GB2165535A

GB2165535A - Carbocyclic compounds

Info

Publication number: GB2165535A
Application number: GB08422455A
Authority: GB
Inventors: Eric William Collington; Peter Hallett; Christopher John Wallis; Norman Frank Hayes
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1984-09-05
Filing date: 1984-09-05
Publication date: 1986-04-16
Also published as: GB8422455D0

Abstract

1) Compounds of the general formula (1> <IMAGE> wherein: 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; R<1> is a) optionally substituted phenyl b) C3-6 alkenyl, C3-6 alkynyl, thienylmethyl, furanylmethyl, pyridinyl or C5-7 cycloalkyl (optionally substituted by one or more C1-4 alkyl groups); c) -CH2COR<6> where R<6> is optionally substituted phenyl; d) -(CH2)mB(CH2)nR<3> where m is 1-3, n is 0-3 and B is -O- or -S-, provided that when m is 1 and n is 0 then R<3> is not a hydrogen atom; e) -(CH2)pR<7> wherein p is 2 or 3 and R<7> is an amino group or an acetylamino or benzoylamino group; f> <IMAGE> where R<8> is a hydrogen atom, methyl or phenyl and R<9> is C1-7 alkyl, C5-7 cycloalkyl or phenyl; g) -CH(CO2R<9>)2; h) -CH2OCOR<10> where R<10> is C1-4 alkyl, methoxy or phenyl; i) 1-(acetyloxy)ethyl, (acetyloxy)phenylmethyl, tetrahydro-5-oxo-2-furanyl or tetrahydro-1-oxo-3-furanyl; j) -CH(CH2OH)2; <IMAGE> where R<11> is OH or CH2OH and R<12> is a hydrogen atom, C1-4 alkyl or CH2OH; l) 2,2-dimethyl-1,3-dioxolan-4-yl-methyl R<2> is C1-5 alkyl substituted by phenyl (optionally substituted) thienyl (optionally substituted), naphthyl (optionally substituted) or cinnamyl; and the physiologically acceptable salts thereof. These compounds inhibit good platelet aggregation, bronchoconstriction and vasoconstriction and may be formulated for use as antithrombotic or antiasthmatic agents.

Description

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

We have now found a new group of compounds which have good endoperoxide and thromboxane antagonist activity, and are therefore of interest in the treatment of cardiovascular diseases, asthma and adult respiratory distress syndrome, and for use in renal transplant and dialysis and in the prevention of relapse of healed peptic ulcers.

The invention thus provides compounds of the general formula (1 )

wherein: n is 1 or 2; W is straight or branched C1.7 alkylene; Xis 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 -0--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; R1 is a) phenyl [optionally substituted by C1.4 alkyl, ClA alkoxy, C1.4 alkanoyl, -NHCOR3 (where R3 is a hydrogen atom, C1.4 alkyl or phenyl) or -NR4R5 (where R4 and R5 may be the same or different and are each a hydrogen atom or C1-4 alkyl)l; b) C3.6 alkenyl, C3.6 alkynyl, thienylmethyl, furanylmethyl, pyridinyl or C5.7 cycloalkyl (optionally substituted by one or more C1-4 4 alkyl groups);; c) -CH2COR6 where R6 is phenyl (optionally substituted by a halogen atom, C1.4 alkyl or C1.4 alkoxy), or -NR3R4 (where R3 and R4 are as defined in a), or where -NR3R4forms a saturated heterocyclic group which has 5-7 ring members and optionally contains in the ring -0-); d) -(CH2)mB(CH2)nR3 where m is 1-3, n is 0-3 and B is -O- or -S-, provided that when m is 1 and n is0 then R3 is not a hydrogen atom; e) -(CH2)pR7 where p is 2 or 3 and R7 is -NR3R4 as defined in c), or an acetylamino or benzoylamino group;

where R8 is a hydrogen atom, methyl or phenyl and R9 is C1.7 alkyl, C5.7 cycloalkyl or phenyl; g) -CH(CO2R9)2; h) -CH20COR10 where R10is C1-4alkyl, methoxy or phenyl; ill -(acetyloxy)ethyl, (acetyloxy) phenyl methyl, tetrahydro-5-oxo-2-fu ranyl or tetrahydro-2-oxo-3-furanyl; j) -CH(CH2OH)2;

where R11 is OH or CH2OH and R12 is a hydrogen atom, C1.4 alkyl or CH20H;;

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)], (b) thienyl [optionally substituted by Cos 7 cycloalkyl or phenyl (optionally substituted by C1.3 alkyl, C1-3 alkoxy or halogen)3, or (c) naphthyl (optionally substituted by C1.4 alkyl or C1-4 alkoxy) or (ii) cinnamyl; 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.

Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, maleates, tartrates, citrates, 2-chlorobenzoates, p-toluenesulphonates, methanesulphonates, salicylates, fumarates, lactates, hydroxy-naphthalenecarboxylates (e.g. 1 -hydroxy- or 3-hydroxy-2naphthalenecarboxylates) orfuroates.

The heterocyclic amino group Y may for example have a 5,6 or 7-membered ring, e.g. pyrrolidino, piperidino, morpholino, piperazino, thiomorpholino, 1,1-dioxothiomorpholino, homomorpholino and hexamethyleneimino. Examples of the optional substitutents (R'3) which may be present on a second nitrogen atom in the ring are methyl, ethyl, butyl, hexyl, benzyl and phenethyl. The carbon atoms of the heterocyclic rings may for example be substituted by methyl, ethyl or butyl.

In general Y is preferably pyrrolidino, piperidino or hexamethyleneimino, optionally substituted by one or two 01.4 alkyl (particularly methyl) groups, e.g. 4-methylpiperidino. Compounds of formula (1 ) in which Y is piperidino are particularly preferred.

Examples of the group R' are phenyl; phenyl substituted by C1-4 alkyl, C1-4 alkoxy, formyl, acetyl, propionyl, butyryl, -NHCOR3 (where R3 is a hydrogen atom, C1-4 alkyl or phenyl), -N H2, -NHCH3, -NHCH2CH3, -N(CH3)2 or -N(CH2CH3)2; propenyl; isopropenyl; propynyl; isopropynyl; thienylmethyl; furanylmethyl; pyridinyl; cyclopentyl, cyclohexyl or cycloheptyl optionally substituted by C1-4 alkyl; -CH2COR6, where Re is -NR3R4, phenyl, or phenyl substituted by a fluorine, chlorine, bromine or iodine atom, Cur 4 alkyl or C, 4 alkoxy; -CH2OCH3; -CH2SCH3; -(CH2)2OCH3; -(CH2)2SCH3; -CH2OCH2CH3; -CH2SCH2CH3; -(CH2)20CH2CH3; -(CH2)2SCH2CH3, -(CH2)20H; -(CH1)BOH; -(CH2)2NR3R4; -(CH2)3NR3R4; (CH2)2N HCOCH3;

or -CH(CO2R9)2 where R9 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl; -CH2OCOR1 where R10 is C1-4 alkyl, methoxy or phenyl; 1 -(acetyloxy)-ethyl; (acetyloxy)phenyl methyl; tetrahydro-5-oxo-2-furanyl; tetrahydro-2-oxo-3-fura nyl; -CH(CH20H)2; -CH2CH(OH)CH20H; -CH2CH(CH20H)2; -CH2C(CH20H)3;

where R12 is C14 alkyl; or

In the definition of the group R1, the term C1-4 alkyl whenever used means a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl ort-butyl group. The term C1-4 alkoxy whenever used means a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy ort-butoxy group. Particular examples of the term -NR3R4 whenever used are -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2,

pyrrolidino, piperidino, hexamethyleneimino, morpholino or homomorpholino.

Particular examples of the group R1 include

-CH2CH(OH)CH2OH,thienylmethyl, propenyl, propynyl, -CH2CON H2, -CH2CON(CH3)2, -CH2OCOCH3, -CH2OCH3, -CH2SCH3, -(CH2)3NHCOCH3, acetamidophenyl, e.g. 4-acetamidophenyl,

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

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

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

In general R2 is preferably (1) a C1.5 alkyl (particularly methyl, ethyl or propyl) group substituted by phenyl, thienyl (optionally substituted by phenyl), naphthyl, or phenyl substituted by phenyl(C1.3)alkyl, thienyl or phenyl (optionally substituted by C1.4 alkyl or C1.4 alkoxy) or (2) cinnamyl. Thus R2 may be, for example, (1 ) methyl, ethyl or propyl (particularly methyl) substituted by naphthyl, thienyl substituted by phenyl and phenyl substituted (preferably in the para position) bythienyl, benzyl, phenyl or phenyl substituted (preferably in the para position) by methyl or methoxy, or (2) cinnamyl.Examples of such R2 groups are benzyl substituted by phenyl or phenyl substituted by methyl or methoxy, for example [(1,1'-biphenyl)-4-yl]methyl, [4'-methoxy(l,l '-biphenyl)-4-yl]methyl or [4'-methyl(1 ,1 '-biphenyl)-4-yl]methyl.

Xis preferbly cis -CH=CH-.

W may contain for example 1-5 carbon atoms in a straight or branched chain, and may be for example -(CH2)2-, -(CH2)3- or -(CH2)4-. Particularly interesting compounds according to the invention are those in which n is 1 and W is -(CH2)3- and n is 2 and W is -(CH2)2- or -(CH2)4-, particularly -(CH2)2-. Preferably, n is 2.

In general, the compounds of formula (1 ) in which the carbon atom carrying the - the(CH2)nXWCOOR1 group is in the R configuration (and mixtures containing this isomer) are preferred.

The preferences indicated above apply both separately and in combination with each other and/or the general definition stated for general formula (1).

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

The ability of the compounds of the invention to inhibitvasoconstriction or bronchoconstriction is determined using the relevant isolated tissue (e.g. spirally cut rat aortic strip or guinea-pig lung parenchymal strip) by measuring the effect of the compound to be tested on the contraction of the tissue to [1 P-[1 eA,5p(Z),6( 1 E,3S*)]]-7-[6-(3-hydroxy-1 -octenyl)-2-oxabicyclo[2,2,1 ]hept-5-yl]-5-heptenoic acid (U46619).

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

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

The compounds may be formulated in a 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 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 oil 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 1 Omg/kg body weight, 1 to 4 times daily, or intravenously, for example in amounts of 0.01 to 25mg/kg body weight 1 to 4times daily.

For use in the treatment of asthma, the compounds may also be administered orally in amounts of 0.05 to 1 Omg/kg body weight, 1 to 4 times daily; preferably however they are administered by inhalation at doses varying from 0.02 to 30mg, preferably 0.02 to 3mg 1 to 4times 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 various groups and symbols being as defined above except where otherwise indicated.

(a) Compounds of formula (1) may be prepared by esterification of the corresponding carboxylic acids of formula (2)

Conventional esterification methods may be used.

Thus, for example, compounds in which R1 is a group of the type b (except 3-pyridinyl) c,d,e,f,g,h or i may be prepared by reacting the corresponding carboxylic acid with an appropriate halide R1Hal, where Hal represents a halogen atom. 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. acetone), for example at a temperature from OOC to room temperature.

Compounds of formula (1 ) in which R1 is a group of the type j, k or I may be prepared by reacting the corresponding carboxylic acid with an alcohol P1OH in the presence of an acid, (e.g. p-toluene sulphonic acid) in a solvent (e.g. a chloroform - benzene mixed solvent) for example at any suitable temperature from room temperature up to reflux. The hydroxy groups of R7 groups of types j and k should be protected in this reaction, for example in the form of a cyclic ketal.

Compounds of formula (1) in which R1 is a group of the type (a) or 3-pyridinyl may be prepared by treating a reactive derivative of the corresponding carboxylic acid with an appropriate alcohol. The reactions may be carried out for example 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 suit able base, e.g. triethylamine or pyridine at -10 C.

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

Compounds in which R1 is thienylmethyl may also be prepared by reaction of the corresponding carboxylic acid with 2-thiophenemethanol in the presence of triphenylphosphine and diethylazodicarboxylate in a solvent e.g. an ether-tetrahydrofuran mixture.

(b) Compounds of formula (1 ) in which R1 is a group of the type (k) in which R11 is -OH and R12 is a hydrogen atom may be prepared by treating the corresponding compound in which R' is the group (1) with an acid, e.g. a mineral acid such as hydrochloric acid.

(c) The compounds of the invention in which Xis -CH2CH2 may be prepared by catalytic hydrogenation of a corresponding compound in which Xis -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.

(d) Compounds of formula (1) in which Xis trans -CH=CH- may be prepared by isomerising the corresponding cis compound. The isomerisation may be effected for example by treatment with p-toluene sulphinic acid in dioxan (e.g. at reflux) or azobisisobutyronitrile and thiophenol, using for example a hydrocarbon solvent (e.g. benzene) and any suitable temperature up to reflux.

(e) Where salts of compounds of the invention are desired such salts of compounds of the invention are desired such salts my be formed by conventional methods, for example by treatment with an acid.

Treatment may for example be effected in a suitable solvent such as an ether (e.g. diethylether), acetonitrile, acetone, chloroform, dichloromethane, ethyl acetate, an alcohol (e.g. methanol, ethanol or isopropanol) or iso-propyl acetate.

Salts may also be formed by conversion of one salt of a compound of the invention into another, e.g. by ion exchange using conventional methods.

The intermediate acids of formula (2) may be prepared by hydrolysis of the corresponding methyl esters ol formula (3)

using for example a base such as sodium hydroxide in a solvent such as methanol at room temperature.

The esters of formula (3) may be prepared by dehydroxylation (homolytic cleavage of the carbon-oxygen bond) of a corresponding alcohol of formula (4)

for example via tri-n-butyltin hydride reduction of a thioester derivative such as the thiocarbonyl imidazolide.

The reduction is preferably carried out in a hydrocarbon solvent (e.g. toluene) at a temperature up to and including reflux in the presence of a radical initiator e.g. azobisisobutyronitrile.

The thioester derivative may be conveniently prepared from the alcohol (4) using a suitable reagent (e.g.

1,1 '-thiocarbonyldiimidazole) in a suitable solvent (e.g. tetrahydrofuran) at room temperature.

Alcohols of formula (4) may be prepared by the methods generally described in UK Patent Specifications 2075503A, 2097397A, 2028805A and 2070591 A.

When a specific enantiomer of formula (1) is required, starting materials having the desired stereochemical configuration should be used in the above processors. Such starting materials may be prepared for example from an enantiomeric bicycloheptenone as described in European Patent specification 74856 using the methods generally described in UK Patent Specifications 2028805A, 2075503A and 2098397A.

The following examples illustrate the invention.

Temperatures are in "C.

T.l.c. - Thin layer chromatography using SiO2 unless stated otherwise; THF - tetrahydrofuran DMF - dimethylformamide EA - ethyl acetate ER -ether PE - petroleum ether (b.p. 40-60") Chromatography was carried out using silica gel unless stated otherwise.

'Dried' refers to drying with MgSO4 'Hyflo' is a filtration aid.

The preparation of the following intermediate is described in the British Patent Specification 2097397A.

Intermediate 1 [1 R-[1 Z), 2(3,3p,5]-( +)-Methyl 7-[5-[[(1,1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(l piperidinyl)cyclopentyl]-4-heptenoate.

Intermediate 2 flr-[la)z,,23p,5o/P()-methy/ 7-15-u) 1,1 '-biphenyl)-4-yI]methoxy]-3-f(lh-imidazol- 1-yl)thioXomoethoxy]-2- I l-piperidinyl)cyclopentylj-4-heptenoate A solution of Intermediate 1 (3.lug) and 1,1 '-thiocarbonyldiimidazole (1.359) in dry THF (12ml) was kept at ambient temperature for 2h then the solvent was removed in vacua. The residue in EA (100ml) was washed with pH 6 phosphate buffer, dried and the solvent evaporated to give the title compound as an oil (3.7g).

T.l.c.ER Rf 0.37.

Intermediate 3 [1R-[α(Z),2α,5ss]-(+)-Methyl 7-[2.[[[(1, 1'-Biphenyl]-4-yl]methoxy]-5-{1-piperidinyl)cyclopentyl]-4-heptenoate A solution of Intermediate 2 (3.79), tri-n-butyltin hydride (5ml) and azobisisobutyronitrile (0.3g) in toluene (25ml) was heated under reflux under a nitrogen atmosphere for 2h. More tri-n-butyltin hydride (2ml) was added and heating continued for a further 2h. The solvent was removed in vacuo and the residue was purified by chromatography using 49:1 ER-ET3N as eluent to give the title compound as an oil (1.359) [oLj21 5 = + 74.9 (CHCl3) Analysis Found: C,77.8;H,8.8;N,3.1.

C31H41NO3 requires C,78.3;H,8.7;N,2.9%.

Intermediate 4 [1R-[1α(Z),2α,5ss]]-(+)-7-[2-[[(1, 1'-Biphenyl]-4-yljmethoxyj-5.(1-piperidinyl)cyclopentyl]-4-heptenoic acid, hydrobromide 5N NaOH (0.5ml) was added to Intermediate 3 (0.49) in methanol (2ml) and the mixture was stirred at ambient temperature for 24h. Most of the methanol was removed in vacuo and the residue was adjusted to pH 6 using 5N HCI (0.5ml) and pH 6 phosphate buffer. The mixture was extracted with CH2CI2 (3x50mj) and the combined extracts were dried and evaporated. The residue was purified by chromatography using 85:10:5 CH2Cl2- methanol-Et3N as eluent to give an oil.A solution of the oil in CH2Cl2 (20m I) was washed with pH 6 phosphate buffer (10ml) dried, and evaporated. The residue in CH2CI2 (2ml) was treated with an excess of ethereal hydrogen bromide. The resulting solid was washed with ether and dried to give the title compound(0,275g) m.p. 134-136 [α]D23. 5 = +69 (CHCl3).

EXAMPLE 1 llR-llu11,2u,53//-/+l-2-Propyny/ 7-[2-ll' 1,1'-Biphenyl)-4-yl]methoxy]-5-(1-piperidinyl)cyclopentyl]-4- heptenoate Propargyl bromide in toluene (80% solution, 1 .336ml) was added to a solution of Intermediate 4, base (0.929) and diisopropylethylamine (1.8g) in acetone (10ml) and the mixture was stirred at ambient temperature for 48h. The solvents were removed in vacuo and the residue in water was extracted with CH2CI2 (1 x50ml,2x40ml). The combined extracts were washed with brine (2x20ml), dried and evaporated and the residue was purified by chromatography using 49:49:2 ER-PE-Et3N as eluantto give the title compound as an oil (0.3289).

I.r. (CHBr3) 3275, 2120, 1730cm-1.

Analysis Found: C,79.2;H,8.3;N,2.9.

C33H41NO3 requires C,79.3;H,8.3;N,2.8%.

[2D1 5 = + 74.8 (CHCI3) EXAMPLE 2 [1R-[1α(Z)(2α,5ss]-(+)-2- Thien methyl 7-[2-[[[1,1 '-BiphenylJ-4-yl]methoxyl-5-01-piperidinylJcyclopentyll-4 heptenoate A solution of triphenylphosphine (393mg) and 2-thiophenemethanol (257mg) in ER (6ml) was added dropwise to a stirred solution of Intermediate 4, base (692mg) and diethylazodicarboxylate (261 mg) in 1:1 ER-THF (1 2ml). After 1 8h further quantities of triphenyiphosphine (393mg), 2-thiophenemethanol (257mg) and diethylazodicarboxylate (261 mg) were added and stirring continued for 24h. The solvents were evaporated and the residue triturated with ER to remove triphenylphosphine oxide.The solvent was evaporated and the residue was purified by chromatography using 49:49:2 ER-PE-Et3N as eluant to give the title compound as an oil (104mg).

I.r. (CHBr3) 1725cm-1 T.l.c. 19:1 ER-Et3N Rf 0.2 [α]D20 8 = + 60.9 (CHCl3) EXAMPLE 3 [1R-[α(Z,2α,5ss-(+)-(2,2-Dimethyl- 1,3-dioxolan-4-yl)methyl7-[2-[[1, I'-Biphenyl)-4-yl]methoxy]-5-(l- piperidinyl)cyclopentyl]-4-heptenoate A mixture of Intermediate 4, base (1,846g), anydrous p-toluenesulphonic acid (1.3789) and 2,2-dimethyl 1,3-dioxolane-4-methanol (15ml) in dry benzene (120ml) was stirred under reflux using a Dean and Stark apparatus for 4h. The cooled mixture was washed with 8% NaHCO3 solution (100ml) and the aqueous layer was washed with ER (2x 50ml). The excess dioxolane-methanol was removed at 50 /1mmHg and the residue was purified by chromatography on activity II alumina using ER as eluant to give the title compound as an oil (1.079).

I.r. (CHBr3) 1725cm-1 T.l.c. (Alumina) 19:1 ER-Et3N Rf 0.25 [a]2D1' 4 = +63.5 (CHCI3) EXAMPLE 4 [1R-[1α(Z),2α,5ss]]-(+)-2,3-Dihydroxypropyl 7-[2-[[(1,1'-Biphenyl)-4-yl]methoxy]-5-( 1- oiperidin yl)cyclopentyU-4-heptenoate A mixture of the compound of example 3 (0.7g), 0.5N HC1 (6ml) and acetone (1 5ml) was stirred at ambient temperature for 90h. The mixture was added to 8% NaHCO3 solution (100ml) and extracted with ER (3x50ml). The combined extracts were washed with brine (20ml) dried and evaporated and the residue was purified by chromatography using 91:5:4 EA-methanol-ET3N as eluant to give the title compound as an oil (0.4219).

I.r. (CHBr3) 3590, 3560, 1730cm1 T.l.c. 91:5:4 EA-methanol-ET3N Rf0.3 [o]2J 7 = +65.6 (CHCl3) EXAMPLE 5 IIR-lcL(Z1,2u,sp/l-li-l-2-/Dimethy/ami 7-[2-g1, 7j2-ff(1, 1 '-Biphenyl)-4-yl]methoxyj-5-(l- piperidinyl)cyclopentyl]-4 heptenoate Diisopropylethylamine (775mg) was added to a stirred solution of Intermediate 4, base (692mg) in acetone (15ml) followed by 2-bromo-N,N-dimethylacetamide (747mg). After 18h at ambient temperature the solvent was removed in vacuo and the residue in water (40ml) was extracted with CH2CI2 (3x50ml). The combined extracts were washed with brine (2x20ml) dried and evaporated and the residue was purified by chromatography using 49:1 ER-Et3N to give the title compound as an oil which solidified on standing. The solid was crystallised from EA-PE (210mg) m.p. 63-64 .

Analysis Found: C,74.6;H,8.5;N,5.1.

C34H46N204 required C,74.7;H,8.5;N,5.1%.

[α]D21. 5 = +73.6

Claims

1. Compounds of the general formula (1)

wherein: n is 1 or 2; W is straight or branched C17 alkylene; Xis 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 -0--S-, -SO2-, or -NRa3 (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 mor C1.4 alkyl groups; R1 is a) phenyl [optionally substituted by C1.4 alkyl, C1.4 alkoxy, C1.4 alkanoyl, -NHCOR3 (where R3 is a hydrogen atom, C1.4 alkyl or phenyl) or - NR4R5 (where R4 and R5 may be the same or different and are each a hydrogen atom or C1.4 alkyl)]; b) C3.6 alkenyl, C3-6 alkynyl, thienylmethyl, furanylmethyl, pyridinyl or C5.7 cycloalkyl (optionally substituted by one or more C1.4 alkyl groups);; c) -CH2COR6 where R6 is phenyl (optionally substituted by a halogen atom, C1.4 alkyl or C1-4 alkoxy), or -NR R4 (where R and R4 are as defined in a), or where -NR R4 forms a saturated heterocyclic group which has 5-7 ring members and optionally contains in the ring -0-); d) -(CH2)mB(CH2)nR3 where m is 1-3, n is 0-3 and B is -O- or -S-, provided that when m is 1 and n is O then R3 is not a hydrogen atom; e) -(CH2)pR7 where p is 2 or 3 and R7 is -NR3R4 as defined in c), or an acetylamino or benzoylamino group;

where R8 is a hydrogen atom, methyl or phenyl and R9 is C1-7 alkyl, C5.7 cycloalkyl or phenyl; g) -CH(CO2R5)2;; h) -CH20COR1 where R70 is C1.4 alkyl, methoxy or phenyl; i) 1 -(acetyloxy)ethyl, (acetyloxy)phenyl methyl, tetrahydro-5-oxo-2-fu ranyl or tetrahydro-2-oxo-3-furanyl; j) -CH(CH2OH)2;

where R11 is OH or CH2OH and R12 is a hydrogen atom, C1-4 alkyl or CH2OH; ;

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)], (b) thienyl [optionally substituted by C5.7 cycloalkyl or phenyl (optionally substituted by C1.3 alkyl, C1-3 alkoxy or halogen)], or (c) naphthyl (optionally substituted by C1.4 alkyl or C1.4 alkoxy) or (ii) cinnamyl; and the physiologically acceptable salts and solvates thereof.