CA1192904A - Ethers - Google Patents

Abstract

A B S T R A C T

Prostacyclin salts, synthesis thereof, pharmaceutical formulations containing them and their use in medicine.

Description

~hls lnv~ntion re1ates to a prostaglal1c~ derlvatlve~
the synthesis thereof 9 ~ormulation~ containing lt anct its use in medIclne.
The applicants r~cently described ~S Moncada et al 9 Nature, ~ , 663, (197~ ~ the discovery and isolation of a new proslaglandin derivative having~ inter alia~ potent an-ti-aggre~atory activity on blood platelets.
Further investigation ~Johnson et al, Prostaglandins, 1976, 12, 915-978~ has sho~n that the prosta~l~ndin, now known as prostacyclin or PGI2, is (5Z)-didehydro-9-deoxy-6, 9~-epoxyprostaglandin ~ as shown in formula (I) (R is hydrogen) below:

R02C -- ~

\ (I) <
r~
OH OH

Prostacyclin is unstable at room temperature in aqueous medium, having a half-life of approximately 10 minutes~ but is more stable in aqueous alkali.
The applicants have now discovered a process for the preparation of salts of prostacyclin (i.e. conlpounds of formula (I) above wherein R is an appropriate cation~
I~articularly the alkali metal salts~ more particulaIly the so~ium salt. Such salts, which may be obtained in B

crystalline form, are stable at room t~ll~Ld~Ul~.
In accordance with the invention ~here is provided a process for yl~kling a crystAll;n~ salt of (5Z)-5,6-didehy~ro-9-d00Ky-6, 9~ xy~lv~ An~;n Fl~ cY~prising:
a) dehydrohalvgenation of a c~ l of fon~

s COY
/ ~
~ (III) ' ozl ~z2 (wherein X is bromide or iodine, Y is OH, NHRl ox OR , R beingaIkyl of 1 to 4 carbon atoms, and Z and z2 are selected frcm hydxogen and hydxoxy blocking groups) with a base, ~ollowed, as n~ y, by hydrolysis of any NHRl or ORl group and by removal of any hydroxy blocking group(s) Z and~or Z , and -formation of a crystAll;n~ salt, other ~han a sodium.salt o~ (5~)-5,6-didehydro-9-deoxy-6,9~ -~U~y~L~stA~l An~ i n Fla;
b) dehydroh~Alo~nAting a ~ v -Kl of formula (III), as ~Pf;ne~
abcve, with a base, where.Ln in said ~ILU~ X is bromine, Y is OH, NHRl or ORl' Rl being alkyl of 1 ~o 4 OE bon atoms and Z
and z2 are hy~rogen or hydLu~ blocking groups, followed, as n~e~sAry, by hydrolysis o~ any NHRl or ORl group an~ by remcval o any Hydluxy blocking group in zl and z2 , and ormation o a crys~ll;nP salt of (5Z)-5,6-didehydro-9-deoxy-6,9~-~L~xy~Lusta-glAn~;n Fl~ ; or c) dehy~luhalogenating a ~'"L'~ 1 Of fon~llA (III), as ~,.

defin~d above~ with a base, wherein in said ormr~lln~ (III), X is brcmine or iodine, Y is OR , R being alkyl of 2 to 4 carbon atoms and zl and 22 are hydrogen or hydroxy blocking groups, followed, as necessary, by hydrolysis of an~ NHRl or oRl group and by removal of any hydroxy blocking group in Zl and z2, and formation of a crys~llinP salt of (5Z)-5,6-dideh~dro-9-deoxy-6,9~ epoxy-prostagl~n~; n F~ ;
or d) dehydrohalogenating a compound of f~n~ III), as ~PfinP~ akove, with an aIkali metal alkoxide, wherein in said ~ y~d (III), X is bromine or iod m e, Y is OH or NHR , R being alkyl of 1 to 4 carbon atoms and Z and Z are hydrogen or hydroxy blocking yroups, followed, as nP~Pss~ry~ by hydrolysis of any NHR
group and by removal of any hydroxy blocking group in zl and z2, ; and formation of a cryst~llinP. salt of ~5Z)-5,6-didehydro-9_deoxy-6,9 ~-e~u~y~u~ n~;n Flo~; or e) hydrolysing the methyl ester group in a f~..q~~ l of formula:
~C~, e~ ~
~, `~ ~

in the ~Les~ ~e of a base other than sodium hydroxide an~ formation ~0 of the sodi~m salt of formula:

~ o~

~o ~

or f) hydrolysing the ester group in a cnmrolln~ of fonmll~
. ~ioo~

~A

~herein R is alkyl of 2 to 4 carbcn atoms, and formation o the sodium salt of formula:

~ ~

0~ 0~

In another aspect of the invention there is provided crystAll;n~
salts of (SZ)-5,6-didehydro-9-deoxy-6,9~ -epoxypros~agl~n~;n Flo_ '~.

~ 5 produced in accordance with the processes of the invention.
In a particular Pmho~;mpnt the salts of prostacyclin may be synthP~ l fro~ a comFound o formula (II) as shx~n in the reaction scheme kelow wherein Z and z2 are select0d from hydrogen an~
hy~roxy blw king group~, for ~x~rlP, acyl, or trialkylsilyl (for ~mrle, trImethylsilyl)~ Oxidative attack, for example by iodine or pOt~`~S;l~n tr;in~;de in the ~l~s~lce of a metal bicarb-onate~ at~the 5,6-do~ible kond of a ~nmrOlln~ of form~la ~II) with simult~n~lls or ~lhse~Pnt cyclisation involving the 9-hydroxy group produces a cnm~olm~ o f~n~lla (III) as shcwn below. Upon LL~L~ L with a suitable kase, for example an organic base or a metal alkoxide, the ~nm~olln~ of fon~ (III) may then be dehydro-halogenatedl resulting in the introduction of a 5,6~double bond.
This reaction seguence is illustration in the following reaction scheme:- l====~ COY
OH I ~
~r ~ (II 3 \f~ ~

/coy <~

~-, YoC- ' 3 (IV) OZ 1 oz2 ~herein Y, X and Z are as ~f;n~ above.
When Z and/or Z in fon~llA~ (II), (III) and ~IV) are blockin~ sroups, these klocking groups may be l~WV~d at _ny desired point in the synthesis, e.g. by methods kncwn in the art, for ~x~m~e, base hydrolysis.
In another particular fmhC~ nt the prostacyclin salts may be ~L~CL~d by treating an ester thereof (formula (I): R is alkyl, for I ~le the meth~l ester), with a strong base, in a suitable solvent and ly~ph;1;c;n~ the resulting reaction nLixture. Gne suitable kase is sodium hydroxide. By way of example the sodi~m s31t may be preFared by the reaction of 5-halo-9-deoxy-6,9~-~J~y~Lost~ n~;n Fl~ methyl ester, where halo is brcmo or icdo, with scdium ~ ^~h~)x;~ and then reacting the so obta med prosta-glAn~;n ester with a sodium base. PreferA~ly the 5-halo-prDsta-gl ~n~; n is either (5R,6R)-5-iodo-9-deoKy-6,9~ -epoxyprost~gl~n~; n Fla or a muxture thereof with the (5S,6S) isomer.
When the sodium salt of prostac~clin is isolated in crystal-line form, it is a*vantageously pro~ided with a cc~t;n~ of sodium c~rhnnate formed, by ~x~mrle by l~qhlng the sodium salt with sodium hydroxide ~ollowed b~ air drying-The reaction may be carried out at or below ~mh;~nt t~mrPr~ture.

r~he dehydrohalogenation reaction is preferably carri~d out under ~n inert atmosphere.
Prostacyclin c~nd its salts are useul as ;~nm~;ateS in the synth~ of prostAgl_ndi~ analogues, _nd exhibit a potent anti-ayyl~y~Lory action on blood platelets, and th~l~L.~l~ have a particuk~r utility in the LLea~e~lLan~/or prophylaxis of mAmm as anti-thrombotic agents.
'mey are also useful in mAmm~l~, including ~an, to reduce an~ control ~essive gastric secretion, thereby r~ ;n~ or av~idiny- gastrointestinal ulcer fonmation, and A~c~l~rating the h~Alin~ of such ulcers and les;~n~ already presen~ in the gastro-intestinal tract.
Prostacyclin and its salts further exhibit v~o~;latory action on blood vessels and thtL~ e have a pqIticular utility as anti-hypertensives for the L~ L of high blood pressure in mAmm~
;n~ ;ng man. Platelets cA~ be A~;m;lAte~ into the vA~ Ar endothPl;l~ or even in~vly~.~Led into endoth~ l cells.
~;nrh~m;r~l co-operation hethe^~ platelets and VAq~llAr endoth~l;
in the generation of Prostacyclin contrihutes to the repair of vAc~llAr endo~hPl;l~m and Prostacyclin and its salts have a ~urther utility in the pramotion of w~und ~PAl;n~ in mAmm~ls, inrlll~;nq man.
Prostacyclin and its salts may be used whenever it is desir0d to ;nh;h;t platelet ayyL~ydLion, to reduce the adhesive character of platelets, and to treat or ~u~v~lL the fonmation of thramLhi in mA~mAl~, inrll~;n~ man. For ~Am~le~ they may be used in the treat-ment and ~v~lLion of myocardial infarcts, in the ~ ~L~ L of peripheral~ llAr ~;~eA~e to treat and ~l~v~lL post operative _ r ~hrambo$is, -to promote F~ate~cy o v~q~ll~r grafts ~ollowing surgery/ and to treat c*mplications of arteriosclerosis and conditions such as atheroscler~sis, blood clotting defects due to l;~Fm;~, and o-ther cl;~;r~l conditions in which the underlying etiology is ~q~ocl~ted with lipid lmh~1~n~e or hyper 1i~id~m;~.
They may also be used as additives to blood, blood products, blood substitutes, and other fluids which are use~ in ar~if;~
extra-corporeal circulation and perfusion of isolated bcdy portions, e.g., limbs and organs, ~h~h~r attached to the original body, detache~ and being preserved or ~ ~d for tr~nqrl~nt, or attached to a new body. During these circulations and perfusions, ayyLtydted platelets tend to block the blood vessels and portions of the circulation d~dLdL~S. miS blocking is avoided by the presence of Prostacyclin. For this purpose, Prostacyclin or its salts may be added graduall~ or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, at~ or ~t~hf~ to the r~c;p;~ntl or to two or all of those at a total steady state dose of.001 to 10 mg., per liter of circulating fluid. It is e.q~P~;~lly useful to use Prost~cyclin Ln lab~Ld~ly ~nim~l~, e.g., cats, dogs,rabbits, monkeys and rats, for these purposes in order to develop new methods and ~e~hn;~l~q fox organ and limb ~r~n~ ntq.
The amount of prostacyclin or a s~lt thereof required (herein-after referred to as the active ingredients) for th~Ld~ ic effect will vary with the route of ~m;n;qtration In ger.eral a suitable dose for a m~mmal will lie in the range of 0.01 to 200 mg. per kilogram bcdyweight, conv~n;~ntly 0.01 to 10 mg per kilogram.
~hile it is possible for the active ingredient to be admin-''. ~

~L!92~
~ 9 _ istered as th~ raw chPmlr~l it is preferable to prevent it as a ph~rn~ tical for~ulation. Such formulations c~re preferably non-~lPo~l~ c~nd non-hydrQYylic in nature, but alkaline ~lfoll~
solutions ma~ b2 used. Unit doses of a formulation contain between 0.5 m~ an~ 1.5 g of the active ingredient.
Such formulations, both for veterLnary and for human ~F~
use, of the present invention con~rise the active in3redient, as above ~Fin~, together with one or more acceptable carriers therefor and opt;on~lly other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other in~redients of the for~ll~tion and not deleterious to the recipient thereof.
The formulations ;n~ those suitable for parenteral (;n~ in~ sub~uL~le~us, intr~ r and inLl~v~ ~us) ~m;n;~tration which must of course be sterile.
The f~n~ tions may convF~;Fntly be p~F~ntp~ in unit dosage form and may be yL~dlffd by any of the m~h~ well-known in the art of ph~rm~ry. All ~ethn~ include the step of bringing into ~oc;ation the active ingredient with the carrier which constit-utes one or more ~rcP~q~ry ingrF~;~nt~. In general the fon~ tions are ~L~dl~d by uniformly and intimateLy bring mg into association the actlve in~redient with liquid carriers or finely divided solid carriers or both, and then, if nP~F~ ry~ ~h~;ng the product into the desired formulation.
~ronr~;ng to the present invention there are thtL~ p~ovided:
(a) cryst~llin~ ph~rm~rolr~;r~lly acceptable salts of (5Z)-5,6-didehydro-9-deoxy-6,9~ -~y~lost~7l~n~in FloL;
(b) the ~ rdLion of such salts;
'~;.

(c) FhArn~c~tical formulations ~on~A i n; n~ ~uch salts;
~d) -the pxeparation of ~ h~rmAret~;r~l formulations;
(e) method for ~he LL~a~ .L or prophylaxis of thrnmh~
in a ma~n~ or m~ n ~ es, ;n~lnrli ~ Ir.an, c~
prising ~te ~m;n;~tration of a non-toxic, prophylactic anti-tl~,~o~ic amot~tt of a salt as defin0d in (a) akove.
(f) methDd ~or ;n~l7~in~ vasodilation in a mammal, in~ ;n~
~m~n~ ~omprising the ~Am;n;~tration of a non-toxic, vA~s~;lAttory _motmt of a salt as def;nPd .in (a) above.

(g) method ~or the prophylaxis or L~ "~ of gastric ~ n~ in a ~ammal, ;n~ln~;n~ m~n, comprising t~te A~min;~tration of a ~ton-toxic, prophylactic or thera-peutic amcQ~tt of a salt as ~Pf;n~ m ~a~ above.
(h) method for the prcm~tion of wound hPAl;n~ i~ a nE~al, ;n~ ;n~ man, comprising the ~m;n;~tration of a non-toxic w wnd-L eGLLL~ amDunt of a salt as ~Pf;nPd in (a) akove.

The following ~mrlP.~ are prcvided by way of an illustration of the present invention and should in no way be construed as constituting a limitation thereof:
EXAr~E 1 A stirred solution o~ PGF2a methyl ester (50 mg) in ~ther (1 ml) was treated with sodium h;~?~"~Le (115.0 n~; 10 m~le~ r e~uivalents3 an~ water (1 ml) and then dropwise during 2 hours with a~l~Dll~ potA~s;~n tr;;~i~e (0.7 molar; 0.261 ~1). After stirring cvP~ h~, the reaction mixture was shaken with ether and aqueous sodium ~h;nS~ hAte; the etheral phase was sL-~cL~Led~ washed with water, dried with mA~nP.~;lTm sulphate, and ~vd~JLdL~ to leave

2!9~

a ye_low ~um oE 5~ ~iodo-9-deoxy-6~,9~_-epo~ypros~;rJl~nrl;n Flo_ mRthyl ester.
A solution of 5~~iodo-9--deoxy-6~,9~ -epQxyprost~glAn~7;n Flo~
methyl ester (100 mg) in mpt~h~n~l;c sodium methoxide ~.~yc~ frGm sodium (46 mg) and dry mP~h~n~l (0.70 ml) was set aside under dry nitrogen or 5 hours, then freed fram solvent in high vacuum.
me rPc;rl~ S solid was washed with hPn7PnP, set aside in the air ovPrn;rJht, and stirred with N ar~foll~ sodium hy~roxide (0.5 m_) to give a ~l~pPn~;~n of coiourless fine nr~r77P~ m e crystals wexe collected, washed with a few drops of N Ar~leou~
sodium hydroxide, an~ dried in the air to give the sodium salt of 9-deoxv-6,9~ -epoxy- ~ 5-prostAgl~nr7;n Fl~ . The inhibition of ar~h;~n;~ acid-induced ayyL~ydLian of human plate7ets at a ~",r~ Lion of 0.2 ng~ml by this salt and its instability in water at acid pH, together with further evidence, is compatible with ~s;gn~tion of the c~nf;~-ration (5Z)-5,6-did~hydro-9-deoxy-6,9~-~J~y~L~st~qlAn~7;n Fl~ .
m e high-resolution 13C n.m.r. spectrum of a solution of the crystals in dimethyl ~ h~ -d6 showed the expect~d 20 reson-ances whose ch~m;r~l shifts were entir~ly consistent with the ~h~m;c~l structure est~hl;~h~ for Prostacyclin. No impurity p~aks were d~L~Led.

5~ -iodo,9-deoxy-6~,9~-~J~y~l~st~gl ~nrl; n Fl methyl es~er (500 ml) was stirred with mrth~n~ NaQMe ~L~dled frcm Na (0.23g, 10 equivs.) and Meca (3.5 ml) un~er N2 at room t~l,~eL~LuL~ over night; lN aq. NaOH (2.5 ml) was added to the yellow reaction solution to bring about hydrolysis of the ester moiety and, after '~

tw~ hours, -the methanol was evaporated in vao~o at room temperature.
m e re~;~n~ OU~ solution gave rise ~o~ eously tc a mass of colourless fine nPP~l~s of ~he desired sodium salt (f~r~~
R-Na) which was cooled (0), collected, washed sparingly with lN
aq. NaOH, air-dried, and stored in a ~J~el~d tube; this salt (383 mg) had~max (KBr disc~ 1692 cm 1 (O-C=C) and twenty 13C
r~n~n~es only were obse~ve~ at 18~.7 (C-l), 158.2 (C-6), 140.0 and 134.3 (C-13,14), 100.7 (C-5), 87.5 ~C-15), 80.6 and 75.5 (C
-9,11), 58.0(C-12), 49.0, 45.8, 42.4, 41.9, 37.5, 35.8 (C-18), 31~6, 29.9, 29,3, 26.7 (C-l9~, 18.4 (C-20) ppm fro~ IMS in DMSO-d6).
The product sodium (5Z)-5,6-dldehydro-9-deoxy-6,9Q-epoxyprosta-~l~n~;n Fl~ (s~n. sodium prostacyclin), thus obtained cnmrlet~ly inhibited ~r~h;~n;o acid-;n~n~Pd platelet a~y~y~l~ion (human platelet-rich plasma) at 1 ng/~l and its profile of biological activity on the rakbit aorta, rabbit ~oPl;~ æ tery, rat s~omach strip an~ rat colon ~vll~vr~ wi~h that of sodium prostacyclin ob~ain~d by bio-synthesis. After air-drying, the salt has a surface coating of sodium c~ Le (ca. 3.5 % ~hy weight) which protects the vinyl ether moiety against ~ P catalysed hydrolysis.

5~-io~o-9-deQxy-6~9~-eFoxypros~ n~; n Fl~ methyl ester was Ll~1Led with 1,5-diazabicyclo-5-nvnene (DBN) at roam t~m~r~L
in the AhsPn~e of a solvent for a few hours. The ~BN and hydro-gen iodide were cvnv~niently ~I~V~d by adsorption on to a column of SiO2, prepared from a sll~pPn~;~n of SiO2 in Etc~c/Et3N 50:1, and the vinyl ether was eluted with the same sol~ent system.
I. R. spectroscopy (thin film, ~ ma~ 1738 (C02Me) and 1696 cm 1 ,~

~' ~9Z~

(-0- ~ )), H n.m-r- m C6D6-Et3N, 19~ 4,?2, triplet of triplPtsl2, J6.9 a~ 1.0 ~ ~C-5 vinyl probon)), and 13C n.m.r.
in C D Et N, 19:1 (distinctive features were ll~cr~n,,~ s at 159.8 (C-l), 155.8 ~C-l), 155.8 (C-6), 137.2 and 130.6(C-13,14), 95.3 (C-~ 4.1(C-15) 77.3 and 72.2(C-9,11) an~ 51.1. (M~ ester) pFm from 'LMS).
The vinyl ether (5Z)-5,6-dLidehydro-9-deoxy-6,9a -epoxy-prost~ n~;n me~hyl ester, was h~rolys0d with ~lfOll~ scdium prostacyclin (fon~ 5I): R=sodiuml).

(SR,6R)-5-Iodo-PGIl methyl ester (13.375 g, o~t~;n;n~ ca.
2% 5S,6S isomer~ was taken up in methanolic scdium meth~ [from Na (6.23 g) and MeOH (94 ml)] at rocm l~ Lule under N2 and set aside at r w m temperature ovPrn;ght. The resulting yellow sollltinn was treated with IN ~lfml~ NaCH (70 ml~, filtered from .s~;m~nt, set aside at roam temp~L~LuLe for 2 h~urs, and freed from MeOH on a Buchi ~vd~oLdLoL in ~acuo at rcam t~nr~.~Lule.
m e r~ syrup was treated with H20 (25 ml) and with ~ore lN
~q~ NdOH (80 ml), cryst~ Ation t~king place ~ ly to give a mass of felted crystals. After cooling to ~l the solid was collected, washed with ice-cold lN ,l~le~u~ NaOH ~caO 40 ml) until the ~ch;n~q were colourless, and dried in the air (2 days) to ~v.~L~L weight, affording 10.15 g, m.p. 164-166 ~following drying at 100) of oolourless prostacyclin sodium salt.
~r;~;f;r~t;on of the ~ ml.~ liquors with ~qllR~ Cl yielded 1.84 g of cxude 6-Qxo-PGFl~which was purified e~her ~ h;n~, column ~ ~l~LoyLd~ly (SiO2,AIX) to give 0.955 g of pure 6-oxo-EGF ~.
~.

Claims (39)

The embodiements of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a crystalline salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?
comprising:
a) dehydrohalogenating a compound of formula (III):

(III) with a base, wherein in said compound (III), X is bromine or iodine, Y is OH, NHR1 or OR1, R1 being alkyl of 1 to 4 carbon atoms and Z1 and Z2 are hydrogen or hydroxy blocking groups, followed, as necessary, by hydrolyis of any NHR1 or OR1 group and by removal of any hydroxy blocking group in Z1 and Z2, and formation of a crystalline physiologically acceptable salt other than a sodium salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?; or b) dehydrohalogenating a compound of formula (III), as defined above, with a base, wherein in said compound (III) X
is bromine, Y is OH, NHR1 or OR R1 being alkyl of 1 to 4 carbon atoms and Z and Z are hydrogen or hydroxy blocking groups, followed, as necessary, by hydrolysis of any NHR1 or OR1 group and by removal of any hydroxy blocking group in Z1 and Z2, and formation of a crystalline salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?; or c) dehydrohalogenating a compound of formula (III), as defined above, with a base, wherein in said compound (III), X is bromine or iodine, Y is OR1, R1 being alkyl of 2 to 4 carbon atoms and Z1 and Z2 are hydrogen ox hydroxy blocking groups, followed, as necessary, by hydrolysis of any NHR1 or OR1 group and by removal of any hydroxy blocking group in Z1 and Z2, and formation of a crystalline salt of (5Z)-5,6-didehydro-9-deoxy-6,9.alpha.-epoxy-prostaglandin F1.alpha.;
or d) dehydrohalogenating a compound of formula (III), as defined above, with an alkali metal alkoxide, wherein in said compound (III), X is bromine or iodine, Y is OH or NHR1, R1 being alkyl of 1 to 4 carbon atoms and Z1 and Z2 are hydrogen or hydroxy blocking groups, followed, as necessary, by hydrolysis of any NHR1 group and by removal of any hydroxy blocking group in Z1 and Z2, and formation of a crystalline salt of (5Z)-5,6-didehydro-9-deoxy-6,9.alpha.-epoxyprostaglandin F1.alpha.;
or e) hydrolysing the methyl ester group in a compound of formula:

in the presence of a base other than sodium hydroxide and formation of the sodium salt of formula:

or f) hydrolysing the ester group in a compound of formula:

wherein Rl is alkyl of 2 to 4 carbon atoms, and formation of the sodium salt of formula:

2. A process for preparing a crystalline physiologi-cally acceptable salt other than a sodium salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?
comprising the dehydrohalogenation of a compound of formula (III):

(III) with a base, wherein X is bromine or iodine, Y is OH, NHR1 or OR1, R1 being alkyl of 1 to 4 carbon atoms and Z1 and Z2 are hydrogen or hydroxy blocking groups, followed, as necessary, by hydrolysis of any NHR1 or OR1 group and by removal of any hydroxy blocking group in or Z2, and formation of a crystalline physiologically acceptable salt other than a sodium salt (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?.

3. A process according to claim 2, wherein X is bromine.

4. A process according to claim 2, wherein Y is OR1, and R1 is alkyl of 2 to 4 carbon atoms.

5. A process according to claim 2, 3 or 4, wherein at least one of Z1 and Z2 is a hydroxy blocking group and said dehydrohalogenation is followed by removal of the at least one hydroxy blocking group.

6. A process according to claim 2, wherein said dehydrohalogenation is carried out under an inert atmosphere.

7. A process for preparing a crystalline salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?
comprising the dehydrohalogenation of a compound of formula (III):

(III) with a base, wherein X is bromine, Y is OH, NHR1 or OR1, R1 being alkyl of 1 to 4 carbon atoms and Z1 and Z2 are hydrogen or hydroxy blocking groups, followed, as necessary, by hydrolysis of any NHR1 or OR group and by removal of any hydroxy blocking group in Z1 or Z2 and formation of a crystalline salt of (5Z)-5,6-didehydro-9 deoxy-6,9.alpha.-epoxyprostaglandin F1.alpha..

8. A process according to claim 7, wherein Z1 and Z2 are hydrogen.

9. A process as claimed in claim 7, wherein R1 is methyl.

10. A process as claimed in claim 7, wherein the dehydrohalogenation is effected with an alkali metal alkoxide.

11. A process as claimed in claim 7 or 10, wherein the dehydrohalogenation is carried out under an inert atmosphere.

12. A process according to claim 10, wherein dehydro-halogenation is effected using sodium methoxide.

13. A process as claimed in claim 10, wherein the alkoxide is sodium methoxide, and hydrolysis is carried out with sodium hydroxide to produce the sodium salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?.

14. A process as claimed in claim 7, wherein the hydrolysis is carried out with an alkali metal hydroxide to produce the alkali metal salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?.

15. A process as claimed in claim 14, wherein the dehydrohalogenation is effected with an alkali metal alkoxide.

16. A process as claimed in claim 14, wherein the alkali metal hydroxide is sodium hydroxide and the salt is the sodium salt.

17. A process as claimed in claim 15, wherein the alkali metal hydroxide is sodium hydroxide and the salt is the sodium salt.

18. A process for preparing a crystalline salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?
comprising the dehydrohalogenation of a compound of formula (III):

(III) with a base, wherein X is bromine or iodine, Y is OR1, R1 being alkyl of 2 to 4 carbon atoms and Z1 and Z2 are hydrogen or hydroxy blocking groups, followed, as necessary, by hydrolysis of any NHR1 or OR1 group and by removal of any hydroxy blocking group in Z1 and Z2 and formation of a crystalline salt of (5Z) 5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin Fl?.

19. A process according to claim 7 or 18, wherein at least one of Z1 and Z2 is a hydroxy blocking group and said dehydrohalogenation is followed by removal of the at least one hydroxy blocking group.

20. A process according to claim 7 or 18, wherein said dehydrohalogenation is carried out under an inert atmosphere.

21. A process according to claim 18, wherein said dehydrohalogenation is carried out with an alkali metal alkoxide.

22. A process according to claim 18, wherein Z1 and Z2 are hydrogen.

23. A process as claimed in claim 18, wherein R1 is ethyl.

24. A process as claimed in claim 18, wherein the hydrolysis is carried out with an alkali metal hydroxide to produce the alkali metal salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?.

25. A process as claimed in claim 24, wherein the dehydrohalogenation is effected with an alkali metal alkoxide.

26. A process as claimed in claim 24, wherein the alkali metal hydroxide is sodium hydroxide and the salt is the sodium salt.

27. A process as claimed in claim 25, wherein the alkali metal hydroxide is sodium hydroxide and the salt is the sodium salt.

28. A process for preparing a crystalline salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?
comprising the dehydrohalogenation of a compound of formula (III):

(III) with an alkali metal alkoxide, wherein X is bromine or iodine, Y is OH or NHR1, R1 being alkyl of 1 to 4 carbon atoms and Z1 and Z2 are hydrogen or hydroxy blocking groups, followed, as necessary, by hydrolysis of any NHR1 group and by removal of any hydroxy blocking group in Z1 and Z2, and formation of a crystalline salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?.

22. A process as claimed in claim 28, wherein Z1 and Z2 are hydrogen.

30. A process as claimed in claim 28, wherein R1 is methyl.

31. A process according to claim 28, comprising the dehydrohalogenation of a compound of formula (III), wherein X is iodine.

32. A process according to claim 28, wherein said dehydrohalogenation is carried out with sodium methoxide.

33. A process for preparing a compound of formula:

which comprises hydrolysing the methyl ester group in a compound of formula:

in the presence of a base other than sodium hydroxide and formation of the sodium salt.

34. A process for preparing a compound of formula:

which comprises hydrolysing the ester group in a compound of formula:

wherein R1 is alkyl of 2 to 4 carbon atoms, and formation of the sodium salt.

35. A process according to claim 34, wherein the hydrolysis is carried out with aqueous sodium hydroxide.

36. A crystalline salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?, whenever prepared by a process of claim 1, or by an obvious chemical equivalent thereof.

37. A physiologically acceptable crystalline salt other than a sodium salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?, whenever prepared by the pro-cess of claim 2, or by an obvious chemical equivalent.

38. A crystalline salt of (5Z)-5,6-didehydro-9-deoxy-6,9?-epoxyprostaglandin F1?, whenever prepared by the process of claim 7, 18 or 28, or by an obvious chemical equivalent.

39. A compound of formula:

whenever prepared by the process of claim 33, 34 or 35, or by an obvious chemical equivalent.