IL43832A

IL43832A - (8rs,12rs,15sr (zeta))-(5z,13e)-15-hydroxy-9-oxo prosta-5,13-dienoic (or9-alkoxy-prosta 5,9,13-trienoic) acid derivatives,process for preparing them and pharmaceutical compositions containing them

Info

Publication number: IL43832A
Application number: IL43832A
Authority: IL
Original assignee: Roussel Uclaf
Priority date: 1972-12-27
Filing date: 1973-12-17
Publication date: 1977-03-31
Also published as: IE38875L; FR2211223A1; GB1438130A; BE808969A; FR2211223B1; CH590226A5; IE38875B1; NL7317745A; DD108268A5; SU668597A3; DE2364706C2; CA1018972A; JPS5724343B2; AU6396873A; ZA739650B; ES421790A1; CH590225A5; DE2364706A1; JPS5046649A; IL43832A0

Description

43832/4 [8RS. 12RS. 15SR ( f )] -(5Z, Ί3Ε)-Ί5 HYDR0XY-9-0X0 PROSTA -5J3- DIENOIC (OR 9-AL OXY - PROSTA 5,9,13-TRIENOIC) ACID DERIVATIVES PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM 43832/2 The present Invention has as I ts subject new derivati ves of prostanolc acid of formula I : 1n which R represents a hydrogen atom or an al kyl radical having from 1 to 4 carbon atoms , m Is an integer equal to 3,4 or 5, n 1s an Integer equal to 2, 3 or 4, R1 1s a lower* al kyl , lower al kenyl , or lower alkynyl radical having up to 4 carbon atoms , A represents either an alkoxy radi cal containing from 1 to 4 carbon atoms , or the oxygen of a ketonl c grouping, the dotted lines representing the possible presence of double bonds , one and one only of these supplementary bonds Inside the ring being present when A represents an al koxy radi cal and these bonds being absent when A represents the oxygen of a ketonlc grouping and the supplementary bond outside the ring being present only when A represents the oxygen of a ketonlc grouping, as well as the salts of the derivati ves of formula I formed wi th a mineral or organi c base when R represents hydrogen. 43832/2 Amongst the values of A, when A represents an alkoxy radical * there will be especially mentioned the mathoxy or ethoxy radical ; amongst the values of R, there will be mentioned the methyl, ethyl , propyl, butyl or tert-butyl radical and amongst the values of ' , there will be mentioned the methyl , ethyl , propyl , 1 sop rop 1, butyl, tertbutyl, vinyl* butenyl, ethynyl or propargyl radical .

Amongst the salts which the products of formula I can form when R represents hydrogen, there may be mentioned for example mineral salts such as the salts of lithium, sodium, potassium, calcium, magnesium or ammon um and the organic salts formed with the anrfnated organic bases.

Amongst the products of formula I. the Invention has more particularly as Its subject the derivatives of prostanolc acid of formula In which R represents a hydrogen atom or an a!Ryl radical having from 1 to 4 carbon atoms, m 1s an Integer equal to 3, 4 or 5, n 1s an nteger equal to 2, 3 or 4 and ' 1s a lower alkyl , lower alkenyl or lower alkynyl radical having up to 4 carbon atoms, as well as their salts formed with a mineral or organic base when R represents hydrogen and especially; - methyl ( 8 RS, 12 RS, 15 RS) (5 Z , 13 E) 15 -ethynyl 15-hydroxy 9-oxo 5,13-prostadlenoata, - methyl (8 RS, 12 RS, 15 SR) (5 Z , 13 E ) 15"^ ethynyl 15-hydroxy 9~oxo 5> lj-prostadienoate , - methyl (8 RS, 12 RS, 15 ξ) (5 Z., 13 E ) 15" hydroxy 15-methyl 9~oxo 5>13 prostadienoate , and methyl (8 RS, 12 RS, .155) ( 5 Z , 13 E .) 15-hydroxy 9~oxo I5- inyl 5> 13~prostadienoate .

The symbol ξ used in the preceding names, as well as the wavy lines figuring in the formulae, signify, here and in what follows that the substituents attached to the carbon atom thus designated may be present in the two possible conformations around this atom. The corresponding therefore products may, / be mixtures from which each of the constituents may be separated by using the usual physical methods, such as, for example, chromatography. ¾e products corresponding to formula I,, as well as their the apeutically compatible salts, may be employed as medicaments. .

Thus, the invention also has as its subject pharmaceutical' compositions which contain these substances as active principle .

The natural products of the prostaglandin family, which are extracts originating from seminal 1iquids have aroused a growing pharmacological interest and have given to rise to various therapeutic tests.

Now, it has been proved that these products had, on the one hand, various activities . namely ' important secondary effects in the treatment of a given complaint and, on the other hand, a very brief term of action, which limited the possibility of using" them.

•It was } therefore, desirable to synthesize products which would offer a dissociation of the activities and which would display an increased term of action. - One could hope to achieve this objective by modifying the structure of the natural products bringing about different behaviour at the time of the metabolism of these new molecules.

It is in accordance with this objective that the products of the invention were brought into being. These products display in pharmacology activities which are hypotensive, contractural of smooth musculature, and antibroncho-constrictive .

In particular, the hypotensive activity of these products 'is proving, for certain amongst them, to be more • the durable than the hypotensive activity of/natural prostaglandins.

The pharmacological properties of the products of the invention make them suitable to be used as medicaments, especially in the treatment of hypertension and of circulatory disorders as well as in the treatment of respiratory complaints such as, for example, asthma.

These products may be used by parenteral, buccal, or rectal route or by local route by topical application on the skin and the mucous membranes.

They may be offered in the form of solutions or of injectable suspensions, of sterile powders ft>r extemporaneous injectable preparations, of plain or coated compressed tablets, of capsules, of syrups, of suppositories, of creams, of ointments and of preparations in aerosols. ' These pharmaceutical forms are prepared in accordance with the classical processes of pharmacotechnology. ^ The dose administered may be varied according to the complaint treated, the subject concerned, the route of administration and the products considered. It may, for example, be included between 10 ¾ and 1 mg with methyl (8 RS, 12 RS, 15 SR) ( 5 Z, 13 E .) 15-ethynyl. I5-hydroxy 9~oxo 5»13-prostadiencee, administered by injectabl route, for example by slow perfusion, in man.

When administering by aerosol, it may be, for example in the order of 50 "to ^> 0 μ¾.

The invention also relates to a process for preparing the products of formula I and their salts when R represents hydrogen, a process illustrated by the attached diagram nnd characterised in that one treats with an acid a product of formula II in which m and n has the meaning already indicated and ale and alc^ each represent an alkyl radical, the same or different, having from' one to four carbon atoms, to-obtain a product of formula III which one treats v/ith a diazoalkane, havin from 1 to i carbon atoms to obtain a product of formula IV : OR al koxy in which A represents an alkyloxy radical having from 1 to 4 carbon atoms, which one saponifies with an alkaline base to ormula V: in which A represents an alkyloxy radical which one subjects to the action of heat to induce decarboxylation on the cyclopentanic nucleus, and, if desired, to the action of a diazoal^ane having from 1 to carbon atoms to obtain < a mixture of products having the formuiasi VI .and VI 1 : OH and OH in which A represents an- aXk ox radical and R represents a hydrogen atom or an alkyl radical having from 1 to carbon atoms, a mixture which one may, if desired, separate into each of its constituents, and one treats the previous mixture or one of its constituents with an oxidizing agent to obtain a mixture of products, or one these latter having the formulae VII and VII 1 : A l di hich one can, if desired, separate into each of its constituents, and one treats the preceding mixture or one of its constituents with a organo-magnesianderivative of formula: R'- Mg X in which X represents a halogen atom and R' has the meaning already given, to obtain a mixture of products having the formulae: and / its constituents, a mixture or constituents v/hich one salify, if desired, "by the usual methods when R = H, then, if desired, one treats with an acid the previous mixture of the products of formula I or one of the constituents of this mixture to obtain in admixture or separately the products having the formulae: with A ss oxygen) , with A = oxygen) a mixture which one can separate, if desired, into each of its constituents, a mixture or constituents which one can salify if desired, by the usual methods when R = H. conversion ¾ie ssage of the products of formula II to the products of formula III is effected using an acid.

Preferably one uses oxalic acid but one can also use other organic acids such as formic acid or acetic acid or mineral acids such as hydrochloric acid or sulphuric acid, conversion The passage of the products of fornula III to the products of formula IV and of the products of formula V to the products of formula VI is effected using a diazcdkane which may be, for example, diazomethane, diazoethane or diazobutane. '•^he saponifying agent used to Cpassrtthe products of 43832/2 hydroxide.

The start of the carboxyl function of the cyclo-pentane ring of product V Is effected by thermal decarboxylation. One can work between 120 and 200°C and preferably at about 140°C.

The oxidizing agent which one reacts with the mixture of the products of formula VI and VI * or with each of Its constltutents 1s preferably si lver silicate. One can also use, for example, chromic anhydride 1n aceton c solution, manganese dioxide or the chromic anhydrlde-pyrldlne complex.

The conversion of the mixture of the products of formula VII and VII ' or of each of the constituents of this m xture Into products of formula I Is effected using organo-magens an der vatives of formula: R' Mg X in which * represents a lower al,kyl , lower al kenyl , or lower alkynyl radical having up to 4 carbon atoms , and X represents a halogen atom selected from among chlorine, bromine or Iodine. The reaction 1s advantageously effected n an organic solvent such as ethyl ether or tetrahydrofuran.

The add wh ch one uses at the end of the process to convert the alkyloxy grouping, attached to the cyclopentane ring. Into a ketone grouping 1s preferably aqueous hydrochloric add. One can also use, for example, aqueous sulphuric add or an organic add such as formic add or oxal ic add, In aqueous med urn.

The Invention also had as Its subject, as a variant, a process for preparing the products of formula I In which m the radical R1 represents an acetylenic radical of formula: R" - C ; C - in which RM represents a hydrogen atom or an alkyl radical having 1 or 2 carbon atoms , characterised one in that/prepares, in accordance with the process of described above, the mixture of products/formula VII and V I ' , or one of these, and in that one reacts with this mixture or with each of its constituents an alkaline derivative of formula: R" - C ^ C - M M representing an alkali metal atom, · in liquid ammonia or in an organic solvent, to obtain a mixture of products alkoy of formula I in which A represents an alle l'oicy radical one and R1 represents the radical Rn - C - C which/can, if desired, convert into other products of formula I in which R' represents ..the radical R" - C jjj C -, in accordance with the process described above.

As alkali metal one can use lithium, sodium or potassium. As organic solvent one can use, for example, benzene or toluene.

The constituents of the mixtures formed by the VII products of formula VI and VI '/and VII1 and the different products of formula I can be separated by the customary physical methods, in particular/chromatography. ¾e salification of the products of formula I in which R represents hydrogen can be carried out by the usual methods. It can be obtained, for example, by the action on these acids of a mineral base such as for base such as triethylaraine . This salification is preferably carried out in a solvent or a mixture of solvents, such as water, ethyl ether, ethanol or acetone.

The process of the invention enables nev; industrial products, especially useful for the preparation of the products of formula I, to be obtained, namely the product of formula VIII: in which R represents a hydrogen atom or an alkyl radical having from 1 to A- carbon atoms, m is an integer equal to 3, 4 or 5> n is an integer equal to 2, or 4, A represents an -o¾_tYoxy radical containing from 1 to 4 carbon atoms, one only of the supplementary bdnds indicated being capable of being present in the ring and B represents either a hydroxyl grouping singly bonded to the chain,' or an oxygen atom doubly bonded to the chain.

The products of formula II used at the start of the process of the invention are described in French Patent No. 2,085,654. ¾e products of formula I and their salts when R = H can exist in racemic or optically active forms.

The optically active isomers can be separated by the methods customarily employed; resolution of the acids using the salts formed with optically active bases may / be mentioned; it is the same with the starting products. j¾ .

The following examples illustrate the invention without, however, limiting it.

Example 1 : Methyl (6 RS, 12 RS, 1¾ SB) (¾ Z , 13 L « 15-ethyny 15-hydroxy 9-oxo < 15-prostadienoate and methyl (8 RS, 12 RS, 1 KG) (5 Z , 15 E ) 15-ethynyl 15-hydroxy 9-oxo 5<13-prostadienoate.

Stage A: Ethyl (8 RS, 12 RS, 15 SR) (5 z ^ 13 E ,) 10-carbethoxy 15-hydroxy 9~oxo 5<13-prostadienoate.

One introduces 2 3 mg of ethyl (8 RS, 12 RS, 15 SR) (5 cis, 13 trans) lO-carbe ho y 9-oxo 15-tetrahydropyranyloxy 5, 13-prostadienoate into the mixture of cm3 of a 2 per thousand aqueous solution of oxalic acid: and 4 cm3 of ethanol. One "brings to 48°C for eight hours then evaporates the ethanol under vacuum. One extracts the residue with ether, washes the ethereal phase with water and dries it on magnesium sulphate. After evaporating the ether, one chromatographs the oil obtained on silica gel, using a cyclohexane ethylacetate mixture 1-1. One thus obtains 93 mg of ethyl (8 RS, 12 RS, 15 SR) (5 Z > 13 E ) 10-carbethoxy 15-hydroxy 9-oxo 5>13-prosta-dienoate in the form of a pale yellow oil.

Analysis : (C2 H40°6^ Calculated : C% 68.80 H 9.24 Found : 68.5 9.2 .

Stage B: Ethyl (8 RS, 12 RS, 15 SR) ( 5 2 - , 9, 15 E. ) 10-carbethoxy 15-hydroxy 9-niethoxy 5> 9, 13-prostatrienoate.

One dissolves 550 mg of the product prepared in accordance with the previous ''stage in4cm3 of methylene chloride. One cools to 0° and adds 15 cm3 of a chloro-methylenic solution of diazomethane at 15 g/1. One allows to return to ambient temperature and continues the reaction for five hours. One then evaporates the excess diazomethane and the methylene chloride under vacuum. One thus obtains 1 E 10-carbethoxy 15-hydroxy 9-methoxy 5> 9» 13-prostatrienoate in the form of a pale yellow oil. ^ U. V« Spectrum (ethanol) λ Max. = 25 nm ε - 9800 I. R. Spectrum (chloroform) 1631cm"1 C=C 1697cm""1 C=0 conjugated 1733cm-1 C=0 not conjugated 3605emel OH Stage C : (8 RS, 12 RS, 15 SR) (5 z> , 13 E .) 10-carboxy 15-hydroxy 9-methoxy 5, ¾ 13~prostatrienoic acid.

One dissolves 2.16 g of product prepared in accordance with the previous, stage in 21 cm3 of ethanol.

Ond adds 14.4 cm3 of normal aqueous soda and- brings to 17°C for six hours; one again adds 4.8 cm3 of normal aqueous soda and heats to 70°C for ten hours. "One then evaporates the ethanol and one dissolves the residue with a water-ether mixture." The separated aqueous phase is acidified with 2N hydrochloric acid then saturated with sodium chloride. One extracts with ether, dries the ethereal phase on magnesium sulphate and concentrates it under vacuum. One thus obtains 1.89 g of (8 RS, 12 R3, 13 SR) (5 Z, 9, 13 E ) 10-carboxy 15-hydroxy 9-methoxy 5>9>13-prostatrienoic acid in the form of a thick yellow o±\, I.R. Sp/ectrum (chloroform) 1626cm"1 C=C 3601cm"1 OH Stage D : Methyl (8 RS, 12 RS, 15 SR) (5 Z , , 13 E ) 15-hydroxy 9-methoxy 5i9< 13-prostatrienoate and methyl (12 RS, 15 SR) (5 z» 8, 1 E ) 15-hydroxy 9-methoxy One introduces 2.35 S of diacid prepared in accordance with the previous stage into 185 cm3 of xylene. One brings the mixture to reflux for eight hours then evaporates the xylene under vacuum. The thick oil obtained is dissolved in 10 cm3 of methylene chloride. One cools the solution to 0° and adds 30 cm3 of chloromethylenic solution of diazomethane at 15 &/1· When the addition is finished, one evaporates the excess diazomethane and the methylene chloride under vacuum.

One obtains a yellow oil which one filters on silica in a 8-2 benzene-ethylacetate mixture/. One obtains 1; 95 g of oil which shows itself, by NMR spectrography, to-be a mixture of methyl . (8 RS, 12 RS, 15 SB) ( 5 Z, 9, 13 E ) 15-hydroxy 9-methoxy 5, 9, 13-prostatrienoate and methyl (12 RS, 1 SR) (5 Z, 8, 13 - E ) 15-hydroxy 9-methoxy »8, 13-prostatrienoate in the approximate proportion of 3/5 for 2/5· NMR Spectrum (deuterochloroforra) Peak of 9-methoxy Δ-9 at 216.5 Hz' Peak of 9^-methoxy Δ-8 at 21?. Hz Starre E : Methyl (8 RS, 12 RS) ( 5 Z, , I7' E ) 9-methoxy 15-o o 9 ^ l^-Pr^a r.i.c oate and methyl (12 RS) (5 Z, 8, 13 E ) 9-methbxy 15-oxo 5<8, 13-prostatrienoate.

One introduces 180 mg of the mixture obtained in the previous stage into 13 cm3 of benzene. One adds 580 mg of silver silicate and brings to reflux for three hours thirty minutes. After cooling, one filters and washes the resi due iltoff - with benzene. One evaporates the filtrate under vacuum, which gives 160 mg of oil which shows itself, by ITI'IR spectrography, to be a mixture of methyl (8 RS, 12 RS) (5 Z, 9, 13 E ) !9-roethoxy 15-oxo 5» 9>13-prostatrienoate and of methyl (12 RS) (5 Z, , 8, 13 E ) 9-methoxy 15-oxo 5,8,13-prostatrienoate in the approximate proportion of 4/5 IIR Spectrum (deuterochloroform) Peak of 9-methoxy Δ-9 at 21 .5 Hz Peak at 9-methoxy Δ-8 at 216.5 Hz Stage F : Methyl (8 RS. 12 RS. 15*0 ( Z, 9.15 15-ethynyl 15-hydroxy 9-methoxy « , 15-prostatrienoate and methyl (12 RS. 1¾ξ) (5 Z> 8.13 £ -) 15-ethyhyl 15-hydroxy 9-methoxy 5.8.13-prostatrienoate.

One dissolves 500 mg o mixture obtained in the previous stage in 3 cm3 of tetrahydrofuran* One adds 3.6 cm3 of a 0.5 H solution of. ethynylmagnesium bromide in tetrahydrofuran. One agitates for one hour at ambient temperature then one adds again 1.4- cm3 of magnesian solution and agitates again for one hour thirty minutes at ambient temperature. One pours the reaction mixture into an iced aqueous saturated solution of ammonium chloride and one extracts with ether. After washings and drying of the organic phase, one evaporates under vacuum and one obtains an oil which one purifies by filtering on silica gel in a benzene-ethyl acetate mixture 95-5» which gives 139 mg of a mixture of methyl (8 RS, 12 RS, 15 (5 Z, 9, 13 E - ■) 15-ethynyl 15-hydroxy 9-methoxy 5, 9, 13-prostatrienoate and of methyl (12 RS, 15 ξ) (5 Z, 8, 13 E ) 15-ethynyl 15-hydroxy 9-methoxy 5,8, 13-prostatrienoate.

NIR Spectrum (deuterochloro orm) Peak of 9-methoxy Δ-9 at 214.5 Hz Peak of 9-methoxy Δ-8 at 217 Hz Stage G : Methyl (8 RS. 12 RS. 15 SR) (5 z* 13 E ) 15-ethynyl 15-hydroxy 9-oxo 5.15-prostadienoate and methyl (8 RS. 12 RS. 15 RS) (5 z» 15 E -) 15-ethynyl 15-hydroxy - - ost dieno te.

One dissolves 139 mg of the mixture obtained in the previous stage in cm3 of ethanol. One adds 5 cmj of a 0.1 N aqueous hydrochloric acid-ethanol solution (1-1). One leaves in contact for forty-five minutes then one evaporates the ethanol under vacuum. One dissolves the residue in ether, washes the ethereal phase with salt water then dries it on magnesium sulphate. After evaporating the ether, one obtains a yellow oil which one chronatographs on silica gel using a benzene-ethyl acetate mixture 8-2. One thus separates 38 mg of methyl (8 RS, 12 RS, 15 RS) (5 Z, 13 E ) 15-ethynyl 15-hydroxy 9-oxo 5>13-prostadienoate and 24 mg of methyl (8 RS, 12.RS, 15 SR) (5 Z, 13 E ) 15-ethynyl I5-hydroxy 9-oxo 5, 13-prostadienoate.

The first product, , by thin-layer chromatography on silica gel in the benzene-ethyl acetate system 8-2, has a f of Ο.34, the second'a Rf of 0.28.

I.R. Spectrum (chloroform) Practically identical for the two products. 3588cm"1 OH 3303cm""1 -CsCH 1739cm"1 CO Example 2: Methyl (8 RS. 12 RS. 1¾Q(5 Z. 15 E ) 15-hydroxy l^-methyl 9-oxo 5, 15-prostadienoate Operating as in Stages F and G of Example 1, at the start of the mixture of methyl (8 RS, 12 RS) (5 Z, 9,13 ) 9-methoxy 15-oxo > 9, 13-prostatrienoate and of methyl (12 RS) (5 Z, 8,13 E ) 9-methoxy 15-oxo 5|8,13-prostatrienQate, but using methyl magnesium iodide one obtains a yellow oil which is methyl (8 RS, 12 RS, 15?) (5 Z, 13 E ) 15-hydroxy 15-methyl 9-oxo 5,13-P:cos adienoate.

Thin-layer chromatography on silica gel in the . cyclohexane-ethyl acetate system 9-1 : £=0.5« I.R. Spectrum (chloroform) 3595cm"1 : OH 1735cm"1 : GO N.M.R. Spectrum (deuterochloroform) Peak at 140 Hz : OH at 1 Peak at 77-5 : CH^ at 15 Example ; Methyl (8 RS, 12 RS, 15 (¾ Z, 13 E ) 1 -hydr'oxy 9-oxo 1 -vinyl 5T 15-prostadienoate , Operating as in Stages F and G of Example 1, at the start of the mixture of methyl (8 RS, 12 RS) (5 Z, 9,13 E) 9-methoxy 15-oxo 5,9,13-prostatrienoate and of methyl (12 RS) (5 Z, 8,13 E ) 9-methoxy 15-oxo 5,8,13-prostatrienoate, but using magnesium vinyl bromide, one obtains a yellow oil which ismethyl (8 RS, 12 RS, 15 (5 Z, 13 E ) 15-hydroxy 9-oxo 15-vinyl 5,13-prostadienoate .

Thin-layer chromatography on silica gel in the benzene-ethyl acetate system 9-1 : R =0.2.

N.M.R. Spectrum (deuterochloro orm) Peak at .146 Hz- : OH at 15 Triplet at 4- 1· 5, 61.5 and 47 Hz : Hg of. the vinyl Quadruplet at 517, 528, 35-5 and 5 6.5 Hz : H of the vinyl.

Claims

43832/2 WHAT IS CLAIMED IS :

1. The der vati ves of prostanolc acid of formula I : 1n which R represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms* m Is an Integer equal to 3, 4 or 5, n 1s an Integer equal to 2, 3 or 4, R' 1s a lower alkyl , lower al kenyl or lower alk nyl radical , having up to 4 carbon atoms , A represents either an alkoxy radical containing from 1 to 4 carbon atoms or the oxygen of a ketonic grouping, the dotted lines representing the possible presence of double bonds , one and one only of these supplementary bonds Inside the r ng being present when A represents an al koxy radical and these bonds being absent when A represents the oxygen of a ketonic grouping and the supplementary bond outside the ring being present only when A represents the oxygen of a ketonic grouping, as wel l as the salts of the derivatives of formula I formed with a mineral or organic base when R represents hydrogen.

2. The derivatives of prostanolc acid of formula I ' : In which R represents a hydrogen atom or an alk l radical having from 1 to 4 carbon atoms , m 1s an Integer equal to 3, 4 or 5, n 1s an Integer equal to 2, 3 or 4 and R' 1s a lower alkyl » lower alkenyl or lower al kynyi radical of up to 4 carbon atoms , as wel l as their salts formed with a mineral or organic base when R represents hydrogen.

3. Methyl (8 RS, 12 RS, 15 RS) (5 Z, 13 E ) 15-ethynyl 15-hydroxy 9-oxo 5,13-prostadlenoate.

4. ~ Methyl (8 RS , 12 RS, 15 SR) (5 Z 13 E ) 15-ethynyl 15-hydroxy 9-oxo 5,13-prostadlenoate.

5. Methyl (8 RS, 12 RS, 15^) (5 Z, 9,13 E ) 15-ethynyl 15-hydroxy 9-methoxy 5,9,13-prostatr1enoate.

6. Methyl (12 RS, 15 ¾) (5 Z, 8,13 E ) 15-ethynyl 15-hydroxy 9-methoxy 5,8,13-prostatrlenoate.

7. Methyl (8 RS, 12 RS, 15^ ) (5 Z, 13 E ) 15-hydroxy 15-methyl 9-oxo 5,13-prostadlenoate.

8. Methyl (8 RS , 12 RS , 15^ ) (5 Z, 13 E ) 15-hydroxy 9-oxo 15-vlnyl 5,13-prostadlenoate.

9. The pharmaceutical compositions containing as active principle at lease one of the therapeutical ly acti ve products defined In claims 1 to 8. the

10. Process for preparing/derivatives of prostanoic acid corresponding to formula I of claim 1 and their salts when R represents hydrogen, characterized in that one treats with an acid a product of formula II: in which m and n have the meaning already indicated and ale and alc^ each represent an alkyl radical, the same or different, having from one to four carbon atoms, to obtain a product of formula III: which one treats with a diazo tkane having from 1 to 4 carbon atoms to obtain a product of formula IV: OH in which A' represents an radical having from 1 to 4- carbon atoms. ..saponifies the product of formula IV with an alkaline base to obtain, after acidification, a product of formula V: OH in which A represents an subjects the product of formula V to the action of heat to induce decarboxylation on the cyclopentanic nucleus and, if desired, to the action of a diazoalkane having from 1 to 4 carbon atoms to obtain a mixture of products having the formulae VI and VI' : OH and OH in which A represents an radical and R repres a hydrogen atom or an alkyl radical having from 1 to carbon atoms, a mixture which one can, if desired, separate into each of its constituents, treatsthe previous mixture or one of its constituents with an oxidizing agent to obtain a mixture of products, or one of these, having the formulae VII and VII ' : in which A represents an alk¾F¾oxy radical, a mixture which one can, if desired, separate into each of its constituents, treats the previous mixture or one of its constituents with an organo-magnesian derivative of formula: R1 Mg X in which X represents a halogen atom and R' has the meaning already given, to obtain a mixture of products having the formulae: ' alkoxy with A = alkytoxy-) and a mixture which one can, if desired, separate into each of its constituents, a mixture or constituents which one can salify, if desired, when R = H, or, if desired, treats with an acid the previous mixture of the products of formula I or one of the constituents of this mixture ■ to obtain, in admixture or separately, the products having the formulae: (I, with A - oxygen) and a mixture which one can separate, if desired, into each of its constituents, a mixture or constituents which one can salif¾ if desired, when R = H.

11. Process according to claim 10, characterized in that the oxidizing agent which one reacts with the mixture of the products of formula VI and VI' or with each of its constituents is silver silicate.

12. Process, according to claim 10, for the. preparation of the products of formula I in which R' represents an acetylenic grouping of formula R"-C^C-, in which R" represents a hydrogen atom or an alkyl radical having .one or two carbon atoms,- characterized in that one the prepares according to the said claim 10 /. mixture of products of formula- VII and VII· or one of these, then reacts with this mixture or wit one of its constituents an alkaline derivative of formula R"-CSC-M, M representing an alkali metal atom, in liquid ammonia, or in an organic solvent, to obtain a mixture of products of formula I in which A represents radical and R1 represents the radical R"-C≡C-, which one can, if desired, convert . into other products of formula I, in which R' represents the radical R"-C≡C-, according to the process described in the said claim 10. -l^--g?h^-i>-pedwts-^f- ^rmu-l -;V:Hi- COHEN ZEDEK & SPISBACII in which R represents a hydrogen atom or an alkyl radical having from 1 to carbon atoms, m is an integer equal to 3, 4· or 5» a. is an integer equal to 2,3, or H-y A represents an alky o radical containing from 1 to 4· carbon atoms, one alone of the supplementary bonds indicated being capable of being present in the ring and B represents either a hydroxyl grouping singly bonded to the chain, or an oxygen atom doubly bonded to the chain. V COHEN ZEDEK & SPISBACH P. O. Box 33116 , Tel-Aviv Attorneys for Applicant