AU768501B2

AU768501B2 - Cyclo-imino depsipeptides and their utilization in controlling endoparasites

Info

Publication number: AU768501B2
Application number: AU52180/00A
Authority: AU
Inventors: Gerhard Bonse; Achim Harder; Peter Jeschke; Georg Von Samson-Himmelstjerna
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1999-06-11
Filing date: 2000-05-30
Publication date: 2003-12-11
Anticipated expiration: 2020-05-30
Also published as: DE19926620A1; CA2374632A1; AU5218000A; BR0011498A; WO2000076985A1; HUP0201592A2; EP1192142A1; JP2003502318A; HK1047589A1; CN1355794A; ZA200109179B

Description

Le A 33 687Foreign Countries Th/wa/NT -1- Novel cycloiminodepsipeptides, processes for their preparation and their use for controlling endoparasites The present invention relates to cycloiminodepsipeptides, in particular 24-membered cycloiminodepsipeptides, to processes for their preparation and to their use for controlling endoparasites.

The interesting backbone modifications of peptides, which are carried out in particular to reduce their lability to enzymatic hydrolysis, include, in addition to the exchange of the amide oxygen for sulfur, without any doubt also the exchange of amide oxygen for an optionally substituted imino grouping.

Naturally occurring peptides having an iminopeptide bond or an amidine grouping in the molecule are extremely rare. Examples which may be mentioned are bottromycin, a peptide antibiotic from Streptomyces bottropensis, amidinomycin and netropsin (J.

M. Waiswisz et al., J. Am. Chem. Soc. 79, 1957, p. 4520; S. Nakamura Chem.

Pharm. 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. Examples which may be mentioned here are the syntheses of amidoxime, cyanamidine and amidrazone analogs of chemotactic peptides Sauve et al., Can. J. Chem. 61, 1985, p. 3089). Chemotactic peptides of the N-formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe-OR) type are of interest as bioregulator prototypes of immune cells they induce, for example, the release of lysozyme from human neutrophiles V. Rao et al., Spectroscopy (Ottawa) 4 1985, p. 153; B. Belleau et al., Int. J. Immunopharmacol. 11 1989, p. 467; E. Schiffmann et al., Proc. Natl. Acad. Sci. U.S.A. 72, 1975, p. 1059; R. J. Freer et al., Biochemistry 21, 1982, p. 257). H. A. Moynihan et al. have described a preparation variant of N'-hydroxy-N'-methyl-L-arginine, a novel NO synthase inhibiter Chem. Soc. Perkin Trans. I 1994, p. 769). Suitable starting materials for preparing the iminopeptides mentioned further above are, according to Le A 33 687-Foreign Countries -2- G. Sauve et al. or H. A. Moynihan et al., preferably the corresponding endothiopeptides.

Also known is the synthesis of iminodipeptides from corresponding a-amino-nitriles (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 1977, p. 1088; analogs 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 peptidic amide group is replaced by an imine nitrogen have been prepared as comparison products for the oligomerization of a-amino-nitriles (cf. A. Eschenmoser et al., Helv. Chim.

Acta 69, 1986, p. 1224).

In contrast to the processes already mentioned for preparing various N-substituted iminopeptides, nothing has been disclosed concerning the preparation of cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids.

In particular, nothing has hitherto been disclosed concerning 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.

A cyclodepsipeptide with the name PF 1022A, for example, and its action against endoparasites is already known (EP-A 382 173 and EP-A 503 538) Le A 33 687-Foreign Countries -3- Further cyclic 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-A 634 408; EP-A 626 375; EP-A 626 376; EP-A 664 297; EP-A 634 408; EP-A 718 298; WO 97/09 331; cyclohexadepsipeptides: WO 93/25 543; WO 95/27 498; EP-A 658 551; cyclotetradepsipeptides: EP-A 664 297; dioxomorpholines: WO 96/38 165; JP08 225 552) and open-chain depsipeptides (EP-A 657 171; EP-A 657 172; EP-A 657 173; WO 97/07 093) and their endoparasiticidal action have been 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 are subject of an earlier patent application (WO 98/43 965) of the applicant.

In addition to the novel cycloiminodepsipeptides, the present invention also provides a process for preparing cycloiminodepsipeptides, in particular cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring building blocks and 24 ring atoms.

The invention also provides the use of cycloiminodepsipeptides, in particular of cycloiminodepsipeptides consisting of amino acids, hydroxyaminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring building blocks and 24 ring atoms for preparing compositions for controlling endoparasites.

The present invention relates in particular to: 1. Cycloiminodepsipeptides of the general formula (I) Le A 33 687-Foreign Countries -4-

R

12 0 XC4 O

R

1 1 R2 N N ,X 3 R 1

"R

10

C

0 R 9 0 0 R R 4 R O X 1 N N R 8 0 R 6 in which

R

4

R

7 and R i 0 independently of one another represent hydrogen, straight-chain or branched alkyl,

R

2

R

5

R

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

R'

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

R

6 and R 1 2 independently of one another represent hydrogen, optionally substituted alkyl or arylalkyl, and also 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, Le A 33 687-Foreign Countries and

C=X

2

C=X

3 and C=X 4 independently of one another each represent one of the groups C=O, C=S or CH 2 or a group C=N-A, where at least one of the groups C=X 2

C=X

3 and C=X 4 must represent C=N-A, in which A represents hydrogen, optionally substituted alkyl, alkenyl, alkinyl, alkylcarbonyl, alkylsulfonyl, and also cyano, nitro, carbamoyl, alkoxycarbonyl, formyl, -(C=NH)-NH 2 -P(O)-O-alkyl, -P(S)-O-alkyl or optionally represents a radical A'

-Y-R

1 3 in which Y represents oxygen, sulfur or -N-R 1 4

R'

3 and R' 4 independently of one another represent hydrogen, optionally substituted straight-chain or branched, alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl, aryl or hetaryl and also represent formyl, alkoxydicarbonyl, alkylsulfonyl, haloalkoxyalkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxycarbonyl, alkinyloxycarbonyl, aryloxyalkyl, hetarylcarbonyl,alkylcarbonyl or optionally represent a radical from the group consisting of B, B 2

B

3 and B 4 Z O II 1 IG R 18

S

S (CHR6)n- R 0 2, tD (D Le A 33 687-Foreign Countries -6- R21 18 Q R Y GG 19 R R 1 R2 Z1 R F z

(B

4 in which Q represents optionally substituted straight-chain or branched alkyl, alkenyl, alkinyl, cycloalkyl, alkoxy, alkenyloxy, alkinyloxy, cycloalkoxy, aryloxy, arylalkoxy, hetaryloxy, hetarylalkoxy, alkylthio, alkenylthio, alkinylthio, cycloalkylthio, arylthio, arylalkylthio, hetarylthio, hetarylalkylthio, alkylamino, alkenylamino, alkinylamino, cycloalkylamino, arylamino, arylalkylamino, hetarylamino, hetarylalkylamino, dialkylamino, dialkenylamino, aryl, arylalkyl, hetaryl or hetarylalkyl, cyano, amino or an optionally substituted cyclic amino group which is attached via nitrogen,

Z

II

G N represents carboxyl, thiocarboxyl, sulfoxy, sulfonyl, -P(O)-O-alkyl, -P(S)-O-alkyl or

R'

5 represents hydrogen, hydroxyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, alkylsulfonyl, nitro or cyano, RI6 represents hydrogen or alkyl, n represents 0, 1 or 2, Y' represents oxygen or sulfur or -N-R, R 8 represents, if Y' represents nitrogen, a cyclic amino group which is attached via this nitrogen atom, Le A 33 687-Foreign Countries -7-

R

7 and R 1 8 independently of one another represent hydrogen, optionally substituted straight-chain or branched alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, aryl, arylalkyl, hetaryl or hetarylalkyl, or

R

1 7 and R' 8 together with the adjacent N atom represent an optionally substituted heterocyclic 6- or 7-membered ring system or represent an optionally substituted 7- to 10-membered bicyclic ring system which may optionally also be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl, carbonyl,

-NR

22 or by quaternary nitrogen,

R

1 9 and R 20 independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl and also optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl, or

R

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

R

20 and R 2 1 together with the atoms to which they are attached represent an optionally substituted 6- or 7-membered ring which may optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl,

R

2 1 represents hydrogen, optionally substituted straight-chain or branched alkyl, cycloalkyl, arylalkyl, hetarylalkyl, and also aryl or hetaryl,

R

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

R

13 may also represent a protective group which can be removed selectively, or a polymeric support which is attached to Y via an anchor group which can be removed selectively, Le A 33 687-Foreign Countries -8and to the pure optical isomers, racemates and physiologically acceptable salts thereof, for controlling endoparasites in medicine and veterinary medicine.

Depending on the nature of the substituents, the compounds of the general formula can exist as geometrical and/or optical isomer mixtures and also as mixtures of regioisomers of varying compositions. The invention relates both to the pure isomers and to the isomer mixtures.

Preference is given to the cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring building blocks and 24 ring atoms of the general formula (I) in which

R

4

R

7 and represent straight-chain or branched C-.

4 -alkyl, in particular methyl,

R

2

R

5

R

8 and R" independently of one another represent Ci-4-alkyl, in particular isobutyl, Le A 33 687-Foreign Countries -9-

R

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

R

3 and R 9 independently of one another represent optionally C 1 4 -alkyl, hetaryl-C- 1 2 -alkyl, C 1

-C

4 -alkoxycarbonylmethyl, aryl-CI 2 -alkyl, in particular optionally substituted benzyl, substituents that may be mentioned being hydrogen, halogen, cyano, carbamoyl, Cl-4-alkyl, hydroxyl which carries a protective group or unprotected hydroxyl, C 1 g-alkoxy, Ci- 4 -alkoxy-CI 4 -alkoxy, C2- 4 alkenyloxy, hetaryl-C- 1 4 -alkoxy, where the heterocycles for their part may be substituted, nitro, or a radical from the group consisting of R 23

R

24 N-Cl-C 6 -alkoxy,

R

2 3

R

24

N-_C

1

-C

8 -alkyl, NR 23

R

2 4 and -S0 2

-NR

23

R

2 4 in which

R

2 3 and R 24 independently of one another each represent hydrogen,

CI-C

6 -alkyl, CI-C 6 -alkoxy-C -C 6 -alkyl, C 3

-C

7 -cycloalkyl,

C

3

-C

7 -cycloalkylamino-C 1

-C

6 -alkyl, wherein the cycloalkyl ring one or more carbon atoms may also be replaced by nitrogen, oxygen or sulfur atoms, hetaryl-C 1

-C

4 -alkyl or a protective group, or

R

23 and R 24 together with the nitrogen atom to which they are attached represent hetaryl or heterocycloalkyl, in particular Npyrrolidino, N-piperazino, N-morpholino, N-thiomorpholino, N-piperidino, N-imidazolo, 2-oxo-pyrrolidinyl, phthalimino or tetrahydrophthalimino, Le A 33 687-Foreign Countries and C=X' represents a group C=N-A, C=X C=X3 and C=X 4 represent C=O, C=S or CH 2 or (iii) C=X 3 represents a group C=N-A, C=X C=X2 and C=X 4 represents C=O, C=S or CH 2 or (iv) C=X' and C=X 3 represent a group C=N-A, C=X2 and C=X 4 represent C=O, C=S or CH 2 in which A represents hydrogen, optionally substituted C 1 4 -alkyl, C 2 4 -alkenyl, C 2 4 -alkinyl, C 1

-C

4 -alkylcarbonyl, C 1 6 -alkylsulfonyl and also cyano, nitro, carbamoyl, C2- 6 -alkoxycarbonyl, formyl, -(C=NH)-NH 2

O-C,-

3 -alkyl, -P(S)-O-C 1 3 -alkyl or optionally represents a radical A' -Y-R 1 3

(A

1 where Y represents oxygen or R 1 3 and R 14 independently of one another represent hydrogen, optionally substituted straight-chain or branched C 1 8 -alkyl, C 2 8 -alkenyl, C 2 8 alkinyl, C 3 7 -CYCloalkyl, C 37 -Cycloalkyl-C 1 2 -alkyl, aryl-CI- 2 -alkyl, Le A 33 687-Foreign Countries hetaryl-C,- 2 -alkyl, aryl or hetaryl and also formyl, CI-C 8 -alkylsulfonyl, C 1

-C

2 -haloalkoxy-C 1 2 -alkylsulfonyl, C 1

-C

8 -alkylcarbonyl, C 1

-C

8 alkoxycarbonyl, C 1

-C

8 -alkyl aminocarbonyl, C 2 -C8-alkenyloxycarbonyl, C 2

-C

8 -al kin yl oxycarbonyl, aryloxy-C 1

-C

2 -alkyl, hetarylcarbonyl, C,- 4 -alkoxydicarbonyl or optionally represent a radical from the group consisting of B1, B 2 B 3and B4 Z 0 RI I I (CR)n- 0 (B2 01 R 18 31 GR 19

R

R' R Z (B 4 in which Q represents optionally substituted straight-chain or branched C 1 8 -aikyl,

C

28 -alkenyl, C 28 -alkinyl, C 3 7 -cycloalkyl, C, 6 -alkoxy, C 2 6 alkenyloxy, C 26 -alkinyloxy, C 3 7 -cycloalkoxy, aryloxy, aryl-C,- 2 alkoxy, hetaryloxy, hetaryl-C 1 2 -alkoxy, C,- 6 -alkylthio, C 2 6 -alkenylthio, C 2 6 -alkinylthio, C 3 7 -cycloalkyl-thio, arylthio, aryl-C, 2 -alkylthio, hetarylthio, hetaryl-C 1 2 -alkylthio, CI- 6 -alkylamino, C 2 6 -alkenyl amino,

C

2 6 -alkinylamino, C 3 6 -cyclo-alkylamino, arylamino, aryl-CI- 2 -alkylamino, hetarylamino, hetaryl -C 1 2al kyl amino, di-C,.

4 -alkylamino, di-

C

2 4 -alkenylamino, aryl, aryl- C, 2 -alkyl, hetaryl, hetaryl-C 1

-C

2 -alkyl and also cyano, amino or an optionally substituted cyclic amino group which is attached via nitrogen, z represents thiocarboxyl or carboxyl, Le A 33 687-Foreign Countries -12-

R

15 represents hydrogen, hydroxyl, Ci-4-alkoxy, C 1 4 -alkylcarbonyl, CI-4alkoxycarbonyl, halogeno-Ci-4-alkylcarbonyl, C 1 4 -alkylsulfonyl, nitro or cyano,

R

6 represents hydrogen or Ci.

4 -alkyl, n represents 0, 1 or 2, Y' represents oxygen, sulfur or -N-R 7

R

18 represents, if Y' represents nitrogen, a cyclic amino group which is attached via this nitrogen atom,

R

17 and R' 8 independently of one another represent hydrogen, optionally substituted straight-chain or branched Ci-6-alkyl, C2-6-alkenyl, C2-6-alkinyl, C 3 7 cycloalkyl, C 3 7 -cycloalkyl-Ci_6-alkyl, C 1 6 -alkoxycarbonyl, aryl, aryl-Ci-2alkyl, hetaryl, hetaryl-C-_2-alkyl, or

R

17 and R' 8 together with the adjacent N atom represent an optionally substituted heterocyclic 6- or 7-membered ring system or represent an optionally 7- to 10-membered bicyclic ring system which may optionally also be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl, carbonyl, -NR 22 or by quaternary nitrogen,

R'

9 and R 20 independently of one another represent hydrogen, optionally substituted straight-chain or branched Ci.

6 -alkyl, C2- 6 -alkenyl, C 3 7 -cycloalkyl and also optionally substituted aryl, aryl-Ci.

2 -alkyl, hetaryl, hetaryl-Ci.

2 -alkyl, or R1 9 and R 2 0 together represent an optionally substituted spirocyclic ring, Le A 33 687-Foreign Countries -13-

R

20 and R 2 1 together with the atoms to which they are attached represent an optionally substituted 5-6- or 7-membered ring which may optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl,

R

2 1 represents hydrogen, optionally substituted straight-chain or branched

C

1 .6-alkyl, C 3 7 -cycloalkyl, aryl-C 1 2 -alkyl, hetaryl-Cl-2-alkyl, and also aryl or hetaryl,

R

22 represents hydrogen, optionally substituted straight-chain or branched Ci.6-alkyl, C 2 -6-alkenyl, C 2 -6-alkinyl, C 3 7 -cycloalkyl, C 3 7 -cycloalkyl-

C

1 -6-alkyl, CI.

6 -alkoxycarbonyl, Ci- 6 -alkylcarbonyl, C 3 7 cycloalkylcarbonyl, cyano, aryl-Ci- 2 -alkyl, hetaryl-Ci.

2 -alkyl, and also aryl or hetaryl,

R

13 also represents a protective group which can be removed selectively, for example allyl, allyloxycarbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl tert-butyloxycarbonyl (Boc), tetrahydropyran- 2-yl (THP) or fluorenylmethoxycarbonyl (Fmoc) and also represents a polymeric support which is attached to Y via an anchor group which can be removed selectively, and optical isomers, racemates and physiologically acceptable salts thereof.

The general formula provides a general definition of the cycloiminodepsipeptides according to the invention and their salts.

The cycloiminodepsipeptides according to the invention and their acid addition salts and metal salt complexes have good endoparasiticidal, in particular anthelmintic, action and can preferably be used in the field of veterinary medicine.

2. Process 1 for preparing the novel compounds of the general formula (1) Le A 33 687-Foreign Countries 14and salts thereof, in which R' to R 12 and the groups C=X' to C=X 4 have the meanings given in point 1, characterized in that cyclothiodepsipeptides of the general formula I)

R

12 0 and salts thereof, in which R' to R 1 2 have the meanings given in point 1, and Le A 33 687-Foreian Countries

C=X

2

C=X

3 and C=X 4 independently of one another represent C=O, C=S or

CH

2 where at least one of the groups C=X 2

C=X

3 and C=X 4 has to represent a C=S group, are reacted with amino compounds of the general formula (II)

H

2

N-A

in which A has the meanings given in point 1 in the presence of suitable metal salts or metal oxides, in particular mercury (II) acetate, mercury(H) chloride or mercury(I) 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 novel cycloiminodepsipeptides of the general formula (Ia) A R 12 0 O /R9 0 0 R R4 R R O N N R8 (1a) and salts thereof, in which A and R' to R 12 have the meanings given in point 1.

Le A 33 687-Foreign Countries 16- The process 2 according to the invention for preparing the novel and preferred cycloiminodepsipeptides of the general formula (Ia) and salts thereof is characterized in that a) the cyclothiodepsipeptides of the general formula (Ib) or salts thereof, R120 R1~ )&R1 R9O (Ib) in which R' to R 12 have the meanings given in point 1 are reacted with amino compounds of the general formula (II)

H

2

N-A

in which A has the meanings given in point 1 in the presence of suitable metal salts or metal oxides, in particular mercury (II) acetate, mercury (II) chloride or mercury(I) oxide, and in the presence of a basic reaction auxiliary and in the presence of a suitable diluent, or b) for preparing the novel cycloiminodepsipeptides of the general formula (Ia) Le A 33 687-Foreign Countries -17and salts thereof, in which R' to R 2 have the meanings mentioned in point 1, A represents a radical -Y-R' 3 in which Y has the meaning given in point 1,

R'

3 represents radicals from the group consisting of B' to B 3 z

II

G (CHR 6 )n- 0 1 II

Y

0

(B

2

(B

3 in which

Z

II

G Q, n, R' 6 and R' 8

-R

20 have the meanings given in point 1, Le A 33 687-Foreign Countries -18the novel cycloiminodepsipeptides of the general formula (Ic) obtained by processes 2a) and 3 according to the invention HY R 12 0 Nt 1, ,R11 C O R2 N N O R1 Ro ,R 0 R9 and salts thereof, in which Y and R' to R 12 have the meanings given in point 1, are reacted with compounds of the general formula ma-c z ZG I I(CHR 6 )n-W Q/ ^(CHRn-W

O

18--<JY R I 11 W 0 R 18 (Imla) (MIb) (mc) in which z

II

Q, Y, n, R 1 6 and R' -R 2 0 have the meanings given in point 1, W represents a suitable leaving group, such as, for example, halogen, Le A 33 687-Foreign Countries -19if 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) to prepare the novel cycloiminodepsipeptides of the general formula (Ia) and salts thereof, in which A represents a radical in which Y has the meanings given in point 1,

R

1 3 represents radicals from the group consisting of B' and B 3

Z

II

G HR 16 (CHR16)n-

O

19

(B

3 in which Q, n, R' -R 20 have the meanings given in point 1, n represents 0,

Z

II

G

and the group represents carboxyl, the compounds of the general formula (Ic) and salts thereof Le A 33 687-Foreign Countries 11

,O

*R9 0 0 R 6 in which Y and R' to R 12 have the meanings given in point 1 are reacted with a carboxylic anhydride of the general formula (IV)

(Q-CO)

2 0 (IV) in which Q has the meaning given in point 1 or

Y

1

R

18 9 2 19 R Rrepresents the radical in which R -R20 have the meaning given in point 1, 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 d) by reacting compounds of the general formula (Ic) Le A 33 687-Foreign Countries -21 ca) with amino acid derivatives of the general formula (V) N O G~ OH II R 19

Z

in which G Q, and R to R have the meaning given in point Q, and R 19 to R 21 have the meaning given in point 1 if appropriate in the presence of coupling agents and if appropriate in the presence of a basic reaction auxiliary and also, if appropriate, in the presence of diluents, or with compounds of the general formulae (VI) and (VII) z 11 G- N=C=Y

R'

5 -N=C=Y (VI) (VII) in which

Z

II

,Y and R' 5 have the meaning given in point 1, if appropriate in the presence of a basic reaction auxiliary or a catalyst, if appropriate in the presence of diluents.

The invention furthermore relates to: Le A 33 687-Foreign Countries -22- 3. Process 3 for preparing cycloiminodepsipeptides of the general formula (Ic) and salts thereof, HY

R

12 0 r N-C 0Oty1

R

2

N

0 Ri R O 9 in which Y and R' to R 1 2 have the meanings given in pointl, characterized in that a) from the cycloiminodepsipeptides of the general formula (Ia) obtainable according to process 2a and salts thereof, A R 12 0

R

2

N

O 1

RO

0 0 R R4 R 7

O(

ONN N- R8 (1a) in which Le A 33 687-Foreign Countries -23- R' to R 12 have the meanings given in point 1, A represents a radical -Y-R' 3 in which Y represents oxygen or -N-H, represents a protective group which can be removed selectively, for example, allyl, allyloxy-carbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl tert-butyloxycarbonyl (Boc), tetrahydropyran- 2-yl (THP) or in fluorenylmethoxycarbonyl (Fmoc), the radical R 1 3 is selectively removed, depending on the removable protective group either in the presence of a hydrogenation catalyst, in the presence of a protic acid or a basic reaction auxiliary and in the presence of a diluent, or b) from the cycloiminodepsipeptides of the general formula attached to a polymeric support, which are obtainable by process 2a, and salts thereof, A R 12 0 A R OIlin which Le A 33 687-Foreign Countries -24- R' to R 12 have the meanings given in point 1, A represents a radical -Y-R 13 in which Y represents oxygen or -N-H,

R

1 3 represents a selectively removable anchor group on a polymeric support, the compounds of the formula (Ic) are released by selective removal of the anchor group from the polymeric support R 13 in the presence of a suitable catalyst or in the presence of a protic acid and in the presence of a diluent.

The definitions of terms below apply to all of the general formulae and descriptions mentioned above or below.

Optionally substituted alkyl, alone or as component of a radical in the general formulae, represents straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be mentioned are optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3- Le A 33 687-Foreign Countries 25 dimethylbutyl, 1,1 -dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2trimethylpropyl, 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 be mentioned as being preferred.

Optionally substituted alkenyl, alone or as component of a radical in the general formulae, represents straight-chain or branched alkenyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be mentioned are optionally substituted vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1 -methyl-2-propenyl, 2-methyl-2propenyl,.- 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2butenyl, 3-methyl-2-butenyl, 1 -methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3butenyl, 1,1 -di methyl-2-propenyl, 1 ,2-dimethyl-2-propenyl, 1 -ethyl-2-propenyl, 2hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3pentenyl, 1 -methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl- 4-pentenyl, 1,1 -di methyl-2-butenyl, 1,1 -dimethyl -3-butenyl, 1 ,2-dimethyl-2-butenyl, 1 ,2-dimethyl-3-butenyl, 1 ,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1 -ethyl-2-butenyl, I -ethyl-3-butenyl, 2ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1 ,2-trimethyl-2-propenyl, 1 -ethyl- I -methyl-2propenyl and 1 -ethyl -2-methyl -2-propenyl.

Optionally substituted ethenyl, 2-propenyl, 2-butenyl or 1-methyl-2-propenyl may be mentioned as being preferred.

Optionally substituted alkinyl, alone or as component of a radical in the general formulae, represents straight-chain or branched alkinyl having preferably 1 to 6, in particular I to 4, carbon atoms. Examples which may be mentioned are optionally substituted ethinyl, 2-propinyl, 2-butinyl, 3-butinyl, I -methyl-2-propinyl, 2-pentinyl, 3-pentinyl, 4-pentinyl, 1 -methyl-3-butinyl, 2-methyl-3-butinyl, 1 -methyl-2-butinyl, Le A 33 687-Foreign Countries -26- 1,1-dimethyl-2-propinyl, 1-ethyl-2-propinyl, 2-hexinyl, 3-hexinyl, 4-hexinyl, hexinyl, 1-methyl-2-pentinyl, 1-methyl-3-pentinyl, 1-methyl-4-pentinyl, 2-methyl-3pentinyl, 2-methyl-4-pentinyl, 3-methyl-4-pentinyl, 4-methyl-2-pentinyl, 1,1dimethyl-3-butinyl, 1,2-dimethyl-3-butinyl, 2,2-dimethyl-3-butinyl, I -ethyl-3-butinyl, 2-ethyl-3-butinyl and 1-ethyl-i -methyl-2-propinyl.

Optionally substituted ethinyl, 2-propinyl or 2-butinyl may be mentioned as being preferred.

Optionally substituted cycloalkyl, alone or as component of a radical in the general formulae, represents mono-, bi- and tricyclic cycloalkyl, preferably having 3 to 10, in particular 3, 5 or 7, carbon atoms. Examples which may be mentioned are optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclo-hexyl, cycloheptyl, cyclooctyl, bicyclo[2.2. 1 ]heptyl, bicyclo[2.2.2]octyl and adamantyl.

Halogenoalkyl, alone or as component of a radical in the general formulae, contains 1 to 4, in particular 1 or 2, carbon atoms having preferably 1 to 9, in particular 1 to identical or different halogen atoms, preferably fluorine, chlorine or bromine, in particular fluorine or chlorine. Examples which may be mentioned are trifluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, chloromethyl, bromomethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2trifluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, pentafluoroethyl and pentafluoro-tert-butyl.

Optionally substituted alkoxy, alone or as component of a radical in the general formulae, represents straight-chain or branched alkoxy having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be mentioned are optionally substituted methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secbutoxy and tert-butoxy.

Optionally substituted alkoxyalkoxy, alone or as component of a radical in the general formulae, represents 2 alkoxy radicals as mentioned above which are C-O- Le A 33 687-Foreign Countries -27attached to each other. Examples which may be mentioned are optionally substituted methoxymethoxy, methoxyethoxy, methoxy-n-propoxy and ethoxyisopropoxy.

Optionally substituted alkoxyalkoxyalkoxy, alone or as component of a radical in the general formulae, represents 3 alkoxy radicals as mentioned above which are in each case C-O-attached to each other. Examples which may be mentioned are optionally substituted methoxymethoxyethoxy, methoxyethoxyethoxy and methoxyethoxy-npropoxy.

Optionally substituted halogenoalkoxy, alone or as component of a radical in the general formulae, represents straight-chain or branched halogenoalkoxy having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be mentioned are optionally substituted difluoromethoxy, trifluoromethoxy, trichloromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy and 2-chloro-1,1,2trifluoroethoxy.

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

Optionally substituted halogenoalkylthio, alone or as component of a radical in the general formulae, represents straight-chain or branched halogenoalkylthio having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be mentioned are optionally substituted difluoromethylthio, trifluoromethylthio, trichloromethylthio, chlorodifluoromethylthio, 1-fluoroethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio, 1,1,2,2-tetrafluoroethylthio, 2,2,2-trifluoroethylthio and 2chloro-1,1,2-trifluoroethylthio.

Le A 33 687-Foreign Countries -28- Optionally substituted alkylcarbonyl, alone or as component of a radical in the general formulae, represents straight-chain or branched alkylcarbonyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be mentioned are optionally substituted methylcarbonyl, ethylcarbonyl, npropylcarbonyl, isopropylcarbonyl, sec-butylcarbonyl and tert-butylcarbonyl.

Optionally substituted cycloalkylcarbonyl, alone or as component of a radical in the general formulae, represents mono-, bi- and tricyclic cycloalkylcarbonyl, having preferably 3 to 10, in particular 3, 5 or 7, carbon atoms. Examples which may be mentioned are optionally substituted cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, bicyclo[2.2.1]heptylcarbonyl, bicyclo[2.2.2]octylcarbonyl and adamantylcarbonyl.

Optionally substituted alkoxycarbonyl, alone or as component of a radical in the general formulae, represents straight-chain or branched alkoxycarbonyl having preferably 2 to 7, in particular 2 to 5, carbon atoms. Examples which may be mentioned are optionally substituted methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl.

Aryl is, for example, a mono-, bi- or polycyclic aromatic radical, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl and the like, but preferably phenyl or naphthyl.

Optionally substituted aryl in the general formula represents preferably optionally substituted phenyl or naphthyl, in particular phenyl.

Optionally substituted arylalkyl in the general formulae represents preferably arylalkyl which is optionally substituted in the aryl moiety and/or alky] and has preferably 6 or 10, in particular 6, carbon atoms in the aryl moiety (preferably phenyl or naphthyl, in particular phenyl) and preferably 1 to 4, in particular 1 or 2, carbon Le A 33 687-Foreign Countries -29atoms in the alkyl moiety, where the alkyl moiety may be straight-chain or branched.

By way of example and by way of preference, optionally substituted benzyl and 1phenylethyl may be mentioned.

The optionally substituted radicals of the general formulae may carry one or more, preferably 1 to 3, in particular 1 to 2, identical or different substituents. Substituents which may be mentioned by way of example and by way of preference are: Alkyl having 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 having preferably 1 to 4, in particular 1 to 2, carbon atoms, such as methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy; alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio; halogenoalkyl having preferably 1 to 5, in particular 1 to 3, halogen atoms, where the halogen atoms are identical or different and halogen atoms preferably represent fluorine, chlorine or bromine, in particular fluorine or chlorine, such as difluoromethyl, trifluoromethyl, trichloromethyl; hydroxyl, halogen, preferably fluorine, chlorine, bromine and iodine, in particular fluorine and chlorine, cyano; nitro; amino; mono- and dialkylamino having 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 having preferably 2 to 4, in particular 2 to 3, carbon atoms, such as methoxycarbonyl and ethoxycarbonyl; alkylsulfinyl having 1 to 4, in particular 1 to 2, carbon atoms; halogenoalkylsulfinyl having 1 to 4, in particular 1 to 2, carbon atoms and 1 to 5 halogen atoms, such as trifluoromethylsulfinyl; halogenoalkylsulfonyl having 1 to 4, in particular 1 to 2, carbon atoms and 1 to 5 halogen atoms, such as trifluoromethylsulfonyl, perfluoro-nbutylsulfonyl, perfluoroisobutylsulfonyl; arylsulfonyl having preferably 6 or 10 aryl carbon atoms, such as phenylsulfonyl; acyl, aryl, aryloxy, which for their part may carry one of the abovementioned Le A 33 687-Foreign Countries substituents and the formimino radical (-HC=N-O-alkyl).

The number of these substituents is not limited, it is preferably from 1 to 4 identical or different substituents. It is also possible for two identical or different substituents to be present at the same atom or at atoms of cyclic amino groups.

Optionally substituted mono- or dialkylamino groups, alone or as component of a radical in the general formulae, represents straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples of substituted monoor dialkylamino groups which may be mentioned are methylamino, ethylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino or dibutylamino.

Optionally substituted mono- or dialkoxyalkylamino groups, alone or as component of a radical in the general formulae, represents straight-chain or branched alkoxyalkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples of substituted mono- or dialkoxyalkyl-amino groups which may be mentioned are methoxymethylamino, methoxyethylamino, di-(methoxymethyl)-amino or di-(methoxyethyl)amino.

Suitable cyclic amino groups are heteroaromatic or aliphatic ring systems having one or more nitrogen atoms as heteroatom, where the heterocycles may be saturated or unsaturated, be one ring system or a plurality of fused ring systems and may optionally contain further heteroatoms, such as, for example, one or two nitrogens, oxygen and sulfur, etc. Moreover, cyclic amino groups may also represent a spiro ring or a bridged ring system. The number of atoms which form the cyclic amino groups is not limited, in the case of a one ring system, for example, the groups consist of 3 to 8 atoms and in the case of a three-ring system, of 7 to 11 atoms.

Examples of cyclic amino groups having saturated and unsaturated monocyclic groups having a nitrogen atom as heteroatom which may be mentioned are 1azetidinyl, pyrrolidino, 2-pyrrolin-l-yl, 1-pyrrolyl, piperidino, 1,4-dihydropyrazin-1yl, 1,2,5,6-tetrahydropyrazin-1-yl, 1,4-dihydropyridin- 1-yl, 1,2,5,6-tetrahydropyridin- Le A 33 687-Foreign Countries -31l-yl, homopiperidinyl; examples of cyclic amino groups having saturated and unsaturated monocyclic groups having two or more nitrogen atoms as heteroatoms which may be mentioned are 1-imidazolidinyl, 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 1-tetrazolyl, 1-piperazinyl, 1-homopiperazinyl, 1,2-dihydro-pyridazin-1-yl, 1,2-dihydro-pyrimidin- l-yl, perhydropyrimidin-1-yl, 1,4-diazacyclo-heptan-1-yl; examples of cyclic amino groups having saturated and unsaturated monocyclic groups having one or two oxygen atoms and one to 3 nitrogen atoms as heteroatoms, such as, for example, oxazolidin-3-yl, 2,3-dihydroisoxazol-2-yl, isoxazol-2-yl, 1,2,3-oxadiazin-2yl, morpholino, examples of cyclic amino groups having saturated and unsaturated monocyclic groups having one to three nitrogen atoms and one to two sulfur atoms as heteroatoms which may be mentioned are thiazolidin-3-yl, isothiazolin-2-yl, thiomorpholino, or dioxothiomorpholino; examples of cyclic amino groups having saturated and unsaturated fused cyclic groups which may be mentioned are indol-1yl, 1,2-dihydrobenzimidazol-1-yl, perhydropyrrolo[1,2-a]pyrazin-2-yl; examples of cyclic amino groups having spirocyclic groups which may be mentioned are 2azaspiro[4,5]decan-2-yl; examples of cyclic amino groups having bridged heterocyclic groups which may be mentioned are 2-azabicyclo[2,2,1 ]heptan-7-yl.

Suitable monovalent amino protective groups are acyl groups having preferably 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, for example, 2-chloro-, 2-bromo-, 2-iodo-, 2,2-dichloroacetyl, 2,2,2-trifluoroacetyl or 2,2,2-trichloroacetyl, alkoxycarbonyl groups having 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 1-[1adamantyl]-1-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 phenoxypropionyl, arylglyoxyloyl groups, such as, for example, phenylglyoxyloyl and naphthylglyoxyloyl, alkoxycarbonyl Le A 33 687-Foreign Countries -32groups having customary substituents, such as, for example, benzyloxycarbonyl (Cbo- or Cbz, 4-methoxybenzyloxycarbonyl, 4-phenylazobenzyl-oxycarbonyl, phenethyloxycarbonyl, nitro-benzyloxycarbonyl, chloro-benzyloxycar-bonyl, a,a-dimethyl-3,5-dimethoxy-benzyloxycarbonyl, 2-nitro- 4,5-dimethoxy-benzyl-oxycarbonyl (Nvoc), fluorenyl-9-methoxycarbonyl (Fmoc), substituted or unsubstituted alkylidene groups, such as, for example, benzylidene, hydroxybenzylidene, mono- (or di- or tri-) phenylalkyl-containing alkyl groups, such as, for example, benzyl, phenethyl, benzhydryl or triphenylmethyl (trityl) and the like. Suitable bivalent amino protective groups which may be are mono- or disubstituted methylidene groups, such as 1-lower-alkoxy (for example methoxy or ethoxy)-lower alky-lidene (for example ethylidene or 1-n-butylidene), for example

=C(CH

3

)(O-C

2

H

5 furthermore, for example, =C(CH 3 2 or =CH-phenyl, and in particular bisacyl radicals, for example the phthalyl radical, which together with the nitrogen atom to be protected forms a 1H-isoindole-1,3(2H)-dione (phthalimide group).

Amino protective group and their introduction and removal are known per se and described, for example, in 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 hydroxyl 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 protective 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, triphenylmethyl and pyridyldiphenylmethyl and the like.

Le A 33 687-Foreign Countries -33- The protective groups mentioned further above have the function, known in peptide chemistry, to protect amino hydroxyl or thiol groups of compounds temporarily.

Suitable synthetic resin for use as polymeric carriers for the solid-phase synthesis of the cyclodepsipeptides according to the invention are appropriately functionalized basic polymers (in the most common form on a chloromethylated polystyrene), such as, for example, amino-oxy- or hydrazino-functionalized resins of the Merrifield type. Particularly suitable here is the commercially available DHP HM resin from Novabiochem which allows simple anchoring using a hydroxylamino- or hydrazino function and thus permits the cyclodepsipeptides according to the invention to be provided.

Particular preference is given to compounds of the general formula (Ia) A R 12 0 NC O R 1

R

2 N NN "R1 R Rio 0 0 R R4 R 7

O

0 N N R 8 (Ia) Rs O O 0 R 6 in which

R

4

R

7 and R'O represent methyl,

R

2

R

5

R

8 and R' represent isobutyl,

R

6 and R 2 represent methyl,

R

3 and R 9 independently of one another represent optionally substituted benzyl, substituents that may be mentioned being hydrogen, halogen, in particular Le A 33 687-Foreign Countries -34bromine, fluorine, chlorine or iodine, cyano, carbamoyl, hydroxyl which carries a protective group or unprotected hydroxyl, CI-s-alkoxy, in particular methoxy, tert-butyloxy, C 1 4 -alkoxy-C -4-alkoxy, in particular methoxymethoxy, 2-methoxyethoxy, C 24 -alkenyloxy, in particular allyloxy, hetaryl-

C

1 -4-alkoxy, in particular fur-2-yl-methoxy, tetrahydrofur-2-yl-methoxy, N- Boc-pyrrolidin-2-yl-methoxy, pyrrolidin-2-yl-methoxy, 5-sec-butyl-1,2,4oxadiazol-3-yl-methoxy, 5-cyclopropyl-1,2,4-oxadiazol-3-yl-methoxy, imithiazolylmethoxy, tetrazol-5-yl-methoxy, thienylmethoxy, nitro, or a radical from the group consisting of -O-CH 2

-CH

2 NR23 R 24, -CH 2 N23R24, -NR23R24 and -S0 2 NR23R24

R

2 3 and R24 independently of one another each represent hydrogen, C 1 4 -alkyl, in particular methyl, ethyl, hetaryl-C 1 4 -alkyl, in particular fur-2-yl-methyl, tetrahydrofur-2-yl-methyl, pyrrolidin-2-yl-,

R

2 3 and R 2 4 together with the nitrogen atom to which they are attached represent hetaryl, in particular N-pyrrolidino, N-piperazino, N-morpholino, Nthiomorpholino, N-piperidino, N-imidazolo, 2-oxo-pyrrolidino, phthalimino or tetrahydrophthalimino, A represents hydrogen, cyano or optionally represents a radical A'

-Y-R'

3

A)

in which Y represents oxygen or -N-R' 4 where

R'

3 and R' 4 independently of one another represent hydrogen, straight-chain or branched C,- 4 -alkyl, in particular methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, Cl-C 4 -alkylcarbonyl, in particular methylcarbonyl, ethylcarbonyl, cyano-C -C 4 -alkyl, amino-C -C 4 Le A 33 687-Foreign Countries alkyl, hydroxy-Cl -C 4 -alkyl, C, 4 -alkylsulfonyl, in particular methylsulfonyl, C, 2 -halogenoalkoxy-C]- 2 -alkylsulfonyl, in particular 1,1,1 -trifluoroethoxyethylsulfonyl, straight-chain or branched CI-4alkyloxy-carbonyl, in particular methoxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, secbutyloxycarbonyl, tert-butyl-oxycarbonyl, straight-chain or branched C, .4-alkylaminocarbonyl, in particular methylaminocarbonyl, ethylaminocarbonyl, C 2 4 -alkenyl, in particular vinyl, 2-propenyl, 2-butenyl,

C

2 4 -alkenyloxycarbonyl, in particular vinyloxycarbonyl, 2propenyloxycarbonyl, 2-butenyloxycarbonyl, C 2 4 -halogenoalkenyloxycarbonyl, in particular 1,1,2-trifluorobut- 1-en-4-yl-oxycarbonyl,

C

2 4 -alkenylaminocarbonyl, in particular 2-propenylaminocarbonyl,

C

2 4 -alkinyl, in particular 2-propinyl, C 2 4 -alkinyloxycarbonyl, in particular 2-propinyloxycarbonyl, cyanomethyl, hydroxyethyl, aminoethyl, aryl-C 1- 2 -alkyl, in particular optionally substituted benzyl, hetaryl-C 1- 2 -alkyl, in particular optionally substituted hetarylmethyl, in particular optionally substituted tetrahydrofurylmethyl, furylmethyl, thienylmethyl, thiadiazolylmethyl, tetrazolylmethyl, pyridylmethyl, aryloxy-C, 2 -alkyl, in particular optionally substituted phenoxyethyl, optionally substituted hetarylcarbonyl, substituents that may be mentioned being hydrogen, nitro, amino, halogen, in particular bromine, chlorine or fluorine, C,- 4 -alkyl, in particular methyl, C,-4halogenalkyl, in particular trifluoromethyl, phenyl, C, A-alkoxy, in particular methoxy, C,- 4 -alkoxycarbonyl, in particular methoxycarbonyl, N-morpholinyl, or hetarylcarbonylmethyl, in particular N-morpholinocarbonylmethyl, N-pyrrolidinocarbonylmethyl, or optionally represent a radical of group B 4 Le A 33 687-Foreign Countries -36- R21 I

SR

19

R

20

(B

4 z in which

Z

II

-G

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

R

1 9 represents hydrogen,

R

20 represents hydrogen, propyl, isopropyl, isobutyl, benzyl, 4hydroxybenzyl, imidazol-4-yl-methyl, indol-3-ylmethyl, phenyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-methylthioethyl, 2carbamoylethyl,

R

2 1 represents hydrogen or C 1

-C

4 -alkyl, and their optical isomers, racemates and their physiologically acceptable salts.

Very particular preference is given to compounds of the general formula (Ia) Le A 33 687-Foreign Countries 37 A R 12 0 N -C 0OyR N N ~NN F 0 0 6 in which R 4

,R

7 and R' 0 R, andR" represent methyl, represent isobutyl, R 6 and R'1 2 R 3 and R'

A

represent methyl, represent benzyl, represents -NHMe or a radical A'

(A'I)

in which Y represents oxygen, R 3 represents hydrogen, straight-chain or branched C,- 4 -alkyl, in particular methyl, ethyl, propyl, tert-butyl, C, 4 -alkylsulfonyl, in particular methylsulfonyl, C 1

-C

4 -alkylcarbonyl, in particular methylcarbonyl, cyano-C 1

-C

4 -alkyl, hydroxy-C 1

-C

4 -alkyl, Le A 33 687-Foreign Countries -38amino-C 1

-C

4 -alkyl, C 1 2 -halogenoalkoxy-CI 2-alkylsulfonyl, in particular 1,1,1 -trifluoroethoxyethylsulfonyl, straight-chain or branched C 1 4 -alkyloxycarbonyl, in particular methoxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, tertbutyloxycarbonyl, C 24 -alkenyl, 2-propenyl, C 2 4 -alkenyloxycarbonyl, in particular vinyloxycarbonyl, 2-propenyloxycarbonyl, C 2 4 -halogenoalkenyloxycarbonyl, in particular 1,1,2-trifluorobut- 1 -en-4-yl-oxycarbonyl, C 2 4 -alkenylaminocarbonyl, in particular 2-propenylaminocarbonyl, C 2 4 -alkinyloxycarbonyl, in particular 2-propinyloxycarbonyl, aryl-C 1 2 alkyl, in particular optionally substituted benzyl, N-morpholinocarbonylmethyl, N-pyrrolidinocarbonylmethyl, hetaryl-

CI-

2 -alkyl, in particular optionally substituted tetrahydrofurylmethyl, furylmethyl, 5-chioro-thiadi azol-4-yl-methyl, Npyridyl-methyl, yl-methyl, aryloxy-CI.

2 -alkyl, in particular optionally substituted phenoxyethyl, trifluoromethylphenoxyethyl, optionally substituted hetarylcarbonyl, in particular optionally substituted furylcarbonyl, pyridylcarbonyl, substituents that may be mentioned being hydrogen, nitro, amino, halogen, in particular bromine, chlorine or fluorine, methyl, trifluoromethyl, phenyl, methoxy, methoxycarbonyl, N-morpholinyl, or 4 optionally represents a radical from the group B 21 G K II R 19

R

20 Z (B4) in which Le A 33 687-Foreign Countries -39-

Z

II

G

represents a selectively removable protective group, for example acetyl allyloxycarbonyl Alloc), benzyloxycarbonyl or tert-butyloxycarbonyl (Boc),

R

9 represents hydrogen,

R

2 0 represents hydrogen, methyl, propyl, isopropyl, isobutyl,

R

2 1 represents hydrogen or methyl, and their optical isomers, racemates and their physiologically acceptable salts.

The general or preferred radical definitions or illustrations listed above can be combined with one another as desired, i.e. including combinations between the respective ranges and preferred ranges. They apply to the end product and, correspondingly, to precursors and intermediates.

The cycloiminodepsipeptides of the general formula to be used according to the invention and their salts furthermore contain one or more centers of chirality, and they can therefore be present as pure stereoisomers or in the form of various enantiomer and diastereomer mixtures which, if required, can be separated in a manner known per se or else be prepared by stereoselective reactions in combination with the use of stereochemically pure starting materials.

However, preference is given to using, according to the invention, the optically active stereoisomeric forms of the compounds of the general formula and their salts.

Particular preference is given to using the cyclic depsipeptides which are constructed of (S)-configured amino acids (L form) and D-configured hydroxycarboxylic acids (D form) as ring building blocks.

Le A 33 687-Foreign Countries Accordingly, the invention relates both to the pure enantiomers and diastereomers and to their mixtures for controlling endoparasites, in particular in the field of medicine and veterinary medicine.

Suitable salts of the cycloiminodepsipeptides of the general formula which may be mentioned are customary nontoxic salts, i.e. salts with differing bases and salts with added acids. Salts with inorganic 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 also with inorganic amines, for example triethylammonium, dicyclohexylammonium, N,N'-dibenzylethylenediammonium, pyridinium, picolinium or ethanolammonium salts, salts with inorganic acids, for example hydrochlorides, hydrobromides, dihydrosulfates, trihydrosulfates, or phosphates, salts with organic carboxylic acids or sulfonic acids, for example formates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates or para-toluenesulfonates, salts with basic amino acids, for example arginates, aspartates or glutamates and the like may be mentioned as being preferred.

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

Suitable for use as starting components are here preferably the corresponding endothiopeptides or heterocyclic thiolactames. By way of example, the syntheses of amidoxime, cyanamidine and amidrazone alalogs of chemotactic peptides from endothiopeptides may be mentioned Sauve et al., Can. J. Chem. 61, 1985, p. 3089). One variant for preparing the NO-hydroxy-N-methyl-(R)-arginine from tert-butyl N-tert-butoxycarbonyl-8-(N-methyl-thioureido)-(R)-norvalinate has been described by H. A. Moynihan et al. Chem. Soc. Perkin Trans. I 1994, p. 769).

Likewise, it is possible to convert heterocyclic thiolactames into amidines (pyrrolo[2,1-c][1,4]benzodiazepine-5,11l-dione: M. Robba et al., Tetrahedron Lett. 33 Le A 33 687-Foreign Countries -41 1992, p. 2803) or, without any problems, azetidine-2-thiones into azetidin-2imines (B-lactams: L. Ghosez et al., J. Chem. Soc., Chem. Commun. 1983, p. 818).

Surprisingly, it has now been found that the novel cyclic iminodepsipeptides of the general formula according to the invention can also be prepared from the corresponding cyclic thiodepsipeptides using amino compounds of the general formula by reacting one or more thioamide groups. Particular preference according to the invention is given to reacting one thioamide group.

The compounds of the general formula are novel, they can be prepared, for example, by processes mentioned above under points 2 and 3.

Below, the processes according to the invention are illustrated using selected examples (cf. also Preparation Examples).

If, in the process 2a according to the invention for preparing the novel cycloiminodepsipeptides of the general formula the compounds of the general formula (Ib) used is the cyclic thiodepsipeptide cyclo(-N-methyl-L-leucinyl-Dthiolactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-Nmethyl-L-leucinyl-D-phenyllactyl-) as amino compound of the general formula (II) the O-methyl-hydroxylamine -O-Me; cf.. route A) or N-methylhydrazine NH-Me; cf. route the process can be represented by the reaction scheme Scheme I below: Le A 33 687-Foreign Countries -42- Scheme I Me Me Me M e N M e M e e Me Me O e o o Me Me Me N Me Me Me

A)

B) MeN H Me Me oMe Me Me e Me syn-/anti- isomer mixtures

H

2 N-O-Me HCI, Hg(O-Ac) 2 base

H

2 N-NH-Me, Hg(O-Ac) 2 base If the amino compounds of the general formula (II) are used, the compounds of the general formula may be formed as a mixture of syn- and anti- isomers in the process 2a according to the invention.

The 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 R' to R 12 preferably represent those radicals which have already been mentioned in connection with the description of the substances of the general formula according to the invention as being preferred for these substituents.

The cyclic thiodepsipeptides used as starting materials are known from an earlier patent application and can be obtained correspondingly via thionation of cyclic depsipeptides using suitable sulfurizing agents (cf. WO 98/43965, see also Preparation Examples).

Le A 33 687-Foreign Countries -43- The general formula (II) provides a definition of the amino compounds further to be used as starting materials for carrying out the process 2a according to the invention.

In this formula A has the meaning which has already been mentioned in connection with the description of the substances of the general formula according to the invention as being preferred for this substituent.

The amino compounds of the formula (II) are commercially available, some are known and can be obtained by known methods for example, hetarylmethoxamine: US-Pat. 5 489 680; DE-OS (German Published Specification) 2119012, alkoxyamines: EP-OS 495 750; DE-OS (German Published Specification) 2206890; D. Favara et al. Farmaco, Ed. Sci. 42 1987, p. 697).

A general route for preparing aminoxy compounds (A -Y-R 1 3 Y: of the formula (II) comprises, for example, reacting a hydroxylamine derivative which has a protective group on nitrogen (for example R' and R" together: phthaloyl, isopropylidene, a-hydroxy-benzylidene group) with a compound R' 3 -E (0alkylation) in a diluent, followed by removal of the corresponding protective group.

In compound RI3-E, R 13 has the same meaning as above and E represents a nucleofugic leaving group, for example aliphatically or aromatically substituted sulfonyloxy, for example methanesulfonyloxy, salts of sulfonic acid, ptoluenesulfonyloxy (tosyloxy), and furthermore also, for example, halogen, in particular bromine, chlorine or iodine. (cf. O-alkylation). In reaction scheme II below, the preparation of amino compounds of the formula (II) is shown (A -Y-

R

1 3 Y: Le A 33 687-Foreign Countries -44- Scheme II 13 R R'

R'

HO-N R R 13 E O-N R-O-NH2

R"

(nI) Alternatively, if a hydroxyl compound (R' 3 -OH) is used, it is also possible to carry out, for example, an intermolecular dehydration reaction. Particularly suitable for this purpose is a variant of the Mitsunobu reaction [Synthesis 1976, p. 682] where the hydroxy compounds with N-protected hydroxylamine derivatives, such as, for example, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-dicarboximide or ethyl acetylhydroxamate, and, for example, triphenylphosphine and diethyl N,N'azodicarboxylate.

The compounds of the formula (II) can expediently be released in the following manner: the hydrazinolysis can preferably be carried out in a diluent, for example alcohol, at boiling point. The hydrolysis can preferably be carried out in an aqueous, aqueous-alcoholic or alcoholic solution, by heating for a number of hours. If R' and R" together represent an isopropylidene group, it is possible to use acid hydrolysis and, if R' and R" together represent an a-hydroxy-benzylidene group or R" represents a carbethoxy group, it is possible to use both alkaline and acidic hydrolysis (cf. DE-OS (German Published Specification) 2119012; D. Favara et al. Farmaco, Ed. Sci. 42 (1987) p. 697).

For preparing the salts, it is preferred to use inorganic acids, such as hydrochloric acid or sulfuric acid, in ethanolic or isopropanolic solution.

The reaction of the thiodepsipeptide of the general formula (Ib) with the amino compounds of the general formula (II) is preferably carried out in the presence of a Le A 33 687-Foreign Countries 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 the I. and II. transition group of the Periodic Table of the Elements. Examples which may be mentioned are 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 trifluoromethansulfonates of the metals of the I. transition group, in particular silver, and the acetates, oxides and the halides of the metals of the II. transition group, in particular mercury.

Suitable for use as basic reaction auxiliaries for carrying out the process 2a according to the invention are all suitable acid binders, such as amines, in particular tertiary amines, and alkali metal and alkaline earth metal compounds.

Examples which may be mentioned are the hydroxides, oxides and carbonates of lithium, sodium, potassium, magnesium, calcium and barium, furthermore further basic compounds such as amidine bases or guanidine bases, such as 7-methyl-1,5,7triazabi-cyclo(4.4.0)dec-5-ene (MTBD); diazabicyclo(4.3.0)nonene (DBN), diazabicyclo(2.2.2)-octane (DABCO), 1,8-diaza-bicyclo(5.4.0)undecene (DBU), cyclohexyl-tetrabutylgua-nidine (CyTBG), cyclohexyltetramethylguanidine (CyTMG), N,N,N,N-tetramethyl-1,8-naphthalenediamine, pentamethylpiperidine, tertiary amines, such as triethylamine, trimethylamine, tribenzylamine, triisopropylamine, tributylamine, tribenzylamine, tricyclohexylamine, triamylamine, trihexylamine, N,N-dimethyl-aniline, N,N-dimethyl-toluidine, N,N-dimethyl-paminopyridine, N-methyl-pyrrolidine, N-methyl-piperidine, N-methyl-imidazole, Nmethyl-pyrrole, N-methyl-morpholine, N-methyl-hexamethylenimine, pyridine, 4pyrrolidinopyridine, 4-dimethylamino-pyridine, quinoline, a-picoline, 3-picoline, Le A 33 687-Foreign Countries -46isoquinoline, pyrimidine, acridine, N,N,N',N'-tetramethylenediamine, tetraethylenediamine, quinoxaline, N-propyl-diisopropylamine, N-ethyldiisopropylamine, N,N'-dimethylcyclohexylamine, 2,6-lutidine, 2,4-lutidine or triethylendiamine.

Preference is given to using tertiary amines, in particular trialkylamines such as triethylamine, N,N-diisopropylethylamine, N-propyl-diisopropylamine, N,N'dimethyl-cyclohexylamine or N-methylmorpholine.

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

Examples which may be mentioned are: halogenated hydrocarbons, in particular chlorinated hydrocarbons, such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloro-ethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, chlorotoluene, trichlorobenzene; alcohols such as methanol, ethanol, isopropanol, butanol; ethers such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenetole, 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 polyethers of ethylene oxide and/or propylene oxide: amines such as trimethyl-, triethyl-, tripropyl-, tributylamine, N-methylmorpholine, pyridine and tetramethylenediamine, nitrohydrocarbons such as niromethane, nitroethane, nitropropane, nitrobenzene, chloronitrobenzene, o-nitrotoluenes; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, benzonitrile, m-chlorobenzonitrile and also compounds such as tetrahydrothiophene dioxide and dimethyl sulfoxide, tetramethylene Le A 33 687-Foreign Countries -47sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, diisoamyl sulfoxide; sulfones, such as dimethyl, diethyl, dipropyl, dibutyl, diphenyl, dihexyl, methyl ethyl, ethyl propyl, ethyl isobutyl and pentamethylene sulfone; aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane and industrial hydrocarbons, for example white spirits with components having boiling points in the range of, for example, from 40'C to 250'C, cymene, benzine fractions within a boiling point range of from 70 0 C to 190 0

C,

cyclohexane, methylcyclohexane, petroleum ether, ligroine, octane, benzene, toluene, chlorobenzene, bromobenzene, nitrobenzene, xylene; esters such as methyl, ethyl, butyl, isobutyl acetate, and also dimethyl, dibutyl, ethylene carbonate; amides such as hexamethylenephosphoric triamide, formamide, N-methyl-formamide, N,Ndimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methyl-caprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)pyrimidine, octylpyrrolidone, octylcaprolactam, 1,3-dimethyl-2-imidazolinedione, Nformyl-piperidine, N,N'-1,4-diformylpiperazine; ketones such as acetone, acetophenone, methyl ethyl ketone, methyl butyl ketone.

It is, of course, also possible to use mixtures of the solvents and diluents mentioned for 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 ether, 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, in particular chlorinated hydrocarbons, such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene Le A 33 687-Foreign Countries -48or pentachloroethane, in particular methylene chloride, chloroform or carbon tetrachloride.

The reaction of amino compounds of the general formula (11) according to process 2a is carried out by reacting the cyclothiodepsipeptides of the general formula (Ib) in the presence of an amino compound of the general formula in the presence of one of metal salts or metal oxides mentioned with elements of the I. and 11. transition group of the Periodic Table of the Elements and, if appropriate, in the presence of one of the basic reaction auxiliaries mentioned in one of the mentioned diluents.

The reaction time is from 10 minutes from 48 hours. The reaction is carried out at temperatures between -10°C and +200'C, preferably between +10 0 C and +180 0

C,

particularly preferably at room temperature. In principle, the reaction can be carried out under atmospheric pressure. It is preferably carried out under atmospheric pressure or at pressures of up to 15 bar and, if appropriate, under an atmosphere of protective gas (nitrogen or helium).

For carrying out the process 2a according to the invention, in general from 0.5 to mol, preferably from 1.0 to 5.0 mol, particularly preferably from 2.0 to 3.0 mol, of amino compound of the general formula (II) are employed per thioamide group present in the cyclothiodepsipeptides of the general formulae (Ib).

Furthermore, for carrying out the process 2a according to the invention, in general from 0.5 to 6.0 mol, preferably from 1.0 to 4.0 mol, particularly preferably from to 2.5 mol, of metal salt or metal oxide are employed per thioamide group present in the compounds of the general formulae (Ib).

After the reaction has ended, the entire reaction mixture is separated from the metal sulfide which precipitates out and, if appropriate, washed. The resulting products can be purified in a customary manner by recrystallization, distillation under reduced pressure or column chromatography (cf. also the preparation examples).

Le A 33 687-Foreign Countries -49- If, in the processes 2b and 2c according to the invention for preparing the novel cycloiminodepsipeptides of the general formula the compounds of the formula (Ic) used is, for example, the cyclic iminodepsipeptide cyclo[-N-methyl-L-leuci-nyl- D-(hydroxy-imino)-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl- D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) and the compounds of the general formula (IIl) used is vinyl chloroformate (cf. route C) and the compounds of the general formula (IV) used is acetic anhydride (cf. route the processes can be represented by reaction scheme II below.

Scheme III H Me Me Me Me N Me e

N

N Me Me[ Me Me o 0 0 Me, Me Me /0 Me Me Me

D)

0 Me Me Me N 'e e Me Me Me Me M Me e oMee Me Me e syn-/anti- isomer mixtures

CI-CO-O-CH=CH

2 base

(CH

3

-CO)

2 0 The formula (Ic) provides a general definition of the cycloiminodepsipeptides required as starting materials in particular for carrying out the processes 2b and 2c according to the invention and their salts.

Le A 33 687-Foreign Countries In this formula Y and R' to R 12 preferably represent those radicals which have already been mentioned in connection with the description of the substances of the general formula according to the invention as being preferred for these substituents.

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

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

Scheme IV Me Me Me H Me0 Me Me Me N Y Me NOU Me N Mek M e

N

Me NMe O Me I O M O 0 '0 Y0 I O Me eo MeA Me Me Me^

M

The formulae (UT) and (IV) provide general definitions of the compounds furthermore to be used as starting materials for carrying out the processes 2b and 2c according to the invention.

Z

II

In the formulae (111) and W, Q and Y have the meaning which have already been mentioned for these substituents in connection with the description of the substances of the general formula according to the invention.

Le A 33 687-Foreign Countries -51 The compounds of the formula (III) are generally known compounds of organic chemistry, and/or some of them can be obtained commercially or by methods known from the literature (for example Houben Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Volume E 4).

The reaction of the cycloiminodepsipeptides (Ic) with compounds of the general formula (1I) is preferably carried out in the presence of basic reaction auxiliaries using diluents.

Suitable for use as basic reaction auxiliaries for carrying out the process 2b according to the invention are all acid binders mentioned under process 2a, such as amines, in particular tertiary amines.

In process 2b, preference is given to using the tertiary amines, in particular trialkylamines such as triethylamine, N,N-diisopropylethylamine, npropyldiisopropylamine, N,N'-dimethylcyclohexylamine or N-methylmorpholine, and also pyridine derivatives, in particular pyridine.

In the process 2b according to the invention it is, of course, also possible to use mixtures of the acid binders mentioned.

Suitable diluents for carrying out the process 2b according to the invention are the inert aprotic solvents mentioned under process 2a, such as, for example, dioxane, acetonitrile or tetrahydrofuran, but also halogenated hydrocarbons, in particular .chlorinated hydrocarbons, such as methylene chloride or chloroform.

The 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 if appropriate in one of the diluents mentioned.

Le A 33 687-Foreign Countries -52- Alternatively and preferably, process 2b can also be carried out directly in a suitable basic reaction auxiliary without a diluent.

The formula (IV) provides a general definition of the carboxylic anhydrides to be used as starting materials for carrying out the process 2c according to the invention.

The reaction time is from 4 to 72 hours. The reaction is carried out at temperatures between -10 0 C and +150 0 C, preferably between -5 0 C and +80 0 C, particularly preferably at from 0°C to room temperature. The reaction is carried out under atmospheric pressure.

For carrying out the process 2b according to the invention, in general from 2.0 to mol, preferably from 2.0 to 4.0 mol, of acetylating agent are employed per mole of compound of the formula (Ic).

For carrying out the process 2c according to the invention, in general from 1.0 to mol, preferably from 1.0 to 1.5 mol, of carboxylic anhydride are employed per mole of compound of the formula (Ic).

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

After the reaction has ended, the reaction solution is washed and the organic phase is separated off, dried and concentrated under reduced pressure. The resulting products can be purified in a customary manner by recrystallization, distillation under reduced pressure or column chromatography (cf. also the Preparation Examples).

If in the process 2d a) and 1) according to the invention for preparing the novel cycloiminodepsipeptides of the general formula (Ia) the compounds of the formula (Ic) used is, for example, the cyclic iminodepsipeptide cyclo[-N-methyl-L-leuci-nyl- Le A 33 687-Foreign Countries -53- D-(hydroxy-imino)-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl- D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) the compounds of the general formula used is (S)-N-tert-butyloxycarbonyl-N-methylalanine ((S)-Boc-MeAla-OH; cf.

route E) and the compounds of the general formula (VI) used is allyl isocyanate (cf.

route the processes can be represented by reaction scheme V below.

Scheme V OH Me M Me N Me Me N o o Me Me\, N N MMe Me Meo Me Me 0 Me I II Me Me O N Me Me OM Me r" Me e NMe o.

Me Me -M e Ij

E)

0 0N O Me OMe Me Me N N I Meo~ M Me MeO syn-/anti- isomer mixtures (S)-Boc-MeAla-OH, BOP, base

O=C=N-CH

2

-CH=CH

2 base The formula (Ic) provides a general definition of the cycloiminodepsipeptides required as starting materials for carrying out the process 2d a) and P) according to the invention.

In these formulae Y and R' to R' 2 preferably represent those radicals which have already been mentioned in connection with the description of the substances of the general formula according to the invention as being preferred for these substituents.

Le A 33 687-Foreign Countries -54- The formula provides a general definition of the compounds to be used as starting materials in particular for carrying out the process 2d a) according to the invention.

Z

II

G

In the formula Q1, RI6, and R 18 have the meaning which has already been mentioned in connection with the description of the substances of the general formula according to the invention for substituents.

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

Examples which may be mentioned are: Aad, Abu, yAbu, Abz, 2Abz, EAca, Acp, Adpd, Ahb, Aib, 3Aib, Ala, 3Ala, AAla, 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, Fel, 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, PLys, ALys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, APro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, 3Thi, Thr, Thy, Thx, Tia, Tie, Tly, Trp, Trta, Tyr, Val, Nal, Tbg, Npg, Chg, Thia for example, Houben- Weyl, Methoden der Organischen Chemie, Volume XV/1 and 2, Stuttgart, 1974).

Some of the compounds of the general formula can be obtained commercially or by methods known from the literature 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., Kontakte (Merck, Darmstadt) 3 (1987), p. 8).

Le A 33 687-Foreign Countries The reaction of the cycloiminodepsipeptides of the general formula (Ic) with amino acid derivatives of the formula is preferably carried out in the presence of coupling agents and in the presence of a basic reaction auxiliary using diluents.

Suitable coupling agents for carrying out process 2d a are all coupling agents which are suitable for forming an amide bond for example: Houben-Weyl, Methoden der organischen Chemie, 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)]. Preference is given to using the following methods: activated ester method using pentachloro- (Pcp) and pentafluorophenol (Pfp), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbonene-2,3dicarboxamide (HONB), I1-hydroxy-benzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4dihydro-1,2,3-benzotriazine as alcohol component, coupling with carbodiimides such as dicyclohexylcarbodiimide (DCCI) according to the DCC additive process, or using n-propanephos-phonic anhydride (PPA) and the mixed anhydride method using pivaloyl chloride, ethyl- (EEDQ) and isobutyl chloroformate (IIDQ) or coupling with phosphonium reagents, such as benzotriazol-1-yl-oxy-tris(dimethylamino-phosphonium) hexafluorophosphate (BOP), bis(2-oxo-3-oxazolidinyl)phosphonium acid chloride (BOP-CI), benzotriazol- 1 -yl-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOBO), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP") or using phosphonic acid ester reagents, such as diethyl cyanophosphonate (DEPC) and diphenylphosphoryl azide (DPPA) or uronium reagents, such as 2-(1Hbenzotriazol-1-yl)-1,1,3,3-tetra-methyluronium tetrafluoro-borate (TBTU), bornene-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 such as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

(HBTU).

Coupling with phosphonium reagents such as bis(2-oxo-3-oxazoli-dinyl)phosphonium acid chloride (BOP-CI), benzotriazol-1-yl-oxy-tris(dimethylaminophosphonium) hexafluorophosphate (BOP), benzotriazol-1-yl-tris-pyrrolidino-phos- Le A 33 687-Foreign Countries -56phonium hexafluorophosphate (Py BOB®), bromo-tris-pyrrolidino-phosphonium hexa-fluorophosphate (PyBroP®) and phosphonic acid ester reagents, such as diethyl cyanophosphonate (DEPC) or diphenylphosphoryl azide (DPPA) is preferred.

Suitable for use as basic reaction auxiliaries for carrying out the process 2d a) according to the invention are likewise all acid binders suitable for process 2a.

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

Suitable for use as diluents for carrying out the process 2d a) are the solvents mentioned under process 2a such as, for example, halogenated hydrocarbons, in particular chlorinated hydrocarbons, such as methylene chloride, chloroform or 1,2dichloroethane and mixtures of these with other solvents mentioned.

The process is generally carried out by reacting compounds of the general formula (Ic) in the presence of one of the basic reaction auxiliaries mentioned with compounds of the general formula in one of the solvents mentioned.

The reaction time is from 4 to 72 hours. The reaction is carried out at temperatures between -10 0 C and +120 0 C, preferably between -5°C and +50 0 C, particularly preferably at from 0°C to room temperature. The reaction is carried out under atmospheric pressure.

For carrying out the process 2d according to the invention, in general from 1.0 to mol, preferably from 1.0 to 1.5 mol, of coupling agent are employed per mole of compound of the formula (Ic).

Le A 33 687-Foreign Countries -57- The formula (VI) or (VII) provides a general definition of the compounds to be used as starting materials in particular for carrying out the process 2d B) according to the invention.

Z

II

G

In these formulae (VI) or (VII), Y and R 1 5 have the meaning which has already been mentioned in connection with the description of the substances of the general formula according to the invention as being preferred for substituents.

Some of the compounds of the general formulae (VI) or (VII) can be obtained commercially or by methods known from the literature for example, Houben- Weyl, Methoden der Organischen Chemie, Volume E 4).

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

Suitable diluents for carrying out the process 2d B) according to the invention are the solvents mentioned under process 2a such as, for example, halogenated hydrocarbons, in particular 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-butyl ether, diethyl ether, dipropyl ether, diisopropyl ether, tetrahydrofuran or dioxane, in particular tetrahydrofuran or dioxane, aliphatic or aromatic hydrocarbons such as nhexane, n-heptane, benzene, toluene or xylenes and mixtures of these with other diluents mentioned.

The process 2d B) can also be carried out in the presence of basic reaction auxiliaries.

Suitable as such basic reaction auxiliaries for carrying out the process 2e according to the invention are all acid binders mentioned further above, but preferably tertiary amines, in particular trialkylamines such as triethylamine, N,N- Le A 33 687-Foreign Countries -58diisopropylethylamine or N-methylmorpholine, and amidine bases or guanidine bases such as diazabicyclo(4.3.0)nonene (DBN), diazabicyclo(2.2.2)octane (DABCO), 1,8diazabicyclo(5.4.0)undecene (DBU), in particular 1,8-diazabicyclo(5.4.0)undecene

(DBU).

The process 2d B) is generally carried out by reacting compounds of the general formula (Ic) with compounds of the general formulae (VI) or (VII), if appropriate in the presence of one of the basic reaction auxiliaries mentioned in one of the diluents mentioned.

The reaction time is from 4 to 72 hours. The reaction is carried out at temperatures between -10 0 C and +180 0 C, preferably between -5 0 C and +120 0 C, particularly preferably at from 0°C to the boiling point of the diluent used. In principle, the reaction is carried out under atmospheric pressure; however, it can also be carried out under elevated or reduced pressure. It is preferably carried out at atmospheric pressure or at pressures of up to 15 bar.

For carrying out the process 2d 1) according to the invention, in general from 1.0 to mol, preferably from 1.0 to 1.5 mol, of compound of the general formulae (VI) or (VII) is used per mole of compound of the formula (Ic).

The invention furthermore relates to novel processes for preparing cycloiminodepsipeptides of the general formula (Ic).

The cycloiminodepsipeptides of the general formula (Ic) can either be prepared directly according to process 2a from the thiodepsipeptides of the general formula (Ib) and hydroxylamine as compound of the general formula (II) or can be obtained according to process 3 from suitable cycloiminodepsipeptides of the general formula (Ia).

Le A 33 687-Foreign Countries -59- If, for example, in process 3a the novel cycloiminodepsipeptide cyclo[-N-methyl-Lleucinyl-D-(benzyloxy-imino)-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl- L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) is used as compound of the general formula (Ia) (A -Y-R 13

-O-CH

2 -phenyl) is used for hydrogenation, the corresponding cycloiminodepsipeptide cyclo[-N-methyl-L-leucinyl-D-(hydroxyimino)-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-Nmethyl-L-leucinyl-D-phenyl-lactyl-) is formed (cf. Scheme VI, route G).

The formula (Ia) provides a general definition of the cycloiminodepsipeptides required as starting materials for carrying out the process 3a according to the invention. In these formulae A, R' to R 1 2 preferably represent those radicals which have already been mentioned in connection with the description of the substances of the general formula according to the invention as being preferred for these substituents.

The cycloiminodepsipeptides of the general formula (Ia) can be prepared according to process 2a mentioned further above from the thiodepsipeptides of the general formula (Ib) and compounds of the general formula (II) in which A represents a radical -Y-R 1 3 having a selectively removable O protective group R 13 for example benzyl-, benzyloxycarbonyl-. Allyl-, tert-butyloxycarbonyl-, tetrahydropyranylhydroxylamine.

Depending on the protective group R 13 in the compounds of the general formula (Ia) this group can either be selectively removed by hydrogenolysis in the presence of a suitable hydrogenation catalyst or by acidolysis in the presence of a protic acid.

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

Le A 33 687-Foreign Countries Scheme VI 13 R.0 Me e Me Me NMe O G Mee N 0 H, NNH Me oMe Me Me Me Me N 0 0 Me N N V'\'OMe M N"Me Me Me1MeO Me Me G: H 2 10% Pd(OH)-carbon, H/Me-OH (R' 3 -benzyl) H: H (R' 3 -THP) THP tetrahydropyranyl I: Pyridine-para-toluenesulfonic acid (R 13

-THP-CH

2

-O-CH

2

-C

6

H

4 -polymer) Suitable catalysts for carrying out the catalytic hydrogenation are all customary hydrogenation catalysts, such as, for example, platinum catalysts (platinum foil, 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, (for example reduced copper, Raney copper, Ullman copper etc.). However, preference is given to using noble metal catalysts, such as, for example, platinum and palladium or ruthenium catalysts, if appropriate on a suitable support, such as, for example, carbon or silicon.

Le A 33 687-Foreign Countries -61- For hydrogenating cycloiminodepsipeptides of the general formula the inert organic solvents mentioned under process 2a, such as, for example, alcohols, in particular methanol or ethanol, are used.

Acid reaction auxiliaries which may be mentioned are, for example, mineral acids.

The mineral acids preferably include hydrohalic acids such as hydrofluoric acid, hydrobromic acid, hydrochloric acid or hydroiodic acid, and also sulfuric acid, phosphoric acid, phosphorous acid and nitric acid.

According to the invention, for carrying 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 acid reaction auxiliary.

Preferred for use as hydrogenation catalysts are palladium catalysts, in particular palladium/ or palladium hydroxide/carbon.

Preferred for use as acid reaction auxiliary are mineral acids, in particular hydrohalic acids such as hydrochloric acid.

The reaction time is from 5 minutes to 20 hours. The hydrogenation is carried out at temperatures between -5 0 C and +100 0 C, preferably between 0°C and +30 0

C.

Alternatively, the cyclic hydroxy-iminodepsipeptides of the general formula (Ic) can also be obtained from cyclic allyloxyiminodepsipeptides of the general formula (Ia) -O-CH 2

-CH=CH

2 )by palladium(lI) acetate-catalyzed cleavage in the presence of triethylammonium formate and triphenylphosphine Yamada et al., Tetrahedron Lett. 28, 1987, p. 4557).

Of course, and according to the invention, the cycloiminodepsipeptides of the general formula (Ic) can also be formed by acid-catalyzed removal of a Le A 33 687-Foreign Countries -62tetrahydropyranyloxy radical -O-THP, cf. route H) or by removal of the anchor group R 13 from polymer-O-bonded cycloiminodepsipeptides of the general formula (Ia) (for example A A' Y-R 1 3 with selectively removable anchor group) (cf.

Scheme VI, route I).

If, for example, in process 3b for the selective removal, the polymer-bound cycloiminodepsipeptide cyclo[-N-methyl-L-leucinyl-D-(polymer-THP-oxy-imino)lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) is used as compound of the general formula (Ia) (A A' -Y-R' 3 with selectively removable anchor group), the corresponding cycloiminodepsipeptide cyclo[-N-methyl-L-leucinyl-D-(hydroxy-imino)-lactyl-Nmethyl-L-leu-cinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-Lleucinyl-D-phenyl-lactyl-) is formed (cf. Scheme VI, route I).

The formula (Ia) provides a general definition of the cycloiminodepsipeptides required as starting materials for carrying out the process 3b according to the invention.

In these formulae A and R' to R 1 2 preferably represent those radicals which have already been mentioned in connection with the description of the substances of the general formula according to the invention for these substituents.

The polymer-bound cycloiminodepsipeptides of the general formula (Ia) can be prepared according to process 2a mentioned further above from the cyclothiodepsipeptides of the general formula (Ib) and polymeric supports with selectively removable anchor group for A -Y-R 1 3 of the general formula (II) (cf. Schema VII).

Le A 33 687-Foreien Countries -63- Scheme VII SMe ,Me S eO- 0 NH Me N Me Me/NI i/ o 0 0,NH Me Me 0 MeV M Me Me Some of the polymeric carriers used as starting materials and having selectively removable anchor group for A -Y-R 1 3 of the general formula (II) are known from the literature for example, Syntheses of Hydroxamic acids: Mitsunobu reaction on Wang resin using N-hydroxyphthalimide: D. Floyd et al. Tetrahedron Lett. 37 1996, p. 8045; Reaction of trityl chloride resin with Nhydroxyphthalimide: U. Bauer et al. Tetrahedron Lett. 38 1997, p. 7233), or they can be obtained by methods known from the literature (cf. Synthesis of ketones: Reactions with DHP HM resin: 0. B. Wallace Tetrahedron Lett. 38 1997, p. 4939; Alcohol coupling: J. A. Ellmann et al. J. Org. Chem. 60, 1995, p. 7712; J. A.

Ellmann et al. Tetrahedron Lett. 35 p. 9333) (cf. Scheme VIII).

Le A 33 687-Foreign Countries -64- Scheme VIII DHP HM resin n (Novabiochem) 0 o o

O

O o O-NH2 For carrying out the process 3b according to the invention, preference is given to using the 6-(aminoxy)-3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene resin obtained according to Scheme VIII (cf. Preparation Examples).

The cyclic hydroxy-iminodepsipeptides formed in this manner are worked up in a customary manner, for example by chromatographic purification (cf. also Preparation Examples). However, they can also be reacted directly (without further purification) according to process 2b.

The iminodepsipeptides of the general formula obtainable by process 2 according to the invention can be present as syn- and anti- isomers; however, under the given reaction conditions for process 2, a mixture of the two isomeric forms is preferably formed.

The "inert solvents" referred to in process variants 2 above in each case refer to solvents which are inert under the respective reaction conditions but which do not have to be inert under any reaction conditions.

Le A 33 687-Foreign Countries The active compounds are suitable for controlling pathogenic endoparasites encountered in humans and in animal husbandry and livestock breeding, in productive livestock, breeding stock, zoo animals, laboratory animals, animals used in experiments, and pets, and have low toxicity toward warm-blooded animals. They are active against resistant and normally sensitive species and against all or some stages of development of the pests. By controlling the pathogenic endoparasites, it is intended to reduce disease, mortality and decreasing performance (for example in the production of meat, milk, wool, hides, eggs, honey, etc.), so that more economical and simpler animal husbandry is possible by using the active compounds. The pathogenic endoparasites include cestodes, trematodes and nematodes, in particular: From the order of the Pseudophyllidea, for example Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoorus spp.

From the order of the Cyclophyllidea, for example Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.

From the subclass of the Monogenea, for example Gyrodactylus spp., Dactylogyrus spp., Polystoma spp.

From the subclass of the Digenea, for example Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp., Paramphistomum spp., Calicophoron spp, Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis Le A 33 687-Foreign Countries 66 spp., Prosthogonismus spp., Dicrocoelium spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus SMp.

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

From the order of the Rhabditida, for example Micronema spp., Strongyloides spp.

From the order of the Strongylida, for example Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonemna spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomnum spp., Chabertia spp., Stephanurus spp., Ancylostomna spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parel aphostrongylus spp., Crenosoma spp., Paracrenosomna spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Ami dostomumn spp., Ollulanus spp., Cyclicocyclus 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 the 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., Parabronemna spp., Draschia spp., Dracunculus spp.

Le A 33 687-Foreign Countries -67- 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 Gigantorhynchida, for example Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.

The productive livestock and breeding stock include mammals, such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals, such as, for example, minks, chinchilla or raccoon, birds, such as, for example chickens, geese, turkeys or ducks, fresh and saltwater fish, such as, for example, trouts, carps, eels, reptiles, insects, such as, for example, honeybee and silkworm.

The laboratory and animals used in experiments include mice, rats, guinea pigs, golden hamsters, dogs and cats.

The pets include dogs and cats.

Administration can be effected prophylactically as well as therapeutically.

The active compounds are administered, either directly or in the form of suitable preparations, enterally, parenterally, dermally, nasally, by treating the habitat or with the aid of shaped articles containing the active compound, such as, for example, strips, plates, tapes, collars, ear tags, limb bands and marking devices.

Enteral administration of the active compounds is effected for example orally in the form of powders, suppositories, tablets, capsules, pastes, drinks, granules, drenches, boluses, medicated feed or drinking water. Dermal application is effected, for example, in the form of dipping, spraying, bathing, washing, pouring-on and spotting-on and Le A 33 687-Foreign Countries -68powdering. Parenteral administration is effected, for example, in the form of injection (intramuscular, subcutaneous, intravenous or intraperitoneal) or by implants.

Suitable preparations include: 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 administration and for injection; semisolid preparations; formulations in which the active compound is incorporated 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, shaped articles containing the active compound.

Solutions for injection are administered intravenously, intramuscularly and subcutaneously.

Solutions for injection are prepared by dissolving the active compound in a suitable solvent and, if desired, adding additives, such as solubilizers, acids, bases, buffer salts, antioxidants, or preservatives. The solutions are sterile-filtered and decanted into containers.

Suitable solvents include: physiologically acceptable solvents, such as water, alcohols, such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols and N-methylpyrrolidone, and their mixtures.

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

Suitable solubilizers include: solvents which facilitate the dissolution of the active compound in the main solvent or which prevent precipitation of the active compound.

Le A 33 687-Foreign Countries -69- Examples of solubilizers are polyvinylpyrrolidone, polyethoxylated castor oil and polyethoxylated sorbitan esters.

The following are preservatives: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic esters or n-butanol.

Oral solutions are administered directly. Concentrates are first diluted to the administration concentration and then administered orally. Oral solutions and concentrates are prepared as described above in the case of the solutions for injection, sterile procedures not being necessary.

Solutions for use on the skin are applied drop by drop, smoothed on, rubbed in, splashed on or sprayed on, or applied by dipping, bathing or washing. These solutions are prepared as described above in the case of the solutions for injection.

It may be advantageous to add thickeners in the preparation process.

The following are thickeners: inorganic thickeners, such as bentonites, colloidal silica, aluminium monostearate, or organic thickeners, such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

Gels are applied to the skin or smoothed on or introduced into body cavities. Gels are prepared by adding such an amount of thickener to solutions which have been prepared as described for the solutions for injection that a clear composition is formed which has an ointment-like consistency. The thickeners used are the thickeners indicated further above.

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

Le A 33 687-Foreign Countries Pour-on and spot-on formulations are prepared by dissolving, suspending or emulsifying the active compound in suitable solvents or solvent mixtures which are tolerated by the skin. If appropriate, other auxiliaries, such as colorants, bioabsorption promoters, antioxidants, photostabilizers or tackifiers are added.

Suitable solvents include: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols, such as benzyl alcohol, phenylethanol or phenoxyethanol, esters, such as ethyl acetate, butyl acetate or benzyl benzoate, ethers, such as alkylene glycol alkyl ethers, such as dipropylene glycol monomethyl ether or diethylene glycol monobutyl ether, ketones, such as acetone or methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, or 2,2-dimethyl-4-oxy-methylene-1,3dioxolane.

Colorants are all colorants which can be dissolved or suspended and which are approved for use in animals.

Examples of bioabsorption promoters are DMSO, spreading oils, such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides or fatty alcohols.

The following are antioxidants: sulfites or metabisulfites, such as potassium metabisulfite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or tocopherol.

Example of photostabilizers are substances from the class of the benzophenones or novantisolic acid.

Tackifiers are, for example, cellulose derivatives, starch derivatives, polyacrylates or natural polymers such as alginates or gelatin.

Emulsions can be administered orally, dermally or as injections.

Le A 33 687-Foreign Countries -71- Emulsions are either the water-in-oil type or the oil-in-water type.

They are prepared by dissolving the active compound either in the hydrophobic or in the hydrophilic phase and by homogenizing this phase with the solvent of the other phase, with the aid of suitable emulsifiers and, if appropriate, other auxiliaries, such as colorants, bioabsorption promoters, preservatives, antioxidants, photostabilizers, and viscosity-increasing substances.

Suitable hydrophobic phases (oils) include: paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil or castor oil, synthetic triglycerides, such as caprylic/capric acid biglyceride, a triglyceride mixture with vegetable fatty acid of chain length C8- 12 or other specifically selected natural fatty acids, mixtures of partial glycerides of saturated or unsaturated fatty acids which may also contain hydroxyl groups, and mono- and diglycerides of the C 8 /Clo-fatty acids.

Fatty acid esters, such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid having a medium chain length with saturated fatty alcohols of chain length C 16

-C

18 isopropyl myristate, isopropyl palmitate, caprylic/capric esters of saturated fatty alcohols of chain length C12-C 1 8 isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid esters such as artificial duck uropygial fat, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter, etc.

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

Fatty acids, such as, for example, oleic acid and its mixtures.

Suitable hydrophilic phases include: water, alcohols, such as, for example, propylene glycol, glycerol, sorbitol and their mixtures.

Le A 33 687-Foreign Countries -72- Suitable emulsifiers include: nonionic surfactants, for example polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate or alkylphenol polyglycol ethers; ampholytic surfactants, such as disodium N-lauryl-P-iminodipropionate or lecithin; anionic surfactants, such as sodium lauryl sulfate, fatty alcohol ether sulfates, and the monoethanolamine salt of mono/dialkylpolyglycol ether orthophosphoric ester; cationic surfactants such as cetyltrimethylammonium chloride.

Other suitable auxiliaries include: substances which increase the viscosity and stabilize the emulsion, such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, methylvinyl ether/maleic anhydride copolymers, polyethylene glycols, waxes, colloidal silica, or mixtures of the listed substances.

Suspensions can be administered orally, dermally or as an injection. They are prepared by suspending the active compound in a liquid excipient, if appropriate with the addition of other auxiliaries, such as wetting agents, colorants, bioabsorption promoters, preservatives, antioxidants, photostabilizers.

Suitable liquid excipients include all homogeneous solvents and solvent mixtures.

Suitable wetting agents (dispersants) include the surfactants indicated further above.

Other suitable auxiliaries include those indicated further above.

Semi-solid preparations can be administered orally or dermally. They are only distinguished from the above-described suspensions and emulsions by their higher viscosity.

To prepare solid preparations, the active compound is mixed with suitable excipients, if appropriate with the addition of auxiliaries, and the mixture is formulated as desired.

Le A 33 687-Foreign Countries -73- Suitable excipients include all physiologically acceptable solid inert substances. All those are inorganic and organic substances. Inorganic substances are, for example, common salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminium oxides, silicas, clays, precipitated or colloidal silica, and phosphates.

Organic substances are, for example, sugars, cellulose, foodstuffs and animal feeds, such as powdered milk, animal meals, cereal meals, coarse cereal meals and starches.

Auxiliaries are preservatives, antioxidants and colorants which have already been mentioned further above.

Other suitable auxiliaries are lubricants and glidants, such as, for example, magnesium stearate, stearic acid, talc, bentonites, disintegrants, such as starch or crosslinked polyvinylpyrrolidone, binders, such as, for example, starch, gelatin or linear polyvinylpyrrolidone, and dry binders, such as microcrystalline cellulose.

The active compound according to the invention can be present in its commercially available formulations and in the use forms, prepared from these formulations, as a mixture with other active compounds, such as insecticides, sterilizing agents, bactericides, acaricides, nematicides or fungicides. The insecticides include, for example, phosphoric acid esters, carbamates, carboxylates, chlorinated hydrocarbons, phenylureas, nicotinyles, neonicotinyles and substances produced by microorganisms, inter alia.

Particularly favourable examples of co-components in mixtures are the following compounds: Fungicides: aldimorph, ampropylfos, ampropylfos-potassium, andoprim, anilazine, azaconazole, azoxystrobin, Le A 33 687-Foreign Countries 74benalaxyl, benodanil, benomyl, benzamacri 1, benzamacril-i sobutyl, bialaphos, binapacryl, biphenyl, bitertanol, blasticidin-S, bromuconazole, bupirimate, buthiobate, calcium polysulfide, capsimycin, captafol, captan, carbendazim, carboxin, carvon, quinomethionate, chiobenthiazone, chiorfenazole, chioroneb, chioropicrin, chiorothalonil, chiozolinate, clozylacon, cufraneb, cymoxanil, cyproconazole, cyprodinil, cyprofuram, debacarb, dichiorophen, diclobutrazole, diclofluanid, diclomezine, dicloran, diethofencarb, difenoconazole, dimethirimol, dimethomorph, diniconazole, diniconazole-M, dinocap, diphenylamine, dipyrithione, ditalimfos, dithianon, dodemorph, dodine, drazoxolon, edifenphos, epoxiconazole, etaconazole, ethinimol, etridiazole, famoxadon, fenapanil, fenarimol, fenbuconazole, fenfuram, fenitropan, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, flumetover, fluoromide, fluquinconazole, flurprimidol, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, fosetyl-aluminium, fosetyl-sodium, fthalide, fuberidazole, furalaxyl, furametpyr, furcarboni I, furconazole, furconazole-ci s, furmecyclox, guazatine, hexachlorobenzene, hexaconazole, hymexazole, imazali 1, imibenconazole, iminoctadine, iminoctadine albesilate, iminoctadine triacetate, iodocarb, ipconazole, iprobenfos (IBP), iprodione, irumamycin, isoprothiolane, isovaledione, kasugamycin, kresoxim-methyl, copper preparations, such as: copper hydroxide, copper naphthenate, copper oxychioride, copper sulfate, copper oxide, oxine-copper and Bordeaux mixture, mancopper, mancozeb, maneb, meferimzone, mepanipyrim, mepronil, metalaxyl, metconazole, methasulfocarb, methfuroxam, metiram, metomeclam, metsulfovax, mildiomycin, myclobutanil, myclozolin, nickel dimethyldithiocarbamate, nitrothal-isopropyl, nuarimol, ofurace, oxadixyl, oxamocarb, oxolinic acid, oxycarboxim, oxyfenthiin, Le A 33 687-Foreign Countries paclobutrazole, pefurazoate, penconazole, pencycuron, phosdiphen, pimaricin, piperalin, polyoxin, polyoxorim, probenazole, prochloraz, procymnidone, propamocarb, propanosine-sodium, propiconazole, propineb, pyrazophos, pyrifenox, pyrimethanil, pyroquilon, pyroxyfur, quinconazole, quintozene (PCNB), sulfur and sulfur preparations, tebuconazole, tecloftalam, tecnazene, tetcyclacis, tetraconazole, thiabendazole, thicyofen, thifluzamide, thiophanate-methyl, thiram, tioxymid, toiclofos-methyl, tolyifluanid, tri adimefon, triadimenol, triazbutil, triazoxide, trichiamide, tricyclazole, tridemnorph, triflumizole, triforine, triticonazole, uniconazole, validamycin A, vinclozolin, viniconazole, zarilamide, zineb, ziram and also Dagger G, OK-8705, OK-880i, a-(I 1, -dimethylethyl)-f3-(2-phenoxyethyl)- 11H-i ,2,4-triazole- 1 -ethanol, c-(2,4-dichlorophenyl)-13-fluoro-b-propyl- 1 H-i ,2,4-triazole- 1 -ethanol, ax-(2,4-dichlorophenyl)-13-methoxy-a-methyl- 1H-1I,2,4-triazole- 1 -ethanol, ca-(5-methyl- 1,3-dioxan-5-yl)-3-[ [4-(trifluoromethyl)-phenyl]-methylene] -1H- 1,2,4triazole- 1 -ethanol, ,6RS)-6-hydroxy-2,2,7,7-tetramethyl-5-( 1H-i ,2,4-triazol- 1 -yl)-3-octanone, (E)-a-(methoxyimino)-N-methyl-2-phenoxy-phenylacetamide, isopropyl 2-methyl- I [I1 -(4-methylphenyl)-ethyl ]-amino] -carbonyl]I -propyl 1 carbamnate, 1 -(2,4-dichlorophenyl)-2-( 1H- 1,2,4-triazol- 1 -yl)-ethanone-O-(phenylmethyl)-oxime, 1 -(2-methyl-i -naphthalenyl)- 1H-pyrrole-2,5-dione, 1 -(3,5-dichlorophenyl)-3-(2-propenyl)-2,5-pyrrolidinedione, 1 [(di iodometh yl)-sulfonyl] -4-methyl -benzene, 1 [2-(2,4-dich lorophenyl)-1I,3-dioxolan-2-yl]-methyl]- 1H-imidazole, 1- [[2-(4-chlorophenyl)-3-phenyloxiranyl]-methyl]- 1H-i ,2,4-triazole, Le A 33 687-Foreign Countries 76 1-[i -[2-[(2,4-dichlorophenyl)-methoxyl-phenyl] -ethenyl]- 1H-imidazole, 1 -methyl-5-nonyl-2-(phenylmethyl)-3-pyrrolidinol, 2',6'-dibromo-2-methyl-4'-trifluoromethoxy-4'-trifluoro-methyl- 1,3-thiazole-5carboxanilide, 2,2-dichloro-N- [1 -(4-chlorophenyl)-ethyl]-I1 -ethyl -3-methyl cyclopropanecarboxamide, 2,6-dichloro-5-(methylthio)-4-pyrimidinyl-thiocyanate, 2,6-dichloro-N-(4-trifluoromethylbenzyl)-benzamide, 2,6-dichloro-N-[ [4-(trifluoromethyl)-phenyl]-methyl] -benzamide, 2-(2,3 ,3-triiodo-2-propenyl)-2H-tetrazole, 1-methylethyl)-sulfonyl]-5-(trichloromethyl)- 1,3,4-thiadiazole, 2- [6-deoxy-4-O-(4-O-methyl -f-D-glycopyranosyl)-a-D-glucopyranosyl ]-amino] -4methoxy- 1H-pyrrolo[2,3-d]pyrimidine-5-carbonitile, 2-aminobutane, 2-bromo-2-(bromomethyl)-pentanedinitrile, 2-chloro-N-(2,3-dihydro- 1,1 ,3-trimethyl- 1H-inden-4-yI)-3-pyridinecarboxamide, 2-chloro-N-(2,6-dimethylphenyl)-N-(isothiocyanatomethyl)-acetamide, 2-phenyiphenol (OPP), 3 ,4-dichloro- 1 [4-(difluoromethoxy)-phenyl -1 H-pyrrole-2,5-di one, 3,5-dichloro-N-[cyano- -methyl-2-propynyl)-oxy]-methyl]-benzamide, 1,1-dimethylpropyl)-l1-oxo- 1H-indene-2-carbonitri le, 3- [2-(4-chlorophenyl)-5-ethoxy-3-i sox azoli dinyl] -pyri dine, 4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)- 1H-imidazole- 1-sulfonamide, 4-methyl-tetrazolo[ 1,5-a]quinazolin-5(4H)-one, 1,1-dimethylethyl)-N-ethyl-N-propyl- 1,4-dioxaspiro [4.5]decane-2-methanamine, 8-hydroxyquinoline sulfate, 9H-xanthene-2- [(phenylamino)-carbonyl] -9-carboxylic hydrazide, bi 1 -methylethyl)-3-methyl-4- -methylbenzoyl)-oxy] -2,5-thi ophenedicarboxyl ate, ci s-i -(4-chlorophenyl)-2-( 1H-i ,2,4-triazol- 1 -yl)-cycloheptanol, cis-4-f 3- 1,1-d'imethylpropyl)-phenyl-2-methylpropyl]-2,6-dimethyl-morpholine hydrochlofide, Le A 33 687-Foreig-n Countries 77 ethyl [(4-chlorophenyl)-azol-cyanoacetate, potassium hydrogen carbonate, methanetetrathiol sodium salt, methyl 1 -(2,3-di hydro-2,2-di methyl- 1 H-inden- I1-yl)-lI H-imi dazole-5 -carboxyl ate, N-(2,6-dimethylphenyl)-N-(5-i sox azolylcarbonyl)-DL-al anin ate, methyl N-(chloroacetyl)-N-(2,6-dimethylphenyl)-DL-alaninate, N-(2,3-dichloro-4-hydroxyphenyl)-l1-methyl-cyclohexanecarboxamide, 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-tichloro- 1 [(ch loroacetyl)-ami no] -ethyl -benzami de, N-[3-chloro-4,5-bis-(2-propinyloxy)-phenyl]-N'-methoxy-methanilmidamide, N-formyl-N-hydroxy-DL-alanine sodium salt, 0,0-diethyl [2-(dipropylamino)-2-oxoethyl]-ethylphosphoramidothioate, 0-methyl S-phenyl phenylpropylphosphoramidothioate, S-methyl 1 ,2,3-benzothi adiazole-7-carbothioate, spiro[2H]- 1-benzopyrane-2, 1'(3YH)-isobenzofuran]-3'-one.

Bactericides: bronopol, dichlorophen, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone, furancarboxylic acid, oxytetracyclin, probenazole, streptomycin, tecloftalam, copper sulfate and other copper preparations, quinoloes, such as ciprofloxacin, danofloxacin, difloxacin, enrofloxacin, flumequine, ibafloxacin, marbofloxacin, norfioxacin, ofloxacin, orbifloxacin, premafloxacin, sarafloxacin.

Le A 33 687-Foreign Countries 78 Insecticides acaricides nematicides: abamectin, acephate, acetamiprid, acrinathrin, alanycarb, aldicarb, aldoxycarb, alphacypermethrin, alphamethrin, amitraz, avermectin, AZ 60541, azadirachtin, azamethiphos, azinphos A, azinphos M, azocyclotin, Bacillus popilliae, Bacillus sphaericus, Bacillus subtilis, Bacillus thuringiensis, Baculoviruses, Beauvenia bassiana, Beauveria tenella, bendiocarb, benfuracarb, bensultap, benzoximate, betacyfluthrin, bifenazate, bifenthrin, bioethanomethrin, biopermethrin, BPMC, bromophos A, bufencarb, buprofezin, butathiofos, butocarboxim, butylpyridaben, cadusafos, carbaryl, carbofuran, carbophenothion, carbosulfan, cartap, chloethocarb, chiorethoxyfos, chloffenapyr, chlorfenvinphos, chlorfluazuron, chiormnephos, chiorpyrifos, chlorpyrifos M, chlovaporthrin, cis-resmethrin, cispermethrin, clocythrin, cloethocarb, clofentezine, clothianidine, coumafos, cyanophos, cycloprene, cycloprothrin, cyfluthrin, cyhalothrin, cyhexatin, cypermethrin, cyromazine, cythioate, chiorothianidin, deltamethrin, demeton M, demeton S, demeton-S-methyl, diafenthiuron, diazinon, dichlorvos, dicyclanil, diflubenzuron, dimethoate, dimethylvinphos, diofenolan, di sulfoton, docusat-sodium, dofenapyn, dinotefuran, eflusi lanate, emamectin, empenthrin, endosulfan, eprinomectin, esfenvalerate, ethiofencarb, ethion, ethiprole, ethoprophos, etofenprox, etoxazole, etrimfos, fenamiphos, fenazaquin, fenbutatin oxide, feni trothion, fenothiocarb, fenoxacrim, fenoxycarb, fenpropathrin, fenpyrad, fenpyrithrin, fenpyroximate, fenthion, fenvalerate, fipronil, fluazinam, fluazuron, flubrocythrinate, flucycloxuron, flucythrinate, flufenoxuron, flumethrin, flutenzine, fluvalinate, fonophos, fosmethilan, fosthiazate, fubfenprox, furathiocarb, flupyrazofos, granulosis viruses, halofenozide, HCH, heptenophos, hexaflumuron, hexythiazox, hydroprene, imidacloprid, indoxacarb, i sazofos, isofenphos, i soxathion, ivermnectin, nuclear polyhedrosis viruses, lambda-cyhalothrin, lufenuron, Le A 33 687-Foreign Countries 79 malathion, mecarbam, metaldehyde, methamidophos, metharhi zium anisopliae, metharhiziurn flavoviride, methidathion, rnethiocarb, methomyl, methoprene, methoxyfenozide, metolcarb, metoxadiazone, metrifonat, mevinphos, milbemnectin, monocrotophos, moxidectin, naled, nitenpyram, nithiazine, novaluron, NEEM, omnethoate, oxamyl, oxydemethon M, Paecilomyces fumnosoroseus, parathion A, parathion M, permethrin, phenthoate, phorate, phosalone, phosmet, phosphamidon, phoxirn, pirimicarb, pirimiphos A, pirimiphos M, profenofos, promecarb, propoxur, prothiofos, prothoate, pymnetrozine, pyraclofos, pyresmethrin, pyrethrum, pyridaben, pyridathion, pyrimidifen, pyriproxyfen, protrifenbute, quinaiphos, ribavirin, salithion, sebufos, selamnectin, si lafluofen, spinosad, spirodiclofen, sulfotep, sulprofos, S 1812, tau-fluvalinate, tebufenozide, tebufenpyrad, tebupirimiphos, tefi ubenzuron, tefluthrin, temephos, temnivinphos, terbufos, tetrachlorvinphos, thetacypermethrin, thiamethoxarn, thiapronil, thiatriphos, thiocyclamn hydrogen oxalate, thiodicarb, thiofanox, thuringiensin, tralocythrin, tralomethrin, triarathene, triazamnate, triazophos, triazurone, trichiopheni dine, trichiorfon, triflumuron, trimethacarb, thiacloprid, vamidothion, vaniliprole, Verticillium lecanii, YI 5302, zeta-cypermethrin, zolaprofos, (1 R-ci s)-[5-(phenylmethyl)-3-furanyl]-methy-3- [(dihydro-2-oxo-3(2H)-furanyli dene)-methyl]J-2,2-dimethylcycl opropanecarboxyl ate, (3-phenoxyphenyl )-methyl 2,2,3 ,3-tetramethylcyclopropanecarboxyl ate, 1 -[(2-chloro-5-thiazolyl)methyljtetrahydro-3 ,5-dimethyl-N-nitro- 1,3 2(IH)-imine, 2-(2-chloro-6-fluorophenyl)-4- 1,1-dimethylethyl)phenyl]-4,5-dihydro-oxazole, 2-(acetyl ox y)-3 -dodecyl 1 ,4-naphthal enedi one, Le A 33 687-Foreign Countries 2-chloro-N- 1 -phenylethoxy)-phenyl -amino] -carbonyl ]-benzami de, 2-ch loro-N- [4-(2,2-dichlIoro- 1, 1 -difluoroethox y)-phenyl]I-amino] -carbonylbenzamnide, 3-methyiphenyl propylcarbamate, 4-[4-(4-ethoxyphenyl)-4-methylpentyl]-l1-fluoro-2-phenoxy-benzene, 4-chloro-2-( 1,1-dimethylethyl)-5- [[2-(2,6-dimethyl-4-phenoxyphenoxy)ethyl]thio]- 3 (2H)-pyridazi none, 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, [2-benzoyl-l1-(1,1 -dimethylethyl)-hydrazinobenzoic acid, 2,2-dimethyl-3-(2,4-dichlorophenyl)-2-oxo-l1-oxaspiro[4.5]dec-3-en-4-yl butanoate, [3 -[(6-chloro-3 -pyri dinyl)methyl ]-2-thi azoli din yl idenej -cyanamide, dihydro-2-(nitromethylene)-2H- I ,3-thiazine-3(4H)-carboxaldehyde, ethyl [1 ,6-dihydro-6-oxo-lI-(phenylmethyl)-4-pyridazinylloxylethyl] -carbamate, N-(3 ,4,4-trifluoro-lI-oxo-3-butenyl)-glycine, N-(4-chlorophenyl)-3- [4-(difluoromethoxy)phenyl]-4,5-dihydro-4-phenyl- 1Hpyrazole-l1-carboxamide, N- [(2-chl oro-5-thi azol yl)methyl ]-N'-methyl -N"-ni tro-guani dine, 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 formulations, as a mixture with synergistic agents. Synergistic agents are compounds which increase the action of the active compounds, without it being necessary for the synergistic agent added to be active itself.

Le A 33 687-Foreign Countries -81- Ready-to-use preparations comprise the active compound in concentrations of from ppm to 20% by weight, preferably from 0.1 to 10% by weight.

Preparations which are diluted prior to use comprise the active compound in concentrations of from 0.5 to 90% by weight, preferably from 5 to 50% by weight.

In general, it has been found to be advantageous to administer amounts of from about 1 to 100 mg of active compound per kilogram of body weight per day to obtain effective results.

Le A 33 687-Foreign Countries -82- Preparation 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-] H NMe Me O Me 0

N

Me NMe

NM

0 0 O Me Me NO Me O Me Me Me a) according to process 2a using mercury(II) acetate 200.0 mg (0.20 mmol) of cyclo(-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-Lleucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-Dphenyllactyl-) (cf. WO 98/43 965) in 5 ml of acetonitrile are treated successively 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 ("Hiinig's Base"), and the mixture is stirred at room temperature for 18 hours. To bring the reaction to completion, 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 ("Htinig's Base") are added, and the mixture is stirred at room temperature for another 6 hours. The entire reaction mixture is then stirred into about 20 ml of aqueous NH 4 CI solution and extracted four times with ml of chloroform. The crude product that remains is chromatographed over a Le A 33 687-Foreign Countries 83 silica gel column (silica gel 60 Merck, particle size: 0.04 to 0.063 mm) using the mobile phase cyclohexane acetone (4 :1I).

This gives 70.4 mg (35% of theory) of cyclo[-N-methyl-L-leucinyl-D-(hydroxyimino)-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-Nmethyl-L-Ieucinyl-D-phenyllactyl-I as anti -/syn -isomer mixture.

b) according to process 2a using mercury(][[) chloride mercury(ll) acetate The reaction with hydroxylamine hydrochloride is carried out similarly to the reaction procedure of Example 1 (Variant a) using: 500.0 mg (0.52 mmol) 107.9 mg (1.55 mmol) 422.0 mg (1.55 mmol) 230.2 mg (1.81 mmol) ml of cyclo(-N-methyl-L-leucinyl-D-thiolactyl-N-methyl- L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-Dlactyl-N-methyl-L-leucinyl-D-phenyllactyl-) of hydroxylamine hydrochloride of mercury(ll) chloride of ethyldiisopropylamine ("HUnig' s Base") of tetrahydrofuran After 20 hours of stirring at 50'C, another 180.0 mg (0.56 mmol) of mercury(ll) acetate are added, and stirring is continued at 50'C for another 24 hours. The entire reaction mixture is then filtered and worked up as under Example 1 (Variante a).

Yield: 250 mg (50% of theory) b) according to process 3a by hydrogenation of derivative 17 400.0 mg (0.37 mmol) of cyclo[-N-methyl-L-leucinyl-D-(benzyloxyimino)-lactyl-Nmethyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl -D-lactyl-N-methyl-Lleucinyl-D-phenyllactyl-] 17 (cf. Table 1) are stirred in 40 ml] of methanol and, in the Le A 33 687-Foreign Countries -84presence of 200 mg of Pd/carbon [palladium content 10%] and 0.7 ml of conc.

hydrochloric acid, hydrogenated at room temperature until hydrogen uptake has ended (about 20 minutes). The catalyst is filtered off and the entire reaction solution is then concentrated under reduced pressure and the crude product that remains is chromatographed over an RP-18 column using the mobile phase acetonitrile water.

Yield: 110 mg (30% of theory) c) according to process 3b by deblocking from a polymeric resin support A mixture of 100 mg cyclodepsipeptide-containing polystyrene resin, 3.0 ml of nbutanol and 3.0 ml of 1,2-dichloroethane is treated with 8.5 mg of pyridine-paratoluenesulfonic acid and stirred at 60 0 C for one hour. The polystyrene resin is then filtered off and washed five times with methylene chloride. Concentration under reduced pressure gives 9.4 mg of crude product in which Example 1 could be demonstrated by APCI-MS.

LC-MS (acidic) m/z 964 100). C 52

H

77

N

5 0 1 2 (964.2) Rt value (HPLC column: 125 x 2.1 Kromasil 0, C-18): 17.54; 17.66 min; anti-/synisomer mixture (20:80).

Le A 33 687-Foreign Countries 85 Example 2 Cyclo[-N-methyl-L-leucinyl-D-(O-methyl-imino)-lactyl-Nmethyl.L..leucinyl.D.

phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl.N..methyluL-euciny1..D.phenylacyl-j Me, M Me Me Me N\M ,N0 Me Me Me 0 0 ~N Me Me ,Me 0 MeM Me Me 0M The reaction with an 0-substituted amine component was carried out similarly to the reaction procedure of Example 1 using: 200.0 mg (0.20 mmol) 52.4 mg (0.62 mmol) 145.0 mg (0.45 mmol) 162.2 mg (1.25 mmol) ml of (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-Lleucinyl-D-phenyllactyl-N-methyl-L-]eucinyl-D-lactyl- N-methyl-L-leucinyl-D-phenyllactyl-) of 0-methyl-hydroxylamine hydrochloride of mercury(ll) acetate of ethyldiisopropylamine ("Hiinig' s Base") of acetonitrile The crude product that remains is chromatographed over a silica gel columne (silica gel 60 Merck, particle size: 0.04 to 0.063 mm), initially using the mobile phase cyclohexane acetone 4 This gives 170 mng (83% of theory) of cyclo[-Nmethyl-L-leucinyl-D-(0-methylimino)lactylNmethylLleucinyl-D-phenyllatyl N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-Dphenyljactyl-j.

Le A 33 687-Foreign Countries 86 'H-NMR (600 MHz, CDCI 3 2.85; 2.87; 2.90; 3.04 (4 x N-Cfi 3 3.65 (-O-CH 3 oxime) ppm.

3 C-NMR (100 M]Hz, CDCI 3 29.3; 30.2; 30.9; 31.0 (4 x N-Cl! 3 61.3 (-O-CH 3 oxime); 66.9; 68.1; 69.7; 71.1; (4 x 56.9; 53.9; 53.9; 59.5 (4 x -HN) 170.3; 170.3; 172.5; (3 x 152.9 (1 x oxime); 170.2; 170.7; 17 1. 1; 172.5 (4 x ppm.

LC-MS (acidic) m/z 978 100). C 53

H

79

N

5 0 12 (978.2) Rt value (HPLC column: 125 x 2.1 Kromasil C- 18): 18.34 min Le A 33 687-Foreign Countries 87 Example 3 Cyclo[-N-methyl-L-leucinyl-D-(O-acetyl-imino)-Iactyl-N-methyl-L-leucinyl-D.

phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-Dphenyllaciyl-] 0 MA 0 e0Me TMe Me Me loll Me: M Li- 0 0 Me meMe 0 Me Me Me 200.0 mg (0.20 mmol) of 1 (see Ex. 1) are treated in I ml of acetic anhydride and stirred at 70'C for about 30 minutes. The entire reaction mixture is then treated with saturated NaHCO 3 solution and extracted three times with 15 ml of ethyl acetate. The organic phase is separated off, dried over magnesium sulfate and concentrated under reduced pressure. The crude product that remains is chromatographed over a silica gel columne (silica gel 60 Merck, particle size: 0.04 to 0.063 mm) using the mobile phase cyclohexane acetone (10 This gives 125.8 mg (60% of theory) of crude product whi ch, after preparati ve HPLC (RP- 18), gi ves 80 mng (38 of theory) of pure cyclo[-N-methyl-L-leucinyl-D-(O-acetyl-i mino)-lactyl-N-methyl-L-leucinyl-Dphenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-pheny...actyl-] as anti/syn isomer mixture (purity: 98.7%).

LC-MS (acidic) mlz 1006 100). C5 4

H

79 N5O, 3 (1006.2) Rt- value (HPLC column: 125 x 2.1 Kromasil 0, C-18): 7.35 min Le A 33 687-Foreign Countries -88- Example 4 Cyclo[-N-methyl-L-leucinyl-D-(O-vinyloxycarbonyl-imino)-lactyl-N-methyl-Lleucinyl-D-phenyllacltyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-Dphenyllactyl-] 0 O O MeMe 0 Me Me Me Me N M

N

0 0

\OO

S Me Me Me At 0 0 C, 300.0 mg (0.31 mmol) of 1 (see Ex. 1) are stirred in 10 ml of dry pyridine and treated with 99.4 mg (0.93 mmol) of vinyl chloroformate. Stirring at OoC is then continued for another 6 hours. The entire reaction mixture is then concentrated under reduced pressure and the residue is taken up in chloroform and washed once with IN HCI and twice with NaHCO 3 solution. The organic phase is separated off and dried over magnesium sulfate and then concentrated under reduced pressure, and the crude product that remains is chromatographed over a silica gel column (silica gel Merck, particle size: 0.04 to 0.063 mm) using the mobile phase cyclohexane ethyl acetate (2 This gives 188.7 mg (58.7% of theory) of cyclo[-N-methyl-L-leucinyl- D-(O-vinyloxycarbonyl-imino)-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl- L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] as anti/syn isomer mixture.

LC-MS (acidic) m/z 1037 (MH, 100) C 55

H

81

N

5 0 1 4 (1036.2) Rt value (HPLC column: 125 x 2.1 Kromasil 0, C-18): 17.82 min Le A 33 687-Foreign Countries 89 Example Cyclo[-N-methyl-L-leucinyl-D-(O-methylsulfonyl-imino)-lactyl-N-methyl-L-leucinyl D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-Dphenyllactylj] The reaction with methanesulfonyl chloride is carried out similarly to the reaction procedure of Example 4 using: 200.0 mg (0.20 mmol) of cyclo[-N-methyl-L-leucinyl-D-(hydroxy-imino)-lactyl-Nmethyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-Nmethyl-L leucinyl-D-phenyllactyl-] (Ex. 1) 71.3 mg (0.62 mmol) 8 ml of methanesulfonyl chloride of dry pyridine The crude product that remains is chromatographed over a silica gel column (silica gel 60 Merck, particle size: 0.04 to 0.063 mm) initially using the mobile phase cyclohexane ethyl acetate (3 This gives 81.8 mg (38% of theory) of cyclo[-Nmethyl-L-leucinyl-D-(O-methylsulfonyl-imino)-l actyl-N-methyl-L-leucinyl-DphnlatlNmty--ecnlDlcylNmty--ecnlDpeylcy- as anti/syn isomer mixture.

Le A 33 687-Foreigzn Countries 90 LC-MS (acidic) m/z 1042 100). C 53

H

79

N

5 0 14 S (1042.3) Rt value (HPLC column: 125 x 2.1 Kromasil 0, C- 18): 17.18 min Le A 33 687-Foreign Countries -91- Example 6 Cyclo[-N-methyl-L-leucinyl-D-(O-allylaminocarbonyl-imino)-lacyl-N-methyl-Lleucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lacyl-N-methyl-L-leucinyl-Dphenyllactyl-] 0 N' 10 Me 0Me Y Me I ?,i Me N Me Me N \NMe 0y o Me Me Me 300.0 mg (0.31 mmol) of cyclo[-N-methyl-L-leucinyl-D-(hydroxy-imino)-lactyl-Nmethyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-Lleucinyl-D-phenyl-lactyl-] (Ex. 1) in 10 ml of abs. toluene are treated successively with 30.4 mg (0.36 mmol) of allyl isocyanate and 2 drops of 1,8diazabicyclo[5.4.0]undec-7-ene and stirred at room temperature for 33 hours. The entire reaction mixture is then concentrated under reduced pressure. The crude product which remains is initially chromatographed 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) and then over 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: This gives 52.4 mg (16.1% of theory) of cyclo[-N-methyl-Lleucinyl-D-(O-allylaminocarbonyl-imino)-lactyl-N-methyl-L-leucinyl-Dphenyllactyl-N-methyl-L-leucinyl-D-lactyl -N-methyl-L-leucinyl-D-phenyllactyl- as anti/syn isomer mixture.

LC-MS (acidic) m/z 1047 100). C 56

H

82

N

6 0 13 (1047.3) R, value (HPLC column: 125 x 2.1 Kromasil D, C-is, pH 17.09; 17.39 min Le A 33 687-Foreign Countries 92 Example 7 Cyclo[-N-methyl-L-leucinyl-D-(O-N-tert-butyloxycarbonyl-N-methyl-alanyl-imino)lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-Lleucinyl-D-phenyllactyl-] Me 0 Me I Me*ON O Me Me M Me Me Me 7 N Me Me'

N;I:,

0 0 N M M\NU Me XMe Me Me At 0 0 C, 184.0 mg (4.1 mmol) of benzotriazol-1-yl-oxy-tris(dimethylaminophosphonium) hexafluorophosphate (BOP) and 124.0 mg (0.95 mmol) N,Ndiisopropylethylamine ("Hilnigs Base") are added to a solution of 300.0 mg (0.31 mmol) of cyclo[-N-methyl-L-leucinyl-D-(hydroxy-imino)-lactyl-N-methyl-Lleucinyl-D-phenyl-Iactyl-N-methyl-L-leucinyl-D-lactyl-N-me-thyl-L-Ieucinyl-Dphenyl-lactyl-] and 75.7 mg (0.37 mmol) of N-tert-butyloxy-carbonyl-Nmethyl-alanine in 10 ml of abs. acetonitrile, and the mixture is stirred at 0 0 C for minutes and then at room temperature for 24 hours. The entire reaction mixture is then concentrated under reduced pressure, the residue is taken up in chloroform and extracted twice with water and the organic phase is separated off, dried over sodium sulfate and then concentrated under reduced pressure. The crude product that remains is purified by preparative IHPLC. This gives 15.6 mg of theory) of cyclo[-Nmethyl-L-leucinyl-D-(O-N-tert-butyloxycar-bonyl-N-methyl-alanyl-imino)-lactyl-Nmethyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-Lleucinyl-D-phenyllactyl-] as anti/syn isomer mixture.

Le A 33 687-Foreign Countries 93 LC-MS (acidic) m/z 1150 (M1H, 100). C 61

H

92

N

6 0 15 (1149.4) R, value (HPLC column: 125 x 2.1 Kromasil 0, C- 18): 7.69; 7.76 min The compounds of the formula (1a)(R1, R 3 ,R 4,R7, R,R1 R 2, R5, R8,R: iso-butyl; X2: X 2

-X

4 listed in Table I below can be prepared analogously.

Le A 33 687-Foreign Countries -94- Table 1 Me Me A Me 0 'r N 0o Me, N N 0e" Me 0 \Me Me o 0 Me Me\ r 0 NR "d /Me 0 Me Me Me Ex. -A R' R" Physical data a) No.

993 100); Rt: 20.05 8 -O-CH 2 -Me -H -H

C

4

H

8 ]N501 2 (992.2) 1005 (MH 100); 20.2 1; 9 -O-CH 2

-CH=CH

2 -H -H 20.31 (anti/syn isomer mixture)

C

55

H

81

N

5 01 2 (1048.3) 1006 100); Rt: 13.75

-O-CH

2

-CH

2 -Me -H -H

CSSH

83 NS01 2 (1006.3) 1006 (MH, 100); Rt: 13.54 11 -O-CHMe 2 -H -H

C

55

H

83

N

5 0 12 (1006.3) Le A 33 687-Foreign Countries 95 Table 1 (Continued) Ex. -A R' R" Physical Data'a) No.

1006 (MH, 100); 22.52; 12 -O-CMe 3 -H -H 22.85 (anti/syn isomer mixture)

C

56

H

85

N

5 01 2 (1006.3) 1003 100); RI: 7.49 13 -O-CH 2 -CN -H -H

C

54

H

78

N

6 01 2 (1003.2) 1008 100); Rt: 17.58 14 -O-CH 2

-CH

2 -OH -H -H

C

54

H

81

N

5 0 13 (1008.2) 1008 100)

-O-CH

2

-CH

2

-NH

2 -H -H

C

54

H

82

N

6 0 12 (1007.3) 978 (IvIH', 100); Rt: 18.33 16 -NHMe -H -H Cs 3

H

8 oN 6 Oii (977.2) 1055 100); 21.23; 17 -O-CH 2 -phenyl -H -H 21.50 (anti/syn isomer mixture)

C

59

H

83

N

5 0 12 (1054.3) 1100 100); 20.50 18 -O-CH 2 -(4-N0 2 -phenyl) -H -H I I I I C- 59

H

82

N

6 0 14 (1099.3) Le A 33 687-Foreign Countries 96 Table 1 (Continued) Ex. -A R' R" Physical Data a) No.

1099 (Me, 100); Rt: 19.06 19 -O-CH 2 -(2-N0 2 -phenyl) -H -H

C.

59

H

82

N

6 0, 4 (1099.3) 1123 (MHi, 100);

-O-CH

2 -(3-CF 3 -phenyl) -H -H Rt: 19.50; 19.68 (anti/syn isomer mixture)

C

60

H

82

N

5 01 2 (1122.3) 21 -O-CH 2 -(4-CF 3 -phenyl) -H -H

C

60

H

82

N

5 0 12 (1122.3) 1088 (MHl 4 100) 22 -O-CH 2 -(2-CI-phenyl) -H -H Rt: 19.65; 20.07 (anti/syn isomer mixture)

C

59

H

82 C1N 5 0 12 (1088.7) 1088 100) 23 -O-CH 2 -(3-CI-phenyl) -H -H 19.61; 19.78

C

59

H

82 C1N 5 0 12 (1088.7) 1088 (MHl 4 100); 24 -O-CH 2 -(4-CI-phenyl) -H -H Rt: 19.65; 19.82 (anti/syn isomer mixture)

C

59

H

82 C1N 5 01 2 (1088.7) 1124 (MLH+, 100);

-O-CH

2 -(3,4-C1 2 -phenyl) -H -H Rt: 20.14; 20.40 (anti/syn isomer mixture) 9

H

8 j1l 2 N501 2 (1123.2) Le A 33 687-Foreign Countries 97 Table 1 (Continued) Ex. -A R' R" Physical Data a) No.

1124 (MIH', 100); 26 -O-CH 2 -(2,6-C1 2 -phenyl) -H -H Rt: 19.82; 20.12 (anti/syn isomer mixture)

C

59

H

81 C1 2

N

5 01 2 (1123.2) 1124 100); 27 -O-CH 2 -(2,4-C1 2 -phenyl) -H -H 20.68; 21.16 (anti/syn isomer mixture) Cs9H8sC2N5012 (1123.2) 1124 100); 28 -O-CH 2 -(2,3-C1 2 -phenyl) -H -H 20.32, 20.79 (anti/syn isomer mixture)

C-

59

H

81 C1 2

N

5 01 2 (1123.2) 1106 100); 29 -O-CH 2 -(2-CI,6-F-phenyl) -H -H 19.24; 19.44 (anti/syn isomer mixture)

C

59

H

8 ClFN 5

O,

2 (1106.8) 1084 (MIW, 100); Rt: 18.97

-O-CH

2 -(4-MeO-phenyl) -H1 -H

C

60

H

85

N

5 01 3 (1084.3) 1112 (MIH, 100); Rt: 18.89 31 -O-CH 2 -(4-MeOOC-phenyl) -H -H

C

6 0

H

85

N

5 013 (1112.3) 1072 100); Rt: 19.48 32 -O-CH 2 -(4-F-phenyl) -H -H

C

59

H

82

FN

5 012 (1072.3) Le A 33 687-Foreign Countries 98 Table 1 (Continued) Ex. -A R' R" Physical Data a) No.

1068 100); Rt: 19.95 33 -O-CH 2 -(4-Me-phenyl) -H -H

C

60

H

85

N

5 0 12 (1068.3) 964 (MW, 100); Rt: 16.24 34 -NH 2 -H -H

C

52

H

78

NV

6 011 (963.2) 1022 (MW, 100); Rt: 7.32 -O-CO-O-Me -H -H

C

54

H

79

N

5 0 14 (1022.2) 1036 100); Rt: 17.69 36 -O-CO-O-CH 2 -Me -H -H

C

55

H

8

]N

5 0 14 (1036.2) 1048 (MWH, 100); Rt: 17.83 37 -O-CO-O-CH 2

-CH=CH

2 -H -H C5dH8]N5O, 4 (1048.3) 1046 3 Rt: 7.3 2 38 -O-CO-O-CH 2 -C-=CH -H -H

C

56

H

79

N

5 0 14 (1046.3) 1064 (MW, 100); Rt: 18.28 39 -O-CO-O-C1-LNe-CH 2 -Me -H -H

C

57

H

85

N

5 0 14 (1064.3) 1064 (MW, 100); Rt: 18.33

-O-CO-O-CH

2 -CHMe 2 -H -H

C

57

H

85

N

5 0 14 (1064.3) Le A 33 687-Foreign Countries -99- Table 1 (Continued) Ex. -A R' R" Physical Data a) No.

1116 (MH 100); Rt: 18.01 41 -O-CO-O-CH 2

-CH

2

-CF=CF

2 -H -H Cs 7

H

8 oF 3 Ns01 4 (1116.3) 42 -O-S0 2

-CH

2

-CH

2

-O-CH

2 -H -H C 56

H

82

F

3 NsS0 1 5 (1154.3)

CF

3 O 1076 (MHI, 100); Rt: 18.01 43 N -H -H Cs 8

H

86

N

6 0 1 3 (1075.3) o 1091 (M 100); Rt: 17.64 44 o -H -H

C

58

H

8 6N60 14 (1091.3) O 1049 (MH 100); 19.94 I -H -H 7 H85NsOi 3 (1048.3) O "1044 (M 100); Rt: 18.73 46 0 -H -H

C

5 sH 83

N

5 0 12 (1044.3) S0 -O -H 1045 (MH 100); Rt: 18.86 47 -H -H

C

55 Hs 3 Ns01 2 (1044.3) CI 1096 (MH, 100);

S

48 -O -H -H Rt: 18.82; 19.02 (anti/syn isomer mixture) CssH 78 ClN 7 0 12 S (1096.8) Le A 33 687-Foreign Countries -100- Table 1 (Continued) Ex. -A R' R" Physical Data a) No.

Me 1060 100);

N-N

49 -H -H Rt: 17.58; 17.70

N

(anti/syn isomer mixture) CssH 8 iN 9 01 2 (1059.8) 1055 100); Rt: 18.08 -H -H

N

C

58

H

82

N

6 0, 2 (1055.3) C1 c1089 100); 18.87 51 -H -H 8

H

8 C1N 6 0 1 2 (1089.7) 520 -H-H 1084 100); Rt: 19.34

C

6

OH

8 SN013 (1084.3) 53 \1152 100); Rt: 19.80 53

H

C

61 H84F 3

N

5

O

13 (1152.3) 54 1059 100); Rt: 17.69 54 ro -H -H

C

57

H

79

N

5 01 4 (1058.3) 1139 100); Rt: 11.24

-O-CH

2 -(4-N-morpholino- -H -H phenyl)

C

63

H

9 0

N

6 013 a) 'H-NMR (400 MHz, 8, ppm); 3 C-NMR (100 MHz, 8, ppm); LC-MS (acidic) m/z Rt-value (min, H9PLC column: 125 x 2.1 Kromasill C-18) Le A 33 687-Foreigzn Countries 101 Example 1-56 Reaction of the polymer-bound hydroxylamine with cycloll-N-methyl-L-leucinylthiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-Nmethyl-L-leucinyl-D-phenyllactyl-] The reaction of 6-(amino-oxy)-3 ,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethylpolystyrene with the cyclothiodepsipeptide is carried out similarly to the reaction procedure of Example 1 (variant a) using- 500.0 mg (0.52 mmol) 200.0 mg 181.0 mg (1.55 mmol) ml of cyclo(-N-methyl-L-leucinyl-D-thiolactyl-N-methyl- L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-DlIactyl-N-methyl-L-leucinyl-D-phenyllactyl-) of 6-(amino-oxy)-3,4,5,6-tetrahydro-2H-pyran-2-ymethox y-methyl -polystyrene of mercury(ll) acetate of dichloromethane The 6-(amino-oxy)-3 ,4,5 ,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene resin is initially stirred at room temperature in dichioromethane for 30 minutes and then treated with the cyclothiodepsipeptide and mercury(ll) acetate. The polystyrene resin is then separated off and washed successively in each case three times with dichloromethane, dimethylformami de/water dimethylformamide and dried under high vacuum.

Yield: 180 mg of polystyrene resin JR (KBr): 1730 cm- 1 (vco; cyclodepsipeptide) Le A 33 687-Foreign Countries -102- Startin materials of the formula (Ib) Example (lb 1) Cyclo[-N-methyl-L-leucinyl-D-thiolacyl-N-methyl-L-leucinyl-D-phenyllaciyl-Nmethyl-L-leucinyl-D-thiolaciyl-N-methyl-L-leucinyl-D-phenylthiolactyl-) Me Me Me 0 Me- iiliN N Me N 1 Meme/N 0 M Me Mem Me 1.0 g (1.05 mmol) of cyclo(-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-Dphenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) PF 1022A (cf. EP-A 382173, US-Pat. 5116815) in 20 ml of toluene were treated with 1.4 g (3.5 mmol) of 2,4-bis-(4-methoxy-phenyl)-2,4-dithioxo- 1,3,2,4dithiadiphosphetane ("Lawesson's Reagent") and stirred at reflux temperature for hours. The entire reaction mixture is then cooled to 0 0 C and filtered and the resulting filtrate is concentrated under reduced pressure. The crude product that remains is chromatographed over a silica gel column (silica gel 60 Merck, particle size: 0.04 to 0.063 mm) using intially the mobile phase methylene chloride and then the mobile phase cyclohexane acetone (3 This gives 0.46 g (43.6% of theory) of cyclo(-Nmethyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenylthiolactyl-N-methyl-Lleu-cinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenylthiolactyl-).

'H-NMR (CDCI 3 2.99, 3.06, 3.26, 3.42 (4 x 4.86, 6.42, 6.61 (4 x -N-

CH

2 Le A 33 687-Foreign Countries 103 5.31, 5.55, 5.81, 5.89 (4 x -O-CH 2 7.26 (phenyl-H) ppm.

LC-MS (acidic) m/z 1013 100); 310 274 198 (42).

C

52

H

76

N

4 0 8

S

4 (1013.4) Le A 33 687-Foreign Countries -104- Example (lb -2) Cyclo(-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-Nmethyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) Me Me Me 0 Me 0 Meme 0 0 Me Me ,O 0 Me- Me Me 0 Me At 0 0 C, 1.0 g (1.05 mmol) of cyclo(-N-methyl-L-leucinyl-D-lactyl-N-methyl-Lleucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-Dphenyllactyl-) PF 1022A (cf. EP-A 382173, US-Pat. 5116815) in 15 ml of tetrahydrofuran was treated with 0.26 g (0.05 mmol) of 2,4-bis-(4-phenoxy-phenyl)- 2,4-dithioxo-1,3,2,4-dithiadiphosphetane ("Belleau's Reagent") and stirred at room temperature for 18 hours. The entire reaction mixture is then concentrated under reduced pressure. The crude product that 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 This gives 0.12 g (11.8% of theory) of cyclo(-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-Nmethyl-L-leucinyl-D-lac-tyl-N-methyl-L-leucinyl-D-phenyllactyl-).

LC-MS (acidic) m/z 965 100); 200 2

H

76

N

4 0 1 1S (965.2) The compounds of the formula (Ib) R 3

R

4

R

7

R

9

R'

0 -Me; R 2

R

5

R

8 R11: iso-butyl) listed in Table 2 below can be prepared analogously.

Le A 33 687-Foreign Countries -105- Table 2 Me Me Me 0 RN/Me Me Me Me Me 0 0 Me Me (Ib) Ex. No. X' X 2

X

3

X

4 R' R" Physical Data a) 3.04, 3.09, 3.25, 3.50 (4 x -N-Me); 4.87, 6.38, 6.56, 6.63 (4 x -N-CHz-); Ib 3 S S S S -NO 2

-NO

2 5.31, 5.52, 5.81, 5.91 (4 x -O-CH 2 8.17; 7.46 (aryl-H).

1103 (MH 100); 392 (38); 177(40); 136 C 5 2

H

74

N

6 0 12

S

4 (1103.4) 1056 39).

Ib -4 S O O O -NO 2 -NOz C 5 2

H

74

N

6 0 15 S (1055.26) O 1184 (MH 100); 986 593 S S S S JN J 392 177 (78).

C

60 oHoN 6 0S 4 (1183.6) Ib-6 Q 1135 56); 361 (100).

S 0 0 0 N

N

C

6 oHNsO60 1 3 S (1135.4) Le A 33 687-Foreign Countries 106 Table 2 (Continued) Ex. No. XI X 2

X

3

X

4 R' R" Physical Data a 120-125 'C 3.15, 3.21, 3.42, 3.57 (4 x -N-Me); 5.03, 6.55, 6.7 8 (4 x -N-CH 2 5.45, lb -7 S S S S 0 I'l-H 5.69, 5.89-6.08 (4 x -O-CH 2 7.05- 7.60 (aryl-H, furyl-H).

1109 1108 370 274 C 57

H

8 oN 4 0 1 0

S

4 (1109.54) lb -8 FA7 1061 100); 198 (58).

S 0 0 0 0 -H C 57

H

80

N

4 01 3 S (1061.3) 107-110 'C 3.01, 3.07, 3.26, 3.41 (4 x -N-Me); lb -9 Q 1 7) 11 f 4.96 (2 x -O-CH 2 4.86, 6.42, 6.62 S S S S 0 0 (4 x -N-CH 2 5.32, 5.56, 5.78, 5.85 (4 x -0-CH 2 6.91-7.44 (aryl-H, fury]-H).

1205 1204 370 (41); 198 (100). C 62 Hs4N 4

O

12

S

4 (1205.63) Ib- 10 Q 4 1158 60); 391 (28).

S 0 0 0 0 0 C 62 H84N 4

O

15 S (1157.4) Le A 33 687-Foreign Countries 107 Table 2 (Continued) Ex. No. XI X 2

X

3

X

4 R' R"Physical Data a) 34.8, 35.2, 37.1, 39.2 71.8, 73.3, 75.4 40.1, 40.6

(-CH

2 62.3, 62.5, 62.6 121.4, 122.8, 136.9, 149.4 Py); 70.7 (-CH 2 115.0, 130.9 phenyl); 203.2, 203.4, 204.8, 205.7 168.8, 169.5, lb-Il1 S S S S ~o N o~170.0 3.01, 3.19, 3.26, 3.41 (4 x -N-Me); 5.17 (2 x -O-Cj1 2 4.86, 6.41, 6.64, 6.66 (4 x -N-C11 2 5.31, 5.75, 5.57, 5.85 (4 x -0-Cfl2-); 6.91, 7.16 (phenyI-Hj), 7.24, 7.51, 7.72, 8.59 (pyridyl-!j).

1228 18); 383 224 (100).

C6,H 86

N

6

O

10

S

4 (1227.68) Ib- 12 N C64~H 86

N

6

O

13

S

S 0 0 0 (1179.5) a) 'H-NMR (400 MHz, 6, ppm); 1 3 C-NNM (100 Mffz, 6, ppm); LC-MS (acidic) m/z Le A 33 687-Foreign Countries -108- Starting materials of the formula (II) Example (II-1) a) (S)-N-[(Tetrahydrofur-2-yl)-methoxy]-phthalimide (cf. S. Bailey et al., J. Med. Chem. 34, 1991, pp. 57-65) 0

OO

1.5 g (14.7 mmol) of (S)-tetrahydrofur-2-yl-methanol Mravik et al., Tetrahedron: Asymmetry 7 1996, pp. 1477-1484), 2.4 g (14.7 mmol) of N-hydroxyphthalimide and 3.85 (14.7 mmol) of triphenylphosphine are stirred in 50 ml of THF and, at 0°C (atmosphere of protective gas) treated with 3.4 g (19.5 mmol) of diethyl azodicarboxylate and stirred at room temperature for 18 hours. The entire reaction mixture is then concentrated under reduced pressure and the residue is taken up in ether and extracted twice with water. The crude product that remains is chromatographed over a silica gel column (silica gel 60 Merck, particle size: 0.04 to 0.063 mm) using the mobile phase cyclohexane acetone (6 This gives 1.7 g (46.8% of theory) of (S)-N-[(tetrahydrofur-2-yl)-methoxy]-phthalimide.

LC-MS-LOOP m/z 248 (MIH, 100) C 13

H

1 3 NO4 (247.2) Rt- value (HPLC column: 125 x 2.1 Kromasil C-18): 7.56 min b) (S)-Tetrahydrofur-2-yl-methoxy-amine H N-O Le A 33 687-Foreign Countries -109- 1.6 g (6.47 mmol) of (S)-N-[(tetrahydrofur-2-yl)-methoxy]-phthalimide are stirred in ml of methylene chloride, 0.6 g (12.9 mmol) of N-methyl-hydrazine are added at 0°C and the mixture is stirred at room temperature for 18 hours. The entire reaction mixture is then filtered and the filtrate is concentrated under reduced pressure. The crude product that remains is chromatographed over a silica gel column (silica gel Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate. This gives 130 mg (17.2% of theory) of (S)-tetrahydrofur-2-yl-methoxy-amine.

LC-MS (acidic) m/z 118 (MH 100). C 52

H

76

N

4 0 11 S (117.1) Le A 33 687-Foreign Countries -110- Example (11-2 a) N-tert-Butyloxycarbonyl-amino-oxyacetomorpholide N-0N Me OO Me Me g (10.5 mmol) of N-tert-butyloxycarbonyl-amino-oxyacetic acid (Novabiochem: 01-63-0060) are stirred in 75 ml of methylene chloride and, at 0°C, treated with 3.1 g (24.0 mmol) of N,N-diisipropylethylamine (Htnig's Base), 3.1 g (12.0 mmol) of bis(2-oxo-3-oxazolidinyl)-phosphonium acid chloride (BOP-C1) and stirred for minutes. 1.05 g (12.0 mmol) of morpholine are then added, and stirring at o0C is continued for 6 hours. The reaction solution is extracted twice with water and the organic phase is separated off and, after drying over sodium sulfate, concentrated under reduced pressure. The crude product that remains is chromatographed over a silica gel column (silica gel 60 Merck, particle size: 0.04 to 0.063 mm) using the mobile phase cyclohexane acetone (3 This gives 1.0 g (37% of theory) of Ntert-butyloxycarbonyl-amino-oxyacetomorpholide.

'H-NMR (CDCI 3 1.47 9H, C(CH 3 3 3.37-3.72 (3m, 8H, 2 x -N-CH2-; 2 x -0- CHi2-;); 4.54 2H, 8.06 1H, N-H) ppm.

LC-MS (acidic) m/z 205 (M H 2 C=CMe 2 12), 161 (100). C IH 20

N

2 0 (260.3) Rt- value (HPLC column: 125 x 2.1 Kromasil C-18): 5.22 min b) Hydrochloride of the amino-oxyacetomorpholide Le A 33 687-Foreign Countries 111 H-N-O N H Cl( For 30 minutes, dry hydrogen chloride gas is introduced into a solution, cooled to 0 0 C, of 0.65 g (2.5 mmol) of N-tert-butyloxycarbonyl-amino-oxyacetomorpholide are into 220 ml of absolute methylene chloride. The mixture is then stirred at room temperature for about 16 hours and the entire reaction mixture is concentrated under reduced pressure. This gives 380 mg (77% of theory) of the hydrochloride of the amino-oxyacetomorpholide.

LC-MS (acidic) m/z 161 (MH-HCl, 100), 146 129

C

6

HI

3

CIN

2 0 3 (196.6) Le A 33 687-Foreign Countries -112- Example (11-3) a) 6-(N-Succinimidyl-oxy)-3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethylpolystyrene resin P 01 N 0, 0 g (0.51 mmol) of DHP HM resin (Novabiochem: 01-64-0192) are allowed to swell in 8.0 ml of 1,2-dichloroethane for about 30 minutes. 293.5 mg (2.5 mmol) of N-hydroxy-succinimide and 261.4 g (1.0 mmol) of pyridinium para-toluenesulfonate (PPTS) are then added, and the mixture is stirred at 80 0 C for 16 hours. The resin is then separated off and washed once with methylene chloride, four times with dimethylformamide/water three times with dimethylformamide and three times with methylene chloride. The purified 6-(N-succinimidyl-oxy)-3,4,5,6-tetrahydro-2Hpyran-2-yl-methoxymethyl-polystyrene resin is dried under high vacuum and can be used for the subsequent reaction step.

IR (KBr): 1730 cm' (vc-o; succinimidyl radical) b) 6-(Amino-oxy)-3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene o 0 0

,NH,

Under an atmosphere of protective gas (argon), 1.0 g of 6-(N-succinimidyl-oxy)- 3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethylI -polystyrene resin is treated in ml of benzene with 127.7 mg (2.55 mmol) of hydrazine hydrate and stirred under Le A 33 687-Foreign Countries 113reflux for 20 hours. The resin is then separated off, washed five times with methylene chloride and dried under high vacuum.

IR (KBr): 1630 cm-' (VN-H deform.; -O-NH 2 3300 cm-' (VN-H valence; -O-NH 2 The compounds of the formula -Y-R 13 listed in Table 3 below can be prepared analogously to Examples 1-1 and II-2 above.

Table 3

H

R13

N-Y

H

Ex. No. Y R 13 Physical Data a) 11-4 149 (M 12); 0 5.02 2H, -CH-O-) 11-5 0 149 (M+-HCI, 100) II 6 N- 0 163 (MH+-HCl, 100); I Me (hydrochloride) Le A 33 687-Foreign Countries -114- Ex. No. Y R 1 3 Physical Data a) 11-7 0-Me INNN163 (MH'-HCl, 100); 'N (hydrochloride) 11-8 124 (MH--2HCI, 100); (dihydrochloride) 11-9 -0- "0 5.26 s, 2H, -O-NH2) ND (hydrochloride) 11-11 207 (MH'-HCI, 4.91 2H, -Cfi 2 7.02; 7.28 (2d, 2x -CH7-. morpholirie) (hydrochloride) a) 'H-NMR (400 MHz, 8, ppm); 1 3 C-NMR (100 MI-z, 6, ppm); LC-MS (acidic) m/z Le A 33 687-Foreign Countries -115- Biological Examples Example A In vivo Nematode test Heterakis spumosa Mouse Mice were experimentally infected with nematodes of the species Heterakis spumosa. To infect the mice, Heterakis spumosa was administered orally as embryonate eggs.

After the prepatency period had expired, the suspended active compounds were administered intraperitoneally on day 46 after the infection.

Determination of the activity: The mice are selected on day 54 after the infection. The adult parasites are counted in the colon and caecum using a microscope. The success of treatment in the dose group as compared to the untreated control group.

Active compounds tested and effective dosages (Dosis effectiva) are shown in the table below.

Le A 33 687-Foreign Countries 116- Active compound Dosis effectiva Reduction rate Example No. in [mg/kg] in[% Cyclo(-Meleu-D-Lac-MeLeu-D-PhLac- 25 0 MeLeu-D-Lac-MeLeu-D-PhLac) PF 1O22A~known a) Cyclo(-MeLeu-D-Lact-MeLeu-D-PhLac- MeLeu-D-Lac-MeLeu-D-PhLac) 25 0 known b) Ex. 1 according to the invention 25 75-90 a) cf. EP-A 382 173, EP-A 503 538 b) cf. WO 98/43 965 MeLeu N-methyl-L-Ieucine, D-Lac D-Iactic acid, D-PhLac D-phenyllactic acid, D-Lact D-thiolactyl Le A 33 687-Foreign Countries -117- Example B In vivo Nematode test Nematospiroides dubius Mouse Mice were experimentally infected with nematodes of the species Nematospiroides dubius. To infect the mice, Nematospiroides dubius was administered orally as embryonate eggs.

0 After the prepatency period had expired, the suspended active compounds were administered intraperitoneally on day 46 after the infection.

Le A 33 687-Foreign Countries 118- Active compound Dosis effectiva Reduction rate Example No. in [mg/kg] in Cyclo(-MeLeu-D-Lac-MeLeu-D-PhLac- 25 0 MeLeu-D-Lac-MeI-eu-D-PhLac) PF 1022A known a) Cyclo(-MeLeu-D-Lact-MeLeu-D-PhLac- MeLeu-D-Lac-MeLeu-D-PhLac) 25 0 known b) Ex. 1 according to the invention 25 100 a) cf. EP-A 382 173, EP-A 503 538 b) cf. WO 98/43 965 MeLeu N-methyl-L-Ieucine, D-Lac D-lactic acid, D-PhLac= D-phenyllactic acid, D-Lact D-thiolactyl Le A 33 687-Foreign Countries 119- Example C In vivo Nematode test Haemonchus contortus Sheep Sheep experimentally infected with Haemonchus contortus were treated after the end of the prepatency period of the parasite. The active compounds were administered orally and/or intravenously as pure active compound.

The efficacy is determined by quantitatively counting the worm eggs excreted with the faeces, before and after treatment.

Complete cessation of the excretion of eggs after treatment means that the worms have been expelled or are so severely damaged that they no longer produce any eggs (Dosis effectiva).

Le A 33 687-Foreign Countries -120- Active compound Dosis effectiva Reduction rate Example No. in [mg/kg] in Cyclo(-MeLeu-D-Lac-MeLeu-D-PhLac- 0.25 100 MeLeu-D-Lac-MeLeu-D-PhLac) 0.01 0 PF 1022A knowna) Ex. 8 according to the invention 0.01 100 Ex. 36 according to the invention 0.01 100 Ex. 46 according to the invention 0.10 100 a) cf. EP-A 382 173, EP-A 503 538; MeLeu N-methyl-L-leucine, D-Lac D-lactic acid, D-PhLac D-phenyllactic acid Persons skilled in the art will appreciate that numerous variations and modifications will become apparent. All such variations and modifications which become apparent to persons skilled in the art, should be considered to fall within the spirit and scope that the invention broadly appearing before described.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers or steps but not the exclusion of any other integer or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in Australia.

r r \i

Claims

1. A compound of the general formula (I) in which R 4 R 7 and R'O independently of one another represent hydrogen, straight- chain or branched alkyl, R 2 R 5 R 8 and R" independently of one another represent hydrogen, S* optionally substituted straight-chain or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl and also aryl or hetaryl, R' 0 and R" together with the atoms to which they are attached represent an optionally substituted 5- or 6-membered ring which may optionally be interrupted by oxygen, sulfur, sulfoxy or sulfonyl, 1. 00: Le A 33 687-Foreign Countries 122 R 6 and R 1 2 independently of one another represent hydrogen, optionally substituted alkyl or arylalkyl, and also 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 2 C=X 3 and C=X 4 independently of one another each represent one of the groups C=O, C=S or CH 2 or a group C=N-A', where at least one of the groups C=X 2 C=X 3 and C=X 4 must represent C=N-A', in which *o A 1 represents a radical -Y-R' 3 in which Y represents oxygen, sulfur or -N-R 4 R' 3 and R 14 independently of one another represent hydrogen, optionally substituted straight-chain or branched, alkyl, alkenyl, alkinyl, cycloalkyl, cyclo-alkylalkyl, arylalkyl, hetarylalkyl, aryl or hetaryl and. Le A 33 687-Foreign Countries 123 also represent formyl, alkoxydicarbonyl, alkylsulfonyl, haloalkoxy- alkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy- carbonyl, alkinyloxycarbonyl, aryloxyalkyl, hetarylcarbonyl, alkyl- carbonyl or optionally represent a radical from the group consisting of 13, B 2 B 3 and B', z 0 Q CH 1 o (B 2 R21 0 ~Q N R 1 -k2011R R 2 R 1 R 2 (B 3 Z (B 4 in which Q represents optionally substituted straight-chain or branched alkyl, alkenyl, alkinyl, cycloalkyl, alkoxy, alkenyloxy, alkinyloxy, cycloalkoxy, aryloxy, arylalkoxy, hetaryloxy, hetarylalkoxy, alkylthio, alkenylthio, alkinylthio, cycloalkylthio, arylthio, arylalkylthio, hetaryl- thio, hetarylalkylthio, alkylamnino, alkenylamino, alkinylamino, cycloalkylamino, arylamnino, arylalkylamino, hetarylamino, hetaryl- alkylamnino, dialkylamino, dialkenylamino, aryl, arylalkyl, hetaryl or hetarylalkyl, cyano, amino or an optionally substituted cyclic amino group which is attached via nitrogen, z G represents carboxyl, thiocarboxyl, sulfoxy, sulfonyl, alkyl, -P(S)-0-alkyl or -C=N-R' 5 Le A 33 687-Foreign Countries 124 R 15 represents hydrogen, hydroxyl, alkoxy, alkylcarbonyl, alkoxy- carbonyl, haloalkylcarbonyl, alkylsulfonyl, nitro or cyano, R 1 6 represents.hydrogen or alkyl, n represents 0, 1 or 2, Y' represents oxygen or sulfur or -N-R 1 7 R' 8 represents, if Y' represents nitrogen, a cyclic amino group which is attached via this nitrogen atom, or R' 7 and R' 8 independently of one another represent hydrogen, optionally substituted straight-chain or branched alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, alkoxycarboiiyl, aryl, arylalkyl, hetaryl or hetarylalkyl, or R' 7 and R 18 together with the adjacent N atom represent an optionally substituted heterocyclic 6- or 7-membered ring system or 20 represent an optionally substituted 7- to 10-membered bicyclic ring system which may optionally also be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl, carbonyl, -NR 22 or by quaternary nitrogen, R' 9 and R 2 0 independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl and also optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl, or R 1 9 and R 2 0 together represent an optionally substituted spirocyclic ring, j Le A 33 687-Foreign Countries 125 R 2 0 and R 2 together with the atoms to which they are attached represent an optionally substituted 6- or 7-membered ring which may optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl, R 21 represents hydrogen, optionally substituted straight-chain or branched alkyl, cycloalkyl, arylalkyl, hetarylalkyl, and also aryl or hetaryl, R 22 represents hydrogen, optionally substituted straight-chain or branched alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cyano, arylalkyl, hetarylalkyl, and also aryl or hetaryl, R 13 may also represent a protective group which can be removed selectively, or a polymeric support which is attached to Y via an anchor group which can be removed selectively, wherein optionally substituted groups of the general formula optionally carry one or more identical or different substituents, selected from the group Sconsisting of: alkyl having preferably 1 to 4, in particular 1 to 2, carbon 0 atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and. tert-butyl; alkoxy having preferably 1 to 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; halogenoalkyl having preferably 1 to 5, in particular 1 to 3, halogen atoms, where the halogen atoms are identical or different and halogen atoms preferably represent fluorine, chlorine or bromine, in particular fluorine, chlorine, such as difluoromethyl, trifluoromethyl, trichloromethyl; hydroxyl, halogen, preferably fluorine, chlorine, bromine and iodine, in particular fluorine and chlorine, cyano; nitro; amino; mono- and dialkylamino having P:\WPDOCS\CRNSu=\sa\Sp\765840.do-1609/03 -125a- preferably 1 to 4, in particular 1 to 2, carbon atom per alkyl group, such as methylamino, methylethylamino, dimethylamino, n-propylamino, isopropylamino, methyl-n-butylamino; alkylcarbonyl radicals, such as methylcarbonyl; alkoxycarbonyl having preferably 2 to 4, in particular 2 to 3, carbon atoms, such as methoxycarbonyl and ethoxycarbonyl; alkylsulfinyl having 1 to 4, in particular 1 to 2, carbon atoms; halogenalkylsulfinyl having 1 to 4, in particular 1 to 2, carbon atoms and 1 to 5 halogen atoms, such as trifluoromethylsulfinyl; halogenalkylsulfonyl having 1 to 4, in particular 1 to 2, carbon atoms and 1 to 5 halogen atoms, such as trifluoromethylsulfonyl, perfluoro-n-butylsulfonyl, perfluoroisobutylsulfonyl; arylsulfonyl having preferably 6 to 10 aryl carbon atoms, such as phenylsulfonyl; acyl, aryl, aryloxy, which for their part may carry one of the abovementioned substituents and the formimino radical (-HC=N-O-alkyl). and/or a pure optical isomer, racemate or physiologically acceptable salts thereof.

2. A cycloiminodepsipeptide as claimed in claim 1 of the general formula (I) R120 *R 0 20 RR1 20 2R N N X 3 O R Rio O O R 3 R4R 7 O 25 8 :x NN R" (I 0 R 6 0.0. 9 *in which 9* Le A 33 687-Foreign Countries 126 R 4 R 7 and R' i represent straight-chain or branched Ci- 4 -alkyl, in particular methyl, R 2 R 5 R 8 and R" independently of one another represent Ci- 4 -alkyl, in particular isobutyl, R 6 and R 12 independently of one another represent optionally substituted CI-4- alkyl or aryl-C 1 -2-alkyl, in particular optionally substituted benzyl, R 3 and R 9 independently of one another represent optionally CI-4-alkyl, hetaryl-C_-2-alkyl, C 1 -C 4 -alkoxycarbonylmethyl, aryl-C 1 2 -alkyl, in particular optionally substituted benzyl, wherein optionally substituted groups R' to R 12 of the general formula (I) optionally carry one or more identical or different substituents, selected from the group consisting of: hydrogen, halogen, cyano, carbamoyl, CI-4-alkyl, hydroxyl which carries a protective group or unprotected hydroxyl, Ci- 8 alkoxy, C 1 -4-alkoxy-CI-4-alkoxy, C24-alkenyloxy, hetaryl-C 1 -4-alkoxy, where the heterocycles for their part may be substituted, nitro, 2 I: or a radical from the group consisting of R 2 3 R 24 N-C 1 -C 6 -alkoxy R 23 R 24 N-C 1 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, C 1 -C 6 alkyl, C-C 6 -alkoxy-C -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cyclo- a r:d. alkylamino-C-C6-alkyl, wherein the cycloalkyl ring one or more carbon atoms may also be replaced by nitrogen, oxygen or sulfur 0 atoms, hetaryl-C -C4-alkyl or a protective group, or Le A 33 687-Foreign Countries 127 R 23 and R 24 together with the nitrogen atom to which they are attached represent hetaryl or heterocycloalkyl, in particular N-pyrrolidino, N- piperazino, N-morpholino, N-thiomorpholino, N-piperidino, N- imidazolo, 2-oxo-pyrrolidinyl, phthalimino or tetrahydrophthalimino, and C=X' represents a group C=N-A, C=X 2 C=X 3 and C=X 4 represent C=O, C=S or CH 2 or (iii C=X 3 represents a group C=N-A, C=XI, C=X2 and C=X4 represents C=O, C=S or CH 2 (iv) C=X' and C=X 3 rpenta group C=N-A, C=X2 and C=X 4 represent C=O, C=S or CH 2 in which A represents hydrogen, optionally substituted C,- 4 -alkyl, C 2 4 -alkenyl, C 2 4 -alkinyl, C 1 -C 4 -alkylcarbonyl, C, 6 -alkylsulfonyl and also cyano, nitro, carbamoyl, C 2 6 -alkoxycarbonyl, formyl, -(C=NH)-NH 2 O-C 1 3 -alkyl, 3 -alkyl or optionally represents a radical A' -Y-R 1 3 where Le A 33 687-Foreign Countries -128- Y represents oxygen or NR1, *R1 3 and R 1 4 independently of one another represent hydrogen, optionally substituted straight-chain or branched C].s-alkyl, C 2 8 -alkenyl, C 2 alkinyl, C 3 7 -CYCloalkyl, C 37 -cycloalkyl-C 2 -alkyl, aryl-C, 2 -alkyl, hetaryl-C,- 2 -alkyl, aryl or hetaryl and also formyl, C 1 -C 8 -alkylsulfonyl, C, -C 2 -haloalkoxy-C, 2 -alkylsulfonyl, C, -C8-alkylcarbonyl, C I-C- alkoxycarbonyl, C 1 -C 8 -alkylaminocarbonyl, C 2 -C8-alkenyloxy- carbonyl, C2-C8-alkinyloxycarbonyl, aryloxy-C, -C 2 -alkyl, hetaryl- carbonyl, C 1 4 -alkoxydicarbonyl or optionally represent a radical from the group consisting. of B 1, B 2 B 3and B4 z 0 III I Q (>CHR 01 1 N 19 11 R 1 9 R. 0 R19 kn Z (B 4 in which Q represents optionally substituted straight-chain or branched C 1 5

8-alkyl, C 28 -alkenyl, C 28 -alkinyl, C 3 7 -CYCloalkyl, C, 6 -alkoxy, C2-6- alkenyloxy, C 2 6 -alkinyloxy, C 3 7 -cycloalkoxy, aryloxy, aryl-Cv- 2 alkoxy, hetaryloxy, hetaryl-C, 2 -alkoxy, C, 6 -alkylthio, C 2 6 alkenylthio, C 2 6 -alkinylthio, C 37 -cycloalkyl-thio, arylthio, aryl-C,.r- alkylthio, hetarylthio, hetaryl-C 2 -alkylthio, C, I 6 -alkyl amino, C 2 6 alkenylamino, C 2 6 -alkinyl amino, C 3 6 -cyclo-alkylamino, arylamino, aryl -C I -2-al kyl amino, hetarylamino, hetaryl I 2 -alkyl amino, di-C, alkylamino, di -C 2 4 -al ken yl amino, aryl, aryl- C, 2 -alkyl, hetaryl, Le A 33 687-Foreign Countries -129- hetaryl-C-C 2 -alkyl and also cyano, amino or an optionally substituted cyclic amino group which is attached via nitrogen, z II G represents thiocarboxyl or carboxyl, R' 5 represents hydrogen, hydroxyl, C 1 4-alkoxy, Ci-4-alkylcarbonyl, C-4- alkoxycarbonyl, halogeno-C 1 -4-alkylcarbonyl, C 1 -4-alkylsulfonyl, nitro or cyano, R6 represents hydrogen or C-4-alkyl, n represents 0, 1 or 2, Y represents oxygen, sulfur or -N-R R 8 represents, if Y' represents nitrogen, a cyclic amino group which is attached via this nitrogen atom, or R' 7 and R'18 independently of one another represent hydrogen, optionally ,20 substituted straight-chain or branched C 1 6 -alkyl, C2- 6 -alkenyl, C 2 6 Salkinyl, C 3 7 -cycloalkyi, C 3 7 -cycoalkyl-C 1 6 -alkyl, C 1 6 -alkoxy- carbonyl, aryl, aryl-C 1 2 -alkyl, hetaryl, hetaryl-C 1 -2-alkyl, or R' 7 and Rs together with the adjacent N atom represent an optionally substituted heterocyclic 6- or 7-membered ring system or represent an optionally 7- to 10-membered bicyclic ring system which may optionally also be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl, carbonyl, -NR 22 or by quaternary nitrogen, Le A 33 687-Foreign Countries -130- R' 9 and R 20 independently of one another represent hydrogen, optionally substituted straight-chain or branched C 1 alkyl, C2-6-alkenyl, C 3 7 cycloalkyl and also optionally substituted aryl, aryl-Cl-2-alkyl, hetaryl, hetaryl-C 1 2 -alkyl, or R' 9 and R 20 together represent an optionally substituted spirocyclic ring, and R21 together with the atoms to which they are attached represent an optionally substituted 5-6- or 7-membered ring which may optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl, R21 represents hydrogen, optionally substituted straight-chain or branched C 1 s 6 -alkyl, C 3 .7-cycloalkyl, aryl-Cl-2-alkyl, hetaryl-C,- 2 -alkyl, and also aryl or hetaryl, R22 represents hydrogen, optionally substituted straight-chain or branched C 1 6 -alkyl, C2-6-alkenyl, C2- 6 -alkinyl, C 3 7 -cycloalkyl: C 3 7 -cycloalkyl- C..-alkyl, C s-alkoxycarbonyl, C 6-alkylcarbonyl, C 3 7 -cycloalkyl- se.. carbonyl, cyano, aryl-C 1 2 -alkyl, hetaryl-C 1 2 -alkyl, and also aryl or S 20 hetaryl, 0 a a R 1 3 also represents a protective group which can be removed selectively, for example allyl, allyloxycarbonyl (Alloc), benzyl benzyloxy- carbonyl tert-butyloxycarbonyl (Boc), tetrahydropyran-2-yl (THP) or fluorenylmethoxycarbonyl (Fmoc) and also represents a polymeric support which is attached to Y via an anchor group which can be removed selectively, wherein optionally substituted groups R13 to R22 of the general formula (I) 0 optionally carry one or more identical or different substituents, selected from P:\WPDOCS\CRN\Ssan\Spec\7658040.doc-1609/03 -130a- the group consisting of alkyl having 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 having preferably 1 to 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; halogenoalkyl having preferably 1 to 5, in particular 1 to 3, halogen atoms, where the halogen atoms are identical or different and halogen atoms preferably represent fluorine, chlorine or bromine, in particular fluorine, chlorine, such as difluoromethyl, trifluoromethyl, trichloromethyl; hydroxyl, halogen, preferably fluorine, chlorine, bromine and iodine, in particular fluorine and chlorine, cyano; nitro; amino; mono- and dialkylamino having preferably 1 to 4, in particular 1 to 2, carbon atom per alkyl group, such as methylamino, methylethylamino, dimethylamino, n-propylamino, isopropylamino, methyl-n-butylamino; alkylcarbonyl radicals, such as methylcarbonyl; alkoxycarbonyl having preferably 2 to 4, in particular 2 to 3, carbon atoms, such as methoxycarbonyl and ethoxycarbonyl; alkylsulfinyl having 1 to 4, in particular 1 to 2, carbon atoms; halogenalkylsulfinyl having 1 to 4, in particular 1 to 2, carbon atoms and 1 to 5 halogen atoms, such as trifluoromethylsulfinyl; halogenalkylsulfonyl having 1 to 4, in particular 1 to 2, carbon atoms and 1 to 5 halogen atoms, such as trifluoromethylsulfonyl, perfluoro-n-butylsulfonyl, perfluoroisobutylsulfonyl; arylsulfonyl having preferably 6 to 10 aryl carbon atoms, such as phenylsulfonyl; acyl, aryl, aryloxy, which for their part may carry one of the abovementioned substituents and the formimino radical (-HC=N-O-alkyl) *or an optical isomer, racemate or physiologically acceptable salt thereof* or an optical isomer, racemate or physiologically acceptable salt thereof. Le A 33 687-Foreign Countries

131- 3. A process 1 for preparing the novel compounds of the general formula as claimed in claim 1 R 12 0 in which R' to R 12 and the groups C=X' to C=X 4 have the meanings given in claim 1, characterized in that cyclothiodepsipeptides of the general formula (I) R 12 0 and salts thereof, in which Le A 33 687-Foreign Countries -132- R' to R 1 2 have the meanings given in claim 1, and C=X 2 C=X 3 and C=X 4 independently of one another represent C=O, C=S or CH 2 where at least one of the groups C=X 2 C=X 3 and C=X 4 has to represent a C=S group, are reacted with amino compounds of the general formula (II) H 2 N-A (II) in which A has the meanings given in claim 1 .0 .2 in the presence of suitable metal salts or metal oxides, in particular mercury (II) acetate, mercury(II) chloride or mercury(I) oxide, in the presence of a basic reaction auxiliary and in the presence of a suitable diluent. 4. A process for preparing the compounds of the formula (la) and/or salts thereof, characterized in that a) the cyclothiodepsipeptides of the general formula (Ib) or salts thereof Le A 33 687-Foreign Countries -133- (Ib) in which R' to R' 2 have the meanings given in claim 1 are reacted with amino compounds of the general formula (II) H 2 N-A o gO o* in which A has the meanings given in claim 1 in the presence of suitable metal salts or metal oxides, in particular mercury (II) acetate, mercury (II) chloride or mercury(II) oxide, and in the presence of a basic reaction auxiliary and in the presence of a suitable diluent, or b) the process for preparing the novel cycloiminodepsipeptides of the general formula (Ia) and/or salts thereof. Le A 33 687-Foreign Countries -134- and salts thereof, in which R' to R' 2 have the meanings mentioned in claim 1, A represents a radical -Y-R' 3 in which Y has the meaning given in claim 1, R' 3 represents radicals from the group consisting of B' to B 3 z I I G >(CHR 6 )n Q 0 181 y 0 0 R>1K R 19 R 20 (B 2 (B 3 in which Z II Q, n, R 1 6 and R18-R 20 have the meanings given in claim 1, compounds of the general formula (Ic) Le A 33 687-Foreign Countries

135- and salts thereof, in which Y and R' to R 1 2 have the meanings given in claim 1 are reacted with compounds of the general formula ma-c Z I G(CHR 16 )n-W 0 I I R 1 8 Y S 0 R 18 Y% R 19-, (mla) (mb) (mc) in which Z Q, n, R 16 and R' 8 -R 20 have the meanings given in claim 1, W represents a suitable leaving group, such as, for example, 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 Le A 33 687-Foreign Countries -136- c) the process for preparing compounds of the general formula (la) and/or salts thereof, in which A represents a radical in which Y has the meanings given in claim 1, R 1 3 represents radicals from the group consisting of B' and B 3 z II G Q (CHR 1 6 )n- 0 189 R R (B 3 in which Q, n, R' 8 -R 2 0 have the meanings given in claim 1, 4-'l n represents 0, and the group Srepresents carboxyl, the compounds of the general formula (Ic) and salts thereof Le A 33 687-Foreign Countries -137- /'R9 0 0 O N N R 8 O R6 in which Y and R' to R 12 have the meanings given in claim 1 are reacted with a carboxylic anhydride of the general formula (IV) (Q-CO) 2 0 (IV) in which Q has the meaning given in claim 1 or Y 1 SR represents the radical in which R'"-R 20 have the meaning given in claim 1, 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 Le A 33 687-Foreign Countries -138- d) the process for preparing the novel cycloiminodepsipeptides of the general formula (Ia) by reacting compounds of the general formula (Ic) and/or salts thereof a) with amino acid derivatives of the general formula (V) 0 N G -OH 1 9 R z in which Z II SQ, and R 1 9 to R 21 have the meaning given in claim 1 if appropriate in the presence of coupling agents and if appropriate in the presence of a basic reaction auxiliary and also, if appropriate, in the presence of diluents, or 1) with compounds of the general formulae (VI) and (VII) is z 11 Y N=C=Y RiS-N=C=Y (VI) (vII '~O in which Z II Y and R 1 5 have the meaning given in claim 1, if appropriate in the presence of a basic reaction auxiliary or a catalyst, if appropriate in the presence of diluents. Le A 33 687-Foreign Countries 139 A process for preparing compounds of the general formula (1c) and/or salts thereof, R e N 1 N 0 0 RiO 0 ~0 0 N N R 8 0 R 6 (Ic) 10 in which Y and R' to R 1 2 have the meanings given in claim 1, characterized in that a) from the compounds of the general formula (Ia) and/or salts thereof, A R 12 0 N-C 0 O y l R2 N .R /N R 1 R0 R4~ R7j 0 N N R 8 (1a) in which Le A 33 687-Foreign Countries -140- R' to R1 2 have the meanings given in claim 1, A represents a radical -Y-R 1 3 in which Y represents oxygen or -N-H, R' 3 represents a protective group which can be removed selectively, for example, allyl, allyloxy-carbonyl (Alloc), benzyl benzyloxycarbonyl tert-butyloxycarbonyl (Boc), tetrahydropyran-2-yl (THP) or in fluorenylmethoxycarbonyl (Fmoc), the radical R 13 is selectively removed, depending on the removable protective group either in the presence of a hydrogenation catalyst, in the presence of a protic acid or a basic reaction auxiliary and in the presence of a diluent, or b) from the compounds of the general formula Ia attached to a polymeric support, and salts thereof, Le A 33 687-Foreign Countries -140- R' to R' 2 have the meanings given in claim 1, A represents a radical -Y-R 1 3 in which Y represents oxygen or -N-H, R" represents a protective group which can be removed selectively, for example, allyl, allyloxy-carbonyl (Alloc), benzyl benzyloxycarbonyl tert-butyloxycarbonyl (Boc), tetrahydropyran-2-yl (THP) or in fluorenylmethoxycarbonyl (Fmoc), the radical R' 3 is selectively removed, depending on the removable protective group either in the presence of a hydrogenation catalyst, in the presence of a protic acid or a basic reaction auxiliary and in the presence of a diluent, or b) from the compounds of the general formula attached to a polymeric support, and/or salts thereof, 9* S* S. S *S FI i Le A 33 687-Foreign Countries 141 in which R' to R 12 have the meanings given in claim 1, A represents a radical -Y-R 1 3 in which 0 .10 Y represents oxygen or -N-H, R 13 represents a selectively removable anchor group on a polymeric support, the compounds of the formula (Ic) are released by selective removal of the anchor group from the polymeric support R' 3 in the presence of a suitable catalyst or in the presence of a protic acid and in the presence of a diluent. 6. A composition, characterized in that it comprises at least one compound of the formula and/or salts thereof as claimed in claim 1. 7. The use of compounds of the formula as claimed in claim 1 for controlling endoparasites. Le A 33 687-Foreign Countries -142- 8. A method for controlling endoparasites, characterized in that compounds of the formula as claimed in claim 1 are allowed to act on endoparasites and/or their habitat. 9. A process for preparing compositions against endoparasites, characterized in that compounds of the formula as claimed in claim 1 are mixed with extenders and/or surfactants. The use of compounds of the formula as claimed in claim 1 for preparing compositions against endoparasites. 11. Compounds of the general formula and/or pure optical isomers, racemates, or physiologically acceptable salts thereof, substantially as hereinbefore described, with reference to the accompanying Exnples. S 12. A process for preparing compounds of the general formula (Ia) and/or salts thereof, substantially as hereinbefore described, with reference to the accompanying Examples. 13. A process for preparing compounds of the general formula (Ic) and/or salts thereof, substantially as hereinbefore described, with reference to the accompanying Examples. 14. Composition comprising at least one compound of general formula and/or salts thereof, substantially as hereinbefore described, with reference to the •accompanying Examples. 15. Use of compounds of general formula for controlling endoparasites, substantially as hereinbefore described, with reference to the Examples. I P:\WPDOCS\CRN\Susn\Spec\7658040.doc-1609/03 -143- 16. Method for controlling endoparasites, substantially as hereinbefore described, with reference to the Examples. 17. Process for preparing compositions against endoparasites, substantially as hereinbefore described, with reference to the accompanying Examples. 18. Use of compounds of the general formula for preparing compositions against endoparasites, substantially as hereinbefore described, with reference 0 to the accompanying Examples. DATED this 15th day of September, 2003 BAYER AKTIENGESELLSCHAFT by its Patent Attorneys DAVIES COLLISON CAVE S 0 S. S S*S S S