Heterocyclic prostaglandin type compounds, medicaments containing them and processes for the preparation and use of these heterocyclic compounds and medicaments

Disclosed are new heterocyclic compounds, medicaments containing them (for oral or parenteral administration) and processes for the preparation and use of these heterocyclic compounds and medicaments. The new compounds which particularly act as inhibitors of blood platelet aggregation and as blood pressure lowering agents correspond to the general formula ##STR1## wherein R.sup.1 is hydrogen, a cation or the residue of an alcohol, R.sup.2 represents hydrogen or methyl, A is a member of the group consisting of the radicals --CH.sub.2 --CH.sub.2 --, (trans)--CH.dbd.CH-- and --C.tbd.C--, and wherein B represents an alkyl or a cycloalkyl radical. In these compounds the phenyl radical may be arranged with respect to the double bond in the E- and/or in the Z-configuration and at the carbon atom bearing the group R.sup.2 (and others) may exist RS- or S-configuration. The compounds of formula I are prepared in a manner known per se starting from derivatives of 3.alpha.,5.alpha.-dihydroxycyclopentane-1.alpha.-acetaldehyde .gamma.-lactol substituted accordingly and phosphonium salts of the formula ##STR2## wherein R.sup.6 represents hydrogen or alkyl and wherein Hal is chlorine, bromine or iodine.

BACKGROUND OF THE INVENTION 
The present invention relates to new heterocyclic compounds, to 
pharmaceutical compositions containing these new compounds for oral or 
parenteral administration, to a process for preparing these new compounds 
and compositions and also to methods of pharmacological treatment 
utilizing the compounds and compositions according to the invention. 
The compounds according to the present invention contain the same basic, 
chemical structure as prostacyclin, which occurs in nature. Prostacyclin 
possesses the properties of inhibiting blood platelet aggregation and 
lowering the blood pressure. These properties are exhibited at generally 
the same dosage level. Prostacyclin is not as stable as would be 
desirable. 
SUMMARY OF THE INVENTION 
It is therefore an object of the present invention to provide new chemical 
compounds which possess valuable pharmaceutical properties. 
A further object of the invention resides in providing improved 
pharmaceutical compositions. 
It is another object of the invention to provide a process for preparing 
the new compounds and compositions according to the invention. 
Still another object of the invention is to provide an improved method of 
pharmacological treatment, in particular to inhibit blood platelet 
aggregation and to lower blood pressure. 
In accomplishing the foregoing objects, there has been provided in 
accordance with the present invention a new class of heterocyclic 
compounds of the formula 
##STR3## 
in which the phenyl radical with respect to the double bond has the E-, 
the EZ- or the Z-configuration and in which at the carbon atom 15 which 
carries the group R.sup.2 there exists the RS- or S-configuration, wherein 
R.sup.1 represents hydrogen, a pharmaceutically acceptable cation or the 
residue of an alcohol being pharmaceutically applicable in esterified 
form, 
R.sup.2 represents hydrogen or a methyl group, 
A represents --CH.sub.2 --CH.sub.2 --, (trans)--CH.dbd.CH-- or --C.tbd.C--, 
and 
B represents an alkyl group containing 5 to 9 carbon atoms and having the 
structure 
##STR4## 
wherein R.sup.3 and R.sup.4 have the same or a different meaning and each 
represents hydrogen, methyl or ethyl, or B represents cyclohexyl or 
cyclohexyl substituted in position 4' by a methyl or an ethyl group. 
In accordance with another aspect of the present invention, there has been 
provided a pharmaceutical composition, comprising a therapeutically 
effective amount of a heterocyclic compound as defined above as active 
ingredient and at least one pharmaceutically acceptable inert carrier or 
diluent. 
In accordance with still another aspect of the present invention, there has 
been provided a process for preparing the heterocyclic compounds defined 
above, comprising the steps of reacting a compound of the formula 
##STR5## 
wherein B represents an alkyl group containing 5 to 9 carbon atoms and 
having the structure 
##STR6## 
wherein R.sup.3 and R.sup.4 have the same or a different meaning and each 
represents hydrogen, methyl or ethyl, or B represents cyclohexyl or 
cyclohexyl substituted in position 4' by a methyl or an ethyl group, 
R.sup.2 represents hydrogen or a methyl group, D represents --CH.sub.2 
--CH.sub.2 --, (trans)--CH.dbd.CH-- or --CH.dbd.CHal--, in which Hal 
represents chlorine, bromine or iodine and wherein R.sup.5 and R.sup.5' 
have the same or a different meaning and each represents hydrogen or a 
protecting group cleavable under mild conditions, in the absence of oxygen 
at about 10.degree. to 30.degree. C. in the presence of a solvent 
containing a strong base, with a compound of the formula 
##STR7## 
wherein R.sup.6 is hydrogen or an alkyl group containing 1 to 6 carbon 
atoms, preferably methyl or ethyl, and wherein Hal represents chlorine, 
bromine or iodine; where R.sup.6 is hydrogen, esterifying the group 
COOR.sup.6 to the group COOR.sup.7, wherein R.sup.7 represents an alkyl 
group containing 1 to 6 carbon atoms; splitting off any protecting groups 
R.sup.5 and R.sup.5' which are present under mild conditions to give a 
compound of the formula 
##STR8## 
halogenating and cyclizing the compound of formula IV by treatment at 
about 0.degree.-30.degree. C. with an electrophilic brominating or 
iodinating agent in the presence of an inert solvent and in the presence 
of an agent capable of binding acids to give a compound of the formula 
##STR9## 
wherein A represents --CH.sub.2 --CH.sub.2 --, (trans)--CH.dbd.CH-- or 
--C.tbd.C--, and X represents bromine or iodine; and dehydrohalogenating 
the compound of formula V to give a compound of the formula 
##STR10## 
In accordance with still another aspect of the present invention there has 
been provided a method for inhibiting blood platelet aggregation, 
comprising the step of administering to a human patient a blood platelet 
aggregation inhibiting amount of a compound as defined above. Preferably, 
the method is for simultaneously inhibiting blood platelet aggregation and 
lowering blood pressure, comprising the step of administering to a human 
patient an amount of a compound as defined above, which is sufficient to 
simultaneously inhibit blood platelet aggregation and lower the blood 
pressure. 
Further objects, features and advantages of the present invention will 
become apparent from the detailed description of preferred embodiments, 
which follows. 
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
The present invention relates to heterocyclic compounds of the formula 
##STR11## 
the basic structure of which, for example, is also contained in the 
naturally occurring prostacyclin. 
In formula I, R.sup.1 represents a hydrogen atom, a pharmaceutically 
acceptable cation or the residue of an alcohol being pharmaceutically 
applicable in esterified form, especially an alkyl radical having a 
straight or a branched chain of 1 to 6 carbon atoms. Preferably, R.sup.1 
represents, however, a methyl or an ethyl radical or, in case this group 
represents a cation, a sodium or a potassium cation. Other suitable 
cations are known from their use in the chemistry of prostaglandins or 
prostacyclin, respectively. For instance, there may be used the ions of 
calcium, magnesium, ammonium or of amines such as mono-, di- or 
trimethylamine, triethylamine, triethanolamine, trishydroxymethylamine and 
others. Furthermore, for the salt formation, basic amino acids like 
arginine or lysine may also be used. 
R.sup.2 represents hydrogen or a methyl radical. At the carbon atom (15) 
bearing the group R.sup.2 (and others) there may exist RS- or 
S-configuration, with the 15S-forms of the compounds of formula I being 
preferred. 
A is a member of the group consisting of the radicals --CH.sub.2 --CH.sub.2 
--, (trans)--CH.dbd.CH-- and --C.tbd.C--. The two last mentioned radicals 
are preferred, and especially in the preferred 15S-forms of the compounds 
of formula I, A is preferably (trans)--CH.dbd.CH--. 
B either represents an alkyl radical containing 5 to 9 carbon atoms and 
having the structure 
##STR12## 
wherein R.sup.3 and R.sup.4 have the same or a different meaning and each 
represent hydrogen, methyl or ethyl or B represents a cyclohexyl radical 
which may be substituted in position 4' by a methyl or an ethyl radical. 
In preferred groups of compounds of formula I, B represents the cyclohexyl 
radical or the alkyl radical of the structure given above wherein both of 
R.sup.3 and R.sup.4 are hydrogen or methyl or wherein R.sup.3 is ethyl and 
R.sup.4 is hydrogen, respectively. 
In the compounds of formula I the phenyl radical may be arranged with 
respect to the double bond in the E-, EZ- or preferably in the 
Z-configuration. 
If A is as preferred the (trans)--CH.dbd.CH-- radical, the compounds 
according to the invention correspond to the formula 
##STR13## 
wherein R.sup.1, R.sup.2 and B have the same meaning as above. 
Accordingly, the especially preferred compounds of formula I in which A is 
the (trans)--CH.dbd.CH-- radical and in which B is the alkyl or cycloalkyl 
radical mentioned above having the following structures 
##STR14## 
wherein R.sup.1 to R.sup.4 have the same meaning as above, and 
##STR15## 
wherein R.sup.1 and R.sup.2 are as defined above and wherein R.sup.8 
represents hydrogen, methyl or ethyl. 
With respect to the nomenclature of the compounds of formula I, reference 
is made to the papers of Nelson, J. Med. Chem. Vol. 17, 911 (1974), and 
Johnson et al., Prostaglandins Vol. 15, 737 (1978). Accordingly, the 
carbon atoms in the basic structure of the compounds of formula I are 
numbered as follows: 
##STR16## 
wherein in consideration of the definition given above for A the carbon 
atoms 13 and 14 may also be connected by a double or triple bond and 
wherein R.sup.1, R.sup.2 and B have the same meaning as in formula I. The 
numbering of the carbon atoms in R.sup.1, R.sup.2 and B needs no special 
explanation besides mentioning that in case B is a cyclohexyl radical, the 
carbon atoms thereof will become numbered as 1', 2', etc. (as may be seen 
also from the definition given for B hereinabove). 
The compounds of formula I have prostacyclin-like properties with respect 
to blood platelet aggregation (in-vitro and in-vivo) and with respect to 
their effect on blood pressure; however, they distinguish from 
prostacyclin, for instance, in that they are far more stable than 
prostacyclin. Compared with 5,6-dihydroprostacyclin, which is considered a 
reference compound due to its chemical stability, e.g., the product 
obtained in Example 3b herein, is several times more active. Surprising 
for the compounds according to the invention is the relation of their 
blood platelet aggregation inhibiting effect to their blood pressure 
lowering activity. Contrary to 5,6-dihydroprostacyclin, which produces 
both these effects at the same dosage range, the compounds of formula I 
produce blood pressure lowering effects only after administering far 
higher dosages then those necessary to produce platelet aggregation 
inhibition, as may be seen from the following Tables 1a-1d in which, for 
some compounds of formula I, the experimentally-obtained (in the 
in-vivo-experiments each time using groups of 4 to 6 animals) values of 
the relative activity in comparison to 5,6-dihydroprostacyclin are given: 
TABLE 1a 
______________________________________ 
Relative activity against the aggregation 
of human thrombocytes induced by arachidonic acid 
in-vitro (the IC.sub.50, i.e., the concentration causing 
under the experimental conditions in 50% of the cases 
inhibition of the platelet aggregation for 5,6-di- 
hydroprostacyclin is 0.18 .mu.Mol/l): 
5,6-Di- 
Test hydro- 
com- prosta- PRODUCT OF EXAMPLE NO. 
pound cyclin 1e)ii) 1e)i) 
2a 2b 3b 4b 
______________________________________ 
rela- 
tive 
acti- 
vity 1.0 0.25 0.86 1.2 1.2 18.0 0.31 
______________________________________ 
TABLE 1b 
______________________________________ 
Relative activity on the ADP induced fall 
in platelet count in-vivo in narcotized rats (urethane 
narcosis; intravenous administration of the test 
compounds; the ED.sub.50 for 5,6-dihydroprostacyclin under 
these experimental conditions is 0.0114 mg/kg): 
5,6-Di- 
Test hydro- 
com- prosta- PRODUCT OF EXAMPLE NO. 
pound cyclin 1e)ii) 1e)i) 3b 4b 
______________________________________ 
rela- 
tive 
acti- 
vity 1.0 0.97 1.3 5.0 0.2 
______________________________________ 
It is remarkable that especially the product of Example 3b is several times 
more active than 5,6-dihydroprostacyclin in-vitro (Table 1a) as well as 
in-vivo (Table 1b). 
TABLE 1c 
______________________________________ 
Relative blood pressure lowering activity in 
conscious, spontaneous hypertensive rats (measurement 
via in-dwelling catheter; intravenous administration 
of the test compounds; the ED.sub.20 for 5,6-dihydroprosta- 
cyclin under these experimental conditions is 0.005 
mg/kg): 
5,6-Di- 
Test hydro- 
com- prosta- PRODUCT OF EXAMPLE NO. 
pound cyclin 1e)ii) 1e)i) 3b 4b 
______________________________________ 
rela- 
tive 
acti- 
vity 1.0 0.014 0.1 0.25 0.012 
______________________________________ 
TABLE 1d 
______________________________________ 
##STR17## 
in comparison to 5,6-dihydroprostacyclin (calculated 
from the values given in Tables 1b and 1c). 
5,6-Di- 
Test hydro- 
com- prosta- PRODUCT OF EXAMPLE NO. 
pound cyclin 1e)ii) 1e)i) 3b 4b 
______________________________________ 
Index 
of se- 
lecti- 
vity 1.0 69.3 13.0 20.0 16.7 
______________________________________ 
These results prove that the compounds of formula I can be used not only in 
diseases which an inhibition of platelet aggregation is desired without 
accompanying lowering of the blood pressure (as for instance 
hyperaggregability in coronary heart disease) but also in higher doses in 
diseases in which a simultaneous vasodilation is desired (as for instance 
ischaemic peripheral vascular disease). 
Natural prostacyclin and also the chemically stable 5,6-dihydroprostacyclin 
produce only for a short time their aggregation inhibiting and blood 
pressure lowering activities. These compounds have therefor to be 
administered in therapeutic use by continuous infusion. 
Surprisingly, the compounds of formula I produce considerably longer 
lasting effects than 5,6-dihydroprostacyclin, i.e., such that they are 
suitable also to produce long lasting platelet aggregation inhibition and 
blood pressure lowering on administration of (one or several consecutive) 
single doses as may be seen from the following Tables 2a and 2b: 
TABLE 2a 
______________________________________ 
Duration of the platelet aggregation inhibiting 
effect in-vivo (measured with the model of ADP induced 
fall in platelet count in narcotized rats on intra- 
venous administration of the test compounds) 
Effect in relation to 
Dose Maximum effect 
maximum effect 
Test (mg/ % Aggregation 
10 min. after 
30 min. after 
compound 
kg) inhibition administration 
administration 
______________________________________ 
5,6-Dihy- 
droprosta- 
cyclin 0.1 62.4 = 100% 33.8% 0% 
Example 
1e)i) 1.0 72.7 = 100% 69.3% 41.3% 
Example 
3b 0.1 72.5 = 100% 62.6% 66.3% 
Example 
4b 1.0 66.8 = 100% 45.4% 24.5% 
______________________________________ 
TABLE 2b 
______________________________________ 
Duration of the blood pressure lowering effect 
in conscious, spontaneous hypertensive rats (intra- 
venous administration of the test compounds): 
Maximum Effect in relation to 
Dose effect % maximum effect 
Test (mg/ Blood pres- 
10 min. after 
30 min. after 
compounds 
kg) sure lowering 
administration 
administration 
______________________________________ 
5,6-Dihy- 
droprosta- 
cyclin 0.0215 28 = 100% 7.1% 0% 
Example 
3b 0.1 23 = 100% 87.0% 39.1% 
Example 
4b 1.0 22 = 100% 90.9% 68.2% 
______________________________________ 
Prostaglandins like PGE.sub.2 or PGF.sub.2.alpha. cause contraction of the 
smooth muscle of the intestine and uterus and accordingly when 
administered in-vivo may induce diarrhea and abortion. Such effects are 
undesired side effects in compounds such as analogs of prostacyclin to be 
used in platelet aggregation inhibition and in blood pressure lowering. 
The new compounds of formula I, in contrast to 5,6-dihydroprotacyclin, have 
only very weak contraction-inducing properties (as can be seen from the 
following Tables 3a and 3b). Accordingly, therapeutic use of doses 
sufficient to produce inhibition of platelet aggregation and lowering of 
the blood pressure causes no risk that such side effects may occur. 
TABLE 3 
______________________________________ 
Relative contraction inducing activities 
Relative contraction 
Test Compound inducing activity 
______________________________________ 
(a) tests on isolated rat uterus 
Prostaglandin F.sub.2.alpha. 
100% (EC.sub.50 50.1 .mu.M) 
5,6-Dihydroprostacyclin 
26.1% 
Product of Example 1e)i) 
0.58% 
(b) tests on isolated rat colon 
Prostaglandin F.sub.2.alpha. 
100% (EC.sub.50 50.14 .mu.M) 
5,6-Dihydroprostacyclin 
23.8% 
Product of Example 1e)i) 
0.002% 
______________________________________ 
Similar results were obtained also in testing other compounds of formula I. 
Inasmuch the compounds of formula I not only possess surprising and 
valuable biological properties but also a good chemical stability, they 
may be used for parenteral and also for oral application to humans and 
mammals to produce an inhibition of blood platelet aggregation in therapy 
and prophylaxis of diseases in which blood platelet aggregation and/or a 
hyper-aggregability are of pathogenetic importance. Such diseases are, for 
instance, arterial thromboses in vascular endothelial disorders, 
atherosclerosis, hemostatic arterial and venous thromboses and myocardial 
infarction. Due to their influence on the blood pressure, the compounds of 
formula I are suitable also for the treatment of pulmonary as well as of 
systemic hypertension. The comdpounds according to the invention are 
useful for diminuation of platelet aggregability in artificial 
extra-corporeal circulations and perfusion of isolated body portions 
(e.g., in dialysis, cardiopulmonary bypass, transplantations etc.) wherein 
the compounds are added in micromolar concentrations to the patients 
blood. 
The invention accordingly relates also to medicaments (i.e., pharmaceutical 
compositions) containing as active ingredients one or more of the 
heterocyclic compounds of formula I. The compound content of the 
individual dose is between about 0.01 and 10 mg, whereby preferably 
compositions for parenteral administration contain about 0.01-1 mg and 
those for oral administration contain about 0.1-10 mg. The medicaments to 
be used for parenteral administration may be solutions or suspensions but 
may also be dry formulations suitable for easy reconstitution, as for 
instance, lyophylized sodium salts of compounds of formula I in single 
dosage form. 
For oral administration, tablets, pills, dragees, capsules, and similar 
application forms including, for example, those from which the active 
ingredients have a delayed release are suitable. In production of these 
pharmaceutical compositions, generally used inorganic or organic adjuvants 
such as diluents, carriers, binders, lubricants and others are added to 
the compounds of the general formula I. 
The pharmaceutical compositions of the invention are prepared in accordance 
with accepted standards in a manner known per se. It should be mentioned 
that the compositions for parenteral use have to be sterile and, if 
prepared in liquid form, isotonic condition. 
A further aspect of the invention involves the preparation of the compounds 
of formula I. The starting material is a lactol of the formula 
##STR18## 
which may be in the 15S-form and wherein B and R.sup.2 have the same 
meaning as in formula I, D is a member of the group consisting of the 
radicals --CH.sub.2 --CH.sub.2 --,(trans)--CH.dbd.CH-- and 
--CH.dbd.CHal--, in which Hal represents chlorine, bromine or iodine, and 
wherein R.sup.5 and R.sup.5' have the same or a different meaning and 
represent hydrogen or a protecting group which can easily split off, as 
for instance, a tetrahydropyranyl group (THP) or a trimethyl silyl group 
(TMS). 
The lactol formula II is reacted at about 10.degree. to 30.degree. C., in 
the presence of a solvent containing a strong base and in the absence of 
oxygen, with a phosphonium salt of the formula 
##STR19## 
wherein R.sup.6 is hydrogen or an alkyl residue with 1 to 6 carbon atoms, 
preferably methyl or ethyl, and wherein Hal represents chlorine, bromine 
or iodine, preferably bromine, followed--if R.sup.6 is a hydrogen atom--by 
esterification of the carboxylic group COOR.sup.6, preferably by treatment 
with diazomethane at about 0.degree.-30.degree. C., and finally splitting 
off the groups R.sup.5 and R.sup.5' (if different from hydrogen) using 
mild conditions. 
Strong bases which may be added during the condensation reaction are 
preferably butyl lithium, sodium hydride or potassium tert.-butoxide which 
are used in the presence of solvents, as for instance, dimethylsulfoxide, 
ether, tetrahydrofurane, dimethylformamide and the like. 
The compound of formula III is used in an amount of 1 to 6 moles per mole 
of the compound of formula II, using 2 or more moles in case D represents 
the radical --CH.dbd.CHal--, because in this case under the conditions of 
the reaction this radical is transformed (with elimination of the 
respective hydrogen halide) to the group --C.tbd.C--. 
The presence of oxygen is preferably prevented by working in an atmosphere 
of inert gases, like argon or nitrogen. 
The reaction is performed in about 1 to 12 hours and may be controlled as 
usual by chromatography. 
To the reaction mixture there is preferably added a small, catalytically 
acting amount of a carboxylic acid, such as formic acid, acetic acid, 
propionic acid, bromoacetic acid, trichloroacetic acid or trifluoroacetic 
acid or, for instance, phenyl acetic acid, p-nitrobenzoic acid, 
p-chlorobenzoic acid or p-methoxybenzoic acid and especially the 
unsubstituted benzoic acid. 
If R.sup.5 or R.sup.5', respectively, represent protecting groups, these 
may be split off by treating for 1 to 5 hours at 30.degree. to 50.degree. 
C. with a mixture of tetrahydrofurane, glacial acetic acid and water in 
the relation 1:3:1. 
Thus, a compound is obtained having the formula 
##STR20## 
wherein R.sup.2, A and B have the same meaning as in formula I and wherein 
R.sup.7 is an alkyl radical having 1 to 6 carbon atoms. 
If desired, this compound may be separated into the 15R- and 15S-isomers by 
column chromatography with silica gel. 
The obtained products of formula IV are then halogenated and cyclisized in 
a conventional manner by treatment at about 0.degree.-30.degree. C. with 
an electrophilic reagent, such as for instance, iodine, iodine-potassium 
iodide or N-bromosuccinimide, in the presence of an inert solvent and 
possibly in the presence of water with addition of an agent capable of 
binding acids, to give a compound of formula V: 
##STR21## 
wherein R.sup.2, R.sup.7, A and B have the same meaning as above and 
wherein X represents a bromine or an iodine atom. Preferably X is an 
iodine atom and R.sup.7 is a methyl or an ethyl radical. 
Solvents which may be used in this reaction are, for instance, 
diethylether, tetrahydrofurane, dichloromethane, chloroform or mixtures of 
these solvents. The reaction is performed within about 30 minutes to 12 
hours, and its progress may be supervised as usual by chromatography. 
Agents capable of binding acids which may be used in this reaction are, for 
instance, sodium hydrogen carbonate, sodium carbonate, potassium 
carbonate, magnesium oxide or calcium carbonate. 
On treating the compound of formula V with 1 to 5 moles of a base at 
temperatures of 0.degree. to 90.degree. C. for about 4 to 12 hours, 
dehydrohalogenation occurs, and a compound is formed having the formula: 
##STR22## 
wherein R.sup.2, R.sup.7, A and B have the same meaning as above and which 
may be saponified at the group COOR.sup.7 to give a compound of formula I 
in which R.sup.1 is hydrogen or a cation. 
Preferably, the reaction of the compound of formula V with the base is 
conducted at 0.degree.-30.degree. C. To induce the dehydrohalogenation, 
the following bases are especially suitable: sodium hydroxide, potassium 
hydroxide, sodium methoxide, sodium ethoxide, potassium tert.-butoxide as 
well as triethylamine, dicyclohexylamine, 
1,5-diazabicyclo-(4,3,0)-non-5-ene (DBN) or 
1,5-diazabicyclo-(5,4,0)-undec-5-ene (DBU) and others. This reaction may 
be conducted in the absence or in the presence of a solvent, such as 
toluene, methanol or ethanol. 
The saponification of the ester group COOR.sup.7 is preferably performed in 
aqueous-alcoholic solutions (like mixtures of water and methanol or 
ethanol) at 10.degree. to 50.degree. C. in the presence of 1 to 5 moles of 
sodium- or potassium hydroxide, calculated on the amount of compound of 
formula Ia present in the reaction mixture. The reaction is completed in 
about 6 to 48 hours. It is also possible to perform the 
dehydrohalogenation and the saponification of the ester group in the same 
reaction vessel without intermediate isolation of the compound of formula 
Ia. 
The compounds of formula I in which R.sup.1 is a cation obtained by 
saponification of compounds of formula Ia may [if desired after separating 
the 5E- and 5Z-isomers by means of high performance liquid chromatography 
(HPLC) using "reversed-phase"-conditions] be transformed in a manner known 
per se into other salts, for instance, by ion exchange chromatography. 
The starting materials of formulae II and III, respectively, are obtained 
as described in the literature or in an analogous manner as follows: 
(A) Phosphonium salts of formula III 
Stoichiometric amounts of the respective aralkyl halogenides and of 
triphenylphosphine are dissolved in acetonitrile and boiled for 90 
minutes. After evaporation at 50.degree.-70.degree. C. in a vacuum, the 
solid residue is thoroughly washed with cold acetone and, if necessary, 
recrystallized from water. Thus, e.g., the m-carboxyphenylmethyl triphenyl 
phosphoniumbromide, melting at 256.degree.-258.degree. C., was obtained. 
(B) 
3.alpha.,5.alpha.-Dihydroxy-2.beta.[(3RS)-3-hydroxy-3-methyl-trans-1-octen 
yl]-cyclopentane-1.alpha.-acetaldehyde .gamma.-lactol 3-trimethylsilyl 
ether was obtained as described by E. W. Yankee et al. in J.A.C.S., Vol. 
96, 5865-5876 (1974). 
(C) The preparation of the starting materials of formula II is described in 
the following publications or may be made in an analogous manner, 
respectively: 
______________________________________ 
15-Alkyl E. W. Yankee et al. J.A.C.S., 
Vol. 96, 5865 (1974) 
15-H E. J. Corey et al. J.A.C.S., 
Vol. 91, 5675 (1969) 
13,14-Dihydro German Offenlegungsschrift 
No. 23 55 540 
13,14-Dehydro Belgian Patent No. 832 891 
16-Alkyl and German Offenlegungsschrift 
16,16-Dialkyl No. 22 17 044 
15(4'-Alkylcyclohexyl) 
Belgian Patent No. 782 822 
______________________________________ 
The following non-limiting examples serve further to illustrate the 
invention. No importance was attached to obtaining maximum yields in 
carrying out the experiments on which the examples are based. All 
temperature references are uncorrected. The nuclear magnetic spectra were 
measured (proton spectra at 60 MHz) with commercially available equipment. 
The R.sub.f -values were determined by thin layer chromatography on silica 
gel.