DE3631387A1 - Agents for combating parasitic pests - Google Patents

Abstract

Ecto- and endoparasitic milbemycins of the formula I <IMAGE> in which R stands for methyl, ethyl, isopropyl or sec-butyl; R1 stands for hydrogen or a protective group, are described, and their use in the agricultural field and their preparation from the underlying 13-oxomilbemycins.

Description

The present invention relates to 13-methylidene-milbemycin derivatives of formula I below, their preparation and their use for Control of pests such as ectoparas and endoparasites, furthermore Pesticides containing at least one of these compounds included as an active ingredient.

The compounds according to the invention have the formula I. wherein
R represents methyl, ethyl, isopropyl or sec-butyl;
R _{1 represents} hydrogen or a protective group.

Under the term alkyl itself or as part of another The following are substituents depending on the number of specified Carbon atoms, for example, the following straight-chain groups understand: methyl, ethyl, butyl, pentyl, hexyl, etc. as well their branched isomers, such as. B. isopropyl, isobutyl, tert.- Butyl, isopentyl, etc. Below halogen is said here and below  Fluorine, chlorine, bromine or iodine are understood, preferably chlorine or bromine. Examples of cycloalkyl itself or as part of Cycloalkoxy are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

OH protective groups for the substituent R ₁ are to be understood here and below to mean the protective functions customary in organic chemistry. These are particularly silyl groups. The 5-OH group can, for. B. also etherified by an araliphatic or alkoxyalkoxymethyl group (e.g. benzyl ether, methoxiethoxymethyl ether, etc.).

Suitable silyl groups for R _{1 are} the radical -Si (R ₂ ) (R ₃ ) (R ₄ ), R ₂ , R ₃ and R ₄ independently of one another preferably for C ₁ -C ₆ alkyl, benzyl or phenyl stand and forms, for example, one of the groups trimethylsilyl, thexyldimethylsilyl, tris (tert-butyl) silyl, diphenyl-tert-butylsilyl, bis (isopropyl) methylsilyl, triphenylsilyl etc. and in particular tert-butyldimethylsilyl.

Compounds of formula I, wherein R _{1 represents} a protecting group, can be by simple, for. B. hydrolytic elimination of the protective function in the highly active free 5-hydroxy derivatives (R ₁ = H) and thus have intermediate character. The protective group does not, in principle, reduce the biological value of these compounds.

Compounds of formula X below are known from the literature as milbemycins: R = CH ₃ milbemycin A ₃ from U.S. Patent 3,950,360
R = C ₂ H ₅ milbemycin A ₄ from U.S. Patent 3,950,360
R = isoC ₃ H ₇ milbemycin D from US Patent 43 46 171
R = sec. C ₄ H ₉ 13-deoxi-22,23-dihydro-C-076-Bla-aglycon, or
13-deoxi-22,23-dihydro-avermectin-Bla aglycone from US Pat. No. 4,173,571.

Compounds in which R represents butyl are intended here and in the following are also classed as milbemycin derivatives, although they follow the usual system of avermectin derivatives are derived. Avermectin aglycones (with an OH group in 13-position), however, according to US Pat. No. 4,173,571 Convince milbemycin homologues.

Due to their parasiticidal activity, the following groups of Compounds of formula I increasingly preferred:

a) Compounds of formula I, wherein
R represents methyl, ethyl, isopropyl or sec-butyl; and
R _{1 represents} hydrogen, araliphatic radical, alkoxyalkoxymethyl or
the group Si (R ₂ ) (R ₃ ) (R ₄ ) is, where
R ₂ , R ₃ and R ₄ independently of one another are C ₁ -C ₆ alkyl, benzyl or phenyl.

b) Compounds of formula I, wherein
R represents methyl, ethyl, isopropyl or sec-butyl; and
R _{1 represents} hydrogen, benzyl or methoxymethoxymethyl or one of the groups trimethylsilyl, thexyldimethylsilyl, tris (tert-butyl) silyl, diphenyl-tert-butylsilyl, bis (isopropyl) methylsilyl, triphenylsilyl or tert.-butyldimethylsilyl.

c) Compounds of formula I, wherein
R represents methyl, ethyl, isopropyl or sec-butyl; and
R ₁ means hydrogen.

Preferred individual substances with R ₁ = H are:
13-methylidene-milbemycin A ₃
13-methylidene-milbemycin A ₄
13-methylidene-milbemycin D
13-methylidene-13-deoxy-22,23-dihydro-avermectin-Bla aglycon
and with R ₁ = protecting groups are:

5-O-tert-butyldimethylsilyl-13-methylidene milbemycin A ₃
5-O-tert-butyldimethylsilyl-13-methylidene milbemycin A ₄
5-O-tert-butyldimethylsilyl-13-methylidene milbemycin D
5-O-tert-butyldimethylsilyl-13-methylidene-22,23-dihydro-avermectin-Bla aglycon.

The compounds in which R _{1 is} hydrogen are clearly preferred.

The present invention relates not only to the compounds of Formula I, but equally the new process for their Manufacturing.

The inventive described in detail below Method allowed in the 13-position of milbemycin and 13-deoxy 22,23-dihydro-avermectin aglycon derivatives an exo-methylidene To introduce a targeted group and thus to highly effective new parasiticides Formula I to get.  

The compounds of the formula I are prepared according to the invention by preparing a compound of the formula II wherein R ₁ and R _{2 have} the meanings given under formula I, with a to release the titanium complex of formula III qualified reagent.

Suitable reagents of this type are compounds of the formula IV, wherein Y represents aluminum; and
R ₅ and R _{6 are} independently C ₁ -C ₆ alkyl;

b) -X (R ₇ ) - represents -CH ₂ -;
Y represents a four-bonded carbon atom; and
R ₅ and R ₆ together form an C ₃ -C ₆ alkylene bridge which is unsubstituted or substituted by C ₁ -C ₆ alkyl or phenyl; or

c) X represents -CH (R ₇ ) -;
R _{5 represents} hydrogen;
Y represents a four-bonded carbon atom; and
R ₆ and R ₇ together form a C ₃ -C ₆ alkylene bridge; or

d) -X (R ₇ ) - represents -CH ₂ -;
Y represents a four-bonded carbon atom; and
R ₅ and R _{6 are} independently hydrogen, phenyl, substituted or unsubstituted C ₁ -C ₆ alkyl.

In a preferred embodiment of the process, compounds of the formula IV are used in which Y represents aluminum; and
R ₅ and R _{6 are} methyl;

b) -X (R ₇ ) - represents -CH ₂ -;
Y represents a four-bonded carbon atom; and
R ₅ and R ₆ together represent an unsubstituted or substituted by methyl, tert-butyl or phenyl or butylene or pentylene bridge; or

c) X represents -CH (R ₇ ) -;
R _{5 represents} hydrogen;
Y represents a four-bonded carbon atom; and
R ₆ and R ₇ together form a propylene or butylene bridge; or

d) -X (R ₇ ) - represents -CH ₂ -;
Y represents a four-bonded carbon atom; and
R ₅ and R ₆ independently of one another represent hydrogen, C ₁ -C ₃ alkyl, tert-butyl or phenyl.

The following table shows typical representatives of compounds of the formula IV, where the cyclopentadiene ring as Cp is called.

Intermediates of formula IV:

Compounds Nos. Z1, Z4, Z8, Z9 and Z11 are particularly suitable.

Compounds of formula IV are from the literature [R. H. Grubbs et al. Pure & Appl. Chem. 55, pp 1733-1738 (1983)] known or can be analogous to the representatives mentioned there produce.

In general, the reaction is carried out so that the compound of the formula III in situ in the reaction medium from a compound Formula IV is formed. You usually work at temperatures from -80 ° C to + 100 ° C, conveniently in the presence of a inert solvent or solvent mixture. It are suitable for this. B. aliphatic or aromatic hydrocarbons such as benzene, toluene, xylenes, petroleum ether, hexane and ethereal Compounds such as dialkyl ether (diethyl ether, diisopropyl ether, tert-butyl methyl ether etc.), dioxane, tetrahydrofuran etc. and mixtures of these with each other.

One often works in the presence of a catalytic amount of one organic base, such as. B. pyridine, 4-dimethylaminopepidene, lutidene, N-dialkylaniline (dimethylaniline) or a trialkylamine (triethylamine).

The starting compounds of formula II (13-oxomilbemycins) can be obtained from 13β-hydroxy-milbemycins of formula V by oxidation produce with dialkyl sulfides or dialkyl sulfoxides, in particular in their activated form, preferably in the presence of a base. Dimethyl sulfide (DMS) and dimethyl sulfoxide (DMSO) are particularly suitable. The combination of dialkyl sulfoxide or sulfide and an activator should serve as the activated form here and below. Suitable activators are e.g. B .: dicyclohexylcarbodiimide (DCC), sulfur trioxide-pyridine (pyridine · SO _3), N-halosuccinimides such as N-chlorosuccinimide (NCS), carboxylic anhydrides such as acetic anhydride and trifluoroacetic anhydride, thionyl chloride (SOCl _2), sulfuryl chloride (SO ₂ Cl ₂₎ and oxalyl chloride . Sometimes the addition of CF ₃ COOH is beneficial. As bases z. B. organic bases such as tertiary amines, especially trialkylamines such as triethylamine and pyridine. The dialkyl sulfides and sulfoxides themselves and aromatic hydrocarbons such as benzene, toluene, xylenes and chlorinated hydrocarbons such as methylene chloride are suitable as solvents. The reactions are carried out at temperatures of -100 ° C and + 60 ° C, preferably -80 ° C to + 40 ° C. The following table provides an overview of activated DMSO, DMS and favorable reaction conditions:

Table Particularly preferred reaction conditions

13β-Hydroxy-Milbemycins of formula V can be prepared according to the following reaction scheme:

The process is characterized by the reaction of a compound of the formula VI with chromate, halochromate or dichromate ions, in particular with pyridinium dichromate (= PDC) [= (Pyr) ₂ H ₂ CrO ₇ ] or with pyridinium chlorochromate [= Pyr · ClCrO ₃ H].

Inert anhydrous, preferably polar solvents, e.g. B. dimethylformamide (= DMF) is used. The reaction is at Temperatures from -10 ° C to + 60 ° C, preferably + 10 ° C to + 40 ° C carried out.

Compounds of the formula VI can be prepared from 14,15-epoxy-milbemycins of the formula VII, according to the reaction scheme:

VII to VI are converted using the complex reagent [HN ₃ ] _m / Al (ethyl) ₃ ] _n , where m and n independently represent the number 1 or 2, a numerical value between 1 and 2, in inert dry solvents in Temperature range from -20 ° C to + 100 ° C, preferably + 20 ° C to + 80 ° C.

Preferred inert solvents are aliphatic and aromatic hydrocarbons such as benzene, toluene, xylene, petroleum ether; Ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, Dioxane, anisole in question.

The reaction is advantageously carried out under a protective gas such as nitrogen or Argon performed.

Hydrogen nitric acid HN ₃ can be converted into the [HN ₃ ] _m / [Al (Et) ₃ ] _n complex in statu nascendi by suspending Na azide in the intended dry solvent or solvent mixture and using a stronger acid, e.g. . B. H ₂ SO ₄ (preferably oleum, in order to ensure absolutely dry reaction conditions), releases HN ₃ in the solution. Al (Et) ₃ should already be in the solution or should be added shortly afterwards. The epoxy compound provided for the reaction can likewise already be present or can be metered into the solution at a suitable time.

The compounds of the formula VII can be prepared according to the reaction scheme below from the known compounds of the formula X mentioned at the outset:

The epoxidation takes place in a solvent phase in the temperature range from -10 ° C to + 20 ° C, preferably -5 ° C to + 5 ° C, performed.

Peracids such as peracetic acid, trifluoroperacetic acid, Perbenzoic acid, chloroperbenzoic acid and others in question.

A protective group (R ₁ = protective group) is introduced into one of the above-mentioned milbemycin derivatives (formulas I to VII) by methods known from the literature. If R _{1 stands} for said silyl group Si (R ₂ ) (R ₃ ) (R ₄ ), the introduction takes place by reaction with a compound of the formula VIII where U is a silyl leaving group. The silyl leaving groups U include, for example, bromide, chloride, cyanide, azide, acetamide, trifluoroacetate, trifluoromethanesulfonate. This list is not a limitation, the person skilled in the art knows other typical silyl leaving groups. Compounds of the formula VIII are known or can be prepared analogously to the known representatives. 5-O-silylations are carried out in an anhydrous environment, preferably in inert solvents and particularly preferably in aprotic solvents. The reaction advantageously takes place in the temperature range from 0 ° C. to 80 ° C., preferably at 10 ° C. to 40 ° C. An organic base is preferably added. Tertiary amines such as triethylamine, triethylenediamine, triazole and preferably pyridine, imidazole or 1,8-diazabicyclo [5.4.0] - undec-7-ene (DBU) are suitable as such.

The removal of these silyl and acyl residues R ₁ in the 5-position is done by selective mild hydrolysis → R ₁ = H) with z. B. arylsulfonic acid in alcoholic solution or by another method familiar to those skilled in the art.

The process described for the preparation of the compounds of Formula I is a component of all sub-steps Invention.

The compounds of formula I are excellent for combating of pests on animals and plants, including animal parasites Ecto parasites. The latter count under the order Acarina especially pests of the families Ixodidae, Dermanyssidae, Sarcoptidae, Psoroptidae; the Mallophaga orders; Siphonaptera, Anoplura (e.g. family of the Haemotopinidae); under the order Diptera in particular pests of the Muscidae, Calliphoridae, Oestridae, Tabanidae, Hippoboscidae, Gastrophilidae.  

The compounds I can also be used against hygiene pests, especially the orders Diptera with the families Sarcophagidae, Anophilidae, Culicidae; of the order Orthoptera, of the order Dictyoptera (e.g. family Blattidae) and the order Hymenoptera (e.g.) Family Formicidae).

The compounds I also have sustainable activity phytosanitary mites and insects. With spider mites of order Acarina they are effective against eggs, nymphs and adults of Tetranychidae (Tetranychus spp. And Panonychus spp.).

They are very active in the sucking insects of the order Homoptera, especially against pests of the families Aphididae, Delphacidae, Cicadellidae, Psyllidae, Loccidae, Diaspididae and Eriophydidae (e.g. the rust mite on citrus fruits): The orders Hemiptera; Heteroptera and thysanoptera; as well as the herbivores Insects of the order Lepidoptera; Coleoptera; Diptera and Orthoptera.

They are also a soil insecticide against pests in the soil suitable.

The compounds of formula I are therefore against all stages of development sucking and feeding insects on crops like cereals, Cotton, rice, corn, soybeans, potatoes, vegetables, fruits, tobacco, Hops, citrus, avocados and other effective.

The compounds of formula I are also active against plant nematodes of the species Meloidogyne, Heterodera, Pratylenchus, Ditylenchus, Radopholus, Rizoglyphus and others.

But the compounds are particularly effective against helminths, under which the endoparasitic nematodes are the cause of severe diseases on mammals and poultry, e.g. B. on sheep, Pigs, goats, cattle, horses, donkeys, dogs, cats, guinea pigs, Ornamental birds. Typical nematodes for this indication are:  Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostonum, Esophagostonum, Charbertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, 19xocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. The particular advantage of the compounds of formula I is their effectiveness against such parasites that act against active substances Benzimidazole base are resistant.

Certain species of the species Nematodirus, Cooperia and Oesophagostomum attack the intestinal tract of the host animal, while others attack the Types of Haemonchus and Ostertagia in the stomach and those of the species Dictyocaulus parasitize in the lung tissue. Parasites of the Filariidae families and Setariidae are found in the internal cell tissue and Organs, e.g. B. the heart, blood vessels, lymphatic vessels and the subcutaneous tissue. Here is the dog’s heartworm, Dirofilaria immitis. The compounds of formula I are highly effective against these parasites.

They are also used to combat human pathogenic parasites suitable, among which as typical, occurring in the digestive tract Representatives of the species Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris and Enterobius to name are. The compounds of the present invention are also effective against parasites of the species Wuchereria, Brugia, Onchocerca and Loa the family of Filariidae, which are found in blood, tissue and various Organs occur, also against Dracunculus and parasites of the species Strongyloides and Trichinella, which specifically target the gastrointestinal canal infect.

The compounds of formula I are in unchanged form or preferably together with those customary in formulation technology Tools used and are therefore z. B. emulsion concentrates, directly sprayable or dilutable solutions, diluted Emulsions, wettable powders, soluble powders, dusts, Granules, also encapsulations in e.g. B. polymeric substances in processed in a known manner. The application methods like spraying,  Nebulization, dusting, scattering or pouring become the same as that Type of funds, the intended goals and the given circumstances chosen accordingly.

The compounds of the formula I are used in warm-blooded amounts from 0.01 to 10 mg / kg body weight applied over closed Cultivated areas, in pens, stables or other rooms in quantities of 10 g to 1000 g per hectare.

The formulations, i.e. H. containing the active ingredient of formula I. Agents, preparations or compositions are known in the art Made way, e.g. B. by intimate mixing and / or grinding the active ingredients with extenders, such as. B. with solvents, solid carriers, and optionally surface-active compounds (Surfactants).

Possible solvents are: Aromatic hydrocarbons, preferably fractions C ₈ to C ₁₂ , such as. B. xylene mixtures or substituted naphthalenes, phthalates such as dibutyl or dioctyl phthalate, aliphatic hydrocarbons such as cyclohexane or paraffins, alcohols and glycols and their ethers and esters such as ethanol, ethylene glycol, ethylene glycol monomethyl or ethyl ether, ketones such as cyclohexanone, strongly polar solvents such as N -Methyl-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide, and optionally epoxidized vegetable oils, such as epoxidized coconut oil or soybean oil; or water.

As solid carriers, e.g. B. for dusts and dispersible Powders, like natural rock flours, are usually used Calcite, talc, kaolin, montmorillonite or attapulgite. For improvement the physical properties can also be highly disperse Silicic acid or highly disperse absorbent polymers added will. Porous types come as granular, adsorptive granulate carriers such as B. pumice, broken brick, sepiolite or bentonite, as not sorptive carrier materials e.g. B. calcite or sand in question. Furthermore  can be a variety of pre-granulated inorganic materials or of an organic nature such as especially dolomite or crushed Plant residues can be used.

Depending on the type of, surface-active compounds are used formulating active ingredient non-ionic, cation and / or anion active Surfactants with good emulsifying, dispersing and wetting properties into consideration. Surfactants are also to be understood as mixtures of surfactants.

Suitable anionic surfactants can be both water-soluble Soaps as well as water-soluble synthetic surface-active Connections.

As soaps are the alkali, alkaline earth or optionally substituted ammonium salts of higher fatty acids (C ₁₀ -C ₂₂ ), such as. B. the Na or K salts of oleic or stearic acid, or of natural fatty acid mixtures, such as. B. can be obtained from coconut or tallow oil. The fatty acid methyl taurine salts should also be mentioned.

However, so-called synthetic surfactants are used more often, especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates.

The fatty sulfonates or sulfates are usually alkali, Alkaline earth or optionally substituted ammonium salts before and have an alkyl radical with 8 to 22 carbon atoms, alkyl also includes the alkyl portion of acyl residues, e.g. B. the Na or Ca salt lignin sulfonic acid, dodecyl sulfuric acid ester or one of Fatty alcohol sulfate mixture produced from natural fatty acids. This subheading also includes the salts of sulfuric acid and sulphonic acids of fatty alcohol-ethylene oxide adducts. The sulfonated Benzimidazole derivatives preferably contain 2-sulfonic acid groups and a fatty acid residue with 8 to 22 carbon atoms. Are alkylarylsulfonates  e.g. B. the Na, Ca or triethanolamine salts of dodecylbenzenesulfonic acid, of dibutylnapthalenesulfonic acid or a naphthalenesulfonic acid Formaldehyde condensation product.

Corresponding phosphates such as z. B. salts of Phosphoric acid ester of a p-nonylphenol (4-14) ethylene oxide adduct or phospholipids in question.

The surfactants commonly used in formulation technology are described in the following publication:
"Mc Cutcheon's Detergents and Emulsifiers Annual"
MC Publishing Corp., Ridgewood, New Jersey, 1982.

The pesticidal preparations usually contain 0.01 to 95%, in particular 0.1 to 80%, active ingredient of the formula I, 5 to 99.99% a solid or liquid additive and 0 to 25%, in particular 0.1 to 25% of a surfactant.

While concentrated goods are preferred as a commodity, the end user usually uses diluted agents 1-10,000 ppm active ingredient content.

Another subject of the present invention therefore relates Pesticide, in addition to usual carriers and / or distribution means as at least one active ingredient Contain compound of formula I.

The agents can also contain other additives such as stabilizers, defoamers, Viscosity regulators, binders, adhesives and Fertilizers or other active ingredients to achieve special effects contain.  

Production examples α-production of intermediates 1. Production of anhydrous HN ₃

1.1. In benzene. The production was carried out according to the instructions of H. Wolf, Org. Reactions 3, 307 (1946). The resulting solution of HN ₃ in benzene was dried twice over anhydrous Na ₂ SO ₄ (heated on a flame for 30 minutes and cooled in a desiccator) and filtered through cotton wool at 0 ° C. → 5 ° C. The solution was stored at 4 ° C in the refrigerator.

1.2. In ether. The preparation was carried out analogously to the above regulation, except that when the sulfuric acid was added, the reaction temperature was kept between -20 ° C and -10 ° C; after the addition of H ₂ SO ₄ , the reaction mixture was warmed to -5 ° C.

2. Preparation of 14,15-Epoxy-Milbemycin D (Formula VII)

A solution of 550 mg of milbemycin D in 5 ml of dichloromethane was added with ice cooling, a solution of 170 mg chloroperbenzoic acid in 5 ml Given dichloromethane. After stirring for 1 hour at 0 ° C to 5 ° C another 170 mg of the oxidizing agent were added, and more 30 min. touched. After the reaction had ended, the solution was poured into a ice-cold solution of sodium sulfite and poured with ethyl acetate extracted. The combined extracts were used once Washed water, dried and evaporated in vacuo. The raw product was by chromatography on a silica gel column (Eluent: n-hexane / ethyl acetate 20:15). It were 450 mg 14,15-epoxy-milbemycin D as an amorphous, white substance receive.

3. Preparation of 15-Hydroxy-Δ ¹³ , ¹⁴ -Milbemycin D (Formula VI)

It was at -20 ° C to a solution of 2.1 ml (1.75 g, 15.3 mmol) of triethyl aluminum in 8.5 ml (0.41 g, 9.53 mmol) of a 6.96 percent. Solution of HN ₃ in diethyl ether was added, which was then added at -10 ° C. under a strongly exothermic reaction to 1.8 g (3.15 mmol) of 14,15-epoxy-milbemycin D (in substance). After 1 hour at room temperature, 4 ml of absolute ether was added and the gelatinous reaction mixture was stirred vigorously. After 4 hours the mixture was worked up as described in procedure 2 and the chromatography on 70 g of silica gel (CH ₂ Cl ₂ / acetone 10: 1) gave 200 mg (10%) of 14-azido-15-hydroxymilbemycin D and 820 mg (45% ) 15-Hydroxy-Δ ¹³ , ¹⁴ -Milbemycin D, m.p .: 151 ° C-153 ° C (from methanol).

4. Preparation of 5-O-t-butyldimethylsilyl-14,15-epoxy Milbemycin D

A solution of 2.21 g (3.86 mmol) of 14.15-epoxy-milbemycin D, 757 mg (5.02 mmol) of t-butyldimethylchlorosilane and 342 mg (5.02 mmol) of imidazole in 4 ml of DMF was added for 90 min . stirred at room temperature. 80 ml of diethyl ether were then added, and the mixture was filtered through 20 g of silica gel and concentrated. 2.65 g (100%) of 5-ot-butyldimethylsilyl-14,15-epoxy-milbemycin D were obtained.
¹ H-NMR (300 MHz. Solvent CDCl _3. Measured values δ based on Si (CH ₃ ) ₄ = TMS).
0.12 ppm (s) (CH ₃ ) ₂ Si-O-;
0.92 ppm (s) (t.-C ₄ H ₉ ) Si-O-;
1.23 ppm (broad s) (C ₁₄ CH ₃ , ie signal of the CH ₃ group in the 14 position);
2.56 ppm (d; J = 9) (C ₁₅ H, ie signal of the proton in the 15 position).

Similar can be done by reaction with trimethylsilyl trifluoromethanesulfonate the corresponding 5-O-trimethylsilyl-14,15-epoxy Prepare Milbemycin D, mp 92-97 ° C.

5. Preparation of 5-Ot-Butyldimethylsilyl-15-hydroxy-Δ ¹³ , ¹⁴ -Milbemycin D (Formula VI)

A solution of the HN ₃ / Et ₃ Al complex reagent (prepared from a solution of 4.97 ml of triethylaluminum in 7 ml of absolute tetrahydrofuran (THF) and 9.15 ml of a 2.39 M solution of NH ₃ (21, 9 mmol) in absolute diethyl ether was added under argon to a solution of 5.0 g (7.29 mmol) 5-O-butyldimethylsilyl-14,15-epoxy-milbemycin D in approx. 20 ml absolute THF, and the mixture was added Heated under reflux for 16 hours, then 250 ml of ether, 2 ml of methanol and finally a mixture of 10 g of Na ₂ SO ₄ .10 H ₂ O and 10 g of Celite were added at room temperature, the mixture was filtered, concentrated and the chromatography the crude product on 160 g of silica gel (0-30% ethyl acetate in hexane) gave 2.37 g (47%) of 5-ot-butyldimethylsilyl-15-hydroxy-Δ ¹³ , ¹⁴ -milbemycin D.
¹ H-NMR (300 MHz, CDCl ₃ ):
1.59 (d; J = 1) (C ₁₄ CH ₃ );
4.06 (dd; J ₁ = 11; J ₂ = 4) (C ₁₅ H);
5.15 (d; J = 8) (C ₁₃ H).

In addition, 109 mg (2%) of 13β-azido-5-O-t-butyldimethylsilyl- Milbemycin D won.

6. Preparation of 14,15-Epoxy-Milbemycin A ₄ (Formula VII) (R ₂ = C ₂ H ₅ )

A solution of 2.43 g (14.08 mmol) was added to a solution of 5.7 g (10.5 mmol) of milbemycin A ₄ in 140 ml of dichloromethane and 120 ml of 0.5 M NaHCO ₃ solution. Chlorobenzoperic acid in 760 ml dichloromethane was added dropwise. The mixture was stirred vigorously for 1 hour at room temperature and then diluted with 300 ml dichloromethane. The organic phase was washed with aqueous NaHCO ₃ solution, dried with Na ₂ SO ₄ and concentrated. 5.7 g of epoxide were obtained as a crude product.

7. Preparation of 5-Ot-Butyldimethylsilyl-14,15-epoxy-Milbemycin A ₄ (Formula VII)

5.7 g of 14,15-epoxy-milbemycin A ₄ was dissolved in 10 ml of dry dimethylformamide (DMF). 0.63 g (9.16 mmol) of imidazole and 1.4 g (9.34 mmol) of t-butyldimethylchlorosilane were added at room temperature. The mixture was stirred for 1 hour at room temperature and chromatographed on 150 g of silica gel (hexane / ether 4: 1), giving 2.84 g (40% of theory, based on milbemycin A ₄ ) of the silylated epoxy derivative were.

8. Preparation of 5-Ot-Butyldimethylsilyl-15-hydroxy-Δ ¹³ , ¹⁴ - Milbemycin A ₄ (Formula VI)

The complex reagent HN ₃ / Al (ethyl) ₃ was prepared as follows: 2.8 ml (12.2 mmol) Al (C ₂ H ₅ ) ₃ in 4 ml abs. THF were slowly under argon at about -20 ° C with 5.28 ml (20.4 mmol) of a 10% solution of HN ₃ in abs. Diethyl ether added. A solution of 2.84 g (4.25 mmol) of the compound obtained in Example 7 was added to this solution under argon, and the mixture thus obtained was heated under reflux for 4 hours. At room temperature, 500 ml of diethyl ether, 10 g of Na ₂ SO ₄ .10H ₂ O and 10 g of Celite were added, and the mixture was filtered and concentrated. Chromatography of the crude product on 100 g of silica gel (hexane / diethyl ether 7: 2) gave 1.72 g (60% of theory) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ):
1.59 (br. S) (C ₁₄ CH ₃ );
4.05 (brs) (C ₁₅ H);
5.15 (d; J = 6) (C ₁₃ H).

In addition, 0.1 g of 13β-azido-5-ot-butyldimethylsilyl-milbemycin A _{4 was} obtained.

9. Preparation of 15-Hydroxy-Δ ¹³ , ¹⁴ -Milbemycin A ₄ (Formula VI)

The hydrolysis of the title compound mentioned in Example 8 with a 1% solution of p-toluenesulfonic acid in methanol and working up in diethyl ether with 5%. Na bicarbonate solution gave the Title link.  

10. Preparation of 14,15-Epoixi-Milbemycin A ₃ (Formula VII) (R ₂ = CH ₃ )

According to the procedure of Example 2, 220 mg of milbemycin A ₃ in 5 ml of dichloromethane and 320 mg of benzoperic acid in 5 ml of dichloromethane at -2 ° C. to + 5 ° C. for 1.5 hours and purification on a silica gel column 190 mg 14,14-epoxy-milbemycin A ₃ obtained.

11. Preparation of 5-O-methyldiphenylsilyl-14,15-epoxy-milbemycin A ₃

According to the procedure of Example 4, 190 mg of 14,15-epoxy-milbemycin A ₃ and 120 mg of diphenylmethylchlorosilane in the presence of imidazole give 217 mg of the title compound.

12. Preparation of 5-O-methyldiphenylsilyl-15-hydroxy-Δ ¹³ , ¹⁴ - milbemycin A ₃ (formula VI)

Analogously to the epoxy cleavage of Example 5, 210 mg of the 5-O-methyldiphenylsilyl-14,15-epoxy-milbemycin A ₃ in absolute diethyl ether with the aid of the complex reagent HN ₃ / Et ₃ Al under argon after subsequent purification Received title link.
¹ H NMR (300 MHz CDCl ₃ );
1.58 (br. S) (C ₁₄ CH ₃ );
4.05 (brs) (C ₁₅ H);
5.15 (d; J = 6) (C ₁₃ H).

13. Preparation of 15-Hydroxy-Δ ¹³ , ¹⁴ -Milbemycin A ₃ (Formula VI)

Analogously to Example 2, the reagent HN ₃ / Al (C ₂ H ₅ ) _{3 is} freshly prepared and at -10 ° C. to a solution of 830 mg (3.05 mmol) 14.15-epoxy-milbemycin A ₃ in 7 ml dripped dry diethyl ether. After working up, 385 mg of 15-hydroxy-Δ ¹³ , ¹⁴ -milbemycin A ₃ and 92 mg of 14-azido-15-hydroxy-milbemycin A ₃ are obtained.

14. Preparation of 13-deoxi-14,15-epoxi-22,23-dihydro-avermectin-Bla-aglykon (R ₂ = sec.C ₄ H ₉ ) (formula VII)

Analogously to Example 6, 520 mg of 13-deoxi-22,23-dihydro- avermectin-Bla-aglykon [Tetrahedron Letters, vol. 24, no. 48, pp. 5333-5336 (1983)] and 210 mg of m-chlorobenzoic acid in 20 ml Dichloromethane 510 mg of the title compound.

15. Preparation of 5-O-t-butyldimethylsilyl-13-deoxi-14.15 epoxi-22,23-dihydro-avermectin-Bla-aglykon (formula VII)

Analogously to Example 7, 220 mg of the title compound are obtained from Example 14 and 55 mg of tert-butyldimethylchlorosilane in the presence of 25 mg imidazole in 5 ml dry DMF 108 mg of the title compound.

16. Preparation of 13-deoxi-15-hydroxy-Δ ¹³ , ¹⁴ -22,23-dihydro-avermectin-Bla aglycone (formula VI)

Analogously to Example 3, 220 mg of the title compound of Example 15 with the complex reagent, consisting of 320 mg of Al (C ₂ H ₅ ) ₃ and 110 mg of a 6.96% solution of HN ₃ in a total of 16 ml of dry Diethyl ether 112 mg of the title compound. In addition, 61 mg of 13-deoxi-14-azido-15-hydroxy-22,23-dihydro-avermectin-Bla aglycone are obtained.

17. Preparation of 13-oxo-milbemycin D (Formula II)

1 ml of a 2% solution of p-toluenesulfonic acid in methanol is added to a solution of 53 mg (0.077 mmol) of 5-O-tert-butyldimethylsilyl-13-oxo-milbemycin D in 1 ml of methanol. After stirring for 1 h at room temperature, filtered through 5 g of silica gel, concentrated and the crude product obtained is chromatographed on 10 g of silica gel with ethyl acetate / hexane 1: 1. 31 mg (70%) of 13-oxo-milbemycin D are obtained.
¹ H-NMR (250 MHz, CDCl ₃ )
3.04 (6t, J = 8) (C ₂₅ H)
4.30 (dt, J _d = 15, J _t = 7) C ₂ H)
4.67 (dd, J ₁ = 15, J ₂ = 2) (C ₂₇ H H)
4.74 (dd, J ₁ = 15, J ₂ = 2) (C ₂₇ H H )
5.86 (dt, J _d = 12, J _t = 2.5) (C ₉ H)
6.05 (dd, J ₁ = 12, J ₂ = 15) (C ₁₀ H)
6.24 (t, J = 9) (C ₁₅ H)

18. Preparation of 5-O-tert-butyldimethylsilyl-13-oxo-milbemycin D (Formula II)

A solution of 280 μl (3.26 mmol) oxalyl chloride in 5 ml methylene chloride is mixed with 460 μl (6.48 mmol) DMSO at -60 ° C. After 5 min. a solution of 1.11 g (1.62 mmol) of 5-O-tert-butyldimethylsilyl-13β-hydroxy-milbemycin D in 5 ml of methylene chloride is added dropwise. After 30 min. at -60 ° C to -40 ° C, 2.3 ml (16.5 mmol) of triethylamine are added. The reaction mixture is allowed to warm to 20 ° C., filtered on 5 g of silica gel and the solution is concentrated. Chromatography of the crude product on 50 g of silica gel (ether / hexane 1: 2) gave 0.99 g (90%) of 5-O-tert-butyldimethylsilyl-13-oxo-milbemycin D.
¹ H NMR (250 MHz; CDCl ₃ );
3.04 (bd, J = 8) (C ₂₅ H)
4.43 (bd, J = 6) (C ₅ H)
4.60 (dd, J ₁ = 15, J ₂ = 3) (C ₂₇ H H)
4.72 (dd, J ₁ = 15, J ₂ = 2) (C ₂₇ H H )
5.82 (bd, J = 12) (C ₉ H)
6.04 (dd, J ₁ = 15, J ₂ = 12) (C ₁₀ H)
6.23 (t, J = 9) (C ₁₅ H)

19. Preparation of 5-O-tert-Butyldimethylsilyl-13-oxo-Milbemycin A ₄ (Formula II)

Analogously to Example 18, 470 mg (0.69 mmol) of 5-O-tert-butyldimethylsilyl-13β-hydroxy-milbemycin A ₄ and 118 μl (1.37 mmol) oxalyl chloride, 195 μl (2.75 mmol) DMSO and 0.96 ml (6.88 mmol) of triethylamine 412 mg (88%) of 5-O-tert-butyldimethylsilyl-13-oxo-milbemycin A _{4 were} obtained.
¹ H-NMR (250 MHz; CDCl ₃ )
3.05 (dt, J _d = 2, J _t = 9) (C ₂₅ H)
4.45 (bd, J = 6) (C ₅ H)
4.61 (dd, J ₁ = 15, J ₂ = 3) (C ₂₇ H H)
4.75 (dd, J ₁ = 15, J ₂ = 3) (C ₂₇ H H )
5.83 (bd, J = 12) (C ₉ H)
6.02 (dd, J ₁ = 15, J ₂ = 12) (C ₁₀ H)
6.22 (t, J = 9) (C ₁₅ H)

20. Preparation of 13-Oxo-Milbemycin A ₄ (Formula II)

A solution of 54 mg (0.081 mmol) of 5-O-tert-butyldimethylsilyl-13-oxo-milbemycin A ₄ in 1 ml of 40% HF / acetonitrile (5:95) is stirred for 1 hour at room temperature, filtered through silica gel and concentrated . Chromatography on 10 g of silica gel with ethyl acetate / hexane (1: 1) gives 35 mg (78%) 13-oxo-milbemycin A ₄
¹ H-NMR (250 MHz, CDCl ₃ )
3.03 (dt, J _d = 3, J _t = 10) (C ₂₅ H)
4.31 (dt, J _d = 2, J _t = 7) C ₅ H)
4.68 (dd, J ₁ = 15, J ₂ = 2) (C ₂₇ H H)
4.74 (dd, J ₁ = 15, J ₂ = 2) (C ₂₇ H H )
5.85 (dt, J _d = 12, J _t = 2) (C ₉ H)
6.03 (dd, J ₁ = 15, J ₂ = 12) (C ₁₀ H)
6.21 (t, J = 9) (C ₁₅ H)

21. Preparation of 5-O-tert-butyldimethylsilyl-13-oxo-milbemycin D (Formula II)

A solution of 158 mg (0.23 mmol) of 5-O-tert-butyldimethylsilyl-15-hydroxy-Δ ¹³ , ¹⁴ -milbemycin D and 500 mg (1.33 mmol) of PDC in 1 ml of DMF was 40 min. stirred at room temperature. The mixture was diluted with 20 ml of dichloromethane, filtered through 5 g of silica gel and concentrated. Chromatography of the crude product on 20 g of silica gel (ethyl acetate / hexane 1: 4) gave 67 mg of 5-ot-butyldimethylsilyl-13-oxo-milbemycin D and showed the NMR spectra mentioned in Example 18.

22a. Preparation of 5-O-tert-butyldimethylsilyl-13β-hydroxy milbemycin D and 13β-hydroxy-milbemycin D (formula V)

A solution consists of 286 mg (0.41 mmol) of 5-O-tert-butyldimethylsilyl-15-hydroxy-Δ ¹³ , ¹⁴ -milbemycin D and 209 mg (0.56 mmol) of pyridinium dichromate (PDC) in 3 ml of dimethylformamide ( DMF) was 30 min. stirred at room temperature. Then 1 ml of isopropanol was added, 5 min. stirred further and then diluted with 50 ml of ether. After another 10 min. the mixture was filtered through silica gel and concentrated. Chromatography of the crude product on 20 g of silica gel (ether / hexane 1: 2) gave 165 mg (57%) of 5-ot-butyldimethylsilyl-13Δ-hydroxy-milbemycin D.
¹ H-NMR (300 MHz; CDCl ₃ ; TMS):
1.59 (br. S) (C ₁₄ CH ₃ )
3.70 (d; J = 10) (C ₁₃ H).

105 mg (0.153 mmol) of the compound obtained in this way were stirred with 1 ml of a 1% strength solution of p-toluenesulfonic acid in methanol for 1 hour at room temperature. The mixture was diluted with 20 ml of ether, filtered through silica gel, concentrated, and the residue was chromatographed on about 10 g of silica gel (acetone / dichloromethane 1: 4), 73 mg (83%) of 13β-hydroxy-milbemycin D being obtained .
¹ H-NMR (300 MHz; CDCl ₃ ; TMS):
1.58 (br. S) (C ₁₄ CH ₃ )
3.71 (d; J = 10) (C ₁₃ H).

22b. Preparation of 5-O-tert-butylmethylsilyl-13β-hydroxymilbemycin A ₄ and of 13β-hydroxymilbemycin A ₄ (formula V)

Analogously to regulation 22a, 5-O-tert.-butyldimethylsilyl-13β-hydroxymilbemycin (mass spectrum m / e: 672) is obtained, which after cleavage of the tert.-butyldimethylsilyl group according to regulation 33a leads to 13β-hydroximilbemycin A ₄ (mass spectrum m / e: 558).

β-preparation examples for end products of the formula I Preparation of compounds of the formula I H1: Preparation of 5-O-tert-butyldimethylsilyl-13-methylidene Milbemycin D

A solution of 102 mg of 5-O-tert-butyldimethylsilyl-13-oxo-milbemycin D in 1.5 ml of toluene and 0.5 ml of tetrahydrofuran was mixed with 10 μl of pyridine and then cooled to -40 ° C. After the addition of 0.45 ml of a 1M solution of Cp ₂ TiCH ₂ AlCl (CH ₃ ) ₂ (IV, Z1) in toluene, the mixture was stirred under argon at -40 ° C. for 5 minutes and then to 0 over a period of 90 minutes Let it warm up. After cooling to -20 ° C, 160 ul 15% NaOH were added and warmed up slowly to room temperature. The reaction mixture was diluted with 50 ml of diethyl ether, dried with MgSO ₄ , filtered with the aid of Celite and evaporated. After chromatography of the crude product on silica gel with diethyl ether / hexane 1: 9, 63 mg of 5-O-tert-butyldimethylsilyl-13-methylidene-milbemycin D could be isolated.
¹ H-NMR (250MH ₃ , CDCl ₃ ):
3.08 ppm (m) (C ₂₅ H and C ₁₂ H)
4.45 ppm (bs) (C ₅ H)
4.73 ppm (bs) (C ₁₂ = C H H)
4.94 ppm (bs) (C ₁₂ = CH H )
MS: m / e: 682 (M⁺; C ₄₀ H ₆₂ O ₇ Si)

H2: Preparation of 5-O-tert-butyldimethylsilyl-13-methylidene-milbemycin A ₃

Analog Production Example H1 can be prepared from 5-O-tert.Butyldimethylsilyl- 13-oxo-milbemycin A ₃ 5-O-tert-butyldimethylsilyl-13-methylidene-milbemycin A win. ₃

H3: Preparation of 5-O-tert-butyldimethylsilyl-13-methylidene-milbemycin A ₄

A solution of 92 mg of 5-O-tert-butylmethylsilyl-13-oxo-milbemycin A ₄ in 2 ml of toluene / tetrahydrofuran (3: 1) is mixed with 10 μl of pyridine and then cooled to -40 ° C. After the addition of 200 μl of a 1M solution of Cp ₂ TiCH ₂ AlCl (CH ₃ ) ₂ (IV, Z1) in toluene, the mixture is stirred for 15 minutes at -40 ° C. under argon and the mixture is stirred for a further 30 minutes until it dissolves Warmed to -20 ° C. After cooling again to -40 ° C., a further 80 μl of a 1M solution of Cp ₂ TiCH ₂ AlCl (CH ₃ ) ₂ (IV, Z1) are added, then the mixture is stirred for 15 minutes at -40 ° C. and within approx. Bring to -20 ° C for 30 min. At this temperature, 70 ul 15% NaOH is added to the reaction mixture and, after warming up to room temperature, diluted with 50 ml diethyl ether. The suspension obtained is dried with MgSO ₄ , filtered using Celite and evaporated. Chromatography of the crude product on silica gel with diethyl ether / hexane (1: 6) gives 66 mg of 5-O-tert-butyldimethylsilyl-13-methylidene-milbemicyin A ₄ .
¹ H-NMR (300 MHz, CDCl ₃ ):
3.04 ppm (m) C ₂₅ H and C ₁₂ H)
4.43 ppm (bs, w = 12) (C ₅ H) 4.69 ppm (bs, w = 5) (C ₁₃ = C H H) 4.91 ppm (bs, w = 5) (C ₁₃ = CH H )
MS: m / e: 668 (M⁺; C ₃₉ H ₆₀ O ₇ Si)

H4: Preparation of 5-O-tert-butyldimethylsilyl-13-methylidene 22,23-dihydro-avermectin-Bla aglycone

Analogously to Example H1, 5-O-tert-butyldimethylsilyl- 13-oxo-22,23-dihydro-avermectin-Bla-aglykon 50 mg 5-O- tert-butyldimethylsilyl-13-methylidene-22,23-dihydro-avermectin Bla-aglykon.

H5: Preparation of 13-methylidene-milbemycin D

A solution of 52 mg of 5-O-tert-butylmethylsilyl-13-methylidene-milbemycin D in 2 ml of 40% HF / acetonitrile 5:95 is stirred for one hour at room temperature and then diluted with 50 ml of diethyl ether. The solution obtained is washed with 20 ml of saturated NaHCO ₃ solution and 20 ml of saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated. After chromatography of the crude product on silica gel with diethyl ether / hexane 1: 1, 40 mg of 13-methylidene-milbemycin D are obtained
¹ H-NMR (250 MHz, CDCl ₃ ):
3.08 ppm (m) (C ₂₅ H and C ₁₂ H)
4.31 ppm (bt, J = 7) (C ₅ H)
4.70 ppm (bs) (C ₁₃ = C H H)
4.94 ppm (bs) (C ₁₃ = CH H )
MS: m / e: 568 (M⁺; C ₃₄ H ₄₈ O ₇ ).

H6: Preparation of 13-methylidene-milbemycin A ₄

61 mg of 5-O-tert-butyldimethylsilyl-13-methylidene-milbemycin A ₄ are treated analogously to Example H5 with 2 ml of 40% HF / acetonitrile (5:95). Chromatography of the crude product on silica gel with ethyl acetate / hexane (1: 2) gives 44 mg of the title compound.
¹ H-NMR (300 MHz, CDCl ₃ ):
3.06 ppm (m) C ₂₅ H and C ₁₂ H)
4.29 ppm (bt, J = 7.5) (C ₅ H) 4.69 ppm (bs, w = 4) (C ₁₃ = C H H) 4.93 ppm (bs, w = 4) (C ₁₃ = CH H )
MS: m / e: 554 (M⁺; C ₃₃ H ₄₆ O ₇ )

H7: Preparation of 13-methylidene-milbemycin A ₃

Analogously to Example H5 can be produced _{3 3} 13-methylidene-milbemycin A of 5-O-tert-butyldimethyl-13-methylidene-milbemycin A.

H8: Preparation of 13-methylidene-22,23-dihydro-avermectin Bla-aglykon

By treating 39 mg of 5-O-tert-butyldimethylsilyl-13- methylidene-22,23-dihydro-avermectin-Bla aglycone with HF / acetonitrile 28 mg of 13-methylidene-22,23-dihydro- are obtained analogously to Example H5 avermectin-Bla aglycon.

According to the working methods described, the prepare the compounds of the formula I listed below, whereby the listing is to be understood as an example and accordingly has no limiting character.

Table 1: Compounds of formula I with R ₁ = H

Table 2: Compounds of formula I, wherein R _{1 represents} a protective group.

Formulation examples for the active ingredient of the formula I.

(% = Weight percent)

The active ingredient is mixed well with the additives and ground well in a suitable mill. You get wettable powder that is dilute with water to form suspensions of any desired concentration to let.  

Emulsion concentrate

This concentrate can be diluted with water to make emulsions any desired concentration.

Dusts

Ready-to-use dusts are obtained by adding the active ingredient the carrier is mixed and ground on a suitable mill.

Extruder granules

The active ingredient is mixed with the additives, ground and moistened with water. This mixture is extruded and then dried in an air stream.

Tables or boluses

Stir methyl cellulose in water and allow to swell; Stir the silica into the swelling and suspend homogeneously. Mix active ingredient and corn starch. Work the aqueous suspension into this mixture and knead into a dough. Granulate this mass through a sieve (mesh size 12 M) and then dry.

Mix all 4 additives well
Mix phases I and II and compress to tablets or boluses.

If the compounds of formula I or corresponding agents for Control of endoparasitic nematodes, cestodes and trematodes in domestic and farm animals such as cattle, sheep, goats, cats and Dogs, used, can be given to animals as a single dose as well as being administered repeatedly, the individual Depending on the animal species, preferably between 0.1 and 10 mg per kg Body weight. Through a protracted administration you can achieve a better effect in some cases or you can with lower total doses. The active ingredient or the him Containing agents can also be added to the feed or the drinkers will. The finished feed contains the active ingredient combinations preferably in a concentration of 0.005 to 0.1% by weight. The Agents can be in the form of solutions, emulsions, suspensions, Powder, tablets, boluses or capsules are administered orally to the animals will. So much for the physical and toxicological Properties of solutions or emulsions allow this Compounds of the formula I or the compositions containing them on animals, too for example injected subcutaneously, administered intraruminally or  applied to the animal's body using the pour-on method will. Furthermore, the active ingredient is administered to the animals also possible with salt licks or molasses blocks.

Biological examples B-1. Insecticidal food poison effect in Spodoptera littoralis

Potted cotton plants in the 5-leaf stage are treated with a sprayed acetone / aqueous test solution, the 3, 12.5 or Contains 50 ppm of the compound to be tested.

After the covering has dried on, the plants are populated with approximately 30 larvae (L ₁ stage) of Spodoptera littoralis. Two plants are used per test compound and per test species. The test is carried out at approx. 24 ° C and 60% relative humidity. Evaluations and intermediate evaluations on moribund animals, growth and larvae and feeding damage take place after 24 hours, 48 hours and 72 hours.

Compounds from Tables 1 and 2 already achieved one Drug concentration of 3 ppm after a complete kill 24 hours.

B-2. Effect against plant-damaging acarids OP-sensitive Tetranychus urticae

The primary leaves of bean plants (Phaseolus vulgaris) are 16 hours before the experiment with a T. urticae-infested Leaf piece originating from a mass breed. The same with everyone Mites stages of infested plants are removed after removal of the Sprayed piece of sheet with a test solution to the point of dripping, either 0.4 ppm or 1.6 ppm of the compound to be tested contains. The temperature in the greenhouse cabin is approx. 25 ° C.

After seven days, the percentage becomes more mobile under the binocular Stages (adults and nymphs) and evaluated for existing eggs.  

Compounds from Tables 1 and 2 already achieved one Drug concentration of 0.4 ppm complete kill.

B-3. Effect against L ₁ larvae of Lucilia sericata

1 ml of an aqueous suspension of the active substance to be tested is mixed with 3 ml of a special larvae growth medium at approx. 50 ° C in such a way that a homogenate of either 250 ppm or 125 ppm active substance content is produced. Approx. 30 Lucilia larvae (L ₁ ) are used in each test tube sample. The mortality rate is determined after 4 days. The compounds from Tables 1 and 2 achieved an activity of 100% with 250 ppm.

B-4. Acaricidal activity against Boophilus microplus (Biarra strain)

An adhesive tape is attached horizontally to a PVC plate so the 10 female Boophilus tick-soaked with blood microplus (Biarra strain) side by side in a row with their backs can be glued on. Each tick comes with an injection needle 1 µl of a liquid injected containing a 1: 1 mixture of Represents polyethylene glycol and acetone and in which a certain Active ingredient amount of either 1, 0.1 or 0.01 µl per tick dissolved is. Control animals are given a drug-free injection. After The animals are treated under normal conditions in one Insectarium at approx. 28 ° C and 80% relative humidity held until the egg is laid and the larvae from the eggs of the Control animals have hatched.

The activity of a tested substance is determined with the IR ₉₀ , ie the active substance dose is determined at which 9 out of 10 female ticks (= 90%) still lay eggs after 30 days that are not capable of hatching.

Compounds from Tables 1 and 2 achieve an IR ₉₀ of 0.1 µg.

B-2. Trial with nematodes (Haemonchus concortus and Trichostrongylus colubriformis) infected sheep

The active ingredient is formulated as a suspension with a gastric tube or given by injection into the rumen of a sheep that has Haemonchus concortus and Trychostrongylus colubriformis artificial has been infected. 1 to 3 animals are used per dose. Each sheep is treated only once with a single dose, and either with 1 mg or 0.5 mg / kg body weight. The evaluation is done by comparing the number of before and after treatment Worm eggs excreted in the droppings of the sheep.

At the same time and similarly infected but untreated sheep serve as a control. Sheep with a connection from the Tables 1 and 2 treated at 1 mg / kg showed comparison no treatment of nematodes to untreated but infected control groups (= complete reduction of the worm eggs in the faeces).

B-6. Contact effect on Aphis craccivora

Pea seedlings, with all stages of development of the louse are infected with one from an emulsion concentrate manufactured drug solution sprayed, the optional 50 ppm, 25 ppm or contains 12.5 ppm of active ingredient. After 3 days, more than 80% dead or fallen aphids evaluated. Only this one A drug is classified as effective.

Compounds from Tables 1 and 2 achieved at one concentration of 12.5 ppm a complete kill (= 100%).

B-7. Larvicidal activity against Aedes aegypti

On the surface of 150 ml of water, which is in a container is so much of a 0.1% acetone solution of Active ingredient pipettes that concentrations of either 10 ppm, 3.3 ppm and 1.6 ppm can be obtained. After the acetone has evaporated the container is loaded with approx. 30-40 Aedes larvae for 3 days. Mortality is checked after 1, 2 and 5 days.  

Compounds from Tables 1 and 2 contribute in this test a concentration of f 1.6 ppm is complete after one day Killing all larvae.

Claims (21)

1. Compounds of formula I. wherein
R represents methyl, ethyl, isopropyl or sec-butyl;
R _{1 represents} hydrogen or a protective group. 2. Compounds of formula I according to claim 2, wherein
R represents methyl, ethyl, isopropyl or sec-butyl; and
R _{1 represents} hydrogen, araliphatic radical, alkoxyalkoxymethyl or the group Si (R ₂ ) (R ₃ ) (R ₄ ), where
R ₂ , R ₃ and R ₄ independently of one another are C ₁ -C ₆ alkyl, benzyl or phenyl. 3. Compounds of formula I according to claim 2, wherein
R represents methyl, ethyl, isopropyl or sec-butyl; and
R _{1 represents} hydrogen, benzyl or methoxymethoxymethyl or one of the groups trimethylsilyl, thexyldimethylsilyl, tris (tert-butyl) silyl, diphenyl-tert-butylsilyl, bis (isopropyl) methylsilyl, triphenylsilyl or tert-butyldimethylsilyl. 4. Compounds of formula I according to claim 3, wherein
R represents methyl, ethyl, isopropyl or sec-butyl; and
R ₁ means hydrogen. 5. A compound of formula I according to claim 4, selected from the series 13-methylidene-milbemycin A ₃
13-methylidene-milbemycin A ₄
13-methylidene-milbemycin D
13-methylidene-13-deoxy-22,23-dihydro-avermectin-Bla aglycon. 6. A compound of formula I according to claim 3, selected from the series 5-O-tert-butyldimethylsilyl-13-methylidenmilbemycin A ₃
5-O-tert-butyldimethylsilyl-13-methylidene milbemycin A ₄
5-O-tert. Butyldimethylsilyl-13-methylidene milbemycin D
5-O-tert. Butyldimethylsilyl-13-methylidene-22,23-dihydroavermectin Bla aglycon. 7. A process for the preparation of compounds of formula I, characterized in that a compound of formula II, wherein R ₁ and R _{2 have} the meanings given under formula I, with a to release the titanium complex of formula III qualified reagent. 8. The method according to claim 7, characterized in that it is in the release of compounds of formula III is a compound of formula IV wherein Y represents aluminum; and
R ₅ and R _{6 are} independently C ₁ -C ₆ alkyl; b) -X (R ₇ ) - represents -CH ₂ -;
Y represents a four-bonded carbon atom; and
R ₅ and R ₆ together form an C ₃ -C ₆ alkylene bridge which is unsubstituted or substituted by C ₁ -C ₆ alkyl or phenyl; or c) X represents -CH (R ₇ ) -;
R _{5 represents} hydrogen;
Y represents a four-bonded carbon atom; and
R ₆ and R ₇ together form a C ₃ -C ₆ alkylene bridge; or d) -X (R ₇ ) - represents -CH ₂ -;
Y represents a four-bonded carbon atom; and
R ₅ and R _{6 are} independently hydrogen, phenyl, substituted or unsubstituted C ₁ -C ₆ alkyl. 9. The method according to claim 8, characterized in that one uses a compound of formula IV, wherein Y represents aluminum; and
R ₅ and R _{6 are} methyl; b) -X (R ₇ ) - represents -CH ₂ -;
Y represents a four-bonded carbon atom; and
R ₅ and R ₆ together represent an unsubstituted or methyl group,
represent tert-butyl or phenyl substituted butylene or pentylene bridge; or c) X represents -CH (R ₇ ) -;
R _{5 represents} hydrogen;
Y represents a four-bonded carbon atom; and
R ₆ and R ₇ together form a propylene or butylene bridge; or d) -X (R ₇ ) - represents -CH ₂ ;
Y represents a four-bonded carbon atom; and
R ₅ and R ₆ independently of one another represent hydrogen, C ₁ -C ₃ alkyl, tert-butyl or phenyl. 10. Means for controlling parasitic pests, thereby characterized that it is in addition to usual formulation auxiliaries contains at least one compound of formula I according to claim 1. 11. A composition according to claim 10, characterized in that it as Compound of formula I at least one compound according to Claims 2 or 6 contains. 12. Use of compounds of formula I according to one of the Claims 1 to 6 for combating ectoparasites, endoparasites and Insects on animals and plants. 13. Use according to claim 12 for combating endoparasites in warm-blooded animals.   14. Use according to claim 13, characterized in that it the endoparasites are nematodes. 15. methods of combating pests on animals and plants, characterized in that a compound of formula I according to one of claims 1 to 6 on or in the animal to which Plant or both habitat applied.