GB2101594A

GB2101594A - 6-substituted-5-hydroxy hexanoic acids and their derivatives

Info

Publication number: GB2101594A
Application number: GB08217589A
Authority: GB
Inventors: Stephen Richard Baker; William James Ross; William Boffey Jamieson; Alec Todd
Original assignee: Lilly Industries Ltd
Current assignee: Lilly Industries Ltd
Priority date: 1981-06-18
Filing date: 1982-06-17
Publication date: 1983-01-19
Also published as: PL236992A1; GB2101594B; GR76838B; PT75058B; ES513221A0; FI822205A0; PL137766B1; AU8500882A; EP0068739B1; CS456582A2; NZ200984A; CS241109B2; PL240483A1; HU192105B; PL240484A1; ZA824294B; RO83706B; IE53522B1; ES8307212A1; KR890000622B1

Description

1 GB 2 101 594 A 1

SPECIFICATION Improvements in or relating to organic compounds

The invention relates to alkanoic acid derivatives.

The invention provides compounds which, in free acid form, are of formula 1, TR, 61 - 4 2 \S/ 0 \3/ 0 \ 1 (1) 5 COOH in which R, is (i) an aliphtaic, saturated or unsaturated hydrocarbyl radical of up to 20 carbon atoms, unsubstituted or substituted by at least one substituent selected from halogen, hydroxy, C --, alkoxy, C3-6 cycloalkyl, aryl or heteroaryl, the cycloalkyl, aryl or heteroaryl being unsubstituted or substituted by at least one substituent selected from hydroxy, halogen and alkyl, alkenyl or alkynyl of up to 10 10 carbon atoms, (H) cycloalkyl of 3 to 8 carbon atoms unsubstituted or substituted by alkyl, alkenyl, or alkynyl of up to 16 carbon atoms, or (iii) aryl or heteroaryl, unsubstituted or substituted by hydroxyl, C,-, alkoxy, halogen or alkyl, alkenyl or akynyl of up to 16 carbon atoms; and R, is (i) alkyl, cycloalkyl or alkenyl of up to 10 carbon atoms, unsubstituted or substituted by one or more substituents selected from aryi, cycloalkyl, halogen, hydroxy, NHR, and COX, where R, is H, C1-4 alkyl, aryi, an amino acid residue or COX, and X is OH, C1-4 alkyl, NH2 or an amino acid residue or (ii) aryl or heteroaryl, unsubstituted or substituted by one or more substituents selected from C1-4 alkyl, C,-, alkoxy, C,-, acyl, halogen, hydroxy, carboxy, nitro, trihalomethyi, phenyl, C,-, acylamino and 20 NHR4, where R4 is hydrogen or C,-, alkyl; and Y is -S-, -SO- or -S02-, with the proviso that when - YR, is glutathiony], cysteinyl or cysteinyiglycinyi, then R, is other than an unsubstituted alkatetraenyl or alkapentaenyl radical of 12 to 16 carbon atoms.

Preferred compounds are those of the above formula 1 in which R,, R, and Y have the stated values, with the proviso that R, is other than an unsubstituted monoalkyl radical of <,5 carbon atoms or 25 an unsubstituted alkatrienyl, alkatetraenyl, alkapentaenyl or alkadiendiynyl group of 12 to 16 carbon atoms.

In the above formula, the compounds are shown in free acid form. They also exist in lactone, salt and ester forms, which forms are embraced by the present invention. When in lactone form, their formula, as will be appreciated, is as follows 1 R2 /\ / 0 \ / 0 R1 i i / 0 0 Of the salt forms, the pharmaceutical ly acceptable salt forms are preferred and as examples may be given the alkali and alkaline earth metal salt forms as well as ammonium and amine salt forms, the alkali metal, especially the sodium and potassium, salt forms being particularly preferred.

Of the ester forms, the pharmaceutically acceptable ester forms are preferred and as examples 35 may be given the alky], silyl, cycloalkyl, cycloalkyl-alkyl and aralkyl ester forms, the C1-4 alkyl ester forms being particularly preferred.

Since the compounds of formula 1 can contain more than one carboxylic acid group, so called partial salts and partial esters, i.e. compounds in which not all the carboxylic acid functions are in salt or ester form, are possible, as, indeed, are mixed salt/ester forms.

In the compounds of formula 1, Y is preferably S or SO,.

Where R, is an unsubstituted aliphatic or saturated hydrocarbyl radical, such is preferably a straight or branched chain alkyl radical of 2 to 18, preferably 6 to 16, carbon atoms, with the straight chain alkyl radicals being more preferred. Where R, is a substituted aliphatic saturated hydrocarbyl radical and the substituents are halogen, alkoxy or hydroxy, it is preferably again a straight or branched 45 alkyl radical of 2 to 18, preferably 5 to 16, carbon atoms, again with the straight chain alkyl radicals being preferred. Where R, is a substituted aliphatic saturated hydrocarbyl radical and the substituents are cycloalkyl, aryl or heteroaryl, it is preferably a C2-, alkyl radical and preferably straight chain. Where the cycloalkyl, aryl or heteroaryl substituents are themselves substituted, the preferred substituents are alkyl, alkenyl or alkynyl of up to 10 carbon atoms, the alkenyl and alkynyl radicals containing up to four 50 carbon-carbon double or triple bonds. The preferred aryl radicals are phenyl and naphthyl radicals, the preferred heteroaryl radicals being pyridyl and thiophene radicals. The most preferred substituents on 2 GB 2 101 594 A 2 the aryl and heteroaryl radical are alkyl and alkenyl radicals. Of the aryl and heteroaryl radicals, the former are preferred.

Where R, is an aliphatic unsaturated hydrocarbyl radical, it may be an alkenyl or alkynyl radical and may contain one or more, preferably up to five, double or triple carbon-carbon bonds anywhere along its length and may, indeed, contain a mixture of double and triple bonds, and can be branched or unbranched. Where unsubstituted or substituted by halogen, alkoxy or hydroxy, the unsaturated hydrocarbyl radical is preferably of 2 to 18, more preferably of 5 to 16 carbon atoms. Where substituted by an aryl or heteroaryl substituent, the alkenyl or alkynyl radical is preferably of 2 to 6 carbon atoms, the preferred aryl and heteroaryl radicals and the preferred substituents on such radicals being as given for when R, is an alkyl radical. Of the unsaturated hydrocarbyl radicals as R, the alkenyl 10 radicals, containing up to 5 carbon-carbon double bonds, are preferred, most preferred being the unsubstituted such radicals. Where R, is aliphatic unsaturated it is most preferably of the form R6 1 R,-em=u- where R, is phenyl, benzyl, naphthyl or alkyl or monoalkenyl of 3 to 14 carbon atoms, and R, is hydrogen or C1-4 alkyl.

Where R, is cycloalkyl radical of 3 to 8 carbon atoms, such is preferably cyclopropyl, cyclopentyl or cyclohexyl. Any alkyl, alkenyl or alkynyl substituent on the cycloalkyl radical is preferably of up to 12 carbon atoms and any alkenyl or alkynyl substituent may contain more than one, preferably up to 5, carbon-carbon double or triple bonds.

As examples of aryl and heteroaryl radicals as R, may be given phenyl, naphthyl, pyridyl and 20 thiophene radicals. Of the aryl and heteroaryl radicals, the former are preferred. The aryl or heteroary] group can for example be substituted by hydroxyl, halogen or alkyl, alkenyl or alkynyl of up to 16 carbon atoms. Any alky], alkenyl or alkynyl substituent on the aryl or heteroaryl radical is preferably of up to 12 carbon atoms and any alkenyl or alkynyl substituent may contain more than one, preferably up to 5, carbon- carbon double or triple bonds. Of the substituted aryl and heteroary] radicals as R,, the 25 preferred are those wherein the substituents are alkyl, alkenyl or alkynyi, particularly those where the substituents are alkyl or alkenyi. Where R, is aryl the most preferred values are phenyl or naphthyl and when the aryl ring is substituted it preferably bears a single Cl-,, alkyl or phenyl group.

Where R2 IS unsubstituted alkyl or alkenyl, such is preferably of 2 to 5 carbon atoms and may be straight or branched, and when R2 is cycloalkyl or is substituted by cycloalkyl, the cycloalkyl group 30 preferably contains 3 to 8 carbon atoms. R, may, for example, be alkyl or alkenyl of up to 10 carbon atoms unsubstituted or substituted by one or more substituents selected from aryl, halogen, hydroxy, NHR, and COX, where R3 is H, Cl-, alkyl, aryl, an amino acid residue or COX where X is OH or an amino acid residue. Any aryl substituent on an alkyl or alkenyl radical as R2'S preferably phenyl. Where R. is substituted alkyl or alkenyl, the preferred substituents are NHR, and COX where R3 is H, Cl_4 alkyl, aryl 35 an amino acid residue or COX, and X is OH or an amino acid residue. Preferred amino acid residues as R3 or X are glycine, glutamic acid, alanine and phenylalanine and when reference is made to an amino acid residue it is to be understood that the protected forms (protected with conventional groups) are also included. Of the alkyl and alkenyl significances of R2, the former is preferred. Particularly preferred significances for the grouping -YR2 are the peptide radicals glutathionyl, cysteinyl and eysteinyiglycinyl of formulae -SCH,-CHCONHCH,COOH 1 NI-ICOCH,Cl-1,CHM,)COOH, -SCH,CH(NH2)COOH and -SCH2CH(NH,)CONHCH2COOH, respectively.

Where R2 is aryi, such is preferably phenyl, and any substituent is preferably C1-4 aikyi, C,-4 45 alkoxy, halogen, hydroxy, carboxy or NHIR4. The substituents are also preferably electron withdrawing groups and in addition can be nitro trihalomethyl especially trifl uoro m ethyl, or C,-, acyl.

Anihalogen in the compounds of formula 1 is preferably chlorine or bromine, particularly the former.

Particularly preferred significances of R, are as follows:

a) unsubstituted C _1. alkyl or alkenyl, the alkenyl containing up to 5 double bonds, b) C,-,, alkyl monosubstituted by phenyl, c) unsubstituted phenyl or naphthyi, and d) R6 1 IR,-CH=C- 55 3 GB 2 101 594 A 3 where R. is phenyl, benzyi, naphthyl or alkyl or monoalkenyl of 3 to 14 carbon atoms, and R. is hydrogen or C,-4 alkyl.

Particularly preferred significances of R2 are as follows:

a) together with the sulphur atom in the grouping -SR2, glutathlonyl, cysteinyl and 5 cysteinylgiyciny], b) phenyl, unsubstituted or substituted by one to three groups selected from C1-4 alky], C1-4 alkoxy, halogen, hydroxy or carboxy.

As will be appreciated, the compounds of formula 1 possess chiral centres at C. and C. and, accordingly, exist in the stereoisomeric forms 5R, 6R; 5S, 6S; 5R, 6S and 5S, 6R. Other chiral centres 10 are also possible, depending on the nature of the substituents R, and R2, leading to further stereoisomeric forms. Further, where the compounds contain alkenyl substituents, for example as or in R,, cis-trans isomeric forms exist. It is not intended that the present invention be limited to any particular isomeric form.

Further instances of preferred groups of compounds are as follows:

(a) Compounds of the formula f R2 R5 --- C.q=c/ \ / \ / COOH 0 in which R, is alkyl, cycloalkyl or alkenyl of up to 10 carbon atoms, unsubstituted or substituted by one or more substituents selected from aryl, cycloalkyl, halogen, hydroxy, NHR, and COX, where R3 is H, Cl4 alkyl, ary], an amino acid res idue or COX and X is OH, C1-4 alkyl, N1412 or an amino acid residue, R.

is alkyl or alkenyl of 3 to 14 carbon atoms, the alkenyl group being of formula R7CH=CH- where R7 is 20 Cl-12 alkyl, or phenyl or naphthyl, and R, is H or C1-4 alkyl; and the lactone, salt and ester forms thereof.

It is preferred that R,'S Cll-14 alkyl, especially C,, alky], or R.CH=CHwhere R. is C8-12 alkyl, and the configuration of the R. group at the position 8 carbon atom can be Z or E configurations and is preferably Z.

The R2 group can be a wide variety of radicals and is preferably C2-, alkyl substituted by one or 25 more substituents selected from NHR3 and COX where R3 is H, an amino acid residue or COX and X is OH, C1-4 alkyl, NH2 or an amino acid residue, such amino acid residues preferably being derived from glyceine, alanine. A preferred formula of R2'S "COX --1)nl R 3 where each R is H or C1-4 alkyl and n is 1 to 3, X is OH or OR and R, is H or COR where R is C,-4 alkyl, 30 preferably methyl.

Thus an especially preferred sub-generic group is of the formula f R2 cl 1 123-CR=CH / \ / \ 0 / \ COOH 6H in which F12S -HCOX n R3 where each R is H or C1-4 alkyl and n is 1 to 3, X is OH or OR and R3 is H or COR where R is C,-4 alkyl, preferably methyl.

Examples of R2 groups include -CH,Cl-1,COOH, (CHICOOH, -CH2CH(NH2)COOH, -CH2CH(WCOOH, 1 COCH3 4 GB 2 101 594 A 4 -CHCONHCH2COOH, 1 CM3 and (b) Compounds of the formula CE2CH2NHCO 2CH3 CH3 NHCOCH3 -C-CH C2H, C02Me R OH 0 COOP in which R, is substituted or unsubstituted phenyl or naphthyl or a group of the formula R,-CH=CH where R, is phenyl, benzy] or naphthyl, and R2 is unsubstituted or substituted phenyl; and the lactone, salt and ester forms thereof. When the R2 substituent is substituted, the substituents may number up to 3 and are preferably chosen from C,-, alkyl, C,-, alkoxy, C2-, acy], (C,-, alkyl CO) halogen, hydroxy, carboxy, nitro, trihalomethyl and C,-, acylamino, being most preferably halogen, trifluoromethyl or nitro.

An especially preferred sub-generic group has the formula R, 1 COOP 011 in which R, is naphthyl and R2 is substituted phenyl preferably substituted with 1 to 3 halogen, nitro or 15 trifluoromethyl groups. (c) Compounds of the formula f 0 2 F2 R1 /0\ /,\. /0\ COOH L in which R, is a group of formula R,CH=CH- or R,CH2CH2- where R' is phenyl and R2'S 20 unsubstituted or substituted C,-, alkyl or unsubstituted or substituted phenyl; and the lactone, salt and 20 ester forms thereof. Substituents on the phenyl nucleus can be any of those listed in (b) above.

The invention also provides a method for the production of the compounds of the invention, which process comprises a) obtaining a compound which, in free acid form, is of formula 1, above, in which Y is -S-, by ai) reacting a compound which in free acid form is of formula 11, 2 H COOH in which R, is as defined above, with a sulphenyl chloride of formula Ill, R 2SCI II (111) in which R2 is as defined above, in an inert solvent and either isolating the resulting lactone form of the compound of formula 1 or hydrolysing the resulting lactone form to obtain a compound of formula 1 in 30 free acid form; or aii) reacting a compound which, in free acid form, is of formula IV, R1 4 / 0 \-/. \ / \l i COOH IV GB 2 101 594 A 5 in which R, is as defined above, with a thiol of formula V, R,SH (V) in which R, is as defined above; b) obtaining a compound which in free acid form is of formula 1, above, in which Y is -SO or -SO,-- by oxidising a corresponding compound which in free acid form is of formula 1 above, but in 5 which Y is -S-; or c) obtaining a compound which in free acid form is of formula 1, above, in which Y is -S02-, by reacting a compound of formula VI, R,-CHI-SO2R, V1 in which R, and R, areas defined above, with a compound which in free acid form is of formula VII; 10 01,C/6\. / '\COOH vii and, where desired, isolating the resulting compound in free acid, lactone, salt or ester form.

Process ai) is preferably carried out in the presence of a base, for example in the presence of an organic amine, preferably a tertiary organic amine, such as a trialkylamine, e.g. triethylamine. The reaction is carried out in an inert solvent such as in an ether, e.g. diethyl ether, or in a halogenated hydrocarbon, such as carbon tetrachloride. A suitable reaction temperature is from -601 to +601C, preferably from -20' to +201. The initial product of the process in the lactone form of the compound of formula 1 which can be hydrolysed to the free acid form, for example using basic hydrolysis. This process ai) is not preferred when compound 11 contains other double or triple bonds, e.g. when R, is an alkenyl grouping, since competing side reactions involving addition of the sulphenyl chloride at other than the C, double bond occurs. For these compounds process ali) is preferred.

Because of the relative instability of the sulphenyl chloride of formula Ill, it is preferred for this reagent to be produced in situ, for example by chlorinating the corresponding thiol (R2SH) or preferably the corresponding disulphide ^S-SR2), employing, as chlorinating agent, molecular chlorine or sulphuryi chloride at a temperature of from -601 to +201C in an inert solvent, e.g. carbon tetrachloride.

The compounds 11 are preferably employed in free acid form.

The C, double bond in compounds 11 can be cis (Z) or trans (E), leading to different diastereoisomers of the final compounds.

Process aii) is suitably carried out in the presence of a strong base (pKa> 12) such as a trialkylamine, e.g. triethylamine and in an inert polar solvent such as in an alkanol, e.g. methanol.

A suitable reaction temperature is from 101 to 501C, preferably at room temperature. The reaction may be catalysed by adsorbing the thiol of formula V onto active alumina.

In the process aii), it is preferred to employ compound R in ester form, particularly in C1-4 aikyi ester form and especially in the methyl ester form. The resulting compound of the invention will then 35 initially be produced in corresponding ester form.

In this reaction, the isomeric 5-thio-6-hydroxy compound may be formed along with the desired 5-hydroxy-6-thio compound of formula 1. The isomeric by-product can be removed from the mixture by formation of the acid form, followed by lactonisation, e.g. by heating in an inert solvent such as toluene, only the 5-hydroxy compound undergoing the lactonisation.

Process b) can be carried out in conventional manner for the oxidation of a sulphide to a sulphoxide or sulphone, for example using a peroxy acid as oxidising agent. A particularly preferred oxidising agent is m-chloroperbenzoic acid. The reaction is suitably carried out in an inert solvent, such as in a halohydrocarbon, for example in methylene chloride. Where it is desired to obtain a sulphoxide, i.e. a compound of formula 1 in which Y is -SO-, it is preferred to use one mole of m chloroperbenzoic acid per mole of sulphide of formula 1 at about 01C. Where it is desired to obtain a sulphone, i.e. a compound of formula 1 in which Y is -SO,-, it is preferred to employ an excess of m chloroperbenzoic acid at room temperature.

In this process it is preferred to employ the sulphide starting material of formula 1 in lactone form, resulting, initially, in production of the corresponding sulphone or suiphoxide in lactone form.

In process c), it is preferred to employ the compound of formula VII in ester form, the preferred ester form being the methyl ester form, i.e. it is most preferred to employ methyl 4-formyibutyrate. The resulting compound of formula 1 is thereby obtained initially in corresponding ester form. The reaction is preferably carried out in the presence of a base, for example ethyl magnesium bromide, and in an inert solvent, such as in an aromatic hydrocarbon, e.g. benzene. Elevated reaction temperatures are 55 preferred, e.g. at reflux.

The resulting compounds of the invention may be isolated and purified in conventional manner.

Interconversion as between the various forms of the compounds of the invention, e.g. salt, free 6 GB 2 101 594 A acid, lactone and ester forms, may also be carried out in conventional manner. For example, ester forms can be converted into salt forms by treatment with the appropriate aqueous dilute base at a pH of from 9 to 10. The salt forms can be converted to the free acid forms by aqueous acidification. The free acid forms can be converted to the lactone forms by acid treatment at a pH of less than 5, and the salt or free acid forms can be converted to ester forms by base or acid catalysed esterification using an 5 appropriate alcohol.

The intermediate compounds employed in the above processes a) to c) are either known or may be obtained from available starting materials in conventional manner.

For example, the compounds of formula 11 can be obtained by a Wittig reaction of 4-carboxybutyi- triphenylphosphoniumbromide, of formula VIII, Br Ph3 P+ 4 2 \5/\3/\ 0 h0H in which Ph signifies phenyl, with an aldehyde of formula IX, R1CHO Vill IX in which R, is as defined above, in the presence of a strong base, such as sodium hydride in DMSO, or potassium tert-butoxide, a suitable reaction temperature being from 0 to 1 001C, preferably from 10 to 15 300C.

The sulphenyl chlorides of formula Ill may be prepared as described above when discussing process a!), i.e. by chlorination of the corresponding thiols or disulphides.

The epoxides of formula IV, used in process aii), above, can be prepared by oxidation of compounds of formula 11, preferably in ester form, employing, for example, as oxidising agent, mchloroperbenzoic acid or hydrogen peroxide. Where m- chloroperbenzoic acid is employed as oxidising agent, the oxidation is suitably carried out in chloroform, and, when hydrogen peroxide is employed, the oxidation is suitably carried out in methanol.

A particularly valuable and novel group of compounds which in free acid form are of formula IV are those which, in free acid form, are of formula M COOH H- ---C H a wherein R,' has the same significance as the R, values above, with the proviso that it is other than a C12-Cl. alkatetraenyl or alkapentaenyl radical.

A preferred significance of R,' is a grouping of formula IR,,-CH=CHwherein RX is an aliphatic saturated or unsaturated hydrocarbyl radical of up to 18 carbon atoms, unsubstituted or monosubstituted by phenyl or naphthenyl, each of which is unsubstituted or monosubstituted by alkyl, alkenyl or alkynyl of up to 10 carbon atoms, with the proviso that Rx is other than an unsubstituted alkatrienyl or alkatetraenyl radical of 10 to 14 35 carbon atoms.

A further preferred group of intermediates is one in which R,' is of the formula IR,-CH=C- R, where R. is alkyl or alkenyl of 3 to 14 carbon atoms, the alkenyl group being of formula FlCH=CH where R, is C,-,, alkyl, or phenyl or naphthyl, and R, is H or C,-, alkyl.

A further preferred group of intermediates is one in which R,' is substituted or unsubstituted 40 phenyl or naphthyl.

The compounds of formula VI, employed in process c) can be prepared by reaction of a bromide of formula X, R,CH,Br in which R, is as defined above, with a sulphinate of formula M, IR,SO,Na in which R, is as defined above, suitably in dimethylformamide at room temperature.

X Xl 7 GB 2 101 594 A 7 The compounds of the present invention, i.e. compounds which in free acid form are of formula 1, above, are pharmacologically active, being SRS-A antagonists as indicated in one or more of the following tests; the in vitro test on guinea pig ileum segments of concentrations of from 10 ng to 50 pg, according to the method of Schild, 1947 Brit. J. Pharm. 2 197- 206 (the compounds of the invention as shown for instance in the following Examples exhibited an 1C50 against SRS-A of less than 10' molar); the in vivo Guinea Pig Pulmonary Function Test of Austen and Drazen 1974 J. Clin. Invest. 53:1679-1685 at intravenous dosage levels of from 0.05 ug to 5.0 mg/Kg and in a modified "Herxheimer" test at doses of from 25-200 mg/Kg. The "Herxheimer" test is based on an allergic bronchospasm induced in guinea pigs and which closely resembles an asthmatic attack in man. The mediators causing the bronchospasm are very similar to those released when sensitised human lung 10 tissue is challenged with an antigen. In the modified test employed in respect of compounds of the present invention, the animals were pretreated with a histamine antagonist, mepyramine, at a dose of 0.5 mg/Kg i.p., 30 mins. before challenge. This modification masks the histamine effect to reveal better the SRS-A effect.

The compounds are accordingly indicated for therapeutic use in the treatment of allergic reactions of the pulmonary system where SRS-A is thought to be a causal mediator of bronchospasm, i.e. in allergic lung disorders such as extrinsic asthma and industrial asthma such as Farmers lung and Pigeon Fanciers lung, as well as in other allergic/inflammatory or lung disorders where SRS-A is believed to be a mediator, such as allergic skin diseases, ectople and atopic exzemas, psoriasis, contact hypersensitivity and angioneurotic oedema, bronchitis and cystic fibrosis.

The compounds may be administred in free acid form, in lactone form or in pharmaceutically acceptable salt or ester form. They may be administered by various routes, for example by the oral or rectal route, by inhalation, topically or parenterally, e.g. by injection, being usually employed in the form of a pharmaceutical composition. Such compositions form part of the present invention and are prepared in a manner well known in the pharmaceutical art and normally comprise at least one active 25 compound in association with a pharmaceutically acceptable diluent or carrier. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier and/or enclosed within a carrier which may, for example, be in the form of a capsule, sachet, paper or other container. Where the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition may be in the form of tablets, lozenges, sachets, cachets, elixirs, suspensions, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, injection solutions and suspensions and sterile packaged powders. For administration by inhalation, particular forms of presentation include aerosols, atomisers and vaporisers.

Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl hydroxybenzoate, tale, magnesium stearate and mineral oil. The compositions of the invention may, as is well known in the art, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.

Where the compositions are formulated in unit dosage form, it is preferred that each unit dosage form contains from 10 mg to 1 g. The term "unit dosage form- refers to physically discrete units suitable as unit dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.

The active compounds areeffective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.5 to 300 mg/Kg, more usually in the range of from 5 to mg/Kg. However, it will be understood that the amount administered will be determined by the physician in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered and the chosen route of administration, and therefore the above dosage 50 ranges are not intended to limit the scope of the invention in any way.

The following Examples illustrate the invention. In some instances it has not been possible to give a melting or boiling point, but it should be understood that all the compounds of the invention have been confirmed by physical methods.

Example 1 (a) (Z)-8-Pheny]-5-octenoic acid A stirred suspension of sodium hydride (12.0 g, 50% dispersion in oil) in dry dimethyl sulphoxide (100 mO was heated to 70 to 750C under nitrogen for 40 minutes. The dark solution was cooled, a solution of 4-carboxybutyitriphenylphosphonium bromide (53 g) in dry dimethyl sulphoxide (100 mi) was added over 20 minutes at 20 to 250C, and the solution was stirred for a further 10 minutes. 3Phenyl-propionaldehyde (12. 5 mi) was added with cooling to maintain a temperature of 30 to 350C and the mixture was stirred for a further 4 hours at room temperature, then poured on to ice-water (600 mi) and washed with chloroform. The aqueous phase was acidified and extracted with chloroform. The extract was washed with water, dried and evaporated. The residual oil was distilled 8 GB 2 101 594 A 8 under vacuum to give the above product, b.p. 134 to 1 391C/0.07 mm. C NIVIR spectroscopy showed the presence of about 5% (E)-isomer.

Following the procedure above and employing appropriate starting materials, 5-heptenoic acid', 65 to 71 'C/0.3 mm (85% W, 15% (E) isomer by "C NIVIR) and 5-undecenolc acid', b.p. 105 to 1061C/0. 1 mm (90% W, 10% (C) were similarly prepared.

1. J.C.S. (C) 217 (1968) 2. J.0.C. 43, 4387 (1978) (b) 0-15-Hexadecenoic acid A stirred suspension of 4-carboxybutyl-triphenylphosphonium bromide (44.8 g) in benzene (200 m[) was dried by heating under a water trap for 20 minutes. The mixture was cooled, solid potassium 10 tert-butoxide (34.0 g) was added under nitrogen, and the stirred suspension was heated under reflux for 15 minutes. A solution of undecyclic aldehyde (20.8 mi) in dry benzene (20 mi) was added to the cooled mixture at 20 to 251C, and afterstirring for a further 1 hour the mixture was diluted with ether and extracted with sodium chloride solution. The aqueous extract was acidified and re-extracted with ether and the ether extract was dried and evaporated. Distillation of the residue gave the product b.p.

to 151 OC/0.1 mm (90% (Z), 10% (E) by "C NMR). (Chemical Abstracts 85:159341 and Chem. Phys. Lipids 16, 215 (1976)).

(c) rei-(6R,1'R)-6-(31-Phenyi-ll-phenyithiopropyi)-tetrahydro-2H-pyran-2one A solution of chlorine (0.9 g) in carbon tetrachloride (10 mi) was added dropwise to a stirred solution of diphenyl disulphide (2.2 9) in carbon tetrachloride (20 m]) at 0 to -51C. The yellow solution 20 was stirred for 10 minutes at OOC then a solution of (Z)-8-phenyl-5- octenoic acid (1.45 g), prepared as in (a) above, and triethylamine (0.93 mO in carbon tetrachloride (20 mO was added at 0 to -51C. The mixture was stirred for 2 hours at room temperature then evaporated under vacuum. A solution of the residue in ether was washed with dilute hydrochloric acid, then with dilute sodium hydroxide solution, dried and evaporated to give a pale oil.

A solution of the crude neutral product in 10% sodium carbonate solution was heated under reflux for 2 hours, cooled, washed with ether, acidified and extracted with ether. The extract was dried and evaporated and a solution of the residual acid in toluene was heated under a water trap for 30 minutes and evaporated to give the crude lactone. This was further purified by chromatography on silica gel in ethyl acetate: petroleum spirit (1:3) to give the pure product.

(d) rei-(5R,6R)-5-Hydroxy-8-phenyi-6-phenyithiooctancic acid A stirred mixture of 6- (3-phenylA -phenylthio-propyi)-tetrahydro-2H- pyran 2-one (2.1 g), prepared as in (c) above, and 10% sodium carbonate solution (50 mO was heated under reflux for 2 hours, cooled, diluted with sodium chloride solution, washed with ether, acidified and extracted with ether. The extract was dried and evaporated without heat to give the product as a pale oil.

(e) rei-(5R,6R)-5-Hydroxy-8-phenyl -6-phenylthiooctanoic acid, sodium salt A solution of 5-hydroxy-8-phenyl-6-phenylthiooctanoic acid (1.45 g), prepared as above, in ethanol (50 mi) was made basic with molar sodium methoxide in methanol (4.1 mO and the solution was evaporated to dryness under vacuum. The residue crystallised from isopropanol-petroleum spirit to give the title product m.p. about 1 501C.

Examples 2 to 4 The lactones shown below were prepared by the method described in Example 1 (c), employing appropriate starting materials and omitting the hydrolysis and re-lactonisation steps and purifying the products only by chromatography SR 2 R 0 \ 0 a R, n-ClOH21 Ph(CH1)2 Ph(CHI and enantiomer R2 Ph 1 r Ph These lactones were hydrolysed as described in Example 1 (d) and converted as described in 50 Example 1 (e) to the sodium salts shown below 9 GB 2 101 594 A 9 SR V 2 R1 /0\ I /0\ /\ OH 0 C02Na and enantiomer Solvent of R, R2 crystallisation M.P. OC n-ClOH21 Ph freeze dried Ph(CHI)2 WrOH/petrol ca 200 5 Ph(CH2)l Ph MeOH/iPrOH Example 5 (a) (Z) And (E)-6-phenyi-S-hexenoic acids A stirred suspension of 4-ca rboxybutyi-tri phenyl phosphoni u m bromide (38.2 9) in benzene (400 mi) was dried by heating under a water trap for 20 minutes. The mixture was cooled, solid potassium 10 tert-butoxide (29.0 9) was added under nitrogen, and the stirred suspension was heated under reflux for 15 minutes. A solution of benzaidehyde (8.73 mi) in dry benzene (20 mi) was added to the cooled mixture at 20 to 250C, and after stirring for a further 1 hour the mixture was diluted with ether and extracted with sodium chloride solution. The aqueous extract was acidified and re-extracted with ether and the ether extract was dried and evaporated. Distillation of the residue gave a mixture of (Z) and W6-phenyi-5-hexenoic acids, b.p. 134 to 1420C/0.1 mm. This mixture was heated under reflux for 2 hours in methanol (250 m[) containing concentrated sulphuric acid (0.4 mi). The solution was evaporated and the residue was dissolved in ether, washed with sodium bicarbonate solution, dried and re-evaporated. The residue was distilled in a spinning band apparatus to separate methyl (Z)-6 phenyl-5-hexenoate, b.p. 122 to 1231C/0.3 mm, and the (E) isomer b.p. 1330C/0.3 mm.

A solution of methyl (Z)-6-phenyi-5-hexenoate (2.0 g) in dioxan (20 mi) and 10% sodium carbonate solution (20 mi) was heated under reflux for 6 hours and evaporated to low volume. The residue was diluted with water, washed with ether, acidified and extracted with ether. The extract was dried and evaporated to give (Z)-6-phenyi-5-hexenoic acid.

The M-isomer was similarly hydrolysed. (J.0.C. 31 1390 (1966)).

(b) rei-(5R,6R)-5-Hydroxy-6-pheny]-6-phenyithiohexanoic acid, sodium salt A solution of chlorine (1.56 g) in carbon tetrachloride (23 mO was added dropwise to a stirred solution of diphenyl disulphide (4.0 g) in carbon tetrachloride (50 mi) at 5 to 1 OOC. The yellow solution was stirred for 10 minutes at 5 to 1 OOC then a solution of (Z)-6-phenyl-5-hexenoic acid (5.2 g) and 30 triethylamine (3.8 m]) in carbon tetrachloride (50 mi) was added at 5 to 1 OOC. The mixture was stirred for 2 hours at room temperature then evaporated under vacuum. A solution of the residue in ether was washed with dilute hydrochloric acid, then with dilute sodium hydroxide solution, dried and concentrated to give crystals of 7 -phenyl6-phenyithio-2-oxepa none, m.p. 1660 C. The mother liquor was evaporated and the residue was chromatographed on silica gel in ethyl acetate:petroleum spirit 35 (11:3) to give an oil which crystallised from ether to give rei-(6R,aR)-6-(a-phenylthiobenzyi)-tetrahydro- 35 2H-pyran2-one, m.p. 82 to 840C. A stirred mixture of this 6-(a-phenylthiobenzyi)tetrahydro-2H-pyran-2-one (1.2 g), dioxan (10 mi) and 10% sodium carbonate solution (20 mi) was heated under reflux for 2 hours and then evaporated. A solution of the residue in water was washed with ether, acidified and extracted with ether. The extract was dried and evaporated and a solution of the residue in ethanol (50 mi) was made 40 basic with molar sodium methoxide in methanol (3.8 mi) and evaporated to dryness under vacuum to give the title product, m.p. 2 1 OIC.

Example 6 rel-(5R,6S)-5-Hydroxy-6-pheny]-6-phenyithiohexanoic acid, sodium salt This compound, m.p. about 1901 C, was prepared as described in Example 5, starting from the 45 corresponding (E) isomer. The crude 6-membered lactone after chromatography was further purified by hydrolysis to the acid as described in Example 5(b) followed by heating in toluene under a water trap to re-lactonise. The toluene solution was evaporated and a solution of the residue in ethyl acetate was washed with 5% sodium carbonate solution, dried and evaporated. The residue crystallised from ether to give pure rei-(6 R,aS)-6-(a-phenyith iobe nzyi)-tetra hyd ro-2 H-pyran- 2 -one, m.p. 1260C.

Example 7 (a) Methyl (Z)-8-pheny]-5-octenoate A solution of (Z)-8-phenyi5-octenoic acid (12.6 g), see Example 1 (a), and concentrated sulphuric acid (0.1 mi) in methanol (300 mi) was heated under reflux for 2 hours. The solution was evaporated 55 and the residue distilled under vacuum to give the ester b.p. 110 to 1 130C/0. 1 mm.

GB 2 101 594 A 10 (b) Methyl 5,6-oxido-8-phenyloctanoate Solid rn-chloroperoxybenzoic acid (10.7 g 80% purity) was added to a stirred solution of methyl (Z)-8-phenyl-5-octenoate (11.0 g), see (a) above, in chloroform (100 mi) at 15 to 2WC. The mixture was stirred for 4 hours at room temperature and filtered. The filtrate was washed with sodium bicarbonate solution, dried and evaporated and the residue was distilled under vacuum to give the product, b.p. 120 to 1251C/0.05 mm.

(c) 6-(R,S)-Ethyithio-S-(R,S)-hydroxy-8-phenyloctanoic acid Ethanethiol (5.6 ml) was added dropwise to a stirred suspension of active (grade Super 1) alumina (150 g) in dry ether (160 mi). The suspension was stirred at room temperature for 5 minutes then a solution of methyl 5,6-oxido-8-phenyl-octanoate (4.8 g), see (b) above, in ether (40 mi) was added. The mixture was stirred for a further 1 hour, poured on to methanol (1 litre) and stirred for 2-1 hours, and filtered. The filtrate was evaporated and the residue chromatographed to give a mixture of methyl 6-ethylthio-5-hydroxy-8-phenyloctanoate and methyl 5-ethylthio-6hydroxy-8phenyloctanoate as a pale oil.

A stirred mixture of this oil and 10% sodium carbonate solution (45 mi) was heated under reflux 15 for 4 hours, cooled, washed with ether, acidified and extracted with ether. The extract was dried and evaporated and a solution of the residue in toluene (25 mi) was heated under a water-trap for 2 hours, diluted with ether, washed with sodium hydroxide solution, dried and evaporated. The residual lactone was stirred with 10% sodium carbonate solution (20 m]) with heating under reflux for 2 hours. The solution was washed with ether, acidified and extracted with ether and the extract was dried and evaporated to give the title product as a pale oil.

Example 8 5-Hydroxy-8-pheny]-6-phenylthiooctanoic acid This compound was prepared by the method described in Example 7(c) employing thiophenol in place of ethanediol.

Example 9 (a) Methyl 5,6(E)oxido-7(Z)nonadecenoate Dodecy[triphenylphosphonium bromide (17.9 g) was dissolved in dry tetrahydrofuran (200 mi), stirred under nitrogen and cooled to -780C. Butyl lithium (1.6 molar solution in hexane, 23 mi) was added gradually with formation of a deep orange colour. After stirring at -780C for 20 minutes, methyl 30 5,6(E)oxido-7-oxoheptanoate (5.6 g) in tetrahydrofuran (20 mi) was added rapidly. The solution lightened in colour and was allowed to warm up to room temperature over 1 hour. The bulk of the solvent was evaporated in vacuo and the residue extracted with ether/hexane 50/50 v/v containing 1 % triethylamine (3x30 m]). The bulked extracts were evaporated in vacuo to small volume and chromatographed on silica gel using the same solvent mixture. The fractions containing the title compound were bulked and evaporated in vacuo to give the product as a colourless oil at room temperature. After storage at -201 C the product solidified.

(b) 5-RS) Hydroxy-6-(S,R)-S-cYstoinyi-7(Z)-nonadecenoic acid Methyl 5,6 (E)oxido-7 W non adecenoate (1.62 g) was reacted with a solution of N trifluoroacetylcysteine methyl ester (2.31 g) (protected form of a compound of formula V) and triethylamine (2.0 m[) in dry methanol (5.0 mO at room temperature for 3 days. The solution was evaporated in vacuo and chromatographed on silica gel using dichloromethane/methanol 95/5 v/v as developing solvent to give the 6-fully protected crysteinyl derivative of the methyl ester of the title compound as a pale yellow oil.

This product (1.50 9) was dissolved in methanol (10 mO and a solution of anhydrous sodium 45 carbonate (0.8 g) in water (5 mO was added with stirring. Additional water was carefully added to give a hazy solution which was stirred at room temperature for 3 days. The resultant clear solution at pH 10 was evaporated in vacuo to remove methanol and the aqueous residue adjusted to pH ca 5.5 with dilute hydrochloric acid followed by glacial acetic acid to pH ca 3. The mixture was extracted with dichloromethane and the dried (NalS04) extract evaporated in vacuo to give the title compound as a 50 viscous colourless oil, which on storage at -20'C slowly solidified.

Examples 10 to 15 By repeating the procedure of Example 9(b), but employing appropriate starting materials there were obtained the following: 5-(R,S)-Hydroxy-6-(S,R)ethylthio-7(Z)- nonadecenoic acid 5-(R,S)-Hydroxy-6-(S,R) (2-carboxyethyithio)-7(Z)- nonadecenoic acid 5-(R,S)-Hydroxy-6-(S,R)S-(N-acetylcysteinyl)-7(Z)- nonadecenoic acid 5-(R,S)-Hydroxy-6-(S,R)-benzylthio 7(E)-9(E)/(Z)- 11 (E)/(Z) 1 4(Z)-eicosatetraenoic acid 5-(R,S)-Hydroxy-6-(S,R)-(2aminoethyithio)-7(E)-9(E)/(Z)-1 1 (E)/(Z)-1 40-eicosatetraenoic acid 5-(R, S)-Hydroxy-6-(S,R)-ethyithio 7(E)-9(E)/(Z)-1 1 (E)/M1 4(Z)eicosatetraenoic acid.

11 GB 2 101 594 A 11 Example 16 (a) (Z)-8-Phenyi-5-octenoic acid A stirred suspension of sodium hydride (12.0 g, 50% dispersion in oil) in dry dimethyl sulphoxide (100 m]) was heated to 70 to 751C under nitrogen for 40 minutes. The dark solution was cooled, a solution of 4-ca rboxybutyltri phenyl phosphoni u m bromide (53 9) in dry dimethyl sulphoxide (100 mi) 5 was added over 20 minutes at 20 to 250 C, and the solution was stirred for a further 10 minutes. 3 Phenyl-propionaldehyde (12.5 mi) was added with cooling to maintain a temperature of 30 to 350C and the mixture was stirred for a further 4 hours at room temperature, then poured on to ice-water (600 mi) and washed with chloroform. The aqueous phase was acidified and extracted with chloroform. The extract was washed with water, dried, and evaporated. The residual oil was distilled 10 under vacuum to give the above product, b.p. 134 to 1391C/0.07 mm. "C NMR spectroscopy showed the presence of about 5% (E)-isomer.

(b) rei-(6R,1'R)-6-(31-Phenyl-ll-phenyithiopropyi)-tetrahydro-2H-pyran-2one A solution of chlorine (0.9 g) in carbon tetrachloride (10 mi) was added dropwise to a stirred solution of diphenyl disulphide (2.2 g) in carbon tetrachloride (20 mi) at 0 to -51C. The yellow solution was stirred for 10 minutes at OIC then a solution of (Z)-8-phenyi-5-octenoic acid (1.45 g), prepared as in (a) above, and triethylamine (0.93 mi) in carbon tetrachloride (20 mi) was added at 0 to -51C. The mixture was stirred for 2 hours at room temperature then evaporated under vacuum. A solution of the residue in ether was washed with dilute hydrochloric acid, then with dilute sodium hydroxide solution, dried and evaporated to give a pale oil.

(c) rei-(SR,6R) 5-Hydroxy-8-phonyi-6-phenyisulphonyl-octanoic acid A solution of m-ch lo rope roxybenzoi c acid (6.0 9, 85%) in dichloromethane (100 mi) was added dropwise to a stirred solution of rei-(6R,1'R) 6A3 '-phenyl- 1 '- phenyithiopropyi)-tetrahydro-2 H-pyran-2 one (4.2 g), in dichloromethane (200 mi) at 5 to 1 OIC. After 24 hours at room temperature the white solid which had precipitated (m-chlorobenzoic acid) was filtered. The filtrate was washed with 1 % 30 aqueous sodium sulphite, 5% aqueous sodium carbonate, and saturated sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to afford rel-(6R,1 'R) 6-W phenyisu 1 phony]-3'-phenyl propyl)-tetra hydro2H-pyran-2-one as a colourless viscous oil which crystallised after chromatography (silica Sorbsil U 30) and trituration with diethyl ether m.p. 830C.

The tetra hydropyran-2-one derivative (1.63 g) in 10% aqueous sodium carbonate (40 ml) was 35 heatedunder reflux for 1 hour. The solution was cooled, washed with diethyl ether, acidified (to about pH2) and extracted with diethyl ether (50 mi). The extracts were washed with saturated aqueous sodium chloride solution, dried, filtered and evaporated to a colourless oil which crystallised on trituration with diethyl ether to give the title compound as a white solid m.p. 100 to 1020C.

Example 17

Methyl 5-hydroxy-6-phenyisulphonyi-8-phenyi-octanoate A solution of ethyl magnesium brom ' ide (7.7 mI, 1.3 M solution in diethyl ether) was added to a stirred solution of phenyl 3-phenylpropyl sulphone (2.6 g) in dry benzene (20 mi). The mixture was heated under reflux for 1 hour and then cooled to room temperature. Methyl formyl butyrate (1.3 g) was added and a white precipitate started to form. After 2 hours at room temperature iced water (70 45 mi) and 2 molar hydrochloric acid (20 mi) were added. The product was extracted into diethyl ether and then chromatographed (Sorbsil U 30 silica) to afford the title compound as a colourless viscous oil.

Example 18

5-Hydroxy-8-phenyl-6-phenyisulphonyloctanoic acid Methyl 5-hydroxy-8-pheny]-6-phenyisulphonyi-octanoate was hydrolysed with aqueous sodium 50 carbonate as in the hydrolysis step of Example 16 to afford the title compound as a viscous oil.

Examples 19 to 21 The following compounds were prepared as described in Examples 17 and 18. 5-Hydroxy-6-(4-chlorophenyl)sulphonyi-8-phenyioctanoic acid 55 5-Hydroxy-6-(4-methylphenyi)sulphonyi-8-phenyi-octanoic acid 5-Hydroxy-6-phenyisulphonyi-8-phenyi-7-octenoic acid.

Example 22 (a) (l-Na phthyl) methyl phenyl sulphone A solution of 1 -(chloromethyl)-naphthalene (17.6 g) in dimethyl formamide (20 mi) was added to a stirred suspension of sodium benzenesulphinate (16.4 g) in dimethyl formamide (80 mi). After 20 60 12 GB 2 101 594 A 12 hours at room temperature the mixture was diluted with water and the white precipitate filtered. Recrystallisation from ethyl acetate- petroleum ether 60-801C gave the title product, m.p. 890C.

(b) 5-Hydroxy-6-(1 -naphthyl)-6-phenyisulphonyl hexanoic acid, sodium salt A solution of ethyl magnesium bromide (1.3 M in diethyl ether) was added to a stirred solution Of (1 -naphthyi) methyl phenyl sulphone as prepared in (a) above (8,46 g) in dry, tetrahydrofuran (80 mi) at 5 -201C. After 1 hour methyl formyl butyrate (7.8 g) was added at -201C. The mixture was allowed to warm to OIC over 1 hour, poured into ice and hydrochloric acid and extracted into dichloromethane to give methyl 5-hydroxy-6-(1 naphthyl)-6-phenyisulphonyl hexanoate ad a colourless viscous oil.

The methyl ester was hydrolysed by heating in dioxan (50 ml), water (45 mi) and with 2 M aqueous hydrochloric acid (1 mi) for 8 hours to give the crude title compound. The product was purified 10 by lactonisation, hydrolysis, and preparation of the sodium salt, m.p. about 1 700C (from iso-propyl alcohol).

Example 23 (a) Cinnarnyl ethyl sulphone Hydrogen peroxide (30% w/w, 0.2 mol) was added to a stirred solution of cinnamyl ethyl sulphide 15 (16.8 9) in acetic acid (100 mi). The mixture became hot (about 800C, exothermic reaction) and was then heated to 1001 C for 2 hours. The mixture was then cooled, diluted with water, the precipitate filtered and recrystallised from carbon tetrachioride-petroleum ether 60 to 800C to give the title product, m.p. 1 001C.

(b) 6-Ethyisulphonyi-5-hydroxy-8-phenyl-7-octenoic acid, sodium salt The above compound was prepared from cinnamyl ethyl sulphone by the method described in Example 22(b) to give the product, m.p. about 1300C.

Example 24 (a) 2-(Cinnarnyl sulphonylpropyloxy)tetrahydropyran Cinnamyithlopropionic acid, m.p. 871C, was prepared from cinnamy] bromide and mercaptopropionic acid and oxidised by the method described in Example 23(a) to cinnamyisulphonylpropionic acid, m.p, 1 601C. This acid was reduced by addition to a stirred suspension of lithium aluminium hydride (2 equivalents) in tetrahydrofuran at -20 to -251C and the product formed isolated by ethyl acetate extraction to give cinnarnyl 3- hydroxypropyl sulphone, m.p.

860C. A solution of cinnamyi 3-hydroxylpropyl, sulphone, para-toluene sulphonic acid (catalytic) and 30 dihydropyran (2 equivalents) in dichloromethane was allowed to stand at room temperature for 24 hours, evaporated, and recrystallised from diethyl ether to give the title compound, m.p. about 451C.

(b) 5-Hydroxy-6-(3-hydroxypropyisulphonyi)-8-phonyi-7-octenoic aid, sodium salt 6-[1-(Hydroxypropylsulphonyi)-3-phenyi-2-propenyll-tetrahydro-2H-pyran-2one was prepared from 2-(cinnamylsulphonylpropyloxy)tetrahydropyran by the method described in Example 22(b) and 35 hydrolysed to the sodium salt of the title compound, m.p. 1 550C.

Example 25

6-(Carboxyethyisulphonyi)-5-hydroxy-8-phenyi-7-octenoic acid, disodiurn salt A mixture of 6-[1 Ahyd roxypropy Is u 1 pho nyl)-3 -ph e nyl -2-p rope nylltetra hyd ro-2 H -pyra n-2-one, (see Example 24) (1.0 g) and pyridinium dichromate (4.67 g) in dimethylformamide (10 mi) was stirred 40 at room temperature for 20 hours. The mixture was diluted with water and extracted with ethyl acetate to give 6-[1 -(carboxyethyisulphonyi-3-phenyl-2-propenylltetrahydro-2H- pyran-2-one as an oil. The lactone was hydrolysed and the disodium salt prepared, as described in Example 22(b) to give the disodium salt of the title compound, m.p. about 2031C.

Example 26 (a) 7-Methyl 5,6(E)oxido-7-(E)/(Z)nonadecenoic acid methyl ester Methyl formyibutyrate (13 g) and 1 -triphenylphosphoranylidene-2propanone (31.4 g) were refluxed together in toluene (200 mO for 30 minutes. The toluene was then evaporated off and ether (200 mi) added to the residue to give a suspenion which was stirred at room temperature for 5 minutes.

The suspended triphenylphosphine oxide was filtered off and washed with a further 100 mi of ether. 50 The combined ether solutions were evaporated to dryness to give a yellow oil which was distilled at 0.1 mm Hg using a Kugelrohr apparatus (air bath temperature 140IC) to yield 7oxo-5-octenoic acid methyl ester as a colourless oil.

Sodium bicarbonate (5 g) was dissolved in water (100 mi) and 50% aqueous hydrogen peroxide (5 mi) added. To this stirred solution at room temperature was added 7- oxo-5-octenoic acid methyl 55 ester (3.4 g) in methanol (10 mi). After 100 minutes the resultant clear solution was extracted four times with dichloromethane (4x50 mi). The combined extracts were then dried (MgSO,) and evaporated to yield 7-oxo-5,6(E)oxido-4-octenoic acid methyl ester.

13 GB 2 101 594 A 13 n-Dodecyl triphenyl-phosphonium bromide (11.02 g) was dissolved in dry tetrallydrofuran (100 mO and the stirred solution cooled to -78"C. n- Butyl lithium (13.3 m], 1.5M in hexane) was added to give an orange solution of the yield which was stirred for 10 minutes at -781C prior to the addition of 7 oxo-5,6(E)oxido-5-octenoic acid methyl ester (3.7 g) in dry tetrallydrofuran (20 mi). The reaction 5 mixture was then allowed to warm up to room temperature over a period of 1 hour. The tetrallydrofuran was evaporated off and ether (200 mi) added to the oily solid. After stirring for 1 hour, the ether was decanted off and the process repeated twice more. The combined ether extracts were evaporated to dryness to give a pale yellow oil which was chromatographed on a silica column eluted with hexane:ether (1:1) to give a mixture of E and Z isomers of 7- methyi-5,6(E)-oxido7-nonadecenoic 10 acid methyl ester.

(b) 5(R,S) Hydroxy-6MR) U2-{Wacetyla m ino 1-2-methoxycarbony]- 1 -ethy]1 -m ethylethyl) thio]7(Z)methyl nonadecenoic acid sodium salt DL N Acetyi-p-mercaptoisoleucine methyl ester (219 mg) was dissolved in dry methanol (2 mi) and triethylamine (202 mg) added. This solution was then added to 7- methyl-5,6(E)-oxido-7 nonadecenoic acid methyl ester (338 mg) to give a pale yellow solution which was allowed to stand at 501C for 5 days. The solution was then evaporated to yield a pale yellow oil which was chromatographed on a silica column eluted with ether to give 5(S)hydroxy- 6(R)[(2-IN-acetylaminol-2- methoxycarbony]-1 -ethyi-l -methylethyl)th iol 7 (Z)/(E) methyl nonadecenoic acid methyl ester and its 511,6S isomer as a colourless oil. This diester was then hydrolysed by dissolving it in methanol (8 m]) and adding aqueous (1.0 M) potassium carbonate solution (12 mi). The resultant turbid solution was 20 then stirred at room temperature until clear (16 hours). Tile pH was then adjusted to 4 with aqueous (2 M) hydrochloric acid and the solution extracted four times with dichloromethane (4x 10 mi). The combined extracts were evaporated to dryness and the resultant oil chromatographed on a silica column eluted with dichloromethane:methanol (95:5) to give the title compound as its free acid. The sodium salt was prepared by reacting the free acid with 1 equivalent of aqueous sodium bicarbonate 25 solution.

Example 27

5(R,S)Hydroxy-6(S,R)[(2-IN-acetylaminol-2-carboxy-1 -ethyi-l -methylethyi)thiol 7 (Z) methyl nonadecenoic acid disodium salt The half ester of Example 26 (100 mg) was dissolved in 2 M lithium hydroxide (3 mt) and the 30 solution allowed to stand at room temperature for 16 hours. The pH of the solution was then adjusted to 3 using 2 M hydrochloric acid and extracted 3 times with dichloromethane (3x 10 mi). The combined extracts were dried (Mg SOJ and then evaporated to yield a viscous oil which was azetroped with benzene (20 m]) for 2 hours to provide the lactone of the title compound. This lactone was then purified by chromatography on a silica column eluted with dichloromethane:methanol:acetic acid (90:9A). Finally the lactone was converted to the title compound by treatment with 2 equivalents of aqueous sodium bicarbonate solution.

Example 28 (a) rei-(6R,1'R)-6-[4-(Chlorophenyithio)undecylltetrahydro-2H-pyran-2-one This compound was prepared by the method described in Example 1 (c).

(b) rei-(5R,6R)-6-(4-Chlorophenyithio)-5-hydroxyhexadecanoic acid, potassium salt The lactone of (a) above was hydrolysed as described in Example 1 (d). The ether extract was neutralised with 1 M potassium hydroxide in ethanol and the solution was evaporated. A solution of the residue in water was freeze-dried to give the title product as a gum.

Example 29 rei-(5R,6R)-5-Hydroxy-6-(4-hydroxyphenyithio)-8-phenyl octanoic acid, sodium salt Boron tribromide (3.0 mO was added dropwise to a stirred cooled solution of rel-(6R, 1'R)-6-[1' (4-methoxyphenylthio)-3-phenyipropyll-tetrahydropyran-2-one (3.4 g), prepared by the method degeribed in Example 1 (c), in dichloromethane (100 mi). The dark solution was stirred for 7 hours at room temperature then treated with water (50 mi). The solvent layer was dried and evaporated and a 50 solution of the residue in ether was extracted with sodium carbonate solution. The aqueous extract was acidified and re-extracted with ether and the ether extract was dried, neutralised with 1 M sodium methoxide in methanol (7.0 mi) and evaporated. Treatment of the residual gum with isopropanol petroleum spirit gave the title compound as a solid.

Example 30 (a) Methyl (E)-8-phenyi-5-octenoate A solution of bromine (4.3 mi) in dichloromethane (50 mi) was added dropwise to a stirred solution of triphenylphospine (22.2 g) in dichloromethane (300 mi). The pale yellow solution was evaporated and the residual solid was suspended in dry benzene (300 mi). Methyl 5,6-oxido-8- 14 GB 2 101 594 A 14 phenyloctanoate (19.0 g) (see Example 7(b)) was added and the mixture was stirred for 4 hours and then evaporated. The residue was extracted with petroleum spirit (400 mi) and the extract was again evaporated to give methyl rei-(5R,6R)-5,6-dibromo-8-phenyloctanoate as an oil.

Zinc powder (27.4 g) was added to a stirred solution of this dibromo compound (27.4 g) in acetic acid (250 mi). The mixture was stirred for 30 minutes, diluted with water (750 mi) and extracted with 5 petroleum spirit (3 x400 mi). The extract was washed with sodium bicarbonate solution, dried and evaporated and the residue was distilled under vacuum to give the title compound, b.p. 110 to 11 31C/0.2 mm (containing about 10% (Z) isomer by HPLC analysis).

(b) Methyl (E)-8-phenyl-S-octenoate (alternative method to (a) above) Chlorine gas was passed into a stirred solution of methyl (Z)-8-phenyl-5octenoate (14.6 g) in 10 dichloromethane (250 mi) at -650C until the solution became pale yellow. The solution was allowed to warm to -200C then poured on to ice/sodium metabisulphite solution. The solvent layer was washed with water, then with sodium bicarbonate solution, dried and evaporated to give methyl rel (5R,6S)-5,6-dichloro-8-phenyloctanoate as a pale oil.

A stirred solution of this dichloro compound and sodium iodide (100 g) in dry dimethyl formamide (500 mi) was heated at 146 to 1491C for 21 hours, poured on to ice/water and extracted with ether. The extract was washed with sodium metabisulphite solution, then with sodium chloride solution, dried and evaporated. The residue was distilled under vacuum to give the title compound (containing about 10% (Z) isomer). (c) (E)-8-Phenyf-S-octenoic acid A stirred solution of methyl

(E)-8-phenyi-5-octenoate (13.6 g) in dioxan (125 mi) and 10% sodium carbonate solution (125 mi) was heated under reflux for 7 hours then evaporated. The residue in water was washed with ether, acidified and extracted with ether and the extract was dried and evaporated. The residue was distilled under vacuum to give the title compound, b.p. 150 to 1 530C/0.2 mm.

(d) W-5-Hexadecenoic acid A stirred mixture of undecyl-triphenyl-phosphonium bromide (45.7 g), methanol (300 mi) and 2 M sodium hydroxide solution (300 mi) was heated at 501C for 3 hours and then concentrated under vacuum until the oily product solidified. The solid was washed with water, dried and recrystallised from petroleum spirit to give dipheyl-undecylphosphine oxide, m.p. 691C.

1.6 M n-Butyl lithium solution in hexane (56 mi) was added to a stirred solution of the phosphine oxide (31.0 g) in dry tetrahydrofuran (400 mi) at -40 to -451C under nitrogen. The deep orange solution was stirred for 10 minutes at -40 to -501C, then a solution of valerolactone (9.0 g) in dry tetrahydrofuran was added. The pale solution was allowed to warm to room temperature, poured on to ice and extracted with ether. The extract was dried and evaporated and the residue was crystallised 35 from ether-petroleum spirit to give 1-(5-hydroxypentanoyi)undecyidiphenylphosphine oxide, m.p.

700C.

A stirred solution of the compound (19.1 g) and sodium borohydride (1.0 g) in ethanol (200 mi) was heated under reflux for 2 hours. The solution was evaporated and a solution of the residue in water was extracted with ether. The extract was dried and evaporated and the residue was crystallised from 40 ether-petroleum spirit to give erythro-1 -(1,5dihydroxypentyi)undecyidiphenylphosphine oxide, m.p.

870C.

A stirred mixture of this diol (16.2 g) and sodium hydride (1.7 g, 50% dispersion in oil) in dry dimethylformamide (200 mi) was heated at 50 to 520C for 1 -1 hours, cooled, diluted with ice/water and extracted with ether. The extract was washed with sodium chloride solution, dried and evaporated 45 to give (E-5-hexadecenol as a pale oil, solidifying to a waxy solid at OIC.

A solution of this alcohol (9.9 g) in acetone (150 mi) was oxidised with aqueous chromic acid/sulphuric acid (Jones reagent) at 20 to 220C. The mixture was poured on to ice and extracted with ether. The extract was dried and evaporated and the residue was distilled under vacuum to give the title compound, b.p. 145 to 1601C/0.2 mm.

(e) Lactones The lactones shown below were prepared by the method described in Example 1 (c) employing (E) isomers of the compounds of formula 11 (see (a), (b), (c) and (d) above) GB 2 101 594 A 15 i R2 RI/ 0 R, and enantiomer R2 Ph(CH2)2 Ph(CH2)2 n-C.1---117 Ph n-ClOH21 Examples 31 to 33 - The lactones of Example 30 were hydrolysed as described in Example 1 (d) and converted as described in Example 1 (e) to the sodium salts shown below i R2 RI m 2Na UH R, and enantiomer R2 Ph(CH2)2 Ph(CH2),, n-Cl,H21 Example 34 15 (a) W and W-6-(2-Naphthyl)-5-hexenolc acids 1 n-C.1---117 Ph A stirred suspension of sodium hydride (24.0 g, 50% dispersion in oil) in dry dimethyl sulphoxide (200 mi) was heated to 70 to 750 under nitrogen for 1 hour. The dark solution was cooled to 20,1C, a solution of 4-carboxy-butyftriphenylphosphonium bromide (106 9) in dry dimethyl sulphoxide (200 mi) was added and the mixture was stirred for a further 10 minutes. A solution of 2-naphthaldehyde (31.2 g) in dry dimethyl sulphoxide (40 mi) was added with cooling to maintain a temperature of 25 to 300C 20 and the mixture was stirred for a further 2 hours at room temperature then poured on to ice-water (1 Q and washed with chloroform. The aqueous phase was acidified and extracted with ether. The extract was dried and evaporated to give a mixture of W and (E)-6-(2-naphthyi)-5- hexenoic acids which was esterified by the method described in Example 5(a) and the mixture of two methyl esters was partially separated by fractional distillation under vacuum.

The partially separated esters were hydrolysed as described in Example 5(a) and the acids were purified by crystallisation from ether-petroleum spirit to give (Z)-6-(2-naphthyl)-5-hexenoic acid, m.p. 660C, and W-6-(2naphthyl)-5-hexenoic acid, m.p. 950C.

(b) Methyl (E)-6-(2-naphthyi)-5-hexenoate A mixture of W and (E) methyl esters prepared as described in (a) above was heated with 3mercaptopropionic acid (few drops) at 150 to 1600 C for 20 hours, to give mainly (E) isomer. The product was distilled under vacuum, b.p. 150 to 1620C/0. 1 mm. Methyl (E)- 6-(4-biphenyiyi)-5 hexenoate, m.p. 690C, was similarly prepared.

(c) Methyl (E)-6-(1-naphthyi)-5-hexenoate A mixture of W and (E)-6-(1 -naphthyi)-5-hexenoic acids was prepared and esterified by the 35 method described in Example 5(a) and isomerised by the method described in (b) above to give the title compound b.p. 160 to 1620C/0.1 mm.

Methyl (E)-6-(4-octylphenyi)-5-hexenoate, b.p. 160 to 1780C/0. 1 mm, was similarly prepared.

(d) Methyl (E)-6-(6-methy]-2-naphthyi)-5-hexenoate 40 A stirred solution of 2-bromomethyl-6-methyi-naphthalene (7.4 g) and triphenylphosphine (8.3 40 g) in toluene (200 mi) was heated under reflux for 8 hours. The solid product, (6-methyi-2-naphthyi)methyl triphenylphosphonium bromide was filtered off and washed with ether, m.p. 2700C. 1.6 M Butyl lithium solution in hexane (6.7 mi) was added to a stirred suspension of the 16 GB 2 101 594 A 16 phosphonium salt (5.0 9) in dry tetrahydrofuran (50 mi) at 50C under nitrogen. The dark solution was cooled to -501C and methyl 4formyibutyrate (1.5 g) was added dropwise. The pale solution was stirred for 30 minutes at about -601C, allowed to warm to -1 OIC, poured on to ice-sodium chloride solution and extracted with ether. The extract was washed with dilute hydrochloric acid, dried and evaporated and the residue was extracted with petroleum spirit to give a mixture of (Z) and (E) esters as an oil (2.8 g). lsomerisation by the method described in (b) above gave the title compound (2.1 g), m.p. 500C.

(e) Methyl 6-(2-naphthyi)-5,6-oxidohexanoate Solid rn-chloroperoxybenzoic acid (15.3 g, 80% purity) was added to a stirred solution of methyl (E)-6-(2-naphthyi)-5-hexenoate (18.0 g) in chloroform (150 mi). The mixture was stirred for 2 hours at 10 room temperature and filtered. The filtrate was washed with sodium bicarbonate solution, dried and evaporated and the residue was crystallised from ether.

The other epoxides shown below were prepared similarly using the (E) esters of (a) to (cl) above. The products were not crystallised in every case.

RI C02Me R 1 0 039 0 G @0000 Me c 8H17 V137 0 1 a / ioi P11 M. P. OC oil 84 oil 76 Example 35

Methyl rei-(5R,6S)-5-hydvo;,V-O-(2-naphthyl)-6-j;-ianyithiobexanoate A mixture of methyl trans-5,6-oxido-6-(2-naphthy!)hexanoate (0.27 g), thiophenol (0.2 m[) and triethylamine (0.5 mi) in methanol (4 mi) was stirred for 16 hours at room temperature under nitrogen. 25 The clear solution was evaporated and the residue was chromatographed on silica-gel using 1:1 ether:petroleum spirit as developing solvent, to give the title compound, m.p. 901C.

Examples 36 to 54 The esters shown below were prepared by the method described in Example 35.

R 1 2 RI/ \CO 2 Meand enantiomer R 1 )TO! 0 0 OH R2 /0\ / cl / io! 0 17 GB 2 101 594 A 17 Ri R2 A /-, / cl ioioi T(DT / 1-"il\cl A /:\ / Cl\ A /Cl TOT /\: /\cl A Tol /e/ CF3 A N02 ioioi IOT 5 CF3 /NHCOMe TOTOT Tol 0 T OT i Pr TOTOT CH2 NHCOCH3 1010T me C02Me A A TOTOT TOT cl loi Me 0 A cl i,o T T T Ph M C8111 7 / io:

10Toi ioi cl 001 cl 18 GB 2 101 594 A 18 R1 0 in, Ph/ 1 R, ?H COCH 0 A / 3 i0T 0 ioi CaHl 7 i0T C81117 C81117 0 /!0! 0 ?H C317\ 0 /C, ioi 'c 1 CH 3\ OT /\ / CO 2Me LGOW 3 Example 55 rei-(5R,6S)-5-Hydroxy-6-(2-naphthyi)-6-phenyithlohexanoic acid, sodium salt A stirred mixture of the methyl ester (0.30 g, prepared as described in Example 35), 10% sodium carbonate solution (10 mi) and methanol (10 mi) was heated under reflux for 11 hours. The methanol 10 was evaporated under vacuum and the residue was diluted with water, washed with ether, acidified and extracted with ether. The extract was dried and evaporated and a solution of the residual acid in ethanol was basified with M sodium methoxide in methanol (0.75 mi) and re-evaporated. The residue solidified under isopropanol-petroleum spirit to give the title compound.

Examples 56 to 72 The esters of Examples 36 to 53 were hydrolysed by the method described in Example 55 to give the sodium salts shown below RI SR2 1 0 10 RI, M 'C02Naand enantiomer bH R2 / \ / cl Go@ 1 1 /- 0 / cl \Cl cl\ /C, M \Cl CF3 19 GB 2 101 594 A 19 R, / 4 \ / a \ / C)IC)T n T 0 'VD T R2 /N02 -0 T CF3 / \tTHCOCH3 /:T i Pr A A ioiol loioi / TOTOT ioi Ph/ Toi C8H17 /0\ /0\ / io-TO! ioi pti" loi pt io! e8H17 10T CSH17 CH 0 / 2 \ /0 0-0 /-, / cl tOT /C, 101 /Cl TOT To! Cl\ ioi h cl COCH 3 T T ?H C3H7\ /'\ /COCH3 T C,\ /0\ /Cl --c l CH 3\ GB 2 101 594 A 20 Example 73 rel-0 IR,2'S)-S-51-Carboxy-21-hydroxy-1 '-(41-oetylphenyi)pentyl cysteine A mixture of the diester of Example 54 (100 mg), 10% sodium carbonate solution (3 mi) and methanol (3 mi) was stirred at room temperature for 24 hours. The mixture was diluted with water, washed with ether, acidified to pH 4.0 and extracted with ethyl acetate. The extract was dried and 5 evaporated to give the title product as a white solid.

Example 74 2(R,S)-3(R,S) rei-(1'F1,2'S)-N-Acetyl-3-[51-carbo;zy-2'hydroxy-1 1-(2naphthyl)pentylthiolisoleucine methyl ester A solution of the diester (Example 44) (73 mg) in methanol (2 mi) and 1 M potassium carbonate 10 solution (1 mi) was stirred at room temperature for 20 hours, diluted with water, washed with dichio,Omethane, acidified and extracted with dichloromethane. The extract was dried and evaporated to give the title compound as a pale solid.

Example 75 (a) WL-N-a cetyl-3 -mere@ pto isol euevi) 9 Iffi no m OthYl ester Ethvl chloroformate (0. 12 mi) was added to a stirred solution of DL-N- acetyl-3mercaptoisoleucine (0,20 9) in dichloromethane (10 mi) and triethylamine (0.28 mi) at -1 OIC. The solution was allowed to warm to room temperature, washed with dilute hydrochloric acid and then with sodium bicarbonate solution, dried and evaporated to give 3 -a ceta m ido4-ethyl -4-m ethyl -2- thietanone as a pale oil.

To a solution of this thiolactone is dichloromethane (5 ml) was added solid glycine methyl ester hydrochloride (0.15 g) and triethylamine (0.20 mi) and the mixture was stirred for 16 hours. The clear solution was washed with dilute hydrochloric acid and then with sodium bicarbonate solution, dried and evaporated and the residue was crystallised from rnethanol-water to give the title compound, m.p. 1360C.

(b) 5(S)-Hydroxy-6(R)-[(2-(N-acetYlaminc)-2- nv(a.hoxyca rbo nyl - 1 ethyl- 1 -methyl ethyOth iol - 70-nonadecenoic acid and its 5(R)-6(S)isomer Methyl 5,6(E)-oxido-7(Z)-nonadecenoate (162 mg) was reacted with a solution of DL-N-acetyl-p mercaptoisoleucine methyl ester (216 mg) and triethylamine (200 M1) in dry methanol (500,ul) at 50c1C for 3 to 4 days. After blowing off the methanol in a stream of nitrogen the residue was dissolved in a 30 mixture of diethylether/n-hexane 50/50 v/v and chromatographed on silica gel. Development with the same solvent mixture initially gave a recovery of unreacted epoxide. Further elution with a mixture of dichloromethane/methanoi 95/5 v/v gave the required dimethyl ester, contaminated with a little of the free thiol, asa pale yellow oil.

The dimethyl ester was then dissolved in methaol (3 m]) followed by the addition of 2 M sodium 35 carbonate solution (1.5 mO and a few drops of water to give a hazy solution. The hydrolysis was allowed to continue at room temperature for 3 days, after which time the nearly clear solution was carefully acidified to pH 3.5 (using dilute hydrochloric acid) and extracted with dichloromethane. The combined extracts were washed with water, dried over magnesium sulphate and evaporated in vacuo to give the title compound as a very pale yellow viscous oil.

Example 76

5-(S)-Hydroxy-6(R)-[(2-(N-acetylamino)-2-carbo;zy-'i -5.thyl-l methylethyi)- thiol-7(Z) nonadecenoic-acid and its 5(R)-6(S)isomer The monomethyl ester, from Example 75, (89 mg) was dissolved in tetrahydrofuran (4 ml) and 2 M lithium hydroxide solution (1 mO added, followed by further water (3 ml) to give a homogeneous solution which was heated at 480C for 4 days. The tetrahydrofuran was then removed by evaporation in vacuo and the residue partitioned between dichloromethane and water at pH 3 (by adjustment with dilute hydrochloric acid). The dichloromethane extract was dried over magnesium sulphate and evaporated in a stream of nitrogen to give the desired dicarboxylic acid as a colourless viscous oil.

Example 77 to 85 (a) The following thiol intermediates were prepared and converted to the end products in part (b) below by the method of Example 9(b).

(i) N-Trifluoroacetyl-L-cysteine carboxamide The acid chloride of N-trifluoroacetyl-L-cysteine (1.0 g) was treated with 0.880 ammonia solution (5 mO at OIC for 30 minutes. The excess ammonia was blown off and the clear solution diluted with a little water and shaken with diethyl ether. The resultant white solid was filtered off and dried. - This solid (0.25 g) was dissolved in dimethoxy ethane/water (5/2.5 ml), triphenylphosphine (0.25 g) added and the mixture stirred at room temperature for 16 hours. The solution was evaporated in vacuo to dryness and the residue dissolved in diethyl ether/ethyl acetate (2 m], 90/10 v/v) and purified 21 GB 2 101 594 A 21 by chromatography an silica gel using the same solvent system, to give the desired thiol as a white crystalline solid.

00 N-(Mercaptoacetyi)aianine methyl ester Dithiodiacetic acid (18.2 g) was dissolved in dry diethyl ether (150 mi), stirred and cooled to OOC.

Oxalyl chloride (18.5 mi) was added dropwise (also 2 drops of dimethylformamide added to catalyse the reaction). A steady stream of gas was produced and the mixture stirred at OOC for 1 hour, then for a further 1 hour at room temperature. The pale yellow solution was evaporated in vacuo to constant weight to give the acid chloride as a straw coloured liquid gradually darkening in colour.

A solution of the acid chloride (3.2 g) in dry tetrahydrofuran (20 mi) was added dropwise with stirring, to a solution of DL alanine methyl ester (5.3 g) in dry tetrahydrofuran (75 mi) at OIC. A precipitate gradually formed and the mixture was stirred and reacted overnight at room temperature. The white precipitate was filtered off and discarded and the filtrate evaporated in vacuo to give the desired disulphide as a straw-coloured oil.

This product was dissolved in dimethoxyethane (20 m]) and added to a stirred solution of triphenylphosphine (3.5 g) in dimethoxyethane/water (20/10 mi). Reaction was complete after 4 hours 15 at room temperature and the mixture was evaporated in vacuo to give a light straw-coloured oil. The product was dissolved in a little dichloromethane and chromatographed on silica gel using dichloromethane as solvent to remove excess triphenylphosphine. Continuing elution of the column with ethyl acetate gave the required thiol which, on evaporation of the eluants, was obtained as a pale yellow oil.

(iii) 2-(N-Methoxycarbonyi)arninoethane thiol 2-Aminoethane thiol hydrochloride (9,08 g) was stirred vigorously in ether (100 mO, cooled to 50C and 50% w/v sodium hydroxide solution added. Methyl chloroformate (6. 5 m 1) was added gradually whilst maintaining the temperature at <50C. When half the chloroformate had been added, a solution of sodium hydroxide (3.2 9/25 mi water) was added simultaneously with the remaining 25 chloroformate.

The mixture was stirred for 1 hour at 5Q then the ether phase separated. The aqueous phase was further extracted with ether and the combined ether extracts washed with water, dried (Mg S04) and evaporated in vacuo to give the title thiol as a light straw-coloured oil.

Ov) N-Carboxamido L-cysteine This thiol was prepared by the method described in German Patent 1,518, 734 (Chemical Abstracts 79:P1 37500p) Diamalt AG (Bayerlein F, et al).

(b) 5-(R.S)-Hydroxy-6-(S,R)-S-penicillaminyi-7(Z)-nonadecenoic acid (The final hydrolysis required 3 days at 40OC) 5-(R,S)-Hydroxy-6-(S,R)-1 1 -[N-(carboxymethyi)carboxamidolethyithiol- 7(Z)-nonadecenoic acid 35 5-(R,S)-Hydroxy-6-(S,R)-cyclohexyimethyithio-7(Z)-nonadecenoic acid (the final hydrolysis required 12 hours at 50OC) 5-(R,S)-Hydroxy-6-(S,R)-5-carboxypentyithio)-7(Z)-nonadecenoic acid (the initial epoxide-thiol reaction required 24 hours at 5011C as did the final hydrolysis) 5-(R,S)-Hydroxy-6-(S,R)-[(2-amino-2-carboxamido)ethyithiol-7(Z)nonadecenoic acid 5-(R,S)-Hydroxy-6-(S,R)-[12-amino-2-(N-ethylcarboxamido)lethyithiol-7(Z)non adecenoic acid 5-(R,S)-Hydroxy-6-(S,R)-S-(N-carboxamido)cysteinyi-7(Z)-nonadecenoic acid 5-(R,S)-Hydroxy-6-(S,R)-[2-(N-methoxycarbonyi)aminoethyithiol-7(Z)nonadecen oic acid 5-(R,S)-Hydroxy-6-(S,R)-[N-(1 -carboxyethyi)carboxamidomethyithiol-7(Z)- nonadecenoic acid Examples 86 and 87 Decyltri phenyl p hosphoniu m bromide (4.26 g) was dissolved in dry tetrahydrofuran (60 mi), stirred under nitrogen and cooled to -78'C. Butyl lithium (1.6 M solution in hexane, 6.2 mi) was added gradually with formation of a deep orange yellow colour. After stirring at -780C for 20 minutes, methyl 5,6(E)oxido-g-oxo-7(E)nonenoate (1.50 g) in tetrahydrofuran (8 mi) was added rapidly. The solution lightened in colour and was allowed to warm up to room temperature over 1 hour. Work up was continued as in Example 9(a) and the title compound was obtained as a colourless oil. This product became solid on storage at -200C.

Reaction of this epoxide with various thiols under the conditions of Example 9(b) gave rise to the compounds listed below 5-(R,S)-Hydroxy-6-(S,R)-ethyithio-7(E),9(Z)-nonadecadienoic acid 5-(R,S)Hydroxy-6-(S,R)-S-cysteinyi-7,9-nonadecadienoic acid Example 88 (a) Mothyi-5,6-(E)-oxido-8-phenyi-7(E,Z)-octenoate To a stirred suspension of benzyl triphenylphosphonium chloride (33.43 9) is dry tetrahydrofuran (600 mO under nitrogen at -700C (acetone/dry ice bath) was added n-butyl lithium (54 mi, 1,6 molar 60 22 GB 2 101 594 A 22 solution in hexane). A deep orange colour developed immediately. The mixture was stirred at -700C for 5 minutes. Then a solution of m ethyl- 5,6-(E)-oxido-6-fo rmyAexa noate (14.8 g) in dry tetrahydrofuran (30 mi) was added, and the reaction mixture allowed to warm gradually to room temperature (accompanied by partial discharge of ylid coloration to final straw yellow colour). Stirring at room temperature was continued for a further 1 hour when the reaction was shown to be complete 5 by tic.

The reaction mixture was evaporated in vacuo and extracted (3x) with diethyl ether. The extracts were evaporated in vacuo to yield an amber oil which was purified by column chromatography on silca (eluant hexane 50% diethyl ether 0. 1 % Et,N) to give a light-yellow oil as the title compound.

(b) 5-(S,R)-Hydroxy-6-(R,S)-(succinyithio)-8-phenyi-7-(E,Z)-octenoic acid To methyi-5,6-oxido-8-phenyi-7-(E,Z)octenoate (0.6 g), prepared as described in (a) above and a trace of hydroquinone under nitrogen, was added a mixture of triethylamine (0.54 g), d'jmethyimercaptosuccinate (0.87 g) and dry methanol, also under nitrogen.

The mixture was allowed to stand at room temperature for 2 hours and then blown down under a nitrogen stream. The residual oil was purified by column chromatography (silica; eluent dichloromethane 2% methanol 196 acetic acid) to give the tri-methyl ester of the title compound as a pale oil.

The above oil (320 mgs), was stirred in methanol 40 mi) with 0.1 molar potassium carbonate solution (136 mi) and a trace of hydroquinone for 72 hours at room temperature. The reaction mixture was acidified with glacial acetic acid and extracted with ethyl acetate to give an oil which was further 20 purified by chromatography, finally yielding the title compound as a yellow oil.

Example 89 5-(S,R)-Hydroxy-6-(R,S)-(2-furyimethanthio)-8-phenyl-7(E,Z)octenoic acid This compound was prepared by the method described in Example 88, employing furfuryl mercaptan in place of di methyl mercaptosuccinate and 2 molar sodium carbonate in place of 0.1 molar 25 potassium carbonate.

Example 90 (a) Methyl-5,6-(E)-oxido-8-(1 -naphthyi)-7-(E,Z)-octenoate To a stirred suspension of 1 -naphthyimethyl triphenyl phosphonium chloride (41.37 g) in dry 30 tetrahydrofuran (700 mi) under nitrogen at -701C was added n-butyl lithium (59 mi, 1.6 molar solution in hexane). A deep orange colour developed immediately. After stirring the mixture at -701C for 15 minutes, a solution of methyl - 5,6-(E)-oxi do-6-fo rmyA exa noate (16.23 g) in dry tetrahydrofuran (50 mi) was added, and the reaction mixture allowed to warm gradually to room temperature (accompanied by partial discharge of ylid coloration to final straw yellow colour). Stirring at room temperature was continued for a further 90 minutes, when the reaction was shown to be complete by 35 tic.

The reaction mixture was evaporated in vacuo and extracted (3 times) with diethyl ether. The extracts were evaporated to yield an amber oil which was purified by chromatography (hexane 50% diethyl ether on silica) to give the title compound as a light-yellow oil.

(b)5-(S,R)-Hydroxy-6-(R,S)-(4-chlorophenyithio)-8-(1 -naphthyl)-7-(E,Z)octenoic acid To methyl -5,6 -(E) -oxi do-8-(1 -naphthyi)-7-(E,Z)-octenoic, (100 mg) prepared as described in (a) above, and a trace of hydroquinone, under nitrogen, was added a mixture of triethylamine (103 M]), 4 chlorothiophenol (100 mg) and dry methanol (100 MO, also under nitrogen.

The reaction mixture was allowed to stand at room temperature for 48 hours and then blown down under a nitrogen stream, the residual oil being purified by chromatography (silica; eluent:dichloromethane) to give the methyl ester of the title compound as a yellow oil.

The above oil (50 mg) was stirred in methanol (1.5 mi) with 2 molar sodium carbonate solution (0.35 mi) and a trace of hydroquinone for 72 hours at room temperature and then 2 hours at 450C. The reaction mixture was acidified with 1 molar hydrochloric acid and extracted with chloroform to give an oil which was purified by chromatography (silica; eluent:chloroform 10% methanol) to give the title 50 compound as a pale yellow oil.

Example 91

5-(S,R)-Hydroxy-6-(R,S)-(2-carboxyethyithio)-8-(1 -naphthyi)-7-(E,Z)octenoic acid This compound was prepared as in Example 78(b) with the epoxide of Example 90(a) and methyl 3-mercaptopropionate.

Example 92 (a) Methyi-5,6-(E)-oxido-8-(2-naphthyi)-7-(E,Z)-octenoate This compound was prepared by the method of Example 90(a) using 2naphthyimethyitriphenyl phosphonium chloride.

23 GB 2 101 594 A 23 (b) 5-(S,R)-Hydroxy-6-(R,S)-(4-chlorophenyithio)-8-(2-naphthyl)-7-(E,Z)octenoic acid This compound was prepared according to the method of Example 90(b), but employing the epoxide of (a) above.

Example 93

5-(S,R)-Hydroxy-6-(R,S)-(methyi-N-trifluoroacetyl-cystoinyi)-8-(2naphthyl)-7 -(E,Z)-octenoic acid 5 This compound was prepared by the method of Example 88(b) with the epoxide of Example 92(a) and methyl-N-trifluoroacetyl cysteine, and omitting the hydrolysis step.

Example 94

5-(S,R)-Hydroxy-6-(R,S)-(cysteinyi)-8-(2-naphthyi)-7-(E,Z)-octonoic acid This compound was prepared by the hydrolysis of the compound of Example 93, by the method 10 described in Example 88(b).

Example 95 (a) Methyl-5,6-(E)-oxido-g-phenyi-7-(Z)-nonenoate This compound was prepared by the method described in Example 90(a) employing phenyl ethyitriphenyl phosphonium bromide.

(b) 5-(S,R)-Hydroxy-6-(R,S)-(4-chlorophenyithio)-9-phenyl-7-(Z)-nononoic acid This compound was prepared by the method of Example 90(b) with the epoxide of Example 95(a) and 4-chlorothiophenol.

95(a).

Example 96

5-(S,R)-Hydroxy-6-(R,S)-(2-furyimethanthio)-9-phenyl-7-(Z)-nonenoic acid This compound was prepared by the method of Example 88(b) with the epoxide of Example Example 97 (a) Methyl-5,6-(E)-oxido-1 3-phenyl-7-(Z)-tridecenoate This compound was prepared by the method of Example 88(a) using phenyl h exyltriphenylphosphoni u m bromide.

(b) 5-(S,R)-Hydroxy-6-(R,S)-(4-ohlorophenylthio)-13-phenyl-7-(Z)tridecenoic acid, sodium salt The corresponding acid of the title compound was prepared by the method of Example 88(b) using the compound of (a) above and 4-chlorothlophenol. The acid, however, was found to form appreciable amount of the 8-1actone and hence was converted to the sodium salt by the following 30 procedure.

5-(S,R)-Hydroxy-6-(R,S)-(4-chlorophenylthio)-1 3-phenyi-7-(Z)-tridecenoic acid (170 mg) was added to 2 M sodium bicarbonate solution (190 AI, 1 equivalent). The mixture was ultrasonicated and allowed to stand at room temperature for 24 hours, to give the title compound in aqueous solution.

Example 98

5-(S,R)-Hydroxy-6-(R,S)-(2-furyimethanthio)-13-phenyl-7'-(Z)-jtridecenoic acid, sodium salt This compound was prepared according to the method of Example 88(b) using the epoxide of Example 97(a) and conversion to the sodium salt as in Example 97(b).

Example 99

5-(S,R)-Hydroxy-6-(R,S)-cysteiny]-13-phenyi-7-(Z)-tridecenoic acid This compound was prepared by the method of Example 88(b) employing the epoxide from Example 97(a) and methyl-N-trifluoroacetyl cysteine.

Example 100 (a) 2-Hydroxy-4-mercapto-acetophenone This thiol was prepared from the corresponding dihydroxy compound by the method of Newman 45 and Karnes (J.0.C. 31 3980-4 (1966).

2,4-Dihydroxyacetophenone (68.4 g), potassium carbonate (68.31 g) and dimethyithlocarbamoyl chloride (65.63 g) in dry acetone (1200 mi) were stirred at room temperature for 2 hours and then refluxed over night. The reaction mixture was poured into water (1500 mi), stirred, filtered and dried in vacuo to give 0-(4-acetyi-3-hydroxyphe nyi)-N,N-dimethyithiocarba mate as a white solid, m.p. 150 to 50 1 520C.

The above compound was added as a powder in one portion to boiling diphenylether (1600 m]) and refluxing was continued for a further 20 minutes under nitrogen. The diphenyl ether was evaporated in vacuo and the residue boiled in carbon tetrachloride solution with decolourising charcoal for 30 minutes. Filtration and evaporation of the filtrates gave S-(4- acetyi-3-hydroxyphenyi)-N,N- 55 dimethylthiocarbamate as a light-brown crystalline solid, m.p. 124 to 1260C.

24 GB 2 101 594 A 24 The above compound was heated to boiling in 10% sodium hydroxide solution and a milky H20/Ph20 mixture distilled off until all diphenyl ether removed. The mixture was then cooled, methanol (2000 mi) added and the suspension refluxed over night. The methanol was evaporated in vacuo, the aqueous layer extracted (2 x) with diethyl ether (extracts discarded) and then acidified with 5 M HCl (340 mi). The acid aqueous layer was then extracted with diethyl ether (2 x), the combined extracts washed with water, dried over MgSO,4, filtered and evaporated. The residue was purified by column chromatography (silica; eluent 100% CHCI,) and treatment with decolourising charcoal in boiling carbon tetrachloride to give the title compound as a light-yellow crystalline solid, m.p. 70 to 720C.

(b) 2-Hydroxy-3-n-propyi-4-mercapto-acatophonone This thiol was prepared by the method of (a) above, employing 2,4- dihydroxy-3-n-propyiacetophenone.

(c) 5-(S,R)-Hydroxy-6-(R,S)-(2-n-propyi-3-hydroxy-4-acetylphenylthio)-9phonyi-7 -(Z)nonenoic acid This compound was prepared by the method of Example 78(b) employing the epoxide of Example 1595(a) and 2-hydroxy-3-n-propyi-4-mercaptoacetophenone (prepared as in (a) above).

Example 101 5-(S,R)-Hydroxy-6-(R,S)-(3-hydroxy-4-acetylphonytthio)-9phonyi-7-(Z-'-nonen oic acid This compound was prepared by the method of Example 88(b) employing the epoxide of Example 95(a) and 2-hydroxy-4-mercaptoacetophenone (prepared as in Example 1 00(a)).

Example 102 5-(S,R)-hydroxy-6-(R,S)-(3hydroxy-4-acetylphenylthio)-1 3phenyi-7-(Z)-trideconoic acid This compound was prepared by the method ofExample 88(b) employing the epoxide of Example 97(a) and 2-hydroxy-4-mercaptoacetophenone from Example 1 00(a).

Example 103 (RR,SS) 6-(1-Phonyisuiphinyf-3-phonylpropyi)-tetrahydro-2H-pyran-2-one (1 -Phenyithio-3-phenylpropyi)-tetrahydro-2H-pyran-2-one, obtained as in Example 1 (c), was oxidised using 1 equivalent of oxidising agent (m-chloroperoxybenzoic acid) as described in Example 16 to afford (R1R,SS) 6-(1 -phenyisulphinyi-3-phenylpropyi)-tetrahydro-2 H-pyran-2-one as a viscous oil (78%).

Typical formulations are prepared, employing one or more of the active compounds of the 30 inventions as follows:

Example 104

Capsules Active ingredient 5 mg Starch flowable 200 mg 35 Silicone fluid 5 mg 210 mg The active ingredient was mixed with part of the starch and combined with the remainder of the starch previously mixed with silicone fluid and filled into hard gelatin capsules.

Example 105 40 Tablets

Active ingredient 10 mg Fumed silica 50 mg Microcrystalline cellulose 200 mg Polyvinyl pyrrolidone 20 mg 45 Sodium carboxymethyl starch 20 mg Magnesium stearate 6 mg 306 mg Fumed silica and the active ingredient were mixed together and m icrocrystal line cellulose added.

The whole was massed with a solution of polyvinyl pyrrolidone in water. The mass was passed through 50 a screen, dried, sized and mixed with the sodium carboxymethyl starch and magnesium stearate prior to compression in a tablet machine to yield tablets weighing 306 mg.

GB 2 101 594 A 25 Example 106

Suspensions Active ingredient 5 mg Sodium carboxymethyl cellulose 100M9 Sucrose 1.25 g 5 p-Hydroxybenzoate 0.5 mg Flavour q.s.

Colour q.s.

Purified water to 5.0 M1 The sucrose was dissolved in part of the water and the sodium carboxymethyl cellulose added to10 form a smooth paste. The p-hydroxybenzoate and colour were dissolved in part of the water and added to the sucrose solution. The active ingredients was passed through a sieve into the aqueous solution and the flavour and sufficient water added to make up to volume.

Example 107

Aerosols 15 Active ingredient 5 mg Ethanol 30 mi Propellent 11/114 q.s.

The active ingredient was dissolved in ethanol, filled into glass bottles, sealed with valve (metered 0.01 mi) and charged with mixed propellant.

Claims

Claims in hich R is 1. A compound which, in free acid form, is of formula

1, TR.1 61 ' 4 2 R / 0 \5/ 0 \3/ a '\\ 1 1 1 L 0 COOH (i) an 1 aliphatic, saturated or unsaturated hydrocarbyl radical of up to 20 carbon atoms, unsubstituted or substituted by at least one substituent selected from halogen, hydroxy, C,-, alkoxy, C3-, cycloalkyl, aryl or heteroaryl, the cycloalkyl, aryl or heteroaryl being unsubstituted or substituted by at least one substituent selected from hydroxy, halogen and alkyl, alkenyl or alkynyl of up to 10 carbon atoms 1 (ii) cycloalkyl of 3 to 8 carbon atoms unsubstituted or substituted by alkyl, alkenyl or alkynyi of up 30 to 16 carbon atoms, or (ill) aryl or heteroaryl, unsubstituted or substituted by hydroxy], C,-4 alkoxy, halogen or alkyl, alkenyl or alkynyl of up to 16 carbon.atoms; and R2S (i) aikyi, cycloalkyl or alkenyl of up to 10 carbon atoms, unsubstituted or substituted by one or more substituents selected from aryi, cycloalkyl, halogen, hydroxy, NHR3 and COX, where R3 is H, C1-4 35 alkyi, aryl or an amino acid residue or COX, and X is OH, C1-4 alkyl, NH2 or an amino acid residue, or (5) aryl or heteroary], unsubstituted or substituted by one or more substituents selected from C1-4 alkyl, C1-4 alkoxy, C2-5 acyl, halogen, hydroxy, carboxy, nitro, trihalomethyl, phenyl, C1-4 acylamino and NHR4, where R4 is hydrogen or C1-4 alkyl; and Y is -S-, -SO- or -S02-, with the proviso that when -YR2 is glutathionyl, cysteinyl or cysteinyigiycinyi, then R, is other than an unsubstituted 40 alkatetraenyl or alkapentaenyl radical of 12 to 16 carbon atoms.

2. A compound according to claim 1 in pharmaceutically acceptable salt form.

3. A compound according to claim 1 in pharmaceutically acceptable ester form.

4. A compound according to claim 1 in lactone form.

5. A compound according to claim 1 in free acid form.

6. A compound according to claim 1 in which R, is (i) or 00 as defined in claim 1 or (ill) aryl or heteroaryl, unsubstituted or substituted by hydroxyl, halogen or alkyl, alkenyl or alkynyl of up to 16 carbon atoms; and R2 is (i) alkyl or alkenyl of up to 10 carbon atoms, unsubstituted or substituted by one or more substituents selected from ary], halogen, hydroxy, NHIR3 and COX, where R3 is H, C,-4 alkyl, aryi, an amino acid residue or COX, and X is OH or an amino acid residue or (H) aryl or heteroaryl, unsubstituted or substituted by one or more substituents selected from C1-4 alkyi, C,-4 alkoxy, halogen, hydroxy, carboxy and NHIR4 where R4's hydrogen or C1-4 alkyl.

7. A compound according to any of the preceding claims in which Y is

S or S02' so 26 GB 2 101 594 A 26 8. A compound according to claim 1 of the formula R2 R 5 -C 13- 0 \ / 0 \ / 0 \ A6 L a COOH in which R2 is alkyl, cycloalkyl or alkenyl of up to 10 carbon atoms, unsubstituted or substituted by one or more substituents selected from aryi, cycloalkyl, halogen, hydroxy, NHR, and COX, where R, is H, C1-4 alkyl, ary], an amino acid residue or COX and X is OH, C,-4 alkyl, NH 2 or an amino acid residue, R. is alkyl or alkenyl of 3 to 14 carbon atoms, the alkenyl group being of formula RCl-l=CH- where R, is Cl-U alkyl, or phenyl or naphthyl, and R. is H or C1-4 alkyl; and the lactone, salt and ester forms thereof.

9. A compound according to claim 8 in which R, is C11-,4 alkyl or RCll=CH- where RI'S Cl-12 alky].

10. A compound according to either of claims 8 and 9 in which R, is of the formula SCOX.THR3 where each R is H or C,-4 alkyl and n is 1 to 3, X is OH and R, is H or COR where R is C,-4 alkyl.

11. A compound according to claim 8 of the formula f R 2 Cl 1 H23-Cl==CH / COOH in which R, is A P COX n 'I R3 where each R is H or C1-4 alkyl and n is 1 to 3, X is OH or OR and R3 is H or COR where R'S C1-4 alkyl.

12. A compound according to claim 1 of the formula R, RI OH 0 a 0 COOH in which R, is substituted or unsubstituted phenyl or naphthyl or a group of the formula R5-CH=CH- 20 where R5'S phenyl, benzyl or naphthyl, and R, is unsubstituted or substituted phenyl; and the lactone, salt and ester forms thereof.

13. A compound according to claim 12 in which R, is naphthyl and R, is phenyl substituted with 1 to 3 halogen, nitro or trifluoromethyl groups.

14. A compound according to claim 1 of the formula f02 r2 R1 /\ /0\ /0\ H 0 COOH in which R, is a group of formula R,-CH=CH- or R,-CH,CH,- where R. is phenyl and R, is unsubstituted or substituted C1-4 alkyl or unsubstituted or substituted phenyl; and the lactone, salt and ester forms thereof.

15. A compound according to claim 1, as described in any one of the foregoing Examples 1 to 30 103.

16. A pharmaceutical composition comprising a compound of any one of the preceding claims in association with a pharmaceutically acceptable diluent or carrier.

17. A comopund of any one of claims 1 to 15, for use as a pharmaceutical.

27 GB 2 101 594 A 27

18. A compound of any one of claims 1 to 15 for use in the treatment of allergic/inflammatory disorders invoving SRS-A as causal mediator.

19. A process for the production of a compound which, in free acid form, is of formula L stated in claim 1, which comprises a) obtaining a compound which, in free acid form, is of formula 1, above, in which Y is -S-, by 5 ai) reacting a compound which in free acid form is of formula 11, 4 2. \3/. \1 R, -:-:H COOH in which R, is as defined above, with a sulphenyl chloride of formula Ill, R2SC1 ii Ill in which R2'S as defined above, in an inert solvent and either isolating the resulting lactone form of the 10 compound of formula 1 or hydrolysing the resulting lactone form to obtain a compound of formula i in free acid form; or all) reacting a compound which, in free acid form, is of formula IV, / 0 \hrl 4 2 R 1 - "-.--C ' 3 COOH in which IR, is as defined above, with a thiol of formula V, -.c R2SH IV V in which R2 is as defined above; b) obtaining a compound which in free acid form is of formula 1, above, in which Y is -SO- or -SOr- by oxidising a corresponding compound which in free acid form is of formula 1 above, but in 20 which Y is -S-; or c) obtaining a compound which in free acid form is of formula i, above, in which Y is S02-, by 20 reacting a compound of formula VI, RI-CHI---SO2R2 V1 in which R, and R2 are as defined above, with a compound which in free acid form is of formula VII; 6 1 \ / 0 \ OH COOH and, where desired, isolating the resulting compound in free acid, lactone, salt or ester form.

20. A process according to claim 19, substantially as hereinbefore described, with reference to any one of the foregoing Examples 1 to 103.

2 1. A compound which, in free acid form, is of formula IT R COOH wherein R,' has the same significances as IR,, given in claim 1, with the proviso that it is other than a C12-Cl, alkatetraenyl or alkapentaenyl radical.

22. A compound according to claim 2 1, wherein R,' is a grouping of formula R,,-CH=CH-, wherein R,, is an aliphatic saturated or unsaturated hydrocarbyl radical of up to 18 carbon atoms, unsubstituted or monosubstituted by phenyl or naphthyl, each of which is unsubstituted or monosubstituted by alkyl, alkenyl or alkynyl of up to 10 carbon atoms, with the proviso that R,, is other than an unsubstituted alkatrienyl or alkatetraenyl radical of 10 to 14 carbon atoms.

23. A compound according to claim 21 wherein R' is of the formula IRS-CH=C- 1 Re vil 25 IV1 30 28 GB 2 101 594 A 28 where R, is alkyl or alkenyl of 3 to 14 carbon atoms, the alkenyl group being of formula R7CH=CHwhere R7'S C,-,2 alkyl, or phenyl or naphthyl, and R, is H or C,-4 alkyl.

24. A compound according to claim 21 wherein R,' is substituted or unsubstituted phenyl or naphthyl.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1983. Published by the Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained