CA2368465A1

CA2368465A1 - Avermectin derivatives

Info

Publication number: CA2368465A1
Application number: CA002368465A
Authority: CA
Inventors: Werner Hallenbach; Achim Harder; Andreas Turberg; Olaf Hansen; Georg Von Samson-Himmelstjerna
Original assignee: Individual
Current assignee: Bayer AG
Priority date: 1999-03-25
Filing date: 2000-03-13
Publication date: 2000-10-05
Also published as: CN1345327A; WO2000058328A2; HK1045698A1; WO2000058328A3; DE19913534A1; BR0009285A; EP1169328A2; AU4394700A; JP2002540214A

Abstract

The invention relates to novel avermectin derivatives of formula (I), in which R1, R2, R3 and R4 have the meanings defined in the description. The invention also relates to various methods for producing them, to agents containing them and to their use for producing agents for combating ecto- and endoparasites in animals.

Description

Le A 33 515-Foreign Countries /Th /Ke/NT
s _1_ Avermectin derivatives The present invention relates to new avermectin derivatives, processes for their preparation, compositions comprising them, and their use for the preparation of compositions for controlling endoparasites and ectoparasites on animals.
The term avermectins refers to a series of substances which are formed when fermenting the microorganism Streptomyces avermitilis. They belong to the group of the macrolides and show anthelmintic, anti-parasitic and insecticidal properties. The general structure of this class of substances is as follows:
zs~Zz The broken bond between positions 22 and 23 marks a single or double bond. In the event of a single bond, Z' may be hydrogen or hydroxyl, in the case of a double bond only hydrogen. ZZ may be isopropyl or sec-butyl, and Z3 methoxy or hydroxyl.
To characterize these structural variations, the natural materials which have been isolated were given the names as shown in the table which follows.

Le A 33 515-Foreign Countries s -_2_ A 1 a 22,23 double bond sec-butyl -OCH3 A 1 b 22,23 double bond iso-propyl -OCH3 A2a -OH sec-butyl -OCH3 A2b -OH iso-propyl -OCH3 B 1 a 22,23 double bond sec-butyl -OH

B 1 b 22,23 double bond iso-propyl -OH

B2a -OH sec-butyl -OH

B2b -OH iso-propyl -OH

As a rule, the compounds are isolated as mixtures of components a and b from the fermentation liquors. The structural variation in substituents ZZ only has a minor effect on the biological activity.
In addition to these natural materials, the literature reveals further derivatives which were prepared by varying the fermentation conditions, altering the microorganism or chemical modification (Fisher, M.H.; Mrozik, H. in Macrolide Antibiotics;
Omura, S., Ed., Academic Press, New York ( 1984); Davis, H.G.; Green, R.H.;
Nat.Prod.Rep., (1986), 3, 87-121; Fisher, M.H. in Pest Control with Enhanced Environmental Safety, ACS Symposion Series 524; Duke, S.O.; Menn, J.J.;
Plimmer, J.R. Eds; American Chemical Society, Washington (1993).
1 S However, the known compounds show an unsatisfactory activity against the parasites to be controlled, in particular when low application rates are used.
There have now been found new compounds of the formula (I) Le A 33 515-Foreign Countries _3_ i O OwRa O
n R' 22 .
O zs~R2 (I) in which the broken bond between positions 22 and 23 represents a single or double bond, in the event of a single bond R~ represents hydrogen, hydroxyl or, together with the carbon atom in position 23, represents a carbonyl group, in the case of a double bond R 1 represents hydrogen, R2 represents an in particular alpha-branched C~-Cg-alkyl or alkenyl group, or a C3-Cg-cycloalkyl group, R' represents hydroxyl, C~-C6-alkyloxy, Ci-C6-alkanoyloxy or, together with the carbon atom in position 5, represents a hydroximino or C~-C6-alkoximino group, Le A 33 515-Foreign Countries O RS O RS
Ry R4 represents the radicals O H N H in which R6 R' RS represents H, branched or unbranched C ~ -C4-alkyl which can optionally be substituted by alkoxy, alkylamino, halogen and hydroxyl groups, R6 represents H, branched or unbranched CI-C4-alkyl, aryl or aralkyl, each of which can optionally be substituted by alkoxy, alkylamino, halogen and hydroxyl groups, R~ and Rg independently of one another represent H, branched or unbranched C~-alkyl which can optionally be substituted by alkoxy, alkylamino, halogen and hydroxyl groups, or R~ and Rg together with the nitrogen to which they are bonded form a heterocyclic ring with 5 to 7 ring members having, if appropriate, 1 to 2 further heteroatoms from the group consisting of oxygen, sulphur or nitrogen.
Depending on the nature of the substituents, the compounds of the formula (I) can also exist as geometric and/or optical isomers or isomer mixtures of various composition, which can be separated in the customary fashion, if so required.
The present invention relates not only to the pure isomers, but also the isomer mixtures, their preparation and use, and the compositions containing them. The following text will always mention compounds of the formula (I) for the sake of simplicity, even though this is to be understood as meaning not only the pure compounds but also, if appropriate, mixtures with various amounts of isomeric compounds.
Furthermore, it has been found that the new compounds of the formula ()) are obtained by one of the processes described hereinbelow:

Le A 33 515-Foreign Countries . z a) starting with compounds of the formula (IIa) Zs~ RZ
(IIa) in which the radicals R~, R2 and R4 have the abovementioned meanings and R3a represents hydroxyl-, C~-C6-alkyloxy- or C~-C6-alkanoyloxy, -SiMe3 is eliminated by reaction with HF in pyridine, or Le A 33 515-Forei;en Countries ~.
b) starting with compounds of the formula (IIb) O OwRa O
R' 25~ R2 J (IIb) -SiMe3 in which the radicals R~, R2 and R4 have the abovementioned meanings and R3b represent a protecting group from the series O-TBDMS (tert-butyl-dime-O RS
thylsilyl) or, only in the event that R4 represents the radical \ H , Rs R3b represent O-Alloc (allyloxycarbonyl), either a) in the event that R3b is O-TBMDS, both protecting groups are eliminated in one step by reaction with HF in pyridine, or (3) in the event that R3b is O-Alloc, the latter is removed by means of NaBH4/Pd(O) and -SiMe3 is eliminated by reaction with HF in pyridine, the sequence being of no importance, or Le A 33 S I 5-Forei;~n Countries ~.
_7_ c) compounds of the formula (IIc) O O~Ra O
n R' 2s~ R2 O
U (IIc) -SiMe3 in which the radicals R1 and R2 have the abovementioned meanings, R4 O RS
represents the radical \
Rs in which RS and R6 have the abovementioned meanings, and R3~ represents a group from the series hydroxyl, O-phenoxyacetyl or O-methoxyacetyl, are reacted with amines of the formula (V) Le A 33 515-Foreign Countries _g_ ..

~NwR~
H
in which R~ and R8 have the abovementioned meanings, and -SiMe3 is subsequently eliminated by reaction with HF in pyridine, or d) compounds of the formula (Ia) R' (Ia) in which the radicals R1 and R2 have the abovementioned meanings and R4 represents - i -C-ORs where RS and R6 have the abovementioned H
meanings O W Ra Le A 33 51 S-Foreign Countries ..
' -9-are reacted with amines of the formula (V) H/N\R~
in which R~ and Rg have the abovementioned meanings, or e) compounds of the formula (Ia') R'

2> R2 (Ia') in which the radicals R~, R2 and R4 have the abovementioned meanings are oxidized in a first step to give compounds of the formula (VII) p ~~Ra Le A 33 515-Foreign Countries y' t - 1 O -R'

3 (VII) and these are subsequently reacted in a second step with compounds of the formula (VIII) /N\ (VIII) H H
where R9 represents hydroxyl, -OSiMe3 or C~-C6-alkoxy.
Furthermore, it has been found that the new avermectin derivatives of the formula (I) have a very good activity as parasiticides, in particular against arthropods in livestock and pet keeping, while having a favourable toxicity to warm-blooded species.
Formula (>7 provides a general definition of the compounds according to the invention. Preferred substituents or ranges of the radicals stated in the formulae mentioned hereinabove and hereinbelow are illustrated in the following text.

~~Ra Le A 33 515-Foreign Countries ,.

The broken bond between positions 22 and 23 preferably represents a single or double bond.
R ~ preferably represents hydrogen.
R2 preferably represents an alpha-branched C3-Cg-alkyl or alkenyl group.
R3 preferably represents a hydroxyl, C ~ -C4-alkyloxy, C I -C4-alkanoyloxy, hydroximino or C~-C4-alkoximino group.
O~ RS
O RS C-t--//
R4 preferably represents the radicals ~~ , R- i H
Rs O H R' RS preferably represents H, branched or unbranched C~-C4-alkyl.
R6 preferably represents H, branched or unbranched C~-C4-alkyl, aryl or aryl-C~-C4-alkyl.
R~ and R8 independently of one another preferably represent H, branched or unbranched C 1-C4-alkyl, and R~ and R8 can furthermore preferably form a heterocyclic ring having 5 to 7 ring members with, if appropriate, oxygen, sulphur or nitrogen as heteroatoms.
The broken bond between positions 22 and 23 especially preferably represents a single or double bond. R~ especially preferably represents hydrogen.
R2 especially preferably represents isopropyl, sec-butyl or an alpha-branched C3-Cg-alkenyl group.

Le A 33 515-Foreign Countries ,.

R3 especially preferably represents hydroxyl.
R4 especially preferably represents the following radicals s ~ a R O H R ~ H
R' RS especially preferably represents H, methyl and ethyl.
R6 especially preferably represents H, methyl, ethyl or benzyl.
R~ and Rg independently of one another especially preferably represent H, methyl, ethyl or isopropyl. R~ and Rg can furthermore form a heterocyclic ring having S to 6 ring members with, if appropriate, oxygen or nitrogen as heteroatoms.
Other especially preferred compounds of the formula (I) which may be mentioned are, for example, the following compounds:

4"-O-(methoxycarbonyl-methyl)-avermectin B 1 a/B 1 b 4"-O-(ethoxycarbonyl-methyl)-avermectin B 1 a/B lb 4"-O-(benzyloxycarbonyl-methyl)-avermectin B 1 a/B 1 b 4"-O-(carbamoyl-methyl)-avermectin B 1 a!B 1 b 4"-O-(N-methyl-carbamoyl-methyl)-avermectin B 1 a/B 1 b 4"-O-(N,N-dimethyl-carbamoyl-methyl)-avermectin B 1 a/B 1 b 4"-O-(N-isopropyl-carbamoyl-methyl)-avermectin B 1 a/B 1 b 4"-O-(morpholinyl-carbonyl-methyl)-avermectin B 1 a/B 1 b 4"-O-(4-methyl-piperazinyl-carbonyl-methyl)-avennectin B 1 alB 1 b 4"-O-(methoxycarbonyl-methyl)-22,23-dihydro-avermectin B 1 a/B 1 b 4"-O-(ethoxycarbonyl-methyl)-22,23-dihydro-avermectin B 1 a/B 1 b 4"-O-(benzyloxycarbonyl-methyl)-22,23-dihydro-avermectin B 1 a/B 1 b 4"-O-(carbamoyl-methyl)-22,23-dihydro-avermectin B 1 a/B 1 b Le A 33 515-Foreign Countries ..
4"-O-(N-methyl-carbamoyl-methyl)-22,23-dihydro-avermectin B 1 a/B 1 b 4"-O-(N,N-dimethyl-carbamoyl-methyl)-22,23-dihydro-avermectin B 1 a/B 1 b 4"-O-(N-isopropyl-carbamoyl-methyl)-22,23-dihydro-avermectin B 1 a/B 1 b 4"-O-(morpholinyl-carbonyl-methyl)-22,23-dihydro-avermectin B 1 a/B 1 b 4"-O-(4-methyl-piperazinyl-carbonyl-methyl)-22,23-dihydro-avermectin B 1 a/B 1 b The above structural formulae are shown without defined stereochemistry. The compounds can take the form of stereoisomers. In particular the substituents in the 4"-,4'-, 13-, 5- and 23-positions can be in alpha- or beta-orientation, that is to say located above or below the molecular plane.
The abovementioned definitions of radicals or illustrations, which are mentioned either in general terms or in preferred ranges, can be combined with each other as desired, that is to say combinations between the respective ranges and preferred ranges are also possible. They apply to the end products and, accordingly, to the precursors and intermediates.
Preferred according to the invention are the compounds of the formula (I) in which a combination of the meanings mentioned above as being preferred (preferable) exists.
Especiall~preferred according to the invention are the compounds of the formula (I) in which a combination of the meanings mentioned above as being especially preferred exists.
Saturated or unsaturated hydrocarbon radicals such as alkyl or alkenyl, also in conjunction with heteroatoms such as, for example, in alkoxy, can be in each case straight-chain or branched as far as this is possible.
The compounds of the formulae (Ia) and (Ia'), which are required for carrying out processes d) and e), respectively, are subsets of the compounds of the formula (I) and can be obtained by processes a) to c).

. Le A 33 515-Foreign Countries The compounds of the formula (II) which are required for carrying out processes a) to c) Zs~ Rz (B) ~3 in which R~, R2 and R4 have the general, preferred and especially preferred meanings mentioned above for formula (I) and R3g represents hydroxyl-, CI-C4-alkyloxy-, C1-C4-alkanyloxy-, O-TBDMS and, only O RS
in the event that R4 represents ~ H , represents O-Alloc, O-phenoxyacetyl or Rs O-methoxyacetyl, where Le A 33 S 1 S-Foreign Countries ,- ' - 15 -R3b preferably represents hydroxyl-, C~-C4-alkyloxy-, C~-C4-alkanyloxy-, O-TBDMS and, only in the event that R4 represents ~ H
represents Rs O-Alloc, O-phenoxyacetyl or O-methoxyacetyl, R3g especially preferably represents hydroxyl-, O-TBDMS and, only in the event that O RS
R4 represents ~ H , represents O-Alloc, O-phenoxyacetyl or Rs O-methoxyacetyl, where RS and R6 in each case have the abovementioned general, preferred and especially preferred meanings, are new and also subject-matter of the present application.
The following compounds of the formula (II) may be mentioned individually:
4"-O-(methoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-tent-butyldimethylsilyl-avennectin-B 1 4"-O-(methoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-tert.-butyldimethylsilyl-22,23-dihydro-avermectin-B 1 4"-O-(methoxycarbonyl-methyl)-7-O-trimethylsilyl-S-O-avermectin-B 1 4"-O-(methoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-22,23-dihydro-avermectin-4"-O-(methoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-phenoxyacetyl-avermectin-4"-O-(methoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-phenoxyacetyl-22,23-dihydro-avermectin-B 1 Le A 33 515-Foreign Countries ,_ 4"-O-(methoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-methoxyacetyl-avermectin-BI
4"-O-(ethoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-methoxyacetyl-22,23-dihydro-avermectin-B I
4"-O-(ethoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-tert-butyldimethylsilyl-avermectin-B 1 4"-O-(ethoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-tent-butyldimethylsilyl-22,23-dihydro-avermectin-B I
4"-O-(ethoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-avermectin-B 1 4"-O-(ethoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-22,23-dihydro-avermectin-B

4"-O-(ethoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-phenoxyacetyl-avermectin-B
I
4"-O-(ethoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-phenoxyacetyl-22,23-dihydro-avermectin-B 1 4"-O-(ethoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-methoxyacetyl-avermectin-B
I
I S 4"-O-(ethoxycarbonyl-methyl)-7-O-trimethylsilyl-5-O-methoxyacetyl-22,23-dihydro-avermectin-B I
4"-O-(N-methyl-carbamoyl-methyl)-7-O-trimethylsilyl-S-O-tert-butyldimethylsilyl-avermectin-B I
4 ' '-O-(N-methyl-carbamoyl-methyl)-7-O-trimethylsilyl-5-O-tent-butyldimethylsilyl-22,23-dihydro-avermectin-B 1 4"-O-(N,N-dimethyl-carbamoyl-methyl)-7-O-trimethylsilyl-S-O-tent-butyldi-methylsilyl-avermectin-B 1 4"-O-(N,N-dimethyl-carbamoyl-methyl)-7-O-trimethylsilyl-5-O-tent-butyldi-methylsilyl-22,23-dihydro-avermectin-B 1 4"-O-(N-isopropyl-carbamoyl-methyl)-7-O-trimethylsilyl-S-O-tent-butyldimethyl-silyl-avermectin-B 1 4 ' '-O-(N-isopropyl-carbamoyl-methyl)-7-O-trimethylsi lyl-5-O-tert-butyldimethyl-silyl-22,23-dihydro-avermectin-B I
4"-O-(morpholinyl-carbonyl-methyl)-7-O-trimethylsilyl-5-O-tent-butyldimethylsilyl-avermectin-B 1 Le A 33 515-Foreign Countries ,.
' -17-4"-O-(morpholinyl-carbonyl-methyl)-7-O-trimethylsilyl-5-O-tert-butyldimethylsilyl-22,23-dihydro-avermectin-B 1 4"-O-(4-methyl-piperazinyl-carbonyl-methyl)-7-O-trimethylsilyl-5-O-tert-butyl-dimethylsilyl-avermectin-B 1 4"-O-(4-methyl-piperazinyl-carbonyl-methyl)-7-O-trimethylsilyl-5-O-tent-butyl-dimethylsilyl-22,23-dihydro-avermectin-B 1 The compounds of the formula (VII) which are required for carrying out process e) for the preparation of compounds of the formula (I) 2s~ R2 (VII) in which RI, R2 and R4 have the abovementioned general, preferred and especially preferred meanings are new and also subject-matter of the present application.
The following compounds of the formula (VII) may be mentioned individually:

~~Ra Le A 33 51 S-Foreign Countries 4"-O-(methoxycarbonyl-methyl)-5-oxo-avermectin-B 1 a/B 1 b 4"-O-(ethoxycarbonyl-methyl)-5-oxo-avermectin-B 1 a/B 1 b 4"-O-(carbamoyl-methyl)-5-oxo-avermectin-B 1 a/B 1 b 4"-O-(N-methyl-carbamoyl-methyl)-5-oxo-avermectin-B 1 a/B 1 b 4"-O-(N,N-dimethyl-carbamoyl-methyl)-5-oxo-avermectin-B 1 a/B 1 b 4"-O-(N-isopropyl-carbamoyl-methyl)-5-oxo-avermectin-B 1 a/B 1 b 4"-O-(4-methyl-piperazinyl-carbonyl-methyl)-5-oxo-avermectin-B 1 a/B 1 b 4"-O-(methoxycarbonyl-methyl)-22,23-dihydro-5-oxo-avermectin-B 1 a/B 1 b 4"-O-(ethoxycarbonyl-methyl)-22,23-dihydro-5-oxo-avermectin-B 1 a/B 1 b 4"-O-(carbamoyl-methyl)-22,23-dihydro-5-oxo-avermectin-B 1 alB 1 b 4"-O-(N-methyl-carbamoyl-methyl)-22,23-dihydro-5-oxo-avermectin-B 1 a/B 1 b 4"-O-(N,N-dimethyl-carbamoyl-methyl)-22,23-dihydro-S-oxo-avermectin-B 1 a/B l b 4"-O-(N-isopropyl-carbamoyl-methyl)-22,23-dihydro-5-oxo-avermectin-B 1 a/B 1 b 4"-O-(morpholinyl-carbonyl-methyl)-22,23-dihydro-5-oxo-avermectin-B 1 a/B 1 b 4"-O-(4-methyl-piperazinyl-carbonyl-methyl)-22,23-dihydro-5-oxo-avermectin-Bla/Blb The compounds of the formula (II) can be prepared by reacting compounds of the formula (III) Le A 33 515-Foreign Countries ' - 19-x zs~ R2 (III) '3 in which R~ and R2 have the abovementioned general, preferred and especially preferred meanings and R3g~ represents C1-C6-alkyloxy-, C~-C6-alkanoyloxy-, O-Alloc, O-TBDMS, O-phenoxyacetyl or O-methoxyacetyl, with diazo compounds of the formula (IV) N-I
Rs / N+
R6 W) ~O O
in which Le A 33 51 S-Foreign Countries RS and R6 have the abovementioned general, preferred and especially preferred meanings, and subsequently, in the event that R3~ represents C1-C6-alkyloxy-, C~-C6-alkanoyloxy-, TBDMS, phenoxyacetyl or methoxyacetyl, reacting the product, if appropriate, with compounds of the formula (V) RS
,N~ ~ (V) H R
in which R~ and Rg have the abovementioned general, preferred and especially preferred meanings, or in the event that R3~ represents Alloc, if appropriate removing the latter by means of NaBH4/Pd(0) and, if appropriate, subsequently reacting the product with compounds of the formula (V) Ra /N~ ~ (V) H R
in which R~ and Rg have the abovementioned general, preferred and especially preferred meanings.
The compounds of the formula (III) Le A 33 515-Foreign Countries 2s~Rz (III) ~3 which are required for carrying out the process for the preparation of compounds of the formula (II) and in which Rl and R2 have the abovementioned meanings, where R3g' preferably represents C~-C4-alkyloxy-, C~-C4-alkanoyloxy-, O-Alloc, O-phen-oxyacetyl or O-methoxyacetyl, R3g' especially preferably represents O-Alloc, O-phenoxyacetyl and O-methoxyacetyl, are new and also subject-matter of the present application.
The following compounds of the formula (III) may be mentioned individually:

Le A 33 515-Foreign Countries ,- ' -22-7-O-trimethylsilyl-5-O-allyloxycarbonyl-avermectin Bl 7-O-trimethylsilyl-5-O-allyloxycarbonyl-22,23-dihydro-avermectin B 1 7-O-trimethylsilyl-5-O-phenoxyacetyl-avermectin BI
7-O-trimethylsilyl-5-O-phenoxyacetyl-22,23-dihydro-avermectin B I
7-O-trimethylsilyl-5-O-methoxyacetyl-avermectin Bl 7-O-trimethylsilyl-5-O-methoxyacetyl-22,23-dihydro-avermectin B I .
The compounds of the formula (III) can be prepared by providing compounds of the formula (VI) (VI) in which R~ and R2 have the abovementioned meanings and R'' represents hydroxyl, C1-C6-alkyloxy, C1-C6-alkanoyloxy, plenoxyacetyl, methoxyacetyl with a trimethylsilyl protecting group at the hydroxyl group marked OH-, Le A 33 515-Foreign Countries ,- ' -23-and, in the event that R3 equally represents a hydroxyl group, also providing the latter with a protecting group from the series Alloc, TBDMS, phenoxyacetyl or methoxyacetyl.
The compounds of the formula (V) required for carrying out the process for the preparation of compounds of the formula (III) are known or can be prepared by known methods (see, for example, Fisher, M.H.; Mrozik, H. in Macrolide Anti-biotics; Omura, S., Ed., Academic Press, New York (1984); Davis, H.G.;
Green, R.H.; Nat.Prod.Rep., (1986), 3, 87-121; Fisher, M.H. in Pest Control with Enhanced Environmental Safety, ACS Syrnposion Series 524; Duke, S.O.; Menn, J.J.; Plimmer, J.R. Eds; American Chemical Society, Washington (1993).
The compounds of the formula (N) are known or can be prepared by known methods (see textbooks on organic chemistry, for example Jerry March, Advanced Organic Chemistry, Wiley Interscience). The following compounds of the formula (IV) may be mentioned individually:
methyl diazoacetate ethyl diazoacetate tert-butyl diazoacetate phenyl diazoacetate methyl diazopropionate ethyl diazopropionate tert-butyl diazopropionate phenyl diazopropionate benzyl diazopropionate.
The amines of the formula (V) are commercially available, known or can be prepared by known methods. The following compounds of the formula (V) may be mentioned individually:

Le A 33 515-Foreign Countries ' -24-ammonia methylamine dimethylamine ethylamine isopropylamine morpholine 4-methyl-piperazine.
The hydroxylamines of the formula (VIII) which are used are hydroxylamine and O-alkyl-hydroxylamine as free bases or in the form of their salts. If the reaction is carried out in anhydrous medium, it may be advantageous to use O,N-bis-trimethyl-silyl or O-trimethylsilylhydroxylamine. Preferred are hydroxylamine hydrochloride and O-methyl-hydroxylamine hydrochloride. The compounds of the formula (VIII) are commercially available, known or can be obtained by known methods.
Process a) for the preparation of compounds of the formula (I) can be represented by way of example by the following formulaic scheme:

o \o~ of o~ o~'' o ° of o~..o o , o~
pyridine ~CH~ CFi3 Le A 33 515-Foreign Countries Process b) a) for the preparation of compounds of the formula (I) can be represented by way of example by the following formulaic scheme:

o~

0 0 "o °/ o~
° o "o ° '' o.~
c pyridine ~H
TBDMS
Process b) (3) for the preparation of compounds of the formula (I) can be represented by way of example by the following formulaic scheme:

Le A 33 515-Foreign Countries ' -26-o~

o~
o~ o ,.o o~
c ~AUoc NaBH4/Pd(O) o \o~ of o~ o~'o 0 0~
% O~~'O
O : O
pyridine _-The silyl protecting groups are eliminated in accordance with processes a), b) a) and the second step of b) (3) by reacting the avermectin derivative with water in a solvent.
The reaction is carried out with protic acids as catalyst.
The reaction is preferably catalysed by protic acids such as hydrochloric acid, methanesulphonic acid, hydrochloric acid or sulphuric acid.
Hydrofluoric acid is especially preferably employed.

Le A 33 51 S-Foreign Countries , _27_ The reaction is carned out in a pH range of 2-8, preferably 2-6.
To obtain the abovementioned pH ranges, a substantial amount of acid may also be added to the reaction medium as required, which is subsequently neutralized by amines (buffering).
Amines which may be mentioned are: pyridine, triethylamine, ammonia.
Pyridine is especially preferred.
The reaction is carried out at a temperature of from -70 to +100°C, preferably from -10 to +50°C.
The process is preferably carried out under atmospheric pressure. However, it may also be carned out under elevated or reduced pressure.
Diluents which can be used are all inert organic solvents. These include, in particular, aliphatic and aromatic hydrocarbons such as pentane, hexane, cyclohexane, petroleum ether, ligroin, benzene; chlorinated hydrocarbons such as methylene chloride, ethylene chloride, chloroform; ethers such as diethyl ether, methyl tert-butyl ether, THF and glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, butanol, isopropanol and mixtures of these solvents.
Preferred are alcohols such as methanol, ethanol and ethers such as THF.
If hydrofluoric acid is used, the reaction can also be carned out without water.
However, in this case, the hydrofluoric acid must be employed in stoichiometric amounts of 1-100 mol, preferably 5-20 mol, per mole of avermectin derivative.
The Alloc protecting group is, in accordance with the first step in b) Vii), removed reductively, using a transition metal catalyst.

. Le A 33 515-Foreign Countries _28_ The following may be mentioned as reducing agents for carrying out the process:
ammonium formate, triethylammonium formate, tributyltin hydride, sodium boro-hydride, lithium borohydride.
The following reducing agents are preferably employed: sodium borohydride and lithium borohydride.
The process is carried out by mixing the avermectin derivative with excess reducing agent in a solvent.
The reaction is carried out using a catalyst.
The catalyst used is palladium. It may be employed in the reaction as Pd(O) or a salt which forms Pd(O) under the reaction conditions.
The following Pd compounds may be mentioned: palladium(O)-tetrakis-triphenylphosphine, palladium(O)-bis-dibenzalacetone, palladium(O)-tris-dibenzalacetone, palladium diacetate, palladium dichloride.
Palladium(O)-tetrakis-triphenylphosphine is preferably employed.
If the palladium compound employed contains no phosphine ligand, a phosphine may be added.
Phosphines which may be mentioned are: triphenylphosphine, 1,2-bis-(diphenylphosphino)-ethane.
Triphenylphosphine is preferably employed.

Le A 33 515-Foreign Countries The reaction is carned out at a temperature of -70 to +150°C, preferably -15 to +50°C.
It is preferably carried out under atmospheric pressure. However, it may also be carried out under elevated or reduced pressure.
Diluents which can be used are all inert organic solvents. These include, in particular, aliphatic and aromatic hydrocarbons such as pentane, hexane, cyclohexane, petroleum ether, ligroin, benzene; ethers such as diethyl ether, methyl tert-butyl ether and glycodimethyl ether, tetrahydrofuran; esters such as ethyl acetate, butyl acetate, alcohols such as methanol, ethanol, propanol, butanol, isopropanol and mixtures of these solvents.
Preferred are alcohols such as methanol and ethanol (see also Cvetovich, R.J.;
Kelly, D.H.; DiMichele, L.M.; Shuman, R.F.; Grabowski, E.J.J., J.Org.Chem. 59 (1994) 7704-7708; EP632725; Fraser-Reid, B.; Barchi, J.; Faghih, Ramin, J. Org. Chem.

(1988) 925-926; Trost, B.M.; Caldwell, C.G.; Murayama, E.; Heissler, D., J.
Org.
Chem. 48 (1983) 3252-3265).

Le A 33 515-Foreign Countries Process c) for the preparation of compounds of the formula (I) can be represented by way of example by the following formulaic scheme:

o' o~
O HzN
O
~ O~
O' ' O ~ O ,, O
O~ O
°., o~
H H
a HF/pyridine O
O~
O ~~ O
O' O~
H

Le A 33 515-Foreien Countries Process d) for the preparation of compounds of the formula (~ can be represented by way of example by the following formulaic scheme:

o' o~
O HzN
O
~ O~
Oi\ O ~O ,~ O
O~ O
., O~

~H
The reaction with amines in accordance with processes c) and d) is carried out by reacting the compounds of the formula (IIc) and (Ia), respectively, with excess amine in a solvent. The amine is preferably employed in a molar ratio of 2-200:1, in particular 10-100:1 (amine:(IIc) or (Ia)). The reaction can be earned out with or without catalyst. Suitable catalysts are protic acids and Lewis acids.
The reaction is preferably catalysed by protic acids.
Hydrochloric acid, formic acid or acetic acid are especially preferably employed for I S catalysis.
The reaction is carried out at a temperature of from -70 to +150°C, preferably from -10 to +50°C.
The process is preferably earned out under atmospheric pressure, but it may also be earned out under elevated or reduced pressure.

Le A 33 515-Foreign Countries Diluents which can be used are all inert organic solvents. These include, in particular, aliphatic and aromatic hydrocarbons such as pentane, hexane, cyclohexane, petroleum ether, ligroin, benzene; chlorinated hydrocarbons such as methylene chloride, ethylene chloride, chloroform; ethers such as diethyl ether, methyl tert-butyl ether and glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, butanol, isopropanol and mixtures of these solvents.
Alcohols such as methanol and ethanol are preferred.
Process e) for the preparation of compounds of the formula (I) can be represented by way of example by the following formulaic scheme:

Le A 33 515-Foreign Countries , -33-O
O
O O
O-'\ O~~ O O , O
O O O
,,. C
O '~'O ~ _ CH3S~CH3 O
C-C
O ~ O CI~
,O
H
O
O HZNOSiMe3 O
O~
O ~O
'O~~
Process e) is carried out by reacting, in a first step, the compounds of the formula {Ia') with an oxidantlactivator mixture and an auxiliary base in a solvent.
Oxidants used for carrying out the process are aliphatic sulphoxides. Dimethyl sulphoxide is especially preferred. The oxidant is employed in a ratio of 1 to 10 mol, preferably 1 to 5 mol, based on the starting material of the formula (Ia').
The reaction is carned out with an activator.

Le A 33 515-Foreign Countries Activators which are suitable are all non-nucleophilic acylating agents. These include, in particular:
acid chlorides such as phosgene, oxalyl chloride, phenyl dichlorophosphate, diphenyl chlorophosphate; acid anhydrides such as trifluoroacetic anhydride, trifluoromethanesulphonic anhydride, phosphorus pentoxide; pyridine/S03 adduct.
Preferred are phenyl dichlorophosphate and oxalyl chloride. The activator is employed in a ratio of 1 to 10 mol, preferably 1 to 3 mol, based on the oxidant.
Auxiliary bases which are suitable are inert tert-amine bases such as triethylamine, diethylcyclohexylamine, diisopropylethylamine, diazabicycloundecene, diazabicyclononene. Triethylamine and diisopropylethylamine are preferred. The amine is employed in a ratio of 2 to 20 mol, preferably 3 to 15 mol, based on the oxidant.
The reaction is corned out at a temperature of from -100 to +100°C, preferably from -70 to +50°C.
The process is preferably corned out under atmospheric pressure; however, it may also be carried out under elevated or reduced pressure.

Diluents which are suitable are all inert organic solvents. These include, in particular, aliphatic and aromatic hydrocarbons such as pentane, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene; chlorinated solvents such as dichloromethane, 1,2-dichloromethane, chloroform, chlorobenzene; ethers such as diethyl ether, methyl tert-butyl ether and glycol dimethyl ether, tetrahydrofuran;
esters such as acetic acid, butyl acetate, and mixtures of these solvents.
Preferred are toluene, dichloromethane, ethyl acetate and isopropyl acetate.

Le A 33 515-Foreign Countries In a second step, the intermediate of the formula (VII) is reacted with a hydroxylamine in a solvent. The hydroxylamine is reacted in a molar ratio of I-20: I, preferably 2-20:1 (hydroxylamine: VII).
S This reaction may be carried out in the presence of a catalyst.
Suitable catalysts are:
in protic medium, acids such as HCI, formic acid, acetic acid, propionic acid;
bases such as triethylamine, pyridine, diisopropylethylamine, tributylamine;
in aprotic medium: Lewis acids such as, for example, ZnCl2.
The reaction can be carried out in a pH range of from I to 8, preferably from I .5 to 6.
The reaction is carned out at a temperature of from -10 to +80°C, preferably from -10 to +SO°C.
The process is preferably carried out under atmospheric pressure; however, it may also be carned out under elevated or reduced pressure.
Diluents which are suitable are all inert organic solvents. These include, in particular, aliphatic and aromatic hydrocarbons such as pentane, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene; chlorinated solvents such as dichloromethane, 1,2-dichloromethane, chloroform, chlorobenzene; ethers such as diethyl ether, methyl tert-butyl ether and glycol dimethyl ether, tetrahydrofuran;
esters such as ethyl acetate, acetic acid, butyl acetate; alcohols such as methanol, ethanol, propanol, isopropanol, butanol and water, and mixtures of these solvents.
Ethyl acetate and isopropyl acetate, isopropanol, ethanol, methanol and water are preferred.

Le A 33 S 15-Foreign Countries The process for the preparation of compounds of the formula (II) can be represented by way of example by the following formulaic scheme:

o/ ~o~ o/
HO O
O/
O ~O O/ O~.~O
p ': O ' ,o~o HBF4 I

HzN~ °/ with or without NH3 o/
o ,,o o~
~TBDMS
or Le A 33 515-Foreign Countries o~ ~o~ o/
HO p O ~~O O~ O~~~O O
O- ' O
o ~~w ~ HBF Auoc \Alloc o with or without NaBH4IPd(o) o~ o HzN
O~~O O O
O/
O~ O n 0 O~~

~H
ith or without 'H
The process for the preparation of the compounds of the formula (II) is carned out by reacting the compound of the formula (III) with excess diazo compound of the formula (IV) in a solvent. The molar ratio of diazo compound (VI) to compound (III) is preferably 1-15:1, in particular 2-7:1. The reaction can be carried out with or without catalyst. Suitable catalysts are protic acid and transition metal complexes.
The reaction is preferably catalysed by protic acids.

Le A 33 515-Foreiwn Countries Tetrafluoroboric acid or trifluoromethanesulphonic acid are especially preferably employed.
The reaction is carried out at a temperature of from -70 to +1 SO°C, preferably from -10 to +50°C.
It is preferably carried out under atmospheric pressure, but may also be carried out under elevated or reduced pressure.
Suitable diluents are all inert organic solvents. These include, in particular, aliphatic and aromatic hydrocarbons such as pentane, hexane, cyclohexane, petroleum ether, ligroin, benzene; chlorinated hydrocarbons such as methylene chloride, ethylene chloride, chloroform; ethers such as diethyl ether, methyl tent-butyl ether and glycol dimethyl ether.
Ethers and chlorinated hydrocarbons are preferred.
The optional subsequent reaction with amine follows the process described further above for processes c) and d). The elimination of the Alloc protecting group which may be necessary follows the processes described further above for processes a) and b).
When carrying out the process for the preparation of compounds of the formula (III), the protecting groups are introduced analogously to processes known from the literature (Cvetovich, R.J.; Kelly, D.H.; DiMichele, L.M.; Shuman. R.F.:
Grabowski, E.J.J., J.Org.Chem. 59 (1994) 7704-7708; EP632725; Fraser-Reid, B.;
Barchi, J.; Faghih, Ramin, J. Org. Chem. 53 (1988) 925-926).
The active compounds of the formula (I) are suitable for controlling pathogenic endo/ectoparasites which are found in humans and in animal keeping and animal Le A 33 515-Forei~Qn Countries breeding in livestock, breeding animals, zoo animals, laboratory animals, experimental animals and pets, while having favourable toxicity to warm-blooded species. They are resistant to all or individual developmental stages of the pests and to resistant and normally sensitive species. Controlling the pathogenic parasites is intended to reduce disease, deaths and reduced performance (for example in the production of meat, milk, wool, hides, eggs, honey and the like), so that more economical and simpler animal keeping is made possible by using the active compounds. The pathogenic endoparasites include cestodes, trematodes, nematodes, and the ectoparasites arthropods, preferably insects and arachnids.
The following endoparasites are enumerated in particular:
From the order of the Pseudophyllidea, for example, Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoporus spp.
From the order of the Cyclophyllidea, for example, Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.
From the subclass of the Monogenea, for example, Cyrodactylus spp., Dactylogyrus spp., Polystoma spp.
From the subclass of the Digenea, for example, Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Le A 33 S 1 S-Foreign Countries Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonismus spp., Dicrocoelium spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp.
From the order of the Enoplida, for example, Trichuris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp.
From the order of the Rhabditia, for example, 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 spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostomum spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp., Cylicocyclus spp., Cylicodontophorus spp.
From the order of the Oxyurida, 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.

Le A 33 515-Foreign Countries From the order of the Spirurida, for example, Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.
From the order of the Filariida, for example, Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp.
From the group of the Gigantohynchida, for example, Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.
The ektoparasites include in particular the following:
From the order of the Anoplura, for example, Haematopinus spp., Linognathus spp., Solenopotes spp., Pediculus spp., Pthirus spp.;

From the order of the Mallophaga, for example, Trimenopon spp., Menopon spp., Eomenacanthus spp., Menacanthus spp., Trichodectes spp., Felicola spp., Damalina spp., Bociola spp., Werneckiella spp., Lepikentron spp.;
From the order of the Diptera, for example, Chrysops spp., Tabanus spp., Musca spp., Hydrotaea spp., Muscina spp., Haematobosca spp., Haematobia spp., Stomoxys spp., Fannia spp., Glossing spp., Lucilia spp., Calliphora spp., Cardylobia spp., Cochliomyia spp., Chrysomyia spp., Sarcophaga spp., Wohlfahrtia spp., Gasterophilus spp., Oesteromyia spp., Oedemagena sp., Hypoderma spp., Oestrus spp., Rhinoestrus spp., Melophagus spp., Hippobosca spp.
From the order of the Siphonaptera, for example, Ctenocephalides spp., Echidnophaga spp., Ceratophyllus spp.

Le A 33 515-Fore~~n Countries From the order of the Metastigmata, for example, Hyalomma spp., Rhipicephalus spp., Boophilus spp., Amblyomma spp., Haemophysalis spp., Dermacentor spp., Ixodes spp., Argas spp., Ornithodorus spp., Otobius spp.;
From the order of the Mesastigmata, for example, Dermanyssus spp., Ornithonyssus spp., Pneumonyssus spp.
From the order of the Prostigmata, for example, Cheyletiella spp., Psorergates spp., Myobia spp., Demodex spp., Neotrombicula spp.;
, From the order of the Astigmata, for example, Acarus spp., Myocoptes spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Neoknemidodoptex spp., Lytodites spp., Laminosioptes spp.
The livestock and breeding animals include mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur bearers such as, for example, mink, chinchilla, racoon, birds such as, for example, chickens, geese, turkeys, ducks, freshwater and salt water fish such as, for example, trout, carp, eels, reptiles, insects such as, for example, honeybee and silkworm.
The laboratory animals and experimental animals include, for example, mice, rats, guinea pigs, golden hamsters, dogs and cats.
The pets include, for example, dogs and cats.
Application can be effected both prophylactically and therapeutically.
The active compounds are applied directly or in the form of suitable preparations either enterally, parenterally, dermally, nasally, by environment treatment or with the Le A 33 515-Foreign Countries aid of active-compound-containing shaped articles such as, for example, strips, slabs, tapes, collars, ear tags, limb bands, marking devices.
Enteral administration of the active compounds is effected for example orally in the form of powder, tablets, capsules, pastes. boluses, drinks, granules, or solutions, suspensions or emulsions for oral administration, medicated feed or drinking water.
Dermal administration is effected for example, in the form of dipping, spraying, pouring-on, spotting-on and dusting. Parenteral administration is effected for example in the form of an injection (intramuscular, subcutaneous, intravenous, I 0 intraperitoneal) or by implants.
Preparations for dermal administration must be particularly emphasized. They include solutions, suspension concentrates, emulsion concentrates and microemulsions which are diluted with water prior to use, pour-on and spot-on formulations, powders and dusts, aerosols and active-compound-containing shaped articles, and also dust bags and back-rubbers.
These preparations are prepared in a known manner, for example by mixing the active compound with extenders, that is to say liquid solvents, optionally with the use of surface-active agents, that is to say emulsifiers and/or dispersants. If water is used as extender, for example organic solvents may also be used as cosolvents.
The liquid diluents include, in addition to water, alcohols such as methanol, ethanol, isopropanol, n-butanol, amyl alcohol, octanol;
glycols such as propylene glycol, 1,3-butylene glycol, ethyl glycol, dipropylene glycol monomethyl ether;
glycerol;
aromatic alcohols such as benzyl alcohol;
carboxylic esters such as, for example, ethyl acetate, benzyl benzoate, butyl acetate, propylene carbonate, ethyl lactate;

Le A 33 S 15-Foreign Countries aliphatic hydrocarbons such as paraffins, cyclohexane, methylene chloride, ethylene chloride;
aromatic hydrocarbons such as xylene, toluene, alkylnaphthalenes, chlorobenzenes;
ketones such as, for example, acetone and methyl ethyl ketone, methyl isobutyl S ketone, cyclohexanone;
natural and synthetic mono- and triglycerides with natural fatty acids such as cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame seed oil;
furthermore dimethyl sulphoxide, dimethylacetamide, dimethylformamide, N-methylpyrrolidone, dioxane, 2,2-dimethyl-4-oxymethyl-1,3-dioxolane.
The surface-active substances include:
emulsifiers and wetters such as anionic surfactants, for example alkylsulphonates, alkyl sulphates, arylsulphonates, sodium lauryl sulphates, fatty alcohol ether sulphates, mono/dialkyl polyglycol ether orthophosphoric ester monoethanolamine 1 S salt, calcium alkylarylsulphonate;
cationic surfactants, for example, cetyltrimethylammonium chloride;
ampholytic surfactants, for example, disodium-N-lauryl-beta-iminodipropionate or lecithin;
nonionic surfactants, for example, polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, polyoxyethylated sorbitan monostearate, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, polyoxyethylated sorbitan monopalmitate, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxy-ethylene mannitan monolaurate, alkyl polyglycol ethers, oleyl polyglycol ether, dodecyl polyglycol ether, ethoxylated nonylphenol, isooctylphenolpolyethoxyethanol.
The preparations may additionally contain:
stickers, for example, carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyr-rolidone, polyvinyl alcohol, methyl vinyl ether/maleic anhydride copolymers, poly-ethylene glycols, paraffins, oils, waxes, hydrogenated castor oil, lecithins and synthetic phospholipids.

Le A 33 515-Foreign Countries The preparations may contain colorants such as inorganic pigments, for example iron oxide, titanium oxide, Prussian Blue and organic dyestuffs such'as alizarin, azo and metal phthalocyanin dyestuffs.
The preparations may contain spreaders, for example silicone oils of varying viscosity, fatty acid esters such as ethyl stearate, di-n-butyl adipate, hexyl laurate, di-propylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols C 16-C 1 g, isopropyl myristate, isopropyl palmitate, caprylic/capric esters of saturated fatty alcohols of chain length C 12-C 1 g, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid esters, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter, and the like;
triglycerides such as caprylic/capric acid triglyceride, triglyceride mixtures with vegetable fatty acids of chain length Cg-C12 or other specifically selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated, if appropriate also hydroxyl-containing fatty acids, monodiglycerides of the Cg-C 10 fatty acids and others;
fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.
To prepare solid preparations, the active compound is mixed with suitable carriers, if appropriate with addition of auxiliaries, and shaped as desired.
Carriers which may be mentioned are all physiologically acceptable solid inert materials. Inorganic and organic materials can be used. Inorganic materials are optionally crushed and fractionated, for example synthetic and natural rock meals such as kaolins, talc, chalk, quartz, diatomaceous earth, sodium chloride, carbonates such as calcium carbonate, hydrogen carbonates, aluminium oxides, silicas, clays, precipitated or colloidal silica, phosphates.

Le A 33 515-Foreign Countries Examples of organic materials are sugars, cellulose, foodstuffs and feedstuffs such as dry milk, animal meals, fine and coarse cereal meals, starches, sawdust.
Adjuvants are preservatives, antioxidants, colorants which have already been mentioned above.
Other suitable adjuvants are lubricants and glidants such as, for example, magnesium stearate, stearic acid, talc, bentonites, disintegrants such as starch or crosslinked polyvinylpyrrolidone, binders such as, for example, starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.
The active compounds in the form of their abovementioned solid or liquid formulations may also be present in encapsulated form.
The active compounds may also be applied in the form of an aerosol. To this end, the suitably formulated active compound is finely distributed under pressure.
It may also be advantageous to use the active ingredients in formulations which release the active compound in a delayed manner. Such formulations which may be mentioned are active-compound-containing shaped articles such as, for example, slabs, tapes, strips, collars, ear tags, tail tags, limb bands, halters, marking devices.
Active-compound-containing implants and boluses may also be mentioned in this context.
The active compounds may also be administered together with the feed and/or the drinking water.
The active compound according to the invention, in its preparations and in the use forms prepared from these preparations, may be present as a mixture with other active compounds such as insecticides, sterilants, bactericides, acaricides.
nematicides or fungicides. The insecticides include, for example, phosphoric esters, Le A 33 515-Forei~~n Countries carbamates, carboxylic esters, chlorinated hydrocarbons, phenylureas, nicotinyls, neonicotinyls, substances produced by microorganisms and the like.
Examples of particularly advantageous components in mixtures are the following:
Fungicides:
aldimorph, ampropylfos, ampropylfos-potassium, andoprim, anilazin, azaconazole, azoxystrobin, benalaxyl, benodanil, benomyl, benzamacril, benzamacryl-isobutyl, bialaphos, binapacryl, biphenyl, bitertanol, blasticidin-s, bromuconazole, bupirimate, buthiobate, calcium polysulphide, capsimycin, captafol, captan, carbendazim, carboxin, carvon, quinomethionate, chlobenthiazone, chlorfenazole, chloroneb, chloropicrin, chlorothalonil, chlozolinate, clozylacon, cufraneb, cymoxanil, cyproconazole, cyprodinil, cyprofuram, debacarb, dichlorophen, diclobutrazole, diclofluanid, diclomezin, dicloran, di-ethofencarb, difenoconazole, dimethirimol, dimethomorph, diniconazole, diniconazole-M, dinocap, diphenylamine, dipyrithione, ditalimfos, dithianon, dodemorph, dodine, drazoxolon, ediphenphos, epoxiconazole, etaconazole, ethirimol, etridiazole, famoxadon, fenapanil, fenarimol, fenbuconazole, fenfuram, fenitropan, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone, flu-azinam, flumetover, fluoromid, fluquinconazole, flurprimidol, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, fosetyl-aluminium, fosetyl-sodium, fthalide, fuberidazole, furalaxyl, furametpyr, furcarbonil, furconazole, furconazole-cis, furmecyclox, guazatine, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imibenconazole, iminoctadine, iminoctadine-albesilate, iminoctadine triacetate, iodocarb, ipconazole, iprobenfos (IBP), iprodione, irumamycin, isoprothiolane, isovaledione, Le A 33 515-Foreign Countries kasugamycin, kresoxim-methyl, copper preparations such as: copper hydroxide, copper naphthenate, copper oxychloride, copper sulphate, copper oxide, oxine-copper and Bordeaux mixture, mancopper, mancozeb, maneb, meferimzone, mepanipyrim, mepronil, metalaxyl, metconazole, methasulfocarb, methfuroxam, metiram, metomeclam, metsulfovax, mildiomycin, myclobutanil, myclozolin, nickel dimethyldithiocarbamate, nitrothal-isopropyl, nuarimol, ofurace, oxadixyl, oxamocarb, oxolinic acid, oxycarboxim, oxyfenthiin, paclobutrazole, pefurazoate, penconazole, pencycuron, phosdiphen, pimaricin, piperalin, polyoxin, polyoxorim, probenazole, prochloraz, procymidon, propamocarb, propanosine-sodium, propiconazole, propineb, pyrazophos, pyrifenox, pyrimethanil, pyroquilon, pyroxyfur, quinconazole, quintozene (PCNB), sulphur and sulphur preparations, tebuconazole, tecloftalam, tecnazene, tetcyclacis, tetraconazole, thiabendazole, thi-cyofen, thifluzamide, thiophanate-methyl, thiram, tioxymid, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazbutil, triazoxide, trichlamide, tricyclazole, tridemorph, triflumizole, triforine, triticonazole, uniconazole, validamycin A, vinclozolin, viniconazole, zarilamid, zineb, ziram and dagger G, OK-8705, OK-8801, a-(1,1-dimethylethyl)-13-(2-phenoxyethyl)-1H-1,2,4-triazole-1-ethanol, a-(2,4-dichlorophenyl)-13-fluoro-b-propyl-I H-1,2,4-triazole-I-ethanol, a-(2,4-dichlorophenyl)-(3-methoxy-a-methyl-1 H-1,2,4-tri azole-1-ethanol, a-(5-methyl-1,3-dioxan-5-yl)-13-[[4-(trifluoromethyl)-phenyl]-methylene]-1 H-1,2,4-triazole-1-ethanol, (SRS,6RS)-6-hydroxy-2,2,7,7-tetramethyl-5-(1H-1,2,4-triazol-1-yl)-3-octanone, (E)-a-(methoxyimino)-N-methyl-2-phenoxy-phenylacetamide, Le A 33 515-Foreign Countries 1-isopropyl {2-methyl-1-[[[1-(4-methylphenyl)-ethyl]-amino]-carbonyl]-propyl}-carbamate, 1-(2,4-dichlorophenyl)-2-(1H-1,2;4-triazol-1-yl)-ethanone O-(phenylmethyl)-oxime, 1-(2-methyl-I-naphthalenyl)-1 H-pyrrole-2,5-dione, S 1-(3,5-dichlorophenyl)-3-(2-propenyl)-2,5-pyrrolidinedione, 1-[(diiodmethyl)-sulphonyl]-4-methyl-benzene, 1-[[2-(2,4-dichlorophenyl)-1,3-dioxolan-2-yl]-methyl]-I H-imidazole, 1-[[2-(4-chlorophenyl)-3-phenyloxiranyl]-methyl]-1 H-1,2,4-triazole, 1-[ 1-[2-[(2,4-dichlorophenyl)-methoxy]-phenyl]-ethenyl]-1 H-imidazole, I -methyl-5-nonyl-2-(phenylmethyl)-3-pyrrolidinol, 2',6'-dibromo-2-methyl-4'-trifluoromethoxy-4'-trifluoro-methyl-1,3-thiazole-5-carboxanilide, 2,2-dichloro-N-[ 1-(4-chlorophenyl)-ethyl]-1-ethyl-3-methyl-cyclopropanecarbox-am ide, 2,6-dichloro-S-(methylthio)-4-pyrimidinyl thiocyanate, 2,6-dichloro-N-(4-trifluoromethylbenzyl)-benzamide, 2,6-dichloro-N-[[4-(trifluoromethyl)-phenyl]-methyl]-benzamide, 2-(2,3,3-triiodo-2-propenyl)-2H-tetrazole, 2-[( 1-methylethyl)-sulphonyl]-5-(trichloromethyl)-1,3,4-thiadiazole, 2-[[6-deoxy-4-O-(4-O-methyl-l3-D-glycopyranosyl)-a-D-glucopyranosylJ-amino]-4-methoxy-1 H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile, 2-aminobutane, 2-bromo-2-(bromomethyl)-pentanedinitrile, 2-chloro-N-(2,3-dihydro-1,1,3-trimethyl-1 H-inden-4-yl)-3-pyridinecarboxamide, 2-chloro-N-(2,6-dimethylphenyl)-N-(isothiocyanatomethyl)-acetamide, 2-phenylphenol (OPP), 3,4-dichloro-1-[4-(difluoromethoxy)-phenyl]-1 H-pyrrole-2,5-dione, 3,5-dichloro-N-[cyano[( 1-methyl-2-propynyl)-oxy]-methyl]-benzamide, 3-( 1,1-dimethylpropyl-1-oxo-1 H-indene-2-carbonitrile, 3-[2-(4-chlorophenyl)-5-ethoxy-3-isoxazolidinyl]-pyridine, 4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)- I H-imidazole-1-sulphonamide, Le A 33 51 S-Foreign Countries 4-methyl-tetrazolo[ 1,5-a]quinazolin-5(4H)-one, 8-( 1,1-dimethylethyl)-N-ethyl-N-propyl-1,4-dioxaspiro[4.5]decane-2-methanamine, 8-hydroxyquinoline sulphate, 9H-xanthene-9-carbo-2-[(phenylamino)-carbonyl]-hydrazide, bis-( 1-methylethyl)-3-methyl-4-[(3-methylbenzoyl)-oxy]-2,5-thiophenedicarboxylate, cis-1-(4-chlorophenyl)-2-( 1 H-1,2,4-triazol-1-yl)-cycloheptanol, cis-4-[3-[4-( 1,1-dimethylpropyl)-phenyl-2-methylpropyl]-2,6-dimethyl-morpholine hydrochloride, ethyl-[(4-chlorophenyl)-azo]-cyanoacetate, potassium hydrogencarbonate, the sodium salt of methanetetrathiol, methyl 1-(2,3-dihydro-2,2-dimethyl-1 H-inden-1-yl)-1 H-imidazole-5-carboxylate, methyl N-(2,6-dimethylphenyl)-N-(5-isoxazolylcarbonyl)-DL-alaninate, methyl N-(chloroacetyl)-N-(2,6-dimethylphenyl)-DL-alaninate, N-(2,3-dichloro-4-hydroxyphenyl)-1-methyl-cyclohexanecarboxamide, N-(2,6-dimethylphenyl)-2-methoxy-N-(tetrahydro-2-oxo-3-furanyl)-acetamide, N-(2,6-dimethylphenyl)-2-methoxy-N-(tetrahydro-2-oxo-3-thienyl)-acetamide, N-(2-chloro-4-nitrophenyl)-4-methyl-3-nitro-benzenesulphonamide, N-(4-cyclohexylphenyl)-1,4,5,6-tetrahydro-2-pyrimidineamine, N-(4-hexylphenyl)-1,4,5,6-tetrahydro-2-pyrimidineamine, N-(5-chloro-2-methylphenyl)-2-methoxy-N-(2-oxo-3-oxazolidinyl)-acetamide, N-(6-methoxy)-3-pyridinyl)-cyclopropanecarboxamide, N-[2,2,2-trichloro-1-[(chloroacetyl)-amino]-ethyl]-benzamide, N-[3-chloro-4,5-bis-(2-propinyloxy)-phenyl]-N'-methoxy-methaneimidamide, the sodium salt of N-formyl-N-hydroxy-DL-alanine, O,O-diethyl [2-(dipropylamino)-2-oxoethylJ-ethylphosphoramidothioate, O-methyl S-phenyl phenylpropylphosphoramidothioates, S-methyl 1,2,3-benzothiadiazole-7-carbothioate, spiro[2H]-1-benzopyran-2, l'(3'H)-isobenzofuran]-3'-one.
Bactericides:

Le A 33 S 15-Foreien Countries bronopol, dichlorophen, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone, furancarboxylic acid, oxytetracyclin, probenazole, streptomycin, teclofta-lam, copper sulphate and other copper preparations.
S Insecticides / acaricides / nematicides:
abamectin, acephate, acetamiprid, acrinathrin, alanycarb, aldicarb, aldoxycarb, alphacypermethrin, alphamethrin, amitraz, avermectin, AZ 60541, azadirachtin, azamethiphos, azinphos A, azinphos M, azocyclotin, Bacillus popilliae, Bacillus sphaericus, Bacillus subtilis, Bacillus thuringiensis, baculoviruses, Beauveria bassiana, Beauveria tenella, bendiocarb, benfuracarb, ben sultap, benzoximate, betacyfluthrin, bifenazate, bifenthrin, bioethanomethrin, biopermethrin, BPMC, bromophos A, bufencarb, buprofezin, butathiofos, buto carboxim, butylpyridaben, cadusafos, carbaryl, carbofuran, carbophenothion, carbosulfan, cartap, chloethocarb, chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron, chlormephos, chlorpyrifos, chlorpyrifos M, cis-resmethrin, cispermethrin, clocythrin, cloethocarb, clofentezine, cyanophos, cycloprene, cycloprothrin, cyfluthrin, cyhalothrin, cyhexa tin, cypermethrin, cyromazin, cymiazole, deltamethrin, demeton M, demeton S, demeton-S-methyl, diafenthiuron, diazinon, dichlorvos, diflubenzuron, dimethoate, dimethylvinphos, diofenolan, disulfoton, docusate sodium, dofenapyn, efusilanate, emamectin, empenthrin, endosulfan, Entomopfthora spp., esfenvalerate, ethiofencarb, ethion, ethoprophos, ethofenprox, etoxazole, etrimphos, fenamiphos, fenazaquin, fenbutatin oxide, fenitrothion, fenothiocarb, fenoxacrim, fenoxycarb, fenpropathrin, fenpyrad, fenpyrithrin, fenpyroximate, fenvalerate, fipronil, fluazinam, fluazuron, flubrocythrinate, flucycloxuron, flucythrinate, flufenoxuron, flumethrin, flutenzine, fluvalinate, fonophos, fosmethilan, fosthiazate, fubfenprox, furathiocarb, granulosis viruses halofenozide, HCH, heptenophos, hexaflumuron, hexythiazox, hydroprene, imidacloprid, indoxacarb, isazofos, isofenphos, isoxathion, ivermectin, Le A 33 515-Foreign Countries nuclear polyhedrosis viruses lambda-cyhalothrin, lufenuron, malathion, mecarbam, metaldehyde, methamidophos, Metharhizium anisopliae, Metharhizium flavoviride, methidathion, methiocarb, methomyl, methoxyfenozide, metolcarb, mevinphos, milbemectin, monocrotophos, naled, nitenpyram, nithiazine, novaluron, omethoate, oxamyl, oxydemethon M, Paecilomyces fumosoroseus, parathion A, parathion M, permethrin, phenthoat, phorat, phosalone, phosmet, phosphamidon, phoxim, pirimicarb, pirimiphos M, pirimiphos A, profenofos, promecarb, propoxur, prothiofos, prothoat, pymetrozine, pyraclofos, pyresmethrin, pyrethrum, pyridaben, pyridathion, pyrimidifen, quinalphos, ribavirin, salithion, sebufos, silafluofen, spinosad, sulfotep, sulprofos, 1 S tau-fluvalinate, tebufenozide, tebufenpyrad, tebupirimiphos, teflubenzuron, tefluthrin, temephos, temivinphos, terbufos, tetrachlorvinphos, theta-cypermethrin, thiamethoxam, thiapronil, thiatriphos, thiocyclam hydrogen oxalate, thiodicarb, thiofanox, thuringiensin, tralocythrin, tralomethrin, triarathene, triazamate, thriazophos, triazuron, trichlophenidine, trichlorfon, triflumuron, trimethacarb, vamidothion, vaniliprole, Verticillium lecanii, YI 5302, zeta-cypermethrin, zolaprofos, ( 1 R-cis)-[5-(phenylmethyl)-3-furanyl)-methyl-3-[(dihydro-2-oxo-3(2H)-furanyli-dene)-methyl)-2,2-dimethylcyclopropanecarboxylate (3-phenoxyphenyl)-methyl-2,2,3,3-tetramethylcyclopropanecarboxylate 1-[(2-chloro-5-thiazolyl)methyl)tetrahydro-3,5-dimethyl-N.-nitro-1,3,5-triazine-2( 1 H)-imine 2-(2-chloro-6-fluorophenyl)-4-[4-( 1,1-dimethylethyl)phenyl]-4,5-dihydro-oxazole 2 -(acetyloxy)-3-dodecyl-1,4-naphthalenedione 2-chloro-N-[[[4-(1-phenylethoxy)-phenyl]-amino)-carbonyl]-benzamide Le A 33 515-Foreign Countries 2-chloro-N-[[[4-(2,2-dichloro-l, I-difluoroethoxy)-phenyl]-amino]-carbonyl]-benzamide 3-methylphenyl-propylcarbamate 4-[4-(4-ethoxyphenyl)-4-methylpentyl]- I -fluoro-2-phenoxy-benzene 4-chloro-2-(I,I-dimethylethyl)-5-[[2-(2,6-dimethyl-4-phenoxyphenoxy)ethyl]thio]-3(2H)-pyridazinone 4-chloro-2-(2-chloro-2-methylpropyl)-5-[(6-iodo-3-pyridinyl)methoxy]-3(2H)-pyridazinone 4-chloro-5-[(6-chloro-3-pyridinyl)methoxy]-2-(3,4-dichlorophenyl)-3(2H)-pyridazinone Bacillus thuringiensis strain EG-2348 [2-benzoyl-1-( 1,1-dimethylethyl)]-benzohydrazide 2,2-dimethyl-3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4,5]dec-3-en-4-yl butanoate [3-[(6-chloro-3-pyridinyl)methyl]-2-thiazolidinylidene]-cyanamide dihydro-2-(nitromethylene)-2H-1,3-thiazine-3(4H)-carboxaldehyde ethyl [2-[[1,6-dihydro-6-oxo-(phenylmethyl)-4-pyridazinyl)oxy]ethyl]-carbamate N-(3,4,4-trifluoro-1-oxo-3-butenyl)-glycine N-(4-chlorophenyl)-3-[4-(difluoromethoxy)phenyl]-4,5-dihydro-4-phenyl-I H-pyrazole-1-carboxamide N-[(2-chloro-S-thiazolyl)methyl]-N'-methyl-N"-nitro-guanidine N-methyl-N'-( I -methyl-2-propenyl)-1,2-hydrazinedicarbothioamide N-methyl-N'-2-propenyl-1,2-hydrazinedicarbothioamide 0,0-diethyl [2-(dipropylamino)-2-oxoethyl]-ethylphosphoramidothioate Furthermore, the active compounds according to the invention may be present, in their commercially available formulations and in the use forms prepared from these formulations, as a mixture with synergists. Synergists are compounds by which the action of the active compounds is increased without it being necessary for the synergist added to be active itself.

Le A 33 515-Foreign Countries Directly applied formulations contain between 10-~ and 5 per cent by weight, preferably between 10-4 and 1 per cent by weight of active compound.
Formulations which are applied only after further dilution contain 1 to 95 per cent by weight, preferably S to 90 per cent by weight of active compound.

Le A 33 515-Foreign Countries f .
The preparation and the use of the active compounds according to the invention can be seen from the examples which follow.
Preparation Examples A 9:1 mixture of avermectin B 1 a/B 1 b was used for the experiments.
Example II-1 4"-0-Ethoxycarbonylmethyl-5-O-Alloc-7-O-trimethylsilyl-avermectin B1 4.67 g (4.5 m) of 5-O-Alloc-7-O-trimethylsilyl-avermectin B 1 were dissolved in 47 ml of dry dichloromethane, and 2.5 g (22 m) of diazoacetic ester, dissolved in 14 ml of dichloromethane, were added at 0°C. 81 mg {0.45 m) of tetrafluoroboric 1 S acid/diethyl ether complex, dissolved in 2 ml of dichloromethane, were subsequently added dropwise and the mixture was stirred for two hours at room temperature.
Then, another 81 mg (0.45 m) of tetrafluoroboric acid/diethyl ether complex, dissolved in 2 ml of dichloromethane, were added dropwise and stirring was continued for one hour at room temperature. The conversion rate was approximately 50%. For work-up, the mixture was poured into 5% strength NaH2P04 solution, and the organic phase was separated off and reextracted once with dichloromethane. The combined extracts were dried with Na2S04 and evaporated.
Crude yield: 5.41 g For purification, the product was chromatographed over silica gel (column 30 x 8 cm) with hexane/ethyl acetate 4:1 (v/v). Fractionation was done generously in order to separate a product which eluted virtually uniformly.
Yield: 1.25 g of 4"-0-ethoxycarbonylmethyl-5-O-Alloc-7-O-trimethylsilyl-avermectin B 1 (25% of theory based on starting material employed) Purity: 90% (HPLC area) Le A 33 515-Foreign Countries a Example II-2 4"-0-Ethoxycarbonylmethyl-7-O-trimethylsilyl-avermectin B 1 1.2 g ( 1.1 m) of 4"-0-ethoxycarbonylmethyl-5-O-Alloc-7-O-trimethylsilyl-avermectin B 1 were dissolved in 6.3 ml of analytical-grade ethanol, the solution was degassed with argon, 12.8 mg (0.011 m) of tetrakis-(triphenylphosphine)-palladium (0) were added at 0°C, and 83.5 mg (2.2 m) of NaBH4 were added in three portions. After 20 minutes at 0°C, the reaction was complete. For work-up, the mixture was poured into NaH2P04 solution and extracted three times with ether. The combined extracts were dried with sodium sulphate and evaporated.
Residue: 0.96 g For purification, the product was chromatographed on silica gel with dichloromethane/ethyl acetate 9:1 (v/v).
Yield: 0.54 g (50% of theory) of 4"-0-ethoxycarbonylmethyl-7-O-trimethylsilyl-aver-mectin B 1 Examule II-3 4"-0-Carbamovlmethyl-7-O-trimethylsilyl-avermectin B1 640 mg (0.62 m) of 4"-0-ethoxycarbonylmethyl-7-O-trimethylsilyl-avermectin B 1 were dissolved in 3.2 ml of methanol, 3.2 ml of ammonia-saturated methanol and 130 mg of ammonium acetate were added. The mixture was stirred for S hours at room temperature. While the conversion was not complete yet, decomposition products were already clearly visible. For work-up, the mixture was poured into 20 ml of 5% sodium dihydrogen phosphate solution, and the organic phase was separated off and reextracted three times with ether. The combined extracts were dried with sodium sulphate and evaporated in vacuo.

Le A 33 515-Foreign Countries _57_ For purification, the product was chromatographed on silica gel. Mobile phase:
first ethyl acetate/dichloromethane 1:1 (v/v) for recovering the starting material, thereuopon ethyl acetate/dichloromethane 2:1 (v/v) for separating off a by-product, and then pure ethyl acetate for eluting the desired product.
Yield: 130 mg (21% of theory) of 4"-0-carbamoylmethyl-7-O-trimethylsilyl-aver-mectin B 1 Example I-1 4"-0-Carbamoylmethyl-avermectin B 1 500 mg ( 17.5 m) of hydrogen fluoride/pyridine complex, 10 ml of THF and 2.5 ml (31 m) of pyridine were mixed, and a solution of 409 mg {0.41 m) of 4"-0-carbamoylmethyl-7-O-trimethylsilyl-avermectin B 1 in 2 ml of THF was added with ice-cooling. The mixture was stirred for 30 minutes at 0°C and then for another 24 hours at room temperature. For work-up, the mixture was poured into 50 ml of saturated bicarbonate solution, and the organic phase was separated off and reextracted three more times with ether. The combined extracts were dried with sodium sulphate and evaporated in vacuo on a rotary evaporator. The residue was stirred with a little ether, during which process it crystallized.
Yield: 270 mg of 4"-0-carbamoylmethyl-avermectin B 1 (71 % of theory) Le A 33 515-Foreign Countries Preparation of the starting materials and intermediates Starting materials for the preparation of the compounds described are ultimately the above-stated avermectin fermentation products. Other avermectin derivatives with alpha-branched alkyl or alkenyl groups in the 25 position, designated R2 in formula (I), have been described in EP-A-214 731, EP-A-276 131 and EP-A-276 103. Other starting materials have a 22-23 single bond. Their preparation by reducing fermentation products is described in US-A-4,199,569 Example III-1

5-O-Alloc-7-O-trimethylsilyl-avermectin B 1 Quantity Moles Text 3.4 g 3.55 m of 5-Alloc avermectin B1 (R.J.Cvetovich, D.H. Kelly, L.M. DiMichele, R.F. Shuman and E.J.J. Grabowski J.Org.Chem. 59 (1994) 7704-7708) were dissolved in 10 ml of dry DMF in argon and 10 ml 37.6 m of bis-(trimethylsilyl)-trifluoroacetamide were added.
Thereupon, the mixture was warmed for 3.5 hours at 60 degrees. The mixture was subsequently transferred into a larger flask, 100 ml of dry toluene were added and the mixture was evaporated to dryness at 40 mb/ 50 degrees. This procedure was repeated twice more.
85 ml of THF, 36 ml of glacial acetic acid and Le A 33 515-Foreign Countries .
Quantity Moles Text 17 ml ~ Of water were added to the residue. The mixture was stirred at room temperature. After approximately 2.5 hours, the reaction was complete (TLC: silica gel, hexane/ethyl acetate 50:50 (v/v). The mixture was then evaporated to dryness, the residue was treated with 20 ml Of dichloromethane, and this was added carefully to 200 ml Of saturated bicarbonate solution. After the mixture had been stirred for five minutes, the phases were separated in a separating funnel, and the aqueous phase was reextracted with dichloromethane. The combined organic phases were washed with 100 ml Of bicarbonate solution, dried with Na2S04 and evaporated. For purification, the product was chromatographed on silica gel.

Column: 5 x 22 cm, eluted with hexane/ethyl acetate:

900 ml 20:10 900 ml 60:40 400 ml 50:50 Yield: 3.03 g (83% of theory) of 5-O-Alloc-7-O-tri-methylsilyl-avermectin Bl, white foam, according to HPLC:
91.8% 5-Alloc-7-trimethylsilyl-avermectin-B 1 a 7.2% 5-Alloc-7-trimethylsilyl-avermectin-Blb Le A 33 515-Foreign Countries S

Example VI-2 5-Phenox~e~l-averrnectin B 1 Quantity Moles Text 2 g 2.3 m avermectin B 1 were dissolved in 10.2 ml of methyl tert-butyl ether under argon and cooled to -15 °C. Then, 0.37 ml 2.47 m of tetramethyl-ethylenediamine and subsequently 0.36 ml 2.65 m of phenoxyacetyl chloride were added. Stirnng was continued for 60 minutes at -10°C. For work-up, the mixture was poured into a 5% sodium dihydrogenphosphate solution, and the organic phase was separated off and reextracted. The combined organic phases were then washed with saturated sodium bicarbonate solution, dried with sodium sulphate and evaporated.
Yield: 2.11 g of 5-phenoxyacetyl-avermectin B 1 Le A 33 515-Foreign Countries Example III-2 5-Phenoxyacetyl-7-trimethYlsilyT-avermectin B 1 Quantity Moles Text 2.1 g 2.1 m of 5-phenoxyacetyl-avermectin B 1 were dissolved in

6 ml of dry DMF under argon and 6 ml 21 m of bis-(trimethylsilyl)-trifluoroacetamide were added.
The mixture was thereupon warmed for 4 hours at 40°C. The mixture was subsequently transferred into a larger flask, 60 ml of dry toluene were added, and the mixture was evaporated to dryness at 40 mb/ 50 degrees. This procedure was repeated twice more.
51 ml of THF, 21 ml of glacial acetic acid and ml of water were added to the residue. The mixture was stirred for 2 hours at room temperature and then stored overnight in a freezer at -15°C. Thereafter, the reaction was complete. (TLC: silica gel, hexane/ethyl acetate 50:50 (v/v). The mixture was evaporated to dryness, the residue was treated with ml of dichloromethane and the mixture was added carefully to 200 ml of saturated bicarbonate solution. The mixture was extracted three times with ether. The combined organic phases were washed with 100 ml of bicarbonate solution, dried with Na2S04 and evaporated.

Le A 33 515-Foreign Countries Yield: 2.5 g of 5-phenoxyacetyl-7-O-trimethylsilyl-avermectin B 1 ' Le A 33 515-Foreign Countries ' , -63-Examples of the biological action Example 1 Blowfly larvae test / development-inhibitory action Test animals: Lucilia cuprina larvae ( 1 st-3rd instar) Solvent: Dimethyl sulphoxide 20 mg of active compound are dissolved in one ml of dimethyl sulphoxide. To produce a suitable formulation, the active compound solution is diluted with water to the concentration desired in each case.
Approximately 20 Lucilia cuprina larvae are introduced into a test tube which contains 1 cm3 of horse meat and 0.5 ml of the active compound preparation to be tested. After 24 and 48 hours, the efficacy of the active compound preparation is determined. The test tubes are transferred into beakers whose bottoms are covered with sand. After a further 2 days, the test tubes are removed and the pupae are counted.
The action of the active compound preparation is assessed with reference to the number of the hatched flies after 1.5 times the development time of an untreated control. 100% means that no flies have hatched; 0% means that all flies have hatched normally.
In this test, an activity of 100% is shown, for example, by the compound of Example I-1 in an exemplary concentration of 1 ppm.

Le A 33 515-Foreign Countries , _64_ Example 2 Test with resistant one-host cattle ticks / SP-resistant Parkhurst strain Test animals: Adult sucked Boophilus microplus females (strain Parkhurst /
SP-resistant) Solvent: Dimethyl sulphoxide 20 mg of active compound are dissolved in one ml of dimethyl sulphoxide. To produce a suitable formulation, the active compound solution is diluted with water to the concentration desired in each case.
10 adult resistant Boophilus microplus are immersed for 1 minute in the active compound preparation to be tested. After the animals have been transferred into plastic beakers and stored in a controlled-environment chamber (28°C, relative atmospheric humidity 85%), the degree of destruction or the inhibitory effect on oviposition are determined after 10 days.
100% means that all the ticks have been destroyed or that no eggs have been laid; 0%
means that no ticks have been destroyed and that oviposition was normal in comparison with the control.
In this test, an activity of 100% is shown, for example, by the compound of Example I-1 in an exemplary concentration of 1 ppm.

Le A 33 515-Foreign Countries ' -65-Example 3 Fly test (Musca domestics) Test animals: Adult Musca domestics, strain WHO(N) (sensitive) Solvent: Dimethyl sulphoxide 20 mg of active compound are dissolved in one ml of dimethyl sulphoxide. To produce a suitable formulation, the active compound solution is diluted with water to the concentration desired in each case.
2 ml of this active compound preparation are pipetted onto filter paper dishes (~ 9.5 cm) located in Petri dishes of a suitable size. After the filter discs had dried, small sponges (approx. 1.5*1.5 cm) soaked in sugar water and located in tablet 1 S blister packs of ~ 2 cm are transferred, and 100 pl of the active compound preparation are pipetted onto the sponges. 25 test animals are subsequently anaesthetized with C02, transferred into the Petri dishes and covered.
The efficacy of the active compound preparation is determined after l, 3, 5 and 24 hours. 100% means that all the flies hatched have been destroyed; 0% means that none of the flies have been destroyed.
In this test, an activity of 100% is shown, for example, by the compound of Example I-1 in an exemplary concentration of 1 ppm.

Claims

1. Compounds of the formula (I) in which the broken bond between positions 22 and 23 represents a single or double bond, in the event of a single bond R1 represents hydrogen, hydroxyl or, together with the carbon atom in position 23, represents a carbonyl group, in the case of a double bond R1 represents hydrogen, R2 represents an in particular alpha-branched C1-C8-alkyl or alkenyl group, or a C3-C8-cycloalkyl group, R3 represents hydroxyl, C1-C6-alkyloxy, C1-C6-alkanoyloxy or, together with the carbon atom in position 5, represents a hydroximino or C1-C6-alkoximino group, R4 represents the radicals in which R5 represents H, branched or unbranched C1-C4-alkyl which can optionally be substituted by alkoxy, alkylamino, halogen and hydroxyl groups, mouse click R6 represents H, branched or unbranched C1-C4-alkyl, aryl or aralkyl, each of which can optionally be substituted by alkoxy, alkylamino, halogen and hydroxyl groups, R7 and R8 independently of one another represent H, branched or unbranched C1-C4-alkyl which can optionally be substituted by alkoxy, alkylamino, halogen and hydroxyl groups, or R7 and R8 together with the nitrogen to which they are bonded form a heterocyclic ring with 5 to 7 ring members having, if appropriate, 1 to 2 further hetero atoms from the group consisting of oxygen, sulphur or nitrogen.

2. Compounds of the formula (I) according to Claim 1 in which the broken bond between positions 22 and 23 represents a single or double bond, R1 represents hydrogen, R2 represents an alpha-branched C3-C8-alkyl or alkenyl group, R3 represents a hydroxyl, C1-C4-alkyloxy, C1-C4-alkanoyloxy, hydroximino or C1-C4-alkoximino group, R4 represents the radicals R5 represents H, branched or unbranched C1-C4-alkyl, R6 represents H, branched or unbranched C1-C4-alkyl, aryl or aryl-C1-C4-alkyl, R7 and R8 independently of one another represent H, branched or unbranched C1-C4-alkyl, R7 and R8, where furthermore can form a heterocyclic ring having 5 to 7 ring members with, if appropriate, oxygen, sulphur or nitrogen as hetero atoms.

Compounds of the formula (I) according to Claim 1 in which the broken bond between positions 22 and 23 especially preferably represents a single or double bond, R1 represents hydrogen, R2 represents isopropyl, sec-butyl or an alpha-branched C3-C8-alkenyl group, R3 represents hydroxyl, R4 represents the following radicals R5 represents H, methyl and ethyl, R6 represents H, methyl, ethyl or benzyl, R7 and R8 independently of one another represent H, methyl, ethyl or isopropyl, it being possible for R7 and R8 furthermore to form a heterocyclic ring having 5 to 6 ring members with, if appropriate, oxygen or nitrogen as hetero atoms.

4. Process for the preparation of compounds of the formula (I) according to Claim 1, characterized in that a) starting with compounds of the formula (IIa) in which the radicals R1, R2 and R4 have the meanings mentioned in Claim 1 and R3a represents hydroxyl-, C1-C6-alkyloxy- or C1-C6-alkanoyloxy, -SiMe3 is eliminated by reaction with HF in pyridine, or, b) starting with compounds of the formula (IIb) in which the radicals R1, R2 and R4 have the meanings mentioned in Claim 1 and R3b represents a protecting group from the series O-TBDMS (tert-butyl-dimethylsilyl) or, only in the event that R4 represents the radical R3b represent O-Alloc, either a) in the event that R3b is O-TBMDS, both protecting groups are eliminated in one step by reaction with HF in pyridine, or .beta.) in the event that R3b is O-Alloc, the latter is removed by means of NaBH4/Pd(O) and -SiMe3 is eliminated by reaction with HF in pyridine, the sequence being of no importance, or c) compounds of the formula (IIc) in which the radicals R1 and R2 have the meanings mentioned in Claim l, R4 represents the radical and R3c represents a group from the series hydroxyl, O-phenoxyacetyl or O-methoxyacetyl, are reacted with amines of the formula (V) in which R7 and R8 have the meanings mentioned in Claim l, and -SiMe3 is subsequently eliminated by reaction with HF in pyridine, or d) compounds of the formula (Ia) in which the radicals R1 and R2 have the meanings mentioned in Claim 1 are reacted with amines of the formula (V) in which R7 and R8 have the meanings mentioned in Claim l, or e) compounds of the formula (Ia1) in which the radicals R1, R2 and R4 have the meanings mentioned in Claim l, are oxidized in a first step to give compounds of the formula (VII) in which R1, R2 and R4 have the meanings mentioned in Claim 1, and these are subsequently reacted in a second step with compounds of the formula (VIII) where R9 represents hydroxyl, O-SiMe3 or C1-C6-alkoxy.

5. Compounds of the formula (II) in which R1, R2 and R4 have the meanings mentioned in Claim 1, R3g represents hydroxyl-, C1-C6-alkyloxy- or C1-C6-alkanoyloxy-, O-TBDMS, and, only in the event that R4 represents , represents O-Alloc, O-phenoxyacetyl or O-methoxyacetyl.

6. Process for the preparation of compounds of the formula (II), characterized in that compounds of the formula (III) in which R1 and R2 have the meanings mentioned in Claim 1, R3g1 represents C1-C6-alkyloxy-, C1-C6-alkanoyloxy-, O-Alloc, O-TBDMS, O-phenoxyacetyl or O-methoxyacetyl, are reacted with diazo compounds of the formula (IV) in which R5 and R6 have the meanings mentioned Claim 1, and subsequently in the event that R3g1 represents C1-C6-alkyloxy-, C1-C6-alkanoyloxy-, O-TBDMS, O-phenoxyacetyl or O-methoxyacetyl, the product is optionally reacted with compounds of the formula (V) in which R7 and R8 have the meanings mentioned in Claim l, or in the event that R3g1 represents O-Alloc, the latter is removed with NaBH4/Pd(O), if appropriate, and, if appropriate, the product is subsequently reacted with compounds of the formula (V) in which R7 and R8 have the meanings mentioned in Claim 1.

7. Compounds of the formula (III) in which R1 and R2 have the meanings mentioned in Claim 1, R3g' represents C1-C6-alkyloxy-, C1-C6-alkanoyloxy-, O-Alloc, O-phenoxyacetyl or O-methoxyacetyl.

8. Process for the preparation of compounds of the formula (III), characterized in that, in the compounds of the formula (VI) in which R1 and R2 have the meanings mentioned in Claim 1 and R31 represents hydroxyl, C1-C6-alkyloxy-, C1-C6-alkanoyloxy-, the hydroxyl group designated OH1 is provided with a trimethylsilyl protecting group, and, in the event that R31 likewise represents a hydroxyl group, the latter is, in a second step, likewise provided with a protecting group from the series Alloc, TBDMS, phenoxyacetyl or methoxyacetyl.

9. Compounds of the formula (VII) in which R1, R2 and R4 have the meanings mentioned in Claim 1.

10. Composition, characterized by a content of at least one compound of the formula (I) according to Claim 1.

11. Use of compounds of the formula (I) according to Claim 1 for the preparation of compositions for controlling ektoparasites and endoparasites on animals.

12. Process for the preparation of compositions for controlling ektoparasites and endoparasites on animals, characterized in that compounds of the formula (I) according to Claim 1 are mixed with extenders and/or surface-active substances