Note: Descriptions are shown in the official language in which they were submitted.
D ~ .6;~;
.
DESCRIPTION
. ''PROSTAGLANDIN ANA~OGUES"
.' - ~ ` '
THIS I~VENTIO~ is concerned with new
prostaglandin analogues.
Prostaglandins are derivatives of
pro~tanoic acid which'has the following formula:
7 5 3
, ~ COOH . I
13 15 17 19
Various types of prostaglandins are known, the
types depending inter alia on the structure and
substituents on the alicyclic ring. For example,
the alicyclic ring of prostaglandin E~PGE) has the
structure: .
: O~I
~he dotted lines in the foregoing formulae and in
other formulae throughout this specification denote,
'
.
f (~ L6
- 2 -
in accordaDce with generally accepted rules of
nomenclature, that the attached grouping lies behind
the general plane of the ring system, i.e. that the
grouping is in a-configuration, the thickened lines
denote that the grouping lies in front of the general
plane of the syYtem, i.e. that the grouping is in ~-
configuration, and the wavy line ~ indicates that the
grouping i6 in G- or ~-configuration.
Such compounds are sub-classified according
to the position of double bond(s) in the side chain(s)
attached to the 8- and 12-p~sitions of the alicyclic ring.
Thus PGl compounds have a trans- double bond between
C13-C14(trans-~ 3) and PG2 compounds have a cis-double b~nd
between C5-C6 and a trans- double bond between
C13-C14(cis_~5, trans-~13). -For example, prostaglandin
El (PGE1) is charac~erised by the following structure III.
O
~ ~ COO~
.. ~
' OH OH
The structure of PGE2, as a member of the PG2 group,
oorresponds to that of formula III with a c~s-double
bond bet~een the ~arbon atoms in positions 5 and 6.
Compounds in which the double bond between the carbon
. . ~ . ,
.
- - 3 -
atoms in positions 13 and ~4 of members of the P
group is replaced by ethylene are known as
dihydroprostaglandins, e.g. dihydro-prostaglandin-E
(dihydro-PGEl).
Moreover, when one or more methylene groups
are eliminated from the aliphatic group attached to
.the 12-position of the alicyclic ring of the
prostaglandins the compounds are known, in accordance
with the usual rules of organic nomenclature, as
nor-prostaglandins and, when more than one methylene
group is eliminated, the number is indicated by di~,
tri- etc. before the prefix "nor".
Prostaglandins are generall-y known to
posqess pharmacological properties, for example they
stimulate smooth muscle, have hypotensive, diuretic,
bronchodilating and antilipolytic activities, and also
- inhibit blood platelet aggregation and gastric acid
secretion, and are-, accordingly, useful in the
treatment of hypertension, thrombosis, asthma and
gastro-intestinal ulcers, in the induction of labour and
abortion in pregnant female mammals, in the prevention
of arteriosclerosis, and as di~retic agents~ They
are fat-soluble substances obtainable in very small
quantities from various tissues of animals w~ich
secrete ~he prostaglandins in the living body.
. .
,
., . ..
~ `
6~
:
For example, PG~'s have an inhibitlng
effect on gastric acid secretion and may,
accordingly, be used in the treatment of gastric
ulcers. They also inhibit the release of free fatty
acid induced by epinephrine and as a result they
reduce the concentration of free fatty acid in blood,
and are, accordingly, useful in the prevention of
arteriosclerosis and hyperlipemia. PGEl inhibits
blood platelet aggregation and also removes the
thrombus and prevents thrombosis. PGE's have a
stimulating effect on smooth muscle and increase
the intestinal peristalsis, these actions indicate
therapeutic utility on post-operative ileus and as
purgativesc PGE's may also be used as oxytocics,
as abortifacients in the first and second trimesters;
in the post-labour abortion of the placenta, and as
oral contraceptives because they regulate the sexual
cycle of female mammals. PGE's have vasodilator
and diuretic activities. They are useful for improvement
in-patients suffering from cerebral vascular disease
because they increase the cerebral blood flow, and are
also useful in the treatment of asthmatic conditions
in patients because of their bronchQdilating activity.
During the past decade widespread
investigations have been carried out in order to discover
.: .
'
. .
- f ~ L62
,
- - 5 - '
inter alia new products possessing the pharmacological
. properties of the 'natural',prostaglandine' or one or
' more of euch properties to an enhanced degree, or
hitherto unknown pharmacological properties. It has now
been found, after research and experimentation, that by
replacing the hydrogen ato,ms-attached to the C-6 carbon
atom of certain analogues of prostaglandin E
~y an oxo .group (i.e. =0), new prostaglandin El -
' analogues are obtained which possess the pharmacological
properties of the 'natural' prostaglandins and are, insome aspects of their activities, an improvement, for
example possessing an enhanced strength of activity and/or
a prolonged duration of activity.
The pre~ent invention accordingly provides the
new prostaglandln El analogues of the general formula:
3z2, COORl _
~ IV
[wherein Y represents ethylene (i.eO -CH2-CH2-) or.
; preferably, trans-vinylene ~i.e. ~ = C-H), Z represents
ethylene or trans-vinylene, Rl repre~ents a hydrogen atom,
a straight- or branched-chain alkyl group containing from
1 to 12 carbon atoms, an aralkyl group containing from
r ~ 11.3iL6;Z~
7 to 1~ carbon atoms, a cycloalkyl group containing from
4 to 7 carbon atoms in the ring and unsubstituted or
substituted by at least one straight- or branched-chain
alkyl group containing from 1 to 6 carbon atoms, a phenyl
group unsubstituted or substituted by at least one
chlorine atom, trifluoromethyl group, straight- or
branched-chain alkyl group containing from 1 to 4 carbon
atoms or phenyl group, a -cmH2mCooR5 group (wherein m
represents an integer of from 1 to 12 and R5 represents
a hydroyen atom or a straight- or branched-chain alkyl
group containing from 1 to 4 carbon atoms), a -CnH2nOR6
group (wherein R6 represents a hydrogen atom or a straight-
or branched-chain alkyl group containing from 1 to 4
carbon atoms and n represents an integer of from 2 to 12),
or a -C~H2nN \ R~ group (wherein R7 and R , which may be -
the same or different, each represent a hydrogen atom ::
or a straight- or branched-chain alkyl group containing
from 1 to 4 carbon atoms and n is as hereinbefoxe defined),
R2 repres~nts a hydrogen atom or a methyl or ethyl group,
R3 represents a single bond or a straight- or branched-
chain alkylene-group containing from 1 to 4 carbon atoms,
R4 represents a cycloalkyl group containing from 4 to 7
carbon atoms in the ring and unsubstituted or substituted
by at least one straight- or branched-chain alkyl group
containing-from 1 to 8 carbon atoms,
.. : ; i - :
' ~
5~ i2
- :
.
and the wavy lIne attached to the C-ll and C-15 carbon
atoms represents a- or ~configuration (i.e. S- or R-
configuration) or mixtures thereof J and cyclodextrin
clathrate~ of 8uch acids and es~ers and, when Rl represents
a hydrogen atom or a group -cmH2mCooR5 in which R5
represents a hydrogen atom and m is as hereinbefore defined,
non-toxlc ~e.g. sodium~ ~alts thereof and, when R
represents a group -C~H2nN ~ R8 in which n, R and R are as
hereinbefore defined, non-toxic acid addition salts thereof.
Preferably the hydroxy groups attache~ to the C-ll and
C-15 carbon atoms of formula IV are in a-configuration~
The present invèntion is concerned with all
compounds of general formula IV in the 'natural' form or
its enantiomeric form, or mixtures thereof, more particularly
the racemic form consisting of equimolecular mixtures of
natural and it~ enantiomeric form.
As will be apparent to those skilled in the art,
the compounds depicted in general formula IV have at least
four centres of chirality, these four centres of chirality
being at the C-8, C-ll, C-12 and C-15 carbon atomsu Still
further centres of chirality occur when Rl is a
branched-chain alkyl group, or R3 is a branched-chain
alkylene group. The presence of chirality leads, as is
well known, to the existence of isomerism. However, the
compounds of ~eneral formula IV all have such a configuration
that the side-chains attached to the ring carbon atoms in
.
,
'~ ~
6~:
-- 8
the positions identified as 8 and 12 are trans with respect
to each other. Accordingly, all isomers of general formula IV,
and mixtures thereof, which have those side-chains attached
to the ring carbon atoms in positions 8 and 12 in the trans
configuration and have hydroxy groups as depicted in the 11-
and 15-positions are to be considered within the scope of
formula IV.
Examples of the straight- or branched-chain alkyl
group containing ~rom 1 to 12 carbon atoms represented by R
are methyl, ethyl, propyl, butyl, pentyl, hexyl,.heptyl, octyl,
nonyl, decyl, undecyl and dodecyl and their!isomers.
Examples of the aralkyl group containing from 7 to 12
carbon atoms represented by Rl are benzyl, l-phenylethyl,
2-phenylethyl, 3-phenylbutyl, 4-phenylbutyl,-1-(2-.
.
naphthyl-)ethyl and 2~ naphthyl)ethyl.
Examples of the.cycloalkyl group containing from
4 to 7 carbon-atoms unsubstituted or substituted by at least
one alkyl group containing from 1 to 6 carbon atoms
represented by Rl are l-propylcyclobutyl, l-butylcyclobutyl,
l-pentylcyclobutyl, l-hexylcyclobutyl, 2-methylcyclobutyl,
- 2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl,
2,3,4-triethylcyciobutyl, cyclopentyl, 3-ethylcyclopentyl,
3-propylcyclopentylj 3-butylcyclopentyl, 3-tert-butylcyclopentyl, i;
~,2-dimethylcyclopentyl, 1-methyl-3-propylcyclopentyl,
2-methyl-3-propylcyclopentyl, 2-methyl-4-propylcyclopentyl,
cyclohexyl, 3-ethylcyclohexyl, 3-isopropylcyclohexyl,
4-methylcyclohexyl,:4-ethylcyclohexyl,
~ . .
- 9 -
4-propylcyclohexyl, 4-tert-butylcyclohexyl, 2,2-
dimethylcyclohexyl, 2,6-dimethylcyclohexyl, ,2,6-
dimethyl-4-propylcyclohexyl and cycloheptyl.
Examples of the phenyl group unsubstituted or
substituted by at least one chlorine atom, trifluoromethyl
group, straight- or branched-chain alkyl group cortaining
from 1 to 4 carbon atoms or phenyl group represented by R
are phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 2-tolyl, 3-tolyl,
4-tolyl, 4-ethylphenyl, 4-tert-butylphenyl, 4-sec-
butylphenyl, 3-trifluoromethylphenyl and 4-biphenyl.
Examples of the CmH2m and CnH2n moieties of the
CmH2mCooR5, -CnH2nOR and -CnH~nN~ 8 groups represented
by R , are methylene (when m in the CmH2m moiety is 1),
ethylene, trimethylene, tetramethylene, pentamethylene,
hexamethylene, heptamethylene, octamethylene, nonamethylene,
decamethylene, undecamethylene, dodecamethylene and their isomers.
The straight- or branched-chain alkyl group
containing from 1 to 4 carbon atoms represented by R5, R6,
~7 and R8, may be methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl or tert-b~tyl.
Preferably Rl represents a hydrogen atom or a
straight- or branched-chain alkyl group containing from
1 to 4 carbon atoms, e.g. methyl.
R preferably represents a hydrogen atom or
methyl.
, ~
.~ 62
- 10 - , . .
Preferably the grouping -R.- R4 represents
cyclpbuty~ propylcyclobutyl, l-butylcyclobutyl,
l-pentylcyclobutyl, l-hexylcyclobutyl, 2-met~ylcyclobutyl,
2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl,
2,3,4-triethylcyclobutyl cyclopentyl, cyclopentylmethyl,
2-cyclopentylethyl, l-cyclopentylethyl, 3-cyclopentylpropyl,
2-cyclopentylpropyl, 2-pentylcyclopentyl, 2,2-
dimethylcyclopentyl, 3-ethy].cyclopentyl, 3- . .
propylcyclopentyl, 3-butylcyclopentyl, 3-tert-
butylcyclopentyl, 1-methyl-3-propylcyclopentyl, 2-methyl-
3-propylcyclopentyl, 2-methyl-4-propylcyclopentyl,
cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 1-
cyclohexylethyl, 3-cyclohexylpropyl, 1-methyl-2-
cyclohexylethyl, 2-cyclohexylpropyl, l-methyl-l-
cyclohexylethyl, 4-cyclohexylbutyl, 3-ethylcyclohexyl,
- 3-isopropylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclo~exyl,
4-propylcyclohexyl, 4 butylcyclohexyl, 4-tert-.
butylcyclohexyl, 2,6-dimethylcyclohexyl, 2,~ dimethyl-
cyclohexyl, 2,6-dimethyl-4-propylcyclohexyl, - .
l-methylcyclohexylmethyl, cycloheptyl, cycloheptylmethyl,
2-cycloheptylethyl, or l-cycloheptylethyl.
Preferably R3 represents a sin~le bond or a
methylene group. Preferably R4 represents a cyclopentyl
or cyclohexyl group, unsubstituted or substituted by an
alkyl group containing from 1 to 4 carbon atoms.
. . ~ . -
,
. ~ . .
According to a feature of the present invention,
the prostaglandin El analogues of general formula IV,
wherein Rl represents a hydrogen atom or a straight- or
branched chain alkyl group containing from 1 to 12 carbon
atoms and the other symbols are as hereinbeforé defined,
., _ . .... . . . . . .
may be prepared by the hydrolysis to hydroxy groups of
the groups OR9 of a compound of the general formula:
Z-COOR
~, O V
3 - R4
OR9 "
wherein R -~repre~ents a hydrogen atom or a straight-
or branche~-chain alkyl group containing from 1 to
12 carbon atoms, R9 represents a tetrahydropyran-2-yl
or tetrahydrofuran-2-yl group, each such group being
unsubstituted or substituted by at least one alkyl group,
or represents a l-ethoxyethyl group, and the other
symbols are as hereinbefore defined.
The groups OR of the compounds of general
formula V may be converted to hyaroxy groups by mild acidic
. : . ::
,
.. ~: . ~ ., :
- : . . ... , -;, : :
. : i,. . . . :~, -
IIL62
- 12 -
hydrolysis (1) with an aqueous solution of an organic
acid ~uch a~ acetic acid, propionic acid, oxalic acid
or p-toluene~ulphonic acid, or an aqueous solution of an
inorganic acid, such as hydrochloric acid or sulphuric
acid, advantageously in the presence of an inert organic
- ~olvent miscible with water, e.g. a lower alkanoi such as
methanol or ethanol (preferably methanol), or an ether
such as 1,2-dimethoxyethane, dioxan or tetrahydrofuran
(preferably tetrahydrofuran), at a temperature ranging f~om
ambient to 75 C (preferably at a temperature below 45C),
or (2) with an anhydrous solution of an organic acid such
as ~-toluenesulphonic acid or trifluoroacetic acid in a
lower alkanol such as methanol or ethanol at a temperature-
ranging from 10 to 45C. Advantageously the mild hydrolysis
may be carried:out with a mixture of hydrochloric acid,
water and tetrahydrofuran, a mixture of hydrochloric acid,
water and methanol, a mixture of acetic acid,water and
tetrahydrofuran, or a mixture of p-toluenesulphonic acid
and methanol.
Compounds of general formula V may be prepared .
by the oxidatio~ of a compound of the general formulao
~ Z-CODR Vl
y R2
62
_ 13 _ - -
(wherein the various symbols are as' hereinbefore defined),
by methods known ~ e for the conversion of a hydroxy
- - group in the 9-position o* a prostaglandin compound to an
oxo group. By the expression "methods known per se" as
used in this specification is meant methods heretofore
used or descrlbed in the chemical literature.
Preferably the oxidation is carried'out under
mild, neutral conditions, for example, by reaction with
~1) dimethyl sulphlde-N-chlorosuccinimide complex,
thioanisole-~-chlorosuccin;mide complex, dimethyl
sulphide-;chlorine complex or thioanisole-chlorine complex
in a haloalkane, e.g. chloroform, methylene chloride or
carbon tetra'~hloride, or-toluene at a temperature of
from -30QC to 0C [cf. J. Amer. Chem. Soc., 94, 7586
lS ~1972)'], (2')i~chr`omium ;trioxide-pyri'dine complex, e.g.- -
~Collins' reagen*,- in~-a haloalkanei e.g. chloroform,
methylene chloride or carbon tetrachloride, at a temperature
of from 0C to ambient, preferably at 0C, or (3~ ~ones'
reagent in the presence o-~ acetone and dilute sulphuric
acid at a temperature of from 0C to ambient.
Compounds of general formula VI, wherein Z
represents ethylene and the other symbols are as
hereinbefore defined, i.e. compounds of the general formula:
',' : '
-~ ~
z
. 14
OH
-. ~ , ~ ~ COOR
\ o . VIA
\~ \~ R - R4
(wherein the various 8ymkols are as hereinbefore defined)
- may be prepared by hydrolysis under acidic condition~ o~
,
a compound of the general ~ormula: -
COOR
_~ / .
S ~ ' VII
OR ~ R3 - R4 ^` -
g ;~
OR
wherein the wavy line~'attached to the carbon atom in
po~ition 5 indicates that the double bond between
C5-C6 i8 Z or E and the other symbols are as hereinbefore
defined.
The hydrolysis must be carried out caxefully to
avoid the elimination of the grouEsRg, and may be carried
out with an aqueous solution of an organic acid, e.g.
acetic acid, propionic acid, oxalic acid or p-toluenesulphonic
acid, or an a~ueous solution o~ an inorganic acid, e.g~
.
~ .
` ' ; ~ ~ ' ' '
i2
hydrochl~ric,or sulphuric acid, in the presence or absence
of an inert organic solvènt miscible with water, e.gO an
ether such as 1,2-dimethoxyethane, dioxan or tetrahydrofuran
,(preferably te~rahydrofuran), at a ~emperature of from 0C
to 75 C (preferably from 0C to ambient)., Advantageously,
the hydrolysis may'be carried out with a mixture of acetic
, acid, water and tetrahydrofuran, a mixture of dilute
hydrochloric acid and tetrahydrofur~n, or dilute hydrochloric
acid. The progress of the hydrolysis is preferably monitored
by thin layer chromatography to avoid elimination of the
groups R9 . ''
Compounds of general formula VII are prepared by
dehydrohalogenation of a compound of the general formula:
' ', .
X - ~ COORl ' ' ' ' ' '
'6 ~ ~
- VIII
~ R 2
OR : ~ R3 - R ,,
wherein X represents a bromine or iodine atom, the
abqolutè configurations of C5 and C6 are (5S, 6S), ~5R, 6R~,
(5S, 6R) or (5R, 6S) or a mixture thereof, and the other
symbols are as hereinbefore defined.
The dehydrohalogenation may ~e carried out with a
known dehydrohalogenation reagent, for example (1)
when X represents a bromine atom, a bicycloamine such as
.
' '~
,
, - 16
- DBU (i.e. 1,5-diazabicyclo[5.4cO]undecene-5), DBN (i.e.
1,5-diazabicyclo[4.3.O~nonene-5) or DABC0 (i.e. 1,4-
; diazabicyclo[2.2.2~octane)~ or an alkali metal, eOg.
sodium or potassium, alcoholate containing from 1 to 4
S carbon atoms, or (2) when X represents an iodine atom,
a bicycloamine such as DBN, DBU or DABC0, or an alkali
metal, e.g. sodium,or potassium~ alcoholate containing
frDm 1 to 4 carbon atoms, superoxide, carbonate, hydroxide,
benzoate, acetate, trifluoroacetate or ~icarbonate, or
silver acetate, or tetramethylammonium super,oxide. The
reaction may be carried out at a temperature from ambient
to 110C, preferably at a temperature from ambient to 80C,
and (1) when the reagent is a bicycloamine, optionally in
the presence of an inert organic solvent, preferably in the
; absence.of~an inert organic solvent or in the presence of
toluene or benzene,.or.:..(,2),when ~the,reagent.is othe,r than a
bicycloamine'~ in~the presence of an inert organic solvent,l ,;
e.g. an alkanol containing from 1 to 4 carbon atoms, such :,.
as methanol or ethanol, or ~,N-dimethylformamide.- --- --
Compounds of ~eneral formula VIII may be prepared
from a compound of the general formula:-
X>~COORl ' '
~\>
- ~ f IX
~ ~RCl ~ ,
. ~ 17 ~
.. [wherein R10 and Rll, which may be the same or different,
each represents'a.hydrogen atom, a tetrahydropyran-2-yl
~r tetrahydrofuran-2-yl group, each such group being
unsubstituted or substituted by at least one alkyl group,
5 or a l-ethoxyethyl group, the absolute configurations of
C5 and C6 are (5S, 6S), (5R,.6R), (5S, 6R) or (&R, 6S)
or a mixture thereof and, the other symbols are as :
hereinbefore defined], when one or both of the symbols
R10 and'Rll represents hydrogen,.by reaction of the
compound of general fQrmula IX with a 2,3-dihydropyran,
2,3-dihydrofuran or ethyl vinyl ether in an 'inert organic ;~
. solvent, e.g. methylene chloride, in the presence of a
condensing agent, e.g. ~-toluenesulphonic acid. It will
. - be appreciated.that compounds~.of general,formula ~III.fall
15 within the scope.of-general.formula IX when~R10'and,R
both represent a-tetrahydropyr'an-2-yl-or tetrahydrofuran-2-yl
group, each-such group being unsubstituted or substituted
by at least one alkyl group, or a l-ethoxyethyl group.'
Compounds of general formula IX, wherein the
absolute configurations at C5 and C6 are ~5R, 6_) or
(5S, 6S~ or a mixture thereof and the other symbols are as
hereinbefore defined, may be prepared by bromination.or
iodination, and simultaneous'cyclisation of a compound of
the ~eneral formula:
-
, ~
: :
:
- 18 - -
O()
OR ~ R3 - R4
OR
wherein-the.double bond between C5-C6 i~ cis and the~
various symbols are as hereinbefore defined. ` .
. The conversion of a compound of general formula X
to-a compound of general formula IX may be suitably carried
out, (1) when X in the compound of general formula IX
c represents a bromine atom, with N-bromosuccinimide or
~-bromoacetamide in an aprotic or~anic solvent, e.g. methylene
- chloride, chIoroform, carbon tetrachloride, dièthyl ether,
- 10 N,~-dimethylformamide or-tetrahydrofurani or.ia.mixture of ..
- . two or more of them,~ at a temperature of~lfrom:-30i to:70C,~
or (2) when X in the compound-of general.ormula IX . .:
represents~an.iodine atom, with -(i) iodine in-pyridine,~
(ii) potassium periodate and potassium iodide in aqueous
acetic acid, (iii~ iodine and potassium iodide in the
presence`of an alkali metal, e.g. sodium or potassium,
. carbonate or bicarbonate in water, or (iv) iodine in the
presence of-an alkali metal, e.g. sodium or potassium, --
carbonate in an inert or~anic solvent, e.g. methylene
chloride or chloroform, at a temperature of from 0C to
ambient. The product of general formula IX, thus obtained,
~ .
,
. .
62
.~ _ 19 -
is a mixture of is-omers in which the absolute configurations
of C5 and C6 are (5R, 6_) and (5S, 6S). If desired, the
mixt~re may be separated by column, thin layer or high-speed -.
liquid chromatography on silica gel to give each of the isomers,
although such separation is not required.
Compounds of general formula IX, wherein the
abs~lute configuratlons at C~ and C6 are (5R, 6S) or :~
(5~, 6B) or a mixture thereof-and the various symbols
are as hereinbefore defined, may be prepared from a
compound of the general formula:-.
OH
`~ trans 5 . COOR
.XI
\~ R 2
~ R3 - R4;~
11, ' ;,,
( R -
(wherein the double~bond!-bètween C5-C6 is trans~and.the.
various symboIs~àre as ~ereinbefore defined) by means
heretofore mentioned for the conversion of compounds of.general .. ..
formula X to those of general formula IX. The product of
gqneral formula IX, thus obtained, is a mixture of isomers in
which the abso-ute configurations of C5 and C6 are (5R, 6S) ahd
(5S, 6R). If desired, the mixture may be separated by column,
thin layer or hi`gh-speed liquid chromatography on sillca gel to . . :
20 .give each of the isomers, although such separation is not
required. -
Compounds of general formula XI may be prepared
.
.: . .
,
- 20
- -- by photoisomerization of compounds of general formula X with
light from a high pressure mercury lamp in the presence of
..
diphenyl-sulphide or diphenyl disulpXide in an inert organic
solvent, e.g. a mixture of benzene and methanol, at room
temperature. Ihe product obtained may be purified by
column or thin layer chromatography on silica gel
pretreated with silver nitrate to give compounds of
general formula XI.
Compounds of general formula VI, wherein Z
repre5ent5 trans-vinylene and the other symbols are as
hereinbefore defined, i.e. compounds of the general
formula:-
OH
, ~ ~ ~C ;, .
R3 - R4
OR
(wherein the double bond between C2-C3 is trans and the
various symbols are as hereinbefore defined), may be
prepared from a compound of the general formula:-
OH 1'
, ~ OOR
\ ~ Q XII
R3 R4
OR
6;~ :
,
- 21 - . .
wherein Q represents the gro~p -SeC6H5 or -SR12, wherein
R12 represents an alkyl group containing from 1 to 4 carbon
atoms or a phenyl group, and the other sy~bols are as
hereinbefore defined.
Compounds of general formula XII, wherein Q
represents the group -SeC6H5, may be converted to compounds
of general formula VIB by reaction (1? with hydrogen
peroxide in a mixture of ethyl acetate and tetrahydrofuran
or methanoi, preferably in the presence of sodium
- 10 bicarbonate at a temperature below 30C, or (2) with
sodium periodate in a mixture of water and a lower alkanol,
e.g. methanol.or ethanol, preferably in the presence of
sodium bicarbonate at a temperature below 30~C.
Compounds of general formula XII, wherein Q
represents the~group -SR 2,-may be converted to compounds .... _
of the general~.formula: ..~- -
QH `- 1'
COOR - ::.
2 ~ XIII
~R ~ R3 - R4
OR
(wherein the various symbols are as hereinbefore defined)
by means heretofore mentioned for the conversion of
compounds of general formula XII, wherein Q represents
the group -SeC6~5, to those of general formula VIB.
.
,
62
- . 22
Compounds of general ~ormula XIII may be
converted to compounds of general formula VIB by
treatment (1) when R12 represents an alkyl group, in
toluene, preferably in the presence of a small amount of
calcium carbonate, at a temperature of 100~ to 120C or
(2) when R12 represents a phenyl group, in carbon
tetrachloride, preferably in the presence of a small amount
of calcium carbonate, at a temperature of about 50C.
Compounds of general formula XII may be prepared
from a compound of the general formula:-
COOR
Q
XIV
2 ~ "
~ R3 - R4, ' ..~i
(wherein the wavy line~fattached to the carbon atom in
position 5 indicates that the double bond betwee C5-C6
is Z or E and the other symbols are as hereinbefore defined)
by means heretofore mentioned for the conversion of
compounds of general formula VII to those of general
formula VIA.
Compounds of. general formula XIV may be
prepared from a compound of the general formula:-
, . , ' ' .
~C COORl ~:
6; ~
0 ~ Q - XV
<~, '.
OR ~ R3 ~ R4 -
_ OR
[wherein the absolute configurations of C5 and C6 are
(5S, 6S), (5R, 6R), (SS, 6R) or (5~, 6~) or a mix-ture
thereof and the various symbols are a~ hereinb~fore
defined] by?means heretofore.mentioned for,-the-conversion .. .
of compounds.of general ~ormula VIII.to:.those.of.general
formula VII.~...I..~,- `.. A . :
Compounds of general formula XV may be prepared
from a compound of the general formula~
COOR 5or CooLi when R
.is a hydrogen atom)
Li XVI
<~ ., ,
. ~ y . ~2
OR
.. . . ..
-, : , ,
r
51~62
_ 24 _
Cwherein the absolute configurations of C5 and C6 are
(5S, 6S), (5R, 6R), (5S, 6R) or (5R, 6S)-or a mixture
: ; thereof and the other symkols are as hereinbefore
defined-3 by reaction with benzeneselenenyl bromide (i.e.
C6H5SeBr) or diphenyl.diselenide (i.e. C6H5SeSeC6H5),
:or a dialkyl disulphide of the formula R12SSR12, wherein
R12 is as~hereinbefore defined, in an inert organic
solvent, e.g. tetrahydrofuran, hexamethylphosphotriamide,
diethyl ether, n-hexane or n-pentane or a mixture of two
or more of then, at a low temperature (when R is an
alkyl group, at -78C, or, when R is a.hydrogen atom, at
. 0C) followed by hydrolysis of the resulting
organolithium compound, for example by treatment with an
aqueous ~olution of ammonium chloride to give compounds .
1~ of general.formula XV.-
- Compounds of.,general formula.. XVI,:may.be~
prepared from-a compound of general.formula ~III by
. reaction with.a compound of general formula~
~13
,f~NLi XVII
R14
(wherein R13 and R14 each represent an alkyl group
containing from l.to 6 carbon atoms or a cycloal.kyl
group containing from 3 to 6 carbon atoms), ~1) when
R reprèsent~ an alkyl group, in tetrahydrofuran at a low
temperature, e.g. at -78C, or (2) w~en Rl represents a
.
.
.
6;~ :
. - .. 2
hyd~ogen atom, in tetr-ahydr.o~ran ln the presence of
he~amethylp~osphotriamide at 0C~
According to a further ~eature of the present
invention, the prostaglandin El analogues of general
formula IV,wherein Rl represents a hydrogen atom or a straight-
or branched-chain alkyl group containing from 1 to 12 carbon
atoms and the other symbols are as hereinbefore defined, may
also be prepared by the hydrolysis ~o hydroxy groups of the.
groups -oR15 and -OR16 of a compound of the general formula: .
Z-COOR
\ C XVIII
~ R3 - R4
3R16
(wherein R 5 and R16, which may be the same or di.fferent, -.
each represent a -~etrahydropyran-2-yl or tetrahydrofuran-2-yl.. .....
'' , , : ,
group, each~~such group being unsubstituted or substituted by~
at least one alkyl group, a l-etho~yethyl group, or a .. . .
trlmethylsilyl group, with the proviso that-at least one of
the sym~ols R15 and R16 represents a trimethylsilyl group, and
the other symbols are as hereinbefore defined) by means
heretofore men~ioned for the conversion of compounds of general
formula V to those of general formula IV.
Compounds of general formula XVIII may be
prepared from a compounS of the general formula:-
- .
. , , .: :
, "
:
- : .,~
--^--
i2
OH . 1'
Z-COOR
o~Rl5 Y ~ R3 - R4
. ;, OR
- . (whereini~he ~ohs.-~ymbol .~are ~s hereinbefore defined~
. ,, . . . ~ . .
by mean3 heretofore mentioned for the conversion of
compounds of general formula ~I to those of general
5 formula V. : .
Compounds of general formula XIX may be
prepared from a compound of the general formula:-
~ . . . . .
~H z COORl'
/ ..
. ~ ~ ;
-;. (wherein R17.and R~ whLch may be thesame or differenti
each represent a hydrogen atom, a tetrahydropyran-2-yl
or tetrahydrofuran-2-yl group, each such group being
unsubstituted or substituted by at least one alkyl group,
or a l-ethoxyethyl-group withlthe proviso that at least
; ` one of the s~mbols ~ and R18 represents a hydrogen atom,
and the other symbols are as hereinbefore defined) by
reaction with a suitable trimethylsilylating reagent, e A g
N-trimethylsilyldiethyl~mine or N,O-bis~trim~thylsilyl~-
acetamide, in an inext o~ganic ~lvent, e~g., aretone or
.
- ~ .
.
. - 27 - -:
methylene chLoride, prefer.ably at room temperature.
Compounds of general formula XX, wherein Z.
: represents ethylene and the other symbols are as
- hereinbefore defined, i.e. compounds of the general formula:
. OH 1'
I ~ OOR
~ - ,-, XXA
~R ~ R3 R4
18
(wherein the variouq sym~ols are as hereinbèfore defined)
. may be prepared from a compound of general formula IX,
wherein at least one of the symbol8 R10 and Rll
represents a hydrogen atom, by means heretofore mentioned
for the conversion of compounds of general formula VIII .. ..
to those of general formula VIA via compounds of general -:~
formula VII.
Compounds of general formula XX, wherein~:Z ;-
~represents trans-vinylene and the other symbols are as
hereinbefore defined, i.eO-compounds of the general
formula-
< ~1 ~ ,oo
17 . ~ R3 R4
oR18
.. .
. '
'
--~ . .
( r ~ 6;Z
_ 28 _
(wherein the double bond between C2-C3 is trans and the
..
various symbols are as hereinbefore defined) may be
prepared from a compound of general formuia IX, wherein
at least one of the symbols R10 and Rll represents a
hydrogen atom, by means heretofore mentioned for the
conversion of compounds of general formula VIII to those
of general formula VIB via compounds of general forn7ula
XVI, XV, X~V and XII~ - -
If desired,-the compoundR of general formula
IX or X, wherein Rl is other than a hydrogen atom and
the other symbols are as hereinbefore defined, may be
prepared by esterification of a compound of general
formula IX or X, wherein Rl is a hydrogen atom and the
other symbols are as hereinbefore defined, by methods
known per se for ~he esterification of carboxylic acids,
for examplë,-by-reaction with (i) the appropriate -
~~ - ; diazoalkane,;e.g.i~diazomethane, in~an inert organic~solvent,~- ~r
- e.g. diethyl-ether,~ at a temperature of from -10 t-o 25~C ~
and preferably 0~, (ii) the appropriate alcohol in the
presence of- dicyclohexylcarbodiimide as condensing agent,
or (iii) the appropriate alcohol 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. our British Patents ~osO
25 1362956 and 1364125~o
If desired, the aclds of general formula
,: ` .
,; .~ .
.
.: , :
~`` `
29
' ,
VI, VII, VIII, IX, XII, XIII, XIV or XV, wherein R
repre~.ents a hydrogen atom, and the other symb~ols.are
as hereinbefore defined, ~ay be prepared from the
corresponding esters of general formula VI, VII, VIII,
: 5 IX, XII, XIII, XIV or XV, wherein R is other than a
hydrogen atom,.and the other symbols are as hereinbefore
defined, by alkaline hydrolysis with an aqueous solution
of an alkali metal,-e.g. sodium or potassium, hydroxide
or carbonate in the presence of an inert organic solvent
miscible with water, e.g. a lower alkanol such as methanol
or ethanol, preferably at ambient temperature.
Startin~ materials of general formula X may be
prepared by the methods described in the following patent
~ specifications, or obviou modification~ thereof:- Japanese - -
-1~ Pa~ent Kokai~Nos. 50-13364,. 50-25549, 50-143339 and. ::--~-. .
51-68547, ~ritish Patent Specifications Nos.- 1450691;- : ;
1464916, 1488~41, 1483240, 1484210 and 154~213, United.l,
States Patent Specifications Nos. 3962312, 3966792, :
4034003, 4024174,4045468 and 4087620 and Belgian Patent
No~ 844256.
- According to a further feature of the present
invention esters of ~he prostag~andin El analogues of
,
~'1'
. 30
general formula IV may be prepared by esterification of the
corresponding acid of general formula IV wherein R
representR a hydrogen atom by methods known E~r se for
example by reaction with ~i~ the appropriate diazoalkane in
an inert organic solvent, e.g. diethyl ether, at a temperature
- .of from -10 to 25C and preferably 0C, ~ii) the appropriate
alcohol in the presence of dicyclohe~ylcarbodiimide as
condensing agent, or ~ili) the appropriate alcohol following
-' ormation of a mixed anhydride by adding a tertiary amine and
pivaloyl halide or an alkylsulphonyl or arylsulphonyl halide
(~f. our British Patents Nos. 1362956 and 1364125)o
Prostaglandin'analogues of general formula IV,
wherein R represents a group -CmH2mCOOR5,in which R5 represents
a hydrogen.atom,may be esterified by methods~kn~wn per se to
15 obtain the corresponding esters in which Rl represents a .-
group -CmH2mCOOR5.in which-R5 repr'esents a straight- or. .
branched- c~a-in alkyl'group containing ~rom l to,4~car.bon:a~
Cyclodextrin clathrates of the prostaglandin
` analogues of general formula IV may be prepared by dissolvIng
the cyclodextrin in water or an organic solvent which is
.miscible with water and adding to the solution the prosta-
' glandin analogue in a water-miscible organic solventO The
mixture is then heated and the desired cyclodextrin
clathrate product isolated by concentrating the mixture under
reduced pressure or by cooling and separating the product by
filtration or decantationO The ratio of organic solvent t.o
"
-31 -
water may be varied according to the solubilities of the
- startin~ materialB and products. Preferably the
temperature iB not allowed to exceed 70C during the
preparation of the cyclodextrin clathrates. ~ or ~-
Cyclodextrins or mixtures thereof may be used in thepreparation of the-cyclodextrin clathrates. Conversi~n
into their cyclQdextrin clathrates serves to increase
the stability of the prostaglandin analogues.
Compounds of general formula IV wherein R
represents a hydrogen atom or a group -CmH2mCooR5 in
which R5 represents a hydrogen atom may, if desired, be
converted by methods known ~ se into salts. Preferably
the salts are non-toxic salt3. 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 dose so that-the -
~beneficial`pharmacological properties of the compounds ofgeneral formula IV are not vitiated by side-effects---
ascribable to those cations. Preferably the salts are
water-soluble. Suitable non-toxic salts include the
alkali metal, e.g. ~odium or potassium, salts, the
alkaline earth metal, ~.g. calcium or magnesium, salts
and ammonium salts, and pharmaceutically acceptable, tiOe.
non-toxic) amine salts. Amines suitable for forming such
salts with carboxylic acids are well known and include for
,
:
- 32 - ' "'
example, amines derived in theory by.the replacement of
one or more of the hydrogen atoms ~f ammonia by groups,
..
which may be the same ox 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~
Suitable non-toxic .amine salts are, e.g. tetraalkyl-
ammonium, such as te'tramethylammonium, salts, and
other organic amine salts such as methylamine salts,
dimethylamine salts, cyclopentylamine salts,
\ benzylamine salts, phenethylamine salts, piperidine
' salts, monoeth'anolamine salts, diethanolamine salts,
lysine salts or arginine salts.
' ' ' Salts may be prepared from the acids of
general formula IV wherein Rl represents a hydrogen
- atom or a group -CmH2mCooR5 in which R5 represents a
...I hydrogen atom, by methods known ~ se, for.~ex~mple by -
' reaction of stoichiometric quantities of an.acid of ~' '' :'
general formula--IV and the appropriate base,ie.gO an
alkali metal or alkaline earth mPtal hydroxide or
carbvnate, ammonium hydroxide, ammonia or an organic
amine, in a ~uitable solvent. The salts may be
isolated by lyophilisation of the solution or, i
sufficiently insoluble in the reaction medium, by
filtration, if necess ry after removal of part of the
. . .
.
.
": ~
'
.~ 33~. . .
.solvent.
- Prostaglandin analogues of general formula
IV wherein R represents a group -CnH2nN R8 wherein
n, R7 and R8 are a~ hereinbefore defined may be converted
by methods known per se into acid addition salts, which
are prefarably non-toxic. Suitable acid addition salts
ar~ those formed with inorgan~ aci~s.(~-uch as
hydrochlorides and sulphates~ and with organlc aclds
- (such as acetates, propionates, succinates and benzoates)~
The prostaglandin El analogues of general
formula IV and their cyclodextrin clathrates and,when
R represents a hydrogen atom or a group CmH2mCooR5
in which R5 represents a hydrogen atom, and m is as
hereinbefore defined,.non-toxic salts and, when R
15 represents a group -CnH2n ~ 8 in which n, R7 and- -~
R are as hereinbefore defined, non-toxic acid addition :. .
salts, possess the valuable pharmacological~properties
typical--of the prostaglandins in~~a selective fashion,
in particular~hypotensive~activity, inhibitory activity on
blood platelet aggregation, inhibitory activity on gastric
acid secretion and gastric ulceration, stimulatory activity
on uterine contraction and abortifacient, luteolytic and
antinidatory activity, and are useful in the treatment
. ' :
.
_ 3~
- of hypertension, in the treatment of disorders of the
peri~heral circulation, in the prevention and treatment
- of cerebral thrombosis and myocardial infarction, in .
the treatment of gastric ulceration,in the termination
5 of pregnancy and in~uction of labour in pregnant female
mammals, in the treatment of impaired fertility and in the
control of 02strus, contraception and menstrual regulation
in ~emale mammals. For example, in standard laboratory
tests, (i)by intravenous administration to the
allobarbital-anaesthetized dog, 6-oxo-15-(3-propylcyclopentyl)-
6;l7~l8~l9~2o-pentanor-pGEl methyl ester produces a fall
in blood pressure of 34 mm Hg and 60 mm Hg lasting 8 and
20 mi~utes at the doses of 0~1 and 0.2 ~g~kg animal body weight,
respectively, 6-oxo-15-(3-propylcyclopentyl)-16,17,18,19,20-
pentanor-PGEl produces a fall in blood pressure of 18 mm
Hg and 34 mm Hg lasting 7 and 11 minutes at the doses of
0.05 and 0.1 ~g/kg animal body weight, respectively, 6-oxo
15-(4-propylcy~clohexyl)-16,17,18,19,20-pentanor-PGEl methyl :~
ester produces a fall in blood pressure of 26 mm Hg and
42 mm Hg lasting 8.and 14 minutes at the doses of 0.2
and 0.5 ~g/kg animal body weight, respectively, and 6-oxo
15-(3-butylcyclopentyl~-16,17,18,19,20-pentanor-PGEl methyl
ester produces a fall in blood pressure of 30 mm Hg and
70 mm Hg lasting 10 and 22 minutes at the doses of 0.2
and 0.5 ~g/kg animal body weight, respectively, (ii) in
increase of coronary flows in isolated rabbit hearts,
,
~ ~ ,
~ 5~
6-oxo-15-(3-propylcyclopentyl)-16,17,18,19,20-pentanor- PGEl
metbyl ester and 6-oxo-15-(3-propylcyclopentyl)-16,17,18,19,20-.
pentanor-PGEl are 10 times and 4.2 times, respectively,
, as potent a~ PGEl, ~iii) 6-oxo-15-(3-propylcyclopentyl)- .
l6~l7~l8~l9~2o~pentanor-pGEl methyl ester and 6-oxo-15-
(3-propylcyclopentyl)-16,17,18,19,20-pentanor-PGEl produce
a 50% inhibition of adenosine diphosphate-induced blood
platele~ aggrega~ion in..platele.t-rich plasma of rats at
the concentrations of 2.9 x 10 3 ~g/ml and 3.1 x 10 3 ~g/ml
. 10 respectively, in comparison with controls, (iv) 6-oxo-15-
(3-propylcyclopentyl)-16,17,18,19,20-pentanor-PGEl methyl
ester, 6-oxo-15-(3-propylcyclopentyl)-16,17,18,19,20-pentanor-
PGEl and 6-oxo-15-t4-propylcyclohexyl~-16,i7,18,19,20-
pentanor-PGEl methyl ester produce an increase in gastric
acid pH from 2.0-2.5-to-at least ~.0 in 50/O of pentagastrin- . .~-
treàted rats when perfused into the stomach at the rates.of
: ~0.5, 0.7-0.9 and-~0.5.~g/animal/minute,--respectively,-~
~v) in stress ulceration of rats [produced according to
the method of Takagi and Okabe - Jap. J. Pharmac., 18,
9-18(1968) by soaking rats in a,water bath at 19C for 6
hours~, 6-oxo-15-(3-propylcyclopentyl)-16,17,18,19,20-
pentanor-PGEl methyl ester produces 65.75% and 90.31%
inhibition of stress ulceration by oral administration at
the doses of S0 and 100 ~g/kg animal body weight, respectively,
6-oxo-l5-(3-propylcyclopenty~ 6~l7tl8~l9~2o-pentanor-pGE
produces 62.19% and 80.95% inhibition of stress ulceration
,
( . - 36 -
by oral administrati~n at the doses of 20 and 50 ~g/kg
animal body weight, respectively, 6-o~o-15-(4-
. propylcyclohèxyl ) -16 ,17,18,19,20-pentanor-PGE1 methyl ester
produces 44.37%-and 63.05% inhibition of stress ulceration
by oral administration at the doses of 50 and 200 ~g/kg
animal body weight, respectively, and 6-oxo-15 (3-
butylcyclopentyl)-16,17,18,19,20-pentanor-PGEl methyl
ester ~roduces 42 ~ 2~/o affd 50 ~ 0~/o i~hi~ition of ~tress
ulceration by oral administration at the doses of 10 and
20 ~g/kg animal body weight, respectively, (vi) in
indomethacin-induced ulceration of rats, 6-oxo-15-(3-
propylcyclopentyl)-16,17,18,19,20-pentanor-PGEl methyl
ester produces 89.9% inhibition of indomethacin-induced
ulceration by oral administration at the dose of 5.0 ~g/kg
15~ animal body weight, 6-oxo-15-~3-propylcyclopentyl) 16,17,18,19,
20-pentanor-PGEl produces 86.87%--inhibition of indomethacin- .-
inducedulceration by oral administrationat thedose oflO ~g/kg ~ `
an~mal body weight and.6-oxo-15-(3-butylcyclopentyl~-16.,.17, ;i,-;.
- 18,19,20-pentanor-PGEl methyl ester produces 66.83% and
63. 4~/D inhibition of indomethacin-induced ulceration,by~
oral administration-at the doses of 2.5 and 5 ~g/kg animal
body weight; respectively, and (vii) 6-oxo-15-~3-propylcyclo- :~
pentyl~-16,17,18,19,20-pentanor-PGEl methyl ester, stimulates
uterine contraotion in the pregnant female ra~ when
administered intravenously on the 20th day of gestation ;`
, ~
~ 6Z
. - 37 - .
.
- . at the dose of 2-5 ~g/kg anImal body weight.
The prostaglandin analogues of the present
~-. invention, their cyclodextrin clathrates, non-toxic salts `
: ' and non-toxic acid addition salts can cause diarrhoea.
The dose~ by oral : administration of 6-oxo-15-
(3-propylcyclopentyl)-16,17,18,19,20-pentanor-PGEl
methyl ester,-6-oxo-l5-(3-propylcyclopentyl~-16,17,18,19,
~0-pentanor-PGEl, 6 o~o-15-(4-pxopylcycloh~xyl)-~6,17,18,
19,20-pentanor-PGEl methyl,ester, and 6-oxo-15-(3-butyl-
cyclopentyl)-16,17,18~,19;20-pentanor-PGE1 methyl ester
required to produce diarrhoea in 5~ of mice so treated
axe 5.0-10, 5.0-10, >10, and 10-20 mg/kg anLmal body
. . weigh~ respectively.
Preferred prostaglandin analogues of the
present invention are as follows:-
6-oxo-15-cyclobutyl-16,17,18,19,20-pentanor-PGEl, .
: 6-oxo-15-(1-propylcyclobutyl)-16,17,1~,19,2~-pentanor- ~ ..
PGEl, 6-oxo-15-(1-butylcyclobutyl)-16,17,18,19,20- - - -
pentanor-PGEl, 6~oxo-15-(1-pentylcyclobutyl~-16,17,18, -
19,20-pentanor-PGEl, 6-oxo-15-(1-hexylcycIobutyl)-16~,17, -
18 ,19, 20-pentanor-PGE~
.
. , ~
62
:
6-oxo-15-(2-methylcyclobutyl)-16,17,18,19,20-pentanor-PGEl,
6-oxo-15-(2-propylcyclobutyl)-16, li ,18, 19,20-pentanor-PGEl,
6-oxo-15-(3-ethylcyclobutyl)-16,17,18,19,20-pentanor-PGEl,
.
6-oxo-15-(3-propylcyclobutyl~-16,17,18,19,20-pentanor-PGEl,
~5 6-oxo-15-(2,3,4-triethylcyclobutyl)-16,17,18,19,20-
:~ pentanor-PGEl, 6-oxo-15-cyclopentyl-16,17,18,19,20-
.
pentanor-PGEl, 6-oxo-16-cyclopentyl-17,18,19,20-tetranor-
.
. PGEl, 6-oxo-17-cyclopentyl-18,19,20-trinor-PGEl, 6-~xo-
16-cyclop.entyl-18,19,20-trinor-PGEl, 6-oxo-18-cyclopentyl-
.I0 19,20-dinor-PGEl, 6-oxo-17-cyclopentyl-19,20-dinor-PGEl,
6-oxo-15-~2-pentylcyclopentyl3-16,17,18,19,20-pentanor-
PGEl, 6-oxo-15-(2 ! 2-dimethylcyclopentyl)-16,17,18,19,20-
pentanor-PGEl, 6-oxo-15-(3-ethylcyclopentyl)-16~17,18,19,20-
pentanor-PGEl, 6-oxo-15-(3-propylcyclopentyl)-16,17,18,19,20-
pentanor-P&El, 6-oxo-15-(3-butylcyclopentyl)-16,17,18,19,20-
pentanor-PGEl,- 6-oxo-15-(3-tert-butylcyclopentyl)-
16,17,18,19,20-pentanor-PGEl, 6-oxo-15-(1-methyl-3-propyl- ` -~:
- cyclopentyl)-16,17,18,19,20-pentanor-PGEl, 6-sxo-15-(2- .. .....
methyl-3-propylcyclopentyl)-16;17,18,19,20-pentanor-P&El,
6-oxo-15-(2-methyl-4-propylcyclopentyl)-16.,17,18,19,20-
pentanor-P&El, 6-oxo-15-cyclohexyl-16,17,18,19,20-
pentanor-PGEl, 6~oxo-16-cyclohexyl-17,18,19,20-te~ranor-
PGEl, 6-oxo-17-cyclohexyl-18,19,20-trinor-PGEl, 6-oxo-
16-cyclohexyl-18,19,20-trinor-PGEl, 6-oxo-18-cyclohexyl-
25 1~,20-dinor-PGEl, 6-oxo-16-mPthyl-17-cyclohexyl-18,19,20-
trinor-PGEl, 6-oxo-17-cyclohexyl-19,20-dinor-PGEl,
62
_ 39 _ .
6-oxo-1~-methyl-16-cyclohexyl-18,19,20-trinor-PGEl,
6-oxo-l9-cyclohexyl-2o-nor-pGEl~ 6-oxo-15-(3-ethyl-
cyclohexyl)-16,17,18,19,20-pentanor-PGE~ oxo-15-.
(3-isopropylcyclohexyl)-16,17,18,19,20-pentanor-PGEl,
5. 6-oxo-15-(4-methylcyclohexyl)-16,17,18,19,20-pentanor-
PGEl, 6-oxo-15-(4-~thylcyclohexyl)-16,17,18,19,20-
pentanor-PGEl, 6-oxo-15-(4-propylcyclohexyl)-16,17,18,19,
- 20-pentanor-P~El, 6-oxa-15-(4-butylcyclohexyl)-16,17,18,
. l9~2o-pentanor-pGEl~ 6-oxo-15-(4-tert-butylcyclohexyl)~
16,17,18,19,20-pentanor-PG~1, 6-oxo-15-(2,6-dirnethylcyclo-
hexyl)-16,17,18,19,20-pentanor-PGEl, 6-oxo-15-(2,2-dimethyl-
cyclohexyl)-16,17,18,19,20-pentanor-PGEl, 6-oxo-15-
- (2,4,6-trimethylcyclohexyl)-16,17,18,19,20-pentanor-PGEl,
6-oxo-16-(1-methylcyclohexyl)-17,13,19,20-tetranor-PGEl,
6-oxo-15-cycloheptyl-16,17,18,19,20-pentanor-PGEl, 6-oxo-
16-cycloheptyl-17~18~19.~20-tetranor-PGEl~ 6-oxo-17-
cyclo~eptyl-18,-19,20-trinor-PGE~ 6-oxo-16-cycloheptyl~
18,19,20-trin.or-PGEl, and.the corresponding 15-methyl- and
- 15-ethyl-PG~l analogues and their esters and non-toxic salts,
and cyclodextrin clathrates of the PGEl and 15-methyl-
and 15-ethyl-PGEl analogues and their esters.
6-Oxo-15-(3-butylcyclopentyl)-16,17,18,19,20-
pentanor-PGEl methyl ester, 6-oxo-15-(4-propylcyclohexyl)-
l6~l7~l8~lg~2o-pentanor-pGEl methyl ester, 6-oxo-15-(3-
propylcyclopentyl)-16,17,18,19,20-pentanor-PGEl methyl
ester and 6-oxo-15-(3-propylcyclopentyl)-16,17,18,19,20-
.
:; ': ' ' "'
pentanor-PGEl, are the most preferred prostaglandin
analogues of the invention.
.Compounds of formulae V, VI, XVIII and XIX
are new.
'
~ . ,' ' ' ' ' .
- .
.
.
`` ~ æ
- 41 -
- ' . ' ' ~1
- In ~he Specification of our Appiication ~o.
311338 (rom which this application is divided) as .
filed on 14th September, 1978, we have described the .
preparative procedures given in the following Reference .
Examples 1 to 6. ¦~
. The following Reference Examples 7 to 12 and
- Examples 1 and 2 illustrate the preparation of new ;
prostaglandin El analogues of the present invention~ In
the Reference Examples and Examples'TLC', 'IR' and 'NMR' :
represent respectively 'Thin layer chromatography',
'Infrared absorption spectrum' and 'Nuclear magnetic ';
resonance spectrum'.
Where solvent ratios are specified in chromatographic
separations, the ratios are by volume. l~
REFERENCE EXAMPLE 1 :- . .
(13E)-(5RS,6RS,9a,11a,-15S)-5-Bromo-6,9-epoxy-11,15-.-. . .. .
is(tetrahydropyran-2-yloxy~prost-13-enoic acid meth~l...... -
ester
Under an atmosphere o~ nitrogen, a solution~ . I
of 3-4 g of (5Z,13E ?-( g a,11 a, 15s)-9-hydroxy-~ 5-bi
(tetrahydropyran-2-yloxy)prosta-5,13-dienoic acid
methyl ester in -a mixture of 30 ml of methylen~ chloride
and 6 ml of N,N-dimethylformamide was added dropwise to `
a suspension of 1.35 g of N-bromo-succinimide in 50 ml of
6Z
r - L~2 -
,
methylene chloride at -20 to -lO~C and the mixture was
stirred for 30 minutes at the s~me tem~erature. The
reaction mixture was then poured into ice-water and
.
- extracted with diethyl ether. The extract was washed
with water and an aqueous solution of sodium chloride,
dried over magnesium ~ulphate and concentrated under
reduced pressureO ~The residue was purified by column
chro~atogr~phy-on silica gel using a mixture of cycl4hexane
and ethyl acetate (4:1) as eluent to give 3.43 g of the
.
title compound having the foll~wing physical characteristics:-
TLC (developing solvent, benzene:ethyl acetate = 2
Rf - 0.65 and 0.69
-IR (liquid film):~ = 1745, 1440, 1030, 980 cm
NMR (CDC13 solution); ~ =5.72-5.30 (2H, m), 4.80-4.46
(3H, m~, 4.32-2.32 (llH, m), 1.00-0~75 (3H, m).
The following compound was prepared by-the
same procedure as-described above. = -
,
(a) (13E)-(5RS,6RS,9a,11~,15S,16S~-5-Bromo-
6,9-epoxy-11,15-bis(tetrahydropyran-2-yloxy)-16-
methylprost-13-enoic acid methyl ester, having the ~
following physical characteristics, was prepared from
(5Z,13E)-(9~,lla,15S,16S~-9-hydroxy-11,15-
bis(tetrahydropyran-2-ylo~y)-16-methylprosta-5,13
dienoic acid methyl ester.
TLC (developing solvent, benæene:ethyl acetate~
methanol - 19:38~
~.
' ~ :
- 43 -
.
Rf = 0.45 and 0.54;
IR (liquid film): ~ = 1710, 1440, 1020, 980 cm 1,
.
' ~MR (CDC13 solution): ~ = 8.70 (lH, broad s), 5,70-5.25
~2H, m), 4~80-4.45 (3H, m~, 4.23-3.~5 t8H, m), '
1.02-0.75 ~6H, m).
REFERENCE-EXAMPLE 2
(l3E)-t5Rs~6Rs~9a~ l5Rs)-5-Iodo~6~9-epoxy~ l5-
bis(tetrahydropyran-2-yloxy)-15-methylprost-13-enoic
acid methyl ester
To a solution of 1.067 g of (13E)-(5RS,6RS,
9~,11a,15RS)-5-iodo-6,9-epoxy-11,15-dihydroxy-15-
methylprost-13-enoic acid methyl ester (pre~ared as
described hereinafter) in 20 ml of methylene chloride were
added 1.4 mg of ~-toluenesulphonic acid and 1.337 g of
2,3-dihydropyran and the~mixture was stirred at -4C
for 4.5 hours. ~-The reaction mixture was then-,~neutralised ~
; with an aqueous -solution-of-sodium bicarbonate and-extracted
with chloroform. The extract was dried over magnesium ,
sulphate and concentrated under reduced pressure. The
residue was purified by column chromatography on silica
gel using a mixture of cyclohexane and ethyl acetate
(2:1) as eluent to give 1.2 g of the title compound having
the following physical characteristics:- -
TLC (developing solvent, cyclohexane:ethyl acetate = l:lj
Rf= 0.67,
IR (li~uid film):~ = 2950, 2880, 1745 cm 1,
., ~ ,
6~:
NM~ (CDC13 solution): ~ = 5.8-5.2 (2H, m) 5.1-4.3 (3H, m),
3.67 (3H, s~. (13E)-(5RS,6RS,9~,lla,15RS)-5-I~do-6,9-
epoxy-11,15-dihydroxy-15-methylpro~t-13-enoic acid
methyl e~ter used as stàrting material in the ab~ve
procedure, having the following physical characteristics,
was prepared from (5Z,13E)-(9a,11~,15RS)-9,11,15-
trihydroxy-15-methylprosta-5,13-dienoic acid methyl
ester by the procedure aescribed in Reference Example 7
hereinafter.
TLC (developing solvent, ethyl acetate):
Rf = 0.45
IR (liquid film): ~ = 2970, 2950, 2880, 1745 cm lî
~MR (CDC13 solution): & = 5.82-5.3 (2H, m~, 4.71-4.45
(lH, m~, 4.3-3.7 ~2H, m), 3~69 (3H, s). ~ --
REFERENCE EXAM2LE 3
(13E)-(9a,11a,15S)-6-Oxo-9-hydroxy-11,15-bis- ~ -
(tetrahydropYran-2-yloxy)~ ost-13-enoic acid~methyl es er -- -
~nder an atmosphere of nitrogen, a solution of -- - -
970 mg of (13E)-(5RS,6RS,9a,11a,15S)-5-~romo-6,9-epoxy-
- 20 11,15-bis(tetràhydropyran-2-yloxy)prost-13-enoic acid
methyl ester (prepared as descri~e~ in Re-ference Example
1) and2ml o~ DBU-^(1,5-diazabicyclo~5.400]undecene-5)was
stirxedat room temperature overnight, and then ~ooledto 0C. 6ml `~
ofwater was added to tha reaction mixturer:which was then acidified
to pH 1 with 1~ hydro~hloric acid at 0C, and extra~ted
with et ~l acetate. The extract was washed with an
: .
.
62
45 -
aqueous solution of s~dium bicarbonate and an aqueous
. ~olution of sodium chloride, dried over magnesium sulphate.
and concentrated under reduced pressure to give the crude
title compound having the following physical characteristic:-
TLC ~developing solvent, ethyl acetate:n-hexane = 1
Rf = 0~31.
REFERENCE EX~PLE 4
(13E)-(9a,11a,15S,16S)-6-O~o-~-hydroxy-11,15-bi~-
(tetrahydropyran-2-yloxy)-16-methylprost-13-en ic acid
.
methYl ester
.
Under an atmosphere of nitrogen, a solution of
2.233 g of (13E)-(5RS,6RS,9, lla,l~S,16S)-5-bromo-6,9-
epoxy-11,15-bi8(tetrahydropyran~2-yloxy)-16-methylprost-
13-enoic acid methyl ester [prepared as described in
Reference Example~.l(a)~.and 7~4 ml of DBU was stirred at
70C for 3 hours,--and-then cooled to 0C.. To,the .: . .-
reaction mixture were added 37 ml o-E-lN hydrochloric~
acid and 37 ml ~f phosphate buffer solution -(pH.6.68~ .-
with cooling to 0C. The reaction mixture.was extracted
quickly with diethyl ether. The extract was dried over
magnesium sulphate and concentrated under reduced
pressure to give an oily product. To a solution of the
oily product thus obtained in 40 ml of tetrahydrofuran
were added dropwise 4 ml o~ water and 4 ml of 65% tv/v)
aqueous acetic acid and the mixture was stirred at room
temperature for 2 hours and then extracted with ethyl
': . ' ~ ' -
- 46 -
~ 62
acetate, The extract was washed with water, an aqueous
solution of ~odium bicarbonate and an aqueous solution
of sodium chloride, dried over magnesium sulphate and
concentrated under reduced pressure. ;~he résidue was
. .
purified by;column chromatography on silica gel using a
mixture of cyclo~exane and ethyl acetate (lol) as eluent
to give 1.323 g of the title compound having the following
physiral characteristics~
. TLC (develQping. S~lV~Rt,- ~yclohexan~:ethyl acetate = 1
Rf = 0.34: ,
IR (liquid film~: ~ = 3425, 1740, 1710, 970 cm 1;
NMR (CDC13 solution): ~ = 5.7-5.3 (2H, m), 4~75-4.4
(2H, m), 3.66 (3H, 8), 4.3-3.25 (7H, m), 1.05-0.7
(6H, m).
REFERENCE EXAMPLE 5
(13E~-~lla,15S)-6,9-Dioxo-11,15-bis~tetrahydropyran-2-
yloxv~p--o-st-l3-enoic ac _ methyl ester
- To a solution of crude (13E)-l9a,11~,15S)-6- -~
oxo-9-hydxoxy-11,15-bis(tetrahyaropyran-2-yloxy)prost- --
20 13-enoic acid methyl ester (prepared as described in ~
Reference Example 3~ in 10 ml of diethyl ether was added
10 ml of a chromic acid solution ~obtained from 760 mg of
chromium trioxide, 2.~6 g of manganese sulphate, 0.84 ml
of sulphuric acid and 19 ml of water) at 0 to 5C, and
the mixture was stirred at the sxme temperature for 1
hour. l~he reaction mixture was extracted with diethyl
ether and the~extract was washea with an aqueous solution
of s~dium bicarbonate and an a~ueous solution of sodium
chloride, dried over magnesium sulphate and concentrated
under reduced pressure. The residue was purified ~y
.
- , . - ~
6~2
-- 47 --
column chromatograph~ on silica gel usin~ a mi~ture of
~ n-hexane and ethyl acetate (17:3) as eluent to give 480 mg
- of the.title compound having the following phy~ical
' characteristic:-
5 TLC ~deve~oping qolvent, ethyl acetate:n-hexane = 1
~f = 0.45.
REFERENCE E:XAMPLE 6
(13E)~ ,15S)-6,9-D~oxo-11,15-dihydroxyprost-13-enoic
.
acid methyl ester ~6-oxo-PGEl methyl ester)
____ _ _ :
To a solution of 480 mg of (13E~-(11,15S)-
6,9-dioxo-11,15-bis(tetrahydropyran-2-yloxy)prost-13-
en~ic acid methyl ester ~repared as descri~ed in Reference
Example 5) in 1 m~ of tetrahydrofuran was added 3 ml of
65% (v/v) aqueous acetic acid and the mixture was stirred
at 45C for 3 hours.- The-reaction mixture was diluted with
16 ml of water and extracted with a mixture of;ethyl --
acetate and n-hexane (1:1~. The extract was washed with
water, an aqueous 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 ethyl acetate and n-hexane
(1~1) as eluent to give 177 mg of the ti~le compound
having the following physical characteristics:-
TLC (developing solvent, ethyl acetate): Rf= 0.32:IR (liquid film):~ = 3630-3510,1740,1723, 1440, 1372,
. . '
~..................................................... ~:
z
~ 8 - .
. .
1242, 1178,1160, 1078, 975 cm 1,
- NMR (CDC13 ~lution):-~ = 5.65-5.40 (2H, m), 4.28-3.85
(2H, m), 3.65 (3H, s), 2093-2.05 (lOH, m), 1.00-0075 (3H, m).
REFERENCE EX~MPLE 7 ~
(13E)-t5RS,6RS,9~,lla,15S)-5-Iodo-6,9-epoxy-11,15-
. . ~
- bis~tetrahydropyran-2-yloxy)-15-(3-propylcyclopentYl)-
16,17,18,19,20-pentanorpro~t-13-enoic acid methy~ester
Toa solution of 980 mg of (5Z,13E)-
( 9 a, 11 a.l5S)-9-hydroxy-11,15-bis(tetrahydropyran-2-
yloxy)-15-(3-propylcyclopentyl~16,17,18,19,20-
: pentanorprosta 5,13-dienoic acid methyl ester in 5 ml
~, ~
of methylene chloride was added a solution of 1.428 g
of sodium bicarbonate in 15 ml ~f water and the mixture
was cooled to 0 to 5C in an ice-bath. A solution
of 0.475 g. of iodine in 20.ml of.. methylene chloride
at the same temperature.~was adde~ in portions to--the`
.
mixture and-then the reaction mixture was stirred-for~
1 hour. An aqueous solution of sodium thio~ulphate was~
added to the reaction mixture until the colour o~ iodine
, 20 vanished. The reaction mixture was extracted with
chloroform and the extract was dried over sodium
~ulphate and concentrated under reduced pres~ure~
The residue was purified by column chromatography
on silica g~l using ~ mixtuxe of cyclohexane and ethyl
~cetate (1:1) as elu~nt to give 974 mg of the title
compound having the following physical ~haractexistics:-
`
62
- -- 49
TLC (developing solvent, cyclohexane:ethyl acetate - 2
Rf = 0 60,
IR ~liquld.fl~m): ~ = 2950, 2875, 1742 cm 1;
NMR (CDC13 solution): ~ = 5.68-5.30 (2H, m) 4.78-4.48
(3H, m), 3.67 (3H, s), 0.98-0.76 (3H, m)~ :
. The following compounds were prepared by the
same procedure as described above.
(aj (13~)-(S~S,6R~,9a,11a,15S)-5 Iodo~6,9-
epoxy-11,15-bis(tetrahydropyran-2-yloxy)-15-(3-
butylcyclopentyl)-16,17,18,19,20-pen~anorp~ost-13-
` enoic acid methyl ester, having the foll~wing physical
characteristic, was prepa~ed from (5Z,13E)-(9 a, 11 a,15S)-
9-hydroxy-11,1~-bis(tetrahydropyran-2-yloxy)-15-(3-
butylcyclopentyl)-16,17,18,19,20-pentanorprosta-
1~ 5,13-dienoic acid methyl ester. .
TLC (developlng solvent, cyclohexane:ethyl acetate = 3
Rf = 0.67.
(b) (13E)-(5RS,6RS,9a,11a,15S)-5-Iodo----
6,9-epoxy-11-(tetrahydropyran-2-yloxy)-15-hydroxy-15-
(4-propylcyclohexyl)-1~,17,18,19,20-pentanorprost-13-
enoic acid methyl ester, having the following physical
characteristic, was prepared from (52,13E)-(9a,11a,15S)-
9,15-dihydroxy-11-(tetrahydropyran-2-yloxy)-15-(4-
propylcyclohexyl)-16,17,18,19,20-pentanorprosta-5,13-
dienoic acid methyl esterO
TLC (developing solvent, ethyl acetate:benzene = 2
Rf = 0.60.
. .
62
- - 50 -
REFERENCE EXAMPLE 8
(13E)--(5RS,6RS/9a,11a,15S)--5--Iodo--6,~--epoxy--11,15--
.
bis~tetrahydropYran-2-Yloxy~-15-(4-propylcyclohexyl)- ' '
16,17,lB,19 ! 20-pentanorprost-13-enoic acid methyl est`er
- 5 The title compound having the following physical
s characteristics, was prepared from (13E~-(5RS,6RS,9a,11,
15S)-5-iodo-6,9~epoxy~ (tetrahydropyran-2-yloxy)-15-
. -. . ..
hydroxy-15-(4-propylcyclohexyl)-16,17,18,19,20-pentanorprost- ,
13-e,noic acid methyl ester [prepared as described in Reference
Example 7 tb)~, ~ollowing the ~rocedure described in
Reference Example 2. `,
IR (liquid film)s ~ = 2950, 2880, 1745 cm 1,
NMR (CDC13 solution): ~ = 5.42~5.15 (2H, m),4.6-4.3
(2H, m), 3.54 ~3H, s).
REFE~E~CE EXAMPLE 9 - -
.. .. . .. .. .... _
(5Z,13E)-(9a,11a,15S)-6,9-Epoxy-11,15-bis(tetrahydropyran-.. , - - -
2-yloxy)-15-(3-propylcyclopentYl~-16,17,18,19l20- - '
pentanorprosta-5,13-dienoic acid methyl ester -
Under an atmosphere of nitrogen, a solution
of 929 mg of (13E)-(5RS,6RS,9a,11a,15S)-5-iodo-6,9-
epoxy-11,15-bis-~etrahydropyran-2-yloxy)-15-(3-
propylcyclopentyl) 16,17,18,19,20-pentanorprost-13-
enoic acid methyl ester ~prepared as described in ,
Reference Example 7) and 3~2 ml of DBU was stirrèd
at ~5 to 50C for 1~5 hours, and then cooled to
- - , .. . .
0~ to 5C. To the reaction , ~ ,
,
.
-', ~ ~ '
.
6Æ
.
- 51 - .
mixture were added 11 ml of lN hydrochloric acid and
11 ml of phosphate buffer ~olution (pH 6.86) with cooling
- to 0 to ~C.~The reaction mixture was extracted quickly
with diethyl ether. The extract was dried over magnesium
sulphate and concentrated under reduced pressure at a
temperature below 0C to give 743 mg of the title compound
having the following physical characteristic:-
IR (liquid film): ~ - 2960, 2880, 1740, 1695 cm lo
REFERENCE E~MPLE 10
.' ' ., ' ~ :
(5Z,13E)-(9a,11a,15S)-6,9-Epoxy-Il,15-bis(tetrahydropy~an-
2-yloxy)-1~-(3-propYlcyclopentyl)-16,17,18,19120
pentanorprosta-5,13-dienoic acid
To a solution of 407.5 mg of (5Z,13E)-(9a,11a,15S)-
6,9-epoxy-11,15-bis(tetrahydropyran-2-yloxy)-15-(3-
propylcyclopentyl)-16,17,18,19/20-pentanorprosta-5,13-
dienoic acid methyl-ester (prepared as described in - ~
Reference Example-9~~in-5 ml of met~anol-was added dropwise - -
a solution of 160 mg of potassium hydroxide in 6.5 ml of
water at room temperature, and the mixture wa stirred for
24 hours at the same temperature to give the title comp~und.
The reaction mixture thus obtained was used immediately in
t~e next reaction [in Reference Example 12(a) described
hereinafter~.
.,
. ~ , . . .
.' :
-- 52 -- .
REFERENCE EXAMPLE 11
(13_~(9~ ,15S)-6-Oxo-9-hydroxy-11,15-bis(tetrahydropyran-
,
2-yloxy)-15-(3-but~lcYclopentyl)-16 17,18,19,20-pentanorprost=
- 13-enoic acid methYl ester
. 5 The title compound, having the following physical
;
characteristics, wa~ prepared from (13E)-(5RS,6RS,9a,11a,
15S)-5-iodo-6,9-epoxy-11,15--bis(tetrahydropyran-2-yloxy)-.
15-(3-butylcyclopentyl)-16,17,18,19,20-pentanorprost-13-
enoic acid methyl e~ter {prepared as described in Referènce
Example 7(a)~, by the procedure de~cribed in Reference
Example 4
TLC ~developing solvent, cyclohexane:ethyl acetate = 1
Rf = 0.46
IR ~liquid film): ~ = 3450, 2950, 2860, 1745, 1730, 1470,
1450,-1440 cm 1,
,
- NMR (CDC13 solution): ~ = 5.8-5.2 ~2H, m), 4.8-4~5
~2H, m), 4.3-3.3 (7H, m), 3~665 and 3.660 (3H, each s),
2.7-1.0 (41~, m), 1.0-0.7 (3H, t),
(a) (13E)-~9a,lla,15S3-6-Oxo-9-hydroxy-11,15
20 bis(tetrahydropyran-2-yloxy)-15-~4-propylcyclohexyl~- .
16,17,18,19,20-pentanorprost-13-enoic acid methyl ester, .
having the followiny physical characteristics, was prepared
from ~13E)-(5RS,6RS,9a,11a,15S)-5-iodo-6,9-epoxy-11,15-
bis(tetrahydropyran-2-yloxy3-15-(4-propylcyclohexyl)- -
16,17,18,19,20-penatnorprost-13-enoic acid methyl ester
~prepared as described in ~eference Example 8), following
6Z
- 53 -
the procedure descrlbed in.Reference Example 4.
TLC (de~el~ping solvent, cyclohexane:ethyl acetate
- . , ~ . .
- - Rf = 0.21: . . . .
IR (liquid film): ~ = 2950, 2870, 1745 cm
NMR (CDC13 solution3: ~ = 5.48-5.2 (2H, m), 4.7-4.45
. - (2H, m), 3.54 (3H, s).
. REFERENCE EX~MPLE 12
(13E)-(9a,11a,15S)-6-Oxo-9-hydroxy-11,15,bis-
(tetrahydrop~ran-2-yloxy)~ 3-propylcyclopentyl1-
6,17,18,19,20-pentanorprost-13-enoic acid meth~l ester
Und~r an atmosphere of nitrogen, 7 ml of 5~/O
aqueous acetic acid was added dropwise to a solution of
743 mg of (5Z,13E)-(9a,11a,15S~-6,9-epoxy-11,15-bis-
(tetrahydropyran-2-yloxy)-15-(3-propylcyclopentyl)-
16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl~
ester (prepared as descr-ibed in-Reference Example 9) in
15 ml of tetrahydrofuran at room temperature and the
; mixture was stirred for 40 minutes. To the mixture thus
obtained were added 3 g of sodium bicarbonate and 30 ml
of water and the reaction mixture was extracted with
diethyl etherO The extract was washed with an aqueous
solution o~ sodium bicarbonate, dried over magnesium
sulphate and concentrated under reduced pressure. The
residue was purified by column chromatography on silica
gel using a mixture of cyclohexane and ethyl acetate (1~13
as eluent to give 678~mg of the title compound.having the
: ~ ,
:
fL6~2
- 54 -
following physical charac~eristics~
TLC (developing solvent, cyclohexane:ethyl acetate = 2:1):
..
Rf =0.18;
IR tliquid film): ~ - 2945, 2?360, 1740, 1715 cm 1,
5 NMR (CDC13 solution): ~ =5.58-5.28 (2H, m), 4.77-4.53
t2H, m), 3.66 and 3.65 (3H, each s), 0.99-0.76 (3H, m~.
The ~ollowing compound was prepared by the
s~me procedure as described above. . ,~ .
.(a) (13E)-(9~,11a,15S)-6-Qxo 9-hydroxy-11,15-
bi (tetxahydropyran-2-yioxy)-15-(3-propylcycl.opentyl)-
16,17,18,19,20-pen~anorprost-13-enoic acid was prepared
~rom (5Z,13E)-(9a,11~,15S)-6,9-epoxy-11,15-bis-
(tetrahydropyran-2-yloxy)-15-(3-propylcyclopentyl)-
16,17,18,19,20-pentanorprosta-5,13-dienoic acid (prepared
as described~in Reference ExamE?le 10)~ The compound thus
obt~ined was-used immediately in the next reaction .-~
[described in Example l(`c) hereafter]. --~ -
EXAMPLE 1
(13E)-(11~,15S)-6,9-Dioxo-11,15-bis-(tetrahydropyran-
2-y~xy)-15-(3~butylcyclopentyl L-l6,17,18,19l20-pentanorprost-
13-enoic acid methyl ester
The title compound, ha~ing the following physical
characteristic, was prepared from ~13E)-t9a,11~,15S)-6-
oxo-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-15-(3-
butylcyclopentyl)-16,17,18,19,20-pentanorprost-13-enoic
-acid methyl estex(prepared as described in Referenc~
, ~ . . . - ~ , .
L6Z
- 55 -
Example 11) by th procedure described in Reference Example 5.
TLC (developing ~olvent, cyclohexane:ethyl acetate = 2:1):
.
Rf = -34~ ~
- (a) (13E)-(lla,15S)-6,9-Dioxo-11,15-bis-
(tetrahydropyran-2-yloxy):15~ propylcyclohexyl)-16,17,
18,19,20-pentanorprost-13-enoic acid methyl ester, having
the following phy~ical characteristics, was prepared from
(13E)-(9~,11a,15S)-6-oxo-9-hydroxy-11,15-bis(tetrahydropyran-
2-yloxy)-15-~4-propylcyclohexyl)-16,17,18,19,20-
pentanorprost-13-enoic acid methyl ester ~prepared aq
described in Reference Example ll(a)~ by the procedure
- described in Refer~nce Example 5
TLC ~developing solvent, cyclohexane:ethyl acetate= 1
Rf = 0.40,
IR ~liquid film) ~ = 2880, 17~0, 1720 cm 1;
~MR (CDC13--solution)~ .54-5.24 ~t2H, m),-4~7-4.4 ---
(2H, m), 3.54 (3H, s~. - -
(b) (13E)-(lla,15S~-6,9-Dio~o-11,15-bis-
(tetrahydropyran-2~yloxy)-15-(3-propylcyclopentyl)-
16,17,18,19,20-pentanorprost-13-enoic acia methyl estex,
having the foll~wing physical characteristics, was prepared
from ~13E~-~9a,11a,15S~-6-oxo-9-hydroxy-11,15-bis-
(tetrahydropyran-2-yloxy)-15-(3-propylcyclopentyl) 16,17,18,
19,20-pentanorprost-13-enoic acid methyl ester ~prepared
-~~ as described in Reference Example 12~, by the procedure
described in Reference Example 5
~LC (developing solvent, cyclohexane:ethyl acetate = 2
.
-
56 - ;
.
= 0.35,
IR (liquid film): ~ = 293~, 2855, 1743, 1718 cm
~MR (CDC13 solution): ~ = 5.63-5.26 (2H, m), 4~76-4.15
(2H, m), 3.63 ~3H, s), 1.02-0.71 (3H, m).
(c) (13E)-(lla,15S)-6,9-Dioxo-11,15-bis-
(tetrahydropyran-2-yloxy)-15-(3-propylcyclopentyl)-
16,17,18,19,20-pentanorprost-13-enoic acid, havîng the
following physical characteristic, was prepared from
(13E)-(9a,11a,15S)-6-oxo-9-hydroxy-11,15-bis(tetrahydropyran-
2-yloxy)-15-(3-propylcyclopent~ 16,17,18,19,20-
pentanorpro~t-13-enoic acid ~prepared as described in
Reference Example 12(a)~, by the procedure described in
Reference Example 5
TLC (developing solvent, ethyl acetate):R = 0.63.
EXAMPLE 2 ` ~~ ~
(13E)-(lla,15S)-6,9-Dioxo-11,15-dihydroxy-15-(3
- .
butylcyclopentyl)-16,17,18,19 ! 20-pentanorprost-13-enoic
acid methyl ester r6-oxo-15-(3-butylcyclopentyl3-16,17,-
8,19,20-pentanor-PGEl.meth~.~ ester3
The title compound having the following physical
characteristics, was prepared ~rom (13E)-(11 a, 15S ) -6, 9-
dioxo-11,15~ tetrahydropyran-2-yloxy)-15-(3--
butylcyclopentyl)-16,17,18,19,20-pentanorprost-13-enoic
acid methyl ester (prepared as described in Example 1~
~ .
by the procedure described in Reference Example 6.
..
TLC (developing solvent, ethyl acetate): Rf - O.45,
.
.
-j
L6;~
- 57 -
IR (CHC13 solution):~ = 3400, 2950,. 2850, 1745, 1720,
. i440, 1225, 1080, 970 cm-l,
~MR (CDC13 solutlon): ~ = 5.7-5.4 (2H, m), 4.3.-3.5
(6H, m), 3.0-2.1 (llH, m), 2.1-1,0 (18H, m), 1.0-0.7
(3H, ~road t),
~a) (13E)-~1,15S~-6,9-Dioxo-11,15-dihydroxy-
l~-t4-propylcyclohexyl)-16,17,18,19 t 20-pentanorprost-13-
enoic acid methyl ester [6-Oxo-15-t4-propylcyclohexyl)-
16,17,18,19,20-pentanor-PGEl methyl ester~, having the
following physical characteristics, was prepared -from
(13E)-( 11~,15S)-6,9~dioxo-11,15-bi~(tetrahydropyran-2-
yloxy)-15-(4-propylcyclohexyl)-16,17,18,19,20-
pentanorprost-13-enoic acid methyl ester [prepared as
described in Example ita)~ by the procedure de~cribed
in Reference Example 6. -- -
TLC (developing-solvent, ethyl acetate): Rf = 0.28,
IR (~Br ta~let): ~ = 2970, 2950, 2880, 1750,-1735, 1720, ~
1385, 1360,- 1260 cm l:
NMR (CDC13 solution): ~ = 5.7-5.5 (2H, m), 4.3-3.3
(4H, m), 3.68 (3H, s).
(b) (13E)-(lla,15S)-6,9-Dioxo-11,15-dihydroxy-
~5-(3-propylcyclopentyl)-16,17,18,19,20-pentanorpro~t-13-
enoic acid methyl ester ~6-oxo-15-(3-propylcyclopentyl)-
16,17,18,19,20-pentanor-PGEl methyl ester~, having the
following physical characteristics, was prepared from
(13E)-~ ,15S)-6,9-dioxo-11,15-bis(tetrahydropyran-2-
,;
,.. :: ,
6Z
- 58 -
~ yloxy)-15-(3-propylcyclopentyl)-16,17,18,19,20-pentanorprost-
13-enoic acid m~thyl ester ~prepared as described in
Example l(b)~ by the procedure described in Reference
Exal~ple 6 --
TLC (develop~ng solvent, ethyl acetate): Rf = 0.~7,
IR (KBr tablet): ~ = 2950, 2870, 1745, 1725, 1710 cm 1;
NMR (CDCl solution). ~ = 5.67-5.47 (2H, mj, ~.30-3~70
(4H, m), 3.66 (3H, 5), 0.99-0.30 (3H, m).
(c) (13E)-(lla,15S)-6,9-Dioxo-11,15-dihy8roxy-
15-(3-propylcyclopentyl)-16,17,18,19,20-pentanorprost-
13-enoic acid C6-oxo-15-(3-propylcyclopentyl~-16,17,18,19,20-
pentanor-PGEl~, having the following phy~ical characteristics,
was prepared ~rom (13E)-(lla,15S)-6,9-dioxo-11,15-bis-
(tetrahydropyran-2-yloxy)-15-(3-propylcyclopentyl)-
16,17,18,19,20-pentanorprost-13-enoic acid ~prepared as
described in Example-l-(c)~-by the procedure described in
Reference-Example 6. ~
TLC (developing solvent, ethyl acetate~formic-acid = 400:53
Rf = 0.38;
IR ~CHC13 solution): ~ = 3450, 2950, 2870, 1750, 1720,
1450, 1430, 1250, 1160, io80, 980 cm~l,
~MR (CDC13 solution): ~ = 5.9~5.3 (5H, m), 4.3-4.0 (lH, m),
4.0-3.7 (lH, m), 3.0-2.2 (lOH, m~, 2.2-1.05 (16H, m3,
1.05-0.7 (3H, broad t).
. . .
'~ IL6~:
:
.
The following Reference Examples 13 and 14,
- which illustrate the preparation o~ cyclodextrin
clathrates, are taken from the Specification of our
Application No. 311338 (from which this application is
divided) as filed on 14th September, 1978O
REFERENCE EXAMPLE 13
- ~-Cyclodextrin clathrate of 6-oxo-17S~20-dimethyl-
PGEl methyl ester
A solution of 3.64 mg of 6-oxo-17S,20-dimethyl-
PGEl methyl ester in 0.6 ml of ethanol was added to a
solution of 110.66 mg of a-cyclodextrin in 2 ml of water
and the mixture was stirred at room temperature ~or 5
minutes. The mixture was concentratèd under reduced
pressure to give 98.22 mg of the ~-cyclodextrin clathrate
of the compound specified in the title. The content of
6-oxo-17S,20-dimethyl-PGEl methyl ester in the product
was 3.2% by weight.
REFERENCE EXAMPLE 14- - -
~-Cyclodextrin-clathrate of 6-oxo-17S,20-dimethyl-PGE
-
methyl ester
A solution of 3.35 mg of 6-oxo-17S,20-
dimethyl-PGE1 methyl ester in 0.6 ml of ethanol was added
to a solution of 41.9 mg of ~-cyclodextrin in 2.1 ml of
water and the mixture was stirred at room temperature
for 5 minutes. The mixture was concentrated under reduced
pressure to give 35.28 mg of the ~-cyclodextrin clathrate of
the compound specified in the title. The content of 6-
oxo-17S,20-dimethyl-PGEl methyl ester in the product was
8.1% by weight.
- 60 ~
.The present invention includes within its scope
pharmaceutical compositions which comprise~at least one ~ew
therapeutlcally useful compound of general formula IV, or cyclo-
dextrin clathrate` thereof,or.~.when Rl ln.form~.lla IV ~epresen.ts a
hydrogen atom or.a group ~CmH2mCoOR5 in ~hich R5 represents a
hydrogen atom and m is as hereinbefore defined, non-toxic salt
R7
thereof, or, when Rl represents a group -CnH2n~ ~ R8 in which n,
R and R .are a~ h~ei~eore def-~-ned,~ non.tox~c acid-addition '
.
salt thereof, together'with a'pharmaceutical carrier or coating.
In clinical practice the new compounds of general.formula IV
will normally be administered orally, vaginally, rectally or ''
parenterally. '
` Solid compositions for oral administration include
- - compressed tablets', pills, dispersible powders, and granules.
In such solid co~positions one or more of the active compounds
is, or are, admixed with at least one inert diluent such as.
calcium carbonate,:potato starch, alginic acid,'.lactose or
mannitolO 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 pharmaceuti'cally-
acceptable emulsions,-solutions, suspensionsj syrups and
elixirs containing inert diluents commonly used in the art,
such as water and liquid paraffin. Besides inert diluents such
compositions may also comprise adjuvants, such as wetting and
. suspending agents,.and sweetening, flavouring, perfuming and
prèserving agents~. ~he compositions'according to
the invention, ~or oral ..
-
lL62
_ 61 _
administration, also include capsules-of absorbable
material such as gelatin containing one or more of thé
`-. active ~ubstances with or without the addition of
; ,diluents or excipients.
. .
-5 :~Solld compositions for vaginal administration
; include pessaries formulated in manner known E~ se
and containing one or more of the active compounds. -
.. . . .
.. ,.~ ., - ~ SQ1i~ compositions for rectal a~m~nistra~
include suppositories formulated in manner known per se ..
and containing one or more of the active compounds~
Preparations accoxding to the invention for
.parenteral administratiQn include sterile aqueous or
.
non-aqueous ~olutions, suspensions, or emulsions.
; - Examples-o~ non-aqueous solvents or suspending media
- 15 are propylene glycol, polyethylene glycol, vegetable
` oils such as~olive oil, and injectable organic esters
: such as ethyl-oleate. These compositions may also
include adjuvants such as preserving, wetting,
emulsifying and dispersing agents~ They may-be
sterilised, for example, by filtration through a
bacteria-retaining filter, by in~orporation of
sterilising agents in the compositions or ~y irradiation~
They may also be manufactured in the form of sterile
solid compositions, which can be dissolved in sterile
water~or some other sterile injectable medium immediately
. before use.
.
. .
~ ,.
:,.
.~ ` . ' '. ~ :, ` : `
- 62 - .
The percenta~e of active ingredlent ln the
compositions of the invention may be varied, it being
. . ~ , ,
- necessary that'it should constitute a proportion such
' .................................. . . .
that a suitable dosage for the therapeutic effect
. .
- desired ~hall be obtained. Obvious1y severa1 unit
dosage forms may be administered at about the same tlme.
- In general, the'preparations should normally contain at
- least 0.025% by wei~ht'of active substance wnen~require~ '
for administration by injection; for oral administration
the preparations will normally contain at ~east 0.l% ~y
weight of active substance. The dose employed depends
upon the desired therapeutic effect, the route of '
- administration and the duration of the treatment~
In the human adult, the doses per person are
generally between O.005 and 5 mg. by oral administration
,
;' in the treatment of hypertension, between 0.005 and 5 mg~
by oral administration in the treatment of disorders of '
the peripheral circulation,' between O.Ol'and 50 mg by
oral adm~nistration in the prevention and treatment of
cerebral thrombosis and myocardial infarction, between
0~0005 and 1 mg. by-oral administration in the treatment
of gastric ulceration ! between 0.00005 and 5 mg. by oral,
intravaginal, intrauterine, intravenous, intram-uscular
and extra-ovu1~r administration in the termination of
pregnancy and induction of labour in pregnant female
mammals and in the treatment of impaired fertil~ty, in the
. . , , ' ~ .
.
t ~ - 63 -
-
control of oestrus, contraception and menstrual regulation'
in female mammals. In domestic female mammals such as
cow~, mares, sows, ew,es and bitches, the doses are
generally between 0,01 and 50 mg/animal by intramuscular,
subcutaneous, intr'auterine, intravaginal and intravenous
administrat1on for the synchronisation of oestrus, treatment
of impaired fertility and the induction of abortion and
labour.
The following Reference Example 15, which ,,
illustrates pharmaceutical compositions,according to
the invention, is taken from the Specification of our
Application No. 311338 ~from which this application is
divided) as filed on 14th September 1978. -
REFERENCE EXAMPLE 15
" 15 - 6-Oxo-17S,20-dimethyl-PGEl methyl ester
(2 mg) was dissolved-in ethanol (10 ml),- mixed with
mannitol (18.5 g), sieved through a 30-mesh sieve, dried
at 30~C for 90 minutes and again sieved through a 30-mesh
sieve. Aerosil (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 ,ug, of 6-oxo-17S,20-dimethyl-PGEl methyl
- ester, which after swallowing of the capsule is released
into the stomach. "Aerosil" is a registered Trade Mark.
:. ~ ,: ~,. . .
