GB2167402A - Prostanoid aminocyclopentane alkenamides, their preparation and pharmaceutical formulation - Google Patents

Abstract

Compounds of the formulae <IMAGE> (in which: R1 is cinnamyl or is unsubstituted or substituted phenylalkyl, thienylalkyl or naphthylalkyl; R2 is -H, -CH3, -CH2CO2H or -CH2CONH2; X is cis or trans -CH=CH-; W is C1-7 alkylene; and Y is a saturated heterocyclic amino group, attached to the cyclopentane ring via N) and their salts and solvates inhibit blood platelet aggregation and bronchoconstriction and may be formulated for use as antithrombotic and antiasthmatic agents.

Description

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

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

These compounds have the general formulae (la) and (ib)

wherein R1 is (i) C alkyl substituted by (a) phenyl [optionally substituted by C, 6 alkyl, C57 cycloalkyl, phenylalkyl having a C 2 alkyl portion, thienyl or phenyl (optionally substituted by C14 alkyl, C14 alkoxy or phenyl)], (b) thienyl [optionally substituted by C16 alkyl, C1 6alkoxy, C57 cycloalkyl or phenyl (optionally substituted by C 2 alkyl, C alkoxy or halogen)] or (c) naphthyl (optionally substituted by C1 -4 alkyl or C14 alkoxy) or (ii) cinnamyl;; R2 is a hydrogen atom, a methyl group, -CH2CO2H or-CH2CONH2; X is cis or trans -CH=CH-; W is straight or branched C1, alkylene; 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 -NRs (where R5 is a hydrogen atom, C1 7 alkyl or aralkyl having a C14 alkyl portion); and/or (b) is optionally substituted by one or more C, 4 alkyl groups; and the physiologicaily 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 invention thus provides a pharmaceutical composition comprising a compound of formula la or ib as defined above, together with one or more pharmaceutical carriers.

Compounds in which R3 is -CH2CO2H or -CH2CONH3 are new and constitute a further feature of the invention.

The alkyl groups referred to above in the definition of the compounds of formulae (la) and (ib) may be straight or branched.

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

In R1 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, R1 is preferably a benzyl group in which the phenyl group is substituted by phenyl (which phenyl group may itself be optionally substituted by C14 alkyl or C14 alkoxy).

Particularly preferred R, groups are in general benzyl groups in which the phenyl portion is substituted (preferably in the para-position) by a phenyl, tolyl or methoxyphenyl substituent. A particularly preferred group of this type is biphenylmethyl.

In general, compounds in which R2 is -H, -CH2CO2H or -CH2CONH2 are preferred, particularly those in which R2 is -H.

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-.

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

hydrochlorides or maleates. Also, when the group R2 is -CH2CO2H salts may be formed with bases. Examples of such salts are alkali metal (e.g. sodium), alkaline earth metal (e.g. calcium) and amino (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, 1,1-dioxothiomorpholino, homo morpholino and hexamethyleneimino. Examples of the optional substituents which may be pre sent 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. In general, Y is preferably a piperidino or morpholino group (with the proviso that when Y is morpholino and R2 is -H, the ring hydroxy group of compounds of formula (la) is in the fl-position). Compounds in which Y is piperidino are particularly preferred.

Compounds of formula (1a) in which the ring hydroxy group is in the fl-position are generally preferred.

In general, the compounds in which the carbon atom carrying the -(CH2)2XWCONHR2 group is in the R-configuration (and mixtures containing this isomer) are preferred.

Thus, compounds of formulae (1a) and (1b) which are generally preferred are those in which: R, is benzyl in which the phenyl group is substituted by phenyl (which phenyl is optionally substituted by C14 alkyl or C14 alkoxy).

R2 is-H, -CH2CO2H or -CH2CONH2, X is cis -CH=CH W is -CH2CH2-, and Y is piperidino or morpholino (with the proviso that when Y is morpholino and R2 is -H, the ring hydroxy group of compounds of formula (1a) is in the ssposition), and the physiologically acceptable salts and solvates thereof.

Particular groups of compounds of the latter type are: (1) compounds of formula (1a) in which the ring hydroxy group is in the position and R1 is benzyl in which the phenyl group is substituted by phenyl, 4-methoxyphenyl or 4-methylphenyl, particularly compounds in which Y is piperidino and R, is biphenylmethyl; (2) compounds of formula (1a) in which the ring hydroxy group is in the a-position, Y is piperidino, R2 is -H and R is benzyl in which the phenyl group is substituted by phenyl, 4 methoxyphenyl or 4-methylphenyl, especially the compound in which R, is biphenylmethyl; and (3) compounds of formula (1b) in which R, is benzyl in which the phenyl group is substituted by phenyl, 4-methoxyphenyl or 4-methylphenyl and R2 is -H, particularly the compound in which Y is piperidino and Rl is biphenylmethyl.

The IR-isomers of the compounds of the above groups 1-3 are generally preferred, and a particularly important compound is [IR-[l rr(Z),2B,3P,5rr]l-( f)-7-[5-[[(1,1 '-biphenyl)-4-yi]methoxyl-3- hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenamide and its salts and solvates.

Compounds of formulae (1a) and (1b) inhibit blood platelet aggregation and bronchoconstric tion. 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 proaggrega tory agent. Alternatively, starved guinea-pigs are dosed orally with the compound to be tested in a suitable vehicle. Platelet rich plasma is prepared from each animal and aggregation to a range of collagen concentrations is measured after the method of Born. Collagen concentration-effect curves for each sample of plasma are calcuiated 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 in the anaesthetised guinea pig by measuring the effect of the compound to be tested on the dose response curve of the bronchoconstrictor [lR-[ 1 a,4a,5fi(Z),6a( 1 E,3S")]]-7-[6-(3-hydroxy- 1 -octenyl)- 2-oxabicyclo[2,2, 1 ]hept-5-yl]-5-heptenoic acid (U-466 19).

The compounds are thus of interest in the treatment of asthma, and as inhibitors of platelet aggregation and thrombosis for use in reneal transplant and 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, pulmo nary embolism, diabetic retinopathy, post operative thrombosis, angina and myocardial infarction.

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

The compounds may be formulated in conventional manner for use, with one or more pharma ceutical 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 continu ous infusion. Formulations for injection 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 10mg/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. The precise dose administered will of course depend on the age and condition of the patient.

Suitable methods for preparing compounds of formula (1) are described below, the groups R1, R2, W, X and Y being as defined above except where otherwise indicated.

(a) Compounds of formulae (1a) and (1b) may be prepared by amidation of the parent carboxylic acid i.e. the corresponding compound containing the side chain-(CH2)2XWCOOH.

Conventional methods for converting acids into amides may be used.

For example, a reactive derivative of the carboxylic acid may be treated with ammonia or an amine R2NH2 in a suitable solvent, e.g. acetone or acetonitrile. 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.

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

Alternatively, the reactive derivative may be an imidazolide, formed for example by treatment of the acid with 1,1'-carbonyldiimidazole.

The ring hydroxy group (when present) may need to be in a protected form during these reactions. Conventional methods of protection and deprotection may be used, as described below in process (d).

The parent carboxylic acids, required as starting materials in this process may be prepared by the methods described in British Patent Specifications 2075503A and 2097397A.

(b) Compounds of formula (1b) may be prepared by oxidising a corresponding compound of formula (1 a).

Suitable methods of oxidation include using a CrVl oxidising agent 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 [RTM]) 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 0-5"C, or (ii) pyridine -SO3 complex in dimethylsulphoxide, preferably at 0"C to room temperature.

(c) Compounds of formula (1a) in which the ring hydroxy group is in the ss-configuration may be prepared by reducing a compound of formula (it).

The reduction may for example be effected with a selective reducing agent such as diisobutyl aluminium-2,6-di-t-butyl-4-methylphenoxide, lithium tris-amylborohydride, 2,6-di-tert-butyl-4-methylphenoxymagnesium hydride or potassium tri-isopropoxyborohydride. The reaction temperature may be from - 10" to -78"C.

(d) In the preparation of the compounds of formula (lea), the ring hydroxy group will sometimes be protected and its liberation may be the final step in the synthesis. Conventional methods of protection may be used, (e.g. using 2,3 dihydro-4H-pyran) and the protecting group may be removed by hydrolysis, e.g. with an acid or alkali, depending on its nature.

(e) Compounds in which R2 is -CH2CO2H may be prepared by hydrolysis of the corresponding compound in which R2 is -CH2CO2R3 where R2 is C16 alkyl, e.g. methyl. The hydrolysis may for example be effected with a base (such as K2CO3) in a solvent such as a water-methanol mixture.

(f) Salts may be prepared by treating an amide of formula (la) or (1b) with an acid, or (when R2 is -CH2CO2H) a base, in a suitable solvent such as ether.

When a specific enantiomer of formula (la) or (1b) 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 bicycloheptenone as described in European Patent Specification 74856, using the methods generally described in UK Patent Specifications 2028805A, 2075503A and 2097397A.

The following examples illustrate the invention.

Temperatures are in "C. Abbreviations-'Dried' refers to drying with anhydrous MgS04; t.l.c.-Thin Layer Chromatography on silica; ER-ether; EA-ethyl acetate; PE-petroleum ether (b.p.

60-80 ); DMSO-dimethylsuiphoxide.

Chromatography was carried out using silica gel. The following abbreviations describe the eluent used for the column chromatography and t.l.c: (A) 85:15 EA-methanol (B) 95:5 ER-methanol (C) 9:1 EA-methanol (D) 20:1 EA-methanol (E) 1:1 EA-methanol (F) 92:8 EA-methanol (G) 4:1 EA-methanol (H) 9:1 ER-methanol (1) 3:1 EA-methanol (J) EA (K) 7:3 ER-methanol (L) 80:20:1 EA-methanol-NH2 (M) 49:49:2 EA-ER-NH2 (N) 17:2:1 CH2CI2-methanol-Et3N Intermediates 1-7 are described in British Patent Specification 2075503A.

Intermediate 1 [ 1a(Z),2ss,3a,5al-(+ J-7-[5-[[(1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4- heptenoic acid Intermediate 2 [1a(Z),2a,3a,5a]-()-9-[5-[[(1, 1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-6- nonenoic acid Intermediate 3 [1 a(Z),2fi, 3a,5a]-(+)- 7-[3-Hydroxy-5j[(4'-meThoxy( 1, 1 '-biphenyl)-4-yl]methoxy]-2-(1-piperidinyl)cy- clopentyl]-4-heptenoic acid, compound with piperazine (2::1) Intermediate 4 [1a(Z),2ss,3a,5a]-()-7-[3-Hydroxy-5-[[4'-methyl(1,1' -biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)cyclo- pentyl]-4-heptenoic acid Intermediate 5 [1 a(Z),2ss,3a,5a]-()-7-[3-Hydroxy-5-[[4'-meThoxy( 1, 1 '-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)cy- clopentyl]-4-heptenoic acid Intermediate 6 [1a(Z),2ss,3a,5a]-()-7-[5[[(1,1'-Biphenyl)-4-yl]-methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4heptenoic acid Intermediate 7 [ 1R1 1a(Z),2ss,3a,5a]]-( +)-7-[5-[[(1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopen- tyl]-4-heptenoic acid.

Intermediate 8 is described in British Patent Specification 2097397A Intermediate 8 [1 R- 1a(Z),2ss,3ss,5a]]-()-7-[5-[[(1, 1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]- 4-heptenoic acid Intermediate 9 [1S-[1a,2a, 3fi(Z), 4fli]-( )-[3-(7-Amino- 7-oxo-3-heptenyl)]-4-[[( 1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1-piper idinyl)cyclopentyl]-2-methylpropyl carbonate Isobutylchloroformate (0.26ml) was added to a stirred, cooled (0 ) solution of Intermediate 8, hydrochloride (0.516g) and triethylamine (0.56ml) in dry CH3CN (15 ml). After 0.5h an excess of ammonia was condensed into the mixture using a dry-ice condenser. The cooled mixture (-78 ) was allowed to warm to ambient temperature over 2h then poured into pH 6.5 phosphate buffer (100ml) and extracted with EA (2X75ml). The combined, dried, extracts were evaporated in vacuo to give an oil (0.65g).

A portion of the oil (0.139) was purified by chromatography (J) to give the title compound as an oil (0.062g).

T.l.c. (J) Rf 0.39 I.r. (CHBr3) 3520, 3400, 1730, 1680cm-1 Intermediate 10 [1 R-[ 1a(Z),2ss,3ss,5a]]-(+)-Methyl N-[7-[5-[[( 1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-( 1-piperidinyl))- cyclopentyl]- 1-oxo-4-heptenyl]-DL-glycinate Isobutylchloroformate (0.25ml) was added to a cold (0 ) stirred solution of Intermediate 8, hydrochloride (0.89) and triethylamine (0.7ml) in acetone (20ml). After 0.5h a suspension of glycine methyl ester, hydrochloride (0.589) and triethylamine (0.75ml) in acetone (10ml) was added and stirring continued for 4h. The acetone was removed in vacuo and the residue in 8% NaHCO2 solution (30ml) was extracted with CH2CI2 (2X50ml).The combined extracts were dried and evaporated and the residue was purified by chromatography (M) to give the title compound (0.6639) m.p. 86-87 .

Analysis Found: C,72.0; H,8.3; N,5.3.

C33H44N205 requires C,72.2; H,8. 1; N,5.1%.

[a]D219 = +62.0 (CHCl3) Example 1 a) [ 1a(Z),2ss,5e]-( +)-7-[5-[[(1, 1'-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-hep- tenamide A solution of Example 7a (0.31g) in DMS0 (2ml) and triethylamine (2ml) was stirred vigorously at room temperature whilst pyridine-S02 complex (0.39) was added in one portion. After about 40 min. a further quantity (0.39) of pyridine-S03 complex was added. The mixture was left for ih, then poured into saturated NH4CI solution (70ml) and extracted with CH2CI2 (3X50ml). The combined extracts were dried, filtered and concentrated, and the residue purified by chromatography (B) to give the title compound as a foam (0.219).

T.l.c. (B) Rf 0.25 I.r. (CHBr3) 3520, 3400, 1740, 1680cm-1 The following compounds were prepared in a similar manner: b) [1a(Z),2ss,5a]-()- 7-[5-ff4 '-MeThyU 1, 1 '-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oXocyclopen- tyl]-4-heptenamide, m.p. 101-106 from Example 7b. Purification initially by chromatography (D) and then by crystallisation from EA-PE.

Analysis Found: C,73.6; H,7.8; N,5.7.

C33H38N204 requires C,73.4; H,7.8; N,5.7%.

c) [1a(Z),2ss,5a]-()-7-[5-[[(1, 1 '-Biphenyl)-4-yl]methoxy]-3-oxo-2-( 1 -piperidinyl)cyclopentyl]-4-hep- tenamide, m.p. 89-91 from the compound of Example 2. Purification initially by chromatography (F) and then by crystallisation from EA-ER-PE.

Analysis Found: C,76.1; H,8.1; N,5.9.

C30H38N?03 requires C,75.9; H,8.1; N,5.9%.

d) [1a(Z),2ss,5a]-()-7-[5-[[4'-Methoxy(1, 1 '-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oXocyclo- pentyl]-4-heptenamide, m.p. 107-108.5 from Example 7C. Purification by chromatography (C).

Analysis Found: C,71.1; H,7.6; N,5.5.

C30H38N2O5 requires C,71.1; H,7.7; N,5.3%.

e) [1a(Z),2ss,5a]-( )-9-[5-[[(1, 1 '-BiphenylI-4-yqmethoxy}-2-(4-morphollnyl)-3-oxocyclopenty6rno- nenamide, m.p. 97-99 from Example 7d. Purification by chromatography (H).

Analysis Found: C,73.7; H,8.0; N,5.5.

C3rH40N204 requires C,73.8; H,8.0; N,5.6%.

f) [ 1 a(Z),2ss,5a]-( + J-7-[5-[[4'-Methoxy(1, 1 '-biphenyl)-4-yl]methoxy]-3-oxo-2-( 1-piperidinyl)cyclopentyl]-4-heptenamide, m.p. 110.5-114.5 from Example 7e. Purification by chromatography (J).

I.r. (CHBr3) 3520, 3400,1735, 1680cm-1 9) [ 1R1 1a(Z),2fi, 5a11-(-)- 7-[5-[[(1, 1 '-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oXocyclopentyl]-4- heptenamide, compound with ethyl acetate (4:1), from Example 7f. Purification by chromato graphy (C). [a]04 =-11.4 (CHCl3) T.l.c. (G) Rf 0.5 Analysis Found: C,72.0; H,7.6; N,5.55.

C29H36N2O4.0.25C4H8O2 requires C,72. 1; H,7.7; N,5.6%.

h) [lR-[ 1 a(Z),2ss,5a]]-(-)-7-[5-[[(1, 1 '-Biphenyl)-4-yl]methoxy]-3-oxo-2-( 1 -piperidmyl)cyclopentyl]-4- heptenamide, m.p. 81-82 from the compound of Example 4. Purification initially by chromatography (B) then by crystallisation from EA-ER-PE. [a]D1 =-21.5 (CHCl3) Analysis Found: C,75.5; H,8.3; N,5.8.

C30H38N203 requires C,75.9; H,8.1; N,5.9%.

Example 2 [1 a(Z),2fi,3a, 5ak()-7-[5-i[( 1,1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl-4- heptenamide, m.p. 130-133 from Intermediate 6 according to the procedure for Example 7a.

Purification by chromatography (G).

T.l.c. (E) Rf 0.22 Example 3 [1R-[1a(Z),2ss,3ss,5&alpha;]]-(+)-7-[5-[[(1,1' tBiphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpho/iny/)cyc/open tyl]-4-heptenamide A solution of DIBAL in hexane (1M, 4.2ml) was added over 5 min to a cooled (0 ), stirred solution of 2,6-di-tert-butyl-4-methyl phenol (1.859) in dry toluene (20ml) under nitrogen. After 1h the solution was cooled to -70 and a solution of the compound of Example lg. (0.29) in toluene (5ml) was added, the mixture was stirred at -70' for 1h then kept at -20 for 18h. 2N HCI (20ml) was added and the mixture allowed to warm to ambient temperature over 1h. 2N Na2CO3 solution (20ml) was added and the mixture was extracted with EA (3X40ml).The combined extracts were dried and evaporated and the residue was purified by chromatography (K) to give the title compound as a solid (0.159), m.p. 93-94.5'. [a]D25 =+61.6 (CHCl3) I.r. (CHBr3) 3520, 3400, 1680 cm- Example 4 [1 [1R-[1&alpha;(Z),2ss,3ss,5&alpha;]]-(+)-7-[5-[[(1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-( 1-piperidinyl)cyclopen- tyl]-4-heptenamide A solution of intermediate 9 (0.49) in methanol (30ml) and 2N NaOH (5ml) was kept at 20 for 3h then diluted with brine (75ml) and extracted with EA (2X50ml).The combined, dried, extracts were evaporated in vacuo and the residue was crystallised from isopropyl acetate to give the title compound as a solid (0.129) m.p. 102-103.5.

I.r. (CHBr3) 3520, 3400, 1680cm-1 [a]'4 =+67.9 (CHCl3) Example 5 [1 [1R[1&alpha;(Z),2ss,3ss,5&alpha;]-(+)-N-(2-Amino-2-oxoethyl) 7-[5-[[(1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2- (1 -piperidinyl)cyclopentyl]-4-heptenamide Isobutylchloroformate (0.2ml) was added to a cold (0 ) stirred solution of Intermediate 8, hydrochloride (0.4y) and triethylamine (0.97ml) in acetone (30ml). After 0.5h glycinamide hydrochloride (0.439) was added and stirring continued for 18h. The mixture was diluted with pH 6.5 phosphate buffer and the acetone was removed in vacuo.The residue was extracted with EA (2X50ml) and the combined extracts were washed with brine (50ml), dried and evaporated. The residue was purified by chromatography (L) to give the title compound as a semi-solid (0. 1 85g) [ai2 =+60.2" (CHCl3) T.l.c. (L) Rf 0.2 I.r. (CHBr3) 3665, 3510, 3400, 1670 (br.) cm-1 Example 6 [1 1R1 1 a(Z),2ss,3ss,5a]]-(+)-N-[7-[5-[[( 1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-( 1-piperidinyl)cyclo- pentyl]- 1 -oxo-4-heptenyl]-DL-glycine A mixture of Intermediate 10 (0.289) and potassium carbonate (85mg) in water (0.5ml) and methanol (2ml) was stirred at ambient temperature for 18h. The methanol was removed in vacuo and the residue was adjusted to pH6 using 2N HCI and pH6 phosphate buffer, then extracted with CH2CI2 (3X50ml). The combined extracts were dried and evaporated to give the title compound as a colourless foam (0.2379).

[a]212 +76 (CHCl3) T.l.c. (N) Rf 0.48 I.r. (CHBr3) 3400, 1660, 1650, 1600(br) cm-1 Example 7 a) [1 1a(Z),2ss,3a,5a]-( +)-7-[5-[[(1, 1 '-Biphenyl)-4-yl]methoxy]-hydroxy-2-(4-morpholiny)cyclopentyl]- 4-heptenamide A solution of Intermediate 1 (1.4g) in acetone (10ml) containing triethylamine (1.5ml) was cooled to -10 and isobutyl chloroformate (1.2ml) was added. After 0.5h liquid ammonia (5ml) was added and the mixture allowed to reach ambient temperature over 1 h. The excess of ammonia was allowed to evaporate and the mixture was poured into water (80ml) and the pH adjusted to 8-9 with 2N NaOH solution.The aqueous layer was extracted with EA (3X70ml) and the combined extracts were washed with brine, dried and concentrated. Purification of the residue initially by chromatography (A) and then by crystallisation from EA gave the title compound (0.489), m.p. 90-92 . TLC (3:1 Er-methanol) R1 0.25.

The following compounds were prepared in a similar manner: b) [ la(Z), 2 3a, 5a]-(±)- 7-[3-Hydroxy-5-4 '-methyl( 1, 1 biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)cy- clopentyl]-4-heptenamide, m.p. 100-103 from Intermediate 4. Purification initially by chromatography (A) and then by crystallisation from EA-PE. TLC (G) R, 0.28.

c) [1 1&alpha;(Z),2ss,3&alpha;,5&alpha;]-()-7-[3-Hydroxy-5-[[4'-methoxy( 1, 1 '-biphenyl)-4-yl]methoxy]-2-(4-morpholnyl)- cyclopentyl]-4-heptenamide, m.p. 109-111" from Intermediate 5. Purification by chromatography (G). TLC (G) R, 0.34.

d) [ a(Z),2,1' 3a, 5a(+)-9j5-ff( 1, 1 '-Biphenyl)-4-yl)methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]- 6-nonenamide from Intermediate 2. Purification by chromatography (H) on alumina (Grade Ill neutral). I.R. (CHBr3) 3540(br), 3520, 3405, 1680cm-1. TLC (Alumina) (H) R, 0.25.

e) [1 &alpha;(Z),2ss,3&alpha;, 5a]-( +)- 7-[3-Hydroxy-5-[[4'-methyl( 1, 1 '-biphenyl)-4-yl]methoxy]-2-( 1 -piperidinyl)cy- clopentyl]-4-heptenamide, m.p. 117.5-125 from the free acid of Intermediate 3. Purification by chromatography (I). TLC (E) R, 0.35.

f) [ 1R-[ 1a(Z),2ss, 3a, 5a]]-( +)- 7-[5-[[{1, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclo- pentyl]-4-heptenamide, m.p. 11 1 from Intermediate 7 methane sulphonate. Purification initially by chromatography (K) and then by crystallisation from EA-PE.

[a]22 = +64.20 (CHCI3) TLC (H) R, 0.15.

Pharmaceutical Examples Tablets These may be prepared by direct compression or wet granulation. The direct compression method is preferred by 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 Compression 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 me 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 (11)

1. Compounds of the general formulae (1a) and (1b)

wherein R, is (i) C15 alkyl substituted by (a) phenyl [optionally substituted by C16 alkyl, C5-7 cycloalkyl, phenylalkyl having a Cl 3alkyl portion, thienyl or phenyl (optionally substituted by C14 alkyl, C1-4 alkoxy or phenyl)], (b) thienyl [optionally substituted by Cl -6 alkyl, C1-6 alkoxy, C5-7 cycloalkyl or phenyl (optionally substituted by C12 alkyl, C1-3 alkoxy or halogen)] or (c) naphthyl (optionally substituted by C1- 4 alkyl or Cl 4alkoxy) or (ii) cinnamyl; R2 is a hydrogen atom, a methyl group, -CH2CO2H or-CH2CONH2; X is a cis or trans -CH=CH-; W is straight or branched C17 alkylene;; 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 -NR6 (where R6 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; and the physiologically acceptable salts and solvates thereof.

2. Compounds as claimed in claim 1 in which: R1 is benzyl in which the phenyl group is substituted by phenyl, which phenyl is optionally substituted by C1-4 alkyl or C1-4 alkoxy, X is cis -CH=CH-, W is -CH2CH2-, and Y is piperidino or morpholino (with the proviso that when Y is morpholino and R2 is -H, the ring hydroxy group of compounds of formula (1a) is in the fl-position).

3. Compounds as claimed in claim 1 or claim 2 in which R2 is -H, -CH2COOH or -CH2CONH2.

4. Compounds as claimed in any of claims 1 to 3 of the formula (1a) in which the ring hydroxy group is in the fl-position.

5. Compounds as claimed in claim 2 of the formula (1a) in which the ring hydroxy group is in the fl-position and: R1 is benzyl in which the phenyl group is substituted by phenyl, 4-methoxyphenyl or 4-methylphenyl, and R2 is -H, -CH2COOH or-CH2CONH2.

6. Compounds as claimed in claim 2 of the formula (la) in which the ring hydroxy group is in the a-position and: R1 is benzyl in which the phenyl group is substituted by phenyl, 4-methoxyphenyl or 4-methylphenyl, R2 is -H, and Y is piperidino.

7. Compounds as claimed in claim 2 of the formula (ib) in which: R1 is benzyl in which the phenyl group is substituted by phenyl, 4-methoxyphenyl or 4-methylphenyl, and R2 is -H.

8. Compounds as claimed in any of the preceding claims in which the carbon atom carrying the -(CH2)2XWCONHR2 group is in the R-configuration.

9. [1 R-[1 a(Z),2ss,3ss,5a]]-(+)-7-[5-[[(1,1 '-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1 -piperidinyl)cyclopentyl]-4-heptenamide and its physiologically acceptable salts and solvates.

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

11. A process for the preparation of a compound as claimed in claim 1 which comprises: (a) amidating the corresponding carboxylic acid containing the side chain -(CH2)2XWCOOH, (b) in the preparation of a compound of formula (lob) oxidising a corresponding hydroxy compound of formula (1a) in which Y is in either the a- or fl-position, (c) in the preparation of a compound of formula (1a) in which the ring hydroxy compound is in the fl-position, reducing a compound of formula (1b), (d) in the preparation of a compound of formula (1a), liberating the hydroxy group from a corresponding compound having a protected ring hydroxy group, (e) in the preparation of compounds in which R2 is -CH2CO2H, hydrolysing the corresponding compound in which R2 is -CH2CO2R3 where R3 is C16 alkyl, or (f) in the preparation of a salt, treating an amide of formula (1a) or (1b) with an acid or (when R2 is-CH2COOH) with a base.