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Patent 1098125 Summary

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(12) Patent: (11) CA 1098125
(21) Application Number: 1098125
(54) English Title: PROCESS FOR THE PREPARATION OF NEW PROSTAGLANDIN ANALOGUES
(54) French Title: PROCEDE DE PREPARATION DE NOUVEAUX ANALOGUES DE LA PROSTAGLANDINE
Status: Term Expired - Post Grant
Bibliographic Data
(51) International Patent Classification (IPC):
  • C08B 37/16 (2006.01)
  • C07C 391/02 (2006.01)
  • C07C 405/00 (2006.01)
  • C07F 1/02 (2006.01)
(72) Inventors :
  • HAYASHI, MASAKI (Japan)
  • KORI, SEIJI (Japan)
  • WAKATSUKA, HIROHISA (Japan)
(73) Owners :
  • ONO PHARMACEUTICAL CO., LTD.
(71) Applicants :
  • ONO PHARMACEUTICAL CO., LTD. (Japan)
(74) Agent: MACRAE & CO.
(74) Associate agent:
(45) Issued: 1981-03-24
(22) Filed Date: 1977-04-13
Availability of licence: N/A
Dedicated to the Public: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data:
Application No. Country/Territory Date
15982/76 (United Kingdom) 1976-04-20

Abstracts

English Abstract


ABSTRACT
Process for the preparation of prostaglandin
analogues of the formula:
<IMG> VI
(wherein R3 represents the 1,1-dimethylpentyl or 2(.epsilon.)-
ethylheptyl group) which comprises reacting a compound of
the formula:
VII
<IMG>
(wherein R4 represents a 2-tetrahydropyranyl group unsubstituted
or substituted by at least one alkyl radical, or a 2-tetra-
hydrofuranyl or 1-ethoxyethyl group, R5 represents an alkyl
group of 1 to 4 carbon atoms, and R6 represents an alkylcarbonyl
group of 2 to 5 carbon atoms) with the sodio derivative of a
dialkyl phosphonate of the formula:
<IMG> VIII
(wherein R7 represents an alkyl group of 1 to 4 carbon atoms,
and R3 is as hereinbefore defined) to obtain a compound of
the formula:

<IMG> IX
. reducing the 15-oxo group in the resulting compound to a
hydroxy group, reacting the obtained hydroxy compound with
dihydropyran unsubstituted or substituted with at least one
alkyl radical, dihydrofuran or ethyl vinyl ether, to obtain
a compound of the formula:
<IMG> XI
. hydrolysing under alkaline conditions the resulting compound
to obtain a compound of the formula:
<IMG> XII
(wherein R represents a hydrogen atom or the methyl radical),
converting the 9.alpha.-hydroxy group in the compound of formula
XII to an oxo group, and hydrolysing the OR4 groups in the
resulting compound of the formula:

<IMG>
XIII
to hydroxy groups to obtain a PGE compound of formula VI
or methyl ester thereof. All the double bonds in the
foregoing formulae are trans, and the wavy line ? indicates
attachment of the group in alpha or beta configuration.
The prostaglandin analogues of formula VI possess
pharmacological properties.


Claims

Note: Claims are shown in the official language in which they were submitted.


The embodiments of the invention, in which an
exclusive privilege or property is claimed, are defined as
follows:
1. Process for the preparation of prostaglandin
analogues of the general formula:
VI
<IMG>
(wherein R3 represents the 1,1-dimethylpentyl or 2(.epsilon.)-
ethylheptyl group, the wavy line ? indicates attachment
of the hydroxy group to the carbon atom in alpha or beta
configuration and the C2-C3 and C13-C14 double bonds are trans)
and methyl esters thereof, and cyclodextrin clathrates of such
acids or esters, and non-toxic salts of such acids, which
comprises reacting a compound of the general formula:
<IMG> VII
(wherein R4 represents a 2-tetrahydropyranyl group unsubstituted
or substituted by at least one alkyl radical, or a 2-tetra-
hydrofuranyl or 1-ethoxyethyl group, R5 represents a straight-
or branched-chain alkyl group containing from 1 to 4 carbon
atoms, R6 represents an alkylcarbonyl group containing from 2 to
5 carbon atoms, and the depicted double bond is trans)
with the sodio derivative of a dialkyl phosphonate of the
general formula:
- 50 -

<IMG>
VIII
(wherein R7 represents an alkyl group containing from
1 to 4 carbon atoms, and R3 is as hereinbefore defined)
to obtain a compound of the general formula:
<IMG> IX
(wherein R3, R4, R5 and R6 have the meanings hereinbefore
specified, and the depicted carbon-carbon double bonds are
trans), reducing the 15-oxo group in the resulting compound
to a hydroxy group to obtain a compound of the general
formula:
<IMG> X
(wherein the various symbols are as hereinbefore specified,
the wavy line ? indicates attachment of the hydroxy group
to the carbon atom in alpha or beta configuration, and the
depicted double bonds are trans), reacting the obtained
compound with dihydropyran unsubstituted or substituted
with at least one alkyl radical, dihydrofuran or ethyl
- 51 -

vinyl ether, to obtain a compound of the general formula:
XI
<IMG>
(wherein the various symbols and ? are as hereinbefore
specified, and the depicted double bonds are trans),
hydrolysing under alkaline conditions the resulting
compound to obtain a compound of the general formula:
<IMG> XII
(herein R represents a hydrogen atom or the methyl
radical, the other symbols and ? have the meanings
hereinbefore specified, and the depicted double bonds
are trans), converting the 9.alpha.-hydroxy group in the
compound of general formula XII to an oxo group, and
hydrolysing the OR4 groups in the resulting compound
of the general formula:-
XIII
<IMG>
- 52 -

(wherein R, R3, R4 and ? have the meanings hereinbefore
specified, and the depicted carbon-carbon double bonds are
trans) to hydroxy groups to obtain a PGE compound of the
general formula VI depicted hereinbefore or methyl
ester thereof, and if desired,
(i) converting a prostaglandin analogue of general formula
VI depicted hereinbefore so obtained into the methyl ester
or into a non-toxic salt, or
(ii) converting a prostaglandin analogue of general
formula VI depicted hereinbefore so obtained, or methyl
ester thereof, into a cyclodextrin clathrate.
2. Process according to claim 1 for the
preparation of a prostaglandin analogue of the
formula:
<IMG> VIA
(wherein R3 represents the 1,1-dimethylpentyl group,
the wavy line ? indicates attachment of the hydroxy
group in alpha or beta configuration and the C2-C3
and C13-C14 double bonds are trans) and cyclodextrin
clathrates thereof which comprises using as a starting
material the sodio derivative of a dialkyl phosphonate
- 53 -

of general formula VIII depicted in claim 1, wherein R3
represents the 1,1-dimethylpentyl group and R7
is as defined in claim 1, to obtain ultimately a PGE
compound of the general formula:
VIB
<IMG>
(wherein R3 and ? have the meanings hereinbefore
specified, the depicted carbon-carbon double bonds are
trans, and R represents a hydrogen atom or the methyl
radical) and, when R in general formula VIB represents
a hydrogen atom. converting the resulting acid into its
methyl ester of formula VIA, and if desired converting
the prostaglandin analogue of formula VIA thus obtained
into a cyclodextrin clathrate.
3. Process according to claim 1 wherein R4
represents the 2-tetrahydropyranyl group.
4. Prostaglandin analogues of the general formula:
- 54 -

<IMG>
VI
(wherein R3 represents the 1,1-dimethylpentyl or 2(.epsilon.)-
ethylheptyl group, the wavy line ? indicates attachment
of the hydroxy group in alpha or beta configuration and
the C2-C3 amd C13-C14 double bonds are trans) and methyl
esters thereof, and cyclodextrin clathrates of such
acids or esters, and non-toxic salts of such acids,
when prepared by a process claimed in claim 1 or 3.
5. A prostaglandin analogue of the formula:
<IMG> VIA
(wherein R3 represents the 1,1-dimethylpentyl group,
the wavy line ? indicates attachment of the hydroxy
group in alpha or beta configuration and the C2-C3
and C13-C14 double bonds are trans) and cyclodextrin
clathrates thereof when prepared by a process claimed
in claim 2 or 3.
- 55 -

Description

Note: Descriptions are shown in the official language in which they were submitted.


l~9B~Z5
THIS INVE~TION relates to a process for the
preparati.on. of new prostaglandin analoyues.
In the Specification of our British Patent ~o.
1416410 we have described and claimed inter alia trans-~2-
prostaglandin analogues of the genera.1 formula:
7 5 3 COOH
8~ ~
~ I
~H
(wherein A represents a grouping of the formula:
or
OH
II III IV
' .
X represents ethylene (i.e. -CH2CH2-) or trans-vinylene
(i.e. -CH=CH-), Rl represents a straight- or branched-
- chain alkyl radical containing from 1 to 10 carbon atoms
.i
or a straight- or branched-chain alkyl radical containing
from 1 to 6 carbon atoms carrying a phenyl substituent or
. a cycloalkyl substituent of 5 to 7 carbon atoms, R2
represents a hydrogen atom or a straight- or branched-
chain alkyl radical containing from 1 to 4 carbon atoms,
the wavy line ~^~ indicates attachment of the hydroxy
:`
- 2
.
.
, , ;` ', ,, : '

98~Z5
radical to the carbon atom in alpha or beta configuration
and the C2-C3 double bond is trans) and alkyl esters
thereof having 1 to 10 carbon atoms in a straight- or
branched-chain, and cyclodextri.n clathrates of such acids
or esters, and non-toxic salts or such acids, with the
exclusion of trans-~ -PGEl. In the aforesaid Specification
it is disclosed that the compounds possess the known
valuable pharmacological properties typical of
prostaglandins in a selective fashion including, in
particular, hypotensive activity, inhibitory activity on
blood platelet aggregation, inhibitory activity on gastric
acid secretion, and gastric ulceration, and bronchodilator
activity 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 and myocardial infarction, in the treatment of
gastric ulceration and in the treatment of asthma.
It has now been found after further research
and experimentation that trans-~2-prostaglandin analogues
of general formula I wherein A represents the grouping of
the formula:
o
A, .
Y~
OH
3 --

10981ZS
X represents trans-vinylene, Rl represents the
l,l-dimethylpentyl group [i.e.
IH3
7 (CH2)3-CH3] or the 2(~)-ethylheptyl group
CH3
~i.e. -CH2-~H-(CH2)4-CH3~ and R2 represents a hydrogen atom
C 2H5
~viz. 16,16-dimethyl-trans-~2~P OE 1~ and 17(~)-ethyl-~-
dihomo-trans-~2-PGEl~ and methyl esters thereof, the
cyclodextrin clathrates of such acids and esters, and
non-toxic salts of the acids, possess unexpectedly
outstanding pharmacological properties.
The present invention is thus concerned with
the hitherto unknown prostaglandin analogues of the
general fonmula:
3 Co
OH OH
(wherein R3 represents the l,l-dimethylpentyl or 2(~)-
ethylheptyl c3roup, the wavy line ~v indicate~ attachment
of the hydroxy group in beta or, preferably, alpha
configuration and the C2-C3 and C13-C14 do
trans) and methyl esters thereof, and cyclodextrin
clathrates of such acids or esters, and non~toxic (e.g.
' ~ ' ' .
.:
.

~O~B~Z~
sodium) salts of such acids.
The present inven~ion is concerned with all
such compound~ in the 'natural' form as depicted.
As will be a~parent to those skilled in the art,
the compounds depicted in general fo~nula VI have four
centres of chirality, these four centres of chirality
being at the alicyclic ring carbon atoms identified as 8,
11 and 12 and at the C-15 carbon atom which has attached
to it a hydroxy group. A further centre of chirality
occurs when the symbol R3 represents a 2(~)-ethylheptyl
group. The presence of chirality leads, as is well
known, to the existence of isomerism. ~11 isomers of
general formula VI and mixtures thereof are to be
considered within the scope of general formula VI.
The prostaglandin analogue of formula Vl wherein
R3 represents the l,l-dimethylpentyl group, and ihe methyl
ester, and non-toxic salts thereof, have been found
to possess exceptionally good abortifacient activity and
stimulatory activity on uterine contraction, activities
not mentioned in the Specification of British Patent ~o.
1416410 in respect of any specific compound conforming
to general formula I disclcsed therein, and are
accordingly useful in the termination of pregnancy and
induction of labour in pregnant female mammals and in the
control of oestrus, contraception and menstrual regulation
in female mammals. Such compounds also have hypotensive
'~

~Cli9~ 25
activity.
l~e prostaglandin analogue of formula VI wherein
R3 represents the 2(~)-ethylheptyl group, and the methyl
ester, and non-toxic salts thereof, have been found to
possess an exceptionally good hypotensive activity and are
accordingly useful in the treatment of hypertension and in
the treatment of disorders of the peripheral circulation.
The prostaglandin compounds of the present
invent~on have relatively low potencies in inducing
diarrhoea in comparison with their poter.cies in respect
of the valuable pharmacological properties hereinbefore
mentioned, and may accordingly be used for the stated
purposes at appropriate rates of administration which
do not induce diarrhoea as an undesired side effect.
The pxeferred compound of the invention in respect
of its abo_tifacient activity and stimulatory activity
on uterine contraction is 16,16-dimethyl-trans-~2-P OE 1
methyl ester, and the preferred compound of the invention
in respect of its hypotensive activity is 17(~)-ethyl-~-
dihomo-trans-~2-PGE1 methyl ester.
For example, in standard laboratory tests, on
oral administration to the conscious spontaneously
hypertensive rat, 17(~)-ethyl-~-dihomo-trans-~2-PGEl
methyl ester produces falls in blood pressure of 15 mm Hg,
~5 10 mm Hg, and 14 mm Hg, at 0.5, 1 and 3 hours after
administration, respectively, at a dose of 0.1 mg/kg

~9~zs
animal body weight, 33 mm Hg, 19 mm Hg, 13 mm Hg and
11 mm Hg, at 0.5, 1, 3 and 5 hours after administration,
respectively ! at a dose of 0.3 mg/kg animal body weight,
and ~4 mm Hg, 39 mm ~Ig, 21 mm Hg and 20 mm Hg, at 0.5,
1, 3 and 5 hours after administratiGn, r~spectively, at
a dose of 1.0 mg/kg animal body weight.
In the above experiments soft faeces were
observed only in one out of six rats at the dose of
0.3 mg/kg animal body weight and in none of six rats at
the doses of 0.1 mg/kg animal body weight and 1.0 mg/kg
animal body weight, respectively. These results indicate
that 17(~)-ethyl-~-dihomo-trans-~2-PGEl methyl ester has
a strong hypotensive activity and a very weak diarrhoea-
producing (side effect) activity.
16,16-Dimethyl-trans-~2-PGEl methyl ester (i)
stimulates uterine contraction when administered
intravenously to the pregnant rat on the 20th day of
gestation at a dose of 0.5 ~g/kg animal body weight,
(ii) produces a fall of the blood pressure when administered
intravenously to the allobarbital-anaesthetised dog at a
dose of 1 ~g/kg animal weight, and (iii) produces diarrhoea
at a dose of 1200 ~g/kg animal body weight by oral
administration in 50% of mice so treated.
Of the pharmacological activities of 16,16-
dimethyl-trans-~2-PGEl methyl ester, (i) uterine
contractile activity is the useful effect and (ii)

~9~3~25
hypotensive and (iii) diarrhoea-producing activiti.es are
consi.dered to be undesired effects. The pharmacological
activities on rats of 16,16-dimethyl-trans-~2-PGEl methyl
ester and of prostaglandin analogues already disclosed in
the Specification of our British Patent No. 1416410, e.g.
16(R)-methyl-trans-~ -PGEl, 16(~)-phenyl-~-trinor-trans-
~2-PGEl and 15(~)-methyl-trans-~2-PGEl, are compared in
the following Table.
-- 8 --
.:
.

- ~9~zs
- ~
_ ~I N ,~1, ~
_
o ~ o '!
.,, o o o o
~ l
-1 U ~ , 0 ~ N N
~ 1 .
~1 ~1 aO ~ O O ~ r~
-C -
rl r fa ~ ,~ In O . In. o
:. ~ g ~ ~ . I
I 1~ hl ~ a ~ al ~D al ~ I
-- ~ h ~) a)
,~ ~ ,~ ~ a ,~ ~ ,~ ~ ~
_

~9~312S
As is to be noted from the Table, 16,16-dimethyl-
trans-~ -PGEl methyl ester produces a strong desired effect
(uterine contraction) which is at least 10 times more potent
than the other ccmpounds. Moreover, the selectivity index
(separation of desired activity from side-effects, i.e.
the (il)/(i) or (iii)/(i) ratio) of 16,16-dimethyl-trans-
-PGEl me~hyl ester is very much higher than those of
the known compounds. These data indicate that 16,16-
dimethyl-trans-~ -PGE1 methyl ester has a strong uterine
contraction activity far superior to the other compounds
tested and is better and safer in use in the termination
of pregnancy and induction of labour in pregnant female
mammals and in the control of oestrus, contraception and
menstrual regulation in female mammals, than the other
compounds tested.
According to the present invention, the trans-
-prostaglandins of general formula Vl and their methyl
esters are prepared by the process which comprises reactiny
a compound of the general formula:-
OR6
~ ~COOR5
~ VII
CHO
OR4
(wherein R4 represents a 2-tetrahydropyranyl group
unsubstituted or substituted by at least one alXyl radical,
-- 10 --
"

zs
or a 2-tetrahydrofuranyl or l-etho~yethyl group, R4
preferably being the 2-tetrhhydropyranyl group, R5
represents a straight- or branched-chain alkyl group
containing from l to 4 carbon atoms, and R6 represents
an alkylcarbonyl group containing from 2 to 5 carbon
atoms) with the sodio derivative of a dialkyl phosphonate
of the general formula:
(R70~2P~cH2fR3 VIII
(wherein R7 represents an alkyl group containing from l to
4 carbon atoms, and R3 is as hereinbefore defined) to
. obtain a compound of the general formula:-
ol R6
COOR5
IX
o 4
(wherein the various symbols are as hereinbefore defined),
reducing the 15-oxo group in the compound of general formula
IX to a hydroxy group by methods known er se to obtain a
compound of the general formula:
; OR
6
COOR5 X
\ f ~ 3
OR4 H
-- 11 --

10981Z5
(wherein the various .symbols are as hereinbefore defined,
and the wavy line ~ indicates attachment of the llydrox~
group to the carbon atom in alpha or beta configuration),
reacting the obtained compound with dihydropyran
unsubstituted or substituted with at least one alkyl radical,
dihydrofuran or ethyl vinyl ether, to obtain a compound of
the general formula:
o~ R6
COOR5 XI
OR4 4
(wherein the various symbols are as hereinbefore defined, and
the wavy line ~v indicates attachment of the OR4 group to
the carbon atom in alpha or beta configuration), hydrolysing
under alkaline conditions the resulting compound to obtain
a compound of the general formula:-
OH COOR XII
R3
OR4 4(wherein R represents a hydrogen atom or a methyl group, and
R3, R4 and ~ have the meanings hereinbefore specified),
converting by methods known per se the 9~-hydroxy group in
the compound of general formula XII to an oxo group, and
_ 12 -

9B~25
hydrolysing the OR4 groups in the resulting co.mpound of the
general fonmula:
COOR
¦ XIII
R3
4 4
(wherein R, R3, R4 and ~ have the meanings hereinbefore
specified) to hydroxy groups to obtain a PGE compound of
general formula VI or a methyl ester thereof. In general
,formulae VII, IX, X, XI, XII and XIII the depicted carbon-
carbon double bonds are trans as are all other double bonds
depicted ~ or ~ in following fo~mulae; a cis
double bond in following formula XIV is depicted thus
'' \
The reaction between an aldehyde of genera~
formula VII and the sodio derivative of a dialkyl phosphonate
of general formula VIII is carried out under the normal
conditions utilized for effecting the Wittig reaction.
Preferably the reaction is effected by suspending sodium
hydride in an inert organic solvent, e.g. tetrahydrofuran
or 1,2-dimethoxyethane, and adding the dialkyl phosphonate
of general formula VIII. The resulting sodio derivative of
the dialkyl phosphonate may then be reacted with the compound
of general formula VII at a temperature of 20C to 45C to
form the trans-enone compound of general formula IX
- 13 -
,

:~9~lZS
stereoselectively.
The reduction of the 15-oxo group of a cornpound
of general formula IX to a hydroxy group i5 suitably
effected (1) with excess sodium borohydride in an alkanol
containing from 1 to 4 carbon atoms, e.g. methanol, at a
low temperature, preferably at -30C to -60C, or (2) with
zinc borohydride in a suitable inert organic solvent, e.g.
1,2-dimethoxyethane, at a temperature of -10C to 10C. The
product thus obtained is a mixture of isomers of general
formula X in which the 15-hydroxy group is in a- or ~-
configuration. If desired, the isomer having the hydrox~
group in ~-configuration may be separated from the isomer
having the hydroxy group in ~-configuration by column
chromatography on silica gel. The separated isomers may be
utilized in the procedures herein described to give
prostaglandin analogues of general formula VI or methyl
esters thereof in which the hydroxy group in position 15 is
in ~- or ~-configuration.
The reaction of a compound of general formula X
with a dihydropyran, dihydrofuran or ethyl vinyl ether is
carried out in an inert organic solvent, e.g. methylene
cnloride, in the presence of a condensing agent, e.g.
E~toluenesulphonic acid.
The hydrolysis of compounds of general formula XI
under alkaline conditions may be effected (1) with an
aqueous solution of an alkali metal, e.g. sodium or potassiurn,
.
-- 14 --
- ::

~98~Z5
hydroxide or carbonate in the pres~nce of a water miscible
olvent, e.g. tetrahydro~uran or an alkanol containing from
1 to 4 carbon atoms, to give compounds of general formula
XII wherein R represents a hydrogen atom, or (2) with
anhydrous potassium carbonate in anhydrous methanol to give
compounds of general formula XII wherein R represents the
methyl radical.
Conversion of the hydroxy group in the 9-position
of the PGF compounds of general formula XII to an oxo group
may be effected by methods known per se for the conversion
of a PGF alicyclic ring into a PGE ring, for example by
means of a chromic acid solution (e.g. obtained from chromium
trioxide, manganese sulphate and sulphuric acid in water) or
Jones' reagent.
The 0~4 groups of the compounds of general formula
XIII may be converted to hydroxy groups by mild hydrolysis
with an aqueous solution of an organic acid, e.g. acetic
acid, or with a dilute aqueous inorganic acid, e.g.
hydrochloric acid, advantageously in the presence of an
organic solvent miscible with water, e.g. tetrahydrofuran or
an alkanol containing from l to 4 carbon atoms, e.g.
methanol. The mild hydrolysis may be carried out at a
temperature ranging from ambient to 60C (preferably at
a temperature below 45C) with an acid mixture, e.g. a
mixture of hydrochloric acid with tetrahydrofuran or
methanol, or a mixture of acetic acid, water and
- 15 -
,
" '

19~ 125
tetrahydrofuran~
Compounds of general formula VII (wherein the
various symbols are as hereinbefore defined) are new
compounds and as such constitute another feature of the
invention. They may be prepared by a new synthetic route
from known compounds of formula XIV depicted hereafter
(cf. Belgian Patent Specification ~o. 838582) by the
series of reactions depicted schematically below in Scheme
A, wherein the various symbols are as hereinbefore defined.
- 16 -
;

9E3~ZS
SCHEME A
O,H O,H
COOR5 ~ ~ ~ COOR5
OH> ~ OH
R4 XIV/ R4
O, H L~ O, H
COOR5 ~ COOR5
H Q> ~ ~OE
4 XVI / R4 XVI I
O,H ~
COOR5
osi ( CH3 ) 3
4 XVIII
ol R6 O, R6
COOR5 ~ ~ COOR5
~osi ( CH3 ) 3 ~OR6 . .. -`
XIX ~ R4 X~
ol R6 ol R6
~COOR5 ~ , ~ COOR5
OH V~CHO
1R ~R4
4 XXI VII
-- 17 --

~98~25
Compounds of general formula XIV may be reduced
to give compounds of general formula XV. Suitably the
reduction may be effected by hydrogenation in the presence
of a hydrogenation catalyst, e.g. palladium on charcoal,
palladium black or platinum dioxide, in an inert organic
solvent, for example a lower alkanol, e.g. methanol or
ethanol, at laboratory temperature at normal or elevated
pressure, e.g. at a hydrogen pressure from atmospheric to
15 kg/cm .
Compounds of general formula XVII may be prepared
by the process which comprises reacting a compound of general
formula XV with a compound of the general formula:
R8\
Il / NLi _ XXII
Rg
' (wherein R8 and Rg, which may be the same or different,
each represents a straight- or branched-chain alkyl group
containing from 1 to 6 carbon atoms or a cycloalkyl group
containing from 3 to 6 carbon atoms), e.g. lithium
` diisopropylamide, to obtain a lithium compound of the
;I general formula:
oLi
' COOR
~ ~ OLi Li XXIII
OR4
- 18 -
; ~ '

~39~3~25
(wherein R4 and R5 are as hereinbefore defined), reactlng
the lithiurn compound with benzeneselenenyl bromide ti~e.
C6H5SeBr), or diphenyldiselenide, or a dialkyldisulphide
or diphenyldisulphide of general formula RloSSRlo. wherein
the symbols Rlo both represent alkyl groups containing from
1 to 4 carbon atoms or phenyl radicals, hydrolysing the
resu~ting intermediate to obtain a compound of general
formula XVI, treating the resulting compound with hydrogen
peroxide or sodium periodate, and decomposing the resulting
compound of the general formula:
OH
COOR5
<I XXIV
OH Q=O
OR4
(wherein the various symbols are as hereinbefore defined)
to convert the grouping ~ ~ 5 attached to
Q=O
the 8-position of the cyclopentane ring to a trans-~2-
grouping ,~ ~ 5 , wherein R5 is as hereinbefore
defined.
The reaction between a compound of general foxmula
XV and a lithiated amine of general formula XXII is carxied
out in an inert organic solvent, e.g. tetrahydrofuran, at a
; 20 low te~perature, e.g. at -78C, the ratio of the molecular
equivalents of a compound of general formula XV to XXII
19 -

~98~ZS
in the reaction mixture being suitably adjusted to obtain
a lithium compound of general formula XXIII.
The reaction between the lithium compound of
general formula XXIII and benzeneselenenyl bromide,
diphenyldiselen.ide or a dialkyldisulphide or diphenyldi-
sulphide is preferably carried out in an inert organic
solvent, e.g. tetrahydrofuran, hexamethylphosphotriamide,
diethyl ether, n-hexane or n-pentane or a mixture of two
or more of them, at a low temperature, e.g. at -78C.
When the product of general formula XVI is a
compound wherein Q represents -SeC6H5, the product is then
treated (1) with hydrogen peroxide in a mixture of ethyl
acetate and tetrahydrofuran or methanol at a temperature
below 30C, or (2) with sodium perioda~e in the presence
of water and a lower alkanol, preferably methanol, at a
temperature below 20C to form a compound of general
formula XXIV wherein 0=Q- represents -Se(O)C6H5, and
stirring of the reaction mixture at a temperature of 25
to 30C results in d~composition of the compound of general
formula XXIV to a trans-~2-compound of general formula
XVII, which can be separated from the reaction medium by
methods known per se and, iI desired, purified by column
chromatography on silica g91.
When the product of general formula XVI is a
compound wherein Q is a group -SRlo, in which Rlo is as
hereinbefore defined, the product is treated with hydxogen
_ 20 -
"~
~ ~.

~(~98~ZS
peroxide or sodium periodate in the same way as hereinbefore
descrihed for a product of general formula XVI wherein Q is
benzeneselenenyl to obtain a compound of general formula
XXIV wherein Q is a group -SRlo, Rlo being as hereinbefore
defined, which can be separated from the reaction medium by
methods known E~ se.
l~hen the compound of general formula XXIV is
one wherein Q represents an alkylthio group -SRlo "
wherein Rlol represents an alkyl group containing from 1 to 4
carbon atoms, the compound is dissolved in toluene and the
solution stirred, preferably in the presence of a small
~nount of calcium carbonate, at a temp~rature of 100 to
120C to decompose the compound to a trans-~2-compound of
general formula XVII. When the compound of general formula
XXIV is one wherein Q represents the phenylthio group, the
compound is dissolved in carbon tetrachloride and the
solution stirred, preferably in the presence of a small
~` amount of calcium carbonate, at a te~perature of about 50C
to decompose the compound to a trans-~2-compound of general
formula XVII.
Compounds of general formula XVIII may be prepared
by reacting compounds of general formula XVII with trimethyl-
chlorosilane in an inert organic solvent, e.g. methylene
chloride, in the presence of a base, e.g. pyridine or a
tertiary amine, at a low temperature, e.g. at -30 to 0C.
Compounds of general formula XIX may be prepared
.
- 21 -

~9~3~Z5
by reacting a trimethylsilyl ether of general formula XVIII
with an appropriate acyl chloride or acid anhydride in an
inert organic so]vent, e.g. methylene chloride, in the
presence of a base, e.g. pyridine or a tertiary amine, at
a low temperature, e.y. at 0 to 30Cu
Compounds of general formula XXI may be prepared
by treating compounds of general formula XIX by methods
known per se for the removal of the trimethylsilyl group,
for example by treatment with an acid: it is p-referable
not to use a strong acid in order to avoid the risX of the
removal of the group R4.
Compounds of general ~ormula XXI may also be
prepared by acylation of compounds of general formula XVII
(by means heretofore mentioned for the conversion of compounds
of general formula XVIII into those of general formula XIX)
to compounds of general formula XX, and hydrolysing those
compounds with an alkali metal, e.g. potassium or sodium,
carbonate in an alkanol containing from 1 to 4 carbon atoms,
e.g. methanol, at a moderately low temperature, e.g. at
0-5C.
Com~ounds of general formula XXI may be converted
to co~pounds of general formula VII under mild and neutral
conditions, for example with chromium trioxide-pyridine
con~plex or Jones' reagent, or dimethyl- or methylphenyl-
sulphide-~ chlorosuccinimide complex or dimethyl- or
methylphenyl-sulphide-chlorine complex [cf. J. Amer. Chem.
,
- 22 -

i~9BlZ5
Soc., 94, 7586, (1972~], or dicyclohexylcarbodiimide-
dimethyl sulphoxide complex [cf. J. Amer. Chem. Soc.,
87, 5661 (1965)~, at a moderately low temperature.
Compounds of general formula XIV used as starting
material in the series of reactions depicted in Scheme A
may be prepared by the methods described in Belgian Patent
Specification ~o. 838582 from the known compound of formula
XXV [prepared as described in J. Amer. Chem. Soc., 91,
, 5675 (1969) and ibid, 92, 397 (1970)] by the series of
1 10 reactions depicted schematically below in Scheme B, wherein
i Ac represents the acetyl group and the other symbols are as
hereinbefore defined.
.

~98~2S
SCHEME B
P~f o~
<XOH <~OH
OH
OAc XXV / XXVI
~Ol~c > ~I~C
OH / ORL~
XXVII / XXVIII
,OH
,0~ 1~ ,OH
<X~ OOH
OR4 / OR4
~X ~ ~X
O,H
</~ ~\C00~5
\,~OH
ORj~
XIV
.. . .
,
~ ' .
., , ~: , . ,:. - ,, : ,
.

3125
Compounds of formula XXVI may be prepared by
hydrolysis under alkaline conditions of compounds of
formula XXV, for example using potassium carbonate in
methanol. Compounds of formula XXVII may be obtained by the
acetylation of compounds of formula XXVI under mild
conditions and may be converted to compounds of general
formula ,YXVIII by reaction with a dihydropyran, dihydrofuran,
or ethyl vinyl ether in an inert organic solvent, e.g.
mekhylene chloride, in the presence of a condensiny agent,
e.g. p-toluenesulphonic acid. Compounds of general formula
~Y~IX may be prepared by reducing compounds of general formula
XXVIII with diisobutylaluminium hydri~e in toluene at a
temperature below -60C. Dimsyl anion, previously prepared
fxom sodium hydride and dimethyl sulphoxide, is reacted
with L~carboxy-n-butyltriphenylphosphonium bromide to form
4-~arboxy-n-butylidenetriphenylphosphorane. To that compound
i3 added a compound of general formula XXIX and the mixture
in dimethyl sulphoxide is made to react at room te~lperature
to yleld compounds of general formula XXX. The acids of
general formula XXX are then esterified to give compounds of
general formula XIV by reaction with (i) diazoalkane
compounds, e.g. diazomethane, (ii) alcohols in the presence
of dicyclohexylcarbodiimide as condensing agent, (iii)
alcohols following the formation of a mixed acid anhydride
by adding a tertiary amine and then a pivaloyl halide or an
a~ylsulphonyl or alkylsulphonyl halide (cf. our British
- 25 -
~., . . :

1~98125
Patentis ~C.5. 136,!g56 and 1364125), (iv) alkyl halides,
e.g. met:hyl iodide, and (a) potassium carbonate in acetone
[cf. ;J. Org. Che~. 34, 3717 (1969)], (b) sodium bicarbonate
in ~,N-dimethylacetamide or N,~-dimethylformamide [cf.
Advan. Org~ Chem. 5, 37 (1965), (c) calcium oxide in
dimethyl sulphoxide [cf. Synthesis, 262 (1972)], or (v)
N,N-dimethylformamide - dialkylacetals, e.g. ~,~-
dimethylformamide-dimethylacetal, in dry benzene [cf. Helv.
Chim. Acta, 48, 1746 (1965)].
The d alkyl phosphonates of general formula VIII
can be prepared byreacti~g a solution of n-butyllithium
j in diethyl ether with a solution of a dialkylmethylphosphonate
of the general formula:
(R7O)2llCH3 XXXI
O
(wherein R7 is as hereinbefore defined), e.~. dimethyl
ethylphosphonate or diethyl methylphosphonate, in
I tetrahydrofuran at a temperature below -50C, and then adding
dropwise to the reaction mixture a solution oI a compound of
- the general formula:
RllOOCR3 XXXII
(wherein Rll represents an alkyl group containing from
1 to 4 carbon atoms, and R3 is as hereinbefore defined)
in tetrahydrofuran at a temperature below -50C, for 2 to 4
hours, and then stirring or 2 to 18 hours at a temperature
ranging from ambient to 0~C, to give the desired dialkyl
phosphonate of general formula VIII.
- 26 -
:
;

~09B12~
The lithiated amines of general formula XXII emp3oyed
in the aforementioned process of the invention, for example
lithium diisopropylamide, and benzeneselenyl bromide and
diphenyldiselenide can be prepared by known methods, for
example as described in J. Amer. Chem. Soc., 95, 6139 (1973)~
Methyl esters of the trans-~2-prostaglandins of
general formula VI can be obtained by reaction of the acids
with (i~ diazomethane, (ii) methanol in the presenc~ of
dicyclohexylcarbodiimide as a condensing agent, and (iii)
methanol following the formation of a mixed acid anhydride
by adding a tertiary amine and then a pivaloyl halide or
an arylsulphonyl or alkylsulphonyl halide (cf. British
Patents Nos~ 1362956 and 1364125)~
Compounds of general formula VI may, if desired,
be converted by methods known per se into non-toxic salts.
By the term "non-toxic salts", as used in this
Specification, is meant salts the cations 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 VI are not
vitiated by side-effects ascribable to those cations.
Preferably, the salts are water-soluble. Suitable salts
include the alkali metal, e.g. sodium and potassium, 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
- 27 -
. .
. ~

:lQ9BlZ5
exam~le, amines derived in theory by the replace~nent 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 from 1 to 3 carbon atoms.
The non-toxic salts may be prepared from acids of
general formula VI, by for exarnple, reaction of stoichiometric
quantities of an acid of general formula VI and the appropriate
base, e.g. an alkali metal hydroxide or carbonate, ammonium
hydroxidel ammonia or an amine, in a suitable solvent. The
; salts may be isolated by lyophilisation of the solution, of, if
sufficiently insoluble in the reaction mediurn, by filtration,
if necessary after removal of part of the solvent.
The trans-~2-prostaglandin analogues of general
formula VI and methyl esters thereof may, if desired by
converted into cyclodextrin clathrates. The clathrates may be
prepared by dissolving the cyclodextrin in water and/or an
organic solvent which is miscible with water and adding to the
solution the prostaglandin compound in a water-miscible organic
solvent. The mixture is then heated and the desired cyclo-
dextrin clathrate product isolat~d by concentrating the mixture
under reduced pressure or by cooling and separating the product
by filtration or decanting. The ratio of organic solvent to
water may be varied according to the solubilities of the
starting materials and products. Preferably the temperature is
not allowed to exceed 70C, during the preparation of the
- 28 -

~9~3~125
cyclodextrin cl~thrates. a, ~ or ~-Cyclodextrins or mixtures
thereof may be used in the preparation of the cyclodextxin
clathrates. Converslon into their cyclodextrin clathrates
serves to incr~ase the stability of the prostaglandin compounds.
The following Reference Examples and Examples
i.llustrate the preparation of new prostaglandin analogues of
the present invention. In them 'IR', '~MR' and 'TLC'
represent 'Infrared absorption spectrum'; '~uclear magnetic
resonance spectrum' and 'Thin layer chromatography'
respectively. Where solvent ratios are specified in
chromatographic separations, the ratios are by volume.
REFERE~CE EXAMPLR 1
2a-(6-Methoxvcarbonvlhexyl)-3~-hydroxymethyl-4a-(2-
tetrahYdro~YranyloxY)cyclopentan-la-ol
14.2 g of 2a-(6-methoxycarbonylhex-cls-2-enyl~-3~-
hydroxymethyl-4a-(2-tetrahydropyranyloxy)cyclopentan-la-ol
(prepared as described in Belgian Patent Specification No.
838582) was hydrogenated at a pressure of one atmosphere in
300 ml. of methanol containing 3 g. of 5% (w/w) palladium on
; 20 charcoal. The reduction was stopped after the absorption of
one equivalent of hydrogen. The catalyst was removed by
filtration and the filtrate was concentrated under reduced
pressure to give 13.8 g~ of the title compound having the
' following physical cha~acteristics:-
; 25 TLC (developing solvent, benzene:ethyl acetate = 1:1):
Rf = 0.28,
IR (liquid film): 3450, 1740, 1440, 1030 cm 1,
~MR (CDC13 solution): 5.00-4.55 (lH, m), 3.70 (3H, s).
- 29 -
`':
~ , ~
: ~ ' . :
.
'.: ,- ~ . .

~o9~z~
REFISRI::NCE EXAIU~LI~ 2
2a-(6-~hc-~nylseleno-6-metho~vcarbony]h~xyl)-3R-
l--ol
Under an atmosphere of nitrogen, a solution
of 19.4 ml. of diisopropylamine in 350 ml. of
tetrahydrofuran was cooled to -78C., and to it was
added dropwise 114 ml. of a 1.2M solution of
n-butyllithium in n-hexane. The mixture was stirred
at -78C. for 20 minutes to give lithium diisopropyi-
amide. To the lithium diisopropyl~mide solution was
added dropwise a solution of 13.8 g. of 2~-(6-methoxy--
carbonylhexyl)-3~-hydroxymethyl-4~-(2-tetrahydro-
pyranyloxy)cyclopentan-l~-ol (prepared as descri~ed in
Reference Example 1) in 100 ml. of tetrahydrofuran at
-78C. and the mixture was stirred at the same
temperature for 30 minutes. A solution of 18.2 g. o
diphenyldiselenide in 50 ml. of tetrahydrofuran was
added dropwise to the reaction mixture at -78C. ar.a the
solution was stirred at the same temperature for one hour
and then at 0C. for 20 minutes. The reaction mix~ure
was poured into an aqueous solution of ammoniur.l chloride
and extracted witn ethyl acetate. The extract was
washed with water and an aqueous solution of sodium
chloride, dried over maynesium sulphate and concentrated
/ - 30 -

~981ZS
under reduced pressure. ~he residue was purified
by colwnn chromatography on silica gel using a mixture
of benzene and ethyl acetate (3:2) as eluent to give
15.8 g. of the title cornpound having the following
physical characteristics:
TLC (developing solvent, benzene:ethyl acetate = 1:1):
Rf = 0.37;
IR (liquid film): 3450, 1740, 15~0, 1440, 1030 cm 1,
NMR (CDC13 solution): 7.75-7.10 (5H, m), 5.00-4.55
lb (lH, m), 3.70 (3H, s).
REFERENCE E~MPTE 3
2a- (6-Metho~car~onylhex-trans-5-enyl)-3~-hydroxymeihyl-
(2-tetrah~drop~ranvloxv)cYclo~ntan-la-ol
~o a solution of 15.8 g. of 2~-(6-p~le~ylseleno-6-
methoxycarbonylhexyl)-3~-hydroxymethyl-4a-(2-tetrahydro-
pyranylo~y)cyclopentan-la-ol (prepared as described in
Reference Example 2) in a mixture of 200 ml. of ethyl
acetate and 100 ml. of tetrahydrofuran were added 4.5 g.
of sodium carbonate and 6.2 ml. o~ 30% hydrogen peroxide
and the mixture was stirred at 30C. for 30 minutes.
~he reaction mixture was then poured into water, was~led
with an aqueous solution of sodium carbonate, waier and
an aqueous solution of sodium chloride, dried over
: magnesium sulphate and concentrated under reduced pressure
to gi~e 10.4 g. of the title compound having the followi-.~g
;
~ 31 -
': :
,,
-
~ , . - :

1~9~2S
phys;cal characteristics:
TLC (developing solvent, benzene:ethyl acetate = 1:1):
~f = 0.2~
IR (liquid film): 3450, 1735, 1660, 1440, 1030 cm 1,
~MR (CDC13 so~ution): 6.90 (lH, dt), 5.82 (lH, d),
5.00-4.55 (lH, m!, 3.70 (3H, s).
REFERENCE E~U~MPLE 4-
la-~cetoxy-2a-(6--methoxycarbonylhex-trans-5-enyl)-3~-
hydroxvmeths~l-4a-(2-tetrahydropvranyloxy)cvclopentane
Under an atmosphere of nitrogen, a solution of
- 4.3 ml. of trimethylchlorosilane in 20 ml. of methylene
chloride was added dropwise to a solution of 10.4 g. of
2a-(6-methoxycarbonylhex-trans-5-enyl)-3~-hydroxymethyl-
4a-(2-tetrahydropyranyloxy)cyclopentan-1~-ol (prepared
as described in Reference Example 3) in a mixture of
lS0 ml. of methylene chloride and 18.8 ml. of pyridine
at -20C. and the mixture was stirred at the same
temperature for 20 minutes. To the solution thus
obtained was added dropwise a solution of 2.~5 ml. of
acetyl chloride in 50 ml. oi methylene chloride a~ -20~C.
and the mixture was stirred at room temperature for 30
minutes. ~hen 3 ml. of ethanol was added to the reaction
mixture in order to decompose the excess of acetyl
I chloride. Pyridine in the solution was quenched with 80 g.
of sodium bisulphate, and the resulting precipit~te was
,
~ 32 - -
. . '
: .

~981ZS
,
filtered off. The filtrate was concentrated under
reduced pressure. The residue was dissolved in 300 ml.
of ethyl acetate, loO ml. of a saturated aqueous
solution of oxalic acid was added and the mixture was
stirred vigorously at room temperature for 30 minutes.
The reaction mixture was extracted with ethyl acetate,
the extract was washed with water, an aq~eous solution
of sodium bisulphate, water and an aqueous solution
of sodium chloride, dried over magnesium sulphate and
concentrated under reduced pressure. The res-due was
purified by column chromatography on silica gel using a
mixture of benzene and ethyl acetate (3:1) as eluent
to give 7.2 g. of the title compound having the following
physical characteristics:
TLC (developing solvent, benzene:ethyl acetate = 1:1):
~f - 0.51;
IR (liquid film): 3450, 1735, 1660, 1440, 1030 cm 1;
NMR (CDC13 solution): 6.90 (lH, dt), 5.82 (lH, d),
5.25-4.90 (lH, m), 4.85-4.45 (lH, m). 3.71 (3H, s),
2.05 (3~I, s).
- REFERE~CE EXAMPLE 5
. lX-Acetoxy-2a-(6-methoxycarbonylhex-trans-5-enyl)-3~-
formyl-4a-t2-tetrahvdropYranyloxy)cyclopentane
Under an atmosphere o~ nitrogen, 34 ml. of
pyridine were dissolved in 440 ml. of methylene chloride,
- 33 -
.

~098~z~
20.2 g. of chromium trioxide were added wiih stirring
and the mixture was stirred at room temperature for lS
minutes. 88 g. of infusorial earth were added to the
reaction mixture which was then cooled to 0C.
S A solution of 7.2 g. of la-acetoxy-2~ (6-methoxy-
carbo-llylhex-trans-5-enyl)-3~-hydroxymethyl-4~-(2-
tetrahydropyranyloxy)cyclopentane (prepared as described
in Reference Example 4) in 100 ml. of methylene
chloride at 0C. was added. After 10 minutes stirring
at 0C., 155 g. of sodium bisulphate were added to the
reaction mixture and stirring was continued for a further
10 minutes. The resulting precipitate was filtered
through a pad of magnesium sulphate and the filtrate wa~
concentrated under reduced pressureO The xesidue was
puri~ied by column chromatography on silica gel using a
mixture of benzene and ethyl acetate t5:1) as eluent to
give 5.85 g. of the title compound having the following
physical characteristics:
I ~LC (developing solvent, benzene:ethyl acetate - 2:1):
1 20 Rf = 0.67;
. IR (llquid film): 1735, 1660, 1440, 1250, 1030 cm 1;
~MR (CDC13 solution): 10.00-9.70 (lH, m), 6.90 (lH, dt~,
5.82 (lH, d), 5.30-4.96 (lH, m), 4.75-4.10 (2H, m),
3.72 (3H, s), 2.06 (3H, s).
~4
.
, : .
. . .. . .

1~98~Z5
.
~XAMPLE 1
M~yl 9a-aceto~-lla-(2 tetrah~drcpyran~lo~ l-15-oY.o-
. .
16,16-dimethylprosta-trans-2,tr_~s-13-dienoate
Under an atmosphere of nitrogen, a solution of
1.62 g. of dimethyl 2-oxo-3,3-dimethyl-heptylphosphollate
(prepared as described in British Patent Specification
No. 1398291) in 6 ml. of tetrahydl-ofuran was added to a
suspension of 230 mg. o~ sodium hydride (63% content)
in 50 ml. of tetrahydrofuran and the mixture ~as
stirred at room temperature for 30 minutes. To the
solution thus obtained was added a solution Oc 1.98 g. oi
la-acetoxy-2a-(6-methoxycarbonylhex-trans-5-enyl)-3~-
formyl-4a-(2-tetrahydropyranyloxy)cyclopentane (prepared
as de.scribed in Reference Example 5~ in 10 ml. of
tetrahydrofuran at room temperature and the solution WaS
stirred at the same temperature for one hour. The
reaction mixture was quenched with acetic acid, filtered
throuyh a pad of silica gel and the filtrate was
concentrated under reduced pressure. The residue was
purified by coiumn chromatography on silica gel us ng a
mixture of benzene and ethyl ace~ate (8:1) as eluent to
give 2.36 g. of the title compound haviny the following
physical characteristics:
TLC (developing solvent, benzene:ethyl acetate = 2:1):
R~ - 0.71,
-35 -
.
.
' ~

1~98~Z5
IR (liquid film): 1730, 1660, 1630, 1440, 1030 cm 1;
~MR (CDCl3 solution): 7.20-6.50 (2H, m), 6.16 (lH, d),
5.80 (lII, d), 5.30-4.90 (lH, m), 4.80-4.50 (lH, m),
3.72 (3H, s), 2.06 (3H, s), 1.10-0.70 (9H, m).
ExAMæLE 2
Methvl 9a-acetoxy~lla--(2-tetrahydropyranyloxy)-15~-
hydroxy-16,16-dimethylprosta-trans-2,trans-13-dienoate
. .
To a solution of 2.36 g. of methyl 9a-acetoxy-
lla-(2-tetrahydropyranyloxy)-15-oxo-16,16-dimethylprosta-
trans-2,trans-13-dienoate (prepared as described in
Example 1) in 40 ml. of methanol was added
700 mg. of sodium borohydride at -40C. and the solution
was stirred at that temperature for 20 minutes. The
reaction mixture was quenched with acetic acid and
concentrated under reduced pressure. The residue was
dissolved in ethyl acetate and the solution was washed
with an ac~eous solution of sodium bicarbonate and an
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 benzene and ethyl acetate (4:1) aS
eluent to give 790 mg. of the title compound, 810 mg. of
its 15~-hydroxy isomer and 480 mg. of a mixture of the
isomers. The titie compound showed the following
physical characteristics:
- 36 -
.
, , , ~ -: :

i~9~
: TLC (developing solvent, benzene:ethyl acetate = 2:1):
Rf = 0.3~, (15~-hydroxy isomer, R~ = 0.47);
IR (li~uid film): 3450, 1730, 1660, 1440, ~030, 980 cm 1;
~MR (CDC13 solution): 7.20-6.70 (lH, m), 6.10-4.90
(4H, m), 4.80-4~50 (lH, m), 3.72 (3H, s), 2.06 (3H, s),
, 1.10-0.70 (9H, m).
EXAMPLE 3-
Methyl 9a-acetoxy-lla,15a-bis-(2-tetrahydropyranylox~r)-
16,16-dimethylprosta-trans-2,trans-13-dienoate
To a solution of,790 mg. of methyl 9~-acetoxy-
a-(2-tetrahydropyranyloxy)-lSa-hydroxy-l6~l6-
I ' , dimethylprosta-trans-2,trans-13-dienoate (prepared as
I ' described in Example 2) in 15 ml. of methylene
I chloride were added 5 mg. of ~-toluenesulphonic acid
¦ 15 and 0.3 ml. of 2,3-dihydropyran and the mixture was
¦ stirred at room temperature for 20 minutes. The reaction
mixture was diluted with 50 ml. of ethyl acetate, washed
with an aqueous solution of sodium chloride, dried over
magnesium sulphate and concentrated under reduced
pressure to give 930 mg. of the crude titie compound
having the following physical characteristics:
TLC (developing solvent, benzene:ethyl acetate = 2
Rf = 0.67:
IR (li~uid film): 1730, 1660 ,1440, 1030, 980 cm 1
NMR (C~C13 solution): 7.20-6.70 tlH, m), 6.10-4.90
(4H, m), 4.80-4.50 (2H, m), 3.72 (3H, s), 2.06 (3H, s),
1.10-0.70 (9H, m).
. . .
~ 37 -
~'
.

~098~25
E~AMPLE 4
Met~,vl 9~-hydroxy-lla,_5a-bis-(2-tetr~y~dropvr~nyloxy~=
16,16-dimethylprosta- rans-2,trans-13-di.enoate
To a solution of 930 mg. of methyl 9a-acetoxy-
11~,15a--bis-(2-tetrahydropyrany.loxy)-16,16-dimethy].prosta-
trans-2,trans-13-dienoate (prepared as described in
Example 3) in 12 ml. of ~ethanol was added
400 mg. of potassium carbonate and the mixture was
stirred at 40C. for 1.5 hours. The reaction mixture
was quenched with acetic acid and extracted with ethyl
acetate. The extract was washed with an aqueous solutlon
of sodium bicarbonate, water and an aqueous solution of
sodium chloride, dried over magnesium sulphat.e and
concentrated under reduced pressure. The residue wa~
purified by column chromatosraphy on silica gel usillg a
mixture of benzene and ethyl acetate (6:1~ as eluent .o
give 745 mg. of the title compound having the:follo~:ing
physical characteristics:
TLC (developing solvent, benzene:ethyl acetate = 2
Rf - 0.47;
- - IR (liquid film): 3450, 1730, 1660, 1440, 1030, 980 cm ~:
NMR (CDC13 solution): 7.20-6.70 (lH, m), 6.10-5.30
(3H, m), 4.80-4.50 (2H, m), 3.72 ~3H, s), 1.10-0.70
(9H, m).
- 38 -
.
:
'
'

~98125
EXAMPLE ~
Met~lyl 9-oxo-11,15a-dihYdroxY-16,16-dimeth_lprosta-
trans-2,trans-13-dienoate [or 16,16-dlmetlly1-trans-a -
PGEl methyl ester]
To a solution of 745 mg. of methyl 9~-hydroxy-
lla~15~-bis-(2-tetrahydropyranyloxy)-16/16-dimethylprost~
trans-2,trans-13-dienoate (prepared as described in
Example 4) in 22 ml. of diethyl ether was added a
chromic acid solution (obtained from 0.94 g. of chromium
trioxide, 4.55 g. of manganese sulphate and 1.06 ml. of
sulphuric acid in 22 ml. of water), and the mixture was
stirred at 0C. for one hour. The reaction mixture was
then extracted with diethyl ether and the extract was
washed with an aqueous solution of sodium chloride, dried
over magnesium sulphate and concentrated under reduced
pxessure to give 732 mg. of methyl 9-oxo-lla,15a-bis-( G-
tetrahydropyranyloxy)-16,16-dimethylprosta-trans-2,trans-
13-diencate having the following physical characterist c:
TLC (developing solvent, benzene:ethyl acetate - 2:1):
Rf = 0.74.
To a solution of 732 mg. of the 9-oxo-compound
(prepared as described above) in 1.9 ml. of tetrahydrofuran
was added 19 ml. of a 65% (v/v) aqueous solution of acetic
acid and the mixture was stirred at 55~ to 60C. for one
2S hour. The reaction mixture was then extracted with ethyl
'
- 39 -
' ''' '
,.
,. ,
- . ; . ,,

1~98125
a~etate and the extract was washed with water and ar.
aqueous solution of so~ium chloride, dried over
magnesium sulphate and concentrated under reduced
pressure to give 119 mg. of the title compound having
the following physical characterFstics:
TI.C (developing solvent, chloroform:tetrahydrofuran:acetic
~cid - 10:2:1): Rf = 0.51;
- IR (liquid film): 3400, 29~0, 2850, 1750, 1730, 1660,
1440, 1280 cm~l;
~MR (CDC13 solution): 7.10-6.75 (lH, m), 5.95-5.40
(3H, m), 3.71 (3H, s3, 4.20-3.60 (2H, m), 2.75 ~lH, dd),
1.00-0.75 (9H, m).
EXAMPLE 6
Methvl 9a-aceto~v~ -(2-tetrahydropyran~oxv)-15-oxo-
17(~)-ethyl-~-dihomoprosta-trans-2,trans-13-dienoate
By proceeding as described in Example
1,~ but replacing the dimethyl 2-oxo-3,3-dimethy]heptyl-
phosphcnate by 1.62 g. of dimethyl 2-oxo-4(~)-ethylnonyl-
phosphonate (prepared as described hereafter~,
there were obtained 2.3 g. of the title compound having
the following physical characteristics:
~LC Cdeveloping solvent, benzene:ethyl acetate = 2 i):
Rf = 0.7Q;
I~ (liquid film~: 1i30, 1660, i630, 1440, 1030 cm 1;
NMR (CDC~3 solution): 7.20-6.50 (2H, m~, 6.16 ;lH, d),
5.80 (lH, d), 5.35-4.90 (lH, m), 4.85-4.50 (lH, m~, 3.72
(3H, s), 2.06 (3H, s), 1.10-0.70 (61I, m).
.
.
- 40 _
. ~

1~9~12s
Dimethyl 2-oxo-4(~)-ethylnonylphosphonate was
synthesi~ed as follows:
65 g. of dimethyl methyl phosphonate were
dissolved in 465 ml.of tetrahydrofura~ and the solution
cooled to -70C. under a nitrogen atmosphere. The
solution of butyl lithium produced from 85.3 g. of butyl
bromide and 10.7 g. of lithium in 400 ml. of diethyl ether
was added dropwise into the other prepared solution
during about 15 minutes at a temperature below -50C.
After stirring for 10 minutes, 44 g. of ethyl 3(~)-
ethyloctanoate in 140 ml. of tetrahydrofuran was added
dropwise at a temperature below -50C., the mixture
was stirred at the same temperature for 2 hours and then
at room temperature for a further 2 hours and then 92 g.
of acetic acid were added. The reaction mixture was
concentrated under reduced pressure and the residue was
dissolved in water, extracted with diethyl ether, and
the ether extract was washed with water, dried over
magnesium sulphate and concentrated under reduced pressure.
, The residue was distilled under reduced pressure. 55 g.
of dimethyl 2-oxo-4(~)-ethylnonylphosphonate (b.p. 113-
121C./0.2 mm Hg) was obtained as a colourless oil.
IR (liquid film): 2950, 2860, 1710, 1455, 1270, 1190,
1040 and 820 cm 1.
. . :. .
.

` 1~91~125
E~AMiPLE 7
Methyl 9a-acetoxy-l]a-(2-tetrahydroP~r~nYloxy~-15a-
hvdroxy-17(~)-et_hyl-~-dihomoprosta~trans-2,trans-
13-dienoate
S By proceeding as described in Example
2 but replacing the methyl 9a-acetoxy-lla-(2-tetrahydro-
pyranyloxy~-15-oYo-16,16-dimethylprosta-trans-2,trans 13-
dienoate by 2.3 g. of methyl 9a-acetoxy-lla-(2-tetrahydrO-
- pyranyloxy)-15-oxo-17(~)-ethyl-w-dihomoprosta-trans-2,-
trans-13-dienoate (prepared as described in
Example 6~ there were obtained 720 mg. of the title
compound, 740 mg. of its 15~-hydroxy isom~r and 500 mg.
of a mixture o~ the isomers. The title compound showed
the ~ollowing physical characteristics:
TLC (developiny solvent, benæene:ethyl acetate -- 2:ij:
Rf - 0.40, (15~-hydroxy isomer, R~ = 0.47):
IR (liquid film): 3450, 1730, 1660, 1440, 1030, g80 cm 1;
~R (CDC13 solution): 7.20-6.70 (lH, m), 6.10-4.gO
(4H, m), 4.80-4.50 (lH, m), 3.72 (3H, s), 2.06 (3H, s~
1.10-0.70 ~6H, m).
EXAMP~E 8
Methyl 9~-acetoxY-lla,15a-bis-(2-tetrahydropyranyloxv~-
17(~)-ethvl-~-dihomoprosta-t-ans-2,trans-13-dienoate
By proceeding as described in Example
3 but replacing the ~.ethyl 9a-acetoxy-lla~(2-tetrahydrc-
.
- 42 -
.` ' :
.
,

~g81ZS
.
pyranyloxy)-15a-hydroxy-16,16~dimethylprosta-trans--2,-
trans-13-dienoate by 720 mg. of methyl 9a-acetoxy-lla-
~2-tetrahydropyranyloxy)-15a-hydroxy-17(~)-ethyl-~-
dihomoprosta-trans-2,trans-13-dienoate (prepared as
described in Example 7~ dissolved in 13 ml.
of methylene chloride and utilizing 5 mg. of ~-toluene-
sulphonic acid and 0.3 ml. of 2,3-dihydropyran there ~iere
-obtained 870 mg. of the title compound having the
f~llowing physical characteristics:
TLC ~developing solvent, benzene:ethyl acetate = 2:1):
Rf = 0.64;
IR (liquid film): 1730, 1660, 1440, 1030, ~80 cm 1;
NMR (CDC13 solution): 7.20-6.70 (lH, m), 6.1C-4.90
(4H, m), 4.80-4.50 (2H, m), 3.72 (3H, s), 2.06 (3H, s),
1.10-0.70 (6H, m).
EXAMPLE 9
Methyl 9a-hydrox~-lla,15a-bis-(2-tetrah~dro~YranY
.
17(~)-ethyl-~-dihomoprosta-trans-2,trans-13-dlenoat2
~ By proceeding as described in Exampie 4 b~
replacing the methyl 9a-acetoxy-lla,15a-bis-(2-
tetrahydropyranyloxy)-16,16-dimethylprosta-trans-2,tr~ns-
13-dienoate by 870 mg. of methyl 9a-acetc~xy-lla,15a-
bis-(2-tetrahydropyranyloxy)-17(~)-ethyl-~-dihomoprost~-
trans-2,trans-13-dienoate (prepared as described in
Example 8) dissolved in 11 ml. of methanol and
. .
- 43 _
,
.. ,

~98125
utilizing 380 mg. of potassium carbonate there were
obtained 700 mg. of the title compound having the
~ollowing physical characteristics:
TLC (developing solvent, benzene:ethyl acetate = 2:1):
-R~ - 0.46;
IR (liquid film): 3450, 1730, 1660, 1440, 1030, 980 cm 1,
~MR (CDC13 solution): 7.20-6.70 (lH, m), 6.10-5.30 (3H, m)
4.80-4.50 (2H, m), 3.72 (3H, s), 1.10-0.70 (6H, m).
EXAMPLE 10
Methyl 9-oxo-lla,15-dihydroxy-17(~)-ethyl-~-dihor~oprost2-
trans-2,trans-13-dienoate [or 17(~)-ethyl-~-dihomo-trans-
_ _ _
a -PGEl methyl ester~
... .. . . .. .. _ _
By proceeding as descrïbed in Exa~nple 5 but
replacing the methyl 9a-hydroxy-lla,75~-bis-(2-tetra-
hydropyranyloxy)-16,16-dimethylpros~a-trans-2,trans-13-
dienoate by 700 mg. of methyl 9a hy~roxy-lla,15a-bis-(2-
tetrahydropyranyloxy)-17(~)-ethyl-~-diilomoprosta-trans-
2,trans-13-dienoate (prepared as déscribed in Example 9)
dissolved in 21 ml. of diethyl ether and utilizin~ 21 ml.
2~ of a chromic acid solution (prepared as described in
Example 5) there was obtained me~.hyl 9-oxo-lla,15a
bis-(2-tetrahydropyranyloxy)-17(~)-ethyl-~-dihomopros~ a-
trans-~,trans--13-dienoate having the following physical
characteristic:
TLC (developing solvent, benzene:ethyl aceta~e _ 2:1):
- 44 -
:, ~
. '

L2S
Rf = 0.68.
Proceeding as described in Example 5 the
9-oxo compound (prepared as described above) wa.s
then dissolved in 1.8 ml.of tetrahyd:cofuran and
utilizing 18 ml~ of 65% (v/v) aqueous acetic acid
there were obtained 99 mg. of the title co~pound
having the following physica' characteristics:
TLC (developing solvent, chloroform:tetrahydrofuran:acetic
acid -- 10:2~ Rf = 0.33
IR (liquid film): 3470, 2920, 2840, 1735, 1720, 1650,
1450, 1430, 1270, 1165, 1080 and 980 cm 1;
NMR ~CDC13 solution). 6.93 (lH, dt), 5.79 (lH, d),
, 5.67-5.40 (2H, m), 4.37-3.83 (2H, m), 3.71 (3H, s),
¦ 2.92-2.53 (lH, dd), 1.06-0.65 (6H, m).
I 15 The present invention includes within its scope
pharmaceutical compositions which comprise, as active
ingredient, at least one prostaglandin analogue of
¦ general for.nula VI or methyl ester thereof, or a
cyclodextrin clathrate of such a prostaglandin analogue
or methyl ester thereof, or a non-toxic salt of such
a prostaglandin analogue, togeth~r with a pharmaceutical
carrier or coating. In clinical practice the new
compounds of the present invention will normally be
.
~ 45 -
,
.. , :

i~981~5
a~ministered orally, vaginally, rectally or
parenterally.
Solid compositior-s for oral administration
include compressed tablets, pills, dispersible powders,
and granules. In such solid compositions one or more
of the ac~ive compounds is, or are, admixed witn at
least one inert diluent such as calcium carbonate, potato
starcli,alginic acid,mannitol,or lactose 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 elix rs containing inert diluents commonly used in
the art, such as water and liquid paraffin. Besides
inert diluents such compositions may aiso comprise
adjuvants, s1lch as wetting and suspending agen~s, and
sweetening, flavouring, perfuming and p.eserving 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 composltions for vaginal administration
2S include pessaries formulated in manner known ~ se and
containing one or more of the active co~lpounds.
.. - L~6 -

i~98~Zs
Sol.id compositions for rectal administration
include suppositories formulated in rnanner known per Se
and conta~.niny one or more of the active compounds,
Preparat.ions 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, The composi'cions rnay also include
adjuvants such as preserving, wetting,emulsirying and
dispersing agents. They may be sterilised, for example,
by filtration through a bacteria-retaining filter, by
incorporation of sterilising agents in the composition3
or hy irradiation, They may also be manufactured in
the form of sterile solid compositions, which can be
~issolved in steri.le 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 proporti~n such
that a suitable dosage for the therapeutic effect desired
shall be obtained, Obviously several unit dosage forms
may be a~ninistered at about the same time, In general,
the preparatior.s shouid normally contain at least 0.02~'
- h7 -

~9l~Z5
by weiyht of actlve substance when required for
administration by injection; for oral a~ninistration
the preparations will normally conthin at least 0 1%
by wei~ht of active substance. The dose employed
depends upon the desired therapeutic effect, the route
of adrninistration and the duration of the treatment.
In the h~man adult, the doses per person are
~enerally between 0.01 and 1 mg. by oral a~ninistration
in the treatment of hypertension, between 1 - 1000 ~g.
by oral, intravaginal, intravenous or extra-amniotic
administration for contraception and the menstrual
regulation in females and in the termination of
pregnancy and the induction of labour .in pregnant
females
In domestic female mammals such as cows, mares,
sows, e~es and bitches, the doses are generally between
0.001 and S0 mg./animal by intramuscular, subcutaneous,
intrauterine, intravaginal and intravenous administration
for the syncnronisation of oestrus, treatment of impaired
fertility and the induction of abortion and of labour.
. m e following Example illustrates pharmaceutica
compositions according to the invention.
EX~MPLE 11
. . .. .
. 16~16-Dimethyi-trans-~ -PGEl methyl ester
(2 mg.) was dissolved in ethanol (10 ml.), mixed with
~ 48 -

~39~25
mannitol (18.5 g.), sieved through a 30-mesh sieve,
dried at 30C, for 90 minutes and again sieved through
a 30-mesh sieve. Aerosil - a regi~tered Trade mark-
(microfine silica; 200 mg.) was added and the powder obtained
was machine~filled into one hundred No. 2 hard gelatin
capsules to give capsules each containing 20 ~g. of
16,16-dimethyl-trans-~2-PGE1 methyl ester which after
swallowing of the capsule is released into the stomach.
- 49 -
12

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Administrative Status

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Event History

Description Date
Inactive: IPC deactivated 2011-07-26
Inactive: IPC from MCD 2006-03-11
Inactive: IPC from MCD 2006-03-11
Inactive: IPC from MCD 2006-03-11
Inactive: First IPC derived 2006-03-11
Inactive: Expired (old Act Patent) latest possible expiry date 1998-03-24
Grant by Issuance 1981-03-24

Abandonment History

There is no abandonment history.

Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
ONO PHARMACEUTICAL CO., LTD.
Past Owners on Record
HIROHISA WAKATSUKA
MASAKI HAYASHI
SEIJI KORI
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Cover Page 1994-03-11 1 13
Abstract 1994-03-11 3 56
Claims 1994-03-11 6 147
Drawings 1994-03-11 1 6
Descriptions 1994-03-11 48 1,405