GB1579118A - Carbohydrate derivatives of milbemycin - Google Patents

Description

(54) CARBOHYDRATE DERIVATIVES OF MILBEMYCIN (71) We, MERCK & CO. INC., a corporation duly organized and existing under the laws of the State of New Jersey, United States of America, of Rahway, New Jersey, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed to be particularly described in and by the following statement:- This invention relates to milbemycin. The antibiotic milbemycin, which is also called B41, is a substance that is isolated from the fermentation broth of a milbemycin-producing strain of Streptomyces. The microorganism, the fermentation conditions, and the isolation procedures are more fully described in U.S. Patents Nos. 3,950,360 and 3,984,564. The structure of seven of the thirteen milbemycin compounds are described in the said patents and the stuctures of all thirteen compounds are described in the Journal of Anitbiotics 29 (6) June 1976 pages 76-35 to 76--42 and pages 76-14 to 76-1 6. The milbemycin compounds described in the said patents have no carbohydrate groups substituted on them.

The milbemycin compounds were originally named as B41 compounds and given the nomenclature A1, A2, A3, A4, B,, B2, B3, C1 and C2. Later, however, four additional milbemycin compounds were isolated from the fermentation broth and the structures of all thirteen compounds determined. The series was then named as milbemycin and the nomenclature was changed to a1 to a10 and P, to p3, recognizing the two basic structural differences between the two series of compounds. The following structural formulae and tables fully describe the milbemycin compounds and the relationship between the old and the nomenclature.

Milbemycin R, R2 R3 R4 R5 B-41 α1 H H CH3 CH3 -OH α2 H H CH3 CH3 -OCH3 α3 H H C2H5 CH3 -OH α4 H H C2H5 CH3 -OCH3

Milbemycin R2 R4 R6 B-41 ss1 CH3 -OCH3 -CH2OH Al ss2 C2H5 -OCH3 -CH2OH ss3 CH3 -OH -CH3 The 13- hydroxy milbemycin compounds may be prepared from the 13unsubstituted milbemycin compounds by allylic bromination with N-bromosuccinimide followed by treatment with an alkali metal alkanoate such as sodium acetate, and finally by removing the alkanoyl group by hydrolysis. This process affords the 13-hydroxy group which is then available for substitution with the below described carbohydrate groups.

In the above formulae, at various times, there are found hydroxy groups at the 5, 13 and 22 positions and on the methyl group at the 8 position of formula 11. Any one or more of these hydroxy groups may be substituted with a carbohydrate or sugar residue (also known as a glycosyl group) to form the compounds of this invention. The compounds of the present invention are more precisely defined in the following formulae:

where R is hydrogen or a sugar (glycosyloxy) residue and R@ R@ R@ R@ and R' are defined as follows: R1 R2 R3 R4 H H CH3 CH3 H or sugar H H CH3 CH3 CH3 H H C2H5 CH3 H or sugar H H C2H5 CH3 CH3

O CH3 -OH or sugar I 1 O-C-CHC4H9 CH1 CH H or sugar O CH3 -OH or sugar -O-C-CH-C4H CH3 CH3 CH3 O CEl3 II I -OH or sugar -OC-CH-C4H9 C2 H5 CH3 H or sugar O CH3 -OH or sugar -OC-CH-C4H9 C2H3 CH3 CH3 H H CH3 H or sugar -CH2-O- CN1 H H H CH3 O H or sugar -CH2-O- C1N1 H

wherein R is hydrogen or a sugar (glycosyloxy) residue and R2, R' and R" are defined as follows: R2 R' R" CH3 CH3 -OH or -O-sugar C2H5 CH3 -OH or -O-sugar CH3 H or sugar H provided that in the first of the above structural formulae at least one of R, R1 and R' is a sugar residue and in the second of the above structural formulae at least one of R, R', and R" is or contains a sugar residue.

The nature of the sugar residue in the above sugar containing goups is not critical and any sugar may be substituted onto the milbemycin substrate using the procedures described below. The preferred sugar residues are glucopyranosyl, galactopyranosyl, mannopyranosyl, maltosyl, arabinopyranosyl, lyxopyranosyl, xylopyranosyl, ribopyranosyl, oleandrosyl, rhamnopyranosyl, fucopyranosyl, lactosyl, ribofuranosyl, mannofuranosyl, glucofuranosyl, arabinofuranosyl, mycarosyl, cladinosyl, desosaminosyl, daunosaminosyl and mycaminosyl.

The foregoing sugars are available generally in the D or L configuration. the present invention includes both of the possible configurations for attachment to the milbemycin substrate.

The above carbohydrate or sugar groups may be substituted on the milbemycin or 13-hydroxy milbemycin compounds as(mono, di or tri)-saccharides in which one of the above sugar groups is further substituted with another of'the same or different sugar. In addition, where there is more than one hydroxy group available for substitution, the sugar groups may be present on only one or on more than one of such hydroxy groups, and the substitution may be with identical or different sugar residues.

The preferred sugar substituents are mono saccharide or disaccharide substitution with glucopyranosyl, rhamnopyranosyl, oleandrosyl or daunosaminosyl groups, particularly glucopyranosyl and oleandrosyl.

The process for the substitution of the carbohydrate groups onto the hydroxy groups of the substrate molecule are the Koenigs Knorr process, the silver triflate process and the orthoester process.

The carbohydrate starting materials for the Koenigs-Knorr process, the Helferich modification thereof and the silver triflate process are protected by acylating all of the free hydroxy groups. The preferred protecting group is the acetyl group, however, other groups such as the benzoate may be used. The processes for the blocking of the hydroxy groups are well known. The acetyl blocking groups are also easily removed at the completion of the reaction by catalytic hydrolysis, preferably base-catalysed hydrolysis such as with an alcoholic ammonia solution.

The Koenigs-Knorr and silver triflate processes use as starting materials the acetohalo-sugars such as the appropriate acetobromohexoses and acetobromopentoses of the sugar groups listed above. The bromine atom is substituted on a carbon atom adjacent to an acetyl group and the sugar residue becomes bonded to the substrate at the carbon atom to which the halogen was attached.

In the Koenigs-Knorr reaction the milbemycin compound is dissolved under anhydrous conditions in an aprotic solvent. Ether is the preferred solvent, however, methylene chloride, acetonitrile, nitromethane and dimethoxy ethane may also be used. To the substrate solution is added the acetohalosugar and silver oxide. A single molar equivalent of the sugar is required however, an addition of 1 to 3 moles occasionally aids the reactions although molar excesses beyond 3 tend to make the isolation of the product more difficult. It has been found preferable to use freshly prepared silver oxide for the reaction, since the material tends to lose its catalytic efficiency upon standing for prolonged periods. The silver oxide is prepared from silver nitrate using known procedures. The reaction may be carried out at from 1050 C, but reaction at room temperature is preferred. The reaction generally requires from 2 to 10 days for completion. Reaction progress is monitored by taking aliquot portions from the reaction mixture and examining them with thin layer chromatographic techniques. Possible side reactions are avoided by carrying out the reaction in the dark, and this method is preferred. The product is isolated using known techniques.

In one modification of the Koenigs-Knorr reaction, known as the Helferich modification, a mercuric halide, such as mercuric chloride or bromide, alone or in combination with mercuric oxide or mercuric cyanide, is substituted for the silver oxide. The above described reaction conditions may be used except that nitromethane and benzene are the preferred solvents and reflux temperature is the preferred reaction temperature.

The silver triflate reaction uses the reagent silver triflate (silver trifluoromethylsulfonate) and the acetohalosugar in the same solvents as those listed above, with ether being preferred. The silver triflate is best if highly purified and prepared fresh just prior to its use. Methods for the preparation of silver triflate as well known. All of the reactants are combined in the solvent and the reaction is conducted at from 10 to 500C for from 2 to 48 hours. Generally, however, the reaction is complete in about 24 hours at room temperature. The progress of the reaction may be followed by thin layer chromatography techniques. Again the reaction is preferably carried out in the dark, and with absolutely dry reactants and equipment.

A single mole of the sugar is required, however, a single molar excess if often used to aid in the course of the reaction.

During the course of the reaction a mole of triflic acid (trifluoromethanesulfonic acid) is liberated. This is a very strong acid and a molar equivalent of a base is required to neutralize the acid. Preferred bases are non-nucleophilic bases such as tertiary amines, preferably triethylamine, diisopropylethylamine diazabicycloundecane and diazabicyclonnonane. Since triflic acid is such a strong acid, if the base used is not a strong enough base to neutralize all of the acid, the residual acid will adversely affect the course of the reaction and the isolation of the product.

The product is isolated using known techniques.

The orthoester process prepares sugar derivatives of the milbemycin compounds from orthoesters of a lower alkanol and of the above sugars at the hydroxy function of the said milbemycins. The ortho esters are prepared from the acetohalosugars using a lower alkanol and well known procedures. The reaction is carried out in an aprotic solvent such as dichloroethane, nitromethane, methylene chloride, dimethoxy ether, acetonitrile or tetrahydrofuran. Dichloroethane, nitromethane, dimethoxy ethane and tetrahydrofuran are preferred. The reaction is preferably carried out at the reflux temperature of the reaction mixture and is generally complete in from about 4 to 24 hours. Catalytic amounts of mercuric bromide or mercuric chloride are added to aid in the reaction. During the course of the reaction one mole of the alcohol used to make the orthoester is liberated. Thus, the preferred method is to azeotropically distil off the solvent to remove the alcohol and to force the reaction to completion. To prevent any volume reduction, fresh solvent is added as the distillation proceeds to maintain a constant volume. To isolate the product, the solvent is generally removed and the residue washed with a reagent to remove the mercury salts, such as aqueous potassium iodide. The product is then isolated using known techniques.

Where there is more than one position with a hydroxy group that is susceptable to reaction (the 7-position tertiary hydroxy has been found to be less reactive towards substitution with a sugar residue than the others), selective substitution may be obtained by careful ordering of the reaction steps. For example if the 13-hydroxy-5-glycosyloxy milbemycin a1 is desired, the sugar reactions may be carried out on the 13-unsubstituted milbemycin a1 and then the reactions required to prepare the 13hydroxy may be carried out. Further glycosylation reactions may then be carried out on the 13-hydroxy-5-glycosyloxy milbemycin a, to prepare a compound with different sugar groups at the 5- and 13-positions. Alternatively selective acylation of one of the hydroxy groups may be used to direct the glycosylation to another hydroxy group. If the 13-glycosyloxy milbemycin a1 is desired, the 5-hydroxy is protected by acylation, using known techniques and standard acylation reagents such as acid halides and anhydrides. Then the 13hydroxy group is introduced and the glycosylation reactions carried out. The desired product would then be prepared by simple hydrolysis of the 5-acyl group.

Milbemycin a6 and a8 have hydroxy groups at the 22 and 13 positions and processes for selectively glycosylating these compounds would follow a procedure similar to that used for glycosylating compounds at the 5 and 13 positions. The milbemycin a5 and a7 compounds have hydroxy groups at the 5,13 and 22 positions.

The selectivity of the 5 and 22 positions has been found to be very similar, thus reactions under the foregoing conditions will produce a mixture of compounds with sugar residues at the 5 or 22 position or both. Chromatographic techniques have been found to be very useful in separating mixtures of these compounds. In this manner, any combination of compounds with more than one available hydroxy group may be selectively substituted with the above sugar residues.

The following examples are provided in order that the reaction might be more fully understood. They should not be construed as limitative of the invention.

Example 1.

13-(2,3,4,6,-Tetra-0-acetyl-0-glucopyranosyloxy) milbemycin a2 To a solution of 13-hydroxy milbemycin a2 (280 mg.) in anhydrous ether (precautions are taken to ensure anhydrous conditions of solvent and glassware) is added freshly prepared silver oxide (230 mg.) and then acetobromoglucose (410 mg.). The mixture is magnetically stirred at ambient temperature for 4 days in the dark. The solids are filtered and washed with ether and the volume of the filtrate is reduced in vacuo. The resulting solution is purified by column chromatography on silica gel using dichloromethane-methanol mixtures as eluant, affording 13 (2,3,4,6,-tetra-O-acetyl-O.glucopyranosyloxy) milbemycin a!2.

Example 2.

13-(D-glucopyranosyloxy) milbemycin a2 The acetylated glucopyranosyl derivative (50 mg.) of Example 1 is treated with sufficient methanolic ammonia (2 ml., presaturated at 00) to cover the starting material, and the reaction is monitored by thin-layer chromatography at one-hour intervals. The reaction is complete in 6 hours and the solvent is removed in vacuo.

The product is purified by column chromatography using a dichloromethanemethanol mixture as eluant.

Example 3 5-O-(2,3 4,6- Tetra-O-acetyl-O-gtucopyranosyl) milbemycin a To a mixture of milbemycin a1 (560 mg.), acetobromoglucose (820 mg.) and diisopropylethylamine (260 mg.) in anhydrous ether (precautions are taken to ensure anhydrous conditions of solvent and glassware) is added silver triflate (280 mg.). The mixture is stirred (magnetically) at ambient temperature in the dark until further reaction stops (as monitored by thin-layer chromatography). 24 hours' reaction time is required. The solids are filtered and washed with ether and the filtrate is partitioned with aqueous dilute sodium bicarbonate, separated, washed with water, and dried over sodium sulfate. The solvent is removed in vacuo and the product is purified by column chromatography on silca gel using dichloromethane-methanol mixtures as eluant.

Example 4 5-O-( -D-Glucopyranosyl) milbemycin a, Following the procedure of Example 2, the peracetylated glucopyranosyl milbemycin a1 of Example 3 is treated with methanolic ammonia and the product, 5-O-(p-D-glucopyranosyl) milbemycin a1, isolated.

Example 5 13-(2,3,4-tri-O-acetyl-r-L-rhamnopyranosyloxy) milbemycin a, To a solution of 13-hydroxy milbemycin a, (250 mg.) in vigorously anhydrous dichloroethane is added 3,4-di-O-acetyl-l ,2-methylorthoacetyl-p-L-rhamno- pyranose (450 mg.) and mercuric bromide (360 mg.) The mixture is heated at reflux under nitrogen with slow removal of solvent (and formed methanol) by distillation.

Solvent removed by distillation is replaced with fresh solvent from a dropping funnel. The reaction is monitored by thin-layer chromatography and when it ceases to make further progress is cooled, washed with 30% aqueous potassium iodide and water, and dried over sodium sulfate. Column chromatography using chloroformmethanol mixtures as eluants resolves the glycosidic products. After lyophilization from benzene the product 13-(2,3,4-tri-O-α-L-rhamnopyranosyloxy)milbemycin α1 is isolated as an amorphous solid.

Example 6.

13-a-L-rhamnopyranosyloxy) milbemycin a1 Following the procedure of Example 2 using the product of Example 5 as starting material, there is obtained 13-a-L-rhamnopyranosyloxy) milbemycin a1.

Example 7.

13-(L-oleandrosyl-α-L-oleandrosyl)-milbemycin α1 The procedure of Example 1 is followed employing 100 mg. of 5-O-acetyl-13hydroxy milbemycin α1 in place of 13-hydroxy milbemycin α2 and 250 mg. of 4-O acetyl-α-L-oleandrosyl-L-oleandrosyl-L-oleandrosyl chloride in place of acetobromoglucose. (The halogenose is also known as 4-O(4-O-acetyl-2,6-dideoxy-3-O methyl-α-L-lyxo-hexopyranosyl)-2,6-dideoxy-3-O-methyl-L- lyxo-hexopyranosyl chloride). The product is purified using preparative-layer chromatography affording 13-(4-O-acetyl-α-L-oleandrosyl-L-oleandrosyl)-5-O-acetyl-milbemycin a1.

The above compound is hydrolysed according to the procedures of Example 2, affording 13-(L-oleandrosyl-a-L-oleandrosyl) milbemycin a1.

Example 8.

5-0-A cetyl-22-(4-0-A cetyl-a-L-Oieandrnsyl-a-L-oleandrnsyThxy) Milbemycin a6 A solution of 100 mg. of milbemycin a6 is treated with 250 mg. of 4-O-acetyl-a- L-oleandrosyl-L-oleandrosyl chloride (also named as 4-O-(4-O-acetyl-2,6-dideoxy 3-O-methyl-α-L- lyxo-hexopyranosyl)-2,6-dideoxy-3-O-methyl-L- lyzo-hexopyranosyl chloride) following the procedure of Example 3. The product 22-(4-O acetyl-α-L-oleandrosyl-α-L-oleandrozyloxy) milbemycin α6 is isolated and purified on preparative-layer chromatography plates using mixtures of methylene chloride and methanol as solvent.

Example 9.

22-(4-O-Acetyl-α-l-Oleandrosyl-α-L-oleandrosyloxy) Milbemycin α6 The product of Example 8 is hydrolysed following the procedure of Example 2 to produce 22-(α-L-oleandrosyl-α-L-oleandrosyloxy) milbemycin α6. Other compounds obtainable by the above procedures are 5-O-(L-oleandrosyl-α-L- oleandrosyl) milbemycin a1 and 13-(L-oleandrosyl-a-L-oleandrosyl) milbemycin a2.

Preparations.

A. I3-Brnmo milbemycin a2 A solution of 542 mg. of milbemycin a2 and 178 mg. of N-bromosuccinimide in 10 ml. of carbon tetrachloride is stirred under irradiation with ultraviolet light for I hour at room temperature. The mixture is cooled to OOC, the succinimide is filtered off and the solvent is removed by evaporation under reduced pressure.

Cromatography of a solution of the residue in a mixture of chloroform and tetrahydrofuran (95:5) over a column of silica yields 13-bromo milbemycin a2.

B. 13-Acetoxy milbemycin α2 A solution of 621 mg. of 13-bromo milbemycin α2 and 82 mg. of anhydrous sodium acetate in 10 ml. of acetate acid is stirred for 24 hours at 20 C-30 C. The acetic acid is evaporated under reduced pressure and the product is separated from the sodium bromide by extraction with ether and evaporation. Chromatography of the product extracted into the ether in a mixture of chloroform and tetrahydrofuran (95:5) over a column of silica yields 13-acetoxy milbemycin a2.

C. 13-Hydroxy milbemycin a2 A solution of 600 mg. of 13-acetoxy milbemycin (t2 and 44 mg. of sodium hydroxide in a mixture of 8 ml. of methanol and 2 ml. of water is stirred for 10 hours at 0"--10"C. The solvent is evaporated under reduced pressure and the residue is dissolved in chloroform. Chromatography of the chloroform solution over a column of silica yields 13-hydroxy milbemycin a2.

D. Other milbemycin compounds such as 3, a4, a5, Q8 a7, a8, 9 a10, 1 2 and 3 may be similarly converted into the 13-hydroxy derivatives either be ore or after the sugar reactions described above.

It has been found that novel compounds of this invention have significant parasiticidal activity as anthelmintics, insecticides and acaricides, in human and animal health and in agriculture.

The disease or group of diseases described generally as helminthiasis is due to infection of an animal host with parasitic worms known as helminths. Helminthiasis is a prevalent and serious economic problem in domesticated animals such as swine sheep, horses, cattle, goats, dogs, cats and poultry. Among the helminths, the group of worms described as nematodes causes widespread and often times serious infection in various species of animals. The most common genera of nematodes infecting the animals referred to above are Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria. Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris.

Certain of these, such as Nematodirus, Cooperia, and Oesophagostomum attack primarily the intestinal tract while others, such as heamonchus and Ostsrtagia, are more prevalent in the stomach, while still others such as Dictyocaulus are found in the lungs. Still other parasites may be located in other tissues and organs of the body such as the heart and blood vessels and sub-cutaneous and lymphatic tissue.

The parasitic infections known as helminthiases lead to anaemia, malnutrition, weakness, weight loss and severe damage to the walls of the intestinal tract and other tissues and organs and, if left untreated, may result in death of the infected host. Milbemycin derivatives of this invention have been found to possess unexpectedly high activity against these parasites, and in addition to be active against Dirofilaria in dogs, Nematospiroides, Syphacia, Aspiculuris in rodents, arthropod ectoparasites of animals and birds such as ticks, mites lice, fleas, blowfly, in sheep Lucilia sp., biting insects and such migrating dipterous larvae as Hypoderma sp. in cattle, Gastrophilus in horses, and Cuterebra sp. in rodents.

Compounds of the present invention have also been found useful against parasites which infect humans. The most common genera of parasites of the gastrointestinal tract of man are Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria. Trichuris, and Enterobius. Other medically important genera of parasites found in the blood or other tissues and organs outside the gastro-intestinal tract are the filiarial worms such as Wuchereria, Brugia, Onchocerca and Loa, Dracunculus and extra intestinal stages of the intestinal worms Strongyloides and Trichinella.

Compounds of the invention are also of value against arthropods prasitizing man, biting insects and other dipterous pests causing annoyance to man.

Compounds of the invention are also active against household pests such as the cockroach, Blatella sp., clothes moth, Tineola sp., carpet beetle, Attagenus sp. and housefly Musca domestica.

Compounds of the invention are also useful against insect pests of stored grains such as Tribolium sp. and Tenebrio sp. and of agricultural plants such as spider mites, (Tetranychus sp.), aphids and (Acyrthiosiphon sp.);against migratory orthopterans such as locusts and immature stages of insects living on plant tissue.

Compounds of the invention are useful as a nematocide for the control of soil nematodes and plant parasites such as Meloidogyne spp. which may be of importance in agriculture.

These compounds may be administered orally in a unit dosage form such as a capsule, bolus or tablet, or as a liquid drench where used as an anthelmintic in mammals. The drench is normally a solution, suspension or dispersion of the active ingredient usually in water together with a suspending agent such as bentonite and a wetting agent or like excipient. Generally, the drenches also contain an antifoaming agent. Drench formulations generally contains from 0.001 to 0.50/ by weight of the active compound. Preferred drench formulations may contain from 0.01 to 0.1% by weight. The capsules and boluses comprise the active ingredient admixed with a carrier vehicle such as starch, talc, magnesium stearate, or dicalcium phosphate.

Where it is desired to administer the milbemycin derivatives in a dry, solid unit dosage form, capsules, boluses or tablets containing the desired amount of active compound are usually used. These dosage forms are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, fillers, disintegrating agents and/or binders such as starch, lactose, talc, magnesium stearate or vegetable gums. Such unit dosage formulations may be varied widely with respect to their total weight and content of the antiparasitic agent depending upon factors such as the type of host animal to be treated, the severity and type of infection and the weight of the host.

When the active compound is to be administered via an animal feedstuff, it is intimately dispersed in the feed or used as a top-dressing or in the form of pellets which may then be added to the finished feed or optionally fed separately.

Alternatively, the antiparasitic compounds of the invention may be administered to animals parenterally, for example, by intraruminal, intramuscular, intratracheal, or subcutaneous injection, in which case the active ingredient is dissolved or dispersed in a liquid carrier vehicle. For parenteral administration, the active material is suitably admixed with an acceptable vehicle, preferably of the vegetable oil variety such as peanut oil or cotton seed oil. Other parenteral vehicles such as organic preparation using solketal, glycerol, formal and aqueous parenteral formulations are also used. The active milbemycin compound or compounds are dissolved or suspended in the parenteral formulation for administration; such formulations generally contain from 0.005 to 5% by weight of the active compound.

Claims (23)

1. WHAT WE CLAIM IS: I. A compound having the formula:

   where R is hydrogen or a sugar (glycosyloxy) residue and R1, R2, R2, R4 and R' are defined as follows: R2 R2 R3 R4 R4 H H CH3 CH3 H or sugar H H CH3 CH3 CH3 H H C2H5 CH3 H or sugar H H C2H5 CH3 CH3

   O CH3 -OH or sugar -O-C-CHC4H9 CH3 CH3 H or sugar O CH3 -OH or sugar -O-C-CH-C4H9 CH3 CH3 CH3 O CH3 II -OH or sugar -OC-CH-C4H9 C2H5 CH3 H or sugar O CH3 II -OH or sugar -OC-CH-C4H9 C2H5 CH3 CH3 H H CH3 O H or sugar II -CH2-O- C H H H CH3 O H or sugar II jj -CH2-O- CON H

   where R is hydrogen or a sugar (glycosyloxy) residue and R2, R' and R" are defined as follows: R2 R' R" CH3 CH3 -OH or -O-sugar C2 H5 CH3 -OH or -O-sugar Cl13 H or sugar H provided that in the first of the above structural formulae at least one of R, R, and R' is a sugar residue and in the second of the above structural formulae at least one of R, R', and R" is or contains a sugar residue.
2. 2. A compound as claimed in Claim I, in which the sugar is a (mono, di or tri)saccharide derived from glucopyranosyl, galactopyranosyl, mannopyranosyl, maltosyl, arabinopyranosyl, lyxopyranosyl, xylopyranosyl, ribopyranosyl, oleandrosyl, rhamnopyranosyl, fucopyranosyl, lactosyl, ribofuranosyl, mannofuranosyl, glucofuranosyl, arabinofuranosyl, mycarosyl, cladinosyl, desosaminosyl, daunosaminosyl and/or mycaminosyl.
3. 3. A compound as claimed in Claim 2, in which the sugar is a (mono, or di)saccharide derived from glucopyranosyl, rhamnopyranosyl, oleandrosyl and/or daunosaminosyl.
4. 4. A compound as claimed in Claim 3, in which the sugar is a (mono, or di)saccharide derived from glucopyranosyl and/or oleandrosyl.
5. 5. 1 3-(p-D-glucopyranosyloxy) milbemycin 32.
6. 6. 5-O-(ss-D-glycopyranosyl) milbemycin a,.
7. 7. A compound as claimed in Claim 4, in which the sugar is a L-oleandrosyl-a L-oleandrosyl.
8. 8. 1 3-(L-oleandrosyl-a-L-oleandrosyl) milbemycin a1.
9. 9. 5-0-(L-oleandrosyl-a-L-oleandrosyl) milbemycin a,.
10. 10. 13-(L-oleandrosyl-a-L-oleandrosyl) milbemycin a2.
11. I I. A process for the preparation of a compound as claimed in Claim 1 that comprises treating a milbemycin compound or a 13-hydroxy milbemycin compound with an aceto halo sugar in the presence of siver oxide, and removing the acetyl protecting groups by hydrolysis.
12. 12. A process for the preparation of a compound as claimed in Claim I that comprises treating a milbemycin compound or a 13hydroxy milbemycin compound with an aceto halo sugar in the presence of a mercuric halide, alone or in combination with mercuric oxide or meruric cyanide, and removing the acetyl protecting groups by hydrolysis.
13. 13. A process for the preparation of a compound as claimed in Claim 1 that comprises treating a milbemycin compound or a 13-hydroxy milbemycin compound with an aceto halo sugar in the presence of silver trifluoromethylsulfonate and a non-nucleophilic base.
14. 14. A process for the preparation of a compound as claimed in Claim I that comprises treating a milbemycin compound or a 13hydroxy milbemycin compound with an ortho ester of a sugar in the presence of a catalytic amount of mercuric bromide or mercuric chloride.
15. 15. A method for the treatment of parasitic infections, that comprise administering to a non-human animal infected with parasites an effective amount of a compound as claimed in Claim 1.
16. 16. An anthelmintic composition comprising a compound as claimed in any one of Claims 1 to 10 and a non-toxic inert carrier.
17. 17. A composition as claimed in Claim 16 in injectable form.
18. 18. A composition as claimed in Claim 16 in the form of a tablet, capsule, bolus or liquid drench.
19. 19. An animal feed containing as an anthelmintic agent a compound as claimed in Claims 1 to 10.
20. 20 A method of killing pests on growing plants comprising applying to the plant a compound as claimed in Claims 1 to 10.
21. 21. Stored grain containing an insecticidal and acaricidal agent a compound as claimed in Claims 1 to 10.
22. 22. Soil containing as nematocidal agent a compound as claimed in Claims 1 to 10.
23. 23. A compound as claimed in Claim I prepared by a process substantially as hereinbefore described in any one of the foregoing Examples.