CA1151162A - Prostaglandin analogues - Google Patents

Abstract

ABSTRACT

Prostaglanain E1 analogues of the general formula:

IV

[wherein Y represents ethylene or trans-vinylene, Z
represents ethylene or trans-vinylene, R1 sepresents a hydrogen atom, an alkyl group containing from 1 to 12 carbon atoms, an aralkyl group containing from 7 to 12 carbon atoms, a cycloalkyl group containing from 4 to 7 carbon atoms and unsubstituted or substituted by at least one alkyl group containing from 1 to 6 carbon atoms, a phenyl group unsubstituted or substituted by at least one chlorine atom, trifluoromethyl group, 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 hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms), a -CnH2nOR6 group (wherein R6 represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms and n represents an integer of from 2 to 12).

or a group (wherein R7 and R8 each represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms and n is as hereinbefore defined), R2 represents a hydrogen atom or a methyl or ethyl group, R3 represents a single bond or an alkylene group containing from 1 to 4 carbon atoms, R4 represents a cycloalkyl group containing from 4 to 7 carbon atoms and unsubstituted or substituted by at least one alkyl group containing from 1 to 8 carbon atoms, and the wavy line attached to the C-11 and C-15 carbon atoms represents .alpha.- or .beta.-configuration or mixtures thereof]
and cyclodextrin clathrates thereof, and, when R1 represents a hydrogen atom or a group CmH2mCOOR5 in which R5 represents a hydrogen atom, non-toxic salts thereof and, when R1 represents a group

Description

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:

, ~ COOH . I

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 . . ~ . , .

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~:

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, ~ . .

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

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,. . . . :~, -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 _ 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:

-, ~
: :

:

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, ~ .
, . .

.~ _ 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 .

.: . .

, - -- 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 ;, .

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

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.

.

, - . 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

(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 (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 (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 ,: ` .
,; .~ .

.
.: , :

~`` `

' , 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 "

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~

.

. , ~

:
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, _ 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

- ' . ' ' ~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 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~
~.

' ~ :

.
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).

(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). ~ --(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 : .
.

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 ': . ' ~ ' -~ 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).

(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 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:-`

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.

. .

(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 -- .

(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 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 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]. --~ -(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~

, ~ . . . - ~ , .

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;~

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-,;
,.. :: , ~ 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

- ~-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.

~-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 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. -" 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.

:. ~ ,: ~,. . .

Claims (35)

The embodiments of the invention, in which an exclusive privilege or property is claimed, are defined as follows:

1. A process for the preparation of prosta-glandin E1 analogues of the general formula:

IV
[wherein Y represents ethylene or trans-vinylene, Z
represents ethylene or trans-vinylene, R1 represents a hydrogen atom, a straight- or branched-chain alkyl group containing from 1 to 12 carbon atoms, an aralkyl group containing from 7 to 12 carbon atoms, a cycloalkyl group containing from 4 to 7 carbon atoms 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 hydrogen 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 group (wherein R7 and R8, which may be the same or different, each represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms and n is as hereinbefore defined), R2 represents 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, and the wavy line attached to the C-11 and C-15 carbon atoms represents .alpha.- or .beta.-configuration or mixtures thereof] and cyclodextrin clathrates of such acids and esters and, when R1 represents a hydrogen atom or a group -CmH2mCOOR5 in which R5 represents a hydrogen atom and m is as hereinbefore defined, non-toxic salts thereof and, when R1 represents a group in which n, R7 and R8 are as hereinbefore defined, non-toxic acid addition salts thereof, which comprises:

(A) hydrolysing to hydroxy groups the groups OR9 of a compound of the general formula:- V

wherein R1' represents a hydrogen atom or a straight-or branched-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, or (B) hydrolysing to hydroxy groups the groups -OR15 and -OR16 of a compound of the general formula:-XVIII
wherein R15 and R16, which may be the same or different, each represents a tetrahydropyran-2-yl or tetxahydrofuran-2-yl group, each such group being unsubstituted or substituted by at least one alkyl group, a 1-ethoxyethyl group, or a trimethylsilyl group, with the proviso that at least one of the symbols R15 and R16 represents a trimethylsilyl group, and the other symbols are as hereinbefore defined, followed optionally by one or more of the following steps:-(i) when the prostaglandin analogue obtained is an acid of general formula IV, wherein R1 represents a hydrogen atom and the other symbols are as hereinbefore defined, converting the acid by methods known per se into a corresponding ester of that formula wherein R1 is other than a hydrogen atom and the other symbols are as hereinbefore defined, (ii) converting by methods known per se a prostaglandin analogue of general formula IV obtained, wherein the various symbols are as hereinbefore defined, into a cyclodextrin clathrate, (iii) when the prostaglandin analogue obtained is an acid of general formula IV, wherein R1 represents a hydrogen atom and the other symbols are as hereinbefore defined, converting the acid by methods known per se into a non-toxic salt thereof, (iv) when the prostaglandin analogue obtained is an acid of general formula IV, wherein R1 represents a group -CmH2mCOOR5 in which R5 represents a hydrogen atom and m is as hereinbefore defined, and the other symbols are as hereinbefore defined, converting the acid by methods, known per se into a non-toxic salt thereof or into a corresponding ester of formula IV, wherein R1 represents a group CmH2mCOOR5 1n which R5 represents a straight-or branched-chain alkyl group containing from 1 to 4 carbon atoms and the other symbols are as hereinbefore defined, (v) when the prostaglandin analogue obtained is a compound of general formula IV wherein R1 represents a group in which n, R7 and R8 are as hereinbefore defined, and the other symbols are as hereinbefore defined, converting the compound into a non-toxic acid addition salt thereof.

2. A process according to claim 1(A) wherein the symbol R9 represents the tetrahydropyran-2-yl group.

3. Process according to claim 1(B) wherein--one of the symbols R15 and R16 represents the tetrahydropyran-2-yl group and the other represents the trimethylsilyl group.

4. Process according to claim 1(A) or 1(B) in which the hydrolysis of the OR9 groups, or the OR15 and OR16 groups, to hydroxy groups is carried out by mild acidic hydrolysis with an aqueous solution of an organic acid, or an aqueous solution of an inorganic acid at a temperature from ambient to 75°C or with an anhydrous solution of an organic acid in a lower alkanol at a temperatuxe of from 10° to 45°C.

5. Process according to claim 1(A) or 1(B) in which the hydrolysis of the OR9 groups, or the OR15 and OR16 groups, to hydroxy groups is carried out by mild acidic hydrolysis using an aqueous solution of an organic acid or an aqueous solution of an inorganic acid, in the presence of an inert organic solvent miscible with water and at a temperature from ambient to 45°C.

6. Process according to claim 1(A) or 1(B) in which the hydrolysis of the OR9 groups, or the OR15 and OR16 groups, to hydroxy groups is carried out by mild acidic hydrolysis 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-toluene-sulphonic acid and methanol.

7. Process according to claim 1 wherein Y in formulae IV, V and XVIII represents trans-vinylene.

8. Process according to claim 1(A), 1(B) or (i) wherein R1 in formula IV, and R1' in formulae V
and XVIII represents a hydrogen atom or a straight-or branched-chain alkyl group containing from 1 to 4 carbon atoms.

9. Process according to claim 1(A), 1(B) or (i) wherein R1 in formula IV, and R1' in formulae V and XVIII represents a hydrogen atom or a methyl group.

10. Process according to claim 1 wherein R2 in formulae IV, V and XVIII represents a hydrogen atom or a methyl group.

11. Process according to claim 1 wherein R3 in formulae IV, V and XVIII represents a single bond or a methylene group.

12. Process according to claim 1 wherein R4 in formulae IV, V and XVIII represents a cyclopentyl or cyclohexyl group, unsubstituted or substituted by an alkyl group containing from 1 to 4 carbon atoms.

13. Process according to claim 1 wherein the hydroxy groups attached to the C-11 and C-15 carbon atoms in general formula IV, and the corresponding groups OR9 in formula V and OR15 and OR16 in formula XVIII are in .alpha.-configuration.

14. Process according to claim 1(A), 1(B), (i), or (ii) in which R1 in formula IV represents a methyl group, R1' in formulae V and XVIII represents a hydrogen atom or a methyl group, Y in formulae IV, V and XVIII represents trans-vinylene, Z in formulae IV, V and XVIII represents ethylene, R2 in formulae IV, V and XVIII represents a hydrogen atom, the grouping -R3-R4 in formulae IV, V and XVIII represents a 3-butylcyclopentyl group, and the hydroxy groups attached to the C-11 and C-15 carbon atoms in general formula IV, and the corresponding groups OR9 in formula V and OR15 and OR16 in formula XVIII, are in .alpha.-configuration.

15. Process according to claim 1(A), 1(B), (i) or (ii) in which R1 in formula IV represents a methyl group, R1' in formulae V and XVIII represents a hydrogen atom or a methyl group, Y in formula IV, V and XVIII represents trans-vinylene, Z in formulae IV, V and XVIII represents ethylene, R2 in formulae IV, V and XVIII represents a hydrogen atom, the grouping -R3-R4 in formulae IV, V and XVIII represents a 4-propylcyclohexyl group, and the hydroxy groups attached to the C-11 and C-15 carbon atoms in general formula IV, and the corresponding groups OR9 in formula V and OR15 and OR16 in formula XVIII, are in a-configuration.

16. Process according to claim 1(A), 1(B), (i) or (ii) in which R1 in formula IV represents a methyl group, R1' in formulae V and XVIII represents a hydrogen atom or a methyl group, Y in formulae IV, V and XVIII represents trans-vinylene, Z in formulae IV, V and XVIII represents ethylene, R2 in formulae IV, V and XVIII represents a hydrogen atom, the grouping -R3-R4 in formulae IV, V and XVIII represents a 3-propylcyclopentyl group, and the hydroxy groups attached to the C-11 and C-15 carbon atoms in general formula IV, and the corresponding groups OR9 in formula V and OR15 and OR16 in formula XVIII, are in .alpha.-configuration.

17. Process according to claim 1(A), 1(B), (ii) or (iii) in which R1 in formula IV represents a hydrogen atom, R1' in formulae V and XVIII
represents a hydrogen atom, Y in formulae IV, V and XVIII represents trans-vinylene, z in formulae IV, V and XVIII represents ethylene, R2 in formulae IV, V and XVIII represents a hydrogen atom, the grouping -R3-R4 in formulae IV, V and XVIII represents a 3-propylcyclopentyl group, and the hydroxy groups -attached to the C-11 and C-15 carbon atoms in general formula IV, and the corresponding groups OR9 in formula V and OR15 and OR16 in formula XVIII, are in .alpha.-configuration.

18. Process according to claim 1(A) or 1(B.) and (iii) for the preparation of non-toxic salts of a prostaglandin analogue of general formula IV
depicted in claim 1 wherein R1 represents a hydrogen atom and the other symbols are as defined in claim 1, in which process R1 in formula IV represents a hydrogen atom, and R1' in formulae V and XVIII

represent hydrogen atoms and the other symbols are as defined in claim 1.

19. Process according to claim 1(A), 1(B) or (i) and (iv) or (v) for the preparation of non-toxic salts of a prostaglandin analogue of general formula IV depicted in claim 1 wherein R1 represents a group -CmH2mCOOR5 in which R5 represents a hydrogen atom and m is as defined in claim 1, and the other symbols are as defined in claim 1, and non-toxic acid addition salts of a prostaglandin analogue of general formula IV depicted in claim 1 wherein R1 represents a group in which n, R7 and R8 are as defined in claim 1, and the other symbols are as defined in claim 1, in which process R1 in formula IV represents a group -CmH2mCOOR5, in which R5 represents a hydrogen atom and m is as defined in claim 1, or a group , in which n, R7 and R8 are as defined in claim 1, and the other symbols are as defined in claim 1, and R1' in formulae V and XVIII represents a hydrogen atom, a group -CmH2mCOOR5, in which R5 represents a hydrogen atom and m is as defined in claim 1, or a group , in which n, R7 and R8 are as defined in claim 1, and the other symbols are as defined in claim 1.

20. Process according to claim 1(A), 1(B), (i) or (iv) and(i1) for the preparation of cyclodextrin clathrates of a prostaglandin analogue of general formula IV depicted in claim 1 wherein the various symbols are as hereinbefore defined.

21. Prostaglandin E1 analogues of the general formula:

IV
[wherein Y represents ethylene or trans-vinylene, Z
represents ethylene or trans-vinylene, R1 represents a hydrogen atom, a straight- or branched-chain alkyl group containing from 1 to 12 carbon atoms, an aralkyl group containing from 7 to 12 carbon atoms, a cycloalkyl group containing from 4 to 7 carbon atoms 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 hydrogen 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 group (wherein R7 and R8, which may be the same or different, each represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carkon atoms and n is as hereinbefore defined), R2 represents 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 atoma in the ring and unsubstituted or substituted by at least one straight- or branched-chain alkyl group containing from 1 to 8 carbon atoms, and the wavy line attached to the C-11 and C-15 carbon atoms represents .alpha.- or .beta.-configuration or mixtures thereof]
and cyclodextrin clathrates of such acids and esters and, wnen R1 represents a hydrogen atom or a group -CmH2mCOOR5 in which R5 represents a hydrogen atom and m is as hereinbefore defined, non-toxic salts thereof and, when R1 represents a group in which n, R7 and R8 are as hereinbefore defined, non-toxic acid addition salts thereof, when prepared by a process claimed in claim 1.

22. Prostaglandin analogues according to claim 21 wherein Y represents trans-vinylene, when prepared by a process claimed in claim 7.

23. Prostaglandin analogues according to claim 21 wherein R1 represents a hydrogen atom or a straight-or branched-chain alkyl gxoup containing from 1 to 4 carbon atoms, when prepared by a process claimed in claim 8.

24. Prostaglandin analogues according to claim 21 wherein R1 represents a hydrogen atom or a methyl group, when prepared by a process claimed in claim 9.

25. Prostaglandin analogues according to claim 21 wherein R2 represents a hydrogen atom or a methyl group, when prepared by a process claimed in claim 10.

26. Prostaglandin analogues according to claim 21 wherein R3 represents a single bond or a methylene group, when prepared by a process claimed in claim 11.

27. Prostaglandin analogues according to claim 21 wherein R4 represents a cyclopentyl or cyclohexyl group, unsubstituted or substituted by an alkyl group containing from 1 to 4 carbon atoms, when prepared by a process claimed in claim 12.

28. Prostaglandin analogues according to claim 21 wherein the hydroxy groups attached to the C-11 and C-15 carbon atoms in general formula lV depicted in claim 1 are in .alpha.-configuration when prepared hy a process claimed in claim 13.

29. (13E)-(11.alpha.,15S)-6,9-Dioxo-11,15-dihydroxy-15-(3.-butylcyclopentyl)-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester and cyclodextrin clathrates thereof when prepared by a process claimed in claim 14.

30, (13E)-(11.alpha.,15S)-6,9-Dioxo-11,15-dihydroxy 15-(4-propylcyclohexyl)-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester and cyclodextrin clathrates thereof when prepared by a process claimed in claim 15.

31. (13E)-(11.alpha.-15S)-6,9-Dioxo-11-15-dihydroxy-15-(3-propylcyclopentyl)-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester and cyclodextrin clathrates thereof when prepared by a process claimed in claim 16.

32. (13E)-(11.alpha.-15S)-6,9-Dioxo-11-15-dihydroxy-15-(3-propylcyclopentyl)-16,17,18,19,20-pentanorprost-13-enoic acid and cyclodextrin clathrates thereof and non-toxic salts thereof when prepared by a process claimed in claim 17.

33. Non-toxic salts of a prostaglandin analogue as claimed in claim 21, wherein R1 represents a hydrogen atom and the other symbols are as defined in claim 1, when prepared by a process claimed in claim18.

34. Non-toxic salts of a prostaglandin analogue as claimed in claim 21, wherein R1 represents a group -CmH2mCOOR5 in which R5 represents a hydrogen atom and m is as defined in claim 1 and the other symbols are as defined in claim 1, and non-toxic acid addition salts of a prostaglandin analogue as claimed in claim 21, wherein R1 represents a group in which n, R7 and R8 are as defined in claim 1, and the other symbols are as defined in claim 1, when prepared by a process claimed in claim 19.

35. Cyclodextrin clathrates of a prostaylandin analogue as claimed in claim 21 when prepared by a process claimed in claim 20.