PH26231A - Macrolide compounds their preparation and their use - Google Patents

Description

Thy 4 26231 » pe a !

This application is a division of Philippine application Serial No. 35070, filed en March 24,1987,

The present invention is concerned with a ae- ries of new macrolide compounds which afe chemically related to certain known classes of macrolides include ‘ ing the milbenmycins and avermecting. Thess compounds ‘ have valuable acaricidal, insecticidal and anthelmin- tio activities. The invention alse provides methods "of preparing these compounds and compositions and me- theds for using them. oo Theme are several classes of knwon compounds with a structure based on a 16-membersd macrolide ring, vhich are obtained by fermentation of various mioroor- ganisms or semi-synthetically by chemical derivatisa- tion of such natural fermentatiom preducts, and which exhibit mcaricidal, insecticidal, anthelmintic and antiparasitic activities. The milbemycins and avermect- ins are examples of two such classes of known compounds, butvarious others also exist and are identified by differ- ent names or code numbers. The names for these various macrolide compounds have generally been taken from the the names or code numbers of the aicroorganisns which roduce the naturally accuring members of each class, and: these names have then been extended to cover the chemical derivatives of the same class, with the result that these

UH) . 26231 i has been no standardised systematic nomenclature for such compounds generally.

In order to avoid confusion, a standardised system of nomenclature will be used herein, which fellows the normal rules for naming derivatives of organic compounds and which is based on the hypothe- tical parent compound hereby defined as “milbemycin" represented by formula (A): c 23

CH, on, c > © (A) 0

Cc is ’ OH 5 For the avoidance of doubt, formula (A) also shows the numbering of positions of the macrolide ring system ap- plied to those positions most relevant to the compounds of the present invention.

The naturally produced milbemycins are a series of macrolide compounds known to have anthelmintic, aca- ricidal and insecticidal activities. Milbemycin D was ;

! 26231 disclosed in US latent No. 4,346,171. where it was referred to a "Compound B-H1p", and milbemycins Ag and A, were disclosed in US latent No. 3,950,350.

These compounds may be represented by the above for- mula (A) in which positicn 25 is substituted with = methyl group, an ethyl group or an isopropyl group, these compounds being deSignatcd as milbemycin Ags milbemycin “y and milbemyein D, respectively, Ths milbemycin analog substituted at position 25 with a sec-butyl was disclosed in U5 latent No. 4,173,571.

Subsequently, various derivatives of the ori- ginal milbemycin have been prepared and their activi- ties investigated. For example, epoxy melbemycins have been discloscd in Japanese latent Applications

Kokai (i.e. laid upon to public inspection) No, 57- 139097, 57-139080, 59-33288 and 59-36681 and in US

Patent No. 4,530,921. b5-csterified milbemycins have been disclosed in US tatents No. 4,201,861, No. U4, 206,205, Ro. 4,173,571, No. 4,171,314, No. 4,203,976,

No. 4,289, 760,No. 1,457,920, No.4579,864 and No. U4, 547, 491, in “uropean Patent publication No. 8184,

No. 102,721, No. 115,930 No . 180,539 and No. 184,989 and in Japanese iatent Applicstions kokai No. 57-120 589 and 59-16894, 20 13-Hy ‘roxy-5~kctomilbemycin derivatives have

TT MN

- hos | loa oman: 5

Us ay : - been disclosed in US *atent No. h,423,209. Milbewmy- cin S-oxime derivatives were disclosed in US Patent

No. 4,547,520 and European Patent Publication No. 203, 832.

Milbemycin derivatives esterified at position 13 are of particular relevance to the present invent- jon and have been disclosed in US patent Ro. 1,093, 629 and buropean Patent Rublication No. 186,403, as well as in published British Fatent Application No. 2, 168,345 which discloses milbemycin derivatives having a carboxy or esterified carboxy substituent at posi- tion 13 in combination with a hydroxy or eanterified hydroxy substituent at position 5. ’

Like the milbemycins, the avermectins are based upon the same 16-membered ring macrolide compound, The avermectins are disclosed, for example in J. Antimicrob.

Agents Chemother., 15(3), 361-367 (1979). These com- : pounds may be represented by the above formula (A) but with a carbon-carbon double bond at positions 22 and 23, and having position 13 substituted with a h'-(@L oleand- rosyl)~-c - L-oleandrosyloxy group. Position 25 may be substituted with an isopropyl group or a sec-butyl group, these compounds being designated as avermectin Bip and avermectin Ba’ respectively. 22,23-Dihydroavermectins

B,, and By, may be obtained by reduction of the double

~ p . CR 26231 bond between the 22 ang 23 Positions ang are diy. closed in yg latent Ng, 4,199,569,

The aglycéne derivatiyeg of the avermectina, which are milbemycipn analogs, have Sometimes been refer red to in the literature as C076 ¢onpounds, and various derivatiyeg of these Are known, For ¢xample,

US Fatent po, 4,201,861 discloses Such derivatives substituted with a lower alkanoy] group at Position 13,

Published L“uropean Patent Application Ro. 170, 006 discloses a family of bioactive Compounds Produced by fermentation, identified collectively by the code number LL-F28249, Some of thege have 5 16~membered Bac- rolide structure corresponding to the above formula (A), substituteq with hydroxy ot position 23 ang with 1. methyl-lepropenyi, 1-methy)-1-buteny; or l13-dinethyl-1-buten nyl at position 25, In theme compounds, the hydroxy at po- sitdon 5 may also pe replaced by methoxy,

Publigheqg British tatapt “Fplication No, 2,176,182 discloses another group of macrolide antibiotica corres- ponding to the above formula (A) with a . hydroxy op subs tituteq hydroxy group at lrositioh 5, a hydroxy substituted hydroxy or kete £Toup at position 23, and an o o Sranched alkeny} group at position 25,

A yet furthey group or related macrolide derivativeg N ‘ -———— ~ 6. lo orc. ow

101 bh) 26231 is disclosed in Japanese Fatent Application Kokai

No. 62-29590. These fave a structure correspond- ing to the above formula (A), with a hydroxy or methoxy group at positions 5. Position 13 of the ring can be substituted with a 4 (Q.-L-olesndresyl) -q -L~ oleandrosyloxy group, as in the avermeotins, and there may be a carbon -carton double bond between positions 22 and 23, or alternatively position 23 may be substituted with hydroxy. The substituent at posi- tion 25 is of a type not found in the naturally preo- duced avermectins and milbemycins, and include various o. -branched alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl andcycloalkylalkyl groups, or oycloalkyl, cycloalkenyl or heterocyclic groups. This 25~substitu- ent is introduced by adding the corresponding earboxylic acid or derivative thereof to the fermentation broth eof an avermectin-producing microorganisms. : The various classes of milbemycin-related macro- lide compounds described above are all disclosed as hav-

Co 20 ing one or more types of activity as antibiotic, anthel- ¢ mintic, ectoparasiticidal, acaricidal er other pestici- dal agents. However, there is still a continuing need to provide such agents with improved activity against ene or more classes of pests,

It has now been discovered that the activity of - 7 - I— -

SAD ORIGIN/". Co we) [3 ¢ “4 26231 euch milbemycin-related derivatives can be improved by appropriately selecting the combination of subs- tituents on the macrolide ring system, especially the substituents at position S and 13. In particu-~ lar, it has now been found that the activity of the 13-esterified derivatives in the above-mentioned prior art can be improved upon by appropriate selection eof certain ester groups at this position, as specified below,

Accordingly, it is an object of the present in vention to provide such macrélide compounds hav : ing improved activity. It is another object of the invention to provide methods for preparing such com- pounds. It is a still further object of the invent- ion to provide peaticidal compositions and metheds containing the said compounds.

In accordance with these objects, the invent- ion provides compounds having the formula (I):

Af 7

Uim)

MY Hil . X r%0 SH ’ ~ 3 M3

A-(W) -C-C-0 x 0 r 17% o> Rr

R’ ; ~ cH > 0 (1) pn o

Cc

Hs or" in which: the broken line represents a carbon-carbon single or double bond between the atoms at the 22 and 23 posi- tions

X represents a hydrogen atoms or a hydroxyl group, or together with the carbon atom to which it is attached re-~ presents the group C=O; provided that X represents a hydrogen atom when the broken line represents a double Mond between the carbon atoms at the 22 and 23 oo positions 1

R™ represents an alkyl, slkenyl, alkynyl, alkoxyalkyl er alkylthie- alkyl group, each having up to & carton atoms; a cycloalkyl-substituted alkyl group wherein the

"Ly 1A) 26231 ow ¢) hl eycloalkyl moiety has from 3 to 6 ring carbon atoms and the alkyl moiety has from 1} te 5 carbon atems; a cycloalkyl or ceycloalkenyl groups having from 3 te 8 ring carbon atoms and which ia unsubstituted or has at least one substituent selected from the group consisting of halogen atoms and alkyl groups having from 1l to 4 carbon atoms; & heterocyclic group having from 3 to 6 ring atoms of which at least one is an oxygen or sulfur atom and which is unsubstituted or has: at least one substituent selected from the group consisting of halogen atoms and alkyl groups hav- ing from 1 to 4 carbon atoms} r2 represents an alkyl group having from 1 to € carbon atoms, a haloalkyl group having from ) to 4 carbon : atoms, an alkoxy group having from 1 to & car- bon atoms, an alkoxyalkyl group having from 1 . to & carten atoms, a phenyl group s Or a cyano groupy rR represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; 2% or r2 and R>

LA) 26231 1 together with the carbon atom to which they are attached, jointly represent a cycloalkyl group having from 3 to 6 ring carbon atoms; i

Bs Oor 1: ‘ w represents a methylene group, or an oxygen or sulfur atomg and

A represents a phenyl group, & naphthyl group, or a hetere- c¢yclids group having from 5 to 10 ring atoms of which at least one ies a nitrogen, oxygen or sulfur atom; and said phenyl, naphthyl er hete- rocyclio group is unsubstituted or has at least one substituent selected from the group consist- ing of alkyl, alkoxy and alkylthio groups each having from 1 te 4 carbon atoms; halogen atoms, trifluoromethyl, amine, nitro cyano, keto, phe- poxy (which may itself optionally be substituted with at least one substituent selected from the group consisting of halogen atoms and trifluoromethyl), and heterocyclfloxy groups having from 5 to 10 ring atoms of which at least one is a nitrogen, oxygen or sul- fur atom; rt reprasents 2% a hydrogen atom, or an ester-forming carboxylic or -1n - |” BN J 'BAD ORIGINAL ¢ hp

1on.9) 20231 carbonic acid residue; and salts and esters of maid compounds of formula (n.

The invention still further provides an anthel- mintic, acaricidal and insecticidal composition compri- sing an anthelmintic, acaricidal and insecticidal com- pound in admixture with a pharmaceutically, agricultu- rally, veterinarily or horticulturally acceptable car- : rier or diluent, wherein said compound is selected from the group consisting of compounds of formula (I) and salts and esters thereof.

The invention still further provides a method of treating an animal, which may be human or non-human, parasitized by a parasite selected from the group con- sisting of helminths, acarids and insects by administer- ing thereto at least one compound of formula (I) and . salts and esters thereof.

The invention still further provides a method of protecting animals or plants from damage by para- sites selected from the group consisting of acarids, helminths and insects, which comprises applying an active compound to said animals, to said plants or to seeds of said plants or to a locus including said animals, plants or seeds, wherein the active compound is at least one compound of formula (I) and salts and - 12 - oo \gpp OREN d \

Wr) 26231 esters thereof. Co

In the compounds of formula (I), where RY re- presents an alkyl group having 1 to 8 carbon atoms, this may be a straight or branched chain alkyl group and examples of such groups include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Bec-butyl, t-butyl, pentyl, isopentyl, heptyl and octyl groups. hecording to one preferred embodiment of the invention, this alkyl group may be methyl, ethyl, isppropyl or sec- butyl. In accordance with another embodiment of the invention, the a -branched alkyl groups having from 3 . to 8 carbon atoms are preferred.

Where Rr! represents an alkenyl group, this may be a straight or branched chain group containing from 2 to 8 carbon atoms and having at least one double bond, for example vinyl, l-propenyl, 2-proprnyl, isopropenyl, l-methyl-l-propenyl, l-mcthyl-l-butenyl or 1,3-dimethyl- l-butenyl. The q -branched alkenyl groups are particular . ly preferred,

Where gt represents am alkynyl group having from 2 to 8 carbon atoms, this may be a straight or branched chain group, for example athynyl, l-propynyl or 2-propyl nyl. . Where rl represents an alkoxyalkyl group er alkyl- thioalkyl group, this may have a total of from 2 to 8 car- - 13 - ano ORIGINAL J

- | U7) . . ” . ’ : a! 26231 i bon atoms and may be straight or branched, for exam-

Ple methoxymethyl, ethoxymethyl, l-methoxyethyl, 2- methoxyethyl, 2-ethoxyethyl, isopropoxymethyl, and . the thio analogs of each of these groups, The methoxy, methyl, methylthiomethyl and l~(methylthio)ethyl-1- ie thibkye thy groups, rcspec'ively, are preferred.

Where .R} represents a cycloalkyl or cycloalkenyl group, this may be a monocyclic or fused polyeyelic (pre- ferably bicyciie) ring system containing from 3 to 8 ring carbon atoms, Lxamples include the cyclopropyl, cyclo- } butyl, cyclopentyl, cyclohexyl, cycloheptyl, ¢yclooctyl, bicyclo [2.2.1 heptyl and norbornanyl groups, and the analogs thereof containinr~ one or more double bonds. It should be understood that this definition also includes partly aroma- - tio fused polycyclie ring systems, for example the tetrahy- : dronaphthyl and trimethylenephenyl groups,

Where rl represents a cycloalkyl-substituted alkyl group, the cycloalkyl moiety thereof may be any of the above-mentioned cycloalkyl groups which have from 3 to 6 ring carbon atoms, and the alkyl moiety may be any of the above-mentioned straight or branched chain alkyl groups } which have from 1 to 5 carbon atoms.

Where rR represents a heterocyclic group, this may have from 3 to 6 ring atoms, of which at least one is an oxygen sulfur hetero-atom. The ring system may .

CN

: CL - 14 [AD ORIGINAL a9 en .

pV) . Lid 26231 be unsaturated, or partly or wholly saturated. Exam- ples of such heterocyclic groups include the oxiranyl, oxetanyl, thiranyly thietanyl, (2,2-dimethyl)=1,3- dioxelanyl, furyl, thienyl, thiazolyl, isothiasolyl, exasolyl, isoxazolyl and pyranyl groups.

Wheres at represents a cycloalkyl, cycloalkenyl or heterocyclic group, this is unsubatituted or has at least one halogen atom (e.g. fluorine, chlorine, brom- mine or iodine) and/or at least one alkyl group having from 1 to 4 carbon atons (e.g. any of those straight or branched chain alkyl groups mentioned above which have up to 4 carbon atoms).

The most preferred groups for rt are methyl,ethyl, isopropyl, sec-butyl, l-methyl-l-propenyl,-l-methyl-l- butenyl and 1,3-dimethyl-l-butenyl.

In the compounds of formula (n, Rt may represent . a hydrogen atom, so that the substituent at position 5 is a hydroxy group. As will readily be appreciated by those skilled in the art, this hydroxy group oan form esters with a wide variety of carboxylic and carbonie acids, without significantly adversely affecting the bio- logical sctivity of the compound which is derived from the S5-hydroxy substituent, Accordingly, the invention also embrances such eaters where rp? reprasents an ester- forming carboxyllie or carbonic acid residue, - 1 |AD ORIGINAL d meee

I. . 269221 i ar . 5 Fad wo A.

Preferred compounds are those in which gt is the hydrogen atom or a group of the following formu- lat -C0-(0) -R?

Co (0), wherein n= 0 or lj and

Rr represents a atraipht or branched chain Cy.18 alkyl group, a C39 8ycloalkyl group, a Cog aralkyl group, a Cog alkenyl or alkynyl group, a Ce.10 aryl group or monocyclic or fused heterocyclic group having from 5 to 10 ring atoms and containing at least one oxygen, sulfur er nitrogen atom. The group Rr’ may optionally have one or more substituents, such as for example al- kyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, alkoxy- : carbonyl, acyloxy, hydroxy, carboxy, amino, monoto tri- ’ alkylamino, acylamino, cyano, carbamoyl, mono or di-alkyl- carbamoyl, mercapto, alkylthio, alkylsulfinyl, alkylsul- fonyl, nitro, phenoxy, halophenoxy, alkylsulfonyloxy, arylsulfonyloxy, cyanothjo, and S5- or 6-msmbered heterocyclic groups containing at least one oxygen, sulfur or nitrogen : ator, Where the substituent contains a carbon atom or atoms, the number of the carbon atoms is feom 1 to 9.

Where Rr’ itself ies an alkyl, alkenyl or alkynyl group, the above-described substituent cannot be an alkyl, al- - 16 - lao ORIGINAL Yl

» Teed R 0 koxyalkyl or haloalkyl group. where R° is a C18 alkyl group, it may be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo/Z.2.1 heptyl. where Rg is a Calg aralkyl group, it may be, for example, benzyl, phenethyl, phenylpropyl, q -methyl- benzyl or o. , @ =-dimethylbenzyl. where rR’ is a Cog alkenyl or alkynyl group, it } may be, for example, vinyl, propyl, ethynyl or propynyl. .

Where rR’ is a Ce-10 aryl group, it may be, for example, a phenyl or naphthyl group.

Where pis a heterocyclic group, it may be, for example, furyl, theinyl, pyrrolyl, pyridyl,thiasolyl, isothiazolyl, oxagolyl, imidazolyl, pyrazolyl, pyranyl, triazole, triazinyl, quinazolinyl, tetrahydrofuranyl, tete rahydrothienyl, pyrrolidinyl, thiazolylidinyl, piperazyl, morpholinyl, thiomorpholinyl, teterahydroquinolyl, qui- nuclidinyl or thienofuranyl.

Where Rr is further substituted, such further subs- tituents include, for example, methyl, ethyl, ispropyl, t-butyl, methoxy,ethoxy, isopropoxy, methoxymethyl, me- - 17 - ’

J" oRiGINAL Jl bo

UU) 9 G 0 m 23 1 ro thoxyearbonyl, ethoxycarbonyl, chloromethyl, trichle- romethyl, trifluoromethyl, 2-chloroethyl, fluorine, : chlorine, bromine, iodine, hydroxy, carboxy, amine, : methylamino, dimethylamino, diethylamino, diisopropyl- amihé, diisopropylamino, (diekhylamino, diisopropyl- amino, (diethyl)methylamino, acetylamino, trifluore- acetylamino, cyano, carbamoyl, methylcarbamoyl, dime- thyle,rbamoyl, acetoxy, fluoroacetoxy, triohloreacséoxy, mercapto, methylthio, cyanothio, methylsulfinyl, methane- sulfonyl, nitre, phenoxy, p-chlorophenoxy, the S5- or 6- membered heterocyclic groupe set out above in the defini- tions of R?, and the 2,2-dimethyl-1,3-dioxolanylmethoxy, 3yh=dihydro-2A-pyran-2-carbonyloxy and 3,4,5,6~diisopro- : pylidene-D- galacturonyloxy groups,

Preferred compounds include those where R’ re- presents hydrogen and the egters whers R represents the group -CO-R. In these esters, the group Rr’ is preferably a (cy 0 alkanoyl)oxymethyl group, a chlore- methyl group, an iodomethyl group, a mono~, di- or tri- alkylaminomethyl group (and particularly a trialkyl- aminome thyl group, wherein the nitrogen is quarternised), a (heterocyclic amino)methyl group (such as l-piperidyl- methyl or L-morpholinylme thyl) , a 2-carboxyethyl or 3- carboxypropyl group, or the 2,2-dimethyl-1,3-dioxolan- 2s h-ylmethoxy group. Compounds where R° is (cy. alkanoyl) - 18 ano ORIGiivAL oH

Co, 701%) 26231 oxymethyl are particularly preferred. The most pre- ferred values for Rr" are hydrogen, acetoxyacetyl and pivaloploxyacetyl.

In the compounds of formula (I), where r® is a C16 alkyl group, it may be a straight or branched chain alkyl group, for example, a methyl, ethyl, pro- pYl, isopropyl, butyl, isobutyl or Bec-butyl group, and it is preferably the methyl or ethyl group.

Where R® is a Cit haloalkyl group, it is a straight or branched chain alkyl group substituted by a halogen atom or atoms and it includes, for example, a chloromethyl, fluoromethyl, trifluoromethyl, bromo- methyl, 2-chloroethyl or 3-fluoropropyl group, prefer- ably the chloromethyl group. 18 Where rR? is a City alkoxyalkyl group, it is an alkyl group substituted by one or more straight or ] branched chain alkoxy groups and it includes , for example, the methoxymethyl, ethoxymethyl, 2-methoxy ~ ethyl, 2-ethoxyethyl and isoproppxymethyl groups, pre- ferably the methoxymethyl group, where RZ is a C,_4 alkoxy group, it is a straight or branched chain alkoxy group and it includes, for example, the methoxy, ethoxy, propoxy, isepropexy , buto- xy, isobutoxy and sec-butoxy group, preferably the me- thoxy group. - 19 - \ INAL 9 nA in ' § . - 26231

Where r® is a Cy alkylthio group, it may have a straight or branched alkyl chain, for exam-

Ple the methylthio, othylthio, propylthio, isopropyl- thio and butylthio groups, preferably the methylthio groups

R? 1s more preferably C13 alkyl (particularly methyl or ethyl), or phenyl, and mest preferably me- thyl er ethyl,

Where R’ is a Cig alkyl group, it may be a straight or branched chain alkyl group and {it includes, for example, the methyl, ethyl, propyl, isopropyl amd : butyl groups, preferably the methyl group,

Compounds in which rR’ is hydrogen or methyl are most preferred.

Where A is a heterocyclie group, it may be, for example, a furyl, thienyl, pyrrolyl, pyridyl, imidaso- 1yl, pyridazinyl, benzofuranyl, bengothienyl, indolyl, quinolyl, quinazolifyl or quinoxalinyl group, prefer-~ ably a furyl, thienyl, pyridinyl, bensothienyl or qui- nolyl group,

Where A is further substituted, such further substituents may be selected, for example, from methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, m~thoxy, ethoxy, propoxy, isopropoxy, fluorine, chlorine, bro- mine, iodine, trifluoromethyl, nitro, cyano, phenoxy, - 20 . BAD ORIGINAL £)

(ns 26231 p-chlorophenoxy, p-fluorophenoxy, O-chlorophenoxy o-fluorophenoxy, p- trifluorophenoxy, o~trifluoro- phenoxy, 2-furyloxy, 2-thienyloxy, 2-pyrrolyloxy, 2-pyridylexy, 3=pyridyloxy, 2-guinolyloxy, 2-benzoxazoly- oxy, 2-quinoxalyloxy, 2-quinasolinylexy, 2,k-dichloro- phenoxy, S5=trifluoromethyl-2-pyridyloxy, S~trifluoroms- thyl-3-chloro-2-pyridyloxy, 3-chloro-2-furyloxy,3-chlore- thienyl-2-thienyloxy, 2-chloro-5-pyridyloxy, 6-chloro-~ 2~benzoxazolylexy and 6-chloro-2-quinoxalinyloxy. Pre- ferred substituents are methyl, methoxy, trifluoromethyl, chlore, fluoro,2-chloro-6-pyridyloxy and 6-chloro-2-benso- xazolyloxy. ’

The preferred groups A-(W) -are those in which m= 0, such a8 phenyl, halophenyl (e.g. chlorophenyl, fluere- phenyl, trifluorophenyl and dichlorophenyl), tolyl, me- thoxyphenyl, phenoxy, chlorophenoxy, bensyl and phenexy- : phenoxy. Phenyl and halophenyl groups are more highly oo preferred, and in particular phenyl,

It will also be appreciated from formula (I) that the compounds of the invention are capable of existing inthe form of various isomers. Thus, the substituent at position 13 of the macrolide ring may bs in either the alpha or beta configuratioh. The compounds which have the beta-configuration at position 13 are preferred, but the invention includes both sets of stereoisomers, as well - 21 = | 3 ‘BAD ORIGINAL 9 . : —

26 23 1 Co as mixtures thereof.

The following Tables give examples of individual compounds in accordance with the present invention, the compounds being identified by m ans of the aubstituenmt groups shown in formula (I) above. In all the compounds of Tables A-D, for brevity the symbol Z has been used in place of A=(W)_-C(R°R’)-. - 22 - i

BAD ORIGINAL ji

Liha ! 9 , Co

TABLE A : : In compounds 1-104, there 1s a cactbon-carbon single hond between the atoms at positions 22 and 23. X represents a hydrogen atcm. and RY, 7 and _or” have the meanings ghown below.

Ho. gr Z -or” 1 pmathyl a-pethylbenzyl -OoH 2, ethyl a-aethylbenzyl ~OH 3 isopropyl c-methylibenzyl _ou : 4 sec-butyl a-methylbenzyl : _on : ethyl a-ethylbenzyl ’ -OH4 - 6 ethyl a-propylbenzyl _OH ~ 7 ethyl a-isopropylbenzyl ~OH 8 ethyl a-butylbenzyl oH ° ethyl a-sec-butylbenzyl * -OH ethyl - benzhydryl ’ _OH 11 ethyl a,a-dimethylbenzyl Lo -OH : 12 sec-butyl u.a-dimethylbenzyl © -oH 13 ethyl a-ethyl-a-methylbenzyl -CH ’ 14 ethyl «_isopropyl-a-methylbenzyl -OH : : 15 ethyl ~ a-methylbenzhydryl ~OH 14 ethyl a,a-diethylbenzyl - Ol §

Jas ethyl @-sathyl-p-cnlogobentyl - ON iy ethyl d-methyl-m-chlorobenzyl -0l ; i 19 ethyl g-mathyl-o -chlorobenzyl -0Otl 29 ethyl a-methyl-p-Einorobenzyl -0OH ol ethyl domothyl-p-trifluoromethylbenzyl -C 22 ethyl torotnyl-a-17i€Tuaromethy lbeniyl - OH 23 ethyl u-methyl-p-cyavobenzyl ~Ot {

Co : . ~ ’

SR - #5 - lwo omama. J)

Ese oe : !

: pt Zz vo) : poe to : , : 26231

Mo. wr! z : CT or? 24 ethyl a-methyl-p-methylbenzy) -OH ethyl a-methyl-p-methoxybenvy) Co. ~ QI 26 ethyl a-methyl-p-nitrobenzyl OH 27 ethyl a,a-dimethyl-p-chlorohenzyl eli za ethyl a,a-dimethyl p.tluoraobenryl OH 2 othyl a, a-dietnvi poehlerohanzyl td 0 ethyl CC u- pethyl-2,4-dichlorobenzy ~ OH 31 ethyl a-methyl-2,6-dich)orobenzyl . OH 32 ethyl a-methyl-2,4-diflvorobenzyl ~ QOH ’ 33 ethyl a-methyl-2,6-difluorobenzyl : ~OH ) 34 ethyl a-methy)-3-nitro-4-.chlorobanzyl -OH ethyl a-met hoxybenzyl ~OH 36 ethyl c-ethoxybenzyl ~-OH 37 ethyl a-methoxymethylbenzyl ~-0Oh 36 ethyl a-methoxyethylhenzyl ~OH 39 ethyl a-chloromethylbenzyl Co ~0OH . CL 40 ethyl a-chloromethyl-a-rethylbenzyl -OH 41 ethyl a-fluoromethylbenzyl ~-0OH a2 ethyl a-f1uorometfyl a. metnyivenzyl ~0OH 43 ethyl a-cyanoboenzyl -OH 44 ethyl 1-(3-pyridyl)evhyd Co -OH 45 ethyl 1-(2-pyridyl)ethyl -OH 46 ethyl 1-(4-pyridyl)ethyl . ~-OH 47 ethyl 1-(2-thienyl)ethy) ~OH - 48 ethyl 1-(2-furyl)ethyl . ~OH 49 ethyl 1-(2-benzothienyl)ethyl -ou 50 eth 1 l-(2-benzofuranyl)ethyl - OH 51 ethyl L-methyl-2-phenylethyl ~OH 52 ethyl 1,1-dSmethyl-2-phenylethyl on’ 53 ~~ ethyl l-phenoxyethyl : -OH : 54 ethyl l-methyl-l-phenoxyethyl -OH to 55 ethyl l-(p-chlorophenoxy)ethyl OH 56 ethyl l-methyl-1-(p-chlorophenoxy)ethyl ~OH 57 ethyl - 1-[p~(phenoxy)phenoxylethyl -OH ‘ j

Meld sae poonan gj

Ce epi ee oe i , bo Co Co : :

Co 14%) . . ot . { . 26231 lio. RY 2 or’ 58 ethyl: 1p (p-chlorophenoxy)phenoxyjethyl OH : 59 ethyl 1-[p-(2,4-dichiorophenoxy). - OH phenoxy lethyl 60 ethyl 1-fp-(n~triflucromethylphenoxy)- OH phenoxylethyl 61 ethyl 1-[p-(S5-trifluoromethyl- OH . 2-pyridyloxy)phenoxyl=thyl 62 ethyl 1-[{p-(3-chloro-% trifluoromethyl - —~ Ot]

Te 2-pyridyloxy)phenoxylethyl . 63 ethyl 1-{3.-chloro-4- (5 trifluoromethyl “OH 2-pyridyloxy)phenoxylathyl 64 ethyl 1-fp-(6-chloro-2 henzovazolyloxy)- =H phenoxy let hyd 65 ethyl 1-{p-{(6-chlero. Lb, a-dinydro-2. NE - guinoxalinyloxy)phenoxylethyl 66 ethyl g-methyl-¢o--ftuorobenzyl ~OH ’ ¢7 ethyl a-cyclohexylbenuyld -0H - 68 ethyl l-phenylceycleopropyl ~-QOH 69 ethyl 1-(phenylthio)ethyl OH ] 70 ethyl 1-phenyleyclopropyl “on 71 ethyl a-methyl--o-methylbenzyl - OH 72 ethyl ) ($)-a-methylbenzyl - OH 73 ethyl (R)-~a-methylbenzyl LOH 74 ethyl a-methyl-p-aminophenyl ~OH : 7% ethyl 1-(2-pyridon-1l-yl)ethyl -OH 76 ethyl 1-(2-piperidon-1-yl)ethyl -OH 77 ethyl 1-(2-pyridyl)ethyl ~OH 78 1.3-dimethyl- a-methylhenzyl ~OH 1-butenyl 79 cyclopentyl a.a-Gimethylbenzyl - OH g0 2-methylcyclo- a-methylbenzyl ~ OH propyl : g1 butyl a,a-dimethylbenzyl ~-OH 82 l-propenyl a-methylbenzyl --OH ) Lo } - 25 = \aao ORIGINAL Ph . fore; CT Lo

. oo } . v

Co 7 - ;

Ce et Lo 26231 HH : No. R’ 7 | cor? : Co 83 2-methoxy- a-methylbenzyl 11] ethyl 84 isobutyl a-methyl-o-fluorobénzyl ~OH : 85 ethyl a-methylbenzyl acetoxy 86 ethyl a-methylbenzyl chloroacetoxy 87 ethyl a-methylbenzyl propionyloxy ‘ 88 ethyl a-iethylbenzyl Acetoxyacetoxy 89 ethyl a-methylbenzyl ethoxycarbonyloxy "90 ethyl a-methylbenzyl 2.3-dihydroxypropoxy- , carbonyloxy 91 ethyl a-methylbenzyl 3.4-dihydro-2H-pyran-

Z2-Yl-carbonyloxy- : methoxycarbonyloxy $2 ethyl a.a-dimethylbenzy) : propionyloxy 93 ethyl @.a-dimethylbenzyl chloroacetoxy : 94 ethyl a,a-dimethylbenzyl pivaloyloxyacetoxy ’ - 95 ethyl a,a-dimethylbenzyl 3-carboxypropionyloxy 96 ethyl a,a-dimethylbenzyl ethoxycarbonyloxy . 97 ethyl a,a~-dimethylbenzyl (2,2-dimethyl-1,3- : dioxolanyl)methoxy- ’ carbonyloxy ’ 98 ethyl a,a-dimethylibenzyl imidazol=l-yi1- : methoxycarbonyloxy 99 ethyl a-methyl-p-chloro- chloroacetoxy . benzyl 100 ethyl a-methyl-p--phenoxy- triflucroacetoxy benzyl 101 ethyl a-methyl-o-chlorobenzyl chloroacetoxy . 102 ethyl a-methyl-o-chlorobenzyl ethoxycarbonyloxy 103 ethyl a,a-dimethylbenzyl chloroacetoxy 104 ethyl a.a-dimethylben«yl acetoxyacetoxy -

Co | CBs ano ORIGINAL *

Leh . ne - e : © : cf Cn oe » ‘

. Lo ! or 1 1d . . ’ Toa , . i. By - ,

J oo ! a ’ 14 oo nl re 6231 ; fod vod

In compounds 105-108, there i's a4 carhon--carbon . single bond between the atome at positions 22 and 23, X represents a hydroxy group, and = 74 and ~or? have the meanings shown below.

No. ®' 2 on” 105 cyclopentyl a-methylhenzyl OH 106 1-(methylthio)ethyl a-methylbenzyl -OH - ’ 107 ethynyl a-methylbenzyl --OH 108 2-cyclohexen-1-yl a-methylbenzyl acetoxycarbonyloxy

FYARLE C .

In compounds 109-115, there ie a <arbon-carbon double bond between the atoms at positions 22 and 23, X a * represents a hydrogen atom, and Rr, Z and —or® have . - the meanings shown below.

Ho. rR Z oR" ’ 109 cyclopentyl a,a-dimethylbenzyl -OH ‘ 110 cyclohexyl a-methylbenzyl ~-OHi 111 propyl a-methylbenzyl -OH 112 2-(methylthio)ethyl a,a-dimethylbenzyl OH 113 cyclopropylmethyl a-methylboenzyl . -OH : 114 cyclobutylmethyl i, a-dimethy tbenzyl -OH 115 cyclobutyl a-methylbenzyl chloroacetoxy : ( i - 27 - - . A

Lo BE so” Pp

CL pin

Chen a hp OT ’ Co oo ' . | .

Ringe T | to - ‘

oy do = “vy 26231 um ‘TABLE D CL } In compounds 116-120, there is 3 carbon-carbon single bond between the atoms at Positions 22 and 23, x and the ring carbon atom to which it is attached : together represent the group C=0, ang rR, Z and ~or? have the meanings shown below, ‘No. gl Z or! lle L.3-dimethyl-1-buteny) a-methylbenzyl -OH ’ 117 1.3-dimethyl-1-buteny] a,a-dimathyl ~ OH -benzy) . 118 1-methyl-1-buteny) a-methylbeniyl - OH . 119 1.3-dimethyl-1-buteny) a-methylbensyl chloroacetoxy 120 1.3-dimethyl-1-buteny1 a-methylibenzyl acetoxyacetoxy

The most highly Preferred compounds are those with ) numbers 2.5, 7. 11, 13, 15, 8g ang 88 in Table A.

The compounds of formula (1) can be Prepared from the corresponding 13-hydroxy-5-ketomilbomycing of : ) formula (II), by the Processes shown in the following - : . , 2 3

Reaction Scheme, ip which RY, R?, RY, X, A, w, n : and the broken line have the meanings already defined, : and ria Iepresents ga carboxylic or carbonic aciqg } } residue. oo . ; | : - 8B - ORIGINAL 2 er co . : i g , 26231 i i Fo Low,

CHy A TH CH A_ CH

HO aN 0. } I | A-tlg =CM) “ a 0 ~ ” T : 4 STR pd J T 07 OR

Chy C3 i rr 0 0 « 00 on] steph 1 oi] he I iL ¢ hd y

It hi uy © © a) 0 step B ! . a? X 0? X : Chy Ae C3 Jy

A-(W),~C-C00 of AW) L-roo | “TC

Sa n Nye MeN 0 ] wv CHa T ow R? 1 L ol

CHy 1 : - EN EE CT oH Lo] i 1 0 I | i X I : CHy TTC hey OR? ay Of t

Cr . : - - 29 - . . - } | | oo | \aa0 ORIGINAL d sores oo a. to :

: | T074) ) . ' 26231

Of the starting compounds (II), those in which rR! is the methyl, ethyl, isopropyl or sec- butyl group may be prepared by the methods disclos- ed in US Patent No, 4,423,209 or Japanese Patent

Kokai 61-103884. Compounds in which R! ig the 1. methyl-l-propeny1, l-methyl-1-tutenyl op 1,3-dimethyl- l-butenyl group may be prepared by dehydrating com- pound LL~F28249 in which the 23-position 4s OR, dies-~ closed in European Fatent Fublications No. 170,006, by the methoq described in "Pesticide Chemistry", by ‘ Jo Miyamoto and ic. Kearny, Fergamon Freas, vol, 1, pp 83 (1983) to give the corresponding compound whose 22- and 23-nositions are the double bond, and then by reducing thig compound, Alternatively, it may be pre- pared by converting the on group at the 23-position te a suitable thioester, by conventional techniques, and then reducing the resulting compound by the same me- thod as before.

Step A in the Reaction Scheme comprises react- ing a compound of formula (II) with a carboxylic said of formula (111), rR? t

A=(¥) ;~C~coon (111) rR . Co =» - ba ORIGINAL 9 ris 26231 ’ , oo (wherein , RZ, 3, Wy, mn and A are as defined above) or a reactive derivative thereof to give the l3.ester compound of formula (IIa).

Step A consists in an esterification reaction s between the hydroxy group at the 13-position fo com- pound (II) and the carboxylic acid (II), end hence, it may be performed by any conventional method known per se.

The reactive derivative of the carboxylic acid (111) includes, for example, acid halides (such as the acid chloride, acid bromide or acid iodide), acid an- hydrides, mixed acid anhydrides, active esters (auch as the p-nitrobenzyl ester) and active amides that may : be normally used in esterification reactions,

Where a carboxylic acid of formula (III) is used as such, there is preferably used a dehydrating agent such as dicyclohexylcarbodiimide (DCC), p-toluenesulfonie acid or sulfuric acid, more preferably DEC, Where DCC is used, there is preferably used a catalytic amount &f py- ridine, b-pyrrolidinopyridine or the like. The amount of DCC is normally from 1 to 5 equivalents, preferably from 1,5 to bk equivalents,

The reaction is normally effected innthe presence of a solvent, the nature of which is not critical, provid- ed that it has no adverse effect upon the reaction. Suit- - 31 - -— dD loan omA-

Top ¥ 26231 uy - SH able solvents include, for example, hydrocarbons Co such aes hexane, petroleum ether, benzene, toluene, xylene, chloroform, methylene chloride or o-chloro-~ benzene, ethers such as diethyl ether, tetrahydro- furan, dioxane of ethylene glycol dimethyl ether, and eaters such as methyl acetate or ethyl acetate,

Normally, the reaction is carried out at a temperature in the range of from 0°C to 100°C, preferably from 20% to s0°c, for a period of from 30 minutes te 3 hours,

Where an acid halide of the carboxylic acid (III) is used, the reaction is prefrrably carried out in the : presence of a base, Suitable bases include, for example triethylamine, N,N-dimethylaniline , pyridine, l4-dimethyl- aminopyridine, 1,5-diarabicyclo/H.3.0/ nonene-5 (DBN) and 1,8-diazabicyclo/5.4.0/ undecene-7 (DBU),

Normally, the amoutnof the acid halide of the car- bocylic acid (III) is from 1 to 10 equivalents and the : amousit of the base is from 2 to 8 squivalents,

The nature of solvents used, the reaction tempera- ture and the reaction time are similar to those when a carboxylic acid itcelf ie used.

Step B consists in rcducing the carbonyl group at the 5-position of the compound (IXa) to the hydroxy group, : and this may he effected by any reducing methed known per 8¢ (see Japanese Fatent Application 60-210748)., However. - 32 - laa ORIGINAL 9

©0031 it is necessary not to damage any part of the mole- cule other than the 5 -position and hence it is desir- able that the reduction is carried out with anionie hydrogen. Reagents capable of liberating anionic hy- drogen include, for example, sodium borohydride and dibsrane, of which sodium borohydride is most prefer- red, The amount of reducing agent is normally from 1 to 5 equivalents, preferably from 1 to 2 equivalents.

The reaction is normally carried out in the pre- lo sence of a solvent, the nature of which is not ecriti- cal, provided that it does not have any adverse effect upon the reaction. Examples of suitable solvents in- clude, for example, methanol, rthanol, diethyl ether, tetrahydrofuran and benzene.

Nermally, the reaction is performed at a tempe- ’ rature in the range of from -10°¢ to 50°C, preferably from 0°C to 20°C for a period of from 30 minutes to 3 hours. .

Step C consists in reacting a compound of for- mula (ITH) with a carboxylic acid or carbonic acid, o: a reactive derivative thereof, to give a S-ester deri- ‘vative of formula (IIc). This reaction is an esterifica- tion reaction between the hydroxy group at the S-positien of the compound (IIb) and an acid, and therefore, it may be any esterification reaction known per_8se as in Step A. - 33 - a0 ORIGINAL 9

J

Ty 19/ 26231

Aire

The nature of the rehétive derivative of the acid, the dehydrating agent, the solvent, the react- ion temperature, the reaction period and the base can all be the same as in Step A.

S After completion of the reaction in ~ach step, the desired compound of formulae (IIa), (YT®) and (IIc) may be recovered from the reaction mixture by well known means and, if necessary, further purified by such comventional techniques as column chromatography,

The compounds of formula (II) which are used as . starting materials are milbymicin compounds or milbemy- cin analogs which are fermentation products, or can be obtained from the natural products by known techniques, such as those mentioned in the prior art references get out earlier in this specification, Normally, the mil- bemycina are produced as mixtures of several compounds, ] the different compounds being produced at different rates,

Each compound may be isolated and subsequently subjected to the reactions. Alternatively, mixtures of the com- pounde may be subjected to the reactions.

Thus, the compound of formula (II) may be either a single compound or a mixture of compounds, and hence, the compound of formula (I) may be either a single com- pound or a mixture of compounds.

The compounds of the invention having a 23~ks te “ ~ T- -—

Ca ao ORIGINAL g

} group can be obtained from the corresponding natural product, for example, by the following sequence of steps. The natural product having a 5-hydroxy group is oxidized to the corresponding Y-oxo compound, e, g. with manganese dioxide. The 5-oxo derivative is treated with a lower alkanoic acid (e.g. formic acid) and selenium dioxide, and then with aqueous hydro- chldric acid, giving the corresponding 13-hydroxy-5- oxo derivative -ife. a compound of formula (II) above.

The 13- hydroxy group can then bo acylated with the appropriate carboxylic acid or feactivedderivative there- of, in the manner already described, to give the corres- ponding 13-esterified-5-ox0 compound, such as a compound of formula (Ila) above. The 5-oxo group can then be con- verted to the S-oxime, uning the methods already des- cribedj or it can be converted to a 5-hydroxy group by reducing it e.g. with sodium borohydride. ’ The compounds of the invention have a strong acaricidal activity against, for example, adults, imagos and egge of letranychus, ianonychus (e.g. janonychus ulmi and }anonychus citri). Aculopa pelekassi and rust mites, which are paresitic to fruit trees, vegetables and flowers. They are also active againat Ixodidae,

Dermenyssidae and Sarcoptidae, which are parasitie to animals. Further, they are active against: : . - 35 a oa '3pD ORIGINAL 9 \ro—

: Uns) 26231 31 ‘ exoparasites, suck as Qestrus, Lucilia, Hypoderma,

Gi :ruphilys, lice and flenas, which are parasitic . to animals and birds, particularly livestock and poultry; domestic insects, such as cockroaches and houseflies; and various harmful insects in agricul- tural and horticultural areaa, such as aphids and larval Lepidoptera. They are also effective against

Meloidoggns in the soil, Bursaphelenchus and

Rhigoglyphus, and against insects of the order Coleop- . 10 tera, Homoptera, Heteroptera, Diptera, Thysanoptera, . Orihoptera, Anoplura, Siphonaptera, Mallophage,

Thysanura, Isoptera, Isocoptera and Rygsenpptera. .

The compounds of the invention equally can be used to control other plant-damnging insects, parti- ‘ - cularly insects that damage plants by eating ‘them.

The compounds can be used to protect both ornamental plants and prodpctive plants, particularly cotton (e.g. against Spodeptera Littoralis and Heliothis virescens), as well as vegetable crops .(e.g. against

Leptinotarsa decemlineata and Myszus persicae) and : . rice crops (e.g. against Chilo suppressalis and Lao- ~ delphix).

The activity of the compounds of the invention is pronounced, both systematically and by contact. Ac~ : cordingly, the compounds are very effec ive against 2: - 36 = - in

BAD ORIGINAL GJ co : be c A 262951 sdcking insects, especially sucking insects of the order Homoptera and most particularly the family

Aphididae (such as Aphis fabae, Aphis craccivora and Myzue persicae), which are difficult to control

S with ¥newn compositions.

Accordingly, the compounds of the invention can be used to treat all manner of plants (as well as the seeds from which such plants are grown and the environment, whether for growth or storage, containing such plants) to protect them from insects such as those exemplified above. Such plants include cereals (e.g. maize or rice) ,vegetables (e.g. potatoes or soy- beens), fruits and other plants (e.g. cotton).

The compounds of the invention can similarly be used to protect animals from a variety of ectopa- rasites, by applying the compounds to the animals er to the animals' environment, e.g. livestock housing, animal boxes, sbattoirs, pasture land and other grass- lands, as well as to any other places liable to be in- feasted. The compounds mey also be applied to external parts of the animals. Freferably before they are infested,

Moreover the compounds of the invention are eof- fectide against various parasiticidal helminths. These parasites can attack livestock, poultry and pet animals (such as pigs, sheep, goats, cows, horses, dogs, oats - 37 - — ~

GAD ORIGINAL d

. Li 5) 26231 and fowl) and can cause grave economic damage. Among the helminths, the nematodes in particular often cause serious infection. Typical genera of nematodes which are parasitic on these animals and against which the compounds of the invention are effective include:

Haemonchus,

Trichostrongylus,

Ostertagia,

Nematodirus,

Cooperia,

Ascaris,

Bunostomum,

Oesophagostomunm,

Chabertia,

Trichuria,

Strongylus,

Trichonema,

Dictyocaulus,

Capillaria,

Hoterakis,

Toxocara,

Ascaridia,

Oxyuris,

Ancylostonma,

Uncinaria, - 38 - a

BAD ORIGINA. 9

1 74/ 26231

Toxascaeris and parascaris.

Certain parasitical species of the genera

Nematodirus, Cooperia and Oesophagostomus attack the intestines, while certain species of the ge- nera }jaemonchus and Ostertagia parasitise the stomach, and parasites belonging to the genus Dic~ tyocaulus are found in the lungs, Parasites belong- ing to the families Filariidae and Setariidase are found in internal tissues and organs, for example, the hemtt, the blood vessels, the subsutaneous tissues and i the lymphatic vessels. The compounds of the invention are active against all these parasites.

The compounds of the invention are also effect- ive against parasites which infect humans. Typical of the parasites which may most commonly be found in the ] | digestive tracts of human beings are parasites of the genera Ancylostoma, Necator, Ascaris, sgrongyloides,

Irichinelis,Capillaria, Trichuris and Enterobius. The compounds are also active against parasites of the ge- gera Wuchereris, Brugia, Onchocerca and Loa of the fa- mily Filariidae (which are found in blood, tissues and organs other than the digestive tract and are medically . important), parasites of the genus Dracunculus of the family Drscunculidae and parasites of the genera - 39 - aap ORIGINAL 9 eo ey od 26231 i

Strongyloides and Irichinella, which in a particular state may parasitize outside the intestinal tract, although they are essentially intestinal parasites,

The form of the compositions of the invention and the nature of the carriers or diluents employed in them will vary depending upon the intended use of the composition. For example, where the compounds eof the invention are to be employed as anthelmintics, they are preferably administered orally, parenterally or topically and the form of compositions chosen will be appropriate to the intended route of administration.

For oral administration, the composition of the invention is preferably in the form of a liquid drink ’ comprising a non-toxic solution, suspension or disper- sion of the active compound in admixture with a suspend- ing agent (such as bentonite), a wetting agent or other diluents, preferably in water or another nonptoxie sol- : vents The drink, in general, also contains an anti- foaming agent. The active compound would normally be oo 20 -pregent in the drink in an amount of from 0.01 to 0.5% : by weight, more preferably from 0.01 to 0.1% by weight,

Compositions for oral administration may alse : oo be in the form of dry solide, preferably in unit de- ) sage form, such a3 capsules, pills or tablets containing the desired amount of the aétive compound. These com- - KO a

(1 74) : | a i 20231 i positions may be prepared by mixing the active com- pound uniformly with suitable diluents, fillers, di- sintegrators and/or bAAding agents, for example starch, lactose, talc, magnesium stearate and vege- table gum. The weight and contents ot the prepara- tion will vary widely, depending upon the nature of the animal “$e be treated, the degree of infection, the natire of the parasite and the body weight of the animal to be treated,

The compounds may also be administered as am i additive to animal feedstuffs, in which case they may be dispersed uniformly in the feedstuffs, used as a top dressing or used in the form of pellets. The con- tent of active compounds in the feedstuff is prefer- ably trom 0.0001 to 0.02%, in order to achieve the de- sired anthelmintic activity,

Co For parenteral administration, the compound of the invention is preferably dissolved or suspended in a liquid vehicle, preferably a vegetable oil, such as peanut oil or cottonseed oil. Where the compound is a salt of a compound of fernula (II), the liquid vehicle may be water or another aqueous medium. Depending upon the animal to be trasated, the injection may be subcuta- neous or into the proventriculus, a muscle or the tra- chea. Such pfepaprations would normally contain the - bh — A : pro omen Go oo lhry ~V edd active compound at a concentration of from 0.05 to 50% by weight,

The compounde of the invention may also be ) oo administered topically in admixture with a suitable bi carrier, such as dimethyl sulfoxide or a hydrocar- bon solvent. Such preparations would be aprlied di rectly to the outside of the animal by srraying (e.g. by a hand spray or in fpray races), by dipping (e.g. in a plunge dip), by a pour -on solution or by manual me- thods (e.g. hend-dressing)., ) : The dore of nctive compound may be varied, deo-. pending upon the nature of the animal to be treated,

Co and the nature sand degree or parasitic infection. How- ever, best results for oral administration are achiev- ed when the dose is from 0.01 to 100 mg, more profer- ably from 0,5 to 50 mgs per 1 kg body weight. The com- : pound may be administered in a mingle dose or in divid- ed doses for a relatively short period, such as from 1 to 5 days, . 20 Where the composition of the invention is {nted- ed for agricultural or horticultural use, a briety of forms and formulations ia rossible. For example, the componition may be formulated as dusts, coarse dusts, soluble powders, microgranules, fine microgranules, wet- table powders, dilute emulsions, omuleifiabie concent : : - b2 : \ GINA y pao OF

. . ‘77 v.</ 9 6 9 cg

C 23 1 + rates, aqueous or oily suspensions, dispersions or solutions (which may be directly sprayable er for dilution), aerosols or capsules in, for exam- ple, polymeric substances. The carrier employed

S may be natural or synthetic and organic or inore ganicy it is generally employed to assist the act- ive compound to reach the substrate to be treated, and to make it casier to store, transport or handle the active compound. Solid, liquid and gaseous car- riers may be employed, chosen from carriers well known in the art for use with compositions of this type.

Such formulations may be prepared by convent- : ional means, e.g. by intimate mixing and/or grinding of the active ingredients with the carrier or diluent, e.g. solvent, solid carrier or, optionally, surface-active agent.

Suitable solvents include: aromatic hydrocarbons, preferably the Co to Cio fractions from petroleum dis- tillation, such ae xylene mixtures or substituted naph- thalenes; esters of phthalic acid, such as dibutyl or dicotyl phthalate; aliphatic hydrocarbons, such as cye- lohexane or the paraffinej alcohols and glycols er es- ters thereof , such as ethanol, ethylene glycol, ethyl- ene glycol monomethyl ether or ethylene glycol monoethyl ether; ketones, such as cyclohexanene; strongly polar ~ - h2p- gy i yo ORIGINAL ol

Th) 26231 solventsjisuch as N-methyl-2-pyrrolidone, dimethyl suifoxide or N,H-dimethylformamides optionally epo~ xidiged vegetable oils, such as epoxidized coconut oil or soybcan oilg and water.

Solid carriers, which may be used, for exam- ple, in dusts and dispersible powders, include natu- ral mineral fillers, such as calcite, talc, kaolin, montmorillonite or attapulgite. In order to improve the physical properties of the composition, 1b is : also possible to add highly dispersed silicie acid or highly dispersed absorbent polymers. Ruitable granulated adeorptive enrriers may be porous (such . . as pumice, ground brick, sepiolite or bentonite) or non- porous (such as caloite or sand). A wide variety of preg- ranulated materials, organic or {norganic, may alee bé used} examples include dolomite and ground plant residues. :

Surfacesactive agents which may be used are well } known in the art and may be non-ionic, cationic or anio- nico agents having good emulsifying, dispersing and wet- : . 20 ting properties. Mixtures of such agents may also be used. } compped tiona may also contain stabilisers, amt}- foaming agents, viscosity regulators, binders or adhe sives or any combination thereof, as vell as adhesives or any combination thereof, as well as fertilisers or ° . - 43 - ‘ gp 07 )

Uy 77) i £N) i i other active substances to achieve special effects.

Festicidal compositions will gmnerally contains from 0.01 to 99%, more preferably from 0.1 to 95%,0fby weight of the active compound; from 1 to 99% of a so- 1id or liquid additive; and from O to 25%, more pre- ferably from 0.1 to 25%, of a surface-active agent.

Whereas commercial products are generally sold as con- : centrated compositions, they are generally diluted by the end-user to a concentration of from 0.001 to 0,0001% by weight (from 10 to 1 ppm).

The invention is further illustrated by the fol- lowing non-limiting Examples and ‘reparations. Examples 1 to 35 illustrate the preparation of compounds of for- mula (I), but for brevity the symbol 2 has been used in place of A=(W) =C(R°R7)- in these Examples. Freparations 1 to 3 illuatrate the synthesis of starting materials . which may be used in preparing the compounds of the in- vention, Examples 36 to 38 illustrate the activity of the invention against various pests.

EXAMPLE 1 13-(2-Methyl-2-phenylprorionyloxy)-25-ethylmilbemycin . (Compound of formula (IIb) wherein: rl = ethyl, Z =o, a ~dimethylbenzyl,~OR ‘= -0H). ‘ 3,5 mg of sodium borohydride were added, under - 4h A } AL “J

Uva) . 26 n 231 jce-gooling, to a solution of 123 mg of 13-(2-methyl- . 2- phenylpropionyloxy)-5-keto-25-ethylmilbemycin in ml of methanol, and then the mixture was stirred at room temperature for 30 minutes. “t the end of this 5 time, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed, in turn, with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and : concentrated Wy evaporation. The residue was purified by column chromatography through silica gel to give 85 "mg (yield: 69%) of the title compound.

Mase Spectrum (W/z); 70B(M’), 686. 6u6, 576, 540, 522.

Nuclear Magnetic Resonance Spectrum (coc lt 3) £ ppm 3,94 (1H, doublet, H at the 6 position, J=6.6Hs)} 4,07 (1H, singlet, OH at the 7 pomsition)s 4.28 (1H, doublet of doublets, B at the 5 position,

Ju6.6, 6.6 Hs)} 4.65 (2H, multiplet, R at the 27 position) : 4.86 (1H, doublet, H at the 13 position, J=10.6Hz)} 7.28 (5H, multiplet). BE

By following the procedure of Example 1, the com- pounds of Examples 2 to 29 were prepared, having the che- “ racteristics shown. - 45 = ( CaN

BAD ORIGINA-

I -

”

TA) . . 0) ¢ ih ' 2 6 ya 3 d : EXAMPLE 2 13-(2-Phenylpropionyloxy)-25-ethylailbenysin (Compound of formula (IIb) wherein: rl = ethyl, Z = q -methylbensyl, or" = -0R).

Mass Spectrum (m/z): 690(N*), 632, 562.

Nuclear Magnetic Resonance Spectrum (ce 4) S ppm 3.947 and 3.952 (1H, doublet, H at the 6 posi- tion, J=6.2 Hs); 4.05 and 4.08 (1H, singlet, OR at the 7 positionm)} h.89 (1H, singlet, H at the 13 position, J-10.6 Hs. ).

EXAMPLE 3 13-(2~Phenylbutyryloxy)-25-e thyimilbemyoin (Compounds of formula (IIb) wherein: rl = ethyl, 2 = a_-ethylbensyl, -or" = «0H). ’ 15 Mass Spectrum (m/z): 704 (M*), 686.

Ruclear Magnetic Resonanck Spectrum (coc fy) S$ ppme 3.95 (1H, doublet, H at the 6 position, I=b.2

Hs): 4.05 and 4.08 (1H, singlet, OH at the 7 positiony 4,89 and 4.90 (1H, doublet, H at the 13 position,

Jul0.6 Hs), : - h6 -

T4004) aot) * 26231 ©

EXEMPLE bh 13-(3-Methyl-2-phenylvaleryloxy)-25-e thyluilbenycin (Compound of formula (IIb) wherein r! = 3thyl, 2 = 0 = sec-butylbenzyl-OR"= -OH). s Mass Spectrum (m/s): 732(N*), 714, 60h, 540,522, Soh.

Nuclear Magnetic Resonance Spectrum (eDG 2 5) & ppms 3.9% (1n, doublet, H at the 6 position J=6.1

As) : 4.09 (1R, multiplet, OH at the 7 position); h.86 and 4,89 (1H, doublet, HE at the 13 posi- tion, J=10.5 Hs).

EXAMPLE 3 13-Benshydrylcarbonyloxy-25-ethylmilbesyocin (Compound of formula (IIb) wherein: : a! = othyl, Z = benshydryl, oR" = 0H).

Mass Spectrum (m/2): 7s2(u*), 734, 716. ’ Nuclear Magnetic Resonance Spectrum (CDC fy) § ppm : 3.95 (1H, doublet, H at the 6 position, J=6.1

Be): 4,07 (1H, singlet, OH at the 7 position); ‘ 4.98 (1H, doublet, H at the 13 position, Ju9.2

He). .

EXAMPLE 6 13-(2~-Methyl-2~phenylbutyryloxy)-25-ethylmilbeaycin (Compound of formula (IIb) wherein:

Ap 11, by) ai ’ ’ 26231 a! = ethyl, % = q ~ethyl-q -methylbensyl, -or" = « OH). ’

Mass Spectrum (m/s): 718(M*), 700.

Nuclear Magne tio Resonance 8pectrum(CDC L 4) S$ pre. 3.94% (1H, doublet, HM at the 6 position, Jub.2 naif 4.08 (1H, broad sinjlet, OH at the 7 position); - 4,87 and 4,90 (1H, doublet, H at the 13 posi- tioa,

J=l0.6 Hs). :

EXAMPLE 7 oo : 13-(2,2-Diphenylpropionyloxy) -25-ethyluilbenycin (Compound ef formula (IIb) wherein: rR = ethyl, Z = «_-methylbenshydryl,-OR" = -0RH). 1s Mass Spectrum (m/x): 766(n*), 748.730. ] Nuclear Magnetio Resonance Bpectrum (coc £4) S ppm 5,28(18, doublet, H at the 5 position, J=5.9

Hs) 4,61 (1H, doublet, H at the 27 positiom, J=15.2 | Bs) . 4,68 (1H, doublet, KE at the 27 position, J=1%.2

Hs)

Cr "4,97 (1H, doublet, H at the 13 position, J=10.6

Bs)y 5.25 - 5.48 (4H, multiplet, H at the 3,11,15 and 2% . — 19 position);

6) CT N57) a 5.70= 5.82 (2H, multiplet, H at the 9 and 10 posi- tion).

EXAMILE 8 13. (s-orchloraphenyipreptonylery) Fae t RII IbeRIESS (Compound of formula (IIb) whereint gt = ethyl, 2 = qemethyl-g -chlorobensyls oR'= -OH) .

Mass Spectrum (m/2)s aau(u’), 706.

Nuclear Hagnetic Resonance Spectrum (coc £5) § ppm 3.95 (18, doublet, H at the 6 position, J=6.2

Be)s . 4,08 (1H, stnglet, OH at the 7 position) 4,92 and h,9k (1H, doublet, Ra &t the 13 posi- tion, J=10,3 Re).

EXAMELES 9 13-/2-0= (tsss1uoross thy sheaylproplonslexi/Z2= ethyl= milbemyocin (Compound of formula (11d) wherein: :

Rr « ethyl, 2 = a, ~methyl-9- (trifluoromethyl)-bensyls iy . -QR = -0H) .

Mass Spectrum (m/s) 758(u), 740, 722.

Nuclear Magnetic R“sonance Spectrum (coe £ 5) § ppmt 4.31 (1H, broad singlet, H at the 5 position)s 4,67 (2H broad singlet, of at the 27 position)s - bh -

Uy 24) 26231 23 1 4.88 (1H, doublet, H at the 13 position,

Ju10.6 Hz); 5.25 = S.41 (4H, multiplet, HE at the 3,11,15 . and 19 position) : 5.70=5.86 (2H, nultiplet, BR at the 9 and 10 position). . EXAMPLE 10 13-(2~-p-Nitrophenylpropionyloxy)-25-ethylmilbemysin (Comppund of formula (IIb) wherein

R! = ethyl, Z = -methyl-p- nitrobensyl, -or"a -OR).

Mass Spectrum (m/e): 735(M*), 607, 589,522.

Nuclear Magnetic Resonance Spectrum (coe Ly) J rpm. 3.95 (1H, doublet, Haat the 6 position, J=6.1.

Hs) 4.07 (1H, singlet, OH at the 7 position); 4,91 and 4.92 (1H, doublet, H at the 13 posi- . ’ tion, IJul0.3 fs).

EXAMPLE 11 13-(12-Methyl~2-p-chlorophenylpropionyloxy)=-25-ethyl- adlbemyocin (Compound of formula (IIb) wherein:

R! = ethyl, Z = q, o -dimethyl-p~ chlorobensyl, -or*a -OH).

Mass Spectrum (m/s): 738(M*), 610,576. - 50m -

Tq 26231 i ot

Nuckdar Magnetic Resonance Spectrum (CDC Ly) 5 ppm 3.95 (1H, doublet, H at the 6 position, Ja 6.2 Hs) k.07 (1H, singlet, OH at the 7 position); Co 5.01 (1H, doublet, H at the 13 position, J= 10.3 Hz).

EXAMPLE 12 13-(12-Me thyl-2-p-fluorophenylpropionyloxy)-25-e thyl- milbemycin (Compound of formula (IIb) wherein; rR? = ethyl, 2 = «, o -dimethyl-p-fluorobensyl, 4

OR = -0H), "Mass Spectrum (m/3): 722(M'), 70h, 686.

Nuclear Magnetic Resonance Spectrum (CDC) 8 ppm: 18 3.95 (1H, doublet, H at the 6 position, Ju6,2

He); 4,0? (1H, broad singlet, OH .at the 7 position); b.86 (1H, doublet, H at the 13 position, J=10.3

Hs). | EXAMPLE 13 13-(@ -Methoxybensylompbonyloxy)-25-ethyimilbeaynin (Compound of formula (IIb) wherein: gl = ethyl, 2 = ao - methoxybensyl, -or" = =0H).

. | 1p ‘V4 26231 i fo! i

Mass Spectrum (m/s): 706(1*), 688,

Nuclear Magnetic Resonance Spectrum (cpcly) S ppm. 3.94 and 3.95 (1H, doublet, BE at the 6 posi- tion, J=6.2 Hs) h.10 (1H, broad singlet, OH at the 7 position); 4.9% and 4.95 (1H, doublet, H at the 13 posi- tion, J=10.6 He).

EXAMPLE 1b 13-72-Methyl -2-(p-chlorophenoxy)propionyloxy/-2-ethyl- nilbemycin . {Compound of formula (IIb) wherein: rR! e ethyl, 2 = l-methyl-l-(p~ chlorophenoxy)ethyl, -or” = -0H) . :

Mass Spectrum (m/z); 754(M*), 736, 718.

Nuclear Magnetic Resonance Spectrum (cpce,) § ppm! 3.95 (1H, doublet, Ha at the 6 position, J=6.2 Hz); : 4,07 (1H, sihglet, OH at the 7 position); 5.01 (1H, doublet, H at the 13 position, J=10,3

Hs) .

EXAMPLE 15 12. [2-{p-(phenoxy)=phenoxg/propionyloxyy ~25- ethylmil- bemycin (“ompound of formula (IIb) wherein: rR! = ethyl, 2 =1-/p-(phenoxy)phenoxyJethyl, -0R"=-0H).

Mass Spectrum (m/z): 798(M*), 780,762,670, B40, 522, 50k. om

Nuclear Magnetic Resonance Spectrum (cpchy) S$ ppm: ' 3.96 (1H, doublet, H at the & joeition,

J=6.2 Hz): 4.06 (1H, sibglet, OH at the 7 position); 4,95 (1H, doublet, H at the 13 position,

J=10.3 Hz). nX MELE 16 13-4 2-/p-(5-Trifluoroms thyl-2-pyridyloxy)phenoxy/ ee ee HY propionyloxy } =25-ethylmilbemycin (Compound of formule (I1b) wherein: 1 Co

R™ = ethyl, 2 = 1-/p-(5=-trifluoromethyl-2-pyridyl- : oxy)phenoxy/ethyl, or” = -CH).

Mase Spectrum (m/z): _672(M%), 849, 831, 813, 540,522, 504,

Nuclear Magnetic Resonance Spectrum (coe by) SS” ppm: 3.96 (1H, doublet, H at the 6 position,

J=6.2 liz); 4.10 (1H, broad singlet, OF at the 7 position); : 4.98 (1H, douklet, H at the 13 position, J=10.3

Hz).

SXAMILE 37 13-(2-o-Fluorophenylpropionyloxy)=25-ethylmilbemycin (Compound of the formula (Ilb) wherein: rt = ethyl, 2 = o -methyl-o- fluorobenzyl, -or" = \ ‘awlivy -0OH). ’ Y - 53 =~ ‘BAD ORIGINAL @

: | J

Mass Spectrum (m/z): 708(m*), €9h, foo, 580, 540, 523.

Nuclear tagnetic Reronanrce Spectrum (CDC 2 3) S$ ppm: 3.95 (1H, doublet, H at the 6 position, J=6.1

Hz) 4,29 (11, doublet, H at the S position, J=6.1

Hz) 4.91 and 4,93 (1H, doublet, H at the 13 position,

J=10.5 He). } OXAMILE 18

LO 13-(1-} henylcyclohexylecarbonyloxy)-25-eathylmilbemycin (Compound of formula (IIb) wherein: rl = ethyl, 2 = q.-cyclohexylbenzyl, or" = -OH).

Mass Spectrum (m/z): 758(M*), 740, 630, 540, 522.

Nuclear Magnetic Resonance Spectrum (CDC Ly) § ppm: 3.95 (1H, doublet, H at the 6 position, J=6.4

Hz) 4,08 (1H, singlet, OH at the 7 position); 4,86 and 1.89 (1H, doublet, H at the 13 position,

J=10.6 Hz).

EXAMPLL 19 : . NN 13-(1-kFhenylcyclopentylcarbonyloxy)~25-ethylmilbemyecin (“ompound of formule (IIb) whereins rt = ethyl, 7 = l-phenylcyclopentylm -or*= -0H).

Mass Spectrum (m/z): 730(M%), 712, 602, 540, S522. - 54

BAD ORIGINAL 9

L

. A ” , pia ¢ 3 9) ;

J

. Nuclear Magnetic Resonance Spectrum (CDC SY § ppm: 3.94 (1H, doublet, H at the 6 position,

J=6.2 Hz i); 4,07 (1H, singlet, OH at the 7 pomition); : 5.80 (1H, doublet, H at the 13 position,

J=10.6 Hz).

SXAMILE 20 13-/2-(+henylthio) propionyloxy J-25-cthylmilbemyctn : (Compound of formula (IIb) whereins rl = ethyl, 4 = 1 (phenylthio)ethyl,-OR"= -0H).

Mass Spectrum (m/z): 722(M%), 70h, 594, 540, S522.

Nuclear Magnetic Resonance Spectrum (coc¥ 4) 4 ppm: . 3.96 (1I', doublet, H at the 6 position, J=6.5

Hz) 4,04 (1H, broad singlet, OH at the 7 position); 4.93 (1H, doublet, H at the 13 pomiticn J=10.5 . Hz). - EXAMI LE 21 13~-(1-Fhenylcyclopropylcarbenyloxy)-25-ethylmilbemycin (Compound of formula (11b) wherein: rt = ethyl, ¢ = 1%phenyleyclopropyl,-OR" = =OH).

Mass Spectrum (m/z): 702(MY), 6Bh4, 574, 540, 522, SObL.

Nuclear llagnetic Resonance Spectrum (CDC £5) § TDppnm: 3.95 (1H, doublet, H at the 6 position, J=6.,2

Hz) 4,02 (1H, singlat, OH at the 7 porition)s 4.87 (1H, dcublet, H at the 13 position, J=10.6 1 La Hz). - 5 'BAD ORIGINAL 9

So Tyr 206231 : ~ gu : EXAMI'LE 22 oo 13-(2-o-Tolylpropionyloxy)-25-ethylmilbemycin (Compound of formula (IIb) wherein:

R' = ethyl, 2 = @ -methyl-o-methyl benzyl,-OR" = : 5 -OH).

Mass Spectrum (m/z): 704(M'), 690, 686,646,604,576, 540, 522.

Nuclear Magnetic Rsonance Spectrum (CDC 3) 4 ppme 4,23 (1H, multiplet, H at the 5 position); - 10 4.66 (2H, broad singlet, 2H at the 27 position); . ‘ 4.25-5,42 (4H, multiplet, H at the 3 ,11,15 and 19 position); 5.7 5.8 (2H, multiplet, H at the 9 and 10 posi-- tion). - .

EXAM LE 23 12-/2-(S)-Fhenylpropionyloxy/-25-ethylmilbemycin . (Compound of formula (IIb) wherein:

R! = ethyl, 2 = (5) =- a methylbenzyl, -OR'=-0M); Co

Mase Spectrum (m/z): 690(M*), 672, 632,562, 540, S22.

Nuclear Magnetic Resonance Spectrum (CbCg4) 3 ppm: 3.94% (1H, doublet, H at the 6 position, J=6.0 Hz); oo hob (1H, singlet OH at the 7? position); 4.88 (1H, doublet, H at the 13 position, J=10.5

Hz). - 56 - | : [BAD ORIGINAL IP

Ltpg=a) 26231 ~ i 1 3 / 2-(R)-Fhe nylpropionyloxy/-25-e thylmilbemycin (Compcund of formula (I1b) wherein:

R} = ethyl, 2 = (R) -q -methylbenzyl, or'= oH),

Mass Spectrum (m/z): 690(M"), 672, 632, B62, Sho, 522. ‘ . ~ Nuclear Magnetic Resonance Spectrum (cocky) S ppm: : 3,95 (1H, doublet, H at the 6 position, J= : 6.0 Hz); 4,08 (1H, broad singlet, OH at the 7 position); 4,89 (11, doublet, H at the 13 position, J= 10.3 Hz).

IXAMI LE 25 13-(2-p-Aminophenylpropionyloxy)-25-ethylmilbemycin (Compound of formula (IIb) wherein: rl = ethyl, %"= q_~- methyl-p-aminophrnyl, -or"= -OH) «

A solution of 131.8 mg of 13-(2-methyl-2-p-nitro- phenylpropionyloxy)-25-ethylmilbemycin in 8 ml of metha- : nol was hydrogenated for 6 hours, with stirring, at room temperature in the preaence of 3 mg of 5% palladium-on- charcoal. At the end of this time, the reaction mixture : was filtercd and the filtrate was concentrated under re- duced pressure. Thc residue was purified by. column chro- - matorpgaphy through silica gel to give (5,0 mg (yield: Sle 4) of the title compound.

MN

- 57 - BAD ORIGINAL <

Try 20231

Mass Spectrum (m/z): 705(M*), 687, 671, Sho, 522, 50k,

Nuclear Magnctic Hgsonance Spectrum (Cpe L 5) % ppm: 3.98 (1/1, doublet , KH at the 6 position, J= 6.1 Hz); 4.05 (1H, singlet, OH at the 7 position); 4.30 (1H, doublet, H at the 6 position, J= © 6.1 Hz) 4,65 -4.8 (2H, multiplet, 2H at the 27 position); 5.16 (1H, doublet, H at the 13 position, J=10.4

Hz); 5¢3 = 5.5 (4H, multiplet); 5.8 ~ 5.95 (2H, multiplet); 6.66 (2H, doublet, J=8.5 lz); 7.85 (2H, doublet, J=8.5 Hz).

SXAMELE 26 13-/2-(2-Fyridon-1-yl)propionyloxy/-25-ethylmilbemycin (Compound of formule (IIb) wherein:

RY = ethyl, # = 1-(2-pyridon-1-y1)ethyl, -OR's -OH).

Mass spectrum (m/z): 707(n*), 689, 540, 522, 504, h6O, uh2, h12, 394,

Nuclear Magnetic Resonance Spectrum (cnc £ 5) § ppm: 3.96 (1H, doublet, H at the 6 position, J=6.0

Hz) 4,04 (1H, singlet, OH at the 7 position): - 58 - loo oman: >

Ars) . - 4 26231 1 . 14,96 and 4,98 (1H, doublet, H at the 13 position,

Je= 10.6 He).

EXAMILE 27 13-/Z-(2-F iperidon-1-y1)propionyloxy/-25=ethylmiibenyelin (Compound of formula (IIb) wherein: a = ethyl, 2 = 1-(2-piperidon-1-yl) ethyl, gpl. “OH

Mass Spectrum (m/z): sho(u')-171), 522, 504, h12, 394, 195, 167, 154.

Nuclear Magnetic Resonance Spectrum (coe L,) & ppm: 3.71 (1H, singlet, OH at the 7 position); 3,97 (1H, doublet, H nt the 6.position, J= 6.1

Hz) 4.93 and 4.96 (1H, doublet, H at the 13 posi- tion J=10.5 He). © 15 “XAMILE 28 13-/2-(2-Fyridyl)propionyloxy/-25-e thylmilbemyoin i 13-/2-(2-Fyridyl)proplonyloxy/=c ce oF ] ( Compound of formula (11b) wherein: gl = ethyl, 2 = 1-(2-pyridyl)ethyl,-OR" = =OH).

Mame Spectrum (m/z)s 691(M’), 673, 540, 522, 50k,

Nuclear Magnetic Resonance Spectrum (coct,) . 8 ppm 3,70 (1H, singlet, CH at the 7 position)y . | 3.92 (1H, doublet, K at the 6 position, J=6.5 : Bz) 4,12 and 4.28 (1H, triplet, H at the 5 posi~ mr sition, J=6.5 He) - PR - 50 - \

Nem

AA) 26231 4,62 = 4.7% (24, multiplet, 2fl.at the 27 posi- tion)e

EXAMELE 29 . 1 (oonenpipreptenpiosy)cazhytrams el matss iE 1-butenyl) milbemycin (Compound of formula (11Ib) whereint 1

R = 1,3-dimethyl-1-butenyls 7 = oq methylbenzyle . i -— : .

X= -OH, -OR = -OH). :

Mass Spectrum (m/z): go’ Ys 742s 7990 710, 33le

Nuclear Hagnetic Resonance Spectrum (cpcL ) § prams 3. : 3,94 (1H, doublet, H at the ¢ positiony J= 6.4 : Hz). 4.28 (1H, triplet, H at the 5 position, Jubolt

Hz)3 4,65 (28, broad singlets on at the 27 position) : 4,88 (1H, doublet, H at the 13 position, J=10.5

He) } -

Examples 30 to 35 jllustrate the preparation of compounds of formula (11c) fron starting materials of formula (IIb) by the reaction of Step C in the React- jon Scheme above. sXAMELE 30 1p (oopospyicz-spsnppreptenyion)sesasentssis Lo "© gthylmilbemycin (Compound of formula (IIc) wherein

ORIGINA J

- 60 - sa

A3/ 2 e ethyl, Z = oC, of. -dimethylbenzyl, or’ = propionyloxy)e 51 sul of propionyl chloride and 38 jul of pyridine were added, under jce~cooling, to a solu- tion of 91 mg of 13-(2-me thyl-2-phenylpropionyloxy)- 25-ethyl milbemycin in methylene chloride, and the mixture was stirred at room temperature for 3 hours.

At the end of this time, the roaction mixture wes poured into water and extracted with ethyl acetate. ] 10 The extract was washed, in turn, with water and a saturated aqucous solution of sodium chloride, dried over megnesium sul fate and concentrated by evapora- : . tion. , The residue was purified by column chromatog- raphy through silica gel to give 75 mg (yield: 76% ) of the title compound

Mass Spectrum (M/2)1 260(H¥) « £86, 596, 540, 522, 50h.

Nuclear Magnetic Resonance Spectrun (cocky) S ppm: 3,99 (1H, brood ainglet, OH at the 7 position): 4,04 (1H, doublet, H at the »@ position, J=5.9 | : Hz) 4,53 (1H, doublet, H at the 27 position, J=1h.3

Bz) 4,62 (1H, doublet, H at the 27 position, J=1l.3

He) . 4,87 (1H, doublet, 1 at the 13 position, 310.3

Hz)

HAD ORiGinaL AN)

C =

; | | 17) 9 5.25 5.45 (3H, multiplet); 5.5 = 5.6 (2H, multiplet); 5.65 = 5.8 (413, multiplet); 7.2 = 7.4 (5H, multiplet. Co : EXAMPLE 31 5-0-(3-Carboxypropiony])=13=(2-ne thyl-2-phenylpro= © donyloxy)=25~-ethylmilbemycin (Compound of formula (IIc) wherein:

R' ethyl, Z = ao , q -dimethylbeneyl, or" = 3-carboxypropionyloxy). :

Following the procedure of Example 30, but using 76 mg of 13-(7-methyl-2-phcnylpropionylexy)-25- . ethylmilbemycin and 100 mg of succinic acid anhydride, . there were obtained £1 mg (yield: 70%) of the title compound.

Mass Spectrum (m/z): Bo(mM*), 704, 686, 668. . Nuclear Magnetic Resonance Spectrum tone £9 § ppm: 4,03 (1H, doublet, at the 6 position, J=5.9 oo le); 4.5% (1H, doublet, R at the 27 position,

Jelb.2 Hz)} 4,62 (1H, doublet, H at the 27 position, - J=1h.2 He)y = 4.87 (1H, doublet, H at the 13 position, J=10.3

He); - 62 - | 9 : ~ BAD ORIGINAL - ,

i 26231 ~ " 5.35 - 55 (3H, mul tiplet)s 5.5 = 5.6 (2H, multiplet); 5.65 - 5.8 (2H, multiplet); 7.3 (5H, multiplet).

The cémpounds of Ixamples 32 to 34 were also prepared by following the procedure of sxample 30,

EXAMLE 32 13-(2-0-Chlorophenylpropionyloxy)-5-0O-chloroacetyl- 25-ethylmilbemycin (Compound of formula (IIc) wherein:

RY = ethyl, 2 = OG =- methyl-o- chlorobenzyl, oR" = chloroacetoxy).

Mass Spectrum (m/z): goo(mM*), 782, 616, S522.

Nuclear Magnetic Resonance Spectrum (coc L 5) $ ppm: 4.57 (1H, doublet , H at the 27 position,

Co J=15.1 Hz) 4.62 (1H, doublet, H at the 27 position,

Je15.1 He) ] 4-.92 (1H, doublet, H at the 13 position,

J=10.6 Bz); : 5.27 -5.41 (3 H, multiplet, H at the 11, 15 and 19 position); 5.56 (1H, multiplet, H at the 3 position) 5.72 - 5.82 (2H, multiplet, H at the 9 and 10 position). : . we .

E - 63 - BAD ORIGINAL oo)

2 ) re rl

EXAMPLE 33 13=(2-0-Chlorophenyliropionyloxy)~5-0-e thoxycarbo- nyl-25-ethylmilbemycin (Comppund of formula (1Jc¢c) wherein: rl = ethyl, Z = o_-methyl-o-chlorobenzyl, y =0R° = ethoxycarbonyloxy).

Mass Spectrum (m/z): 766M" 18), 738, 688, 612, S22, : 504,

Nuclear Magnetic Resonance Spectrum (CDC Ly) &§ ppm: 4,06 (1H, broad singlet, OH at the 7 position); 5 4,10 (1H, doublet, H at the 6 position, J=6.2 . Hz) 4,90 and 4.91 (1H, doublet, H at the 13 posi- tion, J=10.6 Nz),

EXAMELE 3h 13-(2-Methyl-2-phenylpropionyloxy)=5-0O-chloroacetyl= ’ -25-ethylmilbemycin (Compound of formula (Ilc) wherein: : gt = ethyl, 2 = o , of -dimethylbenzyl, : 20 or" = chloroacetoxy),

Mass Spectrum (m/z); 780(M’) , 616, 597, 522.

Nuclear Magnetic R,sonance Spéctrum (cpe L 5) ppm: 4.03 (1H, singlet, OH at the 7 position); 4.08 (1H, doublet, H at the 6 position, J=6.5

Hz)

PT BAD ORIGIN

L AL ©

/ Vv -

Ay v7 06231 87 (1H, doublets # at the 1% positions 3210.9 nz).

ER AMELE 32 . pm saupiest ss (Compound of gormuleé (11¢) whereint

Rt e ethyle 7 Ao o amet

Le

OR" z covoryacetory)” 12% OF of agodium jodide were added tO a aolutio? of 129 ng of en oo ee in aothylene chlorides . and the mixture was atirred ay room remperatyr® gor 1 hourse AL the end of this primey the reaction mixture was poured gnto water and then .xtracted with ethyl } 15 acetates The oxtract was washeds gp turns with water and 8 gaturatesd aqurous golutic? of scdivm® chlorides drivd over magneeiv® guliate and concentrated vo give ‘a crude ens jodo- mea ’ 20 This crude product vee aissolved gn 15 ® of ' poatmeenyineo tem 13% m8 [34 godium acetate were added, and the mixture was stirred at TOOM rempere” gure for 3 hourse at the end of this Lime. yhe re” action mixture wos poured into water and extracted with ethyl acetates The extract was worheds in Lurne with water and 2 anturatesd aqueoud golution of godiuv® . [= ee _ 65 =-RAD - ~ 0 ORIG : IGINAL a)

11s) 26231 chloride and then concentrated. The residue was purified by preparative thin layer chromatography (Merck Art 5717, 20 x 20 cm, thickness 2 mm), deve- loprd with a 1:1 by volume mixture of hexsne and ethyl acetate, to give 93. 8 mg (yield: 70.6%) of the title compound.

Mass Spectrum (m/z): Bol(M*), 640, 622, 5k0, 522, 50k, :

Nuclear Magnetic Resonance spactrum(cinc£ ) 8 ppm: ~ 4,03 (1H, sihglet, OH at the 7 position): 4,05 (1H, doublet, H at the 6 position,

J=6.1 Hz); h.5 - 4.7 (UK, multiplet); 4,87 (1H, doublet, H at the 13 position, .

J=10.4 Hz); 5.25 = 5.4°(2H, multiplet); } 5.5 = 5.6 (2H, multiplet); 5.7 = 5.8 (2H, multiplet); 742 = 7.35 (SH, multiplet). reparations 1 to 3 illustrate the synthesis of starting materials which can be used in preparing the compounds of the invention by the reactions described above, : Coe

BAD ORIGINAL J

’

Uy 17) } JRuFARATICN 1 5-Keto-23-hydroxy-25-(1,3-dimethyl-1-butenyl)milbe- mycin } 0.64 g of activated manganese dioxide was ad- "ded to a solution of 61.2 mg of 23-hy.roxy-25~(1,3- dimethyl-l-butenyl)milbemycin in 5 ml of acetone, and : the resulting mixture was stirred vigorcusly for 30 minutes. The mixture wns then filtered over "Celite" filter aid, and the filtrate was concentrated, giving 59,3 mg of the crude desired compound, : Mass Spectrum (m/z); 610, 592, 57h.

Nuclear Magnetic Resonance Spectrum (CDCL 5) § ppm: 3,78 (1H, singlet, CH at the 7 position) 3,84 (1H, singlet, Hl at the 6 position).

FREPARATION 2 : 13,23-Dihydroxy=5-keto-25-(1,3-dimc thyl-1-butenyl)= milbemycin

The crude S-keto-23-hydroxy-25-(1,3-dimethyl- . J-butenyl)milbemycin, obtained in Ircparation 1 above, was dissolved in 3 ml of formic acid, then 13 mg of selenium dioxide were added to the solution, and the : solution, end the resulting mixture was stirted for 1.5 hours at room temperature, The mixture was then filtered over '"Celite" filter aid, and the filtrate was poured into water and then extracted with ethyl \ L

ZINA JP

Limes orhG 4 oo 4717) 2 26271 acetate, The extract was dried over magnesium sulfate and concentruted, The rcsidue was dissolved ’ in a mixture of 2 ml of methanol, 3 ml of dioxane and 1 ml of 2N hydrochloric acid. The solution waa kept stirred overnight at room temperature, then poured into water and extracted with ethyl acetate,

The extract was dried over magnesium sulfate and concentrated. The rusidue was purified by prepara- tive thin layer chromatography (Merck, Art 5715,20 x 20 cm, 2 mm thick), developed with a 1:1 by vol- ume mixture of hexane and ethyl acetates, to give 13.2 mg of the demired compound (yield: 21.7%).

Mass Spectrum (m/z): 626(M* -36), 608, 590, 349, 331, 259, 242, 179.

Nuclear Magnetic Resonence Spectrum (coc t 4) + D,0) : : | ppm? 3.73 (1H, donblet, H at the 13 position, J=9.7 . . He) 3.75 (1H, doublet, H at the 25 position,J=10.5

Hz) 3.84 (1H, singlet, H at the 6 position),

FREPARATION 3 13-(2-Methyl-2-phenylpropionyloxy)=5-keto-25-ethyl- milbemycin 1.6 g of Z2-methyl-?-phenylpropionyl chloride

Lo a

JE

- 68 - \aa ORIGINAL »

1,17) a : 26231 } and 0.73 ml of pyridine were added, in turn, to a solution of 557 mg of 13-hydroxy-5-keto-25~cthyl- milbemycin in 20 ml of chloroform, and then the mix- : ture was-stirred at 60°C for 3 hours. At the end of this period, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed, in turn, with an aqueous solution of so- dium bicarbonate, water and saturated aqueous solu~- tion of sodium chloride, dried over magnesium sulfate | and concentrated by evaporation. The residue was pu- rified by column chromatography through silica gel to give 353 mg ‘yield: 50%) of the title compound. ‘

Mass Spectrum (m/z): 702(M*), €Bh, 538, 520,

Nuclear Magnetic Resonance Spectrum (CDC L 4) § ppm: 3.84 (in, singlet, H at the 6 position)y . 4,01 (1H, singlet, OH at the 7 position) 4.80 (2H, multiplet, H at the 27 position); 4,87 (1H, doublet, H at the 13 rosition,

J=10.3 Hz): 5.3 - 5.5 (34, multiplet, H at the 11, 15 and 19 position); 5.7 = 5.9 (2H, multiplet, H at the 9 and 10 . : positions : 6.53 (1H, multiplet, H at the 3 position) : 7.3 (5H, multiplet). - 6 - LN

BAD ORIGIN Le

. + “7

U7 <6231

EXAMULE 36

Acaricidal Activity against Tetranychus urticae

The primary leaves of cowpea plants of the species Vigna sinensis Savi Jere dnfected with or- ganic phosphate-aensitive mites (Tetranychus urticae).

One day after infection, the infested plante were Co sprayed, using a lizuho rotary sprayer, with 7 ml of a test solution containing the compound under test at a concentration of 0.3 ppm , at a rate of 3.5 mg of : 10 the test solutirn per 1 em’ of leaf. The plats were © assessed after.’ duys by examining adult mites, under a binocular microccope, to determines living and dead ‘ jndividuals. Two plants were used for each concentra- tion and each test compound. The plantas were kept : 15 during the test in grecnhous- compartments at 25%.

The results are reported in the following Table,

BAD ORIGINAL 9

T9) 26251 fa? A

Compound of Mortality Compound of Mortality ikxample No. (%) Lxample No, (%) 1 100 9 720 2 95 11 70 3 95 12 85 4 100 13 100 5 95 14 100 6 © 100 17 95 ? 70 30 8o 8 100

Control Compound 1 20 : Control Compound 2 hs

Control Compound 3 hs

Control Compound bh 30

The control Compounds were as follews: 1. 25-kthylmilbemycin (milbemycin A) : ] 2. 13-Benzoyloxy-25-ethylmilbemycin, 3, 13-Fivaloyloxy-25-ethylmilbemycin, 4, 13-ihenylacetoxy-25-ethylmilbemycin,

These results clearly demonstrate the markedly superior acaricidal activity of the compounds of the invention, as compared with control Compound No.l oo (i.e. the naturally produced milbemycin Ayds and also as compared with the 13-substituted derivatives used as Control Compounds 2, 3 and 4, - 71 - i

BAD ORIGINAL 9

SE | Ay 17) 26231

EXAMPLE _ 37 : - .

Activity against Dermanmyssus gallinae oo

Compounds of the invention were tested for acti- vity against mites of the species Dermanyssus gallinae.

Groups consisting of 100-200 mites, at various stages of growth, were transferred into test tubes containing 2-3 ml of a solution Bf the test compound at a concentra- tion of 100 ppm. The kestrtubes were stoppered with cot- ton wool and shaken’ for 10 minutes, then the solution was sucked out through the cotton wool and the tubes with the treated mites allowed to stand for 3 days at room tempera- : ture.

The compounds of Lxamples 1-3, 6-9, 12-14, 18-23, 30 and 31 were tested in this way and each produced 100% - mortality in the test groups,

EXAMELE 38

Activity against Lucilla scricata

Groups consisting of 30-50 eggs from the mpecies . Lucilia sericata, collected immediately after oviposi- tion, were added to test tubcs each containing 1 ml of a liquid culture medium and 1 ml bf the test compound in solution at a concentration of 100 prm. The teat tubes were stoppered with cotton wool and allowed to stand for h daye at 30°c. The percentage mortality in each tnst group was a: sessed nt the ond of the 4 days, : - 7” - BAD ORIGINAL 9

Ur) ¢ 6 Me Co y- 2 Fo 3 1 id

The compounds of sxamples 1-9, 12-15, 18, 19, 21- 23 and 30-33 were tested in this way and each produced 100% mortality in the test groups. - 73 - | TN gi emp ©

A | BAD ORIGINAL ~ —

Claims (1)

1. TT ——-. “lr LT) 2623 ’ ) ad 1 . WE CLAIM:

   l. A compound having the formula ! 2 RO CH Zz CH tu 3 = 3 ’ . A=(W)_ «C=C=0 Js 0. 1 n, 0 R R’ (1) : CH 5, 0 ~ CH y 3 OR in which: the broken line represents a carbon-carbon single or ‘double bond between the atoms at the 22 end 23 posi- tions: X represents a hydrogen atom or a hydroxyl group, or toge- . ther with the carbon rtom to which it is attach- ed represents the group C=20¢ provided that X 2 represents a hydrogen atom when the broken line represents a double bond between the carbon atoms at the 22 and 23 positionsy

   1 . R™ represents an alkyl, alkenyl, alkynyl, alkoxyalkyl or alkyl thiomlkyl rroup, each having up to 8 carbon atoms; . - 74 a BAD UriGINAL gf) . ~~ v3) 26231 ~~’ a cycloalkyl-substituted alkyl group wherein . the oycloalkyl moiety has from 3 to 6 ring carbon atoms and the alkyl moiety has from 1 to 5 carbon atoms; . 5 a cycloalkyl or cycloalkenyl group having from 3 to B ring carbon atoms and which ie unsubsti- tuted or has at least one substituént selected ’ from the group consisting of halogon atoms and ‘ alkyl groups having from 1 to h carbon atoms} a heterocyclic group having from 3 to 6 ring atoms of which at least one is an oxygen or sul fur atom and which is unsubstituted or has at least one substituent selected from the group : : consisting of halogen atoms and alkyl groups having from 1 to & carbon atomsj a represents ’ an alkyl group having from 1 to 6 carbon atoms, a haloalkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to b car- bon atoms,an alkoxyalkyl group having from 1} to I carbon atoms, a phenyl group, or a cyano group rR’ represents a hydrogen atom or a an alkyl group having from 1 to 4 carbon atomsj - 75 = | I~ gre BAD ORIGINAL A»

   (1,12) : 26231 or r® and rR’ } together with the carbon atom to which they are attached, jointly represent a cycloalkyl group having from 3 to 6 ring carbon atoms; d= 0or 1: W represents a methylene group, or an oxygen or sulfur atoms; and : A represents a phenyl group, a naphthyl group, or a hetero- cyclie arour having from 5 to 10 ring atoms of which at least one is a nitrogen, oxygen or sul- fur atom; and said phenyl, naphthyl or hetero- eyelte group is unsubstituted or has at least one substituent selected from the group consisting of alkyl, alkoxy and alkylthio groups each having from 1 to bh carbon atoms, halogen atoms,trifluoromethyl, amino, nitro cyano, keto, phenoxy (which may itself optionally be substituted with at least one substituent : selected from the group conristing of halogen atoms and trifluoromethyl), and hcterocyclyloxy groups having from 5 to 10 ring atoma of which at least one is a nitrogen , oxygen or sulfur atom; Co g" represents a hydrogen atom, or an eoter-forming carbpxylic or carbonic acid residue. - 7% - fi.

   ORIGINAL 9 i

   Agen) 969213 «Ud 1 and salts and esters of said compounds of formula

   (nD. 2e A compound as claimed in Claim 1, wherein rl represents an alkyl group having from 1 to 6 car-

   5S. bon atoms or an alkenyl group having from 2 to 6 carbon atoms, and X represents a hydrogen atom. 3, A compound as claimed in Claim 1, wherein Rt reprosents a methyl, ethyl, isopropyl, sec-butyl, l-me thyl-l-propenyl, l-methyl-l-butenyl or 1,3-dime- 10 thyl-l-butenyl group. 4, A compound as claimed in Claim 1, wherein rl represents a methyl, ethyl, isopropyl or sec-butyl group, X represents =a hydrogen atom,and there is a carbon-carbon single bond between the atoms at the 15 22 and 23 positions.

   5. A compound as claimed in Ciaim 1, wherein gt : represents the reaidue of organic acid capable of forming an ester groupe.

   6. A compound as claimed in Claim 1, wherein RY 20 represents a hydrogen atom or a group of the for- mulag -c0-(0) -R Co EY - 77 - 'BAD ORIGINAL 7%

   oo | CAG 26231 wherein nA = 0 or 13 and ’ rR’ represents a straight or branched chain Ci.18 alkyl group a Cs_9 cycloalkyl group, a Chg aralkyl group, a C, . alkenyl or alkynyl group, & C¢_, aryl group or a monocyclic or fused heterocyclic © group having from 5 to 10 ring atoms and containing at least one oxygen, sulfur or nitrogen atom.

   7. A compound as claimed in Y1aiml, wherein r* represents a hydrogen atom, an acetoxyacetyl group or a pivaloyloxyacetyl group.

   8. A compound as claimed in Claim 1, wherein RZ represents a methyl, ethyl or phenyl group, r> ~ represents hydrogen or a methyl group, and the ‘ 15 group A-(W) -represents a phenyl or halophenyl group.

   9. An anthelmintic, acaricidal or insecticidal composition, which comprises a compound as claimed oo in Claim 1 in admixture with a pharmaceutically, agrdculturally, veterinarily or horticultureally acceptable carrier or diluent.

   10. A method of protecting animals or plants from damage by parasites selected from the group consist- aap ORIGINAL )

   “Il (1%) oo CT J oo 26231 ing of acarids, h~lmiths and insects, which com- . prises applying to said animals or plants, or to seeds pf said plants or to a locus including sald animals, plants or seeds, an effective amount of } 5 a compound as claimed in Clainm 1. KAZUO SATO TOSHIAKI YANAI TAKAO KINOTO : KEIJI TANAKA TOSHIMITSU TOYAMA Inventors ’ - 79 = Vg AD ORIGINAL oe