CA1119591A

CA1119591A - Prostane derivatives

Info

Publication number: CA1119591A
Application number: CA000291953A
Authority: CA
Inventors: Keith H. Gibson; Edward R. H. Walker
Original assignee: Imperial Chemical Industries Ltd
Current assignee: Imperial Chemical Industries Ltd
Priority date: 1976-12-08
Filing date: 1977-11-29
Publication date: 1982-03-09
Also published as: DK548177A; IE46170B1; BE861652A; NL7713587A; DE2754741A1; ZA777059B; FR2373538B1; GB1550399A; FR2373538A1; NZ185822A; IE46170L; JPS5371060A; IT1089433B; SE7713895L; AU3104477A

Abstract

ABSTRACT OF THE DISCLOSURE

The disclosure relates to novel .omega.-pentanor prostag-landin E analogs bearing a 4- or 5-membered O or S hetero-ring as 15-substituent, for example 15-(3-butyloxetan-3-yl)-ll.alpha.,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, which are useful as inhibitors of gastric acid production in mammals, together with pharmaceutical and veterinary compositions containing such compounds, and a method of using such compounds to inhibit gastric acid production in mammals.

Description

~ 959~

This invention relates to novel prostane derivatives and processes for their manufacture, and in particular it relates to novel prostane de-rivatives which inhibit gastric acid production in mammals.
According to the invention there is provided ~ ~`cH2 A (C~12)2CHR R
< I CH2 X
~ 2.CR3(OH)-CR -CH2 HO

wherein Rl is a carboxy radical or a C2 5-alkoxycarbonyl radical, R and R3, which may be the same or different, are each a hydrogen atom or a Cl 4alkyl radical, Al is an ethylene or vinylene radical, A2 is an ethylene or trans-vinylene radical, R4 is a Cl 7alkyl radical, or a phenyl, phenoxy, phenylthio or phenyl (Cl 4alkyl) radical in which the phenyl ring is un-substituted or is substituted by one or more halogen atoms, nitro or phenyl radicals, Cl 4alkyl, alkoxy or halogenoalkyl radicals, or di(Cl 4alkyl) amino radicals, and X represents an oxygen or sulphur atom, or a sulphinyl radical, and, for those compounds wherein Rl is a carboxy radical, the pharmaceutically or veterinarily acceptable salts thereof.
A suitable value for Rl when it is an alkoxycarbonyl radical is, for example, a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxy-carbonyl radical.
A suitable value for R2 or R3 when either is an alkyl radical is, for example, a methyl, ethyl, propyl or butyl radical.

A suitable value for R4 when it is an alkyl radical is, for example, a methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl radical, particularly a n-butyl radical.
Suitable halogen substituents in R4 when it is a substituted ,`~ - 2 -i~-5~1 phenyl~ phenoxy, phenylthio or phenyl(Cl 4alkyl) radical are, for example, chlorine, bromine or fluorine atoms, particularly a chlorine atom, and suitable alkyl, alkoxy and halogenoalkyl substituents are, for example, methyl, ethyl, methoxy, ethoxy, trifluoromethyl or 2,2,2-trichloroethyl radicals.
A suitable value for Al when it is a vinylene radical is, for example, a cis-vinylene radical.
Examples of suitable base addition salts are ammonium, alkylammo-nium containing 1 to 4 Cl 4alkyl radicals, alkanolammonium containing 1 to 3 2-hydroxyethyl radicals, and alkali metal salts, for example the ammo-nium, triethylammonium, ethanolammnonium, diethanolammonium, sodium and potassium salts.
A preferred value for X is an oxygen atom.
A preferred group of prostane derivatives of the invention com-prises those compounds wherein Rl is a carboxy, methoxycarbonyl or ethoxy-carbonyl radical, R and R3 are each a hydrogen atom, Al is a cis-vinylene radical, A2 is a trans-vinylene radical, R4 is a Cl 7alkyl radical or a benzyl, phenyl, phenethyl or phenoxy radical, optionally substituted as defined above, and X is an oxygen or sulphur atom or a sulphinyl radical.
A preferred compound of the invention is 15-(3-butyloxetan-3-yl)-lloc,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadi-enoic acid.
It will be observed that a prostane derivative of the invention contains at least four asymmetrically substituted carbon atoms, namely, carbon atoms 8, 11, 12 and 15 of the prostane nucleus, and that carbon atom

2 and the carbon atom of the group CR4 may also be asymmetrically substi-tuted. Therefore, although the relative configurations at carbon atoms 8, 11 and 12 are fixed, it is clear that a prostane derivative of the inven-tion may exist in a variety of racemic and optically active forms. It is B - 3 _ 3S9l to be understood that this invention relates to any racemic or optically active compound of the formula I which possesses the useful gastric acid inhibitory properties referred to above, it being a matter of common ge-neral knowledge how the racemates and optically active forms may be ob-tained, and their gastric acid inhibitory properties determined.
The novel prostane derivatives of the invention may be manufactured by methods known in themselves for the manufacture of chemically analogous compounds. Thus, the invention provides the following processes, in which R , R , R3, R4, Al, A2 and X have the meanings defined above, unless other-wise specified:-(a) for those compounds wherein R3 is a hydrogen atom, the hydrolysis under acidic conditions of a compound of the formula:

'CH2-Al(CH2)2CHRlR2 ~ ~ CH2 X II
R50~ A .CR3(oR5)-CR4-CH2 wherein R5 is a tetrahydropyran-2-yl radical, for example with acetic acid, or with toluene-p-sulphonic acid in a Cl 4alkanol;
or (b) for those compounds wherein Kl is an alkoxycarbonyl radical, the reaction of a carboxylic acid of the formula I, wherein Rl is a carboxy radical, with a Cl 4diazoalkane, or of a salt thereof, for example a sodium or silver salt, with a Cl 4alkyl halide for example an alkyl bromide or alkyl iodide; or (c) for those compounds wherein R3 is an alkyl radical, the hydrolysis of a tri(Cl 4alkyl) silyl ether of the formula:

.~ - 4 -~119591 ~ ,~ CH2Al (CH2)2CHRlR

R6R R SiO~ CH2-X IV
wherein R is a Cl 4alkyl radical, and R , R7 and R8, which may be the same or different, are each a Cl 4alkyl radical; or (d) for those compounds wherein R3 is an alkyl radical, the selective oxidation, for example with Jones' reagent, for those compounds wherein X is an oxygen atom or a sulphinyl radical, or with the Pfit~ner-Moffatt reagent (dicyclohexylcarbodi-imide/pyridinium trifluoroacetate/dimethyl sulphoxide) of a compound of the formula:
HO
~" ` CH2Al (CH2) 2CHRlR

HO ~ 2.CR3(OH)-CR -CH2 V

wherein R3 is a Cl 4alkyl radical, whereafter if necessary iso-meric 9-oxo and ll-oxo products, and sulphinyl and sulphonyl pro-ducts, are separated, by conventional means, for example by chrom-atography.
A starting material of the formula II wherein R5 is a carboxy ra-dical, R2 and R3 are each a hydrogen atom, Al is a cis-vinylene radical and A2 is a trans-vinylene radical may be prepared by reacting 4~-formyl-2,3,3a~,6a~-tetrahydro-2-oxo-5~-(4-phenylbenzyloxy)cyclopenteno[b]furan (VI) with a phosphonate reagent of the formula (Cl 4alkoxy)2PO.CH2CORJ

wherein R represents -CR4 - CH2 wherein X is an oxygen or sulphur atom, in the presence of a strong base, to give an enone VII. The enone VII is reduced, for example with aluminium tri-isopropoxide or di-isobornyloxy aluminium isopropoxide to an enol VIII, which is hydrolysed, for example 59~

with potassium carbonate in methanol, to remove the protecting 4-phenylben-zoyl radical, giving a diol IX. The diol is protected as the bis(tetra-hydropyranyl ether) X, by reaction with dihydropyran, and the lactone ring is reduced to a lactol XI using, for example di-isobutyl aluminium hydride.
The lactol XI is then treated with a (4-carboxybutyl)triphenylphosphonium bromide in the presence of a strong base to give a compound XII, which is oxidised, for example with Jones' reagent, to give a starting material of the formula II. If in the intermediate XII, X is a sulphur atom, Jones' reagent will oxidise the sulphur to a sulphinyl or sulphonyl group. If it is desired to obtain a starting material of the formula II wherein X is a sulphur atom, it is necessary to replace the Jones' reagent by a more se-lective oxidising agent, for example the Pfitzner-Moffatt reagent (dicyclo-hexylcarbodi-imide/pyridinium trifluoroacetate/dimethylsulphoxide). The conditions for forming the compound XII may, of course, be chosen so as to produce predominantly either the 5-cis or the 5-trans compound, in known manner.
~6~ ,~/0 O \ O

~ CHO ~ ~ O.R
PB.O\` PB.O~
VI VII
~,0 ~0 O ~ O

~ CH(OH)R~ / ~ CH(OH)R
PB.O~` HO\
VIII IX

PB = 4-phenylbenzoyl 59~

_ ~ ~OH
O ~ 0 ~

C(5 CH(O.THP)R Ci ~ CH(O.'llIP)R
THP . O THP . O
X XI
HO ~, \CH (O THP) R ~ I I
THP.O `
XII
THP = tetrahydropyran-2-yl A suitable phosphonate reagent (CH3O)2Po.CH2COR wherein R is a

3-butyloxetan-3-yl radical may be prepared by treating hexanal with for-maldehyde to give 2,2-bis(hydroxymethyl)-hexanol, which is converted, by reaction with diethyl carbonate, to the cyclic carbonate, 5-butyl-5-hydroxy-methyl-2-oxo-1,3-dioxin, and pyrolysis of the cyclic carbonate, to 3-butyl-3-(hydroxymethyl)oxetan. Oxidation of 3-butyl-3-(hydroxymethyl)oxetan with potassium permanganate gives 3-butyloxetan-3-carboxylic acid, and esteri-fication with diazomethane gives methyl 3-butyloxetan-3-carboxylate, which on reaction with dimethyl methylphosphonate in the presence of a base gives the required phosphonate reagent.
Other pllosphonate reagents for the manufacture of starting materi-als of the formula II wherein X is an oxygen atom and R4 is other than a butyl radical may be prepared in a similar manner by starting from an ap-propriate aldehyde in place of hexanal.
Other phosphonate reagents for the manufacture of starting materi-als of the formula II wherein X IS a sulphur atom may be obtained by react-ing the cyclic carbonate described above with potassium thiocyanate to give a 3-substituted-3-(hydroxymethyl)thietan derivative, which is further trans-l~9S!g~

formed in the same way as 3-butyl-3-(hydroxymethyl)oxetan, described above.
A phosphonate reagent for the manufacture of starting materials of the formula II wherein R is an oxetan-2-yl radical and R4 is other than a phenoxy or phenylthio radical may also be prepared by reacting an ~-oxo-ester XIII with an ethylene derivative optionally bearin~ one or more Cl 4alkyl substituents, R5 (XIV) in a photochemical reaction to give an oxetan-2-carboxylic ester XV which is reacted with dimethyl methylphos-phonate in the presence of a base to give the desired phosphonate reagent, XVI

\ / o ~ COOEt o CO.CH2Po~Me)2 R .CO.COOEt + ll ~ R ~ R ~ R ¦ ¦- R
C \ R5 R5 R5 R5 XIII XIV XV XVI

S~

A phosphonate reagent for the manufacture of starting materials of the formula II wherein R is a thietan-2-yl radical and R4 is other than a phenoxy or phenylthio radical, may be obtained by the reaction of a halide, R4Br or R I, with the dianion XVII obtained from a thietan-2-carboxylic acid in the presence of a strong base, to give a compound XVIII, which in turn esterified with diazomethane, and the methyl ester XIX
is reacted with dime~hyl methylphosphonate in the presence of a base to give the desired phosphonate, XX.

R5 _ I S ~ R4Br R5 _ S

R5 ~ 2 >R5 , ~ C2 XVII XVIII

R5 _ ~ - S R5 ~ S

R ~ C2Me ~R5 _ ~ CO.CH2Po~oMe)2 : ~5 R4 XIX 5 R XX
Phosphonates containing tetrahydrofur-2-yl and tetra-hydrothien-2-yl radicals are obtained similarly, using the dianions from, respectively, tetrahydrofuran-2-carboxylic acid and tetrahydrothiophen-2-carboxylic acid in place of the dianion XVI.

~1959~

Phosphonate reagellts for the manufacture of starting materials of the formula II wherein R is a tetrahydrofur-3-yl radical and R4 is other than a phenoxy or phenylthio radical may be obtained by alkylating the dianion XXI obtained from the acid P~4CH2CooH in the presence of a strong base, wi.th 2-(tetra-hydropyran-2-yloxy)ethylbromide to give the acid XXII which is ~urther alkylated with alkaline formaldehyde to the hydroxy-acid XXIII. The tetrahydropyranyl ether is hydrolysed wi.th acid to the diol (XXIV), the carboxy group is esterified with diazomethane to the ester XXV, and the diol is converted to the cyclic carbonate XXVI with diethyl carbonate. Pyro].ysis of the cyclic carbonate XXVI gives the tetrahydrofur-2-yl ester XXVII~ which on reaction with dimethyl methylphosphonate in the presence of a base gives the desired phosphonate XXVIII.
Alternatively, the phosphonate required for the manufacture of starting materials of the formula II wherein R
is a tetrahydrothien-~-yl radical and R4 is other than a phenoxy or phenylthio radical, may be obtained by reacting the cyclic carbonate XXVI with sodium thiocyanate to give a tetrahydrot~io phen-3-carboxylic ester XXIX which is converted to the required phosphonate XXX as described above.

R4.gH.Coo ~ R4.CH.CooH~ R4C-CooH I 2 XXI XXII XXIII XXIV
/~
-~2 -5~1 CH2H ll R4 CI-COOMe CH2CH20H ~ COOMe OOMe XXV XXVI XXVII
~ 1 ~ OOMe ~ OCH2PO(OME)2 ~ CO.CH2PO(OME)2 XXIX XXX XXXVIII
Phosphonate reagents for the manufacture of starting materials of the formula II wherein R is a tetrahydrofur-3-yl radical and R4 is a phenoxy radical may be prepared by reacting tetrahydrofuran-3-one (XXI) with methyltriphenylphosphonium bromide in the presence of a base to give 3-methylene-tetrahydro-furan (XXXII) which is hydroxylated with osmium tetroxide to the diol XXXIII. The diol XXXIII is oxidised to the hydroxy-acid XXXIV with potassium permanganate, and the hydroxy-acid is reacted with diazomethane to give the hydroxy-ester, which on reaction with a phenylthienyliodonium iodide gives the phenoxy-ester XXXV. The phenoxy-ester is then converted to the desired phosphonate by reaction with dimethyl methylphosphonate in the presence of a base.

~ ~ ~ C~ CH20H ~

XXXI XXXII XXXIII

II (R4 = phenoxy) ~ COOH I ¦ ~OOMe XXXIV XXXV R
Similar phosphonates wherein R is a tetrahydrothien-3-yl radical and R4 is a phenoxy radical may be obtained similarly from tetrahydrothiophen-3-one, except that the diol corresponding to XXXIII must be purified from minor amounts of the corresponding sulphinyl and sulphonyl compounds which may be also formed during the hydroxylation reaction, and the oxidation of the diol to the hydroxy-acid must be carried out in two stages, first with the PfitzneT-Moffatt reagent to give the intermedia~e hydroxy-aldehyde, which is then further oxidised to the required hydroxy-acid with silver oxide.
A starting material of the formula II wherein Al is an ethylene radical may be obtained by selective hydrogenation or reduction of a corresponding starting material of the formula II wherein Al is a cis-vinylene radical.
A starting material of the formula II wherein A is an ethylene radical may be prepared by hydrogenation or reduction X

~119591 of a corresponding enone intermediate VII to give a saturated ketone, which is then used in the above-described reaction sequence in place of the enone VII.
A starting material of the formula IV may be prepared from a bis(tetrahydropyranyl ether) XII by hydrolysing the tetrahydropyranyl groups to give a starting material of the formula V (R = carboxy), and oxidising with dichloro-dicyanobenzoquinone to an enone XXXVII. The enone XXXVII is silylated to a tris(trimethylsilyl) derivative XXXVIII, which is treated with a Grignard reagent R3Mg.halogen to give an alcohol XXXIX. The silyl groups are removed, and the acid is esterified to give an ester XL, which is mono-silylated with R6R7R8Si.NEt2 in acetone at about -20C. to give a silyl de-rivative XLI, which is oxidised with Collins' reagent to a starting material IV (Rl = methoxycarbonyl).
It is,of course, to be understood that an optically active com-pound of the invention may be obtained either by HO, ~ ~CH2Al~cH2)2cHR .COOH

XII> V ~ ~ <
~ --A2.CO.R
HO~`
XXXVII

TMS.O~ TMS.O, CH2Al(CH2)2CHR COO.TMS ~ CH2Al(CH2)2CHR2COO.TMS

A .CO.R ~ A2 CR3(OH)R
TMS.O` TMS.Oi`
XXXVIII XXXIX

HO ~ CH2A (CH2)2C~lR COOMe ~ CHzA (CH2)2CHR .COOMe A2 CR3~ ~ R A2.CR (OH)R
HO~"' R R R Si.O" XLI

TMS = trimethylsilyl ~,) SCI~

resolving a corresponding racemate, or by carrying out the above described reaction sequences starting from an optically active intermediate, for example an optically active aldehyde VI.
As stated above, the novel prostane derivatives of thc invention possess the ability to inhibit the production of gastric acid secretions in mammals, and they possess an advantage in that they are relatively non-toxic; that is they possess a -~ - 14 -S~l high "therapeutic ratio" of toxic dose to the dose which causes undesirable side effects, for example by causing diarrhoea in mice. Thus, for example, 15-(3-butyloxetan-3-yl)-11~,15-di-hydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prosta-dienoic acid inhibits gastric acid to the extent of 50% in a test in the anaesthetised rat, at intravenous dose of 6.7 ~g./kg., but induces diarrhoea in mice only at an oral dose of 1200 ~g./kg.
When a prostane derivative of the invention is to be used for reducing gastric acid production in man, it is to be used in substantially the same way as it is known to use prosta-glandin E2 or ~15S)- or (15R)-15-methyl-prostaglandin E2 methyl ester for similar purposes. Such prostaglandin analogues have been administered orally, in aqueous solution, at doses of 2.5 to 4.0 mg. for prostaglandin E2, and 100 to 200 ~g. for (15S)-and (15R)-15-methyl-prostaglandin E2 methyl ester. The latter compound has been k~own to promote healing of gastric ulcers in Chinese subjects when administered orally at 150 ~g. in 20 ml.
of water at 6 hourly intervals for 2 weeks.
Thus, according to a further feature of the invention there is provided a pharmaceutical or veterinary composition comprising a prostane derivative of the formula I as defined above, together with a pharmaceutically or veterinarily acceptable diluent or carrier.
The composition is preferably in the form of a tablet or capsule or a substantially aqueous solution, and a preferred composition is a substantially aqueous solution containing 30 to 120 ~g./ml., preferably 30 to 60 ~g./ml. of the prostane derivative.

The compositions of the invention may be manufactured by conventional means, and may contain conventional pharmaceutical excipients in addition to the active constituent and the diluent or carrier. For exa~ple, the compositions of the invention may be stabilised in known manner, such as by addition thereto of dimethylacetamide, an alkali metal or alkaline earth metal bisulphite, or a C4 10 saturated aliphatic tertiary alcohol.
The invention is illustrated, but not limited, by the following Example:-Example 1 A solution of lS-(3-butyloxetan-3-yl~-9-oxo-11,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid (100 mg.) in tetrahydrofuran ~2.8 ml.) and a 2:1 v/v mixture of acetic acid and water (7.0 ml.) was stirred at 45C. for 5 hours. The solvents were evaporated under reduced pressure and the residue was purified by prepara-tive thin layer chromatography on silica gel (Merck "Kieselgel"*
60F254) developed in 3% glacial acetic acid in ethyl acetate to give the more polar C-15 epimer of 15-(3-butyloxetan-3-yl)-lla, 15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prosta-dienoic acid, RF = 0 35 (3% v/v acetic acid in e*hyl acetate).
The n.m.r. spectrum in deuterated acetone showed the following characteristic features (~ values):-

4.15, lH, quartet, C-ll~ proton, 4.25, 2H, doublet ) oxe~an C-2 and C-4 protons, 4.6, 2H, quartet 4.7-5.2, 4H, multiplet, carboxy, 2 x hydroxy and C-15 proton, *Trademark - 16 -

5.4, 2H, cis-olefinic protons, 5.8, 2H, trans-olefinic protons.
The mass spectrum of the 1,11,15-tris(trimethylsilyl) derivative showed ~M-CH3) = 595.3297. ~Calculated for C30 556Si3 595 33 63-The bis~tetrahydropyranyl ether) used as starting material may be prepared as follows:-Hexanal ~10 g.), formalin (37% w/v, 81 ml.) and sodiumhydroxide (4.8 g.) were dissolved in water (20 ml.) and the solution was heated to 50C. and stirred for 1 hour. The reaction mixture was cooled to ambient temperature and extracted with ethyl acetate (3 x 50 ml.), the combined organic extracts were washed with brine ~1 x 50 ml.~ and dried over sodium sulphate, and the solvent was evaporated to a viscous syrup which was purified by distillation under reduced pressure to give the triol, 2,2-bis~hydroxymethyl)hexanol ~b.p. 150-160C., 0.3 mm.
of mercury). The n.m.r. spectrum in deuteriochloroform showed the following characteristic bands (~ values):-0.9, 3H, t~iplet, methyl, 1.25, 6H, broad singlet, 3 x C ~ ~
3.65, 9H, broad singlet, 3 x _ C_20H
A solution of potassium hydroxide (3.0 mg.) in dry ethyl alcohol (0.3 ml.) was added to a mixture of the triol (8.1 g.) and diethyl carbonate ~5.9 g.).

59~L

The reaction mixture was heated under reflux for 15 minutes, the ethanol was evaporated under reduced pressure of 50 mm. of Hg. The temperature was then raised to 200C., the crude alcohol, ~-butyl-3-hydroxymethyloxetan rapidly dis-tilled, and was then purified by re-distillation (b.p. 74-78C., 0.1 mm. of mercury).
The n.m.r. spectrum in deuterioc~oroform showed the following characteristic signals (~ values):-0.9, 3H, triplet, methyl, 1.1-2, 6H, multiplet, 3 x ~CH2, 2.4, lH, broad singlet, hydroxy, 3.8, 2H, singlet, ~ CH20H
4.5, 4H, singlet, oxetan C-2 and C-4 protons.
The alcohol (3.4 g.) was suspended in N sodium hydroxide solution (23.6 ml.), and potassium permanganate (4.93 g.) was added over a period of 1 hour. The reaction mixture was stirred for a further hour, and the manganese dioxide was removed by filtration. The ~iltrate was acidified to pH3 with (+)-sodium hydrogen tartrate and extracted with ethyl acetate (3 x 30 ml.), and the combined organic extracts were dried over sodium sulphate and evaporated to dryness, to give the acid~ 3-butyloxetan-3-carboxylic acid. The n.m.r.
spectrum in deuteriochloroform showed the following characteristic bands (S values):-0.9, 3H, triplet, methyl, 1.0-2.2, 6H, multiplet, 3 x ~CH2 .~ J~
-- 2~ --~195~1 4.5, 2H, doublet ) oxetan C-2 and C-4 protons, 4.95, 211, doublet ) 10.3, lH, broad singlet, carboxyl.
The acid (3.16 g.) was dissolved in diethyl ether ~10 ml.) and ethereal diazomethane added until the Teaction mixture remained yellow. The excess of diazomethane was immediately evaporated under a stream of argon, the resulting clear solution was dried over sodium sulphate, and the solvent waS evapo~ated to leave an oil, which was distilled to give methyl 3-butyloxetan-3-carboxylate, b.p. 98-102C. at 14 mm.
of Hg. The n.m.r. spectrum in deuteriochloroform shows the following characteristic bands (~ values):-0.1, 3H, triplet, methyl, 1.0-1.6, 4H, multiplet -CH2CH2-, 1.7-2.2, 2H, multiplet -CH2-3.8, 3H, singlet, methyl ester~

4.5, 2H, doublet ) oxetan C-2 and C-4 protons.
5.0, 211, doublet n-Butyl-lithium (20.2 ml. of a l.S9M solution in hexane) was added to a solution of dimethyl methylphosphonate ~3.48 ml.) in dry tetrahydrofuran ~150 ml.) at -70C. under an atmosphere of argon. After 10 minutes, methyl 3-butyloxetan-3-carboxylate ~2.77 g.) was added, and the mixture was stirTed for 1.5 hours at -70C. The pH of the cold reaction mixture was adjusted to pH6 with ~)-sodium hydrogen tartrate, and the resulting solution was extracted with ethyl acetate ~3 x 50 ml.).

5~1 The combined organic extracts were washed with brine (50 ml.) and dried over sodium sulphate, and the solvent was evaporated under reduced pressure, to give the phosphonate~ dimethyl 2-(3-butyloxetan-3-yl)-2-oxoethylphosphonate. The n.m.r. spectrum in deuteriochloro~orm showed the following characteristic bands (~ values):-3.15, 2H, doublet (JC~ _p = 22 Hz.), -CO.CH2-3.8, 6H, doublet (JCH _p = 11 Hz.), methoxy, 4.4, 2H, doublet ) ) oxetan C-2 and C-4 protons.
4.9, 2H, doublet ) The phosphonate (3.4 g.) was suspended in toluene ~45 ml.) in an atmosphere of argon and 4~-formyl-2,3,3a~,6a~-tetrahydro-2-oxo-5a-(4-phenylbenzoyloxy)cyclopenteno[b]furan (3.0 g.) was added, followed by aqueous sodium hydroxide (10.7 ml.
Or a lM solution). The two phase mixture was stirred vigorously for 16 hours, poured into a mixture of saturated brine (10 ml.) and ethyl acetate (10 ml.) and filtered through kieselguhr ("Celite"-trade mark), and the organic phase of the filtrate was separated. The aqueous layer was extracted with ethyl acetate (2 x 10 ml.), the combined organic extracts were washed with brine and dried, and the solvent was evaporated to dry~ess.
Trituration of the residue with ether gave the enone, 4~-[3-(3-butyloxetan-3-yl)-3-oxo-1-trans-propenyl]-2,3,3a~,6a~-tetra-hydro-5a-(4-phenylbenzoyloxy)-2-oxocyclopenteno[b]furan, R~ -0.37 (5010 v~v ethyl acetate in toluene). The n.m.r. spectrum 2~ in deuteriochloroform showed the following characteristic bands (~ values)~
B ~

lil~591 4.45, 2H, doublet ) oxetan C-2 and C-4 protons, 4.85, 2H, doublet 5.15, lH, multiplet ) C-5~ and C-6a~ protons, 5.35, lH, multiplet

6.3, lH, doublet, (J = 14 Hz.), -CH=CH-CO-, 6.8, lH, double doublet, (Jl 2 = 14.0 H~.) tJl 4 = 8.0 Hz.),-CH=CH_Co_,

7.5, 7H, multiplet, aromatic protons,

8.0, 2H, doublet, Ph ~ CO-~ H

The enone ~1.026 g.) was stirred under an a~mosphere of argon at reflux temperature with a 0.36M solution of di-iso-bornyloxy aluminium isopropoxide in toluene ~29.2 ml., 5 equivalents) for 1.5 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogen tartrate ~40 ml.) was added, and the solution was stirred rapidly at room temperature for 30 minutes. The mixture was filtered through kieselguhr ~"Celite"), and the aqueous layer was separated and extracted with ethyl acetate ~3 x 25 ml.), the combined organic extracts were dried, and the solvent was evaporated to give a mixture of isoborneol and the mixed epimers of the unsaturated alcohol, 4~-[3-butyloxetan-3-yl)-3-hydroxy-l-trans-propenyl]-2,3,3a~,6a~-tetrahydro-5-t4-phenylbenzoyloxy)-2-oxocyclopenteno[b]furan, ~ = 0.1 (50% v/v ethyl acetate in toluene), which was used without purification in the next reaction.

~' 5~1 The mixture of isoborneol and epimeric unsaturated alcohols produced above was stirred vigorously for 2 hours with finely powdered anhydrous potassium carbonate (350 mg.) in dry methanol ~10.0 ml.).
The reactîon product was added to a mixture of brine (5 ml.) and ethyl acetate (20 ml.) the pH was adjusted to 7 with sodium hydrogen tartrate, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2 x 30 ml.) and the combined organic extracts were dried over sodium sulphate and evaporated to dryness, to give a mixture of the epimeric diols, 4~-[3-(3-butyloxetan-3-yl)-1-trans-propenyl]-2,3,3a~,6a~-tetrahydro-5~-hydroxy-2-oxocyclopenteno-[b]furan, RF = 0.19 (ethyl acetate).
To a solution of the epimeric diols (500 mg.) in methylene dichloride (10 ml.) under an atmosphere of argon were added successively redistilled 2,3-dihydropyran (1.36 ml.) and a solution of anhydrous toluene-p-sulphonic acid in tetrahydro-furan (70 ~1. of a O.lM solution). After 30 minutes, pyridine (10 drops) was added followed by ethyl acetate (40 ml.). The solution was washed successively with saturated sodium bi-carbonate solution and saturated brine, and was dried. Evapor-ation of the solvents gave a mixture of epimeric bis-tetrahydro-pyranyl ethers, 4~[3-(3-butyloxetan-3-yl)-3-(tetrahydropyran-2-yloxy)-1-trans-propenyl~-2,3,3a~,6a~-tetrahydro-2-oxo-5~-(tetrahydropyran-2-yloxy)cyclopenteno[b]~uran as a clear oil, RF = 0.51 (ethyl acetate~.
To a solution of the epimeric bis-tetrahydropyranyl ethers (1.62 mmole) in dry toluene (10 ml.) under an atmosphere 55~

of argon at -78C. was added a solution of di-isobutyl-aluminium hydride in toluene 2.64 ml. of a 1.23M solution.
After 20 minutes the reaction was quenched by the addition of methanol (5 ml.) and the mixture was allowed to warm to ambient temperature. Ethyl acetate (10 ml.) was added and the resulting precipitate was removed by filtration through "Celite". The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3 x 50 ml.). The combined extracts were washed with saturated brine and dried, and the solvents were evaporated to give a mixture of epimers of the lactol, 4~-~3-(3-butyloxetan-3-yl)-3-(tetrahydropyran-2-yloxy) l-trans-propenyl]-2,3,3a~,6a~-tetrahydro-2-hydroxy-5~-(tetrahydropyran-2-yloxy)cyclopenteno[b~furan, RF = 0 3 (ethyl acetate).
(4-Carboxybutyl)triphenylphosphonium bromide (4.88 g.) and potassium t-butoxide (2.45 g.) were suspended in dry toluene (100 ml.) under an atmosphere of argon, and stirred at 90C.
for 30 minutes to give a deep red 0.094M toluene solution of the ylide, which was allowed to cool to room temperature. The lactol (656 mg.) was dissolved in dry toluene (15 ml.) under an atmosphere of argon, and the ylide solution was added (38 ml.
of the 0.094M toluene solution). After 10 minutes at room temperature, water (1 ml.) was added and the toluene evaporated.
The residue was dissolved in water ~6.8 ml.) and the aqueous solution was washed with ether (4 x 5 ml.), adjusted to pH3 with oxalic acid and extracted with a 1:1 v/v mixture of ether/pentane (4 x 5 ml.) to give an acidic extract. The combined acidic extracts were dried, and evaporation of the solvents gave the ~i 15~1 mixed C-15 epimers of 15-(3-butyloxetan-3-yl)-9~-hydroxy-11~, 15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid, RF = 0.1 (50% v/v ethyl acetate in toluene) which were purified by column chromatography on MFC Silica gel developed in 20% v/v acetone in cyclohexane.
A solution of 15-(3-butyloxetan-3-yl)-9~-hydroxy-lla, 15-bis(tetrahydropyran-2-yloxy)-16~17,18,19,20-pentanor-5-cis, 13-tr -prostadienoic acid (300 mg. 0.55 mmole) in acetone (2 ml.) at 0C., was treated with 8N chromic acid (410 ~1.) for 5 minutes.
Isopropanol was added, and the solution was diluted with ethyl ace-tate (15 ml.), washed with brine (10 ml.) and dried. Evaporation of the solvent gave a crude product which was purified by column chrom-atography on Mallinckrod~ CC4 SilicAR* silica gel, developed in a mix-ture of diethyl ether, hexane and ethyl acetate (1:1:2 by volume), to give the mixed C-15 epimers of 15-(3-butyloxetan-3-yl)-9-oxo-lla,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, RF = 0.6 (ethyl acetate).
Example 2 The process described in Example 1 was repeated, using the corresponding 3-hexyloxetan-3-yl bis-ttetrahydropyranyl ether) as starting material, to give 11~,15-dihydroxy-15-(3-hexyloxetan-3-yl)-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid. RF = 0 33 (3% v/v acetic acid in ethyl acetate). The n.m.r. spectrum in deuterated acetone showed the following characteristic features (~ values~:-4.22, 4H, multiplet, oxetan C-2 and C-4 protons and C-11 and C-15 protons, 4.55, 2H, quartet, oxetan C-2 and C-4 protons, 5.35, 2H, cis-olefinic protons3 5.8, 2H, trans-olefinic protons.
The mass spectrum of the 1,11,15-tris~trimethylsilyl)-9-methoxy-amine derivative showed "M ~ 667.4069 (calculated for C34H65NO6Si3 =
667.4119)"
The 3-hexyloxetan-3-yl bis(tetrahydropyranyl ether~ used as the starting material in the above process may be obtained by the se-quence of processes described in the second part of Example 1, using octanal in place of hexanal.
Example 3 The process described in Example 1 was repeated, using the corresponding 3-ethyloxetan-3-yl bis(te*rahydropyranyl ether) as start-ing material, to give 11, 15-dihydroxy-15-(3-ethyloxetan-3-yl)-9-oxo-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid, RF = 0 34 (3% v/v acetic acid in ethyl acetate). The n.m.r. spectrum in deuterat-ed acetone showed the following characteristic features 1~ values):-4.2, 4H, multiplet, oxetan C-2 and C-4 protons, and C~ and C-15 protons, 4.5, 2H, quartet, oxetan C-2 and C-4 protons, 5.35, 2H, multiplet, cIs-olefinic protons, 5.75, 2H, multiplet, trans-olefinic protons.
The mass spectrum of the 1,11,15-tris(trimethylsilyl)-9-methoxy-imine derivatives showed "M = 611.3456 (Calculated for C30H57N05Si3 =
611.3494)"
The 3-Ethyloxetan-3-yl bis(tetrahydropyranyl ether) used as the starting material in the above process may be obtained by the sequence of processes described in the second part of Example 1, but using butyraldehyde in place of hexanal.

11~9591 _Example 4 The process described in Example 1 was repeated, using the corresponding 3-benzyloxetan-3-yl bis(tetrahydropyranyl ether) as starting material, to give the mixed C-15 epimers of 15-(3-benzyloxetan-3~yl)-lla-15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid, RF = 34 and 0.35 (3% v/v acetic acid in ethyl acetate). The n.m.r. spectrum in deuterated acetone showed the following character-istic features (~ values):--f 4.0~4.6, 6H, multiplet, oxetan C-2 and C-4 protons, and C-ll~ and C-15 protons, 5.35, 2H, multiplet, cis-olefinic protons, 5.8, 2H, multiplet, trans-olefinic protons.
7.25, 5H, singlet, aromatic protons.
The mass spectrum of the 1,11,15-tris(trimethylsilyl)-9-methoxy-imine deriviative showed M = 673.3642 (calculated for The 3-benzyloxetan-3-yl bis(tetrahydropyranyl ether) used as the starting material in the above process may be obtained 20 by the sequence of reactions described in the second part of Example 1, but using 3-phenylpropionaldehyde in place of hexanal.
_ample 5 The process described in Example 1 was repeated using the corresponding 3-phenyloxetan-3-yl bis(tetrahydropyranyl 25 ether) as starting material~ to give 11~, 15-dihydroxy-9-oxo-15-(3-pheny]oxetan-3-yl)-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid, RF = 0.2 (3~ v/v acetic acid in ethyl acetate).
The n.m.r. spectrum in deuterated acetone showed the following ~3 characteristic features (~ values):-_ !
i 3.8 - 4.3, complex multiplet, 4H, C-ll and OH protons, 4.55, doublet, lH, C-15 proton, 4.8, multiplet, 4H, C-2 and C-4 oxetan protons, 5.4, multiplet, 2H, cis-olefinic protons, 5 55 and 5.7, two doublets, 2H, trans-olefinic protons, 7.0 - 7.5, multiplet, 5H, aromatic protons.
The mass spectrum o~ the 1,11,15-tris(trimethylsilyl)-9-methoxy-imine derivative showed M+ = 659.3436 (calculated for The 3-phenyloxetan-3-yl bis(tetrahydropyranyl ether) used as the starting material in the above process may be obtained by the sequence of reactions described in the second part of Example 1, but using phenylacetaldehyde in place of hexanal.
Example 6 The process described in Example 1 was repeated, using 15-(3-butyl-1-oxothietan-3-yl)-9-oxo-11~,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13 trans-prostadienoic acid as the starting material, to give 15-(3-butyl-1-oxothietan-3-yl)-]1~,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5 cis,13-trans-prostadienoic acid, RF = 0.2 (3% v/v glacial acetic acid in ethyl acetate). The mass spectrum of the 1,11,15-tris(tri-methylsilyl)-9-methoxyimine derivative showed (M-CH3) = 656.3249 (calculated for C31H58N06SSi3 = 656.3293). The n.m.r. spectrum showed the following characteristic features (~ values):-5.4, multiplet, 2H, cis-olefinic protons.
5.~, multiplet, 2H, trans-olefinic protons 3.1 - ~ multiplet, 7H, C-ll and C-15 protons, OH
protons and C-2 and C-4 thietan protons o.8, triplet, 3H, methyl.

~ 9~ , The 3-butyl-1-oxo-thiet;an-3-yl bis(tetrahydropyran-2-yl ether) used as the starting material in the above process may be obtained by the sequence of reactions described in the latter part of Examp]e 1, but using methyl 3-butylthietan-3-carboxylate 5 in place of methyl 3-butyloxetan-3-carboxylate, to give 15-(3-butylthietan-3-yl)-9a-hydroxy-lla,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, which is oxidised to the required 9-oxo-15~1-oxothietan) starting material as follows:-15-(3-Butylthietan-3-yl)-9a hydroxy-lla, 15-bis(tetrahydropyran-2-yloxy) 16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid (54 mg.) and freshly sublimed N-methylmorpholine-N-oxide (46 mg.) were dissolved in dry acetone (1 ml.) and a catalytic quantity of tris(triphenylphosphine)ruthenium (II) chloride was 15 added. The reaction mixture was stirred under argon at ambient temperature for two ho~lrs, then the solvent was removed under reduced pressure, and the residue was purified by preparative thin layer chromatography on silica gel developed in glacial acetic acid, ethyl acetate and toluene (2;49:49 by volume) to 20 give mixed epimers of 15-(3-butyl-l-oxothietan-3-yl)-9-oxo-lla5 15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis 13-trans-prostadienoic acid, RF = 4 (silica gel, developed with 3% v/v glacial acetic acid in ethyl acetate).
The methyl 3-butylthietan-3-carboxylate used in the 25 above process may be prepared as follows:
A solution of potassium hydroxide (5.0 mg.) in dry ethanol (0.2 ml.) was added to a mixture of 2,2-bis(hydroxymethyl) hexanol (13.4 g.) (prepared by the process described in the i, Z~

i~f ' ,~0 _ ~1195~1 second part of Examp]e 1) and diethyl carbonate (9.9 g.), and refluxed for ten minutes. The ethanol was distil]ed out of the reaction mixture, the residue was cooled, and dry potassium thiocyanate (12.3 g.) was added. The mixture was then heated 5' at 160C. until the evolution of gas had ceased, allowed to cool and partitioned between water (100 ml.) and ethyl acetate (250 ml.) The organic layer was separated, washed with water (50 ml.) and dried, and the solvents were evaporated under reduced pressure, to give t,he crude alcohol, 3-butyl-3-hydroxymethylthietan. Final purification was effected by vaccum distillation, b.p. 76/82C. at 0.1 mm. mercury (13.3 Pa.) , The n.m.r. spectrum in deuteriochloroform showed the following characteristic signals (~ values):-0.95, 3H, triplet, methyl, 0.95 - 1.9~ 6H, multiplet, methylene protons, 2.4, ~H, sinKlet, -OH, 3.0, 4H, singlet~ C-2 and C-4 thietan protons.
3.75~ 2H, singlet, -C~20H., The alcohol (9.4 g.) was added over a period of 1 hour to a stirred solution of nitric acid (22.6 ml., specific gravity l~42) cooled in an ice-bath. The reaction mixture was then warmed to room temperature, stirred for 4 hours and finally heated on a steam bath for 30 mins. The reaction mixture was then c~-oled ~,o room temperature, poured int,o water (100 ml.) and extracted with diethyl ether (2 x 200 ml.). After evaporation of the diethyl ether, the residue was dissolved in ethyl acetate (175 ml.) and extrac~,ed with lM sodium hydroxi~ (2 x 50 ml.).
The combined alkaline solution was acidified to pH 3 with 13 ~7 111~5~1 N hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. The combined organic extracts were dried, and the solvent was evaporated under reduced pressure to give the mixed isomers of the acid, 3-butyl-3-carboxy-thietan-1-oxide.
The n.m.r. spectrum in deuteriochlorofQrm sho~ed the followin~
characteristic signals (~ values):-0.95, 3H,triplet, methyl, 1.1 - 1.6, 4H, multiplet, -CH2.C_2.CH3, 1.8 - 2.2, 2H, multiplet, 3C-CH2-3.3 and 4.1. ~2 doublets, C-2 and C-4 protons in 4H isomer in which fS=O and ~-C-COOH are cis .
3-7, J _singlet, C-2 and C-4 protons in isomer in which ~S=O and -COOH are trans.

9.8, lH, -COO_ The mixed isomeric acids (9.8 g.) and toluene-p-sulph-onic acid (1 g.) were dissolved in dry methanol and refluxed for 16 hours. The methanol was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (150 mls.) and washed with saturated sodium bicarbonate (2 x 25 ml.). The combined sodium bicarbonate solutions were washed with ethyl acetate (100 ml.)~ the combined organic solutions were dried, and the solvent was evaporated under reduced pressure to give the mixed isomers of the ester, methyl 3-butyl-3-carboxy-thietan-l-oxide, RF = -5 (ethyl acetate). The n.m.r. spectrum in deuteriochloroform showed the following characteristic signals (~ values):-_ ~ _ 959~

0.31, 3H, triplet, methyl.
1.0 - ~.5, 4H, multiplet, -C_2.CH2.CH3.
1.6 - 2.1, 2H, multiplet, ,C-C_2-3.1~ ~doublet of triplets ~ C-2 and C-4 protons in 4.1 ¦ ¦ doublet of triplets3 isomer in which \S=0 ~r 4H f and -C02Me are cis.
3.6 J l, multiplet . C-2 and C-4 protons in isomer in which ~S=O and -C02Me are trans.
3.8, 3H, singlet, -C02Me The isomeric esters (4.08 g.) were dissolved in dry tetrahydrofuran in an atmosphere of argon, cooled to 0C. and a solution of dich]oroborane (20 ml. of a 1.1 M solution in 15 tetrahydrofuran) was added slowly. When the addition was complete, the reaction mixture was stirred at 0 for 1 hour, distilled water (10 ml.) and 1 r~ sodium hydroxide (40 ml.) were added, and the mixture was extracted with diethyl ether (2 x 200 ml.). The combined organic extracts were washed with saturated brine and 20 dried, the solvent was evaporated under reduced pressure, and the residue was distilled to give the required methyl 3-butyl-thietan-3-carboxylate, b.p. 114-120C., 12 mm. of mercury (1.6 x 103 Pa.). The n.m.r. spectrum in deuteriochloroform showed the following characteristic signals (~; values):-0.75, 3H, triplet, methyl.
0.9 - 1.3, 4H, multiplet, -CH2.CH2.CH3 1.4 - 2.05, 2H, multiplet, ~C-CH2-'~
_ ~ _ ~llgS9~

2.85 ~doublet 1 4H . 1 C-2 and C-4 protons 3 55 ~ doublet ~
3.6, 3H, singlet, -C02Me _xample 7 The process described in Example 1 was repeated, using the corresponding 3-(3-chlorophenoxy)oxetan-3-yl bis(tetrahydro-pyranyl ether) as starting material, to give 15-[3-(3-chloro-phenoxy)-oxetan-3-yl]-11~, 15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid, R~=o.4 (3% v/v acetic acid in ethyl acetate). The n.m.r. spectrum in deuterated acetone showed the following characteristic feature (~ values):-4.1, lH, quartet, C-ll proton 4.8, 5H, multiplet -lC-2 and C-4 oxetan protons, OH, 5.0-5.8, 5H, multiple~C-15 and cis-olefinic protons 5.8, 2H, multiplet, trans-olefinic protons 6.6-7.4, 4H, multiplet, aromatic protons.
The mass spectrum of the 1,11,15-tris(trimethylsilyl)-9-methoxy-imine deri~ative showed M = 709.3044 (calculated for C34H56ClN07Si3 = 709.3053).
The 3-(3-chlorophenoxy)oxetan-3-yl bis(tetrahydropyranyl ether) used as the starting material in the above process may be obtained by the sequence of reactions described in the second part of Example 1, but using 3-chlorophenoxyacetaldehyde in place of hexanaL.
,'~ Example 8 % w/v _ _ _ 15-(3-Butyloxetan~3-yl)-11~,15-dihydroxy-9-oxo-16,17,1~,19,20-pentanor-5-cis, 13-, trans-prostadienoic acid. 0.0075 ~i~ _ ~

lll9S~l % W/V
Sodium phosphate B.P. 2.90 Sodium acid phosphate B.P. 0.30 Water for injection to 100 The sodium phosphate B.P. was dissolved in about 80% of water, ~ollowed by the prostadienoic acid derivative, and when dissolved, the sodium acid phosphate B.P. The solution was made up to volume with water for injection, and the pH was checked to be between 6.7 and 7.7. The solution was filtered to remove particulate matter, sterilised by ~iltration, and filled into pre-sterilised neutral glass ampoules under aseptic conditions.
The prostadienoic acid derivative may, of course, be replaced by an equivalent amount of another prostanoic acid derivative of the invention.
Example 9 The process described in Example 8 was repeated, omitting the sodium phosphate B.P. and sodium acid phosphate B.P., to give ampouies containing a sterile aqueous solution of 15-(3-butyloxetan-3-yl)~ , 15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, which are used in the manner described in Example 8.
The prostadienoic acid derivative may be replaced by an equivalent amount of another prostanoic acid derivative of the invention, to give other sterile solutions.

~ ~3 _ ,~ _

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the manufacture of a prostane derivative of the formula:- I

wherein R1 is a carboxy radical or a C2-5- alkoxycarbonyl radical, R2 and R3, which may be the same or different, are each a hydrogen atom or a C1-4alkyl radical, A1 is an ethylene or vinylene radical, A2 is an ethylene or trans-vinylene radical, R4 is a C1-7alkyl radical, or a phenyl, phenoxy, phenylthio or phenyl (C1-4alkyl) radical in which the phenyl ring is unsubstituted or is substituted by one or more halogen atoms, nitro or phenyl radicals, C1-4alkyl, alkoxy or halogenoalkyl radicals, or di(C1-4-alkyl)amino radicals, and X represents an oxygen or sulphur atom, or a sulphinyl radical, and, for those compounds wherein R is a carboxy radical, the pharmaceutically or veterinary acceptable salts thereof, which comprises:-(a) for those compounds wherein R3 is a hydrogen atom, the hydrolysis under acidic conditions of a compound of the formula:- II

wherein R5 is a tetrahydropyran -2- yl radical; or (b) for those compounds wherein R1 is an alkoxy-carbonyl radical, the reaction of a carboxylic acid of the formula I, wherein R1 is a carboxy radical, with a C1-4diazoalkane, or of a salt thereof with a C1-4alkyl halide; or (c) for those compounds wherein R is an alkyl radical, the hydrolysis of a tri(C1-4alkyl)silyl ether of the formula:- IV

wherein R3 is a C1-4alkyl radical, and R6, R7 and R8 which may be the same or different, are each a C1-4alkyl radical; or (d) for those compounds wherein R3 is an alkyl radical, the selective oxidation of a compound of the formula:- V

wherein R3 is a C1-4alkyl radical whereafter if necessary isomeric 9-oxo and 11-oxo products, and sulphinyl and sulphonyl products, are separated, by conventional means.

2. A process as claimed in claim 1(a) wherein the hydrolysis is effected by acetic acid.

3. A process as claimed in claim 1(b) wherein the salt is a sodium or silver salt.

4. A process as claimed in claim 1(b) wherein the alkyl halide is an alkyl bromide or alkyl iodide.

5. A process as claimed in claim 1(d) for the manufacture of a com-pound of the formula I wherein X is an oxygen atom or a sulphinyl radical, wherein the oxidation is carried out with Jones' reagent.

6. A process as claimed in claim 1(d) wherein the oxidation is carried out with dicyclohexylcarbodi-imide/pyridinium trifluoroacetate/di-methyl sulphoxide, known as the Pfitzner-Moffatt reagent.

7. A prostane derivative of the formula I wherein R1, R2, R3, R4, A1, A2 and X have the meanings stated in claim 1, whenever prepared by the process claimed in claim 1 or by an obvious chemical equivalent thereof.

8. A process for the manufacture of 15-(3-butyloxetan-3-yl)-11.alpha.,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid which comprises the hydrolysis under acid conditions of 15-(3-butyloxetan-3-yl)-9-oxo-11.alpha., 15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid.

9. 15-(3-Butytoxetan-3-yl)-11.alpha.,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid whenever prepared by the process claimed in claim 8 or by an obvious chemical equivalent thereof.

10. A process for the manufacture of 15-(3-hexyloxetan-3-yl)-11.alpha.,15-dihydro-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid which comprises the hydrolysis under acid conditions of 15-(3-hexyloxetan-3-yl)-9-oxo-11.alpha.,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis 13-trans-prostadienoic acid

11. 15-(3-Hexyloxetan-3-yl)-11.alpha.,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid whenever prepared by the process claimed in claim 10 or by an obvious chemical equivalent thereof.

12. A process for the manufacture of 15-(3-ethyloxetan-3-yl)-11.alpha.,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid which comprises the hydrolysis under acid conditions of 15-(3-ethyloxetan-3-yl)-9-oxo-11.alpha.,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid

13. 15-(3-Ethyloxetan-3-yl)-11.alpha.,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid whenever prepared by the process claimed in claim 12 or by an obvious chemical equivalent thereof.

14. A process for the manufacture of 15-(3-benzyloxetan-3-yl)-11.alpha.,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid which comprises the hydrolysis under acid conditions of 15-(3-benzyloxetan-3-yl)-9-oxo-11.alpha.,15-bis(tetrahydropyran-2-yl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid.

15. 15-(3-Benzyloxetan-3-yl)-11.alpha.,13 trans-prostadienoic acid whenever prepared by the process claimed in claim 14 or by an obvious chemical equi-valent thereof.

16. A process for the manufacture of 11.alpha.,15-dihydroxy-9-oxo-15-(3-phenyloxetan-3-yl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid which comprises the hydrolysis under acid conditions of 9-oxo-15-(3-phenyl-oxetan-3-yl)-11.alpha.,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid.

17. 11.alpha.,15-Dihydroxy-9-oxo-15-(3-phenyloxetan-3-yl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid whenever prepared by the process claimed in claim 16 or by an obvious chemical equivalent thereof.

18. A process for the manufacture of 15-(3-butyl-1-oxothientan-3-yl)-11.alpha.,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid which comprises the hydrolysis under acid conditions of 15-(3-butyl-1-oxothientan-3-yl)-9-oxo-11.alpha.,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid.

19. 15-(3-Butyl-1-oxothietan-3-yl)-11.alpha.,15-dihydroxy-9-oxo-16,17,18, 19,20-pentanor-5-cis,13-trans-prostadienoic acid whenever prepared by the process claimed in claim 18 or by an obvious chemical equivalent thereof.

20. A process for the manufacture of 15-[3-(3-chlorophenoxy)-oxetan-3-yl]-11.alpha.,15-prostadienoic acid which comprises the hydrolysis under acid conditions of 15-[3-(3-chlorophenoxy)-oxetan-3-yl]-9-oxo-11.alpha.,15-bis(tetra-hydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid.

21. 15-[3-(3-Chlorophenoxy)-oxetan-3-yl]-11.alpha.,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid whenever prepared by the process claimed in claim 20 or by an obvious chemical equivalent thereof.