IE53523B1 - Oxiranyl butyric acid derivatives - Google Patents

Description

The invention relates to alkanoic acid derivatives The invention provides compounds of formula IV^ erf— COOH IV ,1 in which R.J is 4 (i) an 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-j_6 alkoxy, 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, (ii) 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, C1-4 alkoxy, halogen or alkyl, alkenyl or alkynyl of up to carbon atoms; with the proviso that it is other than a alkatetraenyl , alkapentaenyl or alkadiendiynyl radical; and salts and esters thereof.

These compounds are intermediates in the preparation of compounds of formula I: R. '1 OH COOH where R^ is a defined for R.J and R^ is (i) 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-j and COX, where Rj is H, alkyl, aryl, an amino acid residue or COX, and X is OH, C1_4 alkyl, NHg or an amino acid residue, or (ii) aryl or heteroaryl, unsubstituted or substituted by one or more substituents selected from C^ alkyl, C^^ alkoxy, Cg_j acyl, halogen, hydroxy, carboxy, nitro, trihalomethyl, phenyl, C^ acylamino and NHR^, where R^ is hydrogen or C1-4 alkyl; and Y is -S-, -SO- or -SOg-, with the proviso that when -YRg is glutathionyl, cysteinyl or cysteinylglycinyl, then R1 is other than an unsubstituted alkatetraenyl or alkapentaenyl radical of 12 to 16 carbon atoms.

Compounds of formula 1 are the subject of the parent Patent Specification No; Preferred compounds of formula I are those in which R^, Rg and Y have the stated values, with the proviso that R^ is other than an unsubstituted monoalkyl radical of 5 carbon atoms or an unsubstituted alkatrienyl, alkatetraenyl, alkapentaenyl or alkadiendiynyl group of 12 to 16 carbon atoms.

Of the salt forms, the pharmaceutically acceptable salt forms 53533 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 may be given the alkyl, silyl, eycloalkyl, cycloalkyl-alkyl and aralkyl ester forms, the Cj_4 alkyl ester forms being particulary preferred.

Since, the compounds of formula IVcan 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.

Where R^ is an unsubstituted aliphatic or saturated hydro15 carbyl radical, such is preferably a straight or branched chain alkyl radical of 2 to 18, preferably 5 to 16, carbon atoms, with the straight chain alkyl radicals being more preferred. Where R^ a substituted aliphatic saturated hydrocarbyl radical and the substituents are halogen, alkoxy or hydroxy, it is preferably again a straight or branched 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 eycloalkyl, aryl or heteroaryl, it is preferably a C2_g alkyl radical a„d preferably straight chain. Where the eycloalkyl, 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 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 the aryl and heteroaryl radical are alkyl and alkenyl radicals. Of the aryl and I heteroaryl radicals, the former are preferred.

Where 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 R1 is an alkyl radical. Of the unsaturated hydrocarbyl radicals as the alkenyl 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 R, R I rs-ch=cwhere Rg phenyl, benzyl, naphthyl or alkyl or monoalkenyl of 3 to 14 carbon atoms, and Rg £a hydrogen or alkyl. 53533 Where a cycloalkyl radical of 3 to 8 carbon atoms, such is preferably cyclopropyl, oyolopentyl 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, carboncar bon double or triple bonds.

As examples of aryl and heteroaryl radicals as may given phenyl, naphthyl, pyridyl and thiophene radicals. Of the aryl and heteroaryl radicals, the former are preferred. The aryl or heteroaryl group can for example be substituted by hydroxyl, halogen or alkyl, alkenyl or alkynyl of up to 16 carbon atoms. Any alkyl, 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 heteroaryl radicals as R^ tj,e preferred are those wherein the substituents are alkyl, alkenyl or alkynyl, particularly those where the substitutents are alkyl or alkenyl. Where R^ £s the most preferred values are phenyl or naphthyl and when the aryl ring is substituted it preferably bears a single C alkyl or phenyl group.

Any halogen in the compounds ol formula IV1 is preferably chlorine or bromine, particularly the former.

Particularly preferred significances of R| are as follows: a) unsubstituted C alkyl or alkenyl, the alkenyl S~*16 containing up to 5 double bonds, b) 5 alkyl monosubstituted by phenyl, c) unsubstituted phenyl or naphthyl, and Rg-CH=C- where Rg is phenyl, benzyl, naphthyl or alkyl or monoalkenyl of 3 to 14 carbon atoms, and R is hydrogen 0 or 0χ_4 alkyl.

Preferred groups of compounds of formula I are as follows: 53533 (a) Compounds of the formula ?* \ COOH in which R2 is alkyl, cycloalkyl or alkenyl of up to 10 carbon atoms, unsub- stituted or substituted by one or more substituents selected from aryl, cycloalkyl, halogen, hydroxy, NHR^ an(j cox, where Rg is nr C]_4 alkyl, aryl, an amino acid residue or COX and X is OH, C^_4 aikyl, hh2 ot an amino acid residue, R5 is alkyl or alkenyl of 3 to 14 carbon atoms, the alkenyl group being of formula R7ch=CH- where R7 is C^^ alkyl, or phenyl or naphthyl, and Rg jS h or Cj_4 alkyl; and the lactone, salt and ester forms thereof.

It is preferred that Rg £s C]_q_]_4 alkyl, especially Cjj alkyl, or RyCH=CH- where Ry is C8_]_2 alkyl, and the configuration of the Rg groUp at the position 8 carbon atom can be Z or E configurations and is preferably Z. 'ihe Rz group can be a wide variety of radicals and is preferably Cg_5 aifcyi substituted by one or more substituents selected from HHR^ an Thus an especially preferred sub-generic group is of the formula C,,h23-ch=c: JR2 ZYV’YoOH OH in which Rg j,s •CHCOX SHR3 where each R is H or aikyl and n is 1 to 3, X is OH or OR and r3 is H or COR where R is Cj_4 alkyl, preferably methyl.

Examples of Rg gEOUps include -CH2CH2COOH, (CH2)SCOOH, -CH2CH(NH2)COOH, -CH2CH(NH)COOH, -CHCONHCH2COOH, CH2CH2NHCO2CH3 and COCHg 1h3 H, NHCOCH, 2H5 CO2Me (b) Compounds of the formula J»s ./Y'V'Yo» OH in which R^ |s substituted or unsubstituted phenyl or naphthyl or a group of the formula Rg-CH»CH where Rg is phenyl, benzyl or naphthyl, and R2 _is unsubstituted or substituted phenyl; and the lactone, salt and ester forms thereof. When the &2 substituent is substituted, the substituents may number up to 3 and are preferably chosen from alkyl, C1-4 alkoxy, C2_5 acyl, (C^ alkyl CO) halogen, hydroxy, carboxy, nitro, trihalomethyl and C^_4 acylamino, being most preferably halogen, trifluoromethyl or nitro.

An especially preferred sub-generic group has the formula /\/\/\ I» COOH in which R^ is naphthyl and R2 is substituted phenyl preferably substituted with 1 to 3 halogen, nitro or trifluoromethyl groups. (c) Compounds of the formula |02H2 \/\ COOH in which R^ js a groUp of formula RjCH=CH- or RjCHjCHjwhere R5 is phenyl and R2 is unsubstituted or substituted C1-4 alkyl or unsubstituted or substituted phenyl; and the lactone, salt and ester forms thereof. Substituents on the phenyl nucleus can be any of those listed in (b) above 3 5 2 3 Compounds of formula I'Ohs' be prepared by a process which comprises a, obtaining a compound which, in free acid form, is of formula I, in which Y is -S-, by ai) reacting a compound which in free acid form is of formula II, R £h=&h / X/' R1CB=CH COOH II in which R^ is as defined above, with a sulphenyl chloride of formula III, R2SC1 HI in which Rj is as defined above, in an inert solvent and either isolating the resulting lactone form of the compound of formula I or hydrolysing the resulting lactone form to obtain a compound of formula I in free acid form; or aii) reacting a compound which, in free acid form, is of formula IV, \/\, COOH in which R^ j,s as defined above, with a thiol of formula V, RjSH IV in which Rg y3 as defined above; b) obtaining a compound which in free acid form is of formula I, above, in which Y is -SOor -SOg- by oxidising a corresponding compound which in free acid form is of formula I above, but in which Y is -S-; or c) obtaining a compound which in free acid form is of formula I, above, in which Y is -SOg_( by reacting a compound of formula VI, ri-ch2-so2R2 VI in which ang Rg are ag defined above, with a compound which in free acid form is of formula VII; OHi w · /\/\ C · I COOH VII and, where desired, isolating the resulting compound in free acid, lactone, salt or ester form.

In the process aii>, it is preferred to employ compound IV in ester form, particularly in alkyl ester form and especially in the methyl ester form. The resulting compound of the invention will .then 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 I. 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.

Interconversion as between the various forms of the compounds of the invention, e.g. salt, free acid 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 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.

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 iZ ✓θ'. s* * /\/\/\ CH-CH . I COOH IV wherein has the same significance as the values above, with the proviso that it is other than a C, -C,_ alkatetraenyl Λ.Λ 10 or alkapentaenyl radical.

A preferred significance of R| is a grouping of formula wherein R* is an Rx-CH=CHaliphatic 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. A further preferred group of intermediates is one in which R.J is of the formula R,- CH=C— I «6 where is alkyl or alkenyl of 3 to 14 carbon etoms, the alkenyl group being of formula R7CH=CH- where R? is alkyl, or phenyl or naphthyl, and Rg is H or alkyl.

A further preferred group of intermediates is one in which Rj is substituted or unsubstituted phenyl or naphthyl.

The compounds of formula I, above, are pharmacologically active, and their activity and uses are more fully described in the parent Patent Specification.

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 are effective 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 100 mg/Kg. However, it jwill be understood that the amount administered will be determined ty 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 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~Phenyl-5-octenoic acid A stirred suspension of sodium hydride (12.0 g, 50% dispersion in oil) in dry dimethyl sulphoxide (100 ml) was heated to 70 to 75°c under nitrogen for 40 minutes. The dark solution was cooled, a solution of 4-carboxybutyltriphenylphosphonium bromide (53 g) in dry dimethyl sulphoxide (100 ml) was added over 20 minutes at 20 to 25°C, and the solution was stirred for a further 10 minutes. 3-Phenyl-propionaldehyde (12.5 ml) was added with cooling to maintain a temperature of 30 to 35°C and the mixture was stirred for a further 4 hours at room temperature, then poured on to ice-water (600 ml) 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 under vacuum to give the above product, b.p. 134 to 139°c/0.07 mm. nmr spectroscopy showed the presence of about 5% (E)-isomer.

Following the procedure above and employing appropriate starting materials, 5-heptenoic acid1, 65 to 71°C/0.3 nun (85% (2), 15% (E) isomer by 12C NMR) and 5-undecenoie acid2, b.p. 105 to 106°C/0.1 nun (90% (Z), 10% (E)) were similarly prepared 1. J.C.S. (C) 217 (1968) 2. J.O.C. 43, 4387 (1978) (b) (Z)-5-Hexadecenoic acid A stirred suspension of 4-carboxybutyl-triphenylphosphonium 20 bromide (44.8 g) in benzene (200 ml) was dried by heating under a water trap for 20 minutes. The mixture was cooled, solid potassium tert-butoxide (34.0 g) was added under nitrogen, and the stirred suspension was heated under reflux for 15 minutes. A solution of undecylic aldehyde (20.8 ml) in dry benzene (20 ml) was added to the cooled mixture at 20 to 25°C, 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 re53523 extracted with ether and the ether extract was dried and evaporated. Distillation of the residue gave the product b.p. 150 to 151°C/0.1 mm (90% (Ζ), 10% (E) by 13C NMR). (Chemical Abstracts 85s 159341 and Chem. Phys. Lipids 16, 215 (1976)). (c) rel-(6R, 1'R)-6-(3'-Pheny1-1'-phenylthlopropyl)-tetrahydro2H-pyran-2-one A solution of chlorine (0.9 g) in carbon tetrachloride (10 ml) was added dropwise to a stirred solution of diphenyl disulphide (2.2 g) in carbon tetrachloride (20 ml) at 0 to -5°C. The yellow solution was stirred for 10 minutes at 0°C then a solution of (Z)-8-phenyl-5-octenoic acid (1.45 g), prepared as in (a) above, and triethylamine (0.93 ml) in carbon tetrachloride (20 ml) was added at to -5°c. 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) rel-(5R,6R)-5-Hydroxy-8-phenyl-6-phenylthiooctanoic acid A stirred mixture of 6-(3-phenyl-l-phenylthio-propyl)18 tetrahydro-2H-pyran-2-one (2.1 g), prepared as in (c) above, and 10% sodium carbonate solution (50 ml) 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) rel-(5R,6R)-5-Hvdroxv-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 ml) was made basic with molar sodium methoxide in methanol (4.1 ml) and the solution was evaporated to dryness under vacuum. The residue crystallised from isopropanol-petroleum spirit to give the title product m.p. about 15Q°C.

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 sr220R/\/\/° Ri A T ξ I and enantiomer \/ 22n-C10H21 Ph Ph(CH2)2 Ph(ca2)4 Ph These lactones were hydrolysed as described in Example 1(d) and converted as described in Example 1(e) to the sodium salts shown below sr2 • · · R,/ χ · C0,Na and enantiomer OH Si S2 Solvent of crystallisation m.p. °C-C10H21 Ph freeze dried - PhiGHgJg iPrOH/petrol ca 200 Ph(CH2)4 Ph MeOH/iPrOH - EXAMPLE 5 (a) (Z) And (E)-6-phenyl-5-hexenolc acids A stirred suspension of 4-carboxybutyl-triphenylphosphoniura bromide (38.2 g) in benzene (400 ml) was dried by heating under a water trap for 20 minutes. The mixture was cooled, solid potassium tert-butoxide (29,0 g) was added under nitrogen, and the stirred suspension was heated under reflux for 15 minutes. A solution of benzaldehyde (8.73 ml) in dry benzene (20 ml) was added to the cooled mixture at 20 to 25°C, 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 (E)-6-phenyl-5-hexenoic acids, b.p. 134 to 142°C/0.1 mm. This mixture was heated under reflux for 2 hours in methanol (250 ml) containing concentrated sulphuric acid (0.4 ml). The solution was evaporated and the residue was dissolved in ether, washed with 53323 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 123°C/0.3 mm, and the (E) isomer b.p. 133°C/0.3 mm. i, A solution of methyl (Z)-6-phenyl-5-hexenoate (2.0 g) in dioxan (20 ml) and 10% sodium carbonate solution (20 ml) 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-phenyl-5-hexenoic acid.

The (E)-isomer was similarly hydrolysed. (J.O.C. 31 1390 (1966)). (b) rel-(5R,6R)-5-Hydroxy-6-phenyl-6-phenylthiohexanoic acid, sodium salt A solution of chlorine (1.56 g) in carbon tetrachloride (23 ml) was added dropwise to a stirred solution of diphenyl disulphide (4.0 g) in carbon tetrachloride (50 ml) at 5 to 10°C. The yellow solution was stirred for 10 minutes at 5 to 10°C then a solution of (Z)-6-phenyl-5-hexenoic acid (5.2 g) and triethylamine (3.8 ml) in carbon tetrachloride (50 ml) was added at 5 to 10°C. 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-phenyl-625 phenylthio-2-oxepanone, m.p. 166°C. The mother liquor was evaporated and the residue was' chromatographed on silica gel in ethyl acetate:petroleum spirit (1:3) to give an oil which crystallised from ether to give rel-(6R/tR)-6-fci-phenyl thiobenzyl) tetrahydro-2H-pyran-2-one, m.p. 82 to 84°C.

A stirred mixture of this 6-fa-phenylthiobenzyl)tetrahydro- 2H-pyran-2-one (1.2 g), dioxan (10 ml) and 10% sodium carbonate solution (20 ml) 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 ml) was made basic with molar sodium methoxide in methanol (3.8 ml) 1D and evaporated to dryness under vacuum to give the title product, m.p. 210°C.

EXAMPLE 6 rel-(5R,6S)-5-Hydroxy-6-phenyl-6-phenylthiohexanoic acid, sodium salt This compound, m.p. about 190°C, was prepared as described in Example 5, starting from the 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 rel-(6R EXAMPLE 7 (a) Methyl (Z)-8-phenyl-5-octenoate A solution of (Z)-8-phenyl-5-octenoic acid (12.6 g), see Example 1(a), and concentrated sulphuric acid (0.1 ml) in methanol (300 nl) was heated under reflux for 2 hours. The solution was evaporated and the residue distilled under vacuum to give the ester b.p. 110 to 113°c/0.1 mm. (b) Methyl 5,6-oxido-8-phenvloctanoate Solid m-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 ml) at 15 to 20°C. 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 125°C/0.05 mm. (o) 6-(R,S)-Ethvlthio-5-(R,S)-hvdroxy-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 ml). 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 ml) was added. The mixture was stirred for a further 1 hour, poured on to methanol (1 litre) and stirred for 2¾ 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-ethylthio6-hydroxy-8-phenyloctanoate as a pale oil.

A stirred mixture of this oil and 10% sodium carbonate solution (45 ml) was heated under reflux 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 ml) 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 ml) 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 -Hydroxy-8-phenyl-6-phenylthiooctanoic acid This compound was prepared by the method described in Example 7(c) employing thiophenol in place of ethanethiol.

EXAMPLE 9 (a) Methyl 5,6 (E) oxido-7 (Z) nonadecenoate Dodecyltriphenylphosphonium bromide (17.9 g) was dissolved in dry tetrahydrofuran (200 ml), stirred under nitrogen and cooled to -78°c. Butyl lithium (1.6 molar solution in hexane, 23 ml) was added gradually with formation of a deep orange colour. After stirring at -78°c for 20 minutes, methyl 5,6 (E, oxido-7oxoheptanoate (5.6 g) in tetrahydrofuran (20 ml, 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 (3 x 30 ml). 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 -20°c the product solidified. (b) 5-(R,S) Hydroxy-6-(S,R)-S-cysteinyl-7(Z)-nonadecenoic acid Methyl 5,6 (E) oxido-7(Z)nonadecenoate (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 ml) in dry methanol (5.0 ml) 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 cysteinyl derivative of the methyl ester of the title compound as a pale yellow oil.

This product (1.50 g) was dissolved in methanol (10 ml) and Ιθ a solution of anhydrous sodium carbonate (0.8 g) in water (5 ml) 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 extract evaporated in vacuo to give the title compound as a 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-carboxyethylthio)-7(Z)-nonadecenoic acid -(R,S)-Hydroxy-6-(S,R)S-(N-aoetylcysteinyl)-7(Z)-nonadecenoic acid -(R,S) -Hydroxy-6-(S,R) -benzylthio 7 (E) -9 (Ε) /(Z) -11(E) /(Z) -14 (Z)eicosatetraenoic acid -(R,S)-Hydroxy-6-(S ,R) -(2-aminoethylthio)-7(E)-9 (E) /(Z) -11(E)/(Z) - 14(Z)-eicosatetraenoic acid 5-(R,S)-Hydroxy-6-(S,R) -ethylthio 7 (E)-9 (E)/(Z) -11 (E)/(Z)-14 (Z) - eicosatetraenoic acid 5 EXAMPLE 16 (a) (Z)-8-Phenyl-5-octenoic acid A stirred suspension of sodium hydride (12.0 g, 50% dispersion in oil) in dry dimethyl sulphoxide (100 ml) was heated to 70 to 75°c under nitrogen for 40 minutes. The dark solution was 10 cooled, a solution of 4-carboxybutyltriphenylphosphonium bromide (53 g) in dry dimethyl sulphoxide (100 ml) was added over 20 minutes at 20 to 25°c, and the solution was stirred for a further 10 minutes. 3-Phenyl-propionaldehyde (12.5 ml) was added with cooling to maintain a temperature of 30 to 35°C and the mixture was 15 stirred for a further 4 hours at room temperature, then poured on to ice-water (600 ml) 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 under vacuum to give the above product, b.p. 134 to 20 139°c/0.07 mm. 13C NMR spectroscopy showed the presence of about 5% (E)-isomer. (b) rel-(6R, l'R)-6-(3'-Phenyl-l'-phenylthiopropvl)- tetrahydro-2H- pyran-2-one A solution of chlorine (0.9 g) in carbon tetrachloride (10 25 5 ml) was added dropwise to a stirred solution of diphenyl disulphide (2.2 g) in carbon tetrachloride (20 ml) at 0 to -5°C. The yellow solution was stirred for 10 minutes at 0°C then a solution of (Z)-8-phenyl-5-octenoic acid (1.45 g), prepared as in (a) above, and triethylamine (0.93 ml) in carbon tetrachloride (20 ml) was added at 0 to -5°c, The mixture was stirred for 2 hours at room tenperature then evaporated under vacuum. A solution of the 5 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. (c) rel-(5R,6R) 5-Hydroxv-8-phenyl-6-phenylsulphonvl-octanoic acid A solution of m-chloroperoxyben2oic acid (6.0 g, 85%) in dichloromethane (100 ml) was added dropwise to a stirred solution of tel -(6R,1'R) 6-(31phenyl-1'-phenylthiopropyl)-tetrahydro-2Hpyran-2-one (4.2 g), in dichloromethane (200 ml) at 5 to 10°C.

After 24 hours at room temperature the white solid which had precipitated (m-chlorobenzoic acid) was filtered. The filtrate was washed with 1% aqueous sodium sulphite, 5% aqueous sodium carbonate, and saturated sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to afford rel (6R,l'R) 6—(l' — phenylsulphony1-3'-phenylpropyl)-tetrahydro- 2H-pyran-2-one as a colourless viscous oil which crystallised after chromatography (silica Sorbsil U 30) and trituration with diethyl ether m.p. 83°C.

The tetrahydropyran-2-one derivative (1.63 g) in 10% aqueous sodium carbonate (40 ml) was heated under reflux for 1 hour. The solution was cooled, washed with diethyl ether, acidified (to about pH2) and extracted with diethyl ether (50 ml). 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 102°C.

EXAMPLE 17 Methyl 5-hydroxy-6-phenylsulphonyl-8-phenyl-octanoate A solution of ethyl magnesium bromide (7.7 ml, 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 ml). The mixture was heated under reflux for % 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 ml) and 2 molar hydrochloric acid (20 ml) were added. The product was extracted into diethyl ether and then chromatographed (Sorbsil U'30 silica) (Sorbsil is a Trade Mark) to afford the title compound as a colourless viscous oil.

EXAMPLE 18 S-Hydroxv-S-phenvl-e-phenylsulphonyloctanoic acid Methyl 5-hydroxy-8-phenyl-6-phenylsulphonyl-octanoate was hydrolysed with aqueous sodium 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.

-Hydroxy-6-(4-chlorophenyl)sulphonyl-8-phenyl-octanoic acid 5 5-Hydroxy-6-(4-methylphenyl)sulphonyl-8-phenyl-octanoic acid -Hydroxy-6-phenylsulphonyl-8-phenyl-7-octenoic acid.

EXAMPLE 22 (a) (1-Naphthyl)methyl phenyl sulphone A solution of l-(chlocomethyl)-naphthalene (17.6 g) in dimethyl formamide (20 ml) was added to a stirred suspension of sodium benzenesulphinate (16.4 g) in dimethyl formamide (80 ml).

After 20 hours at room temperature the mixture was diluted with water and the white precipitate filtered. Recrystallisation from ethyl acetate-petroleum ether 60-80°c gave the title product, m.p. 89°C. (b) 5-Hydroxy-6-(l-naphthyl)-6-phenylsulphonyl· hexanoic acid, sodium salt A solution of ethyl magnesium bromide (1.3 M in diethyl ether) was added to a stirred solution of (1-naphthyl)methyl phenyl sulphone as prepared in (a) above (8.46 g) in dry tetrahydrofuran (80 ml) at -20°C. After 1 hour methyl formyl butyrate (7.8 g) was added at -20°C. The mixture was allowed to warm to 0°C over 1 hour, poured into ice and hydrochloric acid and extracted into dichloromethane to give methyl 5-hydroxy-6-(1-naphthyl)-625 phenylsulphonyl hexanoate as a colourless viscous oil.

The methyl ester was hydrolysed by heating in dioxan (50 ml), water (45 ml) and with 2 M aqueous hydrochloric acid (1 ml) for EXAMPLES 19 to 21 The following compounds were prepared as described in Examples 17 and 18.

-Hydroxy-6-(4-chlorophenyl)sulphonyl-8-phenyl-octanoic acid -Hydroxy-6-(4-methylphenyl)sulphonyl-8-phenyl-octanoic acid S-Hydroxy-6-phenylsulphonyl-8-phenyl-7-octenoic acid.

EXAMPLE 22 (a) (1-Maphthyl)methyl phenyl sulphone A solution of 1-(chloromethyl)-naphthalene (17.6 g) in dimethyl formamide (20 ml) was added to a stirred suspension of sodium benzenesulphinate (16.4 g) in dimethyl formamide (80 ml). After 20 hours at room temperature the mixture was diluted with water and the white precipitate filtered. Recrystallisation from ethyl acetate-petroleum ether 60-80°C gave the title product, m.p. 89°C. (b) 5-Hydroxy-6-(1-naphthyl)-6-phenylsulphonyl hexanoio acid, sodium salt A solution of ethyl magnesium bromide (1.3 M in diethyl ether) was added to a stirred solution of (l-naphthyl)methyl phenyl sulphone as prepared in (a) above (8.46 g) in dry tetrahydrofuran (80 ml) at -20°C. After 1 hour methyl formyl butyrate (7.8 g) was added at -20°C, The mixture was allowed to warm to 0°C over 1 hour, poured into ice and hydrochloric acid and extracted into dichloromethane to give methyl 5-hydroxy-6-(1-naphthyl)-625 phenylsulphonyl hexanoate as a colourless viscous oil.

The methyl ester was hydrolysed by heating in dioxan (SO ml), water (45 ml) and with 2 M aqueous hydrochloric acid (1 ml) for hours to give the crude title compound. The product was purified by laotonisation, hydrolysis, and preparation of the sodium salt, m.p. about 170°C (from iso-propyl alcohol).

EXAMPLE 23 (a) Cinnamyl ethyl sulphone Hydrogen peroxide (30% w/w, 0.2 mol) was added to a stirred solution of cinnamyl ethyl sulphide (16.8 g) in acetic acid (100 ml). The mixture became hot (about 80°c, exothermic reaction) and was then heated to 100°C for 2 hours. The mixture was then cooled, diluted with water, the precipitate filtered and recrystallised from carbon tetrachloride-petroleum ether 60 to 80°c to give the title product, m.p. 100°C. (b) 6-Ethylsulphonyl-5-hydroxy-8-pheny1-7-octenoic aoid, 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 130°C.

EXAMPLE 24 (a) 2-(Cinnamyl sulphonylpropyloxy)tetrahydropyran Cinnamylthiopropionic acid, m.p. 87°C, was prepared from cinnamyl bromide and mercaptopropionic acid and oxidised by the method described in Example’23(a) to cinnamylsulphonylpropionio acid, m.p. 160°c. This acid was reduced by addition to a stirred suspension of lithium aluminium hydride (2 equivalents) in tetrahydrofuran at -20 to -25°C and the product formed isolated by ethyl acetate extraction to give cinnamyl 3-hydtoxypropyl sulphone, m.p. 86°c. A solution of cinnamyl 3-hydroxylpropyl sulphone, para-toluene sulphonic acid (catalytic) and 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 45°c. 5 (b) 5-Hydroxy-6-(3-hydroxvpropylsulphonyl)-8-phenvl-7-octenoic acid, sodium salt 6-[1-(Hydroxypropylsulphonyl)-3-phenyl-2-propenyl] -tetrahydro-2H-pyran-2-one was prepared from 2-(cinnamyl sulphonylpropyloxy)tetrahydropyran by the method described in 10 Example 22(b) and hydrolysed to the sodium salt of the title compound, m.p. 155°C. EXAMPLE 25 6-(Carboxvethvlsulphonvl)-5-hydroxy-8-pheny1-7-octenoic acid, disodium salt. 15 A mixture of 6-[l-(hydroxypropylsulphonyl)-3-pheny1-2- propenyl] tetrahydro-2H-pyran-2-one, (see Example 24) (1.0 g) and pyridinium dichromate (4.67 g) in dimethyl formamide (10 ml) was stirred at room temperature for 20 hours. The mixture was diluted with water and extracted with ethyl acetate to give 6-[l-(carboxy- 20 ethylsulphonyl)-3- phenyl-2-propenyl]tetrahydro-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 203°C. EXAMPLE 26 25 S' (a) 7-Methyl 5,6 (E) oxido-7-(E)/(Z) nonadecenoic acid methyl ester Methyl formylbutyrate (13 g) and 1-triphenylphosphoran•gS§S3 I) 8151 IlSSgg £§?$?' O SB i" !§ SiS^ll: Si! «SS l?gg??ate« 8ff IRS i?te? $188 S! Illg IB §S 511HS1 te i ^issisa M *®§ M il fS5!«??.: B? !W« & S^Bl 5HII5S3 855 ® 5 Ml? m si sf iifeg·. W Mi§H β «i§?5 ^-s to dtynegg tg. i Bii » VSa «Μ & M 3 a, Kagqitoht. life && wa % ?i§w ’*«?*?μ acid methyl ester as a colourless oil* acici metfiVt ee^ec as a colo,u*i«*i; o^;_. 1¾¾ feisKfete 11 iiwas %?g>w in. aS tioo ni), 1¾¾ W 1¾ Taa& W„ « a«d liiejyjjrl minutes the resultant %ieArr ISAMti.™ «as extraptei four times with diphloromethane (4: 55. 5sl ^/. fcM W aM 2^%¾¾¾

Claims (7)

1. λ compound of formula IV* ^COOB IV’ wherein Rj is ,i) an aliphatic, saturated or unsaturated hydrocarbyl radical of UP to 20 carbon atons, unsubstituted or substituted by at least one substituent selected free halogen, hydroxy, C 3-6 alkoxy, Cj_g cycloalkyl, asyl or heteroaryl, the cycloalkyl, aryl or heteroaryl being unsubstituted or substituted ty at least one substituent selected free hydroxy, halogen and alkyl, alkenyl or alkynyl of up to 10 carbon atoas, (ii) eycloalkyl of 3 to 8 carbon atoas unsubstituted or substituted by alkyl, alkenyl or alkynyl of up to 16 carbon atoms, or (iii) aryl or heteroaryl, unsubstituted or substituted by hydroxyl, alkoxy, halogen or alkyl, alkenyl or alkynyl of up to 16 carbon atoms; with the proviso that it it other than a Cjj-Cgg alkatetraenyl , alkapentaenyl or alkadiendiynyl radical; and salts and esters thereof.

2. A compound according to claim 1, wherein Rj ig a grouping of formula R x -ch«CB-, wherein X* is an aliphatic saturated or unsaturated hydrocarbyl radical of up to 18 carbon atoms, unsubstituted or monosubstituted ty phenyl or naphthyl, each of which is unsubstituted or monosubstltuted 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.

3. λ compound according to claim 1 wherein £ e 0 £ the formula where Rg i s alkyl or alkenyl of 3 to 14 carbon atoms, the alkenyl group being of formula R?cB»Ca- where Rj is Cj_jj alkyl, or phenyl or naphthyl, and Rg is B or Cj_4 alkyl.

4. λ compound according to claim 1 wherein R^ substituted or unsubstituted phenyl cc naphthyl.

5. A oatpound of ths formula IV 1 , given and defined in claim 1, or a salt or ester thereof, substantially as hereinbefore described and exsiplified.

6. A process for the production of a caipound of the formula IV 1 given and defined in claim 1, or a salt or ester thereof, substantially as hereinbefore described and exemplified.

7. A compound of the formula IV 1 , given and defined in claim l, or a salt or ester thereof, whenever prepared by a process claimed in claim 6.