CA1077033A - Cyclopentane derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

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

Description

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

: :: ;
.. . .
.....
.
. :
,.. .. ..
:-' . ':. . .,'- : :

,: 1077033 specification will be named as derivatives of prostanoic acid of the formula shown below and numbered as shown:-9 7 5 3 C001l ~\ ~
10 ~ ~ 4 ~ ~ / 20 11 , 13 15 17 l9 According to the invention there is provided a prostanoic acidderivative of the formula:-~\~\~

~ A-CH(oH)-X-Y-R4 HO

wherein Rl is a hydroxymethyl or carboxy radical, an alkoxy-carbonyl radical of up to ll carbon atoms, R2 is a hydroxy radical or an alkanoyloxy radical of l to 4 carbon atoms and R3 is a hydrogen atom, or R2 and R3 together form an oxo radical; A is an ethylene or trans-vinylene radical; X is a methylene radical, bearing 0, l or 2 alkyl substituents each of l to 3 carbon atoms, or a trimethylene radical J each of l to 3 carbon atoms; Y is an oxygen or sulphur atom, a sulphinyl (-S0-) radical or an alkylimino (-NAlXyl-) radical of up to 4 carbon atoms; and R4 is a beni~yl or furfuryl radical, or a phenyl or naphthyl radical which is unsubstituted or which is substituted by not more than two chlorine, bromine or fluorine atoms, hydroxy, nitro, phenyl, or trifluoromethyl radicals, alkyl, alkenyl, or alkoxy radicals each of 1 to 4 carbon atoms or dialkylamino radicals wherein each alkyl is of l to 3 carbon atoms; which compound contains 0 or l alkyl ~ . :

'77(~3 radicals of up to 4 carbon atoms on carbonatom2 thereof and for those compounds wherein R is a carboxy radical, the pharmaceutically acceptable salts thereof.
A suitable value for Rl when it is an alkoxycarbonyl radical of up to 11 carbon atoms is, for example, the methoxycarbonyl~ ethoxycarbonyl~
n-butoxycarbonyl or n-decyloxycarbonyl radical.
A suitable value for R when it is an alkanoyloxy radical of 1 to 4 carbon atoms is, for example, the acetoxy or propionyloxy radical.
A suitable value for X when it is an alkylene radical of 1 to 3 carbon atoms bearing as substituents 0, 1 or 2 alkyl radicals, each of 1 to 3 carbon atoms is, for example a methylene, ethylene or trimethylene radical bearing 0, 1 or 2 methyl substituents, for example the methylene, ethylidene, isopropylidene and trimethylene radicals.
A suitable value for Y when it is an alkyleneimino radical of up to 4 carbon atoms is, for example, the methylimino (CH3-N ~) radical.
A suitable value for A is the trans-vinylene radical.
Suitable alkyl~ alkoxy or alkenyl substituents of 1 to 4 carbon atoms in R4 are, for example methyl, t-butyl, allyl or methoxy radicals.
Suitable dialkylamino radicals wherein each alkyl is of 1 to 3 carbon atoms, which may be substituents in R4 are, for example, dialkylamino radicals wherein the two alkyl radicals are the same, for example the dimethylamino radical.
Suitable substituted phenyl or naphthyl radicals are for example, chlorophenyl, chloronaphthyl, bromophenyl, fluorophenyl, tolyl, xylyl, methylnaphthyl, t-butylphenyl,m~thylchlorophenyl, tri-fluoromethylphenyl, hydroxyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, dimethylamino-phenyl and tetrahydronaphthyl radicals.
Preferred aryl radicals contain not more than two substituents ~ 4 ~
., ```~ 1C~77033 as defined above. Particular values for R4 are, therefore, the phenyl, benzyl, furfuryl, l-naphthyl~ 2-naphthyl, 2-, 3- and 4-chlorophenyl~ 4-bromophenyl, 2-, 3- and 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-di chlorophenyl, 2-, 3- and 4-~ --5 -. ~ æ

~77033 tolyl, 2,3-, 3,4- and 3,5-xylyl, 4-t-butylphenyl, 3-allylphenyl, . 3-trifluoromethylphenyl, 4-hydroxyphenyl, 2-, 3- and 4-methoxy-phenyl, 4-biphenylyl, 3-dimethylaminophenyl, 2-chloro-4-methyl-phenyl, l-chloro-2-naphthyl, 4-chloro-2-naphthyl, 6-methyl-2-naphthyl, 6-methoxy-2-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl radicals.
A suitable value for the alkyl radical of up to 4 carbon atoms which may be present as a substituent on carbon atom

2, 3 or 4 is, for example the methyl radical.
Examples of base-addition salts are the ammonium, alkyl-ammonium containing 1 to 4 alkyl radicals each of 1 to 6 carbon atoms, alkanolammonium containing 1 to 3 2-hydroxyethyl radicals, and alkali metal salts, for example the triethyl-ammonium, ethanolammonium, diethanolammonium, sodium and potassium salts.
It will be observed that the compounds of the formula I
contain at least five asymmetric carbon atoms, namely carbon atoms 8, 9, 11, 12 and 15, the configurations at four of which, 8, 9, 11 and 12 are specified in formula I, and that carbon atoms 2, 3 and 4 may also be asymmetrically substituted, so that it is clear that such compounds can exist in at least two optically active forms. It is to be understood that the useful properties of the racemate may be present to differing extents in the optical isomers, and that tnis invention relates to the racemic form of the compounds of formula I and any optically active form .:, ', .. ~' ; . ' '. ~:' 1C~77033 .

which shows the above useful properties, it being a matter of common general knowledge how the optically active forms may be obtained, and to determine their respective biological properties.
It is also to be understood that the above definition encompasses both C-15 epimers and that in all chemical formulae shown hereafter in this specification, the same fixed stereo-chemistry at C-8, 9, 11 and 12 as that shown in formula I is implied.
Although both C-15 epimers of a compound of the invention possess desirable pharmacological properties, that epimer which is more polar on thin layer chromatography is the more active, for example in the luteolytic test, and the more polar C-15 epimers are therefore preferred.
A preferred group of cyclopentane derivatives of the invention, because of their high luteolytic or smooth muscle stimulant properties, comprises those compounds wherein R4 is a chlorophenyl, fluorophenyl, trifluoromethylphenyl or unsubstituted - naphthyl radical, especially those compounds wherein Rl is the carboxy, methoxycarbonyl or hydroxymethyl radical, and particularly those compounds wherein R4 is the 3- or 4-chloro-- phenyl, 2- or 4-fluorophenyl, 3-trifluoromethylphenyl or unsubstituted naphthyl radical. A particularly preferred sub-group comprises those compounds wherein Rl is the carboxy, methoxy-carbonyl or hydroxymethyl radical, R2 is the hydroxy radical and R3 is a hydrogen atom, or R2 and R3 together form the oxo radical, . : ' ', ' : ", ': . ' ' :: : .. . . -A is the vinylene radical, X is the methylene or isopropylidene radical, Y is an oxygen atom and R4 is the 3- or 4-chlorophenyl, 2- or 4-fluorophenyl, 3-trifluoromethylphenyl or 2-naphthyl radical, optionally bearing a methyl substituent on carbon atom 2.
Particular preferred compounds of the invention are 16-(4-fluorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, methy]. 16-(4-fluorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, 16-(2-fluorophenoxy)-9a,11a,15-trihydroxy-17,18, 19,20-tetranor-5-cis-13-trans-prostadienoic acid, 16-(4-chloro-phenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, methyl 16-(4-chlorophenoxy)-9a,lla,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, 16-(4-chlorophenyl)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienol, 16-(3-chlorophenoxy)-9a,11a,15-tri-hydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, methyl 16-(3-chlorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, 16-(3-chlorophenoxy)-9a,11a,15-trihydroxy-2-methyl-17,18,19,20-tetranor-5-cis-13-trans-prostadienol, 9a,11a,15-trihydroxy-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, 9a,11a,15-trihydroxy-16-(2-naphthyloxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, 16-(4-chlorophenoxy)-9a,11a,15-trihydroxy-16,16-dimethyl-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid and 16-(4-chlorophenoxy)-lla,15-dihydroxy-9-oxo-17,18,19,20-tetranor-, .:: :

:::: :~ -~- : :~: ::: :: , . ., ~ :
,, ., ' 1~)77033 5-cis-13-trans-prostadienoic acid.
The cyclopentane derivatives of the invention may be manufactured by methods known in themselves for the manufacture f chemically analogous compounds. Thus, the following processes for the manufacture of the cyclopentane derivative of the formula I, are provided as further features of the invention:-(a) for those compounds wherein Rl is a carboxy radical, the hydrolysis of a compound of the formula:-R2 ~ (CH2~3'COOH

~ A-CH-X-Y-R4 II

or of a mixed anhydride thereof, wherein A, X, Y, R2, R3 and R4 have the meanings stated above, and R5 and R6 are each a tetra-hydropyran-2-yloxy radical, or an acyloxy radical of 1 to 6 carbon atoms, whereafter when a salt is required the product is reacted with a base; or (b) for those compounds wherein Rl is an alkoxycarbonyl radical of 1 to 11 carbon atoms, the reaction of an acid of the formula:-R2 ~ (CH2)3-COOH

<
~ A-CH-X-Y-R4 III
I
HO OH

_ 9 _ ., ; ::- .:

.

wherein A, X, Y, R , R3 and R4 have the meanings stated above, with a diazoalkane of the formula R7.N2, wherein R7 is an alkyl radical of 1 to 11 carbon atoms; or (c) for those compounds wherein R is an alkoxycarbonyl radical of 1 to 11 carbon atoms, the reaction of a salt, of an acid of the formula II, with an alkyl halide of 1 to 11 carbon atoms, or (d) for those compounds wherein R is the hydroxymethyl radical and Y is the oxygen or sulphur atom or an alkylimino radical, the reduction of an ester of ~he formula I wherein R is an alkoxycarbonyl radical of 1 to 11 carbon atoms, or (e) for those compounds wherein Y is the sulphinyl radical, the oxidation of a thio-compound of the formula:-2 ~ \ ~ R IV

A-CH(OH)-X-SR4 HO

wherein Rl, R2, R3~ R4, A and X have the meanings defined above.
A suitable mixed anhydride is a mixed anhydride with a lower alkanoic acid, for example a lower alkanoic acid of up to 8 carbon atoms, for example acetic acid.

~, - 10 -lQ~77033 The hydrolysis in process (a) may be carried out under either acidic or basic conditions, for example in aqueous acetic acid, or in an aqueous or alcoholic solution of an alkali metal carbonate, for example potassium carbonate in methanol, and it may be carried out at ambient temperature or at an elevated temperature of up to 60C.
The starting material of the f`ormula II wherein A is a vinylene radical, and Y is an oxygen or sulphur atom, used in the process of the invention may be obtained by reaction of the known aldehyde IV (Ac= acetyl or p-phenylbenzoyl) with a phosphonate of the ~ormula (CH30)2P 0. CH.Co.X.Y.R4 (V) (which is prepared from dimethyl methylphosphonate and an ester of the formula R .Y.X.C00 alkyl, in the presence of butyllithium), or with a phosphorane of the formula Ph3P:CH.CO.X.Y.R4 (which is prepared from triphenylphosphine and a compound of the formula R4.Y.X.COCH2I), to give an unsaturated ketone VI. The ketone VI
is reduced with zinc borohydride to the corresponding unsaturated alcohol VII, and the protecting acyl group is then removed with potassium carbonate in methanol to give a diol VIII. The diol VIII is protected as a bis-tetrahydropyranyl ether and the lactone ring is then reduced with di-isobutyl aluminium hydride to give a lactol X, or alternatively the diol VIII is reduced with di-isobutyl aluminium hydride to give a triol which may be acylated and selectively hydrolysed to give the lactol bis-ester (X, R5=R6=acyloxy). The lactol X is reacted with the phosphonium : ~ , ~ .
. ' '- ~. ~

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

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

o ~s)77033 o AoO>~O I (16eO) 2-P-CR.CO-X-Y . R4~ ~/X.Y, R4 IV V VI

Y R4 ~ X.Y . R4 OH OH

VII VIII

O OH

> ~ > II

RSY~.Y.R4 R5Y~,Y.R4 ~ X

Ac represents an acyl radical.

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

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

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

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

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

may be prepared as follows:-n-Butyl lithium (69ml. of a 1.2M solution in hexane) was added to a solution of dimethyl methylphosphonate (10.3g.) in dry tetrahydrofuran at -78C. in an atmosphere of nitrogen.
After 10 minutes, a solution of phenylacetylchloride (4.lg.) in dry tetrahydrofuran (20ml.) was added dropwise, and the mixture was stirred for 4 hours at -78C. The reaction mixture was neutralised with acetic acid and the solvents were removed under reduced pressure. The residue was shaken with a mixture of ether (lOOml;) and water (20ml.), and the organic phase was separated and washed with brine. The solution was dried, the solvents were evaporated and the residue was distilled in a bulb distillation apparatus at an oven temperature of 160C. and 0.1 mm. pressure, ; to give dimethyl 2-oxo-3-phenoxypropylphosphonate.
A solution of dimethyl 2-oxo-3-phenoxypropylphosphonate (l.Olg.) in dry 1,2-dimethoxyethane (20ml.) at -78C. was treated with n-butyl-lithium (2.75ml. of a 1.2M solution in hexane), and the mixture was stirred for 15 minutes. To this mixture was added a solution of 4~-formyl-2,3,3a~,6a~-tetrahydro-2-oxo-5~-(p-phenylbenzoyloxy)cyclopenteno[b~furan (1.95g.) in 1,2-dimethoxy-ethane (lOml:), and after 1 hour the reaction mixture was neutralised with glacial acetic acid and all solvents were removed by evaporation undçr reduced pressure below 35C. The residue was chromatographed on Florisil using solutions of ethyl acetate in methylene chloride as eluant, to yield the unsaturated ketone T~ad-ma~ k '- : ., , ;
. , . - : , , ..
,~::: :, :
.. . :
:: : - :
:: : . :-10'77033 product as a white solid. CRF= 0.6 (1:1 ethyl acetate/benzene)~.
To a solution of the unsaturated ketone (500mg.) in dry 1~2-dimethoxyethane (20ml.) at 0C. was added 1.5ml. of a 0.5M
solution of zinc borohydride in 1,2-dimethoxyethane. The mixture was stirred at room temperature for 30 minutes, then saturated sodium hydrogen tartrate solution was added until effervescence ceased. Ethyl acetate (lOOml.) was added, the organic layer was separated, washed with a 1:1 mixture of saturated brine and water, then dried. The solvents were evaporated to give a mixture of epimeric unsaturated alcohols. ~RF= 3 (1:1 ethyl acetate/
benzene)~.
The mixture of epimeric unsaturated alcohols (500mg.) was stirred vigorously for 2 hours with finely powdered anhydrous potassium carbonate (140mg.) in methanol (lOml;). lN Hydrochloric acid (2.1 ml.) was added, followed by ethyl acetate (50ml.). The organic layer was separated 3 washed successively with saturated sodium bicarbonate solution and saturated brine, and dried, and the solvents were evaporated. The residue was chromatographed on Florisill(20g;). Elution with ether removed by-products, and subsequent elution with ethyl acetate gave a mixture of the C-15 epimeric diols [RF= 0.2 (ethyl acetate)~.
To a solution of the epimeric diols (316mg.) in methylene chloride (3 ml;) under an atmosphere of nitrogen were added successively redistilled 2,3-dihydropyran (1.2ml.) and a solution of anhydrous toluene-p-sulphonic acid in tetrahydrofuran '~ud~A~k .

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

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

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

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

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

OH

COOH

~ A-CH(oH)-X-oR4 OH

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

: :. . :: . : ~

~077~33 No. R A

1 phenyl -CH:CH- -CH2-2 phenyl -CH:CH- -CH(CH3)-

3 phenyl -CH:CH- -C(CH3)2-

4 phenyl -CH:CH- -(CH2)3-

5 benzyl -CH:CH- -CH2-

6 2-naphthyl -CH:CH- -CH2-

7 4-chlorophenyl -CH:CH- -CH2-

8 4-chlorophenyl -CH2CH2- -CH2-

9 3-chlorophenyl -CH:CH- -CH2-

10 2-chlorophenyl -CH:CH- -CH2-

11 2,4-dichloro- -CH:CH- -CH2-phenyl

12 4-bromophenyl -CH:CH- -CH2-

13 4-fluorophenyl -CH:CH- -CH2-

14 4-tolyl -CH:CH- -CH2-

15 3-tolyl -CH:CH- -CH2-

16 4-t-butylphenyl -CH:CH- -CH2-

17 3-trifluoro- -CH:CH- -CH2-methylphenyl

18 4-methoxyphenyl -CH:CH- -CH2-

19 2-methoxyphenyl -CH:CH- -CH2-

20 4-biphenylyl -CH:CH- -CH2-~ _ .;.

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

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

:,~ .: : :~, :
; :, :. , Mass spectrum Phosphonate Enone No. Isomer mm j m.p.(C.) Found Calculated i 14mixed M =692.3738 692.3781 164/0.05 149 15 mp M =692.3752 692.3781 180/0.5 140-141 lp M =692 16mixed M =734.4213 734.4251 _ 17 mp M =746.3467(~ ) 746.3499 115-117 18 mp M =708.3717 708.3731 _ _ lp M =708 19 mp M =708.3710 708.3731 _ _ lp M =708 20 mp M =754.3944 754.3938 m p - _ lp M =754 *mp= more polar, lp= less polar i~omer on silica gel thin layer chromatography.
a) products synthesised from respectively the more polar and less polar enol intermediates.
b) RF- 0.45 after 2 runs on silica gel t.l.c. with 5% acetic acid in ethyl acetate.

c) R~= 0.50 after 2 runs on silica gel t.l.c. as for b).

.:: .

-,, ,, .
.. '' `

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

. . :.:.. - : :

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

. .

,: :: : :, ' ' ~
.. .. .. . .
,, ~: , . ' ~

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

HO

~ ~ OOH
~
~ ~ CH(oH)-X-Y-R4 HO

, .
, - . - . . .: , .
. .
.
' . ': , :'~ : .
" ': ' ' ~.'.

_ r Other 4 substituent No R X Y in . acid ~ _ _

21 phenyl -CH2- -N(CH3)-

22 4-chlorophenyl ( 3 :2 -O-

23 4-chlorophenyl -CH2- -S-

24 3-fluorophenyl -CH2- -O-2-fluorophenyl -CH2- -O-26 3,4-dichlorophenyl-CH2- -O-27 2,5-dichlorophenylCH2 -O-28 2-tolyl -CH2- -O-29 2,3-xylyl -CH2- -O-3,5-xylyl -CH2- -O-31 2-chloro-4-methylphenyl -CH2- -O-32 3-dimethylaminophenyl -CH2- -O-33 l-naphthyl -CH2- -O-34 4-chloro-1-naphthyl -CH2- -O-2-naphthyl -CH2- -O- 2-methyl 36 6-methyl-2-naphthyl -CH2- -O-37 6-methoxy-2-naphthyl-CH2- -O-38 3-chlorophenyl -CH2- -O- 2-methyl 39 2,3-dichlorophenyl-CH2- -O-2,6-dichlorophenyl-CH2- -O-41 3,5-dichlorophenyl-CH2- -O-42 4-chloro-3-methylphenyl -CH2- -O-43 3-methoxyphenyl -CH2- -O-44 1-chloro-2-naphthyl -CH2- -O-5,6,7,8-tetrahydro-2- -CH2- -O-naphthyl : , .
:, .. . .
. ~ : :
: , .. :: : :
. : : .:

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

~ " ' ' ' ,, `'' ; `' ' , -- : . .
: , :

1(:)77033 I Mass Spectrum Phosphonate Enone No. Isomer(a . b pj ( C./ m.p.(C.) FoundCalculated i mlPp 742 742.3937 m.p.85-86 185-187 36 lmpp 742 742.3937 m.p.71-72 153 37 lmp M+=758.3910 758.3887 m.p.58-59 195 38 mlpp M+=726.3346 726.3391 180/0.2 (~) 39 mp + 73~.2644 731.2609 175/0.03 153-155 lp M -CH3=731 4 mlpp 746 746.2844 m.p.89-90 140-142 41 lmpp M+~746.2829 746.2844 m.p.80-82 138-139 42 mlp M+=726.3397 726.3391 _ 143 43 mlpp 708 708.3730 (1) 129-130 ~ 1~

(a) mp= more polar, lp= less polar.
tb) these compounds synthesised from phosphoranes (not phosphonates)~ made as described below.
(c) RF= -5 (5% ethyl acetate in toluene).
(d) RF= 0.2 (40% ethyl acetate in methylene dichloride) . : . , ;
~; :' ., "`.' ' ' :
} , :, :~

(e) RF= 4 (5% acetic acid in ethyl acetate) (~) RF= 0 3 (50% ethyl acetate in chloroform) (g) RF= 0.23 (50% ethyl acetate in chloroform) (h) RF= 0 3 (50% ethyl acetate in methylene dichloride) (i) RF= 4 (10% methanol in ethyl acetate) (j) RF= 0.8 (50% ethyl acetate in toluene) (k) RF= 0.6 (50% ethyl acetate in toluene) (1) RF= 4 (5% ethyl acetate in methylene dichloride) (m) RF= 0.25 (3% acetic acid in ethyl acetate) (n) RF= 3 (3% acetic acid in ethyl acetate) (m) and (n); ~ 6.8 (lH, aromatic), 6.6 (2H, aromatic), 5.4 (2H, olefinic) and 5.7 (2H, olefinic).
The preparation of a phosphorane, which may be used in place of a phosphonate in the preparation of a cyclopentane derivative of the invention J iS exemplified by the preparation of ~3-(3-dimethylaminophenoxy)-acetonylidene~-triphenylphosphorane as follows:-n-Butyl-lithium (3.85ml. of a 1.3M solution in hexane) was added to a solution of 3-dimethylaminophenol (685mg.) in dimèthoxyethane (20ml.) at -70C. under an atmosphere of nitrogen.
The solution was allowed to warm to room temperature, a solution of 3-iodoacetonylidene-triphenylphosphorane (2.22g.) in benzene (lOOml.) was added, and the mixture was heated under reflux for 2 hours. The mixture was then diluted with toluene (lOOml.), washed with water t2 x 50ml.) and dried, the solvents were 1077~33 evaporated and the residue was triturated with ether to give [3-(3-dimethylaminophenoxy)acetonylidene~triphenylphosphorane, m.p.110-115C.
In a similar manner were prepared the analogous N-methylanilino (gum) and 4-chlorophenylthio (m.p.158-165C.) phosphoranes.
Example 5 The process described in Example 3 was repeated, using the appropriate more polar C-15 epimer, in place of the more polar C-15 epimer of 16-(4-chlorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, to give the following methyl esters as single C-15 epimers:-a) methyl 16-(4-fluorophenoxy)-9a,11a,15-trihydroxy-17,18~19,20-tetranor-5-cis-13-trans-prostadienoate, RF= 3 (5% methanol in toluene) 0= 6.8-7.2 (aromatic), 5.3-5.7 (4 olefinic protons), 3.6 (methyl ester).
b) methyl 9a,11a,15-trihydroxy-16-(2-naphthyloxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, M = 670.3542 (calculated 670.3541).
c) methyl 9a,11a,15-trihydroxy-2-methyl-16-(2-naphthyloxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, M~= 684.3678 (calculated 684.3697).
d) methyl 9a,11a,15-trihydroxy-16-(6-methyl-2-naphthyloxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, M = 684.3739 (calculated 684.3698).

:: . - . , :. . :

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

~077033 e) methyl 9~,11a,15-trihydroxy-16-(6-methoxy-2-naphthyloxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, M+= 700.3681 (calculated 700.3647).
f) methyl 16-(3-chlorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, RF= 0 3 (ethyl acetate),M = 654.2973 (calculated 654.2995).
g) methyl 9a,11a,15-trihydroxy-2-methyl-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, RF= 4 (ethyl acetate), M+= 668.3133 (calculated 668.3151). r Example 6 16-(4-Chlorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostanoic acid (20mg. of the more polar C-15 epimer) was treated with an excess of dilute aqueous ammonia to form the ammonium salt. The excess of ammonia was evaporated under reduced pressure, and the residue was treated with the stoichiometric amount of silver nitrate to form the silver salt. The silver salt was filtered off, dried, dissolved in n-butyl iodide (0.5ml;) and stirred at room temperature for 1 hour. The solution was extracted with ethyl acetate, the ethyl acetate extract was evaporated to dryness, and the residue was r~ chromatographed on Florisi~ (lg.) using 50% ethyl acetate in toluene as eluant, to give n-butyl 16-(4-chlorophenyl)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, M+= 696.3427 (calculated 696.346~), RF= 4 (ethyl acetate).
In a similar manner, but using ethyl iodide in place of Qn~ k 1~77033 n-butyl iodide, there was obtained ethyl 16-(4-chlorophenyl)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, M = 668.3086 (calculated 668.3151).
Example 7 A solution of the mixed anhydride of acetic acid and the more polar C-15 epimer of 9a-acetoxy 16-(4-chlorophenoxy)-lla,16-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid (73mg.) in 2ml. of a 2:1 mixture of acetic acid and water, was stirred at 47C. under nitrogen for 4 hours. The solvents were evaporated, the residue was dissolved in dilute aqueous sodium bicarbonate solution (2ml;~ and the solution was extracted with ethyl acetate (3 x 2ml.). The extracts were discarded, the aqueous solution was acidified to pH 3-4 with 2N aqueous oxalic acid and the acidified solution was extracted with ethyl acetate (4 x 5ml;). The ethyl acetate extracts were washed with a 1:1 mixture of saturated brine and water, and were then dried. After evaporation of the ethyl acetate, the residue was purified by thin-layer chromatography on silica gel using 3% acetic-acid in ethyl acetate, to give the 20 more polar C-15 epimer of 9a-acetoxy-16-(4-chlorophenoxy)-lla,15-dihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, M+= 682.2942 (calculated 682.2944).
The bis-tetrahydropyranyl ether used as starting material may be prepared as follows:-A solution of the more polar C-15 epimer of 9a-hydroxy-':,,'. ' ', .
. .
. ~
' .. ' ' . :
-11~77033 16-(4-chlorophenoxy)-lla,15-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid (70mg.~
in 0.15ml. of a 2:1 mixture of pyridine and acetic anhydride was kept at room temperature for 16 hours. The volatile material .
was evaporated and cyclohexane (lOml.) wa5 added to, and boiled off from, the residue three times, leaving the mixed anhydride of acetic acid and 9a-acetoxy-16-(4-chlorophenoxy)-lla,15-bis-(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid as a yellow oil,~max (CHC13) 1720, 1810cm 1.
Example 8 To a solution of 9a-acetoxy-16-(4-chlorophenoxy)-lla,15-dihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid (12mg.) in methanol (lml.) at 0C. was added an excess cf a solution of diazomethane in ether. After 10 minutes, the solvents were evaporated, the residue was dissolved in ether, and the solution was treated with lithium aluminium hydride (50mg.). The mixture was stirred at room temperature for 1 hour, the excess of hydride was destroyed by the addition of water (lml;) and the mixture was extracted with ethyl acetate to give 16-(4-chloro-phenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienol, M = 698.3439 (calculated 698.3441), RF= 0.2 (ethyl acetate).
In a similar manner, there were obtained:-16-(3-chlorophenoxy)-9a,11a,15-trihydroxy-2-methyl-17,18,19,20-tetranor-5-cis-13-trans-prostadienol, RF= 0.15 (ethyl acetate, ~1:)77~33 M+= 712.3575 (calculated 712.3597).
9a,11a,15-trihydroxy-16-(6-methyl-2-naphthyloxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienol, RF= 0.2 (èthyl acetate).
Example 9 The process described in Example 1 was repeated using the appropriate phosphonate reagent,to give:-a) 9a,11a,15-trihydroxy-16-(4-hydroxyphenoxy)-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, RF= 0.2 and 0.3 (3% acetic acid in ethyl acetate). ~=6.82 (4H, aromatic) 9 5.3-5.7 (4H, olefinic), 3.98-5.1 (lOH, ~CH.O- and exchangeable protons); phosphonate, RF= 0.2 (10% methanol in ethyl acetate); enone, m.p.l35-140C.
b) 16-furfuryl-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, RF= 0 5 (3% acetic acid in ethyl acetate), ~= 7.5 (lH) and 6.3 (2H) (furyl protons) 5.1-5.6 (4H, olefinic); phosphonate, b.p.200C./0.2mm;
; enone, m.p.92-93C.
c) 16-(3-allylphenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, M = 718.3892 (calculated 718.3938); phosphonate, RF= 0.32 (ethyl acetate);
enone, m.p.110-112C.
Example 10 The process described in Example 1 was repeated, using a 9-oxo prostanoic acid derivative in place of a 9a-hydroxy prostanoic acid derivative, to give the compounds shown below.

- 35 ~

'' '~: .' :`

~77033 For measurement of mass spectra, the acids were converted to methyl esters with diazomethane, the 9-oxo group was protected by conversion to the methoxime with methoxylamine, and, where indicated, the hydroxy groups at C-ll and C-15 were protected as the trimethylsilyl derivatives. N.m.r. spectra were measured in deuterated acetone.

~~COO~

, CH(OH)-X-Y-R4 HO
.
No. R X

46 phenyl -CH2- -O-47 phenyl -CH(CH3)- -O-48 phenyl . -(CH ) - -O-49 l-naphthyl -CH2- -O-2-naphthyl -CH2- -O-51 4-chlorophenyl -CH2- -O-52 4-chlorophenyl -CH2- -S-53 3-chlorophenyl -CH2- -O-54 2-chlorophenyl -CH2- -O-4-chlorophenyl -C(CH3)2 -O-56 4-bromophenyl -CH2- -O-57 4-fluorophenyl -CH2- -O-58 3-fluorophenyl -CH2- -O-:. . :, : :, - . ,:

~077033 No. R4 X Y ..

59 2-fluorophenyl -CH2- -0-2,4-dichlorophenyl -CH2- -0-61 2,5-dichlorophenyl -CH2- -0-62 3,5-dichlorophenyl -~H - -0-63 4-tolyl -CH2- -0-64 3-tolyl -CH2- -0-2-tolyl -CH2- -0-66 3,5-xylyl -CH2- -0-67 phenyl -CH2- -G-68 2-chloro-4-methyl- -CH2- -0-phenyl 69 3-trifluoromethyl- -CH2- -0-4-methoxyphenyl . -CH2- -0-71 2-methoxyphenyl -CH2- -0-72 ¦ 4-c oro~ CH2- ¦ -0-';' ",,, ' ,; . .~, ' ,;, :~ , 1077033 r No Isomer Characterisine Data 46 mixed RF= 0.2 (acetone/cyclohexane/ethyl acetate -N.m.r.:06.98-7.28 (5H, aromatic), 5.48 (2H, cis olefin), 5.78 (2H, trans olefin), 3.5-4.5 (5H, ~CH.O- and -COOH) 47 mixed M+= 589.3267 rcalculated 589.3255 for methyl ester, 9-methoxime, 11,15-di-(trimethylsilyl) derivative~. R = 0.4 (3% acetic acid in ethyl acetate~
48 mixed RF= 3 (3% acetic acid in ethyl acetate) 49 mixed RF= 4 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at 08.3-8.5 (lH), 7.7-7.9 (lH~, 7.2-7.5 (4H) and 6.8-7.o8 (lH) 50 mixed RF= 3 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at ~7.7 7.8 (3H)and 7.1-7.5 (4H) 51 mp M+= 609.2633 rcalculated 609.2709 for methyl ester, 9-methoxime, 11,15-di(trimethyl-silyl) derivativel. RF= 0.4 (3% acetic acid in ethyl acetate) 52 mixed RF= 5 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at 07.3 (4H) 53 mp RF= 3 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at ~7.15 (lH) and 6.9 ~3H) 54 mixed RF= 4 t3% acetic acid in ethyl acetate) 55 mixed RF= -5 (3% acetic acid in ethyl acetate).
N.m.r.: aromatic protons at 07.28 (2H), 7.19 (2H) and 2 methyls at 01.25 and 1.30 (6H

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

. ~

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

: ; : :

No. Isomer Characterising Data 66 mixed RF= 0.2 (cyclohexane/acetone/ethyl acetate -N.m.r.: aromatic protons at ~6.5 (3H), and methyls (6H) at 2.28 67 mixed RF= 5 (5% acetic aeid in ethyl acetate).
N.m.r.: aromatic protons at ~7.2 (lH) and 6.85 (2H), and methyl at 2.3 68 mixed RF= 4 (eyclohexane/ethyl acetate/acetone-N.m.r.: aromatic protons at o7.18 (lH) and 6.80 (2H), and methyl at 2.2 69 mp RF= 5 (5% ace~ie acid in ethyl acetate).
N.m.r.: aromatic protons at ~7.5 (lH) and 7.25 (3~) 70 mixed RF= 0.6 (3% acetic acid in ethyl acetate) 71 mixed RF= o.65 and 0.7 (3% acetic acid in ethyl acetate) 72 mixed RF= o4 (3% acetie aeid in ethyl aeetate).
N.m.r.: aromatie protons at ~8.4 (lH), 8.15 (lH), 7.6 (3H) and 7.08 (lH) * mp= more polar.

The 9-oxo prostano;e aeid derivatives used as starting materials may be obtained by oxidation of the corresponding 9a-hydroxy eompound, as exemplified below for the preparation of 9-.

' . ' ~

~'~ . " .. " ., . ' ., ,'' ' '.

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

:, .. .. , , :. :

.:. :-: ;:. i :.: .
- .
..

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

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

Claims (25)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

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

II

or of a mixed anhydride thereof, wherein A, X, Y, R2, R3 and R4 have the meanings stated above, and R5 and R6 are each a tetrahydropyran-2-yloxy radical, or an acyloxy radical of 1 to 6 carbon atoms, whereafter when a salt is required the product is reacted with a base; or (b) for those compounds wherein R1 is an alkoxycarbonyl radical of 1 to 11 carbon atoms, the reaction of an acid of the formula:- III

wherein A, X, Y, R2, R3 and R4 have the meanings stated above, with a diazoalkane of the formula R7. N2, wherein R7 is an alkyl radical of 1 to 11 carbon atoms; or (c) for those compounds wherein R1 is an alkoxycarbonyl radical of 1 to 11 carbon atoms, the reaction of a salt of an acid of the formula II with an alkyl halide of 1 to 11 carbon atoms; or (d) for those compounds wherein R1 is the hydroxymethyl radical and Y
is an oxygen or sulphur atom or an alkylimino radical, the reduction of an ester of the formula I wherein R1 is an alkoxycarbonyl radical of 1 to 11 carbon atoms; or (e) for those compounds wherein Y is the sulphinyl radical, the oxidation of a thio-compound of the formula:- IV

wherein R1, R2, R3, R4, A and X have the meanings defined above.

2. A process as claimed in claim 1 wherein the hydrolysis is carried out in aqueous acetic acid.

3. A process as claimed in claim 1 wherein the hydrolysis is carried out in an aqueous or alcoholic solution of an alkali metal carbonate.

4. A process as claimed in claim 1 wherein the salt of an acid of the formula II is the silver salt.

5. A process as claimed in claim 1 wherein the alkyl halide is an alkyl iodide.

6. A process as claimed in claim 1 wherein the reduction is carried out with a complex metal hydride.

7. A process as claimed in claim 6 wherein the complex metal hydride is lithium aluminium hydride.

8. A process as claimed in claim 1a), b), c) or d), for the manu-facture of a prostanoic acid derivative of the formula I wherein in the starting material, R2 is a hydroxy or acetoxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, A is an ethylene or trans-vinylene radical, X is a methylene radical bearing 0, 1 or 2 methyl substit-uents, or a trimethylene radical, Y is an oxygen atom and R4 is a phenyl, naphthyl, chlorophenyl, chloronaphthyl, bromophenyl, fluorophenyl, tolyl, xylyl, methylnaphthyl, t-butylphenyl, methylchlorophenyl, trifluoromethyl-phenyl, hydroxyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, dimethyl-aminophenyl or tetrahydronaphthyl radical, which prostanoic acid derivative optionally bears a 2-methyl substituent.

9. A process as claimed in claim 2, 3 or 4 for the manufacture of a prostanoic acid derivative of the formula I wherein in the starting material, R2 is a hydroxy or acetoxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, A is an ethylene or trans-vinylene radical, X is a methylene radical bearing 0, 1 or 2 methyl substituents, or a trimethylene radical, Y is an oxygen atom and R4 is a phenyl, naphthyl, chlorophenyl, chloronaphthyl, bromophenyl, fluorophenyl, tolyl, xylyl, methylnaphthyl, t-butylphenyl, methylchlorophenyl, trifluoromethylphenyl, hydroxyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, dimethylamino-phenyl or tetrahydronaphthyl radical, which prostanoic acid derivative optionally bears a 2-methyl substituent.

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

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

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

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

14. A process as claimed in claim 1a), b) or c) for the manufacture of a prostanoic acid derivative of the formula 1 wherein in the starting material R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, A is a trans-vinylene radical, X is a methyl-ene or isopropylidene radical, Y is an oxygen atom and R4 is a 3- or 4-chlorophenyl, 2- or 4-fluorophenyl, 3-trifluoromethylphenyl or 2-naphthyl radical.

15. A process as claimed in claim 2, 4 or 5 for the manufacture of a prostanoic acid derivative of the formula I wherein in the starting material R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, A is a trans-vinylene radical, X is a methylene or iso-propylidene radical, Y is an oxygen atom and R4 is a 3- or 4-chlorophenyl, 2- or 4-fluorophenyl, 3-trifluoromethylphenyl or 2-naphthyl radical.

16. A process for the manufacture of 16-(3-chlorophenoxy)-9.alpha.,11.alpha.,15-trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid which com-prises the hydrolysis with aqueous acetic acid of 16-(3-chlorophenoxy)-9.alpha.-hydroxy-11.alpha., 15-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid.

17. A process for the manufacture of 16-(4-chlorophenoxy)-11.alpha.,15-dihydroxy-16,16-dimethyl-9-oxo-17,18,19,20-tetranor-5-cis,13-trans-pro-stadienoic acid which comprises the hydrolysis, with aqueous acetic acid, of 16-(4-chlorophenoxy)-15, 16-dimethyl-9-oxo-11.alpha.,15-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid.

18. A process for the manufacture of 9.alpha.,11.alpha.,15-trihydroxy-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid which comprises the hydrolysis, with aqueous acetic acid, of 9.alpha.-hydroxy-11.alpha.,15-bis(tetrahydropyran-2-yloxy)-16-(3-trifluoromethylphenoxy)-17,18,19, 20-tetranor-5-cis,13-trans-prostadienoic acid.

19. A prostanoic acid derivative of the formula:- I

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

or of a mixed anhydride thereof, wherein A, X, Y, R2, R3 and R4 have the meanings stated above, and R5 and R6 are each of tetrahydropyran-2-yloxy radical, or an acyloxy radical of 1 to 6 carbon atoms, whereafter when a salt is required the product is reacted with a base; or (b) for those compounds wherein R1 is an alkoxycarbonyl radical of 1 to 11 carbon atoms, the reaction of an acid of the formula:- III

wherein A, X, Y, R2, R3 and R4 have the meanings stated above, with a diazoalkane of the formula R7.N2, wherein R7 is an alkyl radical of 1 to 11 carbon atoms; or (c) for those compounds wherein R1 is an alkoxycarbonyl radical of 1 to 11 carbon atoms, the reaction of a salt of an acid of the formula II
with an alkyl halide of 1 to 11 carbon atoms; or (d) for those compounds wherein R1 is the hydroxymethyl radical and Y is an oxygen or sulphur atom or an alkylimino radical, the reduction of an ester of the formula I wherein R1 is an alkoxycarbonyl radical of 1 to 11 carbon atoms; or (e) for those compounds wherein Y is the sulphinyl radical, the oxidation of a thio-compound of the formula:- IV

wherein R1, R2, R3, R4, A and X have the meanings stated above, or by an obvious chemical equivalent thereof.

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

21. A prostanoic acid derivative of the formula I wherein R1 is a carboxy, hydroxymethyl, methoxycarbonyl or ethoxycarbonyl radical, R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form the oxo radical, A is a trans-vinylene radical, X is a methylene or isopropylidene radical, Y is an oxygen atom and R4 is a phenyl, 1-naphthyl, 2-naphthyl, 2-, 3- or 4-chlorophenyl, 4-bromophenyl, 2-, 3- or 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2-, 3- or 4-tolyl, 2,3-, 3,4 or 3,5-xylyl, 4-t-butylphenyl, 3-allylphenyl, 3-trifluoromethylphenyl, 4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 4-biphenylyl, 3-dimethylamino-phenyl, 2-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 1-chloro-2-naphthyl, 4-chloro-2-naphthyl, 6-metnyl-2-naphthyl, 6-methoxy-2-naphthyl or 5,6,7,8-tetrahydro-2-naphthyl adical, whenever prepared by the process claimed in claim 11 or by an obvious chemical equivalent thereof.

22. A prostanoic acid derivative of the formula I wherein R1 is a carboxy, methoxycarbonyl or ethoxycarbonyl radical, R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, A is a trans-vinylene radical, X is a methylene or isopropylidene radical, Y is an oxygen atom and R4 is a 3- or 4-chlorophenyl, 2- or 4-fluorophenyl, 3-trifluoromethylphenyl or 2-naphthyl radical, whenever prepared by the process claimed in claim 14 or by an obvious chemical equivalent thereof.

23. 16-(3-Chlorophenoxy)-9.alpha.,11.alpha.,15-trihydroxy-17,18,199,20-tetranor-5-cis,13-trans-prostadienoic acid whenever prepared by the process claimed in claim 16 or by an obvious chemical equivalent thereof.

24. 16-(4-Chlorophenoxy)-11.alpha.,15-dihydroxy-16,16-dimethhyl-9-oxo-17,18, 19,20-totranor-5-cis,13-trans-prostadienoic acid whenever prepared by the process claimed in claim 17 or by an obvious chemical equivalent thereof.

25. 9.alpha.,11.alpha.,15-Trihydroxy-16-(3-trifluoromethylphenoxy))-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid whenever prepared by the process claimed in claim 18 or by an obvious chemical equivalent thereof.