BE823778A - PRODUCTION OF PROSTAGLANDINS - Google Patents

Description

       

  Production of prostaglandins.

  
The present invention relates to trans-A -prostaglandins.

  
An object of the present invention is a novel process for the preparation of trans - � -prostaglandins of general formula:

  

 <EMI ID = 1.1>


  
in which R <1> represents an alkyl group containing from 1 to 10, and preferably 5, carbon atoms, or an alkyl group containing from 1 to 6 carbon atoms and carrying a phenyl or cycloalkyl substituent having 5 to 7 atoms carbon, R represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, R <3> represents an alkyl group containing

  
1 to 12 carbon atoms, R4 represents a tetrahydropyranyl-2 non-substituted or substituted by at least one alkyl group, or a tetra- group

  
 <EMI ID = 2.1>

  
or, preferably, trans vinylene (-CH = CH-) and Y represents an ethylene linkage or, preferably, cis vinylene. It should be understood that: a) the lines in

  
 <EMI ID = 3.1>

  
description indicate the attachment of the group concerned in the a or P configuration, and b) the alkyl groups referred to in this description may, where appropriate, have straight or branched chains.

  
Compounds of general formula (I) are useful as intermediates for the preparation of therapeutically useful trans- to <2> _prostaglandins. Those of those compounds in which Y represents a cis vinylene linkage are novel compounds and, as such, constitute a feature of the present invention.

  
Prostaglandins are derivatives of prostanoic acid which has the following formula:

  

 <EMI ID = 4.1>
 

  
the dotted line, in accordance with the accepted rules of organic nomenclature, indicating the configuration a of the group's attachment to the cyclopentane ring, indicated by the number 8, that is to say that the group is behind the general plan annular system, and the thickened continuous line indicating the configuration &#65533; in which the group is in front of the plane. Different types of prostaglandins are known, these types depending, among other things, on the structure of the alicyclic ring and the substituents it carries. For example, the alicyclic rings of prostaglandins F (PGF), E (PGE) and A (PGA) have the following structures, respectively:
 <EMI ID = 5.1>
 Such compounds are subdivided according to the position of the double bond (s) in the side chain (s) attached at positions 8 and 12 to the alicyclic ring.

   Thus, PG-1 compounds have a trans double bond between C13 and C14 (trans - 13), PG-2 compounds have a double bond

  
 <EMI ID = 6.1>

  
are characterized, respectively, by the following structures (VI) and (VII):

  

 <EMI ID = 7.1>
 

  
 <EMI ID = 8.1>

  
correspond to those of formulas (VI) and (VII) respectively with a cis double bond between the carbon atoms in positions 5 and 6. Compounds in which the double bond between the carbon atoms in positions
13 and 14 of the members of the group PG-1 is replaced by an ethylene linkage are known as dihydroprostaglandins, for example dihydroprosta-

  
 <EMI ID = 9.1>

  
When there is a double bond between the carbon atoms in positions 2 and 3, the compounds are known as cis- or trans - &#65533; <2> _prostaglandins.

  
Furthermore, when one or more methylene links are added to or removed from the aliphatic group attached at position 12 to the alicyclic ring of prostaglandins, the compounds are, according to the usual rules of organic nomenclature, known as w- homo-prostaglandins (mail-

  
 <EMI ID = 10.1>

  
when more than one methylene link is added or removed, the number is indicated

  
by "di-", "tri-", etc ..., before the prefix "homo" or "nor".

  
Prostaglandins are generally known to have

  
pharmacological properties; for example, they stimulate smooth muscles,

  
have hypotensive, diuretic, bronchodilatory and antilipolytic actions; they also inhibit the aggregation of blood platelets and the secretion

  
stomach acid; therefore, they are useful in the treatment of hypertension, thrombosis, asthma and gastrointestinal ulcers,

  
in the onset of labor and abortion in pregnant females

  
in mammals, in the prevention of arteriosclerosis and as agents

  
diuretics. These are liposoluble substances that are obtained in very small quantities from different animal tissues which secrete prostaglandins in the living organism.

  
For example, PGEs and PGAs have an inhibiting effect on

  
secretion of gastric acid and hence can be used in the treatment of gastric ulcers. They also inhibit the release of acids

  
free fatty acids caused by epinephrine and consequently reduce the concentration of free fatty acids in the blood; they are, therefore, useful

  
 <EMI ID = 11.1>

  
aggregation of blood platelets and also removes thrombus and prevents thrombosis. PGEs and PGFs have a stimulating effect on smooth muscles and increase intestinal peristalsis; these actions are an indication of their therapeutic utility on the postoperative ileus and as purgatives.

  
In addition, PGEs and PGFs can be used as oxytocics, as abortives during the first and second trimesters; they can also be used for the expulsion of the placenta after labor, and as oral contraceptives because they regulate the sexual cycle of female mammals. PGEs and PGAs have vasodilator and diuretic actions. PGEs are useful in improving the condition of patients with cerebrovascular disorders because they increase blood supply to the brain; they are also useful in the treatment of asthmatic conditions because of their bronchodilatory action.

  
During the last decade, extensive research has been carried out to discover, among other things, new products with pharmacological properties.

  
 <EMI ID = 12.1>

  
to a higher degree, or even hitherto unknown pharmacological properties, as well as new processes for the preparation of therapeutically useful prostaglandins.

  
A process is known for the preparation of a prostaglandin analogous to PGE ... and in which there is a trans double bond between

  
&#65533;

  
 <EMI ID = 13.1>

  

 <EMI ID = 14.1>


  
This process, which is described by Van Dorp in Annals New York Academy of Sciences,
180, 185 (1971), is based on a biosynthetic reaction comprising the incubation of sheep seminal vesicular glands with an unsaturated fatty acid as a substrate, according to the reaction scheme:

  

 <EMI ID = 15.1>
 

  
However, this process is difficult and expensive to carry out on a large scale because of the complex synthesis of unsaturated fatty acid and the use of expensive raw materials of animal origin which are difficult to obtain.

  
In the description of the British patent application 60040/73, there has been described, inter alia, a multistage process for the preparation of trans - &#65533; <2> _prostaglandins in accordance with general formula (I) in which represents an ethylene linkage, but this process requiring intermediates of general formula:

  

 <EMI ID = 16.1>


  
 <EMI ID = 17.1>

  
a tetrahydropyranyl-2 unsubstituted or substituted by at least one alkyl or ethoxy-1 ethyl group), is inapplicable for the preparation of trans - &#65533; <2> -prostaglandins of formula (I) in which the symbol Y represents a cis vinylene chain, for example the trans - &#65533; <2> -PG-2.

  
In the description of Belgian patent 792,803 granted to Carlo Erba S.p.A., a process for the preparation, inter alia, of / &#65533; <2> _prostaglandins, but the prostaglandins described therein are diisoprostanoic acids-8,12 or their analogs, i.e. the groups attached to the cyclopentane ring are in the reverse configuration of the trans- &#65533; -prostaglandins of general formula (I) shown above, that is to say that the products described in the Belgian patent have the groups attached to positions 8 and 12 of the structure of prostanolque acid in configuration and a, respectively. The process described in this Belgian patent, applied to 2_prostaglandins, would involve the use of Wittig reagents of general formula:

  

 <EMI ID = 18.1>


  
(in which 0 represents the phenyl radical, and Hal represents a chlorine or bromine atom), which would require, as starting materials, homoallyl halides of the formula:

  

 <EMI ID = 19.1>


  
(in which Hal is as defined above), halides which have not yet been described in the chemical literature and are known to be difficult to synthesize due to their tendency to release hydrogen halide.

  
A new and advantageous process has now been found which enables the production of trans - &#65533; <2> _prostaglandins of general formula (I) in which Y is a cis as well as ethylene vinylene linker; among these compounds of

  
 <EMI ID = 20.1>

  
news.

  
 <EMI ID = 21.1>

  
consists of:
- reacting a compound of general formula:

  

 <EMI ID = 22.1>


  
(in which R <1>, R <2>, R <3>, R4, X and Y are as defined above, R4 preferably being the tetrahydropyranyl-2 group) with a compound of general formula:

  

 <EMI ID = 23.1>


  
(wherein R and R each represent an alkyl group containing 1 to 6 carbon atoms or a cycloalkyl group containing 3 to 6 carbon atoms) to obtain a lithium esterenolate of the general formula:

  

 <EMI ID = 24.1>


  
(in which the various symbols are as defined above);
- react the esterenolate lithium with benzene bromide - <EMI ID = 25.1>

  
Diphenyl diselenide or a dialkyl or diphenyl disulphide of the formula R SSR, in which the symbols R represent either alkyl groups containing 1 to 4 carbon atoms or phenyl radicals;
- hydrolyzing the resulting intermediate to transform the -OLi group attached to the cyclopentane ring into a hydroxy group and to obtain a compound of general formula:

  

 <EMI ID = 26.1>


  
 <EMI ID = 27.1>
- treat the resulting compound with hydrogen peroxide or sodium periodate and
- decompose the resulting compound, of general formula:

  

 <EMI ID = 28.1>
 

  
(in which the different symbols are as defined previously), to transform the grouping

  

 <EMI ID = 29.1>


  
 <EMI ID = 30.1>

  
The reaction between the prostaglandin derivative of general formula

  
(XIII) and the lithiated amine of general formula (XIV) is carried out in an organic solvent, for example by adding dropwise a solution of a

  
prostaglandin derivative of formula (XIII) in tetrahydrofuran at a

  
solution of an amine of formula (XIV) in tetrahydrofuran at low temperature, for example -70 [deg.] C, the ratio of the molar equivalents of the compounds

  
of formula (XIII) to those of the compounds of formula (XIV) in the reaction mixture being from 1/2 to 3. After the addition of the prostaglandin solution is complete, the mixture is stirred at the same temperature for about 30 minutes.

  
to obtain a lithium esterenolate solution of formula (XV).

  
The reaction between the esterenolate of

  
lithium of formula (XV) and benzeneselenyl bromide, diselenide

  
of diphenyl or dialkyl or diphenyl disulfide in tetrahydrofuran, diethyl ether, hexane or pentane or a mixture of

  
two or more of them, tetrahydrofuran being the solvent medium

  
preferred, at low temperature, eg -70 [deg.] C. Thus, to the lithium esterenolate solution obtained as described above, there is added a tetrahydrofuran solution of 3 or 4 molar equivalents of benzeneselenyl bromide or of diphenyl diselenide, or 2 to 3 molar equivalents of dialkyl disulphide or of diphenyl, for each molar equivalent of ester-

  
Lithium enolate present, the temperature of both solutions being -70 [deg.] C. The reaction mixture is stirred at -70 [deg.] C, a) for one hour when the reagent is a selenium compound or b) for 30 minutes when the reagent is a disulfide, and then at room temperature, for example at 15 [deg.] C, for

  
30 minutes. After adding, for example, a small amount of solution

  
saturated aqueous ammonium chloride solution to the solution of the resulting prostaglandin intermediate to hydrolyze the -OLi group attached to the cyclopentane ring to the α-hydroxy group, the compound of formula (XVI) is extracted with ethyl acetate .

  
1 <EMI ID = 31.1>

  
When the product of formula (XVI) is a compound in which Q is a benzenes elenenyl radical, that is to say -Se [hundred], the solution of the product in ethyl acetate is then treated with 5 to 7 molar equivalents of oxy- water

  
 <EMI ID = 32.1>

  
sodium periodate in the presence of a lower alkanol, preferably methanol and water, at a temperature below 20 [deg.] C, preferably for about 24 hours, to form a compound of formula (XVII) in which 0 = Q- is benzeneseleninyl, i.e. -Se (0) 0, and stirring the reaction mixture at 25 [deg.] to 30 [deg.] C for one hour leads to the decomposition of the compound into a derivative of trans - &#65533; -prostaglandin of general formula (I), which can be separated from the reaction medium by methods known per se and purified by column chromatography on silica gel.

  
When the product of formula (XVI) is ur. compound in which Q is

  
 <EMI ID = 33.1>

  
as described above for a product of formula (XVI) in which Q is benzeneselenyl, to obtain a compound of general formula (XVII) in

  
 <EMI ID = 34.1>

  
which can be separated from the reaction medium by methods known per se.

  
When the compound of formula (XVII) is a compound in which Q

  
 <EMI ID = 35.1>

  
represents an alkylthio group -SR, in which R represents an alkyl group containing from 1 to 4 carbon atoms, this compound is dissolved in toluene and the solution is stirred, preferably in the presence of a small amount.

  
 <EMI ID = 36.1>

  
is a compound in which Q represents the phenylthio group, this compound is dissolved in carbon tetrachloride and the solution is stirred, preferably in the presence of a small amount of calcium carbonate, at a temperature of about 50 deg. ] C for 5 to 24 hours to decompose the product

  
 <EMI ID = 37.1>

  
of general formula (I) can be separated from the reaction medium by methods known per se and purified by column chromatography on silica gel.

  
The starting materials of general formula (XIII) used in the process of the present invention can be prepared from the corresponding acids of general formula:

  

 <EMI ID = 38.1>


  
(in which R <1>, R <2>, R4, X and Y are as defined above) by reaction with:
a) diazoalkanes, for example diazomethane; b) alcohols or thiols in the presence of dicyclohexylcarbodiimide as a condensing agent; or c) alcohols following the formation of a mixed anhydride by addition of a tertiary amine followed by a pivaloyl halide or an arylsulfonyl or alkylsulfonyl halide (see British Patents 1,362,956 and 1,364,125 of the Applicant).

  
Compounds of general formula can be prepared by reacting a bicyclo-octane derivative of general formula:

  

 <EMI ID = 39.1>


  
(in which R, R, R and X are as defined above) with a

  
 <EMI ID = 40.1>

  
which 0 is as defined above) to obtain a cyclopentane derivative of general formula:

  

 <EMI ID = 41.1>


  
 <EMI ID = 42.1>

  
general:

  

 <EMI ID = 43.1>


  
in which R, R, R and X are as defined above.

  
 <EMI ID = 44.1>

  
trans vinylene linkage, moderate reducing conditions must be used for this optional reduction step in order to reduce only the double bond at CS-C6 and not affect the double bond at X. It may be advantageous to carry out the reduction. by hydrogenation in the presence of a hydrogenation catalyst,

  
for example palladium on black, in the presence of an inert organic solvent, for example a lower alkanol, such as methanol or ethanol, at laboratory temperature, under normal pressure or higher pressure, for example under a hydrogen pressure ranging from atmospheric pressure to 15 kg / cm2. It is advantageous to monitor, during the reaction, the quantity of hydrogen which reacts, so that the hydrogenation can be stopped before a reduction of the trans vinylene chain X

  
in ethylene linkage occurs.

  
If, in general formula (XXI), X represents an ethylene link [X represents in general formula (XX) either a trans vinylene link or an ethylene link], it is then possible to use, for said optional reduction step , more stringent reducing conditions, especially if, in the general formula (XX), X represents a trans vinylene chain, for example hydrogenation in the presence of a hydrogenation catalyst usually used to hydrogenate double bonds ,:
such as different forms of platinum, palladium or nickel, in a suitable solvent (eg methanol, ethanol, water, dioxane

  
or acetic acid or a mixture of two or more of them), between

  
0 [deg.] And 50 [deg.] C and under normal pressure or higher pressure, for example under hydrogen pressure ranging from atmospheric pressure to
15 kg / cm2.

  
The reaction between the bicyclo-octanes of general formula (XIX) and the 4-carboxy n-butylidenetriphenylphosphorane (obtained by reaction of sodium dimethylsulfinate with 4-carboxy-n-butyltriphenylphosphbnium bromide) is carried out under the normal conditions used for carrying out the Wittig reaction, for example in an inert solvent, at room temperature. The reaction is preferably carried out in dimethylsulfoxide because the phosphoranic compound is practically insoluble in other solvents, for example tetrahydrofuran, and because it must stereospecifically form cis double bond in the Wittig reaction.

   In order for the Wittig reaction to be carried out under the best conditions, more than two molar equivalents of the phosphoranic compound are needed for each mole of bicyclo-octane reagent. The reaction is generally carried out at a temperature of 10 to 40 [deg.] C, and preferably at
20-30 [deg.] C, and is usually completed after about 30 minutes at

  
4 hours at laboratory temperature. The acidic product of formula (XX) can be extracted from the reaction mixture by conventional methods and further purified by column chromatography on silica gel.

  
The starting bicyclo-octane substances, of general formula
(XIX) in which X represents an ethylene link, can be prepared by the series of reactions shown schematically below:

  

 <EMI ID = 45.1>


  
 <EMI ID = 46.1>

  
The compounds of formula (XXII) are dissolved in a suitable solvent, for example methanol or ethanol, and then subjected to catalytic hydrogenation in the presence of a catalyst effective for the reduction of the double bond to an ethylene chain, by example of palladium on black, palladium black or platinum dioxide. The resulting compounds of formula (XXIII) are then reacted with a dihydropyran, a dihydrofuran or ethyl vinyl ether in an inert organic solvent, such as methylene chloride, in the presence of a condensing agent, for example p-toluenesulfonic acid, to obtain the compounds of formula (XXIV).

   These compounds are then reduced at low temperature, preferably below
-50 [deg.] C, using a reagent capable of reducing the oxo group, in position 3, to a hydroxy group, preferably using diisobutylaluminum hydride.

  
The starting bicyclo-octane substances, of general formula
(XIX) in which X represents a trans vinylene linkage, and those of general formula (XXII), can be prepared using initially the 2-oxa-3-oxo-formyl-6 syn-acetoxy-7 anti-bicyclo [3.3. 0] cis-octane (EJ Corey et al,

  
 <EMI ID = 47.1>

  
for example, J. Amer. Chem. Soc. 92, 397 (1970), J. Amer. Chem. Soc. 92, 2586

  
&#65533; 7 (1970), as well as French patent 72-15314 (publication no. 2,134,673) and British patent applications 19706/72 and 21919/73 of the applicant].

  
The lithiated amines of general formula (XIV) employed in the process of the invention, for example lithic diisopropylamine, as well as benzeneselenyl bromide and diphenyl diselenide, can be prepared by known methods, for example as described in J Bitter. Chem. Soc. 95, 6139 (1973).

  
 <EMI ID = 48.1>

  
obtained by the process of the present invention can be converted into trans -A 2 _prostaglandins F, E and A having the useful pharmacological properties typical of "natural" prostaglandins and their known derivatives, by the reactions shown schematically below:

  

 <EMI ID = 49.1>
 

  

 <EMI ID = 50.1>


  
in which the various symbols are as defined above.

  
The hydrolysis of the alkyl esters of general formula (I) into corresponding acids of general formula (XXV) can be carried out according to methods known per se, for example: (1) when Y represents an ethylene, by treatment of the ester in an inert organic solvent (such as tetrahydrofuran)

  
with an aqueous solution of sodium or potassium hydroxide or carbonate,

  
or (2) using baker's yeast [cf. C. J. Sih et al, J. Amer. Chem. Soc.

  
94, 3643 (1972)].

  
The tetrahydropyranyloxy, tetrahydrofuranyloxy and ethoxyethoxy (-OR) groups can be converted into hydroxy groups in the compounds of formulas

  
 <EMI ID = 51.1>

  
an aqueous solution of an organic acid, for example acetic acid, or

  
using a dilute mineral acid, for example dilute hydrochloric acid.

  
A water-miscible organic solvent, such as tetrahydrofuran or an alcohol, is advantageously employed, since the starting acids or esters having the aforementioned general formulas are practically insoluble in water. The treatment of the compounds of general formulas (XXV), (XXVII), (I) and (XXXI) can be carried out at a temperature ranging from room temperature to 60 [deg.] C (preferably, at a temperature below 45 [deg.] C) with an acid mixture such as a mixture of acetic acid, water and tetrahydrofuran or a mixture of hydrochloric acid with tetrahydrofuran or methanol.

  
We can transform into a PGE ring [cf. formulas (XXVII) and
(XXXI)] the alicyclic ring of PGF of compounds of general formula (XXV)

  
and (I), by methods known per se for the transformation of a hydroxy group in position 9 of a protaglandiae into an oxo group, for example by oxidation using a weak oxidizing agent such as solution of chromic acid
(obtained for example from chromium trioxide, manganese sulfate, sulfuric acid and water) or Jones reagent.

  
The PGE compounds of general formulas (XXVIII) and (XXXII) can be converted into corresponding PGA compounds by methods known per se,

  
for example by subjecting these PGEs to dehydration using an aqueous solution of an organic or mineral acid having a higher concentration

  
than that used for the hydrolysis of compounds of general formulas (XXV),
(XXVII), (I) and (XXXI), for example acetic acid or hydrochloric acid

  
 <EMI ID = 52.1>

  
The present invention relates to the preparation of all the compounds of general formula (I) in their "natural" form or in their enantiomeric form, or their mixtures, more particularly the racemic form consisting of equimolecular mixtures of the natural and enantiomeric forms.

  
As can be seen, the compounds represented by the general formula
(I) have at least five chiral centers, these centers being on the carbon atoms of the alicyclic ring designated by the numbers 8 and 12 and 9 and 11 as well as on the C 15 carbon atom to which a group is attached -OR in which R4 is as defined above. Other chiral centers may still appear in the branched chain alkyl groups shown.

  
 <EMI ID = 53.1> knows, to the existence of isomerism. However, the compounds of general formula (I) all have a configuration such that the side chains attached to the carbon atoms of the ring in the 8 and 12 positions are trans to each other and as shown, to namely, respectively of configuration a and

  
 <EMI ID = 54.1>

  
which have these side chains attached to ring carbon atoms at positions 8 and 12 in the trans configuration and have an -OR group, as shown, at position 15 are to be considered to be within the domain of general formula (I ). Those of these compounds in which Y represents a cis vinylene linkage are new compounds.

  
Trans compounds - &#65533; <2> _PGF, -PGE and -PGA of general formulas

  
 <EMI ID = 55.1>

  
means a cis vinylene linkage and the other symbols are as defined above, compounds which are encompassed by the general formula:

  

 <EMI ID = 56.1>


  
[in which A represents a group of formula:

  

 <EMI ID = 57.1>


  
 <EMI ID = 58.1>

  
an alkyl group containing from 1 to 12 carbon atoms, the double bonds in positions 2 and 5 being respectively of trans and cis configuration] are new compounds, and they and the cyclodextrin clathrates of these acids

  
 <EMI ID = 59.1>

  
non-toxic salts constitute another characteristic of the invention. It should be understood that all compounds of general formula (XXXI V) under their

  
 <EMI ID = 60.1> "natural" or enantiomeric form, or mixtures thereof, more particularly the racemic form consisting of equimolecular mixtures of the natural form and its enantiomer, should be considered as part

  
of the invention. As regards the isomers of general formula (XXXIV), reference is made to the explanations given previously concerning the isomers

  
 <EMI ID = 61.1>

  
Particularly interesting compounds are those of general formula (XXXIV), and those of general formulas (XXVI), (XXVIII), (XXIX),
(XXX), (XXXII) and (XXXIII) in which Y represents a cis vinylene chain

  

 <EMI ID = 62.1>


  
is of the general formula:

  

 <EMI ID = 63.1>


  
 <EMI ID = 64.1>

  
identical or different, each represents a hydrogen atom or a group

  
 <EMI ID = 65.1>

  
hydrogen and the carbon atom in position 15 bears a methyl group, or in which the carbon atoms in positions 15 and 16 each bear a methyl group, or a group of the general formula:

  

 <EMI ID = 66.1>


  
 <EMI ID = 67.1>

  
phenyl or cyclohexyl. Preferably, the symbol X, in the general formulas (XXXIV), (XXXVI) and (XXXVII), represents a trans vinylene linkage.

  
Compounds of exceptional importance are the new

  
 <EMI ID = 68.1>

  
7.

  
corresponding PGE and PGA2 compounds, as well as the methyl esters of all these prostaglandin derivatives F, E- and A2. It should be understood that in the above compounds the methyl, phenyl and cyclohexyl substituents may have the R or S configuration, or be a mixture of the R and S configurations, preferably a racemic mixture.

  
Prostaglandins of general formulas (XXVI), (XVIII) and
(XXIX), including those of the prostaglandins of general formula (XXXIV) in

  
 <EMI ID = 69.1>

  
salts or alkyl esters having from 1 to 12 carbon atoms in their

  
alkyl remains.

  
The salts can be prepared from the compounds of general formulas (XXVI), (XXVIII) and (XXIX) by methods known per se, for example

  
by reaction of stoichiometric quantities of acids of said general formulas and suitable bases, such as hydroxides or carbonates

  
of alkali metals, ammonium hydroxide, ammonia or an amine, in a suitable solvent. The salts can be isolated by concentration of the solution

  
or, if these salts are sufficiently insoluble in the reaction medium, by filtration, after removing part of the solvent if necessary. Preferably, the salts are non-toxic salts, that is to say salts whose cations are relatively harmless to the animal organism when used in therapeutic doses, so that the properties pharmacological benefits of prostaglandins of general formulas (XXVI), (XXVIII). and (XXIX) are not affected by side effects attributable to these cations. Preferably, the salts are soluble in water. Among the salts which are suitable, mention may be made of alkali metal salts, such as sodium and

  
potassium, and pharmaceutically acceptable (i.e. non-toxic) ammonium salts and amine salts. Amines which are suitable for forming such salts with carboxylic acids are well known and include,

  
for example, amines deriving, in theory, from the replacement of one or more hydrogen atoms of ammonia by groups (which may be the same or different. when more than one hydrogen atom is replaced) chosen for example among alkyl groups containing from 1 to 6 carbon atoms and hydroxyalkyl groups containing from 1 to 3 carbon atoms.

  
Alkyl esters of prostaglandins of general formulas
(XXVI), (XXVIII) and (XXIX) can be obtained by reacting acids with:

  
(1) diazoalkanes, such as diazomethane; (2) alcohols or thiols in the presence of dicyclohexylcarbodiimide as a condensing agent; or (3) alcohols following the formation of a mixed anhydride by addition of a tertiary amine followed by a pivaloyl halide or an arylsulfonyl or alkylsulfonyl halide (cf. UK Patents 1 362,956 and 1,364,125 of the applicant).

  
Prostaglandins of general formulas (XXVI), (XXVIII) and
(XXIX) can also be converted to prostaglandin alcohols, i.e. compounds in which the carboxy group is replaced by the hydroxymethylene group (i.e. -CH20H), according to the general formula:

  

 <EMI ID = 70.1>


  
 <EMI ID = 71.1>

  
trans alcohols - &#65533; -prostaglandins of general formula (XXXVIII) in which Y is a cis vinylene linkage are new compounds and, as such, constitute another characteristic of the invention.

  
The trans-A <2> _prostaglandin alcohols of general formula (XXXVIII) can be prepared from the corresponding acids by applying the method described by Pike, Lincoln and Schneider in J. Org. Chem. 34, 3552-3557
(1969), for example by transforming the acids of general formulas (XXVI),
(XXVIII) and (XXIX) in their methyl esters then these esters in omîmes, and

  
by reducing the oximes with lithium aluminum hydride to oximesalcohols and by hydrolyzing the latter, for example using acetic acid. The alcohols of PGF can also be obtained directly by reduction of the derivatives of PGF 'of general formula (XXVI) or of their methyl esters, using lithium aluminum hydride. Alcoholic derivatives of prostaglandins of general formula (XXXVIII) have pharmacological properties similar to those of acids of general formulas (XXVI), (XXVIII) and (XXIX) from which they are derived.

  
Prostaglandins of general formulas (XXVI), (XXVIII) and (XXIX) and their alkyl esters, as well as the corresponding alcohols of general formula (XXXVIII), can, if desired, be transfromated into clathrates

  
of cyclodextrin. These clathrates can be prepared by dissolving the cyclodextrin in water and / or in a water-miscible organic solvent and adding

  
to solution the prostaglandin derivative in an organic solvent miscible with water. The mixture is then heated and the cyclodextrin clathrate is isolated.

  
"&#65533;

  
resulting by concentration of the mixture under reduced pressure or by cooling followed by separation of the product by filtration or decantation. The amount of organic solvent relative to the amount of water can vary depending on the solubilities of the starting materials and the reaction products. Preferably, the temperature is not allowed to exceed 70 [deg.] C during the preparation of the products.

  
 <EMI ID = 72.1>

  
mixtures thereof, to prepare these clathrates. Conversion to their cyclodextrin clathrates serves to increase the stability of prostaglandin derivatives.

  
Prostaglandin derivatives of general formulas (XXVI),
(XXVIII) and (XXIX) obtained by the process of the present invention, the esters and alcohols derived therefrom and their cyclodextrin clathrates, as well as their non-toxic salts, have the useful pharmacological properties typical of prostaglandins, of a selectively, comprising, in particular, hypotensive activity, activity of inhibiting the aggregation of blood platelets, activity of inhibiting gastric acid secretion and gastric ulceration and bronchodilatory activity; they are useful in the treatment of hypertension, in the treatment of circulation disorders

  
 <EMI ID = 73.1>

  
of myocardial infarction, in the treatment of gastric ulceration and in the treatment of asthma. The compounds encompassed by the general formula

  
 <EMI ID = 74.1>

  
also have useful immunosuppressive properties.

  
The pharmacological properties of the specific derivatives of prostaglandins encompassed by the general formulas (XXVI), (XXVIII) and (XXIX) in which Y represents an ethylene link have already been described in the English patent application n [deg.] 60040/73 of the plaintiff. For example, in

  
 <EMI ID = 75.1> tes, of the blood pressure of a dog anesthetized with allobarbital, by

  
 <EMI ID = 76.1>

  
body weight of the animal, thus showing itself to be 9.5 times more powerful than

  
PGE1 in this regard; b) 50% inhibition of the aggregation of blood platelets caused by adenosine diphosphate in platelet-rich plasma of rabbits, <EMI ID = 77.1> c) increase in pH of gastric acid by 2, 0-2.5 to at least 4.0 in 50% of rats treated with pentagastrin, when administered by infu- <EMI ID = 78.1>

  
animal and per minute; d) 23.02% and 31.14% inhibitions of acute ulceration in rats [ulceration produced according to the method of Takagi and Okabe-Jap. J. Pharmac.
18, 9-18 (1968)] by oral administration at doses of, respectively, 2 and
10 pg per kg body weight of the animal, and e) inhibitions of 55.9% and 62.0%, by intravenous administration <EMI ID = 79.1>

  
animal, of the increase in resistance in the respiratory tract caused by administration of histamine to guinea pigs, determined by the method of Konzett and Rossler, Arch. exp. Path. Pharmak., 195, 71-74 (1940).

  
In addition, when intravenously administered trans-A -

  
 <EMI ID = 80.1>

  
per kg. body weight. of. In animals, these compounds respectively cause drops of 18 mmHg, 20 mmHg and 18 mmHg in blood pressure. The trans-

  
 <EMI ID = 81.1>

  
adenosine diphosphate in plasma of rats rich in platelets, and also in human blood; with rat blood, its activity is shown to be 2.95 times greater than that of PGE .. and, with human blood, 7.15 times greater.

  
As mentioned above, the prostaglandin derivatives of for-

  
 <EMI ID = 82.1>

  
 <EMI ID = 83.1>

  
believed to be of autoimmune origin e.g. psoriasis, lupus diseases of autoimmune origin e.g. lupus erythematosus, and acute systemic lupus erythematosus, rejection in skin grafts and transplants organs, multiple sclerosis, Crohn's disease (regional ileitis) and ulcerative colitis, glomerulonephritis and nephrotic syndrome of autoimmune origin, i.e. not associated with bacterial infection, atherosclerosis and malignant paraproteinemias of autoimmune origin characterized by abnormal immunoglobulins and abnormal immune cells of the reticuloendothelial system. For example, in laboratory screening tests indicative of immunosuppressive properties: <EMI ID = 84.1> <EMI ID = 85.1>

  
formation of human lymphocyte blasts stimulated by phytohemagglutinin,

  
 <EMI ID = 86.1> <EMI ID = 87.1>

  
The following reference examples illustrate the preparation

  
starting materials having the general formula employed in the process of

  
the present:, nvention. In all examples, "IR", "NMR" and "TLC" respectively represent "Infrared absorption spectrum", "Nuclear magnetic resonance spectrum" and "Thin layer chromatography".

  
REFERENCE EXAMPLE 1 -

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15d

  
methyl trans-oate prosten-13 -

  
1.31 g (2.5 millimoles) of hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15a prosten-13 trans-oic acid is dissolved in 40 ml of diethyl ether [prepared as described in J. Amer. Chem. Soc. 92, 2586 (1970)] and we add

  
to the solution a freshly prepared ethereal solution of diazomethane, so that the reaction mixture turns yellow. This mixture is concentrated under reduced pressure at low temperature and the residue is purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (2/5) as eluent. 1.08 g (80.3%) of the desired product is obtained, which has the following physical characteristics:

  
 <EMI ID = 88.1>

  
 <EMI ID = 89.1>

  
4.66 (2H, m), 3.60 (3H, s), 4.16-3.25 (7H, m).

  
TLC (developing solvent: cyclohexane / ethyl acetate = 2/1):

  
Rf = 0.36.

  
 <EMI ID = 90.1>

  
By operating in the same way as in Reference Example 1, the following compounds, (a) to (m), are obtained from the corresponding acids, general formula (XVIII).

  
In determining the physical characteristics of each of the compounds (a) to (m) below, the NMR spectrum was performed with a solution in deuterochloroform and the developing solvent for TLC was

  
 <EMI ID = 91.1>
(a) 9a-hydroxy bis (tetrahydropyranyloxy-2) -lla, 15a cis 5-prostadiene, 13 methyl trans-oate.

  
 <EMI ID = 92.1>

  
TLC: Rf = 0.39.

  
(c) 9a-hydroxy bis (2-tetrahydropyranyloxy) -lla, 15-methyl-15 cis-5-prostadiene, 13-methyl trans-oate.

  
 <EMI ID = 93.1>

  
 <EMI ID = 94.1>

  
TLC: Rf = 0.40.

  
(d) 9a hydroxy bis (tetrahydropyranyloxy-2) -lla, 15a methyl-16 (R) prosten-13 trans-methyl ester.

  
 <EMI ID = 95.1>

  
TLC: Rf = 0.36.

  
(e) 9a-hydroxy bis (tetrahydropyranyloxy-2) -lla, 15a methyl-16 (R) cis-5-prostadiene, 13-methyl trans-oate.

  
 <EMI ID = 96.1>

  
NMR: ô = 5.65-5.25 (4H, m), 4.67 (2H, m), 3.64 (3H, s), 4.22-3.30 (7H, m).

  
TLC; Rf = 0.37.

  
 <EMI ID = 97.1>

  
 <EMI ID = 98.1>

  
TLC: Rf = 0.37.

  
(h) 9a-hydroxy bis (2-tetrahydropyranyloxy) -11a, 15-dimethyl-15.16 methyl prosten-13 trans-oate.

  

 <EMI ID = 99.1>


  
 <EMI ID = 100.1>

  
5 cis prostadiene, 13 methyl trans-oate.

  

 <EMI ID = 101.1>


  
(j) 9-hydroxy bis (tetrahydropyranyloxy-2) -lla, 15 phenyl-16 w-trinorprosten-13 trans-methyl ester.

  

 <EMI ID = 102.1>


  
(k) 9a-hydroxy bis (2-tetrahydropyranyloxy) -11a, 15-phenyl-16 w-trinorprostadiene-5 cis, 13 methyl trans-oate.

  

 <EMI ID = 103.1>


  
 <EMI ID = 104.1>

  

 <EMI ID = 105.1>


  
 <EMI ID = 106.1>

  
cis-5-trinor-prostadiene, 13-methyl trans-oate.

  
_1

  

 <EMI ID = 107.1>


  
The examples which follow illustrate the process according to the invention and the products thus obtained. In each of Examples 1-14, the NMR spectrum was run with a deuterochloroform solution and the developing solvent for TLC was cyclohexane / ethyl acetate (2/1).

  
EXAMPLE 1

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -11a, 15a

  
prostadiene-2 trans, 13 trans-methyl oate -

  
836 mg of diphenyl diselenide was dissolved in 5 ml of tetrahydrofuran, 430 mg of bromine was added dropwise to the solution at room temperature, and the reaction mixture was stirred for 1 hour to obtain benzeneselenyl bromide.

  
On the other hand, a solution of 470 mg of diisopropylamine in 10 ml of tetrahydrofuran is cooled to -70 [deg.] C, 3.61 ml of a solution of n-butyllithium in hexane are added dropwise thereto. (molar concentration: 1.3) and stirred for 15 minutes at -70 [deg.] C; lithic diisopropylamine is obtained.

  
To the solution of lithic diisopropylamine is added dropwise 1.08 g of hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15a prostene-13 trans-methyl ester prepared as described in Reference Example 1) in 5 ml of tetrahydrofuran, at -70 [deg.] C, and the reaction mixture is stirred for 30 minutes at the same temperature. The solution of benzeneselenyl bromide prepared above is added dropwise to the reaction mixture, at -70 [deg.] C, and stirring is continued for 1 hour at the same temperature and then for 30 minutes at room temperature. The reaction mixture is poured into a small amount of a saturated aqueous solution of ammonium chloride, and extracted with
80 ml of ethyl acetate. The organic layer is washed with a small amount

  
 <EMI ID = 108.1>

  
sodium. While maintaining the temperature below 30 ° C., the resulting product is added to 1.4 ml of 30% hydrogen peroxide, dropwise, and the reaction mixture is stirred for 1 hour at 28 ° C. ]VS. This mixture is washed successively with water, with a saturated aqueous solution of sodium carbonate and with a saturated solution of sodium chloride, the washed mixture is dried over

  
anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel, using a cyclohexane / ethyl acetate (3/1) mixture as eluent; we obtain

  
643 mg (60%) of the desired compound, which has the following physical characteristics:

  

 <EMI ID = 109.1>
 

  
EXAMPLE 2

  
 <EMI ID = 110.1>

  
trans, 5 cis, 13 trans-methyl oate -

  
641 mg (60.0%) of this compound are obtained, by operating as described in Example 1, from 1.07 g of hydroxy-9a bis (tetrahydropyranyloxy-2) -

  
 <EMI ID = 111.1>

  
2 (a)] using diphenyl diselenide instead of benzeneselenyl bromide of Example 1. The compound obtained has the following physical characteristics:

  

 <EMI ID = 112.1>


  
EXAMPLE 3

  
Hydroxy-9a bis (tetrahydropyranyloxy-2), - 11a, 15

  
15-methyl-2-prostadiene trans, 13-methyl trans-oate

  
666 mg (60.5%) of this compound are obtained, by operating as described in Example 1, from 1.10 g of hydroxy-9a bis (tetrahydropyranyloxy-2) 11a, 15 methyl-15 prostene- 13 methyl trans-oate [cf. Reference example 2 (b)]. The compound obtained has the following physical characteristics:

  

 <EMI ID = 113.1>


  
EXAMPLE 4

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15 methyl-15 prostatriene-2 trans, 5 cis, 13 trans-methyl oate -

  
647 mg (59.0%) of this compound are obtained, by operating as described in Example 1, from 1.10 g of hydroxy-9a bis (tetrahydropyranyloxy-2) -

  
 <EMI ID = 114.1> 2 (c)] using diphenyl diselenide in place of the benzeneselenyl bromide of Example 1. The compound obtained has the following physical characteristics:

  

 <EMI ID = 115.1>


  
EXAMPLE 5

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15a methyl-16 (R) prostadiene-2 trans, 13 trans-methyl oate -

  
671 mg (61.0%) of this compound are obtained, by operating as described in Example 1, from 1.10 g of hydroxy-9a bis (tetrahydropyranyloxy-2) -
11a, 15a methyl-16 (R) prosten-13 methyl trans-oate [cf. Reference example 2 (d)]. The compound obtained has the following physical characteristics:

  

 <EMI ID = 116.1>


  
EXAMPLE 6

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15a methyl-16 (R) prostatriene-2 trans, 5 cis, 13 trans-methyl oate -

  
636 mg (58.0%) of this compound are obtained, by operating as described in Example 1, from 1.10 g of hydroxy-9a bis (tetrahydropyranyloxy-2) -

  
 <EMI ID = 117.1>

  
Reference 2 (e)] using diphenyl diselenide in place of benzeneselenyl bromide of Example 1. The compound obtained has the following physical characteristics:

  

 <EMI ID = 118.1>
 

  
EXAMPLE 7

  
 <EMI ID = 119.1>

  
prostadiene-2 trans, 13 trans-methyl oate -

  
652 mg (59.3%) of this compound are obtained, by operating as described in Example 1, from 1.10 g of hydroxy-9a bis (tetrahydropyranyloxy-2) -

  
 <EMI ID = 120.1>

  
2 F)]. The compound obtained has the following physical characteristics:

  

 <EMI ID = 121.1>


  
EXAMPLE 8

  
 <EMI ID = 122.1>

  
prostatriene-2 trans, 5 cis, 13 trans-methyl oate -

  
648 mg (59.1%) of this compound are obtained, by operating as described in Example 1, from 1.10 g of hydroxy-9a bis (tetrahydropyranyloxy-2) -

  
 <EMI ID = 123.1>

  
Reference 2 (g)] using diphenyl diselenide instead of benzeneselenyl bromide of Example 1. The compound obtained has the following physical characteristics:

  

 <EMI ID = 124.1>


  
EXAMPLE 9

  
 <EMI ID = 125.1> reference 2 (h)]. The compound obtained has the following physical characteristics:

  

 <EMI ID = 126.1>


  
EXAMPLE 10

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15-dimethyl-15,16 prostatriene-2 trans, 5 cis, 13 trans-methyl oate -

  
638 mg (56.8%) of this compound are obtained, by operating as described in Example 1, from 1.13 g of 9a-hydroxy bis (2-tetrahydropyranyloxy) -

  
 <EMI ID = 127.1>

  
Reference 2 (i)] using diphenyl diselenide in place of the benzene-selenenyl bromide of Example 1. The compound obtained has the characteristics

  
 <EMI ID = 128.1>

  

 <EMI ID = 129.1>


  
EXAMPLE 11

  
 <EMI ID = 130.1>

  
w-trinor-prostadiene-2 trans, 13 trans-methyl oate -

  
661 mg (58.0%) of this compound are obtained, by operating as described in Example 1, from 1.14 g of 9-hydroxy bis (2-tetrahydropyranyloxy)! La, 15-phenyl-16 w Methyl -trinor-prostene-13 trans-oate [cf. reference example 2 (j)]. The compound obtained has the following physical characteristics:

  
 <EMI ID = 131.1>
 <EMI ID = 132.1>
 EXAMPLE 12

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15 phenyl-16

  
 <EMI ID = 133.1>

  
648 mg (57.0:) of this compound are obtained, by operating as described in Example 1, from 1.14 g of 9a-hydroxy bis (2-tetrahydropyranyloxy) -

  
 <EMI ID = 134.1>

  
Reference 2 (k)] using diphenyl diselenerator instead of the benzeneselenyl bromide of Example 1. The compound obtained has the following physical characteristics:

  

 <EMI ID = 135.1>


  
EXAMPLE 13

  
 <EMI ID = 136.1>

  
 <EMI ID = 137.1>

  
in Example 1, from 1.16 g of 9a-hydroxy bis (2-tetrahydropyranyloxy) 11a, 15a cyclohexyl-16 w-trinor-prostene-13 trans-methyl oate [cf. example

  
reference 2 (1)]. The compound obtained has the following physical characteristics:

  
 <EMI ID = 138.1>
3.68 (3H, s), 4.10-3.20 (7H, m).

  
TLC: Rf = 0.40.

  
EXAMPLE 14

  
 <EMI ID = 139.1>

  
w-trinor-prostatriene-2 trans, 5 cis, 13 trans-methyl oate -

  
669 mg (58.3%) of this compound are obtained, by operating as described in Example 1, from 1.15 g of hydroxy-9a bis (tetrahydropyranyloxy-2) 11a, 15a cyclohexyl-16 w- 5 cis trinor-prostadiene, 13 methyl trans-oate <EMI ID = 140.1>

  
instead of the benzeneselenyl bromide of Example 1. The compound obtained has the following physical characteristics:

  

 <EMI ID = 141.1>


  
By operating as described in the UK patent application

  
 <EMI ID = 142.1>

  
 <EMI ID = 143.1>

  
were transformed into corresponding novel derivatives of trans - 2-prostaglandins as described in Examples 15 to 20 which follow.

  
EXAMPLE 15

  
Ester than trans-A <2> -PGF2a

  
 <EMI ID = 144.1>

  
prostatriene-2 trans, 5 cis, 13 trans-methyl oate (prepared as described in Example 2) in 40 ml of a mixture of IN hydrochloric acid and tetrahydrofuran (1/1), stirred for 1 hour at room temperature, pour

  
in 100 ml of a mixture of ice and water and extracted with acetate

  
ethyl. The combined extracts are washed with water, dried and concentrated under reduced pressure. The residue is purified by column chromatography.

  
on silica gel using a mixture of ethyl acetate and cyclohexane

  
 <EMI ID = 145.1>

  
following physical damage:

  
')
 <EMI ID = 146.1>
 TLC (developing solvent: chloroform / tetrahydrofuran / acetic acid = 10/2/1): Rf = 0.13.

EXAMPLE 16

  
By operating as described in Example 15, the compounds below, (a) to (f), were obtained from the products synthesized in Examples 4, 6, 8, 10, 12 and 14 respectively.

  
In determining the physical characteristics of each

  
 <EMI ID = 147.1>

  
The formulation in deuterochloroform and the developing solvent for TLC was chloroform / tetrahydrofuran / acetic acid (10/2/1).

  
 <EMI ID = 148.1>

  

 <EMI ID = 149.1>
 

  

 <EMI ID = 150.1>


  
EXAMPLE 17

  
 <EMI ID = 151.1>

  
260 mg of hydroxy-9a bis (tetrahydropyranyloxy-2) 11a, 15a prostatriene-2 trans, 5 cis, 13 trans-methyl ester (prepared as described in Example 2) are dissolved in 10 ml of diethyl ether and it is cooled in an ice bath. To the cooled solution is added a solution of 1.7 g of manganese sulfate, 0.34 g of chromium trioxide and 0.38 ml of concentrated sulfuric acid in 8 ml of water and the mixture is stirred for 2 hours. between 0 [deg.] and 5 [deg.] C. 200 ml are added

  
 <EMI ID = 152.1>

  
aqueous with sodium sulfate and extracted with diethyl ether. The combined ethereal extracts are washed with water, dried and concentrated. The residue is purified by column chromatography on silica gel using a mixture of ethyl acetate and benzene (1/6) as eluent; we

  
 <EMI ID = 153.1>

  
13 methyl trans-oate.

  
The bis (tetrahydropyranyl) ether is dissolved in a mixture of

  
4 ml of acetic acid, 2.4 ml of water and 0.5 ml of tetrahydrofuran and stirred

  
 <EMI ID = 154.1>

  
and water and the resulting mixture is extracted with ethyl acetate. The extracts are washed with water, dried and concentrated under reduced pressure.

  
The residue is purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1/2) as eluent; 80 mg of the desired compound are obtained, which has the following physical characteristics:

  

 <EMI ID = 155.1>


  
TLC (developing solvent: chloroform / tetrahydrofuran / acetic acid =

  
10/2/1): Rf = 0.29.

  
EXAMPLE 18

  
By operating as described in Example 17, the compounds were obtained.

  
 <EMI ID = 156.1>

  
4, 6, 8, 10, 12 and 14 respectively.

  
In determining the physical characteristics of each of the compounds (a) to (f) below, the NMR spectrum was performed with a solution in deuterochloroform and the developing solvent for TLC was a mixture of chloroform / tetrahydrofuran / acid. acetic (10/2/1).

  
 <EMI ID = 157.1>
 <EMI ID = 158.1>
  <EMI ID = 159.1>

  
NMR: 6 = 7.26 (5H, m), 7.01 (1H, dt), 5.83 (1H, dt), 5.57-5.33 (4H, m),

  
4.10-3.80 (2H, m), 3.72 (3H, s), 1.15 (3H, d).

  
TLC: Rf = 0.33.

  
 <EMI ID = 160.1>

  

 <EMI ID = 161.1>


  
EXAMPLE 19

  
 <EMI ID = 162.1>

  
as described in Example 17) in 15 ml of 90% acetic acid and

  
stir the solution for 17 hours at 57-60 [deg.] C. The reaction mixture is then concentrated under reduced pressure. The residue is dissolved in diethyl ether, washed with water, dried and concentrated under reduced pressure. The new residue is purified by column chromatography on silica gel using

  
a mixture of cyclohexane and ethyl acetate (4/1) as eluent; we obtain
106 mg of the desired compound, which has the following physical characteristics:

  
IR (liquid film): 3430, 2920, 2850, 1718, 1650, 1590, 1430, 1280,

  
 <EMI ID = 163.1>

  
3.72 (3H, s), 3.22 (1H, m), 2.98 (2H, t), 0.89 (3H, t).

  
TLC (developing solvent: chloroform / tetrahydrofuran / acid

  
acetic = 20/2/1): Rf = 0.72.

  
EXAMPLE 20

  
The following compounds, (a) to (f), were obtained by operating as described in Example 19, from the corresponding products synthesized in Example 18, (a) to (f) respectively.

  
^ 7 In determining the physical characteristics of each of the compounds (a) to (f) below, the NMR spectrum was run with a solution in deuterochloroform and the developing solvent for TLC was a

  
 <EMI ID = 164.1>
 <EMI ID = 165.1>
 
 <EMI ID = 166.1>
 EXAMPLE 21

  
 <EMI ID = 167.1>

  
trans, 13 trans-methyl oate -

  
Cooled to -70 [deg.] C 242 mg of diisopropylamine in 7 ml of tetrahydrofuran, 240 ml of a solution of n-butyllithium in n-hexane (monomolar concentration) are added dropwise thereto and the mixture is stirred. for 15 minutes at -70 [deg.] C to form lithic diisopropylamine. At
- reaction mixture is added dropwise, slowly, 537 mg of hydroxy-9a <EMI ID = 168.1>

  
as described in Reference Example 1) in 6 ml of tetrahydrofuran

  
and the mixture is stirred at the same temperature for 30 minutes. While maintaining the temperature at -70 [deg.] C, the reaction mixture is slowly added dropwise to a cooled solution of 260 mg of dimechyl disulfide in

  
2 ml of tetrahydrofuran, then stirred for 30 minutes at the same temperature

  
 <EMI ID = 169.1>

  
nel in a small amount of a saturated aqueous solution of ammonium chloride, and extracted three times with ethyl acetate. We wash the extracts

  
 <EMI ID = 170.1>

  
of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3/1) as eluent; 356 mg of pure methyl 2-hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15a prosten-13 trans-oate are obtained, having the following physical characteristics:

  

 <EMI ID = 171.1>
 

  
 <EMI ID = 172.1>

  
a solution of 321 mg of sodium periodate in 3 ml of water is added and the mixture is stirred at 20 ° C. for 24 hours. The precipitated colorless solid is filtered off and the filtrate is concentrated under reduced pressure. The residue is dissolved in chloroform, washed with water and with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The new residue is purified by column chromatography on silica gel using a mixture of benzene and ethanol (95/5) as eluent; 246 mg of 2-methylsulfoxy 9a-hydroxy are obtained

  
 <EMI ID = 173.1>

  
the following physical characteristics:

  

 <EMI ID = 174.1>


  
 <EMI ID = 175.1>

  
(2H, m), 3.79 (3H, d), 4.20-3.30 (8H, m), 2.61 (3H, d).

TLC (developing solvent: benzene / ethanol = 90/10): Rf = 0.44.

  
To a solution of 100 mg of the sulfoxide obtained in 10 ml of toluene is added 100 mg of calcium carbonate, the mixture is stirred at 110 [deg.] C for
24 hours, after which the calcium carbonate is separated by filtration. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3/1) known as eluent; 70 mg of the desired compound are obtained, which has the following physical characteristics:

  

 <EMI ID = 176.1>


  
 <EMI ID = 177.1>

  
4.07-3.30 (7H, m).

  
TLC (developing solvent: cyclohexane / ethyl acetate = 2/1):

  
Rf = 0.35.

  
In the examples which follow, the compounds (II), (III) and (IV) are used as intermediates for preparing the desired compound, without isolating them.

  
EXAMPLE 22

  
 <EMI ID = 178.1>

  
trans, 5 cis, 13 trans-methyl oate -

  
1

  
Cooled to -70 [deg.] C 242 mg of diisopropylamine in 7 ml of tetra-

  
t

  
 <EMI ID = 179.1> <EMI ID = 180.1>

  
hydrofuran, 240 ml of a solution of n-butyllithium in n-hexane (monomolar concentration) are added dropwise and the mixture is stirred for

  
15 minutes at -70 [deg.] C to form lithic diisopropylamine. To the reaction mixture is slowly added, dropwise, 536 mg of 9a-hydroxy bis (2-tetrahydropyranyloxy) -lla, 15ct 5-prostadiene cis, 13 methyl trans-oate [cf. example

  
Reference 2 (a)] in 6 ml of tetrahydrofuran and the mixture is stirred at the same temperature for 30 minutes. While maintaining the temperature at -70 [deg.] C, the reaction mixture is slowly added dropwise to a cooled solution of 260 mg of dimethyl disulfide in 2 ml of tetrahydrofuran.

  
and stirred for 30 minutes at the same temperature and then for another 30 minutes at 15 [deg.] C. The reaction mixture is then poured into a small amount of a saturated aqueous solution of ammonium chloride, and extracted three times with ethyl acetate. The organic extracts are washed with acid

  
 <EMI ID = 181.1>

  
it is dried over magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in 25 ml of methanol, a solution of 392 mg of sodium periodate in 4 ml of water is added and the mixture is stirred at 20 [deg.] C for

  
24 hours. The precipitated colorless solid is filtered off and the filtrate is concentrated under reduced pressure. The new residue is dissolved in chloroform, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure.

  
246 mg are added to the new residue dissolved in 25 ml of toluene.

  
of calcium carbonate, the mixture is stirred at 110 [deg.] C for 24 hours and the calcium carbonate is filtered off. The filtrate is concentrated under

  
 <EMI ID = 182.1>. On silica gel using a mixture of cyclohexane and ethyl acetate (3/1) as eluent; 172 mg of the desired compound are obtained, which has the following physical characteristics:
 <EMI ID = 183.1>
 EXAMPLE 23

  
 <EMI ID = 184.1>

  
By operating as described in Example 22, 177 mg of the desired compound were obtained from 552 mg of 9a-hydroxy bis (2-tetrahydropyranyloxy) -

  
 <EMI ID = 185.1>

  
2 (b)].

  

 <EMI ID = 186.1>


  
In each of the following Examples 24-34, the NMR spectrum was run with a deuterochloroform solution and the developing solvent for TLC was cyclohexane / ethyl acetate (2/1).

  
EXAMPLE 24

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15 methyl-15 prostatriene-2 trans, 5 cis, 13 trans-methyl oate -

  
By operating as described in Example 22, 170 mg of the desired compound was obtained from 550 mg of hydroxy-9a bis (tetrahydropyranyloxy-2) -lla,
15 cis-5-methyl-15-prostadiene, 13-methyl trans-oate [cf. Reference example 2 (c)].

  

 <EMI ID = 187.1>


  
EXAMPLE 25

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15a methyl-16 (R) prostadiene-2 trans, 13 trans-methyl oate -

  
By operating as described in Example 22, 180 mg of

  
7 compound sought from 552 mg of hydroxy-9a bis (tetrahydropyranyloxy-2) -lla,
15a methyl-16 (R) prosten-13 trans-methyl oate [cf. Reference example 2 (d)].

  

 <EMI ID = 188.1>


  
EXAMPLE 26

Hydroxy-9a bis (tetrahydropyranyloxy-2) -11a, 15a methyl-16 (R) prostatriene-2 trans, 5 cis, 13 trans-methyl oate -

  
By operating as described in Example 22, 173 mg of the desired compound was obtained from 550 mg of hydroxy-9a bis (tetrahydropyranyloxy-2) 11a, 15a methyl-16 (R) prostadiene-5 cis, 13 trans -methyl oate [cf. reference example 2 (e)].

  

 <EMI ID = 189.1>


  
EXAMPLE 27

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15 methyl-17 prostadiene-2 trans, 13 trans-methyl oate -

  
By operating as described in Example 22, 179 mg of the desired compound was obtained from 552 mg of hydroxy-9a bis (tetrahydropyranyloxy-2) -lla,

  
 <EMI ID = 190.1>

  

 <EMI ID = 191.1>
 

  
EXAMPLE 28

  
 <EMI ID = 192.1>

  
prostatriene-2 trans, 5 cis, 13 trans-methyl oate -

  
By operating as described in Example 22, 167 mg of the desired compound were obtained from 550 mg of hydroxy-9a bis (tetrahydropyranyloxy-2) -

  
 <EMI ID = 193.1>

  
reference 2 (g)].

  

 <EMI ID = 194.1>


  
EXAMPLE 29

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15-dimethyl-15.16 trans 2-prostadiene, 13 methyl trans-oate -

  
By operating as described in Example 22, 183 mg of the desired compound were obtained from 566 mg of hydroxy-9a bis (tetrahydropyranyloxy-2) 11a, 15-dimethyl-15,16 prosten-13 trans-methyl ester. [cf. reference example 2 (h)].

  

 <EMI ID = 195.1>


  
EXAMPLE 30

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15-dimethyl-15,16 prostatriene-2 trans, 5 cis, 13 trans-methyl oate -

  
By operating as described in Example 22, 180 mg of the desired compound were obtained from 564 mg of 9a-hydroxy bis (2-tetrahydropyranyloxy) -

  
 <EMI ID = 196.1>

  
reference 2 (i)].

  
1
 <EMI ID = 197.1>
 EXAMPLE 31

  
 <EMI ID = 198.1>

  
w-trinor-prostadiene-2 trans, 13 trans-methyl oate -

  
By operating as described in Example 22, 185 mg of the desired product was obtained from 572 mg of hydroxy-9a bis (tetrahydropyranyloxy-2) -

  
 <EMI ID = 199.1>

  
reference 2 (j)].

  

 <EMI ID = 200.1>


  
EXAMPLE 32

  
 <EMI ID = 201.1>

  
By operating as described in Example 22, 179 mg of the desired compound were obtained from 570 mg of hydroxy-9a bis (tetrahydropyranyloxy-2) 11a, 15 phenyl-16 w-trinor-prostadiene-5 cis, 13 methyl trans-oate [cf. example

  
 <EMI ID = 202.1>

  

 <EMI ID = 203.1>


  
EXAMPLE 33

  
 <EMI ID = 204.1>

  
w-trinor-prostadiene-2 trans, 13 trans-methyl oate -

  
By operating as described in Example 22, 187 mg of the desired compound were obtained from 578 mg of hydroxy-9a bis (tetrahydropyranyloxy-2) 11a, 15a cyclohexyl-16 w-trinor-prostene-13 trans-oate methyl [cf. reference example 2 (1) 3.

  

 <EMI ID = 205.1>


  
EXAMPLE 34

  
Hydroxy-9a bis (tetrahydropyranyloxy-2) -lla, 15a cyclohexyl-16

  
 <EMI ID = 206.1>

  
By operating as described in Example 22, 182 mg of the desired compound was obtained from 576 mg of 9a-hydroxy (2-tetrahydropyranyloxy) -

  
 <EMI ID = 207.1>

  
[cf. reference example 2 (m)].

  

 <EMI ID = 208.1>


  
By operating as described in the UK patent application
60040/73 of the Applicant, the products of Examples 21, 25 were transformed

  
 <EMI ID = 209.1>

  
Also, by operating as described in the aforementioned patent application, the products of Examples 23, 29, 31 and 33 were transformed into methyl-15 trans - &#65533; 2-

  
 <EMI ID = 210.1> <EMI ID = 211.1>

  
languishes.

  
In the foregoing examples and in the compounds mentioned in the claims, when the configuration of a radical or a group is not specified, it should be understood that in the case of tetrahydropyranyloxy groups and hydroxy groups obtained from from these tetra- groups

  
 <EMI ID = 212.1>

  
a and P, or, in the case of methyl radicals or of phenyl or cyclohexyl radicals, the configuration is R or S or a mixture of the R and S configurations.

  
... / <EMI ID = 213.1>

  
 <EMI ID = 214.1>

  
tablets, pills, dispersible powders and granules. In

  
 <EMI ID = 215.1>. also include, as is common practice, additional substances other than inert diluents, for example lubricating agents such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, containing inert diluents commonly used in pharmacy, such as water and liquid paraffin. In addition to inert diluents, these compositions can also include adjuvants, such as wetting and suspending agents, sweetening agents, flavoring agents, perfumes and preservatives.

   The compositions according to the invention for oral administration also comprise capsules of absorbable substance, such as gelatin, containing one or more of the active substances with or without addition of diluents or excipients.

  
Solid compositions for vaginal administration include pessaries prepared in a manner known per se and containing one or more of the active compounds.

  
Solid compositions for rectal administration include the prepared suppositories. in a known manner. per se and containing one or more of the active compounds.

  
The preparations according to the invention for parenteral administration include sterile aqueous solutions, suspensions or emulsions

  
or non-aqueous. As solvents or non-aqueous suspension media, mention may be made of propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions can also include adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. These compositions can be sterilized, for example by filtration through a filter retaining bacteria, by incorporation of sterilizing agents or

  
by irradiation. They can also be manufactured in the form of sterile solid compositions, which can be dissolved extemporaneously in sterile water or other sterile injectable medium.

  
The percentage of active ingredient in the compositions according to the invention is variable, but it is necessary that it represents a proportion such that a dose suitable for the desired therapeutic effect is obtained. Of course, several unit dosage forms can be administered at approximately the same time. In general, preparations should normally contain at least 0.025% by weight of active substance when they are to be administered by injection; for oral administration, the preparations will normally contain at least 0.1% by weight of active substance. The dose employed depends on the desired therapeutic effect, the route of administration and the duration of treatment.

  
For adults, doses are usually between 0.01

  
and 5 mg per kg body weight when administered orally for milking

  
 <EMI ID = 216.1>

  
 <EMI ID = 217.1>

  
of body weight in aerosol administration for the treatment of asthma, between 0.01 and 5 mg per kg of body weight in oral administration for the treatment of peripheral circulation disorders, and between 0.01 and 5 mg per kg body weight in oral administration for prevention and treatment

  
cerebral thrombosis and myocardial infarction, and, with regard to

  
 <EMI ID = 218.1>

  
feels a hydrogen atom, their non-toxic salts, between 0.1 and 100 mg per day in oral administration for the treatment of autoimmune conditions.

  
The prostaglandin derivatives in accordance with the present invention can be administered orally as bronchodilators by any method known per se for the administration by inhalation of medicaments which are not themselves gaseous under normal conditions of administration. Thus, a solution of the active ingredient in a suitable, pharmaceutically acceptable solvent, for example water, can be nebulized by a mechanical nebulizer, for example a Wright nebulizer, giving an aerosol of finely divided liquid particles, suitable for use. inhalation. It is advantageous if the solution to be nebulized is diluted, and aqueous solutions containing 0.001 to 5 mg, preferably 0.01 to 0.5 mg, of active ingredient per ml of solution are particularly suitable.

   The solution may contain stabilizers, such as sodium bisulfite, and buffer substances which give it an isotonic character, for example sodium chloride, sodium citrate and citric acid.

  
 <EMI ID = 219.1>

  
by inhalation in the form of aerosols obtained from self-propelling pharmaceutical compositions. Compositions suitable for this purpose can be obtained by dissolving or suspending in finely divided form, preferably micronized to an average particle size of less than 5 microns, the active ingredients in pharmaceutically acceptable solvents, e.g. 'ethanol, which are co-solvents helping to

  
dissolving the active ingredients in the volatile liquid propellants described below, or in pharmaceutically acceptable suspending or dispersing agents, for example aliphatic alcohols such as oleic alcohol, and incorporating the solutions or suspensions obtained in Pharmaceutically acceptable volatile liquid propellants, in conventional pressurized packages which can be made of any suitable material, for example metal, plastic or glass, able to withstand the pressures generated by the volatile propellant in the package. Pharmaceutically acceptable pressurized gases, such as nitrogen, can also be used as propellants. The pressurized package is preferably provided with a metering valve which delivers a measured amount of the self-propellant aerosol, as a unit dose.

  
Suitable volatile liquid propellants are known in the art and include fluoro-chlorinated alkanes containing 1 to 4 atoms.

  
carbon, and preferably 1 or 2, for example dichlorodifluoromethane,

  
dichlorotetrafluoroethane, trichloromonofluoromethane, dichloromonofluoromethane and monochlorotrifluoromethane. Preferably the vapor pressure of the volatile liquid propellant is between 1.75 and 4.6 kg / cm2,

  
and more particularly between 2 and 4 kg / cm2, at 21 [deg.] C. As is well known, volatile liquid propellants of different vapor pressures can be mixed in varying proportions to produce a propellant having a vapor pressure suitable for the production of a satisfactory aerosol, and suitable for the container chosen. For example, dichlorodifluoromethane (vapor pressure 5.98 kg / cm2 at 21 [deg.] C) and dichlorotetrafluoroethane (vapor pressure

  
of steam 1.97 kg / cm2 at 21 [deg.] C) can be mixed in varying proportions to produce propellants with intermediate vapor pressures

  
between those of these two constituents; thus, a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane in the respective weight proportions

  
 <EMI ID = 220.1>

  
Self-propelling pharmaceutical compositions can be prepared

  
by dissolving the required amount of active ingredient in the co-solvent or by combining the required amount of active ingredient with a specified amount of suspending or dispersing agent. A determined quantity of this composition is then placed in an open container intended to be used as pressurized packaging. The container and its contents are then cooled below the boiling point of the volatile propellant to be used. The required amount of liquid propellant, cooled below its boiling point, is then added and the contents of the vessel mixed. We then close the latter with

  
valve device required, without allowing the temperature to rise above the boiling point of the propellant. Then the temperature of the closed container is allowed to rise to room temperature while shaking it to ensure the complete homogeneity of its contents and to obtain a pressurized package suitable for the production of aerosols for inhalation. Alternatively, one can place in the open container the solution of the active ingredient in the cosolvent or the combination of the active ingredient and the suspending or dispersing agent, close the container with a valve, and introduce under pressure

  
the liquid propellant.

  
Means for producing self-propelling aerosol generation compositions for drug delivery are, for example, described in detail in US Patents 2,868,691 and 3,095,355.

  
Preferably self-propelling pharmaceutical compositions

  
according to the present invention contain 0.001 to 5 mg, and more particularly-

  
 <EMI ID = 221.1>

  
It is important that the pH of the solutions or suspensions used, in accordance with the present invention, to give rise to aerosols is maintained in the range of 3 to 8 and it is preferable that these are stored at a temperature not exceeding 4 [deg.] C, in order to avoid the loss of pharmacological activity of the active ingredient.

  
For the execution of the present invention, the means of producing an aerosol for inhalation should be chosen according to the physicochemical properties of the active ingredient.

  
By the term "pharmaceutically acceptable" applied in the present description to solvents, suspending or dispersing agents, liquid propellants and gases, is meant solvents, suspending or dispersing agents, liquid propellants and gases which are not toxic when used. uses them in aerosols suitable for inhalation therapy.

  
 <EMI ID = 222.1>

  
 <EMI ID = 223.1>

  
particulates of less than about 10 microns and preferably less than 5 microns, for example between 0.5 and 3 microns, to ensure distribution

  
 <EMI ID = 224.1>

  
done by means of devices allowing the administration of determined quantities of the active ingredients, for example by means of the metering valves mentioned above.

  
The following examples illustrate pharmaceutical compositions according to the invention.

  
EXAMPLE 35

  
 <EMI ID = 225.1>

  
thanol (1 ml) and the resulting solution is added to 12 ml of an aqueous solution containing sodium carbonate (50 mg). An aqueous solution of sodium chloride (2 ml, at 0.9% weight / volume) is then added so as to have a final volume of 15 ml. The solution is then sterilized by passing it through a filter retaining the bacteria and it is introduced in portions of 1.5 ml in ampoules.

  
 <EMI ID = 226.1>

  
its sodium salt) per ampoule. The contents of the ampoules are freeze-dried and they are sealed. If the contents of an ampoule are dissolved in a suitable volume, for example 2 ml, of sterile water or physiological saline, a solution ready for administration by injection is obtained.

  
EXAMPLE 36

  
 <EMI ID = 227.1>

  
ethanol (10 ml), the solution is mixed with mannitol (18.5 g),

  
passed through a 30 mesh sieve (British standard), dried at 30 [deg.] C

  
for 90 minutes and again passed through a 30 mesh sieve (British standard). Aerosil (microfine silica; 200 mg) is added and the powder obtained is introduced, by machine, into one hundred hard gelatin capsules n [deg.] 2 of

  
 <EMI ID = 228.1>

  
 <EMI ID = 229.1>


    

Claims (1)

1. Process for the preparation of trans - &#65533; -prostaglandins of the general formula: <EMI ID = 230.1> (where R represents an alkyl group containing 1 to 10 atoms of <EMI ID = 231.1> a phenyl or cycloalkyl substituent having 5 to 7 carbon atoms, R represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, R represents an alkyl group containing 1 to 12 carbon atoms <EMI ID = 232.1> ethyl, X represents an ethylene or trans vinylene linkage and Y represents an ethylene or vinylene link (cis), characterized in that a compound of general formula is reacted: <EMI ID = 233.1> (in which R, R, R, R, X and Y are as defined above) with a compound of general formula: <EMI ID = 234.1> <EMI ID = 235.1> carbon atoms or a cycloalkyl group containing 3 to 6 carbon atoms) <EMI ID = 236.1> <EMI ID = 237.1> (in which R, R, R, R, X and Y are as defined above), this lithium esterenolate is reacted with benzeneselenyl bromide or diphenyl diselenide or a dialkyl or diphenyl disulphide of formula R SSR (wherein the symbols R represent either alkyl groups containing 1 to 4 carbon atoms or phenyl radicals), the resulting intermediate is hydrolyzed to convert the -OLi group attached to the cyclopentane ring to hydroxy group a and to obtain a compound of general formula: <EMI ID = 238.1> (in which R, R, R, R, X and Y are as defined above and Q re- <EMI ID = 239.1> being as defined above), the resulting compound is treated with hydrogen peroxide or sodium periodate and the resulting compound, of general formula: <EMI ID = 240.1> (in which R, R, R, R, X, Y and Q are as defined above), to transform the group: <EMI ID = 241.1> <EMI ID = 242.1> 2. Method according to claim 1, characterized in that the reaction between the compound of formula (XIII) and the compound of formula (XIV) is carried out in an organic solvent, more particularly tetrahydrofuran, and more particularly at a low temperature, of the order of -70 [deg.] C, the ratio of the molar equivalents of the compound of formula (XIII) to those of the compound of formula (XIV) in the reaction mixture being from 1/2 to 3. 3. Method according to claim 1 or 2, characterized in that the reaction between lithium esterenolate and benzeneselenyl bromide, diphenyl diselenide or dialkyl or diphenyl disulphide is carried out in an organic solvent. chosen from tetrahydrofuran, diethyl ether, hexane, pentane and mixtures of two or more of them, more particularly at a low temperature, of the order of -70 [deg.] C. 4. Method according to claim 3, characterized in that reacting with each molar equivalent of lithium estenolate, 3 or 4 molar equivalents of benzeneselenyl bromide or of diphenyl diselenide or else 2 or 3 molar equivalents of disnlfure dialkyl or diphenyl. 5. Method according to any one of claims 1 to 4, characterized in that one treats with a saturated aqueous solution of ammonium chloride the mixture resulting from the reaction of lithium esterenolate with benzeneselenyl bromide or diphenyl diselenide, the intermediate product resulting from this reaction is extracted with ethyl acetate, then the solution of this product in ethyl acetate is treated with 5 to 7 molar equivalents of hydrogen peroxide, at a temperature below 30 [deg.] C, or by 5 molar equivalents of sodium periodate in the presence of a lower alkanol, at a temperature below 20 [deg.] C, and the reaction mixture is stirred at a temperature of 25 at 30 [deg.] C <EMI ID = 243.1> 6. Method according to any one of claims 1 to 4, characterized in that one treats with a saturated aqueous solution of ammonium chloride the mixture resulting from the reaction of lithium esterenolate with the disulfurp of dialkyl or of diphenyl, the intermediate product is extracted resulting from this reaction with ethyl acetate, then, after separation of this intermediate product of its solution in ethyl acetate, the said intermediate product is treated with 5 to 7 molar equivalents of hydrogen peroxide, at a temperature below 30 [deg.] C &#65533; or with 5 molar equivalents of sodium periodate in the presence of a lower alkanol, at a temperature below 20 [deg.] C, the reaction mixture is stirred at a temperature of 25 to 30 [deg.] C to produce a compound of the general formula (XVII), after which, when Q, in this form <EMI ID = 244.1> <EMI ID = 245.1> spleen (XVII) in toluene and the solution is stirred, preferably in the presence of a small amount of calcium carbonate, at a temperature of 100 to 1200C, or, when Q, in formula (XVII), represents a phenylthio group, the compound of general formula (XVII) is dissolved in carbon tetrachloride and the solution is stirred, preferably in the presence of a small amount of calcium carbonate, at a temperature of about 50 [deg.] C, to produce a <EMI ID = 246.1> 8. Method according to any one of claims 1 to 6, followed by the transformation step (s), by methods known per se, of a <EMI ID = 247.1> <EMI ID = 248.1> R, R, X and Y are as defined in claim 1 and R represents a hydrogen atom or an alkyl group containing from 1 to 12 carbon atoms, the double bond in position 2 being in the trans configuration), or, then <EMI ID = 249.1> <EMI ID = 250.1> (wherein R <1>, R <2> and X are as defined in claim 1 and A and R <3> 'are as defined in claim 8, the double bonds in positions 2 and 5 being respectively in trans and cis configurations) and their cyclodextrin clathrates, and the non-toxic salts of these <EMI ID = 251.1> PGA2, their alkyl esters, the esterified alkyl residue of which contains from 1 to 12 carbon atoms, their non-toxic salts, their cyclodextrin clathrates and the alkyl esters of these cyclodextrin clathrates, the esterified alkyl residue of which contains from 1 to 12 carbon atoms. <EMI ID = 252.1> <EMI ID = 253.1> general: <EMI ID = 254.1> (wherein R <1>, R <2> and X are as defined in claim 1 and A is as defined in claim 8, the double bonds in positions 2 and 5 being in trans and cis configurations, respectively) and their cyclodextrin clathrates. 12. Pharmaceutical compositions comprising, as an ingredient <EMI ID = 255.1> non-toxic, of its cyclodextrin clathrates or of their esters, as specified in claim 9 or 10, in association with a pharmaceutical carrier or coating. 13. Pharmaceutical compositions comprising, as an ingredient <EMI ID = 256.1> of cyclodextrin, as specified in claim 11, in association with a pharmaceutical carrier or coating.