AU631268B2 - 13-beta-phenethylthio-milbemycin derivatives - Google Patents

Abstract

13 beta -Phenylethylthio-milbemycins with the substitution pattern indicated in Claim 1, the preparation thereof and the use thereof for controlling insects and ecto- and endoparasites on productive livestock are described.

Description

ii i ii S F Ref: 147184 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE: Class Int Class Complete Specification Lodged: Accepted: Published: Priority: Related Art: Name and Address of Applicant: Ciba-Geigy AG Klybeckstrasse 141 4002 Basel

SNITZERLAND

Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Address for Service: Complete Specification for the invention entitled:

A

"13-beta-phenethylthio- milbemycin derivatives".

The following statement is a full description of this invention, including the best method of performing it known to me/us i APIS- 178571= "I13-beta-phenethyithia- MI Ibemycin derivatives".

Abstract of the Disclosure There are disclosed novel 131-phenylethylthiornilbemycins which are substituted as indicated in claim 1, their preparation and the use thereof for controlling insects as well as ecto- and endoparasites of productive livestock.

900 0 004.0 o 0 90000 00 0 00, 0 0 9000 0 0 0000 o 600,00 a 0 0c 0

**G

1A- API5-17857/= The present invention relates to novel 13p-phenethylthiomilbemycin derivatives of formula I below, to their preparation, and to the use thereof for controlling insects as well as ecto- and endoparasites of productive livestock. The invention further relates to the use of said novel milbemycin derivatives for the preparation of veterinary medicaments and for the use thereof in the treatment of animals.

0 o oo o o a 0 00 000 a 00 0 9 00 0 The novel compounds have the general formula I oo 0 0 0 0 0 0 0 0 0 Soo0 a o o o o OQ 00 00o a 0 9oo wherein

R

2 is methyl, ethyl, isopropyl, sec-butyl or the group -C(CH 3

)=CHQ

wherein Q is methyl, ethyl or isopropyl; and RI is the group

R

3 -X-NH CH 2

CH

2

-S-

wherein X is a member selected from the group consisting of -NHC(O)-, -2- -NHC(S)- or -SO 2 and

R

3 is hydrogen, Hett, unsubstituted C 1

-C

8 alkyl or C 1

-C

8 alkyl which is substituted by

C

1

-C

4 alkoxy, C 1

-C

4 alkylthio, C 2

-C

5 alkoxycarbonyl, halogen, CN, NO 2 COOH or NH 2 or is unsubstituted C 3

-C

8 cycloalkyl or C 3 -Cgcycloalkyl which is substituted by

CI-C

4 alkoxy, C 1

-C

4 alkylthio, Cz-Csalkoxycarbonyl, halogen, CN, NO 2 COOH or NH 2 or is the group

R

R

(CH2) n R n

C

wherein n is 0, 1 or 2, Ra, Rb and R, are each independently of one another hydrogen, C 1

-C

4 alkyl, CI-C 4 alkoxy, CI-C4alkylthio, Cl-C4haloalkyl, CI-C4haloalkoxy, Cl-C4haloalkylthio, Cz-C6alkoxyalkoxy, C 1 -Csalkanoyloxy, CC 5 alkoxycarbonyl, halogen, CN, NO 2 or NH 2 and Rc may additionally be C 3

-CG

8 cycloalkyl or the group Het 2 and Het, and Het 2 are an unsubstituted or substituted heterocycle which is bound through carbon and is selected from the group consisting of benzimidazole, benzoxazole, benzthiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline and benzotriazine; and the physiologically acceptable acid addition salts thereof.

When Het, or Het 2 is a fused ring system, the heterocyclic part of the molecule is always *j attached to the remainder of the entire molecule.

The heterocycles Hetl and Het2 are always attached to the remainder of the molecule through a ring carbon atom. They may themselves be unsubstituted or substituted.

Compounds of formula I in which Het, which denotes Het, as well as Het 2 has one of the following meanings, constitute one of the following preferred groups of compounds a to u, according to the definition of Het: -3- Group Het Type 3 N- 2/jy benzirnidazol-2-yl benzoxazol-2-yl 6 benzthiazol-2-yl o 000 0000 o 00 00 e 0000 00 0 o 000 00 00 0000 3 N IY

R

1 R8 4 5R Ntt-N4/ N 2 R1 3 N-N 4 25 1 N-N 2 5 N

I

N 3g 4 imidazol-2-yl oxazol-2-yl thiazol-2-yl [1H- 1 ,2,4-triazol] [1 ,2,4-oxadiazol]-5-yl 1,2,4-thiadiazol] [1 ,2,4-oxadiazol]-3-yl 1,2,4-thiadiazoll-3-yl [I1H- 1,2,4-triazoll-3-yl 1,3,4-oxadiazol]-2-yl 1,3 ,4-thiadiazol] -2-yl *[4H-1,2,4-triazol]-3-yl [1H-1 ,2,4-triazol]-5-yl 0000 0 0000 0000 0 00 00 0 0 000000 0 0 000000 0 0 0000 0 fl 0000 00 00 0 0 0 0 0 pyridin-2-yl pyridin-3-yl pyridin-4-yl Group Type 0* ft *~ft ftC CO *000 ft Oft o ft Oft o 00* o Oft o ft *090 E2 No1 2 El

N

3 1Ei 2

N

4

NI

N2 ~E2 4 El N 1 E N2

N

pyrimidin-2-yl pyrimidin-4-yl pyridazin-3-yl pyridazin-4-yl pyrazin-2-yl s-triazin-2-yl ''Oft ft ft o *o ft ft *ftOA Oft 000000 o ft ft~ftO 00)0 ftp Oft ft ft ft ft [1 ,2,4-triazinl-3-yl [1 ,2,4-triazin]-5-yl [1 ,2,4-triazin]-6-yl [1 ,2,3-triazin]-4-yl [1,2,3-triazin]-5-yl quinolin-2-yl quinolin-3-yl quinolin-4-yl Group Type 4 El F-)

N

E

3 1100 a isoquinolin- l-yl isoquinolin-3-yl isoquinolin-4-yl quinoxalin-2-yl phthalazin-3-yl quinazolin-2-yI quinazolin-4-yl [1 ,2,4-benzotriazin]-3-yl 0'CQ a~a a 0 90 'a.b.a a a a a ab Oa a a~aQ a a aaaa 2 N.-

N)

4

E

i- [1 ,2,3-benzotriazin]-4-yl -6in which formulae Y is oxygen, sulfur or NRI 0 Z iK oxygen, sulfur or NH;

R

6 and R 7 are each independently of the other hydrogen, C 1

-C

4 alkyl, Cl-C 4 haloalkyl,

CI-C

4 alkoxy, Cl-C 4 haloalkoxy, C 1 -C~alkylthio, Cl-C 4 alkylsulfonyl, Cl-C 4 alkylsulfinyl, Cl-C 4 haloalkylsulfonyl, Cl-C 4 haloalkylsulfinyl, halogen, nitro or cyano;

R

8 and R 9 are each independently of the other hydrogen, Cl-C 6 alkyl, Cl-C 6 haloalkyl, Cl-C 6 alkoxy, Cl-C 6 alkylthio, halogen or nitro; or are each independently of the other unsubstituted C 3

-C

7 cycloalkyl or C 3

-C

7 cycloalkyl which is substituted by halogen or Cl-C 3 alkyl; 0 R 10 is hydrogen or Cl-C 6 alkyl;

R

11 is Cl-C 6 alkyl; and El, E 2 and E 3 are each independently of one another hydrogen, C 1

-C

4 alkyl, C 1

-C

4 halo- '.oalkyl, Cl-C 4 alkoxy, CI-C 4 haloalkoxy, Cl-C 4 alkylthio, Cl-C 4 haloalkylthio, C 2

-C

6 alkoxy- ',alkoxy, Cl-C 5 alkanoyloxy, C -Csalkoxycarbonyl, C 3

-C

8 cycloalkyl, halogen, CN, NO 2 or Nil 2 Within the definitions of B 1

E

2 and E 3 especially preferred meanings are: hydrogen, methyl, ethyl, CF 3 methoxy, OCF 3 methylthio, CH 3

OCH

2 O, cyclopropyl, fluoro, chloro 0 and bromo.

:0 Within the groups b to f, those compounds of formula I are of interest wherein Y, Z, R 10 and R 11 are as defined above and R 8 and R 9 are each independently of the other.C 3

-C

7 cycloalkyl, preferably cyclopropyl or cyclohexyl, which is unsubstituted or substituted by halogen or Cj-C 3 alkyl.

Selected examples of substituents Het in the groups a to f are: a) -7- N R 8 N8 NR N 0 9 9 Is N R 8 N N N N c) N N' N N NN

H

NN

3 3 N-N 4 3 N-N4 51 2 52 s

N

1

R

9 0 R R11 N R9 in which formulae the substituents R 6 to R 11 are as defined above.

A further example is T51 (v) S N2 wherein R 8 has the meanings given above., -8- All groups a) to u) of compounds of formula I are preferred wherein R 2 is methyl or ethyl, most preferably ethyl.

Within group those compounds of formula I are additionally preferred in which R 6 and

R

7 are each independently of the other hydrogen, methyl, CF 3 methoxy, halomethoxy, fluoro, chloro or bromo, and the other substituents are as defined for formula I.

Within the groups to those compounds of formula I are additionally preferred in which R 8 and R 9 are each independently of the other hydrogen, methyl, ethyl,

C

3

-C

7 cycloalkyl, CF 3

C

2

F

5

C

3

F

7 CCl 3 CHC12, CH 2 Cl, SCH 3 or halogen; R 10 is hydrogen or methyl, and R 11 is C 1

-C

4 alkyl, preferably methyl.

Compounds of formula I meriting special interest are those in which the group Het 2 is .4 para-positioned to the phenyl radical.

o 0o S A further preferred group comprises those compounds of formula I, wherein R 2 and R 3 are S.o each independently of the other methyl, ethyl or isopropyl, and X is as defined for formula

I.

Alkyl by itself or as moiety of another substituent will be understood as meaning, for instance the following straight-chain and branched groups, depending on the indicated number of carbon atoms: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl and the like. Haloalkyl itself or as moiety of haloalkoxy or haloalkylthio is a ono- or perhalogenated alkyl substituent such as CH 2 C, CHC1 2

CC

3

CH

2 F, CHF 2 CF3, CH2Br, CHB, CBr3, CH2, CI 3 CHC1F, CHBrC1, CFBrCl, C 2 F5, CH2CHC1, CHC1CH3, C2C15, CHFCHClI and the like, preferably CF3. Halogen will be understood as meaning throughout this specification fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo, but most pieferably chloro.

Alkoxycarbonyl is a R-OC(O)- group, wherein R is an alkyl radical, for example C2H5OC(O)-, tert-butoxy-C(O)-, and the like. Illustrative examples of C2-C6alkoxyalkoxy are: CH30OCH20, C2H50CH20, C2H50CH2CH20, tert-butoxy- CH2CH20, and the like.

Cycloalkyl by itself or as moiety of a substituent is, depending on the indicated number of carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Cyanoalkyl L ~L 1 S-9is an alkyl group in which one hydrogen atom is substituted by CN, preferably an alkyl group wherein the CN group is at the terminal carbon atom.

Illustrative examples of salt-forming acids are: hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydriodic acid, as well as sulfuric acid, phosphoric acid, phosphorous acid, nitric acid, and organic acids such as acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, glycolic acid, thiocyanic acid, lactic acid, succinic acid, citric acid, formic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, salicylic acid, p-aminosalicylic acid, phthalic acid, 2-phenoxybenzoic or 2-acetoxybenzoic acid.

At room temperature the compounds of formula I are mainly solids. They have valuable insecticidal and parasiticidal properties and can be used for the curative and preventive control of numerous parasites of warm-blooded animals, especially of domestic animals S. and productive livestock, first and foremost of the class of the mammals.

O 00 S- a A preferred subgroup of compounds of formula I comprises those compounds wherein

R

2 is methyl, ethyl, isopropyl or sec-butyl; RI is the group

R

3 -X-NH CH2CH 2

-S-

w X a l

I

wherein X is a gro"", selected from -NHC(S)- and -SO 2 and

R

3 is C 1

-C

8 alkyl, preferably C 1

-C

4 alkyl, or C 3

-C

6 cycloalkyl.

A further preferred subgroup of compounds of formula I comprises those compounds in which

R

2 is methyl, ethyl, isopropyl or sec-butyl;

R

1 is the group

R

3 -X-NH CH 2 CH2-Swherein X is a group selected from -NHC(S)- and -SO 2 and

R

3 is the group Ra

R

S (CH 2 Rc wherein n is 0 or 1, and Ra, Rb and R c are each independently of one another hydrogen, C 1

-C

2 alkyl, C 1

-C

2 alkoxy,

C

1

-C

2 alkylthio, C 1

-C

2 haloalkyl, CI-C 2 haloalkoxy, C 1

-C

2 haloalkylthio, halogen or NO 2 and R c may additionally be the group Het 2 where Het 2 denotes the groups as defined under formula I.

A further preferred subgroup of compounds of formula I comprises those compounds in which

R

2 is methyl, ethyl, isopropyl or sec-butyl; R, is the group 0 R 3 -X-NH CH 2

CH

2

-S-

wherein X is a group selected from or and

R

3 is HetI, unsubstituted C 1

-C

6 alkyl or CI-C 6 alkyl which is substituted by C 1

-C

4 alkoxy,

C

1

-C

4 alkylthio or halogen, unsubstituted C 3

-C

6 cycloalkyl or C 3

-C

6 cycloalkyl which is substituted by C 1

-C

2 alkoxy, C 1

-C

2 alkylthio or halogen, or is the group Ra

R

(CH

2 wherein n is 0 or 1; S" R Ra, Rb and R, are each independently of one another hydrogen, fluoro, chloro, bromo, methyl, methoxy, methylthio, CF 3 or NO 2 and R e may additionally be the group Het 2 wherein Het, and Het 2 are one of the groups to f) as previously defined for Het.

A further preferred subgroup of compounds of formula I comprises those compounds in which

R

2 is methyl, ethyl, isopropyl or sec-butyl; Ri is the group H I

OH

wherein

R

2 is methyl, ethyl, isopropyl, sec-butyl or the group -C(CH 3

)=CHQ

R

3 -X-NH CH 2

CH

2

-S-

wherein X is and

R

3 is unsubstituted C 1

-C

6 alkyl or C 1

-C

6 alkyl which is substituted by Cl-C 4 alkoxy, Cl-C 4 alkylthio or halogen.

A further preferred subgroup of compo unds of formula I comprises those compounds in which

R

2 is methyl, ethyl, isopropyl or sec-butyl; R, is the group

R

3 -X-NH CH 2

CH

2 wherein X is or and S R 3 is hydrogen; unsubstituted CI-C 8 alkyl or C 1

-C

8 alkyl which is substituted by

C

1

-C

4 alkoxy, Cl-C 4 alkylthio, C 2

-C

5 -alkoxycarbonyl, halogen, CN, NO 2 COOR or NH 2 0 or is unsubstituted C 3

-C

8 cycloalkyl or C 3

-C

8 cycloalkyl which is substituted by 0 C 1

-C

4 alkoxy, C 1

-C

4 alkylthio, C 2

-C

5 alko)xycarbonyl, halogen, CN, NO 2 COOH or NH 2 A further preferred subgroup of compounds of formnula I comprises those compounds in which 0 0R 2 is methyl, ethyl, isopropyl or sec-butyl; 0.0 R 1 is the group

R

3 -X-NH CH 2

CH

2

-S-

000 wherein X is or and R 3 is the group 0 R Ra 00:(CH 2 wherein n isO0 or 1, and Ra, Rb and Rc are each independently of one another hydrogen, Cl-C 2 alkyl, C 1

-C

2 alkoxy, Cl-C 2 alkylthio, Cl-C 2 haloalkyl, CI-C 2 haloalkoxy, Cl-C 2 haloalkylthio, halogen or NO 2 and RC may additionally be the group Het 2

-O-

wherein Het 2 is one of the groups to f) as previously defined for Het.

12 A further preferred subgroup of compounds of formnula I comprises those compounds in which

R

2 is methyl, ethyl, isonropyl or sec-butyl; R, is the group

R

3 -X-NH

CH

2

CH

2

-S-

wherein X is or and R 3 is the group Ra

R

(CH

2 wherein n is 0 or 1, and

RX-

a, Rb and R, are each independently of one another hydrogen, C 1

-C

2 alkyl, C 1

-C

2 alkoxy, Cl-C 2 alkylthio, CI-C 2 haloalkyl, CI-C 2 haloalkoxy, CI-C 2 haloalkylthio, halogen or NO 2 jI A further preferred subgroup of compounds of formulaI comprises those compounds in which

R

2 is methyl or ethyl; R, is the group

R

3 -X-NH

CH

2

CH

2

-S-

wherein X is and R 3 is CI-C 6 alkyl.

A further preferred subgroup of compounds of formula I comprises those compounds in 9401 which

SR

2 is methyl or ethyl; R,~t Ris the group

R

3 -X-NH

CH

2

CH

2

-S-

wherein X is and R 3 is phen~yl or benzyl.

Preferred individual compounds of formula I include the following compounds: 1 31-[2-(4-acetaminophenyl)ethylthio]milbemycin A4; 13p-(2-[4-(4-heptylcarbonylamino)phenyl]ethylthio)milbemycin A4; 13j-(2-[4-(2,6-dichloropyridin-4-ylcarbonylamino)phenyllethylthio)-milbemycin A4; I t. t -13l3p-(2-[4-tosylpheny1]ethylthio)milbemycin A4; 1 3p-(2-[4-(methylaminothiocarbonylamino)phenyllethylthio)milbemycin A4; 1 3r-(2-[4-(benz ylaminocarbonylamino)phenyllethylthio)milbemycin A4; 131-(2-[4-(cyclohexylaminocarbonylamino)phenyl]ethylthio)milbemycin A4; 13f-(2-[4-((4-methoxyphenyl)aminocarbonylamino)phenyl]ethylthio)milbemycin A4; 1 3p-(2-[4-(carboxymethylaminocarbonylamino)phenyl]ethylthio)milbemycin A4; and 1 33- [4-(methoxycarbonylamino)phenyl]ethylthio)milbemycin A4.

Throughout this specification, compounds in which R 2 is sec-butyl shall also be considered as belonging to the milbemycin derivatives although, according to conventional classification, they are derived from avermectin derivatives. Avermectin aglycones (containing an oa-OH group in position 13), however, can be converted into milbemycin derivatives in accordance with US patent specification 4 173 571.

Naturally occurring milbemycins (R 2

CH

3

C

2 11 5 or iSOC 3

H

7 have solely hydrogen in 13-position in place of the thioether group (RI) in the compounds of formnula 1, as the formula XXX below shows: 00 960 0 09 .00 0.

00~.0 4 0 0000 0090 9 0 00 0 000900 0 0 909000 0000 O 9 0000 00 00 00 0 0 0

H

3

C

(X~X)

R

2

=CH

3 R= CAH R2= isoC 3

H

7 R2= sec.C 4

H

9 milbemycin

A

3 milbemnycin

A

4 milbemycin D 1 3-deoxy-22,23-dihydro-.C-076-Bla-aglycone.

14- Avermectins, however, carry in 13-position an ca-L-oleandrosyl-a-L-oleandrose radical which is attached through oxygen in the (c-configuration to the macrolide molecule.

Moreover, avermectins differ structurally from milbemycins by the presence of a 23-OH group or A 22 23 double bond and, usually, by the presence of a substituent R 2 sec-C 4

H

9 Hydrolysis of the sugar residue of avermectins readily affords the corresponding avermectin aglycones containing a 13(x-hydroxy group which is adjacent to a C=C double bond. As stated above, avermectin aglycones can be converted into milbemycin homologues. In the milbemycin derivatives of the present invention, the A 22 23 double bond is always in hydrogenated form and the substituent in the 13 position is always B-oriented.

Compounds of formula 1, wherein R 2 is the group -C CH-Q and

CH

3 Q is methyl, ethyl or isopropyl, may be understood as 23-deoxy derivatives of the Snaturally occurring antibiotic S541, but they contain in 13-position a B-thioether group. In this specification, these compounds of formula I will be designated for simplicity's sake as milbemycins too.

The constitution of naturally occurring antibiotics S541 is disclosed in German Offenlegungsschrift 3 532 794 and is as follows:

OH

C C 23 CH 3

CH

3 22 12 C 16 H .13 CH3 0 15 1 31 H3C 32 R2 8c (antibiotics S541) 0 1*

OR

1

R

3 -X-NH CH 2

CH

2

-S-

wherein X is a member selected from the group consisting of -NHC(O)-, 'I II I

I

factor A factor B factor C factor D factor E factor F R2* isoC 3

H

7 R2* CH 3 R2* CH 3 R2* C 2

H

5 R2* ioC 3

H

5 R2* isoC3H 7 RI* =H RI* CH 3 RI* =H

R

I

=H

R

I

CH

3 RI* CH 3 4 4444g 6P D 42 I L 444 Milbemycins containing a 13p-alkylthio group are disclosed as insecticides and parasiticides in European patent application 0 184 173 and in the corresponding British patent GB 2 167 751B. Surprisingly, however, the biological activity of the 13p-ethylthiomilbemycins can be significantly enhanced by introducing the terminal

R

3 -X-NH group (wherein R 3 and X are as defined for formula I) into the 2-position of the 13p-ethyl group. A comparison of, for example, compound No. 1.14 of the above publications CH3 H CH 5 C H 3 CH3CH2,-S 0 [compound A] &4I, 4 .4 4 t €e

'C

2

H

comp. No. 1.14 of EP 0 184 173 and.

GB 2 167 751B with compound 1.13 of this invention Table 1) A4 t -16if f iii *Z 4 I Ii I I '(a a a oii I Ir a x ri 4, 4 O CH3 C H 3

CH

3 0C -NH CH 2

CH

2 -S 0 13 T *O17CH H3C O [compound B] H H O CH3

H

OH

according to Biological Example B-3 in sheep which have been infected with the nematodes Haemonchus contortus und Trichostrongylus colubriformis, gives the following results after one intraruminal administration of 0.1 mg of a.s./kg of bodyweight (expressed as a reduction of worm eggs in the faeces compared with the number of eggs in infected and untreated sheep): Test 1 Test 2 Control (repeat of 1) compound A of the 50% 58% 0 prior art compound B of the present invention A reduction of more than 90 corresponds to almost 100 kill of the eggs, especially as the occasional eggs found in the faeces are not viable. As against this finding, the reduction of less than 60 after treatment with compound A is completely inadequate and, in addition, the majority of the eggs remaining in the faeces are hatchable.

The compounds of formula I are prepared from compounds of formula II 17- SCH3 CH3 CH3

H

2 N CH 2

CH

2 -S 017 13 17 0**O R2

OH

H3

C

compound of formula

IIII),

0 CH

R

3 -X-T (III)

H

OH

wherein R 2 is as defined for formula I, by a) in those cases in which X in formula I is or reacting said compound of I formula II, in the absence, or preferably in the presence, of an acid acceptor, with a o compound of formula III R3-X-T (III) wherein R 3 is as defined for formula I, X is or and T is a leaving group.

Typical examples of suitable leaving groups are preferably halogen, more particularly chloro, bromo or iodo. A leaving group T may also suitably be a OH group.

Further leaving groups are benzenesulfonyloxy, p-tosyloxy, trifluoroacetoxy or lower 0099 alkylsulfonyloxy such as mesyloxy or, if X in Formel III is the corresponding radical -O-C(O)-R 3 of the anhydride of a carboxylic acid, for example of acetic acid.

9 9 0 The process is normally carried out in an inert solvent or in one of the reactants, provided these are liquid. Illustrative of 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), halogenated hydrocarbons such as chlorobenzene, methylene chloride, preferably ethylene chloride, chloroform, carbon tetrachloride, tetrachloroethylene and the like, while aromatic or aliphatic hydrocarbons such as benzene, toluene, xylenes petroleum ether, ligroin, cyclohexane, may also be present. In some cases it may be convenient to carry out the reactions in an inert gas atmosphere (for example argon, helium, nitrogen and the like) and/or in absolute solvents.

u 2 NZk quinolin-4-yl 1 E3 -18- If desired, the final products can be purified in conventional manner, for example by washing, digestion, extraction, recrystallisation, chromatography and the like.

The reaction of compounds of formula II with compounds of formula III is normally carried out in the above mentioned inert solvents, in general in the temperature range from to +100 0 C, preferably from 00 to 50 0 C. To neutralise the acids formed as by-product, the reaction is conveniently carried out in the presence of an acid acceptor.

Suitable acid acceptors are organic bases such as tertiary amines, for example trialkylamines (trimethylamine, triethylamine, diisopropylmethylanine, tripropylamine, and the like), pyridine and pyridine bases (4-dimethylaminopyridine, 4-pyrrolidylaminopyridine and the like). Pyridine is preferred. The acid acceptor is normally used in at least equimolar amount, based on the starting materials.

S3) Where X in formula I is the compound of formula II is reacted with an isocyanate of formula IV R3-N=C=O (IV) or with an aminoacylating agent of formula V

R

3 -NH-C(O)-D (V) wherein R 3 in formulae (IV) and is as defined for formula i and D is a leaving group as defined for T, or is preferably unsubstituted or substituted phenoxy. This reaction too is Spreferably carried out in one of the inert solvents cited in a) and in the temperature range I i indicated therein.

S'y) Where X in formula I is the procedure as described in P) is carried out, i with the proviso that, in place of the isocyanate IV, an isothiocyanate of formula VI SR3-N=C=S (VI), is used, wherein R 3 is as defined for formula I.

i* 8) Where X in formula I is SO 2 the procedure as described in a) is carried out, with the proviso that, in place of the acylating agent of formula III, a sulfonating agent of formula VIa is used,

R

3 -S0 2 -T (VIa), wherein R 3 is as defined for formula I and T is as defined in a).

e) A further process for the preparation of compounds of formula I, wherein X in formula I -19is comprises reacting a compound of formula I, wherein X is and R 3 is 4-nitrophenyl, for example compound 1.17 (Table with an amine of formula VIb

R

3

-NH

2 (VIb) wherein R 3 is as defined for formula I.

The starting compounds of formula II are obtainable from compounds of formula VII CH3 H C H 3

H

02N- cH2CH2-S 0 O S17 0 R2

H

H 3 C o o (VII)

OH

H 0 9 by reduction of the terminal nitro group.

Any suitable method of reducing NO 2 to NH 2 can be used for this purpose, for example catalytic hydrogenation with a palladium catalyst or reduction with zinc, in the presence of acetic acid, in the temperature range from 00 to 50°C. In this reaction it may be advantageous to mask the OH group in 5-position with a protective group prior to the reduction of the nitro group.

I m. Throughout this specification, OH protective groups will be understood as meaning the protective functions customary in organic chemistry. Such groups are, in particular, acyl and silyl groups. Suitable acyl groups are typically the readicals R where R t is

C

1

-C

10 alkyl, C 1

-C

l ohaloalkyl or a member selected from the group consisting of phenyl and benzyl which is unsubstituted or substituted by halogen, Ci-C 3 alkyl, C 1

-C

3 haloalkyl,

C

1

-C

3 alkoxy, C 1

-C

3 haloalkoxy, cyano and/or nitro and, preferably, C 1

-C

6 alkyl,

C

1

-C

6 haloalkyl or phenyl or phenyl which is substituted by halogen, C 1

-C

3 alkyl, CF 3 or nitro. Silyl groups suitable for protecting OH group are the radical -Si(Rx)(Ry)(Rz c R7

RIO

~R7

N

5 N R 7 I I I LC 1 _L r I I r wherein R x Ry and R z are each preferably independently of one another C 1

-C

4 alkyl, benzyl or phenyl and, for example, together with the silicon atom, form one of the groups trimethylsilyl, diphenyl-tert-butylsilyl, bis(isopropyl)methylsilyl, triphenylsilyl and the like, and, preferably, tertbutyldimethylsilyl. The 5-OH group can also be in the form of benzyl ether or methoxyethoxymethyl ether.

The protective group can be removed by hydrolysis.

The compound of formula VII is obtainable from the mercapto compound VIII o 0 oo o o 0 0 0 0* o00 +00 O <D 0 1 0 0 0 I 000

H

3

C

(VIII)

ii ~Ii 0044 001 4500 0 0

I

4 0 040 by reaction with a compound of formula IX 0 2 N CH 2

CH

2

T

(IX)

wherein T is a leaving group as defined for formula III, preferably iodo. The reaction is carried out in the temperature range from 200 to 150 0 C, poreferably from 800 to 110 0 C, in an inert solvent, preferably dimethyl formamide, and an organic amine, preferably ethyl diisopropylamine, is added as acid acceptor.

The mercapto compound VIII is disclosed in European patent application 0 184 173 and in the corresponding British patent 2 167 751B.

c wherein Rg has the meanings given above., -21- The starting compounds of formulae III, IV, V, VI, Via, VIb and IX are known or can be prepared by methods similar to those for preparing the known representatives.

The compounds of formula I are eminently suitable for controlling all development stages of pests of animals and plants, including especially ectoparasites of animals. These latter pests comprise those of the order Acarina, in particular pests of the families Ixodidae, Dermanyssidae, Sarcoptidae and Psoroptidae; of the orders Mallophaga; Siphonaptera, Anoplura family of the Haemotopinidae); those of the order Diptera, in particular 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 (families Sarcophagidae, Anophilidae and Culicidae); of the order Orthoptera, of the order Dictvoptera family of the Blattidae), and of the order Hymenoptera family of the Formicidae).

o 0 The compounds of formula I also have a lasting action against mites and insects which are S parasites of plants. When used to control spider mites of the order Acarina, they are effective against eggs, nymphs and adults of Tetranvchidae (Tetranychus spp. and Panonychus spp.).

They are very effective against sucking insects of the order Homoptera, especially against pests of the families Aphididae, Delphacidae, Cicadellidae, Psyllidae, Loccidae, Diaspididae and Eriophydidae the rust mite on citrus fruit); of the orders Hemiptera, Heteroptera and Thysanoptera; and also against phytophagous insects of the orders Lepidoptera, Coleoptera, Diptera and Orthoptera.

S The compounds of formula I are also suitable for use against soil pests.

C i The compounds of formula I are therefore effective against all development stages of sucking and eating insects in crops such as cereals, cotton, rice, maize, soybeans, potatoes, vegetables, fruit, tobacco, hops, citrus fruit, avocados and other crops.

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

c i. z Cycloalkyl by itself or as moiety of a substituent is, depending on the indicated number of carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Cyanoalkyl I r 7 1 i I I II r~~~r i.

i o0 o oa ooo* 0 0 0 o 0 0 oo00 0 00 o o 0 0 o oo0 oo 00 0 o 0 -22- Furthermore, the compounds of formula I act against all development stages of helminths, among which the endoparasitic nematodes can be the cause of severe diseases in mammals and fowl, for example in sheep, pigs, goats, cattles, horses, donkeys, dogs, cats, guinea pigs, and cage-birds. Typical nematodes having this indication are: Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, 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 efficacy against such parasites which are resistant to benzimidazole pesticides.

Certain species of the genera Nematodirus, Cooperia and Oesophagostomum attack the intestinal tract of the host animal, whereas others of the genera Haemonchus and Ostertagia parasitize in the stomach and those of the genus Dictyocaulus in the lung tissue.

Parasites of the families Filriidae and Setariidae are found in internal cell tissue and internal organs, e.g. in the heart, blood vessels, lymph vessels and in subcutaneous tissue.

Particular mention is to be made in this connection of the heart worm of the dog, Dirofilaria immitis. The compounds of formula I are very 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 genera 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 gastrointestinal 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 emulsifiabhe 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.

r i i 23 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.

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, horses, pigs, 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 mg/kg of body weight. A better action is often achieved by protracted administration, or lower total doses will also suffice. The compounds, or compositions containing them, can also be added to feeds and drinks. The ready-prepared feeds contain the active ingredients preferably in a concentration of 0.005 to 0.1 percent by weight. The compositions can be administered to the animals perorally in the form of solutions, S emulsions, suspensions, powders, tablets, boluses or capsules. If the physical and S 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 i subcutaneously or by intraruminal injection, or applied to the bodies of the animals by the pour-on method. Administration by means of salt licks or molasses blocks is also possible.

4 The compounds of formula I are conveniently applied to enclosed crop areas in amounts of 10 g to 1000 g per hectare. They are also applied to folds, pens, livestock buildings and other buildings.

'The formulations, i.e. the compositions or preparations containing the compounds (active ingredients) of the formula I are prepared in known manner, e.g. by homogeneously mixing and/or grinding the active ingredients with extenders, e.g. solvents, solid carriers SI 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 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 dimethyl formamide, as well as vegetable oils or epoxidised vegetable oils such as epoxidised coconut oil or soybean oil; or water.

I

R

2 is methyl, ethyl, isopropyl or sec-butyl;

R

1 is the group 24- The solid carriers used e.g. for dusts and dispersible powders are normally natural mineral fillers such as calcite, talcum, kaolin, montmorillonite or attapulgite. The physical properties may also be improved by adding highly dispersed silicic acid or highly dispersed absorbent polymers. Suitable granulated adsorptive carriers are porous types, for example pumice, broken brick, sepiolite or bentonite; and suitable nonsorbent carriers are materials 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.

Depending on the nature of the compound of the formula I to be formulated, suitable surface-active compounds are nonionic, cationic and/or anionic surfactants having good emulsifying, dispersing and wetting properties. The term "surfactants" will also be understood as comprising mixtures of surfactants.

o0 Suitable anionic surfactants can be both water-soluble soaps and water-soluble synthetic o surface-active compounds.

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

-C

22 e.g. the sodium or potassium S salts of oleic or stearic acid, or of natural fatty acid mixtures which can be obtained e.g.

from coconut oil or tall oil. Further suitable surfactants are also the fatty acid methyltaurin salts.

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

*cocoa a a The fatty sulfonates or sulfates are usually in the form of alkali metal salts, alkaline earth Smetal salts or unsubstituted or substituted ammonium salts and contain a C 8

-C

22 alkyl o* radical which also includes the alkyl moiety of acyl radicals, e.g. the sodium or calcium o salt of lignosulfonic acid, of dodecylsulfate, or of a mixture of fatty alcohol sulfates .e 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 fatty acid radical containing 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnaphthalenesulfonic acid, or of a naphthalenesulfonic acid/formaldehyde condensation product. Also suitable are Het 2

-O-

wherein Het 2 is one of the groups to f) as previously defined for Het.

corresponding phosphates, e.g. salts of the phosphated adduct of p-nonylphenol with 4 to 14 moles of ethylene oxide, or phospholipds.

Non-ionic surfactants are preferably polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, or saturated or unsaturated fatty acids and alkylphenols, said derivatives containing 3 to 30 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenols.

Further suitable non-ionic surfactants are the water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediamino-propylene glycol and alkylpolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethylene glycol ether groups and 10 to 100 propylene glycol ether groups. These compounds usually contain 1 to 5 ethylene glycol units per propylene glycol unit.

Representative examples of non-ionic surfactants are nonylphenol-polyethoxyethanols, castor oil polyglycol ethers, polypropylene/polycthylene oxide adducts, tributyl- C phenoxypolyethoxyethanol, polyethylene glycol and octylphenoxypolyethoxyethanol.

C o Fatty acid esters of polyoxyethylene sorbitan, e.g. polyoxyethylene sorbitan trioleate, are also suitable non-ionic surfactants.

Cationic surfactants are preferably quaternary ammonium salts which contain, as N-substituent, at least one Cg-C 22 alkyl radical and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl or hydroxy-lower alkyl radicals. The salts are preferably in the form of halides, methylsulfates or ethylsulfates, e.g. stearyltrimethylammonium chloride or benzyl bis(2-chloroethyl)ethylammonium bromide.

ca o The surfactants customarily employed in formulation technology are described in the o0". following publication: °C "1986 International Mc Cutcheon's Emulsifiers and Detergents" The Manufacturing Confectioner Publishing Co., Glen Rock, New Jersey, USA.

The pesticidal compositions normally 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.

13p-(2-[4-(4-heptylcarbonylamino)phenyl]ethylthio)milbemycin A4; 13p-(2-[4-(2,6-dichloropyridin-4-ylcarbonylamino)phenyl]ethylthio)-milbemycin A4; -26- Whereas commercial products are preferably formulated as concentrates, the end user will normally employ dilute formulations having a concentration of 1-10 000 ppm of active ingredient.

Accordingly, the present invention further relates to pesticidal compositions which contain, as active ingredient, a compound of formula I, together with conventional carriers and/or diluents.

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

Preparatory Examples: A. Preparation of the starting materials Example Al: Preparation of 5-O-tert-butvldimethylsilvl-13-(2-[4-nitrophenyl]ethylthio)milbemycin A4 A solution consisting of 2 g (2.9 mmol) of 5-O-tert-butyldimethylsilyl-13p-mercaptomilbemycin A4, 1.6 g (5.82 mmol) of 2-(4-nitrophenyl)ethyl iodide and 2.5 ml (1.9 g; 0* 14.55 mmol) of diisopropylethylamine in 6 ml of dimethylformamide is stirred at 100°C for 60 minutes. The reaction mixture is cooled to room temperature and then taken up in 100 ml of n-hexane, washed first with a 2M aqueous solution of HCI and then twice with a aqueous solution of NaHC03, dried over MgSO 4 and concentrated. Column chromatography on silica gel gives 1.8 g of the title compound.

1H-NMR (300 MHz, CDC1 3

TMS)

3.04 J 10 Hz) C 13

H.

o o Example A2: Preparation of 133-(2-[4-nitrophenyl]ethvlthio)milbenwcin A4 1.7 g (20.3 mmol) of 5-O-tert-butyldimethylsilyl-13p-(2-[4-nitrophenyl]ethylthio)- 0, milbemycin A4 are treated with 20 ml of a 1 methanolic solution of p-toluenesulfonic acid. After 2 hours the reaction product is taken up in ether, washed with 5 aqueous NaHCO 3 dried over MgSO 4 and concentrated. Column chromatography on silica gel (ethyl acetate/hexane 1:1) gives 1.53 g of the title compound.

L R2 sec.C 4

H

9 13-deoxy-22,23-dihydro-&C076Baaglycone.

-27- IH-NMR (300 MHz, CDCI 3

)(TMS)

3.04 J 10 Hz) (C 13

H)

7.32 J 8 Hz)(aromatic H) 8.17 J 8 Hz)(aromatic H) mass spectrum (FD) nile: 723 (C 40

H

53 N0 9

S)

Example A3: Preparation of 131-(2-4-aminophenyllethylthio)mulbenmvcin A4 With stirring, 4 g of zinc dust are added at room temperature to a solution of 4 g (5.53 mmol) of 13 P- ni trophenyl] ethyl thio)rnilbemycin A4 in 40 ml of acetic acid, and the resultant mixtqre is stirred. After 16 hours the reaction mixture is diluted with 150 ml of l~and filtered. The filtrate is washed 3 times with water, dried over MgSO 4 and concentrated. The residue is chromatographed on silica gel (ethyl acetate/hexane 2: affording 2.25 g of 13 3(2- ami nophenyl] ethyl thio)milbemycin A4.

co 'H-NMR (300 MHz, CDC1 3

TMS)

S 3.03 (d J 10OHz)(C 13

H)

.0 6.63 J =8 Hz)(aromatic H) 6.96 J =8 Hz)(aromatic H) mass spectrum (FD) mle: 693 (C 40

H

55 N0 7

S)-

B. Preparation of the final products Example P1: Preparation of 13 .(2-[4-cetylaminophenyllethylthio)milbemycin A4 000~With stirrring, 7 g.l (7 mig, 7.2 tmdi) of acetic anhydride are added at room temperature to a solution of 40 mg (58 grnol) of 13p-(2-[4-aminophenyl]ethylthio)milbemycin A4, 5.8 gl @0 of pyridine and 47 gl (37 mg, 1,15 nimol) of methanol in 0.3 ml of dichioromethane. The 00 reaction mixture is stirred for 2 hours at room temperature, worked up with ethyl acetate and water, and washed with 0.5M citric acid and then with 5 aqueous NaHCO 3 Chromatography on silica gel (ethyl acetate/hexane 2:1) affords 35 mg of 131-(2-[4acetylaminophenyl]ethylthio)milbemycin A4.

0 1 H-NMR (300 MHz, CDCl 3

TMS)

3.04 J 13 Hz)(C 13

H)

7.11 J 8 Hz)(aromatic H) 7.41 J 8 Hz)(aromatic H) -28- Example P2: Preparation of 13 -(2-4-(4-heptylcarbonylamino)phenyll ethylthio)milbemycin A4 With stirring, 12 mg (72 gmol) of 4-heptylcarbonyl chloride are added at room temperature to a solution of 40 mg (58 jtmol) of 13-(2-[4-aminophenyl]ethylthio)milbemycin A4, 6 l1 (73 p mol) of pyridine and 47 R1 (37 mg, 1.15 mmol) of methanol in 0.3 ml of dichloromethane. After 2 hours the reaction mixture is worked up with ether and 1M citric acid, washed with a 5 aqueous solution of NaHCO 3 and dried over MgSO 4 Chromatography on silica gel (ethyl acetate/hexane 1:1) gives 32 g of 13p-(2-[4-(4-heptylcarbonylamino)phenyl]ethylthio)milbemycin A4.

Example P3: Preparation of 13 -(2-E4-(formylamino)phenyllethylthio)milbemycin A4 A mixture of 7 p1 of acetic anhydride and 3 tl of formic acid is added at room temperature to 40 mg (58 lmol) of 13f-(2-[4-aminophenyl]ethylthio)milbemycin A4, 6 p1 of pyridine and 47 p1 (1.15 mmol) of methanol in 0.3 ml of dichloromethane. After 4 hours the reaction mixture is worked up with ethyl acetate and and IM citric acid and washed with water and IM aqueous NaHCO 3 Chromatography on silica gel (ethyl acetate/hexane 2:1) gives 30 mg of 13-(2-[4-(formylamino)phenylethylthio)milbemycin A4.

IH-NMR (300 MHz, CDCl 3

TMS)

8.37 J =1 Hz)(formyl H) 8.64 J 12 Hz)(formyl H).

Example P4: Preparation of 13r-(2-14-(4-toluenesulfonylamino)phenyllethylthio)milbemycin A4 With stirring, 14 mg (72 jtmol) of toluene-4-sulfochloride are added at room temperature to a solution of 40 mg (58 gmol) of 13-(2-[4-aminophenyl]ethylthio)milbemycin A4, 6 g1 (73 pmol) of pyridine and 47 p1 (37 mg, 1.15 mmol) of methanol in 0.3 ml of dichloromethane. After 2 hours the reaction mixture is worked up with ether and IM citric acid, washed with a 5 aqueous solution of NaHCO 3 and dried over MgSO 4 Chromatography on silica gel (ethyl acetate/hexane 2:1) gives 41 mg of 13f-(2-[4-(4-toluenesulfonylamino)phenyl]ethylthio)milbemycin A4.

'H-NMR (300 MHz; CDCl 3

TMS)

6.97 J 3 Hz)(aromatic H) 7.04 J 8 Hz)(aromatic H) 7.23 J 8 Hz)(aromatic H) 7.63 J 8 Hz)(aromatic H) mass spectrum (CI-ve) m/e: 847 (C 4 7

H

6 1

NO

9

S

2 29 Example P5: Preparation of 13 0- r4- (neth ylani noth iocarbonyl amino)phenyll ethylthio)milbemycin A4 With stirring, 5.3 mg (72 .tmol) of methyl isothiocyanate are added at room temperature to a solution of 40 mg (58 jimol) of 131-(2-[4-aminophenyl]ethylthio)milbemycin A4, 6 p1l (73 jimol) of pyridine and 47 j[tl (1.15 mmol) of methanol in 0.3 ml of dichioromethane.

After 16 hours the reaction mixture is worked up with ether and 1M citric acid, washed with 5 aqueous NaHCO 3 and dried over MgSO 4 Chromatography on silica gel (ethyl acetate/hexane 2: 1) gives 38 g of 13[-(2-[4-(miethylaminothiocarbonylamino)phenyl] ethyl thio)mil bemycin A4.

'H-NMR (300 MHz, CDCl 3

TMS)

3.14 J 5 Hz, NHCH 3 Example P6: Preparation of 13 31-(2-r4-(cyclohexyl ami nocarbonylam ino)phen yl] ethyld o thio)milbemycin A4 :0*With stirring, 9 pAl (8 rng, 72 ptmol) of cyclohexyl isocyanate are added at room temperature to a solution of 40 mg (58 gLmol) of 131-(2-[4-aminophenyl]ethyltlhio)milbemycin A4, 6 g~l (73 jtmol) of pyridine and 47 pA 15 mmol) of methanol in 0.3 ml of tetrahydrofuran. After 3 hours at room temperature, the reaction mixture is worked up with ethyl acetate and with 5 aqueous NaH-C0 3 and dried over MgSO 4 Chromatography on silica gel (ethyl acetate/hexane 4:1) gives 46 g of 13j-(2-[4-(cyclohexylaminocarbonylamino)phenyl] ethyl th io)mi lbemyci n A4.

fi 1 H-NMR (300 MHz, CDCL 3

TMS)

4.50 J 8 Hz)(NH) mass spectrum (CI ye): m/e 818 (C 47

H

65

N

2 0 8

S).

Example P7: Preparation of 13 13(2-F4- (carboxymethylaminocarbon y] amino) phenvllethylthio)milbemycin A4 A solution of 50 mg 8 l.Lmol) of 13 P- (4-nitrophenoxy)carbonylaminophenylI ethylthio)milbemycin A4 (prepared according to Examnple B2) and 4.4 mg (58 jimol) of glycine in 2 ml of dimethyl formamid is stirred at 70'C. After 2 hours the reaction mixture is worked up with ethyl acetate and water, and dried over MgSO 4 Chromatography on silica gel (dichloromethane/methanol 4: 1) gives 22 mg of 13p-(2- [4-(carboxymethylaminocarbonylamino)phenyl]ethylthio)milbemycin A4.

1 1 'H-NMR (300 MI-z, D 6 -DMSO, TMS) 4.67 J 8 Hz)(NH) 9.09 (br, s)(COOH) mass spectrum (CI ye): mle 794 (C 43

H

58

N

2 0 10

S).

The following compounds of formula I are prepared in accordance with the procedures described above.

600 400 CO3 present. In some cases it may be convenient to carry out the reactions in an inert gas atmosphere (for example argon, helium, nitrogen and the like) and/or in absolute solvents.

alt t

~NI

t 14 I 4 I1' 31 Table 1: Typical representatives of compounds of formula I wherein R, R3--XNH< CH 2

CH

2

S-

Comp. X R 3 R2 Physical data 1.1 CO CAH CAH nile 749 (Cl-ye) 1.2 CO phenyl C 2

H

5 nmc= 797 (FD) 1.3 CO CH 3 C2H 5 rn/ 735 (FD) 1.4 CO H CAH rn/c 721 (Cl-ye) CO tert-butyl C 2

H

5 rn/c 777 (Cl-ye) 1.6 CO (H 3

CCH

2

CH

2 2 CH- C 2 14 5 n/e 819 (Cl-ye) 1.7 CO ClCH 2 CAH rn/e 769 (Cl-ve) 1.8 CO 2,6-dichloropyrid-4-yl C 2

H

5 rn/c 866 (Cl-ye) 1.9 CO C1 2 CH CAH rn/c 804 (Cl-ye) 1.10 CO C1 3 C C 2 1- 5 rn/c 839 (Cl-ye) 1.11 CO F 3 C CAH rn/c= 789 (CI+vc)

CH

3

N

1.12 CO 11 CAH rn/c 837 (CI+ve NH 3

N

1.13 OCO CH 3 CAH nVe =751 (FD) 1.14 OCO C 2 1- 5 CA We m/=765 (FD) 1.15 OCO bcnzyl CAH in/ 827 (FD) 1.16 OCO phenyl CAH We= 831 (CI+ve NH 3 1.17 OCO p-nitrophcnyl C 2

H

5 rn/c 858 (FD) 1.18 OCO CHCH 2

CH

2

CH

2 CAH rn/c 793 (Cl-ye) 1.19 So 2

CIT

3

C

2 11 5 m/e 771 (Cl-ye) 1.20 So 2 p-tolyl CAH rn/c 847 (Cl-ye) E) A further process for the preparation of compounds of formula 1, wherein X in formula I 32 Table 1 (continued) Comp. x[ R 3 tR2 j~Physial data *9 o 9*9 *499 9,9* 9* o 9 *99* 9* 9 *999 *9eO 9 9 *99* *9*4 49 *9 4 44441 4 *,ItIt 9 4 9449 9 4.9.

4* *4 9 9 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 1.34 1.35 1.36 1.37 1.38 1.39 1.40 1.41 1.42 1.43

SO

2 S0 2

SO

2

NH-CS

NH-CS

NH-CS

NH-CO

NH-CO

NH-CO

NH-CO

NH-CO

NH-CO

NH-CO

NH-CO

NH-CO

NH-CO

CO

CO

OCO

OCO

SO

2

NH-CS

NHI-CO

2-fluorophenyl 2-(2--methoxyethoxy)phenyl 2-difluoromethyithiophenyl

CAH

3-fluorophenyl

CR

3

CH

3

C

2

H

5 cyciohexyl p-tolyl 2-fluorophenyl phenyl p-methoxyphenyl

HOOCCH(CH

3

HOOCCH

2 HOOCCH(isopropyl)

CH

3

CH

3

CR

3

CAH

CH

3

CR

3

CR

3

CAH

C

2

H

5

CAH

CAH

C

2 14 5

C

2

H

5

CAH

CAH

C

2 1-1 5

C

2

H

5 C21- 5

C

2 fH 5

CAH

CAH

C

2 14 5

CAH

CR

3 isopropyl

CR

3 sec-butyl

CR

3 isopropyl

CR

3 m/e 869 (CI+ve, NH 3 m/e 925 (CI+ve NH 3 rn/c 933 (CI+ve NH 3 rn/e 778 (Cl-ye) rn/e 846 (Cl-ye) rn/e 776 (CL-ye) nile 750 (FD) nile 764 (CI+ve) nile 8 18 (Cl-ye) nile 826 (Cl-ye) nile 830 (Cl-ye) nile 812 (Cl-ye) rn/c 842 (Cl-ye) nile 808 (Cl-ve) m/e 794 (CI+ve) nile 836 (Cl-ye) rn/e 721 (Cl-ye) nile =749 (Cl-ye) nile 737 (Cl-ye) nile 779 (Cl-ve) rn/e 757 (Cl-ye) nile 780 (Cl-ve) nile 736 (Cl-ve) q ~1 -i--i 33 Table 1 (coninued) [coR3 R2 I Physical data 00 000 0000 0 00 o 0 00 00 0 0 0000 0000 0 r~ 0000 0 00 00 0 0 000000 0 0 000000 0 0 0000 0 00 00 00 0 0 0 1.44 1.45 1.46 NH-C0O

NH-CO

NH-CO

C1

N

sIN

F

3 CO

F

3

C

C1 F3C/ 0/ 0--0- C 2

H

5

C

2

H

5

C

2

H

5

C

2

H

5

CAH

CAH

mle 1014 (Cl-ye) rn/e 1019 (Cl-ye) rn/e 1045 (Cl-ye) m/e =973 (Cl-ye) mle 1007 (Cl-ye) n/e 1007 (Cl-ve) 1.47 1INH-CO 1.48 1INH-CO

NH-CO

0- I L .1 the corresponding British patent 2 167 751B.

-34- Formulation Examples for a compound of formula I percent by weight) Wettable powder a) b) c) a compound of Table 1 25 50 75 sodium ligninsulfonate 5 5 sodium laurylsulfate 3 5 sodium diisobutylnaphthalenesulfonate 6 10 octylphenol polyethylene glycol ether (7-8 mol EO) 2 highly dispersed silicic acid 5 10 10 kaolin 62 27 o *o The active ingredient is thoroughly mixed with the adjuvants and the mixture is ground in a suitable mill, to give wettable powders which can be diluted with water to any desired S concentration.

000 Emulsifiable concentrate a compound of Table 1 10 octylphenol polyethylene glycol ether (4-5 mol EO) 3 calcium dodecylbenzenesulfonate 3 o castor oil polyglycol ether (36 mol EO) 4 cyclohexanone 30 xylene mixture 50 *o Emulsions of any desired concentration can be prepared from this concentrate by dilution with water.

Dusts a) b) a compound of Table 1 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.

Meloidogyne, Heterodera, Pratylenchus, Ditylenchus, Radopholus, Rizoglyphus and others.

Extruder granulate a compound of Table 1 sodium ligninsulfonate carboxymethyl cellulose kaolin 10 2 1% 87 The active ingredient is mixed and ground with the adjuvants and the mixture is moistened with water. This mixture is extruded and then dried in a stream of air.

aQ 6 00Q o p o a a a a4 o a a a 0 t ft 8 t

C

t tt t al t4 a Tablets and boluses I a compound of Table 1 methyl cellulose highly dispersed silicic acid corn starch 33.0 0.80 0.80 8.40 The methyl cellulose is stirred in water and allowed to swell. The silicic acid is added, with stirring, to give a homogeneous suspension. The active ingredient and corn starch are mixed, the aqueous suspension is added to this mixture, and the mass is kneaded to a paste. This paste is gianulated through a sieve (mesh size 12 M) and the granules are dried.

U

II cryst. lactose corn starch microcryst. cellulose magnesium stearate 22.50 17.00 16.50 1.00 All 4 adjuvants are well mixed.

Phases I and II are mixed and compressed to tablets or boluses Injectables A. Oily vehicle (slow release) a compound of Table 1 groundnut oil 0.1-1.0 g ad 100 ml chosen in accordance with the intended objectives and the prevailing circumstances.

1 -36a compound of Table 1 sesame oil 0.1-1.0 g ad 100 ml Preparation: With stirring and, if appropriate, with gentle heating, the active ingredient is dissolved in a part of the oil, the solution is bulked to the nominal volume after cooling and sterilised by filtration through a suitable 0.22 utm membrane.

B. Water-miscible solution (medium rate of release) a compound of Table 1 0.1-1.0 g 4-hydroxymethyl- 1,3-dioxolane (glycerol formal) 40 g 1,2-propanediol ad 100 ml Qoae o 0 o*0 o 0 a compound of Table 1 glycerol dimethylketal 1,2-propanediol 0.1-1.0 g 40 g ad 100 ml Preparation: With stirring, the active ingredient is dissolved in a part of the solvent and the solution is bulked to the nominal volume and sterilised by filtration through a suitable 0.22 m membrane.

oc 0 000 o 0 C. Aqueous solubilisate (rapid release) a compound of Table 1 polyethoxylated ricinus oil (40 ethylene oxide units)* 1,2-propanediol benzyl alcohol aqua ad inject.

0.1-1.0 g 10 g 20 g 1 g ad 100 ml 000* a Commercially available under the registered trademark CREMOPHOR® EL (BASF

AG);

a compound of Table 1 polyethoxylated sorbitan monooleate ethylene oxide units)** 4-hydroxymethyl- 1,3-dioxolane (glycerol formal) 0.1-1.0 g 8 g 20 g so-- l; orO water. ll Ut soybean oil; or water.

-37benzyl alcohol aqua ad injekt.

i g ad 100 ml 0 o *04 a o a a a3 o 0 o at a aa a ae a a Commercially available under the registered trademark TWEEN® 80 (ICI); Preparation: With stirring, the active ingredient is dissolved in the solvents and the surfactant and the solution is bulked to the nominal volume and sterilised by filtration through a suitable 0.22 .m membrane.

The aqueous systems may also preferably be used for oral and/or intraruminal administration.

Biological Examples B 1: Action against LI larvae of Lucilia sericata 1 ml of an aqueous suspension of the 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 of active ingredient is obtained. About 30 Lucilia larvae (L 1 are put into each test tube. A mortality count is made after 4 days. The compounds of formula I, for example those of Examples P1 to P7, achieve complete kill at 250 ppm.

B2: Acaricidal action against Boophilus microplus (Biarra strain) Adhesive tape is applied horizontally across a PVC plate so that 10 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 pl1 of a liquid consisting of a 1:1 mixture of polyethylene glycol and acetone, in which mixture a specific amount of the test compound of 1.0 pLg per tick is dissolved. Control ticks are injected with liquid containing no test compound. After this treatment, the ticks are detached from the support and kept in an insectarium under normal conditions at about 28°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 90 i.e. the effective dose is determined at which 9 out of 10 female ticks (90 even after days lay eggs from which larvae are unable to hatch.

Compounds of formula I, for example of Table 1, have an IR90 at a c ,centration of gg/g.

salts of dodecylbenzenesulfonic acid, dibutylnaphthalenesulfonic acid, or of a naphthalenesulfonic acid/formaldehyde condensation product. Also suitable are -38- B3: Trial with sheep infected with nematodes (Haemonchus contortus 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 contortus and Trichostrongylus colubriformis. 1 to 3 animals are used for each dose. Each sheep is treated only once with a single dose of 1 mg or 0.5 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 S° 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 o treated with compounds of formula I of Table 1 at 1 mg/kg.

I 0 B4: 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 Aedes aegypti are S. 00 put into each beaker. Mortality counts are made after 1, 2 and 5 days.

0' In this test, compounds of formula I of Table 1 at low concentration achieve complete kill Sof all larvae after 1 day.

B.5 Miticidal action against Dermanyssus gallinae 2 to 3 ml of a test solution containing 100 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 formula I of Table 1 kill the mites at the given concentration.

L

Claims (4)

1. A compound of formula I .CH 3 000 000 0 0 00 0 00"0 00 coo- 060 000. wherein R 2 is methyl, ethyl, isopropyl, sec-butyl or the group -C(CH 3 )=CHQ wherein Q is methyl, ethyl or isopropyl; and R, is the group R 3 -X-NH CH 2 CF1 2 -S- whereir, X is a member selected from the group consisting of -NHC(O)-, -NHC(S)- or -SO 2 and R 3 is hydrogen, Heti, unsubstituted CI-C 8 alkyl or C 1 -C 8 alkyl which is substituted by C 1 -C 4 alkoxy, CI-C 4 alkylthio, C 2 -C 5 alkoxycarbonyl, halogen, CN, N0 2 COOH or NH 2 or is unsubstituted C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkyi which is substituted by Cl-C 4 alkoxy, C 1 -C 4 alkylthio, C 2 -C 5 alkoxycarbonyl, halogen, CN, NO 2 COOH or N-H 2 or is the group /.4f 1 (SQ, i =6z tiz)karomatnc H-) wherein n is 0, 1 or 2, Ra',Rb and R, are each independently of one another hydrogen, CI-C 4 alkyl, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, CI-C 4 haloalky1, C 1 -C 4 haloalkoxy, Cl-C 4 haloalkylthio, C 2 -C 6 alkoxy- alkoxy, Cl-C 5 alkanoyloxy, Cj-C 5 alkoxycarbonyl, halogen, CN, NO 2 or NH 2 and may additionally be C 3 -C~cycloalkyl or the group Het 2 -O- and Het, and Het 2 are an unsubstituted or substituted heterocycle which is bound through carbon and is selected from the group consisting of benzimidazole, benzoxazole, benz- thiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline, phthialazine, quinazoline and benzotriazine; or a physiologically acceptable acid addition salt thereof. 000 0000 0000 0* 0 0 .000 0 00. 0 000.~ 0000 4 0*00 0000 o e 00 0 000C 00 0 4 0 0CC fl 0 0 0004 0400 0 0

2. A compound of formula I according to claim 1, wherein R 2 is methyl, ethyl, isopropyl, sec-butyl or the group -C(CH 3 )=CI-Q wherein Q is methyl, ethyl or isopropyl; and R, is the group R 3 -X-NH CH 2 CH 2 -s- wherein X is a member selected from the group consisting of -NHC(O)-, -NHC(S)- oder -SO 2 and R 3 is hydrogen, HetI, unsubstituted CI-C~alkyl or C 1 -Cgalkyl which is substituted by Cl-C 4 -Alkoxy, Cl-C 4 alkylthio, C 2 -C 5 alkoxycarbonyl, halogcn, CN, NO 2 COOH or NH 2 or is unsubstituted C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkyI which is substituted by Ci-C 4 alkoxy, Cl-C 4 alkylthio, C 2 -C 5 alkoxycarbonyl, halogen, CN, NO 2 COOL- or NH 2 oris the group (CH 2 n

7.63 J 8 Hz)(aromatic H) mass spectrum (CI-ve) m/e: 847 (C 7 H 61 N0 9 S 2 -41- wherein n is 0, 1 or 2, Ra, Rb and Rc are each independently of one another hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalklth-io, C 9 -C 6 alkoxy- alkoxy, C 1 -C 5 alkanoyloxy, CiC 5 alkoxycarbony1, halogen, CN, NO 2 or Ni 2 and R, may additionally be C 3 -C 8 cycloalkyl or the group Het 2 and Het, and Het 2 hereinafter comprised under Het, are each a group selected from the series a to u: 0 a aI .0 o 0 9 0%11 O 0 L silica gel (dichioromethane/methanol 4:1) gives 22 mg of 13p-(2-[4-(carboxymethy1- aminocarbonylarnino)phenyl]ethylthio)milbemycin A4. 42 Group Type 3 N- 2)Y benzimidazol-2-yl benzoxazol-2-yl benzthiazol-2-yl a a a a 0 a a a o 0 00 a a a a 00 a a a 00 4R 8 4 N3 -R 8 5 zI, N 2 N N\I 2 3 4 2x Y" 5 1 2 4 irnidazol-2-yl oxazol-2-yl thiazol-2-yl [1H-l ,2,4-triazol]-5-yl [1 ,2,4-oxadiazol]-5-yl [1 ,2,4-thiadiazol]-5-yl [1 ,2,4-oxacliazol]-3-yl 1,2,4-thiadiazol] -3-yl El H-I ,2,4-triazol]-3-yl [1 ,3,4-oxadiazol]-2-yl [1 ,3,4-thiadiazol]-2-yl *[4H-l,2,4-triazol]-3-yl [1H-1 ,2,4-triazol]-5-yl 0 6 I 4 0 4610 A I I I' II 4 pyridin-2-yl pyridin-3-yl pyrn-4-yl 43 Group Type E2~ 1 pyridazin-3 -yl pyridazin-4-yl pyrimidin-2-yl pyrimidin-4-yI 0 00 0 0 4a 0 0-0 0000 0 000% 'I' 0 0 (*4 4 4 I El __NJLE Ej 2 4 N -4- 2 N 2 N pyrazin-2-yl s-triazin-2-yl 1,2,4-tritzin] -3-yl [1 ,2,4-triazin]-5-yl [1 ,2,4-triazinl-6-yl [1,2,3-triazin]-4-yl [1 ,2,3-triazin]-5-yl quinolin-2-yl quinolin-3-yl quinolin-4-yl 1.20 S0 2 p-tolyl C 2 H 5 m/e 847 (Cl-ye) 44 Group Type isoquinolin- l-yl isoquinolin-3-yl isoquinolin-4-yl El E 2 N "I9 NI E 3 quinoxalin-2-yl o 000 'Ott *9* II 9 Ott' 9 1*4 It 0 I I Gist phthalazin-3-yl quinazolin-2-yl quinazolin-4-yl 4** test *1*f It it 1 El N) 4 F [1 ,2,4-benzotriazin]-3-yl H [1 ,2,3-benzotriazin]-4-yl 1.43 1NH1-CO1 CF! 3 ICF! 3 I me= 736 (CI-ve) rn~ 45 in which formulae 0 0 004 00 0 0 0 0400 0 000 00 0 0 4 0004 0040 0 4400 0000 0 00 t o00Ct~ I 000000 0 4 0000 0 0 04 *4 00 4 0 0 Y is oxygen, sulfur or NRI 0 Z is oxygen, sulfur or NH; R 6 and R 7 are each independently of the other hydrogen, Cl-C 4 alkyl, Cl-C 4 haloalkyl, Cr-C 4 alkoxy, CI-C 4 haloalkoxy, CI-C 4 alkylthio, C 1 -C 4 alkylsulfonyl, Cl-C 4 alkylsulfinyl, CI-C 4 haloalkylsulfonyl, Cl-C 4 haloalkylsulfinyl, halogen, nitro or cyano; R 8 and R 9 are each independently of the other hydrogen, Cl-C 6 alkyl, Cl-C 6 haloalkyl, Cl-C 6 alkoxy, CI-C 6 alkylthio, halogen or nitro; or are each independently of the other unsubstituted C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl which is substituted by halogen or CI-C 3 alkyl; RIO is hydrogen or Cl-C 6 alkyl; RII is Cl-C 6 alkyl; and El, E 2 and E 3 are each independently of one another hydrogen, Cl-C 4 alkyl, Cj-C 4 halo- alkyl, C 1 -C 4 alkoxy, Cl-C 4 haloalkoxy, Cl-C 4 alkylthio, C 1 -C 4 haloalkylthio, C 2 -C 6 alkoxy- alkoxy, Cl-C 5 alkanoyloxy, C-TC 5 alkoxycarbonyl, C 3 -C 8 cycloalkyl, halogen, CN, NO 2 or NH 2 3. A compound of formula I according to claim 2, wherein EI, E 2 and E 3 are each independently of one another hydrogen, methyl, ethyl, CF 3 methoxy, OCF 3 methylthio, CH 3 OCH 2 O, cyclopropyl, fluoro, chloro or bromo, and the other substituents are as defined in claim 2. 4. A compound of formula I according to claim 2, wherein R 8 and R 9 in the groups b to f are each independently of the other C 3 -C 7 cycloalkyl which is unsubstituted or substituted by halogen or CI-C 3 alkyl and the other substituents and Y and Z are as defined in claim 2. A compound of formula I according to claim 2, wherein the substituent Het is R6 A-0 0'R7 R6 N Is -46- N R 8 NR 8 N R 8 N I~ R 9 o Rs NR 8 R 8 R 8 c NNN N N c)N 'N N ,N 'N N 0~ s~ R 8 o R8 s~ H N R 8 N N-- o :0 N N 1 3 N -N 4 3 N-N 4 bo0 N-11 R 9 o R 9 s R 9 0

40. 1 1 0*0~:N R9 and the other substituents are as defined in claim 2. 0 6. A compound of formula I according to any one of claims 2 to 5, wherein R 2 is Methyl or 0 ethyl. 7. A compound of formula I according to claim 1, wherein R 2 and R 3 are each independently of the other methyl, ethyl or isopropyl, and X is as defined for formula I. 8. A compound of formula I according to claim 1, wherein R 2 is methyl, ethyl, isopropyl or sec-butyl R, is the group R 3 -X-NH 0-CH 2 CH 2 -S- Ready for use dusts are obtained by mixing the active ingredient with the carrier and grinding the mixture in a suitable mill. -47- wherein X is a group selected from -NHC(S)- and -SO 2 and R 3 is C 1 -C 8 alkyl or C 3 -C 6 cycloalkyl. 9. A compound of formula I according to claim 1, wherein R 2 is methyl, ethyl, isopropyl or sec-butyl; R 1 is the group R 3 -X-NH CH 2 CH 2 -S- wherein X is a group selected from -NHC(S)- and -SO 2 and R 3 is the group 0 R(C 2 R C o o wherein n is 0 or 1, and Ra, Rb and R, are each independently of one another hydrogen, C 1 -Czalkyl, C 1 -Czalkoxy, CI-C 2 alkylthio, Cl-C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 2 haloalkylthio, halogen or NO 2 Sand R. may additionally be the group Het 2 wherein Het 2 denotes the groups as S indicated for formula I. 10. A compound of formula I according to claim 2, wherein R 2 is methyl, ethyl, isopropyl orsec-butyl; R 1 is the group Ooo R 3 -X-NH CH 2 CH 2 -S- wherein X is a group selected from or and R 3 is Hetj, unsubstituted C 1 -C 6 alkyl or C 1 -C 6 alkyl which is substituted by C 1 -C 4 alkoxy, Cl-C 4 alkylthio or halogen, unsubstituted C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl which is substituted by C 1 -C 2 alkoxy, C 1 -C 2 alkythio or halogen, or is the group groundnut oil ad 100 ml -48- Ra R b (CH2)n ,wherein n is 0 or 1; R Ra, Rb and Re are each independently of one another hydrogen, fluoro, chloro, bromo, methyl, methoxy, methylthio, CF 3 or NOz, and R, may additionally be the group Het 2 -O- wherein Het, and Het 2 are one of the groups to f) defined for Het in claim 5, and the other substituents are as defined for claim 2. 11. A compound of formula I according to claim 1, wherein R 2 is methyl, ethyl, isopropyl or sec-butyl; R 1 is the group :n0R 3 -X-NH CH 2 CH 2 -S- wherein X is and R 3 is unsubstituted C 1 -C 6 alkyl or C 1 -C 6 alkyl which is substituted by CI-C 4 alkoxy, C 1 -C 4 alkylthio or halogen. 12. A compound of formula I according to claim 1, wherein R 2 is methyl, ethyl, isopropyl or sec-butyl; R 1 is the group R 3 -X-NH CH 2 CH 2 -S- wherein X is or and R 3 is hydrogen; unsubstituted C 1 -C 8 alkyl or C 1 -C 8 alkyl which is substituted by Cl-C 4 alkoxy, C 1 -C 4 alkylthio, C 2 -C 5 -alkoxycarbonyl, halogen, CN, NO 2 COOH or NH 2 S unsubstituted C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkyl which is substituted by C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 2 -C 5 alkoxycarbonyl, halogen, CN, NO 2 COOH or NH 2 13. A compound of formula I according to claim 2, wherein R 2 is methyl, ethyl, isopropyl or sec-butyl; R 1 is the group R 3 -X-NH CH 2 CH 2 -S- L Z-U cUlyltuII, UxIUt U111I:') 0 4-hydroxymethyl- 1 ,3-dioxolane (glycerol formal) 20 g -49- wherein X is or and R 3 is the group R a R b!6 nC 2 wherein n is 0 or 1, and Rai Rb and R, are each independently of one another hydrogen, Cl-C 2 alkyl, Cl-C 2 alkoxy, Cr-C 2 alkylthio, Cl-C 2 hialoalkyl, 01 -C 2 haloalkoxy, 0 -C 2 haloalkylthio, halogen or NO 2 and RC may additionally be the group Het 2 wherein Het 2 is one of the groups to F) defined for Het in claim 5 and the other substituents are as defined in claimi 2. 14. A compound of formula I according to claim 1, wherein R R 2 is methyl, ethyl, isopropyl or sec-butyl; R, is the groupR 3 XN CHC 2 S wherein X is or and R 3 is the group R R a b (CH 2 wherein n isO0 or 1, and S RC Ra, Rb and are each independently of one another hydrogen, Cl-C 2 alkyl, CI-C 2 alkoxy, *4~Cl-C 2 alkylthio, CI-C 2 haloalkyl, Cl-C 2 haloalkoxy, CI-C 2 hialoalkylthio, halogen or NO 2 A compound of formula I according to claim 1, wherein 441 R 2 is methyl or ethyl; R, ''Ris the group R 3 -X-NH CH 2 CH 2 -S- wherein X is and R 3 is CI-C 6 alkyl. 16. A compound of formula I according to claim 1, selected from the group consisting of: 1 3p-[2-(4-acetaminophenyl)ethylthio] milbemycin A4; 13 p-(2-[4-(4-heptylcarbonylamino)phenyl]ethylthio)milbemycin A4; Compounds of formula 1, for example of Table 1, have an IR90 at a (icentration of ptg/g. 50 13 [4-(2,6-dichloropyridi n-4-ylcarbonylamino)phenyllethylthio)-milbemycin A4; 13p-(2-[4-tosylphenyl]ethylthio)nmilbemycin A4; 13p-(2-[4-(methylaminothiocarbonylamino)phenyl]ethylthio)milbemycin A4; 3P1-(2- E4-(benzy ltan-inocarbonylarnino)phienyl] ethyl thio)milbemycin A4; 1 33- [4-(cyclohexylaminocarbonylanmino)phenyl] ethylthio)milbemycin A4; 1 3f-(2-[4-((4-methoxyphenyl)arninocarbonylarnino)phenyl]ethylthio)milbemycin A4; 13p-(2-[4-(carboxyrnethylamninocarbonylamino)phenyl]ethylthio)milbemycin A4; and 13 Pj-(2- [4-(methoxycarbonyl amin o)phenyl] ethyl th io)m il bemyci n A4. 17. A process for the preparation of a compound of formula I according to claim 1, which comprises reacting a compound of formula I1 ~4 4, 4*4 ala 4 *a I Ia a I I 4 4 CH 3 H2N--OCH 2 CH 2 -S H 3 C 0 4 wherein R 2 is as defined for formula 1, ca) where X in formula I is or in the absence, or preferably in the presence, of an acid acceptor, with a compound of formula III R 3 -X-T (III) wherein R 3 is as defined for formula 1, X is or and T is a leaving group; 3)where X in formula I is with an isocyanate of formula IV R 3 -N=C=O or with an aminoacylating agent of formula V R -NH-C(O)-D (IV) Compounds of formula I of Table 1 kill the mites at the given concentration. -51- wherein R 3 in formulae (IV) and is as defined for formula I, and D is a leaving group as defined for T or is preferably unsubstituted or substituted phenoxy; y) where X in formula I is with an isothiocyanate of formula VI R 3 -N=C=S (VI), wherein R 3 is as defined for formula I; and 6) where X in formula I is SO 2 with a sulfonating agent of formula VIa R 3 -S0 2 -T (VIa), wherein R 3 is as defined for formula I and T is as defined in ax), in the absence, or preferably in the presence, of an acid acceptor. 18. An insecticidal and parasiticidal composition which contains, as active ingredient, a compound of formula I as claimed in any one of claims 1 to 16 together with at least one insecticidally/parasiticidally acceptable carrier, adjuvant and/or diluent. 19. A method of controlling parasitic pests of animals, which comprises applying to said pest or to the locus thereof, a pesticidally effective amount of a compound of formula I as claimed in any one of claims 1 to 16. A method according to claim 19, wherein the pests are endo- or ectoparasites of productive livestock. 21. A 13p-phenylethylthiomilbemycin derivative substantially as hereinbefore described with reference to any one of the Examples P1-P7 or Table 1. 22. A process for preparing a 13 P-phenylethylthiomilbemycin derivative substantially as hereinbefore described with reference to any one of the r 'mples P1-P7 or Table 1. :23. An insecticidal and parasiticidal composition substantially as hereinbefore described with reference to any one of the Formulation Examples. 25 24. An insecticidal and parasiticidal composition which contains, as active Singredient, a compound of formula I as claim 21 together with at least one insecticidally/parasiticidally acceptable carrier, adjuvant and/or diluent. A method of controlling parasitic pests of animals, which comprises applying to said pest or to the locus thereof, a pesticidally effective amount of a compound of 30 formula I as claimed in claim 21 or of a formulation according to any one of claims 18, 23 or 24. Dated this SEVENTEENTH day of SEPTEMBER 1992 o Ciba-Geigy AG 0 o Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON