CA1173830A - Aminocyclopentane alkenoic acids and esters and their preparation and pharmaceutical formulation - Google Patents

Abstract

ABSTRACT

Compounds are described of the formula (1) (and their salts and solvates) in which:
X is cis or trans -CH=CH-;
R1 is C1-7 alkyl terminated by -COOR3 where R3 is H, C1-6 alkyl or C7-10 aralkyl;
Y is a saturated heterocyclic amino group having 5-8 ring members; and R2 is C2-4 alkanoyl, C3-6 alkenyl (optionally substituted), C1-12 alkyl, or substituted or unsubstituted phenylalkyl, biphenylalkyl or naphthylalkyl.
These compounds inhibit blood platelet aggregation and bronchoconstriction and may be formulated for use as antithrombotic and anti-asthmatic agents.

Description

~ 173830 Aminocyclopentane alkenoic acids and ester_ and their prepara~ion and Pharmaceutical formulation The endoperoxides prostaglandins G2 and H2, and thromboxane A2 are naturally occurring, reactive meta-bolites of arachidonic acid in human platelets. Theyare not only potent aggregatory agents but are also constrictvrs of vascular and bronchial smooth muscle, and therefore substances which antagonise their effects are of considerable interest in human medicine.
We have now ~ound a new group of compounds which have shown endoperoxide and thromboxane antagonist activity, and are therefore o~ interest in the treatment of asthma and cardiovascular diseases. These compounds can broadly be described as cyclopentanealkenoic acids and esters in which the double bond is in the 3,4-position in relation to the cyclopentane ring and in which the ring is substi-tuted by heterocyclic amino, oxo and alkanoyloxy or ether (particularly aralkoxy) groups.
The invention thus provid2es compounds o~ ~he general ~ormula ~1) ~
~ "- (C~12 ) ~XR
~1 ' ~ --~ Y
wherein X is cis or trans -C~=C~-;
~i ~i :, . . ~.

~ ~73~3~V

Rl is straight or branched Cl 7 alkyl bearing as a terminal substituent -CooR3 where R3 is a hydrogen atom, Cl_6 alkyl or C7_l0 aralkyl; Y represents a saturated heterocyclic amino group which has 5 to 8 ring members selected from pyrrolidino, piperidino, morpholino, piperazino, thiamorpholino, l-dioxothiamorpholino~ homo-morpholino, and hexamethyleneimino; R2 is (i) C2 4 alkanoyl; (ii) C3 6 alkenyl, optionally substituted by phenyl (the phenyl being optionally substituted by C
alkyl, Cl 4 alkoxy, halogen, C5~7 cycloalkyl or phenyl (Cl 4 alkyl), biphenyl (optionally substituted by Cl 4 alkyl, Cl 4 alkoxy or halogen), or naphthyl; (iii) Cl 12 alkyl; (iv) Cl 5 alkyl substituted by (a) phenyl [optionally substituted by halogen, hydroxy, Cl_6 alkyl, Cl 6 alkoxy, Cl 4 hydroxyalkoxy, trifluoromethyl, cyano, aryloxy, C5 7 cycloalkyl, aralkoxy, dimethylamino-methyl, carboxamido (~CON~2), thiocarboxamido (-CSNH2), Cl 4 alkanoyl, -NR5R6 (where R5 and R6 are the same or different and are each a hydrogen atom or Cl_~
alkyl, or where -NR5R6 is a saturated heterocyclic amino group as defined above for Y), Cl 3 alkylthio, Cl 3 alkylsulphinyl, Cl 3 alkylsulphonyl, phenylalkyl having a Cl 3 alkyl portion, aminosulphonyl, Cl 3 alkanoylaminosulphonyl, phenylsulphonyl (the phenyl portion being optionally substituted by Cl 3 alkyl or Cl_3 alkoxy), nitro, or thienyll, (b) biphenyl (option-ally substituted by phenyl or one or two Cl 4 alkyl, Cl_4 alkoxy, halogen substituents), or (c) f '~
.'j,~'.')~

~ :1738~

na~lthyl (optionally substituted by Cl 4 alkyl, Cl_4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates (e.g. hydrates) thereof.
The structural formulae herein are to ~e under-stood to include the enantiomers of each of the compounds concerned as well as mixtures of the enantlomers, including racemates, even though the precise structure as set out only relates to one enantiomer~
lU The alkyl groups referred to abo~e in the definition of the compounds of formula (1) may be straight or branched ~he alkyl portion of the group Rl may for example contain 1-5 carbon atoms in a straight or branched chain, and is preferably -CH2CH2-, Examples of s~itable R groups are Cl_3 alkyl (e.g. methyl)~ but R is preferably a hydrogen atom. R is thus prefera~ly -~C~2)2COOH.
When R3 is a hydrogen atom, the compounds are capable of salt formation wi~h bases and the compounds 20 are preferably used in the form of such salts. Examples of suitable salts are alkali metal (e.g. sodium and potassium) r alkaline earth metal (e.g. calcium or magnesium), ammonium, substituted ammonium (e.g.
tromethamine or dimethylaminoethanol), piperazine, 2S N,N-dimethylpiperazine, morpholine, piperidine and tertiary amino (e.g. triethylamine) salt~. Inorganic salts are preferred.

;~1 ' .
, :

~ ~383~

X is preferably a cis -CH=CH- group.
The heterocyclic amino group Y is selected from pyrro-lidino, piperidino, morpholino, piperazino, thiamorpholino, l-dioxothiamorpholino, homomorpholino and hexamethylene-imino. Y is preferably p;peridino, morpholino, homomor-pholino, thiamorpholino or l-dioxothiamorpholino, and compounds in which Y is a morpholino or piperidino group are particulàrly preferred.
The amino group Y enables the compounds to form salts with organic acids, e.g. maleates.
R2 may for example be C5_10 alkyl (e.g. pentyl or decyl); C3_5 alkenyl (e.g. allyl, optionally substituted by phenyl); or Cl_5 alkyl ~e.g. methyl or propyl) sub-stituted by phenyl loptionally substituted by a Cl 4 alkyl (e.g. tert butyl), C5 7 cycloalkyl (e.g. cyclo-hexyl), Cl 3 alkylthio ~e.g~ methylthio), phenyl (Cl 3) alkyl ~e.g. benzyl) or thienyl], r~

~ ~ l 3 8 3 ~

biphenyl [optionally substituted by Cl 3 alkyl (e.g.
methyl), Cl 3 alkoxy ~e.g. methbxy), halogen ~e.g.
chlorine) or phenyl], or naphthyl.
R is preferably a phenylalkyl group in which the alkyl portion contains Cl 3 carbon atoms and the phenyl is substituted with one of the following groups:
Cl 3 alkylthio, thienyl or phenyl optionally substituted by Cl 3 alkyl, Cl 3 alkoxy; halogen or phenyl; or cinnamyl.
Particularly preferred R2 groups are phenylalkyl groups in which the alkyl portion is a Cl 3 alkylene chain and the phenyl group carries a phenyl substituent, preferably in the para-position (which phenyl substituent is optionally substituted by a Cl 3 alkyl, Cl 3 alkoxy or halogen, this additional substituent preferably being in the meta or more particularly the para-position); or cinnamyl.
A particularly preferred group of compounds has the formula (1) in which:
X is cis -CH=CH-, R is -CH2CH2COOH, Y is morpholino or piperidino, and R2 is phenyl (Cl 3) alkyl in which the phenyl group is substituted by phenyl (which phenyl substituent is optionally substituted by Cl 3 alkyl, Cl 3 alkoxy or halogen); or cinnamyl.
and the physiologically acceptable salts and solvates (e.g. hydrates) thereof.

1 ~3~3~

Particularly important compounds in this latter group are those in which Y is morpholino and R2 is l,l'-biphenylmethyl; l,l'-biphenylmethyl su~stituted in the para-position by methyl, methoxy or chloro or in the meta-position by methoxy; l,l'-biphenylpropyl;
or cinnamyl; and those in which Y is piperidino and R2 is 1, l'-biphenylmethyl or 4'-methoxy-1,1'-biphenylmethyl. Especially important are:
[la(Z), 2~,5a~ )-7-[5-~[(1,1'-biphenyl)-4-yl~
methoxy]-2-(4-morpholinyll-3-oxocyclopentyl]-4-heptenoic acid;
and [lR-[la(Z),2~,5a]]-(-)-7-~5-[[(1,1'-biphenyl)-4-yl]
methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid;
and the hydrates and salts thereof, particularly the calcïum, piperidine, piperazine and N,N-dimethylpiperazine salts. The calcium salts are particularly important.
In general, compounds of formula (1) in which the carbon atom carrying the -(CH2)2XRl group is in the R-configuration (and mixtures containing this isomer) are preferred.
Compounds of formula (1) inhibit blood platelet aggregation and bronchoconstriction. The test for inhibition of platelet aggregation is as described by G.V. Born in ~ature 194, 927-929 (1962) except in that collagen is used instead of ADP as the pro-aggregatory agent. The test for potential inhibition o~ broncho-constriction is as described by K.M. Lulich et al in Briti~h Journal o Pharmacology 58, 71-79, ~1976) ~xcept ~uinea-pig lung is used instead o cat lung.

~!
: , .

~, ` "~ ' 3 8 ~

The compounds are thus of interest in the treatment of asthma, and as inhibitors of platelet aggregation and thrombosis for use i~ renal dialysis and thè
teeatment and prevention of occlusive vascular diseases such as arteriosclerosis, a~herosclerosis, peripheral vasculaE disease, cerebral vascular disease including transient ischaemic attacks, stroke, pulmo~ary embolism, diabetic retinopathy, post operative thrombosis, angina and myocardial infarction; They may be formulated in conventional manner for use, with one or more pharmaceutical carriers.
For oral administration, the pharmaceutical composition may take the orm of, for example, tablets, capsules, powders, solutions, syrups, or suspensions lS prepared by conventional means with acceptable excipients.
The compounds may be formulated for paren~eral administration by bolus injections or continuous infusion. Formulations ~or injections may be presented in unit dosage form in ampoules, or in multi-dose 20 containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, e.g. sterile pyrogen free water.
For administration by inhalation the compounds are conveniently delivered in the ~orm o~ an aerosol 30 spray presenta~ion from pressurised packs or a nebuliser, or as a cartridge ~rom which the powdered composition may be inhaled with the aid o~ a suitable device.
In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver 35 a metered amount.
For use as antithrombotic agents, the compounds are pre~erably administered orally, for example in amounts o0.05 to 10 mq/kg body weight, 1 to 4 times daily.
.~

.

, ~17~

For use in the treatment of asthma, the compounds may als~ be administered orally in amount~ of 0.~5 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 t~mes daily.
The compounds may be used in combination with o~her anti-asthmatic agents.
The pxecise dose a~mini~tered will of course ,depend on the age and condition of th~ patent.
Suitable methods for preparing compounds of formula (1) are describea below.
In the following discussion, the groups Rl, R2, R3, X and Y are as defined above except where otherwise indicated.
15 (2) Compounds of formula (1) may be prepe.red by oxidising a corresponding hydroxy compound, e.g. a compound of formula (2) oR2 ~"ICH212XRla ~ ' .
~0 Y
l21 (,wherein Rla i~ Cl 7 alkyl substituted ~y -Coo,R3, -CH2QH or -CHQ~.
Suitable methods o~ oxidatlon include using a CrV~ oxidlsing reage~t in a suitabLe solvent, e.g.
chromic acld in aceton~ (e.g~ Jones reagent, pre~erably used in the presence Q~ a diatomaceous sLlica such as Celite~ or CrO3 in pyrLdine. The~e reagents are .'.

, ~ 1~38.~0 g for example used at temperatures o -20 to room temperature.
Other important methods include using an activated sulphur reagent, e.g. (i) N-chlorosuccin~mide-dimethy}sulphide complex in a suitable solvent (e.g.toluene or dichloromethane) at temperatures of for example -25 to 25, preferably at 0-5, (ii),a dimethylsulphide (e.g. dimethylsulphoxide) activated by a ~uitable electrophilic reagent (such as oxalyl chloride, acetyl bromide or thionyl chloride) in a suitable sol~ent ~e.g. toluene or dichloromethane), e.g. at -70 to -20; di-cyclohexylcarbodiimide can also be used as the electrophllIc reagent (preferably in the presence of CF3COO~ or its pyridinium salt) at for example -10 to room temperature, I5 using the same solvent~, or (iii) pyridine -SO~
complex in dimethylsulphoxide, preferably at 0 to room temperature.
When R3 is a hydrogen atomr better yields are sometimes obtained by prior protection of the carboxyl group, for example in the form of a trialkyl (e.g.
trimethyl, triethyl or dimethyl(l,l-dimethylethyl))silyl ester.
CrV~ oxidising agents are generally preferred. Ihc choice of oxidation method however will depend on the nature of the starting material of formula t2). Thus when Rla is -CH2OH or -CHO, a CrVl oxidising agent will generally be used.
When Y is in the a-configuration conditions should be chosen to effect epimerisation, either at the same time or after oxidation.
Any hydroxy or amino group present in the s~ar~ing material and re~ulred in ~he end product should be suitably protected in this reaction.
~bl Compounds o ~ormula (1) in which R ~s an alkyl or aralkyl group can be prepared ~y esterification o ~he corresponding carboxylic acid in which R is a hydrogen atom, reaction with a diazoalkane being preferred.

: ' .

~ 173~3~

Alternatively, the acid may be con~erted into an activ~ated derivative (e.g. a correspondlng mixed anhydridel e.g. by reaction with an alkyl chl~ro-formate (e.g. isobutyl chloroformate) ir~ the presence of a suitable base, e.g. triethylamine or pyridine.
The activated derivative can then be reacted wlth an appropriate alcohol, for example using a solvent such as acetone and temperatures of -10 to room temperature.
(c~ Compounds of formula (l) in which ~ is Pb~X~
substituted by amino may be prepared by reduction of the corresponding azide, for example using zinc and sodium dihydrogen phosphate (~.g. in tetrahydrofuran~.
(d) Compounds of formula (1) may also be prepared by selective reduction of a corresponding compound o~
formula (l! in whlch X is an acetylene group. These intermediates are also novel compounds. Suitable methods of reduction include using hydrogen in the presence of a catalyst, e.g. palladium on a support (e.g. CaC03 or BaS04) and poisoned or example by lead or pyridine Suitable solvents include ethyl acetate or methanol.
(e) Where salts o compounds of formula t1) are desired such salts may be formed by conventional methods, for example by treating acids o ormula (l) with appropriate bases. Salts may also be formed with acids.
, The salts may be formed in conventional manner.
For example, amlne salts are conveniently prepared by adding the amine to a solution o~ an acid o~ ~ormula ~l) in a solvent such as ether. Salts of inorganic bases may be prepared by adding the base to a 3~ ~olutlon o the acid in an a~ueous organlc solvenb~
Certain salts may also be prepared by exchange o~ catlan;
~or example, calcium salts may be prepared by addition o a aalcium salt (e.g. the chloride or acetate) to a solution o~ a salt of a compound of ormula (l), e.g. an amine or alkali metal salt.

~ i 73~

,_ Th~e principal intermediates required for the reactions described above may be prepared by the-following methods.
It will be appreciated that the following reactions 5 will frequently require the use of, or will conveniently be applied to, starting materials having protected functional groups. It is to be understood generally that the reerences below to specific starting materials are intended to include references to corresponding 1~ materials having protected functional groups.
It will also be appreciated that certain of the reactions described below are capable of affecting other groups in the starting material which are desired in the end product, and account must be taksn of this when performing multi-stage reactions.
~f) Compounds of formula (3) ' ' ' .
., oR2 ,~ z.
HO 5~' ~3~

~where Rl L~ as de~ined abo~e for ~1 where R3 is a hydroc~en atom) may be prepared by reacting a compound of ~ormula ~) ~1 ~ ~383~

I~R
</~ VCH~

y ll,l with an appropriate Wittig reagent, e.g. a phosporane of formula R7P=CHRl (where R7 is Cl 6 alkyl or ary:L, 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), dialkylGulphoxides (e.g. dimethylsulphoxida2, alcohols and halogenated hydrocarbons. The reaction may be carried out at any suitable temperature from -70 to 50C, preferably at room temperature.
The reaction is particularly suitable for the preparation of compounds in which Rl is terminally substituted by -COOH (in salt form). Any hydroxy group present is preferably in a protected state prior to this reaction. Suitable hydroxyl protecting groups are described below. Any -NH2 gro~p present ~hould also be protect~.d, e.g. by t-butoxycarbonyl.
I~ desired, th~ configuration o ~he group

2~ X and Rl and ~ may then be modified to provide other compounds o Eormula (21 e.~. by m~thods (1) - ~o) below or Cbl or ~c) above.

~ 1~ 3~3~

The starting materials of formula ~4) may be prepared by the following sequence: 2 y OR
o/~u ~ \~ oR8 H ~ oR2 ~ (4) (5) HO (6) A lactol of formula (5) is treated with an appropriate Wittig reagent (e.g. R7P=CHoR8, where R7 is as defined above and R8 is Cl 4 alkyl) to give the vinyl ether (6). The reactions may be performed as described for process (f). ~he vinyl ether (6) is then hydrvlysed to give the aldehyde (4), for example using a dilute acid 0 such as hydrochloric acid. Acetone is a suitable solvent.
Lactols of the formula ~7) ~ (7) HO oR2 may be prepared by the method described in Glaxo Group Limited's British Patent Specification 2028805A published on 12 March 1980, using starting materials containing the appropriate R group.

~ ~73~3~

Lactols of formula (8) ~1 18~ :
HO oR2 reql}:i.red a~ starting materials may be prepared by th~ followincJ sequence:

o R ~OH
l 9: 1 1101 \~
Y,~

~-- ~ RhOG~R2 oR2 112) 1~1 ~ 173~3~) (Rh above represen-ts a hydroxyl protecting group) l'hus the n~rbornanone (9) is first redueed (e.g.
wi-th NaBH~) to the alcohol (10) into which the R2 group is then introcluced (e.CJ. by reaction with R L, wllere ~ is a leaving group, e.g. halogen or tosyla-te) -to give the compound (llj. The protectiny group (Rh) is then removed and the hydroxy group oxidlsed (e.g. as d~scribed ~or process (a~) to give the norbornanolle (L2). The latter can then be converted into -the lactol ~8) by Baeyer-Villiger oxidation followed by reduction (e.g. with di-isobutyl aluminium hydride).
(cJ) Compounds of formula (2) in which the groups Y
and Oll are both in tlle B-position may be prepaxed by reducing the corresponding compound of formula (1), e.g.
with lithium tri-see-butyl horohydride.
(h) Compounds oE formula (2) in which R a contains -C112O~I may be prepared by redueing -the corresponding acid or ester of formula (2) or (1), e.g. with LiA1114.
(j) Compounds of formula (2) in whieh Rl~ contains -C~IO may be prepared in the same manner as generally described Eor proeess (f) by reae-ting a eompound o~
~ormula (4) with a phosphorane of formula R7P=C~Rla in whieh Rla is Cl 7 alkyl substituted by a proteeted formyl group (e.g. acetal). Removal of the protecting group then CJiVeS the`rec~uired formyl intermecliate.
(k) Compouncls o formula (2) in whieh Y is in the Cl-eon~i~uration and the r:Lng hydroxy CJroup is ln the ~eon1cJuration may be prepared by epimeri~ing the eorrqspondin~ eompound in whieh the ring hydroxy c3roup ;Ls in th~ ~-pos:Lt.ion. This may Eor example be e~eet~d wlth ~riphenylphosuhine in -the prqs~nee o~ an aeicl ~173~ 3 , ~;

(e.c3. formic or benzoic acid) and ~C2115OOC.N)2 at a low temperature. Tetrahydrofuran is a suitable solvent.
(k) The acetylenes required as startincJ ma-terials for process (d) may be prepared by first reactinc;
a compound o formula (7) with a WitticJ reagent (R7P=CBrRl), as descrihed above for process (f). q'he product is then dehydrobrominated to form the side chain acetylene group, and the ring hydroxy clroup then o~.~iclised, as descrlbed for process (a).
(nl) Com~)o~lnds oE formula (2) in wllich X is trans -CII=CII- may be prepared by isomerising the corresponding cis compound. The isomerisation may for example be effected by treatment with, for example, p-toluene sulphinic acid in dioxan (e.g.` at reflux) or azobisisobutyronitrile and thiophenol, using for example a hydrocarbon solvent (e.c3.
benzene) and any suitable temperature up to reflux.
(n) Compounds of formula (2) in which R2 is phenalkyl substituted by -C~12N(C113)2 may be prepared by -treatmen-t of the corresponding formyl compound with dimethylamine in the presence of a reducing agent, e.q. sodium cyano borohydride. The starting materials for this reaction may be made by the general me-thod (f).
(o) Compounds of formula (2) in which R2 is phenalkyl subs-tituted by -CON~12~ or -CSNE-12 and R3 is hydroyen may be prep~recl roM the corresponclinq cyano compoulld by hydroJ.ysls or hydrosulpllidation, ~.y. with sulphur in the presence o~ a recluciny aCJent.
(p~ C'ompo-lrlcls oE Eormula (2) in which 1~2 i5 phenalkyl substltuted by alkylsulphinyl or alkylsulphonyl may be prep~red by oxidation oE the correspondincJ al]cylthio compou!ld with a peracid, or example per~cetic acid at room tcmperatllr3.

.

~ 1 ~J 3 ~3 ~3 ~

, - 17 -(q) Compounds of formula (3) in which -OR is an ether group and Y is in the ~-configuration may be prepared by etherification of thc correspondinc~ hydroxy compound in which R2 is a hydrogen atom. The reaction may for example be performed with an appropriate rea~ent E~ L (L is as defined above), for example by reaction at room temperature in the presence of a sui-table base te.cJ. sodium hydride) in a suitable solvent (e.g. dimethyl-formamide).
(r) Compounds of formula (3) in which R2 is an - alkanoyl group and Y is in the ~-configuration may be prepared by acylation of the corresponding hydroxy compound, for example with the appropriate alkanoic acid or an anhydride or halide thereof.
Any other hydroxy group present in the startinc3 material-used in process (q) or ~r) should be protected in this reaction, as should the -COOH group in compounds in which R3 is a hydrogen atom.
Suitable starting materials of formula (16) for processes (q) and (r) above may be prepared by the followin~ sequellce:
~OH ~H

Rho~ Y 11~) R!lo"

,~Xv~ - Rl ¢~,~CHO, Rho~ y Rh~ Y
1161 . ll5~

.

:~ ~ 7 ~

A lactol of formula (13~, in which -ORh is a protect~d hydroxy group is first treated with a Wittig reagent to give the vinyl ether ~14), which i~ then converted into the aldehyde (15) by treatment with 5 mercuric acetate. These steps ar~ performed in t~e same general way as for the preparation of compounds of formula (4).
The compound of formula (16) may then be formed from the aldehyde (15) by the method of process (f).
The preparation of the lac~ols (133 is described in British Patent Specification 2028805A.
As an alternative to the formation of the ether group by process (q), it may be formed at an earlier stage, by etherification of the compound of formula (14).
~s) Compounds of formula (2) may also be prepared by modifying the corresponding compound in which Y is N~2 ' This reaction may be performed by treating the starting material with a compound of the formula ~R9Z, where 2 is a readily displaceable group (such ~0 as halo, e.g. iodo, or hydrocarbylsulphonyloxy, e.g.
p-toluenesulphonyloxy) and R9 is the appropriate divalent group ~e.g. -(CH2)2S(C~2)2 ) may be carried out in a solvent such as acetonitrile or methanol at reflux, in the presence of a suitable ~ase, e.g. potassium carbonate or sodium bicarbonate.
~he amines required as starting ma~erial~ ~or process (~) may be prepared by reduction o~ the corres-ponding azide, ~or example as described ~or process (c) .
The azide starting materials may be prepared by methods analogous to those or preparing the compounds o~ formula (3), using reagents in which ~ is an azido ~ 173~3~

group. In particular, -the preparations of 1actols of formula (7) in which Y is azido is described in British Patent Specification 2028805~. ' If desired, modification of the group R1 or the configura-tion of the double bond may be effected before the formation of the group Y by process (s). The amino yroup may need to be protected in such transformations.
In the preparation of the intermedia-tes the ring hydroxy group will often be protected and the liberation of this (or~any other hydroxy group present) will frequently be the last step in the preparation.
Conventional methods of protection may be used, protection in the form of dimethyl~ dimethylethyl-silyloxy or tetrahydropyranyloxy groups beiny preferred. These ~roups may be removed by acid hydrolysis. Hydroxy groups may also be protected in the form of alkanoyloxy groups having up to 7 carbon atoms, e.g. acetoxy. These groups may be removed by alkaline hydrolysis.
~hen a specific enantiomer of formula ~1) is required, intermedia-tes having the required stereochemical configuration should be used in the above processes.
For example, enantiomeric,bromohydrin (17) .,. ~' .

/ 117) ~`~
~r 0~1 ~ 173~
- 20 ~

can be prepared by the me-thod described by Newton et al in J.C.S. Chem. Comm., 1979, 908. This can *hen be converted into a compound of formula (I) in which the carbon atom carrying the -(C112)2XRl group is in the (R)-configuration, via the appropria-te enantiomer of the lactol (7), using the methods described above.
The followiny examples illustrate the invention.
i'Jones reayen-t" is a solution of chromic acid and sulphuric acid in water. A 2.67M solution contains CrO3 (26.7g) arld concentrated il2SO4 (23ml) made up to lOOml with water.

, ~ - . .

'. ' ' ~,., ',' . . , -' .

~ ~7~30 Temperatures are in C. The following abbreviations are used:
TLC - thin layer chromatography using SiO2; PE -petroleum ether (boiling at 40-60 unless otherwise stated);
DIBAL - diisobutylaluminium hydride; THF - tetrahydrofuran;
DMF - dimethylformamide; ER -ether; EA - ethyl acetate;
DMSO - dimethylsulphoxide. Chromatography was carried out using silica gel unless otherwise stated. 'Dried' refers to drying with MgS04. '~yflo' is a filtration aid.
Intermediate 1 (endo!anti)~ 5-Hydroxy-7-(4 morpholinyl)bicyclo~2 2.1]
heptan-2-one A mixture of (endo,anti)-5-acetyl-7-(4-morpholinyl)-bicyclo [2.2.1]heptan-2-one (1649) and 5N NaOH solution (i50 ml) was stirred for 3h and then extracted with - CH2C12 (4 x 500 ml). The dried organic layers were evaporated in vacuo to give a semi-solid. Trituration with ER (500 ml) gave the title compound (83g) as prisms, m.p. 119-121.
Intermediate 2 a) (endo,anti)-(+)-5-[~(1,1'-Biphenyl-4-yl]meth~xy]-7-(4-morpholinyl)bicyclo[2.2.1]heptan-2-one To a solution of In~ermediate 1 (10.5g), 1-(bromomethyl)-l,l'-biphenyl (13.6g) and benzyl-triethyl ammonium chloride (1,14g) in CH2C12 ~(200 ml) was added 17N NaOH (100 ml) and the mixture stirred vigorously for 18h. The layers were separated and the aqueous layer extracted 30- with CH2Cl~ (3xlOOml). The combined organ;c layers were washed with water (200ml), dried and ev'aporated ln vacuo. The residue was cry~tal-lised from iso-propyl acetate to give the t'tle _o ~ (lSg) as prisms, m.p. 1~9.5-151.5.
The following cornpounds were prepared by a similar proced~re.
b) (endo,anti)~ 5-~4-Methoxy(phenylmethoxy)]-7-(4-m~ olinyl)bicvclo~2.2.1]heptan-2-one, _. _ ~ ~7383~

m.p. 109-111, from Intermediate 1 and p~methoxy-benzyl bromide. Purification by chromatography using 3:1 ER-PE through to 5:1 ER-methanol as eluent.
c) (+)-4-[~endo,endo,anti)-2-[[~1,1'-Biphenyl)-4-yl]methoxy]-5-[~tetrahydro-2H-pyran-2-yl)oxy]bicyclo-[2.2.1] heptan-7-yl~morpholine, m.p. 109-110 from Intermediate 27. Purification by chromatography using 7:3 ER-PE as eluent.
d) (endo,anti)-~+)-5-~[(1,1'-Biphenyl)-4-yl]methoxy]-7-(1-piperidinyl)blcyclo[2.2.1]heptan-2-one, m.p. 89-91 from Intermediate 57. Purification by chromatography using 3:2 PE-ER as eluent.
Intermediate 3 a) (endo,anti)-(+)-6-[~(l,l'Biphenyl)-4-yl]methoxY]-8-(4-morpholinyl)-2- oxabicyclo~3.2.1]octan-

3-one 38% Peracetic acid in acetic acid (20ml) ~as added dropwise over 10 min. to a stirred solution of Intermediate 2a (12.5g) in CH2C12 (60 ml) maintained at 12-15. Stirring was continued at 15-20 for 24h, the mixture then cooled to 5 and treated with a solution of Na2SO3 (25.1g) in water (125ml) whilst maintaining the temperature below 20. Isopropyl acetate (90 ml) was added and the aqueous phase was separated. The organic phase was extracted with lN NaOH (60 ml) and water (2 x 60ml), then dried and reduced in volume to about 35ml.
On eooling to 20 the ~ erystallised and was eolleeted and dried ~6 25g), m.p. 137-139.
~he ~ollowing eompounds were prepared by a similar proeedure:
b) (endo,anti)-(~)-6-E4-Methoxy~henylmethoxy)]-~ holinyl)-~-oxabieyeloE3.2.11O_tcln-3-one, m.p. 158-1.60, from Intermediate 2b.
Purifieation from CH2C12-PE.
e) (endo, _t~ 6-[[~l,l'-Biphenyl)-4-yl]methoxy]-~ 1~3~3~

8-(1-piperidinyl)-2-oxabicyclo~3.2.1]octan-3-one, m.p. 88-90 from Intermediate 2d.
d) (endo,anti)-(+)-6-Decyloxy-8-(4-morpholinyl)-2-oxabicyclo~3~2.l]octan-3-one m.p. 59-61, fLom intermedia~e 80. Purification from PE.
Intermediate 4 a) (la,2~,3a,5~)-t~)-5-[[(1,1'-Biphenyl)-4-yi]methOXy~-3-hydroxy-2-(4-morpholinyl)cyclopenta-ne acetaldehyde DIBAL in hexane (1.4M; 6.9 ml) was added dropwise to a sol~tion of Intermediate 3a) (1.9g) in dry CH2C12 (30 ml) under nitrogen at -70.
Stirring was continued for 2h at -70 when methanol (50 ml) was cautiously added and the ' mixture then allowed to come to ambient temperature and stirred for a further 3h. The mixture was filtered through hyflo and the filtrate evaporated in vacuo The residue was taken up into CH2C12 (50 ml), dried, filtered a'nd concentrated to give the title compound as a glass (1.8g~
I.R. (CHBr3) 3580, 1718 cm 1.
The following compounds were prepared by a similar procedure:
b) (la,2~,3,5a)-(+)-3-Hydroxy-5-~4-methoxy(phenyl-methoxy)]-2-(4-morpholinyl)cyclopentane acetaldehyde, '25 from Intermediate 3b. Purification by chromatography using 98:2 CHC13-methanol as eluent.
TLC 95:5 CHCl~-methanol Rf 0.8.
c) (la,2a,3a,5a)-(t)-5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentane acetaldehyde, m.p~ 136-138 rom Intermecliate 30.
d) (3aa,4a,5~,6aa)-(~)-Hexahydro-5-~(tetrahydro-2H-pyranl-2-yl)oxy~-4-(4-thiomorpholinyl)-2 cyclopenta~b)uran-2-ol, 'from Intermediate 55a~
TLC 9:1 Benæene-methanol Rf 0.25 e) ~la,2~,3a,5a)-(t)-5-~[~1,1'-Biphenyl)-4-yl]methox 3-hydroxy-2-(1-piperidinyl)cyclopentane acetal h~
~rom Intermediate 3c. TLC 85:15 ER-methanol R~ 0.38.

~ ~3~^~0 f) ~3a~,4a,5B,6aa)-(+)-Hexahydro-4-(hexahydro-1,4-oxazepin-4-yl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-cyclopenta(b)furan-2-ol, from Intermediate 55b. TLC 9:1 ER-methanol Rf 0.31.
9) (la~2B~3a~5a)-(+)-5-Decyloxy-3-hydroxy-2-(4 morpholinyl)cyclopentane acetaldehyde from Intermediate 3d TLC (SiO2) EA Rf 0~21.
Intermediate 5 a) (la~2B~3a~4a)-(+)-4-[[(~ -Biphenyl)-4-yl]-methoxy~-3-(3-methoxy-2-propenyl)-2-(4-morpholinyl)-cyclopentanol To a cold (0) stirred solution of potass~um t _ -butoxide (1.55g) in dry THF (40 ml) under nitrogen, was added portionwise (methoxymethyl)-trlphenyl phosphonium chloride (4.729). The resulting suspension was stirred for 25 min.
whereupon a solution of Intermediate 4a) (1.829) in dry THF (15 ml) was added dropwise. Stirring was continued at room temperature for l.5h.
The reaction mixture was poured into brine, the pH adjusted to 6.5, and the mixture extracted with EA. The dried extracts were evaporated to leave a viscous oil. This crude material was flash chromatographed on silica. Eluting with 95:5 EA-methanol and recycling of the impure fractions gave the title compound as an oil (1.29g). IR (CHBr3) 3950(br), 3540, 1668 cm~l.
The foll~wing compounds were prepared in a similar manner.
b) ~ L~~3~4a ? - (+ ) -2-(3-Methoxy-2-propenyl L-

4-[(tetrahydro-2EI-pyran-2-yl)oxyl-3-(4-t i~ E~
o nyl)cyclopentanol, from Intermediate 4d.
Puri~ication by chromato~raphy U5 ing ether as eluent. ~LC ~R Rf 0.28.
c) 1~,2~,3B,4a)-~)-?-(3-Methaxy-2 e_o ~ ~
~plperidinyl)-4 ~(tetrahydro-2H-pyran-2-yl)-- oxy]cycl~E~_anol, frorn (3aa,4,5B,6a~3~

~ ~73~33~

hexahydro-4-(1-piperidinyl)-5-~(tetrahydro-2H-pyran~2-yl)oxy]-2H-cyclopenta(b)furan-2-ol. TLC 4:1 EA-methanol Rf 0.22.
Intermediate 6 (1~,2~,3a,5a)-(+)-5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-moryholinyl)-cyclopentane propanal, hydrochloride Intermediate 5a (1.8359) was dissolved in 1:1 acetone/0.5~ ~12SO~ (65 ml) and was left standing overnight at room temperature. The acetone was evaporated and the residue treated with 8~ NaHC03 solution and extracted with EA. The dried extracts were evaporated to give a foam ~1.73g) which was dissolved in ether and treated with ethereal hydrogen chloride. The title compound was filtered off and dried, m.p. 169-172.
Intermediate 7 a) (la,2a,3~,4~ )-2-(3-Methoxy-2-propenyl)-3-(4-morpholinyl)-4-~(tetrahydro-2H-pyran-2-yl)oxy]cyclopentanol, acetate (ester) To a cold (0) stirred solution of potassium tert-butoxide (2.15g) in dry THF (40 ml) under nitrogen, was added portionwise (methoxymethyl~tri-phenyl phosphonium chloride (6.57g). The suspension was stirred for 15 min., whereupon a solution of (3a~,4a,5~,6a~)-hexahydro-4-(4-morpholinyl)-

5-(tetrahydro-2H-pyran-2-yl)oxy-2H-cyclopenta(b)-furan-2-ol (2g) in dry THF (30 ml) was added ~ dropwise. Stirring was continued at room temperature for lh, when methanol (30 ml) was added followed by evaporation of the mixture to dryness.
The residue was treated with acetic anhydride ~3 ml) and pyricline (10 ml) and left for 40h.
Evaporation ~n vacuo gave a residue which was treated with 8% Na~lC03 solution (50 ml) and extracted with CH2C12 (3 x 20 ml). I'he combined extracts were washed with brine (2 x lS ml), dried and concentrated. Purification of the ~ ~73~30 residue, initially by chromatography using 4:1 ER-methanol as eluent, and then by trituration with PE gave the title compound as an oil (13.23g).
IR (Neat) 1735, 1655 cm 1 The following compounds were prepared in a similar manner:
b) (la,2a,3~, 4a) - (~) -2-(3-Methoxy-2-propenyl)-4-~(tetrahydro-2~I-pyran-2-yl)oxy]-3-(4-thiomorph-olinyl)cyclopentanol, acetate (ester), S-dioxide, m.p. 131-13~ from Intermediate 63. Purification initially by chromatography using 1:1 EA-PE
as eluent, followed by crystallisation from isopropanol-ER-isopentane.
c) (l~2a,3~4~)-(+)-3-(Hexahydro-l,4-oxazepin-4-yl)-2~(3-methoxy-2-propenyl)-4-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentanol, acetate (ester), from Intermediate 4f. Purification by chromatography using 95:5 ER-methanol as eluent. T~C 19:1 ER-methanol Rf 0O65.
Intermediate 8 (1,2~,3~,4a) - (+) -2-(3-Methoxy-2-propenyl)-3-(4-morpho-linyl)-4-[~tetrahydro-2H-pyran-2-yl)oxy]cyclopentan ~ solution of Intermediate 7a (0.3g) in 0.5N
NaOH (10 ml) was left to stand for 10 min., then extracted with ER (3 x 20 ml). The combined extracts were dried, filtered and evaporated to given the title compound as an oil (0.25g). IR (Neat) 3450, 1655 cm~l ~`
~ntermediate 9 2- ~ 5-~(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]morpholine Na}l (0.48g, 80~ dispersion in oil) was added to a solution of Intermediate 8 (2.2g) and 2-(bromomethyl)naphthalene t3.56g) in dry DMF
(8 ml) at 0~. After stirring for 7h, the suspension was poured into saturated NH4Cl solution (75 ml) and extracted into ER (3 x 50 ml). The combined ~7383~ ~

extracts were dried and concentrated, and 'the residue chromatographed on silica using ER
as eluent to give the title com~_und as an oil (2.lg). IR (Neat) 1716, 1655 cm 1 The following compounds were prepared by a similar procedure:
b) (la,2~,3~,5~-t+)-4-~2-(3-Methoxy-~E~ropenyl)-3-[4-(1,1-dimethylethyl)phenylmethoxy]-5-[(tetrahydro_ 2H-pyran-2-yl]oxy]cyclopentyl]morpholine, from Intermediate 8 and 4-(1,1-dimethylethyl')phenyl-methyl' bromide. Purification by chromatography using ER as eluent. IR (Neat) 1650, 1120 cm 1 c) (la,2~,3B,5~ )-4-[3-(4-Cyclohexylphenylmethoxy)-2-(3-methoxy-2-propenyl)-5-[(tetrahydro-2H-- 15 pyran-2-yl)oxy]cyclopenty~]morpholine, from Intermediate 8 and 4-cyclohexylphenylmethyl - iodide. Purification by chromatography using ER as eluent.
d) (1~,2B,3~,5~)-(+)-4-[2-(3-Methoxy-2-propenyl)-3-(pentyloxy)-5-[(tetrahydro-2H-pyran-2-yl)oxy]
pentyl]morpholine, from Intermediate 8'and n-pentyl-tosylate. Purification by chromatography using EA as eluent.
e) (la,2~,3~,5B)-(+)-4-[2-(3-Methoxy-2-propen~l)-3-[4-(phenylmethyl)phenylmethoxy]-5-[(tetrahydro-2H-pyran-2-yl~oxy]cyclopentyl]morpholine, from Intermediate 8 and 1-(bromomethylj-4-(phenylmethyl)-- benzene. Purification by chromatography using ~R as eluent.
fj (laL2~L~ R ~ o'ro(l,ll-biphenyl)-thoxy~-2-(3-methoxy-2-propen ~ tetrahydro-2 - ~ l]morpho]ine, from Intermediates 8 and 68. IR (Neat) 1650, 1120 cm 1 y) (la,2~,3~,5~ )-4-~2-(3-Methoxy-2-propenyl)-3-(2-proPenyloxy)-5-~(tetrahydro-2H-pyran-2-yl)oxy]cyclope~]]morpholine, from Intermediate . . .
8 and allyl bromide.
h) (la~2~3~5~)-(+)---[2-(3-Methoxy-2-propenyl) 1 17383t~

3-[4-methylthio(phenylmethoxy)]-5-[(tetrahydro-y_an-2-yl)oxy]cyclopentyl]morpholiner from Intermediate 8 and 1-(bromomethyl)-4-(methylthio)-benzene. Purification by chromatography using ER as eluent. IR (~eat) 1650, 1120 cm 1 i) (la,2~,3~,5~)-(-)-4-[2-(3-Methoxy-2-propenyl)-5-[(tetrahydro-2H-pyran-2-yl~oxy~-3-[(4-thien-2-yl)phenylmethoxy]cyclopentyl]morpholine,-from Intermediates 8 and 24a. Purification by chromatography using ER as eluent.
j) (la,2~,3~,5~)-(+)-4-[2-(3-Methoxy-2-propenyI)-3-[~(1,1':4',1"-terphenyl)-4-yllmethoxy]-5-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]morpholine, from Intermediates 8 and 24b. Purification by chromatography using ER as eluent. TLC
ER Rf 0.18.
1) ~la,2~3~(E),5~]-(-)-4-~2-(3-Methoxy-2-propenyl)-3-[(3-phenyl-2-propenyl)oxy]-5-l(tetrahydro-2H-pyran-2-yl)oxY]cyclopentyl]morpholine, from Intermediate 8 and cinnamyl bromide. Purification by chromatography using ether as eluent.
m) (la,2R,3~,5~)-(-)-4-~3-[[(1,1'-Biphenyl)-4-yl]methoxy]-2-(3-methoxy-2-propenyl~-5-[(tetrahydro-2H-pyran-2-Yl)oxY]cyclopentyl~thiomorpholine, from Intermediate 5b and l-(bromomethyl)-l,1'-biphenyl. Purification by chromatography using 3:2 ER-PE. TLC ER Rf 0.42.
n) ~la,2~,3R,5~ )-4-[3-[[4'-Methoxy(l,1'-biphenyl)-4-yl]methoxY]-2-~3-methoxy-2-propenyl)-5-~(tetrahy-dro-2H-pyran-2-yl)oxy]cyclopentyl]thiomorpholine, S-dloxide, rom Intermediat~ 5~a and 4~(bromomethyl)-4~-methoxyt~ biphenyl)~ Purification by chromato~raphY using CH2C12 ollowed by EEi .

, . .

as eluents. TLC ER Rf 0.41.
- o) (la,2B,3~,5B)-(~)-4-[2-_3-Methoxy-2-propenyl)-3-[~4'-methyl(l,l'-biphenyl)-4-yl]methoxy~-5-(tetrahydro-2H-pyran-2-yl)oxy]cyclopenty]]thi morpholine, S-dioxide, from Intermediates 59a) and 66. Purification by chromatography using CH2C12 followed by 4:1 ER-PE as eluent.
p) (Ia,2~,3~,5B)-(-)-4-~2-(3-Methoxy-2-propenyl)-3-[4-(phenylmethyl)phenylmethoxy]-5-~(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]thiomorpholine, S-dioxide, from Intermediate 59a) and l-(bromomethyl)-4-(phenylmethyl)benzene. Purification by chromato-graphy using CH2C12 fo]lowéd by ER as eluents.
TLC EA Rf 0.5.
q) (la,2~,3B,5B)-(-)-4-[3-~[(1,1'-Biphenyl)-4-yl~methoxy]-2-(3-methoxy-2-propenyl)-5-E(tetrahydr 2H-pyran-2-yl)oxy]cyclopentyl~thiomorpholine, S-dioxide, from Intermediate 59a) and l-(bromomethyl)-l,1'-biphenyl. TLC 95:5 ER-methanol Rf 0.7.
r) (1~,2B,3~,5B)-(~)-4-[3-[(l,li-Biphenyl)-4-yl]-methoxY]-2-(3-methoxy-2-propenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentylIhexahydro-l~4-oxazepin, from Intermediate 59b. TLC 97:3 ER-methanol Rf 0.68.
s) (la,2~,3~,5B)-(-)-1-[3-[[4'-MethoxY(l~
bipherlyl)-~-yl]methoxy]-2-(3-methoxy-2-propenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-piperidine, from Intermediate 5c. Purification by chromatography using 98:2 CH2C12-methanol as eluen~
t) _a ~2 ~ ~) ~ -ropoxy_-2-(3-methoxy-2-propenyl)-5-[(tetra-hydro-2H-pyran-2-yl)oxy]cyclopentyl]morpholine, ~rom Intermediates 8 ancl 60. Puriication by chromatography using EA as eluent.
u) ~ J3B,5B)-(~)-4-[3-[[3'-Methoxy(],1'-bipllenyl)-~yl]methoxy]-2-(3-methoxy-2-propenyl)-5-[ttetra-hydro-2H-pyran-2-yl)oxy]cyclopentyl]morpholine, ~ ~ 73~0 f.rom Intermediates 8 and 2~c. Purification by chromatography using EA as eluent.
, v) (lcll2~,3~,5~)-(+)-4-[3-[~4'-Methoxy(l,l'-biphenyl) 3-yl]methoxy]-2-(3-meth~L-2-propenyl)-5-f(tetra-hydro-2H-pyr~n-2-yl)oxy]cyclopentyl]morpholine, from Intermediate 8 and 3-(bromomethyl)-4'-methoxy(l,l'-biphenyl). Purification by chromato-graphy ~sing EA as eluent~
Intermediate 10 10 a) (1 ,2~,3,5a)-(+)-3-Hydroxy-2-(4-morpholinyl)-5-(2-naphthalenylmethoxy)cyclopentanepropanal A solution of Intermediate 9a (2.19) in acetone (10 ml) containing 2N hydrochloric acid (5 ml) was allowed to stand at room temperature for lh. After evaporation in vacuo the residue was neutralised with 8~.NaHCO3 solution and extracted with CH2C12 (3 x 30 ml). The combined extracts were dried, filtered and concentrated to afford the title compound as a viscous oil . 20 (1.7g). IR (Neat) 3420, 1720 cm 1 The following compounds were prepared by a similar procedure:
b) (la,2~,3a,5~)-(+)-3-Hydroxy-5-~4-(I,l-dimethy~
ethyl)-phenylmethoxy]-2-(4-morpholinyl)cyclopentane-propanal, from Intermediate 9b. TLC 4:1 ER-.~methanol-Rf 0.52.
c) (la,2~,3~,5a)-(+)-5-(4-Cyclohexylphenylmethoxyj-. 3-hyd~oxy-2-(4-morpholinyl)cyclopentanepropanal, from Intermediate 9c. TTJC 17:3 ER-methanol Rf 0.2B.
d) ~la,2~,3a,5a)-(~)-3-~ydroxy-2-(4-morphollnyl)-cyclopentanepropanal, from Intermediate 9d. TLC 95:S F,A-meth~nol Rf 0.08.
~) ~la,2~,3a,5a)~ 3-~ydiox~-2-(4-morpholi~yl)-5-~4-(phenylmethyl)phenylmethoxy]cyclopent~E~opanal, from Intermediat~ 9e. Puri~ication by chromatography uslng 9:1 ER-methanol as eluent.
E~ 2~ L~ (+)-5-[14l-chloro(l~ bipt~

~ ' , ` - 31 - ~3~t~
4-yl]methoxy]-3-hydroxy-2-(4-mor~holinyl)cyclo-r ~ ~, from Intermediate 9f. Purification by chromatography using CHC13 through to 98:2 CHC13-methanol as eluent.
g) (1,2~,3a~5a)-(+~-3-Hydroxy-2-(4-morpholinyl) 5-(2-propenyloxy)cyclopentanepropanal, from Intermediate 9g. Purification by chromatography using 4:1 ER-methanol as eluent.
h) (la,2~3a~5a)-~+)-3-Hydroxy-5-[4-methylthio(phen methoxy)]-2-(4-morpholinyl)cycloperitanepropanal, from Intermediate 9h. Purification by chromatography using S5:15 ER-methanOl as eluent. TLC 85:15 ER-methanol Rf 0 28.
i) (la,2~,3,5a)-(+)-3-Hydroxy-2-(4-morpholinyl)--5-[(4-thien-2-yl)phenylmethox~]cyclopentanepropanal~
from Intermediate 9i. Purification by chromatography using CHC13 through to 98:2 CHC13-methanol as eluent. TLC 95:5 CHC13-methanol Rf 0.3.
j) (la,2~,3a,5a)-~+)-3-Hydroxy-2-(4-morpholiny - 4-~ 4',1"-terphenYl)-4-yl]methoxy]cYcl~o-pentanepropanal, m.p. 151-153 from Intermediate 9j .
1) [la,2~,3a,5a(E)]-(-)-3-Hydroxy-2-(4-morpholinyl)-5-~(3-phenyl-2-propen l)oxy]cyclopentanepropanal, from Intermediate 91. IR (CHBr3) 3580, 3560, 1720 cm m) (la,2~,3a,5a)-(+)-5-~[(1,1'-Biphenyl)-4-yl]rnethoxy]-3-hydroxy-2-(4-thiomorpholinyl)cyclopentanepropanal, m.p. 109-110 from Intermediate 9m.
Purification ~y chromatography using ER as eluent.
n) ~ ~ ~ 1'-biphenyl)- ~ olinyl) 1 173~3~

pentanepropanal, S-dioxide, from Intermediate 9n.
IR (CHBr3) 3580, 2720, 1720 cm 1 o) (la,2~,3~,5a)-(+)-3-Hydroxy-5-~4'-methyl(l,l'-biphenyl)-4-yl]methox~]-2-t4-thiomorpholinyl)cyclopen-tanepropanal, S-dioxide, from Intermediate 9O~
IR (CHBr3) 3580, 2725, 1720 cm p) (la,2~,3a,Sa)-(~)-3-Hydroxy-5-~4-(phenylmethyl)-~henylmethoxy~-2-(4-thiomorpholinyl)cyclopentane-propanal, S-dioxide, from Intermediate 9p.

IR (CHBr3) 3580, 2720, 1720 c~ L
q) (la,2~,3,5a)-t~)-5-~[(1,1l-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-thiomorpholinyl)cyclopentanepropanal, S-dioxide, m.p. 152.5-154 (dec.) from Intermediate 9q .
r) (l~2~r3a~5aj-(+)-s-~[lll~-Biphenyl)-4-yl]methoxy]-2-thexahydro-1,4 oxazepin-4-yl)-3-hydroxycyclopentane-propanal, from Intermediate 9r. IR (CHBr3) 3580, 2730,-1720 cm s) (1~,2~,3a,5a)-(+)-3-Hydroxy~5-~[4'-methoxy(l,l'-biphenyl)-4-yl]methoxy]-2-(1-piperidinyl)cyclopentane-propanal, from Intermediate 9s. IR ~CHBr3) 3520~ 2730, 1720 cm~
t) (la~2~,3a~5~)-(-)-5-[3-[~ Biphenyl)-4-yl3-~ropoxy~-3-hydroxy-2-(4-morpholinyl)cyclopentane-propanal, from Intermediate 9t. IR (CHBr 3580, 2?30, 1723 cm u) (la,2~,3a,5a)-(+)-~3-Hydroxy-5-[~3'-methoxy(l,l'-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)]cyclo-pentanepropanal~ from Intermediate 9u. IR
, (CHBr3) 3580, 2720, 1720 cm ~L
V ) enyl)-3-yl]methoxy~-2-(4-morpholin ~ yclo-pentanepropanal, ~rom Intermediate 9v. IR
(C~IBr3) 3560, 2720, 1720 cm 1 Intermedlate 11 (1~,2R,3~,5~ 3-Hyclroxy-5-[4-methoxytph~ lme h~
2-(4-morpholinyl)cyclopentanepropanal Prepared as an oil from Intermediate 4b according to the methods described for Intermediates 5 and

6. IR (Neat) 3380(br.), 2720, 1720, 1118 cm 1 Intermediate 12 a~ ~la(Z),2~,3,5a~-t-)-7-[5-[(l~ Biphenyl)-, 4-yl~methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-heptenoic acid To an intimate mixture of potassium tert-butoxide (1.29g) and (3-carboxypropyl)triphenylphosphonium bromide (2041g) under nitrogen was added dry THF (50 ml). The suspension formed was stirred for 30 min whereupon a solution of the free base of Intermediate 6 (1.18g) in dry TMF (50 ml) was added dropwise. Stirring was maintained for 1.5h whereupon water was added and all organic solvents were evaporated. The pH of the remaining suspension was adjusted to 10 with 2N NaOH solution and the suspension was then extracted with EA to remove phosphorus contaminants. The pH-was then adjusted to about 6.5 with phosphate buffer and the product extracted from the suspension with EA. The dried extracts were filtered and concentrated to give the title compound as a foam (0.93g).
IR (CHBr3) 3460, 1710 cm 1 Hydrochloride salt To a solution of Intermediate 12a (0.25g) in EA (5 ml~ was added ethereal hydrogen chloride until no more cloudiness was produced. The solvents were decanted and the resulting oil repeatedly washed with dry ER to give a powder 3b (0.13g), m.p. 125.5 - 126.5.
Methanesul~honate salt To a sollltion oE Intermediate 12a (O.O~g) in EA (2 ml) was added methanesulphonic acid (Q.Olg) at 20 and the mixture stirred for 35 ' lh. The solid was filtered off, washed with ' EA and dried. Recrystallisation,,~rom ethanol ' gave material of m.p. 171-174.
The follow;ng compounds were prepared ~y a .

:, :
.. , - , ' ~ ~73~3V

similar procedure:
b) [la(7,),2~,3a,5a]~ 7-[3-Hydroxy-2-~4-morpho]inyl)-5-(2-naphthalenylmethoxy)cyclopentyl]-4-heptenoic acid, from Intermediate lOa. Purification by chromatography using 85:15 ER-methanol as eluent. IR (Neat) 3450-2300(br.), I715 cm 1 c) ~la(Z),2~,3a,5a]-(+)-7-[3-Hydroxy-5-~4-methoxy-(phenylmethoxy)~-2-(4-morpholinyl)cyclopentyl]-4-heptenoic acid, from Intermediate 11. Purifica~ion by chromatography using 95:5 CHC13-methanol as eluent. IR (CHBr3) 3580, 3500, 1720, 1710 cm 1 d) [la(Z),2~;3a,5a]-(+)-7-[3-Hydroxy-5-[4~(1,1-dimethylethyl)phenylmethoxy]-2-(4-morpholinyl)-cyclopentyl]-4-heptenoic acid, from Intermediat-e lOb.
Purification by chromatography using 9:1 ER-methanol as eluent. IR (CHBr3) 3500, 1740, 1710 cm~1 e) [la(Z),2~,3a,5a]-(-)-7-[5-(4-Cyclohexylphenyl-methoxy)-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-heptenoic acid, from Intermediate lOc. IR
(CHBr3) 3500, 1720, 1708 cm f) [la(Z),2~,3a,5a]-(~)-7-[3-Hydroxy-2-(4-morpholinyl)-~ 5-(pentyloxy)cyclopen~y~-4-heptenoic acid, from Intermediate lOd. Purification by chromato-graphy using acetone as eluent.
g) [la(Z),2~,3a,5à]-t-)-7-E3-~Iydroxy-2-(4-morpholinyl)-~ ~DY~ ~ lmethoxy]cyclopentyl]-~-h~te ~ , rom Intermediate lOe. Puriei-cation by chromatography using 4:1 ~R-methanol as eluent.
h) _a(Z),2~,3a,5a~ ( ~ 1'-hiphenyl)-~-yllmethoxyl-3 ~,"~ox _ cyclopentyl]-~-heptenoic ac;d, from Intermedia~e 10. Purific~tion by chromatography using CHC13 through to 96:4 CHC13-methanol as eluent.
IR (CHBr3) 3500, 1710 cm . - , . . .

~ 17383~

i) [la(z~,2~3a,5a]-(+)-7-[3-Hydroxy-2-(4-morpholinyl) enyloxy)cyclopentyl]-4-heptenoic acid, from Intermediate lOg. Purification by chromato-graphy using 9:1 ER-methanol as eluent. IR
(CHBr3) 3500, 1740-1710(br.) cm 1 j) ~la(Z),2~,3a,5a]-(~)~7-~3~Hydroxy-5-[4~methylthio~
(phenylmethoxy)]~2-(4~morpholinyl)cyclopentyl~-4-heptenoic acid/ from Intermediate lOh. Purifi-cation by chromatography using 9:1 ER-methanol as eluent. IR (CHBr3) 3600-3400(br.), 1730~sh.), 1710 cm~l k) [l~(Z),2~,3~,5~]-(+)-7-[3-Hydroxy-2~(4~morpholinyl)~
5~~(4~thien~2-yl)phenylmethoxy]c~ pentyll-4-heptenoic acid, from Intermediate lOi. Purifi-cation by chromatography using CHC13 through to 94:6 CHC13~methanol as eluent. IR (CHBr3) 3500, 1738, 1710~cm 1 1) ~la(z)~2~3a~5a]-(+)-7-~3-Hydroxy-2-(4~morpholinyl)-5-[~(1,1':4,1"-terphenyl)-4-yl]methoxy]cyclopentyl~-4-h~ptenoic acid, from Intermediate lOj. IR
(CHBr3) 3500, 1720 cm 1 m) ~l~(z)~2~3a~5a]-(+)-9~~5-~[(~ -Biphenyl)~
4~yl]methoxy]~3~hydroxy-2-(4-morpholinyl)cyclopentyl]-6-nonenoic acid, from Intermediate 6 and (5-carboxypentyl)triphenylphosphonium bromide.
IR (CHBr3), 3510, 1730 (Sh.), 1710 cm 1 o) [ 1~ (Z ), 2~, 3a, 5~ (E) ] - (+) -7-~3-Hydroxy-2~(4-morpholinyl)-5-~(3~phenyl-2-propenyl)oxy]cyclopentyl]-4-he_tenoic ac`id, from Intermediate 101. Purifi-cation by chromatography using 9:1 ether-methanol as eluent. IR ~cllBr3) 3500, 1720 cm~
p) ~lnlz~,2~3 ~ -7 [5-[[l, ~
vl]mg~b~K~1-3~ thiomorpholinyl)-~ ~ 1-4-h~E~enoic aaid, from Intermediate lOm. IR ~CHBr3) 3S00, 1730, 17:lO cm 1 .

- 36 ~
q) [la(Z),2~,3,5]~ )-7-[3-Hydroxy-5-~[4'-methoxy-(l,l'-biphenyl)-4-yl]methox ~-2-(4-thio~orpholinyl)-cyclopentyl]-4-heptenoic acid, S-dioxide, m.p.
113-115 from Intermediate lOn. Purification by chromatography using 98:2 through to 96:4 ER-methanol as eluent.
r) ~la(~),2~,3a,5a]-(+)-7-~3-Hydroxy-5-[~4'-methyl-(l,l'-biphenyl)-4-yl]methoxy]-2-(4-thiomorpholinyl) cyclopentyl]-4 heptenoic acid, S-d1oxide, m.p.
119.5-121.5 from Intermediate lOo.
s) [l(Z),_~,3a,5a]-(-)-7-[3-Hydroxy-5-~4-(phenylmethyl)-phenylmethoxy]-2-(4-thiomorpholinyl)cyclopentyl]-4-heptenoic acid, S-dioxide, m.p. 127.5-128.5 from Intermediate lOp. Purification by chromato-graphy using 96:4 RR-methanol as eluent .~ t) [la(Z),2~,3a,5]-(-)-7-~5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-thiomorpholinyl)cyclo--pentyl]-4-heptenoic acid, S-dioxicde, m.p. 109.5-111.5 from Intermediate lOq. Purification by chromato-graphy using 9~:2 ER-methanol as eluent.
u) [la(Z),2~,3a,5a]-(+)-7-[5-[[(1,1'-Bipheny~)-4-yl]methoxy}-2-!hexahYdro-1,4-oxazepin-4-yl)-3-hydroxycyclopentyl]-4-heptenoic acid, from Intermediate lOr. TLC (SiO2) 3:1 ER-methanol Rf 0.29.
v) [la(Z),2~,3a,5a]-(+)-7-[3-Hydroxy-5-[[4'-methoxy-(l,l'-biphenyl?-4-yl]-methoxy3-2-(1-piperidinyl)-cyclopentyl]-4-heptenoic acid, compound with ~ zlne (2:1), m.p. 106-112 from Intermediate lOs. The title ~ crystallised from a solution o~ the acid and piperazine in 2-1 EA-ER.
w) [l l~ ~ a,5~ 7-[5-[3-[(1,1'-Biphenyl)-~ rpholi ~ ~ 1-4-heptenoic acid, ~rom Intermediate lOt.
Purification by chromatography using 5:1 EA-methanol as eluent. TLC 5:1 EA-methanol Rf 0.3.

1 ~3~3~) x) [la(Z),26,3~,5a]-(+)-7-~3-Hydroxy-5-[[3'-methQxy-~ biphenyl)-4-yl~-mèthoxy]-2-(4-mo-rpholinyl) cyclopentyl]-4-heptenoic acid, from Intermediate lOu. IR (CHBr3) 3500, 1725(sh.), 1710 cm 1.
y) [la(Z),2~,3a,5~]-(+)-7-[3-HydroxY-5-[[4'-methoxy-(l,l'-biphenyl)-3-yl]-methoxy~-2-~4-morpholinyl)-cyclopentyl~-4-heptenoic ac}d, from Intermediate lOv. IR (CHBr3) 3500, 1735 (sh.), 1710 cm 1.
z) [la(Z),2~,3~,5]-(+?-7-[5-Decyloxy-3-hydroxy-2-(4-mor~ olinyl)cyclopentyl]-4-heptenoic acid, from Intermediate 17d. IR (CHBr3) 3500, 1725(sh), 1710cm~l.
Intermediate 13 [1Q (Z) ,2~3a~5a]-(~)-8-[5-[[(~ -Biphenyl)-4-yl]methoxy]
3-hydroxY-2-(4-morpholinyl)cyclopentyl]-5-octenoic acid Prepared from Intermediate 6 (19) and (4-carboxy-butyl)triphenylphosphonium bromide (3.17 g) in an analogous manner to that described for Intermediate ;~ 12a. The title compound was isolated as a foam ~0.92 9).
IR (CHBr3) 3500, 1740, 1705 cm Intermediate 14 [la(Z),2~,3a,5a~ )-Methyl 7-[5-~[1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-heptenoate A solution of Intermediate 12a (0.7g) in 9:1 methanol-H2S04 (20 ml) was stirred at room temperature for 2h. Solid NaHCO3 was added until pH 7.5-8, followed by water and extraction with ER. The combined extracts were dried, filtered and evaporated to give the title ~E~nd as an oil (O.S~g). LR (C~lBr3) 3580-3510, 1730 cm~ .
IntermecliAte lS
___~ ~ lphenyl)~4-yl]-methoxyl-3-(4 morpholillyl)-2-oxabicyclo[3.2.1~octan-3-one Zinc bromide (27g) in dry THF (lBOml) was stirred under nitrogen at 15-20 during the addition oE p-methylphenylmagnesium bromide ~prepared in ether (160ml) from Mg ~3.24`y) and 4-bromotoluene t20.52g~].
The mixture was stirred at 20 for 2h.

~~ ~
3 ~ ~ ~

Nickel acetylacetonate (1.8g) and triphenylphosphine (7.34g) were taken into THF (40ml) and stirred under nitrogen during the addition of DIBAL (lM in hexane, 7ml). After 5 min. Intermediate 72 (~.75g) in THF
(65ml) was added followed, after a further 5 min.
by the organozinc reagent. The mixture was then stirred at 22 for 30h, whereupon saturated NH4Cl solution (500ml) and EA (300ml) were added. The aqueous solution was adjusted to pH 5-6 with 2N hydro-chloric acid and the layers separated. The aqueoussolution was extracted with EA and the combined extracts dried and evaporated. The residue was chromatographed - on silica using 7:3 through to 9:1 EA-PE (b.p. 60-80) as eluent to give ~he title compound (3.19) as prisms, m.~. 141-144.
Intermediate 16 (la,2R,3a,5a)-(+)-3-Hydroxy-5-~[4'-methyl(l,l'-biphenyl) 4-yl~methoxy]-2-(~-morpho~in~l)cyclopentane acetaldehyde A stirred solution of Intermediate 15 (4.59) in dry CH2C12 (75ml) at -75 under nitrogen was treated with DIBAL (1.43M in hexane, 17.4ml). Stirr~ng was continued for lh, whereupon methanol (75ml) was carefully added and the temperature allowed to rise to ambient.
After 17h, the mixture was filtered and the ~iltrate evaporated to give the title compound as a foam (4.63g).
TLC 9:1 E~-methanol Rf 0.35.
.. ..
Intermediate 17 (la,2~,3a,5a)-(+)-3-Hydroxy-5-[[4'-methyl(l,l'-_iphenyl)-4~yllrnethoxy]~2-(4-morpholinyl)cyclo pentanepropanal To a stirred solution oE potassium t~butoxide (3.899) in dry THF ~ ml) at ~5Q was added (methoxy~
methyl)triphenylphosphonium chloride tll.89g) portionwise over 15 min. A~ter stir~ing ~or 30 rnin. at ~5 to 0 a solution o~ Intermediate 16 (4.039) in dry THF
(35ml) was added. The mixture was stirred at 5 for 15 min. and then at 20 for 1.75h, quenched with water (,ml) and the solvents rernoved ln vacuo. The ~ 17383~

residue was then treated with 2N hydrochloric acid (20ml) in acetone (50ml) at 20 for 3.5h. Aqueous Na2C03 was added to give a solution of pH 8 which was then diluted with water (lOOml) and extracted with EA (3 x 75ml). The combined extracts were dried and evaporated and the residue chromatographed ~n silica (400g) using 97:3 through to 9:1 EA-methanol as eluent to give the title compound as an oil (4.33g).
IR (Neat) 3400(br.), 1720 cm 1.
The following compounds were prepare~ by a similar procedure:
b) (la,2a!3a,5a)-(+)-5-~[1,1'-Biphenyl)-4-yl]methoxy~-- 3-hydroxy-2-(4-morpholinyl)cyclopentanepropanal, m.p. 114-116 from Intermediate 4c.
c) (1~,2~,3a,5a)-(-)-5-[[1,1' Biphenyl~-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentanepropanal, from Intermediate 4e. IR (CHBr3~ 3500-3400(br.), 1718 cm 1.
d) (la,2~,3a,5~ )-5-Decyloxy-3-hydroxy-2-(4-morpholinyl)cyclopentanepropanal~ from intermediate - 49. Purification by chromatography us1ng EA
through to 95:5 EA-methanol as eluents IR (Neat) 3530, 1723 cm 1.
Intermediate 18 Ela (z) ,2~,3a,5a]-(+)-7-[3-Hydroxy-5-~[4'-methyl!l,l'-phenyl)-4-yl]methoxy3-2-(4-morpholinyl)cyclopent 4-heptenoic acid (3-Carboxypropyl)triphenylphosphonium bromide (12.99) was added to a solution of potassium t-butoxide ~0 (6.739) in dry T~IF (170ml) and the res;lltant suspension stirred at 20 ~or 35 min. A solution of Intermediate 17a ~4.23~) in THF (40ml) was added and stirring continued a~ 20 ~or 2h. Water (5ml) was then added, the solvent removed in vacuo and the residue taken into water (300ml) and adjusted to pH 12 with 2N
NaOH Non-acidic material was extracted with EA
(2 x lOOml) and the aqueous solution then re-adjusted to pH 6.5 with 2N hydrochloric acid. This solutio was extracted with EA (3 x lOOml) and the combined extracts dried and evaporated to give the tl e ~ 173830 - ~o - .
as an oil (3.97g). IR (CHBr3) 3580, 3500, 1720, 1710 cm 1 Intermediate 19 (1,2~3~,5~)-(+)-4-~3-~[4'-Methoxy(l,l'-biphenyl)-4-yl]methoxy]-2--(3-methoxy-2-propenyl)-5-[(tetrahydr 2H-pyran~2-yl)oxy]cyclopentyl]morpholine NaH (74% dispersion in oil, 316mg) was added to a solution of Intermediate 8 (l.llg) and 4-(bromomethyl)-4'-methoxy(l,l'-biphenyl) (2.86g) in dry DMF (15ml) under nitrogen at 0. The mixture was stirred at room temperature for 2h whereupon NaH (74~r 52mg) was added and the stirring continued for lh. The mixture was poured into aqueous NH4Cl (150ml) and extracted with CHC13 (4 x 60ml). The dried organic layers were evaporated and the residue chromatographed on silica (400g) using 8:2 ER-PE (b.p. 60-80) through to ER as eluent to give the title Gompound as an oil (1.17g)~ IR (CHBr3) 1675, 1245 cm Intermediate 20 (la,2~,3a,5a)-(+)-~3-Hy.droxy-5-r~4'-methoxy(l,l'-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)cyclopentanepropana A solution of Intermediate 19 (2.99gj in 2~
hydrochloric acid (25ml), acetone (50ml) and CH2C12 (7ml) was s~tirred for 30 min. The mixture was poured into 8% NaHC03 solution (200ml) and extracted with C~2C12 (3 x 85ml~. The dried organic layers were evaporated and the residue chromatographed on silica (lOOg) using ER through to 4:1 ER-methanol as eluent to give the title compound as an oil (2.099). IR
(CHBr3) 3600-3500(br.~, 2725, 1720 cm Intermediate 21 ~ 2~ ~ _4 ~ 1,1'~
biphenyl)-4-yl~methoxy]-2-(4-morpholinYl)cyclopentyll~
~-heptenoic acid (4-Carboxypropyl)triphenylphosphonium bromide ~3.99) and potassiumn t-butoxide (2.049) in dry THF
(9Oml) were stirred at room temperature for 15 min.
A solution of Intermediate 20 (29) in dry THF (40ml) was added and the mixture stirred for 2h. Water (30ml) was added and the solvent evaporated. The ~ 1738.~ .

residue was poured into 0.3N NaOH (150ml) and washed with EA. The basic layer was neutralised by the dropwise addition of 5N hydrochloric acid and then extracted with CH2C12 (70ml). The pH was adjusted to 6.5 and the aqueous layer re-extracted with CH2C12 (70ml). The combined CH2C12 layers were dried and evaporated to give the title compound as a foam (1.669).
IR (CHBr3) 3590, 3500, 1720 cm 1.
Intermedi_te 22 10 a) _ethyl 4-(Thien-2-~l)benzoate The Grignard reagent from 2-bromothiophene (17.5g) and Mg (2.7g) in dry ER (200ml~ was added to a stirred solution of anhydrous ZnBr2 (22.5g) in dry THF (200mll at 5.
Simultaneously a solution of bis(,triphenyl-phosphine)palladium (II) dichloride (lg) in THF (200ml) was treated with ~IBAL in hexane (1.43M, 2ml) at room temperature un~er nitrogen.
After 5 min a solution of methyl p-bromobenzoate (5g) in ER (50ml) was added followed after a further ' 5 min by the organozinc reagent descri~ed above. The mixt,ure was stirred at room temperature for 18h and then poured into NH4Cl solution and extracted with EA. The combined extracts were dried and evaporated, and the residue chromatographed on silica using 1:20 through to 1:1 EA-PE as eluent. The title compound was further purified by crystallisation from PE (b.p. 60-80) (2.8g), m.p. 1~1-142.
Th,e following compound was prepared in a ~imilar manner:
b) Mcl~y~ MLtt:~y_l,lt bi~ _ nyl)-~-carboxylate, m.p. 52-54 from 3-bromoanisole and methyl p-bromobenzoate uslng the catalyst prepared from DIBAL, nickel acetylacetonate and triphenyl-phosphine. The product was purified by chroma~o-graphy using 1:4 EA-PE (b.p. 60-80) as eluent.
Intermediate 23 a) 4-(Thi ~ enzene methanol ~ 1 7~3~

To a stirred suspension of LiAlH4 (2.28g) in THF ~200ml) at room temperature was added dropwise a solution of Intermediate 22a) (6.69) in THF (SOml). The mixture was heated under S reflux for 2h and then stirred at room temperature for 16h. EA (lOml) was careflly added, followed by 2N hydrochloric acid (lOOml). The THF was removed in vacuo and the residue extracted with ER. The combined extracts were dried, filtered and concentrated. Crystallisation of the residue from cyclohexane gave the title compound (4.5g) as plates, m.p. 115.
The following compounds were prepared in a similar manner:
b) 3-E(~ -Biphenyl)-4-yl]propanol~ m.p. 73-74 ; from 3-~ biphellyl)-4-yl~propanoic acid.
c) [3'-Methoxy(l,l'-biphenyl)-4-yl]methanol~ from Intermediate 22b. TLC EA Rf. 0.6.
Intermediate 24 a) 2-(4-Bromomethylphenyl)thiophene A solution of Intermediate 23a (4.3g) in dry CH2C12 (80ml) was treated with a solution of PBr3 (2.15ml~ in CH2C12 (20ml) and the mixture stirred for lh. 10% NaHC03 solution (lOOml) was added, the organic phase separated, and the a~ueous phase fur~her extracted with CM2C12.
The combined organic phase was driedr filtered and concentratèd to give the title compound (4.6g) as a solid, m.p. 80-100.
The ~ollowing compounds were prepared by a similar procedure:
b) 4-Brornomethyl(1,1l:4',1")terphenyl, m.p. 213-215 from 4-[(l,~ ")terphenyllmethanol.
c) 4-Bromome~ l 3' ~ , from Intermediate 23c. TLC ER Rf 0.58.
Inter.med;ate 25 a) [la(E),2~,3,5a]-(~)-7-~3-Hydroxy-5-[[4'-methyl(l,l'-biphenyl)-4-yl]methoxv]-2-(4-mor~ho]i~ cyclopentyl]-_ _ _ ~ ~38~

4-heptenoic acid A solution of Intermediate 18 (1.32g) and p-toluene sulphinic acid ~0.639) in dry 1,4-dioxan (60ml) was heated under refl~x in a nitrogen atomosphere for 3.5h. The mixture was diluted with EA (80ml), washed with pH 6 phosphate buffer (50ml~, dried and evaporated.
The residue was chromatographed on silica using 9:1 EA-methanol as eluent to give the title compound as an oil, which on trituration with ER crystallised (0.639), m.p. 108-111.
The following compounds was prepared in a similar manner: -b) ~la~E),2~,3a,5a]-(~)-7-~5-[[~1;1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-rnorpholinyl)cyclopentyl]-4-hepteno~c acidl from Intermediate 12a. Purifi-; cation by chromatography using 9:1 EA-methanol as eluent. TLC 85:15 ER-methanol Rf 0.24.
Intermediate 26 ~la(Z),2~,3a,5a]-(~)-7-[5-[[1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-hepten A solution of Intermediate 12a (lg) in dry THF (lOml) was added dropwise under nitrogen to a stirred suspension of LiAlH4 (0.169) in dry T~F (lOml~
and the mixture heated under reflux for 2h. After cooling 1:1 water in THF (lOml) was added followed by 5N NaOH (lOml) and the mixture extracted with EA (3 x 20ml)~ The combined extracts were dried, concentrated and the residue chromatographed on silica ~lsing 95:5 ~R-methanol as eluent to give an oil which slowl~ crystallised (0.71g). Recrystallisation from ~R~isopentane gave the title com ~ o~ m.p. 70-71.5.
Intermediate ?7 ~anti,endo,endo)~ 7-(4-Mor 2H-pyran-2 yl)oxyl~ lo~2.2.1]heptan-2-ol NaBH~ (2 29) was added in portions to a stirred solution o IntermedLate 69 (17q) in dry methanol ,' , .
, .
.. . .

~ 1~38'3(~

t250ml) at 0. After 30 min the mixt~re was poured into saturated NH4Cl solution (350ml) and extracted with ER (3 x 200ml). The combined extracts were dried, filtered and concentrated to give the title compound as a foam (17.5g). IR (Neat) 3440(br.), 1120 Cm~l Intermediate 28 (endo,syn,endo)-(+)-5-[[(l,l'-Biphenyl)-4-yl~methoxy]

7-(4-morpholinyl)bicyclo~2.2.1]heptan-2-ol A solution of Intermediate 2c (20.1g) in 10%
concentrated H2SO~ in methanol (60ml) was stood at room temperature for lh. The solution was neutralised with solid NaHC03 and extracted with CH2C12 (3 x 2~0ml).
The combined extracts were dried, filtered and concentrated lS to give the title compound as a solid (179), m.p.
138-140.
Intermediate 29 (endo,syn)-(+)~5-~ E (l~l~-Biphenyl)-4-yl]methoxy]
7-(4-morpholinyl)bicyclo~2.2.1]heptan-2-one A mixture of dry dimethylsulphoxide (13.5ml) and dry CH2C12 (50ml) was added under nitrogen to a solution of oxalyl chloride (15.2ml) in dry CH2C12 (25ml) at -78 and the resultant activated cornplex stirred for 15 min. A solution of Intermediate 28 (15g) in dry C~2C12 (50ml) was added dropwise and stirring continued for 5h. Triethylamine (55.lml) in dry CH2C12 (50ml) was added dropwise and the mixture was then allowed to reach room temperature wi~h further stirring for 1.5h. Water (350ml) was added and the solution extracte~d with CH2C12 (3 x 200ml). The combined extracts were dried, Eiltered and evaporated and the resid-le chromatographed on sillca using ER
as eluent. The title ~ wa5 obtained as a solid Which was further purified by crystallisation from EA-PE (b~p. 60-80) to glve material (6.67g) of m.p. 164-165.

.~! .l 738 Intermediate 30 (endo,syn)-(+ _6-[[(l,l'-Biphenyl)-4-yllmethoxy]-

8-(4-morpholinyl)-2-oxabicyclo[3.2.1]octan-3-one Peracetic acid (4.33ml, 6.12 M) was added dropwise to a mixture of Intermediate 29 (29), sodium acetate (2.179~, acetic acid (20ml) and water (lOml) at 0.
After stirring for 6 days a further quantity of peracetic acid (0.87ml) was added and stirring continued for 24h. Na2S03 was added to destroy excess oxidising agent and the mixture was then evaporated to dryness.
The residue was neutralised with 8% NaHC03 solution and extracted with EA (3 x 75ml). The combined extracts were dried, filtered and evaporated and the residue chromatographed on silica using 1:1 ER-CH2C12 as eluent to give the title compound as a solid (1.59), m.p. 244-246~.
Intermediate 31 ~la(Z),2,3~,5a]-(-)-Methyl 7-~5-[~1,1'-Biphenylj-4-yl]methoxv]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-heptenoate Prepared as an oil from Intermediate lia according to the methods described for Intermediates 12a and 14. IR (Neat) 3440 (br), 1730 cm l Intermediate 32 E la(Z),2~,3~,5a]-(+)-Methyl 7-~3-(Acetyloxy)-5-[[(l,l'-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)cyclopentyl]--heptenoate A solution of Intermediate 31 (1.2g) and acetic anhydride (2ml) in pyridine (lOml) was heatecl at ~5 ~or 18h. The mixture was diluted with }~R (50ml) and therl wa~he~ with ~ Na~lC03 solution (150ml).
The aqueous solution was re-e~tracted with F.R (lOOml) and khe combined orqanic phase dried and concentrated. The residue was chromato~raphed on ~ilica using ~R as eluent to give the title compound as an oil (0.85q).
IR (CHBr3) 1742 cm l.

3~

- Intermediaté 33 a) [l(Z~,2a,3N,5~]~ 7-[5-[[(1~ Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-heptenoic acid A solution of Intermediate 32 tO.83g) in methanol (30ml) containing 2N ~aOH (5ml) was allowed to stand at room ternperature for 2 days. pH 6.5 Buffer (made from 2:3 KH2P04:Na2HP04) (30ml) was added and the solution extracted with CH2C12 12 x 50ml). The combined extracts were dried and concentrated and the residue purified from CH2C12-PE (b.p. 60-80) to give the title compound (0.61g), m.p. 163-165.
The following compound was prepared in a similar manner:
b) [l~(Z) ,2~,3a,5a]-( - )-7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(l-piperidinyl)c~clopent 4-heptenoic acid, from Intermediate 58. IR
(CHBr3) 3500, 1700, 1598 cm Intermediate 34 [la(Z),2~,3~,5a]-(~)-7-[5-[[1,1'-Biphenyl~-4'yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-heptenoic acid A stirred solution of lithium tri-sec-butylboro-hydride in THF (12ml, 1 M) under nitrogen at -28 was treated slowly dropwise with a solution of Example la (0~6g) in dry THF (12ml). After 3h the mixture ' was poured into 2N ~2SO~ (20mll and pH 6.5 phosphate bu~fer (SOml) and washed with ER (1 x lSOml, 1 x SOml).
The a~ueous layer was adjusted to pH 6.5 with ~N NaOH
and extracted with EA (2 x lOOml). The combine~
extracts were dried and evaporated, and the residue chromatograph~d on silica using 4:1 ~A-methanol as eluent to give the title ~ as a foarn (0.359).
3S TLC (SiO~ 20:79 Acetic acid methanol EA Rf 0.17.
Intermediates 3S"~and 36 _S,endo)~ Bicyclo[3.2.0]hept-2-en-6-ol ( (lR,exo)-(-)-Bicyclo~3.2.0~hept-2-en-6-ol (3~) :: ; ~ ' ' ~ 173~0 Bakers yeast (6kg) and glucose (2.5kg) in water ~24 1) was stirred at 25 for 2h. (+)-Bicyclo[3.2.0~hept-2-en-6-one (120g) was added dropwise over 30 min.
Stirring was maintained for 2.5h whereupon a further quantity of glucose (3.5kg) and water (4 1) was added.
This addition was repeated after 20h and 26h, glucose (4.5kg) and water (5 1) being added on each occasion.
The reaction mixture was distilled at atmospheric pressure to give about 11 1 of aqueous ethanol containing 10- starting material and some product-FRACTION A. Then a steam distillation of the remaining reaction mixture gave 36 1 of aqueous distillate which was salted (7.25kg) and extracted with CH2C12(3 x 10 1). The CH2C12 was distilled at atmospheric pressure through a helix filled column (93 x 5cm) to leave a residue (about 400ml)-E~RACTION B. FRACTION A was concen-trated by distilling off most of the solvent through a helix fille~ column (50 x 3cm). The residue was salted and extracted into CH2C12-FRACTION C.
Fractions B and C were combined, dried and the solvent was removed at atmospheric pressure to Ieave a residue (55g) which was distilled at 120C
and 15 mm~g pressure to give an oil (39.8g). This material was chromatographed on silica using 1:4 ether:isopentane as eluent to give the title compound as ethereal solutions after removal of most the solvent.
Intermediate 3S (26.8g) 64.5% w/w in ether.
Intermediate 36 ~33.4g) 30.4% w/w in ether.
The bulk of the material was used as above 3n Eor the next stage. However 2ml portions oE the fiolutions were taken and distilled at atmospheric pressure in a micro distillation apparatus to give:
Intermediate 35 TLC ~:] PE'-ER Rf 0 3 [~D =-~6.1 (CHC1 Intermediate 36 TLC 4:1 PE-ER Rf 0.2 ~a~26__73.9~ (C~IC13).

~ ~ 7 3 ~

Intermediate 37 [lR-(exo,endo)]-(-)-2-Bromo-3-hydroxybicyclo[3.2.0~heptan-6-one To a stirred solution of Intermediate 35 (6.64g) in acetone (220ml) and water (55ml) was added glacial acetic acid (0.65ml) and N-bromosuccinimide (43.22g) and stirring was maintained for 18h~ The mixture was poured into sodium thiosulphate solution (250ml) and extracted with ER (2 x 175ml). The organic layer was washed with 8% NaHC03 solution (150ml), dried and evaporated and the residue chromatographed on silica using 1:1 ER-PE as eluent. The title compound was obtained as a solid which crystallised from CC14 as needles (4.169), m.p. 90-92. [a]2=-60.8 (MeOH).
Intermediate 41 [lR-(endo,anti)]-(+)-5-Hydroxy-7-(4-morpholinyl)bicyclo-~2.2.1]heptan-2-one A solution of Intermediate 37 (8.82g) in CH2C12 (85ml) containing morpholine (15ml) was stirred at room temperature for 20h. The precipitate was filtered off and washed with CH2C12 (lOOml). The combined filtrates were washed with NaHC03 solution and water (75ml each) dried and evaporated to give a semi-solid which was chromatographed on silica using EA as eluent.
The title compound was obtained as a solid which crystalli~ed from 1:1 EA-PE (b.p. 60-80) to give materiàl (6.1g) of m.p. 137-139. Ea]2=~55.73 = (MeOH).
Intermediate 43 0 [lR-(endo,a ~ ~ ~ [(l,l'-Bipheny`l)-~-yl]methoxy]-b~y__o[ ~ llheptan-2-one A mixture Oe Intermediate ~1 (10.459), benzyl triethylammonium chloride (1.59) and biphenylmethyl bromide (l5.3g) in C~l2c12 (50ml) was cooled to 0 whilst NaOH (12g) in water (20ml) was added. The two phases were stirred vigorously ~or 24h at 20.
The mixture was diluted with water (120ml) and extracted with CH~C12 (3 x lOOml). The combined extracts were ~ 173~30 washed with brine (2 x 50ml), dried'and evaporated, and the residue triturated with ER (lOOml) to give a solid (16g). The solid was crystallised from iso-propyl acetate (120ml) to give the title compound (9.6g) as platelets, m.p. 138-140. [a]21=+22.~2 (CHC13).
Intermediate 44 ~l~-(endo,anti)]-(-)-6-~[(1,1'-Biphenyl)-4-yl]methoxy]-8-(4-morpholinyl-2-oxabicyclo[3.2.l]octan-3-one - 10 Peracetic acid (8.7ml, 6.12 M) was added dropwise to a stirred solution of Intermediate 43 (5g) in CH2C12 (25ml) at 0. The mixture was stirred for 24h while allowing the temperature to rise to ambient.
20% w/w Na2SO3 in water (60ml) was added dropwise at 0 and the mixture was stirred at room temperature for 0.75h. Iso-propyl acetate ~25ml) was added and the layers were separated. The aqueous layer was extracted with (1:1) isopropyl acetate-CH2C12 (2 x 25ml), and the combined organic layers were washed with lN NaOH (2 x s0ml) and brine (50ml) then dried and evaporated to give a solid (3.3g). The solid was crystallised from 1:1 EA~PE (80ml) to give the title compound as prisms (6.9g), m.p. 147-148.
[~]21 5=-26.44O (CHC13).
Intermediate 45 [lR-(lal2~l3~5~)]-5-E~ -Biphenyl)-4-yl]meth 3-hydroxy-2-(4-morpholinyl)cyclopentane acetaldehyde -~' A solution of Intermediate 44 (3g) in dry CH2C12 (60ml) was cooled t-78) and stirred under nitrogen whilst a solution of DIB~L in hexane ('10.7ml, 1.43 M) was added dropwise, Methanol ~60ml) was added dropwise at -73 and the cooling bath was removed. After stirring at room temperature for 2h the precipitate was filtered off and was washed well with methanol.
The combined filtrates were evaporated ln vacuo and ' the residue was d'issolved in CH2C12 (lOOml), dried, filtered and evaporated to give the title co~pound as a foam (2.95g). IR ~C~Br3) 3580~ 1718 cm.l.

.

~ ~73~33~3 , Intermediate 46 ~lR-~la~2~3~5~)]-5-~[~ -Biphenyl)-4-yl]methoxy]
3-hydroxy-2-(4-morpholinyl)cyclopentanepropanal (Methoxymethyl)triphenylphosphonium chloride (7.15g) was added to a stirred solution of potassium tert.-butoxide (2.35g) in dry THF (40ml) under nitrogen.
After 15 min a solution of Intermediate 45 ~2.759) in dry THF (20ml) was added dropwise and stirring continued for 30 min.
The reaction mixture was poured into 2N hydrochloric acid (50ml) at 0 and was stirred at 10-15 for 1.5h.
The mixture was adjusted to about pH 10 with saturated K2C03 solution and extracted with CH2C12 (3 x lOOml).
The combined extracts were washed with brine (l~OOml), dried and evaporated and the residue chromatographed on silica using 9:1 EA-methanol as eluent to give the title compound as a foam (2.47g). TLC 9:1 EA-methanol Rf 0.3.
Intermediate 47 [lR-~la(Z),2~,3a,5a]]-(+)-7-[5-[ E (l,l'-Biphenyl)-4-yl]methoxY]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]
4-he tenoic acid hvdrochloride P ~ , Dry THF (9Oml) was added to a stirred mixture of potassium tert.-butoxide (2.469) and 3-(carboxypropyl)-triphenylphosphonium bromide (4.6g) under nitrogen.After about'30 min Intermediate 46 (2.259) in dry THF (50ml) was added dropwise and stirring continued for 2.5h. Water (25m`1)'was added and most of the T}IF was removed ln vacuo. The residue in water (50ml) and 2~ NaO~I (20ml) was extracted with ~A (2 x 50ml).
The aqueous layer was adjustec3 to pT-I 6 with buffer (lM KH2P0~ 3 parts, lM Na2HP04 1 part) and was extracted with CH2C12 (3 x 50ml). The combined extracts were washed with brine, dried and evaporated to give a foam (2.7g). This material was dissolved in EA (lOOm~) and treated with an excess of ethereal hydrogen chloride.
After cooling at 0 for 16h the salt was collected and washed with 1:1 ER-E~ (25ml) followed by .ER (40ml).
Crystalllsation from 5:1 EA-methanol gave the title 1173f3~
.

compound (1.6g) as prisms, m.p. 152-153. [~]D =+54 (CHC13).
Intermediate 51 (endo,anti)-(+)-7-Azido-5-hydroxybicyclo~2.2.1]heptan-2-one A solution of (exo,endo)-~+)-3-acetoxy-2-bromobicyclo-[3.2.0]heptan-6-one (50g? and potassium t-butoxide (27.25g) in THF (1.5 1) was stirred at -75 for lh.
I'he solution was allowed to warm to 0 and a solution of sodium azide (16.45g) in water (600 ml) was added and stirring continued at 20 for 18h.
The t~o layers were separated ancl ether was added to the organic layer which was washed with water (2x250 ml).
The combined aqueous layers were extracted with ER
(2x250 ml). The combined organic layers were dried and evaporated to give a gum (28.1g). A solution of the gum in methanol (225 ml) was stirred with K2CO3 (18.37g) for 3.5h at room temperature. The mixture was filtered and the ~iltrate was evaporated in vacuo to give a solid which was taken into ER (150 ml) and washed with water (150 ml). The aqueous layer was extracted with ER (3x125 ml) and the combined organic layers were dried and evaporated to give an oil (24.5g) which was chromatographed on silica. Elution with 2:1 ER-PE gave an oil (18.7g) which was triturated with ER to give the title compound as a solid (14.6g), m.p. 72-74.
Intermediate 52 ( a,4~,5,6aa)-(+)-4-~zido-hexahydro-5-hy _ oxy-2H-~ penta(b)furan-2-one ____ .

:~ ~73~33~

40~ Peracetic acid ~64.35 ml) was added to a cooled (0) stirred solution of Intermediate 51 (12.9g) and sodium acetate (31.2g) in acetic acid (155 ml) and water (15.5 ml) and the resulting solution then stirred at ambient temperature for 24h. Excess Na2SO3 solution was added to the cooled solution and stirring continued for lh. After evaporation in vacuo the residue was dissolved in 5N NaOH solution (400ml) with cooling and the solution stirred for 0.5h. Concentrated hydrochloric -acid (30 ml) was added with cooling and the solution was continuously extracted with CH2C12 (600 mI) for 18h. The organic extracts were washed with 2N Na2CO3 solution (100 ml) and brine (100 ml), dried and evaporated to give a solid (3.5g). A portion (lg) was recrystallised 15 ~ from ER-PE (b.p. 60-80) to qive the title co'mpound ~816mg), m.p.,73-74.
Intermediate 53 (3aa,4~,5a,6a~)-(+)-4-Azido-hexahydro-5-[(tetrahydro-2H- ran-2-vl)oxv]-2H-cvclopenta(b)furan-2-one PY
Dihydropyran (6.1 ml) was added to a cold (-20) stirred solu'tion of p-toluenesulphonic acid (0.685g) and I,ntermediate 52 (6.63g) in CH2C12 (35 ml). After 2h at -20 the mixture was poured into 8% NaHCO3 'solution (300 ml). The organic layer was separated and the aqueous layer extracted with CH2C12 (3x100 ml). The combin~èd extracts were washed with brine ~200 ml), dried and evaporated in vacuo to give an oil (1'3.23g) which was puri~ied by chromatography on silica. Elution w;ith 2:~ F~-PF. (b.p~ 60-80) gave the title com~ound as an oil (5.39g), IR (Neat) 2100, 1780 cm 1.
~nte~mediat 54 -5-[(tet,rahydro-1 ~7383~

2H-pyran-2-yl)oxy]~2H-cyclopenta(b)furan-2-one A solution of Intermediate 53 (28.4g) in ethanol (175 ml) was hydrogenated at atmospheric pressure over pre-reduced 10~ palladium oxide on charcoal (5.3g) at 20 for 24h. The mixture was filtered ('Hyflo') and the filtcate evaporated to give an oil 524.lg).
IR (CHBr3) 3370, 3300, 1762 cm 1.
Intermediate 55 a) (3a~,4~,5~,6aa)-(+)-Hexahydro-5-[(tetrahy~ro-2H-pyran-2-yl)oxy~-4-(4-thiomorpholinyl)--2H-cyclopenta(b)furan-2-one , A mixture of Intermediate 54 (6g), anhydrous NaHCO3 (5.2g), NaI (9.72g) and bis-(2-chloroethyl)-sulphide (5.15g) in acetonitrile (250 ml) was ' 15 heated under reflux for 18h. The solvent was removed in vacuo and the residue in water (200 ml) was extracted with EA (4x200 ml~. The combined extracts were washed with brine (200 ml), dried and evaporated to give an oi~ (10.2g) which was purified by chromatography on silica.
Elution with ER and then 3:97 methanol-~R gave a solid (4.89). A~portion was crystallised from ER-PE to give the title 'compound, m.p.
83-84.
The following compound was prepared in a sirnilar manner:
b) (3aa,4a,5B,6aa)-(+)-4-(hexahydro-1,4-oxazepin-4-yl)-5-[(tetr`ahydro-2H-pyran-2-yl)oxy]-2H-cyclopenta(b)Euran-2-one, m.p. 68.5-72.5 from Intermediate 5~. Puri~ication by chrormatography using 35:15 E'R-methanol as eluent.
In ~
(anti enclo)-(~)-7-(1~ erld ~ (tet ~ dro-Piperidine (6~.1 ml) was adcled c3ropwise to a solution oE (exo,~endo)-(~)-2-bromo-3-[(tetrahydro-2H-pyran-2-yl)oxy]bicyclo~3.2.0]heptan-6-one (759) in high purity acetone (250 ml) at 0. The ~ixture was ~ ~J383l~

stirred in the dark for 24h and then filtered. The filtrate was washed with water ~2x150 ml), and the aqueous solution extracted with ER ~3 x 200 ml). The combined organic layers were dried, filtered and~evaporated to give the title compound as an oil (77.2g).
TLC 7:3 ER-PE Rf 0.18.
Intermediate 57 (endo,anti)-(+)-5-Hydroxy-7-(1-piperidinyl)bicyclo[2.2.1]-heptan-2-one, hydrochloride Ethereal hydrogen chloride (20 ml) was added dropwise to a solution o~ Intermediate 56 ~77.2g) in methanol (300 ml) at 0. After stirring for 1.5h at room temperature the'solvent was removed in vacuo, and the residue triturated with iso-propanol to give the title compound as a solid (52g), m.p. 246-248.
Intermediate 58 [la(Z),2~,3a,5a]-(+)-Methyl 7-[5-~[(1,1'-Biphenyl)-~4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoate Prepared as an oil from Intermediate 17c according to the methods described for Intermediates l~a and 14. Purification by chromatography using 9:1 EA-methanol as eluent. IR (CHBr3) 3520, 1725 cm Intermediate 5g a) (la,2a,3~,4a)-( )-2-(3-Methoxy-2-propenyl)-4-[(tetrahydro-2R-pyran-2-yl)oxy]-3-~4-thiomorpho-linyl)-cyclopentanol~ S-dioxide h solution of I~ntermediate 7b (12.lg) in methanol (80 ml) containing lN NaOH (60 ml) was stirred at room temperatur'e for Sh. The.mixture was poured into brine (650 ml) and extracted with CH2Cl~ (5xlS0 ~ he combined extracts were dried, 'filtered and concentrated to give an oil, which was chromatographed on silica using 13:7 ~A-PE (b.p. 60-80) through to EA as eluen~t to give the title co_E~ound as an oil (8.389).
.
' IR (Neat) 3510 (br'~, 1650 cm 1.
The following cornpound was prepared by.a similar 3$~ 3 ~

proced~re:
b) (la,2a,3R,4~)-(+)-3-(HexahydrO-1,4-Oxazepin-4-yl)-2-(3-methoxy-2-prope-nyl)-4-[~tetrahydro-2H-pyran-2-yl)oxy]cyclopentanol~ from Intermediate 7c IR (CHBr3) 3500, 1655 cm 1.
Intermediate 60 3-[(1,1'-Biphenyl)-4-yl]propanol,4-methylbenzenesulphonate A stirred solution of Intermediate 23b (4.28g) in pyridine (40 ml) at 0 was treated portionwise with p-toluene sulphonyl chloride (7.71g) over lh.
Stirring was continued at 0 for 7h when water (20 ml) was added and the mixture allowed to warm to room temperature with stirring for a further lh. The mixture was partitioned between 2~.H2SO4 (250 ml) and ER (250 ml), the layers separated and the organic phase washed with a further quantity of 2N.H2SO4 (2x250 ml). The organic phase was then washed with 2N.NaOH (3x100 ml), water (2x100 ml) and dried. Evaporation of the solvent gave the title compound as a solid (4.95g), m.p. 86-87.
Intermediate 61 (3aa,4a,5~,6a~)-(+)-Hexahydro-5-hydroxy-4-(4 thiomorpho-linyl~-2H-cyclopenta(b)furan-2-one, S-dioxide, hydrochloride A solution of (endo,anti?-(-)-6-(phenylmethoxy)-8-~4-thiomorpholinyl)-2-oxabicyclo[3.2.1~octan-3-one, S-dioxide (lOg) in ethanol (60 ml) and water (40 ml) containing ooncentrated hydrochloric acid (40 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal (5g, 50% dispersion in water) in ethanol (40 ml).
The mixture was ~iltered and the filtrate evaporated in vacuo to give the title compound as a solid (B.55g), m,p. ahove 230 (dec.) (~rom water~ethanol).
Intermediate 62 2-yl)oxyl-~ thiornorpholinyl)-2 2-one S-dioxide ~, Dihydropyran (3.1 ml) was added to a stirred solution o~ the free base o~ Intermediate 61 (1.56g) and p-toluene sulphonic acid monohydrate (~.17g) in '~ .

~ 3 ~ 3 () dry DMF (30 ml) at -10. The mixture was allowed to reach ambient temperature and stirring continued for 18h, whereupon it was poured into satura~ed aqueous NaHCO3 solution (50 ml), extracted with EA (4 x 100 ml), washed with water, dried, filtered and concentrated.
The residue was chromatographed using 19:1 ER-methanol as eluent to give the title compound as a viscous oil (1.89g). IR tCHBr3~ 1762 cm 1.
Intermediate 63 (3aa,4~,5~,6aa)-(+)-Hexahydro-5-~(tetrahydro-2H-pyran-2-yl)oxyJ-4-(4-thlomorpholiny].)-2H-cyclopenta(b)furan-2-ol, S-dloxide A solution of Intermediate 62 (lg) in CH2C12 (25 ml) at -70 under dry nitrogen was stirred during the addition of DIBAL (1 M in hexane, 8.7 ml). After 1.5h at -70, methanol (25 ml) was carefully added and the mixture was then allowed to rise to ambient temperature whereupon stirring was continued for 18h.
The mixture was filtered through 'Hyflo' and the filtrate -20 evaporated to give the title compound as an oil (0.959).
Analysis Found: C, 53.2; H, 7.6; N, 3.5.
C16H27NO6S requires: C, 53.2; H, 7.5; N, 3.9 Intermediate 66 [4'Methyl-~ b~hen~ 4-yl]methanol 4-Methyl-(l,l'~biphenyl)-4-carboxylic acid, methyl ester ~(1.43g) -in ER (25 ml) and THF (25 ml) was added over 5 min to LiAlH4~(420 mg) in ER (25 ml). The mixture was stirred at room temperature for 1 h and then cooled in ice. A~ueous NaOH (lM, 2.1 ml) was.added and after stirring (15 min) ~xcess anhydro-ls Na~SO~ was addecl.
The mixture wa~ filtered and the filtrate evaporat~cl to give a solid. Crystallisation from cyclohexane-methanol gave the tltle compound (1.0~g) m.p. 128-31.

. .

3 8 3 ~

Intermediate 67 4-Bromomethyl-4'-methyl ~,1' biphenyl) To a cold (0) solution of Intermediate 66 (0.917 g) in dry CH2C12 (14 ml) was added PBr3 (0.29 ml).
After stirring for 1 h at 0, 8% NaHCO3 solution (30 ml) was added and the layers separated. The aqueous layer was extracted with CH2C12 (2 x 30 ml), dried and evaporated to give a solid (0~99g). Crystal-lisation from PE (b.p. 60-80) afforded the title _ompound (0.91 g) m.p. 100-102.
Intermediate 68 4-Bromomethyl-4'-chloro-1,1'-biphenyl 4'-Chloro(l,l'-biphenyl)-4-methanol (5.8g) ~ was converted into the title c_mpound (6.8g), m.p.
; 15 64-66 by the method for the preparation of Intermediate 67.
Intermediate 69 ~+)-7-anti-(4-Morpholinyl)-5-endo-[tetrahYdrc-2~-pyran-2-yl)oxy~bicyclo~2.2.1]heptan-2-one Morpholine (76 ml) was added dropwise over 15 mins to a stirred solution of 2-exo-bromo-3-endo-[~tetrahydro-2H-pyran-2-yl)oxy]bicyclo[3.2.0~heptan-6-one (100.8g) in acetone (500 ml) at 0. A~ter 2h at 5 the mixture was stirred at 20 for 18h and then filtered. Evaporation of the filtrate gave an oil which was taken into ER (350 ml), filtered and washed (water, 2 x 100 ml). The ethereal solution was dried, filtered cand evaporated to give the title c ~ as a solid. Puriication from PE gave material (85.$g) o m,p. 86-88.
~0 ~ ~ 4 a olinyl)bicYclo[2.2.
heptan-2-one, hydrochloride To a stirred solution of Intermediate 69 (96.4~) in methanol (600 ml) was added an ethereal solution , ~ 1738~
- 5~ -of HCl (240 ml) and the mixture stirred at 20 for 2.5h (pH 1.5-2). Filtration followed by evaporation of the filtrate gave an oil which solidified on trituration with EA (2 x 200 ml)~ Coloured impurities were removed by extraction with boiling isopropanol to leave the title compound as a solid (70.6g), m.p. 181-182.
Intermediat~ 71 (+)-5-endo-(4-Bromophenylmethoxy)-7-anti-~4-morpholinyl)-bicyclo~2.2.1]heptan-2-one Aqueous NaOH solution (10~j 200 ml) was aclded to a solution of the free base of Intermediate 70 (21.19), benzyltriethylammonium chloride (49) and 4-bromobenzyl bromide (27.5g) in CH2C12 (400 ml) and the mixture stirred vigorously for 4h. A further portion of 4-bromobenzylbromide (99) was then added and stirring continued for 68h. Water (~00 ml) was added and the layers separated. The aqueous layer was extracted with ~A (2 x 75 ml), washed with water, dried and evaporated to give an oil (489) which solidified on standing. Excess alkylating agent was removed by triturition with PE (b.p. 60-80) ànd crystallisation from EA-PE (b.p. 60-80) then gave the title compound (34.1g) as a solid, m.p. 130-131.
Intermediate 72 (+)-6-endo-(4-Bromophenylmethoxy)-8-anti-(4-morpholinyl)-2-oxa~bic clot3.2.1]octan-3-one Y
Intermediate 71 (13.2g) in acetic acid (110 ml) and water (55 ml) containing CH3COONa.3H20 (23.7g) was cooled (ca. 5-10) and stirred cluring the dropwise acldition o peracetic acid (6.1M; 28.5 ml). The resulting solution was stirred at 20 or 48h when 10% Na~SO3 solution (200 ml), was added, maintaining the temperature of the mixture at 10-15. A~ter ].5h solvents were removed in vacuo at 35, the res,idue taken into water (150 ml) and basified to p~l 9 with Na2CO3 solution. Extraction with EA (3 x 200 ml) ~ollowed by drying ancl evaporation gave a solid which crystallised ~rom E'A to give the title compound (5.49g), m.p. 154-156.
.~ .

~ 173P~

- 5~ -Intermediate 77 ~la(Z/E),2~,3a,5~]~(+)-7~[5~[[(1,1'-BiPhenyl)-4~
yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-bromo-4-heptenoic acid To a stirred solution of potassium tert-butoxide (6.06q) in dry THF (140 ml) at -70 was added (4-carbethoxypropyl)triphenylphosphonium bromide (22.16g).
After 0.5h at ~70 a solution of bromine in CH2C12 !25~ v/v, 6.7 ml) was added dropwise and then stirring maintained for 0.9h. A sol~tion of Intermediate 6 (4.099) in THF (30 ml) was then added and, after 0.5h, the temperature of the mixt~re allowed to rise to 0 over lh. 2N NaOH (60 ml) and methanol t60 ml~
were added and stirring continued at 20 for 4h.
After evaporation in vacuo the residue was taken into water (200 ml) and adjusted to pH 12 with 2N
NaOH. Non~acidic material was removed by extraction with EA (1 x 100 ml, 2 x 50 ml), and the aqueo~s phase then re~adjusted to pH 6 with 2N hydrochloric acid. Extraction with EA (4 x 60 ml), drying and concentration gave the title compounds as a foam (5.23q)~ IR (CHBr3) 3500, 1725, 1710 cm 1.
Intermediate 78 (la,2~,3a,5a)-(+)~7~[5~[[(1,1'~Biphenyl)-4-y _methoxy]-3~hydroxy~2-(4~morphollnyl)cyclopentyl]~4~heptynoic acid, hydrochloride To a stirred solution o~ Intermediate 77 (2q) in TI~F (15 ml) at 0 was added potassium tert-b~toxide (2.4g) in ~M50 (lS ml). The mixture was stirred L

- 60 - 3 ~3~3~

at 0 for 0.5h and at 20 for 1.5h whereupon water (200 ml) was added and the mixture extracted with EA (1 x 50 ml). The aqueous solution was adjusted to pH 6 with 2N hydrochloric acid and extracted with EA (3 x 60 ml). The combined extracts were washed with water (3 x 60 ml), dried and evaporated to give an oil, which was purified by chromatography on silica (130g) using 4:1 EA-methanol as eIuent to give a foam (0.65g). A sample was treated with ethereal hydrogen chloride to give the title compound. Crystal-lisation from EA gave material of m.p. 162-163.5 .
Intermediate 79 (1~,2~,$~)-(+)-[5-~[(1,1'-Biphenyl)-4-yl]methoxy~-2-(4-morpholinyl)-3-oxo-cYclopentyl]-4-heptynoic acid Prepared from the free base of Intermediate 78 according to the procedure described for Example 3a. Purification by chromatography using ER through - to 98:2 ER-methanol as eluent. Crystallisation from ER-PE (b.p. 60-80) gave material of m.p. 90-93.
Intermediate 80 (endo,anti)-(~)-5-Decyloxy-7-~4-morpholinyl)bicyclo-[2.2.1]heptan-2-one Sodium hydride (46% dispersion in oil, 0.522g) was added portionwise over 10 min to a stirred soIution of Intermediate 1 (1.06g) and decyl tosylate (2.34g) in dry DMF (lOml) under dry nitrogen at room temperature.
The mixture was stirred for 5h, poured into water (SOml) and extracted with ER (SOml, 2 x 25ml). The combined extracts were washed with water (25ml), dried and concentrated to give a solid. Crystallisation from PE gave the t tle ompound (0.59g), m.p; 64--65~.

7 ~73831~

EXAMPLE I
a) [la(2)r2B~5~]-(+)-7-[5-[[~ Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid Method I
To a cold (-11~ stirred solution of Intermediate 12a) (920 mg) and triethylamine (2.14 ml) in CH2C12 (10 ml) and DMSO (10 ml) was added pyridine-sulphur trioxide complex (915 mg) in DMSO (10 ml). Stirring was maintained at 25C for 3h whereupon water (10 ml) was added and the CH2C12 evaporated. To the resulting suspension a solution of citric acid (1.07g) in water (10 ml) was added. The mixture was extracted with EA, the combined extracts dried and concentrated.
i5 The residual oil was chromatographed on silica using ER as eluent to give the title compound as an oil which slowly crystallised (0.37g). Recrystallisation of a sample from ER-iso-pentane at 0 gave material of m~p. 77.5-80, IR (Nujol) 3350-2aoo (br), 1735, 1705cm 1; whereas recrystallisation above 5 gave a different polymorphic form of m.p. 98-100.5, IR
(Nujol) 3400-2300 (br), 1735, 1702, 1250, 1005cm 1.
Analysis ~ound: C, 72.9; H, 7.4; N, 2.9.
C29H35NO5 requires; C, 72.9; H, 7 4; N, 2.9%.
2~ ~ethod 2 Jones reagent (0.54ml, 2.67M) was added to a mix~ure of Intermediate 26 (0.259) and 'Hy~lo' tlg) in acetone (10-ml) and stirred for lh. Isopropanol 3 ~ 3 1~

(lml) was added, the mixture filtered and the filtrate washed with pH 5 buffer ~2 x lOml). After drying and evaporation the residue was purified by chromatography on silica using ER as eluent to give the title compound ~0.024g).
Method 3 From Intermediate 33a) by the procedure described under Method 2.
Method 4 From Intermediate 34 by the procedure described under Method 2 Method 5 A suspension of 5~ Pd on CaCO3 poisoned with lead (70 mg) in EA (5 ml) containing triethylamine (0.2 ml) was hydrogenated at 21 and atmospheric pressure for 0.5h. A solution of Intermediate 79 (36 mg) in EA (4 ml) was added and the hydrogenation continued for 2h. The mixture was- filtered, diluted with ER (20 ml) and washed with pH 6 phosphate buffer solution (30 ml). Evaporation of the dried ethereal solution gave a solid (35 mg) which crystallised : from ER-PE (b.p. 60-80) to give the title compound (23 mg), m.p. 95-98.
- The following compounds were prepared by the procedure described for Method 1.
b) [la(Z), 2~,5~]-(~j-8-[5-[[(1,1'-Biphenyl)-4-yl~met/hoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-5-octenoic acid, m.p. 118-120 from Intermediate 13.
Analysis found: C, 73.6; H, 7.7; N, 2.9.
C30H37NO5 requires; C, 73.3; H, 7-6; N~
2.9%.
c) ~ 5aJ~ 7-[21-Morpholinyl)-5-~ - .
(2-naPhthalenylmethoxxl~3-oxocvclopentvlJ-4 heptenoic acid ~rom Intermediate 12h.
_ Purification by chromatography using ER as eluent IR (CHBr3) 3600 - 2300~br), 1735, 1702 cm 1 ? 1 ~383 Analysis Found: C, 71.1; H, 7.5; Nr 3.2 C27H35NO5 requlres: C, 71.8; H, 7.4; N, 3.1~
d) [la(Z)~ 2~, 5~]~ 7-[5-[4-(1,1-Dimethylethyl)-~henylmethoxy]-2-(4-morpholinyl)-3-oxocyclopentyl~-4-heptenoic acid, from Intermediate 12d.
Purification by chromatography using ER as el~ent.
IR (CHBr3) 3500, 1738, 1705 cm TLC 95:5 ER-methanol Rf 0.53 e) [l~(Z), 2~, 5~]-(+) 7-~5-[4-Methylthio(phenyl-methoxy)]-2-(4-morPholinyl)-3-oxocyclopentyl) 4-heptenoic acid, compound with piperazine (2:1) r from Intermediate 12i.
The acid was p~rified by chromatography using ER as eluént. The title compound (106mg) crystal-lised from a solution Of the acid (168mg) and piperazine (25mg) in ER (5ml) to give material of m.p. 75-76.5.
- IR (CHBr3) 1735 r 1590 cm 1 f) [l(Z), 2~, 5a]~ -7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3-oxo-2-(4-thiomorpholinyl) cyclo-pentyl]-4-heptenoic acid, from Intermediate 12p. Purification by chromatography using 7:3 ER-isopentane as eluent.
IR (CHBr3) 3500, 1740, 1705 cm 1. TLC ER R
0.45 g) [l~Z), 2~, 5a]-(-)-7-[5-[~4'-Methoxy(l,l'-biphenyl)-3-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4~heptenoic acid, ~rom Intermediate 12y. Purification by chromatograp}ly u~ing 4:1 EA-PE (b.p. 60-80) as eluent.
IR (C~IBr3) 3500, 1740, 1710 cm 1 TLC 4:1 E~-PE ~b.p. 60-80) R 0.44 EX~MPLE 2 [l(Z),2~,5a~ )-Methyl 7-~5-~[(1,1'-Biphenyl)-4-y~_~meth~x,~ ~ Eh 1inyl)-3-oxocycloE~n_ ~o_ To a cold (-60), 5tirred solution of ~xalyl ;' - . . .
,, `` ~ 173~30 - 6~ -chloride (0.144 ml) in dry C~2C12 (20ml) was added DMSO (0.133ml). The solution was stirred for 15 min, when a solution of Intermediate 14 (0.37g) in dry CH2Cl2 (20ml) was added. After stirring for 2h, triethylamine tl.04ml) in dry CH2Cl~ (5ml) was added and the temperature then allowed to rise to ambient over 0.75h. ER was then added and the mixture washed with 8% NaHCO3 solution. The organic phase was separated, dried and concentrated, and the residue chromatographed on silica. Elution with 3:1 ER-isopentane gave the title compound as an oil (0.23g). I.R.
(CHBr3) 1730 cm Analysis Found: C, 73.1; H, 7.0; N, 2.8 C30H37NO5 requ-ires: C, 73.3; H, 7.6; N, 2.9%.
Example 3 a) [la(z)~2~5a~-(+)-7-[5-[4-Methoxy(phenylmethoxy)]
2-(4-morphoIinyl)-3-oxocyclopentYl]-4-heptenoic acid, compound with chloroform (3:1) To a solution of Intermediate 12c) (0.189) in acetone (lO ml) at -5 was added 'hyflo' ~0.79) followed by Jones reagent (2.67M, 0.36 ml). The temperature was allowed to rise to 5 during 45 min when isopropanol (1 ml) was added. After 5 min the mixture was filtered and the solid washed thoroughly with ER. The combined organic layers were washed with pH 6.5 phosphate buffer (2x20 ml), dried and concentrated.- Purification by chromatography using 98:2 CHCl3-methanol~as eluent gave the title compound as an oil (0.06g).
IR ~CHBr3) 3500, 1740, 1710 cm TLC 98:2 CHCl3-m~thanol Rf 0 4 The following compounds were prepared using a similar procedure:
b) [la~Z),2~,5a~-(+)-7-E5-[[4'-ChlorO(l,l'-biphenyl)-4-yl]methoxy}-2-(4-m~phQlinyl)-3-oxocyclopent~yl]
4-heptenolc acid, from Intermediate 12h Purification by chromatography using 99:1 CHCl3-meth~nol as eluent. TR (CH~r3) 3490~ 1740, 73~30 -- 65 r 1705 cm 1 Analysis found: C, 67.7; H, 6.6; N, 2.8.
C29H34ClNO5 requires: C, 68.0; H, 6.7; N, c) [la~Z)~2~5a]-~-)-7-[2-~4-Morpholinyl)-3-Ox'O-5-(2-propenYloxy)cyclopentyl}-4-heptenoic acid, from Intermediate 12i. Puri'fication by chromato-graphy using 4:1 ER-PE (b.p. 60-80) as eluent.
IR (CHBr3) 3500, 1735j 1705 cm 1. TLC 4:1 ER-PE (b.p. 60-80) Rf 0.28.
d) ~la(Z),2~,5a]-(+)-7-~2-(4-Morpholinyl)-3-oxo-5-[(4-thien-2-yl)phenylmethoxy]cyclopentyl]-4-heptenoic acid, comPound with piperazine (2:1), from Intermediate 12k. The acid was lS purifi~ed by chromatography uslng~1:99~methanol- ' CHC13 as eluent. The title compound -(140~mg) ;~ precipitated from a solution of the acid (200 mg) and piperazine (100 mg) in ER. Crystallisa~tion from EA gave material of m.p. 115 (dec1.
IR (CHBr3)~1740 cm 1. TLC~ER Rf 0.7.
ej [l(Z),2~,5a]-(+)-7-~2-(4-MorpholinYl)-3-oxo-5-[[(1,1i:4',1"-terphenyl)-4-yl]methoxy]cyclopentyl]-4 l~ , m.p. 105 (dec) from Intermediate 12 1). Purification initially by chromatography using ether as eluent'and then by crystallisation ' from En-isopentane at 0. TLC 9:1 ER-methanol Rf 0.23;
f) [la(E),2~,5a]-(-)-7-[5-[~4l-Methyl(l,l'biphenyl)-' 4-Yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]
_h ~ , m.p. 80-85 f~om Intermediate 25a. Puri~ication initially by chroma~ography using ~R a5 eluent and then by crys~allisation from ER-i~opentane at -20 ~nalysis Found: C, 73.1; ~, 7.7; N, 2.8.
C30H37NO5 requires: C, 73.3; H, 7.6~ N, 2.9~.,

9) ~ a ~ ~
yl]methoxY]-2-(4-morpholinyl)-3-oxocyclopentyl]-4=~ c ~, m.p. 103-105 from Intermediate 25b.~- Puriication initially'by chromatography , '' . ' ` ', ~ .
, . i . - . -.
~ : ' : ' `~' -3~30 66 ~
using ER as eluent and then by crystallisation from ER at -20.
Analysis Found: C, 72.8; H, 7.7; N, 3Ø
C29H35NO5 requires: C, 72.9; H, 7.4; N, 2.9%.
h) [la(Z),2~,5a]~ 9-[5-[[(1,1'-Biphenyl)-4-y~]methoxy]-2-(4-morpholinyl)-3-oxocyclopent 6-nonenoic acid, mOp. 83-84 from Intermediate 12 m. Purification initially by chromatography using ER as eluent and then by crystallisation from ER-isopentane.
Analysis Found: C, 73.3; H, 7.7; N, 2.8.
C31H39NO5 requires: C, 73.6; H, 7.8; N, 2.8%.
i) [la(Z),2~,5a(E)]-(+)-7-[2-(4-Morpholinyl)-3-oxo-5-~(3-phenyl-2-propenyl)oxy]cyclopentyl]-4-heptenoic acid, m.p. 74.5-76 from Intermediate 12O. Purification by chromatography using - ER as eluent.
Analysis Found: C, 70.3; H, 7.9; N, 3.3.
C25H33NO5 requires: C, 70.2; H, 7.8; N, 3.3%.
j) [la(Z),2~,5a]-(+)-7-[5-[[4'-Methyl(l,l'-biphenyl)-4-yl3methoxy3-3-oxo-2-(4-thiomorpholinyl)cyclopentYl]-4-heptenoic acid, S-dioxide, from Intermediate 12r. Purification by chromatography using 98:2 ER-methanol as eluent. IR (CHBr3) 3500, 1740, 1710 cm~l.
Analysis Found: C, 66.5; H, 7.1; N, 2.2;
C30H37NO6S requlres: C, 66.8; H, 6.9; N, 2.6%.
k) [la~Z),2~,5]-(-)-7-[3-Oxo-5-~4-~phenylmethyl)-phenylmet~y_-2-(4-thiomorpholinyl)cyclopentyl]-~-heptenoi _acid, S-dioxide, m.~. 126.5-128 (flec) from Intermediate 12s. Puri~ication by chromato~raphy using ~R as eluent. TLC 95:5 ER-methanol Rf 0.46.
1) [la~Z),2~,5a~ )-7-~5-[~(1,1'-Biphenyl)-4-yl]methoxy]-3-oxo-2-(4-thiomorpholinYl)cyclopen 4-h_~e c acid, S-dioxideL from Intermediate 12t, Purificatic)n by chromatoyraphy using g8:2 ER-methanol as eluent. IR (CHBr3) 3480, 1743, 1710 cm Allalysis Foun~: C, 66.0; H, 6.7; N, 2.6;

3 (3 C29H35~06S requires: C, 66.3; H, 6.7; N, 2.7%-m~ l~(Z),2~5a]-(-)-7-r5-~ Biphenyl)-4-yl)methoxy]-2-(hexahydro-1,4-oxazepin-~-yl-3-oxocyclopentyl]-4-heptenoic acid, from Inter-mediate 12 u. Purification by chromatography using ER as eluent. IR (Neat) 3500-2500 (br), 1740, 1710 cm 1. TLC ER Rf 0.47.
n) Ela(z),2~,5a]-(-)-7-[5-~3~ l'-Biphenyl)-4-yl]propoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid, from Intermediate 12w. Purifi-cation by chromatography using ER as eluent.
IR (Neat) 3700-2200 (br), 1740, 1712 cm 1.
TLC ER Rf 0.25.
) ~l~(z)r2~l5a]-l-)-7-[5-[[3~-Methoxy(l~l'-biphenyl) 4-yl]methoxy~-2-(4-morpholinyl)-3-oxocyclopentyl]
4-heptenoic acid, from Intermediate 12x. Purifi-cation by chromatography using ER as eluent.
IR (CHBr3) 3500, 1740, 1710 cm 1. TLC ER Rf 0.2.
p) [la(Z!,2~,5~)-(-)-7-[5-Decyloxy-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid from Intermediate 12z. Purification by chromatography usi-ng 4:1 ER-PE as eluent. IR (CHBr3) 3500, 1740, 1710 cm 1.
TLC (SiO2) 4:1 ER-PE Rf 0.21.
Example 4 a) [la(Z),2~,5a]-(+)-7-[5-(4-Cyclohexylphenylmethoxy)-2-(4~morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid -~A stirrecl solution of oxalyl chloride (0.612ml) in dry toluene (5mll under nitrogen at -60 was treated dropwise with a solution of dry DMSO (0.5ml) in dry toluene (5ml) and the mixture stirred.for 10 min~
Simultaneously ch~orotrimethylæilane (0.24ml) was added dropwise to a solution of Intermediate 12e, (0.84g) and triethylamine (0.264ml) in dry toluene (lOml) under nitrogen. This mixture was swirled for S min before being added dropwise to the above , reaction mixture~ The resulting solution was stirred at -60 for 15 min and then quenched with triethylamine (2.8ml). The mixture was allowed to warm to O, poured into aqueous KH2P04 (3.5g in 200ml water) and extracted with EA (4 x 50ml). The combined organic - . .

3 ~

extracts were washed with pH 6.5 phosphate buffer (2 x 20ml), dried and concentrated. The residue was purified by chromatography on silica using 3:1 ER-PE as eluent to give the title compound as a gum t56m9)~ IR (CHBr3) 3500, 1740, 1710 cm 1. TLC 80:1 ER-acetic acid Rf 0.39.
The following compounds were prepared using a similar procedure:
b) [la(Z),2~,5a]-(+)-7-[2-(4-Morpholinyl)-3-oxo-5-~pentyloxy)cyclopentyl]-4-heptenolc acid, compound with piperazine (2:1), from Intermediate 12f. Purification of the acid by chromatography using ER as eluent. The title compound (212mg) crystallised from a solution of the acid (271mg) and piperazine (45mg) in ER (lOmI) to give material of m.p. 99-102.5 (dec).
Analysis Found: C, 64.9; H, 9.5; N, 6.8.
C23H40N205 requires: C, 65.1; N, 9.5; N, 6.6~.
c) [la(Z),2~,5]-(+)-7-r2-(4-~orpho]inyl)-3-oxo-5-[4-~phenylmethyl)phenylmethoxy]cyclopentyl}-4-heptenoic acid, compound with piperazine (2:1), m.p. 107-108 from Intermediate 12 g.
Analysis Found: C, 71.6; H, 7.9; N, 5.2 C32H42N205 requires: C, 71.9; H, 7.9; N, 5.2%.
e) [la(Z),2~,5a]-(-)-7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3-oxo-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid, compound with piperazine (2:1), m.p. 91-94 (dec) from Intermediate 33b. IR ~CHar3) 1738 cm 1.
~) ~ 5a~ 7-[5-~[9'~325~ ~L~i Deh9cYl)-methoxyl-3-oxo-2-(4-~thiomorpholinyl)cyclopentyl]-~heptenoic aci~L S-dioxide, from Intermediate ..' ' . ~' ' ' . . '' ' ' ' '.
, ~ ~3~3~0 12q. Purification by chromatography using 98:2 ER-methanol as eluent. TLC 95:5 ER-methanol Rf 0.46. IR (CHBr3) 3480~ 1740, 1710 cm -.
g~ [l(Z),2~,5a]-~)-7-~5-[[4'-Methoxy(l,l'-biphenyl~-4-yl]methoxy)-3-oxo-2-(l-piperidinyl)cyclopentyl]
4-heptenoic acid, compound with piperazine (2:11, m.p. 68-76 (dec) from Intermediate 12v. IR (CHBr3) 1740 cm Example 5 [l(Z~,2~,5]-(~-7-[5-[~4'-Methyl~l,l'-biphenyl)-4-yl]methoxy]-2~(4-morpholinyl)-3-oxocyclopen~yl]-4-heptenoic aci_ A solution of Intermediate 18 ~928mg~ in acetone (30ml) was stirred with Jones reagent (2.67 M; 1.5ml~
lS at -5 to -3 for 40 min. Isopropanol (1.5ml) was added and after stirring for 5 min, the mixture was poured into pH 6 phosphate buffer (lOOml) and extracted with ER (3 x 50ml). The combined extracts were e~aporated and the residue taken into ER and dried; evaporation of this ethereal solution gave a foam (840mg) which was purified by chromatography on acid-washed siIica gel (85g~ using ER as eluent. Crystallisation from ER-isopentane at 0 gave the title compound (0.269) of m.p. 98 102. IR (CHBr3) 3500, 1740, 1710 cm Analysis Found: C, 72.9; H, 7.6; N, 2.9.
C30H37N05 requires: C, 73.3; H, 7.6; N, 2.9%.
Exam~le 6 [la(Z),2R,5a]-(+~-7-~5-[~4'-Methoxy(l,l'-biphenyl)-4-yl]methoxyl-2-(4-morpholinyl~-3-oxocyclopentyl]-_-heptenoic acid, compound with piperazine ~
Jones reagent (0.883ml, 2.7 M) was added to Intermediate 21 (600mg) in acetone (2Sml) at -10 and stirred ~or ~5 min At 10. The mixture was neutralised by (~Sml) dropwise addition of 2N aqueous Na2co3 and then poured into Na2HP04/K~I~PO~ bu~er solution (pH 6). ~he mixture was extracted with CH2C12 (3 x 50ml) and the combined extracts dried, ~iltered and evaporated.
The residue was chromatographed on acid washed silica ~ 1 ~383~

using 1.1 through to 3:1 ER-PE (b.p. 60-80) as eluent to give an oil, which was dissolved in ER and treated with an excess of piperazine in ER to give the title compound as a solid (0.129), m.p. 116-117 (decj.
Analysis Found: C, 69,7; H, 7.6; N, 5.2 ~32H42N26 requires C, 69.8; H, 7.7; N, 5.1%.
Example 7 [la(Z),2~,5a]-(-)-7-~5-~[(l,l'-Biphenyl)-4-ylJmethoxyl-2-(4-morpholinyl)-3-oxocyclopentyl]-4~h compound with piperazine (2:1), hemihydrate To a solution of Example la (0.379) in dry ER (20ml) was added piperazine (0.037g) in dry ER
(4ml). The ER was decanted off and the resid~e crystal-lised from CH2C12-isopentane to give the title compound (0.29) m.p. 113-114.
Analysis found: C, 70.9; H, 7.7; N, 5.4.
C31H40N205.1/4 ~2 requires: C, 70.9; H, 7.7; N, 5.4%.
Example 8 [la (Z) ,2~,5a]-(+)-7-[5-[[(l,l'-BiPhenyl)-4-yl]meth 2-(4-morpholinyl)-3-oxocyclopentyl]-~-heptenoic acid, calcium (2~) (2:1), monohydrate Aqueous 0.2N.NaOH (2ml) was added dropwise with stirring to a solution of Example la (0.259) in aqueous acetone (1:1), lOml) at room temperature until the pH reached 7.8. 7.2~ w/v CaC12 (lml) was then added followed by water (lOml) and stirring ~ continued for 2h. The solid was filtered off, washed with water (5ml) followed by ER (lOml) and dried (35/O.OSmmHg/7h) to aford the title compound tO.163g), m.p. 132-134.
Analysis Found:C, 69.1; El, 6.8; N, 2.6; Ca, 3.9.
C58H6~N2010Ca -H2 requires: C, 68.9; H, 7,0; N, 2.8; Ca, 4.0%.
35 ~xa~ 9 [la(Z)L2~,5a]~7-[5-[[(1,1' Biphenyl)-4-yl]methoxyl-2-(4--morpholinyl)-3--oxocyclopentyl]-9~heptenoic a~
calcium (2-~) (2~ trihydrate .

~ ~73~3(3 Aqueous calcium acetate solution (0.17g in 12ml) was added dropwise with stirring to a solution of Example la) (0.6g) and NaHC03 (001059) in aqueous ethanol (1:1, 24ml). The mixture was stirred for 30 min when the solid was filtered off, washed with water (lOml) followed by ER (5ml) and dried (45/200mmHg/4h) to afford the title _ mpound (0.569), m.p. 135 (dec).
Analysis Found: C, 66.2; H, 6.9; N, 2.6; Ca, 3.6.
C58H68N2010Ca 3H2 requires: C, 66.5; ~, 6.g; N, 2.7; Ca, 3.8~.
Example 10 [l~(Z),2~,5~]-(+)-7-~5-[~(1,1'-8iphenvl)-4-yl]methoxyl-2-(4-morpholinyl)-3-oxocyclopenty~]-4-hePtenoic acid, compound with N~N-dimethyl~iperazine (2:1) A solution of Example la) ~0.359~ in ER (25ml) was treated with a solution of N,N-dimethylpiperazine tO.084g) in ER (5ml) and the mixture was allowed to stand in the cold. ~he title compound was filtered off and dried (0.339), m.p. 106-108.
Analsis Found C, 71.9; H, 7.9; N, 5;1.
C32H42N205 requires: C, 71~9; H, 7.9; N, 5.2%.
Example 11 a) [lR-[l~(Z),2~5a]l-(-)-7-[5-[[(l,l'-Biphenyl)-4-yl]methoxy]-2-(4-morph~linyl)-3-oxocyclopentyl]-4-heptenoic acid . ~ _ Jones reagent (1.83ml, 2.67M~ was added to a stirred mixture o 'hyflo' (4.8g) and the free base o Intermediate 47a) (1.2g) in acetone (~Oml) at 5 and stirring was continued for 40 min. Isopro-panol (1.8ml) was added dropwise and a~ter 10 min the hy~lo was removed by filtration and was washed with acetone (30ml) and pH 5 bufer (50ml, KH2PO~
and Na2HP04 in water). The combined filtrates were, evaporated in vac_o at 10-15 to remove most of the acetone. The residue was diluted with pH 5 buffer (25ml) and extracted with ER (4xSOml). The combined extracts were washed with pH 5 buffer (20r~1) and ` ~ 173~30 brine (20ml), then dried and evaporated to give`an oil. The oil was chromatographed on silica using ER as eluent to give a solid (0.589) which was recrystal-lised from 2:1 ER-iSopentane ~15ml) to give the title compound (0.484g), m.p. 86 88. [a]21~5 = -13.66 (CHC13).
Analysis Found: C, 72.5; H, 7.5; N, 2.7.
C29H35NO5 requires: C, 72.9; H, 7.4; N, 2.9~.
The following compound was prepared starting from Intermediate 35, in a similar manner to the preparation of the lR compound:
b) [lS-~l~(Z),2~,5~]]-(+)-7-[5-~ f (~ BiphenYl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid, m.p. 81-84.
Analysis Found: C, 72.8; H, 7.3; N, 2.7.
C29H35NO5 re~uires: C, 72.9; H, 7.4; N, 2.9%.
Example 13 [lR-~l(Z),2~,5a]]-(-)-7-[5-[[1,1'-Biphenyl)-4-yl]methoxy]-2-(4 morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid, calcium (2+) (2:1), dihydrate Aqueous calcium acetate solution (0.0839 in 4.8ml) was added dropwise with stirring to a solution of Example 11 (0.259) and NaHCO3 (40mg) in aqueous ethanol (1:1, 9.6ml). The mixture was stirred at room temperature for 2h when the solid was filtered o~, washed with water and dried (20/Q.lmmHg/20hJ
to a~ord the title com~ound (0.23g), m.p. 129-131.
~aJ21 ~ -28.47 (CMC13).
Anal~sis Found: C, 67.~; Il, 6.8; N, 2.7; Ca, 3.5.
C58H68N2~l0ca~2~2o req~ires: C, 67.7; H, 7.0; ~, 2.7; Ca, 3.9~.

~ ~738,30 ' 73 -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 The active ingredient is sieved through a 250 m 6 sieve, blended with the excipients and compressed using lO.Omm punches. Ta~lets 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. 238.0 Starch B.P. 40.00 Pregelatinised Maize Starch B.P. 20.00 Magnesium Stearate B.P. 2.00 Compressed Weight 400.00 The active ingredient is sieved through a 250 m 6 sieve and blended wikh the lactose, starch and pre-gelatinised starch, The mixed powders are moistenecl ~V with puri~ied water, granules are made, dried, screened ~ :~73~330 and blended with the magnesium stearate. The lubricated granules are compressed into tablets as described for the direct compression formulae.
The tablets may be film coated with suitable film forming materials, e.g. methyl cellulose or hydroxylpropyl methyl cellulose using standard techniques.
Alternatively the tablets may be sugar coated.

- Capsules mg/capsule Active ingredient 100.00 *STA-RX 1500 99.00 Magnesium Stearate B.P. 1.00 Fill Weight 200.00mg ~ * A form of directly compressible starch supplied by Colorcorn ~td~, 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 Cartridqes /cartridge Active ingredient (micronised) 3 mg ~actose B.P~ to 25 mg ~ :~73%3~
~ 75 -The active ingredient is micronised so that the majority of the particles are between l m 6 and 5 m 6 in longest dimensions and none are greater than lO m 6, The active ingredient is then blended with the lactose and the mix is filled into No. 3 hard gelatin capsules using a suitable filling machine.

Suspensions mg/5ml dose Active ingredient lO0.0 Aluminium monostearate 75.0 Sucrose (powdered) 125.0 Flavour~ as Colour ) required Fractionated coconut oil to 5.00ml.

The aluminium monostearate is dispersed in about 90% of the fractionated coconut oil. The resulting suspension is heated to 115C while stirring and then cooled. The flavour and colour are added and the active ingredient and sucrose are suitably dispersed.
The suspension is made up to volume with the remaining fractionated coconut oil and mixed.

In ection for Intravenous Administration Active ingredient 50mg Suitable vehicle to Sml.

~ A sterile presentation of the active ingredient in an ampoule or vial together with an ampo-lle containin~
a suitable vehicle. The ~ormer may be prepared by (a) 111ing sterile material into vials under aseptic conditions ~b) reexe drying a sterile solution o~
the active ingredient under aseptic conditions.
The vehicle may be ~a) Water ~or Injections B.P. ~b) Water ~or Injections B.P. containing~
Sodium chloride to adjust the tonicity of the solution and/or ~2) buffer salts or di~ute acid or alkali to facilitate solution of the active ingredient.

~ 173~3~

The vehicle is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass. The vehicle is sterilised by heating in an autoclave using one of the acceptable cycles.

~ ' , - '~

Claims (35)

Claims:

1. A process for the preparation of a compound of the general formula (1) wherein X is cis or trans -CH=CH-;
R1 is straight or branched C1-7 alkyl bearing as a terminal substituent -COOR3 where R3 is a hydrogen atom, C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which has 5 to 8 ring members selected from pyrrolidino, piperidino, morpholino, piperazino, thiamorpholino, 1-dioxothiamorpholino, homomorpholino, and hexamethyleneimino;
R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-ally substituted by phenyl (the phenyl being optionally substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7 cycloalkyl or phenyl (C1-4 alkyl), biphenyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or halogen), or naphthyl; (iii) C1-12 alkyl; (iv) C1-5 alkyl substituted by (a) phenyl [optionally substituted by halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-4 hydroxyalkoxy, trifluoro-methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-methylaminomethyl, carboxamido (-CONH2), thiocarboxamido (-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6 are the same or different and are each a hydrogen atom or C1-4 alkyl, or where -NR5R6 is a saturated heterocyclic amino group as defined above for Y), C1-3 alkylthio, C1-3 alkylsulphinyl, C1-3 alkylsulphonyl, phenylalkyl having a C1-3 alkyl portion, aminosulphonyl, C1-3 alkanoylamino-sulphonyl, phenylsulphonyl (the phenyl portion being optionally substituted by C1-3 alkyl or C1-3 alkoxy), nitro, or thienyl], (b) biphenyl (optionally substituted by phenyl or one or two C1-4 alkyl, C1-4 alkoxy, halogen substituents), or (c) naphthyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates thereof; which process comprises:
(a) oxidising a compound of formula (2) in which R1a is a straight or branched alkyl group substituted by -COOR3, -CH2OH or -CHO, the -COOH
group in compounds in which R3 is a hydrogen atom being optionally protected during the reaction;
(b) in the preparation of a compound in which R3 is alkyl or aralkyl, esterifying the corresponding compound in which R3 is a hydrogen atom;
(d) reducing a corresponding compound in which X is an acetylene group; or (e) in the preparation of a salt, treating a compound of formula (1) with an acid or (where R3 is a hydrogen atom) with a base, or converting one salt into another by exchange of cation.

2. A process according to claim 1 for the preparation of a compound of general formula (1) in which Y is morpholino, dioxothiamorpholino, homomorpholino, thiamorpholino or piperidino; or a physiologically acceptable salt or solvate thereof; which process comprises carrying out any one of reactions (a), (b), (d) or (e) defined in claim 1 employing a starting material for each said reaction in which Y is as defined above.

3. A process according to claim 1 for the preparation of a compound of general formula (1) in which X is cis-CH=CH-;
or a physiologically acceptable salt or solvate thereof;
which process comprises carrying out any one of reactions (a), (b) or (e) defined in claim 1 employing a starting material for each said reaction in which X is as defined above, or carrying out reaction (d) and, if necessary, isolating the cis isomer from the reaction product.

4. A process according to claim 1 for the preparation of a compound of general formula (1) in which R1 is -(CH2)2COOR3 where R3 is a hydrogen atom or C1-3 alkyl; or a physiologically acceptable salt or solvate thereof; which process comprises carrying out reaction (a) defined in claim 1 employing a compound of formula (2) in which R1a is the same as R1 defined above or -(CH2)2CH2OH or -(CH2)2CHO; or carrying reaction (b) employing said corresponding compound in which R1 is -(CH2)2COOH and the esterifying compound is a C1-3 alkyl compound; or carrying out reaction (d) in which the corres-ponding compound has a group R1 as defined above; or carrying out reaction (e) to form a salt of the compound of formula (1) in which R1 is -(CH2)2COOH.

5. A process according to claim 1 for the preparation of a compound of general formula (1) in which R2 is phenyl (C1-3)alkyl in which the phenyl group is substituted by C1-3 alkylthio, thienyl or phenyl (optionally substituted by C1-3 alkyl, C1-3 alkoxy, halogen or phenyl); or cinnamyl; or a physiologically acceptable salt or solvate thereof; which process comprises carrying out any one of reactions (a), (b), (d) or (e) as defined in claim 1 employing the starting material for each said reaction in which R2 is as defined above.

6. A process according to claim 1 for the preparation of a compound of general formula (1) in which R2 is phenyl (C1-3) alkyl in which the phenyl group is substituted by phenyl, C1-3 alkylthio, C1-3 alkoxyphenyl or halophenyl;

or cinnamyl; or a physiologically acceptable salt or solvate thereof; which process comprises carrying out any one of reactions (a), (b), (d) or (e) as defined in claim 1 employing the starting material for each said reaction in which R2 is as defined above.

7. A process according to claim 1 for the preparation of a compound of general formula (1) in which:
X is cis -CH=CH-;
R1 is -(CH2)2COOH;
Y is morpholino or piperidino;
R2 is phenyl (C1-3) alkyl in which the phenyl group is substituted by phenyl, C1-3 alkylphenyl, C1-3 alkoxyphenyl or halophenyl; or cinnamyl, or a physiologically acceptable salt or solvate thereof;
which process comprises:
carrying out reaction (a) as defined in claim 1 employing said compound of formula (2) in which X, Y and R2 are as defined above and R1a represents -(CH2)2COOH (in which the -COOH
is optionally protected), -(CH2)2CH2OH or -(CH2)2CHO;
carrying out reaction (d) employing said corresponding compound in which R1, Y and R2 are as defined above, followed if necessary by isolation of the cis isomer; or carrying out reaction (e) on a compound of formula (1) in which X, R1, Y and R2 are as defined above, or an ester or salt theeof.

8. A process according to claim 1 for the preparation of a compound of general formula (1) in which:
X is cis -CH=CH-;
R1 is -(CH2)2COOH;
Y is morpholino;
R2 is 1,1'-biphenylmethyl; 1,1'-biphenylmethyl substituted in the 4'-position by methyl, methoxy or chloro or in the 3'-position by methoxy;
1,1'-biphenylpropyl; or cinnamyl;
or a physiologically acceptable salt or solvate thereof;
which process comprises:

carrying out reaction (a) as defined in claim 1 employing said compound of formula (2) in which X, Y and R2 are as defined above and R1a represents -(CH2)2COOH (in which the -COOH is optionally protected),-(CH2)2CH2OH or -(CH2)2CHO;
carrying out reaction (d) employing said corresponding compound in which R1, Y and R2 are as defined above, followed if necessary by isolation of the cis isomer; or carrying out reaction (e) on a compound of formula (1) in which X, R1, Y and R2 are as defined above, or an ester or salt thereof.

9. A process according to claim 1 for the preparation of a compound of general formula (1) in which the carbon atom carrying the -(CH2)2XR1 group is in the R-configuration;
or a physiologically acceptable salt or solvate thereof;
which process comprises carrying out any one of reactions (a), (b), (d) or (e) either using the R-configuration isomer of the starting material or separating the R-configuration product from the reaction product if an isomer mixture is formed.

10. A process for the preparation of [1.alpha.(Z),2.beta.,5a.alpha.]-(?)-7-[5[[(1,1'-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid or a physiologically acceptable salt or solvate thereof; which process comprises:
(a) oxidising a compound of formula (2) (as defined in claim 1) in which R2 is biphenylmethyl, X is cis-CH=CH-, Y is morpholino and R1a is -(CH2)2CH2OH, -(CH2)2CHO or -(CH2)2COOH (the latter -COOH group being optionally protected during the reaction);
(d) reducing the corresponding 4-heptynoic acid, or (e) in the preparation of a salt, treating the said compound with an acid or a base, or converting one salt into another by exchange of cation.

11. A process for the preparation of [1R[1.alpha.(Z),2.beta.,5.alpha.]]-(-)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid and the physicologically acceptable salts and solvates thereof; which process comprises:
(a) oxidising a compound of formula (2) (as defined in claim 1) in which R2 is biphenylmethyl, X is cis-CH=CH-, Y is morpholino and R1a is -(CH2)2CH2OH, -(CH2)2CHO or -(CH2)2COOH (the latter -COOH group being optionally protected during the reaction);
(d) reducing the corresponding 4-heptynoic acid, or (e) in the preparation of a salt, treating the said compound with an acid or a base, or converting one salt into another by exchange of cation, wherein, in the above reactions, the starting material employed has the carbon atom carrying the -(CH2)2XR1a or -(CH2)2XR1 group in the R-configuration, or the R-configuration isomer is isolated from the reaction product.

12. A process according to claim 10 wherein the calcium salt of the said compound is formed by treating the compound with a basic calcium compound or ion in step (e).

13. A process according to claim 11 wherein the calcium salt of the said compound is formed by treating the compound with a basic calcium compound or ion in step (e).

14. A process according to claim 10 wherein the piperidine, piperazine or N,N-dimethyl-piperazine salt of said compound is formed by treating said compound with piperidine, piperazine or N,N-dimethyl-piperazine.

15. A process according to claim 11 wherein the piperidine, piperazine or N,N-dimethyl-piperazine salt of said compound is formed by treating said compound with piperidine, piperazine or N,N-dimethyl-piperazine.

16. Compounds of the general formula (1) wherein X is cis or trans -CH=CH-;
R1 is straight or branched C1-7 alkyl bearing as a terminal substituent -COOR3 where R3 is a hydrogen atom, C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which has 5 to 3 ring members selected from pyrrolidino, piperidino, morpholino, piperazino, thiamorpholino, 1-dioxothiamorpholino, homomorpholino, and hexamethyleneimino;
R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-ally substituted by phenyl (the phenyl being optionally substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7 cycloalkyl or phenyl (C1-4 alkyl), biphenyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or halogen), or naphthyl; (iii) C1-12 alkyl; (iv) C1-5 alkyl substituted by (a) phenyl [optionally substituted by halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-4 hydroxyalkoxy, trifluoro-methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-methylaminomethyl, carboxamido (-CONH2), thiocarboxamido (-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6 are the same or different and are each a hydrogen atom or C1-4 alkyl, or where -NR5R6 is a saturated heterocyclic amino group as defined above for Y), C1-3 alkylthio, C1-3 alkylsulphinyl, C1-3 alkylsulphonyl, phenylalkyl having a C1-3 alkyl portion, aminosulphonyl, C1-3 alkanoylamino-sulphonyl, phenylsulphonyl (the phenyl portion being optionally substituted by C1-3 alkyl or C1-3 alkoxy), nitro, or thienyl], (b) biphenyl toptionally substituted by phenyl or one or two C1-4 alkyl, C1-4 alkoxy, halogen substituents), or (c) naphthyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates thereof; whenever prepared by the process of claim 1 or an obvious chemical equivalent.

17. Compounds as claimed in claim 16 in which Y is morpho-lino, dioxothiamorpholino, homomorpholino, thiamorpholino or piperidino, whenever prepared according to the process of claim 2, or an obvious chemical equivalent.

18. Compounds as claimed in claim 16 in which X is cis -CH-CH-, whenever prepared according to the process of claim 3, or an obvious chemical equivalent.

19. Compounds as claimed in claim 16 in which R1 is -(CH2)2COOR3 where R3 is a hydrogen atom or C1-3 alkyl, whenever prepared according to the process of claim 4, or an obvious chemical equivalent.

20. Compounds as claimed in claim 16 in which R2 is phenyl (C1-3) alkyl in which the phenyl group is substituted by C1-3 alkylthio, thienyl, or phenyl (optionally substituted by C1-3 alkyl, C1-3 alkoxy, halogen or phenyl); or cinnamyl, whenever prepared according to the process of claim 5, or an obvious chemical equivalent.

21. Compounds as claimed in claim 16 in which R2 is phenyl (C1-3) alkyl in which the phenyl group is substituted by phenyl, C1-3 alkylphenyl, C1-3 alkoxy-phenyl or halophenyl; or cinnamyl, whenever prepared according to the process of claim 6, or an obvious chemical equivalent.

22. Compounds as claimed in claim 16 in which:
X is cis -CH=CH-;
R1 is -(CH2)2COOH;
Y is morpholino or piperidino;
R2 is phenyl (C1-3) alkyl in which the phenyl group is substituted by phenyl, C1-3 alkylphenyl, C1-3 alkoxyphenyl or halophenyl; or cinnamyl;
whenever prepared according to the process of claim 7, or an obvious chemical equivalent.

23. Compounds as claimed in claim 16 in which:
X is cis -CH=CH-;
R1 is -(CH2)2COOH;
Y is morpholino;

R2 is 1,1'-biphenylmethyl; 1,1'-biphenylmethyl substituted in the 4'-position by methyl, methoxy or chloro or in the 3'-position by methoxy;
1,1'-biphenylpropyl; or cinnamyl;
or a physiologically acceptable salt or solvate thereof;
whenever prepared according to the process of claim 8, or an obvious chemical equivalent.

24. Compounds as claimed in claim 16 in which the carbon atom carrying the -(CH2)2XR1 group is in the R-configuration, whenever prepared according to the process of claim 9, or an obvious chemical equivalent.

25. [1.alpha.(Z),2.beta.,5.alpha.]-(?)-7-[5-[[(1,1'-biphenyl)-4-yl] methoxy]
-2-(4-morpholino)-3-oxocyclopentyl]-4-heptenoic acid and the physiologically acceptable salts and solvates thereof, whenever prepared according to the process of claim 10, or an obvious chemical equivalent.

26. [1R[1.alpha.(Z),2.beta.,5.alpha.]]-(-)-7-[5-[[(1,1'-biphenyl)-4-yl]
methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid and the physiologically acceptable salts and solvates thereof, whenever prepared according to the process of claim 11, or an obvious chemical equivalent.

27. The calcium salt of the compound claimed in claim 25;
whenever prepared according to the process of claim 12, or an obvious chemical equivalent.

28. The calcium salt of the compound claimed in claim 26 whenever prepared according to the process of claim 13, or an obvious chemical equivalent.

29. The piperidine, piperazine or N,N-dimethylpiperazine salt of the compound claimed in claim 25; whenever prepared according to the process of claim 14, or an obvious chemical equivalent.

30. The piperidine, piperazine or N,N-dimethylpiperazine salt of the compound claimed in claim 26; whenever prepared according to the process of claim 15, or an obvious chemical equivalent.

31. A process for the preparation of a compound of the general formula (l) wherein X is cis or trans -CH=CH-;
R1 is straight or branched C1-7 alkyl bearing as a terminal substituent -COOR3 where R3 is a hydrogen atom, C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which has 5 to 8 ring members selected from pyrrolidino, piperidino, morpholino, piperazino, thiamorpholino, 1-dioxothiamorpholino, homomorpholino, and hexamethyleneimino;
R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-ally substituted by phenyl (the phenyl being optionally substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7 cycloalkyl or phenyl (C1-4 alkyl), biphenyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or halogen), or naphthyl; (iii) C1-12 alkyl; (iv) C1-5 alkyl substituted by (a) phenyl [optionally substituted by halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-4 hydroxyalkoxy, trifluoro-methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-methylaminomethyl, carboxamido (-CONH2), thiocarboxamido (-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6 are the same or different and are each a hydrogen atom or C1-4 alkyl, or where -NR5R6 is a saturated heterocyclic amino group as defined above for Y), C1-3 alkylthio, C1-3 alkylsulphinyl, C1-3 alkylsulphonyl, phenylalkyl having a C1-3 alkyl portion, aminosulphonyl, C1-3 alkanoylamino-sulphonyl, phenylsulphonyl (the phenyl portion being optionally substituted by C1-3 alkyl or C1-3 alkoxy), nitro, or thienyl], (b) biphenyl (optionally substituted by phenyl or one or two C1-4 alkyl, C1-4 alkoxy, halogen substituents), or (c) naphthyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates thereof; which process comprises:
(a) oxidising a compound of formula (2) in which R1a is a straight or branched alkyl group substituted by -COOR3, -CH2OH or -CHO, the -COOH
group in compounds in which R3 is a hydrogen atom being optionally protected during the reaction.

32.A process for the preparation of a compound of the general formula (1) wherein X is cis or trans -CH=CH-;
R1 is straight or branched C1-7 alkyl bearing as a terminal substituent -COOR3 where R3 is C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which has 5 to 8 ring members selected from pyrrolidino, piperidino, morpholino, piperazino, thiamorpholino, 1-dioxothiamorpholino, homomorpholino, and hexamethyleneimino;
R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-ally substituted by phenyl (the phenyl being optionally substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7 cycloalkyl or phenyl (C1-4 alkyl), biphenyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or halogen), or napthyl; (iii) C1-12 alkyl; (iv) C1-5 alkyl substituted by (a) phenyl [optionally substituted by halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-4 hydroxyalkoxy, trifluoro-methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-methylaminomethyl, carboxamido (-CONH2), thiocarboxamido (-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6 are the same or different and are each a hydrogen atom or C1-4 alkyl, or where -NR5R6 is a saturated heterocyclic amino group as defined above for Y), C1-3 alkylthio, C1-3 alkylsulphinyl, C1-3 alkylsulphonyl, phenylalkyl having a C1-3 alkyl portion, aminosulphonyl, C1-3 alkanoylamino-sulphonyl, phenylsulphonyl (the phenyl portion being optionally substituted by C1-3 alkyl or C1-3 alkoxy), nitro, or thienyl], (b) biphenyl (optionally substituted by phenyl or one or two C1-4 alkyl, C1-4 alkoxy, halogen substituents), or (c) naphthyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates thereof; which process comprises:
esterifying the corresponding compound in which R3 is a hydrogen atom.

33 A process for the preparation of a compound of the general formula (1) wherein X is cis or trans -CH-CH-;
R1 is straight or branched C1-7 alkyl bearing as a terminal substituent -COOR3 where R3 is a hydrogen atom, C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which has 5 to 8 ring members selected from pyrrolidino, piperidino, morpholino, piperazino, thiamorpholino, 1-dioxothiamorpholino, homomorpholino, and hexamethyleneimino;

R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-ally substituted by phenyl (the phenyl being optionally substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7 cycloalkyl or phenyl (C1-4 alkyl), biphenyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or halogen), or naphthyl; (iii) C1-12 alkyl; (iv) C1-5 alkyl substituted by (a) phenyl [optionally substituted by halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-4 hydroxyalkoxy, trifluoro-methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-methylaminomethyl, carboxamido (-CONH2), thiocarboxamido (-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6 are the same or different and are each a hydrogen atom or C1-4 alkyl, or where -NR5R6 is a saturated heterocyclic amino group as defined above for Y), C1-3 alkylthio, C1-3 alkylsulphinyl, C1-3 alkylsulphonyl, phenylalkyl having a C1-3 alkyl portion, aminosulphonyl, C1-3 alkanoylamino-sulphonyl, phenylsulphonyl (the phenyl portion being optionally substituted by C1-3 alkyl or C1-3 alkoxy), nitro, or thienyl], (b) biphenyl (optionally substituted by phenyl or one or two C1-4 alkyl, C1-4 alkoxy, halogen substituents), or (c) naphthyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates thereof; which process comprises:
in the preparation of a salt, treating a compound of formula (1) with an acid or (where R3 is a hydrogen atom) with a base, or converting one salt into another by exchange of cation.

34. A process for the preparation of a compound of the general formula (1) wherein X is cis or trans -CH=CH-;
R1 is straight or branched C1-7 alkyl bearing as a terminal substituent -COOR3 where R3 is a hydrogen atom, C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which has 5 to 8 ring members selected from pyrrolidino, piperidino, morpholino, piperazino, thiamorpholino, 1-dioxothiamorpholino, homomorpholino, and hexamethyleneimino;
R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-ally substituted by phenyl (the phenyl being optionally substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7 cycloalkyl or phenyl (C1-4 alkyl), biphenyl (optionally substituted by C1-4 alkyl, C1-4 alkoxy or halogen), or naphthyl; (iii) C1-12 alkyl; (iv) C1-5 alkyl substituted by (a) phenyl [optionally substituted by halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-4 hydroxyalkoxy, trifluoro-methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-methylaminomethyl, carboxamido (-CONH2), thiocarboxamido (-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6 are the same or different and are each a hydrogen atom or C1-4 alkyl, or where -NR5R6 is a saturated heterocyclic amino group as defined above for Y), C1-3 alkylthio, C1-3 alkylsulphinyl, C1-3 alkylsulphonyl, phenylalkyl having a C1-3 alkyl portion, aminosulphonyl, C1-3 alkanoylamino-sulphonyl, phenylsulphonyl (the phenyl portion being optionally substituted by C1-3 alkyl or C1-3 alkoxy), nitro, or thienyl], (b) biphenyl (optionally substituted by phenyl or one or two C1-4 alkyl, C1-4 alkoxy, halogen substituents), or (c) naphthyl (optionally substituted by Cl-4 alkyl, Cl-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates thereof; which process comprises:
reducing a corresponding compound in which X is an acetylene group

35. A process for the preparation of a compound of the general formula (1) wherein X is cis or trans -CH=CH-;
Rl is straight or branched Cl-7 alkyl bearing as a terminal substituent -COOR3 where R3 is a hydrogen atom, C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which has 5 to 8 ring members selected from pyrrolidino, piperidino, morpholino, piperazino, thiamorpholino, l-dioxothiamorpholino, homomorpholino, and hexamethyleneimino;
R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-ally substituted by phenyl (the phenyl being optionally substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7 cycloalkyl or phenyl (Cl-4 alkyl), biphenyl (optionally substituted by Cl-4 alkyl, Cl-4 alkoxy or halogen), or naphthyl; (iii) Cl-l2 alkyl; (iv) Cl-5 alkyl substituted by (a) phenyl [optionally substituted by halogen, hydroxy, C1-6 alkyl, Cl-6 alkoxy, Cl-4 hydroxyalkoxy, trifluoro-methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-methylaminomethyl, carboxamido (-CONH2), thiocarboxamido (-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6 are the same or different and are each a hydrogen atom or Cl-4 alkyl, or where -NR5R6 is a saturated heterocyclic amino group as defined above for Y), Cl-3 alkylthio, Cl-3 alkylsulphinyl, Cl-3 alkylsulphonyl, phenylalkyl having a Cl-3 alkyl portion, aminosulphonyl, Cl-3 alkanoylamino-sulphonyl, phenylsulphonyl (the phenyl portion being optionally substituted by Cl-3 alkyl or C1-3 alkoxy1), nitro, or thienyl], (b) biphenyl (optionally substituted by phenyl or one or two Cl-4 alkyl, Cl-4 alkoxy, halogen substituents), or (c) naphthyl (optionally substituted by Cl-4 alkyl, Cl-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates thereof; which process comprises:
(a) oxidising a compound of formula (2) in which Rla is a straight or branched alkyl group substituted by -COOR3, -CH20H or -CHO;
(b) in the preparation of a compound in which R3 is alkyl or aralkyl, esterifying the corresponding compound in which R3 is a hydrogen atom;
(d) reducing a corresponding compound in which X is an acetylene group; or (e) in the preparation of a salt, treating a compound of formula (1) with an acid or (where R3 is a hydrogen atom) with a base, or converting one salt into another by exchange of cation.