DE4412492A1 - Use of cyclic depsipeptides with 18 ring atoms - Google Patents

Abstract

The invention concerns the use, to control parasitic protozoans, in particular coccidia, and fish parasites, of cyclic depsipeptides in which the 18-atom ring is made up of amino-acid and hydroxycarboxylic acid units and which have general formula (I), in which R<1>, R<3> and R<5>, independently of each other, are hydrogen, straight-chain or branched-chain alkyl, alkenyl, cycloalkyl, arylalkyl or heteroarylalkyl which may also be substituted and R<2>, R<4> and R<6>, independently of each other, are hydrogen, straight-chain or branched-chain alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl which may also be substituted, plus optical isomers of such compounds and racemic mixtures of such isomers.

Description

The present invention relates to the use of cyclic depsipeptides consisting of amino acids and hydroxycarboxylic acids as ring building blocks and 18 Ring atoms as a means of combating parasitic protozoa, especially of Coccidia and fish parasites.

Certain cyclic depsipeptides with 18 ring atoms (Enniatine) and method are already known for their production (see, for example: Hiroshi Tomoda et al. J. Antibiotics 45 (1992) pp. 1207-1215 [Enniatine A, A₁, B, B₁, D, E and F]; P. Quitt et al., Helv. Chimica Acta 46 (1963) pp. 1715-1720; P. Quitt et al., Helv. Chimica Acta 47 (1964) pp. 166-173 [Enniatin A]).

Cyclic depsipeptides with 18 ring atoms (Enniatine) and their anthelmintic Effect is the subject of a previous patent application (see PCT- Application WO 93/25 543).

Using these compounds as a means to combat parasitic Protozoa and especially as a means to control coccidia as well However, nothing has become known to fish parasites.

It has now been found that cyclic depsipeptides consisting of amino acids and hydroxycarboxylic acids as ring building blocks and 18 ring atoms of the general Formula (I)  

in which
R¹, R³ and R⁵ independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl, arylalkyl or heteroarylalkyl, which may optionally be substituted,
R², R⁴ and R⁶ independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, which may optionally be substituted,
and their optical isomers or racemates have strong activity against parasitic protozoa, in particular against coccidia and fish parasites.

Optionally substituted alkyl in the general formulas means straight chain or branched alkyl having preferably 1 to 8, in particular 1 to 4 Carbon atoms. Exemplary and preferably are optionally substituted ized methyl, ethyl, n.- and i.-propyl, n.-, i.-, s.- and t.-butyl.

Optionally substituted alkenyl in the general formulas straight-chain or branched alkenyl with preferably 2 to 8, in particular 2 up to 4 carbon atoms. Exemplary and preferred are where appropriate substituted ethenyl, propenyl- (1), propenyl- (2) and butenyl- (3).

Optionally substituted cycloalkyl means in the general formulas mono-, bi- and tricyclic cycloalkyl with preferably 3 to 10, in particular 3, 5 or 6 carbon atoms. For example, and preferably, be given  if substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and adamantyl.

Optionally substituted aryl in the general formulas means preferred optionally substituted phenyl, naphthyl or fluorenyl, in particular Phenyl.

Optionally substituted arylalkyl in the general formulas means gege optionally substituted arylalkyl in the aryl part and / or alkyl part with 6 or 10, especially 6 carbon atoms in the aryl part (preferably phenyl, Naphthyl or fluorenyl, especially phenyl) and preferably 1 to 4, in particular special 1 or 2 carbon atoms in the alkyl part, the alkyl part being straight-chain or can be branched. Exemplary and preferred are where appropriate substituted benzyl and phenylethyl called.

Optionally substituted heteroaryl alone or as part of Heteroarylalkyl in the general formulas means heteroaromatic 5- to 7- link rings with preferably 1 to 3, in particular 1 or 2 identical or different heteroatoms. The heteroatoms are oxygen, sulfur or Nitrogen. Exemplified and preferred are optionally substituted furyl, Thiophenyl, pyrazolyl, imidazolyl, 1,2,3- and 1,2,4-triazolyl, oxazolyl, isoxa zolyl, thiazolyl, isothiazolyl, 1,2,3-, 1,3,4-, 1,2,4- and 1,2,5-oxadiazolyl, azepi nyl, pyrrolyl, isopyrrolyl, pyridyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-, 1,2,4- and 1,2,3-triazinyl, 1,2,4-, 1,3,2-, 1,3,6- and 1,2,6-oxazinyl , Oxepi called nyl, thiepinyl and 1,2,4-diazepinyl. As an alkyl part in the case of heteroaryl alkyl may be called alkyl with 1 to 4 carbon atoms, preferably methylene or Ethylene.

The optionally substituted radicals of the general formulas can be one or more, preferably 1 to 3, in particular 1 or 2 identical or different carry their substituents. The substituents are exemplary and preferred listed:

Alkyl with preferably 1 to 4, in particular 1 or 2 carbon atoms, such as Methyl, ethyl, n.- and i.-propyl and n.-, i.-, s.- and t.-butyl; Alkoxy with preference as 1 to 4, in particular 1 or 2 carbon atoms, such as methoxy, ethoxy, n.-  and i.-propyloxy and n.-, i.-, s.- and t.-butyloxy; Alkylthio with preferably 1 to 4, in particular 1 or 2 carbon atoms, such as methylthio, ethylthio, n.- and i.- Propylthio and n.-, i.-, s.- and t.-butylthio; Haloalkyl, preferably 1 to 4, in particular 1 or 2 carbon atoms and preferably 1 to 5, in particular 1 to 3 halogen atoms, the halogen atoms being the same or different and as halogen atoms, preferably fluorine, chlorine or bromine, in particular fluorine hen such as trifluoromethyl, hydroxy; Halogen, preferably fluorine, chlorine, bromine and Iodine, especially fluorine, chlorine and bromine; Cyano; Nitro; Amino; Hydroxy; Mercapto; Monoalkyl- and dialkylamino with preferably 1 to 4, in particular 1 or 2 carbon atoms per alkyl group, such as methylamino, methylethylamino, n.- and i.-propylamino and methyl-n.-butylamino; Carboxyl; Carbalkoxy with preferably 2 to 4, in particular 2 or 3 carbon atoms, such as Carbomethoxy and carboethoxy; Sulfo (-SO₃H); Alkylsulfonyl or alkylsulfinyl with preferably 1 to 4, in particular 1 or 2 carbon atoms, such as methyl sulfonyl, methylsulfinyl, ethylsulfonyl and ethylsulfinyl; Arylsulfonyl with before preferably 6 or 10 aryl carbon atoms, such as phenylsulfonyl; Alkylcarbonyl oxy with preferably 1 to 4 carbon atoms in the alkyl part; Arylalkoxycarbonyl with preferably 1 to 4 carbon atoms in the alkyl part, in particular phenethoxycarbonyl or benzyloxycarbonyl; Carbamoyl; Guanidinyl; Alkoxycarbonylamino with 1 to 4 carbon atoms; Arylalkoxycarbonylamino, preferably with phenyl, naphthyl or Fluorenyl in the aryl part and 1 to 4 carbon atoms, especially methylene in the alkyl part; Cycloalkyl with preferably 3 to 6 carbon atoms, in particular cyclopropyl, cyclo pentyl, cyclohexyl; Aryl, especially phenyl, naphthyl; Heteroaryl, especially Pyridyl, thiazolyl, imidazolyl; the specified residues in turn again can be substituted.

Compounds of the formula (I) in which are preferred
R¹, R³ and R⁵ independently of one another are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, aminoalkyl, carbamoylamino, carbamoylamino, carbamoylamino, carbamoylamino Dialkylaminoalkyl, guanidinoalkyl, which may optionally be substituted by one or two benzyloxycarbonyl radicals or by one, two, three or four alkyl radicals, alkoxycarbonylaminoalkyl, 9-fluorenylmethoxycarbonyl (Fmoc) aminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl and optionally substituted arylalkyl or hetarylalkyl, where as Halogen, hydroxy, alkyl, alkoxy, nitro or amino may be mentioned as substituents,
R², R⁴ and R⁶ independently of one another for hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonyl, alkyl, carbamoylalkylaminoalkylaminoalkyl, aminoalkyl , Dialkylaminoalkyl, alkoxycarbonylaminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl and optionally substituted aryl, arylalkyl or hetarylalkyl, where halogen, hydroxy, alkyl, alkoxy, nitro or amino are mentioned as substituents,
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, 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- alkylsulfinyl-C₁-C₆-alkyl, especially methylsulfinylethyl, C₁-C₄-alkyl sulfonyl-C₁-C₆-alkyl, especially methylsulfonylethyl, carboxy-C₁-C₆-al kyl, especially carboxymethyl, carboxyethyl, C₁-C₄-alk oxycarbonyl-C₁-C₆-alkyl, especially methoxycarbonylmethyl, ethoxycarbonylethyl, C₁-C₄-arylalkoxycarbonyl-C₁-C₆-alkyl, especially benzyloxycarbonylme thyl, carbamoyl-C₁-C₆-alkyl, especially carbamoylmethyl, carbamoyl ethyl, amino-C₁-C₆-alkyl , in particular aminopropyl, aminobutyl, C₁-C₄- alkylamino-C₁-C₆-alkyl, in particular methylaminopropyl, methylamino butyl, C₁-C₄-dialkylamino-C₁-C₆-alkyl, in particular dimethylaminopropyl, dimethylaminobutyl, guanido-C₁-C₆-alkyl, especially guanido propyl, C₁-C₄-alkoxycarbonylamino-C₁-C₆-alkyl, especially tert-butoxy carbonylaminopropyl, tert-butoxycarbonylaminobutyl, 9-fluorenylmethoxy arbonyl (Fmoc) amino-C₁-C₆-alkyl, especially 9-fluorenylmethoxy carbonyl (Fmoc ) aminopropyl, 9-fluorenylmethoxycarbonyl (Fmoc) amino butyl, C₂-C₈-alkenyl, especially vinyl, allyl, butenyl, C₃-C₇-cycloalkyl, especially cyclopentyl, cyclohexyl, cycloheptyl, C₃-C₇-cycloalkyl-C₁-C₄- alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-C₁-C₄-alkyl, especially phenylmethyl which may be substituted by radicals from the halogen, in particular fluorine, chlorine, bromine or iodine, hydroxy, C₁-C₄-alkoxy, in particular 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-methoxy ethyl, 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- Alkoxycarbonyl-C₁-C₆-alkyl, especially methoxycarbonylmethyl, ethoxycarbonylethyl, C₁-C₄-aryl alkoxycarbonyl-C₁-C₆-alkyl, especially benzyloxycarbonylmethyl, carb amoyl-C₁-C₆-alkyl, especially carbamoylmethyl, carbamoylethyl, amino-C₁-C₆- alkyl, especially aminopropyl, aminobutyl, C₁-C₄-alkylamino no-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, especially cyclopentyl, cyclohexyl, cycloheptyl, C₃-C₇- cycloalkyl-C₁-C₄-alkyl, especially cyclopentylmethyl, cyclohexyl methyl, cycloheptylmethyl, phenyl, phenyl-C₁-C₄-alkyl, in particular Phenylmethyl optionally substituted by residues from the halogen series, in particular fluorine, chlorine, bromine or iodine, hydroxy, C₁-C₄-alkoxy, in particular methoxy or ethoxy, C₁-C₄-alkyl, in particular methyl can be,
and their optical isomers and racemates.

Compounds of the formula (I) 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- alkoxycarbonylamino -C₁-C₆-alkyl, especially tert-butoxycarbonylamino propyl, tert-butoxycarbonylaminobutyl, C₂-C₈-alkenyl, especially vinyl, allyl, C₃-C₇-cycloalkyl, especially cyclopentyl, cyclohexyl, cycloheptyl, C₃-C₇-cycloalkyl-C₁ -C₄-alkyl, especially cyclopentyl methyl, 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-aryl-carbonyl -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, especially 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 one or more identical or different of the radicals mentioned above can be,
and their optical isomers and racemates.

Compounds of the formula (I) 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, especially allyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, especially cyclo hexylmethyl, 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 cyclo hexylmethyl, phenyl -C₁-C₄-alkyl, in particular phenylmethyl which may be substituted by one or more of the same or different of the radicals indicated above,
as well as their isotopes and racemates.

All compounds of the general formula (I) can be used in optically active, stereoisomeric forms or as racemic mixtures. Preferably however, the optically active, stereoisomeric forms of the compounds of general formula (I) used according to the invention.

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

Some of the compounds of the general formula (I) are known (by Insulation, cf. e.g. B .: R. Zocher et al., J. Antibiotics 45 (1992) pp. 1273-1277 [Enniatine A, B and C]; Hiroshi Tomoda et al. J. Antibiotics 45 (1992) p. 1207- 1215 [Enniatine A, A₁, B, B₁, D, E and F]; JP Patent 02 229 177 A2; ref. C.A. 114 (23): 227 487k; through synthesis, cf. e.g. E.g .: P. Quitt et al., Helv. Chimica Acta 46 (1963) pp. 1715-1720; P. Quitt et al., Helv. Chimica Acta 47 (1964) pp. 166-173 [Enniatin A]; Pl. A. Plattner et al., Helv. Chimica Acta 46 (1963) pp. 927-935 [Enniatin B]; Yu. A. Ovchinnikov et al. Tetrahedron Lett. 2 (1971) pp. 159-162; R. W. Roeske et al. Biochem. Biophys. Res. Commun. 57 (1974) pp. 554-561 [Beauvericin]; Yu. A. Ovchinnikov et al. Zh. Obshch. Khim. 42 (10) (1972) p. 2320-2334; ref. C.A. 78, 58 77 k; DE 43 17 458) or can according to there specified procedures can be obtained.

The compounds of the formula (I) can be prepared according to the method described by U. Schmidt et al. For methods used in macrocyclic peptide alkaloids (see, for example: U. Schmidt et al. in Synthesis (1991) pp. 294-300 [Didemnin A, B and C]; Appl. Chem. 96 (1984) pp. 723-724 [Dolastatin 3]; Appl. Chem. 102 (1990) pp. 562-563 [Fenestin A]; Appl. Chem. 97 (1985) pp. 606-607 [ulicyclamide]; J. Org. Chem. 47 (1982) Pp. 3261-3264).

The compounds of formula (I) are as in the PCT application WO 93/25 543 described, prepared by

• a) caboxy-activated open-chain hexadepsipeptides of the general formula (IIa) in which
  A stands for an amino protective group which can be selectively removed from the active ester protective group, such as benzyl or benzyloxycarbonyl, and
  R¹, R², R³, R⁴, R⁵ and R⁶ have the meaning given above,
  cyclized in the presence of a suitable hydrogenation catalyst, in the presence of a basic reaction auxiliary and in the presence of a diluent under high dilution conditions, or
• b) open-chain hexadepsipeptides of the general formula (IIb) in which
  R¹, R², R³, R⁴, R⁵ and R⁶ have the meaning given above,
  cyclized in the presence of suitable coupling reagents, in the presence of a basic reaction auxiliary and in the presence of a diluent under high dilution conditions. The process conditions, the output connections and their preparation are described in the PCT application WO 93/25 543.

The active ingredients are suitable for combating parasitic protozoa of humans and those involved in animal husbandry and Animal breeding for farm, breeding, zoo, laboratory, experimental and hobby animals occurrence. They are against all or individual stages of development Pests and effective against resistant and normally sensitive strains. By the fight against parasitic protozoa are said to be illness, death and Reductions in performance (e.g. in the production of meat, milk, wool, skins, Eggs, honey, etc.) can be reduced, so that by using the active ingredients more economical and easier animal husbandry is possible.  

The parasitic protozoa include:

Mastigophora (Flagellata) such as B. Trypanosomatidae z. B. Trypanosoma b. brucei, T.b. gambiense, T.b. rhodesiense, T. congolense, T. cruzi, T. evansi, T. equinum, T. lewisi, T. percae, T. simiae, T. vivax, Leishmania brasiliensis, L. donovani, L. tropica, such as B. Trichomonadidae e.g. B. Giardia lamblia, G. canis.

Sarcomastigophora (Rhizopoda) such as Entamoebidae z. B. Entamoeba histolytica, Hartmanellidae e.g. Acanthamoeba sp., Hartmanella sp.

Apicomplexa (Sporozoa) such as Eimeridae e.g. B. Eimeria acervulina, E. adenoides, E. alabahmensis, E. anatis, E. anseris, E. arloingi, E. ashata, E. auburnensis, E. bovis, E. brunetti, E. canis, E. chinchillae, E. clupearum, E. columbae, E. contorta, E. crandalis, E. debliecki, E. dispersa, E. ellipsoidales, E. falciformis, E. faurei, E. flavescens, E. gallopavonis, E. hagani, E. intestinalis, E. iroquoina, E. irresidua, E. labbeana, E. leucarti, E. magna, E. maxima, E. media, E. meleagridis, E. meleagrimitis, E. mitis, E. necatrix, E. ninakohlyakimovae, E. ovis, E. parva, E. pavonis, E. perforans, E. phasani, E. piriformis, E. praecox, E. residua, E. scabra, E. spec., E. stiedai, E. suis, E. tenella, E. truncata, E. truttae, E. zuemii, Globidium spec., Isospora belli, I. canis, I. felis, I. ohioensis, I. rivolta, I. spec., I. suis, Cystisospora spec., Cryptosporidium spec. such as Toxoplasmadidae z. B. Toxoplasma gondii, such as Sarcocystidae e.g. B. Sarcocystis bovicanis, S. bovihominis, S. ovicanis, S. ovifelis, S. spec., S. suihominis such as Leucozoidae z. B. Leucozytozoon simondi, such as Plasmodiidae z. B. Plasmodium berghei, P. falciparum, P. malariae, P. ovale, P. vivax, P. spec., Such as Piroplasmea z. B. Babesia argentina, B. bovis, B. canis, B. spec., Theileria parva, Theileria spec., such as Adeleina z. B. Hepatozoon canis, H. spec.

Furthermore Myxospora and Microspora z. B. Glugea spec. Nosema spec.

Furthermore Pneumocystis carinii, and Ciliophora (Ciliata) such. B. Balantidium coli, Ichthiophthirius spec., Trichodina spec., Epistylis spec.

The compounds according to the invention are also active against protozoa which act as Parasites occur in insects. Parasites of the tribe should be mentioned as such  Microsporida, especially the genus Nosema. Nosema deserves special mention apis with the honeybee.

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, pigeons, bird species for home and zoo keeping. It also includes Farm and ornamental fish.

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

The pets include dogs and cats.

The fish include utility, breeding, aquarium and ornamental fish of all ages, who live in fresh and salt water. The useful and farmed fish include z. B. Carp, eel, trout, white fish, salmon, bream, roach, rudd, chub, Sole, plaice, halibut, Japanese yellowtail (Seriola quinqueradiata), Japanaal (Anguilla japonica), Red seabream (Pagurus major), Seabass (Dicentrarchus labrax), gray mullet (Mugilus cephalus), Pompano, Gilthread seabream (Sparus auratus), Tilapia spp., Chichlid species such as B. Plagioscion, Channel catlish. The agents according to the invention are particularly suitable for the treatment of Fish fry, e.g. B. Carp of 2 to 4 cm body length. They are very suitable Medium also in the eel mast.

The application can be prophylactic as well as therapeutic.

The active ingredients are used directly or in the form of suitable ones Preparations enterally, parenterally, dermally, nasally.

The enteral application of the active ingredients happens, for. B. orally in the form of powder, Suppositories, tablets, capsules, pastes, waterings, granules, drenches, boluses, medicated feed or drinking water. The dermal application happens for. B. in Form of diving (dipping), spraying (spraying), bathing, washing, pouring (pour-on and spot-on) and powdering. Parenteral use happens  e.g. B. in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or through 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 in an ointment base or in an oil is processed 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, hydrocarbons 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 dissolve the Promote active ingredient in the main solvent or prevent its precipitation. At Games 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 after previous Dilution to the application concentration applied orally. Oral solutions and concentrates are obtained 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, rubbed in rubbed, sprayed on, sprayed on or by diving (dipping), bathing or Wash applied. These solutions will be the same as for the injection solutions described, manufactured.

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

Gels are applied to or spread on or in body cavities brings. Gels are made by using solutions similar to those used for injection solutions have been prepared with so much thickener are added so that a clear mass with ointment-like consistency arises. When 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 suitable 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, ether such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol colmonobutyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dime thylacetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1,3-dioxolane.

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

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

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

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

Adhesives are e.g. B. cellulose derivatives, starch derivatives, polyacrylates, natural Polymers such as alginates, gelatin.

Emulsions can be used orally, dermally or as injections.

Emulsions are either water in oil or oil in water.

They are made by placing the active ingredient in either the hydrophobic or dissolves in the hydrophilic phase and more suitable with the help Emulsifiers and optionally other auxiliaries such as dyes, resorption promotional substances, preservatives, antioxidants, light stabilizers, viscosi substances increasing the homogeneity 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 acids of chain length C _8-12 or other specially selected natural fatty acids, partial glyceride mixtures saturated or unsaturated, possibly also hydroxyl-containing fatty acids, mono- and diglycerides of C₈ / C₁₀ fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipro pylene glycol pelargonate, ester of a branched fatty acid with medium chain length saturated fatty alcohols of chain length C₁₆-C₁₈, isopropyl myristate, isopropylpal mitate, caprylic / capric acid ester of saturated fatty alcohols with chain length C₁₂- C₁₈, isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl esters, waxy fatty acid esters such as dibutyl phthalate, adipic acid diisopropyl esters, the latter related ester mixtures u. a. Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

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

The following can be mentioned as the hydrophilic phase:

Water, alcohols such as B. propylene glycol, glycerin, sorbitol and their mixtures.

The following may be mentioned as emulsifiers:

non-ionic surfactants, e.g. B. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;
ampholytic surfactants such as di-Na-N-lauryl-β-iminodipropionate or lecithin;
anionic surfactants such as Na lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethandamine salt;
cationic surfactants such as cetyltrimethylammonium chloride.

The following may be mentioned as further auxiliaries:

Viscosity increasing and emulsion stabilizing 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 anhydride, polyethylene glycols, Waxes, colloidal silica or mixtures of the listed substances.  

Suspensions can be used orally, dermally or as an injection. she are made by placing the active ingredient in a carrier liquid if with the addition of other auxiliaries such as wetting agents, dyes, resorption promotional substances, preservatives, antioxidants, light stabilizers suspen dated.

Carrier liquids are all homogeneous solvents and solvents called mix.

As surfactants (dispersants) are the surfactants specified above called.

Further additives mentioned are those mentioned above.

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

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

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

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

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

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

The active ingredients can also be mixed with synergists in the preparations or with other active substances.

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

Preparations that are diluted before use contain the active ingredient in Concentrations from 0.5 to 90 percent by weight, preferably from 1 to 50 Ge percent by weight.

In general, it has been found advantageous to use amounts from about 0.5 to about 50 mg, preferably 1 to 20 mg, of active ingredient per kg of body weight per day for education effective results.

The active ingredients can also be taken together with the feed or drinking water of the animals be administered.

Feed and food contain 0.01 to 250 ppm, preferably 0.5 to 100 ppm of the active ingredient in combination with a suitable edible material.

Such feed and food can be used for medicinal purposes as well prophylactic purposes.

Such feed or food is produced by mixing a concentrate or premix containing 0.5 to 30%, preferably 1 to 20 wt .-% of an active ingredient in a mixture with an edible organic or contains inorganic carrier with common feed. Edible carriers are e.g. B. Corn meal or corn and soybean meal or mineral salts, which are preferred a small amount of an edible dust prevention oil, e.g. B. corn oil or soybean oil, contain. The premix obtained in this way can then be completely Feed must be added to the animals before they are fed.  

An example of use in coccidiosis is:

For the healing and prophylaxis of coccidiosis in poultry, in particular for chickens, ducks, geese and turkeys, 0.1 to 100 ppm are preferred wise 0.5 to 100 ppm of an active ingredient with a suitable edible material, e.g. B. a nutritious feed mixed. If desired, you can Amounts are increased, especially if the active ingredient is good from the recipient is tolerated. The administration via drinking water can accordingly respectively.

For the treatment of individual animals, e.g. B. in the case of the treatment of coccidiosis in mammals or toxoplasmosis, amounts of active substance are preferred from 0.5 to 100 mg / kg body weight administered daily to the desired Get results. Nevertheless, it may be necessary at times from the mentioned amounts deviate, especially depending on the body weight of the test animal or the type of administration method, but also because of the animal species and its individual response to the active ingredient or the type of formulation and the time or interval at which it is administered becomes. So it may be enough in certain cases, with less than that above mentioned minimum quantity, while in other cases the mentioned upper limit must be exceeded. When administering larger amounts it may be useful to divide these into several units during the day subdivisions.

In addition, the compounds of the invention are effective against various fish parasites belonging to the helminths (worms).

The parasites in fish include species from the sub-realm of the Protozoa the Ciliata tribe, e.g. B. Ichthyophthirius multifiliis, Chilodonella cyprini, Trichodina spp., Glossatella spp., Epistylis spp. the Myxosporidia tribe, e.g. B. Myxosoma cerebralis, Myxidium spp., Myxobolus spp., Heneguya spp., Hoferellus spp., The class of microsporidia z. B. Glugea spp., Thelohania spp., Pleistophora spp., From the plathelminth tribe: trematodes; Monogenea e.g. B. Dactylogyrus spp., Gyrodactylus spp., Pseudodactylogyrus spp., Diplozoon spp., cestodes, e.g. B. from the groups of the Caryphyllidea (z. B. Caryophyllaeus  laticeps), Pseudophyllidea (e.g. Diphyilobothrium spp.), Tetraphyllidea (e.g. Phyllobothrium spp.) And Protocephalida (e.g. species of the genus Proteocephalus) and various parasitic crustaceans from the Arthropoda tribe, especially from the subclasses of the Branchiura (fish lice) and Copepoda (Oar crabs) and the orders of the Isopoda (woodlice) and Amphipoda (Amphipods).

The fish are treated either orally, e.g. B. over the feed or through Short-term treatment, "medical bath" in which the fish are inserted and in which it for a while (minutes to several hours) e.g. B. when implementing one Breeding tanks are kept to the other.

But it can also be a temporary or permanent treatment of the Habitat of the fish (e.g. whole pond systems, aquariums, tanks or Tanks) in which the fish are kept.

The active ingredient is administered in preparations that are adapted to the applications are.

The concentration of the active ingredient in the preparations is from 1 ppm to 10% by weight.

Preferred preparations for short-term treatment when used as "medical African bath ", for example when treating the fish when they are moved or when Treatment of the habitat (pond treatment) of the fish are solutions of the Active ingredient in one or more polar solvents, which when diluted with React alkaline water.

To prepare these solutions, the active ingredient is in a polar, water soluble solvent, which either reacts alkaline or one alkaline water-soluble substance is added. The latter is advantageous if dissolved in the solvent, but can also be suspended in the solvent be and only dissolve in the water. The water should add the Active ingredient solution has a pH of 7 to 10, but preferably a pH from 8 to 10.  

The concentration of the active ingredient can range from 0.5 to 50% but preferably in a range of 1 to 25%.

All water-soluble solvents are suitable as solvents which the active ingredient is soluble in sufficient concentration and the physiologically are harmless.

These are ethyl alcohol, isopropyl alcohol, benzyl alcohol, glycerin, propylene glycol kol, polyethylene glycols, poly (oxoethylene) poly (oxypropylene) polymers, basic Alcohols such as mono-, di- and triethanolamine, ketones such as acetone or methyl ethyl ketone, esters such as lactic acid ethyl ester, also N-methylpyrrolidone, dimethyl acetamide, dimethylformamide, also dispersing and emulsifying agents such as polyoxy ethylated castor oil, polyethylene glycol sorbitan monooleate, polyethylene glycol stearate, or polyethylene glycol ether, polyethylene glycol alkyl amines.

Organic bases may be mentioned as bases for adjusting the alkaline pH Bases such as basic amino acids such as L or. D, L-arginine, L-resp. D, L-lysine, Methylglucose amine, 2-amino-2-hydroxymethylpropanediol- (1,3) further as N, N, N ', N'-tetrakis (2-hydroxypropyl) ethylenediamine or polyether tetrol on the Basis ethylenediamine (M.G. 480-420), inorganic bases such as ammonia or Sodium carbonate - if necessary with the addition of water.

The preparations can also 0.1 to 20 wt .-%, preferably 0.1 to 10% by weight of other formulation auxiliaries such as antioxidants, surfactants, suspensions sion stabilizers and thickeners such. B. methyl cellulose, alginates, Contain polysaccharides, galactomannans and colloidal silica. The addition of color, aroma and building materials for animal nutrition is also possible. Also acids that form a buffer system together with the base or reduce the pH of the solution should be mentioned here.

The concentration of the active ingredient during use depends on the type and duration the treatment, age and condition of the treated fish. It is z. B. for short-term treatment 2 to 50 mg of active ingredient per liter of water, preferably 5 to 10 mg per liter, with a treatment duration of 3 to 4 hours. In the  Treatment of young carp is e.g. B. with a concentration of 5 to 10 mg / l and a treatment time of about 1 to 4 hours worked.

Eels are treated with concentrations of approx. 5 mg / l for approx. 4 hours.

With longer treatment or with long-term treatment, the concentration can be chosen accordingly lower.

Pond treatments can use 0.1 to 5 mg of active ingredient per liter of water become.

Preparations for use as feed additives are e.g. B. together as follows set:

Example A Coccidiosis in chickens

9 to 11 day old chicks became strongly viru with 80,000 sporulated oocysts lenten strains of Eimeria acervulina, E. maxima and E. tenella, den Krank intestinal coccidiosis.

From 3 days before infection to 8 days after infection (end of experiment) active ingredient was used in the specified concentration in the feed of the animals mixed administered.

The number of oocysts in the feces was determined using the McMaster chamber [see Engelbrecht and co-workers "Parasitdog working methods in medicine and Veterinary Medicine ", p. 172, Akademie-Verlag, Berlin (1965)].

The effective doses are those that excrete Oocysts and / or clinical symptoms of coccidiosis including morta completely or to a high degree. The following table shows the effective doses indicated:  

Table 1

Coccidiosis in chickens

Manufacturing examples Example 1 Cyclo (-N-methyl-L-isoleucyl-D-lactyl-N-methyl-L-isoleucyl-D-lactyl-N - methyl-L isoleucyl-D-lactyl-) Procedure A

In a rapidly stirred suspension of 1.5 g 10% palladium / carbon in 550 ml absolute dioxane, the 12 ml ethanol and 160 mg (1.08 mmol) 4-pyrrolidino contains pyridine, 0.99 g (1.08 mmol) Z - (- L- MeIle-D-Lac-) ₃-O-Pfp in 50 ml of absolute dioxane in the course of 6 hours evenly injected. Hydrogen is passed through the reaction solution. Then another 4 hours at 95 ° C and 12 hours at room temperature temperature stirred. It is filtered and the entire reaction mixture is concentrated in Vacuum on. The colorless oily residue is taken up in chloroform and twice with 5% citric acid, twice with NaHCO₃ solution and twice washed with water. The organic phase is dried over sodium sulfate and then distilled off the solvent in vacuo. The leftover Crude product can be on a silica gel column (silica gel 60 - Merck, grain size: 0.04 to 0.063 mm) with the eluent toluene: ethyl acetate (4: 1) chromato be graphically pre-cleaned (purity 84%). Then the preparative  HPLC cleaning. 710 mg (36.8% of theory) of cyclo (-N-methyl-L- isoleucyl-D-lactyl-N-methyl-L-isoleucyl-D-lactyl-N-methyl-L-isoleuc-yl-D-lactyl-).

Procedure B

To a solution of 500 mg (0.81 mmol) of H- (L-MeIle-D-Lac) ₃-OH in 500 ml of methylene chloride, 262 mg (2.03 mmol) of N, N-diisopropylethylamine ("Hünig's base ") and 240 mg (0.97 mmol) of bis (2-oxo-3-oxazolidiny1) phosphonium chloride (BOP-Cl) were added and the mixture was stirred for 24 hours. It is then cooled again to 0 ° C. and with 262 mg (2.03 mmol) of N, N-diisopropylethylamine (“Hünig's base”) and 240 mg (0.97 mmol) of bis (2-oxo-3-oxazolidinyl) ) -phosphonium chloride (BOP-Cl) added. After stirring for a further 24 hours at room temperature, the reaction solution is shaken twice with water, the organic phase is separated off and, after drying over sodium sulfate, concentrated in vacuo. The remaining crude product is chromatographed on a silica gel column (Kiesel gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent toluene: ethyl acetate (4: 1). 370 mg (76.2% of theory) of cyclo (-N-methyl-L-isoleucyl-D-lactyl-N-methyl-L-isoleucyl-D-lactyl-N-- methyl-L-isoleucyl-D- lactyl).
Mp .: 210-212 ° C
1 H-NMR (400 MHz, CDCl₃, δ): 0.87 (t, 9H, -CH₂- CH ₃; J = 7.3 Hz); 0.98; 1.44 (2d, 18H, -CH- CH₃ ; J = 6.5 Hz); 1.35-1.41 (br. M, 3H- CH -CH₃); 2.02-2.04 (br. M, 6H, - CH ₂-CH₃); 3.03 (s, 9H, -N- CH₃ ); 4.45 (m, 3H N- CH -CO); 5.57-5.62 (m, 3H, O- CH -CO) ppm
13 C-NMR (100 MHz, CDCl₃, δ): 10.9; 16.0; 16.6 (- C H₃); 24.8 (- C H₂-); 33.3 (-CH-); 33.9 (-N- C H₃); 61.9 (-N- C H-); 66.4 (-O- C H-); 169.3 (- C O-N-); 169.9 (- C O-O-) ppm
FAB-MS m / z (%): 598 (M⁺ + H, 12); 597 (37); 541 (42); 524 (14); 182 (100).

Analogously, the compounds listed in Table 2 below Formula (I) can be prepared as LDLDLD stereoisomers.  

Table 2

Examples of compounds of the general formula (I)

Claims (5)

1. Use of cyclic depsipeptides consisting of amino acids and hydroxycarboxylic acids as ring building blocks and 18 ring atoms of the general formula (I) in which
R¹, R³ and R⁵ independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl, arylalkyl or heteroaryl alkyl, which may optionally be substituted,
R², R⁴ and R⁶ independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, which may optionally be substituted,
and their optical isomers or racemates,
as a means of combating parasitic protozoa and in particular coccidia. 2. Agent against parasitic protozoa, characterized by a content of at least one depsipeptide of formula (I) according to claim 1.   3. A method of combating parasitic protozoa, characterized records that depsipeptides of formula (1) according to claim 1 lets them and / or their living space act. 4. A process for the preparation of agents against parasitic protozoa, thereby characterized in that depsipeptides of the formula (I) according to Claim 1 mixed with extenders and / or surfactants. 5. Use of depsipeptides of formula (I) according to claim 1 for Her provision of means against parasitic protozoa.