GB2167403A - Prostanoid aminocyclopentane derivatives, their preparation and pharmaceutical formulation - Google Patents

Abstract

Compounds of the formula <IMAGE> (in which: R<1> is -H or various organic radicals; W is C1-7 alkylene; X is cis or trans -CH=CH- or -CH2CH2-; n is 1 or 2; Y is a saturated heterocyclic amino group, attached to the cyclopentane ring via N; R<2> is cinnamyl, or is substituted or unsubstituted phenylalkyl, thienylalkyl or naphthylalkyl; and R<3> is alkyl (optionally interrupted by O and S), alkanoyl, benzoyl, alkyl- or benzyl-oxycarbonyl, carbamyl or N-mono- substituted carbamyl) and their salts and solvates inhibit blood platelet aggregation and bronchoconstriction and may be formulated for use as antithrombotic and antiasthmatic agents.

Description

SPECIFICATION Carbocyclic compounds The endoperoxides prostaglandins G2 and H2 and thromboxane A2 are naturally occurring reactive metabolites of arachidonic acid in human platelets. They are not only potent aggregatory agents but are also constrictors of vascular and bronchial smooth muscle, and therefore substances which antagonise their effects are of considerable interest in human medicine.

We have now found a new group of compounds which have shown endoperoxide and thromboxane antagonist activity, and are therefore of interest in the treatment of asthma and cardiovascular diseases and in other respects. The invention thus provides compounds of the general formula (1)

wherein R' is a (a) a hydrogen atom; (b) C16 alkyl (c) C36 alkenyl; (d) C7 10 aralkyl (e) -CH2AR4, where A is -O- or -S- and R4 is C1-4 4 alkyl; (f) -CHR5CO2R4, where R5 is a hydrogen atom, methyl or phenyl; (g) -CH2OCOR6 where R6 is C14 alkyl, methoxy or phenyl; (h) pyridinyl; (i) 1 (acetyloxy)ethyl, (acetyloxy)phenylmethyl, tetrahydro-5-oxo-2-furanyl or tetrahydro-2-oxo-3-furanyl; 0) 4-(acetylamino) phenyl; (k) 2,2,2-trichloroethyl; (I) furanylmethyl or (m) -(CH2)p-N(R4)2 where p is 2 or 3; W is straight or branched C1 7 alkylene; X is cis or trans -CH=CH- or -CH2CH2-; n is 1 or 2; Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which has 5-8 ring members and (a) optionally contains in the ring -0-, -S-, -SO2-, or -NR7 (where R7 is a hydrogen atom, C 7 alkyl or aralkyl having a C14 alkyl portion); and/or (b) is optionally substituted by one or more C 4 alkyl groups; R2 is (i) straight or branched C, 5 alkyl substituted by (a) phenyl [optionally substituted by C16 alkyl, C 7 cycloalkyl, phenylalkyl having a C1 3 alkyl portion, thienyl, phenyl (optionally substituted by C1 4 alkyl, C1 4 alkoxy or phenyl)], (b) thienyl [optionally substituted by C1 6 alkyl, C16 alkoxy,, C5 7 cycloalkyl or phenyl (optionally substituted by C13 alkyl, C1 3 alkoxy or halogen)], or (c) napthyl (optionally substituted by C14 alkyl or C1 4 alkoxy), or (ii) cinnamyl; and R3 is (i) C1 4 alkyl; (ii) -CH2AR4 where A is -O- or -S-; (iii) C14 alkanoyl or benzoyl; (iv) -COOR4 or benzyloxycarbonyl; or (v) -CONHR5; including the physiologically acceptable salts and solvates (e.g. hydrates) thereof.

The structural formulae herein are to be understood to include the enantiomers of each of the compounds concerned as well as mixtures of the enantiomers including racemates, even though the precise structure as set out only relates to one enantiomer.

The alkyl groups referred to above in the definition of the compounds of formula (1) may be straight or branched.

The amino group Y enables the compounds to form salts with inorganic or organic acids, e.g.

hydrochlorides or maleates. Also, when R1 represents a hydrogen atom salts may be formed with bases. Examples of such salts are alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium, substituted ammonium (e.g. tromethamine or dimethylaminoethanol), piperazine, N,N-dimethylpiperazine, morpholine, piperidine and tertiary amino (e.g. trimethylamine) salts.

The heterocyclic amino group Y may for example have a 5,6 or 7-membered ring, e.g.

pyrrolidino, piperidino, morpholino, piperazino, thiomorpholino, i,1-dioxothiomorpholino, homomorpholino and hexamethyleneimino. Examples of the optional substituents (R7) which may be present on a second nitrogen atom in the ring are methyl, ethyl, butyl, hexyl, benzyl, and phenethyl. The carbon atoms of the heterocyclic rings may for example be substituted by methyl, ethyl or butyl. In general, Y is preferably a saturated heterocyclic amino group having 5-8 ring members and (a) optionally contains -0- in the ring and/or (b) is optionally substituted by one or more C14 alkyl groups, and more specifically Y is preferably a morpholino or piperidino group.

When R2 is substituted alkyl group, the alkylene portion may for example contain 1-3 carbon atoms (e.g. methylene, ethylene or propylene) and is preferably a methylene group.

In R2 groups of the type (i) (a), the phenyl group may be substituted by, for example, methyl, ethyl, t-butyl, cyclohexyl, benzyl, phenethyl, or phenyl (optionally substituted by methyl, ethyl, methoxy or butoxy) groups.

In R2 groups of the type (i) (b), the thienyl group may be substituted by, for example, methyl, ethyl, methoxy, ethoxy, cyclohexyl or phenyl (optionally subsituted by methyl, ethyl, methoxy, ethoxy, chloro or bromo) groups.

In general R2 is preferably a C15 alkyl group substituted by phenyl, which phenyl is itself substituted (preferably in the para-position) by phenyl (optionally substituted by C,4 alkyl or C14 alkoxy).

Particularly preferred R2 groups are benzyl groups in which the phenyl portion is substituted (preferably in the para-position) by a phenyl, methylphenyl or methoxyphenyl group, especially biphenylmethyl.

In the group -(CH2)nXWCOOR', n is preferably 2 and X is preferably cis -CH=CH-.

W may for example contain 1-5 carbon atoms in a straight or branched chain, and is preferably -CH2CH2CH2-when n is 1 and -CH2CH2-or -(CH2)4-when n is 2.

Examples of R' groups of types (b) and (d) are C12 alkyl, benzyl and phenethyl.

R' is preferably a hydrogen atom, C15 alkyl, -CH2OR4, -CH2OCOR6 where R6 is C14 alkyl, or -(CH2)2N(R)42 where R4 is C14 alkyl. More preferably, R' is hydrogen atom, methyl, -CH2OCOCH3, -(CH2)2N(CH3)2, or -CH2OCH3.

R3 is preferably C14 alkanoyl or C14 alkyl, particularly acetyl or methyl.

Thus a particularly preferred group of compounds has the formula (1) in which: R' is a hydrogen atom, C16 alkyl (especially methyl), -CH20COR6 where R6 is C14 alkyl (especially methyl), -CH20COR6 where R6 is C14 alkyl (especially methyl), -(CH2)2N(R4)2 where R4 is C14 alkyl (especially -(CH2)2N(CH3)3) or-CH2OR4 (especially -CH20CH3), W is -CH2CH2-, X is cis -CH=CH-, n is 2, Y is morpholino or piperidino, R2 is benzyl in which the phenyl group is substituted by phenyl, methylphenyl or methoxyphenyl (especially biphenylmethyl), and R3 is C14 alkanoyl or C14 alkyl (especially acetyl or methyl), including the physiologically acceptable salts and solvates thereof.

A particularly preferred compound of this type is [IR-[la(Z),2ss,3a,5a]]-(+)-7-[3-(acetyloxy)-5- [[(1,1 '-biphenyl)-4yl]methoxy]-2-( 1 -piperidinyl)cyclopentyl]-4-heptenoic acid.

In general, the compounds of formula (1) in which the carbon atom carrying the -(CH2),,XWCOOR group is in the R-configuration (and mixtures containing this isomer) are preferred.

Compounds of formula (1) inhibit blood platelet aggregation and broncho constriction. A test to determine inhibition of blood platelet aggregation is as described by G.V. Born (Nature 194, 927-929, 1962) except in that collagen is used instead of ADP as the pro-aggregatory agent.

Alternatively, starved guinea-pigs are dosed orally with the compound to be tested in a suitable vehicle. Platelet rich plasma is prepared from each animal and aggregation to a range of collagen concentrations is measured after the method of Born. Collagen concentration-effect curves for each sample of plasma are calculated and results are expressed as the shift of the curves following treatment with the compound.

The ability of the compounds of the invention to inhibit bronchoconstriction is determined either in the anaesthetized guinea pig by measuring the effect of the compound to be tested on the dose response curve of the bronchoconstrictor [IR-[la,4a,54(Z), 6a(1E,3S*)]]-7-[6-(3-hydroxy- 1 -octenyl)-2-oxabicyclo[2,2, 1] hept-5yl]-5-heptenoic acid (U-46619) or by the test described by K.M. Lulich et al in British Journal of Pharmacology 58, 71-79 (1976) except guinea pig lung or rat aorta is used instead of cat lung.

The compounds are thus of interest in the treatment of asthma, and as inhibitors of platelet aggregation and thrombosis for use in renal dialysis and transplant and the treatment and prevention of occlusive vascular diseases such as arteriosclerosis, atherosclerosis, peripheral vascular disease, cerebral vascular disease including transient ischaemic attacks, stroke, pulmonary embolism, diabetic retinopathy, post operative thrombosis, angina and myocardial infarction.

The compounds are also of potential use in the treatment of adult respiratory distress syndrome and the prevention of relapse of healed peptic ulcers.

The compounds may be formulated in conventional manner for use, with one or more pharmaceutical carriers.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions or syrups, prepared by conventional means with acceptable excipients.

The compounds may be formulated for parenteral administration by bolus injections or continuous infusion. Formulations for injections may be presented in unit dosage form in ampoules, or in multi-dose containers, with an added preservative.

For administration by inhalation the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, or as a cartridge from which the powdered composition may be inhaled with the aid of a suitable device. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

For use as antithrombotic agents, the compounds are preferably administered orally, for example in amounts of 0.05 to 10 mg/kg body weight, 1 to 4 times daily.

For use in the treatment of asthma, the compounds may also be administered orally in amounts of 0.05 to 10 mg/kg body weight, 1 to 4 times daily; preferably however they are administered by inhalation at doses varying from 0.3 to 30 mg, 1 to 4 times daily. The compounds may be used in combination with other antiasthmatic agents.

The precise dose administered will of course depend on the age and condition of the patient.

Suitable methods for preparing compounds of formula (1) are described below. The R groups and n, W,X and Y are as defined above except where otherwise indicated.

(a) Compounds of formula (1) in which R3 is a group of the type (i) or (ii) and R' is other than a hydrogen atom may be prepared by alkylation of the corresponding cyclopentanol in which R3 represents a hydrogen atom.

The reaction may be performed in the presence of a base (e.g. NaH) in a suitable solvent (e.g.

dimethylformamide) at low temperatures, e.g. 200 up to 00. The alkylating agent may be a compound of formula R3L where L is a leaving group e.g. halogen or tosylate.

The starting materials for this reaction may be prepared by the methods generally described in British Patent Specifications 2097397A and 21081 16A.

(b) Compounds in which R' is a hydrogen atom and R3 is a group of the type (i) or (ii) may be prepared by hydrolysing a corresponding ester (e.g. a C16 alkyl ester), e.g. using a base such as NaOH or KOH in a suitable solvent (e.g. ethanol) at room temperature to 50"C.

(c) Compounds of formula (1) in which R3 is a group of the type (iii) or (iv) may be prepared by esterification of a corresponding compound in which R3 is a hydrogen atom. The reaction may be performed using a reactive derivative of an acid R30H, e.g. an acid anhydride, acid chloride or chloroformate in the presence of a base e.g. triethylamine or pyridine at a temperature of 0 up to room temperature.

(d) Compounds of formula (1) in which R3 is a group of the type (v) may be prepared by treatment of the corresponding compound in which R3 is -H with an appropriate isocyanate e.g.

methyl isocyanate or sodium isocyanate/-trifluoroacetic acid. The reaction may be performed in an organic solvent such as dichloromethane at room temperature.

(e) Compounds of formula (1) in which R1 is a hydrogen atom may be prepared by removing the protecting group from a corresponding carboxylic acid in which the carboxyl group is protected, for example in the form of a labile ester, e.g. a trityl ester of a 2,2,2 trichloroethyl ester. The protecting group may be removed under mild conditions, e.g. with trifluoroacetic acid either neat or in an organic solvent (e.g. dichloromethane) or (in the case of a trichloroethyl ester) by treatment with zinc, for example at a pH of 4.2 -7.2, Tetrahydrofuran, dioxan and dimethoxyethane are suitable solvents. These deprotections are preferably effected at 0 up to room temperature.The starting materials required for this reaction may be prepared by first protecting the carboxyl group of the parent carboxylic acid (in which R and R3 are both -H), followed by use of processes (a), (c) or (d).

(f) Compounds of formula (1) in which R' is other than a hydrogen atom may be prepared by esterification of the corresponding carboxylic acid. Conventional esterification techniques, may be used.

For example, compounds of formula (1) in which R' is a group of the type h, j, k and 1 and R3 is not a group of the type (iv) or (v) may be prepared by treating a reactive derivative of the corresponding carboxylic acid with an appropriate alcohol R1OH. The reactions may for example be carried out at room temperature using a solvent such as acetone and, where appropriate, in the presence of pyridine.

The reactive derivative is conveniently a mixed anhydride of the acid, formed for example by treatment of the acid with a chloroformate in the presence of a suitable base, e.g. triethylamine or pyridine at -100C.

The chloroformate may for example be a C16 alkyl (e.g. iso-butyl), aryl (e.g. phenyl) or aralkyl (e.g. benzyl) chloroformate.

Again for example, compounds of formula (1) in which R' is a group of the type b-g or i may be prepared by reacting the corresponding carboxylic acid with an appropriate halide Ra Hal, where Hal represents halogen and Ra is as just defined for R'. The reaction may be carried out in the presence of a suitable base e.g. potassium t-butoxide or a sterically hindered amine such as N,N-diisopropylethylaminei in a suitable solvent (such as acetonitrile or dimethylsulphoxide), for example at a temperature from 0 to room temperature.

Compounds in which R' is a group of type (b) may be prepared by treating the corresponding acid with an appropriate diazoalkane, using a solvent such as CH2CI2, e.g. at room temperature.

(g) Compounds of formula (1) in which R' is a group of the type (m) and R3 is a group of the type (i) or (ii) may be prepared by transesterification, for example, by heating (e.g. at 1300C) an appropriate alcohol (r4)2N(CH2)pOH with a compound of formula (1) in which R3 is as just defined and R' is an alkyl group such as a methyl group.

(h) Where salts of compounds of formula (1) are desired such salts may be formed by conventional methods, for example by treating acids of formula (1) with appropriate bases. Salts may also be formed with acids.

For example, amine salts are conveniently prepared by adding the amine to a solution of an acid of formula (1) in a solvent such as ether. Salts of inorganic bases may be prepared by adding the base to a solution of the acid in an aqueous organic solvent. Certain salts may also be prepared by exchange of cation; for example, calcium salts may be prepared by addition of a calcium salt (e.g. the chloride or acetate) to a solution of a salt of a compound of formula (1), e.g. an amine or alkali metal salt.

Salts of acids may be prepared by adding the acid (e.g. hydrogen chloride) to a solution of the compound of formula (1) in an organic solvent such as ether.

When a specific enantiomer of formula (1) is required, starting materials having the desired stereo-chemical configuration should be used in the above processes. Such intermediates may for example be prepared starting from an enantiomeric bicycloheptenone as described in European Patent Specification 74 856 using the methods generally described in UK Patent Specifications 2028805A, 2075503A, 2097397A and 2108116A.

The following examples illustrate the invention.

Temperatures are in C.

Abbreviations: 'Dried' refers to drying with anhydrous MgSO4; T.l.c. -Thin Layer Chromatography on silica unless otherwise stated; ER -ether; EA -ethyl acetate; PE -petroleum ether (b.p. 60-80 unless otherwise stated); DIBAL -diisobutylaluminium hydride; THF -tetrahydrofuran; DMSO -dimethylsulphoxide; DMF -dimethylformamide; NaH -80% dispersion of sodium hydride in oil; AcOH -acetic acid; Ac20 -acetic an hydride; Chromatography was carried out using silica gel unless otherwise stated.

The preparations of intermediates 1-4 are described in British Patent Specification 2097397A.

Intermediate 1 [1 R-(endo, anti)]-(+)-5-Hydroxy 7-( 1-piperidinyl)bicyclof2.2. l]heptan-2-one Intermediate 2 [ 1R1 1a(ZJ,2ss,3g5a]]-(+J-Methyl 7-[5-g1. 1. 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-( 1 -piperidinyl)cy- clopentyl]-4-heptenoate Intermediate 3 [ 1Rl 1a(Z),2a,3ss,5a]]-(+)-7-[5-[[( 1, 1 '-Biphenyl]-4-yl]methoxy]-3-hydroxy-2-( 1 -piperidinyl)cyclopen- tyl]-4-heptenoic acid Intermediate 4 [1R-[ 1a(Z),2ss,3ss,5a]](+)-7-[5-[[(1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopen- tyl]-4-heptenoic acid Intermediate 5 a) [1R-[ 1a-(Z),2fi,3fi,5aj( )-(Triphenylmethyl) 7-[3-(Acetyloxy)-5-ff( 1, 1 '-biphenyl)-4-yl]methoxy]-2- (l-piperidinyl)cyclopentyl-4-heptenoate Triphenylmethyl chlorine (0.149) was added at - 100 to a stirred solution of Intermediate 3 (0.29) and triethylamine (0.135ml) in CH2CI2 (5ml). After 45 min at 0 pyridine (0.09ml) and Ac2O (0.12ml) were added and the mixture was stirred at 20 for 2h. The mixture was poured into pH 6.5 phosphate buffer (70ml) and extracted with CH2CI2 (3X15ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using 4:1 EA-PE as eluent to give the title compound as an oil (0.2259).

T.l.c. 4:1 EA-PE Rf 0.6.

The following compounds were prepared in a similar manner.

b) [lR-[ la-(Z),2P,3P,5a]]-(+)-(Triphenylmethyl) 7-[3-(Benzoyloxy)-5-[[( 1, 1 '-biphenyi)-4-yI]methoxy 2-(1-piperidinyl)cyclopentyl]-4-heptenoate, from Intermediate 3 using benzoic anhydride. Purification by chromatography on alumina using 4: 1 PE-ER as eluent.

Analysis Found: C,81.65; H,6.9; N,1.5.

C56H57NO5 requires C,81.6; H,7.0; N,1.7%.

[ai228 =+63.5 (CHCla).

c) [1R-[1a-(Z),2ss,3ss,5a]]-()-(Triphenylmethyl)7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3-( 1-oxobutoxy)- 2-(1-piperidinyl)cyclopentyl]-4-heptenoate, from Intermediate 3 using butyryl chloride.

T.I.c. ER Rf 0.61.

Intermediate 6 [1R-(endo,anti)]-(+)-5-[[4'-Methoxy(1,1 '-biphenyl)-4-yl]methoxy]-7-(1-piperidinyl)bicyclo[2.2. 1]heptan-2-one A mixture of Intermediate 1 (30.51g), benzyltriethylammonium chloride (6.659) and 4-(bromomethyl)-4'-methoxy(1,1'-biphenyl)(52.6g) in CH2CI2 (365ml) and 17N NaOH (325ml) was vigorously stirred at ambient temperature for 18h.The mixture was diluted with water (11) and extracted with CH2CI2 (3X 150ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using ER-PE (1:1 followed by 7:3) as eluent to give the title compound (40.29). A portion was recrystallised from EA-PE m.p. 109.5-110.5 [a]0227 =+22.7" (CHCl3) Intermediate 7 [1R-(endo,anti)]-(-)-6-[[4'-Methoxy(1,1 '-biphenyl)-4-yl]methoxy]-8-( 1 -piperidinyl)-2-oxabicyclo[3.2. 1]octan-3-one A solution of peracetic acid in acetic acid (5.6M, 124ml) was added slowly to a stirred mixture of Intermediate 6 (429) in CH2CI2 (235ml), 2N H2SO4 (29ml) and water (159ml) and the mixture stirred at ambient temperature for 24 h.The mixture was adjusted to ca. pH7 using 5N NaOH and pH 6.5 phosphate buffer then extracted with CH2CI2 (3X200ml). The combined organic extracts were added to an excess of sodium metabisulphite solution and stirred for 24h.

The mixture was extracted with EA (1X500, 2X250ml) and the combined organic extracts were dried and evaporated and the residue was purified by chromatography using 1:1 EA-PE as eluent to give the title compound (24.49).

A portion was recrystallised from EA-PE m.p. 116.5-117.5 [a]D34 24.50 (CHCla) Intermediate 8 [1 R-(1a,2ss,3a, 5a)]-( )-(3-Hyoroxy-5-ff4'-methoxy( 1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1 -piperidinyl)cyclopentane acetaldehyde DIBAL in hexane (1M, 114ml) was added slowly to a cold (-70 ) stirred solution of Intermediate 7 (249) in CH2CI2 (240ml). After 0.5h methanol (240ml) was added, slowly at first, and the mixture was stirred at ambient temperature for 16h. The precipitate was filtered off and the filtrate evaporated to give the title compound as a foam (24.1g).

T.l.c. 9:1 EA-methanol Rf 0.35.

Intermediate 9 [1 R-( 1a,2ss,3a, 5a)]-(+)-4-[[4'-Methoxy( 1, 1 "biphenyl)-4-yl]methoxy]-3-(3-methoxy-2-propenyl)-2-( 1- piperidinyl)cyclopentanol, hydrochloride A solution of Intermediate 8 (24.19) in THF (75ml) was added to a cooled (-5 to 0 ), stirred solution of the ylid derived from methoxymethyltriphenylphosphonium chloride (789) and potassium tert-butoxide (25.59) in THF (800ml). After 1.5h methanol (100ml) was added and the solvents removed in vacuo. The residue in pH6.5 phosphate buffer (600ml) was extracted with CH2CI2 (3X150ml) and the combined extracts were dried and evaporated. The residue was purified by chromatography using 4:1 EA-methanol as eluent to give the title compound, base as an oil (24.89).

A portion was converted into the hydrochloride salt m.p. 150-151 (dec) [a]naal +38.1 (CHCl3) Intermediate 10 [1 R-( 1 a, 2,"', 3a, 5a)(+)-3-Hydroxy-5-ff4'-meThoxy( 1, 1 '-biphenyl)-4-yl]methoxy]-2-(1-piperidinyl)cyclo- pentanepropanal, hydrochloride A solution of Intermediate 9 (24.39) in 2N HCI (55ml) and acetone (250ml) was stirred at ambient temperature for 1h. Most of the acetone was removed in vacuo and the residue in water was extracted with CH2CI2 (3X150ml).The combined extracts were dried and evaporated -to-give a solid (23.69). A portion was triturated with ether to give the title compound as a powder m.p. 182-185 (dec) [a]2D2-7 =+51.5" (CHCI2) Intermediate 11 [1R-[1a(Z),2ss,3a,5a]]-(+)-Methyl 7-[3-Hydroxy-5-[[4'-methoxy(1,1'-biphenyl)-4-yl]methoxy]-2-(1-pi peridinyl)cyclopentyl]-4-heptenoate, hydrochloride.

A suspension of Intermediate 10 (23.69) in THF (300ml) was added to the ylid derived from 3-(carboxypropyl)triphenylphosphonium bromide (69.59) and potassium tert-butoxide (36.39) in THF (1000ml). After 2h water (200ml) was added and the THF was removed in vacuo. The residue was diluted with water (250ml) and extracted with ER (3X200ml; discarded). The aqueous layer was neutralised using 5N HCI and extracted with CH2CI2 (3X200ml). The com bined extracts were dried and evaporated and the residue was left to stand in methanol (250ml) containing concentrated sulphuric acid (5ml) for 19h. Most of the methanol was removed in vacuo and the residue neutralised using 2N NaOH and pH 6.5 phosphate buffer (150ml). The mixture was extracted with EA (3X150ml) and the combined extracts were dried and evapo rated.The residue was purified by chromatography using initially 9:1 ER-methanol followed by 4:1 ER-methanol as eluent to give the title compound, base as an oil (15.99). A portion was converted into the hydrochloride salt m.p. 122-125" (dec).

[a]D225 =+55.9 (CHCb) Intermediate 12 [1 R-[ 1a(Z),2ss,5a]]-(-J-Methyl 7-[5-ff4'-MeThoxy( 1, 1 '-biphenyl)-4-yl]methoxy]-3-oxo-2-( 1 -piperidinyl)- cyclopentyl]-4-heptenoate A solution of pyridine-sulphur trioxide complex (10.339) in dry DMSO (17ml) was added to a cold (0") solution of Intermediate 11, base (8.479) in Et3N (13.5ml), CH2CI2 (30ml) and DMSO (20ml). After 1h at 0" the mixture was diluted with pH 6.5 phosphate buffer (140ml) and extracted with EA (3X50ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using 1:3 EA-PE as eluent to give the title compound as a solid (5.699). A portion was recrystallised from ER-PE m.p. 61.5-62.5".

[a]2 2 = - 19.80 (CHC13) Intermediate 13 [ 1a(Z),2ss,3ss,5a]]-(+)-Methyl 7-[3-Hydroxy-5-[[4'-methoxy( 1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1-pi- peridinyl)cyclopentyl]-4-heptenoate A solution of dibal in hexane (1M, 93ml) was added dropwise to a cold (-5") stirred solution of 2,6-di-tert-butyl-4-methylphenol (30.759) in dry toluene (350ml). After lh at-5 the mixture was cooled to -70" and a solution of Intermediate 12 (9.679) in toluene (50ml) was added dropwise. After 1h at -70 and lh at -10" the mixture was washed with 2N Hcl (7X60ml) and the toluene was discarded.The acidic extracts were neutralised with 5N NaOH solution (200ml) and extracted with CH2CI2 (4X80ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using 17:3 ER-methanol as eluent to give the title compound (7.029) as an oil.

Analysis Found: C,73.5; H,8.5; N,2.7.

C32H43NOs requires C,73.7; H,8.3; N,2.7%.

[a]D1 =+63.2" (CHCI3) Intermediate 14 [ la(Z),2,"', 3,"', 5all-(+)- 7-[3-Hydroxy-5-j4'-methoxy( 1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1-piperidinyl) cyclopentyl]-4-heptenoic acid, hydrochloride A mixture of Intermediate 13 (5.899) 5N NaOH solution (6.77ml) and methanol (40ml) was vigorously stirred at ambient temperature for 18h. Most of the methanol was removed in vacuo and the residue in pH 6.5 phosphate buffer (150ml) was extracted with CH2CI2 (3X40ml). The combined extracts were dried and evaporated to give the title compound, base as a foam (5.799).

A portion (0.679) in ER-CH2CI2 was treated with an excess of ethereal HCI to give the title compound (0.619) m.p. 122-124".

[a]D215 =+61.2" (CHCl3) Example 1 a) [1R-[ 1a(Z),2ss,3ss,5a]]-(+)-Methyl 7-[5-[[(1, 1 '-Biphenyl)-4-yl]methoxy]-3-methoxy-2-( 1-piperidinyl)- cyclopentyl]-4-heptenoate A solution of Intermediate 2 (0.5g) in dry DMF (2ml) was added over Smin to a cold (-20") stirred suspension of NaH (92mg) in dry DMF (15ml) under nitrogen. After 10min iodomethane (0.19ml) was added and the mixture stirred at between -10" and 0" for 2.5h. The mixture was poured into pH 6.5 phosphate buffer (100ml) and extracted with EA (2X50ml). The extracts were washed with brine (2X30ml), dried and evaporated to give an oil which was purified by chromatography on alumina using 1:9 ER-CH2CI2 as eluent to give the title compound as an oil (0. 1 269).

T.l.c. (Al203) 1:9 ER-CH2CI2 Rf 0.36.

I.r. (CHBr3) 1730cm-' [a]D25 =+89.3" (CHCl3) The following compound was prepared in a similar manner.

b)[lR-[ 1a(Z),2ss,3ss,5a]]-(+)-Methyl 7-[5-g 1, 1'Biphenyl)-4-yl]methoxy]-3-(methoxymethoxy)-2-(1-pi- peridinyl)cyclopentyl]-4-heptenoate, from Intermediate 2 using methoxymethyl chloride. Purification by chromatography on alumina using 2:1 CH2CI2-ER as eluent.

T.l.c. (Al2O3) 2:1 ER-PE Rf 0.63.

Analysis Found: C,74.25; H,8.5; N,2.9.

C33H4sNO5 requires C,74.0; H,8.5; N,2.6%.

[a]g4 =+74.5" (CHCl3).

Example 2 a) [1 R-[ 1a(Z),2ss,3ss, 3ss,5a]]-(+)-7-[5-[[( 1, 1 'Biphenyl)-4-yl]methoxy]-3-methoxy-2-( 1 -piperidinyl)cyclopen- tyl]-4-heptenoic acid A solution of Example 1a (0.219) in ethanol (1 ml) and 5N NaOH (0.5ml) was stirred at 20" for 48h. The solution was poured into pH 6.5 phosphate buffer (50ml) and extracted with CH2Cl2 (3X25ml). The combined extracts were dried and evaporated to give the title compound as a foam (0.2g).

T.l.c. 25:15:8:2 EA-iPrOH-H2O-NH3Rf 0.56.

I.r. (CHBr3) 1710cm [a]D3 =+70.9" (CHCl3) The following compound was prepared in a similar manner.

b) [ 1R-[ 1a(Z),2ss,3ss,5a]]-(+)-7-[5-[[(1, 1 '-Biphenyl)-4-yl]methoxy]-3-(methoxymethoxy)-2-( 1 -piperidi- nyl)cyclopentyl]-4-heptenoic acid, from Example 1 b.

T.l.c. 25:15:8:2 EA-iPrOH-H2O-NH3 Rf 0.38.

Analysis Found: C,74.0; H,8.2; N,2.45.

C22H43NO5 requires C,73.65; H,8.3; N,2.7%.

[a]D3 =+71.20 (CHCl3) Example 3 a) [1R-[ 1 a(Z),2ss,3ss,5a]]-(+)-7-[3-(A cetyloxy)-5-[[( 1, 1 biphenyl)-4-yl]methoxy]-2-( 1 -piperidinyl)cyclo- pentyl]-4-heptenoic acid, hydrochloride Trifluoroacetic acid (0.33ml) was added to a cooled (0"), stirred solution of Intermediate 5a (0.4669) in CH2Cl2 (5 ml). After 45min at 20 the mixture was poured into 8% NaHCO3 solution (30ml) and pH 6.5 phosphate buffer (200ml) and extracted with CH2CI2 (3X40ml). the combined extracts were dried and evaporated and the residue was purified by chromatography using 9:1 EA-methanol as eluent. The purified product in CH2CI2 was treated with ethereal HCI and the solvents were removed to give the title compound as a foam (0.318g).

T.l.c. 7:3 EA-methanol Rf 0.28.

I.r. (CHBr3) 3500-2500 (br), 1750-1700 (br) cm [a]D4 =+65.9 (CHCI3) The following compounds were prepared in a similar manner.

b) [1R-[1a(Z),2ss,3ss, Safl-(+)- 7-[3-(Benzoyloxy)-5-[[( 1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1-piperidinyl)cy- clopentyl]-4-heptenoic acid, from Intermediate 5b. Purification by chromatography using 49:1 EA-methanol as eluent.

T.l.c. 49:1 EA-methanol Rf 0.37.

Analysis Found: C,76.45; H,7.4; N,2.2.

C37H43NO5 requires C,76.4; H,7.4; N,2.4%.

[a]D236 = + 101 (CHCl3) c) [1R-[ 1 a(Z),2,"',3,"', Safl-(+)- 7-[5-[[( 1, 1 '-Biphenyl)-4-yl]methoxy]-3-( 1-oxobutoxy)-2-( 1-piperidinyl)cyclopentyl]-4-heptenoic acid. from Intermediate 5C. Purification by chromatography using ER as eluent.

T.l.c. ER Rf 0.19.

I.r. 1720(br)cm-1.

[aW-5 +85.4" (CHCl2) Example 4 [ 1R-[1a(Z),2ss,3ss,5a]]-(+)-Methyl 7-[3-(Acetyloxy)-5-[[(1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1-piperidinyl)- cyclopentyl]-4-heptenoate.

Method a) A solution of Example 3a (0.089) in CH2CI2 (10ml) was treated with an excess of ethereal diazomethane. The solution was treated with few drops of AcOH, diluted with 8% NaHCO3 solution and extracted with EA (3X25ml). The combined extracts were dried and evaporation and the residue was purified by chromatography on alumina eluting initially with 1:1 ER-PR increasing to ER to give the title compound as an oil (0.0779).

T.l.c. (Al2XO3) 1:1 ER-PE Rf 0.45.

Analysis Found: C,74.4; H,8.1; N,3.0.

C33H43NO5 requires C,74.3; H,8.1; N,2.6%.

[a]D224 =+85.9 (CHCl3).

Method b) A solution of Intermediate 2 (0.089) in DMSO (1 ml), AcOH (0.2ml) and Ac2O (0.7ml) was stirred at 20" for 18h. The mixture was diluted with 2N Na2CO3 (30ml) and extracted with CH2CI2 (3X20ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using ER as eluent to give the title compound as an oil (0.0649).

T.l.c. (Al2O3) 1:1 ER-PE Rf 0.45.

Example 5 [1R-[1a(Z),2ss,3ss,5a]]-(+)-Methyl 7-[3-[(Aminocarbonyl)oxy]-5-[[(1.1'-biphenyl)-4-yl]methoxy]-2-(1- piperidinyl)cyclopentyl]-4-heptenoate Three portions of trifluoroacetic acid (0.75ml) and sodium isocyanate (474mg) were added to a solution of Intermediate 2 (0.6 g) in CH2CI2 (15ml) at 2 hourly intervals and then the mixture was stirred at 20 for 64h. The mixture was poured into pH 6.5 phosphate buffer (50ml) and extracted with CH2CI2 (3X25ml). The combined organic extracts were dried and evaporated and the residue was purified by chromatography on alumina using 7:3 ER-PE as eluent to give the title compound as an oil (0.172g).

T.l.c. (Al2O3) 7:3 ER-FE Rf 0.28.

Analysis Found: C,72.0; H,8.0; N,4.9.

C32H42N2Os requires C,71.9; H,7.9; N,5.2%.

[a]D24 = +94.3" (CHCk) Example 6 [1R-[ 1 a(Z),2,"', 3,"',5afl-(+)-Methyl 7-[5-[[(1, 1 '-Biphenyl)-4-yl]methoxy]3-[[(phenylmethoxy)carbonyl]- oxy]-2-(1-piperidinyl)cyclopentyl]-4-heptenoate Benzyl chloroformate (1.32ml) and triethylamine (1.92 ml) were added in portions over 6h to a cooled (0 ) stirred solution of Intermediate 2 (0.3769) in CH2CI2 (4ml). After a further 2h the mixture was poured into pH 6.5 phosphate buffer (50ml) and extracted with EA (3X30ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using 1:1 ER-PE as eluent to give the title compound as an oil (0.093g).

T.l.c. 1:1 ER-FE Rf 0.5 Analysis Found: C,75.2; H,7.5; N,2.4.

C39H47NO6 requires C,74.9; H,7.6; N,2.2%.

[a]D23 =+65.1 (CHCl3) Example 7 [ 1Rl 1a(Z),2ss,3ss,5a]]-(+)-(Acetyloxy)methyl 7-[3-(Acetyloxy)-5-[[(1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1- piperidinyl)cyclopentyl]-4-heptenoate Bromomethyl acetate (1.089) in CHAIN (7ml) was added to a stirred solution of Intermediate 3 (0.514g) and triethylamine (1.2ml) in CH3CN (10ml). After 10h the mixture was cooled to 5 and pyridine (2ml) and Ac20 (1 ml) were added. After a further 23h at 20" the mixture was poured into pH 6.5 phosphate buffer (100ml) and extracted with ER (3X70ml).The combined extracts were dried and evaporated and the residue was purified by chromatography using 2:1 ER-Pe as eluent to give the title compound as an oil (0.1429).

T.l.c. 4:1-methanol Rf 0.66.

I.r. (CHBr3) 1760, 1730 cm [a]D5 +82.8" (CHCl3).

Example 8 [1 R-[ 1a(Z),2ss,3ss,5a]]-(+)-Methyl 7-[3-Benzyloxy)-5-[[( 1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1 -piperidinyl)- cyclopentyl]-4-heptenoate, from the compound of Example 3b according to the procedure for Example 4, method a. Purification by chromatography using 3:2 EA-PE as eluent.

T.l.c. 3:2 EA-PE Rf 0.65.

I.r. (CHBr3) 1730, 1713 cm ' [a]D3 =+98.8" (CHCl3) Example 9 [1R-[1a(Z),2ss,3ss, 5a]]-(+)-2-(Dimethylamino)ethyl 7-[3-(Acetyloxy)-5-[[( 1, 1 '-biphenyl)-4-yl]methoxy]- 2-( 1-piperidinyl)cyclopentyl]-4-heptenoate.

A mixture of Intermediate 2 (0.6g) and N,N-dimethylethanolamin (6ml) was heated at 130" for 18h. The dark solution was diluted with water (50ml) and extracted with CH2CI2 (3X50ml). The combined extracts were dried and evaporated and the residue in CH4CI2 (5ml) was treated with Ac20 (5ml) and pyridine (10ml) for 18h at ambient temperature. The solvent and the excess reagents were removed in vacuo and the residue in 8% NaHCO3 solution (30ml) was extracted with CH2CI2 (3X50ml). The combined extracts were dried and evaporated and the residue was purified by chromatography on Alumina (Grade II) using ER as eluent to give the title compound as an oil (0.1239).

I.r. (CHBr3) 1725 cm 1.

Analysis Found: C,73.2; H,8.6; N,4.6.

C36HsoH2Os requires C,73.2; H,8.5; N,4.7%.

[a]D23 =+82 (CHCI3) Example 10 a) [1R-[1a(Z),2ss,3ss,5a-(+)-7-(Acetyloxy)-5-[[(1,1'-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)cyclopentyl]-4-heptenoate acid.

A solution of Intermediate 4, hydrochloride (0.39) in Ac2O (0.5ml) and pyridine (2.5ml) was kept at ambient temperature for 18h. Ice (5g) was added and the mixture stirred for 0.5h. The mixture was diluted with pH 6.5 phosphate buffer (80ml) and extracted with EA (100ml). The organic extract was washed with buffer (3X50ml) dried and evaporated and the residue was purified by chromatography using 17:1 EA-methanol as eluent to give the title compound as a gum (0.1169).

T.l.c. 4:1 EA-methanol Rf 0.6.

I.r. 3490, 3400-2400, 1725 (br) cm [a]D96 = +87.5" (CHCl3) The following compound was prepared in a similar manner.

b) [ 1R-[ 1a(Z),2ss,3ss,5a]]-(+)-7-[3-(Acetyloxy)-5-[[4'-methoxy( 1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1-piper idinyl)cyclopentyl]-4-heptenoic acid, from Intermediate 14, base. Purification by chromatography using 9:1 EA-methanol as eluent.

T.l.c. 9:1 EA-methanol Rf 0.2.

I.r. (CHBr3) 3200-2400, 1725cm ' [a]0216 = + 85 (CHCl3) Example 11 a) [1R-[1a(Z),2ss,3ss,5a]]-(+)-Methoxymethyl 7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3-(1-oxobutoxy)-2 (1-piperidinyl)cyclopentyl]-4-heptenoate Chloromethylmethyl ether (0.104ml) was added to a cold (0 ), stirred solution of the compound of Example 3c (0.5g) and diisopropylethylamine (0.24ml) in dry DMF (10ml). Stirring was continued for 1.5 h during which time ambient temperature was reached. The mixture was diluted with pH 6 phosphate buffer (100ml) and extracted with EA (3X50ml).The combined extracts were dried and evaporated and the residue was purified by chromatography using 7:3 ER-PE as eluent to give the title compound as an oil (0.3459) I.r. (CHBr3) 1723 cm-1 Analysis Found: C,72.9; H,8.7; N,2.3.

C,5H49NO6 requires C,73.1; H,8.3; N,2.5%.

[a]22-7 = +91.5" (CHCI3) The following compound was prepared in a similar manner: b) [1R-[ 1a(Z),2ss,3,A,5a]]-(f )-(Acetyloxy)methyl 7-[3-(AcetyloxyJ-5-[[4'-methoxy( 1,1 '-biphenyl)-4-yl]- methoxy]-2-(1-piperidinyl)cyclopentyl]-4-heptenoate, from the compound of Example 10b, bromoethyl acetate and Et3N in acetone. Purification by chromatography using 4:1 ER-PE as eluent.

T.l.c. 4:1 ER-PE Rf 0.4 Analysis Found: C,69.5; H,7.7; N,2.3.

C36H47NO6 requires C,69.5; H,7.6; N,2.3%.

[a]02 =+82" (CHCl2) Pharmaceutical Examples Tablets These may be prepared by direct compression or wet granulation. The direct compression method is preferred but may not be suitable in all cases as it is dependent upon the dose level and physical characteristics of the active ingredient.

A. Direct Compression mg/tablet Active ingredient 100.00 Microcrystalline Cellulose B.P.C. 298.00 Magnesium Stearate 2.00 Compression Weight 400.00 mg The active ingredient is sieved through a 250 m 6 sieve, blended with the excipients and compressed using 10.0mm punches. Tablets of other strengths may be prepared by altering the compression weight and using punches to suit.

B. Wet Granulation mg/tablet Active ingredient 100.00 Lactose B.P. 238.00 Starch B.P. 40.00 Pregelatinised Maize Starch B.P. 20.00 Magnesium Stearate B.P. 2.00 Compressed Weight 400.000 mg The active ingredient is sieved through a 250 m 6 sieve and blended with the lactose, starch and pregelatinised starch. The mixed powders are moistened with purified water, granules are made, dried, screened and blended with the magnesium stearate. The lubricated granules are compressed into tablets as described for the direct compression formula.

The tablets may be film coated with suitable film forming materials, e.g. methyl cellulose or hydroxylpropyl methyl cellulose using standard techniques. Alternatively the tablets may be sugar coated.

Capsules mg/capsule Active ingredient 100.00 STA-RX 1500 99.00 Magnesium Stearate B.P. 1.00 Fill Weight 200.00 mg * A form of directly compressible starch supplied by Colorcorn Ltd., Orpington, Kent.

The active ingredient is sieved through a 250m 6 sieve and blended with the other materials.

The mix is filled into No.2 hard gelatin capsules using a suitable filling machine. Other doses may be prepared by altering the fill weight and if necessary changing the capsule size to suit.

Inhalation cartridges mg/cartridge Active ingredient (micronised) 3.00 Lactose B.P. to 25.00 The active ingredient is micronised in a fluid energy mill to a fine particle size range prior to blending with normal tabletting grade lactose in a high energy mixer. The powder blend is filled into No.3 hard gelatin capsules on a suitable encapsulating machine.

The contents of the cartridges are administered using a powder inhaler.

Metered Dose Pressurised Aerosol mg/metered dose Per can Active ingredient (micronised) 0.500 120 mg Oleic Acid B.P. 0.050 12 mg Trichlorofluoromethane B.P. 22.25 5.34 g Dichlorodifluoromethane B.P. 60.90 14.62 g The active ingredient is micronised in a fluid energy mill to a fine particle size range. The oleic acid is mixed with the trichiorofluoromethane at a temperature of 10-15"C and the micronised drug is mixed into this solution with a high shear mixer. The suspension is metered into aluminium aerosol cans and suitable metering valves, delivering a metered dose of 85 mg of suspension, are crimped onto the cans and the dichlorodifluoromethane is pressure filled into the cans through the valves.

Syrup mg/5ml dose Active ingredient 100.00 Sucrose B.P. 2750.00 Glycerine B.P. 500.00 Buffer Flavour Colour ) as required Preservative Distilled Water to 5.00 ml The active ingredient, buffer, flavour, colour and preservative are dissolved in some of the water, and the glycerine is added. The remainder of the water is heated to 80"C and the sucrose is dissolved in this and cooled. The two solutions are combined, adjusted to volume and mixed. The syrup produced is clarified by filtration.

Injection for Intravenous Administration Active ingredient 50 mg Water for injections B.P. to 5 ml Sodium chloride or any other suitable material may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability of the active ingredient using dilute acid or alkali or by the addition of suitable buffer salts. The solution is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass. The injection is sterilised by heating in a autoclave using one of the acceptable cycles. Alternatively the solution may be sterilised by filtration and filled into sterile ampoules under aspectic conditions. The solution may be packed under an inert atmosphere of nitrogen.

Claims (11)

1. Compounds of the general formula (1)

wherein R1 is a (a) a hydrogen atom; (b) C16 alkyl (c) C26 alkenyl; (d) C710 aralkyl (e) -CH2AR4, where A is -O- or -S- and R4 is C14 alkyl; (f) -CHR5CO2R4, where R5 is a hydrogen atom, methyl or phenyl; (g) -CH20COR6 where R6 is C14 alkyl, methoxy or phenyl; (h) pyridinyl; (i) 1 (acetyloxy)ethyl, (acetyloxy)phenylmethyl, tetrahydro-5-oxo-2-furanyl or tetrahydro-2-oxo-3-furanyl; (j) 4-(acetylamino)phenyl (k) 2,2,2-trichloroethyl; (I) furanylmethyl or (n)-(CH2)pN(R4)2 where p is 2 or 3; W is straight or branched C17 alkylene; X is cis or trans -CH=CH- or -CH2CH2-; n is 1 or 2; Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which has 5-8 ring members and (a) optionally contains in the ring -0-, -S-, -SO2-, or -NR7 (where R7 is a hydrogen atom, C1-7 alkyl or aralkyl having a C14 alkyl portion); and/or (b) is optionally substituted by one or more C14 alkyl groups; R2 is (i) straight or branched C15 alkyl substituted by (a) phenyl [optionally substituted by C16 alkyl, C5-7 cycloalkyl, phenylalkyl having a C12 alkyl portion, thienyl, phenyl (optionally substituted by C14 alkyl, C1-4 alkoxy or phenyl)], (b) thienyl [optionally substituted by C16 alkyl, C1-6 alkoxy, C6-7 cycloalkyl or phenyl (optionally substituted by C12 alkyl, C1-3 alkoxy or halogen)], or (c) naphthyl (optionally substituted by C14 alkyl or C14 alkoxy), or (ii) cinnamyl; and R3 is (i) C14 alkyl; (ii) -CH2AR4 where A is -O- or -S- (iii) C14 alkanoyl or benzoyl; (iv) -COOR4 or benzyloxycarbonyl; or (v) -CONHR5 and the physiologically acceptable salts and solvates thereof.

2. Compounds as described in claim 1 in which Y is morpholino or piperidino and R2 is a C15 alkyl group substituted by phenyl, which phenyl is substituted by phenyl, (C14 alkyl)phenyl or (C1 4 alkoxy) phenyl.

3. Compounds as claimed in claim 1 or claim 2 in which n is 2, X is cis -CH=CH- and W is -CH2CH2-.

4. Compounds as claimed in any of the preceding claims in which R' is a hydrogen atom, C1 6 alkyl or -CH2OCOR6 where R6 is C1 4 alkyl.

5. Compounds as claimed in any of the preceding claims in which R3 is C14 alkanoyl or C14 alkyl.

6. Compounds as claimed in claim 1 in which: R1 is a hydrogen atom, C1 6 alkyl, -CH2OCOR6 where R6 is C1 4 alkyl or -(CH2)2N(R4)2 where R4 is C14 alkyl, W is -CH2CH-, X is cis -CH=CH-, n is 2, Y is morpholino or piperidino, R2 is benzyl in which the phenyl group is substituted by phenyl, methylphenyl or methoxyphenyl, and R3 is C1 4 alkanoyl or C14 alkyl, and the physiologically acceptable salts and solvates thereof.

7. Compounds as claimed in claim 6 in which: R' is a hydrogen atom, methyl, -CH70COCH3, or -(CH2)2-N(CH2)2, R2 is biphenylmethyl, and R3 is acetyl or methyl.

8. Compounds as claimed in any of the preceding claims in which the carbon atom carrying the -(CH7),,XWCOOR group is in the R- configuration.

9. A compound as claimed in claim 1, said compound being: [1 R-[ 1 a(Z),2ss,3ss,5a]]-( +)-7-[3-(acetyloxy))-5-[[(1,1 'biphenyl)-4-yl]methoxy]-2-( 1 -piperidinyl) cyclopentyl]-4-heptanoic acid and its physiologically acceptable salts and solvates.

10. A pharmaceutical composition containing a compound as claimed in any of the preceding claims and one or more pharmaceutical carriers.

11. A process for the preparation of a compound as claimed in claim 1 which comprises: (a) in the preparation of a compound in which R3 is a group of the type (i) or (ii) and R' is other than a hydrogen atom, alkylating the corresponding compound in which R3 is a hydrogen atom; (b) in the preparation of a compound in which R' is a hydrogen atom and R3 is a group of the type (i) or (ii), hydrolysing a corresponding ester; (c) in the preparation of a compound in which R3 is a group of the type (iii) or (iv), esterifying the corresponding compound in which R3 is a hydrogen atom; ; (d) in the preparation of a compound in which R3 is a group of type (v), treating the corresponding compound in which R3 is a hydrogen atom with an appropriate isocyanate; (e) in the preparation of a compound in which R' is a hydrogen atom, removing the protecting group from a corresponding carboxylic acid having a protected carboxyl group; (f) in the preparation of a compound in which R' is other than a hydrogen atom, esterifying the corresponding carboxylic acid; or (g) in the preparation of a salt, treating a compound of formula (1) with an acid or (where R' is a hydrogen atom) a base.