4-methoxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 3,4- Di chlorobenzyl, 4-iodobenzyl, α-naphthylmethyl, β-naphthylmethyl 3-indolylmethyl, 4-imidazolylmethyl, 1,2,3-triazol-1-yl-methyl, 1,2,4-triazol-1-yl-methyl , 2-pyridylmethyl or 4-pyridylmethyl, functional groups may optionally be protected.
R ²⁰ particularly preferably represents hydrogen, C ₁ -C ₄ alkyl or phenyl.
R ¹⁹ and R ²⁰ together also particularly preferably represent - (CH ₂ ) _p -, in which p = 2, 3, 4 or 5, or - (CH ₂ ) ₂ -NR ²³ - (CH ₂ ) ₂ -, wherein R ^{23 is} C ₁ -C ₄ alkyl, phenyl or benzyl.
R ²¹ particularly preferably represents hydrogen or C ₁ -C ₄ 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. 5. Deoxycyclodepsipeptides of formula (I) according to claim 1 in which
C = X ¹ , C = X ² , C = X ³ and C = X ⁴ each independently of the other very particularly preferably represent one of the groups CO or CH ₂ , at least one of these groups being CH ₂ .
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 very particularly preferably each represent benzyl optionally substituted by a radical W.
R ⁵ , R ⁶ , R ⁷ and R ⁸ each independently of the other are particularly preferably be 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-furyl methoxy, 2-thienylmethoxy, 2-pyrrolylmethoxy, -NR ¹⁶ R ¹⁷ or -SO2 -NR ¹⁶ R ¹⁷ .
R ¹³ very particularly preferably represents hydrogen or carboxy.
R ¹⁴ very particularly preferably represents hydrogen, acetyl, chloroacetyl or benzoyl.
R ¹⁵ very particularly preferably represents hydrogen.
R ¹⁴ and R ¹⁵ , together with the nitrogen atom to which they are bound, also very particularly preferably represent 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxo-azepane 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-1-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 (l) :
R ¹⁷ very particularly preferably represents hydrogen or one of the same radical from the series, depending on R ¹⁶ : methyl, ethyl, n-propyl, isopropyl, 2-chloroethyl, 2-bromoethyl, 2-chloro-1-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-fluorophthaloyl, 3,4-difluorophthaloyl, 4,5-difluorophthaloyl, 3,6-difluorophthaloyl, tetrafluorophthaloyl, 3-chlorophthaloyl, 4,5-dichlorophthaloyl, tetra chlorophthaloyl, 4-nitrophthaloyl, 3-methylphthaloyl, 4-methylphthaloyl, tetramethylphthaloyl, 4-tert-butylphthaloyl or together with the nitrogen atom to which they are bound, for a fluorine, chlorine, methyl, ethyl, n-propyl, if appropriate , Isopropyl, methoxy or ethoxy substituted and optionally N-acetylated monocyclic with 5 to 8 ring members or bicyclic with 7 to 11 ring members, optionally bridged, optionally condensed with one or two carbocyclic ring systems, saturated or unsaturated heterocycle, the 1 or 2 further hetero can contain atoms from the series 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. 6. Deoxycyclodesipeptides according to claim 1 of the formulas (Ia) to (1-d)
wherein the radicals R ¹ -R ^{12 have} the meaning given in claim 1. 7. deoxycyclodesipeptides according to claim 1 of formula (I-1)
in which
C = X ¹ , C = X ² , C = X ³ and C = X ⁴ each independently have the meanings given in claim 1 above and
W ¹ and W ² each independently represent hydrogen or one of the radicals W according to claim 1. 8. Use of deoxycyclodepsipeptides of the formula (I) according to Claim 1 for controlling endoparasites. 9. Use of deoxycyclodepsipeptides of the formula according to claim 1 for the production of endoparasiticidal agents. 10. Endoparasiticidal agents characterized by a content of deoxycyclo depsipeptides of formula (I) according to claim 1, optionally in a mixture with common diluents and additives.