DE4031039A1 - O-Oleandrosyl-substd. milbemycin derivs. - used for control of animal and plant ectoparasites and endoparasites - Google Patents

Abstract

Mibemycin derivs. (I) are new, where R1 = H or SiR4 R5 R6; R2 = alpha-linked gp. (a) R3 = H or SiR4R5R6; R4, R5, R6 = 1-4C alkyl, phenyl or benzyl; the wavy line is an alpha- or beta-orientated bond. 6 Cpds. (I), e.g. 5-O-tert.butyldimethylsilyl-13alpha- O-(4'-O-(4''-O-tert.butyldimethyl silyl-alpha-L-oleandrosyl)-alpha-L- oleandrosyl) milbemycin A4.

Description

The present invention relates to novel 13α-sugar derivatives of Milbemycin A₄ of the following formula I, their preparation and their Use for controlling pests such as ecto- and endoparasites Animals and plants.

The compounds according to the invention are 13α-sugar derivatives of Milbemycin A₄ having the general formula I.

wherein
R₁ is hydrogen or Si (R₄) (R₅) (R₆);
R₂ occupies the α-position on the C13 atom and for one of the sugar residues

stands; in which
R₃ is hydrogen or Si (R₄) (R₅) (R₆); and
R₄, R₅ and R₆ independently represent C₁-C₄-alkyl, benzyl or phenyl.

The residue Si (R₄) (R₅) (R₆) thus forms, for example, the following groups Trimethylsilyl, tris (t-butyl) silyl, diphenyl-tert.-butylsilyl, bis (isopropyl) methylsilyl, dimethyl- (2,3-dimethyl-2-butyl) silyl, triphenylsilyl etc., and especially tert-butyl-dimethylsilyl.

By the term alkyl itself or as part of another Substituents are, for example, depending on the number of carbon atoms given to understand the following groups: methyl, ethyl, propyl, butyl, Pentyl, etc., and the isomers, such as. Isopropyl, isobutyl, tert-butyl, etc.

The above formula I and the formula images of the sugar residues (R₂) - namely the Groups (α, α) and (β, α) reflect stereochemical relationships again, d. h., They show in principle the spatial structure of the molecule, since the solid lines of bonding as lying in the (paper) plane while dotted lines are under the (paper) plane and arrows stick out of the (paper) plane. The rest R₂ is z. B. with a dotted line linked to the carbon atom C13 of the macrocycle and thus always occupies the α-position on said C13 atom, while the β-position is occupied by hydrogen. Conversely, the OR₁ group decreases at the C5 atom, the β-position, while the α-position at the C5 atom by Hydrogen is occupied. Accordingly, the sugar residue with respect to the bridge oxygen atom occupy the α or β position.

Preferred individual substances of the formula I are z. B .:

5-O-tert-butyldimethylsilyl-13α-O- [4'-O- (4 '' - O-tert-butyldimethylsilyl
α-L-oleandrosyl) -α-L-oleandrosyl] milbemycin A₄;
5-O-tert-butyldimethylsilyl-13α-O- [4'-O- (4 '' - O-tert-butyldimethylsilyl
α-L-oleandrosyl) -β-L-oleandrosyl] milbemycin A₄;
13α-O- [4'-O- (4 "-O-tert-butyldimethylsilyl-α-L-oleandrosyl) -α-L-oleandrosyl] milbemycin A₄;
13α-O- [4'-O- (4 "-O-tert-butyldimethylsilyl-α-L-oleandrosyl) -β-L-oleandrosyl] milbemycin A₄;
and particularly
13α-O- [4'-O- (α-L-oleandrosyl) -α-L-oleandrosyl] milbemycin A₄; and
13α-O- [4'-O- (α-L-oleandrosyl) -β-L-oleandrosyl] milbemycin A₄.

13β-O- [4'-O- (L-oleandrosyl) -L-oleandrosyl] milbemycins, their preparation and use are in the European patent application EP-O 02 35 085 describes the 13α-milbemycins of the invention However, formula I are the parasiticidal activity significantly superior to previously known 13β isomers.

Formula I thus represents milbemycin derivatives that are in the 5-position have either a free OH group or a silyl group and in 13α-position an oxygen-bound 4'-O- (L-oleandrosyl) - L-oleandrosyl radical as substituents [cf. the groups (α, α) and (β, α) in claim 1].

The present invention relates not only to the compounds of Formula I, but equally the process for their preparation. It namely, it was surprisingly found that the compounds of the Formula I by reaction of a compound of formula II

wherein R₁ has the meanings given under formula I, with a reactive, optionally at the terminal hydroxy group Si (R₄) (R₅) (R₆) protected 4'-O- (olenadrosyl) -L-oleandrosederivat where R₁, R₄, R₅ and R₆ are those of formula I have given meanings.  

The inventive method thus forms the possibility in the 13α-position of milbemycin A₄ derivatives targeted under formula I. defined sugar moiety bonded via an oxygen atom [4'-O- (Oleandrosyl) -L-oleandrose] introduce and thus highly effective Parasiticides and insecticides, which, moreover, for further Derivatizations can be used.

The preparation of compounds of the formula I which are attached to the oxygen atom in the 5-position carry a Si (R₄) (R₅) (R₆) group, provides a derivatization the reactive 13α-hydroxy group of 13α-hydroxy Milbemycin A₄ is and is one of the one used in sugar chemistry Linking methods, eg. B. after the Koenigs-Knorr synthesis, the Ag triflate process, according to the so-called orthoester method, the Phenylthio synthesis or 2-pyridylthio synthesis performed.

A) After the Koenigs-Knorr synthesis or the silver triflate process leaves a 13α-hydroxy-milbemycin of the formula II (R₁ = Si (R₄) (R₅) (R₆)) in Presence of a silver salt or mercury salt as a condensing agent with the sugar residue of the formula III to be introduced

Hal is halogen, preferably chlorine or bromine; and R₃ for Si (R₄) (R₅) (R₆), wherein R₄, R₅ and R₆ are those given under formula I. Meanings, in the temperature range from -30 ° C to + 60 ° C, preferred -5 ° C to + 30 ° C with exclusion of light gain.

As a silver salt can be freshly precipitated Ag₂O use, preferably but Ag₂CO₃ or CF₃-COOAg. Particularly preferred is silver trifluoromethanesulfonate (Ag triflate = CF₃-SO₃Ag), in whose presence the Glycosidation proceeds rapidly even at minus temperatures. To the Activation of the 13α-OH group of the 13α-hydroxy-milbemycin A₄ and the  Neutralizing the optionally resulting GF₃-SO₃H or CF₃-COOH it is expedient to use a tertiary amine (triethylamine, diisopropylethylamine, Diazabicycloundecane u. a.) Of the reaction solution.

If desired, the protecting group Si (R₄) (R₅) (R₆) on the sugar residue by mild saponification [K₂CO₃ / CH₃OH or (C₄H₉-n) ₄N⊕F⊖ / THF] then be split off. Solvents are used in this partial step in particular anhydrous aprotic representatives such as dichloromethane, acetonitrile, Benzene, toluene, nitromethane, dioxane, THF, ethylene glycol dimethyl ether in question; Diethyl ether is particularly suitable.

The protected 1-chloro or 1-bromo-sugar is added in equimolar amount to 13α-hydroxy-milbemycin used A₄ (II), but preferably in one 1.5 to 3 times the excess. The reaction time is one to achieve satisfactory yield, 5 to 72 hours.

Instead of the silver salt can also be Hg-cyanide or a combination of HgO optionally use Hg chloride or Hg bromide (helper Synthesis).

According to another variant, the reactivity of the 4'-O- (Oleandroxyl) -L-oleandrosylrestes, whose OH group must be protected, by initial conversion to the 1'-phenylthio derivative and subsequent reaction with DAST (= diethylaminosulfur trifluoride) in absolutely dry dichloromethane (molecular sieve) at + 5 ° C to -30 ° C for Increase 1'-fluoro derivative. More reactive than the corresponding, at the Koenigs-Knorr synthesis used 1'-chloro or 1'-bromine derivative the thus obtained 1'-fluoro derivative of the carbohydrate reactant with 13a-Hydroxy-Milbemycin A₄ (II) in the presence of SnCl₂ and AgClO₄ in one dry aprotic solvents such as diethyl ether under inert gas such Linking argon at + 5 ° C to -30 ° C (J. Am. Soc., 1984, 106, 4189-4192).

B) A better reaction is achieved when the terminally protected 4'-O- (Oleandrosyl) -L-oleandrose with 2,2'-dithiopyridine in dry dichloromethane at about 0 ° C and under argon atmosphere in the 1'-S- (2-pyridyl) - Converted with the free 13α-OH group of 13α-hydroxy  Milbemycin A₄ of the formula II in the presence of Pb (ClO) ₄ or AgClO₄ as Condensing agent at -30 ° C to room temperature in tetrahydrofuran (THF) as a solvent slightly to form the glycosidic bond reacts (J. Org. Chem., 1983, 48, 3489-3493).

The process for the preparation of 13α-O- [4'-O- (oleandrosyl) -L- oleandrosyl] milbemycin A₄ derivatives of the formula I, wherein R₁ and R₂ are the have meanings given under formula I is characterized in by the reaction of 5-O-protected 13α-hydroxy-milbemycin A₄ of formula II

• a) in the presence of a silver salt or mercury salt as condensing agent with the sugar residue of the formula III to be introduced wherein R₃ is Si (R₄) (R₅) (R₆), Hal is halogen, preferably chlorine or bromine and R₄, R₅ and R₆ have the meanings given under formula I, with light connection in the temperature range from -30 ° C to + 60 ° C, preferably -5 ° C to + 30 ° C; or
• b) in the presence of SnCl₂ and AgClO₄ as condensing agent with the Sugar residue of formula III, wherein Hal is fluorine, with light connection at + 5 ° C to -30 ° C; or
• c) in the presence of Pb (ClO₄) ₂ or AgClO₄ as condensing agent with the introduced 4'-O- (oleandrosyl) -L-oleandrose of formula IV wherein R₃ is Si (R₄) (R₅) (R₆) and R₄, R₅ and R₆ have the meanings given under formula I, at -30 ° to room temperature in tetrahydrofuran (THF) as a solvent; and, if desired, mild saponification of the hydroxyl-protecting groups, wherein trisubstituted silyl groups with fluoride ions or z. B. with K₂CO₃ / methanol at 0-5 ° C can be saponified. After the glycosidation reaction, the silyl protecting group is conveniently prepared by treatment of the compound of formula I with a dilute acid such. With 1proz. p-toluenesulfonic acid in methanol with an aqueous HF solution in acetonitrile in the temperature range -30 ° to 0 ° C, preferably at -10 ° or with pyridinium fluoride in pyridine cleaved again.

O-4'-O- (oleandrosyl) -L-oleandrose is known and can be per se convert known methods into the compounds of formulas III or IV.

The 13α-hydroxy compounds of the formula II are known from the European Publication EP 1 80 539 known.

The compounds of formula I are excellent for controlling pests on animals and plants, including animal parasitic ecto- Parasites. To the latter belong under the order Acarina in particular Pests of the families Ixodidae, Dermanyssidae, Sarcoptidae, Psoroptidae; the orders Mallophaga; Siphonaptera, Anoplura (eg. Family of Haemotopinidae); under the order Diptera in particular Pests of the families Muscidae, Calliphoridae, Oestridae, Tabanidae, Hippoboscidae, Gastrophilidae.

The compounds I can also be used against hygiene pests, in particular the orders Diptera with the families Sarcophagidae, Anophilidae, Culicidae; order Orthoptera, order Dictyoptera (eg family Blattidae) and the order Hymenoptera (eg family Formicidae).  

The compounds I also have sustained activity in plant parasitics Mites and insects. In spider mites of the order Acarina are they are effective against eggs, nymphs and adults of Tetranychidae (Tetranychus spp., And Panonychus spp.).

They have high activity in sucking insects of order Homoptera, in particular against pests of the families Aphididae, Delphacidae, Cicadellidae, Psyllidae, Loccidae, Diaspididae and Eriophydidae (eg the rust mite on citrus fruits): the orders Hemiptera; Heteroptera and Thysanoptera; as well as herbivorous Insects of the orders Lepidoptera; Coleoptera; Diptera and Orthoptera.

They are also used as soil insecticide against pests in the soil suitable.

The compounds of formula I are therefore against all stages of development sucking and eating insects on crops such as cereals, cotton, Rice, Corn, Soya, Potatoes, Vegetables, Fruit, 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 especially the compounds against helminths are effective, under the endoparasitic nematodes are the cause of serious diseases Mammals and poultry may be, for. Sheep, pigs, goats, Cattle, horses, donkeys, dogs, cats, guinea pigs, ornamental birds. Typical nematodes of this indication are: Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. The particular advantage of the compounds of Formula I is their effectiveness against those parasites that are active against are benzimidazole-based resistant.  

Certain species of the species Nematodirus, Cooperia and Oesophagostomum attack the intestinal tract of the host animal, while others of the species Haemonchus and Ostertagia in the stomach and those of the species Dictyocaulus in the Parasitic lung tissue. Parasites of the families Filariidae and Setariidae are found in the internal cell tissue and the organs, eg. B. the Hearts, blood vessels, lymphatic vessels and subcutaneous tissue. Here is especially the heartworm of the dog, Dirofilaria immitis, too call. The compounds of formula I are high against these parasites effective.

They are also suitable for controlling human pathogenic parasites, among those as typical, occurring in the digestive tract such representatives of the species Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris and Enterobius are mentioned. Effective are the Compounds of the present invention also against parasites of the species Wuchereria, Brugia, Onchocerca and Loa from the Filariidae family, which occur in the blood, in the tissues and in various organs, and against Dracunculus and parasites of the species Strongyloides and Trichinella, the specifically infect the gastro-intestinal canal.

The compounds of the formula I are used in unchanged form or preferably together with the usual in formulation technology tools used and therefore z. B. to emulsion concentrates, directly sprayable or dilutable solutions, dilute emulsions, Wettable powders, soluble powders, dusts, granules, too Encapsulations in z. B. polymeric substances processed in a known manner. The application methods such as spraying, misting, dusting, scattering or casting will be the same as the type of means to the desired goals and chosen according to the given circumstances.

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

The formulations, d. H. containing the active ingredient of the formula I. Agents, preparations or compositions are prepared in known manner prepared, for. B. by intimately mixing and / or grinding the Active ingredients with extenders, such as. As with solvents, solid Carriers, and optionally surface-active compounds (Surfactants).

Suitable solvents may be: aromatic hydrocarbons, preferably the fractions C₈ to C₁₂, such as. B. xylene mixtures or substituted naphthalenes, phthalic acid esters 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, strong 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, for. For dusts and dispersible powders, As a rule, ground natural minerals are used, such as calcite, Talc, kaolin, montmorillonite or attapulgite. To improve the physical properties can also be fumed silica or highly dispersed absorbent polymers are added. As a grained, adsorptive granule carriers come porous types such. Pumice, Brick fracture, sepiolite or bentonite, as non-sorptive support materials z. As calcite or sand in question. In addition, a variety of pre-granulated materials of inorganic or organic nature such as especially dolomite or crushed plant residues used become.

As surface-active compounds are used depending on the type of formulating agent non-ionic, cationic and / or anionic Surfactants with good emulsifying, dispersing and wetting properties in Consideration. Surfactants are also surfactant mixtures.

Suitable anionic surfactants may be both so-called water-soluble soaps also be water-soluble synthetic surface-active compounds.  

As soaps are the alkali, alkaline earth or optionally substituted Ammonium salts of higher fatty acids (C₁₈-C₂₂), such as. B. the or K salts of oleic or stearic acid, or of natural fatty acid mixtures, the z. B. be obtained from coconut or tallow can, called. Furthermore, the fatty acid methyl taurine salts are too mention.

More often, however, so-called synthetic surfactants are used in particular, 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 having 8 to 22 carbon atoms, wherein alkyl and the alkyl moiety of acyl radicals, e.g. B. the Na or Ca salt of lignosulfonic acid, of dodecylsulphuric acid ester or one of natural Fatty acids produced fatty alcohol sulfate mixture. Also belong here the salts of sulfuric acid esters and sulfonic acids of fatty alcohol Ethylene oxide adducts. The sulfonated benzimidazole derivatives contain preferably 2-sulfonic acid groups and a fatty acid residue with 8 to 22 C atoms. Alkylarylsulfonates are z. As the sodium, calcium or triethanolamine salts dodecylbenzenesulfonic acid, dibutylnaphthalenesulfonic acid or a naphthalenesulfonic acid-formaldehyde condensation product.

Furthermore, corresponding phosphates such. B. salts of phosphoric acid ester a p-nonylphenyol (4-14) -ethylene oxide adduct or Phospholipids in question.

The surfactants commonly used in formulation technology are u. a. in 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 compound of the formula I, 5 to 99.99% of a solid or liquid additive and 0 to 25%, especially 0.1 to 25%, of a surfactant.

While as a commodity rather concentrated funds are preferred, The end user usually uses diluted drugs 1-10,000 ppm active ingredient content.

A further subject of the present invention therefore relates to pesticides, in addition to conventional carriers and / or Distribution agents as at least one active ingredient a compound of Formula I included.

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

Preparation Examples Example 1 Preparation of 5-O-tert-butylmethylsilyl-13α-O- [4'-O- (4 '' - O-tert-butyldimethylsilyl-α-L- oleandrosyl) -α-L-oleandrosyl] -milbemycin A₄ and 5-O-tert-butyldimethylsilyl-13α-O- [4'-O- (4 '' - O-tert-butyldimethylsilyl-α-L- oleandrosyl) -β-L-oleandrosyl] -milbemycin A₄

In a suspension of 200 mg 4 Å molecular sieves in 2.5 ml toluene 114 mg (0.17 mmol) of 5-O-tert-butyldimethylsilyl-13α-hydroxymilbemycin A₄ and 170 mg (0.33 mmol) of pyridin-2-yl-1-thio (5'-O-tert. butyldimethylsilyl-α-L-oleandrosyl) -α / β-L-oleandroside under nitrogen added. At -10 ° C 840 .mu.l (0.33 mmol) of silver triflate (10% Solution in toluene) slowly added dropwise. After removal of the cooling bath is the reaction mixture stirred for 15 min, diluted with ether / CH₂Cl₂ (10: 1), with saturated NaHCO₃ sol. washed and filtered through silica gel. The organic phase is separated, with saturated Nachsgs. washed,  dried on magnesium sulfate and concentrated. The chromatographic Purification on silica gel (mobile solvent: dimethoxy-ethane / hexane 1:10). you receives the following fractions:

5-O-tert-butyldimethylsilyl-13α-O- [4'-O- (4 '' - O-tert-butyldimethylsilyl-α-L-oleandrosyl) -
α-L-oleandrosyl] -milbemycin A₄: 92 mg (51%)
5-O-tert-butyldimethylsilyl-13α-O- [4'-O- (4 '' - O-tert-butyldimethylsilyl-α-L-oleandrosyl) -
β-L-oleandrosyl] -milbemycin A₄: 51 mg (28%)

• 1 H-NMR (300 MHz, CDCl₃, TMS) of 5-O-tert-butyldimethylsilyl-13α-O- [4'-O- (4 "-O-tert-butyldimethylsilyl-α-L-oleandrosyl) -α-L-oleandrosyl] - milbemycin A₄
  5.30, d, J = 3HZ, HC (1 '')
  5.02-4.93, m, HC (15)
  4.77, d, J = 3.9 HC (1 ')
  3.92, brs, HC (13)
  3.41, S, OCH₃
  3.32, S, OCH₃
• MS (DCI-NH₃) of 5-O-tert-butyldimethylsilyl-13α-O- [4'-O- (4 '' - O-tert-butyldimethylsilyl-
  α-L-oleandrosyl) -α-L-oleandrosyl] -milbemycin A₄
  1092 (M + NH₄⊕)
  1074 (M⊖)
• 1 H-NMR (300 MHz, CDCl₃, TMS) of 5-O-tert-butyldimethylsilyl-13α-O- [4'-O-]
  (4 "-O-tert-butyldimethylsilyl-α-L-oleandrosyl) -β-L-oleandrosyl] -milbemycin A₄
  5.49-5.42, m, HC (15)
  5.33-5.26, m, HC (1 "), HC (3)
  4.41, brd, J = 8 HC (1 ')
  3.80, brs, HC (13)
  3.35, S, OCH₃
  3.29, S, OCH₃
• MS (DCI-NH₃) of 5-O-tert-butyldimethylsilyl-13α-O- [4'-O- (4 '' - O-tert-butyldimethylsilyl-
  α-L-oleandrosyl) -β-L-oleandrosyl] -milbemycin A₄
  1092 (M + NH₄⊕)
  1074 (M⊖)

example 2 Preparation of 13α-O- [4'-O- (α-L-oleandrosyl) -α-L- oleandrosyl] -milbemycin A₄

A solution of 48.3 mg (0.045 mmol) 5-O-tert-butyldimethylsilyl-13α- O- [4'-O- (4 '' - O-tert-butyldimethylsilyl-α-L-oleandrosyl) -α-L-oleandrosyl] - Milbemycin A₄ in 3 ml HF / pyridine / THF (1: 5: 10) is incubated at room temperature Stirred for 48 hours. The reaction mixture is diluted with ether, with 2N HCl, saturated NaHCO₃ solution. and saturated NaCl solution. successively washed, dried on magnesium sulfate and filtered. The residue, chromatographed over silica gel (ethyl acetate / hexanes 2: 1). You get 24.7 mg of the title compound (65%).

• 1 H-NMR (300 MHZ, CDCl₃, TMS) of 13α-O- [4'-O- (α-L-oleandrosyl) -α-L-oleandrosyl] -
  milbemycin A₄
  5.43-5.37, m, HC (1 "), HC (3)
  5.04-4.95, m, HC (15)
  4.68, d, J = 3.0 HC (1 ')
  3.95, brs, HC (13)
  3.43, S, OCH₃
  3.32, S, OCH₃
• MS (DCI-NH₃) of 13α-O- [4'-O- (α-L-oleandrosyl) -α-L-oleandrosyl] -milbemycin A₄
  848 (M + H)
  846 (MH⊖)

example 3 Preparation of 13α-O- [4'-O- (α-L-oleandrosyl) -β-L- oleandrosyl] -milbemycin A₄

The preparation is analogous to the preparation of 13α-O- [4'-O- (α-L-) Oleandrosyl) -α-L-oleandrosyl] -milbemycin A₄.

• 1 H-NMR (300 MHZ, CDCl₃, TMS) of 13α-O- [4'-O- (α-L-oleandrosyl) -β-L-oleandrosyl] -milbemycin A₄
  5.60-5.42, m, HC (15)
  5.42-5.33, m, HC (1 "), HC (3)
  4.43, dxd, J = 8.0 and 0.2, HC (1 ')
  3.83, brs, HC (13)
  3.39, S, OCH₃
  3.37, S, OCH₃
• MS (DCI-NH₃) of 13α-O- [4'-O- (α-L-oleandrosyl) -β-L-oleandrosyl] -milbemycin A₄
  864 (M + NH₄⊕)
  847 (MH⊖)

Analogous to the procedures described can also be the following produce mentioned representative of formula I.  

Table 1

Compounds of formula I wherein R₂ is the group

Table 2

Compounds of formula I wherein R₂ is the group

Formulation Examples of the Active Ingredient of Formula I (% = Wt%) wettable powder

The active ingredient is well mixed with the additives and in one milled well. You get spray powder that deals with Dilute water to suspensions of any desired concentration.

Emulsion concentration

Active ingredient from the tables | 10% Octylphenol polyethylene glycol ether (4-5 moles of AeO) 3% Calcium dodecylbenzenesulfonate 3% Castor oil polyglycol ether (36 moles of AeO) 4% cyclohexanone 30% xylenes 50%

From this concentrate, by diluting with water emulsions each desired concentration can be produced.

dusts

It is ready to use dusts by the active ingredient with the Carrier is mixed and ground on a suitable mill.

Extruder granules

Active ingredient from the tables | 10% Na ligninsulfonate 2% carboxymethylcellulose 1% kaolin 87%

The active ingredient is mixed with the additives, ground and with Moistened with water. This mixture is extruded and then in Air flow dried.  

Tables or Boli

I. An Active Ingredient from the Tables | 33.0% methylcellulose 0.80% Silica, highly dispersed 0.80% corn starch 8.40%

Stir methylcellulose in water and allow to swell; Silica in Stir in the swelling and suspend homogeneously. Active ingredient and corn starch Mix. Incorporate the aqueous suspension into this mixture and add knead a dough. This mass through a sieve (mesh size 12 M) granulate and then dry.

II. Milk sugar, krist. | 22,50% corn starch 17.00% microcrystalline. cellulose 16.50% magnesium stearate 1.00%

Mix all 4 excipients well.

Mix phases I and II and compress into tablets or boluses.

If the compounds of the formula I or corresponding agents for Combat endoparasitic namatodes, cestodes and trematodes Domestic and farm animals such as cattle, sheep, goats, cats and dogs, They can be used both as a single dose and as an animal be administered repeatedly, with each dose depending on the species preferably between 0.1 and 100 mg per kg of body weight. By a protracted administration can be achieved in some cases better effect, or you can get by with lower total doses. The Active substance or the agent containing it may also be the food or be added to the drinkers. The ready-to-eat food contains the active ingredient combinations preferably in a concentration of 0.005 to 0.1 Wt .-%. The agents may be in the form of solutions, emulsions, suspensions, Powders, tablets, boluses or capsules administered orally to the animals become. As far as the physical and toxicological properties of  Solutions or emulsions allow, the compounds of the Also, for example, Formula I or the animals containing the same injected subcutaneously, administered intraruminally or by means of the pour-on Method can be applied to the body of animals. Furthermore, a Administration of the active substance to the animals also by licking stones (salt) or Molasse blocks possible.

Biological examples B-1. Action against L₁ larvae of Lucilia sericata

1 ml of an aqueous suspension of the active substance to be tested are so with 3 ml of a special Larvenzuchtmediums at about 50 ° C mixed that a homogenate of either 100 ppm or 10 ppm active ingredient content arises. In each test tube sample are about 30 Lucilia larvae (L₁) used. After 4 days, the mortality rate is determined. All Compounds of the formula I from the preparation examples achieved with 100 ppm has an effect of 100%. At a dilution to approx. 10 ppm obtained compounds from Table 1 and 2 also still full effect.

B-2. Acaricidal activity against Boophilus microplus (Biarra strain)

On a PVC plate horizontally an adhesive tape is attached, the on it 10 blood-sucked female ticks of Boophilus microplus (Biarra strain) attached side by side in a row with the back can be. Each tick is made with a hypodermic needle 1 ul Liquid injected containing a 1: 1 mixture of polyethylene glycol and Acetone represents and in which a certain amount of active ingredient of optional 1, 0.5 or 0.1 μl per tick is dissolved. Control animals receive one drug-free injection. After treatment, the animals are under Normal conditions in an insectarium at about 28 ° C and 80% relative Humidity kept until oviposition occurs and the larvae off the eggs of the control animals hatched.

The activity of a tested substance is determined by the IR₉₀, i. H., it is determined that drug dose in which still after 30 days 9 of 10 female ticks (= 90%) lay eggs that are not hatchable.  Compounds of formulas I from the tables contribute to IR₉₀ 0.5 μg.

B-3. Attempt on 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 with Haemonchus concortus and Trychostrongylus colubriformis have been artificially infected is. 1 to 3 animals are used per dose. Every sheep will only treated once with a single dose, optionally with 0.5 mg or 0.2 mg / kg body weight. The evaluation is done by comparison the number of excreted in the faeces of the sheep before and after treatment Worm eggs.

Simultaneously and similarly infected but untreated sheep serve as a control. Sheep containing one of the compounds of formulas I at 1 mg / kg were treated compared to untreated but infected control groups no nematode infestation (= complete Reduction of worm eggs in the feces). Even at 0.2 mg achieved compounds from Tables 1 and 2, in particular No. 1.1 and 2.1 still full Effect.

B-4. Larvicide action against Aedes aegypti

On the surface of 150 ml of water, which is in a container is so much 0.1% acetone solution of the active ingredient pipetted to concentrations of optionally 10 ppm, 3.3 ppm and 1.6 ppm can be obtained. After evaporation of the acetone the container becomes loaded with about 30-40 3 day old Aedes larvae. After 1, 2 and 5 days the mortality is checked.

Compounds of formulas I from the tables contributed to this test a concentration of 1.6 ppm already complete after one day Killing of all larvae.

Claims (8)

1. Compounds of the formula I wherein
R₁ is hydrogen or Si (R₄) (R₅) (R₆); R₂ occupies the α-position on the C13 atom and for one of the sugar residues stands; in which
R₃ is hydrogen or Si (R₄) (R₅) (R₆); and
R₄, R₅ and R₆ independently represent C₁-C₄-alkyl, benzyl or phenyl. 2. A compound of formula I according to claim 1 selected from the group:
5-O-tert-butyldimethylsilyl-13α-O- [4'-O- (4 '' - O-tert-butyldimethylsilyl
α-L-oleandrosyl) -α-L-oleandrosyl] milbemycin A₄;
5-O-tert-butyldimethylsilyl-13α-O- [4'-O- (4 '' - O-tert-butyldimethylsilyl
α-L-oleandrosyl) -β-L-oleandrosyl] milbemycin A₄;
13α-O- [4'-O- (4 "-O-tert-butyldimethylsilyl-α-L-oleandrosyl) -α-L-oleandrosyl] milbemycin A₄;
13α-O- [4'-O- (4 "-O-tert-butyldimethylsilyl-α-L-oleandrosyl) -β-L-oleandrosyl] milbemycin A₄;
and particularly
13α-O- [4'-O- (α-L-oleandrosyl) -α-L-oleandrosyl] milbemycin A₄; and
13α-O- [4'-O- (α-L-oleandrosyl) -β-L-oleandrosyl] milbemycin A₄. 3. A process for preparing a compound of formula I according to claim 1, characterized in that a compound of formula II wherein R₁ has the meanings given under formula I, with a reactive, optionally protected at the terminal hydroxy group by Si (R₄) (R₅) (R₆) protected 4'-O- (oleandrosyl) -L-oleandrosederivat, wherein R₄, R₅ and R₆ as defined under formula I, implemented. 4. Pesticides against ecto-, endoparasites on warm-blooded animals and against insects, characterized in that it is in addition to usual Formulation aids at least one compound of the formula I according to one of claims 1 or 2 contains. 5. Use of compounds of the formula I according to one of claims 1 or 2 for the control of ecto-, endoparasites and insects on animals and Plants.   6. Use according to claim 5 for controlling endoparasites in Warm-blooded animals. 7. Use according to claim 6, characterized in that it is at the endoparasites are nematodes. 8. Method for controlling pests on animals and plants, characterized in that a compound of the formula I according to one or more of claims 1 or 2 on or in the animal, on the plant or their habitat applied.