EP0986549A1 - Desoxycyclodepsipeptides and their use for combatting endoparasites - 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

DESOXYCYCLODEPSIPEPTIDE AND THEIR USE FOR COMBATING ENDOPARASITES

The invention relates to new deoxycyclodepsipeptides, processes for their preparation and their use for controlling parasites, in particular helminths in the

Veterinary and human medicine.

Various cyclodepsipeptides with antiparasitic activity have been described in the literature. A cyclooctadepsipeptide with the designation PF 1022 is known from EP-A 382 173. Further 24-membered cyclodepsipeptides are known from EP-A 626 376, EP-A 634 408 and EP-A 718 293. Their anthelmintic effect is not satisfactory in all cases.

The invention relates to new deoxycyclodepsipeptides which, through complete or partial chemoselective reduction of the carbonyl groups, increase the amide function

Methylene groups with suitable reduction processes from cyclodepsipeptides with 24 ring members, which are alternately made up of α-aminocarboxylic acids and α-hydroxycarboxylic acids, as well as mixtures and derivatives thereof.

The cyclodepsipeptides serving as starting products are alternately composed of 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 CC ₄ alkyl group, preferably a methyl group, which in turn can be substituted.

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

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

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

Complete or partial reduction means that e.g. in the case of an octadepsipeptide with a number of 4 amidic carbonyl groups, all 4 carbonyl groups concerned or 1 to 3 of these carbonyl groups are reduced.

The reduction generally gives mixtures of the deoxydepsipeptides with different degrees of reduction. The individual components are available in different proportions, depending on the stoichiometry and type of reduction process. Uniform deoxydepsipeptides are obtained from the mixtures by using the usual physical or chemical separation processes.

The products obtained in the reduction reaction can be converted chemically to further derivatives.

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

in which C = X *, 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 being CH2,

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, alkoxycarbonylalkynyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, dialkylaminoalkoxy, in each case optionally substituted aryl, arylalkyl, aiyloxy or arylmethoxy, for 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, alkylcarbonyl or benzoyl optionally substituted by halogen or

R ¹⁴ and R ¹⁵ together represent a radical - (CH ₂ ) ₀ -CO-, in which o = 3, 4 or 5, a diacyl radical of a C4-C5-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 alkyl substituted by halogen, hydroxy or alkoxy, heterocyclylmethyl, alkylcarbonyl or optionally substituted arylmethyl or benzoyl,

R ¹⁶ and R ¹⁷ together represent optionally substituted phthaloyl or together with the nitrogen atom to which they are attached represent an optionally substituted mono- or polycyclic, optionally bridged and / or spirocyclic, saturated or unsaturated heterocycle, which is one to 3 more Can contain heteroatoms from the series nitrogen, oxygen and sulfur,

Rl ^{8 represents} alkyl or optionally substituted phenyl or benzyl,

R ^{19 stands} for one of the residues of a natural or synthetic α-amino acid, functional groups being optionally protected,

R ^{20 represents} hydrogen, alkyl or phenyl,

R ¹⁹ and R ²⁰ together for - (CH) _P -, where p = 2, 3, 4 or 5, or for

- (CH ₂ ) ₂ -NR ²³ - (CH ₂ ) ₂ -, in which R ^{23 represents} alkyl, phenyl or benzyl,

R ^{21 represents} hydrogen or alkyl,

R ¹⁹ and R ²¹ together represent - (CH ₂ ) ₃ - and - (CH ₂ ) - and R ^{22 represents} hydrogen or a protective group known from peptide chemistry, such as acetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or benzyl (Bzl),

R ⁵ , R ⁶ , R ⁷ and R ⁸ each independently of one another for hydrogen, optionally substituted by amino or hydroxy-substituted alkyl, for mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl, for optionally by amino, nitro, halogen , Hydroxy or methoxy substituted phenyl or benzyl, stand for naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl or pyridylmethyl, where functional groups can optionally be protected and

R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each independently represent hydrogen or optionally substituted C 1 -C ₄ -alkyl.

The protective groups known from peptide chemistry are listed, for example, in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 2 ^nd Ed., John Wiley & Sons, New York 1991.

The configuration on the chiral carbons is arbitrary, i.e. the compounds of formula (I) according to the invention are composed of D- and / or L-configured amino acids and hydroxycarboxylic acids. The invention relates to the pure stereoisomers and mixtures thereof. The compounds are preferably built up alternately from D-hydroxycarboxylic acids and L-amino acids.

The invention further relates to processes for the preparation of the compounds according to the invention, characterized in that cyclodepsipeptides with 24 ring members are produced by fermentation or synthetics

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

the compounds according to the invention obtained by one of the processes a) or b) optionally further derivatized.

Furthermore, it was found that the compounds according to the invention are outstandingly suitable for controlling helminths in human and veterinary medicine.

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

C = X ¹ , CX 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, -CC ₆ - alkyl, hydroxymethyl or Ci-Cβ-alkoxymethyl.

R ³ and R ⁴ independently of one another each preferably represent CrC ₆ alkyl or optionally phenyl or benzyl substituted once or twice by a radical W.

R ⁵ , R ⁶ , R ⁷ and R ⁸ each independently of one another preferably represent hydrogen, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, 3-aminopropyl, 4-aminobutyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 3-guanidino-propyl, phenyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2- Aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 3,4-dichlorobenzyl, 4-iodobenzyl, α-naphthylmethyl, β-naphthylmethyl 3-indolylmethyl, 4-imidazolylmethyl, 1,2,3-triazol-l-yl-methyl , 1,2,4-triazol-l-ylmethyl, 2-pyridylmethyl or 4-pyridylmethyl, functional groups being optionally protected. R ⁹ , R ¹⁰ , R ⁿ and R ¹² each independently of one another preferably represent hydrogen, methyl or ethyl.

W preferably represents halogen, nitro, cyano, carbonyl, -CC ₆ alkoxycarbonyl,

Ci-Cβ-alkyl, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , C ₂ -C ₆ alkenyl, C, -C ₆ alkoxycarbonyl-C ₂ -C ₄ - alkenyl, C ₂ -C6 alkynyl, C C6 -Alkoxycarbonyl-C ₂ -C ₄ -alkynyl, hydroxy, -C-C ₆ -alkoxy, -C-C6-alkoxy-C C6-alkoxy, Cι-C ₆ -alkoxy-Cι-C6-alkoxy-Cι-C ₆ -alk - oxy, di- (-CC6-alkyl) -amino-C ₂ -C ₆ -alkoxy, each optionally up to three times independently of one another by halogen, nitro, cyano, -C-C-alkyl,

Cι-C ₄ -alkoxy, C ₄ haloalkoxy, hydroxy or amino-substituted phenyl, benzyl, phenoxy or Benzylmethoxy for heterocyclylmethoxy with a 5- to 6-membered monocyclic or 8- to 10-membered bicycle containing 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 preferably represents hydrogen, CC ₆ alkyl, optionally by fluorine or

Chlorine substituted Ci-Cβ-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, -CC ₆ alkyl, CC ₆ - alkylcarbonyl or benzoyl.

R ¹⁴ and R ¹⁵ also preferably together represent a radical - (CH ₂ ) ₀ -CO-, where o = 3, 4 or 5, a diacyl radical of a C 1 -C 6 -dicarboxylic acid or phthaloyl optionally substituted by halogen. R ¹⁶ preferably represents hydrogen, optionally substituted by halogen, hydroxy or C _ö alkoxy-substituted Ci-Cβ-alkyl, represents heterocyclylmethyl with a 5- to 6-membered monocyclic or 8- to 10-membered bicycle containing 1 to four hetero atoms with 1 up to 4 nitrogen atoms, 1 to 2 oxygen or 1 to 2 sulfur atoms, for formyl, -C-C ₆ alkylcarbonyl or in each case optionally substituted one to three times independently of one another by halogen, nitro, cyano, Ci-C ₄ -alkyl or dC -alkoxy Benzyl or benzoyl or for the rest -CO-R ¹⁹ R ²⁰ -NR ²¹ R ²² .

R ¹⁷ preferably represents hydrogen, optionally by halogen, hydroxy or

Ci-C _ö -alkoxy-substituted Ci-Cβ-alkyl, for heterocyclylmethyl with a 5- to 6-membered monocycle or 8 to 10-membered bicyclus with 1 to four heteroatoms with 1 to 4 nitrogen atoms, 1 to 2 oxygen or 1 to 2 sulfur atoms, Ci-C _ö alkylcarbonyl or in each case optionally mono- to trisubstituted independently of one another by halogen, nitro, cyano, C -Al- alkyl or Cι-C -alkoxy-substituted benzyl or benzoyl.

R ¹⁶ and R ¹⁷ also preferably together represent phthaloyl substituted by halogen, nitro, cyano, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy or together with the nitrogen atom to which they are attached, optionally for a

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 condensed with one or two carbocyclic ring systems, saturated or unsaturated heterocycle, which can 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 -CC ₄ alkyl or mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl or phenyl optionally substituted by amino, nitro, halogen, hydroxy or methoxy or Benzyl or for naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl or pyridylmethyl, where functional groups can optionally be protected.

R ²⁰ preferably represents hydrogen, CC ₄ alkyl or phenyl.

R 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} CC ₄ alkyl, phenyl or benzyl.

R ²¹ preferably represents hydrogen or -CC alkyl.

R ¹⁹ and R ²¹ together also preferably represent - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ -.

R ²² preferably represents hydrogen or a protective group known from peptide chemistry, such as acetyl, tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.

C = X ', C = X ² , C = X ³ and C = X ⁴ each independently, particularly preferably, each represent 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 each independently of one another are particularly preferably methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, benzyl, 4-hydroxybenzyl, where hydroxyl groups can optionally be present in a protected manner.

R ⁹ , R ¹⁰ , R ^u and R ¹² each independently of one another are particularly preferably

Hydrogen, methyl.

W particularly preferably represents fluorine, chlorine, bromine, iodine, nitro, cyano, carbonyl, CC ₄ -alkoxycarbonyl, CC ₄ -alkyl, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , C ₂ -C ₆ -alkenyl, CC ₄ -alkoxycarbonyl-C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkenyl, C ₁ -C ₄ -alkoxycarbonyl-

C -C ₄ -alkynyl, hydroxy, CC ₄ -alkoxy, -C-C ₄ -alkoxy-Cι-C -alkoxy, Cι-C - alkoxy-Cι-C ₄ -alkoxy-Cι-C ₄ -alkoxy, di- ( CC ₄ -alkyl) -amino-C ₂ -C -alkoxy, in each case, if appropriate, once or twice independently of one another by fluorine, bromine, nitro, cyano, CC ₄ -alkyl, methyl or ethyl substituted by fluorine and / or chlorine, -C -C ₄ alkoxy, trifluoromethoxy, hydroxy or

Amino substituted phenyl, benzyl, phenoxy or benzyl methoxy, for furyl methoxy, benzofuryl methoxy, thienyl methoxy, pyrrolyl methoxy, indolyl methoxy, imidazolyl methoxy, pyridyl methoxy, -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, -CC alkyl, optionally mono- to trisubstituted by fluorine or chlorine -CC ₄ alkylcarbonyl or benzoyl.

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 stand for a radical - (CH ₂ ) ₀ -CO-, where o = 3, 4 or 5, for a diacyl radical of a C ₄ -C ₆ -dicarboxylic acid or for optionally through 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, Cj-Cr alkylcarbonyl or in each case optionally once or twice independently of one another by fluorine, chlorine, bromine, iodine, nitro, cyano, Cι -C -Alkyl or -CC ₄ -alkoxy substituted benzyl or benzoyl or for the rest -CO-CR19R20_R21R22

R ¹⁷ particularly preferably represents hydrogen or, depending on R ¹⁶ , the same radical from the series: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, simply by Chlorine, bromine, hydroxyl, methoxy or ethoxy substituted methyl, ethyl or n-propyl, for furylmethyl, benzofurylmethyl, thienylmethyl, pyrrolylmethyl, indolylmethyl, imidazolylmethyl, pyridylmethyl or in each case, if appropriate, once or twice independently of one another by fluorine, chlorine, bromine, iodine, nitro , Cyano, -CC ₄ alkyl or CrC ₄ alkoxy substituted benzyl.

R ¹⁶ and R ¹⁷ together also particularly preferably represent phthaloyl which is optionally monosubstituted to tetrasubstituted by fluorine, chlorine or methyl and / or monosubstituted or disubstituted by bromine, nitro, cyano, C ₂ -C 4 -alkyl or methoxy or together with the nitrogen atom, to which they are bound, for an optionally substituted by fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, methoxy or ethoxy and optionally by C \ - C4-alkylcarbonyl N-acylated, monocyclic with 3 to 8 ring members or bicyclic with 7 to 11 ring members, optionally bridged and / or spirocyclic, optionally condensed with one or two carbocyclic ring systems, saturated or unsaturated heterocycle, the 1 to 3 can contain further heteroatoms from the series 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom.

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-l-yl-methyl,

1,2,4-triazol-l-yl-methyl, 2-pyridylmethyl or 4-pyridylmethyl, where functional groups can optionally be protected.

R ²⁰ particularly preferably represents hydrogen, -CC alkyl or phenyl.

R ¹⁹ and R ²⁰ together also particularly preferably stand 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} CC ₄ alkyl, phenyl or benzyl.

R ²¹ particularly preferably represents hydrogen or -CC alkyl.

R ¹⁹ and R ²¹ together also particularly preferably represent - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ -.

R ²² particularly preferably represents hydrogen or a protective group known from peptide chemistry, such as acetyl, tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.

C = X ', C = X ² , C = X ³ and C = X ⁴ each independently 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 each very particularly preferably represent benzyl optionally substituted by a radical W.

R ⁵ , R ⁶ , R ⁷ and R ⁸ each independently of the other are very particularly preferably isopropyl, isobutyl or sec-butyl.

R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each very particularly preferably represent methyl.

W very particularly preferably represents bromine, iodine, nitro, cyano, carbonyl, methoxycarbonyl, ethoxycarbonyl, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , 2-oxopyrrolidin-5-yl, 2-oxopiperidine-6 -yl, 2-methoxycarbonyl-vinyl, 2-methoxycarbonyl-ethynyl, hydroxy, methoxy, 2-methoxy-ethoxy, 2-dimethylamino-ethoxy, in each case, if appropriate, once or twice independently of one another by fluorine, bromine, nitro, cyano, methyl, ethyl , Trifluoromethyl, difluoromethyl, chlorodifluoromethyl, trichloromethyl, methoxy, ethoxy, trifluoromethoxy, hydroxy or amino substituted phenyl, benzyl, phenoxy or benzylmethoxy, for 2-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, very particularly preferably represent 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxo-azepan-1 -yl, succinimino, maleinimino, dimethylmaleinimino, Glutarimino, phthalimino, tetrafluorophthalimino, 4,5-dichlorophthalimino or tetrachlorophthalimino.

R 16 very particularly preferably represents hydrogen, methyl, ethyl, n-propyl, isopropyl, 2-chloroethyl, 2-bromoethyl, 2-chloro-l-propyl, 2-hydroxyethyl, 2-methoxyethyl, 2-furylmethyl, 2-thienylmethyl , 2-pyrrolylmethyl, 2-imidazolylmethyl, formyl, acetyl, propionyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, benzoyl, 2-chlorobenzoyl, 4-chlorobenzoyl or 4-nitrobenzoyl or for the residues (a) to (1 ):

(c)

(d)

(e) (f)

(g) (h) (i)

R ¹⁷ very particularly preferably represents hydrogen or a radical from the series which is the same depending on R ¹⁶ : methyl, ethyl, n-propyl, Isopropyl, 2-chloroethyl, 2-bromoethyl, 2-chloro-l-propyl, 2-hydroxyethyl, 2-methoxyethyl, 2-furylmethyl, 2-thienylmethyl, 2-pyrrolylmethyl, 2-imidazolylmethyl, benzyl, 2-chlorobenzyl or 4-chlorobenzyl.

R ¹⁶ and R ¹⁷ together also very particularly preferably represent phthaloyl, 3-

Fluorophthaloyl, 3,4-difluorophthaloyl, 4,5-difluorophthaloyl, 3,6-difluorophthaloyl, tetrafluorophthaloyl, 3-chlorophthaloyl, 4,5-dichlorophthaloyl, tetrachlorophthaloyl, 4-nitrophthaloyl, 3-methylphthaloyl, 4-methylphthaloyl, Tetramethylphthaloyl, 4-tert-butylphthaloyl or together with the nitrogen atom to which they are attached, for one optionally by fluorine,

Chlorine, methyl, ethyl, n-propyl, 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 to 2 more

Heteroatoms from the series can contain 1 or 2 nitrogen atoms, 1 oxygen atom and 1 sulfur atom, such as in particular morpholinyl, pyrrolyl or piperazinyl.

R ¹⁹ very particularly preferably represents hydrogen, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, 3-aminopropyl, 4-aminobutyl, carboxymethyl, 2-carboxyethyl, Carbamoylmethyl, 2-carbamoylethyl, 3-guanidinopropyl, phenyl, benzyl, 4-hydroxybenzyl.

R ²¹ very particularly preferably represents hydrogen or methyl.

R ²² very particularly preferably represents hydrogen or a protective group known from peptide chemistry, such as acetyl, tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.

Preferred groups of the compounds of the formula (I) according to the invention are the compounds of the formulas (Ia) to (1-d)

(I-a) (I-b)

(I-c) (I-d)

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

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 (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 definitions or explanations of residues or explanations listed above or in preferred areas can be used with one another, ie also between the respective ones

Areas and preferred areas can be combined as desired. They apply accordingly to the end products as well as to the preliminary and intermediate products.

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

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

According to the invention, very particular preference is given to the compounds of the formula (I) in which there is a combination of the meanings listed above as being very particularly preferred. Saturated or unsaturated hydrocarbon radicals, such as alkyl or alkenyl, can also be straight-chain or branched as far as possible, also in conjunction with heteroatoms, such as, for example, in alkoxy.

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

The terms heterocyclyl or hetaryl are used in addition to purely heterocyclic

Ring systems also understood those that are condensed with carbocyclic ring systems.

If, for example, PF 1022A [cf. e.g. J. Antibiot. 45, 692 (1992)] with borohydride / tetrahydrofuran

Complex around, 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:

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

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

The sulfurization reagent that may be required to carry out process (b) is a thionylation reagent, such as, for example, phosphorus pentasulfide or

[2,4-bis (4-methoxyphenyl)] - l, 3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson reagent).

The complex hydrides which may also be required for carrying out process (b) are, for example, sodium boranates such as sodium borohydride or sodium cyanoboranate or lithium alanates such as lithium aluminum hydride.

The further derivatization of the compounds according to the invention is carried out, for example, by the following reactions: alkylation on one or more of the 4 ring nitrogen atoms, nucleophilic or electrophilic aromatic substitution on aromatic radicals, derivatization of substituents on the aromatic radicals. Aromatic radicals are preferably understood in the formula (I) to represent R ³ and R ⁴ phenyl or benzyl. The introduction, substitution or derivatization of at least one radical W ¹ and W ² other than hydrogen in compounds of the formula (II) is particularly preferably meant.

For the alkylation of compounds of formula (I) according to the invention are used in which at least one of R ^9, R ¹ 1, R ^10, R ¹² is hydrogen and the other radicals and groups have the meanings and preferred meanings given above.

Compounds of the formula (I) in which at least one of the radicals R 1, R ⁴ , R 5 _; R6 R7 R8 f ^ _r, where appropriate, substituted phenyl or benzyl. These phenyl or benzyl radicals are substituted for the alkylation by at least one OH, NH ₂ , NHR16 or SH group.

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

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

Acylations of the OH, NH ₂ , NHRI "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 that are optionally activated as amino acid fluorides or by coupling with coupling reagents that are known from peptide chemistry. In these cases, the amino group is protected by protective groups such as e.g. Acetyl, t-butyloxycarbonyl or benzyloxycarbonyl protected. The amino acids can be used in the form of their racemates or their pure enantiomers (D or L form). The L-form of the natural amino acids is preferred.

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

in which P stands for H or the rest of common protective groups (eg acetyl, Boc, Cb _z ), and

R ^ represents one of the following residues:

-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 R19 can together for one of the following divalent residues

- (CH ₂ ) ₃ - - (CH ₂ ) ₄ - stand.

Nucleophilic aromatic substitution is preferably understood to mean the substitution of fluorine, chlorine, bromine, iodine, nitro by halides, alkanolates or primary or secondary amines or their metal amides. Furthermore, the term encompasses, depending on the reaction conditions and nucleophile, also radical substitution of diazo groups. Examples include diazotization and subsequent hydrolysis in aqueous acid to the phenol derivative or with sulfur nucleophiles to the thiophenol derivative or sulfide, in bulk in the presence of fluoride or tetrafluoroborate as the nucleophile (Balz-Schiemann reaction), and under Sandmeyer conditions, for example with copper (I) halides or cyanide.

Compounds according to the invention of the formula (I) in which at least one of the radicals R 1, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^{8 is} substituted phenyl or benzyl are preferably used for nucleophilic aromatic substitution.

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 C4 alkanolates or primary or secondary amines of the formula HNRlÖR-V ^" _m which R ^ and R ^, which have the meaning given above, or with metal amides.

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

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 1 to R ^{8 represents} optionally substituted phenyl or benzyl, at least one of these phenyl - or benzyl radicals is substituted by amino. Such compounds are obtained by the processes described, for example, in EP-A 634 408, by nitrating the unsubstituted compounds and then reducing the nitro group to the amino group. Electrophilic aromatic substitution is preferably to be understood as meaning nitration, amidoalkylation, sulfation, sulfochlorination, sulfonylation, bromination, iodination, 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 1 to R ^{8 is} phenyl or benzyl. The implementation of these substitutions is described, for example, in EP-A 634 408 and WO 95/3926. We expressly refer 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, in particular monoalkylation with a bifunctional alkylation reagent followed by intramolecular alkylation to a heterocyclic radical of the formula -NR ¹⁶ R ¹⁷ , alkylation of a Hydroxy group, oxidation of an alkylthio group to the sulfoxide or sulfone.

The active ingredients are suitable for combating pathogenic endoparasites, which occur in humans and in animal husbandry and animal breeding in useful, breeding, zoo, laboratory, experimental and hobby animals, with favorable warm-blooded toxicity. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive species. By combating the pathogenic endo-parasites, illness, deaths and reduced performance (for example in the production of meat, milk, wool, hides, eggs, honey, etc.) are to be reduced, so that the use of the active compounds enables more economical and simple animal husbandry is. Pathogenic endoparasites include cestodes, trematodes, nematodes, in particular:

From the order of the Pseudophyllidea, for example: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoorus spp .. From the order of the Cyclophyllidea, for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosmsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyella spp. , Taenia spp., Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp.,

Diplopylidium spp ..

From the subclass of Monogenea e.g. Cyrodactylus spp., Dactylogyrus spp., Polystoma spp ..

From the subclass of Digenea, for example: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma. , Echinochasmus spp., Hypoderaeum spp., Fasciola spp., Fas- ciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocoe - derius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonismus spp., Dicrocoelium spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchiseter spp., spp., Metagonimus spp ..

From the order of the Enoplida, for example: Trichuris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp ..

From the order of the Rhabditia e.g .: Micronema spp., Strongyloides spp ..

From the order of the Strongylida, for example: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus sppum, spp., Oesophag. , Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylrong spp., Neost. , Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Cooperemato- spp., Marshallemat dirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp ..

From the order of the Oxyurida, for example: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp ..

From the order of Ascaridia, for example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp ..

From the order of the Spirurida, for example: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp ..

From the order of the Filariida, for example: Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp ..

From the group of the Gigantohynchida, for example: Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp ..

For example, the active compounds according to the invention have excellent activity against worms such as Haemonchus contortus.

Livestock and breeding animals include mammals such as Cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon, birds such as Chickens, geese, turkeys, ducks, fresh and salt water fish such as Trout, carp, eels, reptiles, insects such as Honey bee and silkworm.

Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats. The pets include dogs and cats.

The application can be prophylactic as well as therapeutic.

The active ingredients are used directly or in the form of suitable preparations enterally, parenterally, dermally, nasally, by treating the environment or with the aid of shaped articles containing active ingredients, e.g. Strips, plates, ribbons, collars, ear tags, limb straps, marking devices.

The enteral application of the active ingredients takes place e.g. orally in the form of powder, suppositories, tablets, capsules, fasting, watering, granules, drenches, boluses, medicated feed or drinking water. The dermal application happens e.g. in the form of diving (dipping), spraying (spraying), bathing, washing, pouring (pour-on and spot-on) and powdering. Parenteral use happens e.g. in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants.

Suitable preparations are:

Solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on formulations, gels;

Emulsions and suspensions for oral or dermal use as well

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 with active ingredients. Solutions for injection are administered intravenously, intramuscularly and subcutaneously.

Injection solutions are prepared by dissolving the active ingredient in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives. The solutions are sterile filtered and filled.

The following may be mentioned as solvents: physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof.

If appropriate, the active compounds can also be dissolved in physiologically tolerable vegetable or synthetic oils which are suitable for injection.

The following may be mentioned as solubilizers: solvents which promote the dissolution of the active ingredient in the main solvent or prevent its precipitation. Examples are polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol.

Oral solutions are applied directly. Concentrates are used orally after previous dilution to the application concentration. Oral solutions and concentrates are prepared as described above for the injection solutions, whereby sterile work can be dispensed with.

Solutions for use on the skin are dripped on, spread on, rubbed in, sprayed on, sprayed on or applied by diving (dipping, bathing or washing). These solutions are prepared as described above for the injection solutions.

It may be advantageous to add thickeners during manufacture. Thickeners are: inorganic thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

Gels are applied to or spread on the skin or placed in body cavities. Gels are produced by adding enough thickening agent to solutions which have been prepared as described for the injection solutions to form a clear mass with an ointment-like consistency. The thickeners specified above are used as thickeners.

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

Pour-on formulations are prepared by dissolving, suspending or emulsifying the active ingredient in suitable skin-compatible solvents or solvent mixtures. If necessary, other auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers and adhesives are added.

The following may be mentioned as solvents: water, alkanols, glycols, polyethylene glycols,

Polypropylene glycols, glycerin, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones such as acetone, methyl ethyl or ketone, aromatic and / aromatic and / vegetable or synthetic oils, DMF, dimethyl acetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-l, 3-dioxolane.

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

Resorption-promoting substances are, for example, DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols. Antioxidants are sulfites or metabisulfites such as potassium metabisulfate, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.

Light stabilizers are e.g. Substances from the class of benzophenones or novantisolic acid.

Adhesives are e.g. Cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.

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

Emulsions are either water in oil or oil in water.

They are produced by dissolving the active ingredient either in the hydrophobic or in the hydrophilic phase and homogenizing it with the solvent of the other phase with the aid of suitable emulsifiers and, if necessary, other auxiliaries such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers, viscosity-increasing substances .

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 ₂ -C ₂ or other specially selected natural fatty acids, partial glyceride Mix saturated or unsaturated fatty acids which may also contain hydroxyl groups, mono- and diglycerides of C ₈ / C ₀ fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length C ₆ -C ₈ , isopropyl myristate, isopropyl palmitate, caprylic / capric alcohol ester of the saturated chain length ₂ -Cι ₈ , iso-propyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duck pancreas fat, dibutyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures, etc. Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids such as Oleic acid and its mixtures.

The following can be mentioned as the hydrophilic phase:

Water, alcohols such as e.g. Propylene glycol, glycerin, sorbitol and their mixtures.

The following may be mentioned as emulsifiers: nonionic surfactants, e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether; 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 substances and substances that stabilize the emulsion, such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride , Polyethylene glycols, waxes, colloidal silica or mixtures of the listed substances.

Suspensions can be used orally, dermally or as an injection. They are produced by suspending the active ingredient in a carrier liquid, optionally with the addition of other auxiliaries such as wetting agents, dyes, substances which promote absorption, preservatives, antioxidants and light stabilizers.

All homogeneous solvents and solvent mixtures may be mentioned as carrier liquids. 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. They differ from the suspensions and emulsions described above only in their higher viscosity.

To prepare solid preparations, the active ingredient is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and brought into the desired shape.

All physiologically compatible solid inert substances may be mentioned as carriers. All of these serve inorganic and organic substances. Inorganic substances are e.g. Common salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides,

Silicas, clays, precipitated or colloidal silicon dioxide, phosphates.

Organic substances are e.g. Sugar, cellulose, food and animal feed such as milk powder, animal meal, cereal flour and meal, starches.

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

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

The active substances can also be present in the preparations in a mixture with synergists or with other active substances which act against pathogenic endoparasites.

Such active ingredients are, for example, L-2,3,5,6-tetrahydro-6-phenyl-imidazolethiazole, benzimidazole carbamates, praziquantel, pyrantel, febantel. Ready-to-use preparations contain the active ingredient in concentrations of 10 ppm to 20% by weight, preferably 0.1 to 10% by weight.

Preparations which are diluted before use contain the active ingredient in concentrations of 0.5 to 90% by weight, preferably 5 to 50% by weight.

In general, it has proven advantageous to administer amounts of approximately 1 to 100 mg of active ingredient per kg of body weight per day in order to achieve effective results.

The preparation and use of the active compounds according to the invention can be seen from the examples below.

Manufacturing examples

example 1

(Method a)

(1-b)

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-l, 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), 51 ml of a 1 molar solution of borane-THF complex in THF were quickly added dropwise. 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 concentration, 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, l, 1.17.23-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) as a colorless solid with melting point 149 up to l50 ° C. MS (FAB): m / z (nominal mass): 921 (M + H +) HR-MS: calc. For C5 ₂ H8θN ₄ OιoNa 943.5772 found 943.5776

From the side fractions and the mother liquor of the crystallization, the mono, the tri and the tetrar reduction product were isolated by means of further column chromatography and crystallization.

Monoreduction product (1-a): mp: 130 to l32 ° C MS (FAB): m / z (nominal mass): 935 (M + H +), 957 (M + Na ⁺ )

HR-MS: calcd for C ₅₂ H7 ₈ N ₄ O ₁ ιNa 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-cyclotetracosan-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-hexamethyl- 1,7,13,19- tetraoxa-4, 10, 16,22-tetraaza-cyclotetracosane-6,9, 12, 18,21, 24-hexaone (for example according to example 1) were introduced 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 extracting the aqueous phase three times with dichloromethane,

Drying over sodium sulfate and evaporation of the solvent were 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) -l, 7.13, 19-tetraoxa-4, 10, 16.22-tetra-cyclotetracosane-6,9,12,18,21,24-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

(4-a)

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-cyclotetracosan-6,9, 12,18,21, 24-hexaone (eg according to example 3) were dissolved in a mixture of 40 ml of ethyl acetate and 8 ml of ethanol , mixed with 297 mg 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, 10, 14, 16,22-hexamethyl fell -l, 7, 13, 19-tetraoxa-4, 10, 16,22-tetraazatetracosane-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) yielded 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-l, 7, 13, 19-tetraoxa-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) of sodium iodide are placed in 10 ml of dimethylformamide (DMF), 621.8 mg (2.68 mmol) of bis (2-bromethyl) ether are added 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) 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 (masseominal mass): 1091 (M + H ⁺ ) Example 6

Analogously to Example 5, 227.8 mg became 8- (4-aminobenzyl) -20- (2-aminobenzyl) - 5.1 l, 17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl -l, 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% i.e., 5, ll, 17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-8- [4- (N- morρholinyl) benzyl] -20- [2- (N- morρholinyl) benzyl] - 1, 7, 13, 19-tetraoxa-4, 10, 16,22-tetra-cyclotetracosane-6,9, 12,18,21, 24-hexaone. MS (MALDI): m / z (masseominal mass): 1091 (M + H ⁺ )

Example 7

(Method a)

223 mg (0.2 mmol) 5.1 l, 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-3,6,9, 12,15, 18,21,24-octaone (cf. EP 634 408 AI) were dissolved in 2 ml of dry THF. 2.16 ml of an IM solution of borane-THF complex in THF were added at room temperature. The solution was refluxed for 1.5 hours. The mixture was cooled to 0 ° C., 249 mg (2.8 mmol) of 2-amino-2-methyl-l-propanol in 2 ml of dry THF were added and the mixture was stirred for about 1 h. The reaction solution was taken up in methyl tert-butyl ether and washed with saturated sodium chloride solution. After the solution had been dried over sodium sulfate and concentrated, the crude product was filtered through a little silica gel (cyclohexane: ethyl acetate 1: 1 to 1: 3). The reduction products were isolated using preparative HPLC.

Direct reduction product 5, 1 l, 17,23-tetraisobutyl-2,4, 10, 14, 16,22-hexamethyl-8,20-bis-

[4- (N-morpholinyl) benzyl] -l, 7, 13, 19-tetraoxa-4, 10, 16,22-tetraaza-cyclotetra-cosan-6,9, 12,18,21,24-hexaone (7th -b) = (Ex. 5): 37 mg MS (MALDI): m / z (Νominal mass): 1091 (M + H +), 1113 (M + Νa ⁺ )

Trireduction product 5, l l, 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-pentaone (7-c ): 10 mg

MS (MALDI): m / z (nominal mass): 1077 (M + H +) tetrareduction 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-cyclotetracosane-6,12,18,24-tetraone (7-d): 22 mg

MS (MALDI): m / z (nominal mass): 1063 (M + H +); 1085 (M + Νa ⁺ ) Example 8

(Method a)

(8-b)

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] -l, 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) ber-zyl] - 1,7,13, 19-tetraoxa-4, 10, - 16,22-tetraaza-cyclotetracosane-6,9, 12,18,21,24-hexaone (8-b) from the melting point 1 16 to 119 ° C obtained. MS (ESI): m / z (nominal mass): 1113 (M + H +), 1135 (M + Na ⁺ )

Furthermore, 76 mg of monoreduction product and 32 mg of tetrareduction product were obtained. Example 9

(Method a)

37.5 ml (37.5 mmol) of a 1 molar solution of borane-THF complex in THF were quickly added dropwise to a solution of 30.88 g (31.5 mmol) of PF 1022 in 190 ml of THF. The solution was refluxed for 2 hours. Then cooled to 0 ° C and hydrolyzed by adding 30 ml of 2-amino-2-methylpropanol. The mixture was subsequently stirred at room temperature for 45 minutes, then semi-saturated sodium chloride solution was added and the mixture was extracted 3 times with ethyl acetate. After drying over magnesium sulfate and evaporation, the crude product was filtered through a glass frit filled with silica gel (0 = 10 cm) with cyclohexane / ethyl acetate (15: 1 to 7: 1). 9.11 g (31% of theory) of 8,20-dibenzyl-5, ll, 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

(1-a) (see Ex. 1).

Example 10

(Method a)

2.99 g (3.25 mmol) 8,20-dibenzyl-5, 11,17,23-tetraisobutyl-2,4, l 0,14,16,22-hexamethyl-1, 7, 13, 19 -tetraoxa-4, 10, 16,22-tetraaza-cyclotetracosane-6,9, 12, 18,21, 24-hexa- one (1-b) (e.g. from Example 1) were mixed in 20 ml THF with 9, 75 ml (9.75 mmol) of 1 molar borane solution reacted analogously to Example 1. After column chromatography (silica gel, 0 = 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, 1 l, 17.23 -tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4, 10, 16,22-tetraaza-cyclotetracosane-6, 12, 18,24-tetraone (2) (see Ex. 2), 0.22 g trireduction product (1-c) and 0.91 g unreacted starting material.

Example 11

1.34 g (3.6 mmol) of O-benzyl-Nt-butoxycarbonyl-L-tyrosine were placed in 15 ml of acetonitrile and 485.7 mg (4.8 mmol) of triethylamine and 520.9 mg (4, 8 mmol) of chloroform ethyl ester was 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-l, 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 Acetonitrile is added and stirring is continued for 3-4 h at room temperature. The reaction mixture was taken up in ethyl acetate, washed with half-concentrated saline, dried and evaporated in vacuo. Column chromatography (0 = 4.5 cm, 1 = 20 cm; cyclohexane: ethyl acetate 2: 1) gave 1.81 g (73% of theory) of 8.20-bis- [4-ß- (4-benzyloxyphenyl ) -α-tert-butoxycarbonylamino-propionylaminobenzyl] -

5.1 l, 17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-l, 7,13,19-tetraoxa-4,10, 16,22-tetraaza-cyclotetracosane-6,9 , 12, 18, 21, 24-hexaone. MS (ESI): m / z (nominal mass): 1657 (M + ET) Example 12

829.0 mg (0.50 mmol) double-protected tyrosine derivative from Example 12 and 83 mg

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 renewed check of conversion of the catalyst through a filter aid (Celite ^®) was filtered off, the filtrate evaporated, and (cm 0 = 4.5, 1 = 10 cm; cyclohexane: ethyl acetate 2: 1) purified by column chromatography. 0.52 g (70% of theory) of 8.20-bis- [4-α-tert-butoxycarbonylamino-β- (4-hydroxyphenyl) propionylaminobenzyl] -5, 11, 17, 23 were obtained -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 received hexaon.

MS (ESI): m / z (nominal mass): 1477 (M + tf), 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 boiled under reflux with 162.9 mg (1.1 mmol) of phthalic anhydride 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 evaporated again and then filtered through a short silica gel column (0 = 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) -5.1 l, 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) of 2,5-dimethoxytetrahydrofuran were added. At 0 ° C., 851.7 mg (3.0 mmol) of phosphorus pentoxide were added and the mixture was subsequently stirred at this temperature, then at room temperature. Because the conversion was incomplete (TLC control), the mixture was cooled again to 0 ° C. and the same amounts of 2,5-dimethoxytetrahydrofuran and phosphorus pentoxide were added again and allowed to react. For working up, water was added, the mixture was extracted with ethyl acetate, and the combined extracts were dried and evaporated. To complete the extraction, the aqueous phase was then shaken out again with dichloromethane. The combined residues of the organic extracts were then purified by column chromatography (0 = 4 cm, 1 = 28 cm; cyclohexane: ethyl acetate 3: 1). 353.9 mg (22% of theory) of 8.20-bis- [4- (l-pyrrolyl) -benzyl] - 5, 11, 17,23-tetraisobutyl-2,4,10,14, 16,22-hexamethyl-l, 7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosane-6,9, 12, 18,21, 24-hexaone.

MS (ESI): m / z (nominal mass): 1051 (M + tf), 1073 (M + Na ⁺ ) Example 15

100 mg (0.1048 mmol) 8.20-bis- (4-aminobenzyl) -5.1 l, 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 of trifluoroacetic acid and 16.6 mg (0.24 mmol) of sodium nitrite were 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 times in each case after adding dry toluene, 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 passed through a semi-preparative HPLC column (RP phase;

Acetonitrile / water) cleaned. 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 (1H, 500 MHz). MS (MALDI): m / z (nominal mass): 953 (M + H ⁺ ), 975 (M + Na ⁺ ) Example 16

Example No.X ² nm

16-a H ₂ 1 1

16-b H ₂ 2 1

16-c, 17-b H ₂ 2 2

17-a O m + n = 3

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. 613 mg (415 μl; 4.41 mmol) of l-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 (for example from Example 4) in 5 ml of DMF, heated to 80 ° C and stirred for 20 h. A further 306 mg (2.20 mmol) of l-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 by "flash chromatography" (column: 0 = 4.5 cm, 1 = 25 cm; silica gel; cyclohexane: ethyl acetate =

2: 1) separated. The 462.5 mg residue of 497 mg evaporation residue of the middle main fraction was further separated in several runs after a mass and NMR spectroscopic analysis on a semipreparative HPLC column (RP phase; acetonitrile / water). In the order of elution, 204.9 mg two- polyalkylated 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 of triple alkylated compound 8- [4-bis- (ß-methoxyethyl ) aminobenzyl] -20- (4-ß-methoxyethylaminobenzyl) - 5.1 l, 17.23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-l, 7,13,19-tetraoxa-4 , 10, 16,22-tetraaza-cyclotetracosane-6,9,12,18,21,24-hexaone (16-b) and 24.8 mg of tetraalkylated compound 8,20-bis- [4-bis- (ß -methoxyethyl) aminobenzyl) -5, l 1, 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) obtained. 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-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 in 3 ml DMF with 613 mg

(415 µl; 4.41 mmol) l-bromo-2-methoxyethane in the presence of 435.9 mg (3.15 mmol) potassium carbonate, 784.5 mg (5.26 mmol) sodium iodide in 10 ml DMF for 22 h at 100 ° C reacted. The same amount of fresh l-bromo-2-methoxyethane was then added again and the mixture was left to react at 100 ° C. for a further 6 h. After analogous workup and "flash chromatography" were after a

30 mg 104 mg of 8 (or 20) - [4-bis (ß-methoxyethyl) aminobenzyl] - 20 (or 8) - (4-ß-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- (ß-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) received. 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 arose in the preceding synthesis sequence due to non-separation when the

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-l, 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) l-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 for 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-cyclotetracosane-6,9, 12, 18,21,24-hexaone. MS (MALDI): m / z (nominal mass): 1069 (M + lT), 1091 (M + Na ⁺ ) Example 19

500 mg (0.526 mmol) 8.20-bis- (4-aminobenzyl) -5.1 l, 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) of sodium cyanoboronate were dissolved in 5 ml of methanol at 0 ° C., 141.4 mg (1.471 mmol) of Furfüral were added and the mixture was then stirred at room temperature for 3 h. The same amounts of reagents were then added again and the mixture was stirred for a further 17 h. The

The reaction mixture was concentrated and then separated by "flash chromatography" (column: 0 = 4.5 cm, 1 = 15 cm; silica gel; cyclohexane: ethyl acetate = 5: 1). 407.3 mg (70% of theory) .) 8,20-Bis-N- [4- (2-furylmethylamino) benzyl] -5, ll, - 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 + lf)

Example 20

At 0 ° C, 200 ml of trifluoromethanesulfonic acid were placed in succession 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-hexaon (1-b) (e.g. from Ex. 1) and 6.2 Add g (0.0434 mmol) N-hydroxymethyl-ε-caprolactam and stir for 20 h at room temperature. The mixture was then poured onto ice, neutralized by adding solid sodium bicarbonate and then extracted with dichloromethane. The combined extracts were washed with a little water, dried and evaporated. The 26 g of crude product obtained were separated by MPLC. The first main fraction was 1.22 g of simply amidoalkylated compound 20-benzyl-8- [4- (2-oxoazepan-1-methyl) benzyl] -5, 11,17,23-tetraisobutyl-2,4,10 , 14, 16,22-hexamethyl-1, 7, 13, 19-tetraoxa-4, 10, 16,22-tetraaza-cyclotetra-cosan-6,9, 12,18,21,24-hexaone (20-a ), receive. After intermediate fractions totaling 4.21 g, 5.59 g of doubly amidoalkylated compound 8.20-bis- [4- (2-oxo-azepan-1-methyl) benzyl] -5, 11,17,23-tetraisobutyl-2 , 4, 10,14,16,22-hexamethyl-1,7, 13, 19-tetraoxa-4, 10,16,22-tetraaza-cyclotetracosane-6,9, 12, 18,21,24-hexaone (20th - b) received. MS (ESI): m / z (nominal masses):

Monoalkylation Product (16-a): 1045 (M + FT) Bisalkylation Product (16-b): 1170 (M + H ⁺ )

Example 21

At 0 ° C 1.00 g (1.085 mmol) of 8,20-dibenzyl-5,1 l, 17,23-tetraisobutyl-

2,4, 10, 14, 16,22-hexamethyl-l, 7, 13, 19-tetraoxa-4, 10, 16,22-tetraaza-cyclotetracosane-6,9, 12,18,21,24-hexaone ( 1-b) (for example from Example 1) in 15 ml of dichloromethane, 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 ethyldiisopropylamine, 69.1 mg (0.564 mmol) of 4-dimethylaminopyridine and 612.2 mg (4.77 mmol) of N-acetylpiperazine in 10 ml of dichloromethane were 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: 0 = 4.5 cm, 1 = 20 cm; silica gel; ethyl acetate: methanol = 9: 1). 379.3 mg (25% of theory) were 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- one (21-a) and then 226.4 mg 8- [4- (4-acetylpiperazin-l-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). MS (ESI): m / z (nominal masses):

Nerbinding (21-a): 1300 (M + HT)

Nerbinding (21-b): 1190 (M + H ⁺ )

Examples 22 to 39

Analogously to Examples 1 to 21 or according to the general information on the preparation, the compounds of the formula (I-l-a) listed in Table 1 below were obtained.

Table 1

Abbreviations: boc = tert. -Butoxycarbonyl bzl = benzyl

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 quantitatively counting the worm eggs excreted in the faeces before and after the treatment.

A complete suspension of egg excretion after treatment means that the worms have been aborted or are so damaged that they no longer produce eggs (effective dose).

The following results were obtained:

Claims

claims

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, 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,

Alkoxycarbonylalkynyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, dialkylaminoalkoxy, in each case optionally substituted aryl, arylalkyl, aryloxy or arylmethoxy, for heterocyclylmethoxy, -NR ¹⁶ R ¹⁷ , -SO ₂ -NR ¹⁶ R ¹⁷ , -SR ¹⁸ , -S ( O) R ^{! 8} or -S (O) ₂ 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, alkylcarbonyl or benzoyl optionally substituted by halogen or

R ¹⁴ and R ¹⁵ together represent a radical - (CH ₂ ) ₀ -CO-, in which o = 3, 4 or 5, a diacyl radical of a C4-Cg-dicarboxylic acid or phthaloyl which is optionally substituted by halogen,

R ¹⁶ for hydrogen, optionally by halogen, hydroxy or

Alkoxy substituted alkyl, for heterocyclylmethyl, formyl, alkylcarbonyl or optionally substituted arylmethyl or benzoyl or for the radical -CO-CR ¹⁹ R ⁰ -NR ²¹ R ²² and

R ^{17 represents} hydrogen, optionally alkyl substituted by halogen, hydroxy or alkoxy, heterocyclylmethyl, alkylcarbonyl or optionally substituted arylmethyl or benzoyl,

R ¹⁶ and R ¹⁷ together represent optionally substituted phthaloyl or together with the nitrogen atom to which they are attached represent an optionally substituted mono- or polycyclic, optionally bridged and / or spirocyclic, saturated or unsaturated heterocycle, which can contain one to three further heteroatoms from the series nitrogen, oxygen and sulfur,

R ^ ^{8 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} for Is alkyl, phenyl or benzyl,

R ^{21 represents} hydrogen or alkyl,

R ¹⁹ and R ²¹ together represent - (CH ₂ ) ₃ - and - (CH ₂ ) - and

R ^{22 is} hydrogen or one known from peptide chemistry

Protecting group such as acetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or benzyl (Bzl),

R ⁵ , R ⁶ , R ⁷ and R ⁸ each independently of one another for hydrogen, optionally substituted by amino or hydroxy-substituted alkyl, for mercapto-methyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoyl-methyl, carbamoylethyl, guanidinopropyl, for optionally by amino, nitro , Halogen, hydroxyl or methoxy-substituted phenyl or benzyl, are naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl or pyridylmethyl, where functional groups may be protected and R ⁹ , R ¹⁰ , R ^u and R ¹² each independently represent hydrogen or optionally substituted C 1 -C 4 -alkyl.

A process for the preparation of the deoxycyclodepsipeptides of the formula (I) according to claim 1

in which

C = X ^! , 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 each independently 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,

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, alkylcarbonyl 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, alkylcarbonyl or benzoyl optionally substituted by halogen or

R ¹⁴ and R ¹⁵ together represent a radical - (CH ₂ ) ₀ -CO-, in which o = 3, 4 or 5, a diacyl radical of a C4-Cg-dicarboxylic acid or phthaloyl which is optionally substituted by halogen,

R ¹⁶ for hydrogen, optionally by halogen, hydroxy or

Alkoxy substituted alkyl, for heterocyclylmethyl, formyl, alkylcarbonyl or optionally substituted arylmethyl or benzoyl or for the radical -CO-CR ¹⁹ R ²⁰ -NR ²¹ R ²² and

R ^{17 represents} hydrogen, optionally alkyl substituted by halogen, hydroxy or alkoxy, heterocyclylmethyl, alkylcarbonyl or optionally substituted arylmethyl or benzoyl,

R ¹⁶ and R ¹⁷ together represent optionally substituted phthaloyl or together with the nitrogen atom to which they are attached are an optionally substituted mono- or polycyclic, optionally bridged and / or spirocyclic, saturated or unsaturated heterocycle, which can contain one to 3 further heteroatoms from the series nitrogen, oxygen and sulfur,

R ^ ^{8 represents} alkyl or optionally substituted phenyl or benzyl,

R ¹⁹ for one of the residues of a natural or synthetic α-

Amino acid, where functional groups can optionally be 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} for Is alkyl, phenyl or benzyl,

R ^{21 represents} hydrogen or alkyl,

R ¹⁹ and R ²¹ together represent - (CH ₂ ) ₃ - and - (CH ₂ ) - and

R ^{22 represents} hydrogen or a protective group known from peptide chemistry, such as acetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or benzyl (Bzl),

R ⁵ , R ⁶ , R ⁷ and R ⁸ each independently of one another for hydrogen, optionally substituted by amino or hydroxy-substituted alkyl, for mercapto-methyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoyl-methyl, carbamoylethyl, guanidinopropyl, for optionally by amino, nitro , Halogen, hydroxy or methoxy substituted phenyl or benzyl, are naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl or pyridylmethyl, functional groups optionally being able to 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 (Borwasserstoö) 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

the compounds according to the invention obtained by one of the processes a) or b) optionally further derivatized.

Deoxycyclodepsipeptides of the formula (I) according to Claim 1

in which

C = X *, C = X ² , C = X ³ and C = X ⁴ independently of one another each 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 are each independently preferably represents hydrogen, Ci-C _δ -alkyl, hydroxymethyl, or Cι-C ₆ alkoxymethyl.

R ³ and R ⁴ independently of one another each preferably represent -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 represent preferably

Hydrogen, methyl, iso-propyl, iso-butyl, 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, -naphthylmethyl, ß-naphthylmethyl 3-indolylmethyl, 4-imidazolylmethyl, 1,2,3-triazol-l-yl-methyl, 1,2,4-triazol-l-yl-methyl,

2-pyridylmethyl or 4-pyridylmethyl, where functional groups can 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, dC ₆ alkyl, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , C ₂ -C ₆ alkenyl, C, -C ₆ -Alk-oxycarbonyl-C ₂ -C -alkenyl, C ₂ -C ₆ -alkynyl, Cι-C6-alkoxycarbonyl-C ₂ - C ₄ -alkynyl, hydroxy, Cι-C ₆ -alkoxy, Cι-C ₆ -alkoxy- CrC ₆ -alkoxy, d-

C ₆ -alkoxy-C6-alkoxy-Cι-C6-alkoxy, di- (-C-C ₆ alkyl) -amino-C ₂ - Cβ-alkoxy, each optionally up to three times independently of one another by halogen, nitro, cyano , -C-C ₄ - alkyl, CC ₄ - alkoxy, -C-C -halalkalkoxy, hydroxy or amino substituted phenyl, benzyl, phenoxy or benzylmethoxy, for heterocyclylmethoxy 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 -NR ¹⁶ R ¹⁷ , -SO ₂ -NR ¹⁶ R ¹⁷ , -SR ¹⁸ , -S (O) R ¹⁸ or -S ^ R, ¹ 18

R preferably represents hydrogen or carboxy. R ¹⁴ preferably represents hydrogen, -CC ₆ alkyl, optionally substituted by fluorine or chlorine Ci-Ce 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, -CC ₆ alkyl, C] -C ₆ alkylcarbonyl or benzoyl.

R ¹⁴ and R ¹⁵ also preferably together represent a radical - (CH ₂ ) ₀ -CO-, where o = 3, 4 or 5, a diacyl radical of a C4-Cg-dicarboxylic acid or phthaloyl which is optionally substituted by halogen .

R ¹⁶ preferably represents hydrogen, optionally by halogen,

Hydroxy or d-Cβ-alkoxy-substituted -CC ₆ alkyl, for heterocyclylmethyl 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 atoms or 1 to 2 sulfur atoms, for formyl, CrCβ-alkylcarbonyl or each optionally 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 rest -CO-R ¹⁹ R ²⁰ -NR ²¹ R ²² .

R ¹⁷ preferably represents hydrogen, optionally by halogen,

Hydroxy or -CC ₆ -alkoxy-substituted -CC ₆ alkyl, for heterocyclylmethyl 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 Ci-C _ö alkylcarbonyl or in each case optionally up to three times independently of one another by halogen, nitro, cyano, CC ₄ - alkyl or -CC ₄ -alkoxy-substituted benzyl or benzoyl. R ¹⁶ and R ¹⁷ together also preferably represent halogen, nitro,

Cyano, C -C4 -alkyl or -CC-C4-alkoxy substituted phthaloyl or together with the nitrogen atom to which they are bound, for an optionally substituted by halogen, -CC-alkyl or -C-alkoxy 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 fused 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 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 CrC-alkyl or mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl or optionally by amino, nitro, halogen,

Hydroxy or methoxy substituted phenyl or benzyl or for naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl or pyridylmethyl, functional groups optionally being protected.

R ²⁰ preferably represents hydrogen, -CC ₄ alkyl or phenyl.

R ¹⁹ and R ²⁰ together also preferably 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, -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 ) -.

R ²² preferably represents hydrogen or a protective group known from peptide chemistry, such as acetyl, tert. -Butoxycarbonyl, benzyloxycarbonyl or benzyl.

Deoxycyclodepsipeptides of the 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 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, -CC ₄ alkyl, hydroxymethyl or CC 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 ⁿ and R ¹² each independently of one another are particularly preferably hydrogen, methyl.

W particularly preferably represents fluorine, chlorine, bromine, iodine, nitro, cyano, carbonyl, CC ₄ -alkoxycarbonyl, CC ₄ -alkyl, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , C ₂ -

C ₆ -alkenyl, -C-alkoxycarbonyl-C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkenyl, Ci- C ₄ -alkoxycarbonyl-C ₂ -C -alkynyl, hydroxy, -C-C - alkoxy, Cι -C -alk- oxy-Cι-C ₄ -alkoxy, Cι-C -alkoxy-Cι-C ₄ -alkoxy-Cι-C -alkoxy, di- (C C ₄ -alkyl) -amino-C ₂ -C ₄ -alkoxy, in each case optionally mono- or disubstituted independently by fluorine, bromine, nitro, cyano, C ₄ alkyl, substituted by fluorine and / or chlorine, methyl or ethyl, Cι-C ₄ - alkoxy, trifluoromethoxy, hydroxy or amino-substituted phenyl, benzyl, phenoxy or benzylmethoxy, for furyl methoxy, benzofüryl methoxy, thienyl methoxy, pyrrolyl methoxy, indolyl methoxy, imidazolyl methoxy, pyridyl methoxy, -NR ^I6 R ¹⁷ or -SO ₂ - NR ¹⁶ R ¹⁷ .

R ¹³ particularly preferably represents hydrogen or carboxy.

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

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 ) ₀ -CO-, where o = 3, 4 or 5, a diacyl radical of a C ₄ - C _ö 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 alkyl or Cj-C _t -alkoxy-substituted benzyl or benzoyl or the radical -CO-CR ¹⁹ R ²⁰ R ²¹ R ^22nd

R ¹⁷ particularly preferably represents hydrogen or a radical from the series which is the same depending on R ¹⁶ : methyl, ethyl, n-

Propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, simply methyl, ethyl or n-propyl substituted by chlorine, bromine, hydroxy, methoxy or ethoxy, for furylmethyl, benzofurylmethyl, thienylmethyl, pyrrolylmethyl, indolylmethyl , Imidazolylmethyl, pyridylmethyl or in each case optionally mono- or disubstituted independently of one another by fluorine, chlorine, bromine, iodine, nitro, cyano, CC -alkyl or -CC alkoxy substituted benzyl.

R ¹⁶ and R ¹⁷ together also particularly preferably represent phthaloyl which is optionally monosubstituted to tetrasubstituted by fluorine, chlorine or methyl and / or monosubstituted or disubstituted by bromine, nitro, cyano, C ₂ -C 4 -alkyl or methoxy or together with the nitrogen atom, to which they are attached, for a substituted by fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, methoxy or ethoxy and optionally by C1-C4-alkylcarbonyl N-acylated, monocyclic with 3 to 8 ring members or bicyclic with 7 to 1 1 ring members, optionally bridged and / or spirocyclic, optionally condensed with one or two carbocyclic ring systems, 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 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-indolyl-methyl, 4-imidazolylmethyl, 1,2,3-triazol-l-yl-methyl, 1,2,4-triazol-l-yl-methyl , 2-pyridylmethyl or 4-pyridylmethyl, where functional groups can optionally be protected.

R ²⁰ particularly preferably represents hydrogen, -CC alkyl or phenyl.

R ¹⁹ and R ²⁰ together also particularly preferably stand 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} Ci-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 the formula (I) according to claim 1

in which

C = X ^! , 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 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 very particularly preferably isopropyl, isobutyl or sec-butyl.

R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each very particularly preferably represent methyl.

W very particularly preferably represents bromine, iodine, nitro, cyano, carbonyl, methoxycarbonyl, ethoxycarbonyl, -CH (R ¹³ ) NR ¹⁴ R ¹⁵ , 2-oxopyrrolidin-5-yl, 2-oxopiperidine-6 -yl, 2-methoxycarbonyl-vinyl, 2-methoxycarbonyl-ethynyl, hydroxy, methoxy, 2-methoxy-ethoxy, 2-dimethylamino-ethoxy, in each case, if appropriate, once or twice independently of one another by fluorine, bromine, nitro, cyano, methyl, ethyl , Trifluoromethyl, difluoromethyl, chlorodifluoromethyl, trichloromethyl, methoxy, ethoxy, trifluoromethoxy, hydroxy or amino substituted phenyl, benzyl, phenoxy or benzylmethoxy, for 2-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 also, together with the nitrogen atom to which they are attached, very particularly preferably represent 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxo-azepan-1 -yl, succinimino, maleinimino,

Dimethylmaleinimino, glutarimino, phthalimino, tetrafluorophthalimino, 4,5-dichlorophthalimino or tetrachlorophthalimino. R 16 very particularly preferably represents hydrogen, methyl, ethyl, n-propyl, isopropyl, 2-chloroethyl, 2-bromoethyl, 2-chloro-l-propyl, 2-hydroxyethyl, 2-methoxyethyl, 2-furylmethyl, 2-thienylmethyl , 2-pyrrolylmethyl, 2-imidazolylmethyl, formyl, acetyl, propionyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, benzoyl, 2-chlorobenzoyl, 4-chlorobenzoyl or 4-nitrobenzoyl or for the residues (a) to (1 ):

(d)

(e) (f)

R 17 very particularly preferably represents hydrogen or one, depending on R ¹⁶ , of the same radical from the series: methyl, ethyl, n-propyl, isopropyl, 2-chloroethyl, 2-bromoethyl, 2-chloro-l-propyl, 2 -Hydroxyethyl, 2-methoxyethyl, 2-furylmethyl, 2-thienylmethyl, 2-pyrrolylmethyl, 2-imidazolylmethyl, benzyl, 2-chlorobenzyl or 4-chlorobenzyl. R ¹⁶ and R ¹⁷ together also very particularly preferably represent phthaloyl, 3-fluorophthaloyl, 3,4-difluorophthaloyl, 4,5-difluorophthaloyl, 3,6-difluorophthaloyl, tetrafluorophthaloyl, 3-chlorophthaloyl, 4,5-dichlorophthaloyl, Tetrachlorophthaloyl, 4-nitrophthaloyl, 3-methylphthaloyl, 4-methylphthaloyl,

Tetramethylphthaloyl, 4-tert-butylphthaloyl or together with the nitrogen atom to which they are attached, for an optionally substituted by fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, methoxy or ethoxy and optionally N-acetylated monocyclic with 5 up 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, which may contain 1 or 2 further heteroatoms 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. Deoxycyclodesipeptides according to claim 1 of the formulas (Ia) to (1-d)

(I-a) (I-b)

(I-c) (I-d)

wherein the radicals Rl - R ^ ^{2 have} the meaning given in claim 1.

Deoxycyclodesipeptides according to claim 1 of the formula (I-I)

in which

C = X ^! , 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 combating endoparasites.

9. Use of deoxycyclodepsipeptides of the formula according to claim 1 for the preparation of endoparasiticidal agents.

10. Endoparasiticidal agents characterized by a content of deoxycyclodepsipeptides of the formula (I) according to claim 1, optionally in a mixture with customary diluents and additives.