AU608507B2 - 5-acyloxy-13 beta-alkylmilbemycin derivatives for controlling pests that are parasites of animals or plants - Google Patents

Description

FORM 10 SPRUSON FERGUSON COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 C0850O COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE: o Class Int. Class Complete Specification Lodged: This documenteonta-ns tamendments made .r Section 49 and is correct luor printing.

So o 3 Accepted: Published: S Priority: o o o 0 0 oo o o o oa 0 0 Related Art: Name of Applicant: Address of Applicant: Actual Inventor(s): Address for Service: CIBA-GEIGY AG Klybeckstrasse 141, 4002 Basle, Switzerland PETER MAIENFISCH and ANTHONY CORNELIUS

O'SULLIVAN

Spruson Ferguson, Patent Attorneys, Level 33 St Martins Tower, 31 Market Street, Sydney, New South Wales, 2000, Australia Complete Specification for the invention entitled: "5-Acyloxy-138-alkylmilbemycin derivatives for controlling pests that are parasites of animals or plants" The following statement is a full description of this invention, including the best method of performing it known to us SBR/TGK/221 r i li- I- L- 1A 5-Acyloxy-13p-alkylmilbemycin derivatives for controlling pests that are parasites of animals or plants The present invention relates to novel 5-acyloxy-13p-alkylmilbemycin derivatives of formula I below, to their preparation, and to the use thereof for controlling pests such as ecto- and endo-parasites of animals and plant parasites.

According to a first embodiment of the present invention there is provided a 5-acyloxy-13B-alkylmilbemycin of the general formula I R H3 0 ,CH3 i R *O 13 17 15 00 R2 H3C (I) O\

CH

3 &Ri o i9 wherein R is C 1

-C

10 alkyl, R1 is an acyl group selected from 0 0 0 a) -C-CH-Y

R

3 0

II

b) -C-CH-X-R 4 C C o 0 0 I i 20 c) -C-CH-X-C-R 4

R

R

3 d) -C-CH-R I 4

R

3 t- 1__1 I_ 1B wherein X is oxygen or sulfur, Y is chlorine, bromine, iodine, benzenesulfonyloxy, paratosyloxy or mesyloxy, R3 is hydrogen, C 1

-C

4 alkyl or halogen, and R4 is hydrogen; C 1

-C

10 alkyl, unsubstituted or substituted by halogen, hydroxy, C -C 6 alkoxy, or C 1

-C

6 haloalkoxy, an unsubstituted or substituted radical selected from the group consisting of C3-Cl 0 cycloalkyl, C 2

-C

6 alkenyl and C3-C 6 alkynyl, the substituents of said radicals being selected from the group consisting of halogen, hydroxy, C 1

-C

6 alkoxy and

C

1

-C

6 alkanoyloxy; phenyl or phenyl which is substituted by halogen, cyano, C 1

-C

3 alkyl, C 1

-C

3 haloalkyl, C 1

-C

3 alkoxy,

C

1

-C

3 haloalkoxy and/or 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,

C

1

-C

4 alkyl, C 1

-C

4 haloalkyl and C -C4alkoxy, and 290 R is methyl, ethyl, isopropyl or sec-butyl; or an acid addition salt or a metal complex thereof.

Formula I thus represents a milbemycin derivatives that contain a 13-alky1 group and which are acylated in 5-position and, if the acyl radical carries an N-heterocycle, may be in the form of acid addition salts 25 or metal complexes.

2 g -2- Within the scope of this invention, the term "acyl" by itself or as moiety of an acyloxy group shall be understood as meaning e.g.

unsubstituted or substituted alkylcarbonyl alkanoyl), arylcarbonyl and aralkylcarbonyl, preferably unsubstituted or substituted acetyl, propionyl, butyryl or benzoyl, the alkanoyl moieties of which radicals may be substituted e.g. by halogen, alkoxy, haloalkoxy, aryloxy, hydroxy, aryl, 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, /0 oxygen and sulfur, whereas the aryl moieties may be substituted by halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylthio and/or nitro, and are e.g. a- or B-naphthyl or, preferably, phenyl.

Aralkyl denotes an aromatic radical which is bound through a straight chain or branched alkylene bridge. The simplest represen- Soo tative is the benzyl group.

Depending on the number of carbon atoms indicated, alkyl by itself or as moiety of another substituent will be understood as meaning for example the following straight chain groups: methyl, ethyl, aoo*" propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, 0 dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl etc. and the branched isomers thereof, e.g. isopropyl, o o* isobutyl, tert-butyl, isopentyl etc. Alkenyl by itself or as moiety o1 of an alkenyloxy group is e.g. 1-propenyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl etc. Alkynyl is for example ethynyl, o 1-propynyl, propargyl, 1-butynyl etc. Throughout this specification, halogen and the prefix "halo" will be understood as meaning fluorine, chlorine, bromine or iodine, with chlorine or bromine 0 00 oo. being preferred. Cycloalkyl by itself or as moiety of cycloalkoxy is e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, D cyclooctyl and the like. Haloalkyl by itself or as moiety of haloalkoxy is a mono- to perhalogenated alkyl radical, e.g. CH2I, CH 2 Br,

CH

2 Cl, CH 2 F, CHC12, CC1 3 CBr 3

CF

3

C

2

F

5

C

2 C1 5 CFClBr and the like, which radical may also be substitued simultaneously by -N i -L -1 -3different halogen atoms; the CF 3 radical is preferred. Typical representatives of 5-membered heterocyclic ring systems are: furan, thiophene, pyrrole, isoxazole, isothiazole, furazan, imidazole, 1,2,4-triazole, 1,2,3-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, 0 piperazine, morpholine, perhydrothiazine, dioxane and the partially hydrogenated or partially saturated homologs thereof, and the like.

Throughout this specification, oxo-substituted heterocyclic systems are in particular 5- and 6-membered lactones and lactams, e.g.

butyrolactones, valerolactones, butyrolactam, valerolactam, and also bicyclic systems such as camphane.

Examples of heterocyclic substituents are: imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole or tetrazole, as well as azoles which are substituted by one or two C 1

-C

6 alkyl groups, e.g. 2-ethyl-4-methylimidazole, 2-isopropylimidazole, methylimidazole, 3, 5-dimethyltriazole, ethyltriazole, 3,4-diethylpyrazole and the like.

A number of typical representatives of acyl radicals R 1 are listed hereinafter. This recitation implies no restriction:

COCH

3

COCH

2 Cl, COCF 3

COCH

2 Br, COCH 2 F, COCzHs, COCzCl 5

COCH

2

OCOCH

3

COCH

2 OCOC4H 9

GOCH

2 00H 3

COCHFOCOCH

3

COCH(CH

3

)OCOCH

3

COCH

2

OCOCZH

5

COCH

2

OCOCH

2 Cl, COCH 2

OCOC

6

H

4 F(3),

COCH

2 0OCG 6

H

4

OCH

3

COCH

2 00H 2 0CH 3

COCH

2

OC

2

H

5

COCH

2

SCH

3

COCH

2

OCOC

6 H4Cl(3), COCH 2 -(1H-1,2,4-triazol-1-yl), COCH 2 -(2,3-dihydropyran-2-yl), COCH 2 (1H-imidazol-1-yl) and COCH2CO-(pyrrolid- 3v Salts of compounds of formula I are formed with inorganic or organic acids. Suitable salt-forming acids are for example: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric 4 acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, oxalic acid, tartaric acid, citric acid, ascorbic acid, sorbic acid, trimethylacetic acid, benzoic acid, salicylic acid, succinic acid and maleic acid.

Metal complexing agents are in particular cations of metals of auxiliary groups I and II or IV to VIII of the Periodic Table, e.g.

copper, zinc, manganese, chromium, iron, nickel, cobalt and molybdenum.

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

Within the scope of formula I, preference is given to those milbemycin derivatives wherein R and Rz are methyl or ethyl and RI has the given meanings.

o Within the scope of formula I, the following groups are preferred: Group la: Compounds of formula I, wherein R is C 1 -C6alkyl,

R

2 is methyl, ethyl, isopropyl or sec-butyl, RI is an acyl group selected from Sa) -CH-Y b) b) -C-CH-X-R4 R3 d) -C-XH-R4 a wherein X is oxygen or sulfur, L_ Y is chlorine, bromine, iodine, benezenesulfonyloxy, paratosyloxy or mesyloxy,

R

3 is hydrogen, Cl-C 4 alkyl or halogen; and R4 is hydrogen; Cl-C 10 alkyl, unsubstituted or substituted by halogen, hydroxy, C 1

-C

6 alkoxy or C 1

-C

6 haloalkoxy; an unsubstituted or substituted radical selected from the group consisting of C 3

-C

10 cycloalkyl, C 2

-C

6 alkenyl and

C

3

-C

6 alkynyl, the substituents of said radicals being selected from the group consisting of halogen, hydroxy, C 1

-C

6 alkoxy and

C

1

-C

6 alkanoyloxy; phenyl or phenyl which is substituted by halogen, cyano, C 1

-C

3 alkyl, C 1

-C

3 haloalkyl, C 1

-C

3 alkoxy,

C

1

-C

3 haloalkoxy and/or 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,

C

1

-C

4 alkyl, C 1

-C

4 haloalkyl and C 1

-C

4 alkoxy, and the acid addition salts and metal complexes thereof.

Within group la, the following compounds constituting group Ib are preferred: Group Ib: SCompounds of formula I, wherein o Oo R is C 1

-C

6 alkyl, R2 is methyl, ethyl, isopropyl or sec-butyl, R1 is an acyl group selected from 0 a) -C-CH-Y

R

3 b) -C-CH-X-R 4

R

3 0 0 II II -C-CH-X-C-R and R 4 R3 ii.

6 0

II

d) -C-CH-R 4 3 wherein o S0000 0 0 0 00 o o a X is oxygen or sulfur, Y is chlorine, bromine, iodine, benzenesulfonyloxy, paratosyloxy or mesyloxy,

R

3 is hydrogen, fluorine or methyl, and

R

4 is hydrogen; C 1

-C

6 alkyl, unsubstituted or substituted by fluorine, chlorine, bromine, hydroxy, C 1

-C

3 alkoxy or

C

2

-C

3 haloalkoxy; an unsubstituted or substituted radical selected from the group consisting of C 3

-C

7 cycloalkyl, C 2

-C

4 alkenyl and C 2

-C

4 alkynyl, the substituents of said radicals being selected from the group consisting of fluorine, chlorine, bromine, hydroxy, C 1

-C

3 alkoxy and C 1

-C

4 alkanoyloxy; phenyl or phenyl which is substituted by fluorine, chlorine, bromine, methyl, ethyl, methoxy, halomethoxy, trifluoromethyl and/or 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, C 1

-C

4 alkyl, C 1

-C

4 haloalkyl and C,-C 4 alkoxy, and the acid addition salts and metal complexes thereof.

Within group Ib, the following groups Ic, Id, le and If are preferred.

Group Ic: Compounds of formula I, wherein R is C 1

-C

6 alkyl, R2 is methyl, ethyl, isopropyl or sec-butyl,

R

1 is the group

-C-CH-Y

R

3

R

3 is hydrogen, fluorine or methyl, and ~CI~ i I 7 Y is chlorine, bromine, iodine, benzenesulfonyloxy, paratosyloxy or mesyloxy.

Group Id: Compounds of formula I, wherein R is C 1 -Csalkyl, Rz is methyl, ethyl, isopropyl or sec-butyl, RI is the group H- -R4 wherein (t X is oxygen or sulfur,

R

3 is hydrogen, fluorine or methyl; and R4 is hydrogen; Ci-Csalkyl, unsubstituted or substituted by fluorine, chlorine, bromine, hydroxy, Ci-C 3 alkoxy or C 1

-C

3 haloalkoxy; an unsubstituted or substituted radical selected from the group consisting of C 3

-C

7 cycloalkyl, Cz-C 4 alkenyl and C 2 -C4alkynyl, the substituents of said radicals being selected from the group consisting of fluorine, chlorine, bromine, hydroxy,

SC

1

-C

3 alkoxy and Ci-Coalkanoyloxy; phenyl or phenyl which is Soo° substituted by fluorine, chlorine, bromine, methyl, ethyl, Smethoxy, halomethoxy, trifluoromethyl and/or 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 d d a S°group consisting of oxo, halogen, Ci-C4alkyl, Ci-C4haloalkyl and

C

1

-C

4 alkoxy, and the acid addition salts and metal complexes thereof.

Group le: Compounds of formula I, wherein 3^O R is Ci-Csalkyl, Rz is methyl, ethyl, isopropyl or sec-butyl, RI is the group -8 r3-X- -R4 i; ~c o r:; o oo i; u o o o ucoo Ea o 1 i I ni wherein X is oxygen or sulfur,

R

3 is hydrogen, fluorine or methyl; and R4 is hydrogen; Ci-C6alkyl, unsubstitu-d or substituted by fluorine, chlorine, bromine, hydroxy, C 1 -C3alkoxy or Ci-C3haloalkoxy; an unsubstituted or substituted radical selected from the group consisting of C 3 -C7cycloalkyl, C2-C4alkenyl and C 2 -C4alkynyl, the substituents of said radicals being selected from the group consisting of fluorine, chlorine, bromine, hydroxy, Ci-C 3 alkoxy and Ci-C4alkanoyloxy; phenyl or phenyl which is substituted by fluorine, chlorine, bromine, methyl, ethyl, methoxy, halomethoxy, trifluoromethyl and/or 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, Ci-C4alkyl, Ci-C4haloalkyl and Ci-C 4 alkoxy, and the acid addition salts and metal complexes thereof.

Group If: Compounds of formula I, wherein R is Ci-Cgalkyl,

R

2 is methyl, ethyl, isopropyl or sec-butyl, RI is the group H-R4 wherein

R

3 is hydrogen, fluorine or methyl; and -9- R4 is an aromatic heterocyclo-1-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 C 1 -Csalkyl groups, and the acid addition salts thereof with organic and inorganic acids as well as the metal complexes thereof with metal cations of auxiliary groups I, II, IV or VIII of the Periodic Table.

The following compounds are also preferred: Group Ig: /1 Compounds of formula I, wherein R is Ci-C 6 alkyl, Rz is methyl, ethyl, isopropyl or sec-butyl, RI is an acyl group selected from a) H- -Y b) 3 ao b) -CH-X-R4 and o o c) and d) H-R4 wherein X is oxygen or sulfur, Y is halogen

R

3 is hydrogen, halogen or methyl; and R4 is hydrogen; Ci-C 4 alkyl, unsubstituted or substituted by halogen 4 44 or C 1 -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-dihydropyran-2-yl or an aromatic heterocyclo-1-yl group consisting of an unsubstituted or substituted 5-membered heterocyclic ring which contains 2 to 3 nitrogen atoms, the substituents of said 10 ring being selected fron 1 to 3 Cj-C 6 alkyl groups, and the acid addition salts thereof with organic and inorganic acids as well as the metal complexes thereof with metal cations of auxiliary groups I, II, IV or VIII of the Periodic Table.

Exanples of particularly preferred individual compounds of formula I are: 5-0-chloroacetyl-13a-methylmilbenycin D, 35-nethylmilbemycin A 3 5-0-chloroacetyl-13 -methylmilbemycin A 4 5-0-chloroacetyl-13 -ethylmilbenycin D, 5-0--chloroacetyl-1 3R-ethylmilbemycin A 3 5-0-chloroacetyl-13 -ethylmilbemycin A 4 5-0-acetoxyacetyl-13R-nethylmilbemycin D, 5-0-acetoxyacetyl-13 -methylmilbemycin A 3 5-0-acetoxyacetyl-13 3-methylmilbemycin A 4 5-0-acetoxyacetyl-130-ethylmilbemycin

D,

5-0-acetoxyacetyl-13 -ethylmilbemycin A 3 o 5-0-acetoxyacetyl-13R-ethylmilbemycin A 4 5-0-[I3, 4-dihydro-2H-pyran-2-yl ]carboxyacetyl-1 3 -methylmi] bemycin D, 4-dihydro-2H-pyran-2-yl] carboxyacetyl-1 31-methylmilbemycin A 3 4-dihydro-2H-pyran-2-yl] carboxyacetyl-1 3R-methylmilbenycin A 4 3, 4-dihydro-2H-pyran-2-yl ]carboxyacetyl-1 3R-ethylmilbemycin D3, 4-dihydro-2H-pyran-2-yl ]carboxyacetyl-l bemycin A4, 5-0[1,,4-riaol-'-ylac- 1 Rmtymleyi D, 5-0-[1,2,4-triazol-4'-y1]acetyl-l3R-methylmilbemycin D3, 5-0-[1,2,4-triazol-4'-yllacety1-130-methylmilbemycin A4, 5-0-[1,2,4-triazol-4'-y11acetyl1-3R-ethylmilbetnycin AD, 5-0-I1,2,4-triazol-4'-yllacetyl-130-ethylmilbemycin D3, 5-0-I1,2,4-triazo1-4'-yllacetyl130-ethylmilbenycin A4, 5-0-methxactizl4yaeyl33-methylmilbemycin AD, 5-0-methoxyacetyl-l3 -metylnilbemycin A3, 5-0-methoxyacetyl-13R-methylmilbemycin A4, to5-0-methoxyacetyl-133-methyltilbemycin AD, (0 5-0-methoxyacetyl-130-ethylmilbemycin D3, 5-0-methoxyacetyl-1 30-ethylmilbemycin A 3 5-0-methxyacetyl-1 313-et l1-ehymilbemycin AD, 5-01 3-chlorobenzoyloxylacetyl-13H-methylmilbemycin A3, 5-0-[3-chlorobenzoyloxyIlacetyl-l30-methylmilbemycin A 3 5-0-[f3-chlorobenzoyloxylacetyl-l3B-ethylmibemycin AD, 5-0-Il3-chlorobenzoyloxylacetyl-l35--ethiylmilbemycin D3,an 5-0-[3-chlorobenzoyloxyElacetyl-13B-ethylmilbemycin A 3 ,an Further preferred compounds of formula I are those selected from the group consisting of: 01 3R-propylmilbem-rcin D, 5-0-acetoxyacetyl-133-propylnilbemycin A 3 5-0-acetoxyacetyl-l30-propylmilbemycin A 4 5-0-acetyl-130-ethylmilbemycin D, 30-ethylmilbemycin A 3 3R-ethylmilbemycin A 4 -12 5-O-acetyl-130-methylmilbemycin D, 5-O-acetyl-130-methylmilbemycin

A

3 5-O-acetyl-131-methylmilbemycin A4, 5-O-methoxyacetyl-13R-butylmilbemycin D, 5-O-methoxyacetyl-13 -butylmilbemycin A 3 5-O-methoxyacetyl-13 -butylmilbemycin A 4 -O-benzoyloxy-130-methylmilbemycin D, 5-0-benzoyloxy-13R3-methylmilbemycin A 3 and 5-O-benzoyloxy-130-methylmilbemycin

A

4 (0 The present invention also relates to processes which make it possible to introduce a 5-0-acyl group selectively at the position of 130-alkylmilbemycin or 13-deoxy-13R-alkyl-22,23-dihydroavermectin-aglycon derivatives and thus to obtain very effectii7e novel parasiticides and insecticides of formula I.

The process for the preparation of compounds of formula I comprises esterifying a 13R-alkylmilbemycin derivative of formula II Y H 3

CH

3

H

3 C'*0A' H0/ HO-Rj (I) with an acid of formula III, or an acid halide or acid anhydride thereof, at the 5-OH group, the substituents R, R, and R 2 being as defined for formula I.

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

I_ 1 11-_4 .1.111...11 11-^1111~*IIN I(X~(O1-I~IVI li-~ -1 -11.1111111 13 If the compound of formula III is an acid halide or acid anhydride, the reaction is preferably carried out in a non-hydroxylated inert solvent and in the presence of an organic base, e.g. pyridine, 4 -dimethylaminopyridine, lutidine, collidine, trialkylamine, N-dialkylaniline, or a bicyclic non-nucleophilic base, e.g. 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5ene (DBN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction is generally carried out in the temperature range from -300 to +70 0 C, preferably from -100 to +50 0 C. It is convenient to carry (0 out the reaction in the 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-butylmethyl ether etc.), anisole, dioxane, tetrahydrofuran; nitriles such as acetonitrile, propionitrile; esters such as ethyl acetate, propyl acetate or butyl S.o acetate; ketones such as acetone diethyl ketone, methyl ethyl o ketone; compounds such as dimethyl sulfoxide (DMSO), dimethylo formamide (DMF) and mixtures of such solvents with one another. The oo reaction may also be carried out in an excess of one of the above So bases.

00 If the compound of formula III is an acid, then the esterification of the compound of formula II with a compound of formula III is oo conveniently carried out in the presence of a condensing agent customarily employed in esterification reactions, e.g in the 0 00 presence of a carbodiimide [dicyclohexyldiimide (DCC)I or of a S° 1° l-alkyl-2-halopyridinium salt [l-methyl-2-chloropyridinium iodide].

340 This reaction is preferably carried out in one of the above inert solvents and in the temperature range from -300 to +70 0 C, preferably from -100 to +50 0 C. It is preferred to carry out the esterification reaction in the presence of a base, for example in the presence of

"LI

14 an organic amine, e.g. a trialkylamine (trimethylamine, triethylamine, tripropylamine, diisopropylethylamine and the like), a pyridine (pyridine itself, 4-dimethylaminopyridine, 4-pyrrolidylaminopyridine etc.), a morpholine (N-methylmorpholine), an N,N-dialkylaniline (N,N-dimethylaniline, N-methyl-N-ethylaniline) and the like.

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

For example, a compound in which RI -CO-CH 2 Cl can be converted (0 into a compound in which RI -CO-CH 2

-OCOCH

3 by reaction with sodium acetate in dimethylformamide at 80 0 C. This compound can in turn be prepared e.g. from a compound in which RI -CO-CH 2 -OH by esterification with acetyl chloride or acetic anhydride. Such conversions of compounds of formula I into other representatives of formula I are considered as belonging to the main process.

The described process, including all partial steps, constitutes an essential object of the present invention.

O

SMost of the acids of formula III, and the halides and anhydrides o thereof, are known or can be prepared by methods analogous to those o' employed for preparing the known representatives.

d The 13B-alkyl-5-hydroxymilbemycins of formula II can be prepared by treating an allyl ester of formula IV 00 0 16 CH 3 o o o O 0 00 17 1 Soo 0

(IV)

U 0\\H I\

CH

3 6RI 15 wherein A is a group a or b H3 1 3

R

0\ C or y H3 (b) S 15 ORe 13B-ester-A 14 15 A13,14-15-ester] Re is an acyl group, RI is hydrogen or, preferably, a silyl group, and R 2 is as defined for formula I, with a trialkylaluminium compound of formula V Al(R) 3

(V)

wherein R is as defined for formula I, and, if free compounds are desired, subsequently removing the silyl group RI by hydrolysis.

The process is generally carried out in an inert solvent. Suitable solvents are ethers and ethereal compounds such as dialkyl ethers (diethyl ether, diisopropyl ether, tert-butylmethyl ether, dimethoxyethane, dioxane, tetrahydrofuran, anisole and the like); o halogenated hydrocarbons such as chlorobenzene, methylene chloride, O /o ethylene chloride and the like; or sulfoxides such as dimethyl sulfoxide. Aromatic or aliphatic hydrocarbons such as benzene, 00o toluene, xylenes, petroleum ether, ligroin, cyclohexane and the like Smay also be present. In some cases it may be advantageous to carry out the reaction or partial steps thereof in an inert gas atmosphere o(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, o e.g. by washing, digestion, extraction, recrystallisation, chromato- Sgraphy and the like. However, such purification steps may be dispensed with and only carried out with the corresponding final products.

_L CI~ iL- -1II~LI__.II 16 Trialkylaluminium compounds suitable for the introduction of the 13-alkyl group are tri(Ci-Cloalkyl)aluminium compounds such as trimethylaluminium, triethylaluminium, triisobutylaluminium, trihexylaluminium etc. The reaction is generally carried out in the temperature range from -100 0 C to +100 0 C, preferably from -20 0 C to 0 C. The trialkylaluminium compound of formula III is added in substance or in an inert solvent, e.g. hexane, toluene or benzene, in at least equimolar amount to the solution of the compound of formula II.

f0 When the reaction is complete, the silyl protective group is conveniently removed by treating the compound of formula I with a dilute acid, e.g. with 1 p-toluenesulfonic acid in methanol or with an aqueous HF solution in acetonitrile, in the temperature range from -20°C to +50 0 C, preferably from 0 C to +30°C, or with pyridinium fluoride in pyridine.

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

ooo. The starting esters of formula IV can be prepared from the SoW, corresponding allyl alcohols of formula VI 0 16 CH3 0 12 I j.0R H3C" (VI) oo o io.

CH

SRI

wherein A is a group a or b 17 H3 CH3 HO C or 1HC11 (b) 415 1H 138-hydroxy-A 14 15 A13,14-15-hydroxy] Rz is as defined for formula I and RI is hydrogen or a silyl group, by customary methods of acylation known in the literature, e.g. by reaction with an acid chloride (RsCOCI) or acid anhydride (RsCO) 2 0, wherein R 8 is as defined for formula IV, in the presence of a base (triethylamine, pyridine, N,N-dimethylaminopyridine and the like), in one of the inert solvents mentioned above, e.g. dichloromethane, chloroform and the like, and in the temperature range from -20°C to 100 0 C, preferably from 0 C to 70 0

C.

fO The compounds of formula VIb A 3,14-15-hydroxy] can be obtained from 14,15-epoxymilbemycins of formula VII

CH

3

.CH

3 *13 17 I IR2 H3C" (VII) 1 o

CH

3 o 36 wherein RI is hydrogen or a silyl group and R 2 is as defined for o formula I, with the complex reagent [HN3]x/Al(ethyl)3] wherein x 0 cy o 0 and y are each independently 1 or 2 or a value between 1 and 2, in

S'

0 an inert dry solvent and in the temperature range from -200 to o o. +150 0 C, preferably from +200 to +80 0

C.

0 0 0 Preferred inert solvents are aliphatic and aromatic hydrocarbons such as benzene, toluene, xylene, and petrrleum ether; ethers such OL as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, and anisole.

x -J 18 The reaction is conveniently carried out in an inert gas such as nitrogen or argon.

Hydrazoic acid (HN 3 can also be converted, in the nascent state, into the [HN3] /[Al(Et) 3 complex by suspending sodium azide in the x y stipulated dry solvent or mixture of solvents and generating HN 3 in the solution with a stronger acid, e.g. H 2 S0 4 (preferably oleum in order to ensure absolutely dry reaction conditions). Al(Et) 3 should already be present in the solution or added thereto shortly afterwards. The epoxy compound to be reacted can also already be present fO in the solution or added thereto at a suitable time.

The starting compounds of formula VII employed for the preparation of compounds of formula 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-A", later called "milbemycin A" compounds, and of the compounds known from US patent specification 4 346 171 and designated as "B-41-D" or Soo "milbemycin as well as of the 13-deoxy-22,23-dihydroavermectins (Rz sec-butyl) of formula VIII o YH3 .CH 3 a0 0 13 17 (VIII) 15

VIII

o *o CH3 0 0

\HCH

OH

SRz CH 3 milbemycin A 3 R2 C 2

H

5 milbemycin A 4 Ra isoC 3

H

7 milbemycin D R2 sec-C4H 9 13-deoxy-22,23-dihydro-C-076-Bla-aglycon.

19 The epoxidation is carried out in a solvent phase in the temperature range from -100 to +200C, preferably from to Peracids such as peracetic acid, trifluoroperacetic acid, perbenzoic acid and chloroperbenzoic acid are suitable for the epoxidation.

The 138-hydroxy-A 14 15 compounds of formula VIa can be prepared by reacting compounds of formula IVb, wherein RI is a protective group, with pyridinium dichromate (Pyr)zCr207]. This reaction is carried out in dimethylformamide and in the temperature range from -100 to 0 C. If desired, the protective group RI is subsequently removed fo by hydrolysis.

Acylation or silylation of the 5-OH group affords all those derivatives of formulae II to VIII wherein Ri has a meaning other than hydrogen (RI OH protective group). For the silylation it is convenient to use a silane of the formula Y-Si(Rs)(R 6

)(R

7 wherein each of Rs, R 6 and R 7 are preferably independently of one another Ci-C 6 -alkyl, benzyl or phenyl, and form e.g. a group selected from trimethylsilyl, tris(tert-butyl)silyl, thexyldimethylsilyl, diphenyl tert-butylsilyl, bis(isopropyl)methylsilyl, triphenylsilyl and the like, and, preferably, tert-butyldimethylsilyl. The 5-OH group can S also be present as benzyl ether or methoxyethoxymethyl ether and Y

I

is a silyl leaving group. Examples of silyl leaving groups Y are o bromide, chloride, cyanide, azide, acetamide, trifluoroacetate or trifluoromethanesulfonate. This recitation constitutes no limitation; further typical silyl leaving groups are known to the skilled person.

00 0 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 00 to +80 0 C, preferably from +100 to +40 0 C. It is preferred to add an J0 organic base. Examples of suitable bases are tertiary amines such as triethylamine, triethylenediamine, triazole and, preferably, pyridine, imidazole or 1,8-diazabicyclo[5.4.0]-undec-7-ene

(DBU).

I~ I I 20 The removal of these silyl radicals RI in the 5-position is effected by selective mild hydrolysis H) with e.g. arylsulfonic acid in alcoholic solution or in accordance with another method known to the skilled person.

The described process for the preparation of compounds of formula I constitutes in all its partial steps an object of the present invention.

The present invention also relates to pesticidal compositions for controlling ecto- and endoparasites as well as harmful insects, (C which compositions contain as active ingredient at least one compound of formula I, together with customary carriers and/or dispersing agents.

The compounds of formula I are most suitable for controlling pests of animals and plants, including 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 family of the Haematopinidae); and of the order o o Diptera, in particular pests of the families Muscidae, o Calliphoridae, Oestridae, Tabanidae, Hippoboscidae, and Gastro- 0 d* philidae.

The compounds of formula I can also be used to combat hygiene pests, no especially of the order Diptera (families Sarcophagidae, Anophilidae o, and Culicidae); of the order Orthoptera, of the order Dictyoptera family of the Blattidae), and of the order Hymenoptera (e.g.

o' ,s 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 of the order Acarina, they are effective against eggs, nymphs and adults of Tetranychidae (Tetranychus spp. and Panonychus ,K I Xjlsyl i^li _i _i_j I I 21 spp.) They also have excellent activity against sucking insects of the order Homoptera, in particular against pests of the families Aphididae, Delphacidae, Cicadellidae, Psyllidae, Coccidae, Diaspididae and Eriophyidae 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 I are also suitable for use against soil pests.

/O The compounds of formula I 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 I are also effective against plant nematodes of the species Meloidogyne, Heterodera, Pratylenchus, Ditylenchus, Radolphus, Rhizoglyphus and others.

In particular, however, the compounds of formula I 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, Strongylus, 0o Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, a Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. The particular advantage of the compounds of formula I Sis their activity against those parasites which are resistant to benzimidazole-based parasiticides.

Certain species of the genera Nematodirus, Cooperia and 2O Oesophagostomum attack the intestinal tract of the host animal, whereas others of the species Haemonchus and Ostertagia parasiticise I I I o 4 4, 4 4 040,r 22 in the stomach and those of the species Dictyocaulus in the lung tissue. Parasites of the families Filariidae and Setariidae 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 is to be made of the dog heartworm, Dirofilaria immitis. The compounds of formula I are highly effective against these parasites.

The compounds of formula I are also suitable for controlling pathogenic parasites in humans, among which parasites there may be mentioned as typical 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 the family of the Filariidae 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 particular the gastro-intestinal tract.

The compounds of formula I are used in unmodified form or, preferably, together with the adjuvants conventionally employed in the art of formulation, and are therefore formulated in known manner to 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 of the compositions, the methods of application such as spraying, atomising, dusting, scattering or pouring, are chosen in accordance with the intended objectives and the prevailing circumstances.

The compounds of formula I are administered to warm-blooded animals at rates of application of 0.01 to 10 mg/kg of body weight, and are applied to enclosed crop areas, to pens, livestock buildings or other buildings in amounts of 10 g to 1000 g per hectare.

_L I I 23 The formulations, i.e. the compositions, preparations or mixtures containing the compound of formula I (active ingredient) are prepared in known manner, e.g. by homogeneously mixing and/or grinding the active ingredients with extenders, e.g. solvents, solid carriers and, in some cases, surface-active compounds (surfactants).

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

The solid carriers used e.g. for dusts and dispersible powders are normally natural mineral fillers such as calcite, talcum, kaolin, a montmorillonite or attapulgite. In order to improve the physical properties it is also possible to add highly dispersed silicic acid or highly dispersed absorbent polymers. Suitable granulated adsorpn tive carriers are porous types, for example pumice, broken brick, a sepiolite or bentonite; and suitable nonsorbent carriers artmaterials such as calcite or sand. In addition, a great number of pregranulated materials of inorganic or organic nature can be used, e.g. especially dolomite or pulverised plant residues.

00 o 0" Depending on the nature of the active ingredient to be formulated, suitable surface-active compounds are nonionic, cationic and/or iS a anionic surfactants having good emulsifying, dispersing and wetting properties. The term "surfactants" will also be understood as 3comprising mixtures of surfactants.

Suitable anionic surfactants can be both water-soluble soaps and water-soluble synthetic surface-active compounds.

I

I

I I I 24 Suitable soaps are the alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts of higher fatty acids (C 10

-C

2 2 e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures which can be obtained, e.g. from coconut oil or tallow oil. Further suitable surfactants are also the fatty acid methyltaurin salts.

More frequently, however, so-called synthetic surfactants are used, especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates.

fo The fatty sulfonates or sulfates are usually in the form of alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts and contain a Cs-Czzalkyl radical which also includes the alkyl moiety of acyl radicals, e.g. the sodium or calcium salt of lignosulfonic acid, of dodecylsulfate, or of a mixture of fatty alcohol sulfates obtained from natural fatty acids.

These compounds also comprise the salts of sulfated and sulfonated fatty alcohol/ethylene oxide adducts. The sulfonated benzimidazole derivatives preferably contain 2 sulfonic acid groups and one latty So 0 o acid radical containing 8 to 22 carbon atoms. Examples of alkylarylog- sulfonates are the sodium, calcium or triethanolamine salts of aol dodecylbenzenesulfonic acid, dibutylnaphthalenesulfonic acid, or of o 0 a condensate of naphthalenesulfonic acid and formaldehyde. Also ,,suitable are corresponding phosphates, e.g. salts of the phosphoric acid ester of an adduct of p-nonylphenol with 4 to 14 moles of 0 ethylene oxide; or phospholiphids.

oeoo 0 0 0 0 ooC The surfactants customarily employed in the art of formulation are S00 described e.g. in "McCutcheon's Detergents and Emulsifiers Annual", S MC Publishing Corp. Ridgewood, New Jersey, 1982.

25 The pesticidal compositions usually contain 0.01 to 95 preferably 0.1 to 80 of a compound of formula I, 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 user will 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 at least one (0 compound of formula I, together with customary carriers and/or dispersing agents.

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

Preparatory Examples 0 a Preparation of starting materials and intermediates 0 Example Sl: Preparation of 14,15-epoxymilbemycin D (formula VII) o While cooling with ice, a solution of 170 mg of chloroperbenzoic o2z acid in 5 ml of dichloromethane is added to a solution of 550 mg of o, milbemycin D in 5 ml of dichloromethane. After stirring for 1 hour at 00 to 5 0 C, 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

~L

26 silica gel (elution with a 20:15 mixture of n-hexane and ethyl acetate), affording 450 mg of amorphous, white 14,15-epoxymilbemycin D.

13 14 Example S2: Preparation of 15-hydroxy-A314 -milbemycin D (formula VIb) ml (0.41 g; 9.53 mmol) of a 6.96 solution of HN 3 in diethyl ether are added at -20 0 C to a solution of 2.1 ml (1.75 g; 15.3 mmol) of triethylaluminium in 8.5 ml of absolute diethyl ether. The reaction mixture is then added at -10 0 C to 1.8 g (3.15 mmol) of f/ 14,15-epoxymilbemycin D (in substance). The ensuing reaction is strongly exothermic. After 1 hour at room temperature, 4 ml of absolute ether are added and the gelatinous reaction mixture is vigorously stirred. After 4 hou- the reaction mixture is worked up as described in Example Sl. Chromaography through 70 g of silica gel (elution with a 10:1 mixture of CH 2 C12 and acetone) affords 200 mg (10 of 14-azido-15-hydroxymilbemycin D and 820 mg (45 13,14 of 15-hydroxy-A -milbemycin D; m.p. 151 0 -153 0 C (recrystallisation from methanol).

o 0 Example S3: Preparation of 5-0-tert-butyldimethylsilyl-14,15-epoxy- 2- ~milbemycin D (formula VII) o 4 a° A solution of 2.21 g (3.86 mmol) of 14,15-epoxymilbemycin D, 757 mg 0 00 00** (5.02 mmol) of tert-butyldimethylchlorosilane and 342 mg (5.02 mmol) of imidazole in 4 ml of dimethylformamide is stirred for 90 minutes so at room temperature. Then 80 ml of diethyl ether are added and the 00o mixtrre is filtered through 20 g of silica gel and the filtrate is o° 0 concentrated, affording 2.65 g (100 of o silyl-14,15-epoxy-milbemycin D.

'H-NMR (300 MHz., solvent CDC1 3 6 values based on Si(CH 3 4

TMS).

0.12 ppm (CHa) 2 Si-0-; j 0.92 ppm (t-C4H 9 )Si-0-; C1__ I _11_1_~1 27 1.23 ppm (broad s) (C 1 4CH 3 i.e. signal of the CH 3 group in the 1 4 -position); 2.56 ppm J 9 Hz) (C 15 H, i.e. signal of the proton in the Following the same procedure, the corresponding 1 4 ,15-epoxymilbemycin D 92 0 -97 0 C) can be prepared by reaction with trimethylsilyl trifluoromethanesulfonate.

Example S4: Preparation of 5-O-tert-butyldimethylsilyl-15-hydroxy- 13 14 A 314-milbemycin D (formula VIb) (0 A solution of the HN 3 /EtaAl complex reagent (prepared from a solution of 4.97 ml of triethyl aluminium in 7 ml of absolute tetrahydrofuran and 9.15 ml of a 2.39 molar solution of HN 3 (21.9 mmol) in absolute diethyl ether) is added, under argon, to a solution of 5.0 g (7.29 mmol) of 14,15-epoxymilbemycin D in about 20 ml of absolute tetrahydrofuran, and the mixture is heated under reflux for 15 hours. Then 250 ml of ether, 2 ml of methanol, and finally a mixture of 10 g of 0\ Na 2

SOQ

4 10H 2 0 and 10 g of celite are added at room temperature. The mixture is filtered and the filtrate is concentrated and chromatoooo |o6 graphy of the crude product through 160 g silica gel (elution with .o 0-30 of ethyl acetate in hexane) affords 2.37 g (47 of o 5-0-tert-butyldimethylsilyl-15-hydroxy-A 314-milbemycin D.

'H-NMR (300 MHZ, CDC13): :0 1.59 ppm J 1 Hz) (C14CH 3 4.06 ppm (dd; J 1 11 Hz; J 2 4 Hz) o. 5.15 ppm J 8 Hz) (C13H).

In addition, 109 mg (2 of 138-azido-5-0-tert-butyldimethylsilylmilbemycin D are obtained.

L 1. rr 1 28 Example S5: Preparation of 14,15-epoxymilbemycin Aq (R 2

=C

2

H

s (formula VII) A solution of 2.43 g (14.08 mmol) of m-chloroperbenzoic acid in ml of dichloromethane is added dropwise at room temperature to a solution of 5.7 g (10.5 mmol) of milbemycin Ai in 140 ml of dichloromethane and 120 ml of a 0.5 molar solution of NaHCO 3 The mixture is vigorously stirred for 1 hour at room temperature and then diluted with 300 ml of dichloromethane. The organic phase is washed with an aqueous solution of NaHC03, dried over NazS04 and concen- (Q trated, affording 5.7 g of epoxide as crude product.

Example S6: Preparation of 5-0-tert-butyldimethylsilyl-14,15-epoxymilbemycin A4 (formula VII) 5.7 g of 14,15-epoxymilbemycin A4 are dissolved in 10 ml of dry dimethylformamide. Then 0.63 g (9.16 mmol) of imidazole and 1.4 g (9.34 mmol) of tert-butyldimethylchlorosilane are added at room temperature. The mixture is stirred for 1 hour at room temperature and chromatographed through 150 g of silica gel (elution with a S 4:1 mixture of hexane and ether), affording 2.84 g (40 of theory, based on milbemycin A) of the silylated epoxy derivative.

Example S7: Preparation of 5-0-tert-butyldimethylsilyl-15-hydroxyo o o 13,14 A -milbemycin Aq (formula VIb) The complex reagent HN 3 /Al(ethyl) 3 is prepared as follows: ao To 2.8 ml (12.2 mmol) of Al(C 2 Hs) 3 in 4 ml of absolute tetrahydrofuran are slowly added at about -20 0 C, under argon, 5.28 ml (20.4 mmol) of an 10 solution of HN 3 in absolute diethyl ether. To oa 0 this solution is added, under argon, a solution of 2.84 g S (4.25 mmol) of the compound obtained in Example S6, and the mixture so obtained is heated for 4 hours under reflux. Then 500 ml of diethyl ether and 10 g of NazSO10H 2 0 and 10 g of celite are added Sat room temperature. The mixture is filtered and the filtrate is L -L 29 concentrated. Chromatography of the crude product through 100 g of silica gel (elution with a 7:2 mixture of hexane and diethyl ether) affords 1.72 g (60 of theory) of the title compound.

'H-NMR (300 MHz, CDC1 3

TMS):

1.59 ppm (broad s) (C 14

CH

3 4.05 ppm (broad s) (CisH); 5.15 ppm J 6 Hz) (C 13

H).

In addition, 0.1 g of 138-azido-5-0-tert-butyldimethylsilylmilbemycin A4 is obtained.

13 14 Example S8: Preparation of 15-hydroxy-A314 -milbemycin A4 i'O (formula VIb) Hydrolysis of 5 mg of the title compound of Example S7 with 1 ml of a 1 solution of p-toluenesulfonic acid in methanol and working up in diethyl ether with a 5 solution of sodium bicarbonate affords the title compound.

Example S9: Preparation of 14,15-epoxymilbemycin A 3

(R

2

CH

3 (formula VII) 0 In accordance with the procedure described in Example SI, reaction Sof 220 mg of milbemycin A 3 in 5 ml of dichloromethane and 75 mg of .o chloroperbenzoic acid in 5 ml of dichloromethane at -20 to +5°C over °E 1 1/2 hours and purification through a column of silica gel affords Oa* 190 mg of 14,15-epoxymilbemycin A 3 oo Example S10: Preparation of 5-0-tert-butyldimethylsilyl-14,15epoxymilbemycin A 3 (formula VII) o In accordance with the procedure of Example S3, reaction of 190 mg of 14,15-epoxymilbemycin A 3 and 120 mg of tert-butyldimethylchlorosilane in the presence of imidazole affords 217 mg of the title compound.

"~ce I I I Example Sll:. Preparation of 5-0-tert-butyldimethylsilyl-15-hydroxy- A 13 4 -milbemycin A 3 (formula VIb) In accordance with the epoxy cleavage of Example S7, 203 mg of the title compound are obtained from 210 mg of silyl-14,15-epoxymilhemycin A 3 in absolute diethyl ether using the complex reagent HN 3 /Et 3 Al under argon, and subsequent purification.

'H-NNR (300 M4Hz, GDCl 3

INS):

1.58 ppm (broad s) (C1 4

CH

3 4.05 ppm (broad s) (C 15

H);

5.15 ppm J =6 Hz) (C 13

H).

(4 Example S12: Preparation of 15-hydroxy-A 131 -milbemycin A 3 (formula VIb) In accordance with the procedure described in Example Si, the reagent HN 3 /Al(C 2

H

5 3 is freshly prepared and added dropwise at 0 C to a solution of 830 mg (3.05 mmol) of 14,15-epoxymilbemycin A 3 in 7 ml of dry diethyl ether. After working up, 385 mg of 15-hydroxy-A 13 ,1 4 -milbemycin A 3 and 92 mg of 14-azido-15-hydroxymilbemycin A 3 are obtained.

Example S13: Preparation of 13-deoxy-14,15-epoxy-22,23-dihydroavermectin-Bla-aglycon (R 2 sec-C!H 9 (formula VII) In accordance with the procedure described in Example S5, 510 mg of the title compound are obtained from 520 mg of 13-deoxy-22,23-dihydroavermectin-Bla--aglycon [Tetrahedron Letters, Vol. 24, No. 48, pp. 5333-5336 (1983)] and 210 mg of m-chloroperbenzoic acid in 20 ml of dichloromethane.

Example S14:.Preparationl of 5-0-tert-butyldimethylsilyl-13-deoxy- 14, lS-epoxy-22,23-dihydroavermectin-Bla-aglycon (formula VII) 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 31 Example S13 and 55 mg of tert-butyldimethyldichlorosilane in the presence of 25 mg of imidazole in 5 ml of dry dimethylformamide.

Example S15: Preparation of 13-deoxy-15-hydroxy-A 13 14 -22,23-dihydroavermectin-Bla-aglycon (formula VIb) In accordance with the procedure described in Example S2, 112 mg of the title compound are obtained by reacting 220 mg of the title compound of Example S14 with the complex reagent consisting of 320 mg of Al(C 2 Hs) 3 and 110 mg of a 6.96 solution of HN 3 in a total of 16 ml of dry diethyl ether. In addition, 61 mg of 13-deoxy- 14-azido-15-hydroxy-22,23-dihydroavermectin-Bla-aglycon are obtained.

Example S16: a) Preparation of 5-0-tert-butyldimethylsilyl-13-hydroxymilbemycin D and 13B-hydroxymilbemycin D (formula VIa) A solution comprising 286 mg (0.41 mmol) of o silyl-15-hydroxy-A 13 14 -milbemycin D and 209 mg (0.56 mmol) of 0 a pyridinium dichromate (PDC) in 3 ml of dimethylformamide (DMF) is 0 stirred for 30 minutes at room temperature. 1 ml of isopropanol is subsequently added and the mixture is stirred tir 5 minutes and then 2 diluted with 50 ml of ether. After a further 10 minutes, the mixture is filtered through silica gel and the filtrate is concentrated.

Chromatography of the crude product through 20 g of silica gel (elution with a 1:2 mixture of ether and hexane) affords 165 mg a (57 of 5-0-tert-butyldimethylsilyl-138-hydroxymilbemycin

D.

'H-NMR (300 MHz; CDC13; TMS): 1.59 ppm (br.s) (C 14

CH

3 3.70 ppm J= 10 Hz) (C 1 3

H).

L .L Y 32 105 mg (0.153 mmol) of the compound so obtained are stirred at room temperature in 1 ml of a 1 solution of p-toluenesulfonic acid in methanol for 1 hour. The mixture is diluted with 20 ml of ether, filtered through silica gel and the filtrate is concentrated. The residue is chromatographed through about 10 g of silica gel (elution with a 1:4 mixture of acetone and dichloromethane), affording 73 mg (83 of 138-hydroxymilbemycin D.

IH-NMR (300 MHz; CDC1 3

TMS):

1.58 ppm (br.s) (C14CH 3 (o 3.71 ppm J 10 Hz) (C 13

H).

b) Preparation of 5-O-tert-butyldimethylsilyl-138-hydroxymilbemycin A 4 By following a procedure analogous to that described in but starting from 5-O-tert-butyldimethylsilyl-15-hydroxy-A 13 1 4 -milbemycin A 4 the title compound with the following physical data is obtained: 0 0 s o 'H-NMR (300 MHz; CDCI 3

TMS):

cooJ° 3.05 ppm J 9 Hz) (C 2 5

H)

o 0 o3.71 ppm (dd; J 3 and 10 Hz) (C 1 3

H)

ao mass spectrum (FD) m/e: 672 C3H600oOSi).

Example S17: 0 o a) Preparation of 5-O-tert-butyldimethylsilyl-138-acetoxymiloo o bemycin D (formula IVa) 0 00 A solution of 200 mg (0.29 mmol) of 13B-hydroxymilbemycin D and 1 ml of pyridine in 2 ml of acetanhydride is stirred for 2 hours at room temperature. Working up in diethyl ether affords 212 mg of 5-O-tert-butyldimethylsilyl-130acetoxymilbemycin D in the form of an amorphous powder.

33 b) Preparation of 5-0-tert-butyldimethylsilyl-13B-acetoxymilbemycin A4 (formula IVa) By following a procedure analogous to that described in but starting from 5-0-tert-butyldimethylsilyl-130-hydroxymilbemycin A4, the title compound with the following physical data is obtained: 'H-NNR (360 MHz; CDCl 3 TI4S): 1.53 ppm (C 1 4CH 3 2.03 ppm (CH 3

COO)

4.94 ppm J =10 Hz) (C 13

H)

(0 mass spectrum (FD) in/a: 714 Ci~oH 62 0 9 Si).

Example S18: a) Preparation of 5-0-tert-butyldimethylsilyl-15-acetoxy- A13' 1 4 _milbemycin D (formula I*Th) A solution of 627 mng (0.914 mmol) of -314milbemycin D in 2 ml of acetanhydride and 2 ml of pyridine is stirred for 1/2 hour at room temperature. Working up in diethyl ether with 5 aqueous NaHCO 3 solution and then with 1M4 HUl and filtration through silica gel affords 624 mng (94 of -314milbenycin D.

'H-NMR (300 M4Hz; CDCl 3

TMS):

1.58 ppm (br. s) (C 1 4CH 3 1.79 ppm (br. S) (C 4 cH 3 '4 2.02 ppm (CH 3 C0O) 5.12 5.26 ppm (in) (C 10 H; C 13 H; C 15

H)

b) Preparation of 5-0-tert-butyldimethylsilyl-15-acetoxy- A 13 1 4 _milbemycin A 4 (formula IVb) 34 By following the procedure described in but starting from 5-0-tert-butyldimethylsilyl-15-hydroxy-A 1314-milbemycin A 4 the title compound with the following physical data is obtained: 'H-NMR (250 MHz; CDC13; TMS): 1.59 ppm (C 14 CHa) 2.03 ppm (CH 3

COO)

3.02 ppm J 8 Hz) (C 25

H)

3.88 ppm J 6 Hz) (CsH) mass spectrum m/e: 714 C40H6209Si), 639, 579, 497, 472, (0 437, 413, 412, 394, 349.

c) Preparation of 5-0-tert-butyldimethylsilyl-15-acetoxy- A 3,14-milbemycin A 4 (formula IVb) The title compound is prepared by following a procedure entirely analogous to that described in a) and but starting from 5-0-tert-butyldimethylsilyl-15-hydroxy-A 13 14 -milbemycin A 3 o Example S19: Preparation of 13B-methylmilbemycin D (formula II) Under argon and at 0 0 C, 1.2 ml of a 17 solution of trimethylon aluminium in toluene are added dropwise with stirring to a solution o°0 of 203 mg (0.28 mmol) of 5-0-tert-butyldimethylsilyl-15-acetoxy- Al3,14-milbemycin D in 2 ml of dichloromethane. The solution is stirred for 2 hours at room temperature, then 0.3 ml of methanol is added dropwise, and the mixture is diluted with diethyl ether and stirred in celite. Filtration through silica gel (elution with diethyl ether) affords 177 mg of 5-0-tert-butyldimethylsilyl-13Bmethylmilbemycin D.

a4 A solution of this material in 0.5 ml of dichloromethane is stirred in 1 ml of a 40 aqueous solution of HF in acetonitrile (5:95) for 1 hour at room temperature. The mixture is worked up in diethyl 35 ether and filtered through silica gel. HPLC (SiO 2 0.5 methanol in dichloromethane; pressure 50 bar) of the crude prodct (154 mg) affords (57 of 138-methylmilbemycin D.

'H-NMR (300 MHz; CDC13; TMS): 1.01 ppm J 6.7 Hz) (C 13

CH

3 5.03 ppm (dd; J 10.5 and 4.6 Hz) (C 15

H)

mass spectrum m/e: 570 (M C 34

H

50 0 7 442, 292, 273, 262, 210, 209, 181, 163, 152, 151.

Example 13 14 a) Preparation of 13B-ethylmilbemycin D and 15-ethyl-A 14 -milbemycin D (formula II) Under argon and at 0 0 C, 0.75 ml (0.63 g; 5.5 mmol) of triethylaluminium is added dropwise with stirring to a solution of 340 mg 13 14 (0.47 mmol) of 5-0-tert-butyldimethylsilyl-15-acetoxy-A 314-milbemycin D in 2 ml of dichloromethane. The solution is stirred for 1 hour at room temperature, and then diluted with diethyl ether.

Celite/NazS04:10 HzO is added and the resultant mixture is stirred for 1 hour. Filtration through silica gel (elution with diethyl ether) affords 258 mg of a mixture which is dissolved in ml of dichloromethane. This solution is then stirred in 1 ml of a 4 aqueous solution of HF in acetonitrile (5:95) for 1 hour at room temperature. Working up in diethyl ether, filtration through silica gel (elution with diethyl ether) and HPLC (reversed phase: water/methanol 1:9; pressure 50 mbar) of the crude product (183 mg) affords 88 mg (32 of 13B-ethylmilbemycin D.

'H-NMR (300 MHz; CDC13; TMS): 0.73 ppm J 7.2 Hz) (C 1 3

CH

2

CH

3 5.03 ppm (dd; J 10.5 und 4.4 Hz) (C 15

H)

mass spectsum m/e: 584 C 35

H

52 0 7 456, 287, 276, 210, 209, 181, 163, 151.

o oo

I

4i"" a 0 4 4 O 0 0

__L

36 and 57 mg (21 of 15-ethyl-A1 3 1 4 -milbemycin D 'H-NNR (300 MHz; CDCl 3

TMS):

3.03 ppm (in) (C 12

H)

4.93 ppm (dd; J 8.7 und 1.2 Hz) (C 13

H)

mass spectrum m/e: 584 (M C 35

H

52 0 7 456, 438, 277, 276, 206, 181, 171, 163, 151, 150, 149.

By following procedures analogous to that of S2Oa, the following milbemycins of formula I indicated in S20b to S2Oh are obtained by reaction with the corresponding trialkyl compounds: to S2Ob) 130-methylmilbemycin A 4 'H-NMR (250 MHz; CDC1 3

TMS):

3.07 ppm (dt; J =12 and 10 Hz) (C 25

H)

5.05 ppm (dd; J =10 and 5 Hz) (C 15

H)

mass spectrum (FD) m/e: 556 (M C 33

H

48 0 7 S2Oc) 13B-ethylmilbemycin A 4 1 H-NMl( (250 MHz; CDCl 3 T14S): 3.W3 ppm (broad t; J =10 Hz) (C 2 sH) 5.02 ppm (dd; J =10 and 7 Hz) (C 15

H)

mass spectrum (FD) m/e: 570 C 34

H

50 0 7 S2Od) 13f-n-hexylmilbemycin D Ii-NMR (250 1MHz; CDCla; TMS): 3.08 ppm J 8 Hz) (C 2 5.00 ppm (broad t; J 8 Hz) (C 15

H)

000 0 mass spectrum (FD) m/e: 640 (M4+ C 39

H

60 0 7 S2Oe) 130-n-butylmilbemycin A 4 IH-NMR (250 MHz; CDCl1 3

TNS):

3.03 ppm (broad t; J =10 Hz) (C 2 5.02 ppm (broad t; J 10 Hz) (C 15

H)

mass spectrum (FD) m/e: 598 (M C 36

H

54 0 7 37 130-isobutylmilbemycin A4 'H-NMR (250 MHz; CDCl 3

TMS):

3.09 ppm (broad t; J 10 Hz) (C 25

H)

5.05 ppm (dd; J =10 and 7 Hz) (C 15

H)

mass spectrum (FD) m/e: 598 C 36

H

5 4O 7 S2Og) 130-methylmilbemycin A 3 IH-Nl{R (300 MHz; CDCl 3

TMS):

3.27 ppm (in) (CzsH) 5.06 ppm (dd; J 10 and 6 Hz) (omass spectrum (FD) m/e: 542 (M C 32 H4 6

O

7 S2Oh) 13 -ethylmilbemycin A 3 'H-NNR (300 MHz; CDCl 3

TMS):

3.25 ppm (in) (C 2 5

H)

5.06 ppm (dd; J 10 and 6 Hz) (C 15

H)

mass spectrum (FD) m/e: 556 C 3 3Hi,80 7 Example S21: Preparation of 13R3-methylmilbemycin D (formula II) from 5-0-tert-butyldimethylsilyl-1 3 -acetoxymilbemycin D fK Under argon and at 0 0 C, 0.5 ml of a 17 solution of trimethylaluminium in toluene is added dropwise with stirring to a solution of 14 mg (0.019 mmol) of 5-O-tert-butyldimethylsilyl-13R-acetoxymilbemycin D in 0.5 ml of dichloromethane. The solution is stirred overnight at 5'C. Working up as indicated in S20 affords 10 mng of 5-0-tert-buyldimethylsilyl--130-methylmilbemycin D.

J A solution of this material in 0.5 ml of dichloromethane is stirred in 1 ml of a 40 aqueous solution of HF in acetonitirle (5:95) for 1 hour at room temperature. The mixture is worked up in diethyl and filtered through silica gel, affording 8 mg of 130-methylmilhemycin D.

I 38 Preparation of the Final Products Fl. Preparation of 5-0-chloroacetyl-138-methylmilbemycin A 4 A solution of 350 mg of 13B-methylmilbemycin A4 and 0.50 ml of pyridine in 3 ml of methylene chloride is cooled to 0 C and then il of chloroacetyl chloride are added over 2 hours. The reaction mixture is stirred for 1 hour at 0 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.

'H-NMR (250 MHz; CDC13): 3.07 ppm (dt, Jd 3, Jt 10) (C 25

H)

4.18 ppm (CH 2 C1) F2. Preparation of 5-0-acetoxyacetyl-13B-methylmilbemycin A 4 a) 2 ml of a 0.09 M solution of acetoxyacetyl chloride in benzene are added at 0 0 C over 30 minutes to a solution of 50 mg of 138methylmilbemycin A 4 73 pl of pyridine and 1 mg of dimethylaminopyridine in 1 ml of methylene chloride. The reaction mixture is stirred for 3 hours and then worked up. The crude product is chromatographed through a column of silica gel (elution with a 3:1 mixture of hexane/ethyl acetate), affording 49 mg of title compound.

IH-NMR (300 MHz; CDC13): 2.16 ppm (CH 3

-CO)

3.07 ppm (dt; Jd 3, Jt 10) (C 25

H)

5.03 ppm (dd, J 11 und 6) (C 1 5

H)

b) 16 mg of sodium acetate and 2 mg of sodium iodide are added to a solution of 80 mg of 5-0-chloroacetyl-13-methylmilbemycin A 4 in 3 ml of dimethylformamide. The reaction mixture is heated for r..

c r.

i c i a~r~R Ivs 4'1 I :j

I

to i aic oc n np -U .L i I I 39

(V

o 3 o coo o 0 4 4o 0 4 0 0i 4 31 hours to 60 0 C and then worked up. The crude product is chromatographed through a column of silica gel (elution with a 3:1 mixture of hexane/ethyl acetate), affording 53 mg of 5-0-acetoxyacetyl-130methylmilbemycin A 4 F3. Preparation of 5-0-(3,4-dihydro-2H-pyran-2-yl)carboxyacetyl-13Bmethylmilbemycin D A solution of 80 mg of 5-0-chloroacetyl-138-methylmilbemycin D, 29 mg of sodium (+)-3,4-dihydro-2H-pyran-2-carboxylate and 2 mg of potassium iodide in 3 ml of dimethylformamide is stirred for 6j hours at 60 0 C under an atmosphere of argon and subsequently diluted with 50 ml of diethyl ether. The resultant solution is washed with 20 ml of water and then with 20 ml of saturated NaCl solution, dried over MgSO4 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 hexane/ethyl acetate), affording 59 mg of product.

MS 724 (M 'H-NMR (250 MHz; CDC13): 3.07 ppm (dt; Jd 3, Jt 10) 5.05 ppm (dd, J 6 und 10) 6.44 ppm J 8) (0-CH=CH) F4. Preparation of 5-0-(1,2,4-triazol-l-yl)acetyl-13B-methylmilbemycin A 4 0.30 ml of pyridine, 2 mg of dimethylaminopyridine and 74 mg of N,N-dicyclohexylcarbodiimide are added to a solution of 100 mg of 13B-methylmilbemycin A 4 and 57 mg of 1H-1,2,4-triazol-l-yl-acetic acid in 2 ml of tetrahydrofuran. The reaction mixture is stirred for 2} hours at eoom temperature and worked up. The crude product is suspended in 3 ml of diethyl ether, and the suspension is filtered and concentrated by evaporation. Chromatography through a column of silica gel (elution with 5 methylene chloride/methanol) 'affords 100 mg of title compound.

jL I I I t ('0 40 MS (mle): 665 (M 'H-NNR (300 MHz; CDCl 3 3.07 ppm (dt; J d ,i 10) (C 25

H)

5.07 ppm (CH 2

N)

7.97 ppm (N'CH-N) 8.24 ppm (N=CH-N) Preparation of 5-0-(l,2,4-triazol--l-yl)acetyl-1313-methylmilbemycin A4~ zinc(II) complex 200 jil of a 0.19 M4 solution of zinc (II) chloride in ethanol are added to a solution of 47 mg of 5-0-(1,2,4-triazol--l-yl)acetyl-130methylmilbemycin A4 in 2 ml of benzene. The resultant solution is allowed to stand for 1 hour at room temperature and then lyophilised. The title compound is obtained in a yield of 52 mg.

'H-NMR (300 M4Hz; CDCla): 3.06 ppm (dt; i d 3,i 10) (C 2 5

H)

5.12 ppm (CH 2

N)

8.21 ppm (N=CH-N) 8.65 ppm (N=CH-N) F6. Preparation of 5-0-acetoxyacetyl-130-ethylmilbemycin AL 0.92 ml of a 0.25 M4 solution of acetoxyacetyl chloride in benzene are added at 0 0 C to a solution of 65 mg of 130-ethylmilbemycin A4, 92 111 of pyridine and 1 mg of dimethylaminopyridine in 1 ml of methylene chloride. The reaction mixture is stirred for 4 hours at 0 0 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 70 mg of title compound.

MS 670 (M C 38

H

5 z4010) 'H-NMR (300 MHz; CDCl 3 0.71 ppm J (C 13

CH

2 CHjI) 2.16 ppm (GH 3

-CO)

3.07 ppm (dt, J d=3, Jt 9) (C 25

H)

5.60 ppm J (C 5

H)

o C 0 0 0 0 00 0 o 00 00 o o o 0~0 0 00 0 00 00 00 00 0 o a I I I 41 5-0-Acetoxyacetyl-138-ethylmilbemycin A 3 and 5-0-acetoxyacetyl-138-ethylmilbemycin D can be obtained in analogous manner.

F7. Preparation of 5-0-chloroacetyl-13-ethylmilbemycin A 4 Follwing the procedure of Example Fl, the product can be obtained in a yield of 59 mg from 61 mg of 130-ethylmilbemycin A4.

MS 646 C3 6 HsiC10 8 1 H-NMR (300 MHz; CDCl 3 3.06 ppm (dt; Jd 3, Jt 10) /O 4.15 ppm (CH 2 Cl) 5.01 ppm (dd, J 6 und 10) (C 15

H)

F8. Preparation of 5-0-tert-butyldimethylsilyloxyacetyl-13B-methylmilbemycin A 4 One drop of dimethylformamide 30 il) is added to a solution of 956 mg of tert-butyldimethylsilyl tert-butyldimethylsilyloxyacetate in 4 ml of methylene chloride, followed by the addition of 222 pl of oxalyl chloride at 00C over 45 minutes. The reaction mixture is then .G stirred for 30 minutes at 000 and for 2 hours at room temperature.

The resultant solution of the acid chloride is subsequently added 2' dropwise over 20 minutes to a solution, cooled to 0°C, of 900 mg of 13B-methylmilbemycin A 4 and 1.31 ml of pyridine- in 2 ml of methylene chloride. The reaction mixture is stirred for 90 minutes at 0 0

C,

o then partitioned between ether and lN HC1 solution, and the organic phase is washed with saturated NHCO 3 solution and with saturated NaCI solution and concentrated by evaporation. The residue is chromatographed through a column of silica gel (elution with a 10:1 mixture of hexane/ethyl acetate), affording 988 mg of title compound.

MS 728 C41H6eOeSi) 3 1H'-NMR (300 MHz; CDCI 3 0.10 ppm ((CH 3 )2Si) LI I I 42 0.80 ppm (tert-C4HsSi) 3.05 ppm (dt, Jd 3, Jt 9) (C 25

H)

5.57 ppm J 6) (CsH) F9. Preparation of 5-0-hydroxyacetyl-13-methylmilbemycin A4 934 mg of 5-0-tert-butyldimethylsilyloxyacetyl-13W-methylmilbemycin A 4 are added to 5 ml of a 5 solution of 40 HF in acetonitrile. The reaction mixture is stirred for 2 hours at room temperature, then partitioned between diethyl ether and saturated

NHCO

3 solution and the organic phpase is washed with saturated NaCI /O solution and concentrated by evaporation. The residue is purified by chromatography (elution with a 2:1 mixture of hexane/ethyl acetate), affording 690 mg of title compound.

MS 614 C 35

H

50 0 9 'H-NMR (300 MHz; CDC13): 2.38 ppm J 6) (CH0OH) 3.05 ppm (dt, Jd 2,5, Jt 9) (C 25

H)

S4.21 ppm (dd, J 1 6, Jz 16) (CO-CHHOH) 4.28 ppm (dd, J 1 6, Jz 16) (CO-CHHOH) o F10. Preparation of 5-O-methoxycarbonyloxyacetyl-13-methylc milbemycin A 4 13 1 of methyl chloroformate are added at 0°C to a solution of mg of 5-0-hydroxyacetyl-138-methylmilbemycin A 4 and 66 1 of 1 pyridine in 2 ml of methylene chloride. The reaction mixture is stirred for 15 minutes at 0 C and the cooling bath is removed and stirring is continued for a further 2 hours at room temperature.

After working up, the crude product is chromatographed through a column of silica gel (elution with hexane/ethyl acetate), affording mg of title compound.

MS 672 C 37

H

52 0 11 .03 'H-NMR (300 MHz; CDC13): 3.05 ppm (dt, Jd 2,5, Jt 9) (C 25

H)

3.78 ppm (CH 3 0) I I ~I -43 4.68 ppm J -16) (CO-CHHO) 4.74 ppm J =16) (CO-CHRO) 5.60 ppm (bd, J (C 5

H)

Fil. Preparation of 5-O-methoxymethoxyacetyl-13B-methylmilbemycin A4~ 168 jil of bromomethyl methyl ether are added to a solution of 50 mg of 5. -hydroxyacetyl-13R-methylmilbemycin A4 and 580 jil of N-ethyl diisopropylamine in 1 ml of methylene chloride. The reaction mixture is stirred for 2 days at room temperature and then worked up. the (C crude product is chromatographed through a column of silica gel (elution with a 4:1 mixture) of hexane/ethyl acetate), affording 23 mg of title compound.

MS 658 C 37

H

5 4010) 'H-NNR (300 M4Hz; CDCl 3 3.05 ppm (dt, J d 2,5, Jt 9) (C 25

H)

3.38 ppm (CH 3

O)

4.21 ppm J 16) (CO-CHH0) 4.28 ppm J 16) (CO-CHHO) 5.60 ppm J F12. Preparation of 5-0-(3-chlorobenzoyloxy)acetyl-130-methylmilbemycin A4 21 iii of 3-chlorobenzoyl chloride are added to a solution of 50 mg of 5-0-hydroxyacetyl-130-methylmilbemycin At, and 66 jil of pyridine 00,0 in 2 ml of methylene chloride and the reaction mixture is stirred 0for 3 hours. After working up, the crude product is chromatographed through a column of silica gel (elution with a 6:1 mixture of 0 hexane/ethyl acetate), affording 54 mg of title compound.

MS 752 (MN C 42 11 53 C10 10 'H-NMR (300 M4Hz; CDCl 3 3.05 ppm (dt, J d Jt 9) (C 25

H)

JD 4.90 ppm J 16) (CO-CHHQ) 4.98 ppm J 16) (CO-CHHO) 5.61 ppm (bd, J (C 5

H)

i I -44 7.39 ppm (in (aromatic ring proton) 7.55 ppm (in) (aromatic ring proton) 7.97 ppm (in) (aromatic ring proton) 8.06 ppm (in) (aromatic ring proton) F13. Preparation of 5-0-(2-tetrahydropyranyl)oxyacetyl-13B-methylmilbemycin A 4 2 mg of pyridinium (toluene-4-sulfonate) are added to a solution of mg of 5-0-hydroxyacetyl-13B--methylmilbemycin A 4 and 74 41 of 3,4-dihydro--2H-pyrane in 2 ml of methylene chloride. The reaction /0 mixture is stirred for 90 minutes 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 hexane/ethyl acetate), affording 49 mg of title compound.

MS 698 (M C 4 oH 58 0 10 H-NMR (300 M~iz; CDCl 3 3.05 ppm (dt, J d 2,5, Jt 9) (C 25

H)

4.27 ppm J =16) (C0-CHH0) 4.33 ppm J =16) (CO-CHH0) 4.78 ppm (in) (OCH(CH 2

)O)

F1 4. Preparation of 4-chlorobutanoyl) oxyacetyl-1 3 -methyl- 0 0 0 0 milbemycin A 4 18 lil of chiorobutyryl chloride are added at 0 0 C to a solution of mg of 5-0-hydroxyacetyl-13-methylmilbemycin A 4 ad6 1o Co ~opyridine in 2 ml of methylene chloride. The reaction mixture is stirred for 2 hours at 0 0 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.

a MS 718 (M C 39

H

55 C10 10 3.O H-NMR (300 MHz; CDCl 3 3.05 ppm (dt, J d Jt 9) (C 25

H)

3.61 ppm J 7) (CH 2 01) I I I I 4.68 ppm J 16) (CO-CHHO) 4.75 ppm J 16) (CO-CHHO) 5.59 ppm (bd, J 6) (C 5

H)

Preparation of 5-0-(thiophene-2-carhonyloxy) acetyl-130-methyl milbemycin A4 52 1il of thiophene-2-carboxylic chloride are added to a solution of mg of 5-0-hydroxyacetyl-130-methylmilbemycin At, and 66 ILl of pyridine in 2 ml of methylene chloride. The reaction mixture is stirred for 4 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 55 g of title compound.

MS (mle): 724 C 4 0

H

5 2 0 1 0

S)

IH-NMR (300 MHz; CDCl 3 3.05 ppm (dt, J d 2,5, Jt 9) (C2 5

H)

4.8 pm dJ 4.93 ppm J =16) (C0-CHH0) 5.60 ppm (bd, J 6) (C 5

H)

7.11 ppm (in) (thiophene proton) 7.60 ppm (in) (thiophene proton) 7.88 ppm (in) (thiophene proton) Fl16. Preparation of 5-0-vinyloxycarbonyloxyacetyl-1 milbemycin A 4 00000065 lil of acrylyl chloride are added to a solution of 50 mng of 5-0-hydroxyacetyl-130-methylmilbemycin A 4 and 132 4i of pyridine in 2 ml of methylene chloride. The reaction mixture is stirred for 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 10 mng of title .3-3 compound.

MS (mle): 668 (M C 38

H

52 0 1 o) 'H-NMR (300 MHz; CDC1 3 I T -46 3.05 ppm (dt, ~d Jt 9) (C 2 4.75 ppm =16) (CO-CHHO) 4.18 ppm J 16) (CO-Cilia) 5.60 ppm (bd, J 6) (C 5

H)

5.91 ppm (dd, J 1 1,5, J 2 =10) (HHC=CHCO) 6.20 ppm (dd, J 1 =10, J 2 17) (HHG=CHCO) 6.50 ppm (dd, J 1

J

2 17) (iH=CIICO) F17. Preparation of 5-O-phenoxyacetyl-1313-methylmilbemycin A4 iii of phenoxyacetyl chloride are added at C to a solution of 0 50 mg of 5-0-hydroxyacetyl-13 methylmilbemycin A4 and 73 iii of pyridine in 2 ml of methylene chloride. The reaction mixture is stirred for 2 hours at 0 0 G 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 compound.

MS 690 (M C 41

H

5 4O 9 o 'IH-NNR (300 14Hz; CDCl 3 3.05 ppm (dt, J 25, J 9) (C 25

H)

0 dt 4.71 ppm (COCH 2 0) 5.60 ppm (bd, J (C 5

H)

6.93 ppm (in) (C 6

H

3

H

2 6.98 ppm (in) (C 6

H

4 7.27 ppm (in) (C 6

H

3

H

2 o0 o F18. Preparation of 5-O-acetoxyacetyl-1313-n-butylmilbemycin A 4 In accordance with the procedure of Example F6, 8 mg of title ~0 compound are obtained from 8 mg of 13R-n-butylmilbemycin A 4 698 (M C4oH 5 8010) IH-NMR (300 MHz; CDCl 3 0.85 ppm J 7) (CH 3

CH

2 2.16 ppm (CH 3

CO)

3.05 ppm (dt, J d-2.5, Jt 9) (C 25

H)

4.66 ppm J =16) (CO-CHHb) 47 0 4.73 ppm J 16) (CO-CHHO) 5.59 ppm (bd, J 16) (CsH) F19. Preparation of 5-0--p-tosyloxyacetyl-1313-methylmilbemycin A4 2 mg of 4 -dimethylaminopyridine are added at 0 0 C to a solution of mg of 5-O-hydroyacetyl-l3R-methylmilbemycin

A

4 and 260 111 of pyridine in 2 ml of diethyl ether, followed by the addition of 150 mg of toluene-4-sulfochloride. The reaction mixture is stirred for 24 hours at room temperature and then worked up. Chromatography of the crude product through silica gel (elution with a 4:1 mixture of hexane/ethyl acetate) affords, in addition to 7 mg of acetyl-13R-methylmilbemycin, 15 mg of title compound.

MS (mle): 768 (MN C 4 2

H

5 6 01 1

S)

'H-NMR (300 MHz; CDCl 3 2.43 ppm (C 6

H

4 -CH!i) 3.05 ppm (dt, J d Jt 9) (C 2 4.67 ppm (COCH 2 0) Preparation of 5-0--methoxyacetyl-13B-methylmilbemycin A4~ One drop of dimethylformamide 30 p1) is added to a solution of 81 p1l of riethoxyacetic acid in 5 ml of benzene, followed by the addition of 80 p1l of oxalyl chloride at 0 0 C over 5 minutes. The reaction mixture is then stirred for 2 hours at room temperature.

1.56 ml of this solution are added at 0 0 C over 20 minutes to a solution of 50 mg of 13p-methylmilbemycin A 4 73 p1. pyridine and 0.6 mg of 4-dimethylaminopyridine in 2 ml of methylene chloride. The reaction mixture is stirred for 2 hours at 0 0 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 628 (M C 36

H

52 0 9 'H-NMR (300 MHz; CDCl 3 3.48 ppm (CH 3

O)

4.10 ppm J 16) (COCHHO) 4.18 ppm J =16) (COCHHO) C ~C 00 0 0000 48 F21. Preparation of 5-0-chloroacetyl-135--ethylmilbemycin

A

4 Following the procedure of Example Fl, 22 mg of

A

3 are obtained from 25 mg of l3R-ethylmilbemycin A 3 MS 632 (MN C 35

H

49 C10 8 'H-NI4R (300 MHz; ODC1 3 3.25 ppm (in) (C 2 sH) 4.16 ppm (CH 2 C1) F22. Preparation of 5-0-acetyloxyacetyl-13R-methylmilbemycin

A

3 to Following the procedure of Example F6, 30 mg of 135-methylmilbemycin A 3 are obtained from 31 mg of 135-methylmilbemycin A 3 MS (mle): 642 (MN G 36

H

5 o0 10 1 H-NMR (300 MHz; CDCl 3 0.70 ppm J 7) (C 13

CH

2

CH

3 2.15 ppm (CH 3 cO) 3.25 ppm (in) (C 25

H)

5.59 ppm J 7) (C 5

H)

F23. Preparation of 5-0-methoxyacetyl-l30--methylmilbemycin

D

Following the procedure of Example F20, 21 mg of 01, 135-methylmilbemycin D are obtained from 25 mg of 13R-methylmilbemycin D MS (mle): 642 (M C 37

H

54 0 9 IH-MR (300 MHz; CDCl 3 3.07 ppm (bd, J =10) (C 25

H)

3.49 ppm (CH 3

O).

49 F24. Preparation of 5-0-acetyl-13B-methylmilbemycin A 4 29 il of pyridine are added at 0 C to a solution of 20 mg 13B-methylmilbemycin A 4 in 1 ml of methylene chloride, followed by the addition of 6 pl of acetyl chloride. The reaction mixture is stirred for 3- hours at 0 0 C and then worked up. Chromatography of the crude product through silica gel (elution of a 4:1 mixture of hexane/ethyl acetate) affords 20.5 mg of product.

MS 598 C 35 Hso0 8 'H-NMR (300 MHz; CDC13): 2.14 ppm (CH3CO) 3.06 ppm (dt, Jd 2,5, Jt 9) (C 25

H)

5.03 ppm (dd, J 1 11, J 2 5) (C 15

H)

The following compounds of formula I are also prepared by the procedures described in the foregoing Examples. The following Tables imply no restriction to what is contained therein.

o I i 1 i 50 Table 1: Typical representatives of compounds

R

2 is Gil 3 milbemycin A 3 derivatives): of formula I, wherein Compond RPhysical data or Compund RIPreparatory Example 1.1 Gil 3

GOGH

3 1.2 C 2

H

5

GOGH

3 1.3 C 3 H7-n GOGH 3 1.4 C 3

H

7

GOGH

3

C

4 Hq-n GOGH 3 1.6 C 6

H

13 -n GOGH 3 1.7 CloH 2

COCH

3 1.8 Gil 3

GOCH

2 Cl 1.9 GH 3 COCHzBr 1.10 C2H 5

COCH

2 Cl F21 1.11 GH 3

GOCH

2 ErF 1.12 C 2

H

5

COGH

2

F

1.13 Gil 3

COCH

2

CH

3 1.14 G 2

H

5

GOCH

2 0CH 3 1.15 Gil 3 GOCH2SGH 3 1.16 Gil 3

GOCH

2 0GH 3 1.17 Gil 3

GOCH

2 0OOH 3 F22 1.18 G 2

H

5

GOCH

2 0OOH 3 1.19 G 3

H

7 -n COCHZOCOGH 3 1.20 G 6

H

13 -n GOGH 2 0OOH 3 1.21 Gil 3

GOGHFOGOGH

3 1.22 Gil 3

GOGH(CH

3

)OGOGH

3 1.23 Gil 3

GOGH

2

OGOGH

2 Gl 1.24 Gil 3

COCH

2 0OO 2

H

1.25 Gil 3

GOGH

2 0OO 6

H

4 F(3) 1.26 Gail 5

GOCH

2 0OC 6 il4Gl(3) 1.27 Gil 3

COCH

2 0OGO 6 H40CHi 3 (3) 1.28 Gil 3

GOGH

2 0OO 6

H

3 Gl 2 (2,4) 1.29 Gil 3

GOGH

2 0OO 3

H

7 -n 1.30 G 2

H

5

GOGH

2

OGH

2 0GH 3 0 440 0 00 4 44 -51- Table 1 (continuation) Physical data or Compound R RIPreparatory Example_ 0 1.31 CH 3 C0CH 2 0C0-*~~ 1.32 C 2 Hs COCH 2 0CO- 1 1.33 CH3 COCH 2 N,/-f 1.34 C 2

H

5

COCH

2

N/-

1.35 CH 3

COCH

2 NK x 1/2 ZnCl 1.36 C 2

H

5

COCH

2 N~ x 1/2 ZnCI 1.37 CH- 3

COCH

2 NK x 1/2 CuCl

N=

1.38 CZH 5

COCH

2 x 12 CuCl \N=-X1 0 1.39 CH 3 C0CH 2 0C0/~ :1.40 C2H COH0I 1.2 C2H 5 C0CH 2 0CO-N/ 1.43 CH- 3

COCH

2

OCH

3 1.44 Cl-I COCHZ0C0C 6 H4Cl(3) 52 Table 2: Typical representatives of compounds

R

2

=G

2

H

5 milbemycin A4 derivatives): of formula I, wherein Compund R1Physical data or Compond RPreparatory Example 2.1 CH 3

GOGH

3 F24 2.2 C 2 H5 GOGH 3 2.3 C3H7-n COCH 3 2.4 G 3

H

7 -i COCH 3

C

4

H

9 -n GOGH 3 2.6 G 6

H

13 -n GOGH 3 2.7 C 10

H

2

GOGH

3 2.8 GH 3 COCHaCl Fl 2.9 GH 3

COCH

2 Br 2.10 GH 3

COCH

2

F

2.11 CH 3

COCH

2 BrF 2.12 G 2

H

5 COCH2F 2.13 GH 3

COCH

2

CH

3 2.14 GaH 5

COCH

2

OGH

3 2.15 GH 3

COCH

2

SCH

3 2.16 GH 3

COCH

2

OC

2

H

2.17 GH 3

COCH

2 0OCH 3 F2 2.18 G 2

H

5

COCH

2 0OCH 3 F6 2.19 C 3

H

7 -n COCH 2 0OCH 3 2.20 G6HI3-n GOGH 2 0OOH 3 2.21 CH 3

GOCHFOCOGH

3 2.22 CH 3

COCH(GHOOGOH

3 2.23 CH3 COCH 2

OCOCH

2 G1 2.24 CH 3 COGH20OC 2

H

2.25 CH 3

COCH

2 0OCGH 4 F(3) 2.26 G 2

H

5 COCH20OC 6 H4Cl(3) 2.27 GH 3

COCH

2 0OC 6 H40CH 3 (3) 2.28 GH 3 COCH20OC 6

H

3 Cl 2 (2,4) 2.29 GH 3

COCH

2 0OC 3

H

7 -n 2.30 G 2

H

5

COCH

2

OGH

2

OGH

3 I 114 -53- Table 2 (continuation) Compound R RI Physical data or Example 2.31 OH 3 C0CH2000-t F3 2.32 C 2

H

5 C0CH 2 0C0-*~~ 2.33 CH 3

COCH

2 F4 2.34 C2H5 C00H 2

N=

2.35 CH 3 COCH2N/>=l x 1/2 ZnCl 2 2.36 C 2

H

5 COCHAN >j x 1/2 ZnC1 2 2.37 CH3 COCH2NK x 1/2 CuC1 2 2.39 C2H5 COH 2 0C0-* x u 2.40 0H3 COCH 2 0O- O0 0 2.41 OH 3

COH

2 0CO-< 2.42 O 2

H

5 C0CHZ0C0--N/0-1 2.43 OH 3

COCH

2 0CH 3 2.44 OH 3

COH

2 0C00 6

H

4 Cl(3) F12 I I I 54 Table 2 (continuation) Compound R R1Physical data or Preparatory Example 2.45 C2H 5

COCH

2 Cl F7 2.46 CH 3

COCH

2 0H F9 2.47 CH 3

COCH

2 0C00CH 3 2.48 OH 3

COCH

2 0CH 2

OCH

3 Fil 2.49 OH 3

COCH

2 F13 2.50 CH 3

COCH

2 0C0CH 2

CH

2

CH

2 C3 F14 2.51 CH 3

COCH

2 0C-/

\S/

2.52 CH 3

GOGH

2 0CO-CH=CH 2 F16 2.53 CH 3

COCH

2

OC

6

H

5 F17 2.54 C4H 9 -n COCH 2 0COCH 2 F18 2.55 OH 3 G0CH 2 0S0 2

-O

6 H4CH 3 F19 2.56 CH 3

GOCH

2 OSi(CH 3 )zt-Butyl F8 o o o o..

00 00 I I I 55 Table 3: Typical representatives of compounds

R

2 isoC 3

H

7 milbemycin D derivatives): of formula I, wherein Compound R RiPhysical data or _______Preparatory Exam-ples 3.1 GB 3

GOGH

3 F24 3.2 C 2

H

5

COCH

3 3.3 C 3

H

7 -n GOCH 3 3.4 G 3

H

7 -i GOGH 3

G

4

H

9 -n COCH 3 3.6 C 6

H

13 -n COCH 3 3.7 C 10

H

21 -n COCH 3 3.8 GB 3

COCH

2 Gl 3.9 GB 3

COCH

2 Br 3.10 GB 3

GOGH

2

F

3.11 GB 3

GOCH

2 BrF 3.12 G 2

H

5

GOCH

2

F

3.13 GB 3

GOGB

2

OGB

3 F23 3.14 G 2 H5 GOGH 2

OGB

3 3.15 GB 3

COGH

2

SGH

3 3.16 GB 3

GOGH

2

OG

2

H

3.17 GB 3

COCH

2 0OCH 3 3.18 G 2

H

5

GOGH

2 0OOH 3 3.19 G 3

H

7 -n GOGH 2 0OCG 3 3.20 G6H 13 -n GOGH 2 0OOH 3 3.21 GB 3

GOGBFOGOGH

3 3.22 GB 3

COGH(GH

3

OOGOH

3 3.23 GB 3

COCH

2 0OOH 2 Gl 3.24 GB 3

COGB

2 0OO 2

H

3.25 GB 3

GOCH

2 0OO 6

H

4 F(3) 3.26 C2B 5

COCH

2 0OC 6

H

4 Cl(3) 3.27 GB 3

GOCH

2 0OC 6

H

4

OGB

3 (3) 3.28 GB 3

COGH

2 0OO 6

H

3 Gl 2 (2,4) 3.29 GB 3

GOGH

2 0OC 3

H

7 -n 3.30 G 2 H5 COCH2OGH 2

OGH

3 0 40 I I I -56 Table 3 (continuation) Compund RIPhysical data or Compond RPreparatory Examples 3.31 CH 3

COCH

2 0C0-.~' 3.32 C 2

H

5 C0CH 2 0CO-* 3.33

CH

3 COCH 2 N/(=l 3.34 CzH 5

COCH

2

,O=

3.35 CH 3 C0CH 2 x 1/2 ZnCl 2 3.36 CZH 5 C,0G 2 x 1/2 ZnCl 2 3.37 CH 3

COCH

2 K'r x 1/2 CUC1 2 03.38 CaH5 C0CH2N\ !x 1/2 CuClz 43.39

OH

3 C0OCH 2 0C0- 1 S3.40 C 2

H

5

COCH

2

OCO-#

3.41 CH 3 COCH2OCO-NT 73.42 C2H 5

COCH

2 0C0-NC(' 3.43 CH 3

COCH

2 00H 3 3.44 CH3 COCH20C0C 6 H4Cl(3) I I I I 57 Table 4: Typical representatives of compounds of formula I, wherein R= sec-butyl (=13-deoxy-22,23-dihydro--C-076-Bla-aglycon derivatives): Compound R R 4.1 CH 3

COCH

3 4.2 C 2

H

5

GOGH

3 4.3 C 3

H

7 -n COCH 3 4.4 C 3

H

7 -i COCH 3

C

4 Hq-n COCH 3 4.6 C 6

H

1 3 -n COCH 3 4.7 C 10 Hz 1 -n COCH 3 4.8 CR 3

COCH

2 Cl 4.9 CR 3

COCH

2 Br 4.10 CR 3 COCH2F 4.11 CR 3

COCH

2 BrF 4.12 C 2 HS COCH 2

F

4.13 CH 3

COCH

2

CH

3 4.14 C 2

H

5

COCH

2 0CH 3 4.15 CH 3

COCH

2

SCH

3 4.16 CR 3

COCH

2

OC

2

H

4.17 CR 3

COCH

2 0COCH 3 4.18 C 2

H

5

COCH

2

OCOCH

3 4.19 C 3

FI

7 -n COCH 2

OCOCH

3 4.20 C 6

H

13 -n COCH 2

OCOCH

3 4.21 CR 3

COCHFOCOCH

3 4.22 CR 3

COCR(CH

3

)OCOCH

3 4.23 CR 3

COCH

2 0COCH 2 Cl 4.24 CR 3

COCH

2

OCOC

2

H

4.25 CR 3

COCH

2 0COCGH 4 F(3) 4.26 C2H 5

COCH

2 0COC6H4Cl(3) 4.27 CR 3 COCH20COC 6 H40CH 3 (3) 4.28 CR 3

COCH

2 0COC 6

R

3 Cl 2 (2,4) 4.29 CR 3

COCH

2 0COC 3

H

7 -n 4.30 C 2

H

5

COCH

2

OCH

2 0CH 3 o 00 00 0 a a a 58 Table 4 (continuation) Compound R R 4.31 CH 3

COCH

2 0C0-".

4.32 C2H CCH 2 0O-/~ 4.33 CH 3 GOCHa<? 4.34 C2H

CCH

2

N/"

1 l 4.35 CH 3

COCH-

2 x 1/2 ZnCl 2

\N=

4.36 C2H5 COCH 2 x 1/2 ZC1 2 4.38 C 2

H

5

COCH

2 N< x 1/2 CuCl 2 4.39 CH 3 0 00 4.40 C 2

H

5 C0CH 2

ODCO-.

0 4.41 CH 3

COCH

2 0C-~ '00 4.42 C 2

H

5

COCH

2 OC-KT0- 4.43 GH 3

COCH

2

OCH

3 4.44 CH 3

COCH

2 0COC 6

H

4 Cl(3) I I II 59 Table 5: Typical representatives of starting compounds of formula II, wherein R, hydrogen, are: Compound R 2

R

5.1 CH 3 Gil 3 5.2 CH 3

C

2

H-

5.3 Gil 3

C

3

H

7 -n 5.4 CH 3

C

3

H

7 -iSO Gila C 4

H

9 -n 5.6 Gil 3 C4H9-sec 5.7 CH 3 C4H 9 -iso 5.8 CH 3

C

5

H

11 -n 5.9 Gil 3

G

6

H

13 -n 5.10 Gil 3 GCil 15 -n 5.11 CH 3 G8H17-n 5.12 Gil 3 CqH 18 -n 5.13 Gil 3 Co2 5.14 C 2 H5 CH 3 5.15 C 2

H

5

G

2

H

5.16 G 2

H

5

C

3 il 7 -iSO 5.17 C 2

H

5

C

4

H

9 -n 5.18 C 2

H

5 C4H 9 -sec 5.19 C 2 il 5 C4H 9 -iso 5.20 G 2

H

5 C5HI 1 -n 5.21 C 2 H5 C6H 13 -n 5.22 C 3 11 7 -iso Gil 3 5.23 C 3 il 7 -iSO C 2 il 5.24 C 3

H

7 -iso C 3

H

7 -n 5.25 C 3

H

7 -iSO G 3

H

7 -iSO 5.26 C 3 il 7 -iSO G4H 9 -n 5.27 C 3

H

7 -iso C4Hi 9 -sec 3.28 C 3 il 7 -iSO C4il 9 -iso 5.29 C4H 9 -sec Gil 3 5.30 C 4

H

9 -sec C 2

H

0 00 4,4, 0 00 CC o 0 0 i (a 60 Table 5 (continuation) Verb. Nr. Rz R 5.31 C4H 9 -sec C3H 7 -n 5.32 C 4

H

9 -sec C 3

H

7 -iso 5.33 C4H 9 -sec C4H9-n 5.34 C4Hg-sec C4H 9 -sec 5.35 C4H 9 -sec Cq4H-tert 5.36 C4Hg-sec C 4 H9-iso 5.37 C3Hy-iso C6HI3-n 5.38 C 3

H

7 -iso CsHI 1 -n 5.39 CaH 5

C

3

H

7 -n Formulation Examples for (throughout, percentages active ingredients of formula I are by weight) o 00 o a ft a 0 0-0 00 3 S) O Wettable powders a compound of the Tables sodium lignosulfonate sodium laurylsulfate sodium diisobutylnaphthalenesulfonate octylphenol polyethylene glycol ether (7-8 moles of ethylene oxide) highly dispersed silicic acid kaolin b) 50 6% c) 75 10 10 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 water to give suspensions of the desired concentration.

Emulsifiable concentrate a compound of the Tables octylphenol polyethylene glycol ether moles of ethylene oxide) calcium dodecylbenzenesulfonate 10 3% 3% L I 1 I 61 castor oil polygycol ether (36 moles of ethylene oxide) 4 cyclohexanone 30 xylene mixture 50 Emulsions of any required concentration can be obtained from this concentrate by dilution with water.

Dusts a) b) a compound of the Tables 5 8 talcum 95 (O kaolin 92 Ready for use dusts are obtained by mixing the active ingredient with the carrier, and grinding the mixture in a suitable mill.

Extruder granulate a compound of the Tables 10 1o sodium lignosulfonate 2 0 carboxymethylcellulose 1 kaolin 87 The active ingredient is mixed and ground with the adjuvants, and the mixture is subsequently moistened with water. The mixture is 0 extruded and then dried in a stream of air.

i Tablets or boluses I a compound of the Tables 33.00 methyl cellulose 0.80 A A highly dispersed silicic acid 0.80 maize starch 8.40 I I If 62 The methyl cellulose is stirred in water and allowed to swell. Then the silicic acid is stirred in to give a homogeneous suspension. The compound of formula I and the maize starch are mixed and the aqueous suspension is added to the mix, which is kneaded to a paste. This paste is granulate' through a 12M sieve and the granulate is dried.

II crystalline lactose 22.50 maize starch 17.00 microcrystalline cellulose 16.50 magnesium stearate 1.00 /O All 4 adjuvants are thoroughly mixed. Phases I and II are mixed and compressed to tablets or boluses.

If the compounds of formula I, or compositions containing them, are used for controlling endoparasitic nematodes, cestodes and trematodes in domestic animals and productive livestock, for example cattle, sheep, goats, cats and dogs, they can be administered to the animals in both single and repeated doses.

Depending on the species of animal, the individual doses are preferably administered in amounts ranging from 0.1 to 10 mg/kg of body weight. A better action is often achieved by protracted -C 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 0.005 to 0.1 percent by weight. The compositions can be administered to the animals perorally in the form of solutions, emulsions, suspensions, powders, tablets, boluses or capsules.

If the physical and toxicological properties of solutions or emulsions permit it, the compounds of formula I, or compositions containing them, can also be injected into animals for example ayZ subcutaneously, administered intraruminally or applied to the bodies of the animals by the pour-on method. Administration by means of dalt licks or molasses blocks is also possible.

i 63 Biological Examples Bl: Insecticidal stomach 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 the test compound in acetone/water.

After the coating has dried, the plants are populated with about larvae (LI stage) of Spodoptera littoralis. Two plants are used for each test compound and test species. The test is carried out at about 24 0 C and 60 relative hbmidity. Evaluations and intermediate /1O 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 I of the Tables, e.g. compounds 2.8, 2.33, 2.43 and 2.35, at a concentration of 3 ppm.

B2: Action against plant-destructive acarids: OP-sensitive Tetranychus urticae 16 hours before the start of the test, the primary leaves of bean plants (Phaseolus vulgaris) are infected with an infested piece of leaf from a mass culture of Tetranychus urticae. Upon removal of the piece of leaf, the plants infested with all stages of the mites are sprayed to drip point with a solution containing 0.4 ppm or 1.6 ppm of the test compound. The temperature in the greenhouse compartment is about 25 0

C.

The percentage of mobile stages (adults and nymphs) and of eggs is evaluated under a stereoscopic microscope after 7 days. Compounds of formula I of the Tables, e.g. compounds 2.8, 2.17 and 2.43, achieved complete kill at a concentration of 0.4 ppm.

L 64 B3: Action against LI larvae of Lucilia sericata 1 ml of an aqueous suspension of test compound is mixed with 3 ml of a special larval culture medium at about 50°C such that a homogeneous composition containing 250 ppm or 125 ppm is obtained. About Lucilia sericata larvae (Li) are put into each test tube containing active ingredient. A mortality count is made after 4 days. The compounds of formula I of the Tables, e.g. compounds 2.8, 2.17, 2.31, 2.33, 2.35, 2.43, 2.1, 2.18 and 2.45, achieved complete kill at 100 ppm.

(O B4: Acaricidal action against Boophilus microplus (Biarra strain) Adhesive tape is applied vertically across a PVC plate so that fully replete female Boophilus microplus 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 Il of 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 ig per tick is dissolved. Control ticks are injected with liquid containing no test compound. After this treatment, the ticks Sare detached from the support and kept in an insectarium under normal conditions at about 28 0 C and 80 relative humidity until 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 IR 3 0 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.

o Compounds of formula I of the Tables, e.g. compounds 2.8, and 2.33, were very effective in this test.

C C -L i.- 65 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 intraruminal injection to sheep which have been artificially infected with Haemonchus concortus and Trichostrongylus 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 faeces of the sheep before and after treatment.

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 I, 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 Sco° 0.2 mg/kg.

aB6: Contact action against Aphis craccivora a Pea plantlets which have been infested with all development stages 2 of the aphid are sprayed with a solution prepared from an emulsifiable concentrate of the test compound and containing 50 ppm, ppm or 12.5 ppm of active ingredient. After 3 days evaluation is made to establish whether at least 80 of the aphids are dead or as have dropped from the plants. A composition is only rated as effective at this level of activity.

0 C Compounds of formula I 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.

L 'Y 66 B7: Larvicidal action against Aedes aegypti A 0.1 solution of the test compound in acetone is pipetted onto the surface of 150 ml of water in beakers in amounts sufficient to 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 Andes aegypti are put into each beaker. Mortality counts are made after 1, 2 and 5 days.

In this test, the compounds of formula I of the Tables, e.g.

compounds 2.8, 2.17, 2.31, 2.33, 2,1, 2.18 and 2.43, achieved O )complete kill of all larvae at a concentration of 1.6 ppm after 1 day.

B.8 Action against Meloidogyne incognita Eggs of Meloidogyne incognita are mixed into sand. This mixture is then placed in 200 ml earthenware pots (5000 eggs per pot). On the same day, a three-week-old tomato plant is planted in each pot and the formulated test compound is introduced into the pots by pressure o Sapplication (0.002 active ingredient, based on the volume of the soil). The potted plants are stood in a greenhouse at a temperature C°o of 26±1 0 C and a relative humidty of 60 After 4 weeks evaluation o o ',o0 is made by examining the plants for root-knot formation in Saccordance with the Knot Index.

Compounds of the Preparatory Examples exhibit good activity against Oo Meloidogyne incognita in that they substantially reduce root-knot So 0formation. On the other hand, untreated and infected control plants o exhibit severe root-knot formation 100 Thus, in this test, no oo compounds 2.17, 2.33 and 2.18 reduce root-knot formation almost completely (0-10 attack).

c -Y -1 67 B.9 Milbicidal action against Dermanyssus gallinae 2 to 3 ml of a test solution (100, 10, 1 and 0.1 ppm of test compound) are put into a glass container which is open at the top and about 200 mites in different stages of development are put into this container. The container is then sealed with cotton wool and shaken uniformly for 10 minutes until the mites are completely wetted. The container is then inverted until excess test solution has been absorbed by the cotton wool. The container is again inverted and the treated ticks are kept under observation for 3 days under laboratory conditions to evaluate the effectiveness of test compounds. Mortality is the 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 at a concentration of 100 ppm.

S00 006 0 00 4 00 L i L

Claims (16)

1. A 5-alkoxy-13p3-alkylmilbemIycin of the general formula I CH 3 1 3 17 H 3 C 0 R *H wherein R is C 1 C 10 alkyl, Rl is an acyl group selected from 0 a) -C-GH-Y KR 3 0 b) -C-CH-X- R 3 0 0 c) -C-CH-X-C-R 4 I R 3 wherein X is oxygen or sulfur, Y is chlorine, bromine, iodine, benzenesulfonyloxy, paratosyloxy or mesyloxy, R 3 is hydrogen, C 1 -C 4 alkyl or halogen, and I I I 69 R 4 is hydrogen; C 1 -C 10 alkyl, unsubstituted or substituted by halogen, hydroxy, C1-C 6 alkoxy, or C1-C 6 haloalkoxy, an unsubstituted or substituted radical selected from the group consisting of C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl and C 3 -C 6 alkynyl, the substituents of said radicals being selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy and C 1 -C 6 alkanoyloxy; phenyl or phenyl which is substituted by halogen, cyano, C 1 -C 3 alkyl, C -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and/or 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, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C1-C 4 alkoxy, and R 2 is methyl, ethyl, isopropyl or sec-butyl; or an acid addition salt or a metal complex thereof.

2. A compound of formula I according to claim 1, wherein R is C -C 6 alkyl, R 2 is methyl, ethyl, isopropyl or sec-butyl, R1 is an acyl group selected from 0 R 3 0 b) -C-CH-X-R R 3 o 0 o ona aoa> a> S a a a> 0 0 C) H- 4 and 3 wherein X is oxygen or sulfur, Y is chlorine, bromine, iodine, benzenesulfonyloxy, paratosyloxy or mesyloxy, R 3 is hydrogen, C 1 -C~alkyl or halogen, and R4 is hydrogen; Cl-Cloalkyl, unsubstituted or substituted by halogen, hydroxy, CI-C~alkoxy or Cl-C 6 haloalkoxy; an unsubstituted or substi- tuted radical selected from the group consisting of C3-CJlocycloalkyl, C 2 -C~alkenyl and C 3 -C6alkynyl, the substituents of said radicals being selected from the group consisting of halogen, hydroxy, CI-C 6 alkoxy CI-Ccalkanoyloxy; phenyl or phenyl .,hich izzu-brtituted byhalo- gen. cyano, Cl-C 3 alkyl, C 2 I-C 3 haloalkyl, CI-C 3 alkoxy, CI-C 3 haloalkoxy and/or nitro; or is an unsubsticuced or substituted, unsaturated or saturated 5- or 6-memberod hoterocy..clic ring containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and o sulfur, the substituents of said ring being selected from the group consisting of oxo, halogen, Ci-Ci 4 alkyl, C 1 -C4haloalkyl and Cl-Cr+- alkoxy, or an acid addition salt or a metal complex thereof.

3. A compound of formula I according to claim 2, wherein R is Ci-Csalkyl, Rz is methyl, ethyl, isopropyl or sec-butyl, o R 1 is an acyl group selected from a) Y b) Zg~X-L C) H-X- -Ri. and 71 0 II d) -C-CH-R 4 R 3 wherein X is oxygen or sulfur, Y is chlorine, bromine, iodine, benzenesulfonyloxy, paratosyloxy or mesyloxy, R 3 is hydrogen, fluorine or methyl; and R 4 is hydrogen; C1-C 6 alkyl, unsubstituted or substituted by fluorine, chlorine, bromine, hydroxy, C -C 3 alkoxy or C 2 -C 3 haloalkoxy; an unsubstituted or substituted radical selected from the group consisting of C 3 -C 7 cycloalkyl, C -C 4 alkenyl and C 2 -C 4 alkynyl, the substituents of said radicals being selected from the group consisting of fluorine, chlorine, bromine, hydroxy, C -C 3 alkoxy and C -C 4 alkanoyloxy; phenyl or phenyl which is substituted by fluorine, chlorine, bromine, methyl, ethyl, inethoxy, halomethoxy, trifluoromethyl and/or 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 substitutents of said ring being selected from the group consisting of oxo, halogen, C -C 4 alkyl, Ci-C 4 haloalkyl and Cl-C 4 alkoxy, or an acid addition salt or a metal complex thereof.

4. A compound of formula I according to claim 3, wherein R is C.-C 6 alkyl, R 2 is methyl, ethyl, isopropyl or sec-butyl, R1 is the group -C-CH-Y 3 R is hydrogen, fluorine or methyl, and SY is chlorine, bromine, iodine, benzenesulfonyloxy, paratosyloxy or mesyloxy. So 5. A compound of formula I according to claim 1, wherein R is C 1 -C 6 alkyl, R 2 is methyl, ethyl, isopropyl or sec-butyl, R 1 is the group I 72 S- H-X-R4 wherein X is oxygen or sulfur, R 3 is hydrogen, fluorine or methyl, and R4 is hydrogen; C 1 -Csalkyl, unsubstituted or substituted by fluorine, chlorine, bromine, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 haloalkoxy; an unsub- stituted or substituted radical selected from the group consisting of C3-C7cycloalkyl, Cz-C4alkenyl and Cz-Cialkynyl, the substituents of said radicals being selected from the group consisting of fluorine, chlorine, bromine, hydroxy, Ci-C 3 alkoxy and Ci-Caalkanoyloxy; phenyl or phenyl which is substituted by fluorine, chlorine, bromine, methyl, ethyl, methoxy, halomethoxy, trifluoromethyl and/or nitro; or is an unsubstituted or substituted, unsaturated or saturated 5- or 6- Smembered heterocyclic ring containing I to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, the substi- ,tuents of said ring being selected from the group consisting of oxo, halogen, Ci-Cualkyl, Ci-C4haloalkyl and C 1 -C 4 alkoxy, or an acid addition salt or a metal complex thereof.

6. A compound of formula I according to claim 3, wherein S R is C 1 -Csalkyl, R 2 is methyl, ethyl, isopropyl or sec-butyl, RI is the group 3 wherein X is oxygen or sulfur, R 3 is hydrogen, fluorine or methyl, and Ru is hydrogen; Cl-Csalkyl, unsubstituted or substituted by fluorine, chlorine, bromine, hydroxy, C 1 -C 3 alkoxy or Ci-C 3 haloalkoxy; an unsub- stituted or substituted radical selected from the group consisting of C3-C7cycloalkyl, Cz-Cialkenyl and Cz-Calkynyl, the substituents of said radicals being selected from the group consisting of fluorine, chlorine, bromine, hydroxy, CI-C 3 alkoxy and Ci-C 4 alkanoyloxy; phenyl 73 or phenyl which is substituted by fluorine, chlorine, bromine, methyl, ethyl, methoxy, halomethoxy, trifluoromethyl and/or 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 substi- tuents of said ring being selected from the group consisting of oxo, halogen, Ci-Calkyl, C 1 -C4haloalkyl and C 1 -C4alkoxy, or an acid addition salt or a metal complex thereof.

7. A compound of formula I according to claim 3, wherein R is Ci-Csalkyl, R 2 is methyl, ethyl, isopropyl or sec-butyl, RI is the group H-Ri R 3 is hydrogen, fluorine or methyl; and R 4 is an aromatic heterocyclo-1-yl group consisting of an unsubstituted or substituted 5-membered hecerocyclic ring which contains 2 to 3 nitrogen atoms, the substituents of said ring being selected from 1 to 3 C 1 -Csalkyl groups, or an acid addition salt thereof with an organic or inorganic acid, or a metal complex thereof with a metal cation of auxiliary groups I, II, IV or VIII of the Periodic Table.

8. A compound of formula I according to claim 1, wherein R is C 1 -Csalkyl, R is methyl, ethyl, isopropyl or sec-butyl, oo. R 1 is an acyl group selected from a) -H-Y 4H-X-R4 c3 c) H-X- -R4 and Z 74 d)3 wherein X is oxygen or sulfur, Y is halogen R 3 is hydrogen, halogen or methyl; and R4 is hydrogen; Cl-Ci~alkyl, unsubstituted or sub.stituted by halogen or C 1 -C4alkoxy; is cyclopropyl, cyclopentyl, cyclohexyl, phenyl or phenyl which is substituted by fluorine, chlorine, bromine, methoxy, tri- fluoromethyl and/or nitro; or is 4H-2,3-dihydropyran-2-yl or an aromatic heterocyclo-1-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-Csalkyl groups, or an acid addition salt thereof with an organic or inorganic acid. or a metdl complex thereof with a metal cation of auxiliary groups I, II, IV or VIII of the Periodic Table.

9. A compound of formula I according to claim 1, selected from the group consisting of: 5-O-chloroacetyl-13B-methylmilbemycin D, 5-O-chloroacetyl-13B--methylmilbemycin A 3 5-0-chloroacetyl-13R-methylmilbemycin A4, 5-O-chloroacetyl-13B-ethylmilbemycin D, 5-O-chloroacetyl-138-ethylmilbemycin A 3 5-O-chloroacetyl-13B-ethylmilbemycin A4, 5-O-acetoxyacetyl-13B-methylmilbemycin D, 5-O-acetoxyacetyl-13B-methylmilbemycin A 3 5-O-acetoxyacetyl-13R-methylmilbemycin A4, 5-O-acetoxyacetyl-13B-ethylmilbemycin D, 5-O-acetoxyacetyl-13B-ethylmilbemycin A 3 5-O-acetoxyacetyl-1 3Q-ethylmilbemycin A4., 75 3,4-dihydro-2H-pyran--2-yllcarboxyacetyl-13 methylmilbemycin D, 3, 4-dihydro-2H-pyran-2-yllcarboxyacetyl-13B-methylmilbemycin A 3 3,4-dihydro-2H-pyran-2-yllcarboxyacetyl-13B-methylmilbemycin A4, 3,4-dihydro-2H-pyran-2-yllcarboxyacetyl-13B-ethylmilbemycin D, 3,4-dihydro-2H-pyran-2-yllcarboxyacetyl-13B--ethylmilbemycin A 3 3,4-dihydro-2H--pyran-2-yllcarboxyacetyl--13 -ethylmilbemycin A4, 5-0-f1,2,4-triazol-4'-yllacetyl-13 -methylmilbemycin D, 5-0-f,2,4-triazol-4'-yllacetyl-138-methylmilbemycin A 3 5-0-[1,2,4-triazol-4'-yllacetyl-138-methylmilbemycin A4, 5-0-[1,2,4-triazol-4'-yllacetyl-13B-ethylmilbemycin D, 2, 4 -triazol-4'-yllacetyl-13B-ethyniil bemycin A 3 -yaeyl-13-methylmilbemycin D,, 5-0-methoxyacetyl-'13 -methylmilbemycin D3, 5-0-methoxyacetyl-1 3B-methtylmilbemycin A3+, 5-0-methoxyacetyl-13 -ethylmilbemycin D, 5-0-methoxyacetyl-13B-ethylmilbemycin A 3 5-0-methoxyacetyl-13B-ethylmilbemycin A3, 3-horoenyloxy3etyl1-ehylmilbernyci D,, 3-chlorobenzoyloxylacetyl-135-methylmilbemycin A 3 3-chlorobenzoyloxylacetyl-13B-methylmilbemycin A3, 3-chlorobenzoyloxylacetyl-13B-ethylmilbemycin D, 3-chlorobenzoyloxylacetyl-13B-ethylmilbemycin A 3 ,an 3-chlorobenzoyloxylacetyl-13B-ethylmilbemycin A3 n A compound of formula I according to claim 1, selected from the group consisting of: toxyacetyl-1 38-propylmilbemycin D, "I 76 5-O-acetoxyacety-13p--propylmi ibemycin A 3 5-O-acetoxyacetyl-1 3f-propylmil1bemyci n A 4 5-0-acetyl-13p3-ethylmilbemycin ID, 5-O-acetyl-13p3-ethylmilbemycini A 3 3f-ethyl mil1bemyci n A 4 5-O-acetyl1l3p3-methylmilbemycin D, 5-O-acetyl--13p-methylmi ibemycin A 3 5-O-acetyl-1313-methylmi ibemycin A 4 5-O-methoxyacetyl-133-butylmi ibemycin ID, 5-O-methoxyacetyl-133-butylmi ibemycin A 3 5-O-methoxyacetyl-l3p3-butylmi lbemycin A 4 5-O-benzoyloxy-l3p3-methylmi ibemycin ID, 5-O-benzoyloxy-13f3-methylmilbemycin A 3 and 5-O-benzoyloxy-13f3-methylmilbemycin A 4

11. A process for the preparation of a 5-acyloxy-13 -alkylmil- bemycin of the general formula ~H 3 CH 3 1 3 1 *H H. R CH 3 o 0 wherein R is C 1 -C 10 alkyl, 6. is an acyl group selected from 0 11 a) -C-CH-Y KR 3 I 77 0 b) -C-CH-X-R R 3 0 0 c) -C-CH-X-C-R and 4 R 3 0 d) -C-CH-R 4 R 3 wherein X is oxygen or sulfur, Y is chlorine, bromine, iodine, benzenesulfonyloxy, paratosyloxy or mesyloxy, R 3 is hydrogen, C 1 -C 4 alkyl or halogen, and S R 4 is hydrogen; C 1 -C 10 alkyl, unsubstituted or substituted by halogen, hydroxy, C 1 -C 6 alkoxy, or C1-C6haloalkoxy, an o 0 unsubstituted or substituted radical selected from the group consisting of C 3 -C 10 cycloalkyl, C2-C 6 alkenyl and C 3 -C 6 alkynyl, the substituents of said radicals being selected from the group consisting of halogen, hydroxy, Ci-C 6 alkoxy and C 1 -C 6 alkanoyloxy; phenyl or phenyl which is substituted by halogen, cyano, C1-C 3 alkyl, C -C 3 haloalkyl, C1-C 3 alkoxy, C 1 -C 3 haloalkoxy and/or nitro; or is an unsubstituted or 0 0 substituted, unsaturated or saturated 5- or 6-membered heterocyclic ,oo °ring containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, the substituents of said o ring being selected from the group consisting of oxo, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C -C 4 alkoxy, and W:12 I^L I I 78 R 2 is methyl, ethyl, isopropyl or sec-butyl, or an acid addition salt or a metal complex thereof, which process comprises esterifying a 13-alkylmilbemycin derivative of formula II H3 ,.CH 3 I I 0 H 3 C H\ HO-RI (I) (III) I H, CH 3 6H (II) with an acid of formula III, of an acid halide or acid anhydride thereof, in which formulae the substituents R, R 1 and R 2 are as defined for o o formula I.

12. A process according to claim 11, which comprises using an acid C 0 So chloride or acid bromide as acid halide of the acid of formula III. go, 13. A composition for controlling parasites of animals or plants, S which contains as active ingredient at least one 5-acyloxy-133-alkylmil- S bemycin of the general formula I c0 0ooo TH 3 CHa S0 R 0000 H 3 C (I) 0 0 O1 0000 ooo\ o a CH S c o H co II I' R is C 1 -C 10 alkyl, R1 is an acyl group selected from a) -C-CH-Y R 3 I ii i 79 0 b) -C-CH-X-R R 3 0 0 II 11 c) -C-CH-X-C-R and S4 R 3 0 d) -C-CH-R 4 R 3 wherein X is oxygen or sulfur, Y is chlorine, bromine, iodine, benzenesulfonyloxy, paratosyloxy or mesyloxy, 0 R 3 is hydrogen, C 1 -C 4 alkyl or halogen, and S R 4 is hydrogen; C 1 -C 10 alkyl, unsubstituted or substituted by ooo ohalogen, hydroxy, C 1 -C alkoxy, or C 1 -C 6 haloalkoxy, an goo unsubstituted or substituted radical selected from the group consisting of C3-C 10 cycloalKyl, C 2 -C 6 alkenyl and O o C 3 -C 6 alkynyl, the substituents of said radicals being selected ,o from the group consisting of halogen, hydroxy, C -C 6 alkoxy and 0 00 C 1 -C 6 alkanoyloxy; phenyl or phenyl which is substituted by halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and/or nitro; or is an unsubstituted or o,00* substituted, unsaturated or saturated 5- or 6-membered heterocyclic o0 0 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, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C1-C 4 alkoxy, and S R 2 is methyl, ethyl, isopropyl or sec-butyl, or an acid addition salt or a metal complex thereof, together with conventional formulation assistants.

14. A composition as claimed in claim 13, which contains as active ingredient at least one compound of formula I according to any one of claims 2 to 80 A method of controlling pests of animals or plants, which comprises applying to said animals or plants, or to the locus of said pests, an effective amount of a 5-acyloxy-13f3-alkylmilbemycin of the general formula I ~H3 CH 3 1 3 *17 5 0H Rz H 3 C3 RI a) CH 3 H~ 00 0 K0 3 0 0 C -L-CH-Y-'R n KR 3 000 1 4, KR 3 p, 'I, a -dC-X n mes1loRy 81 R 3 is hydrogen, C 1 -C 4 alkyl or halogen, and R 4 is hydrogen; C 1 -ClOalkyl, unsubstituted or substituted by halogen, hydroxy, C -C 6 alkoxy, or C 1 -C 6 haloalkoxy, an unsubstituted or substituted radical selected from the group consisting of C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl and C 3 -C 6 alkynyl, the substituents of said radicals being selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy and C 1 -C 6 alkanoyloxy; phenyl or phenyl which is substituted by halogen, cyano, C 1 -C 3 alkyl, C -C 3 haloalkyl, C1-C 3 alkoxy, C 1 -C 3 haloalkoxy and/or 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, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C -C 4 alkoxy, and R 2 is methyl, ethyl, isopropyl or sec-butyl, or an acid addition salt or a metal complex thereof.

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

17. A substituted 5-acyloxy-13B-alkylmilbemycin derivative, substantially as hereinbefore described with reference to any one of the Examples Fl to F24 or any one of compounds 1.1 to 1.44, 2.1 to 2.56, 3.1 to S3.44 or 4.1 to 4.44.

18. A process for the preparation of a substituted 5-acyloxy-133-alkylmilbemycin derivative, substantially as hereinbefore described with reference to any one of the Examples Fl to F24.

19. A composition for controlling parasites of animals or plants, o which contains a substituted 5-acyloxy-13p-alkylmilbemycin derivative, substantially as hereinbefore described with reference to any one of the Formulation Examples. A composition for controlling parasites of animals or plants, comprising a compound as claimed in claim 17 together with a pesticidally acceptable carrier, adjuvant and/o diluent.

21. A method of controlling pests of animals or plants which comprises applying to said animals or plants, or to the locus of said pests, an effective amount of a compound as claimed in claim 17 or a composition as claimed in claim 19 or claim KX C KXNf/2 I E c I- 82 DATED this SEVENTH day of JANUARY 1991 Ciba-Geigy AG Patent Attorneys for the Applicant SPRUSON FERGUSON 09 10. 0 0 0 0 000a Q 4 t 4t t