Inter-m-phenylene-prostacyclin analogues and use thereof in inhibiting blood platelet aggregation

New inter-m-phenylene-PGI.sub.2 derivatives are prepared of the general formula I ##STR1## wherein R.sup.1 stands for hydrogen, alkyl containing 1 to 4 carbon atoms or a pharmaceutically acceptable primary, secondary, tertiary or quaternary ammonium cation or a metal cation, PA0 R.sup.2 and R.sup.3 stand independently on each other for hydrogen, alkanoly, aroyl or an acetal type or alkyl silyl type protecting group, PA0 R.sup.4 represents hydrogen or an alkyl group containing 1 to 4 carbon atoms, PA0 X stands for oxygen, or a--CH.sub.2 --group, PA0 Y stands for--C.tbd.C-- or a trans--CH.dbd.CW group, wherein W stands for chlorine, bromine or fluorine, PA0 Z represents an alkyl group having 6 to 9 carbon atoms, optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms or fluorine or it stands for an optionally substituted arylmethyl or aryloxy methyl group. The new compounds are active ingredients of pharmaceutical compositions having antiaggregatory activity.

The present invention relates to new inter-m-phenylene-prostacycline 
analogues and process for the preparation thereof. 
The invention further relates to pharmaceutical compositions mainly of 
blood platelet antiaggregatory activity containing as active ingredient 
the new compounds. 
The new inter-m-phenylene-prostacycline analogues can be characterized by 
the formula I 
##STR2## 
wherein R.sup.1 stands for hydrogen, alkyl containing 1 to 4 carbon atoms, 
or a pharmaceutically acceptable primary, secondary, tertiary or 
quaternary ammonium cation or a metal cation, 
R.sup.2 and R.sup.3 are independently of each other hydrogen, alkanoyl, 
aroyl or an acetal type or alkylsilyl type protecting group, 
R.sup.4 stands for hydrogen or alkyl containing 1 to 4 carbon atoms, 
X stands for oxygen or a --CH.sub.2 -- group, 
Y represents --C.tbd.C-- or CH.dbd.CW wherein W represents chlorine, 
bromine or fluorine, 
Z stands for an alkyl group containing 6 to 9 carbon atoms, optionally 
substituted by one or more fluorine or alkyl containing 1 to 4 carbon 
atoms or for an optionally substituted arylmethyl or aryloxymethyl group. 
The compounds according to the invention exhibit valuable antiaggregatory 
activity which is comparable with the same activity of PGI.sub.2, and 
possess a hypotensive activity being by orders of magnitude lower than 
PGI.sub.2, i.e. the activity-selectivity of the new compounds is by orders 
of magnitude higher, and the stability thereof is also higher than that of 
PGI.sub.2. Thus the compounds can be used in the human and veterinary 
therapy for inhibiting or controlling blood clotting and as thrombolytic 
agents. 
Prostacycline (PGI.sub.2) was first disclosed in 1976 [Nature, 1976, 263 
and 663; Prostaglandins, 1976, 12, 915; Angew. Chem. Int. Ed. Engl. 1978, 
17, 293]. 
It was found that prostacycline is the most active antiaggregatory and 
desaggregatory agent and possesses further physiological activities, such 
as relaxation of the coronary arteries of the heart and dilatation of the 
peripheral circulation vessels. Since the discovery of prostacycline an 
intensive search has been carried out to synthetize compounds the anti- 
and desaggregatory activity of which would come close to that of 
prostacycline being simultaneously more stable chemically than the natural 
substance and the activity of which is more selective, than the activity 
of prostacycline and their metabolism is inhibited in the direction of the 
known main metabolism. 
In DOS No. 29 45 781 prostacycline analogues have been disclosed which 
contain an o-phenylene group in the side chain bearing a carboxylic group. 
The compounds are disclosed to have a broad spectrum of activity and to be 
suitable for stimulating the smooth muscle at a dosage of 0.01-50 .mu.g/kg 
body weight/min. administered intravenously, for controlling the 
thrombocyte aggregation at a dosage of 0.01-10 mg./kg. body weight 
administered intravenously, for decreasing blood pressure at a dosage of 
0.01-50 .mu.g./kg. body weight/min. administered intravenously, for 
reducing gastric acid secretion at a dosage of 0.1-20 .mu.g./kg. body 
weight/min. administered intravenously, for the treatment of 
gastro-intestinal disorders caused by non-steroidal antiinflammatory 
agents at an indefinite dosage, for bronchodilatation (anti-asthmatic 
activity) at an oral dosage of 0.01-5 mg./kg. and for the treatment of 
various dermatosis at an indefinite dosage. The above list shows that as a 
consequence of the prostacycline structure modified as given in the above 
DOS, the end products show simultaneously several activities. Apart from 
the desired main activity all the other activities have to be considered 
as being undesired side-effects, i.e. a disadvantage in the therapy, as 
these side-effects can occur during the therapy and further drug-treatment 
is then required against these side-effects. 
In European Patent Publication No. 0 045 842 Patent Application No. 
81104982.4 PGI.sub.2 -analogues containing m-phenylene in the side chain 
bearing the carboxylic group are disclosed. As an advantage of the end 
products the narrower spectrum of activity compared with 
5,6-dihydro-prostacycline and the better selectivity in the field of the 
antihypertensive side-effect compared to the same 
5,6-dihydro-prostacycline is mentioned. The higher stability related to 
the prostacycline is emphasized. According to the published European 
application the compounds bear ethylene, vinylene or --C.tbd.C-- group in 
13,14-positon, and the 16,20 alkyl group is replaced by pentyl optionally 
mono- or disubstituted in position 1 or by cyclohexyl optionally 
substituted in position 4. 
The compounds may optionally be substituted by a methyl group in position 
15 as well. 
Substantially similar compounds are disclosed in the European Patent 
Publication No. 0062902 (Patent Application No. 82103024.4). These 
end-products differ from PGI.sub.2 in containing m-phenylene in the side 
chain bearing the carboxylic group and containing in the lower side chain 
in position 20 a methyl or ethyl group or containing instead of the 16,20 
side chain a phenoxymethyl, m-trifluoromethyl-phenoxymethyl group, or a 
1-(optionally substituted)-amino-(C.sub.4-6)alkyl- or phenyl- or benzyl 
group. The antiaggregatory activity according to the published 
specification is lower (by one order of magnitude) than that of PGI.sub.2 
though a significant advantage is the 1/50-1/80 activity in the field of 
antihypertensive activity compared with PGI.sub.2 and that its stability 
exceeds the stability of PGI.sub.2 considerably. 
We have now found that the desired blood platelet antiaggregatory activity 
could be further increased and the undesired antihypertensive activity 
could be further reduced by using the new compounds according to the 
invention. At the same time the stability of the compounds is also 
maintained. 
Comparative tests were carried out to compare antiaggregatory and 
antihypertensive activity. 
As test-substances the following compounds were used: the known PGI.sub.2, 
5(Z)-2,3,4-trinor-1,5-inter-m-phenylene-PGI.sub.2 (hereinafter referred to 
as 45842/A), 5(Z)-2,3,4-trinor-1,5-inter-m-phenylene-20-methyl-PGI.sub.2 
(hereinafter referred to as 62902), 
5(Z)-2,3,4-trinor-1,5-inter-m-phenylene-13,14-didehydro-PGI.sub.2 
(referred to hereinafter as 45842/B), 
5(Z)-2,3,4-trinor-1,5-inter-m-phenylene-13,14-didehydro-20-methyl-PGI.sub. 
2 (referred to hereinafter as compound "A") and 
5(Z)-2,3,4-trinor-inter-m-phenylene-13,14-didehydro-20-ethyl-PGI.sub.2 
(referred to hereinafter as compound "B") in the form of their sodium 
salts. 
The thrombocyte aggregation was measured with a Payton type aggregometer of 
two channels in 0.5 ml. end volume. The necessary amount of blood was 
taken from such persons who had previously not taken any agent influencing 
thrombocyte aggregation for two weeks and did not suffer in kidney or 
liver disease. The cubital venal blood was mixed with a 3.8% Na-citrate 
solution at a ratio of 9:1 and in order to obtain a plasma enriched in 
thrombocytes (PRP) blood was centrifuged for 5 minutes at 230 g, while 
plasma poor in thrombocytes was obtained after 10 minutes of centrifuging. 
The blood platelet number of the plasma was adjusted to 2-3.times.10.sup.5 
/ml. The tests were performed within 1 hour after the blood taking. The 
prostacycline sensitivity of each plasma was controlled before measuring 
the test substances. IC.sub.50 value of prostacycline on plasma enriched 
in thrombocytes: 0.6-1.0 ng/ml. 
Thrombocyte aggregation was induced with 2 .mu.M ADP. The test compounds 
were dissolved in 0.1M tris-HCl buffer of pH=7.8 and the temperature was 
maintained at 0.degree. to 4.degree. C. 
The compounds were tested repeatedly after some time and were kept in 
solution at 0.degree.-4.degree. C. IC.sub.50 values were calculated 
graphically. 
The antihypertensive activity was determined on narcotized rats. From the 
data of the blood pressure tests the molar dose /ED.sub.25 / inducing 25 
mmHg /3.33 kPa/ blood pressure reduction was calculated. 
The antiaggregatory and antihypertensive efficacy related to PGI.sub.2 is 
given in the following Table. 
TABLE 
______________________________________ 
relative anti- 
relative anti- 
aggregatory hypertensive 
efficiency efficiency 
IC.sub.50 PGI.sub.2 /IC.sub.50 
ED.sub.25 PGI.sub.2 /ED.sub.25 
Test substance 
test-compound 
test-compound 
______________________________________ 
PGI.sub.2 1/1 1/1 
45842/A 1/50-1/70 1/10 
45842/B 1/20-1/30 1/20-1/30 
62902 1/15-1/20 1/50-1/80 
compound "A" 1/2-1/4 1/100-1/150 
compound "B" 1/1-1/2 1/200-1/230 
______________________________________ 
The table unambiguously shows that compounds "A" and "B" exhibit a better 
activity and less side effects than the compounds according to the state 
of art. Compound "B" is particularly important as its useful 
antiaggregatory activity is substantially the same as that of PGI.sub.2 
whereas the undesired side-effect, i.e., the antihypertensive activity of 
the compound is about 2/100 part of the activity of PGI.sub.2. The 
stability of the end-products of the invention is characterized by having 
a several days long half-life even in strong acidic medium (pH=1), thus 
they can be prepared as compositions suitable for oral administration. 
Apart from the higher chemical stability and strong antiaggregatory and 
desaggregatory activity a further advantageous property of the compounds 
according to the invention is the several times longer duration of 
activity thereof compared with prostacycline. The metabolism of the 
natural prostaglandins is very rapid. The metabolism products where 
determined by physico-chemical methods and it was found that the 
metabolism consists of the chemical hydrolysis, or the beta-oxydation of 
the upper chain or oxydation of the 15-hydroxy group to 15-keto group. 
These metabolism routes are inhibited in case of the compounds according to 
the invention. The aromatic ring built in to the so called upper chain 
eliminates the aliphatic beta-oxydation. From the point of view of the 
activity the critical chain length does not change even in case of various 
metabolistic reactions of the phenyl group, such as hydroxylation. 
The oxydation of the 15-hydroxyl group is carried out by the so called 
15-hydroxy-prostaglandine dehydrogenase (PGDH) enzyme system. It is known 
from the chemistry of the natural prostaglandins that by certain 
structural modifications the compounds are not substrates of the PGDH 
enzyme system, thus the inactivation process does not occur. 
In order to examine the duration of activity the "ex vivo" method was used 
on rabbit test animals. The duration of antiaggregatory activity is 5-10 
times longer than that of prostacycline. 
According to the invention the compounds of the formula I 
##STR3## 
can be prepared by 
(a) reacting lactols of the general formula II 
##STR4## 
with phosphorans of the general formula IX 
##STR5## 
wherein Ph is phenyl and reacting the obtained PGF.sub.2 -derivative of 
the general formula IV 
##STR6## 
with an electrophilic agent of the general formula E-L, wherein L stands 
for halogen or 2,5-dioxo-pyrrolidine-1-yl and E stands for halogen, 
phenyl-selenyl, phenyl-sulfenyl or E-L stands for pyridinium 
bromide-per-bromide or N-halogen-hydantoine, subjecting the obtained 
5-substituted-PGI.sub.1 -derivative of the general formula V 
##STR7## 
to elimination in order to prepare compounds of the general formula I, 
wherein X stands for oxygen, or 
(b) reacting a ketone of the general formula III 
##STR8## 
with a phosphorane of the general formula IX 
##STR9## 
in order to get a compound of the general formula I, wherein X is 
--CH.sub.2 -- and converting optionally an obtained compound of the 
general formula I by halogen-hydrogen elimination, saponification, 
introducing or splitting off a protecting group, salt formation, 
esterification, 
in order to get another compound of the general formula I. 
The compounds of the general formulae II and III used as starting compounds 
are known or can be prepared by known methods by using suitable starting 
compounds [IL. Farmaco. Ed. Sc. 1976, 31, 763; IL. Farmaco 1972, 27, 1125; 
J. Org. Ch., 1981, 46, 1954-57; JACS, 1974, 96, 5865]. 
Phosphoranes of the general formula IX are preferably prepared from 
triphenyl-m-substituted-benzyl-phosphonium bromide, with a strong base, 
such as sodium methyl sulphonyl-methide /DIMSYL-Na/. The reaction and the 
further reaction of the obtained product is carried out preferably in 
anhydrous dimethyl sulfoxide. 
When using as starting material a compound of the general formula II in the 
Wittig-reaction new PGF.sub.2.alpha. -derivatives of the general formula 
IV are obtained which can be isolated after acidification by extraction. 
When considering the 5,6-double bond of the formed product is a 1:1 
mixture of E and Z isomers. The E and Z isomers can be easily separated by 
column chromatography. The thus obtained compounds per se possess a 
significant smooth muscle stimulating activity. 
Unexpectedly upon the effect of the strong base, phosphorane the 14-halogen 
does not undergo an elimination leading to a 13,14-triple bond. At the 
same time elimination can be, if desired, carried out with alkoxide bases, 
such as potassium tert.butoxide or sodium tert. butoxide or sodium 
methoxide, or upon the effect of an excess of DIMSYL-Na. 
If an elimination reaction is performed e.g. with an obtained 
PGF.sub.2.alpha. -derivative of the general formula VI 
##STR10## 
then a 13,14-didehydro-PGF.sub.2.alpha. -derivative of the general formula 
VII 
##STR11## 
is obtained. 
The elimination reaction is conducted in a polar protic organic solvent, 
such as alcohols, preferably in an alcohol corresponding to the alcoholate 
or in aprotic solvents, such as tetrahydrofuran, dimethylsulfoxide etc. 
The obtained compounds of the general formula IV can be converted to 
PGI.sub.1 derivatives of the general formula V with an electrophilic agent 
of the general formula E-L by a method known in prostacycline chemistry 
/see JACS 1977, 2006/. 
As electrophilic agents of the general formula E-L halogens, such as 
bromine or iodine /E.dbd.Br, I, L.dbd.Br, I/, or reactants giving 
electrophilic halonium /e.g. N-bromosuccinic imide/, complexes giving 
halogen /such as pyridinium bromide perbromide/, aryl selenyl derivatives 
/e.g. phenyl selenyl bromide, phenyl selenyl chloride/ and sulfenyl 
halides /e.g. phenyl selenyl chloride/ or N-halo-hydantoines may be used. 
In the cyclization reaction halogenated hydrocarbons, e.g. methylene 
chloride, chloroform or aprotic solvents, such as tetrahydrofuran, toluene 
can serve as medium. The raw products formed in the reaction may be 
employed without purification in the elimination reactions. 
All the compounds of the general formula V are a mixture of exo- and 
endo-isomers according to position 6. The separation of the isomers may be 
performed by column chromatography, but the separation is not necessary as 
the mentioned elimination results in PGI.sub.2 analogue of the general 
formula I in both cases. 
No side reaction occurs as the elimination can take place only in one 
direction. The compounds of the general formula V can be converted to 
compounds of the general formula I by elimination reaction. The 
elimination may be performed by several methods according to the nature of 
E. If E stands for halogen than the elimination may be carried out with a 
suitable base. As bases alcoholates, such as potassium tert. botoxide, 
sodium ethylate, organic bases, such as 1,5-diazabicyclo[4,3,0]-non-5-ene 
/DBN/, 1,5-diazabicyclo[5,4,0]undec-5-ene /DBU/, pyridine, triethylamine 
or other strong conjugated bases, e.g. sodium methyl sulfinyl methide are 
preferred. 
If E represents an iodine or bromine atom then potassium tert. butoxide, 
1,5-diazabicyclo[4,3,0]non-5-ene or sodium methyl sulfinyl methide are 
preferred. 
If E stands for phenyl selenyl or phenyl-thio then the elimination can be 
conducted by the following two methods: 
One may oxidize Ph-S or PH-Se to the corresponding sulfone or selenone /E 
stands for 
##STR12## 
and eliminate same with the above mentioned base. 
One may also prepare only sulfoxide or selenoxide /E stands for 
##STR13## 
and the compounds of the general formula V are then subjected to thermal 
elimination. 
When the desired product of the general formula I is a compound having 
--CH.sub.2 -- group as X, then as starting material compounds of the 
general formula III are used /J. Org. Chem. 1981, 46, 1954/. The reaction 
of the compounds of the general formula III and phosphoranes of the 
general formula IX may be performed under same conditions as described for 
the reaction of the compounds of the general formula II with phosphoranes 
of the general formula IX. Compounds of the general formula I are directly 
obtained. 
R.sup.1, R.sup.2 and R.sup.3 in the obtained compounds of the general 
formula I can be split off after elimination separately or optionally 
simultaneously and can be exchanged for other groups R.sup.1, R.sup.2 and 
R.sup.3. 
For example if during the elimination a compound is obtained in which 
R.sup.1 is methyl, R.sup.2 and R.sup.3 are hydrogen, then R.sup.2 and 
R.sup.3 may be replaced by acyl, such as acetyl, or acetal such as 
tetrahydro-pyranyl, or silyl, such as dimethyl tert. butyl silyl by 
chemical methods known per se. 
When preparing an ester during the elimination and R.sup.1 stands for 
methyl then in order to prepare a metal salt of the product one may 
proceed as follows: the methyl ester is hydrolysed with an alkali base, 
such as sodium hydroxide, potassium hydroxide, lithium hydroxide in a 
mixture of water-alcohol and then the reaction mixture is acidified. The 
formed acid is isolated by extraction and the desired salt is obtained by 
adding a calculated amount of lye in methanol. 
The salts of the compounds of the general formula I are crystalline 
compounds. 
Compounds containing --CH.dbd.CW-- in place of Y may be converted to a 
derivative containing --C.tbd.C-- in place of Y at any stage of the 
reaction by method given for the intermediate of the general formula IV. 
The term alkyl stands for C.sub.1-6 alkyl groups, preferably methyl, ethyl, 
n- and iso-propyl, n-, iso-, sec.- and tert. butyl groups, various amyl 
and hexyl groups. The term alkenoyl represents groups of the general 
formula C.sub.n H.sub.2n+1 --CO--, containing 1 to 6, preferably 1 to 4 
carbon atoms, such as formyl, acetyl, propionyl and butyryl. The terms 
aryl and aryloxy stand for aromatic groups with one or two rings 
containing 6 to 10 carbon atoms. Latter groups may optionally be 
substituted by aryl, C.sub.1-4 alkyl or alkoxy, halogen, trifluormethyl, 
or nitro, e.g. phenyl, chlorophenyl, trifluoromethylphenyl and the 
corresponding phenoxy and naphthyl groups. The acyl groups may be alkanoyl 
and aroyl groups. Examples of the aroyl groups are benzoyl or 
p-phenylbenzoyl. 
The acetal type protecting groups may be for example tetrahydro pyranyl, 
1-ethoxy-ethoxy and 1,4-dioxanyl. As silyl type protecting groups, 
preferably trialkyl silyl groups may be mentioned which have three same or 
different alkyl groups, e.g. dimethyl tert. butyl silyl. 
Cations in place of R.sup.1 may be metal or amine cations. All cations can 
be used which in the employed dosage do not possess any or only 
insignificant biological activity. As cations sodium, potassium, calcium, 
lithium, magnesium, further ammonium, and mono-, di-, tri- and 
tetra-substituted ammonium ions may be mentioned. The substituents may 
optionally favourably act upon the crystallization of the obtained salt or 
its processing. As cation e.g. tris-hydroxymethyl-methylammonium cation 
may be mentioned. The ammonium ions may be substituted by the alkyl groups 
given above. 
The end product according to the invention may be employed in human and 
veterinary therapy in the form of pharmaceutical compositions for the 
inhibition of thrombocyte aggregation, as thrombolytic agents or for 
influencing the blood clotting. The pharmaceutical compositions contain 
one or more compounds of the invention in an efficient dosage and the 
pharmaceutically acceptable excipients, such as filling agents, diluents, 
pH-adjusting, osmotic pressure influencing and flavouring agents, and 
agents promoting flowability, tabletting, other formulation excipients, 
solvents, co-solvents etc. 
The pharmaceutical compositions can be prepared in the form of tablets, 
drag/e/ es, powders, encapsulated powders, solutions /injectable and 
infusion solutions, fluid medicine, drops etc./, suppositories, and 
ointments. The most preferred forms are the tablets, drag/e/ es, and 
injectable or infusion solutions. 
One dosage unit of the composition /tablet, drag/e/ e, injection vial/ 
contains preferably the dosage to be administered at once, or a part 
thereof e.g. the half of it or a multiple e.g. the double thereof. 
As the compounds of the invention show similar biological activity as 
PGI.sub.2, the dosage is also in the same range. The physician can differ 
from the known doses in both directions on the basis of his knowledge, 
considering the disorder to be treated and the desired effect. The doses 
can be increased all the more, that the compounds according to the 
invention show only 1/100-1/200 part of the undesired anti-hypertensive 
activity of PGI.sub.2.

Further details of the invention can be found in the following Examples 
which serve only for illustration and not for limitation. 
EXAMPLE 1 
2,3,4-Trinor-1,5-inter-m-phenylene-14-bromo-20-methyl-PGF.sub.2.alpha. 
-methyl ester 
722 mg. /30.2 mmoles/ of sodium hydride and 35 ml. of dry dimethyl 
sulfoxide are introduced under nitrogen atmosphere to a 100 ml. round 
bottomed flask. The suspension is stirred for 30 minutes at 
65.degree.-70.degree. C. and for 30 minutes at 70.degree.-75.degree. C. 
The formed hydrogen gas is removed e.g. by a mercury seal bubble-maker. To 
the thus obtained solution 7.2 g. /15.1 mmoles/ of 
triphenyl-m-carboxy-benzyl-phosphonium bromide are added under nitrogen 
atmosphere. 
The obtained suspension is stirred for 30 minutes at 35.degree. C. The red 
viscous solution of the phosphorane thus obtained is added within 10 
minutes at room temperature to a solution of 1.37 g. /3.77 mmoles/ of 
3a.beta.,4,5,6,6a.beta.-hexahydro-2-hydroxy-4.beta.-[2-bromo-3/S/-hydroxy- 
1-nonenyl]-5.alpha.-hydroxy-2H-cyclopenta/b/furan in 1 ml. of anhydrous 
tetrahydrofuran. The reaction mixture is stirred at 40.degree. C. for 20 
minutes. 
The reaction mixture is then poured on a mixture of 100 ml. of water and 30 
g. of ice and the pH is adjusted to 3-4 by adding 1N sulfuric acid 
solution. The solution is extracted with 4.times.30 ml. of ethyl acetate. 
The combined organic layers are extracted with 3.times.15 ml. of 1N sodium 
hydroxide solution. The combined alkaline extracts are adjusted to 
pH=3.5-4 by adding a 1N sulfuric acid solution and 80 ml. of diethyl ether 
and 10 ml. of 1 molar ethereal diazo-methane solution are added. The ether 
layer is separated, washed with saturated salt solution, dried and 
evaporated. 
1.78 g. of raw product is obtained, which is chromatographed on silica gel 
column and eluted with a 3:1 mixture of ethyl acetate and benzene. 
The fractions corresponding to 0.31 R.sub.f /on Merck silica gel plate Art 
5715/ are collected in a system of 3:1 ethyl acetate and benzene and 
evaporated. 929 mg. /50%/ of end product are obtained. 
Analysis of the product 
Thin layer chromatography: R.sub.f =0.31 /in 3:1 mixture of ethyl 
acetate:benzene/. 
NMR /CDCl.sub.3,.delta./: 7.3-8.1 /4H/; 6.2-6.7 /trans H-5, H-6 olephine 
protons/; 5.7-5.95 /cis-H5, H-6, H-13 olephine protons/; 4.0-4.35 /3H, 
H-9, H-11, H-15/; 3.92 /3H, methyl-ester CH.sub.3 /. 
EXAMPLE 2 
2,3,4-Trinor-1.5-inter-m-phenylene-13,14-didehydro-10-methyl-PGF.sub.2.alph 
a. -methyl ester 
532 mg. /1.08 mmole/ of 
2,3,4-trinor-1,5-inter-m-phenylene-14-bromo-20-methyl-PGF.sub.2.alpha. 
-methyl ester are dissolved in 12 ml. of abs. dimethyl sulfoxide, 
whereafter 1.22 g. /10.8 mmoles/ of potassium tert. butoxide is added. The 
obtained mixture is then stirred for 5 minutes and diluted with 20 ml. of 
saturated salt solution, 20 ml. of water and 80 ml. of ethyl acetate. 
The aqueous layer is acidified with 1N sodium hydrogen sulphate to pH=3. 
The organic layer is separated, and the aqueous layer is extracted with 
2.times.10 ml. of ethyl acetate. The organic layers are combined, cooled 
to 0.degree. C. and treated with an ether solution of diazomethane /1M 
solution, 10-20 ml./. 
The organic layer is dried on anhydrous sodium sulphate, the drying agent 
is filtered and the solvent is distilled off at reduced pressure. 474 mg. 
of raw product are obtained and chromatographed on silica gel column and 
eluted with a 3:1 mixture of ethyl acetate and benzene. The fractions 
corresponding to R.sub.f =0.35 are collected, the solvent is distilled off 
at reduced pressure. 
Yield: 247 mg. /59.8%/. 
Analytical Results 
Thin layer chromatography: R.sub.f =0.35 in 3:1 mixture of ethyl acetate 
and benzene. 
NMR /CDCl.sub.3,.delta./: 7.25-8.1 /4H, aromatic protons/; 6.3-6.58 /2H; 
H-5; H-6/; 4.0-4.5 /3H, H-9, H-11, H-15/; 3.95 /s, 3H, CH.sub.3 ester /. 
EXAMPLE 3 
2,3,4-Trinor-1,5-inter-m-phenylene-5iodo-14-bromo-20-methyl-PGI.sub.1 
-methyl ester 
577 mg. /1.17 mmole/ of 2,3,4,-trinor-1,5-inter-m-phenylene-14-bromo-20 
-methyl-PGF.sub.2.alpha. -methyl ester are dissolved in 2 ml. of 
methylene-chloride and under stirring 11.6 ml. /11.6 mmoles/ of 1 
mmole/ml. concentrated sodium hydrogen carbonate solution is added. 
To the reaction mixture of two layers 23.4 ml. /2.34 mmoles/ of a 0.1 
mmole/ml methylene chloride iodine solution are added. The reaction 
mixture is vigorously stirred for 1 hour at room temperature, diluted with 
100 ml. of ethyl acetate and the excess iodine is removed with a 5% sodium 
thiosulphate solution. The organic layer is separated and the aqueous part 
is extracted with 2.times.15 ml. of ethyl acetate. The organic layers are 
collected and washed with saturated salt solution, dried above anhydrous 
sodium sulphate, filtered and the solvent is distilled off at reduced 
pressure. 
Yield: 720 mg. 
Analysis 
Thin layer chromatography: R.sub.f =0.6 and 0.65. developed twice in a 3:1 
system of ethyl acetate and benzene. 
EXAMPLE 4 
2,3,4-Trinor-1,5-inter-m-phenylene-5-iodo-13,14-didehydro-20-methyl-PGI.sub 
.1 -methyl ester 
One may proceed as disclosed in Example 3 but as starting material 483 mg. 
/1.17 mmole/ of 2,3,4-trinor-1,5-inter-m-phenylene-13,14 
-didehydro-20-methyl-PGF.sub.2.alpha. -methyl ester are used. 
Yield: 603 mg. 
Analysis 
Thin layer chromatography: R.sub.f =0.67 and 0.60 /in a 3:1 mixture of 
ethyl acetate and benzene/. 
EXAMPLE 5 
2,3,4-Trinor-1,5-inter-m-phenylene-14-bromo-20-methyl-PGI.sub.2 -methyl 
ester 
689 mg. /1.11 mmole/ of 
2,3,4-trinor-1,5-inter-m-phenylene-5-iodo-14-bromo-20-methyl-PGI.sub.1 
-methyl ester are added into a 10 ml. round-bottomed flask. The air space 
of the flask is several times rinsed with nitrogen gas. 1 ml. of 
1.5-diazabicyclo[4,3,C]-non-5-ene is added under inert gas atmosphere. The 
obtained mixture is then stirred for 2 hours at 40.degree. C. and then 
cooled to room temperature, diluted with 50 ml. ether and the ether layer 
is washed with 3.times.5 ml. of water. The ether layer is dried above 
anhydrous sodium sulphate, filtered and evaporated at reduced pressure. 
543 mg. of raw product are obtained, and chromatographed on silica gel 
column, and eluted with a 5:1 mixture of dichloroemethane and acetone. 
R.sub.f =0.73 and 0.69. The corresponding fractions are collected and 
evaporated separately. 
The product having R.sub.f =0.73 corresponds to a 5,6/Z/ geometrical isomer 
containing a double bond. 
Yield: 216 mg. /39.5%/. 
The product having R.sub.f =0.69 corresponds to a 5,6/E/-geometrical isomer 
containing a double bond. 
Yield: 206 mg. L/37.7%/. 
Analysis 
Thin layer chromatography: R.sub.f =0.73 and 0.69 /on Merck silica gel 
plate--Art 5715--developed twice in a 3:1 mixture of dichloromethane and 
acetone. 
NMR /CDCl.sub.3 .delta./: 7.3-8.2 /m, 4H, aromatic protons/; 5.85 /d, 1H, 
H-19/; 5.3 /s, 1H, H-5/; 4.83 /m, 1H, H-9/; 3.95-4.2 /m, 2H, H-11, H-15/; 
3.94 /s, 3H, CH.sub.3 ester/. 
EXAMPLE 6 
2,3,4-Trinor-1,5-m-phenylene-13,14-didehydro-20-methyl-PGI.sub.2 -methyl 
ester 
One proceeds according to Example 5 but as starting material 599 mg. /1.11 
mmole/ of 
2,3,4-trinor-1,5-inter-m-phenylene-5-iodo-13,14-didehydro-20-methyl-PGI.su 
b.1 -methyl ester are used. 
Yield: 218 mg. /52.8%/. 
Analysis 
Thin layer chromatography: Rf.sub.2 =0.50 in a 3:1 mixture of benzene and 
ethyl acetate. 
NMR /CDCl.sub.3 .delta./: 7.3-8.1 /m, 4H, aromatic protons/; 5.95 and 5.3 
/s, 1H, E or Z H-5/; 4.05-4.5 /2H, H-11and H-15/; 4.75 /dt, 1H, H-9/; 4.95 
/3H, CH.sub.3 ester/. 
EXAMPLE 7 
2,3,4-Trinor-1,5-inter-m-phenylene-13,14-didehydro-20-methyl-PGI.sub.2 
-methyl ester 
494 mg. /1 mmole/ of 
2,3,4-trinor-1,5-inter-m-phenylene-14-bromo-20-methyl-PGI.sub.2 -methyl 
ester are dissolved in 5 ml. of abs. dimethyl sulfoxide. 550 mg. /5mmoles/ 
of potassium tert. butoxide are added to the solution at room temperature. 
The suspension is stirred for 5-10 minutes, diluted with 50 ml. of water 
and the pH of the obtained aqueous solution is adjusted to 4 by adding 1N 
oxylic acid solution and the mixture is then extracted with 30+20+20 ml. 
of ethylacetate of 0.degree. C. The organic layers are combined, dried 
above anhydrous sodium sulphate, filtered and the solution is treated with 
10 ml. 1 Mol/1 ether-diazomethane solution at 0.degree. C. The solvent is 
distilled off at reduced pressure and the raw product is chromatographed 
on silica gel column in a 5:1 mixture of dichloromethane and acetone. 
Fractions having R.sub.f =0.50 are collected in 3:1 mixture of 
benzene:ethylacetate and are evaporated at reduced pressure. 255.6 mg. 
/62%/ of the title product are obtained. 
Analysis is the same as given in Example 6. 
If the process according to the Example is employed for the 5,6/Z/ product 
prepared as disclosed in the Example as starting material, then the 5/Z/ 
isomer of the title compound is obtained as a product. If the same process 
is employed for the 5,6/E/ product prepared as given in Example 5 as 
starting material then as a product the 5/E/ isomer of the title compound 
is obtained. 
EXAMPLE 8 
2,3,4-Trinor-1,5-inter-m-phenylene-14-bromo-20-methyl-PGI.sub.2 sodium salt 
988 mg. /2mmoles/ of 2,3,4-trinor-1,5-inter-m-phenylene 
14-bromo-20-methyl-PGI.sub.2 methyl ester are dissolved in 1 ml. methanol. 
1 ml. /10 mmoles/ of 5N aqueous sodium hydroxide solution is added at room 
temperature. The reaction mixture is stirred at room temperature for 1 
hour. Methanol is then distilled off at reduced pressure and 10 ml. of an 
1:1 mixture of saturated salt solution and water are added to the residue 
and the solution is extracted with 3.times.5 ml. ether. The aqueous layer 
is cooled to 0.degree. C., whereafter 20 ml. of ethyl acetate are added 
and the pH of the mixture is adjusted to 4-4.5 under vigorous stirring. 
The layers are then separated and the aqueous layer is extracted with 
3.times.5 ml. of ethyl acetate. The organic layers are combined, dried 
above anhydrous sodium sulphate, filtered and evaporated. 841 mg. of raw 
acid are obtained, this acid is then dissolved in 0.5 ml. of methanol and 
to the obtained solution. 1.75 ml. of a methanolic solution of 1N sodium 
hydroxide is added. Methanol is removed by distillation at reduced 
pressure. The obtained raw product is suspended in 1 ml. abs. 
tetrahydrofuran and filtered. 
Yield: 878.5 mg. /87.5%/. 
Analysis 
Thin layer chromatography: R.sub.f =0.54 /on Merck silica gel plate--Art 
5715 in a 20:20:1 mixture of benzene:dioxane:acetic acid/. 
EXAMPLE 10 
2,3,4-Trinor-1,5-inter-m-phenylene-20-methyl-13,14-didehydro-6a-carbaprosta 
glandin-I.sub.2 -methyl ester 
20 mmoles of sodium methyl sulfinyl methide are dissolved in 20 ml. of 
dimethylsulfoxide (prepared from 480 mg. of sodium hydride and 20 ml. of 
abs. sulfoxide). The solution is cooled to 15.degree.-20.degree. C. and 
4.77 g. (10 mmoles) of triphenyl-3-carboxy-benzyl-phosphonium bromide are 
added. The formed red solution is stirred for 30 minutes at 35.degree. C. 
and cooled to room temperature. 1.34 g. (3 mmoles) of 
7.alpha.-(tetrahydropyrane-2-yl-oxy)-6.beta.-[3s-(tetrahydropyrane-2-yl-ox 
y)-1-noninyl]-bicyclo[3,3,0]-octane-3-one dissolved in 1 ml. abs. 
tetrahydrofuran is added. The reaction mixture is stirred at 40.degree. C. 
for 48 hours, cooled to room temperature. 10 ml. of water are added and 
the pH of the solution is adjusted to neutral by adding 1N sodium hydrogen 
sulphate, and the solution is extracted with 3.times.20 ml. of ethyl 
acetate. The organic extracts are combined and washed with 3.times.10 ml. 
of water and 1.times.10 ml. of saturated salt solution, dried above 
anhydrous sodium sulphate and filtered. The solution is cooled to 
0.degree. C. and treated with 10 ml. of a 1 mmole/ml ether diazomethane 
solution and the solvent is distilled off at reduced pressure and the 
obtained raw product (2 g.) is chromatographed on silica gel column with a 
4:1 mixture of benzene and ethyl acetate. 
Fractions corresponding to R.sub.f -values 0.48 and 0.43 are collected 
(after developing in a 3:1 mixture of benzene and ethyl acetate) and 
evaporated at reduced pressure. 
Yield: 644.5 mg. (37%) of 5/Z/ isomer R.sub.f =0.48 
Yield: 679.3 mg. (39%) of 5/E/ isomer R.sub.f =0.43. 
The obtained fractions are dissolved separately in a 3:1:1.5 mixture of 
acetic acid-water-tetrahydrofuran and stirred at 45.degree. C. for 3 
hours. The reaction mixture is cooled to room temperature and 40 ml. of a 
saturated salt solution and 40 ml. of ethyl acetate are added. The organic 
layer is separated, the aqueous layer is extracted with 2.times.5 ml. of 
ethyl acetate. The organic layers are combined and washed to neutral with 
2.times.10 ml. of saturated sodium hydrogen carbonate solution. The 
organic layer is dried above anhydrous sodium sulphate, filtered and the 
solvent is evaporated at reduced pressure. The raw product is 
chromatographed on silica gel column with ethyl acetate. 
Yield: 380.4 mg. (31.9%) of 5/Z/ and 387.6 mg (32. 5%) of 5/E/ isomers. 
(R.sub.f =0.28 and 0.25 in ethyl acetate.) 
Analysis 
Thin layer chromatography: R.sub.f =0.28 and 0.25 resp. (on Merck silica 
gel plate=Art 1715--in ethyl acetate). 
NMR (CDCl.sub.3 .delta.): 7.25-8.0 (4H); 5.6 (1H); 3.5-4.25 (5H). 
EXAMPLE 11 
2,3,4-Trinor-1,5-inter-m-phenylene-20-methyl-13,14-didehydro-6a-carbaprosta 
glandine-I.sub.2 sodium salt 
One may proceed according to Example 8 but as starting material 385.6 mg. 
(0.97 mmole) of 
2,3,4-trinor-1,5-inter-m-phenylene-20-methyl-13,14-didehydro-6a-carba-pros 
taglandin-I.sub.2 -methyl ester are used. 
Yield: 352.8 mg. (87%). 
Analysis 
Thin layer chromatography: R.sub.f =0.6 (on Merck silica gel plate--Art 
5715 in a 20:10:1 mixture of benzene-dioxan-acetic acid). 
According to the process given in Examples 1 to 11 the following compounds 
are prepared from the appropriate starting materials: 
2,3,4-trinor-1,5-inter-m-phenylene-13,14-didehydro-20-ethyl-PGI.sub.2 
sodium salt (R.sub.f =0.57) in a 20:10:1 system of benzene-dioxan-acetic 
acid on Merck silica gel plate Art 5719), 
2,3,4,17,18,19,20-heptanor-1,3-inter-m-phenylene-13,14-didehydro-16-phenoxy 
-PGI.sub.2 sodium salt, R.sub.f =0.6 (in the above system), 
2,3,4,17,18,19,20-heptanor-1,5-inter-m-phenylene-13,14-didehydro-16-(3-trif 
luormethyl-phenoxy)-PGI.sub.2 sodium salt R.sub.f =0.62 (in the above 
system), 
2,3,4-trinor-1,5-inter-m-phenylene-14-bromo-20-ethyl-PGI.sub.2 sodium salt 
R.sub.f =0.57 (in the above system), 
2,3,4,17,18,19,20-heptanor-1,5-inter-m-phenylene-16-phenyl-13,14-didehydro- 
PGI.sub.2 sodium salt R.sub.f =0.69 (in the above system), 
2,3,4-trinor-1,5-inter-m-phenylene-11,15-bis(tetrahydropyran-2-yl-oxy)-13,1 
4-didehydro-20-methyl-PGI.sub.2 methyl ester, R.sub.f =0.87 (in a 3:1 
mixture of benzene and ethyl acetate). 
2,3,4-trinor-1,5-inter-m-phenylene-11,15-bis(dimethyl-tert.butyl-silyloxy)- 
13,14-didehydro-20-methyl-PGI.sub.2 -methyl ester, R.sub.f =0195 (in a 3:1 
mixture of benzene and ethyl acetate).