JP2002524453A - Aza-cyclodepsipeptides and their use as anthelmintics - Google Patents

Abstract

(57) Abstract: The present invention relates to novel aza-cyclodepsipeptides of formula (I), wherein X ¹ , X ² , X ³ and X ⁴ are independently N or C—H, At least one of the variables X represents nitrogen. The invention also relates to their preparation and to their use for controlling parasites, especially helminths. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel aza-cyclodepsipeptides, processes for their preparation and their use for controlling parasites, especially helminths, in veterinary and human medicine.

The present invention relates to α-hydroxycarboxylic acids on the one hand and α-amino acids or α-amino acids on the other hand.
The present invention relates to novel 24-membered heterocycles consisting of alternating units of aza-amino acids and containing at least one aza-amino acid. No such aza-cyclodepsipeptide has been previously disclosed.

The present invention relates to a compound of formula (I)

[0004]

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[0005] [wherein, X ^1, X ^2, X ³ and X ⁴ represents N or C-H independently of each other, wherein at least one of these variables X represents nitrogen, R ^1, R ² , R ³ and R ⁴ independently of one another are each hydrogen, alkyl, alkenyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthio, each optionally halogen-substituted Alkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl,
A cycloalkyl, a cycloalkylalkyl, an aryl, an arylalkyl, a hetaryl or a hetarylalkyl, which represents a dialkylaminoalkyl or which may each be optionally substituted, and represents a grouping -NR ⁹ -X ¹ R ⁵ -Represents a group of the formula -NR ^9-1 -CHR ^5-1- or a group of the formula -NR ^9-2 -NR ^5-2- , and the group -NR ¹⁰ -X ² R ^6- represents a group of the formula -NR ^{10- 1-} CHR ^6-1 -group or formula -NR ^10-2- -N
R ^6-2- represents a group of the formula: —NR ¹¹ —X ³ R ⁷ — represents a group of the formula —NR ^11-1 —CHR ^7-1 — or a group of the formula —NR ^11-2- N
R ^7-2- represents a group of the formula: -NR ¹² -X ⁴ R ^8- represents a group of the formula -NR ^12-1 -CHR ^8-1- or a group of the formula -NR ^12-2- N
R ^8-2 - indicates the ^{group, R 5-1, R 6-1, R} 7-1 and R ^8-1 independently of one another each represent hydrogen, optionally amino - or hydroxyl - be substituted Indicates a possible alkyl, indicates a mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl or is optionally amino-, nitro-, halogen-, hydroxyl- or alkoxy-substituted. Represents phenyl or benzyl, naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl, thienylmethyl,
Represents benzothienylmethyl or pyridylmethyl, wherein the functional groups may be optionally protected, and R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 are each independently of the other hydrogen Or C ₁ -C ₄
-Alkyl, wherein the group pairs R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1
Come together each also independently of each other group - (CH _{2) 3} - and - (CH ₂
) ₄ - indicates, R ^5-2 to R ^12-2 independently of one another each represent hydrogen, alkyl which may optionally be halogenated, each optionally substituted hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, Mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl,
A cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl, which represents dialkylaminoalkyl, alkoxycarbonylaminoalkyl or is each optionally substituted, wherein the group of radicals R ^{5 -2} / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2
Each together, and independently of one another, represent optionally substituted C ₁ -C ₄ -alkyl-substituted radicals — (CH ₂ ) ₃ — and — (CH ₂ ) ₄ —. A novel aza-cyclodepsipeptide is provided.

Functional groups are protected, for example, by protecting groups known from the chemistry of peptides (eg, TW Greene, PGM Wuts, Protective Gr).
ups in Organic Synthesis, 2nd Ed. , Jo
hnWiley & Sons, New York 1991).

[0007] The chiral carbon can have any configuration, ie, the compounds of formula (I) according to the present invention are constructed from D- and / or L-configuration amino acids and hydroxycarboxylic acids. The present invention relates to the pure stereoisomers and their mixtures.
The compounds are preferably constructed from D-hydroxycarboxylic acids and L-amino acids. However, for the sake of simplicity, in the following, a compound of formula (I) will always be understood to mean both a pure compound and, where appropriate, a mixture with various proportions of isomer compounds, To tell.

It has further been found that the novel compounds of the formula (I) can be obtained by one of the methods described below. A) Formula (II)

[0009]

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[Wherein X ¹ , X ² , X ³ , X ⁴ and R ^{1 to} R ¹² are each as defined above], and optionally a base in the presence of a reaction assistant and a solvent. By cyclization in the presence of

[0011]

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Wherein X ¹ , X ² , X ³ , X ⁴ and R ¹ -R ¹² are each as defined above, can be prepared. B) Formula (III)

[0013]

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Wherein X ² , X ³ and X ⁴ each independently represent N or CH, and R ^{1 to} R ¹² are each as defined above. An azadepsipeptide of the formula ( IV)

[0015]

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[0016] [wherein, Y ¹ represents chlorine, trichloromethoxy, C ₁ -C ₄ - shows alkoxy, can be optionally substituted phenoxy, 1-imidazolyl or 1,2,4-triazolyl, Y ² Represents chlorine, trichloromethoxy, 1-imidazolyl or 1,2,4-triazolyl] with a compound in the presence of a suitable diluent and a suitable reaction aid, and condensed and cyclized. , Formula (Ia)

[0017]

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Wherein X ² , X ³ and X ⁴ each independently represent N or CH, and R ^{1 to} R ¹² are each as defined above, to produce the azacyclodepsipeptide of the formula can do. C) Formula (V)

[0019]

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Wherein X ² , X ³ and X ⁴ each independently represent N or CH, and R ^{1 to} R ¹² and Y ¹ are each as defined above. Is condensed and cyclized in the presence of a diluent as appropriate and in the presence of a reaction aid as appropriate, whereby the azacyclodepsipeptide of the above formula (Ia) can be produced.

Furthermore, it has been found that the compounds according to the invention are suitable for controlling helminths in veterinary and human medicine.

Formula (I) provides a general definition of the new compounds. Preference is given to compounds of the formula (I) in which the substituents or the ranges have the following meanings: R ¹ , R ² , R ³ and R ⁴ independently of one another are each preferably hydrogen, C ₁ -C _16.
C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl, C ₄ -alkyl ₃ -C ₇ - cycloalkyl -C ₁ -C ₄ - alkyl, C ₁ -C ₆ - hydroxyalkyl, C ₁ -C ₄ - alkanoyloxy -C ₁ -C ₆ - alkyl,
In particular acetoxymethyl or 1-acetoxyethyl, C ₁ -C ₄ - alkoxy -
C ₁ -C ₆ - alkyl, in particular methoxymethyl or 1-methoxyethyl, aryl -C ₁ -C ₄ - alkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - mercaptoalkyl, especially mercaptomethyl, C ₁ -C ₄ - alkylthio -C ₁ -C ₆ - alkyl, in particular methylthioethyl, C ₁ -C ₄ - alkoxycarbonyl -C ₁ -C ₆ - alkyl,
Aryloxycarbonyl-C ₁ -C ₆ -alkyl, especially phenoxycarbonylmethyl, aryl-C ₁ -C ₄ -alkyloxycarbonyl-C ₁ -C ₆ -alkyl,
Carbamoyl-C ₁ -C ₆ -alkyl, especially carbamoylmethyl or carbamoylethyl, amino-C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkylamino-C _1-
C ₆ - alkyl, di -C ₁ -C ₄ - alkylamino -C ₁ -C ₆ - or an alkyl or aryl, -C ₁ -C ₄ - alkyl, hetaryl or hetaryl -C ₁ -C ₄ - an alkyl, optionally substituted by halogen they are, hydroxyl, cyano, C ₁ -C ₆ - alkyl, C ₁ -C ₄ - halogenoalkyl, C ₁ -C ₄ - alkoxy, C ₁ -C ₄ - halogenoalkoxy, benzyl It can be substituted by oxy or silyloxy trisubstituted by C ₁ -C ₄ -alkyl and / or phenyl.

R ^5-1 , R ^6-1 , R ^7-1 and R ^8-1 are each independently preferably hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, hydroxymethyl,
-Hydroxyethyl, mercaptomethyl, 2-methylthioethyl, 3-aminopropyl, 4-aminobutyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 3-guanidinopropyl, phenyl,
Benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 3,4-dichlorobenzyl, -Iodobenzyl, α-naphthylmethyl, β-naphthylmethyl, 3-indolylmethyl, 4-
Imidazolylmethyl, 1,2,3-triazol-1-yl-methyl, 1,2,2
Denotes 4-triazol-1-yl-methyl, 3-thienylmethyl, 3-benzothienylmethyl, 2-pyridylmethyl or 3-pyridylmethyl, wherein the functional group may be optionally protected.

R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 each independently preferably represent hydrogen, methyl or ethyl.

The group pairs R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1 are each taken together. in addition, independently of one another are preferably a group - (CH _{2) 3} - and - (
CH ₂ ) ₄ —.

R ^{5-2 to} R ^12-2 independently of one another each preferably represent hydrogen, C ₁ -C ₁₅ -alkyl, in particular also 3,7,11-trimethyldodecyl, or in each case optionally fluorine- C ₁ -C ₈ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkyl, C _1- , which may be chlorine- or bromine-substituted C ₆ - hydroxyalkyl, C ₁ -C ₄ - alkanoyloxy -C ₁ -
C ₆ - alkyl, C ₁ -C ₄ - alkoxy -C ₁ -C ₆ - alkyl, aryl -C ₁ -
C ₄ - alkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - mercaptoalkyl, especially mercaptomethyl, C ₁ -C ₄ - alkylthio -C ₁ -C ₆ - alkyl, in particular methylthioethyl, C ₁ -C ₄ - alkylsulfinyl -C ₁ -C ₆ - alkyl, in particular methylsulfinyl ethyl, C ₁ -C ₄ - alkylsulfonyl -C ₁ -C ₆ - alkyl,
In particular methylsulfonylethyl, carboxy -C ₁ -C ₆ - alkyl, in particular carboxymethyl, carboxyethyl or carboxy -tert- butyl, C ₁ -C ₄ - alkoxycarbonyl -C ₁ -C ₆ - alkyl, or in particular methoxycarbonylmethyl Ethoxycarbonylethyl, aryloxycarbonyl-C ₁ -C ₆ -alkyl, especially phenoxycarbonylmethyl, aryl-C ₁ -C ₄ -alkyloxycarbonyl-C ₁ -C ₆ -alkyl, especially benzyloxycarbonylmethyl, carbamoyl-C ₁ -C ₆ - alkyl, in particular carbamoylmethyl or carbamoylethyl, amino -C ₁ -C ₆ - alkyl, in particular aminopropyl or aminobutyl, C ₁ -C ₄ - alkylamino -C ₁ -C ₆ - alkyl, in particular Mechiruaminopu Pills or methylamino-butyl, di - (C ₁ -C ₄₎ - alkylamino -C ₁ -
C ₆ -alkyl, especially dimethylaminopropyl or dimethylaminobutyl,
Represents C ₁ -C ₄ -alkoxycarbonylamino-C ₁ -C ₆ -alkyl, or aryl, aryl-C ₁ -C ₄ -alkyl, hetaryl or hetaryl-C ₁
-C ₄ - represents an alkyl, optionally substituted by halogen they are, hydroxyl, nitro, cyano, amino, C ₁ -C ₄ - alkylamino, di - (C ₁ -C ₄₎ - alkylamino, benzylamino, dibenzyl Amino, protected amino such as acetyl-, t-butoxycarbonyl-, benzyloxycarbonyl- or FMO
C- amino, C ₁ -C ₆ - alkyl, C ₁ -C ₄ - halogenoalkyl, C ₁ -C ₄ - alkoxy or C ₁ -C ₄ - can be substituted by halogenoalkoxy, optionally wherein One NH function in a heterocyclic ring can be derivatized with an amino protecting group such as, for example, those described above.

The group pairs R ^5-2 / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2 are each taken together. And independently of one another, preferably the radicals-(CH ₂ ) _3- and-(C _{1, which} may optionally be mono- or tetra-substituted by C ₁ -C ₄ -alkyl.
H _{2) 4} - shows a.

R ¹ , R ² , R ³ and R ⁴ are each independently of one another particularly preferably hydrogen, C _1-
Represents C ₁₂ -alkyl or, as the case may be, fluorine-, chlorine- or bromine-
C ₁ -C ₄ -alkyl, C ₂ -C ₆ -alkenyl, C ₃ which may be substituted
-C ₇ - cycloalkyl, in particular cyclopentyl, cyclohexyl or cycloheptyl, C ₃ -C ₇ - cycloalkyl -C ₁ -C ₄ - alkyl, C ₁ -C ₆ - hydroxyalkyl, phenyl -C ₁ -C ₄ - alkoxy -C ₁ -C ₆ - alkyl, in particular benzyloxymethyl or 1-benzyloxyethyl, C ₁ -C ₄ - alkylthio -C ₁ -C ₆ - alkyl, in particular methylthioethyl, C ₁ -C ₄ - alkoxycarbonyl -C ₁ -C ₆ - alkyl, especially methoxycarbonylmethyl or ethoxycarbonylethyl, phenyl -C ₁ -C ₄ - alkyloxycarbonyl -C ₁ -C ₆ -
Alkyl, in particular benzyloxycarbonylmethyl, amino -C ₁ -C ₆ - alkyl, in particular aminopropyl or aminobutyl, C ₁ -C ₄ - alkylamino -C ₁
-C ₆ - alkyl, in particular methyl aminopropyl or methylamino-butyl, di - (C ₁ -C ₄₎ - alkylamino -C ₁ -C ₆ - alkyl, in particular showing a dimethylaminopropyl or dimethylaminobutyl, or phenyl , Phenyl-
C ₁ -C ₄ - alkyl, naphthylmethyl, 5- or 6-membered hetaryl, in particular thienyl, thiazolyl or pyridyl, indolyl, benzo-1,3-dioxolyl, 5- or 6-membered hetaryl -C ₁ -C ₄ - Alkyl, in particular thienylmethyl, thiazolylmethyl, imidazolylmethyl or pyridylmethyl or indolyl-C ₁ -C ₄ -alkyl, which are each optionally fluorine, chlorine,
Bromine, iodine, hydroxyl, cyano, C ₁ -C ₆ - alkyl, C ₁ -C ₄ - halogenoalkyl, C ₁ -C ₄ - alkoxy, C ₁ -C ₄ - halogenoalkoxy, benzyloxy or, C ₁ -C It can be substituted by silyloxy trisubstituted by ₄ -alkyl and / or phenyl.

Each of R ^5-1 , R ^6-1 , R ^7-1 and R ^8-1 independently of one another is particularly preferably methyl, iso-propyl, iso-butyl, sec-butyl, Shows hydroxymethyl, benzyl, 4-hydroxybenzyl, wherein the hydroxyl group can be optionally protected.

R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 each independently and particularly preferably each represent hydrogen or methyl.

The group pairs R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1 are also particularly preferably Each together, independently of one another, the radicals-(CH ₂ ) _3- and-
(CH ₂ ) ₄ —.

R ^{5-2 to} R ^12-2 independently of one another are each particularly preferably hydrogen, C ₁ -C ₁₀ -alkyl, C which can in each case be optionally fluorine-, chlorine- or bromine-substituted. ₁ -C ₄ - alkyl, C ₃ -C ₇ - cycloalkyl, in particular cyclopentyl, cyclohexyl or cycloheptyl, C ₃ -C ₇ - cycloalkyl -C ₁
-C ₄ - alkyl, C ₁ -C ₆ - hydroxyalkyl, especially hydroxymethyl or 1-hydroxyethyl, C ₁ -C ₄ - alkanoyloxy -C ₁ -C ₆ - alkyl, in particular acetoxymethyl or 1-acetoxyethyl, C ₁ -C ₄ - alkoxy -C ₁ -C ₆ - alkyl, in particular methoxymethyl or 1-methoxyethyl, phenyl -C ₁ -C ₄ - alkoxy -C ₁ -C ₆ - alkyl, in particular benzyloxymethyl or 1- Benzyloxyethyl, C ₁ -C ₄ -alkoxycarbonylamino-C ₁ -C ₆ -alkyl, especially tert-butoxycarbonylaminopropyl or tert-butoxycarbonylaminobutyl, or phenyl,
Phenyl -C ₁ -C ₄ - alkyl, 5- or 6-membered hetaryl, in particular thienyl, thiazolyl or pyridyl, 5- or 6-hetaryl -C ₁ -C ₄ - alkyl - alkyl or indolyl -C ₁ -C ₄ Which are each optionally fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, C _1-
C ₄ - alkylamino, di - (C ₁ -C ₄₎ - alkylamino, benzylamino,
Dibenzylamino, protected amino, such as acetyl-, t-butoxycarbonyl-
Benzyloxycarbonyl- or FMOC-amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -halogenoalkyl, C ₁ -C ₄ -alkoxy or C ₁ -C ₂ -halogenoalkoxy it can.

The group pairs R ^5-2 / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2 are also particularly preferably Each together, independently of one another, denote the radicals-(CH ₂ ) _3- and-(CH ₂ ) ₄ -which may optionally be mono- or tetra-substituted by methyl.

R ¹ , R ² , R ³ and R ⁴ independently of one another are each particularly preferably hydrogen, C ₁
-C ₁₂ - alkyl, in particular methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, sec- butyl, tert- butyl, n- pentyl, isopentyl, sec- pentyl, tert- pentyl, n- hexyl, isohexyl , Sec-hexyl, n-heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, n-decyl or n-dodecyl, or each optionally fluorine- or chlorine-substituted. ₁ -C ₄ - alkyl, in particular fluoromethyl, or shows a trifluoromethyl or trichloromethyl, C ₂ -C ₆ - alkenyl, especially if showing a vinyl or allyl, or shows a cyclopentyl or cyclohexyl, C ₃ -C ₇ - Cycloalkyl-C ₁ -C ₄ Alkyl, especially cyclopropylmethyl, methylthioethyl, or each optionally fluorine-, chlorine-, bromine-, iodine-,
Hydroxyl-, cyano-, methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, sec-butyl-, tert-butyl-,
Phenyl, phenyl-C ₁ -C ₄ -alkyl, in particular benzyl, 3-naphthylmethyl, which may be trifluoromethyl-, trichloromethyl-, methoxy-, difluoromethoxy-, trifluoromethoxy- or benzyloxy-substituted Benzo-1,3-dioxol-5-yl, thienylmethyl, imidazolylmethyl or indolylmethyl.

R ^5-1 , R ^6-1 , R ^7-1 and R ^8-1 are each independently of one another particularly preferably methyl, iso-propyl, iso-butyl or sec-butyl Is shown.

R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 each particularly preferably represent hydrogen or methyl.

The group pairs R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1 are
Also particularly preferably , they are taken together and independently of one another, a group — (CH ₂ ) ₃ —
And - (CH _{2) 4} - shows a.

R ^{5-2 to} R ^12-2 independently of one another are each particularly preferably hydrogen, C ₁ -C _10-
Alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,
sec-pentyl, tert-pentyl, n-hexyl, isohexyl, sec
-Hexyl, n-heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl or 3,7-dimethyloctyl, or C ₃
-C ₇ -cycloalkyl-C ₁ -C ₄ -alkyl, in particular cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl, or, as the case may be, respectively, fluorine-, chlorine-, bromine-, hydroxyl-, cyano-, methyl- ,
Ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, s
ec-butyl-, tert-butyl-, trifluoromethyl-, trichloromethyl-, methoxy-, difluoromethoxy-, trifluoromethoxy- or benzyloxy-substituted phenyl, benzyl, phenylethyl, 5- Or 6-membered hetarylmethyl, especially thienylmethyl, thiazolylmethyl, furylmethyl or pyridylmethyl, or indolylmethyl.

The group pairs R ^5-2 / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2 are
Particular preference is given to the radicals-(CH ₂ ) ₄ -which, taken together, are, independently of one another, optionally mono- or di-substituted by methyl.

The definitions or illustrations of the above general or preferred radicals can be combined with one another at will, ie including combinations between the ranges of interest and the preferred ranges. The definitions apply to both the final product and the corresponding precursors and intermediates.

R ¹ , R ² , R ³ and R ⁴ independently of one another each represent methyl, which may be optionally substituted by phenyl, which itself is halogen, cyano, nitro, amino, dialkyl Can be substituted with amino or morpholino, and the groups X ¹ -R ⁵ , X ² -R ⁶ , X ³ -X ⁷ and X ⁴ -R ⁸ are each independently a group

[0042]

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Wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently of the other C ₁ -C ₄ -alkyl, in particular branched C ₄ -alkyl, in particular i-butyl. Wherein at least one of the radicals X ¹ , X ² , X ³ and X ⁴ is

[0044]

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Preference is given to compounds of the formula (I) in which R ⁹ , R ¹⁰ , R ¹¹ and R ¹² independently of one another each represent C ₁ -C ₄ -alkyl, in particular methyl.

Compounds of the formula (I) in which one of the radicals X ¹ , X ² , X ³ and X ⁴ represents N are preferred according to the invention.

Compounds of the formula (I) in which two of the radicals X ¹ , X ² , X ³ and X ⁴ represent N are likewise preferred according to the invention.

A saturated or unsaturated hydrocarbon radical, for example alkyl or alkenyl, is in each case straight-chain or branched, including in combination with a heteroatom, for example in the case of alkoxy. It can be as branched as possible.

The groups that can be optionally substituted can be mono- or polysubstituted, and in the case of polysubstitution, the substituents can be the same or different.

In the present specification, the following abbreviations are used in addition to the three-letter codes for commonly known amino acids and the abbreviations for alkyl groups: Lac: 2-hydroxypropionic acid (lactic acid) Ph: Phenyl Bn: Benzyl Boc: tert-butoxycarbonyl PhLac: 2-hydroxy-3-phenylpropionic acid (β-phenyllactic acid) AzaAla: 2-azaalanine (N-methyl-N-aminocarbamic acid) Azayzz: 2-aza-similar amino acid “xyz” For example, H-MeLeu-D-PhLac-MeLeu-D-Lac-MeL
eu-D-PhLac-MeAzaAla-D-Lac-OH as well as bis- (2-oxo-3-oxazolidinyl) -phosphoryl (B
Using (OP-Cl) as a reaction aid and ethyldiisopropylamine as a base, the course of the reaction in the process (A) according to the invention can be represented by the following reaction formula:

[0051]

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For example, H-PhLac-MeLeu-D-Lac-MeLeu-D-PhL
The ac-MeLeu-D-Lac- N (CH 3) -N (s-Bu) H and diphosgene as starting materials, and the use of triethylamine as a reaction aid, the course of the reaction in process (B) according to the present invention This can be illustrated by the following reaction formula:

[0053]

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For example, F ₅ Ph-CO-PhLac-MeLeu-D-Lac-MeAza
Leu-D-PhLac-MeLeu- D-Lac-N (CH 3) -N (s-B
u) Using H as a starting material and pyridine as a reaction aid, the course of the reaction in process (C) according to the invention can be represented by the following reaction scheme:

[0055]

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Formula (II) gives a general definition of the azadepsipeptide required to carry out the method (A) according to the invention. In this formula, X ¹ , X ² , X ³ , X ⁴ and R ^{1 to} R ¹²
Represents, in each case, preferably the radicals already mentioned as preferred substituents in connection with the description of the aza-cyclodeptipeptide of the formula (I). The azadepsipeptide of formula (II) is new.

The azadepsipeptide of formula (II) can be produced, for example, by removing the protecting group of the C-terminal protected azadepsipeptide of formula (VI) according to the following reaction scheme in method (A.a): Can:

[0058]

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In the formula (VI), A ⁴ represents a C-terminal protecting group, for example, tert-butyl or benzyl (for example, TW Greene, PGM Wuts, Pr)
active Groups in Organic Synthesis
, 2nd Ed. , John Wiley & Sons, New York
1991).

The reaction can be carried out by conventional C-terminal deprotection methods such as, for example, acidolysis in the case of tert-butyl ester or catalytic hydrogenation in the case of benzyl ester, for example.

For example, in the method (A.b), the N-
The azadepsipeptide of formula (II) can also be prepared by removing the protecting group of the end-protected azadepsipeptide:

[0062]

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In formula (VII), A ¹ is an N-terminal protecting group such as tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz) or benzyl (B
n) (eg, TW Greene, PGM Wuts, Prot)
active Groups in Organic Synthesis, 2
nd Ed. , John Wiley & Sons, New York 19
91).

For example, the reaction can be carried out by a conventional N-terminal deprotection method such as acidolysis for a BOC group or catalytic hydrogenation for a benzyl group.

The C-terminally protected azadepsipeptide of formula (VI) required to perform the method (A.a) and the N-terminally protected azadepsipeptide of formula (VII) required to perform the method (A.b) Is of the formula (VIII)

[0066]

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Starting with the N- and C-terminally protected azadepsipeptides of the formula (Aab), the N-terminal protecting group is removed in a manner analogous to (Ab), or (A .
It can be prepared analogously to a) by removing the C-terminal protecting group in the process (Aba). Depending on the type of protecting group, in certain embodiments of the method, both protecting groups can be removed in one step to reach the compound of formula (II) directly from the compound of formula (VIII) (Method A.a / b).

The aza-octadepsipeptide of formula (VIII) can be obtained, for example, by converting a compound of formula (IX) with a compound of formula (X), a reaction aid such as BOP-Cl or HATU (among others) and a Hunig base (Hünig). base), in the presence of a base,
And optionally in the presence of a diluent such as dichloromethane by reacting according to the following reaction formula:

[0069]

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Suitable reaction auxiliaries, bases and solvents are listed below under method (A).

The N-terminally protected azadepsipeptide of formula (IX) can be prepared, for example, by converting the O-protecting group A ³ of the two-sided protected azadepsipeptide of formula (XI) analogously to the generally known methods described above. The C-terminally protected azadepsipeptide of formula (X) can be prepared by removal of the N-protected N-side of the azadepsipeptide of formula (XII).
It can be prepared by removing the protecting group A ² analogously to the generally known methods described above.

[0072]

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In the formula (XI), A ³ represents the C-terminal protecting group mentioned for A ⁴ . The formula (X
In II), A ² represents the N-terminal protecting group mentioned for A ¹ . In general, the two-sided protected (aza) -tetradepsipeptide can be grouped into one general formula, which consists of the group denoted by an odd number in formula (XI) and its odd number in formula (XII) This is because a group represented by an even number greater than 1 indicates a list of the same group. It has to be mentioned that in each synthesis of the individual compounds of the formula (I), the groups can be chosen independently of one another, ie the building blocks (XI) and (XII) can be the same or different. In the following, the synthesis of the compound of formula (XI) is shown as a representative, since it also applies to the preparation of (XII).

The pure tetradepsipeptide of formula (XI) (X ¹ , X ² ＣＨCH) was prepared according to Annu. R
ep. Sankyo Res. Lab. 46 , 67-75 (1994);
Antibiot. 47 , 1322-1327 (1994),
Alternatively, they can be manufactured by a similar method. For example, BOP-C
In the presence of a reaction aid such as 1 or HATU and a base such as Hunig's base, and optionally in the presence of a diluent such as dichloromethane, the structural unit of formula (XIII) is converted to a compound of formula (XIV) according to the following reaction formula. The compound of the formula (XI) can be produced by conjugation with a structural unit of the formula:

[0075]

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Suitable reaction auxiliaries, bases and solvents are those listed under method (A).

The monoprotected didepsipeptides of the formulas (XIII) and (XIV) are known from the above-mentioned documents or can be prepared, for example, analogously to the methods indicated there. The monoprotected aza-didepsipeptides of the formulas (XIII) and (XIV) are known from DE-A1 196 126 644, or they can be prepared, for example, analogously to the methods indicated there.

Formula (III) provides a general definition of the compounds required to carry out process (B) according to the invention. In this formula, X ^{2 to} X ⁴ and R ^{1 to} R ¹² preferably denote the groups already mentioned as preferred substituents in connection with the description of the aza-cyclodepsipeptide of the formula (I).

Compounds of formula (III) can be prepared, for example, using the usual methods shown above, of formula (XV
The N- terminal protecting group A ⁵ from the compound of) can be prepared by removal.

[0080]

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In formula (XV), A ⁵ represents the N-terminal protecting group mentioned for A ¹ .

Compounds of formula (XV) can be prepared, for example, by reacting an (aza) -depsipeptide ester of formula (XVI) with a hydrazine of formula (XVII) according to the following reaction scheme:

[0083]

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In formula (XVI), R ¹³ represents an optionally substituted alkyl or aryl. The (aza) -depsipeptide ester of formula (XVI)
For example, analogously to the synthesis of compound (VII), it can be used there or prepared by methods of peptide chemistry described therein.

Some of the hydrazines of formula (XVII) are known, or they can be obtained by known methods (eg, J. Chem. Soc. Perkin).
Trans. I 1975 , 1712).

Formula (IV) provides a general definition of the compounds further required to carry out process (B) according to the invention. In this formula, Y ¹ is preferably chlorine, trichloromethoxy, methoxy, ethoxy, 1-imidazolyl, 1,2,4-triazolyl or Z
Represents substituted aryloxy, in particular pentafluorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl, wherein Y ² is preferably chlorine, trichloromethoxy, methoxy, ethoxy, 1-imidazolyl or 1,2,4-triazolyl Show.

The compounds of formula (IV) are generally known as phosgene or phosgene equivalents (
For example, Org. Synthesis Coll. Vol. 5 , 201 (197
See 3)).

Formula (V) provides a general definition of the compounds required to carry out process (C) according to the present invention. In this formula, X ² , X ³ , X ⁴ , R ^{1 to} R ¹² each preferably denote a group which has already been mentioned as a preferred substituent in connection with the description of the aza-cyclodepsipeptide of the formula (I). Y ¹ preferably represents chlorine, trichloromethoxy, 1-imidazolyl, 1,2,4-triazolyl or Z-substituted aryloxy, especially pentafluorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl.

The compound of the formula (V) can be produced, for example, by removing the N-terminal protecting group A ⁵ from the compound of the formula (XVIII) by the method shown above.

[0090]

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Compounds of formula (XVIII) can be prepared, for example, by converting a compound of formula (XV) as described above in method B)
Reacting with one of the phosgenating reagents of formula (IV) described below and optionally converting the resulting product of formula (XVIII), wherein Y ¹ does not represent Z-substituted aryloxy, to a suitable phenol or It can be prepared by reacting with a phenolate, for example, 2,4-dinitrophenol.

Suitable reaction auxiliaries for carrying out the process (A) according to the invention are all compounds which are suitable for the formation of amide bonds (for example Houben-Weyl, Method)
ender Organischen Chemie, volume 15 /
2; Bodensky et al. ; Peptide Synthesis
2nd ed. , Wiley & Sons, New York 1976). Preferably, the following method is used: pentafluorophenol (
Activated ester method using PfP), N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBt), cup using carbodiimide such as dicyclohexylcarbodiimide or N '-(3-dimethylaminopropyl) -N-ethylcarbodiimide (EDC) Ring and mixed anhydride methods, or phosphorus reagents such as 1-benzotriazolyloxy-tris- (dimethylamino) -phosphonium (BOP) hexafluorophosphate, O-hexafluorophosphate
(7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HATU), bis- (2-oxo-3-oxazolidinyl) phosphoryl (BOP-Cl), diphenylphosphoryl azide Coupling using (DPPA) or diethyl cyanophosphonate (DEPC). Coupling with BOP-Cl, HATU or EDC in the presence of HOBt is particularly preferred.

Suitable solvents for performing the method (A) according to the present invention are organic solvents and mixtures thereof. Examples are: aliphatic, cycloaliphatic or aromatic hydrocarbons such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, methylene chloride Chloroform, tetrachloromethane, dichloro-, trichloroethane or tetrachloroethylene; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2- Diethoxyethane, diethylene glycol dimethyl ether or anisole; ketones such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles For example, acetonitrile, propionitrile,
n- or i-butyronitrile or benzonitrile; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-
N-oxides: methylformanilide, N-methylpyrrolidone, 1,3-dimethyl-tetrahydro-2-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone, tetramethylurea or hexamethylphosphoric triamide; N-oxides For example, N-methylmorpholine N-oxide; esters such as methyl acetate, ethyl acetate or butyl acetate; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane.

The cyclisation is preferably carried out in the presence of a base. Suitable bases are inorganic or organic bases. These are preferably alkaline earth metal or alkali metal hydroxides, alkoxides, acetates, carbonates or bicarbonates, such as sodium hydroxide, potassium hydroxide or ammonium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium acetate, potassium acetate, calcium or ammonium acetate, sodium carbonate, potassium carbonate or ammonium carbonate, sodium or potassium bicarbonate, and also tertiary amines such as trimethylamine, triethylamine, tributylamine, Ethyl-diisopropylamine, N, N-dimethylaniline, N, N
-Dimethyl-benzylamine, pyridine, picoline, N-methylpiperidine, N
-Methylmorpholine, N, N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).

When carrying out the process (A) according to the invention, the reaction temperatures can be varied within a relatively wide range. Generally, the cyclization is carried out at a temperature between -40 ° C and + 150 ° C, preferably at -2 ° C.
The reaction is carried out at 0 ° C to 100 ° C, particularly preferably at 0 ° C to room temperature.

When carrying out process (A) according to the invention, the compound of formula (II) and the base are generally 1
: 1 to 1: 3, preferably in a molar ratio of 1: 2. The process is preferably carried out at high dilution, i.e. generally from 50 to 50 per mole of compound of formula (II)
5000 ml of solvent are used.

The method (B) according to the invention can be performed in the presence of a diluent. Suitable diluents are those listed under method (A).

The process (B) according to the invention can be carried out in the presence of suitable reaction auxiliaries. Suitable reaction auxiliaries are all bases listed under process (A).

When carrying out process (B) according to the invention, the reaction temperatures can be varied within a relatively wide range. Generally, the process is carried out between -20 ° C and + 150 ° C, preferably between + 20 ° C and
The reaction is carried out at a temperature of 120 ° C. and, if appropriate, two reactants (reaction pa
The cyclization is initiated by the first temperature rise after the reaction has been completed.

When carrying out process (B) according to the invention, 1 per mole of compound of formula (III)
. 0 to 2.0 mol, preferably 1.0 to 1.2 mol of compound (IV) and 1
. 0-5 moles of reaction aid are used.

The method (C) according to the invention can be performed in the presence of a diluent. Suitable diluents are those listed under method (A).

The process (C) according to the invention can be carried out in the presence of suitable reaction auxiliaries. Suitable reaction auxiliaries are all bases listed under process (A).

When carrying out process (C) according to the invention, the reaction temperatures can be varied within a relatively wide range. Generally, the process is carried out between -20 ° C and + 150 ° C, preferably between + 20 ° C and
Performed at a temperature of 120 ° C.

When carrying out the process (C) according to the invention, if appropriate the compounds of the formula (IX) and the base are generally employed in a molar ratio of from 1: 1 to 1: 3, preferably in equimolar amounts.

The reaction of the process according to the invention can be carried out at atmospheric pressure or under pressure. They are preferably performed at atmospheric pressure. The reaction is carried out, worked up and the reaction products are isolated by generally known methods. The final product is preferably purified by crystallization, chromatographic separation or, if appropriate, by removing volatile constituents under reduced pressure (see also the Preparation Examples).

The active compounds are useful in humans and in dairy and livestock raising,
Suitable for controlling pathogenic endoparasites encountered in farmed livestock, zoo animals, laboratory animals, laboratory animals and pets, and has low toxicity to warm-blooded animals.
They are active against resistant and normally susceptible species, and against all or some stages of pest development. By controlling pathogenic endoparasites,
The aim is to reduce illness, mortality and loss of performance (for example in the production of meat, milk, wool, leather etc.) and to allow more economical and simple animal breeding through the use of active compounds. Pathogenic endoparasites include tapeworms, trematodes, nematodes, especially: from the order of Pseudophyllidea, for example, the cleft tapeworm species (Di)
phyllobothrium spp. ), Spirometra species (Spirome)
tra spp. ), Sistocephalus species
spp. ), Ligura spp., Botulium sp.
ridium spp. ), Diphlogonooru species
s spp. ), From the order of Cyclophyllidea, for example, Mesocestoides spp., Anoprosephala species (Anopl)
ocephala spp. ), Paranoprocephara species (Paranoproc)
ephala spp. ), Moniesia spp., Thysanosmsa spp., Tisaniesia spp. (Thy)
saniezia spp. ), Abiterina species (Avitellina spp.)
. ), Stilesia spp., Citota ennia (Cit
totaenia spp. ), Anhyra spp., Bertiella spp., Taenia sp.
p. ), Echinococcus spp., Hydratigera spp., Davinea sp.
a spp. ), Raillietina spp., Hymenolepsis spp., Echinolepsis sp. (E
chinolepsis spp. ), Echinococci species
le spp. ), Diorchis spp., Dipyridium spp., Joyeuella sp.
xiella spp. ), Dipropyridium species
spp. ), From the subclass of Monogenea, for example, Cyrodactylus spp., Dactyrogillus (Da)
ctylogyrus spp. ), Polystoma sp.
p. ), From the suborder Digenea, for example, Diprostomum species (Diplos)
tomum spp. ), Postdiprostomum species (Posthodiplos)
tomum spp. ), Cystosoma species (Schistosoma spp.)
, Trichobirharzia spp., Ornithobirharzia spp., Austrobilharzia spp., Gigantobirharzia sp. Species (Leucochloridium spp.), Brachyleima species (
Brachylima spp. ), Echinostoma species (Echinostom)
a spp. ), Echinopariphyium sp.
pp. ), Echinochasmus spp., Hypoderaeum spp., Faciola sp. (Fasc)
iola spp. ), Fasciolides spp.
), Fasciolopsis spp., Cyclocoelum spp., Tifuroserm sp.
ccelum spp. ), Paramfistum species
um spp. ), Calicophoron spp.
, Cotylophoron spp., Gigantocotyle spp., Fisco Edelius sp.
choederius spp. ), Gastrotrophic species
lacus spp. ), Notocotylus spp.
), Catatropis spp., Plagiorkis sp.
Plagiorchis spp. ), Prostgonismus species (Prostho)
gonismus spp. ), Dicrocoelium species (Microcoeliu)
m spp. ), Collyliclum spp., Nanophytus spp., Opistolkis (Op.)
isthorchis spp. ), Clonorchis species
spp. ), Metorchis spp., Heterophies spp., Metagonimus sp. (Metagoni)
mus spp. ), From the order of the Enoplidae, for example, Trichris species (Trich)
uris spp. ), Capillaria spp., Trichromosoides spp., Trichinella spp., Rhabditia species, for example, Micronema spp.
ema spp. ), Strongyloides s
pp. ), From the order of the Strongylidae, for example, the species Stronylus
nylus spp. ), Tridontophors
us spp. ), Oesophagodontus species (Oesophagodontus)
spp. ), Trichomema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostomum sp. (Po)
teriostomum spp. ), Cyclococerx species (Cyclococ)
ercus spp. ), Silicostephanus species
us spp. ), Oesophagostomum species (Oesophagostomum)
spp. ), Cabertia spp., Stefanurus spp., Ansilostoma sp.
stoma spp. ), Uncinaria spp.,
Bunostomum spp., Globocephalus sp.
lobocephalus spp. ), Singhamus s species
pp. ), Cyatostoma spp., Metastrongilus spp., Dictiocaulus spp., Muellerius sp.
us spp. ), Protostrongillus species
spp. ), Neostrongylus spp.
), Cystocaurus spp., Pneumostrongylus spp., Spicocaurus spp., Elafostrogylus sp.
phosphongylus spp. ), Parellafostrongilus (Pa)
relaphostrongylus spp. ), Clenosoma species (Creno)
soma spp. ), Paracrenosoma sp.
p. ), Angiostrongylus spp.
. ), Aerulostrongilus spp.
. ), Philaroides spp., Parafilaroides spp., Tricholongylus spp., Haemonks sp. (Haem)
onchus spp. ), Ostertagia spp.
. ), Marshallaggia spp., Cooperia spp., Nematodirus sp.
spp. ), Hyostrongylus spp.
), Obeliscoides spp., Amidostomum spp., Orlanus sp.
us spp. ), Silicocyclus spp.
Silicodontophorus spp .;
From the eyes of the pinworms (Oxyurida), for example, Oxyuris species (Oxyuris)
spp. ), Enterobius spp., Passalurus spp., Sifasia species (Syphaci)
a spp. ), Aspiculuris spp., Heterakis spp., Ascaridia, from the eyes of, for example, Ascaris sp.
spp. ), Toxascaris spp., Toxocara spp., Parascari sp.
s spp. ), Anisakis spp., Ascaridia spp., Spirurida, for example, Gnatostoma sp.
hostoma spp. ), Physaloptera species
spp. ), Thelazia spp., Gongironema sp. (G
ongylonema spp. ), Habronema sp.
p. ), Parabronema spp., Dracia spp.
Drashia spp. ), Dracunculus species
spp. ), From the order of Filariida, for example, the Stefanofilaria species (S
tephanofilaria spp. ), Parafilaria species (Parafi)
laria spp. ), Setaria species (Setaria spp.), Lore species (
Loa spp. ), Dirofilaria spp.)
, Litomosoides spp., Bulgia species (B
rugia spp. ), Species of Ucereria (Wuchereria spp.),
From the order of Onchocerca spp., Gigantohynchida, for example, Filicollis spp., Moniliformis sp.
iliformis spp. ), Macracan Trinks species (Macracan)
thorhynchus spp. ), Prostenorkis species (Prosten)
orchis spp. ) Is included.

The active compounds according to the invention include, for example, Trichinella sp.
ella spiralis) larvae and nematodes, such as Nippon Longylus.
Brass reensis (Nippostrongyrus brasiliensi)
has excellent activity against s).

Livestock and farmed livestock include mammals such as cattle, horses, sheep, pigs, goats, camels, buffaloes,
Includes donkeys, rabbits, yellows, redheads, fur animals such as mink, chinchilla or raccoon.

The laboratory and test animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.

[0110] Pets include dogs and cats.

Administration can be both prophylactic and therapeutic.

The active substances are administered directly or in the form of suitable preparations enterally, parenterally, dermally.

Enteral administration of the active compounds includes, for example, powders, suppositories, tablets, capsules, pastes, beverages, granules, solutions, suspensions and emulsions, pills, drug additions which can be applied orally. It is taken orally in the form of a medicated feed or drinking water. Dermatological applications include, for example, dipping, spraying, bathing, washing or pouring-
On and spotting-on and in the form of powdering. Parenteral administration is carried out, for example, in the form of injections (intramuscular, subcutaneous, intravenous or intraperitoneal) or by implantation.

Suitable formulations include: solutions, for example, injectable solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on preparations, gels; Emulsions and suspensions for oral or dermal administration and for injection; semi-solid preparations; active compound introduced in cream base or oil-in-water or water-in-oil emulsion base Formulations; solid preparations, such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; aerosols and inhalants, shaped articles containing the active compound.

The solutions for injection are administered intravenously, intramuscularly and subcutaneously.

Injectable solutions dissolve the active compound in a suitable solvent, if necessary, with a solubilizer, an acid,
It is prepared by adding additives such as bases, buffer salts, antioxidants or preservatives. The solution is sterile-filtered and decanted into containers.

Suitable solvents include: physiologically acceptable solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerin, hydrocarbons, propylene glycol, polyethylene glycol and N-methylpyrrolidone and mixtures thereof. Is included.

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

Suitable solubilizers include: solvents that promote the dissolution of the active compound in the main solvent or prevent the precipitation of the active compound. Examples of solubilizers are polyvinylpyrrolidone, polyethoxylated castor oil and polyethoxylated sorbitan esters.

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

Oral solutions are administered directly. The concentrate is first diluted to a dosage concentration and then administered orally. Oral solutions and concentrates are prepared as described above for injectable solutions, and no sterilization procedures are required.

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

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

The following are thickeners: inorganic thickeners such as bentonite, colloidal silica, aluminum monostearate, or organic thickeners such as cellulose derivatives, polyvinyl alcohol and their copolymers, acrylates and methacrylates.

The gel is applied to the skin, or stroked on or introduced into a body cavity. Gels are prepared by adding an amount of thickening agent to a solution prepared as described for injectable solutions, to form a clear composition having an ointment-like consistency. The thickeners used are all those mentioned above.

The pour-on and spot-on preparations are poured over a limited area of the skin,
Or sprinkled, the active compound penetrates the skin and acts systemically or spreads over the body surface.

Pour-on and spot-on preparations are prepared by dissolving, suspending or emulsifying the active compound in suitable solvents or solvent mixtures for which the skin is resistant. If appropriate, other auxiliaries such as coloring agents, absorption promoters, antioxidants, light stabilizers or tackifiers are added.

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

Coloring agents are all coloring agents that can be dissolved or suspended and that are approved for use in animals.

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

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

Examples of light stabilizers are benzophenones or novantisoleic acid (novantisolic acid).
lic acid).

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

Emulsions may be administered orally, dermally or as injections.

The emulsions are either water-in-oil or oil-in-water.

They dissolve the active compound in a hydrophobic or hydrophilic phase and combine this phase with the solvents of the other phases, as well as suitable emulsifiers and, if appropriate, other auxiliaries, such as coloring agents, absorption enhancers, preservatives, It is prepared by homogenizing with an antioxidant, a light stabilizer and a thickening substance.

Suitable hydrophobic phases (oils) include: paraffin oil, silicone oil, natural vegetable oils such as sesame oil, almond oil or castor oil, synthetic triglycerides such as caprylic / capric acid biglyceride, chain lengths of C _8-12 . Mixtures of triglycerides with vegetable or other specially selected natural fatty acids, mixtures of partial glycerides of saturated or unsaturated fatty acids which can also contain hydroxyl groups and C ₈ / C ₁₀ −
Fatty acid mono- and diglycerides, fatty acid esters such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, C ₁₆ -C ₁₈ of branched fatty acids with medium chain length Esters with saturated fatty alcohols of chain length, isopropyl myristate, isopropyl palmitate, caprylic / capric acid esters of saturated aliphatic alcohols with C ₁₂ -C ₁₈ chain length, isopropyl stearate, oleyl oleate, decyl oleate , Ethyl oleate, ethyl lactate, waxy fatty acid esters such as artificial duck tail fat (artificial du)
aliphatic alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, fatty acids such as oleic acid, and the like. And mixtures thereof.

Suitable hydrophilic phases include: water, alcohols such as propylene glycol, glycerin, sorbitol and mixtures thereof.

Suitable emulsifiers include: nonionic surfactants, such as polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerin monostearate, polyoxyethyl stearate or alkylphenol polyglycol ethers An amphoteric surfactant, such as disodium N-lauryl-β-iminodipropionate or lecithin; an anionic surfactant, such as sodium lauryl sulfate, aliphatic alcohol ether sulfate and mono / dialkyl polyglycol ether orthophosphate; Monoethanolamine salts; cationic surfactants such as cetyltrimethylammonium chloride.

Other auxiliaries which are suitable are: substances which increase the viscosity and stabilize the emulsion, for example carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinyl Includes pyrrolidone, polyvinyl alcohol, methyl vinyl ether / maleic anhydride copolymer, polyethylene glycols, waxes, colloidal silica or mixtures of the above substances.

[0141] Suspensions can be administered orally, dermally or as injections. They are prepared by suspending the active compound in a liquid vehicle, if appropriate with the addition of other auxiliaries, such as wetting agents, coloring agents, absorption enhancers, preservatives, antioxidants and light stabilizers. You.

Suitable liquid excipients include all homogeneous solvents and solvent mixtures.

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

Other auxiliaries which are suitable include those enumerated above.

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

For preparing solid preparations, the active compounds are mixed with suitable excipients, if appropriate with the addition of auxiliaries and the mixture is prepared as desired.

Suitable excipients include all physiologically acceptable solid inert substances. Inorganic and organic substances are suitable for this purpose. Inorganic substances are, for example, salt, carbonates such as calcium carbonate, bicarbonate, aluminum oxide, silica, clay, precipitated or colloidal silica and phosphates.

Organic substances are, for example, sugars, cellulose, food and animal feed, such as milk powder, animal meal, cereal meal, coarse cereal meal and starch.

Auxiliaries are the preservatives, antioxidants and coloring agents already mentioned above.

Other suitable auxiliaries are lubricants and glidants such as magnesium stearate, stearic acid, talc, bentonite, disintegrants such as starch or cross-linked polyvinylpyrrolidone, binders such as starch, gelatin or starch. Chain polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.

In the preparations the active compounds can also be present as a mixture with synergists or other active compounds active against pathogenic endoparasites. Examples of such active compounds are L-2,3,5,6-tetrahydro-6-phenyl-imidazolylthiazole, benzimidazole carbamate, praziqant (praziquant)
el), pyrantel or fevantel
).

The prepared preparations contain from 10 ppm to 20% by weight, preferably from 0 ppm, of the active compound.
. Contains at a concentration of 1 to 10 weight percent.

Preparations which are diluted before use contain the active compound in a concentration of 0.5 to 90% by weight, preferably 5 to 50% by weight.

Generally, to obtain effective results, about 1-100 m / kg body weight per day
It has proven advantageous to administer amounts of g of active compound.

The preparation and use of intermediates or active compounds according to the invention is illustrated by the following examples.

Production Examples Example I-1 (Method A)

[0157]

Embedded image

Under an argon atmosphere, 800 mg (0.825 mmol) of H-MeLeu-
D-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac
-MeAzaLeu-D-Lac-OH (e.g. from Example II-1) was first placed in 1000 ml of dichloromethane. 266 mg (2.06
Mmol) ethyldiisopropylamine and 252 mg (0.99 mmol)
Of BOP-Cl was added to the solution. Subsequently, the mixture was warmed to room temperature and stirred for 24 hours. The reaction solution was then washed with saturated sodium bicarbonate solution and water, dried over sodium sulfate and concentrated. Column chromatography (silica gel, φ = 4.5c)
m, l = 25 cm; cyclohexane: ethyl acetate 1: 1) contains 247 mg of 6
, 18-Dibenzyl-3,9,15,21-tetraisobutyl-4,10,12
, 16,22,24-Hexamethyl-1,7,13,19-tetraoxa-3,
4,9,10,16,22-hexaaza-cyclotetracosane-2,5,8,1
1,14,17,20,23-octane (cyclo- [MeLeu-D-PhL
ac-MeLeu-D-Lac-MeAzaLeu-D-PhLac-MeAz
aLeu-D-Lac]) as a yellowish solid, which is 90-91 ° C.
Melted.

Further purification by HPLC (Reversed Phase RP18, 5 μm, acetonitrile / water gradient) gave 121 mg of analytically pure material after freeze-drying. HR-MS: m / z C 50 H 74 N 6 O 12 prepared in Example Calculated 973.5262 measured value 973.5265 precursor relates Na II-1

[0160]

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850 mg (0.80 mmol) of H-MeLeu-D-PhLac-MeL
eu-D-Lac-MeAzaLeu-D-PhLac-MeAzaLeu-D
-Lac-O-Bn (e.g. from Example VII-1) was dissolved in about 30 ml of ethyl acetate and hydrogenated with hydrogen at atmospheric pressure in the presence of Pd / C (10%). After the reaction was completed, the catalyst was filtered off, and the solvent was removed under reduced pressure. This is 8
06 mg of H-MeLeu-D-PhLac-MeLeu-D-Lac-MeA
zaLeu-D-PhLac-MeAzaLeu-D-Lac-OH was provided as a slightly colored foam. Example VII-1

[0162]

Embedded image

Under argon, 1.36 g (1.173 mmol) of Boc-MeLeu-D
-PhLac-MeLeu-D-Lac-MeAzaLeu-D-PhLac-
MeAzaLeu-D-Lac-O-Bn (eg from Example VII-1) was first placed in 100 ml of dichloromethane. At 0 ° C., 1.34 g (11
. (73 mmol) trifluoroacetic acid was slowly added dropwise to the solution, which was then stirred at this temperature overnight. Subsequently, the mixture was concentrated under reduced pressure, the residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. Drying and removal of the solvent under reduced pressure resulted in 0.95 g (76% of theory) of H-
MeLeu-D-PhLac-MeLeu-D-Lac-MeAzaLeu-D
-PhLac-MeAzaLeu-D-Lac-O-Bn was provided as a dark highly viscous oil. Example VIII-1

[0164]

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Under argon, 2.67 g (4.5 mmol) of the carboxylic acid Boc-MeLe
u-D-PhLac-MeLeu-D-Lac-OH (Annu. Rep. Sa
nkyo Res. Lab. 46 , 67-75 (1994); Antib
iot. 47 , 1322-1327 (1994)) was first placed in 45 ml of dry dichloromethane. At 0 ° C., 1.40 g (5.5 mmol) of BOP
-Cl and 0.59 g (5.8 mmol) of N-methylmorpholine were slowly added continuously. After about 1 hour, 2.62 g (dissolved in a small amount of dichloromethane)
4.5 mmol) of hydrazine H-MeAzaLeu-D-PhLac-MeA
ZaLeu-D-Lac-O-Bn (eg from Example X-1) was added slowly. Subsequently, a further 0.59 g of N-methylmorpholine was added. The mixture was warmed to room temperature and stirred for 12 hours. Subsequently, the mixture was concentrated, the residue was taken up in ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent was removed under reduced pressure. Column chromatography (silica gel, φ = 4.5 cm, l
= 25 cm; cyclohexane: ethyl acetate 3: 1) is 2.40 g (46% of theory) of Boc-MeLeu-D-PhLac-MeLeu-D-Lac-M.
eAzaLeu-D-PhLac-MeAzaLeu-D-Lac-O-Bn was provided as a yellow highly viscous oil. HR-MS: m / z C 62 H 90 N 6 O 15 Calculated 1181.6362 measurements for Na 1,181.6349 Example X-1

[0166]

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Under argon, 3.08 g (4.5 mmol) of Boc-MeAzaLeu-
D-PhLac-MeAzaLeu-D-Lac-O-Bn (for example, Example XI
1-1) was first taken up in 60 ml of dry dichloromethane. At 0 ° C., 5.14 g (45 mmol) of trifluoroacetic acid were slowly added dropwise to the solution. The mixture was warmed to room temperature and stirred for about 15 hours. Subsequently, the solution was concentrated, the residue was taken up in dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture was dried over sodium sulfate and the solvent was removed under reduced pressure. This is 2.67 g (quantitative) of H-MeAzaLeu-D-PhLac-MeAz.
aLeu-D-Lac-O-Bn was provided as a slightly dark viscous oil. MS (FAB): m / z (relative intensity): 585 (M + H ⁺ , 35), 584 (
M ⁺ , 20) Example XI-1

[0168]

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Under argon, 11.9 g (30 mmol) of benzyl 2- (1-isobutyl-2-methylhydrazyl) -carbonyloxypropionate (eg, Example XI)
V-1 or WO 9736883) and 9.22 g (30 mmol) of 2-
(2-tert-Butoxycarbonyl-1-isobutyl-2-methylhydrazyl) -carbonyloxy-3-phenylacetic acid (e.g. from Example XIII-1) was initially placed in 120 ml of dry dichloromethane. 9.69 g at 0 ° C
(75 mmol) of ethyldiisopropylamine and then 9.16 g (36 mmol) of BOP-Cl were slowly added to the solution. The mixture was stirred at 0 ° C. for 2 hours, then warmed to room temperature and stirred for another 12 hours. Column chromatography (silica gel, φ = 6 cm, l = 30 cm; cyclohexane: ethyl acetate 6: 1)
Is 9.25 g (45% of theory) of Boc-MeAzaLeu-D-PhLa
c-MeAzaLeu-D-Lac-O-Bn was provided as a yellow viscous oil.
HR-MS: m / z C 36 H 52 N 4 O 9 Calculated 707.3632 measurements for Na 707.3634 Example XIII-1

[0170]

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15.54 g (30 mmol) of 2- (2-tert-butoxycarbonyl-
Benzyl 1-isobutyl-2-methylhydrazyl) -carbonyloxy-3-phenylacetate (e.g., from WO 9736883) is dissolved in 150 ml of ethyl acetate under atmospheric pressure in the presence of Pd / C (10%). And hydrogenated with hydrogen.
After the reaction was completed, the catalyst was filtered off, and the solvent was removed under reduced pressure. This is 11.9g
(Quantitative) 2- (2-tert-butoxycarbonyl-1-isobutyl-2-
Methylhydrazyl) -carbonyloxy-3-phenylacetic acid was provided as a yellowish brown oil. MS: m / z (relative intensity): 417 (M + Na ⁺ , 20); 395 (M + H ⁺ ,
10); 394 (M ⁺ , 5); 393 (M-H ⁺ , 10); 339 (70);
1 (40); 295 (100); 173 (60); 148 (50); 131 (3
^{5); 101 (35) 1} H NMR (500MHz, CDCl 3): δ (ppm) 0.95 ( complex _{signal, 6H, CH (C H 3} ) 2); 1.35-1.55 ( complex signal, 10H, C
_{(C H 3) 3, C} H (CH 3) 2); 2.6-3.45 ( complex _{signal, 8H, CH 2 Ph, OCH} , NCH 2, NCH 3); 7.35 (m, 5H, C ₆ H ₅₎ example XIV-1

[0172]

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Under argon, firstly 12.25 g (30 mmol) of benzyl 2- (2-tert-butoxycarbonyl-1-isobutyl-2-methylhydrazyl) -carbonyloxypropionate (eg from WO 9736883) Take up in 100 ml of dry dichloromethane. 27.36 g (240 mmol) at 0 ° C
Of trifluoroacetic acid was slowly added dropwise to the solution. The mixture was warmed to room temperature and stirred for 24 hours. Subsequently, the solution was concentrated under reduced pressure, the residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. Drying over sodium sulfate and removal of the solvent under reduced pressure gave 7.21 g (78% of theory) of benzyl 2- (1-isobutyl-2-methylhydrazyl) -carbonyloxy-propionate as a light-yellow. Given as a viscous oil. MS: m / z (relative intensity): 309 (M + H ⁺ , 100); 308 (M ⁺ , 89).
); 101 (28); 91 (PhCH ₂ ⁺ , 100) ¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 0.90 (2d, 6H)
_{, CH (C H 3) 2} ); 1.53 (d, 3H, CHC H 3); 2.70 ( broad _{s, 3H, NCH 3);} 3.27 (m, 2H, NCH 2); 5. 18 (m, 3H,
_{CH 2 Ph, OCH); 7.35} (m, 5H, C 6 H 5).

[0174]Example of use Example A Trikina test (in vitro test) Trikinella sp.
From 20 μg ml^-10.9% concentration of N supplemented with clotrimazole
Stored in aCl solution. Incubation of 20 larvae per measurement
10 g of Bacto Cistone / 500 g of yeast extract per 500 ml
2.5 g glucose, 0.4 g KH_TwoPO_FourAnd 0.4 g of K_TwoHPO_Four(P
H7.2) containing 10 μg ml^-1Sisomycin and 1 μg ml^-1Croto
Performed in 2 ml of solution supplemented with limazole. 10mg to be tested
The active substance is dissolved in 0.5 ml of dimethylsulfoxide and 100, 10, 1
, 0.1 or 0.01 μgml^-1Incubation so that a final concentration of
Was added to the medium. After 5 days incubation at 19 ° C, the experiment was stopped.
Stopped. The effect of the tested substances was quantified as follows.
): 3 = complete effect (all larvae are dead); 2 = excellent effect (larval larvae)
1 = weak effect (all of the larvae)
But not more than half are alive); 0 = no effect (of surviving larvae)
Number equals the number of raw standards). (Tropened. Parasitol. 32 , 31-34 (1981)).

In this test, for example, the compound according to the invention of Preparation Example I-1 was obtained at 100 μg /
At a typical active compound concentration of ml, a level 3 effect was demonstrated. Example B Nippo stolons Gills test (in vitro experiment) isolated Nippo stolons Gills brush Lien cis adult small intestine of female Wistar rats, clotrimazole sisomicin and 2Myugml ^-1 of 20Myugml ^-1 is supplemented 0 Stored in 0.9% NaCl solution. Incubations of each group of male or female worms without (standard) or with the active compound to be tested dissolved in dimethyl sulfoxide were carried out in 1.0 ml of nutrient medium. The medium was removed to determine acetylcholinesterase activity as an indicator of insect vitality. Determination of enzyme activity as a test for incubation and anthelmintic action is described in Z. et al. Parasitenkd. 73 , 1
90-191 (1987). The activity level of the test compound was quantified as follows: 3 = complete effect (95% to 100% inhibition of enzyme); 2 = excellent effect (75% to 95% inhibition); 1 = weak effect (50 % = 75% inhibition); 0 = negligible effect (less than 50% inhibition).

In this test, for example, the compound according to the invention of Preparation Example I-1 was obtained in an amount of 100 μg /
At a typical active compound concentration of ml, a level 3 effect was demonstrated.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL , IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (71) Applicant Bayerwrk, Leverkuse n, BRD (72) Inventor Menke, Norbert Deutsche D-51381 Reef Erkusen Grundermiure 2 (72) Inventor Huon Zamzon-Himelstojerna, Georg Deutsche D-42657 Solingen Neu-encampus TRACE 21 F term (reference) 4C056 AA10 AB10 AC10 AD01 AE10 AF01 FA03 FB01 FC01 4C086 AA01 AA02 AA03 AA04 BC76 MA01 MA02 MA04 MA05 NA14 ZB37

Claims (7)

[Claims] (1) Formula (I) Wherein X ¹ , X ² , X ³ and X ⁴ each independently represent N or CH, wherein at least one of these variables X represents nitrogen, R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, alkyl, alkenyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, alkoxy, each of which may optionally be halogen-substituted. Carbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl,
A cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl, which represents dialkylaminoalkyl or can each be optionally substituted, wherein the group -NR ⁹ -X ¹ R ⁵ -has the formula -NR ^9-1 -CHR ^5-1 - group or the formula -NR ^9-2 -NR ^{5- 2} - shows a group, group -NR ¹⁰ -X ² R ⁶ - has the formula -NR ^10-1 -CHR ^6-1 -a group or a formula -NR ^10-2 -N
R ^6-2- represents a group of the formula: —NR ¹¹ —X ³ R ⁷ — represents a group of the formula —NR ^11-1 —CHR ^7-1 — or a group of the formula —NR ^11-2- N
R ^7-2- represents a group of the formula: -NR ¹² -X ⁴ R ^8- represents a group of the formula -NR ^12-1 -CHR ^8-1- or a group of the formula -NR ^12-2- N
R ^8-2 - indicates the ^{group, R 5-1, R 6-1, R} 7-1 and R ^8-1 independently of one another each represent hydrogen, optionally amino - or hydroxyl - be substituted Indicates a possible alkyl, indicates a mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl or is optionally amino-, nitro-, halogen-, hydroxyl- or alkoxy-substituted. Represents phenyl or benzyl, naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl, thienylmethyl,
Represents benzothienylmethyl or pyridylmethyl, wherein the functional groups may be optionally protected, and R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 are each independently of the other hydrogen Or C ₁ -C ₄
-Alkyl, wherein the group pairs R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1
Come together each also independently of each other group - (CH _{2) 3} - and - (CH ₂
) ₄ - indicates, R ^5-2 to R ^12-2 independently of one another each represent hydrogen, alkyl which may optionally be halogenated, each optionally substituted hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, Mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl,
A cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl, which represents dialkylaminoalkyl, alkoxycarbonylaminoalkyl or is each optionally substituted, wherein the group of radicals R ^{5 -2} / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2
Each together, and independently of one another, represent optionally substituted C ₁ -C ₄ -alkyl-substituted radicals — (CH ₂ ) ₃ — and — (CH ₂ ) ₄ —. Aza-cyclodepsipeptide. 2. A) Formula (II) Wherein X ¹ , X ² , X ³ and X ⁴ each independently represent N or CH, wherein at least one of these variables X represents nitrogen, R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, alkyl, alkenyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl, alkoxy, each of which may optionally be halogen-substituted. Carbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl,
A cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl, which represents dialkylaminoalkyl or can each be optionally substituted, wherein the group -NR ⁹ -X ¹ R ⁵ -has the formula -NR ^9-1 -CHR ^5-1 - group or the formula -NR ^9-2 -NR ^{5- 2} - shows a group, group -NR ¹⁰ -X ² R ⁶ - has the formula -NR ^10-1 -CHR ^6-1 -a group or a formula -NR ^10-2 -N
R ^6-2- represents a group of the formula: —NR ¹¹ —X ³ R ⁷ — represents a group of the formula —NR ^11-1 —CHR ^7-1 — or a group of the formula —NR ^11-2- N
R ^7-2- represents a group of the formula: -NR ¹² -X ⁴ R ^8- represents a group of the formula -NR ^12-1 -CHR ^8-1- or a group of the formula -NR ^12-2- N
R ^8-2 - indicates the ^{group, R 5-1, R 6-1, R} 7-1 and R ^8-1 independently of one another each represent hydrogen, optionally amino - or hydroxyl - be substituted Indicates a possible alkyl, indicates a mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl or is optionally amino-, nitro-, halogen-, hydroxyl- or alkoxy-substituted. Represents phenyl or benzyl, naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl, thienylmethyl,
Represents benzothienylmethyl or pyridylmethyl, wherein the functional groups may be optionally protected, and R ^9-1 , R ^10-1 , R ^11-1 and R ^12-1 are each independently of the other hydrogen Or C ₁ -C ₄
-Alkyl, wherein the group pairs R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1
Come together each also independently of each other group - (CH _{2) 3} - and - (CH ₂
) ₄ - indicates, R ^5-2 to R ^12-2 independently of one another each represent hydrogen, alkyl which may optionally be halogenated, each optionally substituted hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, Mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl,
A cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl, which represents dialkylaminoalkyl, alkoxycarbonylaminoalkyl or is each optionally substituted, wherein the group of radicals R ^{5 -2} / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2
Each together, and independently of one another, represent optionally substituted C ₁ -C ₄ -alkyl-substituted radicals — (CH ₂ ) ₃ — and — (CH ₂ ) ₄ —. The azadepsipeptide is cyclized in the presence of a reaction aid and a solvent, optionally in the presence of a base, or B) Formula (Ia) Wherein X ² , X ³ , and X ⁴ each independently represent N or CH, and R ^{1 to} R ¹² are each as defined above. , Formula (III) [Wherein X ² , X ³ and X ⁴ each independently represent N or CH, and R ^{1 to} R ¹² are each as defined above], wherein the azadepsipeptide of the formula (IV) Embedded image Wherein Y ¹ represents chlorine, trichloromethoxy, C ₁ -C ₄ -alkoxy, optionally substituted phenoxy, 1-imidazolyl or 1,2,4-triazolyl, Y ² is chlorine, Trichloromethoxy, 1-imidazolyl or 1,2,4-triazolyl], and in the presence of a suitable diluent and a suitable reaction aid, and condensed cyclized, or C) Formula (V) Wherein X ² , X ³ , and X ⁴ each independently represent N or CH, and R ^{1 to} R ¹² and Y ¹ are each as defined above. Formula (I) wherein condensation cyclization is carried out in the presence of a suitable diluent and optionally in the presence of a reaction aid. [Wherein X ¹ , X ² , X ³ , X ⁴ and R ¹ -R ¹² are each as defined above]. 3. The substituents are defined as follows: R ¹ , R ² , R ³ and R ⁴ independently of one another each represent hydrogen, C ₁ -C ₁₆ -alkyl or each optionally fluorine- , chlorine - or bromine - C ₁ -C ₆ it can be substituted - alkyl, C ₂ -C ₈ - alkenyl, C ₃ -C ₇ - cycloalkyl, C ₃ -C ₇ - cycloalkyl -C ₁ - C ₄ - alkyl, C ₁ -C ₆ - hydroxyalkyl, C ₁ -C ₄ - alkanoyloxy -C ₁ -C ₆ - alkyl, C ₁ -C ₄ - alkoxy -C ₁ -C ₆ - alkyl, aryl -C ₁ -C ₄ - alkoxy -C ₁ -C ₆ -
Alkyl, C ₁ -C ₆ -mercaptoalkyl, C ₁ -C ₄ -alkylthio-C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxycarbonyl-C ₁ -C ₆ -alkyl, aryloxycarbonyl-C ₁ -C ₆ - alkyl, aryl -C ₁ -C ₄ - alkyloxycarbonyl -C ₁ -C ₆ - alkyl, carbamoyl -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₄ -alkylamino-C ₁ -C ₆ -alkyl, di-
C ₁ -C ₄ -alkylamino-C ₁ -C ₆ -alkyl, or aryl,
Aryl-C ₁ -C ₄ -alkyl, hetaryl or hetaryl-C ₁ -C ₄ -alkyl, which are each optionally halogen, hydroxyl, cyano, C ₁ -C ₄ -alkyl.
-C ₆ - alkyl, C ₁ -C ₄ - halogenoalkyl, C ₁ -C ₄ - alkoxy, C ₁ -
May be substituted by C ₄ -halogenoalkoxy, benzyloxy or silyloxy trisubstituted by C ₁ -C ₄ -alkyl and / or phenyl; R ^5-1 , R ^6-1 , R ^{7- 1} and R ^8-1 are each independently hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, 3-aminopropyl, Aminobutyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-
Carbamoylethyl, 3-guanidinopropyl, phenyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-amino Benzyl, 3,4-dichlorobenzyl, 4-iodobenzyl, α-naphthylmethyl, β-naphthylmethyl, 3-indolylmethyl, 4-imidazolylmethyl, 1,2,3-triazol-1-yl-methyl, 1 , 2,4-triazole-
1-yl - methyl, 3-thienylmethyl, 3-benzothienyl methyl, shows a 2-pyridylmethyl or 3-pyridylmethyl, wherein the functional groups can be protected by the case, R ^9-1, R ^10-1 , R ^11-1 and R ^12-1 each independently represent hydrogen, methyl or ethyl, and a group of groups R ^5-1 / R ^9-1 , R ^6-1 / R ^10-1 , R ^7-1 / R ^11-1 and R ^8-1 / R ^12-1 are each taken together and independently represent a group — (CH ₂ ) ₃ — and — (CH ₂ ) ₄ —, R ^{5-2 to} R ^12-2 each independently represent hydrogen or C ₁ -C ₁₅ -alkyl,
Fluorine each optionally -, chlorine - or bromine - C ₁ -C ₈ can be substituted - alkyl, C ₃ -C ₇ - cycloalkyl, C ₃ -C ₇ - cycloalkyl -C ₁ -C ₄ - Alkyl, C ₁ -C ₆ -hydroxyalkyl, C ₁ -C ₄ -alkanoyloxy-C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₆ -alkyl,
Aryl -C ₁ -C ₄ - alkoxy -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - mercaptoalkyl, C ₁ -C ₄ - alkylthio -C ₁ -C ₆ - alkyl, C ₁ -C ₄ - alkyl sulfinyl -C ₁ -C ₆ - alkyl, C ₁ -C ₄ - alkylsulfonyl -C ₁ -C ₆ - alkyl, carboxy -C ₁ -C ₆ - alkyl, carboxyethyl or carboxy -tert- butyl, C ₁ -C ₄ - alkoxycarbonyl -C ₁ -C ₆ - alkyl, aryloxycarbonyl -C ₁ -C ₆ - alkyl, aryl -C ₁ -C ₄ -
Alkyloxycarbonyl -C ₁ -C ₆ - alkyl, carbamoyl -C ₁ -C ₆ - alkyl, amino -C ₁ -C ₆ - alkyl, C ₁ -C ₄ - alkylamino -C ₁ -C ₆ -
Alkyl, di- (C ₁ -C ₄ ) -alkylamino-C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxycarbonyl-amino-C ₁ -C ₆ -alkyl, or halogen, hydroxyl -, nitro -, cyano -, amino -, C ₁ -C ₄ -
Alkylamino -, di - (C ₁ -C ₄₎ - alkyl - amino -, benzylamino -
, Dibenzylamino -, protected amino -, C ₁ -C ₆ - alkyl -, C ₁ -C ₄ - halogenoalkyl -, C ₁ -C ₄ - alkoxy - or C ₁ -C ₄ - halogenoalkoxy - substituted Aryl, aryl-C ₁ -C ₄ -alkyl, hetaryl or hetaryl-C ₁ -C ₄ -alkyl, where optionally 1 in the heterocyclic ring
One NH function can be derivatized, for example, by an amino protecting group as described below, and the group of groups R ^5-2 / R ^9-2 , R ^6-2 / R ^10-2 , R ^7-2 / R ^11-2 and R ^8-2 / R ^12-2 are each taken together and independently of one another, optionally with C ₁ -C ₄ -alkyl.
Or tetrasubstituted can have group - (CH _{2) 3} - and - (CH _{2) 4} - azacycloalkyl depsipeptide of formula (I) according to claim 1 showing a. 4. R ¹ , R ² , R ³ and R ⁴ independently of one another each represent methyl, which may be optionally substituted by phenyl, which itself is halogen, cyano, nitro, amino , Dialkylamino, morpholino, the groups X ¹ -R ⁵ , X ² -R ⁶ , X ³ -R ⁷ , X ⁴ -R ⁸ can be each independently a group Wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another each represent C ₁ -C ₄ -alkyl, in particular branched C ₄ -alkyl, in particular i-butyl; ⁹ , R ¹⁰ , R ¹¹ and R ¹² independently of one another each represent C ₁ -C ₄ -alkyl, in particular methyl, compounds of the formula (I). 5. Aza of the formula (I) according to claim 1 for the control of endoparasites.
Use of cyclodepsipeptide. 6. Formula (I) according to claim 1 for the preparation of an endoparasiticidal composition.
)) Use of the aza-cyclodepsipeptide. 7. The aza-cyclodepsipeptide of formula (I) according to claim 1,
An endoparasiticidal composition, which is optionally contained as a mixture with ordinary diluents and additives.