compounds of formula ( i ) wherein r 1 is oh and the double bond is absent or wherein the double bond is present and r 1 is absent and r 4 is 4 &# 39 ;-( alpha - l - oleandrosyl )- alpha - l - oleandrosyloxy are prepared by fermenting a streptomyces avermitilis mutant organism atcc 53567 , 53568 or 53692 , as described in european patent applications 88300354 . 3 and 88300426 . 9 in the presence of the appropriate n - alkanoyl cysteamine thioester of the formula ( iii ). wherein r 2 is as defined above , and r 6 is a c 1 - c 10 alkyl group . the thioester is added to the fermentation either at the time of inoculation or at intervals during the fermentation . production of the compounds of formula ( i ) may be monitored by removing samples from the fermentation , extracting with an organic solvent and following the appearance of the compound of formula ( i ) by chromatography , for example using high pressure liquid chromatography . incubation is continued until the yield of the compound of formula ( i ) has been maximised , generally for a period of from 12 to 16 days . a preferred level of each addition of the thioester is between 0 . 05 and 4 . 0 grams per liter . the best yields of the compounds of formula ( i ) are obtained by gradually adding the acid to the fermentation , for example by daily additions of the thioester over a period of several days . the medium used for the fermentation may be a conventional complex medium containing assimilable sources of carbon , nitrogen and other trace elements . after fermentation for a period of several days at a temperature preferably in the range of from 24 ° to 33 ° c ., the fermentation broth is centrifuged or filtered and the mycelial cake is extracted with acetone or methanol . the solvent extract is concentrated and the desired product is then extracted into a water - immiscible organic solvent , such as methylene chloride , ethyl acetate , chloroform , butanol or methyl isobutyl ketone . the solvent extract is concentrated and the crude product containing the compounds of formula ( i ) is further purified as necessary by chromatography , for example using preparative reverse phase , high pressure liquid chromatography . the product is generally obtained as a mixture of the compounds of formula ( i ) wherein r 4 is 4 &# 39 ;-( alpha - l - oleandrosyl ) alpha - l - oleandrosyloxy , r 1 is oh and the double bond absent or r 1 is absent and the double bond is present and wherein r 3 is h or ch 3 ; however the proportions can vary depending on the particular thioester employed and the conditions used in the fermentation . when the micro - organism used is atcc 57692 only the b - type avermectin in which r 3 is h is obtained . it has been found that a range of thioesters as described by formula ( iii ) may be added to the fermentation to yield avermectins having a range of substituent groups at the c - 25 position . examples of particular thioesters which may be employed include the following : a thioester of formula ( iii ), in which r 2 is phenyl and r 6 is methyl ; a thioester of formula ( iii ) in which r 2 is a group as defined in formula ( ii ) in which a and b are 0 , c and d are 1 and x is ch 2 , and r 6 is methyl ; a thioester of formula ( iii ) in which r 2 is a group as defined in formula ( ii ) in which a and b are 0 , c is 1 , d is 2 and x is ch 2 and r 6 is methyl ; and a thioester of formula ( iii ) in which r 2 is a group as defined in formula ( ii ) in which a and b are 0 , c and d are 1 and x is 0 and r 6 is methyl . in one particular and preferred aspect of the invention , the fermentation is performed in the presence of a thioester of formula ( iii ) in which r 2 is phenyl and r 6 is methyl , to yield predominantly the compound of formula ( i ) wherein r 1 is oh and the double bond is absent , r 2 is phenyl , r 3 is h and r 4 is 4 &# 39 ;-( alpha - l - oleandrosyl )- alpha - 4 - oleandrosyloxy , referred to herein as 25 - phenyl avermectin b2 . in another preferred aspect of the invention , the fermentation is performed in the presence of a thioester of formula ( iii ) in which r 2 is 2 - bicyclo [ 3 . 1 . 0 ] hexyl and r 6 is methyl , to yield predominantly the compound of formula ( i ) wherein r 1 is oh and the double bond is absent , r 2 is 2 - bicyclo [ 3 . 1 . 0 ] hexyl , r 3 is h and r 4 is 4 &# 39 ;-( alpha - l - oleandrosyl )- alpha - 4 - oleandrosyloxy , referred to herein as 25 -( 2 - bicyclo [ 3 . 1 . 0 ] hexyl ) avermectin b2 . thioesters of formula ( iii ) may be prepared from the corresponding carboxylic acids of the formula r 2 -- co 2 h by coupling with a thiol of the formula r 6 conhch 2 ch 2 sh in the presence of a dehydrating agent such as dicyclohexylcarbodiimide in an inert solvent or using diphenylphosphorylazide and a base such as triethylamine in dimethylformamide . thiols of the formula r 6 conhch 2 ch 2 sh may be prepared from cysteamine hydrochloride by treatment with a base such as triethylamine followed by trimethylsilyl chloride then an acid chloride of the formula r 6 cocl and a further amount of a base such as triethylamine . the resulting crude thioester is then purified by , for example , column chromatography on silica gel . carboxylic acids of the formula r 2 co 2 h in which r 2 is a group of formula ( ii ), wherein a and b are 0 , and c , d and x are as previously defined may be prepared by the addition of alkyl diazoacetate esters to cycloalkenes of the formula ## str6 ## in the presence of rhodium ( ii ) acetate , followed by cleavage of the resultant carboxylic acid may then be purified by conventional means , for example distillation or crystallization . preparation of bicyclo [ 3 . 1 . 0 ] hexane - 2 - carboxylic acid is described in j . amer . chem . soc ., 85 , 582 - 585 , 1963 ( meinwald j ., labana s . s ., chadha m . s .). compounds of the formula ( i ) wherein the double bond is present and r 1 is absent may alternatively be prepared from the corresponding compound of formula ( i ) wherein r 1 is oh and the double bond is absent by a dehydration reaction . the reaction is performed by first selectively protecting the hydroxyl groups at the 5 and 4 &# 34 ; positions , e . g . as the t - butyldimethylsilyloxy acetyl derivative , then reacting with a substituted thiocarbonyl halide , such as ( 4 - methylphenoxy ) thiocarbonyl chloride , followed by heating in a high boiling point solvent , e . g . trichlorobenzene , to effect the dehydration . the product is finally deprotected to give the unsaturated compound . these steps together with appropriate reagents and reaction conditions are described in u . s . pat . no . 4328335 . the compounds of formula i wherein r 3 is h may also be prepared from the corresponding compounds wherein r 3 is ch 3 by demethylation . this reaction is achieved by treating the 5 - methoxy compound , or a suitably protected derivative thereof , with mercuric acetate and hydrolysing the resulting 3 - acetoxy enol ether with dilute acid to give the 5 - keto compound . this is then reduced using , for example , sodium borohydride to yield the 5 - hydroxy derivative . appropriate reagents and reaction conditions for these steps are described in u . s . pat . no . 4 , 423 , 209 . the compounds of formula i wherein r 1 is h and the double bond is absent can be prepared from the corresponding compound wherein the double bond is present and r 1 is absent , by selective catalytic hydrogenation using an appropriate catalyst . for example the reduction may be achieved using tris ( triphenylphosphine ) rhodium ( i ) chloride as described in european patent application publication no . 0001689 . the compounds of formula ( i ) wherein r 4 is h may be prepared from the corresponding compounds wherein r 4 is 4 &# 39 ;-( alpha - l - oleandrosyl )- alpha - l - oleandrosyloxy by removing the 4 &# 39 ;-( alpha - 6 - oleandrosyl )- alpha - l - oleandrose group by mild hydrolysis with an acid in an aqueous organic solvent to yield the aglycone wherein r 4 is oh ; this is then halogenated , for example by reacting with a benzene sulphonyl halide , to yield the 13 - deoxy - 13 - halo derivative which is finally selectively reduced , for example using tributyltin hydride . in order to avoid unwanted side reactions it is desirable to protect any other hydroxy groups which may be present , for example using a tert - butyldimethylsilyl group . this is then readily removed after the halogenation or reduction step by treatment with methanol containing a trace of acid . all these steps together with appropriate reagents and reaction conditions for their performance are described in european patent application publication no . 0002615 . the compounds of the invention are highly active antiparasitic agents having particular utility as anthelmintics , ectoparasiticides , insecticides , acaricides , and animal growth promoters . thus the compounds are effective in treating a variety of conditions caused by endoparasites including , in particular , helminthiasis which is most frequently caused by a group of parasitic worms described as nematodes and which can cause severe economic losses in swine , sheep , horses and cattle as well as affecting domestic animals and poultry . the compounds are also effective against other nematodes which affect various species of animals including , for example , dirofilaria in dogs and various parasites which can infect humans including gastro - intestinal parasites such as ancylostoma , necator , ascaris , strongyloides , trichinella , capillaria , trichuris , enterobius and parasites which are found in the blood or other tissues and organs such as filiarial worms and the extra intestinal stages of strongyloides and trichinella . the compounds are also of value in treating ectoparasite infections including in particular arthropod ectoparasites of animals and birds such as ticks , mites , lice , fleas , blowfly , biting insects and migrating dipterous larvae which can affect cattle and horses . the compounds are also insecticides active against household pests such as the cockroach , clothes moth , carpet beetle and the housefly as well as being useful against insect pests of stored grain and of agricultural plants such as spider mites , aphids , caterpillars , fire ants , termites and against migratory orthopterans such as locusts . the compounds of formula ( i ) are administered as a formulation appropriate to the specific use envisaged and to the particular species of host animal being treated and the parasite or insect involved . for use as an anthelmintic the compounds say be administered orally in the form of a capsule , bolus , tablet or preferably a liquid drench , or alternatively , they may be administered by injection or as an implant or as a pour - on formulation . such forsulations are prepared in a conventional manner in accordance with standard veterinary practice . thus capsules , boluses or tablets may be prepared by mixing the active ingredient with a suitable finely divided diluent or carrier , additionally containing a disintegrating agent and / or binder such as starch , lactose , talc , magnesium stearate etc . a drench formulation may be prepared by dispersing the active ingredient in an aqueous solution together with dispering or wetting agents etc . and injectable formulations may be prepared in the form of a sterile solution which may contain other substances , for example , enough salts or glucose to make the solution isotonic with blood . these formulations will vary with regard to the weight of active compound depending on the species of host animal to be treated , the severity and type of infection and the body weight of the host . generally for oral administration a dose of from about 0 . 001 to 10 mg per kg of animal body weight given as a single dose or in divided doses for a period of from 1 to 5 days will be satisfactory but of course there can be instances where higher or lower dosage ranges are indicated and such are within the scope of this invention . as an alternative the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed . for use as an insecticide and for treating agricultural pests the compounds are applied as sprays , dusts , emulsions and the like in accordance with standard agricultural practice . for use as a growth promotant or for improving the lean meat to fat ratio in farm or domestic animals , the compounds may be administered with the animal feedstuff or drinking water . alternatively , they may be administered orally in the form of a capsule , bolus , tablet or liquid drench , or parenterally by injection or as an implant . for human use the compounds are administered as a pharmaceutically acceptable formulation in accordance with normal medical practice . the invention is illustrated by the following examples in which example 1 is an example of the preparation of a compound of the formula ( i ) example 2 is an example of the preparation of another compound of formula ( i ). example 3 is an example of a drench formulation and examples 4 and 5 illustrate the antiparasitic and insecticidal activity of the compounds of examples 1 and 2 . a frozen inoculum ( 2 ml ) of a culture of streptomyces avermitilis mutant organism atcc 53568 was inoculated into 50 mls of a medium containing starch ( 1 g ), pharmamedia ( trademark ) ( 0 . 75 g ), ardamine ph ( 0 . 25 g ), and calcium carbonate ( 0 . 1 g ) in a 300 ml flask and incubated at 28 ° c . for 2 days . this inoculum ( 50 ml ) was transferred to a second inoculum flask ( 1 liter ) containing starch ( 20 g ), pharmamedia ( 15 g ), ardamine ph ( 5 g ) and calcium carbonate ( 2 g ) and incubated at 28 ° c . for a further 2 days . this inoculum was used to inoculate 70 liters of a medium containing starch ( 7 kg ), magnesium sulphate ( 70 g ), pharmamedia ( 350 g ), dipotassium hydrogen phosphate ( 70 g ), ferrous sulphate ( 0 . 7 g ), calcium carbonate ( 490 g ), glutamic acid ( 42 g ), zinc sulphate ( 0 . 07 g ) and manganous sulphate ( 0 . 07 g ) contained in a 70 liter fermenter . the fermentation was incubated at 28 ° c ., with agitation at 350 r . p . m . and aeration at 70 liters per minute . s - benzoyl n - acetyl cysteamine ( 24 g ) was added after 24 hours . after 288 hours the mycelium was removed by filtration and extracted with acetone ( 2 × 50 liters ). the acetone extract was concentrated to approximately 10 liters and extracted with ethyl acetate ( 30 liters ) in three portions . the resulting ethyl acetate layers were combined and evaporated to give a brown oil ( 97 . 5 g ). the latter was dissolved in methylene chloride ( 1200 ml ) and stirred with silica gel ( 100 g ) and charcoal ( 100 g ) for 1 hour . the silica and charcoal were removed by filtration through arbacel and the filtrate was evaporated to give a yellow oil ( 74 . 5 g ). the latter was dissolved in 100 ml petrol ( b . p . 40 °- 60 ° c .) and filtered . the filtrate was added to a 500 g alumina ( woelm . akt . b ) column and eluted with petrol ( b . p . 60 °- 80 ° c . ), ( 1 . 5 liter ), ethyl acetate ( 2 liters ) and finally methanol ( 1 liter ). relevant fractions were combined to give 4 . 12 g of a pale brown oil . this was dissolved in methanol ( 200 ml ) and cooled to - 75 ° c . a waxy precipitate appeared and was filtered off . the filtrate was evaporated to give 2 . 98 g of a mobile oil which was dissolved in diethyl ether and added to a column of silica gel ( 35 g ) and eluted with diethyl ether . fractions ( 100 ml ) were collected and fraction numbers 13 to 20 were combined and evaporated to yield partially purified material . the product was dissolved in methanol ( 0 . 7 mm ) and chromatographed on a c18 zorbax ods ( trademark , dupont ) column ( 21 mm × 25 cm ) eluting with a mixture of methanol and water ( 75 : 25 ) at a flowrate of 9 ml per minute . 4 . 5 ml fractions were collected and fractions 86 to 96 were combined and evaporated to yield a compound of formula ( i ) wherein r 1 is oh , the double bond is absent , r 2 is phenyl , r 3 is h and r 4 is 4 &# 39 ;-( alpha - l - oleandrosyl )- l - oleandrosyloxy , as a white powder , m . p . 150 °- 155 ° c . the structure of the product was confirmed by fast atom bombardment mass spectrometry , performed on a vg model 7070e mass spectrometer using a sample matrix of triethylene glycol with solid sodium chloride . ( m + na ) + observed at m / e 933 ( theoretical 933 ). electron impact mass spectrometry was performed using a vg model 7070f mass spectrometer . the m / e values for the principal fragments were : 343 , 325 , 259 , 241 , 231 , 145 , 127 , 113 , 111 , 95 and 87 . a frozen inoculum ( 2 ml ) of a culture of streptomyces avermitilis mutant organism atcc 53568 was inoculated into 50 mls of a medium containing starch ( 1 g ), pharmamedia ( trademark ) ( 0 . 75 g ), ardamine ph ( 0 . 25 g ), and calcium carbonate ( 0 . 1 g ) in a 300 ml flask and incubated at 28 ° c . for 2 days . this inoculum ( 50 ml ) was transferred to a second inoculum flask ( 1 liter ) containing starch ( 20 g ), pharmamedia ( 15 g ), ardamine ph ( 5 g ) and calcium carbonate ( 2 g ) and incubated at 28 ° c . for a further 2 days . this inoculum was used to inoculate 100 liters of a medium containing starch ( 10 kg ) magnesium sulphate ( 100 g ), pharmamedia ( 500 g ), dipotassium hydrogen phosphate ( 100 g ), ferrous sulphate ( 1 . 0 g ), calcium carbonate ( 700 g ) glutamic acid ( 60 g ), zinc sulphate ( 0 . 1 g ) and manganous sulphate ( 0 . 1 g ) contained in a 100 liter fermenter . the fermentation was incubated at 28 ° c . with agitation at 200 r . p . m . and aeration at 80 liters per minute . the n - acetyl cysteamine thioester of bicyclo [ 3 . 1 . 0 ] hexane carboxylic acid ( 16 g ) was added after 43 hours , and again at 115 hours ( 16 g ). after 234 hours the mycelium was removed by filtration and extracted with acetone ( 2 × 50 liters ). the acetone extract was concentrated to approximately 10 liters and extracted with ethyl acetate ( 3 × 15 liters ). the resulting ethyl acetate layers were combined and evaporated to give a brown oil ( 67 . 8 g ). the oil was dissolved in petroleum ether ( b . p . 40 °- 60 ° c .) ( 250 ml ) and chromatographed on alumina ( 340 g ). unwanted material was eluted with a mixture of ethyl acetate and dichloromethane ( 1 : 1 ) and the product eluted with a mixture of ethyl acetate and methanol ( 1 : 1 ). after evaporation a pale brown oil ( 17 . 8 g ) was obtained which was re - dissolved in petroleum ether ( b . p . 40 °- 60 ° c .) and chromatographed on silica gel ( 460 g ). unwanted materials were eluted with petroleum ether ( b . p . 40 °- 60 ° c . ), followed by diethyl ether . the product was eluted with a mixture of ethyl acetate and diethyl ether ( 1 : 9 ). after evaporation an off - white foam was obtained ( 1 . 3 g ); which was dissolved in methanol ( 4 ml ) and purified by chromatography using a c - 18 dynamax ( trademark rainin ) column ( 41 . 4 mm × 25 cm ), eluting with a mixture of methanol and water ( 80 : 20 ) at a flowrate of 60 ml / min . relevant fractions were combined to yield a compound of formula ( i ) wherein r 1 is oh , the double bond is absent , r 2 is 2 - bicyclo [ 3 . 1 . 0 ] hexyl , r 3 is h and r 4 is 4 &# 39 ;-( alpha - l - oleandrosyl )- l - oleandrosyloxyl as a white powder , m . p . 173 °- 176 ° c . ( decomp ). the structure of the product was confirmed by fast atom bombardment mass spectrometry performed on a vg model 7070e mass spectrometer using a sample matrix of triethylene glycol with solid sodium chloride . ( m + na ) + observed at m / e 937 ( theoretical 937 ). electronic impact mass spectrometry was performed using a vg model 7070 f mass spectrometer . the m / e values for the principal fragments were : 608 , 480 , 347 , 329 , 263 , 257 , 179 , 145 , 127 , 113 , 95 and 87 . the product of the preceding examples 1 and 2 were dissolved in polyethylene glycol ( average molecular weight 300 ) to give solutions containing 400 micrograms / ml for use as drench formulations . anthelmintic activity was evaluated against caenorhabditis elegans using the in vitro screening test described by k . g . simpkin and g . l . coles in parasitology , 1979 , 79 , 19 . the products of examples 1 and 2 killed 100 % of the worms at a well concentration of 0 . 1 micrograms per ml . activity against the larval stage of the blowfly lucilia cuprina ( q strain ) is demonstrated using a standard procedure in which first instar larvae are kept in contact with filter paper treated with test compound . the test compound is first applied to the paper as an acetone solution . the treated filter papers are then placed into tubes containing 1 ml of newborn calf serum and the first instars are added . the products of examples 1 and 2 killed 100 % of the larvae when applied to the filter paper at a level of 1 milligram per square meter . cysteamine hydrochloride ( 50 g ) in dry methylene chloride ( 800 ml ) was treated at 0 ° to 5 ° c . with triethylamine ( 140 ml ) and the slurry stirred for 1 / 2 hour . trimethylsilyl chloride ( 72 ml ) was then added with a further 100 ml of methylene chloride over a period of 20 mintutes at 0 ° c . stirring was continued at 0 ° c . for 11 / 2 hours . acetyl chloride ( 31 ml ) is 100 ml methylene chloride was then added at 0 °- 5 ° c . over a period of 20 minutes , then triethylamine ( 61 ml ) was added at the same temperature . the resulting white slurry was stirred vigorously for 2 hours at room temperature . water ( 50 ml ) was then added and the mixture evaporated to dryness in vacuo . the resulting white solid was treated with saturated brine ( 200 ml ) and extracted with ethyl acetate ( 400 ml ). the aqueous layer was then extracted again with ethyl acetate ( 3 × 400 ml ) and the combined organic layers were dried over anhydrous sodium sulphate , filtered and evaporated to give n - acetyl cysteamine a pale yellow oil , which was distilled to give 27 g of clear oil b . pt . 103 °- 108 ° c ./ 0 . 8 mmhg . benzoic acid ( 51 . 6 g ) and 100 g of n - acetyl cysteamine were dissolved in dimethylformamide ( 100 ml ) and methylene chloride ( 300 ml ). the resulting mixture was stirred under nitrogen at 0 ° c . and 184 ml of diphenylphosphorylazide was added slowly , followed after 5 minutes by 238 ml of triethylamine . the temperature was maintained below 10 ° c . the mixture was then stirred overnight at room temperature under nitrogen . the mixture was diluted with 100 ml methylene chloride and washed with 400 ml 5 % aqueous citric acid , saturated sodium bicarbonate solution ( 400 ml ) and saturated sodium chloride solution ( 400 ml ), then dried over anhydrous sodium sulphate and concentrated to a yellow oil . the oil was applied to a 1 kg column of silica gel and eluted with 2 % ethyl acetate in methylene chloride increasing to 100 % ethyl acetate . fractions 6 to 19 were combined to give 128 g of waxy solid . this was mixed with 40 g of arbacel and extracted with hexane using a soxhlet extractor . the extract was evaporated to give 101 . 7 g of the title compound as a white solid . m . pt . 54 °- 57 ° c . the structure of the product was confirmed by fast atom bombardment mass spectrometry performed on a vg model 7070e mass spectrometer using a sample matrix of triethylene glycol . a strong mh + signal was seen at m / e 224 ( theoretical 224 ). bicyclo [ 3 . 1 . 0 ] hexane carboxylic acid ( 1 . 1 g ), diphenylphosphorylazide ( 4 . 9 g ) and n - acetyl cysteamine ( 2 g ) were stirred in dimethylformamide ( 5 ml ) at 0 ° c . triethylamine ( 5 ml ) was added dropwise and stirring was continued at ambient temperature for 24 hours . the reaction mixture was diluted with toluene ( 100 ml ) and the solution washed with 5 % aqueous citric acid ( 100 ml ), saturated sodium bicarbonate solution ( 100 ml ) and finally , saturated brine ( 100 ml ). then the organic layer was separated , dried over sodium sulphate , filtered and evaporated . the residue ( 2 . 2 g ) was purified by chromatography on silica ( 50 g ), eluting with methylene chloride and ethyl acetate ( a gradient of ethyl acetate from 2 to 40 %). the fractions were analysed by thin layer chromatography and fractions 13 to 20 were combined to give the product as an oil ( 1 . 2 g ). the structure of the product was confirmed by electron impact mass spectrometry using a vg model 7070 f mass spectrometer . the m / e value for the molecular ion was 227 ( theoretical 227 ) and the principal fragments were : 184 , 168 , 119 , 109 and 81 .
antiparasitic compounds of formula : ## str1 ## the broken line at the 22 - 23 position representing an optional double bond and either r 1 is h or oh and the double bond is absent or the double bond is present and r 1 is absent ; r 2 is optionally substituted phenyl , or a group of formula : ## str2 ## wherein x is o , s or -- ch 2 --, abc and d are 0 - 2 and a + b + c + d ≦ 5 r 3 is h or me r 4 is h , oh or 4 &# 39 ;-- alpha - l - oleandrosyloxy . the compounds are prepared by fermentation of streptomyces avermitilis in the presence of an n - alkanoyl cysteamine thioester containing r 2 .