EP1169328A2

EP1169328A2 - Avermectin derivatives

Info

Publication number: EP1169328A2
Application number: EP00925111A
Authority: EP
Inventors: Werner Hallenbach; Achim Harder; Andreas Turberg; Olaf Hansen; Georg Von Samson-Himmelstjerna
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1999-03-25
Filing date: 2000-03-13
Publication date: 2002-01-09
Also published as: WO2000058328A3; AU4394700A; CN1345327A; DE19913534A1; BR0009285A; HK1045698A1; CA2368465A1; WO2000058328A2; JP2002540214A

Abstract

The invention relates to novel avermectin derivatives of formula (I), in which R?1, 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

Avermectin derivatives

The present invention relates to new avermectin derivatives, processes for their preparation, compositions containing them and their use for the preparation of compositions for controlling endo- and ectoparasites on animals.

The term avermectine describes a series of substances that are formed during the fermentation of the microorganism Streptomyces avermitilis. They belong to the group of macrolides and show anthelmintic, anti-parasitic and insecticidal properties. The general structure of the substance class is as follows:

The dashed bond between positions 22 and 23 indicates a single or double bond. In the case of a single bond, Z ¹ can be hydrogen or

Hydroxy, with a double bond only hydrogen. Z ² can be isopropyl or sec

Butyl and Z ^{3 be} methoxy or hydroxy. To identify this structural

REPLACEMENT B π (RULE 26) The isolated natural products were given the names according to the following table.

The compounds are usually iissoolliieerrtt as mixtures of the a and b components from ddeenn FFeerrmmeennttaattiioonnssbbrrüühheenn .. TThhee SSttrruukkttuurrvvaaririation has the substituents Z ² has little effect on the biological activity.

In addition to these natural products, other derivatives are known in the literature which have been produced by influencing the fermentation conditions, changing the microorganism or chemical modification (from Fisher, MH; Mrozik, H. in Macrolide Antibiotics; Omura, S., Ed., Academic Press , New York (1984); Davis, HG; Green, RH; Nat.Prod.Rep., (1986), 3, 87-121; Fisher, MH in Pest Control with Enhanced Environmental Safety, ACS Symposion Series 524; Duke, SO; Menn, JJ; Plimmer, JR Eds; American Chemical Society, Washington

(1993).

However, the known compounds show unsatisfactory activity against the parasites to be controlled, especially when small amounts are applied.

SPARE BLADE (RULE 26) New compounds of the formula (I) have now been found.

in which

the dashed bond between positions 22 and 23 stands for a single or double bond, in the case of a single bond R ¹ stands for hydrogen, hydroxyl or together with the carbon atom in position 23 for a carbonyl group, in the case of a double bond for hydrogen,

R ² for a, in particular alpha-branched C _j -CG alkyl or alkenyl group, or a C 3 C ₈ cycloalkyl group represents,

R ^{3 represents} hydroxyl, C ₆ alkyloxy, C ₆ alkanoyloxy, or together with the carbon atom in position 5 represents a hydroximino or CpCg alkoximino group, R4 stands in which

R ^{5 represents} H, branched or unbranched C _j -C ^ alkyl, which may optionally be substituted by alkoxy, alkylamino, halogen and hydroxy groups.

R ^{6 represents} H, branched or unbranched C _] -C ₄ -alkyl, aryl or aralkyl, which may optionally be substituted by alkoxy, alkylamino, halogen and hydroxyl groups,

R ⁷ and R ⁸ independently of one another are H, branched or unbranched C1-C4-alkyl, which may optionally be substituted by alkoxy, alkylamino, halogen and hydroxyl groups, or

R ⁷ and R ⁸ together with the nitrogen to which they are attached form a heterocyclic ring with 5 to 7 ring members with optionally 1 to 2 further heteroatoms from the group consisting of oxygen, sulfur or nitrogen.

Depending on the nature of the substituents, the compounds of the formula (I) can be present in different compositions as geometric and / or optical isomers or isomer mixtures, which can optionally be separated in a customary manner. Both the pure isomers and the isomer mixtures, their preparation and use and agents containing them are the subject of the present invention. For the sake of simplicity, the following always refers to compounds of the formula (I), although both the pure compounds and, if appropriate, also mixtures with different proportions of isomeric compounds are meant. It was also found that the new compounds of formula (I) can be obtained by one of the processes described below:

a) From compounds of the formula (Ha)

in which the radicals R ¹ , R ² and R ^{4 have} the abovementioned meanings and R ^{3a is} hydroxy-, C] -C ₆ -alkyloxy- or C _j -C ₆ -alkanoyloxy, -SiMe ₃ is reacted with HF in Cleaved pyridine, or from compounds of the formula (IIb)

in which the radicals R ¹ , R ² and R ^{4 have} the meanings given above and R ^b for a protective group from the series O-TBDMS (tert-butyldime-

thylsilyl) or, only if R ^{4 represents} the radical,

O-Alloc (allyloxycarbonyl) are either

α) in the case of R ^3b equal to O-TBMDS, both protective groups are split off in one step by reaction with HF in pyridine, or β) in the case of R ^3b equal to O-Alloc, this is removed by means of NaBH ₄ / Pd (0) and -SiMe _{3 is} eliminated by reaction with HF in pyridine, the order being irrelevant, or

Compounds of formula (IIc)

in which the radicals R ¹ and R ^{2 have} the meanings given above, R ⁴

stands for the rest, in which R ⁵ and R ^{6 have} the meanings given above, and

R ^{3c represents} a group from the series hydroxy, O-phenoxyacetyl or O-methoxyacetyl with amines of the formula (V)

R ^ö

H R 'in which

R ⁷ and R ^{8 have} the abovementioned meanings,

implemented and then -SiMe3 is cleaved by reaction with HF in pyridine, or

Compounds of the formula (Ia)

in which the radicals R ¹ and R ^{2 have} the meanings given above and

R ⁴ represents, where R ⁵ and R ^{6 have} the abovementioned meanings have stanchions

with amines of the formula (V)

in which

R ⁷ and R ^{8 have} the meanings given above,

implemented, or

Compounds of formula (la ')

in which the radicals R ¹ , R ² and R ^{4 have} the meanings given above

in a first step to compounds of the formula (VII)

oxidized, and then in a second step with compounds of formula (VIII)

where R ^{9 is} hydroxy, -OSiMe3 ° ^ ^er Cj-C5-alkoxy, implemented.

Furthermore, it has been found that the new avermectin derivatives of the formula (I), with favorable warm-blooded toxicity, have a very good activity as parasite control agents, in particular against arthopods in livestock and hobby animal husbandry. The compounds according to the invention are generally defined by the formula (I). Preferred substituents or ranges of the radicals listed in the formulas mentioned above and below are explained below.

The dashed bond between positions 22 and 23 preferably represents one

Single or double bond.

R ¹ preferably represents hydrogen.

R ² preferably represents an alpha-branched C ₃ -C ₈ alkyl or alkenyl group.

R ³ preferably represents a hydroxy, C _] -C alkyloxy, -CC ₄ alkanoyloxy. Hydroximino or C _] -C ₄ alkoximino group.

R ⁴ preferably represents the radicals

R ⁵ preferably represents H, branched or unbranched C _j -C ₄ alkyl.

R ⁶ preferably represents H, branched or unbranched C 1 -C ₄ -alkyl, aryl or aryl-C _r C ₄ -alkyl.

R ⁷ and R ⁸ independently of one another are preferably H, branched or unbranched C] -C ₄ -alkyl, R ⁷ and R ⁸ can furthermore preferably be a heterocyclic ring having 5 to 7 ring members with optionally oxygen, sulfur or nitrogen as heteroatoms form. The dashed bond between positions 22 and 23 particularly preferably represents a single or double bond. R ¹ particularly preferably represents hydrogen.

R ² particularly preferably represents isopropyl, sec-butyl or an alpha-branched C3-

Cg alkenyl group.

R ³ particularly preferably represents hydroxy.

R ⁴ particularly preferably represents the following radicals

R ⁵ particularly preferably represents H, methyl and ethyl.

R ⁶ particularly preferably represents H, methyl, ethyl or benzyl.

R ⁷ and R ⁸ independently of one another particularly preferably represent H, methyl. Ethyl or isopropyl. R ⁷ and R ⁸ can furthermore form a heterocyclic ring with 5 to 6 ring members with optionally oxygen or nitrogen as heteroatoms.

Examples of particularly preferred compounds of the formula (I) are as follows

Connections called:

4 "-O- (methoxycarbonyl-methyl) -Avermectin B 1 a / B 1 b 4" -O- (Ethoxycarbonyl-methyl) -Avermectin B 1 a / B 1 b 4 "-0- (Benzyloxycarbonyl-methyl) -Avermectin B 1 a / B 1 b

4 "-0- (carbamoyl-methyl) -Avermectin B 1 a / B 1 b 4" -0- (N-methyl-carbamoyl-methyl) -Avermectin B 1 a / B 1 b 4 "-0- (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" -0- (Morpholinyl-carbonyl-methyl) -Avermectin B 1 a / B lb 4 "-0- (4th -Methyl-piperazinyl-carbonyl-methyl) -Avermectin B 1 a B 1 b 4 "-O- (methoxycarbonyl-methyl) -22.23-dihydro-avermectin B 1 a / B 1 b 4" -0- (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 la / Blb 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 la B 1 b 4" -0- (4-methyl-piperazinyl-carbonyl-methyl) -22,23-dihydro-avermectin Bla / Blb

The structural formulas given above are drawn without defined stereochemistry. The compounds can occur as stereoisomers. In particular, the substituents in the 4 "-, 4'-, 13-, 5- and 23-position can have an alpha or beta orientation, i.e. be below or above the level of the molecule.

The general definitions or explanations listed above or in preferred areas or explanations can be combined with one another, that is, also between the respective areas and preferred areas. They apply accordingly to the end products as well as to the preliminary and intermediate products.

According to the invention, preference is given to the compounds of the formula (I) in which there is a combination of the meanings listed above as preferred (preferred).

According to the invention, particular preference is given to the compounds of the formula (I) in which there is a combination of the meanings listed above as being particularly preferred. Saturated or unsaturated hydrocarbon radicals, such as alkyl or alkenyl, can also be used in conjunction with heteroatoms. such as in alkoxy, where possible, be straight-chain or branched.

The compounds of the formulas (Ia) and (Ia ') required to carry out processes d) and e) are aliquots of the compounds of the formula (I) and can be obtained by processes a) to c).

The compounds of formula (II) required to carry out processes a) to c)

in which

R ¹ , R ² and R ^{4 have} the general, preferred and particularly preferred meanings given above for formula (I), and R ^3§ for hydroxy, C _r C ₄ alkyloxy, C _r C ₄ alkanyloxy, O-TBDMS and, only

if R ⁴ is O-Alloc, O-phenoxyacetyl or O-methoxyacetyl stands,

in which

R ^3§ preferred for hydroxy, C, -C ₄ alkyloxy, C _r C ₄ alkanyloxy, O-TBDMS

and, only if R ⁴ is O-Alloc, O-phenoxyacetyl or O-

Methoxyacetyl,

R ^{3§ is} particularly preferred for hydroxy, O-TBDMS and, only if R ⁴ for

stands for O-Alloc. Is O-phenoxyacetyl or O-methoxyacetyl,

where R ⁵ and R ^{6 can} each have the abovementioned general, preferred and particularly preferred meanings, are new and likewise the subject of these

Registration.

The following compounds of the formula (II) may be mentioned in particular:

4 "-O- (methoxycarbonyl-methyl) -7-0-trimethylsilyl-5-O-tert-butyldimethylsilyl-avermectin-B 1

4 "-0- (methoxycarbonyl-methyl) -7-0-trimethylsilyl-5-0-tert-butyldimethylsilyl-22.23-dihydro-avermectin-B 1 4 "-0- (methoxycarbonyl-methyl) -7-0-trimethylsilyl-5-0-avermectin-Bl

4 "-0- (methoxycarbonyl-methyl) -7-0-trimethylsilyl-5-0-22,23-dihydro-avermectin

Bl

4 "-0- (methoxycarbonyl-methyl) -7-0-trimethylsilyl-5-O-phenoxyacetyl-avermectin-Bl

4 "-0- (methoxycarbonyl-methyl) -7-0-trimethylsilyl-5-O-phenoxyacetyl-22,23-dihydro-avermectin-B 1

4 "-0- (methoxycarbonyl-methyl) -7-O-trimethylsilyl-5-O-methoxyacetyl-avermectin-B 1 4" -O- (ethoxycarbonyl-methyl) -7-O-trimethylsilyl-5-0-methoxyacetyl- 22,23-dihydro-avermectin-B 1

4 "-0- (ethoxycarbonyl-methyl) -7-0-trimethylsilyl-5-0-tert-butyldimethylsilyl-avermectin-B 1

4 "-O- (ethoxycarbonyl-methyl) -7-O-trimethylsilyl-5-O-tert-butyldimethylsilyl-22,23-dihydro-avermectin-B 1

4 "-O- (ethoxycarbonyl-methyl) -7-O-trimethylsilyl-5-O-avermectin-Bl

4 "-O- (ethoxycarbonyl-methyl) -7-O-trimethylsilyl-5-O-22,23-dihydro-avermectin

Bl

4 "-O- (ethoxycarbonyl-methyl) -7-0-trimethylsilyl-5-0-phenoxyacetyl-avermectin-Bl

4 "-O- (ethoxycarbonyl-methyl) -7-O-trimethylsilyl-5-0-phenoxyacetyl-22,23-dihydro-avermectin-B 1

4 "-O- (ethoxycarbonyl-methyl) -7-O-trimethylsilyl-5-O-methoxyacetyl-avermectin

Bl 4 "-O- (ethoxycarbonyl-methyl) -7-O-trimethylsilyl-5-0-methoxyacetyl-22,23-dihydro-avermectin-B 1

4 "-0- (N-methyl-carbamoyl-methyl) -7-0-trimethylsilyl-5-O-tert-butyldimethylsilyl-avermectin-B 1

4 "-0- (N-methyl-carbamoyl-methyl) -7-0-trimethylsilyl-5-0-tert-butyldimethyl-sily 1-22,23 -dihydro-avermectin-B 1 4 "-0- (N, N-dimethyl-carbamoyl-methyl) -7-0-trimethylsilyl-5-0-tert-butyldimethylsilyl-avermectin-B 1

4 "-0- (N, N-dimethyl-carbamoyl-methyl) -7-0-trimethylsilyl-5-0-tert-butyldimethylsilyl-22.23-dihydro-avermectin-B 1 4" -0- ( N-isopropyl-carbamoyl-methyl) -7-0-trimethylsilyl-5-0-tert-butyldimethylsilyl-avermectin-B 1

4 "-0- (N-isopropyl-carbamoyl-methyl) -7-0-trimethylsilyl-5-O-tert-butyldimethylsilyl-22,23-dihydro-avermectin-B 1

4 "-O- (morpholinyl-carbonyl-methyl) -7-O-trimethylsilyl-5-0-tert-butyldimethylsilyl-avermectin-B 1

4 "-0- (morpholinyl-carbonyl-methyl) -7-0-trimethylsilyl-5-0-tert-butyldimethylsilyl-22,23-dihydro-avermectin-Bl

4 "-O- (4-methyl-piperazinyl-carbonyl-methyl) -7-O-trimethylsilyl-5-0-tert-butyl-dimethylsilyl-avermectin-B 1 4" -O- (4-methyl-piperazinyl- carbonyl-methyl) -7-O-trimethylsilyl-5-O-tert-butyl-dimethylsilyl-22,23-dihydro-avermectin-Bl

The compounds of the formula (VII) required for carrying out the process e) for the preparation of compounds of the formula (I)

in which R ¹ , R ² and R ^{4 have} the abovementioned general, preferred and particularly preferred meanings,

are new and also the subject of the present application.

The following compounds of the formula (VII) may be mentioned in particular:

4 "-O- (methoxycarbonyl-methyl) -5-oxo-avermectin-B 1 a B lb

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-Bla / Blb 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 lb 4" -O- (methoxycarbonyl-methyl) -22.23-dihydro-5-oxo-avermectin Bla / Blb 4 "-O- (ethoxycarbonyl-methyl) -22,23-dihydro-5-oxo-avermectin-B la / Blb 4" -0- (carbamoyl-methyl) -22.23-dihydro-5-oxo-avermectin-Bla / Blb 4 "-0- (N-methyl-carbamoyl-methyl) -22.23-dihydro-5-oxo-avermectin-Bla / Blb 4" -O- (N, N-dimethyl-carbamoyl-methyl) -22.23- dihydro-5-oxo-avermectin-Bla / Blb 4 "-O- (N-isopropyl-carbamoyl-methyl) -22.23-dihydro-5-oxo-avermectin-Bla / Blb

4 "-O- (Mo holinyl-carbonyl-methyl) -22,23-dihydro-5-oxo-avermectin-Bla / Blb 4" -O- (4-methyl-piperazinyl-carbonyl-methyl) -22,23- dihydro-5-oxo-avermectin Bla Blb

The compounds of formula (II) can be prepared by using compounds of formula (III)

in which

R ¹ and R ^{2 have} the abovementioned general, preferred and particularly preferred meanings, and R ³ s' for C _r C ₆ alkyloxy, C, -C ₆ alkanoyloxy, O-Alloc, O-TBDMS. O-phenoxyacetyl or O-methoxyacetyl.

with diazo compounds of the formula (IV)

in which

R ⁵ and R ^{6 are} the above general, preferred and particularly preferred

Have meanings

implements

and then, if R ³ § for C _r C ₆ -alkyloxy-, C _r C ₆ -alkanoyloxy-, TBDMS,

Phenoxyacetyl or methoxyacetyl, optionally with compounds of the formula (V)

(V)

/

H ^* R '

in which

R ⁷ and R ^{8 have} the abovementioned general, preferred and particularly preferred meanings,

implements, or, if R ³ S stands for Alloc, this is optionally removed using NaBH ₄ / Pd (0) and then optionally with compounds of the formula (V)

in which

implements.

The compounds of the formula (III) required for carrying out the process for the preparation of compounds of the formula (II)

in which

R ¹ and R ^{2 have} the meanings given above,

in which

R § 'preferably represents -C ₄ alkyloxy, C _j -C ₄ alkanoyloxy, O-Alloc, O-phenoxyacetyl or O-methoxyacetyl,

R ³ °>'particularly preferably represents O-Alloc, O-phenoxyacetyl and O-methoxyacetyl,

are new and also the subject of the present application.

The following compounds of the formula (III) may be mentioned in particular:

7-0-trimethylsilyl-5-0-allyloxycarbonyl-avermectin B 1 7-0-Trimethylsilyl-5-0-allyloxycarbonyl-22,23-dihydro-avermectin Bl 7-0-Trimethylsilyl-5-0-phenoxyacetyl-avermectin B 1 7-0-Trimethylsilyl-5-0-phenoxyacetyl-22.23-dihydro avermectin B l 7-0-trimethylsilyl-5-0-methoxyacetyl-averrnectin Bl 7-0-trimethylsilyl-5-0-methoxyacetyl-22.23-dihydro-avermectin B 1.

The compounds of the formula (III) can be prepared by

in which R ¹ and R ^{2 have} the meanings given above, and

R ^{3 'represents} hydroxy, CC ₆ alkyloxy, C _j -Cg alkanoyloxy, plenoxyacetyl, methoxyacetyl, provides a trimethylsilyl protecting group on the hydroxyl group labeled OH ".

and if R ³ also represents a hydroxy group, this also provides a protective group from the Alloc, TBDMS, phenoxyacetyl or methoxyacetyl series.

The compounds of the formula (VI) required to carry out the process for the preparation of compounds of the formula (III) are known or can be prepared by known methods (see eg Fisher, MH; Mrozik, H. in Macrolide Antibiotics; Omura, S. , Ed., Academic Press, New York (1984); Davis. HG; 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).

The compounds of formula (IV) are known or can be made according to known ones

Produce processes (see textbooks on organic chemistry, e.g. Jerry March, Advanced Organic Chemistry, Wiley Interscience). The following compounds of the formula (IV) may be mentioned in particular:

Diazoacetic acid hylester

Diazoacetic acid ethyl ester

Diazoacetic acid tert-butyl ester

Phenyl diazoacetate

Methyl Diazopropionate Methyl Diazopropionate

Diazopropionic acid tert-butyl ester

Phenyl diazopropionate

Benzyl diazopropionate. The amines of the formula (V) are commercially available, known or can be prepared by known processes. The following compounds of the formula (V) are specifically mentioned:

ammonia

Methylamine Dimethylamine Efhylamine Isopropylamine Morpholine

4-methyl-piperazine.

As hydroxylamines of the formula (VIII), hydroxylamine and O-alkyl-hydroxylamine are used as the free base or in the form of their salts. If the reaction is carried out in an anhydrous medium, it may be advantageous to use 0, N-bis-trimethylsilyl or O-trimethylsilylhydroxylamine. Hydroxylamine hydrochloride and O-methyl-hydroxylamine hydrochloride are preferred. The compounds of formula (VIII) are commercially available, known or can be obtained by known methods.

Process a) for the preparation of compounds of formula (I) can be exemplified by the following formula scheme:

Process b)) for the preparation of compounds of the formula (I) can be exemplified by the following formula:

Process b) β) for the preparation of compounds of the formula (I) can be exemplified by the following formula:

The silyl protective groups are split off in accordance with process a), b) α) and the second step of b) β) is carried out by reacting the avermectin derivative with water in a solvent. The reaction is carried out with protonic acids as a catalyst.

The reaction is preferably catalyzed by protonic acids such as hydrochloric acid, methanesulfonic acid, hydrofluoric acid or sulfuric acid.

Hydrofluoric acid is particularly preferably used. The reaction is in a pH range of 2-8. preferably carried out 2-6.

To achieve the pH ranges mentioned, a larger amount of acid than required can also be added to the reaction medium and neutralized again by amines (buffering).

The following may be mentioned as amines: pyridine, triethylamine, ammonia.

Pyridine is particularly preferred.

The reaction is carried out at a temperature of -70 to + 100 ° C, preferably -10 to + 50 ° C.

It is preferred to work at normal pressure. However, it is also possible to work at elevated or reduced pressure.

All inert organic solvents are used as diluents. 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; Alcohols such as methanol, ethanol, propanol, butanol, isopropanol and mixtures of these solvents.

Alcohols such as methanol, ethanol and ethers such as THF are preferred.

If hydrofluoric acid is used, the reaction can also be carried out without water. The hydrofluoric acid must then be used in stoichiometric amounts of 1-100 mol, preferably 5-20 mol, per mol of avermectin derivative. The Alloc protective group is removed in accordance with the first step in process b) β) reductively with the participation of a transition metal catalyst.

The following may be mentioned as reducing agents for carrying out the process:

Ammonium formate, triethylammonium formate, triburyltin hydride, sodium borohydride, lithium borohydride.

The following reducing agents are preferably used: sodium borohydride and lithium borohydride.

The process is carried out by reacting the avermectin derivative with excess reducing agent in a solvent.

The reaction is carried out with a catalyst.

Palladium is used as the catalyst. It can be used as a Pd (O) or salt which forms Pd (O) under the reaction conditions for the reaction.

The following Pd compounds are mentioned: palladium (0) -tetrakis-triphenylphosphine,

Palladium (0) -bis-dibenzalacetone, palladium (0) -tris-dibenzalacetone, palladium-diacetate, palladium-dichloride.

Palladium (0) -tetrakis-triphenylphosphine is preferably used.

If the palladium compound used contains no phosphine ligand, a phosphine can be added.

The following may be mentioned as phosphines: triphenylphosphine, 1,2-bis (diphenylphosphino) ethane. Triphenylphosphine is preferably added.

The reaction is carried out at a temperature of -70 to + 150 ° C. preferably -15 to + 50 ° C, carried out.

All inert organic solvents are used as diluents. 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, tetrahydrof ran; Esters such as ethyl acetate, butyl acetate, alcohols such as methanol, ethanol, propanol, butanol, isopropanol and mixtures of these solvents.

Alcohols such as methanol and ethanol (see also Cvetovich, RJ; Kelly, DH; DiMichele, LM; Shuman, RF; Grabowski, EJJ, J.Org.Chem. 59 (1994) 7704-7708; EP632725; Fraser-Reid, B .; Barchi, J .; Faghih, Ramin, J. Org. Chem. 53 (1988) 925-926; Trost, BM; Caldwell, CG .; Murayama, E .; Heissler, D., J. Org. Chem. 48 (1983) 3252-3265).

Process c) for the preparation of compounds of formula (I) can be exemplified by the following formula scheme:

Process d) for the preparation of compounds of the formula (I) can be exemplified by the following formula scheme:

The reaction with amines according to processes c) and d) is carried out by reacting the compounds of the formulas (IIc) and (Ia) with excess amine in a solvent. The amine is preferably used in a molar ratio of 2-200: 1, in particular 10-100: 1 (amine: (IIc) or (Ia)). The reaction can be carried out with or without a catalyst. Protonic acids and Lewis acids can be used as catalysts.

The reaction is preferably catalyzed by protic acids.

Hydrochloric acid, formic acid or acetic acid are particularly preferably used for the catalysis.

The reaction is carried out at a temperature of -70 to + 150 ° C, preferably -10 to + 50 ° C. It is preferably carried out at normal pressure, but it can also be carried out under increased or reduced pressure.

All inert organic solvents are used as diluents. 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 exemplified by the following formula scheme:

Process e) is carried out by reacting the compounds of the formula (Ia ') in a first step with an oxidizing agent / activator mixture and an auxiliary base in a solvent.

Aliphatic sulfoxides are used as oxidizing agents. Dimethyl sulfoxide is particularly preferred. The oxidizing agent is used in a ratio of 1 to 10 mol, preferably 1 to 5 mol, based on the starting material of the formula (Ia ¹ ).

The reaction is carried out with an activator. All non-nucleophilic acylating agents are suitable as activators. These include in particular:

Acid chlorides such as phosgene, oxalyl chloride, phenyl dichlorophosphate. Diphenyl chlorophosphate; Acid anhydrides such as trifluoroacetic anhydride, trifluoromethanesulfonic anhydride. Phosphorus pentoxide; Pyridine / Sθ ₃ adduct. Phenyl dichlorophosphate and oxalyl chloride are preferred. The activator is used in a ratio of 1 to 10 mol, preferably 1 to 3 mol, based on the oxidizing agent.

Inert tert are suitable as auxiliary bases. Amine bases such as triethylamine. Diethylcyclohexylamine, diisopropylethylamine, diazabicycloundecene, diazabicyclonones. Triethylamine and diisopropylethylamine are preferred. The amine is used in a ratio of 2 to 20 mol, preferably 3 to 15 mol, based on the oxidizing agent.

The reaction is carried out at a temperature of -100 to + 100 ° C, preferably -70 to + 50 ° C.

It is preferred to work at normal pressure, but it is also possible to work at elevated or reduced pressure.

All inert organic solvents are used as diluents. 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.

Toluene, dichloromethane, ethyl acetate and isopropyl acetate are preferred. In a second step, the intermediate of formula (VII) is reacted with a hydroxylamine in a solvent. The hydroxylamine is reacted in a molar ratio of 1-20: 1, preferably 2-20: 1 (hydroxylamine: VII).

This reaction can be carried out in the presence of a catalyst.

Suitable catalysts are:

in the protic medium acids such as HC1, formic acid, acetic acid, propionic acid;

Bases such as triethylamine, pyridine, diisopropylethylamine, tributylamine;

in non-protic medium: Lewis acids such as ZnCl ₂ .

The reaction can be carried out in a pH range from 1 to 8, preferably 1.5 to 6.

The reaction is carried out at a temperature of -10 to + 80 ° C, preferably -10 to + 50 ° C.

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. Tetrahydroftiran; Esters such as ethyl acetate, acetic acid. Butyl acetate: alcohols such as methanol, ethanol, propanol, isopropanol, butanol and water as well as mixtures of these solvents. Preferred are ethyl acetate and isopropyl acetate, isopropanol. Ethanol, methanol and water.

The process for the preparation of compounds of the formula (II) can be exemplified by the following formula scheme:

or

The process for the preparation of the compounds of the formula (II) is carried 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 a catalyst. Protonic acid and transition metal complexes can be used as catalysts.

The reaction is preferably catalyzed by protic acids. Tetrafluoroboric acid or trifluoromethanesulfonic acid are particularly preferably used.

The reaction is carried out at a temperature of -70 to + 150 ° C, preferably -10 to

+ 50 ° C.

It is preferably carried out at normal pressure, but it can also be carried out under increased or reduced pressure.

All inert organic solvents are used as diluents. 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.

Ethers and chlorinated hydrocarbons are preferred.

The optional subsequent reaction with amine follows the process described above for processes c) and d). The necessary, if necessary

The Alloc protecting group is split off following the processes described above for processes a) and b).

When carrying out the process for the preparation of compounds of the formula (III), the protective groups are introduced analogously to processes known from the literature

(Cvetovich, RJ; Kelly, DH; DiMichele, LM; Shuman, RF; Grabowski, EJJ, 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, with favorable warm-blood toxicity

Combating pathogenic endo- / ectoparasites that occur in humans and in the Animal husbandry and animal breeding 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 combating the pathogenic parasites, illness, deaths and reduced performance (e.g. in the production of meat, milk, wool, hides, eggs,

Honey, etc.) can be reduced, so that the use of the active ingredients enables more economical and simple animal husbandry. Pathogenic endoparasites include cestodes, trematodes, nematodes, and ectoparasites include arthropods, preferably insects and arachnids.

In particular, the following endoparasites are listed:

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., Avitelina spp., Stilesia spp., Cittotaenia spp., Anhyra spp., Bertiella spp., Taema spp., Echinococcus spp., Hydratigera spp. Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidiurn spp., Joyeuxiella spp., Diplopylidium spp.

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 spp., Echinoparyphium spp., Echinochasmus spp., Hypoderasciol spp., Hypoderascol spp ., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocotyle spp ,,

Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagicr- chis spp., prosthogonism 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., Trichiomosoides spp., Trichinella spp.

From the order of the Rhabditia, for example: Micronema spp., Strongyloides spp.

From the order of the Strongylida, e.g .: Stronylus spp., Triodontophorus spp.,

Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostomaost. mum spp., Globocephalus spp., Syngamus spp., Cyathostomum spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp.,

Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongyras spp., Aelurostrongylus spp., Pararoafilar spp., Filaroides spp., Filaroides spp., Filaroides 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 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 s p.,

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.

Ectoparasites include in particular:

From the order of the anoplura e.g. Haematopinus spp., Linognathus spp., Solenopotes spp., Pediculus spp., Pthirus spp .;

From the order of the Mallophaga e.g. 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 e.g. Chrysops spp., Tabanus spp., Musca spp., Hydrotaea spp., Muscina spp., Haematobosca spp., Haematobia spp., Stomoxys spp., Fannia spp., Glossina spp., Lucilia spp., Calliphora spp., Cardylobia spp., Cochliomyia spp., Chrysomyia spp., Sarcophaga spp., Wohlfahrtia spp., Gasterophilus spp., Oesteromyia spp., Oedemagena sp., Hypoderma spp. Oestrus s snppn., Rhhiinnnopesςftrrπnpnon ., H Hiirpvpnnohbnosςnc.fla s ςnpnp.

From the order of the Siphonaptera e.g. Ctenocephalides spp., Echidnophaga spp.,

Ceratophyllus spp.

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 e.g. Chevletiella spp., Psorergates spp., Myobia spp., Demodex spp., Neotrombicula spp .;

From the order of the astigmata e.g. Acarus spp., Myocoptes spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Neoknemidodoptex spp., Lytodites spp., Laminosioptes spp.

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, fresh and salt water fish such as Trout, heads, eels, reptiles, insects such as Honey bee and silkworm.

Laboratory and experimental animals include e.g. Mice, rats, guinea pigs, golden hamsters, dogs and cats.

Hobby animals include e.g. Flounder 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 bodies containing the active ingredient, e.g. Strips, plates, ribbons, collars, ear tags, limb straps, marking devices.

The enteral application of the active ingredients takes place e.g. orally in the form of powder. Tablets, capsules, pastes, boluses, drinkers, granules, orally administrable solutions,

Suspensions or emulsions, medicated feed or drinking water. The dermal Application takes place, for example, in the form of dipping (dipping), spraying (spraying) or pouring on (pour-on and spot-on) and powdering. Parenteral use is, for example, in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants.

The preparations for dermal use are particularly noteworthy. This includes solutions, suspension and emulsion concentrates as well as microemulsions that are diluted with water before use, pour-on formulations, powders and dusts, aerosols and molded articles containing active ingredients as well as dust bags, back-rubber.

These preparations are made in a known manner, e.g. by mixing the active ingredient with extenders, that is to say liquid solvents, if appropriate using surface-active agents, that is to say emulsifiers and / or dispersants. If water is used as an extender, e.g. organic solvents can also be used as auxiliary solvents.

In addition to water, liquid diluents include alcohols such as methanoi,

Ethanol, isopropanol, n-butanol, amyl alcohol, octanol;

Glycols such as propylene glycol, 1,3-butylene glycol, ethyl glycol, dipropylene glycol monomethyl ether;

Glycerin; aromatic alcohols such as benzyl alcohol;

Carboxylic acid esters such as Ethyl acetate, benzyl benzoate, butyl acetate, propylene carbonate, lactic acid ethyl ester; aliphatic hydrocarbons such as paraffins, cyclohexane, methylene chloride, ethylene chloride; aromatic hydrocarbons such as xylene, toluene, alkylnaphthalenes, chlorobenzenes:

Ketones such as acetone and methyl ethyl ketone, methyl isobutyl 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 oil; continue dimethyl sulfoxide. Dimethylacetamide, dimethylformamide, N-methylpyrrolidone, dioxane, 2,2-dimethyl-4-oxymethyl-1,3-dioxolane.

Surfactants include: emulsifiers and wetting agents such as anionic surfactants, e.g. Alkyl sulfonates. Alkyl sulfates, aryl sulfonates, sodium lauryl sulfates, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt, calcium alkylarylsulfonate; cationic surfactants, e.g. Cetyltrimethylammonium chloride; ampholytic surfactants, e.g. Di-Na-N-lauryl-beta-iminodipropionate or lecithin; non-ionic surfactants, e.g. 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, polyoxyethylene menitanmonolaurate, alkyl polyglycol ether, oleyl polyglycol ether, dodecyl polyglycol ether, ethoxylated polyphenyl ether

The preparations can also contain:

Adhesion promoter, e.g. Carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, glatine, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, paraffins, oils, waxes, hydrogenated castor oil, lecithins and synthetic phospholipids.

The preparations can contain dyes such as inorganic pigments, e.g. Contain iron oxide, titanium oxide, ferrocyan blue and organic dyes such as alizarin, azo and metal phthalocyanine dyes.

The preparations can contain spreading agents, for example silicone oils of different viscosities, fatty acid esters such as ethyl stearate, di-n-butyl adipate. Hexyl laurate. Dipropylene glycol pelargonate, ester of a branched fatty acid of medium chain length with saturated fatty alcohols Cig-C ^, isopropyl myristate, isopropyl palmitate, Caprylic / capric acid esters of saturated fatty alcohols with chain length Cj2-C _j g, isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters, dibutyl phthalate, adipic acid diisopropyl ester. ester mixtures related to the latter; Triglycerides such as caprylic / capric triglyceride, triglyceride mixtures with vegetable fatty acids of chain length Cg-C ^ or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated, possibly also hydroxyl-containing fatty acids, monodiglycerides of Cg-CiQ fatty acids and others; Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

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

All physiologically compatible solid inert substances may be mentioned as carriers. Inorganic and organic substances serve as such. Inorganic substances are broken and fractionated, e.g. synthetic and natural rock powders such as kaolins, talc, chalk, quartz, diatomaceous earth, common 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 feed such as milk powder, animal meal, cereal meal, meal, starch, sawdust.

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

Other suitable auxiliaries are lubricants and lubricants such as, for example, magnesium stearate, stearic acid, talc, bentonite, substances which promote decay, such as starch or cross-linked polyvinylpyrrolidone, binders such as starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.

The active compounds can also be encapsulated in the form of their solid or liquid formulations mentioned above.

The active ingredients can also be used in the form of an aerosol. For this purpose, the active ingredient in a suitable formulation is finely distributed under pressure.

It may also be advantageous to use the active substances in formulations which release the active substance with a delay. As such, active ingredient-containing molded bodies such as Plates, tapes. Called strips, collars, ear tags, tail tags, limb tapes, holsters, marking devices. As such, implants and boluses containing active ingredients may also be mentioned.

The active ingredients can also be administered together with the feed and / or the drinking water.

The active substance according to the invention can be present in its preparations and in the use forms prepared from these preparations in a mixture with other active substances, such as insecticides, sterilants, bactericides, acaricides, nematicides or fungicides. Insecticides include, for example, phosphoric acid esters, carbamates, carboxylic acid esters, chlorinated hydrocarbons, phenylureas. Nicotinyls, neonicotinyls, substances produced by microorganisms, etc.

Particularly cheap mixing partners are e.g. the following:

Fungicides: Aldimoφh, Ampropylfos. Ampropylfos potassium, andoprim, anilazine, azaconazole,

Azoxystrobin, Benalaxyl, Benodanil, Benomyl, Benzamacril, Benzamacryl-Isobutyl, Bialaphos, Binapacryl, Biphenyl, Bitertanol. Blasticidin-S, bromuconazole, bupirimate, buthiobate,

Calcium polysulfide, capsimycin. Captafol, Captan, Carbendazim. Carboxin. Carvone, quinomethionate (quinomethionate), chlobenthiazon, chlorfenazole. Chloroneb, chloropicrin, chlorothalonil, chlorozolinate. Clozylacon, Cufraneb. Cymoxanil, Cyproconazol, Cyprodinil, Cyprofuram,

Debacarb, dichlorophene, diclobutrazole, diclofluanide, diclomezin, dicloran, diethofencarb, difenoconazole, dimethirimol, dimethomoφh, diniconazole, diniconazol-M, dinocap, diphenvlamine, dipyrithione, ditalimfos, dithian

Dodemoφh, Dodine, Drazoxolon,

Ediphenphos, Epoxiconazol, Etaconazole, Ethirimol, Etridiazol, Famoxadon, Fenapanil, Fenarimol, Fenbuconazol, Fenfuram, Fenitropan, Fenpiclonil, Fenpropidin, Fenpropimoφh, Fentinacetat, Fentinhydroxyd, Ferba, Ferimzidol, Fluimidolidol, Ferimzonid, Fluorimidonid, Fluorimidone

Flusilazole, Flusulfamide, Flutolanil, Flutriafol, Folpet, Fosetyl-Alminium, Fosetyl-Sodium, Fthalide, Fuberidazole, Furalaxyl, Furametpyr, Furcarbonil, Furconazole, Furconazole-cis, Furmecyclox, Guazatin, Hexaconobolene, Hexazonymol

Imazalil, imibenconazole, iminoctadine, iminoctadineal besilate, iminoctadine triacetate,

Iodocarb, Ipconazol, Iprobefos (IBP), Iprodione, Irumamycin, Isoprothiolan, Isovededione,

Kasugamycin, Kresoxim-methyl, copper preparations, such as: copper hydroxide. Copper naphthenate, copper oxychloride, copper sulfate, copper oxide, oxy-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, oxolinicacid, oxycarboxim. Oxyfenthiin, Paclobutrazole, pefürazoate. Penconazole, pencycuron. Philosophers. Pimaricin,

Piperalin, polyoxin, polyoxorim, probenazole, prochloraz, procymidone. Propamocarb,

Propanosine sodium, propiconazole, propineb. Pyrazophos, pyrifenox. Pyrimethanil.

Pyroquilon, Pyroxyfur, Quinconazol, Quintozen (PCNB),

Sulfur and sulfur preparations,

Tebuconazole, tecloftalam, tecnazen, tetcyclacis, tetraconazole, thiabendazole. Thicyofen, thifluzamide, thiophanate-methyl, thiram, tioxymid. Tolclofos-methyl,

Tolylfluanid, Triadimefon, Triadimenol, Triazbutil, Triazoxid, Trichlamid, Tricyclazol, Tridemoφh, Triflumizol, Triforin, Triticonazol,

Uniconazole,

Validamycin A. vinclozolin, viniconazole,

Zarilamid, Zineb, Ziram as well

Dagger G, OK-8705,

OK-8801, α- (l, 1-dimethylethyl) -ß- (2-phenoxyethyl) - 1 H-1, 2,4-triazole-l -ethanol, α- (2,4-dichloro phhenyl) -ß-fluorine -b-propyl-1 H-1, 2,4-triazole-1-ethanol, α- (2,4-dichloro phhenyl) -ß-methoxy-a-methyl-1 H-1, 2,4-triazole-1 -ethanol, α- (5-methyl-l, 3-dioxan-5-yl) -ß - [[4- (trifluoromethyl) phenyl] methylene] -lH-l, 2,4-triazol-1-ethanol ,

(5RS, 6RS) -6-hydroxy-2,2,7,7-tetramethyl-5- (1 H-1, 2,4-triazol-1-yl) -3-octanone,

(E) -a- (methoxyimino) -N-methyl-2-phenoxy-phenylacetamide,

{2-methyl-l - [[[l- (4-methylphenyl) ethyl] amino] carbonyl] propyl} carbamic acid 1-isopropyl ester,

1 - (2,4-dichloφhenyl) -2- (1 H- 1,2,4-triazol-1-yl) -ethanone-0- (phenylmethyl) -oxime,

1 - (2-Methyl-1-naphthalenyl) - 1 H-pyrrole-2,5-dione, l- (3.5-dichloro-phenyl) -3- (2-propenyl) -2,5-pyrrolidinedione, l - [(diiodomethyl ) sulfonyl] -4-methyl-benzene. l - [[2- (2,4-dichlorothenyl) -1, 3-dioxolan-2-yl] methyl] -1 H -imidazole, l - [[2- (4-chlorothenyl) -3-phenyloxiranyl] methyl ] -lH-l, 2,4-triazole, l- [l- [2 - [(2,4-dichloro-phenyl) methoxy] phenyl] ethenyl] -1 H-imidazole, l-methyl-5-nonyl-2- (phenylmethyl) -3-pyrrolidinol,

2 ', 6'-dibromo-2-methyl-4'-trifluoromethoxy-4'-trifluoromethyl-1,3-thiazole-5-carboxanilide, 2,2-dichloro-N- [l- (4-chlθφhenyl) -ethyl] -l-ethyl-3-methyl-cyclopropanecarboxamide,

2,6-dichloro-5- (methylthio) -4-pyrimidinyl-thiocyanate,

2,6-dichloro-N- (4-trifluoromethylbenzyl) benzamide,

2,6-dichloro-N - [[4- (trifluoromethyl) phenyl] methyl] benzamide,

2- (2,3,3-triiodo-2-propenyl) -2H-tetrazole, 2 - [(l-methylethyl) sulfonyl] -5- (trichloromethyl) -1, 3,4-thiadiazole,

2 - [[6-Deoxy-4-0- (4-0-methyl-β-D-glycopyranosyl) -aD-glucopyranosyl] -amino] -4- methoxy-lH-pyrrolo [2,3-d] pyrimidine- 5-carbonitrile,

2-aminobutane,

2-bromo-2- (bromomethyl) pentandinitrile, 2-chloro-N- (2,3-dihydro-1, 1, 3-trimethyl 1- 1 H-inden-4-yl) -3-pyridinecarboxamide,

2-chloro-N- (2,6-dimethylphenyl) -N- (isothiocyanatomethyl) acetamide,

2-phenylphenol (OPP),

3,4-dichloro-l- [4- (difluoromethoxy) phenyl] -IH-pyrrole-2,5-dione,

3,5-dichloro-N- [cyan [(1-methyl-2-propynyl) -oxy] -methyl] -benzamide, 3 - (1, 1-dimethylpropyl-1-oxo-1 H-indene-2-carbonitrile ,

3- [2- (4-chloro-phenyl) -5-ethoxy-3-isoxazolidinyl] pyridine,

4-chloro-2-cyan-N, N-dimethyl-5- (4-methylphenyl) -lH-imidazole-l-sulfonamide,

4-methyl-tetrazolo [1,5-a] quinazolin-5 (4H) -one,

8- (l, l-dimethylethyl) -N-ethyl-N-propyl-l, 4-dioxaspiro [4.5] decane-2-methanamine, 8-hydroxyquinoline sulfate,

9H-xanthene-9-carboxylic acid 2 - [(phenylamino) carbonyl] hydrazide, bis- (l-methylethyl) -3-methyl-4 - [(3-methylbenzoyl) -oxy] -2,5-thiophene dicarboxylate, cis-1 - (4-chloro-phenyl) -2- (lH-l, 2,4-triazole-l -yl) -cycloheptanol, cis-4- [3- [4- (l, l-dimethylpropyl) -phenyl- 2-methylpropyl] -2,6-dimethyl-moφholin hydrochloride,

Ethyl - [(4-chloro-phenyl) -azo] cyanoacetate, Potassium hydrogen carbonate,

Methane tetrathiol sodium salt,

Methyl 1 - (2,3-dihydro-2,2-dimethyl-1 H-inden-1-y 1) - 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-hydroxypheny 1) -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-benzenesulfonamide, N- (4-cyclohexylphenyl) -l, 4,5,6-tetrahydro-2-pyrimidinamine,

N- (4-hexylphenyl) -l, 4,5,6-tetrahydro-2-pyrimidinamine,

N- (5-chloro-2-methylphenyl) -2-methoxy-N- (2-oxo-3-oxazolidinyl) acetamide,

N- (6-methoxy) -3-pyridinyl) cyclopropanecarboxamide,

N- [2,2,2-trichloro-1 - [(chloroacetyl) amino] ethyl] benzamide, N- [3-chloro-4,5-bis (2-propynyloxy) phenyl] -N ' -methoxy-methanimidamide,

N-formyl-N-hydroxy-DL-alanine sodium salt,

0.0-diethyl [2- (dipropylamino) -2-oxoethyl] ethyl phosphoramidothioate,

O-methyl-S-phenyl-phenylpropylphosphoramidothioate,

S-methyl-l, 2,3-benzothiadiazole-7-carbothioate, spiro [2H] - 1-benzopyran-2, 1 '(3Η) -isobenzoftιran] -3'-one.

Bactericides:

Bronopol, dichlorophene, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone, furan carboxylic acid, oxytetracycline, probenazole, streptomycin, teclofalam, copper sulfate and other copper preparations.

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. Butocarboxime, butylpyridaben,

Cadusafos, Carbaryl, Carbofuran, Carbophenothion, Carbosulfan, Cartap, Chloetho- carb, Chlorethoxyfos, Chlorfenapyr, Chlorfenvinphos, Chlorfluazuron, Chlormephos, Chloφyrifos, Chloφyrifos M, Cis-Resmethrin, Cispermethrin, Clocytezhrin, Clocytezhrin, Clocytezhrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin, Clocythrin Cyclin , Cyfluthrin, Cyhalothrin, Cyhexatin, Cypeπnethrin, Cyromazin, Cymiazole,

Deltamethrin, Demeton M, Demeton S, Demeton-S-methyl, Diafenthiuron. Diazinon, Dichlorvos, Diflubenzuron, Dimethoat, Dimethylvinphos, Diofenolan, Disulfoton, Docusatsodium, Dofenapyn, Efusilanate, Emamectin, Empenthrin, Endosulfan, Entomopfthora spp., Esfenvalerat, Ethiofencarb, Exxxxpho, Exionoxophone, Exionofox, Exionofro, Exoxo, Exoxo

Fenamiphos, Fenazaquin, Fenbutatin oxide, Fenitrothion, Fenothiocarb, Fenoxacrim, Fenoxycarb, Fenpropathrin, Fenpyrad, Fenpyrithrin, Fenpyroximate, Fenvalerate, Fipronil, Fluazinam, Fluazuron, Flubrocythrinate, Flucycloxoxinon, Fluthrinoxin, Fluutinoxin, Fluutinoxin , Fubfenprox, Furathiocarb,

Granulosis viruses

Halofenozide, HCH, Heptenophos, Hexaflumuron, Hexythiazox, Hydroprene, Imidacloprid, Indoxacarb, Isazofos, Isofenphos, Isoxathion, Ivermectin, Kernpolyederviruses Lambda-cyhalothrin, Lufenuron,

Malathion, Mecarbam, Metaldehyde, Methamidophos, Metharhician anisopliae, Metharhician flavoviride, Methidathione, Methiocarb, Methomyl, Methoxyfenozide, Metolcarb, Mevinphos, Milbemectin. Monocrotophos, Naled, Nitenpyram, Nithiazine, Novaluron, Omethoat, Oxamyl, Oxydemethon M, Paecilomyces fosmosoroseus, 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. Pyridathione, pyrimidifene. Quinalphos,

Ribavirin,

Salithion, Sebufos, Silafluofen, Spinosad. Sulfotep, Sulprofos,

Tau fluvalinate, tebufenozide, tebufenpyrad. Tebupirimiphos, teflubenzuron,

Tefluthrin, Temephos, Temivinphos, Terbufos, Tetrachlorvinphos, Theta-cyper-methrin, Thiamethoxam, Thiapronil, Thiatriphos, Thiocyclam hydrogen oxalate.

Thiodicarb, Thiofanox, Thuringiensin. Tralocythrin. Tralomethrin, triarathene.

Triazamates, thriazophos, triazuron, trichlophenidines, trichlorfon, triflumuron,

Trimethacarb,

Vamidothion, Vaniliprole, Verticillium lecanii, YI 5302,

Zeta-cypermethrin, zolaprofos,

(IR-cis) - [5- (phenylmethyl) -3-furanyl] methyl-3 - [(dihydro-2-oxo-3 (2H) -furanylidene) methyl] -2,2-dimethylcyclopropane carboxylate

(3-phenoxyphenyl) methyl 2,2,3,3-tetramethylcyclopropane decarboxylate l - [(2-chloro-5-thiazolyl) methyl] tetrahydro-3,5-dimethyl-N.-nitro-l, 3,5- triazine-2flH) - imine

2- (2-chloro-6-fluoro-phenyl) -4- [4- (l, l-dimethylethyl) phenyl] -4,5-dihydro-oxazole

2 - (Acetyloxy) -3-dodecyl-1,4-naphthalenedione 2-chloro-N - [[[4- (l-phenylethoxy) phenyl] amino] carbonyl] benzamide 2-chloro-N - [[ [4- (2,2-dichloro-l, l-difluoroethoxy) phenyl] amino] carbonyl] benzamide

3-methylphenyl propyl carbamate

4- [4- (4-ethoxyphenyl) -4-methylpentyl] -1-fluoro-2-phenoxy-benzene 4-chloro-2- (l, l-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-dichloφheny l) -3 (2H) -pyridazinone

Bacillus thuringiensis strain EG-2348

Benzoic acid [2-benzoyl-1 - (1, 1-dimethylethyl)] hydrazide

Butanoic acid 2,2-dimethyl-3- (2,4-dichloro-phenyl) -2-oxo-l-oxaspiro [4,5] dec-3-en-4-yl ester

[3- [(6-chloro-3-pyridinyl) methyl] -2-thiazolidinyidenes] 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-chloro-phenyl) -3- [4- (difluoromethoxy) phenyl] -4,5-dihydro-4-phenyl- lH-pyrazole

1-carboxamide

N - [(2-chloro-5-thiazolyl) methyl] -N'-methyl-N "-nitro-guanidine

N-methyl-N '- (1-methyl-2-propenyl) - 1, 2-hydrazinedicarbothioamide

N-methyl-N'-2-propenyl-1, 2-hydrazinedicarbothioamide 0.0-diethyl- [2- (dipropylamino) -2-oxoethyl] ethylphosphoramidothioate

The active compounds according to the invention can furthermore be present in their commercially available formulations and in the use forms prepared from these formulations in a mixture with synergists. Synergists are compounds through which the action of the active ingredients is increased without the added synergist itself having to be active.

Formulations used directly contain between 10 "^7" and 5 percent by weight, preferably between 10 ^~ 4 and 1 percent by weight of active ingredient.

Formulations that are used only after further dilution contain 1 to 95 percent by weight, preferably 5 to 90 percent by weight of active ingredient. The preparation and use of the active compounds according to the invention can be seen from the examples below.

Manufacturing examples

A 9: 1 mixture of Avermectin Bla / Blb was used for the experiments.

Example H-1

4 "-0-ethoxycarbonylmethyl-5-O-Alloc-7-O-trimethylsilyl-avermectin Bl

4.67 g (4.5 m) 5-0-Alloc-7-0-trimethylsilyl-avermectin Bl were dissolved in 47 ml of dry dichloromethane and 2.5 g (22 m) of diazoacetic ester, dissolved in 14 ml of dichloromethane at 0 ° C. added. 81 mg (0.45 m) of tetrafluoroboric acid-diethyl ether complex, dissolved in 2 ml of dichloromethane, were then added dropwise, and two

Stirred for hours at room temperature. A further 81 mg (0.45 m) of tetrafluoroboric acid-diethyl ether complex, dissolved in 2 ml of dichloromethane, were then added dropwise and the mixture was stirred at room temperature for a further hour. The turnover was about 50%. For working up, the mixture was poured onto 5% NaH2P0 ₄ solution, the organic phase was separated off and extracted once again with dichloromethane. The United

Extracts were dried with Na ₂ S0 ₄ and evaporated.

Crude yield: 5.41 g

For purification, it was chromatographed on silica gel (column 30 × 8 cm) with hexane / ethyl acetate 4: 1 (v / v). The fractions were cut generously to separate an almost identical product.

Yield: 1.25 g of 4 "-0-ethoxycarbonylmethyl-5-O-Alloc-7-O-trimethylsilyl-avεr-mectin Bl (25% of theory based on the starting material used)

Purity: 90% (HPLC area) Example H-2

4 "-0-ethoxycarbonylmethyl-7-O-trimethylsilyl-avermectin B 1

1.2 g (1.1 m) 4 "-0-ethoxycarbonylmethyl-5-O-Alloc-7-O-trimethylsilyl-avermectin

B l were dissolved in 6.3 ml of ethanol pA, degassed with argon, 12.8 mg (0.01 1 m) of tetrakis (triphenylphosphine) palladium (0) were added at 0 ° C. and 83.5 mg (2, 2 m) NaBH _{4 added} in three portions. The reaction was complete after 20 minutes at 0 ° C. For working up, the mixture was poured onto NaH ₂ PO solution and extracted three times with ether. The combined extracts were dried with sodium sulfate and evaporated. Residue: 0.96 g

For purification, it 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-avermectin B 1

Example II-3

4 "-0-carbamoylmethyl-7-O-trimethylsilyl-avermectin B 1

640 mg (0.62 m) of 4 "-0-ethoxycarbonylmethyl-7-O-trimethylsilyl-avermectin B1 were dissolved in 3.2 ml of methanol, 3.2 ml of methanol saturated with ammonia and 130 mg of ammonium acetate were added. The mixture was 5 The reaction was then not yet complete, but already clearly visible decomposition products. For working up, the mixture was poured onto 20 ml of 5% sodium dihydrogenphosphate solution, the organic phase was separated off and extracted three more times with ether. The combined extracts were dried with sodium sulfate and evaporated in vacuo. For purification, it was chromatographed on silica gel. Mobile phase: First ethyl acetate / dichloromethane 1: 1 (v / v) to recover the educt, then ethyl acetate / dichloromethane 2: 1 (v / v) to separate a by-product and then pure ethyl acetate to elute the desired product. Yield: 130 mg (21% of theory) of 4 "-0-carbamoylmethyl-7-O-trimethylsilyl-avermectin B 1

Example 1-1

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, then a solution of 409 mg (0.41 m) of 4 "-0-carbamoylmethyl-7 was cooled with ice -O-trimethylsilyl-avermectin B1 in 2 ml of THF was added and the mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for a further 24 hours.

For working up, the mixture was poured onto 50 ml of saturated bicarbonate solution, the organic phase was separated off and extracted three more times with ether. The combined extracts were dried with sodium sulfate and evaporated in vacuo on a rotary evaporator. The residue was stirred with a little ether and thereby crystallized.

Yield: 270 mg of 4 "-0-carbamoylmethyl-avermectin Bl (71% of theory)

Manufacture of raw materials and intermediates

The starting materials for the preparation of the compounds described are ultimately the avermectin fermentation products specified above. Other avermectin derivatives with alpha-branched alkyl or alkenyl groups in the 25-position, denoted R2 in formula (I), have been described in EP-A-214 731, EP-A-276 131 and EP-A-276 103. Other starting substances have a 22-23 single bond. Their production by reduction of fermentation products is described in US-A-4, 199,569

Example IH-1

5-0-Alloc-7-0-trimethylsilyl-avermectin B 1

Amount of moles of text

3.4 g 3.55 m 5-Alloc Avermectin Bl (R.J. Cvetovich, D.H. Kelly,

L.M. DiMichele, R.F. Shuman and E.J.J. Grabowski J.Org.Chem. 59 (1994) 7704-7708) under argon in

10 ml of dry DMF dissolved and

10 ml of 37.6 m bis (trimethylsilyl) trifluoroacetamide were added. The mixture was then heated to 60 degrees for 3.5 hours. It was then transferred to a larger flask

100 ml of dry toluene are added and the mixture is evaporated to dryness at 40 mb / 50 degrees. The process was repeated two more times. They gave up the backlog

85 ml THF,

36 ml glacial acetic acid and Amount of moles of text

17 ml water. It was stirred at room temperature. After about 2.5 hours the reaction was complete (TLC: silica gel, hexane / ethyl acetate 50:50 (v / v). It was then evaporated to dryness, the residue with

20 ml of dichloromethane are added carefully

Given 200 ml of saturated bicarbonate solution. After five

Minutes of stirring, the phases were separated in a separating funnel and the aqueous phase was subsequently extracted with dichloromethane. The combined organic phases were with

Washed 100 ml bicarbonate solution, dried with Na2S04 and evaporated. For purification, it was chromatographed on silica gel. Column: 5 x 22 cm, eluted with hexane / ethyl acetate: 900 ml l 20:10

900 ml 60:40

400 ml 50:50

Yield: 3.03 g (83% of theory) of 5-0-Alloc-7-0-trimethylsilyl-avermectin Bl, white foam, according to HPLC

91.8% 5-Alloc-7-trimethylsilyl-avermectin-Bla 7.2% 5-Alloc-7-trimethylsilyl-avermectin-Blb Example VI-2

5-phenoxyacetyl avermectin Bl

Amount of moles of text

2 g 2.3 m avermectin B 1 were added under argon

10.2 ml of methyl tert-butyl ether dissolved and cooled to -15 ° C. Then were

0.37 ml of 2.47 M tetramethylethylenediamine and then

0.36 ml 2.65 M phenoxyacetyl chloride. The mixture was stirred at -10 ° C for 60 minutes. For working up, the mixture was poured onto 5% sodium dihydrogenphosphate solution, the organic phase was separated off and extracted again. The combined organic phases were then washed with saturated sodium bicarbonate solution, dried with sodium sulfate and evaporated. Yield: 2.11 g of 5-phenoxyacetyl avermectin B 1

Example III-2

5-phenoxyacetyl-7-trimethylsilyl avermectin B 1

Amount of moles of text

2.1 g of 2.1 m of 5-phenoxyacetyl-avermectin Bl were dissolved in argon

6 ml of dry DMF dissolved and

6 ml of 21 M bis (trimethylsilyl) trifluoroacetamide were added.

The mixture was then heated to 40 ° C. for 4 hours. It was then transferred to a larger flask

60 ml of dry toluene are added and the mixture is evaporated to dryness at 40 mb / 50 degrees. The process was repeated two more times. They gave up the backlog

51 ml THF,

21 ml glacial acetic acid and

10 ml water. The mixture was stirred at room temperature for 2 hours and then stored in a freezer at -15 ° C. overnight. The reaction was then complete. (TLC: silica gel, hexane / ethyl acetate 50:50 (v / v). It was evaporated to dryness, the residue with

20 ml of dichloromethane are added carefully

200 ml sat. Given bicarbonate solution. It was extracted three times with ether. The combined organic phases were with

Washed 100 ml bicarbonate solution, dried with Na2SO4 and evaporated.

Yield: 2.5 g of 5-phenoxyacetyl-7-0-trimethylsilyl-avermectin B 1 Examples of biological effects

example 1

Blowfly larva test / development-inhibiting effect

Test animals: Lucilia cuprina larvae (1st-3rd stage)

Solvent: dimethyl sulfoxide

20 mg of active ingredient are dissolved in one ml of dimethyl sulfoxide. To prepare a suitable formulation, the active ingredient solution is diluted with water to the desired concentration.

About 20 Lucilia cuprina larvae are placed in a test tube containing approx. 1 cm ³ horse meat and 0.5 ml of the active ingredient preparation to be tested. The effectiveness of the active substance preparation is determined after 24 and 48 hours. The test tubes are transferred to beakers with a sand-covered bottom. After a further 2 days, the test tubes are removed and the dolls are counted.

The effect of the preparation of active substance is assessed according to the number of flies hatched after 1.5 times the development time of an untreated control. 100% means that no flies have hatched; 0% means that all flies hatched normally.

In this test, e.g. the compound according to Example I-1 in an exemplary

Concentration of 1 ppm an effectiveness of 100%. Example 2

Test with resistant single-host cattle ticks / SP-resistant Parkhurst strain

Test animals: adult sucked females of Boophilus microplus (strain

Parkhurst - SP resistant) Solvent: dimethyl sulfoxide

10 adult Boophilus microplus res. are immersed in the drug preparation to be tested for 1 minute. After being transferred to a plastic cup and stored in an air-conditioned room (28 ° C, 85% rel. RH), the degree of killing or the inhibition of oviposition is determined after 10 days.

100% means that all ticks have been killed or no eggs have been laid; 0% means that no ticks have been killed or that, compared to the control, normal egg laying has taken place.

In this test, for example, the compound according to Example II shows an effectiveness of 100% in an exemplary concentration of 1 ppm.

Example 3

Test with flies (Musca domestica)

Test animals: adult Musca domestica, strain WHO (N) (sensitive)

Solvent: dimethyl sulfoxide

2 ml of this active ingredient preparation are pipetted onto filter paper dishes (0 9.5 cm), which are located in Petri dishes of the appropriate size. After the filter disks have dried, sponges (approx. 1.5 * 1.5 cm) soaked in sugar water (approx. 1.5 * 1.5 cm) are transferred to tablet blisters of 2 cm. Then 25 test animals are anesthetized with C0 ₂ and transferred to the Petri dishes and covered.

The effectiveness of the active substance preparation is determined after 1, 3, 5 and 24 hours. 100% means that all flies hatched have been killed; 0% means that no flies have been killed.

In this test, e.g. the compound according to Example I-1 in an exemplary concentration of 1 ppm an activity of 100%.

Claims

claims

Compounds of formula (I)

in which

R ² for a, in particular alpha-branched C _j -CG alkyl or alkenyl group, or a C ₃ -C ₈ cycloalkyl group, R ^{3 represents} hydroxyl, C _r C ₆ alkyloxy, C _r C ₆ alkanoyloxy, or together with the carbon atom in position 5 represents a hydroximino or C] -C ₆ alkoximino group,

R ^{4 represents} the radicals in which

R ^{5 represents} H, branched or unbranched C _j -C ₄ alkyl, which may optionally be substituted by alkoxy, alkylamino, halogen and hydroxyl groups, mouse click

R ⁶ represents H, branched or unbranched C _j -C alkyl, aryl or aralkyl kyl, which may be optionally substituted by alkoxy, alkylamino, halogen and hydroxy groups, is,

R ⁷ and R ^{8 are} independently H, branched or unbranched

C _j -C ₄ alkyl, which may optionally be substituted by alkoxy, alkylamino, halogen and hydroxy groups, or

R ⁷ and R ⁸ together with the nitrogen to which they are attached form a heterocyclic ring with 5 to 7 ring members with optionally 1 or 2 further heteroatoms from the group consisting of oxygen, sulfur or nitrogen.

2. Compounds of formula (I) according to claim 1, in which the dashed bond between positions 22 and 23 for a single or

Double bond stands,

R ^{1 represents} hydrogen, R ^{2 represents} an alpha-branched C ₃ -C 6 alkyl or alkenyl group,

R ³ ₄ alkanoyloxy, hydroximino or Cι-C is ₄ -Alkoximinogruppe a hydroxy, C] -C alkyloxy, C] -C,

R ^{4 represents} the radicals,

R ^{5 represents} H, branched or unbranched Cj-C-alkyl,

R ^{6 represents} H, branched or unbranched C 1 -C ₄ -alkyl, aryl or aryl-C _j C ₄ -alkyl,

R ⁷ and R ⁸ are each independently H, branched or unbranched C _j -C ₄ alkyl, R ⁷ and R ^8, which further may form a heterocyclic ring having 5 to 7 ring members optionally having oxygen, sulfur or nitrogen hetero atoms.

3. Compounds of the formula (I) according to Claim 1, in which the dashed bond between positions 22 and 23 particularly preferably represents a single or double bond,

R ^{1 represents} hydrogen,

R ^{2 represents} isopropyl, sec-butyl or an alpha-branched C ₃ -Cg alkenyl group,

R ^{3 represents} hydroxy, R ⁴ for the following radicals

stands,

R ^{5 represents} H, methyl and ethyl,

R ^{6 represents} H, methyl, ethyl or benzyl,

R ⁷ and R ⁸ independently of one another are H, methyl, ethyl or isopropyl, where R ⁷ and R ^{8 can} furthermore form a heterocyclic ring with 5 to 6 ring members, optionally with oxygen or nitrogen as heteroatoms.

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

1, characterized in that one

from compounds of the formula (Ha)

in which the radicals R ¹ , R ² and R ^{4 have} the meaning given in claim 1 and R ^{3a represents} hydroxy-, C] -C ₆ -alkyloxy- or C _j - Cg-alkanoyloxy,

-SiMe ₃ cleaved by reaction with HF in pyridine, or

b) from compounds of the formula (IIb)

in which the radicals R ¹ , R ² and R ^{4 have} the meaning given in claim 1 and R ^3b for a protective group from the series O-TBDMS (tert-butyldimethylsilyl) or, only if R ⁴ for the rest

stands,

O-Alloc stand, either

α) in the case of R ^3b equal to O-TBMDS, both protective groups are split off in one step by reaction with HF in pyridine, or β) in the case of R ^3b equal to O-Alloc, this is removed by means of NaBH ₄ / Pd (0) and -SiMe ₃ is split off by reaction with HF in pyridine, the sequence being irrelevant, or

Compounds of formula (IIc)

in which the radicals R ¹ and R ^{2 have} the meanings given in claim 1,

R ^{4 represents} the rest, and R ^{3c represents} a group from the series consisting of hydroxy, O-phenoxyacetyl or O-methoxyacetyl, with amines of the formula (V)

^RÖ I

H in which

R ⁷ and R ^{8 have} the meanings given in Claim 1,

implemented and then -SiMe ₃ cleaved by reaction with HF in pyridine, or

Compounds of formula (Ia)

in which the radicals R ¹ and R ^{2 have} the meaning given in claim 1

with amines of the formula (V)

R ⁸ I

H '' R 'in which

R ⁷ and R ^{8 have} the meanings given in claim 1, or

Compounds of formula (Ia ')

in which the radicals R ¹ , R ² and R ^{4 have} the meaning given in claim 1, in a first step to compounds of the formula (VII)

in which R ¹ , R ² and R ^{4 have} the meanings given in Claim 1, oxidized, and then in a second step with compounds of the formula (VIII)

where R ^{9 is} hydroxyl, 0-SiMe ₃ or Ci-Cg-alkoxy. Compounds of formula (II)

in which R ¹ , R ² and R ^{4 have} the meanings given in Claim 1,

R ³ g for hydroxy, C _r C ₆ alkyloxy or C _r C ₆ alkanoyloxy, O-TBDMS, and

only if R ⁴ is O-Alloc, O-Phenoxyacetyl or

O-methoxyacetyl. Process for the preparation of compounds of formula (II), characterized in that compounds of formula (III)

in which R ¹ and R ^{2 have} the meanings given in Claim 1,

R ^3§ 'represents C _r C ₆ -alkyloxy-, C _r C ₆ -alkanoyloxy-, O-Alloc, O-TBDMS, O-phenoxyacetyl or O-methoxyacetyl,

with diazo compounds of the formula (IV)

in which R ⁵ and R ^{6 have} the meanings given in Claim 1,

implements

and thereafter if R ^3g 'is _Cj-C6 alkyloxy, C _j -CG-alkanoyloxy, O-TBDMS, O-phenoxyacetyl or O-methoxyacetyl, if appropriate with compounds of the formula (V)

in which R ⁷ and R ^{8 have} the meanings given in Claim 1,

implements, or

if R ³ g 'is O-Alloc, this is optionally removed by means of NaBH4 / Pd (0) and then, if appropriate, using compounds of the formula (V)

in which R ⁷ and R ^{8 have} the meanings given in Claim 1.

implements.

7. Compounds of formula (III)

in which R ¹ and R ^{2 have} the meanings given in Claim 1,

R ³ g 'represents C _r C ₆ alkyloxy, C _r C ₆ alkanoyloxy, O-Alloc, O-phenoxyacetyl or O-methoxyacetyl.

8. A process for the preparation of compounds of the formula (III), characterized in that in the compounds of the formula (VI)

in which R ¹ and R ^{2 have} the meanings given in Claim 1,

R ³ 'represents hydroxy, C _j -C ₆ alkyloxy, C i -C ₆ alkanoyloxy,

provides the hydroxy group labeled OH 'with a trimethylsilyl protective group,

and if R ³ 'is also a hydroxyl group, this in a second step also provides a protective group from the series Alloc, TBDMS, phenoxyacetyl or methoxyacetyl.

9. Compounds of formula (VII)

in which R ¹ , R ² and R ^{4 have} the meanings given in Claim 1.

10. Agent, characterized by a content of at least one compound of formula (I) according to claim 1.

11. Use of compounds of formula (I) according to claim 1 for the preparation of agents for combating ectoparasites and endoparasites on animals.

12. A process for the preparation of agents for combating ectoparasites and endoparasites on animals, characterized in that compounds of the formula (I) according to Claim 1 are mixed with extenders and / or surface-active agents.