DE19545044A1 - Endoparasiticidal agents - Google Patents

Abstract

The invention relates to orally administered endoparasiticidal agents which contain cyclic and open-chain depsipeptides comprising amino acids and hydroxycarboxylic acids as structural components and 6 to 30 ring atoms or chain atoms.

Description

The present invention relates to orally administrable agents, the cyclic and contain open chain depsipeptides.

A cyclic depsipeptide PF1022 and its activity against endoparasites is known from EP-OS 382 173.

Other cyclic depsipeptides and their endoparasiticidal activity are counter state of the German patent applications DE-A 43 17 432.9; 43 17 457.4; 43 17 458.2.

The present invention relates to endoparasiticides which can be administered orally Agent, the cyclic and open chain depsipeptides consisting of amino acids and hydroxycarboxylic acids, as building blocks and 6 to 30 ring or chain atoms contain.

The depsipeptides used in the agents according to the invention are heavy water soluble. Solutions that can be administered orally can only be prepared with Using suitable cosolvents.

In order to ensure good bioavailability of the active ingredients, it is desirable to administer the drug solution in a gelatin capsule. The solution may be neither attack the gelatin capsule, nor should the solvent slowly come out of the Diffuse the gelatin capsule out. That said, a solution was needed to develop a system in which the poorly water-soluble depsipeptides in sufficiently high concentration are kept in solution for a long time and which at the same time does not attack the gelatin capsule that envelops each dose.

The present invention relates to:

• 1. Means for oral administration of cyclic and / or open chain Depsipeptides alone or in a mixture with other active ingredients characterized in that these active ingredients in a solvent mixture  
• - propylene glycol
• - fatty acid esters of polyhydric alcohols (oils)
• - emulsifiers
• are solved.
• 2. Agents which are characterized in that the active ingredient solution in one Soft gelatin capsule is included.
• 3. Agents that are characterized in that the solvent mixture has the following composition:
• - propylene glycol: 5 to 20%
• - Oil: 50 to 70%
• - Emulsifier: 1 to 10%.
• 4. Means that are characterized in that a soft gelatin capsule System of the following composition contains:
• - Active ingredient: 0.1 to 20%
• - propylene glycol: 5 to 20%
• - Oil: 50 to 70%
• - Emulsifier: 1 to 8%.

The present invention furthermore relates to the production by oral administration barer endoparasiticidal agent, the cyclic depsipeptides consisting of amino acids and hydroxycarboxylic acids as ring building blocks and 6 to 30 ring atoms contain.

Preferred cyclic depsipeptides are those with 18 to 24 ring atoms.

Depsipeptides with 18 ring atoms include compounds of the general type Formula (I):

in which
R¹, R³ and R⁵ independently of one another for hydrogen straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, carbamoylalkylamino, carbamoylalkylamino, amino Guanidinoalkyl, which can optionally be substituted by one or two benzyloxycarbonyl radicals or by one, two, three or four alkyl radicals, alkoxycarbonylaminoalkyl, 9-fluorenyl methoxycarbonyl (Fmoc) aminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl and optionally substituted arylalkyl, where halogen may be mentioned as a substituent , Hydroxy, alkyl, alkoxy, stand,
R², R⁴ and R⁶ independently of one another for hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, mercaptoalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthio alkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, carboxyalkyl, alkoxy carbonylalkyl, arylalkoxycarbonylalkyl, carbamoylamino, carbamoylamino, carbamoylamino, carbamoylamino, carbamoylamino, carbamoylamino, carbamoylamino, carbamoylamino , Dialkylaminoalkyl, alkoxycarbonylaminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl optionally substituted aryl or arylalkyl where halogen, hydroxy, alkyl, alkoxy are mentioned as substituents,
and their optical isomers and racemates.

Compounds of the formula (I) are preferred
in which
R¹, R³ and R⁵ independently of one another for straight-chain or branched C₁-C₈ alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, sec.-pentyl, hexyl , Isohexyl, sec.- hexyl, heptyl, isoheptyl, sec.-heptyl, tert.-heptyl, octyl, isooctyl, sec.- octyl, hydroxy-C₁-C₆-alkyl, especially hydroxymethyl, 1-hydroxyethyl, C₁-C₄- Alkanoyloxy-C₁-C₆-alkyl, especially acetoxymethyl, 1-acetoxy ethyl, C₁-C₄-alkoxy-C₁-C₆-alkyl, especially methoxymethyl, 1-meth oxyethyl, aryl-C₁-C₄-alkyloxy-C₁-C₆-alkyl, especially benzyloxymethyl, 1-benzyloxy-ethyl, mercapto-C₁-C₆-alkyl, especially mercaptomethyl, C₁-C₄-alkylthio-C₁-C₆-alkyl, especially methylthioethyl, C₁-C₄-alkyl sulfinyl-C₁-C₆-alkyl, especially methylsulfinylethyl , C₁-C₄-alkylsulfonyl-C₁-C₆-alkyl, especially methylsulfonylethyl, carboxy-C₁-C₆-alkyl, especially carboxymethyl, carboxyethyl, C₁-C₄-alk oxycarbonyl-C₁-C₆ alkyl, especially methoxycarbonylmethyl, ethoxycarbonylethyl, C₁-C₄- arylalkoxycarbonyl-C₁-C₆-alkyl, especially benzyloxycarbonylmethyl, carbamoyl-C₁-C₆-alkyl, especially carbamoylmethyl, carbamoylethyl, amino-C₁-C₆-alkyl, especially aminoprop , Aminobutyl, C₁-C₄-alkyl amino-C₁-C₆-alkyl, especially methylaminopropyl, methylaminobutyl, C₁-C₄-dialkylamino-C₁-C₆-alkyl, especially dimethylaminopropyl, dimethylaminobutyl, guanido-C₁-C₆-alkyl, especially guanidopropyl, C₁-C₄-alkoxycarbonylamino-C₁-C₆-alkyl, especially tert-butoxycarbonyl aminopropyl, tert-butoxycarbonylaminobutyl, 9-fluorenylmethoxycarbonyl- (Fmoc) amino-C₁-C₆-alkyl, especially 9-fluorenyl-methoxycarbonyl- (Fmoc) aminopropyl , 9-fluorenylmethoxycarbonyl (Fmoc) aminobutyl, C₂-C₈-alkenyl, especially vinyl, allyl, butenyl, C₃-C₇-cycloalkyl, in particular cyclopentyl, cyclohexyl, cycloheptyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, i Especially cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-C₁-C₄-alkyl, especially phenylmethyl which may be substituted by radicals from the halogen, especially fluorine, chlorine, bromine or iodine, hydroxy, C₁-C₄-alkoxy, especially methoxy or ethoxy, C₁-C₄ Alkyl, in particular methyl, can be substituted,
R², R⁴ and R⁶ independently of one another for straight-chain or branched C₁-C₈ alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, sec.-pentyl, hexyl , Isohexyl, sec.- hexyl, heptyl, isoheptyl, sec.-heptyl, tert.-heptyl, octyl, isooctyl, sec.- octyl, hydroxy-C₁-C₆-alkyl, especially hydroxymethyl, 1-hydroxyethyl, C₁-C₄- Alkanoyloxy-C₁-C₆-alkyl, especially acetoxymethyl, 1-acetoxy ethyl, C₁-C₄-alkoxy-C₁-C₆-alkyl, especially methoxymethyl, 1-meth oxyethyl, aryl-C₁-C₄-alkyloxy-C₁-C₆-alkyl, especially benzyloxymethyl, 1-benzyloxy-ethyl, mercapto-C₁-C₆-alkyl, especially mercaptomethyl, C₁-C₄-alkylthio-C₁-C₆-alkyl, especially methylthioethyl, C₁-C₄-alkyl sulfinyl-C₁-C₆-alkyl, especially methylsulfinylethyl , C₁-C₄-alkylsulfonyl-C₁-C₆-alkyl, especially methylsulfonylethyl, carboxy-C₁-C₆-alkyl, especially carboxymethyl, carboxyethyl, C₁-C₄-A lkoxycarbonyl-C₁-C₆-alkyl, especially methoxycarbonylmethyl, ethoxycarbonylethyl, C₁-C₄-arylalk oxycarbonyl-C₁-C₆-alkyl, especially benzyloxycarbonylmethyl, carbamoyl-C₁-C₆-alkyl, especially carbamoylmethyl, carbamoylethyl, amino-C₁-C₆-alkyl , in particular aminopropyl, aminobutyl, C₁-C₄-alkylamino-C₁-C₆-alkyl, in particular methylaminopropyl, methylaminobutyl, C₁-C₄-dialkylamino-C₁-C₆-alkyl, in particular dimethylaminopropyl, dimethyl aminobutyl, C₂-C₈-alkenyl, in particular vinyl, Allyl, butenyl, C₃-C₇- cycloalkyl, especially cyclopentyl, cyclohexyl, cycloheptyl, C₃-C₇- cycloalkyl-C₁-C₄-alkyl, especially cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl, phenyl-C₁-C₄-alkyl, especially phenylmethyl which is optionally substituted by radicals from the series halogen, in particular special fluorine, chlorine, bromine or iodine, hydroxyl, C₁-C Alkalkoxy, in particular methoxy or ethoxy, C₁-C₄alkyl, in particular methyl can be,
and their optical isomers and racemates.

Compounds of the formula (I) are particularly preferred
in which
R¹, R³ and R⁵ independently of one another for straight-chain or branched C₁-C₈ alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, pentyl, isopentyl, sec.-pentyl, hexyl, isohexyl, sec. -Hexyl, heptyl, isoheptyl, sec.-heptyl, octyl, isooctyl, sec.-octyl, hydroxy-C₁-C₆-alkyl, especially hydroxymethyl, 1-hydroxyethyl, C₁-C₄-alkanoyloxy-C₁-C₆- alkyl, especially acetoxymethyl , 1-acetoxyethyl, C₁-C₄-alkoxy-C₁-C₆- alkyl, especially methoxymethyl, 1-methoxyethyl, aryl-C₁-C₄-alkyloxy- C₁-C₆-alkyl, especially benzyloxymethyl, 1-benzyloxyethyl, C₁-C₄-alk oxycarbonylamino-C₁-C₆-alkyl, especially tert-butoxycarbonylaminopro pyl, tert-butoxycarbonylaminobutyl, C₂-C₈-alkenyl, especially vinyl, allyl, C₃-C₇-cycloalkyl, especially cyclopentyl, cyclohexyl, cyclo heptyl, C₃-C₇-cycloalkyl -C₁-C₄-alkyl, especially cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-C₁-C₄-alkyl, in particular special phenylmethyl which may optionally be substituted by one or more identical or different of the radicals indicated above,
R², R⁴ and R⁶ independently of one another for straight-chain or branched C₁-C₈ alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, sec.-pentyl, hexyl , Isohexyl, sec.- hexyl, heptyl, isoheptyl, sec.-heptyl, tert.-heptyl, octyl, isooctyl, sec.- octyl, hydroxy-C₁-C₆-alkyl, especially hydroxymethyl, aryl-C₁-C₄- alkyloxy- C₁-C₆-alkyl, especially benzyloxymethyl, 1-benzyloxyethyl, carboxy-C₁-C₆-alkyl, especially carboxymethyl, carboxyethyl, C₁-C₄- alkoxycarbonyl-C₁-C₆-alkyl, especially methoxycarbonylmethyl, ethoxycarbonylethyl, C₁-C₄-arylalkoxycarbonyl -C₁-C₆-alkyl, especially benzyloxycarbonylmethyl, C₁-C₄-alkylamino-C₁-C₆-alkyl, especially methylaminopropyl, methylaminobutyl, C₁-C₄-dialkylamino-C₁-C₆-alkyl, especially dimethylaminopropyl, dimethylaminobutyl, C₂-C₈-alkenyl, in particular vinyl, allyl, butenyl, C₃-C₇-cycloalkyl, in particular Cyclo pe ntyl, cyclohexyl, cycloheptyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptyl-methyl, phenyl, phenyl-C₁-C₄-alkyl, in particular phenylmethyl which may or may not be the same or different the radicals indicated above may be substituted,
and their optical isomers and racemates.

Compounds of the formula (I) are very particularly preferred
in which
R¹, R³ and R⁵ independently of one another for straight-chain or branched C₁-C₈ alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, pentyl, isopentyl, sec.-pentyl, hexyl, isohexyl, sec. -Hexyl, heptyl, isoheptyl, sec.-heptyl, octyl, isooctyl, sec.-octyl-C₂-C₈-alkenyl, in particular allyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, especially cyclohexylmethyl, phenyl-C₁- C₄-alkyl, especially phenylmethyl,
R², R⁴ and R⁶ independently of one another for straight-chain or branched C₁-C₈ alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, pentyl, isopentyl, sec.-pentyl, hexyl, isohexyl, sec. -Hexyl, heptyl, isoheptyl, sec.-heptyl, octyl, isooctyl, sec.-octyl, C₂-C₈-alkenyl, in particular special vinyl, allyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, especially cyclohexylmethyl, phenyl -C₁-C₄-alkyl, especially phenylmethyl which may be substituted by one or more of the same or different of the radicals given above,
and their optical isomers and racemates.

For the purposes of the present invention, all compounds of the general Formula (I) in optically active, stereoisomeric forms or as a racemic Mixtures can be used. However, preferably optically active, stereoisomeric forms of the compounds of the general formula (I) used according to the invention.

The following compounds of the general formula (I), in which
the radicals R¹ to R⁶ have the following meaning:

Furthermore, the compound PF known from EP-OS 382 173 is a depsipeptide 1022 of the following formula:

In addition, the depsipeptides are those from PCT application WO 93/19053 known compounds called.

In particular, from PCT application WO 93/19053 the compounds of called the following formula:

in which
Z represents N-morpholinyl, amino, mono- or dimethylamino.

Compounds of the following formula may also be mentioned:

in which
R¹, R², R³, R⁴ are independently hydrogen C₁-C₁₀ alkyl or aryl, especially phenyl, which are optionally substituted by hydroxy, C₁-C₁₀ alkoxy or halogen.

Some of the compounds of the general formula (I) are known, they are e.g. B. made by

• a) carboxy-activated open-chain hexadepsipeptides of the general formula (II-a) in which
  A represents an amino protective group which can be removed selectively from the active ester protective group, such as benzyl or benzyloxycarbonyl, and
  R¹, R², R³, R⁴, R⁵ and R⁶ have the meaning given above,
  cycli siert in the presence of a hydrogenation catalyst, in the presence of a basic reaction auxiliary and in the presence of a diluent, or
• b) open-chain hexadepsipeptides of the general formula (II-b) in which
  R¹, R², R³, R⁴, R⁵ and R⁶ have the meaning given above,
  cycli in the presence of a coupling reagent, in the presence of a basic reaction auxiliary and in the presence of a diluent.

Is used in process a) for the preparation of the new cyclic hexadepsipeptides (Enniatine) (I) as compounds of the formula (II) N-benzyloxycarbonyl-N-methyl L-isoleucyl-D-lactyl-N-methyl-L-isoleucyl-D-lactyl-N-methyl-L-isoleu-cyl-D- lactic acid pentafluorophenyl ester, the process can be carried out by the following Play back reaction scheme:

The carboxy required as starting materials for carrying out process a activated derivatives of the open-chain hexadepsipeptides are represented by the formula (II) generally defined. In this formula, A and R¹ to R⁶ are preferably for those residues that were already in connection with the description of the Invention according substances of formula (I) was mentioned as preferred for these substituents the.

The carboxy-activated pentafluorophenyl used as starting materials Esters of the formula (II-a) can be obtained by processes known from the literature  (see L. Kisfaludy et al. J. Org. Chem. 35 (1970), p. 3563; L. Kisfaludy et al. J. Org. Chem. 44 (1979), pp. 654-655).

The following compounds of the general formula (IIa) may be mentioned in particular: in which the radicals A and R¹ to R⁶ have the following meaning:

The cyclization of the compounds of formula (II) is preferably carried out in counter were a suitable hydrogenation catalyst and in the presence of a basic reac tion aid carried out using diluents.

All conventional Hy come as catalysts for carrying out the process a three catalysts in question. Precious metal catalysts are preferably used, such as platinum, platinum oxide, palladium or ruthenium, if necessary on a suitable carrier such as carbon or silicon dioxide.  

All suitable acid binders can be used as basic reaction auxiliaries are used like amines, especially tertiary amines and alkali and alkaline earths liver ties.

Examples include the hydroxides, oxides and carbonates of Lithium, sodium, potassium, magnesium, calcium and barium, and others basic compounds such as triethylamine, trimethylamine, tribenzylamine, Triisopropylamine, tributylamine, tribenzylamine, tricyclohexylamine, triamylamine, Trihexylamine, N, N-dimethyl-aniline, N, N-dimethyl-toluidine, N, N-dimethyl-p- aminopyridine, N-methyl-pyrrolidine, N-methyl-piperidine, N-methyl-imidazole, N- Methyl-pyrrole, N-methyl-morpholine, N-methyl-hexamethyleneimine, pyridine, 4- Pyrrolidino-pyridine, 4-dimethylamino-pyridine, quinoline, α-picoline, β-picoline, Isoquinoline, pyrimidine, acridine, N, N, N ′, N′-tetramethylene diamine, N, N, N ′, N′- Tetra-ethylenediamine, quinoxaline, N-propyl-diisopropylamine, N-ethyl diisopropylamine, N, N'-dimethyl-cyclohexylamine, 2,6-lutidine, 2,4-lutidine, Triethylenediamine, diazabicyclooctane (DABCO), diazabicyclonones (DBN) or Diazabicycloundecene (DBU).

It is preferred to use heteroaromatics, such as pyridine, N- Methyl imidazole or 4-pyrrolidinopyridine.

All inert substances come as diluents for carrying out process a organic solvents in question.

Examples include: halogenated hydrocarbons, especially chlorine carbon Hydrogen oils, such as tetrachlorethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichlor ethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene, dichloro benzene, chlorotoluene, trichlorobenzene; Alcohols such as methanol, ethanol, isopropanol, Butanol; Ethers such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, di-n- butyl ether, di-isobutyl ether, diisoamyl ether, diisopropyl ether, anisole, phenetol, Cyclohexyl methyl ether, diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, Dioxane, dichlorodiethyl ether; Nitro hydrocarbons such as nitromethane, nitroethane, Nitrobenzene, chloronitrobenzene, o-nitrotoluene; Nitriles such as acetonitrile, butyronitrile, Isobutyronitrile, benzonitrile, m-chlorobenzonitrile; aliphatic, cycloaliphatic or aromatic hydrocarbons such as heptane, hexane, nonane, cymol, gasoline frac ions within a boiling point interval of 70 ° C to 190 ° C, cyclohexane,  Methylcyclohexane, petroleum ether, ligroin, octane, benzene, toluene, xylene; Esters like Ethyl acetate, isobutyl acetate; Amides e.g. B. formamide, N-methylformamide, N, N-di methylformamide, N-methyl-pyrrolidone; Ketones such as acetone, methyl ethyl ketone.

Mixtures of the solvents and diluents mentioned are also used dress.

Preferred are ethers, such as dioxane, and mixtures of alcohols and ether.

Process a is carried out by converting compounds of the formula (IIa) into Presence of a basic reaction auxiliary and a suitable hydrogenation catalyst in the presence of hydrogen in a diluent High dilution conditions heated.

The reaction takes about 4 to 20 hours. The reaction is at Tempe temperatures between + 20 ° C and + 200 ° C, preferably between + 70 ° C and + 155 ° C carried out. It is preferable to work under an inert gas atmosphere and at the pressure which, when heated to the required reaction temperature sets the reaction conditions.

A dioxane solution is used to carry out process 3a according to the invention of N-benzyloxycarbonyl-N-methyl-L-isoleucyl-D-lactyl-N-methyl-L-isoleuc-yl-D- pentafluorophenyl lactyl-N-methyl-L-isoleucyl-D-lactic acid of the formula (IIa) within 2 to 10 hours more equimolar in the rapidly stirred suspension Amounts of a suitable hydrogenation catalyst, for example palladium / carbon, in excess dioxane with constant passage of hydrogen at 95 ° C. dripped. The solution generally contains 0.5 to 2.5 mol as catalysts, preferably 1.0 to 2.0 moles of 4-pyrrolidinopyridine and 0.5 to 10% preferably 2 to 5% alcohol (based on the solvent).

Alternatively, in addition to N-benzyloxycarbonyl, N-benzyl and N-tert.- Butoxycarbonyl-substituted pentafluorophenyl esters of the formula (IIa) use The latter can be found according to U. Schmidt (see e.g. U. Schmidt et al., Synthesis (1991) pp. 294-300 [Didemnin A, B and C]) in a two-phase system cyclize.  

When the reaction is complete, the reaction mixture is cooled, the whole The reaction mixture was concentrated in vacuo with an organic solvent extracted and worked up in a manner known per se. The resulting products can be in the usual way by recrystallization, vacuum distillation or Clean column chromatography.

If method b is used to produce the new cyclic hexadepsipeptides (Enniatine) as compounds of the formula (IIb) N-methyl-L-isoleucyl-D-lactyl-N- methyl-L-isoleucyl-D-lactyl-N-methyl-L-isoleucyl-D-lactic acid, so can reproduce the process using the following reaction scheme:

The raw materials required to carry out process b are open chain hexadepsipeptides are generally defined by formula (II). In this Formula R¹ to R⁶ are preferably those radicals which are already together Menhang with the description of the substances of formula (II) according to the invention as were preferred for these substituents.

The hexadepsipeptides of the formula (II) used as starting materials can NEN can be obtained by the methods described below.  

The following compounds of the general formula (IIb) may be mentioned in particular: in which the radicals R¹ to R⁶ have the following meaning:

As coupling reagents for carrying out the method b find all who Production of an amide bond are suitable (cf. e.g .: Houben-Weyl, methods der organic chemistry, volume 15/2; Bodanszky et al., Peptide Synthesis 2nd ed. (Wiley & Sons, New York 1976) or Gross, Meienhofer, The Peptides: Analysis synthesis, biology (Academic Press, New York 1979), use. Preferably the following methods are used: active ester method with pentachloro- (Pcp) and pentafluorophenol (Pfp), N-hydroxysuccinimide, N-hydroxy-5-norbornene 2,3-dicarboxamide (HONB), 1-hydroxy-benzotriazole (HOBt) or 3-hydroxy-4- oxo-3,4-dihydro-1,2,3-benzotriazine as alcohol component, coupling with carbo diimides such as dicyclohexylcarbodiimide (DCC) using the DCC additive process, or with n-propanephosphonic anhydride (PPA) and mixed anhydride method with pivaloyl chloride, ethyl (EEDQ) and isobutyl chloroformate (IIDQ) or Coupling with phosphonium reagents such as benzotriazol-1-yl-oxy-tri (dimethyl aminophosphonium) hexafluorophosphate (BOP), bis (2-oxo-3-oxazolidinyl) phos Phonic acid chloride (BOP-Cl), or with phosphonic acid ester reagents such as cyan phosphonic acid diethyl ester (DEPC) and diphenylphosphoryl azide (DPPA) or Uronium reagents such as 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetra fluoro borate (TBTU).

Coupling with phosphonium reagents such as bis (2-oxo-3-oxazo lidinyl) -phosphonium chloride (BOP-Cl), benzotriazol-1-yl-oxy-tris (dimethyl aminophosphonium) hexafluorophosphate (BOP) and phosphonic acid ester reagents zien, such as diethyl cyanophosphonate (DEPC) or diphenylphosphoryl azide (DPPA).  

The basic reaction auxiliaries for carrying out process b are the in process a mentioned tertiary amines, especially trialkylamines such as tri ethylamine, N, N-diisopropylethylamine or N-methylmorpholine, use.

The diluents used to carry out process b are those described in process ren a called halogenated hydrocarbons, especially chlorinated coal use of substances.

Process b is carried out by using compounds of the formula (II) in Presence of one of the specified coupling reagents and in the presence of a basic reaction auxiliary in a diluent under high dilution conditions are combined and stirred. The response time is 4 to 72 hours. The reaction takes place at temperatures between -5 ° C and + 100 ° C, preferably between -5 ° C and + 50 ° C, particularly preferably at 0 ° C to room temperature. It is operated under normal pressure.

To carry out process b according to the invention, Methyl-L-isoleucyl-D-lactyl-N-methyl-L-isoleucyl-D-lactyl-N-methyl-L - isoleucyl- D-lactic acid of formula (II) generally 1.0 to 3.0 mol, preferably 1.0 up to 1.5 moles of coupling reagent.

When the reaction is complete, the reaction solution is washed to be slightly alkaline the organic phase separated, dried and concentrated in vacuo. The products obtained can be recrystallized in the usual way, Clean vacuum distillation or column chromatography.

The open-chain depsipeptides used as starting compounds can are produced by methods known per se, for example that as suggested by H.-G. Lerchen and H. Kunz (Tetrahedron Lett. 26 (43) (1985) pp. 5257-5260; 28 (17) (1987) pp. 1873-1876) using the esterification method according to B. F. Gisin (Helv. Chim. Acta 56 (1973) p. 1476).

Cyclic depsipeptides with 24 ring atoms include compounds of general formula (Ia)

in which
R ^1a , R ^2a , R ^11a and R ^12a independently of one another represent C _1-8 alkyl, C _1-8 haloalkyl, C _3-6 cycloalkyl, aralkyl, aryl,
R ^3a , R ^5a , R ^7a , R ^9a independently of one another represent hydrogen or straight-chain or branched C _1-8 alkyl, which may be substituted by hydroxy, C _1-4 alkoxy, carboxy,

Carboxamide,

Imidazolyl, indolyl,
Guanidino, -SH or C _1-4 alkylthio may be substituted and furthermore aryl or aralkyl which may be substituted by halogen, hydroxy, C _1-4 alkyl, C _1-4 alkoxy,
R ^4a , R ^6a , R ^8a , R ^10a independently of one another represent hydrogen, straight-chain C _1-5 alkyl, C _2-6 alkenyl, C _3-7 cycloalkyl, which are optionally substituted by hydroxy, C _1-4 alkoxy, Carboxy, carboxamide, imidazolyl, indolyl, guanidino, SH or C _1-4 -alkylthio can be substituted, and for aryl or aralkyl which can be substituted by halogen, hydroxy, C _1-4 -alkyl, C _1-4 -alkoxy, stand
and their optical isomers and racemates.

Compounds of the formula (Ia) in which
R ^1a , R ^2a , R ^11a and R ^12a independently of one another represent methyl, ethyl, propyl, isopropyl, n-, s-, t-butyl or phenyl, which is optionally substituted by halogen, C _1-4 -alkyl, OH, C _1-4 alkoxy, as well as benzyl or phenylethyl, which may optionally be substituted by the radicals specified for phenyl;
R ^3a to R ^{10a have} the meaning given above.

Compounds of the formula (Ia) in which
R ^1a , R ^2a , R ^11a and R ^12a independently of one another represent methyl, ethyl, propyl, isopropyl or n-, s-, t-butyl,
R ^3a , R ^5a , R ^7a , R ^9a for hydrogen, straight-chain or branched C _1-8 alkyl, in particular methyl, ethyl, propyl, i-propyl, n-, s-, t-butyl, which may be by C _1-4 alkoxy, in particular methoxy, ethoxy, imidazolyl, indolyl or C _1-4 alkylthio, in particular methylthio, ethylthio, may furthermore be phenyl, benzyl or phenethyl, which may optionally be substituted by halogen, in particular chlorine.
R ^4a , R ^6a , R ^8a , R ^10a independently of one another for hydrogen, methyl, ethyl, n-propyl, n-butyl, vinyl, cyclohexyl, which may optionally be substituted by methoxy, ethoxy, imidazolyl, indolyl, methylthio, ethylthio and represent isopropyl, s-butyl, and also optionally halogen-substituted phenyl, benzyl or phenylethyl.

The compounds of formula (Ia) can be prepared by open chain octadepsipeptides of formula (IIc)

in which
R ^1a to R ^{12a have} the meaning given above,
cyclized in the presence of a diluent and in the presence of a coupling reagent.

Coupling reagents are all compounds which are suitable for the formation of a Amide bonds are suitable (cf. e.g .: Houben-Weyl, methods of organic Chemistry, Volume 15/2; Bodanszky et al., Peptide Synthesis 2nd ed. (Wiley / Sons, New York 1976).

The following reagents and methods are preferred, active esters method with pentafluorophenol (Pfp), N-hydroxysuccinimide, 1-hydroxybenzotria zol, coupling with carbodiimides such as dicyclohexylcarbodiimide or N ′ - (3- Dimethylaminopropyl) -N-ethyl-carbodiimide (Ebc) and the mixed anhydride- Method or coupling with phosphonium reagents such as benzotriazol-1-yl oxy-tris (dimethylaminophosphonium) hexafluorophosphate (BOP), bis (2-oxo-3-oxa zolidinyl) -phosphonium chloride (BOP-Cl), or with phosphonic acid ester reagents tien, such as diethyl cyanophosphonate (DEPc) and diphenylphospharyl azide (DPPA).

Coupling with bis (2-oxo-3-oxazolidinyl) phospho is particularly preferred nium acid chloride (BOP-Cl) and N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDC) in the presence of 1-hydroxybenzotriazole (HOBt).

The reaction takes place at temperatures of 0-150 ° C, preferably at 20 to 100 ° C, particularly preferably at room temperature.

All inert organic solvents are suitable as diluents. These include in particular aliphatic and aromatic, optionally halo hydrogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, Petrol, ligroin, benzene, toluene, methylene chloride, ethylene chloride, chloroform, Carbon tetrachloride, chlorobenzene and o-dichlorobenzene, furthermore ethers such as diethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, furthermore ketones such as acetone, methylethyl, methylisopropyl and Methyl isobutyl ketone, also esters, such as methyl acetate and ethyl acetate, also nitriles, such as. B. acetonitrile and propionitrile, benzonitrile, glutaronitrile, in addition amides, such as. B. dimethylformamide, dimethylacetamide and N-  Methyl pyrrolidone, as well as dimethyl sulfoxide, tetramethylene sulfone and hexams thylphosphoric triamide.

The compounds of the formulas (IIc) and the coupling reagents are described in Ratio 1: 1 to 1: 1.5 used to each other. An approximately equimolar one is preferred Relationship.

After the reaction, the diluent is distilled off and the Ver Bonds of formula (Ia) in the usual way, for. B. chromatographically cleaned.

The agents according to the invention are suitable for beneficial warm-blooded toxicity for combating pathogenic endoparasites which occur in humans and in animal husbandry and animal breeding in farm animals, breeding, zoo, laboratory, experimental and hobby animals. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive species. By combating the pathogenic endoparasites, illness, deaths and reduced performance (e.g. in the production of meat, milk, wool, skins, eggs, honey, etc.) are to be reduced, so that the use of the active compounds makes animal husbandry more economical and easier is possible. Pathogenic endoparasites include cestodes, trematodes, nematodes, acantocephals in particular:
From the order of the Pseudophyllidea z. E.g .: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoporus spp.
From the order of the Cyclophyllidea z. For example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp. , Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymeno lepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.
From the subclass of Monogenea z. E.g .: Gyrodactylus spp., Dactylogyrus spp., Polystoma spp.
From the subclass of Digenea z. For example: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma sppium, Echinopary, Echinopary. , Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp., Paramphistomum spp., Calicophoron spp-, Cotylophoron spp., Gigantocotyle spp., Gastoederothy spp., Gastoederius spp spp., Catatropis spp., Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimus spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis Metorchis spp., Heterophyes spp., Metagonimus spp.
From the order of the Enoplida z. For example: Trichuris spp., Capillaria spp., Tri chomosoides spp., Trichinella spp.
From the order of the Rhabditia z. E.g. Micronema spp., Strongyloides spp.
From the order of Strongylida z. For example: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostomum 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., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Spicocaulus spp. Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Cooperemat. Spp., Marshallemat ., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp.
From the order of the Oxyurida z. For example: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.
From the order of Ascaridia z. For example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.
From the order of the Spirurida z. E.g .: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., 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 order of the Gigantorhynchida z. For example: Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.

The livestock and breeding animals include mammals such as B. cattle, horses, sheep, Pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, Fur animals such as B. mink, chinchilla, raccoon, birds such. B. chickens, geese, Turkeys, ducks, ostriches, fresh and salt water fish such as B. trout, carp, Eels, reptiles, insects such as. B. honey bee and silkworm.

Laboratory and experimental animals include mice, rats, guinea pigs, Golden hamster, dogs and cats.

The pets include dogs and cats.

The application can be prophylactic as well as therapeutic.

Suitable vegetable or synthetic fatty acid esters of polyhydric alcohols (oils) are fatty acid triglycerides, preferably fatty acid triglycerides with a medium chain length. Neutral oils, such as neutral vegetable oils, and in particular fractionated coconut oils, as are known, for example, under the trade name Miglyol and are commercially available, are particularly suitable, for which purpose again on Lexicon of auxiliary materials, 3rd edition, pages 808 to 809, (1989) by Fiedler is pointed out. These include, for example: Miglyol 810: This is a fractionated coconut oil that contains triglycerides of caprylic acid and capric acid and has a molecular weight of approximately 520. It has a fatty acid composition with C₆ at most 2%, C₈ about 65 to 75%, C₁₀ about 25 to 35% and C₁₂ at most 2%, has an acid number of about 0.1, has a saponification number of about 340 to 360 and has over an iodine number of maximum 1. Miglyol 812: This is a fractionated coconut oil that contains triglycerides of caprylic acid and capric acid and has a molecular weight of about 520. It has a fatty acid composition with C₆ at most 3%, C₈ about 50 to 65%, C₁₀ about 30 to 45% and C₁₂ at most 5%, has an acid number of about 0.1, has a saponification number of about 330 to 345 and has over an iodine number of 1. Miglyol 818: triglycerides of caprylic acid, capric acid and linolenic acid with a molecular weight of about 510. It has a fatty acid composition with C₆ at most 3%, C₈ about 45 to 60%, C₁₀ about 25 to 40%, C₁₂ about 2 to 5% and C _{18: 1} about 4 to 6, has an acid number of about 0.2, has a saponification number of about 315 to 335 and has an iodine number of up to 10. Captex 355 ⁽¹⁾ : triglyceride from Caprylic acid and capric acid. This triglyceride has a fatty acid content of about 2% caproic acid, about 55% caprylic acid and about 42% capric acid. It has a maximum acid number of 0.1, a maximum saponification number of approximately 325 to 340 and an iodine number of maximum 0.5. Triglycerides of caprylic acid and capric acid are also suitable, such as the products known under the trademark Myritol and commercially available, for which reference is made, for example, to Lexicon of Auxiliaries, 3rd Edition, page 834 (1989) by Fiedler. The associated product Myritol 813 has an acid number of at most 1, has a saponification number of about 340 to 350 and has an iodine number of about 0.5.

Also suitable are: monoglycerides, diglycerides and mono / di-glycerides, in particular esterification products of caprylic acid or capric acid with Glycerin. Preferred products in this class are, for example, the products which contain monoglycerides and diglycerides of caprylic acid / capric acid or consist essentially or practically of such products Available under the trade name Imwitor, for which on the Lexicon Auxiliaries, 3rd edition, page 645 (1989) by Fiedler. On Particularly suitable product from this class for use in the compositions according to the invention is the product Imwitor 742, in which it is an esterification product from a mixture of about 60 parts by weight (ppw) caprylic acid and about 40 parts by weight (ppw) capric acid with glycerin acts. Imwitor 742 is usually a yellowish crystalline mass that is around 26 ° C is liquid. It has an acid number of at most 2 and an iodine number of maximum 1, has a saponification number of about 235 to 275, contains about 40 to 50% monoglycerides, has a free glycerin content of  maximum 2%, has a melting point of about 24 to 26 ° C non-saponifiable components of a maximum of 0.3% and has a Peroxide number of maximum 1.

Sorbitan fatty acid esters of various known types, such as, for example are commercially available under the trade name Span, and include these for example sorbitan monolauryl esters, sorbitan monopalmitylesters, sorbitan mono stearyl esters, sorbitan tristearyl esters, sorbitan monooleylesters and sorbitan trioleyl ester, and for this purpose, for example, on Lexicon of auxiliaries, 3rd edition, Pages 1139 to 1140 (1989) referenced by Fiedler.

Pentaerythritol fatty acid and polyalkylene glycol ethers such as pentaerythritol dioleate, penta erythritol distearate, pentaerythritol monolaurate, pentaerythritol polyglycol ether and penta erythritol monostearate and also pentaerythritol fatty acid esters, for which on the lexicon of Auxiliaries, 3rd edition, pages 923 to 924 (1989) by Fiedler.

Monoglycerides such as glycerol monooleate, glycerol monopalmitate and glycerol mono stearate, such as those under the trade names Myvatex, Myvaplex and Myverol are known and commercially available, including encyclopedia of adjuvants, 3rd edition, page 836 (1989) by Fiedler, and acetylated, at for example monoacetylated and diacetylated, monoglycerides, such as those known as the Myvacet name and commercially available are, why on Lexicon of auxiliary materials, 3rd edition, page 835 (1989) by Fiedler is referred.

Mono- and difatty acid esters of propylene glycol, such as propylene glycol dicaprylate, Propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, Propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate and same, for which purpose on Lexikon der Hilfsstoffe, 3rd edition, pages 1013 ff. (1989) von Fiedler is pointed out. Propylene glycol caprylic acid is particularly preferred capric acid diester, known under the trade name Miglyol 840 and in Commercially available, for which purpose on Lexicon of auxiliary materials, 3rd edition, page 809 (1989) by Fiedler. Miglyol 840 has a fatty acid content of C₆ maximum about 3 percent, C₈ about 65 to 80 percent, C₁₀ about 15 to 30 percent and C₁₂ at most 3 percent, and has an acid number of at most 0.1, a ver soaping number from about 320 to 340 and a maximum iodine number of 1.  

Other suitable products in this class are Capmul MC ⁽¹⁾ , Captex 300 ⁽¹⁾ , Captex 800 ⁽¹⁾ , Neobee M5 ⁽²⁾ and Mazol 1400 ⁽³⁾ Imwitor ⁽⁴⁾

⁽¹⁾ = Capital City Products, POBox 569, Columbus, OH, V. St. A.
⁽²⁾ = Stepan, PVO Dept., 100 West Hunter Ave., Maywood, NJ 07607, V. St. A.
⁽³⁾ = Mazer Chemicals, 3938 Porett Drive, Gurnee, IL, V. St.A,
⁽⁴⁾ = Hüls AG, 14370 Marl, Germany.

Imwitor 742 is particularly preferred as the glycerol fatty acid ester. The agents according to the invention furthermore contain a pharmaceutically acceptable emulsifier. Nonionic hydrophilic surfactants and nonionic lipophilic surfactants are preferred here. Examples of suitable hydrophilic surface-active agents which can be used as surface-active components are reaction products of natural or hydrogenated vegetable oils and ethylene glycol, namely polyoxyethylene-glycolated, natural or hydrogenated vegetable oils, such as polyoxyethylene-glycolated natural or hydrogenated castor oils. Such products can be obtained in a known manner, for example by reacting a natural or hydrogenated castor oil or fractions thereof with ethylene oxide in a molar ratio of, for example, from about 1:35 to about 1:60 and with optional removal of the free polyethylene glycol components from the product, as described in DE-B 11 82 388 and DE-B 15 18 819 is described. The various surfactants available under the Cremophor brand are particularly suitable. Of these, the products with the designations Cremophor RH40 with a saponification number of approximately 50 to 60, an acid number of less than 1, an iodine number of less than 1, a water content (according to Fischer) of less than 2%, a refractive index n²⁰ _D of approximately are suitable 1.453 to 1.457 and an HLB value of about 14 to 16, Cremophor RH60 with a saponification number of about 40 to 50, an acid number of less than 1, an iodine number of less than 1, a water content (according to Fischer) of about 4.5 to 5 , 5%, a refractive index n²⁰ _D of about 1.453 to 1.457 and an HLB value of about 15 to 17, and Cremophor EL with a molecular weight (determined by vapor osmometry) of about 1630, a saponification number of about 65 to 70, an acid number of about 2, an iodine number of about 28 to 32 and a refractive index n²⁰ _D of about 1.471, for which reference is again made, for example, to Lexicon of auxiliary materials, 3rd edition, pages 326 to 327 (1989) by Fiedler. The various surfactants available under the Nikkol product name are also suitable as such products, for example Nikkol HCO-60. The product Nikkol HCO-60 is a reaction product of hydrogenated castor oil and ethylene oxide, which has the following properties: acid number = approximately 0.3, saponification number = approximately 47.4, hydroxyl value = approximately 42.5, pH value (5%) = approximately 4.6, APHA color = about 40, melting point = about 36.0 ° C, freezing point = about 32.4 ° C, water content (percent, according to Karl Fischer) = about 0.03.

Polyoxyethylene sorbitan fatty acid esters, for example the mono- and trilauryl esters, mono- and tripalmyl esters, mono- and tristearyl esters and mono- and trioleylesters, as are known and commercially available under the trade name Tween, for which purpose on Lexicon of auxiliaries, 3rd edition, pages 1300 to 1304 (1989) by Fiedler. These include, for example, the following products:
Tween 20 = polyoxyethylene (20) sorbitan monolaurate,
Tween 40 = polyoxyethylene (20) sorbitan monopalmitate,
Tween 60 = polyoxyethylene (20) sorbitan monostearate,
Tween 80 = polyoxyethylene (20) sorbitan monooleate,
Tween 65 = polyoxyethylene (20) sorbitan tristearate,
Tween 85 = polyoxyethylene (20) sorbitan trioleate,
Tween 21 = polyoxyethylene (4) sorbitan monolaurate,
Tween 61 = polyoxyethylene (4) sorbitan monostearate and
Tween 81 = polyoxyethylene (5) sorbitan monooleate.

Particularly preferred products from this class for use in the Compositions according to the invention are the Tween products mentioned above 40 and Tween 80.

Polyoxyethylene fatty acid esters, for example the known types of polyoxyethylene stearic acid esters which are commercially available under the trade name Myrj, for which reference is made to Lexicon of auxiliary materials, 3rd edition, page 834 (1989) from Fiedler, and also the known polyoxyethylene fatty acid esters which are commercially available under the Trade name Cetiol HE are available, for which reference is made to Lexicon der Hilfsstoffe, 3 edition, page 284 (1989) by Fiedler, and a particularly preferred product from this class for use in the compositions according to the invention is the product Myrj 52, which has a refractive index n²⁰ _{D has} about 1.1, has a melting point of about 40 to 44 ° C, has an HLB of about 16.9, has an acid number of about 0 to 1 and has a saponification number of about 25 to 35.

Copolymers of polyoxyethylene and polyoxypropylene, such as those known as Pluronic and Emkalyx and commercially available are available, for which purpose on Lexicon of auxiliary materials, 3rd edition, pages 956 to 958 (1989) by Fiedler. A particularly preferred product of this class for use in the compositions of the invention is the product Pluronic F68.

Block copolymers of polyoxyethylene and polyoxypropylene, for example as known under the brand name Poloxamer and commercially available are, why on Lexicon of auxiliary materials, 3rd edition, page 959 (1989) by Fiedler is referred. A particularly suitable product in this class for users The product in the compositions according to the invention is poloxamer 188.

Dioctyl succinate, dioctyl sodium sulfosuccinate, di- [2-ethylhexyl] succinate or Sodium lauryl sulfate.

Phospholipids, in particular lecithins, for which purpose on lexicon of auxiliary substances, 3. Edition, pages 731 to 733 (1989) by Fiedler. To lecithins that are suitable for use in the compositions according to the invention, include soybean lecithins in particular.

Examples of suitable lipophilic surfactants for use as Emulsifiers are transesterification products of natural vegetable oil glycerides and Polyalkylene polyols. Such transesterification products are state of the art are known and can be used, for example, using the method described in US Pat. No. 3,288,824 Manufacture generally described procedures. They include transesterification pro Products from various natural, for example non-hydrogenated, vegetable oils such as corn oil, kernel oil, almond oil, peanut oil, olive oil and palm oil, and mixtures of these with polyethylene glycols, in particular with polyethylene glycols, the one have an average molecular weight of 200 to 800. Preferred products received by transesterification of 2 mol of a natural vegetable oil triglyceride with 1  Mol polyethylene glycol, for example, an average molecular weight of 200 up to 800. Different forms of this class of transesterification products are known and commercially available under the name Labrafil, for what to Lexicon of auxiliary materials, 3rd edition, page 707 (1989) by Fiedler becomes. Particularly as components in the compositions according to the invention Labrafil M 1944 CS products are suitable esterification product of core oil and polyethylene glycol, which has an acid number of about 2, has a saponification number of about 145 to 175 and over one Iodine number from about 60 to 90, and Labrafil M 2130 CS, which is is a transesterification product of C₁₂-C₁₈ glyceride and polyethylene glycol, the has a melting point of about 35 to 40 ° C, has an acid number of less than 2, has a saponification number of about 185 to 200 and an iodine number of under 3.

It may be advantageous to add thickeners to the agents according to the invention put. 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.

The active compounds can also be mixed with the agents according to the invention Synergists or with other active substances that fight pathogenic endoparasites act, exist. Such active ingredients are e.g. B. L-2,3,5,6-tetrahydro-6-phenylimide azothiazole, benzimidazole carbamates such as febrantel, also pyrantel, traziquantel, Ivermectin.

Ready-to-use preparations contain the active ingredients in concentrations of 10 ppm - 20 weight percent, preferably 0.1-20 weight percent.

In general, it has proven advantageous to use amounts of the invention appropriate mixture of about 1 to about 100 mg of active ingredient per kg of body weight to be administered per day for effective results. 1 to are preferred 10 mg of active ingredient per kg of body weight.

The following examples illustrate the invention without restricting it.  

example 1

8 g of active ingredient PF 1022
8 g of active ingredient praziquantel
6 g Cremophor RH 40 (as an emulsifier)
12 g propylene glycol
66 g Imvitor 742 (as oil).

Emulsifier, oil and propylene glycol are heated gently (40 ° C) mixed and added the active ingredients with stirring. A clear one emerges Solution which is filled into soft gelatin capsules.

Claims (5)

1. Means for oral administration of cyclic and / or open-chain depsipeptides consisting of amino acids and hydroxycarboxylic acids as building blocks, alone or in a mixture with other active substances, characterized in that these active substances consist of a solvent mixture

• - propylene glycol,
• - vegetable or synthetic fatty acid esters of polyhydric alcohols (oils),
• - emulsifiers

are solved. 2. Composition according to claim 1, characterized in that the active ingredient solution is contained in a soft gelatin capsule. 3. Composition according to claim 1, characterized in that the solvent mixture has the following composition:

• - propylene glycol: 5 to 20%
• - Oil: 50 to 70%
• - Emulsifier: 1 to 10%.

4. Composition according to claim 1, characterized in that a soft gelatin capsule contains a system of the following composition:

• - Active ingredient: 0.1 to 20% (weight),
• - propylene glycol: 5 to 20% (weight),
• - Oil: 50 to 70% (weight)
• - Emulsifier: 1 to 8% (weight).