GB2070591A

GB2070591A - Prostanoid compounds and their preparation and pharmaceutical formulation

Info

Publication number: GB2070591A
Application number: GB8100483A
Authority: GB
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1980-01-09
Filing date: 1981-01-08
Publication date: 1981-09-09
Also published as: AU6603681A; EP0032432B1; GB2070591B; AU542949B2; EP0032432A1; DE3171437D1

Description

1 GB 2 070 591 A 1

SPECIFICATION Prostanoid Compounds and Their Preparation and Pharmaceutical Formulation

Prostaglandins are a class of naturally occurring cyclopentane derivatives which are biologically active in many physiological systems and they and substances which antagonise their effects are 5 therefore of considerable interest in both human and veterinary medicine.

In view of the activity found in the natural prostaglandins, considerable effort has been directed towards the preparation of synthetic analogues. Many such compounds have been described, and in general it has been reported that these compounds possess activity within the same spectrum as the natural compounds. The synthetic compounds can however have increased selectivity of action, longer duration of activity or different potency, and in some cases they can antagonise the activity of natural 10 prostaglandins.

In most of the synthetic prostanoids previously reported, the side chains have been attached to the cyclopentane ring via carbon atoms, as in the natural prostaglandin structure. We have now found that a new class of prostanoid compounds in which the a-side chain has the same or similar structure to that of the natural compounds, while the P-side chain is attached to the ring via a nitrogen atom and the ring is also substituted by certain aralkoxy or heteroaralkoxy groups. Compounds in this class have shown prostanoid activity in our tests and in particular they inhibit blood platelet aggregation and have bronchodilatatory action.

The invention provides prostanoids of the general formula (1) oe' H2XR 1 A (.1) 20 Y in which 4 A represents OR 4- OR4 (a) or (b) HO 0 X is cis or trans -CH=CH- or -(CH2)2-; R' is straight or branched Cl-7 alkyl bearing as a terminal substituent - COOR10 where R10 is a 25 hydrogen atom, Cl-, alkyl or C7-1. aralkyl (e.g. benzyi); Y represents (i) -NIR2113 where R2 and R3 are the same or different and are each a hydrogen atom, aralkyl having a C,-7 alkyl portion or Cl-10 alkyl, both alkyls being optionally substituted by one or more substituents -OR7 (where R7 is a hydrogen atom, C,-7 alkyl, aryl or aralkyl having a Cl-4 alkyl portion) or-NIRI1R9 (where K' and R9 are the same or different and are each a hydrogen atom or Cl-4 30 alky], or where -NRIR11 is a saturated heterocyclic amino group (as defined below for Y); any aryl group in R 2 or R3 being optionally substituted by one or more Cl-4 alkyl or trifluoromethyl groups; always provided that the total number of carbon atoms in the group -NIR2R 3 does not exceed 15; or 0i) a saturated heterocyclic amino group which has 5-8 ring members and (a) optionally contains in the ring -0-1 -S-, -S02-NRI4(where R 14 is a hydrogen atom, Cl-7 alkyl or aralkyl 35 having a C,-4 alkyl portion), >C(O1-1)R6 (where R6 is a hydrogen atom, Cl- 7 alkyl, phenyl or aralkyl having a Cl-4 alkyl portion), and/or (b) is optionally substituted by one or more Cl-4 alkyl groups; R4 is (i) aralkyl (having a C,-3 alkyl portion and the aryl portion being substituted by Cl-, alkylthio, Cl-3 alkyisulphinyi, Cl-3 alky[sulphonyi, Cl-3 alkanoylamino, aroylamino (e.g. benzoylamino), phenylalkyl having a C,-3 alkyl portion, aminosulphony], (the amino group being optionally substituted 40 by one or two C,-3 alkyl groups), Cl-3 alkanoylaminosulphonyl (the amino group being optionally substituted by Cl, alkyl), phenyisulphonyl (the phenyl portion being optionally substituted by Cl-3 alkyl), nitro, tetrazol-5-yI, phenyl substituted by R5 (where R5 is Cl-4 alkyl, C,-, alkoxy, halogen or phenyl), or thienyl); or (ii) the group:

where alk is Cl-3 alkylene; Z is 0 or S; R' l is a hydrogen atom; C,-, alkyl; C,-, alkoxy; aryl (e.g. phenyl) or phenylaikoxy or phenylalkyl having a Cl-3 alkyl portion (the aryl portion in each case being optionally substituted by C,-3 alkyl, Cl-3 50 alkoxy or halogen); aryloxy (e.g. phenoxy); C5-7 cycloalkyl; halogen or nitro; -alk Y%., R' l 4T Z,3 2 GB 2 070 591 A 2 and the physiologically acceptable salts thereof.

The formulae used herein are to be understood to depict either or both optical isomers of each of the compounds concerned as well as mixtures of the isomers, including racemates, even though the precise structure as set out only relates to one optical isomer.

Compounds having the ring type (b) are particularly important.

In the group -CH2XRI, the alkyl portion of the group R' may for example contain 2-5 carbon atoms (straight or branched) and is preferably (CH2)3COORIO. R10 is preferably a hydrogen atom or Cl-4 alkyl, e.g. methyl, particularly hydrogen.

b When R' is terminally substituted by -COOH, the compounds are capable of salt formation with bases, examples of suitable salts being alkali metal (e.g. sodium and potassium), alkaline earth metal 10 (e.g. calcium), ammonium, substituted ammonium (e.g. tromethamine or di methyl am inoethanol), piperazine, morpholine, piperidine and tertiary amine (e.g. triethylamine) salts.

1 X is preferably -CH2CHi-- or cis -CH=CH-, particularly the latter.

In the group Y, when one of R 2 and R3 is alkyl or substituted alkyl, the alkyl group preferably contains no more than 7 (e.g. 2-7) carbon atoms and preferably has a straight chain. Examples of such groups are n-hexyl and n-hep'tyi. In such compounds, the other group of R 2 or R 3 is preferably hydrogen or methyl. When R 2 orR 3 is an aralkyl group, it may for example be benzyi, phenethyl or phenpentyl.

In the optional substituent -OR 7 on R 2 or R3, examples of R 7 are a hydrogen atom, methyl, n- butyl, phenyl, benzyi and phenethyl. The optional amino substituent - NRI1R9 may for example be -H2. -NHMe, --NHEt, -NIVIe2 or -NEt2. These optional substituents may for example be carflecl at the P-position, as in P-hydroxyalkyl groups. Two -OR7 groups may be present, particularly on an R 2 or R 3 alkyl group; for example, there may be a hydroxy group at the 0-position and a scond -OR 7 group at the terminal position.

Aryl (e.g. phenyl) groups in R2 and R3 may themselves be substituted, e.g. by C, alkyl or 25 trifluoromethyl.

Compounds in which Y is a saturated heterocyclic amino group are however preferred. The types of heterocyclic group which are generally preferred are those in which the ring has 5-8 members and (a) optionally contains -0-, -S-, -SO2- or -NRI4- and/or (b) is optionally substituted by one or more C,-4 alkyl (e.g. methyl) groups. The groups may for example have a 5, 6 or 7-membered ring, e.g. pyrrolidino, piperidino, morpholino, piperazino, thiamorpholino, 1 - dioxothiamorpholino, homomorpholino and hexamethyleneimino.

Examples of the optional substituents which may be present on a second nitrogen atom in the ring are methyl, ethyl and benzyl. The carbon atoms of the heterocyclic rings may for example be substituted by methyl or ethyl. The group >C(OH)RO may for example be present in a piperidino ring 35 and when R6 is other than hydrogen it may for example be methyl, ethyl or butyl.

Compounds in which Y is a morpholino, dioxothiamorpholino or piperidino group are particularly preferred.

The amino group in the group Y enables the compounds to form salts with inorganic or organic acids, e.g. hydrochlorides, sulphates, acetates, maleates and succinates.

When R4 is aralkyl it is preferably an aryimethyl (particularly benzyi) group substituted by Cl-3 1 alkylthio (e.g. methylthio), Cl, alkylsulphinyl (e.g. methyisulphinyl), Cl3 alkanoylamino (e.g.

acetylamino), C,-3 alkylsulphonyl (e.g. methyIsulphonyl), aryisulphonyl (e.g. phenyisulphonyl), aminosulphonyl (e.g. dimethylaminosulphonyl), phenylalkyl (e.g. phenethyl or benzyi), phenyl substituted by the groups R5 (where R5 represents Cl Cl4 -4 alkyl (e.g. methyl), alkoxy (e.g. methoxy), 45 halogen (e.g. chlorine), or phenyl), or thienyl. Particularly preferred substituents of this type are phenylalkyl (e.g. phenethyl or benzyi), or, more particularly, phenyl substituted by Cl-3 alkoxy (e.g.

methoxy) or Cl-3 alkyl (e.g. methyl).

When R 4 is a group of the type (H) the alkylene group is preferably methylene, and Z is preferably S. Where Z is S, the thienyl group is preferably substituted by Cl-3 alkyl (e.g. methyl), aryl (e.g. phenyl, so optionally substituted by C,-, alkoxy, e.g. methoxy), C, cycloalkyl (e.g. cyclohexyl), halogen (e.g.

bromine) or phenalkyl (e.g. phenethyl), and where Z is 0 the furanyl group is preferably substitued by an aryl, e.g phenyl group. Particularly preferred groups of this type are phenyithienylaikyl and alkoxyphenyithienylaikyi.

A particularly preferred group of compounds has the formula 1 (b) where:

X is cis -CH=CH-, R' is -(CH2)3COOH, Y is morpholino, piperidino, or 1-dioxothiamorpholino, and R4 is benzyl substituted by phenethyl, benzy] methoxyphenyl or methylphenyl, or is methoxyphenylthienyimethyl.

As indicated above, our tests have shown that compounds of formula (1) inhibit blood platelet aggregation and/or have bronchodilatatory activity. The test we have used for bronchodilatation is as described by K. M. Lulich, et al in British Journal of Pharmacology 58, 71-79, (1976) except guinea pig lung is used instead of cat lung. The test for inhibition of platelet aggregation is as described by G.

3 GB 2 070 591 A 3 V. Born in Nature 194, 927-929 (1962) except collagen is used instead of ADP as the pro aggregatory agent.

The compounds are thus of interest in the treatment of asthma and as antithrombotic agents for use in the treatment and prevention of cardiovascular diseases or conditions such as arteriosclerosis, atherosclerosis and myocardial infarcts. They may be formulated for use in convenional manner, with 5 one or more pharmaceutical carriers.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups, or suspensions prepared by, conventional means with acceptable excipients.

The compounds may be formulated for parenteral administration by bolus injections or continuous infusion. Formulations for injections may be presented in unit dosage form in ampoules, or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, e.g. sterile pyrogen-free water.

For administration by inhalation the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a nebullser, or as a cartridge from which the powdered composition may be inhaled with the aid of a suitable device. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

For use as antithrombotic agents, the compounds are preferably administered orally, for example 20 in amounts of 0. 1 to 10 mg/kg body weight, 1 to 4 times daily. For use in the treatment of asthma, the compounds may also be administered orally in amounts of 0.1 to 10 mg/kg body weight, 1 to 4 times daily; preferably however they are administered by inhalation in the form of aerosols or solutions for nebulisers, at doses varying from 0.3 to 30 mg, 1 to 4 times daily. The compounds may be used in combination with other anti-asthmatic agents. It will be appreciated that the precise dose administered 25 will always depend on the age and condition of the patient.

The compounds of formula (1) may be prepared by selection and adaptation of methods known in prostanoid chemistry (see for example British Patent Specification 2028805M. Method (a) below is particularly important in forming certain prostanoids of the desired class, and other compounds in the class can be prepared from them by known techniques for example using one or more of methods (b) 30 to (m) below.

The following reactions will frequently require the use of (or will conveniently be applied to) starting materials having protected functional groups (e.g. hydroxy). It is to be understood that references to the use of starting materials of a particular structure are intended to include starting materials having protected functional groups. Certain of the reactions described below are capable of 35 affecting other groups in the starting material which are desired in the @nd product, and this must be taken into account when performing multi-stage reactions.

In the discussion below, the groups X and Y and the various R groups are as defined above except where otherwise indicated.

(a) Compounds of formula (2) qR4 ja R :y ow (2) (where R18 is as defined above for R' where RIO is a hydrogen atom) may be prepared by reacting lactols of formula (3) or their aldehyde isomers of formula (3a) Y OR 0 ON 6H (3) 6R4' with appropriate Wittig reagents, e.g. a phosphorane of formula R12P=CHRI, (where R 12 is C,-, alkyl or 45 3 aryl, e.g. monocyclic aryl such as phenyl), or a salt thereof, e.g. the potassium salt. Suitable reaction solvents include hydrocarbons (e.g. benzene and toluene), ethers (e.g. tetra hydrofu ran), dialkylsulphoxides (e.g. dimethylsulphoxide), alcohols and halogenated hydrocarbons. The reaction may be carried out at any suitable temperature up to 501C, preferably at room temperature.

4 GB 2 070 591 A 4 The reaction is particularly suitable for the preparation of compounds in which R' is terminally substituted by -COOH (in salt form). Any hydroxy group in Y should preferably be in a protected state prior to this reaction. Suitable hydroxy protecting groups are described below. Any -NH, group present should also be protected, e.g. by t-butoxycarbonyl.

Except as regards the nature of R 4, this reaction is the same as process (a) of British Patent Specification 2028805A. The intermediates of formulae (3) and (3a) may thus be prepared by the methods described in that specification, using starting materials containing the desired R 4 group.

These starting materials may themselves be prepared by the same general methods as described in Specification 2028805A. However, when R 41S an aralkyl group substituted by phenyimethyi, substituted phenyl or thienyl, it can be more convenient to introduce first an aralkyl R 4 group substituted by halo; after the formation of the intermediate lactone, this group can then be modified to form the desired R 4 group, for example by treatment with the appropriate aryl or benzyl zinc halide in the presence of a catalyst such as M(PPH34 or C12Pcl (PPh3)2/diisobutylaluminium hydride in a solvent such as tetrahydrofuran at e.g. 1 00-ambient temperature.

(b) Compounds of ring type (b) may be prepared by oxidising the corresponding hydroxy compound of ring type (a), for example with a CrIll oxidising reagent, e. g. Jones reagent, at -101 to room temperature, preferably -10-01, in a solvent such as acetone. Other conventional methods can also be used, for example using dimethyisulphoxide and a suitable electrophilic reagent, such as acetyl bromide, oxalyl chloride, thionyl chloride, or dicyclohexylcarbodlimide in a hydrocarbon solvent such as toluene at low temperature e.g.-700. With the latter reagent, the reaction is preferably carried out in 20 the presence of trifluoroacetic acid or its pyridinium salt.

Other suitable reagents are N-chforosuccinimidedimethyisulphide complex (used for example in a hydrocarbon solvent, such as toluene, e.g. at 0-50), and pyridine-sulphur trioxide complex in di methyl su lphoxide (e.g. at 01 to room temperature).

When the a-side chain has a terminal -COOH group (i.e. when RIO is hydrogen), better yields are 25 sometimes obtained by prior protecting the carboxyl group, for example in the form of a trialkyl (e.g.

trimethyl or triethyl) silyl ester.

Any other hydroxy group present should be protected in this reaction.

(c) Compounds in which RIO is alkyl or aralkyl can be prepared by esterification of the corresponding carboxylic acid (in which RIO is hydrogen). Conventional esterification techniques may 30 be used, reaction with a diazoalkene being preferred. The alkyl esters may also be formed by reaction with an appropriate alcohol in the presence of a mineral acid, e.g. hydrochloric or sulphuric acid.

(d) Compounds in whch R' is terminally substituted by a -COOH group can be prepared by saponifying a corresponding ester, e.g. using KOH or NaOH in methanol.

(e) Compounds in which X is trans -CH=CH- may be prepared by isomerising the corresponding cis compound. The isomerisation may 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 and any suitable temperature up to reflux. Where an oxo group is desired in the end product, it should be introduced after this reaction.

(f) Compounds in which X is -(CH2)._ may be prepared by catalytic hydrogenation of a corresponding compound in which X is -CH=CH-. Conventional catalysts may be used, preferably palladium or platinum on carbon, in a suitable solvent (e.g. an alcohol such as methanol) e.g. at room temperature.

(g) Compounds of formula (1 a) may be prepared by etherification of the corresponding hydroxy compound (in which R represents hydrogen), for example by reaction with an appropriate halide (R 4) 45 Hal), for example by reaction at room temperature in the presence of a suitable base (e.g. sodium hydride) in a suitable solvent (e.g. dimethylformamide).

Any other hydroxy group present in the starting material (e.g. the ring hydroxy group) should be protected in this reaction.

Starting materials for this reaction may be prepared by the same general technique as described 50 above for process (a), using intermediates in which the group -OR 4 is a protected hydroxy group and removing the protecting group prior to etherification.

Starting materials of the formula (4) Y R 0 (where RIO is as defined above and -OR h represents a protected hydroxy group) may also be prepared 55 by method (b) of British Patent Specification 2028805A.

Q GB 2 070 591 A (h) Compounds having ring type (a) can be prepared by removing the protecting group from the corresponding compound in which the ring hydroxy group is protected, for example by reduction or acid or alkaline hydrolysis. This is discussed below in connection with hydroxy group protection.

(i) Compounds in which R 4 is aralkyl substituted by alkanoylamino may be prepared by acylation of the corresponding amine, e.g. with the appropriate acid anhydride in an organic base such as 5 pyridine at 01C.

(j) Compounds of formula (1 a) in which R4 is aralkyl substituted by alkylsulphinyl or alkylsulphonyl may be prepared by oxidation of the corresponding alkylthio compound with a peracid for example peracetic acid at room temperature.

(k) Compounds of formula (1 a) in which Y is a substituted amino group may be prepared by 10 substitution of the corresponding compound in which Y is -NH2.

This reaction may be performed by treating the starting material with a compound of the formula JR 13j, where J is a readily displaceable group (such as halo, e.g. iodo, or hydrocarbyisulphonyloxy, e.g. ptoluenesulphonyloxy) and R13 is the appropriate divalent group (e.g. (CH2)20(CH2)2--). The reaction may be carried out in a solvent such as acetonitrile or methanol, in the presence of a suitable base, e.g. 15 potassium carbonate or sodium bicarbonate.

Alternatively, the starting material may be reacted with an appropriate dialdehyde or diketone in the presence of a reducing agent. For example, reaction with glutardialdehyde gives a compound in which Y is piperidino. The reducing agents which may be used are those generally known for the reduction of imines, e.g. formic acid, or an alkali metal borohydride or cya noborohyd ride (e.g. sodium 20 borohydride or potassium cyanoborohydride, using an alcohol such as ethanol as solvent, suitably at room temperature, preferably at pH 4-6), or hydrogen in the presence of a metal catalyst, e.g.

palladium.

The amines required as starting materials may be prepared by reduction of the corresponding azide, for example as described for process (1). 25 (1) Compounds of ring type (a) in which Y is -NH2 and RIO is hydrogen may be prepared by reducing the corresponding compound in which Y represents an azido group.

Compounds in which X is -(CH,),-, may thus be prepared by catalytic hydrogenation, using for example platinum or palladium on carbon as thd datalyst. However, When dorhpdunds in which X is ---CH=CH- are required, selective reduction methods specific for the azide function should be used. 30 Examples of suitable reagents are zinc and sodium dihydrogen phosphate in a suitable solvent (e.g.

tetra hydrofu ran); zinc and methanol/sulphuric acid; or triphenyl phosphine followed by methanol/sulphuric acid.

The azido starting materials required for this reaction may be prepared by methods analogous to those for preparing the compounds of formula (2), using reagents in which Y is azido. These methods 35 are analogous to those of process (c) of British Patent Specification No.. 2028805A.

(m) Salts of the compounds of formula (1) may be prepared by conventional methods, e.g. by treatment with an acid or (where RIO is hydrogen) a base in a suitable solvent e.g. water or an organic solvent such as ether.

In the preparation of compounds of formula (1) the ring hydroxy group (or any other hydroxy 40 group present) will often be protected and its liberation will frequently be the last step in the preparation. Conventional methods of protection may be used, protection in the form of t butyidimethyisilyloxy or tetra hyd ropyra nyloxy groups being preferred. These groups may be removed by acid hydrolysis. The group may also be protected in the form of an alkanoyloxy group having up to 7 carbon atoms, e.g. acetoxy. Such groups may be removed by alkaline hydrolysis.

The examples below illustrate the invention. The preparation of the intermediates required is described first.

The preparation of the following intermediates is described in British Patent Specification 2028805 A:

Intermediate 4..

( )-3-endo-Hydroxy-2-exo-(4-morpholinyi)bicyclo[3.2.01-heptan-6-one Intermediate 5:

(3aa,4a,5p,6aa)-( )-Hexahydro-5-hydroxy-4-(4-morpholinyi)-2.Hcyclopenta(b)f uran-2-one Intermediate 6:

(3aa,4a,5p,6aa)-( )-Hexahydro-4-(4-morpholinyi)-5-(tetrahydro-2H-pyran-2yi)o xy-2H- 55 cyclopenta(b)furan-2-one Intermediate 7:

(3aa,4a,5p,6aa)-( )-Hexahydro-4-(4-morpholinyl)-5-(tetrahydro-2H-pyran-2yi) oxy-2H- cyclopenta(b)furan-2-ol 6 GB 2 070 591 A 6 Intermediate 8:

[1 a(Z),2p,3 a,5 a]-( )-M ethyl 7-[5-Acetoxy-2-(4-morpholinyi)-3[(tetrahydro-2H-pyran2- yi)oxyleyclopentyll-5-heptenoate Intermediate 9:

[1 a(Z),2p,3 cv,5 al-M ethyl 7-[5-Hydroxy-2-(4-morpholinyl)-3[(tetrahydro-2H-pyran-2- yi)oxyl cyclopentyll-5-h eptenoate intermediate 10:

[ 1 a(Z),2p,3 a,5 a]-( )-M ethyl 7- [5[4-Am ino (phenyl m ethoxy)1-3hydroxy-2-(4- morpholinyl)cyclopenyll-5-heptenoate Intermediatell:

( )-6-endo-(Phenyimethoxy)-8-anti-(4-thiomorpholinyi)-2-oxabicyclo[3.2.1 loctan-3-one Intermediate 41:

[1 a-(Z), 2p,3 a,5 a]-( )-M ethyl 7-[5-Hydroxy-2-(1 -piperidinyi)-3[(tetrahydro-2H-pyran-2yi)oxylcyclopentyll-5-heptenoate Temperatures are in 'C. The following abbreviations are used:

TI-C-thin layer chromatography, PE-petroleum ether (boiling at 40-601 unless otherwise stated), TI-IF-tetrahydrofuran, EA-ethyl acetate, PTSA-ptoluenesulphonic acid monohydrate, DMF--dimethy[formamide, DMSOdimethyisulphoxide, Dibal-diisobutyaluminium hydride.

Chromatography was carried out using silica gel. TLC was carried out using Si02. The following abbreviations illustrate the eluent used for the chromatography and TILC:

(A) 9:1 PE (b.p. 60-800)-EA; (B) 4:1 PE (b.p. 60-80')-EA; (C) 3:1 PEether; (D) ether-EA; (E) 9:1 EA-PE; (F) ether-PE; (G) 4:1 ether-PE; (H) 7:3 ether-PE; (1) 9:1 ether-methanol; (J) ether; (K) EA; (L) 19:1 ether-methanol; (M) 1:1 ether-PE (b.p. 60-800); (N) 9:1 EA-PE (b. p. 60-801); (0) EA-PE (b.p. 60-800); (P) 19:1 EA-methanol; (Q) 95:5 ether-methanol; (R) 85:15 EA-methanol; (S) 3:1 EA methanol; (T) 98:2 chloroform-methanol; (U) 95:5 EA-methanol; (V) 4:1 ether-methanol; (W) PE; (X) 25 9:1 EA-methanol; (Y) 7:3 EA-PE; W 3:2 ether-PE; (AB) 1:1 EA-PE; (AC) 4:1 ether-isopentane; (AD) 39:1 ether-methanol; (AE) 4:1 ether-PE hp. 60-801); (AF) ether-isopentane; (AG) chloroform; (AH) 97:3 chloroform-methanol; (AI) 7:3 EA-PE (b.p. 60-800); (AJ) 85:15 ethermethanol; (AK) 97:3 ether-methanol; AL 99:1 ether-methanol; (AM) ether-methanol.

Intermediate 1 1 -(Bromomethyl)-4-(2-phenylethyi)benzene A solution of methyl 4-(2-phenethenyi)benzoate (5.4 9) in EA (200 mi) was hydrogenated over pre reduced 10% Pd on charcoal (1 g) at atmospheric pressure. When hydrogen uptake had ceased the mixture was filtered and evaporated to give a solid (5.4 g).

A solution of the solid (4.7 g) in dry THF (20 mi) was added dropwise to a stirred suspension of 35 LiAH4 (0,59 g) in dry THF (20 mi) at 00. After 1 h Rochelle salt solution (50 mi) was added and the mixture extracted with EA (3x50 mi), washed with brine and dried (M9S04), P13r3 (0,81 mi) was added to a solution of the dried extracts (3.4 g) in dry ether (75 ml) at 01 and the mixture was stirred for 0.5 h.

Ice-water (70 mi) was added and stirring continued for a further 0.5 h. The aqueous phase was separated and extracted with ether (2x70 mi) washed with NaHC03 solution, brine and then dried (M9S04). Evaporation in vacuo gave the title compound as a solid (3.8 g) which was purified from PE (bp 60-800) to give material of m.p. 52-30.

Intermediate 2 [4'Methyi-(1,1 -biphenyi)-4-yil methanol 4-Methyi-(1,1'-biphenyi)-4-carboxylic acid, methyl ester (1.43 g) in ether (25 mi) and THF (25 45 rr.1) was added over 5 min to UAH4 (420 mg) in ether (25 mO. The mixture was stirred at room temperature for 1 h and then cooled in ice. Aqueous NaOH (1 M, 2.1 mi) was added and after stirring (15 min) excess anhydrous Na2S04 was added. The mixture was filtered and the filtrate evaporated to give a solid. Crystallisation from cyclohexane-methanol gave the title compound (1.04 g) m.p. 128 311 Intermediate 3 4-Bromomethyl-4'-mothyl (1,1 1-biphenyO To a cold (00) solution of Intermediate 2 (0.917 g) in dry CH2C12 (14 mi) was added PBr3 (0.29 mi). After stirring for 1 h at 00, 8% Nal-IC03 soluton (30 mi) was and the layers separated. The aqueous layer was extracted with CH2C12 (2x30 mO, dried (M9S04) and evaporated to give a solid (0.99 g). Crystallisation from PE (b.p. 60-80) afforded the title compound (0.91 g) m.p. 100-1020.

i 7 GB 2 070 591 A 7 Intermediate 12 ( )-7-anti-(4-Morpholinyi)-5-endo-[tetrahydro-2H-pyran-2-yi)oxylbicyclo[2. 2. 1 lheptan-2-one Morpholine (76 m]) was added dropwise over 15 mins to a stirred solution of 2-exo-bromo-3 en M (tetra hyd ro-2 H-pyra n-2-yi) oxyl bicyclo[3.2.01 hepta n-6-one (100.8 9) in acetone (500 mi) at 01.

After 2 h at 51 the mixture was stirred at 201 for 18 h and then filtered. Evaporation of the filtrate gave 5 an oil which was taken into ether (350 mi), filtered and washed (water, 2 x 100 mi). The ethereal solution was dried (M9S04), filtered and evaporated to give the title compound as a solid. Purification from PE gave material (85.5 g) of m.p. 86-880 Intermediate 13 (a) 1 -Bromomethyl-4-phenyisulphonyl benzene A solution of p-toly] phenyisulphone (20 g) in refluxing CC14 (400 m]) containing dibenzoyl peroxide (0.4 g) was treated with N-bromosuccinimide (15.3 g) in portions rapidly. The mixture was heated under reflux for 30 min., filtered whilst hot and the filtrate allowed to cool. Evaporation gave the title compound (26.8 g), m.p. 103-1041.

(b) N,N-Dimethy], 4-brornomethyibenzonesulphonamide m.p. 94-961 was prepared by a similar procedure from N,N-dimethyi-p- toluenesulphonamide.

Intermediate 14 4-(1,3-Dioxolan-2-yl)-2-phenyithiophene A solution of 5-bromo-3-thiophenecarboxaldehyde (32,5 g) in benzene (500 mi) was treatedwith PTSA (0.323 g) and ethylene glycol (2 1.1 g), and the mixture heated under reflux in a Dean and Stark 20 apparatus until the theoretical volume of water had been removed. After cooling the mixture was washed with water, (2x) then brine, dried (M9S04), filtered and concentrated, and the residue distilled (b.p. 961000 at 0.4 m m) to give the title compound as an oil (24 g).

Analysis Found: C, 35.13; H, 3.0; C71-1713r02S requires: Q 353; H, 3.0%. 25 Intermediate 15 (a) 5-Phenyl-3-thiophenecarboxaldehyde A solution of phenyimagnesium chloride in THF (82.94 m], 2.39 M) was added to a stirred solution of ZnW2 (44.6 g) in dry THF (350 mi) under nitrogen. The mixture was stirred at room temperature for 15 min.

Dibal (9.91 m[, 1 M) in hexane solution was added dropwise to a stirred mixture of triphenylphosphine (10.39 g) and nickel acetoacetonate (2.55 g) in dry.THF (160 mi) under nitrogen. A solution of Intermediate 14 (23. 3 g) in dry THF (150 mi) was added after 10 min. The solution containing the organozinc reagent was then added dropwise and the mixture was stirred for 1 h.

2N Hydrochloric acid (400 mi) was added at 00 and the mixture was stirred at room temperature 35 of 0.5 h. The two layers were separated and the aqueous layer was extracted with ether (2x400 mi), washed with NaHC03 solution and brine and then dried (M9S04), Solvent removal in vacuo gave a solid (32.8 g) which was chromatographed (A) to give the title compound (13.35 g), m.p. 64-651 (from PE 4p. 60-809).

The following compounds were prepared by a similar procedure:

(b) 4-(4-Methoxyphenyi)-2-thlophenecarboxaldehyde m.p. 75-76.50 (from PE (b.p. 60-8011)-EA, 2:1), from 4-bromo-2-dioxolan-2- yi)- thiophene and p-methoxyphenyl zinc bromide [from 4-bomoanisole, zinc bromide] (c) 4-(Phenyimethyi)-2-thiophene carboxaldehyde from 4-bromo-2-(1,3-dioxolan-2-yi)thiophene and a solution of activated zinc dust and benzyi 45 bromide in dry THR Purification by chromatography (B) Analysis Found: C, 71.3; H, 5.0 C121-11,0S requires: C, 71.3; H, 5.0%.

Intermediate 16 4-(4Methoxyphenyl)-2-thiophenemethanoI so Intermediate 15(b) (9.85 g) in THF (40 mi) and absolute ethanol (160 mi) was stirred with NaBH4 (1.9 9) at room temperature for 1 h. Saturated aqueous KHPO, (60 m]) was added and the mixture evaporated in vacuo. Extraction of the residue with CHP2 (3 x 50 mi), drying (M9S04) and evaporation gave a solid. Crystallisation from EA gave the title compound (7.49 g), m. p. 136.5-1380 8 GB 2 070 591 A 8 Intermediate 17 (a) 5-Phenyi-3-thiophenemethanol A stirred solution of Intermediate 15 (12 g) in methanol (120 mi) was treated with NaBH, (1.82 g) at room temperature for 15 min. The mixture was cooled to 00 and treated with NI-14C1 solution (200 m[), followed by water (200 mi) and ether (400 mi). The ether extract was separated and the aqueous phase further extracted with ether (400 mO, washed with brine, dried (M9S04), filtered and evaporated to afford the title compound as a solid (11.5 g), m.p. 92-93 '>.

(b) 4-(Phenyimethyi)-2-thiophene methanol m.p. 33-340 was prepared by a similar procedure from Intermediate 15(c).

Intermediate118 2-(11 -Cyclohexenyi)thiophene n-Butyllithium (40.7 mi, 1.5 M) was added dropwise to a stirred solution of thiophene (5 g) in dry ether (50 mi) and the mixture heated under reflux for 30 min. After cooling to -781, cyclohexanone (6.21 mi) in dry ether (30 m]) was added dropwise and the temperature allowed to rise to ambient.

After 1 h 2N hydrochloric acid (80 mi) was added and stirring continued for 16 h. The organic layer was separated and the aqueous layer extracted with ether (2x40 mi). The combined extracts were washed with water, dried (M9S04), filtered and evaporated to give an oil, which was dissolved in benzene (50 m[) and heated under reflux in the presence of PTSA for 0.75 h. The cooled solution was washed twice with 8% NaHC03 solution and the aqueous solution extracted with ether (2x40 mi), dried (M9S04) filtered and evaporated to give the title compound as an oil (9.83 g). TLC (F) Rf 0.73. 20 Intermediate 19 2-Cyclohexylthiophene A solution of Intermediate 18 (9.8 g) in absolute alcohol (75 mi) was hydrogenated over prereduced 10% palladium oxide on charcoal (2 g). The mixture was filtered ('Hyfio') and the filtrate evaporated. Distillation of the residue gave the title compound (6.6 g) of b.p. 70-800/0.2 mm. 25 Intermediate 20 5-Cyclohexyl-2-thiophene methanol n-Butyllithium (25.3 m[, 1.5 M) was added dropwise to a stirred solution of Intermediate 19 (6 g) in dry THF (75 mi). After 15 min the solution was cooled to 00 and paraformaidehyde (3.25 g) was added. After a further 20 min at room temperature saturated NH4C1 solution (30 mi) was added, the 30 organic layer separated and the aqueous solution extracted with ether (2 x 50 mi), dried (M9S04), filtered and evaporated, and the residue chromatographed (C). The title compound was obtained as a solid (5.36 g), m.p. 31-31.51.

Intermediate 21 (a) 4-Phenyi-2-thlophenernethanol A stirred suspension of 4-phenyl-2-thiophenecarboxaldehyde (4.32 g) in absolute ethanol (85 mi) was cooled in an ice-bath and treated with NaBH4 (1.06 g). After 20 min. the mixture was allowed to attain ambient temperature when stirring was continued for 6 h. Saturated aqueous M4C1 (30 mi) was then carefully added to the vigorously stirred mixture, and the resulting suspension extracted with ether (2x200 mi). The combined extracts were dried (Na2SO4/K2CO.), filtered and evaporated to give 40 the title compound (4.2 g) as crystals, m.p. 112-1131.

(b) 4-Bromo-2-thiophone methanol was similarly prepared from 4-bromo-2-thiophene carboxaldehyde.

AnalysisFound: C,31.1; H,2.6 C.1---1.13r0S requires: Q30.8; H,2.6%. 45 Intermediate 22 4-Methy]-2-thiophenemethanol A solution of 4-methyl-2-thiophene carboxylic acid (6 g) in dry ether (50 mO was added to a stirred suspension of LiAIH, (2 9) in dry ether (100 m]) and the mixture kept at room temperature for 2 h and 30cl for 1 h. Wet THf (50 mO was cautiously added followed by 1 N hydrochloric acid (150 mi). The 50 layers were separated and the aqueous soluton extracted with ether (100 mi), washed with Na2C03 solution (2 x), water (2 x), brine and then dried NgSO,). Evaporation gave a liquid which was distilled (b.p. 901/1 mm) to give the title compound (4.25 g).

Intermediate 23 (a) 2-(Bromomethyl)-4-pheny[thiophene A cooled, stirred suspension of Intermediate 21 a) (3.86 g) in dry CH2C12 (60 mO was treated dropwise with a solution of PB., (1.27 mi) in dry CH2C1. (20 mi), and stirring continued for 30 min. The 9 GB 2 070 591 A 9 mixture was treated with 8% aqueous Nal-ICO, (100 mi), stirred for 20 min. , extracted with ether (1 x 150 mi, 1 x50 mi), and the extracts dried (M9S04), filtered and evaporated to give the title compound (5.01 g) as a solid, m.p. 87-88.5 0. The following compounds were prepared by a similar procedure:

(b) 2-Bromomethyl-4-(phenyimethyi)thiophene from Intermediate 17b); TI-C (M) Rf 0.58.

(c) 2-Bromomethyl-5-cyclohexylthiophene from Intermediate 20; TLC (M) Rf 0.72.

(d) 4-Bromo-2-(bromomethyi)thiophene from Intermediate 21 b), Analysis Found: C, 23.5; H, 1.6.

C.H413r2S requires: C, 23.5; H, 1.6%.

(a) 2-(Bromomethyi)-4-(4-methoxyphenyl)thiophene from. Intermediate 16; Analysis Found: C, 50.6; H, 4.1 15 C121-11,13r0S requires:C, 50.9; H, 3.9%.

(f) 4-(Bromomethyl)-2-phenylthiophone from Intermediate 17; TLC Q) Rf 0.58.

(g) 2-Bromomethyi-4-methyithiophene from Intermediate 22; TLC (0) Rf 0.55.

Intermediate 24 2-(Bromomethyl)-5phenylthiophene To a boiling solution of 2-methyi-5-phenyithiophene (2 g) in dry CC14 (100 mi) was rapidly added N-bromosuccinimide (1.94 g) and dibenzoylperoxide (0.15 g). After heating under reflux for 30 min., the mixture was cooled and filtered. Evaporation in vacuo gave the title compound as an oil (1.5 g). 25 AnalysisFound: Q52.0; H,14; C11H.BrS requires; Q52.2; H,21.6%.

Intermediate 25 ( )-5-ondo-Hydroxy-7-anti-(4-morpholinyi)bicyclo[2.2. llheptan-2-'one, hydrochloride To a stirred solution of Intermediate 12 (96.4 g) in methanol (600 mi) was added an ethereal 30 solution of HCI (240 mi) and the mixure stirred at 200 for 2.5 h (pH 1.5- 2). Filtration followed by evaporation of the filtrate gave an oil which solidified on trituration with EA (2 x200 mi). Coloured impurities were removed by extraction with boiling isopropanol to leave the title compound as a solid (70.6 g), m.p. 181-1820.

Intermediate 26 (a) ( )-5-endo-(4-Bromophenyimethoxy)-7-enti-(4-morpholinyi)bicyclo[2.2. 1]heptan-2 -one Aqueous NaGH solution (1 ON; 200 mi) was added to a solution of the free base of Intermediate (2 1.1 g), benzyitriethylammonium chloride (4 g) and 4-bromobenzyl bromide (27.5 g) in CH2C12 (400 mi) and the mixture stirred vigorously for 4 h. A further portion of 4- bromobenzyibromide (9 g) was then added and stirring continued for 68 h. Water (200 mi) was added and the layers separated. The 40 aqueous layer was extracted with EA (2x75 mi), washed with water, dried (M9S04) and evaporated to give an oil (48 g) which solidified on standing. Excess alkylating agent was removed by trituration with PE hp. 60-801) and crystallisation from EA-PE (b.p. 60-801) then gave the title compound (34.1 g) as a solid, m.p. 130-1310.

The following compounds were prepared by a similar procedure:

(b) ( )-7-a nti-(4-Morphol inyl)-5-endo [4-phenyisulphonyl (phenyl m ethoxy)l bicyclo [2.2.11heptan2-one m.p. 133-1350, from Intermediates 25 and 13a). Purification by chromatography twice (D), then (E) (c) 7-anti-(4-Morpholinyl)-5-endo-[(5-pheny[thien-2-yl)methoxylbicyclo[2. 2.1]hep tan-2-one 50 m.p. 129-1300. from Intermediates 25 and 24. Purification by chromatography (F) (d) 5-endo-[(5-Cyclohexy[thien-2-yi)methoxy]-7-anti(4morpholinyl)bicyclo[2.2.ll heptan-2-one m.p. 56-571, from Intermediates 25 and 23c). Purification by chromatography (G) GB 2 070 591 A 10 intermediate 27 ( )-8-anti-(4-Morpholinyl)-6-endo-[4-phenyisulphonyi(phenyimethoxy)lcyclope ntyll-2oxabicyclo[3.2.1 loctan-3-one To a stirred solution of Intermediate 26b) (2.12 g) in CH2C12 (22 mO at 01 was added peracetic acid (3.14 mi, 6.12 M) and the resulting solution then stirred at ambient temperature for 18 h. Excess Na2S03 solution,,,jas added to the cooled solution and stirring continued for 1 h. After evaporation in vacuo the residue was suspended in Nal-IC03 solution (50 mi), extracted with EA (3x70 mi), dried (M9S04), filtered and concentrated to give the title compound as a solid (1.16 g), m.p. 170-1711 (from EA-acetone-PE).

Intermediate 28 (a) ( )-6-endo-(4-Bromophenyimethoxy)-8-anti-(4morpholinyi)-2-oxabicyclo[3.2.1 loctan-3-one Intermediate 26a) (13.2 g) in acetic acid (110 mi) and water (55 ml) containing CH3COONa.31-120 (23.7 g) was cooled (ca. 5-100) and stirred during the dropwise addition of peracetic acid (6.1 M; 28.5 mi). The resulting solution was stirred at 200 for 48 h when 10% Na2S03 solution (200 mi), was added, maintaining the temperature of the mixture at 10-151. After 1.5 h solvents were removed in vacuo at 351, the residue taken into water (150 mi) and basified to pH 9 with Na2C03 solution. Extraction with EA (3x200 mi) followed by drying and evaporation gave a solid which crystallised from EA to give the title compound (5.49 g), m.p. 154-15 6 1.

The following compounds were prepared by a similar procedure:

(b) 8-anti-(4-Morpholinyi)-6-,endo[(5-phenyithien-2-yi)methoxy]-2oxabicyclo[3.2.1loctan-3-one 20 m.p. 135-1370, from Intermediate 26c). Purification by chromatography (H) through to (0).

(c) 6-endo-[(5-Cyclohexylthien-2-yi)methoxy]-8-anti(4-morpholinyl)-2oxabicyclo[ 3.2.1 loctan-3one from Intermediate 26d). TLC 002) Ether Rf 0.38. Purification by chromatography Q) Intermediate 29 ( )-8-anti-(4-Morpholinyi)-6-endo-[[[4-(phenyimethyi)-phenyll-4yilrnethoxyl -2- oxabcyclo[3.2.1 loctan-3-one To a stirred suspension of activated Zn dust (13.08 9) in THF (40 mi) was added dropwise over 0.5 h a solution of benzyi bromide (11.9 mi) in THF (40 mi), the internal temperature being maintained at 100. The mixture was then stirred at 10-150 for 1 h.

Nickel acetylacetonate (0.774 g) and triphenylphosphine (3.14 g) were dissolved in THF (15 mi) and stirred at 201 under nitrogen during the dropwise addition of Dibal (1 M in hexane, 3 mi). After 5 min. a solution of Intermediate 28a) (2.77 g) in THF (35 mi) was added, followed after a further 5 min.

by the solution of benzylzinc bromide described above. The mixture was stirred at 291 for 19 h and then poured into NI-1.Cl solution (250 mi) and EA (150 mi). 2N hydrochloric acid was added to pH 6 35 and the layers were separated. The aqueous solution was extracted with EA (100 mO, dried and concentrated. Purification by chromatography (K). Crystallisation from EA- PE gave the title compound (2.3 g), m.p. 119-121 1.

Intermediate 30 (a) ( )-6-endo[[41-Methoxy(1,1 1-phanyi)-4-yilmethoxy]-8-anti-(4- morpholinyl)-2oxabicyclo[3.2.1]octan-3-one 4-Bromoanisole (7.48 9) in ether (30 mi) was added to Mg turnings (1.06 g) in THF (40 mi) containing a small iodine crystal. After 0.5 h an exothermic reaction took place which was moderated by water bath cooling. The resultant mixture was stirred at 201 for a further 0.5 h and then added, under nitrogen, to a stirred, cooled (50) solution of anhydrous ZnBr2 (9. 0 g) in THF (40 mi) and stirred 45 for 1 h.

Dibal (1 M in hexane; 5.72 mi) was added dropwise to a suspension of bis(triphenylphosphine)pailadium chloride (2.0 g) in THF (20 m[). After stirring for 5 min. a solution of Intermediate 28a) (2.38 g) in THF (35 m]) was added followed after a further 5 min. by the solution of 4-methoxyphenyizinc bromide described above. The resultant mixture was stirred under nitrogen at 50 201 for 18 h. The solvent was then removed in vacuo, NH4C1 solution (150 mi) added and the mixture extracted with EA (3 x 100 mi). Evaporation of the dried extracts gave an oil which was chromatographed (K) to give the title compoundas, a solid. Crystallisation from EA-PE (b.p. 60-801) gave material (1.58 g) of m.p. 123-1250.

(b)( )-8-anti-(4-Morpholinyl)-6-endo-[[(1,11:4,111-terphenyl)-4yilmethoxyl-2 oxabicyclo[3.2.11]octan-3-one m.p. 196-1981 was similarly prepared from intermediate 28a) and biphenylzinc chloride.

1 11 GB 2 070 591 A 11 (c) ( )-6-endo-[4-(Thien-2-yi) phenyl m ethoxy]-8-a nti-(4-morphol inyl)- 2-oxab icyclo [3.2.11octan3-one m.p. 216-2171 was similarly prepared from Intermediate 28a) and a solution of anhydrous ZnBr2 and the Grignard reagent from 2- bromothiophene and Mg in dry THE Purification by 5 chromatography, EA-PE hp. 60-80') W2, 1:1 and 2:1 successively).

Intermediate 31 (3aa,4a,5p,6aa)-( )-Hexahydro-5-hydroxy-4-(4-thiomorpholinyl)-2Hcyclopenta( b)furan-2-one, S-dioxide, hydrochloride A solution of the product of Preparation 30 (British Patent Specification 2028805A) (10 g) in ethanol (60 mi) and water (40 mi) containing concentrated hydrochloric acid (40 mi) was hydrogenated 10 over prereduced 10% palladium oxide on charcoal (5 g, 50% dispersion in water) in ethanol (40 mi).

The mixture was filtered and the filtrate evaporated in vacuo to give the title compound as a solid (8.55 g), m.p. above 2301 (dec.) (from water-ethanol).

Intermediate 32 (3aa.4a,BP,6aa)-( )-Hexahydro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-(4thiomorp holinyl)-2H- 15 cyclopenta(b)furan-2-one, S-dioxide Dihydropyran (3.1 mi) was added to a stirred solution of the free base of Intermediate 31 (1.56 g) and PTSA (1.17 g) in dry DIVIF (30 mi) at -100. The mixture was allowed to reach ambient temperature and stirring continued for 18 h, whereupon it was poured into saturated aqueous Nal-IC03 solution (50 m]), extracted with EA (4x 100 m]), washed with water, dried (M9S04), filtered and concentrated. The 20 residue was chromatographed (L) to give the title compound as a viscous oil (1.89 g). IR (CHBr3) 1762 cmi.

Intermediate 33 (a) (1 a,2p,3a,Sa)-( )-3-Hydroxy-5-[[41-rnethoxy(1,1 1biphenvi)-4-yilmethoxy]-2-(425 morpholinyUcyclopentane acetaidehyde A solution of Intermediate 30a) (1.6 g) in CH2C12 (25 mi) at -700 under dry nitrogen was stirred during the addition of Dibal (1 M in hexane, 8.7 mi). After 1.5 h at -700, methanol (25 mi) was carefully added and the mixture was then allowed to rise to ambient temperature whereupon stirring was continued for 18 h. The mixture was filtered through 'Hyflo' and the filtrate evaporated to give the 30 title compound as a foam (1.68 g). IR(CHBr3) 3580/3560(br), 1715,1240,1040 cm-1.

The following compounds were prepared by a similar procedure:

(b) (1 a,2p,3a,5cv)-( )-3-Hydroxy-2-(4-morpholinyi)-5-[[(1,11:4,1 Rerphenyi)-4-yilmethoxy]- cyclopentane acetaldehyde m.p. 154-1560C from Intermediate 30b).

(c) (1 a.20,3a, 5a)-( )-3-Hydroxy-2-(4-morphol inyi)-5-[4-phenyl methyl) phenyl] methoxyl- 35 cyclopentane acetaldehyde from Intermediate 29, IR (CHBr3 3590,1715 cm-1.

(d) (1 a.2p,3a,5a)-( )-3-Hydroxy-2-(4-morpholinyl)-5-[4-(thion-2-yi) phenyl methoxy] cyclopentane acetaidehyde from Intermediate 30c), TLC (U) Rf 0.3.

(a) (1 a,2p,3a,Sa)-( )-3-Hydroxy-2-(4-morpholinyl)-5-[4phenyisulphonyi(phenyimethox y)]- cyclopentane acetaidehyde from Intermediate 27, IR (CHBr3) 1705 cm-1.

M (3aa,4a,5p,6aa)-( )-Hexahydro-S-[(tetrahydro-2H-pyran-2-yi)oxy]-4-(4thiomorp holinyi-2H- cyclopenta(b)-furan-2-ol, S-dioxide from Intermediate 32 Analysis Found: C, 53.2; H,7.6; N, 3.5.

C1.1---127NO.S requires:C, 53.2; H, 7.5; N, 3.9% Intermediate 34 (a) 0 a,2p,3a,5a)-( )-3Hydroxy-2-(4-morpholinyi)-5-[(5-phenyithien2yl)methoxylcyclopentane acetaldehyde A stirred solution of Intermediate 28b (0.5 g) in dry CH 2C12 (20 mO at - 701 under nitrogen was treated dropwise with Dibal (1 M in hexane, 2.5 mi). After 1 h at -701, methanol (20 mi) was added and the temperature of the mixture allowed to rise to ambient over 3 h. The mixture was filtered through 'Hyflo' concentrated and the residue taken up into CH2R. (100 mi). After drying NgSOJ, 55 filtration and concentration gave the title compound as a foam (0.4 g). IR (CHI3r,) 1715 cm-1 GB 2 070 591 A 12 (b) [1 a,2p,3a.5a]-( )-5-[(5-Cyclohexyithien-2-yi)-methoxy]-3-hydroxy-2(4morpholinyl)cyclopentane acetaidehyde was prepared by a similar procedure from Intermediate 28c), M (CHBr,) 3580-3530 (broad), 17 10 cm-1.

Intermediate 35 [1 a(Z),2p,3a,5a]-( )-Methyl 7-[3-Acetoxy-5-[4acetylamino(phenyimethoxy)1-2-(4morpholinyi)cyclopentyll-5-heptenoate Intermediate 10 (0.7 g) in acetic anhydride (10 mi) and pyridine (15 mi) was stood at room temperature for 18 h. After evaporation in vacuo the residue was treated with 8% aqueous Nal-IC03 solution (50 mi), extracted with ether (3x30 mi), dried (MgSO 4), filtered and concentrated to give the 10 title compound as an oil (0.62 g). IR (CHBr 3) 3430,1730,1690,1510 cm-1.

Intermediate 36 (a) [1 a(Z),2p,3a,5a]-( )-Methyl 7-[2-(4-Morpholinyl)-5[[4-phenyimethyi)thien-2-yl[methoxy]-3[(tetrahydro-2H-pyran-2yi)oxylcyclopentyll-5-heptenoate Sodium hydride (1.34 g, 50% in oil) was added to a stirred solution of Intermediates 9 (3.83 g) and 23b) (7.75 g) in dry DMF (20 mi) at 01 under nitrogen. The mixture was stirred at 01 for 15 min and then at room temperature for 1 h, whereupon NH4C1 solution (100 m[) was added and the pH adjusted to 6.5 with KH2P04 solution. The mixture was extracted with ether (3 x 100 mi), washed with water (2x) and brine and then dried (M9S04). Evaporation in vacuo gave a residue which was purified by chromatography (M) to give the title compound as an oil (2.1 g).

AnalysisFound: Q67.9; H,8.1; N,22.

C34H47NO.S requires: Q683; H,7.9; K2.4%.

The following compounds were prepared by a similar procedure:

(b) [1 a(Z),2p,3a,Sal-( )-Methyl 7-[5-[(4-Bromothien-2-yl)methoxy]-2-(4morpholinyi)-3- [(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyll-5-heptenoate from Intermediates 9 and 23a). Purification by chromatography (N) Analysis Found: C, 55.5; H, 63; N, 2.1 C27H4.BrNO.S requires: C, 55.21; H, 6.9; N, 2.4%.

(c) [1 a(Z),2p,3a,5a]-( )-Methyl 7-[5-[[4-(4-Methoxyphenyl)thien-2yllmethoxy]-2-(4morpholinyi)-3-[(tetrahydro-2H-pyran-2-yi)oxylcyclopentyll-5-heptonoate from Intermediates 9 and 23e). Purification by chromatography (0).

Analysis Found: C, 66.6; H, 7.8; N, 2.4 C34H.7NO7S requires: Q66.5; H,7.71; N,2.3%.

Intermediate 37 [1 a(Z),2p,3a,5a]-( )-Methyl 7-[5-Hydroxy-3-[(tetrahydro-2H-pyran-2yl)oxy]-2-(4thiomorpholinyi)cyclopentyll-5-heptenoetc, S-oxide To a stirred solution of potassium t-butoxide (1.12 g) in dry THF (10 mi) under dry nitrogen was added (4-carboxybutyl)triphenylphosphonium bromide (2.21 g) and the mixture stirred at 221 for 15 min., whereupon a solution of Intermediate 33f) (0.9 g) in THF (5 mi) was added and stirring continued for a further 30 min. Water (50 mi) was added and the mixture extracted with EA (3x25 mi). The aqueous phase was adjusted to pH 6.5 with KH2P04 solution and then extracted with EA (3x30 mi), washed with brine, dried (MgSO.) and treated with ethereal diazomethane. Concentration gave an oil which was chromatographed (L) to give the title compound (0.63 g).

Analysis Found: C, 57.8; H, 8.3; N, 2.9 C22H37NO7S requires:C, 57.5; H, 8.1; N, 3.1%.

Intermediate 38 [1 a(Z),2p,3a,5a]-( )-Methyl 7-[3-Acetoxy-5- [4-N,N-d i methyla minosulphonyl (phenyl methoxy)l 2-(4-morpholinyi)-cyclopentyll-5-heptenoate Intermediates 9 (2.5 g) and 13b (5.08 g) were converted into the hydroxy analogue of the title compound by the method of Example 1. The residue was treated with acetic anhydride (0.9 mi) in dry 50 pyridine (10 mi) at room temperature for 18 h. The mixture was diluted with ether, washed with NaHCO, solution and brine, dried (M9S04) and concentrated. Purification of the residue by chromatography (J) gave the title compound as an oil (0.8 g).

IR (Neat) 1730,1340,1160 cm-1.

1 13 GB 2 070 591 A 13 Intermediate 39 4-Bromomethyl-41-chloro-1,1 '-biphenyl 4'-chloro(1,1'-biphenyi)-4-methanoI (5,8 g) was converted into the title compound (6.8 g), m.p. 64-661 by the method for the preparation of Intermediate 3.

Intermediate 40 [1 A4,2P,3 a,5a]-W-M ethyl 7-[5-[[41-Chloro(1,1 1biphenyi)-4-yil mothoxy]-2-(4-morpholinyi)-3[(tetrahydro-2H-pyran-2yl)oxylcyclopentyll-5-he ptenoate To a stirred solution of Intermediate 9 (2.6 g) and NaH (75% dispersion in oil 0.6 g) in dry DMF (20 mi) was added after 5 min. a solution of Intermediate 39 (5.3 9) in DMF (10 mi). The mixture was stirred for 5 h at room temperature, then poured into NH#Cl solution and extracted with ether. 10 The dried (M9S04) extracts were evaporated and the residue chromatographed eluting successively with OA; 12, 1:1; 2:1) EA-PE (b.p. 60-800) and 4:1 EA-methanol to give the title compound as an (oil (1.8 g).

IR (Neat) 1732,1090 cm-1.

Example 1 (a) [l a(Z),2p,3a,5a]-( )-M ethyl 7-[5-[[41-methyi(1,1'-biphenyl)-4- yilmethoxy]-3-hydroxy-2-(4morpholinyl)cyclopentyll-5-heptenoate A solution of Intermediates 9 (0.43 g) and 3 (0.68 g) in dry DMF (6 mi) was stirred at 0' under nitrogen during the addition of NaH (0.08 g, 80% dispersion in oil). After 4 h at 200, the mixture was carefully poured into saturated aqueous NH4C1 (70 mi) and extracted with ether (3x40 m]). The 20 combined extracts were dried (M9S04), filtered and evaporated, and the residue then stirred with 5% methanolic sulphuric acid (20 mi) at 200 for 2 h. The mixture was poured into 8% NaHCO, solution (100 mi), extracted with ether (3x 50 mi), dried (MgSO4), evaporated and the residue purified by chromatography (P). The title compoundwas crystallised from ether-PE as needles (0.14 g), m.p. 7577'. The following compounds were prepared by a similar procedure: 25 (b) [1 a(Z),2p,3a,5a]-( )-Methyl 7-[3-Hydroxy-5-[4methylthio(phenyimethoxy)1-2-(4morpholinyi) cyclopentyll-5-heptenoate from Intermediate 11 and 1-(bromomethyi)-4-(methylthio)benzene AnalysisFound: Q65.1; H,8.0; N,2.9; CUl-137NO.S requires: Q64.8; H,8.0; N,21.0%.

(c) [1 a(Z),2p,3a,5a]-( )-Methyl 7-3-Hydroxy-2-(4-morpholinyl)-5-[4(2phenyl ethyl)phenyl methoxyl cyclopentyll-5-heptenate from Intermediates 9 and 1, IR (Neat) 3460, 1740 cml. Purification by chromatography (Q).

(d) [1 a(Z),2p,3a,5a]-( )-Methyl 7-[3-Hydroxy-5-[[41-methyoxy(1,1 'biphenyi)-4-yil methoxy]-2- 35 (1 -piperidinyi)cyclopentyi]-5-heptenoate IR (Neat) 1735 cm-1, from Intermediate 41 and 4-bromomethyi-41-methoxy(1, 1'-biphenyi).

Purification by chromatography (R).

(a) [1 a (Z),2P.3a,5a]-( )-Methyl 7-[3-Hydroxy-5-[4(phenyimethyi)phenyimethoxy]-2-(1 - 4C piperidinyl)cyclopentyll-5-heptenoate 40 [R (Neat) 3440, 1735 cm-1, from Intermediate 41 and 1-bromomethy]-4- (phenyimethyi)benzene.

Purification by chromatography (R).

M [1 a(Z),2p,3a, 5a]-( )-M ethyl 7-[3-Hydroxy-5-[[41-methyl(1,1 1biphenyi)-4-yilmethoxy]-2-(1piperidinyi)cyclopentyll-5-heptenoate from Intermediate 41 and Intermediate 3, purification by chromatography (S). IR (CHBr3) 45 3600/3500,1722 cm-1. TLC (S) Rf 0.28 (9) [1 aM,2P,3 a,5a]-( )-M ethyl 7-[3-Hydroxy-5-[[41-mothoxy(1,1-1- biphenyi)-4-yilmethoxy]-2(4-thiomorpholinyl)cyclopentyi]-5-heptenoate, S-dioxide from Intermediate 37 and 4-bromomethyi-41-methoxy(1,1'-biphenyi). Purification by chromatography (L). [R (CHBr.) 3580/3500,1723 cm-1.TI-C (1) Rf 0.36.

(h) [1 a(Z),2p,3a.5a]-( )-Methyl 7-[3-Hydroxy-5-[4(phenyimethyl)phenyimethoxy]-2-(4thiomorpholinyl)cyclopentyll-5-heptenoate, S-dioxide from Intermediate 37 (1 g) and 1-bromomethyi-4-(phenyimethyi)benzene (1. 76 g). Purification by chromatography (J) increasing to (Q). IR (CHBr3) 3580-3480 (br.), 1730 cm- 1.TI-C (Q) Rf 0.42 14 GB 2 070 591 A 14 i) [1 a(Z),2p,3a,5a]-( )-Methyl 7-[3-Hydroxy-5-[[41-methyl(1,1 1biphenyl)-4-yllmethoxy]-2-(4thiomorpholinyi)cyclopentyll-5-heptenoate, Sdioxide. from Intermediates 37 and 3. Purification by chromatography (L). M (Neat) 3520 (br.), 1740, 1302, 1123 cm. TLC (1). Rf 0.6 1.

j)la(Z),2,3a.5a]-( )-Methyl7-[3-Hydroxy-2-(4-morpholinyl)-5-(2thienylmethox y) cyclopentyll-5-hoptenoate, from Intermediate 9 and 2bromomethylthiophene, IR (Neat) 3410,1730 cm-1. TLC (S'02) 95:5 chloroform-methanol Rf 0.4. Purification by chromatography (T).

(k) [1 a(Z),2,3a,5a]-( )-Methyl 7-[3-Hydroxy-2-(4-morpholinyi)-5-[(2phonylthien-410 yl)rnethoxylcyclopentyll-5-heptenoate from Intermediates 9 and 23f). IR (CHBr3) 3590, 1628 cml. Purification by chromatography (1).10.

(1) [1 ce(Z),2p,3a,5a]-( )-M ethyl 7-[3-Hydroxy-2-(4-morpholinyi)-5-(3thienyimethoxy)cyclopentyll-5-heptenoate from Intermediate 9 and 3bromomethylthlophene. Purification by chromatography using 1-4% methanol in ether as eluent. IR (CHBr3) 3500,1735 cm-1. TLC (Q) Rf 0.34.

(m) [1 a(Z),2p,3a,5a]-( )-Methyl 7-[3-Hydroxy-5-[(4-methyithien-2yi)methoxy]-2-(4- morpholinyi)cyclopentyll-5-heptenoate from Intermediates 9 and 23g). Purification by chromatography (L). IR (CHBr.) 3580 (Broad), 1728 cm-1.

(n) [l a(Z),2P.3a,5a]-( )-7-[3-Hydroxy-2-(4-morpholinyl)-5-[(5phenylfuran-2- yl)methoxylcyclopentyll-5-heptenoic acid from Intermediate 9 and 2- (bromom ethyl)-5-pheny[fu ran, IR(CHI3r3) 3500,1720,1700,1018, 788 cm1.TI-C (S'02) (1) Rf 0.18. Purification by chromatography (1).

(o) [1 a(Z),2p,3a,5a]-( )-Methyl 7-[3-Hydroxy-2-(4-morpholinyi)-5-[(4phenylthien-225 yi)methoxy)cyclopentyll-5-heptenoate (U).

from Intermediates 9 and 23a), m.p. 78-801. Purification by chromatography (K) followed by Example 2 (a) [1 a(Z),2p,3a,5a]-( )-7-[3-Hydroxy-5-[[41-methyi(1,1 1biphenyi)-4-yilmethoxy]-2-(430 morpholinyl)cyclopentyll-5-heptenoic acid A suspension of the product of Example 1 a) (0.44 g) in methanol (2 mi) and water (4 mi) -25 containing KOH (0.35 g) was stirred at room temperature for 7 h. The methanol was removed and the residue further diluted with water (75 mi), washed with ether (75 mi) and then carefully acidified to pH 6 with 2N hydrochloric acid. Extraction with ether (4x50 m[) followed by drying and evaporation gave the title compound (0.35 g) as a foam. IR (CHBr.) 3500,3200 (br.), 1730, 1700 cm-1. TLC (X) Rf 025. 35 The following compounds were prepared by a similar procedure:

(b) [1 AZL2p,3 cy,5a]-( )-7-3-Hydroxy-5-[4-methyithio (phenyl methoxy)-2(4rnorpholinyi)cyclopentyll-5-heptenoic acid from the product of Example 1 b). Purification by chromatography (1). Analysis Found: C, 63.5; H, 8.11; N, 3.0; C24H3.NO.S requires: Q64.1; H,M;

N,11%.

(c) [1 a(Z),2p,3a,Sal( )-7-[3-Hydroxy-2-(4-morpholinyi)-5-[4-(2phenylethyl)phonyime thoxy]cyclopentyll-5-heptenoic acid IR (Neat) 3350,1700 cm-1, from the product of Example 1 c).

d) [l a(Z),2p,3a,5a]-( )-7-[3-Hydroxy-2-(4-morpholinyl)-5-(3thienyimethoxy)cyclope ntyll-5- 45 heptenoic acid from the product of Example 11), IR (CHBr3) 3500 (br), 1730, 1700 cm-1, TCL 002) (Q) Rf 0. 13.

Purification by chromatography (Q).

Example 3 (a) [1 a,(Z),2p,3 a,5a]-W-M ethyl 7-[3-Hydroxy-S-[4-methyisulphonyl (phenyl methoxy)1-2-(4morpholinyi)-cyclopentyll-5-heptenoate Peracetic acid (6.12M, 0.49 mO in acetic acid (10 mi) was added dropwise to a mixture of the product of Example 1 b) (0.7 g) and CH,COONa (0.25 g) in acetic acid (15 mi) at 01. After stirring for 2h GB 2 070 591 A 15 saturated Na2S03 solution was added and the suspension evaporated to dryness. The residue was neutralised with 8% NaHC03 solution, extracted with CH2C12 (3x75 mi), dried (M9S04), filtered and evaporated to afford an oil (0.83 g). Column chromatography (V) gave the title compound as an oil (0.4 g). TLC (V) Rf 0.36.

(b) [1 a(Z),2p,3a,5a]-( )-Methyl 7- [3-Hydroxy-5- [4-methyisu lphinyl (phenyl methoxy)1-2-(4morpholinyi)cyclopentyll-5-heptenoate was prepared from the product of Example 1 b) (0.7g) according to the method of Example 3a). Continued elution of the column using (V) gave the title compound as an oil (0.13 g). IR (CHBr3) 3580/3440,1723,1040 em-'. TLC (V) Rf 0.2.

Example 4 (a) [1 a(Z),2p,3a,5a]-( )-7-[3-Hydroxy-5-[[41-mothoxy(1,1 1biphenyl)-4-yil methoxy]-2-(4morpholinyi)cyclopentyll-5-heptenoic acid, hydrochloride To a solution of potassium t-butoxide (2.28 g) in THF (15 m]) under dry nitrogen was added (4carboxybutyi)triphenylphosphonium bromide (4.5 g). After 15 min at 201 a solution of Intermediate 33 (1.6 g) in THF was added and stirring continued for a further 1 h. Water (2 mi) was added and the THF removed in vacuo. The residue was taken up into water (100 mi), basified (pH 10) with NaOH solution and washed with ether (2 x75 mi). The aqueous layer was adjusted to pH 6 with 2N hydrochloric acid, extracted with ether (5x75 mi), dried, evaporated and re-dissolved in EA (25 m]) and ether (40 mi). To the solution was added an excess of ethereal hydrogen chloride solution followed by cooling until crystallisation occurred. Filtration and purification from EA-methanol gave the title compound (1.2 g) 20 m.p. 164-166 0.

The following compounds were prepared by a similar procedure:

(b) [1 a(Z),2p,3a,5crl( )-7-3-Hydroxy-2- (4-morpholinyi)-5-[4(phenyimethyl)phonyi- methoxylcyclopentyll-5-heptenoic acid hydrochloride, m.p. 167-1690 from Intermediate 33c).

(c) [1 a(Z),2p,3ce,5a]-( )-7-3-Hydroxy-2-(4-morpholinyi)-.5-[[(1,1 1A1,11 "-terphenyi)-4-yil methoxy], cyclopentyl-5-heptenoic acid hydrochloride, m.p. 188-1900 from Intermediate 33b).

(d) [1 a(Z),2p,3a,5a]-( )-7-[3-Hydroxy-2-(4-morpholinyi)-5-[4phenyisulphonyl(phenyl - methoxy)lcyclopentyll-5-heptenoic acid from Intermediate 33e). Purification by chromatography (Q). (IR (CHBr3), 1730(sh), 1705 em-', TLC (V) Rf 0.27.

(a) [1 a(Z),2P.3a,5a]-( )-7-[3-Hydroxy-2-(4-morpholinyl)-5-(4-thien-2yl)phenyl- methoxylcyclopentyll-5-heptenoic acid 1 from Intermediate 33d). Purification by chromatography (W) followed by (X). IR (Neat 3360, 35 1710 em-', TLC (X) Rf 0.4.

M [11 a(Z),2p,3ce,5a]-( )-7-[3-Hydroxy-2-(4-morpholinyl)-5-[(6phenylthien-2-yl)met hoxy]- cyclopentyl]-5-hoptenoic acid from Intermediate 34a), IR (CHBr3) 3500,1740,1705 cm-1, TLC 002) 92.5:7.5 CH2Cl2 - 40 methanoIRfO.16.

(9) [1 a(Z),2p,3a,5a]-( )-7-[5-[(5-Cyclohexyithien-2-yl)methoxy]-3hydroxy-2-(4-morp holinyi)cyclopentyll-5-heptenoic acid from Intermediate 34b), IR (Neat) 1720 em-' (broad), TLC (Q) Rf 0.33.

Example 5 '(a) [la,(Z),20,5a]-( )-7-[5-[[41-Methyi(1,1'-biphenyi)-4-yilmethoxy]-2(4,-morpho linyl)-3- 45 oxocyclopentyll-5-heptenoic acid To a stirred solution of the product of Example 2 (0.393 g) in IDMSO) (3 mi) and CH2C12 (3 mi) containing triethylamine (0.95 mi) at -100 was added pyridine SO, complex (0.4 g) in DIVISO (3 mi).

After 1.5 h at -100 to -50 a further portion of pyridine-S03 complex (0.3 g) was added and stirring continued for 0.5 h. The mixture was poured into water and the CH2C12 removed in vacuo. The aqueous 50 solution was acidified to pH 6 with citric acid solution, EA (3x50 mi), washed with water, dried (M9S04) and concentrated, and the residue purified by chromatography (V) gave the title compound as an oil (0. 154 g). IR (CHBr3) 3490,1740,1703 cm-1. TLC (K) Rf 0.48.

The following compounds were prepared by a similar procedure:

16 GB 2 070 591 A 16 (b)[11 a(Z),2A,5a]-( )-7-[5-[4-Methylthio-(phanylmethoxy)1-2-(4- morpholinyl)-3oxocyclopentyll-5-heptenoic acid from the product of Example 2b). IR (CHBr3) 3500,1735, 1700 cm-1. TLC M Rf 0.29.

(c)[1 a(Z),20,5cel-( )-7-[2-(4-Morpholinyl-3-oxo-5-[4-(2phenylethyl)phenylmethoxyl - cyclopentyll-5-heptenoic acid from the product of Example 2c). IR (CHBr 3) 3590,3500,1735,1700 cm-1. TLC (J) Rf 0.3 1.

Purification by chromatography (J).

(d) [1 a(Z),2p,5a]-( )-Methyl 7-[5-[4-Methyisulphonyi-(phenyirnethoxy)1-2(4-morpholinyi-3oxocyclopentyll-5-heptenoate from the product of Example 3b). IR (CHBr3) 1735, 1300 cm-1. Purification by chromatography 10 (Q).

(e) [I a(Z),2A,5aj-( )-Methyl 7-[5-[4-methylsulphinyl-(phenylmethoxy)1-2(4-morpholinyl-3oxocyclopentyll-5-heptenoate from the product of Example 3b). IR (CHBr3) 1730,1040 cm-1 TLC (1) Rf 0.41. Purification by chromatography (1).

(f) [l a(Z),2p,5a]-( )-7-[2-(4-Morpholinyl)-3-oxo-S-[4-(thien-2yl)phenyimethoxylcyc lopentyll-5heptenoic acid from the product of Example 4e), m.p. 921 IR (CHBr 3) 3500,1705 cm. Purification by chromatography (T).

(9) [l a(Z),2p,5a]-( )-7-[5-[(5-Cyclohexyithien-2-yi)methoxy]-2-(4morpholinyi)-3-ox ocyclopentyll-5-heptenoic acid from the product of Example 4g). M (Neat) 1740, 1710 cm-1, TLC (S'02) (G) Rf 0.27. Purification by chromatography (Z).

Example 6 [la(Z),2p,5a]-( )-7-[2-(4-Morpholinyl)-3-oxo-5-(2thienyimethoxy)cyclopentyll -5-heptenoic acid 25 A mixture of the product of Example 'I j) (1.2 g) and KOH (3.3 g) in methanol (15 mi) and water (7.5 mi) was stirred for 5 h. at room temperature. The methanol was removed in vacuo and the aqueous residue was diluted with water (20 m]) and acidified to pH 6.5 with NaHS04. Extraction with CH2C12 gave, after drying over M9S04 and concentrating, the crude acid as an oil (0.5 g). A solution of this acid was converted to the title compound according to the method of Example 5a). IR (CHBr3) 30 3490,1733,1700 cm-1. TLC (T) Rf 0.2. Purification by chromatography (AB).

Example 7 (a) (1 a,2P.3a,5a)-( )-3-Hydroxy-5-[[41-methyl (1.1 1-biphenyi)4-Vilmethoxy]-2-(4-morpholinyl)cyclopentane heptanoic acid A solution of the product of Example 2a) (0.78 g) in EA (35 mi) was hydrogenated at atmospheric 35 pressure over pre-reduced 10% palladium oxide on charcoal (0.4 g) at 201 for 4 h. The mixture was filtered ('Hyfio') and the filtrate evaporated to give the title compound as an oil (0.75 g). IR (CHBr3) 3580/3560,3500,1725,1715 cm-1. TLC (X) Rf 0.4.

The following compounds were prepared by a similar procedure:

(b) 0 a,2P,3 a, 5a)-( )-3-Hydroxy-2-(4-rnorpholinyi)-5-[4-phenyl methyl) phenyl methoxylcyclopentane heptanoic acid from the product of Example 4b). A sample as converted in the hydrochloride salt to give material of m.p. 125-1280 (dec). IR (Nujol) 3300,2800/2400,1690 em-'.

(c) (1 a,2p,3a,5a)-( )-3-Hydroxy-5[(41-rnethoxy(1,1 '-biphenyi)-4yilmethoxy]-2-(4- morpholinyl)cyclopentane heptanoic acid from the free base of the product of Example 4a). IR (CHBr.) 3500, 1725, 1703 cml.

Example 8 [1 a(Z),2p,3a,5a]-( )-Methyl 7-[3-Hydroxy-2-(4-morpholinyl)-5-[[4- (phenyimethyi)thien-2-yllmethoxylcyclopentyll-5-heptenoate A solution of Intermediate 36a) (2 g) in 9:1 methanol-sulphuric acid (15 mi) was stirred for 2 h at 50 room temperature, whereupon NaHC03 solution (100 mi) was added. The mixture was extracted with EA (3 x 70 mO, the extracts washed with brine, dried (MgSO,,) and concentrated. The residue was 17 B 2 070 591 A 17 chromatographed (1) to give the title compound as an oil (1.44 g). IR (CHBr3) 3500-3400 (broad), 1728 cm-1.

Analysis Found: C, 67.4; H, 7.5; N, 2.7 C2.H3.NO5S requires:C, 67.8; H, 73; N, 2.7%.

Example 9 (a) [1 a(Z),2p,3a,5a]-( )-7-[5-[4-N,N-Dimethylaminosulphonyi(phenyimethoxy)]-3-hydr oxy-2(4-morpholinyi)cyclopentyll-5-heptenoic acid A solution of Intermediate 38 (0.77 g) in methanol (30 mi) containing 2N NaOH (5 mi) was stirred at room temperature for 18 h. The solution was treated with pH 6.5 buffer (Na 2HP04/KI-12P04) and extracted with CHP2, The dried (M9S04) extracts were evaporated to give the title compound 10 (0.612 9) as a foam. IR (CHBr3) 3580, 3500,1730,1703,1340 cm-1 Analysis Found: C, 58.6; H, 7.4; N, 5.1 C2.H..NAS requires: C, 58.8; H, 7.5; N, 5.5%.

The following compounds were prepared using a similar procedure:

(b) [la(Z),2P,3a,5a]-( )-7-[3-Hydroxy-S-[[41-mothoxy(1,1'-biphonyi)-4yilmethoxy] -2-(1- 15 piperidinyi)cyclopentyll-5-heptenoic acid from the product of Example 1 d), m.p. 94-101 Analysis Found: C, 73.0; H, 8.1; N, 2.6.

C3,H4,NO, requires: C, 73.3; H, 8.1; N, 2.8%.

(c) [la,(Z),2,6,3a,5a]-( )-7-3-Hydroxy-5-4-(phenyimethyi)-phenyimethoxy]2-(1-pip eridinyl)- 20 cyclopentyll-5-heptenoic acid from the product of Example 1 e), m.p. 103-110.50. IR (CHBr3) 3500,1730- 1700 (br) cm-1 (d) [1 a(Z),2p,3a,5a]-( )-7-[3-Hydroxy-5-[[41-methyl(l,1 '-biphenyl)-4yI1methoxy1-2-(1 piperidinyl)cyclopentyll-5-heptenoic acid from the product of Example 1 f), m.p. 52-65 1. TLC 3.1 Methanol-EA Rf 0, 26.

(e) [l a(Z),2p,3a.5a]-( )-7-[3-Hydroxy-5-[[41-methoxy(1,11-biphenyi)-4yllmethoxy1-2 -(4- thiomorpholinyi)cyclopentyll-5-hoptenoic acid, S-dioxide from the product of Example 1 g), IR (CHBr3) 3500, 1735, 1705 cml. TLC (1) Rf 0.33.

(f) [1 a(Z),2P.3a,5a]-( )-7-[3Hydroxy-5-[4-(phenyimethyi)-phenyimethoxy]2-(4- thiomorpholinyi)cyclopentyll-5-heptenoic acid, S-dioxide from the product of Example 1 h), IR (CHBr.) 3580,3500,1733,1710 cm-1. TLC (Q) Rf 0.35.

(9) [1 a(Z),2p,3a,5a]-( )-7-[3-Hydroxy-5[[41-methyi(1,1 1-biphenyi)-4yllmethoxy-2-(4- thiomorpholinyi)cyclopentyll-5-heptenoic acid, S-dioxide from the product of Example 1 i), IR (CHBr3) 3600 (br.), 3500,1740, 1710 cm-1. TLC (1) Rf 0.36.

(h) [l a(Z),2 3a,5a]-( )-7-[3-Hydroxy-2-(4-morpholinyi)-5-[(4-phenyithien2- yi)methoxyfj;"clopentyll-5-heptenoic acid from the product of Example 1 o), m.p. 119.5-121.511.

0) [1 a(Z),2p,3a,Sal-( )-7-[3-Hydroxy-2-(4-morpholinyi)-5-[[4(phenyimethy[thien-2yilmethoxylcyclopentyll-5-heptenoic acid from the product of Example 8. Purification by chromatography (L), IR (Neat) 3370, 1705 cm-1, 40 TLC (1) Rf 0.29.

0.23.

(j) [1 a(Z),2p,3a.5a]-( )-7-[3-Hydroxy-5-[(4-methyithien-2-yi)methoxy]-2(4-morpholi nyi)- cyclopentyll-5-heptenoic acid from the product of Example 1 m), IR (CHBr3) 3600-3500 broad, 1730, 1705 cm-1, TLC (1) Rf Example 10 (a) [1 a(Z).2p,3 a.5a]-( )-7-[5-[(4-Bro moth ien-2-yi) methoxy]-3-hydroxy- 2-(4-morphol inyi) cyclopentyll-5-heptonoic acid A stirred solution of Intermediate 36b) (1.29 g) in methanol (100 mi) was treated with concentrated sulphuric acid (3.5 mi) and the mixture stirred at room temperature for 1 h. After 50 quenching by carefully pouring into 8% NaHCO, solution (250 mi) the methanol was removed and the residue extracted with EA (3 x 50 mi). The combined extracts were evaporated and the residue was 18 GB 2 070 591 A 18 dissolved in a mixture of 2N NaOH (5 mO and methanol (10 mO with stirring at room temperature. After 18 h the mixture was evaporated in vacuo and the residue acidified to pH 6.5 with 1 M aqueous KH2P04. Extraction with EA (3x50 mi), drying (M9S04) and evaporation gave the title compoundas a. glass (0.98 g). IR (CHBr3 3580,3560, 3500,1725,1700 em-' TLC (X) Rf 0.22.

(b) [l a(Z),2P,3r-t-,5a]-( )-7-[3-Hydroxy-S-[[4-(4-methoxyphenyi)thien-2yilmethoxy] -2-(4- 5 morpholinyi)cyclopentyll-5-heptenoic acid was similarly prepared from Intermediate 36c), m.p. 95-1000.

Analysis Found: C, 65.6; H, 7.4; N, 2.7 C2^,NO.S requires: C, 65.2; H, 7.2; N, 2.7%.

Example 11 (a) [l a(Z),2p,5a]-(+)-7-[5-[[41-Methoxy(1,11-biphenyi)-4-Vilmethoxy]-2(4-morpholi nyl)-3-oxo- cyclopentyll-5-heptonoic acid To a solution of the product of Example 4a) (1.3 g) and triethysilyl chloride (0.56 mO in CH2C12 (8 mi) at 01 was added triethylamine (0.475 m]) and the mixture stirred at 00 for 15 min. Simultaneously, a solution of oxalyl chloride (0.68 mi) in CH2C12 (8 mi) was cooled to - 701' under nitrogen and DMSO (1.35 mi) added dropwise. After stirring for 10 min. the solution of triethylsilyl ester described above was added and stirring continued at -700 for 0.75 h. Triethylamine (4 mi) was added and the cooling bath removed. When room temperature was attained the mixture was poured into NH4C1 solution (100 mO and extracted with ether (3x70 mi). The combined extracts were evaporated to leave an oily residue which was stirred with KH2P04 (1 g) in acetone (5 mi), water (20 mi) and ether (5 mi) at 200 20 for 1.5 h. After dilution with water (100 mO the mixture was extracted with ether (2 x 100 mi), dried and evaporated to give an oil (1.71 g). A portion (1.25 g) was chromatographed (J) to give an oil which crystallised from ether-isopentane at -200 to give the title compound (0. 175 g), m.p. 79-82 0, Analysis Found: C, 70.7; H, 7.2; N, 2.8.

C3.H.7NO, requires: C,71.0; H,7.4; N,2.8%.

The following compounds were prepared by a similar.procedure:

(b) [1 a(Z),2p,5a]-( )-7-[2-(4-Morpholinyi)-3-oxo-5-[[4(phenyimethyl)phenyllmethoxy lcyclopentyll-5-heptenoic acid m.p. 68-71 1 (from ether-isopentane from the free base of the product of Example 4b).

(c)[1a(Z),2p,5a]-( )-7-[2-(4-Morpholinyi)-3-oxo-5-[[1,11;4.111-terphenyi)4-y llmethoxylcyclopentyll-5-heptenoic acid m.p. 126-1280 (dec.) (from EA-PE (b.p. 60-800)) from the product of Example 4c). Purification by chromatography (AB).

(d) (l a,2p,5a)-( )-2-(4-Morpholinyl)-3-oxo-5-[4(phenyimethyi)phenyimethoxy]35 cyclopentaneheptanoic acid from the product of Example 7b), m.p. 83-851. Purification by chromatography (J) IR (Nujol) 1740,1718 cm-1.

(a) [l a(Z),2p,5a]-( )-7-[5-[[4-Methoxy(1,11-biphenyi)-4-yllmethoxy]-3oxo-2-(1-pipe ridinyl)cyclopentyll-5-heptenoic acid from the product of Example 9b) except that trimethylsilyl chloride and toluene were used instead 40 of triethylsilyl chloride and CH2C12. Purification by chromatography (J) IR (Nujol) 1740, 1710 cm-1 AnalysisFound: Q733; H,El.0; N,18 C3,HUNO,, requires: Q73.6; H,7.8; N,2.8%.

M [1 a(Z),2p,5a]-( )-7-[3-Oxo-5-[4-(phenylmethyl)phenylmethoxyl-2-(1 piperidinyl)- cyclopentyll-5-heptenoic acid from the product of Example 9c. Purification by chromatography (AC). IR (Neat) 2800-2500, 1735,1710 cm-1. TLC M Rf 0.32.

(g) [1 a(Z),2p,5a]( )-7-[5-[[41-Methyi(1,1 1-biphenyl)-4-yi]methoxy]-3oxo-2-(1 -piperidinyl) cyclopentyll-5-heptenoic acid from the product of Example 9d. Purification by chromatography (J). IR (CHBr3) 3500, 1735, 50 1700 cm-1. TLC (J) Rf 0.27.

(h) [1 a(Z),2p,5a]-( )-7-[5-[[41-Methoxy(1,1 1-biphonyi)-4-yilmethoxy]-3oxo-2-(4-thio- morpholinyi)cyclopentyll-5-heptenoic acid, S-dioxide from the product of Example 9e). Purification by chromatography (AD) IR (CHBr3) 3450, 1740, 1700cm-1.TLC(I)RfO.38.

10.

19 GB 2 070 591 A 19 (i) [1 a(Z),2p,5a]-( )-7-[3-Oxo-5-[4-(phenyimethyl)-phenyimethoxy] -2-(4thiornorpholinyi)cyclopentyll-5-heptenoic acid, S-dioxide from the product of Example 9f) m.p. 100-10 1.5. IR (CHBr3) 3490, 1745, 1710 em-'.

Purification by chromatography (J).

(j)[lce(Z),2p,5a]-( )-7-[5-[[41-Methyl(I.1-Methyl(l,ll-biphenyl)-4yllmethoxy]-3-oxo-2-(4-thio- 5 morpholinyl)-cyclopentyll-5-heptenoic acid, S-dioxide from the product of Example 9g) Purification by chromatography Q). IR (CHBr3) 3480, 1740, 1700 cm-1 TLC (1) Rf 0.5.

The following compounds were prepared by a similar procedure except that trimethylsilyl chloride and toluene were used instead of triethylsilyl chloride and CH2Cl2 respectively:

(k) [1 a(Z),2p,5a]-( )-7-[2-(4-Morpholinyi)-3-oxo-5-[(4-phenyithien-2yl)methoxylcyc lopentyll- 5-heptenoic acid from the product of Example 9h), m.p. 114-1161. Purification by chromatoqraphv (J).

(1) [1 a(Z),2P, 5a]-( )7-2-(4-Morpholinyi)-3-oxo-5-(3thienyimethoxy)cyclopentyll-5-heptenoi c 15 acid from the product of Example 2d). Purification by chromatography (H). M (CHBr,) 3500, 32002300 (broad), 1735, 1700 cm-1. TLC (Q) Rf 0.2.

(m) [1 aM, 2P,5a]-( )-7-[2-(4-Morpholinyi)-3-oxo-5-[[4(phenyimethyi)thion-2- yllmethoxylcyclopentyll-5-heptenoic acid from the product of Example 9i). Purification by chromatography (AE). IR (CHBr3) 1738, 1700 20 em-' TLC. (J) Rf 0.3.

(n) [1 a(Z),2p,5a]-( )-7-[5-[(4-Bromothien-2-yl)rnethoxy]-2-(4rnorpholinyl)-3-oxocy clopentyll- 5-heptenoic acid from the product of Example 1 Oa). Purification by chromatography (AF). IR (CHBr3) 1738, 1700 cm-'TLC(J)R,:0.19.

(o) [l a(Z),2p,5a]-( )-7-[5-[[4-(4-Methoxyphenyi)thion-2-yi]methoxy]-2-(4morpholiny i)-3-oxocyclopentyll-5-heptenoic acid from the product of Example 1 Ob). Purification by chromatography (AF). m.p. 107.5-1091. Analysis Found: C, 65.6; H, 6.9; N, 2.6 C2,3HUN0,3 requires: C, 65.5; H, 6.9; N, 2.7%.

(p) [1 a(Z),2p,5a]-( )-7-5-[(4- Mathylthien-2-yl)methoxy]-2-(4morpholinyl-3-oxocyclopentyll5-heptenolc acid from the product of Example 9j). Purification by chromatography (J). IR (CHBr3) 3500, 1735, 1700 cm-1 TLC (L) Rf 0.4.

Example 12 [1 a(E).2P.3a,5a]-( )-7-[3-Hydroxy-5-[[41-methyi(1,1 1-biphonyl)-4- yllmethoxy]-2-(4 morpholinyi)cyclopentyll-5-heptenoic acid A solution of the product of Example 2a) (0.28 g) and p-toluene sulphinic acid (0.133 g) in dry M-dioxan (20 mi) was heated under reflux under nitrogen for 3 h. After cooling, EA (25 ml) was - 40 added, the solution washed with aqueous pH 6 phosphate buffer (30 m]), dried and concentrated. 40 Purification by chromatography (X) EA-methanol gave the title compound as an oil (0.228 g). IR (CHBr3) 3580, 3500,1720,1705 cm-1 Example 13 [1 a(Z),2p,3a,5a]-( )-7-[5-[[41-Chloro(1,1 1-biphenyi)-4yilmethoxy]-3-hydroxy-2-(4- morpholinyi)cyclopentyi]-5-heptenoic acid A solution of Intermediate 40 (1.7 g) in 10% concentrated sulphuric acid in methanol (30 mi) was stirred for 16 h. The solution was neutralised with 8% Nal-IC03 solution and exiracted into CH2C12. The extracts were evaporated and the residue then dissolved in a solution of KOH (0.4 9) in methanol (20 mi) and water (10 mi). After 24 h at room temperature, the solution was treated with NaHS04 solution until pH 6.5, whereupon the mixture was extracted with CH2C12. The dried (M9S04) extracts were 50 concentrated and the residue purified by chromatography (AG) followed by (AH) to give the title compound as a foam (0.45 g). IR (CHBr3 3600-3440,1730,1700 cm-1. TLC 9:1 Chloroform methanol Rf 0.7.

_GB 2 070 591 A 20 Example 14 [1 ct(Z),2p,Sal-(±)-7-[2-(4-Morpholinyi)-3-oxo-5-[(5phenyifuran-2-yi)methoxyI cyclopentyll-5heptenoic acid Trimethylsily] chloride (0.073 mi) was added to a solution of the product of Example 1 n) (0.25 9) and triethylamine (0.082 mi) in dry toluene (5 mi) at 00. After stirring for 5 min. the mixture was then added to a mixture of N-chloro-succinimide (0. 178 g) and dimethyisulphide (0. 107) in dry toluene (10 m]) and stirring continued for 45 min. Triethylamine (0.28 mi) was added followed after 5 min. by water (10 mi) and KH2P04 solution until pH 6. The mixture was extracted with ether (3 x20 mi) and the combined extracts washed with brine (50 mi) and dried (M9S04). Filtration and evaporation gave an oil 1() which was purified by flash chromatography (M). The title compound was obtained as a solid (0.084 10 g), which crystallised from ether, m.p. 91.5-92.51.

* Example 15 [1 a(Z),2p,3a,5a]-( )-Mathyl 7-[5-[4Acetylamino(phenyimethoxy)1-3-hydroxy-2-(4morpholinyi)cyclopentyll-5heptenoate Anhydrous K 2C03 (0.21 9) was added to a stirred solution of Intermediate 35 (0.61 9) in dry 15 methanol (20 mi). After 2.5 h, the suspension was poured into saturated NI-140 solution (50 mi), extracted with CH2C12 (3x30 mO, dried (M9S04), filtered and evaporated, and the residue purified by column chromatography (AJ) to give the title compound as an oil (0.5 g). IR (CHBr3) 3500 (br), 3420, 1725, 1685, 1510 cm-1. TLC (AJ) Rf 0.38.

Example 16 20 [1 a(Z),20,5a]-( )-Methyl 7-[5-[4-Acetylamino(phenyimethoxy]-2-(4- morpholinyi)-3-oxocyclopentyll-5-heptenoate Pyridinium trifluoroacetate (0.21 9) was added to a stirred mixture of the product of Example 15 (0.35 g) and dicyclohexylcarbodlimide (0.61 g) in dry DMSO (6 mi). After 30 min. the suspension was poured into water (50 mi), extracted with ether (3x40 mi), dried (M9S04), filtered and evaporated to 25 afford an oil, which was purified by column chromatography (AK) to give the title compound as a solid (0.3 g) m.p. 88-88.5'.

Example 17 (a) [l a(Z),2p,5a]-( )-Methyl 7-i[5-[4Methyithio(phonyimethoxy)1-2-(4-morpholinyi)-3-oxocyclopentyll-5-heptenoate A solution of the product of Example 5b) (0.5 g) in ether (10 mi) was treated with an excess ot ethereal CH2N2 at room temperature. Excess CH2N2 was destroyed by the addition of acetic acid. The solution was diluted with water and washed with 8% Nal-IC03 solution followed by water. Evaporation of the dried solvent afforded an oil which was purified by chromatography (G) to give the title compound(O.3 g) IR (CHBr3) 1735 cm-1 The following compounds were prepared by a similar procedure:

(b) [1 a(Z),2P.5a]-( )-Methyl 7- [5-[[4'-Methyl(1,1 1-biphonyl)-4-yl] rnothoxy]-2-(4-morpholinyi)-3oxocyclopentyll-5-heptenoate m.p. 82-860 (from ether-PE (b.p. 60-801)) from the product of Example 5a).

(C)[1"(Z),2P.5a]-( )-Methyi7-[5-[[4'-Methoxy(1,11-biphenyi)-4yl]rnetboxyl-2-( 4-niorpholinyi)- 40 3-oxocyclopentyll-5-heptonoate m.p. 79-840 (from EA-PE hp. 60-800)) from the product of Example 11 a).

(d) [1 a(Z),2p,5a]-( )-Methyl 7-[2-(4-Morpholinyl-3-oxo-5-[[[4(phenyimethyl)phenyl]4-yi]- rnethoxylcyclopentyll-5-heptenoate m.p. 30-3311 (from ether-isopentane at-200 from the product of Example 11 b).

Example 18 (a) (1 ct,2p,5a)-( )-5-[[41-Mothyl(1,1 1-biphenyl-4-yllmethoxy]-2-(4- morpholinyl)-3-oxo- cyclopentaneheptanoic acid A stirred solution of the product of Example 7a) (0.695 9) in acetone (20 mO was cooled to -100 and Jones reagent (2.67 M, 0.75 m[) added dropwise. After 1.25 h at-101 to -51 a further aliquot of 50 Jones reagent (0. 15 mO was added and stirring continued for a further 0. 5 h, whereupon the mixture was poured into pH 6.5 phosphate buffer (100 mi) and extracted with CHP2 (3 x30 mO, dried (M9S04), filtered and evaporated, and the residue purified by chromatography (J) followed by (AL) to give the title compound which crystallised from ether-EA-PE hp. 60-8011) as needles (0.345 g), m.p.

88-890.

Analysis Found: C, 72.5; H, 7.7; N, 2.6 C3.1---139NO, requires:C, 73.0; H, 8.0; N 2.8%.

21 GB 2 070 591 A -15 The following compounds were prepared using a similar procedure:

(b) [1 a(Z),2p,5a]-( )-7-2-(4-Morpholinyi)-3-oxo-5-[4phenyisulphonyi(phenyimethoxy) l- cyclopentyll-5-heptenoic acid from the product of Example 4d). Purification by chromatography (J) IR (CHBr3) 3490, 1730, 5 1730,1700, 1070cm-1.TLC(J)RfO.16.

(c) [l a(EL2p, 5a]-( )-7-5-[[41-M ethyl (1, l l-biphenyi)-4-yilmethoxy]-2(4-rnorpholinyi)-3-oxo- cyclopentyll-5-heptenoic acid from the product of Example 12. Purification by chromatography (J). m.p. 82-931.

Analysis Found: C, 73.0; H, 7.6; N, 2.6 C30H37NOr, requires: C, 73.3; H, 7.6; N, 2.9%.

(d) (1 a,2p,5a)-( )-5-[[41-Methoxy(1,1 1-biphenyi)-4-yil-2-(4morpholinyi)-3-oxo- cyclopentaneheptanoic acid from the product of Example 7c) m.p. 87-901.

AnalysisFound: C,70.7; H,8A; N,3.0.

C3,)H00. requires: Q70.7; H,7.7; K2.8%.

(a) [1 a(Z),2p,5a]-( )-7-[5-[4-N,N-Dimethylaminosulphonyi(phenyimethoxy)]2-(4-rnorp holinyi)- 3-oxocyclopentyll-5-heptenoic acid from the product of Example 9a). Purification by chromatography (AL). IR (CHBr3) 3480, 1738, 1700,1340 cm-1.

AnalysisFound: Q58.9; H,7.1; IN1,53 C25HaqN207S requires:Q59.0; H,7.1; N,5.5%.

(f) [1 a(Z),2p,5a]-( )-7-[5-[[41-Chloro(1,1 1-bipheny]-4-yilmethoxy]-2-(4morpholinyi)-3-oxo- cyclopentyll-5-heptenoic acid from the product of Example 13. Purification by chromatography (AG) followed by (T). IR (CHBr3) 3500,1740,1700cm-1.TLC95:5chloroform-methanoiRfO.4. 25 (9) [1 a(Z),2p,5cvl-( )-7-[2-(4-Morpholinyl)-3-oxo-5-[(5-phenyithien-2yi)methoxylcy clopentyll5-heptenoic acid from the product of Example 4f). IR (CHBr3) 3500,1740, 1705 cml. TILC 92. 5:7.5 CH2C12 -methanol Rf 0.35. Purification by chromatography (F) followed by (AM).

Example 19 [1 a(Z),2p,5a]-( )-7-[2-(4-Morpholinyl)-3-oxo-5-[(2phenylthien-4-yi)methoxylcyc lopentyll-5heptenoic acid The product of Example 1 k) (0.9 g) was stirred with 2N NaOH (5 mi) in methanol (10 mi) for 3h. The methanol was removed in vacuo and KH2P04 solution added until pH 6.5. The mixture was then extracted with EA (3xl 5 mi), washed with brine, dried (M9S04) and concentrated. The product (0.49 g) was oxidised according to the method of Example 11 a), except that trimethylsilyl chloride and toluene were used instead of triethylsilyl chloride and CH2C12 respectively, to give the title compound (0.31 g), m.p. 111-112 0.

Pharmaceutical Examples Tablets 40

Direct Compression Mg/tablet Active ingredient 100.00 Microcrystal line Cellulose 13.P.C. 298.00 Magnesium Stearate 2.00 Compression Weight 400.00 45 The active ingredient is sieved through a 250 m-8 sieve, blended with the excipients and compressed using 10.0 mm punches. Tablets of other strengths may be prepared by altering the compression weight and using punches to suit.

1 ection for intravenous Administration %W/V Active ingredient 0.50 Water for injections 13.P. to 100.00 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the active ingredient using either dilute acid 55 or alkali.

22 GB 2 070 591 A 22 The solution is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass. The injection is sterilised by heating in an autoclave using one of the acceptable cycles. Alternatively the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen.

Inhalation Cartridges Active ingredient (micronised) Lactose 13.P. to Icartridge 3 mg 25 mg The active ingredient is micronised so that the majority of the particles are between 1 m-6 and 5 m-6 in longest dimension and none are greater than 10 m6. The active ingredient is then blended with10 the lactose and the mix is filled into No. 3 hard gelatin capsules using a suitable filling machine.

Claims

1. Prostanoids of the general formula (1) in which A represents OR 4_ HO X is cis or trans -CH=CH- or -(CH,),7-; R, is straight or branched C, alkyl bearing as a terminal substituent - COORIO where RIO is a hydrogen atom, C,-, alkyl or C7-1. aralkyl; CA --- CH2 X R 1 Y G0 9R4' 1 or (h) 0 Y is a saturated heterocyclic amino group which has 5-8 ring members and (a) optionally contains in the ring -0-, -S-' -S02. -NIR14- (where R14 is a hydrogen atom, Cl-7 alkyl or aralkyl having a Cl-4 alkyl portion), >C(OffiR6 (where R5 is a hydrogen atom, Cl-7 alkyl, phenyl, or aralkyl having a Cl-4 alkyl portion); and/or (b) is optionally substituted by one or more Cl-4 alkyl groups; R4 is M aralkyl (having a Cl-3 alkyl portion and the aryl portion being substituted by Cl-3 alkylthio 25 Cl-3 alkylsulphinyl, Cl-3 alkylsulphonyl, Cl3 alkanoyl amino, aroylamino, phenylalkyl having a C,-3 alkyl portion, aminosulphonyl (the amino group being optionally substituted by one or two Cl-3 alkyl groups), Cl-3 alkanoylaminosulphonyl (the amino group being optionally substituted by Cl-3 alkyl, phenyisulphonyl (the phenyl portion being optionally substituted by Cl-3 alkyl), nitro, tetrazol-5-yl, phenyl substituted by R5 (where R5 is Cl-4 alkyl. Cl-4 alkoxy, halogen or phenyl), or thienyl); or (10 the group:

-alk R' l z,> where alMS C,-3 alkyiene; Z is 0, or S; W' is a hydrogen atom; Cl-, alkyl; Cl-, alkoxy; aryl or phenylalkoxy or phenylalkyl having a C 1-3 35 alkyl portion (the aryl portion in each case being optionally substituted by C,-3 alkyl, Cl3 alkoxy or halogen); aryloxy; C.-7 cycloalkyl; halogen or nitro; and the physiologically acceptable salts thereof.

2. Compounds as claimed in claim 1 in which A is the group (b).

3. Compounds as claimed in claim 1 or claim 2 in which Y is morpholino, dioxothiamorpholino 40 or piperidino.

4. Compounds as claimed in any of the preceding claims in which X is cis CH=CH,

5. Compounds as claimed in any one of the preceding claims in which R' is -(CH2)3COOR" where RIO is a hydrogen atom or Cl-4 alkyl.

6. Compounds as claimed in any one of the preceding claims in which R 4 is benzyl substituted by 45 phenyl-(Cl_3) alkyl or phenyl substituted by C,., alkoxy or Cl., alkyl, or is thienyimethyl substituted by phenyl or (C 3 alkoxy) phenyl.

23 GB 2 070 591 A 23

7. Compounds as claimed in claim 1 in which: A is the group (b), X is cis -CH=CH; R1 is -(CH2),COOH, Y is morpholino, piperidino or dioxothlamorpholino, and R 4 is benzyl substituted by phenethyl, benzyl, methoxyphenyl or methylphenyl, or is m ethoxyphenylth ienyl m ethyl.

8. Compounds as claimed in any one of the preceding claims, other than those in which R4 is aralkyl substituted by thienyl, substituted aminosulphonyl or substituted alkanoylaminosulphonyl.

9. A pharmaceutical composition comprising a compound as claimed in anyone of the preceding 10 claims together with one or more pharmaceutical carriers.

10. A process for the preparation of a compound as claimed in claim 1 which comprises:

(a) in the preparation of compounds of formula (2) qR4 fa R - Y (2) (whereYandR 4 are as defined in claim 1 and R18 is as defined for R' where RIO is a hydrogen atom), 15 reacting a compound of formula (3) or (3a) Y 0 QR OH # Y (3a) (3) 611 6R4 with a phosphorane R121"=CHR1a or a salt thereof (where R12 is C 3 1-6 alkyl or aryi); (b) in the preparation of a compound in which A is (b), oxidising a pompound as defined in claim 1 20 in which A is (a) (c) esterifying a compound as defined in claim 1 in which R10 is hydrogen to prepare a compound in which RIO is alkyl or aralkyl; (d) saponifying a corresponding ester to prepare a compound as defined in claim 1 in which RIO is hydrogen; (e) isomerising a compound as defined in claim 1 in which A is the group (a) and X is cis 25 -CH=CH- to prepare the corresponding trans compound; (f) catalytically hydrogenating a compound as defined in claim 1 in which X is -CH=CH- to produce a compound in which X is -(CH2)2_; (g) etherifying a compound as defined in claim 1 in which A is the group (a) and -OR 4 represents hydroxy, any other hydroxy group present being protected during the reaction; (h) in the preparation of a compound as defined in claim 1 in which A is (a), removing the protecting group from a corresponding compound in which the ring hydroxy group is protected; (i) in the preparation of a compound as defined in claim 1 in which R' is aralkyl substituted by alkanoylamino, acylating the corresponding amine; (j) in the preparation of a compound as defined in claim 1 in which A is the group (a) and R 4 is 35 aralkyl substituted by alkylsulphinyl or alkylsulphonyl oxidising the corresponding alkylthio compound; (k) in the preparation of a compound as defined in claim 1 in which A is the group (a) and Y is a substituted amino group, substituting the corresponding compound in.which Y is -NH,; or (1) treating a compound as defined in claim 1 with an acid (where RIO is hydrogen) a base to form a salt.

11. A compound as claimed in claim 1, said compound being the title compound of any one of the Examples herein.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1981. Published by the Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.