DE19840320A1 - Aza cyclodepsipeptides - Google Patents

Abstract

The invention relates to new aza-cyclodepsipeptides of formula (I) in which X<1>, X<2>, X<3> and X<4> independently of each other are N or C-H and at least one of these variables X represents nitrogen. The invention also relates to a method for their production and to their use for combating parasites, notably helminthes.

Description

The invention relates to new aza-cyclodepsipeptides, processes for their preparation and their use for controlling parasites, especially helminths in of veterinary and human medicine.

The invention relates to new 24-membered heterocycles made from α-hydroxycarbon acids on the one hand and α-amino acids or α-aza-amino acids on the other hand older are constructed in a manner that contains at least one aza-amino acid. about Such aza-cyclodepsipeptides have so far been unknown.

New aza-cyclodepsipeptides of the formula (I)

found in which
X ¹ , X ² , X ³ and X ⁴ each independently represent N or CH, where at least one of these variables X represents nitrogen,
R ¹ , R ² , R ³ and R ⁴ are each independently of one another hydrogen, in each case optionally substituted by halogen, alkyl, alkenyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonyl alkyl, carbamoylalkyl, aminoalkyl , Alkylaminoalkyl, dialkylaminoalkyl or optionally substituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl, and
the grouping -NR ⁹ -X ¹ R ⁵ - represents a radical of the formula -NR ^9-1 -CHR ^5-1 - or a radical of the formula -NR ^9-2 -NR ^5-2 -,
the grouping -NR ¹⁰ -X ² R ⁶ - represents a radical of the formula -NR ^10-1 -CHR ^6-1 - or a radical of the formula -NR ^10-2 -NR ^6-2 -,
the grouping -NR ¹¹ -X ³ R ⁷ - represents a radical of the formula -NR ^11-1 -CHR ^7-1 - or a radical of the formula -NR ^11-2 -NR ^7-2 -,
the grouping -NR ¹² -X ⁴ R ⁸ - represents a radical of the formula -NR ^12-1 -CHR ^8-1 - or a radical of the formula -NR ^12-2 -NR ^8-2 -,
R ^5-1 , R ^6-1 , R ^7-1 and R ^8-1 independently of one another each for hydrogen, optionally alkyl or amino substituted for mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl, for phenyl or benzyl, optionally substituted by amino, nitro, halogen, hydroxyl or alkoxy, stand for naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl, thienylmethyl, benzothienylmethyl or pyridylmethyl, where functional groups can optionally be present in a protected manner,
R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 each independently represent hydrogen or C ₁ -C ₄ alkyl,
where the pairs of residues R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1 also together independently of one another for the residues - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ -, and
R ^5-2 to R ^12-2 are each independently of one another hydrogen, in each case optionally substituted by halogen-substituted alkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl , Alkoxy carbonylaminoalkyl or represent in each case optionally substituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl,
where the pairs of residues R ^5-2 / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2 also together, independently of one another, for the if necessary C ₁ -C ₄ alkyl-substituted radicals - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ - are available.

Functional groups are protected e.g. B. by protective groups known from peptide chemistry (e.g. listed 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. H. the invention compounds of the formula (I) are of D- and / or L-configured Amino acids and hydroxycarboxylic acids built. The invention relates to the pure Stereoisomers and mixtures thereof. The compounds from D- Hydroxycarboxylic acids and L-amino acids built. The following is the one for the sake of simplicity, however, always spoken of compounds of the formula (I), although both the pure compounds and optionally mixtures with under different proportions of isomeric compounds are meant.

Furthermore, it was found that the new compounds of the formula (I) are used one of the methods described below.  

• A) aza-cyclodepsipeptides of the formula (I)
  in which
  X ¹ , X ² , X ³ , X ⁴ and R ¹ to R ^{12 have} the meanings given above,
  can be prepared by using azadepsipeptides of the formula (II)
  in which
  X ¹ , X ² , X ³ , X ⁴ and R ¹ to R ^{12 have} the meanings given above,
  cyclized in the presence of a reaction auxiliary and a solvent and optionally in the presence of a base.
• B) Azacyclodepsipeptides of the formula (Ia)
  in which
  X ² , X ³ , X ⁴ each independently represent N or CH and
  R ¹ to R ^{12 have} the meanings given above,
  can be prepared by using azadepsipeptides of the formula (III)
  in which
  X ² , X ³ , X ⁴ each independently represent N or CH and
  R ¹ to R ^{12 have} the meanings given above,
  with compounds of formula (IV)
  in which
  Y ^{1 represents} chlorine, trichloromethoxy, C ₁ -C ₄ alkoxy, optionally substituted phenoxy, 1-imidazolyl or 1,2,4-triazolyl and
  Y ^{2 represents} chlorine, trichloromethoxy, 1-imidazolyl or 1,2,4-triazolyl,
  if appropriate in the presence of a diluent and if appropriate in the presence of a reaction auxiliary and cyclocondensed.
• C) Azacyclodepsipeptides of the above formula (Ia) can be prepared by using azadepsipeptides of the formula (V)
  in which
  X ² , X ³ , X ⁴ each independently represent N or CH and
  R ¹ to R ¹² and Y ^{1 have} the meanings given above,
  optionally cyclocondensed in the presence of a diluent and optionally in the presence of a reaction auxiliary.

It has also been found that the compounds according to the invention are suitable for Combating helminths in veterinary and human medicine.

The new compounds are generally defined by the formula (I). Prefers are compounds of formula (I) in which substituents or Areas have the following meanings:

R ¹ , R ² , R ³ and R ⁴ independently of one another each preferably represent hydrogen, C ₁ -C ₁₆ alkyl, each optionally substituted by fluorine, chlorine or bromine, C ₁ -C ₆ alkyl, C ₂ -C _8- alkenyl, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkyl, C ₁ -C ₆ -hydroxyalkyl, C ₁ -C ₄ -alkanoyloxy-C ₁ -C ₆ -alkyl, in particular acetoxymethyl or 1-acetoxyethyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₆ -alkyl, in particular methoxymethyl or 1-methoxyethyl, aryl-C ₁ -C ₄ -alkoxy-C ₁ - C ₆ - alkyl, C ₁ -C ₆ mercaptoalkyl, especially mercaptomethyl, C ₁ -C ₄ alkyl thio-C ₁ -C ₆ alkyl, especially methylthioethyl, C ₁ -C ₄ alkoxycarbonyl-C ₁ - C ₆ alkyl, aryloxycarbonyl -C ₁ -C ₆ alkyl, especially phenoxycarbonyl methyl, aryl-C ₁ -C ₄ alkyloxycarbonyl-C ₁ -C ₆ alkyl, carbamoyl-C ₁ -C ₆ alkyl, especially carbamoylmethyl or carbamoylethyl, amino-C ₁ -C ₆ alkyl, C ₁ -C ₄ alkylamino-C ₁ -C ₆ alkyl, di-C ₁ -C ₄ alkylamino-C ₁ -C ₆ alkyl or given for each optionally by halogen, hydroxy, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, benzyloxy or silyloxy, which is substituted by C ₁ - C ₄ -alkyl and / or phenyl is trisubstituted, substituted aryl, aryl-C ₁ -C ₄ -alkyl, hetaryl or hetaryl-C ₁ -C ₄ -alkyl.

R ^5-1 , R ^6-1 , R ^7-1 and R ^8-1 each independently of one another preferably represent hydrogen, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, Mercaptomethyl, 2-methylthioethyl, 3-aminopropyl, 4-aminobutyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 3-guanidinopropyl, phenyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 3,4-dichlorobenzyl, 4-iodobenzyl, α-naphthylmethyl, β-naphthylmethyl 3-indolylmethyl, 4-imidazolylmethyl, 1,2,3-triazol-1 -yl-methyl, 1,2,4-triazol-1-yl-methyl, 3-thienylmethyl, 3-benzothienylmethyl, 2-pyridylmethyl or 3-pyridylmethyl, where functional groups can optionally be protected.

R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 each independently of one another preferably represent hydrogen, methyl or ethyl.

R ^7-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1 also together, independently of one another, preferably represent the radicals - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ -.

R ^5-2 to R ^12-2 are, independently of one another, preferably hydrogen, C ₁ -C ₁₅ -alkyl, in particular also 3,7,11-trimethyldodecyl, for any C ₁ -C _{8 which may be} substituted by fluorine, chlorine or bromine -Alkyl, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkyl, C ₁ -C ₆ -hydroxyalkyl, C ₁ -C ₄ -alkanoyl oxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₆ -alkyl, aryl-C ₁ -C ₄ -alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -ercaptoalkyl, in particular mercaptomethyl, C ₁ -C ₄ -alkylthio-C ₁ -C ₆ -alkyl, in particular methylthioethyl, C ₁ -C ₄ -alkylsulfinyl-C ₁ -C ₆ -alkyl, in particular methylsulfinylethyl, C ₁ -C ₄ -alkylsulfonyl-C ₁ -C ₆ -alkyl, in particular methylsulfonylethyl, carboxy-C ₁ -C ₆ -alkyl, in particular carboxymethyl, carboxyethyl or carboxy-tert-butyl, C ₁ -C ₄ -alkoxycarbonyl-C ₁ -C ₆ -alkyl, in particular methoxycarbonylmethyl or ethoxycarbonylethyl, aryloxy carbonyl-C ₁ -C ₆ -alkyl, especially phenoxycarbonylmethyl, aryl-C ₁ -C ₄ -alkyloxycarbonyl-C ₁ -C ₆ -alkyl, especially benzyloxycarbonylmethyl, carb amoyl-C ₁ -C ₆ -alkyl, especially carbamoylmethyl or carbamoylethyl, amino-C ₁ -C ₆ -alkyl, especially aminopropyl or aminobutyl, C ₁ -C ₄ - alkylamino-C ₁ -C ₆ alkyl, especially methylaminopropyl or methyl amino, di- (C ₁ -C ₄ ) alkylamino-C ₁ -C ₆ alkyl, especially dimethylamino propyl or dimethylaminobutyl, C ₁ -C ₄ alkoxycarbonylamino-C ₁ -C _6- alkyl, or for each optionally protected by halogen, hydroxy, nitro, cyano, amino, C ₁ -C ₄ alkylamino, di (C ₁ -C ₄ ) alkylamino, benzylamino, dibenzyl amino, protected amino such as. B. acetyl, t-butoxycarbonyl, benzyl oxycarbonyl or FMOC-amino, C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ haloalkoxy substituted Aryl, aryl-C ₁ -C ₄ -alkyl, hetaryl or hetaryl-C ₁ -C ₄ -alkyl, where an NH function in the heterocyclic ring can optionally be derivatized by an amino protective group, such as the above.

R ^5-2 / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2 also together, independently of one another, preferably represent the optionally simple to radicals substituted four times by C ₁ - C ₄ alkyl - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ -.

R ¹ , R ² , R ³ and R ⁴ independently of one another each particularly preferably represent hydrogen, C ₁ -C ₁₂ -alkyl, C ₁ -C ₄ -alkyl, C ₂ -C ₄ which are each optionally substituted by fluorine, chlorine or bromine _6- alkenyl, C ₃ -C ₇ -cycloalkyl, in particular cyclopentyl, cyclohexyl or cycloheptyl, C ₃ -C ₇ -cycloalkyl-C ₁ - C ₄ -alkyl, C ₁ -C ₆ -hydroxyalkyl, phenyl-C ₁ -C _4- alkoxy-C ₁ -C ₆ -alkyl, in particular benzyloxymethyl or 1-benzyloxyethyl, C ₁ -C ₄ -alkylthio-C ₁ -C ₆ -alkyl, in particular methylthioethyl, C ₁ -C ₄ -alkoxycarbonyl-C ₁ - C ₆ -alkyl, in particular methoxycarbonylmethyl or ethoxycarbonylethyl, phenyl-C ₁ -C ₄ -alkyl oxycarbonyl-C ₁ -C ₆ -alkyl, in particular benzyloxycarbonylmethyl, amino-C ₁ -C ₆ alkyl, in particular aminopropyl or aminobutyl, C ₁ - C ₄ alkylamino C ₁ -C ₆ alkyl, especially methylaminopropyl or methylamino, di (C ₁ -C ₄ ) alkylamino C ₁ -C ₆ alkyl, especially dimethylaminopropyl or dimethyl aminobutyl or for each given optionally by fluorine, chlorine, bromine, iodine, hydroxy, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, benzyloxy or silyloxy, which is trisubstituted by C ₁ -C ₄ alkyl and / or phenyl, substituted phenyl, phenyl-C ₁ -C ₄ alkyl, naphthylmethyl, 5- or 6-membered hetaryl, in particular thienyl, thiazolyl or pyridyl, indolyl, benzo -1,3-dioxolyl, 5- or 6-membered hetaryl-C ₁ -C ₄ -alkyl in particular thienylmethyl, thiazolylmethyl, imidazolylmethyl or pyridylmethyl or indolyl-C ₁ -C ₄ -alkyl.

R ^5-1 , R ^6-1 , R ^7-1 and R ^8-1 independently of one another each particularly preferably represent methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, benzyl, 4-hydroxybenzyl, where Hydroxy groups can optionally be protected.

R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 each independently of one another are particularly preferably hydrogen or methyl.

R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1 also together, particularly independently of one another, particularly preferably represent the radicals - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ -.

R ^5-2 to R ^12-2 independently of one another particularly preferably represent hydrogen, C ₁ -C ₁₀ -alkyl, C ₁ -C ₄ -alkyl, C ₃ -C ₇ -cycloalkyl, which are each optionally substituted by fluorine, chlorine or bromine , in particular cyclopentyl, cyclohexyl or cycloheptyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ alkyl, C ₁ -C ₆ hydroxy alkyl, in particular hydroxymethyl or 1-hydroxyethyl, C ₁ -C ₄ alkanoyl oxy-C ₁ -C ₆ alkyl, especially acetoxymethyl or 1-acetoxyethyl, C ₁ -C ₄ alkoxy-C ₁ -C ₆ alkyl, especially methoxymethyl or 1-methoxyethyl, phenyl-C ₁ -C ₄ alkoxy-C ₁ - C ₆ alkyl, especially benzyloxymethyl or 1-benzyloxyethyl, C ₁ -C ₄ alkoxycarbonylamino-C ₁ -C ₆ alkyl, especially tert-butoxycarbonylaminopropyl or tert-butoxycarbonylaminobutyl, or for each optionally by fluorine, chlorine, bromine, Iodine, hydroxy, nitro, cyano, amino, C ₁ -C ₄ alkylamino, di (C ₁ -C ₄ ) alkylamino, benzylamino, dibenzylamino, protected amino such as. B. acetyl, t-butoxycarbonyl, benzyloxycarbonyl or FMOC-amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₂ haloalkoxy substituted phenyl , Phenyl-C ₁ -C ₄ -alkyl, 5- or 6-membered hetaryl, in particular thienyl, thiazolyl or pyridyl, 5- or 6-membered hetaryl-C ₁ -C ₄ -alkyl or indolyl-C ₁ -C ₄ - alkyl.

R ^5-2 / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2 are also, independently of one another, particularly preferred for the optionally simple up to four times methyl-substituted radicals - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ -.

R ¹ , R ² , R ³ and R ⁴ independently of one another each very particularly preferably represent hydrogen, C ₁ -C ₁₂ alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.- Butyl, tert-butyl, n-pentyl, isopentyl, sec.-pentyl, tert.-pentyl, n-hexyl, isohexyl, sec.-hexyl, n-heptyl, isoheptyl, sec.-heptyl, octyl, isooctyl, sec .-Octyl, n-decyl or n-dodecyl, for each optionally substituted by fluorine or chlorine substituted C ₁ -C ₄ alkyl, especially fluoromethyl, trifluoromethyl or trichloromethyl, for C ₂ -C ₆ alkenyl, especially vinyl or allyl , for cyclopentyl or cyclohexyl, for C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkyl, in particular cyclopropylmethyl, for methylthio ethyl or for each optionally by fluorine, chlorine, bromine, iodine, hydroxy, cyano, methyl, ethyl, n-Propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, trifluoromethyl, trichloromethyl, methoxy, difluoromethoxy, trifluoromethoxy or benzyloxy substituted phenyl, phenyl-C ₁ -C ₄ alkyl, especially benzyl, 3-naphthylmethyl, benzo-1,3-dioxol-5-yl, thienyl methyl, imidazolylmethyl or indolylmethyl.

R ^5-1 , R ^6-1 , R ^7-1 and R ^8-1 independently of one another each very particularly preferably represent methyl, isopropyl, isobutyl or sec-butyl.

R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 each very particularly preferably represent hydrogen or methyl.

R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1 also together independently of one another very particularly preferably represent Residues - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ -.

R ^5-2 to R ^12-2 independently of one another very particularly preferably represent hydrogen, C ₁ -C ₁₀ alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert. -Butyl, n-pentyl, isopentyl, sec.-pentyl, tert.-pentyl, n-hexyl, isohexyl, sec.-hexyl, n-heptyl, isoheptyl, sec.-heptyl, octyl, isooctyl, sec.-octyl or 3,7-dimethyloctyl, for C ₃ -C ₇ cycloalkyl-C ₁ - C ₄ alkyl, in particular cyclopentylmethyl, cyclohexylmethyl or cyclo heptylmethyl, for each optionally by fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, n -Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, trichloromethyl, methoxy, difluoromethoxy, trifluoromethoxy or benzyloxy substituted phenyl, benzyl, phenylethyl, 5- or 6-membered hetarylmethyl, especially thienylmethyl , Thiazolyl methyl, furylmethyl or pyridylmethyl or for indolylmethyl.

R ^5-2 / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2 also together, independently of one another, very particularly preferably represent the optionally monosubstituted or disubstituted by methyl - (CH ₂ ) ₄ -.

The radicals listed above or listed in preferred areas Definitions or explanations can be made with each other, i.e. also between the respective areas and preferred areas can be combined as desired. they seem for the end products as well as for the preliminary and intermediate products accordingly.

Compounds of the formula (I) in which
R ¹ , R ² , R ³ and R ⁴ independently of one another represent methyl, which is optionally substituted by phenyl, which in turn can be substituted by halogen, cyano, nitro, amino, dialkylamino, morpholino,
the groups X ¹ -R ⁵ , X ² -R ⁶ , X ³ -R ⁷ , X ⁴ -R ⁸ independently of one another for the radicals

stand in which
R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are C ₁ -C ₄ alkyl, in particular branched C ₄ alkyl, very particularly i-butyl, at least one of the radicals X ¹ , X ² , X ³ and X ⁴ for

stands;
R ⁹ , R ¹⁰ , R ¹¹ and R ¹² independently of one another are C ₁ -C ₄ alkyl, in particular methyl.

According to the invention, preference is given to the compounds of the formula (I) in which one of the radicals X ¹ , X ² , X ³ and X ^{4 represents} N.

According to the invention, particular preference is given to the compounds of the formula (I) in which two of the radicals X ¹ , X ² , X ³ and X ^{4 are} N.

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

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

In addition to the generally known three-letter codes for amino acids and the abbreviations for alkyl groups, the following abbreviations are used in the present text:

Lac: 2-hydroxypropionic acid (lactic acid)
Ph: phenyl
Bn: benzyl
Boc: tert-butoxycarbonyl
PhLac: 2-hydroxy-3-phenylpropionic acid (β-phenyllactic acid)
AzaAla: 2-azaalanine (N-methyl-N-aminocarbamic acid)
Azaxyz: 2-aza analog amino acid "xyz"

If, for example, H-MeLeu-D-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac-MeAzaAla-D-Lac-OH is used as the starting material and bis- (2-oxo-3-oxazolidinyl) -phosphoryl chloride (BOP- Cl) as reaction auxiliary and ethyldiisopropylamine as base, the course of the reaction of process (A) according to the invention can be represented by the following formula:

If, for example, H-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac-MeLeu-D-Lac-N (CH ₃ ) -N (s-Bu) H and diphosgene as starting materials and triethylamine as reaction aids are used, the The reaction sequence of process (B) according to the invention can be represented by the following formula:

If, for example, F ₅ Ph-CO-PhLac-MeLeu-D-Lac-MeAzaLeu-o-PhLac-MeLeu-D-Lac-N (CH ₃ ) -N (s-Bu) H is used as starting material and pyridine as reaction aid, the reaction sequence of process (C) according to the invention can be represented by the following formula:

Formula (II) provides a general definition of the Azadepsi peptides required to carry out process (A) according to the invention. In this formula, X ¹ , X ² , X ³ , X ⁴ and R ¹ to R ¹² preferably represent those radicals which have already been mentioned as preferred substituents in connection with the description of the aza-cyclodepsipeptides of the formula (I). The azadepsipeptides of formula (II) are new.

Azadepsipeptides of the formula (II) can, for. B. produce by cleaving in a process (Aa) the protecting group of C-terminally protected azadepsipeptides of the formula (VI) according to the following reaction scheme:

In formula (VI), A ^{4 represents} a C-terminal protective group such as, for example, tert-butyl or benzyl (see, for example, BTW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley & Sons, New York 1991).

The reaction can be carried out using conventional C-terminal deblocking methods such as Acidolysis, for example in the case of a tert-butyl ester, or catalytic hydrie tion, for example in the case of a benzyl ester.

Azadepsipeptides of the formula (II) can, for. B. also produce by cleaving in a process (Ab) the protective group of N-terminally protected azadepsipeptides of the formula (VII) according to the following reaction scheme:

In formula (VII) A ^{1 represents} an N-terminal protective group such as, for example, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz) or benzyl (Bn) (see, for example, BTW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 2. Ed., John Wiley & Sons, New York 1991).

The reaction can be carried out using conventional N-terminal deblocking methods such as Acidolysis, for example in the case of the BOC group, or catalytic hydrogenation, for example in the case of a benzyl group.

The C-terminally protected azadepsipeptides of the formula (VI) required for the implementation of the process (Aa) or the N-terminally protected azadepsipeptides of the formula (VII) required for the implementation of the process (Ab) can be prepared by using N- and C terminally protected azadepsipeptides of the formula (VIII)

goes out and either in a process (A.a.b) analogous to (A.b) the N-terminal Splits off protective group or in a process (A.b.a) analogous to (A.a) the C- splits off terminal protective group. Depending on the type of protective group, one can special embodiment of the method both in one step Remove protective groups and directly from compounds of formula (VIII) Compounds of the formula (II) arrive (process A.a / b).

Aza-octadepsipeptides of the formula (VIII) can, for. B. by making compounds of formula (IX) with compounds of formula (X) in the presence of a reaction auxiliary such as BOP-Cl or HATU (among others) and a base such as Hünig base and optionally in the presence of a diluent such as dichloromethane according to the following Reaction scheme implements:

As reaction aids, bases and solvents are the below in Method (A) listed suitable.

N-terminally protected azadepsipeptides of the formula (IX) can, for. B. produce by the O-protecting group A ³ bilaterally protected azadepsipeptides of the formula (XI), C-terminally protected azadepsipeptides of the formula (X) by analogously the N-protecting group A ² bilaterally protected azadepsipeptides of the formula (XII) splits off the generally known methods given above.

In formula (XI), A ^{3 represents} a C-terminal protective group as indicated for A ⁴ . In formula (XII), A ^{2 represents} an N-terminal protective group as indicated for A ¹ . The bilaterally protected (aza) tetradepsipeptides could in principle be combined into a single general formula because the odd-numbered residues in formula (XI) and the next higher even-numbered residues in formula (XII) stand for the same lists of residues. It should be expressed that in each synthesis of an individual compound of formula (I), the radicals can be selected independently of one another, ie the building blocks (XI) and (XII) can be the same or different. The synthesis of the compound of the formula (XI) is to be explained as a representative here because the same also applies to the preparation of (XII).

Pure tetradepsipeptides of the formula (XI) (X ¹ , X ² = CH) are from Annu. Rep. Sankyo Res. Lab. 46, 67-75 (1994) and J. Antibiot. 47, 1322-1327 (1994) or can be prepared by analogous methods. The compounds of formula (XI) can e.g. B. can be prepared by building blocks of the formula (XIII) with building blocks of the formula (XIV) in the presence of a reaction auxiliary such as BOP-Cl or HATU and a base such as Hünig base and optionally in the presence of a diluent such as dichloromethane according to the following reaction scheme:

As reaction aids, bases and solvents are those in process (A) listed.

Simply protected didepsipeptides of the formulas (XIII) and (XIV) are from the above. Known literature or z. B. prepared analogously to the methods specified there become. Simply protected aza didepsipeptides of the formulas (XIII) and (XIV) are known from DE-A1 196 12 644 or can e.g. B. analogous to those specified there Methods are made.  

Formula (III) provides a general definition of the compounds required for carrying out process (B) according to the invention. In this formula, X ² to X ⁴ and R ¹ to R ¹² preferably represent those radicals which have already been mentioned as preferred substituents in connection with the description of the aza-cyclodepsipeptides of the formula (I).

Compounds of formula (III) can, for. B. produce by splitting off the N-terminal protective group A ⁵ from compounds of the formula (XV) by the usual methods given above

In formula (XV) A ^{5 represents} an N-terminal protective group as indicated for A ¹ .

Compounds of formula (XV) can, for. B. prepared by reacting (aza) - depsipeptide ester of the formula (XVI) with hydrazines of the formula (XVII) according to the following reaction scheme:

In formula (XVI), R ^{13 represents} optionally substituted alkyl or aryl. (Aza) - Depsipeptide esters of the formula (XVI) can, for. B. analogous to the synthesis of the compound (VII) by the peptide chemical methods used or described there.

Hydrazines of the formula (XVII) are known in some cases or can be prepared according to known ones Methods are obtained (see, for example, J. Chem. Soc. Perkin Trans. I 1975, 1712).

Formula (IV) provides a general definition of the compounds required for carrying out process (B) according to the invention. In this formula, Y ¹ preferably represents chlorine, trichloromethoxy, methoxy, ethoxy, 1-imidazolyl, 1,2,4-triazolyl or Z-substituted aryloxy, in particular pentafluorophenyl, 4-nitro phenyl or 2,4-dinitrophenyl, Y ² preferably for chlorine, trichloromethoxy, meth oxy, ethoxy, 1-imidazolyl or 1,2,4-triazolyl.

The compounds of formula (IV) are as phosgene or phosgene equivalents generally known (see e.g. Org. Syntheses Coll. Vol. 5, 201 (1973)).

The compounds required for carrying out the process (C) according to the invention are generally defined by the formula (V). In this formula, X ² , X ³ , X ⁴ , R ¹ to R ¹² preferably represent those radicals which have already been mentioned as preferred substituents in connection with the description of the aza-cyclodepsipeptides of the formula (I). Y ¹ preferably represents chlorine, trichloromethoxy, 1-imidazolyl, 1,2,4-triazolyl or Z-substituted aryloxy, in particular pentafluorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl.

Compounds of formula (V) can, for. B. produce by splitting off the N-terminal protective group A ⁵ from compounds of the formula (XVIII) according to the methods given above.

Compounds of formula (XVIII) can, for. B. produce by reacting the compounds of formula (XV) described above with one of the phosgenation reagents of formula (IV) described in process B) and, if desired, the product of formula (XVIII) obtained in which Y ^{1 is} not for Z. -substituted aryloxy is reacted with a corresponding phenol or phenolate such as 2,4-dinitrophenol.

As reaction aids for carrying out process (A) according to the invention all compounds which are suitable for forming an amide bond are suitable (see e.g. Houben-Weyl, Methods of Organic Chemistry, Volume 15/2; Bodensky et al .; Peptide Synthesis 2nd ed., Wiley & Sons, New York 1976). Preferably the following methods are possible: active ester method with pentafluorophenol (PfP), N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBt), coupling with carbo diimides such as dicyclohexylcarbodiimide or N '- (3-dimethylaminopropyl) -N-ethyl  carbodiimide (EDC) as well as the mixed anhydride method or the coupling with Phosphorus reagents such as 1-benzotriazolyloxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP), O- (7-azabenzotrial-1-yl) -l, 1,3,3-tetramethyluronium hexafluorophosphate (HATU), bis (2-oxo-3-oxazolidinyl) phosphoryl chloride (BOP- Cl), diphenylphosphoryl azide (DPPA) or diethyl cyanophosphonate (DEPC). Coupling with BOP-Cl, HATU or EDC in the presence is particularly preferred by HOBt.

Com as a solvent for carrying out process (A) according to the invention Men organic solvents and any mixtures thereof into consideration. At The following may be mentioned as examples: aliphatic, alicyclic or aromatic hydrocarbons substances such as petroleum ether, hexane, heptane, cyclohexane, methylcyclo hexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons, such as for example chlorobenzene, dichlorobenzene, methylene chloride, chloroform, tetra chloromethane, dichloro, trichloroethane or tetrachlorethylene; Ethers, such as diethyl, Diisopropyl, methyl t-butyl, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2- Dimethoxyethane; 1,2-diethoxyethane, diethylene glycol dimethyl ether or anisole; Ketones such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; Nitriles, like Acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; Amides, like form amide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-Me thylpyrrolidone, 1,3-dimethyl-tetrahydro-2-pyrimidinone (DMPU), 1,3-dimethyl-2- imidazolidinone, tetramethylurea or hexamethylphosphoric triamide; N- Oxides such as N-methylmorpholine-N-oxide; Esters such as methyl, ethyl or butyl acetate; Sulfoxides such as dimethyl sulfoxide; Sulfones such as sulfolane.

The cyclization is preferably carried out in the presence of a base. As a sol inorganic or organic bases are possible. These include preferential as alkaline earth metal or alkali metal hydroxides, alcoholates, acetates, carbonates or bicarbonates, such as sodium, potassium or ammonium hydroxide, sodium methylate, sodium ethylate, potassium tert-butoxide, sodium,  Potassium, calcium or ammonium acetate, sodium, potassium or ammonium car bonate, sodium hydrogen or potassium hydrogen carbonate and tertiary amines, such as Trimethylamine, triethylamine, tributylamine, ethyldiisopropylamine, N, N-dimethyl aniline, N, N-dimethyl-benzylamine, pyridine, picoline, N-methylpiperidine, N-methyl morpholine, N, N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyc ionone (DBN) or diazabicycloundecene (DBU).

In the process (A) according to the invention, the reaction temperature can be within can be varied over a wide range. Generally one works at the Cyclization at temperatures between -40 ° C and + 150 ° C, preferably at -20 ° C to 100 ° C, particularly preferably at 0 ° C to room temperature.

When carrying out process (A) according to the invention, the verb tion of the formula (II) and the base in general in a molar ratio of 1: 1 to 1: 3, preferably 1: 2, used. It is advantageous to work with high dilution nung, d. H. in general, 50 to per mole of compound of formula (II) 5000 ml of solvent.

Process (B) according to the invention can be carried out in the presence of a diluent be performed. As such, those in process (A) are preferably listed used.

Process (B) according to the invention can be carried out in the presence of a suitable Reaction aids are carried out. As such, everyone comes to the process (A) listed bases in question.

The reaction temperature in process (B) according to the invention can be within can be varied over a wide range. Generally one works at Tempe temperatures between -20 ° C and + 150 ° C, preferably between + 20 ° C and 120 ° C,  where appropriate, the cyclization only after the reaction of the two Initiates reaction partner by increasing the temperature.

When carrying out process (B) according to the invention, the per mole of Compound of formula (III) 1.0 to 2.0 moles, preferably 1.0 to 1.2 moles Ver bond (IV) and optionally 1.0 to 5 mol of reaction auxiliaries.

Process (C) according to the invention can be carried out in the presence of a diluent be performed. As such, those in process (A) are preferably listed used.

Process (C) according to the invention can be carried out in the presence of a suitable reac tion aids are carried out. As such, everyone comes to process (A) listed bases in question.

In the process (C) according to the invention, the reaction temperature can be within can be varied over a wide range. Generally one works at Temperatures between -20 ° C and + 150 ° C, preferably between + 20 ° C and 120 ° C.

When carrying out process (C) according to the invention, if appropriate the compound of formula (IX) and the base generally in a molar ratio from 1: 1 to 1: 3, preferably used in equimolar amounts.

The reactions of the processes according to the invention can be carried out at normal pressure or be carried out under increased pressure. Preferably at normal pressure worked. Carrying out the reaction, working up and isolating the reaction Products are made using generally known methods. The end products are preferably by crystallization, chromatographic separation or by  Removal of the volatile constituents, if necessary in a vacuum, cleaned (cf. also the manufacturing examples).

The active ingredients are suitable for combating pathogenic endoparasites in humans and in animal husbandry and breeding occur in livestock, breeding, zoo, laboratory, experimental and hobby animals. they are against all or individual stages of development of the pests and against resistant and normally sensitive species are effective. By fighting the Pathogenic endoparasites are said to cause illness, death and reduced performance (e.g. in the production of meat, milk, wool, skins, etc.), so that by using the active ingredients a more economical and simple Animal husbandry is possible. Pathogenic endoparasites include cestodes, Trematodes, nematodes, in particular:

From the order of the Pseudophyllidea z. E.g .: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoorus spp.

From the order of the Cyclophyllidea z. E.g .: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosmsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.

From the subclass of Monogenea z. E.g .: Cyrodactylus spp., Dactylogyrus spp., Polystoma spp.

From the subclass of Digenea z. E.g .: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp.,  Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonismus spp., Dicrocoelium spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp.

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

From the order of the Rhabditia z. E.g. Micronema spp., Strongyloides spp.
From the order of Strongylida z. E.g .: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp.,. , Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus. Spp., Neostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostia. spp., Trichostrong. , Marshallagia spp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amido stomum spp., Ollulanus spp.

From the order of the Oxyurida z. E.g .: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.  

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

From the order of the Spirurida z. E.g .: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.

From the order of the Filariida z. 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 z. E.g. Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.

For example, the active compounds according to the invention have an excellent action against larvae of Trichinella spiralis and worms such as Nippostrongylus brasiliensis.

The livestock and breeding animals include mammals such as B. cattle, horses, sheep, Pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, Fur animals such as B. mink, chinchilla, raccoon.

Laboratory and experimental animals include mice, rats, guinea pigs, gold hamsters, dogs and cats.

The pets include dogs and cats.

The application can be prophylactic as well as therapeutic.

The active ingredients are used directly or in the form of suitable accessories Horse enteral, parenteral, dermal.  

The enteral application of the active ingredients happens, for. B. orally in the form of powder, Suppositories, tablets, capsules, fasting, watering, granules, drenches, boluses, medi feed or drinking water. The dermal application happens for. B. in the form diving (dipping), spraying (spraying), bathing, washing, pouring (pouring) on and spot-on) and powdering. Parenteral use happens e.g. B. in 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, infusion formulations, gels;
Emulsions and suspensions for oral or dermal use and for injection; semi-solid preparations;
Formulations in which the active ingredient is processed in an ointment base or in an oil in water or water in oil emulsion base;
solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; Aerosols and inhalants, molded articles containing active ingredients.

Solutions for injection are administered intravenously, intramuscularly and subcutaneously.

Injection solutions are made by adding the active ingredient in a suitable Solvent is dissolved and possibly additives such as solubilizers, acids, Bases, buffer salts, antioxidants, preservatives can be added. The Solutions are sterile filtered and filled.  

The following may be mentioned as solvents: Physiologically compatible solvents such as Water, alcohols such as ethanol, butanol, benzyl alcohol, glycerin, coal water substances, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures the same.

The active ingredients can, if appropriate, also be physiologically tolerated Dissolve vegetable or synthetic oils that are suitable for injection.

The following may be mentioned as solubilizers: solvents which are the solution of the active ingredient in the main solvent or prevent it from falling out. examples are Polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

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

Oral solutions are applied directly. Concentrates are made according to the previous one Dilution to the application concentration applied orally. Oral solutions and concentrates are prepared as described above for the injection solutions provides, whereby sterile work can be dispensed with.

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

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

Gels are applied or spread onto the skin or in body cavities brought in. Gels are made by using solutions similar to Injek tion solutions have been prepared with so much thickening agent be set that a clear mass with ointment-like consistency arises. As Thickeners are added to the thickeners specified above puts.

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

Pour-on formulations are made by adding the active ingredient in appropriate skin-compatible solvents or solvent mixtures dissolved; suspended or is emulsified. If necessary, other auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers, adhesives added.

The following may be mentioned as solvents: water, alkanols, glycols, polyethylene glycols, Polypropylene glycols, glycerin, aromatic alcohols such as benzyl alcohol, phenyl ethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as Alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol mono-butyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, Di methylacetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1,3-dioxolane.

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

Resorption promoting substances are e.g. B. DMSO, spreading oils such as isopropyl myristate, Dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.  

Antioxidants are sulfites or metabisulfites such as potassium metabisulfate, ascorbin acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.

Light stabilizers are e.g. B. substances from the class of benzophenones or Novan tisolic acid.

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

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

Emulsions are either water in oil or oil in water.

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

The following may be mentioned as hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid biglyceride, triglyceride mixture with vegetable fatty acid of chain length C ₈ -C ₁₂ or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated, possibly also hydroxyl-containing fatty acids, mono- and diglycerides of C ₈ / C ₁₀ fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length C ₁₆ -C ₁₈ , isopropyl myristate, isopropyl palmitate, caprylic / capric acid esters of saturated fatty alcohols ₁₂ - C ₁₈ , isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duckling gland fat, di butyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures and others

Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

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

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

The following may be mentioned as emulsifiers: nonionic surfactants, e.g. B. 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 agents and the emulsion stabi substances such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic acid anhydride, polyethylene glycols, waxes, colloidal silica or mixtures of listed substances.  

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

Carrier liquids are all homogeneous solvents and solvents called mix.

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

Further additives mentioned are those mentioned above.

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

For the preparation of solid preparations, the active ingredient is used with a suitable carrier substances may be mixed with additives and added to the ge desired shape brought.

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

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

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

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

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

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

Preparations that are diluted before use contain the active ingredient in Concentrations from 0.5 to 90% by weight, preferably from 5 to 50% by weight.

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

The production and use of the active compounds according to the invention or Intermediates are shown in the examples below.  

Manufacturing examples Example I-1 (Method A)

800 mg (0.825 mmol) H-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac- MeAzaLeu-D-Lac-OH (e.g. from Example II-1) were dissolved in an argon atmosphere in 1000 ml of dichloromethane submitted. At 0 ° C, 266 mg was added to the solution (2.06 mmol) ethyldiisopropylamine and 252 mg (0.99 mmol) BOP-Cl added. The mixture was then allowed to warm to room temperature and stirred for a further 24 h. The reaction solution was then washed with sat. Sodium bicarbonate solution and Washed water, dried over sodium sulfate and concentrated. According to pillars chromatography (silica gel, ∅ = 4.5 cm, l = 25 cm; cyclohexane: ethyl acetate 1: 1) 247 mg of 6,18-dibenzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl- 1,7,13,19-tetraoxa-3,4,9,10,16,22-hexaaza-cyclotetracosane-2,5,8,11,14,17,20,23-oc taon (cyclo- [MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac]) obtained as a yellowish solid melting at 90-91 ° C.

Additional purification by HPLC (reversed phase RP18, 5 µm, acetonitrile / water gradient) gave 121 mg of analytically pure substance after freeze-drying.
HR-MS: m / z
calculated:
for C ₅₀ H ₇₄ N ₆ O ₁₂ Na 973.5262
found:
for C ₅₀ H ₇₄ N ₆ O ₁₂ Na 973.5265

Manufacture of intermediate products Example II-1

850 mg (0.80 mmol) H-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac- MeAzaLeu-D-Lac-O-Bn (e.g. from Ex. VII-1) were dissolved in approx. 30 ml of ethyl acetate and hydrogenated at normal pressure with hydrogen in the presence of Pd / C (10%). After the reaction had ended, the catalyst was filtered off and the solvent removed in vacuum. 806 mg of H-MeLeu-D-PhLac-MeLeu-D-Lac- MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-OH obtained as a slightly colored foam.  

Example VII-1

1.36 g (1.173 mmol) Boc-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac- MeAzaLeu-D-Lac-O-Bn (e.g. from Ex. VII-1) were dissolved in 10 ml dichloro under argon submitted methane. At 0 ° C, 1.34 g (11.73 mmol) was slowly added to the solution Trifluoroacetic acid added dropwise and stirred overnight at this temperature. On was then concentrated in vacuo, the residue taken up in ethyl acetate and with sat. Sodium bicarbonate solution and sat. Sodium chloride solution washed. After drying and removal of the solvent in vacuo 0.95 g (76% of theory) of H-MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac- Obtain MeAzaLeu-D-Lac-O-Bn as a dark colored, highly viscous oil.

Example VIII-1

2.67 g (4.5 mmol) carboxylic acid Boc-MeLeu-D-PhLac-MeLeu-D-Lac-OH (Annu. Rep. Sankyo Res. Lab. 46, 67-75 (1994) and J. Antibiot. 47 , 1322-1327 (1994)) were placed under argon in 45 ml of dry dichloromethane. At 0 ° C., 1.40 g (5.5 mmol) of BOP-Cl and 0.59 g (5.8 mmol) of N-methylmorpholine were slowly added in succession. After about 1 hour, 2.62 g (4.5 mmol) of hydrazine H-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn (e.g. from Example X-1) were dissolved in a little dichloromethane slowly added. A further 0.59 g of N-methyl morpholine was then added. The mixture was allowed to warm to RT and stirred for a further 12 h. The mixture was then concentrated, the residue was taken up in ethyl acetate, washed with sat. Washed sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. After column chromatography (silica gel, ∅ = 4.5 cm, l = 25 cm; cyclohexane: ethyl acetate 3: 1), 2.40 g (46% of theory) of Boc-MeLeu-D-PhLac-MeLeu-D-Lac -MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn obtained as a yellow, highly viscous oil.
HR-MS: m / z
calculated:
for C ₆₂ H ₉₀ N ₆ O ₁₅ Na 1181.6362
found:
for C ₆₂ H ₉₀ N ₆ O ₁₅ Na 1181.6349

Example X-1

3.08 g (4.5 mmol) of Boc-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn (e.g. from Example XII-1) were placed under argon in 60 ml of dry dichloromethane. At 0 ° C., 5.14 g (45 mmol) of trifluoroacetic acid were slowly added dropwise to the solution. The mixture was allowed to warm to RT and stirred for about 15 h. The solution was then concentrated, the residue taken up in dichloromethane and washed with sat. Sodium bicarbonate solution and sat. Washed sodium chloride solution. After drying over sodium sulfate, the solvent was removed in vacuo. 2.67 g (quantitative) of H-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn were obtained as a slightly dark colored viscous oil.
MS (FAB): m / z (rel. Int.): 585 (M + H ⁺ , 35), 584 (M ⁺ , 20)

Example XI-1

11.9 g (30 mmol) of benzyl ester of 2- (1-isobutyl-2-methylhydrazyl) -carbonyloxypropionate (e.g. from example XIV-1 or WO 9736883) and 9.22 g (30 mmol) of 2- ( 2-tert-Butoxycarbonyl-1-isobutyl-2-methylhydrazyl) -carbonyloxy-3-phenylacetic acid (e.g. from Example XIII-1) were placed under argon in 120 ml of dry dichloromethane. At 0 ° C., 9.69 g (75 mmol) of ethyldiisopropylamine and then 9.16 g (36 mmol) of BOP-Cl were slowly added to the solution. After stirring at 0 ° C. for 2 h, the mixture was allowed to warm to RT and stirred for a further 12 h. After column chromatography (silica gel, ∅ = 6 cm, l = 30 cm; cyclohexane: ethyl acetate 6: 1), 9.25 g (45% of theory) of Boc-MeAzaLeu-D-PhLac-MeAzaLeu-D-Lac- Obtain O-Bn as a yellow viscous oil.
HR-MS: m / z
calculated:
for C ₃₆ H ₅₂ N ₄ O ₉ Na 707.3632
found:
for C ₃₆ H ₅₂ N ₄ O ₉ Na 707.3634

Example XIII-1

15.54 g (30 mmol) of benzyl 2- (2-tert-butoxycarbonyl-1-isobutyl-2-methylhydrazyl) -car bonyloxy-3-phenylacetate (for example from WO 9736883) were dissolved in 150 ml of ethyl acetate and hydrogenated under normal pressure with hydrogen in the presence of Pd / C (10%). When the reaction was complete, the catalyst was filtered off and the solvent was removed in vacuo. 11.9 g (quantitative) of 2- (2-tert-butoxycarbonyl-1-isobutyl-2-methylhydrazyl) carbonyloxy-3-phenylacetic acid were obtained as a tan oil.
MS: m / z (rel. Int.): 417 (M + Na ⁺ , 20); 395 (M + H ⁺ , 10); 394 (M ⁺ , 5); 393 (MH ⁺ , 10); 339 (70); 321 (40); 295 (100); 173 (60); 148 (50); 131 (35); 101 (35)
¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm) 0.95 (complete range, 6H, CH (C H ₃ ) ₂ ); 1.35-1.55 (complete range, 10H, C (C H ₃ ) ₃ , C H (CH ₃ ) ₂ ); 2.6-3.45 (complete range, 8H, CH ₂ Ph, OCH, NCH ₂ , NCH ₃ ); 7.35 (m, 5H, C ₆ H ₅ )

Example XIV-1

12.25 g (30 mmol) of benzyl 2- (2-tert-butoxycarbonyl-1-isobutyl-2-methylhydrazyl) -carbonyloxy-propionate (e.g. from WO 9736883) were dissolved in 100 ml of dry dichloromethane under argon submitted. At 0 ° C., 27.36 g (240 mmol) of trifluoroacetic acid were slowly added dropwise to the solution. The mixture was allowed to warm to RT and stirred for a further 24 h. The solution was then concentrated in vacuo, the residue was taken up in ethyl acetate and washed with sat. Sodium bicarbonate solution and sat. Washed sodium chloride solution. After drying over sodium sulfate and removal of the solvent in vacuo, 7.21 g (78% of theory) of benzyl 2- (1-isobutyl-2-methylhydrazyl) -carbonyloxy-propionate were obtained as a light yellow viscous oil.
MS: m / z (rel. Int.): 309 (M + H ⁺ , 100); 308 (M ⁺ , 89); 101 (28); 91 (PhCH ₂ ⁺ , 100)
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 0.90 (2d, 6H, CH (C H ₃ ) ₂ ); 1.53 (d, 3H, CHC H _3); 2.70 (br. S, 3H, NCH ₃ ); 3.27 (m, 2H, NCH _2); 5.18 (m, 3H, CH ₂ Ph, OCH); 7.35 (m, 5H, C ₆ H ₅ )

Examples of use Example A Trichinen test (in vitro experiment)

Trichinella spiralis larvae were isolated from skeletal muscles and diaphragms of SPF / CFW1 mice and stored in 0.9% NaCl solution, which had been supplemented with 20 µg ml ^-1 clotrimazole. The incubation of 20 larvae per determination was carried out in 2 ml of a solution containing 500 g 10 g Bacto Casitone, 5 g yeast extract, 2.5 g glucose, 0.4 g KH ₂ PO ₄ and 0.4 g K ₂ HPO ₄ (pH 7.2) supplemented by 10 ug ml ^-1 sisomicin and 1 ug ml ^-1 clotrimazole contained. 10 mg of the active ingredient to be tested were dissolved in 0.5 ml of dimethyl sulfoxide and added to the incubation medium in the amount that final concentrations of 100, 10, 1, 0.1 or 0.01 µg ml ^{-1 were} obtained. After 5 days of incubation at 19 ° C, the experiment was stopped. The activity of the tested compounds was quantified as follows: 3 = full activity (all larvae are dead); 2 = good effect (not all, but more than half of the larvae are dead); 1 = weak effect (not all, but more than half of the larvae live); 0 = no effect (number of live larvae is the same as in the untreated control). (See Tropenmed. Parasitol. 32, 31-34 (1981).

In this test, for example, the compound according to the invention showed Preparation example I-1 at an exemplary active ingredient concentration of 100 µg / ml an effect of level 3.  

Example B Nippostrongyl test (in vitro experiment)

Adult Nippostrongylus brasiliensis was isolated from the small intestine of female Wistar rats and stored in 0.9% NaCl solution, which had been supplemented with 20 µg ml ^-1 sisomicin and 2 µg ml ^-1 clotrimazole. The incubation of each group of male or female worms without (control) or with the active ingredient to be tested dissolved in dimethyl sulfoxide was carried out in 1.0 ml of nutrient medium. The medium was removed to determine the activity of acetylcholinesterase as an indicator of the life status of the worms. The incubation and determination of enzyme activity as a test for anthelmintic effects is described in Z. Parasitenkd. 73 190-191 (1987). The level of activity of the test compound was quantified as follows: 3 = full activity (95% -100% inhibition of the enzyme); 2 = good effect (75% -95% inhibition); 1 = weak effect (50% -75% inhibition); 0 = negligible effect (less than 50% inhibition).

In this test, for example, the compound according to the invention showed Preparation example I-1 at an exemplary active ingredient concentration of 100 µg / ml an effect of level 3.

Claims (7)

1. Aza-cyclodepsipeptides of the formula (I)
in which
X ¹ , X ² , X ³ and X ⁴ each independently represent N or CH, where at least one of these variables X represents nitrogen,
R ¹ , R ² , R ³ and R ⁴ each independently represent hydrogen, in each case optionally substituted by halogen, alkyl, alkenyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, aryloxycar bonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl , Dialkylaminoalkyl or for optionally substituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl, and
the grouping -NR ⁹ -X ¹ R ⁵ - represents a radical of the formula -NR ^9-1 -CHR ^5-1 - or a radical of the formula -NR ^9-2 -NR ^5-2 -,
the grouping -NR ¹⁰ -X ² R ⁶ - represents a radical of the formula -NR ^10-1 -CHR ^6-1 - or a radical of the formula -NR ^10-2 -NR ^6-2 -,
the grouping -NR ¹¹ -X ³ R ⁷ - represents a radical of the formula -NR ^11-1 -CHR ^7-1 - or a radical of the formula -NR ^11-2 -NR ^7-2 -,
the grouping -NR ¹² -X ⁴ R ⁸ - represents a radical of the formula -NR ^12-1 -CHR ^8-1 - or a radical of the formula -NR ^12-2 -NR ^8-2 -,
R ^5-1 , R ^6-1 , R ^7-1 and R ^8-1 independently of one another each for hydrogen, optionally substituted by amino or hydroxy-substituted alkyl, for mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl, for optionally substituted by amino, nitro, halogen, hydroxyl or alkoxy-substituted phenyl or benzyl, are naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl, thienylmethyl, benzothienylmethyl or pyridylmethyl, where functional groups can optionally be present in a protected manner,
R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 each independently represent hydrogen or C ₁ -C ₄ alkyl,
where the pairs of residues R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1 also together independently of one another for the residues - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ - stand,
R ^5-2 to R ^12-2 independently of one another each represent hydrogen, in each case optionally substituted by halogen, alkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl , Dialkylaminoalkyl, alkoxycarbonylamino alkyl or for optionally substituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl and
where the pairs of residues R ^5-2 / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2 also together, independently of one another, for the if necessary C ₁ - C ₄ alkyl-substituted radicals - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ - are. 2. Process for the preparation of the aza-cyclodepsipeptides of the formula (I)
in which
X ¹ , X ² , X ³ and X ⁴ each independently represent N or CH, where at least one of these variables X represents nitrogen,
R ¹ , R ² , R ³ and R ⁴ are each independently of one another hydrogen, in each case optionally substituted by halogen, alkyl, alkenyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl , Dialkylaminoalkyl or for optionally substituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl, and
the grouping -NR ⁹ -X ¹ R ⁵ - represents a radical of the formula -NR ^9-1 -CHR ^5-1 - or a radical of the formula -NR ^9-2 -NR ^5-2 -,
the grouping -NR ¹⁰ -X ² R ⁶ - represents a radical of the formula -NR ^10-1 -CHR ^6-1 - or a radical of the formula -NR ^10-2 -NR ^6-2 -,
the grouping -NR ¹¹ -X ³ R ⁷ - represents a radical of the formula -NR ^11-1 -CHR ^7-1 - or a radical of the formula -NR ^11-2 -NR ^7-2 -,
the grouping -NR ¹² -X ⁴ R ⁸ - represents a radical of the formula -NR ^12-1 -CHR ^8-1 - or a radical of the formula -NR ^12-2 -NR ^8-2 -,
R ^5-1 , R ^6-1 , R ^7-1 and R ^8-1 independently of one another each for hydrogen, optionally substituted by amino or hydroxy-substituted alkyl, for mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl, for optionally substituted by amino, nitro, halogen, hydroxyl or alkoxy-substituted phenyl or benzyl, are naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl, thienylmethyl, benzothienylmethyl or pyridylmethyl, where functional groups can optionally be present in a protected manner,
R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 each independently represent hydrogen or C ₁ -C ₄ alkyl,
where the pairs of residues R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1 also together independently of one another for the residues - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ - stand,
R ^5-2 to R ^12-2 independently of one another each represent hydrogen, in each case optionally substituted by halogen, alkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl , Dialkylaminoalkyl, alkoxycarbonylamino alkyl or for optionally substituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl and
where the pairs of residues R ^5-2 / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2 also together, independently of one another, for the if necessary C ₁ - C4-alkyl-substituted radicals - (CH ₂ ) ₃ and - (CH ₂ ) ₄ - are,
characterized in that one

• A) Azadepsipeptides of the formula (II)
  in which
  X ¹ , X ² , X ³ , X ⁴ and R ¹ to R ^{12 have} the meanings given above,
  cyclized in the presence of a reaction auxiliary and a solvent and optionally in the presence of a base or
• B) in the event that azacyclodepsipeptides of the formula (Ia) are prepared
  in which
  X ² , X ³ , X ⁴ each independently represent N or CH and
  R ¹ to R ^{12 have} the meanings given above,
  azadepsipeptides of the formula (III)
  in which
  X ² , X ³ , X ⁴ each independently represent N or CH and
  R ¹ to R ^{12 have} the meanings given above,
  with compounds of formula (IV)
  in which
  Y ^{1 represents} chlorine, trichloromethoxy, C ₁ -C ₄ alkoxy, optionally substituted phenoxy, 1-imidazolyl or 1,2,4-triazolyl and
  Y ^{2 represents} chlorine, trichloromethoxy, 1-imidazolyl or 1,2,4-triazolyl,
  optionally in the presence of a diluent and, if appropriate, in the presence of a reaction auxiliary and cyclocondensed or
• C) by using azadepsipeptides of the formula (V)
  in which
  X ² , X ³ , X ⁴ each independently represent N or CH and
  R ¹ to R ¹² and Y ^{1 have} the meanings given above,
  optionally cyclocondensed in the presence of a diluent and optionally in the presence of a reaction auxiliary.

3. azacyclodepsipeptides of formula (I) according to claim 1, in which the substituents have the following meanings:
R ¹ , R ² , R ³ and R ⁴ independently of one another represent hydrogen, C ₁ -C ₁₆ -alkyl, each optionally substituted by fluorine, chlorine or bromine, C ₁ -C ₆ -alkyl, C ₂ -C ₈ - Alkenyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl-C ₁ -C ₄ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₄ alkanoyloxy-C ₁ - C ₆ alkyl, C ₁ -C ₄ alkoxy-C ₁ -C ₆ alkyl, aryl-C ₁ -C ₄ alkoxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ mercaptoalkyl, C ₁ -C ₄ alkylthio- C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy carbonyl-C ₁ -C ₆ alkyl, aryloxycarbonyl-C ₁ -C ₆ alkyl, aryl C ₁ -C ₄ alkyl oxycarbonyl-C ₁ -C _6- alkyl, carbamoyl-C ₁ -C ₆ -alkyl, amino-C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkylamino-C ₁ -C ₆ -alkyl, di-C ₁ -C ₄ -alkylamino- C ₁ -C ₆ alkyl or for each optionally halogen, hydroxy, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, Benzyloxy or silyloxy, which is trisubstituted by C ₁ -C ₄ -alkyl and / or phenyl, substituted aryl, aryl-C ₁ -C ₄ -alkyl, hetar yl or hetaryl-C ₁ -C ₄ alkyl.
R ^5-1 , R ^6-1 , R ^7-1 and R ^8-1 independently represent hydrogen, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercapto methyl, 2- Methylthioethyl, 3-aminopropyl, 4-aminobutyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 3-guanidinopropyl, phenyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4- Nitrobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 3,4-dichlorobenzyl, 4-iodobenzyl, α-naphthylmethyl, β-naphthylmethyl 3-indolylmethyl, 4-imidazolylmethyl, 1,2,3-triazol-1- yl-methyl, 1,2,4-triazol-1-yl-methyl, 3-thienylmethyl, 3-benzothienylmethyl, 2-pyridylmethyl or 3-pyridylmethyl, where functional groups may optionally be protected.
R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 independently represent hydrogen, methyl or ethyl.
R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1 also together stand independently for the residues - ( CH ₂ ) ₃ - and - (CH ₂ ) ₄ -.
R ^5-2 to R ^12-2 independently of one another stand for hydrogen, C ₁ -C ₁₅ alkyl, for C ₁ -C ₈ alkyl optionally substituted by fluorine, chlorine or bromine, C ₃ -C ₇ cycloalkyl, C. ₃ -C ₇ cycloalkyl-C ₁ -C ₄ alkyl, C ₁ -C ₆ - hydroxyalkyl, C ₁ -C ₄ alkanoyloxy-C ₁ -C ₆ alkyl, C ₁ -C ₄ -alkoxy-C ₁ - C ₆ -alkyl, aryl-C ₁ -C ₄ alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -ercaptoalkyl, C ₁ -C ₄ -alkylthio-C ₁ -C ₆ -alkyl, C ₁ -C _4- alkylsulfinyl-C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkyl sulfonyl-C ₁ -C ₆ -alkyl, carboxy-C ₁ -C ₆ -alkyl, carboxyethyl or carboxy-tert-butyl, C ₁ -C ₄ -alkoxycarbonyl-C ₁ -C ₆ -alkyl, aryloxy carbonyl-C ₁ -C ₆ -alkyl, aryl-C ₁ -C ₄ -alkyloxycarbonyl-C ₁ -C ₆ -alkyl, carbamoyl-C ₁ -C ₆ -alkyl, amino-C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkylamino-C ₁ -C ₆ -alkyl, di- (C ₁ -C ₄ ) -alkylamino-C ₁ -C ₆ -alkyl, C ₁ -C ₄ alkoxycarbonylamino-C ₁ -C ₆ alkyl, or for each optionally by halogen, hydroxy, nitro, cyano, amino, C ₁ -C ₄ alkylamino, di- (C ₁ -C ₄ ) - alkyl amino, benzylamino, dibenzylamino, protected amino, C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ haloalkoxy substituted aryl, aryl-C ₁ -C _4- alkyl, hetaryl or hetaryl-C ₁ -C ₄ -alkyl, where an NH function in the heterocyclic ring can optionally be derivatized by an amino protecting group, such as the above.
R ^5-2 / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^{12-2 also} stand together independently of one another for those that may be simple to radicals substituted four times by C ₁ -C ₄ alkyl - (CH ₂ ) ₃ - and - (CH ₂ ) ₄ -. 4. Compounds of formula (I) according to claim 1
in which
R ¹ , R ² , R ³ and R ⁴ independently of one another represent methyl, which is optionally substituted by phenyl, which in turn can be substituted by halogen, cyano, nitro, amino, dialkylamino, morpholino,
the groups X ¹ -R ⁵ , X ² -R ⁶ , X ³ -R ⁷ , X ⁴ -R ⁸ independently of one another for the radicals
stand in which
R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are C ₁ -C ₄ alkyl, in particular branched C ₄ alkyl, very particularly i-butyl,
R ⁹ , R ¹⁰ , R ¹¹ and R ¹² independently of one another are C ₁ -C ₄ alkyl, in particular methyl. 5. Use of aza-cyclodepsipeptides of formula (I) according to claim 1 to fight endoparasites.   6. Use of aza-cyclodepsipeptides of the formula according to claim 1 for Manufacture of endoparasiticidal agents. 7. Endoparasiticidal agents characterized by a content of aza Cyclodepsipeptides of formula (I) according to claim 1 optionally in Mix with common diluents and additives.