Prostaglandin I.sub.2 analogues of the formula: ##STR1## [wherein R.sup.1 represents hydrogen, alkyl of 1 to 12 carbon atoms, aralkyl of 7 to 12 carbon atoms, cycloalkyl of 4 to 7 carbon atoms optionally substituted by alkyl of 1 to 4 carbon atoms, phenyl optionally substituted by chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms or phenyl, or represents a group --C.sub.p H.sub.2p COOR.sup.5, --C.sub.q H.sub.2q OR.sup.6 or ##STR2## (wherein R.sup.5, R.sup.7 and R.sup.8 represent alkyl of 1 to 4 carbon atoms, R.sup.6 represents hydrogen or alkyl of 1 to 4 carbon atoms, p represents an integer of from 1 to 12, and q represents an integer of from 2 to 12), R.sup.2, R.sup.3 and R.sup.4, represent hydrogen or alkyl of 1 to 8 carbon atoms, B represents a single bond, or alkylene of 1 to 4 carbon atoms, n represents 3, 4, 5 or 6, and the symbol represents a single or double bond] and, when appropriate, non-toxic salts, including acid addition salts, thereof are new compounds possessing pharmacological properties typical of the prostaglandins.

DESCRIPTION "6,9-NITRILO(IMINO)-PROSTAGLANDIN ANALOGUES" 
This invention relates to new prostaglandin I.sub.2 (PGI.sub.2) analogues, 
to a process for their preparation and pharmaceutical compositions 
containing them. 
PGI.sub.2 is a physiologically active substance having the following 
formula: 
##STR3## 
and its chemical name is 
(5Z,13E)-(9.alpha.,11.alpha.,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-die 
noic acid [Nature, 263, 663 (1976), Prostaglandins, 12, 685 (1976), ibid, 
12, 915 (1976), ibid, 13, 3 (1977), ibid, 13, 375 (1977) and Chemical and 
Engineering News, Dec. 20, 17 (1976)]. 
It is well known that PGI.sub.2 can be prepared by incubation of 
prostaglandin G.sub.2 (PGG.sub.2) or prostaglandin H.sub.2 (PGH.sub.2) 
with microsomal fractions prepared from thoracic aorta of swine, 
mesenteric artery of swine, rabbit aorta or the stomach fundus of rats. 
PGI.sub.2 has a relaxing activity on the artery, which is peculiar to the 
artery and which does not operate on other smooth muscle. Furthermore, 
PGI.sub.2 strongly inhibits arachidonic acid-induced blood platelet 
aggregation of the human. 
Taking into consideration that thromboxane A.sub.2 prepared by incubation 
of PGG.sub.2 or PGH.sub.2 with blood platelet microsome has a contracting 
activity on the artery and an aggregating activity on blood platelets, the 
properties of PGI.sub.2 heretofore mentioned show that PGI.sub.2 fulfils a 
very important physiological part in a living body. PGI.sub.2 may be 
useful in the treatment of arteriosclerosis, cardiac failure or 
thrombosis. 
Widespread investigations have been carried out in order to discover inter 
alia new products possessing the pharmacological properties of the 
`natural` PGI.sub.2, or one or more of such properties to an enhanced 
degree, or hitherto unknown pharmacological properties. As a result of 
extensive research and experimentation it has been discovered that by 
replacing the 6,9-epoxy group (i.e. --O--) by a group .dbd.N--, in which 
the double bond is attached to the 6-position (hereinafter referred to as 
a 6,9-nitrilo group), or by a group --NH-- (hereinafter referred to as a 
6,9-imino group), and by replacing the pentyl group at the end of the 
aliphatic group linked to the 12-position of the aliphatic ring of 
PGI.sub.2 by a cycloalkyl group or an alkyl group substituted by a 
cycloalkyl group, the pharmacological properties of the `natural` 
PGI.sub.2 are, in some aspects of its activities, improved or modified. 
The present invention accordingly provides new prostaglandin I.sub.2 
analogues of the general formula: 
##STR4## 
[wherein R.sup.1 represents a hydrogen atom, a straight- or branched-chain 
alkyl group containing from 1 to 12 carbon atoms, an aralkyl group 
containing from 7 to 12 carbon atoms, a cycloalkyl group containing from 4 
to 7 carbon atoms unsubstituted or substituted by at least one straight- 
or branched-chain alkyl group containing from 1 to 4 carbon atoms, a 
phenyl group unsubstituted or substituted by at least one substituent 
selected from the chlorine atom, the trifluoromethyl group, straight- or 
branched-chain alkyl groups containing from 1 to 4 carbon atoms and the 
phenyl group or represents a group -C.sub.p H.sub.2p COOR.sup.5, -C.sub.q 
H.sub.2q OR.sup.6 or 
##STR5## 
(wherein R.sup.5, R.sup.7 and R.sup.8, which may be the same or different, 
each represent a straight- or branched-chain alkyl group containing from 1 
to 4 carbon atoms, R.sup.6 represents a hydrogen atom or a straight- or 
branched-chain alkyl group containing from 1 to 4 carbon atoms, p 
represents an integer of from 1 to 12, and q represents an integer of from 
2 to 12), R.sup.2, R.sup.3 and R.sup.4, which may be the same or 
different, each represent a hydrogen atom or a straight- or branched-chain 
alkyl group containing from 1 to 8 carbon atoms, B represents a single 
bond, or a straight- or branched-chain alkylene group containing from 1 to 
4 carbon atoms, n represents 3, 4, 5 or 6, the symbol attached to the 
C.sub.6 carbon atom represents a single or double bond, the double bond 
between C.sub.13 -C.sub.14 is trans (i.e. E), and the hydroxy groups 
attached to the C.sub.11 and C.sub.15 carbon atoms of formula II are in 
.alpha.-configuration] and non-toxic acid addition salts thereof and, when 
R.sup.1 represents a hydrogen atom, non-toxic (e.g. sodium) salts thereof. 
It will be appreciated that acid addition salt formation may take place 
with a 6,9-nitrilo or 6,9-imino group; acid addition salt formation is 
also possible with a group 
##STR6## 
within the definition of the symbol R.sup.1, in which q, R.sup.7 and 
R.sup.8 are as hereinbefore defined. 
Preferred compounds of formula II are those wherein R.sup.1 represents a 
hydrogen atom or a straight- or branched-chain alkyl group containing from 
1 to 12 carbon atoms, more preferably from 1 to 4 carbon atoms, especially 
methyl, B preferably represents a single bond or a methylene group. One of 
R.sup.2, R.sup.3 and R.sup.4 preferably represents an alkyl group 
containing from 1 to 4 carbon atoms and the other two represent hydrogen 
atoms, and n is preferably 4 or 5. 
It is to be understood that the structure 
##STR7## 
in general formula II and in subsequent formulae appearing in this 
specification represents an optionally substituted cyclobutyl, 
cyclopentyl, cyclohexyl or cycloheptyl group, and that one of the 
substituents R.sup.2, R.sup.3 and R.sup.4 may be attached to the carbon 
atom by which the cycloalkyl group is attached to the symbol B. 
The present invention is concerned with all compounds of general formula II 
in the optically active `natural` form or its enantiomeric form, or 
mixtures thereof, more particularly the racemic form, consisting of 
equimolecular mixtures of the optically active `natural` form and its 
enantiomeric form. 
As will be apparent to those skilled in the art, the compounds depicted in 
general formula II have at least five centres of chirality, these five 
centres of chirality being at the C-8, C-9, C-11, C-12 and C-15 carbon 
atoms. Still further centres of chirality may occur when R.sup.1, R.sup.2, 
R.sup.3 or R.sup.4 is a branched-chain alkyl group, or B or the moiety 
C.sub.p H.sub.2p or C.sub.q H.sub.2q is a branched-chain alkylene group. 
The presence of chirality leads as is well known to the existence of 
isomerism. However, the compounds of general formula II all have such a 
configuration that the substituent groups attached to the ring carbon 
atoms in positions identified as 8 and 12 are trans with respect to each 
other and that the substituent groups attached to the ring carbon atoms in 
the positions identified as 8 and 9 are cis with respect to each other. 
Accordingly, all isomers of general formula II, and mixtures thereof, 
which have those substituent groups attached to the ring carbon atoms in 
positions 8 and 12 in the trans-configuration, those attached in 8 and 9 
in the cis-configuration and have hydroxy groups as depicted in the 11- 
and 15-positions are to be considered within the scope of general formula 
II. 
Examples of the straight- or branched-chain alkyl group containing from 1 
to 12 carbon atoms represented by R.sup.1 are methyl, ethyl, propyl, 
butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and 
their isomers. 
Examples of the aralkyl group containing from 7 to 12 carbon atoms 
represented by R.sup.1 are benzyl, 1-phenylethyl, 2-phenylethyl, 
3-phenylbutyl, 4-phenylbutyl, 1-(2-naphthyl)ethyl and 2-(1-naphthyl)ethyl. 
Examples of the cycloalkyl group containing from 4 to 7 carbon atoms 
unsubstituted or substituted by at least one straight- or branched-chain 
alkyl group containing from 1 to 4 carbon atoms represented by R.sup.1 are 
cyclobutyl, 1-propylcyclobutyl, 1-butylcyclobutyl, 2-methylcyclobutyl, 
2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl, 
2,3,4-triethylcyclobutyl, cyclopentyl, 3-ethylcyclopentyl, 
3-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butylcyclopentyl, 
2,2-dimethylcyclopentyl, 1-methyl-3-propylcyclopentyl, 
2-methyl-3-propylcyclopentyl, 2-methyl-4-propylcyclopentyl, cyclohexyl, 
3-ethylcyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclohexyl, 
4-ethylcyclohexyl, 4-propylcyclohexyl, 4-tert-butylcyclohexyl, 
2,2-dimethylcyclohexyl, 2,6-dimethylcyclohexyl, 
2,6-dimethyl-4-propylcyclohexyl and cycloheptyl. 
Examples of the phenyl group unsubstituted or substituted by at least one 
substituent selected from the chlorine atom, the trifluoromethyl group, 
straight- or branched-chain alkyl groups containing from 1 to 4 carbon 
atoms and the phenyl group represented by R.sup.1 are phenyl, 
2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 
2,4,6-trichlorophenyl, 2-tolyl, 3-tolyl, 4-tolyl, 4-ethylphenyl, 
4-tert-butylphenyl, 4-sec-butylphenyl, 3-trifluoromethylphenyl and 
4-biphenyl. 
The straight- or branched-chain alkylene group represented by -C.sub.p 
H.sub.2p - and -C.sub.q H.sub.2q - may be methylene (when p in the 
-C.sub.p H.sub.2p - moiety is 1), ethylene, trimethylene, tetramethylene, 
pentamethylene, hexamethylene heptamethylene, octamethylene, 
nonamethylene, decamethylene, undecamethylene, dodecamethylene, and the 
isomers thereof, with straight-chain alkylene groups being preferable. 
Examples of the straight- or branched-chain alkyl groups containing from 1 
to 8 carbon atoms represented by R.sup.2, R.sup.3 and R.sup.4, are methyl, 
ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the isomers 
thereof. 
Examples of the straight- or branched-chain alkyl groups containing from 1 
to 4 carbon atoms represented by R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are 
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and 
tert-butyl. 
Examples of the straight- or branched-chain alkylene group containing from 
1 to 4 carbon atoms represented by B are methylene, ethylene, 
methylmethylene, trimethylene, 1-methylethylene, 2-methylethylene, 
ethylmethylene, dimethylmethylene, tetramethylene, 1-methyltrimethylene, 
2-methyltrimethylene, 3-methyltrimethylene, 1,1-dimethylethylethylene, 
1,2-dimethylethylene, 2,2-dimethylethylene, 1-ethylethylene, 
2-ethylethylene, methylethylmethylene, propylmethylene and 
isopropylmethylene. 
Preferably the 
##STR8## 
group represents cyclobutyl, 1-propylcyclobutyl, 1-butylcyclobutyl, 
1-pentylcyclobutyl, 1-hexylcyclobutyl, 2-methylcyclobutyl, 
2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl, 
2,3,4-triethylcyclobutyl, cyclopentyl, cyclopentylmethyl, 
1-cyclopentylethyl, 2-cyclopentylethyl, 2-cyclopentylpropyl, 
3-cyclopentylpropyl, 2-pentylcyclopentyl, 2,2-dimethylcyclopentyl, 
3-ethylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 
3-tert-butylcyclopentyl, (1-methyl-3-propyl)cyclopentyl, 
(2-methyl-3-propyl)cyclopentyl, (2-methyl-4-propyl)cyclopentyl, 
cyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, 
3-cyclohexylpropyl, (1-methyl-2-cyclohexyl)ethyl, 2-cyclohexylpropyl, 
(1-methyl-1-cyclohexyl)ethyl, 4-cyclohexylbutyl, 3-ethylcyclohexyl, 
3-isopropylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 
4-propylcyclohexyl, 4-butylcyclohexyl, 4-tert-butylcyclohexyl, 
2,6-dimethylcyclohexyl, 2,2-dimethylcyclohexyl, 
(2,6-dimethyl-4-propyl)cyclohexyl, 1-methylcyclohexylmethyl, cycloheptyl, 
cycloheptylmethyl, 1-cycloheptylethyl and 2-cycloheptylethyl: 
3-propylcyclopentyl, 1-cyclopentylethyl, cyclohexyl, 4-ethylcyclohexyl, 
4-propylcyclohexyl and 3-butylcyclopentyl are especially preferred. 
Examples of suitable non-toxic acid addition salts are the salts with 
inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic 
acid, sulphuric acid, phosphoric acid and nitric acid, and with organic 
acids such as acetic acid, propionic acid, lactic acid, tartaric acid, 
citric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic 
acid, toluenesulphonic acid, isethionic acid and succinic acid. 
According to a feature of the present invention, the prostaglandin I.sub.2 
analogues of general formula II, wherein the symbol attached to the 
6-position represents a double bond, and the other symbols are as 
hereinbefore defined, i.e. compounds of the general formula: 
##STR9## 
(wherein the various symbols are as hereinbefore defined) are prepared by 
cyclisation of a compound of the general formula: 
##STR10## 
[wherein the double bond between C.sub.5 -C.sub.6 is cis (i.e. Z) and the 
other symbols are as hereinbefore defined] in an inert organic solvent, 
e.g. toluene, benzene or acetonitrile, at a temperature from ambient to 
110.degree. C. 
If desired, products of general formula IIA may be purified by conventional 
means, e.g. by thin layer or column chromatography on silica gel, to give 
the pure PGI.sub.2 analogues. 
Esters of general formula III, wherein R.sup.1 is other than a hydrogen 
atom, and the other symbols are as hereinbefore defined, may be prepared 
by esterification of the corresponding acid of general formula III, 
wherein R.sup.1 represents a hydrogen atom, and the other symbols are as 
hereinbefore defined, by methods known per se (i.e. methods heretofore 
used or described in the chemical literature), for example, when R.sup.1 
is an alkyl group, by reaction with (1) a diazoalkane, (2) an alkyl 
halide, or (3) an N,N-dimethylformamidedialkyl acetal, or when R.sup.1 is 
an alkyl group or any other esterifying group within the definition of 
R.sup.1, (4) using dicyclohexylcarbodiimide (by the procedure described in 
our Japanese Patent No. 762305), (5) using a pivaloyl halide (by the 
procedure described in our British Patent No. 1364125), or (6) using an 
arylsulphonyl or alkylsulphonyl halide (by the procedure described in our 
British Patent No. 1362956). 
The preparation of esters using a diazoalkane is carried out by reacting 
the corresponding acid with an appropriate diazoalkane in an inert organic 
solvent, e.g. diethyl ether, ethyl acetate, methylene chloride, or 
acetone, or a mixture of two or more of them, at a temperature from 
ambient to -10.degree. C., preferably 0.degree. C. The preparation of 
estes using an alkyl halide is carried out by reacting the corresponding 
acid with an appropriate alkyl halide, e.g. methyl iodide, (i) in acetone 
in the presence of an alkali metal, e.g. potassium or sodium, carbonate 
[cf. J. Org. Chem., 34, 3717 (1969)], (ii) in N,N-dimethylacetamide or 
N,N-dimethylformamide in the presence of an alkali metal, e.g. potassium 
or sodium, bicarbonate [cf. Advan. Org. Chem., 5, 37 (1965)], or (iii) in 
dimethyl sulphoxide in the presence of calcium oxide [cf. Synthesis, 262 
(1972) ], at a temperature from 0.degree. C. to ambient. The preparation 
of esters using an N,N-dimethylformamide-dialkyl acetal is carried out by 
reacting the corresponding acid with an N,N-dimethylformamide-dialkyl 
acetal, e.g. N,N-dimethylformamide-dimethyl acetal, in anhydrous benzene 
[cf. Helv. Chem. Acta, 48, 1746 (1965)]. The preparation of esters using 
dicyclohexylcarbodiimide is carried out by reacting the corresponding acid 
with an appropriate alcohol R.sup.1 OH, wherein R.sup.1 is other than a 
hydrogen atom, in an inert organic solvent such as a halogenated 
hydrocarbon, e.g. chloroform or methylene chloride, in the presence of a 
base such as pyridine or picoline, preferably pyridine, at a temperature 
from 0.degree. C. to ambient. The preparation of esters using a pivaloyl, 
arylsulphonyl or alkylsulphonyl halide is carried out by reacting the 
corresponding acid with a tertiary amine, e.g. triethylamine or pyridine, 
and a pivaloyl halide, e.g. pivaloyl chloride, arylsulphonyl halide, e.g. 
p-toluenesulphonyl chloride or benzenesulphonyl chloride, or 
alkylsulphonyl halide, e.g. methanesulphonyl chloride or ethanesulphonyl 
chloride, in the presence or absence of an inert organic solvent such as a 
halogenated hydrocarbon, e.g. chloroform or methylene chloride, or diethyl 
ether, to prepare a mixed acid anhydride of the acid, and adding thereto, 
at a temperature from 0.degree. C. to ambient, an alcohol R.sup.1 OH, 
wherein R.sup.1 is other than a hydrogen atom, to obtain the esters. 
Compounds of general formula III, wherein R.sup.1 represents a hydrogen 
atom, or a straight- or branched-chain alkyl group containing from 1 to 4 
carbon atoms, and the other symbols are as hereinbefore defined, i.e. 
compounds of the general formula: 
##STR11## 
(wherein R.sup.9 represents a hydrogen atom or a straight- or 
branched-chain alkyl group containing from 1 to 4 carbon atoms, and the 
other symbols are as hereinbefore defined) may be prepared by reaction of 
a compound of the general formula: 
##STR12## 
(wherein R.sup.10 represents an alkylsulphonyl or arylsulphonyl group, and 
the other symbols are as hereinbefore defined) with a reagent for the 
replacement of the group OR.sup.10 by the azido group, e.g. sodium azide 
or lithium azide, in an inert organic solvent such as dimethyl sulphoxide, 
N,N-dimethylformamide or N,N-dimethylacetamide, at a temperature from 
ambient to 110.degree. C. 
Compounds of general formula V may be prepared by the series of reactions 
depicted schematically below in Scheme A, wherein R.sup.11 represents a 
tetrahydropyran-2-yl or tetrahydrofuran-2-yl group, each such group being 
unsubstituted or substituted by at least one alkyl group, or a 
1-ethoxyethyl group, R.sup.12 represents the benzoyl group, and the other 
symbols are as hereinbefore defined. 
##STR13## 
Referring to Scheme A, compounds of general formula VII may be prepared by 
reacting a compound of general formula VI with benzoic acid in the 
presence of triphenylphosphine and diethyl azodicarboxylate in 
tetrahydrofuran at ambient temperature, and may then be converted into 
compounds of general formula VIII by hydrolysis under alkaline conditions. 
The hydrolysis under alkaline conditions may be carried out with an 
aqueous solution of an alkali metal, e.g. potassium or sodium, hydroxide 
or carbonate in the presence of a water-miscible solvent such as an ether, 
e.g. dioxan or tetrahydrofuran, or a lower alkanol, e.g. methanol or 
ethanol, or with anhydrous potassium carbonate in an anhydrous lower 
alkanol, such as methanol, usually at ambient temperature. 
Compounds of general formula IX may also be converted into compounds of 
general formula VIII by methods known per se for the reduction of an oxo 
group in the 9-position of a prostaglandin E compound to a hydroxy group, 
for example by means of sodium borohydride in methanol. The product is a 
mixture of compounds of general formula VIII and those of general formula 
VI, and the mixture is separated by conventional means, for example by 
thin layer, column or high-speed liquid chromatography on silica gel to 
give each isomer. 
Compounds of general formula X may be prepared by sulphonylation of a 
compound of general formula VIII with an alkylsulphonyl halide such as 
methanesulphonyl chloride or ethanesulphonyl chloride, or an arylsulphonyl 
halide such as benzenesulphonyl chloride or p-toluenesulphonyl chloride, 
in an inert organic solvent such as methylene chloride in the presence of 
a tertiary amine such as triethylamine or pyridine, or in a basic solvent 
such as pyridine, at a temperature of -30.degree. to 50.degree. C. 
The conversion of compounds of general formula X to those of general 
formula V may be carried out by mild hydrolysis under acidic conditions 
with (1) an aqueous solution of an organic acid such as acetic acid, 
propionic acid, oxalic acid or p-toluenesulphonic acid, or an aqueous 
solution of an inorganic acid such as hydrochloric acid, sulphuric acid or 
phosphoric acid, advantageously in the presence of an inert organic 
solvent miscible with water, e.g. a lower alkanol such as methanol or 
ethanol, preferably methanol, or an ether such as 1,2-dimethoxyethane, 
dioxan or tetrahydrofuran, preferably tetrahydrofuran, at a temperature of 
ambient to 75.degree. C., preferably at a temperature below 45.degree. C., 
or (2) an anhydrous solution of an organic acid such as p-toluenesulphonic 
acid or trifluoroacetic acid in a lower alkanol such as methanol or 
ethanol at a temperature of 10.degree. to 45.degree. C., or (3) an 
anhydrous solution of p-toluenesulphonic acid-pyridine complex in a lower 
alkanol such as methanol or ethanol at a temperature of 10.degree. to 
60.degree. C. Advantageously the mild hydrolysis under acidic conditions 
may be carried out with a mixture of dilute hydrochloric acid and 
tetrahydrofuran, a mixture of dilute hydrochloric acid and methanol, a 
mixture of acetic acid, water and tetrahydrofuran, a mixture of phosphoric 
acid, water and tetrahydrofuran, a mixture of p-toluenesulphonic acid and 
methanol or a mixture of p-toluenesulphonic acid-pyridine complex and 
methanol. 
Starting materials of general formula VI or IX may be prepared by the 
methods described in the following patent specifications and applications, 
or obvious modifications thereof: Japanese Patent Kokai Nos. 50-13364, 
50-25549, 50-148339 and 51-68547, Japanese Patent Application No. 
52-88919, British Patent Specifications Nos. 1450691, 1464916, 1488141, 
1483240 and 1484210, British Patent Applications Nos. 30072/75 and 
18651/76, U.S. Pat. Nos. 3962312, 3966792, 4034003, 4024174, 4045468 and 
4087620 and Belgian Patent No. 844256. 
According to a further feature of the present invention, the prostaglandin 
I.sub.2 analogues of general formula II, wherein the symbol represents 
the single bond, and the other symbols are as hereinbefore defined, i.e. 
compounds of the general formula: 
##STR14## 
(wherein the absolute configuration of C.sub.6 is R or S or a mixture 
thereof, and the other symbols are as hereinbefore defined) are prepared 
by reduction of a compound of general formula IIA with a borohydride 
reducing reagent such as lithium borohydride, potassium borohydride, 
sodium borohydride, zinc borohydride or sodium cyanoborohydride, in an 
inert organic solvent such as a lower alkanol, e.g. methanol or ethanol, 
at a temperature from ambient to -20.degree. C. The product of general 
formula IIB, thus obtained, is a mixture of isomers in which the absolute 
configuration of C.sub.6 is R and S. If desired, the mixture may be 
separated by thin layer, column or high-speed liquid chromatography on 
silica gel to give each of the isomers. 
Esters of the PGI.sub.2 analogues of general formula II, wherein R.sup.1 
represents a staight- or branched-chain alkyl group, and the other symbols 
are as hereinbefore defined, may be prepared by esterification of the 
corresponding acid of general formula II, wherein R.sup.1 represents a 
hydrogen atom, by methods known per se, for example by reaction with the 
appropriate diazoalkane in an inert organic solvent, e.g. diethyl ether, 
ethyl acetate, methylene chloride, acetone or a mixture of two or more of 
them, at a temperature from ambient to -10.degree. C., preferably 
0.degree. C. 
Acids of the PGI.sub.2 analogues of general formula II, wherein R.sup.1 
represents a hydrogen atom, and the other symbols are as hereinbefore 
defined, may be prepared by saponification of the corresponding ester of 
general formula II, wherein R.sup.1 is other than a hydrogen atom, by 
methods known per se, for example by reaction with an aqueous solution of 
an alkali metal, e.g. sodium or potassium, or an alkaline earth metal, 
e.g. calcium or barium, hydroxide or carbonate in the presence of a 
water-miscible solvent such as an ether, e.g. dioxan or tetrahydrofuran, 
or a lower alkanol, e.g. methanol or ethanol, at a temperature from 
-10.degree. to 70.degree. C., preferably ambient temperature. 
Compounds of general formula II, wherein R.sup.1 represents a hydrogen 
atom, may, if desired, be converted by methods known per se into salts. 
Preferably the salts are non-toxic salts. By the term `non-toxic salts`, 
as used in this specification, is meant salts the cations (or in the case 
of acid addition salts referred to hereinafter the anions) of which are 
relatively innocuous to the animal organism when used in therapeutic doses 
so that the beneficial pharmacological properties of the compounds of 
general formula II are not vitiated by side-effects ascribable to those 
cations (or anions). Preferably the salts are water-soluble. Suitable 
non-toxic salts include the alkali metal, e.g. sodium or potassium, salts, 
the alkaline earth metal, e.g. calcium or magnesium, salts and ammonium 
salts, and pharmaceutically acceptable (i.e. non-toxic) amine salts. 
Amines suitable for forming such salts with carboxylic acids are well 
known and include, for example, amines derived in theory by the 
replacement of one or more of the hydrogen atoms of ammonia by groups, 
which may be the same or different when more than one hydrogen atom is 
replaced, selected from, for example, alkyl groups containing from 1 to 6 
carbon atoms and hydroxyalkyl groups containing 2 or 3 carbon atoms. 
Suitable non-toxic amine salts are, e.g. tetraalkylammonium, such as 
tetramethylammonium salts, and other organic amine salts such as 
methylamine salts, dimethylamine salts, cyclopentylamine salts, 
benzylamine salts, phenylethylamine salts, piperidine salts, 
monoethanolamine salts, diethanolamine salts, lysine salts and arginine 
salts. 
Salts may be prepared from the acids of general formula II, wherein R.sup.1 
represents a hydrogen atom, by methods known per se, for example by 
reaction of stoichiometric quantities of an acid of general formula II and 
the appropriate base, e.g. an alkali metal or alkaline earth metal 
hydroxide or carbonate, ammonium hydroxide, ammonia or an organic amine, 
in a suitable solvent. The salts may be isolated by lyophilisation of the 
solution or, if sufficiently insoluble in the reaction medium, by 
filtration, if necessary after removal of part of the solvent. 
The PGI.sub.2 analogues of general formula II may, if desired, be converted 
by methods known per se into acid addition salts, which are preferably 
non-toxic as hereinbefore defined. 
Acid addition salts may be prepared from the compounds of general formula 
II by methods known per se, for example by reaction of stoichiometric 
quantities of a compound of general formula II and the appropriate acid, 
e.g. an inorganic acid such as hydrochloric acid, hydrobromic acid, 
hydroiodic acid, sulphuric acid, phosphoric acid or nitric acid, or an 
organic acid such as acetic acid, propionic acid, lactic acid, tartaric 
acid, citric acid, methanesulphonic acid, ethanesulphonic acid, 
benzenesulphonic acid, toluenesulphonic acid, isethionic acid or succinic 
acid, in a suitable solvent. The acid addition salts may be purified by 
recrystallisation from a suitable solvent or suitable mixture of two or 
more solvents. 
The PGI.sub.2 analogues of general formula II and their non-toxic acid 
addition salts and, when R.sup.1 represents a hydrogen atom, their 
non-toxic salts, possess the valuable pharmacological properties typical 
of the prostaglandins in a selective fashion, in particular hypotensive 
activity, inhibitory activity on blood platelet aggregation and 
stimulatory activity on uterine contraction, and are useful in the 
treatment of hypertension, in the treatment of disorders of the peripheral 
circulation, in the prevention and treatment of cerebral thrombosis, 
myocardial infarction and arteriosclerosis. 
For example, in standard laboratory tests, (i) by intravenous 
administration to the allobarbital-anaesthetized dog, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-pro 
pyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester 
produces a fall in blood pressure of 14 mmHg and 36 mmHg lasting 9 and 24 
minutes at the doses of 1 and 2 .mu.g/kg animal body weight, respectively, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-pro 
pyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid produces a fall 
in blood pressure of 26 mmHg and 66 mmHg lasting 4 and 12 minutes at the 
doses of 0.5 and 2 .mu.g/kg animal body weight, respectively, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(4-pro 
pyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester 
produces a fall in blood pressure of 10 mmHg and 42 mmHg lasting 20 and 65 
minutes at the doses of 10 and 30 .mu.g/kg animal body weight, 
respectively, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(4-pro 
pyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid produces a fall 
in blood pressure of 26 mmHg and 38 mmHg lasting 9 and 11 minutes at the 
doses of 5 and 10 .mu.g/kg animal body weight, respectively, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-but 
yl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid produces a fall 
in blood pressure of 22 mmHg and 38 mmHg lasting 9 and 10 minutes at the 
doses of 1 and 2 .mu.g/kg animal body weight, respectively, and 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-but 
yl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester 
produces a fall in blood pressure of 12 mmHg and 32 mmHg lasting 26 and 40 
minutes at the doses of 4 and 10 .mu.g/kg animal body weight, 
respectively, and (ii) 
(13E)-(6RS,9.alpha.,11.alpha.,15.alpha.)-6,9-imino-11,15-dihydroxy-15-(3-p 
ropyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-pro 
pyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester, 
(13E)-( 
9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-propyl)cyc 
lopentyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(4-pro 
pyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(4-pro 
pyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-but 
yl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid and 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-but 
yl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester 
produce a 50% inhibition of adenosine diphosphate-induced blood platelet 
aggregation in platelet-rich plasma of rats at the concentrations of 21.5, 
2.07.times.10.sup.-2, 2.15.times.10.sup.-2, 9.9.times.10.sup.-2, 
9.5.times.10.sup.-2, 3.5.times.10.sup.-2 and 2.8.times.10.sup.-2 .mu.g/ml, 
respectively, in comparison with controls. 
Preferred PGI.sub.2 analogues of the present invention are as follows: 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-cyclob 
utyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(1-pro 
pyl)cyclobutyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(1-but 
yl)cyclobutyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15- 
dihydroxy-15-(1-pentyl)cyclobutyl-16,17,18,19,20-pentanorprost-13-enoic 
acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(1- 
hexyl)cyclobutyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(2-met 
hyl)cyclobutyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)--(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(2-pr 
opyl)cyclobutyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-eth 
yl)cyclobutyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-pro 
pyl)cyclobutyl-16,17,18,19,20-pentanorprost- 13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(2,3,4 
-triethyl)cyclobutyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-cyclop 
entyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-16-cyclop 
entyl-17,18,19,20-tetranorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-17-cyclop 
entyl-18,19,20-trinorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-16-cyclop 
entyl-18,19,20-trinorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-18-cyclop 
entyl-19,20-dinorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-17-cyclop 
entyl-19,20-dinorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(2-pen 
tyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(2,2-d 
imethyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-eth 
yl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-pro 
pyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid, ( 
13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-buty 
l)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-ter 
t-butyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(1-met 
hyl-3-propyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(2-met 
hyl-3-propyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(2-met 
hyl-4-propyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-cycloh 
exyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-16-cycloh 
exyl-17,18,19,20-tetranorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-17-cycloh 
exyl-18,19,20- trinorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-16-cycloh 
exyl-18,19,20-trinorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-18-cycloh 
exyl-19,20-dinorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-16-methyl 
-17-cyclohexyl-18,19,20-trinorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy- 
17-cyclohexyl-19,20-dinorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-11,15-dihydroxy-16- 
methyl-16-cyclohexyl-18,19,20-trinorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-19-cycloh 
exyl-20-norprost-13-enoic acid, (13E)-(9.alpha.,11.alpha., 
15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-ethyl)cyclohexyl-16,17,18,19, 
20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-iso 
propyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(4-met 
hyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(4-eth 
yl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(4-pro 
pyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(4-ter 
t-butyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(2,6-d 
imethyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(2,2-d 
imethyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15 
-dihydroxy-15-(2,6-dimethyl-4-propyl)cyclohexyl-16,17,18,19,20-pentanorpro 
st-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-16-(1-met 
hyl)cyclohexyl-17,18,19,20-tetranorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-cycloh 
eptyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-16-cycloh 
eptyl-17,18,19,20-tetranorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-17-cycloh 
eptyl-18,19,20-trinorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-16-cycloh 
eptyl-18,19,20-trinorprost-13-enoic acid and the corresponding PGI.sub.2 
analogues of general formula II in which the 6,9-nitrilo group is replaced 
by the 6,9-imino group, and esters, non-toxic salts and non-toxic acid 
addition salts thereof. 
Particularly preferred PGI.sub.2 analogues of the present invention are the 
esters 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-pro 
pyl)cyclopentyll-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-16-cyclop 
entyl-18,19,20-trinorprost-13-enoic acid methyl ester, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-cycloh 
exyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(4-eth 
yl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester. 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(4-pro 
pyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-but 
yl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester, and 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-imino-11,15-dihydroxy-15-(3-propy 
l)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester and 
their non-toxic acid addition salts, and the acids 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-pro 
pyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid, 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(4-pro 
pyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid, and 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-but 
yl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid, and their 
non-toxic salts and non-toxic acid addition salts. 
The following Reference Examples and Examples illustrate the preparation of 
prostaglandin I.sub.2 analogues of the present invention. In the Reference 
Examples and Examples `TLC`, `IR`, `NMR` and `MS` represent respectively 
`Thin layer chromatography`, `Infrared absorption spectrum`, `Nuclear 
magnetic resonance spectrum` and `Mass spectrum`. Where solvent ratios are 
specified in chromatographic separations, the ratios are by volume: the 
solvents in parentheses show the developing solvent used. Except when 
specified otherwise, infrared spectra are recorded by the liquid film 
method, and nuclear magnetic resonance spectra are recorded in 
deuterochloroform (CDCl.sub.3) solution. By the expression "50% (v/v) 
saturated aqueous solution of sodium chloride" is meant a saturated 
solution to which an equal volume of water has been added.

REFERENCE EXAMPLE 1 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-Benzoyloxy-11,15-bis(tetrahydropyr 
an-2-yloxy)-15-(3-propyl)cyclopentyl-16,17,18,19,20-pentanorprosta-5,13-die 
noic acid methyl ester 
To a mixture of 1.04 g of 
(5Z,13E)-(9.alpha.,11.alpha.,15.alpha.)-9-hydroxy-11,15-bis(tetrahydropyra 
n-2-yloxy)-15-(3-propyl)cyclopentyl-16,17,18,19,20-pentanorprosta-5,13-dien 
oic acid methyl ester, 709 mg of triphenylphosphine, 329 mg of benzoic acid 
and 15 ml of tetrahydrofuran, was added dropwise 0.47 ml of diethyl 
azodicarboxylate, and the mixture was stirred at room temperature for 2 
hours. The reaction mixture was diluted with ethyl acetate, washed with 1 
N hydrochloric acid, water, a saturated aqueous solution of sodium 
bicarbonate, water and a saturated aqueous solution of sodium chloride, 
dried over sodium sulphate, and concentrated under reduced pressure. The 
residue was purified by column chromatography on silica gel using a 
mixture of cyclohexane and ethyl acetate (10:1) as eluent to give 989 mg 
of the title compound having the following physical characteristic: 
TLC (cyclohexane:ethyl acetate=4:1): Rf=0.69. 
REFERENCE EXAMPLE 2 
(5Z,13E)-(9.alpha.,11.alpha.,15.alpha.)-9-Hydroxy-11,15-bis 
(tetrahydropyran-2-yloxy)-15-(3-propyl)cyclopentyl-16,17,18,19,20-pentanor 
prosta-5,13-dienoic acid methyl ester 
A mixture of 989 mg of the 9-benzoyloxy compound, prepared as described in 
Reference Example 1, 240 mg of potassium carbonate and 10 ml of methanol 
was stirred at 40.degree. C. for 5 hours. The reaction mixture was diluted 
with ethyl acetate, washed with 1 N hydrochloric acid, water, a saturated 
aqueous solution of sodium bicarbonate, water and a saturated aqueous 
solution of sodium chloride, dried over magnesium sulphate, and 
concentrated under reduced pressure. The residue was purified by column 
chromatography on silica gel using a mixture of cyclohexane and ethyl 
acetate (2:1) as eluent to give 523 mg of the title compound having the 
following physical characteristic: 
TLC (cyclohexane:ethyl acetate=4:1): Rf=0.24. 
REFERENCE EXAMPLE 3 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-(p-Toluenesulphonyloxy)-11,15-bis( 
tetrahydropyran-2-yloxy)-15-(3-propyl)cyclopentyl-16,17,18,19,20-pentanorpr 
osta-5,13-dienoic acid methyl ester 
A mixture of 523 mg of the 9.beta.-hydroxy compound, prepared as described 
in Reference Example 2, 346 mg of p-toluenesulphonyl chloride and 1.46 ml 
of pyridine was stirred at room temperature for 17 hours. The reaction 
mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, 
water, a saturated aqueous solution of sodium bicarbonate, a 50% (v/v) 
saturated aqueous solution of sodium chloride and a saturated aqueous 
solution of sodium chloride, dried over sodium sulphate, and concentrated 
under reduced pressure. The residue was purified by column chromatography 
on silica gel using a mixture of cyclohexane and ethyl acetate (4:1) as 
eluent to give 638 mg of the title compound having the following physical 
characteristics: 
TLC (benzene:ethyl acetate=4:1) Rf=0.61; 
IR:.nu.=1740, 1600, 980 cm.sup.-1 ; 
NMR:.delta.=7.80(2H,d), 7.34(2H,d), 5.62-5.10(4H,m), 4.75-4.50(3H,m), 
3.69(3H,s), 2.47(3H,s), 2.30(2H,t); 
MS:m/e=544, 372, 172. 
REFERENCE EXAMPLE 4 
The following compounds were prepared by the same procedure as described in 
Reference Examples 1, 2 and 3 replacing the 
(5Z,13E)-(9.alpha.,11.alpha.,15.alpha.)-9-hydroxy-11,15-bis(tetrahydropyra 
n-2-yloxy)-15-(3-propyl)-cyclopentyl-16,17,18,19,20-pentanorprosta-5,13-die 
noic acid methyl ester by the indicated starting materials:- (1) 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-(p-Toluenesulphonyloxy)-11,15-bis 
(tetrahydropyran-2-yloxy)-16-cyclopentyl-18,19,20-trinorprosta-5,13-dienoic 
acid methyl ester using as starting material 
(5Z,13E)-(9.alpha.,11.alpha.,15.alpha.)-9-hydroxy-11,15-bis(tetrahydropyra 
n-2-yloxy)-16-cyclopentyl-18,19,20-trinorprosta-5,13-dienoic acid methyl 
ester. 
TLC (benzene:ethyl acetate=4:1) Rf=0.62; 
IR:.nu.=1740, 1600, 980 cm.sup.-1 ; 
NMR:.delta.=7.79(2H,d), 7.33(2H,d), 5.6-5.1(4H,m), 4.80-4.50 (3H,m), 
3.68(3H,s), 2.46(3H,s), 2.31(2H,t), 0.88(3H,m); 
MS:m/e=530, 358, 172. (2) 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-(p-Toluenesulphonyloxy)-11,15-bis 
(tetrahydropyran-2-yloxy)-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13- 
dienoic acid methyl ester using as starting material 
(5Z,13E)-(9.alpha.,11.alpha.,15.alpha.)-9-hydroxy-11,15-bis(tetrahydropyra 
n-2-yloxy)-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid 
methyl ester. 
TLC (benzene:ethyl acetate=4:1) Rf=0.67; 
IR:.nu.=1740, 1600, 980 cm.sup.-1 ; 
NMR:.delta.=7.80(2H,d), 7.34(2H,d), 5.6-5.1(4H,m), 4.77-4.45 (3H,m), 
3.70(3H,s), 2.48(3H,s), 2.30(2H,t); 
MS:m/e=516, 344, 172. (3) 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-(p-Toluenesulphonyloxy)-11,15-bis 
(tetrahydropyran-2-yloxy)-15-(4-ethyl)cyclohexyl-16,17,18,19,20-pentanorpro 
sta-5,13-dienoic acid methyl ester using as starting material 
(5Z,13E)-(9.alpha.,11.alpha.,15.alpha.)-9-hydroxy-11,15-bis(tetrahydropyra 
n-2-yloxy)-15-(4-ethyl)cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoi 
c acid methyl ester. 
TLC (benzene:ethyl acetate=4:1) Rf=0.65; 
IR:.nu.=1740, 1600, 980 cm.sup.-1 ; 
NMR:.delta.=7.81(2H,d), 7.35(2H,d), 5.6-5.1(4H,m), 4.80-4.50 (3H,m), 
3.69(3H,s), 2.47(3H,s), 2.30(2H,t), 0.85(3H,t); 
MS:m/e=544, 372, 172. (4) 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-(p-Toluenesulphonyloxy)-11,15-bis 
(tetrahydropyran-2-yloxy)-15-(4-propyl)cyclohexyl-16,17,18,19,20-pentanorpr 
osta-5,13-dienoic acid methyl ester using as starting material 
(5Z,13E)-(9.alpha.,11.alpha.,15.alpha.)-9-hydroxy-11,15-bis(tetrahydropyra 
n-2-yloxy)-15-(4-propyl)cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dieno 
ic acid methyl ester. 
TLC (cyclohexane:ethyl acetate=1:1) Rf=0.67; 
IR:.nu.=2970, 2950, 1745, 1605 cm.sup.-1 ; 
NMR:.delta.=7.36(4H,q), 5.5-5.0(4H,m), 4.6-4.3(2H,m), 3.51(3H,s), 
2.36(3H,s). (5) 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-(p-Toluenesulphonyloxy)-11,15-bis 
(tetrahydropyran-2-yloxy)-15-(3-butyl)cyclopentyl-16,17,18,19,20-pentanorpr 
osta-5,13-dienoic acid methyl ester using as starting material 
(5Z,13E)-(9.alpha.,11.alpha.,15.alpha.)-9-hydroxy-11,15-bis(tetrahydropyra 
n-2-yloxy)-15-(3-butyl)cyclopentyl-16,17,18,19,20-pentanorprosta-5,13-dieno 
ic acid methyl ester. 
TLC (cyclohexane:ethyl acetate=3:1) Rf=0.49; 
IR:.nu.=1600, 1500 cm.sup.1. 
REFERENCE EXAMPLE 5 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-(p-Toluenesulphonyloxy)-11,15-dihy 
droxy-15-(3-propyl)cyclopentyl-16,17,18,19,20-pentanorprosta-5,13-dienoic 
acid methyl ester 
A mixture of 300 mg of the 11,15-bis(tetrahydropyran-2-yloxy) compound 
prepared as described in Reference Example 3, 10 mg of p-toluenesulphonic 
acid-pyridine complex and 4 ml of methanol was stirred at 50.degree. C. 
for one hour. The reaction mixture was diluted with ethyl acetate, washed 
with water, a 50% (v/v) saturated aqueous solution of sodium chloride and 
a saturated aqueous solution of sodium chloride, dried over sodium 
sulphate, and concentrated under reduced pressure. The residue was 
purified by column chromatography on silica gel using a mixture of 
cyclohexane and ethyl acetate (1:1) as eluent to give 198 mg of the title 
compound having the following physical characteristics: 
TLC (benzene:ethyl acetate=1:1) Rf=0.50; 
IR:.nu.=3400, 1740, 1600, 980 cm.sup.-1 ; 
NMR:.delta.=7.78(2H,d), 7.34(2H,d), 5.54-5.10(4H,m), 4.69-4.48(1H,m), 
3.68(3H,s), 2.46(3H,s), 2.29(2H,t); 
MS:m/e=372, 354, 172. 
The following compounds were prepared from the corresponding 
11,15-bis(tetrahydropyran-2-yloxy) compounds, prepared as described in 
Reference Example 4, by the same procedure as described above: 
(1) 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-(p-Toluenesulphonyloxy)-11,15,-di 
hydroxy-16-cyclopentyl-18,19,20-trinorprosta-5,13-dienoic acid methyl ester 
from the product of Reference Example 4(1): 
TLC (benzene:ethyl acetate=1:1) Rf=0.52; 
IR:.nu.=3400, 1740, 1600, 980 cm.sup.-1 ; 
NMR:.delta.=7.77(2H,d), 7.33(2H,d), 5.6-5.1(4H,m), 4.68-4.48 (1H,m), 
3.67(3H,s), 2.45(3H,s), 2.30(2H,t), 0.87(3H,m). 
(2) 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-(p-Toluenesulphonyloxy)-11,15-dih 
ydroxy-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl 
ester from the product of Reference Example 4(2): 
TLC (benzene:ethyl acetate=1:1) Rf=0.57; 
IR:.nu.=3400, 1740, 1600, 980 cm.sup.-1 ; 
NMR:.delta.=7.78(2H,d), 7.34(2H,d), 5.6-5.1(4H,m), 4.70-4.50 (1H,m), 
3.69(3H,s), 2.47(3H,s), 2.29(2H,t); 
MS:m/e=344, 326, 172. 
(3) 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-(p-Toluenesulphonyloxy)-11,15-dih 
ydroxy-15-(4-ethyl)cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoic 
acid methyl ester from the product of Reference Example 4(3): 
TLC (benzene:ethyl acetate=1:1) Rf=0.55; 
IR:.nu.=3400, 1740, 1600, 980 cm.sup.-1 ; 
NMR:.delta.=7.79(2H,d), 7.35(2H,d), 5.6-5.1(4H,m), 4,69-4.50 (1H,m), 
3.68(3H,s), 2.46(3H,s), 2.29(2H,t), 0.84(3H,t). 
(4) 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-(p-Toluenesulphonyloxy)-11,15-dih 
ydroxy-15-(4-propyl)cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoic 
acid methyl ester from the product of Reference Example 4(4): 
TLC (ethyl acetate:cyclohexane=1:1) Rf=0.24; 
IR:.nu.=2970, 2950, 2870, 1745, 1605 cm.sup.-1 ; 
NMR:.delta.=7.36(4H,q), 5.5-5.0(4H,m), 3.51(3H,s), 2.33(3H,s); 
MS:m/e=386, 368, 325, 271, 172, 91. 
(5) (5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9 
-(p-Toluenesulphonyloxy)-11,15-dihydroxy-15-(3-butyl)cyclopentyl-16,17,18, 
19,20-pentanorprosta-5,13-dienoic acid methyl ester from the product of 
Reference Example 4(5): 
TLC (ethyl acetate:cyclohexane=1:1) Rf=0.10; 
IR:.nu.=3400, 3020, 2970, 2940, 2870, 1745, 1601, 1500, 1440, 1370, 1190, 
1180, 1100, 980, 890 cm.sup.-1 ; 
NMR:.delta.=7.7(2H,d), 7.3(2H,d), 5.7-5.0(4H,m), 4.8-4.3(1H,m), 
4.3.-3.3(2H,m), 3.7(3H,s), 2.4(3H,s), 1.1-0.5(3H,t); 
MS:m/e=386, 368, 355, 342, 337, 329, 311, 285, 245, 227, 205, 91. 
EXAMPLE 1 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-Azido-11,15-dihydroxy-15-(3-propy 
l)cyclopentyl-16,17,18,19,20-pentanorprosta- 5,13-dienoic acid methyl ester 
A mixture of 182 mg of the title 9-(p-toluenesulphonyloxy) compound, 
prepared as described in Reference Example 5, 43 mg of sodium azide and 3 
ml of dimethyl sulphoxide was stirred at 50.degree.-55.degree. C. for two 
hours. The reaction mixture was diluted with ethyl acetate, washed with 
water and a saturated aqueous solution of sodium chloride, dried over 
sodium sulphate and concentrated under reduced pressure. The residue was 
purified by column chromatography on silica gel using a mixture of 
cyclohexane and ethyl acetate (1:2) as eluent to give 113 mg of the title 
compound having the following physical characteristics: 
TLC (benzene:ethyl acetate=1:2) Rf=0.42; 
IR:.nu.=3380, 2120, 1745, 980 cm.sup.-1 ; 
NMR:.delta.=5.60-5.20(4H,m), 4.03-3.74(3H,m), 3.67(3H,s), 2.32(2H,t). 
The following compounds were prepared from the corresponding 
9-(p-toluenesulphonyloxy) compounds prepared as described in Reference 
Example 5, by the same procedure as described above. 
(1) (5Z,13E)-(9.beta.,11.alpha., 
15.alpha.)-9-Azido-11,15-dihydroxy-16-cyclopentyl-18,19,20-trinorprosta-5, 
13-dienoic acid methyl ester from the product of Reference Example 5(1): 
TLC (benzene:ethyl acetate=1.2) Rf=0.43; 
IR:.nu.=3400, 2120, 1740, 980 cm.sup.-1 ; 
NMR:.delta.=5.57-5.13(4H,m), 4.10-3.75(3H,m), 3.66(3H,s), 2.33(2H,t), 
0.87(3H,m). 
(2) 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-Azido-11,15-dihydroxy-15-cyclohex 
yl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester from the 
product of Reference Example 5(2): 
TLC (benzene:ethyl acetate=1:2) Rf=0.48; 
IR:.nu.=3400, 2120, 1745, 980 cm.sup.-1 ; 
NMR:.delta.=5.62-5.18(4H,m), 4.05-3.78(3H,m), 3.68(3H,s), 2.31(2H,t). 
(3) 
(5Z,13E)-(9.beta.,11.alpha.,15.alpha.)-9-Azido-11,15-dihydroxy-15-(4-ethyl 
)cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester 
from the product of Reference Example 5(3): 
TLC (benzene:ethyl acetate=1:2) Rf=0.45; 
IR:.nu.=3400, 2120, 1740, 980 cm.sup.-1 ; 
NMR:.delta.=5.55-5.10(4H,m), 4.12-3.76(3H,m), 3.67(3H,s), 2.32(2H,t), 
0.86(3H,t). 
(4) 
(5Z,13E)-(9.alpha.,11.alpha.,15.alpha.)-9-Azido-11,15-dihydroxy-15-(4-prop 
yl)cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester 
from the product of Reference Example 5(4): 
TLC (ethyl acetate:methanol=9:1) Rf=0.46; 
IR:.nu.=2970, 2950, 2880, 2130, 1750 cm.sup.-1 ; 
NMR:.delta.=5.54-5.00(4H,m), 3.51(3H,s); 
MS:m/e=419, 402, 401, 390, 388, 376, 357, 346, 332, 294, 266, 264. 
(5) 
(5Z,13E)-(9.alpha.,11.alpha.,15.alpha.)-9-Azido-11,15-dihydroxy-15-(3-buty 
l)cyclopentyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester 
from the product of Reference Example 5(5): 
TLC (ethyl acetate:cyclohexane=3:1) Rf=0.51; 
IR:.nu.=3400, 3050, 2950, 2870, 2120, 1745, 1650, 1440, 1250, 970 cm.sup.-1 
; 
NMR:.delta.=6.0-5.0(4H,m), 4.5-3.5(3H,m), 3.7(3H,s), 1.1-0.6(3H,t); 
MS:m/e=419, 401, 398, 319, 294. 
EXAMPLE 2 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-Nitrilo-11,15-dihydroxy-15- 
(3-propyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl 
ester 
A mixture of 100 mg of the 9-azido compound, prepared as described in 
Example 1, and 2 ml of toluene was stirred at 55.degree.-60.degree. C. for 
20 hours. The reaction mixture was purified by column chromatography on 
silica gel using a mixture of ethyl acetate and methanol (9:1) as eluent 
to give 81 mg of the title compound having the following physical 
characteristics: 
TLC (ethyl acetate:methanol=3:1) Rf=0.70; 
IR:.nu.=3380, 1745, 1640, 980 cm.sup.-1 ; 
NMR:.delta.=5.61-5.45(2H,m), 4.54-4.24(1H,m), 3.97-3.40(4H,m), 3.70(3H,s); 
MS:m/e=405, 387, 374, 369, 332, 318, 305, 294. 
The following compounds were prepared from the corresponding 9-azido 
compounds, prepared as described in Example 1, by the same procedure as 
described above. 
(1) (13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-Nitrilo-11,15-dihydroxy-16- 
cyclopentyl-18,19,20-trinorprost-13-enoic acid methyl ester from the 
product of Example 1(1): 
TLC (ethyl acetate:methanol=3:1) Rf=0.72; 
IR:.nu.=3380, 1745, 1640, 980 cm.sup.-1 ; 
NMR:.delta.=5.63-5.42(2H,m), 4.55-4.25(1H,m), 4.00-3.41(2H,m), 3.68(3H,s), 
0.89(3H,m); 
MS:m/e=391, 373, 360, 355, 318, 304, 291, 280. 
(2) 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-Nitrilo-11,15-dihydroxy-15-cycloh 
exyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester from the 
product of Example 1(2): 
TLC (ethyl acetate:methanol=3:1) Rf=0.78; 
IR:.nu.=3380, 1745, 1640, 980 cm.sup.-1 ; 
NMR:.delta.=5.65-5.47(2H,m), 4.51-4.21(1H,m), 4.02-3.45(2H,m), 3.69(3H,s); 
MS:m/e=377, 359, 346, 341, 304, 290, 277, 266. 
(3) 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-Nitrilo-11,15-dihydroxy-15-(4-eth 
yl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester from 
the product of Example 1(3): 
TLC (ethyl acetate:methanol=3:1) Rf=0.76; IR:.nu.=3380, 1745, 1640, 980 
cm.sup.-1 ; NMR: .delta.=5.60-5.43(2H,m), 4.52-4.23(1H,m), 
4.00-3.40(2H,m), 3.70(3H,s), 0.88(3H,t); 
MS: m/e=405, 387, 374, 369, 332, 318, 305, 294. 
(4) 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-Nitrilo-11,15-dihydroxy-15-(4-pro 
pyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester from 
the product of Example 1(4): TLC (ethyl acetate:methanol=7:3) Rf=0.50; 
IR:.nu.=2970, 2950, 2870, 1745, 1640, 1440 cm.sup.-1 ; NMR: 
.delta.=5.58-5.35(2H,m), 4.5-4.1(1H,m), 3.66(3H,s), 3.9-3.5(2H,m); 
MS: m/e=402, 401, 390, 388, 376, 357, 346, 332, 294, 266, 264. 
(5) 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-Nitrilo-11,15-dihydroxy-15-(3-but 
yl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester from 
the product of Example 1(5): 
TLC (ethyl acetate:methanol=9:1) Rf=0.16; IR:.nu.=3350, 2950, 2870, 1745, 
1640, 1440, 1090, 970 cm.sup.-1 ; NMR:.delta.=5.6-5.4(2H,m), 
4.5-4.1(1H,m), 4.0-3.5(2H,m), 3.66(3H,s), 1.0-0.7(3H,t); 
MS: m/e=419, 401, 388, 319, 294. 
EXAMPLE 3 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-Nitrilo-11,15-dihydroxy-15-(3-prop 
yl)cyclopentyl-16,17,18,19, 20-pentanorprost-13-enoic acid 
A mixture of 74 mg of the methyl ester, prepared as described in Example 2, 
0.40 ml of 0.5N aqueous sodium hydroxide and 1.5 ml of methanol was 
stirred at 35.degree. C.-40.degree. C. for 3.5 hours. The reaction mixture 
was concentrated under reduced pressure. The residue was dissolved in 
water, washed with diethyl ether, and the aqueous layer was neutralized 
with 0.349 ml of 0.5N hydrochloric acid, and then concentrated under 
reduced pressure. The residue was dissolved in isopropanol, filtered, and 
the filtrate was concentrated under reduced pressure to give 67 mg of the 
title compound having the following physical characteristics: 
TLC (methanol:ethyl acetate=1:1) Rf=0.34; IR:.nu.=3350, 1720, 1645, 980 
cm.sup.-1 ; NMR:.delta.=6.00-5.38(5H,m), 4.63-4.34(1H,m), 4.04-3.73(2H,m). 
The following compounds were prepared from the corresponding methyl ester, 
prepared as described in Example 2, by the same procedure as described 
above. (1) 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-Nitrilo-11,15-dihydroxy-15-(4-pro 
pyl)cyclohexyl-16,17,18,19,20-pentanorprost-13-enoic acid from the product 
of Example 2(4): 
TLC (methanol:ethyl acetate=1:1) Rf=0.32; 
IR:.nu.=2980, 2950, 2880, 1720, 1645, 1575 cm.sup.-1 ; 
NMR:.delta.=5.60-5.37(2H,m), 4.6-3.5(3H,m); 
MS:m/e=405, 387, 376, 362, 319, 280. 
(2) 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-Nitrilo-11,15-dihydroxy-15-(3-but 
yl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid from the product 
of Example 2(5): TLC (methanol:ethyl acetate=1:1) Rf=0.37; 
IR:.nu.=3450, 2950, 2870, 2500, 1720, 1640, 1570, 1090, 1040, 970 cm.sup.-1 
; 
NMR: (CD.sub.3 OD solution): .delta.=5.7-5.4(2H,m), 4.7-4.2(1H,m), 
4.0-3.6(2H,m), 1.0-0.7(3H,t); 
MS: m/e=405, 387, 369, 319, 280, 262, 244, 162. 
EXAMPLE 4 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-Imino-11,15-dihydroxy-15-(3-propyl 
)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester 
A mixture of 19 mg of the 6,9-nitrilo compound, prepared as described in 
Example 2, 8.8 mg of sodium borohydride and 1 ml of methanol was stirred 
at ambient temperature for 10 minutes, and water was then added. The 
mixture was stirred at ambient temperature for 20 minutes, and extracted 
with chloroform. The extract was dried over magnesium sulphate, and 
concentrated under reduced pressure. The residue was purified by 
recrystallisation with a mixture of ethyl acetate and hexane to give 5 mg 
of the title compound having the following physical characteristics: 
TLC (methanol) Rf=0.15; 
IR:.nu.=3350, 1745, 980 cm.sup.-1 ; 
NMR:.delta.=5.61-5.40(2H,m), 4.00-3.55(5H,m), 3.67(3H,s), 2.62(3H,bs), 
2.32(2H,t). 
The present invention includes within its scope pharmaceutical compositions 
which comprise at least one new therapeutically useful compound of general 
formula II or non-toxic acid addition salt thereof or, when R.sup.1 in 
formula II represents a hydrogen atom, non-toxic salt thereof, together 
with a pharmaceutical carrier or coating. In clinical practice the new 
compounds of the present invention will normally be administered orally, 
vaginally, rectally or parenterally. 
Solid compositions for oral administration include compressed tablets, 
pills, dispersible powders and granules. In such solid compositions one or 
more of the active compounds is, or are, admixed with at least one inert 
diluent such as calcium carbonate, potato starch, alginic acid, lactose or 
mannitol. The compositions may also comprise, as is normal practice, 
additional substances other than inert diluents, e.g. lubricating agents 
such as magnesium stearate. Liquid compositions for oral administration 
include pharmaceutically-acceptable emulsions, solutions, suspensions, 
syrups and elixirs containing inert diluents commonly used in the art, 
such as water and liquid paraffin. Besides inert diluents such 
compositions may also comprise adjuvants such as wetting and suspending 
agents, and sweetening, flavouring, perfuming and preserving agents. The 
compositions according to the invention, for oral administration, also 
include capsules of absorbable material such as gelatin containing one or 
more of the active substances with or without the addition of diluents or 
excipients. 
Solid compositions for vaginal administration include pessaries formulated 
in manner known per se and containing one or more of the active compounds. 
Solid compositions for rectal administration include suppositories 
formulated in manner known per se and containing one or more of the active 
compounds. 
Preparations according to the invention for parenteral administration 
include sterile aqueous or non-aqueous solutions, suspensions, or 
emulsions. Examples of non-aqueous solvents or suspending media are 
propylene glycol, polyethylene glycol, vegetable oils such as olive oil, 
and injectable organic esters such as ethyl oleate. These compositions may 
also include adjuvants such as preserving, wetting, emulsifying and 
dispersing agents. They may be sterilised, for example by filtration 
through a bacteria-retaining filter, by incorporation of sterilising 
agents in the compositions or by irradiation. They may also be 
manufactured in the form of sterile solid compositions, which can be 
dissolved in sterile water or some other sterile injectable medium 
immediately before use. 
The percentage of active ingredient in the compositions of the invention 
may be varied, it being necessary that it should constitute a proportion 
such that a suitable dosage for the therapeutic effect desired shall be 
obtained. Obviously several unit dosage forms may be administered at about 
the same time. In general, the preparations should normally contain at 
least 0.025% by weight of active substance when required for 
administration by injection; for oral administration the preparations will 
normally contain at least 0.1% by weight of active substance. The dose 
employed depends upon the desired therapeutic effect, the route of 
administration and the duration of the treatment. 
In the human adult, each dose per person is generally between 0.05 and 500 
.mu.g by parenteral administration in the treatment of hypertension or 
disorders of the peripheral circulation, and between 0.05 and 500 .mu.g by 
parenteral administration in the prevention and treatment of cerebral 
thrombosis, myocardial infarction and arteriosclerosis. 
The following Example illustrates pharmaceutical compositions according to 
the invention. 
EXAMPLE 5 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-Nitrilo-11,15-dihydroxy-15-(3-prop 
yl)cyclopentyl-16,17,18,19,20-pentanorprost-13- enoic acid methyl ester 
(500 .mu.g) was dissolved in ethanol (5 ml). The solution was then 
sterilised by passage through a bacteria-retaining filter and placed in 
0.1 ml portions in 1 ml ampoules, to give 10 .mu.g of 
(13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(3-pro 
pyl)cyclopentyl-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester per 
ampoule. The ampoules were sealed. The contents of an ampoule diluted to a 
suitable volume, e.g. with 1 ml of tris-HCl-buffer solution (pH 8.6), gave 
a solution ready for administration by injection.