IE67058B1 - Macrolide compounds their preparation and their use - Google Patents

Description

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 and avermectins. These compounds have valuable acaricidal, insecticidal and anthelmintic activities. The invention also provides methods of preparing these compounds and compositions and methods for using them.

There are several classes of known compounds with a structure based on a Ιό-membered macrolide ring, which are obtained by fermentation of various microorganisms or semi-synthetieally by chemical derivatization of such natural fermentation products, and which exhibit acaricidal. insecticidal, anthelmintic and antipaeasitic activities. The milbemycins and avermectins are examples of two such classes of known compounds, but various others also exist and are identified by different names or code numbers. The names for these various macrolide compounds have generally been taken from the names or code numbers of the microorganisms which produce che naturally occurring members of each - 2 class, and these names have then been extended to covet the chemical derivatives of the same class, with the result that there has been no standardized systematic nomenclature for such compounds generally.

In order co avoid confusion, a standardized system of nomenclature will be used herein,, which follows the normal rules for naming derivatives of organic compounds and which is based on the hypothetical parent compound hereby defined as milbemycin represented by formula "3 OH For che avoidance of doubt, formula (A) also shows th® numbering of positions of the macrolide ring system applied co those positions most relevant to the compounds of the present invention.

The naturally produced milbemycins are a series of macrolide compounds known to have anthelmintic, acaricxdal and insecticidal activities. Milbemycin D was disclosed ia US Patent Wo. 4,346,171, where it was refereed to as Compound B-41D, and milbemycins &3 and A. were disclosed in US Patent No, 3,950,360.

These compounds may 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 milbemycia &3, milbemycin A and milbemycin D, respectively. The milbemycin analogue substituted at position 25 with a see-butyl was disclosed in U.S. Patent No. 4,173,571.

Subsequently, various derivatives of the original milbemycins have been prepared and their activities investigated. For example, epoxy milbemycins have been disclosed in Japanese Patent Applications Kokai (i.e. laid open to public inspection) No. 57-139079, 57-139080, 59-33288 and 59-36681 and in US Patent No. 4,530,921. 5-Esterified milbemycins have been disclosed in US Patents No. 4,201,861, No. 4,206,205, No, 4,173,571, No. 4,171,314, No. 4,203,976, No. 4,289,760. NO. 4,457,920, No. 4,579,864 and No. 4,547,491, in European Patent Publications No. 8184, No. 102,721, No. 115,930, No. 180,539 and No. 184,989 and in Japanese Patent Applications Kokai No. 57-120589 and 59-16894. - 4 13-Hydroxy-5-ketomilbemycin derivatives have been disclosed ia US Patent Mo. 4„423„209. Milbemycin 5-oxime derivatives were disclosed ia US Patent Mo. 4»547„520 and European Patent Publication No. 203 832.

Milbemycin derivatives esterified at position 13 are of particular relevance to the present invention and have been disclosed in US Patent No. 4.093,,629 and European Patent Publication No. 186403» as well as ia published British Patent Application No. 2.168.345 which discloses milbemycin derivatives having a carboxy or esterified carboxy substituent at position 13 in combination with a hydroxy or esterified hydroxy substituent at position 5.

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

Agents Chemother,, 15(3),, 361-367 (1979). These compounds may be represented by the above formula (A) but with a carbon-carbon double bond at positions 22 and 23» and having position 13 substituted with a 4'~(n-holeandrosyD-n-L-oleandrosyloxy group. Position 25 may be substituted with an isopropyl group oc a sec-butyl group, these compounds being designated as avermectin B,. and avermectin B, „ respectively.

Id is 22»23-Dihydroavermectins Β^_ and 3^ may be obtained - 5 by reduction of the double bond between the 22 aad 23 positions aad ate disclosed ia US Patent Ko. 4.199,569. The aglyclone derivatives of the avermectins, which are milbemycin analogues, have sometimes been referred to ia the literature as C-076 compounds, and various derivatives of these are known. For example, US Patent No. 4.201,861 discloses such derivatives substituted with a lower 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 number LL-F28249. Some of these have a 16-membered macrolide structure corresponding to the above formula (A), substituted with hydroxy at position 23 and with 1-methyl-l-propenyl. 1-methyl-l-butenyl or 1,3-dimethyl1-butenyl at position 25. In these compounds, the hydroxy at position 5 may also be replaced by methoxy.

Published British Patent Application No. 2.176,182 discloses another group of macrolide antibiotics corresponding to the above formula (A) with a hydroxy or substituted hydroxy group at position 5. a hydroxy, substituted hydroxy or keto group at position 23, and an α-branched alkenyl group at position 25. - 6 A yet further group of related macrolide derivatives is disclosed in Japanese Patent Application Kokai .

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 can be substituted with a 4'-(a-L-oleandrosyl)-a-Loleandrosyloxy group,, as in the avermectins, and there may be a carbon-carbon double bond between positions 22 and 23,, or alternatively position 23 may be substituted with hydroxy. The substituent at position 25 is of a type not found in the naturally produced avermectins and milbemycins, and includes various α-branched alkyl, alkenyl, alkynyl. alkoxyalkyl, alkylthioalkyl and cycloalkylalkyl groups, or eyeloalkyl. cycloalkenyl or heterocyclic groups. This 25-substituent is introduced by adding the corresponding carboxylic acid or derivative thereof to th© fermentation broth of an avermectin-producing microorganism.

Summary of the Invention The various classes of milbemycin-related macrolide compounds described above are all disclosed as having one or more types of activity as antibiotic, anthelmintic, ectoparasiticidal, acaricidal or other pesticidal agents. However, there is still a continuing need to provide such agents with improved activity against one or more classes of pests.

IT' - 7 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 found, that the activity of the 13-esterifxed derivatives in the above-mentioned prior art can be improved upon by appropriate selection of certain ester groups at this position, as specified below.

Accordingly, It is an object of the present invention to provide such macrolide compounds having improved 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 pesticidal compositions and methods containing the said compounds.

In accordance with these objects, the invention provides compounds having the formula fr ιΆ-° OH i (!) 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 th® carbon atom to which it is attached represents the group C=O; provided that X represents a hydrogen atom when the broken line represents a double bond between the carbon atoms at the 22 and 23 positions; Y represents the group -OR e - 9 wherein R^ represents a hydrogen atom, or an ester-forming carboxylic or carbonic acid residue: R1 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 atoms, a cycloalkyl or cycloalkenyl group having from 3 to 8 ring carbon atoms and optionally substituted with at least one substituent selected from halogen atoms and alkyl groups having from l to 4 carbon atoms: a heterocyclic group having from 3 to 6 ring 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 atoms; - 10 R represents the group A-(W),n -C(rV)-, wherein n = 0 or Ί; RS represents carbon atoms, carbon atoms* carbon atoms, carbon atoms an alkyl group having from 1 to 6 a haloalkyl group having from 1 to 4 an alkoxy group having from 1 to 4 an alkoxyalkyl group having from 1 to , a phenyl group* or a cyano group; R represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; δ 7 or R and R , together with the carbon atom to which they are attached, jointly represent a cycloalkyl group having from 3 to 6 ring carbon 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 nitrogen, oxygen or sulfur atom; and said phenyl, naphthyl or heterocyclic group may optionally be substituted with at least one substituent selected from alkyl, alkoxy and alkylthio groups each having from 1 to 4 carbon atoms, halogen atoms, trifiuoromethyl. amino, nitro, cyano. keto, phenoxy (which may itself optionally be substituted with at least one substituent selected from halogen atoms and trifiuoromethyl), and heterocyclyloxy groups having from 5 to 10 ring atoms of which at least one is a nitrogen, oxygen or sulfur atom; and salts and esters of said compounds of formula (I).

The invention still further provides an anthelmintic, acaricidal and insecticidal composition comprising an anthelmintic, acaricidal and insecticidal compound in admixture with a pharmaceutically, agriculturally, veterinarilv or horticulturally acceptable carrier or diluent, wherein said compound is selected from the group consisting of compounds of formula (I).

The invention still further provides the use for the manufacture of a medicament for treating an animal, which may be human or non-human, parasitised by a parasite 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 comprises applying an active compound to said animals, to said plants or to seeds of said plants or to a locus including said animals, plants or seeds,, wherein the active compound is at least one compound of formula (I).

Detailed Description of the Invention In th® compounds of formula (I), where R1 represents an alkyl group having from 1 to 8 carbon atoms,, this may be straight or branched chain alkyl group and 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 accordance with another embodiment of the invention, the α-branched alkyl groups having from 3 to 8 carbon atoms ace preferred.

Where S1 represents an alkenyl group, this may be a straight or branched chain group containing from 2 to 8 carbon atoms and having at least one double bond, for example vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-methyl-l-propenyl, 1-methyl-l-butenyl and V - 13 1»3-dimethyl-l-butenyl. The α-branched alkenyl groups are particularly preferred.

Where R1 represents an alkynyl group having fro® 2 to 8 carbon atoms, this may be a straight or branched chain group, for example ethynyl, 1-propynyl or 2-propynyl.

Where R1 represents an alkoxyalkyl group or alkylthioalkyl group,, this may have a total of from 2 to 8 carbon atoms and may be straight or branched, for example methoxymethyl, ethoxymethyl. 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, isopropoxymethyl, and the thio analogues of each of these groups. The methoxymethyl. 1-methoxyethyl, methylthiomethvl and 1-(methylthio)ethyl groups, respectively, are preferred. where R1 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. Examples include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.Ijheptyl and norbornarnyl groups, and the analogues thereof containing one or more double bonds. It should be understood that this definition also includes partly aromatic fused polycyclic ring systems, for example the tetrahydronaphthyl and trimethylenephenyl groups. -14 Where represents a cycloalkyl-substituted alkyl group, th® eyeloalkyl moiety thereof may he any of the above-mentioned eyeloalkyl groups which have from 3 to 6 ring carbon atoms, and the alkyl moiety may be any of the above-mentioned straight or branched chain alkyl groups which have from 1 to 5 carbon atoms. where R1 represents a heterocyclic group, this may have from 3 to 6 ring atoms, of which at least one is an oxygen or sulfur hetero-atom. The ring system may be unsaturated, or partly or wholly saturated. Examples of such heterocyclic groups Include che oxiranyl, oxetanyl. thiranyl, thietanyl, (2,2-dimethyl)-l,3-dioxoranyl, furyl, thienyl, thiazolyl, isothiazolyl„ oxazolyl. isoxazolyl and pyranyl groups.

Where R1 represents a cycloalkvl, 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 having 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).

It is preferred that, when X represents a hydrogen atom, R represents an alkyl group having from 1 to δ carbon atoms, or an alkenyl group having from 2 to 6 carbon atoms.

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

In the compounds of formula (I), RZ' may represent a hydrogen atom, so that the substituent at position 5 is a hydroxy group. As will readily be appreciated by those skilled in the art, this hydroxy group can form esters with a wide variety of carboxylic and carbonic acids, without significantly adversely affecting the biological activity of the compound which is derived from the 5-hydroxy substituent. Accordingly, the invention also embraces such esters where R represents an ester-forming carboxylic or carbonic acid residue.

. Preferred compounds ace chose xn which B is the hydrogen atom or a group of the following formula :-CO-(O)a-S8 wherein n = 0 or 1; and Ω B represents a straight or branched chain alkyl group, a C3 ? cycloalkyl group, a C?, c aralkyl group, a 6 alkenyl or alkynyl group, a C„ aryl group or a monocyclic or fused heterocyclic group having from 5 to 10 ring atoms and containing at least one 8 oxygen, sulfur or nitrogen atom. The group R may optionally have one or more substituents, such as for example alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, alkoxycarbonyl, acyloxy, hydroacy, carboxy, amino, monoto trialkyl-amino, acylamino, cyano, carbamoyl, mono- or di-alkylcarbamoyl, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, nitro, phenoxy, halophenoxy, alkylsulfonyloxy, arylsulfonyloxy, cyanothio, and 5- or S-membered heterocyclic groups containing at least one oxygen, sulfur or nitrogen atom. Where the substituent contains a carbon atom or atoms, the number of the carbon atoms Is from 1 to 9. Where R itself is an alkyl, alkenyl or alkynyl group, the above-described substituent cannot be an alkyl, alkoxyalkyl or haloalkyl group.

Q Where R is a alkyl group, it may be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bieyeXo[2„2.1Jheptyl.

Where R Is a C? Q aralkyl group, it may be, for example, benzyl, phenethyl, phenyIpropyl, c-methylbenzyl or α,α-dimethylbenzyl. - 17 8 Where R is a alkenyl or alkynyl group, it may be, for example, vinyl, propenyi, ethynyl or propynyl.

Where S is a cq_i0 aryl group,, it may be, for example, a phenyl or naphthyl group.

Where R is a heterocyclic group, it may be, for example, furyl, thienyl, pyrrolyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrrazolyl, pyranyl, triazolyl. triazinyl, quinazolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyi, thiazolidinyl, piperazyl, morpholinyl, thiomorpholinyl, tetrahydroquinolyl, quinuclidinyl or thienofuranyl.

Where R is further substituted, such further substituents include, for example, methyl, ethyl, isopropyl, t-butyl, methoxy, ethoxy, isopropoxy, methoxymethyl, methoxycarbonyl, ethoxycarbonyl, chloromethyl, trichloromethyl, trifluoromethyl, 2-chloroethyl, fluorine, chlorine, bromine, iodine, hydroxy, carboxy, amino, methylamino, dimethylamino. diethylamino, diisopropylamino, (diethyl)methylamino, acetylamino, trifluoroacetylamino, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoy1, fluoroacetoxy, trichloroacetoxy, mercapto, methylthio, cvanothio, methylsulfinyl, methanesulfonyl, nitro, phenoxy, D-chlorophenoxy, the 5- or δ-membered heterocyclic heterocyclic groups set out above in the definitions of R8, and the 2»2-dimethyl-l, 3-dioxolanylmethoxy» 3,4-dihydro-2H- pyran-2-carbonyloxy and 3,4,5,, 6-diisopropvlidene- D-galacturonyloxy groups.

Preferred compounds include those where R 4 represents hydrogen and the esters where R represents 8 the group -CO-R . In these esters, the group R is preferably a (C^ ? alkanoyl)oxymethyl group, a chloromethyl group,, an iodomethyl group, a mono-, di- or trialkylaminomethyl group (and particularly a trialkylaminomethyl group, wherein the nitrogen is quarternized), a (heterocyclic amino)methyl group (such as 1-piperidylmethyl or X-morphoXinyimethyl), a 2-carboxyethyl or 3-carboxypropyl group, or the 2,2-dimethyl-l»3-dioxolan-4-ylmethoxy group. Compounds 8 where R is (C^ ? alkanoyl)oxymethy1 are particularly preferred. The most preferred values for 4 R are hydrogen, acetoxyacetyl and pivaloyloxyacetyl.

Where R® is a C^_g alkyl group, it may be a straight or branched 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 R6 is a C1 haloalkyl group, it is a straight or branched chain alkyl group subsituted by a halogen atom or atoms and it includes,, for example, a chloromethyl, fluoromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or 3-£luocopcopyl group, preferably the chloromethyl group. δ Where R is a alkoxyalkyl group, it is an alkyl group subsituted by one or more of straight or branched chain alkoxy groups and it includes, for example, the methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl and isopropoxymethyl groups, preferably the methoxymethyl group.

Where R6 is a alkoxy group, it is a straight or branched chain alkoxy group and it includes, for example, the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and sec-butoxy group, preferably the methoxy group.

Where R5 is a ci_« alkylthio group, it may have a straight or branched alkyl chain, for example the methylthio, ethylthio, propylthio, isopropylthio and butylthio groups, preferably che methylthio group. - 20 £ Η is more preferably C,_3 alkyl (particularly methyl or ethyl), or phenyl, and most preferably methyl or ethyl.

Where Rz is a C’14 alkyl group, it may be a straight or branched chain alkyl group and it includes, for example, the methyl, ethyl, propyl, isopropyl and butyl groups, preferably the methyl group.

. Compounds xn which R 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, benzothiophenyl, indolyl, quinolyl, quinazolinyl or quinoxalinyl group,, preferably a furyl, thienyl, pyridinyl, benzothiophenyl or quinolyl group.

Where A is further substituted, such further substituents may be selected, for example, from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, nitro, cyano, phenoxy. p-chlorophenoxy, o-fluorophenoxy, o-chlorophenoxy. o-fluorophenoxy, o-trifluorophenoxy, o-trifluorophenoxy, 2- furyloxy, 2-thienyloxy, 2-pyrrolyloxy. 2-pyridyloxy„ 3- pyridyloxy, 2-quinolyloxy. 2-benzoxazolyloxy, *i · — - 21 2- quinoxalyloxy, 2-quinazolinyloxy, 2,4-dichlorophenoxy, -trifluoromethyl~2-pyridyloxy, - trifluoromethyl-3-chloro-2-pyridyloxy, 3- ehloro-2-fuEyloxy„ 3-chlorothienyl-2-thienyloxy, 2-chloro-5-pyridyloxy, 6-ehloro-2-benzoxazolyloxy and 6- chloro-2-quino2£alinyloxy„ Preferred substituents are methyl, methoxy, trifluoromethyl. chloro, fluoro. 2-chloro-6-pyridyloxy and 6-chloro-2-benzoxazolyoxy.

The preferred groups A-(W)n- are those in which n = 0. such as phenyl, halophenyl (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 2 carboxyl group may be present in the substituent R or Y. As will be readily understood, esters and salts of such compounds may be formed by conventional techniques, and such esters and salts are also included within the scope of the invention.

In particular, such salts include chose with alkali metals such as lithium, sodium or potassium, alkaline earth metals such as calcium or barium, other metals λ such as magnesium or aluminium, and organic amines, particularly tertiary amines such as triethylamine and - 22 triethanolamine. The alkali metal salts are preferred, and particularly the sodium and potassium salts.

Xt will also be appreciated from formula (X) 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 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 ¥ represents the group =N-OK3„ can exist in the form of syn- and anti-isomers; and the individual syn- and anti-isomers are included within the scope of the invention, as well as mixtures thereof. - 23 The following Tables give examples of individual compounds in accordance with the present invention, the compounds being identified by means ef the substituent groups shown in formula (I) above, in all the compounds of Tables 1(A)-(D), V represents the group -0R\ - 24 TABLE .I: gAl In compounds 1-104,., there is a carbon-carbon single bond between the atoms at positions 22 and 23, X represents a hydrogen atom, and H , R~ and Y have the meanings below. shown Ko. R1 B2 Y 1 methyl a-methylbenzyl -OH 2 ethyl G-methylbenzyl -OH 3 isopropyl α-methy1benzv1 -OH 4 see-butyl α-methy1benzy1 -OH 5 ethyl c-ethylbenzyl -OH 6 ethyl G-propylbenzyl -OH 7 ethyl a-isopropylbenzyl -OH 8 ethyl G-butylbenzyl -OH 9 ethyl a-sec-butvlbenzyl -OH 10 ethyl benzhydrvl -OH 11 ethyl a„c-dimethylbenzyl -OH 12 sec-butyl c,α-d imethy1benzyl -OH 13 ethyl G-ethyl-G-methylbenzyl -OH 14 ethyl G-isopropyl-G-methylbenzyl -OH 15 ethyl G-methylbenzhydrvl -OH 18 ethyl g,G-diethylbenzyl -OH 17 ethyl G-methy1-p-chlorobenzyl -OH 18 ethyl G-methy1-m-chlorobenzyl -OH 19 ethyl G-methy1-p-chlorobenzyl -OH - 25 No. a1 a4 Υ ethyl a-methyl-u-fi luorobeazy 1 -OH 21 ethyl c-methyl-u-trifluoromethylbeazyl -OH 22 ethyl κ-methyl-o-trifluoromethylbenzyl -OH 23 ethyl G-methyl-o-cyaaobeazyl -OE 24 ethyl a-methyl-jj-saethylbenzyl -OH 25 ethyl a-methyl-m-methoxybenzyl -OH 26 ethyl a-methyl-o-aitrobenzyl -OH 27 ethyl -OH 28 ethyl α, <&-d ί me thy 1 -p- £luorobenzy1 -OH 29 ethyl cz ,,, α-d i ethy 1 chi o r obenzy 1 -OH 30 ethyl a-methyi"2,4-dichlocobensyl -OH 31 ethyl c-methyl-2,6-dichlorobenzyl -OH 32 ethyl ct-methyl-2,4-difluorobeazyl -OH 33 ethyl c-methyl-2,6-di£luorobenzyl -OH 34 ethyl c-methyX~3-nitro-4-chlorobenzyX -OH 35 ethyl a-methoxybeazyl -OH 36 ethyl a-ethoxybeazyi -OH 37 ethyl c-methoxymethylbenzyl -OH 38 ethyl a-tae thoxye thy 1 benzy 1 -OH 39 ethyl c-chlOEomethylbe&zyl -OH 40 ethyl a-chloromethyl-a-methylbenzyl -OH 41 ethyl α-fluoromethylbenzyl -OH 42 ethyl -OE 43 ethyl c-cyanobenzyl -OH 44 ethyl 1-(3-pyridy1>ethyl -OH 45 ethyl 1-(2-pyridyl)ethyl -OH No. R1 R2 Y 5 <6 ethyl 1-C 4-pyridy1)ethyl -OH 47 ethyl 1-C 2-thienyl)ethyl -OH 48 ethyl 1-(2-fury 1)ethyl -OH 49 ethyl 1-(2-benzothieay1)ethy1 -OH 10 50 ethyl 1-(2-benzofuranyl)ethyl -OH 51 ethyl l-methyl-2-pheaylethyl -OH 52 ethyl 1,1-diraethy1-2-phenylethyl -OH 15 53 . ethyl 1-phenoxyethy1 -OH 54 ethyl 1-raethyl-l-phenoxyethyl -OH 55 ethyl l-(u~ehlorophenoxy)ethyl -OH 5S ethyl l-methyl-l-(a-chlorophenoxy)ethyl -OH 20 57 ethyl 1-[o-(phenoxy)phenoxy 3ethyl -OH 58 ethyl l-[o-(£-chlorophenoxy)phenoxy3ethyl -OH 59 ethyl 1-[o-(2,4-dichlorophenoxy)- -OH 25 SO ethyl phenoxy3 ethyl I-(o-(o-tritluororaethyIphenoxy)- -OH SI ethyl phenoxy3 ethyl !-(£-( 5-trifluororaethy1-2-pyridyloxy)- -OH 30 52 ethyl phenoxy)ethyl l-i£-(3-chloro-5-trifluoromethy1-2- -OH S3 ethyl pyri dy1oxy)phenoxy3 ethy1 1-[3-chloEO-4-(5-trifluororaethy1-2- -OH 35 64 ethyl pyridyloxy)phenoxy3 ethyl l-fu-(6-chloro~2-benzoxazolyloxy)- -OH p he noxy 3 e thyl No. R1 a2 ¥5ss ethyl 1-Efi- C 6-chloro-l,4-dihydro-2~ -OH quinoxa1inyloxy)phenoxy3 ethyl 66 ethyl G-methyl-o-fluorobenzyl -OH 57 ethyl G-cyclohexyIbenzy1 -OH 10 58 ethyl l~phenyIcyclopropyl -OH 55 ethyl 1-{pheny1thio)ethyl -OH 70 ethyl l-phenylcyclopropyl -OS 71 ethyl G-methyl-o-methyIbenzy1 -OH 15 72 ethyl (S)-c-methylbenzy1 -OH 73 ethyl (R)-c-methyIbenzy1 -OH 74 ethyl G-methyl-n-aminophenyl -OH 75 ethyl 1-(2-pyridon-l-y1)ethyl -OH 20 76 ethyl l-(2-piperidon-l-yl)ethyl -OH 77 ethyl 1-(2-piridyl)ethyl -OH 78 1,3-dimethyl- c-xne t hy1be nzy1 -OH 25 1-butenyl 79 cyclopentyl a,α-diraethyIbenzy1 -OB 80 2-methyIcyclopropyl G-methyIbenzy1 -OH 81 butyl G„G-dimethyIbenzy1 -OH 30 82 l-propenyl a-metfeylbenzyl -OH 83 2-methoxyethyl α-methyIbenzy! -OS 84 isobutyl α-metfeyl-o-fluorobenzyl -OH Mo. R1 R2 v 85 ethyl «-aethy1benzv1 acetoxy SS ethyl «-aethylbenzyl chloroacetoxy 87 ethyl «-methyIbenzyl propionyloxy 88 ethyl a~mathy1be nzy1 acetoxyacetoxy 89 ethyl «-methyIbenzyl ethoxycarbonyloxy 90 ethyl «-methylbenzyl 2,3-dihydEoxypropoxy- carbonyloxy 91 ethyl «-methylbenzyl 3,4-dihydro-2H-pyran- 2-yl-carbonyloxy- aethoxycarbonyloxy 92 ethyl «,α-dimethylbenzyl propionyloxy 93 ethyl a,«-dimethylbenzyl chloroacetoxy 94 ethyl a„«-dimethylbenzyl pivaloyloxyacetoxy 95 ethyl a,«-dimethyIbenzyl 3-carboxypropionyloxy 9S ethyl a,a-dimethyIbenzyl ethoxycarbonyloxy 97 ethyl a,a-diaethylbenzyl (2,2-dimethyl-l,3- dioxolanyl)methoxy- carbonyloxy 98 ethyl «,«-dimethyIbenzyl imidazol-l-yl- methoxycarbonyloxy 99 ethyl a-methyl-£>-chloEo- benzyl chloroacetoxy 100 ethyl «-methyl-^-phenoxy- trifluoroacetoxy benzyl - 29 Y chloroacetoxy ethoxycarboayloxy chloroacetoxy acetoxyacetoxy Mo. 8 a g 101 ethyl a-methyl-o-'Chlorobenzyl 102 ethyl c-methyl-q-ehlorobenzyl 103 ethyl c.,a-diaaethylben2yl 104 ethyl α,α-dimethylbenzyl - 30 TABLE 1(B) In compounds 1Ο5-ΪΟ8» there is a carbon-carbon single bond between the atoms at positions 2,2 and 23» X represents a hydroxy group» and r\ R2 and Y have the meanings shown below.

No. R1 R2 Y 105 cyclopentyl G-methylbenzyl -OH 106 1-(methylthio)ethyl «-methylbenzyl -OH 107 ethynyl «-methylbenzyl -OH 108 2-cyclohexen-X-yl «-methylbenzyl acetoxycarbonyloxy TABLE HO In compounds 109-115, there is a carbon-carbon double bond between the atoms at positions 22 and 23, X represents a hydrogen atom, and R , R and Y have the meanings shown below. mo. a1 a2 y 109 cyclopentyl α,α-diiaethylbenzyl -OH 110 cyclohexyl «χ-methyl benzyl -OH 111 propyl G-methylbenzyl -OH 112 2-(methylthio)ethyX G.G-dimethylbenzyl -OH 113 cyclopropyImethyl G-methylbenzyl -OH 114 cyclo bu tyImethy1 c„g—dimethylbenzyl -OH 115 cyclobutyl G-saethylbenzyl chloroacetox^ TABLE 1 (Ρ) In compounds 116-120, there is & carbon-carbon single bond between th© atoms at positions 22 and 23, X and the ring carbon atom to which it is attached together represent the group C=O, and X 2 B , a and Y have the meanings shown below.

No. a1 a2 y 116 1,3-dimethyl-l-butenyl G-methylbenzyl -OH 117 1,3-dimethyl-l-butenyl G,a-dimethylbenzyl -OH 118 1-methyl-l-butenyl G-methylbenzyl -OH 119 1,3-dimethyl-l-butenyl a-methylbenzyl chloroacetoxy 120 1,3-dimethyl-l-butenvl G-methylbenzyl acetoxyacetoxv The most highly preferred compounds are those with numbers 2, 5, 7, 11, 13, 19, 85 and 88 in Table 1 (A). - 33 The compounds of the invention can be prepared from the corresponding 13-hydroxy-5-ketomilbeaxycins of formula (II), by the processes shown in Reaction Scheme Ho. 1, 7 in which 3 , S , 8 . X. 5., W, a and the broken line have the meanings already defined» and R~a represents a carboxylic or carbonic acid residue.

REACTION SCHEME No. 1 - 34 10 Of the starting compounds (II), those in which R1 is the methyl, ethyl, isopropyl or sec-butyl group may be prepared by the methods disclosed in USP 4423209 or Japanese Patent Kokai 81-103884. Compounds in which R1 is the 1-methyl-l-propenyl, 1-methyl-l-butenyl or 1,3-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. 170 005, by the method described in Pesticide Chemistry, by J. Miyamoto and p.c. 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-positxon to a suitable thioester, by conventional techniques, and then reducing the resulting compound by fhe same method as before.

Step A in Reaction Scheme 1 comprises reacting a compound of formula (II) with a carboxylic acid of formula (Vi): E6 I A-(W) -C-COOH (VI) η ι ί 7 R 7 (wherein., R , R , W, n and A are as defined above) or a reactive derivative thereof to give the 13-estec compound of formula (IXa). - 35 Step A consists ia aa esterification reaction between the hydroxy group at the 13-position of compound (II) aad che carboxylic acid (VI). aad 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 anhydrides, mixed acid anhydrides, active esters (such as p-nicrobenzvl 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), p-toluenesulfonic 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 co 5 equivalents, preferably from 1.5 to 4 equivalents.

The reation is normally effected in the presence of a solvent, the nature of which is not critical, provided that it has no adverse effect upon th© reaction.

Suitable solvents include, for example, hydrocarbons such as hexane, petroluem ©ther. benzene, toluene, xylene, chloroform, methylene chloride or o-chlorobenzene, ethers such as diethyl ether. - 36 tetrahydrofuran. dioxane or ethylene glycol dimethyl ether, and esters such as methyl acetate or ethyl acetate. Normally, the reaction is carried out at a temperature in the range of from 0°C to 100°C„ preferably from 2O°C to 5O°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 base.

Suitable bases include,, for example, triethylamine, N.N-dimethyXanilxne. pyridine, 4~aimethylamxn.opyridi.ne, 1, S-diazabxcycloi4.3.0]nonene-5 (D3N) and l,8-dia2abicyclo[5.4.0)-undecene-7 (DBU).

Normally, che amount of che 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 temperature and the reaction time are similar to those when a carboxylic acid itself Is used.

Step B consists in reducing the carbonyl group at the 5-positioa of the compound (Ila) to the hydroxy group, and this may be effected by any reducing method, known per se (see Japanese Patent Application ΊΤ - 37 60-210748). However, it is necessary not to damage any part of the molecule other than the 5-position and hence it is desirable that the reduction is carried out with anionic hydrogen. Reagents capable of liberating anionic hydrogen include, for example, sodium borohydride and diborane. of which sodium borohydride 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 critical, provided that it does not have any adverse effect upon the reaction. Examples of suitable solvents include, for example, methanol, ethanol, diethyl ether, tetrahydrofuran and benzene.

Normally, the reaction is performed at a temperature in the rang® of from -10**C to 50°C, preferably from O°C to 20®C for a period of from 30 minutes to 3 hours.

Step C consists in reacting a compound of formula (lib) with a carboxylic acid or carbonic acid, or a reactive derivative thereof, to give a 5-ester derivative of formula (lie). This reaction is an esterification reaction between the hydroxy group at the 5-position of the compound (Hb) and an acid, and therefore, if may be performed by any esterification reaction known per se as in Step A. - 38 The nature of fhe 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 (IXa), (lib) and (lie) may be recovered from the reaction mixture by well known means and, if necessary, further purified by such conventional techniques as column chromatography.

The compounds of formula (II) which are used as starting materials are milbemycin compounds or milbemycin analogues which are fermentation products, or can be obtained from the natural products by known techniques, such as those mentioned in the prior art references set out earlier in this specification. Normally, the milbemycins are produced as mixtures of several compounds, the different compounds being produced at different rates. Each compound may be isolated and subsequently subjected to the reactions. Alternatively, mixtures of the 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. - 39 The compounds of the invention having a 23-keto group can be obtained from th® corresponding natural product, for example, by the following sequence of steps. The natural product having a 5-hydroxy group is oxidised to the corresponding 5-oxo compound, e.g. with manganese dioxide. The 5-oxo derivative is treated with a lower alkanoic aeid (e.g. formic acid) and selenium dioxide, and then with aqueous hydrochloric acid., giving the corresponding 13-hydroxy-5~oxo derivative - i.e. a compound of formula (XI) 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 13-esterified-5-oxo compound, such as a compound of formula (la) or (Ila) above. The 5-oxo group can then be converted to the 5-oxime, using the methods already described: or it can be converted to a 5-hydroxy group by reducing it e.g. with sodium borohydride.

The compounds of the invention have a strong acaricidal activity against, for example, adults, imagos and eggs of Tetranvchus. Panonychus (e.g. Panonychus ulmi and Panonychus citril. Aculopa pelekassi and rust mites, which·are parasitic to fruit trees, vegetables and flowers. They are also active against Ixodida.e, Dermanyssidae and Sarcoptidae. which are parasitic to animals. Further, they are active against: exoparasxtes, such as Oestrus, Lucilia, Hypo_derma, - 40 Gautrophilus. lice and fleas, which are parasitic to animals and birds, particularly livestock and poultry; domestic insects, such as cockroaches and houseflies; aad various harmful insects in agricultural and horticultural areas, such as aphids and larval Lepidoptera. They are also effective against Meloidogyne in the soil, Bursaphelenchus and Rhizoglvphus. They are also effective against insects of the orders Coleoptera. Homoptera, Heteroptsra,, Piptera. Thysanoptera, Orthoptera,, Rnoplura, Siphonaptera, Ma llo phage,, Thysanura, Isoptera.

Psocoptera. and Hymenoptera.

The compounds of the invention equally can be used to control other plant-damaging insects,, particularly 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 Helio this, virescens), as well as vegetable crops (e.g. against Leptxnotarsa decemlineata and Myzus persicae) and rice crops (e.g. against Chilo suppressalis and Laodelphax).

The activity of the compounds of the invention is pronounced, both systemically aad by contact. Accordingly, the compounds are very effective against sucking insects, especially sucking insects of the order Homoptera and most particularly the family Aphididae (such as Aphis faba®, Aphis craccivora and Myzus persica®), which ace difficult to control with known compositions.

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

The compounds of the invention can similarly be used to protect animals from a variety of ectoparasites, by applying the compounds co the animals or to the animals' environment, e.g. livestock housing, animal boxes, abattoirs, pasture land and other grasslands, as well as to any other places liable to be' infested. The compounds may also be applied to external parts of the animals, preferably before they are infested.

Moreover, the 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 economic damage. Among the helminths, the nematodes in particular often cause serious infection. Typical genera of nematodes which are parasitic on these animals and against which the compounds of the invention are effective include: Haemonchus, Trichostrongylus, Ostertagia« Netaatodirus, Cooperia, Ascaris,, Bunostomum, Oesophagostomum,, Chabertia, Trichuris, Strongylus,, Trichonema a Dictyocaulus, Capillaria, Heterakis.

Toxocara,, Ascaridla, Oxyuris„ Ancylostoma„ Uncinaria, Toxascaris and Parascaris.

Certain parasitical species of the genera Merna t od irus,,, Cooperica and Oesophagostomum attack the - 43 intestines, while certain species of the genera Haemonchus and Ostertagia parasitize the stomach.., and parasites belonging to the genus Dietyocaulus are found in the lungs. Parasites belonging to the families Filariidae and Setariidae are found in internal tissues and organs, for example, the heart, the blood vessels, the subcutaneous tissues and the lymphatic vessels. The compounds of the invention are active against all these parasites.

The compounds of the invention are also effective against parasites which infect humans. Typical of the parasites which may most commonly be found in the digestive tracts of human beings are parasites of the genera Ancylostoma. Necator. Ascaris, Strongyloides, Trichinella. Capillaria. Trichurxs and Enterobius. The compounds are also active against parasites of the genera Wuchereria. Bruqia, Onchocerca and Loa of the family Filariidae (which are found in blood, tissues and organs other than the digestive tract and are medically important), parasites of the genus Dracunculus of the family Pracunculidae and parasites of the genera Strongyloides and Trichinella, 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 - 44 will vary depending upon the intended use of the composition. For example, where the compounds of the invention are to he employed as anthelmintics,, they are preferably administered orally, parenterally or topically and the form of compositions chosen will he appropriate to the intended route of administration.

For oral administration, the composition of the invention is preferably in the form of a liquid drink comprising a non-toxic solution,, suspension or dispersion of the active compound in admixture with a suspending agent (such as bentonite), a wetting agent or other diluents, preferably in water or another non-toxic solventb The drink, in general, also contains an anti-foaming agent. The active compound would normally 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 weight.

Compositions for oral administration may also be in the form of dry solids, preferably in unit dosage form, such as.capsules, pills or tablets containing the desired amount of the active compound. These compositions may be prepared by mixing the active, compound uniformly with suitable diluents, fillers, disintegrators and/or binding agents, for example starch, lactose, talc, magnesium stearate and vegetable gum. The weight and contents of the preparation will - 45 vary widely, depending upon the nature of che 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 co 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 preferably from 0.0001 to 0.02%, in order to achieve the desired anthelmintic activity.

For parenteral administration, the compound of the invention is preferably dissolved or suspended in a liquid vehicle, preferably a vegetable oil, such as peanut oil or cottonseed oil. Where the compound is a salt of a compound of formula (Ii), the liquid vehicle may be water or another aqueous medium. Depending upon the animal to be treated, the injection may be subcutaneous or into the proventriculus, a muscle or the trachea- Such'preparations would normally contain the active compound at a concentration of from 0.05 to 50% by weight.·.

The compounds of the invention may also be administered topically in admixture with a suitable carrier, such as dimethyl sulphoxide or a hydrocarbon solvent. Such preparations would be applied directly to - 46 the outside of th© animal by spraying (e.g. by a hand spray or ia spray races), by dipping (e.g. in a plunge dip), by a pour-on solution or by manual methods (e.g. hand-dressing).

The dose of active compound may be varied, depending 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 frora 0.01 co 100 mg, more preferably from 0.5 to 50 mgs, per 1 kg body weight. The compound may be administered in a single dose or ia divided doses for a relatively short period, such as from 1 to 5 days.

Where the composition of the invention is intended 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 suspensions, dispersions or 'solutions (which may be directly 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 th® substrate to be treated, and to make it easier to store, transport or handle the active compound. - 47 Solid,, liquid aad gaseous carriers may be employed, chosen from carriers well known in the art for use with compositions of this type.

Such formulations may be prepared by conventional means, e.g. by intimate mixing and/or grinding of the active ingredient(s) with the carrier or diluent, e.g. solvent, solid carrier or, optionally, surface-active agent.

Suitable solvents include: aromatic hydrocarbons, preferably the C. to C fractions from petroleum δ JL& distillation, such as xylene mixtures or substituted naphthalenes; esters of phthalic acid, such as dibutyl or dioctyl phthalate: aliphatic hydrocarbons, such as cyclohexane or the paraffins; alcohols and glycols or esters thereof, such as ethanol, ethylene glycol, ethylene glycol monomethyl ether or ethylene glycol monoethyl ether; ketones, such as cyclohexanone; strongly polar solvents, such as N-methyl-2-pyrrolidone, dimethyl sulfoxide or N,N-dimethylformamide; optionally epoxidized vegetable oils, such as epoxidized coconut oil or soybean oil; and water.

Solid carriers, which may be used, for example, in dusts and dispersible powders, include natural mineral fillers, such as calcite. talc, kaolin, montmorillonite or attapulgite, In order to improve the physical - 48 properties of the composition, it is also possible to add highly dispersed silicic acid or highly 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 pregranulated materials, organic or inorganic, may also be used; examples include dolomite and ground plant 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,, dispersing 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 contain: from 0.01 to 99%, more preferably from 0.1 to 95%, by weight of the active compound; from 1 co 99.99% of a solid or licuid additive; and from 0 to 25%, more preferably from 0.1 to 25%, of a surface-active agent. Whereas commercial products are generally sold as concentrated compositions, they are generally diluted by - 49 the end-user to a concentration of from 0.001 to 0.0001% by weight (from 10 to 1 ppm).

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

Examples 1 to 35 illustrate the preparation of compounds of formula (I) and, for brevity, the symbol Z has been used in place of A-(W)n~C(RV)- in these Examples.

Preparations 1 to 4 illustrate the synthesis of starting materials for use in preparing the compounds of the invention.

Examples 35 to 38 illustrate the activity of the compounds of the invention against various pests.

Unless otherwise specified, the group X at position 23 always represents a hydrogen atom» throughout all of the Examples.

Examples 1 to 29 illustrate the preparation of compounds of formula (Hb) from starting materials of formula (Ila) , by the reaction of Step 0 in the above Reaction Scheme No. 1. - 50 EXAMPLE 1 13-(2-Methyl-2-phenylpropionyloxy)-25-ethylmilbemycin (Compound of formula (IXb) wherein; R1 = ethyl, Z = α,α-dimethylbenzyl, Y = -OH). 3.5 mg of sodium borohydride were added,, under ice-cooling, to a solution of 123 mg of 13-(2-methyl-2phenylpropionyloxy)-5-keto-25-ethylmilbemycin in 5 ml of methanol, and then the mixture was stirred at room temperature for 30 minutes. 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 sulfate and concentrated by evaporation. The residue was purified by column - 51 chromatography through silica gel to give 85 mg (yield: 69¾) of the title compound.

Mass Spectrum (M/z): 704(M~). 585, 645«, 576, 540, 522.

Nuclear Magnetic Resonance Spectrum (CDC13) 5 ppm: 3.94 (Ik, doublet, H at the 5 position, 3 = 5.6 Hz): 4.07 (IH, singlet, OH at the 7 position); 4.28 (IH, doublet of doublets, H at the 5 position, J=5.6, 5.5 HZ); 4.65 (2H, multiplet, H at the 27 position): 4.85 (IH, doublet,, H at the 13 position, 3=10.6 Hz) 7.28 (5H, multiplet).

By following the procedure of Example 1, the compounds of Examples 2 to 120 were prepared, having the characteristics shown.

EXAMPLE 2 13-(2-PhenYlatoptoayloxy)~25~ethylfflilbeiayei.n (Compound of formula (Xlb) wherein: S1 = ethyl, Z = α-methylbenzyl, Y = -OH).

Mass· Spectrum (m/z): 69O(M:) 632, 552. - 52 Nuclear Magnetic Resonance Spectrum (CDC13) δ ppm: 3.947 and·3.952 (IH. doublet, H at the 6 position, J =s 5,2 Hz ) ; 4.05 and 4.08 (IH/ singlet, OH at the 7 position); 4.89 (IH. singlet,, H at the 13 position, J=10.S Hz).

EXAMPLE 3 13-(2-Phenylbutyryloxy)-25-ethyImiIbemycin (Compound of formula (IXb) wherein; R1 = ethyl, % = «-ethylbenzyl, Y = -OH).

Mass Spectrum (m/z); 704(M*), 686.

Nuclear Magnetic Resonance Spectrum (CDCip δ ppm; 3.95 (IH, doublet, K at the 6 position, J=6.2 Hz); 4.05 and 4.08 (IH, singlet, OH at the 7 position); 4.89 and 4.90 (IH, doublet, H at the 13 position, 7=10..5 Hz).

EXAMPLE 4 13-(3-Methyl-2-phenylvalegyloxy)-25-ethylmilbemyein (Compound of formula (lib) wherein; R1 = ethyl, Z = c-sec-butylbenzyl, γ = -OH).

Mass Spectrum (m/z); 732(>T), 714, 604, 540, 522, 504. - 53 Nuclear Magnetic Resonance Spectrum (CDCip δ ppm: 3.95 (IH, doublet, H at the 6 position J=6.I Hz); 4.09 (IH, multiplet, OH at the 7 position); 4.86 and 4.89 (IK, doublet, B. at the 13 position, 0=10.5 Hz).

EXAMPLE 5 13-Benzhydrylcarbonyloxy-25-ethylmilbea>ycin (Compound of formula (lib) wherein: R" = ethyl, Z = benzhydrvl, ¥ - -OH).

Mass Spectrum (m/z): 752(M*), 734, 716.

Nuclear Magnetic Resonance Spectrum (CDCip δ ppm: 3.95 (IH, doublet, H at the 6 position, 0=6.1 Hz): 4.07 (IH, singlet, OH at the 7 position); 4.98 (IH, doublet, H at the 13 position, 3=9.2 Hz).

EXAMPLE 6 13-(2-Methvl~2-phenyIbutyryloxy)-25-ethylmilbemycin (Compound of formula (lib) wherein: R1 = ethyl, z = α-ethyl-a-metfeylbenzyl, ¥ = -OH).

Mass Spectrum (m/z): 718(M*)„ 700. - 54 Nuclear Magnetic Resonance Spectrum (CDClj) δ ppm: 3.94 (IH, doublet,, H at the 6 position, 1=6.2 Hz); 4.08 (IH, broad singlet., OH at the 7 position); 4.87 and 4.90 (IH, doublet, H at the 13 position, 1:-10,. ά HZ) .

EXAMPLE 7 13-(2 ,2-Diphenylpropionyloxy)-25~ethyImilbemyein (Compound of formula (lib) wherein: R1 - ethyl, Z = α-methylbenzhydryl, Y = -OH).

Mass Spectrum (m/z): 766(ΐ·Γ), 748, 730.

Nuclear Magnetic Resonance Spectrum (CDCl^) δ ppm: 4.28 (IB, doublet. H at the 5 position. J«5.9 Hz); 4.51 (IH, doublet. H at the 27 position. 1=15.2 Hz); 4.58 (IH, doublet. H at the 27 position. 1=15.2 Hz); 4.97 (IH, doublet. H at the 13 position. 1=10.6 Hs); .25 - 5.48 (4H, multiplet, H at the 3, 11, 15 and 19 position); .70 - 5.82 (2H, multiplet, H at the 9 and 10 position). - 55 EXAMPLE 8 13-(2-o-.Chlogophenylpgopionyloxy)-25-et.hylmilbeiftycin (Compound of formula (lib) wherein: K~ = ethyl, Z = a-methyl~o~chlorobenzyl, ¥ = -OH).

Hass Spectrum (m/z): 724(M+)„ 70S.

Nuclear Magnetic Resonance Spectrum (CDCl^) δ ppm: 3.95 (IH, doublet, H at the S position, J=6.2 Hz); 4.08 (IH, singlet, OH at the 7 position); 4.92 and 4.94 (IH, doublet, H at the 13 position, j-XO.S Hz).

EXAMPLE 9 13-f2-o-(Trifluoromethyl)phenyIpropionyloxyl-25ethyImi1bemyc1n (Compound of formula (lib) wherein: R = ethyl, z = α-methyl-o-(trifluoromethyl)benzyl, Y = -OH).

Hass Spectrum (m/z): 758(M*). 740, 722.

Nuclear Magnetic Resonance Spectrum (CDC13) δ ppm: 4.31 (IH, broad singlet, H at fhe 5 position); 4.67 <2H, broad singlet, 2H at the 27 position); 4.88 (1H, doublet, H at the 13 position, 3=10.6 Hz); 5.25 - 5.41 (4H, multiplet, H at the 3» 11, IS and 19 position); .70 ~ 5,86 (2H, multiplet, H at the 9 and 10 position).

EXAMPLE 10 . 13- (Z-p-NitroPheaylpropionyloxy )-25-ethylmilbetaycitt (Compound of formula (lib) wherein; R - ethyl, Z = α-methy1-p-nitrobenzyl, γ = -OH).

Mass Spectrum (m/z): 735(M~)„ 607» 589... 522.

Nuclear Magnetic Resonance Spectrum (CDC13) ό ppm: 3.95 (1H, doublet, H at the 6 position, J«6.1 Hz); 4.07 (1H, singlet, OH at the 7 position): 4.91 and 4.92 (IB, doublet, H at the 13 position, 3=10.3 HZ). - 57 EXAMPLE Ή 13>-f2-Methyl-2-o-chloro;ohenylproaionylo: R1 = ethyl,, Z = a,G-disaethyl-p-chlorobenzyl, Y xx -OH) .

Mass Spectrum (m/z): 738(ΜΓ)„ 610, 576.

Nuclear Magnetic Resonance Spectrum (CDCl^) δ ppm: 3.95 (IH, doublet, H at the 6 position, 4=6.2 Hz); 4.07 (IH, singlet, OH at the 7 position); .01 (IH, doublet, H at the 13 position, ,1 = 10.3 Hz).

EXAMPLE .12 13-(2-Methyl-2-p-£luorophenylpropionyloxy)-;25ethyImi1bemycin (Compound of formula (lib) wherein: R1 s ethyl, Z - G.c-diraethyl-o-fluorobenzyl, Y = -OH).

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

Nuclear Magnetic Resonance Spectrum (CDCip δ ppm: 3.95 (IH, doublet, K at the 6 position, 4=6.2 Hz); - 58 4.07 (IH, broad singlet, OH at the 7 position); 4.86 (IH, doublet, H at the 13 position, J=10.3 Hz).

EXAMPLE 13 13-(G-Methoxvbenzvlcar bony loxy )-2 5-e thy Imilbetnycin (Compound of formula (xlb) wherein: R1 = ethyl, Z = ct-methoxybenzyl, Y = -OH).

Mass Spectrum (m/z); 706(Ml·), 688.

Nuclear Magnetic Resonance Spectrum (CDCip δ ppm: 3.94 and 3.95 (IH, doublet, H at the 6 position, J=6.2 Hz); 4.10 (IH, broad singlet, OH at the 7 position): 4.94 and 4.95 (IH, doublet, H at the 13 position, 7--10 6 Hz).

EXAMPLE 14 13-r2-Kethyl~2-(p-chlorophenoxy)pgopionyloxyl-25ethylmilbemycin (Compound of formula (lib) wherein: R1 = ethyl, Z = l-methyl~l-(j>-chlorophenoxy)ethyl. Y 2= ~OH) .

Mass Spectrum (m/z): 754{M ), 736, 718. - 59 Nuclear Magnetic Resonance Spectrum (CDC13) 6 ppm: 3.95 (IH, doublet, H. at the 5 position, 3=6.2 Hz); 4.07 (IH, singlet, OH at the 7 position): .01 (IB, doublet, H at the 13 position, 3=10.3 Hz).

EXAMPLE 15 13-{2-rp(phenoxy)phenoxylpropionyloxy)-25ethylmilbemycin (Compound of formula (lib) wherein: R1 = ethyl, z = l-(p~(phenoxy)phenoxy3ethyl, Y = -OH).

Mass Spectrum (m/z): 798(H*), 780,, 752, 670, 540, 522, 504.

Nuclear Magnetic Resonance Spectrum (CDClj) 5 ppm: 3.96 (IK, doublet, H at the 5 position, 3=6.2 Hz); 4.06 (IH, singlet, OH at the 7 position); 4.95 (IH, doublet, E at the 13 position, 3=10.3 Hz), - 60 EXAMPLE 16 13-{2-ίp-(5-Trifluoromethy1-2-pyridyloxy)phenoxy 1peopionyloxy}-25-ethylmilbemvcin (Compound of formula (Ilb) wherein: R = ethyl, Z = X-[p-(5-ttifluoromethyl-2pyridyloxy)phenoxy)ethyl, ¥ = -OH).

Mass Spectrum (m/z): 867(M+), 849, 831,, 813, 540, 522, 504.

Nuclear Magnetic Resonance Spectrum (CDC13) δ ppm: 3.96 (IH, doublet, H at the 6 position, J=6.2 Hz); 4.10 (IH, broad singlet, OH at the 7 position); 4.98 (IH, doublet, H at the 13 position, 3=10.3 Hz) EXAMPLE Ί7 13-(2-o-Fluorophenylpgo_pionyloxy )-25-ethylmilbemycia (Compound of formula (lib) wherein: R1 - ethyl, Z ~ α-methyl-o-fluorobenzyl, ¥ = -OH).

Mass Spectrum (m/z): 7O8(M^). 694; '690, 580, 540, 523.

Nuclear Magnetic Resonance Spectrum (CDCip 6 ppm: 3.95 (IH, doublet, H at the 6 position. 1=6.1 Hz); 4.29 (IH, doublet, H at the 5 position. 1=6.1 Hz); 4.91 and 4.93 (IK, doublet. H at the 13 position. u = 10.5 Hz), EXAMPLE JS. 13-(1-Phenylcyclohexylearbonyloxy)-25-ethylmilbemycin (Compound of formula (lib) wherein: R1 = ethyl, z = a-cyclohexylbenzyl, Y = -OH).

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

Nuclear Magnetic Resonance Spectrum (CDCl^) δ ppm: 3.95 (IH, doublet, H at the 6 position, 1=6.4 Hz); 4.08 (IH, singlet, OH at the 7 position); 4.86 and 4.89 (IH, doublet, H at the 13 position, 1=10.6 Hz).

EXAMPLE IQ 13-(l-Phenylcyclopentylcarbonyloxy)-25-ethylmilbeBiycin (Compound of formula (lib) wherein: R1 = ethyl, Z = 1-phenylcyclopentyl, Y = -OH). - 62 Hass spectrum (m/s): 730(M ) 712,, 602 540, 522.

Nuclear Magnetic Resonance Spectrum (CDCip 5 ppm: 3.94 (1H, doublet, H at the 6 position, 3=6.2 Hz); 4.07 (IK, singlet, OH at the 7 position): 4.80 (1H, doublet, H at the 13 position, 3=10.6 Hz).

EXAMPLE 2Q 13-Γ2-(Pheny1thio)propionyloxy1-25-ethyimilbemycin (Compound of formula (lib) wherein: R1 = ethyl, 2 = 1-(phenylthio)ethyl, Y - -OH).

Mass Spectrum (m/z): 722(if), 704» 594, 540,. 522.

Nuclear Magnetic Resonance Spectrum (CDCl^) δ ppm: 3.96 (1H, doublet, H at the 6 position, 3=6.5 Hs): 4.04 (IB, broad singlet, OH at the 7 position): 4.93 (1H, doublet, Ή at the 13 position, 3=10.5 Hz).

EXAMPLE 21 13-(l-PhenylcyclopropyIcarbonyloxy)-25-ethylmilbemycin (Compound of formula (lib) wherein: R1 = ethyl» Z = 1-phenylcyclopropyl„ Y = -OH).

Mass Spectrum (m/z): 702(24*)» 684» 574, 540» 522» 504. - 63 Nuclear Magnetic Resonance Spectrum (CDCip δ ppm: 3.95 (IH, doublet, H at the 6 position, J=6.2 Hs): 4.02 (IH, singlet, OH at the 7 position); 4,.87 (IH, doublet, H at the 13 position, J=1O.5 Hz) EXAMPLE 13-(2-o-ToIy lor opiqny lory )-25-e thy Imi Ibetnyein (Compound of formula (IXb) wherein: R1 = ethyl, Z = α-methyl-o-methyIbenzy1, Y = -OH).

Mass Spectrum (m/z): 704(M+), 690, 686, 846, 604, 578, 540, 522.

Nuclear Magnetic Resonance Spectrum (CDCip 6 ppm: 4.23 (IH, multiplet, H at the 5 position); 4.66 (2H, broad singlet, 2H at the 27 position); 4.89 (IH, doublet, H at fhe 13 position, 3=10.6 Hz); 5.25 - 5.42 (4H„ multiplet, H at the 3, 11, 15 and 19 position); .7 - 5.8 (2H, multiplet. H at the 9 and 10 position). - 64 EXAMPLE 23 13-f 2~(S)-P_henylprop_ionyloxy Ί-25-ethylmilbemyein (Compound of formula (lib) wherein: S1 = ethyl, Z = (S)-«-methy Ibenzyl,, Y = -OH).

Mass Spectrum (m/2): 590(7/), 672, 632, 562, 540, 522.

Nuclear Magnetic Resonance Spectrum (CDC13) δ ppm: 3.94 (IH, doublet, H at the 6 position, 3=6.0 Hz); 4.04 (IH, singlet, OH at the 7 position); 4.88 (IH, doublet, H at the 13 position, 7=10,,5 Hz).

EXAMPLE 24 13-Γ2-(R)-PhenylproPionyloxy)-25-ethylmiIbemycin (Compound of formula (lib) wherein: R1 - ethyl, Z - (R)-«-methylbenzyl, Y = -OH).

Mass Spectrum (m/z): 690(1-/), 672, 632, 562, 540, 522.

Nuclear Magnetic Resonance Spectrum (CDCip δ ppm: 3.95 (IB, doublet, H at the 6 position, J>6.0 Hz): 4.08 (IH, broad singlet, OK at the 7 position); 4.89 (IH, doublet, E at fhe 13 position, 3=10.3 Hz). ------- 65 EXAMPLE25 13~(2-p-Aminophenylpropionyloxy)~25-ethylmilbemyein (Compound of formula (lib) wherein: R1 = ethyl, Z = G-methyl-p-aroinophenyl„ ¥ = -OH).

A solution of 131.8 mg of 13-(2-methyl-2-E.-nitrophenylpropionyloxy)-25-ethylmilbemycin in 8 ml of methanol was hydrogenated for δ hours, with stirring,, 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, 504.

Nuclear Magnetic Resonance Spectrum (CDCl^) δ ppm: 3.98 (IH, doublet, H at the 6 position, 1=6.1 Hz); 4.05 (IH, singlet, OH at the 7 position); 4.30 (IH, doublet, H at the 6 position, 1=6,1 Hz): 4.65 - 4.8 (2H, multiplet, 2H at the 27 position); .16 (IH, doublet, H at the 13 position, 1=10.4 Hz); .3 - 5.5 (4H, multiplet): .8 - 5.95 (2H, multiplet): - 66 6-66 (2H, doublet, 4=8.5 Hz); 7.85 (2H. doublet, 4=8.5 Hz).

EXAMPLE 26 13-r2-(2-Pyrldon-l-y 1 )propionyioxy1-25-ethylmilbemycin (Compound of formula (Xlb) wherein; R1 = ethyl, Z = l-(2-pyridon-l-yl)ethvl, Y = -OH).

Mess Spectrum (m/z): 707(M^), 689, 540, 522, 504, 460, 442, 412, 394.

Nuclear Magnetic Resonance Spectrum (CDCip δ ppm: 3.96 (IH, doublet, H at the 6 position, 4=6.0 Hz); 4.04 (IH, singlet, OH at the 7 position); 4.96 and 4.98 (IH, doublet, H at the 13 position, 4=10.6 Hz).

EXAMPLE 27 13-r2-(2-Plperidon-l-yl)pronionyloxy1-25-ethyImiIbemycin (Compound of formula (lib) wherein: R1 = ethyl, Z = i-(2-piperidon-l-yl)ethyl, Y = -OH).

Mass Spectrum (m/z): 540(M -171), 522, 504, 412, 394, 195, 167, 154. - 67 Nuclear Magnetic Resonance Spectrum (CDCip δ ppm: 3.71 (IH, singlet, OH at the 7 position); 3-97 (IH, doublet, H at the 6 position, 3=6.1 Hz); 4.93 and. 4.96 (IH, doublet, H at the 13 position, 3=10.5 Hz).

EXAMPLE ?8 13-f 2-(2-Pyridyl)propionyloxyΊ-25-ethylmilbemycin (Compound of formula (XXb) wherein: S1 = ethyl, Z = l-(2~piridyl)ethyl, Y = -OH).

Mass Spectrum (m/z): 691(¾-5-). 673, 540, 522, 504.

Nuclear Magnetic Resonance Spectrum (CDC13) δ ppm: 3.70 (IH, singlet, OH at the 7 position); 3.92 (IH, doublet, H at the 6 position, 3=6.5 Hz); 4.12 aad 4.28 (IH, triplet, H at the 5 position, 3=6-5 Hz); 4.62 - 4.73 (2H, multiplet, 2H at the 27 position). = 68 EXAMPLE ?Q 13-(2-Phenylpropionyloxy)-23-hydroxy-25-(l.3-dimethyll-butenyl )milbemycin (Compound of formula (IXb) wherein: R1 - 1,3-dimethyl-l-butenyl, Z = a-methylbenzyl, Ϊ0 X = -OH, ¥ = -OH).

Mass Spectrum (m/z): 7SQ(M*), 742,, 725,, 710,, 331.

Nuclear Magnetic Resonance Spectrum (CDCip δ ppm: 3.94 (IH, doublet, H at the 6 position, 3=6.4 Hz),: 4.28 (IH, triplet, H at the 5 position, 3=6.4 Hz); 4.65 (2H, broad singlet, 2H at the 27 position); 4.88 (IH, doublet, H at the 13 position, 3=10.5 Hz) Examples 158 to 163 illustrate the preparation of compounds o£ formula (lie) from starting materials of formula (lib), by the reaction of Step C in Reaction Scheme No. 2 above. - 69 EXAMPLE 30 i3-(2~Methyl~2-phenylpropionylo}ry)--5-O-proPio_nyl25-ethylmilbemycia (Compound of formula (He) wherein: R1 = ethyl, Z ~ c,„«~dimethylbenzyl„ ¥ = propioayloxy). p.1 of propionyl chloride and 38 ul of pyridine were added, under iee-cooling, to a solution of 91 mg of 13-(2"iaethyl-2-pheaylpEopionyloxy)-25-ethylrailbeaycin 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, ia turn, with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated by evaporation. The residue was purified by column chromatography through silica gel to give 75 mg (yield: 76¾) of the title compound.

Mass Spectrum (M/z): 7SO(M*)» 686,, 596» 54,0» 522» 504.

Nuclear Magnetic Resonance Spectrum (CDCl^) δ ppm; 3.99 (1H„ broad singlet» OH at the 7 position); 4.04 (IK, doublet» H at the 6 position, 3=5.9 Hz); 4.53 (1H, doublet, H at the 27 position, 3=14.3 Hz); 4.62 (IH, doublet, H at the 27 position, 3=14.3 Hz); 4.87 (IH, doublet, H at the 13 position, 3=10.3 Hz); 5.25 - 5.45 (3H, multiplet); .5 - 5.6 (2H, multiplet): .65 - 5.8 (4H, multiplet); 7.2 - 7.4 (SH, multiplet).

EXAMPLE 3* -0-(3-Carboxypropionyl)-13-(2-methyl-2-phenylpicopionyloxy)-25-ethylmilbemycin (Compound of formula (lie) wherein: R1 = ethyl, Z = α,α-dimethylbenzyl, Y = 3-carboxypropionyloxy).

Following the procedure of Example 30, but using mg of 13-(2-methyI-2-phenylpropionyloxy)-25-ethyImilbemyein and 100 mg of succinic acid anhydride, there were obtained 61 mg (yield: 70%) of the title compound.

Mass Spectrum (m/z): 804(MA), 704, 686, 668.

Nuclear Magnetic Resonance Spectrum (CDCl^) δ ppm: 4.03 (IH, doublet, H at the 6 position, 3=5.9 Hz); 4,53 (IH, doublet, H at the 27 position, 3=14.2 Hz); 4.62 (IH, doublet, H at the 27 position, 3=14.2 Hz); 4.87 (IH, doublet, H at the 13 position, 3=10.3 Hz); - 71 ~ .35 - 5.5 (3H, multiplet); .5 - 5.6 (2H, multiplet); .65 ~ 5.8 (2H, multiplet); 7.3 (5H, multiplet).

The compounds of Examples 32 to 34 were also prepared by following the procedure of Example 30.

EXAMPLE 32 13-(2-o-ChIorophenylpropionyloxy)-5-O-chloroacetyl25-ethyImi1bemycin (Compound of formula (He) wherein; R = ethyl, Z = a-methyl-o-chlorobenzyl, Y = chloroacetoxy.

Mass Spectrum (m/z): 800(Μ*), 782, 616, 522.

Nuclear Magnetic Resonance Spectrum (CDCl^) δ ppm: 4.57 (IH, doublet, H at the 27 position, 3=15.1 Hz); 4.62 (IH, doublet, H at the 27 position, 3=15.1 Hz); 4.92 (IK, doublet, K at the 13 position, 3=10.6 Hz); 5.27 - 5.41 (3H, multiplet, H at the 11, 15 and 19 position); .56 (IH, multiplet, H at the 3 position); 5.72 - 5.82 (2H, multiplet, H at the 9 and 10 position. - 72 EXAMPLE 33 l3-(2~o-Chlogophenylpropionyloxy)-_5-0-ethoxvcarbonyl25-ethylmilbemycin (Compound of formula (lie) wherein: R1 = ethyl, Z = a-methyl-o^-chlorobenzyl, Y = ethoxycarbonyloxy.

Mass Spectrum (m/z): 796(M+-18), 738, 688, 612, 522, 504, Nuclear Magnetic Resonance Spectrum (CDCl^) δ ppm: 4.06 (IH, broad singlet, OH at the 7 position); 4..10 (IH, doublet, H at the 6 position, 3=5.2 Hz); 4.90 and 4.91 (IH, doublet, K at the 13 position, 3=10.5 HZ).

EXAMPLE 34 13-(2-Methyl-2-phenylpgopionyloxy)-5-0-chloroacetyl25-ethylmilbemycin (Compound of formula (lie) wherein: R1 = ethyl, Z = G,G-dimethylbenzyl„ Y = chloroacetoxy.

Mass Spectrum (m/z): 780(>Γ ),. 616, 597, 522. - 73 Nuclear Magnetic Resonance Spectrum (CDCip δ ppm: 4.03 (IH, singlet, OH at the 7 position),; 4.08 (IH, doublet, H at the 6 position, 3=6.5 Hz); 4.87 (IH, doublet, H at the 13 position, 3=10.5 Kz).

EXAMPLE 3513-(2-Methyl-2-phsnylPcopionyloxy)-5-O-aeetoxyaeetylZS-etbylrailbsmyein (Compound of formula (He) wherein: R1 = ethyl, 2 = «,α-dimethylbenzyl, ........

Y = acetoxyacetoxy. 123 mg of sodium iodide were added to a solution of 129 mg of 13-(2-methyl-2-phenylpropionyloxy)-5-0chloroacetyl-25-ethylmilbemycin in methylene chloride, 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 concentrated to give a crude 13-(2-raethyl-2-phenylpropionyloxy)-5-0-iod.oac6tyl25-ethylmilbemycin, This crude product was dissolved in 15 ml of Ν,Ν-dimethylacetamide, 135 mg of sodium acetate were - 74 added, and 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 and then concentrated. The residue was purified hy preparative thin layer chromatography (Merck Art 5717, 20 x 20 ca. thickness 2 mm), developed with a 1:1 by volume mixture of hexane and ethyl acetate, to give 93.8 mg (yield: 70.6¾) of the title compound.

Mass Spectrum (m/z).: 804(M) 640, 622, 540, 522, 504.

Nuclear Magnetic Resonance Spectrum (CDCl^) 6 ppm: 4.03 (IH, singlet, OH at the 7 position); 4.05 (IH, doublet, H at the 6 position, 4=6.1 Hz); 4.5 - 4.7 (4H, multiplet); 4.87 (IB, doublet, H at the 13 position, 4=10.4 Hz); 5.25 - 5.4 (2H, multiplet); .5 - 5.6 (2H, multiplet); .7 - 5.8 (2H, multiplet); 7.2 - 7.35 (5H, multiplet). - 75 Preparations 1 to 4 illustrate the synthesis of starting materials for use in preparing the compounds of the invention by the reactions described above» PREPARATION 1 13-p-FluoEOphenoxyacetoxy-5-keto-25-ethylmilbemyein (Compound of formula (III) wherein; 7 R = ethyl, R"* = p-fluorophenoxymethyl, n = 0). mg of 1,3-dicyclohexylcarbodxitaide, 62 mg of 13"hydroxy-5-keto-25-ethylmxlbemycin and a trace of 4-pyrrolidinopyridine were added successively to a solution of 17 mg of o-£luorophenoxyacetic acid in 15 ml of methylene chloride, and the resulting mixture was then stirred for 30 minutes at room temperature. After completion of the reaction, the mixture was filtered and the filtrate- was poured info water, followed by extraction with ethyl acetate. The ethyl acetate extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off from the extract, and the residue was subjected to column chromatography over silica gel,, giving 44 mg of the desired compound. - 76 Mass Spectrum (m/z): 708(NT).

Nuclear Magnetic Resonance Spectrum (270 MHz, CDC13) δ ppm: 3.86 (IH, 4.01 (IH, .06 (IH, singlet, singlet, doublet.

OH at the 7 position): H ac the 6 position): H at the 13 position, 1=10.3 Hz).

PREPARATION 2 -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-(I,3-dimethyl-lbutenyl)milbemycin in 5 ml of acetone, and the resulting mixture was stirred vigorously for 30 minutes. The mixture was then filtered over Celite filter aid, and the filtrate was concentrated, giving 59.3 mg of the crude desired compound.

Mass Spectrum (m/z): 610, 592, 574.

Nuclear Magnetic Resonance Spectrum (CDC13) δ ppm: 3.78 (IH, singlet, OH at the 7 position): 3.84 (IH, singlet, H at the 6 position).

PREPARATION 3 f,23-DihyQroxy-5-keto-25-(l,3-dimethyl-i-butenyl)miIbemycin The crude 5-keto-23-hydroxy-25-(l,3-dimethyl-lbutenyl )railbemycin, obtained in preparation 2 above, was dissolved in 3 ml of formic acid, then 13 mg of selenium dioxide were added to the solution, and the resulting mixture was stirred for 1.5 hours at room temperature. The mixture was then filtered over Celite filter aid, and the filtrate was poured into water and then extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was dissolved in a mixture of 2 ml of methanol, 3 ml of dioxane and 1 ml of 2N hydrochloric acid. The solution was kept stirred overnight at room temperature, then poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (Merck, Art 5715, 20 x 20 cm, mm thick), developed with a 1:1 by volume mixture of hexane and ethyl acetate, to give 13.2 mg of the desired compound (yield: 21.7¾). - 78 Mass Spectrum (m/z): S25(M -36), 608, 590, 349, 331, 259, 242, 179.

Nuclear Magnetic Resonance Spectrum (CDC13 + D^O) δ ppm: 73 (IH, doublet,, H at the 13 position, 3=9.7 Hz); 75 (IH, doublet, H at the 25 position. 3=10.5 Hz): 84 (IH, singlet, H at the 6 position).

PREPARATION 4 13-(2-Hethyl-2-phenyIpropionyIoxy)-"5-Reto~25ethylmilbemycin 1.6 g of 2-methyl-2-phenylpropionyl chloride and 0.73 ml of pyridine were added, in turn, co a solution of 557 mg of 13-hydroxy-5-keto-25~ethylmilbemycin 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 purified by column chromatography through silica gel to give 353 mg (yield: 50%) of the title compound. - 79 Mass Spectrum (m/z): 702 (M~~) 684, 538, 520.

Nuclear Magnetic Resonance Spectrum (CDCip δ ppm: 3.84 (IH, singlet, H at the 6 position): 4.01 (IH, singlet, OH at the 7 position); 4.80 (2H, multiplet, H at the 27 position); 4.87 (IH, doublet, H at the 13 position, 4=10.3 Hz); .3 - 5.5 (3H, multiplet, H at the 11, 15 and 19 position): .7 - 5.9 (2H, multiplet, H at the 9 and 10 position); 6.53 (IH, multiplet, H at the 3 position); 7.3 (5H, multiplet).

EXAMPLE 36 Aearicidal activity against Tetranychus urticae The primary leaves of cowpea plants of the species Vigna sinensis Savi were infected with organic phosphate-sensitive mites (Tetranychus urticae). One day after infection, the infested plants were sprayed, using a Mizuho rotary sprayer, with 7 ml of a test solution containing the compound under test at a concentration of0-3ppm, at a rate of 3.5 mg of the test 2 solution per 1 cm of leaf. The plants were assessed after 3 days by examining adult mites, under a binocular microscope, to determine living and dead individuals. - 80 Two plants were used for each concentration and each test compound. The plants were kept during the tes.t in greenhouse compartments at 25°C. The results are reported in the following Table.

Compound of Example No.

Mortality (%) Compound of Example No.

Mortality (%) 1 100 9 70 2 95 11 70 3 95 12 85 4 100 13 100 5 95 14 100 6 100 17 95 7 70 30 80 8 100 Control Compound 1 20 Control Compound 5 45 Control Compound 6 45 Control Compound 7 30 ΤΓ = 81 The Control Compounds were as follows: 1. 25-Ethylmilbemycin (milbemycin ). . 13-Benzoyloxy_25-ethylmilberaycin. 6. l3-Pivaloyloxy-25-ethylmilbemycin. 7. l3-Phenylacetoxy-25-ethylmilbemycin.

These results clearly demonstrate the markedly superior acaricidal activity of the compounds of the invention, as compared with Control Compound No. 1 (i.e. the naturally produced milhemyein Ά ). and also as compared with the 13-substituted derivatives used as Control Compounds 5, 6 and 7. - 82 Example 37 Activity against Dermanyssus gallxnae Compounds of the invention were tested for activity against mites of the species Decmanyssus qallinae.

Groups 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 che treated mites allowed to stand for 3 days at room temperacure.

The compounds of Examples 1-3, 5-9, 12-14, 18-23, 30 and 31, were tested in this way and each produced 100% mortality in the test groups.

Example J.8 Activity against Lucilia serlcata Groups consisting of 30-50 eggs from the species Lucilia sericata, collected immediately after oviposition, were added to test tubes each containing 1 ml of a liquid culture medium and 1 ral of the test compound in solution at a concentration of 100 ppm. 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 end of the 4 days.

The compounds of Examples 1-9, 12-15, 18, 19, 21-23 and 30-33 were tested in this way and each produced 100% mortality in the test groups.

Claims (13)

1. Compounds having the formula 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 carbon atom to which if is attached represents the group C=O; provided that X represents a hydrogen atom when the- broken, line represents a double bond between che carbon atoms ac the 22 and 23 positions: - 85 Y represents the group OR 5 and R represents a hydrogen atom, or an ester-forming carboxylic or carbonic acid residue; R represents an alkyl, alkenyl, alkynyl, alkoxyalkyl or 10 alkylthioalkyl group, each having up to 8 carbon atoms; a cycloalkyl-substituted alkyl group wherein the cycloalkyl moiety has from 3 co ό ring carbon atoms and the alkyl moiety has from 1 to 5 carbon atoms; 15 a cycloalkyl or cycloalkenyl group having from 3 to 8 ring carbon atoms and optionally substituted with ac least one substituent selected from halogen atoms aad alkyl groups having from 1 to 4 carbon atoms; a heterocyclic group having from 3 to 6 ring atoms 20 of which at least one is an oxygen or sulfur atom - 86 aad which may optionally be substituted with at least one substituent selected from halogen atoms and alkyl groups having from 1 to 4 carbon atoms; ·? R” represents the group A-(W) ^-C(R%”) wherein n = 0 or 1; R represents carbon atoms, carbon atoms, carbon atoms, 4 carbon atoms an alkyl group having from 1 to 6 a haloalkyl group having from 1 to 4 an alkoxy group having from 1 to 4 an alkoxyalkyl group having from 1 to , a phenyl group, or a cyano group; R represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; ό 7 anc 5 R and R , together with the caEbon atom to which they are attached, jointly represent a eyeloalkyl group having from 3 to 6 ring carbon atoms; W represents a methylene group, or an oxygen or sulfur atom; and - 87 A represents & phenyl group, a naphthyl group, or a heterocyclic group having from 5 to 10 ring atoms of which at least one is a nitrogen, oxygen or sulfur atom; and said phenyl, naphthyl or heterocyclic group may optionally he substituted with at least oae substituent selected from alkyl, alkoxy and alkylthio groups each having from 1 to 4 carbon atoms, halogen atoms, trifluoromethyl, amino, nitro, cyano, keto, phenoxy (which may itself optionally be substituted with at least one substituent selected from halogen atoms and trifluoromethyl), and heterocyclyloxy groups having from 5 to 10 ring atoms of which at least one is a nitrogen, oxygen or sulfur atom; and salts and esters of said compounds of formula (I).

2. Compounds as claimed in Claim 1, wherein R 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 positions,

3. Compounds as claimed in Claim 1 or 2, wherein R^ represents the residue of organic acid capable of forming an ester group. - 88

4. Compounds as claimed in Claim 1 or 2, wherein R^ represents a hydrogen atom or a group of the formula: -co-(O) n -a 8 wherein n = 0 or 1; and R represents a straight or branched chain C, 1O 1 — lo alkyl group, a 7 cycloalkyl group, a C„ Q aralkyl group, a CL· , alkenyl or alkynyl group, a C. ,. aryl group or a monocyclic or fused heterocyclic group having from 5 co 10 ring atoms and containing ac least on© oxygen, sulfur or nitrogen atom.

5. Compounds as claimed in Claim 1 or 2 f wherein R Z ' represents a hydrogen atom, an acetoxyacetyl group or a pivaloyloxyacetyl group. - 89 6

6. Compounds as claimed in any preceding Claim, wherein R represents a methyl, ethyl or phenyl group, R represents hydrogen or a methyl group, and the group A-(W) n ~ represents phenyl or a halophenyl group. L . 1

7. Compounds as claimed in any preceding Claim, wherein R“ represents an alkyl group having from 1 to δ carbon atoms or an alkenyl group having from 2 to δ carbon atoms, and X represents a hydrogen atom.

8. Compounds as claimed in any preceding Claim, wherein R' represents a methyl, ethyl, isopropyl, sec-butyl. 1-methyl-l-propenyl, 1-methyl-1-butenyl or 1,3-dimethvl-l-butenvl group.

9. A compound as claimed in Claim 1, selected from the group consisting of: 13-(2-phenvlpropionyloxy)-25-ethylmi1bemvcin, 13-(2-phenvlbutyryloxy)25-ethy1mi 1bemvci n, 13-(2-phenvl-3-methylbutyryloxy)-25-ethy1mi 1bemvci n, 13-(2-methvl-2-pheny1propionv 1 oxy)-25-ethylmi1bemvci n, 13-(2-methvl-2-phenylbutyryloxy)-25-eihylmi1bemvci n, 13-(2-o-chlorophenvlpropi onyloxy)-25-ethy1mi 1bemvci n, 13-(2-phenvlpropi onv1oxy)-5-Q-ch1oroacetv1-25-ethy1mi 1bemyc i n, and 13-(2-phenvlpropi onyloxy)-5-Q-aeetoxycetyl-25-ethylmi1bemvci n.

10. An anthelmintic, acaricidal or insecticidal composition, which comprises a compound as claimed in any preceding Claim in admixture with a pharmaceutically, agriculturally, veterinarily or horticulturally acceptable carrier or diluent. - 90

11. A process for preparing a compound as claimed in Claim l e which comprises the steps of reacting a compound of formula 1 2 (in which the broken line X, R and R have the meanings already defined) with a reducing agent capable of reducing the 5-oxo group in said compound of formula (XI) to a 5-hydroxy group, to give a product of formula (in which the broken line, X, R 1 , R®, F, A, VI and n have the meanings already defined) and if desired esterifying said product of - 91 formula (11b) with a carboxylic or carbonic acid or a reactive derivative thereof, to give the corresponding 5-ester of formula 15 7 (in which the broken line, X, R , R , R , A, W and n have the meanings already defined and R^ a represents an ester-forming carboxylic or carbonic acid residue) and, if desired, salifying or esterifying the resulting product of formula (1) to obtain a salt or ester thereof.

12. A process for preparing a compound of Claim 1 substantially as defined herein with reference to Examples 1 to 35.

13. A compound of Claim 1 whenever prepared by a process as claim in Claim 11 or claim 12.