GB2167404A - Prostanoid aminocyclopentane alkenoic acids and esters, their preparation and pharmaceutical formulation - Google Patents

Abstract

Pharmaceutical compositions in which the active ingredient has the formula <IMAGE> (in which R1 is H or various organic radicals; R2 is cinnamyl or is substituted or unsubstituted phenylalkyl, thienylalkyl or naphthylalkyl; R3 is -H, alkyl (optionally interrupted by -O- or -S-), alkanoyl, benzoyl, alkoxy- or benzyloxycarbonyl, or carbamyl or N-substituted carbamyl; Y is a 5-8 ring membered saturated heterocyclic amino group attached to the cyclopentane ring via N; X is -CH=CH-; and W is C1-7 alkylene> or is a salt or solvate thereof may be used as antithrombotic or antiasthmatic agents. Certain of the compounds (e.g. where R3 is other than -H) are new.

Description

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

We have now found a new group of compounds which have shown endoperoxide and thromboxane antagonist activity, and are therefore of interest in the treatment of asthma and cardiovascular diseases and in other respects.

The invention thus provides a pharmaceutical composition comprising a compound of the general formula (i)

wherein R, is a) a hydrogen atom; b) C1 6 alkyl; c) Ca 6 alkenyl; d) C7 10 aralkyl; e) -CH2AR4, where A is -O- or -S- and R4 is C, 4 alkyl; f) -CHRsCO2R4, where R5 is a hydrogen atom, methyl or phenyl; g) -CH2OCOR6, where R6 is C1 4 alkyl; methoxy or phenyl; h) pyridinyl; i) 1 (acetyloxy)ethyl, (acetyloxy)phenylmethyl, tetrahydro-5-oxo-2-furanyl or tetrahydro-2-oxo- 3 furanyl; j) 4-(acetylamino)phenyl; k) 2,2,2-trichloroethyl;I) furanylmethyl; or m) -(CH2)pN(R4)2 where p is 2 or 3; R2 is i) straight or branched C1 5 alkyl substituted by a) phenyl [optionally substituted by C1 alkyl, C 7 cycloalkyl, phenylalkyl having a C1 a alkyl portion, thienyl, phenyl (optionally substi tuted by C, 4 alkyl, C, 4 alkoxy or phenyl)], b) thienyl [optionally substituted by C, 6 alkyl, C16 alkoxy, C, 7 cycloalkyl or phenyl (optionally substituted by C, 3 alkyl, C1 a alkoxy or halogen)], or c) naphthyl (optionally substituted by Cl 4 alkyl or C, 4 alkoxy), or (ii) cinnamyl;; Ra is a hydrogen atom or a (i) C, 4 alkyl; (ii) -CH2AR4; (iii) C, 4 alkanoyl or benzoyl; (iv) -COOR4 or benzyloxycarbonyl or (v) -CONHR5 group; Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which has 5-8 ring members and (a) optionally contains in the ring -0-, -S-, -SO2, or -NR7 (where R, is a hydrogen atom, Cl, alkyl or aralkyl having a C1 4 alkyl portion); and/or (b) is optionally substituted by one or more C, 4 alkyl groups; W is straight or branched C, 7 alkylene; X is cis or trans -CH=CH-;; or a physiologically acceptable salt or solvate (e.g. hydrate) thereof, together with one or more pharmaceutical carriers.

The structural formulae herein are to be understood to include where appropriate 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 inorganic or organic acids, e.g.

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

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

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

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

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

In general R2 is preferably a C16 alkyl group substituted by phenyl, which phenyl is itself substituted (preferably in the para-position) by phenyl (optionally substituted by C14 alkyl or C14 alkoxy).

R2 is more preferably a benzyl group in which the phenyl group is substituted by thienyl or phenyl (which phenyl group itself may be optionally substituted by C14 alkyl or C14 alkoxy); or cinnamyl.

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

In the group -(CH2)2XWCOORí, X is preferably cis -CH=CH-.

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

R1 may be for example a hydrogen atom or a group of the type b) (particularly methyl or butyl), a group of the type c) (particularly allyl), a group of the type e) (particularly -CH2SCH3 or -CH20CH3), a group of the type g) (particularly -CH,OCOCH,), or 4-(acetylamino)phenyl or a group of the type m) (particularly -(CH2)2N(CH3)2).

Compounds in which R1 is a hydrogen atom, a methyl group -CH20COCH3, -(CH2)2N(CH2)2 or (when Y is piperidino) -CH20CH3 are particularly important.

Examples of suitable Ra groups are methyl, ethyl, methoxymethyl, ethoxymethyl, acetyl, benzoyl, methoxycarbonyl, benzyloxycarbonyl and -CONH2. Compounds in which Ra is a hydrogen atom are particularly important.

A particularly preferred group of compounds (especially their 1R-isomers) has the formula (I) in which W is CHaCH.

X is cis -CH=CH R, is a hydrogen atom, -CH3, -CH2CCOCH2, (CH2)2N(CHa)2, or (when Y is piperidino) CH2OCHa R2 is benzyl in which the phenyl group is substituted by phenyl, tolyl or methoxyphenyl, Ra is a hydrogen atom, Y is morpholino or piperidino; and their physiologically acceptable salts and solvates thereof.

Examples of particularly preferred compounds are the 1R-isomers of the compounds in which X is cis -CH=CH-, W is -CH2CH2-, R2 is biphenylmethyl, Ra is a hydrogen atom, Y is piperidino and Rl is a hydrogen atom, methyl or -CH2OCOCHa; and their salts and solvates.

In general the compounds of formula (I) in which the carbon atom carrying the -(CH7)2XWCOOR" group is in the R- configuration (and mixtures containing this isomer) are 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 guinea-pigs are dosed orally with the compound to be tested in a suitable vehicle. Platelet rich plasma is prepared from each animal and aggregation to a range of collagen concentrations is measured after the method of Born (Nature 194, 927-929, (1962). Collagen concentration-effect curves for each sample of plasma are calculated and results are expressed as the shift of the curves following treatment with the compound.

The ability of the compounds of the invention to inhibit bronchoconstriction is determined either in the anaesthetised guinea pig by measuring the effect of the compound to be tested on the dose response curve of the bronchoconstrictor [1R-[1a,4s,5ss(Z),6a(1E,3S*)]]-7-[6-(3-hydroxy- 1 -octenyl)-2-oxabicyclo[2,2, 1 ]hept-5-yl]-5-heptenoic acid (U-46619).

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

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

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 or syrups prepared by conventional means with acceptable excipients.

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

For administration by inhalation the compounds are conveniently delivered in the form of an aerosol spray presentation from 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 anti-asthmatic agents. Unit dose formulations of the compositions of the invention thus usually contain 3.5 to 350 mg of the active ingredient.

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

A further aspect of the invention comprises compounds of formula (I) in which R1, R2, X, W and Y are as defined for formula (I) and Ra is as defined for formula (I) other than a hydrogen atom; and the physiologically acceptable salts and solvates thereof.

In another aspect, the invention comprises compounds of formula (I) in which R1, R2, X, W and Y are as defined for formula (I), and Ra is a hydrogen atom, with the proviso that when R, is a hydrogen atom the carbon atom carrying the group -(CH2)2XWCOOR, is in the R- configuration and Y is not morpholino; and with the proviso that when X is cis -CH=CH- and W is -CH2CH2- the carbon atom carrying the group -(CH2)2XWCOOR, is in the R- configuration when R1 is methyl, -CH20COCH3 or -CH2SCH3, R2 is biphenylmethyl and Y is morpholino; or when R, is CH2OCOCHa, R2 is 4-(thien-2-yl) phenylmethyl and Y is morpholino; or when R, is -CH,OCH,, Ra is biphenylpropyl and Y is morpholino; or when R, is methyl or -CH(CH3)COOCH2CH3, Ra is biphenylmethyl and Y is piperidino; or when R, is 4-(acetylamino)phenyl, Ra is 3'-(methoxy)biphenylmethyl and Y is morpholino; and with the proviso that when X is cis -CH=CH-, W is -(CH2)4-, R1, is -CH2SCH3, Y is morpholino and R2 is biphenylmethyl, the carbon atom carrying the group -(CH,),XWCOOR, is in the R- configuration; and with the exception of the compound in which X is -CH=CH-, W is -CH2CH2-, R1 is -CH,OCH,, Y is morpholino and R2 is biphenylmethyl; and the physiologically acceptable salts and solvates thereof.

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

a) Compounds of formula (1) in which Ra is a group of the type (i) or (ii) and R, is a group of the type b), c), d), e), h), k), I) or m) may be prepared by alkylation of the corresponding compound of formula (2)

wherein Rl is as just defined.

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

dimethylformamide) at low temperatures e.g. -20" up to 0 . The alkylating agent may be a compound of formula RaL where L is a leaving group, e.g. halogen or tosylate.

The compounds of formula (2) may be prepared by esterification of the corresponding acid of formula (1) (i.e. in which Rl is a hydrogen atom) e.g. by the methods described for process d) below.

b) Compounds of formula (I) in which Ra is a group of the type (iii) or (iv) may be prepared by esterification of a corresponding compound of formula (2). The reaction may be performed using a reactive derivative of an acid RASH, e.g. an acid anhydride, acid chloride or chloroformate in the presence of a base e.g. triethylamine or pyridine at a temperature of 0 up to room temperature.

c) Compounds of formula (1) in which Ra is a group of the type (v) may be prepared by treatment of a corresponding compound of formula (2) with an appropriate isocyanate, e.g.

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

d) Compounds of formula (1) in which R1 is other than a hydrogen atom may be prepared by esterification of the corresponding carboxylic acid of formula (1) (i.e. in which R1 is a hydrogen atom). Conventional esterification techniques may be used.

For example, compounds of formula (1) in which R1 is a group of the type b), c), or d) and Ra is a hydrogen atom may be prepared by treating the corresponding carboxylic acid with an appropriate alcohol R,OH in the presence of a mineral acid such as hydrochloric acid or sulphuric acid.

Alternatively, compounds of formula (1) in which R1 is a group of the type b) may be prepared by treating the corresponding carboxylic acid with an appropriate diazoalkane, using a solvent such as dichloromethane, e.g. at room temperature.

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

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

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

Again, for example, compounds of formula (I) in which R1 is a group of the type b, c, d, e, f, g and i, may be prepared by reacting the corresponding carboxylic acid with an appropriate halide R6 Hal, where Hal represents halogen and R8 is as just defined for R1. The reaction may be caried out in the presence of a suitable base e.g. potassium t-butoxide or a sterically hindered amine such as N,N-diisopropylethylamine, in a suitable solvent (such as acetonitrile or dimethylsulphoxide), for example at a temperature from 0 to room temperature.

The carboxylic acids of formula (1) required as starting materials for process (d) may be prepared from the corresponding compounds of formula (2) in which R1 is a labile ester group (e.g. a trityl ester of a 2,2,2-trichloroethyl ester). Where R2 is other than a hydrogen atom this group may first be introduced (using processes a, b or c above), and the protecting group then removed under mild conditions e.g. with trifluoroacetic acid either neat or in an organic solvent (e.g. dichloromethane) or in the case of trichloroethyl ester by treatment with zinc, for example at a pH of 4.2-7.2. Tetrahydrofuran, dioxan and dimethoxyethane are suitable solvents. These deprotections are preferably effected at 0 up to room temperature.

e) Compounds of formula (1) in which R, is a hydrogen atom and Ra is a hydrogen atom or a group of the type (i) or (ii) may be prepared by hydrolysis of a corresponding ester (e.g. a C16 alkyl ester), e.g. using a base such as aqueous NaOH or KOH in a suitable solvent (e.g. ethanol) at for example room temperature.

f) Compounds of formula (I) in which X is cis -CH=CH-, Rl is a hydrogen atom and R3 is -H or a group of the type (i) or (ii) may be prepared by reacting a compound of formula (3)

with an appropriate Wittig reagent, e.g. a phosphorane of formula (Rg)3P=CHWCOOH (where R6 is C1 6 alkyl or aryl, e.g. monocyclic aryl such as phenyl) or a salt thereof, e.g. the potassium salt. Suitable reaction solvents include hydrocarbons (e.g. benzene and toluene), ethers (e.g.

tetrahydrofuran), dialkylsulphoxides (e.g. dimethylsulphoxide), alcohols and halogenated hydrocarbons. The reaction may be carried out at any suitable temperature from -70 to 50"C, preferably at room temperature.

The preparation of the intermediates of formula (3) in which Ra is a hydrogen atom is described in British Patent Specification 2075503A. Intermediates of formula (3) in which Ra is other than a hydrogen atom may be prepared from the corresponding compounds in which Ra is a hydrogen atom by by the methods described above.

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

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

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

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

The following examples illustrate the invention.

Temperatures are in "C.

Abbreviations: 'Dried' refers to drying with anhydrous MgSO4.

T.l.c.-Thin Layer Chromatography on silica unless otherwise stated.

Chromatography was carried out using silica gel.

ER-ether EA-ethyl acetate PE-Petroleum ether (b.p. 60-80" unless otherwise stated) DIBAL-diisobutylaluminium hydride THF-tetrahydrofuran DMF-dimethylformamide Ac2O-acetic anhydride The preparation of Intermediates 1 and 2 are described in UK Patent Specification 2075503A.

Intermediate 1 [1R-( 1R-( 1a,2ss,3a,5a)]-(+)-5-[[1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentanep- ropanal.

Intermediate 2 (1 a,2% 3a, 5a)-()-5j[( 1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentanepro- panal, hydrochloride The preparation of Intermediates 3 and 4 are described in UK Patent Specification 2097397A.

Intermediate 3 [1 R-( 1a,2ss,3a,5a)]-(+)-5-[[( 1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-( 1-piperidinyl)cyclopentane acetaldehyde Intermediate 4 [1 R- (en do, anti)]-(+)-5-Hydroxy- 7-(1 -piperidinyl)bicyclo[2. 2. 1]heptan-2-one Intermediate 5 [ 1R-(1a,2ss,3a,5a)]-(+)-5-[[( 1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentanepro- panal A solution of Intermediate 3 (139) in toluene (39ml) was added dropwise to a suspension of potassium tert-butoxide (5.969) in toluene (52ml). Methoxymethyltriphenylphosphonium chloride (15.939) was added and the mixture stirred overnight (18h).

2N Hydrochloric acid (52ml) was added and the mixture heated with stirring at 40 for 30min.

Solid K2CO3 (13g) was added, the organic phase separated, washed with water (52ml) and dried azeotropically to give a solution of Intermediate 5 in toluene (115ml). A portion of the solution (8.8ml), was purified by chromatography eluting with 9:1 EA-methanol to give the title compound as a foam (0.53g).

T.l.c. 4:1 EA-methanol Rf 0.15 [a]D3=+42.8 (CHCla).

Intermediate 6 [1 R-[ 1 a(Z), 2% 3a, 5a11-( )- Triphenylmethyl 7-[3-(A cetyloxy)-5-[[( 1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1 -pi- peridinyl)cyclopentyl]-4-heptenoate A solution of the compound of Example la, base (0.579) in CH2CI2 (15ml) containing Et3N (0.75ml) and trityl chloride (0.449) was stirred at 0 for 1h. Pyridine (0.5ml) and Ac2O (0.2ml) were added and stirring continued at ambient temperature for 20h. The mixture was diluted with 8% NaHCO2 solution (25ml) and extracted with CH2CI2 (3X20ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using 4:1 EA-PE as eluent to give the title compound as an oil (0.9g).

T.l.c. 4:1 EA-PE Rf 0.65.

Intermediate 7 [1R-[1a(Z),2ss,3a,5a]]-(+)-Methyl 7-[5-[[( 1, 1 '-Biphenyl)-4-yl]methoxy]-3-methoxy-2-( 1-piperidinyl)cy- clopentyl]-4-heptenoate A solution of the compound of Example 2, base (lug) in dry DMF (5ml) was added dropwise to a cold (-20") stirred mixture of sodium hydride (0.29, 75% dispersion in oil) and dry DMF (3ml) under nitrogen. After 15min, iodomethane (0.41ml) was added and stirring continued at between -20" and -5" for 3h. The mixture was diluted with pH6.5 phosphate buffer (150ml) and extracted with EA (3X50ml).The combined extracts were washed with brine (2X75 ml), dried and evaporated and the residue was purified by chromatography using. 9:1 EA-methanol as eluent to give the title compound as an oil (0.489).

T.l.c. 9:1 EA-methanol Rf 0.35 Analysis Found: C,75.8; H,8.7; N,2.7.

C32H43NO4 requires C,76.0; H,8.6; N,2.8%.

[a]22-7=+25 (CHCI3) Intermediate 8 [ 1R-{endo,anti)]-{+J-5-[[4'-Methoxy 1, 1 '-biphenyl)-4-yl]methox.y]-7-{ 1-piperidinyl)bicyclo[2.2. 1]heptan-2-one A mixture of Intermediate 4 (30.519), benzyltriethylammonium chloride (6.659) and 4-(bromome thyl)-4'-methoxy(1,1'-biphenyl) (52.69) in CH2CI2 (365ml) and 17N NaOH (325ml) was vigorously stirred at ambient temperature for 18h. The mixture was diluted with water (1 I) and extracted with CH2CI2 (3 X 1 50ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using ER-PE (1:1 followed by 7:3) as eluent to give the title compound (40.29).

A portion was recrystallised from EA-PE m.p. 109.5-1 10.5 [a]D3 7= +22.7 (CHCl2) Intermediate 9 [1 R-(end'o,anWk(-)-6- ff4 '-Me th ox y( 1, 1'-biphenyl)-4-yl]methoxy]-8-(1-piperidinyl)-2-oxabicy- clo[3.2. 1]octan-3-one A solution of peracetic acid in acetic acid (5.6M, 124ml) was added slowly to a stirred mixture of Intermediate 8 (429) in CH2CI2 (235ml), 2N H2SO4 (29ml) and water (159ml) and the mixture stirred at ambient temperature for 24h. The mixture was adjusted to ca. pH7 using 5N NaOH and pH 6.5 phosphate buffer then extracted with CH2CI2 (3X200ml). The combined organic extracts were added to an excess of sodium metabisulphite solution and stirred for 24h.The mixture was extracted with EA (1X500, 2X250ml) and the combined organic extracts were dried and evaporated and the residue was purified by chromatography using 1:1 EA-PE as eluent to give the title compound (24.49).

A portion was recrystallised from EA-PE m.p. 116.5-117.5 [&alpha;]D234=-24.5 (CHCla) Intermediate 10 [1R-(1a,2ss,3a,5a)]-( )-3-Hydroxy-5-[[4'-methoxy(1,1'-biphenyl)-4-yl]-methoxy]-2-(1-piperidinyl)cyclo- pentane acetaldehyde DIBAL in hexane (1M, 114ml) was added slowly to a cold (-70") stirred solution of Intermediate 9 (249) in CH2CI2 (240ml). After 0.5h methanol (240ml) was added, slowly at first, and the mixture was stirred at ambient temperature for 16h. The precipitate was filtered off and the filtrate evaporated to give the title compound as a foam (24.1g).

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

Intermediate 11 [ 1R-( 1a,2ss,3a,5a)]-{+J-4-[[4'-Methoxy( 1, 1'-biphenyl)-4-yl]methoxy]-3-{3-methoxy-2-propenyl)-2-( 1- piperidinyl)cyclopentanol, hydrochloride A solution of Intermediate 10 (24.19) in THF (75ml) was added to a cooled (-5 to 0 ), stirred solution of the ylid derived from methoxymethyltriphenylphosphonium chloride (789) and potassium tert-butoxide (25.59) in THF (800ml). After 1.5h methanol (100ml) was added and the solvents removed in vacuo. The residue in pH6.5 phosphate buffer (600ml) was extracted with CH2CI2 (3X150ml) and the combined extracts were dried and evaporated. The residue was purified by chromatography using 4:1 EA-methanol as eluent to give the title compound, base as an oil (24.89).

A portion was converted into the hydrochloride salt m.p. 150-151 (dec) [&alpha;]23.1D = +38.1 (CHOl.3) Intermediate 12 [1 R-( 1a,2ss,3a,5a)]-(+)-3-Hydroxy-5-[[4'-methoxy( 1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1-piperidinyl)cyclo- pentanepropanal, hydrochloride A solution of Intermediate 11 (24.39) in 2N HCI (55ml) and acetone (250ml) was stirred at ambient temperature for 1h. Most of the acetone was removed in vacuo and the residue in water was extracted with CH2CI2 (3X150ml).The combined extracts were dried and evaporated to give a solid (23.69). A portion was triturated with ether to give the title compound as a powder m.p. 182-185 (dec) [a]D2-7=+51.5 (CHCl3) Example 1 a) [1R-[1a(Z),2ss,3a, Safl-(+)- 7-[5-ff( 1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-( 1 -piperidinyl)cyclo- pentyl]-4-heptenoic acid, hydrochloride To a solution of potassium tert-butoxide (21.499) in toluene (198ml) and THF (52ml) under N2 was added 3-(carboxypropyl)triphenylphosphonium bromide (41.149). After 1.5h a solution of Intermediate 5 (24.59) in toluene (220ml) was added and the mixture stirred for 3h. Water (125ml) was added, the mixture vigorously shaken and the phases separated.The aqueous phase was washed with toluene (2X225ml) (discarded), then acidified (to pH 7.5) with 2N HCI and extracted with CH2CI2 (2X225ml). The combined CH2CI2 extracts were dried and evaporated to give the title compound, base (24.479) as a gum. A solution of the base (93mg) in CH2CI2 (1.5ml) was treated with an excess of ethereal hydrogen chloride. The solvents were removed and the residual oil triturated with ER (5ml). The resulting solid was filtered, washed with ER and dried to give the title compound (82mg) m.p. 132.5-136 (softens at 128 ).

Analysis Found: C,69.7; H,8.1; N,2.9.

C30H39NO4.HCI requires C,70.1; H,7.8; N,2.7%.

[a]D5=+52.9O (CHCl3) The following compounds were prepared in a similar manner: b) [1R-[ [ 1R1 1a(Z),2a,3a,5a]]-(+)-7-[5-[[( 1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-{4-morpholinyl)cyclo- pentyl]-4-heptenoic acid, methanesulphonate m.p. 134-136 from Intermediate 1 using THF as solvent. The base in 9:1 EA-ethanol was treated with an excess of methanesulphonic acid in 9:1 EA-ethanol. After 1 h the solid was filtered off and dried in vacuo to give the title compound.

Analysis Found: C,62.3; H,7.3; N,2.3.

C26H27N05.CH402S requires C,62.6; H,7.2; N,2.4%.

[]1 = +47.7' (CHCl3) c) [1a(Z),2ss,3&alpha;,5&alpha;]-()7-]5-[[(1,1'-Biphenyl)-4-yl]methoxy-3-hydroxy-2-(4-morpholinyl]cyclopentyl]- 4-he p tenoic acid, hydrochloride m.p. 125.5-126.5 from Intermediate 2 using THF as solvent.

Analysis Found: C,67.2; H,7.6; N,2.7.

C29H37NO5.HCI requires C,67.5; H,7.4; N,2.1%.

Example 2 [1R[1a(Z),2ss,3a,5a]]-(+)-Methyl 7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoate, hydrochloride A solution of the compound of Example 1 a, base (1.3379) in methanol (20ml) containing concentrated sulphuric acid (0.4ml) was kept at 20 for 3h then poured into 2N Na2CO3 (75ml) and extracted with EA (3X50ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using 9:1 EA-methanol as eluent to give the title compound, base as an oil (0.8679). A portion of the oil (0.4459) in CH2CI2 (3ml) was treated with an excess of ethereal hydrogen chloride and the solvents were removed in vacuo.The residue was triturated with ER and then crystallised from EA-methanol to give title compound (0.2539) m.p. 130-133 .

Analysis Found: C,70.2; H,8.0; N,2.6.

C3lH4lNO4.HCl requires C,70.5; H,8.0; N,2.65%.

[a]D4=+56.8 (CHCIa) Example 3 I 1R-[1a(Z),2ss,3a,5a]]-(+)-Butyl 7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclo- pentyl]-4-heptenoate A solution of the compound of Example 1a, base (0.4659) in butanol (15ml) and ethereal hydrogen chloride (10ml) was kept at 20 for 18h then poured into 2N Na2CO3 (55ml) and extracted with EA (3X20ml). The combined extracts were dried and evaporated and the residue was purified by chromatography on alumina eluting initially with 3:2 ER-PE then ER to give the title compound as an oil (0.2759).

T.l.c. (Al202) ER Rf 0.4 Analysis Found: C,76.i; H,8.95; N,2.6.

C34H47NO4 requires C,76.5; H,8.9; N,2.6%.

[aW= +52.5' (CHCl3) Example 4 a) [1R-[ la(Z),2P,3a,5a]]-(+)-(Acetyloxy)methyl 7-[5-ff( 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-( 1piperidin yl)cyclopentyl]-4-heptenoate A solution of bromomethyl acetate (1.189) in acetone (11ml) was added to a stirred solution of the compound of Example la, base (0.839) in acetone (17ml) containing Et3N (1.22ml). After 96h at room temperature the mixture was diluted with 8% NaHCO3 solution (60ml) and extracted with EA (3X30ml).The combined extracts were dried and evaporated and the residue was purified by chromatography using ER containing 1% Et3N as eluent to give the title compound as an oil (0.429).

T.l.c. 2:1 ER-methanol Rf 0.44 Analysis Found: C,71.7; H,7.8; N,2.5.

C33H43NO6 requires C,72.1; H,7.9; N,2.55%.

[a]D24= +52.5 (CHCI2) The following compounds were prepared in a similar manner: b) [ 1R-[ 1a(Z),2,ffl,3a,5a]]-(+)-Methoxymethyl 7-[5-ff(1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-pi- peridinyl)cyclopentyl]-4-heptenoate, from the compound of Example 1 a, base using chloromethyl methyl ether and diisopropylethylamine in DMF. Purification by chromatography using EA containing 1% Et3N as eluent.

T.l.c. 89:10:1 EA-methanol-Et3N Rf 0.4 I.r. (CHBr3) 3600, 3500, 1733 cm [a]D3=+62.7 (CHCl3) c) [1R-[1a(Z),2ss,3a, 5a]]-(+)-(Acetyloxy)methyl 7-[3-Hydroxy-5-[[4'-methoxy( 1, 1 '-biphenyl)-4-yl]methoxy]-2-(1-piperidinyl)cyclopentyl]-4-heptenoate, from the compound of Example 7b, base. Purification by chromatography using 95:5:1 EA-methanol-Et3N as eluent.

T.l.c. 95:5:1 EA-methanol-Et3N Rf 0.31 I.r. (CHBr3) 3540, 1760 cm [a]D27=+56 (CHCl3) Example 5 [ 1R1 1a(Z),2ss,3a,5a]]-(+)-2-(Dimethylamino)ethyl 7-[5-ff(1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2- (4-morpholinyl)cyclopentyl]-4-heptenoate lsobutylchloroformate (0.85ml) was added to a cold (-10"), stirred solution of the compound of Example 1b (1.39) and Et3N (1.25ml) in acetone (30ml). After 0.5h N,N-dimethylethanolamine (0.95ml) was added and the cooling bath was removed. After a further 6h the mixture was diluted with 8% NaHCO3 solution (100ml) and extracted with EA (3X100ml). The combined extracts were dried and evaporated to give an oil (1.699).A portion of the oil (0.39) was purified by chromatography on Et3N deactivated silica using 4:1 EA-methanol as eluent to give the title compound as an oil (0.1039).

T.l.c. (SiO,-Et3N) 4:1 EA-methanol Rf 0.3 I.r. (CHBr3) 3590, 3520, 1728 cm [a]D3=+55.9 (CHCl3) Example 6 [1R-[ 1a(Z),2ss,3a,5a]]-(+)-7-[3-(Acetyloxy)-5-[[( 1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1-piperidinyl)cyclo pentyl]-4-heptenoic acid A solution of Intermediate 6 (0.869) in CH2CI2 (10ml) containing trifluoroacetic acid (0.5ml) was stirred at 0 for 0.5h. The mixture was diluted with 8% NaHCO3 solution (20ml), adjusted to pH 6.5 using phosphate buffer then extracted with CH2CI2 (3X20ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using 9:1 EA-methanol as eluent to give the title compound as a foam (0.2559).

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

I.r. (CHBr3) 1725 (br) cm [a]D21=5.7 (CHCl3) Example 7 a) [1R-[1a(Z),2ss,3a,5a]]-(-)-7-[5-[[( 1, I '-Biphenyl)-4-yl]methoxy]-3-merhoxy-2-( 1 -piperidinyl)cyclo- pentyl]-4-heptenoic acid A solution of Intermediate 7 (250mg) in ethanol (3ml) and 5N NaOH (1.25ml) was stirred at ambient temperature for 2h then diluted with pH 6.5 phosphate buffer (75ml) and extracted with CH2CI2 (3X50ml). The combined extracts were dried and evaporated to give the title compound as a foam (225mg).

T.l.c. 1:1 EA-methanol Rf 0.28 Analysis Found: C,76.0; H,8.5; N,2.7.

C3,H41NO4 requires C,75.7; H,8.4; N,2.9%.

[a]O= -12" (CHC13) The following compound was prepared in a similar manner: b)[lR-[la(Z),2a,3a, 5a-(+)- 7-[3-Hydroxy-5-[[4'-methoxy( 1, '-biphenyl)-4-yl]merhoxy]-2-( 1 -piperidi- nyl)cyclopen tyl]-4-heptenoic acid, hydrochloride m.p. 137-138.5 (dec.) from the compound of Example 9. The base in ER-CH2CI2 was treated with an excess of ethereal HCI to give the title compound.

Analysis Found: C,68.6; H,7.8; N,2.5.

C3,H41NO5 requires C,68.4; H,7.8; N,2.6%.

[a]241=+51 (CHCI3) Example 8 [1R-[1a(Z),2ss,3a, 5a11-(+)-Methyl 7-[3-(Acetyloxy)-5-[[( 1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1 -piperidinyl)- cyclopentyl1-4-heptenoate A solution of the compound of Example 2, base (0.489) in Ac20 (0.5ml) and pyridine (2ml) was kept at 20 for 24h. The mixture was diluted with pH 6.5 phosphate buffer (50ml) and extracted with ER (3X30ml). The combined extracts were washed with buffer (30ml) and brine (30ml) then dried and evaporated and the residue purified by chromatography using ER as eluent to give the title compound as a solid (0.49) m.p. 56-58 .

Analysis Found: C,74.5; H,8.3; N,2.6.

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

[a]234=+22.1 (CHCb) Example 9 [1R-[1a(Z),2ss,3a,5a]]-(+)-Methyl 7-[3-Hydroxy-5-[[4tmethoxy( 1, 1 tbiphenyl)-4-yl]methoxy]-2-(1-pi- peridinyl)cyclopentyl]-4-heptenoate, hydrochloride A suspension of Intermediate 12 (23.6g) in THF (300ml) was added to the ylid derived from 3 (carboxypropyl)triphenylphosphonium bromide (69.59) and potassium tert-butoxide (36.39) in THF (1000ml). After 2h water (200ml) was added and the THF was removed in vacuo. The residue was diluted with water (250ml) and extracted with ER (3X200ml; discarded). The aqueous layer was neutralised using 5N HCI and extracted with CH2CI2 (3X200ml). The combined extracts were dried and evaporated and the residue was left to stand in methanol (250ml) containing concentrated sulphuric acid (5ml) for 19h.Most of the methanol was removed in vacuo and the residue neutralised using 2N NaOH and pH 6.5 phosphate buffer (150ml). The mixture was extracted with EA (3X150ml) and the combined extracts were dried and evaporated. The residue was purified by chromatography using initially 9:1 ER-methanol followed by 4:1 ER-methanol as eluent to give the title compound, base as an oil (15.9g). A portion was converted into the hydrochloride salt m.p. 122-125 (dec).

Analysis Found: C,68.9; H,7.9; N,2.6.

C32H43NO5.HCI requires C,68.9; H,8.0; N,2.5%.

[a]D225 = + 55.9 (CHCla) Example 10 [1R-[1a(Z),2ss,3a,5a]]-(+)-7-[3-(Acetyloxy)-5-[[4'-methoxy(1,1'-biphenyl)-4-yl]methoxy]-2-(1-piperidi nyl)cyclopentyl]-4-heptenoic acid Ac20 (0.5ml) was added to a cold (0 ) stirred solution of the compound of Example 7b, base (0.43g) in pyridine (3ml). The mixture was kept at ambient temperature for 19h then cooled to 0 and ice (2g) added. After 15min the cooling bath was removed and stirring continued for 45min. The mixture was diluted with 10% KH2PO4 solution (120ml) and extracted with EA (100ml). The extract was washed with 10% KH2PO4 solution (2X60ml) and brine (20ml) then dried and evaporated.The residue was purified by chromatography using initially 19:1 EAmethanol followed by 9:1 EA-methanol as eluent to give the title compound as a foam (0.15g).

T.l.c. 9:1 EA-methanol Rf 0.23.

Analysis Found: C,72.0; H,8.1; N,2.4.

C33H43NO6 requires C,72.1; H,7.9; N,2.6%.

[a]D3=+5 (CHCI3) Pharmaceutical Examples Tablets These may be prepared by direct compression or wet granulation. The direct compression method is preferred but may not be suitable in all cases as it is dependent upon the dose level and physical characteristics of the active ingredient.

A. Direct Compression mg/tablet Active Ingredient 100.00 Microcrystalline Cellulose B.P.C. 298.00 Magnesium Stearate 2.00 Compression Weight 400.00 mg The active ingredient is sieved through a 250 m 6 sieve, blended with the excipients and compressed using 10.00mm 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 250m 6 sieve and blended with the lactose, starch and pre-gelatinised starch. The mixed powders are moistened with purified water, granules are made, dried, screened and blended with the magnesium stearate. The lubricated granules are compressed into tablets as described for the direct compression formula.

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

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

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

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

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

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

Claims (16)

1. A pharmaceutical composition comprising a compound of the general formula (1)

wherein R, is a) a hydrogen; b) C1 6 alkyl; c) Ca 6 alkenyl; d) C7 10 aralkyl; e) -CH2R4, where A is -O- or -S- and R4 is Cl 4 alkyl; f) -CHR > CO2R4, where R5 is a hydrogen atom, methyl or phenyl; g) -CH2OCOR6, where R6 is C14 alkyl; methoxy or phenyl; h) pyridinyl; i) 1-(acetyloxy)ethyl, (acetyloxy)phenylmethyl, tetrahydro-5-oxo-2-furanyi or tetrahydro-2-oxo- 3-furanyl; j) 4 (acetylamino)phenyl; k) 2,2,2-trichloroethyl;I) furanylmethyl; or m) -(CH2)"N(R4)2 where p=2 or 3; Ra is i) straight or branched C1 6 alkyl substituted by a) phenyl [optionally substituted by C16 alkyl, C.7 cycloalkyl, phenylalkyl having a C1 a alkyl portion, thienyl, phenyl (optionally substi tuted by C14 alkyl, C1 4 alkoxy or phenyl], b) thienyl [optionally substituted by C16 alkyl, C16 alkoxy, Cos 7 cycloalkyl or phenyl (optionally substituted by C1a alkyl, C1-3 alkoxy or halogen)], or c) naphthyl (optionally substituted by Cl 4 alkyl or C14 alkoxy), or (ii) cinnamyl; Ra is a hydrogen atom or a (i) C14 alkyl; (ii) -CH2AR4; (iii) C14 alkanoyl or benzoyl; (iv) -COOR4 or benzyloxycarbonyl or (v) -CONHR6 group; Y is a saturated hetercyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which has 5-8 ring members and (a) optionally contains in the ring -0-, -S-, -SO2, or -NR7 (where R7 is a hydrogen atom, C17 alkyl or aralkyl having a C14 alkyl portion); and/or (b) is optionally substituted by one or more C1 -4 alkyl groups; W is straight or branched C17 alkylene; X is cis or trans -CH=CH-; or a physiologically acceptable salt or solvate thereof, together with one or more pharmaceutical carriers.

2. A composition as claimed in claim 1 in which the compound of formula (1) is a compound in which Y is morpholino or piperidino.

3. A composition as claimed in claim 1 or claim 2 in which the compound of formula (1) is a compound in which X is cis -CH=CH- and W is -CH2CH2- or -(CH2)4-.

4. A composition as claimed in any of the preceding claims in which the compound of formula (1) is a compound in which Ra is a benzyl group in which the phenyl group is substituted by phenyl, tolyl or methoxyphenyl.

5. A composition as claimed in any of the preceding claims in which the compound of formula (1) is a compound in which Ra is a hydrogen atom.

6. A composition as claimed in any of the preceding claims in which the compound of formula (1) is a compound in which R1 is a hydrogen atom, methyl, -CH2OCOCH2, -(CH2)2N(CH3)2 or (when Y is piperidino) -CH2OCH2.

7. A composition as claimed in claim 1 in which the compound of formula (1) is a compound in which: W is -CH2CH2-, X is cis -CH=CH-, R, is a hydrogen atom, -CH2, -CH2OCOCH2, -(CH2)2N(CH3)2 or (when Y is piperidino) -CH2OCH2, R2 is benzyl in which the phenyl group is substituted by phenyl, tolyl or methoxyphenyl, Ra is a hydrogen atom, Y is morpholino or piperidino, or a physiologically acceptable salt or solvate thereof.

8. A composition as claimed in any of the preceding claims in which the compound of formula (1) is a 1R-isomer.

9. A composition as claimed in claim 1 in which the compound of formula (1) is the 1R isomer of a compound in which X is cis -CH=CH-, W is -CH2CH R2 is biphenylmethyl, R is a hydrogen atom, Y is piperidino and R1 is a hydrogen atom, methyl or -CH2OCOCHa; or in which X is cis -CH=CH-, W is -CH2CH2-, R is -CH2CH2N(CH2)2, Ra is biphenylmethyl, Ra is a hydrogen atom, and Y is morpholino; or a salt or solvate thereof.

10. A composition as claimed in any of the preceding claims in the form of a tablet, capsule, powder, solution, syrup, ampoule or an aerosol spray formulation.

11. A composition as claimed in claim 10 in a unit dose form containing 3.5 to 350 mg of the compound of formula (1).

12. Compounds of formula (1) as defined in claim 1 (a) in which Ra is other than a hydrogen atom, and (b) in which Ra is a hydrogen atom, with the proviso that when R, is a hydrogen atom, the carbon atom carrying the group -(CH2)2XWCOOR is in the R-configuration and Y is not morpholino, and with the proviso that the carbon atom carrying the group -(CH2)2XWCOOR1 is in the R-configuration when X is cis -CH=CH-, W is -CH2CH2 and (i) Rl is methyl, CH2OCOCHa or -CH2SCH2, R2 is biphenylmethyl and Y is morpholino, (ii) R1 is -CH2OCOCH2, R2 is 4-(thien-2-yl)phenylmethyl and Y is morpholino, (iii) R1 is CH2OCHa, R2 is biphenylpropyl and Y is morpholino, (iv) R, is methyl, or -CH(CH2)COOCH2CH2, R2 is biphenylmethyl and Y is piperiodino, or (v) R1 is 4-(acetylamino)phenyl, R2 is 3'-(mwethoxy)-biphenylmethyl and Y is morpholino, and with the proviso that the carbon atom carrying the group -(CH2)2XWCOOR1 is in the Rconfiguration when X is cis -CH=CH-, W is -(CH2)4-, R1 is -CH2SCH2, R2 is biphenylmethyl and Y is morpholino, and excluding the compound in which X is cis -CH=CH-, W is -CH2CH2-, R is -CH,OCH,, R2 is biphenylmethyl and Y is morpholino, and the physiologically acceptable salts and solvates thereof.

13. Compounds as claimed in claim 12, said compounds being the 1R-isomers of the compounds of formula (1) as defined in claim 1; excluding the compounds in which R1 and Ra are hydrogen atoms and Y is morpholino, and excluding the compound in which X is cis -CH=CH-, W is -CH2CH2-, R1 is -CK2OCH2, R2 is biphenylmethyl, Ra is a hydrogen atom and Y is morpholino.

14. Compounds as claimed in claim 12, said compounds being the 1R-isomers of the compounds of formula (1) as defined in claim 1 in which: W is -CH2CH2-, X is cis-CH=CH-, R1 is a hydrogen atom, -CH2, -CH,OCOCH,, -(CH2)2N(CH3)2 or (when Y is piperidino) -CH2OCH2, R2 is benzyl in which the phenyl group is substituted by phenyl, tolyl or methoxyphenyl, Ra is a hydrogen atom, Y is morpholino or piperidino, and the physiologically acceptable salts and solvates thereof.

15. Compounds as claimed in claim 12, said compounds being the 1R-isomers of the compounds of formula (1) as defined in claim 1 in which X is cis -CH=CH-, W is -CH2CH2-, R2 is biphenylmethyl, R2 is a hydrogen atom, Y is piperidino and R1 is a hydrogen atom, methyl or -CH2OCOCH2; or in which X is cis -CH=CH-, W is -CH2CH2-, R1 is -CH2CH2N(CH3)2, R2 is biphenylmethyl, Ra is a hydrogen atom, and Y is morpholino; and the physiologically acceptable salts and solvates thereof.

16. A process for the preparation of a compound as claimed in claim 12, which comprises: (a) in the preparation of a compound in which R2 is a group of the type (i) or (ii) and R1 is a group of the type b, c, d, e, h, k, I or m, alkylating a corresponding compound of formula (2)

where R1 is as just defined, (b) in the preparation of a compound in which R2 is a group of the type (iii) or (iv), esterifying a compound of formula (2) above in which R1 is as defined in claim 1, (c) in the preparation of a compound in which R2 is a group of the type (v), treating a compound of formula (2) above (in which R1 is as defined in claim 1) with an appropriate isocyanate, (d) in the preparation of a compound in which R1 is other than a hydrogen atom, estierfying the corresponding carboxylic acid of formula (1) in which R1 is a hydrogen atom, (e) in the preparation of a compound in which R1 is a hydrogen atom and R2 is a hydrogen atom or a group of the type (i) or (ii), hydrolysing a corresponding ester, (f) in the preparation of a compound in which X is cis -CH=CH- and R1 is a hydrogen atom, reacting a compound of formula (3)

with a compound of the formula (R6)2P=CHWCOOH (where R8 is C1 6 alkyl or phenyl) or a salt thereof, or (g) in the preparation of a salt, treating a compound of formula (1) with an acid or (where R is a hydrogen atom) with a base, or converting one salt into another by exchange of cation.