AU596853B2 - 13beta-alkyl derivatives of the S541-antibiotics for controlling parasites in productive livestock and plants - Google Patents

Description

7j f' x 596853 S F Ref: 31518 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE: Class Int Class Complete Specification Lodged: Accepted: Published: a C1 n r ioil 1n 9 ai d is corcv~ict I{A Ii n Iiig.J A g Priority: Related Art: Name and Address of Applicant: Address for Service: Ciba-Geigy AG Klybeckstrasse 141 4002 Basle

SWITZERLAND

Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia p? Complete Specification for the invention entitled: 13beta-alkyl derivatives of S541-antibiotics for controlling parasites in productive livestock and plants The following statement is a full description of this invention, including the best method of performing it known to me/us 5845/3

I-

-1I- 5-16005/+ o 0 0 0 0900 0 00 o 0 0000 00 0 000 0 00 0 0 0 060 0 0 0 0 o 000 o 90 0 0 0 o 00 09 0 040 135-alkyl derivatives of S541-antibiotics for c ontrolling parasites in productive livestock and plants The present invention relates to novel improved 13B-alkyl derivatives of antibiotics S541 of the formula I below, their preparation anef ,ieir use for controlling pests such as ecto- and endo-parasites in animals and p arasites in plants.

The compounds according to the invention are 136-alkyl derivatives of antibiotics S541 of the general formula I *0 0 o 000 9Q0069 0 YH3 3 CH3 .0 \l*'R 2

H

3 C. &3 tR1 -2in which R is C 1

-C

10 -alkyl;

R

1 is hydrogen or methyl, acetyl, haloacetyl, methoxyacetyl, methylthioacetyl, acetyloxyacetyl, acetyloxyfluoroacetyl, propionyloxyacetyl, benzoyloxyacetyl, halobenzoyloxyacetyl, methoxybenzoyloxyacetyl, or the group -Si(R 4

)(R

5

)(R

6 wherein R 4

R

5 and R 6 independently of one another, each represents C 1

-C

4 -alkyl, benzyl or phenyl;

R

2 is methyl, ethyl or isopropyl; and

R

3 is hydrogen or an OH group; wherein when R 3 is hydrogen a 22,23-double bond or -single bond is present and when R 3 is an OH group a 22,23-single bond is present.

Formula I thus represents derivatives of antibiotics S541 that contain a 13B-alkyl group and contain in the 5-position either a free OH group, a methoxy group or a silyloxy group, and the 23-deoxy and 23-deoxy- 22,23-dehydro analogues thereof.

Depending on the number of carbon atoms indicated, alkyl by itself or as a moiety of another substituent will be understood as meaning, for example, the following straight-chained or branched groups: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., as well as the isomers thereof, such as, for example isopropyl, isobutyl, tert.-butyl, isopentyl etc.

Halogen is fluorine, chlorine, bromine and iodine, but preferably fluorine, chlorine or bromine. The prefix "halo" indicates that the 25 corresponding substituent may be substituted by one or more halogen atoms S*o from the series fluorine, chlorine, bromine and iodine.

Preferred acyl groups for the substituent R 1 are, for example, the 0 groups o a) -C(O)-CH-X-R 11 0 R I 10 b) -C(O)-CH-X-C(O)-R 1 0900 Q o 00 0 0; e o 0 0°000 o0J° {H/6512F j 171 i 3 and c) -C(0)-CH-R 1 1 R1 o 0 o 00 0 o 00 o 0 o o0 O0 o 0 00 0 009 0 0 0 4 0 00 in which X is oxygen or sulphur; is hydrogen, C 1

-C

4 -alkyl or halogen; and R11 is hydrogen, C 1

-C

10 -alkyl, C 1

-C

10 -alkyl substituted by halogen, hydroxy, C 1

-C

6 -alkoxy or by C 1

-C

6 -haloalkoxy, phenyl, or phenyl substituted by halogen, cyano, C 1

-C

3 -alkyl, C 1

-C

3 -alkoxy, C 1

-C

3 -haloalkoxy and/or by nitro.

i0 Especially preferred acyl groups b) and c) are those in which X is oxygen; RI0 is hydrogen, methyl, fluorine, chlorine or bromine and R11 is hydrogen, C1-C4-alkyl, C1-C4-alkyl substituted by fluorine, chlorine, bromine, hydroxy, C -C 4 alkoxy or by C 1

-C

4 -haloalkoxy, phenyl, or phenyl substituted by fluorine, chlorine, bromine, methyl, methoxy or by trifluoromethyl.

o A suitable silyl group R 1 is the radical -Si(R 4

(R

5

(R

6 in which R 4

R

5 and R 6 preferably independently of one another, each represents C 1

-C

4 alkyl, benzyl or phenyl and is, for example, one of the groups trimethylsilyl, tris(tert.-butyl)silyl, dimethyl-(2,3-dimethyl-2-butyl)-silyl, diphenyl-tert.butylsilyl, bis(isopropyl)-methylsilyl, triphenylsilyl etc., and especially tert.-butyl-dimethylsilyl. The group may also be in etherified form as methyl ether, benzyl ether or methoxyethoxymethyl ether.

Compounds of the formula I in which R1 is a silyl group can be converted by simple, for 1)'i 4 example hydrolytic, removal of these functions into the highly active free 5-hydroxy derivatives (R 1 H) and are thus rather of the character of intermediates.

However, the biological value of these compounds is in principle not diminished by the protecting group.

The substituents R in the 13-position are always hydrogen in naturally occurring antibiotics S541 (R1 H or CH3; R 2 CH3, C 2

H

5 or isoC 3

H

7

R

3

OH).

An important group within the scope of formula I lo are those compounds in which SR is C 1

-C

1 0 -alkyl; RI is hydrogen or a methyl or silyl group; R2 is methyl, ethyl or isopropyl; and

R

3 is hydrogen or an OH group; wherein when R 3 is hydrogen a 22,23-double bond or -single bond is present and when R 3 is an OH group a o.o" 22,23-single bond is present.

o E The natural antibiotics S541 are known from DE-35 32 794 and DE-35 19 834. Their constitution is °o go as follows:

OH

SH

3 23 CH 3 I 022 CH3 o° 000 I 1 I T1 3 2 II

H

3 C 3 S1

CH

3 Ip r Hs o o 6Ri o Factor A R2=isoC 3 H7

R]=H

Factor B R2=CH 3 Ri=CH 3 Factor C R 2

=CH

3

R

1

=H

1 p 1_ 5 Factor D R 2

=C

2 5 Ri=H Factor E R 2

=C

2

H

5 R1 CH 3 Factor F R 2 =isoC 3

H

7

R

1

=CH

3 In the following, to simplify the naming, the derivatives of antibiotic S541 are classified in accordance with factor A, B, C, D, E, or F as derivatives S54iA, S541B, S541C, S541D, S541E and S541F.

The following sub-groups of compounds of the /0 formula I are preferred owing to their pronounced parasiticidal and insecticidal activity, there being especially preferred those in which R is C1-C 3 alkyl and R 1 is hydrogen: Group Ia: Compounds of the formula I in which R is

C

1

-C

1 0 -alkyl; R 1 is H, CH 3 or the group -Si(R 4

(R

5

(R

6 wherein R 4

R

5 and R6, independently of one another, 1° each represents C 1

-C

4 -alkyl, benzyl or phenyl; R 2 o is methyl, ethyl or isopropyl; and R 3 is hydrogen or an OH group; wherein when R 3 is hydrogen a 22,23- -o double bond or -single bond is present and when R 3 is an OH group a 22,23-single bond is present.

oo S0 Group Ib: Those compounds within sub-group Ia in which R is C -C 4 -alkyl; R 1 is hydrogen, CH 3 trimethylsilyl, tris(tert.-butyl)silyl, dimethyl(2,3-dimethyl-2butyl)-silyl, diphenyl-tert.-butylsilyl, bis(isopropyl)methylsilyl, triphenylsilyl or tert.-butyl-dimethyl- 0 silyl; R 2 is methyl, ethyl or isopropyl; and R 3 is an OH group.

0o0u00 Group Ic: Compounds of the formula I in which R is 0g C 1

-C

10 -alkyl; R1 is hydrogen; R 2 is methyl, ethyl or isopropyl; and R 3 is an OH group.

6 Group Id: Compounds of the formula I in which R is

C

1

-C

10 -alkyl; R1 is hydrogen; and R 2 is methyl, ethyl or isopropyl; and R3 is hydrogen, a 22,23-double or -single bond being present and, when R3 is an OH group, a 2 2,23-single bond being present. These are especially preferred.

Group Ie: Compounds of the formula I in which R is C1-C 6 -alkyl; R 1 is hydrogen; R 2 is methyl, ethyl or isopropyl; and R3 is hydrogen, a 22,23-double or -single bond being present and, when R3 is an OH group, a 22,23-single bond being present.

Group If: Compounds of the formula I in which R is C -C6-alkyl; R is hydrogen; R 2 is methyl, ethyl or isopropyl; and R3 is hydrogen, a 22,23-double bond being present.

SGroup Ig: Compounds of the formula I in which R is methyl, ethyl or n-propyl; R 1 is hydrogen or methyl; os eo R 2 is methyl, ethyl or isopropyl; and R3 is hydrogen, a 22,23-double bond being present.

00 00 o Group Ih: Compounds of the formula I as in sub-group o Ig, but in which R3 is hydrogen and a 22,23-single bond is present.

'Especially preferred individual substances of the formula I are, for example: 0 13B-methyl-antibiotic S541A 138-methyl-antibiotic S541B 0 136-n-propyl-antibiotic S541A 13B-ethyl-antibiotic S541A 13B-ethyl-antibiotic S541B 3o 13B-n-propyl-antibiotic S541B 13B-ethyl-antibiotic S541C -7 138-methyl-antibiotic S541C 138-ethyl-antibiotic S541D 138-methyl-antibiotic S541D 135-ethyl-antibiotic S541E 138-methyl--antibiotic S541E 138-ethyl-antibiotic S541F 1 3 -methyl-antibiotic S54 1F 138-methyl-23-deoxy-antibiotic S541A 138'D-ethyl-23-deoxy-antibiotic S541A /0 1 3 -methyl-23-deoxy-antibiotic S54 1F 1 3 -ethyl-23-deoxy-antibiotic S54 1? 1 3B-methyl-22,23-dehydro-23-deoxy-antibiotic S541A 1 36-ethyl-22 ,23-dehydro-23-deoxy-antibiotic S541 F.

The following are also especially preferred: 138-methyl-5-acetoxy-antibiotic S541A 1 3-methyl-5-acetoxy-antibiotic S541B 13 -eh l 5-c t x -n ibo i 5 1 136-methyl-5--acetoxy-antibiotic S541D 13 8-methyl-5-acetoxy-antibiotic S541ED r1 3 8-methyl-5-acetoxy--antibiotic S54 1FE The present invention relates not only to the compounds of formula I but also to the novel process for the preparation thereof. It has been found that the allyl esters of the formula II defined below, wherein the allylic OR 7 group is in the of the molecule, can be converted by reaction with trialkylaluminium compounds of the formula Al(R) 3 into compounds of formula I, such that the substituent R to be introduced occupies the 138-position of the go molecule stereospecifically and affords only small amounts of by-products which are substituted in the position and which can be removed from the desired end 1.

8 products by chromatographic methods. R 7 is acyl, for example: formyl, acetyl, benzoyl, ethoxycarbonyl or P(=O)(alkoxy) 2 such as P(=O)(OEt) 2 alkylsulphonyl, preferably lower alkylsulphonyl, especially mesyl, and, in certain cases, also tetrahydropyranyl, but may also be higher homologues thereof.

It has also been found that compounds of formula II containing a 13B-OR 7 group can also be converted into compounds of formula I while retaining the 138j0 orientation. The process according to the invention therefore makes it possible to introduce selectively an alkyl group R into the 138-position of derivatives of antibiotics S541 and so to obtain highly effective novel parasiticides and insecticides of the formula I which may also be used for the formation of further derivatives and have distinct advantages over the basic substance.

Accordingly, the present invention relates to a process for the preparation of compounds of formula I, a which process comprises treating an allyl ester of formula II o tr~ 01 00 a ~I o OB 0.

6Od

U

OH

16 *CH 3 17* 12: \R2 R H c H 3 0i1/ fl.

CH

3 RI1

(II)

wherein A is one of the groups a or b 9 3 3

R

7 0 H/ or (b) 138-ester-A14' 1 5 A13,14-15-ester]

R

7 is an acyl group, and R 1 and R2 are as defined for formula I, with a trialkylaluminium compound of 0000 c. formula III 0 4 9 000 o Al(R) 3

(III)

00 o 000 wherein R is as defined for formula I, and, if free o°o 5-hydroxy compounds are desired, subsequently removing o0' the silyl group R 1 by hydrolysis.

C The process is generally carried o t in an inert 0.0 solvent. Suitable solvents are, for example, ethers and ethereal compounds such as dialkyl ethers (diethyl ether, diisopropyl ether, tert.-butylmethyl ether, o dimethoxyethane, dioxane, tetrahydrofuran, anisole etc.); halogenated hydrocarbons such as chlorobenzene, methylene chloride, ethylene chloride, etc.; or sulphoxides such as dimethyl sulphoxide. Aromatic or aliphatic hydrocarbons such as benzene, toluene, xylenes, petroleum ether, ligroin, cyclohexane etc. may o0 also be present. It may be advantageous to carry out the reaction or partial steps thereof in a protective gas atmosphere (for example 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, for example by washing, digesting, extraction, recrystallisation, chromatography etc.

However, purification steps may be dispensed with and carried out only with the corresponding final products.

Trialkylaluminium compounds suitable for the /0 introduction of the 138-alkyl group are (C1-C10alkyl) 3 aluminium compounds, such as, for example, trimethylaluminium, triethylaluminium, triisobutylaluminium, trihexylaluminium etc. The reaction is generally carried out in a temperature range from -100 C to +100 C, preferably from -20 C to +600C.

S"o The trialkylaluminium compound of formula III is added o 0o in at least an equimolar amount, in substance or in an 00 0 inert solvent, such as, for example, hexane, toluene or benzene, to the solution of the compound of formula 0p II.

0 0 o 0 When the reaction is complete, the silyl 0o protecting group is conveniently removed by treating the compounds of formula I with a dilute acid, such as, 00\ for example, with 1% p-toluenesulphonic acid in methanol or with an aqueous HF solution in acetonitrile, in the temperature range from -20 0 C to +50 0 C, preferably from 0°C to +30 0 C, or with pyridinium fluoride in pyridine.

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

The starting esters of formula II can be prepared from the corresponding allyl alcohols of formula IV 11

OH

16 .CH 3 127 3* 0

H

3 C /H ,IH (IV) \C CHa

ARI

wherein A is one of the groups a or b

I

i 1 '3 H3 HO or 1A is H O, hH/ gz o 0 0 o. 13B-hydroxy-6 1 4 1 5 A13,14-15-hydroxy] R2 is as defined for formula I and R 1 is hydrogen 0" or a methyl, acyl or silyl group indicated in the definition of formula I; by customary methods of 'acylation known in the literature, such as, for example, by reaction with an acid chloride (R 7 COCl) or acid anhydride (R 7

CO)

2 0, wherein R 7 is as'defined for formula II, in the presence of a base (triethylamine, pyridine, N,N-dimethylaminopyridine etc.), in an inert solvent mentioned above, for example dichloromethane, chloroform etc., and in the temperature range 12 from -20 0 C to 100°C, preferably from 0°C to 0

C.

The compounds of formula IVb A13,14-15hydroxy] can be obtained from 14,15-epoxy compounds of formula V

OH

1H3 CH3 1 3 1 7* H*C HH H. i L I 0 5/6

(V)

0* H.

Ri from +20 to wh erein R and inert solvents ared for formula I, aromatic hydrocarbons such as benzene, toluene, xylene and petroleum ether; ethers such as diethyl) wherein tert.-butyl methyl ether, tetrahydrofuran, dioxane and anisole.

x and y areaction independentageously carried out in protective gas, such as nitrogen or argon.

Hydrazoic acid (HN 3 can also be converted, in the nasc nt state, into the [HN 3 1x/[Al(Et) 3 3y complex Sbetwey suspendi and 2, inum azide in the stipulated in the temperature range from -20° to +150°C, preferably from +20° to +80°C.

solvent or mixture of solvents are aliphgeneratinc and the saromatic hydrocarbons stronger as benzene, toluene, xylene and (preferably oleum ether; ethers such as diethyl ether, tert.-butyl methyl ether, tetrahydrofuran, dioxane and anisole.

The reaction is advantageously carried out in protective gas, such as nitrogen or argon.

.0 Hydrazoic acid (HN3) can also be converted, in the nasc-nt state, into the [HN3]x/[Al(Et)3]y complex by suspending sodium azide in the stipulated dry solvent or mixture of solvents and generating HN 3 in the solution with a stronger acid, for example H2SO.

(preferably oleum in order to ensure absolutely dry 13 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 in the solution or added thereto at a suitable point in time.

The starting compounds of formula V, which are employed for the preparation of compounds of formula IVb, can easily be prepared by epoxidation of the compounds known from DE-35 32 794 and are designated as o1 "Antibiotics S541 (factors A to of the following formula

VI

oaa 0 OH CH3 CH3 *0 0 \1 I S 1 3 17 0 00 15 I0/\2 S CH 3 H3 0. V I

,/CH

3 ORi 09 4 1' 0

A

Factor A R 2 =isoC 3

H

7

R,=H

Factor B R 2

=CH

3 R 1

=CH

3 d Factor C R 2

=CH

3 R =H Factor D R 2

=C

2

H

5

RI=H

Factor E R 2

=C

2

H

5

R=CH

3 Factor F

R

2 =isoC 3

H

7 RI=CH 3 The epoxidation is carried out in a solvent phase Ro in the temperature range from -100 to +20 0

C,

preferably from -50 to The epoxidation is carried out with peracids such as peracetic acid, trifluoroperacetic acid, perbenzoic 14 acid, chloroperbenzoic acid. Di- and tri-epoxides (as by-products) can be removed by chromatography.

The 138-hydroxy-A 1 4 15 compounds of formula IVa can be prepared by reacting compounds of formula IIb, wherein R I is a protecting group, with pyridinium dichromate (Pyr) 2 Cr20 7 This reaction is carried out in dimethylformamide and in the temperature range from approximately -100 to +60 0 C. If desired, the protecting group R 1 is subsequently removed by lo hydrolysis.

By selective acylation or silylation of the group, all those derivatives of formulae I to VI are .0o* prepared wherein R 1 has a meaning other than hydrogen I' or CH 3

(R

1 OH-protecting group). For the .silylation it is convenient to use a silane of the formula Y-Si(R 4

(R

5

(R

6 wherein each of R 4

R

5 and R 6 0" is one of the radicals indicated above and Y is a silyl leaving group. Examples of silyl leaving groups Y are o bromide, chloride, cyanide, azide, acetamide, trio o, o. 0o fluoroacetate or trifluoromethanesulphonate. This recitation constitutes no limitation; further typical silyl leaving groups are known to the skilled person.

are carried out in anhydrous medium, preferably in inert solvents and, most preferably, in aprotic solvents. The reaction advantageously takes place in the temperature range +80 C, preferably from +100 to +40 0 C. It is preferred to add an organic base. Examples of suitable organic bases are tertiary amines, such as triethylamine, tri- 3o ethylenediamine, triazole and, preferably, pyridine, imidazole or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

The removal of these silyl radicals Ri in the position is effected by selective mild hydrolysis H) with, for example, arylsulphonic acid in alcoholic solution or in accordance with another method 15 known to the skilled person.

The acylation (R 1 acyl) is advantageously carried out on one of the compounds of the formulae I to VI in which RI is hydrogen, with a corresponding acid halide, especially acid chloride, and is effected, for example, under analogous conditions to the silylation.

The 138-alkyl derivatives of antibiotics S541 of formula I in which R, R 1 and R2 have the meanings given above and R3 is an OH group can be converted analogously to the method disclosed in US-PS 4,328,335 into the corresponding 23-deoxy or 22,23-dehydro-23deoxy derivatives of the formula I. Here, those .o compounds of the formula I having a free 5-OH group

(R

1 must first of all be selectively protected by :o reaction with one of the above-mentioned silylation o a ll reagents Y-Si(R 4

)(R

5

)(R

6 or with tert.-butyldimethylsilyloxyacetyl chloride. The reaction of these protected compounds of the formula I in which S go RI=Si(R4) (Rg) or C(=O)CH 2 Si (CH)2t-CH 9 and R 3

=OH

with p-methylphenylchlorothionoformate yields o0 .derivatives of the formula I in which R 3 represents O-C(=S)-OC6H4-CH 3 These 23-0-(4-methylphenoxy)thiocarbonyl derivatives of antibiotics S541 are then 0, used as starting materials for reduction with tributyltin hydride in toluene in the presence of azobisisobutyronitrile at 80-120 0 C to form the 23deoxy derivatives of the formula I (RI=H) or for the thermolysis (150-250 0 C) to form the 22,23-dehydro-23deoxy derivatives of the formula I (RI=H, 22,23double bond).

The preparation of compounds of the formula I wherein R3 is an OH group can also be carried out according to the invention in accordance with the following reaction scheme: 16 Antibiotic S541A MnO 2 Oxidation of the group to the 5-keto group derivative of the formula XV 1) SeO 2

/HCOOH

2) H introduction of the 13-OH group 0taI ar 'd *It- 0000* o 0 13-Hydroxy-5-keto derivative of the formula XII C1COOC 2

H

5 introduction of the 13-

OCOOC

2

H

5 group 10 13-Ethoxycarbonyloxy-5-keto derivative of the formula

XIV

NaBH 4 reduction of the group to the 5-OH group 13-Ethoxycarbonyloxy-5-hydroxy derivative of the formula X (alkyl) 3 Al introduction of an alkyl group into the 13-position 13-Alkyl-antibiotics S541A of the formula I wherein R 3 represents OH.

The preparation of compounds of the formula I wherein R 3 represents OH is accordingly also carried out in accordance with the invention by reacting an antibiotic S541A derivative of the formula X i 17

OH

S H3 6 *3 ,CH3 22 G

C

S/32/ Si It 6 \CH CH3)2 C \H 3 cH l wherein R20 is C 1

-C

4 -alkyl, with a compound of the t 'n formula XI ti t I 3 A (XI) wherein R has the meanings given under formula I.

The reaction of compounds of the formula X with the compounds of the formula XI is normally performed in the atmosphere of an inert gas such as, for example, nitrogen or argon, and in the presence of at least one /o anhydrous solvent. Such solvents include, for example, halogenated hydrocarbons such as methylene chloride, S..o chloroform and dichloroethane, aromatic hydrocarbons such as benzene and toluene, aliphatic hydrocarbons such as n-hexane and n-heptane, and ethers such as tetrahydrofuran and dimethoxyethane.

Normally, the reaction is performed by slowly adding the trialkylaluminium (XI) dropwise at a low temperature and is then completed by elevating the temperature gradually to a temperature in a range of 2o from -78 0 C to 50 0 C, preferably from -50°C to 250C, over a period of from 0.5 to 24 hours, usually from 2 to 4 hours.

7--r 18 0 0 0 ~0 O 0 The'starting material of the formula X may be prepared by reacting a 13-hydroxy-5-keto--antibiotic S541A derivative of the formula XII

OH

YH3~~ 16*\-CH 3 HO LT3 0 /22 NI /6 ~CH( CH 3 z II

,H

CH

3 with a carbonate of the formula XIII

R

20 0COOH (XII wherein R 20 is as defined above, or with a reactive derivative thereof, to give a 13-alkoxycarbonyloxy-5keto-antibiotic 'S541A derivative of the formula XIV I

OH

2 3 R aOO CO /H3 16 0 CH 3 0 4 3 2' %IC \/CH(CH 3 2 Al CH3

(XIV)I

-n*lr~p~c9 19 wherein R20 is as defined above, and then reducing the compound of the formula XIV to give a compound of the formula X.

The reaction of compounds of the formula XII with carbonates of the formula XIII is a customary esterification, which can be carried out according to methods known per se. The reactive derivatives of compounds of the formula XIII include, for example, the corresponding acid chlorides, acid anhydrides, mixed acid anhydrides and active esters, of which ethyl chloro- 0.o formate is preferred.

o The reaction is normally performed in an inert o solvent in the presence of an acid-binding agent.

0 0 Preferred solvents include, for example, halogenated S hydrocarbons such as carbon tetrachloride, chloroform, K" methylene chloride and dichloroethane, aromatic hydrocarbons such as benzene and toluene, and ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane.

0 Preferred acid-binding agents include, for Ro example, organic amines such as pyridine, 4-dimethylaminopyridine, triethylamine, tri-n-butylamine and o *3 tert.-octylamine.

Normally, the reaction is performed at a temperature in a range of from -20 0 C to 80 0

C,

O0 Io, preferably 0°C to 20 0 C, over a period of from o..ooo minutes to 24 hours, usually from 30 minutes to 3 hours.

The reduction of compounds of the formula XIV to compounds of the formula X may be performed in g0 principle by any reducing methods known per se.

However, it is necessary not to damage other parts of the molecule besides the 5-position at which the reduction takes place, and hence reduction by anionic hydrogen is preferred. Reducing agents that liberate anionic hydrogen include, for example, sodium 20 borohydride and diborane.

The reduction is normally performed in an inert solvent such as, for example, methanol, ethanol, diethyl ether, tetrahydrofuran or benzene at a temperature in a range of from 0°C to 20 0 C over a period of from 10 minutes to 3 hours.

The alkyl group R 2 0 includes, for example, methyl, ethyl, propyl and butyl, and it is preferably the ethyl group.

)o The 13-OH-5-keto-antibiotics S541A of the formula XII can be prepared from the 5-keto-antibiotic S541A of o the formula XV

OH

H3C CH 3 S/ U 0\ 22 1 3 CH3 32 lei 6 CH(CH3)2 (XV) 0DI 3 1 I II l CH 3 b t from which they are derived by reacting the compounds of the formula XV with selenium dioxide in the presence of an acid of the formula XVI

R

2 1 -COOH (XVI) wherein R 2 1 is hydrogen or C 1

-C

4 -alkyl.

This reaction is an oxidation of the allyl-type configuration around the 13-position of the antibiotic S541A and is effected by reacting the compound of formula XV with selenium dioxide in the presence of the 21 acid XVI. Where R21 in XVI is a C 1

-C

4 -alkyl group, it may be any one of the straight or branched

C

1

-C

4 -alkyl chains. The acid of formula XVI is preferably formic acid or acetic acid, but especially formic acid. It is preferable to employ at least one mole of the acid XVI per mole of the 5-keto compound of formula XV, especially more than one mole of the acid per mole of the 5-keto compound. The acid may be employed in significant excess and act simultaneously to as the reaction medium, and this procedure is in fact preferred.

a Where a solvent other than the acid is employed, the nature of such a solvent is not critical, provided that it has no adverse effect upon the reaction.

Examples of such solvents include, for example, r hydrocarbons, preferably aliphatic and aromatic hydrocarbons, such as hexane or benzene; halohydrocarbons, preferably aliphatic halohydrocarbons, such as methylene chloride or chloroform; ethers, such as S a 0 diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol or ethanol; esters, such as ethyl f acetate or phenyl acetate; amides, such as dimethylformamide or dimethylacetamide; dimethyl sulphoxide; water; and mixtures of any two or more of these solvents.

The amount of selenium dioxide used is preferably from 1 to 10 moles, especially from 1 to 3 moles, per mole of the 5-keto compound of formula XV.

There is no particular limitation on the reaction o3 temperature since the reaction will take place over a wide range of temperatures. Conveniently the reaction is carried out at a temperature of from 0 to 80 0

C,

preferably at room temperature or with gentle heating.

At such temperatures, the time required for the reaction will normally be within the range of from 22 minutes to 1 day.

The 5-keto compounds of the formula XV may be prepared from the antibiotics S541A in a simple manner by oxidation, for example with manganese dioxide or other conventional oxidising agents, using conventional oxidising methods.

to The starting materials of the formulae XI, XIII and XVI are known or can be prepared analogously to their known representatives.

The intermediates of the formulae X, XII, XIV and XV are in view of their specific structure predestined for use for the preparation of the highly active Ssubstances of the formula I. They, too, exhibit para- Ssiticidal activity and form part of the present invention.

The described process for the preparation of compounds of the formula I constitutes in all its :04 partial steps a part of the present invention.

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

o 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 (for example the Haematopinidae family); and of the order Diptera, especially pests of the families Muscidae, Calliphoridae, Oestridae, Tabanidae, Hippoboscidae and Gastrophilidae.

The compounds of formula I can also be used against hygiene pests especially of the order Diptera 23 0 09 o 00 0 0 0 00 o 0 o 000 o 00 0 9 0 0 00 0 0 0 00 44 0 0

O

(families Sarcophagidae, Anophilidae and Culicidae); of the order Orthoptera, of the order Dictyoptera (for example the Blattidae family), and of the order Hymenoptera (for example the Formicidae family).

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 10 Panonychus spp.).

They also have a high degree of activity against sucking insects of the order Homoptera, especially against pests of the families Aphididae, Delphacidae, Cicadellidae, Psyllidae, Loccidae, Diaspididae and Eriophydidae (for example 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.

o The compounds of formula I are also suitable as insecticides for use against soil pests.

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, Radopholus, Rhizoglyphus and others.

The compounds of formula I are especially effective 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, 24 guinea pigs, cage-birds. Typical nematodes having this indication are: Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. The particular advantage of the compounds of formula I is their activity against those parasites which are resistant to benzimidazoleo0 based active substances.

Certain species of the genera Nematodirus, Cooperia and Oesophagostomum attack the intestinal tract of the host animal, whereas others of the species I Haemonchus and Ostertagia parasiticise 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, for example in the heart, blood 0 vessels, lymph vessels and in subcutaneous tissue. In go this connection, particular mention is to be made of S, the dog heartworm, Dirofilaria immitis. The compounds of formula I are highly effective against these parasites.

Bo The compounds of formula I are also suitable for controlling pathogenic parasites in humans, among which parasites there may be mentioned as typical represen- Statives occuring in the alimentary tract those of the species Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris and Enterobius. The 3o 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 -71 25 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, for example to emulsion concentrates, directly sprayable or dilutable s lutions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, and also encapsulations in, for example, polymer substances. As with the nature of )0 the compositions, the methods of application, such as spraying, atomising, dusting, scattering or pouring, i are chosen in accordance with the intended objectives and the prevailing circumstances.

It ,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.

The formulations, i.e. the compositions, preparations or formulations containing the active ingredient of formula I are prepared in known manner, for example by homogeneously mixing and/or grinding the active ingredients with extenders, such as, for example, 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, such as, for example, xylene mixtures or substituted naphthalenes, phthalates such as dibutyl 3~ phthalate or dioctyl phthalate, aliphatic hydrocarbons such as cyclohexane, or paraffins, alcohols and glycols and their ethers and esters, such as ethanol, ethylene glycol, ethylene glycol monomethyl or monoethyl ether, ketones such as cyclohexanone, strongly polar solvents such as N-methyl-2-pyrrolidone, 26 dimethyl sulphoxide 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, for example for dusts and dispersible powders, are normally natural powdered minerals such as calcite, talcum, kaolin, 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.

lo Suitable granulated adsorptive carriers are porous types such as, for example, pumice, broken brick, 4.9 sepiolite or bentonite; and suitable nonsorbent carriers are materials such as calcite or sand. In addition, a great number of pregranulated materials of Sinorganic or organic nature can be used, such as especially dolomite or pulverised plant residues.

Depending on the nature of the active ingredien: to be formulated, suitable surface-active compounds are nonionic, cationic and/or anionic surfactants having .o good emulsifying, dispersing and wetting properties.

a, The term "surfactants" will also be understood as comprising mixtures of surfactants.

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

Suitable soaps are the alkali metal salts, alkaline earth metal salts or unsubstituted or substitituted ammonium salts of higher fatty acids CIO-C22), such as, for e.ample, the sodium or potassium salts of *o oleic or stearic acid, or of natural fatty acid mixtures which can be obtained, for example, 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 sulphonates, c 27 fatty sulphates, sulphonated benzimidazole derivatives or alkylarylsulphonates.

The fatty sulphonates or sulphates are usually in the form of alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts and contain a C 8

-C

2 2 -alkyl radical which also includes the alkyl moiety of acyl radicals, for example the sodium or calcium salt of lignosulphonic acid, of dodecylsulphates, or of a mixture of fatty alcohol oo lo sulphates obtained from natural fatty acids. These compounds also comprise the salts of sulphuric acid esters and sulphonic acids of fatty alcohol/ethylene oxide adducts. The sulphonated benzimidazole derivatives contain preferably 2 sulphonic acid groups o, and one fatty acid radical containing 8 to 22 carbon atoms. Examples of alkylarylsulphonates are the sodium, calcium or triethanolamine salts of dodecylo3. benzenesulphonic acid, dibutylnaphthalenesulphonic acid, or of a naphthalene3ulphonic acid/formaldehyde go condensation product.

o Also suitable are corresponding phosphates, such as, for example, salts of the phosphoric acid ester of an adduct of p-nonylphenol-(4-14)-ethylene oxide, or oo phospholiphids.

The surfactants customarily employed in the art of formulation are described, inter alia, in the following publications: "McCutcheon's Detergents and Emulsifiers Annual", MC Publishing Corp., Ridgewood, New Jersey, 1982.

So The pesticidal compositions usually contain 0.01 to 95%, especially 0.1 to 80%, of active ingredient of formula I, 5 to 99.99% of a solid or liquid adjuvant, and 0 to 25%, especially 0.1 to 25%, of a surfactant.

Whereas commercial products are preferably formulated as concentrates, the end user will normally V- 28 employ dilute formulations having a concentration of 1-10,000 ppm of active ingredient.

The present invention therefore also relates to pesticidal compositions which contain as at least one active ingredient a compound of formula I, together with customary carriers and/or dispersing agents.

The compositions may also contain further adjuvants, such as stabilisers, antifoams, viscosity regulators, binders, tackifiers as well as fertilisers I0 or other active ingredients for obtaining special o. effects.

0 0 Preparation Examples Preparation of starting materials and intermediates Unless specifically mentioned, in the following o methods of preparation the reactants are used in equimolar amounts. As a rule, the macrocyclic reactant is taken first and the other reactant is added in portions in an equimolar amount or in slight excess.

Example Al: Preparation of 14,15-epoxy-antibiotic S541A 00 9o A solution of m-chloroperbenzoic acid in o dichloroethane is added, while cooling with ice, to a solution of antibiotic S541A (factor A) in dichloromethane. After stirring for one hour at room temperature, extraction is carried out between dichloromethane and 5 aqueous NaHCO 3 solution.

Chromatography of the crude product on silica gel yields 14,15-epoxy-antibiotic S541A.

m 29 Example A2: Preparation of silyl-14,15-epoxy-"antibiotic S541A *9#t 9 0 0490 4, 0 4at 0E .94 9 9 It, 9 991 I S S 4 004 4:000: A solution of 14,15-epoxy-antibiotic S541A, tert.butyldimethyichiorosilane and imidazole in dimethylformamide (DMF) is stirred for 2 hours at room temperature. Subsequently, diethyl ether is added and the mixture is filtered over silica gel. After concentration, 5-0-tert.-butyldimethylsilyl-14,15epoxy-antibiotic S541A is obtained, which is purified to by column chromatography.

Example A3: Preparation of silyl-15-hydroxy-LA) 3 14 antibiotic S541A A solution of HN 3 /Et 3 Al complex reagent (prepared from Et3Al and HN 3 in tetrahydrofuran) is added under argon to a solution of silyl-14,15-epoxy-antibiotic S541A in tetrahydrofuran and the mixture is heated under reflux for 12 hours.

Diethyl ether, methanol and Na 2

SO

44 1OH 2 0 are then added at room temperature.

The mixture is f4iltered and concentrated and chromatography of the crude product on silica gel yields 5-0-tert.-butyldimethylsilyl-15-hydroxy-AI 3 14 antibiotic S541A.

Example A4: Preparation of 13 14 antibiotic S541A A solution of 5-0-tert.-butyldimethylsilyl-15hydroxy-A] 3 14 -antibiotic S541A in acetic anhydride and pyridine is stirred at room temperatue for hours. Working up in diethyl ether with 5 aqueous NaHCO 3 solution and one molar HCl and filtration through silica gel yields 13 ,1_atiioi S541A.

30 Preparation of the final products Example H1: Preparation of silyl-13-methyl-antibiotic S541A A 17% solution of trimethylaluminium in toluene is added dropwise to 0°C under argon, while stirring, to a solution of 5-0-tert.-butyldimethylsilyl-15-acetoxy-

A

13 14 -antibiotic S541A in dichloromethane. The solution is stirred for 2 hours at room temperature, then diluted with diethyl ether and stirred with to celite. Filtration through silica gel yields t butyldimethylsilyl-138-methyl-antibiotic S541A.

i I "Example H2: a) Preparation of 138-methyl-antibiotic S541A A solution of 5-0-tert.-butyldimethylsilyl-138methyl-antibiotic S541A in dichloromethane is stirred together with a 40 aqueous solution of HF in acetonitrile (5:95) for 1 hour at room temperature. The mixture is taken up in diethyl ether, washed with .o dilute aqueous NaHCO 3 solution and water, dried with Do MgSO 4 and filtered through silica gel. Chromatography on silica gel yields 138-methyl-antibiotic S541A.

1 H. -NMR (270 MHz; CDC13; TMS): 3.75 1H, H in 25 position; J 10.9 Hz), 3.95 1H, H in 6-position; J 6.4 Hz), 4.28 (broad s, 1H, H in 5.05 (dd, 1H, H in 15-position; J 10.0 Pz, 5 Hz).

Mass spectrum 626 608, 590, 480, 151.

b) Preparation of 138-ethyl-antibiotic S541A The 13B-ethyl compound is obtained analogously to SO the preparation of the 133-methyl compound of Example H2a.

L, c 0 31 1 H-NMR (270 MHz; CDC1 3

TMS):

3.59 1H, OH in 23-position; J 10.1 Hz), 3.75 IH, H in 25-position; J =10.9 Hz), 3.95 1H, H in 6-position; J 6.4 Hz), 4.29 1H, H in 5-position; J3 6.4 Hz), 5.03 (dd, 1H, H in 15-position; 3 11.3 Hz, 4.4 Hz).

Mass spectrum 640 622, 604, 586, 494, 382, 342, 151.

Example H3: Preparation of 0 o silyl- 1 3-methyl-23-0- (4-methylphenoxy) thiocarbonyl-antibiotic S541A p-Methylphenylchlorothionoformate is added to a solution of 5-0-tert.-butyldimethylsilyl-13B-methylantibiotic S541A in pyridine at 0 0 C under argon.

After stirring for 5 hours at room temperature, the mixture is taken up in diethyl ether, washed with water 0 and dried with MgSO 4 Chromatography on silica gel yields 5-0-tert.-butyldimethylsilyl-13B-methyl-23-0- (4-methylphenoxy)-thiocarbonyl-antibiotic S541A.

91 Example H4: Preparation of zoo silyl-1 36-methyl-23-deoxy-antibiotic 0 S541lA A solution of tributyltin hydride in toluene is added to a solution of 1 36-methyl-23-0- -methylphenoxy) -thiocarbonylantibiotic S541A and azobisisobutyronitrile in toluene at 120 0 C under argon. After 60 minutes, the solvent is evaporated off and the crude product is chromatographed on silica gel. Ssilyl-13B-methyl-23-deoxy-antibiotic S541A is obtained.

ILI- I 32 Example H5: Preparation of 131-methy>--23-deoxyantibiotic S541A A solution of 5-O-tert.-butyldimethylsilyl-13amethyl-23-deoxy-antibiotic S541A in dichioromethane is stirred together with a 40% aqueous solution of HF in acetonitrile (5:95) for 1 hour at room temperature. The mixture is worked up in diethyl ether as described in Example H2 and filtered through silica gel.

Chromatography on silica gel yields 13B-methylto 1 antibiotic S541A.

0 0 Example H6: Preparation of o ~silyl-] 3B-methyl-22, 23-dehydro-23-deoxyantibiotic S541A A solution of 5-O--tert.-butyldimethylsilyl-136methyl-23-O- (4 '-methylphenoxy) -thiocarbonyl-antibiotic S541A in 1,2,4-trichlorobenzene is heated for 2 hours at 200 0 C under argon. Chromatography of the crude 00 product on silica gel yields silyl-22,23-dehydro-23-deoxy-antibiotic S541A.

n~Example H7: Preparation of 13B-methyl--22,23-dehydrodeoxy-antibiotic S541A solution of 5-O-tert.-butyldimethylsilyl-13amethyl-A 2 2 -2-deoxy-antibiotic S541A in dichloromethane is stirred for 1 hour at room temperature together with a 40% aqueous solution of HF in acetonitrile The mixture is worked up in diethyl ether as described in Example H2 and filtered through silica gel. Chromatography on silica gel yields 1 3 -nethyl-22 ,23-dehydro-23-deoxy-antibiotic S54 1A.

33

II

I I I

((I

I

*t t 40 0 0 4* 04S004 Example H8: Preparation of 138-methyl-5-acetoxyantibiotic S541A A solution of 133-methyl-antibiotic S541A in pyridine/methylene chloride is cooled to 0 C and then acetyl chloride is added dropwise thereto over a period of 2 hours. After stirring for a further 2 hours at 0°C, the solvents and excess acetyl chloride are removed in vacuo and the oily residue is purified by column chromatography on silica gel. 138- (O methyl-5-acetoxy-antibiotic S541A is obtained.

H-NMR (270 MHz; CDCl 3

TMS):

3.59 1H, OH in 23-position; J 10.1 Hz), 3.74 1H, H in 25-position; J 10.9 Hz), 4.05 1H, H in 6-position; J 5.6 Hz), 5.05 (dd, 1H, H in 15-position; J 11.3 Hz, 4.0 Hz).

Mass spectrum 682 664, 590, 572, 480, 151, Example H9: Preparation of 5-keto-antibiotic S541A 0.64 g of activated manganese are added to a 9o solution of 61.2 mg of antibiotic S541A in 5 ml of acetone. The mixture is then stirred vigorously for minutes at room temperature. The mixture is subsequently filtered over celite and the filtrate is concentrated by evaporation to give 59.3 mg of the title substance as a crude product.

H-NMR (270 MHz; CDCl 3

TMS):

3.78 1H, OH in 7-position), 3.84 1H, H in 6-position).

Mass spectrum 610, 592, 574.

34 Example 10: Preparation of 13-hydroxy-5-ketoantibiotic S541A 13 mg of selenium dioxide are added to a solution of all of the crude product obtained in H9 in 3 ml of formic acid. The mixture is then stirred at room temperature for 1.5 hours and filtered over celite to remove the selenium dioxide. The filtrate is poured into water and extracted with ethyl acetate. The dried exract is concentrated by evaporation and the residue lo is mixed with 2 ml of methanol, 3 ml of dioxane and 1 ml of 2N hydrochloric acid, then the mixture is stirred overnight at room temperature. This reaction *mixture is again poured into water and extracted with ethyl acetate. The extract is dried over magnesium o sulphate and concentrated by evaporation. The residue is purified by preparative thin layer chromatography (Merck Art 5715, 20 cm x 20 cm, thickness 2 mm), eluted 1* with a 1:1 mixture of hexane and ethyl acetate, to give 13.2 mg (21.7% yield) of the title substance.

04 S *o ao H-NMR (270 MHz; CDC1 3

D

2 0; TMS): 3.73 1H, H in 13 position; J=9.7 Hz), 3.75 1H, H in 25-position; J=10.5 Hz), r.o 3.84 1H, H in 6-position).

o 0*0 o Mass spectrum 626 (M 608, 590, 349, 331, 259, 242, 179.

Example H11: Preparation of 13-ethoxycarbonyloxy-5keto-antibiotic S541A 58 ul of pyridine and 35 ul of ethyl chloroformate are added, with ice-cooling, to a solution of 76 mg of 13-hydroxy-5-keto-antibiotic S541A in a mixture of methylene chloride and tetrahydrofuran (2 ml 1ml).

The mixture is then stirred at room temperature for 4 i 35 hours, poured into ice-water and extracted with ethyl acetate. The extract is washed, in turn, with water and with a saturated aqueous solution of sodium chloride and dried over magnesium sulphate. The solvent is then distilled off to give 93 mg of the title substance as a crude product.

Example H12: Preparation of 13-ethoxycarbonyloxyantibiotic S541A All of the crude product obtained according to H11 1O is dissolved in 2 ml of methanol. 2.5 mg of sodium .o borohydride are added, with ice-cooling, to the o solution and the mixture is stirred for 15 minutes at the same temperature. The reaction mixture is poured into ice-water and extracted with ethyl acetate. The extract is washed, in turn, with water and with a saturated aqueous solution of sodium chloride and dried over sodium sulphate. The solvent is distilled off and the residue is purified by column chromatography (silica gel) to give 55 mg (65% yield) of the title 0 oo substance.

1 H-NMR (270 MHz; CDCl 3

TMS);

3.48 1H, OH in 23-position; J=10.1 Hz), 3.72 H in 25-position; J=10.9 Hz), 3.96 1H, H in 6-position; J=6.0 Hz), 4.19 2H, Me-CH 2

-OCOO-),

4.32 1H, H in 4.73 1H, H in 13-position; J=10.5 Hz).

Example H13: Preparation of 13-methyl-antibiotic S541A 5.7 ml of 19% trimethylaluminium in hexane are added, with ice-cooling, to a solution of 30 mg of 13ethoxycarbonyloxy-antibiotic S541A in 0.5 ml of ~r;nx 36 methylene chloride and the mixture is stirred at room temperature for 4 hours. The mixture is then poured into ice-water and, after the addition of 10 ml of ethyl acetate, filtered over celite. The celite is washed with 50 ml of ethyl acetate and, after separation of the phases, the aqueous phase is extracted with ethyl acetate. The filtrate and the acetate washing are combined and washed, in turn, with water and with a saturated aqueous solution of sodium 0, I chloride and dried over sodium sulphate. The solvent is removed and the residue is purified by column chromatography on silica gel to give 17 mg (63% yield) of the title substance.

4 1 H-NMR (270 MHz; CDC13; TMS): 3.75 1H, H in 25-position; J=10.9 Hz), 3.95 1H, H in 6-position; J=6.4 Hz), 4.28 (broad s, 1H, H in 5.05 (dd, 1H, H in 15-position; J=10.0 Hz, 5 Hz).

Mass spectrum 626 608, 590, 480, 151.

O Example H14: Preparation of 13-ethyl-antibiotic S541A S0.8 ml of 15% triethylaluminium in hexane is ,added, with ice-cooling, to a solution of 20 mg of 13-ethoxycarbonyloxy-antibiotic S541A in 0.5 ml of methylene chloride and the reaction mixture is stirred at room temperature for 4.5 hours. The reaction mixture is worked up in the same manner as in H13 to give 4.6 mg (25% yield) of the title substance and, as by-product, 1.4 mg yield) of 15-ethyl-A 13 14 antibiotic S541A.

37 13-Ethyl compound: o 4 4 o pr P dI a p p 1r @4 4oar o 1 H-NMR (270 MHz; CDC1 3

TMS):

3.59 1H, OH in 23-position; J=10.1 Hz), 3.75 1H, H in 25-position; J=10.9 Hz), 3.95 1H, H in 6-position; J=6.4 Hz), 4.29 1H, H in 5-position; J=6.4 Hz), 5.03 (dd, 1H, H in 15-position, J=11.3 Hz, 4.4 Hz).

Mass spectrum 640 622, 604, 586, 494, 382, 342, 151 [0 15-Ethyl compound: 1 H-NMR (270 MHz; CDC1 3

TMS):

3.58 1H, OH in 23-position, J=9.7 Hz), 4.02 1H, H in 6-position, J=6.5 Hz), 4.92 1H, H in 13-position, J=9.7 Hz).

Mass spectrum 640 622, 604, 494, 476, 378.

The following compounds of the formula I also are prepared analogously to the described methods, but the Tables that follow do not imply any limitation: c- 38- Table

I-

formula I group.

Typical representatives of compounds of the in which Ris hydrogen and R3is an OH Comp. No.(I R 2

IR

0000 0000 o oo 00 0 0000 0 0 000 0 00 0 0 0 000 0 00 o ott 00 0 0 0 Ott 0 00 0 0 0 0 00 0 000 0 0 0,0004 0 0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1 .20 1.21 1.22 1.23 1. 24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 CH3

CH

3 OH 3

CH

3

CH

3 CH 3

CH

3

CH

3

CH

3

CH

3 C3 Cl' 3

CH

3

C

2 H5 C 2 H 5

C

2 H5 0 21H 5 C~ H1 5 C2H~s C 2

H

5

C

2 H5 0 3 H1 7 i 1So0

C

3

H

7 -iso

C

3

H

7 -iSO 0 311 H1 0i 03 H 7 -iso

C

3

H

7 -iSO

C

3

H

7 -iSO

C

3

H

7 -iSO

C

3

H

7 -iSO O 2

H

5

CH

3 03 H 7 -n

C

3

H

7 -iSO Ci4H 9 -n Cil11 9 -sec C H9-i so C5H 1 1-n C 6111 3 -n

C

7

H

1 5 -n

CBH

1 7 -n C9Hi B-f

C

1 oH2 1-n

CH

3

C

3 11 7 -iSO C 411 9fl C0 4 9 -sec C4H9-iso C5 1 1-n C 611 3-fl 0113 C3H 7 -n C0 3 11 7 iS0 O 4H 9 -n C4H 9 C0 4 9 -iso C 6111 3 -n CsHi I-n C3H 7 -n 39 Table 2 Typical formula I in which and a 22,23-double representatives of compounds of the Ri is hydrogen, R 3 is hydrogen bond is present.

Comp._No.j R 2

R:

0000 0 000* 00 0 0 0 0000 00 000 0 00 0 0 000 1 00 00 000 00 o 0 0 **o 0 00 0 0 0 0 00 0 0 0 0*0 0 .00 000 0 0 2.1 2.2 2.3 2.4 2.6 2.7 2.8 2.9 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 2.28 2.29 2.30 2.31

CH

3

CH

3

OH?~

CH

3 0113

OH

3

CH

3 011 3 CH13 0113

CH

3

CH

3 C3

C

2 Hs 02Hj 0 2 Hs

C

2 Hs 0 2

H

5 02115 C2H5 O 2

H

5

C

3

H

7 -iSO

C

3

H

7 -iSO C3H7-iGa 0317-iso

C

3

H

7 -iSO 0317-iso

C

3 1 7 -iso 0317-iso 0317-iso

C

2

H

5 OH3 0215 03117-n 03117-J.SO 04119-fl

C

4 1 9 -sec C4119-iSO 0 sH 1 -n

C

6

H

1 3-nl 07113 08111 7-n 09111 8-n C, oH2 1-n

OH

3 02115 0317-iSO 04119-l C0 9 -sec 04119-iSO C5HI~ jjf 06111 3f

OH

3 02115 03117-fl 0317-iSO 04119-n

C

4 19-Se c C4119-iso 06111 3fl C5H1 1-n 03117-fl Table 3 Typical formula I in which and a 22,23--single representatives of compounds of Ris hydrogen, R 3 is hydrogen bond is present.

Cm.No.1_R 2

R

'ow.

6*4t or 6 4 6 'If, 6$

I

I',

I,

144 .4 a S o 0 004 too 0.4,4, 3.1 3.2 3.3 3.4 3.6 3.7 3.8 3.9 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 3.22 3.23 3.24 3.25 3.26 3.27 3.28 3.29 3.30 3.31 0H13 C11 3 C11 3 C11 3

OH

3 011 3 0113

CH

3

CH

3 Gil 3

CH

3

CH

3 C11 3

C

2 1-1 0 21If5

C

2 H5

C

2

HS

C2Hs C 2 If 5 C 2 If 0 2 Hs

C

3

H

7 -iSO 03117 iso

C

3 1 7 -iSO

C

3 H7-iso

C

3

H

7 -iSO

C

3 11 7 -iSO

C

3 11 7 -iSO

C

3

H-

7 -iSO 0317-iso 0 2

H

5 0113 0 2 1-15 0 3117-fl C3H 7 -iSO

C

4 1-19-fl

C

4 9 -sec O i411 9 -iso

C

5 Hi 1 i-n C61 113-fl C71-11 COHi 7fl 09111 B-fl

C

1 oH 1 -n~f 0113 C 2 1 C317-iSO 0 4 1-19fl C41- 9 -sec 0 4 119-iso Os 8 -1 1- C61H1 3fl 0113 02115 03117--n 0317-iso 014 119-n C411 9 -sec 014119-iso C061113 3fl C5Hi rfl C3l17-fl 41 Table 4 formula I OH group.

Typical representatives of compounds of the in which RIis a silyl group and R 3 is an *Comp. No. I R 2

JR

0449 44*4 #0 0 4 *404 '4 I 4 4 (04 4 44 4* 0 544 4 494 o *0 o 0 9 o *0 0 0 0 04* 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 C11 3

CH

3

CH

3 CH3

CH

3 0H13 CH3 C2H5

C

3

H

7 -iSO C3H 7 -iSO

C

2 H5

C

2 H5 C 3 11H 7iSO

CH

3 0113

CH

3

OH

3

CH

3 CH 3

C

2 Hs C 3 11 7 -n

C

3

H

7 -iSO Ci 4

H

9 -sec

C

4 H-tert CH 3 0113

CH

3 0 2115

C

3

H

7 -iSO C2H5

CH

3

CH

3 0113

CH

3

CH

3 tert. -Butyldimethylsilyl tert. -Butyldimethylsilyl tert. -Butyldimethylsilyl tert. -Butyldimethylsilyl tert. -Butyldimethylsilyl tert,-Butyldimethylsilyl tert Butyldimethylsilyl tert Butyldimethylsilyl tert.-Butyldirnethylsilyl tert Butyld~methylsilyl tert. -Butyldirnethylsilyl tert.-Butyldimethylsilyl tert.-Butyldimethylsilyl Trimethylsilyl tris( tert.-Butyl) silyl Diphenyl-tert butylsilyl bis(Isopropyl)methylsilyl Triphenylsilyl 0 0 o 000 4 4*4009 0 4 42 Table 5 which

RI

Typical representatives of the formula I in is an acyl group and R 3 is an OH group.

iii, I 'i I I tIll It

II

Itt

II

o 0 I o Pt 0 0 I $00 I, 000 O:.00: Comp. No. RR2I 5.1 CH 3 C11 3

GOCH

3 5.2 CH 3

CH

3

COGH

2 Cl 5.3 CH 3 C11 3

COCH

2 Br 5.4 CH 3

OH

3 COCHBrF 5.5 CH 3

CH

3

COCH

2

F

5.6 CH 3

CH

3 COCH2OCI1 3 5.7 CH 3

OH

3

COCH

2

OSCH

3 5.8 CH 3

CH

3

COCH

2

OCOCH

3 5.9 CH 3

CH

3

COCHFOCOCH

3 5.10 OH 3

CH

3 COCH20COC 2

H

5.11 OH 3

CH

3

COCH

2

OCOC

6 H4F(3) 5.12 CH 3 cH 3

GOI

2

OCC

6 114Cl(3) 5.13 CH 3

CH

3

COCH

2

OCOC

6 H4OCH 3 (3) 5.14 OH 3

OH

3

COGH

2 0C00 6

H

3 Cl 2 (2,4) 5.15 C 2 H5 OH 3

COCH

3 5.16 C 2

H

5 GH3 COCH 2

OCH

3 5.17 C 2

H

5

OH

3

COGH

2

OCOC

6

H

5.18 C11 3

G

2 HS GOGH 3 5.19 G11 3

G

2 Hs COCH2OGH 3 5.20 0113 C3H 7 -iSO GOGH 3 5.21 OH 3

C

3

H

7 -iSO COGH 2 0CH 3 5.22 GaH 5

C

3

H

7 -iSO GOGH 3 5.23 G 2 Hs C 3

H

7 -iSO COHgCl ~I r '-i 111~ lj:;~:~iiiii 43 Formulation Examples for the active ingredient of formula 1 percentage by weight) Wettable powders a) an active ingredient of the Tables 25% sodium lignosulphonate 5% sodium laurylsulphate 3% sodium diisobutylnaphthalenesulphonate octylphenol polyethylene glycol ether to (7-8 moles of ethylene oxide) highly dispersed silicic acid 5% kaolin 62% b) c) 50% 6% 2% 27% The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill. Wettable powders are obtained which can be diluted with water to give suspensions of the desired concentration.

Emulsion concentrate cI 08 0 4 6 000 0 90 0 0 an active ingredient of the Tables It octylphenol polyethylene glycol ether (4-5 moles of ethylene oxide) calcium dodecylbenzenesulphonate castor oil polygycol ether (36 moles of ethylene oxide) cyclohexanone xylene mixture 3% 3% 4% Emulsions of any required concentration can be obtained from this concentrate by dilution with water.

L

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

.o Extruder granulate o, an active ingredient of the Tables sodium lignosulphonate 2% l, carboxymethylcellulose 1% kaolin 87% The active ingredient is mixed and ground with the adjuvants, and the mixture is subsequently moistened °o with water. The mixture is extruded and then dried in a stream of air.

Tablets or boluses S.I an active ingredient of the Tables 33.00% omethyl cellulose 0.80% S highly dispersed silicic acid 0.80% C: maize starch 8.40% The methyl cellulose is stirred in water and allowed to swell. Then the silicic acid is stirred in to give a homogeneous suspension. The active ingredient and the maize starch are mixed and the aqueous suspension is added to the mix, and the whole is kneaded to a paste.

This paste is granulated through a sieve (mesh width 1 45 12 M) and the granulate is then dried.

II crystalline lactose maize starch microcrystalline cellulose magnesium stearate 22.50% 17.00% 16.50% 1.00% 0.0* o 0r #41.

I.

*01 a.

I V It. f 4

*I

All 4 adjuvants are thoroughly mixed. Phases I and II are mixed and compressed to tablets or boluses.

If the compound of formula I, or corresponding compositions, are used for controlling endoparasitic jo nematodes, cestodes and trematodes in domestic animals and productive livestock, such as 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. By protracted administration a better action is often achieved or lower total doses will suffice. The active ingredient, or compositions containing it, can also be added to feeds or drinks.

'o The ready-prepared feeds contain the active ingredient combinations 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 subcutaneously, administered intraruminally or applied I0 to the bodies of the animals by the pour-on method.

Administration of the active ingredient by means of salt licks or molasses blocks is also possible.

IIIII 1 46 Biological Examples B-1: Insecticidal stomach poison action against Spodoptera littoralis Potted cotton plants in the 5-leaf stage are sprayed with a test solution containing 3, 12.5 or ppm of the test compound in acetone/water.

After the coating has dried, the plants are populated with about 30 larvae (LI stage) of Spodoptera littoralis. Two plants are used for each O1 test compound and test species. The test is carried out at about 24 0 C and 60 relative humidity. Evaluations S°and intermediate evaluations of moribund insects, growth and larvae and feeding damage are made after 24, o' 48 and 72 hours.

Complete kill was achieved after 24 hours with the compounds of formula I, especially those of Tables 1-3 and 4 at a concentration of only 3 ppm.

B-2: Action against plant-destructive acarids: o OP-sensitive Tetranychus urticae 16 hours before the start of the test, the primary S leaves of bean plants (Phaseolus vulgaris) are infected quj with a piece of leaf infested by Tetranychus urticae from a mass culture. Upon removal of the piece of leaf, the plants infested with all stages of the mites are sprayed to drip point with a test solution containing 0.4 ppm or 1.6 ppm of the test compound. The temperature in the greenhouse comparLment is about 0

C.

The percentage of mobile stages (adults and ?k nymphs) and of eggs is evaluated under a stereoscopic microscope after 7 days.

47 Compounds of formula I in which R, is hydrogen and R is a lower alkyl radical achieve complete kill at a concentration of active ingredient of only 0.4 ppm.

B-3: Action against L 1 larvae of Lucilia sericata 1 ml of an aqueous suspension of the test active substance is mixed with 3 ml of a special larval culture medium at about 50 0 C such that a homogeneous composition containing 250 ppm or 125 ppm of active S l( ingredient is obtained. About 30 Lucilia larvae (L 1 are put into each test tube sample. The mortality rate is determined after 4 days. The compounds of formula I of the Tables 1-3 and 4 achieve complete kill at 100 ppm.

B-4: Acaricidal action against Boophilus microplus (Biarra strain) Adhesive tape is applied horizontally across a PVC S plate so that 10 fully replete female Boophilus microplus ticks (Biarra strain) can be affixed thereto G 2o with their backs, side by side, in a row. Each tick is injected from an injection needle with 1 p1 of a liquid which contains a 1:1 mixture of polyethylene glycol and acetone, in which mixture a specific amount of active ingredient of 1, 0.1 or 0.01 pg per tick is dissolved.

Control ticks are injected with liquid containing no active ingredient. After this treatment, the ticks are 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

I

1.

48 with the IR 9 0 i.e. the effective dose is determined at which 9 out of 10 female ticks (90 even days lay eggs from which larvae are unable to hatch.

Compounds of formula I of the Tables 1-3 and 4, especially those in which R represents lower alkyl radicals, achieve an IR 90 of 0.1 yg.

Trial with sheep infected with nematodes (Haemonchus concortus and Trichostrongylus colubriformis) 0o The active ingredient is administered in the form 0, of a suspension with a stomach probe or by intraruminal S, injection to sheep which have been artificially infected with Haemonchus concortus and Trichostrongylus o colubriformis. 1 to 3 animals are used for each dose.

Each sheep is treated only once with a single dose of Oo 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 from Tables 1-3 and 4, preferably with a compound of the formula I in which R is lower alkyl.

B-6: Contact action against Aphis craccivora Pea plantlets which have been infested with all development stages of the aphid are sprayed with a solution of active ingredient prepared from an emulsion concentrate and containing 50 ppm, 25 ppm or 12.5 ppm 49 I II

I

0 04 uo0 it, 0 of active ingredient. After 3 days an evaluation is made to establish whether more than 80 of the aphids are dead or have dropped from the plants. A composition is rated as effective only at this level of activity.

Compounds of formula I, such as, for example, representatives of the Tables 1-3 and 4, achieve complete kill 100 at a concentration of 12.5 ppm.

iw B-7: Larvicidal action against Aedes aegypti A 0.1 solution of the active ingredient 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, about 30 to 40 three-day-old Aedes larvae are put into each beaker. Mortality counts are made after 1, 2 and 5 days.

In this test, the compounds of formula I, especially those of the Tables 1-3 and 4, achieve complete kill of all larvae at a concentration of 1.6 ppm after only 1 day.

B-8: Miticidal action against Dermanyssus gallinae 2 to 3 ml of a test solution (100, 10, 1 and 0.1 ppm of active ingredient) are introduced into glass containers which are open at the top, and approximately 200 mites at different stages of development are put into each of these containers. The glass containers are sealed with a cotton plug and shaken uniformly for minutes until the mites are completely wet. The 3c containers are then placed upside-down until the excess test solution has been absorbed by the plug. The

T~S=PI

50 containers are turned upright again and the treated ticks are observed for three days under laboratory conditions to evaluate the activity of the test substances, the mortality being used as a scale for the activity. Compounds from the Preparation Examples show 100 action at 100 ppm.

In all of the biological tests B1-B8, compounds of the formula I in which R is methyl or ethyl, R 3 is hydroxy R 2 is methyl, ethyl or isopropyl and R 1 /0 is hydrogen achieve excellent action and tend to be 0o00 O.O more active than the corresponding representatives in O.6 which R 3 is hydrogen.

o 3 0 t o ae o 8 o 0 0 0 t4 0 0

Claims (7)

1. 2. Compounds of the formula I according to claim 1 in which R is C 1 -C4-alkyl; RI is hydrogen, CH trimethyl- silyl, tris(tert.-butyl)silyl, dimethyl-(2,3-dimethyl-2- butyl)-silyl, diphenyl-tert.-butylsilyl, bis(isoprop- yl)methylsilyl, briphenylsilyl or tert.-butyl-dimethyl- silyl; R 2 is methyl, ethyl or isopropyl; and R 3 is an OH group.
2. 3. Compounds of the formula I according to claim 2 in which R is C -C 10 -alkyl; R 1 is hydrogen; R 2 is methyl, ethyl or isopropyl; and R 3 is an OH group.
3. 4. Compounds of the formula I according to claim 2 in which R is C -C 0-alkyl; R 1 is hydrogen; and R 2 is methyl, ethyl or isopropyl; and R 3 is hydrogen, a 22,23-double or -single bond being present. b. Compounds of the formula I according to claim 2 in which R is C -C -alkyl; R 1 is hydrogen; R 2 is S° methyl, ethyl or isopropyl; and R 3 is hydrogen, a S" 22,23-double or -single bond being present. 0
4. 6. Compounds of the formula I according to claim in which R is C -C6-alkyl; R is hydrogen; R 2 is methyl, ethyl or isopropyl; and R 3 is hydrogen, a 22,23-double bond being present. 0I 0 i 0 53 7* Compounds of the formula I according to claim 6 in which R is methyl, ethyl or n-propyl; R 1 is hydrogen or methyl; R 2 is methyl, ethyl or isopropyl; and R3 is hydrogen, a 22,23-double bond being present.
5. 8. Compounds of the formula I according to claim 3 in which R is methyl, ethyl or n-propyl; R 1 is hydrogen or methyl; R 2 is methyl, ethyl or isopropyl; and R is hydrogen, a 22,23-single bond being present.
6. 9. A compound of the formula I according to claim 2 selected from the series:
7. 138-methyl-antibiotic S541A 135-methyl-antibiotic S541B 138-n-propyl-antibiotic S541A 13B-ethyl-antibiotic S541A I38-ethyl-antibiotic S541B 1 3B-n-propyl-antibiotic S541B 1 38-ethyl-antibiotic S541C 4s 138-methyl-antibiotic S541C 4O. 13-etLhyl-antibiotic S541D 138-me thyl-antibiotic S541D 0138-ethyl-antibiotic S541E 138-methyl-antibiotic S541E 13-ethyl-antibiotic S541F 138-methyl-antibiotic S541F 13-ethyl- -antibiotic S541 13B-methyl-23-deoxy-antibiotic S5 IA 13 8-methyl-23-deoxy-antibiotic S54 13B-ethyl-23-deoxl-anibiotic S541A oa a 1 13e-metthy l- 3 d eo xy-an t ib o ic S54 1 ,,13 B-ethyl-23-deox~y-an t ibioti S 541 F 138-methyl-22,23-dehvdro-23-deoxy-antibiotic S541A and I 3B-ethyl-22,23-dehvdro-23-deox/-antibiotic S541F. A compound of the formula I according to claim 1 54 selected from the series: 1 3 5-methyl-5-ace'toxy-anuibioic 13 5 m e' h v1- 5- a ce L.ox v- ant i bioti c 1 35-methyl-S-ac etoxy-antibiot"ic I 38-methyl--acet oxy-antibiot-ic I 35-methyl-5-acetoxy-antibiotic I 33-methyl-5-ace'toxy-antibio ic S54 1 A S54 118 S54 1 C S 54 1ID S541E and S34 I F. 0 0 04 11. A process for the preparation of compounds of formula I, 13 13 H 3C 3 C(I) in which R is Cj-C 10 -alkyl; R 1is hydoe or methyl, acetyl, haloacetyl, methoxvacetyl, Lo- -en L ietvtoaeyacetvlox-vacetyl, acetvloxyfluoroacetyl, pro- pionyloxyacetyl, ben-zovloxvacatvl, halobenzoyloxvacetyl, me tho xy benz oy loxy''ace ty or the group -Si(R 4 )(CR 3) (R 6) wherein R.5 and R 61independently of one another, each represents C j-C 4 -alkyl, benzvl or phenyl; Ris methyl, ethyl1 or isoopyo-l; and R 3 is hydrocen or an OF grol-2; wherein when R 3 is hvdrogen a 22,23-double bond or -single bond is -,resent and when R 3 is an OH 'group a 22,23-single bond is pres'ent, characterised in that an ally! ster of forMUla IT I 55 'OH ,CH 3 1 7 H3C H3 H oi,. (II) 'CH 3 wherein A is one of the groups a or b R 7 0 1 CH3 or H (b) R7 138-ester-A 1 4, 1 5 A 1 3, 1 4 0 044 R 7 is an acyl group, and R and R 2 are as defined o oo for formula I, is treated in an inert solvent and optionally in a protective gas atmosphere in a temperature range from 00 O -lOO0C to +100OO, with a tri- alkylaluminium compound of formula III A1 (R)3 (I) w'wherein R is as defined for formula I, and, if free oJ. 030.3 a 5-hydVroxy compocunds are desired, subsecuently o0 the silyl group R 1 is removed by hydrolysis with a dilute acid in a temperature range from -20'C to +50 0 C, and if desired the 23-hydroxy group is reduced or eliminated. Ok O. 56' 12.- A pesticidal composition for controlling ecto- and enido-parasites in animals or plants and for controlling harmful insects, charactezrised in that 'it contains together with customary carriers and/or dispersing agents at least one compound of the formula I H3 2 CH 3 R 13 3 C', 0~ 0. 06 0 R Iis hyroe o-Ctv 1 ,acty,-aoaevkyl 7 oxaetl 00 aehlhoctl ctlxyacetyl, acetyloxyfluoroacetyl, :Dro- 0 0 0 00 pionyloxyacetyl, benzovloxyacetyl, halobenzoyloxyacetyl, rnethoxybenzoyloxvacetyl, or the groupc -Si (R 4 wherein R 1R. and R,6 independently of one another, each recresents CI-C 4 -alkyl, benzyl or phenyl; o oo 0 Ono.> R is methyl, ethyl or iSopropyl; and 2 0 o is hydrogen or an OH croup; wnerein wnen Ris hydrccen a 22,23-double bond or 0 0 0 -single bond is present and when R3~ is an nOH group a 22,23-single bond is present. 000 13. A composition according to claim 12, characterized in 0:00 6 that it contains as an active ingredient a compound as claimed in claims 2 to 57 14. A method of controlling pests in productive livestock and plants, characterised in that a compound of the formula I 1 3 CH 3 R* 17 15 I *c/flY kR H3C H3 *H II 1/ f CH 3 6hR in which R is Cj-C 1 0 -alkyl; R1 is hydrogen or methyl, acetyl, haloacetyl, methoxyacetyl, methylthioacetyl, acetyloxyacetyl, acetyloxyfluoroacetyl, pro- pionyloxyacetyl, benzoyloxyacetyl, halobenzoyloxyacetyl, methoxybenzoyloxyacetyl,or the group S -Si(R 4 (R 5 wherein R 4 R 5 and R 6 independently of one another, each represents C]-CA-alkyl, benzvl or phenyl; 0 0 0 R 2 is methyl, ethyl or isopropyl; and 0 00 o R 3 is hydrogen or an OH group; 0 o wherein when R 3 is hydrogen a 22,23-double bond or -single bond is present and when R 3 is an OH group a 22, 2 3-single bond is present, is administered to warm-blooded animals at rates of application of 0.01 to .o 10 mg/kg of body weight, and are applied to enclosed crop areas, to pens, livestock buildings or other S buildings in amounts of 10 g to 1000 g per hectare. A method according to claim 14, characterised in that the substance administered is a compound of the formula I according to any one of claims 2 to 0 0 -58 16. A process for the preparation of compounds of 'the formula I 3CCn in whnich R i~s C 1 -Cio-alkyl; Ris hydrogen or methyl, acetyl, haloacetyl, methoxyacetyl, rethyl-thioacetyl, acetyloxyacetyl, acetyloxyfluoroacetyli, pro- 0 pionyloxyacetyl, benzoyloxyacetyl, haloberizoyloxvacetyl, 00 0. 4 ethoxybenzoyloxyacetvl, or the group -Si(R 4 C 5 )(RG6) wherein R 4 f R 5 and R V independently of one another, each represents C 1 -C-akl benzyl 0or phenyl; 000 R 2 is methyl, ethyl or isopropyl; and to3 is an OFi group, 0 c-haraCterised in that an antibiotic S54]A deri-vative off "e formula X 0000 59 OH i\ 1 H3CH SIi II \C 3 in which R20 is C1-C4-alkyl is reacted normally in an atmos- phere of an inert gas and at least in the presence of at least one anhydrous solvent at a temperature range from -78°C to 0 C, over a period of from 0.5 to 24 hours with a compound of the formula XI 00*t o oo o QQ o 0o 0o oo d A1 -3 (XI) in which R h-s the meanings given under formula I and, if desired, acylated or silylated at the 5-OH group. 17. Compounds of the formula X 0 0 On 0 0 0t 0000 0) 0 000000 0 0 OH H3 CH 3 R i O O "CH I I II\ R*z0 01 0 C 22 HC 32 CH which R 2 0 is C -C -alkyl. i 1-Comoounds of the formula XII OH OH 3 16 23 H 3 HO C. 3 6 a SH 3 CH(CH 2 2 (XII) 1-9. Comoound of the formula XIV OH Vt3 16 /~O RZQOO-CO\ \M0122 3 2 a, a, ta a~ a, a aaOa a, a, a, 0-a. o 04 00 4 a, o a) 0 004 ai3~ 3 "H 3 CH(CH 2 xIV in which R 0is C I- C 4 alkyl. 4 00 O a, 4 'a a, a, 4 a. 0 a. 4 44 a. 0444 a, 044a. 61 131-alkyl derivatives of S541 antibiotics, substantially as hereinbefore described with reference to any one of Examples HI, H2a, H2b, H4, H5-H8, H13, H14 and any one of Compounds 1.1 to 1.31, 2.1 to 2.31, 3.1 to 3.31, 4.1 to 4.18 or 5.1 to 5.23. 21. A process for the preparation of 133-alkyl derivatives of S541 antibiotics, substantially as hereinbefore described with reference to any one of Examples HI, H2a, H2b, H4, H5-8, H13 or H14. 22 A 13-alkoxycarbonyloxy-5-keto-antibiotic S541A derivative, substantially as hereinbefore described with reference to Example H11. 23. A pesticidal composition for controlling ecto- and endo- parasites in animals or plants and for controlling harmful insects, substantially as hereinbefore described with reference to any one of the Formulation Examples. DATED this TWELFTH day of FEBRUARY 1990 Ciba-Geigy AG Patent Attorneys for the Applicant SPRUSON FERGUSON 0 0 t C0 0 405 0 ti o 0 0 i 2 0 V Q