IE57762B1 - Unsaturated oxyranylbenzene derivatives - Google Patents

Description

This intermediates The invention relates to novel compounds useful as in the production of pharmaceutical compounds, compounds of the invention are of the formula (I) in which R is an alkenyl or alkynyl group optionally substituted with an optionally substituted phenyl group and 3 4 5 containing from 5 to 30 carbon atoms, and R , R and R are each selected from hydrogen, carboxyl, alkoxycarbonyl, alkyl, alkoxy, hydroxyl, optionally protected tetrazolyl, halo, trifluoromethyl, nitrile, nitro and -CONR^ . , _10 is hvdrogen or C„ . alkyl, where each R ' i & * * * te 1-4 3 The compounds of the invention are useful in the preparation of pharmaceutical compounds disclosed in parent Patent Specification No. , of the formula in which n is 0, 1 or 2, R is a hydrocarbyl group optionally substituted with an optionally substituted phenyl group and 2 containing from 5 to 30 carbon atoms, R is optionally substituted phenyl or ^alkyl optionally substituted by one or more substituents selected from optionally protected hydroxyl, optionally protected carboxyl, nitrile, optionally protected 6 ό tetrazolyl, -COR where R is Cj_^alkvl, C1_^alkoxy, an option7 7 ally protected amino acid residue or "’^2 w^ere each R is 8 8 hydrogen or C^ ^alkyl, and -NHR where R is hydrogen, a protecting group, an optionally protected amino acid residue, 9 C .alkyl or -COR where R is C. .alkyl or C .alkoxy, and 34 5 R , R and R are each selected from hydrogen, carboxyl.

Co _alkoxycarbonyl, C, .alkyl, C .alkoxy, hydroxyl, optionally protected tetrazolyl, halo, trifluoromethvl, nitrile, nitro and -CONrIQ where each R^ is hydrogen or C, . alkyl; and salts thereof. These compounds, ia unprotected form, have been shown to be pharmacologically active in tests which demonstrate their antagonist effect on leukotriene receptors and indicate their use in the treatment of allergic disorders.

In the above general formula (II) representing the pharmaceutical end-products, the optionally substituted hydrocarbyl group includes an optionally substituted alkyl group or optionally substituted, alkenyl and alkynyl groups, the substituents on such groups being phenyl and substituted phenyl.

The hydrocarbyl group preferably contains from 5 to 20 carbon , atoms, for example fror 10 to 20 carbon atoms and especially 1 from 10 to 15 carbon atoms. When R is alkyl it can be » branched or unbranched and is preferably one containing 10 to 1 carbon atoms. When is alkenyl it can be branched or unbranched preferably containing 10 to 15 carbon atoms, such as for example 12 to 15 The alkenyl group preferably contains to 4 double bonds and can be, for example, of the general formula R11CH=CHCH=CH5 where R11 is C^^alkyl or CH3(CH9)nC.H=CH-CH?-CH=CH- where n is 0 to 4. It will be appreciated that such double bonds provide opportunities for cis-trans isomeric forms. Two especially preferred examples of alkenyl groups are: 'V \ c \ e and ‘T When R is alkynyl it can be branched or unbranched, and preferably contains from 10 to 15 carbon atoms having 1 to triple bonds. It is to be understood that such alkynyl groups can also contain one or more, for example, 1 to 3 double bonds in addition to its triple bond or bonds.

SSHCiUKSEIl When R is substituted hydrocarbyl it is substituted by an optionally substituted phenyl ring, preferably phenyl itself, or a phenyl group substituted with one or more, preferably 1 to 3, substituents selected from C alkyl, especially methyl, C . alkoxy, especially methoxy and ethoxy, hydroxy, —Q nitro, cyano, halo, especially chloro, trifluoromethyl, carboxyl, tetrazolyl and -CONH^. When R is substituted with an optionally substituted phenyl group it is preferably an alkenyl group.

It is preferred that R^ is one of the above defined alkenyl groups. 4 5 As defined above, the groups R , R and R can be hydrogen, carboxyl, C^,. alkoxycarbonyl, C^^alkyl, C^ ^alkoxy, hydroxyl, optionally protected tetrazolyl, halo, trifluoromethyl, nitrile, nitro and -C0NR^wbere each is hydrogen or _^alkyl. The tetrazolyl group is preferably lH-tetrazol-5-yl. Preferably there is a single substituent on the phenyl ring and it is preferred that the substituent be nitrile, -CONH^, tetrazolyl or carboxyl, acid substituents such as tetrazolyl and carboxyl being best of all. Maximum biological activity is given by the compounds in which the tetrazolyl or carboxyl group is attached at the ortho or meta positions, and the most preferred groups are of the formula In the above general formulae ^alkyl means a straight or branched chain alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl, and is preferably methvl or ethvl. Similarly a C .alkoxy group is any such alkyl group attached through oxygen to the appropriate moiety, and alkoxycarbonyl is a group of the form ROCO- where R is a C .alkyl group as described above.

When tetrazolyl substituents on the pharmaceutical end-products of formula (II) require protection during preparation they may be protected by conventional protecting groups.

It is usually necessary to protect any tetrazolyl group during the process of preparation of the pharmaceutically active end products, and suitable and well known protecting groups for this purpose include the trityl and benzhydryl groups formed by reaction with the appropriate halide in the presence of base for example by reacting the tetrazolyl reactant with trityl chloride and triethylamine.

The pharmaceutically active compounds of formula (II) above, which are the subject of parent patent Specification No. 1’///.'ftf,-,can be produced by reacting a compound of formula with a thiol of formula R SH, optionally followed when it is desired to prepare a compound in which n is 1 or 2, by oxidation, 1 or when it is desired to prepare a compound in which R is optionally substituted alkyl, by reduction, or by removal of any neanraawsrit-irr , 2 3 4 protecting groups, or by interconversioa of an R , R , R or r5 group.

The reaction of compound of formula (I) with thiol is preferably carried out in an inert organic solvent such as an alcohol, for example methanol, in the presence of a base such as a triethylamine and at a temperature of from 0°C to 50°C. Thiol reactants containing potential anion especially if it is sterically close to the thiol group are, desirably, protected before reaction.

When it is desired to prepare the sulphoxide compounds in which n is 1 ia formula (II) above, the corresponding sulphide in which n is 0 is reacted in substantially equivalent proportions with a suitable oxidising agent such as for example sodium periodate in an aqueous medium such as aqueous methanol at a temperature of, for example, from 0°C to 50°C. The sulphone cpmpounds in which n is 2 in formula (II) can be prepared by reacting the sulphide with an excess of oxidising agent such as for example potassium persulphate, or by reacting the appropriate sulphoxide with an excess of oxidising agent, both reactions being carried out under similar conditions to those employed in the preparation of the sulphoxide and preferably at a temperature of from 0°C to 100°C.

It will be appreciated that it may be desired to remove any protecting groups attached to the product of the reaction. Such reactions can readily be carried out by use of a base In an inert organic solvent, such as for example, lithium hydroxide ia tetrahydrofuran, or potassium carbonate in methanol, at a temperature of from 0°C to 80°C, or by use of acid such as hydrochloric acid for removal of protecting groups from tetrazolyl, or by reduction in the case of protected amino groups, by well known procedures described for example in the authorities referred to above..

Also it will be appreciated that one or more of the 2 3 4 5 substituents on the R group or R , R and R groups can be interconverted. It is often preferred, depending on the nature of the group, that such interconversions are carried out after reaction of compound of formula (I) with thiol. 4 5 For example, compounds in which R , R or R is 9 ^alkoxycarbonyl or in which R",bears such a group can be converted to the corresponding free carboxyl by hydrolysis by means of base in an inert organic solvent, such as for example, lithium hydroxide in tetrahydrofuran. Such methods are well 4 5 known in the art. Conversely, compounds in which R , R or R 2 is alkoxycarbonyl or R has such a group can be prepared from the free acid by esterification of the free carboxyl group with the appropriate alcohol or by treatment with alkyl halide in the presence of base. Salts of the free acid can, of course, be prepared simply by reaction with alkali. 102 Compounds in which R , R or R is -C0NR9 or R bears a -CONR? group can be prepared by reacting a compound with an appropriate alkoxycarbonyl substituent with ammonia or the appropriate amine of formula Κ''θΝΗ or R?NH, respectively, or they can be prepared by the reaction of an amine of formula Η?θ 7 NH or R^^ with the appropriate acyl chloride, which can in its turn be derived from the free carboxyl derivative by the reaction of thionyl chloride. Such reactions are well known in the art.

Compounds in which R , R or R is a nitrile group or R has such a group can be prepared by dehydration of the appropriate amide (-CONH^), a convenient dehydrating agent being, for example, a mixture of triphenylphosphine and carbon tetrachloride. 4 5 2 Compounds in which R , R or R is tetrazolyl or R has such a group can be prepared by reaction of the cyano derivative prepared as above with, for example sodium azide and ammonium chloride in dimethylformamide. Salts can be prepared from the tetrazolyl derivatives by the addition of base according to standard techniques.

It will be appreciated that the steps of reduction to provide the saturated R1 substituents, oxidation to provide sulphones and sulphoxides, removal of protecting group or interconversion of .groups, can be carried out in whatever sequence best suits convenience and the aim of maximising yield.

The reactants of formula R SH are known compounds or can be prepared by methods of a type well known in the art.

When they bear amino, carboxyl or hydroxyl groups the reaction may benefit in yield if these groups are first protected, but such initial protection is by no means necessary in all cases.

Compounds of formula (I) above may be prepared by the 13 + Wittig reaction of a phosphonium salt of formula R CH^P Ph^Br , 13 R being an appropriate optionally substituted alkyl, alkenyl or alkynyl group, in the presence of a base such as butyl lithium, with an aldehyde of formula (III) or (IV) Ο The reaction is generally carried out in an inert organic solvent such as for example, tetrahydrofuran, at a temperature of from -80°C to 0°C.

Compounds of formula (III) may be prepared from known intermediates by, for example, two principal routes. Firstly, they may be prepared, as racemic mixtures, by oxidation with, for example, hydrogen peroxide and sodium hydrogen carbonate in methanolic solution, of an aldehyde of the formula and, in its turn, aldehyde of formula (III) may be converted to one of formula (IV) by reaction with formylmethylenetriphenylphosphorane.

Alternatively, the compounds of formula (III) may be 5 prepared by oxidation of an epoxy alcohol of the formula (V) with an oxidising agent such as, for example, chromium trioxide in pyridine. Compounds of formula (V) can be prepared in stereospecific form and since the steric configuration is retained on oxidation to provide the aldehyde of formulae (III) and, ultimately, of formula (IV), this route can be employed to provide stereospecific compounds of formula (I).

Compounds of formula (V) are prepared from the allyl alcohol 2 using as epoxidising agent a reagent such as titanium isopropoxide t-butyl peroxide in the presence of L or D diethyl tartrate which yields the S,S or R,K epoxide with the above E olefin.

When the Z olefin is used as starting material, the appropriate 5 S,R and R,S stereosisoraers result. Compounds of formula (VI) can be prepared from the appropriate benzaldehyde via a sequence of reactions involving reaction with malonic acid to provide the cinnamic acid derivative, treatment with oxalyl chloride to give the acid chloride, and reduction with a reagent such as lithium tri-t-butoxyaluminohydride.

The following scheme gives examples of the way in which preferred compounds may be prepared: 3 Key: (a) reaction with (b) reaction with (c) reaction with toluene (d) reaction with malonic acid in pyridine and piperidine. oxalyl chloride in ether formyImethylenetriphenylphosphorane in lithium tri-t-butoxyaluminohydride in (e) tetrahydrofuran reaction with hydrogen peroxide and sodium hydrogen carbonate in methanolic solution (f) reaction with (g) reaction with (h) reaction with (i) reaction with (j) (k) in dichloromethane and L-diethvl tartrate 13 © Θ reaction with R CH2P Ph^Br in the presence of butyl lithium and in tetrahydrofuran as solvent 2 reaction with R SH in methanol.

The invention is illustrated by the following Examples. The structure of the compounds prepared was confirmed by I.R. and/or n.m.r. and/or mass spectra and the purity of the product was checked in most cases by HPLC. The involatile products were examined by mass spectrometry using the fast atom bombardment (FAB) technique in the negative ion mode. Significant [M-H] ions (and characteristic fragment ions) were observed.

EXAMPLE 1 (a) 3-Carboxycinnamaldehyde, methyl ester 3-Carboxybenzaldehyde methy] ester (]6.4 g) was dissolved in toluene (125 ml) and crystalline formylmethylene 5 triphenvlphosphorane (30.4 g) added with stirring under nitrogen. The mixture was brought to 100°C and stirred for 4=5 hours. The dark straw coloured solution was evaporated in vacuo and the residue extracted with diethyl ether. The I 6 insoluble triphenylphosphine oxide was removed by filtration and the dark yellow filtrate was concentrated in vacuo and chromatographed on silica gel using diethylether/n-hexane 50/50 v/v as developing solvent. The required compound was obtained as a pale yellow crystalline solid, m.p. 86-87°C. (b) 3-(2-Formyl-la2-oxido-ethyl)benzoic acid, methyl ester 3-Carboxycinnamaldehyde methyl ester (400 mg) was dissolved in methanol (12 ml) and added dropwise to a stirred solution of sodium bicarbonate (640 mg) and 28Z hydrogen peroxide (1.6 ml) in water (24 ml). After the addition was complete che mixture was stirred for 1 1/2 hours at room temperature. At this point TLC showed absence of starting aldehyde. The hazy solution was extracted via dichlormethane (3 x 10 ml) and evaporated In vacuo to give a nearly colourless oil (453 mg) mainly as the required aldehyde hydrate. Azeotropic distillation of this product from benzene led to the title compound as a nearly colourless oil (340 mg) which readily crystallised on storage in the freezer. (c) 3-(4-Formyl-l,2-oxido-but-3(E)-enyl)benzoic acid, methyl ester The product of (b) was dissolved in benzene (40 ml) and crystalline formyImethylenetriphenylphosphorane (2 g) was added and the mixture stirred at room temperature under nitrogen for 2 hours. The benzene was evaporated in vacjo and the residue extracted via diethylether to remove insoluble triphenylphosphine oxide. The ether extract was evaporated and tha residue dissolved in a little diethylether/n-hexane, 50/50 v/v„ and chromatographed on silica gel using the same solvent mixture for development» The fractions containing the title compound were bulked and evaporated to give the compound as a pale yellow oil. (d) 3-(1., 2-Oxido-pentadeca-3(E) ,5(Z)-dianyl)benzolc acid, methyl ester n-Decyltriphenylphosphonium bromide (2.45 g) was dissolved in dry tetrahydrofuran (50 ml) ,, sitrred under nitrogen and cooled to -78°C. Butyl lithium (1.55 M solution in hexanes 3.4 al) was added gradually with immediate formation of an orange yellow colour. After 15 minutes a solution of the product froa (c) in tetrahydrofuran (5 ml) was added rapidly and the solution kept at -78°C for 20 minutes, then allowed to come slowly to room temperature. The solution was evaporated in vacuo and the residue extracted with diethylether/n-hexane 50/50 v/v. The solvent extract was concentrated and chromatographed on silica gel using the same solvent mixture for development. Tha title compound was obtained as a colourless oil crystallizing on refrigeration. (e) Rel(1RS2S)-3-(2-S-cysteinyl-l-hydroxypentadeca-3(E)e5(Z)~ dienyl)benzoic acid The compound from (d) was reacted under nitrogen with a solution of N-trifluoroacetylcysteine methyl ester (0.88 g) and triethylamine (1.1 ml) in dry methanol (4.5 ml) at room temperature for 24 hours. After this time the bulk of the starting epoxide had disappeared as indicated by TLC.

The solution was evaporated in vacuo, then dissolved in a little diethylether/n-hexane 50/50 v/v and chromatographed on silica gel developing at first with the same solvent mixture 8 to remove trace amounts of the starting epoxide„ then with diethylether to give the fully protected version of the title compound as a very pale straw coloured oil. The product was dissolved in tetrahydrofuran (7 ml) and lithium hydroxide solution (1 M, 8 ml) added, followed by additional water to give a hazy solution. After 3 days the hydrolysis was incomplete, and further lithium hydroxide solution (4 ml) was added.

After further 4 days the clear solution at pH ca 11 was extracted with diethylether. The residual aqueous phase was then carefully adjusted to pH 3.5-4 (dilute hydrochloric acid) then extracted several times with dichloromethane/methanol (3/1 v/v). The bulked organic phase was carefully evaporated in vacuo to give the title compound initially a pale straw coloured oil which gradually turned to a brittle solid.

The following compound was similarly prepared.

Re1-(IR,2S)-3-(2-S-cysteinylglyclnyl-l-hydroxypentadeca-3(E),5(2)dienyl)benzoic acid obtained as a light straw coloured oil.

EXAMPLE 2 (a) 3-Methoxycarbonylcinnamlc acid 3-Carboxybenzaldehyde methyl ester (82 g) was dissolved in dry pyridine (250 ml) and malonic acid (52 g) added to the stirred solution. Piperidine (5 ml) was then added and the solution slowly heated to reflux. There was a slightly exothermic reaction accompanied by the evolution of carbon dioxide. After refluxing the solution for 1 hour an additional portion of malonic acid (25.1 g) was added. The solution was 9 chan refluxed for g further 30 minuces before being cooled and added co ice and 5 M hydrochloric acid (1 litre). The resultant white solid was filtered off and washed with water before being dried in vacuo at 50°C for 2 days. The crude product was then recrystallized from glacial acetic acid to give colourless plates, m.p. 189~190°C exclusively the E isomer. (b) (E)-3~Methoxycarbonylcinnamyl chloride Oxalyl chloride (13.9 g) was added to a stirred suspension of 3-methoxycarbonylcinnamic acid (20.6 g) in dry ether (200 ml) and chan 1 drop of DMF was added co catalyse the reaction. After being stirred for 1 hour at room temperature all the solid had dissolved and the solution' was evaporated to dryness to yield the white crystalline acid chloride m.p. 70-71 °C» (c) (E)~3~MethoxycarbonyIcinnamyl alcohol 3-Methoxycarbonylcinnamyl chloride (24 g) was dissolved in dry tetrahydrofuran and then this solution added to lithium tri-terc-butoxyaluminohydride (63.5 g) dissolved In tetrahydrofuran (250 ml) at -78°C. The resultant clear solution was stirred at -78°C for 30 minutes then it was added to ice and 2 M hydrochloric acid (750 al). The two phase mixture was extracted 4 times wich dichloromethane. After drying the dichloromethane was evaporated to yield the title compound as a pale yellow oil. (d) (E)-3(3-Hydroxy-l.2-oxidopropyl)benzoic acid methyl ester 3-Methoxycarbonylcinnamyl alcohol (1.92 g) was dissolved in dichloromethane (50 ml), cooled to 0°C and metachloroperoxybenzoic acid (1.72 g) in dichloromethane 10 ml was added to the cooled solution dropwise. The temperature of the reaction mixture was then allowed to rise to room temperature.

After 2 hours the meta-chlorobenzoic acid was filtered off and the solution washed with saturated sodium bicarbonate solution twice. After drying evaporation of the dichloromethane layer yielded the title compound as a colourless oil. (e) (Alternative Method) (1S,2S) 3-(3-Hydroxy-l ^-oxidopropyDbenzoic acid, methyl ester Titanium tetra-isopropoxide (1.3 ml) was dissolved in dry dichloromethane (12 ml) and the stirred solution cooled to -60°C. L-Diethyl tartrate, (6.0 mM) was then added and the solution allowed to warm to -20°C and stirred for a further 10 minutes. 3-Methoxycarbonylcinnamyl alcohol (960 mg) was then added. Finally a 3 M solution of tert-butyl hydroperoxide (6 ml) in 1,2-dichloroethane was added and the solution stored at -18°C for 16 hours. Ether (15 ml) was then added to the reaction mixture followed by a saturated solution of aqueous sodium sulphate (2 ml). · The mixture was stirred at room temperature for 1 hour and filtered through Celite (Trade Mark) . Toluene (100 ml) was added to the solution and it was evaporated to afford a colourless oil which was chromatographed on a silica column eluted with ether. The diethyl tartrate eluted first followed by the title compound which was obtained after evaporation of solvent as a colourless oil. (f) 3-(2-Formyl-1,2-oxidoethyl)benzoic acid, methyl ester Chromium trioxide (2.5 g) was added to a solution of pyridine (3.9 g) in dichloromethane (100 ml) at 7°C. The temperature of the stirred solution was allowed to rise to 14°C and 3(3-hydroxy-l,2-oxidopropyl)benzoic acid methyl ester (1.04 g) was added in dichloromethane (2 ral). The solution darkened and a black oil came out of solution. After 30 minutes at 22°C the dichloromethane layer was decanted off and filtered through Fluorosil. Upon evaporation this solution yielded the title compound as a colourless oil. (g) Rel (lR,2S)-3-(2-S-cysteinyl~l"hydroxypentadeca-3(E) ,5(2)dienyl)benzoic acid The above compound was prepared from the compound of step (f) above by the processes described in steps (c), (d) and (e) of Example 1.

EXAMPLE 3 (a) Rel (IR,2S)-3-[2-(2-carboxyethylthio)-l-hydroxypentadec3(Ε),5(Z)-dienyl]benzoic acid dimethyl ester Methyl 3-mercaptopropionate (240 mg) was dissolved in dry methanol (3 ml). Triethylamine (250 pi) was then added and the resultant solution added to 3-(1,2-oxidopentadeca3(E),5(Z)-dienyl)benzoic acid methyl ester (712 mg). The resultant clear solution was then stored at 40°C for 16 hours after which time it was evaporated to dryness and chromatographed on a silica column eluted with ether. The title compound was obtained as a colourless oil. (b) Rel (lR,2S)-3-[2-( 2-carbo3tye thy lthio)-1-hydroxypentadec3(E),5(Z)-dienyl)benzoic acid Rel (IR,2S)-3[2-(2-carboxyethvlthio)-1-hydroxypentadec-3(E),5(Z)-dienyl]benzoic acid dimethyl ester (476 mg) was dissolved in tetrahydrofuran (10 ml) and a 1 M lithium hydroxide ο ο rS α*ι solution (3 ml) was added to it. The mixture was then stirred at room temperature for 2 days, the pH of the solution was then adjusted to 4 using dilute hydrochloric acid. Finally this solution was extracted four times with dichloromethane which, after drying (MgSO^) and evaporation, yielded the title compound as an off-white solid, m.p. 87-90°C.

EXAMPLE 4 a) (lS,2S)-3-(l,2-Oxidopentadeca~3(E),5(Z)-dienyl)benzoic acid, methyl ester The above compound was prepared from the product of Example 2(e) by the processes described in Examples 2(f), 1(c) and 1(d). MS M*356. (b) (IS,2R)-3-(2-(2-Carboxyethylthio)-1-hydroxy-pentadeca3(E),5(Z)-dienyl]ben2oic acid, dimethyl ester The chiral epoxide prepared as described in step (a) was reacted by the process described in Example 3(a) to give the title compound as a pale oil. MS (FAB) M 477 (c) (lS,2R)-3°[2-(2-Carboxyethylthio)-l-hydroxy-pentadeca3(E),5(Z)-dienyllbenzoic acid The diester was hydrolysed by the method described in Example 3(b) to give the title compound as a white solid, m.p. ca 50°C, [a] + 50.1° (c = 2.3, MeOH), MS (FAB) [M-H]_447 EXAMPLE 5 (!R,2S)-3-[2-(2~Carboxyethylthio)-l-hydroxypentadeca-3(E), 5(Z)~ dienylJbenzoic acid (lR,2R)-3-(3-Hydroxy-l,2-oxidopropyl)benzoic acid, methyl ester was prepared by the method described in Example 2(e) using D(-)diethyl tartrate in place of the L(+) isomer.

This epoxide was then reacted by the processes described in title ί» R Examples 2(f). 1(c). 1(d), 3(a) and 3(b) to give che compound as a pale oil, EXAMPLE 6 (a) (£)-2-Methoxycarbonylcinnamyl alcohol 2-Methoxycarbonylcinnamlc acid, m.p. 176°C, was prepared by the method described in Example 2(a) and converted to the acid chloride, m.p. 75-80°C, by the method described in Example 2(b). A solution of this acid chloride (15.5 g) in ether (250 ml) was added to a stirred suspension of sodium borohydride on alumina (60 g - prepared by addition of a solution of 1 part of sodium borohydride in 2 parts of water to 10 parts of alumina, with cooling, followed by drying under vacuum) In ether (360 ml). The mixture was stirred for 2 hours at room temperature and filtered. The filtrate was washed with 10a sodium carbonate solution, then with saturated sodium chloride solution, dried and evaporated to yield the title compound as a colourless oil. (b) (E)-2-(3°Hydroxy-l,2-oxidopropyl)benzoic acid, methyl ester Oxidation of (E)-2-methoxycarbonylcinnamyl alcohol with meta-chloroperoxybenzoic acid as described In Example 2(d) followed by chromatography of the crude product on a silica column eluted with 2:1 ether:hexane gave the title compound as a pale oil. (c) 3-[l~(2-Methoxycarbonylethylthio)-tecradec-2(E),4(Z)-dienyl]1,3-dihydro-isobenzofuran-l-one 2-(4-Formyl-l,2-oxidobut-3(E)-eny1)benzoic acid methyl ester, m.p. <50°C, was prepared from the compound of step (b) above by the processes described in Examples 2(d), 2(f) and 1(c). Further reaction of this compound by the methods described in Examples 1(d) and 3(a) gave as the major product the lactone title compound. (d) Rel (IR,2S)-2-(2-(2-CarboxyethyIthio)-1-hydroxy-pentadeca3(E),5(Z)-dienyl]benzoic acid, disodium salt A solution of 3-[l-(2-methoxycarbony!ethylthio)tatradeca~2(E)„4(Z)-d±enyl]-l,3-dihydro-isobenzofuran-l-one (115 mg) in tetrahydrofuran (1 ml) and 0.5 M sodium hydroxide solution (0.96 ml) was stirred at room temperature for 16 hours. The solution was evaporated and the residue was washed with ether to leave the title compound as a viscous gum.

EXAMPLE 7 (a) 9-Bromo~2~methyl-4-decena n-Buty1 lithium (1.5 M solution in hexane, 6,8 ml) was added to a stirred suspension of (3-methyIbutyl)-triphenylphosphonium bromide (4.1 g) in dry tetrahydrofuran (50 ml) at -60°C under nitrogen. The dark mixture was stirred for 40 minutes at -70°C then a solution of ό-bromohexanal (1.8 g) In dry tetrahydrofuran (6 ml) was added. The pale mixture was stirred for a further 1 hour at -70°C then evaporated under vacuum. Tha residue was extracted with ether and the extract was evaporated to a pale oil which was chromatographed on silica gel, eluting with 1:1 ether:hexane, to give the title "4 compound as a colourless oil. MS M 232/234. (b) (9-Methy1-6-decenyl)-triphenylphosphonium bromide A solution of 9-bromo-2-methyl-4-decene (0.9 g) and triphenylphosphine (1.5 g) in xylene (50 ml) was heated under reflux for 4 days. The mixture was cooled, the supernatant was decanted and the residue was washed with ether and dried under vacuum to give the title compound as a pale gum. (c) (IS,2S)-3-(4-Formy1-1,2-oxidobut-3(E)-enyl)benzoic acid methyl ester This compound was prepared from the product of Example 2(e) by the processes described in Examples 2(f) and 1(c). (d) (IS,2R)-3-[2-(2-Carboxyethylthio)-l-hydroxy-14-methylpentadeca-3(E),5(Z)s11(Z)-trienylJbenzoic acid The above compound was prepared from the compounds of steps (b) and (c) above by the processes described In Examples 1(d), 3(a) and 3(b). MS (FAB) [M-H] 459 EXAMPLE 8 (a) l-Bromo-9-mechyIdecane A solution of 9-bromo-2-methyl"4-decane (l.Og) in ethanol (40 ml) was hydrogenated for 20 minutes at 60 p.s.i. over platinum oxide (10 mg). The catalyst was filtered off and the filtrate was evaporated to give the title compound as a pale oil. (b) (9-Methyldecyl)-triphenylphosphonium bromide A solution of l-bromo-9-methyldecane (1.0 g) and triphenylphosphine (1.7 g) in xylene (50 ml) was heated under reflux for 24 hours. The mixture was cooled, the supernatant was decanted and the residue was washed with ether and further dried by addition of benzene and evaporation to give the title compound as a pale gum. (c) (IS ,2R)~3-[2-(2-Carboxyechylthio)-l-hydroxyl4-methylpenta~ deca-3(E),5(Z)-dienyl]benzoic acid The above compound was prepared from the compound of step (b) above and (lSs2S)-3"(4-formyl-ls2-oxidobut-3(E)-enyl) benzoic acid methyl ester (Example /(c)) by the processes described in Examples 1(d)» 3(a) and 3(b). MS (FAB) [M-H] 461 EXAMPLE 9 (IS.2R)"-3-[2-(2-Aminocarbonylethylthio)-l-hydroxypentadeca3(E),5(E)-dienyl]benzamide A solution of (lSj2R)-3-[2-(2-carboxyethylthio)-lhydroxypentadeca-3(E)»5(Z)-dienyl]benzoic acid, dimethyl ester (50 mg) in methanolic ammonia solution (2 ml) was stored at 50°C in a sealed bottle for 3 weeks. The brown solution was evaporated and the residue was purified by preparative reverse I phase HPLC to give the title compound as a pale solid, m.p. 83-84°C MS (FAB) [M-H] 445.

EXAMPLE 10 (a) 3-Cyanocinnamic acid 3-Cyanobenzaldehyde was reacted with malonic acid by the method described in Example 2(a) to give the title product, m.p. ca 240eC. (b) 3-Aminocarbonylcinnamic acid A solution of 3-carboxymethylcinnamic acid (427 g) (Example 2(a)) in dimethyl formamide (4.25 1) and aqueous ammonia (specific gravity 0.88, 8.5 1) was stored at room temperature for 4 days, concentrated to ca 11 1, and then treated with ice (8 kg) and concentrated hydrochloric acid (1 1). The precipitated title product was washed with water and dried, m.p. >260eC. (c) 3-Cyanocinnamic acid (Alternative method) Phosphorus oxychloride (746 ml) was added to a stirred suspension of 3-aminocarbonylcinnamlc acid (765 g) in dimethyl formamide (7.65 1). The resulting solution was heated at 7O-8O°C for 50 minutes» cooled to 50-60°Cf, and poured onto ice (40 1) to precipitate the title compound which was washed with water and dried» m.p. 242eC. (d) 3-Cyanocinnamyl alcohol The acid of steps (a) and (c) above was converted to the alcohol by the processes described in Example 6(a) giving the title compound as a low melting white solid. (e) (IS,2R)-3-(2-(2-Carboxyethylthio)-1-hydroxy-pentadeca3(E),5(Z)-dlenyl]benzonitrile8 methyl ester The above compound was prepared from the compound of step (d) above by the processes described in Examples 2(e), 2(f). 1(c), 1(d) and 3(a). (f) (IS,2R)-3-[2-(2-Carboxyethylthio)-1-hydroxypentadeca3(E)»5(Z)-dlenyl]bengonitrlle A solution of the methyl ester (step (e)) (950 mg) in methanol (200 ml) and 0.2 M potassium carbonate solution (95 ml) was stirred at room temperature for 16 hours, concentrated to 70 ml, diluted with water (50 ml) and washed with ether (50 ml). The aqueous phase was acidified to pH3 and extracted with dichloromethane (3 x 50 ml). The extract was dried and evaporated to give the title product as a pale gum.

MS (FAB) [M-H] 428.

EXAMPLE 11 (IS ,2R)-5-(3-[2-(2-CarboxyethyIcnio)-1-hydroxy-pentadeca3(E),5 (Z)-dienyl]phenyll-lH-tetrazole A stirred suspension of ammonium chloride (5 g) and sodium azide (5 g) in a solution of (lSj.ZRj-S-IZ-iZ-carboxyethylthio)-l-hydroxy-pentadeca-3(E),5(Z)-dienyl]benzonitrile (Example 10, 780 mg) in dimethyl formamide (25 ml) was heated at 100-105°C for 12 hours. The dark mixture was filtered and the filtrate was diluted with M hydrochloric acid (250 ml) and extracted with dichloromethane (3 x 150 ml). The extract was washed with water, dried and evaporated to give a dark oil containing the 3(E),5(Z) and 3(E),5(E) isomers in the ratio 30:70. The isomers were separated by preparative reverse phase HPLC to give the title compound as a crisp solid.

EXAMPLE 12 (a) (IS .2R)-5-j 3-[2-(2-Carboxyethylthio)-l-hydroxypentadeca3(E),5(E)-dienyl]phenyl)-IH-tetrazole The above compound was separated from the reaction described in Example 11. MS (FAB) [M-H] 471. (b) (IS,2R)-5-{3-[2-(2-Carboxyethylthio)-1-hydroxypentadeca3(Ε),5(E)-dienyl]phenyl^-IH-tetrazole, sodium salt A solution of the product of (a) (273 rag) was dissolved in 0.5 M sodium bicarbonate solution (1.16 ml) and the solution was freeze dried to give the title ccnpound as a pale solid.

EXAMPLE 13 (IS ,2R)-3-[2-(2-Carboxyethylsulphinyl)-1-hydroxypentadeca3(Ε),5(Z)-dienyl]benzoic acid 0.5 M Sodium periodate solution (1.8 ml) was added to a stirred solution of (lS,2R)-3-[2-(2-carboxyethylthio)-lhydroxypentadeca-3(E) ,5(Z)-dienyl]benzoic acid (372 mg) in 0.5 M sodium bicarbonate solution (3.2 ml) and methanol (3.2 ml) at 0-5°C. The mixture was stirred for 1.5 hours at 0-5°C then further 0.5 M sodium periodate solution (0.36 ml) was added. The mixture was stirred for a further 3 hours at 0-5°C then diluted with water, acidified to pH3 and extracted with 3:1 dichloromethane:methanol. The extract was dried and evaporated to give the title compound as a crisp solid shown by reverse phase HPLC and nmr studies to contain two diastereoisomeric sulphoxldes in che ratio 2:1. MS (FAB) [M-H] 463 EXAMPLE 14 (IS 8 2R)-5-{3-[2-(2-Carboxy ethy Isul'phiny 1)-1-hydroxypentadeca3(E)>5(E)dlenyl]phenyl} -IH-tetrazole The above compound was prepared from (ISP2R)-5-(3-[2(2-carboxyechylthio)-l-hydroxypentadeca-3(E),5(E)-dienyl]phenyl|IH-tetrazole by che process described in Example 13. The two diastereoisomers were separated by preparative reverse phase HPLC. MS (FAB) [M-H]" 487 EXAMPLE 15 (IS,2R)-5-(3-[2-(2-Carboxyethylsulphonyl)-l-hydroxypentadeca3(E),5(E)-dienyllphenyl]-IH-tetrazole A solution of potassium persulphate (150 mg) in water (0.5 ml) was added to a stirred solution of (lSs2R)-5-{3"[2-(2carboxyethylthio)-l~hydroxypentadeca-3(E),5(E)-dienyl]phenyl}IH-tetrazole (50 mg) in 0.5 M sodium bicarbonate solution (2 ml) and methanol (1 ml) at 0-5°C. The mixture was stirred G for 4 hours at 0-5°Ce diluted with water, acidified and extracted with 3:1 dichloromethaneimethanol. The extract was dried and evaporated to give the title compound as a crisp solid. MS (FAB) [M-H] 503.

EXAMPLES 16 and 17 (IS,2R)-3—\ 2-(2-(lH-Tetrazol-5-yl)ethyIthio]-1-hydroxypentadeca3(E),5(E)-dienyl}benzoic acid and 3(E).5(2) isomer (IS,2S)-3(1„ 2-Oxidopentadeca-3 (E) , 5 (Z)-dienyl) benzoic acid, methyl ester (1.78 g) prepared as in Example 4(a) was dissolved in a solution of 3-thiopropionitrile (0.44 g) in methanol (5 ml) and triethylamine (0.5 ml) under nitrogen.

This clear solution was allowed to stand ac room temperature for 6 hours and then evaporated to dryness. The resultant pale yellow oil was chromatographed on a silica column eluted with ether/hexane 50/50. The required product (1SS2R)-3-(2-(2cyanoethylthio]-l-hydroxypentadeca-3(E) ., 5 (Z)-dienyl( benzoic acid methyl ester (1.39 g) was obtained as a colourless oil.

This ester (1.25 g) was dissolved in tetrahydrofuran (10 ml) and 1 M aqueous lithium hydroxide solution (3 ml) added. This solution was then stirred overnight at room temperature under nitrogen. Ac the end of this period further 1 M aqueous lithium hydroxide solution (2 ml) was added and the solution warmed to 30°C for 3 hours. The solution was then evaporated to remove the tetrahydrofuran and the remaining aqueous solution was adjusted to a pH of 3 with 2 M hydrochloric acid. This solution was then extracted 3 times with ether and the combined ether extracts dried (Mg^SO^) and evaporated to an almost colourless oil which slowly crystallized at 0°C to yield (IS,2R)-3- l2-[2-cyanoethyl]-l-hydroxypentadeca-3(E),5(Z)-dienyl\ benzoic acid. This free acid (500 mg) was dissolved in dimethylformamide (10 ml) „ sodium azide (2 g) and ammonium chloride (2 g) were added and the scirred suspension heated co 120°C for 5.5 hours. At the end of that period the mixture was diluted with water (30 al) and the pH of the solution adjusted co 3 with dilute hydrochloric acid prior to extraction five times with ether. The ether extracts were dried (Mg SO.) and evaporated to a brown oil. The oil was dissolved in a mixture of methanol:water (85:15) and applied to a preparative reverse phase HPLC column which was eluted with methanol:water (85:15) containing O.SZ acetic acid. The 3(E)P5(Z) isomer of (IS, 2R)-3-^2-[2-1 H-tetrazol-5-yl) ethyl thio ]-l-hydroxypen tads cadienylj benzoic acid eluted first followed closely by the more abundant 3(E).5(E) isomer.

EXAMPLES 18-25 The compounds shown in the Tabla below were prepared using the processes described in Example 3 with the appropriate thiols.

CO^’H 2 R ch2co2h CH(CH3)CO2H Cm(CH3)CH2CO9H CH2CH(CH3)CO,H (ch2)3co2h (ch2)5co2h CH(CH3)C0NHCH7C02H (ch2)2cn EXAMPLE 26 (a) 3(l>2-Oxidopentadeca-3(Z)-enyl)benzoic acid, Methyl ester n-Butyl lithium (1.5 M solution in hexane, 3.3 al) was added dropwise to a stirred solution of dodecyltriphenyl phosphonium bromide (2.66 g) in dry tetrahydrofuran (50 al) at -70°C under nitrogen. The deep orange solution was stirred for 10 minutes at -70°C then a solution of 3-(2-formyl-l,2oxidoethyl)benzoic acid, methyl ester (Example 1(b), 1.03 g) In tetrahvdrofuran (5 ml) was added. The pale suspension was allowed to warm to room temperature, and evaporated and the residue was extracted with 1:1 ether:hexane. The extract was evaporated and the residue chromatographed on silica gel eluting with 1:1 ether:hexane. The title compound was obtained as a colourless oil which solidified on cooling. (b) Rel (IR,2S)-3-[2-(2-Carboxyethylthio)-l-hydroxypentadeca3(Z)-enyl]benzoic acid The above compound was prepared from the product of step (a) by the processes described in Example 3.

EXAMPLES 27 and 28 Rel (lR,2S)-3-[2-(2-Carboxyethylthio)-l-hydroxyundeca-3(E)„ 5(2)dianyljbenzoic acid and Rel (lR>2S)-3-[2-(2Carboxyethylthio)-l-hydroxynonadeca-3(E),5(2)dlenyl]benzoic acid Tha above compounds were prepared from the appropriate phosphonium bromides by the processes described in Examples 1(d), 3(a) and 3(b), EXAMPLE 29 (a) (8-Tetrahydropyranyloxyoctyl)triphenylphosphonium bromide A solution of l-bromo-8~cetrahydr0pyranyloxyoctane (9.8 g) and triphenyl phosphine (8.8 g) in acetonitrile (50 ml) was heated under reflux for 8 hours. The solution was evaporated and the residue washed with ether to give the title compound as a hygroscopic white solid which was dried by addition of benzene and re-evaporation. (b) 2-(1l-Phenyl-8-undacenyloiry)-tetrahydropyran n-Butyl lithium (1.6 M solution in hexane, 20 ml) was added to a stirred solution of the product of step (a) (11.0 g) in dry tetrahydrofuran at -/Q°C under nitrogen. Tha orange solution was stirred for 30 minutes at -70°C then a solution of 3-phenyl-propionaldehyde (2.75 g) In tetrahydrofuran (7 ml) was added. The pale solution was allowed, to warm to room temperature and then evaporated. The residue was extracted with ether and the extract again evaporated and the residue was chromatographed on silica-gel eluting with 1:1 ether:hexane to give the title compound as a pale oil. -3 (c) 1 l-Phenyl~8-undecenol A solution of the product of step (b) (8.7 g) in tetrahydrofuran (150 ml) and 2 M hydrochloric acid was stirred at room temperature for 4 hours. The mixture was neutralised with sodium bicarbonate solution and extracted with dichloromethane. Evaporation of che extract and chromatography of the residue on silica gel eluting with 1:1 ether:hexane co remove starting material, then with ether, gave the title product as a pale oil. (d) 1l-?henyl-8-undecenol tosylate 4-Toluenesulphonyl chloride (1.3 g) was added in portions to a stirred solution of the product of step (c) (1.5 g) in pyridine at 0-5°C. The mixture was stirred for 16 hours at 0-5 °C then poured onto ice-hydrochloric acid and extracted with ether. The extract was washed with sodium bicarbonate and sodium chloride solutions, dried and evaporated to give the title compound as a pale oil. (e) (lS»2S)-3-(l,2-Oxido-l6-phenylhexadeca-3(E),5(Z) ,13(Z)trienyl)benzoic acid, methyl ester A solution of the product of step (d) (1.9 g) and triphenyl phosphine (1.3 g) in acetonitrile (20 ml) was heated under reflux for 48 hours. The solution was evaporated and the residue was washed with ether and further dried by addition of benzene and re-evaporation to leave the crude phosphonium salt as a semi-solid mass. n-Butyl lithium (1.6 M solution in hexane, 1.5 ml) was added to a stirred solution of this phosphonium salt in dry tetrahydrofuran (50 ml) at -70°C under nitrogen. The deep yellow solution was stirred for 30 minutes at -70°C then a solution of (IS.2S)-3-(4-formyl-l,2-oxidobut~3(E)-enyl)benzoic acid, methyl ester (Example 7(c)) (0.5 g) in tecrahydrofuran was added. The mixture was allowed to warm to room temperature, evaporated and the residue was extracted with 4:1 ether:dichloromethane. The extract was again evaporated and the residue was chromatographed on silica gel eluting with 1:1 ether:hexane to give the title compound as a pale oil. (f) (IS»2R)-3-[2-(2-Carboxyethylthio)-1-hydroxy-l6-phenyIhexadeca3(E),5(Z),13(Z)-trienyl]ben2oic acid The above compound was prepared from the product of step (e) by the processes described in Example 3.

EXAMPLE 30 (a) 11-Phenyl-undecanol A solution of ll-phenyl-8-undecenol (Example 29(c), 2.S g) in ethanol (300 ml) was hydrogenated at 60 p.s.i. over 10% palladium on charcoal (0.6 g) for 1 hour. The catalyst was filtered off and the filtrate was evaporated to give the title compound as a colourless oil. (b) 11-Phenylundecanol tosylate 4-Toluenesulphonyl chloride (2.6 g) was added in portions to a stirred solution of the product of step (a) (2.9 g) in pyridine (10 ml) at 0-5°C. The solution was stirred for 16 hours at 0-5°C then poured onto ice-hydrochloric acid and extracted with ether. The extract was washed with sodium bicarbonate and sodium chloride solutions, dried and evaporated. The residue was chromatographed on silica gel ;3G eluting with 1:1 dichloromethane:hexane to give the title compound as a colourless oil. (c) (IS ,2R)-3-(2-(2-CarboxyethyIthio)-1-hydroxy-16-phenylhexadeca-3(E),5(Z)-dienyl]benzoic acid The above compound was prepared from the product of step (b) by the processes described in Examples 29(e) and 3. EXAMPLES 31 and 32 (IS,2R)~3-{ (2~S~Glutathionyl)-»l-hydroxypentadeca-3(E)s5(E)dienyl] benzoic acid and its 3(E),5(Z) isomer Glutathione (300 mg) was dissolved in a mixture of dry methanol (3 ml) and triethylamine (1 ml) and the solution added to (IS,2S)-3-(1,2-oxidopentadaca-3(E),5(Z)-dienyl)benzoic acid, methyl ester (prepared In Example 4(a)) under nitrogen.

The resultant solution was allowed to stand at room temperature for 6 hours and the solvent then evaporated to dryness.

Aqueous 2 M lithium hydroxide solution (3 ml) was added and the solution stirred under nitrogen for 3 hours at room temperature. The pH of the solution was then adjusted to 4 with acetic acid and extracted with ether to remove non-polar impurities. The aqueous solution was extracted 5 times with chloroform:methanol 1:1, The combined extracts were evaporated to dryness to give a crude mixture of the title compounds which were separated on a preparative reverse phase HPLC column eluted with methanol‘.water 70:30 buffered with acetic acid and 0.88 ammonia to a pH of 5.3. The title compounds were pale yellow amorphous solids.

EXAMPLE 33 Rel (IR,2S)-3-(2-S-Cysteinyl-l-hydroxypentadeca-3(E),5(Z)-dienyl) benzoic acid, methyl ester 7 A solution of 3-(1,2-oxidopenradeca-3(E),5(2)-dienyl)benzoic acid, methyl ester (Example 1(d), 0.5 g) „ K-crifluoroacety Icysteine methyl ester (0.4 g) and triethylamine (0.5 ml) in dry methanol (2.0 ml) was stored at room temperature for 3 days and then evaporated. The residue was chromatographed on silica gels eluting first with 1:1 ethershexane and then with ether to give the fully protected version of the title compound as a pale oil.

A solution of this compound (0.4 g) in methanol (7 ml) and 2 M sodium carbonate solution (4 ml) was diluted with water to give a slight haziness and then stored at room temperature for 30 hours. The solution was' diluted with water (20 ml), acidified to pH4 and extracted with dichloromethane (3 x 15 ml). The extract was evaporated and the residue was chromatographed on· silica gel eluting with 1:1 dichloromethane: methanol Co give the title compound as a pale oil.

EXAMPLE 34 (a) 3-(6Pormyl-l,2-oxidohexa~3(E) ,,5(E)-dienyl)benzoic acid. methyl ester A solution of 3—(2—formyl-i.2-oxido~echyl)benzoic acid, methyl ester (Example 1(b)9 0.7 g) in dichloromethane (10 ml) was added'over 1 hour to a stirred solution of triphenylphosphoranylidene-crotonaldehyda (1.5 g) in dichloromethane (10 ml). The solution was stirred for a further 1.5 hours and then evaporated and the residue was extracted with ether. The extract was evaporated and the residue was chromatographed on silica gel, eluting with ether to give a pale yellow oil containing the title compound mixed with the 3(Z).5(E) isomer. 8 A solution of this mixture (230 mg) and iodine (10 mg) in dichloromethane (20 al) was stirred for 2 hours at room temperature and then evaporated. The residue was washed wich hexane to remove iodine, leaving the title compound as a yellow oil. (b) 3-(1J2-Oxidohexadeca-3(E).5(E),7(2).10(Z)-tetraenyl) benzoic acid, methyl ester n-Butyl lithium (1.5 M solution in hexane. 0.65 ml) was added slowly to a stirred solution of 3-(Z)-nonenyl-triphenylphosphonium tosylate (0.56 g) in dry tetrahydrofuran (5 ml) at -70°C. The dark orange-brown solution was stirred for 10 minutes at -70°C then a solution of the product of step (a) (210 mg) in tetrahydrofuran (2 ml) was added. The mixture was stirred for a further 15 minutes at -70°C, allowed to warm to room temperature and evaporated. The residue was chromatographed A on silica gel eluting with 1:1 ether:hexane containing IZ triethylamine and further purified by HPLC to give tha title compound as a pale oil. (c) Rel (lR,2S)-3-[2-(2-Carboxyethylthio)-l-hydroxy-hexadeca3(Ε),5(Ε),7(Ζ),10(Z)~cetraenyl]benzoic acid, dimethyl ester A solution of the product of step (b) (3 mg), methyl 3-mercaptopropionate (2.4 pi) and triethylamine (5 pi) in dry methanol (100 pi) was stored at room temperature for 3 hours then the title compound was isolated by HPLC. MS M 486 (d) Rel (IR,2S)-3-[2-(2-carboxyethylthio)-l-hydroxy-hexadeca3(E) ,5(E) ,7 (Z) ,10(Z)-tetr£.:enyl]benzoic acid A solution of the product of step (c) (2.2 mg) is methanol and 0.5 M potassium carbonate solution was stored at 3 room temperature for 16 hours than the title compound was isolated by reverse phase HPLC.

EXAMPLE 35 (a) 3-Mercaptopropionamide Methyl 3-mercaptopropionate (1.2 g) was dissolved in 0.88 ammonia (75 ml) and the solution stirred at 40°C under nitrogen for 6 hours. The solution was chen evaporated to dryness and che resultant white solid redissolved in dichloromethane this solution then being washed with 2 M aqueous hydrochloric acid (10 ml) and dried (Mg9S0^). This solution upon evaporation yielded the title compound as white plates, m.p. 106oC, which were washed with ether. (b) (IS,2R)g"3-[2-(2-Carbamylethylthio)-l-hydroxypentadeca3(E),5(Z)-dlenyl]benzoic acid, methyl aster 3-Mercaptopropioamide (12 mg) was dissolved In dry methanol (200 pi) under nitrogen and triethylamine (100 pi) added. This solution was chen added to (1SS2S) 3(1,2-oxidopentadeca-3(E),5(Z)-dienyl)benzoic acid, methyl ester and the resultant solution allowed to stand at 40°C for 3 hours. The solution was then evaporated to dryness and the residue chromatographed on a silica column eluted with ethyl acetate. The title compound was obtained as off white crystals, m.p. 65-67°C. (c) (IS„2R)-3-[2-(2-carbamylethyIthio)-1-hydroxypentadeca3(E),5(Z)-dienyl]benzoic acid A solution of the product of step (b) (40 mg) in tetrahydrofuran (2 ml) and M lithium hydroxide solution (0.2 ml) was stirred for 16 hours at room temperature. Further M lithium hydroxide solution (0.2 ml) was added and the solution Ο was stirred for a further 24 hours then diluted with water, acidified to pH 3 and extracted with dichloromethane. The extract was dried and evaporated and the residue was further purified by preparative reverse phase HPLC to give the title compound.

EXAMPLE 36 Rel (lR„2S)"3-[2-(2-Carboxyethylthio)-l~hydroxypentadeca3(E).5(E)-dienyl]benzoic acid The product of Example 3(b) was shown by HPLC to contain about 10% of a second component. Isolation of this minor component by reverse phase HPLC on a Ο,θ Hucleosil column eluting with 80:20 methanol:water buffered to pH5.3 with acetic acid and ammonia gave the title compound as a crystalline solid.

EXAMPLE 37 (a) 3-Cyanocinnamaldehyde A suspension of active manganese dioxide (20 g) in a solution of 3-cyanocinnamyl alcohol (Example 10(d), 4.0 g) in dichloromethane (100 ml) was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was evaporated to give the title product as a white solid, m.p. 100°C. (b) 3(3~Cyanophenyl)-l,2-oxidopropanol A solution of 3-cyanocinnamaldehyde (2.0 g) in methanol (20 ml) was added dropwise to a stirred solution of sodium bicarbonate (2.0 g) and 50% hydrogen peroxide (1.0 ml) in water (10 ml). The solution was stirred for 3 hours at room temperature then extracted with dichloromethane. The 1 extract was dried and evaporated to give a colourless oil which was mainly the hemiacetal of the title aldehyde. (c) 5-(3-Cyanophenyl)-4,5-oxido-2-pencenal A mixture of the product of (b) and formylmethylenetriphenylphosphorane (3.0 g) in benzene (150 ml) was stirred at room temperature for 2 hours then filtered. The filtrate was evaporated and the residue was extracted with ether. The extract was again evaporated and the residue was chromatographed on silica gel eluting with 3:1 ether:hexane to give the title compound as a pale oil. (d) Rel (IR,2S)-3-(1,2-Oxido-pentadeca-3(E),5(Z)-dienyl) benzonitrile The above compound was prepared from the product of step (c) by the process described in Example 1(d). (e) Rel (IR,2S)-3-[2-(2-Carboxyethylthio)-l-hydroxypentadeca3(E),5(Z)-dienyl]benzonicrile, methyl ester The above compound was prepared from the product of step (d) by the process described in Example 3(a). (f ) Rel (IR.2S)-3-[2~(2-Cagboxyethylthio)-l-hydroxypentadeca3(Ε),5(Z)-dienyllbenzonitrile The above compound was prepared from the product of step (e) by tha process described in Example 3(b). (g) Rel (IR,2S)-5-l3-[2-(2-Carboxyethylthio)-l-hydroxypentadeca3(E),5(Z)-dienyl]phenylI-IH-tatrazole A mixture of the product of step (f) (100 mg), ammonium chloride (1.0 g)·and sodium azide (1.0 g) in dimethylformamide (5 ml) was heated at 100°C for 4 hours and then filtered. The filtrate was diluted with 2 M hydrochloric acid 2 (50 al) and extracted with dichloromethane. The extract was evaporated to give a dark oil containing the title coapound and its 3(E)S5(E) isomer in the ratio 40:60. The isomers were separated by preparative reverse phase HPLC (on a LP^ODS silica column eluting with 85:15:0.1 methanol :wat' er:acetic acid) to give the title compound as a crystalline solid, m.p. 153-155°C. MS (FAB) 473.

EXAMPLE 38 Rel (IR, 25)-5-( 3-[2-(2-Carboxyathylthio)"-l-hydroxypentadeca3(Ε),5(E)-dienylIphenyl]-lH-tecrazole The above compound was separated from the reaction described in Example 37(g).

EXAMPLE 39 (a) (IS,2R)-3-[2-(3-Methoxycarbonylpheny1thio)-1- hydroxypentadeca-3(E),5(Z)-dienyl]-benzoic acid, methyl ester To a solution of methy1-3-mercaptobenzoate (0.42 g) in methanol (2 ml) under nitrogen was added triethylamine (0.38 ml) (development of light yellow colouration). The mixture was then transferred co another flask containing (IS,2S)-3-[1,2-oxido-pentadeca-3(E).5(Z)-dienyl]benzoic acid, methyl ester (0.8 g) under nitrogen. The reaction mixture was stirred at room temperature under nitrogen for 2 hours.

The volatiles were removed under a nitrogen stream and the residual oil purified by column chromatography (silica; eluant hexane 50% diethyl ether) , to give the product as a light-yellow oil. (Proton NMR indicates predominantly (Ξ),(Z) stereochemistry). 3 (b) (lS,2R)-3-[2-(3-Carboxyphenylthio)-l-hydroxypentadeca3(E) t,5(Z)dlenyl]banzolc acid To a solution of the diester (from step (a) (0, 46 g) in tecrahydrofuran (2 ml) was added 2 M lithium hydroxide solution (2.6 ml). The biphasic system was stirred vigorously for 20 hours at room temperature.

The tetrahydrofuran was removed in vacuo, and the aqueous phase cautiously acidified to pH4 with 2 M hydrochloric acid. Extraction with chloroform. followed by drying (magnesium sulphate) and evaporation gave tha title compound as a lightyellow solid, m.p. 90° (with resinification).

EXAMPLES 40-42 Similarly prepared, by the methods of Example 39 were the following:t (IS, 2R)-3-[2-(4-Carboxyphenylthio)"l-hydroxypentadeca-3(E)S5(Z)dienyljbenxoic acid (sticky yellow solid).

(IS s 2R)-3-[2-(2-Carboxyphenylthio)-l-hydroxypentadeca-3(E) s 5(Z) dienyljbenzoic acid (sticky solid).

(IS,2R)-3-[2-(butylthio)-l~hydroxypentadeca-3(E)„5(Z)-dienyl] benzoic acid.

EXAMPLE 43 (a) (lS,2R)-3-[1-(3-Cyanophenyl)-l-hydroxypentadeca-3(E),5(Z)~ dien-2-ylthio]benzoic acid, methyl ester To a solution of methy1-3-mercaptobenzoate (0.29 g) in methanol (1 ml) under nitrogen was added triethylamine (0.26 ml) (development of yellow colouration). The mixture was then added to (IS,2S)-3-(l-oxidopentadeca-3(E),5(Z)-dienyl)benzonitrile 2 (0.5 g) under nitrogen, and the reaction mixture stirred at room temperature for 4 hours.

The volatiles were removed under a nitrogen stream and the residual oil purified by chromatography (silica; eluant hexane/ether) to yield the product as a yellow oil. (b) (lS,2R)-3-[l-(3-Cyanophenyl)-l-hydroxypentadeca-3(E),5(Z)~ dien-2-ylthio]benzoic acid To a solution of the methyl ester from step (a) (50 mg) in tetrahydrofuran (0.3 ml) was added 2 M lithium hydroxide solution (0.15 ml), and the mixture stirred at room temperature for 24 hours.

The tetrahydrofuran was evaporated in vacuo, the aqueous phase acidified with 2 M hydrochloric acid, and extracted twice with dichloromethane. Drying (magnesium sulphate) and evaporation of the organic extracts gave the title compound as a light-amber oil. (Proton NMR and reverse phase HPLC Indicate about 302 of the (E),(E) isomer present.) EXAMPLE 44 (a) 2,3-0xido-3-phenylpropionaldehyde To 502 hydrogen peroxide solution (16 ml), (buffered with saturated sodium hydrogen carbonate solution) was added dropwise, with ice-bath cooling, a solution of cinnamaldehyde (26.4 g) in methanol (100 ml). The mixture was stirred at room temperature for 4 hours.

The methanol was removed In vacuo, and the aqueous phase extracted twice with toluene. The dried extracts were used, without isolation of the title compound, directly in step (b). (b) 4,5-Oxido-5-phenyl-2~pentenal The solution of 2,3-oxido-3-phenylpropionaldehyde In dry toluene (300 ml) from step (a) was treated with formylmethylene triphenyl phosphorane (60.8 g) and the mixture stirred at room temperature for 20 hours» The reaction mixture was filtered and evaporated in vacuo, and the residual solid extracted three times with ether using an ultrasonic bath. The ether extracts were filtered and evaporated to give an oil which was further purified by column chromatography (silica; eluant hexane:ether, 1:1) to give the product as a yellow oil. (c) 1>2-Oxido-l-phenylpentadeca-3(E),5(Z)-diene To a solution of n-decyl-triphenylphosphonium bromide (20.54 g) in dry tetrahydrofuran (200 al),. cooled to -/0°C (dry ice/acetone bath) under nitrogen was added n-butyl lithium (26.6 ml of 1»6 M hexane solution). There was immediate generation of orange colour of ylid. The mixture was stirred for 10 minutes, then a solution of 4.»5-oxido-5-phenyl-2-pentenal (from step (b) in dry tetrahydrofuran (100 ml) added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours.

The tetrahydrofuran was evaporated in vacuo, the residual semi-solid extracted four times with diethyl ether using ultrasonification, and tha extracts filtered and evaporated to give a yellow oil. This oil was further purified by chromatography (silica: eluant hexane:water, 1:1) to give the product as a mobile yellow oil, which crystallised upon cooling to -20°C (m.p. <50°C). 3 (d) Rel (1RS 2S)-2-( 2-Methoxycarbonylethyl thio) -1-hydroxy-1phenylpentadeca-3(E),5(Z)-diene To a solution of methyl-3-mercaptopropionate (0.44 g) In methanol (2 ml) under nitrogen was added triethylamine (0.5 ml). The mixture was transferred to a flask containing the epoxide from step (c) (1.00 g) under nitrogen. The reaction mixture was stirred for 20 hours, then further thiol (0.44 g) and triethylamine (0.5 ml) added.

After an additonal 20 hours at room temperature the volatiles were removed under a nitrogen scream and the residue subjected to column chromatography (silica.; eluant hexane:diethyl ether. 3:1), to give the title compound as a'colourless oil. deca- 3(E)85(Z)-diene A mixture of the methyl ester from,step (d) (0.49 g) tetrahydrofuran (3 ml) and 1 M lithium hydroxide solution (3.5 ml) was stirred at room temperature for 24 hours.

The tetrahydrofuran was evaporated in vacuo, the aqueous phase acidified with 2 M hydrochloric acid, and extracted twice with diethyl ether. The combined organic extracts were dried (magnesium sulphate) and evaporated to give the title compound as an amber oil.

EXAMPLE 45 (Alternative method) (a) 3-(3-( 2-Tr ipheny Ime thy l"-2H-tetrazol-5-yl) pheny 1 ] -2-propenol To a solution of 3[3-(lH-tetrazol-5-yl)phenyl]-2propenol (2.02 g) in dry dichloromethane (50 ml) was added triethylamine (1.5 ml) followed by triphenylchloromethane (2.8 g) in dry dichloromethane. The solution was stirred at 7 room temperature for 90 minutes., washed with water (50 ml), followed by sodium bicarbonate solution (5Z; 50 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a pale brown viscous oil which crystallised on standing to a cream solid. (b) (2S,3S)-3-[3-(2-TrlphenyImethyl-2H-tecrasol~5-yl)phenyl]2,3-oxidopropanol L-(+)-Dimethyl tartrate (1.85 g) was added in dry dichloromethane (10 ml) dropwise to a stirred solution of titanium (IV) isopropoxide (3.1 ml) in dry dichloromethane (30 ml) at -20 to -25°C under nitrogen. The solution was stirred for 10 minutes and a solution of 3-’['3-(2-trIphenylmethyl2H~tetrazol-5~yl)phenyl]-2-propsnol (4.5 g) in dry dichloromethane (20 ml) was added, followed by a 3.7 M solution of t-butylhydroperoxide in toluene (6.7 ml), both at -20 to -25°C. The pale orange solution was left to stand in a freezer for 3 hours.

To the stirred solution was added aqueous tartaric acid (10%; ml) and the mixture stirred for 1 hours, filtered and separated. The dichloromethane layer was dried over magnesium sulphate filtered and evaporated under reduced pressure to give a yellow oil. The oil was dissolved in carbon tetrachloride, washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a pale yellow oil.

The oil was chromatographed on a silica gel column using diethyl ether and hexane (2:1) and the required fractions evaporated under reduced pressure to give a colourless crystalline solid. 3 (c) (4S,5S)-5-[3-(2-Triphenylmethyl-2H-tetrazol-5-yljphenyl]4,5-oxido-2-pentenal Solid chromium trioxide (5.0 g) was added to a stirred solution of pyridine (7.9 ml) in dry dichloromethane (200 ml) at 5°C. The mixture was stirred for 45 minutes, warming to 13°C, allowing all the chromium trioxide to dissolve, then a solution of the epoxyalcohol of step (b) (4.61 g) in dry dichloromethane (50 ml) was added rapidly. The dark mixture was stirred for 90 minutes, warming to room temperature, then filtered through a pad of Florisil (Trade Mark) to remove the chromium salts, and the colourless filtrate was evaporated under reduced pressure to leave a pale yellow oil.

To a solution of the oil (1.8 g) in benzene (75 ml) under nitrogen, was added formylmethylenetriphenylphosphorane (1.34 g) in one portion. The suspension was stirred at room temperature under nitrogen for eight hours, unreacted ylid was filtered off and the filtrate evaporated under reduced pressure to a brown oil. The brown oil was extracted with hot ether, cooled, filtered and evaporated under reduced pressure to give a yellow oil, which crystallised on standing to give a yellow solid. (d) (IS,2S)-5-(3-[2-(1,2-Oxido)pentadeca-3(E),5(Z)-dienyl]phenyl)2-tripbenylmethy1-2H-tetrazole n-Butyl lithium (8.91 ml; 1.5 M) in hexane was added dropwise to a stirred solution of n-decyl triphenylphosphonium bromide (6.07 g) (dried at 80°C under reduced pressure for 16 hours) in dry tetrahydrofuran (130 ml) at -70°C under nitrogen.

The clear deep orange solution obtained was stirred for a « y further 10 minutes at -70°C, then a solution of 5-(3-(2-triphenylmethyl-2si"tetrasol"5"yl)phenyl]-4s5-oxido-2-pantenal (6.4 g) in dry tetrahydrofuran (75 sl) was added dropwise. The pale yellow solution was stirred at -70eC for 1 hour, allowed to warm to room temperature and evaporated under reduced pressure to a brown oil. The oil was extracted with ether :he:tana (1:2; x 200 ral) and the pale hazy extract evaporated under reduced pressure to give the title compound as a yellow oil. (e) (IS 5 2R)-5-(3-[2-(2-KethoxycarbonylethyIthio)-1-hyroxypentadeca-3 (E), 5 (Z)-disnyl]phenyl) -2-triphenylraethyl-2ri-cetra2ole A solution of (IS,2S)-5-{3-[2-( 12-oxido)pentadec-3(E), 5(Z)-dienyl]phenyl}"2-triphenylmethyl-2H-cetrasole (4.5 g) and triethylamine (2.06 ml) In methanol (15 ml) was placed la a flask under nitrogen. This solution was then added to methyl 3-thiopropionate (900 mg) under nitrogen and the solution was then stirred for 24 hours at room temperature until reaction was complete. The solution was evaporated under reduced pressure to leave a brown oil which was chromatographed on a silica column using ether:hexane (1:1). Tha required fractions were evaporated under reduced pressure to give the title compound as a yellow oil. (f) (IS -2R)-5-]3-[2-(2-CarboxyethyIthio)-1-hydroxypentadeca3(E),5(Z)-dienyl]phenyl)-lH-tetrazole, sodium salt (IS, 2R)-5~{3- [2-Methoxy._arbonylethylChio)-l-hydroxypentadeca-3(E),5(Z)-dienyl]phenyl)-2~triphenylmethyl"2H-tetrazole (2.74 g) was dissolved in ether (50 ml) to which was added aqueous hydrochloric acid (20 ml; 5 M) and the mixture stirred at room temperature for 4 hours, when t.l.c. showed che loss of Ο triphenylmethyl protection was completed. The ether was evaporated under reduced pressure, tetrahydrofuran (30 ml) was added, followed by the addition of aqueous lithium hydroxide (2 M) until the solution was alkaline. The mixture was then left to stir overnight at room temperature. The aqueous basic phase was then separated, acidified with aqueous hydrochloric acid (2 M), extracted with ether (2 x 50 ml) and the ether extract evaporated under reduced pressure to give a brown oil. The oil was chromatographed on a silica column using ether and the required fraction evaporated under reduced pressure to give a pale yellow oil. The oil was dissolved in aqueous sodium bicarbonate (0.5 M; 1 eq) and freeze-dried to give the sodium salt.

Claims (8)

1. A compound of the formula in uhich R is an alkenyl or alkynyl group optionally substituted 5 with an optionally substituted phenyl group and containing 3 4 , 5 from 5 to 30 carbon atoms, and R , R and R are each selected from hydrogen, carboxyl, C„ ? alkoxy carbonyl, alkyl, C 1 & alkoxy» hydroxyl, optionally protected tecraaolyl, halo, trifluoromethyl, nitrile, nitro and -COKR^ where each is LO hydrogen or f alkyl.

2. A compound according to claim I, in which R^ is an alkenyl group.

3. A compound according to either of claims 1 and 2,in which is an alkenyl group containing 10 to 15 carbon atoms. 5 3 A compound according 'Co claim 3,1a which the alkenyl group is of the formula R 1 ^-CHCH-CHwhere R U is C ? , χ slkyl.

4. 5. A compound according Co claim 3,in which the alkenyl group is of the formula R ll CHCKCH-CHwhere R 11 is CH,(CH„) CH«CH-Cd.-CH“CH3 2 a 2

5. 6. A compound according to claim 1 or 4, 3 4 5 in which R , R’ and R are selected from hydrogen, nitrile, -CONH2» tetrazolyl or carboxyl.

6. 7. A compound of the formula (I) given and defined in claim 1, which is any one of those specifically hereinbefore mentioned.

7. 8- A process for preparing a compound of the formula (I) given and defined in claim 1, substantially as hereinbefore described and exemplified.

8. 9· A compound of the formula (I) given and defined in claim 1, whenever prepared by a process claimed in claim 8.