CA1098125A - Process for the preparation of new prostaglandin analogues - Google Patents

Abstract

ABSTRACT
Process for the preparation of prostaglandin analogues of the formula:

VI

(wherein R3 represents the 1,1-dimethylpentyl or 2(.epsilon.)-ethylheptyl group) which comprises reacting a compound of the formula:

VII
(wherein R4 represents a 2-tetrahydropyranyl group unsubstituted or substituted by at least one alkyl radical, or a 2-tetra-hydrofuranyl or 1-ethoxyethyl group, R5 represents an alkyl group of 1 to 4 carbon atoms, and R6 represents an alkylcarbonyl group of 2 to 5 carbon atoms) with the sodio derivative of a dialkyl phosphonate of the formula:

VIII

(wherein R7 represents an alkyl group of 1 to 4 carbon atoms, and R3 is as hereinbefore defined) to obtain a compound of the formula:

IX

. reducing the 15-oxo group in the resulting compound to a hydroxy group, reacting the obtained hydroxy compound with dihydropyran unsubstituted or substituted with at least one alkyl radical, dihydrofuran or ethyl vinyl ether, to obtain a compound of the formula:

XI

. hydrolysing under alkaline conditions the resulting compound to obtain a compound of the formula:

XII

(wherein R represents a hydrogen atom or the methyl radical), converting the 9.alpha.-hydroxy group in the compound of formula XII to an oxo group, and hydrolysing the OR4 groups in the resulting compound of the formula:

XIII

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

Description

l~9B~Z5 THIS INVE~TION relates to a process for the preparati.on. of new prostaglandin analoyues.
In the Specification of our British Patent ~o.
1416410 we have described and claimed inter alia trans-~2-prostaglandin analogues of the genera.1 formula:

8~ ~

~ I

~H

(wherein A represents a grouping of the formula:

or OH

II III IV
' .
X represents ethylene (i.e. -CH2CH2-) or trans-vinylene (i.e. -CH=CH-), Rl represents a straight- or branched-- chain alkyl radical containing from 1 to 10 carbon atoms .i or a straight- or branched-chain alkyl radical containing from 1 to 6 carbon atoms carrying a phenyl substituent or . a cycloalkyl substituent of 5 to 7 carbon atoms, R2 represents a hydrogen atom or a straight- or branched-chain alkyl radical containing from 1 to 4 carbon atoms, the wavy line ~^~ indicates attachment of the hydroxy :`

- 2 .

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

3 --X represents trans-vinylene, Rl represents the l,l-dimethylpentyl group [i.e.

7 (CH2)3-CH3] or the 2(~)-ethylheptyl group ~i.e. -CH2-~H-(CH2)4-CH3~ and R2 represents a hydrogen atom ~viz. 16,16-dimethyl-trans-~2~P OE 1~ and 17(~)-ethyl-~-dihomo-trans-~2-PGEl~ and methyl esters thereof, the cyclodextrin clathrates of such acids and esters, and non-toxic salts of the acids, possess unexpectedly outstanding pharmacological properties.
The present invention is thus concerned with the hitherto unknown prostaglandin analogues of the general fonmula:

3 Co OH OH
(wherein R3 represents the l,l-dimethylpentyl or 2(~)-ethylheptyl c3roup, the wavy line ~v indicate~ attachment of the hydroxy group in beta or, preferably, alpha configuration and the C2-C3 and C13-C14 do trans) and methyl esters thereof, and cyclodextrin clathrates of such acids or esters, and non~toxic (e.g.

' ~ ' ' .
.:
.

~O~B~Z~

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

~Cli9~ 25 activity.
l~e prostaglandin analogue of formula VI wherein R3 represents the 2(~)-ethylheptyl group, and the methyl ester, and non-toxic salts thereof, have been found to possess an exceptionally good hypotensive activity and are accordingly useful in the treatment of hypertension and in the treatment of disorders of the peripheral circulation.
The prostaglandin compounds of the present invent~on have relatively low potencies in inducing diarrhoea in comparison with their poter.cies in respect of the valuable pharmacological properties hereinbefore mentioned, and may accordingly be used for the stated purposes at appropriate rates of administration which do not induce diarrhoea as an undesired side effect.
The pxeferred compound of the invention in respect of its abo_tifacient activity and stimulatory activity on uterine contraction is 16,16-dimethyl-trans-~2-P OE 1 methyl ester, and the preferred compound of the invention in respect of its hypotensive activity is 17(~)-ethyl-~-dihomo-trans-~2-PGE1 methyl ester.
For example, in standard laboratory tests, on oral administration to the conscious spontaneously hypertensive rat, 17(~)-ethyl-~-dihomo-trans-~2-PGEl methyl ester produces falls in blood pressure of 15 mm Hg, ~5 10 mm Hg, and 14 mm Hg, at 0.5, 1 and 3 hours after administration, respectively, at a dose of 0.1 mg/kg ~9~zs animal body weight, 33 mm Hg, 19 mm Hg, 13 mm Hg and 11 mm Hg, at 0.5, 1, 3 and 5 hours after administration, respectively ! at a dose of 0.3 mg/kg animal body weight, and ~4 mm Hg, 39 mm ~Ig, 21 mm Hg and 20 mm Hg, at 0.5, 1, 3 and 5 hours after administratiGn, r~spectively, at a dose of 1.0 mg/kg animal body weight.
In the above experiments soft faeces were observed only in one out of six rats at the dose of 0.3 mg/kg animal body weight and in none of six rats at the doses of 0.1 mg/kg animal body weight and 1.0 mg/kg animal body weight, respectively. These results indicate that 17(~)-ethyl-~-dihomo-trans-~2-PGEl methyl ester has a strong hypotensive activity and a very weak diarrhoea-producing (side effect) activity.
16,16-Dimethyl-trans-~2-PGEl methyl ester (i) stimulates uterine contraction when administered intravenously to the pregnant rat on the 20th day of gestation at a dose of 0.5 ~g/kg animal body weight, (ii) produces a fall of the blood pressure when administered intravenously to the allobarbital-anaesthetised dog at a dose of 1 ~g/kg animal weight, and (iii) produces diarrhoea at a dose of 1200 ~g/kg animal body weight by oral administration in 50% of mice so treated.
Of the pharmacological activities of 16,16-dimethyl-trans-~2-PGEl methyl ester, (i) uterine contractile activity is the useful effect and (ii) ~9~3~25 hypotensive and (iii) diarrhoea-producing activiti.es are consi.dered to be undesired effects. The pharmacological activities on rats of 16,16-dimethyl-trans-~2-PGEl methyl ester and of prostaglandin analogues already disclosed in the Specification of our British Patent No. 1416410, e.g.
16(R)-methyl-trans-~ -PGEl, 16(~)-phenyl-~-trinor-trans-~2-PGEl and 15(~)-methyl-trans-~2-PGEl, are compared in the following Table.

.:
.

- ~9~zs - ~

_ ~I N ,~1, ~

_ o ~ o '!
.,, o o o o ~ l -1 U ~ , 0 ~ N N

~ 1 .

~1 ~1 aO ~ O O ~ r~
-C -rl r fa ~ ,~ In O . In. o :. ~ g ~ ~ . I

I 1~ hl ~ a ~ al ~D al ~ I
-- ~ h ~) a) ,~ ~ ,~ ~ a ,~ ~ ,~ ~ ~
_ ~9~312S

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

(wherein R4 represents a 2-tetrahydropyranyl group unsubstituted or substituted by at least one alXyl radical, "

zs or a 2-tetrahydrofuranyl or l-etho~yethyl group, R4 preferably being the 2-tetrhhydropyranyl group, R5 represents a straight- or branched-chain alkyl group containing from l to 4 carbon atoms, and R6 represents an alkylcarbonyl group containing from 2 to 5 carbon atoms) with the sodio derivative of a dialkyl phosphonate of the general formula:
(R70~2P~cH2fR3 VIII

(wherein R7 represents an alkyl group containing from l to

4 carbon atoms, and R3 is as hereinbefore defined) to . obtain a compound of the general formula:-ol R6 IX

o 4 (wherein the various symbols are as hereinbefore defined), reducing the 15-oxo group in the compound of general formula IX to a hydroxy group by methods known er se to obtain a compound of the general formula:
; OR

\ f ~ 3 (wherein the various .symbols are as hereinbefore defined, and the wavy line ~ indicates attachment of the llydrox~
group to the carbon atom in alpha or beta configuration), reacting the obtained compound with dihydropyran unsubstituted or substituted with at least one alkyl radical, dihydrofuran or ethyl vinyl ether, to obtain a compound of the general formula:
o~ R6 (wherein the various symbols are as hereinbefore defined, and the wavy line ~v indicates attachment of the OR4 group to the carbon atom in alpha or beta configuration), hydrolysing under alkaline conditions the resulting compound to obtain a compound of the general formula:-OH COOR XII

OR4 4(wherein R represents a hydrogen atom or a methyl group, and R3, R4 and ~ have the meanings hereinbefore specified), converting by methods known per se the 9~-hydroxy group in the compound of general formula XII to an oxo group, and _ 12 -9B~25 hydrolysing the OR4 groups in the resulting co.mpound of the general fonmula:

COOR
¦ XIII

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

, :~9~lZS

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

- ::

~98~Z5 hydroxide or carbonate in the pres~nce of a water miscible olvent, e.g. tetrahydro~uran or an alkanol containing from 1 to 4 carbon atoms, to give compounds of general formula XII wherein R represents a hydrogen atom, or (2) with anhydrous potassium carbonate in anhydrous methanol to give compounds of general formula XII wherein R represents the methyl radical.
Conversion of the hydroxy group in the 9-position of the PGF compounds of general formula XII to an oxo group may be effected by methods known per se for the conversion of a PGF alicyclic ring into a PGE ring, for example by means of a chromic acid solution (e.g. obtained from chromium trioxide, manganese sulphate and sulphuric acid in water) or Jones' reagent.
The 0~4 groups of the compounds of general formula XIII may be converted to hydroxy groups by mild hydrolysis with an aqueous solution of an organic acid, e.g. acetic acid, or with a dilute aqueous inorganic acid, e.g.
hydrochloric acid, advantageously in the presence of an organic solvent miscible with water, e.g. tetrahydrofuran or an alkanol containing from l to 4 carbon atoms, e.g.
methanol. The mild hydrolysis may be carried out at a temperature ranging from ambient to 60C (preferably at a temperature below 45C) with an acid mixture, e.g. a mixture of hydrochloric acid with tetrahydrofuran or methanol, or a mixture of acetic acid, water and , " ' 19~ 125 tetrahydrofuran~
Compounds of general formula VII (wherein the various symbols are as hereinbefore defined) are new compounds and as such constitute another feature of the invention. They may be prepared by a new synthetic route from known compounds of formula XIV depicted hereafter (cf. Belgian Patent Specification ~o. 838582) by the series of reactions depicted schematically below in Scheme A, wherein the various symbols are as hereinbefore defined.

;

9E3~ZS

SCHEME A
O,H O,H
COOR5 ~ ~ ~ COOR5 OH> ~ OH

O, H L~ O, H
COOR5 ~ COOR5 H Q> ~ ~OE

O,H ~

osi ( CH3 ) 3 ol R6 O, R6 COOR5 ~ ~ COOR5 ~osi ( CH3 ) 3 ~OR6 . .. -`

XIX ~ R4 X~
ol R6 ol R6 ~COOR5 ~ , ~ COOR5 OH V~CHO

1R ~R4 ~98~25 Compounds of general formula XIV may be reduced to give compounds of general formula XV. Suitably the reduction may be effected by hydrogenation in the presence of a hydrogenation catalyst, e.g. palladium on charcoal, palladium black or platinum dioxide, in an inert organic solvent, for example a lower alkanol, e.g. methanol or ethanol, at laboratory temperature at normal or elevated pressure, e.g. at a hydrogen pressure from atmospheric to 15 kg/cm .
Compounds of general formula XVII may be prepared by the process which comprises reacting a compound of general formula XV with a compound of the general formula:

R8\
Il / NLi _ XXII
Rg ' (wherein R8 and Rg, which may be the same or different, each represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms or a cycloalkyl group containing from 3 to 6 carbon atoms), e.g. lithium ` diisopropylamide, to obtain a lithium compound of the ;I general formula:
oLi ' COOR

~ ~ OLi Li XXIII

; ~ ' ~39~3~25 (wherein R4 and R5 are as hereinbefore defined), reactlng the lithiurn compound with benzeneselenenyl bromide ti~e.
C6H5SeBr), or diphenyldiselenide, or a dialkyldisulphide or diphenyldisulphide of general formula RloSSRlo. wherein the symbols Rlo both represent alkyl groups containing from 1 to 4 carbon atoms or phenyl radicals, hydrolysing the resu~ting intermediate to obtain a compound of general formula XVI, treating the resulting compound with hydrogen peroxide or sodium periodate, and decomposing the resulting compound of the general formula:
OH

<I XXIV
OH Q=O

(wherein the various symbols are as hereinbefore defined) to convert the grouping ~ ~ 5 attached to Q=O
the 8-position of the cyclopentane ring to a trans-~2-grouping ,~ ~ 5 , wherein R5 is as hereinbefore defined.
The reaction between a compound of general foxmula XV and a lithiated amine of general formula XXII is carxied out in an inert organic solvent, e.g. tetrahydrofuran, at a ; 20 low te~perature, e.g. at -78C, the ratio of the molecular equivalents of a compound of general formula XV to XXII

~98~ZS

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

~(~98~ZS

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

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

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

.

~98~2S

SCHEME B
P~f o~

<XOH <~OH
OH
OAc XXV / XXVI

~Ol~c > ~I~C
OH / ORL~
XXVII / XXVIII
,OH
,0~ 1~ ,OH

<X~ OOH

~X ~ ~X
O,H

</~ ~\C00~5 \,~OH

ORj~
XIV

.. . .
, ~ ' .

., , ~: , . ,:. - ,, : , .

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

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

:
;

~09B12~

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

:lQ9BlZ5 exam~le, amines derived in theory by the replace~nent of one or more of the hydrogen atoms of ammonia by groups, which may be the same or different when more than one hydrogen atom is replaced, selected from, for example, alkyl groups containing from 1 to 6 carbon atoms and hydroxyalkyl groups containing from 1 to 3 carbon atoms.
The non-toxic salts may be prepared from acids of general formula VI, by for exarnple, reaction of stoichiometric quantities of an acid of general formula VI and the appropriate base, e.g. an alkali metal hydroxide or carbonate, ammonium hydroxidel ammonia or an amine, in a suitable solvent. The ; salts may be isolated by lyophilisation of the solution, of, if sufficiently insoluble in the reaction mediurn, by filtration, if necessary after removal of part of the solvent.
The trans-~2-prostaglandin analogues of general formula VI and methyl esters thereof may, if desired by converted into cyclodextrin clathrates. The clathrates may be prepared by dissolving the cyclodextrin in water and/or an organic solvent which is miscible with water and adding to the solution the prostaglandin compound in a water-miscible organic solvent. The mixture is then heated and the desired cyclo-dextrin clathrate product isolat~d by concentrating the mixture under reduced pressure or by cooling and separating the product by filtration or decanting. The ratio of organic solvent to water may be varied according to the solubilities of the starting materials and products. Preferably the temperature is not allowed to exceed 70C, during the preparation of the ~9~3~125 cyclodextrin cl~thrates. a, ~ or ~-Cyclodextrins or mixtures thereof may be used in the preparation of the cyclodextxin clathrates. Converslon into their cyclodextrin clathrates serves to incr~ase the stability of the prostaglandin compounds.
The following Reference Examples and Examples i.llustrate the preparation of new prostaglandin analogues of the present invention. In them 'IR', '~MR' and 'TLC' represent 'Infrared absorption spectrum'; '~uclear magnetic resonance spectrum' and 'Thin layer chromatography' respectively. Where solvent ratios are specified in chromatographic separations, the ratios are by volume.
REFERE~CE EXAMPLR 1 2a-(6-Methoxvcarbonvlhexyl)-3~-hydroxymethyl-4a-(2-tetrahYdro~YranyloxY)cyclopentan-la-ol 14.2 g of 2a-(6-methoxycarbonylhex-cls-2-enyl~-3~-hydroxymethyl-4a-(2-tetrahydropyranyloxy)cyclopentan-la-ol (prepared as described in Belgian Patent Specification No.
838582) was hydrogenated at a pressure of one atmosphere in 300 ml. of methanol containing 3 g. of 5% (w/w) palladium on ; 20 charcoal. The reduction was stopped after the absorption of one equivalent of hydrogen. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give 13.8 g~ of the title compound having the ' following physical cha~acteristics:-; 25 TLC (developing solvent, benzene:ethyl acetate = 1:1):
Rf = 0.28, IR (liquid film): 3450, 1740, 1440, 1030 cm 1, ~MR (CDC13 solution): 5.00-4.55 (lH, m), 3.70 (3H, s).

`':
~ , ~
: ~ ' . :
.
'.: ,- ~ . .

~o9~z~

REFISRI::NCE EXAIU~LI~ 2 2a-(6-~hc-~nylseleno-6-metho~vcarbony]h~xyl)-3R-l--ol Under an atmosphere of nitrogen, a solution of 19.4 ml. of diisopropylamine in 350 ml. of tetrahydrofuran was cooled to -78C., and to it was added dropwise 114 ml. of a 1.2M solution of n-butyllithium in n-hexane. The mixture was stirred at -78C. for 20 minutes to give lithium diisopropyi-amide. To the lithium diisopropyl~mide solution was added dropwise a solution of 13.8 g. of 2~-(6-methoxy--carbonylhexyl)-3~-hydroxymethyl-4~-(2-tetrahydro-pyranyloxy)cyclopentan-l~-ol (prepared as descri~ed in Reference Example 1) in 100 ml. of tetrahydrofuran at -78C. and the mixture was stirred at the same temperature for 30 minutes. A solution of 18.2 g. o diphenyldiselenide in 50 ml. of tetrahydrofuran was added dropwise to the reaction mixture at -78C. ar.a the solution was stirred at the same temperature for one hour and then at 0C. for 20 minutes. The reaction mix~ure was poured into an aqueous solution of ammoniur.l chloride and extracted witn ethyl acetate. The extract was washed with water and an aqueous solution of sodium chloride, dried over maynesium sulphate and concentrated ~981ZS

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

1~9~2S

phys;cal characteristics:
TLC (developing solvent, benzene:ethyl acetate = 1:1):
~f = 0.2~
IR (liquid film): 3450, 1735, 1660, 1440, 1030 cm 1, ~MR (CDC13 so~ution): 6.90 (lH, dt), 5.82 (lH, d),

5.00-4.55 (lH, m!, 3.70 (3H, s).
REFERENCE E~U~MPLE 4-la-~cetoxy-2a-(6--methoxycarbonylhex-trans-5-enyl)-3~-hydroxvmeths~l-4a-(2-tetrahydropvranyloxy)cvclopentane Under an atmosphere of nitrogen, a solution of - 4.3 ml. of trimethylchlorosilane in 20 ml. of methylene chloride was added dropwise to a solution of 10.4 g. of 2a-(6-methoxycarbonylhex-trans-5-enyl)-3~-hydroxymethyl-4a-(2-tetrahydropyranyloxy)cyclopentan-1~-ol (prepared as described in Reference Example 3) in a mixture of lS0 ml. of methylene chloride and 18.8 ml. of pyridine at -20C. and the mixture was stirred at the same temperature for 20 minutes. To the solution thus obtained was added dropwise a solution of 2.~5 ml. of acetyl chloride in 50 ml. oi methylene chloride a~ -20~C.
and the mixture was stirred at room temperature for 30 minutes. ~hen 3 ml. of ethanol was added to the reaction mixture in order to decompose the excess of acetyl I chloride. Pyridine in the solution was quenched with 80 g.
of sodium bisulphate, and the resulting precipit~te was , ~ 32 - -. . ' : .

~981ZS

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

~098~z~

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

~4 .

, : .
. . .. . .

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

.
' ~

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

.

, , , ~ -: :

i~9~

: TLC (developing solvent, benzene:ethyl acetate = 2:1):
Rf = 0.3~, (15~-hydroxy isomer, R~ = 0.47);
IR (li~uid film): 3450, 1730, 1660, 1440, ~030, 980 cm 1;
~MR (CDC13 solution): 7.20-6.70 (lH, m), 6.10-4.90 (4H, m), 4.80-4~50 (lH, m), 3.72 (3H, s), 2.06 (3H, s), , 1.10-0.70 (9H, m).

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

~ 37 -~' .

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

.

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

,. , - . ; . ,, 1~98125 a~etate and the extract was washed with water and ar.
aqueous solution of so~ium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give 119 mg. of the title compound having the following physical characterFstics:
TI.C (developing solvent, chloroform:tetrahydrofuran:acetic ~cid - 10:2:1): Rf = 0.51;
- IR (liquid film): 3400, 29~0, 2850, 1750, 1730, 1660, 1440, 1280 cm~l;
~MR (CDC13 solution): 7.10-6.75 (lH, m), 5.95-5.40 (3H, m), 3.71 (3H, s3, 4.20-3.60 (2H, m), 2.75 ~lH, dd), 1.00-0.75 (9H, m).

Methvl 9a-aceto~v~ -(2-tetrahydropyran~oxv)-15-oxo-17(~)-ethyl-~-dihomoprosta-trans-2,trans-13-dienoate By proceeding as described in Example 1,~ but replacing the dimethyl 2-oxo-3,3-dimethy]heptyl-phosphcnate by 1.62 g. of dimethyl 2-oxo-4(~)-ethylnonyl-phosphonate (prepared as described hereafter~, there were obtained 2.3 g. of the title compound having the following physical characteristics:
~LC Cdeveloping solvent, benzene:ethyl acetate = 2 i):
Rf = 0.7Q;
I~ (liquid film~: 1i30, 1660, i630, 1440, 1030 cm 1;
NMR (CDC~3 solution): 7.20-6.50 (2H, m~, 6.16 ;lH, d), 5.80 (lH, d), 5.35-4.90 (lH, m), 4.85-4.50 (lH, m~, 3.72 (3H, s), 2.06 (3H, s), 1.10-0.70 (61I, m).
.
.
- 40 _ . ~

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

. . :. .

.

` 1~91~125 E~AMiPLE 7 Methyl 9a-acetoxy-l]a-(2-tetrahydroP~r~nYloxy~-15a-hvdroxy-17(~)-et_hyl-~-dihomoprosta~trans-2,trans-13-dienoate S By proceeding as described in Example 2 but replacing the methyl 9a-acetoxy-lla-(2-tetrahydro-pyranyloxy~-15-oYo-16,16-dimethylprosta-trans-2,trans 13-dienoate by 2.3 g. of methyl 9a-acetoxy-lla-(2-tetrahydrO-- pyranyloxy)-15-oxo-17(~)-ethyl-w-dihomoprosta-trans-2,-trans-13-dienoate (prepared as described in Example 6~ there were obtained 720 mg. of the title compound, 740 mg. of its 15~-hydroxy isom~r and 500 mg.
of a mixture o~ the isomers. The title compound showed the ~ollowing physical characteristics:
TLC (developiny solvent, benæene:ethyl acetate -- 2:ij:
Rf - 0.40, (15~-hydroxy isomer, R~ = 0.47):
IR (liquid film): 3450, 1730, 1660, 1440, 1030, g80 cm 1;
~R (CDC13 solution): 7.20-6.70 (lH, m), 6.10-4.gO
(4H, m), 4.80-4.50 (lH, m), 3.72 (3H, s), 2.06 (3H, s~
1.10-0.70 ~6H, m).
EXAMP~E 8 Methyl 9~-acetoxY-lla,15a-bis-(2-tetrahydropyranyloxv~-17(~)-ethvl-~-dihomoprosta-t-ans-2,trans-13-dienoate By proceeding as described in Example 3 but replacing the ~.ethyl 9a-acetoxy-lla~(2-tetrahydrc-.

.` ' :

.
, ~g81ZS

.

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

Methyl 9a-hydrox~-lla,15a-bis-(2-tetrah~dro~YranY
.
17(~)-ethyl-~-dihomoprosta-trans-2,trans-13-dlenoat2 ~ By proceeding as described in Exampie 4 b~
replacing the methyl 9a-acetoxy-lla,15a-bis-(2-tetrahydropyranyloxy)-16,16-dimethylprosta-trans-2,tr~ns-13-dienoate by 870 mg. of methyl 9a-acetc~xy-lla,15a-bis-(2-tetrahydropyranyloxy)-17(~)-ethyl-~-dihomoprost~-trans-2,trans-13-dienoate (prepared as described in Example 8) dissolved in 11 ml. of methanol and . .

- 43 _ , .. , ~98125 utilizing 380 mg. of potassium carbonate there were obtained 700 mg. of the title compound having the ~ollowing physical characteristics:
TLC (developing solvent, benzene:ethyl acetate = 2:1):
-R~ - 0.46;
IR (liquid film): 3450, 1730, 1660, 1440, 1030, 980 cm 1, ~MR (CDC13 solution): 7.20-6.70 (lH, m), 6.10-5.30 (3H, m) 4.80-4.50 (2H, m), 3.72 (3H, s), 1.10-0.70 (6H, m).

Methyl 9-oxo-lla,15-dihydroxy-17(~)-ethyl-~-dihor~oprost2-trans-2,trans-13-dienoate [or 17(~)-ethyl-~-dihomo-trans-_ _ _ a -PGEl methyl ester~
... .. . . .. .. _ _ By proceeding as descrïbed in Exa~nple 5 but replacing the methyl 9a-hydroxy-lla,75~-bis-(2-tetra-hydropyranyloxy)-16,16-dimethylpros~a-trans-2,trans-13-dienoate by 700 mg. of methyl 9a hy~roxy-lla,15a-bis-(2-tetrahydropyranyloxy)-17(~)-ethyl-~-diilomoprosta-trans-2,trans-13-dienoate (prepared as déscribed in Example 9) dissolved in 21 ml. of diethyl ether and utilizin~ 21 ml.
2~ of a chromic acid solution (prepared as described in Example 5) there was obtained me~.hyl 9-oxo-lla,15a bis-(2-tetrahydropyranyloxy)-17(~)-ethyl-~-dihomopros~ a-trans-~,trans--13-dienoate having the following physical characteristic:
TLC (developing solvent, benzene:ethyl aceta~e _ 2:1):

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

i~981~5 a~ministered orally, vaginally, rectally or parenterally.
Solid compositior-s for oral administration include compressed tablets, pills, dispersible powders, and granules. In such solid compositions one or more of the ac~ive compounds is, or are, admixed witn at least one inert diluent such as calcium carbonate, potato starcli,alginic acid,mannitol,or lactose The compositions may also comprise~ as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elix rs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents such compositions may aiso comprise adjuvants, s1lch as wetting and suspending agen~s, and sweetening, flavouring, perfuming and p.eserving agents.
The compositions according to the invention, for oral administration, also include capsules of absorbable material such as gelatin containing one or more of the active substances with or without the addition of diluents or excipients.
Solid composltions for vaginal administration 2S include pessaries formulated in manner known ~ se and containing one or more of the active co~lpounds.

.. - L~6 -i~98~Zs Sol.id compositions for rectal administration include suppositories formulated in rnanner known per Se and conta~.niny one or more of the active compounds, Preparat.ions according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
Examples of non-aqueous solvents or suspending media are - propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate, The composi'cions rnay also include adjuvants such as preserving, wetting,emulsirying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilising agents in the composition3 or hy irradiation, They may also be manufactured in the form of sterile solid compositions, which can be ~issolved in steri.le water or some other sterile injectable medium immediately before use.
The percentage of active ingredient in the compositions of the invention may be varied, it being ; necessary. that it should constitute a proporti~n such that a suitable dosage for the therapeutic effect desired shall be obtained, Obviously several unit dosage forms may be a~ninistered at about the same time, In general, the preparatior.s shouid normally contain at least 0.02~' - h7 -~9l~Z5 by weiyht of actlve substance when required for administration by injection; for oral a~ninistration the preparations will normally conthin at least 0 1%
by wei~ht of active substance. The dose employed depends upon the desired therapeutic effect, the route of adrninistration and the duration of the treatment.
In the h~man adult, the doses per person are ~enerally between 0.01 and 1 mg. by oral a~ninistration in the treatment of hypertension, between 1 - 1000 ~g.
by oral, intravaginal, intravenous or extra-amniotic administration for contraception and the menstrual regulation in females and in the termination of pregnancy and the induction of labour .in pregnant females In domestic female mammals such as cows, mares, sows, e~es and bitches, the doses are generally between 0.001 and S0 mg./animal by intramuscular, subcutaneous, intrauterine, intravaginal and intravenous administration for the syncnronisation of oestrus, treatment of impaired fertility and the induction of abortion and of labour.
. m e following Example illustrates pharmaceutica compositions according to the invention.
EX~MPLE 11 . . .. .
. 16~16-Dimethyi-trans-~ -PGEl methyl ester (2 mg.) was dissolved in ethanol (10 ml.), mixed with ~ 48 -~39~25 mannitol (18.5 g.), sieved through a 30-mesh sieve, dried at 30C, for 90 minutes and again sieved through a 30-mesh sieve. Aerosil - a regi~tered Trade mark-(microfine silica; 200 mg.) was added and the powder obtained was machine~filled into one hundred No. 2 hard gelatin capsules to give capsules each containing 20 ~g. of 16,16-dimethyl-trans-~2-PGE1 methyl ester which after swallowing of the capsule is released into the stomach.

Claims (5)

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

1. Process for the preparation of prostaglandin analogues of the general formula:

VI
(wherein R3 represents the 1,1-dimethylpentyl or 2(.epsilon.)-ethylheptyl group, the wavy line ? indicates attachment of the hydroxy group to the carbon atom in alpha or beta configuration and the C2-C3 and C13-C14 double bonds are trans) and methyl esters thereof, and cyclodextrin clathrates of such acids or esters, and non-toxic salts of such acids, which comprises reacting a compound of the general formula:

VII

(wherein R4 represents a 2-tetrahydropyranyl group unsubstituted or substituted by at least one alkyl radical, or a 2-tetra-hydrofuranyl or 1-ethoxyethyl group, R5 represents a straight-or branched-chain alkyl group containing from 1 to 4 carbon atoms, R6 represents an alkylcarbonyl group containing from 2 to 5 carbon atoms, and the depicted double bond is trans) with the sodio derivative of a dialkyl phosphonate of the general formula:

VIII

(wherein R7 represents an alkyl group containing from 1 to 4 carbon atoms, and R3 is as hereinbefore defined) to obtain a compound of the general formula:

IX

(wherein R3, R4, R5 and R6 have the meanings hereinbefore specified, and the depicted carbon-carbon double bonds are trans), reducing the 15-oxo group in the resulting compound to a hydroxy group to obtain a compound of the general formula:

X

(wherein the various symbols are as hereinbefore specified, the wavy line ? indicates attachment of the hydroxy group to the carbon atom in alpha or beta configuration, and the depicted double bonds are trans), reacting the obtained compound with dihydropyran unsubstituted or substituted with at least one alkyl radical, dihydrofuran or ethyl vinyl ether, to obtain a compound of the general formula:

XI
(wherein the various symbols and ? are as hereinbefore specified, and the depicted double bonds are trans), hydrolysing under alkaline conditions the resulting compound to obtain a compound of the general formula:

XII

(herein R represents a hydrogen atom or the methyl radical, the other symbols and ? have the meanings hereinbefore specified, and the depicted double bonds are trans), converting the 9.alpha.-hydroxy group in the compound of general formula XII to an oxo group, and hydrolysing the OR4 groups in the resulting compound of the general formula:-XIII
(wherein R, R3, R4 and ? have the meanings hereinbefore specified, and the depicted carbon-carbon double bonds are trans) to hydroxy groups to obtain a PGE compound of the general formula VI depicted hereinbefore or methyl ester thereof, and if desired, (i) converting a prostaglandin analogue of general formula VI depicted hereinbefore so obtained into the methyl ester or into a non-toxic salt, or (ii) converting a prostaglandin analogue of general formula VI depicted hereinbefore so obtained, or methyl ester thereof, into a cyclodextrin clathrate.

2. Process according to claim 1 for the preparation of a prostaglandin analogue of the formula:

VIA

(wherein R3 represents the 1,1-dimethylpentyl group, the wavy line ? indicates attachment of the hydroxy group in alpha or beta configuration and the C2-C3 and C13-C14 double bonds are trans) and cyclodextrin clathrates thereof which comprises using as a starting material the sodio derivative of a dialkyl phosphonate of general formula VIII depicted in claim 1, wherein R3 represents the 1,1-dimethylpentyl group and R7 is as defined in claim 1, to obtain ultimately a PGE
compound of the general formula:

VIB
(wherein R3 and ? have the meanings hereinbefore specified, the depicted carbon-carbon double bonds are trans, and R represents a hydrogen atom or the methyl radical) and, when R in general formula VIB represents a hydrogen atom. converting the resulting acid into its methyl ester of formula VIA, and if desired converting the prostaglandin analogue of formula VIA thus obtained into a cyclodextrin clathrate.

3. Process according to claim 1 wherein R4 represents the 2-tetrahydropyranyl group.

4. Prostaglandin analogues of the general formula:

VI

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

5. A prostaglandin analogue of the formula:

VIA

(wherein R3 represents the 1,1-dimethylpentyl group, the wavy line ? indicates attachment of the hydroxy group in alpha or beta configuration and the C2-C3 and C13-C14 double bonds are trans) and cyclodextrin clathrates thereof when prepared by a process claimed in claim 2 or 3.