DE19926620A1 - New cycloiminodepsipeptides, processes for their preparation and their use in combating endoparasites - Google Patents

Abstract

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

Description

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

The interesting backbone modifications of peptides, especially theirs To reduce enzymatic hydrolysis stability, counts in addition to the exchange of Amide oxygen for sulfur also undoubtedly the exchange of amide acid Substance against an optionally substituted imino group.

Naturally occurring peptides with an iminopeptide bond or an amidine Grouping in the molecule is extremely rare. The bottro are exemplary mycin, a peptide antibiotic from Streptomyces bottropensis, the amidinomycin or called the 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. Antibiotic. 17A, 1964, p. 220).

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

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

Poly (dipeptamidine), in which the carbonyl oxygen every second peptide Amide group replaced by an imine nitrogen were used as comparative products for the oligomerization of α-amino nitriles (see A. Eschenmoser et al., Helv. Chim. Acta 69, 1986, p. 1224).

In contrast to the processes already mentioned for the production of various N- Substituted iminopeptides is about the representation of cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarboxylic acids and optionally hydroxy carboxylic acids, hydroxythiocarboxylic acids nothing known.

In particular, the presentation of cycloiminodepsipeptides consists of Amino acids, hydroxyiminocarboxylic acids and optionally hydroxycarbon acids, hydroxythiocarboxylic acids as ring building blocks and 24 ring atoms, from ent speaking cyclothiodepsipeptides have so far become unknown.

Cyclic depsipeptides and their production and use as endoparasiticides are already the subject of numerous publications.

For example, a cyclodepsipeptide called PF 1022A and its Effect against endoparasites known (EP-OS 382 173 and EP-OS 503 538).  

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; WHERE 96/11 945; WO 95/07 272; WO 94/19 334; WO 93/19 053; EP-OS 634 408; EPOS 626 375; EP-OS 626 376; EP-OS 664 297; EP-OS 634 408; EP-OS 718 298; WHERE 97/09 331; Cyclohexadepsipeptides: WO 93/25 543; WO 95/27 498; EP-OS 658 551; Cyclotetradepsipeptides: EP-OS 664 297; Dioxomorpholines: WO 96/38 165; JP 08 225 552) and open-chain depsipeptides (EP-OS 657 171; EP-OS 657 172; EP-OS 657 173; WO 97/07 093) and their endoparasiticidal activity are described.

Cyclothiodepsipeptides consisting of amino acids, hydroxythiocarboxylic acids and optionally hydroxycarboxylic acids as ring units and 24 ring atoms, their Manufacture and their use for controlling endoparasites is counter was a prior patent application (WO 98/43 965) of the applicant.

The present invention relates to the new cycloiminodepsipepti which also a method for the preparation of cycloiminodepsipeptides, in particular of cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarbon acids and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as Ring building blocks and 24 ring atoms.

Another subject is the use of cycloiminodepsipeptides, in particular of cycloiminodepsipeptides, consisting of amino acids, hydroxy iminocarboxylic acids and optionally hydroxycarboxylic acids, hydroxythiocarbon acids as ring building blocks and 24 ring atoms, for the preparation of agents for loading fighting endoparasites.

The present invention relates in particular to:

1. Cycloiminodepsipeptides of the general formula (I)

in which
R ¹ , R ⁴ , R ⁷ and R ¹⁰ independently of one another represent hydrogen, straight-chain or branched alkyl,
R ² , R ⁵ , R ⁸ and R ¹¹ independently of one another represent hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl and aryl or hetaryl,
R ¹⁰ and R ¹¹ together with the atoms to which they are attached represent an optionally substituted 5- or 6-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxy or sulfonyl,
R ⁶ and R ¹² independently of one another represent hydrogen, optionally substituted alkyl or arylalkyl, and optionally substituted cycloalkylalkyl,
R 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 ¹ , C = X ² , C = X ³ and C = X ⁴ each independently represent one of the groups C = O, C = S or CH ₂ or represent a group C = NA, at least one of the groups C = X ¹ , C = X ² , C = X ³ and C = X ⁴ must stand for C = NA,
in which
A for hydrogen, optionally substituted alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, and also cyano, nitro, carbamoyl, alkoxycarbonyl, formyl, - (C = NH) -NH ₂ , -P (O) -O-alkyl, -P ( S) -O- alkyl or optionally for a radical A ¹

-YR ¹³ (A ¹ )

in which
Y represents oxygen, sulfur or -NR ¹⁴ ,
R ¹³ and R ¹⁴ independently of one another are hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl, aryl or hetaryl and also for formyl, alkoxydicarbonyl, alkylsulfonyl, haloalkoxyalkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, al Alkynyloxycarbonyl, aryloxyalkyl, hetarylcarbonyl, alkylcarbonyl or optionally represents a radical from the group B ¹ , B ² , B ³ or B ⁴ ,

wherein
Q represents optionally substituted, straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, aryloxy, arylalkoxy, hetaryloxy, hetarylalkoxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, arylthio, arylalkylthio, arylalkylthio, arylalkylthio, arylalkylthio, arylalkylthio Alkylamino, alkenylamino, alkynylamino, cycloalkylamino, arylamino, arylalkylamino, hetarylamino, hetarylalkylamino, di alkylamino, dialkenylamino, aryl, arylalkyl, hetaryl or hetarylalkyl, cyano, amino or an optionally substituted cyclic amino group linked via nitrogen,

represents carboxy, thiocarboxy, sulfoxy, sulfonyl, -P (O) -O-alkyl, -P (S) -O-alkyl or -C = NR ¹⁵ ,
R ^{15 represents} hydrogen, hydroxy, alkoxy, alkylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, alkylsulfonyl, nitro or cyano,
R ^{16 represents} hydrogen or alkyl,
n represents 0, 1 or 2,
Y ^{1 represents} oxygen, sulfur or -NR ¹⁷ ,
R ¹⁸ , when Y ^{1 is} nitrogen, can mean a cyclic amino group linked via this nitrogen atom,
R ¹⁷ and R ¹⁸ independently of one another represent hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, aryl, arylalkyl, hetaryl or hetarylalkyl, or
R ¹⁷ and R ¹⁸ together with the adjacent N atom for an optionally substituted heterocyclic 4-, 5-, 6- or 7-membered ring system or for an optionally substituted 7- to 10-membered bicyclic ring system, optionally also by oxygen , Sulfur, sulfoxyl, sulfonyl, carbonyl, -NO, -N =, -NR ²² or can be interrupted by quaternized nitrogen,
R ¹⁹ and R ²⁰ independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl and optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl, or
R ¹⁹ and R ²⁰ together represent an optionally substituted spirocyclic ring,
R ²⁰ and R ²¹ together with the atoms to which they are attached represent an optionally substituted 5-, 6- or 7-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl,
R ^{21 represents} hydrogen, optionally substituted, straight-chain or branched alkyl, cycloalkyl, arylalkyl, hetarylalkyl, and aryl or hetaryl,
R ^{22 represents} hydrogen, optionally substituted straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cyano, arylalkyl, hetarylalkyl, and aryl or hetaryl,
R ¹³ can also stand for a selectively cleavable protective group, or a polymeric carrier which is connected to Y via a selectively cleavable anchor group,
as well as their pure optical isomers, racemates and physiologically acceptable salts,
to fight endoparasites in medicine and veterinary medicine.

The compounds of general formula (I) can, depending on the type of the substituents as geometric and / or optical isomer mixtures and Regioisomer mixtures of different composition occur. The Erfin dung affects both the pure isomers and the isomer mixtures.

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

in which
R ¹ , R ⁴ , R ⁷ and R ^{10 represent} straight-chain or branched C _1-4 alkyl, in particular methyl,
R ² , R ⁵ , R ⁸ and R ¹¹ independently of one another are C _1-4 -alkyl, in particular isobutyl,
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 are optionally C _1-4 -alkyl, hetaryl-C _1-2 -alkyl, C ₁ -C ₄ -alkoxycarbonylmethyl, aryl-C _1-2 -alkyl, in particular optionally substituted benzyl,
where substituents are hydrogen, halogen, cyano, carbamoyl, C _1-4 alkyl, a protective group-bearing hydroxy or unprotected hydroxy, C _1-8 alkoxy, C _1-4 alkoxy-C _1-4 alkoxy, C _2-4 - alkenyloxy, hetaryl-C _1-4 alkoxy, where the heterocycles can in turn be substituted, nitro, or
a radical from the series R ²³ R ²⁴ NC ₁ -C ₆ alkoxy, R ²³ R ²⁴ NC ₁ -C ₈ alkyl, NR ²³ R ²⁴ and -SO ₂ -NR ²³ R ²⁴ , in which
R ²³ and R ²⁴ each independently represent hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkylamino -C ₁ -C ₆ -alkyl, where one or more carbon atoms in the cycloalkyl ring can 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 are hetaryl or heterocycloalkyl, in particular N-pyrrolidino, N-piperazino, N-morpholino, N-thiomorpholino, N-piperidino, N-imidazolo, 2-oxo- pyrrolidinyl, phthalimino or tetrahydrophthalimino, stand, and

• a) C = X ^{1 represents} a group C = NA,
  C = X ² , C = X ³ and C = X ⁴ stand for C = O, C = S or CH ₂ , or
• b) C = X ^{3 represents} a group C = NA,
  C = X ¹ , C = X ² and C = X ⁴ stand for C = O, C = S or CH ₂ , or
• c) C = X ¹ and C = X ^{3 represent} a group C = NA,
  C = X ² and C = X ⁴ stand for C = O, C = S or CH ₂ ,

in which
A for hydrogen, optionally substituted C _1-4

-Alkyl, C _2-4

- alkenyl, C _2-4

-Alkynyl, C ₁

-C ₄

-Alkylcarbonyl, C _1-6

-Alkylsulfo nyl and cyano, nitro, carbamoyl, C _2-6

-Alkoxycarbonyl, formyl, - (C = NH) -NH ₂

, -P (O) -OC _1-3

-Alkyl, -P (S) -OC _1-3

- Alkyl or optionally for a radical A ¹

-YR ¹³ (A ¹ ),

in which
Y represents oxygen or -NR ¹⁴ ,
R ¹³ and R ¹⁴ independently of one another are hydrogen, optionally substituted, straight-chain or branched C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl -C _1-2 alkyl, aryl C _1-2 alkyl, hetaryl C _1-2 alkyl, aryl or hetaryl and formyl, C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₂ haloalkoxy C _{1 -2-} alkylsulfonyl, C ₁ -C ₈ alkyl carbonyl, C ₁ -C ₈ alkoxycarbonyl, C ₁ -C ₈ alkylaminocarbonyl, C ₂ -C ₈ alkenyloxycarbonyl, C ₂ -C ₈ alkynyloxycarbonyl, aryloxy-C ₁ -C ₂ - alkyl, hetarylcarbonyl, C _1-4 alkoxydicarbonyl or optionally represents a radical from the group B ¹ , B ² , B ³ or B ⁴

wherein
Q represents optionally substituted, straight-chain or branched C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-7 cycloalkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-7 cycloalkoxy, aryloxy, aryl-C _1-2 alkoxy, hetaryloxy, hetaryl-C _1-2 alkoxy, C _1-6 alkylthio, C _2-6 alkenyl thio , C _2-6 -alkynylthio, C _3-7 -cycloalkylthio, arylthio, aryl-C _1-2 -alkyl thio, hetarylthio, hetaryl-C _1-2 -alkylthio, C _1-6 -alkylamino, C _2-6 - Alkynylamino, C _2-6 -alkynylamino, C _3-6 -cycloalkylamino, arylamino, aryl-C _1-2 -alkylamino, hetarylamino, hetaryl-C _1-2 -alkylamino, di-C _1-4 -alkylamino, di- C _2-4 alkenylamino, aryl, arylC _1-2 alkyl, hetaryl, hetarylC ₁ -C ₂ alkyl and cyano, amino or an optionally substituted cyclic amino group linked via nitrogen,

represents thiocarboxy or carboxy,
R ^{15 represents} hydrogen, hydroxy, C _1-4 alkoxy, C _1-4 alkylkylcarbonyl, C _1-4 alkoxycarbonyl, haloC _1-4 alkylcarbonyl, C _1-4 alkylsulfonyl, nitro or cyano,
R ^{16 represents} hydrogen or C _1-4 alkyl,
n represents 0, 1 or 2,
Y ^{1 represents} oxygen, sulfur or -NR ¹⁷ ,
R ¹⁸ , when Y ^{1 is} nitrogen, can mean a cyclic amino group linked via this nitrogen atom,
R ¹⁷ and R ¹⁸ independently of one another are hydrogen, optionally substituted, straight-chain or branched C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl -C _1-6 -alkyl, C _1-6 -alkoxycarbonyl, aryl, aryl-C _1-2 -alkyl, hetaryl, hetaryl-C _1-2 -alkyl, or
R ¹⁷ and R ¹⁸ together with the adjacent N atom stand for an optionally substituted, heterocyclic 4-, 5-, 6- or 7-membered ring system or for an optionally 7- to 10-membered bicyclic ring system, which may also be represented by Oxygen, sulfur, sulfoxyl, sulfonyl, carbonyl, -NO, -N =, -NR ²² or can be interrupted by quaternized nitrogen,
R ¹⁹ and R ²⁰ independently of one another for hydrogen, optionally substituted straight-chain or branched C _1-6 alkyl, C _2-6 alkenyl, C _3-7 cycloalkyl and optionally substituted aryl, aryl-C _1-2 alkyl, hetaryl , Hetaryl-C _1-2 alkyl, or
R ¹⁹ and R ²⁰ together represent an optionally substituted spirocyclic ring,
R ²⁰ and R ²¹ together with the atoms to which they are attached represent an optionally substituted 5-, 6- or 7-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl,
R ^{21 represents} hydrogen, optionally substituted, straight-chain or branched C _1-6 alkyl, C _3-7 cycloalkyl, arylC _1-2 alkyl, hetarylC _1-2 alkyl, and aryl or hetaryl,
R ²² for hydrogen, optionally substituted, straight-chain or branched C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _3-7 - cycloalkyl-C _{1- 6} -alkyl, C _1-6 -alkoxycarbonyl, C _1-6 -alkylcarbonyl, C _3-7 - cycloalkylcarbonyl, cyano, aryl-C _1-2 -alkyl, hetaryl-C _1-2 -alkyl, and aryl or hetaryl ,
R ¹³ also for a selectively removable protective group, for example allyl, allyloxycarbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl (Z), tert-butyloxycarbonyl (Boc), tetrahydropyran-2-yl (THP) or fluorenyl methoxycarbonyl (Fmoc) as well represents a polymeric carrier which is bonded to Y by means of a selectively cleavable anchor group,
and their optical isomers, racemates and physiologically acceptable salts.

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

The cycloiminodepsipeptides according to the invention and their acid addition salts and Metal salt complexes have good endoparasiticides, especially anthelmintic ones Effect and can preferably be used in the field of veterinary medicine.

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

and their salts,
in which
R ¹ to R ¹² and the groups C = X ¹ to C = X ^{4 have} the meanings given under point 1,
characterized in that one
Cyclothiodepsipeptides of the general formula (I)

and their salts,
in which
R ¹ to R ^{12 have} the meanings given under point 1, and
C = X ¹ , C = X ² , C = X ³ and C = X ⁴ independently of one another mean C = O, C = S or CH ₂ , where at least one of the groups C = X ¹ , C = X ² , C = X ³ and C = X ⁴ must stand for a C = S group,
with amino compounds of the general formula (II)

H ₂ NA (II)

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

The process according to the invention particularly and preferably relates to the production of the new cycloiminodepsipeptides of the general formula (Ia)

and their salts,
in which
A and R ¹ to R ^{12 have} the meanings given under point 1.

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

• a) the cyclothiodepsipeptides of the general formula (Ib) or their salts,
  in which
  R ¹ to R ^{12 have} the meanings given under point 1,
  with amino compounds of the general formula (II)
  H ₂ NA (II)
  in which
  A has the meanings given under point 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) for the preparation of the new cycloiminodepsipeptides of the general formula (Ia)
  and their salts,
  in which
  R ¹ to R ^{12 have} the meanings given under point 1,
  A stands for a residue -YR ¹³ (A ¹ ),
  in which
  Y has the meaning given under point 1,
  R ^{13 represents} radicals from group B ¹ to B ³ ,
  wherein
  Q, Y ¹ , n, R ¹⁶ and R ¹⁸ -R ^{20 have} the meanings given under point 1,
  the new cycloimino depsipeptides of the general formula (Ic) obtained by processes 2a) and 3 according to the invention
  and their salts,
  in which
  Y and R ¹ to R ^{12 have} the meanings given under point 1,
  with compounds of the general formula (IIIa-c)
  wherein
  Q, Y ¹ , n, R ¹⁶ and R ¹⁸ -R ^{20 have} the meanings given under point 1,
  W stands for a suitable leaving group, such as halogen,
  if appropriate in the presence of a catalyst, if appropriate in the presence of a basic reaction auxiliary and if appropriate in the presence of diluents, or
• c) for the preparation of the new cycloiminodepsipeptides of the general formula (Ia) and their salts,
  in the A for a residue -YR ¹³ (A ¹ )
  in which
  Y has the meanings given under point 1,
  R ^{13 represents} radicals from the groups B ¹ and B ³ ,
  wherein
  Q, Y ¹ , n, R ¹⁸ -R ^{20 have} the meanings given under point 1,
  n stands for 0,
  and the group
  
• d) represents carboxy,
  the compounds of the general formula (Ic) and their salts
  in which
  Y and R ¹ to R ^{12 have} the meanings given under point 1,
  with a carboxylic anhydride of the general formula (IV)
  (Q-CO) ₂ O (IV)
  in which
  Q has the meaning given under point 1 or for the rest
  stands,
  wherein
  Y ¹ , R ¹⁸ -R ^{20 have} the meaning given under 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
• e) by compounds of the general formula (Ic)
  • 1. α) with amino acid derivatives of the general formula (V)
    in which
    Q, and R ¹⁹ to R ^{21 have} the meaning given under point 1
  if appropriate in the presence of coupling reagents and if appropriate in the presence of a basic reaction auxiliary and if appropriate in the presence of diluents, or
  • 1. β) with compounds of the general formulas (VI) and (VII)
    in which
    Y and R ^{15 have} the meaning given under point 1,
  if appropriate in the presence of a basic reaction auxiliary or a catalyst, if appropriate in the presence of diluents.

The invention further relates to:

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

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

• a) of the cycloiminodepsipeptides of the general formula (Ia) and their salts obtainable according to process 2a,
  in which
  R ¹ to R ^{12 have} the meanings given under point 1,
  A stands for a residue -YR ¹³ (A ¹ ),
  in which
  Y represents oxygen or -NH,
  R ^{13 stands} for a selectively removable protective group, for example allyl, allyloxycarbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl (Z), tert-butyloxycarbonyl (Boc), tetrahydropyran-2-yl (THP) or in fluorenylmethoxycarbonyl (Fmoc),
  depending on the removable protecting group either in the presence of a hydrogenation catalyst, in the presence of a protonic acid or a basic reaction aid and in the presence of a diluent, the radical R ^{13 is} selectively split off, or
• b) from the cycloiminodepsipeptides of the general formula (Ia) obtainable according to process 2a and bound to a polymeric support and their salts,
  in which
  R ¹ to R ^{12 have} the meanings given under point I,
  A for a residue -YR ¹³ (A ¹ )
  in which
  Y is oxygen or -NH,
  R ^{13 represents} a selectively cleavable anchor group on a polymeric support,
  in the presence of a suitable catalyst or in the presence of a protonic acid and in the presence of a diluent by selective cleavage of the anchor group from the polymeric support R ^13, the compounds of the formula (Ic) are released.

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

The cycloiminodepsipeptides according to the invention and their acid addition salts and Metal complexes have good endoparasiticides, especially anthelmintic ones Effect and can preferably be used in the field of veterinary medicine.

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

Optionally substituted alkyl alone or as part of a radical in the general formulas means straight-chain or branched alkyl with preference example 1 to 6, in particular 1 to 4 carbon atoms. Examples are given optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.- Butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2- Dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1- Methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- Dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,2,2-trimethyl called propyl, 1-ethylbutyl and ethylbutyl.

Preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and called tert-butyl.

Optionally substituted alkenyl alone or as part of a residue in the general formulas means straight-chain or branched alkenyl with before preferably 1 to 6, in particular 1 to 4 carbon atoms. Be exemplary optionally substituted vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2- propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2- butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3- butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1- Ethyl-2-propenyl, 2-hexenyl, 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-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,  3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-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, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2- butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2- called propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl.

Optionally substituted ethenyl, 2-propenyl, 2-butenyl are preferred or called 1-methyl-2-propenyl.

Optionally substituted alkynyl alone or as part of a radical in the general formulas means straight-chain or branched alkynyl with preference example 1 to 6, in particular 1 to 4 carbon atoms. Examples are given optionally substituted ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2- propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3- Hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl- 4-pentinyl, 2-methyl-3-pentinyl, 2-methyl-4-pentinyl, 3-methyl-4-pentinyl, 4- Methyl-2-pentynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3- butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl called.

Optionally substituted ethynyl, 2-propynyl or 2-butynyl are preferred called.

Optionally substituted cycloalkyl alone or as part of a radical in the general formulas mean mono-, bi- and tricyclic cycloalkyl preferably with 3 to 10, in particular 3, 5 or 7 carbon atoms. Exemplary be optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and Called Adamantyl.  

Haloalkyl alone or as part of a radical in the general formulas contains 1 to 4, especially 1 or 2 carbon atoms with preferably 1 to 9, in particular 1 to 5 identical or different halogen atoms, preferably fluorine, Chlorine or bromine, especially fluorine or chlorine. Examples include trifluoromethyl, Trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, chloromethyl, bromine methyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2- Trichloro-ethyl, 2-chloro-2,2-difluoroethyl, pentafluoroethyl and pentafluoro-tert-butyl called.

Optionally substituted alkoxy alone or as part of a radical in the general formulas means straight-chain or branched alkoxy with preference example 1 to 6, in particular 1 to 4 carbon atoms. Examples are given optionally substituted methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobut called oxy, sec-butoxy and tert-butoxy.

Optionally substituted alkoxyalkoxy alone or as part of a radical in the general formulas 2 means C-O-linked alkoxy radicals such as aforementioned. Examples include optionally substituted methoxymethoxy, Methoxyethoxy, methoxy-n-propoxy and ethoxyisopropoxy called.

Optionally substituted alkoxyalkoxyalkoxy alone or as part of one The rest in the general formulas mean 3 each C-O-linked Alkoxy radicals as mentioned above. Examples are optionally substituted ones Methoxymethoxyethoxy, methoxyethoxyethoxy and methoxyethoxy-n-propoxy called.

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

Optionally substituted alkylthio alone or as part of a radical in the general formulas mean straight-chain or branched alkylthio preferably 1 to 6, in particular 1 to 4 carbon atoms. Be exemplary optionally substituted methylthio, ethylthio, n-propylthio, isopropylthio, n- Butylthio, Isobutylthio, sec-Butylthio and tert-Butylthio called.

Optionally substituted haloalkylthio alone or as part of a The rest in the general formulas mean straight-chain or branched halo genalkylthio with preferably 1 to 6, in particular 1 to 4 carbon atoms. Examples include optionally substituted difluoromethylthio, trifluoro methylthio, trichloromethylthio, chlorodifluoromethylthio, 1-fluoroethylthio, 2-fluorine ethylthio, 2,2-difluoroethylthio, 1,1,2,2-tetrafluoroethylthio, 2,2,2-trifluoroethylthio and called 2-chloro-1,1,2-trifluoroethylthio.

Optionally substituted alkylcarbonyl alone or as part of a radical in the general formulas means straight-chain or branched alkylcarbonyl with preferably 1 to 6, in particular 1 to 4 carbon atoms. Be exemplary optionally substituted methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, Isopropylcarbonyl, sec-butylcarbonyl and tert-butylcarbonyl called.

Optionally substituted cycloalkylcarbonyl alone or as part of a The rest in the general formulas mean mono-, bi- and tricyclic cyclo alkylcarbonyl, preferably with 3 to 10, in particular 3, 5 or 7 carbon atoms. Examples include optionally substituted cyclopropylcarbonyl, Cyc lobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, Cyclooctylcarbonyl, bicyclo [2.2.1] heptylcarbonyl, bicyclo [2.2.2] octylcarbonyl and Called adamantylcarbonyl.  

Optionally substituted alkoxycarbonyl alone or as part of a radical in the general formulas means straight-chain or branched alkoxycarbonyl with preferably 2 to 7, in particular 2 to 5 carbon atoms. Be exemplary optionally substituted methoxycarbonyl, ethoxycarbonyl, n-propoxy carbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxy called carbonyl and tert-butoxycarbonyl.

Aryl is, for example, a mono-, polynuclear or polynuclear aromatic radical such as Phenyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl and the like, preferred however, phenyl or naphthyl.

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

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

The optionally substituted radicals of the general formulas can carry one or more, preferably 1 to 3, in particular 1 to 2 identical or different substituents. Examples of preferred substituents are:
Alkyl with preferably 1 to 4, in particular 1 to 2 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; Alkoxy preferably having 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; Haloalkyl preferably having 1 to 5, in particular 1 to 3, halogen atoms, the halogen atoms being identical or different and halogen atoms, preferably fluorine, chlorine or bromine, in particular fluorine or chlorine, such as difluoromethyl, trifluoromethyl, trichloromethyl; Hydroxy; Halogen, preferably fluorine, chlorine, bromine and iodine, especially fluorine and chlorine; Cyano; Nitro; Amino; Monoalkyl- and dialkylamino with preferably 1 to 4, in particular 1 or 2 carbon atoms per alkyl group, such as methylamino, methylethylamino, dimethylamino, n-propylamino, isopropyl amino, methyl-n-butylamino; Alkylcarbonyl radicals such as methylcarbonyl; Alkoxy carbonyl with preferably 2 to 4, in particular 2 to 3 carbon atoms such as methoxycarbonyl and ethoxycarbonyl; Alkylsulfinyl with 1 to 4, in particular 1 to 2, carbon atoms; Haloalkylsulfinyl with 1 to 4, in particular 1 to 2, carbon atoms and 1 to 5 halogen atoms, such as trifluoromethylsulfinyl; Halogen alkylsulfonyl with 1 to 4, in particular 1 to 2 carbon atoms and 1 to 5 halogen atoms such as trifluoromethylsulfonyl, perfluoro-n-butylsulfonyl, perfluoro isobutylsulfonyl; Arylsulfonyl preferably having 6 or 10 aryl carbon atoms such as phenylsulfonyl; Acyl, aryl, aryloxy, which in turn can carry one of the above-mentioned substituents and the formimino radical (-HC = NO-alkyl).

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

Optionally substituted mono- or dialkylamino groups alone or as Part of a radical in the general formulas means straight-chain or branched alkyl with preferably 1 to 6, in particular 1 to 4 carbons atoms of matter. Examples of substituted mono- or dialkylamino groups are Methylamino, ethylamino, dimethylamino, diethylamino, di-n-propylamino, diiso called propylamino or dibutylamino.  

Optionally substituted mono- or dialkoxyalkylamino groups alone or as Part of a radical in the general formulas means straight-chain or branched alkoxyalkyl with preferably 1 to 6, in particular 1 to 4 carbons atoms of matter. Exemplary for substituted mono- or dialkoxyalkylamino groups be methoxymethylamino, methoxyethylamino, di (methoxymethyl) amino or Called di (methoxyethyl) amino.

Suitable cyclic amino groups are heteroaromatic or aliphatic ring systems with one or more nitrogen atoms as heteroatom in Question where the heterocycles are saturated or unsaturated, a ring system or can be several condensed ring systems, and optionally further Heteroatoms such as one or two nitrogen, oxygen and sulfur etc. included. In addition, cyclic amino groups can also have a spiro ring or mean a bridged ring system. The number of atoms, the cyclic Forming amino groups is not limited, for example they exist in the case of a Single ring system from 3 to 8 atoms and in the case of a three ring system from 7 to 11 Atoms.

Exemplary for cyclic amino groups with saturated and unsaturated mono cyclic groups with a nitrogen atom as hetero atom are 1-azetidinyl, Pyrrolidino, 2-pyrrolin-1-yl, 1-pyrrolyl, piperidino, 1,4-dihydropyrazin-1-yl, 1,2,5,6-tetrahydropyrazin-1-yl, 1,4-dihydropyridin-1-yl, 1,2,5,6-tetrahydropyridin- 1-yl, called homopiperidinyl; exemplary for cyclic amino groups with saturated and unsaturated monocyclic groups with two or more Nitrogen atoms as heteroatoms are 1-imidazolidinyl, 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 1-tetrazolyl, 1-piperazinyl, 1-homopiperazinyl, 1,2-dihydropyridazine 1-yl, 1,2-dihydro-pyrimidin-1-yl, perhydropyrimidin-1-yl, 1,4-diazacyclo-heptan-1- called yl; exemplary of cyclic amino groups with saturated and unsaturated monocyclic groups with one or two oxygen atoms and one to three nitrogen atoms as heteroatoms, such as oxazolidin-3-yl,  2,3-dihydroisoxazol-2-yl, isoxazol-2-yl, 1,2,3-oxadiazin-2-yl, morpholino playful for cyclic amino groups with saturated and unsaturated mono cyclic groups with one to three nitrogen atoms and one to two Sulfur atoms as heteroatoms are thiazolidin-3-yl, isothiazolin-2-yl, thio called morpholino, or dioxothiomorpholino; exemplary of cyclic amino groups with saturated and unsaturated condensed cyclic groups Indol-1-yl, 1,2-dihydrobenzimidazol-1-yl, perhydropyrrolo [1,2-a] pyrazin-2-yl called; that is exemplary of cyclic amino groups with spirocyclic groups Called 2-azaspiro [4,5] decan-2-yl; exemplary for cyclic amino groups with bridged heterocyclic groups is 2-azabicyclo [2,2,1] heptan-7-yl called.

Suitable monovalent amino protecting groups are acyl groups, preferably having 1 to 6, in particular 1 to 4, carbon atoms, such as, for example, formyl, acetyl, propionyl, pivaloyl, hexanoyl or mono- (or di- or tri-) halogen-containing acyl groups, such as 2-chlorine -, 2-bromo, 2-iodo, 2,2-dichloroacetyl, 2,2,2-trifluoroacetyl or 2,2,2-trichloroacetyl, alkoxycarbonyl groups with preferably 1 to 14, in particular 1 to 4 carbon atoms, such as, for example Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxy carbonyl (Boc), tert-amyloxycarbonyl (Aoc), hexyloxycarbonyl, methylsulfonylethoxycarbonyl, adamantyloxycarbonyl (Adoc) and 1- [1-adamantyl] -1-methylethoxycarbonyl (Adpoc), carbamoyl groups, aroyl groups such as phenyl acetyl and phenylpropionyl, aryloxycarbonyl groups such as phenoxy carbonyl and naphthyloxycarbonyl, aryloxyalkanoyl groups such as phenoxyacetyl, and phenoxypropionyl, arylglyoxyloyl groups such as For example, phenylglyoxyloyl and naphthylglyoxyloyl, alkoxycarbonyl groups with common substituents, such as benzyloxycarbonyl (Cbo- or Cbz, Z), 4-methoxybenzyloxycarbonyl, 3,5-dimethoxy-benzyloxycarbonyl, 4-phenylazo benzyl-oxycarbonyl, phenethyloxycarbonylcarbonyl, nitro-chlorobenzene -benzyl oxycar-bonyl, α, α-dimethyl-3,5-dimethoxy-benzyloxycarbonyl, 2-nitro-4,5-dimethoxy-benzyl-oxycarbonyl (Nvoc), fluorenyl-9-methoxycarbonyl (Fmoc), substituted or unsubstituted alkylidene groups , such as benzylidene, hydroxybenzylidene, mono- (or di- or tri-) phenylalkyl-containing alkyl groups, such as benzyl, phenethyl, benzhydryl or triphenylmethyl (trityl), and the like, in question. Suitable bivalent amino protecting groups are mono- or disubstituted methylidene groups, such as 1-lower alkoxy (for example methoxy or ethoxy)-lower alkylidene (for example ethylidene or 1-n-butylidene), for. B. = C (CH ₃ ) (OC ₂ H ₅ ), further z. B. = C (CH ₃ ) ₂ or = CH-phenyl, and in particular bisacyl radicals, e.g. B. the phthalyl radical, which forms a 1H-isoindole-1,3 (2H) -dione (phthalimide group) together with the nitrogen atom to be protected.

Amino protecting groups, and their introduction and splitting off are known per se and e.g. B. 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.

Optionally substituted alkyl come as suitable hydroxy protecting groups groups with preferably 1 to 6, in particular 1 to 4 carbon atoms, as in for example tert-butyl, methylthiomethyl and trimethylsilyl, phenylalkyl-containing Alkyl groups such as benzyl or diphenylmethyl, heterocyclic Groups such as tetrahydropyranyl and the like are questionable.

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

The protective groups mentioned above have those known in peptide chemistry Function, amino, hydroxy or thiol groups of compounds temporarily protect.  

As suitable synthetic resins for use as polymeric supports for the solid phase Synthesis of the cyclodepsipeptides according to the invention come accordingly nalized base polymers (in the most common form on a chloromethylated Polystyrene), such as amino-oxy- or hydrazino-functionalized resins of the Merrifield type. This is particularly suitable commercially Available DHP HM resin from Novabiochem, it allows easy anchoring with a hydroxylamino or hydrazino function and thus enables Provision of the cyclodepsipeptides according to the invention.

Compounds of the general formula (Ia) are particularly preferred

in which
R ¹ , R ⁴ , R ⁷ and R ^{10 represent} methyl,
R ² , R ⁵ , R ⁸ and R ^{11 represent} isobutyl,
R ⁶ and R ^{12 represent} methyl,
R ³ and R ⁹ independently of one another for optionally substituted benzyl, hydrogen, halogen, in particular bromine, fluorine, chlorine or iodine, cyano, carbamoyl, a protective group-bearing hydroxy or unprotected hydroxy, C _1-8 alkoxy, in particular being mentioned as substituents Methoxy, tert-butyloxy, C _1-4 alkoxy-C _1-4 alkoxy, especially methoxymethoxy, 2-methoxyethoxy, C _2-4 alkenyloxy, especially allyloxy, hetaryl-C _1-4 alkoxy, especially Fur-2 -yl-methoxy, tetrahydrofur-2-yl-methoxy, N-Boc-pyrrolidin-2-yl-methoxy, pyrrolidin-2-yl-methoxy, 5-sec-butyl-1,2,4-oxadia zol-3- yl-methoxy, 5-cyclopropyl-1,2,4-oxadiazol-3-yl-methoxy, imidazol-5-yl-methoxy, thiazolylmethoxy, tetrazol-5-yl-methoxy, thienylmethoxy, nitro, or a radical from the series -O-CH ₂ -CH ₂ -NR ²³ R ²⁴ , -CH ₂ -NR ²³ R ²⁴ , -NR ²³ R ²⁴ and -SO ₂ -NR ²³ R ²⁴ ,
R ²³ and R ²⁴ 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, tetra hydrofur-2-yl-methyl, Pyrrolidin-2-yl-,
R ²³ and R ²⁴ together with the nitrogen atom to which they are attached, for hetaryl, in particular N-pyrrolidino, N-piperazino, N-morpholino, N-thiomorpholino, N-piperidino, N-imidazolo, 2-oxopyrrolidino , Phthalimino or tetrahydrophthalimino, stand,
A represents hydrogen, cyano or optionally a radical A ¹

-YR ¹³ A ¹ )

in which
Y represents oxygen or -NR ¹⁴ , where
R ¹³ and R ¹⁴ independently of one another are hydrogen, straight-chain or branched C _1-4 -alkyl, in particular methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C ₁ -C ₄ -alkylcarbonyl, in particular methylcarbonyl, Ethylcarbonyl, cyano-C ₁ -C ₄ -alkyl, amino-C ₁ -C ₄ -alkyl, hydroxy-C ₁ -C ₄ -alkyl, C _1-4 -alkylsulfonyl, especially methyl sulfonyl, C _1-2 -haloalkoxy- C _1-2 alkylsulfonyl, in particular 1,1,1-trifluoroethoxyethylsulfonyl, straight-chain or branched C _1-4 alkyloxycarbonyl, in particular methoxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, tert-butyloxycarbonyl, straight-chain carbonyl _1-4 alkylaminocarbonyl, especially methylamino carbonyl, ethylaminocarbonyl, C _2-4 alkenyl, especially vinyl, 2-propenyl, 2-butenyl, C _2-4 alkenyloxycarbonyl, especially vinyl oxycarbonyl, 2-propenyloxycarbonyl, 2-butenyloxycarbonyl, C. _2-4 - haloalkenyloxycarbonyl, especially ere 1,1,2-trifluorobut-1-en-4-yl-oxycarbonyl, C _2-4 -alkenylaminocarbonyl, especially 2-propenylaminocarbonyl, C _2-4 -alkynyl, especially 2-propynyl, C _2-4 -alkynyl oxycarbonyl, in particular 2-propynyloxycarbonyl, cyanomethyl, hydroxyethyl, aminoethyl, arylC _1-2 alkyl, in particular optionally substituted benzyl, hetarylC _1-2 alkyl, in particular optionally substituted hetarylmethyl, in particular optionally substituted tetrahydrofurylmethyl, furylmethyl, Thienylmethyl, thiadiazolylmethyl, tetrazolylmethyl, pyridylmethyl, aryloxy-C _1-2 alkyl, in particular optionally substituted phenoxyethyl, optionally substituted hetarylcarbonyl, hydrogen, nitro, amino, halogen, in particular bromine, chlorine or fluorine, C _1-4 being mentioned as substituents -Alkyl, especially methyl, C _1-4 - haloalkyl, especially trifluoromethyl, phenyl, C _1-4 alkoxy, especially methoxy, C _1-4 alkoxycarbonyl, especially methoxy carbonyl, N-morpholinyl, or H etarylcarbonylmethyl, in particular N-morpholinocarbonylmethyl, N-pyrrolidinocarbonylmethyl, or optionally represents a radical of group B ⁴ ,

in which

represents a selectively removable protecting group, for example acetyl (Ac), allyloxycarbonyl (Alloc), benzyloxycarbonyl (Z) or tert-butyloxycarbonyl (Boc),
R ^{19 represents} hydrogen,
R ^{20 represents} hydrogen, propyl, isopropyl, isobutyl, benzyl, 4-hydroxybenzyl, imidazol-4-yl-methyl, indol-3-ylmethyl, phenyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-methylthioethyl, 2-carbamoylethyl ,
R ^{21 represents} hydrogen or C ₁ -C ₄ alkyl,
and their optical isomers, racemates and their physiologically acceptable salts.

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

in which
R ¹ , R ⁴ , R ⁷ and R ^{10 represent} methyl,
R ² , R ⁵ , R ⁸ and R ^{11 represent} isobutyl,
R ⁶ and R ^{12 represent} methyl,
R ³ and R ^{9 represent} benzyl,
A for -NHMe or a radical A ¹

-YR ¹³ (A ¹ )

in which
Y stands for oxygen,
R ¹³ for hydrogen, straight-chain or branched C _1-4 alkyl, in particular methyl, ethyl, propyl, tert-butyl, C _1-4 alkyl sulfonyl, in particular methylsulfonyl, C ₁ -C ₄ alkylcarbonyl, in particular methylcarbonyl, cyano- C ₁ -C ₄ -alkyl, hydroxy-C ₁ -C ₄ -alkyl, amino-C ₁ -C ₄ -alkyl, C _1-2 -haloalkoxy-C _1-2 - alkylsulfonyl, in particular 1,1,1-trifluoroethoxyethylsulfonyl , straight-chain or branched C _1-4 alkyloxycarbonyl, in particular methoxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, sec-butyl oxycarbonyl, tert-butyloxycarbonyl, C _2-4 alkenyl, 2-propenyl, C _2-4 alkenyloxycarbonyl , in particular vinyloxycarbonyl, 2-propenyloxycarbonyl, C _2-4 -haloalkenyloxycarbonyl, in particular 1,1,2-trifluorobut-1-en-4-yl-oxycarbonyl, C _2-4 -alkenyl aminocarbonyl, in particular 2-propenylaminocarbonyl, C _{2 -4} - alkynyloxycarbonyl, in particular 2-propynyloxycarbonyl, aryl-C _1-2 -alkyl, in particular optionally substituted benzyl, N-morpholinocarbonylmethyl, N-pyrrolidinocarbonylmethyl, hetaryl-C _1-2 -alkyl, in particular optionally substituted tetrahydrofurylmethyl, furylmethyl, 5-chlorothia diazol-4-yl-methyl, N-methyl-tetrazol-5-yl-methyl , Pyridyl methyl, 2-chloro-pyrid-5-yl-methyl, aryloxy-C _1-2 alkyl, in particular special optionally substituted phenoxyethyl, trifluoromethylphenoxyethyl, optionally substituted hetaryl carbonyl, in particular optionally substituted furyl carbonyl, pyridylcarbonyl, where as substituents Hydrogen, nitro, amino, halogen, in particular bromine, chlorine or fluorine, methyl, trifluoromethyl, phenyl, methoxy, methoxycarbonyl, N-morpholinyl, or optionally a radical from group B ⁴ , may be mentioned,

in which

stands for a selectively removable protective group, for example acetyl (Ac), allyloxycarbonyl Alloc), benzyloxy carbonyl (Z) or tert-butyloxycarbonyl (Boc),
R ^{19 represents} hydrogen,
R ^{20 represents} hydrogen, methyl, propyl, isopropyl, isobutyl,
R ^{21 represents} hydrogen or methyl,
and their optical isomers, racemates and their physiologically acceptable salts.

The general or preferred areas listed above Residual definitions or explanations can be among themselves, that is, between the respective areas and preferred areas can be combined as desired. they seem for the end products as well as for the preliminary and intermediate products accordingly.

The cycloiminodepsipeptides of the general to be used according to the invention Formula (I) and its salts also contain one or more centers of chirality and can therefore be used as pure stereoisomers or in the form of various enantiomer and mixtures of diastereomers are present, if necessary in a manner known per se Can be separated or by stereoselective reactions in Combination with the use of stereochemically pure starting materials getting produced.

However, the optically active, stereoisomeric forms of Ver bonds of the general formula (I) and their salts used according to the invention.  

The cyclic depsipeptides which result from (S) -configured amino acids (L-form) and D-configured hydroxycarbon Assemble acids (D-form) as ring building blocks.

The invention therefore relates to both the pure enantiomers and diastereomers, as well as their mixtures for controlling endoparasites, especially on the Field of medicine and veterinary medicine.

Suitable salts of the cycloiminodepsipeptides of the general formula (I) can be: usual non-toxic salts, i. H. Salts with different bases and salts with added acids. Salts with inorganic are preferred Bases, such as alkali metal salts, for example sodium, potassium or cesium salts, Alkaline earth metal salts, for example calcium or magnesium salts, ammonium salts, salts with organic bases and with inorganic amines, for example Triethylammonium, dicyclohexylammonium, N, N'-dibenzylethylene diammonium, Pyridinium, picolinium or ethanolammonium salts, salts with inorganic Acids, for example hydrochlorides, hydrobromides, dihydrosulfates, trihydro sulfates, or phosphates, salts with organic carboxylic acids or organic sul fonic acids, for example formates, acetates, trifluoroacetates, maleates, tartrates, Me thanesulfonates, benzenesulfonates or para-toluenesulfonates, salts with basic ami non acids, for example arginates, aspartates or glutamates and the like nen.

Methods for the introduction of optionally substituted imino functions in synthetic peptides or pharmacologically interesting heterocycles are from the Literature known.

The appropriate endothiopeptides or heterocyclic thiolactams can preferably be used as suitable starting components. The syntheses of amidoxime, cyanamidine and amidrazone alalogas of chemotactic peptides from endothiopeptides may be mentioned as examples (G. Sauve et al., Can. J. Chem. 61, 1985, p. 3089). A representation variant of the N ^ω -hydroxy-N ^ω -methyl- (R) -arginine from N ^α -tert-butoxycarbonyl-δ- (N-methyl-thioureido) - (R) -norvaline-tert-butyl ester was described by HA Moynihan et al. (J. Chem. Soc. Perkin Trans. I 1994, p. 769). Likewise, heterocyclic thiolactams in amidines (pyrrolo [2,1-c] [1,4] benzodiazepin-5,11-dione: M. Robba et al., Tetrahedron Lett. 33 (20), 1992, p. 2803) or convert azetidin-2-thione into azetidin-2-imine without problems (β-lactams: L. Ghosez et al., J. Chem. Soc., Chem. Commun. 1983, p. 818).

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

The compounds of the general formula (I) are new and can be used, for example Manufacture wisely according to the procedures given in points 2 and 3 above.

The methods according to the invention are selected below on the basis of Examples explained (see also manufacturing examples).

If method 2a is used to produce the new ones Cycloiminodepsipeptides of the general formula (Ia) as compounds of general formula (Ib) the cyclic thiodepsipeptide cyclo (-N-methyl-L-leucinyl- D-thiolactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N- methyl-L-leucinyl-D-phenyllactyl-) as amino compounds of the general formula (II) the O-methyl-hydroxylamine (A: -O-Me; see route A) or N-methylhydrazine (A: -NH-Me; see route B), the method can be described by the following Play reaction scheme Scheme I:  

Scheme I

When using the amino compounds of the general formula (II), the process 2a according to the invention the compounds of the general formula (I) arise as a mixture of syn and anti isomers.

Those used to carry out process 2a according to the invention as starting materials required cyclothiodepsipeptides are generally defined by the formula (Ib).

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

The cyclic thiodepsipeptides used as starting materials are from one previous patent application known and can accordingly via thionation  cyclic depsipeptides obtained using suitable sulfurization reagents are (see WO 98/43965, see also manufacturing examples).

The also for the implementation of the method 2a as Starting materials to be used are amino compounds by the general Formula (II) defined.

In this formula (II) A has the meaning already in connection with the Description of the substances of the general formula (I) according to the invention as before is called for this substituent.

The amino compounds of formula (II) are e.g. T. commercially available, partially known and can by known methods (see, for example, hetaryl methoxamine: US Pat. 5,489,680; DE-OS 21 19 012, alkoxyamines: EP-OS 495 750; DE-OS 22 06 890; D. Favara et al. Farmaco, Ed. Sci. 42 (10), 1987, p. 697).

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

Scheme II

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

The release of the compounds of formula (II) can be conveniently in the following Were carried out: The hydrazinolysis can preferably be carried out in one Diluents, for example alcohol, are carried out at boiling temperature. The Hydrolysis can preferably be carried out in an aqueous, aqueous-alcoholic or alcoholic holic solution can be carried out by heating for several hours. In case that R 'and R' 'together represent an isopropylidene group, can be of the acidic Hydrolysis and, in the event that R 'and R' 'together form an α-hydroxy-benzylidene Group or R '' means a carbethoxy group, both of the alkaline as well as acid hydrolysis can be used (see DE- OS 21 19 012; D. Favara et al. Farmaco, Ed. Sci. 42 (10), (1987) p. 697).

Inorganic salts, such as hydrochloric acid, are preferred for the preparation of the salts or sulfuric acid, in ethanolic or isopropanolic solution, used.  

The implementation of the thiodepsipeptides of the general formula (Ib) with the amino Compounds of the general formula (II) are preferably carried out in the presence a metal salt or metal oxide and optionally in the presence of a basic reaction auxiliary using diluents.

As suitable metal salts or metal oxides for carrying out the invention According to the process, all metal salts come with elements of I. and II. Subgroup of the periodic table in question. The Acetates, chlorides, bromides, iodides, fluorides, nitrates, sulfates, carbonates, tri fluoroborate, trifluoromethanesulfonate of copper, silver, gold, zinc, cadmium or mercury.

However, the carbonates, trifluoroborates and are preferably used Trifluoromethanesulfonate of metals of subgroup I, especially silver, and the acetates, oxides and the halides of the metals of subgroup II, especially mercury.

As a basic reaction auxiliary for carrying out the process according to the invention All suitable acid binders such as amines, ins special tertiary amines as well as alkali and alkaline earth compounds.

Examples include the hydroxides, oxides and carbonates of lithium, Sodium, potassium, magnesium, calcium and barium, as well as other basic ones Compounds such as amidine bases or guanidine bases such as 7-methyl-1,5,7-triazabi cyclo (4.4.0) dec-5-ene (MTBD); Diazabicyclo (4.3.0) nonen (DBN), diazabicyclo- (2.2.2) octane (DABCO), 1,8-diazabicyclo (5.4.0) undecene (DBU), cyclohexyl tetra butylguanidine (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-p-aminopyridine, N-methyl-pyrrolidine,  N-methyl-piperidine, N-methyl-imidazole, N-methyl-pyrrole, N-methylmorpholine, N- Methyl-hexamethyleneimine, pyridine, 4-pyrrolidinopyridine, 4-dimethylamino-pyridine, Quinoline, α-picoline, β-picoline, isoquinoline, pyrimidine, acridine, N, N, N ', N' - Tetramethylene diamine, N, N ', N'-tetra-ethylene diamine, quinoxaline, N-propyl diiso propylamine, N-ethyl-diisopropylamine, N, N'-dimethylcyclohexylamine, 2,6-lutidine, 2,4-lutidine or triethylene diamine.

Preferably tertiary amines, especially trialkylamines such as triethylamine, N, N-diisopropylethylamine, N-propyl-diisopropylamine, N, N'-dimethylcyclohexyl amine or N-methylmorpholine, use.

In general, it is advantageous to process 2a according to the invention in the presence of diluents. Diluents are advantageous in such an amount used that the reaction mixture throughout Process remains stirrable. As a diluent to carry out the inventions Process 2a according to the invention all inert organic solvents Question.

Examples include: halogenated hydrocarbons, especially chlorine hydrocarbons, such as tetrachlorethylene, tetrachloroethane, dichloropropane, methy lenchloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, Trichlorethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene, Bromobenzene, dichlorobenzene, chlorotoluene, trichlorobenzene; Alcohols like methanol, Ethanol, isopropanol, butanol; Ethers such as ethyl propyl ether, methyl tert-butyl ether, n- Butyl ether, anisole, phenetol, cyclohexyl methyl ether, dimethyl ether, diethyl ether, Dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, Ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, dichlorodiethyl ether and Polyethers of ethylene oxide and / or propylene oxide: amines such as trimethyl, Triethyl, tripropyl, tributylamine, N-methylmorpholine, pyridine and Tetramethylene diamine, nitro hydrocarbons such as niromethane, nitroethane, Nitropropane, nitrobenzene, chloronitrobenzene, o-nitrotoluene; Nitriles such as acetonitrile,  Propionitrile, butyronitrile, isobutyronitrile, benzonitrile, m-chlorobenzonitrile as well Compounds such as tetrahydrothiophene dioxide and dimethyl sulfoxide, tetra methylene sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, Dibutyl sulfoxide, diisoamyl sulfoxide; Sulfones such as dimethyl, diethyl, dipropyl, Dibutyl, diphenyl, dihexyl, methylethyl, ethylpropyl, ethylisobutyl and Pentamethylene sulfone; aliphatic, cycloaliphatic or aromatic carbons Hydrogen such as pentane, hexane, heptane, octane, nonane and technical coals Hydrogen, for example so-called white spirits with boiling components score in the range, for example, from 40 ° C to 250 ° C, Cymol, gasoline fractions within a boiling point interval of 70 ° C to 190 ° C, cyclohexane, Methylcyclohexane, petroleum ether, ligroin, octane, benzene, toluene, chlorobenzene, Bromobenzene, nitrobenzene, xylene; Esters such as methyl, ethyl, butyl, isobutyl acetate, as well as dimethyl, dibutyl, ethylene carbonate; Amides such as hexamethylenephos phosphoric triamide, formamide, N-methyl-formamide, N, N-dimethylformamide, N, N- Dipropylformamide, N, N-dibutylformamide, N-methyl-pyrrolidine, N-methyl caprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidine, octylpyrrolidone, Octylcaprolactam, 1,3-dimethyl-2-imidazolinedione, N-formylpiperidine, N, N'-1,4- Diformylpiperazine; Ketones such as acetone, acetophenone, methyl ethyl ketone, methyl butyl ketone.

Of course, you can also in the process of the invention mixtures of Use the solvents and diluents mentioned.

Preferred diluents for carrying out the ver according to the invention However, nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, Benzonitrile or m-chlorobenzonitrile, especially 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, especially chlorinated hydrocarbons, such as tetra  chlorethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, Chloroform, carbon tetrachloride, trichloroethane, trichlorethylene or penta chloroethane, especially methylene chloride, chloroform or carbon tetrachloride.

The reaction of amino compounds of the general formula (II) according to the process ren 2a is carried out by using the cyclothiodepsipeptides of the general Formula (Ib) in the presence of an amino compound of the general formula (II), in Presence of a specified metal salt or metal oxide with elements of I. and II. subgroup of the periodic table and optionally in the presence of a specified basic reaction auxiliary in one of the specified ver implement fertilizer.

The reaction time is 10 minutes to 48 hours. The implementation takes place at Temperatures between -10 ° C and + 200 ° C, preferably between + 10 ° C and + 180 ° C, particularly preferably at room temperature. It can basically be under Normal pressure can be worked. Preferably one works at normal pressure or at pressures up to 15 bar and possibly under a protective gas atmosphere (stick fabric or helium).

To carry out the method 2a according to the invention, one is used for each existing one Thioamide group in the cyclothiodepsipeptides of the general formulas (Ib) in generally 0.5 to 7.0 mol, preferably 1.0 to 5.0 mol, particularly preferably 2.0 up to 3.0 moles of an amino compound of the general formula (II).

Furthermore, 2a pro is used to carry out the method according to the invention Thioamide group present in the compounds of the general formulas (Ib) generally 0.5 to 6.0 moles, preferably 1.0 to 4.0 moles, particularly preferred 1.5 to 2.5 moles of metal salt or metal oxide.

After completion of the implementation, the entire reaction batch is replaced by the one that fails Metal sulfide separated and optionally washed. The resulting products  can be in the usual way by recrystallization, vacuum distillation or Clean column chromatography (see also the preparation examples).

If the processes 2b and 2c according to the invention are used to prepare the new cycloiminodepsipeptides of the general formula (Ia) as compounds of Formula (Ic), for example, the cyclic iminodepsipeptide cyclo [-N-methyl-L-leuci nyl-D- (hydroxy-imino) lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leu cinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) and as compounds of all general formula (III) chloroformic acid vinyl ester (see. Route C) and as Compounds of the general formula (IV) acetic anhydride (see. Route D), see above the processes can be represented by the following reaction scheme III.

Scheme III

The in particular for performing the methods 2b and 2c according to the invention Cycloiminodepsipeptides and their salts are required by the Formula (Ic) generally defined.

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

The cycloiminodepsipeptides of the general used as starting materials Formula (Ic) (Y: -O-) are new and can be either according to the above described method 2a or according to method 3 described below be preserved.

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

Scheme IV

The also for the implementation of the methods 2b and 2c according to the invention Compounds to be used are generally represented by the formulas (III) and (IV) defined.

Have in formulas (III) and (IV)

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

The compounds of formula (III) are generally known compounds of organic chemistry or z. T. commercially or according to literature Methods are obtained (e.g. Houben Weyl, methods of organic chemistry, Volume E4).

The implementation of the Cycloiminodepsipeptide (Ic) with compounds of the general Formula (III) is preferably carried out in the presence of basic reaction aids averages using diluents.

As a basic reaction aid for carrying out the Ver 2b, all acid binders mentioned in process 2a, such as amines, in particular tertiary amines.

Process 2b preferably finds the tertiary amines, in particular trialkyl amines such as triethylamine, N, N-diisopropylethylamine, n-propyldiisopropylamine, N, N'-dimethylcyclohexylamine or N-methylmorpholine and pyridine derivatives, especially pyridine, use.

Mixtures can of course also be used in process 2b according to the invention use the acid binders mentioned.  

As a diluent for performing method 2b according to the invention find the inert, aprotic solvents mentioned in process 2a such as e.g. B. Dioxane, acetonitrile or tetrahydrofuran but also halogenated hydrocarbons, in particular chlorinated hydrocarbons, such as methylene chloride or chloroform, Use.

Process 2b is carried out using compounds of the general Formula (Ic) in the presence of basic reaction auxiliaries with compounds of general formula (III) optionally in one of the specified dilutions medium implemented.

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

To carry out process 2c according to the invention as starting materials Carboxylic anhydrides using are generally defined by formula (IV).

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

To carry out process 2b according to the invention, the starting point is per mole Compound of formula (Ic) generally 2.0 to 8.0 moles, preferably 2.0 to 4.0 Mole of acylating agent, a.

To carry out process 2c according to the invention, one starts out per mole Compound of formula (Ic) generally 1.0 to 3.0 moles, preferably 1.0 to 1.5 moles of carboxylic anhydride, a.  

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

When the reaction is complete, the reaction solution is washed, the organic one Phase separated, dried and concentrated in vacuo. The resulting products can be in the usual way by recrystallization, vacuum distillation or Clean column chromatography (see also the preparation examples).

If 2d α) and β) are used to produce the new cycloiminodepsipeptides of the general formula (Ia) as compounds of Formula (Ic), for example, the cyclic iminodepsipeptide cyclo [-N-methyl-L-leuci nyl-D- (hydroxy-imino) lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leu cinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) as compounds of the gen my formula (V) (S) -N-tert-butyloxycarbonyl-N-methylalanine ((S) -Boc-MeAla- OH; see. Route E) and as compounds of the general formula (VI) allyl isocyanate (see route F), the processes can be described by the following reaction scheme V play.

Scheme V

The to carry out the process 2d α) and β) as off Cycloiminodepsipeptides required are general by the formula (Ic) Are defined.

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

Which in particular for the implementation of the method 2d α) as Compounds to be used are generally represented by the formula (V) defined.

Have in formula (V)

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

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

Examples include:
Aad, Abu, γAbu, Abz, 2Abz, εAca, Acp, Adpd, Ahb, Aib, βAib, Ala, βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys) ₂ , Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla , hArg, hCys, hGln, hGlu, His, hIle, hLeu, hLys, hMet, hPhe, Pro, hSer, hThr, hTrp, hTyr, HyI, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu , Lsg, Lys, βLys, ΔLys, Met, 75717 00070 552 001000280000000200012000285917560600040 0002019926620 00004 75598Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Pya, P , Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, βThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, Nal, Tbg, Npg, Chg, Thia (see e.g. Houben-Weyl, Methods of Organic Chemistry, Volume XV / 1 and 2, Stuttgart, 1974).

The compounds of general formula (V) z. T. commercial or after methods known from the literature can be obtained (cf., for example, N-methylamino acids: R. Bowmann et al., J. Chem. Soc. 1950, p. 1346; J.R. McDermott et al., Can J. Chem. 51 (1973), p. 1915; H. Wurziger et al., Contacts (Merck, Darmstadt) 3 (1987), p. 8).

The implementation of the cycloiminodepsipeptides of the general formula (Ic) with amino Acid derivatives of the formula (V) are preferably carried out in the presence of Coupling reagents and in the presence of a basic reaction auxiliary Use of diluents.

As coupling reagents for carrying out the method 2d α find all those for Production of an amide bond are suitable [cf. e.g. E.g .: Houben-Weyl, methods der organic chemistry, volume 15/2; Bodanszky et al., Peptide Synthesis 2nd ed. (Wiley & Sons, New York 1976) or Gross, Meienhofer, The Peptides: Analysis Synthesis, Biology (Academic Press, New York 1979)], use. Preferably The following methods are used: Active ester method with pentachlor (Pcp) and pentafluorophenol (Pfp), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbor nen-2,3-dicarboxamide (HONB), 1-hydroxy-benzotriazole (HOBt) or 3-hydroxy-4- oxo-3,4-dihydro-1,2,3-benzotriazine as alcohol component, coupling with carbo diimides such as dicyclohexylcarbodiimide (DCCI) according to the DCC additive process, or with n-propanephosphonic anhydride (PPA) and mixed anhydride method with pivaloyl chloride, ethyl (EEDQ) and isobutyl chloroformate (IIDQ) or coupling with phosphonium reagents such as benzotriazol-1-yl-oxy-tris (dimethylamino-phos phonium) hexafluorophosphate (BOP), bis (2-oxo-3-oxazolidinyl) phosphonic acid chloride (BOP-Cl), benzotriazol-1-yl-tris-pyrrolidinophosphonium hexafluorophos  phate (PyBOB®), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP®) or with phosphonic acid ester reagents such as cyanophosphonic acid diethyl ester (DEPC) and diphenylphosphoryl azide (DPPA) or uronium reagents, such as 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2- (5-norbornene-2,3-dicarboxamido) -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-tetramethyluro nium hexafluorophosphate (HBTU).

Coupling with phosphonium reagents such as bis (2-oxo-3-oxazoli is preferred dinyl) phosphonium chloride (BOP-Cl), benzotriazol-1-yl-oxy-tris (dimethyl aminophosphonium) hexafluorophosphate (BOP), benzotriazol-1-yl-tris-pyrrolidino phos-phonium hexafluorophosphate (Py BOB®), Bromo-tris-pyrrolidino-phospho nium hexafluorophosphate (PyBroP®) and phosphonic acid ester reagents, such as cyan phosphonic acid diethyl ester (DEPC) or diphenylphosphoryl azide (DPPA).

As a basic reaction auxiliary for carrying out the process according to the invention ens 2d α) can also be used with all acid binding agents suitable for varing 2a be used.

Tertiary amines are preferred, especially trialkylamines such as triethyl amine, N, N-diisopropylamine, N-propyldiisopropylamine, N, N'-dimethylcyclo hexylamine or N-methylmorpholine in question.

As a diluent for carrying out process 2d α) find the solvents mentioned in method 2a such as. B. halogens Hydrogen, especially chlorinated hydrocarbons, such as methylene chloride, chloro form or 1,2-dichloroethane and mixtures of these with others mentioned Thinners, use.  

The process is generally carried out in such a way that compounds of general formula (Ic) in the presence of one of the basic reactions indicated auxiliaries with compounds of the general formulas (V) in one of the specified given diluent.

The reaction time is 4 to 72 hours. The implementation takes place at Tem temperatures between -10 ° C and + 120 ° C, preferably between -5 ° C and + 50 ° C, particularly preferably at 0 ° C to room temperature. It will be under normal pressure worked.

To carry out process 2d according to the invention, the starting point is per mole Compound of formula (Ic) generally 1.0 to 3.0 moles, preferably 1.0 to 1.5 Mole of coupling reagent.

Which in particular for the implementation of the method 2d β) as Compounds to be used are generally represented by the formula (VI) or (VII) defined.

In these formulas (VI) or (VII)

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

The compounds of general formulas (VI) or (VII) can, for. T. can be obtained commercially or according to methods known from the literature (cf. e.g. Houben-Weyl, Methods of Organic Chemistry, Volume E4).

The implementation of the Cycloiminodepsipeptide of general formula (Ic) with Compounds of the general formulas (VI) or (VII) are preferably carried out in Presence of diluents, optionally in the presence of a basic one Reaction aid, by.  

As a diluent for carrying out process 2d β) according to the invention find the solvents mentioned in method 2a such as. B. halogens Hydrogen, especially chlorinated hydrocarbons, such as methylene chloride, chloro form 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 n-hexane, n-heptane, benzene, toluene or xylene and mixtures of these with other diluents mentioned, use.

Process 2d β) can also be carried out in the presence of basic reaction auxiliaries be performed. As such basic reaction aids to carry out of process 2e according to the invention can all acid mentioned above binders, but preferably tertiary amines, especially trialkylamines such as Triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, and amidine bases or guanidine bases such as diazabicyclo (4.3.0) nonen (DBN), diazabi cyclo (2.2.2) octane (DABCO), 1,8-diazabicyclo (5.4.0) undecene (DBU), in particular 1,8-diazabicyclo (5.4.0) undecene (DBU), use.

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

The reaction time is 4 to 72 hours. The implementation takes place at Tempe temperatures between -10 ° C and + 180 ° C, preferably between -5 ° C and + 120 ° C, particularly preferably at 0 ° C to the boiling point of the dilution used by means of. Basically, it can work under normal pressure, but also at elevated pressure or reduced pressure. It is preferable to work at Normal pressure or for pressures up to 15 bar.  

To carry out process 2d β) according to the invention, the reaction is carried out per mole Compound of formula (Ic) generally 1.0 to 3.0 moles, preferably 1.0 to 1.5 mol of compound of the general formulas (VI) or (VII).

The invention further relates to new processes for the preparation of cycloiminode psipeptides of the general formula (Ic).

The cycloiminodepsipeptides of the general formula (Ic) (Y: -O-) are either directly according to method 2a from the thiodepsipeptides of the general formula (Ib) and Hydroxylamine as a compound of general formula (II) representable or can according to method 3 from suitable cycloiminodepsipeptides general formula (Ia) can be obtained.

If, for example, in method 3a for hydrogenation, the new cycloimino depsipeptide cyclo [-N-methyl-L-leucinyl-D- (benzyloxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl is used -L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) as a compound of the general formula (Ia) (A = A ¹ = -YR ¹³ : -O- CH ₂ -phenyl), the corresponding cycloiminodepsipeptide cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D- lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-) (see Scheme VI, route G).

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

The cycloiminodepsipeptides of the general formula (Ia) are, according to the process 2a mentioned above, from the thiodepsipeptides of the general formula (Ib) and compounds of the general formula (II), in which A is a radical -YR ¹³ (A ¹ ) with selectively removable O Protective group R ¹³ is, for example, benzyl, benzyloxycarbonyl, allyl, tert-butyloxycarbonyl, tetrahydropyranyl hydroxylamine, representable.

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

According to the invention and particularly preferred is the hydrogenolysis of cycloimino depsipeptides of the general formula (Ia) in the presence of a hydrogenation catalyst, in the presence of a diluent and optionally in the presence of a acidic reaction auxiliary (see Scheme VI, route G, H, I).

Scheme VI

As suitable catalysts for carrying out the catalytic hydrogenation come all the usual hydrogenation catalysts, such as platinum catalysts (Platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, Platinum wire, etc.), palladium catalysts (e.g. palladium sponge, Palladium black, palladium oxide, palladium-carbon, colloidal palladium, palla dium-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 (e.g. reduced iron, Raney Iron, etc.), copper catalysts (e.g. reduced copper, Raney Copper, Ullman copper, etc.) in question. However, it is preferably used Precious metal catalysts, such as platinum and palladium or ruthenium Catalysts optionally on a suitable support such as Carbon or silicon.

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

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

According to the invention, an alcoholic solution is used to carry out the hydrogenation the cyclic benzyloxyiminodepsipeptides of the formula (Ia) in the presence of a suitable hydrogenation catalyst and optionally in the presence of an acidic Reaction auxiliary implemented.  

Palladium catalysts are particularly preferred as hydrogenation catalysts, in particular palladium or palladium hydroxide carbon, use.

Mineral acids, in particular, are preferably found as acidic reaction auxiliaries Hydrohalic acids such as hydrochloric acid, use.

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

Alternatively, the cyclic hydroxyiminodepsipeptides of the general formula (Ic) (Y: -O-) can also be obtained from cyclic allyloxyiminodepsipeptides of the general formula (Ia) (A: -O-CH ₂ -CH = CH ₂ ) using palladium (II) - Acetate catalyzed cleavage can be obtained in the presence of triethylammonium formate and triphenyl phosphine (T. Yamada et al., Tetrahedron Lett. 28, 1987, p. 4557).

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

For example, in method 3b for selective cleavage, the polymer-bound cycloiminodepsipeptide cyclo [-N-methyl-L-leucinyl-D- (polymer-THP-oxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl is used -N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) as a compound of the general formula (Ia) (A = A ¹ = -YR ¹³ = -O- with selectively cleavable Anchor group), the corresponding cycloiminodepsipeptide cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L- leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-) (see Scheme VI, route I).

Those used to carry out process 3b according to the invention as starting materials The required cycloiminodepsipeptides are generally defined by the formula (Ia).

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

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

Scheme VII

The polymeric supports used as starting materials with selectively cleavable anchor groups for A = -YR ¹³ (A ¹ ) of the general formula (II) are known in part from the literature (cf., for example, syntheses of hydroxamic acids: Mitsunobu reaction on the Wang resin with N- Hydroxyphthalimide: D. Floyd et al. Tetrahedron Lett. 37 (44), 1996, p. 8045; Reaction of trityl chloride resin with N-hydroxyphthalimide: U. Bauer et al. Tetrahedron Lett. 38 (41), 1997, p. 7233) or by methods known from the literature (cf. synthesis of ketones: reactions with DHP HM resin: OB Wallace Tetrahedron Lett. 38 (28), 1997, p. 4939; alcohol coupling: JA Ellmann et al. J. Org. Chem. 60, 1995, p. 7712; JA Ellmann et al. Tetrahedron Lett. 35 (50), p. 9333) (see Scheme VIII).

Scheme VIII

This is preferred for performing method 3b according to the invention Scheme VIII obtained 6- (aminoxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxy methyl polystyrene resin used (see. Manufacturing Examples).

The cyclic hydroxyiminodepsipeptides thus formed are used in a conventional manner, worked up, for example, by chromatographic purification (cf. also Her position examples). But you can also directly (without further purification) be implemented according to method 2b.

The iminodepsipeptides obtainable by process 2 according to the invention general formula (I) can be present as syn and anti isomers, preferred  arises, however, under the specified reaction conditions of process 2 Mixture of both isomeric forms.

With the "inert solution" designated in the above process variants 2 means "are solvents that are meant under the respective reaction conditions are inert, but not inert under any reaction conditions have to.

The active substances are suitable for combating pathogenic endoparasites, which occur in humans and in animal husbandry and animal breeding in useful, breeding, zoo, laboratory, experimental and hobby animals, with favorable warm-blooded toxicity. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive species. By combating the pathogenic endoparasites, illness, deaths and reduced performance (e.g. in the production of meat, milk, wool, skins, eggs, honey, etc.) are to be reduced, so that the use of the active compounds makes animal husbandry more economical and easier is possible. Pathogenic endoparasites include cestodes, trematodes, nematodes, in particular:
From the order of the Pseudophyllidea z. E.g .: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diplogonorus spp.

From the order of the Cyclophyllidea z. E.g .: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosma spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.

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

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

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

From the order of the Rhabditia z. E.g. Micronema spp., Strongyloides spp.

From the order of Strongylida z. E.g. Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunosto mum spp., Globocephalus spp., Syngamus spp., Cyathostomum spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma 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., Amidostomum spp., Ollulanus spp., Cylicocyclus spp., Cylicodontophorus spp.  

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

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

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

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

From the group of the Gigantohynchida z. For example: Filicollis spp., Moniliformis spp., Macra canthorhynchus spp., prosthenorchis spp.

The livestock and breeding animals include mammals such as B. cattle, horses, sheep, Pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as B. mink, chinchilla, raccoon, birds such. B. chickens, geese, turkeys, Ducks, freshwater and saltwater fish such as B. trout, carp, eels, reptiles, Insects such as B. honey bee and silkworm.

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

The pets include dogs and cats.

The application can be prophylactic as well as therapeutic.  

The active ingredients are used directly or in the form of suitable accessories riding enterally, parenterally, dermally, nasally, by treating the environment or with the help of active ingredient-containing shaped bodies such. B. strips, plates, ribbons, neck bands, ear tags, limb bands, marking devices.

The enteral application of the active ingredients happens, for. B. orally in the form of powder, Suppositories, tablets, capsules, fasting, watering, granules, drenches, boluses, medi feed or drinking water. The dermal application happens for. B. in the form diving (dipping), spraying (spraying), bathing, washing, pouring (pouring) on and spot-on) and powdering. Parenteral use happens e.g. B. in Form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by Implants.

Suitable preparations are:
Solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, infusion formulations, gels;
Emulsions and suspensions for oral or dermal use and for injection; semi-solid preparations;
Formulations in which the active ingredient is processed in an ointment base or in an oil in water or water in oil emulsion base;
Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; Aerosols and inhalants, molded articles containing active ingredients.

Solutions for injection are administered intravenously, intramuscularly and subcutaneously.

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

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

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

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

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

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

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

It may be advantageous to add thickeners during manufacture.

Thickeners are: inorganic thickeners such as bentonites, colloidal Silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates.  

Gels are applied or spread onto the skin or in body cavities brought in. Gels are made by using solutions similar to those used for injection solutions have been prepared, mixed with as much thickener that a clear mass with ointment-like consistency arises. As ver thickeners, the thickeners specified above are used.

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

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

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

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

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

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

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

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

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

Emulsions are either water in oil or oil in water.

They are made by either the active ingredient in the hydrophobic or dissolved in the hydrophilic phase and this with the help of suitable emulsions gates and possibly other auxiliaries such as dyes, absorption-promoting Substances, preservatives, antioxidants, light stabilizers, increase viscosity de substances homogenized with the solvent of the other phase.

The following may be mentioned as hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid biglyceride, triglyceride mixture with vegetable fatty acid of chain length C _8-12 or other specially selected natural fatty acids, partial glyceride mixtures saturated or unsaturated, possibly also hydroxyl-containing fatty acids, mono- and diglycerides of C ₈ / C ₁₀ fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length C ₁₆ -C ₁₈ , isopropyl myristate, isopropyl palmitate, cypryl / capric acid esters of saturated fatty alcohols ₁₂ -C ₁₈ , isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, wax-like fatty acid esters such as artificial duck pancreas fat, dibutyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures and others fatty alcohols such as isotridecyl alcohol alcohol 2-alcohol-octyl alcohol alcohol 2 alcohol

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

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

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

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

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

Carrier liquids are all homogeneous solvents and solvents called mix.

The surfactants specified above may be mentioned as wetting agents (dispersants). The additives given above may be mentioned as further auxiliaries.

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

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

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

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

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

Other suitable auxiliaries are lubricants and lubricants such as. B. Magne sium stearate, stearic acid, talc, bentonite, decay promoting substances such as Starch or cross-linked polyvinylpyrrolidone, binders such. B. starch, gela tine or linear polyvinylpyrrolidone and dry binders such as microcri stalline cellulose.  

The active substance according to the invention can be found in its preparations and in the these preparations prepared use forms mixed with others Active ingredients, such as insecticides, sterilants, bactericides, acaricides, nematicides or fungicides. Insecticides include, for example, phosphorus acid esters, carbamates, carboxylic acid esters, chlorinated hydrocarbons, Phenylureas, nicotinyls, neonicotinyls, produced by microorganisms Fabrics and a.

Particularly cheap mixing partners are e.g. B. the following:
Fungicides:
Aldimorph, ampropylfos, ampropylfos potassium, andoprim, anilazine, azaconazole, azoxystrobin,
Benalaxyl, benodanil, benomyl, benzamacril, benzamacrylic isobutyl, bialaphos, binapacrylic, biphenyl, bitertanol, blasticidin-S, bromuconazole, bupirimate, buthiobate,
Calcium polysulfide, capsimycin, captafol, captan, carbendazim, carboxin, carvone, quinomethionate (quinomethionate), chlobenthiazon, chlorfenazol, chloroneb, chloropicrin, chlorothalonil, chlozolinate, clozylacon, cufraneb, cymoxazilol, cyprodinilanol, cyproinilanol, cyproinilanol, cyproconol
Debacarb, dichlorophene, diclobutrazole, diclofluanide, diclomezin, dicloran, diethofencarb, difenoconazole, dimethirimol, dimethomorph, diniconazole, diniconazol-M, dinocap, diphenylamine, dipyrithione, ditalimfos, dithorphoxinodonine, dithorphononodine
Ediphenphos, Epoxiconazole, Etaconazole, Ethirimol, Etridiazole,
Famoxadone, Fenapanil, Fenarimol, Fenbuconazol, Fenfuram, Fenitropan, Fenpiclonil, Fenpropidin, Fenpropimorph, Fentinacetat, Fentinhydroxyd, Ferbarn, Ferimzon, Fluazinam, Flumetover, Fluoromid, Fluquinconazol, Flurprimolol, Flusulfosolutol, Flusulfazolutol, Flusulfazolutol, Flusulfazolutol, Flusulfazolutol, Flusulfazolutol, Flusulfazolutol, Flusulfazolutol, Flusulfazolutol, Flusulfazolutol, Flusulfidolol, Flusulfazolutol, Flusulfazolutol, Flusulfosolutol, Flusulfidol, Flusulfazolutol, Flusulfidol, Flusilazolutol, Flusulfidol, Flusilazolutol, Flusilazolutol Fosetyl sodium, fthalide, fuberidazole, furalaxyl, furametpyr, furcarbonil, furconazole, furconazole-cis, funnecyclox,
Guazatin,
Hexachlorobenzene, hexaconazole, hymexazole,
Imazalil, Imibenconazol, Iminoctadin, Iminoctadinealbesilat, Iminoctadinetriacetat, Iodocarb, Ipeonazol, Iprobefos (IBP), Iprodione, Irumamycin, Isoprothiolan, Isovaledione,
Kasugamycin, Kresoxim-methyl, copper preparations, such as: copper hydroxide, copper naphthenate, copper oxychloride, copper sulfate, copper oxide, oxine-copper and Bordeaux mixture,
Mancopper, Mancozeb, Maneb, Meferimzone, Mepanipyrim, Mepronil, Metalaxyl, Metconazol, Methasulfocarb, Metrifuroxam, Metiram, Metomeclam, Metsulfovax, Mildiomycin, Myclobutanil, Myclozolin,
Nickel dimethyldithiocarbamate, nitrothal isopropyl, Nuarimol,
Ofurace, Oxadixyl, Oxamocarb, Oxolinicacid, Oxycarboxim, Oxyfenthiin,
Paclobutrazole, pefurazoate, penconazole, pencycuron, phosdiphen, pimaricin, piperalin, polyoxin, polyoxorim, probenazole, prochloraz, procymidon, propamocarb, propanosine sodium, propiconazole, propineb, pyrazophos, pyrifen, pyifenox, pyrroyilonil
Quinconazole, quintozen (PCNB),
Sulfur and sulfur preparations,
Tebuconazole, tecloftalam, tecnazene, Tetcyclacis, tetraconazole, thiabendazole, Thicyofen, Ihifluzamide, thiophanate-methyl, thiram, Tioxymid, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, Triazbutil, triazoxide, Trichlamid, tricyclazole, tridemorph, triflumizole, triforine, triticonazole,
Uniconazole,
Validamycin A, vinclozolin, viniconazole,
Zarilamid, Zineb, Ziram as well
Dagger G,
OK-8705,
OK-8801,
α- (1,1-dimethylethyl) -β- (2-phenoxyethyl) -1H-1,2,4-triazole-1-ethanol,
α- (2,4-dichlorophenyl) -β-fluoro-b-propyl-1H-1,2,4-triazole-1-ethanol,
α- (2,4-dichlorophenyl) -β-methoxy-a-methyl-1H-1,2,4-triazole-1-ethanol,
α- (5-methyl-1,3-dioxan-5-yl) -β - [[4- (trifluoromethyl) phenyl] methylene] -1H-1,2,4-triazol-1-ethanol,
(5RS, 6RS) -6-hydroxy-2,2,7,7-tetramethyl-5- (1H-1,2,4-triazol-1-yl) -3-octanone,
(E) -a- (methoxyimino) -N-methyl-2-phenoxy-phenylacetamide,
{2-methyl-1 - [[[1- (4-methylphenyl) ethyl] amino] carbonyl] propyl} carbamic acid 1-isopropyl ester,
1- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-yl) -ethanone-O- (phenylmethyl) oxime,
1- (2-methyl-1-naphthalenyl) -1H-pyrrole-2,5-dione,
1- (3,5-dichlorophenyl) -3- (2-propenyl) -2,5-pyrrolidinedione,
1 - [(diiodomethyl) sulfonyl] -4-methyl-benzene,
1 - [[2- (2,4-dichlorophenyl) -1,3-dioxolan-2-yl] methyl] -1H-imidazole,
1 - [[2- (4-chlorophenyl) -3-phenyloxiranyl] methyl] -1H-1,2,4-triazole,
1- [1- [2 - [(2,4-dichlorophenyl) methoxy] phenyl] ethenyl] -1H-imidazole,
1-methyl-5-nonyl-2- (phenylmethyl) -3-pyrrolidinol,
2 ', 6'-dibromo-2-methyl-4'-trifluoromethoxy-4'-trifluoromethyl-1,3-thiazole-5-carboxanilide,
2,2-dichloro-N- [1- (4-chlorophenyl) ethyl] -1-ethyl-3-methyl-cyclopropanecarboxamide,
2,6-dichloro-5- (methylthio) -4-pyrimidinyi-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,
2 - [(1-methylethyl) sulfonyl] -5- (trichloromethyl) -1,3,4-thiadiazole,
2 - [[6-Deoxy-4-O- (4-O-methyl-β-D-glycopyranosyl) -aD-glucopyranosyl] amino] -4- methoxy-1H-pyrrolo [2,3-d] pyrimidine- 5-carbonitrile,
2-aminobutane,
2-bromo-2- (bromomethyl) pentandinitrile,
2-chloro-N- (2,3-dihydro-1,1,3-trimethyl-1H-inden-4-yl) -3-pyridinecarboxamide,
2-chloro-N- (2,6-dimethylphenyl) -N- (isothiocyanatomethyl) acetamide,
2-phenylphenol (OPP),
3,4-dichloro-1- [4- (difluoromethoxy) phenyl] -1H-pyrrole-2,5-dione,
3,5-dichloro-N- [cyan [(1-methyl-2-propynyl) oxy] methyl] benzamide,
3- (1,1-dimethylpropyl-1-oxo-1H-indene-2-carbonitrile,
3- [2- (4-chlorophenyl) -5-ethoxy-3-isoxazolidinyl] pyridine,
4-chloro-2-cyan-N, N-dimethyl-5- (4-methylphenyl) -1H-imidazole-1-sulfonamide,
4-methyl-tetrazolo [1,5-a] quinazolin-5 (4H) -one,
8- (1,1-dimethylethyl) -N-ethyl-N-propyl-1,4-dioxaspiro [4.5] decane-2-methanamine,
8-hydroxyquinoline sulfate,
9H-xanthene-9-carboxylic acid 2 - [(phenylamino) carbonyl] hydrazide,
bis- (1-methylethyl) -3-methyl-4 - [(3-methylbenzoyl) -oxy] -2,5-thiophene dicarboxylate,
cis-1- (4-chlorophenyl) -2- (1H-1,2,4-triazol-1-yl) cycloheptanol,
cis-4- [3- [4- (1,1-dimethylpropyl) phenyl-2-methylpropyl] -2,6-dimethylmorpholine hydrochloride,
Ethyl - [(4-chlorophenyl) azo] cyanoacetate,
Potassium hydrogen carbonate,
Methane tetrathiol sodium salt,
Methyl 1- (2,3-dihydro-2,2-dimethyl-1H-inden-1-yl) -1H-imidazole-5-carboxylate,
Methyl N- (2,6-dimethylphenyl) -N- (5-isoxazolylcarbonyl) -DL-alaninate,
Methyl N- (chloroacetyl) -N- (2,6-dimethylphenyl) -DL-alaninate,
N- (2,3-dichloro-4-hydroxyphenyl) -1-methyl-cyclohexane carboxamide,
N- (2,6-dimethylphenyl) -2-methoxy-N- (tetrahydro-2-oxo-3-furanyl) acetamide,
N- (2,6-dimethylphenyl) -2-methoxy-N- (tetrahydro-2-oxo-3-thienyl) acetamide,
N- (2-chloro-4-nitrophenyl) -4-methyl-3-nitro-benzenesulfonamide,
N- (4-cyclohexylphenyl) -1,4,5,6-tetrahydro-2-pyrimidinamine,
N- (4-hexylphenyl) -1,4,5,6-tetrahydro-2-pyrimidinamine,
N- (5-chloro-2-methylphenyl) -2-methoxy-N- (2-oxo-3-oxazolidinyl) acetamide,
N- (6-methoxy) -3-pyridinyl) cyclopropanecarboxamide,
N- [2,2,2-trichloro-1 - [(chloroacetyl) amino] ethyl] benzamide,
N- [3-chloro-4,5-bis (2-propynyloxy) phenyl] -N'-methoxymanimidamide,
N-formyl-N-hydroxy-DL-alanine sodium salt,
O, O-diethyl- [2- (dipropylamino) -2-oxoethyl] ethylphosphoramidothioate,
O-methyl-S-phenyl-phenylpropylphosphoramidothioat,
S-methyl-1,2,3-benzothiadiazole-7-carbothioate,
spiro [2H] -1-benzopyran-2,1 '(3'H) -isobenzofuran] -3'-one,
Bactericides:
Bronopol, dichlorophene, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone, furan carboxylic acid, oxytetracycline, probenazole, streptomycin, teclofta lam, copper sulfate and other copper preparations, quinolones such as ciprofloxacin, danofloxacin, enfloxacin, difloxacin, difloxacin Ofloxacin, orbifloxacin, premafloxacin, sarafloxacin,
Insecticides / acaricides / nematicides:
Abamectin, Acephate, Acetamiprid, Acrinathrin, Alanycarb, Aldicarb, Aldoxycarb, Alpha-cypermethrin, Alphamethrin, Amitraz, Avermectin, AZ 60541, Azadirachtin, Azamethiphos, Azinphos A, Azinphos M, Azocyclotin,
Bacillus popilliae, Bacillus sphaericus, Bacillus subtilis, Bacillus thuringiensis, Baculoviruses, Beauveria bassiana, Beauveria tenella, Bendiocarb, Benfuracarb, Bensultap, Benzoximate, Betacyfluthrin, Bifenazate, Bifenthrin, Biethanomofufoxin, Bethanomethofinoxin, Bethenomethrin Butyl pyridaben
Cadusafos, Carbaryl, Carbofuran, Carbophenothion, Carbosulfan, Cartap, Chloethocarb, Chlorethoxyfos, Chlorfenapyr, Chlorfenvinphos, Chlorfluazuron, Chlormephos, Chlorpyrifos, Chlorpyrifos M, Chlovaporthrin, Cis-Resmethrin, Cispermocethrin, Clocytocethrin, Clofentzhrinophenin, Clocentermethrin, Clo , Cyfluthrin, Cyhalothrin, Cyhexatin, Cypermethrin, Cyromazine, Cythioat, Chlothianidin,
Deltamethrin, Demeton M, Demeton S, Demeton-S-methyl, Diafenthiuron, Diazinon, Dichlorvos, Dicyclanil, Diflubenzuron, Dimethoat, Dimethylvinphos, Diofenolan, Disulfoton, Docusat-sodium, Dofenapyn, Dinotefuran,
Eflusilanate, Emamectin, Empenthrin, Endosulfan, Eprinometin, Esfenvalerate, Ethiofencarb, Ethion, Ethiprole, Ethoprophos, Etofenprox, Etoxazole, Etrimfos,
Fenamiphos, Fenazaquin, Fenbutatin oxide, Fenitrothion, Fenothiocarb, Fenoxacrim, Fenoxycarb, Fenpropathrin, Fenpyrad, Fenpyrithrin, Fenpyroximate, Fenthion, Fenvalerate, Fipronil, Fluazinam, Fluazuron, Flubrocythrinate, Flucoxufenurinate, Flucycloxuronin, Flucycloxuronin, Flucycloxuronin, Flucycloxuronin, Flucycloxuronin, Flucycloxuronin, Flucycloxuronin, Flucycloxuronin, Flucycloxuronin, Flucycloxuronin, Flucycloxuronin , Fosthiazate, Fubfenprox, Furathiocarb, Flupyrazofos,
Granulosis viruses
Halofenozide, HCH, Heptenophos, Hexaflumuron, Hexythiazox, Hydroprene,
Imidacloprid, indoxacarb, isazofos, isofenphos, isoxathion, ivermectin,
Nuclear polyhedron viruses,
Lambda cyhalothrin, lufenuron,
Malathion, Mecarbam, Metaldehyde, Methamidophos, Metharhizin anisopliae, Metharhizin flavoviride, Methidathion, Methiocarb, Methomyl, Methoprene, Methoxyfenozide, Metolcarb, Metoxadiazone, Metrifonat, Mevinphos, Milbemectin, Monocrotinos, Moxidin
Naled, Nitenpyram, Nithiazine, Novaluron, NEEM,
Omethoate, oxamyl, oxydemethone M,
Paecilomyces fumosoroseus, Parathion A, Parathion M, Permethrin, Phenthoat, Phorat, Phosalone, Phosmet, Phosphamidon, Phoxim, Pirimicarb, Pirimiphos A, Pirimiphos M, Profenofos, Promecarb, Propoxur, Prothiofos, Prothoat, Pyromhrhridosine, Pymmethrofinos, Pymmethrofinos , Pyridathione, pyrimidifen, pyriproxyfen, protrifenbute,
Quinalphos,
Ribavirin,
Salithion, Sebufos, Silafluofen, Spinosad, Sulfotep, Sulprofos,
Tau-fluvalinate, oxalate hydrogen tebufenozide, tebufenpyrad, Tebupirimiphos, teflubenzuron, tefluthrin, temephos, Temivinphos, terbufos, tetrachlorvinphos, theta cypermethrin, thiamethoxam, Thiapronil, Thiatriphos, thiocyclam, thiodicarb, thiofanox, thuringiensin, Tralocythrin, tralomethrin, triarathene, Triazamate, triazophos , Triazuron, trichlophenidines, trichlorfon, triflumuron, trimethacarb, thiacloprid,
Vamidothion, Vaniliprole, Verticillium lecanii,
YI 5302,
Zeta-cypermethrin, zolaprofos,
(1R-cis) - [5- (phenylmethyl) -3-furanyl] methyl-3 - [(dihydro-2-oxo-3 (2H) - furanylidene) methyl] -2,2-dimethylcyclopropane carboxylate
(3-phenoxyphenyl) methyl 2,2,3,3-tetramethylcyclopropane decarboxylate
1 - [(2-Chloro-5-thiazolyl) methyl] tetrahydro-3,5-dimethyl-N-nitro-1,3,5-triazine-2 (1H) - imine
2- (2-chloro-6-fluorophenyl) -4- [4- (1,1-dimethylethyl) phenyl] -4,5-dihydro-oxazole
2- (acetyloxy) -3-dodecyl-1,4-naphthalenedione
2-Chloro-N - [[[4- (1-phenylethoxy) phenyl] amino] carbonyl] benzamide
2-Chloro-N - [[[4- (2,2-dichloro-1,1-difluoroethoxy) phenyl] amino] carbonyl] benzamide
3-methylphenyl propyl carbamate
4- [4- (4-ethoxyphenyl) -4-methylpentyl] -1-fluoro-2-phenoxy-benzene
4-chloro-2- (1,1-dimethylethyl) -5 - [[2- (2,6-dimethyl-4-phenoxyphenoxy) ethyl] thio] - 3 (2H) pyridazinone
4-chloro-2- (2-chloro-2-methylpropyl) -5 - [(6-iodo-3-pyridinyl) methoxy] -3 (2H) - pyridazinone
4-chloro-5 - [(6-chloro-3-pyridinyl) methoxy] -2- (3,4-dichlorophenyl) -3 (2H) pyridazinone
Bacillus thuringiensis strain EG-2348
Benzoic acid [2-benzoyl-1- (1,1-dimethylethyl) hydrazide
Butanoic acid 2,2-dimethyl-3- (2,4-dichlorophenyl) -2-oxo-1-oxaspiro [4.5] dec-3-en-4-yl ester
[3 - [(6-chloro-3-pyridinyl) methyl] -2-thiazolidinylidene] cyanamide
Dihydro-2- (nitromethylene) -2H-1,3-thiazine-3 (4H) carboxaldehyde
Ethyl [2 - [[1,6-dihydro-6-oxo-1- (phenylmethyl) -4-pyridazinyl] oxy] ethyl] carbamate
N- (3,4,4-trifluoro-1-oxo-3-butenyl) glycine
N- (4-chlorophenyl) -3- [4- (difluoromethoxy) phenyl] -4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamide
N - [(2-chloro-5-thiazolyl) methyl] -N'-methyl-N "-nitro-guanidine
N-methyl-N '- (1-methyl-2-propenyl) -1,2-hydrazinedicarbothioamide
N-methyl-N'-2-propenyl-1,2-hydrazinedicarbothioamide
O, O-Diethyl- [2- (dipropylamino) -2-oxoethyl] ethyl phosphoramidothioate

The active compounds according to the invention can also be used in their commercially available form formulations and in the use forms prepared from these formulations in Mix with synergists. Synergists are connections through which the effect of the active ingredients is increased without the added synergist itself must be active.

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

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

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

Manufacturing examples

example 1

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

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

200.0 mg (0.20 mmol) cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N -methyl-L-leucinyl-D-phenyllactyl-) (see WO 98/43 965) in 5 ml of acetonitrile in succession with 43.6 mg (0.62 mmol) of hydroxylamine hydrochloride, 145.0 mg (0, 45 mmol) of mercury (II) acetate and 162.2 mg (1.25 mmol) of ethyldiisopropylamine ("Hünig's Base") were added and the mixture was stirred at room temperature for 18 hours. To complete the reaction, another 21.8 mg (0.31 mmol) of hydroxylamine hydrochloride, 72.5 mg (0.45 mmol) of mercury (II) acetate and 107.4 mg (1.25 mmol) of ethyldiisopropylamine ("Hünig's Base ") and stirred for a further 6 hours at room temperature. The entire reaction mixture is then stirred in about 20 ml of aqueous NH ₄ Cl solution and extracted four times with 15 ml of chloroform. The remaining crude product is chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane: acetone (4: 1). 70.4 mg (35% of theory) of cyclo [-N-methyl-L-leucinyl-D- (hydroxyimino) -lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L- leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] as an anti / syn isomer mixture.

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

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

500.0 mg (0.52 mmol) of cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N -methyl-L-leucinyl-D-phenyllactyl-)
107.9 mg (1.55 mmol) hydroxylamine hydrochloride
422.0 mg (1.55 mmol) of mercury (II) chloride
230.2 mg (1.81 mmol) of ethyldiisopropylamine ("Hünig's Base")
30 ml tetrahydrofuran

After stirring for 20 hours at 50 ° C., another 180.0 mg (0.56 mmol) of mercury (II) acetate are added and the mixture is stirred at 50 ° C. for a further 24 hours. The entire reaction mixture is then filtered and worked up as in Example 1 (variant a).
Yield: 250 mg (50% of theory)

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

400.0 mg (0.37 mmol) of cyclo [-N-methyl-L-leucinyl-D- (benzyloxyimino) lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D -lactyl-N-methyl-L-leu cinyl-D-phenyllactyl-] 17 (see Table 1) are stirred in 40 ml of methanol and in the presence of 200 mg of Pd carbon [10% palladium content] and 0.7 ml conc. Hydrochloric acid is hydrogenated at room temperature until the hydrogen uptake has ended (approx. 20 minutes). After filtering off the catalyst, the entire reaction solution is concentrated in vacuo and the crude product which remains is chromatographed on an RP-18 column using the eluent acetonitrile: water.
Yield: 110 mg (30% of theory)

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

A mixture of 100 mg of cyclodepsipeptide-containing polystyrene resin, 3.0 ml of n-buta nol and 3.0 ml of 1,2-dichloroethane is mixed with 8.5 mg of pyridine para-toluenesulfonic acid and stirred at 60 ° C for one hour. The polystyrene resin is then filtered off and washed five times with methylene chloride. After concentration in vacuo, 9.4 mg of crude product remain, in which example 1 could be detected by means of APCI-MS.
LC-MS (acidic) m / z (%): 964 (M ⁺ , 100). C ₅₂ H ₇₇ N ₅ O ₁₂ (964.2)
R _t (HPLC column: 125 × 2.1 Kromasil ©, C-18): 17.54; 17.66 min. anti / syn isomer mixture (20:80).

Example 2

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

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

200.0 mg (0.20 mmol) (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N - methyl-L-leucinyl-D-phenyllactyl-)
52.4 mg (0.62 mmol) of O-methyl-hydroxylamine hydrochloride
145.0 mg (0.45 mmol) of mercury (II) acetate
162.2 mg (1.25 mmol) of ethyldiisopropylamine ("Hünig's Base")
5 ml acetonitrile

The remaining crude product is first chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane: acetone (4: 1). 170 mg (83% of theory) of cyclo [-N-methyl-L-leucinyl-D- (O-methyl-imino) -lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L are obtained -leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-].
¹ H NMR (600 MHz, CDCl ₃ , δ): 2.85; 2.87; 2.90; 3.04 (4 x NC H ₃ ); 3.65 (-OC H ₃ , oxime) ppm.
¹³ C NMR (100 MHz, CDCl ₃ , δ): 29.3; 30.2; 30.9; 31.0 (4 x NC H ₃ ); 61.3 (-O- C H ₃ , oxime); 66.9; 68.1; 69.7; 71.1; (4 × - C H-O-); 56.9; 53.9; 53.9; 59.5 (4 x - C H-N-); 170.3; 170.3; 172.5; (3x -N- C = O); 152.9 (1 x - C = NO, oxime); 170.2; 170.7; 171.1; 172.5 (4 x -O- C = O) ppm.
LC-MS (acidic) m / z (%): 978 (M ⁺ , 100). C ₅₃ H ₇₉ N ₅ O ₁₂ (978.2)
R _t value (HPLC column: 125 × 2.1 Kromasil ©, C-18): 18.34 min

Example 3

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

200.0 mg (0.20 mmol) 1 (see Example 1) are added to 1 ml acetic anhydride and stirred at 70 ° C. for about 30 minutes. The entire reaction mixture is then mixed with saturated 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 in vacuo. The remaining crude product is chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane: acetone (10: 1). This gives 125.8 mg (60% of theory) of crude product, which according to preparative HPLC (RP-18) to 80 mg (38% of theory) of pure cyclo [-N-methyl-L-leucinyl-D- (O-acetyl -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 (purity: 98.7%) leads.
LC-MS (acidic) m / z (%): 1006 (M ⁺ , 100). C ₅₄ H ₇₉ N ₅ O ₁₃ (1006.2)
R _t value (HPLC column: 125 × 2.1 Kromasil ©, C-18): 7.35 min

Example 4

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-phe nyllactyl-]

300.0 mg (0.31 mmol) 1 (see Example 1) are stirred at 0 ° C. in 10 ml dry pyridine and 99.4 mg (0.93 mmol) vinyl chloroformate are added. The mixture is then stirred for a further 6 hours at 0 ° C. The entire reaction mixture is then concentrated in vacuo, the residue is taken up in chloroform and washed once with 1N HCl and twice with NaHCO ₃ solution. After the organic phase has been separated off and dried over magnesium sulfate, the mixture is concentrated in vacuo and the crude product which remains is chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the mobile phase cyclohexane: ethyl acetate (2: 1). 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 an anti / syn isomer mixture.
LC-MS (acidic) m / z (%): 1037 (MH ⁺ , 100). C ₅₅ H ₈₁ N ₅ O ₁₄ (1036.2)
R _t value (HPLC column: 125 × 2.1 Kromasil ©, C-18): 17.82 min

Example 5

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-D-phenyllactyl-]

The reaction with methanesulfonic acid chloride is carried out analogously to the reaction procedure of Example 4, using:
200.0 mg (0.20 mmol) cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L -leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] (Ex. 1)

71.3 mg (0.62 mmol) methanesulfonic acid chloride
8 ml dry pyridine

The remaining crude product is first chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the mobile phase cyclohexane: ethyl acetate (3: 2). 81.8 mg (38% of theory) of 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-D-phenyllactyl-] as an anti / syn isomer mixture.
LC-MS (acidic) m / z (%): 1042 (MH ⁺ , 100). C ₅₃ H ₇₉ N ₅ O ₁₄ S (1042.3)
R _t value (HPLC column: 125 × 2.1 Kromasil ©, C-18): 17.18 min

Example 6

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

300.0 mg (0.31 mmol) of cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L -leucinyl-D-lactyl-N-methyl-L-leu cinyl-D-phenyl-lactyl-] (Ex. 1) are absolute in 10 ml. 30.4 mg (0.36 mmol) of allyl isocyanate and 2 drops of 1,8-diazabicyclo [5.4.0] undec-7-ene ("DBU") were added to the toluene in succession and the mixture was stirred at room temperature for 33 hours. The entire reaction mixture is then concentrated in vacuo. The remaining crude product is first passed over a silica gel column (Kieselgel 60 - Merck, particle size: 0.04 to 0.063 mm) with the eluent cyclohexane: acetone (3: 1) and then over a second silica gel column (Kieselgel 60 - Merck, particle size: 0 , 04 to 0.063 mm) with the eluent cyclohexane: ethyl acetate (2: 1 to 1: 1) chromatographed. 52.4 mg (16.1% of theory) of cyclo [-N-methyl-L-leucinyl-D- (O-allylaminocarbonyl-imino) -lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N are obtained -methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] as an anti- / syn-isomer mixture.
LC-MS (acidic) m / z (%): 1047 (M ⁺ , 100). C ₅₆ H ₈₂ N ₆ O ₁₃ (1047.3)
R _t (HPLC column: 125 x 2.1 Kromasil ©, C-18, pH 2.3): 17.09; 17.39 min

Example 7

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

To a solution of 300.0 mg (0.31 mmol) of cyclo [-N-methyl-L-leucinyl-D- (hydroxy-imino) -lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N -methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-] (Ex. 1) and 75.7 mg (0.37 mmol) N-tert-butyloxycarbonyl-N- methyl alanine in 10 ml absolute. Acetonitrile are 184.0 mg (4.1 mmol) benzotriazol-1-yl-oxy-tris (dimethylamino-phosphonium) - hexafluorophosphate (BOP) and 124.0 mg (0.95 mmol) N, N- at 0 ° C Diisopropylethylamine ("Hünigs Base") added and stirred for 30 minutes at 0 ° C, then 24 hours at room temperature. The entire reaction mixture is then concentrated in vacuo, the residue is taken up in chloroform, shaken twice with water, the organic phase is separated off and, after drying over sodium sulfate, concentrated in vacuo. The remaining crude product is purified by means of preparative HPLC. 15.6 mg (4.4% of theory) of cyclo [-N-methyl-L-leucinyl-D- (ON-tert-butyloxycarbonyl-N-methyl-alanyl-imino) -lactyl-N-methyl-L are obtained -leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] as an anti / syn isomer mixture.
LC-MS (acidic) m / z (%): 1150 (MH ⁺ , 100). C ₆₁ H ₉₂ N ₆ O ₁₅ (1149.4)
R _t (HPLC column: 125 x 2.1 Kromasil ©, C-18): 7.69; 7.76 min

Analogously, the compounds of the formula (Ia) listed in Table 1 below (R ¹ , R ³ , R ⁴ , R ⁷ , R ⁹ , R ¹⁰ : -Me; R ² , R ⁵ , R ⁸ , R ¹¹ : - iso-butyl; X ² : = NA; X ² -X ⁴ : = O).

Table 1

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Example I-56 Reaction of the polymer-bound hydroxylamine with cyclo [-N-methyl-L-leucinyl- thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N- methyl-L-leucinyl-D-phenyllactyl-]

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

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

The 6- (amino-oxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene resin is first stirred in dichloromethane at room temperature for 30 minutes and then with the cyclothiodepsipeptide and mercury (II ) acetate added. The separated polystyrene resin is then washed three times in succession with dichloromethane, dimethylformamide / water (1: 1), dimethylformamide and dried under high vacuum.
Yield: 180 mg polystyrene resin
IR (KBr): 1730 cm ^-1 (ν _{C = O} ; cyclodepsipeptide)

Starting materials of the formula (Ib)

Example (Ib-1)

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

1.0 g (1.05 mmol) of cyclo (-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl -N-methyl-L-leucinyl-D-phenyllactyl-) PF 1022A (cf. EP-OS 382173, US Pat. 5116815) were dissolved in 20 ml of toluene with 1.4 g (3.5 mmol) of 2,4- Bis- (4-methoxy-phenyl) -2,4-dithioxo-1,3,2,4-dithiadiphosphetane ("Lawesson's Reagens") was added and the mixture was stirred under reflux temperature for 3.5 hours. The entire reaction mixture is then cooled to 0 ° C., filtered and the filtrate obtained is concentrated in vacuo. The remaining crude product is chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) first with the eluent methylene chloride and then with the eluent cyclohexane: acetone (3: 1). 0.46 g (43.6% of theory) of cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenylthiolactyl-N-methyl-L-leucinyl-D are obtained -thiolactyl-N-methyl-L-leucinyl-D-phenylthiolactyl-).
¹ H NMR (CDCl ₃ , δ): 2.99, 3.06, 3.26, 3.42 (4 x -N-Me); 4.86, 6.42, 6.61 (4 x -N-CH ₂ -);
5.31, 5.55, 5.81, 5.89 (4 x -O-CH ₂ -); 7.26 (phenyl-H) ppm.
LC-MS (acidic) m / z (%): 1013 (M ⁺ , 100); 310 (21); 274 (30); 198 (42).
C ₅₂ H ₇₆ N ₄ O ₈ S ₄ (1013.4)

Example (Ib-2)

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

1.0 g (1.05 mmol) of cyclo (-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl -N-methyl-L-leucinyl-D-phenyllactyl-) PF 1022A (cf. EP-OS 382173, US Pat. 5116815) were dissolved in 15 ml of tetrahydrofuran at 0 ° C with 0.26 g (0.05 mmol) 2,4-bis (4-phenoxy-phenyl) -2,4-dithioxo-1,3,2,4-dithiadiphosphetane ("Belleau's Reagens") was added and the mixture was stirred at room temperature for 18 hours. The entire reaction mixture is then concentrated in vacuo. The remaining crude product is chromatographed twice over a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane: acet (3: 1). 0.12 g (11.8% of theory) of cyclo (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D is obtained -lactyl-N-methyl-L-leucinyl-D-phenyllactyl-).
LC-MS (acidic) m / z (%): 965 (M ⁺ , 100); 200 (45).
C ₅₂ H ₇₆ N ₄ O ₁₁ S (965.2)

Analogously, the compounds of the formula (Ib) listed in Table 2 below (R ¹ , R ³ , R ⁴ , R ⁷ , R ⁹ , R ¹⁰ : -Me; R ² , R ⁵ , R ⁸ , R ¹¹ : - iso-butyl) who made the.

Table 2

Table 2 (continued)

Table 2 (continued)

Starting materials of formula (II)

Example (II-1)

a) (S) -N - [(tetrahydrofur-2-yl) methoxy] phthalimide (see S. Bailey et al., J. Med. Chem. 34, 1991, pp. 57-65)

1.5 g (14.7 mmol) (S) -tetrahydrofur-2-yl-methanol (A. Mravik et al., Tetrahedron: Asymmetry 7 (5), 1996, pp. 1477-1484), 2.4 g (14.7 mmol) N-hydroxy-phthalimide and 3.85 (14.7 mmol) triphenylphosphine are stirred in 50 ml THF and 3.4 g (19.5 mmol) diethyl azodicarboxylic acid are added at 0 ° C (protective gas atmosphere) and Stirred for 18 hours at room temperature. The entire reaction mixture is then concentrated in vacuo, the residue is taken up in ether and shaken twice against water. The remaining crude product is chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane: acetone (6: 1). 1.7 g (46.8% of theory) of (S) -N - [(tetrahydrofur-2-yl) methoxy] phthalimide are obtained.
LC-MS-LOOP m / z (%): 248 (MH ⁺ , 100); C ₁₃ H ₁₃ NO ₄ (247.2)
R _t value (HPLC column: 125 × 2.1 Kromasil ©, C-18): 7.56 min

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

1.6 g (6.47 mmol) (S) -N - [(tetrahydrofur-2-yl) methoxy] phthalimide are stirred in 30 ml methylene chloride, at 0 ° C with 0.6 g (12.9 mmol ) N-methyl-hydrazine was added and the mixture was stirred at room temperature for 18 hours. The entire reaction mixture is then filtered and the filtrate is concentrated in vacuo. The remaining crude product is chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) with the eluent ethyl acetate. 130 mg (17.2% of theory) of (S) -tetrahydrofur-2-yl-methoxyamines are obtained.
LC-MS (acidic) m / z (%): 118 (MH ⁺ , 100). C ₅₂ H ₇₆ N ₄ O ₁₁ S (117.1)

Example (II-2)

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

2.0 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 with 3.1 g (24.0 mmol) of N, N-diisipropylethylamine (Hünig's base), 3.1 g (12.0 mmol) of bis ( 2-oxo-3-oxazolidinyl) -phosphonium chloride (BOP-Cl) was added and the mixture was stirred for 30 minutes. Then 1.05 g (12.0 mmol) of morpholine are added and the mixture is stirred at 0 ° C. for a further 6 hours. The reaction solution is shaken twice with water, the organic phase is separated off and, after drying over sodium sulfate, concentrated in vacuo. The remaining crude product is chromatographed on a silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane: acet (3: 1). 1.0 g (37% of theory) of N-tert-butyloxy carbonyl-amino-oxyacetic acid morpholide are obtained.
¹ H NMR (CDCl ₃ , δ): 1.47 (s, 9H, C (C H ₃ ) ₃ ); 3.37-3.72 (3m, 8H, 2 x -NC H ₂ -; 2 x -O- C H ₂ -); 4.54 (s, 2H, -OC H ₂ -); 8.06 (s, 1H, N- H ) ppm.
LC-MS (acidic) m / z (%): 205 (M ⁺ -H ₂ C = CMe ₂ , 12), 161 (100). C ₁₁ H ₂₀ N ₂ O ₅ (260.3)
R _t value (HPLC column: 125 × 2.1 Kromasil ©, C-18): 5.22 min

b) Hydrochloride of amino-oxyacetic acid morpholide

Dry hydrochloric acid gas is passed into 220 ml of absolute methylene chloride in a solution of 0.65 g (2.5 mmol) of N-tert-butyloxycarbonylamino-oxyacetic acid morpholide cooled to 0 ° C. for 30 minutes. The mixture is then stirred for about 16 hours at room temperature and the entire reaction mixture is concentrated in vacuo. 380 mg (77% of theory) of hydrochloride of amino-oxyacetic acid morpholide are obtained.
LC-MS (acidic) m / z (%): 161 (MH ⁺ -HCl, 100), 146 (12), 129 (45).
C ₆ H ₁₃ ClN ₂ O ₃ (196.6)

Example (II-3)

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

1.0 g (0.51 mmol) of DHP HM resin (Novabiochem: 01-64-0192) in 8.0 ml of 1,2-dichloroethane is allowed to swell for about 30 minutes. Then 293.5 mg (2.5 mmol) of N-hydroxysuccinimide and 261.4 mg (1.0 mmol) of pyridinium para toluenesulfonate (PPTS) are added and the mixture is stirred at 80 ° C. for 16 hours. The resin is then separated off, washed once with methylene chloride, four times with dimethylform amide / water (1: 1), three times with dimethylformamide and three times with methylene chloride. The purified 6- (N-succinimidyl-oxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene resin is dried under high vacuum and can be used for the subsequent reaction step.
IR (KBr): 1730 cm ^-1 (ν _{C = O} ; succinimidyl residue)

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

1.0 g of 6- (N-succinimidyl-oxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene resin are dissolved in 20 ml of benzene under a protective gas atmosphere (argon) with 127.7 mg (2.55 mmol) hydrazine hydrate were added and the mixture was stirred under reflux for 20 hours. The resin is then separated off, washed five times with methylene chloride and dried under high vacuum.
IR (KBr): 1630 cm ^-1 (ν _{NH deformity} ; -O-NH ₂ ); 3300 cm ^-1 (ν _{NH valence} ; -O-NH ₂ )

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

Table 3

Biological examples Example A

In vivo nematode test
Heterakis spumosa / mouse

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

After the prepatent period, the suspended active ingredients become intraperitoneal applied on the 46th day after infection.

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

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

Example B

In vivo nematode test
Nematospiroides dubius / mouse

Mice are experimented with nematodes of the species Nematospiroides dubius infi graces. For infection, the mice Nematospiroides dubius orally as 90 embryo eggs are applied.

After the prepatent period, the suspended active ingredients become intraperitoneal applied on the 46th day after infection.

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

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

Example C

In vivo nematode test
Haemonchus contortus / sheep

Sheep experimentally infected with Haemonchus contortus were identified after the expiration of the Prepatency of the parasite treated. The active ingredients were as a pure active ingredient administered orally and / or intravenously.

The efficiency is determined by shooting them out with the feces which worm eggs count before and after treatment.

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

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

Claims (9)

1. Compounds of the general formula (I)
in which
R ¹ , R ⁴ , R ⁷ and R ¹⁰ independently of one another represent hydrogen, straight-chain or branched alkyl,
R ² , R ⁵ , R ⁸ and R ¹¹ independently of one another represent hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl and aryl or hetaryl,
R ¹⁰ and R ¹¹ together with the atoms to which they are attached represent an optionally substituted 5- or 6-membered ring which can optionally be interrupted by oxygen, sulfur, sulfoxy or sulfonyl,
R ⁶ and R ¹² independently of one another represent hydrogen, optionally substituted alkyl or arylalkyl, and 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 ¹ , C = X ² , C = X ³ and C = X ⁴ each independently represent one of the groups C = O, C = S or CH ₂ or represent a group C = N-A, at least one of the groups C = X ¹ , C = X ² , C = X ³ and C = X ⁴ must stand for C = NA,
in which
A for hydrogen, optionally substituted alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, and also cyano, nitro, carbamoyl, alkoxycarbonyl, formyl, - (C = NH) -NH ₂ , -P (O) -O- alkyl, -P ( S) -O-alkyl or optionally for a radical A ¹
-YR ¹³ (A ¹ )
in which
Y represents oxygen, sulfur or -NR ¹⁴ ,
R ¹³ and R ¹⁴ independently of one another for hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl, aryl or hetaryl as well as for formyl, alkoxydicarbonyl, alkylsulfonyl, haloalkoxyalkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylaminocarbonyl Alkenyl oxycarbonyl, alkynyloxycarbonyl, aryloxyalkyl, hetaryl carbonyl, alkylcarbonyl or optionally represents a radical from the group B ¹ , B ² , B ³ or B ⁴ ,
wherein
Q represents optionally substituted, straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, aryloxy, arylalkoxy, hetaryloxy, hetarylalkoxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, arylthio, arylthio, arylthio, arylalioalkyl, Alkylamino, alkenylamino, alkynylamino, cycloalkylamino, arylamino, arylalkylamino, het arylamino, hetarylalkylamino, dialkylamino, dialkenylamino, aryl, arylalkyl, hetaryl or hetarylalkyl, cyano, amino or an optionally substituted cyclic amino group linked via nitrogen,
represents carboxy, thiocarboxy, sulfoxy, sulfonyl, -P (O) -O- alkyl, -P (S) -O-alkyl or -C = NR ¹⁵ ,
R ^{15 represents} hydrogen, hydroxy, alkoxy, alkylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, alkylsulfonyl, nitro or cyano,
R ^{16 represents} hydrogen or alkyl,
n represents 0, 1 or 2,
Y ^{1 represents} oxygen, sulfur or -NR ¹⁷ ,
R ¹⁸ , when Y ^{1 is} nitrogen, can mean a cyclic amino group linked via this nitrogen atom,
R ¹⁷ and R ¹⁸ independently of one another represent hydrogen, optionally substituted, straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, aryl, arylalkyl, hetaryl or hetarylalkyl, or
R ¹⁷ and R ¹⁸ together with the adjacent N atom for an optionally substituted heterocyclic 4-, 5-, 6- or 7-membered ring system or for an optionally substituted 7- to 10-membered bicyclic ring system, which may also be substituted by Oxygen, sulfur, sulfoxyl, sulfonyl, carbonyl, -NO, -N =, -NR ²² or can be interrupted by quaternized nitrogen,
R ¹⁹ and R ²⁰ independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl and optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl, or
R ¹⁹ and R ²⁰ together represent an optionally substituted spirocyclic ring,
R ²⁰ and R ²¹ together with the atoms to which they are attached represent an optionally substituted 5-, 6- or 7-membered ring which may optionally be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl,
R ^{21 represents} hydrogen, optionally substituted, straight-chain or branched alkyl, cycloalkyl, arylalkyl, hetarylalkyl, and aryl or hetaryl,
R ^{22 represents} hydrogen, optionally substituted straight-chain or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cyano, arylalkyl, hetarylalkyl, and aryl or hetaryl,
R ¹³ can also stand for a selectively cleavable protective group, or a polymeric carrier which is connected to Y via a selectively cleavable anchor group,
as well as their pure optical isomers, racemates and physiologically tolerable salts. 2. Process 1 for the preparation of the new compounds of general formula (I) according to claim 1
in which
R ¹ to R ¹² and the groups C = X ¹ to C = X ^{4 have} the meanings given in Claim 1,
characterized in that one
Cyclothiodepsipeptides of the general formula (I)
and their salts,
in which
R ¹ to R ^{12 have} the meanings given in Claim 1, and C = X ¹ , C = X ² , C = X ³ and C = X ⁴ independently of one another are C = O, C = S or CH ₂ , at least one the groups C = X ¹ , C = X ² , C = X ³ and C = X ⁴ must be a C = S group,
with amino compounds of the general formula (II)
H ₂ NA (II)
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, in the presence of a basic reaction auxiliary and in the presence of a suitable diluent. 3. Process for the preparation of the compounds of formula (Ia) and their salts, characterized in that

• a) the cyclothiodepsipeptides of the general formula (Ib) or their salts,
  in which
  R ¹ to R ^{12 have} the meanings given in claim 1,
  with amino compounds of the general formula (II)
  H ₂ NA (II)
  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) for the preparation of the new cycloiminodepsipeptides of the general formula (Ia)
  and their salts,
  in which
  R ¹ to R ^{12 have} the meanings given in Claim 1,
  A stands for a residue -YR ¹³ (A ¹ ),
  in which
  Y has the meaning given in claim 1,
  R ^{13 represents} radicals from group B ¹ to B ³ ,
  wherein
  Q, Y ¹ , n, R ¹⁶ , and R ¹⁸ -R ^{20 have} the meanings given in Claim 1,
  Compounds of the general formula (Ic)
  and their salts,
  in which
  Y and R ¹ to R ^{12 have} the meanings given in claim 1,
  with compounds of the general formula (IIIa-c)
  wherein
  Q, Y ¹ , n, R ¹⁶ , and R ¹⁸ -R ^{20 have} the meanings given in claim 1,
  W stands for a suitable leaving group, such as halogen,
  if appropriate in the presence of a catalyst, if appropriate in the presence of a basic reaction auxiliary and if appropriate in the presence of diluents, or
• c) for the preparation of the compounds of the general formula (Ia) and their salts,
  in the A for a residue -YR ¹³ (A ¹ )
  in which
  Y has the meanings given in claim 1,
  R ^{13 represents} radicals from the groups B ¹ and B ³ ,
  wherein
  Q, Y ¹ , n, R ¹⁸ -R ^{20 have} the meanings given in Claim 1,
  n stands for 0,
  and the group
  stands for carboxy,
  the compounds of the general formula (Ic) and their salts
  in which
  Y and R ¹ to R ^{12 have} the meanings given in claim 1,
  with a carboxylic anhydride of the general formula (IV)
  (Q-CO) ₂ O (IV)
  in which
  Q has the meaning given in claim 1 or for the rest
  stands,
  wherein
  Y ¹ , R ¹⁸ -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
• d) by compounds of the general formula (Ic)
  • 1. α) with amino acid derivatives of the general formula (V)
    in which
    Q and R ¹⁹ to R ^{21 have} the meaning given in claim 1,
    if appropriate in the presence of coupling reagents and, if appropriate, in the presence of a basic reaction auxiliary and, if appropriate, in the presence of diluents, or
  • 2. β) with compounds of the general formulas (VI) and (VII)
    in which
    Y and R ^{15 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.

4. Process for the preparation of compounds of the general formula (Ic) and their salts,
in which
Y and R ¹ to R ^{12 have} the meanings given in Claim 1, characterized in that

• a) of the compounds of the general formula (Ia) and their salts,
  in which
  R ¹ to R ^{12 have} the meanings given in claim 1,
  A stands for a residue -YR ¹³ (A ¹ ),
  in which
  Y represents oxygen or -NH,
  R ¹³ for a selectively removable protective group, for example allyl, allyloxycarbonyl (Alloc), benzyl (Bn), benzyloxycarbonyl (Z), tert-butyloxycarbonyl (Boc), tetrahydropyran-2-yl (THP) or in fluorenylmethoxycarbonyl (Fmoc) stands,
  depending on the removable protecting group, either in the presence of a hydrogenation catalyst, in the presence of a protonic acid or a basic reaction auxiliary and in the presence of a diluent, the radical R ^{13 is} selectively eliminated, or
• b) from the compounds of the general formula (Ia) and their salts bound to a polymeric carrier,
  in which
  R ¹ to R ^{12 have} the meanings given in claim 1,
  A for a residue -YR ¹³ (A ¹ )
  in which
  Y represents oxygen or -NH,
  R ^{13 represents} a selectively cleavable anchor group on a polymeric support,
  in the presence of a suitable catalyst or in the presence of a protonic acid and in the presence of a diluent by selective cleavage of the anchor group from the polymeric support R ^13, the compounds of the formula (Ic) are released.

5. Agent, characterized by a content of at least one compound of formula (I) according to claim 1. 6. Use of compounds of formula (I) according to claim 1 for Control of endoparasites. 7. A method for controlling endoparasites, characterized in that compounds of formula (I) according to claim 1 on endoparasites and / or let their living space take effect. 8. Process for the preparation of agents against endoparasites, characterized is characterized in that compounds of formula (I) according to claim 1 Extenders and / or surfactants mixed. 9. Use of compounds of formula (I) according to claim 1 for the preparation provision of anti-endoparasitic agents.