Thienyoxy and furyl containing analogs of prostacyclin and their use as medicaments

What is disclosed are prostacyclin analogs of the general formula I ##STR1## which have a more specific action and/or a longer action than the naturally occurring prostacyclin PGI.sub.2, as well as intermediate products for their preparation and a process for their preparation. The compounds of formula I are distinguished by inhibitory action on thrombocyte aggregation and by relaxation of the vascular walls, in particular of the coronary arteries. They can thus be used as medicaments.

Prostacyclin or PGI.sub.2, a recently isolated naturally occurring 
substance of the prostaglandin family, is distinguished by very pronounced 
inhibitory properties with regard to thrombocyte aggregation (The Lancet 
1977, 18). In addition, PGI.sub.2 is able to relax some blood vessels, for 
example coronary arteries (Prostaglandins 13, 3, 1977), so that it could 
find use in the therapy and prophylaxis of thromboses and infarctions. 
The present invention relates to new analogs of the general formula I 
##STR2## 
which have a more specific action and/or a longer period of action than 
PGI.sub.2 and in which R.sup.1 denotes hydrogen, a straight-chain or 
branched alkyl radical with up to six carbon atoms, a straight-chain or 
branched unsaturated aliphatic hydrocarbon radical with three to six 
carbon atoms, a cycloaliphatic hydrocarbon radical with three to seven 
carbon atoms, an araliphatic hydrocarbon radical with seven to nine carbon 
atoms or a physiologically acceptable metal ion or NH.sub.4 ion, or 
ammonium ion which is derived from a primary, secondary or tertiary amine, 
or a tetraalkylammonium ion and R.sup.2 denotes a cycloalkyl radial with 3 
to 7 carbon atoms or a straight-chain or branched alkyl radical with up to 
8 carbon atoms, which can in turn be substituted by (a) halogen, or an 
.alpha.- or .beta.-thienyl radical or an .alpha.- or .beta.-furyl radical, 
which can in turn be mono-, di- or tri-substituted in the nucleus by 
halogen, trifluoromethyl and/or alkyl or alkoxy with in each case 1-6 C 
atoms, or (b) an oxyphenyl radical or an .alpha.- or .beta.-oxythienyl 
radical, which can in turn be mono-, di- or tri-substituted in the nucleus 
by halogen, trifluoromethyl and/or alkyl or alkoxy with in each case 1-6 C 
atoms. 
The invention also relates to a process for the preparation of the 
prostacyclin derivatives of the formula I, which comprises 
(a) cyclizing a compound of the formula II 
##STR3## 
in which R.sup.1 and R.sup.2 have the meanings indicated for formula I and 
R.sup.3 and R.sup.4 can be identical or different and denote hydrogen or a 
protective group which can easily be split off, in the presence of a 
suitable electrophilic reagent to give a compound of the formula III 
##STR4## 
in which R.sup.1 and R.sup.2 have the meanings indicated for formula I, 
R.sup.3 and R.sup.4 have the meaning indicated for formula II and X 
denotes chlorine, bromine or iodine, 
(a.sub.1) if R.sup.3 and/or R.sup.4 in a compound of the formila III denote 
a protective group, optionally splitting off this group whereupon a 
compound of the formula III in which R.sup.1 and R.sup.2 have the meanings 
indicated for formula I, X has the meanings indicated for formula III and 
R.sup.3 and R.sup.4 denote hydrogen is obtained, 
(b) splitting off HX from a compound of the formula III, whereupon a 
compound of the formula IV 
##STR5## 
in which R.sup.1 and R.sup.2 have the meanings indicated for formula I and 
R.sup.3 and R.sup.4 have the meanings indicated for formula II is 
obtained, 
(c) if R.sup.3 and/or R.sup.4 in a compound of the formula IV do not denote 
hydrogen but a protective group, splitting off this group under suitable 
neutral or alkaline conditions, whereupon a compound of the formula I in 
which R.sup.1 and R.sup.2 have the meanings indicated for formula I is 
formed, 
(c.sub.1) if appropriate, if R.sup.3 and/or R.sup.4 do not denote hydrogen 
but a protective group, splitting this off from a compound of the formula 
III simultaneously with HX, whereupon a compound of the formula I in which 
R.sup.1 and R.sup.2 have the meanings indicated for formula I is obtained, 
(d) if appropriate esterifying a compound of the formula I in which R.sup.1 
denotes hydrogen or a cation and R.sup.2 has the meanings indicated for 
formula I, to give a compound of the formula I in which R.sup.1 is an 
alkyl radical with the meaning indicated for formula I and R.sup.2 has the 
meaning indicated for formula I, 
(e) if appropriate, saponifying a compound of the formula I in which 
R.sup.2 has the meanings indicated for formula I and R.sup.1 denotes an 
alkyl radical, to give a compound of the formula I in which R.sup.2 has 
the meanings indicated for formula I and R.sup.1 denotes hydrogen or a 
physiologically acceptable cation, and 
(f) if appropriate, in a compound of the formula I in which R.sup.2 has the 
meaning indicated for formula I and R.sup.1 denotes a physiologically 
acceptable metal ion or NH.sub.4 ion, or ammonium ion which is derived 
from a primary, secondary or tertiary amine, replacing the cation R.sup.1 
by another cation. 
Amongst the substituents mentioned, the following are preferred: 
For R.sup.1 : hydrogen, a straight-chain or branched alkyl radical with up 
to six carbon atoms, a cycloaliphatic hydrocarbon radical with five to 
seven carbon atoms or a physiologically acceptable metal ion or NH.sub.4 
ion, or ammonium ion which is derived from a primary, secondary or 
tertiary amine. 
For R.sup.2 : a cycloalkyl radical with 5-7 carbon atoms or a 
straight-chain or branched alkyl radical which has up to five carbon atoms 
and can be substituted by (a) fluorine, chlorine or an .alpha.- or 
.beta.-thienyl radical or an .alpha.- or .beta.-furyl radical, which can 
in turn be substituted by halogen, trifluoromethyl and/or alkyl or alkoxy 
with in each case 1-6 C atoms, or (b) an oxyphenyl radical or an .alpha.- 
or .beta.-oxythienyl radical, which can in turn be mono-, di- or 
trisubstituted in the nucleus by halogen, trifluoromethyl and/or alkyl or 
alkoxy with in each case 1-6 C atoms. 
Amongst the substituents for R.sup.2, those listed below are very 
particularly preferred: 1-fluoropentyl, 1-chloropentyl, 5-fluoropentyl, 
5-chloropentyl, 3-thienyl-2-ethyl, 2-thienyl-2-ethyl, 
3-(2-chloro-thienyl)-2-ethyl, 2-(5-chloro-thienyl)-2-ethyl, phenoxymethyl, 
3-chlorophenoxymethyl, 3-trifluoromethyl-phenoxymethyl, 
3-thienyloxymethyl, 2-thienyloxymethyl, 3-(2-chlorothienyl)-oxymethyl), 
2-(5-chlorothienyl)oxymethyl, 3-furyl-2-ethyl, 2-furyl-2-ethyl, 
cyclopentyl, cyclohexyl and cycloheptyl. 
The prostaglandin derivatives of the general formula II used as the 
starting material in the process according to the invention can be 
prepared by processes analogous to those such as are described, for 
example, in JACS 91, 5675 (1969), Tetrahedron Lett., 1970, 311, 
Netherlands Pat. No. 7,206,361 and Netherlands Pat. No. 7,209,758, and in 
German Offenlegungsschrift No. 2,524,955 and German Offenlegungsschrift 
No. 2,742,407. 
Electrophilic reagents which react with .gamma.-hydroxyolefins to form 
tetrahydrofuran derivatives by cyclization, such as, for example, iodine, 
iodine chloride, KI.sub.3, N-bromoimides, such as N-bromosuccinimide and 
N-bromocamphorimide, or 1,3-dibromo-5,5-dimethylhydantoin, are suitable 
for the cyclization of compounds of the formula II to give compounds of 
the formula III. The reaction is preferably carried in an inert solvent, 
such as, for example, water, methylene chloride, chloroform diethyl ether, 
tetrahydrofuran or 1,2-dimethoxyethane. Heterogeneous or homogeneous 
solvent mixtures can also be used. The reaction can be carried out at 
temperatures between -70.degree. and +30.degree. C., if appropriate in the 
presence of an acid-binding agent, such as, for example, calcium 
carbonate, sodium carbonate or sodium bicarbonate. A preferred embodiment 
of the process consists in stirring a compound of the general formula II 
with 1.2-3 equivalents of KI.sub.3 in water at 0.degree.-10.degree. in the 
presence of sodium carbonate and under an inert gas, reducing the excess 
KI.sub.3 with sodium thiosulfate solution and extracting the cyclization 
product III (X=I) with chloroform. The product can be further reacted 
without special purification. 
If R.sup.3 and/or R.sup.4 in a compound of the formula III denote a 
protective group, this can optionally be split off. This is appropriate if 
it is a protective group which must be removed with acid catalyst, such 
as, for example, an acetal group or tetrahydropyranyl group, since 
compounds of the formula IV are unstable to acid. The protective groups 
can appropriately be split off with acid catalysis in an alcoholic or 
aqueous/organic solvent. Suitable acids are dilute mineral acids or 
organic acids, such as p-toluenesulfonic acid, oxalic acid or acetic acid. 
If the protective group is an acyl group, this can be split off in an 
alkaline medium. 
The splitting off of HX from compounds of the formula III with the 
formation of compounds of the general formula IV proceeds under the 
influence of bases in the presence or absence of a solvent. 
Possible bases are both inorganic and organic bases such as, for example, 
alkali metal hydroxides or carbonates, alcoholates such as, for example 
sodium methylate or potassium tertiary butylate, amines such as, for 
example, triethylamine, 4-dimethylaminopyridine, dicyclohexylethylamine or 
1,4-diazabicyclo[2,2,2]octane, or amidines such as, for example, 
1,5-diazabicyclo[3,4,0]non-5-ene (DBN) or 
1,5-diazabicyclo[5,4,0]undec-5-ene (DBU). 
If R.sup.3 and/or R.sup.4 in a compound of the formula IV do not denote 
hydrogen but a protective group, such as, for example, an acyl group, this 
group can be split off under mild alkaline conditions, for example with 
sodium carbonate or potassium carbonate in alcoholic or alcoholic-aqueous 
solution. This reaction is carried out at -10.degree. to +30.degree. C. 
HX and the protective groups R.sup.3 and/or R.sup.4, if they denote acyl 
groups, can also be split off simultaneously from compounds of the formula 
III. A suitable reaction is, for example, that with alkali metal 
hydroxides or metal alcoholates in water or a lower alkyl alcohol, such 
as, for example, sodium methylate in methanol. The prostacyclin derivative 
of the formula I can thereby be obtained directly. 
Compounds of the formula I in which R.sup.1 denotes hydrogen or a cation 
and R.sup.2 has the meanings indicated for formula I can be esterified to 
give compounds of the formula I in which R.sup.1 denotes an alkyl radical. 
Because of the instability of the enol ether structure in the prostacyclin 
molecule, only processes which proceed rapidly and under mild conditions 
in a neutral or weakly acid medium, or advantageously in an alkaline 
medium, can be used for this esterification. Thus, for example, a 
prostacyclin derivative of the formula I (R.sup.1 =H) can be esterified 
with diazoalkanes of the formula R.sup.1 -N.sub.2 (R.sup.1 =alkyl) at 
temperatures between -40.degree. and +20.degree., it being possible to use 
the customary solvents, such as, for example, diethyl ether, 
tetrahydrofuran, chloroform or low-molecular alcohols, such as methanol. 
The resulting esters can be isolated in a simple manner by evaporating off 
the solvent and, if appropriate, they can be purified by chromatography. A 
preferred esterification method consists in reacting the salt of the 
corresponding prostacyclin derivative I (R.sup.1 =a cation) with an 
alkylating agent R.sup.1 --X in the presence of a base such as, for 
example, a metal alcoholate or metal carbonate, in a suitable solvent. 
Possible metal alcoholates are, for example, sodium methylate, sodium 
ethylate or potassium tertiary butylate, and suitable carbonates are, for 
example, calcium carbonate or sodium bicarbonate. Suitable solvents which 
are possible are alcohols such as, for example, methanol or tert.-butanol, 
ethers such as tetrahydrofuran or 1,2-dimethoxyethane, and, in particular, 
dipolar aprotic solvents such as dimethylformamide, dimethylsulfoxide, 
acetonitrile or N-methylpyrrolidone. In the alkylating agents R.sup.1 --X, 
X preferably denotes bromine, iodine or a sulfonic acid radical. 
Compounds of the formula I in which R.sup.1 denotes an alkyl radical can be 
saponified in the customary manner in an alkaline medium to give compounds 
of the formula I in which R.sup.1 denotes hydrogen or, preferably, a 
cation, for example using NaOH or KOH in a low-molecular alcohol such as 
methanol, or an ether such as dimethoxyethane or tetrahydrofuran, if 
appropriate in the presence of water. An equimolar amount or a very slight 
excess of an alkali metal hydroxide is advantageously used so that the 
alkali metal salt of the formula I (R.sup.1 =an alkali metal ion) is 
obtained by evaporating off the solvent. 
The alkali metal cation can be replaced by any other cations on ion 
exchangers in the customary manner. For this, a solution of the alkali 
metal salt of a claimed prostacyclin derivative is allowed to run through 
a column packed with a cation exchanger such as, for example, Amberlite 
CG-50 or Dowex CCR-2. 
The cation exchanger is charged with the desired cation, for example with 
an ammonium ion which is derived from a primary, secondary or tertiary 
amine. The desired salt is obtained by evaporating the eluate. 
The compounds of the general formulae II and III can be employed for the 
subsequent reactions as a mixture of diastereomers, with regard to the 
position of the hydroxyl groups on carbon atom 15 (prostaglandin 
nomenclature), as pure .alpha.- or .beta.-isomers or in the form of 
optically active antipodes. However, the stereoisomers or antipodes can 
also be separated after any subsequent reaction stage. This means that all 
the reactions described can be carried out with mixture of diastereomers, 
pure diastereomers or optically active antipodes. If the individual 
reaction products are not already obtained in a form which is sufficiently 
pure that they can be employed for the following reaction step, 
purification by means of, for example, column chromatography, thin layer 
chromatography or high-pressure liquid chromatography is advisable. 
In addition to the compounds mentioned in the examples, the following 
compounds, in particular, can also be prepared by the process according to 
the invention: 20-fluoro-PGI.sub.2 methyl ester, 16-chloro-PGI.sub.2, 
16-chloro-PGI.sub.2 methyl ester, 17-(2-thienyl)-18,19,20-trinor-PGI.sub.2 
methyl ester, 17-(3-(2-chlorothienyl)-18,19,20-trinor PGI.sub.2, 
16-phenoxy-17,18,19,20-tetranor-PGI.sub.2 ethyl ester, 
16-(3-trifluoromethyl-phenoxy)-17,18,19,20-tetranor-PGI.sub.2 -n-butyl 
ester, 16-(3-(2-chloro)thienyloxy)-17,18,19,20-tetranor-PGI.sub.2 methyl 
ester, 16-(2-thienyloxy)-17,18,19,20-tetranor-PGI.sub.2, 
17-(3-furyl)-18,19,20-trinor-PGI.sub.2, 
15-cyclopentyl-16,17,18,19,20-pentanor-PGI.sub.2 propyl ester and 
15-cyclopentyl-16,17,18,19,20-pentanor-PGI.sub.2. 
The compounds according to the invention are distinguished by: (1) an 
inhibitory action on thrombocyte aggregation; (2) relaxation of the 
vascular walls, in particular of the coronary arteries; and (3) 
hypotensive properties. They can thus be used as medicaments. 
A possible unit dose for hypotensive action is 0.1 .mu.g/kg-10 .mu.g/kg, 
preferably 5 .mu.g/kg-100 .mu.g/kg, of body weight, and a possible daily 
dose is 0.001 mg/kg-1 mg/kg, preferably 0.05 mg/kg-1 mg/kg, of body 
weight. 
The same doses or even smaller doses can be used for the two other 
indications. 
__________________________________________________________________________ 
Pharmacological parameters of the compounds of the 
general formula I (R.sup.1 = CH.sub.3) 
Lowering of blood pressure, 
.mu.g/kg, intravenous admini- 
stration Relaxation of coronary arteries 
Blood 
Period of 
in cattle in % relative to 
platelet 
Ex- (rats) action 
particular standard 
aggrega- 
ample 
R.sup.2 = ED 25 
Dose 
% minutes 
1 10 100 
1,000 ng/ml 
tion 
__________________________________________________________________________ 
2d 
##STR6## 0.23 
0.1 0.3 1.0 
-7 -28 -61 
2.4 7.4 18.0 
14 40 89 5 .times. 10.sup.-7 
2a 
##STR7## 0.23 
0.1 0.3 1.0 
-13 -19 -46 
2.4 4.2 6.4 
34 74 152 
2c 
##STR8## Slight lowering (15 mm Hg) on intravenous administration 
of 1 .mu.g/kg 250 41 
500 106 
1000 257 4 .times. 10.sup.-6 
2f 
##STR9## 0.31 
0.1 0.3 1.0 
-6 -20 -49 
1.7 4.4 11.0 
14 31 60 4 .times. 10.sup.-7 
2e 
##STR10## 0.93 
0.1 1.0 10.0 100.0 
-3 -24 -52 -64 
0.4 4.1 8.0 28.8 
24 48 105 9 .times. 10.sup.-8 
__________________________________________________________________________ 
__________________________________________________________________________ 
Pharmacological parameters of the compounds of the 
general formula I (R.sup.1 = Na) 
Lowering of blood pressure, 
.mu.g/kg, intravenous admini- 
Relaxation of coronary 
stration arteries in cattle in % 
Blood 
Period of 
relative to the particular 
platelet 
Ex- (rats) action 
standard aggrega- 
ample 
R.sup.2 = ED 25 
Dose 
% minutes 
1 
10 
100 
1,000 ng/ml 
tion 
__________________________________________________________________________ 
3a 
##STR11## 0.25 
0.1 1.0 10.0 
-12 -46 -58 
1.0 4.2 15.1 
29 
50 
115 5 .times. 10.sup.-9 
3d 
##STR12## 0.39 
0.1 0.3 1.0 
-5 -17 - 42 
0.7 1.8 4.5 
13 
25 
79 
3d 
##STR13## 0.27 
0.1 1.0 10.0 100.0 
-11 -46 -64 -68 
2.0 5.2 16.6 33.0 
14 
32 
75 2 .times. 10.sup.-8 
__________________________________________________________________________ 
The compounds of formula I according to the invention can be used as the 
free acid, but preferably in the form of their physiologically acceptable 
inorganic or organic salts or as esters. 
The acids and salts or esters can be used in the form of their aqueous 
solutions or suspensions, or also as solutions or suspensions in 
pharmacologically acceptable organic solvents, such as monohydric or 
polyhydric alcohols, for example ethanol, ethylene glycol or glycerol; 
oils such as, for example, sunflower oil or cod-liver oil; ethers such as, 
for example, diethylene glycol dimethyl ether; or also polyethers such as, 
for example polyethylene glycol; or also in the presence of other 
pharmacologically acceptable polymeric excipients such as, for example, 
polyvinylpyrrolidone. 
Possible formulations are the customary galenical infusion or injection 
solutions and tablets, as well as formulations which can be applied 
locally, such as creams emulsions, suppositories or aerosols. 
A further way of using the new compounds is in combination with other 
active compounds. These include, in addition to other suitable substances, 
above all: circulatory agents in the broadest sense, for example cardiac 
glycosides such as digitoxin; sympathomimetic agents such as Suprifen; 
.beta.-sympatholytic agents such as Inderal; coronary dilators such as 
Chromonar or prenylamine; hypotensive substances such as reserpine or 
clonidine; antiarrythmic agents; substances which stimulate the blood 
flow; anticoagulants or fibrinolytic agents; diuretic agents, such as, for 
example, furosemide; substances which lower the lipid level or substances 
for use in geriatrics and other preparations which have an effect on 
metabolism; prostaglandins or prostaglandin antagonists or prostaglandin 
biosynthesis inhibitors such as, for example, non-steroid antiphlogistic 
agents; thromboxane synthetase inhibitors; psychopharmaceuticals; and 
vitamins.

The compounds of the formula III and IV are new, valuable intermediate 
products for the preparation of compounds of the formula I. 
EXAMPLE 1 
(a) 5-Bromo-16-(3-thienyloxy)-17,18,19,20-tetranor-PGI.sub.1 (III) 
132 mg of N-bromosuccinimide are added to 360 mg of 
16-(3-thienyloxy)-18,19,20-tetranor-PGF.sub.2.alpha. 
11,15-bis-tetrahydropyranyl ether in 7 ml of tetrahydrofuran/chloroform, 
1:1, while stirring and under argon. After 2 hours, chloroform and aqueous 
sodium thiosulfate solution are added and the organic layer is evaporated, 
after drying with magnesium sulfate. The residue is warmed in 5 ml of 
glacial acetic acid/water/tetrahydrofuran, 3:1:1, to 45.degree. for five 
hours, under argon, and the solvent is then evaporated off in vacuo. The 
residue can be purified by column chromatography on about 20 g of silica 
gel. Ethyl acetate/glacial acetic acid, 99:1, is used as the eluting 
agent. NMR: as for Example (1c). 
(b) 5-Iodo-16-(3-thienyloxy)-17,18,19,20-tetranor-PGI.sub.1 methyl ester 
(III) 
200 mg of 16-(3-thienyloxy)-17,18,19,20-tetranor-PGF.sub.2.alpha. methyl 
ester (II) are dissolved in 1.5 ml of diethyl ether and, after adding 0.3 
g of potassium bicarbonate in 1 ml of H.sub.2 O, the mixture is cooled to 
0.degree., under argon. 5.4 ml of a 2.5% strength solution of iodine in 
ether are added dropwise in the course of 2 hours, and thereafter the 
mixture is stirred for a further two hours at 0.degree.. After adding 
about 10 ml of ether, the organic layer is washed first with sodium 
thiosulfate solution and then with water, dried and evaporated. The 
reaction product is sufficiently pure, but can be freed from small amounts 
of impurities by chromatography on silica gel (cyclohexane/ethyl acetate, 
2:8). 
Yield: 250 mg, R.sub.f value in ethyl acetate=0.54, NMR: as for Example 
(1c). 
(c) 5-Iodo-16-(3-thienyloxy)-17,18,19,20-tetranor-PGI.sub.2 methyl ester 
(III) 
200 mg of 16-(3-thienyloxy)-17,18,19,20-tetranor-PGF.sub.2.alpha. methyl 
ester (II) are stirred together with 50.8 mg of iodine, 66 mg of potassium 
iodide and 42.4 mg of sodium carbonate in 2 ml of water at 
5.degree.-10.degree. C. for two hours, under an inert gas. The excess 
iodine is then decolorized with sodium thiosulfate solution and the 
reaction mixture is extracted with chloroform. The organic phase is washed 
with water, dried and evaporated. 
Yield: 244 mg; R.sub.f value in ethyl acetate=0.54 
NMR: .delta.=5.5-5.7 (m, 2H) olefinic protons, 3.60 (S,3H) O--CH.sub.3, 
1.1-2.7 (m,12H) --CH.sub.2 -- and &gt;CH--, and 6.15-7.7 (m,3H) thiophene. 
(d) 5-Iodo-17-(3-thienyl)-18,19,20-trinor-PGI.sub.1 methyl ester (III) 
Obtained from 17-(3-thienyl)-18,19,20-trinor-PGF.sub.2.alpha. methyl ester 
(II) by a reaction analogous to Example (1c). 
NMR: .delta.=1.1-2.9 (m,16H), CH.sub.2 and --CH--, 3.6 (S,3H) OCH.sub.3, 
5.5-5.65 (m,2H) olefinic protons, and 6.9-7.3 (m,3H) thiophene. 
R.sub.f =0.48 (ethyl acetate/acetic acid=97.5/2.5). 
(e) 5-Iodo-16-(3-chlorophenoxy)-17,18,19,20-tetranor-PGI.sub.1 methyl ester 
(III) 
Obtained from 16-(3-chlorophenoxy)-17,18,19,20-tetranor-PGF.sub.2.alpha. 
methyl ester (II) by a reaction analogous to Example (1c). 
NMR: .delta.=1.2-2.8 (m,12H) CH.sub.2 and --CH--, 3.7 (S,3H) OCH.sub.3, 4.0 
(d,2H) --CH.sub.2 --O--, 4.15 (1H) --CH--I--, 4.3-4.8 (m,3H) --CH--OH, 
5.7-5.9 (m,2H) olefinic protons, and 6.7-7.4 (m,4H) aromatic protons. 
R.sub.f value (ethyl acetate)=0.35 
(f) 5-Iodo-15-cyclohexyl-16,17,18,19,20-pentanor-PGI.sub.1 methyl ester 
(III) 
Obtained from 15-(cyclohexyl)-16,17,18,19,20-pentanor-PGF.sub.2.alpha. 
methyl ester (II) by a reaction analogous to Example (1b). 
NMR: .delta.=0.8-2.8 (m,23H) --CH.sub.2 and --CH--, 3.6 (S,3H) OCH.sub.3 
and 5.5-5.6 (m,2H) olefinic protons. 
(g) 5-Iodo-16-fluoro-PGI.sub.1 methyl ester (III) 
Obtained from 16-fluoro-PGF.sub.2.alpha. methyl ester (II) by a reaction 
analogous to Example (1b). 
NMR: .delta.=0.9-2.9 (m,21H) --CH.sub.2 -- and --CH--, 3.65 (S,3H) 
OCH.sub.3 and 5.6-5.7 (m,2H) olefinic protons. 
(h) 5-Iodo-17-(2-furyl)-18,19,20-trinor-PGI.sub.1 methyl ester (III) 
Obtained from 17-(3-furyl)-18,19,20-trinor-PGF.sub.2.alpha. methyl ester 
(II) by a reaction analogous to Example (1c). 
NMR: .delta.=1.0-2.9 (m,12H) --CH.sub.2 -- and --CH--, 3.6 (S,3H) 
--OCH.sub.3, 5.5-5.6 (m,2H) olefinic protons, 5.9-6.05 and 6.15-6.3 (m,2H) 
aromatic protons and 7.2-7.35 (m,1H) aromatic protons. 
(i) 5-Iodo-17-(3-thienyl)-18,19,20-trinor-PGI.sub.1 methyl ester 
11,15-bistetrahydropyranyl ether (III, R.sup.3 and R.sup.4 
=tetrahydropyranyl) 
Obtained from 17-(3-thienyl)-18,19,20-trinor-PGF.sub.2.alpha. methyl ester 
11,15-bistetrahydropyranyl ether (II, R.sup.3 and R.sup.4 
=tetrahydropyranyl) by a reaction analogous to Example (1c). 
Colorless oil, R.sub.f value in ethyl acetate: 0.89 
EXAMPLE 2 
(a) 16-(3-Thienyloxy)-17,18,19,20-tetranor-PGI.sub.2 methyl ester (I) 
300 mg of 16-(thienyloxy)-5-bromo-17,18,19,20-tetranor-PGI.sub.1 (Example 
1a) are warmed with 224 mg of potassium tertiary butylate in 10 ml of 
tert.-butanol to 45.degree.-50.degree. under an argon atmosphere. After 
stirring the mixture for two hours, the solvent is evaporated off in 
vacuo, ice-water and cold ether are added to the residue and the aqueous 
phase is brought rapidly to pH 5 with a cold solution of sodium dihydrogen 
phosphate. Excess diazomethane in cold ether is immediately added to the 
ether phase. After stirring the mixture at -5.degree. to 0.degree. for the 
30 minutes, the product is purified on 15 g of silica gel, which had 
previously been suspended in a mixture of ethyl acetate/triethylamine, 
95:5, for some hours. Ethyl acetate/triethylamine, 98:2, is used as the 
eluting agent. 
R.sub.f =0.15 (15.alpha.-epimer) (in ethyl acetate/0.5% strength N(C.sub.2 
H.sub.5).sub.3) 
NMR: .delta.=1.1-2.8 (m,12H) CH.sub.2 and CH, 2.8-3.0 (S,2H) OH, 3.6 (m,3H) 
OCH.sub.3, 5.6-5.7 (m,2H) olefinic protons, and 6.2-7.2 (m,3H) thiophene. 
(b) 17-(3-Thienyl)-18,19,20-trinor-PGI.sub.2 methyl ester (I) 
290 mg of 5-iodo-17-(3-thienyl)-18,19,20-trinor-PGI.sub.1 methyl ester 
(Example 1d) are stirred with 1.3 ml of 1,5-diazobicyclo[5,4,0]undec-5-ene 
at room temperature. After 130 minutes, the reaction has ended. 3 ml of 
ice-water are added to the reaction solution and the product is extracted 
three times with ether. The organic phase is dried with anhydrous sodium 
sulfate and evaporated and the residue is purified, as described above in 
Example 2a, on silica gel with ethyl acetate/triethylamine, 98:2. 
R.sub.f value=0.17 (15.alpha.-epimer) (in ethyl acetate/0.5% strength 
N(C.sub.2 H.sub.5).sub.3) 
(c) 16-(3-Chlorophenoxy)-17,18,19,20-tetranor-PGI.sub.2 methyl ester (I) 
Obtained from 5-iodo-16-(3-chlorophenoxy)-17,18,19,20-tetranor-PGI.sub.1 
methyl ester (Example 1e) by a reaction analogous to Example (2b). 
NMR: .delta.=3.6 (S,3H) OCH.sub.3, 4.0 (d,2H) --CH.sub.2 O--, 5.7-5.9 
(m,2H) olefinic protons, and 6.7-7.3 (m,4H) aromatic protons. 
R.sub.f value=0.22, running agent: ethyl acetate/Et.sub.3 N, 50/l; 
SiO.sub.2 plates pre-treated with ether/Et.sub.3 N (3:1) 
(d) 15-Cyclohexyl-16,17,18,19,20-pentanor-PGI.sub.2 methyl ester (I) 
Obtained from 5-Iodo-15-cyclohexyl-16,17,18,19,20-pentanor-PGI.sub.1 methyl 
ester (Example 1f) by a reaction analogous to Example (2). 
NMR: .delta.=0.8-2.8 (m,23H) --CH.sub.2 -- and --CH--, 3.65 (S,3H) 
OCH.sub.3, 3.65-4.8 (m,4H) --CHOH and --O--C.dbd.CH and 5.5-5.7 (m,2H) 
olefinic protons. 
(e) 16-Fluoro-PGI.sub.2 methyl ester (I) 
Obtained from 5-iodo-16-fluoro-PGI.sub.1 methyl ester (Example 1g) by a 
reaction analogous to Example (2b). 
NMR: .delta.=0.9-2.8 (m,22H) --CH.sub.2 -- and --CH--, 3.6 (S,3H) 
OCH.sub.3, 3.6-4.8 (m,4H) --CH--OH and --O--C.dbd.CH-- and 5.5-5.7 (m,2H) 
olefinic protons. 
(f) 17-(2-Furyl)-18,19,20-trinor-PGI.sub.2 methyl ester (I) 
Obtained from 5-iodo-17-(3-furyl)-18,19,20-trinor-PGI.sub.1 methyl ester 
(Example 1h) by a reaction analogous to Example (2b). 
NMR: .delta.=1.0-2.85 (m,12H) --CH.sub.2 -- and --CH--, 3.6 (S,3H) 
OCH.sub.3, 3.6-4.8 (m,4H) --CHOH and --O--C.dbd.CH--, 5.9-6.05 and 
6.15-6.3 (m,2H) aromatic protons and 7.2-7.35 (m,1H) aromatic protons. 
(i) 17-(3-Thienyl)-18,19,20-trinor-PGI.sub.2 methyl ester 
11,15-bistetrahydropyranyl ether (IV, R.sup.3 and R.sup.4 
=tetrahydropyranyl 
Obtained from 5-iodo-17-(3-thienyl)-18,19,20-trinor-PGI.sub.1 methyl ester 
11,15-bistetrahydropyranyl ether (Example 1i) by a reaction analogous to 
Example (2b). Colorless oil; R.sub.f value=0.85 in ethyl acetate. 
EXAMPLE 3 
(a) The sodium salt of 16-(3-thienyloxy)-17,18,19,20-tetranor-PGI.sub.2 (I) 
268 mg (0.5 mmole) of 
5-iodo-16-(3-thienyloxy)-17,18,19,20-tetranor-PGI.sub.1 methyl ester 
Example (1c) are dissolved in 50 ml of a 90% strength ethanol. A solution 
of 57.5 mg of sodium in 5 ml of ethanol are added to this solution, while 
stirring. The mixture is stirred at 60.degree. C. under argon for 3 hours, 
the solution is filtered over active charcoal and the solvent is removed 
from the filtrate in vacuo at -10.degree. C. (freeze-drying). The sodium 
salt of the prostaglandin derivative is obtained as a colorless powder. 
(b) The potassium salt of 16-(3-thienyloxy)-17,18,19,20-tetranor-PGI.sub.2 
(I) 
192 mg of pure 16-(3-thienyloxy)-17,18,19,20-tetranor-PGI.sub.1 methyl 
ester (Example 2a), 1.1 ml of 0.5 M potassium hydroxide solution and 2 ml 
of methanol are left to stand under an inert gas at room temperature for 
24 hours. The methanol is stripped off in vacuo and the aqueous solution 
of the potassium salt is freeze-dried. The potassium salt of the 
prostacyclin derivative is obtained as a colorless powder. 
(c) The triethylammonium salt of 
16-(3-thienyloxy)-1718,19,20-tetranor-PGI.sub.2 
An aqueous solution of 50 mg of the sodium salt of 
16-(3-thienyloxy)-17,18,19,20-tetranor-PGI.sub.2 (Example 3b) is 
discharged onto a column containing 15 g of Amberlite CG-50 
(triethylammonium form). The column is eluted with a 3% strength aqueous 
solution of triethylammonium carbonate. The product is obtained as a 
crystalline powder (decomposition &gt;50.degree. C.) by freeze-drying the 
eluate. p (d) The corresponding alkali metal salts or ammonium salts can 
be prepared, analogously to Examples 3a to c, from the compounds of 
Examples 1a to 1f or 2a-2f by alkaline saponification of the ester or 
(compare Example 3a) by elimination of HX and simultaneous saponification 
of the ester and, if appropriate, chromatography on ion exchangers.