AMINOCYCLOPENTANE ESTERS AND THEIR PREPARATION AND PHARMACEUTICAL FORMULATION

Abstract: Compounds are described of the formulae in which -COR¹ is a complex ester or haloester group, W is alkylene, X is cis or trans -CH=CH or -CH₂CH₂-, n is 1 or 2, Y is a saturated heterocyclic amino group having 5 - 8 ring members, and R² is unsubstituted or substituted phenylalkyl, thienylalkyl, naphthylalkyl or cinnamyl, and their salts and solvates. These compounds inhibit blood platelet aggregation and bronchoconstriction and may be formulated for use as antithrombotic and antiasthmatic agents.

Description: AMINOCYCLOPENTANE ESTERS AND THEIR PREPARATION AND PHARMACEUTICAL FORMULATION The endoperoxides prostaglandins G2 and H2 and thromboxane A2 are naturally occurring reactive re 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. The invention thus provides compounds of the general formula (la) and (ib) EMI1.1 wherein R1 is (a) -AR3 where A is -O- or -S- and R3 is phenyl [optionally substituted by C1-4 alkyl (e.g. methyl, ethyl or t-butyl), C1-4 alkoxy, (e.g. methoxy, ethoxy or butoxy), C14 alkanoyl (e.g. acetyl), methylthio, methylsulphinyl, methylsulphonyl, halogen (e.g. chlorine or bromine), -CO2R4 [where R4 is a hydrogen atom or C14 alkyl (e.g. methyl or ethyl) or phenyl], -NHCOR4 (e.g. acetamido), -CONR5R6 [where R5 and R6 may be the same or different and are each a hydrogen atom or C14 alkyl (e.g. methyl or ethyl)l, C1-4 alkylsulphonyl- amino (e.g. CH3SO2NH- or C2H5SO2NH-), formyl, nitro, cyano, phenyl or -NR5R6 (e.g. amino, dimethylamino or diethylamino)]; (b) -OCH2COR7 where R7 is phenyl [optionally substituted by a halogen atom (e.g. C1 or Br), C1-4 alkyl (e.g. methyl, ethyl or t-butyl) or C1-4 alkoxy, (e.g. methoxy, ethoxy or butoxy)] or -NH2; (c) -A(CH2)mBR5 where m is 1-3 and B is -O- or S-, provided that when m is 1, R5 is not a hydrogen atom (e.g. CH3OCH2O-, CH3CH2OCH2O-, CH3SCH2O- or HOC2H4O-); (d) -A(CH2)pR where p is 2 or 3 and R 8 is an N-attached C1-4 dialkylamino (e.g. dimethyl- or diethylamino) morpholino, piperidino, pyrrolidino, acetylamino or benzoylamino group; (e) -OCH(CH2N (CH3)2)2; EMI2.1 where R9 is a hydrogen atom, methyl or phenyl; examples of suitable R5 groups being methyl and ethyl; (g) -OCH2OCOR10 where R10 is C1-4 alkyl (e.g. methyl or ethyl), methoxy or phenyl; (h) -OCH2SCOR11 where R11 is C1-4 alkyl (e.g. methyl or ethyl); (i) pyridinyloxy or pyridinylthio; (j) l-(acetyloxy)ethoxy, (acetyloxy)phenylmethoxy, tetrahydro-5-oxo-2-furanyloxy, tetrahydro-2-oxo-3furanyloxy, triphenylmethoxy or diphenylmethoxy; or (k) -OR12 where R12 is C3-6 alkenyl (e.g. propenyl or butenyl), C5-7 cycloalkyl (e.g. cyclopentyl, cyclohexyl or cycloheptyl) optionally substituted by one or more C1-4 alkyl (e.g. methyl, ethyl or t-butyl) groups, -CH2CC13 or furanylmethyl; n is 1 or 2; W is straight or branched C1-7 alkylene; X is cis or trans -CH=CH- or -CH2CH2-; 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 -O-, -S-, -SO2-, or NR13 (where R13 is a hydrogen atom, C17 alkyl or aralkyl having a C14 alkyl portion); and/or (b) is optionally substituted by one or more C1-4 alkyl groups; Rê is (i) straight or branched C1-5 alkyl substituted by (a) phenyl [optionally substituted by C1-6 alkyl, C5-7 cycloalkyl, phenylalkyl having a C1-3 alkyl portion, thienyl, phenyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or phenyl) , benzoyl (optionally substituted by C14 alkyl, C1-4 alkoxy, halogen, trifluoromethyl or phenyl) or C57 cycloalkanoyl], (b) thienyl [optionally substituted by C57 cycloalkyl or phenyl (optionally substituted by C1-3 alkyl, C1-3 alkoxy or halogen)] or (c) naphthyl (optionally substituted by C14 alkyl or C14 alkoxy), or (ii) cinnamyl (optionally substituted by benzoyl); and the physiologically acceptable salts and solvates 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 amino group Y enables the compounds to form salts with acids. Compounds of formula (la) can form salts with inorganic or organic acids, e.g. hydrochlorides or maleates, and compounds of formula (lb) can form salts with organic acids. Also, when the group R1 contains a -COOH group, salts may be formed with bases. Examples of such salts are alkali metal (e.g. sodium), alkaline earth metal (e.g. calcium) and amine (e.g. piperazine) salts. The heterocyclic amino group Y may for example have a 5,6 or 7-membered ring, e.g. pyrrolidino, piperidino, morpholino, piperazino, thiomorpholino, l,l-dioxothiomorpholino, homomorpholino and hexamethylene imino. Examples of the optional substituents which may be present on a second nitrogen atom in the ring are methyl, ethyl and benzyl. The carbon atoms of the heterocyclic rings may for example be substituted by methyl or ethyl. Y is preferably a morpholino or piperidino group. In the group -(CH2)nXWCORÚ, n is preferably 2. X is preferably a cis -CH=CH- group. The W group 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 -CH2CH2CH2CH2- when n is 2. In the RÚ groups, A (where present) is preferably -O-. In RÚ groups of the type (a), R is preferably phenyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyl, methylsulphonyl, -COOR4 (where R4 is a hydrogen atom or C alkyl) , -NHCOR (where R4 is C1-4 alkyl) or -CONR5R6). In RÚ groups, of the type (b), R7 is preferably -NH2, phenyl or halophenyl. In RÚ groups of the type (c), m is preferably 1 or 2 and R5 is preferably C1-4 alkyl. In R1 groups of the type (d), R8 is preferably C1-4 dialkylamino, morpholino or acetylamino. In RÚ groups of the type (f), R9 is preferably methyl and R5 is preferably C1-4 alkyl. Particularly preferred R1 groups are -OCH2OCOCH3, -OCH2SCH3, -OCH2CH2CH2NHCOCH3, -OCH2CONH2, 4-acetamidophenoxy and allyloxy. When R2 is a 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 Rê groups of the type (i) (a), the phenyl group may be substituted by, for example, methyl, ethyl, t-butyl, cyclohexyl, benzyl, phenethyl, phenyl (optionally substituted by methyl, ethyl, methoxy or butoxy), benzoyl (optionally substituted by methyl, ethyl, methoxy, butoxy, chlorine or bromine) or cyclohexanoyl 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 substituted by methyl, ethyl, methoxy, ethoxy, chlorine or bromine) groups. Rê is preferably a benzyl group in which the phenyl group is substituted by thienyl or phenyl (which phenyl group may itself be optionally substituted by C14 alkyl or C14 alkoxy). Particularly preferred R2 groups are benzyl groups in which the phenyl portion is substituted (preferably in the para-posiion) by a phenyl, tolyl or methoxyphenyl substituent. A particularly preferred group of compounds has the formula (la) or (lb) in which: R1is -OCH2OCOCH3, -OCH2SCH3, -OCH2CH2CH2NHCOCH3, -OCH2CONH2, 4-acetamidophenoxy, or allyloxy, W is -CH2CH2 - n is 2 X is cis -CH=CH-, Y is morpholino or piperidino in compounds of formula (lb) or is piperidino in compounds of formula (la), and R2 is benzyl in which the phenyl group is substituted by phenyl, tolyl or methoxyphenyl and the physiologically acceptable salts and solvates thereof. In general, the compounds of formula (1) in which the carbon atom carrying the -(CH2)nXWCORl group is in the P- configuration (and mixtures containing this isomer) are preferred. Compounds of formula (la) are also generally preferred. Compounds of formula (1) inhibit blood platelet aggregation and bronchoconstriction. A test to determine inhibition of blood platelet aggregation is as described by G.V. Born in Nature 194, 927-929 (1962) except in that collagen is used instead of ADP as the proaggregatory agent. Alternatively, starved guineapigs 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 (Nature 194, 927-929, (1962)). Collagen concentrationeffect 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 [lR-[la, 4a, 5ss(Z), 6a-(1E, 3S*)1 -7-[6-(3-hydroxy-l-octenyl)-2-oxabicyclo [2,2,1Jhept-5-yl]-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 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 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. They 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, syrups, or suspensions 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. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, e.g. sterile pyrogen-free water. For administration by inhalation the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurised 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 pressurised 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 the compounds of the invention are described below, the groups R1 R2, R3, R5, A, B, W, X and Y being as defined above except where otherwise indicated. (a) The compounds of of the invention may be prepared by esterification of the corresponding carboxylic acid, i.e. a compound in which RÚ represents a hydroxyl group. Conventional esterification methods may be used. For example, compounds in which R1 is a group of the type a, c (other than those in which m is 1), d, e, f, and k may be prepared by treating a reactive derivative of the corresponding carboxylic acid with an appropriate alcohol or thiol R1H. The reactions may for example be carried out at room temperature using a solvent such as a ketone (e.g. methylethyl ketone or acetone) or acetonitrile 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 -10 0C. The chloroformate may for example be a C16 alkyl (e.g. iso-butyl), aryl (e.g. phenyl) or aralkyl (e.g. benzyl) chloroformate. The same group of esters may also be prepared by first reacting the corresponding carboxylic acid with dicyclohexylcarbodiimide in the presence of 4pyrrolidinopyridine, and then treating the product with the alcohol or thiol R1H. This reaction is conveniently performed at room temperature in a solvent such as ether or CH2C12. Again for example, compounds in which R1 is a group of the type b, c, d, f, g, h, or j and A (when present) is -0- may be prepared by reacting the corresponding carboxylic acid with an appropriate halide R14 Hal, where Hal represents halogen and R14 is as just defined for RÚ, excluding the terminal -O-. The reaction is carried out in the presence of a suitable base, e.g. potassium t-butoxide or potassium carbonate or a sterically hindered amine such as N,N-diisopropylethylamine, triethylamine or dicyclohexylamine in a suitable solvent (such as acetonitrile, dimethylformamide, CH2C12 or a ketone, e.g. methylethyl ketone or acetone), for example at a temperature from 0 C to room temperature. This latter reaction may also be used to prepare compounds in which R1 is a group of type (c) in which A is -S- and m is 1, by reacting the corresponding thioacid (i.e. in which R1 is -SH) with a halide R5BCH 2 Hal. The thioacid starting material may be prepared in situ by treating a reactive derivative of the corres ponding carboxylic acid (e.g. a mixed anhydride, as above) with a hydrosulphide (e.g. NaHS). Compounds in which R1 is a group of the type (f) where A is -0- may also be prepared by reacting the corresponding carboxylic acid with the appropriate diazoalkane in a solvent such as dioxan in the presence of a salt such as copper (II) chloride, for example at room temperature. Compounds in which R1 is a group of the type (i) where A is -S- may also be prepared by reacting the corresponding carboxylic acid with the appropriate pyridyldisulphide in the presence of triphenylphosphine in a solvent such as benzene, for example at room temperature. Many of the carboxylic acids corresponding to the esters of formula (lib) required as starting materials for process (a), i.e. compounds of formula (2) EMI9.1 are described in British Patent Specifications 2028805A, 2070591A and 2075503A and those containing other R2 groups may be prepared by the same general methods, using starting materials containing the desired R2 group. Carboxylic acids required as starting materials for the preparation of compounds of formula (la) by process (a) may be prepared by selective reduction of the corresponding acid of formula (2) using for example a selective reducing agent such as lithium tri-sec-butylborohydride in a solvent such as tetrahydrofuran at a temperature from 0 to -78"C. Where a carbonyl group is present in R2 this will need to be in a protected state during this reaction. Conventional protection methods may be used, with regard to the reducing conditions. (b) The compounds of the invention may also be prepared by reduction of a corresponding compound in which X is an acetylene group. Suitable methods of reduction include using hydrogen in the presence of a catalyst, e.g. palladium on a support (e.g. CaCO3 or BaSO4) and poisoned for example by lead or quinoline. Suitable solvents include ethyl acetate and methanol. This reaction is particularly suitable for preparing compounds in which X is cis -CH=CH-. The acetylenes required as starting materials may be prepared by first brominating (e.g. with bromine in CH2C12) a compound of formula (3) EMI10.1 (where R15 is C16 alkoxy, e.g. methoxy) to give the corresponding compound in which X is -CHBr.CHBr-. The latter dibromo compound is then dehydrobrominated to form the acetylene group, for example in two stages, using potassium t-butoxide first at 0 C and then at room temperature. Hydrolysis of the resulting acetylene ester to the corresponding acid (RÚ=OH) using a base such as NaOH at e.g. room temperature, followed by oxidation of the ring hydroxy group (using e.g. chromic acid in acetone at a low temperature e.g. -20 C to room temperature) gives a corresponding acid of formula (lb) in which X is an acetylene group and R1 is -OH. Reduction of the product using e.g. lithium tri-secbutylborohydride as described above for method (a) gives a corresponding compound of formula (la) in which X is an acetylene group and R is -OH. Esterification of the acetylene acids as described in method (a) then gives the required acetylene ester starting materials. The starting materials of formula (3) may be prepared by the methods generally described in British Patent Specifications 2028805A, 2070591A and 2075503A. (c) Compounds in which R1 is a group of type (a) in which R3 is phenyl substituted by amino may be prepared by reduction of the corresponding compound in which R3 is phenyl substituted by azido. The reduction may for example be effected with zinc and potassium dihydrogen phosphate in a suitable solvent, e.g. tetrahydrofuran. (d) Compounds in which X is -CH2CH2- may be prepared by catalytic hydrogenation of a correspond ing compound in which X is -CH=CH-, using a catalyst such as palladium oxide. Alcohols such as ethanol are suitable solvents and the reaction may be performed at room temperature. (e) Compounds of formula (lb) may be prepared by oxidising a corresponding hydroxy compound, e.g. a compound of formula (4) EMI11.1 Suitable methods of oxidation include using a Cr vi oxidising reagent in a suitable solvent, e.g. chromic acid in acetone (e.g. Jones reagent, preferably used in the presence of a diatomaceous silica such as Celite) or CrO3 in pyridine. These reagents are for example used at temperatures of -20 C to room temperature. Other important methods include using an activated sulphur reagent, e.g. (i)N-chlorosuccinimide- dimethylsulphide complex in a suitable solvent (e.g. toluene or dichloromethane) at temperatures of for example -25 to 25 C, preferably at 0-50C, (ii) a dialkylsulphoxide (e.g. dimethylsulphoxide) activated by a suitable electrophilic reagent (such as oxalyl chloride, acetyl bromide or thionyl chloride) in a suitable solvent (e.g. toluene or dichloromethane), e.g. at -70 to -20"C; dicyclohexylcarbodiimide can also be used as the electrophilic reagent (preferably in the presence of CF3COOH or its pyridinium salt) at for example -10eC using the same solvents, or (iii) pyridine-SO3 complex in dimethylsulphoxide, preferably at 00C to room temperature. When Y is in the a-configuration conditions should be chosen to effect epimerisation, either at the same time or after oxidation. The esters of formula (4) may be prepared by esterification of the corresponding carboxylic acid in which R1 is a hydroxyl group, for example using the methods described above in connection with process (a). The carboxylic acid starting materials may be prepared by the methods generally described in British Patent Specifications 2028805A, 207059lA and 2075503A. Compounds of formula (lb) in which the ester group is sensitive to oxidation are preferably prepared by the esterification process (a). (f) Compounds of formula (1b) in which RÚ is -OCH2SCH3 may be prepared by simultaneous oxidation and ester fiction of the corresponding hydroxy carboxylic acid, i.e. a compound of formula (4) in which R1 is -OH. This reaction may be performed by treating the hydroxy carboxylic acid with dimethylsulphoxide in the presence of an electrophilic reagent, for example as described above for process (e), preferably using dicyclohexylcarbodiimide in the presence of pyridinium trifluoroacetate. The reaction is preferably carried out at room temperature. (g) Where salts of compounds of formula (1) are desired such salts may be formed by conventional methods, for example by treatment with an acid or when R1 contains a -COOH group, with a base. Salts of acids may be prepared by adding the acid to a solution of the compound of formula (1) in an organic solvent such as ether. Salts of bases may be prepared by adding the base (e.g. an amine such as piperazine) in a solvent such as ether. When a specific enantiomer of formula (1) is required, starting materials having the desired stereochemical configuration should be used in the above processes. Such starting materials may for example be prepared from an enantiomeric bromohydrin as generally described in British Patent Specification 2075503A. The following test results were obtained with the compounds of the invention. Inhibition of Blood Platelet Aggregation Starved guinea pigs were dosed orally (lmg/kg) with the compound to be tested in 1% NaHCO3 solution. Platelet rich plasma was prepared from each animal and aggregation to a range of collagen concentrations (0.2ug/ml - 20ug/ml) was measured after the method of Born (Nature 194., 927929 (1962). Collagen concentration-effect curves for each sample of plasma were calculated. Thus for example the compounds of Examples la, 2a, 2b, 2c, 2i, 2j, 21, 2m, 3a, 3b, 3c, 4, 5, 6a, 7, 9a, 10, 11, 12, 13, 14, 15, 16c, 16g, 16h, 16i, 17, l9a, 20, 23a, 23c, 24a, 24b, 25, 28 and 30 produced shifts of the curves greater than 2.or. Toxicity The compounds of the invention are non-toxic at therapeutically useful doses. Thus for example, the compounds of the examples produced no adverse effects when administered orally to guinea pigs at a dose of lmg/kg. The following examples illustrate the invention. 'Jones reagent' is a solution of chromic acid and sulphuric acid in water. A 2.67M solution contains Cr03 (26.7q) and concentrated H2SO4 (23ml) made up to 100ml with water. Temperatures are in C. The following abbreviations are used: 'Dried' refers to drying with MgSO4; T.L.C. - thin layer chromatography using SiO2; PE - petroleum ether (boiling at 40-60 unless otherwise stated); THF - tetrahydrofuran; DMF - dimethylformamide; ER - ether; EA - ethyl acetate;DMSO - dimethylsulphoxide; IPA - isopropyl alcohol; DIBAL - diisobutylaluminium hydride. Chromatography was carried out using silica gel unless otherwise stated. The following abbreviations define the eluent used for the chromatography and T.L.C. (A) 19:1 EA-CH2C12 (B) 9:1 ER-methanol (C) ER (D) 92:8 EA-methanol (E) EA (F) 9:1 EA-methanol (G) 19:1 ER-methanol (H) 4:1 ER-PE (b.p. 60-80 ) (I) 49:1 ER-methanol (J) 2:1 ER-PE (b.p. 60-80 ) (K) 2:1 ER-PE (L) 1:1 ER-PE (b.p. 60-80") (M) 3:1 ER-PE (N) 4:1 ER-PE (0) 4:1 ER-methanol (P) 39:1 ER-methanol (Q) 3:1 EA-PE (R) 94:5:1 ER-methanol-Et3N (S) 1:1 ER-PE (T) 7:3 ER-isopentane (U) 65:35 ER-PE (b.p. 60-80 ) (V) 7:3 ER-PE (b.p. 60-80 ) (W) 9:1 ER-PE (b.p. 60-80 ) (X) 4:1 PE (b.p. 60-80 )-EA (Y) 75:24:1 ER-PE-CH2C12 (Z) 3:1 ER-CH2C12 (AA) 5:4 PE (b.p. 60-80 ):ER (BB) 13: :9 EA-PE (b.p. 60-80 ) (CC) 3:1 ER-PE (b.p. 60-80 ) (DD) 13:7 PE (b.p. 60-80 )-EA (EE) 7:3 ER-PE (FF) 4:1 EA-methanol (GG) 24:1 ER-methanol (HH) 21:4 ER-methanol (II) 4:1 EA-PE (b.p. 60-80 ) (JJ) 3:1 ER-isopentane (KK) 13:7 ER-PE (b.p. 60-80 ) (LL) 99:1 EA-Et3N (MM) 199:1 EA-Et3N (NN) 97:3 EA-CH30H (OO) 75:24:1 CH2Cl2-ER-Et3N (PP) 80:20:1 CH2Cl2-ER-Et3N (QQ) 66:34:1 CH2Cl2-ER-Et3N (RR) 95:5:0.5 EA-CH3OH-Et3N (SS) 4:1 PE-ER (TT) 2:1 EA-CH30H (UU) 1:1 EA-PE (b.p. 60-80 ) (W) 50:50:1 CH2C12-ER-Et3N (WW) 90:10:1 CH3OH-Et3N The preparation of Intermediates 1-20 is described in British Patent Specification 2075503A. Intermediate 1 [la(Z),2,5a]-(+)-7-[5-[[(l,l -Biphenyl)-4-yl]methoxy]2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid. Intermediate 2 [1&alpha;(Z),2ss,5&alpha;]-(#)-7-[5-[[4'-Methoxy(1,1'-biphenyl)4-yl]methoxy]-3-oxo-2-(4-thiomorpholinyl)cyclopentyll- 4-heptenoic acid, S-dioxide. Intermediate 3 [1&alpha;(Z),2ss,5&alpha;]-(#)-7-[2-(4-Morpholinyl)-3-oxo-5-[4- (phenylmethyl) phenylmethoxy] cyclopentyl] -4-heptenoic acid, compound with piperazine (2:1). Intermediate 4 [1&alpha;(Z),2ss,5&alpha;(E)]-(#)-7-[2-(4-Morpholinyl)-3-oxo-5- [(3-phenyl-2-propenyl)oxy]cyclopentyl]-4-heptenoic acid. Intermediate 5 [1&alpha;(Z),2ss,5&alpha;]-(#)-7-[5-[[1,1'-Biphenyl)-4-yl]methoxy]- 3-oxo-2-(4-thiomorpholinyl)cyclopentyl]-4-heptenoic acid. Intermediate 6 [1&alpha;(Z),2ss,5&alpha;]-(#)-7-[3-Hydroxy-5-[[4'-methoxy(1,1'- biphenyl)-4-y]methoxy]-2-(4-morpholinyl)cyclopentyl]4-heptenoic acid. Intermediate 7 [la(Z) ,2,3a,5 -(+) -7-[3-Hydroxy-5-[ [4'-methyl(l,l'- biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)cyclopentyl]4-heptenoic acid. Intermediate 8 [1&alpha;(Z),2ss,3&alpha;,5&alpha;(E)]-(#)-7-[3-Hydroxy-2-(4-morpholinyl)5-1 (3-phenyl-2-propenyl) oxy] cyclopentyl -4-heptenoic acid. Intermediate 9 [latZ),2S,3a,5a]-(+)-7-[5[[(1,1'-Biphenyl)-4-yllmethOxy]- 3-hydroxy-2-(1--piperidinyl)cyclopentyl]-4-heptoic acid. Intermediate 10 [1R-[1&alpha;(Z),28,5&alpha;]-(-)-7-[5-[[(1,1-Biphenyl)-4-yl]methoxy]- 2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptoic acid. Intermediate 11 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-7-[5-[3-[(1,1'-Biphenyl)-4-yll]propoxy] 3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-heptenoic acid. Intermediate 12 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-9-[5-[[(1,1'-Biphenyl)-4-yl]methoxy] -3-hydroxy-2-(4-morpholinyl)cyclopentyl]-6-nonenoic acid. Intermediate 13 [la(Z) ,2,3a,5 -(+)-7-[3-Hydroxy-5-[ [3'-methoxy(l,l'- biphenyl)-4-ylzmethoxy]-2-(4-morpholinyl)cyclopentyll- 4-heptenoic acid. Intermediate 14 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-7-[3-Hydroxy-2-(4-morpholinyl)- 5-[(2-phenylthien-4-yl)methoxy]cyclopentyl]-4-heptenoic acid. Intermediate 15 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-7-[3-Hydroxy-5-[[4'-methyl(1,1'biphenyl)-4-yllmethoxy]-2-(4-thiomorpholinyl)cyclo- pentyl] -4-heptenoic acid, S-dioxide. Intermediate 16 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-7-[3-Hydroxy-2-(4-morpholinyl)- 5-[4-(thien-2-yl)phenylmethoxy]cyclopentyl]-4-heptenoic acid. Intermediate 17 [la(Z) ,2B,3a,5al-I+)-7-[ 3-Hydroxy-2- (4-morpholinyl)- 5-(2-naphthalenylmethoxy)cyclopentyl]-4-heptenoic acid. Intermediate 18 [la(Z),2a,3a,5a]-(+)-7-[5-[[(1,1'-Biphenyl)-4-ylamethoxy]- 3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-heptenoic acid. Intermediate 19 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]- 3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-heptenoic acid. Intermediate 20 (1&alpha;,2ss,5&alpha;)-(#)-7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]- 2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptynoic acid. Intermediate 21 (a) [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-(Acetyloxy)methyl 7-[5-[[(1,1' Biphenyl)-4-yllmethoxyl-3-hydroxy-2-(4-morpholinyl)cyclo- pentyll-4-heptenoate, m.p. 69-71 from Intermediate 18 by the procedure described for the preparation of Example 3a (Method 1). Purification by chromatography (A).I.R. (CHBr3) 3480, 1760cm 1. The following compounds were prepared by a similar procedure: (b) (1&alpha;,2ss,5&alpha;)-(#)-(Acetyloxy)methyl 7-[5-[[(1,1' B iphenyl) -4-yl] methoxy] -2- (4-morphol inyl) -3-oxocyclo- pentyl]-4-heptynoate, from Intermediate 20. Purification by chromatography (C) gave the title compound as an oil. I.R. (Neat) 1760, 1740cm-1. (c) [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-(Acetyloxy)methyl 7-[3 Hydroxy-2-(4-morpholinyl)-5-[4-(thien-2-yl)phenylmethoxy]cyclopentyl]-4-heptenoate, from Intermediate 16. Purification by chromatography (F) gave the title compound as an oil. I.R. (Neat) 3430, 1765cm Intermediate 22 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-Methoxymethyl 7-[5-[3-[(1,1' Biphenyl)-4-ylgpropoxy]-3-hydroxy-2-(4-morpholinyl)cyclo- pentyl]-4-heptenoate Chloromethylmethyl ether (0.008 ml) was added to a mixture of Intermediate 11 (0.05 g) and dicyclohexylamine (0.02 ml) in dry DMF (0.75 ml). After 10 min saturated NH4C1 solution (10 ml) was added and the suspension extracted with EA (3x20 ml). The combined extracts were dried, filtered and evaporated to afford the title compound as an oil (0.042 g). I.R. (Neat) 3400, 1740cm 1, Intermediate 23 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-(methylthio)methyl 9-[5-[[(1,1' Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-6-nonenoate From Intermediate 12 (1.25 g), chloromethyl methyl sulphide (0.61 ml) and diisopropylethylamine (1.5 ml) according to the method described for the preparation of Intermediate 22. Purification by chromatography (D) gave the title compound as an oil (0.37 g). I.R. (CHBr3) 3430, 1733cm 1. Intermediates 24-27 were prepared by a similar procedure to that of Example 2a (Method 1). Intermedate 24 [lcx(Z) ,28 r3a,5a] - (+)-4-(Acetylamino)phenyl 7-[3-Hydroxy- 5-[[3'-methoxy (1,1'-biphenyl)-4-yl]methoxy]-2-(4morpholinyl)cyclopentyl]-4-heptenoate From Intermediate 13 and 4-(acetylamino)phenol, in pyridine. Purification by chromatography initially using (E) then (F) gave the title compound as a foam. I.R. (CHBr3) 3580, 3430, 1755, 1690, 1510cm 1. Intermediate 25 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-4-Methylphenyl 7-[3-Hydroxy-2 (4-morpholinyl)-5-1(2-Phenylthien-4-yl)methoxyacyclo- pentyl]-4-heptenoate From Intermediate 14 (0.26g) and p-cresol (0.286 g). Purification by chromatography (D) gave the title compound as an oil (0.127 g). I.R. (Neat 3450, 1755cm 1 Intermediate 26 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-4-(Methylsulphonyl)phenyl 7-[3 Hydroxy-5-[[4'-methyl(1,1'-biphenyl)-4-yl]methoxy]2-(4-thiomorpholinyl)cyclopentyl]-4-heptenoate, Sdioxide From Intermediate 15 (0.284 g) and 4-(methylsulphonyl)phenol (0.473 g) using CH3CN as solvent. Purification by chromatography (G) gave the title compound as a foam (0.312 g). I.R. (CHBr3) 3580, 3550, 1760cm 1. Intermediate 27 [la(Z) ,28 r 3a,5a'j - (+)-L-(-)-[l-tEthoxycarbonyl)ethyll 7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1piperidinyl)cyclopentyl]-4-heptenoate Prepared from Intermediate 9 (0.6 g) and L-ethyl lactate (0.385 g) using CH3CN as solvent. Chromatography (B) gave a mixture (1:1) of the title compound and [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-2-methylpropyl 7-[4-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]4-heptenoate as an oil (0.22g). I.R. (CHBr3) 3600, 1730cm-1. Intermediate 28 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-(Acetylthio)methyl 7-[5-[[(1,1' Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoate From Intermediate 9 according to the procedure described for Example 8. Purification by chromatography (F). I.R. (Neat) 3360, 1740, 1705cm 1. Intermediate 29 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-[2-(4-Bromophenyl)-2-oxoethyl] 7-[3-Hydroxy-2- (4-morpholinyl) -5- (2-naphthalenylmethoxy) cyclopentyl]-4-heptenoate Intermediate 17 and 4-bromophenacyl bromide in an analogous manner to the preparation of Example 6a. Purification by chromatography initially using (G) followed by (B). I.R. (Neat) 3450, 1740, 1700 cm-1. The preparation of Intermediate 30 is described in British Patent Specification 2028805A. Intermediate 30 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]- 2-(4-morpholinyl)-3-oxocyclopentyl]-5-heptenoic acid Intermediate 31 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-7-[5-[[(1,1'-Biphenyl)-4-yl]- methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-5heptenoic acid, compound with piperazine, (2:1) A solution of Intermediate 30 (lg) in THF (10 ml) was added dropwise to a stirred solution of lithium tri-sec-butylborohydride (1M in THF; 12 ml) under nitrogen at 0 - 5e. After 2.25h, the mixture was poured into 2N.H2 SO4 (30 ml) and pH 6.5 phosphate buffer (50 ml) and washed with ER. The aqueous layer was adjusted to pH 6.5 with 2N NaOH and extracted with EA (3 x 50 ml). The combined extracts were dried, evaporated and the residue purified by chromatography (FF) to give a foam (0.81 g). A portion of the foam (0.105 g) in ER (30 ml) was treated with piperazine (20.3 mg) in ER (1.8 ml) to give the title compound as a solid (0.11 g), m.p. 121 - 127 . The preparation of Intermediates 32-34 is described in British Patent Specification 2028805A. Intermediate 32 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-Methyl 7-[5-Hydroxy-2-(4-morpho linyl)-3-1(tetrahydro-2B-pyran-2-yl)oxygcyclopentyla- 5-heptenoate Intermediate 33 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-7-[5-[[(1-1'-Biphenyl)-4-yl]- methoxyl-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-5heptenoic acid Intermediate 35 4- (Bromomethyl) phenyl-4-methoxyphenyl methanone Benzoyl peroxide (lg) was added to a solution of 4methoxyphenyl-4-methylphenyl methanone (22.6g) and N-bromosuccinimide (17.8g) in CC14 (100 ml). The mixture was heated under reflux for 3.25h, then cooled to 00. The precipitated succinimide was filtered off, the filtrate evaporated and the residue purified by crystallisation from cyclohexane to give the title compound (8.9 g), m.p. 76 - 78 . Intermediate 36 lla(Z)2S3a5a (+)-7-[5-[4-(4-MethoxySenzoyl)phenyl- methoxy]-2-(4-morpholinyl)-3-[(tetrahydro-2H-pyran 2-yl)oxylcyclopentyl7-5-heptenoic acid NaH (74% dispersion in oil, 0.74g) was added in portions over 4.5h to a solution of Intermediates 32 (0.93g) and 35 (2.77g) in DMF (10 ml). After a further lh, the mixture was diluted with water (100 ml). Saturated NH4C1 solution (100 ml) was added, the mixture extracted with CH2C12 (4 x 50 ml), the combined extracts were dried and evaporated and the residue purified by chromatography using gradient elution (I) up to (HH) to give the title compound as an oil (1.lg). I.R. (CHBr3) 3500, 1730 - 1700(br), 1666cm 1. Intermediate 37 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-7-[3-Hydroxy-5-[4-(4-methoxybenzoyl)phenylmethoxyi -2- (4-morpholinyl) cyclopentyl] -5-heptenoic acid A solution of Intermediate 36 (0.89g) in acetone (40 ml) and saturated ethereal hydrogen chloride (15 ml) was kept at ambient temperature for 4.5h. The solvents were removed in vacuo and the residue in pH 6.5 phosphate buffer (50 ml) was extracted with CH2C12 (3 x 40 ml). The combined extracts were dried and evaporated and the residue purified by chromatography (HH) to give the title compound (0.33g). I.R. (CHBr3) 1730 1700 (br.), 1665cm1 Intermediate 38 [la(Z) Z),2ss,3a,5al-(-)-2-Oxo-2-phenylethyl 7-[5-[[(l,1'- Biphenyl) -4-yli methoxyi -3-hydroxy-2- (4-morpholinyl) - cyclopentyli -5-heptenoate A suspension of Intermediate 33 (lg) in water (10 ml) was treated with potassium t-butoxide (0.234g) and the resulting solution was added to a solution of phenacyl bromide (0.6g) in ethanol (10 ml). The mixture was heated under reflux for 4h, poured into water and extracted with ER. The combined extracts were dried and evaporated and the residue purified by chromatography (G) to give the title compound as an oil (0.99). I.R. (CHBr3) 3540 (br.), 1740, 1705cm 1. Intermediate 39 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-4-Acetylaminophenyl 7-[5-[[(1,1' Biphenyl) -4-y11 methoxyl -3-hydroxy-2- (4-morphol inyl) - cyclopentyl) -5-heptenoate Isobutylchloroformate (0.82 ml) was added to a stirred solution of Intermediate 33 (lg) and triethylamine (1.16 ml) in acetone (10 ml) at -10 . After 0.6h, N-(4-hydroxyphenyl)acetamide (1.26 g) in acetone (24 ml) containing pyridine (7 drops) was added and stirring continued for a further 0.6h. The solvent was removed in vacuo and saturated NH4C1 solution (80 ml) added. The mixture was extracted with EA (2 x 60 ml), the dried extracts evaporated and the residue purified by chromatography (B) to give the title compound as an oil (1.13 ). I.R. (CHBr3) 3425, 1748, 1685cm 1. The preparation of Intermediates 40-42 is described in British Patent Specification 2070591A. Intermediate 40 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-7-[3-Hydroxy-2-(4-morpholinyl)5-[4- (phenylmethyl) phenylmethoxyi cyclopentylj -5-heptenoic acid, hydrochloride Intermediate 41 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-7-[3-Hydroxy-2-(4-morpholinyl)5-[ [ (1,1': :4' ,l"-terphenyl) -4-yl] methoxy'j cyclopentyl- 5-heptenoic acid, hydrochloride Intermediate 42 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-7-[3-Hydroxy-5-[[(4'methoxy(1,1'biphenyl) -4-yll methoxyl -2- (4-morpholinyl) cyclopentyli - 5-heptenoic acid, hydrochloride Intermediate 43 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-[4-(Aminocarbonyl)phenyl) 7-[3 Hydroxy-5-[[(4'-methoxy(1,1'-biphenyl)-4-yl]methoxy]2-(4-morpholinyl)cyclopentyl]-5-heptenoate A solution of the base derived from Intermediate 42 (0.5g) and triethylamine (0.28 ml) in dry CH3CN (30 ml) at -10 was treated with iso-butylchloroformate (0.26 ml) and 0.5h later with 4-hydroxybenzamide (0.685 g) and dry pyridine (10 ml). After 1.5h the mixture was poured into pH 6.5 phosphate buffer (100 mly, extracted with EA (2 x 100 ml), the combined extracts were washed with water (50 ml), dried and evaporated, and the residue purified by chromatography (HH) to give the title compound as a foam (0.49 g). I.R. (CHBr3) 3520, 3400, 1755, 1675Cm Intermediate 44 [1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(#)-(Acetylthiomethyl) 7-5[[(1,1' Biphenyl) -4-yl} methoxy) -3-hydroxy-2- (4-morpholinyl) - cyclopentylf -5-heptenoate A mixture of Intermediate 33 (0.4 g), bromomethyl thioacetate (0.42 g) and anhydrous K2CO3 (0.23g) in dry DMF (9 ml) was stirred at 20 for 5.5h. The mixture was poured into pH 6.5 phosphate buffer (175 ml), extracted with EA (3 x 60 ml), the combined extracts dried and evaporated, and the residue purified by chromatography (G) to give the title compound as an oil (0.34g). I.R. (CHBr3) 3520, 1732, 1695 cm-1. The preparation of Intermediate 45 is described in British Patent Specification 2075503A. Intermediate 45 [lR-(exo,endo))-(-)-2-Bromo-3-hydroxybicyclo[3.2.0]heptan- 6-one Intermediate 46 [lR-(endo,anti)-t+)-5-Hydroxy-7-(1-piperidinyl)bicyclo [2.2.1]heptan-2-one A solution of Intermediate 45 (5.25g) in acetone (50ml) containing piperidine (6.3ml) was stirred at 20 for 2.5h in the dark. The mixture was poured into 8% NaHCO3 solution (150ml) and extracted with CH2C12 (3 x 100ml). The combined extracts were dried and evaporated and the residue was purified by chromatography (C). The title compound was obtained as a solid (4.7g). A portion was recrystallised from ER-PE to give material of m.p. 87-88 . [&alpha;]DF25.5=68.7 (CHCl3) Intermediate 47 [1R-(endo,anti)]-(+)-5-[[(1,1'-Biphenyl)-4-yl]methoxy]7-(1-piperidinyl)bicyclo[2.2.1]heptan-2-one A mixture of Intermediate 46 (4.34g) , benzyltriethylammonium chloride (29) and biphenylmethyl bromide (6.7g) in CH2C12 (100 ml) and 17N NaOH (60 ml) was stirred vigorously at 20 for 18h. The phases were separated and the aqueous phase, diluted with water (100 ml), was extracted with CH2C12 (3 x 100ml). The combined organic layers were washed with water (100 ml), dried and evaporated and the residue was purified by chromatography (SS through to S). The title compound was obtained as a solid (6.2g). A portion was recrystallised from EA-PE (b.p. 60-80 ) to give material of m.p. 108-110 . [&alpha;]D22 = +25.45 (CHCl3) Intermediate 48 [lR-(endo,anti)]-(-)-6-[[ (l,l'-Biphenyl)-4-yljmethoxy]- 8-(l-piperidinyl) 2-oxabicyclo[3.2.lloctan-3-one Peracetic acid (13ml; 6.12 M) was added dropwise to stirred solution of Intermediate 47 (5.8 g) in CH2C12 (150 ml) at 20 . The mixture was stirred for 20h, then diluted with water (250ml). The phases were separated and the aqueous layer was extracted with CH2C12 (l00ml). The combined organic layers were added to a cold (0 ) saturated solution of Na2SO3 (150ml), then stirred vigorously at 20 for 1.5h. The mixture was diluted with isopropyl acetate (200ml) and the phases were separated. The aqueous layer was extracted with isopropyl acetate (2 x 100ml) and the combined organic layers were washed with 0.5N NaOH (looms) and brine (150ml), then dried and evaporated. The residue was purified by chromatography (EE) to give a solid which was recrystallised from ER-PE (b.p. 60-80 ) to give the title compound as a colourless solid (2.39), m.p. 129.5-130 . [&alpha;]D22 = -26.5 (CHCl3) Intermediate 49 [1R-(1&alpha;,2ss,3&alpha;,4&alpha;)]-5-[[(1,1'-Biphenyl)-4-yl]methoxy]- 3-hydroxy-2-(1-piperdinyl)-cyclopentane acetaldehyde A solution of Intermediate 48 (1.2g) in dry CH2C12 (20ml) was cooled (-78 ) and stirred under nitrogen whilst a solution of DIBAL in hexane (5.25m1; 1.43 M) was added dropwise. Methanol (20ml) was added dropwise at -70 after 0.75h and the cooling bath was removed. After stirring at 20 for lh, the precipitate was filtered off and washed well with methanol. The combined filtrates were evaporated to give the title compound as a foam (1.2g). I.R. (CHBr3) 3580, 3560, 2730, 1720cm 1 Intermediate 50 [1R-(1&alpha;,2ss,3&alpha;,4&alpha;)]-4-[[(1,1'-Biphenyl)-4-yl]lmethoxy-] 3-(3-methoxy-2-propenyl)-2-tl-piperidinylÇcyclopentanol (Methoxymethyl) triphenylphosphonium chloride (3.8g) was added over 10min to a cold (-5 ) stirred solution of potassium tert-butoxide (l.27g) in dry THF (35ml). After 30 min, a solution of Intermediate 49 (1.18g) in THF (15ml) was added at 0 and stirring maintained for 30 min. The mixture was poured into 8% NaHCO3 solution (150ml) and extracted with EA (2 x l00ml). The combined extracts were dried and evaporated and the residue was purified by chromatography (FF) to give the title compound as a semi-solid (0.9g). I.R. (CHBr3) 3580, 3500, 1650cm 1 Intermediate 51 [2R-(2&alpha;,3ss,4ss)]-4-[[(1,1'-Biphenyl)-4-yl]methoxy]3- (3-methoxy-2-propenyl) -2- (1-piperidinyl) cyclopentanone A solution of Intermediate 50 (0.84g) in CH2C12 (8 ml) was cooled (5 ) whilst triethylamine (1.95ml) followed by pyridine-sulphur trioxide complex (1.27g) in DMSO (8ml) were added. After lh at 5 the mixture was poured into pH 6 phosphate buffer (100ml) and extracted with ER (2 x 75ml). The combined extracts were washed with water (50ml) dried and evaporated and the residue was purified by chromatography (L) to give the title compound as an oil (0.725g). I.R. (CHBr3) 1735, 1656 cm Intermediate 52 [1R-(1&alpha;,2ss,3ss,5&alpha;)]-(+)-5-[[(1,1'-Biphenyl-4-yl]methoxy]- 3-hydroxy-2-(1-piperdinyl)cyclopentanepropanal A stirred solution of Intermediate 51 (0.69g) in THF (15ml) was cooled (-10 ) whilst lithium tri-sec-butylborohydride in THF (5ml; 1M) was added. After lh at 10 , 2N HC1 (20ml) was added, cautiously at first, and the mixture was stirred at 20 for 2h. The mixture was washed with ER (50ml) and then adjusted to pH 9 with 2N Na2C03 and extracted with EA (4 x 50ml). The combined extracts were dried and evaporated and the residue was purified by chromatography (TT) to give the title compound as a foam (0.206g). [aiD23 = +54.90 (CHC13) T.L.C. (TT) RfO.13 Intermediate 53 [1R-[1&alpha;(Z),2ss,3ss,5&alpha;]-(+)-Methyl 7-[5[[1,1'-Biphenyl)4-yl]methoxy]- 3-hydroxy-2-(1-piperidinyl)cyclopentyl]4-heptenoate To a stirred solution of potassium t-butoxide (2.059) in THF (80ml) was added (3-carboxypropyl)triphenylphosphonium bromide (3.99). After 0.5 h at 200 a solution of Intermediate 52 (0.463g) in THF (10ml) was added and stirring continued at 20 for 0.75h. Water (2ml) was added and the solvent removed in vacuo. The residue was taken into water (100ml), basified to pH 14 with 2N NaOH and washed with ER (3 x 60ml). The aqueous solution was adjusted to pH 6.5 with 2N HC1 and extracted with CH2C12 (3 x 50ml). The combined extracts were concentrated, re-dissolved in 1:1 EA CH2C12 (lSml) and then treated with an excess of an ethereal solution of diazomethane. Excess diazomethane was destroyed with acetic acid and the solution then diluted with EA (30ml) and washed with 2N Na2CO3 (40ml). The organic solution was dried and evaporated and the residue purified by chromatography (FF) to give the title compound as an oil (0.428g). [&alpha;]D23 = +60.10 (CHCl3) I.R. (Neat) 3600-3100(br.), 1735 cm-1 Intermediate 54 [1R-[1&alpha;(Z),2ss,3ss,5&alpha;]-(+)-7-[5-[[(1,1'-Biphenyl)-4yl} methoxvi -3-hydroxy-2- (1-piperidinyl) cyclopentyll - 4-heptenoic acid, hydrochloride Intermediate 53 (10.38g) was stirred with 74 OP ethanol (60 ml) and 5N NaOH (30ml) at 20 for lóh. The solution was diluted with water (400ml) and ther extracted with ER (2 x 150ml). The aqueous phase was adjusted to pH 6 with 2N HCl and extracted with CH2C12 (3 x 200ml). Evaporation of the combined extracts gave a foam (9.459), the majority (9.3g) of which was taken up into CH2Cl2 (50ml) and treated With an excess of an ethereal solution of hydrogen chloride. Evaporation in vacuo and trituration of the residue with ER (4 x 75ml) gave the title compound as a powder (9.28g). Crystallisation of a sample from EA-rnethanol gave material of m.p. 124-126 . [&alpha;]D25 = +63.1 (CHCl3) The preparation of Intermediate 55 is described in British Patent Specification 2075503A. Intermediate 55 (endo,anti)-(#)-5-Hydroxy-7-(1-piperindinyl)bicyclo[2.2.1]heptan- 2-one, hydrochloride Intermediate 56 (endo, anti)-(#)-5-[[4'-Methoxy(1,1'-Biphenyl)-4-yl]methoxy]- 7-(1-piperindinyl)bicylo[2.2.1]lheptan-2-one A mixture of Intermediate 55 (6.649), benzyltriethylammonium chloride (2g) and 4-(bromomethyl)-4'-methoxy(1,1'- biphenyl) (9.73g) in CH2C12 (100ml) and 17N NaOH (70ml) was vigorously stirred at 20° for 16h. The mixture was poured into water (140ml), the phases separated and the aqueous layer was extracted with CH2C12 (100ml). The combined organic layers were dried and evaporated and the residue was triturated with PE (b.p. 60-80 ) (50ml) to give a solid which was recrystallised from 5:2 EA-PE (b.p. 60-80 ) to give the title compound as a solid (6.63g) , m.p. 112-115 . Intermediate 57 (endo,anti)-(#)-6-[[4'-Methoxy(1,1'-biphenyl)-4-yl]methoxy 8-(1-piperdinyl)-2-oxobicyclo[3.2.1]octan-3-one Peracetic acid (11.2ml; 6.12M) was added slowly to a cooled (5 ) stirred solution of Intermediate 56 (6.lg) in CH2C12 (25ml). The mixture was stirred at 20 for 64h then added slowly to a cooled (5 ) stirred mixture of saturated Na2S03 (70ml) and water (30ml). After lh, isopropyl acetate (50ml) was added and the layers were separated. The aqueous layer was extracted with isopropyl acetate (2 x 50ml) and the combined organic layers were washed with 1N NaOH (100ml) dried and evaporated. The residue was purified by chromatography (UU) to give an oil which was triturated with ER to give the title compound as a solid (2g), m.p. 105-106 . Intermediate 58 (1&alpha;,2ss,3&alpha;,5&alpha;)-(#)-3-Hydroxy-5-[[4'-methoxy(1,1'-biphenyl)- 4-yl]methoxy]-2-(1-piperidinyl)cyclopentane acetaldehyde DIBAL in hexane (7.9ml; 1.43M) was added over 0.5h to a cold (-70 ), stirred solution of Intermediate 57 (1.9g) in CH2C12 (15ml). After 1.5h methanol (15ml) was added dropwise and the mixture was stirred at 20 for 2h. The preparation was filtered off and the solid was washed with methanol. The combined filtrates were evaporated and the residue was dissolved in CH2C12 (50ml), dried and the solvent was removed to give the title compound as a foam (1.89g). I CHBr3) 3580, 3535, 2730, 1710cm Intermediate 59 (1&alpha;,2ss,3&alpha;,4&alpha;)-(#)-4-[[4'-Methoxy(1,1'-biphenyl)-4yl) metboxyi -3- (3-methoxy-2-propenyl) -2- (1-piperidinyl) cyclopentanol (Methoxymethyl) triphenylphosphonium chloride (6.179) was added over lOmin to a cold (0 ) solution of potassium tert-butoxide (2.02g) in dry THF (35ml). After 15 min, a solution of Intermediate 58 (1.86g) in THF (lOml) was added dropwise and stirring was maintained for 1.5h. The mixture was poured into pH 6 phosphate buffer (100ml) and extracted with EA (2 x 50 ml). The combined extracts were dried and evaporated and the residue was purified by chromatography (FF) to give the title compound as a semi-solid (1.29g). I.R. (CHBr3) 3520, 3330, 1653cm 1. Intermediate 60 (2&alpha;,3ss,4ss)-(#)-4-[[4'-Methoxy(1,1'-biphenyl)-4-yl]methoxy]- 3-(3-methoxy-2-propenyl)-2-(1-piperindinyl) cyclopentanone A solution of Intermediate 59 (0.4g) in CP2C12 (4ml) was cooled (0 ) whilst triethylamine (0.95ml) followed by pyridine-sulphur trioxide complex (0.65g) in DMSO (4ml) were added. After lh at 0 the mixture was poured into pH 6.5 phosphate buffer (50ml) and extracted with ER (2 x 50ml). The combined extracts were washed with brine (2 x 25ml) dried and evaporated and the residue was purified by chromatography (S) to give the title compound as an oil. I.R. (Neat) 1740, 1655 cm-1 Intermediate 61 [1&alpha;,2ss,3ss,5&alpha;]-(#)-3-Hydroxy-5-[[4'-methoxy(1,1'-biphenyl)4-y) methoxyj -2-(l-piperidinyl) cyclopentanepropanal DIBAL (1.43M in hexane, 14ml) was added over 10 min under nitrogen to an ice cooled solution of 2,6-dit-butyl-p-cresol (8.8g) in dry toluene (100ml). After Ih, the solution was cooled to -45 and a solution of Intermediate 60 (0.62g) in toluene (20ml) was added over 3min. The temperature was allowed to rise to -10 over lh, then 2N HCl (40ml) was added and the mixture stirred at room temperature for 1.5h. The mixture was diluted with ER (100ml) and the organic layer extracted with 1N H2SO4 (30ml). The combined aqueous solutions were washed with ER (100ml) , basified with solid NaHCO3 and the product extracted into CH2Cl2 (3 x 80ml). The combined extracts were dried (Na2SO4) and concentrated, and the residue purified by chromatography (TT) to give the title compound as an oil (0.43g). I.R. (Neat) 3400(br.), 1720 cm 1. Intermediate 62 [1&alpha;(Z),2ss,3ss,5&alpha;]-(#)-7-[3-Hydroxy-5-[[4'-methoxy(1,1'- biphenyl)-4-yl]methoxy]-2-(1-piperidinyl)cyclopentyl] -4-heptenoic acid, compound with ethyl acetate and dichloromethane (20:3:2) (3-Carboxypropyl)triphenylphosphonium bromide (1.559) was added under nitrogen to a stirred solution of potassium t-utoxide (0.775g) in dry THF (25ml). After 40min a solution of Intermediate 61 (0.439) in THF (7ml) was added and the mixture stirred for 35 min at room temperature. Water (80ml) followed by 2N NaOH (5ml) were added and the mixture extracted with ER (2 x 100ml) . The aqueous solution was neutralised with 2N H2S04, treated with pH 6.5 phosphate buffer (10%, 25ml) and extracted with EA (2 x 70ml). The combined extracts were washed with phosphate buffer (3 x 50ml), dried (Na2S04) and evaporated in vacuo to give the title compound as a foam (0.3g). I.R. (CHBr3) 3200-2300(br.), 1720(br.) cm 1. Intermediate 63 [R-[1&alpha;(Z),2ss,3&alpha;,5&alpha;]-(+)-7-[5-[[(1,1'-Biphenyl)-4yl methoxyi -3-hydroxy-2- (1-piperidinyl) cyclopentyl - 5-heptenoic acid To a stirred solution of potassium-t-butoxide (5.99) in dry THF (70ml) was added (4-carboxybutyl)triphenylphosphonium bromide (11.08g) with stirring maintained at 20 under dry nitrogen for 0.5h. A solution of Intermediate 49 (3.Og) in dry THF (30ml) was added and stirring continued at 200 for 50min, whereupon water (15ml) was added and excess solvent removed in vacuo. After dilution with water (20ml) the solution was basified with 2N NaOH (30ml) and extracted with ER (3 x l00ml) . The aqueous phase was adjusted to pH 7 with 2N HC1 (35ml) and extracted with CH2C12 (2 x 100ml) . The solution was then adjusted to pH 6 and extracted with CH2C12 (2 x l00ml) and final-ly to pH 5.5 and extracted with CH2C12 (100ml). The combined extracts were dried and evaporated to afford the crude title compound as a foam (3.71g) which was purified via its methyl ester as described below. To a stirred solution of the foam (0.496g) in methanol (10ml) at 20 was added concentrated H2S04 (0.2ml) and the mixture stirred for 2.75h. The solution was then poured into 8% aqueous NaHC03 (20ml) and extrac-ted with CH2C12 13 x 20ml). The combined extracts were dried and evaporated, and the residue purified by chromatography (FF) to give an oil (0.438g). To a solution of this oil (0.49) in methanol (2ml) was added 5N NaOH (1.5ml) and the mixture stirred at 20 for 2.3h. After dilution with water (20ml) the solution was extracted with ER (2 x 20ml). The aqueous solution was adjusted to pH 6 with 2N HC1 (2ml) followed by pH 6 phosphate buffer solution (20ml) and extracted with CH2C12 (3 x 20ml). The combined extracts were dried and evaporated to afford the pure title compound as a foam (0.376g). I.R. (CHBr3) 3500, 1710(br), 1520 cm [&alpha;]D26 = +30.5 (CHCl3) Intermediate 64 [1R-1&alpha;(Z),2ss,5&alpha;]-Triphenylmethyl 7-[5-[[(1,1'-Biphenyl)4-yl]methoxy]-3-oxo-2-(1-piperidinyl)cyclopentyl)5-heptenoate To a solution of Intermediate 63 (0.503g) in CH2C12 (5ml) at 4 was added trityl chloride (0.3919) followed by triethylamine (0.22ml) and the mixture stirred in an ice-bath for 0.5h. More triethylamine (1.03ml) was added followed by a solution of pyridine-sulphur trioxide complex (0.679) in dry DMSO (5ml) and stirring maintained at 0-10 for 3h. The mixture was poured into pH 6 phosphate buffer solution (100ml) then extracted with ER (100ml, 2 x 50ml). The combined extracts were washed with water (50ml), dried and evaporated, and the residue purified by chromatography (L) to give the title compound as a foam (0.462g). I.R. (CHBr3) 1740cm 1 Intermediate 65 [1R-[1&alpha;(Z),2ss,3ss,5&alpha;]]-(+)-7-[5-[[(1,1'-Biphenyl)-4- yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]5-heptenoic acid, compound with dicyclohexylamine (1:1) DIBAL in hexane (1M, 32ml) was added dropwise at 0 over Smin to a solution of 2,6-di-t-butyl-4-methylphenol (13.47g) in dry toluene (75ml) under dry nitrogen and stirring maintained at 0 for lh. The solution was then cooled to -65 and a solution of Intermediate 64 (1.39g) in dry toluene (25ml) added dropwise. The mixture was stirred at -70 for 0.75h, allowed to warm to -20 over 0.5h and stored at that temperature for 14h. After addition of 2N HC1 (100 ml) the mixture was stirred at 200 for 2h, then poured into water (l00ml) and ER (100ml). The aqueous phase was separated, washed with ER (l00ml), then adjusted to pH 6 with 5N NaOH (35ml) followed by pH 6 phosphate buffer solution (50ml). This mixture was then extracted with CH2C12 (4 x 100ml) and the combined extracts dried and concentrated to yield a foam (l.lg). A portion (0.22g) was dissolved in CH2C12 (2ml) and treated with dicyclohexylamine (0.09ml). After evaporation in vacuo the residue was triturated with solvent mixture (L) whereupon the title compound (0.23g) crystallised, m.p. 101-103 . [aiD24 = +27.3 e (CHC13) The preparation of Intermediate 66 is described in British Patent Specification 2075503A. Intermediate 66 [1&alpha;(Z),2ss,5&alpha;]-(#)-7-[5-[[4'-Methyl(1,1'-biphenyl)- 4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]4-heptenoic acid. Intermediate 67 [1&alpha;(Z),2ss,3ss,5&alpha;]-(#)-7-[3-Hydroxy-5-[[4'-methyl(1,1'biphenyl) -4-yli methoxy -2- (4-morpholinyl) cyclopentyl) - 4-heptenoic acid A solution of Intermediate 66 (0.105g) in dry THF (25ml) was added over Smin under nitrogen to a stirred solution of lithium tri-sec-butylborohydride (1M in THF; 3ml) at -30 . After 2h the solution was allowed to rise to ambient temperature and then poured into 2N H2SO4 (15ml) and extracted with ER (2 x 30ml). The aqueous phase was adjusted to pH 6 and extracted with EA (3 x 30ml). The combined extracts were washed with pH 6.5 phosphate buffer solution (15ml), dried and concentrated. The residue was purified by chromatography (FF) to give the title compound as a foam (0.063g). I.R. (CHBr3) 3500, 3400-2300, 1730, 1710cm-1. Example 1 a) [1&alpha;(Z),2ss,5&alpha;]-(#)-(Methylthio)methyl 7-[5-[[(1',1 B iphenyl) -4-yli methoxyi -2- (4-morpholinyl) -3-oxo- cyclopentyl3-4-heptenoate Chloromethyl methyl sulphide (0.11 ml) was added to a stirred solution of Intermediate 1 (0.4 g) and dicyclohexylamine (0.18 ml) in dry CH3CN (6 ml). After 24h the suspension was poured into saturated NH4C1 solution (40 ml) and extracted with EA (3 x 30 ml). The combined extracts were dried, filtered, and evaporated to afford a mobile oil. Purification by chromatography (H) gave the title compound as a solid (0.178 g), m.p. 36-38 . I.R. (Neat) 1740cm-1. The following compound was prepared by a similar procedure: b) [1&alpha;(Z),2ss,5&alpha;]-(#)-(Methylthio)methyl 7-[5-[[4' Methoxy(1,1'-biphenyl)-4-yl]methoxy]-3-oxo-2-(4-thiomorpholinyl)cyclopentyl)-4-heptenoate, S-dioxide, m.p. 100-101.5 from Intermediate 2. Purification initially by chromatography (C) and then by trituration with ER. I.R. (CHBr3) 1740cm 1. Example 2 a) [1&alpha;(Z),2ss,5&alpha;]-(#)-4-(Acetylamino)phenyl 7-[5 [[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl) 3-oxocyclopentyl] -4-heptenoate Method 1 Iso-butylchloroformate (0.20 ml) was added to a cold (-10 ) solution of Intermediate 1 (0.24 g) and triethylamine (0.28 ml) in high purity acetone (5 ml). The mixture was stirred for 10 min whereupon 4-(acetylamino) phenol (0.38 g) was added and stirring maintained for a further 2.5h. Excess solvent was removed in vacuo, the residue treated with pH 6.5 buffer solution (30 ml) and extracted with EA (3 x 25 ml). The combined extracts were dried, filtered and evaporated to afford a crude product which was dissolved in ER (50 ml) and washed with 88 NaHC03 solution (2 x 20 ml) to removed excess phenol. The organic layer was dried, filtered and evaporated, and the residue purified by chromatography (I) to give the title compound as a foam (0.235g). I.R. (CHBr3) 3420, 1755(sh), 1740, 1685, 1510cm 1. T.L.C. (I) Rf 0.24. Method 2 To a solution of the compound of Example 21 (0.045 g) in CH2C12 (1 ml) at 20 was added triethylamine (0.08 ml) and pyridine sulphur trioxide complex (0.lg) in DMSO (1 ml). After 2h the solution was poured into pH 6 phosphate buffer solution (25 ml), extracted with ER (2 x 25 ml), the combined extracts washed with H20 (20 ml), dried and evaporated. The residue was purified by chromatography (F) to give the title compound (0.028 g). I.R. (CHBr3) 3420, 1755(sh), 1740, 1690, 1510cm 1. The following compounds were prepared according to the procedure described for Method 1: b) [1&alpha;(Z),2ss,5&alpha;]-(#)-2-Methoxyethyl 7-[5-[[(1,1' Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoate, from Intermediate 1 (0 5 g) and 2-methoxyethanol (0.43 ml). Purification by chromatography (N) gave an oil (0.39 g). I.R. (Neat) 1740cm 1 Analysis Found: C,71.8; H,7.9; N,2.9; C32H41NO6 requires: C,71,7; H,7.7; N,2.68 c) [1&alpha;(Z),2ss,5&alpha;]-(#)-2-(4-Morpholinyl)ethyl 7-[2 (4-Morpholinyl) -3-oxo-5-t4-(phenylmethyl) phenylmethoxy - cyclopentyl-4-heptenoate, from the free acid derived from Intermediate 3 (0.152 g) and N-2-hydroxyethyl morpholine (0.44 g) in dry CH3CN (6 ml). Purification by chromatography (G) gave an oil (0.071 g). I.R. (CHBr3) 1735cm-1. Analysis Found: C,71.3; H,8.0; N,4.5; C36H48N206 requires: C,71.5; H,8.0; N,4.68 d) [1&alpha;(Z),2ss,5&alpha;]-(#)-2-(Dimethylamino)ethyl 7-[5 [[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoate. from Intermediate 1 (0.35 g) and N,N-dimethylethanolamine (0.22 ml). Purification by chromatography (0) gave an oil (0.366 g). I.R. (Neat) 1740cm Analysis Found: C,72.2; H,7.7; N,5.2; C33H44N205 requires: C,72.2; H, 8.1; N, 5.1 % e) [1&alpha;(Z),2ss,5&alpha;]-(#)-2-(Acetylamino)phenyl 7-[ [[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl) 3-oxocyclopentyl) -4-heptenoate, m.p. 82-84 from Intermediate 1 (0.477g) in dry CH3CN (30 ml) and 2- (acetylamino) phenol (0.755g) in dry pyridine (10 ml). Purification initially by chromatography (P) and then recrystallisation from EA/PE (b.p. 60800) gave 0.102g of the title compound. I.R. (CHBr3) 3440, 1760, 1740, 1695cm 1. f) [1&alpha;(Z),2ss,5&alpha;]-(#)-3-(Acetylamino)phenyl 7-[5 [[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoate, from Intermediate 1 (0.4779) in dry CH3CN (30 ml) and 3-(acetylamino)phenol (0.7559) in dry pyridine (10 ml). Purification by chromatography (P) gave an oil (0.533g). I.R. (CHBr3) 3470, 1738, 1689, 1520cm Analysis Found: C, 72.3; H, 6.6; N, 4.4; C37H42N206 requires: C 72.8; H, 6.9; N, 4.6% g) lla(Z),2ss,5a )-S-4-(Acetylamino)phenyl 7- [5-[[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenethioate, from Intermediate 1 (0.275 g) and 4-(acetylamino)thiophenol (0.484 g). Purification twice by chromatography, firstly with (Q) and then (E) afforded a foam (0.227 g). I.R. (CHBr3) 3420, 1732, 1690cm 1. T.L.C. (Q) Rf 0.22. h) [1&alpha;(Z),2ss,5&alpha;(E)]-(#)-1,3-Bis(dimethylamino)- 2-propyl 7-[2-(4-Morpholinyl)-3-oxo-5-[(3-phenyl-2 propenyl)oxylcyclopentyl7-4-heptenoate, from Intermediate 4 (0.4g) and 1,3-Bis(dimethylamino)2-propanol (0.45 ml). Purification by chromatography (R) gave an oil (0.13g). I.R. (Neat) 1740, 968cm 1 Analysis Found: C, 69.1; H, 9.2; N, 7.5; C32H49N305 requires: C, 69.2; H, 8.9; N, 7.6% i) [1&alpha;(Z),2ss,5&alpha;]-(#)-2,2,2-Trichloroethyl 7-[5 [[(1,1'-Biphenyl)-4-yl]methoxy-2-(4-morpholinyl)-3 oxocyclopentylj -4-heptenoate, m.p. 86.5-88 from Intermediate 1 (0.8g) and 2,2,2trichloroethanol (0.76 ml). Purification initially by chromatography (S) and then by trituration with ER gave a solid (0.22 g). I.R. (CHBr3) 1740cm 1. Analysis Found: C, 61.3; H, 5.9; N, 2.4; C31H36Cl3NO5 requires: C, 61.0; H, 6.0; N, 2.3% j) [1&alpha;(Z),2ss,5&alpha;]-(#)-3,3,5-Trimethylcyclohexyl 7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)3-oxocyclopentyl]-4-heptenoate, from Intermediate 1 (1.09 g) in acetone (12 ml) and 3,3,5-trimethylcyclohexanol (1.028 g) in dry pyridine (8 ml). Purification by chromatography (X) gave an oil (0.114 g). I.R. (Neat) 1740cm 1. T.L.C. (X) Rf 0.1. k) [1&alpha;(Z),2ss,5&alpha;]-(#)-S-2-(Methoxythio)ethyl 7-[5 [[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)3-oxocyclopentyl]-4-heptenethioate, m.p. 35-37 from Intermediate 1 (0.66 g) in dry CH3CN (40 ml) and 2-(methylthio)ethane thiol (0.68 g) in dry pyridine (10 ml). Purification initially by chromatography (C) and then by trituration with icecold PE (b.p. 40-60 ) gave a solid (0.251 g). I.R. (CHBr3) 1740, 1690cm 1. l) [1&alpha;(Z),2ss,5&alpha;]-(#)-2-Propenyl 7-[5-[[(1,1'-Biphenyl)4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]4-heptenoate, from Intermediate 1 (0.57 g) and 2-propen-l-ol (1.8 ml). Purification by chromatography (K) gave an oil (0.17 g). I.R. (Neat) 1735cm 1. Analysis Found:- C, 74.2; H, 7.5; N, 2.7; C32H39NO5 requires: C, 74.25; H, 7.6; N, 2.7% m) [1&alpha;(Z),2ss,5&alpha;]-(#)-(2-Furanylmethyl) 7-[4-[[(1,1' Biphenyl)-4-yl7methoxyl-2-(4-morpholinyl)-3-oXocyclo- pentyl]-4-heptenoate, compound with water (1:0.5), from Intermediate 1 (0.5 g) and 2-furanmethanol (0.616g). Purification by chromatography (V) gave an oil (0.442g). I.R. (Neat) 3665, 1739cm-1 Analysis Found: C, 72.3; H, 7.1; N, 2.4; C34H39NO6.0.5H2O requires: C, 72.0; H, 7.0; N, 2.5% Example 3 a) [1&alpha;(Z),2ss,5&alpha;]-(#)-(Acetyloxy)methyl 7-[4-[[(1,1' Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclo pentyll-4-heptenoate Method 1 Bromomethyl acetate (0.12 g) was added to a solution of Intermediate 1 (0.25 g) and triethylamine (0.146 ml) in acetone (5 mll and the mixture stirred at room temperature for 2.5h. The mixture was poured into water (100 ml) and extracted with ER (4 x 40 ml). The organic layers were dried and evaporated to give an oil (0.287 9). Purification by chromatography (J) gave the title compound as a solid (0.175 g), m.p. 35-37 . I.R. (CHBr3) 1760, 1740cam 1. Method 2 To a cold (0 ), stirred solution of Intermediate 21a (0.199) in acetone (10 ml) was added Jones reagent (2.67M, 0.17 ml). The mixture was kept at 0 for 6h, whereupon IPA (0.5 ml) was added, followed 10 min later by 8% NaHCO3 solution (35 ml). The resulting suspension was extracted with EA (2 x 40 ml). The dried extracts were evaporated and the residue purified by chromatography (K) to give the title compound (0.0569). I.R. (CHBr3) 1760, 1740cm 1. Method 3 To a solution of the compound of Example 20 (0.054 g) in CH2C12 (0.75 ml) was added triethylamine (0.15 ml), followed by pyridine sulphur trioxide complex (0.13 g) in DMSO (1 mlY. The mixture was stirred at 21 for lh, poured into pH 6 phosphate buffer solution (30 ml) and extracted with ER (2 x 25 ml). The combined extracts were dried and evaporated and the residue purified by chromatography (C) to give the title compound (0.04 g). I.R. (CHBr3) 1760, 1740cm 1. Method 4 Lindlar catalyst (0.007 g) was hydrogenated at 18 and atmospheric pressure in EA (4 ml) containing quinoline (0.003 g) until uptake ceased. A solution of Intermediate 21b (0.04 g) in EA (4 ml) was added and hydrogenation continued for 54 min (uptake ceased). The catalyst was filtered off, the filtrate evaporated and the residue purified by chromatography (L) to give the title compound (0.039 g). I.R. (CHBr3) 1760, 1740cm 1 The following compounds were prepared using a similar manner to Method 1. b) [1&alpha;(Z),2ss,5&alpha;]-(#)-1-(Acetyloxy)ethyl 7-[5-[[(1,1' Biphenyl) -4-vil methoxy] -2- (4-morpholinyl) -3-oxocyclopent- yl]-4-heptenoate, compound with diethyl ether (10:1), from Intermediate 1 (0.435g) and l-bromoethyl acetate (0.4569). Purification by chromatography (T) gave an oil (0.234 g). I.R. (Neat) 1760, 1745cm 1 Analysis Found: C, 69.8; H, 7.6; N, 2.4; C33H41NO7.0.lC4H100 requires: C, 70.2; H, 7.4; N, 2.48 c) [1&alpha;(Z),2ss,5&alpha;]-(#)-(Acetyloxy)methyl 7-[5-[[(1,1' Biphenyl)-4-yl)]methoxy]-3-oxo-2-(4-thiomorpholinyl)cyclopentyl]-4-heptenoate, from Intermediate 5 (0.251 g) and bromomethyl acetate (0.155g). Purification by chromatography (U) afforded an oil (0.211g). I.R. (Neat) 1765, 1745cm Analysis Found: C, 67.9; H, 6.9; N, 2.45; C32H39NO6S requires: C,67.9; H, 6.95; N, 2.58 Example 4 [1&alpha;(Z),2ss,5&alpha;]-(#)-Triphenylmethyl 7-[5-[[(1,1'-Biphenyl)4-yl]methoxy]-2-(4-morpholinyl]-3-oxocyclopentyl]4-heptenoate From Intermediate 1 (1.5 g) and triphenylmethyl chloride (1.315 g) in CH2Cl2 (9 ml) according to the method described for Example 3a (Method 1). Purification by chromatography (C) gave a foam (1.843 g). I.R. (CHBr3) 1740cm-1. Analysis Found: C, 80.2; H, 6.9; N, 2.1; C48H49N05 requires: C, 80.1; H, 6.9; N, 1.958 Example 5 [1&alpha;(Z),2ss,5&alpha;]-(#)-(Ethoxycarbonyl)methyl 7-[5-[[(1,1' Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclo pentyll -4-heptenoate Method 1 From Intermediate 1 (0.3g) and ethyl bromoacetate (0.222 ml) in dry CH3CN (5 ml) using the procedure described for Example 3a, Method 1 Purification by chromatography (V) gave an oil (0.329 g). I.R. (Neat) 1750 (sh), 1740cm 1 Analysis Found: C, 70.3; H, 7.7; N, 2.1; C33H41NO7 requires: C, 70.3; H, 7.3; N, 2.5% Method 2 A solution of Intermediate 1 (0.245 g) and ethyl diazoacetate (0.065 ml) in dioxan (5 ml) containing copper (II) chloride (0.0039) was stirred for 18h at room temperature. The reaction mixture was poured into pH 6 phosphate buffer (40 ml) and extracted with CH2C12 (3 x 30 ml). The combined extracts were dried and evaporated, and the residue purified by chromatography (H) to give the title compound (0.119g). I,R. (Neat) 1750 (sh) 1740cm Example 6 a) [la(z) ,2B,5cr7--2-0xo-2-phenylethyl 7-[5-[F(l,l'- BiphenYl)-4-yllmethoxy)-2-(4-morpholinyl)-3-oXocyclo- pentyll -4-heptenoate a-Bromoacetophenone (0.2529) was added to a stirred solution of Intermediate 1 (0.3g) and diisopropylethylamine (0.24 ml) in dry CH3CN (8 ml). After lh the solution was poured into pH 6.5 buffer (30 ml) and extracted with EA (3 x 25 ml). The combined extracts were dried, filtered and evaporated, and the residue purified by chromatography (N) to afford the title compound as an oil (0.353 g). I.R. (Neat) 1740, 1700 cm-1. Analysis Found: C, 74.1; H, 7.3; N, 2.1; C37H41NO6 requires: C, 74.6; H, 6.9; N, 2.4% The following compound was prepared in a similar manner: b) [1&alpha;(Z),2ss,5&alpha;]-(#)-Tetrahydro-2-oxofuran-3-yl 7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)3-oxocyclopentyll-4-heptenoate from Intermediate 1 (0.3g) and 3-bromo-dihydro-2(3H)furanone (0.24 ml). Purification by chromatography (C) gave an oil (0.272 g). I.R. (Neat) 1790, 1740cm T.L.C. (C) Rf 0.24. Example 7 [1&alpha;(Z),2ss,5&alpha;]-(#)-Tetrahydro-5-oxofuran-2-yl 7-[5 [[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl) 3-oxocyclopentyll -4-heptenoate 5-Chloro-dihydro-2(3H)-furanone (0.1529) was added to a mixture of Intermediate 1 (0.29) and trioctylpropyl ammonium bromide (0.49) in diisopropylethylamine (0.44 ml) and dry CH3CN (3 ml). The mixture was stirred at room temperature for 2h, poured into aqueous pH 6.5 phosphate buffer (65 ml) and then extracted with EA (3 x 20 ml). The dried extracts were evaporated and the residue purified by chromatography (W) to give the title compound as an oil (0.16g). I.R. (Neat) 1800, 1750cm 1 T.L.C. (C) Rf 0.23. Example 8 [1a(2),2B,5a )-(Acetylthio)methyl 7-[5-1[(1,1'- Biphenyl) -4-yli methoxyi -2- (4-morpholinyl) -3-oxocyclo- pentyll -4-heptenoate Bromomethylthioacetate (0.377 g) was added to a mixture of Intermediate 1 (0.426 g) and anhydrous K2C03 (0.246 g) in dry DMF (8 ml) and the mixture then stirred for 3h. The mixture was poured into aqueous pH 6.5 phosphate buffer (170 ml) and extracted with EA (3 x 60 ml). The combined organic layers were dried and evaporated, and the residue purified by chromatography (C) to give the title compound as an oil (0.269 g). I.R. (Neat) 1740, 1708cm 1. T.L.C. (C) Rf 0.44. Example 9 a) [1&alpha;(Z),2ss,5&alpha;]-(#)-(Methylthio)methyl 7-[5-[[4' MethOxy(l,l'-biphenyl)-4-ylamethoxyl-2-(4-morpholinyl)- 3-oxocyclopentyll-4-heptenoate Pyridinium trifluoroacetate (0.375 g) was added to a stirred mixture of Intermediate 6 (0.5 g) and dicyclohexylcarbodiimide (1 g) in dry DMSO (5 ml), under nitrogen, with water bath cooling. After 5.5 h, the mixture was diluted with H20 (130 ml) and extracted with CH2C12 (3x50 ml). The organic solution was dried (Na2SO4) and evaporated in 2cu O to leave a semi-solid (1.5 g) which was triturated with ER (4 x 5 ml), the solid filtered off and the ER solution evaporated to give an oil(l g). Chromatography (H) gave, after trituration with ER, the title compound (0.31 g) as a solid m.p. 68-72". I.R. (CHBr3) 1740cm The following compounds were similarly prepared: b) [1&alpha;(Z),2ss,5&alpha;]-(#)-(Methylthio)methyl 5-[5-[[4' Methyl(l,l'-biphenyl)-4-ylmethoxv]-2-(4-morpholinyl)- 3-oxocyclopentyl]-4-heptenoate, m.p. 56.5-59.5 from Intermediate 7 (0.3 g). Purification by chromatography (N) gave an oil (0.14 g) which crystallised on standing. I.R. (CHBr3) 1735cm 1. c) [1&alpha;(Z),2ss,5&alpha;(E)]-(#)-(Methylthio)methyl 7-[2-(4 Morpholinyl)-3-oxo-5-[(3-phenyl-2-propenyl)oxy]cyclopentyl]4-heptenoate, from Intermediate 8 (0.257 g). Purification by chromatography (T) gave an oil (0.136 g). I.R. (Neat) 1735, 970 cm 1 Analysis Found: C, 66.3; H,7.6; N, 2.9; C27H37NO5S requires: C,66.5; H,7.7; N,2.9% Example 10 [1&alpha;(Z),2ss,5&alpha;]-(#)-(Methylthio)methyl 7-[5-[[1,1'-Bi phenyl) -4-yl) methoxy) -3-oxo-2- (1-piperidinyl) cyclo- pentyl) -4-heptenoate To a solution of Intermediate 9 (0.37 g) and dicyclohexylcarbodiimide (0.64 g) in DMSO (8 ml) at 20 was added pyridinium trifluoroacetate (0.254 g) and the mixture stirred for 2 h. Aqueous pH 6 phosphate buffer (75 ml) was added and the mixture extracted with ER (2 x 50 ml). The combined extracts were dried and evaporated and the residue partially purified by chromatography (L) to give an oil (0.224 g). A portion (0.097 g) of this material was converted into its maleate salt by the addition of an excess of an ER solution of maleic acid. The resultant oily precipitate was triturated with ER (5 x 3 ml) and then converted back to the free base by the addition of pH 6 phosphate buffer (10 ml) and extraction with ER (3 x 10 ml). Finally, chromatography (C) afforded pure title compound as an oil (0.047 g). I.R. (Neat) 1740cm 1 T.L.C. (L) Rf 0.27. Example 11 [1R-[1&alpha;(Z),2ss,5&alpha;]]-(#)-(Methylthio)methyl 7-[5-[[(1,1' Biphenyl) -4-yl methoxyi -2- (4-morpholinyl) -3-oxocyclo- pentyl) -4-heptenoate A solution of Intermediate 10 (0.43 g) in CH3CN (3 ml) containing triethylamine (0.3 ml) was added to a stirred mixture of chloromethylmethylsulphide (0.15 ml) and NaI (0.05 g) in CH3CN (1 ml) at room temperature. The mixture was stirred at room temperature for 4h and then kept at 0 overnight. The mixture was diluted with pH 6.5 phosphate buffer (75 ml) and extracted with ER (3 x 50 ml). The combined extracts were dried and evaporated and the residue was purified by chromatography (M) to give the title compound as an oil (0.136 g) which solidified on standing, m.p. 48-50 . [&alpha;]D21.5 = -9.0" (CHC13). I.R. (CHBr3) 1735cm Example 12 [1&alpha;(Z),2ss,5&alpha;]-(#)-3-(Acetylamino)propyl 7-[5-[[(1,1' Biphenyl)-4-ylgmethoxyl-2-(4-morpholinyl)-3-oXocyclo- pentyll-4-heptenoate A solution of Intermediate 1 (0.477 g) in dry CH3CN (30 ml) containing triethylamine (0.28 ml) was cooled to -10 under dry nitrogen and treated with isobutylchloroformate (0.26 ml). After stirring at -10 for lh a solution of N-3-hydroxypropylacetamide (0.585 g) in dry pyridine (10 ml) was added and the mixture allowed to warm to room temperature over 2 h. The mixture was poured into pH 6 phosphate buffer (100 ml), extracted into EA (2 x 100 ml), the combined extracts were washed with H2O (4 x 50 ml), aqueous CuSO4 (2 x 50 ml), H2O (50 ml) and brine (50 ml), dried and evaporated. Purification of the residue by chromatography (G) gave the title compound as an oil (0.103 g). I.R. (Neat) 3310, 1740, 1680, 1550cm 1 Analysis Found: C,70.4; H,8.1; N,4.8; C34H44NO6 requires: C,70.8; H,7.7; N,4.9% Example 13 [1R-[1&alpha;(Z),2ss,5&alpha;]]-(#)-(Acetyloxy)methyl 7-[5-[[1,1' Biphenyl)-4-yllmethoxy]-2-(4-morpholinyl)-3-oXocyclo- pentyl]-4-heptenoate A solution of Intermediate 10 (0.436 g) in acetone (6 ml) containing triethylamine (0.3 ml) and bromomethylacetate (0.3 g) was stirred at 20 for 2h. The mixture was poured into pH 6.5 phosphate buffer (50 ml) and extracted with ER (3 x 50 ml). The combined extracts were dried and evaporated to give an oil (0.45 g). Purification by chromatography (C) gave 21 5 the title compound as an oil (0.351 g). [aJ = -8.8 (CHCl3). I.R. (Neat) 1765, 1740cm 1 Analysis Found: C,69.8; H,7.3; N,2.4; C32H39N07 requires: C,69.9; H,7.15; N,2.55% Example 14 [1&alpha;(Z),2ss,5&alpha;]-(#)-2-Amino-2-oxoethyl 7-[5-[[(1,1' Biphenyl) -4-yl] methoxy] -2- (4-morpholinyl) -3-oxocyclo- Pentyll-4-heptenoate A mixture of Intermediate 1 (0.3 g), NaI (0.12 g), chloroacetamide (0.294 g) and dicyclohexylamine (0.12 ml) in dry DMF (3 ml) was stirred under nitrogen for 20h. The suspension was poured into pH 6.5 buffer solution (30 ml) and extracted with EA (3 x 25 ml). The combined extracts were washed with brine (30 ml), dried, filtered and evaporated to afford a mobile oil (0.7 g). Chromatography (E) gave impure title compound (0.272 g) as an oil. The oil was dissolved EA (20 ml) washed with H20 (30 ml) and brine (30 ml), dried, filtered and evaporated to give a viscous oil (0.2 g). On taking up into EA/PE (b.p. 60-80 ) the title compound crystall ised out (0.157 g) , m.p. 94-94.5 . I.R. (CHBr3) 3520, 3400, 1735, 1690, 1665cm-1. Example 15 [1&alpha;(Z),2ss,5&alpha;]-(#)-S-(2-Pyridinyl) 7-[5-[[(1,1'-Biphenyl)4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]4-heptenethioate 2,2-Dipyridyldisulphide (0.070 g) was added to a stirred solution of Intermediate 1 (0.1 g) and triphenylphosphine (0.084 g) in benzene (0.6 ml). After 3 days the mixture was poured into pH 6.5 buffer solution (30 ml) and extracted into EA (3 x 25 ml). The combined extracts were dried, filtered and evaporated, and the residue purified by chromatography (C) to give the title compound as an oil (0.1 g). I.R. (Neat) 1738, 1705cm-1 T.L.C. (C) Rf 0.24. Example 16 a) [1&alpha;(Z),2ss,5&alpha;]-(#)-Methoxymethyl 7-[5-[3-[[1,1' Biphenyl)-4-yl]propoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]4-heptenoate Pyridine sulphur trioxide complex (0.193 g) in dry DMSO (2 ml) was added to a cold (0 ) mixture of Intermediate 22 (0.22 g), triethylamine (0.45 ml), dry DMSO (2 ml) and dry CH2C12 (2 ml). After stirring for 1.5 h H20 (4 ml) was added and excess CH2C12 removed in vacuo. The residue was treated with citric acid (0.22 g) in H20 (4 ml) and extracted with EA (3 x 20ml). The combined extracts were dried, filtered and evaporated and the residue purified by chromatography (N) to give pure title compound as an oil (0.175 g). I.R. (CHBr3) 1735cm Analysis Found: C,71.8; H,8.0; N,2.5; C33H43NO6 requires: C,72.1; H,7.9; N,2.6% The following compounds were similarly prepared: b) [1&alpha;(Z),2ss,5&alpha;]-(#)-(Methylthio)methyl 9-[5-[[(1,1' Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclo pentyll-6-nonenoate/ from Intermediate 23 (0.35 g). Purification by chromatography (Y) gave an oil (0.166 g). I.R. (Neat) 1740cm 1 Analysis Found: C,70.0; H,7.9; N,2.4; C33H43NO5S requires: C,70.0; H,7.7; N,2.5% c) [1&alpha;(Z),2ss,5&alpha;]-(#)-4-(Acetylamino)phenyl 7-[5-[[3' Methoxy(l,l'-biphenyl)-4-yllmethoxy)-2-(4-morpholinyl)- 3-oxocyclopentyl]-4-heptenoate, from Intermediate 24 (0.206 g). Purification by chromatography initially (C) followed by (E) gave a foam (0.182 g). I.R. (CHBr3) 3420, 1755, 1740, 1690, 1520cm T.L.C. (E) Rf 0.26 d) [1&alpha;(Z),2ss,5&alpha;]-(#)-4-Methylphenyl 7-[2-(4-Morpholinyl)3-oxo-5-[(2-phenylthien-4-yl)methoxy]cyclopentyl]4-heptenoate, m.p. 78-80 from Intermediate 25 (0.21 g). Purification by chromatography (Z) gave an oil (0.104 g) which solidified on standing. I.R. (Nujol) 1760, 1742cm 1 Analysis Found: C,70.7; H,6.9; N,2.1; C34H39NO5S requires: C,71.2; H,6.85; N,2.4% e) [1&alpha;(Z),2ss,5&alpha;]-(#)-4-(Methylsulphonyl)phenyl 7 [5-L[4'-Methyl (l,l'-biphenyl)-4-yl]methoxy]-3-oxo- 2-(4-thiomorpholinyl)cyclopentyl]-4-heptenoate, Sdioxide, from Intermediate 26 (0.312 g). Purification by chromatography (I) gave a foam (0.191 g). I.R. (CHBr3) 1760, 1745cm 1 Analysis Found: C,63.6; H,6.2; N,1.8; C27H43NO8S2 requires: C,64.0; H,6.2; N,2.08 f) [1&alpha;(Z),2ss,5&alpha;]-(#)-L-(-)-1-(Ethoxycarbonyl)ethyl 7-[5-[[(1,1'-Biphenyl]-4-yl]methoxy]-3-oxo-2-(1-piper idinyl)cyclopentyl)-4-heptenoate, from the product mixture of Intermediate 27 (0.2 g). Purification by chromatography (AA) gave an oil (0.046 g) i.R (CHBr3) 1740(sh), 1732cm1 Analysis Found: C,73.0; H,8.1; N,2.7; C35H4SNO6 requires: C,73.0; H,7.9; N,2.48 + g) [1&alpha;(Z),2ss,5&alpha;]-(#)-(Acetylthio)methyl 7-[5-[[(1,1' Biphenyl)-4-yllmethoxyl-3-oxo-2-(l-piperidinyl)cyclo- pentyl]-4-heptenoate, from Intermediate 28 (0.089 g). Chromatography initially (L) followed by (V) gave an oil (0.05 g). I.R. (CHBr3) 1733, 1700cm 1 T.L.C. (C) Rf 0.59 h) [1&alpha;(Z),2ss,5&alpha;]-(#)-(Acetyloxy)methyl 7-[2-(4-Morpholinyl)-3-oxo-5-[4-(thien-2-yl)phenylmethoxy]cyclopentyl]4-heptenoate, m.p. 78-80.5 from Intermediate 21c. Purification initially by chromatography (BB) and then by recrystallisation from ER/isopentane. I.R. (CHBr3) 1740cm-1 i) [1&alpha;(Z),2ss,5&alpha;]-(#)-2-(4-Bromophenyl)-2-oxoethyl 7-[2-(4 Morpholinyl)-5-(2-naphthyalenylmethoxy)-3-oxocyclopentyl]-4-heptenoate, from Intermediate 29 (0.889 g). Purification by chromatography (CC) gave an oil (0.704 g). I.R. (Neat) 1745, 1708cm 1 Analysis Found: C,64.8; H,6.0; N,1.9; C35H38BrNO6 requires: C,64.8; H,5.9; N,2.2% Example 17 [1&alpha;(Z),2ss,5&alpha;]-(#)-(Benzoyloxy)methyl 7-[5-[[(1,1' Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoate To a solution of Intermediate 1 (0.477 g), sodium iodide (0.3 g) and triethylamine (0.3 ml) in acetone (5 ml) was added chloromethylbenzoate (0.34 g). After 4h further quantities of chloromethylbenzoate (0.68 g) and triethylamine (0.6 ml) were added and stirring maintained for 20H. The reaction mixture was poured into pH 6.5 phosphate buffer (50 ml) and partitioned with CH2C12 (3 x 50 ml). The dried extracts were evaporated to give a semi-solid (0.95 g). Purification by chromatography (EE) gave the title compound as an oil (0.31 g). I.R. (Neat) 1740cm Analysis Found: C,73.1; H,7.15; N,2.1; C37H41NO7 requires: C,72.65; H,6.8; N,2.3% Example 18 [1&alpha;(Z),2ss,5&alpha;]-(#)-S-Methoxymethyl 7-[4-[[(1,1'-Biphenyl)4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]4-heptenethioate Isobutylchloroformate (0.19 ml) was added to a solution of Intermediate 1 (0.527 g) and triethylamine (0.4 ml) in dry DMF (4 ml), under nitrogen, at 0 . After 0.5h sodium hydrogen sulphide (0.185 g) was added and the mixture stirred at room temperature for lh. The suspension was cooled (0 ) and triethylamine (0.46 ml) added followed by chloromethyl methyl ether (0.25 ml). After a further lh the mixture was poured into pH6.5 phosphate buffer (150 ml) and extracted with EA (3 x 50 ml). The dried organic extracts were evaporated in vacuo to give an oil (0.72 g). Purification by chromatography (DD) gave the title compound as an oil (0.4 g). I.R. (Neat) 1740, 1695cm 1 Analysis Found: C,68.9; H,7.4; N,2.6; C31H39NO5S requires: C,69.2; H,7.4; N,2.6% Example 19 (a) [1&alpha;(Z),2ss,3ss,5&alpha;]-(#)-(Methylthio)methyl 7-[5 [[(l,l'-BiPhenyl)-4-yllmethoxy]-3-hydroxy-2-(4-morpho- linyl)cyclo-pentyl7-4-heptenoate Chloromethyl methyl sulphide (0.08 ml) was added to a stirred solution of Intermediate 19 (0.3 g) and dicyclohexylamine (0.14 ml) in dry DMF (3 ml) at room temperature. After 20h the suspension was poured into saturated NH4C1 solution (30 ml) and extracted with EA (3 x 25 ml). The combined extracts were dried, filtered and evaporated to afford a mobile oil (0.3 g) Column chromatography using (C) as eluent gave the title compound as an oil (0.122 g). TLC (C) Rf 0.26 Analysis Found: C, 68.7; H, 7.7; N, 2.6; C31H41NO5S requires: C, 69.0; H, 7.7; N, 2.6% b) [1&alpha;(Z),2ss,3ss,5&alpha;] and [1&alpha;(E),2ss,3ss,5&alpha;]-(#)-(Methyl- thio)methyl 7-[3-Hydroxy-5-[[4'-methyl(1,1'-biphenyl)4-yl]methoxy]-2-(4-morpholinyl) cyclopentyl]-4-heptenoate, from Intermediate 67, by the method of Example 19(a) Purification by chromatography (E) gave material of Z:E/2:1 I.R. (CHBr3) 3500-3100, 1730cm m/e Found: 554.2955 (m+1) C32H44NOsS requires: 554.2940 (m+l) Example 20 [la(Z),2B,3B,Sa]-I+) (Acetyloxy)methyl 7-[5-[[(1,1'- Biphenyl)-5-yl]methoxy]-3-hydroxy-2-(4-morpholinyl) cyclo-pentyl] -4-heptenoate, compound with ethyl acetate (3:1) To a solution of Intermediate 19 (0.431 g) in pure acetone (4 ml) at 20 was added triethylamine (0.31 ml) followed by bromomethyl acetate (0.305 g) in acetone (2 ml). The mixture was stirred at 20 for 2h and then poured into pH 6 phosphate buffer (75 ml) and extracted with EA (2 x 40 ml). The combined extracts were dried, filtered and concentrated, and the residue purified by chromatography (B) to give the title compound as an oil (0.353 g). TLC (F) Rf 0.3.IR (Neat) 3440(br) , 1760, 1120cm 1 Example 21 [1&alpha;(Z),2ss,3ss,5&alpha;]-(#)-4-(Acetylamino)phenyl 7-[5-[[(1,1' Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclo pentyii-4-heptenoate, compound with ethyl acetate (5:1) To a solution of Intermediate 19 (0.5 g) in pure acetone (i0 ml) was added triethylamine (0.58 ml) and the mixture cooled to -10" (ice/EtoH). Isobutylchloroformate (0.41 ml) was added, followed after 0.5h at -10" by 4-(acetylamino)phenol(0.474g) in acetone (8 ml). After another 0.5h at -100, pyridine (1 ml) was added and the temperature allowed to rise to 20 over 2h. The mixture was poured into 15% pH 6 phosphate buffer solution (100 ml) and extracted with EA (3 x 50 ml). The combined extracts were dried and evaporated, and the residue purified by chromatography (B) to give the title compound as a viscous gum (0.367 g). TLC (FF) Rf 0.43 IR (CHBr3) 3420, 3380, 1750, 1685, 1505 cm Example 22 [la(Z),26,36,5a (Acetyloxy)methyl 7-[5-[((l,l'- Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl]cyclo pentyl] -5-heptenoate A solution of the acid derived from Intermediate 31 (0.64 g) in acetone (10 ml) containing triethylamine (0.55 ml) and bromomethyl acetate (0.51 g) was stirred at 20 for 2.5h then poured into pH 6.5 phosphate buffer (150 ml) and extracted with EA (3 x 50 ml). The combined extracts were dried and evaporated and the residue was purified by chromatography (GG) to give the title compound as an oil (0.47 g). I.R. (CHBr3) 3500-3100, 1755 cm 1 Analysis Found : C, 69.4; H, 7.5; N, 2.5 C32H41NO7 Requires: C, 69.7; H, 7.5; N, 2.5% Example 23 a) [1&alpha;(Z),2ss,5&alpha;]-(#)-(Methylthio)methyl 7-[5-[[1,1' Biphenyl) -4-yl) methoxyl -2-(8-morpholinyl) -3-oxocyclo- pentyll-5-heptenoate Pyridinium trifluoroacetate (0.3 g) was added to a stirred solution of Intermediate 33 (0.48 g) and dicyclohexylcarbodiimide (0.82 g) in dry DMSO (4 ml) at ambient temperature. After 5h, the mixture was poured into water (25 ml) and extracted with CH2C12 (3 x 25 ml) The combined extracts were dried and evaporated and the residue was purified by chromatography (H) to give the title compound (0.25 g) as a solid, m.p. 45-47 . Analysis Found: C, 69.7; H, 7.6! N, 2.7; C31H39NO5S requires: C, 69.3; H, 7.3; N, 2.6% The following compounds were prepared by a similar procedure: b) [la(Z) 2ss,5&alpha;]-(#)-(Methylthio)methyl 7-15-[4-(4- Methoxybenzoyl)phenylmethoxy]-2-(4-morpholinyl)-3oxocyclopentyll-5-heptenoate, from Intermediate 37 Purification by chromatography (I). T.L.C. (I) Rf 0.39 Analysis Found: C, 66.2; H, 6.95; N, 2.4; C33H41NO7S requires: C, 66.5; H, 6.90; N, 2.35% c) [1&alpha;(Z),2ss,5&alpha;]-(#)-(Methylthio)methyl 7-[2-(4-Morpholinyl)-3-oxo-5-[4-(phenylmethyl)phenylmethoxy]cyclopentyl]-5-heptenoate, from Intermediate 40 Purification by chromatography (C) I.R. (CHBr3) 1738 cm 1 Analysis Found: C, 69.6; H, 7.25; N, 2.6; C33H41NO5S requires: C, 69.7; H, 7.5 ; N, 2.5% d) [1&alpha;(Z),2ss,5&alpha;]-(#)-(Methylthio)methyl 7-[2-(4-Morpho linyl) -3-oxo-5-([1,1':4' ,l"-terphenyl) -4-yll methoxy7 cyclo- pentyli -5-heptenoate, m.p. 115-118 from Intermediate 41. Purification initially by chromatography (C) and then by crystallisation (EA-PE). Analysis Found: C, 72.6; H, 7.0;; N, 2.4; C37H43NO5S requires: C, 72.4; H, 7.1; N, 2.3% Example 24 a) [1&alpha;(Z),2ss,5&alpha;]-(#)-2-(Dimethylamino)ethyl 7-[5 [[1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl) 3-oxocyclopentyll-5-heptenoate A solution of Intermediate 30 (0.5 g) and triethylamine (0.29 ml) in acetone (10 ml) at -10 was treated with isobutyl chloroformate (0.28 ml) and 15 min later with N,N-dimethyl ethanolamine (0.22 ml). The cooling bath was removed and stirring continued at ambient temperature for 5h. The mixture was poured into 8% NaHCO3 solution (20 ml) and extracted with EA (3 x 30 ml). The combined extracts were washed with brine (50 ml), dried and evaporated. The residue was purified initially by chromatography (0) and then by recrystallisation [ether-PE (b.p. 60-80 )] to give the title compound (0.25 g), m.p. 72-73 . Analysis Found: C, 71.8; H, 7.8; N, 4.8; C33H44N205 requires: C, 72.2; H, 8.1; N, 5.1% The following compounds were prepared by a similar procedure: b) [1&alpha;(Z),2ss,5&alpha;]-(#)-Phenyl 7-[5-[[(1,1'-Biphenyl) 4-ylemethoxyl-2-(4-morpholinyl)-3-oxocyclopentyla- 5-heptentoate, m.p. 72.5 - 74 , from Intermediate 30 and phenol. Purification by chromatography (M) Analysis Found: C, 75.9; H, 7.1; N, 2.7; C35H39NO5 requires: C, 75.9; H, 7.1; N, 2.58 c) [1&alpha;(Z),2ss,5&alpha;]-(#)-4-Methoxyphenyl 7-[5-[[(1,1' Biphenyl)-4-Yllmethoxy]-2-(4-morpholinyl)-3-oXocyclo- pentyl]-5-heptenoate, m.p. 75-76.5 , from Intermediate 30 and 4-methoxyphenol. Purification by chromatography (M). Analysis Found: C, 74.25; H, 7.1; N, 2.4; C36H41NO5 requires: C, 74.1; H, 7.1; N, 2.4% d) [1&alpha;(Z),2ss,5&alpha;]-(#)-4-Acetylphenyl 7-[5-[[(1,1' BiphenYl)-4-yllmethoxyl-2-(4-morpholinyl)-3-oXocyclopent 5-heptenoate, m.p. 73-75 , from Intermediate 30 and 1-(4-hydroxyphenyl)ethanone. Purification by hromato graphy (C) and trituration with ER. Analysis Found: C, 74.75; H, 6.8; N, 2.5; C37H41NO6 requires: C, 74.6; H, 6.9; N, 2.35% + e) [1&alpha;(Z),2ss,5&alpha;]-(#)-4-Methylphenyl 7-[5-[[(1,1' Biphenyl) -4-yll methoxy] -2-(4-morpholinyl) -3-oxocyclo pentyll-5-heptenoatet m.p. 81-83 , from Intermediate 30 and 4-methylphenol. Purification by chromatography (M) Analysis Found: C, 75.9; H, 7.2; N, 2.5; C36H41NO5 requires: C, 76.15; H, 7.3; N, 2.5% f) [1&alpha;(Z),2ss,5&alpha;]-(#)-4-[[7-[5-[[(1,1'-Biphenyl)-4- yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-5 heptenoyl]-oxylbenzoic acid, m. p. 95-102 from Intermediate 30 and 4-hydroxybenzoic acid using pyridine as cosolvent. The reaction mixture was poured into 0.1M KH2PO4 solution and extracted with ER. The ER extract was washed with 0.2M sulphuric acid, pH6.5 phosphate buffer, dried and evaporated. The residue was purified initially by chromatography (C) and then by crystallisat ion from ether-isopentane. Analysis Found: C, 71.9; H, 6.9; N, 2.5; C36H39NO7 requires: C, 72.3; H, 6.6; N, 2.38 Example 25 [1&alpha;(Z),2ss,5&alpha;]-(#)-2-Oxo-2-phenylethyl 7-[5-[[(1,1' Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclo pentyl] -5-heptenoate A well stirred solution of Intermediate 38 (0.7 g) in DMSO (5 ml) and triethylamine (5 ml) was treated with pyridine-sulphur trioxide complex (0.65 g) and was kept at ambient temperature for 0.8h. The mixture was poured into saturated NH4C1 solution (100 ml) and extracted with CH2C12 (3 x 70 ml). The combined extracts were dried and evaporated and the residue was purified by chromatography (C) to give the title compound as an oil 0.56 g. I.R. (Neat) 1740, 1700 cm 1 Analysis Found: C, 74.25; H, 6.8; N, 2.3; C37H41NO6 requires: C, 74.6; H, 6.9; N, 2.35% Example 26 [1&alpha;(Z),2ss,5&alpha;]-(#)-4-Acetylaminophenyl 7-[[(1,1'-Biphenyl)4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]5-heptenoate, compound with ethyl acetate (10:1) DMSO (0.61 ml) in CH2C12 (14 ml) was added dropwise to a stirred solution of acetyl bromide (0.57 ml) in CH2C12 (7 ml) under dry nitrogen at -78 . After 10 min. a solution of Intermediate 39 (1.05 g) in CH2Cl2 (14 ml) was added and stirring continued for 45 min. Triethylamine (2.87 ml) in CH2C12 (14 ml) was added at -78 e and the mixture was stirred at ambient temperature for 45 min. The mixture was poured into water (100 ml) and extracted with CH2C12 (3 x 30 ml). The combined extracts were dried and evaporated and the residue was purified by chromatography (E) to give the title compound as a solid (0.73 g), m.p. 45-470. Analysis Found: C, 72.9; H, 7.0; N, 4.5; C37H42NO6. 0 .lC4H8O2 requires: C, 72.5; H, 7.0; N, 4.5% Example 27 [1&alpha;(Z),2ss,5&alpha;]-(#)-(Acetyloxy)methyl 7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-5-heptenoate A solution of Intermediate 30 (0.4 g), triethylamine (0.23 ml) and bromomethyl acetate (0.19 g) in dry acetone (6 ml) was stirred at 20 for 2h then poured into pH 6.5 phosphate buffer (20 ml) and extracted with EA (2 x 20 ml). The combined extracts were dried and evaporated, and the residue was purified by chromatography (K) to give the title compound as an oil (0.3 g). I.R. (CHBr3) 1755, 1740 cm 1 Analysis Found: C, 69.7; H, 7.05; N, 2.3; C32H39NO7 requires: C, 69.9; H, 7.15; N, 2.55% Example 28 [1&alpha;(Z),2ss,5&alpha;]-(#)-(3-Pyridinyl) 7-[5-[[(1,1'-Biphenyl) 4-yl methoxy -2-(8-morpholinyl) -3-oxocyclopentyl7 - 5-heptenoa te A solution of Intermediate 30 (0.35 g) and triethylamine (0.41 ml) in acetone (7.5 ml) at -10 was treated with iso-butylchloroformate (0.29 ml) and 0.25h later with 3-hydroxypyridine (0.35 g). After 0.75h, the solvent was removed in vacuo and the residue in pH 6.5 phosphate buffer (30 ml) was extracted with EA (3 x 25 ml). The combined extracts were washed with 0.2N NaOH (30 ml), dried and evaporated, and the residue was purified by chromatography (II) to give the title compound as a solid (0.37 g), m.p. 74-75 . Analysis Found: C, 73.5; H, 6.9; N, 5.0; C34H38N205 requires: C, 73.6; H, 6.9; N, 5.1% Example 29 [1&alpha;(Z),2ss,5&alpha;]-(#)-[4-Aminocarbonyl)phenyl] 7-[5-[[4' Methoxy(1,1'-biphenyl)-4-yl]methoxy]2-(4-morpholinyl)3-oxocyclopentyl]-5-heptenoate A well stirred solution of Intermediate 43 (0.395 g) in DMSO (5 ml) and triethylamine (0.7 ml) was treated with pyridine-sulphur trioxide complex (0.3 g) in DMSO (5 ml) and was kept at 20 for 2h. The mixture was poured into pH 6.5 phosphate buffer and extracted with CH2C12. The combined extracts were dried and evaporated, and the residue was purified by chromatography (C through to B) to give the title compound as an oil (0.335 g). I.R. (CHBr3) 3520, 3400, 1753(sh.), 1745, 1680 cm Analysis Found: C, 70.6; H, 7.0; N, 4.8; C37H42N207 requires: C, 70.9; H, 6.75; N, 4.5% Example 30 + [1&alpha;(Z),2ss,5&alpha;]-(#)-(Acetylthio)methyl 7-(5-[[(1,1' Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl-3-oxocyclo pentyll -5-heptenoate A well stirred solution of Intermediate 44 (0.31 g) in DMSO (4 ml) and triethylamine (0.6 ml) was treated with pyridine-sulphur trioxide complex (0.26 g) in DMSO (3 ml) and was kept at 20 for 1.5h. The mixture was poured into EA (175 ml) and was washed with pH 6.5 phosphate buffer (3 x 30 ml) and brine (30 ml), then dried and evaporated. The residue was chromatographed twice (T then JJ) to give the pure title compound as an oil (0.2 g). I.R. (CHBr3) 1740, 1700 cm 1. T.L.C. (KK) RfO.27 Example 31 [1R-[la(Z) ,2B,3B,5a]]-(+) -2-Propenyl 7-15-[[(lfl'- Biphenyl)-4-yllmethoxy]-3-hydroxy-2-(l-piperidinyl)- cyclopentyll -4-hePtenoate To a solution of Intermediate 54 (0.4g) and diisopropylethylamine (0.68ml) in DMF (5ml) was added dropwise 3-bromopropene (0.27ml). The mixture was stirred for 20h then poured into pH 6 phosphate buffer (50ml) and extracted with EA (3 x 50ml). The combined extracts were dried and evaporated and the residue purified by chromatography (LL) to give the title compound (0.23g) as an oil. [&alpha;]D25 = +61.9 (CHCl3) I.R. (Neat) 3400, 1730 cm-1 Analysis Found: C,76.3; H,8.7; N,2.8; C33H43NO4 requires: C,76.6; H,8.4; N,2.78 Example 32 [1R-[1&alpha;(Z),2ss,3ss,5&alpha;]]-(+)-Methoxymethyl 7-[5-[[(1,1' Biphenyl) -4-yl0 methoxyl -3-hydroxy-2- (1-piper idinyl) - cyclopentyl]-4-heptenoate To a cold (0 ) solution of Intermediate 54 (0.5g) and diisopropylethylamine (0.42ml) in DMF (6ml) was added dropwise chloromethyl methyl ether (0.11ml). The mixture was stirred for 3h during which time ambient temperature was reached. The solution was poured into pH 6 phosphate buffer (50ml) and extracted with EA (3 x 50ml). The combined extracts were dried and evaporated and the residue purified by chromatography on alumina initially (C) then (B)1 to give the title compound (0.285g) as an oil. [&alpha;]D23.5 = +60.3 (CHCl3) I.R. (Neat) 3400, 1745cm 1 Analysis Found: C, 73.5; H,8.5; N,2.95; C32H43NO5 requires: C, 73.7; H, 8.3; N, 2.78 Example 33 [1R-[1&alpha;(Z),2ss,3ss,5&alpha;]]-(+)-(2-Oxo-2-phenylethyl) 7 [5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1piperindinyl)cyclopentyl]-4-heptenoate, compound with ethyl acetate (2.5 : 1) A solution of Intermediate 54 (0.4g) in CH3CN (12ml) containing diisopropylethylamine (0.4ml) was treated with a-bromoacetophenone (0.3g) and stirred for 3h. EA (100ml) was added and the mixture washed with pH 6.5 phosphate buffer (2 x 40ml) and brine (40ml). The organic layer was dried and evaporated, and the residue purified by chromatography (MM) to give the title compound (0.4g) as an oil. [&alpha;]D23.8 = +59.2 (CHCl3) I.R. (Neat) 1750, 1710cm Analysis Found: C, 75.4; H,7.7; N,2.5; C38H24NO5.0.4C4H8O2 requires: C,75.4; H,7.7; N,2.2% Example 34 [1R-[1&alpha;(Z),2ss,3ss,5&alpha;]]-(+)-(2-Amino-2-oxoethyl) 7-[5 [[(1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1piperidinyl)cyclopentyl]-4-heptenoate, compound with ethyl acetate (2:1) A solution of Intermediate 54 (0.5g) in DMF (7.5ml) containing diisopropylethylamine (0.5ml) was treated with chloroacetamide (0.459) and sodium iodide (0.25g) then stirred for 48h. The mixture was poured into pH 6.5 phosphate buffer (80ml) and extracted with EA (4 x 40ml). The combined extracts were washed with brine, dried and evaporated, and the residue purified by chromatography [initially (MM) then (RR)] to give the title compound as an oil (0.242g). [&alpha;]D25 = +57.4 (CHCl3) I.R. (CHBr3) 3520, 3400, 1740, 1695cm Analysis Found: C,70.8; H,8.4; N,5.1; C32H42N205.0.5C4H802 requires: C,70.6; H,8.0; N,4.8% Example 35 [1R-[la(Z),2,3$,5a]]-(+)-(Methy1thio)methy1 7-[5 [[(1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1 piperidinyl)cyclopentyl]-4-heptenoate Chloromethylmethyl sulphide (0.15ml) was added to a stirred mixture of Intermediate 54 (0.5g) , triethylamine (0.75ml) and sodium iodide (about 5mg) in dry DMF (7ml). After 22h further triethylamine (0.75ml) and chloromethylmethyl sulphide (0.15ml) were added and stirring continued for 18h. The reaction mixture was diluted with pH 6.5 phosphate buffer (100ml) and extracted with EA (2 x 50ml). The combined extracts were washed with brine (40ml), dried and evaporated, and the residue purified by chromatography [initially (PP) then (QQ)] to give the title compound (0.2859) as an oil. [&alpha;]D24 = +57.8 (CHCl3) I.R. (Neat) 3400, 1740 cm T.L.C. (LL) Rf 0.28 Example 36 [1R-[1&alpha;(Z),2ss,3ss,5&alpha;]]-(+)-(Acetyloxy)methyl 7-[5-[[(1,1' Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl) cycloPentyll-4-heptenoate Bromomethyl acetate (0.25ml) was added to an ice cooled, stirred mixture of Intermediate 54 (0.359) and triethylamine (0.8ml) in acetone (8ml). After lh the ice bath was removed and the mixture stirred at room temperature for 2.5h. The mixture was diluted with pH 6.5 phosphate buffer (80ml) and extracted with EA (2 x 50ml). The organic extracts were washed with brine (50ml), dried and evaporated, and the residue purified by chromatography (00) to give the title compound (0.224g) as an oil. [&alpha;]D26 = +59.6 (CHCl3) I.R. (Neat) 3400, 1760 cm Analysis Found: C,71.8; H, 7.9; N,2.4 C33H43N06 requires: C, 72.1; H,7.9; N,2.55% Example 37 lla(Z),2B,3B,5a -(-)-(Acetyloxy)methyl 7-[3-Hydroxy5-[[4'-methoxy(1,1'-biphenyl)-4-yl]methoxy]-2-(1 piperidinyl)cyclopentyll-4-heptenoate Bromomethyl acetate (0.06ml) was added to an ice cooled, stirred solution of Intermediate 62 (0.125g) and triethylamine (O.lml) in acetone (3ml). After 1H at 0 and 0.5h at room temperature, further triethylamine (O.lml) and bromomethyl acetate (0.03ml) were added. After lh, the mixture was diluted with pH 6.5 phosphate buffer (30ml) and extracted with EA (2 x 30ml). The combined extracts were washed with brine (20ml), dried and evaporated, and the residue purified by chromatography [initially (E) then (NN) to give the title compound (0.05g) as an oil. I.R. (CHBr3) 1755 cm 1 Analysis Found: C, 70.5; H,7.9; N,2.6; C34H45N07 requires: C,70.3; H,8.0; N,2.4% Example 38 [1R-[1&alpha;(Z),2ss,3ss,5&alpha;]]-(+)-(Acetyloxy)methyl 7-[[(1,1' Biphenyl) -4-yl] methoxy] 3-hydroxy-2- (1-piper idinyl) cyclopentyll-5-heptenoate To a solution of Intermediate 65 (0.64g) in acetone (13ml) was added triethylamine (0.93ml) followed by a solution of bromomethyl acetate (0.9029) in acetone (6ml) and the mixture stirred at 20 for 4h, then stored at 0-5 for 13.5h. The solution was then poured into pH 6 phosphate buffer solution (100mlj and extracted with CH2C12 (3 x 80ml). The combined extracts were dried, evaporated in vacuo, and the residue purified by column chromatography (PP) to give the title compound as an oil (0.313g). I.R. (CHBr3) 3500-2600, 2810, 2760, 1760 cm 1 T.L.C. (FF) Rf 0.48 [a]D25 = +33.60 (CHC13) Example 39 [1R-[1&alpha;(Z),2ss,3ss,5&alpha;]]-(+)-[4-(Acetylamino)phenyl] 7-[5 [[(1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1piperidinyl)cyclopentyl]-4-heptenoate Isobutyl chloroformate (0.24ml) was added under nitrogen to a stirred, cooled (bath temp. -10 D) mixture of the Intermediate 54 (0.3g) and triethylamine (0.47ml) in pure acetone (7.5ml). After 20 min, p-acetamidophenol (0.5g) was added and the mixture stirred at -10 for 2.5h and then at room temperature for 1 h. The mixture was diluted with pH 6.5 phosphate buffer (80ml) and extracted with EA (2 x 60ml). The combined organic extracts were washed with brine (30ml), dried and evaporated in vacuo to give a gum (0.76g). The gum was redissolved in CH2C12 (20ml), the solid filtered off and the filtrate evaporated in vacuo. The residue was purified by chromatography [initially (LL) then (W)] to give the title compound as a foam (0.1759). I.R. (CHBr3) 3425, 1750, 1690 cm 1 T.L.C. (WW, double elution) Rf 0.34 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 m The active ingredient is sieved through a 250 m 6 sieve, blended with the excipients and compressed using lO.Omm 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 400.00 mg The active ingredient is sieved through a 250 m 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 magnesiuE-stearate. The lubricated granules are compressed into tablets as described for the direct compression formulae. 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 200.00mg * A form of directly compressible starch supplied by Colorcorn Ltd., Orpington, Kent. The active ingredient is sieved through a 250 m 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 /cartridge Active ingredient (micronised) 3 mg Lactose B.P. to 25 mg The active ingredient is micronised so that -6 the majority of the particles are between 1 m 6 and 5 m in longest dimensions and none are greater than 10 m 6. The active ingredient is then blended with the lactose and the mix is filled into No. 3 hard gelatin capsules using a suitable filling machine. Suspensions mg/5ml dose Active ingredient 100.0 Aluminium monostearate 75.0 Sucrose (powdered) 125.0 Flavour) as Colour ) required Fractionated coconut oil to The aluminium monostearate is dispersed in about 9 of the fractionated coconut oil. The resulting suspension is heated to 115 CC while stirring and then cooled. The flavour and colour are added and the active ingredient and sucrose are suitably dispersed. The suspension is made up to volume with the remaining fractionated coconut oil and mixed. Injection for Intravenous Administration Active ingredient 50mg Suitable vehicle to 5ml. A sterile presentation of the active ingredient in an ampoule or vial together with an ampoule containing a suitable vehicle. The former may be prepared by (a) filling sterile material into vials under aseptic conditions (b) freeze drying a sterile solution of the active ingredient under aseptic conditions. The vehicle may be (a) Water for Injections B.P. (b) Water for Injections B.P. containing: (1) sodium chloride to adjust the tonicity of the solution and/or (2) buffer salts or dilute acid or alkali to facilitate solution of the active ingredient. The vehicle is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass. The vehicle is sterilised by heating in an autoclave using one of the acceptable cycles.

Claims: CLAIMS 1. Compounds of the general formulae (la) and (lb) EMI65.1 wherein R1 is (a) -AR3 where A is -O- or -S- and R3 is phenyl [optionally substituted by C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyl, methylthio, methylsulphinyl, methylsulphonyl, halogen, -CO2R4 [where R4 is a hydrogen atom, C1-4 alkyl or phenyl], -NHCOR4, -CONR5R6 [where R5 and R6 may be the same or different and are each a hydrogen atom or C1-4 alkyl], C1-4 alkylsulphonylamino, formyl, nitro, cyano, phenyl or -NR5R6] (b) -OCH2COR7 where R7 is phenyl (optionally substituted by a halogen atom, C1-4 alkyl or C1-4 alkoxy) or -NH2; (c) -A(CH3)TBR5 where m is 1-3 and B is -O- or S-, provided that when m is 1, R5 is not a hydrogen atom; ; (d) -A(CH2)pR8 where p is 2 or 3 and R8 is an Nattached C14 dialkylamino, morpholino, piperidino, pyrrolidino, acetylamino or benzoylamino group; (e) -OCH(CH9N (CH3)2)2 where R9 is a hydrogen atom, methyl EMI65.2 or phenyl; (g) -OCH2OCOR10 where R10 is C1-4 alkyl, methoxy or phenyl; (b) -OCH2SOR11 is C1-4 alkyl; (i) pyridinyloxy or pyridinylthio; (j) 1- (acetyloxy) ethoxy, (acetyloxy) phenylmethoxy, tetrahydro-5-oxo-2-furanyloxy, tetrahydro-2-oxo-3furanyloxy, triphenylmethoxy or diphenylmethoxy; or (k) -OR12 where R12 is C36 alkenyl, C57 cycloalkyl (optionally substituted by one or more C1-4 alkyl groups), -CH2CC13 or furanylmethyl; n is 1 or 2; W is straight or branched C1 7 alkylene; X is cis or trans -CH=CH- or -CH2CH2-; 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 -O-, -S-, -SO2-, or NR13 (where R13 is a hydrogen atom, C1-7 alkyl or aralkyl having a C1 4 alkyl portion); and/or (b) is optionally substituted by one or more C14 alkyl groups; R2 is (i) straight or branched C1-5 alkyl substituted by (a) phenyl [optionally substituted by C1-6 alkyl, C5-7 cycloalkyl, phenylalkyl having a C1-3 alkyl portion, thienyl, phenyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or phenyl), benzoyl (optionally substituted by C14 alkyl, C14 alkoxy, halogen, trifluoromethyl or phenyl) or C57 cycloalkanoyl], (b) thienyl [optionally substituted by C5-7 cycloalkyl or phenyl (optionally substituted by C1-3 alkyl, C13 alkoxy or halogen)], or (c) naphthyl (optionally substituted by C1-4 alkyl or C1-4 alkoxy), or (ii) cinnamyl (optionally substituted by benzoyl); and the physiologically acceptable salts and solvates thereof. 2. Compounds as claimed in claim 1 in which Y is morpholino or piperidino. 3. Compounds as claimed in any one of the preceding claims in which X is cis -CH=CH-. 4. Compounds as claimed in any one of the preceding claims in which n is 2 @@ W is CH2CH2- or CH2CH2CH2CH2- 5. Compounds as claimed in any one of the preceding claims in which R2 is a benzyl group in which the phenyl group is substituted by thienyl or phenyl, which latter phenyl is optionally substituted by C14 alkyl or C14 alkoxy. 6. Compounds as claimed in any one of the preceding claims in which R1 is -OCH2OCOCH3, -OCH2SCH3, -O(CH2) 3NHCOCH3, -OCH2CONH2, 4-acetamidophenoxy or allyloxy. 7. Compounds as claimed in claim 1 in which: R1 is -OCH2OCOCH3, -OCH2SCH3, -O(CH2)3NHCOCH -OCH2CONH2, 4-acetamidophenoxy or allyloxy W is -CH2CH2-, n is 2, X is cis -CH=CH Y is morpholino or piperidino in compounds of formula (lb) or in piperidino in compounds of formula (la) , and R2 is benzyl in which the phenyl group is substituted by phenyl, tolyl or methoxyphenyl, and the physiologically acceptable salts and solvates thereof. 8. Compounds as claimed in any one of the preceding claims in which the carbon atom carrying the -(CH2)nXWCOR group is in the R- configuration. 9. Compounds as claimed in any one of the preceding claims, said compounds having the formula (la). 10. A pharmaceutical composition comprising a compound as claimed in any one 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) esterifying the cdrresponding compound in which R1 is -OH, or, in the preparation of a compound in which R1 is a group of the type (c) and A is -S-, reacting the corresponding compound in which R1 is -SH with a halide, R5BCH2Hal; (b) reducing the corresponding compound in which X is an acetylene group; (c) reducing the corresponding compound in which R is phenyl substituted by azido to prepare a compound in which R3 is phenyl substituted by amino; (d) in the preparation of a compound in which X is -CH2CH2-, catalytically hydrogenating a corresponding compound in which X is -CH=CH-; ; (e) in the preparation of a compound of formula (lb), oxidising a corresponding hydroxy compound of formula (4) EMI68.1 (f) in the preparation of a compound of formula (lib) in which R1 is -OCH2SCH3, simultaneously oxidising and esterifying the corresponding compound of formula (4) in which R1 is -OH; or (g) in the preparation of a salt, treating a compound of formula (la) or (lb) with an acid, or, when R1 contains a -COOH group, with a base. CLAIMS FOR AUSTRIA ONLY 1. A process for the preparation of a compound of the general formula (la) or (1b) EMI69.1 wherein R1 is (a) -AR3 where A is -O- or -S- and R3 is phenyl [optionally substituted by C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyl, methylthio, methylsulphinyl, methylsulphonyl, halogen, -CO2R4 [where R4 is a hydrogen atom, C1-4 alkyl or phenyl], -NHCOR4, -CoNR5R6 [where R5 6 and R6 may be the same or different and are each a hydrogen atom or C1-4 alkyl], C1-4 alkylsulphonylamino, formyl, nitro, cyano, phenyl or -NR5R6]; (b) -OCH2COR7 where R7 is phenyl (optionally substituted by a halogen atom, C14 alkyl or C1-4 alkoxy) or -NH2; (c) -A(CH2)mBR5 where m is 1-3 and B is -O- or S-, provided that when m is 1, R5 is not a hydrogen atom; ; (d) -A(CH2) pR8 where p is 2 or 3 and R8 is an Nattached C1-4 dialkylamino, morpholino, piperidino, pyrrolidino, acetylamino or benzoylamino group; (e) -OCH(CH2N (CH3)2)2 EMI69.2 where R9 is a hydrogen atom, methyl or phenyl; (g) -OCH2OCOR10 where R10 is C1-4 alkyl, methoxy or phenyl; (h) -OCH2SCOR11 is C1-4 alkyl; (i) pyridinyloxy or pyridinylthio; (j) 1-(acetyloxy)ethoxy, (acetyloxy)phenylmethoxy, tetrahydro-5-oxo-2-furanyloxy, tetrahydro-2-oxo-3- furanyloxy, triphenylmethoxy or diphenylmethoxy; or (k) -OR12 where R12 is C3-6 6 alkenyl, C5-7 cycloalkyl (optionally substituted by one or more C1-4 alkyl groups), -CH2CC13 or furanylmethyl; n is 1 or 2; W is straight or branched C1-7 alkylene; X is cis or trans -CH=CH- or -CH2CH2-; 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 -O-, -S-, -SO2-, or NR13 (where R13 is a hydrogen atom, C1-7 alkyl or aralkyl having a C1 4 alkyl portion); and/or (b) is optionally substituted by one or more C1-4 alkyl groups; R is (i) straight or branched C15 alkyl substituted by (a) phenyl loptionally substituted by C16 alkyl, C57 cycloalkyl, phenylalkyl having a C1-3 alkyl portion, thienyl, phenyl (optionally substituted by C14 alkyl, C1-4 alkoxy or phenyl), benzoyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl or phenyl) or C5-7 cycloalkanoyl], (b) thienyl [optional- ly substituted by C5-7 cycloalkyl or phenyl (optionally substituted by C13 alkyl, C13 alkoxy or halogen)] or (c) naphthyl (optionally substituted by C1-4 alkyl or C1-4 alkoxy), or (ii) cinnamyl (optionally substituted by benzoyl); and the physiologically acceptable salts and solvates thereof, which process comprises: (a) esterifying the corresponding compound in which RÚ is -OH, or, in the preparation of a compound in which RÚ is a group of the type (c)and A is -S-, reacting the corresponding compound in which RÚ is -SH with a halide, R5BCH2Hal; (b) reducing the corresponding compound in which X is an acetylene group; (c) reducing the corresponding compound in which R3is phenyl substituted by azido to prepare a compound in which R3 is phenyl substituted by amino; (d) in the preparation of a compound in which X is -CH2CH2-, catalytically hydrogenating a corresponding compound in.which X is -CH=CH-; ; (e) in the preparation of a compound of formula (lb), oxidisinq a corresPondina hvdroxv compound of formula (4) EMI71.1 (f) in the preparation of a compound of formula (lb) in which R1 is -OCH2SCH3, simultaneously oxidising and esterifying the corresponding compound of formula (4) in which R1 is -OH; or (g) in the preparation of a salt, treating a compound of formula (la) or (lb) with an acid, or, when R1 contains a -COOH group, with a base. 2. A process as claimed in claim 1 in which Y in the product is morpholino or piperidino. 3. A process as claimed in any one of the preceding claims in which X in the product is cis -CH=CH-. 4. A process as claimed in any one of the preceding claims in which, in the product, n is 2 and W is CH2CH2 - or CH2CH2CH2CH2-. 5. A process as claimed in any one of the preceding claims in which R2 in the product is a benzyl group in which the phenyl group is substituted by thienyl or phenyl, which latter phenyl is optionally substituted by C1-4 alkyl or C14 alkoxy. 6. A process as claimed in any one of the preceding claims in which R1 in the product is -OCH2OCOCH3, -OCH2SCH3, -O(CH2)3NHCOCH3, -OCH2CONH2, 4-acetamidophenoxy or allyloxy. 7. A process as claimed in claim 1 in which the product is a compound of formula (la) or (lb) in which: R1 is -OCH2OCOCH3, -OCH2SCH3, -O(CH2)3NHCOCH3, -OCH2CONH2, 4-acetamidophenoxy or allyloxy W is -H2CH2-, n is 2, .X-ts cis -CH=CH Y is morpholino or piperidino in compounds of formula (lb) or in piperidino in compounds of formula (la), and R2is benzyl in which the phenyl group is substituted by phenyl, tolyl or methoxyphenyl, or a physiologically acceptable salt or solvate thereof. 8. A process as claimed in any one of the preceding claims in which the carbon atom carrying the -(CH2) n XWCOR1 group is in the R- configuration in the product. 9. A process as claimed in any one of the preceding claims in which the product is a compound of formula (la). 10. A process for the manufacture of a pharmaceutical composition comprising a compound of formula (1) as defined in any of the preceding claims, which comprises formulating said compound with one or more pharmaceutical carriers. 11. A process as claimed in claim 10 in which a unit dose of the compound of formula (1) is formulated as a tablet or liquid for injection, or in which the compound of formula (1) is formulated as an aerosol, solution or inhalation cartridge for the inhalation of a metered amount of said compound.

Inventors: BRADSHAW, JOHN, CARTER, MALCOLM, COLLINGTON, ERIC W., HALLETT, PETER, HAYES, NORMAN F., WADSWORTH, ALAN, WALLIS, CHRISTOPHER J.
Applicants: GLAXO GROUP LIMITED
Application year: 1982
Main classification: C07D295
IPC codes: C07C45, C07D307, C07D295, C07D309, C07D333, C07D213, C07D311