WO2000076985A1

WO2000076985A1 - Cyclo-imino depsipeptides and their utilization in controlling endoparasites

Info

Publication number: WO2000076985A1
Application number: PCT/EP2000/004935
Authority: WO
Inventors: Peter Jeschke; Achim Harder; Georg Von Samson-Himmelstjerna; Gerhard Bonse
Original assignee: Bayer Aktiengesellschaft
Priority date: 1999-06-11
Filing date: 2000-05-30
Publication date: 2000-12-21
Also published as: AU5218000A; AU768501B2; DE19926620A1; CA2374632A1; BR0011498A; CN1355794A; ZA200109179B; EP1192142A1; HUP0201592A2; JP2003502318A; HK1047589A1

Abstract

The invention relates to cyclo-imino depsipeptides of formula (I), especially 24-membered cyclo-imino depsipeptides. The invention also relates to methods for their preparation and to their utilization in controlling endoparasites.

Description

CYCLOΠVΠNODEPSIPEPTIDE AND THEIR USE FOR COMBATING ENDOPARASI-

The present invention relates to cycloiminodepsipeptides, in particular 24-membered cycloiminodepsipeptides, processes for their preparation and their use for combating endoparasites.

Among the interesting backbone modifications of peptides, which are primarily intended to reduce their enzymatic hydrolysis reliability, is undoubtedly the replacement of the amide oxygen with sulfur and the exchange of amide oxygen with an optionally substituted imino group.

Naturally occurring peptides with an iminopeptide bond or an amidine group in the molecule are extremely rare. Examples include bottromycin, a peptide antibiotic from Streptomyces bottropensis, amidinomycin or netropsin (JM Waiswisz et al., J. Am. Chem. Soc. 79, 1957, p. 4520; S. Nakamura Chem. Phar. Bull 9, 1961, p. 641; S. Nakamura et al, J. Antibiot. 17A, 1964, p. 220).

Methods for introducing optionally substituted imino functions into synthetic peptides are known from the literature. The syntheses of amidoxime, cyanamidine and amidrazone analogs of chemotactic peptides may be mentioned here as examples (G. Sauve et al., Can. J. Chem. 61, 1985, p. 3089). Chemotactic peptides of the type N-FonΗyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe-OR) are interesting as prototype bioregulators of immune cells - for example, they induce the release of lysozyme from human neutrophils (SV Rao et al, Spectroscopy (Ottawa) 4 (3), 1985, p. 153; B. Belleau et al., Int. J. Immunopharmacol. 11 (5), 1989, p. 467; E. Schiffmann et al., Proc. Natl Acad. Sci. USA 72, 1975, p. 1059; RJ Freer et al., Biochemistry 21, 1982, p. 257). By HA Moynihan et al. a representation variant of the N ^ω -hydroxy-N ^ω -methyl-L-arginine, a new NO synthase inhibitor, has been described (J. Chem. Soc. Perkin Trans. I 1994, p. 769). Suitable starting components for the preparation of the iminopeptides mentioned above, according to G. Sauve et al. or HA Moynihan et al. preferably the corresponding endothiopeptides used.

The synthesis of iminodipeptides from corresponding α-aminonitriles is also known (cf. N-benzyloxycarbonyl-iminodipeptides: W. Ried et al. Chem. Ber. 95, 1962, p. 728; Ann. Chem. 661, 1963, p 76; T. Yamada et al., Bull. Chem. Soc. Jpn. 50 (5), 1977, p. 1088; analogues of N-phthalyl (iminoglycyl) - (S) -valine: E. Vargha et al. Studia Univ. Babes-Bolyai, Ser. Chem. 11, 1966, p. 85, ref. Chem. Abstr. 66, 1967, 2757).

Poly (dipeptamidines), in which the carbonyl oxygen of every second peptide amide group is replaced by an imine nitrogen, were produced as comparison products for the oligomerization of α-aminonitriles (cf. A. Eschenmoser et al., Helv. Chim. Acta 69, 1986, p. 1224).

In contrast to the processes already mentioned for the preparation of various N-substituted iminopeptides, nothing is known about the preparation of cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids.

In particular, nothing has been known about the preparation of cycloiminodepsipeptides, consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring building blocks and 24 ring atoms, from corresponding cyclothiodepsipeptides.

Cyclic depsipeptides and their preparation and use as endoparasiticides have already been the subject of numerous publications.

For example, a cyclodepsipeptide called PF 1022A and its

Effect against endoparasites known (EP-OS 382 173 and EP-OS 503 538). - - j -

Further cycüsche depsipeptides (cyclooctadepsipeptides: WO 98/55 469; WO 98/43 965; WO 98/15 523; WO 98/37 088; WO 97/02 256; WO 97/09 331; WO 96/11 945; WO 95 / 07 272; WO 94/19 334; WO 93/19 053; EP-OS 634 408; EP-OS 626 375; EP-OS 626 376; EP-OS 664 297; EP-OS 634 408; EP-OS 718 298; WO 97/09 331; Cyclohexadepsipeptides: WO 93/25 543; WO 95/27 498; EP-OS 658 551;

Cyclotetradepsipeptides: EP-OS 664 297; Dioxomorpholines: WO 96/38 165; JP 08 225 552) and open-chain depsipeptides (EP-OS 657 171; EP-OS 657 172; EP-OS 657 173; WO 97/07 093) and their endoparasiticidal activity are described.

Cyclothiodepsipeptides consisting of amino acids, hydroxythiocarboxylic acids and optionally hydroxycarboxylic acids as ring building blocks and 24 ring atoms, their preparation and their use for controlling endoparasites is the subject of a previous patent application (WO 98/43 965) by the applicant.

In addition to the new cycloiminodepsipeptides, the present invention also relates to a process for the preparation of cycloiminodepsipeptides, in particular cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring components and 24 ring atoms.

Another subject is the use of cycloiminodepsipeptides, in particular cycloiminodepsipeptides, consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring building blocks and 24 ring atoms, for the preparation of agents for controlling endoparasites.

The present invention relates in particular to:

1. Cycloiminodepsipeptides of the general formula (I)

in which

R ¹ , R ⁴ , R ⁷ and R ¹⁰ independently of one another represent hydrogen, straight-chain or branched alkyl,

R ² , R ⁵ , R ⁸ and R ⁿ independently of one another represent hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl and aryl or hetaryl,

R ¹⁰ and R ^u together with the atoms to which they are attached represent an optionally substituted 5- or 6-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxy or sulfonyl,

R ⁶ and R ¹² independently of one another represent hydrogen, optionally substituted alkyl or arylalkyl, and optionally substituted cycloalkylalkyl,

R ³ and R ⁹ independently of one another represent hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, cycloalkyl, alkoxycarbonylalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl, aryl or hetaryl, and

C = X, C = X, C = X and C = X independently of one another each represent one of the groups C = 0, C = S or CH ₂ or denote a group C = NA, at least one of the groups C = X ' , C = X ² , C = X ³ and C = X ⁴ for

C = N-A must be

in which

A for hydrogen, optionally substituted alkyl, alkenyl, alkynyl,

Alkylcarbonyl, alkylsulfonyl, and cyano, nitro, carbamoyl, alkoxycarbonyl, formyl, - (C = NH) -NH ₂ , -P (0) -0-alkyl, -P (S) -0- alkyl or optionally for a radical A. ¹

-YR ¹³ (A ¹ ) in which

Y represents oxygen, sulfur or -NR ¹⁴ ,

R ¹³ and R ¹⁴ independently of one another for hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl, aryl or hetaryl as well as for formyl, alkoxydicarbonyl, alkylsulfonyl, haloalkoxyalkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl, allyloxycarbonylyl , Aryloxyalkyl, hetarylcarbonyl, alkylcarbonyl or optionally represents a radical from the group B ¹ , B ² , B ³ or B ⁴ ,

wonn

for optionally substituted, straight-chain or branched alkyl,

Alkenyl, alkynyl, cycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, aryloxy, arylalkoxy, hetaryloxy, hetarylalkoxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, arylthio, arylalkylthio, hetarylthio, hetaminoalkyl amino, arylamino, arylalkylamino, hetarylamino, hetarylalkylamino, dialkylamino, dialkenylamino, aryl, arylalkyl, hetaryl or hetarylalkyl, cyano, amino or an optionally substituted cyclic amino group linked via nitrogen,

for carboxy, thiocarboxy, sulfoxy, sulfonyl, -P (0) -0- alkyl,

-P (S) -0- alkyl or -C = NR ¹⁵ ,

R ¹⁵ for hydrogen, hydroxy, alkoxy, alkylcarbonyl, alkoxycarbonyl,

Haloalkylcarbonyl, alkylsulfonyl, nitro or cyano,

R ^{16 represents} hydrogen or alkyl,

n represents 0, 1 or 2,

Y ^{1 represents} oxygen, sulfur or -NR ¹⁷ , R ¹⁸ , when Y ¹ is nitrogen, can mean a cyclic amino group linked via this nitrogen atom,

R ¹⁷ and R ¹⁸ independently of one another represent hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, aryl, arylalkyl, hetaryl or hetarylalkyl, or

R ¹⁷ and R ¹⁸ together with the adjacent N atom for an optionally substituted heterocyclic 4-, 5-, 6- or 7-membered ring system or for an optionally substituted 7- to 10-membered bicyclic ring system, which may also be substituted by oxygen, Sulfur, sulfoxyl, sulfonyl, carbonyl, -NO, -N =, -NR ²² or can be interrupted by quaternized nitrogen,

R ¹⁹ and R ²⁰ independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl and optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl, or

R ¹⁹ and R ²⁰ together represent an optionally substituted spirocyclic ring,

R ²⁰ and R ²¹ together with the atoms to which they are attached represent an optionally substituted 5-, 6- or 7-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl,

R ^{21 represents} hydrogen, optionally substituted, straight-chain or branched alkyl, cycloalkyl, arylalkyl, hetarylalkyl, and aryl or hetaryl, R ^{22 represents} hydrogen, optionally substituted straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cyano, arylalkyl, hetarylalkyl, and aryl or hetaryl,

R ¹³ can also stand for a selectively cleavable protective group, or a polymeric carrier which is connected to Y via a selectively cleavable anchor group,

as well as their pure optical isomers, racemates and physiologically compatible

Salts,

to fight endoparasites in medicine and veterinary medicine.

Depending on the nature of the substituents, the compounds of the general formula (I) can occur as geometric and / or optical isomer mixtures and also regioisomer mixtures of different compositions. The invention relates to both the pure isomers and the isomer mixtures.

The cycloiminodepsipeptides, consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring units and 24 ring atoms, of the general formula (I) are preferred

in which

R ¹ , R ⁴ , R ⁷ and R ^{10 are} straight-chain or branched C ₄ alkyl, in particular methyl,

R ² , R ⁵ , R ⁸ and R ¹¹ independently of one another are C - alkyl, in particular isobutyl,

R ⁶ and R ¹² independently of one another for optionally substituted d ₄ -alkyl or aryl-C 1 -C ₂ -alkyl, in particular optionally substituted

Benzyl standing

R ³ and R ⁹ independently of one another for optionally

Hetaryl -C ₂ alkyl, C ₄ alkoxycarbonylmethyl, aryl C ₂ alkyl, in particular optionally substituted benzyl,

where hydrogen, halogen, cyano,

Carbamoyl, C-alkyl, a protective group-bearing hydroxy or unprotected hydroxy, Cι- ₈ - alkoxy, C -alkoxy-Ci ^ -alkoxy, C _2-4 - alkenyloxy, Hetaryl-Cι- alkoxy, where the heterocycles can be substituted again Nitro

or

a radical from the series R ²³ R ⁴ NC _r C ₆ -alkoxy, R ²³ R ²⁴ NC _r C ₈ - alkyl, NR ²³ R ²⁴ and -S0 ₂ -NR ²³ R ²⁴ , in which

R ²³ and R ²⁴ independently of one another each represent hydrogen, Ci -Cg-

Alkyl, C _r C ₆ -alkoxy-C _r C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ - cycloalkylamino-Ci-C ^ -alkyl, where one or more carbon atoms in the cycloalkyl ring by nitrogen Oxygen or sulfur atoms can be replaced, hetaryl-Ci ^ alkyl or a protecting group, or

R ²³ and R ²⁴ together with the nitrogen atom to which they are attached for hetaryl or heterocycloalkyl, in particular N-

Pyrrolidino, N-piperazino, N-morpholino, N-thiomorpholino, N-piperidino, N-imidazolo, 2-oxopyrrolidinyl, phthalimino or tetrahydrophthalimino,

and

(i) C = X ^{1 represents} a group C = NA,

C = X ² , C = X ³ and C = X ⁴ stand for C = 0, C = S or CH ₂ ,

or

(iii) C = X ^{3 represents} a group C = NA,

C = X ² and C = X ⁴ stand for C = 0, C = S or CH ₂ ,

or

(iv) C = X ^* and C = X ^{3 represent} a group C = NA,

C = X ² and C = X ⁴ stand for C = 0, C = S or CH ₂ ,

in which

A for hydrogen, optionally substituted C ^ - alkyl, 0 ₂ ^ - alkenyl, C _2- alkynyl, C ₁ -C ₄ alkylcarbonyl, Cι. ₆ - alkylsulfonyl and cyano, nitro, carbamoyl, C ₂ - ₆ alkoxycarbonyl, formyl, - (C = NH) -NH ₂ , -P (0) -0-Cι _-3 -alkyl, -P (S) -0 -Cι _-3 -

Alkyl or optionally for a radical A ¹ YR, 1 ¹ 3 ^J (A ¹ ),

in which

Y represents oxygen or -NR ¹⁴ ,

R ¹³ and R ¹⁴ independently of one another for hydrogen, optionally substituted, straight-chain or branched C ₈ alkyl, C ₂ ₈ alkenyl, C ₂ ₈ alkynyl, C _3-7 cycloalkyl, C ₃ . _7- cycloalkyl-C ₁ . ₂ -alkyl,

_Aryl-2 Cι- alkyl, hetaryl-CJ ₂ alkyl, aryl or hetaryl, and formyl, C _r C ₈ alkylsulfonyl, C ₁ -C ₂ -haloalkoxy-C. ₁ _2- alkylsulfonyl, C _r C ₈ -alkylcarbonyl, C] -C - alkoxycarbonyl, C _j -Cg-alkylaminocarbonyl, C2-C ₈ -alkenyloxycarbonyl, C2-C ₈ -alkynyloxycarbonyl, aryloxy-C _] - C2-alkyl, hetarylcarbonyl, C _M alkoxydicarbonyl or optionally represents a radical from the group B ¹ , B ² , B ³ or B ⁴

wonn

Q for optionally substituted, straight-chain or branched Cι_ ₈ -

Alkyl, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, C. ₃ _7- cycloalkyl, -C _-6 alkoxy, C _2-6 - alkenyloxy, C2-6-alkynyloxy, C3_ ₇ -cycloalkoxy, aryloxy, aryl-Cι. ₂ - alkoxy, hetaryloxy, hetaryl -C 2 alkoxy, C ₆ alkyl thio, C ₂ ₆ alkenyl thio, C ₂ - ₆ alkynylthio, C. ₃ _7- cycloalkyl-thio, arylthio, aryl-Cι- ₂ alkylthio, hetarylthio, hetaryl-Cι- ₂ alkylthio, Cι _-6 alkylamino, C ₂ . ₆ -Alke- nylamino, C2-6-alkynylamino, C ₃ - ₆ -cycloalkyl-alkylamino, arylamino, aryl-Cι-2-alkylamino, Hetarylamino, hetaryl-Cι- ₂ alkylamino, di-Ci- ₄ alkylamino, di -C ₂ - ₄ -alkenylamino, aryl, aryl- Cι. ₂ -alkyl, hetaryl, hetaryl -CC ₂ -alkyl and cyano, amino or an optionally substituted cyclic amino group linked via nitrogen,

Z I I

^G \ stands for thiocarboxy or carboxy,

R ^{15 represents} hydrogen, hydroxyl, C _M - alkoxy, C _M - alkylcarbonyl, Cμ- alkoxycarbonyl, halogen -CC-4-alkylcarbonyl, C _M - alkylsulfonyl, nitro or cyano,

R ^{16 represents} hydrogen or C _M - alkyl,

n represents 0, 1 or 2,

Y ^{1 represents} oxygen, sulfur or -NR ¹⁷ ,

R ¹⁸ , when Y ¹ is nitrogen, can mean a cyclic amino group linked via this nitrogen atom,

R ¹⁷ and R ¹⁸ independently of one another for hydrogen, optionally substituted, straight-chain or branched Ci -6- alkyl, C2-6-alkenyl, C2-6-alkynyl, C ₃ . ₇ -

Cycloalkyl, C ₃ . -Cycloalkyl-Cι- ₆ alkyl, -Cι _-6 - alkoxycarbonyl, aryl, aryl-Cι- ₂ - alkyl, hetaryl, hetaryl-Cι_ ₂ -alkyl, or

R ¹⁷ and R ¹⁸ together with the adjacent N atom for an optionally substituted, heterocyclic 4-, 5-, 6- or 7-membered ring system or represent an optionally 7- to 10-membered bicyclic ring system which can optionally also be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl, carbonyl, -NO, -N =, -NR ²² or by quaternized nitrogen,

R ¹⁹ and R ²⁰ independently of one another for hydrogen, optionally substituted straight-chain or branched C ₆ alkyl, C2 6 alkenyl, C ₃ 7 cycloalkyl and optionally substituted aryl, aryl C ₂ alkyl, hetaryl, hetaryl Cι- ₂ alkyl, or

R ²⁰ and R ²¹ together with the atoms to which they are attached represent an optionally substituted 5-6- or 7-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl,

R ^{21 represents} hydrogen, optionally substituted, straight-chain or branched C ₆ alkyl, C ₃ .7 cycloalkyl, aryl C ₂ alkyl, hetaryl C ₂ alkyl, and aryl or hetaryl,

R ²² is hydrogen, optionally substituted, straight or branched Cι-, ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C. ₃ _7- Cycloalkyl, C _3- - Cycloalkyl-Cι _-6 -alkyl, Cι. ₆ - alkoxycarbonyl, Cι_ ₆ - alkylcarbonyl, C _3-7 -

Cycloalkylcarbonyl, cyano, aryl -CC ₂ alkyl, hetaryl -CC ₂ alkyl, and aryl or hetaryl,

R ¹³ also for a selectively removable protective group, for example allyl, allyloxycarbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl (Z), tert.-

Butyloxycarbonyl (Boc), tetrahydropyran-2-yl (THP) or fluorenyl methoxycarbonyl (Fmoc) and stands for a polymeric carrier which is bonded to Y by means of a selectively cleavable anchor group,

and their optical isomers, racemates and physiologically acceptable salts.

The cycloiminodepsipeptides according to the invention and their salts are generally defined by the general formula (I).

The cycloiminodepsipeptides according to the invention and their acid addition salts and metal salt complexes have good endoparasiticides, in particular anthelmintic ones

Effect and can preferably be used in the field of veterinary medicine.

2. Process 1 for the preparation of the new cycloiminodepsipeptides of the general formula (I)

and their salts, in which

R ¹ to R ¹² and the groups C = X 'to C = X ^{4 have} the meanings given under point 1,

characterized in that one

Cyclothiodepsipeptides of the general formula (I)

and their salts,

in which

R to R have the meanings given under point 1, and

C = X \ C = X ² , C = X ³ and C = X ⁴ independently of one another are C = O, C = S or CH ₂ , where at least one of the groups C = X, CX ² , C = X ³ and C = X ⁴ must stand for a C = S group,

with amino compounds of the general formula (II)

H ₂ NA (II)

in which

A has the meanings given under point 1,

in the presence of suitable metal salts or metal oxides, especially mercury

(LT) acetate, Quecksüber (II) chloride or Quecksilber (II) oxide, in the presence of a basic reaction auxiliary and in the presence of a suitable diluent. The process according to the invention relates in particular and preferably to the preparation of the new cycloiminodepsipeptides of the general formula (Ia)

and their salts, in which

A and R, l ι b.:i-s τ R> 12 have the meanings given under point 1.

Process 2 according to the invention for the preparation of the new and preferred cycloiminodepsipeptides of the general formula (Ia) and their salts is characterized in that

a) the cyclothiodepsipeptides of the general formula (Ib) or their salts,

in which R ¹ to R ^{12 have} the meanings given under point 1,

with amino compounds of the general formula (II)

H ₂ NA (LT) in which

A has the meanings given under point 1,

in the presence of suitable metal salts or metal oxides, in particular mercury (IΙ) acetate, mercury (IΙ) chloride or mercury (II) oxide, and in the presence of a basic reaction auxiliary and in the presence of a suitable diluent, or

b) for the preparation of the new cycloiminodepsipeptides of the general formula (la)

and their salts, in which

R, 1 b.is. τ R> 12 have the meanings given under point 1,

A stands for a residue -YR ¹³ (A ¹ ), in which

Y has the meaning given under point 1,

R ^{13 stands} for residues from group B ¹ to B ³ ,

wherein

Z ^, Q, Y ¹ , n, R ¹⁰ , and R ^lδ -R ^{υ have} the meanings given under point 1,

the new cycloiminodepsipeptides of the general formula (Ic) obtained by processes 2a) and 3 according to the invention

(Ic) and their salts,

in which Y and R ¹ to R ^{12 have} the meanings given under point 1,

with compounds of the general formula (Illa-c)

wonn

^, Q, Y ¹ , n, R ¹⁶ , and R ¹⁸ -R ^{20 have} the meanings given under point 1,

W stands for a suitable leaving group, such as halogen,

if appropriate in the presence of a catalyst, if appropriate in the presence of a basic reaction auxiliary and if appropriate in the presence of diluents, or

c) for the preparation of the new cycloiminodepsipeptides of the general formula (Ia) and their salts,

in the A for a residue -YR ¹³ (A ¹ )

in which

Y has the meanings given under point 1,

R ^{13 represents} radicals from the groups B ¹ and B ³ ,

wonn

Q, Y ¹ , n, R ¹⁸ -R ^{20 have} the meanings given under point 1,

n stands for 0,

Z I I and the group represents carboxy,

the compounds of the general formula (Ic) and their salts

in which

Y and R ¹ to R ^{12 have} the meanings given under point 1,

with a carboxylic anhydride of the general formula (IV)

(Q-CO) ₂ 0 (IV) in which

Q has the meaning given under point 1 or

stands,

wonn

Y ¹ , R ¹⁸ -R ^{20 have} the meaning given under point 1,

d) by compounds of the general formula (Ic)

α) with amino acid derivatives of the general formula (V)

in which

Z I I

, Q, and R, 19 τ b_i-s r R> 21 have the meaning given under point 1 if appropriate in the presence of coupling reagents and if appropriate in the presence of a basic reaction auxiliary and if appropriate in the presence of diluents, or

ß) with compounds of the general formulas (VI) and (VII)

R, 15

R ^{, 5} -NOY (VI) Y ^' N = C = Y

(VII)

in which

Z

I I

. G.

Y and R ^{12 have} the meaning given under point 1,

if appropriate in the presence of a basic reaction auxiliary or a catalyst, if appropriate in the presence of diluents.

The invention further relates to:

3. Process 3 for the preparation of cycloiminodepsipeptides of the general formula (Ic) and their salts,

in which

Y and R to R »12 have the meanings given under point 1,

characterized in that one

a) of the cycloiminodepsipeptides of the general formula (Ia) and their salts obtainable according to process 2a,

in which R ¹ to R ^{12 have} the meanings given under point 1,

A stands for a residue -YR ¹³ (A ¹ ),

in which

Y represents oxygen or -N-H,

R ¹³ for a selectively removable protective group, for example allyl, allyloxycarbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl (Z), tert-

Butyloxycarbonyl (Boc), tetrahydropyran-2-yl (THP) or in fluorenylmethoxycarbonyl (Fmoc),

depending on the removable protective group, either in the presence of a hydrogenation catalyst, in the presence of a protonic acid or a basic reaction auxiliary and in the presence of a diluent, the radical R ^{13 is} selectively eliminated,

or

b) from the cycloiminodepsipeptides of the general formula (Ia) obtainable according to method 2a and bound to a polymeric support and their salts,

in which

R ¹ to R ^{12 have} the meanings given under point 1,

A for a residue -YR ¹³ (A ¹ )

in which

Y is oxygen or -N-H,

R ^{13 represents} a selectively cleavable anchor group on a polymeric support,

in the presence of a suitable catalyst or in the presence of a protonic acid and in the presence of a diluent by selective cleavage of the anchor group from the polymeric support R the compounds of the formula (Ic) f are added.

The cycloiminodepsipeptides according to the invention and their salts are generally defined by the general formula (I). The cycloiminodepsipeptides according to the invention and their acid addition salts and metal complexes have good endoparasiticidal, in particular anthelmintic, effects and can preferably be used in the field of veterinary medicine.

The following definitions apply to all general formulas and descriptions mentioned above or below.

Optionally substituted alkyl alone or as part of a radical in the general formulas means straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples include optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1, 1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3- Dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-

Dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl and ethylbutyl.

Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl may preferably be mentioned.

Optionally substituted alkenyl alone or as part of a radical in the general formulas means straight-chain or branched alkenyl with preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples include optionally substituted vinyl, 2-propenyl, 2-butenyl, 3-butenyl, l-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, l-methyl- 2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, l-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, l, l-dimethyl 2-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, l-methyl-2-pentenyl, 2-methyl- 2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-

Methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, l, l-dimethyl-2-butenyl, l, l-dimethyl-3-butenyl, l, 2-dimethyl-2-butenyl, l, 2- Dimethyl-3-butenyl, l, 3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, l-ethyl- 2-butenyl, l-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 1, 2-trimethyl-2-propenyl, 1-ethyl-l-methyl-2- called propenyl and l-ethyl-2-methyl-2-propenyl.

Optionally substituted ethenyl, 2-propenyl, 2-butenyl or 1-methyl-2-propenyl may preferably be mentioned.

Optionally substituted alkynyl alone or as part of a radical in the general formulas means straight-chain or branched alkynyl with preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples include optionally substituted ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, l-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-methyl-3-butynyl, 2-methyl- 3-butynyl, l-methyl-2-butynyl, l, l-dimethyl-2-propynyl, l-ethyl-2-propynyl, 2-hexynyl, 3-

Hexynyl, 4-hexynyl, 5-hexynyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, l, l-dimethyl-3-butynyl, l, 2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, l-ethyl- 3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-l-methyl-2-propynyl called.

Optionally substituted ethynyl, 2-propynyl or 2-butynyl may be mentioned.

Optionally substituted cycloalkyl alone or as part of a radical in the general formulas means mono-, bi- and tricyclic cycloalkyl, preferably having 3 to 10, in particular 3, 5 or 7, carbon atoms. Examples of optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and adamantyl may be mentioned. Haloalkyl alone or as a constituent of a radical in the general formulas contains 1 to 4, in particular 1 or 2, carbon atoms with preferably 1 to 9, in particular 1 to 5 identical or different halogen atoms, preferably fluorine, chlorine or bromine, in particular fluorine or chlorine. Examples include trifluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, chloromethyl, bromomethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2, 2-difluoroethyl, pentafluoroethyl and pentafluoro-tert-butyl called.

Optionally substituted alkoxy alone or as part of a radical in the general formulas means straight-chain or branched alkoxy with preferably 1 to 6, in particular 1 to 4, carbon atoms. Substituted methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy may be mentioned as examples.

Optionally substituted alkoxyalkoxy alone or as a constituent of a radical in the general formulas means 2 C-O-linked alkoxy radicals as mentioned above. Substituted methoxymethoxy, methoxyethoxy, methoxy-n-propoxy and ethoxyisopropoxy may be mentioned as examples.

Optionally substituted alkoxyalkoxyalkoxy, alone or as part of a radical in the general formulas, 3 each means C-O-linked alkoxy radicals as mentioned above. Substituted methoxymethoxyethoxy, methoxyethoxyethoxy and methoxyethoxy-n-propoxy may be mentioned as examples.

Optionally substituted haloalkoxy alone or as part of a radical in the general formulas means straight-chain or branched haloalkoxy with preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples include optionally substituted difluoromethoxy, trifluoromethoxy, trichloromethoxy, Chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy and 2-chloro-l, l, 2-trifluoroethoxy.

Optionally substituted alkylthio alone or as part of a radical in the general formulas means straight-chain or branched alkylthio with preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples of optionally substituted methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio and tert-butylthio may be mentioned.

Optionally substituted haloalkylthio alone or as part of a

The rest in the general formulas mean straight-chain or branched haloalkylthio having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples include optionally substituted difluoromethylthio, trifluoromethylthio, trichloromethylthio, chlorodifluoromethylthio, 1-fluoroethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio, 1,1,2,2-tetrafluoroethylthio, 2,2,2-trifluoroethylthio and 2- Chlorine-l, l, 2-trifluoroethylthio called.

Optionally substituted alkylcarbonyl alone or as part of a radical in the general formulas means straight-chain or branched alkylcarbonyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples of optionally substituted methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, sec-butylcarbonyl and tert-butylcarbonyl may be mentioned.

Optionally substituted cycloalkylcarbonyl alone or as part of a radical in the general formulas means mono-, bi- and tricyclic cycloalkylcarbonyl, preferably having 3 to 10, in particular 3, 5 or 7, carbon atoms. Examples of optionally substituted cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, bicyclo [2.2.1] heptylcarbonyl, bicyclo [2.2.2] octylcarbonyl and adamantylcarbonyl may be mentioned. Optionally substituted alkoxycarbonyl alone or as part of a radical in the general formulas means straight-chain or branched alkoxycarbonyl with preferably 2 to 7, in particular 2 to 5, carbon atoms. Examples of optionally substituted methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl may be mentioned.

Aryl is, for example, a mononuclear, polynuclear or polynuclear aromatic radical such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl and the like, but preferably phenyl or naphthyl.

Optionally substituted aryl in the general formulas preferably means optionally substituted phenyl or naphthyl, especially phenyl.

Optionally substituted arylalkyl in the general formulas preferably means optionally substituted arylalkyl in the aryl part and / or alkyl having preferably 6 or 10, in particular 6 carbon atoms in the aryl part (preferably phenyl or naphthyl, in particular phenyl) and preferably 1 to 4, in particular 1 or 2 carbon atoms in the Alkyl part, where the alkyl part can be straight-chain or branched. Exemplified and preferred are optionally substituted benzyl and 1-phenyl ethyl.

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

Alkyl with preferably 1 to 4, in particular 1 to 2 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; Alkoxy with preferably ibis 4, in particular 1 to 2 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy; Alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio, n- Butylthio, isobutylthio, sec-butylthio; Haloalkyl preferably having 1 to 5, in particular 1 to 3, halogen atoms, the halogen atoms being identical or different and halogen atoms, preferably fluorine, chlorine or bromine, in particular fluorine or chlorine, such as difluoromethyl, trifluoromethyl, trichloromethyl; Hydroxy; Halogen, preferably fluorine, chlorine, bromine and iodine, especially fluorine and chlorine; Cyano; Nitro; Amino; Monoalkyl- and dialkylamino with preferably 1 to 4, in particular 1 or 2 carbon atoms per alkyl group, such as methylamino, methylethylamino, dimethylamino, n-propylamino, isopropylamino, methyl-n-butylamino; Alkylcarbonyl radicals such as methylcarbonyl; Alkoxycarbonyl with preferably 2 to 4, in particular 2 to 3 carbon atoms such as

Methoxycarbonyl and ethoxycarbonyl; Alkylsulfmyl having 1 to 4, in particular 1 to 2, carbon atoms; Haloalkylsulfinyl with 1 to 4, in particular 1 to 2, carbon atoms and 1 to 5 halogen atoms, such as trifluoromethylsulfinyl; Haloalkylsulfonyl with 1 to 4, in particular 1 to 2, carbon atoms and 1 to 5 halogen atoms, such as trifluoromethylsulfonyl, perfluoro-n-butylsulfonyl, perfluoroisobutylsulfonyl; Arylsulfonyl preferably having 6 or 10 aryl carbon atoms such as phenylsulfonyl; Acyl, aryl, aryloxy, which in turn is one of the above

Can carry substituents and the formimino radical (-HC = N-0- alkyl).

The number of these substituents is not limited, it is preferably one to four identical or different substituents. The presence of two identical or different substituents on the same atom or on atoms of cyclic amino groups is also conceivable.

Optionally substituted mono- or dialkylamino groups alone or as part of a radical in the general formulas means straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples of substituted mono- or dialkylamino groups are methylamino, ethylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino or dibutylamino. Optionally substituted mono- or dialkoxyalkylamino groups alone or as part of a radical in the general formulas means straight-chain or branched alkoxyalkyl with preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples of substituted mono- or dialkoxyalkylamino groups are methoxymethylammo, methoxyethylamino, di- (methoxymethyl) -amino or di- (methoxyethyl) -amino.

Suitable cyclic amino groups are heteroaromatic or aliphatic ring systems with one or more nitrogen atoms as the heteroatom

Question in which the heterocycles can be saturated or unsaturated, one ring system or several condensed ring systems, and optionally contain further heteroatoms such as one or two nitrogen, oxygen and sulfur, etc. In addition, cyclic amino groups can also mean a spiro ring or a bridged ring system. The number of atoms, the cyclic

Forming amino groups is not limited, for example they consist of 3 to 8 atoms in the case of a single-ring system and 7 to 11 atoms in the case of a three-ring system.

Examples of cyclic amino groups with saturated and unsaturated monocyclic groups with a nitrogen atom as heteroatom are 1-azetidinyl, pyrrolidino, 2-pyrrolin-l-yl, 1-pyrrolyl, piperidino, 1,4-dihydropyrazin-l-yl, 1, 2,5,6-tetrahydropyrazine-1-yl, 1,4-dihydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-l-yl, called homopiperidinyl; exemplary of cyclic amino groups with saturated and unsaturated monocyclic groups with two or more

Nitrogen atoms as heteroatoms are 1-imidazolidinyl, 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 1-tetrazolyl, 1-piperazinyl, 1-homopiperazinyl, 1,2-dihydro-pyridazin-1-yl, 1,2-dihydro- called pyrimidin-l-yl, perhydropyrimidin-1-yl, 1,4-diazacyclo-heptan-l-yl; exemplary of cyclic amino groups with saturated and unsaturated monocyclic groups with one or two oxygen atoms and one to 3 nitrogen atoms as heteroatoms, such as oxazolidin-3-yl, 2,3-dihydroisoxazol-2-yl, isoxazol-2-yl, l, 2,3-oxadiazin-2-yl, morpholino, for example for cyclic amino groups with saturated and unsaturated monocyclic groups with one to three nitrogen atoms and one or two sulfur atoms heteroatoms which may be mentioned are thiazolidin-3-yl, isothiazolin-2-yl, thimorpholino or dioxothiomorpholino; examples of cyclic amino groups with saturated and unsaturated condensed cyclic groups are indol-1-yl, 1,2-dihydrobenzimidazol-l-yl, perhydropyrrolo [1,2-a] pyrazin-2-yl; 2-azaspiro [4,5] decan-2-yl may be mentioned as an example of cyclic amino groups with spirocyclic groups; 2-Azabicyclo [2,2, l] heptan-7-yl may be mentioned as an example of cyclic amino groups with bridged heterocyclic groups.

Suitable monovalent amino protecting groups are acyl groups, preferably having 1 to 6, in particular 1 to 4, carbon atoms, such as, for example, formyl, acetyl, propionyl, pivaloyl, hexanoyl or mono- (or di- or tri-)

Halogen-containing acyl groups, such as 2-chloro, 2-bromo, 2-iodo, 2,2-dichloroacetyl, 2,2,2-trifluoroacetyl or 2,2,2-trichloroacetyl, alkoxycarbonyl- g ppen with preferably 1 to 14, in particular 1 to 4 carbon atoms, such as, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl (Boc), tert-amyloxycarbonyl (Aoc), hexyloxycarbonyl, methylsulfonylethoxycarbonyl, adamantyloxycarbonyl (Adoc) and l- [l-adamantyl] -l-methylethoxycarbonyl (Adpoc), carbamoyl groups, aroyl groups, such as, for example, phenylacetyl and phenylpropionyl, aryloxycarbonyl groups, such as, for example, phenoxycarbonyl and naphthyloxycarbonyl, aryloxyalkanoyl groups, such as, for example, phenoxyacetyl, and phenylacetyl groups, such as aryloxypropionyl, aryloxy, for example, aryloxy, for example

Phenylglyoxyloyl and naphthylglyoxyloyl, alkoxycarbonyl groups with common substituents, such as, for example, benzyloxycarbonyl (Cbo- or Cbz, Z), 4-methoxybenzyloxycarbonyl, 3,5-dimethoxy-benzyloxycarbonyl, 4-phenylazo-benzyl-oxycarbonyl, phenethyloxycarbonylcarbonyl, nitro-chlorobenzyl benzyl-oxycar-bonyl, α, α-dimethyl-3,5-dimethoxy-benzyloxycarbonyl, 2-nitro-4,5-dimethoxy-benzyl-oxycarbonyl (Nvoc), fluorenyl-9-methoxycarbonyl (Fmoc), Substituted or unsubstituted alkyl groups, such as, for example, benzylidene, hydroxybenzylidene, mono- (or di- or tri-) phenylalkyl-containing alkyl groups, such as, for example, benzyl, phenethyl, benzhydryl or triphenylrnethyl (trityl), and the like, in question. Suitable bivalent amino protecting groups are mono- or disubstituted methylidene groups, such as 1-lower alkoxy (for example methoxy or ethoxy) lower alkylidene (for example ethylidene or 1-n-butylidene), for example = C (CH ₃ ) (0-C ₂ H ₅ ), further z. B. = C (CH ₃ ) ₂ or = CH-phenyl, and in particular bisacyl radicals, e.g. B. the phthalyl radical, which together with the nitrogen atom to be protected forms an 1H-isoindole-1,3 (2H) -dione (phthalimide group).

Amino protection groups, and their introduction and separation are known per se and z. B. J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, and T. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York, 1984.

Suitable hydroxy protective groups are optionally substituted alkyl groups having preferably 1 to 6, in particular 1 to 4, carbon atoms, such as, for example, tert-butyl, methylthiomethyl and trimethylsilyl, phenylalkyl-containing alkyl groups, such as, for example, benzyl or diphenylmethyl, heterocyclic groups such as tetrahydropyranyl and the like .

Suitable thiol protecting groups are optionally substituted alkyl groups having preferably 1 to 6, in particular 1 to 4, carbon atoms, such as, for example, acetamidomethyl and chloroacetamidomethyl, arylalkyl-containing alkyl groups, such as, for example, benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylrnethyl and pyridyldiphenylmethyl and the like.

The protective groups mentioned above have the function known in peptide chemistry of temporarily protecting amino, hydroxyl or thiol groups of compounds. Suitable synthetic resins for use as polymeric supports for the solid-phase synthesis of the cyclodepsipeptides according to the invention are appropriately functionalized basic polymers (in the most widespread form on a chloromethylated polystyrene), such as amino-oxy- or hydrazino-functionalized resins of the Merrifield type . The commercially available DHP HM resin from Novabiochem is particularly suitable here, it allows simple anchoring with a hydroxylamino or hydrazo function and thus enables the cyclodepsipeptides according to the invention to be provided.

Compounds of the general formula (Ia) are particularly preferred

in which

R ¹ , R ⁴ , R ⁷ and R ^{10 represent} methyl,

R ² , R ⁵ , R ⁸ and R ^{1 * represent} isobutyl,

R ⁶ and R ^{12 represent} methyl,

R ³ and R ⁹ independently of one another represent optionally substituted benzyl, may be mentioned being the substituents hydrogen, halogen, in particular bromine, fluorine, chlorine or iodine, cyano, carbamoyl, carries a protective group hydroxy or unprotected hydroxy, Cι _-8 - alkoxy, especially methoxy , tert-butyloxy, C _M alkoxy-C _M alkoxy, especially methoxymethoxy, 2- Methoxyethoxy, C2- alkenyloxy, especially allyloxy, hetaryl-C _M - alkoxy, especially fur-2-yl-methoxy, tetrahydrofur-2-yl-methoxy, N-Boc-pyrrolidin-2-yl-methoxy, pyrrolidin-2- yl-methoxy, 5-sec-butyl-l, 2,4-oxadiazol-3-yl-methoxy, 5-cyclopropyl-l, 2,4-oxadiazol-3-yl-methoxy, imidazol-5-yl- methoxy, thiazolylmethoxy, tetrazol-5-yl-methoxy, thienyl methoxy,

Nitro, or a radical from the series -0-CH ₂ -CH ₂ -NR ²³ R ²⁴ , -CH ₂ -NR ²³ R ²⁴ , -NR ²³ R ²⁴ and -S0 ₂ -NR ²³ R ²⁴ ,

R ²³ and R ²⁴ independently of one another each represent hydrogen, C _M -alkyl, in particular methyl, ethyl, hetaryl-CM-alkyl, in particular fur-2-yl-methyl, tetrahydrofur-2-yl-methyl, pyrrolidin-2-yl- , stands,

R ²³ and R ²⁴ together with the nitrogen atom to which they are attached for hetaryl, in particular N-pyrrolidino, N-piperazino, N-morpholino, N-thiomorpholino, N-piperidino, N-imidazolo, 2-oxopyrrolidino, phthalimino or tetrahydrophthalimino, stand,

for hydrogen, cyano or optionally for a radical A ¹

-YR 13 A ¹ )

in which

Y represents oxygen or -NR ¹⁴ , where

R ¹³ and R ¹⁴ independently of one another are hydrogen, straight-chain or branched C _M -alkyl, in particular methyl, ethyl, propyl,

Isopropyl, isobutyl, sec-butyl, tert-butyl, -C-C - alkylcarbonyl, especially methylcarbonyl, ethylcarbonyl, cyano-C ₁ -C alkyl, amino-C _r C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl , C - alkylsulfonyl, especially methylsulfonyl, -C-2-haloalkoxy -CC. _2- alkylsuffonyl, in particular 1,1,1-Trifluorethoxyethylsulfonyl, straight or branched C _M alkyloxy-carbonyl, in particular methoxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, tert-butyloxycarbonyl, straight or branched C _M alkylaminocarbonyl, especially methylaminocarbonyl , Ethylaminocarbonyl, 0 ₂ ^ - alkenyl, especially vinyl, 2-propenyl, 2-butenyl,

Alkenyloxycarbonyl, in particular vinyloxycarbonyl, 2-propenyloxycarbonyl, 2-butenyloxycarbonyl, C _I - _A - haloalkenyloxycarbonyl, in particular l, l, 2-trifluorobut-l-en-4-yloxycarbonyl, C _2-4 -alkenylaminocarbonyl, in particular 2-propenylaminocarbonyl , C ₂ - -alkynyl, in particular 2-propynyl, 0, ₂ ^ - alkynyloxycarbonyl, in particular 2-propynyloxycarbonyl,

Cyanomethyl, hydroxy ethyl, aminoethyl, aryl-C _{_1-2} alkyl, especially optionally substituted benzyl, hetaryl-C. ₁ ₂ -alkyl, in particular optionally substituted hetarylmethyl, in particular optionally substituted tetrahydrofurylmethyl, furylmethyl, thienylethyl, thiadiazolylmethyl, tetrazolylmethyl, pyridylmethyl, aryloxy-Cι- ₂ -alkyl, in particular optionally substituted phenoxyethyl, optionally substituted hetarylcarbonyl, where hydrogen may be mentioned as a substituent , Nitro, amino, halogen, especially bromine, chlorine or fluorine, C _M -alkyl, especially methyl, C _M -haloalkyl, especially trifluoromethyl, phenyl, C _M -alkoxy, especially methoxy, C _M -alkoxycarbonyl, especially methoxycarbonyl, N- Morpholinyl, or hetarylcarbonylmethyl, in particular N-morpholinocarbonylmethyl, N-pyrrolidinocarbonylmethyl, or optionally represents a radical of group B ⁴ ,

in which

Z

I I stands for a selectively removable protective group, for example acetyl (Ac), allyloxycarbonyl (Alloc), benzyloxycarbonyl (Z) or tert-butyloxycarbonyl (Boc),

R ^{19 is} hydrogen,

R ²⁰ for hydrogen, propyl, isopropyl, isobutyl, benzyl, 4-

Hydroxybenzyl, imidazol-4-yl-methyl, indol-3-ylmethyl, phenyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-methylthioethyl, 2-carbamoylethyl,

R ^{21 represents} hydrogen or C _r C ₄ alkyl,

and their optical isomers, racemates and their physiologically acceptable salts.

Compounds of the general formula (Ia) are very particularly preferred.

in which

R ¹ , R ⁴ , R ⁷ and R ^{10 represent} methyl,

R ² , R ⁵ , R ⁸ and R ¹ 'represent isobutyl,

R ⁶ and R ^{12 represent} methyl,

R ³ and R ^{9 represent} benzyl,

A for -NHMe or a residue A

-YR 13 (A ¹ )

in which

Y stands for oxygen,

R 13 for hydrogen, straight-chain or branched C _M - alkyl, in particular methyl, ethyl, propyl, tert-butyl, C _M - alkylsulfonyl, in particular methylsulfonyl, C1-C ₄ - alkylcarbonyl, in particular methylcarbonyl, cyano -CC ₄ -alkyl , Hydroxy- C _r C -alkyl, amino -CC-C ₄ alkyl, C1.2-haloalkoxy-C ₁ . ₂ - alkylsulfonyl, in particular 1,1,1-trifluoroethoxyethylsulfonyl, straight-chain or branched C _M alkyloxycarbonyl, in particular methoxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, sec-butyl

5 oxycarbonyl, tert-buryloxycarbonyl, C ₂ - alkenyl, 2-propenyl,

C ₂ - ₄ alkenyloxycarbonyl, especially vinyloxycarbonyl, 2-propenyloxycarbonyl, C ₂ - haloalkenyloxycarbonyl, especially l, l, 2-trifluorobut-l-en-4-yl-oxycarbonyl, C _2-4 - alkenylaminocarbonyl, especially 2-

10 Propenylaminocarbonyl, C2- ₄ -alkynyloxycarbonyl, in particular 2-propynyloxycarbonyl, Äryl-Cι. _2- alkyl, in particular optionally substituted benzyl, N-

Morpholinocarbonylmethyl, N-pyrrolidinocarbonylmethyl, hetaryl-Cι- ₂ alkyl, especially optionally substituted

15 tetrahydrofurylmethyl, furylmethyl, 5-chloro-thiadiazol-4-yl-methyl, N-methyl-tetτazol-5-yl-methyl, pyridyl-methyl, 2-chloro-pyrid-5-yl-methyl, aryloxy-Cι. _2- alkyl, in particular optionally substituted phenoxyethyl, trifluoromethylphenoxyethyl, optionally substituted hetarylcarbonyl,

20 in particular optionally substituted furylcarbonyl,

Pyridylcarbonyl, where substituents are hydrogen, nitro, amino, halogen, especially bromine, chlorine or fluorine, methyl, trifluoromethyl, phenyl, methoxy, methoxycarbonyl, N-morpholinyl, or optionally for

25 is a radical from group B ⁴ ,

in which Z

I I stands for a selectively removable protective group, for example acetyl (Ac), allyloxycarbonyl Alloc), benzyloxycarbonyl (Z) or tert-butyloxycarbonyl (Boc),

R ^{19 represents} hydrogen,

R ^{20 represents} hydrogen, methyl, propyl, isopropyl, isobutyl,

R ^{21 represents} hydrogen or methyl,

The general or preferred areas listed above

Residual definitions or explanations can be combined with one another, i.e. also between the respective areas and preferred areas. They apply accordingly to the end products as well as to the preliminary and intermediate products.

The cycloiminodepsipeptides of the general to be used according to the invention

Formula (I) and its salts also contain one or more centers of chirality and can thus be present as pure stereoisomers or in the form of various enantiomer and diastereomer mixtures which, if necessary, can be separated in a manner known per se or also by stereoselective reactions in combination with the use of stereochemically pure starting materials can be produced.

However, the optically active, stereoisomeric forms of the compounds of the general formula (I) and their salts are preferably used according to the invention. The cyclic depsipeptides which result from (S) -configured amino acids (L-form) and D-configured hydroxycarboxylic acids (D-form) as ring building blocks.

The invention therefore relates both to the pure enantiomers and diastereomers and to their mixtures for combating endoparasites, particularly on the

Field of medicine and veterinary medicine.

Suitable suitable salts of the cycloiminodepsipeptides of the general formula (I) are customary non-toxic salts, i. H. Salts with different bases and salts with added acids. Salts with inorganic are preferred

Bases, such as alkali metal salts, for example sodium, potassium or cesium salts, alkaline earth metal salts, for example calcium or magnesium salts, ammonium salts, salts with organic bases and with inorganic amines, for example triethylammonium, dicyclohexylammonium, N, N'-dammonylethylendiumbenzene Pyridinium, picolinium or ethanolammonium salts, salts with inorganic

Acids, for example hydrochlorides, hydrobromides, dihydrosulfates, trihydrosulfates, or phosphates, salts with organic carboxylic acids or organic sulfonic acids, for example for iates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates or para-toluenesulfonates, salts with basic amino acids, for example arginates, aspartates or glutamates and the like.

Methods for introducing optionally substituted imino functions into synthetic peptides or pharmacologically interesting heterocycles are known from the literature.

The appropriate endothiopeptides or heterocyclic thiolactams can preferably be used as suitable starting components. The syntheses of amidoxime, cyanamidine and amidrazone analogues of chemotactic peptides from endothiopeptides may be mentioned as examples (G. Sauve et al., Can. J.

Chem. 61, 1985, p. 3089). A representation variant of the N ^ -Hydroxy-N ^ methyl- (R) -arginine from N ^α- tert-butoxycarbonyl-δ- (N-methyl-thioureido) - (R) -norvaline tert-butyl ester was described by HA Moynihan et al. (J. Chem. Soc. Perkin Trans. I 1994, p. 769). Likewise, heterocyclic thiolactams can be dissolved in amidines (pyrrolo [2, lc] [1,4] benzodiazepin-5, l l-dione: M. Robba et al., Tetrahedron Lett. 33 (20), 1992, p. 2803) or Convert azetidm-2-thione into azetidin-2-imine without problems (β-lactams: L. Ghosez et al., J. Chem. Soc, Chem. Commun. 1983, p. 818).

It has now surprisingly been found that the new cyclic iminodepsipeptides of the general formula (I) according to the invention can also be obtained from the corresponding cyclic thiodepsipeptides with amino compounds of the general formula (II) by reaction of one or more thioamide groups. According to the invention, the reaction of a thioamide group is particularly preferred.

The compounds of the general formula (I) are new, they can be prepared, for example, by the processes given under 2 and 3 above.

The methods according to the invention are explained below on the basis of selected examples (cf. also production examples).

If, in the process 2a according to the invention for the preparation of the new cycloiminodepsipeptides of the general formula (Ia), the cyclic thiodepsipeptide cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L- leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) as amino compounds of the general formula (II) the O-methyl-hydroxylamine (A: -O-Me; see route A) or N-methylhydrazine (A: -NH-Me; see route B), the process can be represented by the following reaction scheme, Scheme I:

Scheme I

^ «- / απtz isomer mixtures

A): H ₂ N-0-Me HC1, Hg (0-Ac) ₂ , base

B): H ₂ N-NH-Me, Hg (0-Ac) ₂ , base

When using the amino compounds of the general formula (II) in the process 2a according to the invention, the compounds of the general formula (I) can be formed as a mixture of syn and α «tt isomers.

Formula (Ib) provides a general definition of the cyclothiodepsipeptides required as starting materials for carrying out process 2a according to the invention.

In this formula (Ib), R ¹ to R ¹² preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the substances of the general formula (I) according to the invention.

The cyclic thiodepsipeptides used as starting materials are known from a previous patent application and can accordingly be obtained via thionation of cyclic depsipeptides using suitable sulfurizing reagents (cf. WO 98/43965, see also preparation examples). The amino compounds also to be used as starting materials for carrying out process 2a according to the invention are defined by the general formula (II).

In this formula (II) A has the meaning already in connection with the

Description of the substances of general formula (I) according to the invention as being preferred for this substituent.

The amino compounds of formula (II) are e.g. T. commercially available, some are known and can be prepared by known methods (see, for example, hetaryl methoxamine: US Pat.

Pat. 5,489,680; DE-OS 2119012, alkoxyamines: EP-OS 495 750; DE-OS 2206890; D. Favara et al. Farmaco, Ed. Be. 42 (10), 1987, p. 697).

A general way of producing aminoxy compounds (A = A ¹ : -YR ¹³ , Y: -0-) of the formula (II) is, for example, that a hydroxylamine derivative which has a protective group on nitrogen (e.g. R 'and R "together: phthaloyl, isopropylidene, α-hydroxy-benzylidene group), is reacted with a compound R ¹³ -E (O-alkylation) in a diluent and then the corresponding protective group is split off. In compound R ¹³ - E ^{13 has} the same meaning as above and E represents a nucleofugic leaving group, for example aliphatic or aromatic substituted sulfonyloxy, e.g. methanesulfonyloxy, salts of sulfonic acid, p-toluenesulfonyloxy (tosyloxy), but also also e.g. halogen, in particular bromine, chlorine or iodine (cf. O-alkylation) The reaction scheme II below shows the representation of amino compounds of the formula (II) (A = A ¹ : -YR ¹³ , Y: -0-): Scheme II

13

R R "

\ /

HO- N: ₊ R ^ -E. * _- O- NR, 13-O-NhL R "

R "

(II)

Alternatively, when using a Hydroxyverbmdung (R ¹³ -OH) z. B. perform an intermolecular dehydration reaction. In particular, there is a variant of the Mitsunobu reaction [Synthesis 1976, p. 682] in which the hydroxy compounds with N-protected hydroxylamine derivatives, such as. B. N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-dicarboximide or ethyl acetamate, and z. B. triphenylphosphine and N, N'-azodicarboxylic acid diethyl ester.

The compounds of the formula (II) can advantageously be released in the following manner: The hydrazinolysis can preferably be carried out in one

Diluents, for example alcohol, are carried out at boiling temperature. The hydrolysis can preferably be carried out in an aqueous, aqueous-alcoholic or alcoholic solution by heating for several hours. In the event that R 'and R "together represent an isopropylidene group, acid hydrolysis and, in the event that R' and R" together represent an α-hydroxy-benzylidene

Group or R "represents a carbethoxy group, use can be made of both alkaline and acid hydrolysis (cf. DE-OS 2119012; D. Favara et al. Farmaco, Ed. Sci. 42 (10), (1987 ) P. 697).

Inorganic salts, such as hydrochloric acid or sulfuric acid, in ethanolic or isopropanolic solution are preferably used to prepare the salts. The reaction of the thiodepsipeptides of the general formula (Ib) with the amino compounds of the general formula (II) is preferably carried out in the presence of a metal salt or metal oxide and, if appropriate, in the presence of a basic reaction auxiliary using diluents.

Suitable metal salts or metal oxides for carrying out the process according to the invention are all metal salts with elements of subgroups I and II of the periodic table. Examples include the acetates, chlorides, bromides, iodides, fluorides, nitrates, sulfates, carbonates, trifluoroborates, trifluoromethanesulfonates of copper, silver, gold, zinc, cadmium or mercury.

However, preference is given to using the carbonates, trifluoroborates and trifluoromethanesulfonates of the metals of subgroup I, in particular silver, and the acetates, oxides and halides of metals of subgroup II, in particular mercury.

All suitable acid binders, such as amines, in particular tertiary amines, and alkali and alkaline earth compounds can be used as basic reaction auxiliaries for carrying out process 2a according to the invention.

Examples include the hydroxides, oxides and carbonates of lithium, sodium, potassium, magnesium, calcium and barium, further basic compounds such as amidine bases or guanidine bases such as 7-methyl-l, 5,7-triazabicyclo (4.4.0) dec-5-en (MTBD); Diazabicyclo (4.3.0) nonen (DBN), diazabicyclo-

(2.2.2) octane (DABCO), l, 8-diaza-bicyclo (5.4.0) undecene (DBU), cyclohexyl-tetra-butylguanidine (CyTBG), cyclohexyltetramethylguanidine (CyTMG), N, N, N, N-tetramethyl-1,8-naphthalenediarnine, pentamethylpiperidine, tertiary amines such as triethylamine, trimethylamine, tribenzylamine, triisopropylamine, tributylamine, tribenzylamine, tricyclohexylamine, triamylamine, trihexylamine, N, N-dimethylaniline, toluene, N, N-toluene , N-dimethyl-p-aminopyridine, N-methyl-pyrrolidine, N-methyl-piperidine, N-methyl-imidazole, N-methyl-pyrrole, N-methyl-morpholine, N-methyl-hexamethyleneimine, pyridine, 4-pyrrolidinopyridine, 4-dimethylamino-pyridine, quinoline, α-picoline, ß- Picoline, isoquinoline, pyrimidine, acridine, N, N, N \ N "- tetramethylene diamine, N, N \ N tetraethylene diamine, quinoxaline, N-propyl-diisopropylamine, N-ethyl-diisopropylamine, N, N ^' - Dimethylcyclohexylamine, 2,6-lutidine,

2,4-lutidine or triethylene diamine.

Tertiary amines, in particular trialkylamines such as triethylamine, N, N-diisopropylethylamine, N-propyldiisopropylamine, N, N'-dimethylcyclohexylamine or N-methylmorpholine, are preferably used.

In general, it is advantageous to carry out process 2a according to the invention in the presence of diluents. Diluents are advantageously used in an amount such that the reaction mixture remains readily stirrable throughout the process. Suitable diluents for carrying out process 2a according to the invention are all inert organic solvents.

Examples include: halogenated hydrocarbons, in particular chlorinated hydrocarbons, such as tetrachlorethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroefhan, trichloroethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethene, chlorobenzene, chlorobenzene, chlorobenzene, chlorobenzene Chlorotoluene, trichlorobenzene; Alcohols such as methanol, ethanol, isopropanol, butanol; Ethers such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenetol, cyclohexyl methyl ether, dimethyl ether, diethyl ether,

Dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, dichlorodiethyl ether and polyether of ethylene oxide and or propylene oxide: amines such as trimethyl, triethyl, tripropyl, tributylamine, pyridine amine, pyridine Nitro hydrocarbons such as niromethane, nitroethane,

Nitropropane, nitrobenzene, chloronitrobenzene, o-nitrotoluene; Nitriles such as acetonitrile, Propionitrile, butyronitrile, isobutyronitrile, benzonitrile, m-chlorobenzonitrile and compounds such as tetrahydrothiophene dioxide and dimethyl sulfoxide, tetamethylene sulfoxide, dipropyl sulfoxide, benzylmethyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, diisoamyl sulfoxide; Sulfones such as dimethyl, diethyl, dipropyl, dibutyl, diphenyl, dihexyl, methylethyl, ethylpropyl, ethylisobutyl and

Pentamethylene sulfone; aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane and technical hydrocarbons, for example so-called white spirits with components with boiling points in the range from 40 ° C to 250 ° C, cymol, gasoline fractions within a boiling point interval of 70 ° C up to 190 ° C, cyclohexane,

Methylcyclohexane, petroleum ether, ligroin, octane, benzene, toluene, chlorobenzene, bromobenzene, nitrobenzene, xylene; Esters such as methyl, ethyl, butyl, isobutyl acetate and dimethyl, dibutyl, ethylene carbonate; Amides such as hexamethylenephosphoric triamide, formamide, N-methylformamide, N, N-dimethylformamide, N, N-dipropylformamide, N, N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl 3,4,5,6-tetrahydro-2 (1H) pyrimidine, octyl pyrrolidone, octyl caprolactam, 1,3-dimethyl-2-imidazolinedione, N-formyl-piperidine, N, N'-1,4-diformylpiperazine; Ketones such as acetone, acetophenone, methyl ethyl ketone, methyl butyl ketone.

Of course, mixtures of the solvents and diluents mentioned can also be used in the process according to the invention.

However, preferred diluents for carrying out the process according to the invention are nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile,

Benzonitrile or m-chlorobenzonitrile, in particular acetonitrile, propionitrile or butyronitrile, ethers such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, cyclohexyl methyl, dimethyl ether, diethyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether , Tetrahydrofuran or dioxane, in particular tetrahydrofuran or dioxane,

Halogenated hydrocarbons, especially chlorinated hydrocarbons, such as tetrahedral chlorethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichlorethylene or pentachloroethane, in particular methylene chloride, chloroform or carbon tetrachloride.

The reaction of amino compounds of the general formula (II) according to method 2a is carried out by the cyclothiodepsipeptides of the general formula (Ib) in the presence of an amino compound of the general formula (II), in the presence of a specified metal salt or metal oxide with elements of I. and II. Side group of the periodic table and optionally in the presence of a specified basic reaction auxiliary in one of the specified diluents.

The reaction time is 10 minutes to 48 hours. The reaction takes place at temperatures between -10 ° C and +200 ° C, preferably between +10 ° C and + 180 ° C, particularly preferably at room temperature. It can basically be under

Normal pressure can be worked. The process is preferably carried out at normal pressure or at pressures of up to 15 bar and, if appropriate, under a protective gas atmosphere (nitrogen or helium).

To carry out the method 2a according to the invention, one is used for each existing one

Thioamide group in the cyclothiodepsipeptides of the general formulas (Ib) generally 0.5 to 7.0 mol, preferably 1.0 to 5.0 mol, particularly preferably 2.0 to 3.0 mol of an amino compound of the general formula (II) .

Furthermore, in order to carry out process 2a according to the invention, in general from 0.5 to 6.0 mol, preferably 1.0 to 4.0 mol, particularly preferably 1.5 to 2, of thioamide group present in the compounds of the general formulas (Ib), 5 moles of metal salt or metal oxide.

After completion of the implementation, the entire reaction batch is replaced by the one that fails

Metal sulfide separated and optionally washed. The resulting products can be purified in the usual way by recrystallization, vacuum distillation or column chromatography (cf. also the preparation examples).

If processes 2b and 2c according to the invention are used to prepare the new cycloiminodepsipeptides of the general formula (Ia) as compounds of

Formula (Ic), for example, the cyclic iminodepsipeptide cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leu - Cinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) and as compounds of the general formula (III) chloroformic acid vinyl ester (cf. path C) and as compounds of the general formula (IV) acetic anhydride (cf. path D), the processes can be represented by the following reaction scheme III.

Scheme III

v «- / α« tt isomer mixtures

C): Cl-CO-0-CH- = CH ₂ , base D): (CH ₃ -CO) ₂ 0

Formula (Ic) generally defines the cycloiminodepsipeptides and their salts which are required as starting materials for carrying out processes 2b and 2c according to the invention. 1 19

In this formula (Ic), Y and R to R preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the substances of the general formula (I) according to the invention.

The cycloiminodepsipeptides of the general formula (Ic) (Y: -0-) used as starting materials are new and can be obtained either by process 2a described above or by process 3 described below.

According to method 2a, the cycloiminodepsipeptides of the general formula (Ic) (Y: -OH) can be prepared from the cyclothiodepsipeptides of the general formula (Ib) and hydroxylamine as a compound of the general formula (II) (cf. Scheme IV).

Scheme TV

The also for the implementation of the methods 2b and 2c according to the invention

Compounds to be used as starting materials are generally defined by the formulas (III) and (IV). Z

Have in formulas (III) and (IV)

, W, Q and Y the meaning that are already mentioned in connection with the description of the substances of the general formula (I) according to the invention for these substituents.

The compounds of formula (III) are generally known compounds of organic chemistry or can, for. T. can be obtained commercially or by methods known from the literature (e.g. Houben Weyl, Methods of Organic Chemistry, Volume E 4).

The implementation of the Cycloiminodepsipeptide (Ic) with compounds of the general

Formula (III) is preferably carried out in the presence of basic reaction auxiliaries using diluents.

All the acid binders mentioned in process 2a, such as amines, in particular tertiary amines, can be used as basic reaction auxiliaries for carrying out process 2b according to the invention.

Process 2b preferably uses the tertiary amines, in particular tri-alkylamines such as triethylamine, N, N-diisopropylethylamine, n-propyldiisopropylamine, N, N'-dimethylcyclohexylamine or N-methylmorpholine and pyridine derivatives, in particular pyridine.

It is of course also possible to use mixtures of the acid binders mentioned in process 2b according to the invention.

The inert, aprotic solvents mentioned in process 2a, such as, for example, are used as diluents for carrying out process 2b according to the invention. B.

Dioxane, acetonitrile or tetrahydrofuran, but also halogenated hydrocarbons, in particular chlorinated hydrocarbons, such as methylene chloride or chloroform, are used. Process 2b is carried out by reacting compounds of the general formula (Ic) in the presence of basic reaction auxiliaries with compounds of the general formula (III), if appropriate, in one of the diluents indicated.

Alternatively and preferably, method 2b can also be carried out directly in a suitable basic reaction auxiliary without a diluent.

The carboxylic acid anhydrides to be used as starting materials for carrying out process 2c according to the invention are generally defined by the formula (IV).

The reaction time is 4 to 72 hours. The reaction takes place at temperatures between -10 ° C and + 150 ° C, preferably between -5 ° C and +80 ° C, particularly preferably at 0 ° C to room temperature. It is operated under normal pressure.

To carry out process 2b according to the invention, 2.0 to 8.0 mol, preferably 2.0 to 4.0 mol, of acylating agent are generally employed per mol of compound of the formula (Ic).

To carry out process 2c according to the invention, 1.0 to 3.0 mol, preferably 1.0 to 1.5 mol, of carboxylic anhydride are generally employed per mol of compound of the formula (Ic).

Alternatively, process 2c can also be carried out with excess carboxylic anhydride of the formula (IV) without a diluent, provided the reaction mixture remains readily stirrable.

When the reaction is complete, the reaction solution is washed, the organic one

Phase separated, dried and concentrated in vacuo. The resulting products can be purified in the usual way by recrystallization, vacuum distillation or column chromatography (cf. also the preparation examples).

If 2d α) and β) are used in the process according to the invention to prepare the new cycloiminodepsipeptides of the general formula (Ia) as compounds of

Formula (Ic), for example, the cyclic iminodepsipeptide cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leu cinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) as compounds of the general formula (V) (S) -N-tert-butyloxycarbonyl-N-methylalanine ((S) -Boc-MeAla- OH; see route E) and as compounds of the general formula (VI) allyl isocyanate

(see route F), the processes can be represented by the following reaction scheme V.

Scheme V

«- 3« tt mixtures of isomers

E): (S) -Boc-MeAla-OH, BOP, base F): 0 = C = N-CH ₂ -CH- = CH ₂ , base Formula (Ic) provides a general definition of the cycloiminodepsipeptides required as starting materials for carrying out process 2d α) and β) according to the invention.

In these formulas (Ic), Y and R to R preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the substances of the general formula (I) according to the invention.

The compounds to be used as starting materials in particular for carrying out process 2d α) according to the invention are generally of the formula

(V) defined.

Z

In formula (V), Q ¹ , R ¹⁶ , R ¹⁷ and R ^{18 have} the meaning which has already been mentioned for substituents in connection with the description of the substances of the general formula (I) according to the invention.

The natural or synthetic amino acids used as starting materials, if chiral, can be in the (S) or (R) form (or L or D form).

Examples include:

Aad, Abu, γAbu, Abz, 2Abz, εAca, Acp, Adpd, Ahb, Aib, ßAib, Ala, ßAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys) ₂ , Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fei, Gin, Glu, Gly, Guv, hAla , hArg, hCys, hGln, hGlu, His, hlle, hLeu, hLys, hMet, hPhe, Pro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn,

Leu, Lsg, Lys, ßLys, ΔLys, Met, Mim, Min, nArg, Nie, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, ΔPro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, See, Sem, Ser, Thi, ßThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Tita, Tyr, Val, Nal, Tbg, Npg, Chg, Thia (see, for example, Houben-Weyl, Methods of Organic Chemistry, Volume XV / 1 and 2, Stuttgart, 1974).

The compounds of general formula (V) z. T. can be obtained commercially or by methods known from the literature (cf., for example, N-methylamino acids: R.

Bowmann et al, J. Chem. Soc. 1950, p. 1346; J.R. McDermott et al., Can J. Chem. 51 (1973), p. 1915; H. Wurziger et al, contacts (Merck, Darmstadt) 3 (1987), p. 8).

The reaction of the cycloiminodepsipeptides of the general formula (Ic) with amino acid derivatives of the formula (V) is preferably carried out in the presence of

Coupling reagents and in the presence of a basic reaction auxiliary using diluents.

Coupling reagents for carrying out process 2d α are all which are suitable for producing an amide bond [cf. eg: Houben-Weyl, Methods of 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)]. The following methods are preferably used: active ester method with pentachloro- (Pcp) and pentafluorophenol (Pfp), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboxamide (HONB), 1-hydroxy-benzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-l, 2,3-benzotriazine as alcohol component, coupling with carbodiimides such as dicyclohexylcarbodiimide (DCCI) according to the DCC additive method, 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-l-yl-oxy-tris (dimethylamino-phosphonophonium) - hexafluorophosphate (BOP), bis (2-oxo-3-oxazolidinyl) phosphonic acid chloride (BOP-Cl), benzotriazole-1-yl-tris-pyrrolidino-phosphonium-hexafluorophosphate (PyBOB ^® ), bromo-tris-pyrrolidino- phosphonium hexafluorophosphate (PyBroP ^® ) or with phosphonic acid ester reagents such as diethyl cyanophosphate (DEPC) and diphenylphosphoryl azide (DPPA ) or uronium reagents, such as 2- (1H-benzotriazol-l-yl) -l, 1,3,3-tetra-methyluronium tetrafluoroborate (TBTU), 2- (5-norbomen-2,3-dicarbox-amido) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TNTU), 2- (2-oxo-1 (2H) -pyridyl- 1, 1, 3, 3-bis-pentamethylene-tetramethyluronium tetrafluoroborate (TSTU) or as 2- ( 1H-Benzotriazol-l-yl) -l, 1,3,3-tetramethyluronium hexafluorophosphate (7TBTU).

Coupling with phosphonium reagents such as bis (2-oxo-3-oxazolidinyl) phosphonium acid chloride (BOP-Cl), benzotriazol-1-yl-oxy-tris (dimethylamino-phosphonium) hexafluorophosphate (BOP), benzotriazole is preferred - 1 -yl-tris-pyrrolidinophosphonium hexafluorophosphate (Py BOB ^® ), bromotris-pyrrolidinophosphonium hexa-fluorophosphate (PyBroP ^® ) and phosphonic acid ester reagents, such as diethyl cyanophosphate (DEPC) or Diphenylphosphoryl azide (DPPA).

As basic reaction aids for carrying out the process 2d α) according to the invention it is also possible to use all acid binders which are suitable for the Var process 2a.

Tertiary amines, in particular trialkylamines such as triethylamine, N, N-diisopropylamine, N-propyldiisopropylamine, N, N'-dimethylcyclohexylamine or N-methylmorpholine, are preferably suitable.

As a diluent for carrying out process 2d α) according to the invention, the solvents mentioned in process 2a, such as, for. B. halogenated hydrocarbons, especially chlorinated hydrocarbons, such as methylene chloride, chloroform or 1,2-dichloroethane and mixtures of these with others mentioned

Thinners, use.

The process is generally carried out in such a way that compounds of the general formula (Ic) are reacted with compounds of the general formulas (V) in one of the specified diluents in the presence of one of the basic reaction auxiliaries specified. The reaction time is 4 to 72 hours. The reaction takes place at temperatures between -10 ° C and +120 ° C, preferably between -5 ° C and +50 ° C, particularly preferably at 0 ° C to room temperature. It is worked under normal pressure.

To carry out process 2d according to the invention, 1.0 to 3.0 mol, preferably 1.0 to 1.5 mol, of coupling reagent are generally employed per mol of compound of the formula (Ic).

The compounds to be used as starting materials in particular for carrying out process 2d β) according to the invention are generally defined by the formula (VI) or (VII).

Z

In these formulas (VI) or (VII), Y and R ^{15 have} the meaning which has already been mentioned as preferred for substituents in connection with the description of the substances of the general formula (I) according to the invention.

The compounds of general formulas (VI) or (VII) can, for. T. can be obtained commercially or by methods known from the literature (cf., for example, Houben-Weyl, Methods of Organic Chemistry, Volume E 4).

The reaction of the cycloiminodepsipeptides of the general formula (Ic) with compounds of the general formulas (VI) or (VII) is preferably carried out in the presence of diluents, if appropriate in the presence of a basic reaction auxiliary.

As a diluent for carrying out process 2d β) according to the invention, the solvents mentioned in process 2a, such as B. halogenated hydrocarbons, especially chlorinated hydrocarbons, such as methylene chloride, chloroform or 1,2-dichloroethane, nitriles such as acetonitrile, propionitrile, butyronitrile, in particular acetonitrile, ethers such as ethyl propyl ether, n-buryl ether, diethyl ether, dipropyl ether, diisopropyl ether, tetrahydrofuran or dioxane, in particular tetrahydrofuran or dioxane, aliphatic or aromatic hydrocarbons such as n-hexane, n-heptane, benzene, toluene or xylene and mixtures of these with others mentioned diluents, use.

Process 2d β) can also be carried out in the presence of basic reaction auxiliaries. All such acid binders mentioned above, but preferably tertiary amines, in particular trialkylamines such as

Triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, and amidine bases or guanidine bases such as diazabicyclo (4.3.0) nonen (DBN), diazabicyclo (2.2.2) octane (DABCO), 1,8-diazabicyclo (5.4 .0) undecene (DBU), in particular 1,8-diazabicyclo (5.4.0) undecene (DBU), use.

Process 2d β) is generally carried out by reacting compounds of the general formula (Ic) with compounds of the general formulas (VI) or (VII), optionally in the presence of one of the basic reaction auxiliaries specified in one of the diluents specified.

The reaction time is 4 to 72 hours. The reaction takes place at temperatures between -10 ° C and +180 ° C, preferably between -5 ° C and +120 ° C, particularly preferably at 0 ° C to the boiling point of the diluent used. In principle, it is possible to work under normal pressure, but it is also possible to work with increased or reduced pressure. It is preferable to work at

Normal pressure or for pressures up to 15 bar.

To carry out process 2d β) according to the invention, 1.0 to 3.0 mol, preferably 1.0 to 1.5 mol, of compound of the general formulas (VI) or (VII.) Are generally employed per mole of compound of the formula (Ic) ) on. The invention further relates to new processes for the preparation of cycloiminodepsipeptides of the general formula (Ic).

The cycloiminodepsipeptides of the general formula (Ic) (Y: -0-) are either directly according to method 2a from the thiodepsipeptides of the general formula (Ib) and

Hydroxylamine can be prepared as a compound of the general formula (II) or can be obtained according to process 3 from suitable cycloiminodepsipeptides of the general formula (Ia).

For example, in process 3a for hydrogenation, the new cycloimino-depsipeptide cyclo [-N-methyl-L-leucinyl-D- (benzyloxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N- methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) as a compound of the general formula (Ia) (A = A '= -YR ¹³ : -O- CH ₂ -phenyl) , the corresponding cycloiminodepsipeptide cyclo [-N-methyl-L-leucinyl-D- (hydroxy-irnino) -lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-

N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-) (see Scheme VI, route G).

Formula (Ia) generally defines the cycloiminodepsipeptides required as starting materials for carrying out process 3a according to the invention. In these formulas (Ia), A, R ¹ to R ¹² preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the substances of the general formula (I) according to the invention.

The cycloiminodepsipeptides of the general formula (Ia) are, according to process 2a mentioned above, from the thiodepsipeptides of the general formula (Ib) and compounds of the general formula (LT), in which A is a residue - YR ¹³ (A ¹ ) with selectively removable O Protective group R ¹³ is, for example benzyl, benzyloxycarbonyl. Allyl, tert-butyloxycarbonyl, tetrahydropyranyl hydroxylamine, can be prepared. Depending on the protective group R ¹³ , this can be selectively removed in compounds of the general formula (Ia) either by means of hydrogenolysis in the presence of a suitable hydrogenation catalyst or by means of acidolysis in the presence of a protonic acid.

The hydrogenolysis of cycloiminodepsipeptides of the general formula (Ia) in accordance with the invention is particularly preferred in the presence of a hydrogenation catalyst, in the presence of a diluent and, if appropriate, in the presence of an acidic reaction auxiliary (cf. Scheme VI, route G, H, I).

Scheme VI

.s α77tz isomer generic

G: H ₂ , 10% Pd (OH) -coal, H ⁺ / Me-OH (R ¹³ : -Benzyl) H: H ⁺ (R ¹³ : -THP) THP = tetrahydropyranyl

I: pyridine-αrα-toluenesulfonic acid (R ¹³ - -THP-CH ₂ -0-CH ₂ -C ₆ H ₄ polymer)

Suitable catalysts for carrying out the catalytic hydrogenation are all customary hydrogenation catalysts, such as platinum catalysts (platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (for example palladium sponge, Palladium black, palladium oxide, palladium-carbon, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, palladium hydroxide, etc.), nickel catalysts, for example reduced nickel, nickel oxide, Raney nickel, etc.), ruthenium catalysts , Cobalt catalysts (for example reduced cobalt, Raney cobalt etc.), iron catalysts (for example reduced iron, Raney

Iron, etc.), copper catalysts (e.g. reduced copper, Raney copper, Ullman copper, etc.). However, noble metal catalysts, such as, for example, platinum and palladium or ruthenium catalysts, are preferably used, if appropriate on a suitable support, for example on carbon or silicon.

For the hydrogenation of cycloiminodepsipeptides of the general formula (Ia), the inert organic solvents mentioned in process 2a, such as, for. B. alcohols, especially methanol or ethanol, use.

Mineral acids may be mentioned, for example, as acidic reaction auxiliaries. The mineral acids preferably include hydrohalic acids such as hydrofluoric acid, hydrobromic acid, hydrochloric acid or hydroiodic acid as well as sulfuric acid, phosphoric acid, phosphorous acid and nitric acid.

According to the invention, to carry out the hydrogenation, an alcoholic solution of the cyclic benzyloxyiminodepsipeptides of the formula (Ia) is reacted in the presence of a suitable hydrogenation catalyst and, if appropriate, in the presence of an acidic reaction auxiliary.

Palladium catalysts, in particular palladium or palladium hydroxide carbon, are preferably used as hydrogenation catalysts.

Mineral acids, in particular hydrohalic acids such as hydrochloric acid, are preferably used as acidic reaction auxiliaries. The reaction time is 5 minutes to 20 hours. The hydrogenation is carried out at temperatures between -5 ° C and +100 ° C, preferably between 0 ° C and +30 ° C.

Alternatively, the cyclic hydroxy iminodepsipeptides of the general formula (Ic) (Y: -0-) can also be obtained from cyclic AUyloxyimmodepsipeptiden of the general formula (la) (A: -0-CH -CH- = CH ₂ ) using palladium (II) - Acetate-catalyzed cleavage can be obtained in the presence of triethylammonium formate and triphenylphosphine (T. Yamada et al., Tetrahedron Lett. 28, 1987, p. 4557).

Of course and according to the invention, the cycloiminodepsipeptides of the general formula (Ic) (Y: -0-) can also be obtained by acid-catalyzed cleavage of a tetrahydropyranyloxy radical (A: -O-THP, see path H) or by cleaving the anchor group R ¹³ from polymer O-linked cycloiminodepsipeptides of the general formula (Ia) (e.g. A = A ¹ = YR ¹³ = -O- with selectively cleavable

Anchor group) (see Scheme VI, path I).

For example, if method 3b is used for selective cleavage, the polymer-bound cycloiminodepsipeptide cyclo [-N-methyl-L-leucinyl-D- (po / ymer-THP-oxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl is used -lactyl-N-methyl-L-leucinyl-

D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) as a compound of the general formula (Ia) (A = A ¹ = -YR ¹³ = -O- with selectively cleavable anchor group), this is the result corresponding cycloiminodepsipeptide cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) -lactyl-N-methyl-L-leu-cinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl -N-methyl-L-leucinyl-D-phenyl-lactyl-) (see Scheme VI, route I).

Formula (Ia) generally defines the cycloiminodepsipeptides required as starting materials for carrying out process 3b according to the invention. 1 1 ")

In these formulas (Ia), A and R to R preferably represent those radicals which have already been mentioned for these substituents in connection with the description of the substances of the general formula (I) according to the invention.

The polymer-bound cycloiminodepsipeptides of the general formula (Ia) are, according to process 2a mentioned above, from the cyclothiodepsipeptides of the general formula (Ib) and polymers, carriers with selectively cleavable anchor groups for A = -YR ¹³ (A ¹ ) of the general formula (II ) can be displayed (see Scheme VII).

Scheme VII

The polymeric supports used as starting materials with selectively cleavable

Anchor groups for A = -YR ¹³ (A ¹ ) of the general formula (II) are known from the literature in some cases (cf. e.g. syntheses of hydroxamic acids: Mitsunobu reaction on Wang resin with N-hydroxyphthalimide: D. Floyd et al. Tetrahedron Lett. 37 (44), 1996, p. 8045; reaction of trityl chloride resin with N-hydroxyphthalimide: U. Bauer et al. Tetrahedron Lett. 38 (41), 1997, p. 7233) or can be found in the literature

Methods (cf. synthesis of ketones: reactions with DHP HM resin: OB Wallace Tetrahedron Lett. 38 (28), 1997, p. 4939; alcohol coupling: JA Ellmann et al. J. Org. Chem. 60, 1995, p. 7712; JA Ellmann et al. Tetrahedron Lett. 35 (50), p. 9333) can be obtained (see Scheme VIII).

Scheme VIII

DHP HM resiπ

(Novabiochem)

The 6- (aminoxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxy-methyl-polystyrene resin obtained in accordance with Scheme VIII is preferably used to carry out process 3b according to the invention (cf. Preparation Examples).

The cyclic hydroxy-iminodepsipeptides formed in this way are worked up in a conventional manner, for example by chromatographic purification (cf. also preparation examples). However, they can also be implemented directly (without further purification) in accordance with method 2b.

The iminodepsipeptides of the general formula (I) obtainable by process 2 according to the invention can be present as syn and α «tt isomers, but a mixture of both isomer forms is preferably formed under the reaction conditions of process 2 specified.

The “inert solvents” referred to in the above process variants 2 mean in each case solvents which are included under the respective reaction conditions. conditions are inert, but need not be inert under any reaction conditions.

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

From the order of the Pseudophyllidea, for example: Diphyllobothrium spp., Spirometra spp.,

Schistocephalus spp., Ligula spp., Bothridium spp., Diplogonorus spp ..

From the order of the Cyclophyllidea, for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosma spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyella spp., Berti , Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium

From the subclass of Monogenea e.g. Gyrodactylus spp., Dactylogyrus spp.,

Polystoma spp ..

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

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

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

From the order of the Strongylida, for example: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylmdropharynx spp., Poteriostromum spp., Cyclococercus spp., Cyhcostephanus sppum., Opp. , Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostomum spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., , Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Pararoafylo spp., Filaroidesylpp spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodims spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp., Cylicocyclus spp., Cylicodontophorus spp ..

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

From the order of Ascaridia, for example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp .. From the order of the Spirurida, for example: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp ..

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

From the group of the Gigantohynchida e.g .: Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp ..

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

Insects such as Honey bee and silkworm.

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

The pets include dogs and cats.

The application can be prophylactic as well as therapeutic.

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

The enteral application of the active ingredients takes place e.g. orally in the form of powder,

Suppositories, tablets, capsules, fasting, watering, granules, drenches, boluses, medicinal feed or drinking water. The dermal application takes place, for example, in the form of dipping (dipping), spraying (spraying), bathing, washing, pouring on (pour-on and spot-on) and applying the powder. Parenteral use is for example in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants.

Suitable preparations are:

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

Emulsions and suspensions for oral or dermal use and for injection; semi-solid preparations;

Formulation in which the active ingredient is processed in an ointment base or in an oil in water or water in oil emulsion base; Solid preparations such as powders, premixes or concentrates, granules, pellets,

Tablets, boluses, capsules; Aerosols and inhalants, molded articles containing active ingredients.

Solutions for injection are administered intravenously, intramuscularly and subcutaneously.

Injection solutions are made by adding the active ingredient in a suitable

Solvent is dissolved and additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives may be added. The solutions are sterile filtered and filled.

The following are mentioned as solvents: Physiologically compatible solvents such as

Water, alcohols such as ethanol, butanol, benzyl alcohol, glycerin, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof. If appropriate, the active compounds can also be dissolved in physiologically tolerable vegetable or synthetic oils which are suitable for injection. The following may be mentioned as solubilizers: solvents which promote the dissolution of the active ingredient in the main solvent or prevent its precipitation. Examples are polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

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

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

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

It may be advantageous to add thickeners during manufacture.

Thickeners are: inorganic thickeners such as bentonites, colloidal

Silicic acid, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

Gels are applied to or spread on the skin or placed in body cavities. Gels are produced by adding enough thickening agent to solutions which have been prepared as described for the injection solutions to form a clear mass with an ointment-like consistency. The thickeners specified above are used as thickeners. Pour-on formulations are poured onto or sprayed onto limited areas of the skin, the active ingredient either penetrating the skin and acting systemically or being distributed over the surface of the body.

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

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

Polypropylene glycols, glycerin, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones such as acetone, hydrocarbon or alkenyl, aromatic and aromatic substances synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1, 3-dioxolane.

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

Absorbing substances are e.g. DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.

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

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

Adhesives are, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin. Emulsions can be used orally, dermally or as an injection.

Emulsions are either water in oil or oil in water.

They are produced by dissolving the active ingredient either in the hydrophobic or in the hydrophilic phase and then using the solvent with the aid of suitable emulsifiers and possibly other auxiliary substances such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers, viscosity-increasing substances homogenized the other phase.

Hydrophobic phases (oils) may be mentioned are: paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / - capric acid triglyceride mixture with vegetable fatty acid of chain length Cg_j2 ° ^he d other natural fatty acids, specifically selected, Partialglycerid- mixtures saturated or unsaturated, possibly also hydroxyl-containing fatty acids, mono- and diglycerides of Cg / Cio fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length Cig-Ci g, isopropyl myristate, isopropyl palmitate, cypryl / capric alcohol esters of saturated fatty acid length Ci2-Cι g, isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duck pancreas fat, dibutyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures, etc.

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

Fatty acids such as oleic acid and their mixtures. The following can be mentioned as the hydrophilic phase:

Water, alcohols such as e.g. Propylene glycol, glycerin, sorbitol and their mixtures. The following may be mentioned as emulsifiers: nonionic surfactants, e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether; ampholytic surfactants such as di-Na-N-lauryl-β-iminodipropionate or lecithin; anionic surfactants, such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt; cationic surfactants such as cetyltrimethylammonium chloride.

The following may be mentioned as further auxiliaries: substances which increase viscosity and stabilize the emulsion, such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes , colloidal silica or mixtures of the listed substances.

Suspensions can be used orally, dermally or as an injection. They are prepared by placing the active ingredient in a carrier liquid, if necessary

Addition of other auxiliaries such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers suspended.

All homogeneous solvents and solvent mixtures may be mentioned as carrier liquids.

The surfactants specified above may be mentioned as wetting agents (dispersants). The additives given above may be mentioned as further auxiliaries. Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only in their higher viscosity.

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

All physiologically compatible solid inert substances may be mentioned as carriers. Inorganic and organic substances serve as such. Inorganic substances are e.g.

Table salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, phosphates.

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

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

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

The active substance according to the invention can be present in its preparations and in the use forms prepared from these preparations in a mixture with other active substances, such as insecticides, sterilants, bactericides, acaricides, nematicides or fungicides. Insecticides include, for example, phosphoric acid esters, carbamates, carboxylic acid esters, chlorinated hydrocarbons, Phenylureas, nicotinyls, neonicotinyls, substances produced by microorganisms and others

Particularly cheap mixing partners are e.g. the following:

Fungicides:

Aldimorph, ampropylfos, ampropylfos-kahum, andoprim, anilazine, azaconazole,

Azoxystrobin,

Benalaxyl, benodanil, benomyl, benzamacril, benzamacrylic isobutyl, bialaphos, binapacrylic, biphenyl, bitertanol, blasticidin-S, bromuconazole, bupirimate, buthiobate,

Calcium polysulfide, capsimycin, captafol, captan, carbendazim, carboxin, carvone, quinomethionate (quinomethionate), chlobenthiazone, chlorfenazole, chloroneb, chloropicrin, chlorothalonil, chlozolinate, clozylacon, cuffaneb, cymoxanilob, cyphodolinazol, cofodolinazol, cypodolinazol, cypodoblazolobin, cypodolinazol, cypodolinophenol, cypodolinazol, cypodolinazol, cypodoblazolobin, cypodolinosol, cypodolinazol, cypodolinosol, cypodolinosol, cypodolinosol, dodecylconol, dodecyl chloro , Diclofluanide, diclomezin, dicloran,

Diethofencarb, Difenoconazol, Dimethirimol, Dimethomorph, Diniconazol, Diniconazol-M, Dinocap, Diphenylamine, Dipyrithione, Ditalimfos, Dithianon, Dodemorph, Dodine, Drazoxolon, Ediphenphos, Epoxiconazol, Etaconazam, Fenirazolol, Ethiriazolol, Ethiriazolol, Ethiradololox, Fenitropan, fenpiclonil,

Fenpropidin, h Fenpropimo, fentin acetate, Fentinhydroxyd, ferbam, Ferirnzon, fluazinam, Flurnetover, fluoromide, fluquinconazole, flurprimidol, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, fosetyl-Alminium, fosetyl-sodium, fthalide, fuberidazole, furalaxyl, furametpyr, Furcarbonil , Furconazole, furconazole-cis, furmecyclox,

Guazatin,

Hexachlorobenzene, hexaconazole, hymexazole,

Imazahl, Imibenconazol, Iminoctadin, Iminoctadinealbesilat, Iminoctadinetriacetat, Iodocarb, Ipconazol, Iprobefos (IBP), Iprodione, Irumamycin, Isoprothiolan, Isovaledione, Kasugamycin, Kresoxim-methyl, copper preparations such as: copper hydroxide,

Copper phthalate, copper oxychloride, copper sulfate, copper oxide, oxy-copper and

Bordeaux mix,

Mancopper, Mancozeb, Maneb, Meferimzone, Mepanipyrirn, Mepronil, Metalaxyl, Metconazol, Methasulfocarb, Methfuroxam, Metiram, Metomeclam, Metsulfovax,

Mildiomycin, myclobutanil, myclozolin,

Nickel dimethyldithiocarbamate, nitrothal isopropyl, Nuarimol,

Ofurace, Oxadixyl, Oxamocarb, Oxolinicacid, Oxycarboxim, Oxyfenthiin,

Paclobutrazole, pefurazoate, penconazole, pencycuron, phosdiphen, pimaricin, piperalin, polyoxin, polyoxorim, probenazole, prochloraz, procymidon, propamocarb,

Propanosine sodium, propiconazole, propineb, pyrazophos, pyrifenox, pyrimethanil,

Pyroquilon, Pyroxy for,

Quinconazole, quintozen (PCNB),

Sulfur and sulfur preparations, tebuconazole, tecloftalam, tecnazen, tetcyclacis, tetraconazole, thiabendazole,

Thicyofen, Thifluzamide, Thiophanate-methyl, Thiram, Tioxymid, Tolclofos-methyl,

Tolylfluanid, Triadimefon, Triadimenol, Triazbutil, Triazoxid, Trichlamid, Tricyclazol,

Tridemorph, triflumizole, triforin, triticonazole,

Uniconazole, validamycin A, vinclozolin, viniconazole,

Zarilamid, Zineb, Ziram as well

Dagger G,

OK-8705,

OK-8801, α- (1, 1-dimethylethyl) -ß- (2-phenoxyethyl) - 1H- 1, 2,4-triazole-1-ethanol, α- (2,4-dichlorophenyl) -ß-fluoro- b-propyl-1 H-1, 2,4-triazole-1-ethanol, α- (2,4-dichlorophenyl) -ß-methoxy-a-methyl-1H-1, 2,4-triazole-1-ethanol , α- (5-methyl-l, 3-dioxan-5-yl) -ß - [[4- (trifluoromethyl) phenyl] methylene] -lH-l, 2,4-triazol-1-ethanol, ( 5RS, 6RS) -6-hydroxy-2,2,7,7-tettame l-5- (lH-l, 2,4-triazol-l-yl) -3-octanone,

(E) -a- (methoxyirmno) -N-methyl-2-phenoxy-phenylacetamide, {2-Methyl- 1 - [[[1 - (4-methylphenyl) ethyl] amino] carbonyl] propyl} carbamic acid 1-isopropyl ester

1 - (2,4-dichlorophenyl) -2- (1 H- 1, 2,4-tτiazol-1-yl) -ethanone-0- (phenylmethyl) -oxime,

1 - (2-methyl-1-naphthalenyl) - 1 H-pyrrole-2,5-dione, 1 - (3, 5-dichlorophenyl) -3- (2-propenyl) -2,5-pyrrolidinedione, l- [ (Diiodomethyl) sulfonyl] -4-methyl-benzene, l - [[2- (2,4-dichlorophenyl) -l, 3-dioxolan-2-yl] methyl] -IH-imidazole,

1 - [[2- (4-chlorophenyl) -3-phenyloxiranyl] methyl] - 1H- 1, 2,4-triazole,

1 - [1 - [2 - [(2,4-dichlorophenyl) methoxy] phenyl] ethenyl] -1 H-imidazole, 1-methyl-5-nonyl-2- (phenylmethyl) -3-pyrrolidinol,

2 ', 6'-dibromo-2-memyl-4'-trifluoromethoxy-4'-trifluoromethyl-l, 3-l azole-5-carboxanilide,

2,2-dichloro-N- [1 - (4-chlorophenyl) ethyl] -1-ethyl-3-methyl-cyclopropanecarboxamide,

2,6-dichloro-5- (methylthio) -4-pyrimidinyl-thiocyanate,

2,6-DicMor-N- (4-trifluoromethylberιzyl) benzamide, 2,6-dichloro-N - [[4- (trifluoromethyl) phenyl] methyl] benzamide,

2- (2,3,3-triiodo-2-propenyl) -2H-tetrazole,

2 - [(l-methylethyl) sulfonyl] -5- (trichloromethyl) -1, 3,4-thiadiazole,

2 - [[6-Deoxy-4-0- (4-0-methyl-β-D-glycopyranosyl) -aD-glucopyranosyl] amino] -4- methoxy-lH-pyιolo [2,3-d] pyrimidine- 5-carbonitrile, 2-aminobutane,

2-bromo-2- (bromomethyl) pentandinitrile,

2-chloro-N- (2,3-d ydro-l, l, 3-trimemyl-lH-mden-4-yl) -3-pyridinecarboxarnide,

2-chloro-N- (2,6-dimethylphenyl) -N- (isothiocyanatomethyl) acetamide,

2-phenylphenol (OPP), 3,4-dichloro-l- [4- (difluoromethoxy) phenyl] -lH-pyrrole-2,5-dione,

3,5-dichloro-N- [cyan [(1-methyl-2-propynyl) oxy] methyl] benzamide,

3 - (1,1-dimethylpropyl-1-oxo-1 H-indene-2-carbonitrile,

3- [2- (4-C oιτJhenyl) -5-ethoxy-3-isoxazolidmyl] pyridine,

4-chloro-2-cyan-N, N-dimethyl-5- (4-methylphenyl) -lH-imidazole-l-sulfonamide, 4-methyl-tetrazolo [l, 5-a] quinazolin-5 (4H) -one ,

8- (1,1-dimethylethyl) -N-ethyl-N-propyl-1,4-dioxaspiro [4.5] decan-2-me anamine, 8-hydroxyquinoline sulfate,

9H-xanthene-9-carboxylic acid 2 - [(phenylamino) carbonyl] hydrazide, bis- (l-methylethyl) -3-methyl-4 - [(3-methylbenzoyl) -oxy] -2,5-thiophene dicarboxylate, ice-1 - (4-chlorophenyl) -2- (1 H-1, 2,4-triazole-1-yl) cycloheptanol, cis-4- [3- [4- (l, l-dimethylpropyl) phenyl -2-methylpropyl] -2,6-dimethyl-morpholine hydrochloride,

Ethyl - [(4-chlorophenyl) azo] cyanoacetate,

Potassium hydrogen carbonate,

Methane tetrathiol sodium salt, methyl l- (2,3-dihydro-2,2-dimethyl-lH-inden-l-yl) -lH-imidazole-5-carboxylate,

Methyl N- (2,6-dimethylphenyl) -N- (5-isoxazolylcarbonyl) -DL-alaninate,

Methyl N- (chloroacetyl) -N- (2,6-dimethylphenyl) -DL-alaninate,

N- (2,3-dichloro-4-hydroxyphenyl) -1-methylcyclohexane carboxamide.

N- (2,6-dimethylphenyl) -2-methoxy-N- (tetrahydro-2-oxo-3-furanyl) acetamide, N- (2,6-dimethylphenyl) -2-methoxy-N- (tetrahydro-2 -oxo-3-thienyl) -acetamide,

N- (2-chloro-4-nitrophenyl) -4-methyl-3-nitro-benzenesulfonamide,

N- (4-cyclohexylphenyl) - 1, 4,5,6-tetrahydro-2-pyrimidinamine,

N- (4-hexylphenyl) - 1, 4,5, 6-tetrahydro-2-pyrimidinamine,

N- (5-chloro-2-methylphenyl) -2-methoxy-N- (2-oxo-3-oxazolidinyl) acetamide, N- (6-methoxy) -3-pyridinyl) cyclopropanecarboxamide,

N- [2,2,2-trichloro-l - [(cUoracetyl) amino] ethyl] benzamide,

N- [3-CUor-4,5-bis (2-propmyloxy) phenyl] -N'-methoxy-methanimidamide,

N-formyl-N-hydroxy-DL-alanine sodium salt,

0.0-diethyl- [2- (dipropylarnmo) -2-oxoethyl] ethylphosphoramidothioate, O-methyl-S-phenylphenylpropylphosphoramidothioate,

S-methyl-1, 2,3-benzothiadiazole-7-carbothioate, spiro [2H] - 1 -B enzopyran-2, 1 '(3 Η) -isobenzofuran] -3' -one,

Bactericides: bronopol, dichlorophene, nitrapyrin, nickel-dimethyldithiocarbamate, kasugamycin,

Octhilinone, furan carboxylic acid, oxytetracycline, probenazole, streptomycin, teclofta lam, copper sulfate and other copper preparations, quinolones such as ciprofloxacin, danofloxacin, difloxacin, enrofloxacin, flumequine, ibafloxacin, marbofloxacin, norfloxacin, ofloxacin, orbifloxacin, premafloxacin, sarafloxacin

Insecticides / acaricides / nematicides:

Abamectin, acephate, acetamiprid, acrinathrin, alanycarb, aldicarb, aldoxycarb, alpha-cypermethrin, alphamethrin, amitraz, avermectin, AZ 60541, popilliae azadirachtin, azamethiphos, azinphos A, azinphos M, azocyclotin, Bacillus, Bacillus sphaericus, Bacillus subtilis, Bacillus thuringiensis , Baculoviruses, Beauveria bassiana, Beauveria tenella, Bendiocarb, Benfüracarb,

Bensultap, benzoximate, betacyfluthrin, bifenazate, bifenthrin, bioethanomethrin, biopermethrin, BPMC, bromophos A, bufencarb, buprofezin, butathiofos, butocarboxim, butylpyridaben, cadusafos, carbaryl, carboffenethobos, chlorosulfonethosarbon, carboshenfonothobos ,

Chlormephos, Chlorpyrifos, Chlorpyrifos M, Chlovaporthrin, Cis-Resmethrin, Cispermethrin, Clocythrin, Cloethocarb, Clofentezine, Coumafos, Cyanophos, Cycloprene, Cycloprothrin, Cyfluthrin, Chhalophrin, Cythermethrin, Cythermethrin, Cythermethrin, Cythermethrin, Cypermin , Demeton-S-methyl, diafenthiuron, diazinon,

Dichlorvos, dicyclanil, diflubenzuron, dimethoate, dimethylvinphos, diofenolan, disulfoton, docusat-sodium, doenapyn, dinotefuran,

Eflusilanate, Emamectin, Empenthrin, Endosulfan, Eprinometin, Esfenvalerate, Ethiofencarb, Ethion, Ethiprole, Ethoprophos, Etofenprox, Etoxazole, Etrimfos, Fenamiphos, Fenazaquin, Fenbutatin oxide, Fenitrothion, Fenothimiocarb, Fenothimocarb,

Fenoxycarb, Fenpropathrin, Fenpyrad, Fenpyrithrin, Fenpyroximate, Fenthion, Fenvalerate, Fipronil, Fluazinam, Fluazuron, Flubrocythrinate, Flucycloxuron, Flucythrinate, Flufenoxuron, Flumethrin, Flutenzine, Fluvalinatexofosulfonos, Granofinosulfonate, Fonvalosfonosulfonate, Fungronosulfonate, Fungronosulfonate, Fifronosilane, Fungronosolate, Fifronosulfate, Fungronosolate, Fifronosulfate, Fungate, Fungus

Halofenozide, HCH, Heptenophos, Hexaflumuron, Hexythiazox, Hydroprene, Imidacloprid, indoxacarb, isazofos, isofenphos, isoxathion, ivermectin,

Kempolyeder viruses,

Lambda cyhalothrin, lufenuron

Malathion, mecarbam, metaldehyde, methamidophos, metharhilic anisopliae, metharhilic flavoviride, methidathione, methiocarb, methomyl, methoprene,

Methoxyfenozide, metolcarb, metoxadiazone, metrifonate, mevinphos, milbemectin,

Monocrotophos, moxidectin,

Naled, Nitenpyram, Nithiazine, Novaluron, NEEM,

Omethoat, Oxamyl, Oxydemethon M Paecilomyces fiimosoroseus, Parathion A, Parathion M, Permethrin, Phenthoat,

Phorat, Phosalone, Phosmet, Phosphamidon, Phoxim, Pirimicarb, Pirimiphos A,

Pirimiphos M, Profenofos, Promecarb, Propoxur, Prothiofos, Prothoat, Pymetrozine,

Pyraclofos, Pyresmethrin, Pyrethrum, Pyridaben, Pyridathion, Pyrimidifen,

Pyriproxyfen, Protrifenbute, Quinalphos,

Ribavirin

Salithion, Sebufos, Silafluofen, Spinosad, Sulfotep, Sulprofos,

Tau fluvalinate, tebufenozide, tebufenpyrad, tebupirimiphos, teflubenzuron,

Tefluthrin, Temephos, Temivinphos, Terbufos, Tetrachlorvinphos, Thetacypermethrin, Thiamethoxam, Thiapronil, Thiatriphos, Thiocyclam hydrogen oxalate, Thiodicarb, Thiofanox, Thuringiensin, Tralocythrin, Tralomethrin

Triarathenes, triazamates, triazophos, triazuron, trichlophenidines, trichlorfon,

Triflumuron, trimethacarb, thiacloprid,

Vamidothion, Vaniliprole, Verticillium lecanii Yl 5302

Zeta-cypermethrin, zolaprofos

(IR-cis) - [5- (phenylmethyl) -3-furanyl] methyl-3 - [(dihydro-2-oxo-3 (2H) - furanylidene) methyl] -2,2-dimethylcyclopropane carboxylate

(3-phenoxyphenyl) methyl 2,2,3,3-tetramethylcyclopropane decarboxylate l - [(2-chloro-5-thiazolyl) methyl] tetrahydro-3,5-dimethyl-N-nitro-l, 3,5-triazine -2 (lH) - imine 2- (2-chloro-6-fluorophenyl) -4- [4- (l, l-dimethylethyl) phenyl] -4,5-dihydro-oxazole

2- (acetyloxy) -3-dodecyl-1,4-naphthalenedione

2-Chloro-N - [[[4- (l-phenylethoxy) phenyl] amino] carbonyl] benzamide

2-Chloro-N - [[[4- (2,2-dichloro-1,1-difluoroethoxy) phenyl] amino] carbonyl] benzamide 3-methylphenyl propyl carbamate

4- [4- (4-ethoxyphenyl) -4-methylpentyl] -1-fluoro-2-phenoxy-benzene

4-chloro-2- (l, l-dimethylethyl) -5 - [[2- (2,6-dimethyl-4-phenoxyphenoxy) ethyl] thio] -

3 (2H) pyridazinone

4-chloro-2- (2-chloro-2-methylpropyl) -5 - [(6-iodo-3-pyridinyl) methoxy] -3 (2H) - pyridazinone

4-chloro-5 - [(6-chloro-3-pyridinyl) methoxy] -2- (3,4-dichlorophenyl) -3 (2H) pyridazinone

Bacillus thuringiensis strain EG-2348

Benzoic acid [2-benzoyl-1 - (1, 1-dimethylethyl) hydrazide

Butanoic acid 2,2-dimethyl-3- (2,4-dichlorophenyl) -2-oxo-l-oxaspiro [4.5] dec-3-en-4-yl ester

[3 - [(6-chloro-3-pyridinyl) methyl] -2-thiazolidinylidene] cyanamide

Dihydro-2- (nitromethylene) -2H-l, 3-thiazine-3 (4H) carboxaldehyde

Ethyl [2 - [[1,6-dihydro-6-oxo-1- (phenylmethyl) -4-pyridazinyl] oxy] ethyl] carbamate

N- (3,4,4-trifluoro-l-oxo-3-butenyl) glycine N- (4-chlorophenyl) -3- [4- (difluoromethoxy) phenyl] -4,5-dihydro-4-phenyl- lH-pyrazole

1-carboxamide

N - [(2-chloro-5-thiazolyl) methyl] -N'-methyl-N "-nitro-guanidine

N-methyl-N '- (1-methyl-2-propenyl) - 1, 2-hydrazinedicarbothioamide

N-methyl-N'-2-propenyl-1, 2-hydrazinedicarbothioamide 0.0-diethyl- [2- (dipropylamino) -2-oxoethyl] ethylphosphoramidothioate

The active compounds according to the invention can furthermore be present in their commercially available formulations and in the use forms prepared from these mold inhibitors in a mixture with synergists. Synergists are compounds through which the action of the active ingredients is increased without the added synergist itself having to be active. Ready-to-use preparations contain the active ingredient in concentrations of 10 ppm to 20% by weight, preferably 0.1 to 10% by weight.

Preparations that are diluted before use contain the active ingredient in

Concentrations from 0.5 to 90% by weight, preferably from 5 to 50% by weight.

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

Manufacturing examples

example 1

Cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl -L-leucinyl-D-phenyllactyl-]

a) according to method 2a with mercury (II) acetate

200.0 mg (0.20 mmol) cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N -methyl-L-leucinyl-D-phenyllactyl-) (cf. WO 98/43 965) in 5 ml of acetonitrile in succession with 43.6 mg (0.62 mmol) of hydroxylamine hydrochloride, 145.0 mg (0 , 45 mmol) of mercury (II) acetate and 162.2 mg (1.25 mmol) of ethyldiisopropylamine ("Hünig's Base") were added and the mixture was stirred at room temperature for 18 hours. To complete the reaction, another 21.8 mg (0.31 mmol) of hydroxylamine hydrochloride, 72.5 mg (0.45 mmol) of mercury (II) acetate and 107.4 mg (1.25 mmol) of ethyldiisopropylamine ("Hünig's Base") were added and the mixture was stirred for a further 6 hours at room temperature.

The entire reaction mixture is then stirred in about 20 ml of aqueous NH C1 solution and extracted four times with 15 ml of chloroform. The remaining crude product is chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane: acetone (4: 1). 70.4 mg (35% of theory) of cyclo [-N-methyl-L-leucinyl-D- (hydroxyimino) -lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L are obtained -leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] as an anti / syn isomer mixture.

b) according to method 2a with mercury (II) chloride / mercury (II) acetate

The reaction with hydroxylamine hydrochloride is carried out based on the reaction procedure of Example 1 (variant a) using:

500.0 mg (0.52 mmol) of cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N -methyl-L-leucinyl-D-phenyllactyl-)

107.9 mg (1.55 mmol) of hydroxylamine hydrochloride 422.0 mg (1.55 mmol) of mercury (II) chloride

230.2 mg (1.81 mmol) of ethyldiisopropylamine ("Hünig's Base")

30 ml tetrahydrofuran

After stirring for 20 hours at 50 ° C., another 180.0 mg (0.56 mmol) of mercury (II) acetate are added and the mixture is stirred at 50 ° C. for a further 24 hours.

The entire reaction mixture is then filtered and worked up as in Example 1 (variant a).

Yield: 250 mg (50% of theory)

b) according to method 3a by hydrogenation of the derivative 17

400.0 mg (0.37 mmol) of cyclo [-N-methyl-L-leucinyl-D- (benzyloxyimino) lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D -lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] 17 (see Table 1) are stirred in 40 ml of methanol and in

Presence of 200 mg Pd carbon [10% palladium content] and 0.7 ml conc. Salt- acid until the hydrogen uptake has ended (approx. 20 minutes) at room temperature. After filtering off the catalyst, the entire reaction solution is concentrated in vacuo and the crude product which remains is chromatographed on an RP-18 column using the eluent acetonitrile: water.

Yield: 1 10 mg (30% of theory)

c) by method 3b by deblocking the polymeric resin support

A mixture of 100 mg of polystyrene resin containing cyclodepsipeptide, 3.0 ml of n-butanol and 3.0 ml of 1,2-dichloroethane is mixed with 8.5 mg of pyridine-pαrα-toluenesulfonic acid and stirred at 60 ° C. for one hour. The polystyrene resin is then filtered off and washed five times with methylene chloride. After concentration in vacuo, 9.4 mg of crude product remain, in which example 1 could be detected by means of APCI-MS.

LC-MS (acidic) m / z (%): 964 (M ⁺ , 100). C ₅₂ H ₇₇ N ₅ 0 ₁₂ (964.2)

R _t - value (HPLC column: 125 x 2.1 Kromasil ^®, C-18): 17.54; 17.66 min; anti / syn isomer mixture (20:80).

Example 2

Cyclo [-N-methyl-L-leucinyl-D- (0-methyl-imino) lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N -methyl-L-leucinyl-D-phenyllactyl-]

The reaction with an O-substituted amine component is carried out analogously to the reaction procedure of Example 1 using:

200.0 mg (0.20 mmol) (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl- N-methyl-L-leucinyl-D-phenyllactyl-) 52.4 mg (0.62 mmol) O-methyl-hydroxylamine hydrochloride 145.0 mg (0.45 mmol) mercury (II) acetate

162.2 mg (1.25 mmol) of ethyldiisopropylamine ("Hünig's Base")

5 ml acetonitrile

The remaining crude product is first passed through a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane:

Acetone (4: 1) chromatographed. 170 mg (83% of theory) of cyclo [-N-methyl-L-leucinyl-D- (0-methyl-imino) -lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L are obtained -leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-]. 1H NMR (600 MHz, CDC1 ₃ , δ): 2.85; 2.87; 2.90; 3.04 (4 x N-CH ₃ ); 3.65 (-O-CH ₃ , oxime) ppm.

¹³ C NMR (100 MHz, CDC1 ₃ , δ): 29.3; 30.2; 30.9; 31.0 (4 x N-CH ₃ ); 61.3 (-O-CH ₃ , oxime); 66.9; 68.1; 69.7; 71.1; (4 x -CH-0-); 56.9; 53.9; 53.9; 59.5 (4 x -CH-N-);

170.3; 170.3; 172.5; (3 x -N-C = 0); 152.9 (1 x -C = N-0, oxime); 170.2; 170.7; 171.1; 172.5 (4 x -O-C = O) ppm.

LC-MS (acidic) mz (%): 978 (M ⁺ , 100). C ₅₃ H ₇₉ N ₅ 0 ₁₂ (978, 2)

R _t - value (HPLC column: 125 x 2.1 Kromasil ^®, C-18): 18.34 min

Example 3

Cyclo [-N-methyl-L-leucinyl-D- (0-acetylimino) lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N -methyl-L-leucinyl-D-phenyllactyl-]

200.0 mg (0.20 mmol) 1 (see Example 1) are added to 1 ml acetic anhydride and stirred at 70 ° C. for about 30 minutes. The entire reaction mixture is then mixed with saturated NaHC0 ₃ solution and extracted three times with 15 ml of ethyl acetate. The organic phase is separated off, dried over magnesium sulfate and concentrated in vacuo. The remaining crude product is chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane: acetone (10: 1). This gives 125.8 mg (60% of theory) of crude product, which according to preparative HPLC (RP-18) to 80 mg (38% of

Theory) pure cyclo [-N-methyl-L-leucinyl-D- (0-acetyl-imino) -lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl- N-methyl-L-leucinyl-D-phenyl-lactyl-] leads as an anti- / syn-isomer mixture (purity: 98.7%).

LC-MS (acidic) m / z (%): 1006 (M ⁺ , 100). C ₅₄ H ₇₉ N ₅ 0 ₁₃ (1006.2)

R _t value (HPLC column: 125 x 2.1 Kromasil ^c , C-18): 7.35 min Example 4

Cyclo [-N-methyl-L-leucinyl-D- (0-vinyloxycarbonyl-imino) lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl -L-leucinyl-D-phenyllactyl-]

300.0 mg (0.31 mmol) 1 (see Example 1) are stirred at 0 ° C. in 10 ml dry pyridine and 99.4 mg (0.93 mmol) vinyl chloroformate are added.

The mixture is then stirred for a further 6 hours at 0 ° C. The entire reaction mixture is then concentrated in vacuo, the residue is taken up in chloroform and washed once with 1N HC1 and twice with NaHCO ₃ solution. After the organic phase has been separated off and dried over magnesium sulfate, the mixture is concentrated in vacuo and the crude product which remains is passed over a silica gel column

(Kieselgel 60 - Merck, particle size: 0.04 to 0.063 mm) with the eluent cyclohexane: ethyl acetate (2: 1). 188.7 mg (58.7% of theory) of cyclo [-N-methyl-L-leucinyl-D- (0-vinyloxycarbonyl-imino) -lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N are obtained -methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] as an anti / syn isomer mixture.

LC-MS (acidic) m / z (%): 1037 (MH ⁺ , 100) C ₅₅ H ₈₁ N ₅ 0 ₁₄ (1036.2)

R _t - value (HPLC column: 125 x 2.1 Kromasil ^®, C-18): 17.82 min Example 5

Cyclo [-N-methyl-L-leucinyl-D- (0-methylsulfonyl-imino) lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl -L-leucinyl-D-phenyllactyl-]

The reaction with methanesulfonic acid chloride is carried out analogously to the reaction procedure of Example 4, using:

200.0 mg (0.20 mmol) cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L -leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] (Ex. 1)

71.3 mg (0.62 mmol) methanesulfonic acid chloride

8 ml dry pyridine

Chromatographed ethyl acetate (3: 2). 81.8 mg (38% of theory) of cyclo [-N-methyl-L-leucinyl-D- (0-methylsulfonyl-imino) -lactyl-N-methyl-L- leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] as a mixture of α "ti-A" isomers.

LC-MS (acidic) m / z (%): 1042 (MH ⁺ , 100). C ₅₃ H ₇₉ N ₅ 0 ₁₄ S (1042.3)

R _t - value (HPLC column: 125 x 2.1 Kromasil ^®, C-18): 17.18 min

Example 6

Cyclo [-N-methyl-L-leucinyl-D- (0-allylaminocarbonyl-imino) lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl -L-leucinyl-D-phenyllactyl-]

300.0 mg (0.31 mmol) of cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L -leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-] (Ex. 1) are absolute in 10 ml. Toluene in succession with 30.4 mg (0.36 mmol) of allyl isocyanate and 2 drops of l, 8-diazabicyclo [5.4.0] undec-7-ene

("DBU") are added and the mixture is stirred at room temperature for 33 hours. The entire reaction mixture is then concentrated in vacuo. The crude product which remains is first passed through a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) with the mobile phase cyclohexane: Acetone (3: 1) and then chromatographed on a second silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the mobile phase cyclohexane: ethyl acetate (2: 1 to 1: 1) to give 52.4 mg (16.1% of theory) Cyclo [-N-methyl-L-leucinyl-D- (0-allylaminocarbonyl-imino) -lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl -D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] as an anti / syn isomer mixture.

LC-MS (acidic) mz (%): 1047 (M ⁺ , 100). C ₅₆ H ₈₂ N ₆ Oι ₃ (1047.3)

R _t - value (HPLC column: 125 x 2.1 Kromasil ^®, C-18, pH 2.3): 17.09; 17.39 min Example 7

Cyclo [-N-methyl-L-leucinyl-D- (0-N-tert-butyloxycarbonyl-N-methyl-alanyl-imino) - lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L -leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-]

To a solution of 300.0 mg (0.31 mmol) of cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N -methyl-L-leucinyl-

D-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-] (Ex. 1) and 75.7 mg (0.37 mmol) of N-tert-butyloxy-carbonyl-N-methyl-alanine in 10 ml absolute. Acetonitrile at 0 ° C 184.0 mg (4.1 mmol) benzotriazol-l-yl-oxy-tris (dimethylamino-phosphonium) - hexafluorophosphate (BOP) and 124.0 mg (0.95 mmol) N, N- Düsopropylethylamine ("Hünigs Base") added and 30 minutes at 0 ° C, then at 24 hours

Room temperature stirred. The entire reaction mixture is then concentrated in vacuo, the residue is taken up in chloroform, shaken twice with water, the organic phase is separated off and, after drying over sodium sulfate, concentrated in vacuo. The remaining crude product is purified by means of preparative HPLC. 15.6 mg (4.4% of theory) of cyclo [-N-methyl-

L-leucinyl-D- (0-N-tert-butyloxycar-bonyl-N-methyl-alanyl-imino) -lactyl-N-methyl- L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D- lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] as an anti / syn isomer mixture. LC-MS (acidic) m / z (%): 1150 (MH ⁺ , 100). C ₆₁ H ₉₂ N ₆ 0 ₁₅ (1149, 4)

R _t - value (HPLC column: 125 x 2.1 Kromasil ^®, C-18): 7.69; 7.76 min

Analogously, the compounds listed in Table 1 below

Formula (Ia) (R ¹ , R ³ , R ⁴ , R ⁷ , R ⁹ , R ¹⁰ : -Me; R ² , R ⁵ , R ⁸ , R ^u : - / so-butyl; X ² : = NA; X ² -X ⁴ : = 0).

Table 1

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

^a) 1H NMR (400 MHz, δ, ppm); ¹³ C NMR (100 MHz, δ, ppm); LC-MS (acidic) m / z (%); R value (min, HPLC column: 125 x 2.1 Kromasil ^® , C-18)

Example 1-56

Reaction of the polymer-bound hydroxylamine with cyclo [-N-methyl-L-leucinyl-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl- D-phenyllactyl-]

The reaction of 6- (amino-oxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene with the cyclothiodepsipeptide is carried out in accordance with the reaction procedure of Example 1 (variant a) using of:

500.0 mg (0.52 mmol) of cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N -methyl-L-leucinyl-D-phenyllactyl-) 200.0 mg of 6- (amino-oxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxy-methyl-polystyrene 181.0 mg (1.55 mmol) mercury (II) acetate

15 ml dichloromethane

The 6- (amino-oxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene resin is first stirred in dichloromethane at room temperature for 30 minutes and then with the cyclothiodepsipeptide and mercury (II) acetate added. The separated polystyrene resin is then washed three times in succession with dichloromethane, dimethylformamide / water (1: 1), dimethylformamide and dried in a high vacuum.

Yield: 180 mg polystyrene resin

IR (KBr): 1730 cm ^"1 (v _{c = 0} ; cyclodepsipeptide) Substances of the formula (Ib)

Example (Ib - 1)

Cyclo [-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenylthiolactyl -)

1.0 g (1.05 mmol) of cyclo (-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl -N-methyl-L-leucinyl-D-phenyllactyl-) PF 1022A (cf. EP-OS 382173, US Pat. 5116815) were dissolved in 20 ml of toluene with 1.4 g (3.5 mmol) of 2,4- Bis- (4-methoxy-phenyl) -2,4-dithioxo-l, 3,2,4-dithiadiphosphetane ("Lawesson's Reagens") are added and the mixture is stirred under reflux temperature for 3.5 hours. The entire reaction mixture is then brought to 0 Cooled, filtered and the filtrate obtained was concentrated in vacuo and the crude product which remains is passed through a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) first with the eluent methylene chloride and then with the eluent cyclohexane: acetone (3 : 1) Chromatographed, 0.46 g (43.6% of theory) of cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenylthiolactyl-

N-methyl-L-leu-cinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenylthiolactyl-).

1H NMR (CDC1 ₃ , δ): 2.99, 3.06, 3.26, 3.42 (4 x -N-Me); 4.86, 6.42, 6.61 (4 x -N-CH ₂ -); 5.31, 5.55, 5.81, 5.89 (4 x -0-CH ₂ -); 7.26 (phenyl-H) ppm.

LC-MS (acidic) m / z (%): 1013 (M ⁺ , 100); 310 (21); 274 (30); 198 (42). C ₅₂ H ₇₆ N ₄ 0 ₈ S ₄ (1013.4)

Beisyiel (Ib - 2)

Cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl -)

1.0 g (1.05 mmol) of cyclo (-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl -N-methyl-L-leucinyl-D-phenyllactyl-) PF 1022A (cf. EP-OS 382173, US Pat. 5116815) were dissolved in 15 ml of tetrahydrofuran at 0 ° C with 0.26 g (0.05 mmol) 2,4-bis (4-phenoxy-phenyl) -2,4-dithioxo-l, 3,2,4-dithiadiphosphetane ("Belleau's Reagens") are added and the mixture is stirred at room temperature for 18 hours. The entire reaction mixture is then stirred in vacuo The crude product which remains is chromatographed twice over a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the mobile phase cyclohexane: acetone (3: 1), giving 0.12 g (11.8% of Theory) cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucmyl-D-lac-tyl-N-methyl-L-leucinyl -D-phenyllactyl-).

LC-MS (acidic) m / z (%): 965 (M ⁺ , 100); 200 (45).

C ₅₂ H ₇₆ N ₄ O _u S (965.2) Analogously, the compounds of the formula (Ib) listed in Table 2 below (R ¹ , R ³ , R ⁴ , R ⁷ , R ⁹ , R ¹⁰ : -Me; R ² , R ⁵ , R ⁸ , R ¹¹ : - wo-butyl) are produced.

Table 2

Table 2 (goal setting)

Table 2 (continued)

a) iχ H ^j - ΛNjMλ / TRD (4n0n0 M Λ IHIzT, δ X, ™ ppmm); ¹ " ³ C-NMR (100 MHz, δ, ppm); LC-MS (acidic) m / z Starting materials of formula (II)

Example (TI-1)

a) (S) -N - [(tetrahydroiur-2-yl) methoxy] phthalimide

(see S. Bailey et al., J. Med. Chem. 34, 1991, pp. 57-65)

1.5 g (14.7 mmol) (S) -tetrahydrofur-2-yl-methanol (A. Mravik et al., Tetrahedron:

Asymmetry 7 (5), 1996, pp. 1477-1484), 2.4 g (14.7 mmol) N-hydroxy-phthalimide and 3.85 (14.7 mmol) triphenylphosphine are stirred in 50 ml THF and at 0 ° C (protective gas atmosphere) with 3.4 g (19.5 mmol) of diethyl azodicarboxylate and stirred for 18 hours at room temperature. The entire reaction mixture is then concentrated in vacuo, the residue is taken up in ether and shaken twice against water. The remaining crude product is chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane: acetone (6: 1). 1.7 g (46.8% of theory) of (S) -N - [(tetrahydrofur-2-yl) methoxy] phthalimide are obtained.

LC-MS-LOOP m / z (%): 248 (MH ⁺ , 100) d ₃ H ₁₃ N0 ₄ (247.2)

R _t - value (HPLC column: 125 x 2.1 Kromasil ^®, C-18), 7.56 min

b) (S) -tetrahydrofur-2-yl-methoxy-amines

1.6 g (6.47 mmol) (S) -N - [(tetrahydrofür-2-yl) methoxy] phthalimide are stirred in 30 ml methylene chloride, at 0 ° C with 0.6 g (12.9 mmol ) N-methyl-hydrazine was added and the mixture was stirred at room temperature for 18 hours. The entire reaction mixture is then filtered and the filtrate is concentrated in vacuo. The remaining crude product is chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) with the eluent ethyl acetate. 130 mg (17.2% of theory) of (S) -tetrahydroiur-2-yl-methoxy-a ine are obtained.

LC-MS (acidic) m / z (%): 118 (MH ⁺ , 100). C ₅₂ H ₇₆ N ₄ 0nS (117.1)

Example (II-2

a) N-tert-Butyloxycarbonyl-amino-oxyacetic acid morpholide

N - 0

M ^M e Α, ° ^ OO

Me me

2.0 g (10.5 mmol) of N-tert-butyloxycarbonylamino-oxyacetic acid (Novabiochem: 01-63-0060) are stirred in 75 ml of methylene chloride and at 0 ° C. with 3.1 g (24.0 mmol) N, N-diisipropylethylamine (Hünig's base), 3.1 g (12.0 mmol) of bis (2-oxo-3-oxazolidinyl) -phosphonium chloride (BOP-Cl) were added and the mixture was stirred for 30 minutes. Then 1.05 g (12.0 mmol) of morpholine are added and the mixture is stirred at 0 ° C. for a further 6 hours. 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 (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane: acetone (3: 1). 1.0 g (37% of theory) of N-tert-butyloxycarbonylamino-oxyacetic acid morpholide are obtained.

1H NMR (CDC1 ₃ , δ): 1.47 (s, 9H, C (CH ₃ ) ₃ ); 3.37-3.72 (3m, 8H, 2 x -N-CH ₂ -; 2 x -O-CH ₂ -;); 4.54 (s, 2H, -O-CH ₂ -); 8.06 (s, 1H, NH) ppm.

LC-MS (acidic) m / z (%): 205 (M ⁺ - H ₂ C = CMe ₂ , 12), 161 (100). CπH ₂₀ N ₂ O ₅ (260.3)

R _t - value (HPLC column: 125 x 2.1 Kromasil ^®, C-18), 5.22 min b) Hydrochloride of amino-oxyacetic acid morpholide

^• ^• ou

\ ⁽⁺⁾

H - NN --00

/ H

Cl, i

Dry hydrochloric acid gas is passed into 220 ml of absolute methylene chloride in a solution of 0.65 g (2.5 mmol) of N-tert-butyloxycarbonylamino-oxyacetic acid morpholide cooled to 0 ° C. for 30 minutes. The mixture is then stirred for about 16 hours at room temperature and the entire reaction mixture is concentrated in vacuo. 380 mg (77% of theory) of hydrochloride of amino-oxyacetic acid morpholide are obtained.

LC-MS (acidic) m / z (%): 161 (MH ⁺ -HC1, 100), 146 (12), 129 (45).

Example QI-3)

a) 6- (N-succinimidyl-oxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-

Polystyrene resin

1.0 g (0.51 mmol) of DHP HM resin (Novabiochem: 01-64-0192) in 8.0 ml of 1,2-dichloroethane is allowed to swell for about 30 minutes. Then 293.5 mg (2.5 mmol) of N-hydroxysuccinimide and 261.4 mg (1.0 mmol) of pyridinium para-toluenesulfonate (PPTS) are added and the mixture is stirred at 80 ° C. for 16 hours. The resin is then separated off, washed once with methylene chloride, four times with dimethylformamide / water (1: 1), three times with dimethylformamide and three times with methylene chloride. The purified 6- (N-succinimidyl-oxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene resin is dried under high vacuum and can be used for the subsequent reaction step.

LR (KBr): 1730 cm ^"1 (v _{c = 0} ; succinimidyl residue)

b) 6- (Amino-oxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene

1.0 g of 6- (N-succinimidyl-oxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene resin are mixed in 20 ml of benzene under a protective gas atmosphere (argon)

127.7 mg (2.55 mmol) of hydrazine hydrate were added and the mixture was refluxed for 20 hours touched. The resin is then separated off, washed five times with methylene chloride and dried under high vacuum.

LR (KBr): 1630 cm ^"1 (v _NH - _D efom ,; -0-NH ₂ ); 3300 cm ^{" 1} (v _N. _H .vaieπz; -0-NH ₂ )

Analogously to the preceding Examples II-1 and II-2, the compounds of the formula (II) (A = -YR ¹³ ) listed in Table 3 below can be prepared.

Table 3

H

R 13

\ Y

N - Y

/

H (II)

^a) 'H NMR (400 MHz, δ, ppm); ¹³ C NMR (100 MHz, δ, ppm); LC-MS (acidic) m / z (%) Biological examples

Example A

In vivo nematode test

Heterakis spumosa I mouse

Mice are experimentally infected with nematodes of the species Heterakis spumosa. For infection, Heterakis spumosa is administered orally to the mice as 90 embryonated eggs.

After the prepatence period, the suspended active substances are administered intraperitoneally on the 46th day after the infection.

Determination of effectiveness:

The mice are selected on the 54th day after infection. The adult parasites in the colon and caecum are counted microscopically. The success of treatment in the dose group is related to the untreated control group.

Tested active ingredients and effective doses (dose effectiva) are shown in the table below.

a) cf. EP-OS 382 173, EP-OS 503 538; ^b) cf. WO 98/43 965 MeLeu = N-methyl-L-leucine, D-Lac = D-lactic acid, D-PhLac = D-phenyllactic acid, D-Lact = D-thiolactyl

Example B

In vivo nematode test

Nematosyiroides dubius I mouse

Mice are experimentally infected with nematodes of the species Nematospiroides dubius. For infection, the mice Nematospiroides dubius are administered orally as 90 embryonic eggs.

Determination of effectiveness:

a) cf. EP-OS 382 173, EP-OS 503 538; ^b) cf. WO 98/43 965 MeLeu = N-methyl-L-leucine, D-Lac = D-lactic acid, D-PhLac D-phenyllactic acid, D-Lact = D-thiolactyl

Example C

In vivo nematode test

Haemonchus contortus / sheep

Sheep experimentally infected with Haemonchus contortus were treated after the prepatent period of the parasite, the active substances were administered orally and / or intravenously as a pure active substance.

The efficiency is determined by quantitatively counting the worm eggs excreted in the faeces before and after the treatment.

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

a) cf. EP-OS 382 173, EP-OS 503 538;

MeLeu = N-methyl-L-leucine, D-Lac = D-lactic acid, D-PhLac D-phenyllactic acid

Claims

claims

1. Compounds of the general formula (I)

in which

R ² , R ⁵ , R ⁸ and R ¹¹ independently of one another represent hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl and aryl or hetaryl,

R ¹⁰ and R ¹¹ together with the atoms to which they are attached represent an optionally substituted 5- or 6-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxy or sulfonyl,

R ⁶ and R ¹² independently of one another represent hydrogen, optionally substituted alkyl or arylalkyl, and optionally substituted cycloalkylalkyl, R and R independently of one another represent hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, cycloalkyl, alkoxycarbonylalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl, aryl or hetaryl,

and

C = X ", C = X ² , C = X ³ and C = X ⁴ each independently represent one of the groups C = 0, C = S or CH ₂ or a G ppe C = N-

Denote A, where at least one of the groups C = X ", C = X ² , C = X ³ and C = X ⁴ must stand for C = NA,

in which

A for hydrogen, optionally substituted alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, and cyano, nitro, carbamoyl, alkoxycarbonyl, formyl, - (C = NH) -NH ₂ , -P (0) -0- alkyl, -P ( S) -0- alkyl or optionally for a radical A ¹

YR, 1 ¹ 3 ^J (A ¹ ) in which

Y represents oxygen, sulfur or -NR 1 ¹ 4

d R ¹⁴ independently of one another for hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl, aryl or hetaryl as well as for formyl, alkoxydicarbonyl, alkylsulfonyl, haloalkoxyalkylsulfonyl, alkoxycarbonyl, acylaminocarbon Alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxyalkyl, hetaryl carbonyl, alkylcarbonyl or optionally represents a radical from the group B ¹ , B ² , B ³ or B ⁴ ,

Z O

II I I. R 18. A

G .s.

I I

Q (CHR ¹⁶⁾ n-

(B ¹ ) o (B ² )

wonn

Q for optionally substituted, straight-chain or branched

Alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, aryloxy, arylalkoxy, hetaryloxy, hetarylalkoxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, arylthio, arylalkylthio, hetarylthio, hylaminoalkyl Arylamino, arylalkylamino, het-arylamino, hetarylalkylamino, dialkylamino, dialkenylamino, aryl, arylalkyl, hetaryl or hetarylalkyl, cyano, amino or an optionally substituted cyclic amino group linked via nitrogen,

Z

I I

, G.

^ represents carboxy, thiocarboxy, sulfoxy, sulfonyl, -P (O) -O- alkyl, -P (S) -0-alkyl or -C = NR ¹⁵ , R ^{15 represents} hydrogen, hydroxy, alkoxy, alkylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, alkylsulfonyl, nitro or cyano,

R ^{16 represents} hydrogen or alkyl,

n represents 0, 1 or 2,

Y ^{1 represents} oxygen, sulfur or -NR ¹⁷ ,

R in the event that Y is nitrogen can mean a cyclic amino group linked via this nitrogen atom,

R ¹⁷ and R ¹⁸ independently of one another for hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, alkynyl,

Cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, aryl, arylalkyl, hetaryl or hetarylalkyl, or

R ¹⁷ and R ¹⁸ together with the adjacent N atom for an optionally substituted heterocyclic 4-, 5-, 6- or 7-membered ring system or for an optionally substituted 7- to 10-membered bicyclic ring system, which may also be substituted by Oxygen, sulfur, sulfoxyl, sulfonyl, carbonyl, -NO, -N = -NR ²² or can be interrupted by quaternized nitrogen,

R ¹⁹ and R ²⁰ together represent an optionally substituted spirocyclic ring, R ²⁰ and R ²¹ together with the atoms to which they are attached represent an optionally substituted 5-, 6- or 7-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl,

R ^{21 represents} hydrogen, optionally substituted, straight-chain or branched alkyl, cycloalkyl, arylalkyl, hetarylalkyl, and aryl or hetaryl,

R represents hydrogen, optionally substituted straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cyano, arylalkyl, hetarylalkyl, and aryl or hetaryl,

R ¹³ can also represent a selectively cleavable protective group, or a polymeric carrier which is connected to Y via a selectively cleavable anchor group,

as well as their pure optical isomers, racemates and physiologically acceptable salts,

2. Cycloiminodepsipeptides according to claim 1 of the general formula (I)

in which

R ¹ , R ⁴ , R ⁷ and R ^{10 represent} straight-chain or branched C _M alkyl, in particular methyl,

R ² , R ⁵ , R ⁸ and R ¹¹ independently of one another represent C _M alkyl, in particular isobutyl,

R and R independently of one another for optionally substituted C _M -

Alkyl or aryl-Cι. ₂ -alkyl, in particular optionally substituted benzyl,

R ³ and R ⁹ independently of one another, optionally for C _M alkyl, hetaryl -CC. ₂ -alkyl, -CC -alkoxycarbonylmethyl, aryl -CC- ₂ -alkyl, in particular optionally substituted benzyl,

where hydrogen, halogen, cyano,

Carbamoyl, C _M -alkyl, a protective group-bearing hydroxy or unprotected hydroxy, Cι- alkoxy, C _M -alkoxy-C _M -alkoxy,

Alkenyloxy, hetaryl-C _M -alkoxy, where the heterocycles can in turn be substituted, nitro,

or a radical from the series R ²³ R ²⁴ NC _r C ₆ -alkoxy, R ²³ R ⁴ NC _r C ₈ -alkyl, NR23 _R 24 and -S0 ₂ -NR ²³ R ²⁴ , in which

R ²³ and R ²⁴ independently of one another each represent hydrogen, CJ-C _Ö -alkyl,

C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ -

Cycloalkylamino-Ci-Cg-alkyl, wherein one or more carbon atoms in the cycloalkyl ring can also be replaced by nitrogen, oxygen or sulfur atoms, hetaryl-Ci-C ^ alkyl or a protective group, or

R ²³ and R ²⁴ together with the nitrogen atom to which they are attached for hetaryl or heterocycloalkyl, in particular N-pyrrolidino, N-

Piperazino, N-morpholino, N-thiomorpholino, N-piperidino, N-imidazolo, 2-oxopyrrolidinyl, phthalimino or

Tetrahydrophthalfmino, standing,

and

(i) C = X ^{* represents} a group C = NA,

C = X ² , C = X ³ and C = X ⁴ stand for C = 0, C = S or CH ₂ ,

or

(iii) C = X ^{3 represents} a group C = NA,

C = X ¹ , C = X ² and C = X ⁴ stand for C = 0, C = S or CH ₂ ,

or (iv) C = X ^* and C = X ³ stand for a group C = NA, C = X ² and C = X ⁴ stand for C = 0, C = S or CH ₂ ,

in which

A for hydrogen, optionally substituted C _M alkyl, C _2-4 -

Alkenyl, C _2- alkynyl, C ₁ -C ₄ alkylcarbonyl, Cι _-6 - alkylsulfonyl and

Cyano, nitro, carbamoyl, C ₂ - ₆ alkoxycarbonyl, formyl, - (C = NH) -

NH ₂ , -P (0) -O-Cι. ₃ -alkyl, -P (S) -O-Cι- ₃ alkyl or optionally for a radical A ¹

-YR ¹³ (A ¹ ),

in which

Y represents oxygen or -NR ¹⁴ ,

R ¹³ and R ¹⁴ independently represent hydrogen, substituted or unsubstituted, straight or branched Cι- ₈ - alkyl, C ₂ - _S - alkenyl, C. ₂ ₈ - alkynyl, C ₃ .7-Cyclo.dkyl. C _3-7 cycloalkyl-C ₁ . ₂ -alkyl,

Aryl-C ₂ alkyl, hetaryl C ₂ alkyl, aryl or hetaryl and formyl, C ₁ -C 6 -alkylsulfonyl, C ₁ -C ₂ haloalkoxy-C ₁ . _2- alkylsulfonyl, C _r C ₈ - alkylcarbonyl, Ci-Cg-alkoxycarbonyl, Ci-Cg-alkylaminocarbonyl, C2-Cg-alkenyloxycarbonyl, C2-Cg-alkynyloxycarbonyl, aryloxy- Cι-C2-alkyl, hetarylcarbonyl, C _M -alkoxydicarbonyl or optionally represents a radical from G ppe B ¹ , B ² , B ³ or B ⁴

Z O

I I II

G. , 18th N «.s.

/, 16 II

Q ^' (CHR' °) n- _!

(B ¹ ) O ^υ (B ² )

woπn

Q for optionally substituted, straight-chain or branched Cι _-8 -

Alkyl, C2 ₈ alkenyl, C2 ₈ alkynyl, C ₃ - ₇ cycloalkyl, Cμ ₆ alkoxy, C ₂ - ₆ - alkenyloxy, C 2-6 alkynyloxy, C ₃ _ ₇ cycloalkoxy, aryloxy, aryl Cι- ₂ - alkoxy, hetaryloxy, hetaryl-Cι-2-alkoxy, Cj. ₆ alkylthio, C ₂ - ₆ alkenyl thio, C2-ö-alkynylthio, C. ₃ _7- Cycloalkyl-thio, arylthio, aryl-Cι. ₂ -alkyl-thio, hetarylthio, hetaryl-Cι- ₂ -alkylthio, Cι. ₆ alkylamino, C ₂ - ₆ nylamino -Alke-, C ₂ - ₆ alkynylamino, C ₃ - ₆ -cycloalkyl-alkylamino, arylamino, aryl-Cι-2-alkylamino, Hetarylamino, hetaryl-Cι- ₂ alkylamino, di -Ci. -alkylamino, di-C _2-4 -alkenylamino, aryl, aryl -CC ₂ -alkyl, hetaryl, hetaryl -CC ₂ -alkyl and cyano, amino or an optionally substituted cyclic amino group linked via nitrogen,

Z I I represents thiocarboxy or carboxy,

R ¹⁵ for hydrogen, hydroxy, C _M - alkoxy, C _M - alkylcarbonyl, C _M - alkoxycarbonyl, halogen-C _M -alkylcarbonyl, C _M - alkylsulfonyl,

Nitro or cyano,

R ^{16 represents} hydrogen or C _M alkyl,

n represents 0, 1 or 2,

R ¹⁷ and R ¹⁸ are independently hydrogen, optionally substituted, linear or branched Cι _-6 - alkyl, C ₂ - ₆ - alkenyl, C ₂ - ₆ - alkynyl, C _3-7 cycloalkyl, C. ₃ ₇ -cycloalkyl-C _1-6 -alkyl, Cι_ ₆ - alkoxycarbonyl, aryl, aryl-Cι- ₂ alkyl, hetaryl, hetaryl-Cι- ₂ alkyl, or

R ¹⁷ and R ¹⁸ together with the adjacent N atom stand for an optionally substituted, heterocyclic 4-, 5-, 6- or 7-membered ring system or for an optionally 7- to 10-membered bicyclic ring system, which optionally can also be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl, carbonyl, -NO, -N =, -NR ²² or by quaternized nitrogen,

R ¹⁹ and R ²⁰ are independently hydrogen, optionally substituted straight or branched Cι _-6 - alkyl, C ₂ - ₆ - alkenyl, C ₃ - ₇ cycloalkyl, and optionally substituted aryl, aryl-Cι- ₂ - alkyl, hetaryl, hetaryl -Cι- ₂ -alkyl, or

R ²⁰ and R ²¹ together with the atoms to which they are attached represent an optionally substituted 5-6- or 7-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl, R ²¹ for hydrogen, optionally substituted, straight-chain or branched Cι. ₆ - alkyl, C ₃ .7-cycloalkyl, aryl-Cι- ₂ alkyl, hetaryl-Cι _-2 - alkyl, and aryl or hetaryl,

R ²² is hydrogen, optionally substituted, linear or branched d-, ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C. ₃ _7- cycloalkyl, C ₃ . ₇ - Cycloalkyl-Cι-6-alkyl, Cι_ ₆ - alkoxycarbonyl, Cι- ₆ - alkylcarbonyl, C ₃ . ₇ - cycloalkylcarbonyl, cyano, aryl -CC ₂ alkyl, hetaryl -C _-2 alkyl, and aryl or hetaryl,

R ¹³ also for a selectively removable protective group, for example allyl,

Allyloxycarbonyl (Alloc), Benzyl (Bn), Benzyloxycarbonyl (Z), tert.-

Butyloxycarbonyl (Boc), tetrahydropyran-2-yl (THP) or fluorenylmethoxycarbonyl (Fmoc) and stands for a polymeric carrier which is bonded to Y by means of a selectively cleavable anchor polymer,

and their optical isomers, racemates and physiologically acceptable salts.

Process 1 for the preparation of the new compounds of the general formula

(I) according to claim 1

in which R ¹ to R ¹² and the groups C = X ^* to C = X ^{4 have} the meanings given in spoke 1,

characterized in that one

Cyclothiodepsipeptides of the general formula (I)

and their salts,

in which

R ¹ to R ^{12 have} the meanings given in spoke 1, and

C = X ¹ , C = X ² , C = X ³ and C = X ⁴ independently of one another are C = 0, C = S or CH ₂ , where at least one of the groups C = X ¹ , C = X ² , C = X ³ and C = X ⁴ must stand for a C = S group,

with amino compounds of the general formula (II)

H ₂ NA (II)

in which A has the meanings given in spoke 1,

in the presence of suitable metal salts or metal oxides, in particular mercury (IΙ) acetate, mercury (II) chloride or mercury (II) oxide, in the presence of a basic reaction auxiliary and in the presence of a suitable diluent.

4. A process for the preparation of the compounds of formula (Ia) and their salts, characterized in that

a) the cyclothiodepsipeptides of the general formula (Ib) or their salts,

in which

R ¹ to R ^{12 have} the meanings given in spoke 1,

with amino compounds of the general formula (II)

H ₂ NA (11) in which

A has the meanings given in claim 1, in the presence of suitable metal salts or metal oxides, in particular mercury (IΙ) acetate, mercury (IΙ) chloride or mercury (II) oxide, and in the presence of a basic reaction auxiliary and in the presence of a suitable diluent, or

and their salts, in which

R ¹ to R ^{12 have} the meanings mentioned in spoke 1,

A stands for a residue -YR ¹³ (A ¹ ),

in which

Y has the meaning given in address 1,

R ^{13 represents} radicals from group B ¹ to B ³ ,

wherein

Z

I I

/ ->

, Q, Y ¹ , n, R ¹⁶ , and R ¹⁸ -R ^{20 have} the meanings given in Claim 1,

Compounds of the general formula (Ic)

(1 °) and their salts,

in which

Y and R ¹ to R ^{12 have} the meanings given in spoke 1,

with compounds of the general formula (Illa-c)

woπn

ZII ^, Q, Y ¹ , n, R ¹⁶ , and R ¹⁸ -R ^{20 have} the meanings given in spoke 1,

W stands for a suitable outlet group, such as halogen,

optionally in the presence of a catalyst, optionally in the presence of a basic reaction auxiliary and optionally in the presence of

Converts diluents, or

c) to prepare the compounds of the general formula (Ia) and their salts,

in the A for a residue -YR 1 ¹ 3 ^J (A _A l ¹ >)

in which

Y has the meanings given in address 1,

R ^{13 represents} radicals from the groups B ¹ and B ³ ,

wherein

Q, Y, n, τ R> 18 - τR> 20 have the meanings given in Claim 1, n stands for 0,

Z II and the group / ^G \ stands for carboxy,

the compounds of the general formula (Ic) and their salts

in which

Y and R to R have the meanings given in spoke 1,

with a carboxylic anhydride of the general formula (IV)

(Q-CO) ₂ 0 (IV) in which

has the meaning given in spoke 1 or

for the rest

stands, woπn

Y ¹ , R ¹⁸ -R ^{20 have} the meaning given in claim 1,

d) by compounds of the general formula (Ic)

α) with amino acid derivatives of the general formula (V)

in which

Z I I G.

, Q, and R to R have the meaning given in spoke 1

if appropriate in the presence of coupling reagents and if appropriate in the presence of a basic reaction auxiliary and if appropriate in the presence of diluents, or

ß) with compounds of the general formulas (VI) and (VII)

in which

Z

I I

. G.

Y and R ^{15 have} the meaning given in spoke 1,

5. Process for the preparation of compounds of general formula (Ic) and their salts,

in which

Y and R ¹ to R ^{12 have} the meanings given in spoke 1,

characterized in that one

a) of the compounds of the general formula (Ia) and their salts,

in which

R ¹ to R ^{12 have} the meanings given in spoke 1,

A stands for a residue -YR ¹³ (A ¹ ),

in which

Y represents oxygen or -N-H,

R ^{13 stands} for a selectively removable protective group, for example allyl, allyloxycarbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl (Z), tert-butyloxycarbonyl (Boc), tetrahydropyran-2-yl (THP) or in fluorenylmethoxycarbonyl (Fmoc) ,

or b) from the compounds of the general formula (Ia) bound to a polymeric carrier and their salts,

in which

R ¹ to R ^{12 have} the meanings given in claim 1,

A for a residue -YR ¹³ (A ¹ )

in which

Y is oxygen or -N-H,

R ^{13 represents} a selectively cleavable anchor group on a polymeric support,

in the presence of a suitable catalyst or in the presence of a protonic acid and in the presence of a diluent by selective cleavage of the anchor group from the polymeric support R ^13, the compounds of the formula (Ic) are released.

6. Agent, characterized by a content of at least one compound of the formula (I) according to spoke 1.

7. Use of compounds of formula (I) according to claim 1 for combating endoparasites.

8. A method for controlling endoparasites, characterized in that compounds of the formula (I) according to spoke 1 are allowed to act on endoparasites and / or their habitat.

9. A process for the preparation of agents against endoparasites, characterized in that compounds of the formula (I) according to claim 1 with

Extenders and / or surfactants mixed.

10. Use of compounds of formula (I) according spoke 1 for the preparation of agents against endoparasites.