NZ236290A

NZ236290A - 13beta-(aminophenylethylthio) milbemycin derivatives, use as parasiticides

Info

Publication number: NZ236290A
Application number: NZ236290A
Authority: NZ
Inventors: Anthony Cornelius O'sullivan
Original assignee: Ciba Geigy Ag
Priority date: 1989-12-01
Filing date: 1990-11-30
Publication date: 1993-04-28
Also published as: DK0430884T3; ZA909627B; EP0430884B1; TW202452B; CA2031149A1; EP0430884A1; ATE116992T1; ES2066191T3; KR910011860A; AU6764790A; DE59008250D1; KR0155167B1; AU631268B2

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

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £36290 Henry Hughes Ltd 236290 Priority Date(s): ..IJX Complete Specification Filed: &Q\V:.C<S?. Class: ;_ Publication Date: ^7.^ . j^93 P.O. Journal, No: /3.^> 7. NO DRAWINGS Patents Form 5 N.Z. No. NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION (L.oes INSECTICIDES AND PARATICIDES We, CIBA-GEIGY AG, a Swiss Corporation of Klybeckstrasse 141, 4002 Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement - 1 - (Followed by 1A) 2362 1A I ) ii.pitf ngfiif. Insecticides and parasiticides 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. The novel compounds have the general formula I wherein R2 is methyl, ethyl, isopropyl, sec-butyl or the group -C(CH3)=CHQ wherein Q is methyl, ethyl or isopropyl; and R.! is the group wherein X is a member selected from the group consisting of -C(O)-, -OC(O)-, -NHC(O)-, (I) OH 23 6 - 2 - -NHC(S)- or -S02-; and R3 is hydrogen, Hetlt unsubstituted CpCgalkyl or CpCgalkyl which is substituted by CpQalkoxy, C1-C4alkylthio, C2-C5alkoxycarbonyl, halogen, CN, NO2, COOH or NH2; or is unsubstituted C3-C8cycloalkyl or C3-Cgcycloalkyl which is substituted by C]-C4alkoxy, C1-C4alkylthio, C^Cjalkoxycarbonyl, halogen, CN, N02, COOH or NH2; or is the group wherein n is 0, 1 or 2, Ra, Rband Rc are each independently of one another hydrogen, Cj-C4alkyl, Ci-C4alkoxy, CrC4alkylthio, CrC4haloalkyl, CrC4haloalkoxy, CrC4haloalkylthio, C2-C6alkoxy-alkoxy, Cj-Csalkanoyloxy, Cj-Csalkoxycarbonyl, halogen, CN, N02 or NH2, and Rc may additionally be C3-Cscycloalkvl or the group and Het! and Hct2 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, phthalazine, quinazoline and benzotriazinc; and the physiologically acceptable acid addition salts thereof. When Hetj or Het2 is a fused ring system, the heterocyclic pan of the molecule is always attached to the remainder of the entire molecule. The heterocycles Heti 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 Het2, has one of the following meanings, constitute one of the following preferred groups of compounds a to u, according to the definition of Het: Het2-0-, 23 6 2 90 -3- Group Het Type a) 3 N' 4 /6 Y 1 7 R7 benzimidazol-2-yl benzoxazol-2-yl bcnzthiazol-2-yl b) 3 N ■ R9 imidazol-2-yl oxazol-2-yl thiazol-2-yl c) d) 4 N n 3 z 4 c ,Rs N: >>Vv [ 1H-1,2,4-triazol]-5-yl [ 1,2,4-oxadiazol J-5-yl [l,2,4-thiadiazol]-5-yl [ 1,2,4-oxadiazol]-3-yl [ 1,2,4-thiadiazol]-3-yl [ 1H-1,2,4-triazol]-3-yl ln e) (2*) 3 N N 4(1«) (3*) Wv>\5(5*) , R9 (4*) [ 1,3,4-oxadiazol]-2-yl [l,3,4-thiadiazol]-2-yl * [4H-1,2,4-triazol]-3-yl f) Rn 1 NN N 2 5 N 3 R. [ 1H-1,2,4-triazol]-5-yl g) N' pyridin-2-yl pyridin-3-yl pyridin-4-yl 236290 -4 Group Het Type h) i) E2 El n 1 N 3 pyridazin-3-yl pyridazin-4-yl pyrimidin-2-yl pyrimidin-4-yl pyrimidin-5-yl k) 1 e, 'N' A pyrazin-2-yl 1) 5N^/N3 E2 s-triazin-2-yl m) 1 /E> *n' 4 [l,2,4-triazin]-3-yl [l,2,4-triazin]-5-yl [l,2,4-triazin]-6-yl n) «—E2 ^ 2 N [l,2,3-triazin]-4-yl [l,2,3-triazin]-5-yl o) 4 /E] Z2 quinolin-2-yl quinolin-3-yl quinolin-4-yl 2362 9 o -5- Group Het Type 4 E P) q) ,N. -N *n 1 H e3 e2 E3 isoquinolin-l-yl isoquinolin-3-yl isoquinolin-4-yl quinoxalin-2-yl /2 iN ■ e3 phthalazin-3-yl s) U) /E1 /2 e3 e, e2 e, n' quinazolin-2-yl quinazolin-4-yl [l,2,4-benzotriazin]-3-yl [ 1,2,3-benzotriazin]-4-yl 2362 9 -6- in which formulae Y is oxygen, sulfur or NR10; Z is oxygen, sulfur or NH; Rg and R7 are each independently of the other hydrogen, Ci-C4alkyl, Cj-Qhaloalkyl, CrC4alkoxy, CpQhaloalkoxy, Ci-C4alkylthio, CrC4alkylsulfonyl, CpQalkylsulfinyl, Ci-C4haloalkylsulfonyl, CpCjhaloalkylsulfinyl, halogen, nitro or cyano; Rg and R9are each independently of the other hydrogen, Cj-C^alkyl, CpCghaloalkyl, CpCgalkoxy, CrC6alkylthio, halogen or nitro; or are each independently of the other unsubstituted C3-C7cycloalkyl or C3-C7cycloalkyl which is substituted by halogen or Cj^alkyl; R10 is hydrogen or CrC6alkyl; rjj is Ci*C6alkyl; and Ej, E2 and E3 are each independently of one another hydrogen, Cj-Qalkyl, Q-Qhalo-alkyl, Ci-C4alkoxy, Cj-C4haloalkoxy, Ci-C4alkylthio, CrC4haloalkylthio, C^-Qalkoxy-alkoxy, CpCsalkanoyloxy, C|-C5alkoxycarbonyl, C3-C8cycloalkyl, halogen, CN, N02 or NH2. Within the definitions of Elt E2 and E3, especially preferred meanings are: hydrogen, methyl, ethyl, CF3, methoxy, OCF3, methylthio, CH30CH20, cyclopropyl, fluoro, chloro and bromo. Within the groups b to f, those compounds of formula I are of interest wherein Y, Z, R10 and Rn are as defined above and Rg and R9 are each independently of the other C3-C7-cycloalkyl, preferably cyclopropyl or cyclohexyl, which is unsubstituted or substituted by halogen or C]-C3alkyl. Selected examples of substituents Het in the groups a to f are: W-JcCf-Jcrf-JcCf i R' R|o R' flpplll■ 23 6 2 9 n -7 N b') I' N K9 I H «8 R9 Rg 'O^ r9 Rg S ^ R9 10 N iI^R* N j]^"8 N N N c,) -^O •• jC5 rA j N O R8O 8 S H n' r-^ d'» Rs N"' R11 e') Ml f) •N N II N' ' R9 in which formulae the substituents R6 to Rn are as defined above. A further example (v) is 8 ' N 3 'J 11 ^N2 (v) wherein Rg has the meanings given above. 236 29 - 8- AU groups a) to u) of compounds of formula 1 are preferred wherein R2 is methyl or ethyl, most preferably ethyl. Within group a'), those compounds of formula I are additionally preferred in which R6and R7 are each independently of the other hydrogen, methyl, CF3, methoxy, halomethoxy, fluoro, chloro or bromo, and the other substituents are as defined for formula I. Within the groups b') to f), those compounds of formula I are additionally preferred in which R8 and R9 are each independently of the other hydrogen, methyl, ethyl, C3-C7cycloalkyl, CF3, C2F5, C3F7, CC13, CHC12, CH2C1, SCH3 or halogen; R10 is hydrogen or methyl, and Rn is CpCjalkyl, preferably methyl. Compounds of formula I meriting special interest are those in which the group Het2-0- is para-positioned to the phenyl radical. A further preferred group comprises those compounds of formula I, wherein R2 and R3 are 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 haloalkyhhio is a mono- or perhalogenated alkyl substituent such as CH2C1, CHC12, CC13, CH2F, CHF2, CF3, CH2Br, CHBr2, CBr3, CH2I, CI3, CHC1F, CHBrCl, CFBrCl, C2F5, CH2CH2C1, CHCICH3, C2CI5, CHFCHC12 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 preferably chloro. Alkoxycarbonyl is a R-OC(O)- group, wherein R is an alkyl radical, for example CH30C(0)-, C2H50C(0)-, tert-butoxy-C(O)-, and the like. Illustrative examples of C2-C6aIkoxyalkoxy are: CH30CH20, 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 23 6 2 90 9 is 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-phenoxybcnzoic 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 and productive livestock, first and foremost of the class of the mammals. A preferred subgroup of compounds of formula I comprises those compounds wherein R2 is methyl, ethyl, isopropyl or sec-butyl; Ri is the group wherein X is a group selected from -C(O)-, -OC(O)-, -NHC(O)-, -NI IC(S)- and -SO2-; and R3 is Cj-Cgalkyl, preferably Cj^alkyl, or C3-C6cycloalkyl. A further preferred subgroup of compounds of formula I comprises those compounds in which R2 is methyl, ethyl, isopropyl or sec-butyl; Rj is the group wherein X is a group selected from -C(O)-, -OC(O)-, -NHC(O)-, -NHC(S)- and -S02-; and R3 is the group 236 2 90 -10- r^: R a R R c wherein n is 0 or 1, and Ra, Rb and Rc arc each independently of one another hydrogen, Cj-C2alkyl, Cj-C2alkoxy, CpC^alkylthio, C1-C2haloalkyl, CrC2haloalkoxy, CrC2haloalkylthio, halogen or N02, and R,. may additionally be the group Het2-0-, where Het2 denotes the groups as defined under formula I. A further preferred subgroup of compounds of formula I comprises those compounds in which R2 is methyl, ethyl, isopropyl or sec-butyl; Rj is the group wherein X is a group selected from -C(O)-, -OC(O)- or -NHC(O)-; and R3 is Hetj, unsubstituted Cj-C6alkyl or Cj-C6alkyl which is substituted by Cj-C4alkoxy, Cj-C4alkylthio or halogen, unsubstituted C3-C6cycloalkyl or C3-C6cycloalkyl which is substituted by Q-Qalkoxy, CrC2alkylthio or halogen, or is the group Ra, Rb and Rc are each independently of one another hydrogen, fluoro, chloro, bromo, methyl, methoxy, rnethylthio, CF3 or N02, and Rc may additionally be the group Het2-0-, wherein Hetj and Het2 are one of the groups a') to f) as previously defined for Het. A further preferred subgroup of compounds of formula I comprises those compounds in which R2 is methyl, ethyl, isopropyl or sec-butyl; Rj is the group , wherein n is 0 or 1; 236290 -11 - R3-X-NH —$ \ ch2CH2-S- wherein X is -OC(O)-; and R3 is unsubstituted CpQalkyl or CpQalkyl which is substituted by CpQalkoxy, Cj^alkylthio or halogen. A further preferred subgroup of compounds of formula I comprises those compounds in which R2 is methyl, ethyl, isopropyl or sec-butyl; Ri is the group r3-x-nh y ch2ch2-s- wherein X is -C(O)-, -OC(O)- or -NHC(O)-; and R3 is hydrogen; unsubstituted CpCgalkyl or Cj-Cgalkyl which is substituted by C1-C4alkoxy, C1-C4alkylthio, C2-C5-alkoxycarbonyl, halogen, CN, N02, COOH or NH2; or is unsubstituted C3-C8cycloalkyl or C3-C8cycloalkyl which is substituted by CpC^alkoxy, C1-C4alkylthio, C2-C5alkoxycarbonyl, halogen, CN, N02, COOH or NH2. A further preferred subgroup of compounds of formula I comprises those compounds in which R2 is methyl, ethyl, isopropyl or sec-butyl; Rj is the group R3-X-NH \ CH2CH2-S- wherein X is -C(O)-, -OC(O)- or -NHC(O)-; and R3 is the group R. _i! 'TV 6\_ (CH2)^ wherein n is 0 or 1, and Ra, Rb and Rc are each independently of one another hydrogen, CrC2alkyl, Cj^alkoxy, CrC2alkylthio, CrC2haloalkyl, CrC2haloalkoxy, C1-C2haloalkylthio, halogen or N02, and Rc may additionally be the group Het2-0- wherein Het2 is one of the groups a') to f) as previously defined for Het. 236290 - 12 - A further preferred subgroup of compounds of formula 1 comprises those compounds in which R-2 is methyl, ethyl, isopropyl or sec-butyl; R! is the group r3x-nh —$ \ ch2ch2-s- wherein X is -C(O)-, -OC(O)- or -NHC(O)-; and R3 is the group R. ' a R. 6^. ^ (CH2hj ( wherein n is 0 or 1, and R'c Ra, Rb and Rc are each independently of one another hydrogen, CrC2aIkyl, Ci-C2alkoxy, C^^alkylthio, Ci-C2haloalkyl, C]-C2haloalkoxy, Ci-C2haloalkylthio, halogen or N02. A further preferred subgroup of compounds of fomiula I comprises those compounds in which R2 is methyl or ethyl; Rj is the group r3-x-nh $ \ ch2ch2-s- wherein X is -OC(O)-, and R3 is CrC6alkyl. A further preferred subgroup of compounds of formula I comprises those compounds in which R2 is methyl or ethyl; Rj is the group r3-X-nh $ y ch2ch2-s- wherein X is -OC(O)-, and R3 is phenyl or benzyl. Preferred individual compounds of formula I include the following compounds: 13p-[2-(4-acetaminophenyl)ethylthio]milbemycin A4; 13P-(2-[4-(4-heptylcarbonylamino)phenyl]ethylthio)milbemycin A4; 13P-(2-[4-(2,6-dichloropyridin-4-ylcarbonylamino)phenyl]ethylthio)-milbemycin A4; €> 236290 - 13- 13P-(2-[4-tosylphenyl]cthyIthio)milbemycin A4; 13P-(2-[4-(methylaminothiocarbonylamino)phenyl]cthylthio)milbemycin A4; 13P-(2-[4-(benzoylaminocarbonylamino)phenyl]ethylthio)milbemycin A4; 13P-(2-[4-(cyclohexylaminocarbonylamino)phenyl]ethylthio)milbemycin A4; 13p-(2-[4-((4-methoxyphcnyl)aminocarbonylamino)phcnyl]ethylthio)milbcmycin A4; 13P-(2-[4-(carboxymethylaminocarbonylamino)phenyl]cthylthio)milbemycin A4: and 13P-(2-[4-(methoxycarbonylamino)phenyl]ethylthio)milbemycin A4. Throughout this specification, compounds in which R2 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 a-OH group in position 13), however, can be converted into milbemycin derivatives in accordance with US patent specification 4 173 571. Naturally occurring milbemycins (R2 = CH3, C2H5 or isoC3H7) have solely hydrogen in 13-position in place of the thioether group (R,) in the compounds of formula I, as the formula XXX below shows: • / (XXX) OH r2 = CH3 r2 = c2h5 r2 = isoC3H7 r2 = sec.c4h9 milbemycin A3 milbemycin A4 milbemycin D 13-deoxy-22,23-dihydro-C-076-Bla-aglycone. 236290 - 14 - Avermectins, however, carry in 13-position an a-L-oleandrosyl-a-L-oleandrose radical which is attached through oxygen in the a-configuration to the macrolide molecule. Moreover, avermectins differ structurally from milbemycins by the presence of a 23-OH group or A22'23 double bond and, usually, by the presence of a substituent Rj = sec-C4H9. Hydrolysis of the sugar residue of avermectins readily affords the corresponding avermectin aglycones containing a 13a-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 422,23 double bond is always in hydrogenated form and the substituent in the 13 position is always C-oriented. Compounds of formula I, wherein R2 is the group —C=CH—Q and CH3 Q is methyl, ethyl or isopropyl, may be understood as 23-deoxy derivatives of the naturally occurring antibiotic S541, but they contain in 13-position a P-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 „ /corresponding to GB 2166 436 Offenlegungsschnft 3 532 794 and is as follows: \ °^° OH h 1/ O- h ch3 or, (antibiotics S541) 2362 90 - 15- factor A factor B factor C factor D factor E factor F R2* = isoC3H7 R2*=CH3 R2* = CH3 R2* = C2H5 . R2* = C2H5 R2* = isoC3H7 Ri* =H Rj* = CH3 R,* =H Rj* = H R,* = CH3 R!* = CH3 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 75IB. Surprisingly, however, the biological activity of the 13p-ethylthiomilbemycins can be significantly enhanced by introducing the terminal r3-x-nh group (wherein R3 and X are as defined for fomiula I) into the 2-position of the 13(3-ethyl group. A comparison of, for example, compound No. 1.14 of the above publications ch3ch2-s HiC [compound A] oh O c2H5 comp. No. 1.14 of EPO 184 173 and. GB2 167 751B h ch3 oh with compound 1.13 of this invention (q.v. Table 1) 236290 © - 16- ch3oc — nh O II 17 '-o- V " h3c [compound B] oh according to Biological Example B-3 in sheep which have been infected with the nematodes Hacmonchus contortus und Trichostrongylus colubriformis, gives the following results after one intraluminal 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 (repeat ofl) Control compound A of the prior art 50% 58% 0 compound B of the present invention 99 % 93% 0 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 236290 - 17 - n\ h2n f \ h2ch2-s HiC N °v° h oh >h (II). o- 'Clb OH wherein R2 is as defined for formula I, by a) in those cases in which X in fomiula I is -C(O)- or -OC(O)-, reacting said compound of formula II, in the absence, or preferably in the presence, of an acid acceptor, with a compound of fonnula III R3-X-T (III) wherein R3 is as defined for formula I, X is -C(O)- or -OC(O)-, 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 alkylsulfonyloxy such as mesyloxy or, if X in Formel III is -C(O)-, the corresponding radical -0-C(0)-R3 of the anhydride of a carboxylic acid, for example of acetic acid. 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. © 23 62 9 -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 -20° to +100°C, preferably from 0° to 50°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, diisopropylmethylamine, tripropylamine, and the like), pyridine and pyridine bases (4-diinethylaminopyridine, 4-pyrrolidylaminopyridine and the like). Pyridine is preferred. The acid acceptor is normally used in at least equimolar amount, based on the starting materials. (3) Where X in formula I is -NH-C(O)-, the compound of fomiula II is reacted with an isocyanate of fomiula IV R3-N=C=0 (IV) or with an aminoacylating agent of fomiula V R3-NH-C(0)-D (V) wherein R3 in formulae (IV) and (V) is as defined for fomiula I and D is a leaving group as defined for T, or is preferably unsubstituted or substituted phenoxy. This reaction too is preferably carried out in one of the inert solvents cited in a) and in the temperature range indicated therein. y) Where X in formula I is -NH-C(S)-, the procedure as described in (5) is carried out, with the proviso that, in place of the isocyanate IV, an isothiocyanate of formula VI R3-N=C=S (VI), is used, wherein R3 is as defined for formula I. 5) Where X in formula I is S02, the procedure as described in a) is carried out, with the proviso that, in place of the acylating agent of fomiula III, a sulfonating agent of fomiula Via is used, R3-S02-T (Via), wherein R3 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 236290 -19- is -NH-C(O)-, comprises reacting a compound of formula I, wherein X is -OC(O)- and R3 is 4-nitrophenyl, for example compound 1.17 (Table 1), with an amine of formula Vlb R3-NH2 (Vlb) wherein R3 is as defined for formula I. The starting compounds of formula II are obtainable from compounds of formula VII 0-)n f S h2ch2-s H-.C \ (VII) oh O' >CH3 oh by reduction of the terminal nitro group. Any suitable method of reducing N02 to NH2 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 0° 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. 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 Rt-C(0)-, where Rt is Cj-Cjoalkyl, Cj-C10haloalkyl or a member selected from the group consisting of phenyl and benzyl which is unsubstituted or substituted by halogen, CrC3alkyl, Cp^haloalkyl, CrC3alkoxy, CrC3haloalkoxy, cyano and/or nitro and, preferably, C]-C6alkyl, CpCghaloalkyl or phenyl or phenyl which is substituted by halogen, Cj-C3alkyl, CF3 or nitro. Silyl groups suitable for protecting OH group are the radical -Si(Rx)(Ry)(Rz_) 0., © 236290 -20- whercin Rx, Ry and Rz are cach preferably independently of one another CrC4alkyl, benzyl or phenyl and, for example, together with the silicon atom, form one of the groups trimethylsilyl, diphenyl-tert-butylsilyl, bis(isopropyl)mcthylsilyl, 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 fomiula VII is obtainable from the mercapto compound VIII wherein T is a leaving group as defined for formula III, preferably iodo. The reaction is carried out in the temperature range from 20° to 150°C, poreferably from 80° to 110°C, in an inert solvent, preferably dimethyl formamide, and an organic amine, preferably ethyl diisopropylamine, is added as acid acceptor. (VIII) OH by reaction with a compound of fomiula IX (IX) The mercapto compound VIII is disclosed in European patent application 0 184 173 and in the corresponding British patent 2 167 75IB. o 2 3 6 2 9 -21 - The starting compounds of formulae III, IV, V, VI, Via, Vlb 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, Deimanvssidae, Sarcoptidae and Psoroptidae; of the orders Mallophaga; Siphonaptera, Anoplura (e.g. 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 Qrthoptera, of the order Dictvoptera (e.g. family of the Blattidae), and of the order Hvmenoptera (e.g. family of the Fomiicidae). 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 Tetranvchidae (Tetranvchus spp. and Panonvchus spp.). They are very effective against sucking insects of the order Homoptera, especially against pests of the families Aphididae. Delphacidae, Cicadellidae, Psvllidae, Loccidae, Diaspididae and Eriophvdidae (e.g. the rust mite on citrus fruit); of the orders Hemiptera, Heteroptera and Thvsanoptera; and also against phytophagous insects of the orders Lepidoptera, Coleoptera, Diptera and Qrthoptera. The compounds of formula I are also suitable for use against soil pests. 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. Ditvlenchus, Radopholus, Rizoglvphus and others. 23 6 2 0 - 22 - Furthermore, the compounds of fomiula 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, catties, horses, donkeys, dogs, cats, guinea pigs, and cage-birds. Typical nematodes having this indication are: Haemonchus, Trichostrongvlus. Ostertagia, Nematodinis, Cooperia, A scans, Bunostomum. Oesophagostomuro, Charbertia. Trichuris. Strongvlus. Trichonema. Dictvocaulus, Capillaria, Heterakis, Toxocara. Ascaridia, Oxvuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. The particular advantage of the compounds of fomiula I is their efficacy against such parasites which arc resistant to benzimidazole pesticides. Cenain species of the genera Nematodirus. Cooperia and Oesophagostomum attack the intestinal tract of the host animal, whereas others of the genera Haemonchus and Ostenagia parasitize in the stomach and those of the genus Dictvocaulus in the lung tissue. Parasites of the families Filariidae and Setariidae are found in internal cell tissue and internal organs, e.g. in the heart, blood vessels, lymph vessels and in subcutaneous tissue. Particular mention is to be made in this connection of the heart worm of the dog, Dirofilaria immitis. The compounds of fomiula 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 occuning in the alimentary tract those of the species Ancvlostoma. Necator, Ascaris. Strongvloides, Trichinella, Capillaria, Trichuris and Enterobius. The compounds of this invention are also effective against parasites of the genera NVuchereria, 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 Strongvloides 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 emulsifiable concentrates, directly sprayable or dilutable solutions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, and also encapsulations in e.g. polymer substances. As with the nature of the compositions, the methods of application such as spraying, atomising, dusting, scattering or pouring, are chosen in accordance with the intended objectives and the prevailing circumstances. © 23 6 2 9 0- -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 10 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, emulsions, suspensions, powders, tablets, boluses or capsules. If the physical and toxicological properties of solutions or emulsions permit it, the compounds of fomiula I, or compositions containing them, can also be injected into animals, for example 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. 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 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. © 2362 -24- The solid carriers used e.g. for dusts and dispersible powders are normally natural mineral fillers such as calcite, talcum, kaolin, montmorillonitc 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. Suitable anionic surfactants can be both water-soluble soaps and water-soluble synthetic surface-active compounds. Suitable soaps are the alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts of higher fatty acids (C10-C22), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures which can be obtained e.g. from coconut oil or tall oil. Further suitable surfactants are also the fatty acid methyltaurin salts. More frequently, however, so-called synthetic surfactants arc used, especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates. The fatty sulfonates or sulfates are usually in the form of alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts and contain a C8-C22alkyl radical which also includes the alkyl moiety of acyl radicals, e.g. the sodium or calcium salt of lignosulfonic acid, of dodecylsulfate, or of a mixture of fatty alcohol sulfates obtained from natural fatty acids. These compounds also comprise the salts of sulfated and sulfonated fatty alcohol/ethylene oxide adducts. The sulfonated benzimidazole derivatives preferably contain 2 sulfonic acid groups and one 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 © 236290 -25 - corresponding phosphates, e.g. salts of the phosphated adduct of p-nonylphenol with 4 to 14 moles of ethylene oxide, or phospholipids. 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/polyethylene oxide adducts, tributyl-phenoxypolyethoxyethanol, polyethylene glycol and octylphenoxypolyethoxyethanol. 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-Coialkyl 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. The surfactants customarily employed in formulation technology are described in the following publication: "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 1,5 to 99.99 % of a solid or liquid adjuvant, and 0 to 25 %, preferably 0.1 to 25 %, of a surfactant. 2 3 6 2 9 0 -26- Whercas 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 fomiula I, together with conventional carriers and/or diluents. The compositions may also contain further ingredients, such as stabilisers, antifoams, viscosity regulators, binders, 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 5-0-tert-butvldimethvlsilvl-138-(2-f4-nitrophenyllethvlthio)-milbemvcin A4 A solution consisting of 2 g (2.9 mmol) of 5-0-tert-butyldimethylsilyl-13P-mercapto-milbemycin A4,1.6 g (5.82 mmol) of 2-(4-nitrophenyl)ethyl iodide and 2.5 ml (1.9 g; 14.55 mmol) of diisopropylcthylamine 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 HC1 and then twice with a 5 % aqueous solution of NaHC03, dried over MgS04 and concentrated. Column chromatography on silica gel gives 1.8 g of the title compound. !H-NMR (300 MHz, CDC13, TMS) 3.04 (d, J = 10 Hz) C13H. Example A2: Preparation of 13B-(2-f4-nitrophenyl]ethvlthio)milbemvcin A4 1.7 g (20.3 mmol) of 5-0-tert-butyldimethylsilyl-13P-(2-[4-nitrophenyl]ethylthio)-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 NaHC03, dried over MgS04 and concentrated. Column chromatography on silica gel (ethyl acetate/hexane 1:1) gives 1.53 g of the title compound. © 0 2 3 o 2 9 0 -27- JH-NMR (300 MHz, CDC13)(TMS) 3.04 (d, J = 10 Hz)(C13H) 7.32 (d, J = 8 Hz)(aromatic H) 8.17 (d, J = 8 Hz)(aromatic H) mass spectrum (FD) m/e: 723 (C40H53NO9S) Example A3: Preparation of l3B-(2-r4-aminophenvlle[hvlthio)milbemvcin A4 With stirring, 4 g of zinc dust are added at room temperature to a solution of 4 g (5.53 mmol) of 13(M2-[4-nitrophenyl]ethylthio)milbemycin A4 in 40 ml of acetic acid, and the resultant mixture is stirred. After 16 hours the reaction mixture is diluted with . /acetate 150 ml of ethyl and filtered. The filtrate is washed 3 times with water, dried over MgSC>4 and concentrated. The residue is chromatographed on silica gel (ethyl acetate/hexane 2:1), affording 2.25 g of l3(H2-[4-aminophenyl]eihylthio)milbcmycin A4. 'H-NMR (300 MHz, CDC13, TMS) 3.03 (d J= 10Hz)(Ci3H) 6.63 (d, J = 8 Hz)(aromatic H) 6.96 (d, J = 8 Hz)(aromatic H) mass spectrum (FD) m/e: 693 (c40h55no7s). B. Preparation of the final products Example PI: Preparation of l3B-(2-|4-acetvlaminophenvllethylthio)milbemvcin A4 With stirrring, 7 |il (7 mg, 72 nmol) of acetic anhydride are added at room temperature to a solution of 40 mg (58 nmol) of 13P-(2-[4-aminophenyl]ethylthio)milbemycin A4,5.8 |il of pyridine and 47 pi (37 mg, 1,15 mmol) of methanol in 0.3 ml of dichloromethane. The 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 NaHC03. Chromatography on silica gel (ethyl acetate/hexane 2:1) affords 35 mg of 13f3-(2-[4-acetylaminophenyl]ethylthio)milbemycin A4. 'H-NMR (300 MHz, CDC13, TMS) 2.17 (ch3co) 3.04 (d, J = 13 Hz)(C13H) 7.11 (d, J = 8 Hz)(aromatic H) 7.41 (d, J = 8 Hz)(aromatic H) 23629c 28- Example P2: Preparation of 13B-(2-f4-(4-heptvlcarbonvIamino)phenvllethylthio)-milbemycin A4 With stirring, 12 mg (72 jimol) of 4-heptylcarbonyl chloride are added at room temperature to a solution of 40 mg (58 |imol) of 13p-(2-[4-aminophenyl]ethylthio)-milbemycin A4, 6 pi (73 jimol) of pyridine and 47 pi (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 NaHC03 and dried over MgS04. Chromatography on silica gel (ethyl acetate/hexane 1:1) gives 32 g of 13P-(2-[4-(4-heptyl-carbonylamino)phenyl]ethylihio)milbemycin A4. Example P3: Preparation of 13B-(2-f4-(formvlamino)phenvllethvlthio)milbemycin A4 A mixture of 7 pi of acetic anhydride and 3 pi of formic acid is added at room temperature to 40 mg (58 pniol) of 13P-(2-[4-aminophenyl]ethylthio)milbemycin A4, 6 p.1 of pyridine and 47 pi (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 1M citric acid and washed with water and 1M aqueous NaHC03. Chromatography on silica gel (ethyl acetate/hexane 2:1) gives 30 mg of 13P-(2-[4-(fonnylamino)phenyl]cthylthio)milbemycin A4. !H-NMR (300 MHz, CDC13, TMS) 8.37 (d, J = 1 Hz)(formyl H) 8.64 (d, J = 12 Hz)(formyl H). Example P4: Preparation of 13B-(2-[4-(4-toluene.sulfonvlamino)phenvllethvlthio)-milbemvcin A4 With stirring, 14 mg (72 p.mol) of toluene-4-sulfochloride are added at room temperature to a solution of 40 mg (58 pmol) of 13P-(2-[4-aminophenyl]ethylthio)milbemycin A4, 6 p.1 (73 pmol) of pyridine and 47 pi (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 NaHC03 and dried over MgS04. Chromatography on silica gel (ethyl acetate/hexane 2:1) gives 41 mg of 13p-(2-[4-(4-toluenesulfonylamino)phenyl]ethylthio)milbemycin A4. !H-NMR (300 MHz; CDC13, TMS) 6.97 (d, J = 8 Hz)(aromatic H) 7.04 (d, J = 8 Hz)(aromatic H) 7.23 (d, J = 8 Hz)(aromatic H) 7.63 (d, J = 8 Hz)(aromatic H) mass spectrum (Cl-ve) m/e: 847 (C47H61N09S2). © 23 3 2 -29- Example P5: Preparation of 13B-(2-[4-(methvlaminothiocarbonvlamino)phcnvl1ethyl-thio)miIbemycin A4 With stirring, 5.3 mg (72 (imol) of methyl isothiocyanate are added at room temperature to a solution of 40 mg (58 p.mol) of 13P-(2-[4-aminophenyl]ethylthio)milbemycin A4, 6 fil (73 M.mol) of pyridine and 47 |il (1.15 mmol) of methanol in 0.3 ml of dichloromethane. After 16 hours the reaction mixture is worked up with ether and 1M citric acid, washed with 5 % aqueous NaHC03 and dried over MgS04. Chromatography on silica gel (ethyl acetate/hexane 2:1) gives 38 g of 13p-(2-[4-(methylaminothiocarbonylamino)-phenyl]ethylthio)milbemycin A4. JH-NMR (300 MHz, CDC13, TMS) 3.14 (d, J = 5 Hz, NHCH3). Example P6: Preparation of 13B-(2-[4-(cvclohexvlaminocarbonvlamino)phenyllethvl-thio)milbemvcin A4 With stirring, 9 |il (8 mg, 72 jimol) of cyclohexyl isocyanate are added at room temperature to a solution of 40 mg (58 jimol) of 13P-(2-[4-aminophcnyl]ethylthio)-milbemycin A4, 6 (4.1 (73 nmol) of pyridine and 47 nl (1.15 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 NaHC03 and dried over MgS04. Chromatography on silica gel (ethyl acetate/hexane 4:1) gives 46 g of 13P-(2-[4-(cyclohexylamino-carbonylamino)phenyl]ethylthio)miibemycin A4. 'H-NMR (300 MHz, CDC13, TMS) 4.50 (d, J = 8 Hz)(NH) mass spectrum (CI - ve): m/e 818 (C47H65N2OsS). Example P7: Preparation of 13B-(2-f4-(carboxvmethylaminocarbonvlamino)phenvllethvl-thio)milbemycin A4 A solution of 50 mg (58 jimol) of 13p-(2-[4-(4-nitrophenoxy)carbonylaminophenyl]ethyl-thio)milbemycin A4 (prepared according to Examnple B2) and 4.4 mg (58 |imol) 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 MgS04. Chromatography on silica gel (dichloromethane/methanol 4:1) gives 22 mg of 13P-(2-[4-(carboxymethyl-aminocarbonylamino)phenyl]ethylthio)milbemycin A4. 236290 30- !H-NMR (300 MHz, D6-DMSO, TMS) 4.67 (d, J = 8 Hz)(NH) 9.09 (br, s)(COOH) mass spectrum (CI + vc): m/e 794 (C43H5gN201oS). The following compounds of formula I are prepared in accordance with the procedures described above. •"■TN, - v 236290 -31 - /*~N Table 1: Typical representatives of compounds of formula I wherein Rj = r3—x — nh- ■ ch->ch->s- Comp. X r3 r2 Physical data 1.1 CO c2h5 c2h5 m/e =749 (CI-ve) 1.2 CO phenyl c2h5 m/e = 797 (FD) 1.3 CO ch3 c2h5 m/e = 735 (FD) 1.4 CO H c2h5 m/e = 721 (CI-ve) 1.5 CO tcrt-butyl c2h5 m/e = 777 (CI-ve) 1.6 CO (h3cch2ch2)2ch- c2h5 m/e = 819 (CI-ve) 1.7 CO cich2 c2h5 m/e = 769 (CI-ve) 1.8 CO 2,6-dichloropyrid-4-yl c2h5 m/e = 866 (CI-ve) 1.9 CO C12CH c2h5 m/e = 804 (CI-ve) 1.10 CO C13C C2H5 m/e = 839 (CI-ve) 1.11 CO f3c C2H5 m/e = 789 (Cl+ve) 1.12 CO n yc"3 n c2h5 m/e = 837 (Cl+ve NH3) 1.13 oco o ch3 c2h5 m/e = 751 (FD) 1.14 OCO c2h5 c2h5 m/e = 765 (FD) 1.15 oco benzyl c2h5 m/e = 827 (FD) 1.16 OCO phenyl c2h5 m/e = 831 (Cl+ve NH3) 1.17 OCO p-nitrophenyl C2H5 m/e = 858 (FD) 1.18 OCO CH3CH2CH2CH2 c2h5 m/e = 793 (CI-ve) 1.19 so2 ch3 c2h5 m/e = 771 (CI-ve) 1.20 so2 p-tolyl c2h5 m/e = 847 (CI-ve) 236290 Comp. X *3 r2 Physial data 1.21 so2 2-fluorophenyl c2h5 m/e = 869 (Cl+ve NH3) 1.22 so2 2-(2-methoxyethoxy)phenyl c2h5 nVe = 925 (CI+vc NH3) 1.23 so2 2-difluoromethylthiophenyl C2H5 m/e = 933 (Cl+ve NH3) 1.24 NH-CS c2h5 C2H5 m/e = 778 (CI-ve) 1.25 NH-CS 3-fluorophcnyl C2H5 m/e = 846 (CI-ve) 1.26 NH-CS ch3 qhs m/e = 776 (CI-ve) 1.27 NH-CO ch3 c2h5 m/e = 750 (FD) 1.28 NH-CO c2h5 c2h5 m/e = 764 (Cl+ve) 1.29 NH-CO cyclohexyl C2H5 m/e = 818 (CI-ve) 1.30 NH-CO p-tolyl C2H5 m/e = 826 (CI-ve) 1.31 NH-CO 2-fluorophenyl c2hs m/e = 830 (CI-ve) 1.32 NH-CO phenyl c2h5 m/e = 812 (CI-ve) 1.33 NH-CO p-methoxyphenyl c2h5 m/e = 842 (CI-ve) 1.34 NH-CO HOOCCH(CH3)- c2h5 m/e = 808 (CI-ve) 1.35 NH-CO HOOCCH2- c2h5 m/e = 794 (Cl+ve) 1.36 NH-CO HOOCCH(isopropyl) c2h5 m/e = 836 (CI-ve) 1.37 co CH3 ch3 m/e = 721 (Cl-ve) 1.38 co ch3 isopropyl m/e = 749 (CI-ve) 1.39 OCO ch3 ch3 m/e = 737 (CI-ve) 1.40 OCO c2h5 sec-butyl m/e = 779 (CI-ve) 1.41 so2 ch3 ch3 m/e = 757 (CI-ve) 1.42 NH-CS ch3 isopropyl m/e = 780 (CI-ve) 1.43 NH-CO ch3 ch3 m/e = 736 (CI-ve) 32- Tablc 1 (continued) Table 1 (continued) 236290 -33- 23 6 2 9 (T © -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 diisobutylnaphthalencsulfonate - 6 % 10 % octylphenol polyethylene glycol ether (7-8 mol EO) — 2 % - highly dispersed silicic acid 5 % 10 % 10 % kaolin 62 % 27 % - 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 concentration. Emulsifiable concentrate a compound of Table 1 10 % octylphenol polyethylene glycol ether (4-5 mol EO) 3 % calcium dodecylbenzenesulfonate 3 % castor oil polyglycol ether (36 mol EO) 4 % cyclohexanone 30 % xylene mixture 50 % 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. 2362 -35- Extrudcr 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. Tablets and boluses 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 granulated through a sieve (mesh size 12 M) and the granules are dried. II cryst. lactose 22.50 % cornstarch 17.00 % microcryst. cellulose 16.50 % magnesium stearate 1.00 % All 4 adjuvants are well mixed. Phases I and II are mixed and compressed to tablets or boluses Iniectables A. Oily vehicle (slow release) a compound of Table 1 0.1-1.0 g groundnut oil ad 100 ml I a compound of Table 1 methyl cellulose highly dispersed silicic acid corn starch 33.0 % 0.80 % 0.80 % 8.40 % © 236290 - 36- a compound of Table 1 0.1-1.0 g sesame oil 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 urn membrane. B. Water-miscible solution (medium rate of release) a compound of Table 1 0.1-1.0 g 4-hydroxymethyl-l ,3-dioxolane (glycerol fonnal) 40 g 1,2-propanediol ad 100 ml a compound of Table 1 0.1-1.0 g glycerol dimcthylketal 4 0 g 1,2-propanediol 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 filtnition through a suitable 0.22 Jim membrane. C. Aqueous solubilisate (rapid release) a compound of Table 1 0.1-1.0 g polyethoxylated ricinus oil (40 ethylene oxide units)* 10 g 1,2-propanediol 20 g benzyl alcohol 1 g aqua ad inject. ad 100 ml * Commercially available under the registered trademark CREMOPHOR® EL (BASF AG); a compound of Table 1 polyethoxylated sorbitan monooleate (20 ethylene oxide units)** 4-hydroxymethyl-1,3-dioxolane (glycerol fonnal) 0.1-1.0 g 8 g 20 g © 23 6 2 9 - 37 - benzyl alcohol aqua ad injekt. i g ad 100 ml ** Commercially available under the registered trademark TWEEN® 80 (IC1); 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 |im membrane. The aqueous systems may also preferably be used for oral and/or intraruminal administration. Biological Examples Bl: Action against Li larvae of Lucilia scricata 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 (Lt) are put into each test tube. A mortality count is made after 4 days. The compounds of formula I, for example those of Examples PI 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 (i.1 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 ^g 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 IRgo, i.e. the effective dose is determined at which 9 out of 10 female ticks (90 %) even after 30 days lay eggs from which larvae are unable to hatch. Compounds of formula I, for example of Table 1, have an IR90 at a concentration of 5 M-g/g- </div>

Claims

<div class="application article clearfix printTableText" id="claims"> o 2962 9 0 -38- B3: Trial with sheep infected with nematodes (Haemonchus contortus and Trichostrongvlus colubriformis) The test compound is administered in the form of a suspension with a stomach probe or by intraluminal injection to sheep which have been artificially infected with Haemonchus contortus and Trichostrongvlus 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 arc used as controls. In comparison with untreated and infectcd 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 compounds of fomiula I of Table 1 at 1 mg/kg. B4: Larvicidal action against Aedes aegvpti 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 threc-day-old larvae of Aedes aegvpti are put into each beaker. Mortality counts are made after 1, 2 and 5 days. In this test, compounds of formula I of Table 1 at low concentration achieve complete kill of all larvae after 1 day. B.5 Miticidal action against Demianvssus 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. - XV -39- WHAT WE CLAIM IS:

1. A compound of formula I lhC \ OH O- ch3 OH 2S« (I). wherein R-2 is methyl, ethyl, isopropyl, sec-butyl or the group -C(CH3)=CHQ wherein Af-\ Q is methyl, ethyl or isopropyl; y and Rj is the group r3-x-nh —^ ^— ch2ch2-s- wherein X is a member selected from the group consisting of -C(O)-, -OC(O)-, -NHC(O)-, -NHC(S)- or -S02-; and R3 is hydrogen, Het^ unsubstituted Cj-C8alkyl or C^Cgalkyl which is substituted by CrC4alkoxy, C1-C4alkylthio, C2-C5alkoxycarbonyl, halogen, CN, N02, COOH or NH2; or is unsubstituted C3-CgCydoalkyl or C3-C8cycloalkyl which is substituted by CrC4alkoxy, CrC4alkylthio, C2-C5alkoxycarbonyl, halogen, CN, N02, COOH or NH2; or is the group (ch2> 236290 -40- wherein n is 0, 1 or 2, Ra, Rb and Rc are each independently of one another hydrogen, CrC4alkyl, C1-C4alkoxy, Q-Qalkylthio, Q-Qhaloalkyl, Q-Qhaloalkoxy, CpQhaloalkylthio, C2-C6alkoxy-alkoxy, Q-Csalkanoyloxy, C.2-C5alkoxycarbonyl, halogen, CN, N02 or NH2, and Rc may additionally be C3-C8cycloalkyl or the group and Het! and Het2 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, phthalazine, quinazoline and benzotriazine; or a physiologically acceptable acid addition salt thereof.

2. A compound of formula I according to claim 1, wherein R2 is methyl, ethyl, isopropyl, sec-butyl or the group -C(CH3)=CHQ wherein Q is methyl, ethyl or isopropyl; and R1 is the group wherein X is a member selected from the group consisting of -C(O)-, -OC(O)-, -NHC(O)-, -NHC(S)- Oder -SOr ; and R3 is hydrogen, Het], unsubstituted CpCgalkyl or Q-Qalkyl which is substituted by Cj-Q-Alkoxy, CrC4alkylthio, C2-C5alkoxycarbonyl, halogen, CN, N02, COOH or NH2; or is unsubstituted C3-Cgcycloalkyl or C3-Cscycloalkyl which is substituted by C1-C4alkoxy, C1-C4alkylthio, C2-C5alkoxycarbonyl, halogen, CN, N02, COOH or NH2; or is the group Het2-0- R a 0 236290 -41 - wherein n is 0, 1 or 2, Ra, Rb and Rc are each independently of one another hydrogen, CpQalkyl, Cj-C4alkoxy, CrC4alkylthio, CrC4haloalkyl, C1-C4haloalkoxy, C1-C4haloalkylthio, C2-C6alkoxy-alkoxy, Cj-Cjalkanoyloxy, C2 Csalkoxycarbonyl, halogen, CN, N02 or NH2, and Rc may additionally be C3-C8cycloalkyl or the group Het2-0-, and Het1 and Het2, hereinafter comprised under Het, are each a group selected from the series a to u: \\ c.i - 5 OCT 1992 'j 2362 90 42- Group Het Type a) 4 *6 benzimidazol-2-yl benzoxazol-2-yl benzthiazol-2-yl b) ,Rs 3 n- * Rg imidazol-2-yl oxazol-2-yl thiazol-2-yl c) d) 4 n- —tr * Rs 5 2 i 4 n: r" 3A N 1 n \ 11 [ 1H-1,2,4-triazol]-5-yl [ 1,2,4-oxadiazol]-5-yl [ 1,2,4-thiadiazol]-5-yl [ 1,2,4-oxadiazol]-3-yl [ 1,2,4-thiadiazol]-3-yl [ 1H-1,2,4-triazol]-3-yl e) (2») 3 n n 4 (i») (3*) 1 r9 1(4*) [ 1,3,4-oxadiazol]-2-yl [ 1,3»4-thiadiazol]-2-yl [4H-1,2,4-triazol]-3-yl f) Rn 1 nn n 2 r9 5 n' 3 [ 1H-1,2,4-triazol]-5-yl g) pyridin-2-yl pyridin-3-yl pyridin-4-yl © 236290 -43 - Group Het Type h) pyridazin-3-yl pyridazin-4-yl n E2 "n* 3 pyrimidin-2-yl pyrimidin-4-yl pyrimidin-5-yl k) ' /El ■ e2 pyrazin-2-yl 1) 5 3 s-triazin-2-yl m) 1 /El *n' 4 [l,2,4-triazin]-3-yl [l,2,4-triazin]-5-yl [l,2,4-triazin]-6-yl n) [l,2,3-triazin]-4-yl [l,2,3-triazin]-5-yl o) 4 /El quinolin-2-yl quinolin-3-yl quinolin-4-yl 236 2 90 -44- Group Het Type P) 4 ,El E, •)N ; isoquinolin-l-yl isoquinolin-3-yl isoquinolin-4-yl q) ✓Ei ^2 S,-^X quinoxalin-2-yl /l /2 2n^>V^i phthalazin-3-yl '--a s) U) E1 Eo 3N<^>V^1 2n^NvY^^ E3 Ei E2 E, N' -4- n^n^< E2 quinazolin-2-yl quinazolin-4-yl [ 1,2,4-benzotriazin]-3-yl [ 1,2,3-benzotriazin]-4-yl P* 23ti2yO 45- o in which formulae Y is oxygen, sulfur or NR10; Z is oxygen, sulfur or NH; R6 and R7 are each independently of the other hydrogen, Cj-C4alkyl, CpC4haloalkyl, CrC4alkoxy, CrC4haloalkoxy, CrC4alkylthio, CrC4alkylsulfonyl, CrC4alkylsulfinyl, Ci-C4haloalkylsulfonvl, Q-Qhaloalkylsulfinyl, halogen, nitro or cyano; Rg and R9 are each independently of the other hydrogen, Cj-C6alkyl. CrC6haloalkyl, Cj-C6alkoxy, CrC6alkylthio, halogen or nitro; or arc each independently of the other unsubstituted C3-C7cycloalkvl or C3-C7cycloalkyl which is substituted by halogen or Ci-C3alkyl; Rjois hydrogen or Cj-C6alkyl; Rn is Cj-Qalkyl; and Ej, E2 and E3 are each independently of one another hydrogen, Cj-C4alkyl, CpQhalo-alkyl, CrC4alkoxv, C[-C4haloalkoxy, C[-C4alkylthio, CrC4haloalkylthio, C2-C6alkoxy-alkoxy, CpCfalkanovloxy, C^-Cjalkoxycarbonyl. C3-Cscycloalkyl, halogen, CN, N02 or NH2.

3. A compound of formula I according to claim 2, wherein E^ E2 and E3 are each independently of one another hydrogen, methyl, ethyl, CF3, methoxy, OCF3, methylthio, CH30CH20, 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 R8 and R9 in the groups b to f are each independently of the other C3-C7cycloalkyl which is unsubstituted or substituted by halogen or Cj-C3alkyl and the other substituents and Y and Z are as defined in claim 2.

5. A compound of formula I according to claim 2, wherein the substituent Het is a') • .A 2 - r r " " ' ' 1^ d / n v'i.? 23 6 2 9 0 and the other substituents are as defined in claim 2.

6. A compound of formula I according to any one of claims 2 to 5, wherein R2 is methyl or ethyl.

7. A compound of formula I according to claim 1, wherein R2 and R3 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 R2 is methyl, ethyl, isopropyl or sec-butyl Ri is the group R3-X-NH CH2CH2-S- 236290 -47 - wherein X is a group selected from -C(O)-, -OC(O)-, -NHC(O)-, -NHC(S)- and -S02-; and R3 is Cj-Cgalkyl or C3-C6cycloaIkyl.

9. A compound of formula I according to claim 1, wherein R2 is methyl, ethyl, isopropyl or sec-butyl; o Rt is the group r3-x-nh v y ch2ch2-s- wherein X is a group selected from -C(O)-, -OC(O)-, -NHC(O)-, -NHC(S)- and -S02-; and R3 is the group wherein n is 0 or 1, and Ra, Rb and Rc are each independently of one another hydrogen, CrC2alkyl, Cj-C^alkoxy, C1-C2alkylthio, Cj-C2haloalkyl, Cj-C2haloalkoxy, Ci-C2haloalkylthio, halogen or N02, and Rc may additionally be the group Het2-0-, wherein Het2 denotes the groups as indicated for formula I.

10. A compound of fomiula I according to claim 2, wherein R2 is methyl, ethyl, isopropyl or sec-butyl; Rj is the group "O r3-x-nh (* — ch2ch2-s- wherein X is a group selected from -C(O)-, -OC(O)- or -NHC(O)-; and R3 is Het!, unsubstituted CrC6alkyl or CrC6alkyl which is substituted by C1-C4alkoxy, Ci-C4alkylthio or halogen, unsubstituted C3-Cgcycloalkyl or C3-C6cycloalkyl which is substituted by C1-C2alkoxy, Cj-C^alkylthio or halogen, or is the group 2362 90 -48- r a r , wherein n is 0 or 1; r c Ra, Rb and Rc are each independently of one another hydrogen, fluoro, chloro, bromo, methyl, methoxy, methylthio, CF3 or N02, and Rc may additionally be the group wherein Het] and Het2 are one of the groups a') to f) defined for Het in claim 5, and the other substituents are as defined for claim 2.

11. A compound of formula 1 according to claim 1, wherein R2 is methyl, ethyl, isopropyl or sec-butyl; R! is the group wherein X is -OC(O)-; and R3 is unsubstituted CrC6alkyl or Cj-C6alkyl which is substituted by Cj-Qalkoxy, CrC4alkylthio or halogen.

12. A compound of formula I according to claim 1, wherein R2 is methyl, ethyl, isopropyl or sec-butyl; Rj is the group wherein X is -C(O)-, -OC(O)- or -NHC(O)-; and R3 is hydrogen; unsubstituted Cj-Qalkyl or Cj-C8alkyl which is substituted by Ci-C4alkoxy, Cj-C4alkylthio, C2-C5-alkoxycarbonyl, halogen, CN, N02, COOH or NH2; unsubstituted C3-C8cycloalkyl or C3-C8cycloalkyl which is substituted by CrC4alkoxy, CrC4alkylthio, C2-C5alkoxycarbonyl, halogen, CN, N02, COOH or NH2.

13. A compound of formula I according to claim 2, wherein R2 is methyl, ethyl, isopropyl or sec-butyl; Rj is the group Het2-0- 236290 -49- wherein X is -C(O)-, -OC(O)- or -NHC(O)-; and R3 is the group ?• Rb^r\_ ) (CH2*U , wherein n is 0 or 1, and ^ c Ra, Rb and Rc are each independently of one another hydrogen, Ci-Coalkyl, Cj^alkoxy, Cj^alkylthio, Ci-C2haloalkyl, Ci-C2haloalko.\y, CpC2haloalkylthio, halogen or N02, and Rc may additionally be the group Het2-0-, wherein Heb is one of the groups a') to f) defined for Het in claim 5 and the other substituents are as defined in claim 2.

14. A compound of fomiula I according to claim 1, wherein R2 is methyl, ethyl, isopropyl or sec-butyl; R! is the group r3-X-nh $ 7 ch2ch2-s- wherein X is -C(O)-, -OC(O)- or -NHC(O)-; and R3 is the group R, (ch2>^ , wherein n is 0 or 1, and Ra, Rb and Rc are each independently of one another hydrogen, Cj^alkyl, CrC2alkoxy, Cj-C2alkylthio, Cj-C2haloalkyl, Cj^haloalkoxy, Ci-C2haloalkylthio, halogen or N02.

15. A compound of formula I according to claim 1, wherein R2 is methyl or ethyl; Rj is the group r3-X-nh v \ ch2ch2-s- wherein X is -OC(O)-, and R3 is CrC6alkyl.

16. A compound of formula I according to claim 1, selected from the group consisting of: 13P-[2-(4-acetaminophenyl)ethylthio]milbemycin A4; 13P-(2-[4-(4-heptylcarbonylamino)phenyl]ethylthio)milbemycin A4; -50- 13P-(2-[4-(2,6-dichloropyridin-4-yIcarbonylamino)phenyl]ethylthio)-milbemycin A4; 13P-(2-[4-tosylphenvl]ethylthio)milbemycin A4; 13P-(2-[4-(methylaminothiocarbonylamino)phenyl]ethylthio)milbemycin A4; 13P-(2-[4- (benzylaminocarbonylamino)phenyl ] ethylthio)milbemycin A4; 13p-(2-[4-(cyclohexylaminocarbonylamino)phenyl]ethylthio)milbemycin A4; 13P-(2-[4-((4-methoxyphenyl)aminocarbonylamino)phenyl]ethylthio)milbemycin A4; 13P-(2-[4-(carboxymethylaminocarbonylamino)phenyl]ethvlthio)milbemycin A4; and 13P-(2-[4-(methoxycarbonylamino)phenyl]ethylthio)milbemycin A4.

17. A process for the preparation of a compound of formula I according to claim 1, which comprises reacting a compound of formula II OH wherein R2 is as defined for formula I, a) where X in formula I is -C(O)- or -OC(O)-, in the absence, or preferably in the presence, of an acid acceptor, with a compound of formula III R3-X-T (III) wherein R3 is as defined for formula I, X is -C(O)- or -OC(O)-, and T is a leaving group; P) where X in formula I is -NH-C(O)-, with an isocyanate of formula IV R3-N=C=0 (IV) or with an aminoacylating agent of formula V R3-NH-C(0)-D (V) 236290 - 51 - wherein R3 in formulae (IV) and (V) 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 -NH-C(S)-, with an isothiocyanate of formula VI R3-N=C=S (VI), wherein R3 is as defined for formula I; and 5) where X in formula I is SOn, with a sulfonating agent of formula Via R3-SO2-T (Via), wherein R3 is as defined for formula I and T is as defined in a), in the absence, or preferably in the presence, of an acid acceptor.

18. An insecticidal and parasinoidal composition which contains, as active ingredient, a compound of formula I as claimed in any one of claims 1 to 16.

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, with the proviso that the method does not include the medical treatment of humans.

20. A method according to claim 19, wherein the pests are endo- or ectoparasites of productive livestock.

21.A compound according to claim 1 substantially as herein described or exemplified.

22.A process according to claim 17 substantially as herein described or exemplified.

23.A composition according to claim 18 substantially as herein described or exemplified.

24.A method according to claim 19 substantially as herein described or exemplified. CIBA-GEIGY AG By Their Attorneys HENRY HUGHES LIMITED Per: / 4,/1 . /„ s r? * //f Wa& iritis-) </div>