CYCLOPENTANE DERIVATIVES

DERIVES DE CYCLOPENTANE

English Abstract

ABSTRACT OF THE DISCLOSURE
The disclosure relates to novel 17,18,19,20-tetranor-
prostanoic acid derivatives having prostaglandin-type properties,
to a method for their manufacture, and also to pharmaceutical
or veterinary compositions containing said novel derivatives and
a method of inducing luteolysis in an animal host by use of said
novel derivatives.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of a prostanoic acid derivative of
the formula:-
<IMG> I
wherein R1 is a hydroxymethyl or carboxy radical, or an alkoxycarbonyl
radical of up to 11 carbon atoms, R2 is a hydroxy radical or an alkanoyloxy
radical of 1 to 4 carbon atoms and R3 is a hydrogen atom or R2 and R3 together
form an oxo radical, A is an ethylene or trans-vinylene radical, X is a
methylene radical, bearing 0, 1 or 2 alkyl substituents each of 1 to 3 carbon
atoms, or a trimethylene radical, Y is an oxygen or sulphur atom, a sulphinyl
radical or an alkylimino (-NAlkyl-) radical of 1 to 4 carbon atoms, and R4 is
a benzyl or furfuryl radical, or a phenyl or naphthyl radical which is unsub-
stituted or which is substituted by not more than two chlorine, bromine or
fluorine atoms, hydroxy, nitro, trifluoromethyl, or phenyl radicals, alkyl,
alkenyl or alkoxy radicals each of 1 to 4 carbon atoms, or dialkylamino radi-
cals wherein each alkyl is of 1 to 3 carbon atoms, which compound contains
0 to 1 alkyl radical as substituent on carbon atom 2 thereof, and for those
compounds wherein R1 is a carboxy radical the pharmaceutically acceptable
salts thereof, which comprises:-
(a) for those compounds wherein R1 is a carboxy radical, the
hydrolysis of a compound of the formula:
<IMG> II
43

or of a mixed anhydride thereof, wherein A, X, Y, R2, R3 and R4 have the
meanings stated above, and R5 and R6 are each a tetrahydropyran-2-yloxy
radical, or an acyloxy radical of 1 to 6 carbon atoms, whereafter when a salt
is required the product is reacted with a base; or
(b) for those compounds wherein R1 is an alkoxycarbonyl radical of 1
to 11 carbon atoms, the reaction of an acid of the formula:-
<IMG> III
wherein A, X, Y, R2, R3 and R4 have the meanings stated above, with a
diazoalkane of the formula R7. N2, wherein R7 is an alkyl radical of 1 to 11
carbon atoms; or
(c) for those compounds wherein R1 is an alkoxycarbonyl radical of 1 to
11 carbon atoms, the reaction of a salt of an acid of the formula II with an
alkyl halide of 1 to 11 carbon atoms; or
(d) for those compounds wherein R1 is the hydroxymethyl radical and Y
is an oxygen or sulphur atom or an alkylimino radical, the reduction of an
ester of the formula I wherein R1 is an alkoxycarbonyl radical of 1 to 11
carbon atoms; or
(e) for those compounds wherein Y is the sulphinyl radical, the oxidation
of a thio-compound of the formula:-
<IMG> IV
wherein R1, R2, R3, R4, A and X have the meanings defined above.
44

2. A process as claimed in claim 1 wherein the hydrolysis is carried
out in aqueous acetic acid.
3. A process as claimed in claim 1 wherein the hydrolysis is carried
out in an aqueous or alcoholic solution of an alkali metal carbonate.
4. A process as claimed in claim 1 wherein the salt of an acid of
the formula II is the silver salt.
5. A process as claimed in claim 1 wherein the alkyl halide is an
alkyl iodide.
6. A process as claimed in claim 1 wherein the reduction is carried
out with a complex metal hydride.
7. A process as claimed in claim 6 wherein the complex metal hydride
is lithium aluminium hydride.
8. A process as claimed in claim 1a), b), c) or d), for the manu-
facture of a prostanoic acid derivative of the formula I wherein in the
starting material, R2 is a hydroxy or acetoxy radical and R3 is a hydrogen
atom or R2 and R3 together form an oxo radical, A is an ethylene or trans-
vinylene radical, X is a methylene radical bearing 0, 1 or 2 methyl substit-
uents, or a trimethylene radical, Y is an oxygen atom and R4 is a phenyl,
naphthyl, chlorophenyl, chloronaphthyl, bromophenyl, fluorophenyl, tolyl,
xylyl, methylnaphthyl, t-butylphenyl, methylchlorophenyl, trifluoromethyl-
phenyl, hydroxyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, dimethyl-
aminophenyl or tetrahydronaphthyl radical, which prostanoic acid derivative
optionally bears a 2-methyl substituent.
9. A process as claimed in claim 2, 3 or 4 for the manufacture of
a prostanoic acid derivative of the formula I wherein in the starting
material, R2 is a hydroxy or acetoxy radical and R3 is a hydrogen atom or

R2 and R3 together form an oxo radical, A is an ethylene or trans-vinylene
radical, X is a methylene radical bearing 0, 1 or 2 methyl substituents, or a
trimethylene radical, Y is an oxygen atom and R4 is a phenyl, naphthyl,
chlorophenyl, chloronaphthyl, bromophenyl, fluorophenyl, tolyl, xylyl,
methylnaphthyl, t-butylphenyl, methylchlorophenyl, trifluoromethylphenyl,
hydroxyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, dimethylamino-
phenyl or tetrahydronaphthyl radical, which prostanoic acid derivative
optionally bears a 2-methyl substituent.
10. A process as claimed in claim 5, 6 or 7 for the manufature of a
prostanoic acid derivative of the formula I wherein in the starting material,
R2 is a hydroxy or acetoxy radical and R3 is a hydrogen atom or R2 and R3
together form an oxo radical, A is an ethylene or trans-vinylene radical, X is
a methylene radical bearing 0, 1 or 2 methyl substituents, or a trimethylene
radical, Y is an oxygen atom and R4 is a phenyl, naphthyl, chlorophenyl,
chloronaphthyl, bromophenyl, fluorophenyl, tolyl, xylyl, methylnaphthyl,
t-butylphenyl, methylchlorophenyl, trifluoromethylphenyl, hydroxyphenyl,
methoxyphenyl, methoxynaphthyl, biphenylyl, dimethylaminophenyl or tetra-
hydronaphthyl radical, which prostanoic acid derivative optionally bears a
2-methyl substituent.
11. A process as claimed in claim 1a), b), c) or d) for the manufacture
of a prostanoic acid derivative of the formula I wherein in the starting
material, R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3
together form the oxo radical, A is a trans-vinylene radical, X is a methylene
or isopropylidene radical, Y is an oxygen atom and R4 is a phenyl,,1-naphthyl,
2-naphthyl, 2-, 3-, or 4-chlorophenyl, 4-bromophenyl, 2-, 3- or 4-fluoro-
phenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2-, 3- or
4-tolyl, 2,3-, 3,4- or 3,5-xylyl, 4-t-butylphenyl, 3-allylphenyl, 3-
trifluoromethylphenyl, 4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 4-bi-
46

phenylyl, 3-dimethylaminophenyl, 2-chloro-4-methylphenyl, 4-chloro-3-
methylphenyl, 1-chloro-2-naphthyl, 4-chloro-2-naphthyl, 6-methyl-2-
naphthyl, 6-methoxy-2-naphthyl or 5,6,7,8-tetrahydro-2-naphthyl radical.
12. A process as claimed in claim 2, 3 or 4 for the manufacture of a
prostanoic acid derivative of the formula I wherein in the starting material,
R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together
form the oxo radical, A is a trans-vinylene radical, X is a methylene or
isopropylidene radical, Y is an oxygen atom and R4 is a phenyl, 1-naphthyl,
2-naphthyl, 2-, 3- or 4-chlorophenyl, 4-bromophenyl, 2-, 3- or 4-fluoro-
phenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2-, 3- or 4-
tolyl, 2,3-, 3,4- or 3,5-xylyl, 4-t-butylphenyl, 3-allylphenyl, 3-trifluoro-
methylphenyl, 4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 4-biphenylyl, 3-
dimethylaminophenyl, 2-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 1-
chloro-2-naphthyl, 4-chloro-2-naphthyl, 6-methyl-2-naphthyl, 6-methoxy-2-
naphthyl or 5,6,7,8-tetrahydro-2-naphthyl radical.
13. A process as claimed in claim 5, 6 or 7 for the manufacture of a
prostanoic acid derivative of the formula I wherein in the starting
material, R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3
together form the oxo radical, A is a trans-vinylene radical, X is a methylene
or isopropylidene radical, Y is an oxygen atom and R4 is a phenyl, 1-
naphthyl, 2-naphthyl, 2-, 3- or 4-chlorophenyl, 4-bromophenyl, 2-, 3- or
4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2-, 3-
or 4-tolyl, 2,3-, 3,4- or 3,5-xylyl, 4-t-butylphenyl, 3-allylphenyl, 3-
trifluoromethylphenyl, 4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 4-bi-
phenylyl, 3-dimethylaminophenyl, 2-chloro-4-methylphenyl, 4-chloro-3-
methylphenyl, 1-chloro-2-naphthyl, 4-chloro-2-naphthyl, 6-methyl-2-naphthyl,
6-methoxy-2-naphthyl or 5,6,7,8-tetrahydro-2-naphthyl radical.
14. A process as claimed in claim 1a), b) or c) for the manufacture
47

of a prostanoic acid derivative of the formula 1 wherein in the starting
material R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3
together form an oxo radical, A is a trans-vinylene radical, X is a methyl-
ene or isopropylidene radical, Y is an oxygen atom and R4 is a 3- or 4-
chlorophenyl, 2- or 4-fluorophenyl, 3-trifluoromethylphenyl or 2-naphthyl
radical.
15. A process as claimed in claim 2, 4 or 5 for the manufacture of a
prostanoic acid derivative of the formula I wherein in the starting material
R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form
an oxo radical, A is a trans-vinylene radical, X is a methylene or iso-
propylidene radical, Y is an oxygen atom and R4 is a 3- or 4-chlorophenyl,
2- or 4-fluorophenyl, 3-trifluoromethylphenyl or 2-naphthyl radical.
16. A process for the manufacture of 16-(3-chlorophenoxy)-9.alpha.,11.alpha.,15-
trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid which com-
prises the hydrolysis with aqueous acetic acid of 16-(3-chlorophenoxy)-9.alpha.-
hydroxy-11.alpha., 15-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis,13-
trans-prostadienoic acid.
17. A process for the manufacture of 16-(4-chlorophenoxy)-11.alpha.,15-
dihydroxy-16,16-dimethyl-9-oxo-17,18,19,20-tetranor-5-cis,13-trans-pro-
stadienoic acid which comprises the hydrolysis, with aqueous acetic acid,
of 16-(4-chlorophenoxy)-15, 16-dimethyl-9-oxo-11.alpha.,15-bis(tetrahydropyran-2-
yloxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid.
18. A process for the manufacture of 9.alpha.,11.alpha.,15-trihydroxy-16-(3-
trifluoromethylphenoxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic
acid which comprises the hydrolysis, with aqueous acetic acid, of 9.alpha.-hydroxy-
11.alpha.,15-bis(tetrahydropyran-2-yloxy)-16-(3-trifluoromethylphenoxy)-17,18,19,
20-tetranor-5-cis,13-trans-prostadienoic acid.
48

19. A prostanoic acid derivative of the formula:-
<IMG> I
wherein R1 is a hydroxymethyl or carboxy radical, or an alkoxycarbonyl
radical of up to 11 carbon atoms, R2 is a hydroxy radical or an alkanoyloxy
radical of 1 to 4 carbon atoms and R3 is a hydrogen atom or R2 and R3
together form an oxo radical, A is an ethylene or trans-vinylene radical,
X is a methylene radical, bearing 0, 1 or 2 alkyl substituents each of 1 to 3
carbon atoms, or a trimethylene radical, Y is an oxygen or sulphur atom,
a sulphinyl radical or an alkylimino(-NAlkyl-) radical of 1 to 4 carbon
atoms, and R4 is a benzyl or furfuryl radical, or a phenyl or naphthyl
radical which is unsubstituted or which is substituted by not more than
two chlorine, bromine or fluorine atoms, hydroxy, nitor, trifluoromethyl,
or phenyl,radicals, alkyl, alkenyl, or alkoxy radicals each of 1 to 4 carbon
atoms, or dialkylamino radicals wherein each alkyl is of 1 to 3 carbon atoms,
which compound contains 0 or 1 alkyl radical as substituent on carbon atom
2 thereof, and for those compounds wherein R1 is a carboxy radical the
pharmaceutically acceptable salts thereof, whenever prepared by:-
(a) for those compounds wherein R1 is a carboxy radical the
hydrolysis of a compound of the formula:
<IMG> II
49

or of a mixed anhydride thereof, wherein A, X, Y, R2, R3 and R4 have the
meanings stated above, and R5 and R6 are each of tetrahydropyran-2-yloxy
radical, or an acyloxy radical of 1 to 6 carbon atoms, whereafter when a
salt is required the product is reacted with a base; or
(b) for those compounds wherein R1 is an alkoxycarbonyl radical
of 1 to 11 carbon atoms, the reaction of an acid of the formula:-
<IMG>
III
wherein A, X, Y, R2, R3 and R4 have the meanings stated above, with a
diazoalkane of the formula R7.N2, wherein R7 is an alkyl radical of 1 to 11
carbon atoms; or
(c) for those compounds wherein R1 is an alkoxycarbonyl radical
of 1 to 11 carbon atoms, the reaction of a salt of an acid of the formula II
with an alkyl halide of 1 to 11 carbon atoms; or
(d) for those compounds wherein R1 is the hydroxymethyl radical
and Y is an oxygen or sulphur atom or an alkylimino radical, the reduction
of an ester of the formula I wherein R1 is an alkoxycarbonyl radical of 1
to 11 carbon atoms; or
(e) for those compounds wherein Y is the sulphinyl radical, the
oxidation of a thio-compound of the formula:-
<IMG>
IV
wherein R1, R2, R3, R4, A and X have the meanings stated above, or by an
obvious chemical equivalent thereof.

20. A prostanoic acid derivative of the formula I wherein R1 is a
carboxy, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl or butoxycarbonyl
radical, R2 is a hydroxy or acetoxy radical and R3 is a hydrogen atom or R
and R3 together form an oxo radical, A is an ethylene or trans-vinylene
radical, X is a methylene radical bearing 0, 1 or 2 methyl substituents, or a
trimethylene radical, Y is an oxygen atom and R4 is a phenyl, naphthyl,
chlorophenyl, chloronaphthyl, bromophenyl, fluorophenyl, tolyl, xylyl,
methylnaphthyl, t-butylphenyl, methylchlorophenyl, trifluoromethylphenyl, hydro-
xyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, dimethylaminophenyl or
tetrahydronaphthyl radical, which prostanoic acid derivative optionally bears
a 2-methyl substituent, whenever prepared by the process claimed in claim 8
or by an obvious chemical equivalent thereof.
21. A prostanoic acid derivative of the formula I wherein R1 is a
carboxy, hydroxymethyl, methoxycarbonyl or ethoxycarbonyl radical, R2 is a
hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form the oxo
radical, A is a trans-vinylene radical, X is a methylene or isopropylidene
radical, Y is an oxygen atom and R4 is a phenyl, 1-naphthyl, 2-naphthyl,
2-, 3- or 4-chlorophenyl, 4-bromophenyl, 2-, 3- or 4-fluorophenyl, 2,3-,
2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2-, 3- or 4-tolyl, 2,3-, 3,4
or 3,5-xylyl, 4-t-butylphenyl, 3-allylphenyl, 3-trifluoromethylphenyl,
4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 4-biphenylyl, 3-dimethylamino-
phenyl, 2-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 1-chloro-2-
naphthyl, 4-chloro-2-naphthyl, 6-metnyl-2-naphthyl, 6-methoxy-2-naphthyl or
5,6,7,8-tetrahydro-2-naphthyl adical, whenever prepared by the process
claimed in claim 11 or by an obvious chemical equivalent thereof.
22. A prostanoic acid derivative of the formula I wherein R1 is a
carboxy, methoxycarbonyl or ethoxycarbonyl radical, R2 is a hydroxy radical
and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, A is a
trans-vinylene radical, X is a methylene or isopropylidene radical, Y is an
51

oxygen atom and R4 is a 3- or 4-chlorophenyl, 2- or 4-fluorophenyl, 3-
trifluoromethylphenyl or 2-naphthyl radical, whenever prepared by the process
claimed in claim 14 or by an obvious chemical equivalent thereof.
23. 16-(3-Chlorophenoxy)-9.alpha.,11.alpha.,15-trihydroxy-17,18,199,20-tetranor-5-
cis,13-trans-prostadienoic acid whenever prepared by the process claimed
in claim 16 or by an obvious chemical equivalent thereof.
24. 16-(4-Chlorophenoxy)-11.alpha.,15-dihydroxy-16,16-dimethhyl-9-oxo-17,18,
19,20-totranor-5-cis,13-trans-prostadienoic acid whenever prepared by the
process claimed in claim 17 or by an obvious chemical equivalent thereof.
25. 9.alpha.,11.alpha.,15-Trihydroxy-16-(3-trifluoromethylphenoxy))-17,18,19,20-
tetranor-5-cis,13-trans-prostadienoic acid whenever prepared by the process
claimed in claim 18 or by an obvious chemical equivalent thereof.
52

Description

~(~77033
This invention relates to new cyclopentane derivatives,
and in particular it relates to new cyclopentane derivatives
which are analogues of the naturally occurring compounds known as
prostaglandin F2a and prostaglandin E2, showing a similar spectrum
of pharmacological properties and being useful for similar
purposes. The relative potency of the new compounds, however, in
respect of the particular pharmacological effects shown is
different from that of the above naturally occurring prostaglandins,
and in particular they are more potent as luteolytic agents than
the corresponding natural prostaglandins. That is to say, the
prostaglandin F2a analogues of the present invention are more
potent than natural prostaglandin F2a, and the prostaglandin E2
analogues of the present invention are more potent than natural
prostaglandin E2. The new compounds are, in a similar way, more
potent as stimulants of uterine smooth muscle than the
corresponding natural prostaglandins F2a and E2, and the
prostaglandin E2 analogues of the invention are particularly
valuable in this respect. The new compounds are therefore
advantageous when used as contraceptives, for the termination of
pregnancy or for control of the oestrus cycle, as hypotensives or
for the relief of bronchospasm. The new compounds of the
invention are also useful for addition to semen intended for
artificial insemination of domestic animals, the success rate of
insemination being thereby increased, especially in pigs.
The cyclopentane derivatives described in this
,
-- 2 --
, ~ , . . ....
: :: ;
.. . .
.....
.
. :
,.. .. ..
:-' . ':. . .,'- : :

,: 1077033
specification will be named as derivatives of prostanoic acid of the formula
shown below and numbered as shown:-
9 7 5 3 C001l
~\ ~
10 ~ ~ 4 ~ ~ / 20
11 , 13 15 17 l9
According to the invention there is provided a prostanoic acidderivative of the formula:-
R2 R3
~\~\~
~ A-CH(oH)-X-Y-R4
HO
wherein Rl is a hydroxymethyl or carboxy radical, an alkoxy-carbonyl radical
of up to ll carbon atoms, R2 is a hydroxy radical or an alkanoyloxy radical of
l to 4 carbon atoms and R3 is a hydrogen atom, or R2 and R3 together form an
oxo radical; A is an ethylene or trans-vinylene radical; X is a methylene
radical, bearing 0, l or 2 alkyl substituents each of l to 3 carbon atoms, or
a trimethylene radical J each of l to 3 carbon atoms; Y is an oxygen or sulphur
atom, a sulphinyl (-S0-) radical or an alkylimino (-NAlXyl-) radical of up
to 4 carbon atoms; and R4 is a beni~yl or furfuryl radical, or a phenyl or
naphthyl radical which is unsubstituted or which is substituted by not more
than two chlorine, bromine or fluorine atoms, hydroxy, nitro, phenyl, or
trifluoromethyl radicals, alkyl, alkenyl, or alkoxy radicals each of 1 to 4
carbon atoms or dialkylamino radicals wherein each alkyl is of l to 3 carbon
atoms; which compound contains 0 or l alkyl
~ . :

'77(~3
radicals of up to 4 carbon atoms on carbonatom2 thereof and for those
compounds wherein R is a carboxy radical, the pharmaceutically acceptable
salts thereof.
A suitable value for Rl when it is an alkoxycarbonyl radical of
up to 11 carbon atoms is, for example, the methoxycarbonyl~ ethoxycarbonyl~
n-butoxycarbonyl or n-decyloxycarbonyl radical.
A suitable value for R when it is an alkanoyloxy radical of
1 to 4 carbon atoms is, for example, the acetoxy or propionyloxy radical.
A suitable value for X when it is an alkylene radical of 1 to 3
carbon atoms bearing as substituents 0, 1 or 2 alkyl radicals, each of 1
to 3 carbon atoms is, for example a methylene, ethylene or trimethylene
radical bearing 0, 1 or 2 methyl substituents, for example the methylene,
ethylidene, isopropylidene and trimethylene radicals.
A suitable value for Y when it is an alkyleneimino radical of up
to 4 carbon atoms is, for example, the methylimino (CH3-N ~) radical.
A suitable value for A is the trans-vinylene radical.
Suitable alkyl~ alkoxy or alkenyl substituents of 1 to 4 carbon
atoms in R4 are, for example methyl, t-butyl, allyl or methoxy radicals.
Suitable dialkylamino radicals wherein each alkyl is of 1 to 3 carbon
atoms, which may be substituents in R4 are, for example, dialkylamino
radicals wherein the two alkyl radicals are the same, for example the
dimethylamino radical.
Suitable substituted phenyl or naphthyl radicals are for example,
chlorophenyl, chloronaphthyl, bromophenyl, fluorophenyl, tolyl, xylyl,
methylnaphthyl, t-butylphenyl,m~thylchlorophenyl, tri-fluoromethylphenyl,
hydroxyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, dimethylamino-
phenyl and tetrahydronaphthyl radicals.
Preferred aryl radicals contain not more than two substituents
~ 4 ~
.,

```~ 1C~77033
as defined above. Particular values for R4 are, therefore, the phenyl,
benzyl, furfuryl, l-naphthyl~ 2-naphthyl, 2-, 3- and 4-chlorophenyl~ 4-
bromophenyl, 2-, 3- and 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and
3,5-di chlorophenyl, 2-, 3- and 4-
~ --5 -
. ~ æ

~77033
tolyl, 2,3-, 3,4- and 3,5-xylyl, 4-t-butylphenyl, 3-allylphenyl,
. 3-trifluoromethylphenyl, 4-hydroxyphenyl, 2-, 3- and 4-methoxy-
phenyl, 4-biphenylyl, 3-dimethylaminophenyl, 2-chloro-4-methyl-
phenyl, l-chloro-2-naphthyl, 4-chloro-2-naphthyl, 6-methyl-2-
naphthyl, 6-methoxy-2-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl
radicals.
A suitable value for the alkyl radical of up to 4
carbon atoms which may be present as a substituent on carbon atom
2, 3 or 4 is, for example the methyl radical.
Examples of base-addition salts are the ammonium,
alkyl-ammonium containing 1 to 4 alkyl radicals each of 1 to 6
carbon atoms, alkanolammonium containing 1 to 3 2-hydroxyethyl
radicals, and alkali metal salts, for example the triethyl-
ammonium, ethanolammonium, diethanolammonium, sodium and
potassium salts.
It will be observed that the compounds of the formula I
contain at least five asymmetric carbon atoms, namely carbon
atoms 8, 9, 11, 12 and 15, the configurations at four of which,
8, 9, 11 and 12 are specified in formula I, and that carbon atoms
2, 3 and 4 may also be asymmetrically substituted, so that it is
clear that such compounds can exist in at least two optically
active forms. It is to be understood that the useful properties
of the racemate may be present to differing extents in the
optical isomers, and that tnis invention relates to the racemic
form of the compounds of formula I and any optically active form
.:, ',
.. ~' ; . ' '. ~:'

1C~77033
.
which shows the above useful properties, it being a matter of
common general knowledge how the optically active forms may be
obtained, and to determine their respective biological properties.
It is also to be understood that the above definition
encompasses both C-15 epimers and that in all chemical formulae
shown hereafter in this specification, the same fixed stereo-
chemistry at C-8, 9, 11 and 12 as that shown in formula I is
implied.
Although both C-15 epimers of a compound of the
invention possess desirable pharmacological properties, that
epimer which is more polar on thin layer chromatography is the
more active, for example in the luteolytic test, and the more
polar C-15 epimers are therefore preferred.
A preferred group of cyclopentane derivatives of the
invention, because of their high luteolytic or smooth muscle
stimulant properties, comprises those compounds wherein R4 is a
chlorophenyl, fluorophenyl, trifluoromethylphenyl or unsubstituted
- naphthyl radical, especially those compounds wherein Rl is the
carboxy, methoxycarbonyl or hydroxymethyl radical, and
particularly those compounds wherein R4 is the 3- or 4-chloro-
- phenyl, 2- or 4-fluorophenyl, 3-trifluoromethylphenyl or
unsubstituted naphthyl radical. A particularly preferred sub-
group comprises those compounds wherein Rl is the carboxy, methoxy-
carbonyl or hydroxymethyl radical, R2 is the hydroxy radical and
R3 is a hydrogen atom, or R2 and R3 together form the oxo radical,
. : '
', ' : ", ': . ' '
:: : .. . . -

7033
A is the vinylene radical, X is the methylene or isopropylidene
radical, Y is an oxygen atom and R4 is the 3- or 4-chlorophenyl,
2- or 4-fluorophenyl, 3-trifluoromethylphenyl or 2-naphthyl
radical, optionally bearing a methyl substituent on carbon atom 2.
Particular preferred compounds of the invention are
16-(4-fluorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-
5-cis-13-trans-prostadienoic acid, methy]. 16-(4-fluorophenoxy)-
9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-
prostadienoate, 16-(2-fluorophenoxy)-9a,11a,15-trihydroxy-17,18,
19,20-tetranor-5-cis-13-trans-prostadienoic acid, 16-(4-chloro-
phenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-
prostadienoic acid, methyl 16-(4-chlorophenoxy)-9a,lla,15-
trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate,
16-(4-chlorophenyl)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-
cis-13-trans-prostadienol, 16-(3-chlorophenoxy)-9a,11a,15-tri-
hydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid,
methyl 16-(3-chlorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-
tetranor-5-cis-13-trans-prostadienoate, 16-(3-chlorophenoxy)-
9a,11a,15-trihydroxy-2-methyl-17,18,19,20-tetranor-5-cis-13-trans-
prostadienol, 9a,11a,15-trihydroxy-16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, 9a,11a,15-
trihydroxy-16-(2-naphthyloxy)-17,18,19,20-tetranor-5-cis-13-trans-
prostadienoic acid, 16-(4-chlorophenoxy)-9a,11a,15-trihydroxy-16,16-
dimethyl-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid and
16-(4-chlorophenoxy)-lla,15-dihydroxy-9-oxo-17,18,19,20-tetranor-
, .:: :
:::: :~ -
~- : :~: ::: :: ,
. ., ~ :
,, ., '

1~)77033
5-cis-13-trans-prostadienoic acid.
The cyclopentane derivatives of the invention may be
manufactured by methods known in themselves for the manufacture
f chemically analogous compounds. Thus, the following
processes for the manufacture of the cyclopentane derivative of
the formula I, are provided as further features of the
invention:-
(a) for those compounds wherein Rl is a carboxy radical, the
hydrolysis of a compound of the formula:-
R3
R2 ~ (CH2~3'COOH
~ A-CH-X-Y-R4 II
R5 R6
or of a mixed anhydride thereof, wherein A, X, Y, R2, R3 and R4
have the meanings stated above, and R5 and R6 are each a tetra-
hydropyran-2-yloxy radical, or an acyloxy radical of 1 to 6
carbon atoms, whereafter when a salt is required the product is
reacted with a base; or
(b) for those compounds wherein Rl is an alkoxycarbonyl radical
of 1 to 11 carbon atoms, the reaction of an acid of the formula:-
R3
R2 ~ (CH2)3-COOH
<
~ A-CH-X-Y-R4 III
I
HO OH
_ 9 _
., ; ::- .:

77033
.
wherein A, X, Y, R , R3 and R4 have the meanings stated above, with a
diazoalkane of the formula R7.N2, wherein R7 is an alkyl radical of 1 to
11 carbon atoms; or
(c) for those compounds wherein R is an alkoxycarbonyl radical of 1 to
11 carbon atoms, the reaction of a salt, of an acid of the formula II,
with an alkyl halide of 1 to 11 carbon atoms, or
(d) for those compounds wherein R is the hydroxymethyl radical and Y is
the oxygen or sulphur atom or an alkylimino radical, the reduction of an
ester of ~he formula I wherein R is an alkoxycarbonyl radical of 1 to 11
carbon atoms, or
(e) for those compounds wherein Y is the sulphinyl radical, the oxidation
of a thio-compound of the formula:-
2 ~ \ ~ R IV
A-CH(OH)-X-SR4
HO
wherein Rl, R2, R3~ R4, A and X have the meanings defined above.
A suitable mixed anhydride is a mixed anhydride with a lower
alkanoic acid, for example a lower alkanoic acid of up to 8 carbon atoms,
for example acetic acid.
~, - 10 -

lQ~77033
The hydrolysis in process (a) may be carried out under
either acidic or basic conditions, for example in aqueous acetic
acid, or in an aqueous or alcoholic solution of an alkali metal
carbonate, for example potassium carbonate in methanol, and it
may be carried out at ambient temperature or at an elevated
temperature of up to 60C.
The starting material of the f`ormula II wherein A is
a vinylene radical, and Y is an oxygen or sulphur atom, used in
the process of the invention may be obtained by reaction of the
known aldehyde IV (Ac= acetyl or p-phenylbenzoyl) with a
phosphonate of the ~ormula (CH30)2P 0. CH.Co.X.Y.R4 (V) (which is
prepared from dimethyl methylphosphonate and an ester of the
formula R .Y.X.C00 alkyl, in the presence of butyllithium), or
with a phosphorane of the formula Ph3P:CH.CO.X.Y.R4 (which is
prepared from triphenylphosphine and a compound of the formula
R4.Y.X.COCH2I), to give an unsaturated ketone VI. The ketone VI
is reduced with zinc borohydride to the corresponding unsaturated
alcohol VII, and the protecting acyl group is then removed with
potassium carbonate in methanol to give a diol VIII. The diol
VIII is protected as a bis-tetrahydropyranyl ether and the lactone
ring is then reduced with di-isobutyl aluminium hydride to give a
lactol X, or alternatively the diol VIII is reduced with di-
isobutyl aluminium hydride to give a triol which may be acylated
and selectively hydrolysed to give the lactol bis-ester
(X, R5=R6=acyloxy). The lactol X is reacted with the phosphonium
: ~ ,
~ .
. ' '- ~. ~

1~77033
ylide anion obtained from (4-carboxybutyl)triphenylphosphonium
bromide and a strong base, to give a carboxylic acid of the
formula II.
. The starting material of the formula II wherein A is an
ethylene radical, and Y is an oxygen or sulphur atom, used in the
process of the invention, may be obtained by hydrogenating an
unsaturated ketone VI in the presence of 5% palladium-on-carbon
catalyst, or with nickel boride, to give a saturated ketone XI,
and repeating the procedure outlined above using the saturated
ketone XI in place of the unsaturated ketone VI.
The starting material of the formula II wherein R2 is
an alkanoyloxy radical may be obtained from the corresponding
compound wherein R2 is a hydroxy radical by acylation with an acid
anhydride in pyridine to give a 9-ester-1-mixed anhydride.
The starting material of the formula I, II or III,
wherein R2 and R3 together form the oxo radical, may be obtained
from the corresponding starting material of the formula II,
wherein R2 is hydroxy and R3 is hydrogen, by oxidation with Jones'
reagent (chromic acid in acetone), followed, as required, by
hydrolysis of the tetrahydropyranyl protecting groups and
esterification of the carboxylic acid group.
It is, of course, to be understood that an optically
active compound of the invention may be obtained either by
resolving the corresponding racemate, or by carrying out the
above-described reaction sequences starting from an optically
- 12 -
.- . ..
. :.' .'' .- : .:
:: ~ :.- :: ,: -. :
. ~ - : :
: : .- : : :
::: ~ :: : . .
., : :
,
., ' ' -:

o ~s)77033
o
AoO>~O I (16eO) 2-P-CR.CO-X-Y . R4~ ~/X.Y, R4
IV V VI
Y R4 ~ X.Y . R4
OH OH
VII VIII
O OH
> ~ > II
RSY~.Y.R4 R5Y~,Y.R4
~ X
Ac represents an acyl radical.
-- 13 --
.
:- . . . .: .
. . ~. , . ~

~077033
active intermediate, for example from an optically active
aldehyde of the formula IV (Ac = acetyl or p-phenylbenzoyl).
As stated above, the compounds of the invention
possess a profile of pharmacological properties which differs
from that of the naturally occurring prostaglandins F2a and E2.
Thus, for example, 16-(4-fluorophenoxy)-9N,lla,15-trihydroxy-
17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid is
approximately 200 times as active as prostaglandin F2a in a
luteolytic test in the hamster (oral dosing), and about 10 times
the smooth muscle stimulant activity of prostaglandin F2a.
Also as stated above, the compounds of the invention
are useful, for example, for the induction of labour in childbirth,
and for this purpose are used in the same way as it is known to
use the naturally-occurring prostaglandins El and E2, that is to
say, by administering a sterile, substantially aqueous solution
containing from 0.01 to lO~g./ml., preferably 0.01 to l~g./ml. of
active compound, by intravenous infusion until labour commences.
Also, for this purpose, the compounds of the invention may be used
in combination, or concurrently, with a uterine stimulant, for
example oxytocin, in the same way that it is known to use
prostaglandin F2a in combination, or concurrently with oxytocin
for the induction of labour~
When a compound of the invention is to be used for the
control of the oestrus cycle in animals, it may be used in
combination, or concurrently, with a gonadotrophin, for example
- 14 -
: . ,: ., .
:: ;.: : - - ~ .
: ., : :

- ~077033
PMSG (pregnant mare serum gonadotrophin) or HCG (human chorionic
gonadotrophin) to hasten the onset of the next cycle.
Thus, according to a further feature of the invention
there is provided a pharmaceutical or veterinary composition
comprising a prostanoic acid derivative of the invention,
together with a pharmaceutically or veterinarily acceptable
diluent or carrier.
The compositions may be in a form suitable for oral
administration, for example tablets or capsules, in a form
suitable for inhalation, for example an aerosol or a solution
suitable for spraying, in a form suitable for parenteral
administration, for example sterile injectable aqueous or oily
solutions or suspensions, or in the form of a suppository,
suitable for anal or vaginal use. As stated above, when the
compound of the invention is to be used for the induction of
labour in childbirth, a preferred composition of the invention is
a sterile, substantially aqueous, injectable solution.
The compositions of the invention may be prepared by
conventional means, and may incorporate conventional excipients.
The invention is illustrated, but not limited, by the
following Examples:-
Example 1
A solution of 9a-hydroxy-16-phenoxy-lla,15-bis(tetra-
hydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis-13-trans-
prostadienoic acid (120mg;) in 1.5ml. of a 2:1 mixture of acetic
- 15 -
;.- .
, , ~- , . .
.- .. : .,:
: ~, ,.: , - '''.
:

107~033
acid and water, was stirred at 50C. for 4 hours. The solvents
were evaporated, the residue was dissolved in dilute aqueous
sodium bicarbonate solution (2ml.) and the solution was extracted
with ethyl acetate (3 x 2ml.) and the extracts were discarded.
The aqueous solution was acidified to pH 3-4 with 2N aqueous
oxalic acid and the acidified solution was extracted with ethyl
acetate (4 x 5ml.). The ethyl acetate extracts were washed with
a 1:1 mixture of saturated brine and water, and were then dried.
After evaporation of the ethyl acetate, the residue consisted of
a mixture of the C-15 epimers of 9a,11a,15-trihydroxy-16-phenoxy-
17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid. Thin-
layer chromatography on silica gel plates, supplied commercially
by Merck of Darmstadt, using a mixture of benzene: dioxan:
acetic acid (20:10:1) as the developing solvent, separated the
C-15 epimers, having RF values of 0.3 and 0.4, respectively.
(Throughout this Example RF values refer to silica gel plates
supplied commercially by Merck of Darmstadt, and the spots were
detected either by fluorescence, or by spraying the plates with a
solution of ceric ammonium nitrate in sulphuric acid). The n.m.r.
spectrum of each isomer (in deuterated acetone) showed the
following characteristic bands (~ values):-
5.6-6.1, broad multiplet, 5 aromatic protons
4.2-4.8, broad multiplets, 4 olefinic protons
2.9-3.8, broad multiplets, 3H, H-C-0 and 4 exchangeable protons
The bis-tetrahydropyranyl ether used as starting material
- 16 -
-
, ~' ~, - . , -
: . ;:

77033
may be prepared as follows:-
n-Butyl lithium (69ml. of a 1.2M solution in hexane)
was added to a solution of dimethyl methylphosphonate (10.3g.)
in dry tetrahydrofuran at -78C. in an atmosphere of nitrogen.
After 10 minutes, a solution of phenylacetylchloride (4.lg.) in
dry tetrahydrofuran (20ml.) was added dropwise, and the mixture
was stirred for 4 hours at -78C. The reaction mixture was
neutralised with acetic acid and the solvents were removed under
reduced pressure. The residue was shaken with a mixture of ether
(lOOml;) and water (20ml.), and the organic phase was separated
and washed with brine. The solution was dried, the solvents were
evaporated and the residue was distilled in a bulb distillation
apparatus at an oven temperature of 160C. and 0.1 mm. pressure,
; to give dimethyl 2-oxo-3-phenoxypropylphosphonate.
A solution of dimethyl 2-oxo-3-phenoxypropylphosphonate
(l.Olg.) in dry 1,2-dimethoxyethane (20ml.) at -78C. was treated
with n-butyl-lithium (2.75ml. of a 1.2M solution in hexane), and
the mixture was stirred for 15 minutes. To this mixture was
added a solution of 4~-formyl-2,3,3a~,6a~-tetrahydro-2-oxo-5~-
(p-phenylbenzoyloxy)cyclopenteno[b~furan (1.95g.) in 1,2-dimethoxy-
ethane (lOml:), and after 1 hour the reaction mixture was
neutralised with glacial acetic acid and all solvents were removed
by evaporation undçr reduced pressure below 35C. The residue was
chromatographed on Florisil using solutions of ethyl acetate in
methylene chloride as eluant, to yield the unsaturated ketone
T~ad-ma~ k
- 17 -
'- : ., , ;
. ,
. - : , ,
..
,~::: :, :
.. . :
:: : - :
:: : . :-

10'77033
product as a white solid. CRF= 0.6 (1:1 ethyl acetate/benzene)~.
To a solution of the unsaturated ketone (500mg.) in dry
1~2-dimethoxyethane (20ml.) at 0C. was added 1.5ml. of a 0.5M
solution of zinc borohydride in 1,2-dimethoxyethane. The mixture
was stirred at room temperature for 30 minutes, then saturated
sodium hydrogen tartrate solution was added until effervescence
ceased. Ethyl acetate (lOOml.) was added, the organic layer was
separated, washed with a 1:1 mixture of saturated brine and water,
then dried. The solvents were evaporated to give a mixture of
epimeric unsaturated alcohols. ~RF= 3 (1:1 ethyl acetate/
benzene)~.
The mixture of epimeric unsaturated alcohols (500mg.)
was stirred vigorously for 2 hours with finely powdered anhydrous
potassium carbonate (140mg.) in methanol (lOml;). lN Hydrochloric
acid (2.1 ml.) was added, followed by ethyl acetate (50ml.). The
organic layer was separated 3 washed successively with saturated
sodium bicarbonate solution and saturated brine, and dried, and
the solvents were evaporated. The residue was chromatographed on
Florisill(20g;). Elution with ether removed by-products, and
subsequent elution with ethyl acetate gave a mixture of the C-15
epimeric diols [RF= 0.2 (ethyl acetate)~.
To a solution of the epimeric diols (316mg.) in
methylene chloride (3 ml;) under an atmosphere of nitrogen were
added successively redistilled 2,3-dihydropyran (1.2ml.) and a
solution of anhydrous toluene-p-sulphonic acid in tetrahydrofuran
'~ud~A~k
- 18 -
.
.,
.
': '~-, - ~ ~ ' ` .,
: ' : ~ '' . :

1~77033
(O.lml. of a 1% solution).
After 10 minutes, pyridine (3 drops) were added,
followed by ethyl acetate (50ml.). The solution was washed
successively with saturated sodium bicarbonate solution and
saturated brine, and was dried. Evaporation of the solvents gave
a mixture of epimeric bis-tetrahydropyranyl ethers as a clear oil.
[RF= 0.6 (ethyl acetate)~.
To a solution of the epimeric bis-tetrahydropyranyl
ethers (420mg.) in dry toluene (lOml.) under an atmosphere of
nitrogen at -78C. was added 1 ml. of a 2.2mmole/ml. solution of
di-isobutyl aluminium hydride in toluene. After 15 minutes the
reaction was quenched by the dropwise addition of methanol (3ml.)
and after a further 15 minutes at room temperature a mixture of
1:1 saturated brine/water (25ml.) was added, and the mixture was
extracted with ethyl acetate (3 x 50ml.). The extract was washed
with saturated brine, and dried, and the solvents were evaporated
to give a mixture of epimers of 2,3,3a~,6a~-tetrahydro-2-hydroxy-
4~-[4-phenoxy-3-(tetrahydropyran-2-yloxy)-1-trans-butenyl~-5a-
(tetrahydropyran-2-yloxy)cyclopenteno~b~furan. ~R~= 0.4
(1:1 ethyl acetate/benzene)~.
Finely powdered (4-carboxybutyl)triphenylphosphonium
bromide (l.llg.) was heated to 100C. under vacuum for 1 hour.
The evacuated reaction vessel was filled with an atmosphere of dry
nitrogen, the solid was disc;olved in dimethylsulphoxide (5ml.) and
the solution was cooled to room temperature. To this solution was
- 19 -
. .
, " ' ~. '' ~ , :
:~ , :, . .
::: : , .
,: . ., r
, . ~ . , .
- ~

1077033
added dropwise 2.35ml. of a 2M solution of methanesulphinylmethyl
sodium in dimethyl sulphoxide followed by a solution of the
mixture of epimers of the cyclopenteno[b~furan bis-tetrahydro-
pyranyl ether (400mg.) in a mixture of dimethylsulphoxide (lOml.)
and benzene (2ml.). The solution was stirred for 3 hours, and
the solvent was removed by evaporation under reduced pressure at
a temperature below 40C. The residue was shaken with water
(lOml.) and ethyl acetate (lOml.) and the aqueous phase was
separated, extracted with ethyl acetate (2 x lOml.) and the
extracts discarded. The aqueous solution was acidified to pH 3-4
with 2N aqueous oxalic acid, and extracted with a mixture of equal
parts of ether and petroleum ether (b.p.4~-60C.) (5 x lOml.).
The organic phase was separated, washed with saturated brine and
was dried. Evaporation of the solvents gave 9a-hydroxy-16-
phenoxy-11~15-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-
5-cis-13-trans-prostadienoic acid as a clear oil. [RF= 0.5
(ethyl acetate)~.
Example 2
The process described in Example 1 was repeated, using
the appropriate phosphonate reagent, to give the compounds shown
below. The products were identified by n.m.r. spectroæcopy and
are characterised below either by RF value on thin layer
chromatography, or by accura've mass measurement by mass spectrometry
of either the molecular ion or the (M - methyl) ion, whichever
is more appropriate, of the tetra (trimethylsilyl) derivative,
- 20 -
r
t
:'', "' ' ' ',: ' ' ' .

~077C~33
which is prepared by adding to the compound to be mass measured
bis-trimethylsilyl-trifluoroacetamide containing 1~ trimethyl-
chlorosilane (Regisil-trade mark) and leaving the mixture for 1 ,
hour. In some cases, the phosphonate reagent, or the unsaturated
ketone intermediate have been characterised and appropriate data
for these compounds are also given.
OH
COOH
~ A-CH(oH)-X-oR4
OH
, . - . . - -
, - -- . - .~ :: . -
:.. : . . . .
: :. . :: . : ~

~077~33
No. R A
1 phenyl -CH:CH- -CH2-
2 phenyl -CH:CH- -CH(CH3)-
3 phenyl -CH:CH- -C(CH3)2-
4 phenyl -CH:CH- -(CH2)3-
5 benzyl -CH:CH- -CH2-
6 2-naphthyl -CH:CH- -CH2-
7 4-chlorophenyl -CH:CH- -CH2-
8 4-chlorophenyl -CH2CH2- -CH2-
9 3-chlorophenyl -CH:CH- -CH2-
10 2-chlorophenyl -CH:CH- -CH2-
11 2,4-dichloro- -CH:CH- -CH2-
phenyl
12 4-bromophenyl -CH:CH- -CH2-
13 4-fluorophenyl -CH:CH- -CH2-
14 4-tolyl -CH:CH- -CH2-
15 3-tolyl -CH:CH- -CH2-
16 4-t-butylphenyl -CH:CH- -CH2-
17 3-trifluoro- -CH:CH- -CH2-
methylphenyl
18 4-methoxyphenyl -CH:CH- -CH2-
19 2-methoxyphenyl -CH:CH- -CH2-
20 4-biphenylyl -CH:CH- -CH2-
~ _
.;.
- 22 -
: : . , ., , .: ,
~ :

10~77033
,
No. Isomer Mass spectrum PhOsphoOnat/e Enone
Found Calculated
_ i
1 mp M =678.3610 678.3625 178-185/0.0~ 155-158
lp M =678
2 mp M 6CH77 3540 677.3545 175/0.2 _
lp M =692 692
3 mixed M -CH = 691.3703 130/0.1
6931.3660
4 mp M =706.3921 706.3938 166-168/0.1 12n-122
lp M =706
mixed M =692.3753 692.3781 17010.1 99-101
6 mp M =728.3744 728.3781 m-p ~ 185-187
7 mp M -CH = 697.3001 170-173/0.1 132-135
6937.2948
lp M =712 712
8 mp(a) M =714.3399 714.3391 170-173/0.1 132-135
lp(a) M =714
9 mp M 6CH97-2297 697.3000 180/0.2 _
lp M =712 712
mp M =712.3216 712.3235 174-178/0.1 129-132
lp M -712
11 mp M -CH = 731.2609 _ 136-138
73~.2599
12 mixed M -CH = 741.2497 _
74~.2485
13 mp M =696.3468 696.3529 _ 162
lp M =696
- 23 -
: : '' : ~: ,: : : , :
~: . : i. .. .
'` : ' . ~ :
:,~ .: : :~, :
; :, :. ,

77033
Mass spectrum Phosphonate Enone
No. Isomer mm j m.p.(C.)
Found Calculated i
14mixed M =692.3738 692.3781 164/0.05 149
15 mp M =692.3752 692.3781 180/0.5 140-141
lp M =692
16mixed M =734.4213 734.4251 _
17 mp M =746.3467(~ ) 746.3499 115-117
18 mp M =708.3717 708.3731 _ _
lp M =708
19 mp M =708.3710 708.3731 _ _
lp M =708
20 mp M =754.3944 754.3938 m p - _
lp M =754
*mp= more polar, lp= less polar i~omer on silica gel thin
layer chromatography.
a) products synthesised from respectively the more polar and
less polar enol intermediates.
b) RF- 0.45 after 2 runs on silica gel t.l.c. with 5% acetic
acid in ethyl acetate.
c) R~= 0.50 after 2 runs on silica gel t.l.c. as for b).
- 24 -
.:: .
-
,,
,, .
.. '' `

~c)77o33
In the manufacture of compounds 8, wherein A is an
ethylene radical, the unsaturated ketone intermediate is reduced
to the saturated ketone as follows:-
The more polar epimer (epimers at C-3 of the butenyl
side-chain) of 4~-(4-p-chlorophenoxy-3-hydroxybut-1-enyl)-
2,3,3a~,6a~-tetrahydro-2-oxo-5a-(p-phenylbenzoyloxy)cyclopenteno-
[b~furan (360mg.) was dissolved in ethanol (25ml.) and the
solution was added to nickel boride, previously prepared from
nickel acetate (620mg.) and sodium borohydride (2.5ml. of a
lM solution). The mixture was shaken with hydrogen for 3 hours
and was then filtered, and the filtrate was evaporated to
dryness to give 4~-(4-p-chlorophenoxy-3-hydroxybutyl)-2,3,3a~,6a~-
tetrahydro-2-oxo-5a-(p-phenylbenzoyloxy)cyclopenteno[b~furan,
RF= 4 (5% ethyl acetate in toluene). The saturated ketone was
then used, in place of the unsaturated ketone, in the remainder
of the process described in Example 1.
Example 3
To a solution of the more polar C-15 epimer of 16-(4-
chlorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-
13-trans-prostadienoic acid (15mg;) in methanol (lml;) at 0C.
was added an excess of a solution of diazomethane in ether. After
10 minutes the solvents were evaporated to give a single C-15
epimer of methyl 16-(4-chlorophenoxy)-9a,11a,15-trihydroxy-
17,18,19,20-tetranor-5-cis-13-trans-prostadienoate as a clear oil,
RF= 3 (ethyl acetate). The n.m.r. spectrum showed the
. .
- 25 -
. . :.:.. - : :
.. .: ;. ~-,, .. . - ~
. .
,: :: : :, ' ' ~
.. .. .. . .
,, ~: , . ' ~

~77~33
following characteristic bands (~ values):-
6.8-7.2, 4 aromatic protons
5.3-5.7, 4 olefinic protons
3.6, COOCH3
Example 4
The process described in Example 1 was repeated, using
the appropriate phosphonate reagent, or an equivalent phosphorane
R4CH2.CO.CH:PPh3 to give the compounds shown below. The
products were identified by n.m.r. spectroscopy and are
characterised below either by RF value on thin layer
chromatography, or by accurate mass measurement by mass
spectrometry of the molecular ion of the appropriate fully
protected (trimethylsilyl) derivative, which is prepared by
adding, to the compound to be mass measured, bis-trimethylsilyl-
trifluoroacetamide containing 1% trimethylchlorosilane (Regisil-
trade mark) and leaving the mixture for 1 hour. In some cases,
the phosphonate reagent, or the unsaturated ketone intermediate
have been characterised and appropriate data for these compounds ;
are also given.
HO
~ ~ OOH
~
~ ~ CH(oH)-X-Y-R4
HO
- 26 -
, .
,
- . - . . .: , .
. .
.
' . ': , :'~ : .
" ': ' ' ~.'.

-- 1077033
_ r Other
4 substituent
No R X Y in
. acid
~ _ _
21 phenyl -CH2- -N(CH3)-
22 4-chlorophenyl ( 3 :2 -O-
23 4-chlorophenyl -CH2- -S-
24 3-fluorophenyl -CH2- -O-
2-fluorophenyl -CH2- -O-
26 3,4-dichlorophenyl-CH2- -O-
27 2,5-dichlorophenylCH2 -O-
28 2-tolyl -CH2- -O-
29 2,3-xylyl -CH2- -O-
3,5-xylyl -CH2- -O-
31 2-chloro-4-methylphenyl -CH2- -O-
32 3-dimethylaminophenyl -CH2- -O-
33 l-naphthyl -CH2- -O-
34 4-chloro-1-naphthyl -CH2- -O-
2-naphthyl -CH2- -O- 2-methyl
36 6-methyl-2-naphthyl -CH2- -O-
37 6-methoxy-2-naphthyl-CH2- -O-
38 3-chlorophenyl -CH2- -O- 2-methyl
39 2,3-dichlorophenyl-CH2- -O-
2,6-dichlorophenyl-CH2- -O-
41 3,5-dichlorophenyl-CH2- -O-
42 4-chloro-3-methylphenyl -CH2- -O-
43 3-methoxyphenyl -CH2- -O-
44 1-chloro-2-naphthyl -CH2- -O-
5,6,7,8-tetrahydro-2- -CH2- -O-
naphthyl
- 27 -
: , .
:, .. . .
. ~ : :
: , .. :: : :
. : : .:

` lU 77033
_ Mass spectrum ¦Phosphonate Enone
No. Isomer(a) Pj ( C. m.p.(C.)
Found Calculated
.
21 mlPp691 691.3940 l~ (b) 145-150
22 mp M-CH = 725.3313 ,150/0.05 (c)
lp7~5.3302
23 mlppM =728.2977 728.3006 ¦ (b) 135-138
24 lmppM+=696.3496 696.3531 ¦ (d) 138-139
mlppM+=696.3510 696.3531 , (e) 144
26 mlppM+=746.2791 746.2844 ' (~) 150-152
27 mlPp746 746.2844 1 (g) 187-190 .
I28 Im1P IM;=692383!6923781I14-060/ l165-167l
29 mlPp 706 706.3935 180/0.15 166-168
mlppM+=706.3922 706-3935 1 _ ~ 140-142
31 mlP 726 726 ~ ~ 1 113-115
¦ 32 mlppM+-721.4020 721.4047 ¦ (b) ¦ 138-145
33 mlppM+=728.3830 728.3781 ~~ (h) ~ 185-187
~ 34 ¦ mp ~M 762 335 ~ 762 3388 (i
I ( j~ I
!
- 28 -
~ " ' ' ' ,, `'' ; `' ' ,
-
- : . .
: , :

1(:)77033
I Mass Spectrum Phosphonate Enone
No. Isomer(a . b pj ( C./ m.p.(C.)
FoundCalculated
i
mlPp 742 742.3937 m.p.85-86 185-187
36 lmpp 742 742.3937 m.p.71-72 153
37 lmp M+=758.3910 758.3887 m.p.58-59 195
38 mlpp M+=726.3346 726.3391 180/0.2 (~)
39 mp + 73~.2644 731.2609 175/0.03 153-155
lp M -CH3=731
4 mlpp 746 746.2844 m.p.89-90 140-142
41 lmpp M+~746.2829 746.2844 m.p.80-82 138-139
42 mlp M+=726.3397 726.3391 _ 143
43 mlpp 708 708.3730 (1) 129-130
~ 1~
(a) mp= more polar, lp= less polar.
tb) these compounds synthesised from phosphoranes (not
phosphonates)~ made as described below.
(c) RF= -5 (5% ethyl acetate in toluene).
(d) RF= 0.2 (40% ethyl acetate in methylene dichloride)
- 29 -
. : . , ;
~; :' ., "`.' ' ' :
} , :,
:~

77033
(e) RF= 4 (5% acetic acid in ethyl acetate)
(~) RF= 0 3 (50% ethyl acetate in chloroform)
(g) RF= 0.23 (50% ethyl acetate in chloroform)
(h) RF= 0 3 (50% ethyl acetate in methylene dichloride)
(i) RF= 4 (10% methanol in ethyl acetate)
(j) RF= 0.8 (50% ethyl acetate in toluene)
(k) RF= 0.6 (50% ethyl acetate in toluene)
(1) RF= 4 (5% ethyl acetate in methylene dichloride)
(m) RF= 0.25 (3% acetic acid in ethyl acetate)
(n) RF= 3 (3% acetic acid in ethyl acetate)
(m) and (n); ~ 6.8 (lH, aromatic), 6.6 (2H, aromatic), 5.4
(2H, olefinic) and 5.7 (2H, olefinic).
The preparation of a phosphorane, which may be used in
place of a phosphonate in the preparation of a cyclopentane
derivative of the invention J iS exemplified by the preparation of
~3-(3-dimethylaminophenoxy)-acetonylidene~-triphenylphosphorane
as follows:-
n-Butyl-lithium (3.85ml. of a 1.3M solution in hexane)
was added to a solution of 3-dimethylaminophenol (685mg.) in
dimèthoxyethane (20ml.) at -70C. under an atmosphere of nitrogen.
The solution was allowed to warm to room temperature, a solution
of 3-iodoacetonylidene-triphenylphosphorane (2.22g.) in benzene
(lOOml.) was added, and the mixture was heated under reflux for
2 hours. The mixture was then diluted with toluene (lOOml.),
washed with water t2 x 50ml.) and dried, the solvents were
- - 30 -

1077~33
evaporated and the residue was triturated with ether to give
[3-(3-dimethylaminophenoxy)acetonylidene~triphenylphosphorane,
m.p.110-115C.
In a similar manner were prepared the analogous N-
methylanilino (gum) and 4-chlorophenylthio (m.p.158-165C.)
phosphoranes.
Example 5
The process described in Example 3 was repeated, using
the appropriate more polar C-15 epimer, in place of the more
polar C-15 epimer of 16-(4-chlorophenoxy)-9a,11a,15-trihydroxy-
17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, to give
the following methyl esters as single C-15 epimers:-
a) methyl 16-(4-fluorophenoxy)-9a,11a,15-trihydroxy-17,18~19,20-
tetranor-5-cis-13-trans-prostadienoate, RF= 3 (5% methanol
in toluene) 0= 6.8-7.2 (aromatic), 5.3-5.7 (4 olefinic
protons), 3.6 (methyl ester).
b) methyl 9a,11a,15-trihydroxy-16-(2-naphthyloxy)-17,18,19,20-
tetranor-5-cis-13-trans-prostadienoate, M = 670.3542
(calculated 670.3541).
c) methyl 9a,11a,15-trihydroxy-2-methyl-16-(2-naphthyloxy)-
17,18,19,20-tetranor-5-cis-13-trans-prostadienoate,
M~= 684.3678 (calculated 684.3697).
d) methyl 9a,11a,15-trihydroxy-16-(6-methyl-2-naphthyloxy)-
17,18,19,20-tetranor-5-cis-13-trans-prostadienoate,
M = 684.3739 (calculated 684.3698).
- 31 -
:: . - . , :. . :
. ..... :, , . :~ . :
., `'`- ' ':

~077033
e) methyl 9~,11a,15-trihydroxy-16-(6-methoxy-2-naphthyloxy)-
17,18,19,20-tetranor-5-cis-13-trans-prostadienoate,
M+= 700.3681 (calculated 700.3647).
f) methyl 16-(3-chlorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-
tetranor-5-cis-13-trans-prostadienoate, RF= 0 3 (ethyl
acetate),M = 654.2973 (calculated 654.2995).
g) methyl 9a,11a,15-trihydroxy-2-methyl-16-(3-chlorophenoxy)-
17,18,19,20-tetranor-5-cis-13-trans-prostadienoate,
RF= 4 (ethyl acetate), M+= 668.3133 (calculated 668.3151). r
Example 6
16-(4-Chlorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-
tetranor-5-cis-13-trans-prostanoic acid (20mg. of the more polar
C-15 epimer) was treated with an excess of dilute aqueous
ammonia to form the ammonium salt. The excess of ammonia was
evaporated under reduced pressure, and the residue was treated
with the stoichiometric amount of silver nitrate to form the
silver salt. The silver salt was filtered off, dried, dissolved
in n-butyl iodide (0.5ml;) and stirred at room temperature for
1 hour. The solution was extracted with ethyl acetate, the ethyl
acetate extract was evaporated to dryness, and the residue was
r~ chromatographed on Florisi~ (lg.) using 50% ethyl acetate in
toluene as eluant, to give n-butyl 16-(4-chlorophenyl)-9a,11a,15-
trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate,
M+= 696.3427 (calculated 696.346~), RF= 4 (ethyl acetate).
In a similar manner, but using ethyl iodide in place of
Qn~ k
- 32 -

1~77033
n-butyl iodide, there was obtained ethyl 16-(4-chlorophenyl)-
9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-
prostadienoate, M = 668.3086 (calculated 668.3151).
Example 7
A solution of the mixed anhydride of acetic acid and
the more polar C-15 epimer of 9a-acetoxy 16-(4-chlorophenoxy)-
lla,16-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis-
13-trans-prostadienoic acid (73mg.) in 2ml. of a 2:1 mixture of
acetic acid and water, was stirred at 47C. under nitrogen for
4 hours. The solvents were evaporated, the residue was dissolved
in dilute aqueous sodium bicarbonate solution (2ml;~ and the
solution was extracted with ethyl acetate (3 x 2ml.). The
extracts were discarded, the aqueous solution was acidified to
pH 3-4 with 2N aqueous oxalic acid and the acidified solution was
extracted with ethyl acetate (4 x 5ml;). The ethyl acetate
extracts were washed with a 1:1 mixture of saturated brine and
water, and were then dried. After evaporation of the ethyl
acetate, the residue was purified by thin-layer chromatography on
silica gel using 3% acetic-acid in ethyl acetate, to give the
20 more polar C-15 epimer of 9a-acetoxy-16-(4-chlorophenoxy)-lla,15-
dihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid,
M+= 682.2942 (calculated 682.2944).
The bis-tetrahydropyranyl ether used as starting
material may be prepared as follows:-
A solution of the more polar C-15 epimer of 9a-hydroxy-
':,,'. ' ', .
. .
. ~
' .. ' ' . :
-

11~77033
16-(4-chlorophenoxy)-lla,15-bis(tetrahydropyran-2-yloxy)-
17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid (70mg.~
in 0.15ml. of a 2:1 mixture of pyridine and acetic anhydride was
kept at room temperature for 16 hours. The volatile material .
was evaporated and cyclohexane (lOml.) wa5 added to, and boiled
off from, the residue three times, leaving the mixed anhydride
of acetic acid and 9a-acetoxy-16-(4-chlorophenoxy)-lla,15-bis-
(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis-13-trans-
prostadienoic acid as a yellow oil,~max (CHC13) 1720, 1810cm 1.
Example 8
To a solution of 9a-acetoxy-16-(4-chlorophenoxy)-lla,15-
dihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid
(12mg.) in methanol (lml.) at 0C. was added an excess cf a
solution of diazomethane in ether. After 10 minutes, the solvents
were evaporated, the residue was dissolved in ether, and the
solution was treated with lithium aluminium hydride (50mg.). The
mixture was stirred at room temperature for 1 hour, the excess of
hydride was destroyed by the addition of water (lml;) and the
mixture was extracted with ethyl acetate to give 16-(4-chloro-
phenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-
prostadienol, M = 698.3439 (calculated 698.3441), RF= 0.2 (ethyl
acetate).
In a similar manner, there were obtained:-
16-(3-chlorophenoxy)-9a,11a,15-trihydroxy-2-methyl-17,18,19,20-
tetranor-5-cis-13-trans-prostadienol, RF= 0.15 (ethyl acetate,
- 34 -

~1:)77~33
M+= 712.3575 (calculated 712.3597).
9a,11a,15-trihydroxy-16-(6-methyl-2-naphthyloxy)-17,18,19,20-
tetranor-5-cis-13-trans-prostadienol, RF= 0.2 (èthyl acetate).
Example 9
The process described in Example 1 was repeated using
the appropriate phosphonate reagent,to give:-
a) 9a,11a,15-trihydroxy-16-(4-hydroxyphenoxy)-17,18,19,20-
tetranor-5-cis-13-trans-prostadienoic acid, RF= 0.2 and 0.3
(3% acetic acid in ethyl acetate). ~=6.82 (4H, aromatic) 9
5.3-5.7 (4H, olefinic), 3.98-5.1 (lOH, ~CH.O- and
exchangeable protons); phosphonate, RF= 0.2 (10% methanol
in ethyl acetate); enone, m.p.l35-140C.
b) 16-furfuryl-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-
13-trans-prostadienoic acid, RF= 0 5 (3% acetic acid in
ethyl acetate), ~= 7.5 (lH) and 6.3 (2H) (furyl protons)
5.1-5.6 (4H, olefinic); phosphonate, b.p.200C./0.2mm;
; enone, m.p.92-93C.
c) 16-(3-allylphenoxy)-9a,11a,15-trihydroxy-17,18,19,20-
tetranor-5-cis-13-trans-prostadienoic acid, M = 718.3892
(calculated 718.3938); phosphonate, RF= 0.32 (ethyl acetate);
enone, m.p.110-112C.
Example 10
The process described in Example 1 was repeated, using
a 9-oxo prostanoic acid derivative in place of a 9a-hydroxy
prostanoic acid derivative, to give the compounds shown below.
- 35 ~
'' '~: .' :`

~77033
For measurement of mass spectra, the acids were converted to
methyl esters with diazomethane, the 9-oxo group was protected
by conversion to the methoxime with methoxylamine, and, where
indicated, the hydroxy groups at C-ll and C-15 were protected as
the trimethylsilyl derivatives. N.m.r. spectra were measured in
deuterated acetone.
~~COO~
, CH(OH)-X-Y-R4
HO
.
No. R X
46 phenyl -CH2- -O-
47 phenyl -CH(CH3)- -O-
48 phenyl . -(CH ) - -O-
49 l-naphthyl -CH2- -O-
2-naphthyl -CH2- -O-
51 4-chlorophenyl -CH2- -O-
52 4-chlorophenyl -CH2- -S-
53 3-chlorophenyl -CH2- -O-
54 2-chlorophenyl -CH2- -O-
4-chlorophenyl -C(CH3)2 -O-
56 4-bromophenyl -CH2- -O-
57 4-fluorophenyl -CH2- -O-
58 3-fluorophenyl -CH2- -O-
- 36 -
:. . :, : :,
- . ,:

~077033
No. R4 X Y ..
59 2-fluorophenyl -CH2- -0-
2,4-dichlorophenyl -CH2- -0-
61 2,5-dichlorophenyl -CH2- -0-
62 3,5-dichlorophenyl -~H - -0-
63 4-tolyl -CH2- -0-
64 3-tolyl -CH2- -0-
2-tolyl -CH2- -0-
66 3,5-xylyl -CH2- -0-
67 phenyl -CH2- -G-
68 2-chloro-4-methyl- -CH2- -0-
phenyl
69 3-trifluoromethyl- -CH2- -0-
4-methoxyphenyl . -CH2- -0-
71 2-methoxyphenyl -CH2- -0-
72 ¦ 4-c oro~ CH2- ¦ -0-
- 37 -
';' ",,, ' ,; . .~, ' ,;, :~ ,

1077033 r
No Isomer Characterisine Data
46 mixed RF= 0.2 (acetone/cyclohexane/ethyl acetate -
N.m.r.:06.98-7.28 (5H, aromatic), 5.48
(2H, cis olefin), 5.78 (2H, trans
olefin), 3.5-4.5 (5H, ~CH.O- and -COOH)
47 mixed M+= 589.3267 rcalculated 589.3255 for
methyl ester, 9-methoxime, 11,15-di-
(trimethylsilyl) derivative~. R = 0.4
(3% acetic acid in ethyl acetate~
48 mixed RF= 3 (3% acetic acid in ethyl acetate)
49 mixed RF= 4 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at 08.3-8.5 (lH),
7.7-7.9 (lH~, 7.2-7.5 (4H) and 6.8-
7.o8 (lH)
50 mixed RF= 3 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at ~7.7 7.8 (3H)and 7.1-7.5 (4H)
51 mp M+= 609.2633 rcalculated 609.2709 for methyl
ester, 9-methoxime, 11,15-di(trimethyl-
silyl) derivativel. RF= 0.4 (3% acetic
acid in ethyl acetate)
52 mixed RF= 5 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at 07.3 (4H)
53 mp RF= 3 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at ~7.15 (lH) and
6.9 ~3H)
54 mixed RF= 4 t3% acetic acid in ethyl acetate)
55 mixed RF= -5 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at 07.28 (2H), 7.19
(2H) and 2 methyls at 01.25 and 1.30 (6H
... . - ..,, , . , ., . ..: . .. .
.. . .. . ..
. ~

1077033 r
No. Isomer Characterising Data
56 mixed M+= 509.1417 (calculated 509.1413 for methyl
ester, 9-methoxime)
57 mixed RF= 3 (3% acetic acid in ethyl acetate)
N.m.r.: aromatic protons at ~6.91 (2H) and
7.o8 (2H)
58 mixed RF= 3 (2% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at a7.25 (lH) and
6.65 (3H)
59 mixed RF= 4 (5% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at ~7.05 (4H)
mixed RF= 4 (0.25% dcetic acid in ethyl acetate)
N.m.r.: aromatic protons at ~7.12 (lH), 7.3
(lH) and 7.41 (lH)
61 mixed RF= 34 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at ~7.3 (lH), 7.15
(lH) and 6.9 (lH)
62 mixed RF= 34 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at ~ 6.9 (3H)
63 mixed RF= 0.2 (cyclohexane/ethyl acetate/acetone,
2:2:1).
N.m.r.: aromatic protons at ~6.7 (2H) and
7.1 (2H), and methyl at ~2.28
64 mixed RF= 5 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at ~7.05 (lH) and
' 6.73 (3H), and methyl at ~2.28
mixed M+= 589.3284 rcalculated 589.3254 for methyl
ester, methoxime, di(trimethylsilyl)
derivative~ RF= 0 35 (3% acetic acid in
ethyl acetate)
- 39 ~
: ; : :

1077033
No. Isomer Characterising Data
66 mixed RF= 0.2 (cyclohexane/acetone/ethyl acetate -
N.m.r.: aromatic protons at ~6.5 (3H), and
methyls (6H) at 2.28
67 mixed RF= 5 (5% acetic aeid in ethyl acetate).
N.m.r.: aromatic protons at ~7.2 (lH) and
6.85 (2H), and methyl at 2.3
68 mixed RF= 4 (eyclohexane/ethyl acetate/acetone-
N.m.r.: aromatic protons at o7.18 (lH) and
6.80 (2H), and methyl at 2.2
69 mp RF= 5 (5% ace~ie acid in ethyl acetate).
N.m.r.: aromatic protons at ~7.5 (lH) and
7.25 (3~)
70 mixed RF= 0.6 (3% acetic acid in ethyl acetate)
71 mixed RF= o.65 and 0.7 (3% acetic acid in ethyl
acetate)
72 mixed RF= o4 (3% acetie aeid in ethyl aeetate).
N.m.r.: aromatie protons at ~8.4 (lH), 8.15
(lH), 7.6 (3H) and 7.08 (lH)
* mp= more polar.
The 9-oxo prostano;e aeid derivatives used as starting
materials may be obtained by oxidation of the corresponding 9a-
hydroxy eompound, as exemplified below for the preparation of 9-
- 40 -
.
' . ' ~
~'~ . " .. " ., . ' ., ,'' ' '.

1077033
oxo-16-phenoxy-lla,15-bis(tetrahydropyran-2-yloxy)-17,18,19,20-
tetranor-5-cis-13-trans-prostadienoic acid:-
To a solution of 9~-hydroxy-16-phenoxy-11~,15-bis-
(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis-13-trans-
prostadienoic acid (270mg.) in acetone (5ml.) at -10C. was
added Jones' reagent (chromic acid in acetone), (0.163ml.).
After 15 minutes, isopropanol (1 drop) was added, followed by
ethyl acetate (20ml.). The solution was washed with 1:1 saturated
brine/water, and was dried. Evaporation of the solvents, and
chromatography of the residue on silica, using 1:1 ether/
petroleum ether (b.p.40-60C;) as eluting solvent, gave the
required 9-oxo-bis(tetrahydropyranyl ether), RF= 0.2 (50% ethyl
acetate in toluene).
Example 11
The process described in Example 3 was repeated, using
lla,15-dihydroxy-16-(2-naphthyloxy)-9-oxo-17,18,19,20-tetranor-
5-cis-13-trans-prostadienoic acid, in place of 16-(4-chlorophenoxy)-
9~ ,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-
prostadienoic acid, to give methyl lla,15-dihydroxy-16-(2-
naphthyloxy)-9-oxo-17,18,19,20-tetranor-5-cis-13-trans-
prostadienoate, RF= 3 (ethyl acetate).
Example 12
To a solution of 16-(4-chlorophenylthio)-9a,11~,15-tri-
hydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid
(12mg:) in methanol (0.5ml.) at 0C. was added a solution of
- 41 -
-
- : .-: ..
:, .. .. , , :. :
.:. :-: ;:. i :.: .
- .
..

1~77033
sodium periodate (5mg.) in water t0.5ml.). After 18 hours the
solvents were evaporated, and the residue was extracted with
acetone to give 16-(4-chlorophenylsulphiny1)-9~ ,15-tri-
hydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid,
M+= 744.2918 (calculated 744.2956), RF- 0.2 (3% acetic acid in
ethyl acetate).
Example 13
% w/v
16-(4-fluorophenoxy)-9~ ,15-trihydroxy-
17,18,19,20-tetranor-5-cis-13-trans-
prostadienoic acid 0.003
Sodium phosphate 2.90
Sodium hydrogen phosphate 0.30
Water for injection to 100
The sodium phosphate was dissolved in about 80% of the
water, followed by the prostadienoic acid derivative, and, when
dissolved, the sodium hydrogen phosphate. The solution was made
up to volume with water for injection, and the pH was checked to
be between 6.7 and 7.7. The solution was filtered to remove
particulate matter, sterilised by filtration, and filled into
presterilised neutral glass ampoules under aseptic conditions.
Immediately before use, the contents of an ampoule are diluted in
sodium chloride B.P. for administration by intravenous infusion.
The prostadienoic acid derivative may, of course, be
replaced by an equivalent amount of another prostanoic acid
derivative of the invention.
- 42 -
.:: . . .
:: . -, .