WO1999047506A1 - Cyclooctadepsipeptides and their use for combating endoparasites - Google Patents

Abstract

The invention relates to novel cyclooctadepsipeptides of formula (I), wherein R1 represents cyano, C-C-bonded heterocyclyl or optionally, substituted alkenyl, alkinyl or aryl and R2 represents hydrogen or the same radical as R1. The invention also relates to a method for producing the cyclooctadepsipeptides, to intermediate products for producing them, to their use for combating endoparasites and to agents containing these active agents.

Description

 - 1 -

CYCLOOCTADEPSIPEPTIDE AND THEIR USE FOR COMBATING ENDOPARASITES

The invention relates to new cyclooctadepsipeptides, processes for their preparation and their use for controlling parasites, in particular helminths in veterinary and human medicine, and intermediates for their production.

Various cyclodepsipeptides with antiparasitic activity have been described in the literature. A cyclooctadepsipeptide with the name PF1022 is known from EP 382 173 A2. From EP 626 376 AI, EP 634 408 AI and EP 718 293 AI further 24-membered cyclodepsipeptides are known. Their anthelmintic effect is not satisfactory in all cases.

New cyclooctadepsipeptides of the formula (I)

H, C _{^ ^} CH,

H ³ ^ y ³

(I),

\ H / 4 O O. CH

D

CH ₃ \ CH, CH

H ₃ C CH, ³

found in which

Pv.1 represents cyano, C-C-linked heterocyclyl or optionally substituted alkenyl, alkynyl or aryl and

R.2 represents hydrogen or the same radical as R ¹ . 2. A process for the preparation of the compounds of formula (I)

CH,

H ₃ C H. ³ y

H ₃ Q

H vT

H ₃ C

OHOOOO

o OH N-CH ₃ (I), O% ^ (CH,

, CH, CH.

HC CH, ^3rd

in which Rl and R ^ have the meanings given above,

found, characterized in that compounds of the formula (II)

o O H. N-CH (II),

₃ CH.

O

CH,

L ^. CH, CH, H ₃ C CH ₃ ^{3 3}

in which

X ^{1 represents} bromine, iodine, -O-Sθ2-R ^f , amino or -N2 ⁺ (X ³ ) ^" , in which - 3 -

R ^{f represents} fluorinated Cj-C4-alkyl and

X ^{3 represents} a diazonium salt stabilizing anion such as, for example, tetrafluoroborate and

X ^ represents hydrogen or the same radical as X ¹ ,

with a suitable reagent which splits off the group Rl in the presence of a transition metal catalyst with a C-C linkage.

3. The cyclooctadepsipeptides of the formula (II) in which χ is bromine, iodine, -OSθ2R ^f - where R ^{f is} fluorinated Cj-C-alkyl are new and are the subject of the present invention.

4. The new compounds of formula (II) are obtained by

a) in the case of bromo-substituted cyclooctadepsipeptides of the formula (II-a)

(Il-a),

in which ^■ 4 -

X ^ - represents hydrogen or bromine,

the cyclooctadepsipeptide designated as PF 1022

H, C. .CH,

HC HC ³

1 1

H ₃ C

\\ /

-O

PF 1022

brominated or

b) in the case of iodinated cyclooctadepsipeptides of the formula (II-b)

(Il-b),

, H o

N

i CH.

CH, CH,

H ₃ C ^{^} CH,

in which

χ2A represents hydrogen or iodine, - 5 -

iodines the cyclooctadepsipeptide designated PF 1022 or

c) in the case of sulfonic acid cyclooctadepsipeptide esters of the formula (II-c)

H, C, CH, ^3rd

(II-c),

H, C CH,

in which

R ^{f represents} fluorinated C 4 -C 4 -alkyl 1 and

X ^{2 "3 stands} for hydrogen or for -O-SÜ2-R ^f ,

hydroxy-substituted cyclooctadepsipeptides of the formula (III)

- 6 -

H, C

H ₃ C

Λ TH II H ^{^}

H ₃ C) ^ - O Λ-OW HC-NHOOH ^« , _QH 0 = o OH N-CH ₃ (III),

^ o ^ (CH, H ΓΛ ^

f CH, _z ^ CH, CH, HC CH, ^{3 3}

in which

X ^{3 represents} hydroxy or hydrogen,

with sulfonic anhydrides or halides of the formula (IV)

R ^f -SO ₂ -Y (IV), in which

Y represents -O-SO -R ^f , F or chlorine,

in the presence of an acid binder, or

d) in the case of sulfonic acid cyclooctadepsipeptide esters of the formula (II-c) diazotized amino-substituted cyclooctadepsipeptide of the formula (V) H, C _{^ /} CH,

H, 3C 1 H, C

H, 3C \, N

O ^'

TH II H

H ₃ CO Λ-OH ₃ C- HO ⁰ _O H ^ - ^ ^ _(χ3) .

o OH N-CH ₃ (V), o -y CH,

CH, CH, H, C CH, ^{3 3}

in which

X ^{4 represents} -N ₂ ⁺ (X ³ ) "or hydrogen,

X ^{3 represents} a diazominium salt stabilizing anion,

in the presence of a sulfonic acid of formula (VI)

HO-SO ₂ -R ^f (VI),

in which R ^{f has} the meaning given above,

implements.

5. It has also been found that the compounds of the formula (I) are extremely suitable for combating helminths in human and veterinary medicine.

The new cyclooctadepsipeptides are generally defined by the formulas (I) and (II). - 8th -

The substituents χl and X ^ or R and R ^ are preferably in the para or ortho position. The /? Αrα position is particularly preferred.

Preferred compounds of the formula (I) are those in which:

R for cyano, C5-Cg-cycloalkenyl, CC-linked 5- to 10-membered, optionally mono- or polyunsaturated heterocyclyl with one or more heteroatoms from the series oxygen or nitrogen, which may be substituted by -C4-alkyl, benzyl, Cι- C4-alkylcarbonyl or t-butoxycarbonyl is substituted, a radical of the series -C (R ³ ) = CH2, -CH = CR ⁴ R ⁵ ,

-CH = C (R ⁶ ) CO ₂ R ⁷ or -C≡CR ⁸ or for optionally single or multiple independently of one another by nitro, halogen. Cj-Cg-alkyl, C2-C4-alkenyl, Cj-C4-haloalkyl, hydroxy, Cj-Cö-alkoxy, Cι-C4-haloalkoxy, tetrahydropyranyloxy, amino, morpholino, piperidino, di- (Cj-C4-alkyl ) amino, C 1 -C 4 -alkylcarbonylamino, C 1 -C 4 -alkoxycarbonylamino,

Benzyloxycarbonylamino, carboxy, -C -C-alkoxy carbonyl or phenyl substituted phenyl or naphthyl is, wherein

R ^{3 represents} C 1 -C 4 alkoxy or C 4 -C 4 alkylcarbonyloxy,

R ^{4 represents} cyano or -CC-alkyl,

R ^ and R6 each represent hydrogen or methyl,

R? for C 1 -C 2 -alkyl, one or more times by halogen or simply by cyano, hydroxy, Cj-C4-alkoxy, C ^ -C4-dialkylamino or three- to eight-membered cyclic amino (= C2-C7-alkylene amino, with a methylene group by an oxygen, sulfur or nitrogen atom can be replaced) substituted C2-Ci 2-alkyl, represents (tetrahydro) furfuryl, C3-Cg-2-alkenyl, C3-Cg-cycloalkyl, optionally substituted by halogen-substituted phenyl or benzyl and - 9 -

R8 for -CC -alkyl, C ₃ -C ₈ -cycloalkyl, Ci-Cg-hydroxyalkyl, C1 -C4- alkoxy-Ci-Cg-alkyl, tetrahydropyranyloxy-Cι -C4-alkyl, 1-

Hydroxy-C3-Cg-cycloalkyl, α-amino-Ci-Cg-alkyl, (X-C1-C4- alkylaminocarbonyl-amino-Cι-C4-alkyl, carboxy-Ci-Cn -alkyl, C \ - C4- alkoxycarbonyl- C \ -C \ \ -alkyl, phenoxycarbonyl-C -C \ \ -alkyl, tri (Cι-C4-alkyl) silyl, C ^ -Cu-alkylcarbonyl, optionally substituted by halogen phenyl-Cι-C4-alkyl or α- Hydroxybenzyl stands.

R ² represents hydrogen or one of the radicals specified for R ¹ .

Compounds of the formula (I) in which:

R for cyano, C5-Cg-cycloalkenyl, CC-linked 5- to 6-membered, optionally mono- to tri-unsaturated heterocyclyl with one or two heteroatoms from the series oxygen or nitrogen, which is optionally substituted by C1-C4-alkyl, benzyl, C ] -C4 alkylcarbonyl or t-butoxycarbonyl substituted nitrogen atoms, one of the radicals -C (R ³ ) = CH2, -CH = CR ⁴ R ⁵ , -CH = C (R ⁶ ) C02R ⁷ or -C≡CR ⁸ or for optionally one to four times independently of one another by nitro, fluorine, chlorine, bromine, C1-C4-alkyl, C2-C4-alkenyl, hydroxyl, C 1 -C 4 -alkoxy, tetrahydropyranyloxy, C1-C4-alkyl or Cj- substituted by fluorine or chlorine C4-alkoxy, amino, morpholino, piperidino, di- (-C-C4-alkyl) amino, Cj-C3-alkylcarbonylamino, Cι -C4-alkoxycarbonylamino, benzyloxycarbonylamino, carboxy,

-C -C4 alkoxycarbonyl or phenyl substituted phenyl or naphthyl, where

R ^{3 represents} C 4 -C 4 -alkoxy or C 1 -C 4 -alkylcarbonyloxy,

R ^{4 represents} cyano or C 1 -C 4 alkyl, - 10 -

R5 and R6 each represent hydrogen or methyl,

R ⁷ for Ci-Cg-alkyl, n-Ccj-C ^ -alkyl, mono- or polysubstituted by fluorine-substituted C2-Cg-alkyl or nCjC \ 2- alkyl, or in the 2-position by chlorine, bromine, cyano hydroxy, Cj -C4-alkoxy, -C-C4-dialkylamino or five- to six-membered cyclic amino (= C4-C5-alkylene amino, where a methylene group can be replaced by an oxygen, sulfur or nitrogen atom) substituted ethyl, for ( Tetrahydro) furfuryl, C3-Cg-2-alkenyl, C3-Cg-cycloalkyl, phenyl or benzyl optionally substituted by fluorine, chlorine or bromine and

R ⁸ for C 1 -C 4 alkyl, nC ₅ -C γ 2 alkyl, C ₅ -C ₆ cycloalkyl, -hydroxy-C \ - Cg-alkyl, ω-hydroxy-n-C2-C8-alkyl, α -Cι-C4-alkoxy-Cι-C ₈ -alkyl, ω-tetrahydropyranyloxy-nC \ -C4-alkyl, 1-hydroxy ^ -Cß-cycloalkyl, α-amino-C _j -Cg-alkyl, α-Cι -C4-Alkylaminocarbonylamino- -C-C3-alkyl, ω-carboxy-n-Ci -Cu -alkyl, Cι -C4-alkoxycarbonyl-n- 1 -C 11 alkyl, phenoxycarbonyl-C \ -C \ \ -alkyl, tri (C \ -C4) alkylsilyl, -C -C5-alkylcarbonyl, n-Cö-Cu-alkylcarbonyl, optionally substituted by fluorine, chlorine or bromine, phenyl-Cι -C2 ~ alkyl or α-hydroxybenzyl.

R ² represents hydrogen or one of the radicals specified for R ¹ .

Compounds of the formula (I) in which:

R is cyano, 1-cyclopentenyl, 2-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, furyl, dihydrofuryl, optionally substituted by methyl, benzyl, acetyl, propionyl or t-butoxycarbonyl, N-substituted 2- or 3-pyrrolyl, pyrro lin-2-yl, for dihydropyranyl, 1,3-dioxinyl, one of the radicals -C (R ³ ) = CH2, - 11 -

-CH = CR ⁴ R ⁵ , -CH = C (R ⁶ ) Cθ2R ^{7 or} -C≡CR ⁸ or for optionally single to triple independently of one another by nitro, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n -Butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propen-1-yl, 1-buten-1-yl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , Isobutoxy, sec.-butoxy, tert.-butoxy, tetrahydropyranyloxy,

Trifluoromethyl, trifluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, amino, morpholino, piperidino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, acetylamino, propionylamino, methoxycarbonylamino, ethoxycarbonylamino, carbyloxycarbonoxy methoxycarbonoxy n-Butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxy or phenyl substituted phenyl, where

R ^{3 represents} methoxy, ethoxy, n-propoxy, isopropoxy, acetyloxy or propionyloxy,

R ^{4 represents} cyano or C 1 -C 4 alkyl,

R5 and R6 each represent hydrogen or methyl,

R ⁷ for methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert-butyl, neo-pentyl, n-pentyl, 2-ethylbutyl, n-hexyl, n-heptyl, 2- Ethylhexyl, n-octyl, n-nonyl, n-decyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1,1,3,3,3-hexafluoroisopropyl, heptafluoroisopropyl, 2,2,3, 3, 4,4-hexafluorobutyl, 2-chloroethyl, 2-bromoethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-methoxymethyl, 2-ethoxymethyl, 2-NN-dimethylaminomethyl, 2-N, N- Diethylaminomethyl, 2-pyrrolinoethyl, 2-piperidinoethyl, 2-morpholinoethyl, for furfuryl, tetrahydrofurfuryl, allyl, 2-butenyl, cyclopentyl, cyclohexyl, optionally monosubstituted to trisubstituted independently by fluorine, chlorine or bromine

Phenyl or benzyl and - 12 -

R ⁸ for methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n -Decyl, cyclopentyl, cyclohexyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxypropyl, 1 -hydroxy-1-methylpropyl, 1-hydroxy-2-methylpropyl, 1-hydroxybutyl, 1-hydroxy - 1,2-dimethylpropyl, l-hydroxy-3-methylbutyl, 1-hydroxypentyl, 2-ethyl-l-hydroxybuty 1, 1 -hydroxy-1, 3 -dimethylbuty 1, 1 -hydroxy-1, 2.2 -trimethylpropyl, 1 -hydroxyhexyl, l-hydroxy-l, 4-dimethylpentyl, 1-hydroxy-l-isopropyl-2-methylpropyl, 2-ethyl-l-hydroxy-hexyl, 2-

Hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2-tetrahydropyranyloxyethyl, 1-hydroxycyclopropyl, 1-hydroxycyclopentyl, 1-hydroxycyclohexyl, 1-aminomethyl, 1-aminoethyl, 1-amino-1- methylethyl, 1-amino-1-ethylpropyl, methylaminocarbonyldimethylmethyl, tert-butylaminocarbonyldimethylmethyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, carboxyheptyl, carboxyoctyl, phenoxycarbonylmethyl, trimethylsilylethyl, trimethylsilylethyl, trimethylsilylethyl , Isobutyryl, Isovaleryl, Caproyl, optionally optionally up to three times independently substituted by fluorine, chlorine or bromine substituted benzyl, phenethyl or α-hydroxybenzyl.

R ² represents hydrogen or one of the radicals specified for R ¹ .

Compounds of the formula (II) are preferred in which:

χl is bromine, iodine, trifluoromethylsulfonyloxy, nonafluorobutylsulfonyloxy, amino or -N2 ⁺ (X ³ ) ^" , where X ^{3 is} tetrafluoroborate;

X ^ represents the radicals indicated at χl or hydrogen. - 13th

Compounds of the formula (II) in which X ^{1 is} bromine, iodine or trifluoromethylsulfonyloxy and X ^{2 is} hydrogen or one of the radicals indicated at X ¹ are particularly preferred.

Compounds of the formula (II) in which X ^{1 is} iodine and X ^{2 is} hydrogen or iodine are very particularly preferred.

If, for example, 8- (2-bromobenzyl) -20- (4-bromobenzyl) -5, 1.17.23-tetra-isobutyl-2,4, 10, 14, 16,22-hexamethyl-1,7, 13,19-tetraoxa-4, 10, 16,22-tetraaza-cyclotetracosan-3, 6,9, 12, 15, 18,21, 24-octaone and 4-trifluoromethoxyphenylboronic acid as starting materials, the reaction sequence of the invention can Process (2) can be represented by the following formula:

H, C. .CH,

H 3, CH, C ³ Br

H ₃ C

. ^ H OCF.

O ^ - \\ /

H ₃ C

H.C-N H O O H-

= O O- OOH -CH ₃ o CH. _/ B

, H HO OH

CH,

CH. CH,

H ₃ C CH ₃

- 14

OCF,

H, C. .CH, \\ / H ₃ CH ₃ C ^{3 3 H} 3 ^C ^ 1 _{\ /} N

OCF, \\ /

H ₃ CHO

Pd (PPh ^■ 3,) / 4 ₄ '/' C ^" - ^, u" l ° O H-

OO = o OH N-CH. ₃ CH,

N

I

CH.

CH. CH.

H, C ^{^} CH,

For example, if 8,20-dibenzyl-5, 11, 17.23-tetraisobutyl-2,4,10, -14, 16,22-hexamethyl-1,7,13,19-tetraoxa-4, 10, 16, 22-tetraaza-cyclotetracosane-3,6,9, - 12,15,18,21,24-octaon (PF1022) as starting material and bromine / T, RBis (trifluoroacetoxy) -iodobenzene as reagent, the reaction course of the Method (4a) according to the invention can be represented by the following formula:

H, C ^ ^CH,; H ₃ CH ₃ C ^{3 3}

" _O A

/ \ IH II H ^v HOO

O H. N-CH ₃ O. ,

H II H

CH,

,

CH, CH, CH, ^{3 3}

If, for example, PF1022 is used as the starting material and iodine / / bis (trifluoroacetoxy) iodobenzene is used as the reagent, the reaction sequence of process (4b) according to the invention can be represented by the following formula: - 15 -

H- ^ C ^ ^ CH- H, C. .CH ₃

^H 3? H ₃ C ³

H, C

//

^H 3 ^C y, y ^H T 0

H ₃ CN Η o ^' K 0 _H -

-H n ° «N-CH ₃ f ^~ 0 H <CH. ^ t.ι 'A

1 "ϊ ¹ 1 CH.

H CH, CH ₃

H ₃ A CH ₃ ³

If, for example, PF1022E and perfluorobutyl fluoride are used as starting materials, the reaction sequence of process (4c) according to the invention can be represented by the following formula:

For example, 4- (14-benzyl-5, 11, 17.23-tetraisobutyl-4,8,10,16,20, - 22-hexamethyl-1,7,13,19-tetraoxa-4, 10,16 is used , 22-tetraaza-cyclotetracosan-3, 6.9, 12.15, -

18,21, 24-octaon-2-yl-methyl) phenyldiazonium chloride and trifluoromethanesulfonic acid as starting materials, the course of the reaction of process (4d) according to the invention can be represented by the following formula: 16 -

Η o = 0 ooy

CH,

H ₃ C H.

Some of the cyclooctadepsipeptides of the formula (II) required to carry out the process (2) according to the invention are new compounds. The new connections can be made using methods (4a), (4b), (4c) or (4d).

EP-A 634 408 describes the preparation of compounds of the present formula (I), in which R ¹ and / or R ^{2 represent} amino, by catalytic reduction of the corresponding nitro-substituted compounds. In example 14 of EP-A 634 408, the conversion of the amino group into an OH residue by so-called

Diazo cooking described. If the reaction described there is carried out at low temperatures (-50 ° C. to + 10 ° C.), preferably at -10 ° C. to + 5 ° C., the corresponding diazonium salts can be isolated. In this way, compounds of the formula (II) can be obtained in which X ¹ and / or X ² stand for a diazonium radical.

The cyclooctadepsipeptide PF1022 required to carry out processes (4a) and (4b) according to the invention is known from EP 382 173 AI and can be used e.g. be produced by fermentation.

The cyclooctadepsipeptides of the formula (III) required for carrying out the process (4c) according to the invention are, for example, as PF1022E and PF1022H from JP 06184126 (cited in CA 122: 104043) or WO 97/11064 (cited in CA) - 17 -

126: 293615) or can be prepared analogously to the processes described there.

The diazotized cyclooctadepsipeptides of the formula (V) required for carrying out the process (4d) according to the invention can be prepared according to generally known methods

Produce methods by diazotizing the corresponding amino compounds, which are known, for example, from EP 634 408 AI, WO 97/11064 (cited in CA 126: 293615) or WO 97/02256 (cited in CA 126: 171904) or can be obtained there are. This is done either with inorganic nitrites, such as sodium nitrite in aqueous acids such as hydrochloric acid,

Trifluoroacetic acid or tetrafluoroboric acid or with alkyl nitric acid such as e.g. Isoamyl nitrite or butyl nitrite in anhydrous media such as acetic acid containing hydrogen chloride.

Reagents for carrying out process (2) according to the invention are, for example, compounds of the formula (VII)

R ^ -H (VII),

in which

R "! Stands for one of the CC-linked heterocyclyl or optionally substituted alkenyl or alkynyl radical given for R ¹ there,

Boron compounds of the formula (VIII)

O-R

, 1-2

R - B

10

O-R (VIII),

in which - 18 -

R! "2 stands for one of the CC-linked heterocyclyl, optionally substituted alkyl, alkenyl or aryl radicals given there for R ¹ ,

R ^ and Rio each for hydrogen, isopropyl or together for propylene,

Cycloocta-l, 5-diyl or o-phenylene,

Tin compounds of formula (IX)

R ¹ -Sn (Rl l) ₃ (IX),

in which

R has the meaning given above and

Rl I represents methyl, butyl or phenyl, or

Zinc cyanide.

The compounds of formula (VII) are generally known compounds of organic chemistry. The boron compounds of the formula (VIII), in particular the boronic acids, are known and some are commercially available, or they can be prepared by known methods [cf. e.g. Chem. Rev. 45, 2457 (1995); Pure appl. Chem. 66, 213 (1994); Synlett 1990, 221]. The tin compounds of the formula (IX) are known or can be prepared by known methods [cf. e.g. M. Pereyre, J.-P.

Quintard, A. Rahm: Tin In Organic Synthesis, Butterworths, London, 1987; Org. Chem. 54, 5064 (1989)].

As a catalyst for carrying out process (2) according to the invention, use is made, for example, of compounds, in particular complex compounds, of metals from subgroup VIII of the periodic table, such as of palladium or nickel. - 19 -

preferably of palladium. Examples include: bis (1,5-cyclooctadiene) nickel (O), nickel (II) chloride, dichlorobis (triphenylphosphine) nickel, nickel (II) acetylacetonate, palladium (II) acetate, chloride , Dichloro-bis (triphenylphosphine) palladium, dichloro-bis [tri (2-methylphenyl) phosphine] palladium, diacetonitriiodichloropalladium, bis [μ- (acetato-κO: κO ')] to [[2- [bis ( 2-methylphenyl) phosphino-κP] phenyl] methyl-κC] dipalladium, tris (dibenzylidene acetone) dipalladium, di (dibenzylidene acetone) palladium, tetrakis (triphenylphosphine) palladium or one of the above Compounds in combination with a free complexing ligand such as triphenylphosphine, tri-o-tolylphosphine, trif rylphosphine, bis (diphenylphoshino) ethane, bis (diphenylphoshino) propane, bis (diphenylphoshino) butane, diphenylphosphinoferrocene or triphenylarsine. Nickel (O) or nickel (II) compounds can be used as nickel catalysts. The nickel (II) compounds can be reduced in situ to suitable nickel (O) compounds in the presence of suitable ligands, e.g. through zinc powder. Couplings with alkynes use copper iodide as the cocatalyst, which can also be useful in reactions with tin compounds.

Process (2) according to the invention is optionally carried out in the presence of a reaction auxiliary. The following are suitable for this purpose: alkali metal halides, such as lithium chloride, lithium bromide, cesium fluoride or acid binders. Alkaline earth metal or alkali metal hydroxides, acetates, carbonates or hydrogen carbonates, such as, for example, sodium, potassium, barium or ammonium hydroxide, sodium, potassium, calcium, are preferably used as acid binders in the reaction with boron compounds of the formula (VIII) - or ammonium acetate, sodium, potassium or ammonium carbonate, sodium hydrogen or potassium hydrogen carbonate, silver carbonate, phosphates such as trisodium or tripotassium phosphate, alkali fluorides such as cesium fluoride, and tertiary amines such as trimethylamine, triethylamine, tributylamine, ethyldiisopropylamine, N, N-dimethylaniline, N, N-dimethyl-benzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N, N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclonones (DBN) or

Diazabicycloundecene (DBU). in the implementation of compounds of formula (II), the - 20 -

are amino-substituted, alkali metal nitrites such as sodium nitrite are used for diazotization.

Process (2) according to the invention is preferably carried out in the presence of a diluent. Water, organic solvents and any mixtures thereof can be used in the reaction with boron compounds of the formula (VIII). Examples include: aliphatic, alicyclic 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, carbon tetrachloride, dichloro, trichloroethane or carbon tetrachloride; Ethers such as diethyl, diisopropyl, methyl t-butyl, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl ether or anisole; Alcohols, such as methanol, ethanol, n- or i-propanol, n-, iso-, sec- or tert-butanol, ethanediol, propane-1,2-diol, ethoxy ethanol, methoxy ethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether; Water. In the reaction of compounds of formula (II) which are (diazotized) amines, aqueous acids, such as hydrochloric acid, trifluoroacetic acid or tetrafluoroboric acid, optionally in the presence of a solubilizer, such as alcohols such as methanol, are used. In the other reactions, dipolar aprotic solvents are advantageous as diluents. Examples include: ethers, such as diethyl, diisopropyl, methyl t-butyl, 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, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile;

Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; Sulfoxides such as dimethyl sulfoxide. Amines specified above as acid binders can also serve as diluents when used in a large excess. - 21 -

Process (2) according to the invention can also be carried out in a two-phase system such as, for example, methylene chloride / water, preferably using a suitable phase transfer catalyst. Examples of such catalysts are: tetrabutylammonium iodide, bromide or chloride, tri-butylmethylphosphonium bromide, trimethyl-C 1-4 alkyl alkyl ammonium chloride or

-bromide, dibenzyldimethylammonium methyl sulfate, dimethyl-C 12 / C \ 4-alkylbenzylammonium chloride, 15-crown-5, 18-crown-6 or tris- [2- (2-methoxyethoxy) ethyl] amine.

The reaction temperatures can be carried out when carrying out the process according to the invention

Process (2) can be varied over a wide range. In general, temperatures between 20 ° C and 200 ° C, preferably between 50 ° C and 150 ° C. In the case of an upstream diazotization, if appropriate, the process is initially carried out at from -20 ° C. to + 30 ° C.

A bromination reagent is required to carry out process (4a) according to the invention. Bromine in the presence of 1,1-bis (trifluoroacetoxy) iodobenzene is suitable for this.

Process (4a) according to the invention is preferably carried out in the presence of a diluent. Water, organic solvents and any mixtures thereof can be considered. Examples include: aliphatic, alicyclic 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, carbon tetrachloride, dichloro, trichloroethane or carbon tetrachloride; Ethers, such as diethyl, diisopropyl, methyl t-butyl, 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, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; Amides, such as formamide, N, N-dimethylformamide, N, N- - 22 -

Dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; N-oxides such as N-methylmorpholine-N-oxide; Esters such as methyl, ethyl or butyl acetate; Sulfoxides such as dimethyl sulfoxide; Sulfones such as sulfolane; Alcohols, such as methanol, ethanol, n- or i-propanol, n-, i-, s- or t-butanol, ethanediol, propan-l, 2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether; Water.

The reaction temperatures can be varied within a substantial range when carrying out process (4a) according to the invention. In general, temperatures between -50 ° C and + 50 ° C, preferably between -20 ° C and + 30 ° C.

To carry out process (4a) according to the invention, 0.5 to 5 moles of bromine are generally used per mole of PF 1022. Preferably the monobromo compound (X ^ -l = H) desired, 0.5 to 1.0 mol, preferably the di- bromo compound (χ2 ^_ l = Br) desired, one uses a 3 to 5 moles of bromine . In general, 1.0 to 1.2 mol / ₎ / bis (trifluoroacetoxy) iodobenzene are used per mol of bromine.

An iodination reagent is required to carry out process (4b) according to the invention. For example, iodine in the presence of 1,1-bis (trifluoroacetoxy) iodobenzene or iodine in the presence of alkali metal iodate, such as e.g. Sodium iodate and in the presence of a protonic acid such as acetic acid or sulfuric acid or bis (pyridine) iodonium (I) tetrafluoroborate in the presence of a protonic acid such as trifluoromethanesulfonic acid or hydrogen tetrafluoroborate (J. Org. Chem. 58, 2058 (1993)).

Process (4b) according to the invention is preferably carried out in the presence of a diluent. For this purpose, for the reaction with 7, / - bis (trifluoroacetoxy) iodobenzene, for example, all solvents listed in process (4a) are considered, for those with iodate, for example acetic acid and sulfuric acid. - 23 -

The reaction temperatures can be varied within a substantial range when carrying out process (4b) according to the invention. In general, when using /, / - bis (trifluoroacetoxy) iodobenzene at temperatures between -50 ° C and + 50 ° C, preferably between -20 ° C and + 30 ° C, when using iodate at temperatures between 0 ° C and + 100 ° C, preferably between 20 ° C and + 80 ° C.

To carry out process (4b) according to the invention, 1 to 5 moles of iodine are generally used per mole of PF 1022. If the monoiodo compound (χ2-2 = H) is preferred, 1 to 5 moles of iodine and 2 to 10 moles of I / bis (trifluoroacetoxy) iodobenzene are used. If the diiodic compound (χ2 ^~ 2 = I) is preferred, 1.5 to 2 mol iodine and 0.5 to 1.5 mol iodate are used.

Organic bases are primarily suitable as acid binders for carrying out process (4c) according to the invention. Examples include: Tertiary amines such as trimethylamine, triethylamine, tributylamine, N, N-dimethylaniline, N, N-dimethylbenzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N, N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclonones (DBN) or diazabicycloundecene (DBU).

Process (4c) is optionally carried out in the presence of a diluent. Organic solvents and any mixtures thereof can be used for this. Examples include: aliphatic, alicyclic 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, carbon tetrachloride, dichloro, trichloroethane or carbon tetrachloride; Ethers such as diethyl, diisopropyl, methyl t-butyl, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl ether or anisole; as well as an excess of organic base itself. - 24 -

The reaction temperatures can be varied within a substantial range when carrying out process (4c) according to the invention. In general, temperatures between -50 ° C and + 50 ° C, preferably between -20 ° C and + 30 ° C.

To carry out process (4c) according to the invention, 1 to 10 mol, preferably 1.2 to 5 mol, of sulfonic acid derivative (IV) and 1 to 10 mol, preferably 1 to 5, are generally employed per equivalent of hydroxy-substituted cyclooctadepsipeptide of the formula (III) Mole of acid binder.

The reaction temperatures can be varied within a substantial range when carrying out process (4d) according to the invention. In general, temperatures between 50 ° C and 180 ° C, preferably between 60 ° C and 140 ° C. Otherwise, one still irradiates with a light source that emits UV radiation.

The fluorinated sulfonic acid of formula (VI) is generally used in a larger excess.

The reactions of the processes according to the invention can be carried out under normal pressure or under elevated pressure. Is preferably carried out at normal pressure. The reaction is carried out, worked up and isolated by generally customary, known methods. The end products are preferably by crystallization, chromatographic separation or

Removal of the volatile constituents, if necessary in a vacuum, cleaned (see also the preparation examples).

The active substances are suitable for combating pathogenic endoparasites in humans and in animal husbandry and animal breeding if the warm-blooded animal toxicity is favorable - 25 -

occur in livestock, breeding, zoo, laboratory, experimental and hobby animals. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive species. By controlling the pathogenic endoparasites, disease, mortality and decreasing performance (for example in the production of meat, ^'milk, wool, hides, eggs, honey, etc.) are reduced, so that by using the active compounds more economical and simpler animal husbandry is possible. Pathogenic endoparasites include cestodes, trematodes, nematodes, in particular:

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

Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoorus spp ..

From the order of the Cyclophyllidea, for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosmsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyella spp. , Taenia spp., Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium

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

Polystoma spp ..

From the subclass of Digenea e.g .: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma

Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciola spp. Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocotyle spp Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropispp., Catatropispp. Dicrocoelium spp., Collyriclum spp - 26 -

Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp ..

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

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

From the order of the Strongylida, for example: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus sppum, spp., Oesophag. , Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostr spp., Pneumostrongylus spp., Spicocaulus spp.,

Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonertusiapp., Ostemonchusagia ., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp ..

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

From the order of the Ascaridia, for example: Ascaris spp., Toxascaris spp., Toxocara spp.,

Parascaris spp., Anisakis spp., Ascaridia spp ..

From the order of the Spirurida, for example: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp .. - 27 -

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

Onchocerca spp ..

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

Macracanthorhynchus spp., Prosthenorchis spp ..

For example, the active compounds according to the invention show outstanding activity against worms such as Haemonchus contortus, Trichostrongylus colubriformis, Nematospiroides dubius and Heterakis spumosa.

Livestock and breeding animals include mammals such as Cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon, birds such as Chickens, geese, turkeys, ducks.

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

The pets include dogs and cats.

The application can be prophylactic as well as therapeutic.

The active ingredients are used directly or in the form of suitable preparations enterally, parenterally, dermally, nasally, by treating the environment or with the aid of shaped articles containing the active ingredient, e.g. Strips, plates, tapes.

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

Suppositories, tablets, capsules, pastes, drinkers, granules, drenches, boluses, medicated feed or drinking water. The dermal application takes place, for example, in the form of diving (dipping), spraying (spraying), bathing, washing, pouring on (pouring) - 28 -

on and spot-on) and powdering. Parenteral use happens e.g. in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants.

Suitable preparations are:

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

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

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 prepared by dissolving the active ingredient in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives. 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, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof. - 29 -

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

The following may be mentioned as solubilizers: solvents which promote the dissolution of the active ingredient in the main solvent or prevent its precipitation. Examples are polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

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

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

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

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

Gels are applied to or spread on the skin or placed in body cavities. Gels are produced by adding enough thickening agent to solutions which have been prepared as described for the injection solutions to form a clear mass with an ointment-like consistency. The thickeners specified above are used as thickeners. - 30 -

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

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

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

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

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

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

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

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

Adhesives are, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin. - 31 -

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

Emulsions are either water in oil or oil in water.

They are produced by dissolving the active ingredient either in the hydrophobic or in the hydrophilic phase and using the solvent with the aid of suitable emulsifiers and, if necessary, other auxiliaries such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers, viscosity-increasing substances homogenized 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 Cg-Ci 2 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids, which may also contain hydroxyl groups, mono- and diglycerides of Cg / Ci Q 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 Cjg-Cig, isopropyl myristate, isopropyl palmitate, caprylic / capric alcoholic acid esters of fatty acid esters ~ l8 _> isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duckling gland fat, dibutyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures, etc.

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

Fatty acids such as oleic acid and their mixtures. - 32 -

The following can be mentioned as the hydrophilic phase:

Water, alcohols such as e.g. Propylene glycol, glycerin, sorbitol and their mixtures.

The following may be mentioned as emulsifiers: nonionic surfactants, e.g. polyoxyethylated

Castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;

ampholytic surfactants such as di-Na-N-lauryl-β-iminodipropionate or lecithin;

anionic surfactants, such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt;

cationic surfactants such as cetyltrimethylammonium chloride.

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

Suspensions can be used orally, dermally or as an injection. They are produced by adding the active ingredient in a carrier liquid, if necessary with the addition of other auxiliary substances such as wetting agents, dyes, substances that require absorption,

Preservatives, antioxidants, sunscreen suspended.

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

The surfactants specified above may be mentioned as wetting agents (dispersants). - 33 -

Further additives mentioned are those mentioned above.

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

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

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

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

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

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

The active substances can also be present in the preparations in a mixture with synergists or with other active substances which act against pathogenic endoparasites. Sol- - 34 -

Che active ingredients are e.g. L-2,3,5,6-tetrahydro-6-phenyl-imidazolethiazole, benzimide azole carbamates, praziquantel, pyrantel, febantel.

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

Preparations which are diluted before use contain the active ingredient in concentrations of 0.5 to 90% by weight, preferably 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.

The preparation and the use of the active substances or intermediate products according to the invention can be seen from the examples below.

- 35 -

Manufacturing examples

example 1

Preparation of the diiod derivative of PF1022

H, C CH. ³

CH ₃

_/ ^ H ₃ C CH ₃ ^{3 3}

PF 1022 (0.95 g; 1 mmol) was suspended in glacial acetic acid (4 ml) under argon. After adding sulfuric acid (conc .; 0.44 ml) sodium iodate (166 mg; 0.84 mmol) and iodine (406 mg; 1.60 mmol) were added. With vigorous stirring

Oil bath heated to 70 ° C. After 7 hours, the mixture was allowed to cool and a little chloroform was added to dilute it. The reaction mixture was washed with sodium sulfate solution (30%, aq.). After the phases had been separated, the aqueous phase was neutralized with sodium carbonate and extracted again with chloroform. The combined organic phases were washed with sodium bicarbonate solution (sat., Aq.), Then with sodium chloride solution (sat., Aq.). After drying (magnesium sulfate) the solvent was distilled off. The remaining oil was purified by column chromatography (silica gel; 0 x 1 = 5 cm x 50 cm; cyclohexane / ethyl acetate = 4 + 1). 0.9 g (75% of theory) of a colorless solid was obtained. After semi-prep. HPLC (acetonitrile / H2θ = 75 + 25) gave 0.6 g of the isomers

Bis-iodobenzyl compounds.

FAB-MS: m / z (nominal mass): 1223 (M + Na ⁺ ); 1201 (M + H +) mp: 84 ° C - 36 -

Example 2

Preparation of the mono-iodine derivative of PF 1022

HC .CH, ^3rd

//

, "CH, H ₃ C CH ₃ ^{3 3}

PF 1022 (0.96 g; 1 mmol) was dissolved in chloroform (25 ml) under argon. At 0 ° C., i-bis (trifluoroacetoxy) iodobenzene (= PhIL2) (2.76 g; 6.44 mmol) and then iodine (1.10 g; 4 mmol) were metered in. The mixture was allowed to warm to room temperature. After 7 days at room temperature, the reaction solution was poured into sodium sulfite solution (30%, aq.). The phases were separated.

After the phases had been separated, the aqueous phase was neutralized with sodium carbonate and extracted again with chloroform. The combined organic phases were washed with sodium bicarbonate solution (sat., Aq.), Then with sodium chloride solution (sat., Aq.). After drying (magnesium sulfate) the solvent was distilled off. The remaining oil was purified by column chromatography (silica gel; 0 x 1 = 5 cm x 50 cm; cyclohexane / ethyl acetate = 4 + 1). 0.44 g of a colorless solid was obtained. Using semi-prep. HPLC (acetonitrile / H2θ = 75 + 25) isolated 0.2 g of the isomeric mono-iodobenzyl compounds. FAB-MS: m / z: 1097 (M + Na +); 1075 (M + H +) mp: 95 ° C - 37 -

Example 3

Preparation of the dibromo derivative of PF1022

PF1022 (1.9 g; 2 mmol) was dissolved in chloroform (30 ml) under argon. P L2 (3.6 g; 8.4 mmol) was metered in at 0 ° C. and then bromine (1.28 g; 8 mmol) was added dropwise. The mixture was allowed to warm to room temperature. After five days at room temperature, the reaction mixture was poured into sodium sulfite solution (30% aq.). The phases were separated. The aqueous phase was extracted with chloroform. to

The aqueous phase was neutralized with sodium carbonate and extracted again with chloroform. The combined organic phases were washed with sodium bicarbonate solution (sat., Aq.), Then with sodium chloride solution (sat., Aq.). After drying (magnesium sulfate) the solvent was distilled off. The remaining oil was purified by column chromatography (silica gel; 0 x 1 = 5 cm x 50 cm; ethyl acetate cyclohexane = 1 + 4). 1.24 g (62% of theory) of the isomeric bis-bromobenzyl compounds were obtained. F AB-MS m / z: 1127 (M + Na +), 1105 (M + H +) mp: 99 ° C 38 -

Example 4

Preparation of the monobromo derivative of PF1022

H ₃ C

H ₃ C

o HO

O

OOH N-CH ₃ o H

"ri% - C

I CH,

_% CH, CH,

HC CH, ^3rd

The reaction and working up was analogous to Example 3, but in the presence of

1.5 eq bromine and 1.6 eq PML2 (see above).

Separation of still existing PF 1022 by semi-prep. HPLC (acetonitrile / -

H2O = 70 + 30) gave 0.3 g of the isomeric monobromobenzyl compounds.

FAB-MS m / z: 1049 (M + Na ⁺ )

Mp: 136 ° C

- 39 -

Example 5

Preparation of the monotriflate derivative of PF1022

,

H ^• . ₃ C ^' CH. ³

Trifluoromethanesulfonic anhydride (79.1 μl; 135.4 mg; 0.22 mmol) was added dropwise to a solution of the monohydroxy compound PF1022E (386 mg; 0.40 mmol) in dry pyridine (2 ml) at -20 ° C. The mixture was allowed to warm to 0 ° C. and stirred at this temperature for 24 h. After checking by TLC, the mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with 10% hydrochloric acid, water and saturated sodium chloride solution, dried over magnesium sulfate and then concentrated. The residue was purified by column chromatography (silica gel; 0 x 1 = 5 cm x 50 cm; cyclohexane ethyl acetate = 4 + 1; conditioning: +1% trifluoroacetic acid). 304.4 mg (73% of theory) of 20-benzyl-5,1,1,17,23 -tetraisobuty 1-2,4,10, 14,16,22-hexamethyl-8- (4th -trifluoromethylsulfonyloxybenzyl) - 1,7,13,19-tetraoxa-4, 10,16,22-tetra-azatetracosane-3, 6,9, 12, 15, 18,21, 24-octaone. ESI-MS: m / z (nominal mass): 1097 (M + H +), 1119 (M + Na ⁺ ) - 40

Example 6

Preparation of the bis (l-ethoxycarbonylethen-2-yI) derivative of PF1022

H, C

OHO

O

O o H N-CH ₃ o CH,

, H

N

I

CH. CH. CH,

H.C XH.

The mixture of the isomeric bis-iodobenzyl compounds from Example 1 (0.87 g; 0.72 mmol) and ethyl acrylate (0.36 g; 3.6 mmol) were introduced under argon. Tributylamine (0.4 g; 2.20 mmol) and palladium (II) acetate (41 mg; 25 mol%) were added with stirring at room temperature. The reaction was carried out at 100 ° C for 27 hours. For working up, it was taken up in 10 ml of chloroform. The organic phase was washed with H2O and then dried (magnesium sulfate). Further purification by column chromatography (1st cyclohexane; 2nd cyclohexane / ethyl acetate = 3 + 1; 3rd cyclohexane / ethyl acetate = 1 + 1) gave 0.5 g of crude product. By means of semipreparative HPLC (acetonitrile / H2θ = 80 + 20), 0.14 g was isolated twice product substituted by 1-ethoxy carbonylethen-2-yl.

FAB-MS: m / z: 1167 (M + Na +) 41

Example 7

Reaction of the diiodic derivative of PF1022 with 2-methylbut-3-in-2-ol

H, C

H, C yi- - Η O O

= 0 o OA-JO ^ CH, ³

CH ₃

(7-1) (7-2)

The mixture of the isomeric bis-iodobenzyl compounds from Example 1 (0.80 g; 0.67 mmol) and 2-methylbut-3-yn-2-ol (0.22 g; 2.6 mmol) was introduced under argon . Triethylamine (1 ml), bis (triphenylphosphine) palladium dichloride (94 mg; 20 mol%) and copper iodide (19 mg;

15 mol%) added. The reaction was carried out at 80 ° C for 15 hours. For working up, it was taken up in 10 ml of chloroform. The organic phase was washed with water and then dried (magnesium sulfate). Further purification by column chromatography (cyclohexane / ethyl acetate = 1 + 1) gave 0.5 g of crude product. Using semipreparative HPLC (acetonitrile / H2θ = 70 + 30), mono- and bis-

Substitution product separated. B is (3-hydroxy-3-methyl 1- 1 -butin-1 -yl) derivative (7- 1): FAB-MS: m / z: 1135 (M + Na +) mp: 179 ° C

Mono (3-hydroxy-3-methyl-1-butyn-1-yl) derivative (7-2): FAB-MS: m / z: 1053 (M + Na ⁺ ) mp: 85 ° C - 42 -

Example 8

Preparation of the bis (4-methoxyphenyl) derivative of PF1022

H.C. "CH

H ₃ CH ₃ CN.

H HA

o ^ -q HOO H-

OO = OO H. N-CH ₃ o CH.

CH, ³ y ^ CH,

N ^' CH, CH, ^3rd

The mixture of the isomeric bis-iodobenzyl compounds from Example 1 (0.50 g; 0.42 mmol) and p-methoxyphenylboronic acid (0.14 g; 0.92 mmol) was dissolved in toluene (4 ml) under argon. 2M sodium bicarbonate solution (0.6 ml) and tetrakis (triphenylphosphine) palladium (100 mg; 20 mol%) were added with stirring at room temperature. After 18 h at 80 ° C was torture. HPLC no longer detectable educt. For working up, it was taken up in 10 ml of chloroform. The organic phase was washed with water and then dried (magnesium sulfate). Further purification by column chromatography (cyclohexane / ethyl acetate = 1 + 1) gave 0.42 g (85% of theory) of bis-methoxybiphenyl compound. FAB-MS: m / z: 1183 (M + Na +)

- 43 -

Example 9

Preparation of the dicyano derivative of PF1022

The mixture of the isomeric bis-bromobenzyl compounds from Example 3 (0.87 g; 0.79 mmol) and zinc cyanide (0.11 g; 0.9 mmol) was dissolved in dimethylformamide (5 ml) under argon. Tetrakis (triphenylphosphine) palladium (0.137 g; 15 mol%) was added with stirring at room temperature. After 6 h at 80 ° C was worked up. For working up, it was diluted with toluene. The organic

Phase was washed with ammonia solution and then dried (magnesium sulfate). Further purification by column chromatography (cyclohexane / ethyl acetate = 2 + 1) gave 0.5 g of bis-cyanobenzyl compound. FAB-MS: m / z: 1021 (M + Na ⁺ )

44

Example 10

Preparation of the bis (cyanoethenyI) derivative of PF1022

CN

H, C "CH, - / ³

H ₃ C

N.

H ₃ C o -q ^ HOO H-

O O =

H N-CH ₃ A ₀

CH, CH, ^> CH. CH, ^{3 3}

Under an argon atmosphere, 8,20-bis (4-aminobenzyl) -5, 11, 17,23-tetra-isobutyl-2,4, 10, 14, 16,22-hexamethyl-1,7,13, 19-tetraoxa-4, 10,16,22-tetraaza-cyclotetracosan-3,6,9,12,15,18,21,24-octaone (979.2 mg; 1.0 mmol) in tetrafluoroboric acid (653 μl; 5.0 mmol), water (1.5 ml) added and diazotized at 0 ° C. by dropwise addition of a sodium nitrite solution (141.5 mg; 2.05 mmol in 0.5 ml degassed water). After stirring for 30 min at 0 ° C., methanol (4 ml), acrylonitrile (163.3 μl; 212.2 mg; 4.0 mmol) and palladium (II) acetate (9 mg) were added, followed by 1-2 h cooked under reflux. After TLC control, the filter was filtered through Cellite® filter aid, washed with dichloromethane and the filtrate was evaporated in vacuo. Column chromatography (silica gel; 0 x 1 = 2.5 cm x 32 cm; cyclohexane / ethyl acetate = 1 + 1) provided 370 mg (35% of theory) of 8,20-bis- [4- (2-cyanoethenyl ) benzyl] -5, 11, 17,23-tetraisobutyl-2,4, 10, 14, 16,22-hexamethyl-1, 7, 13, 19-tetra-oxa-4, 10, 16,22-tetraaza- cyclotetracosane-3,6,9, 12, 15, 18,21, 24-octaone. ESI-MS: m / z (nominal mass): 1053 (M + H +) - 45 -

Examples of use

Example A

Anthelmintic activity in the mouse

Male mice of the strain SPF / CFWI, 16-18 g body weight, were used in all experiments. 5 animals were kept together in Makrolon® cages (polycarbonate) and were given water and "Sniff '" rat feeds ad libitum. Mice were mixed-infected with the nematodes Nematospiroides dubius

(= Heligmosomoides polygyrus) and Heterakis spumosa. The infection material of the L3 larvae of N. dubius worms was isolated from the mouse colon 35-42 days after infection and incubated at 27 ° C. for 3 weeks. Test substances (1 g) were dissolved or suspended in the Cremophor EL emulsifier. 0.5 ml of the solution or suspension was applied once a day for 4 consecutive days per 20 g mouse. A

Mouse received 100 mg / kg as a dosage. The mixed infection of the mouse was gradual. She was first infected orally with 90 embryonic H spumosa eggs. 27 days later 60-70 filariform larvae of N. dubius were applied. Treatment with the substances started on the 46th day after infection and ended on the 49th day. After a further 8 days, the mice were killed with CO2 and dissected. H. spumosa were isolated from the caecum and colon and counted microscopically. The N dubius worms were counted from a squeeze preparation of the duodenum. If no parasites were visible in the specimens, this gave a rating of 3. 46

In this test, e.g. the following compounds have the stated effect:

Active ingredient dose Nematospiroides Heterakis preparation example No. [mg / kg] dubius spumosa

1 100 p.o. 2

4 100 p.o. 3 3

7-1 100 po 2

po oral

2 = good effect (75-95% reduction); 3 = full effect (> 95% reduction)

Example B

Anthelmintic effectiveness in sheep

Merino or Schwarzkopf sheep, 25-35 kg body weight, were experimentally infected with 5000 Haemonchus contortus L3 larvae and treated with the test substances at the end of the prepatent period of the parasites (3-4 weeks). The test substances were administered orally using gelatin capsules. In the case of Trichostrongylus colubriformis, 12000 L3 larvae were infected. The anthelmintic effectiveness was measured by the reduction of the eggs excreted with feces. For this purpose, freshly obtained faeces were processed according to the usual McMaster method and the number of eggs was determined per gram of faeces. The egg counts were taken at regular intervals (3-4 days) before and after treatment over 6-

Determined 8 weeks. Over 95% egg reduction is referred to as 3 in the test. 47 -

In this test, e.g. the following compounds have the stated effect:

Active ingredient Haemonchus contortus Trichostrongylus Manufacturing example No. 0.05 mg / kg p.o. colubriformis

0.25 mg / kg

2 3 3

4 3

7-2 3

p.o. oral 3 = full effect (> 95% reduction)

Claims

- 48 -

claims

Cyclooctadepsipeptides of formula (I)

"CH,

H II l - ° l

OH o O

O

.O o N-CH, (I), H

N i

CH.

CH. CH

H, C XH.

in which

R represents cyano, C-C-linked heterocyclyl or optionally substituted alkenyl, alkynyl or aryl and

R2 represents hydrogen or the same radical as R ¹ .

2. A process for the preparation of the compounds of formula (I) according to claim 1

49

(I), o / \ \, ^ H

^{^} N

CH,

. CH, CH,

H, C CH, ^3rd

in which

R represents cyano, C-C-linked heterocyclyl or optionally substituted alkenyl, alkynyl or aryl and

R2 represents hydrogen or the same radical as R ¹ .

characterized in that compounds of the formula (II)

H, C _/ CH,

H, 3C H ₃ C

N.

o HOO

O

o O H. N-CH ₃ (II), o CH,

*H

O

CH. CH, CH,

HC CH, ^3rd

in which

X ^{1 represents} bromine, iodine, -O-Sθ2-R ^f , amino or -N ₂ ⁺ (X ³ ) ^" , wherein - 50 -

R ^{f represents} fluorinated C i -C4 alkyl and

X ^{3 represents} a diazonium salt stabilizing anion and

χ2 represents hydrogen or the same radical as X ¹ ,

with a suitable reagent which splits off the group Rl in the presence of a transition metal catalyst with a C-C linkage.

Cyclooctadepsipeptides of the formula (II)

H, C. "CH, ^3rd

(II)

.

H, C CH,

in which

X ^{1 is} bromine, iodine, -OSO ₂ R ^f - where R ^{f is} fluorinated C _r C ₄ alkyl, and

X ^{2 represents} hydrogen or the same radical as X ¹ . - 51 -

4. A process for the preparation of compounds of formula (II) according to claim 3

in which

X ^{1 is} bromine, iodine, -OSO ₂ R ^f - where R ^{f is} fluorinated C _r C ₄ alkyl, and

X ^{2 represents} hydrogen or the same radical as X ¹ ,

characterized in that one

a) in the case of bromo-substituted cyclooctadepsipeptides of the formula (II-a)

-52-

"CH,

H ° °

O o OH N-CH ₃ (Il-a), OA CH,

_{,, ^} / ^ y CH, CH °, H, C CH, ^{3 3}

in which

χ2-1 represents hydrogen or bromine,

the cyclooctadepsipeptide of the following formula, designated PF 1022

H.C. "CH,

H 3, C H, 3C I

H ₃ C o

^{N ^} H

H ₃ C - ^ ^H ö ^"

H ₃ CN Η OO

^: O

PF 1022

, _X 'H o OH N-CH ₃

^Ö _. ^W -. _A1 CCHH ,, CCHH ,, H ₃ C CH ₃ ^{3 3A} : brominated or

b) in the case of iodinated cyclooctadepsipeptides of the formula (II-b) 53

H, .CH, H, 3C. H 3, C | ³ ^^ ³

H ₃ C

\ \ /

H ₃ C

o Λ — Ό

H.C-N H O O H-

, 2- ₂ A oo OH N-CH, (II-b),

/ 4th

J Üψ H A> ^{CH <}

<

CH.

. CH, CH,

HC CH, ^3rd

in which

χ2-2 represents hydrogen or iodine,

iodines the cyclooctadepsipeptide designated PF 1022 or

c) in the case of sulfonic acid cyclooctadepsipeptide esters of the formula (II-c)

HC _^ / CH, H ₃ CH ₃ C ³ Y ³

H, Q

H II

H ₃ C

O

H ₃ CN H ° ° H 2-s = 0 0 =

(II-c),

\ / - ^TH _/ 0 OH

\ CH, CH, H, C CH, ^{3 3}

in which

R ^{f represents} fluorinated C 4 -C 4 alkyl and

χ -3 stands for hydrogen or for -O-Sθ2-R ^f - 54 -

hydroxy-substituted cyclooctadepsipeptides of the formula (III)

H, C "CH. ³

,

H CH, 3rd

in which

X ^{3 represents} hydroxy or hydrogen,

with sulfonic anhydrides or halides of the formula (IV)

R ^f -SO -Y (IV), in which

Y represents -O-Sθ2-R ^f , F or chlorine, where R ^{f represents} fluorinated C j _ ₄ -alkyl,

in the presence of an acid binder, or

d) in the case of sulfonic acid cyclooctadepsipeptide esters of the formula (II-c), diazotized amino-substituted cyclooctadepsipeptide of the formula (V) - 55 -

H, C "CH,

H, C HC ³ .

H II H "\\ H O O H *> 3 -

= OO = N ₂ (X)

HOOH N-CH ₃ (V), O - CH,

CH, CH,

H, C CH, ^{3 3}

in which

X ^{4 represents} -N ₂ ⁺ (X ³ ) "or hydrogen,

X ^{3 represents} a diazominium salt stabilizing anion,

in the presence of a sulfonic acid of formula (VI)

HO-SO ₂ -R ^f (VI),

in which R ^{f has} the meaning given above,

implements.

5. Use of cyclooctadepsipeptides of the formula (I) according to Claim 1 for combating helminths in human and veterinary medicine.

6. Use of cyclooctadepsipeptides of formula (I) according to claim 1 for the preparation of agents for controlling endoparasites in human and veterinary medicine. - 56 -

7. agents for combating endoparasites characterized by a content of cyclooctadepsipeptides of the formula (I) according to claim 1 in addition to extenders and diluents and, if appropriate, conventional additives.