CA1067490A - Prostanoic acid derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The disclosure relates to novel 11.beta.-hydroxy prostaglandin analogues, for example 16-(3-chlorophenoxy)-9.alpha.,11.beta.,15.alpha.-trihydroxy-17,18,19-20-tetranor-5-cis,13-trans-prostadienoic acid, to processes for their manufacture and pharmaceutical or veterinary compositions containing them, and to a method of inducing luteolysis in an animal bost, using the novel 11.beta.-hydroxy prostaglandin analogues.

Description

. ~ ~0~'74~0 :`
This invention relates to novel prostanoic acid derivatives, and in particular it relates to novel ll-epi-prostanoic acid derivatives which possess luteolytic activity. The new compounds are therefore advan-tageous when used as contraceptives or for control of the oestrous cycle in animals. The compounds may also be useful for the induction of labour, or as hypotensives, for the relief of bronchospasm, or as inhibitors of gastric secretion or of blood platelet aggregation.
According to the invention there is provided a process for the manufacture of ll-epi-prostanoic acid derivatives of the formula:-R ~
~ ,- CH2.A~CH2)3R

\ ~I) ~ Y.CHR2.XR3 ~0 wherein Rl is a carboxy or hydroxymethyl radical or an alkoxycarbonyl radical of up to 11 carbon atoms, R2 is a hydroxy radical or an alkoxy radical of 1 to 4 carbon atoms, A is an ethylene or cis-vinylene radical, Y is an ethylene or trans-vinylene radical, X is a direct bond, an alkylideneoxy radical of 1 to 6 carbon atoms wherein the alkylidene is bonded to -CHR and the oxygen is bonded to R3, or an alkylene radical of 1 to 6 carbon atoms) and R3 is a phenyl radical which is unsubstituted or which bears one or two substituents selected from halogen atoms and trifluoromethyl radicals, R4 is a hydroxy radical and R5 is a hydrogen atom~or R4 and R5 together form an oxo radical, and, for those compounds wherein Rl is the carboxy radical, the pharmaceut-ically or veterinarily acceptable salts thereof, which comprises:-~a) ~ for those compounds where m Rl is a carboxy radical, and X is other than a direct bond, the hydrolysis of a compound of the formula:-~ - 2 -,. ' ' ' . ' .

.

R8` ~ R5 ~ _~ CH2.A~CH2)3R

< (II) ~ ~ Y.CHR7.XR

wherein Rl, R3,R5J A and Y have the meanings defined above, R6 lS a tetra-hydropyran-2-yloxy or C4 1O-alkoxydialkylmethoxy radical, R is an alkoxy :~ radical of 1 to 4 carbon atoms or a tetrahydropyran-2-yloxy or C4 10- alkoxy-: dialkylmethoxy radical and R8 has the meaning defined above for R4, or is a tetrahydropyran-2-yloxy radical; OT R6 lS a hydroxy radical or an aroyloxy radical of up to 15 carbon atoms, R7 is a hydroxy radical and R8 is an aroyl-: oxy radical of up to 15 carbon atoms, whereafter when a salt is required, the product so obtained is reacted with a base; or (b) for those compounds wheTein Rl is a carboxy radical, R4 is an ~-hydroxy radical, A is a vinylene radical and X is a direct bond, the re-action of the lactol of the formula:-: r~r OH
o~
> (III3 \~--Y . CHR2 . XR3 HO

wherein R2 and R3 have the meanings defined above, with a (4-carboxybutyl)-triphenylphosphonium salt, in the presence of a strong base, whereafter when`
a salt is required, the product so obtalned is reacted with a base; or ~c) for those compounds wherein Rl is an alkoxycarbonyl radical., : the reaction o the corresponding compound of the formula I wherein Rl 15 a carboxy radical, with a diazoalkane of 1 to 1~ carbon atoms, or of a sal~t thereof with an alkyl halide; or .
~ J

~ ~,o~t749,0 ~d) for those compounds wherein Rl is a hydroxymethyl radical, the reduction of a corresponding compound of the formula I wherein Rl is an alkoxycarbonyl radical; or ~e) for those compo~mds wherein R is an alkoxy radical, the re-action of the corresponding compound of the formula I wherein R2 is a hydroxy radical with an alkyl halide of 1 to 4 carbon atoms in the presence of a strong base.
A suitable value forRl when it is an alkoxycarbonyl radical is, for example, a methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycar-bonyl or decyloxycarbonyl radical, especially such as an alkoxycarbonyl ra-dical of up to 6 carbon atoms.
A suitable value for R is in particular a hydroxy radical, but it may also be for example, a methoxy, ethoxy, propoxy or butoxy radical.
A suitable value for X when it is an alkylideneoxy radical is, for example, a methyleneoxy, ethylideneoxy ~-CH~CH3).0-), isopropylideneoxy ~-C~CH ) .0-), l-methylpropylideneoxY (-C(CH3)(C2H5).0-) or l-ethylpropyl ideneoxy (-C~C2H5)2.0-) radical, and a suitable value for X ~hen it is an alkylene radicai is, for example, a methylene, e~hylidene, isopropylidene, propylidene, l-methylpropylidene, l-ethylpropylidene, ethylene, l-methylethyl-ene, l,l-dimethylethylene, 2-methylethylene or trimethylene radical.
A suitable value for a halogen substituent in R3 is, for example, a chlorine, bromine or fluorine atom.
A suitable pharmaceutically or veterinarily acceptable salt is, for example, an ammonium, alkylammonium containing 1 to 4 alkyl substituents each of 1 to 6 carbon atoms, alkanolammonium containing 1 to 3 2-hydroxyethyl radicals, or alkali metal salt, for example a triethyl ammonium, ethanolam-monium, diethanolammonium, sodium or potassium salt.
It will be observed that the compounds of the formula I contain five asymmetric carbon atoms, namely, carbon atoms 8,9,11~12 and 15, thc relative configuration of the first four of which are ixed, so that it is clear that the compounds may exist in at least two optically active forms.
It is to be understood that the useful properties of the racemates (comprising the compound of the formula I and its mirror image) described in this speci-fication may be present to differing extents in the optical isomers, and that this invention relates to the racemic form and to any optically active form which possesses the same useful properties, it being a matter of common ge-neral knowledge how the optically active forms may be obtained and their re-spective biological properties determined. It is also to be understood thatthis invention - 4a -1(:167490 :
relates to both C-15 epimers, that is, the epimers at the -CHR2- carbon atom of the;lower side-chain.
A pre~erred group of prostane derivatives of the invention comprises khose compounds wherein Rl is a carboxy, hydroxymethyl, methoxycarbonyl or ethoxyoarbonyl radical, R is a hydroxy radical, A is a cis-vinylene radical, Y is a trans-vinylene radicalg X is a direct bond or a methyleneoxy radical wherein the methylene is bonded to -CHR - and the oxygen is bonded to R3, and R3 is a chlorophenyl or trifluoromethylphenyl radical.

A preferred value for~R', when X is a methyleneoxy radical, is a 3-chlorophenyl or 3-trifluoromethylphenyl radical, and a preferred value for R3 when X is a direct bond, is a 4-trifluoromethyl radical.
Particular ll-ep-i-prostanoic acid derivatives of the invention are 16-~3-chlorophenoxy)-9~ ,15 trihydrOxy - 17,~18,19,20-tetranor-5-cis,13-trans-prostadienoic~
acid, 16-(3-chlorophenoxy)-9~ ,15~trihydroxy-17,18,19,20-- :
tetranor-5-cis,13-trans-prostadienoic acid, methyl 16-(3-chlorophenoxy)-9~ ,15~-trlhydroxy-17,18,19,20-tetranor-5-cis,l3-trans-prostadienoate, 16-(3-chlorophenoxy)-17,18,19,20-.
tetranor-5-cis,13-trans-pro~tadien-1,9~ ,15~-tetraol, 16-(3-chlorophenoxy)-11~,15-dihydroxy-9-oxo-17,18,~19,20-~
tetranor~5-cis,13-trans-prostadienoic acid and 9~ ,15~-trihydroxy-15-(4-trifluoromethylphenylj-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid.

~ ;

'' ' " ' ~
. . : ',, ' ~067~9~
In process (a), a suitable C~ 10 alkoxydlalkylmethoxy radical is, for example, a l-methoxy-l-methylethoxy radical. In process ~b), a suit-able ~4-carboxybutyl~triphenylphosphonium salt is, for exampleJ the bromide.
In process ~c)~ a suitable salt of a corresponding compound of the formula I
wherein Rl is a carboxy radical is, for exampleJ a sodium or silver salt, and a suitable alkyl halide is, for examp~Jan!alky-I lodide. In process (d)~ a suitable complex metal hydride is, for example, lithium aluminium hydride. In process (e)J a suitable strong base isJ for example, sodium hydride.
The hydrolysis in process (a) may be carrled out with an acîd, for example, aqueous acetic acid or a sulphonic acid, for example, toluene-~-sulphonic acid in a Cl 4 alkanol~when R6 or R7 is a tetrahydropyranyloxy ra-dical, or buffered`citric acid ~e.g. pH 3) when R6 or Rl lS an alkoxydialkyl-methoxy radical, or it may be carried out with a base, for example, an alkali metal carbonate such as potassium carbonate, when R6 or R7 is an aroyloxy ra-dical, and it may be carried out at ambient temperature or at an elevated temperature of up to 60C.
In process ~b)~, when the strong base used is a sodium base, for example, methanesulphinylmethyl sodium in dimethyl sulphoxide, or potassium t-butoxide, the product I obtained is one wherein, substantially completely, A is c -vinylene, whereas if n-butyl-lithium in sulpholane is used as the strong base, the product obtained is one which contams a mixture of the com-pound wherein A is trans-vinylene and the compound wherein A is cis-vinylene.
The starting material of the formula III, used in the process of the invention, wherein R2 is a hydroxy radical may be obtained by reacting a lactone IV with an azodicarboxylate ester in the presence of triphenyl-phosphine and benzoic acid to give the dibenzoate V which is hydrolysed to :
the diol VI. Reduction of the lactone with di-isobutyl aluminium hydride gives the required starting material III, ~R = hydroxy3.
Many of the required lactones of the formula IV are known com-:~ :

067~90 pounds, and any others which are novel may be prepared by methods completely analogous to those used in the preparation of the known lactones of the formula IV.

)~ ~
O I ~O

Y.CH.XR~ ~ Y.CH.XR3 HO OH IV V
~:
O\~
III (R2 =
hydroxy) Y.CH.XR
HO ~H
VI

The starting material of the formula III wherein R2 is an alkoxy radical may be obtained by reacting the corresponding compound VI wherein R2 is a hydroxy radical with an alkyl halide, for example, an alkyl bromide or iodide, in the presence of one equivalent of a strong base, for example, sodium hydride, followed by the reduction of the product so obtained with di-isobutyl aluminium hydride, as described above, to give the required starting material III ~R2 = alkoxy).
The starting material of the formula II, used in the process of the invention, wherein A is a vinylene radical, R6 and R7 are each a t:tra-hydropyran-2-yloxy radical, and R8 is a hydroxy radical, may be obtained by reacting the corresponding compound VI with dihydropyran, to give a bis-~tetra-hydropyran-2-yl ether), which is reduced with diisobutyl aluminium hydride, as .. s - 7 -~06749(~

described above for compound VI, and the resulting lactol is reacted with a ~4-carboxybutyl)triphenylphosphonium saltJ as described above for a lactol III, to give a starting material II wherein A is c -vinylene, if methanesul-phlnylmethyl sodium or potassium t-butoxide is used as the strong base, or a mixture of compounds of the formula II wherein A is tr -vinylene and cis-vinylene, if n-butyl-lithium in sulpholane is used as the strong base, from which mixture the starting material II wherein A is c -vinylene may be ob-tained by chromatography on silica gel impregnated with silver nitrate.
~ Corresponding starting materials of the formula II wherein R6 and R7 are each an alkoxydialkylmethoxy radical, .

1~67~9,Q

may be prepared similarly, using an alkoxyalkane, for example 2-methoxypropene, in place of dihydropyran.
The starting material of the.formula II wherein R and R7 are ea.ch a tetrahydropyran-2-yloxy radiaal and R5 and R8 together form an oxo radical, may be obtained by oxidation of the corresponding compound II wherein R8 is a hydroxy radical, for example with Jones' reagent.
The starting material of the formula II, used in the process of the invention, wherein Y is a trans-lO vinylene radical, R8 is an aroyloxy radical and R6 and R7 are each a hydroxy radical, may be obtained by treating the known lactone~ 4R-dimethoxymethyl-2,3,3ag,6a~-tetra-hydro-5~-hydroxy-2-oxocyclopenteno~bJfuran (VII) with an azodicarboxylic ester in the presence of triphenylphosphine and benzoic acid, to give the benzoate of the C-5 epimer of VII (VIII), which is hydrolysed and then protected as the tetrahydropyranyl ether (IX). The lactone is reduced ; with di-isobutyl aluminium hydride to the lactol X, and : the lactol is reacted with a phosphonium salt of the formula Ph3P(CH2)4.COOH.Br in the presence of a strong base, to give a cyclopentanol derivative XI, wherein A is cis-vinylene if methanesulphinylmethyl sodium or potassium t-butoxide is used as the st:rong base, or a mixture of cyclopentanol derivatives XI wherein A is cis vinylene and trans-vinylene when n-butyl-lithium in sulpholane is used as the strong base, from which mixture the cyclopentanol derivative XI

9 ~:

~ ~ 10~;7~
~ ~ ~ o o~ ~

CHtOCH3)2 ~ ( 3)2 ~ H(OCH3)2 HO B~O THP.O
VII VIII ~O~ IX ;

H ~ 2-A~CH2)3.~co2H
~ > <~ >
THP Or ~H(CH})2~;

THP,O

HO~ CH2-A(CH2)3CO2CH3 PB.O~ ~ CH2.A~CH2)3c02cH3 CH(OCH~)2 ~

GH2-A~CV2~ C!1~ ~ ~H2A~(CH2)~C02CH3 CH(OCH3)2 ~ ~ HO
HO

XIV ~ ~ ~ XV
PB.O~ ~eH2-A~¢H2~CO2CH3~

> ~ R6 , R7~- OH, R8 = PBO) HO
XVI ~
`' Bz ~ benzoyl~ THP = tetrahydropyran- ~ 1, PB - 4-phenylbenzoyl ~06'7490 wherein A is the c -vinylene radical may be separated by chromatography on silica gel impregnated with silver nitrate. Alternatively, the mixture may be processed through one or more subsequent steps of the synthesis, and thè corresponding c - intermediate may be separated at any convenient subsequent stage. A cyclopentanol derivative XI is converted by reaction with diazomethane to the methyl ester XII. The methyl ester XII is reacted with an acylating agent derived from an aroic acid, for example, 4-phenyl-benzoyl chloride~ to give a 4-phenylbenzoate ester XIII, which is select-ively hydrolysed in two steps, first to remove the tetrahydropyranyl pro-tecting group ~XIV), and then to hydrolyse the acetal to give thealdehyde (XV). The aldehyde XV is treated with a phosphonate ~CH30)2-PO.CH2CO.XR or a phosphorane Ph3P:CH.CO.XR3 in the presence of a`strong base to give the enone XVI, reduction of which with aluminium tri-iso-propoxide or di-isobornyloxy aluminium isopropoxide gives the required starting material II wherein A is a cis-vinylene radical, Y is trans-vinylene, R6 = R7 = hydroxy, and R8 = aroyloxy.
The starting material of the formula II, used in the process of the invention, wherein A is a cis-vinylene radical, Y is a trans-vinylene radical, R6 and R8 are each an aroyloxy radical and R7 is a hydroxy radical may be obtained from the methyl ester XII by selective hydrolysis of the tetrahydropyranyl radical, ~or example, with toluene-p-~(~6'7~30 : sulphonic acid in tetrahydro~uran, to a diol XVII, which is reacted with an acylating agent derived from an aroic acid, for example 4-phenylbenzoyl chloride, to give a bis-(phenylbenzoate ester) XVIII, which is selectively hydrolysed with dilute aqueous acid to the corresponding aldehyde XIX.
The aldehyde XIX is reacted wi:th a phosphonate or phosphorane as described above to give an enone XX, whioh is reduced, as described above for similar:~enones XVI, to the required .starting material II (R6 R8~- aroyloxy, R7 ~ hydroxy).
: Starting materials of the formula II wherein Y
is an ethylene radical and either R6 and R7 are each~a hydroxy.radical and~R8 la an ar~oyloxy radioal, or R7 is ~ ~ a hydroxy radical and R6 and R8 are each an aroyloxy : radical, may be obtained by reducing respectively an enone XVI or an enone XX with, for example, sodium borohydride to give~a mixture of 13,;14-trans and 13,14-dihydro e~nol~s,~
:from:which the~13,14-dihydro~enol~ Y~: èthylene)~may be separated by oonventional procedures.
Starting materials of the formula II~wherein A :~
is an:ethylene radical may:be obtained by hydrogenation of ~: : a corresponding starting material II wherein A is a cis- ::
:: : ~
vinylene radical, or by hydrogenation of an intermediate :of the formula XIV or XVIII,~and using the hydrogenated :

~:: intermediate in place of XIV or XVIII in the subsequent :

25: stages of the syntheses described~above.

~: : In an alternative synthesis, bhe intermediate XIV

~ ~ used in the above process may be obtained by treatin~ the : 3 : - ~~ : ~
~' :: :

1~36749(:~

HO ~ .
~' '\~----\C2 CH 3 XI I
HO H(OCH3)2 XVII
, :
PB . O . PB . O~
O~ q 1~

~--\ CH ( cH3 ) 2 ~\ CHO
PB, O Pl3.
XVIII XIX

: PB . O

~Co.XR3 H7 - OH) PB. O
` XX

, :

`' '''''''' -1~674~0 known compound XXI with an azodicarboxylate ester, as described above, to give a di-ester XXII which is converted via intermediates analogous to XV and X~I to the required starting material II (R6 = benzoyloxy, : 5 R7 - hydroxy, R8 _ 4-phenylbenzoyloxy).

:: PBO PBQ
H~ ~ C2C~l3 CH(OCH3) H~OCH3)2 HO ~ BzO
:: ~ : : `
: XXI : ~: ~ X~I : :

In a further alternative synthesis, a starting material of the ~ormula II ~R6 -~benzoyloxy, R7 ~ hydroxy, R8 - 4-phenylbenzoyloxy) may be obtained by treating a :10~ c~ompound~of the formula~

PBO~

H~ OH
.
with an azodicarboxylate ester as;described above, to give a starting materia1~of~the ~ormula II (R6 = benzoyloxy, n :R7 - hydroxy, R! ~ 4-phenylbenzoyloxy). ;; :: :~
~15 Compounds of the formula XXIII are known for certain values of -XR3, for example where -XR3 is 3-:: ~ :
:
: I I

; :

; .

.

7~90 chlorophenoxy, and corresponding compounds for other values of -XR3 may be manufactured in a completely analo~ous manner.
Starting materials o~ the ~ormula II wherein Rl is a carboxy or hydroxymethyl radical may be obtained from the corresponding compound wherein Rl is an alkoxycarbonyl radical by, respectively, saponification or complex metal hydride reduction, for example with lithium aluminium hydride.
;~ Starting materials of the formu1a II wherein Rl is an alkoxycarbonyl radical may be obtained from an prostanoic acid derivative of the invention of the ~ormula I wherein Rl is an alkoxycarbonyl radical by reaction with 2,3-dihydropyran to give a tris(tetrahydro-pyranyl ether) XXIV which ie reduced with lithium aluminium ~; 15 hydride to a hydroxymethyl~compound XXV which~in turn is :
, : ~ alkylated to give a starting matéri:al:~II (Rl = alkoxymethyl~

; R6 = R7 = R8 = tetrabydropyran-2-yloT~ O : ~ ~

CH2A(CH2)3R ~:
I(R1=alkoxycarbonyl) ~ Y.CH(o,THP).XR3 THP.O
X~V

:
THP.O

2 ( 2)3CH2H
II (Rl- alkoxymethyl, : ~ Y.CH(O.THP). ~3 R6=R7=R8=THP-o) THP.O

X~N

THP = tetrahydropyran-2-yl \S : :

,~ ~

. :

lQ67 ~9~) As stated above, the compounds of the invention possess luteolytic properties. For example, 16-(3- ~
chlorophenoxy)-9~ ,15~-trihydroxy-17,18,19,20-tetranor-5-cis,l3-trans-prostadienoic acid is approximately 50Q times as active as natural prostaglandin ~2~ in a luteolytic test in the hamster (or~I dosing), but possesses only 1/12 of the smooth muscle stimulant activity of the natural compound. The compounds of the invention are therefore more selective than the natural compound in terms of luteolytic activity. No indication Or toxicity to small animals has been noted at the luteolytically effective doses tested.
The compounds of the invention are;therefore useful, for example, for the induction of labour in childbirth, and for this purpose are used in the same way as it is known ;~ to use the naturally-occurring prostaglandins El and E2, that is to say, by administering a sterile, substantially~
aqueous solution containing from 0.01 to 10 ug./ml., preferably 0.01 to 1 ug./ml. of active compound, by intravenous, extraovular or intra-amniotic administratlon until labour commences. Also, for this purpose, the compounds of the invention may be used in combination, or concurrently~ with a uterine stimulant, for example oxytocin, in the same way , that it is known to use prostaglandin F2~ in combination, F concurrently, with oxytocin for the induction of labour.

- ~~

1~67~g When a compound of the invention is to be used ~or the control of the oestrus cycle in animals, it may be used in combination, or concurrently, with a gonadotrophin, for example, PMSG ~regnant mare serum gonado~rophin) or HCG ~human chorionic gonadotrophin) to hasten the onset of the next cycle.
Thus, the compounds may be formulated as a pharmaceutical or veterinary composition comprising an ll-epi-prostanoic acid derivative of the invention, ~ogether with a pharmaceutically or veterinarily accept-able diluent or carrier.
The compositions may be in a form suitable for oral adminis-tration, for example, tablets or capsules, in a form suitable for inhala-tion, for example, an aerosol or a solution suitable for spraylng, in a form suitable for parenteral administration, for example, sterlle inject-able aqueous or oily solutions or suspensions, or in the form of a supposi-tory, suitable for anal or vaginal use.
~: :
; The compositions of the invention may be;prepared by con-ventional means, and may incorporate conventional excipients.
The invention is lllustrated, but not limited by the follow-ing Examples.
Example 1 A solution of 16-~3-chlorophenoxy)-9a-hydroxy-11~,15a-blsttetra-hydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid (108 mg.) in 2 mls. of a ~aG~9~o 2:1 mixture of acetic acid and water, was stirred at 50C.
for 4 hours. The solve~ts were evaporated, the residue was dissolved in dilute aqueous sodium bicarbonate solution (2 ml.), the solution was extracted with ethyl aoetate (3 x 2 ml.) and the extracts were discarded. The aqueous solution was acidi~ied to pH 3-4 with 2N aqueous oxalic acid and the acidified solution was extracted with~ethyl acetate (4 x 5 ml.). The ethyl acetate extracts were washed with a 1:1 mixture of saturated brine and water, and were then dried. After evaporation of the ethyl acetate, the residue consisted ofi16-(3-chlorophenoxy)-9~ ,15~-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid. Thin-layer chromatography on silica gel plates, supplied commercially by Merck of Darmstadt, using a mixture of 3% acetic acid in ethyl acetate as the developing solvent, gave the pure compound, RF - 0.2. The n.m.r.-spectrum in deuteriated acetone showed the following characteristic bands ( ôvalues):- ~
6.9 - 7.2, broad multiplet, 4 aromatic~protons, 5.2 - 6.1, broad multiplets~ 4 olefinic and 4 exchangeable protons

3.95 - 4.5 broad multiplets, 5H, >CH.0-protons The mass spectrum of the tetra(trimethylsilyl) derivative showed (M-CH3)+ = 697.2990, (calculated for C34H61C106Si4-~

697.3Q01). ~ ~
The bis(tetrahydropyranyl ether) used as starting material may be obtained as follows:- ~

_ _~J _ ~ ~
'' ' 7~0 To a solution of 4~-r4-(3-chlorophenoxy)-3R-hydroxybut-l-trans-enyl]-2~3,3a~,6a~-tetrahydro-5~-hydroxy-2-oxocyclopenteno~b]furan (838 mg.), triphenylphosphine (1.63 g.) and benzoic acid (758 mg.) in tetrahydrofuran - 5 (15 ml.) was added dropwise during 10 minutes diethyl azodicarboxylate (1.06 g.). After 45 minutes, the solvent was removed by evaporation, and the residue was extracted with ethyl acetate (3 x ~0 ml.). The combined extracks were washed successively with sodium bicarbonate solution and brine, and dried, and the solvents were evaporated to give the bis-benzoate ester, 5B-benzoyloxy-4~-~3~-benzoyloxy-4-(3-chlorophenoxy)but-1-trans-enyl~-2,~,3aB,6a~-tetrahydro-2-oxocyclopentenorb]furan, RF = 0.6 (5% ethyl acetate in methylene dichloride).
To a solution of the bis-benzoate ester (1.03 g.) in-a mixture of methanol and methylene dichloride (2:1) ; was added anhydrous potassium~carbonate (578 mg.). ~The~
mixture was stirred for 6 hours at room temperature, acidified to pH 5 with lN hydrochloric acid, and dilu~ed with ethyl acetate (100 ml.). The mixture was washed successively with saturated sodium bicarbonate solution and brine, the organic phase was separated and dried, and the solvents were evaporated under reduced pressure~

The crude product was chromatographed on MFC silica gel, using ethyl acetate in`methylene dichloride as eluant, to yield the diol, 4~-r4-(3-chlorophenoxy)-3~hydroxybut-1-trans-enyl]-2,3,3a~,6a~-tetrahydro-5~-hydroxy-2-oxocyclo-pentenorb]furan, RF ~ .4 (ethyl acetate). The n.m.r.

It~
_ ~ -- :

~1~6~ 0 spectrum (ln deuterated chloroform) showed the following characteristic bands ( ~values):-6;8 - 7 6, broad multiplets, 4 aromatic protons, 5.8 - 6.o, 2 olefinic protons, 3.7 - 5.2, broad multiplets, 5H,~ CH.0- protons To a solution of the diol (215 mg.) in methylene dichloride (8 ml.) under an atmosphere of nitrogen were added successively redistilled 2,3-dihydropyran (0.58 ml.) and a solution of anhydrous toluene-p-sulphonic acid in tetrahydrofuran (0.6 ml. of a 1% solution). After 10 minutes, pyridine (3 drops) was added, fo]3owed by ethyl acetate (50 ml.). The solution was washed successively with saturated sodium bicarbonate solution and sat~urated brine, and was dried. Evaporation of the solvents gave a bis(tetrahydropyranyl ether) as a clear oil, RF = o.6 (ethyl acetate). ~ - ;
To a solution of the~bis(tetrahydropyranyl ether) ~ ;
(320 mg.) in dry toluene (15 ml.~) under an atmosphere of nitrogen at -78C. was added o.86 ml. of a 1~95M solution of di-isobutyl aluminium hydride in toluene. After 15 minutes, the reaction was quenched by the dropwise addition of methanol (3 ml.) and after a further 15 minutes at room temperature a mixture of 1:1 saturated brine~/water (25 ml.) was added, and the mixture was extracted with ethyl acetate (3 x 50 ml.). The extract was washed with saturated brine, and dried, and the solvents were evaporated to give the lactol~ 4~-~4-(3-chlorophenoxy)-3~-(tetrahydropyran-2-yloxy)-1-_ ~ _ trans-butenyll-2,3,3a~,6a~-tetrahydro-2-hydroxy-5~-(tetrahydropyran-2-yloxy)cyclopenteno~b]furan, RF ~ 0 3 (25% ethyl acetate in methylene dichloride).
A stirred solution o~ (4-carboxybutyl)triphenyl-phosphonium bromide (6.21 g.) in dry toluene (125 ml.) was treated under argon at 90C. with potassium t-butoxide (3.01 g.) to form a solution of the corresponding ylide.
The ylide solution (22.3 ml.) was then added to a solution of the lactol (388 mg.) in dry toluene (5 ml.~ at room temperature. The mixture was stirred for 40 minutes, then water (1 ml.) was added. The toluene was evaporated, and the residual gum was partitioned between ether (4 x 10 ml.) and water (4 ml.). The aqueous layer was separated, acidified with 2N oxalic acid to pH 4, and extracted with a 1:1 mixture of ether and pentane (6 x 15 ml ). The combined extracts were washed with brine, dried over magnesium sulphate and filtered, and the solvent was evaporated to give the required bis(tetrahy~ropyranyl ether), 16-(3-chlorophenoxy)9~-hydroxy-llB,15~-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid, RF = 5 (ethyl acetate).
Example 2 The process described in Example 1 was repeated, using the corresponding 11~,15~ bis(tetrahydropyranyl ether) as starting material, to give 16-(3-chlorophenoxy)-9~ ,15~-os~ `e ~o ~G' trihydroxy-17,18,19,20-tetranor-5-cis jl3-trans-~
.

` 11367'4~0 acid, RF ~ .3 (3% acetic acid in ethyl acetate). The n.m.r. spectrum ~in deuterated acetone) showed the following characteristic bands ~ ovalues):-6~9 - 7.3, broad multiplets, 4 aromatic protons, 5.2 - 6.1, broad multiplets, 4 olefinic and 4 exchangeable protons,

4.0 - 4.6, broad multiplets, 5H, >CH.0- protons The mass spectrum o~ the tetra(trimethylsilyl) derivative showed (M-CH3) 697.2970, (calculated for C~4U~61C106Si4 ~

697.3001).
The bis(tetrahydropyranyl etherj used as starting material may be obtained by the sequence of steps described in the second part of Example 1, starting from 4B~4-(3-chlorophenoxy)-3~-(tetrahydropyran-2-yloxy)-1-trans-butenyl]-2,3,3aB,6aB-tetrahydro-2-oxo-5~-(tetrahydropyran~2-yloxy)-cyclopenteno~b]furan,~via~the following in~termediates:-bis-benzoate ester", RF ~ o.6 (5% ethyl acetate in~
methylene dichloride) ; ~ "diol", RF~= 4 (ethyl acetate). The n.m.r. spectrum in deuterated acetone showed the following characteristic bands ( ~ values)0-6.8 - 7.6, broad multiplet, 4 aromatic protons,

5.8 - 6.0, 2 olefinic protons, 3.7 - 5.2, broad multiplet, SH~ ~CH.0- protons "bis(tetrahydropyranyl ether)", RF = o.6 (25% ethyl acetate in methylene dichlorlde) "lactol", RF = 0.3 (25% ethyl acetate in methylene dichloride).

- ~67~

Example 3 The process described in Example 1 was repeated, using 16-(3-chlorophenoxy)-9-oxo-11~,15~-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis,13-trans-prostanoic acid as starting material, to give 16-(3-chlorophenoxy)-11~,15a-dihydroxy-9-oxo-17,18,19,20~tetranor-5-cis,13-trans-prostadienoic acid, RF = 4 (2.5% acetic acid in ethyl acetate). The n.m.r. spectrum (in deuterated acetone) showed the following characteristic bands (~values):-

6.9 - 7.2, broad multiplets, 4 aromatic protons, 5.2 - 6.1, broad multiplets, 4 olefinic and 3 exchangeable protons, 3.95 - 4.6, 4H,>-CH.0- protons The mass spectrum of the tris(trimethylsilyl)derivative showed M = 667.2936, (calculated for C32H54ClN06Si3= 667.2946).
The bis(tetrahydropyranyl ether) used as starting material may be obtained as follows:-A solution of 16-(3-chlorophenoxy)-9~-hydroxy~
15~-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid (92 mg.) in acetone (5 ml.) at 0C. was treated with 8N chromic acid (50.4 ~1.) for 25 minutes. Isopropanol was added, and the solution was diluted with ethyl acetate (50 ml.), washed with brine and dried. Evaporation of the solvent gave the required 9-oxo-bis(tetrahydropyranyl ether), RF = 4 (5% methanol in methylene dichloride).

_ ~ _ ;

lQ67~9,0 Example 4 The process described in Example 3 was repeated, using the corresponding llB315~-bis(tetrahydropyranyl ether) as starting material, to give 16-~3-chlorophenoxy)~ ,15B-dihydroxy-9-oxo-17,18,19,20-tetranor-5-cis,l~-trans-prostadienoic acid, RF = 5 ~2.5% acetic acid in ethyl acetate). The n.m.r. sp~ectrum ~in deuterated acetone) showed the ~ollowing characteristic bands (~ values)~
5.g - 7.2, broad multiplets, 4 aromatic protons, 5.2 - 6.1, broad multiplets, 4 olefinic and 3 ~ exchangeable protons, 3.95 - 4.6, 4H~ >CH.0- protons The mass spectrum of the tris(trimethyIsilyl) derivative showed M = 667.2928, (calculated ror C32H54ClN06Si~= 667-2946)-The bis(tetrahydropyranyl ~ther) u~ed as starting~
material may be obtained by oxidation of the corresponding 9a-hydroxy 11~,15~-bis(tetrahydropyranyl ether) dqscribed in Example 2, by the process described in the second part;of Example 3, RF = -4 (5% ethyl acetate in methylene dichloride).
` 20 Example 5 The process described in Example 1 was repeated, using the appropriate bis(tetrahydropyranyl ether) as ~- starting material to give the compounds shown in the table~
below. Mass spectrum data are for the tetra~trimethylsilyl) derivatives. RF values, for thin layer chromatography on silica gel3 eluted with ethyl acetate, are alsa given I

'' :

)6~490 ~or the corresponding diol intermediates of the ~ormula VI.

Y.CH(OH).X ~

- Maas sp~ectrum ~ ~ Diol of R Y XFound Calculated the ` ~ formula VI
~ , ~ . _: : : ~ :
3-trifluoromethyl trans- ~CH20 M =746.3492 746.3458~ RF - 0.4 vi~nylene hydrogen trans-vinylene CH2 (M-CH3) 647.3441 Rp - 0.2 = 647.3431 4-chloro trans- ~
vinylene CH20 (M-CH3) ; ~ 697,2999~ RF;-~0.2 ~; ~ ~ - 697.2913 3-chIoro ethylene CH20 M = 714.3371 ~ ~
714.3391~ RF ~ 0 3 : _ _. _ :: ' ~
In the manufacture~of the compound wherein;Y
is an ethylene radical, the required starting materlal is obtained as follows~
:
A mixture of epimers (epimers at C-3 of the~
butenyl side chain) of 4~-~4-(3~-chlorophenoxy)-3-hydroxybut-1-t~ans-enyl]-2,3,3a~,6a~-tetrahydro-2-~oxo-5~ -phenylbensoyl-oxy)-oyclopenteno~b]furan (1.83 g.)~was dissolved in ethanol :
~ ~ , - ' ':

~0~7~90 (28 ml.) and the solution was added to nickel boride, previously prepared from nickel acetate (3.5 g.) and sodium borohydride-(551 mg.). The mixture was shaken with hydrogen for 4 hours and was then filtered, and the filtrate was evaporated to dryness to give a mixture of epimeric unsaturated alcohols, 4~-~4-(3-chlorophenoxy-3-hydroxybutyl]-2,3,3a~,6a~-tetrahydro-21-oxo-5~ (p-phenylbenzoyloxy)cyclo-penteno~b]furan, RF = 0 3 ~50% ethyl acetate in~toluene).
The mixture of epimeric saturated alcohols (1.47 g.3 was I0 stirred vigorously ~or 2~hours with finely powdered~anhydrous potassium carbonate (1.02 g.) in methanol~(40 mI.).`~ ~
lN Hydrochloric acid (15 ml.) was added, followed by ethyl acetate (200 ml.). The organic layer was separated, washed succe~sively with saturated sodium bicarbonate~solution and brine, and dried, the solvents were evaporated, and the residue was chromatographed on "Florisil" (trade mark) magnesium silicate (50 g.). ~ Elution with ether removed by-products, and subsequent elution with ethyl acetate gave ~a~mixture of the corresponding sakurated epimeric 11~,15-diols, R~ = 0.3 (ethyl acetate~
Example 6 ~ `
To a solution of the more polar C-15 epimer of 16-(3-chlorophenoxy)-9a,11~,15~-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid (59 mg.) in :
methanol (1 ml.) at 0C. was added~an excess of a solution of diazomethane in ether~ After~10 minutes, the solvents were evaporated to give the single C-15 epimer5 methyl b : :

:

16-(3-chlorophenoxy)-9~ ,15~-trihydroxy-17,18,19,20-tetranor-5-c ,13-trans-prostadienoate as a clear oil ~ = 0.15 (ethyl acetate) (M~CH3) 639-2754, (calculated for C31H52C106Si3 = 639.2760).
Example 7 A solution of methyl 16-(3-chlorophenoxy)-9a,11~,15~-trihydroxy-17,18,19,20-tetranor-5-c ,13-trans-prostadlenoate (14 mg.) in a mixture of ether (1 ml.) and tetrahydro~uran (1 ml.) was added to a suspension of lithium aluminium hydride (25 mg.) in ether (3 ml.). me mixture was stirred at room temperature ~or 1 hour, the excess of hydride was destroyed by the addition of water ~1 ml.) and the mixture was extracted with ethyl acetate.
The extract was dried, and the solvent was evaporated to give 16-~3-chloro-phenoxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadien-1,9a,11~,15a-tetraol, = 0.5 (10% methanol in ethyl acetate). The mass spectrum of the tetra (trimethylsilyl)derivative showed M = 698.3412, (calculated for C34H63C15si4 = 698-3441)-Example 8 To a solution o~ methyl 16-(3-chlorophenoxy)-9~ ,15~-trihydroxy-17,18,19,20-tetranor-5-cis,13-tra s-prostadienoate (22 mg.) in 1,2-dimethoxy-ethane (2 ml.) were added successively methyl iodide (1 ml.) and sodium hydrlde (2.25 mg. of` a 60% suspension in oil), and the mixture was stirred at room temperature for 2 hours. The sol ents wer ~B

~(~6~490 evaporated under reduced pressure, and the residue was shaken with a mixture of ethyl acetate (3 x 15 ml.) and water (3 ml.). The organic phases were separated, combined and dried, the solvent was evaporated ancl the residue was puri~ied by thin layer chromatography on silica gel plates, using ethyl acetate as the developing solvent, to give methyl 16-(3-chlorophenoxy)-9~,llB-dihydroxy-15~-methoxy-17,18,19,20-tetranor-5-cis,I3-trans-prostadienoate, RF = -3 (ekhyl acetate). The mass spectrum of the bis-(trimethylsilyl)derivative showed (M-CH3) = 581,2490, ~calculated for C29H46C106Si2= 581,2521).

Example 9 To a solution of 16-(3-chlorophenoxy)-11~,15~-dihydroxy-9-oxo-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid (24 mg.) in methanol (3 ml.) was added sodium borohydride (15 mg.). After 15 minutes~ the reaction was quenched by the addition of aqueous oxalic acid, and the mixture was extracted with methy~ene dichloride (2 x 50 ml~
The extrac~s were combined, washed with saturated brine, .

and dried, and the solvents were evaporated to give a orude product which was esterified using an excess of diazomethane in ether (2 ml.). The methyl ester was purified by chromatography on 1.5 g. of silica gel, using ethyl acetate as eluenk, to give methyl 16-(3-chlorophenoxy)-9~ ,15~-trihydroxy-17,18,19,20-tetranor-5--cis,13-trans-prostadienoate, - ~6'7~90 RF 3 0 30 ~50% acetone~meth~lene dichloride). The mass spectrum of the tris~trimethylsilyl) derivative showed ~M-CH3) = 639.2798, ~calculated for C31H52C1065i3 = 639.2758).
Example 10 The process descrihed in Example 9 was repeated, using the corresponding 11~,15~-isomer as starting material, to give methyl 16-~3-chlorophenoxy)-9~ ,15~-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoate, RF = 0 33 ~50% acetone in methylene chloride~.
Example 11 A solution of 9~-hydroxy-11~,15-bis~l-methoxy-1-methylethoxy)-15-~4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid ~123 mg.) in 0.8 ml. of pH 3 citric acid buf~er and 1.8 ml. of acetone was stirred at room temperature for l8 hours. The solvents ~ere evaporated and the residue was extracted with ethyl acetate ~3 x 3 ml.). The extracts were combined, washed with a 1:1 mixture of saturated brine and water, and were then dried. After evaporation of the ethyl acetate, the residue consisted of a mixture of the C-15 epimers of 9a,11~, 15-trihydroxy-15-~4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid. Chromatography of this residue on CC4 Malinkrodt silica gel ~2 g.), and elution with acetone/cyclohexane gave the separated C-15 *

epimers of 9a,11~,15-trihydroxy-15-~4-trifluoromethylphenyl)~

16,17,18519,20-pentanor-5-cis,13-trans-prostadienoic acid, *

i.e. the 15a-OH and 15~-OH epimers ~` - 2g _ :

.

~06~7490 RF = 0.15 and 0.20 (2.5% acetic acid in ethyl acetate).
The n.m.r. spectrum of each epimer (in deuterated acetone) showed the following characteristic bands (:Svalues):-

7~65, 4 aromatic protons 5.4 - 6.1, 5H, 4 olefinic protons and PhCH(OH).CH=CH-4.2 - Ll,9, 6H, C-9, C-ll and 4 exchangeable protons.
The mass spectrum of the tris(trimethylsilyl) derivative showed M+ = 716.3353, (calculated for C34H5gF3sSi4 = 716-3394)- ~ ;

~ le bis-ether used as starting material may be prepared as follows:-To a solution of 2,3,3a~,6a~tetrahydro-5~-hydroxy-4~-~3-hydroxy-3-(4-trifluoromethylphenyl)-1-trans-propenyl]-2-oxocyclopenteno~b]furan (250 mg.) (prepared by the process described in the second part of Example 1) in methylene dichloride (4 ml.), under an atmosphere of nitrogen, were added successlvely redistilled 2-methoxypropene (528 mg.) and a~solution of anhydrous toluene-p-sulphonic acid in tetrahydrofuran (0.073 ml. of a 1% solution). After 25 minutes, pyridine (2 drops) was added, followed by ethyl acetate (30 ml.). The so~lution was washed successively with saturated sodium bicarbonate and saturated brine and was dried. Evaporation of the solvents gave a mixture of epimeric l-methoxy-l-methylethyl ethers as a clear oil, RF = 0.65 (ethyl acetate).

~0 ~ 7~9Q

To a solution of the epimeric ether (260 mg.) in dry toluene ~17 ml.) under an atmosphere of nitrogen at ~78C., was added 0.75 ml. of a 1.95 m mole/ml. solution of di-isobutyl aluminium hydride in toluene. After 30 minutes, the reaction was quenched by the dropwise addition of methanol (2 ml.), and after a further 15 minutes at room temperature, a mixture of 1:1 saturated brine/water (15 ml.) was added, and the mixture was extracted with ethyl acetate ~3 x 25 ml.). The extract was washed with saturated brine and dried, and the solvents were evaporated to give a mixture of epimers of the lactol, 2,3,3a~,6aR-tetrahydro-2-hydroxy-5R-(l-methoxy-l-methylethoxy)-4~-~3-(1-methoxy-1-methylethoxy)-3-(4-trifluoromethylphenyl)-1-trans-propenyl}-cyclopenteno~b]furan, RF = 0.15 (40% ethyl acetate~toluene).
A solution of the lactol(260 mg.) in toluene (7 ml.) was added to a solution of potassium 5-triphenyl-phosphoranylidene valerate prepared from 1 mole of (4-carboxybutyl)triphenyl phosphonium bromide with 2 moles of potassium t-butoxide in toluene. The solution was stirred for 1 hour, and the solvent was removed by evaporation under reduced pressure. The residue was shaken with water (5 ml.) and ether (3 ml.), the aqueous layer was separated and extracted with ether (4 x 3 ml.) an~ the extracts were discarded. The aqueous~solution was acidified 2~5 to pH 5.5 with oxalic acid and extracted with a mixture of equal parts of ether and~petroleum ether (b.p. 40-60C.) _ ~ _ rla6~ .0 (6 x 4 ml.). The combined extracts were washed with saturated brine and dried, and evaporation of the solvents gave 9~-hydroxy~ ,15-bis-(1-methoxy-1-methylethoxy)-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid. RF = 0.38 (10% methanol in methylene chloride).
Example 12 The process described in Example 1 was repeated, using the corresponding llR,15-bis(tetrahydropyranyl ether) as starting material, to give the C-15 epimers of 16-(3-chlorophenoxy)-9~ ,15-trihydroxy-16,16-dimethyl-17,18~19,20-tetranor-5-cis,13-trans-prostadienoic acid~ RF = 0.15 and 0,20 (2.5% acetic acid in ethyl acetate?-The mass spectrum of the tetra(trimethylsilyl) derivative showed M = 725.3224, (calculated for C36H65C106Si4 = 725.3312).
The bis(tetrahydropyranyl ether) used as starting material may be obtained as follows:-To a solution of 4~- r4- (3-chlorophenoxy)-3-;~ hydroxy-4,4-dimethylbut-1-trans-enyl)-2,3,3a~,6a~
tetrahydro-2-oxo-5~-(4-phenylbenzoyloxy)cyclopenteno~bJ-furan (1.97 g.) in methylene dichloride (36 ml.) were added successively 2,3-dihydropyran (3~3 ml.) and a solution of anhydrous toluene-p-sulphonic acid in tetrahydrofuran (1.8 ml. of a 1% solution). After 10 minutes, pyrldine (1 ml.) was added, followed by ethyl acetate (200 ml.).
The solution was washed successively with sodium bicarbonate _~ _ 1~6~7~9,0 solution and brine, and was dried. Evaporation of` the solvents gave the epimeric tetrahydropyranyl ether as a clear oil, RF = -5 (20% ethyl acetate in methylene dichloride).
To a solution of the epimeric tetrahydropyranyl ether (2.0 g.) in methanol ~50 ml.) was added finely powdered anhydrous potassium carbonate (648 mg.). The mixture was stirred vigorously for 6 hours, then lN hydroahloric acid (7 ml.) was added, followed by ethyl acetate (200 ml.).
The organic layer was separ~ted, washed successively with 10~ saturated sodium bicarbonate solution and brine and dried, and the solvents were evaporated. ~ ~he residue was chromatographed on "Florisil" (trade mark) magnesium silicate (40 g.). Elution with ether removed the by-products, subsequent elution with ethyl acetate gave a mixture of the C-15 epimers of 4~-~4-(3-chlorophenoxy)-4,4-dimethyl-3-(tetrahydropyran-2-yl)but-1-tranR-enyl~-2,~,3aR,6a~-; tetrahydro-5~-hydroxy-2-oxo-cyclopenteno[b]furan, RF = 0.25 (40% ethyl acetate in methylene chloride). The process described in the latter part of Rxample 1 was repeated, using the above compound in place of the diol.
::

:

~3 : :
_ 3~ --,~

t7~9~

Example 13 The process described in Example 3 was repeated, using the appropriate 9-oxo-bis(tetrahydropyranyl ether) as starting material, to give the derivatives shown in the following table.

O (CH2)3-cOOH
~\ , ' \e~ . .

~Y.CH(OH).X ~ R
HO

__ _ _ Mass Spectrum R X Found Calculated ..... : ..
3-trifluoromethyl trans- CH20 M = 701.3202 702.3210 (a) vinylene hydrogen ~ ns- CH2 M = 617.3338 617.3388 (a) 4-chloro trans- CH20 (M-CH3~ =
vinylene 623.2438 623.2433 (b) 3-chloro ethylene CH20 M+ = 640.2850 640.2823 ~b) 3-chloro trans- ( 3)2 M = 695.3240 695.3260 (a) vlnylene _ (a) - for 9 methoxime-tris(trimethylsilyl) derivative (b) - for 9-oxo-tris(trimethylsilyl) derivative _ ~ _ ~67~L90 Example 14 A solution of 11~,15-bis(l-methoxy-1-methyl-ethoxy)-9-oxo-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadîenoic acid (143 ~g.) in a mixture of 0.7 ml. of pH 3 citric acid buffer and 2.1 ml.
of acetone was stirred a~ room temperature for 18 hours.
The solvents were evaporated, and the residue was extracted with ethyl acetate ~3 x 20 ml.~. The extracts were combined, washed with a 1:1 mixture of saturated bri;ne and water, and then dried. After evaporation of the ethyl acetate, the residue consisted of a mixture of the C-15 epimers of 11~,15-dihydroxy-9-oxo-15-(4-trifluoro-methylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, RF ~ .45 (2~% acetic acid in ethyl acetate). The n.m.r. spectrum (in deuterated acetone) showed the following characteristic bands (ôvalues):-7.67, 4 aromatic protons, 5.3 - 6.3, 4 olefinic protons, C15 proton and 3 exchangeable protons The mass spectrum of the bis(trimethylsilyl)-9-methoxime-methyl ester showed M = 671.3080, (calculated for C32H52F3No5si3 = 671.3104).
The 9-oxo-bis-ether used as starting material may be obtained as follows:-A solution of 9~-hydroxy-1]~,15-bis-(l~methoxy-1-methylethoxy)-15-(4-trifluoromethylphenyl)-16,17,18,19,20-~06~74~ ~

The prostadienoic acid derivative may, ofcourse, be replaced by an equivalent amount o~ another prostadieno;c acid derivative of the invention.
Example 16 % w/v ; 5 15-(4-trifluoromethylphenoxy)-9~ ,15~-trihydroxy-16,17,18,19,~20-pentanor-5-cis,13-trans-prostadienoic acid 0-003 Sodium phosphate ~ ~ 2.90 10 ~ Sodium hydrogen phosphate ~0.30 Water for injection to 100 : ~ :
he sodium phosphate was dissolved in about 80%
of the water, followed by the prostadienoic acid derivative~
and, when dissolved, the sodium hydrogen phosphate. The ~olution was made up to volume with water`for injection, and the pH was checked t~o be between 6.7;and 7.7. ~The~
solution was filtered to re~ove part1culate matter,~
sterilised by filtration, and filled into pre-sterilised neutral glass ampoules under~aseptic conditions.~
Immediately before use, the contents of an ampoule~are ~; diluted in sodium chloride B.P. for adm1nistration by intravenous infusion.
The prostadienoic acid~derivat1ve may, of course, be replaced by an equivalent amount of another prostanoic acid derivative of the invention.
:

:

:~ :
:
, ' .;~

Claims (14)

I.C.I. Case PH. 2795 THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the manufature of an 11-epi-prostanoic acid derivative of the formula:-I
wherein R1 is a carboxy or hydroxymethyl radical or an alkoxycarbonyl radical of up to 11 carbon atoms, R2 is a hydroxy radical or an alkoxy radical of 1 to 4 carbon atoms, A is an ethylene or cis-vinylene radical, Y is an ethylene or trans-vinylene radical, X is a direct bond, an alkylideneoxy radical of 1 to 6 carbon atoms wherein the alkyidene is bonded to -CHR2 and oxygen is bonded to R3, or an alkylene radical of 1 to 6 carbon atoms, and R3 is a phenyl radical which is unsubstituted or which bears one or two substituents selected from halogen atoms and trifluoromethyl radicals, R4 is a hydroxy radical and R5 is a hydrogen atom or R4 and R5 together form an oxo radical, and, for those compounds wherein R1 is the carboxy radical, the pharmaceutically or veterinarily acceptable salts thereof, which comprises:-(a) for those compounds wherein R1 is a carboxy radical, and X is other than a direct bond, the hydrolysis of a compound of the formula:-pentanor-5-cis,13-trans-prostadienoic acid (200 mg.) in methylene dichloride (2 ml.) was added to a stirred solution of Collins' reagent, prepared from chromium trioxide (280 mg.) and pyridine (0.45 ml.) in methylene dichloride (5 ml.). After 15 minutes at room temperature the mixture was extracted with ether (2 x 10 ml.), and the combined extracts were washed with saturated brine and dried. Evaporation of the solvents gave the required 9-oxo-bis-ether, RF = 0.43 (10% methanol in methylene chloride).
Example 15 16-(3-Chlorophenoxy)-9.alpha.,11.beta.,15.alpha.-trihydroxy 17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid 250 ug.
Sodium citrate B.P. 30.5 mg.
Citric acid, anhydrous, B.P. 2.8 mg.
Sodium chloride, Ph.Eur. 35.0 mg.
Water for injections, Ph.Eur. to 5.0 ml.
The sodium citrate, citric acid and sodium chloride are dissolved in most of the water, the 16-(3-chlorophenyl)-9.alpha.,11.beta.,15.alpha.-trihydroxy-17,18,19,20-tetranor-5 cis,13-trans-prostadienoic acid is added, and the solution is made up to volume with water for injections. The solution is filtered to remove particulate matter, filled into neutral glass ampoules and autoclaved, to give an injectable pharmaceutical or veterinary composition.

II
wherein R1, R3, R5, A and Y have the meanings defined above, R6 is a tetrahydropyran-2-yloxy or C4-10-alkoxydialkylmethoxy radical, R7 is an alkoxy radical of 1 to 4 carbon atoms or a tetrahydropyran-2-yloxy or C4-10 alkoxydialkylemthoxy radical and R8 has the meaning defined above for R4, or is a tetrahydropyran-2-yloxy radical; or R6 is a hydroxy radical or an aroyloxy radical of up to 15 carbon atoms, R7 is a hydroxy radical and R9 is an aroyloxy radical of up to 15 carbon atoms, whereafter when a salt is required, the product so obtained is reacted with a base; or (b) for those compounds wherein R1 is a caroxy radical, R4 is an .alpha.-hydroxy radical, A is a vinylene radical and X is a direct bond, the reaction of a loactol of the formula:- III
wherein R2 and R3 have the meanings defined above, with a (4-carboxybutyl) triphenylphosphonium salt, in the presence of a strong base, whereafter when a salt is required, the product so obtained is reacted with a base; or (c) for those compounds wherein R1 is an alkoxycarbonyl radical, the reaction of the corresponding compound of the formula I wherein R1 is a carboxy radical, with a diazoalkane of 1 to 10 carbon atoms, of a salt thereof with an alkyl halide; or (d) for those compounds wherein R1 is a hydroxymethyl radical, the reduction of a corresponding compound of the formula I wherein is an alkoxycarbonyl radical; or (e) for those compounds wherein R2 is an alkoxy radical, the reaction of the corresponding compound of the formula I wherein R2 is a hydroxy radical with an alkyl halide of 1 to 4 carbon atoms in the presence of a strong base.

2. An 11-epi-prostanoic acid derivative of the formula I
given in claim 1, wherein R1, R2, R3, R4, R5, A, X and Y have the mean-ings stated in claim 1 whenever prepared by the process claimed in claim 1 or by an obvious chemical equivalent thereof.

3. A process as claimed in claim 1 for the manufacture of an 11-epi- prostanoic acid derivative, wherein in the starting materials when appropriate and in the product of the formula I, R1 is a carboxy, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hex-yloxycarbonyl or decyloxycarbonyl radical, R2 is a hydroxy or methoxy radical, A, Y, R4 and R5 have the meanings stated in claim 1, X is a direct bond or a methyleneoxy, ethyleneoxy, isopropylideneoxy, 1-methyl-propylideneoxy, 1-ethylpropylideneoxy, methylene, ethylidene, isopropyl-idene, propylidene, 1-methylpropylidene, 1-ethylpropylidene, ethylene, 1-methylethylene, 1,1-dimethylethylene, 2-methylethylene or trimethylene radical, and R3 is a chloro-, bromo-, fluoro- or trifluoromethyl- phenyl radical, and for those compounds wherein R1 is a carboxy radical, the ammonium, alkylammonium containing 1 to 4 alkyl substituents each of 1 to 4 carbon atoms, alkanolammonium containing 1 to 3 2-hydroxy radicals, and alkali metal salts thereof.

4. A process as claimed in claim 3 for the manufacture of an 11-epi-prostanoic acid derivative, wherein in the starting materials when appropriate and in the product of the formula I, R1 is a carboxy, hydroxymethyl or methoxycarbonyl radical, A is a cis-vinylene radical, R4,R5 and Y have the meanings stated in claim 1, R2 is a hydroxy or methoxy radical, X is a direct bond or a methyleneoxy or methylene radical, and R3 is a phenyl, chlorophenyl or trifluoromethylphenyl radical.

5. A process as claimed in claim 1 for the manufacture of an 11-epi-prostanoic acid derivative, wherein in the starting materials when appropriate and in the product of the formula I, R1 is a carboxy or hydroxymethyl radical, or an alkoxycarbonyl radical of up to 11 carbon atoms, and R2, R3, R4, R5, A, X and Y have the meanings stated in claim 1.

6. A process as claimed in claim 1 for the manufacture of an 11-epi-prostanoic acid derivative, wherein in the starting materials when appropriate and in the product of the formula I, R1 is a carboxy, hydroxymethyl, methoxycarbonyl or ethoxycarbonyl radical, R2 is a hydroxy radical, A is a cis-vinylene radical, Y is a trans-vinylene radical, X is a direct bond or a methyleneoxy radîcal wherein the methylene is bonded to -CHR2- and the oxygen is bonded to R3, and R3 is a chlorophenyl or trifluoromethylphenyl radical.

7. A process as claimed in claim 1 for the manufacture of an 11-epi-prostanoic acid derivative, wherein in the starting materials and in the prod-uct of the formula I, X is a methyleneoxy radical and R3 is a 3-chlorophenyl or 3-trifluoromethylphenyl radical.

8. A process as claimed in claim 1 for the manufacture of an 11-epi-prostanoic acid derivative, wherein in the starting materials and in the prod-uct of the formula I, X is a direct bond and R3 is a 4-trifluoromethylphenyl radical.

9. A process for the manufacture of 16-(3-chlorophenoxy)-9.alpha.,11.beta.,15.alpha.-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid, 16-(3-chlorophenoxy)-11.beta.,15.alpha.-dihydroxy-9-oxo-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic aeid or 9.alpha.,11.beta.,15.alpha.-trihydroxy-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, whieh comprises:-the hydrolysis of respectively 16-(3-chlorophenoxy)-9.alpha.-hydroxy-11.beta.,15.alpha.-bis (tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid, 16-(3-chlorophenoxy)-9-oxo-11.beta.,15-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid or 9.alpha.-hydroxy-11.beta.,15-bis (1-methoxy-1-methylethoxy)-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, whereafter when a salt is re-quired the product so obtained is reacted with a base.

10. A process as claimed in claim 1 for the manufacture of methyl 16-(3-chlorophenoxy)-9.alpha.,11.beta.,15.alpha.-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoate which comprises the reaction of 16-(3-chlorophenoxy)-9.alpha.,11.beta., 15.alpha.-trihydroxy-17,18,19,20-tetranor-5-cis,13-transs-prostadienoic acid with diazomethane, or the reaction of a salt thereof with a methyl halide.

11. A process as claimed in claim 1 for the manufacture of 16-(3-chloro-phenoxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadien-1,9.alpha.,11.beta.,15.alpha.-tetraol which comprises the reduction of methyl 16-(3-chlorophenoxy)-9.alpha.,11.beta.,15.alpha.-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoate.

12. 16-(3-chlorophenoxy)-9a ,11.beta.,15.alpha.-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid, 16-(3-chlorophenoxy)-11.beta.,15-dihyroxy-9-oxo-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid or 9.alpha..11.beta.,15.alpha.-tri-hydroxy-15-(4-trifluoromethylphenyl)-16,17,18,19,20 pentanor-5-cis,13-trans-prostadienoic acid, whenever prepared by the process claimed in claim 9 or by an obvious chemical equivalent thereof.

13. Methyl 16-(3-chlorophenoxy)-9.alpha.,11.beta.,15.alpha.-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoate whenever prepared by the process claim-ed in claim 10 or by an obvious chemical equivalent thereof.

14. 16-(3-chlorophenoxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadien-1,9.alpha.,11.beta.,15.alpha.-tetraol whenever prepared by the process claimed in claim 11 or by an obvious chemical equivalent thereof.