PH26158A

PH26158A - Macrolide compounds and their use

Info

Publication number: PH26158A
Application number: PH35070A
Authority: PH
Inventors: Kazuo Sato; Toshiaki Yanai; Akira Nishida; Bruno Frei; Anthony O'sulliven
Original assignee: Sankyo Co
Priority date: 1986-03-25
Filing date: 1987-03-24
Publication date: 1992-03-18
Also published as: ZA872140B; JPH0819133B2; JPS6310791A

Description

.

So .

The present invention is concerned with a series of new macrolide compounds which are chemically related to certain known classes of macrolides including the milbemycins end avermectins. These compounds have valuable acaricidal, insecticidal and anthelmintic activities, The invention also provides methods of pre- ) paring these compounds and compositions and methods for using them,

There are several classes of known compounds with a structure based on a l6-membered macrolide ring, . which are obtained by fermentation of various microor=- ganisms or semi-synthetically by chemical derivatization of such natural fermentation products, and which exhibit acaricidal, insecticidal, anthelmintic and antiparasitic activities, The milbemycins and avermectins are exem— ples of two such classes of known compounds, but various others also exist end are identified by different nemes or code mumbers, The names for these various macrolide : compounds have generally been taken from the names or code numbers of the microorganisms which produce the \ naturally occurring members of each class, end these names have bhen been extended to cover the chemical de~ rivatives of the seme class, with the result that there has been no standardized systematic namenclature for such compounds generally

/ . * ’ .

In order to avoid confusion, a stendardized sys— tem of nomenclature will be used herein, which follows the normal rules for naming derivatives of organic com- pounds and which is based on the hypothetical parent compound hereby defined as "milbemycin" represented by formula (a): 23 CH,

CH 22 3 0 (a)

NY . 13 25 oH, 0 0

I ox

C

% "OH

For the avoidance of doubt, formula (A) also shows the mmbering of positions of the macrolide ring system applied to those positions most relevant to the com—~ pounds of the present invention.

The naturally produced milbemycins are a series of macrolide compounds known to have anthelmintic, aca- ricidal end insecticidal activities, Milbemycin D was = disclosed in U.S. Pat, No, 4,346,171, where it was re- ferred to as "Compound B41", end milbemycine Ay and

: , : , 26158

A, were disclosed in U.S. Pat, No. 3,950,360, These compounds msy be represented by the above formula (a) in which position 25 is substituted with a methyl group, an ethyl group or an isopropyl group, these compounds being designated as milbemycin Asy milbemycin

A, and milbemycin D, respectively. The milbemycin ena~ logue substituted at position 25 with a sec-butyl was disclosed in U.S. Pat. No. 4,173,571,

Subsequently, various derivatives of the original ' 10 milbemycins have been prepared and their activities in- vestigated, For example, epoxy milbemycins have been disclosed in Japanese Patent Application Kokei (i.e. laid "open to public inspection) Nome 57-139079, 57-139080, 59-33288 and 59-36681 and in U.S. Pat. No. 4,530,921. 5-

Esterified milbemycins have been disclosed in U.S. Pat,

Nos. 4,201,861, 4,206,205, 4,173,571, 4,171,314, 4,203,976, } 4,289,760, 4,457,920, 4,579,864 end 4,537,491, in Buro- peen Patent Publications Nos. 8184, 102,721, 115,930, 180,539 and 184,989 and in Japsmese Patent Application

Kokei Nos, 57-120589 and 59-16894. \ 13-Hydroxy-5-ketomilbemycin derivatives have been disclosed in U.S. Pat, No. 4,423,200. Milbemycin 5-oxime derivatives were aisclosed in U.S. Pat. Noo 4,547,520 and

European Patent Publication No. 203 832.

J

Of IC 26158

Milbemycin derivatives esterified at position 13 are of particular relevance to the present invention end have been disclosed in U.S. Pat, No: 4,093,629 and . ~~ Buropean Patént Publication No: 186403, as well gs in published British Patent Application No. 2,168,345 which discloses milbemycin derivatives having a carboxy or esterified carboxy substituent at position 13 in combi~ nation with a hydroxy or esterified hydroxy substituent at position 5,

Iike the milbemycins, the avermectins are based upon the same l6-membered ring macrolide compound, The avermectins are disclosed, for exemple in J, Antimicrob,

Agents Chemother, 15(3), 361-367 (1979). These compounds may be represented by ‘the above formila (A) but with a carbon-carbon double bond at positions 22 and 23, and having position 13 substituted with a 4'~({~I~oleandrosyl )- g-L~oleandrosyloxy groupe Position 25 may be substituted with an isopropyl group or a sec-butyl group these com- pounds being designated as avermectin Bly and avermectin

Big? respectively, 224 23-Dihydrogvermecting Bla and Bip may be obtained by reduction of the double bond between the 22 and 23 positions and are disclosed in U.S. Pat. No, 451995569, The eglyclone derivatives of the avermectins, which are milbemycin analogues, have sometimes been re- ‘ 25 ferred to in the literature as C-Q% compounds, end various

— derivatives of these are known, For example, U.S. Pat.

No. 4,201,861 discloses such derivatives substituted with a ldwer alkanoyl group at position 13. ; Published European Patent Application No, 170006 discloses a family of bioactive compounds produced by fermentation, identified collectively by the code rumber

LL-F28249, Some of these have a 16-membered macrolide : structure corresponding to the above formula (a), substi- tuted with hydroxy at position 23 and with l-methyl-l- propenyl, l-methyl-l-butenyl or 1,3~-dimethyl-l~butenyl at position 25. In these compounds, the hydroxy at posi- tion 5 may also be replaced by methoxy.

Published British Patent Application No, 2,176,182 discloses another group of macrolide antibiotics corres- ponding to the above formula (A) with a hydroxy or substi- tuted hydroxy group at position 5, a hydroxy substituted hydroxy or keto group at position 23, and an g-branched alkenyl group at position 25.

A yet further group of related macrolide deriva—~ tives is disclosed in Japanese Patent Application Kokal

No, 62~29590, These have a structure corresponding to the above formula (A), with a hydroxy or methoxy group at position 5, position 13 of the ring cen be substituted with a 4'-(¢-I~oleandrosyl)-g-I~oleandrosyloxy group, as in the avermectins, and, there may be a carbon-carbon double bond between positions 22 and 23%, or elternative- ly position 23 may be substituted with hydroxy. The substituent at position 25 1s of a type not found in the naturally produced avermectins and milbemycins, and in- cludes various d-branched alkyl, alkenyl, alkynyl, =l- koxyalkyl, alkylthioalkyl and cyeloalkylaliyl groups, or cycloalkyl, cycloslkenyl or heterocyclic groups.

This 25-substi tuent is introduced by adding the corres— ponding carboxylic acid or derivative thereof to the fermentation broth of an avermectin-producing microor- ganism, !

SUMMARY OF THE INVENTION

The various classes of milbemycin-~related macro- ide compounds described sbove are all disclosed as hav- ing one or more types of activity as antibiotic, anthel- mintic, ectoparasi tigidl acaricidal or other pesticidal agents, However there is still a continuing need to pro- vide such agents with improved activity sgeinst one or more classes of pests,

It has now been discovered that the activity of such milbemycin-related derivatives can be improved by appropriately selecting the combination of substituents > } on the macrolide ring system, especially the substituents at positions 5 and 13. In particular, it has now been

Coq

\ : 26158 found that the activity of the 13-esterified deriva- tives in the above-mentioned prior art can be ime proved upon by appropriate selection of certain ester groups at this position as specified below.

Accordingly, it is sn object of the present in- ‘ vention to provide such macrolide compounds having im- proved activity, It is another object of the invention to provide methods for preparing such compounds, It is a still further object of the invention to provide pesti- cidal compositions and methods containing the said com= pounds,

In accordance with these objects, the invention . provides compounds having the formula ~ 1 CH, 0 CH 3

R2-G~0 2 rr en,”

Oy 0 (1)

N f

Uo

: / ~ 26158 in which: the broken line represents a carbon-carbon single or double bond between the atoms at the 22 and 23 positions;

X represents a hydrogen atom or a hydroxyl group, or together with the -rembon atom to which it is , attached represents the group C==0; provided that \ X represents a hydrogen atom when the broken line ~ represents a double boyd between the carbon atoms at the 22 and 23 positions;

Y represents the group ==N— OR? or the group ort wherein Rr’ represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms snd which may optionally be substituted with at least one carboxy group, a cycloalkyl group having from 3 to 10 ring cerbon atoms, or an aralkyl group hav- } ing from 6 ‘to 10 ring carbon atoms in the aryl moiety and from 1 to 6 carbon gtoms in the alkyl moiety; and rt represents a hydrogen atom, or en ester~-forming carboxylic or carbonic acid residue; rt represents an alkyl, alkenyl, alkynyl, alkoxyal~ kyl or alkylthioalkyl group, each having up to 8 carbon atoms; a cycloalkyl-substituted alkyl group wherein the cycloalkyl moiety has from 3 to 6 ring ’

SE .

carbon atoms and the alkyl moiety hes from 1 to carbon atoms; a cycloalkyl or cycloalkenyl group having from 3 to 8 ring carbon atoms and optionally substituted with at least one subs- 5 tituent selected from halogen atoms end alkyl groups having from 1 to 4 carbon atoms; a hetero- cyclic group having from 3 to 6 ring atoms of which at least one is an oxygen or sulfur atom end which may optionally be substituted with at least one substituent selected from halogen », atoms and alkyl groups having from 1 to 4 car- , bon atoms;

R rR represents the group R-(0) - (whew Y represents sald group =N-OR) or the group A=(w-)_~c(r°RT )- (when Y represents said group -ort) wherein =O or 1;

Rr’ represents a hydrogen atom, an alkyl group hav- ing from 1 to 22 carbon atoms an alkenyl or al- kynyl group having from 2 to 6 carbon atoms, a cycloalkyl group having from 3 to 10 carbon atoms, en aryl group having from 6 to 10 ring carbon atoms, an aralkyl — having from 6 to 10 ring carbon atoms in the aryl moiety and from 1 to 6 carbon atoms in the alkyl mod ety;

or a heterocyclic group having from 4 to 14 ring carbon atoms of which at least one is an oxygen, sulfur or nitrogen atom; wherein : said alkyl group of R° mgy optionally be substituted with at least one substituent selected from: (a) cycloaliyl groups having from 3 to 10 : carbon atoms; alkoxy groups having from . 1 to 6 carbon atoms; alkoxycerbonyl groups having from 2 to 7 carbon atoms; halogen atoms; aryloxy and arylthio groups having o from 6 to 10 ring carbon atoms, which may themselves optionally be substituted with at least one halogen atom; protected or unprotected hydroxy, carboxy; amino mono- alkylamino and dielkylamino groups having from 1 to 6 carbon atoms in the or each : alkyl moiety; aliphatic acylemino groups having from 1 to 6 carbon atoms; aromatic acylamino groups; cyanoj carbamoyl; mono- alkylcarbamoyl and dialkylearbamoyl groups having from 1 to 6 carbon atoms in the or each alkyl moiety; mercapto; alkylthio, alkylsulfinyl and alkylsulfonyl groups, in each case having from 1 to 6 carbon .

. nd 26158 atoms; nitro; and heterocyclic groups having from 4 to 14 ring carbon stoms of which at least one is an oxygen, sulfur or nitrogen atom; and wherein said alkenyl and alkynyl groups or R’ : may optionally be substituted with at least one substituent selected from the group consisting of: (vb) the said substituents(a); snd aryl groups hav- ing from 6 to 10 ring carbon atoms; end wherein the seid cycloalkyl, aryl, aralkyl end heterocyclic groups of Rr may optionally be substituted with at least one substituent selected from: (¢) the said substituents (a); alkyl groups hav- ing from 1 to 6 carbon atoms each in the al~ kexy and alkyl moieties. haloalkyl groups having from 1 to 6 carbon atoms; end haloal- kenyl groups having from 2 to 6 carbon atoms; 0 represents an alkyl group having from 1 to 6 cer- bon atoms, a haloalkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms an glkoxyalkyl group having from 1 to 4 carbon atoms, a phenyl group, or a cyano goo rR! represents a hydrogen atom or an alkyl group have ing from 1 to 4 earbon atomsy or r® and rR, together with the carbon atoms +o which they are attached, jointly, represent . cycloalkyl group having from 3 to 6 ring car=- bon atoms;

W represents a methylene group, or an oxygen or sulfur atom; and

A represents a phenyl group, a naphthyl group, or a heterocyclic group having from 5 to 10 ring atoms of which at least one is a nitro- gen, oxygen or sulfur atom; and said rhenyl, naphthyl or heterocyclic group may optionally be substituted with at least one substituent ' selected fram alkyl, alkoxy and alkylthio groups each having from 1 to 4 carbon atoms, halogen atoms, trifluoromethyl, emino, nitro, eyéno, keto, phenoxy (which may itself op- tionally be substituted with at least one subs tituent selected from halogen atoms and tri. fluoromethyl), and heterocyclyloxy groups hav- ing from 5 to 10 ring atoms of which at least one is a nitrogen, oxygen or sulfur atom; end salts ond esters of said compounds of formula (1),

The invention still further provides en anthelmin- ticy acaricidal and insecticidal composition comprising an mthelmintic, acaricidal and insecticidal compound in admixture with a pharmaceutically, agriculturally, vete- rinarily or horticulturelly acceptable carrier or di- luent, wherein said compound is selected from the group consisting of compounds of formula (I);

The invention still further provides the use for the mamufacture of a medicament for treating an enimal ~ which mgy be humen or non-human, parasitized by a para- site selected from helminths acarids and insects of at least one compound of formula (I),

The invention still further provides a method of ‘protecting animals or plants from damage by parasites selected from acarids, helminths and insects, which com~ prises applying an active compound to said animals, to sald plants or to seeds of said plants or to a locus in- cluding said animals plants or seeds, wherein the active compound is at least one compound of formula (1)s . DETAILED DESCRIPTION OF THE INVENTION

In the compounds of formula (I), where RE repre- sents an alkyl group having from 1 to 8 carbon atoms, this may be straight or branched chain alkyl group end : examples of such groups include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl; t-butyl, pentyl, | _ isopentyl, heptyl and octyl groups, According to one preferred embodiment of the invention, this alkyl group / may be methyl ethyl isopropyl or sec-butyl, In accor- dance with another embodiment of the invention, the q- branched alkyl groups having from % to 8 carbon atoms are preferred,

Where grt represents an alkenyl group, this mey 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-propenyl, isopropenyl, . 1-methyl-l-propenyl, l-methyl-l-butenyl and 1,3-dimethyl~ l-butenyl, The of-branched alkenyl groups are particulgr- ly preferred,

Where rl represents an alkynyl group having from 2 to 8 carbon atoms, this may be a straight or branched chain group, for example ethynyl, l-propynyl or 2=propynyl.

Where rt represents en alkoxyalkyl group or alkyl- thioalkyl group, this may have a total of from 2 to 8 : @arbon atoms and may be straight or branched, for example methoxymethyT, ethoxymethyl, l-methoxyethyl, 2-methoxy- ethyl, 2-ethoxyethyl, isopropoxymethyl, and the thio ang- logues of each of these groups. The methoxymethyl, 1- methoxyethyl, methylthiomethyl and 1-(methylthio ethyl groups, respectively, are preferred. : Where 7 represents a cycloalkyl or cycloalkenyl group, this may have a monocyclic or fused polycyclic

(preferably bicyclic) ring system containing from 3 to 8 ring carbon atoms, Exemples include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cy- clooctyl, bieyelo/2.2.1/heptyl and norbornarmyl groups and the analogues thereof containing one or more double ‘ bonds. It should be understood that this definition also includes partly aromatic fused polycgelic ring systems for example the tetrohydronaphthyl and trimethylenephenyl groups,

Where Rr represents a cycloalkyl~substituted al- kyl group, the cycloalkyl moiety thereof mgy be any of the above-mentioned cycloalkyl groups vhich 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 atomss

Where R* represents a heterocyclic group, this mgy have from 3 to 6 ring atoms, of which at least one : is an ox}gen or sulfur hetero-atom. The ring syctem may be unsaturated, or partly or wholly saturated. Exemples of such heterocyclic groups include the oxiranyl, oxetanyl, thiranyl, thietanyl, (2,2-dimethyl)-1,3-dioxoranyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl and pyrenyl groups.

Where RY represents a cycloalkyl, cycloalkenyl or heterocyclic group, this may optionally be substituted with at least one halogen atom (e.g. fluorine, chlorine, . bromine or iodine) and/or at least one alkyl group hav- ing from 1 to 4 carbon atoms (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 Rr are methyl; ethyl, isopropyl, sec+butyl, l-methyl-l-propenyl, 1~ methyl-l-butenyl end 1,3-dimethyl-l-butenyl.

In the above formula (I), where R represents an alkyl group having from 1 to 6 carbon atoms, this may have a straight or branched chain and may be for example any of those alkyl groups mentioned above for r and heav- : ing up to 6 carbon atoms. The alkyl group Ro mgy also optionally be substituted with one or more carboxy groups,

Where Rr’ represents a cycloalkyl group having from 3 to 10 ring carbon atoms, this may have a monocy-- clic or .fused polyayolic (prefersbly bicyclic) ring system . and examples include those cycloalkyl groups mentioned » above for rt as well as the cyclononyl, cyclodecyl and adamantyl groups.

Where R° represents an aralkyl group, it mgy have from 6 to 10 ring carbon gtoms in the aryl moiety and from 1 to 6 carbon atoms in the alkyl moiety, The alkyl moiety may have a straight or branched chain and mey be, for example, any of those alkyl groups having up to 6 / wo 17 ’

: C= carbon stoms mentioned sbove for RY, The aralkyl group preferably has from 7 to 12 carbon atoms in total, end examples include benzyl, qmetiyLbenzyl, A f-dimethyl- benzyl, phenethyl, phenylpropyl, naphthyl, methyl and naphthylethyle

The compounds of formule (I) where R is a hydro- gen atom are oximes and can therefore form ester derive- tives, The biological activity of the compounds of the ] invention arises from the structure showm in formula (1) and is not essentially dependent on the nature of any ester group, £0 there is no particular restriction on the acids which may be chosen to form such esters, provided thet the activity of the resulting compound remains acceptable, Examples include carboxylic acid esters, car- bemic acid esters, carbonic acid esters, sulfonic acid esters and phosphoric acid esters:

Such oxime esters are preferably compounds having the following formula (X): J oo / Co } Ce -

20luu

X (x) 0 cH " CH, 3 oro J

Rr :

Ch,

SENT po “OR. 3 . . | . ; : cnn ER 5 . - So ah To ‘ Lo to J Co 7 Sl Hh where r, BR” and n have the meanings previously defined ~ .. ~~ ..- and RS represents one of the following groups (a)-(e): . - , (a) the group cord, wherein RMT represents an | PT 5 alkyl group which mgy optionally be substi- sl SEE tuted, a cycloalkyl group en aralkyl group. =: .: wei

CL Cae Fan } vhich may optionally be substitiited on its CL CEES aryl ring or en aryl group which may opt righ tionally be substituted on its ring; CL ita (b) the group —Q-NRIORYS Gherein Q vepresemts Vin on oxygen atom or a mfr atoms wd BO ma rte mgy be the same or different amd each re~- | Na presents a hydrogen atom, en alkyl alkenyl Co Fa , or alkynyl group in each case having up to 6 - Lo A carbon atoms, or en aryl group which mgy op~ = - .. I tionally be substituted on its ring: LC TE

BAD CT 3INAL 7 Slmpniy { & ey Fold

Cy

~ 26158 (c) the group -co-grL7, wherein Q is as pre- y, viously defined; gnd all represents en gl- kyl group having from 1 to 6 carbon atoms; : : an aralkyl group which may optionally be ' substituted on its ring an aryl group which / mgy optionally be substituted on its ring " or a carboxy-protecting group capable of be- ing hydrolyzed in vivos i (a) the group ~S0,R'S, vherein ri8 represents sn alkyl group having from 1 to 6 carbon atoms or en aryl group which may optionglly be substituted on its ring; or (e) tne group ~Po-(0R1?)(0R??), wherein Q 1s es previously defined; and RY and RC mey be the same or different and each represents alkyl group having from 1 to 6 carbon atoms, . Where rH or yall represents m aralkyl group subse tituted on its aryl ring the substituent or substituents mey suitsbly be selected from C; alkyl, Halogen atoms; and the nitro group, Preferred aralkyl groups include alkyl-substituted benzyl groups heving from 1 to 6 car- bon atoms in the alkyl moiety, such as 3- or 4-methyl- benzyl; halogenated benzyl groups, such as 4-chloro- , benzyl, 4-bromobenzyl end 4-fluorobenzyl; end the 4- nitrobenzyl groups /

Where any of ri4 to re represents an aryl group substituted on its ring, the substituent or substituents may be selected from alkyl groups having from 1 to 6 cerbon atoms, halogen atoms, nitro, carboxyl, and al- koxycarbonyl groups having from 2 to 7 carbon atoms.

Preferred aryl groups include alkyl-substituted phenyl groups having from 1 to 6 carbon atoms in the alkyl ~ moiety, such as 2-tolyl, 3-tolyl, 4-tolyl or 2,4,6~ trimethylphenyl; halogenated phenyl groups, such as 2- chlorophenyl, 3-chlorophenyl, 4~chlorophenyl, 2-bromo- phenyl, 3-bromophenyl or 4=bromophenyl; nitrophenyl groups, such as 4-nitrophenyl; carboxyphenyl groups} such as 2-carboxyphenyl, 3=carboxyphenyl or 4~carboxy=- phenyl; and alkoxycarbomylphenyl groups such as 2-methoxy- } carbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycar~ bonylphenyl, 2-ethoxycarbonylphenyl, 3~ethoxycarbonyl- phenyl or 4~ethoxycarborylphenyl” : :

Where AL or 16 represents an alkenyl or allgmyl group, this is preferably vinyl alyl, 1-propynyl, 2~pro-

Pynyl or isopropenyl,

Where rt is a carboxy-protecting group capable of being hydrolyzed in vivo, this may be for example en aliphatic acyloxymethyl group, such ag acetoxymethyl, propionyloxymethyl, butyryloxymethyl or pivaloyloxy- methyl; a 1-(alkoxycarbonyloxy Jethyl group with a C6 alkoxy moiety, such as l-methoxycarbonyloxyethyl, 1- ethoxycerbonyloxyethyl, l-propoxycarbonyloxyethyl, 1- isopropoxycarbonyloxyethyl, l-butoxycarbonyloxyethyl or . 1-1sobutoxycarbonyloxyethyl; a phthalidyl group; a (2- oxo=5-methyl-1,3~ dioxolanyl-4-yl)methyl group; a (2,2~ dimethyl-1, 3-dioxolan=-4-y1 methyl group or a (3,4-dihydro- pyran-2-carbonyloxy Jnethyl group. The (2,2~dimethyl~l,3- : dioxolan-4-yl)methyl and (3,4-dihydropyran~2-carbonyloxy)- methyl groups are preferred, .

A preferred group of compounds of formula (I) are those wherein RB represents hydrogen, Cy. 6 alkanoyl, Cy. -£ haloalkaroyl or ai(c, > alkyl )carbamoyl: Of these com= pounds, the more preferred ones are those in which Rr is hydrogen and the Cy —g 8lkanoyl esters; and the most high- ly preferred are those in which R is hydrogen, and the propionyl and pivaloyl esters,

In the compounds of formula (I) where Y represents the group ~ort, rt may represent a hydrogen atom, so that the substituent at position 5 is a hydroxy groups Ag will readily be appreciated by those skilled in the ert; this hydroxy group can form esters with a wide variety of car- boxylic and carbonic acids, without significantly edverse~ ly effecting the biological activity of the compound which is derived from the 5-hydroxy substityent. Accordingly, the invention also embraces such esters where pt repre=~ /

sents an ester-forming carboxylic or carbonic acid re~ sidueo : Preferred compounds are those in which gt is the hydrogen stom or a group of the following formula: ~c0-(0)_-&° vherein n=0orl; and

RS represents a straight or branched chain Cy.18 : alkyl group, a C37 cycloalkyl group, a Cog aralkyl group, a C, celkenyl or alkynyl group, a Csn10 aryl group or a monocyclic or fused heterocyclic group having from 5 to 10 ring atoms and containing at least one oxygen, sule fur or nitrogen atom, The group ® mgy oOp=- tionally have one or more substituents, such as for example alkyl, alkoxy, alkoxyellyl, : halogen, haloalkyl, alkoxycarbonyl, acyloxy; hydroxy, carboxy, amino, mono- or trialkyl- gmino, acylamino, cyano, carbamoyl, mono=-, or di-alkylearbamoyl, mercapto, alkylthio, alkyl- sulfinyl, alkylsulfonyl, nitro, phenoxy, halo- phenoxy, alkylsulfonyloxy, arylsulfonyloxyy cyanothio, and 5- or 6-membered heterocyclic groups containing at least on oxygen, sulfur or nitrogen atop, Where the substituent con-

tains a carbon atom or atoms, the mmber of the carbon atoms is from 1 to 9° Where R° itself is en allyl, alkenyl or alkynyl ot group, the above-described substituent can not be an alkyl, alkoxyalkyl or haloalkyl groupe

Where RC is a Cy.1g 81kyl group, it may be, for example, methyl, ethyl, propyl, isopropyl, butyl, iso~- butyl, sec butyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, cyclo- propyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyelo- : [2.2.1 heptyl,

Where EC 1s a Cr_g eralkyl group, it mey be, for exemple, benzyl, phenethyl, phenylpropyl, cHmethylbenzyl or dy -dimethylbenzyl,

Where EC is a 0, alkenyl or alkynyl group, it } mgy be, for example, vinyl, propenyl, ethynyl or pynyls

Where RC is o Co1o Yl group, it may be, for example, a phenyl or naphthyl groups here B® is a heterocyclic group, 1% may be, for example, furyl, thienyl, pyrrolyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, 180%az0ly]; imidazolyl, pyrra- zolyl, pyranyl, triazolyl, triazinyl, quinezolinyly te~ trehydrofuranyl, tetrshydrothienyl, pyrrolidinyl, thia- : ;

zolidinyl, piperazgl; morpholinyl, thiomorpholinyl, te- : treahydroquinolyl, quimieclidinyl or thienofuranyl’

Where re is further substituted, such further substituents include, for example, methyl, ethyl, iso- propyl, t-butyl, methoxy, ethoxy,isopropoxy, methoxy- methyl, methoxycarbonyl, ethoxy carbonyl, chloromethyl, trichloromethyl, trifluoromethyl, 2-chloroethyl, fluo- rine, chlorine, bromine, iodine, hydroxy, carboxy, emino, methylemino, dimethylemino, diethylamino, diisopropyl- amino, (diethyl)methylamino, acetylemino, trifluoroacetyl- amino, cyano, carbemoyl, methylcarbamoyl, dimethylecar- bamoyl, fluoroacetoxy, trichloroscetoxy, mercapto, methyl=- thio, cyanothio, methylsulfinyl, methanesulfonyl, nitro, phenoxy, p-chlorophenoxy, the 5- or 6-membered heterocy- clic BTOUPS set out above in the definitions of BS, and / : the 2, 2-dimethy1-1, 3-d1 oxoleny Imothoxy, 39 4~dihydro~2H- pyran=~2-carbonyloxy and 3,4,5,6-diisopropylidene~D=galac~ turonyloxy groups,

Preferred compounds include those where at repre- sents hydrogen and the esters where gt represents the group ~c0-58, In these esters, the group gS is prefer~ ably a (c, 4 alkanoyl)oxymethyl group, a chloramethyl group, an iodomethyl group, a mono-, di or trialkylsmino- methyl group (end perticulerly a triallyleminomethyl group, vherein the ni trogen is quaternized), a (hetero-

cyclic emino)methyl group (such as l-piperidylmethyl or l-morpholinylmethyl),a2-carboxgétilyl or 3-carboxy- propyl group, or the 2,2-dimethyl-1,3-dioxolan-4-yl- : methoxy group. Compounds where © is (Chg alkanoyl )- oxymethyl are particularly preferred, The most pre~ ferred values for rt are nydrogen, acetoxXyacetyl and ' pivaloyloxyacetyly :

Where R° represents the group R°-(0) _~ and BR’ re- presents en alkyl group, this may have a straight or branched chein with from 1 to 22 cerbon stomss Examples include methyl, ethyl, propyl, isopropyl, butyl, sec butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 3-methylnonyl, 8-methylnomyl, 3-ethyloctyl,

So 3 7~dimethyloctyl, undecyl, dodecyl, tridecyl, tetra- decyl, pentadecyl, hexadecyl, l-methylpentadecyl, 1,4~ methylpentadecyl, 13,13-dimethyl’tetradecyl; heptedecyl, : Co © 15-methylhexedecyl, octadecyl, l-methylheptadecyl, nona=- : decyl, icosyl, henicosyl and docosyl: Alkyl groups hev~

Lo | ing from 1 to 18 carbon atoms are preferred:

Where B represents no cycloalkyl groups this may | BB have a monocyclic or fused polysgeiie (preferably bicy- clic) ring aysten containing from 3 to 10 ring carbon * atoms, and examples include those mentioned above for Ro,

Where R’ represents an alltenyl or alkynyl group, this may have a straight or branched chain with fram 2 to 6 carbon atoms end with one or more double or triple : bonds, respectively. Examples include those already men— tioned above for R- end having up to 6 carbon atoms’

Where : represents an aryl group containing from 6 to 10 carbon atoms, examples of such groups include the phenyl, l-naphthyl and 2-nephthyl groups: Te phenyl group is preferred.

Where R’ represents sn aralkyl group, it may have from 6 to 10 ring carbon atoms in the aryl moiety and from 1 to 6 carbon atoms in the allyl moiety, and it pre~ ferably has a total of from 7 to 12 carbon atoms. FExem~ ples include those already mentioned above for the aralkyl group of ©;

Where R? represents a heterocyclic group, it con~ : 15 tains from 4 to 14 ring atoms, of which at least one,’ and preferably from 1 to 3, are hetero-stoms selected from nitrogen oxygen and sulfur. The ring system may be mono=- - cyclic or fused polycyclic (preferably bicyclic), end may be unsaturated, or partly or completely saturated, FExeam~ ples of such groups include oxiranyl, oxetanyl, aziri- dinyl, azetidinyl, thiranyl, thietanyl, (2, 2~timetiy1 )~ 1,3-dioxoranyl, furyl, thienyl, pyrrolyl, pyridyl, thia- zolyl, isothiazolyl, oxezolyl, isoxazolyl, imidazolyl,

Pyrezolyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzofurenyl, benzothiophenyl, indolyl, quinolyl, iso- /

* | . 26158 quinolyl, quinazolyl, quinoxalinyl; naphthyridinyl, xenthenyl, tetrehydrofuranyl, tetrshydrothienyl; pyr- rolidinyl, thiezolidinyl, imidazolidinyl, imidazolinyl, oxazolinyl, oxazolidinyl, pyrazolidinyl, piperazyl, te- trahydropyrimidinyl, dihydropyridezinyl, morpholinyl, indolinyl and tetrahydroquinolyl) Preferred groups in- 7 clude oxirenyl, oxetanyl, eziridinyl; szetidinyl, furyl, thienyl, pyrrolyl, pyridyl, thiazolyl, oxazolyl, tetra- hydrofuranyl, tetrahydrothienyl, pyrrolidinyl, morpholi- nyl, benzofuranyl, (2,2-dimethyl)-1,3-dioxoranyl and a quinolyls

The group Rr’ may optionally carry one or more substituents, as set out in the definitions for formula (I)s Where en alkyl group is present as a substituent, . this may be eny of the alkyl groups having from 1 to 6 carbon atoms mentioned above. Where there is em alkoxy substituent having from 1 to 6 carbon atoms, this may correspond to any of the said alkyl groups, for example methoxy or ethoxy, Where there is an alkoxycarbonyl substituent having from 2 to 7 carbon atoms, the alkoxy moiety of this may correspond to any of the said alkoxy groups, for example methoxycarbonyl, ethoxy carbonyl] pro- poxycarbonyl or t-butoxycerbonmyls Where the substituent oo is a halogen atom, it may be fluorine, chlorine, bromine or iodine, Where the substituent is en aryloxy or aryl- :

oo 26158 i - thio group, which may optionally itself be halogen- substituted, examples include phenoxy, phenylthio, chlorophenoxy, bromdphenoxy, iodophenoxy, fluoro~ phenoxy, dichlorophenoxy, chlorophenylthio and bromo- phenylthio groups.

Where ® is substituted with a protected hydroxy group, the hydroxy~-protecting group may be any of those conventionally employed for this purpose. For example, the protecting group may be a tri-(lower)alkylsilyl group such as trimethylsilyl, triethyleilyl, isopro= pyldimethylsilyl, t-butyldimethylsilyl, methyldiiso- propysilyl, methyldi-t-butylsilyl, or triisopropyle i silyl, a lower aliphatic acyl group such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, propionyl, n-butyryl, (E)-2-methyl-2-butenoyl, isobutyryl, pentanoyl, or pivaloyl; or an aromatic acyl group such as benzoyl, : o-(dibromoethyl)=~benzoyl, o~(methoxycarbonyl)benzoyl, o-phenylbenzoyl, 2,4,6=trimethylbenzoyl, p-toluoyl, p-anisoyl, p-chlorobenzoyl, p-nitrobenzoyl, o-nitro=- benzoyl or p-naphthoyly When the group protects two or more hydroxy groups simultaneously, it may be an alkylidene group such as isopropylidenes

Where the substituent on ® is a monoalkylamino or dialkylamino group, the or each alkyl moiety may be any of the alkyl gréups having from 1 to 6 carbon atoms

, - already mentioned above, and examples include methyl: © gnino, ethylemino, propylemino, isobutylemino; dimethyl amino, diethylemino, methylethylemino and methylbutyl- anino groups, Where the substituent is an acylemino group, the acyl moiety may be aliphatic with from 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl or hexanoyl, or it may be aromatic, such as benzoyl or nephthoyl; and the group is preferably an aliphatic acyl- emino group having from 2 to 4 carbon atoms, such as acetylamino, propionylemino, or butyrylaminds Where the : substituent is a monoalkylcarbemoyl or dislkylcarbemoyl group, the or each alkyl moiety mgy be any of the alkyl groups having from 1 to 6 carbon atoms already mentioned above, and examples include methylearbamoyl, dimethyl- carbamoyl and diethylcarbamoyl, Vhere there is a substi- tuent on Rr which is an alkylthio, alkylsulfinyl or al=- kylsulfonyl group having from 1 to 6 carbon atoms, the elkyl moiety thereof may be any of the alkyl groups al- readyy mentioned above having from 1 to 6 cerbon atoms, and examples of these include, respectively, methylthio, ) ethylthio, propylthio, tutylthio end sec~butylthios methylsulfinyl and ethylsulfinyl; and methanesulfonyl end ethenesulfonyl, © Where R’ hes an alkoxyalkyl substituent? the al- koxy and elkyl moieties each having from 1 to 6 carbon /

‘ _, atoms mey be any of those already mentioned above, and each moiety preferably has from 1 to 4 cerbon atoms, for example mothoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-butoxyethyl or 3-propoxy- propyl. Where R? hos as a substituent a haloalkyl group with from 1 to 6 carbon atoms or a haloalkenyl group with from 2 to 6 carbon atoms, this may correspond to any of the alkyl or alkenyl groups already mentioned above and preferably substituted with from 1 to 4 halogen atoms (selected from the halogen substituents already mentioned above), for exémple chloromethyl, bromomethyl, iodomethyl, fluoromethyl, dichloromethyl, trifluoromethyl, trichloro=- methyl, 2-chloroethyl, 2,3-dibromopropyl, 2,2,2-trichloro- ethyl, 1,2,2,2~tetrabromoethyl, 2,2-dibromovinyl or 2,2- dichlorovinyl.

Examples of preferred values for R° include the fol- lowing: a hydrogen atom; an alkyl group having from 1 to 22 carbon atoms such as methyl ethyl isopropyl, t-butyl, pentyl, heptyl or pentadecyl; an optionally condensed cycloalkyl group having from 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyckohexyl, l-methylcyclopro- pyl, l-methylcyclohexyl or adementyl; a halogenated alkyl group having from 1 to 6 carbon atoms such es trifluoro- methyl, iodomethyl, chloromethyl, bremomethyl, trichloro-- methyl, tribromomethyl, 2-chloroethyl, fluoromethyl, 2-

fluoroethyl, 2-bromoethyl, 1l,1-dichloroethyl, 1,1 dimethyl-2~chloroethyl, 2,2,2~trichloroethyly 2,2,2~ tribromoethyl or 2,2,2-trifluoroethyl; an alkoxyal- kyl group having from 1 to 4 carbon atoms each in the alkyl and alkoxy moieties such as methoxymethyl, ethoxymethyl, methoxyethyl or 2-methoxyethyl; an aryl- oxyalkyl group having from 1 to 6 carbon atoms in the alkyl moiety wherein the ring may optionally be halo- genated such as phenoxymethyl or 4~fluorophe noxymew thyl; an optionally protected hydroxyalkyl group have ing from 1 to 6 carbon atoms such as 2~hydroxyethyl, : hydroxymethyl, 2,3-dihydroxypropyl, acetoxymethyl or pivaroyloxymethyl; a mercaptoalkyl group having from 1 to 6 carbon atoms such as 2-mercaptoethyl; an alkyl- thioalkyl group having from 1 to 4 carbon atoms in each of the alkyl moieties such as methylthiomethyl; a dialkylaminoalkyl group having from 1 to 4 carbon : atoms in each of the alkyl moieties such as dime thyl- aminomethyl; an alkenyl-substituted cycloalkyl group such as 2-isobutenyl-3,3-dimethylcyclopropyl; a halo- alkyl-substituted cycloalkyl group having from 1 to 4 carbon atoms in the haloalkyl moiety such as 2-(1,2,2,2~ tetrabromoethyl)=-3,3=~dimethylcyclopropyl; a haloalkenyl substituted cycloalkyl group such as 2=-(2,2-dichloro= vinyl)=3,3~-dimethylcyclopropyl; a heterocyclylalkyl /

CC me group having from 1 to 6 carbon atoms in the alkyl moiety such as 2-furfuryl, imidazolylmethyl, 4-py- ridylmethyl, 2-thienylmethyl or 2,2-dimethyl-1,3- dioxoran~U-ylmethyl; a halogenated alkenyl group such as 2,2-dichlorovinyl; an alkenyl group having from 2 to 4 carbon atoms such as vinyl, l-propenyl or l-isobutenyl; an alkynyl group having from 2 to 4 carbon atoms such as l-propynyl or ethgnyl; an . aralkyl group having from 7 to 9 carbon atoms such as benzyl, phenethyl, of-methylbenzyl or oh -dimethyl- benzyl; an aryl group such as phenyl; a halogenated "aryl group, in particular a halophenyl group such as 2-, 3- or li-bromophenyl 2-, 3- or L-fluorophenyl, 2,4=dichlorophenyl, 2,5~dichloro-6-methoxyphenyl, 2,3,4,5,6-pentafluorophenyl or 2,6-difluorophenyl; an alkoxyaryl group, in particular an alkoxyphenyl group having from 1 to 4 carbon atoms in the alkoxy : moiety, such as methoxyphenyl; a nitroaryl group, in particular, a nitrophenyl group such as 4-nitrophe~ / nyl; an alkylaryl group, in particular an alkyl phenyl group having from 1 to 4 carbon atoms in the alkyl moiety such as 2-, 3- or 4-tolyl or bfetebptyl- phenyl; a haloalkyl-substituted aryl ZT OUD, in parti- cular a haloalkyl-substituted phenyl group having from 1 to 4 carbon atoms in the haloalkyl, moiety, such as’ 2-, 3- or b-trifluordmethylphenyl or 2,5~di(trifluoro=~ methyl)phenyl; a hydroxy-substituted aryl group, in a particular a hydroxy-substituted phenyl

. group which may optionally be protected, such as Lea acetoxyphenyl; and a 5~ or 6-membered heterocyclic group containing one or two hetero atoms in its ring such as 2-oxetanyl, 2-azetidinyl, 2- or 3-furyl, 2m or 3-thienyl, 1-isoquinolyl or 2- or A4-pyridyl.

Rr’ is more preferably an ¢~branched alkyl or haloalkyl group having from 4 to 7 carbon atoms; br a phenyl or benzyl group which may be substituted with one or two substituents selected from trifluoro- methyl, halogen (particularly fluorine or chlorine) methyl and amino. Most preferably, rR’ is a 246~di- fluorophenyl, o~(trifluoromethyl)phenyl, ofeme thyle benzyl, qsq-dimethylbenzyl, tert-butyl and fluoro-tert- butyl groupe.

In the compounds of formula (I) where R® ree presents the group A-(w)_~6(r8R7)-, where g® is a C, ¢ alkyl group, it may be a straight or pranched chain : alkyl group, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl group, and it is preferably the methyl or ethyl group.

Where r® is a C,_jhaloalkyl group, it is a straight or branched chain alkyl group substituted by a halogen atom or atoms and it includes, for example, a chlorom thyl, fluoromethyl, trifluoromethyl, bromo methyl, 2-chloroethyl or 3-fluoropropyl group, preferw / oo ozh ably the chloromethyl groupe.

Where r® is a C,. alkoxyalkyl group, it is an alkyl group substituted by one or more of straight or branched ch#&in alkoxy groups and it includes, for example, the methoxymethyl, ethoxymethyl, 2-methoxyw ethyl, 2~ethoxyethyl and isopropoxymethyl groups, preferably the me thoxymethyl group.

Where r® is a Cig alkoxy group, it is a straight or branched chain alkoxy group and it ine cludes, for example, the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and sec-butoxy group, preferably the methoxy group. .

Whe re r® is a Cols alkylthio group, it may have a straight or branched alkyl chain, for example the methylthio, e thylthio, propylthio, isopropylthio and butylthio groups, preferably the methylthio groups . r® is more preferably C13 alkyl (particularly methyl or ethyl), or phenyl, and most preferably me~ i thyl or ethyl. : :

Where R’ is a Cin alkyl group, it may be a straight or branched chen alkyl group and it includes, for example, the methyl, ethyl, propyl, isopropyl and } butyl groups, preferably the methyl groupe. : 25 Compounds in which Rr’ is hydrogen or methyl ' /

are most preferred.

Where A is a heterocyclic group, it may be, for example, a furyl, thienyl, pyrrolyl, pyridyl, ~ imidazolyl, pyridazinyl, benzofuranyl, benzothiow phenyl, indolyl, quinolyl, quinazolinyl or quinoxali- nyl group, preferably a furyl, thienyl, pyridinyl, benzothiophenyl or quinolyl group.

Where A is further substituted, such further substituents may be selected, for example, from me- , 10 thyl, ethyl, propyl, isopropyl, butyl, sec-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluorine, chlo rine, bromine, iodine, trifluoromethyl, nitro, cyano, phenoxy, m-chlorghenoxy p<fluorophenoxy, o~chlore- phenoxy, o~fluorophenoxy, p~trifluorophenoxy, Os trifluorophenoxy, 2-furyloxy, 2-thienyloxy, 2-pyr- rolyloxy, 2-pyridyloxy, 3-pyridyloxy, 2~quinolyloxy, 2-benzoxazolyloxy, 2~quinoxalyloxy, 2-quinazolinyloxy, 2,4~dichlorophenoxy, Swtrifluoromethyl-2-pyridyloxy,

S5.trifluoromethyl-3~chloro-2-pyridyloxy, 3-chloro-2- furyloxy, 3-chlorothienyl-2-thienyloxy, 2=chloxro~Sew pyridyloxy, 6-chloro-2-bensoxazolyloxy and 6~chloro=- 2-quinoxalinyloxy. Preferred substituents are methyl, methoxy, trifluoromethyl, chloro, fluoro, 2-chlorow= 6-pyridyloxy and 6-chloro~2~benzoxazolyoxyo

The preferred groups A-(W) are those in which n=0, such as phenyl, haldphenyl (e.g. chlorophenyl, fluorophenyl, trifluorophenyl and dichlorophenyl), tolyl, methoxyphenyl, phenoxy, chlorophenoxy, benzyl and phenoxyphenoxy. Phenyl and halophenyl groups are more highly preferred, and in particular phenyl. . The compounds of formula (I) include some in which a carboxyl group may be present in the substi- tuent RZ or Y. As will be readily understood, esters and salts of such compounds may be formed by conven tional techniques, and such esters and salts are also included within the scope of the invention.

In particular, such salts include those with alkali metals such as lithium, sodium or potassium, alkaline earth metals such as calcium or barium, other metals such as magnesium or aluminium, and orw ganic amines, particplarly tertiary amines such as triethylamine and triethanolamine. The alkali metal salte are preferred, and particularly the sodium and potassiun salts,

It will also be appreciated from formula (I) that the compounds of the invention are capable of existing in the form of various isomers. Thus, the substituent at position 13 of the macrolide ring may be in either the alpha or beta configuration. The compounds which have beta-configuration at position / wry

. ro 26150 ' . 13 are preferred, but the invention includes both sets of stereoisomers, as well as mixtures thereof.

Equally, those compounds having an oxime group at position 5, i.e. where Y represents the group =N-OR>, can exist in the form of syn- and anti-isomers; and oo the individual syn- and anti~isomers are included within the scope of the invention as well as mixtures : thereof,

The following Tables give examples of indivi. dual compounds in accordance with the present inven tion, the compounds being identified by means of the substituent groups shown in formula (I) above. In all the compounds of Tables 1(A)-(H), ¥ in formula (I) represents the group =N-OR>; whereas in all the com- pounds of Tables 2(A) « (D), Y represents the group “or*, . TABLE 1(A)

In all of the following compounds 1-194, there is a single carbon-carbon double bond between the atoms at positions 22 end 23, X represents a hydrogen atom, gl represents an ethyl group, and R® and R> have the mean- ings shown,

No. R° r> 1 t-butyl acetyl 2 t-butyl / propionyl

TABLE 1(A) ~ continued 3 t-butyl dimethylcarbamoyl 4 trichloromethyl tosyl dime thylaminomethyl hydrogen 5 6 methylthiomethyl carboxymethyl 7 l~imidazolylme thyl hydrogen 8 2,242=trichloroethoxy diethoxyphosphoryl 9 24242=-trichloroe thoxy 24y3=dihydro~i4H=pyran- 2-yl-carboxymethoxy~ carbonyl 10 2=-chloroethyl hydrogen 11 © 2=thienyl hydrogen 12 “3-thienyl me thyl 13 hepyridyl ~ hydrogen 14 l-isoquinolyl propionyl 15 p~fluorophenoxymethyl hydrogen 16 p~fluorophenoxyme thyl pivaloyl ’ 17 ethoxy hydrogen 18 methyl ’ hydrogen 19 methoxy hydrogen . 20 ethoxy pivaloyl 21 methoxy dimethylcarbamoyl 22 ethyl acetyl 23 ethoxy | palmitoyl 2k t-butyl diethoxythiophosphoryl ,

’ » 26158 i

TABLE 1(A)-continusd 25 t-butyl me thylcarbamoyl 26 t-butyl hydrogen 27 2y242=trichloro~ hydrogen ethoxy 28 2,2-dichloroethyl hydrogen 29. trichloromethyl hydrogen 30 iodomethyl | hydrogen 31 24242~trichloro~- dime thylcarbamoyl

B ethoxy 32 24242=~trichloro~ dimethylcarbamoyl ethyl 33 2-chloroethyl tosyl . zh trichloromethyl propionyl 35 24242=trichloro- propionyl ethoxy : 36 2,242=trichloro= isobutyryl ethoxy 37 24242=trichloros acetyl ethoxy 38 benzyloxy hydrogen : 39 benzyl hydrogen } Lo benzyloxy carboxymethyl 41 benzyl dime thylcarbamoyl 42 2-me thoxyethoxy ’ hydrogen

TABLE 1(A)~continued 43 2-methoxyethoxy dimethoxycarbamoyl

Ly 2-hydroxy=3-(t-butyle hydrogen dime thylsiloxy)propoxy 4s (2y2-dimethyl-1,3= hydrogen dioxolanyl)methoxy 46 (2y2~dimethyl=l,3=dioxo~ dimethylcarbamoyl lanyl)methoxy 47 2,3~dihydroxypropoxy hydrogen 48 2, 3=dihydroxypropyl hydrogen 4o 243-dihydroxypropyl propionyl 50 l-propenyl | hydrogen 51 hydrogen hydrogen 52 p~chlorophenyl hydrogen 53 p-t=butylphenyl hydrogen

Sh p-t-butylphenyl dimethylcarbamoyl 55 o~trifluoromethylphenyl hydrogen 56 o~trifluoromethylphenyl dimethylcarbamoyl 57 p~bromophenyl hydrogen 58 p~bromophenyl octanoyl 59 p~trifluoromethylphenyl benzyl x 60 p~trifluoromethylphenyl methyl 61 2~-furyl hydrogen 62 2-furyl dime thylcarbamoyl 63 p~bromophenyl hydrogen 64 iodomethyl propionyl y 26158

TABLE 1(A)=continued 65 acetoxymethyl hydrogen 66 acetoxymethyl propionyl 67 pivaloyloxyme thyl hydrogen ‘ 68 hydroxymethyl hydrogen 69 2=(2,2«dimethylvinyl)=3, 3= hydrogen dimethylcyclopropyl 70 2-(242~dibromovinyl)= propionyl 3,3~dimethylcyclopropyl 71 2«(1,2,2,2~tetrabromoethyl)~ dimethylcarbamoyl 3,3~dimethylcyclopropyl 72 24,242=trifluoroethyl diethylcarbamoyl 73 242=difluoroethoxy diisopropylcarbamoyl 7 2-fluoroethoxy me thylcarbamoyl 75 trifluoromethyl ethylcarbamoyl 726 difluoromethyl isopropylcarbamoyl . 77 fluoromethoxy methylethylcarbamoyl 78 2,242=tribromoethoxy methylisopropylcarbamoyl 79 242~dibromoethyl acetyl 80 2~bromoethyl trifluoroacetyl 81 2,2=dichloroethoxy butyryl 82 pentafluoroethoxy valery 83 2,2,2-trichloroethyl 3,3,3=trifluoropropionyl 84 metho xyme thyl carboxymethyl 85 ethoxymethoxy propionyl

1 26158 ! O

TABLE 1(A)-continued 86 2-(2,2=dichlorovinyl)e dime thylcarbamoyl 3,3~-dimethylcyclopropyl 87 2-(2,2=dichlorovinyl)w propienyl 3,3-dimethylcyclopropyloxy 88 2-(2y2-dichlorovinyl)=3,3= pentaacetylgluconyl dime thylcyclopropyl 89 t-butyl pentaacetylgluconyl 90 2-chloro=l,l=dimethylethyl hydrogen 91 2y2~dichloro-lyl=dimethyl~ hydrogen a 10 ethyl 92 1,1=bis(chlorome thyl)ethyl hydrogen 93 qs f-dimthylbenzyl hydrogen 9k ¢=methylbenzyl hydrogen 95 l,1~dichloroethyl hydrogen 96 cyclopropyl hydrogen . 9? l-methylcyclopropyl hydrogen 98 cyclobutyl hydrogen 99 cyclohexyl hydrogen 100 1-methyleyclohexyl hydrogen 101 3-oxacyclobutl hydrogen 102 2-fluoro-1lyl-~dimethylethyl hydrogen 103 heptanyl hydrogen 104 pentadecyl hydrogen 105 o=chlorophenyl hydrogen 106 2,4-dichlorophenyl hydrogen

TABLE 1(A)-continued

107 o~fluorophenyl hydrogen

108 2,6-difluorophenyl hydrogen

109 o«bromophenyl hydrogen

110 m~trifluoromethylphenyl hydrogen

111 p~trifluoromethylphenyl hydrogen

112 3,5-~bis(trifluoromethyl)- hydrogen phenyl vo 113 2,5~dichloro~6-methoxy« hydrogen phenyl

114 m-télyl hydrogen

115 pentafluorophenyl hydrogen

116 L4-pyridyl hydrogen

117 o~ace toxyphenyl hydrogen

118 o~allyloxyphenyl hydrogen : | 119 2-benzofuranyl hydrogen 120 J-sdamantyl hydrogen 121 o-trifluoromethylphenyl pentaacetylgluconyl

122 ¢~methylbenzyl hydrogen

123 qyq~dimethylbenzyl hydrogen

12h 2-(2,2-dichlorovinyl)=3,3~ hydrogen

: dimethylcyclopropyl

125 methoxymethyl hydrogen

126 l-methoxy-l-methylethyl hydrogen

127 2,2, 2-trifluoroethyl hydrogen

128 1l-chloro-2,2,2-trifluoro= hydrogen ethyl

———— TABLE 1(A)~continued 129 l,242,2=tetrachloroethyl hydrogen 130 trichlorovinyl hydrogen 131 l1,1~dichloro=2,2,2=trie hydrogen fluoroethyl 132 le-chloro-l-methylethyl hydrogen 133 1,1-dichlorcethyl hydrogen 134 t-pentyl hydrogen 135 ly1,242«tetramethylpropyl hydrogen 136 neopentyl hydrogen 137 chloromethyl hydrogen 138 2-fluoro=l,l~dimethylethyl hydrogen 139 l-methylecyclobutyl hydrogen 140 l-methylcyclopentyl hydrogen 141 3-methyl-3~oxacyclobutyl hydrogen 142 3-methylcyclohexyl hydrogen 143 3,4-dimethylcyclohexyl hydrogen 144 4-t-butylcyclohexyloxy hydrogen 145 cycloheptyl hydrogen 146 1,3-pentadienyl hydrogen 147 2,2-dichloro=3,3,3 hydrogen trifluar oppopoxy 148 1-ethylvinyl hydrogen 149 1-propylbutyl hydrogen 150 1,1~difluoro-3~butenyl hydrogen ! 1 ow

'

TABLE 1(A)-continued 151 1l-methyl-l-methylthicethyl hydrogen 152 p-nitrophenyl hydrogen 153 p~aminophenyl hydrogen 154 o~phenoxyphenyl hydrogen 155 2-m~xylyl hydrogen 156 lLemesityl hydrogen 157 m~phenoxyphenyl hydrogen 158 2,5,748-tetramethyl-6- hydrogen methoxy-2~chromenyl 159 9-fluorenyl hydrogen 160 2,3-dihydro-3-oxopyrido- hydrogen [24167142 bi=triazol-2-31 161 9-xanthenyl hydrogen / 162 3-chloro-2-benzothienyl hydrogen 163 2,6-dichloro-4-pyridyl hydrogen 164 3-methyl-3-oxacyclobutyl hydrogen 165 2-ethylthio-3-pyridyl hydrogen 166 phenethyl hydrogen 167 cyclohexylmethyl ; hydrogen 168 1-/Up-phenoxy)phenoxy/ethyl hydrogen 169 1-/(5-trifluoromethylpyrid- hydrogen _ 2~yl)oxyphenoxy/ethyl. : 170 ome thyl-p~nitrobenzyl hydrogen 171 q~me thyl-p-aminobenzyl hydrogen 172 ohms thyleo~fluorobenzyl hydrogen

TABLE 1(A)-continued 173 ¢-cyclohexylbenzyl hydrogen 174 1l-phenylcyclopentyl hydrogen 175 1~(phenylthio)ethyl hydrogen 176 g-sec-butylbenzyl hydrogen 177 1l-phenylcyclopropyl hydrogen 178 d-methyl-o~methylbenzyl hydrogen 179 (8)=d-methylbenzyl hydrogen 180 (B)-df-methylbenzyl hydrogen 181 oy of- dime thyl-p~chlorobenzyl hydrogen 182 of-me thyl-p-chlorobenzyl hydrogen 183 of-me thyl-o~trifluoromethyl- hydrogen benzyl \ 184 d-methyl-g~chlorobenzyl hydrogen 185 d-me thoxy benzyl hydrogen 186 d-methylbenzhydryl hydrogen 187 g-ethyl-g-methylbenzyl hydrogen : . 188 dy of-dimethyl-p-fluorobenzyl hydrogen 189 1l-methyl=1l=(p-chlorophenoxy)= hydrogen ethyl 190 benzhydryl hydrogen 191 o-ethylbenzyl | hydrogen 192 o-me thylbenzyl pivaloyl 193 2,6~difluorophenyl pivaloyl 194 2-furyl / pentaacetylgluconyl

TABIE 1(B) —

Compounds 195-388 : In all of the compounds 195-388, there is a carbon- carbon single bond between the atoms at positions 22 and 23, X represents a hydrogen atom, rR! represents \ a methyl group, and R® and R> have the corresponding ~ meanings as in compounds 1-194 above. :

TABLE 1(C)

Compounds 389~582

In all of the compounds 389-582, there is a carbonw carbon single bond between the atoms at positions 22 and 23, X represents a hydrogen atom, Rt represents an isopropyl group, and R® and R have the correspond- ing meanings as in compounds 1-194 above.

TABLE 10) ’ ] ompounds 506377

In all of the compounds 583.776, there is a car= bon~carbon single bond between the atoms at positions 22 and 23, X represents a hydrogen atom. To represeats a sec-butyl group, and Rr? and R’ have the correspond~ ing meanings as in compounds 1-194 above, /

ES

TABLE 1(E) ———

In compounds 777-782, there is a carbon-carbon single bond between the atoms at positions 22 and 23, X re- presents a hydrogen atom, and the groups RY, Rr? and rR’ have the meanings shown below.

Noo RI R® RS 777 cyclopentyl 2,6~difluorophenyl pivaloyl 778 2-methylcyclo~ o-trifluoromethyl~ hydrogen propyl phenyl 779 butyl qr dime thylbenzyl hydrogen 780 l-propenyl ome thylbenzyl pivaloyl 781 2~-methoxyethyl ¢f-me thylbenzyl "hydrogen 782 isobutyl of-ne thyl-o~ hydrogen fluorobenzyl ;

TABLE 1(F) :

Ct eA ARPA

In Compounde 783-786, there is a carbon-carbon single bond between the atoms at positions 22 and 23, X re- . presents a hydroxy group, and rt, R® and R> have the meanings shown below. .

Noo _ R: RS B> 783 cyclopentyl 2,6-difluorophenyl hydrogen 784 2-cyelohexen-1- qsf-dime thylbenzyl hydrogen y 785 1~(methylthio)= t-butyl hydrogen ethyl 786 ethynyl q~methylbenzyl hydrogen

TABLE 1(G) —

In compounds 787-793, there is a carbon-carbon double bond between the atoms at positions 22 and 23. X re- presents a hydrogen atom, and RY, R® and rR’ have the / meanings shown below.

No. _ R' rR? R> 787 cyclobutyl of-me thylbenzyl hydro gen 788 cyclohexyl os dime thyle dime thyle benzyl carbamoyl 789 propyl 246=difluoro- hydro gen phenyl 790 pentyl d-me thylbenzyl hydrogen 791 2-(methylthio)~ qsq-dimethyl~ hydrogen ethyl benzyl 18 | 792 cyclopropylmethyl ¢-methylbenzyl hydrogen 793 cyclobutylmethyl dyd-dimethyl- hydrogen benzyl . I

TABLE 1(H) \

In compounds 794-799, there is a carbon-carbon bond - between the atoms at podtions 22 and 23, X and the ring carbon atom to which it is attached together represent the group C = O, and RY, R® and rR? have the meanings below

.

KX

26158

Nos rl TG RO 794 1,3~dimethyl=l-butenyl 2,6-difluorophenyl hydrogen 795 1l,3-dimethyl-l~butenyl 2,6-~difluorophenyl prepipnyl 796 1,3-dimethyl-l-butenyl ¢f-me thylbenzyl hydrogen , 5 797 l-methyl-l-butenyl 9» §-dime thylbenzyl hydrogen 798 1,3~-dimethyl-l~butenyl o-trifluorophenyl hydrogen 799 1,3-dimethyl~l-butenyl t-butyl hydrogen

TABLE 2(A)

In compounds 1-104, there is a carbon-carbon single 10 bond between the atom at positions 22 and 23, X re- presents a hydrogen atom, and rt, R? and Y have the — meanings shown below

Noo rR B® Y 1 methyl of-me thylbenzyl ~OH 15 2 "ethyl d-methylbenzyl ~OH : 3 isopropyl of-methylbenzyl ~OH

I sec-butyl gfome thylbenzyl ~OH ethyl of-ethylbenzyl ~OH 6 ethyl of-propylbenzyl. @OH 20 7 ethyl d-isopropylbenzyl ~OH 8 ethyl “of-butylbenzyl ~OH : 9 ethyl of-sec-butylbenzyl ~OH ethyl , benzhydryl ~OH

. 26158

TABLE 2(A)-continued

In compounds 1-104, there is a carbon=~ carbon single bond between the atom at positions 22 and 23, X represents a hydrogen atom, and RY,

R> and Y have the meanings shown below

Noe. rR! R® : Y 11 ethyl os f-dime thylbenzyl ~OH - 12 sec.~butyl os f-dimethylbenzyl ~OH 13 ethyl q-ethyl-g~me thylbenzyl ~-0H 14 ethyl q-1isopropyl-cfsme thyle ~OH benzyl ethyl of-me thylbenzhydryl ~OH 16 ethyl ds of-die thylbenzyl Ne): 17. ethyl | of-me thyl«p=chlorobenzyl «OH 15 18 ethyl ofmethyl-m-chlorobenzyl ~OH 19 ethyl of-methyl-o-chlorobenzyl ~0H . 20 ethyl of-methyl-p-fluorobenzyl ~OH 21 ethyl of-me thyl~p~-trifluoromethyl -OH benzyl 22 ethyl ¢-methyl-o-trifluoro- ~CH

Co me thylbenzyl 23 ethyl of~me thyl-p~cyanobenzyl «OH 2h ethyl q-methyl-p-methylbenzyl ~OH ethyl d-me thyl-p-methoxybenzyl «OH ’ 25 26 ethyl ome thyl~p-nitrobenzyl ~OH

TABLE 2(A)-continued

In compounds 1-104, there is a carbon-carbon bond between the atom at posi tions 22 and 23, X represents a hydrogen atom, and Rr, BR? and Y have : the meanings shown below.

Noo rt R® Y 27 ethyl os f-dimethyl-p~chlorobenzyl ~OH 28 ethyl qs §-dime thyl-p-fluorobenzyl -OH j 29 ethyl qrq-diethyl-p-chlorobenzyl ~OH 30 ethyl of-methyl-2,k-dichlorobenzyl -OH 31 ethyl of-me thyl-2,6~dichlorobenzyl oOH 32 ethyl d-methyl-2,4~difluorobenzyl ~OH 33 ethyl q-me thyl-2,6-difluorobenzyl ~OH \ ' 34 ethyl of-me thyl=3-ni tro=h~chlorow ~OH benzyl 35 ethyl d-methoxybenzyl «OH : 36 ethyl of-ethoxybenzyl ~OH 37 ethyl -methoxyme thylbenzyl ~OH 38 ethyl of-me thoxyethylbenzyl ~OH 39 ethyl d-chloromethylbenzyl ~OH bo ethyl d-chlorome thyl-grme thyl- ~OH benzyl | )

Hn ethyl o-fluoromethylbenzyl ~OH h2 ethyl of-fluorome thyl-ojme thylbenzyl ~OH b3 ethyl {eganobenzyl ~0H

TABLE 2(A)~continued

In compounds 1-104, there is a carbon-carbon single bond between the atom at positions 22 and 23,

X represents a hydrogen atom, and RY, R® and Y have the meanings shown below. BN bh ethyl 1§(3-pyridyl)ethyl 80 4s ethyl 1-(2-pyridyl)ethyl «OH . : 46 ethyl 1=(h=pyridyl)ethyl -OH 47 ethyl 1-(2-thienyl)ethyl ~OH 48 ethyl 1-(2-furyl)ethyl -~OH 4g ethyl 1~(2-benzothienyl)ethyl : ~OH 50 ethyl 1-(2-benzofuranyl)ethyl ~OH 51 ethyl l-methyl-2-phenylethyl ~O0H , 15 52 ethyl 1,1~dimethyl-2-phenylethyl ~OH 53 ethyl l-phenoxyethyl -OH 54 ethyl l-me thyl=l-phenoxyethyl «OH 55 ethyl 1-(p~chlorophenoxy)lethyl OH 56 ethyl 1-methyl-1~(p-chlorophenoxy)« ~OH ethyl 57 ethyl 1-/p-( phenoxy) phenoxy/ethyl «0H 58 ethyl 1/p-( p-chlorophenoxy ) phenoxy/ ~OH ethyl 59 ethyl 1-/p=(2,4=dichlorophenoxy)- I): pKenoxy/ethyl :

TABLE 2(A)-continued er o—————————————————————————————————————————————t ee ———e

In compounds 1-104, there is a carbon-carbon single bond between the atom at positions 22 and 23, X represents a hydrogen atom, and RY, R® and

Y have the meanings shown below. ‘No. R 8 Y 60 ethyl 1~/p-(p-trifluoromethylphen- ~OH oxy)-phenoxy/ethyl 61 ethyl 1~/p-(5-trifluoromethyl-2-py~ =OH ridyloxy)phenoxy)ethyl 62 ethyl 1-/p=(3-chloro-5~trifluorow -OH me thyl-2-pyridyloxy)phenoxy/ ethyl 63 ethyl 1=/3=chloro-k~(5~trif luorome thyle 2-pyridyloxy)phenoxy/ethyl ~OH 6b ethyl 1=/p=(6wchloro-2~benzoxazolyls ~OH : i oxy)~phe noxy/e thyl 65 ethyl 1- /5-(6=chlorosl, b=dihydrom2e ~OH quinoxalinyloxy)phenoxy/« ethyl 66 ethyl of-methyl~o-fluorobenzyl -OH 67 ethyl q-cyclohexylbenzyl ~OH 68 ethyl 1-phenylecyclopropyl ~OH / 69 ethyl 1-(phenylthio)ethyl’ «OH 70 ethyl l-phgnylcyclopropyl ~OH ww Bs

. TABLE 2(A)-~continued

Y have the meanings shown belows

Noo _ R* rR Y 71 ethyl of-methyl-g-methylbenzyl ~OH : 72 ethyl (8)-gf-methylbenzyl ~OH 73 ethyl (R)-cf-methylbenzyl ~OH

RO 7h ethyl ¢methyl-p-aminophenyl «OH 75 ethyl 1=(2-pyridon-l=yl)ethyl «OH ‘ 76 ethyl 1-(2-piperidon~1l-yl)ethyl ~OH 77 ethyl 1=(2~piridyl)ethyl ~OH 78 1,3-dimethylels ¢-methylbenzyl ~OH butenyl 79 cyclopentyl " ohq-dimethylbenzyl OH 80 2-me thylcyclo= me thylbenzyl ~OH : propyl 81 butyl ofyof-dime thylbenzyl ~OH 82 l-propenyl d-me thylbenzyl ~OR 83 2-methoxyethyl of-methylbenzyl ~OH 84 isobutyl f-me thyl-o-fluorobenzyl «OH 85 ethyl d-me thylbenzyl acetoxy 86 ethyl ofme thylbenzyl chloroacetoxy 87 ethyl of-me thylbenzyl propionyloxy =f

’ . -

TABLE 2(A)-continued

In compounds 1~104, there is a carbon-carbon single bond between the atom at positions 22 and 23,

X represents a hydrogen atom, and Rt, RZ and Y have the meanings shown below.

No. RY R : Y 88 ethyl of-me thylbenzyl acetoxyacetoxy : 89 ethyl of-me thylbenzyl ethoxycarbonyloxy : 90 ethyl of-me thylbenzyl 243-dihydroxypro= poxycarbonyloxy 91 ethyl ome thylbenzyl 3,4=dihydro=2H«

Pyran=2=yle : carbonyloxye methoxycarbonylox; 92 ethyl dsq-dimethylbenzyl propionyloxy 93 ethyl qd f-dimethylbenzyl chloroacetoxy 9h ethyl dyof-dimethylbenzyl pivaloyloxyacetoxy 95 ethyl dsqf-dime thylbenzyl 3~carboxypropionylos 96 ethyl dyof-dimethylbenzyl ethoxycarbonyloxy 97 ethyl ofyq-dimethylbenzyl (2,2-dime thyl=1,3- dioxolanyl)methoxys carbonyloxy 98 ethyl dyq-dimethylbenzyl imidazol=le=yle methoxycarbonyloxy 99 ethyl of-me thyl-=p~chlorobenzyl chloroacetoxy 100 ethyl of me thyl-p-phenoxybanzyl trifluoroacetoxy 101 ethyl g-me thyl-o=chlorobenzyl chloroacetoxy 102 ethyl of-me thyl=o=chlorobenzyl ethoxycarbonyloxy /

SAD ORIGINAL A v 26158

TABLE 2(A)=~continued

X represents a hydrogen atom, and Rr, R® and Y have $ the meanings shown below.

Noo R- rR Y 103 ethyl oly §~dime thylbenzyl chloroacetoxy 104 ethyl ofs-dime thylbenzyl acetoxyace toxy : TABLE 2(B)~ | —

In compounds 105-108, there is a carbon-carbon single bond between the atoms at positions 22 and 23,

X represents a hydroxy group, and rt, RZ and Y have the meanings shown belows

No. RY r X 105 cyclopentyl qf-me thylbenzyl / -OH 106 1~(methylthio) ofmethylbenzyl ~OH : ethyl 107 ethynyl of-me thylbenzyl ~OH 108 2=-cyclohexen=l-yl ¢methylbenzyl acetoxycarbonyloxy / - 58 ano ORIGINAL 9 oo | 20158

TABLE 2(C)

In compounds 109-115, there is a carbon-carbon double bond between the atoms at positions 22 and 23,

X represents a hydrogen am RY, R® and Y have the > meanings shown below.

Noo RB oe 00. 109 cyclopentyl dyof-dimethylbenzyl ~OH 110 cyclohexyl o-methylbenzyl ~OH 111 propyl d-me thylbenzyl ~OH 112 2-(methylthio)ethyl qs of dime thylbenzyl ~OH 113 cyclopropylmethyl q-methylbenzyl ~OH 114 cyclobutylmethyl qr q-dimethylvenzyl WOH 115 cyclobutyl of me thylbenzyl chloroacetaxy

TABLE 2(D)

In compounds 116-120, there is a carbon-carbon single bond between the atoms at positions 22 and 23,

X and the ring carbon atom to which it is attached represent the group C = 0, and rt, R® snd Y have the meanings shown belowe :

No. _ R: ° 1 116 1y3~dime thyl-1- of-me thylbenzyl ~OH butenyl 117 1,3~dimethyle~l~ dy &-dime thylbenzyl «OH butenyl 118 l~methyl-1l-butenyl ol-me thylbenzyl «OH — © .119 1,3~dimethyl=lw op-methylbenzyl . chloroacetoxy

BAD ORIGINAL J on butenyl i - mm 4 7 Atm bowl Yo Admathvibenzyvl sce toxyacetoxy

The most highly preferred compounds are those with numbers 1, 2, 3, 26, 45, 55, 61, 90, 102, 108, 122, 123, 171 and 191 in Table 1(A), and those with numbers 1, 5, 7, 11, 13, 19, 86 and 88 in Table 2(A)e

The compounds of formula (I) wherein Y repre- sents the group =N-OR> and R® represents the group

R5=(0) ~ can be prepared from the corresponding 13- substi tu ted S5-ketomilbemycins of formula (111), by the processes shown in Reaction Scheme No. 1, in which

RY, rR, rR, X, n and the broken line have the meanings already defined.

REACTION SCHEME NO, 1

X

0 CH CH . » 3 3

R ~(0) co ~ .

CH

3 0

OH x

CH

0 CH 3 “ n 3

R’~(0)_~CO a step A CH, n 1 N-oH (Ia)

R

CF . 3 0 a © step C

CH, : | XX. . o CH OH, 5 " 3 } 0 : (111) nox gl

CH

5 1 0 i : oH oH, _. NeoR’ (1)

I

~~ 26158 : In reaction Scheme No. 1, Step A is for pre- paring a compound of the formula (Ia) by allowing a compound of the formula III) to react with hy- droxylamine or with one of its salts (for example, t the salt with a mineral acid such as hydrochloric : acid, nitric acid or sulfuric acid) to introduce the oxime group at the 5 position. The reaction is usual- ly carried out in an inert solvent, for example an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran or dioxane, an aliphatic acid such as acetic acid, water or a mixture of such sol- vents. The reaction temperature is preferably from 10° to 80° C. and the reaction usually requires from 1 hour to 24 hours to be complete.

Step B is for preparing a compound of the for- mula (Ib) by allowing the compound (III) to react : with an oxime compound having the general formula ’ NH,0R> (wherein R has the same meaning as before) ’ or with one of its salts (e.g. the same salts as in

Lo 20 Step A), to introduce the oxime group at the 5 posi : tion. The conditions required for this reaction are : similar to those for Step A.

Step C is for preparing a compound of formula (Ib) by esterification of the oxime group of the come pound (Ia). This reaction can be used to prepare the ,

n 26158 . preferred compounds of formula (X) above, in which the group corresponding to rR’ is R13 and represents : an ester residue of a carboxylic acid, an N,N-di substituted carbamic acid, a carbonic acid, a sul- fonic acid or a phosphonic acid by allowing a coms pound (Ia) in which R> is a hydrogen atom to react with a corresponding acid halide, usually in an inert solvent, preferably in the presence of a base. This method is a preferred embodiment of the invention.

The base employed is not particularly limited provided that it has an acid binding ability and an organic amine such as triethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1l,k~diazabicyclo= [242,2F0ctane, 5-diazabicyclo/F.3.0/nonene=5 or 1,8e diazabicyclo/5. 4.0 undecene~7~ is preferred.

The inert solvent employed is not particularly limited provided that it does not interfere with the reaction, and a hydrocarbon such as hexane, benzene, toluene ar xylene, an ether such as diethyl ether, tetrahydrofuran or #ioxane, or a halogenated hydro- carbon such as methylene chlorkde, chloroform or car- bon tetrachloride is preferred.

The compound of the formula (X) in which RY is a residue of an N-substituted carbamic acid can be prepared by allowing a compound of the formula (I) / ~ 63 t in which rR’ is a hydrogen &om to react with a core responding isocyanate in an inert solvent, in the presence of a base. The base and the inert solvent employed can be the same as in the steps mentioned before. The reaction is usually carried out at near room temperature and the reaction usually requires from 1 to 20 hours to be complete.

The compound in which RL is an N-trihaloacetyl- carbamoyl group, obtained by the above reaction, can 10 . be converted into a compound in which g13 is a carba- moyl group by reaction with zinc~acetic acid or zinc- methanole

After completion of each of these reactions, the target compound of the reaction can be obtained easily from the reaction mixture by conventional means. For example, the reaction mixtre is poured into water and, if necessary, after filtering off the insoluble matter followed by neutralization with an acid or an alkali, extracted with a water-immiscible organic solvent. The organic layer is dried and the solvent distilled off to give the desired product. If desired, purification by conventional means such as recrystal- lization, column chromatography, etc., may be applied.

The starting material of formula (III) can be prepared from ae 1 3-hydroxy-5-ke toni 1bemycin compound /

having the general formula (IV) by the reaction shown in Reaction Scheme No, 3, in which RY, R, X, n and the broken line have the meanings already defined.

REACTION SCHEME NO, 1

X

CH

CH 3 3

HO JN 0 "1 step D oH, / | _— 0 0

A .

Ch, 0

X

(Iv) oH 0 | 3 . " CH, r°=-(0) ~CO 0 n a. ; N rt

CH

>

Co ° ou eens [9%

Step D is for preparing a compound of the formula (III) by allowing a 13-hydroxy-S-ketomilbew ] mycin compound indicated by the formula (IV) to re~ act with a carboxylic acid or its reactive derivative indicated by the formula (V). Compounds of formula (IV) are known from U.S. Pat. No. 4,423,209,

The reaction of Step D is an esterification of the hydroxyl group at position 13 6f the compound (IV) with a carboxylic acid (V), and can be carried out accordng to any of the conventional procedures known for esterification reactions. The reactive derivative of a carboxylic acid employed may be for example an acid halide (an acid chloride, acid bromide or the : like), an acid anhydride a mixed acid anhydride an active ester such as a p-nitrobenzyl ester, an active amide or the like, which can be conventionally used in esterification.

CC When a carboxylic acid of the formula (V) is employed as such, it is preferred to use a dehydrating agent such as dicyclohexylcarbodiimide (DCC), p~to= luenesulfonic acid or sulfuric acid. In particular,

DCC is preferably used, and when DCC is used, pre- ) ferably a catalytic amount of pyridine or b-pyrroli- dinopyridine may be jointly used

When DCC is used as the dehydrating agent, its /

amount is usually from 1 to 5 equivalents, prefer- ably from 1¢5 to 4 equivalents.

The reaction is usually carried out in a sol- vent, The solvent employed is not particularly" limited provided that it does not interfere with tie reaction, and a hydrocarbon such as hexane, petroleum ether, benzene, toluene, xylene, chloroform, methylene chloride or o-chlorobengzene, an ether such as diethyl ether, tetrahydrofuran, dioxane or ethyleneglycol di- methyl ether, or an ester such as methyl acetate or ethyl acetate or the like may be employed, : The reaction is usually carried out at from 0%. to 50° C., preferably from 0°C. to 20° Co The : reaction usually requires from 30 minutes to 3 hours oo 15 to be complete.

When an acid halide derived from a carboxylic acid of the formula (V) is employed, the reaction : is preferably carried out in the presence of a base, preferably an organic base such as triethylamine,

N,N~dimethylaniline, pyridine, l-dime thylaminopyri= dine, 1,5-diazabicyclo/h.3.0/nonene~5 (DBN) or 1,8-di- azabicyclo/5.4.0/undecene~7 (DBU). a - :

The amount of this acid halide is usually from 1 to 10 equivalents, and from 2 to 5 equivalents } of the base is usually used. / .

: 26158

The solvent, reaction temperature and re= action time employed for this reaction are similar : to those when a carboxylic acid is used.

After completion of the reaction, the target compound having the formula (III) can be isolated : from the reaction mixture by conventional means and, if desired, further purified by conventional means such as column chromatography.

The starting material of formula (IV) can be derived from one of the milbemycins or milbemycin : analogues of natural origin, by per se known methods, such as those described in the various prior art re- ferences mentioned earlier in this speci fication.

Natural milbemycins are produced as mixtures of : various compounds, the different compounds being prow duced at different rates. Each fraction may be subjected to reaction after isolation thereof, or in the form of . mixtures of the individual products. Therefore, the compound having the formula (IV) may be either a single

Co 20 compound or a mixture thereof, which may result in forming the compound (I) either as a single compound or as a mixture. ’

The compounds of formula (1) wherein Y repree sents the group or" and g2 represents the group A- (W)_~C(R°R7)= can be prepared from the corresponding

13~hydroxy-S5~ketomilbemycins of formula (II), by the processes shown in Reaction Scheme No. 2, in which

RY, RS, RY, X, Ay, Wy n and the broken line have the meanings already defined, and gta represents a car- boxylic or carbonic acid residue. : é ,

Cw 69 = o 5. ¢ 26158 © + — oe os : . oO > MN tq 4 1 oO o - o } o . _ J =

Q 5 —~ —\ a / — c° — bd — = ©

MN

3S m 9 oO o MA

O by 0 ~~ 7 © Me)» ~

Fe - . I . oN =

S | : = <q . = 5 3 o o <t e o e + £

E : . 1a) — ’ mo — od x oO ~ vy

Mn iv m of ) © i © + —_— O —_ x o 7 © ~~ oO 22] o ~ ___ H mo Hn —_ ~ nm / ~ Hu td — o 0 oh a od" | 1 tr} oO Tes Sp 2

Of the starting compounds (II), those in which rt is the methyl, ethyl, isopropyl or sec- butyl group may be prepared by the methods disclosed in U.8. Pat. No. 4,423,209 or Japanese Patent Kokai 61103884. Compounds in which R® is the l-methylele propenyl l-methyl-l-butenyl or 1l,3~dimethyl~l-butenyl group may be prepared by dehydrating compound LL-F28249 in which the 23-position is OH, disclosed in European

Patent Publication No. 170 006, by the method described 10 . in "Pesticide Chemistry", by J. Miyamoto and P. Co

Kearny, Pergamon Press, Vol. 1, pp 83 (1983) to give the corresponding compound whose 22- and 23 positions are the double bond, and then by reducing this compound,

Alternatively, it may be prepared by converting the OH group at the 23-position to a suitable thioester, by conventional techniques, and then reducing the result ing compound by the same method as before. : Step A in Reaction Scheme 2 comprises reacting ‘ a compound of formula (II) with a carboxylic acid of formula (VI):

RS -

A=W), ~C—COOH (v1)

Rr’ (wherein R6, rR’, W, n 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 between the hydroxy group at the 13-position of com pound (II) and the carboxylic acid (VI), and hence it may be performed by any conventional method known per se. : The reactive derivative of the carboxylic acid (VI) includes, for example, acid halides (such as the acid chloride, acid bromide or acid iodide), acid an= hydrides, mixed acid anhydrides, active esters (such as p-nitrobenzyl ester) and active amides that may be normally used in esterification reactions.

Where a carboxylic acid of formula (VI) is used as such, there is preferably used a dehydrating agent such as dicyclohexylcarbodiimide (DCC), pwto- luenesulf onic acid or sulfuric acid more preferably ’ DCC, Where DCC is used, there is preferably used a catalytic amount of pyridine, 4-pyrrolidinopyridine or the like, The amount of DCC is normally from 1 tp 5 equivalents, preferably from 1.5 to 4 quivalents.

The reaction is normally effected in the pre- sence of a solvent, the nature of which is not criti- cal, provided that it has no adverse effect upon the reaction. Suitable solvents include, for example, hy« / .

/ 26158 drocarbons such as hexane, petroleum ether, benzene, toluene, xylene, chloroform methylene ¢hloride or o- : chlorobenzene, ethers such as diethyl ether, tetra- hydrofuran, dioxane or ethylene glycol dimethyl ether, and esters such as methyl acetate or ethyl acetates

Normally, tle reaction is carried out at a temperature in the range of from o°c. to 100°¢C.,, preferably from 20%c., to 50°C, for a period of from 30 minutes to 3 hours,

Where an acid halide of the carboxylic acid (VI) is used, the reaction is preferably carried out in the presence of a bases

Suitable bases include, for example, triethyl- amine, N,N-dimethyleniline, pyridine, U4-dimethylamino- pyridine, 1,5-diazabicyclo/F.3.0/nonene~5 (DBN) and 1,t ~diazabicyclo/5.k4.0/~undecene=7? (DBU)»

Normally, the amount of the acid halide of the carboxylic acid (VI) is from 1 to 10 equivalents and the amount of the base is from 2 to 8 equivalents.

The nature of solvents used, the reaction tem perature and the reaction time are similar to those when a carboxylic acid itself is used.

Step B consiets in reducing the carbonyl group at the S-position of the compound (IIa) to the hy- droxy group, and this may be effected by any reducing /

‘method known per se (see Japanese Patent Application 60-210748) . However, it is necessary not to damage any part of the molecule other than the S5-position and hence it is desirable that the reduction is car- ried out with anionic hydrogen. Reagents capable of liberating anionic hydrogen include, for example, B80= dium borohydride and diborane, of which sodium boro- hydride is most preferred. 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 presence of a solvent, the nature of which is not cri- tical, provided that it does not have any adverse

I. effect upon the reaction. Examples of suitable sol- vents include, for example, methanol, ethanol, diethyl ether, tetrahydrofuran and benzenee

Normally, the reaction is performed at a tem~ perature in the range of from -10%c. to 50°C. , prefer- ably from 0°c. to 20%. for a period of from 30 minutes to 3 hourse

Step C consists in reacting a compound of for- mula (IIb) with a carboxylic acid or carbonic acid, or a reactive derivative thereof, to give a 5-ester deri- vative of formula (IIc). This reaction is an esteri- fication reaction between the hydroxy group at the 5- . / mh position of the compound (IIb) and an acid, and therefore, it may be performed by any esterification reaction known per se as in Step A.

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

After completion of the reaction in each step, the desired compound of formulae (IIa), (IIb) and (IIc) may be recovered from the reaction mixture by well known means and, if necessary, further purified by such conventional techniques as column chromato- graphy.

The compounds of formula (II) which are used as starting materials are milbemycin compounds or mil- bemycin analogues which are fermentation products, or can be obtained from the naturel products by known no techniques, such as those mentioned in the prior art references set out earlier in this specification. Nor~ mally, the milbemycins are produced as mixtures of several compounds, the different compounds being pro=- duced at different pates. Each compound may be iso~ lated and subsequently subjected to the reactions. Al ternatively, mixtures of the compounds 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 compound or a mixture of compounds. :

The compounds of the invention having a 23m keto 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 5-oxo compound e.g. with manganese dioxide. The 5-.o0x0 derivative is treatedwith a lower alkanoic acid (e.g. formic acid) and selenium dioxide, and then with aqueous hydro- chloric acid, giving the corresponding 1l3~hydroxy=->5- oxo derivative~i.e. a compound of formula (II) above.

The 13-hydroxy group can then be acylated with the ] appropriate carboxylic acid or reactive derivative . thereof, in the manner already described, to give ‘the corresponding l3-esterified-5-oxo compound, such as a compound of formula (Ia) or (IIa) above. The 5- 0X0 group can then be converted to the S5~oxime, using the methods already described; or it can be converted to a S~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 eggs of Tetranychus, Panonychus (ego

Panonychus ulmi and Penonychus citri), Aculopa pele- kassi and rust mites, which are parasitic to fruit trees, vegetables and flowers. They are also active - against Ixodidae, Dermanyssidae and Sarcoptidae, which are parasitic to animals. Further, they are active against: exoparasites, such as QOestrus, Lucilia, Hypo- derma Gautrophilus, lice and fleas which are parasitic to animals and birds, particularly livestock and poul- : try; domestic insects, such as cockroaches and house~ flies; and various harmful insects in agricultural and : ‘horticultural areas, such as aphids and larval Lepi-~ doptera. They are also effective against Meloidogyne in the soil, Bursaohelenchus and Rhizoglyphus. They 15° are also effective against insects of the orders

Coleoptera Homoptera, Heteroptera, Diptera, Thysanop- tera, Orthoptera, Anoplura, Siphonaotera, Mallophage ’ Thysanura, Isoptera, Psocoptera, and Hymenoptera.

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

The compounds can be used to protect both ornamental plants and productive plants, particularly cotton (e.g. against Spodoptera littoralis and Heliothis virescens), as wel 1 as vegetable crops (esg. against ff a 7)

'Leptinotarsa decemlineata and Myzus persicae) and rice crops (e.g. against Chilo suppressalis and

Laodelphax)e - The activity of the compounds of the inven- tion is pronounced, both systemically and by contact,

Accordingly, the compounds are very effective again sucking insects, especially sucking insects of the . order Homoptera and most particularly the family

Aphididae (such as Aphis fabae, Aphis craccivora and ‘Myzus persicae), which are difficult to control with known 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, contain~ ing 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 soybeans), fruits and other plants (e.g. cotton)

The compounds of the invention can similarly be used to protect animals from a variety of ecto~ : parasites, by applying the compounds to the enimals or to the animals environment, e.g. livestock housing, animal boxes, abattoirs, pasture land and other grass- lands, as well as to any other places liable to be ’ , } mR infested. The compounds may also be applied to ex-~ ternal parts of the animals, preferably before they are infested.

Moreover, tle compounds of the invention are effective against various parasitical helminths.

These parasites can attack livestock, poultry and pet animals (such as pigs, sheep, goats, cows, horses, dogs, cats and fowl) and can cause grave economica 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,

Bunoatomumg

Oesophagostomum,

Chabertis,

Trichuris,

Strongylus,

Trichonema, —

Dictyocaulus, / :

Capillaria,

Heterakis,

Toxocara,

Ascaridia,

Oxyuris,

Ancylostoma, ’

Uncinaria, .- Toxascaris and

Parascar is.

Certain parasitical species of the genera

Nemarodirus, Cooperia and Oesophagostomum attack the intestines, while certain species of the genera Hae~ monchus and Ostertagia parasitize the stomach, and parasités. belonging to the genus Dictyocaulus are found in the lungs. Parasites belonging to the families

Filariidee and Setariidae are found in internal tissues ] and orgsns, for example, the heart, tle blood vessels, the subcutaneous tissues and the lymphatic vessels.

The compounds of the invention are active against all these parasitéss. .

The compounds of the invention are algo effec- tive against parasites whi ch infect humans. Typical of the parasites which may most commonly be found in the digestive tracts of human beings are parasities of the genera Ancylostoma, Necator, Mscaris, Strongy=-

260158 oo loides, Trichinella, Capillaria, Trichuris and En- terobius. The compounds are also active against parasites of the genera Wuchereria, Brugia, Oncho~ cerca and Loa of the family Filariidae (which are found in blood tissues and organs other than the di~ gestive tract and are medically important), parasites . of the genus Dracunculus of the family Dracunculidae and parasites of the genera Strongyloides and Tri- | : : chinella, 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 of the invention are to be employed as anthelmintics, - they are preferably administered orally, parenterally or topically end the form of compositions chosen will be appropriate to the intended route of administra=- tion. | CL

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 if water or another non-toxic solvent. The drink, in general, also contains an anti-foaming agent. The active compound would normal- ® ly be present in the drink in an amount of from 0.01 to 0.5% by weight, more preferably from 0.01 to 0.1% by weighto

Compositions for oral administration may also be in the form of dry solids, preferably in unit dos- age form, such as capsulesy pills or tablets contain ing the desired amount of the active compound. These compositions may be prepared by mixing the active com= pound uniformly with suitable diluents, fillers disin- tegrators and/or binding agents, for example starch, lactose, talc, magnesium stearate and vegetable gum.

The weight and contents of the preparation will vary ' widely, depending upon the nature of the animal to be treated, the degree of infection, the nature of the parasite and the body weight of the animal to be treated.

The compounds may also be administered as an 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 content of active compound in the feedstuff is prefer- ably frm 0.0001 to 0.02%, in order to achieve the de-~ sired anthelmintic activity.

For parenteral administration, the compound /

of the invention is preferably dissolved or sus= pended 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 formula (II), the liquid vehicle may be water or another aqueous medium. Depending upon the animal to be treated, tle injection may be subcutaneous or into the proventri- culus, a muscle or the trachea. Such preparations would normally contain tre active compound at a con- centration of from 0.05 to 50% by weight.

The compounds of the invention may also be ad ministered topically in admixture with a suitable carrier, such as dimethyl sulphoxide or a hydrocarbmn solvent. Such preparations would be applied directly to the outside of the animal by spraying (e.g. by a hand spray or in spray races), by dipping (e.g. in a plunge dip), by a pour-on solution or by manual methods (e.g. hand-dressing)o

The dose of active compound may be varied, de- pending upon the nature of the animal to be treated, and the nature and degree of parasitic infection,

However, best results for oral administration are achieved when the dose is from 0.01 to 100 mg, more preferably from 0.5 to 50 mg. per 1 kgs body weight.

The compound may be administered in a single dose or /

Qe in divided doses for a relatigely short period, such Bh as from 1 to 5 days.

Where the composition of the invention is in- tended for agricultural or horticultural use, a variety of forms and formulations is possible. For example, the composition may be formulated as dusts, coarse dusts, soluble powders, microgranules, fine microgranules, wettable powders, dilute emulsions, emulsifiable concentrates, aqueous or oily suspen— sions, dispersions or solutions (which may be direct- ly sprayable or for dilution), aerosols or capsules in, for example, polymeric substances, The carrier employed may be natural or synthetic and organic or inorganic; it is generally employed to assist the active compound to reach the substrate to be treated, \ and to make it easier to store, transport or handle thé 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 conven tional means, e.g. by intimate mixing and/or grinding of the active, ingredient(s) with the carrier or di- luent, e.g. solvent, solid carrier or, optionally, sur- face-active agent,

Suitable solvents include: aromatic hydrocar= / - Bl bons, preferably the Cg to Cys fractions from petro- : leum distillation, such as Eylene mixtures or subs- tituted naphthalenes; esters of phthalic acid, such as dibutyl or dioctyl phthalate; aliphatic hydrocar- bons, such as cyclohexane or the paraffins; alcohoks ) and glycols or esters thereof, such as ethanol, ethy- lene glycol, ethylene glycol monomethyl ether or ethylene glycol monoethyl ether; ketones, such as cyclohexanone; strongly polar solvents, such as Ne | me thyl-2-pyrrolidone, dimethyl sulfoxide or N,N-di- methylformamide, optionally epoxidzed vegetable oils, such as epoxidized coconut oil or soybean oil; and water.

Solid carriers, which may be used, for exam- ple, in dusts and dispersible powders, include natural mineral fillers, such as calcite, talc, ksolin, mont- morillonite or attapulgite. In order to improve the . physical properties of the composition, it is also possible to add highly dispersed silicic acid or highw ly dispersed absorbent polymers. Suitable granulated adsorptive carriers may be porous (such as pumice, ground brick, sepiolite or bentonite) or non-porous (such as calcite or sand). A wide variety of pre- : granulated materials, organic or inorganic, may also be used; examples include dolomite and ground plant

Cr 4 ‘26158 residues.

Surface-active agents which may be used are well known in the art and may be non-ionic, cationic or anionic agents having good emulsifying, disperse ing and wetting properties. Mixtures of such agents may also be used. )

Compositions may also contain stabilizers, anti~foaming agents, viscosity regulators, binders or adhesives or any combination thereof, as well as fertilizers or other active substances to achieve special effects.

Pesticidal compositions will generally containt from 0.01 to 99%, more preferably from O.l to 95%, by weight of the active compound; from 1 to 99.99%, of } a solid or liquid additive; and from O to 25%, more preferably from 0.1 to 25%, of a surface-active agente.

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

The invention is further illustrated by the following non-limiting Examples and Preparations.

Examples 1 to 128 illustrate the preparation of compounds of formula (1) wherein Y represents the group =N-OR® and R® represents the group R°-(0) =e . / — B66 =

Examples 129 to 163 illustrate the preparation of compounds of formula (I) wherein Y represents the group oR" and r® represents the group A-(w)_~0(rR°R7)- but for brevity the symbol Z has been used in place of A-(0)_-a(r%R7)- in these Examples.

Preparations 1 to 4 illustrate the synthesis of starting materials for use in preparing the com- pounds of the invention. : Examples 164 to 168 illustrate the activity of the compounds of the invention against various pests. ~~ Unless otherwise specified, the group X at posi tion 23 always represents a hydrogen atom, through- out all of the Examples. Examples 1 to 94 illustrate the preparation of compounds of formula (Ia) from starting materials of formula (III), by tie reaction of

Step A in the above Reaction Scheme No. 1. } EXAMPLE 1 13~p~Fluorophenoxyacetoxy-5~keto-25~ethylmilbemycin=~5- oxime (Compound of formula (Ia) wherein: Rr? =z ethyl,

R = p-fluorophenoxymethyl, n=0).

A solution.of 121 mg of 13-p-fluorophenoxy- acetoxy-5-keto~25-ethylmilbemycin in a mixture of 4 ml. of methanol and 4 ml. of dioxane was added dropwise to 3 ml. of an aqueous solution containing 59 mg of hy-

droxylamine hydrochloride, and the resulting mix ture was stirred at room temperature for 8 hours.

After completion of the reaction, the mixture was poured into water and extracted with ethyl acetate.

The ethyl acetate extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated. The residue was subjected to column chromatography over silica gel, giving 76 mg of the target product (yield: 61.8%).

Mass Spectrum (m/z): 709 my, 675.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1;) § ppm: 3.97 (1H, singlet, OH at the 7 posi- tion); 4.67 (1H, singlet, H at the 6 position); 5.06 (1H, doublet, H at the 13 position, J = 10.6 Hz).

By following the procedure of Example 1, the compounds of the following Examples 2 to 94 were ob- tained, having the characteristics shown.

EXAMPLE 2 13-Ethoxycarbonyloxy=-5-ke to-25-isopropylmilbemycin 5~oxime (Compound of formula (Ia) wherein: rl = isopro- pvl, R® = ethyl, n = 1).

Mass Spectrum (M/z): 657 Mf), 639.

Nuclear Magnetic Resonance Spectrum (270 MHz,

COC13) f ppm: 3.94 (1H, &inglet,OH at the 7 position);

4.46 (1H, singlet, H at the 6 position); 4.49 (1H, doublet, H at the 13 position, J = 11.7 Hz).

EXAMPLE 3 13-Acetoxy-5-keto-25-isopropylmilbemycin 5~oxime (Compound of formula (Ia) wherein: rl = is0w propyl, rR = methyl, n = 0).

Mass Spectrum (m/z): 618 Mh). : Nuclear Magnetic Resonance Spectrum (270 MHz,

CoC1,) 4 ppm: 3.92 (lH, singlet, OH at the 7 position); 4.66 (1H, singlet, H at the 6 position); 4.95 (1H, doublet, H at the 13 position, J = 10.8 Hz).

EXAMPLE & 13-p~Chlorobenzoyloxy-5-keto~-25-ethylmilbemycin 5- oxime (Compound of formula (Ia) wherein: rl = ethyl, . R® = p-chlorophenyl, n= 0).

Mass Spectrum (m/z): 709M"), 675.

Nuclear Magne$ic Resonance Spectrum (270 MHz,

COC14). d ppm: 3.97 (1H, singlet, OH at the 7 pasition); 4.70 (1H, singlet, H at the 6 position); 5.20 (1H, doublet, H et the 13 position, J = 10.6 Hz).

EXAMPLES

13-p=-t-Butylbenzoyloxy=5-keto-25-ethylmilbemycin 5- oxime (Compound of formula (Ia) wherein: al = ethyl,

R> = p=-t-butylphenyl, n = 0).

Mass Spectrum (m/z): 731 (MY), 713, 553.

Nuclear Magnetic Resonance Spectrum (270 MHz,

COC1,) J ppm: 3.98 (1H, singlet, OH at the 7 position); 4.69 (1H, singlet, H at the 6 position); 5.19 (1H, 10. doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 6 13-0~Trifluoromethylbenzoyloxy-5-keto~25-ethylmilbe- myc in-5-oxdme (Compound of formula (Ia) wherein: rl = ethyl, : 15 rR? = o-trifluoromethylphenyl, n = 0).

Mass Spectrum (m/z): 743 mh, 725, 709. : Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC14) $ ppm: 3.98 (1H, singlet, oH at the 7 position); 4,68 (1H, singlet, H at the 6 position); 5.23 (1H, doublet, H at the 13 position, J = 10.3 Hz). . EXAMPLE 7 13-(2-Furoyloxy)=5-keto-25=-athylmilbemycin S-axime (Compound of formula (Ia) wherein: rl = ethyl,

R® = 2-furyl, n = 0)

Mass Spectrum (m/z): 665 (M*), 647, 631.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CoCl3) Jd ppm: 3.96 (1H, singlet, OH at the 7 posi- tion); 4.68 (1H, singlet, H at the 6 position); 5.17 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 8 13-Benzyloxycarbonyloxy-5-keto-25-sthylmilbemycin

S5-oximee (Compound of formula (la) wherein: rl - ethyl,

R° = benzyl, n= 1).

Mass Spectrum (m/z): 705 Mh), 553

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC14) § ppm: 3.96 (1H, singlet, UH at the 7 position); 4.67 (1H, singlet, H at the 6 position); 4.76 (1H, doublet, H at the 13 position, J = 10.3 Hz).

EXAMPLE 9 13-Methoxycarbonyloxy-5-keto=-25-ethylmilbemycin and 25-methylimilbemycin 5-oxime (mixture of two compounds in the ratio 8:2) (Compound of formula (Ia) wherein: rl = ethyl or methyl, R? = methyl, n= 1).

Mass Spectrum (m/z): 629 (M%).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl) J ppm: 3.97 (1H, singlet, OH at the 7 position);

4.67 (1H, singlet, H at the 6 position); 4.7-L4.85 (3H, multiplet, CH, at the 27 position, H at the 13 position).

EXAMPLE 10 13-(2,2,2~-Trichloroasthoxycarbonyloxy )=5-keto-25~- ethylmilbemycin 5-oxime (Compound of formula (Ia) wherein: rl = ethyl,

R° = 2,2,2-trichloroethyl, n = 1).

Mass Spectrum (m/z): 745 +3, 727.

Nuclear Magnetic Resonance Spectrum (270 MHz,

COCl,) f ppm: 3.97 (1H, singlet, OH at the 7 position); 4,67 (1H, singlet, H at the 6 position); 4.80 (1H, doublet, H at the 13 position, J = 10.3 Hz).

EXAMPLE 11 13~(2-Butenoyloxy)=-5-keto-25-gthylmilbemycin and 25- methylmilbemycin 5-oxime (mixture of two compounds in the ratio 2.6:1) (compound of formula (Ia) wherein: rl = ethyl or methyl, R° = propenyl, n= 0).

Mass Spectrum (m/z): 639 (MY)o

Nuclear Magnetic Resonance Spectrum (270 Mhz,

GDG14) df ppm: 3.95 (1H, singlet,0H at the 7 position); 4.67 (1H, singlet, H at the 6 position); 5.01 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 12 - 13-/2(2,2~Dichlorovinyl)=3,3~dimethylcycloprop§l. : carbonyloxy/=5-keto-25-ethylmilbemycin and =25« methylmilbemycin S5-oxime (mixture of two compounds in the ratio 2.6:1) (Compound of formula (Ia) wherein: rt = ethyl or methyl, R = 2=-(2,2~dichlorovinyl)~3,3~dimethylcy~ clopropyl, n = 0),

Mass Spectrum (m/z): 761 ord

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d' ppm: 3.97 (1H, singlet, OH at the 7 position)} 4,67 (1H, singlet, H at the 6 position); 5.40 (1H, doublet, H at the 13 position, N = 11 Hz),

EXAMPLE 13 13~Phenylacetoxy~S5-keto~25~ethylmilbemycin and 25 . methylmilbemycin 5-oxime (mixture of two compounds in the ratio 2.8:1) (Compound of formula (Ia) wherein: R: = ethyl or methyl, R = benzyl, n = 0), :

Mass Spectrum (m/z): 689 mt), 655,

Nuclear Magnetic Resonance Spectrum (270 MHz, cDC1,) § ppm: 3.95 (1H, singlet, OK at the 7 position); 4.66 (1H, singlet, H at the 6 position); 4.93 (1K, doublet, H at the 13 position, J = 10.6 Hz),

EXAMPLE 14 134/2-Hydroxy-3-(t-butyldimethylsiloxy)propoxy~- carbonyloxy/~5-keto-25~ethylmilbemycin and 25-methylmilbemycin 5-oxime (mixture of two compounds in the ratio 3.U4:1) (Compound of formula (Ia) wherein: rR! = ethyl or methyl, R = 2-hydroxy-3-(t-butyldimethylsiloxy)=~ propyl, n = 1).

Mass Spectrum (m/z): 803 (M*)

Nuclear Magnetic Resonance Spectrum (270 MHz, : opel.) J ppm: 3,97 (1H, singlet, OH at the 7 position); 4.67 (1H, singlet, H, at the 6 position); 4.74% (1H, doublet, H at the 13 position, J = 9.7 Hz)e

EXAMPLE 15 13-(2,2-Dimethyl-1,3~dioxolanylmethoxycarbonyloxy)~

S-keto=25~ethylmilbemycin and ~25-methylmilbemycin 5- oxime mixture of two compounds in the ratio 2.3:1) (Compound of formula (Ia) whereint Rl = ethyl or methyl, Rr’ = 2,2-dimethyl-1,3-dioxolanylmethyl, n= 1). . ;

Mass Spectrum (m/z): 729 and 715 mh).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl) J ppm: 3.97 (1H, singlet, OH at the 7 posim tion); 4.69 (1H, singlet, H at the 6 position); 4,65-4.85 (3H, multiplet, CH, at the 27 position, :

H at the 13 position).

EXAMPLE 16 13-(2,3-Dihydroxypropoxycarbonyloxy)=-5-keto-25~ ethylmilbemycin and -25~methylmilbemycin 5~oxime (mixture of two compounds in the ratio 2.3:1) (Compound of formula (Ia) wherein: Re ethyl or methyl, R = 2,3~dihydroxypropyl, n = 1).

Mass Spectrum (m/z): 689 and 675(M*).

Nuclear Magnetic Resonance Spectrum (270 MHz, cncl,) d ppm: 3.96 (1H, singlet, OH at the 7 posi- tion); 4.67 (1H, singlet, H at the 6 position); 4.74 (1H, doublet, H at thel3 position, J = 10.3 Hz).

EXAMPLE 17 13-(3-Chloropropionyloxy)-5-keto~25-ethylmilbemycin and ~25~methylmilbemycin S~oxime (mixture of two compounds in the ratio 2.7:1) (Compound of formula (Ia) wherein: 7 = ethyl or methyl, Rr’ w= 2-chloroethyl, n = 0). = : Mass Spectrum (m/z): 662 a)

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC) ppm: 3.96 (1H, singlet, OH at the 7 posi- tion); 4.67 (1H, singlet, H at the 6 position); 5.00 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 18 ~ 13-( 2~Methoxyet hoxycarbonyloxy)=5-keto-25=ethylmmil- bemycin S5-oxime : (Compound of formula (Ia) wherein: rR! - ethyl,

RB = 2~methoxyethyl, n = 1)o

Mass Spectrum (m/z): 673 (M*), 655, 640.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC14) J ppm: 3.95 (1H, singlet, OH at the 7 position); 4,67 (1H, singlet, H at the 6 position); 4.75 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 19 13-~Pivaloyloxy-5-keto=25-ethylmilbemycin S-oxime (Compound of formula (Ia) wherein: rR! = ethyl,

R? = t.butyl, n = O)e

Mass Spectrum (m/z): 655 Mh), 637, 621e : Nuclear Bagnetic Resonance Spectrum (270 MHz, :

CD01) ppmt 3.97 (1H, singlet, OH at the 7 position); 4.66 (1H, singlet, H at the 6 position); 4,91 (1H doublet,

H at the 13 position, J = 10.2 Hz)e

EXAMPLE 20 13-Trichloroacetoxy-5-keto-25-ethylmilbemycin S~oxime (Compound of formula (Ia) wherein: R! = ethyl,

R’ = trichloromethyl, f = O)o

26158 i

Mass Spectrum (m/z): 715 (MY), 697. -

Nuclear Magnetic Resonance Spectrum (270 MHz, cDC1,) J ppm: 3.96 (1H, singlet, OH at the 7 posi- tion); 4.68 (1H, singlet, H at the 6 position); 4.99 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 21 13-Jodoacetoxy~5~keto~25=ethylmilbemycin S~oxime (Compound of formula (Ia) wherein: rl = ethyl,

R’ = iodomethyl, n = 0).

Mass Spectrum (m/z): 739 3, 721,

Nuclear Magnetic Resonance Spectrum (270 MHz, cDC1,) § ppm: 3.97 (1H, singlet, OH at the 7 posie tion); 4.66 (1H, singlet, H at the 6 position); 4.94 (1H, doublet, H at the 13 position, J = 10.8 Hz)e

EXAMPLE 22 . ~ 1p=Formyloxy-5-keto-25-ethylmilbemycin S-mxime (Compound of formula (Ia) wherein rR! = ethyl,

R= hydrogen, n = O)e :

Mass Spectrum (m/z): 599(M*%), 585, 581.

Nuclear Magnetic Resonance Spectrum (270 MHz,

Co coer) & ppm: 3.97 (1H, singlet, OH at the 7 position); 4,68 (1H, singlet, H at the 6 position); 5.05 (1H, doublet, H at the 13 position, J = 10.6 Hz), / /

- :

EXAMPLE 23 13-p~Bromobenzoyloxy-5-keto-25~ethylmilbemycin Sm oxime (Compound of formula (Ia) wherein: RY = ethyl,

R = p-bromophenyl, n = 0).

Mass Spectrum (m/z): 753 (v*, with Br’), 735, 719.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d' ppm: 3.98 (1H, singlet, OH at the 7 posi tion); 4.69 (1H, singlet, H at the 6 position); 5.19 (1H, doublet, H at the 13 position, J = 10.4 Hz), © EXAWPLE 24 13-Cyclobutylcarbonyloxy-5-keto-25~ethylmilbemycin See oxime 1p (Compound of formula (Ia) wherein: rR: = ethyl, i Rr’ = cyclobutyl, n = 0).

Mass Spectrum (m/z): 653 (MY),

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) & ppm: 3.95 (1H, singlet, OH at the 7 posi tion); 4.67 (1H, singlet, H at the 6 position); 4.94 : (1H, doublet, H at the 13 position, J = 10.6 Hz)o : ! / ~ 98 Py

EXAMPLE 25 13-0-Chlorobenz0yloxy=5-ke tom25-ethylnilbemycin and ~25~methylmilbemycin 5-oxime (mixture of two compounds in the ratio 2.3:1) (Compound of formula (Ia) wherein: Rl = ethyl or methyl, RO = o~chlorophenyl, n = 0),

Mass Spectrum (m/z): 709 (M'),

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d ppm: 3.97 (iH, singlet, OH at the 7 posi- tion); 4.67 (1H, singlet, H at the 6 position); 5.23 (1H, doublet, H at the 13 position, J = 10.6 Hz),

EXAMPLE 26 13=(2,4=Dichlorobenzoyloxy)~5-ke to=25~ethylmilbemyein and =-25-methylmilbemycin 5-oxime (mixture of two compounds in the ratio 2.311) (Compound of formula (Ia) whereint r! = ethyl : or methyl; rR’ = 2,4~dichlorophenyl, n = 0),

Mass Spectrum (m/z): / 743 (M*).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) J ppm: 3.98 (1H, singlet, OH at the 7 position); 4,66 (1H, singlet, H at the 6 position); 5.23 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 27 15-m~Fluorobenzoyloxy~5~keto=25~ethylmilbemycin and ’ : ~25~me thylmilbemycin S-oxime (mixture of two compounds in the ratio 2.3:1) (Compound of formula (Ia) wherein: RY = ethyl or methyl, R’ = m-fluorophenyl, n = 0),

Mass Spectrum (m/z): 693 (M*).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC15) d ppm: 3.71 (1H, singlet, OH at the 7 position);

L,69 (1H, singlet, H at the 6 position); 5.21 (1H, doublet, H at the 13 position, J = 10.6 Hz),

EXAMPLE 28 . 13-m-frifluoromethylbenzoyloxy=5e-keto=25=~ethylemilbew mycin and -25~methylmilbemycin S-oxime (mixture of two compounds in the ratio 2.3:1) (Compound of formula (Ia) wherein: RY = ethyl or ’ methyl, R = m-trifluoromethylphenyl, n = 0),

Mass Spectrum (m/z): 743 Mh).

Nuclear Magnetic Resonance Spectrum (290 MHz, cpc1,)d ppm: 4.0 (1H, singlet, OH at the 7 position); 4469 (1H, singlet, H at the 6 position); 5.24 (1H, doublet, H at the 13 position, J = 10.3 Hz), / = 100 w

. . 26158

EXAMPLE 29 13-(2,5-Dichloro-6-methoxybenzoyloxy)-5-ke to~25- ethylmilbemycin and =25-methylmilbemycin S-oxime (mixture of two compounds in the ration 2.3:1) (Compound of formula (Ia) wherein: r = ethyl or methyl, Rr’ = 2.5-dichloro~6~-methoxyphenyl, n= 0).

Mass Spectrum (m/z): 773 CP

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) § ppm: 3,90 (1H, singlet, OH at the 7 position); 4,69 (1H, singlet, H at the 6 position), 5.20 (1H, doublet), H at the 13 position, J = 10.6 Hz).

EXAMPLE 30 13-Cyclohexylcarbonyloxy-5-keto-25-ethylmilbenycin and ~25-me thylmilbemycin S-oxime (mixture of two compounds in the ration 2.311) (Compound of formula (Ia) wherein: rR! = {Je thyl or methyl, RS = cyclohexyl, n = 0)e

Mass Spectrum (m/z): 681 m*)o

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl) J ppm: 3.90 (1H, singlet, OH at the 7 position)s 4.68 (1H, singlet, H at the 6 position); 4.93 (1H, doublet, H at the 13 position, J = 1006 Hz).

EXAMPLE 31 ~ 13-(2-Phenylpropionyloxy)-5-ke to-25~ethylmilbemycin and -25-methylmilbemycin 5-oxime (mixture of two compounds in the ratio 2.3:1) ' (Compound of formula (Ia) wherein: RT =m ethyl or methyl, R® = of-me thylbenzyl, n=0),

Mass Spectrum (m/z): 703 (M%),

Nuclear Magnetic Resonance Spectrum (270 MHz, cDC1,) $opm: 3.98 (1H, singlet, OH at the 7 position); 4,66 (1H, singlet, HE at the 6 position); 4.89 (1H, doublet, H at the 13 position, J = 10.6 Hz),

EXAMPLE 32 13~o0~Bromobenzoyloxy-5-keto~25=ethylmilbemycin S5~oxime (Compound of formula (Ia) wherein: RI = ethyl,

R’ = o~bromophenyl, n = 0),

Mass Spectrum (m/z): 753 (M*, with Br’9), . Nuclear Magnetic Resonance Spectrum (270 MHz, ¢DCl,) d'ppm: 3.71 (1H, singlet, OH at the 7 position); i 4.68 (1H, singlet, H at the 6 position); 4.94 (1H, doublet, KE at the 13 position, J = 10.6 Hz),

EXAMPLE 33 13-(2,2-Dichloropropionyloxy)-5-ke to-25-¢ thy lnilbemycin and ~25-methylmilbemycin S5-oxime (mixture of two compounds in the ratio 2.3:1) ‘

" ) 26158 (Compound of formula (Ia) wherein: Rr! = ethyl . or methyl, R® = 1l,1~dichloroethyl, N = 0),

Mass Spectrum (m/z): 695 *).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d ppm: 3.95 (1H, singlet, OH at the 7 position); 4,68 (1H, singlet, H at the 6 position); 4.95 (1H, doublet, H at'the 13 position, J = 10.3 Hz).

EXAMPLE 3h 13-Cyclopropylcarbonyloxy-5-keto~25-ethylmilbemycin 5« oxime (Compound of formula (Ia) wherein: RY = ethyl,

R = cyclopropyl, n = 0).

Mass Spectrum (m/z): 639 Mh).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) J ppm: 3,90 (1H, singlet, OH at the ? posi~ tion); 4.57 (1H, singlet, H at the 6 position); 4.98 i (1H, doublet, H at the 13 position, J = 10.6 Hz),

EXAMPLE 55 1%~(1-Methylcyclohexylcarbonyloxy)=5~ke to«25~ethylm milbemycin and -25-methylmilbemycin S-oxime (mixture of two compounds in the ratio 2.311) (Compound of formula (Ia) wherein: rR! = ethyl or methyl, Rr = l-methylcyclohexyl, n = 0)o / ~ 103 w= a 26158

Mass Spectrum (m/z): 695 (M*),

Nuclear Magnetic Resonance Spectrum (270 MHz, cel) d'ppm: © 3,97 (1H, singlet, OH at the 7 posi- : tion; 4.67 (1H, singlet, H at the 6 position); 4.9% (1H, doublet, H at the 13 position, J = 10.6 Hz). ’ EXAMPLE 36 13-Octanoyloxy-5-keto~25-ethylmilbemycin and —25m methylmilbemycin 5-oxime (mixture of two compounds in the ratio 2.3:1) (Compound of formula (Ia) wherein: RY = ethyl or methyl, R - heptyl, n = 0).

Mass Spectrum (m/z): 697 (MY),

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d ppm: 3.96 (1H, singlet, OH at the 7 position); 4.68 (1H, singlet, H at the 6 position); 4.95 (1H, doublet, H at the 13 position, J = 10.2 Hz).

EXAMPLE 37 13-Palmitoyloxy-5-keto-25-e thylmilbemycin and —=25e methylmilbemycin S5-oxime ; (mixture of two compounds in the ratio 2.311) (Compound of formula (Ia) wherein: RY & ethyl or methyl, R = pentadecyl, n = 0),

Mass Spectrum (m/z): 809 (M%).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) 4 ppm: 2.95 (1H, singlet, OH at the 7 posi tion); 4.68 (1H, singlet, H at the 6 position); 4.96 (1H, doublet, H at the 13 position, J = 10.3 Hz)o

EXAMPLE 38 13-Isonicotinyloxy-5-ke to-25~ethylmilbemycin 5-oxime (Compound of formula (Ia) wherein: rR! = ethyl

Rr = Yopyridyl, n = 0).

Mass Spectrum (m/z): 676 mh).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d' ppm: 4.01 (1H, singlet, OH at the 7 posi- tion); 4.70 (1H, singlet, H at the 6 position); 5.22 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 39 13-m-Toluoyl-5-keto-25-ethylmilbemycin and -25-methyl- milbemycin 5-oxime . (mixture of two compounds in the ratio 2.311) (Compound of formula (Ia) wherein: rR! = ethyl or methyl, R = m-tolyl, n = 0), .

Mass Spectrum (m/z): 689 ih).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) ¢ ppm: 3.99 (1H, singlet, OH at the 7 posi- tion); 4.69 (1H, singlet, H at the 6 position); 5.21 - (1H, doublet, H at the 13 positiong J = 10.3 Hz)o

26158 i

EXAMPLE 40 13-Pentafluorobenzoyloxy-5-keto-25-ethylmikhbemycin and ~25~methylmilbemycin S5-oxime (mixture of two compounds in the ratio 2.3:1) (Compound of formula (Ia) wherein: R* = ethyl or methyl, RO = pentafluorophenyl, n = 0).

Mass Spectrum (m/z): 765 (MY).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCL,) d ppm: 3.97 (1H, singlet, OH at the 7 position); 4.68 (1H, singlet, H at the 6 position); 5.21 (1H, doublet, at the 13 position, & = 10.6 Hz),

EXAMPLE 41 13-(3~Adamantylcarbonyloxy)=-S-keto=25~ethylmilbemycin

S~oxime (Compound of formula (Ia) whereint RY = e thyl, : BR = 3~adamantyl, n % 0), ’ Mass Spectrum (m/z): 733 (m*). :

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d ppm: 3.95 (1H, singlet, OH at the 7 position); b.67 (1H, singlet, H at the 6 position); 4.92 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 42 13-/3,5-Bis( trifluoromethyl) benzoyloxy/=5-keto=25+ ethylmilbemycin 5-oxime (Compound of formula (Ia) wherein: Rlzethyl,

R = 3,5-bis(trifluoromethyl)phenyl, n = 0),

Mass Spectrum (m/z): 811 wh.

Nuclear Magnetic Resonance Spectrum (270 Mhz,

CDC1,) d ppm: 3.97 (1H, singlet, OH at the 7 position); 4,69 (1H, singlet, H at the 6 position); 5.26 (1H, doublet), H at the 13 position, J = 10.6 Hz),

EXAMPLE 43 13-(2gRenoyloxy)-5-ke to-25-ethylmilbemycin and ~25- methylmilbemycin S5-oxime (mixture of two compounds in the ratio 1.231) (Compound of formula (Ia) wherein: rR! = ethyl or methyl, R’ = 2~thienyly, n = 0),

Mass Spectrum (m/z8: 681 Mh).

Nuclear Magnetic Resonance Sfiectrum (270 MHz to €DC1,) 4 ppm: 3.97 (1H, singlet, OH at’ the 7 posi- . 20 tion); 4.68 (1H, singlet, H at the 6 position); 5.1h (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE &4h4 13-(2,6-Difluorobenzoyloxy)-5-keto-~25~ethylmilbemycin and =25-methylmilbemycin S~oxime (mixture of two compounds in the ratio 2.6:1)

(Compound of formula (Ia) wherein: RY = ethyl or methyl, R = 246~difluorophenyl, n = 0),

Mass Spectrum (m/z): 711 (M%).

Nuclear Magnetic Resonance Spectrum (270 MHz, coo1,) d ppm: 3.98 (1H, singlet, OH at the 7 position); 4.68 (1H, singlet, H at the 6 position); 5.21 (1H, doublet, H at the 13 position, J = 10.6 Hz),

EXAMPLE 45 13-Chloropivaloyloxy~5-keto~25~ethylmilbemycin and «25 ” 10 methylmilbemycin S5-oxime : : (mixture of two compounds in the ratio 2.3:1) (Compound of formula (Ia) wherein: RY = ethyl © or methyl, RB’ = 1,l-dimethyl-2-chloroethyl, n = 0).

Mass Spectrum (m/z): 689 (M%),

Nuclear Magnetic Resonance Spectrum (270 MHz,

CBC1,) d' ppm: 3.96 (1H, singlet, OH at the 7 posi- i tion); 4.67 (1H, singlet, H at the 6 position); 4.95 (1H, doublet, H at the 13 position, J = 10.6 Hz),

EXAMPIE 46 . 13-(1-Methylcyclopropylcarbonkloxy)=Seketom25me thy le nilbemycin S5~oxime (Compound of formula (Ia) wherein: R> = ethyl,

R’ = l-methyleyclopropyl, n = 0), / /

{ 26158 -

Mass Spectrum (m/z): 653 Me / Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl) § ppm: 3.96 (1H, singlet, OH at the 7 posi tion); 4.67 (1H, singlet, H at the 6 position); 4.95 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 7 , 13-(qyd-Dime thylbenzoyloxy-5-keto-25-ethylnilbemycin

Co S5-oxime (Compound of formula (Ia) wherein: rR! = ethyl ; 10 ® = oy {-dime thylbenzyl, n= 0)

Mass Spectrum (m/z): 717 ot). . Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC) J ppm: 3.96 (1H, singlet, OH at the 7 position); 4.65 (1H, singlet, H at the 6 position); 4.87 (1H, doublet, H at the 13 position, J = 10.3 Hz)»

EXAMPLE 48 13-0-Acetoxybenzoyloxy-5-keto-25-ethylmilbemycin Sa oxime Co (Compound of formula (Ia) wherein: rR} = ethyl,

R? = o-acetoxyphenyl, n = 0)

Mass Spectrum (m/z): 699 Mt ~34)0

Nuclear Magnetic Resonance Spectrum (270 MHz, cpe1,) d ppm: 3.8 (1H, broad singlet, OH at the 7 position); 4.68 (1H, sifiglet, H at the 6 position);

v . ! 26158 x ! ——y 5-18 (1H, doublet H at the 13 position, J = 10.6 Hz).

EXAMPLE ho 13-Methoxycarbonylace toxy-5-ke to-25~e thylmilbemycine

S5~oxime (Compound of formula (Ia) wherein: rt = ethyl,

R = me thoxycarbonylmethyl, n = 0),

Mass Spectrum (m/z): 671 m*), 653, 629,

Nuclear Magnetic Resonance Spectrum (270 MHz, ope) d pom: 3.96 (1H, singlet, OH at the 7mpOSinm tion); 5.02 (1H, doublet, H at the 13 position, J = 10,7

Hz),

EXAMPLE 50 13-t-Butoxycarbonylace toxy-5-ke to=25-ethylmilbemycin

S5-oxime (Compound of formula (Ia) wherein: RY = ethyl, i R = t-butoxycarbonylmethyl, n = 0),

Mass Spectrum (m/z): 713 (M*3, 695, 679.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d ppm: 3.96 (1H, singlet, OH at the 7 position); 5.00 (1H, doublet, H at the 13 position, J = 10.6 Hz),

EXAMPLE 51 13-(3~Fluoro=2,2-dimethylpropionyloxy)-~5nketo=25wothyle milbemycin S-oxime / (Compound of formula (Ia) wherein: RY = ethyl,

R? = 2-fluoro-l,l-dimethylethyl, n = 0).

Mass Spectrum (m/z): 658, 640, 538, 520.

Nuclear Magnetic Resonance Spectrum (270 MHz, ccl,) ppm: 4.67 (1H, singlet, H at the 6 position); 4.95 (1H, doublet, H at the 13 position, J = 10.3 Hzd.

EXAMPLE 52 13-p-(Trifluoromethyl)benzoyloxy~5-keto-25-ethylmilbe~ mycin S-oxime (Compound of formula (Ia) wherein: rR! = ethyly,

R = p=(trifluoromethyl)phenyl, n = 0),

Mass Spectrum (m/z): 743 (M'), 725, 709, 553.

Nuclear Bagnetic Resonance Spectrum (270 MHz,

CDC1,) d ppm: 4.69 (1H, singlet, H at the 6 position); 5,23 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 53 : 13-(3,3,3-Trifluoropropionyloxy)-5-keto-25~ethylmilbew mycin S-oxime (Compound of formula (Ia) wherein: rR! = ethyl,

R° = 2,2,2-trifluorocethyl, n = 0)s =

Mass Spectrum (m/z): 681 ty, 663, 647.

Nuclear Magnetic Resonance Spectrum (270~MHz,

CDC1,) d ppm: 4.67 (1H, singlet, H at the 6 position); 5,02 (1H, doublet, H at the 13 position, J = 10.6 Hz)

.

EXAMPLE 5b 13~p~Nitrobenzoyloxy~5-keto~-25~ethylmilbemycin S-oxime 1 4 (Compound of formula (Ia) wherein: R™ = ethyl,

R = p-nitrophenyl, n = 0)

Mass Spectrum (m/z): 720(M%), 702, 589, 553, 519.

Nuclear Magnetic Resonance Spectrum (270 MHz, : CDCL,) d ppm: 4.69 (1H, singlet, H at the 6 posi= -! tion); 5.23 (1H, doublet, H at the 13 position, J TM 10.9 Hz). i

EXAMPLE

\ . 13-p-Phenoxybenzoyloxy~5-keto~25~ethylmilbemycin 5« : oxime : (Compound of formula (Ia) whereins. -R* = ethyl

Rr = o-phenoxyphenyl, n = 0)o . .°

Mass Spectrum (m/z): 767 (mh), 733, 7073 5534 519.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl) d ppm: 4.68 (1H, singlet, H at the 6 posi- tion); 5.14 (1H, doublet, H at the 13 position, J = 10.3 Hz).

EXAMPLE 56 13-(2,6~-Dimethylbenzoyloxy)-5-ke to-25-ethylmilbemycin—~

S5-oxime (Compound of formula (Ia) wherein: rR! = ethyl,

Rr’ = 2,6-xylyl, n = 0), ’

Mass Spectrum (m/z); 703 (M*), 685, 669, 6i45, 553, 5360

Nuclear Magnetic Resonance Spectrum (270 MHz, cpC1,) J ppm: 4.68 (1H, singlet, H at the 6 position); 5,26 (1H, doublet, H at the 13 position, J = 10.3 Hz),

EXAMPLE 57 13-(2,4,6-Trimethylbenzoyloxy)-5-keto-25-ethylmilbemycin- 5-oxime (Compound of formula (Ia) wherein: rl = ethyl,

R = mesityl, n = 0).

Mass Spectrum (m/z): 717 (M%), 699, 683, 519,

Nuclear Magnetic Resonance Spectrum (270 MHz, cDC15) d ppm: 4.68 (1H, singlet, H at the 6 positions); 5.25 (1H, doublet, H at the 13 position, J = 10.7 Hz),

EXAMPLE 58 13-m-Phenoxybenzoyloxy-5-ke to-25-¢ thy lmilbemycin 5 oxime (Compound of formula (Ia) wherein: RY = ethyl,

R° « m~phenoxyphenyl, n = 0).

Mess Spectrum (m/z): 767 mt), 749, 733, 553, 5354 510.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d' ppm: 4.68 (1H, singlet, H at the 6 position); 5.18 (1H, doublet, H at the 13 position, J = 10.6 Hz),

EXAMPLE 59 13-(2,5,7,8~Tetrame thyl-6-me thoxy-2~-chromanylcarbonyl- oxy)=5-keto-25~e thylmilbemycin 5~oxime (Compound of formula (Ia) wherein: RY = ethyl, rR’ = 2154748-tetramethyl-6-methoxy-2~chromanyl, n = 0,

Mass Spectrum (m/z): 817 (M*), 799, 783, 589, ’ 571.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl,) of ppm: 4.65 - 4.85 (5H, multiplet).

EXAMPLE 60 13-(~Fluorenylcarbonyloxy)=5-keto-25-e thylmilbemycines5— osime (Compound of formula (Ia) wherein: rl = ethyl, /

» 26158 blo i =X

BR? = 9-fluorenyl, n = 0).

Mass Spectrum (n/z): 763(M*), 745.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC14) ppm: 4.67 (1H, singlet, H at the 6 position)y 4.80 (1H, doublet, H at the 13 position, J = 10.4 Hz).

EXAMPLE 61 13-(2,3-Dihydro-g-oxopyrido=/2,1-¢/~1,2, i~triazol-2~ yl-carbonyloxy)=-5-keto-25~ethylmilbemycin S-oxime (Compound of formula (Ia) wherein: rR! = ethyl, - R= 2,3-dihydro-3-oxopyrido=/2,1-c/~1,2,4~triazol-2~ yl, n = O)o

Mass Spectrum (m/z): 688 (M¥ 4k), 676, S571, 5534 5375 519.

Nuclear Magnetic Resonance Spectrum 270 MHz, cpe1,) d ppm: 4.70 (1H, singlet, H at the 6 position) 5.16 (1H, doubler, H at the 13 position, J = 1006 Hz)o

EXAMPLE 62 13-(9-Xanthenylcarbonyloxy)-5-keto=25~e thylmilbemycin= 5~0xime “ (Compound of formula (Ia) wherein: rR! = ethyl,

R = g-xanthenyl, n = 0)o

Mass Spectrum (m/z): 779 (M'), 761, 745, 701, 553, 535, 519.

Nuclear Magnetic Resonance Spectrum (270 MHz,

, 26158

CDC1,) d ppm: 4,64 (1H, singlet, H at the 6 posi. tion); 4.76 (1H, doublet, H at the 13 position, J = 10.3 Hz).

EXAMPLE 63 13-(3~Chloro-2~benzothenoyloxy)-5-keto-25-e thylmilbew mycin~5-oxime (Compound of formula (Ia) wherein: Rl = ethyl

R’ = 3-chloro-2-benzoythienyl, n= 0,

Mass Spectrum (m/z): 765 (M*), 749, 731, 553, , 10 535, 519.

Nuclear Magnetic Resonance Spectrum (270 MHz, cDC1,) J ppm: 4.69 (1H, singlet, H at the 6 position); 5.22 (1H, doublet, H at the 13 position, J = 10,6 Hz).

EXAMPLE 64 13-(2,6-Dichloroisonicotinoyloxy)~5-ke tow25-ethyl- milbemycin S-uoxime (Compound of fofmula (Ia) wherein: RY = ethyl,

R = 2y6~dichloro-b-pyridyl, n = 0), a

Mass Spectrum (m/z): 744(M*), 726, 710, 553, 535, 519,

Nuclear Magnetic Resonance Spectrum (270 MHz, cpel,) J ppm: 4.69 (1H, singlet, H at the 6 position); 5.21 (1H, doublet, H at the 13 position, J = 10.6 Hz). . /

EXAMPLE 65 13-(3-Methyl-1-o0za-3~cyclobutylcarbonyloxy)=S-keto= } 25~ethylmilbemycin S-oxime (Compound of formula (Ia) wherein: rR! = ethyl, rR’ = 3-me thyl-l-oxa-3-cyclobutyl, n = 0).

Mass Spectrum (mfg): 669(M*) 651, 635.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDG1,) § ppm: 4.67 (1H, singlet, Ii at the 6 position); 5,00 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 66 13-(2-Ethylthionicotinoyloxy)-5-keto-25-ethylmilbemycin~ 5-oxime ’ (Compound of formula (Ia) wherein: Rhu 1 = ethyl, rR’ = 2-ethylthio~3-pyridyl, n = 0). -

Mass Spectrum (m/z): 736(M%), 720, 702, 553, 535, 519.

Nuclear Magnetic Resonance Specttrum (270 MHz,

CDCl.) d ppm: 4,68 (1H, singlet, H at the 6 position); 5.22 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 67 13-( 3-Phenylpropionyloxy)~5-keto-25-ethylmilbemycin 5-o0xime : (Compound of formula (Ia) wherein: I. = ethyl,

R? = phenethyl, n = 0)

BAD ORIGINAL 9 ee .

Mass Spectrum (m/z): 703(M%), 685, 645, 553, 536, 519.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d ppm: 4.68 (1H, singlet, H at the 6 posi- tion); 4.96 (1H, doublet, H at the 13 position, J = 10.4 Hz).

EXAMPLE 68 13~Cyclohexylacetoxy~5~keto~25~ethylmilbemycin 5~ oxime : 1 (Compound of formula (Ia) wherein: R = ethyl, ® = cyclohexylmethyl, n = 0). : +

Mass Spectrum (m/z): 695 (M)), 677, 662, 519.

Nuclear Magnetic Resonance Spectrum (270 MHz, aN 15 cDe1,) d' ppm: 4.67 (1H,, singlet, H at the 6 position)}’ 4.95 (1 doublet, H at the 13 position, J = 10.6 Hz). \

EXAMPLE 69 13- { 2~/p-phenoxy) phenoxy/propionyloxy }-5-keto-25~ ethylmilbemycin S-oxime : (Compound of formula (Ia) wherein: 7 = ethyl,

R = 1-/Tp-phenoxy)phenoxy/ethyl, n = 0), . : a9 Q

Mass Spectrum (m/z): 811 MY), 793, 777, 603, 552, 519. .

Nuclear Magnetic Resonance Spectrum (270 MHz,

CCL) J ppm: 4.67 (1H, singlet, H at the 6 posi- tion); 4.96 (1, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 70 13-{2-/p-(5-trifluoromethyl-2-pyridyloxy) phenoxy/- propionyloxy} ~5-keto-25-ethylnilbemycin 5~oxime (Compound of formula (Ia) wherein: rR = ethyl,

R = 1-/5~(5-tri fluor ome thyl-2~pyridyloxy)phenoxy/- ethyl, n = 0).

Mass Spectrum (m/z): 880(M%), 537, 368, 327. ’ Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl) ppm: 4.67 (1H, dinglet, M at the 6 posi~ tion); 4.98 (1H, doublet, H at the 13 positiony J = 10.6 Hz). g

EXAMPLE 71 - 13-(2-p-Nitrophenylpropionyloxy)~5-keto-25-ethylmil- bemycin 5-oxime (Compound of formula (Ia) wherein rt = ethyl,

R = o-methyl-p-nitrobenzyl, n = 0).

Mass Spectrum (m/z): 748 (M*), 730, 714, 553, 519.

Nuclear Magnetic Resonance Spectrum (270 MHz;

CDCl) ppm: 4.66 (1H, singlet, H at the 6 posi- tion); 4.92 (0.5 H, doublet, H at the 13 position, .

J = 10.6 Hz); 4.93 (0.5 H, doublet, H at the 13 posi- tion, J = 10.6 Hz).

EXAMPLE 72 , 13-(2-o0~Fluorophenylpropionyloxy)~5-keto~25~ethylmil- bemycin 5-oxime (Compound of formula (Ia) wherein: r! = ethyl,

R = df-me thyl-o-fluorobenzyl, n= 0).

Mass Spectrum (m/z): 721 my, 703, 687,

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC) d' ppm: L,67 (1H, singlet, H at the 6 posi- tion); 4.95 (1H, doublet, fat the 13 position, J = 10.7 Hz)o a 26158

EXAMPLE 73 13-(d-Cyclohexylbenzylcarbonyloxy)-5-keto-25-ethyl- nilbemycin S5-oxime ' (Compound of formula (Ia) wherein: Rh = ethyly

R = o-cyclohexylbenzyl, n = 0)e

Mass Spectrum (m/z): 771 (u*), 755, 737, 553, 535, 519.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl) d ppm: 4.66 (1H, singlet, .H at the 6 position); : 10 4.90 (1H, doublet, H at the 13 position, J = 10.6 Hz). i :

EXAMPLE 74 13-(1-Phenylcyclopentylcarbonyloxy)~5~keto-25~ethyl~ milbemycin 5-oxime (Compound of formula (Ia) wherein: Rl = ethyl, rR = l~phenylcyclopentyl, n = 0)

Mass Spectrum (m/z): 743 mY), 725, 709, 553, ! 519, | Co

Nuclear Magnetic Resonance Spectrum (270 MHz, €DC15) d ppm: 4.65 (1H, singlet, H at the 6 position);

\ 26158 4 4.80 (1H, doublet, H at the 13 position, J = 10,3 Hz).

EXAMPLE 75 13-/2~ (Fhenylthio ) propionyloxy/~5-keto=25-e thy lm Tbemy-~ cin-5~oxime (Compound of formula (Ia) wherein: RY = ethyl,

R® = 1-(phenylthio)ethyl, n = 0),

Mass Spectrum (m/z): 735 mh), 17, 701, 553, 519,

Nuclear Magnetic Resonance Spectrum (270 Miz,

CDC, ) d pm: 4.67 (1, singlet, H at the 6 position); 4.94 (1H, doublet, H at the 13 position, J = 10.5 Hz).

EXAMPLE 76 13~(3-Methyl-2-phenylvaleryloxy )-5-keto-25-ethy ni Lbemyoin . 5-oxime (Compound of formula (Ia) wherein: RY = ethyl,

R = of-sec-butylbenzyl, n = 0),

Mess Spectrum (m/z): 745 (u'), 727, 11, 530, 515.

Nuclear Magnetic Resonance Spectrum (270 WHz,

DCL, ) pom: 4.66 (1H, singlet, H at the 6 position); 4.87 (0,5H, doublet, M at the 13 position, J = 10.6 Hz); 4.90 (0.5H, doublet, H at the 13 position, J = 10°6 Hz),

EXAMPLE 77 13-(1-Phenyleyclopropylearbonyloxy )=5-ktet0~25~ethyimilbe- mycin 5-oxime (Compound of formufa (Ia) wherein: RL w= ethyl,

RO = 1-phenylcyclopropyl, n = 0).

Mass Spectrum (m/z): 715 ah), 697, 681, 553, 535, 519,

Nuclear Magnetic Resonance Spectrum (270 MHz,

J 5 CDC, ) of ppm: 4.65 (1H, singlet, H at the 6 position); 4.87 (1H, doublet, H at the 13 pasition, J = 1056 Hz):

EXAMPLE 78 13-(2-0-Tolylpropionyloxy )-5~keto=25-ethylmi lbemycin 5 : oxime (Compound of formule (Ia) wherein: RY: = ethyl;

RO = ofmethyl-o-methylbenzyl, n = 0),

Mass Spectrum (m/z): 702 art), 684, 670, 538, 520,

Huclear Magnetic Resonance Spectrum (270 MHz,

Coe, ) d pm: 4.65 (1H, singlet, H at the 6 position); 4.90 (1H, doublet, H at the 13 position, J = 1036 Hz)®

EXAMPLE 79 : 13=/2~(8 )-Phenylpropionyloxy/~5-keto~25-ethylni lbemyein 5- oxime "(Compound of formula (Ia) wherein: RT = ethyl,

BR = (5)-ghmethylbenzyl, n = oy

Mass Spectrum (m/z): 703 ar) 685, 670, 519% :

Nuclear Magnetic Resonance Spectrum 270 Miz, CD01) ppm: 4.65 (1H, singlet, H at the 6 position); 4.89 (1H, doublet, H at the 13 position, J = 10.6 Hz)i - 12F -

EXAMPLE 80 13-/2~(R)~Preny1propionyloxy/-5-ire to-25-sthy Ini Themyoin 5-oxime (Compound of formula (Ia) wherein: RY = ethyl,

R® = (R)~o-methylbenzyl, n = 0).

Mass Spectrum (m/z): 703(nt), 685, 669, 519%

Nuclear Magnetic Resonance Spectrum (270 mz, . \ CDC) JS ppm: 4.66 (1H, singlet, Il at the 6 position); 4,90 (1H, doublet, H at the 13 position, J w 10)3 Hz)

EXAMFLE 8) 13-(2~p~Chloropheny1-2 -methylpropionylpxy )~5-keto~25- ethylmilbemycin 5-oxime (Compound of formula (Ia) vherein: R* w ethyl,

R° = oh f-dimethyl+p-chlorobenzyl, n = 0),

Mass Spectrum (m/z): 751 (u'), 717, 553, 535, 5195

Nuclear Magnetic Resonance Spectrum (270 MHz, : CDC) d ppm: 4.66 (1H, singlet, H at the 6 position); 4.88 (1H, doublet, H at the 13 position, J = 10:7 Hz)’

EXAMPLE 82 13~(2-p~Chlorophenylpropionyloxy )-5-keto-25~ethylni Ibemy~ : cin 5-oxime (Canpound of formula (Ia) wherein: RY = ethyl,

R? = domethyl-p~chlorobenzyl, n=o), /

Mass Spectrum (m/z): 737 hy, 719, 703, 5534 535, 519.

Nuclear Magnetic Resonance Spectrum (270 MHz, €DC1,) $ ppm: 4.66 (1H, singlet, H at the 6 posi- tion); 4.90 (1H, doublet, H at the 13 position, J = ‘ 10.6 Hz)»

EXAMPLE 83 13-/2-6~(Trifluoromethyl)phenylpropionyloxy/-5-keto~ 25~milbemycin S5~oxime : (Compound of formula (Ia) wherein: R* = ethyl,

R = of-methyl-o-trifluoromethylbenzyl, n = 0)e

Mass Spectrum (m/z): 771 MY), 753, 737. .

Nuclear Magnetic Resonance Spectrum (270 MHz, cDC1,) d ppm: 4.65 (1H, singlet, H at the 6 position); 4,88 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 84 ] 13-(2-0-Chlorophenylpropionyloxy)=-5-keta-25-ethyl~ : : milbemycin S5-oxime (Compound of formula (Ia) whéreins Rr = ethyl,

Rr = d-methyl-o-~chlorobenzyl, n= 0). . 20 Mass Spectrum (m/z): 737, 719, 703, 553.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC14) J ppm: 4.66 (1H, singlet, H at the 6 position);

4.92 (1H, doublet, H at the 13 position, J = 10,6 Hz):

EXAMPLE 85 13- (2-Methoxy-2-phenylacetoxy )~5-ket0-25~e thy Imi Ibemycin— 5~oxime (Compound of formula (Ia) wherein: RY: m= ethyl,

R? = omethoxybenzyl, n = 0),

Mass Spectrum (m/z): 719 a), 701, 685, 553.

Nuclear Magnetic Resonance Spectrum (270 MHz, eDC1, ) d pom: 4.65 (1H, singlet, H at the 6 positiom); 4:94 (0.6H, doublet, Hl at the 13 position, J = 103 Hz); 4.96 (0.4H, doublet, M at the 13 position, J = 10,3 Hz) } ’

EXAMPIE gg 13-(2, 2-Di pheny1propi onyloxy )-5-keto~25~ethylmi 1bemycin 5-oxime (Compound of formula (Ia) wherein: RY = ethyl,

RO = d-methylbenzyhyaryl, n = 0);

Mass Spectrum (m/z): 779 art), 161, 745%

Nuclear Negmetic Resonance Spectrum (270 MHz,

CDe1,) & ppm: 4.65 (1H, singlet, H at the 6 position); 4.98 (1H, doublet, H at the 13 position, J = 10,6 Hz)’

EXMIPIE g7 13-(2-Methy1~2-phenylbutyryloxy )-5-keto-25-ethylni 1bemycin 5-oxime (Compound of forfmila (Ia) wherein: R* = ethyl,

26 1 5 8 4 rR = dre thyl-o-mothylbenzyl, n = 0). -

Mass Spectrum (m/z): 731 wh, 713, 589, 553, 535, 519.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCL,) d ppm: 4.65 (1H, singlet, H at the 6 position); 4,88 (0.5 H, doublet, H at the 13 positions J = 10.6

Hz) 4.90 (0.5 H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 88 13-(2-p-Fluorophenyl-2-methylpropionyloxy)~5-keto-25~

ETHYLmilbemycin S5-oxime (Compound of formula (Ia) wherein: rt = ethyl,

R = dsd-dimethyl-p-fluorobenzyl, n= 0),

Mass Spectrum (m/z): 737(M%), 717, 701, 553, 519.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC) J ppm: 4.65 (1H, singlet, H at the 6 posi tion}; 4.87 (1H, doublet, H at the 13 positiony J = 10.6 Hz).

EXAMPLE 89 1 5-/Z-Hethyl-2-(p-chlorophenoxy) propionylaxy/ 5-ke to- 25-ethylmilbemycin S5-oxime (Compound of formula (1a) wherein: r* = ethyl, : rR = l-methyl-l-(p-chlorophenoxy)ethyl, n = 0).

Mass Spectrum (m/z): 767 mY), 733%, 519,

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl) d ppm: 4.66 ‘(n, singlet, H at the 6 position); 5.01 (1H, doublet, H at the 13 position, J = 10.6 Hz).

- EXAMPLE 90 13-Diphenylacetoxy-5-keto~25~ethylmilbemycin 5-oxime (Compound of formula (1a) wherein: RY = ethyl,

R° a benzhydryl, n = 0),

Mess Spectrum (m/z: 765 at), 747, 31d

Nuclear Magnetic Resonnnce Spectrum (270 MHz, : oDC1, ) J pm: 4.66 (1H, singlet, H at the 6 position)g 4,99 (1H, doublet, H at the 13 position, J = 10)6 Hz):

EXAMPLE al 13~(2-Phenylbutyryloxy )-5-keto-25-ethylmilbemycin 5~oxime (Compound of formula (Ia) wherein: R: = ethyl,

R = drethylbenzyl, n = 0),

Mass Spectrum (m/z): 717 wh), 699, 683, 553, 536, 519,

Nuclear Magnetic Resonance Spectrum (270 MHz, \ CDC1;) J pom: 4.66 (1H, singlet, H at the 6 position); 4490 (0.2 H, doublet, H at the 13 position, J = 1006 Hz); 4091 (0.8H, doublet, H at the 13 position, J = 10%6 Iz)?

EXMELE go 13/2 (2-Pyridon-1-y1 Jpropionyloxy/-5-keto~25-ethylmi1- bemycin 5-oxime (Compound of formula (Ia) wherein: RY = ethyl,’ :

R® = 1y(2-pyridon-1-y1 Jethyl, n = 0)%

Mass Spectrum (m/z): 720 ait), 702, 553, 520.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC, ) d ppm: 4.67 (1H, singlet, H at the 6 position); 4.95 (0.5 H, doublet, H at the 13 position, J = 10.5 Hz); 4.97 (0,5 H, doublet, H at the 13 position, J = 1005 Hz). ; EXAMPLE 93 13-(2, 6-Difluorobenzoyloxy }-5-keto-23-hydroxy=25=(1,3~ dimethyl-1-butenyl Jnilbemycin S~-oxime (Compound of formula (Ia) wherein: rt = 1,3~dimethyl~ 1-butenyl, R’ = 2,6-difluorophenyl, X = ~Ol, n = 0):

Mass Spectrum (m/z): 780 (a -1), 762, 746, TA4,

Nuclear Magnetic Resonance spectrum (270 MHz,

CDC1,) d ppm: 4.67 (1H, singlet, II at the 6 position); 5.21 (1H, doublet, H at the 13 position, J = 10.5 Hz).

EXAMPLE 94 13-(2-Phenylpropionyloxy )-5-keto=23-hydroxy=25-(1,3~ dimethyl-l-butenyl Jmilbemycin 5-oxime (Compound of formula (Ia) wherein: Rl = 1, 3=di=- methyl-1-butenyl, R° = gfmethylbenzyl, X = ~Of, n = 0)7

Mass Spectrum (m/z): 773 (%) 755, 739, 331%

Nuclear Magnetic Resonance Spectrum (270 Miz, 00C1,) d' ppm: 4.65 (1H, singlet, H at the 6 position);

4.89 (1H, doublet, H at the 13 position, J = 10,5 Hz).

Examples 95 to 97 illustrate the preparation of compounds of formula (Ib) from starting materials of for=- mula (III), by the reaction of Step B in the above re~ - action scheme,

EXAMPLE 95 15-Benzyloxycarbonyloxy~5-keto-25~ethylmilbemyein and ~25 methylmilbemycin 5-O-carboxymethyloxime (mixture of two compounds in the ratio 2,5:1) (Compound of formula (Ib) wherein: R* = ethyl or methyl, BR’ = benzyl, R3 = carboxymethyl, n = 1)7

By following the procedure of Example 1 and re=- acting 180 mg, of a mixture of 13-benzyloxycarbonyloxy- 5-keto~25-ethylmilbemycin and ~25-methylmilbemyein (in the ratio of 2,3:1) with 340 mg of O~-cerboxymethylhy- droxylamine hydrochloride, 198 mg of the target product : were obtained (yield: 994).

Mass Spectrum (m/z): 671 ot - 92), 627.

Nuclear Magnetic Resonance Spectrum (270 MHz, ene, ) d pm: 3.70 (1H, singlet, OH at the 7 position); 4.70 (1H, singlet, H at the 6 position); 4,72 (1H, doublet,

H at the 13 position, J = 10.6 Hz). : The campounds of Examples 96 and 97 were prepared from the corresponding hydroxylamine hydrochlorides, ug=- /

{ : db 26158 ing the procedure of Example 95.

EXAMPLE 96 \ 13~p~Trifluoromethylbenzoyloxy~-5-keto=25~ethylmilbemycin and -25-methylmilbemyecin 5-0-benzyloxime (mixture of two compounds in the ratio 3:1 ) (compound of forymla (Ib) wherein: rR = ethyl or methyl, R5 = p~trifluoromethylphenyl, BR - benzyl, n= 0),

Mass Spectrum (m/z): 833 mh):

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC) d pm: 3.89 (1H, singlet, OH at the 7 position) 4.61 (1H, singlet, H at the 6 position); 5.22 (1H, doublet,

H at the 13 position, J = 10,6 Hz).

EXAMPLE 97 13-p~Trifluoronethylbenzoyloxy-5-keto=25~ethy ni Ibemyein and =25-methylmilbemyecin 5~O-methyloxime (mixture of two compounds in the ratio 2.6:1) (Compound of formula (Ib) wherein: RY = ethyl or methyl, R’ = p-trifluoromethylphenyl, R = methyl, n = 0),

Mass Spectrum (m/z): 1758 a), 743,

Nucleer Magnetic Resonance Spectrum (270 MHz, €DC1,) d' pm: 3.94 (1H, singlet, OH at the 7 position); 4.57 (1H, singlet, H at the 6 Position); 5.22 (1H, doublet

H at the 13 position, J = 10.6 Hz),

Examples 98 to 128 illustrate the preparation of compounds of formula (Ib) from starting materials of formula (Ia), by the reaction of Step C in Rew action Scheme No. 1,

EXAMPLE 98 13-Ethoxycerbonyloxy~5-keto=25~e thylmilbemycin 5=0m pivaloyloxime : (Compound of formula (Ib) wherein: rR! = ethyl,

R” = ethyl, R> = pivaloyl, n = 1).

To a solution of 129 mg. of 13-ethoxycarbonylw oxy-~5-ke to=25~ethylmilbemycin 5 oxime in 5 ml. of ben- zene were added 22 ul of pivaloyl chloride and 31 ul of triethylamine, under ice-cooling, and the resulting mixture was stirred at room temperature for 4 hours.

After completion of the reaction, the mixture was poured into water and extracted with ethyl acetate, . The extracts were washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography over silica gel, giving 113 mg. of the target product (yield: 77.4%).

Mass Spectrum (m/z): 727 (M%),

i Nuclesr Magnetic Resonance Spectrum (270 MHz, cpe1,) d ppmt 3.98 (1H, singlet, OH at the 7 posi- tion); 4.57 (1H, singlet, H at the 6 position); 4.75 (1H, doublet, H at the 13 position, J = 10.6 Hz),

The compounds of Examples 99 to 127 were pre pared from the corresponding acid halides by the pro- cedure of Example 98.

EXAMPLE 99 13-p~Fluorophenoxyacetaxy-5-keto~25-ethylmilbemycin

S5=-0-pivalo¥loxime (Compound of formula (Ib))wherein: RY = ethyl,

R = p~fluorophenoxymethyl, R’ = pivaloyly, n = 0),

Mass Spectrum (m/z): 745 (M* -62), 689.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl) d ppm: 3.99 (1H, singlet, OH at the 7 position); 4.57 (1H, singlet, H at the 6 positdon); 5.05 (1H, doublet, H at the 13 position, J = 10.3 Hz)e

EXAMPLE 100 13~p-t-Butylbenzoyloxy-5~ke to~25-ethylmilbemycin 5-0 (N,N-dimethylcarbamoyl) oxime (Compound of formula (Ib) wherein: rR! = ethyl,

R? = p-t-butylphenyl, R> = N,N-dimethylcarbamoyl, n= 0).

Mass Spectrum (m/z): 697(M* ~106).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl) ppm: 3.99 (1H, singlet, OH at the 7 posi- tion); 4.58 (1H, singlet, H at the 6 position); 5.20 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 101 " 13-o~Trifluoromethylbenzoyloxy~5-keto=25~ethylmilbe~ mycin 5-0m(M,N~dimethylcarbamoyl) oxime (Compound of formula (Ib) wherein: R' = ethyl,

R® = o-trifluoromethylphenyl, Rr’ = N,N~dimethylcar- bamoyl, n = 6),

Mgss Spectrum (m/z) 753(M* -61), 709,

Nuclear Magnetic Resonance Spectrum (270 MHz, €DC15) ppm: 3.99 (1H, singlet, OH at the 7 posiw tion); 4.58 (1H, singlet, H at the 6 position); 5.24 (1H, doublet, H at the 13 position, J # 10.6 Hz),

EXAMPLE 102 13-(2-Furoyloxy)-5-keto-25-e thylmilbemycin SmO (N,N-dimethylcarbamoyl)oxime (Compound of formula (Ib) wherein: RY = ethyl,

R’ = 2-furyl, R> = N,N-dimethylcarbamoyl, n = 0).

Mass Spectrum (m/z): 675 (M* -61), 649, 631.

Nuclear Magnetic Resonance Spectrum (270 MHz,

coe1,) 4 ppm: 3.96 (1H, singlet, OH at the 7 posiw tion); 4.58 (1H, singlet, H at the 6 position); 5.17 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPIE 103 13-Benzyloxycarbonyloxy-5-~keto~25~ethylmilbemycin 5~0~ (N,N-dimethylcarbamoyl)oxime (Compound of formula (Ib) wherein: rt = ethyl,

R = benzyl, R’ = NyN-dimethylcarbamoyl, n = 1).

Mase Spectrum (m/z): 688 (M*) -88).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl) d' ppm: 3.96 (1H, singlet, OH at the 7 position); 4,56 (1H, singlet, H at the 6 position); 4.76 (1H, doublet, H at the 13 position, J = 10.6 Hz). : EXAMPLE 104 " 13-Methoxycarbonyloxy-5-keto-25-ethylmilbemycin 5=0m (N,N-dime thylcarbamoyl)oxime (Compound of formula (Ib) whereint R! = ethyl,

R = methyl, R? = N,N-dimethylcarbamoyl, n = 1).

Mass Spectrum (m/z): 700 mh). Ls : 20 Nuclear Magnetic Resonance Spectrum (270 MHz, col, ) ppm: 3.95 (1H, singlet, OH at the 7 position); 4.57 (1H, singlet, H at the 6 position); 4.72 (1H, doublet, H at the 13 position, J = 11 Hz),

EXAMPLE 105 13-(2,2,2-Trichloroethoxycarbonyloxy)-5-keto-25=ethyl- milbemycin 5-O=(N4N~dimethylcarbamoyl)oxime (Compound of formula (Ib) whereint Rl = ethyl,

R° = 2,242=trichloroethyl, R = NyN-dimethylcarbamoyl, n=1,

Mass Spectrum (m/z): 815(m*).

Nuclear Magnetic Resonance Spectrum (270 MHz, : cDC1,) J ppm: 3.97 (1H, singlet, OH at the 7 position); 4,59 (1H, singlet, H at the 6 position); 4.81 (1H, doublet, H at the 13 position, J = 10,3 Hz)o . EXAMPLE 106 13%-(2,2-Dimethyl=1,3~dioxolanylme thoxycarbonyloxy)=5~ keto=25-e thy lmilbemycin and 25~-methylmilbemycin 5=0~ : (N,N~dimethylcarbamoyl)oxime (mixture of two compounds in the ratio 2:1) (Compound of formula (Ib) wherein: rt = ethyl : or methyl, Rr = 2,2~dimethyl~1,3~dioxoclanylmethyl,

BR? = N,N-dimethylcarbamoyl, n = 1), Cn

Mass Spectrum (m/z): 734 (mM? Z66)«

Nucleer Magnetic Resonance Spectrum (270 MHz,

CDC1,) J ppm: 3.96 (1H, singlet, OH at the 7 position); . 4,57 (1H, singlet, H at the 6 position); 4.74 (1H, doublet, H at the 13 position, J = 12.8 Hz), oo /

EXAMPLE 10 13~(3-Chloropropionyloxy)-5-keto-25~ethylmilbemycin 5-0-tosyloxime (Compound of formula (Ib) wherein: rt = ethyl, rR = 2-chloroethyl, rR = tosyl, n = 0),

Mass Spectrum (m/z): 64b (m* -155). f

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d'ppm: 3.84 (1H, singlet, OH at the 7 position); 4,51 (1H, singlet, H at the 6 position); 5.00 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 108 13~{(3~Chloropropionyloxy)~-5~keto~25~methylmilbemycin- .5-0-tosyloxime (Compound of formula (Ib) wherein: rt = methyl, 1 ® ’ 5 = 2-chloroethyl, R” = tosyl, n = 0).

Mass Spectrum (m/z): 630(M* - 155).

Nuclear Magnetic Resonance Spectrum (270 MHz, cDC1,) d ppm: 3.84 (1H, singlet, OH at the 7 position); 4,51 (1H, singlet, H at the 6 position); 5.00 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 109 13~(2-Methoxyethoxycarbonyloxy)-5~keto~25~ethylmil~ bemycin 5-0=(N,N~-dimethylcarbamoyl)oxime . . 1 ' (Compound of forgula (Ib) wherein: R™ = ethyl,

R® = 2-methoxyethyl, R> = N,N-dimethylecarbamoyl, n=1).

Mass Spectrum (m/z): 744 (M*), 640.

Nuclear Magnetic Resonance Spectrum (270 MHz,

COCl,) d ppm: 3.96 (IH, singlet, OH at the 7 position); 4.57 (1H, singlet, H at the 6 position); 4.75 (1H, doublet, H at the 13 position, J = 10.6 Hzle.

EXAMPLE 110 13-/2-(2,2-Dichlorovinyl)-3,3-dimethylcyclopropylcar- bonyloxy-5-keto-25-ethylmilbemycin and -25- methylmilbemycin 5-0=-propionyloxime (mixture of two compounds in the ratio 2.6:1). (Compound of formula (Ib) wherein: rl = ethyl or methyl, R> = 2-(2,2-dichlorovinyl)-3, 3-dimethylcy- clopropyl, rR? = propionyl, n = 0).

Mass Spectrum (m/z): 745 (M" -72). : Nuclear Magnetic Resonance Spectrum (270 MHz,

COC14). of ppm: 3.96 (1H, singlet, OH at the 7 position); 4.60 (1H, singlet, H at the 6 position}; 5.43. (1H,, doublet, H at the 13 position, J = 10.6 Hz)s

EXAMPLE 111 13-Trichloroacetoxy-5-keto-25-gthylmilbemycin 5-0-propionyloxime (Compound of formula (Ib) wherein: RY = ethyl,

R® = trichloromethyl, RS = propionyl, n = 0).

Mags Spectrum (m/z): 771(M%).

Nuclear Magnetic Resonance Spectrum (270 MHz,

COC1,).d ppm: 3.96 (1H, singlet, OH at the 7 position); 4.61 (1H, singlet, H at the 6 position); 4.99 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 112 13-Ethoxycarbonyloxy-5-keto-25-gthylmilbemycin and -25- mathylmilbemycin 5-0-acetyloxima (mixture of two compounds in the ratio 2.8:1) (Compound of formula (Ib) wherein: RY = ethyl or methyl, R® = ethyl, rR? = acetyl, n = 1).

Mags Spectrum (m/z): 685(M%).

Nuclear Magnetic Resonance Spectrum (270 MHz,

COC14) & ppm: 3.96 (1H, singlet, OH at the 7 posie tion); 4.60 (1H, singlet, H at the 6 position); 4.75 . (1H, doublet, H at the 13 position, J = 11 Hz).

EXAMPLE 113 13-Ethoxycarbonyloxy-5-keto~25«~ethylmilbemyclin and « © 20 25-methylmilbemycin 5-0-palmitoyloxime (mixture of two compounds in the ratio 3.3:1) (Compound of formula (Ib) wherein: rl = ethyl or methyl, rR? = ethyl, RO = palmitoyl, n = 1).

Mass Spectrum (m/z): 610(M* =271).

Nuclear Magnetic Resonance Spectrum (270 MHz,

COC1,) J ppm: 3.95 (1H, singlet, OH at the 7 posi- tion); 4.59 (1H, singlet, H at the 6 position); 4.70 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 114 13-(2,2,2=Trichloroethoxycarbonyloxy)=5~keto=-25=-ethyle milbemycin S-0-propionyloxime (Compound of formula (Ib) wherein: RY = Bthyl,

R® = 2,2,2-trichloroethyl, R> = propionyl, N = 1).

Mass Spectrum (m/z): 801 (MY).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) J ppm: 3.96 (1H, singlet, OH at the 7 posi- tion); 4.60 (lH, singlet, H at the 6 position); 4.81 (1H, doublet, H at the 13 position, J = 10.3 Hz).

EXAMPLE 115 13-(2,2,2-Trichloroethoxyecarbonyloxy)-5-kato-25-ethyl- milbemycin 5-0-(N,N-dimethylcarbamoyl)oxime (Compound of formula (Ib) wherein: RY = ethyl,

R> = 2,2,2~trichloroethyl, R> = N,N-dimethylcarbamoyl, n=1).

Mass Spectrum (m/z): 815 Mh).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDG14) 4 ppm: 3.93 (1H, singlet, UH at the 7 position); 4.59 (1H, singlet, H at the 6 position); 4.81 (1H,

. ~ doublet, H at the 13 position, J = 10.8 Hz). : EXAMPLE 116 13-(2,2,2-Trichloroathoxycarbonyloxy )=5-kato-25=-ethyl- milbemycin 5-0~acetyloxime (Compound of formula (Ib) wherein: RY = ethyl, rR? = 2,2,2-trichloroethyl, r> = acetyl, n = 1).

Mass Spectrum (m/z): 787(MY).

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC15) J ppmz 3.96 (1H, singlet, UH at the 7 position); 4.60 (1H, singlet, H at the 6 position); 4.82 (1H, doublet,

H at the 13 position, J = 10.7 Hz).

EXAMPLE 117 13-p-Bromobenzoyloxy-5-keto-25-ethylmilbemycin 5-0=- cctanoyloxime (Compound of formula (Ib) wherein: RY = ethyl, rR? = p-bromophenyl, R> = octanoyl, n = 0).

Mass Spectrum (m/z): 719(M' -16l. with Br 2).

Nuclear Magnetic Resonance Spectrum (270 MHz,

COC14) J ppm: 3.6 (1H, broad singlet, UGH at the 7 position); 4.61 (1H, singlet, H at the 6 position); 5.19 (1H, doublet, H at the 13 position, J = 10.4 Hz). 7

EXAMPLE 118 13-Fivaloyl-5-keto-26-ethylmilbemycin 5-0-diethoxy- thiophosphoryloxime (Compound of formula (Ib) wherein: RY = ethyl, . 5 rR? = t-butyl, RO = diethoxythiophosphoryl, n = 0).

Mass Spectrum (m/z): 649 (MY -158), 621.

Nuclear Magnetic Resonance Spectrum (270 MHz,

GDC1,) § ppm: 3.85 (1H, singlet, UH at the 7 position); 4,70 (1H, singlet, H at the 6 position); 4.91 (1H, doublet, H at the 13 position, J = 10.6 Hz),

EXAMPLE 119 13-p-Trifluoromethylbenzoyloxy-5-keto-25-ethylmilbe- mycin 5-0-pentaacetylgluconyloxime (Compound of formula (Ib) wherein: rY = ethyl

R® = g-trifluoromethylphenyl, R> = pentaacetylgluco- nyl, n= 0).

Mass Spectrum (m/z): 727(MY ~uon).

Nuclear Bagnetic Resonance Spectrum 270 (MHz,

CoC1,) J ppm: 3.93 (1H, singlet, UH at the 7 position), 4.54 (1H, singlet, H at the 6 position); 5.42 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 120 13-/2-(2,2-Dichlorovinyl)-3,3-dimethylcyclopropylcar- bonyloxy/-5-kato-25-ethylmilbemycin and -25-methyl- milbemycin 5-0-(N,N-dimethylcarbamoyl)oxime (mixture of two compounds in the ratio 2.6:1) (Compound of formula (Ib) wherein: rt = ethyl or methyl, R° = 2-(2,2~dichlorovinyl)-3,3-dimathylcy- clopropyl, RS = N,N-dimethylcarbamoyl, n = 0).

Nuclear Magnetic Resonance Spectrum (270 MHz,

COC1,) J ppm: 2.99 (BH, singlet, N(CH;),); 3.98 (1H, singlet, OH at the 7 position); 4.57 (1H, singlet, H at the 6 position); 4.72 (2H, singlet, CH, at the 27 position); 4.96 (0.5H, doublet, H at the 13 position,

J = 10.3 Hz); 5.00 (0.5 H, doublet, H at the 13 posi tion, J = 10.3 Hz).

EXAMPLE 121 13-Ipdoacetoxy-5-keto-25-athylmilbemycin and -25= methylmilbemycin 5-0-propionyloxime (mixture of two compounds in the ratio 2.3:1) (Compound of formula (Ib) wherein: RY = ethyl or methyl, R® = iodomethyl, R> = propionyl, n = 0).

Mass Spectrum (m/z): 795 (M%), 781, 703.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC15) d ppm: 3.68 (4H, singlet, OH at the 7 posi- tion); 4.60 (1H, singlet, H at the 6 position); 4.93 (0.5H, doublet, H at the 13 position, J = 10.5 Hz); 5.01 (0.5H, doublet, H at the 13 position, J = 10.5 Hz).

EXAMPLE 122 13-Hcetoxyacetoxy-5-keto-25-gthylmilbemycin and -25-~ mgthylmilbemycin 5-0-propionyloxime (mixture of two compounds in the ratio 2.3:1) (Compound of formula (Ib) wherein: Rl = ethyl or methyl, rR? = acetoxymethyl, rR> = propilonyl, n = 0).

Mass Spectrum (m/z): 727 Mh, 637.

Nuclear Magnetic Resonance Spectrum (270 MHz,

COC) d' ppm: 3.94 (1H, singlet, OH at the 7 position); 5.03 (1H, doublet, H at the 13 position, J = 10.3 Hz).

EXAMPLE 123 : 13-Propilonyloxyacetoxy-5-keto-25-ethylmilbemycin and =-25-methylimilbemycin 5-0-propionyloxime (mixture of two compounds in the ratio 2.3:1) (Compound of formula (Ib) wherein: rl = gthyl or methyl, R° = propionyloxymethyl, rR = propionyl, n= 0)

Mass Spectrum (m/z): 741 wh), 703.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CoGl;) & ppm = 3.95 (1H, singlet, OH at the 7 posi-

tion); 5.02 (1H, doublet, H at the 13 position, J = 10.6 Hz),

EXAMPLE 124 } 13-Pivaloyloxy-5-keto~25~ethylmilbemycin 5+~0w= pentaacetylgluconyloxime (Compound of formula (Ib) wherein: rt = ethyl,

R = t-butyl, R= pentaacetylgluconyl, n = 0). | :

Mass Spectrum (m/z): 1044(M* 1); 943, 941, 655, 639, 637.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d ppm: 4.53 (1H, singlet, H at the 6 position); 4,83 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 225 13-(2-Phenylpropionyloxy)-5-keto-25-ethylmilbemycin 5=0~pivaloyloxime (Compound of formula (Ib) wherein: R= ethyl,

R = ¢rmethylbenzyl, rR = pivaloyl, n = 0).

Mass Spectrum (m/z): 801(M*) 4 536, 279

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) d ppm: 4.55 (1H, singlet, H at the 6 position), 4.88 (1H, doublet, H at the 13 position, J = 10.5 Hz).

EXAMPLE 126 13-(2,6-Di fluorobenzoyloxy)-S-ke tom25-ethylmilbemycin 5-0-pivaloyloxime (Compound of formula (Ib) wherein: rR ethyl,

R = 2,6~difluorophenyl, R’ = pivaloyl, n = 0).

Mass Spectrum (m/z):, 694, 676, 535. :

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDCl) d' ppm: 4.58 (1H, singlet, H at the 6 posi~ tion); 5.22 (1H, doublet, H at the 13 position, J = 10.5 Hz).

EXAMPLE 127 13-(2~Furoyloxy)-5-keto~25~ethylmilbemycin 5-O=penta- acetyloluconyloxime (Compound of formula (Ib) whereins gL = ethyl,

R = 2-furyl, R = pentaacetylgluconyl, n = 0).

Mass Spectrum (m/z): 648 (vt -405), 646, 631, 535, 519.

Nuclear Magnetic Resonance Spectrum (270 MHz,

CDC1,) 4 ppm: 4.54 (1H, singlet, H at the 6 position); 5.18 (1H, doublet, H at the 13 position, J = 10.6 Hz). 13-pivaloyloxy-5-keto-25-ethylnilbemycin’ 5-O-f~methyln carbamoyl)oxime (Compound of formula (Ib) wherein: gt = ethyl,

R = t-butyl, R = N-methylcarbamoyl, n = 0).

To a solution of 131 mg. of 13~pivaloyloxy-=5- keto~25~ethylmilbemycin 5-oxime in 5 ml. of tetrahys= a,

drofuran was added 1 ml. of methylisocyanate and the mixture was allowed to stand for 8 hours. After completion of the reaction, the solvent was distilled off and the residue subjected to column chromatogras phy over silica gel, giving 118 mg. of the target pro=- duct (yield: 83.1%).

Mass Spectrum (m/z): 655(M* ~57), 637, 553.

Nuclear Magnetic Resonance Spectrum (270 Miz, . CDCl) J ppm: 3.90 (1H, singlet, OH at the 7 position); 4,67 (1H, singlet, H at the 6 position); 4.91 (1H, dow- blet, H at the 13 position, J = 10.6 Hz).

Examples 129 to 157 illustrate the preparation of compounds of formula (IIb) from starting materials of formula (IIa), by the reaction of Step B in Rew action Scheme No. 2 above,

EXAMPLE 129 ’ 13-(2-Methyl-2-phenylpropionyloxy)-25-ethylmilbemycin (Compound of formula (IIb) wherein: Rl = ethyl, 7 = dyofdimethylbenzyl, Y = -OH). . " 3.5 mge of sodium borohydride vere added, under jce-cooling, to a solution of 123 ng. of 13~(2-methyl~ ’ 2~phenylpropionyloxy)-5S-keto-25-ethylmilbemycin in 5 ml. of methanol, and then the mixture was stirred . at room temperature for 30 minutes. At the end of

~~ 26158 this 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 mag- nesium sulfate and concentrated by evaporation. The residue was purified by column chromatography through silica gel to give 85 mg (yield: 69%) of the title compound.

Mass Spectrum (M/z): 704(K%), 686, 646, 576, 540, 522.

Nuclear Magnetic Resonance Spectrum (cool) J ppm: 3.94 (1H, doublet, H at the 6 position, J = 6.6

Hz)3 4,07 (1H, singlet, OH at the 7 position) 4.28 (1H, doublet of doublets, H at the 5 position, J = 6,6, 6.6 Hz); 4.65 (2H, multiplet, H at the 27 posi tion); 4.86 (1H, doublet, H at the 13 position, J = 10.6 Hz); 7.28 (5H, multiplet). : | By following the procedure of Example 129, the compounds of Examples 130 to 157 were prepared; have ing the characteristics shown,

EXAMPLE 130 - 13-(2-Phenylpropionyloxy)=-25~é thylmilbemycin (Compound of formula (IIb) wherein: Rl = ethyl,

Z = of-methylbenzyl, Y = ~OH) »

Mass Spectrum (m/z): 690(M"), 632, 562.

Nuclear Magnetic Resonance Spectrum (cDC1,)

J ppm: 3.947 and 3.952 (1H, doublet, H at the 6 position, J = 6.2 Hz); 4.05 and 4.08 (1H, singlet,

OH at the 7 position); 4.89 (1H, singlet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 131 13~(2-Phenylbutyryloxy)-25~ethylmilbemyecin (Compound of formula (IIb) wherein: R= ethyl,

Z = f-ethylbenzyl, Y = ~OH)o. }

Mass Spectrum (m/z); 7ol(mhy, 686.

Nuclear Magnetic Resonance spectrum (cpc1,) & ppm: 3.95 (1H, doublet, H at the 6 position, J = 6.2

Hz); 4.05 and 4.08 (1H, singlet, OH at the 7 position); 4.89 and 4.90 (1H, doublet, H at the 13 position, J = 10.6 Hz).

B

. EXAMPLE 132 13-(3-Methyl-2-phenylvaleryloxy)-25~ethylmilbemycin (Compound of formula (IIb) wherein: rR = ethyl,

Z = d-sec-butylbenzyl, Y = ~0H)o -

Mass Spectrum (m/z): 732(M%), 71k, 604, 540, 522, 504.

Nuclear Magnetic Resonance Spectrum (CDC) Jd ppm: 3.95 (1H, doublet, H are the 6 position, J = 6.1 Hz); 4,09 (1H, multiplet, OH at the 7 position), 4.86 and 4.89

~ 2615¢ oo (1H, doublet, H at the 13 position, J - 10.5 Hz). :

EXAMPLE 133 13-Benzhydrylcarbonyloxy-25~ethylmilbemycin (Compound of formula (IIb) wherein: RY = ethyl,

Z = benzhydryl, Y = ~OH). :

Mass Spectrum (m/z): 752 (MY), 7344 7164

Nuclear Magnetic Resonance Spectrum (cDCl,) of ppm: 3.95 (1H, doublet, H at the 6 position, J = 6.1 fz); 4.07 (1H, singlet, OH at the 7 position); 4.98 (1H, doublet, H at the 13 position, J = 9.2 Hz)e . EXAMPLE 134 13-(2~-Methyl~2-phenylbutyryloxy)~-25~ethylmilbemycin ~ (Compound of formula (IIb) wherein: rt = ethyl

Z = drethyl-cf-methylbenzyl, ¥ = -OH)o

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

Nuclear Magnetic Resonance Spectrum (cooly) of : : ppm: 3.9% (1H, doublet, H at the 6 position, J = 6.2

Hz); 4.08 (1H, broad singlet, OH at the 7 position); 4.87 and 4,90 (1H, doublet, H at the 13 position, J = oo 10.6 Hz). RE oo , EXAMPLE 135 =~. 13-(2,2~Di phenyl propionyloxy)=25-e thylmilbemycin (Compound of formula (IIb) wherein: rt = ethyl,

Co 2 . frmethylbenshydryl, = ~OH). oo . | - 150 w ‘

Mass Spectrum (m/z): 766 hy, 748, 730.

Nuclear Magnetic Resonance Spectrum (cDC15)

J ppm: 4.28 (1H, doublet, H at the 5 position, J = 5.9 Hz); 4.61 (1H, doublet, H at the 27 position, J = 15.2 Hz); 4.68 (1H, doublet, H at the 27 position?

J = 15.2 Hz); 4.97 (1H, doublet, H at the 13 position, : J = 10.6 Hz); 5.25 —- 5.48 (4H, multiplet, H at the 3, 11, 15 and 19 position); 5.70-5.82 (2H, multiplet, H at the 9 and 10 position). | EXAMPLE 136 13-(2-0-Chlorophenylpropionyloxy)-25-ethylmilbemycin (Compound of formula (IIb) wherein: rt = ethyl,

Z = d-methyl-o-chlorobenzyl, Y = -OH).

Mass Spectrum (m/z): 728(u%), 706. ‘

Nuclear Magnetic Resonance Spectrum (cpel;) : d ppm: 3.95 (1H, doublet, H at the 6 position, J = . 6.2 Hz); 4.08(1H, singlet, OH at the 7 position); 4,92 ‘and 4.9% (1H, doublet, H at the 13 position, J = 10.3

Hz). oo 20 EXAMPLE 137 13~/Z-0~(Trifluoromethyl) phenylpropionyloxy/~25-ethyl= : nilbemycin (Compound of formula (IIb) wherein: rR =ethyl,

Z = of methyl-o-(trifluoromethyl)benzyl, Y = ~OH)e

Mass Spectrum (m/z): 758(Mh), 740, 722,

Nuclear Hpgnetic Resonance Spectrum (cpe1,) df ppms 4.31 (1H, broad singlet, H at the 5 position); 4.67 (2H, broad singlet, 2H at the 27 position); 4.88 (1H, doublet, H at the 13 position, J = 10.6 Hz); 5.25~

So41 (4H, multiplet, H at the 3, 11, 15 and 19 posi tion); 5.70 = 5.86 (2H, multiplet, H at the 9 and 10 position).

EXAMPLE 138 13~(2-p-Nitrophenylpropionyloxy)~25~ethylmilbemycin (Compound of formula (IIb) wherein: rR! = ethyl,

Z = q-methyl-p-nitrobenzyl, Y = ~0H).

Mass Spectrum (m/z): 735 (MY), 607, 589, 522.

Nuclear Magnetic Resonance Spectrum (cel) d ppm: 3.95 (1H, doublet H at the 6 position, J = 6.1

Hz); 4.07 (1H, singlet, OH at the 7 position);L4.91 | oo oo and 4.92 (1H, doublet, H at the 13 position, J = 10.3 :

Hz).

EXAMPLE 139 13-(2-Me thyl-2~p-chlorophenylpropionyloxy)=25-ethyls milbemycin (Compound of formula (IIb) wherein: rR = ethyl, z= dy df-dimethyl-p-chlorobenzyl, Y = -0H)»

Mass Spectrum (m/z): 738(M%), 610, 576. /

Nuclear Magnetic Resonance Spectrum (CDCLhd 3) oo J ppm: 3.95 (1H, doublet, H at the 6 position, J = 6.2

Hz); 4.07 (1H,singlet, OH at the 7 position, $.01.(1H, doublet, H at the 13 position, J = 10.3 Hz).

EXAMPLE 140 13~(2-Me thyl-2-p~fluorophenylpropionyloxy)~25=~ethyl= milbemycin (Compound of formula (IIb) wherein: Rt = ethyl,

Z = os §-dimethyl-p~fluorobenzyl, Y = -OH),

Mass Spectrum (m/z): 722 (m*), 704, 686.

Nuclear Magnetic Resonance Spectrum (cpc1y) ppm: 3.95 (1H, doublet, H at the 6 position, J = 6.2

Hz); 4.07 (1H, broad singlet, OH at the 7 position); 4.86 (1H, doublet, H at the 13 position, J = 10.3 Hz).

EXAMPLE 141 13-(cf-Methoxybenzylearbonyloxy)-25-ethylnilbemyein ’ (Compound of formula (IIb) wherein: rl ethyl,

Z = ofmethpkybenzyl, Y = ~OH) »

Mass Spectrum (M/z): 706(M%), 688.

Nuclear Magnetic Resonance spectrum (CDC1;) d ppm¢ 3.94 (and 3.95 (1H, doublet, H at the 6 position,

J = 6.2 Hz); 4.10 (1H, broad singlet, OH at the 7 posi- tion); 4.94 and 4.95 (1H, doublet, H at the 13 posi~. tion, J = 10.6 Hz).

. ¢

EY

~~. 26158 , ]

EXAMPLE 142 13-/2-Methyl-2-(p~chlorophenoxy)propionyloxy/=25= ethylmilbemycin (Compound of formula (IIb) wherein: rt = ethyl, -

Cs Z = l-methyl-l-(p-chlorophenoxy)ethyl, ¥ = —OH).

Mass Spectrum (mz/): 754% (M%), 736, 718.

Nuclear Magnetic Resonance Spectrum (cDC1,) d ppm: 3.95 (1H, doublet, H at the 6 position, J m 6.2 Hz); 4.07 (1H, singlet, OH at the 7 position); 5.01 (1H, doublet, H at the 13 position, J = 10.3 Hz),

EXAMPLE 143 oo 13- {2-/p~phenoxy) phenoxy/propionyloxy}~25~ethylmilbemycin (Compound of formula (IIb) wherein: rl = ethyl,

Z = 1~/p-(phenoxy)phenoxy/éthyl, Y = ~OH).

Mass Spectrum (m/z): 798 mY, 780, 762, 670, 540, 522, 50k, BE . Nuclear Magnetic Resonance Spectrum (opel) ppm: 3.96 (1H, doublet, H at the 6 position, J = 6.2 Hz) : 4.06 (1H, singlet, OH at the 7 position); 4.95 (1H,

Co 20 doublet, H at the 13 position, J = 10.3 Hz).

EXAMPLE 144 13-§2~/p~(5-Trifluoromethyl-2-pyridyloxy) phenoxy/~pro- pionyloxy}-255ethylmilbemycin (Compound of formula (IIb) wherein: Rl = ethyl, / or i: 26158 vw ’ 2 = J [5-(5-tri Piuoronsthyl-2-pyridyLoxy) phenoxy/- ethyl, Y = -0H).

Pass Spectrum (m/z): 867 (mt), 849, 831, 813, 540, 522, 50%.

Nuclear Magnetic Resonance Spectrum (cnc) i § ppm: 3.96 (1H, doublet, H at the 6 position, J = 6.2

Hz); 4.10 (1H, broad singlet, OH at the 7 position); 4.98 (1H, doublet, H at the 13 position, J = 10.3 Hz)o

EXAMPLE 145 3 (2-o-Fluorophenylpropionylosy) -25-ethyLmi oem en (Compound of formula (IIb) wherein: gt = ethyl,

CC Z= of me thyl-o- fluor obenzyls Y = =OH)o

Mass spectrum (m/z): 208(M%) , 69, 690, 580, ’ 540, 523

Nuclear Magnetic Resonance Spectrum (cDC1,) i J ppm: 3.95 (1H, doublet, H at the 6 position, J = 6.1

Hz); 4.29 (1H, doublet, H at the 5 position, J = 6.1 : Hz); 4.91 and 4.9% (1H, doublet, H at the 13 position,

J == 10.5 Hz)»

EXAMPLE 146 5 (3-phenyloyolohexyloarbonyloxy)-23-o IT AILEORT ET (Compound of formula (1Ib) whereint R* = ethyl,

Z = dhoyclohexylbenzyls Y = ~0H).

Mass Spectrum (m/z): 758(MT) 4 740, 630, 5404

Nuclear Magnetic Resonance Spectrum (cpely) Co d 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 4.89 (1H, doublet, H®at the 13 position, J = 10.6

Hz). | : :

EXAMPLE 147 -13-(1~Phenylcyclopentylcarbonyloxy)=25~ethylmilbemycin oo (Compound of formula (IIb) whereins gt = ethyl,

Z = l-phenylcyclopentyl, ¥ = ~OH).

Mass Spectrum (mz/): 730(M*3, 712, 602, 540, 522,

Nuclear Magnetic Resonance Spectrum (CDCl) d ppm 3.94 (1H, doublet, H at the 6 position, J = 6.2 Ho); 4,07 (1H, singlet, OH at the 7 position); 4.80 : (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 148 13-/2~(Phenylthio)propionyloxy/-25~ethylmilbemycin (Compound of formula (Ib) wherein: rt = ethyl,

Nuclear Magnetic Resonance Spectrum (cpel,) : : 4 ppm: 3.96 (1H, 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 position, J = 10.5 Hz).

t

EXAMPLE 149 13-(1-Phenylcyclopropylcarbonyloxy)-25-ethylmilbemycin (Compound of formula (IIb) wherein rt - ethyl, 2 = l-phenylcyclopropyl, Y = -OH).

Mass Spectrum (m/z): 202(M%) 684, 574, 540, 522, 504, }

Nuclear Magnetic Resonance Spectrum (cpCl5) ppm: 3.95 (1H, doublet, H at the 6 position, J = 6.2

Hz); 4.02 (1H, singlet, OH at the 7 position); 4.87 (1H, doublet, H at the 13 position, J = 10.6 Hz). ’

EXAMPLE 150 13-(2-0~Tolylpropionyloxy)-25~ethylmilbemycin (Compound of formula (IIb) wherein: rt = ethyl, : Z = df-methyl-o-methylbenzyl, Y = -0H).

Mass Spectrum (m7/z): 204(M*), 690, 686, 646, 604, 576, 540, 522.

Nuclear Magnetic Resonance Spectrum (cpel,) d ppm: 4.23 (1H, multiplet, H at the 5 position); 4.66 (2H, broad singlet, 2H at the 27: position); 4.89 (1H, doublet, H at the 13 position, J = 10.6 Hz)j 5.25~

S.42 (4H, multiplet, H at the 3, 11, 15 and 19 posi- tion); 5.7-5.8 (2H, multiplet, H at the 9 and 10 posi~- 1 tion).

EXAMPLE 151 13~/2-(8)~Phenylpropionyloxy/~25~ethylmilbemycin (Compound of formula (IIb) wherein: rt = ‘ethyl, 7 = (5)~q-methylbenzyl, Y = -OH).

Mass Spectrum (m/z): 690(n*), 672, 632, 562, 540, 522.

Nuclear Magnetic Resonance Spectrum (cpely)

Jd ppm: 3.94 (1H, doublet, H at the 6 position, J = 6.0

Hz); 4.04 (1H, singlet, OH at the 7 position); 4.88 (1H, doublet. H at the 13 position, J = 10.5 Hz).

EXAMPLE 152 13-/2-(R)~Phenylpropionyloxy/=25~ethylmilbemycin (Compound of formula (IIb) wherein: rR = ethyl,

Z = (R)-cf-methylbenzyl, Y = «0H). :

Mass Spectrum (m/z): 690(M*), 672, 632, 562, 540, 522. : Nuclear Magnetic Resonance Spectrum (cDC15) 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 (1H, doublet, H at the 13 position, J = 10.3 Hz).

EXAMPLE 153 13-(2-p-Aminophenylpropionyloxy)=~25=-ethylmilbemycin (Compound of formula (IIb) wherein: rR = ethyl,

Z = d-methyl-p-aminophenyl, Y = ~OH).

« 26158

A solution of 131.8 mg. of 13-(2-methyl-2-p- nitrophenylpropionyloxy)-25-ethylmilbemycin in 8 ml. of methanol was hydrogenated for 6 hours, with stirr- ing, at room temperature in the presence of 3 mg. of : 5% palladium-on-charcoal. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography through silica gel to give 65.0 mg. (yield: 51.4%) of the title compound.

Mass spectrum (m/z): 705(M"), 687, 671, 540, 522,

Soh.

Nuclear Magnetic Resonance Spectrum (cpCly) d ppm: 3.98 (1H, doublet, H 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); Uo65~ 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,

Cs multiplet); 5.8 - 5.95 (2H, multiplet); 6.66(2H, doublet,

J = 8.5 Hz); 7.85 (2H, doublet, J = 8.5 Hz). | EXAMPLE 154 13-/B-(2-Pyridon-1-y1) propionyloxy/-25-ethylnilbenycin (Compound of formula (IIb) wherein: Rr! = ethyl, 2 = 1-(2-pyridon-l-yl)ethyl, Y = ~OH) «

Mass Spectrum (m/z): 707 (M'), 689, 540, 522, sob, 460, 4h2, 412, 39%. \

S oo 261 ’ Nuclear Magnetic Resonance Spectrum (cde)

J ppm: 3.96 (1H, doublet, H at the 6 position, J = 6.0 Hz); 4.08 (1H, singlet, OH at the 7 position); 4,96 and 4.98 (1H, doublet, H at the 13 position, J = 5 10.6 Hz),

EXAMPLE 155 13-/2~(2~Piperidon~-1-yl)propionyloxy/~25-ethylmilbe~ mycin (Compound of formula (IIb) wherein: rt = ethyl, % = 1-(2-piperidon-l-yt)ethyl, Y = ~OH).

Mass Spectrum (m/z): 540(M* -171), 522, SOk, b12, 394, 195, 167, 154.

Nuclear Magnetic Resonance Spectrum (cpCl5)

J ppm: 3.71 (1H, singlet, OH at the 7 position); 3.97 (1H, doublet, H at the 6 position, J = 6.1 Hz); 4.93 and 4.96 (1H, doublet H at the 13 position, J = 10.5

Hz).

EXAMPLE 156 CT 13~/Z-(2-Pyridyl)propionyloxy/-25-ethylnilbemycin (Compound of formula (1Ib) wherein: rR! = ethyl, 2 = 1-(2-pjridyl)ethyl, Y = ~OH)o . Mass Spectrum (m/z): 691(M"), 673, 540, 522, 50k.

Nuclear Hagnetic Resonance Spectrum (eDC15)

§ ppm: 3.70 (1H, singlet, OH at the 7 position) 3.92 (1H, doublet, H at the 6 position, J = 6.5 Hz); 4.12 and 4.28 (1H, triplet, H at the 5 position, J = 6.5 Hz); B4.62~4.73 (2H, multiplet, 2H at the 27 posi- tion). : }

EXAMPLE 157 : 13~(2-Phenylpropionyloxy)=23-hydroxy-25~(1,3~dimethyl- ~l~butenyl)milbemycin (Compound of formula (IIb) wherein: Rl = 1,3= dimethyl-l~butenyl, 2 = ¢methylbenzyl, X= ~0Hy Y = : ~O0H) o

Mass Spectrum (m/z): 760(M%), 742, 725, 710, 331.

Nuclear Magnetic Resonance Spectrum (cDC14) d' ppm: 3.9% (1H, doublet, H at the 6 position, J = 6k

Hz); 4.28 (1H, triplet, H at the 5 position, J = 6.4 Hz), 4,65 (2H, broad singlet, 2H at the 27 position); 4.88 . (1H, doublet, H at the 13 position, J = 10.5 Hz). . Examples 158 to 163 illustrate the preparation of compounds of formula (IIc) from starting materials of formula (IIb), by the reaction of Step O in Reaction

Scheme No. 2 above,

oo 26158 «+ . ’ ¢ oo ( EXAMPLE 158 B 13~(2~Methyl-2~-phenylpropionyloxy)~5-0~propionyle25~ ethylmilbemycin (Compound of formula (IIc) wherein: BR: = ethyl,

Z = qs ¢-dimethylbenzyl, Y = propionyloxy). 5 - of propionyl chloride and 38 pL of pyri- dine were added, under ice-cooling, to a solution of 91 mg of 13-(2-me thyl-2-phenylpropionyloxy)=25-e thy lm milbemycin in methylene chloride, and then the mixture | was stirred at room temperature for 3 hours. At the end of this 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 sul- . 15 fate and concentrated by evaporation. The residue was : purified by column chromatography through silica gel to give 75 mg (yield: 76%) of the title compound. oo oo Mass Spectrum (M/z): 760(M*), 686, 595, 540, 522, 504, a - :

Nuclear Magnetic Resonance Spectrih (CDOL,) d ppm: 3.99 (1H, broad singlet, OF at the 7 position);

L,o4 (1H, doublet, H at the 6 position, J = 5.9 Hz); - - 4,53 (1H, doublet, H at the 27 position, J = 14.3 Hz); - 4.62 (1H, doublet, H at the 27 position, J = 14.3 Hz); 4.87 (1H, doublet, H at the 13 position, J = 10.3 Hz); -

5.25~5.45 (3H, multiplet); 5.5-5.6-(2H, multiplet); : 5.65-5.8 (4H, multiplet); 7.2-744 (5H, multiplet).

EXAMPLE 159 5-0~-(3~Carboxypropionyl)~13~(2-methyl-2-phenylpro~ pionyloxy)-25-ethylmilbemycin : (Compound of formula (IIc) wherein rt = ethyl, 2 = q»q-dimethylbenzyl, Y = 3-carboxypropionyloxy).

Following the procedure of Example 158, but using 76 mg of 13-(2-methyl-2-phenylpropionyloxy)-25- ethylmilbemycin and 100 mg. of succinic acid anhydride, there were obtained 61 mg (yield: 70%) of the title compound.

Mass Spectrum (m/z): 80k (M*), 704, 686, 668. . Nuclear Magnetic Resonance Spectrum (cpel,)

J ppm: 4.03 (1H, doublet, H at the 6 position, J = 5.9

Hz); 4.53 (1H, doublet, H at the 27 position, J = 14.2 : | Hz); 4.62 (1H, doublet, H at the 27 position, J = 1lh.2

Hz); 4.87 (1H, doublet H at the 13 position, J = 10.3

Hz); 5.35-5.5 (3H, multiplet); 5.5-5.6" (2H, multiplet); 5.65-5.8 (2H, multiplet); 7.3 (5H, multiplet). :

The compounds of Examples 160 to 162 were also prepared by following the procedure of Example 158.

- »

Ul 96 15 8 ¢ - SY . " ERAMPLE 160 13-(2-0-Chlorophenylprppionyloxy)=~5-0O-chloroacetyl= : 25~ethylmilbemycin (Compound of formula (IIc) wherein: R = ethyl, 2 = ¢-methyl-o-chlorobenzyl, Y = chloroacetoxy. S

Nass Spectrum (m/z): 8oo(M*), 782, 616, 522.

Nuclear Magnetic Resonance Spectrum (cpely)

J ppm: 4.57 (1H, doublet, H at the 27 position, J = 15.1 Hz); 4.62 (1H, doublet, H at the 27 position, J = 15.1 Hz); 4.92 (1H, doublet, H at the 13 position, J = 10.6 Hz); 5.27-5.41 (3H, multiplet, H at the 11, 15 and 19 position); 5.56 (1H, multiplet, H at the 3 posi~ tion); 5.72 - 5.82 (2H, multiplet, H at the 9 and 10 position.

EXAMPLE 161 13-(2~0~Chlorophenylpropionyloxy)~5-0-ethoxycarbonyl~ 25~ethylmilbemycin (Compound of formula (IIc) wherein R= ethyl, 2 = {-methyl-o-chlorobenzyl, Y'= ethoxycarbonyloxy,

Mass Spectrum (m/z) 3 796 (M+ -18), 738, 688, 612, 522, 50k.

Nuclear Magnetic Resonance Spectrum (cDC1,) d' ppm: 4.06 (1H, broad singlet, OH at the 7 posim oo tion); 4.10 (1H, doublet, H at the 6 position, J =

20158 = 6.2 Hz); 4.90 and 4.91 (1H, doublet, H at the 13 position, J = 10.6 Hz).

EXAMPLE 162 13-(2-Methyl-2~phenylpropionyloxy)~5-O~chloroacetyl=- / 5 25~ethylmilbemycin (CompBund of formula (IIc) wherein: 7 = ethyl, 2 = q+ q~dimethylbenzyl,

Y = chloroacetoxy.

Mass Spectrum (m/z): 780(M%), 616, 597, 522. oo

Nuclear Magnetic Resonance Spectrum (cDC1,) 10 Jd ppm: 4,03 (1H, singlet, OH at the 7 position) y 4,08 (1H, doublet, H at the 6 position, J = 6.5 Hz); 4.87 (1H, doublet, H at the 13 position, J = 10.5 Hz).

EXAMPLE 163 ‘ 13~(2-Me thyl~-2-phenylpropionyloxy)=-5-O-acetoxyacetyl~ 15 25~ethylmilbemycin ’ (Compound of formula (IIc) wherein: R= ethyl, = d,f-dimethylbenzyl, Y = acetoxyacetoxy. 123 mg. of sodium iodide were added to a solu- tion of 129 mg of 13-(2-methyl~2~phenylpropionyloxy)= 5-0-chloroacetyl-25-ethylmilbemycin in methylene chlo~ ride, and the mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was poured into water and then 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 concen trated to give a crude 13-(2~methyl-2-phenylpropionyl=- oxy)-5-0-iodoacetyl-25~-ethylmilbemycin. :

This crude product was dissolved in 15 ml. of

N,N-dimethylacetamide, 135 mg. of sodium acetate were added, and the mixture was stirred at room temperature for 3 hours. Af the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate, The e®tract was washed, in turn, with water and a saturated aqueous solution of sodium chloride and then concentrated. The residue was purified by preparative thin layer chromatography (Merck Art 5717, 20 x 20 cm, thickness 2 mm), developed with a 1:1 by volume mixture of hexane and ethyl acetate, to give 93.8 mg. (yield: 70.6%) of the title compounde oo | Mass Spectrum (m/z): got (n*), 640, 622, 540, 522, 504.

Nuclear Magnetic Resonance Spectrum (coe) d ppm: 4.03 (1H, singlet, OH at the 7? position) 4,05 (1H, doublet, H at the 6 position, J = 6.1 Hz); L4.5~ 4.7 (4H, 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); 7.2-7.35

(5H, multiplet). :

Preparations 1 to 4 illustrate the synthesis of starting materials for use in preparing the com- pounds of the invention by the reactions described above,

PREPARATION 1 13-p-Fluorophenoxyacetoxy~5-keto~25~ethylmilbemycin (Compound of formula (III) wherein: Rl ethyl,

R° = p-fluorophenoxymethyl, n = 0)a - 23 mg. of 1,3-dicyclohekylcarbodiimide, 62 mg of 13-hydroxy-5-keto-25~ethylmilbemycin and a trace of b-pyrrolidinopyridine were added successively to a solution of 17 mg. of p-fluorophenoxyacetic acid in oo ml. of methylene chloride, and the resulting mix- 15 ture was then stirred for 30 minutes at room tempera- ture. After completion of the reaction, the mixture was filtered and the filtrate was poured into water, ’ followed by extraction with ethyl acetates The ethyl acetate extracts were washed with saturated aqueous 20 . sodium chloride solution and dried over magnesium sul- fate. The solvent was distilled off trom the extract, and the residue was subjected to column chromatography over silica gel, giving 44 mg. of the desired com- pound.

aN 26158

Mass Spectrum (m/z): 208(M*).

Nuclear Magnetic Resonance Spectrum (270 MHz, '

CDC1;) ppm: 3,86 (1H, singlet, OH at the 7 position); 4.01 (1H, singlet, H at the 6 position); 5.06 (1H, doublet, H at the 13 position, J = 10.3 Hz),

PREPARATION 2 5-Keto~23-hydroxy-25=(1,3-dimethyl-l-butenyl)milbemycin 0.64 g of activated manganese dioxide was added to a solution of 61.2 mg of 23~hydroxy~-25-(1,3-dimethyl- 1-butenyl)milbemycin in 5 ml. of acetone, and the re~ sulting mixture was stirred vigorously for 30 minutes. :

The mixture was then filtered over "Celite" filter Co aid, and the filtrate was concentrated, giving 59.3 mg. of the crude desired compounds

Mass Spectrum (m/z): 610, 592, 574.

Nuclear Magnetic Resonance Spectrum (cne1,)

J ppm: 3.78 (1H, singlet, OH at the 7 position); 3.84 (1H, singlet, H at the 6 position). . PREPARATION 3 =~ 13,23-Dihydroxy-5-keto-25-(1,3-dimethyl-1-butenyl)= oo milbemyoin:

The crude 5-keto-23-hydroxy~25-(1,3-dimethyl- 1-butenyl)}milbemycin, obtained in Preparation 2 above, was dissolved in 3 ml. of formic acid, then 13 mg. of gelenium dioxide were added to the solution, and the resulting mixture was stirred for 1.5 hours at room temperatures The mixture was then filtered over ngelite" filter aid, and the filtrate was, poured jnto water and then extracted with ethyl acetate. The ex~= tract was dried over magnesium sulfate and concen trated. The residue was dissolved in @& mixture of 2 ml of methanol, 3 ml. of dioxane and 1 ml of 2N hydro- chloric acide The solution was kept stirred overnight at room temperatures then poured into water and ex~- tracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was purified by preparative thin Layer chromatography = (Merck, Art 5715, 20 X 20 cm, 2 mm thick), developed : 15 with a 1:1 bY volume mixture of hexane and ethyl acet~- ate, to give 13.2 mg. of the desired compound (yield: 21.7%) | Co

Mass Spectrum (m/z) 626(M" ~36), 608, 590, 3494 331, 259 22, 179.

Nuclear Magnetic Resonance Spectrum (oDCly +

D,0) J ppm: 3.73 (1H, doublet, H at the 13 position,

J = 9.7 Hz) 3.75 (1H, doublet H at .the 25 position,

J = 10.5 Hz)3 3, 8k (1H; singlet, H at the 6 position).

PREPARATION 4 13-(2-Me thyl-2-phenylpropionyloxy)-5-keto-25~ethyl- milbemycin 116.g. of 2-methyl-2-phenylpropionyl chloride and 0.73 ml. of pyridine were added, in turn to a so- lution of 557 mg. of l3~hydroxy-S-keto-25-ethylmilbe- mycin in 20 ml. of chloroform, and then the mixture 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 sodium . | bicarbonate, water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated by evaporation. The residue was puri-~ fied by column chromatography through silica gel to give 353 mg. (yield: 50%) of the title compound.

Mass Spectrum (m/z): 702 (M'), 684, 538, 520.

Nuclear Magnetic Resonance Spectrum (cpe1,)

JS ppm: 3.84 (1H, singlet, H at the 6 position); 4.01 (1H, singlet, OH at the 7 position); 4.80. (2H, multi~ - plet, H at the 27 yphbeition); 4.87 (1H, doublet, H at the 13 position, J = 10.3 Hz)3 5.3=5.5 (3H, multiplet,

H at the 11, 15 and 19 position); 7.3 (5H, multiplet).

EXAMPLE 164

Acaricidal activity against Tetranychus urticae

The primary leaves of cowpea plants of the spe- cies Vigna sinensis Savi were infected with organic phosphate-sensitive mites (Tetranychus uritcae). One day after infection, the infested plants were sprayed, using a Mizuho rotary sprayer, with 7 nl. of a test solution containing the compound under test at a con~ : centration of 3 ppm, at a rate of 3.5 mg. of the test ‘10 solution per 1 en? of leaf. The plants were assessed after 3 days by examining adult mites, under a binocu-~ lar microscope, to determine living and dead indivi- duals. Two plants were used for each concentration and each test compound. The plants were kept during the test in greenhouse compartments at 25%. The re~ sults are reported in the following Tables . JR

Compound of Mortality 2 29 : 10 : co 93 11 EY 12 100 13 94 : 17 93 / 18 100

: : ~continued~

Compound of Mortality

Example No. ~ (%) 19 97? 41 93 bb 92

C62 100

Co 66 | 9 - 68 90 71 100 oo | 72 200 k | 73 100 / 24 : 100 76 100 oo 79 95 80 100 : 82 : 100 83 100

C 84 : 93 - 86 98 . | 20 87 ~ 100 88 9? g. 97 90 | 100 91 100 oo 98 , 94 101 | 91 : 102 97

» 26158 . — + ' ~continued—

Compound of Mortality

Example No. (%) : | 103 100 104 9k 105 100 106 96 109 } 100 110 100 112 92 114 . 100 115 100 : 116 98 :

Control Compound Uk 4s ee

The Control Compounds were as follows: 1. 25-Ethylmilbemycin (milbemycin A) 2. S5-Keto-25~ethylmilbemycin 5-oximes 3. S—Keto-25-¢ thylmilbemyoin S-Owdimethyle carbamoyloxime. Lo 4, 5-Keto-25~ethylmilbemycin 5-O-pivaloyloxime. is can be seen clearly from the above results, the compounds of the present invention have a far stronger acaricidal activity than that of Control

Compound No. 1 (i.e. the naturally produced milbemy- cin AL) and also of the other milbemycin derivatives unsubstituted at the 13-position used as Control 0

Compounds 2, 3 and 4. Co

EXAMPLE 165 : Acaricidal activity against Tetranychus urticae : The procedures of Example 164 were repeated with a different set of test compounds, except that the concentration of the compound in the test solution was 0.3 ppme The results obtained are shown in the oo . following table. .

Compound of Mortality

EE

136 100 137 70 : 139 ‘ 70

—cont inued=

Compound of Mortality

Example No. (%) 140 85 141 100 142 100 145 95 188 80

Control Compound 1 20 : Control Compound 5 4s

Control Compound 6 Ls . 10 Control Compound 7 30

The control Compounds were as follows: 1. 25-Ethylmilbemycin (milbemycin Ade Co

Se 13-Benzayloxy-25~ethylmilbemycin. ’ 6. 13-Pivaloyloxy-25-ethylmilbemycins - 7. 13-Phenylacetoxy-25-ethylmilbemycino

These results clearly demonstrate the markedly E superior acaricidal activity of the compounds of the invention, as compared with Control Compound No. 1 : (i.e. the naturally produced milbemycin Ay) and also as compared with the 13-substituted derivatives used as Control Compounds 5, 6 and 7o

EXAMPLE 166

Acaricidal activity against Boophilus microplus

Groups of 10 engorged femaleticks of the spe- cies Boophilus microplus were immobilized on poly~

. LI - vinyl chloride panels by means of double~sided ad- hesive tape. The test compounds were administered to each group at varying dosages ranging from 0.0005 pe to 5 pg, dissolved in 2 or 1 pl of solvent, in order to determine their IRgg value -i.e. the con- centration of the test compound which would result in 90% inhibition of reproduction by division, 3 days after treatment.

The compounds of Examples 2, 3, 6, 7, 9, 10, 11, 18 and 19 were found to exhibit an IRgq value of 0.5 pg/groups

EXAMPLE 167

Activity against Dermanyssus gallinae

Compounds of the invention were tested for activity sagainst mites of the species Dermanyssus gal~ linae. Qroups consisting of 100-200 mites, at various ’ - stages of growth, were transferred into test tubes containing 2-3 ml. of a solution of the test compound at a concentration of 100 ppm. The test tubes were stoppered with cotton wool and shaken for 10 minutes, then the solution was sucked out through’ the cotton wool and the tubes with the treated nites allowed to stand for 3 days at room temperatures

The compounds of Examples 6-13, 15, 17-20, 22-25,

~~ ee 20158 1 27, 31-36, 38, 39, 43-47, 51-53, 56, 57s 6h, 65, : 67, 68, 74, 75, 77-79, Bl, gz, 84, 87-89, 91, 98, 102-106, 109-119, 124, 127, 129-131, 134-137, 1l40=- 142, 146-151, 158 and 159 were tested in this way and each produced 100% mortality in the test groups.

EXAMPLE 168

Activity sgainst tucilia serlcata

Groups consisting of 30-50 eggs £ rom the spe- cies Lucllia sericata, collected immediately af ter oviposition, were added to test tubes each containing 1 ml. of a liquid culture medium and 1 ml. of the test compound in solution at a concentration of 100 pple ) The test tubes were stoppered with cotton wool and allowed to stand for 4 days at 30°C. The percentage mortality in each test group was assessed at the and : of tha & days. B

Bh The compounds of Examples 6, 7, 9, 13, 17,. 19, 20, 23-29, 31-36, 38, bl, W3=45, 47, 51-53, 56-58, 62, : 65, 66, 68-70, 73, 7%, 76-79, 81-Bh, 87-91, 96, 101, 105,. 108, 111-114, 116, 124, 127, 129-137, 140-1043, 146, 147, 149-151 and 158-161 were tested in this way and each produced 100% mortality in the test groups.

Claims

’ as af SY Tr ——— . s ’ ’ ' i a i ov ash Co N Ar NATERTS TEASER . may TEE 9} APR 1 p2:30 Co aging oo WE CLAIM: 26 1 5 8 1

- 1. Compounds having the formula X CH (1) : 0 CH, 3 Co 2 n . : rt on” > 0 0 on Hy

' . Y in which: the broken lire represents a carbon-carbon ’ single or double bond between the atoms at the 22 and 23 positions; ~~ X represents : 8 hydrogen atom or a hydroxyl group, or to- gether with the carbon etom to which it is attached represents thas group Ci=0; pro=- vided that X represents a hydrogen atom . when the broken ling represents a double bond betwsen tha carbon atoms at the 22 \ 7 . and 23 positions;

¥ represents the group =N-OR°, wherein R> represents a hydrogen atom, an alkyl group having from 1 to 6 carbon ‘5 | atoms and which may optionelly be subati- tuted with at least one carboxy group, &: cycloalkyl group having from 3 to 10 ring carbon atoms, or en aralkyl group having from 6 to 1D ring carbon atoms in the aryl moiety and from 1 to 6 carbon atoms . in the alkyl moiety; R! represents an alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, each having up: to 8 carbon atoms; a cycloalkyl-substituted alkyl group wherein the cycloalkyl moiety has from 3 to 6 ring ' carbon atoms and the alkyl moiety has from 1 to 5 carbon atomsj; a cycloalkyl or cycloalkenyl group having fram 3 to 8 ring carbon atoms and optlonale ’ ly substituted with at least one substituent : | selected from halogen atome end alkyl groups having from 1 to & carbon atoms; a heterocyclic group having from 3 to 6 ring . :

‘ 26158 atoms of which at least one is an oxygen } or sulfur atom and which may optionally be substituted with at least one substituent selected from halogen atoms and alkyl groups having from 1 to 4 carbon stoms; RZ represents the group R= (0) ~ wherein n =0 or 1; R® represents a hydrogen atom, an alkyl group having from 1 to 22 carbon atoms,. an alkenyl or alkynyl group heaving from 2 ta 6 carbon atoms, a cycloalkyl group having from 3 to 10 carbon atoms, an aryl group having from 6 to 10 ring carbon atoms, an aralkyl group having from 6 to 10 ring carbon atoms in the aryl moiety - and from 1 to 6 carbon atoms in the alkyl moiety, wherein said alkyl group of R> may optional be substituted with at least one substi- tuent selected From:

(a). cycloalkyl groups having from 3 tao 10 carbon atoms; alkoxy groups having from 1 to 6 carbon atoms; alkoxycarbonyl groups having from Z to 7 carbon atoms;

halogen atoms; aryloxy and arylthlo : groups having from 6 to 10 ring car- bon atoms, which may themselves op- tionally be substituted with at least 5: one halogen atom;, protected or unpro- ted hydroxy; carboxy; amino; monoalkyl- amino and dialkylamino groups having from 1 to 6 carbon atoms in the or each alkyl moiety; aliphatic ecyl-amino groups having from 1 to 6 carbon atoms; aromatic acylamino groups;. cyanoj. car- bemoyl; mongalkylcarbamoyl and dialkyle carbamoyl groups heaving from 1 to 6 carbon atoms in the or each alkyl : 15 moiety; mercapta; slkylthio, alkylsul- finyl and alkylsulfonyl groups, in each case having from 1 to 6 carbon atoms; nitrog; and wherein said alkenyl and alkynyl groups of R® may optionally be substituted with - at leaat ons substituent selected from the group consisting of: : (b) the said substituent (a); and acyl groups having from 6 to 10 ring carbon atoms; and the said cycloalkyl, aryl,

\ ‘aralkyl; and salts and esters of sald compounds of formula (I),
2. Compounds as claimed in Claim 2, wharein R> represents a hydrogen atom.
3. Compounds as claimad in Cleim 1, wherein rl represents a methyl, ethyl, isopropyl, sec-butyl, l- mathyl-l-propenyl, l-methyl-l-butenyl or 1,3-dimethyl- l-butenyl groupe.
4, Compounds 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 22 and 23 pasitions. .
5+ Compounds as claimed in Claim 1, wherein R° : represents an alkyl or haloalkyl group having from & to 7 carbon atoms, phenyl, benzyl or a phanyl or ben- zyl group substituted with one or two substituents } gelected from trifluoromethyl, halogen, methyl and. amino. ’
6. Compounds according to Claim 1, wherein rR? represents a t-butyl, fluoro-t-butyl, 2,6-difluoro- phenyl or o-(trifluoromethyl)phenyl group.

/ .
7. An anthelmintic acaricidal and insecticidal : composition which comprises an effective amount of a compound as claimed in Claim 1 in admixture with a pharmaceutically, agrioklturally, veterinarily or horticulturally acceptable carrier or diluent.
8. A meShod of protecting animals or plants oo from demage by parasites selected from acarids, hel minths and insects, which comprises applying to said animals or plants, or to said seeds of sald plants or to a locus including said animals, plants or seeds, : and effective amount of a compound as claimed in Claim

1.
9. A compound selected from the group consist- oo | ing of x 13-pivaloyloxy=5-keto-25~ethylmilbemycin 5« . . oxime, 13-(2,2~dimethyl-1,3-dioxolanyl)methoxycarbonyle . : oxy=~5-kato-25-athylmilbamycin-5~-0xima, 13-p-trifluoromethylbenzoyloxy=-5-keto-25=bthyl- milbemycin-5-oxime oo . 13-(2=furoyloxy)-5-kato-25-athy Ini Lbenycin 5e oxima, oo ' 13-(3-chloro-2,2-dimethylpropionyloxy)«5«keto=- 25-sthylmilbemycin 5-oxime,

+ 13=(3=-fluoro-2,2-dimethylpropionyloxy)-5-keto- 25-gthylmilbemycin 5-oxime, © 13-(2,6-difluorobenzoyloxy)-5-keto-25~gthylmil- bemycin 5-oxime, © 13-(2-phenylpropionyloxy)-5-keto-25-ethylmil= bemycin S5-oxime, 13=-(2=-methyl-2-phenylpropionyloxy)=-5-keto=-25= ethylmilbemycin S-oxime, 13-(2-p-aminophenylpropionyloxy)=5-keto=25« ethylmilbemycin 5-oxime, and © 13-(2=~-phenylbutyryloxy)=5-keto-25~ethylmilbemy- cin 5-oxime, ’
10. The compound as claimed in Cleim 9 selected from the group consisting of: / 13=pivaloyloxy-5-keto=25-gthylmilbemycin 5-oxime, ? 13-(2, 2-dimethyl-1, 3-dioxalanyl)methoxycarbonyl- . : oxy=5-keto-25~-ethylmilbemycin 5-oxime, ” 13-(2=-furoyloxy=-5~-keto~25-gthylmilbemycin S- oxime, ' 13-(3-chloro-2,2-dimethylpropionyloxy)-5-keto- 25-gthylmilbemycin 5-oxima, 13-(3-f luoro-2, 2-dimethy Lpropiony loxy )~5-ke tom 25«gthylmilbemycin 5-oxime, { 13=(2-phenylprapionyloxy)-5-keto-25-ethylmilbe- : 25 mycin 5—xox Ima,

. i -— TT — © 13-(2-methyl-2-phenylpropionyloxy)=-5-keto=25- ethylmilbemycin 5~oxime, . . 13=-(2-p-aminophenylpropionyloxy)=5-keto=25- - gthylmilbemycin 5-oxime, and. oo 5, 13-(2-phenylbutyryloxy)=-5-kato-25-ethylmilbamy- cin 5-oxime.
11. The compound as claimed in Claim 9, se- lected from the group. consisting of: 13-(2, 6-dif luorobenzoyloxy)=5-keto-25-athylmil- oo bemycin and 5-oxima, and : b : oC 13-0-trifluoromethylbenzoyloxy-5-keto=25-ethyl- milbemycin 5-oximae
12. The compound as claimed in Claim 9, se- lected from the group consisting of: Co | 13-(2,6~-dif luorobenzoyloxy)=5-keto-25-athylmil- bemycin S5-oximay KAZUO SATO ) : TOSHIAKI YANAI .: TAKAO KINOTO: KEIJI TANAKA AKIRA NISHIDA :

~~. 'POSHIMITSU TOYAMA BRUNO FREI : ANTHONY O'SULIVAN : ’ Inventors / ] - 185 = oo