GB2187453A - 5-acyloxy-13 beta -alkylmilbemycin derivatives for controlling pests that are parasites of animals or plants - Google Patents

Description

GB 2 187 453 A 1

SPECIFICATION

5-Acyloxy-13p-alkyimilbemycin derivatives for controlling pests that are parasites of animals or plants The present invention relates to novel 5-acyloxy-13p-alkyimilbemycin derivatives of formula 1 below, to their 5 preparation, and to the use thereof for controlling pests such as ectoand endo-parasites of animals and plant parasites.

The compounds of this invention are 5-acyloxy- 13p-alkylmilbemycins of the general formula 1 H3 -ICH3 10 R 13 0 / kf/ W 013 17 1 /p 0 R? is H3C V 15 % 1 / 6 H R1 CH3 wherein 25 R is cl -Cl 0a 1 kyl, IR, is an acyl group, and R2 i S m ethyl, ethyl, i so p ro pyl o r sec-butyl, and the acid addition salts and metal complexes thereof.

Formula] thus represents milbemycin derivatives that contain a 13p-alkyl group and which are acylated in 30 5-position and, if the acyl radical carries an Wheterocycle, maybe in the form of acid addition salts or metal complexes.

Within the scope of this invention, the term "acyV by itself or as moiety of an acyloxy group shall be understood as meaning e.g. unsubstituted or substituted alkylcarbonyl (= alkanoyl), arylcarbonyl and aralkylcarbony], preferably unsubstituted or substituted acetyl, propionyl, butyryl or benzoy], the alkanoyl 35 moieties of which radicals may be substituted e.g. by halogen, alkoxy, haloalkoxy, aryloxy, hydroxy, ary], aryloxy or an unsaturated or saturated 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, whereas the aryl moieties may be substituted by halogen, cyano, alky], alkoxy, haloalkyl, haloalkoxy, alkylthio and/or nitro, and are e.g. a- or 0-naphthyl or, preferably, phenyl. 40 Aralkyl denotes an aromatic radical which is bound through a straight chain or branched alkylene bridge.

The simplest repwesentative is the benzyi group.

Depending on the number of carbon atoms indicated, alkyl by itself or as moiety of another substituentwill be understood as meaning for example the following straight chain groups: methyl, ethyl, propyl, butyl, penty], hexyi, heptyl, octyl, nonyl, decyl, undecyl, clodecyl, tridecyl, tetradecyl, pentadecyl, hexaclecyl, 45 heptadecyl, octadecyl etc. and the branched isomers thereof, e.g. isopropyl, isobutyl, tert-butyl, isopentyl etc. Alkenyl by itself or as moiety of an alkenyloxy group is e.g. 1 propeny], alIVI, 1 -buteny], 2-butenyl, 3-butenyl etc. Alkynyl is for example ethynyl, 1 -propyny], propargyl, 1 - butynyl etc. Throughoutthis specification, halogen and the prefix "halo" will be understood as meaning fluorine, chlorine, bromine or iodine, with chlorine or bromine being preferred. Cycloalkyl by itself or as moiety of cycloalkoxy is e.g. 50 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Haloalkyl by itself oras moiety of haloalkoxy is a mono- to perhalogenated alkyl radical, e.g. CH21, CH2Br, CH2Ci, CH2F, CHC12, CC13, CBr3, CF3, C2F5, C2C15, CM13r and the like, which radical may also be substituted simultaneously by different halogen atoms; the CF3 radical is preferred. Typical representatives of 5- membered heterocyclic ring systems are: furan, thiophene, pyrrole, isoxazole, isothiazole, furazan, imidazole, 1,2,4-triazole, 55 11,2,3-triazole, pyrazole, pyrroline, oxazole, thiazole, thiadiazoles, pyrazoline, thiazoline, pyrazolidine, pyrrolidine, oxazolidine, thiazolidine, oxadiazole, imidazoline, imidazolidine, tetrahydrofuran; and typical representatives of 6-membered heterocyclic ring systems are: pyridine, pyridazine, pyrimidine, pyrazine, thiazine,thiadiazines, pyrans, piperidine, piperazine, morpholine, perhydrothiazine, dioxane andthe partially hydrogenated or partially saturated homologs thereof, and the like. Throughoutthis specification, W oxo-substituted heterocyclic systems are in particular 5- and 6-membered lactones and lactams, e.g.

butyrolactones, valerolactones, butyrolactam,valerolactum, and also bicyclicsystems such as camphane.

Examples of heterocyclic substituents are: imidazole, pyrazole, 1,2,3triazole, 1,2,4-triazole, 11,3,4-triazole ortetrazole, as well as azoles which are substituted by one ortwo Cl- C6alkyl groups, e.g.

2-ethyl-4-methyl i m idazol e, 2-isopro pyl i m idazo 1 e, methyl irn i dazole, 3,5-d i m ethyltriazole, ethyltriazol e, 65 2 GB 2 187 453 A 2 3,4-diethylpyrazole andthe like.

Anumberof typical representatives of acyl radicals R, are listed hereinafter. This recitation impliesno restriction:

COCH3, COCH2C1, COCF3, COCH2Br, COCH2F, COC2H5, COC2CIS, COCH20COCH3 COCH2OCOC4Hg(t), COCH2OCH3, COCH FOCOCH3, COCH(C1-13)0COCH3, COCH2OCOC2H5, COCH2OCOCH2C1, COCH2OCOC61-14F(3), 5 COCH2OCOC6H4OCH30, COCH2OCH2OCH3, COCH20C21-15, COCH2SCH3, COCH2OCOC61- 14C1 (3), COCH2-M-1,2,4-triazol-l-yI), COCH2-(2,3-dihydropyran-2-yl), COCHAHimidazol-l-y1) and COCH2OCO-(pyrrolid-2-one-5-yl).

Salts of compounds of formula 1 are formed with inorganic ororganicacids. Suitable salt-forming acids are forexample: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoricacid, 10 methanesulfonic acid, p-toluenesulfonic acid, acetic acid, oxalic acid, tartaric acid, citric acid, ascorbicacid, sorbic acid, trimethylacetic acid, benzoic acid, salicyclic acid, succinic acid and maleicacid.

Metal complexing agents are in particular cations of metals of auxiliary groups 1 and 11 or Rto V111 ofthe PeriodicTable, e.g. copper, zinc, manganese, chromium, iron, nickel, cobalt and molybdenum.

The above recitations imply no restriction. Other physiologically tolerable salts and complex agents are 15 known tothe skilled person.

Within the scope of formula 1, preference is given to those milbemycin derivatives wherein R and R2are methyl or ethyl and R, hasthe given meanings.

Within the scope of formula 1,thefollowing groups are preferred:

20 Gro up la:

Compounds of formula 1, wherein R is Cl -C6a 1 kyl, R2 is m ethyl, ethy 1, i so p ro pyl o r sec-b utyl, R, is an acyl group selected from 25 0 a 30 h3 0 35 11 b -C-CH-X-R4, 1 h3 40 0 0 il 11 c) -C-CH-X-C-R4 and 45 1 h3 so so 0 11 d) h3 55 wherein Xis oxygen orsulfur, Yis a leaving group which maybe replaced by nucleophilic exchange, R3 is hydrogen, Cl-C4alkyl or halogen; and 60 R4 is hydrogen, Cl-Cloalkyl, unsubstituted or substituted by halogen, hydroxy, Cl-C6alkoxy or Cl-C6haloalkoxy; an unsubstituted or substituted radical selected from the group consisting of C3-CE)cycloalkyl, C2-C6alkenyl and C3-C6alkyriVI, the substituents of said radicals being selected from the group consisting of halogen, hydroxy, Cl-C6alkoxy and Cl-C6alkanoyloxy; phenyl or phenyl which is substituted by halogen, cyano, Cl-C3alkyl, Cl-C3haloalkyl, Cl-CAlkoxy, Cl- C3haloalkoxy, andlor nitro; or is an 65 3 GB 2 187 453 A 3 unsubstituted or substituted, unsaturated or saturated 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, the substituents of said ring being selected from the group consisting of oxo, halogen, Cl-COlkyl, Cl- C4haloalkyl and Cl-COlkoxy, and the acid addition salts and metal complexes thereof.

Within group la, the following compounds constituting groups lb are preferred: 5 Group lb:

Compounds of formula 1, wherein R is Cl -C6 a] kyl, R2 is methyl, ethyl, isopropyl or sec-butyl, 10 R, is an acyl group selected from 0 a) is t13 20 0 11 b) M3 25 0 0 H 11 30 c) -C-Cl-1-X-C-R4 and 1 h3 35 0 cl) 40 H3 wherein Xis oxygen orsulfur, Y is halogen, azido or a sulfonic acid radical, 45 R3 is hydrogen, f luorine or methyl, and R4 is hydrogen; Cl-COlkyl, unsubstituted or substituted byfluorine, chlorine, bromine, hydroxy, Cl-CAlkoxy or C2-C3haloalkoxy; an unsubstituted or substituted radical selected from the group consisting of C3-CAYCloalkyl, C2-COlkenyl and C2-COlkynyl, the substituents of said radicals being selected from the group consisting of fluorine, chlorine, bromine, hydroxy, Cl-C3alkoxy and Cl- C4alkarloyloxy; phenyl or phenyl so which is substituted byfluorine, chlorine, bromine, methyl, ethyl, methoxy, halomethoxy, trifluoromethyl andlor nitro; or is an unsubstituted or substituted, unsaturated or saturated 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur,the substituents of said ring being selected from the group consisting of oxo, halogen, Cl-COlkyl, Cl-C4haloalkyl and Cl-C4al koxy, and the acid addition salts and metal complexes thereof. 55 Within group 1b, the following groups lc, ld, le and If are preferred.

4 GB 2 187 453 A 4 Group lc:

Compounds of formula 1, wherein R is Cl-C6alky], R2 is methyl, ethyl, isopropyl orsec-butyl, R, is the group 5 0 11 -t--CH-Y 1 10 h3 R3 is hydrogen, fluorine or methyl, and Y is chlorine, bromine, iodine, benzenesulfonyloxy, paratosyloxy or mesyloxy.

Group Id:

Compounds of formu la 1, wherein R is Cl-C6alky], R2 is methyl, ethyl, isopropyl or sec-butyl, R, isthegroup 20 0 11 -C-CH-X-R4 1 25 h3 wherein Xis oxygen orsulfur, R3 is hydrogen, fluorine or methyl; and 30 R4ishydrogen; Cl-C6alkyl, unsubstituted or substituted by fluorine, chlorine, bromine, hydroxy, Cl-C3alkoxyorCl-C3haloalkoxy; an unsubstituted or substituted radical selected from the group consisting of C3-C7CYCloalkyi,C2-C4a]kenyl and C2-COlkyny], the substituents of said radicals being selected from the group consisting of fluorine, chlorine, bromine, hydroxy, Cl-C3alkoxy and Cl- COlkanoyloxy; phenyl orphenyl which is substituted byfluorine, chlorine, bromine, methyl, ethyl, methoxy, halomethoxy,trifluoromethyl 35 andlor nitro; or is an unsubstituted orsubstituted, unsaturated orsaturated 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur,the substituents of said ring being selected from the group consisting oxo, halogen, Cl-COlkyl, Cl-C4haloalkyl and Cl-C4alkoxy, and the acid addition salts and metal complexes thereof.

40 Group le:

Compounds ofjormula 1, wherein R is Cl -C6a I kyl, R2 is methyl, ethyl, isopropyl or sec-butyl, R, is the group 45 0 0 so 50 h3 wherein Xis oxygen or sulfur, R3 is hydrogen, fluorine or methyl; and 55 R4 is hydrogen; Cl-C6alky], unsubstituted or substituted by fluorine, chlorine, bromine, hydroxy, Cl-CAlkoxy Or Cl-C3haloalkoxy; an u nsubstituted or substituted radical selected from the group consisting of C3-C7CYCioaikyl, C2-C4al kenyl and C2-C4alkyny], the su bstituents of said radicals being selected from the group consisting of fluorine, chlorine, bromine, hydroxy, Cl-C3alkoxy and Cl- COlkanoyloxy; phenyl or phenyl which is substituted byfluorine, chlorine, bromine, methyl, ethyl, methoxy, ha lomethoxy, trifl uoro methyl 60 andlor nitro; or is an unsubstituted or substituted, unsaturated or saturated 5- or 6-membered heterocyclic ring containing 1 to 3 heteio atoms selected from the group consisting of nitrogen, oxygen and sulfur,the substituents of said ring being selected from the group consisting of oxo, halogen, Cl-COlkyl, Cl-C4haloalkyl and Cl-C4alkoxy, and the apid addition salts and metal complexes thereof.

GB 2 187 453 A 5 Group If.

Compounds of formula [,wherein R is Cl-C6alkyl, R2 is methyl, ethyl, isopropyl orsec-butyl, R, is the group 5 0 11 10 h3 wherein R3 is hydrogen, fluorine or methyl; and R4 is an aromatic heterocyclo-l-yl group consisting of an unsubstituted orsubstituted 5-membered 15 heterocyclic ring which contains 2to 3 nitrogen atoms,the substituents of said ring being selected from 1 to3 Cl-COlkyl groups, and the acid addition saltsthereof with organicand inorganic acids aswell asthe metal complexes thereof with metal cations of auxiliary groups 1, 11, IV orVill of the PeriodicTable.

Thefollowing compounds are also preferred:

20 Group lg:

Compounds of formula 1, where R is Cl-COlkyl, R2 is methyl, ethyl, isopropyl or sec-butyl, R, is an acyl group selected from 25 0 a) 30 h3 0 35 b) h3 40 0 0 11 11 c) -C-CH-X-C-R4 and 45 1 h3 W 50 0 11 d) h3 55 wherein Xisoxygen orsulfur, Yishalogen R3 is hydrogen, halogen or methyl; and 60 R4 is hydrogen; Cl-COlkyl, unsubstituted or substituted by halogen or Cl- C4alkoxy; or is cyclopropyl, cyclopentyl, cyclohexyl,phenyl or phenyl which is substituted by fluorine, chlorine, bromine, methoxy, trifluoromethyl and/or nitro; or is 4H-2,3-di-hydropyran-2-yl or an aromatic heterocyclo-l-yl group consisting of an unsubstituted or substituted 5-membered heterocyclic ring which contains 2 to 3 nitrogen atoms,the substituents of said ring being selected from 1 to 3 Cl-C6alkyl groups, and the acid addition salts thereof with 65 6 GB 2 187 453 A 6 organicand inorganic acids aswell asthe metal complexes thereof with metal cations of auxillarygroups 1, 11, IVorVill of the PeriodicTable.

Examples of particularly preferred individual compounds offormula 1 are:

5-0-chloroacetyl-13p-methyimilbemycin D, 5-0-chloroacetyi-13p-methyimilbemycin A3, 5 5-0-chloroacetyi-13p-methyimilbemycin A4, 5-0-chforoacetyi-13p-ethyimilbemyein D, 5-0-chloroacety]-13p-ethyimilbemycinA3, 5-0-chloroacetyi-13p-ethyimilbemycinA4, 10 5-0-acetoxyacety]-1 3p-m ethyl m i 1 bemyci n D, 5-0-acetoxyacetyl-1 3p-methyimilbemycin A3, 5-0-acetoxyacetyl-1 3p-methyimilbemycin A4, is 15 5-0-acetoxyacetyi-13p-ethyimilbemycin D, 5-0-acetoxyacetyi-13p-ethyimilbemycin A3, 5-0-acetoxyacetyi-13p-ethyimilbemycin A4, 5-0-[3,4-dihydro-2H-pyran-2-yilcarboxyacetyi-13p-methyimilbemycin D, 20 5-0-[3,4-di hyd ro-21-1-pyra n-2-y] Ica rboxyacety]-1 3p-m ethyl m il bemyci n A3, 5-0-[3,4-dihydro-2H-pyran-2-yilcarboxyacetyi-13p-methyimilbemycin A4, 5-0-[3,4-dihydro-2H-pyran-2-yilcarboxyacetyi-13p-ethyimilbemycin D, 5-0-[3,4-dihydro-2H-pyran-2-yilcarboxyacetyi-13p-ethyimilbemycin A3, 25 5-0-[3,4-dihydro-2H-pyran-2-yilcarboxyacety]-13p-ethyimilbemycinA4, 5-0-[1,2,4-triazol-4'-yilacetyi-13p-methyimilbemycin D, 5-0-[1,2,4-triazol-4'-yilacetyi-13p-methyimilbemycin A3, 5-0-[1,2,4-triazol-4'-yi]acetyi-13p-methyimilbemycin A4, 30 5-0-[1,2,4-triazol-4'-yilacetyi-13p-ethyimilbemycin D, 5-0-[1,2,4-triazol-4'-yilacetyi-13p-ethyimilbemycinA3, 5-0-[1,2,4-triazol-4'-yilacety]-13p-ethyimilbemycinA4, 35 5-0-methoxyacetyi-13p-methyimilbemycin D, 5-0-methoxyacetyi-13p-methyimilbemycinA3, 5-0-methoxyacetyi-13p-methyimilbemycin A4, 5-0-methoxyacetyil3p-ethyimilbemycin D, 40 5-0-methoxyacetyil3p-ethyimilbemycinA3, 5-0-methoxyar,ety]13p-ethyimilbemycin A4, 5-043-ch lo ro benzol oxylacetyl-1 3p-m ethyl m i 1 bemyci n D, 5-043-ch lo ro benzol oxylacetyl-1 3p-m ethyl m i 1 bemycin A3, 45 5-0-[3-chlorobenzoloxylacetyi-13p-methyimilbemycinA4, 5-0-[3-chlorobenzoloxylacetyl-13p-ethyimilbemycin D, 5-0-[3-chlorobenzoloxylacetyi-13p-ethyimilbemycinA3, and 5-0-[3-chforobenzoloxylacetyi-13p-ethyimilbemycin A4. 50 Further preferred compounds of formula 1 arethose selectedfrom the group consisting of:

5-0-acetoxyacety]-13p-propyimilbemycin D, 5-0-acetoxyacetyl-13p-propyimilbemycin A3, 55 5-0-acetoxyacety]-13p-propyimilbemycin A4, 5-0-acety]-13p-ethyimilbemycin D, 5-0-acety]-13p-ethyimilbemycin A3, 5-0-acetyi-13p-ethyimilbemyein A4, 60 5-0-acetyl-1 3p-m ethyl m i 1 bemycin D, 5-0-acetyl- 1 3p-m ethyl m i 1 bemycin A3, 5-0-acetyl-1 3p-m ethyl m i 1 bemycin A4, 7 GB 2 187 453 A 7 5-0-methoxyacetyl-13p-butyimilbemycin D, 5-0-methoxyacetyl-13pbutyimilbemycin A3, 5-0-methoxyacetyl-13p-butyimilbemycin A4, 5-0-benzoyloxy-13p-methyimilbemyein D, 5 5-0-benzoyloxy-13p-methyimilbemycinA3, and 5-0-benzoyloxy-1 3p-methyimilbemycin A4.

The present invention also relates to processes which make it possible to introduce a 5-0-acyl group selectively atthe 5-0-position of 130-alkylmilbemycin or 10 13-deoxy-1 3p-alkyi-22,23-dihydroavermectin-aglycon derivatives and thus to obtain very effective novel parasiticides and insecticides of formula 1.

The process forthe preparation of compounds of formaula 1 comprises esterifying a 13p-alkylmilbemycin derivative of formula 11 is R VH3 0..CH3 H3c 01h\R 20 c + HO-Rl H (M) 25 11 CH3 (11) 30 with an acid of formula 111, or an acid halide or acid anhydride thereof, at the 5-01-11 group, the substituents R, R, and R2 being as defined forformula 1.

Preferred acid halides of acids of formula Ill are the chlorides and bromides thereof.

If the compound of formula Ill is an acid halide or acid anhydride, the reaction is preferably carried out in a 35 non-hydroxylated inert solvent and in the presence of an organic base, e. g. pyridine, 4-dimethylaminopyridine, lutidine, collidine, trialkylamine, Ndialkylaniline, or a bicyclic non-nucleophilic base, e.g. 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3. Olnon-5-ene (DBN) or 1,8-diazabicyclo[5.4.Olundec-7-ene (1.5-5) (DBU). The reaction is generally carried out in thetemperature rangefrom -30'to +70'C, preferablyfrom -10'to +WC. It is convenientto carry outthe reaction inthe 40 presence of an inert solvent or mixture of solvents. Suitable solvents are e.g. aliphatic and aromatic hydrocarbons such as benzene, toluene, xylenes, petroleum ether, hexane; halogenated hydrocarbons such as chlorobenzene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrachloroethylene; ethers and ethereal compounds such as dialkyl ethers (diethyl ether, diisopropyl ether, tert-butyl methyl ether etc.), anisole, dioxane,tetrahydrofuran; nitriles such as acetonitrile, propionitrile; 45 esters such as ethyl acetate, propyl acetate or butyl acetate; ketones such as acetone diethyl ketone, methyl ethyl ketone; compounds such as dimethyl sulfoxide (DIVISO), climethylformamicle (DIVIF) and mixtures of such solvents with one another. The reaction may also be carried out in an excess of one of the above bases.

If the compound of formula Ill is an acid,then the esterification of the compound of formula 11 with a compound of formula Ill is conveniently carried out in the presence of a condensing agent customarily so employed in esterification reactions, e.g. in the presence of a carbodiimide [dicyclohexyidiimide (DCC)1 or of a 1 -alkyl-2-halopyridinium salt 11 -methyl-2-chloropyridinium iodide]. This reaction is preferably carried out in one of the above inert solvents and in the temperature range from 30'to +70'C, preferably from -1 00to +WC. It is preferred to carry outthe esterification reaction in the presence of a base, for example inthe presence of an organic amine, e.g. a trialkyiamine (trimethylamine, triethylamine, tripropylamine, 55 diisopropylethylamine and the like), a pyridine (pyridine itself, 4- dimethylaminopyridine, 4-pyrrolidylaminopyridine etc.), a morpholine (N-methyimorpholine), an N, N-dialkylaniline (N,N-dimethylaniline, N-methy]-N-ethylaniline) and the like.

Compounds of formula 1 can also be prepared by suitable reactions from other compounds of formula 1.

For example, a compound in which IR,= -CO-CH2C1 can be converted into a compound in which IR,= 60 -CO-CH2-OCOCI-13 by reaction with sodium acetate in dimethylformamide at80'C. This compound can in turn be prepared e.g. from a compound in which IR,= -CO-CH2-OH by esterification with acetyl chloride or acetic anhydride. Such conversions of compounds of formula] into other representatives of formula 1 are considered as belonging to the main process.

The described process, including all partial steps, constitutes an essential object of the present invention. 65 8 GB 2 187 453 A 8 Most of the acids of formula Ill, and the halides and anhydrides thereof, are known or can be prepared by methods analogous to those employed for preparing the known representatives.

The 13p-alkyi-5-hydroxymilbemycins of formula 11 can be prepared by treating an ally] ester of formula IV 16 CH3 5 17 12:

H3C' 0 11 R2 IV) 10 H CH 15 wherein A is a group a or b 20 H 3 H3 R80 1 15 0\ c H/ (a) or "gv (b) is R8 25 130-ester-A 14 ' 15 A 13 ' 14 -15-ester] R8 is an acyl group, R, is hydrogen or, preferably, a silyl group, and R2 is as defined forformula 1, with a trialkylaluminium compound of formula V 30 AI(R)3 (V) wherein R is as defined forformula 1, and, if free 5-hydroxy compounds are desired, subsequently removing the silyl group R, by hydrolysis. 35 The process is generally carried out in an inertsolvent. Suitable solvents are e.g.: ethers and ethereal compounds such as dialkyl ethers (diethyl ether, diisopropyl ether, tert- butyl methyl ether, dimethoxyethane, dioxane, tetra hydrof u ran, anisole and the like); halogenated hydrocarbons such as chlorobenzene, methylene chloride, ethylene chloride and the like; or sulfoxides such as dimethyl sulfoxide. Aromatic or aliphatic hydrocarbons such as benzene, toluene, xylenes, petroleum ether, Pgroin, cyclohexane and the like 40 may also be present. In some cases it may be advantageous to carry outthe reaction or partial steps thereof in an inert gas atmopphere (e.g. argon, helium, nitrogen etc.) and/or in absolute solvents. If desired, intermediates may be isolated from the reaction medium and, if desired, purified in conventional manner before further reaction, e.g. by washing, digestion, extraction, recrystallisation, chromatography and the like. However, such purification steps may be dispensed with and only carried out with the corresponding 45 final products.

Trial kylaluminiu m compounds suitable for the introduction of the 13palkyl group are tri(C1-Cloalkyi)aiuminium compoundssuch astrimethylaluminium, triethylaluminium, triisobutylaluminium,trihexylaluminium etc.The reaction is generally carried outin thetemperature range from -100'Cto +100'C, preferablyfrom -20'Cto +60C. The trialkylaluminium compound of formula Ill is so added in substance or in an inertsoivent, e.g. hexane, toluene or benzene, in at least equimolar amount to the solution of the compound of formula 11.

Whenthe reaction is complete, the silyl protective group is conveniently removed bytreatingthe compound offormula Iwith a dilute acid, e.g. with 1 % p-toluenesulfonic acid in methanol orwith anaqueous HFsolution in acetonitrile, in thetemperature rangefrom -20'Cto +50'C, preferablyfrom O'Cto +WC,or 55 with pyridinium fluoride in pyridine.

The trialkylaluminium compounds of formula V are generally known or can be prepared by methods analogousto those of the preparation of known representatives.

9 GB 2 187 453 A 9 Thestarting esters of formula Wcan be prepared from the corresponding allyi alcohols of formulaVI 16 CH3 11 0 \I/ 5 17 '1 12 O"CRz H3C (VI) 0 1/6 H 10 CH3 15 6R1 whereinAisa group a orb H, H3 20 3 13 is HO CH/ (a) or H \ / (b) 9H 130-hydroxy-A 14 ' 15 1= A 13,14_ 15-hydroxyl 25 R2 is as defined for formula land R, is hydrogen ora sily] group, by customary methods of acylation known in the literature, e.g. byreactionwith an acid chloride (R8COCI) or acid anhydride (R8C0)20, wherein R8isas defined for formula IV, in the presence of a base (triethylamine, pyridine, N,N-dimethylaminopyridine and 30 the like), in one of the inert solvents mentioned above, e.g. dichioromethane, chloroform andthe like, and in the temperature range from -20OCto 1 OWC, preferably from WC to 700C.

The compounds of formula Vib 413,14_1 5-hydroxylcan beobtainedfrom 14,15epoxymilbemycinsof formula V11 35 Y113..CH3 0 0 00 0 13 171 1 H3C \5/0 0 H 2 (VII) 40 H 45 8 \5 A R1 CH3 so 50 wherein R, is hydrogen or a silyi group and R2 is as defined forformula 1, with the complex reagent [HN3]x/Ai(ethyi)3]y, wherein x and y are each independently 1 or 2 or a value between 1 and 2, in an inert dry solvent and in the temperatu re range from -200 to + 1 WC, preferably from +20't +80'C.

Preferred inert solvents are aliphatic and aromatic hydrocarbons such as benzene, toluene, xylene, and petroleum ether; ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, and anisole. 55 The reaction is conveniently carried out in an inert gas such as nitrogen or argon.

Hyd razo ic a c i d (H N 3) ca n a i so b e co nve rted, i n th e n asce nt state, i nto th e [H N31x/[A1 (Et)3]y co m p 1 ex by suspending sodium azide in the stipulated dry solvent or mixture of solvents and generating HN3 in the solution with a stronger acid, e.g. H2S04 (preferably oleum in orderto ensure absolutely dry reaction conditions). AI(R6 should already be present in the solution or added thereto shortly afterwards. The epoxy 60 compound to be reacted can also already be present in the solution or added thereto at a suitabletime.

The starting compounds of formula V1 1 employed for the preparation of compounds of form u la Vib can be easily prepared by epoxidation of the compounds known from US patent specification 3 950 360 and originally designated as "antibiotics B-41 W, later called "milbemycin X' compounds, and of the compounds known from US patent specification 4 346 171 and designated as "BA1 -W or "milbemycin W; 65

GB 2 187 453 A 10 aswell asof the 13-deo)(y-22,23-dihydroavermectins (R2sec-butyl) of formulaVill H3 5 0 CH3 ji 171 '1 (Viii) 5 4!\R d'\ 0/H 2 H 10 s\CH, OE 1 15 R2 = CH3 milbemycin A3 R2 = C2H5 milbemycin A4 R2 = isoC31-17 milbemycin D R2 = seC-C41-19 13-deoxy-22,23-dihydro-C-076-Bia-aglycon. 20 The epoxidation is carried outin a solvent phase in thetemperature rangefrom -10'to +20'C, preferably from -5'to +YC.

Peracids such as peracetic acid, trifluoroperacetic acid, perbenzoic acid and chloroperbenzoic acid are suitableforthe epoxidation.

The 13p-hydroXy_A14,15 compounds of formula Via can be prepared by reacting compounds of formula Nb, 25 wherein R, is a protective group, with pyridinium dichromate [= (Pyr)2Cr2071. This reaction is carried out in dimethylformamide and in the temperature range from - 1 O't +60'C. If desired, the protective group R, is subsequently removed by hydrolysis.

Acylation or silylation of the 5-01-1 group affords all those derivatives of formulae 11 to VIII wherein R, has a meaning otherthan hydrogen (R, = OH protective group). Forthe silylation it is convenient to use a silane of 30 the formula Y-Si(R5)(R6)(R7), wherein each of R5, R6 and R7 are preferably independently of one another Cl-C6-alkyl, benzyi or phenyl, and form e.g. a group selected from trimethyisiiyi,tris(tert-butyi)siiyi, thexyidimethyisiiyi, diphenyl tert-butylsilyl, bis(isopropyl)methyisily], triphenylsilyl and the like, and, preferably, tert-butyidimethyisiiyi. The 5-01-1 group can also be present as benzyi ether or methoxyethoxymethyl ether and Y is a sily] leaving group. Examples of silyl leaving groups Y are bromide, 35 chloride, cyanide, azide, acetamide, trifluoroacetate ortrifluoromethanesuifonate. This recitation constitutes no limitation; furthertypical silyl leaving groups are known to the skilled person.

5-0-silylations are carried out in anhydrous medium, preferably in inert solvents and, most preferably, in aprotic solvents. The reaction conveniently takes place in the temperature range from O'to +80'C, preferably from + 10'to +40oC. It is preferred to add an organic base. Examples of suitable bases are tertiary amines 40 such as triethylamine,triethylenediamine, triazole and, preferably, pyridine, imidazole or 1,8-diazabicyclo[5.4.01-undec-7-ene (DBU).

The removal of these sily] radicals R, in the 5-position is effected by selective mild hydrolysis ('R = H) with e.g. aryisuifonic acid in alcoholic solution or in accordance with another method known to the skilled person.

The described process forthe preparation of compounds of formula 1 constitutes in all its partial steps an 45 object of the present invention.

The present invention also relates to pesticidal compositions for controlling ecto- and endoparasites as well as harmful insects, which compositions contain as active ingredient at least one compound of formula 1, togetherwith customary carriers andlor dispersing agents.

The compounds of formula 1 are most suitable for controlling pests of animals and plants, including W ectoparasites of animals. These last mentioned pests comprise those of the order Acarina, in particular pests of the families Ixodidae, Dermanyssidae, Sarcoptidae, Psoroptidae; of the orders Mallophaga, Siphonaptera, Anoplura (e.g. family of the Haematopinidae); and of the order Diptera, in particular pests of thefamilies Muscidae, Calliphoridae, Oestridae, Tabanidae, Hippoboscidae, and Gastrophilidae.

The compounds of formula 1 can also be used to combat hygiene pesespecially of the order Diptera 55 (families Sareophagidae, Anophilidae and Culicidae); of the order Orthoptera, of the order Dictyoptera (e.g.

family of the Blattidae), and of the order Hymenoptera (e.g. family of the Formicidae).

The compounds of formula i also have a lasting action against mites and insects which are parasites of plants. When used to control spider mites f the order Acarina, they are effective against eggs, nymphs and adults of Tetranychidae (tqRranychus spp. and Panonychus spp.) They also have excellent activity against 60 sucking insects of the order Homoptera, in particular against pests of the families Aphididae, Delphacidae, Cicadellidae, Psyllidae, Coccidae, Diaspididae and Eriophyidae (e.g. the rust mite on citrus fruit); of the orders Hemiptera, Heteroptera and Thysanoptera; and against plant-feeding insects of the orders Lepidoptera, Coleoptera, Diptera and Orthoptera.

The compounds of formula 1 are also suitable for use against soil pests. 65 11 GB 2 187 453 A 11 The compounds of formula 1 are therefore effective against all development stages of sucking and feeding insects in crops such as cereals, cotton, rice, maize, soybeans, potatoes, vegetables, fruit, tobacco, hops, citrus fruit, avocados and others.

The compounds of formula 1 are also effective against plant nematodes of the species Meloidogyne, Heterodera, Pratylenchus, Ditylenchus, Radolphus, Rhizoglyphus and others. 5 In particular, however, the compounds of formula 1 act against helminths, among which the endoparasitic nematodes can be the cause of severe diseases in mammals and fowl, for example in sheep, pigs, goats, cattle, horses, donkeys, dogs, cats, guinea pigs, cage-birds. Typical nematodes having this indication are:

Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia,Ascaris, Bunostomum, Oesphagostomum, Charbertia,Trichuris, Strongyius, Trichonema, Dictyocaulus, Capillaria, Heterakis, 10 Toxocara,Ascaridia, Oxyuris,Ancylostoma, Uncinaria, Toxascaris and Parascaris. The particular advantage of the compounds of formula 1 istheir activity againstthose parasiteswhich are resistantto benzimidazole-based parasiticides.

Certain species of the genera Nematodirus,Cooperia and Oesophagostomum attackthe intestinal tractof the host animal, whereas others of the species Haemonchus and Ostertagia parasiticise in the stomach and 15 those of the species Dictyocaulus in the lung tissue. Parasites of the families Filaffidae and Setaffidae are found in internal cell tissue and internal organs, e.g. in the heart, blood vessels, lymph vessels and in subcutaneous tissue. In this connection, particular mention isto be made of the dog heartworm, Dirofilaria immitis. The compounds of formula 1 are highly effective againstthese parasites.

The compounds of formula 1 are also suitable forcontrolling pathogenic parasites in humans, among 20 which parasites there may be mentioned astypical representatives occurring in the alimentary tract those of the species Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria,Trichuris and Enterobius.

The compounds of this invention are also effective against parasites of the species Wuchereria, Brugia, Onchocerca and Loa of thefamily of the Filaffidae which occur in the blood, in tissue and various organs, and, in addition, against Dracunculus and parasites of the species Strongyloides and Trichinella which infest in 25 particularthe gastro-intestinal tract.

The compounds of formula 1 are used in unmodified form or, preferably, togetherwith the adjuvants conventionally employed in the art of formulation, and aretherefore formulated in known mannerto emulsifiable concentrates, directly sprayable or dilutable solutions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, and also encapsulations in e.g. polymer substances. As with the nature 30 of the compositions, the methods of application such as spraying, atomising, dusting, scattering or pouring, are chosen in accordancewith the intended objectives and the prevailing circumstances.

The compounds of formula 1 are administered to warm-blooded animals at rates of application of 0.01 to 10 mg/kg of bodyweight, and are applied to enclosed crop areas,to pens, livestock buildings or otherbuildings in amounts of 10 g to 1000 g per hectare. 35 The formulations, i.e. the compositions, preparations or mixtures containing the compound of formula 1 (active ingredient) are prepared in known manner, e.g. by homogeneously mixing and/orgrinding the active ingredients with extenders, e.g. solvents, solid carriers and, in some cases, surface-active compounds (surfactants).

Suitable solvents are: aromatic hydrocarbons, preferablythe fractions containing 8to 12 carbon atoms, 40 e.g. xylene mixtures or substituted naphthalenes, phthalates such as dibutyl phthalate or dioctyl phthalate, aliphatic hydrocabons such as cyclohexane or paraffins, alcohols and glycols and their ethers and esters, such as ethanol, ethylene glycol, ethylene glycol monoethyl or monomethyl ether, ketones such as cyclohexanone, strongly polar solvents such as N-methyi-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide, as well as vegetable oils or epoxidised vegetable oils such as epoxidised coconut oil or 45 soybean oil; orwater.

The solid carriers used e.g. for dusts and dispersible powders are normally naturally mineral fillers such as calcite,talcum, kaolin, montmorillonite or attapulgite. In orderto improvethe physical properties it isalso possible to add highly dispersed silicic acid or highly dispersed absorbent polymers. Suitable granulated adsorptive carriers are poroustypes, for example pumice, broken brick, sepiolite or bentonite; and suitable 50 nonsorbent carriers are materials such as calcite orsand. In addition, a great number of pregranulated materials of inorganic or organic nature can be used, e.g. especially dolomite or pulverised plant residues.

Depending on the nature of the active ingredientto beformulated, suitable surface-active compoundsare nonionic, cationic and/or anionic surfactants having good emulsifying, dispersing and wetting properties.

Theterm "surfactants" will also be understood as comprising mixtures of surfactants. 55 Suitable anionic surfactants can be both water-soluble soaps and water- soluble synthetic surface-active compounds.

Suitable soaps are the alkali metal salts, alkaline earth metal salts or unsubstituted orsubstituted ammonium salts of higherfatty acids (C10-C22), e.g. the sodium or potassium salts of oleic or stearic acid, orof natural fatty acid mixtures which can be obtained, e.g. from coconutoil ortallowoil. Furthersuitable 60 surfactants are also the fatly acid methyltaurin salts.

Morefrequently, however, so-called synthetic surfactants are used, especiallyfatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylaryisuifonates.

Thefatty sulfonates or suifates are usually in theform of alkali metal salts, alkaline earth metal salts or unsubstitued orsubstituted ammonium salts and contain a C8-C22alkyl radical which also includesthe alkyl 65 12 GB 2 187 453 A 12 moietyof acyl radicals, e.g.the sodium orcalcium saltof lignosulfonic acid, of dodecyisulfate, orof a mixture of fatty alcohol sulfates obtainedfrom natural fatty acids. Thesecompounds also comprisethe saltsof sulfated and sulfonated fatty alcohollethylene oxide adducts. The sulfonated benzimidazole derivatives preferably contain 2sulfonic acid groups and onefattyacid radical containing 8to 22 carbon atoms.

Examples of alkylaryisuifonates arethesodium, calcium ortriethanolamine salts of dodecylbenzenesulfonic 5 acid, dibutyinaphthalenesuifonic acid, orof a condensate of naphtha] enesu Ifon ic acid and formaldehyde.

Also suitable are corresponding phosphates, e.g. salts of the phosphoric acid ester of an adduct of p-nonylphenol with 4to 14 moles of ethylene oxide; or phospholiphids.

The surfactants customarily employed in the art of formulation are described e.g. in "McCutcheon's Detergents and Emulsifiers AnnuaV, MC Publishing Corp. Ridgewood, NewJersey, 1982. 10 The pesticidal compositions usually contain 0.01 to 95 %, preferably 0.1 to 80 %, of a compound of formula 1, 5 to 99.99 % of a solid or liquid adjuvant, and 0 to 25 %, preferably 0.1 to 25 %, of a surfactant.

Whereas commercial products are preferably formulated as concentrates, the end userwill normally employ dilute formulations having a concentration of 1 -10,000 ppm.

The present invention therefore also relates to pesticidal compositions which contain as active ingredient 15 at least one compound of formula 1, togetherwith customary carriers andlor dispersing agents.

The compositions may also contain further ingredients such as stabilizers, antifoams, viscosity regulators, binders, tackifiers as well as fertilisers or other active ingredients for obtaining special effects.

Preparatory examples 20 Preparation of starting materials andintermediates Example S 1: Preparation of 14,15-epoxymilbemycin D (formula VII) While cooling with ice, a solution of 170 mg of chloroperbenzoic acid in 5 mi of dichloromethane is added 25 to a solution of 550 mg of milbemycin D in 5 mi of dichloromethane. Afterstirring for 1 hour at Ooto 50C, another 170 mg of the oxidising agent are added and stirring is continued for 30 minutes. When the reaction is complete, the solution is poured into an ice-cooled solution of sodium sulfite and extracted with ethyl acetate. The combined extracts are washed once with water, dried, and concentrated by evaporation in vacuo. The crude product is purified by chromatography through a column of silica gel (elution with a 20:15 30 mixture of n-hexane and ethyl acetate), affording 450 mg of amorphous, white 14,15-epoxymilbemycin D.

Example S2: Preparation of 15-hydroxy-AL". "'-milbemycin D (formula VIb) 9.5 mi (0.41 g; 9.53 mmoi) of a 6.96% solution of HN3 in diethyl ether are added at -20'Cto a solution of 2.1 mi (1.75 g; 15.3 mmol) of triethylaluminium in 8.5 mi of absolute diethyl ether. The reaction mixture isthen 35 added at - 1 O'C to 1.8 g (3.15 mmol) of 14,15-epoxymilbemycin D (in substance). The ensuing reaction is strongly exothermic. After 1 hour at room temperature, 4 mi of absolute ether are added and the gelatinous reaction mixture is vigorously stirred. After4 hours, the reactioin mixture is worked up as described in Example S1. Chromatography through 70 g of silica gel (elution with a 10: 1 mixture of CH2C12 and acetone) affords 200 mg (10%) of 14-azido-1 5-hydroxymilbemycin D and 820 mg (45%) of 40 15-hydroxy-A,1 3,14_M ilbemycin D; m.p. 151'-1 53'C (recrystallisation from methanol).

Example S3: Pre;aration of 5-0-tert-butyldimethylsilyl- 14,15epoxymilbemycin D (formula VII) Asolution of 2.21 g (3.86 mmol) of 14,15-epoxymilbemycin D, 757 mg (5.02 mmol) of tert-butyidimethylchlorosilane and 342 mg (5.02 mmol) of imidazole in 4 m] of dimethylformamide is stirred 45 for 90 minutes at room temperature. Then 80 m] of diethyl ether are added and the mixture is filtered through g of silica gel and the filtrate is concentrated, affording 2.65 g (100%) of 5-0-tert-butyidimethyisiiyi-14,15-epoxy-milbemycin D.

H-NMR (300 MHz., solvent CDC1 3.A values based on Si(CH34 = TMS).

0. 12 ppm (s) (CH3)2Si-O-; 50 0.92 ppm (S) (t-C4H9)lSi-0-; 1.23 ppm (broad s) (C14CH3, i.e. signal of the CH3 group in the 14- position); 2.56 ppm (d; J = 9 Hz) (C15H, i.e. signal of the proton in the 15- position).

Following the same procedure, the corresponding 5-0-trimethyisilyi-14,15epoxymilbemycin D (m.p.

92'-97'C) can be prepared by reaction with trimethylsilyl trifluoromethanesuifonate. 55 Example S4.. Preparation of 5-0-tert-butyldimethylsilyl- 15-hydroxy-A 13, 14 -Milbemycin D (formula VIb) Asolution of the HN3/R3A1 complex reagent (prepared from a solution of 4. 97 mi of triethyl aluminium in 7 mi of absolute tetrahydrofuran and 9.15 mi of a 2.39 molar solution of HN3 (21.9 mmol) in absolute diethyl ether) is added, under argon, to a solution of 5.0 9 (7.29 mmol) of 60 5-0-ter-t-butyidimethyisiiyl,-1 4,15-epoxymilbemycin D in about 20 mi of absolute tetrahydrofuran, and the mixture is heated under refluxfor 15 hours. Then 250 mi of ether, 2 mi of methanol, and finally a mixture of 10 g of Na2SO4A 0H20 and 10 g of celite are added at room temperature. The mixture is filtered and thefiltrate is concentrated and chromatography of the crude productthrough 160 g silica gel (elution with 0-30% of ethyl acetate in hexane) affords 2.37 g (47%) of 5-0-tert-butyidimethyisiiyi-l 5-hydroxy-A13,14_M ilbemycin D. 65 13 GB 2 187 453 A 13 1 H-N M R (300 M HZ, CD03):

1.59 ppm (d; J = 1 Hz) (C14CH3); 4.06 ppm (dd; J1 = 11 Hz; J2 = 4 Hz) (C, 5H); 5.15 ppm (cl; J = 8 Hz) (C13H).

In addition, 109 mg (2 %) of 13p-azido-5-0-tertbutyidimethyisilyimilbemycin D are obtained.

5 Example S5: Preparation of 14,15-epoxymilbemycinA4 (R2= C2H5) (formula V10 A solution of 2.43 g (14.08 mmol) of m-chloroperbenzoic acid in 70 mi of dichloromethane is added dropwise at room temperature to a solution of 5.7 g (110.5mmol) of m ilbemycinA4 in 140mi of dichloromethane and 120 m] of a 0.5 molar solution of NaHCO3. The mixture is vigorously stirred for l hour at room temperature and then diluted with 300 m I of dichloromethane. The organic phase is washed with an 10 aqueous solution of NaHC03, dried over Na2SO4 and concentrated, affording 5.7 9 of epoxide as crude product.

Example S6.. Preparation of5-0-tert-butyldimethylsilyl-14,15epoxymilbemycinA4(fOrmUla V11) 5.7 g of 14,15-epoxymilbemycinA4 are dissolved in 10 m[ of dry dimethylformamide. Then 0.63 g (9.16 15 m mol) of imidazole and 1.49 (9.34mmol) of tert-butyl di methylch 1 o rosi lane are added at room temperature.

The mixture is stirred for l hour at room temperature and chromatographed through 150 g of silica gel (elution with a 4:1 mixture of hexane and ether), affording 2.84 g (40 % oftheory, based on milbemycin A4) Of the silylated epoxy derivative.

20 Example S7.. Preparation of5-0-tert-butyldimethylsilyl- 15-hydroxy-A 13, 14 -MilbemycinA4(fOrMUla VIN The complex reagent I-IN3/Al(ethy16 is prepared as follows: To 2.8 mi (12. 2 mmol) ofAI(C2H5)3 in 4 mi of absolute tetrahydrofuran are slowly added at about -200C, under argon, 5. 28 mi (20.4 mmol) ofan 10 % solution of H N3 in absolute diethyl ether. To this solution is added, under argon, a solution of2.84 g (4.25 mmol) ofthe compound obtained in Example S6, and the mixture so obtained is heated for4 hours under 25 reflux. Then 500 mi of diethyl ether and 10 g of Na2S04'1 0H20 and 10 g oftelite are added at room temperature. The mixture is filtered and the filtrate is concentrated. Chromatography ofthe crude product through 100 9 of silica gel (elution with a 7:2 mixture of hexane and diethyl ether) affords 1.72 g (60 % of theory) ofthe title compound.

'H-NMR (300 MHz, CDC13; TMS): 30 1.59 ppm (broad s) (C14CH3); 4.05 ppm (broad s) (C151-1); 5.15 ppm (d; J = 6Hz) (C131-1).

Inaddition,0A g of 13p-azido-5-0-tert-butyidimethyisilyimilbemycinA4iS obtained.

Example S8: Preparation of 15-hydroxy-A3, 14 -MilbemycinA4(fOrMUla Vib) 35 Hydrolysisof5mg ofthe title compound of Example S7 with 1 mlofa 1 %solution of p-toluenesulfonic acid in methanol andworking up indiethyl etherwith a 5% solution ofsodium bicarbonate affords the title compound.

Example S9: Preparation of 14,15-epoxymilbemycinA3 (R2 = CH3) (formula V11) 40 In accordance with the procedure described in Example S1, reaction of220 mgofmilbemycinA3in5miof dichloromethang and 75 mg ofchloroperbenzoic acid in 5 mi ofclichloromethane at -20to +WC over 11/2 hours and purification through a column of silica gel affords 190 mg of 14,15-epoxymilbemycin A3.

Example S10: Preparation of5-0-tert-butyldimethylsilyl-14,15epoxymilbemycinA3 (formula VY) 45 In accordance with the procedure of Example S3, reaction of 190 mg of 14, 15-epoxymilbemycin A3 and 120 mg oftert-butyidimethylchlorosilane in the presence of imidazole affords 217 mg ofthe title compound.

Example S1 1: Preparation of5-0-tertbutylmethylsilyl- 15-hydroxy-A'3, 14 MilbemycinA3(fOrMUla V1b) In accordance with the epoxy cleavage of Example S7,203 mg ofthe title compound are obtained from 210 so mg of 5-0-tert-butyidimethyisiiyi-l 4,15-epoxymilbemycin A3, in absolute diethyl ether using the complex reagent NI-13/R3A1 under argon, and subsequent purification.

H-NMR(300MHz,CDC13;TMS):

1.58 ppm (broads) (C14CH3); 4.05 ppm (broads) (C151-1); 5.15 ppm (cl; J = 6Hz) (C13H). 55 Example S 12: Preparation of 15-hydroxy-A'3, "-milbemycinA3 (formula V1b) In accordancewith the procedure described in Example Sl,the reagent I- IN3/AI(C2H56 isfreshly prepared and added dropwise at -110'Cto a solution of830 mg (3.05 mmol) of 14,15epoxymilbemyein A3 in 7 mi ofdry diethyl ether. After working up, 385 mg f 15-hydroxy-A 13,14_M ilbemycin A3 and 92 mg of 60 14-azido-1 5-hydroxymilbemycin A3 are obtained.

14 GB 2 187 453 A 14 Example S 13: Preparation of 13-deoxy14,15-epoxy-22,33- dihydroavermectin-Bla-aglycon (R2 = sec-C4H9) (formula V10 In accordance with the procedure described in ExampleS5,51Orng of thetitle compound are obtained from 520 mg of 13-deoxy-22,23-di-hydroavermectin-Bia-aglycon [Tetrahedron Letters, Vol. 24, No. 48, pp.

5333-5336 (1983)] and 210 mg of m-chloroperbenzoic acid in 20 mi of dichloromethane. 5 Example S 14. Preparation of 5-0-tert-butyldimethylsilyf-13-deoxy-14,15-epoxy-22,23-dihydroavermectinBla -aglycon (formula V11) In accordance with the procedure described in Example S6,108 mg of the title compound are obtained from 220 mg of the title compound of Example S1 3 and 55 mg of tert- butyidimethyl dichlorosilane in the 10 presence of 25 mg of imidazole in 5 mi of dry dimethylformamide.

Example S 15.. Preparation of 13-deoxy- 15-hydroxyA 13,'4-22,23dihydroavermectin-Bla-aglycon (formula V1b) In accordance with the procedure described in Example S2,112 mg of the title compound are obtained by 15 reacting 220 mg of thetitle corn pound of Example S1 4 with the complex reagent consisting of 320 mg of AI(C2H5)3 and 110 mg of a 6.96 % sol ution f H N3 in a total of 16 mi of dry diethyl ether. In addition, 61 mg of 13-deoxy-1 4-azido-1 5-hydroxy-22,23-dihydroavermectin-Bia-ag lycon are obtained.

ExampleS16: 20 a) Preparation of 5-0-tert-butyldimethylsilyl13p-hydroxymilbemycin D and 13p-hydroxymilbemycin D (formula V1a) Asolution comprising 286 mg (0.41 mmol)of 5-0-tert-butyidimethyisiiyi-15hydroxy-41 1,14-milbemycin D and 209 mg (0.56 mmol) of pyridinium dichromate (PDC) in 3 mi of dimethylformamide (DMF) is stirred for30 minutes at room temperature. 1 mi of isopropanoi is subsequently added and the mixture is stirred for5 25 minutes, and then diluted with 50 mi of ether. After a further 10 minutes, the mixture isfiltered through silica] gel and theffitrate is concentrated. Chromatography of the crude productthrough 20 g of silica gel (elution with a 1:2 mixture of ether and hexane) affords 165 mg (57 %) of 5-0-tert-butyidimethyisiiyi-13p-hydroxymilbemycin D.

'WNMR (300 MHz; CDC13; TMS): 30 1.59 ppm (br.s) (C14CH3) 3.70 plam (d; J = 10 Hz) (C131-1).

mg (0.153 mmol) of the compound so obtained are stirred at room temperature in 1 mi of a 1 %solution of p-toluenesulfonic acid in methanol for 1 hour. The mixture is diluted with 20 mi of ether, filtered through silica gel andthefiltrate is concentrated. The residue is chromatographed through about 10 g of silica gel 35 (elution with a 1:4 mixture of acetone and dichloromethane), affording 73 mg (83 %) of 13p-hydroxymilbemycin D.

H-NMR (300 MHz; C13C13; TMS):

1.58 ppm (br.s) (C14CH3) 3.71 ppm (d; J = 10 Hz) (C131-1). 40 b) Preparation pf5-0-tert-butyldimethylsilyl- 13p-hydroxymilbemycinA4 Byfollowing a procedure analogous to that described in a), butstarting from 5-0-tert-butyidimethyisiiyi-l 5-hydroxy-A 13,14_Mi Ibemycin A4, the title compound with the following physical data is obtained: 45 WNMR (300 MH,; CDC13; TMS):

3.05 ppm (t; J = 9 Hz) (C251-1) 3.71 ppm (dd; J = 3 and 10 Hz) (C13H) mass spectrum (FID) m/e: 672 (M'; C3BH6008Si).

so 50 ExampleS17 a) Preparation of 5-0-tert-butyldimethylsilyl13p-acetoxymilbemycin D (formula 1Va) A solution of 200 mg (0.29 mmol) of 5-0-tert-butyidimethyisily]-1 3p- hydroxymilbemycin D and 1 mi of pyridine in 2 mi of acetanhydride is stirred for 2 hours at room temperature. Working up in diethyl ether affords 212 mg of 5-0-tert-butyidimethyisilyi-l 3p-acetoxymilbemycin D in the form of an amorphous powder. 55 b) Preparation of5-0-tert-butyldimethylsilyl13p-acetoxymilbemycin A4 (formula 1Va) Byfol lowing a procedure analogus to that described in a), but starting from 5-0-tert-butyidimethyisily]-1 3p-hydroxymilbemycin A4, the title compound with the fol lowing physical data is obtained:

'H-NMR (360 MHz; CDC13; TMS): 60 1.53 ppm (S) (C14CH3) 2.03 ppm (s) (CH3C00) 4.94 ppm (d; J = 10 Hz) (C13H) mass spectrum (FD) m/e: 714 (M'; C4ol-16209SO.

GB 2 187 453 A 15 Example S 18: 14 a) Preparation of5-0-tert-butyldimethylsilyl-15-acetoxy-A'3, -milbemycin D (formula 1Vb) A solution of 627 mg (0.914 mmol) of 5-0-tert-butyidimethyisiiyi-l 5hydroxy-A 13,11-milbemycin D in 2 mi of acetanhydride and 2 mi of pyridine is stirred for 1/2 hour at room temperature. Working up in diethyl ether with 5 %aqueous NaHC03 solution and then with 1 M HCI and filtration through silica gel affords 624 mg (94 5 %)of 5-0-te rt-butyl d i methyl si lyi-l 5-acetoxy-Al 3,14_M ilbemycin D.

WNMR (300 MHz; CDC13; TMS):

1.58 ppm (br. s) (C14CH3) 1.79 ppm (br. s) (C4CH3) 2.02 ppm (s) (CH3C00) 10 5.12- 5.26 ppm (m) (CloH; C13H; C15H) b) Preparation of 5-0-tert-butyldimethylsilyl- 15-acetoxy-A 13 14 - Milbemycin A4 (fOrMUla IVb) By following the procedure described in a), but starting f rom 5-0-tert-butyldi methylsily1A 5-hydroxy-A 13,14_M ilbemycin A4, the title compound with the following physical dataisobtained: is H-NMR (250 MHz; CDC13; TMS):

1.59 13PM (S) (C14CH3) 2.03 ppm (s) (CH3C0) 3.02 ppm (t; J 8 Hz) (C25H) 3.88 ppm (d; J 6 Hz) (CeH) 20 mass spectrum m/e: 714 (M'; C40H6209Si), 639,579,497,472,437,413,412,394, 349.

c) Preparation of 5-0-tert-butyldimethylsilyl- 15-acetoxy-A 13,14 -milbem ycin A 4 (formula 1Vb) The title compound is prepared by following a procedure entirely analogous to that described in a) and b), but starting from 5-0-tert-butyidimethyisiiyi-l 5-hydroxy-A 11 '1 4- milbemycin A3.

25 Example S 19: Preparation of 130-methylmilbemycin D (formula 11) Under argon and at OOC, 1.2 mi of a 17% solution of trimethylaluminium in toluene are added dropwisewith stirring to a solution of 203 mg (0.28 mmol) of 5-0-tert- butyidimethyisiiyi-l 5-acetoxy-A 13,14_M ilbemycin D in 2 mi of dichloromethane. The solution is stirred for 2 hours at room temperature, then 0.3 mi of methanol is added dropwise, and the mixture is diluted with diethyl ether and stirred in celite. Filtration through silica gel 30 (elution with diethyl ether) affords 177 mg of 5-0-tertbutyldimethylsilyl- 13p-methylmilbemycin D.

A solution of this material in 0.5 mi of dichloromethane is stirred in 1 m] of a 40% aqueous solution of HF in acetonitrile (5:95) for 1 hour at room temperature. The mixture is worked up in diethyl ether andfiltered through silica gel. HPLC (Si02; 0.5 % methanol in dichloromethane; pressure 50 bar) of the crude procict (154 mg) affords (57 %) of 13p-methylmilbemycin D. 35 H-NMR (300 MHz; CDC13; TMS):

1.01 ppm (d, J = 6.7 Hz) (C13CH3) 5.03 ppm (d; J = 10.5 and 4.6 Hz) (C15H) mass spectrum m/e: 570 (M+; C34H5007),442,292,273,262,210,209,181,163,152, 151.

40 Example S20:

a) Preparationpf 13p-ethylmilbemycin Dand 15-ethyl-A 13,14 -Milbem ycin D (formula//) Underargon and atO'C, 0.75 mi (0.63 g; 5.5 mmol) of triethylaluminium is added dropwisewith stirring to a solution of 340 mg (0.47 mmol) of 5-0-tert-butyidimethyisily]-15-acetoxy- A 13,14_M ilbemycinDin2miof dichloromethane. The solution is stirred for 1 hour at room temperature, and then diluted with diethyl ether. 45 Celite/NaS04: 10 H20 0: 1) is added and the resultant mixture is stirred for 1 hour. Filtration through silica gel (el ution with diethyl ether) affords 258 mg of a mixture which is dissolved in 0.5 mi of dich 1 orom ethane. This solution is then stirred in 1 m 1 of a 4% aqueous solution of HF in aceton itrile (5:95) for 1 hou r at room temperatu re. Working u p in diethyl ether, filtration th roug h sil ica gel (elution with diethyl ether) and H PLC (reversed phase: water/methanol 1: 9; pressu re 50 mbar) of the crude product (183 mg) affords 88 mg (32 %) so of 130-ethylmilbemycin D.

H-NMR (300 MHz; CDC13; TMS):

0.73 ppm (t, J = 7.2 Hz) (C13CH2CH3) 5.03 ppm (dd; J = 10.5 und 4.4 Hz) (C15H) mass spectrum m/e: 584 (M'; C35H52H5207),456,287,276,210,209,181,163,151 and 57 mg (21 %) of 55 15_ethyl_A13,14 -Milbemycin D.

H-NMR (300 MHz; CDC13; TMS):

3.03 ppm (M) (C12H) 4.93 ppm (dd; J = 8.7 und 1.2 Hz) (C13H) massspectrum m/e: 584(W; C35H5207),456,438,277,276,206,181,171,163,151, 150,149. 60 Byfollowing procedures analogous to that of S20a, the following milbemycinsof formula 1 indicated in S20bto S20h areobtained by reaction with the corresponding trialkyl compounds:

16 GB 2 187 453 A 16 S20b) 13p-methylmilbemycinA4 H-NIVIR (250 MHz; CDC13; TMS):

3.07 ppm (dt; J 12 and 10 Hz) (C25H) 5.05 ppm (dd; J 10 and 5 Hz) (C15H) r) mass spectrum (FD) m/e: 556 (M'; C33H4807). 5 S20c) 130-ethylmilbemycinA4 H-NMR (250 MHz; CDC13; TMS):

3.03 ppm (broad t; J = 10 Hz) (C25H) 5.02 ppm (dd; J = 10 and 7 Hz) (C15H) 10 mass spectrum (FD) mle: 570 (M'; C34H5007).

S20d) 13p-n-hexylmilbemycin D H-NMR (250 MHz; CDC13; TMS):

3.08 ppm (d; J = 8 Hz) (C25H) 15 5.00 ppm (broad t; J = 8 Hz) (C15H) mass spectrum (FID) m/e: 640 W; C39H6007).

S20e) 13p-n-butylmilbemycinA4 'WNMR (250 MHz; C1303; TMS): 20 3.03 ppm (broad t; J = 10 Hz) (C25H) 5.02 ppm (broad t; J = 10 Hz) (C,5H) mass spectrum (FID) m/e: 598W; C36H5407).

S20f) 130-isobutylmilbemycinA4 25 H-NMR (250 MHz; C13C13; TMS):

3.09 ppm (broad t; J = 10 Hz) (C25H) 5.05 ppm (dd; J = 10 and 7 Hz) (C15H) mass spectrum (FD) m/e: 598W; C36H5407).

30 S20g) 13p-methylmilbemycinA3 1 H-N M R (300 M Hz; CDC13; TM S):

3.27 ppm (M) (C25H) 5.06 p p m (dd; J = 10 a n d 6 Hz) (Cl 5 H) mass spectrum (FD) m/e: 542 (M'; C32H4607). 35 S20h) 13p-ethy[milbemycinA3 H-NMR (300 MHz; CDC13; TMS):

3.25 ppm (M) (C2sH) 5.06 ppm (dd; J = 10 and 6 Hz) (C15H) 40 mass spectrum (FD) m/e: 556 (M'; C33H4807) Example S2 1: Preparation of 13p-mothylmilbemycin D (formula 11) from 5-0-tert-butyldimethylsilyl-13p-acetoxymilbemycin D Underargon and atOOC, 0.5 mi of a 17 % solution of trimethylaluminium in toluene is added dropwisewith 45 stirring to a solution of 14 mg (0.019 mmol) of 5-0-tertbutyidimethyisiiyi-13p-acetoxymilbemycin D in 0.5 mi of dich lo rom ethane. The solution is stirred overnight at 50C. Working up as indicated in S20 affords 10 mg of 5-0-tert-buyldimethylsilyl- 13p-methylmilbemycin D.

A solution of this material in 0.5 m] of dichloromethane is stirred in 1 mi of a 40 % aqueous solution of HF in acetonitrile (5:95) for 1 hour at room temperature. The mixture!s worked up in diethyl and filtered through 50 sil ica gel, affording 8 mg of 130-methylmilbemycin D.

Preparation of the FinalProducts Fl. Preparation of5-0-chloroacetyl13p-methylmilbemycinA4 55 A solution of 350 mg of 13p-methyl milbemycin A4 and 0.50 mI of pyridine in 3 mi of methylene chloride is cooled to OOC and then 80 lil of chloroacetyl chloride are added over 2 hours. The reaction mixture is stirred for 1 hour at O'C and then worked up. Chromatography through a column of silica gel (elution with a 4:1 mixture of hexane/ethyl acetate) affords 324 g of title compound. 60 'H-NMR (250 MHz; C13C13):

3.07 ppm (dt, Jd = 3, Jt = 10) (C25H) 4.18 ppm (s) (CH2C1) 17 GB 2 187 453 A 17 F2. Preparation of 5-0-acetoxyacetyl13p-methylmilbemycinA4 a) 2 mi of a 0.9 M solution of acetoxyacetyl chloride in benzeneare added atO'Cover30 minutestoa solution of 50 mg of 13p-methyimilbemycinA4,73 [xl of pyridineand 1 mg of dimethylaminopyridine in 1 mi of methylene chloride.The reaction mixture isstirredfor3 hoursand thenworked up.The crude productis chromatographed through a column of silica gel (elution with a3:1 mixture of hexane/ethyl acetate), 5 affording 49 mg of title compound.

1 H-N M R (300 M Hz; WC13):

2.16 ppm (s) (CH2-CO) 3.07 ppm (dt; Jd 3, Jt = 10) (C25H) 5.03 ppm (dd, J 11 u nd 6) (C15H) 10 b) 16 mg of sodium acetate and 2 mg of sodium iodide are added to a solution of 80 mg of 5-0-chloroacetyi-1 3p-methyimilbemycin A4 in 3 mi of dimethyiformamide. The reaction mixture is heated for 3 112 hours to WC and then worked up. The crude product is chrornatographed through a column of silica gel (elution with a 3:1 mixture of hexane/ethyl acetate), affording 53 mg of 5-0-acetoxyacetyi-13p-methyimilbemycin a4. 15 F3. Preparation of 5-0-(3,4-dihydro-2H-pyran-2-yl)carboxyacetyl-13pmethylmilbemycin D A solution of 80 mg of 5-0-chloroacety]-1 3p-methyimilbemycin D, 29 mg of sodium (-L)-3,4-dihydro-2H-pyran-2-carboxylate and 2 mg of potassium iodide in 3 mi of dimethylformamide is stirred for 6 1/2 hours at WC under an atmosphere of argon and subsequently diluted with 50 mi of diethyl 20 ether. The resultant solution is washed with 20 mi of water and then with 20 mi of saturated NaCI solution, dried over M9S04 and filtered. The filtrate is concentrated by evaporation and the resultant crude product is chromatographed through silica gel (elution with a 3:1 mixture of hexanelethyl acetate), affording 59 mg of product.

MS (m/e): 724 (M1 25 1 H-N M R (250 M Hz; C13C13):

3.07 ppm (dt; Jd 3, Jt = 10) (C25H) 5.05 ppm (dd, J 6 und 10) (Cl 5H) 6.44 ppm (d, J = 8) (O-CH= CH) 30 F4. Preparation of 5-0-(1,2,4-triazoll-yl)acetyl- 13p-methylmilbemycin A4 0.30 m 1 of pyridine, 2 mg of dimethylaminopyridine and 74 mg of N,N- dicyclohexylcarbodiimide are added to a solution of 100 mg of 13p-methyimilbemycin A4 and 57 mg of 1 H-1,2,4triazol-l-yl-acetic acid in 2 mi of tetrahydrofuran. The reaction mixture is stirred for 2 112 hours at room temperature and worked up. The crude product is suspended in 3 m] of diethyl ether, and the suspension is filtered and concentrated by 35 evaporation. Chromatographed through a column of silica gel (elution with 5 % methylene chloride/methanol) affords 100 mg of title compound.

MS (m/e): 665 (M1 H-NMR (300 MHz; C13C13):

3.07 ppm (dt; Jd = 3, Jt = 10) (C25H) 40 5.07 ppm (s) (CH2N) 7.97 ppm (s) (N=CH-N) 8.24 ppm (s) (N =CH-N) F5. Preparation of 5-0-(1,2,4-triazol-l-yl)acetyl- 13p-methylmilbemycin A14zinc(I1) complex 45 K] of a 0. 19 M solution of zinc (11) chloride in ethanol are added to a solution of 47 mg of 5-0-(1,2,4-triazol-l-yi)acetyi-1 3p-methyim ilbemycin A4 in 2 mi of benzene. The resultant solution is allowed to standforl hour at room temperature and then lyophilised. The title compound is obtained in a yield of 52 mg.

WNMR (300 MHz; C13C13):

3.06 ppm (dt; Jd = 3, Jt = 10) (C25H) so 5.12 ppm (s) (CH2N) 8.21 ppm (s) (N = CH-N) 8.65 ppm (s) (N =CH-N) F6. Preparation of 5-0-acetoxyacetyl13p-ethylmilbemycinA4 55 0.92 m] of a 0.25 M solution of acetoxyacetyl chloride in benzene are added atOoCto a solution of 65 mg of 13p-ethyimilbemycin A4,92 K] of pyridine and 1 mg of dimethylaminopyridine in 1 m] of methylene chloride.

The reaction mixture is stirred for4 hours at OT andthen worked up. The crude product ischromatographed through a column of silica gel (elution with a 4:1 mixture of hexane/ethyl acetate), affording 70 mg of title compound. 60 MS (m/e): 670 (M'; C38H54010) H-NMR (300 MHz; WC13):

0.71 ppm (t, J = 7), (C13CH2CH3) 2.16 ppm (s) (CH3-CO) 3.07ppm(dt,Jd=3,Jt=g)(C25H) 65 is GB 2 187 453 A 18 5.60 ppm (d, J = 7) (C514) 5-0-Acetoxyacety]-1 3p-ethyl mil bemycin A3 and 5-0-acetoxyacetyl-1 3p- ethyimilbemycin D can be obtained in analogous manner.

F7. Preparation of 5-0-chloroacetyl-13p-ethylmilbemycinA4 5 Following the procedure of Example F1, the product can be obtained in a yield of 59 mg from 61 mg of 13p-ethyimilbemycin a4.

MS (m/e): 646 (M'; C36H51C1 08) H-NMR (300 MHz; CD03):

3.06 ppm (dt; Jd = 3, Jt = 10) (C2511) 10 4.15 ppm (s) (CH2C1) 5.01 ppm (dd, J = 6 und 10) (C15F1) F8. Preparation of 5-0-tert-butyldimethylsilyloxyacetyl- 13p- methylmilbemycinA4 One drop of dimethylformamide (c. 30 111) is added to a solution of 956 mg of tert-butyidimethyisilyl 15 tert-butyidimethyisilyloxyacetate in 4 mi of methylene chloride, followed bythe addition of 222 KI of oxaly] chloride at OOC over 45 minutes. The reaction mixture is then stirred for 30 minutes at O'C and for 2 hours at room temperature. The resultant solution of the acid chloride is subsequently added dropwise over 20 minutesto a solution, cooled to WC, of 900 mg of 13p-methyimilbemycin A4 and 1.31 m] of pyridine in 2 mi of methylene chloride. The reaction mixture is stirred for 90 minutes at WC, then partitioned between ether and 20 1 N HCl solution. and the organic phase is washed with saturated NHC03 solution and with saturated NaCI solution and concentrated by evaporation.The residue is chromatographed through a column of silica gel (elutionwitha10:1 mixture of hexane/ethyl acetate), affording 988 mg of title compound.

MS (m/e): 728 (M'; C41 H6409Si) 'H-NMR (300 MHz; CDC13) 25 0. 10 ppm (s) ((C113)2SO 0.80 ppm (s) (tert-C4H9Si) 3.05 ppm (dt,Jd = 3,Jt = 9) (C2511) 5.57 ppm (d, J = 6) (C511) 30 F9. Preparation ofS-O-hydroxyacetyl13p-methylmilbemycinA4 934 mg of 5-0-tert-butyidimethyisilyloxyacetyi-13p-methyimilbemycin A4are added to 5 mi of a 5% solution of 40% HF in acetonitrile. The reaction mixture is stirred for2 hours at room temperature, then partitioned between diethyl ether and saturated NHC03 solution andthe organic phpase iswashedwith saturated NaCI solution and concentrated by evaporation. The residue is purified by chromatography 35 (elution with a 2:1 mixture of hexane/ethyl acetate), affording 690 mg of title compound.

MS (mle): 614 W; C35115o09) H-NMR (300 NHz; C13C13):

2.38 ppm (t, J = 6) (CH20H) 3.05 ppm (dt, Jd 2,5, Jt = 9) (C25H) 40 4.21 ppm (dd, J1 6, J2 = 16) (CO-CHHOH) 4.28 ppm (dd, J1 6, J2 = 16) (CO-CHHOH) F1 0. Preparation of 5-0-methoxycarbonloxyacetyl- 13p-methylmilbemycinA4 13 Ll of methyl chloroformate are added to WC to a solution of 50 mg of 45 5-0-hydroxyacety]-1 3p-methyimilbemycin A4 and 66 gi of pyridine in 2 mi of methylene chloride. The reaction mixture is stirred for 15 minutes at OOC and the cooling bath is removed and stirring is continued fora further 2 hours at room temperature. Afterworking up,the crude product is chromatographed through a column of silica gel (elution with hexanelethyl acetate), affording 50 mg of title compound.

MS (m/e): 672 W; C37H5201 1) so H-NMR (300 MHz; WC13):

3.05 pp (dt, Jd = 2,5, Jt = 9) (C2511) 3.78 ppm (s) (CH30) 4.68 ppm (d, J = 16) (CO-CHHO) 4.74 ppm (d, J = 16) (CO-CHHO) 55 5.60 ppm (bd, J = 6) (CrH) F1 1. Preparation of 5-0-methoxymethoxyacetyl13p-methyl-milbemycinA4 168 gi of bromomethyl methyl ether are added to a solution of 50 mg of 5-0-hydroxyacetyl-1 3p-methy[milbemycin A4 and 580 111 of Wethyl diisopropylamine in 1 mi of methylene 60 chloride. The reaction mixture is stirred for 2 days at room temperature and then worked up. The crude product is chromatographed through a column of silica gel (elution with a 4:1 mixture) of hexanelethyl acetate), affording 23 mg of title compound.

MS (m/e): 658 (M'; C37H54010) 'H-NMR (300 MHz; CD03):

3.05 ppm (dt, J d = 2,5, Jt = 9) (C251-1) 65 19 GB 2 187 453 A 19 3.38 ppm (s) (CH30) 4.21 ppm (d, J = 16) (CO-CHHO) 4.28 ppm (d, J = 16) (CO-CHHO) 5.60 ppm (d, J = 6) (C5H) F1 2. Preparation of 5-0-(3-chlorobenzoyloxy)acetyl- 13p-methyl- milbemycin A4 21 jil of 3-chlorobenzyl chloride are added to a solution of 50 mg of 5-0-hyd roxyacety]-1 3p-methyl mi 1 bemycin A4 and 66 gi of pyridine in 2 mi of methylene chloride and the reaction mixtu re is stirred for 3 hours. After working up, the crude product is chromatographed through a column of silica gel (elution with a 6:1 m ixture of hexanelethyl acetate), affording 54 mg of title compound. 10 MS (m/e): 752 (M'; C42H53C1010) 1 H-N M R (300 M Hz; CD03):

3.05 ppm (dt, Jd = 2,5, Jt = 9) (C25H) 4.90 ppm (cl, J = 16) (CO-CHHO) 4.98 ppm (d, J = 16) (CO-CHHO) 15 5.61 ppm (bd,J = 6) (C5H) 7.39 ppm (m) (aromatic ring proton) 7.55 ppm (m) (aromatic ring proton) 7.97 ppm (m) (aromatic ring proton) 8.06 ppm (m) (aromatic ring proton) 20 F1 3. Preparation of 5-0-(2-tetrahydropyranyl)oxyacetyl- 13p- methylmilbemycinA4 2 mg of pyridinium (toluene-4-sulfonate) are added to a solution of 50 mg of 5-0-hydroxyacetyi-13p-methyimilbemycin a4and 74 jil of 3,4-dihydro-2Hpyrane in 2 m] of methylene chloride. The reaction mixture is stirred for90 minutes at room temperature and then worked up. Thecrude 25 product is chromatographed through a column of silica gel (elution with a 4:1 mixture of hexanelethyl acetate), affording 49 mg of title compound.

MS (m/e): 698 (M'; C40H58010) WNMR (300 MHz; CD03):

3.05 ppm (dt, Jd = 2,5, Jt = 9) (C25H) 30 4.27 ppm (d, J = 16) (CO-CHHO) 4.33 ppm (d, J = 16) (CO-CHH) 4.78 ppm (m) (OCH(CH2)0) F1 4. Preparation of 5-0-(4-chlorobutanoyl)oxyacetyl- 13p- methylmilbemycinA4 35 18 KI of chlorobutyryl chloride are added at OOC to a solution of 50 mg of 5-0-hydroxyacetyi-l 30-methyimilbemycin A4 and 66 [L1 of pyridine in 2 mi of methylene chloride. The reaction mixture is stirred for 2 hours at O'C and then for 2 hours at room temperature and worked up. The crude product is chromatographed through a column of silica gel (elution with a 4:1 mixture of hexane/ethyl acetate), affording 53 mg of title compound. 40 MS (m/e): 718 (M'; C39H55C1 010) H-NMR (300 MHz; CIDC1a):

3.05 ppm (dt, Jd = 2,5, Jt = 9) (C25H) 3.61 ppm (t, J 7) (CH2C1) 4.68 ppm (d,J 16) (C-CHHO) 45 4.75 ppm (d, J 16) (CHHO) 5.59 ppm (db, J = 6) (C0 F1 5. Preparation of 5-0-(thiophene-2-carbonyloxy)acetyl- 13pmethylmilbemycin A4 52 KI of thiophene-2-carboxyl ic chloride are added to a solution of 50 mg of so 5-0-hydroxyacetylA 3p-methyl m ilbemycin A4 and 66 K] of pyridine in 2 mi of methylene chloride. The reaction mixture is stirred for 4 hours at room temperature and worked u p. The crude product is chromatog raphed through a colum n of silica gel (elution with a 4:1 mixture of hexane/ethyl acetate), affording 55 g of title compound.

MS (m/e): 724 (M'; C40H5201OS) 55 H-NMR (300 MHz; WC13):

3.05 ppm (dt, Jd = 2,5, Jt = 9) (C25H) 4.85 ppm (d, J = 16) (CO-CHHO) 4.93 ppm (d, J = 16) (CO-CHHO) 5.60 ppm (bd, J = 6) (C5H) 60 7.11 ppm (m) (thiophenp proton) 7.60 ppm (m) (thiophene proton) 7.88 ppm (m) (thiophene proton) GB 2 187 453 A 20 F1 6. Preparation of 5-0-vinyloxycarbonyloxyacetyl- 13p- methylmilbemycinA4 A of acryly] chloride are added to a solution of 50 mg of 5-0hydroxyacetyi-13p-methyimilbemycinA4 and 132 [LI of pyridine in 2 mi of methylene chloride. The reaction mixture is stirred for 5 hours at room temperature and worked up. The crude product is chromatographed through a column of silica gel (elution witha4A mixture of hexane/ethyl acetate), affording 10 mg of title compound. 5 MS (m/e): 668 (M'; C38H52010) H-NMR (300 MHz; CDC13):

3.05 ppm (dt, Jd = 2,5, Jt = 9) (C251-1) 4.75 ppm (cl, J = 16) (CO-CHHO) 4.18 ppm (d, J = 16) (CO-CHHO) 10 5.60 ppm (bd, J = 6) (C5H) 5.91 ppm (dd, J1 = 1,5, J2 10) (HI-IC=CHCO) 6. 20 ppm (dd, J1 = 10, J2 = 17) (HI-IC=CHCO) 6.50 ppm (dd, J1 = 1,5, J2 17) (HI-IC=CHCO) is 15 F1 7. Preparation of 5-0-phenoxyacetyl- 13p-methylmilbemycinA4 [LI of phenoxyacetyl chloride are added at O'Cto a solution of 50 mg of 50-hydroxyacetyl-1 3p-methyimilbemycin A4 and 73 [LI of pyridine in 2 mi of methylene chloride. The reaction mixture is stirred for 2 hours at O'C and then worked up. The crude product is chromatographed through a column of silica gel (elution with a 4:1 mixture of hexane/ethyl acetate), affording 57 mg of title 20 compound.

MS (m/e): 690 (M'; C41 H5409) H-NMR (300 MHz; CDC13):

3.05 ppm (dt, Jd = 2.5, Jt = 9) (C251-1) 4.71 ppm (s) (COCH20) 25 5.60 ppm (bd, J = 6) (C5H) 6.93 ppm (M) (C6H3HA2)) 6.98 ppm (m) (C6H4H-(4)) 7.27 ppm (m) (C6H3H2-(3)) 30 F1 8. Preparation of 5-0-acetoxyacetyl13p-n-butylmilbemycinA4 In accordance with the procedure of Example F6,8 mg of title compound are obtained from 8 mg of 13p-n-butyimilbemycin A4.

MS (m/e): 698 (M'; C401-15801o) 'H-NMR (300 MHz; CDC13): 35 0.85 ppm (t, J = 7) (CH3CH2) 2.16 ppm (s) (CH3C0) 3.05 ppm (dt, Jd = 2.5, Jt = 9) (C251-1) 4.66 ppm (d, J = 16) (CO-CHHO) 4.73 ppm (cl, J = 16) (CO-CHHO) 40 5.59 ppm (bd, J = 16) (CsH) F1 9. Preparatiin of 5-0-p-tosyloxyacetyl-1 3p-methyl milbemycin A4 2 mg of 4-dimethylaminopyridine are added at OOC to a solution of 50 mg of 5-0-hydroacetyl-1 3J3-methyl milbemycin A4 and 260 RI of pyridine in 2 mi of diethyl ether, followed bythe 45 addition of 150 mg of toluene-4-su Ifochloride. The reaction mixture is stirred for 24 hours at room temperatu re and then worked up. Chromatography of the crude product through silica gel (el ution with a 4:1 mixture of hexanelethyl acetate) affords, in addition to 7 mg of 5-0chloroacetyi-13p-methyimilbemycin, 15 mg of title compound.

MS (m/e): 768 (M'; C42H56011S) 50 1 H-N M R (300 M Hz; CDC13):

2.43 ppm (s) (C6H4-CH3) 3.05 ppm (dt, Jd = 2.5, Jt = 9) (C251-1) 4.67 ppm (s), (COCH20) 55 F20. Preparation of 5-0-methoxyacetyl13p-methylmilbemycinA4 One drop of dimethylformamide (c. 30 0) is added to a solution of 81 RI of methoxyacetic acid in 5 mi of benzene, followed bythe addition of 80 [LI of oxaly] chloride at OOC over 5 minutes. The reaction mixture is then stirred for 2 hours at room temperature. 1.56 mi of this solution are added at OOC over 20 minutes to a solution of 50 mg of 13p-methyimilbemycin A4,73 1A pyridine and 0.6 mg of 4-dimethylaminopyridine in 2 mi 60 of methylene chloride. The reaction mixture is stirred for 2 hours at O'C and then worked up.

Chromatography of the crude product through silica gel (elution with hexane/ethyl acetate) affords 46 mg of title compound.

MS (m/e): 628 (M+; C36H5209) 'I-I-NIVIR(300 MHz; C13CIA: 65 21 GB 2 187 453 A 21 3.48 ppm (s) (CH30) 4.10 ppm (d, J = 16) (COCHHO) 4.18 ppm (d, J = 16) (COCHHO) F21. Preparation of 5-0-chloroacetyl- 13p-ethylmilbemycinA4 5 Following the procedure of Example F1, 22 mg of 5-0-chloroacetyl-l 3pethyimilbemycin A3 are obtained from 25 mg of 13p-ethyimilbemycin A3.

MS (m/e): 632 (M'; C35H49C1 08) 1 H-N M R (300 M Hz; CDC13):

3.25 ppm (M) (C2511) 10 4.16 ppm (s) (CH2C1) F22. Preparation of 5-0-acetyloxyacetyl- 13p-methylmilbemycin A3 Fol lowing the procedure of Example F6,30 mg of 5-0-acetoxyacetyl-1 3p- methyl mil bemycin A3 are obtainedfrom31mgofl3p-methyimilbemycinA3. 15 MS (m/e): 642 (M'; C361150010) H-NMR (300 MHz; C13C13):

0.70 ppm (t, J = 7) (C13CH2CH3) 2.15 ppm (s) (CH3C0) 3.25 ppm (M) (C2511) 20 5.59 ppm (d, J = 7) (C5H) F23. Preparation of 5-0-methoxyacetyl13p-methylmilbemycin D Fol lowing the procedure of Example F20,21 mg of 5-0-methoxyacetyl-1 3p- methyl milbemycin D are obtained from 25 mg of 13p-methyimilbemycin D 25 MS (m/e): 642 (M+; C37H5409) WNMR (300 MHz; CD03):

3.07 ppm (bd, J = 10) (C25H) 3.49 ppm (s) (CH30).

30 F24. Preparation of 5-0-acetyl- 13p-methylmilbemycinA4 29 lil of pyridine are added at WC to a solution of 20 mg 13p- methyimilbemycin A4 in 1 mi of methylene chloride, followed bythe addition of 6 jil of acetyl chloride. The reaction mixture is stirred for3 1/2 hours at O'C and then worked up. Chromatography of the crude productthrough silica gel (elution of a 4:1 mixtureof hexane/ethyl acetate) affords 20.5 mg of product. 35 MS (m/e): 598 (M'; C35115008) H-NMR (300 MHz; CDC13):

2.14 ppm (s) (CH3C0) 3.06 ppm (dt, Jd 2,5, Jt = 9) (C25H) 5.03 ppm (dd, J1 11, J2 = 5) (ClrH) 40 The fol lowing compou nds of formula 1 are also prepared by the procedures described in the foregoing Examples. The fq11owing Tables imply no restriction to what is contained therein.

22 GB 2 187 453 A 22 Table 1: Typical representatives of compounds of formula I, wherein R2 is CH3 (= milbemycin A3 derivatives):

Compound R R1 Physical data or Preparatory Example 1.1 CH3 COCH3 1.2 C2H5 COCH3 1.3 C3H7-n COCH3 1.4 e3H7-i COCH3 1.5 C4Hg-n COCH3 1.6 C6H13-n COCH3 1.7 CloHzi-n COCH3 1.8 CH3 COCH2C1 1.9 CH,3 COCH2Br 1.10 C2H5 COCH2C1 F21 1.11 CH3 COCH2BrF 1.12 C2H5 COCH2F 1.13 CH3 COCH2CH3 1.14 C2Hs COCH2OCH3 1.15 CH3 COCH2SCH3 1.16 CH3 COCH2OCH3 1.17 CH3 COCH20COCH3 F22 1.18 G2H5 COCH20COCH3 1.19 C3H7-n COCH20COCH3 1.20 C6H13-n COCH20COCH3 1.21 CH3 COCHFOCOCH3 1.22 CH3 COCH(CH3)OCOCH3 1.23 CH3 COCHZOCOCH2C1 1.24 CH3 COCH20COC2H5 1.25 CH3 COCH20COCO4F0) 1.26 C?H5 COCH20COCO4C1(3) 1.27 CH3 COCH20COCO4OCH30) 1.28 CH3 COCH20COC6H3C12(2,4) 1.29 CH3 COCH20COC3H7-n 1.30 C2H5 COCH2OCH2OCH3 23 GB 2 187 453 A 23 Table 1 (continuation) Compound R R1 Physical data or Preparatory Example 1.31 CH3 COCH20CO 1.32 C2H5 COCH20CO-1 it 1.33 CH3 COCH2 1.34 C2Hs COCHZ./= \'N=.

-N 1.35 CH3 COCH2N/ x 112 ZnCl 1.36 C2H5 COCH2NI X 112 ZnCl.

A= 4=N 1.37 CH3 COCH 2 NI 1 x 112 CuCl \N=.

1.38 C2H5 COCH2N x 112 CuCl \N= 1.39 CH3 COCH20CO-i \ i o 1.40 CaHS COCH20CO- Jy/O 1.41 CH3 COCH20CO-b,-/- 1.42 C2H5 COCH2OCO- /- 1.43 CH3 COCH?OCH3 L1,44 CH3 COCH20COC6R4C1(3) 24 GB 2 187 453 A Table 2: Typical representatives of compounds of formula I, wherein Rz - C2H5 (- milbemycin A4 derivatives):

Compound R R1 Physical data or 1 Preparatory Example 2.1 CH3 COCH3 F24 2.2) C2H5 COCH3 2.3 C3H7-n COCH3 2.4 C3H7-i COCH3 2.5 C4Hg-n COCH3 2.6 C61i13-n COCH3 2.7 CloH21-n COCH3 2.8 CH3 COCH2C1 Fl 2.9 CH3 COCH2Br 2.10 CH3 COCH2F 2.11 CH3 COCH2BrF 2.12 C2Hs COCH2F 2.13 CH3 COCH2CH3 2.14 C2Hs COCH2OCH3 2.15 CH3 COCH2SCH3 2.16 CH3 COCH20C2H5 2.17 CH3 COCH20COCH3 F2 2.18 C2Hs COCH20COCH3 F6 2.19 C3H7-n COCH20COCH3 2.20 C6H13-n COCH20COCH3 2.21 CH3 COCHFOCOCH3 2.22 CH3 COCH(CH3)OCOCH3 2.23 CH3 COCHZOCOCH2C1 2.24 CH3 COCH20CM2H5 2.25 CH3 COCH20COC6M(3) 2.26 C2H5 COCH20COCO4C1(3) 2.27 CH3 COCH20COC6H4OCH3(3) 2.28 CH3 COCH2OCOC6H3C12(2,4) 2.29 CH3 COCH20COC07-n 2.30 C2Hs COCH2OCHZOCH3 GB 2 187 453 A 25 Table 2 (continuation) Compound R R1 Physical data or Preparatory Example 2.31 CH3 COCH20CO-4 F3 2.32 C2H5 COCH20CO 2.33 CH3 COCH F4 N= 2.34 C2H5 COCH2N.

2.35 CH3 COCH2N.=. 112 ZnC12 F5 2.36 CzHs COCH21X/1 x 112 ZnC12 \N=.

2.37 CH3 COCHZN/=::.x 1.12 CuC12 2.38 C2H5 COCH2N/ x 112 CUC12 2.39 CH3 COCHACO 0 2.40 C2H5 COCH20CO-6 2.41 CH3 COCH20C0-N/ 2.42 C2H5 COCH20C0-N/-j 2.43 CH3 COCH2OCH3 F20 2.44 CH3 COCH20COCO4C1(3) F12 26 GB 2 187 453 A 26 Table 2 (continuation) Compound R R1 Physical data or Preparatory Example 2.45 e2H5 COCH2C1 F7 2.46 CH3 COCH20H F.9 2.47 CH3 COCH20CO0CH3 F10 2.48 CH3 COCH2OCH2OCH3 F11 2.49 CH3 COCH2-0-i F13 2.50 CH3 COCH20COCH2CH2CH2C1 F14 2.51 CH3 COCH2OCO-# FIS \ S / 2.52 CH3 COCH20CO-CH=CH2 F16 2.53 CH3 COCH20C6% F17 2.54 C4Hg-n COCH20COCH2 F18 2.55 CH3 COCH2OS02-CO4CH3(4) F19 2.56 CH3 COCH2OWCH3)zt-Butyl F8 27 GB 2 187 453 A 27 Table 3: Typical representatives of compounds of formula I, wherein R2 - iSOC3H7 (- milbemycin D derivatives):

Compound R R1 Physical data or Preparatory Examples 3.1 CH3 COCH3 F24 3.2 C2H5 COCH3 3.3 C3H7-n COCH3 3.4 C3H7-i COCH3 3.5 C4Hg-n COCH3 3.6 C6H13-n COCH3 3.7 C10H21-n COCH3 3.8 CH3 COCH2C1 3.9 CH3 COCH2Br 3.10 CH3 COCH2F 3.11 CH3 COCH2BrF 3.12 C2H5 COCH2F 3.13 CH3 COCH2OCH3 F23 3.14 C2Hs COCH2OCH3 3.15 CH3 COCH2SCH3 3.16 CH3 COCH2OG2Hs 3.17 CH3 COCH20COCH3 3.18 C2Hs COCH20COCH3 3.19 C3H7-n COCH20COCH3 3.20 C6H13-n COCH20COCH3 3.21 CH3 COCHFOCOCH3 3.22 CH3 COCH(CH3)OCOCH3 3.23 CH3 COCH20COCH2C1 3.24 CH3 COCH2OCOC2H5 3.25 CH3 COCH20CM6H4F(3) 3.26 C2Hs COCH20COCO4C1(3) 3.27 CH3 COCH20COCO4OCH3(3) 3.28 CH3 COCH20COC6H3C12(2,4) 3.29 CH3 COCH20CM3H7-n 3.30 e2Hs COCHZOCH2OCH3 28 GB 2 187 453 A 28 Table 3 (continuation) Compound R RI Physical data or Preparatory Examples 3.31 CH3 COCH20CO 0 3.32 CzH5 COCHAW-0 0 3.33 CH3 COCH2N.

3.34 CzHs (",OCH2N.

3.35 CH3 COCH2N/---N x 112 ZnC12 3.36 C2Hs COCH2M/ x 112 ZnCl? \'N=.

3.37 CH3 1"ZOCH2N. x 112 CuC12 ---N 3.38 C2Hs COCH2N. =. x 112 CuC12 3.39 CH3 COCH20CO 3.40 C2H5 COCH20CO- j ? 3.41 CH3 COCH20C0-N&- 3.42 C2Hs COCH20CO-IT/4 3.43 CH.3 C0C.H2OCH3 3.44 CH3 COCH20COC6H4C1(3) 29 GB 2 187 453 A 29 Table 4: Typical representatives of compounds of formula I, wherein R2 - sec-butyl (.13-deoxy-22,23-dihydro-C-076-Bla-aglycon derivatives):

Compound R R1 4.1 CH3 COCH3 4.2 C2H5 COCH3 4.3 C3H7-n COCH3 4.4 C3H7-i COCH3 4.5 C4Hg-n COCH3 4.6 C6H13-n COCH3 4.7 CloH21-n COCH3 4.8 CH3 COCH2C1 4.9 CH3 COCH2Br 4.10 CH3 COCH2F 4.11 CH3 COCH2BrF 4.12 C2H5 COCH2F 4.13 CH3 COCH2CH3 4.14 C2H5 COCH2OCH3 4.15 CH3 COCH2SCH3 4.16 CH3 COCH2M2Hs 4.17 CH3 COCH20COCH3 4.18 C2H5 COCH20COCH3 4.19 C3H7-n COCH20COCH3 4.20 C6H13-n COCH20COCH3 4.21 CH3 COCHFOCOCH3 4.22 CH3 COCH(CH3)OCOCH3 4.23 CH3 COCH20COCHZC1 4.24 CH3 COCH20COC2H5 4.25 CH3 COCH,,0COCO4F(3) 4.26 CLHS COCH20COC6H4C.1(3) 4.27 CH3 COCH20COC6MCH3(3) 4.28 CH3 COCH20COC6H3C12(2,4) 4.29 CH3 COCH20CM3H7-n 4.30 C2H5 COCH2OCH2OCH3 GB 2 187 453 A 30 Table 4 (continuation) Compound R R1 0 4.31 CH3 COCH20CO-9 1 A 0 4.32 C2H5 COCH2OCG- 4.33 CH3 COCH2N= ---N 4.34 C2Ht COCH2N._ 4.35 CH3 COCH2N.2- x 112 ZnC12 4.36 C2H5 COCH2N---N x 112 ZnC12 \N= 4.37 CH3 iCOCH2N'@= x 112 UC12 \N=.

4.38 C2Hs COCH22M/1 x 112 UC12 \N=.

J\ /0 4.39 CH3 COCH20CO 4.40 C2Hs COCH20CO- JV/ 0 4.41 CH3 COCH20C0-N/ 4.42 C2H5 COCH20C0-N- 4.43 CH3 COCH2OCH3 4.44 1 CH3 1 COCH20COCO4C1(3) 31 GB 2 187 453 A 31 Table 5: Typical representatives of starting compounds of formula II, wherein RI - hydrogen, are:

Compound R2 R 5.1 CH3 CH3 5.2 CH3 C2Hs 5.3 CH3 C3H7-n 5.4 CH3 C3H7-iSO 5.5 CH3 e4Hg-n 5.6 CH3 C4Hg-sec, 5.7 CH3 C4Hg-iso 5.8 CH3 CsHil-n 5.9 CH3 G6H13-n 5.10 CH3 C7H15-n 5.11 CH3 C9H17-n 5.12 CH3 CgHlen 5.13 CH3 C10H21-n 5.14 C2Hs CH3 5.15 C2H5 C2H5 5.16 C2Hs C3H7-i50 5.17 G2H5 C4Hg-n 5.18 C2H5 G4Hg-sec 5.19 C2H5 C4Hg-iso 5.20 CzHs C5H11-n 5.21 C2Hs C6H13-n 5.22 C3H7-iSO CH3 5.23 C3H7-iSO C2H5 5.24 G3H7-iSO C3H7-n 5.25 C3H7-iSO C3H7-iSO 5.26 C3H7-i50 C4Hg-n 5.27 C3H7-iSO G4Hg-sec 5.28 C3H7-i50 C4Hg-iso 5.29 C4Hg-sec CH3 5.30 C4Hg-sec. C2H5 32 GB 2 187 453 A 32 Table 5(continuation) Verb. Nr. R2 R 5.31 C4Hg-sec C3H7-n 5 5.32 C4Hg-sec C3H7-iSO 5.33 C4Hg-sec C4Hg-n 5.34 C41-19-sec C41-19-sec 5.35 C4Hg-sec C4Hg-tert 5.36 C4Hg-sec C41-19-iso 10 5.37 C3H7-iSO C61-113-n 5.38 C31-174SO C5H11-n 5.39 C2H5. C3H7-n Formulation Examples foractive ingredients of formula 1 15 (throughout, percentages are byweight) Wettablepowders a) b) c) a compound of theTables 25% 50% 75% 20 sodium lignosulfonate 5% 5% - sodium lauryisulfate 3% - 5% sodium diisobutyl naphtha lenesu Ifonate - 6% 10% octylphenol polyethylene glycol ether P-8 moles of ethylene oxide) - 2% - 25 highly dispersed silicic acid 5% 10% 10% kaolin 62% 27% - The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders which can be diluted with waterto give suspensions of the desired 30 concentration.

Emulsiflable concentrate a compound of the Tables 10% octylphenol polyethylene glycol ether 35 (4-5 moles of ethylene oxide) 3% calcium dodecylbenzenesulfonate 3% castor oil polyglycol ether (36 moles of ethylene oxide) 4% cyclohexanone 30% 40 xylenemixture 50% Emulsions of ay required concentration can be obtained from this concentrate by dilution with water.

Dusts a) b) 45 a compound of the Tables 5% 8% talcum 95% - kaolin - 92% so 50 Readyfor use dusts are obtained by mixing the active ingredient with the carrier, and grinding the mixtures in a suitable mill.

Extrudergranulate a compound of the Tables 10% 55 sodium lignosulfonate 2% carboxymethylcellulose 1% kaolin 87% The active ingredient is mixed and groundwith theadjuvants, andthe mixture issubsequently moistened 60 withwater. The mixture is extruded andthen dried in a stream of air.

33 GB 2 187 453 A 33 Tablets orboluses 1 a compound of the Tables 33.00% methyl cellulose 0.80% highlydispersed silicicacid 0.80% maizestarch 8.40% 5 The methyl cellulose isstirred in waterand allowedtoswell. Then thesilicicacid is stirred in to givea homogeneous suspension. Thecompound of formula 1 andthe maizestarch are mixed andtheaqueous suspension is added to the mix,which is kneadedto a paste. This paste is granulated through a 12M sieve and the granulate is dried. 10 crystalline lactose 22.50% maizestarch 17.00% microcrystalline cellulose 16.50% is magnesium stearate 1.00% is All 4adjuvants are thoroughly mixed. Phases 1 and 11 are mixed and compressed totablets orboluses.

If the compounds of formula 1, orcompositions containing them, are used forcontrolling endoparasitic nematodes, cestodes andtrematodes in domestic animals and productive livestockJor example cattle, sheep, goats, cats and clogs,theycan be administered to the animals in both single and repeated doses. 20 Depending on the species of animal, the individual doses are preferably administered in amounts ranging from 0.1 to 10 mg/kg of bodyweight. A better action is often achieved by protracted administration, or lower total doses will also suffice. The compounds. or compositions containing them, can also be added to feeds and drinks. The ready-prepared feeds contain the active ingredients preferably in a concentration of 0.005to 0.1 percent by weight. The compositions can be administered to the animals perorally in the form of 25 solutions, emulsions, suspensions, powders, tablets, boluses or capsules.

If the physical and toxicological properties of solutions or emulsions permit it. the compounds of formula 1, or compositions containing them, can also be injected into animaisfor example subcutaneously, administered intraruminally or applied to the bodies of the animals bythe pour-on method. Administration by means of salt licks or molasses blocks is also possible. 30 Biological examples 8 1: Insecticidalstomach poison action against Spodoptera littoralis Potted cotton plants in the 5-leaf stage are sprayed with a solution containing 3,12.5 or 50 ppm of thetest 35 compound in acetone/water. Afterthe coating has dried, the plants are populated with about 30 larvae (L, stage) of Spodoptera littoralis. Two plants are used for each test compound and test species. The test is carried out at about 240C and 60 % relative humidity. Evaluations and intermediate evaluations of moribund insects, larval growth and feeding damage are made after 24,48 and 72 hours.

Complete kill was achieved after 24 hours with the compounds of formula 1 of the Tables, e.g. compounds 40 2.8,2.33,2.43 and 2.35, at a concentration of 3 ppm.

B2:Action again;tplant-destructive acarids: OP-sensitive Tetranychus urticae 16 hours before the start of the test, the primary leaves of bean plants (Phaseolusvulgaris) are infected with an infested piece of leaf from a mass culture of Tetranychus urticae. Upon removal of the piece of leaf,the 45 plants infested with all stages of the mites are sprayed to drip pointwith a solution containing 0.4 ppm or 1.6 ppm of the tested compound. The temperature in the greenhouse compartment is about 25'C.

The percentage of mobile stages (adults and nymphs) and of eggs is evaluated under a stereoscopic microscope after 7 days. Compounds of formula 1 of the Table, e.g. compounds 2.8,2.17 and 2.43, achieved complete kill at a concentration of 0.4 ppm. 50 83:Action againstL 1 larvae ofLuciliasericata 1 mi of an aqueous suspension of test compound is mixed with 3 mi of a special larval culture medium at about 500C such that a homogeneous composition containing 250 ppm or 125 ppm is obtained. About30 Lucilia sericata (L,) are put into each testtube containing active ingredient. A mortality count is made after4 55 days. The compounds of formula 1 of the Tables. e.g. compounds 2.8,2.17,2. 31,2.33,2.35, 2.43,2.1,2.18and 2.45, achieved complete kill at 100 ppm.

84..Acaricidalaction against Boophilus microplus (Biarra strain) Adhesivetape is applied vertically across a PVC plate so that 10fully repletefemale Boophilus micoplus 60 ticks (Biarra strain) can be affixed thereto with their backs, side by side, in a row. Each tick is injected from an injection needle with 1 A 6f a liquid which contains a 1: 1 mixture of polyethylene glycol and acetone, in which mixture a specific amount of test compound of 1, 0.1 or 0.01 i.Lg pertick is dissolved.Control ticks are injected with liquid containing no test compound. After thistreatment, the ticks are detached from the support and kept in an insectarium under normal conditions at about 28C and 80 %relative humidity until 65 34 GB 2 187 453 A 34 oviposition has taken place and the larvae have hatched from the eggs of the control ticks. The activity of the test compound is determined with the 11390, i.e. the effective dose is determined at which 9 out of 10 female ticks (90%) even after 30 days lay eggs from which larvae are unable to hatch.

Compounds of formula 1 of the Tables, e.g. compounds 2.8, and 2.33, were very effective in thistest.

5 85. Trial with sheep infected with nematodes (Haemonchus concortus and Trichostrongylus colubriformis) The test compound is administered in the form of a suspension with a stomach probe or by intraru mina[ injection to sheep which have been artificially infected with Haemonchus concortus and Tri-chostrongylus colubriformis. 1 to 3 animals are used for each dose. Each sheep is treated only once with a single dose of 0.5 mg or 0.2 mg/kg of body weight. Evaluation is made by comparing the number of worm eggs excreted in the 10 faeces of the sheep before and aftertreatment.

Untreated sheep infected simultaneously and in the same manner are used as controls. In comparison with untreated and infected control groups, there is no nematode infestation (=complete reduction of the number of worm eggs in the faeces) in sheep which have been treated with one of the compounds of formula 1, e.g.

compound 2.8,2.17,2.31,2.33,2.35,2.43,2.1,2.18,2.45,2.44 and 2.53, at 0.2 mglkg. 15 86: Contactaction againstAphis craccivora Pea plantlets which have been infested with all development stages of the aphid are sprayed with a solution prepared from an emulsifiable concentrate of the test compound and containing 50 ppm, 25 ppm or 12.5 ppm of active ing redient. After3 days evaluation is made to establish whether at least 80% of the aphids 20 are dead or have dropped from the plants. A composition is only rated as effective at this level of activity.

Compounds of formula 1 of the Tables, e.g. compounds 2.8,2.17,2.33,2.35 and 2.43, achieved complete kill (= 100%) at a concentration of 12.5 ppm.

87. Larvicidalaction againstAbdes aegypti 25 A 0. 1 % so] ution of the test compou nd in acetone is pipetted onto the su rface of 150 mi of water in beakers in amounts sufficientto give concentrations of 10 ppm, 3.3 ppm and 1.6 ppm. After the acetone has evaporated, 30 to 40 three-day-old larvae of Addes aegypti are put into each beaker. Mortality counts are made after 1, 2 and 5 days.

In this test, the compounds of formula 1 of the Tables, e.g. compounds 2. 8,2.17,2.31,2.33,2,1,2.18 and 30 2.43, achieved complete kill of all larvae at a concentration of 1.6 ppm after 1 day.

8. 8Action againstMeloidogyne incognita Eggs of Meloidogyne incognita are mixed into sand. This mixture isthen placed in 200 mi earthenware pots (5000 eggs per pot). On the same day, q three-week-old tomato plant is planted in each pot and the 35 formulated test compound is introduced intihe pots by pressure application (0.002 % active ingredient, based on the volume of the soil). The potted plants are stood in a greenhouse at a temperature of 26 1 OC and a relative humidity of 60 %. After 4weeks evaluation is made by examining the plantsfor root-knotformation in accordance with the Knot Index.

Compounds of the Preparatory Examples exhibit good activity against Meloidogyne incognita in thatthey 40 substantially reduce root-knot formation. On the other hand, untreated and infected control plants exhibit severe root-knotformation (= 100%). Thus, in this test, compounds 2.17, 233 and 2.18 reduce root-knot formation almost completely (0-10 % attack).

8.9 Milbicidal action against Dermanyssus galfinae 45 2 to 3 mi of a test solution (100, 10, 1 and 0.1 ppm of test compound) are put into a glass containerwhich is open atthetop and about 200 mite in different stages of development are put into this container. The container is then sealed with cotton wool and shaken uniformlyfor 10 minutes until the mites are completely wetted. The container is then inverted until excess test solution has been absorbed bythe cotton wool.The container is again inverted and thetreated ticks are kept under observation for3 days under laboratory so conditions to evaluate the effectiveness of test compounds. Mortality isthe criterion for effectiveness.

Compounds of the tables, e.g. compounds 2.8,2.17,2.31,2.33,2.35,2.48,2.51 and 2.53, effect 100 %kill ata concentration of 100 ppm.

GB 2 187 453 A 35

Claims (16)

1. A4-acyioxy-1 3p-alkyimilbemycin of the general formula] H3 0 CH3 5 13 17 '1 H3c is '04\Rz 10 o',C/ 8 &__1 is A CH3 RI wherein 20 R is Cl -Cl Oa 1 ky], R, is an acyl group, and R2 is methyl, ethyl, isopropyl or sec-butyl; or an acid addition salt or a metal complexthereof.

2. A compound of formula 1 according to claim 1, wherein 25 R is Cl -C6a I kyl, R2 is methyl, ethyl, isopropyl or sec-butyl, R, is an acyl group selected from 0 30 11 a) h3 35 0 11 b) -;-,-tm-A-R4, 40 1 h3 45 0 0 11 11 C) -C-CH-X-(;-r14 and 1 t13 50 0 11 55 d) h3 wherein 60 Xis oxygen orsulfur, Yisa leaving groupwhich maybereplaced by nucleophilic exchange, R3 is hydrogen, Cl-C4alkyl orhalogen,and R4ishydrogen; Cl-C6alky], unsubstituted or substituted by halogen, hydroxy, Cl-C6alkoxy or Cl-C6haloalkoxy; an unsubstituted or substituted radical selectedfrom the group consisting of 65 36 GB 2 187 453 A 36 C3-Clocycloalkyl, C2-C6alkenyl and C3-C6alkynyl, the substituentsofsaid radicals being selected from the group consisting of halogen, hydroxy,Cl-C6alkoxy and Cl-C6alkanoyloxy; phenyl or phenyl which is substituted by halogen, cyano, Cl-C3-alkyl, Cl-C3haloalkyl, Cl-C3alkoxy, Cl-C3haloalkoxy and/or nitro; or is an unsubstituted or substituted, unsaturated orsaturated 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from the group consisting of nitrogen,oxygen and sulfur, the substituents of said ring 5 being selected from the group consisting ofoxo, halogen, Cl-COlkyl, ClC4haloalkyl and Cl-C4alkoxy, oran acid addition salt or a metal complexthereof.

3. A compound offormula 1 according to claim 2, wherein R is Cl -C6a I kyl, R2 is methyl, ethyl, isopropyl or sec-butyl, 10 R, is an acyl group selected from 0 a) 15 M3 0 20 b) f13 25 0 0 11 11 C) -C-CH-X-C-R4 and 1 30 M3 0 11 35 d) h3 40 wherein Xis oxygen orsuffur, Y is halogen, Ado or a sulfonic acid radical, R3 is hydrogen; fluorine or methyl; and R4 is hydrogen; Cl-COlkyl, unsubstituted or substituted by fluroine, chlorine, bromine, hydroxy, 45 Cl-CAkoxy or C2-C3haloalkoxy; an unsubstituted or substituted radical selected from the group consisting of C3-C7cycloalky], C2-COlkenyl and C2-COlkynyl,the substituents ofsaid radicals being selected from the group consisting offluorine, chlorine, bromine, hydroxy, Cl-COlkoxy and Cl- COlkanoyloxy; phenyl or phenyl which is substituted byfluorine, chlorine, bromine, methyl, ethyl, methoxy, halomethoxy, trifluoromethyl and/or nitro; or is an unsubstituted or substituted, unsaturated or saturated 5- or 6-membered heterocyclic 50 ring containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur,the substituents ofsaid ring being selected from the group consisting ofoxo, halogen, Cl-COlkyl, Cl-C4haloalkyl and Cl-C4aikoxy, or an acid addition salt or a metal complexthereof.

4. A compound offormula 1 according to claim 3, wherein 5s R is Cl -C6a I kyl, 55 R2 is methyl, ethyl, isopropyl or sec-butyl, R, is the group 0 11 60 -C-CH-Y 1 M3 R3 is hydrogen, fluorine or methyl, and 65 37 GB 2 187 453 A 37 Y is chlorine, bromine, iodine, benzenesulfonyloxy, paratosyloxy or mesyloxy.

5. A compound of formula 1 according to claim 1, wherein RiSC1-COlkyl, R2 is methyl, ethyl, isopropyi orsec-butyl, R, is the group 5 0 11 -C-CH-X-114 10 wherein Xis oxygen or sulfur, R3 is hydrogen, fluorine or methyl, and 15 R4 is hydrogen; Cl-C6alky], unsubstituted or substituted by fluorine, chlorine, bromine, hydroxy, Cl-CAlkoxy or Cl-C3haloalkoxy; an unsubstituted orsubstituted radical selected from the group consisting of C3-CAYCloalkyl, C2-COlkenyl and C2-C4alkynyi, the substituents of said radicals being selected from the group consisting of fluorine, chlorine, bromine, hydroxy, Cl-C3alkoxy and Cl- C4alkarvoyloxy; phenyl or phenyl which is substituted by fluorine, chlorine, bromine, methyl, ethyl, methoxy, halomethoxy,trifluoromethyl 20 and/or nitro; or is an unsubstituted or substituted, unsaturated orsaturated 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from the group consisting 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur,the substituents of said ring being selected from the group consisting of oxo, halogen, Cl-COlkyl, Cl-C4haloalkyl and Cl-COlkoxy, or an acid addition salt or a metal complexthereof. 25

6. A compound of formul& according to claim 3, wherein R is Cl-C alky], R2 is mel Y1, ethyl, isopropyl or sec-butyl, R, is the group 30 0 0 113 35 wherein X is oxygen or sulfur, R3 is hydrogen, fluorine or methyl, and R4 is hydrogen; Cl-COlkyl, unsubstituted or substituted byfluorine, chlorine, bromine, hydroxy, 40 Cl-CAlkoxy or Cl-C3haloalkoxy; an unsubstituted or substituted radical selected from the group consisting of C3-CAYCloalkyl, 92-C4a]kenyl and C2-COlkynyl, the substituents of said radicals being selected from the group consisting of fluorine, chlorine, bromine, hydroxy, Cl-C3alkoxy and Cl- C4alkanoyloxy; phenyl or phenyl which is substituted byfluorine, chlorine, bromine, methyl, ethyl, methoxy, halomethoxy, trifluoromethyl and/or nitro; or is an unsubstituted or substituted, unsaturated or saturated 5- or 6-membered heterocyclic 45 ring containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur,the substituents of said ring being selected from the group consisting of oxo, halogen, Cl-COlkyl, Cl-C4haloalkyl and Cl-COlkoxy, or an acid addition salt or a metal complexthereof.

7. A compound of formula 1 according to claim 3, wherein RisCII-C6alkyl, so R2 is methyl, ethyl, isopropyl or sec-buty], R, is the group 0 11 55 -C-CH-R4 1 K3 R3 is hydrogen, fluorine or methyl; and 60 R4 is an aromatic heterocyclo-l-yl group consisting of an unsubstituted or substituted 5-membered heterocyclic ring which contains 2 or3 nitrogen atoms, the substituents of said ring being selected from 1 to 3 Cl-C6alkyl groups, or an acid addition saitthereof with an organic or inorganic acid, or a metal complex thereof with a metal cation of auxiliary groups 1, 11, IV or Vill of the PeriodicTable.

8. A compound of formula 1 according to claim 1, wherein 65 38 GB 2 187 453 A 38 R is Cl-C6alkyl, R2iS methyl, ethyl, isopropyl orsec-butyl, R, is an acyl group selected from 0 5 a) t13 10 0 b) 15 M3 20 0 0 11 11 C) -C-CH-X-C-R4 and 1 h3 25 0 30 d) h3 wherein 35 Xis oxygen orsulfur, Yishalogen R3 is hydrogen, halogen or methyl; and R4 is hydrogen; Cl-C4alkyl, unsubstituted orsubstituted by halogen or Cl- COlkoxy; Cl-COlkoxy; is cyclopropy], cyclopentyl, cyclohexy], phenyl or phenyl which is substituted by fluorine, chlorine, bromine, 40 methoxy,trifluoromethyl and/ornitro; oris4H-2,3-dihydropyran-2-yi oran aromatic heterocyclo-l-yl group consisting of an unsubstituted or substituted 5-membered heterocyclic ring which contains 2 to 3 nitrogen atoms, the su bstituents of said ring being selected from 1 to 3 ClCOlkyl groups, or an acid addition salt thereof with an organic or inorganic acid, or a metal complexthereof with a metal cation of auxiliary groups, 1, 11, IV orVill of the PeriodicTable. 45

9. A compound of formula 1 according to claim 1, selected from the group consisting of:

5-0-chloroacetyi-13p-methyimilbemycin D, 5-0-ch 1 oroacety]-1 3p-m ethyl m i 1 bemyci n A3, 50 5-0-chloroacetyi-13p-methyimilbemycinA4, 5-0-chloroacety]-13p-ethyimilbemycin D, 5-0-chloroacety]-13p-ethyimilbemycin A3, 5-0-chloroacety]-130-ethy[milbemycinA4, 55 5-0-acetoxyacetyi-13p-methyimilbemycin D, 5-0-acetoxyacetyl-13p-methyimilbemycin A3, 5-0-acetoxyacetyi-13p-methyimilbemycin A4, 5-0-acetoxyacetyl-13p-ethyimilbemycin D, 60 5-0-acetoxyacetyi-13p-ethyimilbemycinA3, 5-0-acetoxyacetyl-13p-ethyimilbemycinA4, 39 GB 2 187 453 A 39 5-0-[3,4-dihydro-2H-pyran-2-yilcarboxyacetyf-130-methyimilbemycin D, 5-0[3,4-dihydro-2H-pyran-2-yilcarboxyacetyi-13p-methyimilbemycinA3, 5-0-13,4dihydro-2H-pyran-2-yilcarboxyacetyi-13p-methyimilbemycin A4, 5-0-[3,4-dihydro-2H-pyran-2-yijcarboxyacetyi-13p-ethyimilbemycin D, 5 5-0-[3,4-dihydro-2H-pyran-2-yilcarboxyacetyf-130-ethyimilbemycin A3, 5-0-[3,4-dihydro-2H-pyran-2-yi]carboxyacetyi-13p-ethyimilbemycin A4, 5-0-[1,2,4-triazoi-4'-yijacetyi-13p-methyimilbemycin D, 5-0-[1,2,4-triazol-4'-yllacetyl-13p-methyimilbemycinA3, 10 5-0-[1,2,4-triazol-4'-yilacetyi-1 3p-m ethyl m il bemycin A4, 5-0-[1,2,4-triazol-4'-yilacetyi-13p-ethyimilbemycin D, 5-0-[1,2,4-triazoi-4'-yilacety]-130-ethyimilbemycinA3, 5-0-[1,2,4-triazol-4'-yllacetyi-13p-ethyimilbemycin A4, 15 5-0-methoxyacetyi-13p-methyimilbemycin D, 5-0-meth oxyacetyl- 1 3p-m ethyl m il bemycin A3, 5-0-methoxyacetyi-13p-methyimilbemycin A4, 20 5-0-methoxyacetyl-13p-ethyimilbemycin D, 5-0-methoxyacety]-13p-ethyimilbemycinA3, 5-0-methoxyacetyi-13p-ethyimilbemycinA4, 5-0-[3-chlorobenzoyloxylacetyi-13p-methyimilbemycin D, 25 5-0-[3-chlorobenzoyloxylacety]-130-methyimilbemyeinA3, 5-0-[3-chlorobenzoyloxylacetyi-13p-methyimilbemycin A4, 5-0-[3-chlorobenzoyloxylacetyi-13p-ethyimilbemycin D, 5-0-[3-chlorobenzoyloxylacetyi-130-ethyimilbemycin A3,and 30 5-0-[3-chforobenzoyioxylacety]-13p-ethyimilbemycin A4.

10. A compound of formula 1 according to claim 1, selected from the group consisting of:

5-0-acetoxyacety]-13p-propyimilbemycin D, 5-0-acetoxyacetyi-13p-propyimilbemycin A3, 35 5-0-acetoxyacety]-13p-propyimilbemycinA4, 5-0-acetyi-13p-ethyimilbemycin D, 5-0-acetyi-13p-ethyimilbemycinA3, 5-0-acetyi-13p-ethyimilbemycin A4, 40 5-0-acetyi-13p-nlethyimilbemycin D, 5-0-acetyi-13p-methyimilbemycinA3, 5-0-acetyl-1 3p-m ethyl m

i 1 bemycin A4, 45 5-0-methoxyacety]-13p-butyimilbemycin D, 5-0-methoxyacetyi-13p-butyimilbemycin A3, 5-0-methoxyacetyl-13p-butyimilbemycin A4, 5-0-benzoyloxy-130-methyimilbemycin D, so 5-0-benzoyloxy-1 3p-m ethyl m il bemyci n A3, and 5-0-benzoyloxy-130-methyimilbemycin A4, GB 2 187 453 A 40 11. A process for the preparation of a 5-acyloxy-l 3p-aikyimilbemycin of the general formula 1 R H3 13 0 CH3 5 13 17 H3C is 04'R, (I) Cl 10 H on R1 CH3 15 wherein RisCl-Cloalky], R, is an acyl group, and 20 R2iS methyl, ethyl, isopropyl orsec-butyl,or an acid addition saltora metal complex thereof, which process comprises esterifying a 13p-alkylmilbemycin derivativeof formula 11 R H3 CH3 25 H3c 0 A\R, R\ \A + RO-Rl 30 H (M) /\CH3 35 6H with an acid of formula Ill, or an acid halide or acid anhydride thereof, in which formulae the substituents R, 40 R, and R2 areas defined forformula 1.

12. A process according to claim 11, which comprises using an acid chloride or acid bromide as acid halide of the acid of formula Ill.

13. A composition for controlling parasites of animals or plants, which contains as active ingredient at least one 5-acyloxy-13p-alkyimilbemycin of the general formula 1 45 R YH3 1J 0 CH3 W 13 171 1 is a 6 H3c 04'R, 0 11 M H 55 4 CH3 60 wherein R is Cl-C1c)alky], R, is an acyl group, and R2 is methyl, ethyl, isopropyl orsec-butyl, or an acid addition salt ora metal complex thereof, together with 65 41 GB 2 187 453 A 41 conventional formulation asistants.

14. A composition as claimed in claim 14, which contains as active ingredient at least one compound of formula 1 according to anyone of claims 2to 10.

15. A method of controlling pests of animals or plants, which comprises applying to said animals or plants, orto the locus of said pests, a 5-acyloxy-13p-alky[milbemycin of the general formula 1 5 H3 CH3 R JJ 0 13 17 10 1 H3C 0 \S/ I '04\R2 H Ll p# 15 /B fl R1 CH3 20 wherein R is Cl -Cl 0a 1 kyl, R, is an acyl group, and R2 is methyl, ethyl, isopropyl or sec-butyl, or an acid addition salt ora metal complexthereof. 25

16. A method according to claim 15, wherein application is made with a compound of formula 1 as claimed in any one of claims 2 to 10.

Printed for Her Majesty's Stationery Office by Croydon Printing Company (UK) Ltd,7187, D8991685.

Published byThe Patent Office, 25 Southampton Buildings, London WC2A lAY, from which copies maybe obtained.

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