IE43453B1 - New 15-(1,3-benzodioxan-2-yl)-16,17,18,19,20-pentanor prostanoic acid derivatives and process for their manufacture - Google Patents

Abstract

1,3-Benzodioxane-prostanoic acid derivatives of the formula I and their antipodes and racemates in which the substituents are defined in Claim 1, are prepared. These compounds are obtained by reacting lactols of the formula II with a Wittig reagent of the formula Ph3P=CH-(CH2)3-COR1 to introduce the side chain located in position 8. Likewise, the corresponding 9-keto compounds are prepared from compounds of the formula I which have a hydroxyl group in position 9. The compounds have prostaglandin-like properties and can be used for the same purposes as known prostaglandins.

Description

The present invention is concerned with new 15-(l,3-benzodioxan-2-yl)16.17.13.19.20- pentanor prostanoic acid derivatives and with their manufacture and use.

It has generally been known that the numerous actions of prostaglandins both in the mammalian organism and in vitro are only of short duration, as they are rapidly converted into pharmacologically inactive metabolic products. Thus, by the oxidation of the allylic hydroxy group at carbon atom 15 by 15-hydroxy-prostaglandin dehydrogenases there is formed a largely inactive metabolite.

It has therefore been desirable to develop prostaglandin analogues having a spectrum of action comparable to the natural prostaglandins and to bring about structural alterations by means of which the duration and selectivity Of the activity is increased.

It has now surprisingly been found that the 1,3-benzodioxanyl-prostaglandins of the present invention have a longer duration of action, greater selectivity and a better activity than the natural prostaglandins.

The present invention accordingly provides 15-(1,3-benzodioxan-2-yl)16.17.18.19.20- pentanor prostanoic acid derivatives of the general formula I - 2 434B3 in which Ri represents a hydroxyl group, an aliphatic hydrocarbonyloxy group containing 1 to 10 carbon atoms, a methanesulphonamido group, an unsubstituted or substituted aryloxy group or a group of the formula —0—CH2—U—V, in which U represents a direct bond, a carbonyl group or a carbonyloxy group (the carbonyl part of which is attached to the —CH2— group) and V represents a phenyl group substituted by one or more substituents selected from phenyl, methoxy, ethoxy, vinyloxy and ethynyloxy and halogen atoms, preferably bromine atoms, A represents a —CH2—CH2— or a trans—CH=CH— group, B represents a —CH2—CH2— or a cis or trans —CH=CH— group, Z represents a hydroxy methylene or a carbonyl group, X...Y, when Z represents a hydroxymethylene group, represents a —CH2—CH— or —CH?—C— Hi OH 0 group and, when Z represents a carbonyl group, represents a —CH2—CH— or —CH=CH— group, OH R2 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms, and R3 and Rh each represents a hydrogen, fluorine, chlorine, bromine or iodine atom or a trifluoromethyl, methyl, methoxy, ethoxy, vinyloxy or ethynyloxy group, and physiologically tolerable salts with bases of such compounds in which Ri represents a hydroxyl group. - 3 43453 The present invention includes within its scope both the antipodes and the racemates of the new compounds as defined above.

Ri, when it represents an unsubstituted or substituted aryloxy group, may be, for example, a phenoxy, 1-naphthyloxy or 2-naphthyloxy group, each of which may be substituted by 1 to 3 halogen atoms, 1 phenyl group, to 3 alkyl groups each containing 1 to 4 carbon atoms or 1 chloromethyl, fluoromethyl, trifluoromethyl, carboxyl or hydroxyl group.

Ri, when it represents an aliphatic hydrocarbonyloxy group may be a straight or branched chained, saturated or unsaturated aliphatic hydrocarbonyl oxy group, preferably a saturated group containing 1 to 10, and especially 1 to 6, carbon atoms, for example a methoxy, ethoxy,.propoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, 2- or 3-butehyloxy, and 2-methyl-2-propenyloxy or 2-propenyloxy group.

The alkyl groups represented by R2 may be, for example, those containing 1 to 5 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl groups.

The symbols R3 and Rk may have identical or different meanings.

For salt formation there are suitable all those inorganic and organic bases known to those skilled in the art for forming physiologically tolerable salts. There may be mentioned, for example, alkali metal hydroxides, for example sodium or potassium hydroxide, alkaline earth metal hydroxides, for example calcium hydroxide, ammonia and amines, for example ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine and tris(hydroxymethyl)-aminomethane.

The present invention also provides a process for the manufacture of . 4 . the new 15-(1,3-benzodioxan-2-yl)-16,17,18,19,20-pentanor prostanoic acid derivatives of the general formula I and physiologically tolerable salts group, wherein with bases of such compounds in which Rx represents a hydroxyl a lacto! of the general formula II OH Λ or5 (Π) in which R2, R3, Ru and A have the meanings given above and R5 and Rg each represents a hydrogen atom or a hydroxyl-protecting group, is reacted with a Wittig reagent of the general formula III Ph3P=CH—(CH2)3—CORi (III) in which Ph represents a phenyl group and Rx has the meaning given above, to form a compound of the general formula - 5 43453 in which Rls R2> R3, R'4, Rs> R6 and A have the meanings given above and B represents a cis or trans —CH=CH— group, and then, if desired after any oxidation, as defined below, in the 9-position, any hydroxyl-protect!ng group in the Π-position is removed by hydrolysis and, if desired after any oxidation, as defined below, in the 9- and/or 11-position(s), any hydroxyl-protecting group in the 15-position is removed by hydrolysis, and, if desired and in any desired sequence, any free 1-carboxyl group is esterified or any’esterified 1-carboxyl group is hydrolysed, and/or the 5,6-double bond and, if desired, also any 13,14-double bond is/are hydro0 genated, and/or either (a) the 9a-hydroxyl group is oxidized in the presence of protected hydroxyl groups in the 11- and 15-positions to form a 9-oxo group, which oxidation is, if desired, followed by removal of the hydroxylprotecting group in the Π-position by hydrolysis and then dehydration with the elinination of the Π-hydroxyl group and the formation of the 10,115 double bond, or (b) the 9a-hydroxyl group is oxidized in the presence of protected hydroxyl groups in the 11- and 15-positions to form a 9-oxo group, which oxidation is followed by reduction to form a 9p-hydroxyl group, and/or, if necessary after removal of any hydroxyl-protecting group in the Π-position by hydrolysis, the Πα-hydroxyl group is oxidized after interI mediate protection of the 9a- or 9e-hydroxyl group and in the presence of a protected hydroxyl group in the 15-position to form an Π-oxo group, and/or any 1-carboxyl compound is converted into a physiologically tolerable salt thereof with a base and/or any racemate is resolved into its antipodes.

The reaction of the lactol of the general formula II with the Wittig reagent of the general formula III, which is prepared from the corresponding - 6 43453 phosphonium bromide by reaction with sodiummethylsulphinylmethide or potassium tert.-butoxide in the usual manner in dimethyl sulphoxide, is preferably carried out at a temperature of 0°C to 100°C, most preferably at 20°C to 80°C, in an aprotic solvent, preferably dimethyl sulphoxide or dimethyl formamide. The Wittig reagent may also be formed during the reaction from (4-RpCO-butyl)-triphenyl-phosphonium bromide by reaction with potassium tert.-butoxide.

The oxidation of the 9-hydroxyl group to the oxo group, which may be carried out before the removal of any hydroxyl-protecting groups, is carried out with the usual oxidizing agents, for example with Jones reagent (J.

Chem. Soc. 1953, 2555). There is used an excess ο* the oxidizing agent in a suitable diluent, for example acetone, at a temperature between 0°C and -50°C, and preferably at -20°C. The reaction has generally terminated after 5 to 30 minutes.

The oxidation of the 9-hydroxyl group is preferably carried out after intermediate protection of any free 11- and 15-hydroxyl groups, for example, by silylation (Chem. Comm. (1972), 1120). As other oxidizing agents there are suitable silver carbonate on Celite (registered Trade Mark) or a mixture of chromium trioxide and pyridine (Tetrahedron Letters 1968, 3363).

The oxidation of the 11-hydroxyl group is carried out with the usual oxidizing agents, for example with Jones reagent or Collins reagent after intermediate protection of the 9- and 15-hydroxyl groups. There is used a temperature between -40°C and +20°C, and preferably -20°C.

Suitable hydroxyl-protecting groups are known to those skilled in the art, for example 2-tetrahydropyranyl, 2-tetrahydrofuranyl and 1-ethoxyethyl - 7 43483 groups, and carboxylic acyl groups, for example aromatic and aliphatic carboxylic acyl groups, but preferably benzoyl and acetyl groups.

The removal of the hydroxyl-protect!ng groups, for example 2-tetrahydropyranyl and 2-tetrahydrofuranyl groups, to form the compounds of the general formula I is carried out by hydrolysis with an aqueous solution of an organic acid, for example acetic acid or propionic acid, or with an aqueous solution of an inorganic acid, for example hydrochloric acid. In order to improve the solubility it is of advantage to add an inert organic solvent miscible with water. Suitable organic solvents are, for example, alcohols, for example methanol and ethanol, and ethers, for example 1,2-dimethoxyethane, dioxan and tetrahydrofuran. Tetrahydrofuran is preferably used. The hydrolysis is preferably carried out at a temperature between 20°C and 80°C. In the case of compounds of the prostaglandin E-type the hydrolysis is carried out at below 45°C in order to avoid the formation of prostaglandin-A compounds as by-products. The removal of acyl groups is carried out by hydrolysis with alkali metal carbonates for example potassium carbonate in methanol at 0 to 5O°C, and preferably at 25°C.

The reduction of the 9-oxo group to form a mixture of the epimeric 9a- and 9e-alcohols is carried out in the usual manner, preferably in an organic solvent with sodium borohydride on zinc borohydride. When zinc borohydride is used, suitable solvents are, for example, 1,2-dimethoxyethane, diethyl ether, dioxan, benzene and diisopropyl ether. When sodium borohydride is used, suitable solvents are, for example, methanol, ethanol, - 8 43453 isopropanol and n-propanol. The resulting epimeric mixture is separated, for example, in the usual manner by column or layer chromatography and/or fractional crystallization.

The dehydration of the 9-oxo-compound, by which the 11-hydroxyl group and a hydrogen atom from the 10-position are removed to form a prostaglandinA derivative, may be carried out under conditions that are generally known to those skilled in the art. In general the dehydration is carried out in a solution of an organic acid, for example acetic acid, or of an inorganic acid, for example hydrochloric acid, at a temperature between 20°C and 80°C. The reaction has terminated after approximately 2 to 17 hours.

The hydrogenation of the 5,6-double bond and, if desired, also any 13,14-double bond is carried out in a known manner per se in an atmosphere of hydrogen in the presence of a noble metal catalyst. A suitable catalyst is, for example, 10% palladium on carbon. When the hydrogenation is carried out at room temperature both the 5,6-double bond end also any 13,14-double bond are hydrogenated. At low temperatures, preferably at -80°C to -10°C, the cis-5,6-double bond is hydrogenated before the trans-13,14-double bond.

A selective hydrogenation of the cis-5,6-double bond in the presence of a · trans-13,14-double bond is also effected by hydrogenation in the presence of nickel boride or tris-(triphenylphosphine)-rhodium(I) chloride as catalyst.

For preparing esters of the general formula I, in which Κχ represents an aliphatic hydrocarbonyl-oxy group containing 1 to 10 carbon atoms, the 1-carboxy-compound is reacted, for example, with a diazohydrocarbon in a manner known per se. The esteritication with a diazohydrocarbon is carried our, for example, by mixing a solution of the diazohydrocarbon in an inert - 9 43453 solvent preferably in diethyl ether, with the 1-carboxy-compound in the same solvent or in another inert solvent, for example methylene chloride.

The reaction is terminated after 1 to 30 minutes, and then the solvent is removed and the ester is purified in the usual manner.

Diazoalkanes are either known or can be prepared by known methods {Org. Reactions, Vol. 8, pages 389—394 (1954)}.

For preparing compounds of the general formula I in which Rj represents an ester group of the formula —0—CH2—U—V the 1-carboxy-compound of the general formula I is reacted, for example, in the presence of a hydrogen halide acceptor vzith a halogen-compound of the general formula Hal—CH2—U—V, in which Hal represents a halogen atom, preferably a bromine atom, U has the meaning given above and V represents a phenyl group substituted by one or more substituents selected from phenyl, methoxy, ethoxy, vinyloxy and ethynyloxy groups ahd halogen atoms, preferably bromine atoms.

A suitable hydrogen halide acceptor is, for example, silver oxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or an amine, for example trimethylamine, triethylamine, tributylamine, triocfylamine or pyridine. The reaction with the halogen-compound is carried out in an inert solvent, preferably in acetone, acetonitrile, Ν,Ν-dimethylacetamide,’dimethylformamide or dimethyl sulphoxide at a temperature from -80°C to +100°C, and preferably at room temperature.

For preparing esters of the general formula I, in which R1 represents an unsubstituted or substituted aryloxy group, the 1-carboxy-compound is reacted, for example, with the corresponding hydroxyaryl compound with di- 10 434S3 cyclohexylcarbodiimide in the presence of a suitable base, for example pyridine or triethylamine, in an inert solvent. Suitable solvents are methylene chloride, ethylene chloride, chloroform. The reaction is carried out at a temperature between -30°C and +50°C, and preferably at 10°C.

The hydrolysis o* the prostaglandin esters ’s carried out by methods known to those skilled in the art, for example with potassium hydroxide in methanol.

The prostaglandin derivatives of the general formula I in which Rx represents a hydroxyl group can be converted into salts by neutralization with equivalent quantities of the corresponding inorganic bases. For example, the solid inorganic salt is obtained by first dissolving the corresponding PG-acid in water, which contains the stoichiometric quantity of the base, and then evaporating off the water or adding a solvent miscible with water, for example alcohol or acetone.

For preparing an amine salt the PG-acid is dissolved in a suitable solvent, for example ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric quantity of the amine is added to this solution.

In this way the salt is usually obtained in the solid form.

The lactols of the general formula II used as starting compounds in the process of the present invention can be prepared by reacting a 2-hydroxymethylphenol (a saligenin) with a dihaloalkanoic acid to form a 1,3benzodioxane-2-carboxylic acid of the general formula IV - 11 3453 in which R2, R3 and Ri, have the meanings given above. The 1,3-benzodioxane-2-carboxylic acid so obtained, owing to the asymmetric carbon atom in the 2-position, is in the form of a racemate, which can be separated by salt formation with optically active bases into the optical antipodes.

The subsequent esterification may be carried out with the racemate or with the enantiomers. The l,3-benzodioxane-2-carboxylic acid ester so obtained is reacted with triphenyl-phosphine-methylene or a methylphosphonic acid dialkyl ester, and therefrom is subsequently prepared in a manner known per se by a Wittig reaction or Wittig-Horner reaction with an aldehyde (preferably in the form of the corresponding antipodes) a ketone of the general formula V in which R2, R3, Rt, and R5 have the meanings given above. The optionally resulting mixture of C16-diastereoisomers may be separated by the usual methods.

In the presence of a noble metal salt catalyst the ketone of the general formula V can be hydrogenated in an inert solvent, if desired, in the 13,14-position (PG-numbering).

The subsequently effected reduction to the a- and p-C15-alcohols is - 12 434S3 carried out with sodium borohydride or zinc borohydride. The mixture of epimers can be resolved by the usual known methods. After introducing hydroxyl-protecting groups, for example with hydropyran, in the 15-posttion and, if desired, in the 11-position (PG-numbering), the lactone is reduced with diisobutylaluminium hydride or lithium tri-(tert?butoxy)-aluminium hydride to form the desired lactol of the general formula II.

The reduction to form the lactol of the general formula II may also be carried out without protecting groups by a simplified Corey synthesis according to United Kingdom Patent Specification No. 1,473,670 with diisobutylaluminium hydride or lithium tri-(tert.-butoxy)- aluminium hydride.

For introducing the hydroxyl-protecting groups the 11,15-diol (PGnumbering) is reacted, for example, with dihydropyran in methylene chloride or chloroform with the use of an acid condensing agent, for example paratoluenes ul phonic acid. The dihydropyran is used in excess, preferably in a quantity 4 to 10 times the theoretical requirement. The reaction has normally terminated after 15 to 30 minutes at 0°C to 30°C.

One way of preparing the starting compounds acetylated in the 11-position is to react the lactol etherified in the 15-position (PG-numbering) with acetic anhydride in pyridine. This reaction will also acetylate the lactol-hydroxyl group which then has to be liberated in order to form a lactol of the general formula II.

The new prostanoic acid derivatives of the general formula 1 are valuable pharmaceutical products, because, coupled with a similar spectrum of action, they have a considerably stronger and above all considerably more prolonged action than the corresponding natural prostaglandins. - 13 43453 The new prostaglandin analogues of the E-, D- and F-types have a very strong luteolytic action, that is to say, to cause luteolysis considerably smaller dosages are required than in the case of the corresponding natural prostaglandins.

Also for causing abortions in non human animals considerably smaller quantities of the new prostaglandin anaolgues are required as compared with those required by. the natural prostaglandins.

In the recording of isotonic uterus contraction on the narcotized rat and on the isolated rat uterus it is found that the compounds of the present invention are considerably more active and their actions last longer than in the case of the natural prostaglandins, as is shown in the following Table by way of example with the compounds numbered 1 to 8 of the present invention as compared with natural PGF2a. The tests are carried out on pregnant rats by the usual methods. Thus, pregnant rats at the 4th and 7th day of gestation were treated subcutaneously with the compounds of the present invention. On the 9th day the animals were killed and the uteri examined at the places of implantation.

TABLE Tested compound Relative action PGF2a= 1 on abortion in rats (5Z,13E)-(8R,9S,llR,12R,15R)-9,n,15-Trihydroxy- 15-({2S}-1,3-benzodioxan-2-yl)-16,17,18,19,20- pentanorprostadienoic acid methyl ester (5Z,13E)-(8R,9S,11R,12R,15S)-9,11,1S-Trihydroxy- 300 15-({2RS}-1,3-benzodi oxan-2-yl)-16,17,18,19,20- pentanorprostadienoic acid methyl ester 30 - 14 434S3 TABLE (continued) Tested compound (5Z,13E)-(8R,9S,11R,12R,15R)-9.11.15-Trihydroxy -({2S}-l,3-benzodioxan-2-yl)Tl6, 17, 18, 19, 20pentanorpostadienoic acid 4-penylphenacyl ester (5Z,13E)-(8R,9S,11R,12R,15R)-9.11.15-Trihydroxy15-({2S}-l,3-benzodioxan-2-yl)-16,17,lC,19,20pentanorprostadienoic acid 4-pheny1 phenacyl ester (5Z,13E)-(8R,9S,HR,12R,15R)-9,11,15-Tri hydroxy15-({2R}-1,3-benzodioxan-2-yl)-16,17,18,19,20pentanorprostadienoic acid (5Z,13E)-(8R,9S,11R,12R,15R)-9,11,15-Trihydroxy15-({2R}-1,3-benzodioxan-2-yl)-16,17,18,19,20pentanorprostadienoic acid methyl ester (5Z,13E)-(8R,9S,HR,12R,155)-9,11,15-Trihydroxy15-({2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,20pentanorprostadienoic acid methyl ester (5Z,13E)-(8R,9S,11R,12R,15S)-9,11,15-Trihydroxy15-({2R}-1,3-benzodioxan-2-yl)-16,17,18,19,20pentanorprostadienoic add methyl ester Relative action PGFj>u= 1 on abortion in rats As shown in the Table the compounds of the present invention in doses - 15 43453 to 300 times smaller have as good an abortive action as 1 mg per animal of PGF2ct.

The new prostanoic acid derivatives are suitable, after a single intrauterine application, for inducing menstruation or for interrupting a pregnancy in non-human animals and for inducing a birth. They are suitable for syncronization of the sexual cycle in non-human female · mammals, for example cattle, apes, pigs and rabbits.

The good dissociation cf action of the compounds of the present invention is exhibited in the investigation of other unstriated muscular Lo organs, for example on the ileum of a guinea-pig or on the isolated trachea of a rabbit, where a considerably smaller stimulation is observed than by the natural prostaglandins.

The active compounds of the PGE-series of the present invention exhibit on the isolated trachea of the rabbit in vitro a bronchodilatory action and strongly check the secretion of gastric acid and have a regulating action in disturbances of cardiac rhythm. The new compounds of the PGA- and PGE-series also lower the blood pressure and have a diuretic action.

The active compounds of the F-series of the present invention have a less bronchoconstrictive action than does natural prostaglandin F2a, which o is a great advantage when using them therapeutically.

For medicinal use the active substances can be converted into a form suitable for inhalation, or for oral or parenteral application.

The present invention accordingly further provides a pharmaceutical preparation which comprises a compound of the present invention, in admix’ ture or conjunction with a pharmaceutically suitable carrier. The preparations may contain the usual carriers and auxiliary substances. - 16 43453 For inhalation the pharmaceutical preparations are advantageously in the form of aerosol solutions or spray solutions.

For oral application there are suitable, for example, tablets, dragees or capsules.

For parenteral administration there are prepared sterile aqueous or oily solutions suitable fo.r injection.

The active compounds of the present invention may be used in combination with the auxiliary substances known and normally used in galenical medicine, for example, for making preparations for causing an abortion or for regulation menstruation in non-human animals and for inducing a birth. For this purpose there may be used sterile aqueous solutions containing the active substance in an amount of 0.01 to 10 p grams per ml, in the form of an intravenous infusion solution. The compounds of the general formula I and the salts of such compounds in which Rx represents a hydroxyl group are especially suitable for preparing aqueous isotonic solutions. For increasing their solubility alcohols, for example ethanol and propylene glycol, may be added.

The following Examples illustrate the invention:Example 1 (52,13E)-(8R,9S,llR,12R,15R)-9,n,15-Trihydroxy-15-( 2RS -1,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester.

General formula I; Α» trans CH = CH; B - cis CH = CH; X... Y = CHZ—CH; ar OH - 17 43453 Ri = 0CH3, OH; R2, R3, Ri, = H; the OH group at C-15 is in the a-confi gyration. (a) 1,3-Benzodioxane-2-carboxy1ic acid methyl ester.

To a suspension of 9.6 grams of 50% sodium hydride in 100 ml of dimethylformamide was added dropwise while cooling with ice-water a solution of 12.4 grams of saligenin in 100 ml of dimethylformamide. The reaction mixture was stirred overnight at room temperature. ml of dichloracetic acid were added while cooling with ice to 50 ml of dimethylformamide. While cooling with ice, there was added a suspension of 5.3 grams of 50% sodium hydride in 150 ml of dimethylformamide. The sodium hydride may also be added without a solvent.

This solution of sodium dichloracetate was added dropwise at room temperature to the previously prepared disodium saligenin solution. The i reaction mixture was stirred with the addition of potassium iodide for a total of 5 hours at 60°C. During the last three hours the dimethylformamide was distilled off under the reduced pressure of an oil pump. The semisolid brown residue was acidified to pH 3 with a concentrated aqueous solution. of citric acid, and extracted with methylene chloride. The organic phase was dried over magnesium sulphate, and concentrated in a rotary evaporator, and a solution of diazomethane was added at about 10°C. After stirring for one hour at roam temperature, the excess of diazomethane and - 18 43453 the solvent were removed under the reduced pressure of a water jet pump.

The residue was added to a saturated solution of sodium chloride, and extracted with methylene chloride, and the organic phase was dried with magnesium sulphate, concentrated and purified by column chromatography over silica gel with hexane/5—10% by volume ethyl acetate. There were obtained 6 grams of 1,3-benzodioxane-2-carboxylic acid methyl ester melting at 28— 29°C. (b) {2-0xo-2-(l,3-benzodioxan-2-yl)-ethylidene}-triphenyl-phosphorane.

To a suspension of 39 grams of triphenyl-methyl-phosphonium bromide in 250 ml of absolute diethylether were added dropwise at room temperature under argon 40 ml of a 2.52 m butyl lithium solution in hexane, and the whole was stirred for 15 hours, also under argon and at room temperature.

To the yellow ylene-solution was added dropwise a solution of 9.78 grams of l,3-benzodioxane-2-carboxylic acid methyl ester in 100 ml of absolute diethyl ether, the mixture was stirred for one hour at room temperature, and filtered to remove the white precipitate, which was then dissolved in water and extracted with diethyl ether. The organic phase was combined with the filtrate, washed with water, dried over magnesium sulphate and concentrated to dryness. The residue was purified by column chromatography over silica gel with hexane/20—-100% by volume ethyl acetate and then recrystallized from ethyl acetate.

Yield: 12 grams, melting at 95—98°C. (c) (1S,5R,6R,7R)-6-{(E)-3-0xo-3-({2RSJ-1,3-benzodioxan-2-yl)-l-propenyl}7-benzoyloxy-2-oxabicyc1o{3,3,0}octan-3-one. 7 Grams of (lS,5R,6R,7R)-6-formy1-7-benzoyloxy-2-oxabicyc1o{3,3,0}octan-3-one {E. J. Corey et al. J. Amer. Chem. Soc. 91, 5675 (1969)} and - 19 43483 11.2 grams of {2-oxo-2-(l,3-benzodioxan-2-yl)-ethylidene}-triphenylphosphorane were stirred for 16 hours in 300 ml of benzene under argon at room temperature. The mixture was then evaporated to dryness in vacuo. The residue was purified by column chromatography of silica gel with hexane/20— 60% by volume ethyl acetate as eluting agent. 5 Grams of an oil were obtained. (d) (lS,5R,6R,7R,3'R)-6-t(E)-3-Hydroxy-3-{{2RS)-l,3-benzodioxan-2-yl)1- propenyl}-7-benzoyloxy-2-oxabicyclo{3,3,0)octan-3-one.

To a solution of 2 grams of the ketone obtained as described under (c) in 140 ml of absolute 1,2-dimethoxyethane were added 140 ml of an ethereal solution of zinc borohydride (preparation: Neurere Methoden der praparativen organischen Chemie, Vol. 4, page 241, Verlag Chemie), and the whole was stirred under argon for 2 hours at room temperature. After dilution with 100 ml of diethyl ether, water was cautiously added to the reaction solution, which was then extracted by agitation with a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness jn vacuo. The isomeric reaction products were separated by column chromatography over silica gel with hexane/30—60% by volume ethyl acetate as eluant. The first product eluted was the a-alcohol.

Yield: 0.8 gram. (e) (2RS,3aR,4R,5R,6aS,3'R)-4-{(E)-3-Hydroxy-3-({2RS)-l,3-benzodioxan2- yl)-l-propenyl}-5-hydroxyperhydrocyclopentafb)furan-2-ol.

General formula II: A = trans CH = CH; R2, R3, Ru, Rs, R6, = H; the OH group at C-3' is in the α-configuration.

To a solution cooled to -60°C of 550 mg of the lactone-alcohol prepared - 20 43453 as described under (d) in 20 ml of absolute toluene were added under argon 5.5 ml of a 20% w/v diisobutylaluminium hydride (DIBAH) solution in toluene, the whole was stirred for 30 minutes at -60°C and the reaction was terminated by adding dropwise 2 ml of isopropanol. After the addition of 20 ml of water the mixture was stirred for 15 minutes at 0°C, extracted with ethyl acetate and/or methylene chloride, agitated with a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness vn vacuo. There were obtained 520 mg of crude product of the abovementioned lactol, which was used in the next stage without further purifi10 cation. (f) (5Z,13E)-(8R,9S,llR,12R,15R)-9,ll,15-Trihydroxy-15-({2RS}-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid.

General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y = CH2—CH j gg OH \ z 2/cv OH Rj = OH; R2,R3,Ri+ = H; the OH group at C-15 is in the a-configuration. To a solution of 3.46 grams of (4-carboxybutyl)-triphenylphosphonium bromide in 10 ml of absolute dimethyl sulphoxide (DMSO) were added 14,98 ml of a solution of sodium methylsulphinylmethide in absolute DMSO (pre20 paration of the solution: 2 grams of a 50% w/v sodium hydride suspension were dissolved in 40 ml of absolute DMSO at 70°C), and the whole was stirred for 30 minutes at room temperature. This red-brown coloured solution was added dropwise while cooling with water to a solution of - 21 520 mg of the lactol obtained as described under (e) in 5 ml of absolute DMSO. The reaction mixture was then stirred for 2 hours at 50°C under argon, then the greater part of the DMSO was distilled off under the reduced pressure of an oil pump (bath temperature 40—50°C), 50 ml of ice5 water were added to the residue, and extraction with diethyl ethe*· was carried out 3 times. This diethyl ether extract was discarded. The aqueous phase was acidified to pH 4 with a solution of 10% w/v citric acid, and extracted by agitation four times with a diethyl ether/hexane mixture (1/1 v/v) and three times with methylene chloride. The organic phases · were washed with a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness. The residue was purified by chromatography over silica gel with methylene chi oride/1—10% by volume ethanol as eluant.

Yield: 310 mg. (g) The prostadienoic acid obtained as described under (f) was dissolved in methylene chloride and esterified with an ethereal solution of diazomethane. The evaporation residue was chromatographed over silica gel with methylene chloride/4% by volume isopropanol as eluting agent. There was obtained the prostadienoic acid methyl ester identified in the heading l of this Example.

Yield: 288 mg; ία}θ23 = +0.8° (c = 0.25; CHC13); IR: 3400 (wide), 1730, 1590, 1490, 980, 750 cm-1.

Example 2 (52,13E)-(8R,9S,11R,12R,15S)-9,11,15-Trihydroxy-15-({2RS}-1,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester. - 22 43 General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y = CH2—CH; OH Rx = 0CH3, OH; R2, R3, Ru = H; the OH group at C-15 is in the e-con5 figuration.

In the reaction of (lS,5R,6R,7R)-6-{E)-3-oxo-3-({2RS}-1,3-benzodioxan2-yl)-l-propenyl}-7-benzoyloxy-2-oxabicyclo{3,3,0)octan-3-one described in Example 1(d) the s-alcohol was eluted from the column as 2nd product: (a) (lS,5R,6R,7R,3'S)-6-{(E)-3-Hydroxy-3-({2RS}-l,3-benzodioxan-2-yl-l10 propenyl}-7-benzoyloxy-2-oxabicyclo{3,3,0}octan-3-one.

Yield; 0.5 gram. (b) (2RS,3aR,4R,5R,6aS,3'S)-4-{(E)-3-Hydroxy-3-({2RS}-l,3-benzodioxan-2yl)-l-propenyl}-5-hydroxy-perhydrocyclopenta{b)furan-2-ol.

General formula II: A « trans CH = CH; R2, R3, Ri,, Rs, Rg = H; the OH 15 group at C-3' is in the 6-configuration. 410 mg of the e-alcohol obtained as described under (a) were reacted in a manner analogous to that described in Example 1(e) with diisobutylaluminium hydride, 400 mg of crude product were obtained. (c) (5Z,13E)-(8R,9S,11R,12Rt15S)-9,ll,15-Trihydroxy-15-({2RS}-1,3-benzo20 dioxan-2-y1)-16,17,18,19,20-pentanorprostadienoic acid. - 23 3453 General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y = CH2—CH; OH Rj = OH; R2, R3, Ri, = H; the OH group at C-15 is in the B-configuration.

The 400 mg of lactol obtained as described under (b) were reacted without further purification in a manner analogous to that described in Example 1(f) with 2.66 grams of (4-carboxybutyl)-triphenylphosphonium bromide and 11.52 ml of the sodium methylsulphinylmethide solution described therein.

Yield: 220 mg. (d) The prostadienoic acid obtained as described under (c) was dissolved in methylene chloride and esterified with an ethereal solution of diazomethane. The evaporation residue was chromatographed over silica gel with methylene chloride/4% by volume isopropanol as eluting agent. There was obtained the prostadienoic acid methyl ester identified in the heading of · this Example.

Yield: 198 mg. {a}023= -0.8° (c = 0.25; CHCla); IR: 3400 (wide)', 1730, 1590, 1490, 980, 750 cm1.

Example 3 ) (5Z,13E)-(8R,9S,llR,12R,15R)-9,n,15-Trihydroxy-15-(i2R}-l.,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester - 24 43453 General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y - CH2.—-CH; OH \ ^0H A *H Rj = OCH3 OH; R2, R3, R4 = H; the OH group at C-15 is in the (a) (lS.5P,6R,7R)-6-{(E)-3-0xo-3-({2R}-l,3-benzoaioxan-2-yl)-l-propenyl}7-benzoyloxy-2-oxabi cyclοί 3,3,0}octar-3-one.

The product was obtained in the form of colourless crystals by crystallizing the oil described under Example 1(c) from benzene/diethyl ether. 10 Melting point: 129—130°C; {«}D23 = -147.4° (c = 0.25; CHC13). (b) (lS,5R,6R,7R,3'R)-6-{(E)-3-Hydroxy-3-({2R}-l,3-benzodioxan-2-yl)-lpropenyl}-7-benzoy1oxy-2-oxabi cyclo{3,3,0}octan-3-one.

From 1.5 grams of the ketone obtained as described in Example 3(a) there was obtained according to the reduction with zinc borohydride de15 scribed in Example 1(d) the «-alcohol as the first product of column chromatography.

Yield: 0.61 gram; {«)D23 = -101.3° (c = 0.25; CHC13). (c) (2RS,3aR,4R,5R,6aS,3'R)-4-{(E)-3-Hydroxy-3-({2R}-1,3-benzodi oxanZ-yl)-1-propenyl}-5-hydroxyperhydrocyclopentafb}furan-2-ol.

General formula II: A « trans CH · CH; R2, R3, RUl Rs, R6 * H; the OH group at C-3' is in the «-configuraion. - 25 43453 600 mg of the α-alcohol obtained as described under (b) were reacted in a manner analogous to that described in Example 1(e) with diisobutylaluminium hydride. 450 mg of crude product were obtained. (d) (5Z,13E)-(8R,9S,nR,12R,15R)-9,H,15-Trihydroxy-15-({2R}-l,3-benzo5 dioxan-Z-ylJ-iejlZjlS.igjZO-pentanorprostadienoic acid.

General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y = CH2—CH; OH Z-V d)H Rj = OH; R2, R3', R4 = H; the OH group at C-15 is in the a-config10 uration.

The 450 mg of lactol obtained as described under (c) were reacted without further purification in a manner analogous to that described in Example 1(f) with 3.8 grams of (4-carboxybutyl)-triphenylphosphonium bromide and 16.5 ml of the sodium methylsulphinylmethide solution described therein.

Yield: 315 mg. (e) The prostadienoic acid obtained as described under (d) was dissolved in methylene chloride and esterified with an ethereal solution of diazomethane. The evaporation residue was chromatographed over silica gel with methylene chloride/1—6% by volume isopropanol as eluant. There was obtained the prostadienoic acid methyl ester identified in the heading of - 26 43483 this Example.

Yield: 299 mg; -21.2° (c - 0.4; CHC13); IR: 3400 (wide), 1730, 1590, 1490, 980, 750 cm1.

Example 4 (5Z,13E)-(8R,9S,11R,12R,15S)-9,11,15-Trihydroxy-15-( 2R -1,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester.

General formula I: A = trans CH » CH; B = cis CH =CH; X Y = CH2—CH; % OH H Ri = OCH3, OH; R2, R3, Ri, = H; the OH group at C-15 is in the β-configuration.

In the reduction of (lS,5R,6R,7R)-6-{(E)-3-oxo-3-({2R}-l,3-benzo15 dioxan-2-yl)-1-propenyl}-7-benzoyloxy-2-oxabicyclof3,3,0}octan-3-one {the product of Example 3(a) with zinc borohydride described under Example 3(b) the s-alcohol was eluted as second product from the column: (a) (lS,5R,6R,7R,3'S)-6-{(E)-3-Hydroxy-3-({2R}-l,3-benzodioxan-2-yl)-lpropenyl}-7-benzoy1oxy-2-0xab1cyclo{3,3,O}octan-3-one, Yield: 0.41 gram; {«)D23 « -128° (c » 0.25; CHC13). - 27 43453 (b) (2RS,3aR,4R,5R,6aS,3'S)-4-{(E)-3-Hydroxy-3-({2R}-l,3-benzodioxan-2yl)-1-properiy 1 }-5-hydroxy-perhydrocyclopenta{b}furan-2-ol.

General formula II: A = trans CH = CH; R2, R3, R5, R6 = H; the OH group at C-3' is in the s-configuration. 410 mg of the e-alcohol obtained as described under (a) were reacted in a manner analogous to that described in Example 1(e) with diisobutylaluminium hydride, 400 mg of crude product were obtained. (c) (5Z,13E)-(8R,9S,llR,12R,15S)-9,n,15-Trihydroxy-15-({2R}-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid.

General formula I: A = trans CH = CH; 8 = cis CH = CH; X ... Y = CH2—CH; OH z\Z A OH Ri = OH; R2, R3, Ri* = H; the OH group at C-15 is in the S-configuration, The 400 mg of lactol obtained as described under (b) were reacted without further purification in a manner analogous to that described in Example 1(f) with 2.66 grams of (4-carboxybutyl)-triphenylphosphorrium bromide and 11.52 ml of the sodium methylsulphinylmethide solution described therein.

Yield: 230 mg. ) (d) The prostadienoic acid obtained as described under (c) was dissolved in methylene chloride and esterified with an ethereal solution of diazomethane. The evaporation residue was chromatographed over silica gel with methylene chloride/1—6% by volume isopropanol as eluant. There was obtained the prostadienoic acid methyl ester identified in the heading of this Example.

Yield: 212 mg; {«}D23= -46-4° (C = 0.25; CHC13); IR: 3400 (wide), 1730, 1590, 1490, 980, 750 cm’1.

Example 5 (5Z,13E)-(8R,9S,llR,12R,15R)-9,ll,15-Trihydroxy-15-({2S}-l,3-benzodioxan2-yl)-16,17,18,19,20«pentanorprostadienoic acid and its methyl ester.

General formula I: A = trans CH = CH; B a cis CH = CH; X Y = CHZ—CH; OH Rx = 0CH3, OH Rz, R3, Ri, = H; the OH group at C-15 is in the a-con15 figuration. (a) (lS,5R,6R,7R)“6-{(E)-3-0xo-3-({2S)-l,3-benzodioxan-2-yl)-l-propeny1}· 7-benzoyloxy-2-oxabi cyclo{3,3,0}octan-3-one.

The mother liquor obtained as described in Example 3(a) was chromato· graphed by column chromatography over silica gel with hexane/20—50% by volume ethyl acetate as eluting agent. {a)D23 » -18.8° (c χ 0.25; CHC13). - 29 43453 (b) (lS,5R,6R,7R,3'R)-6-{(E)-3-Hydroxy-3-({2S}-l,3-benzodioxan-2-yl)1- propenyi1-7-benzoyloxy-2-oxabi cyclo{3,3,0}octan-3-one.

From 3 grams of the ketone obtained as described in Example 5(a) there was obtained according to the reduction with zinc borohydride described in Example 1(d) the α-alcohol as the first product produced by a column chromatography repeated several times.

Yield: 1,1 grams. (c) (2RS,3aR,4R,5R,6aS,3'R)-4-{(E)-3-Hydroxy-3-({2S}-l ,3-benzodioxan2- y1)-1-propenyl}-5-hydroxy-perhydrocyclopenta{b}furan-2-ol.

General formula II; A = trans CH = CH; R2, R3, Ri,, R5, R6 = H; the OH group at C-3' is in the a-configuration. 800 mg of the α-alcohol obtained as described under 5(b) were reacted in a manner analogous to that described in Example 1(e) with diisobutylaluminium hydride. 750 mg of crude product were obtained. (d) (5Z,13E)-(8R,9S,nR,12R,15R)-9,n,15-Trihydroxy-15-({2SM,3-benzodioxan-2-yl)-15,17,18,19,20-pentanorprostadienoic acid. General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y = CH2—CH OH !0 Ri = OH; R2, R3, Rq. = H; the OH group at C-15 is in the a-configuration The 750 mg of lactol obtained as described under (c) were reacted - 30 43453 without further purification in a manner analogous to that described in Example 1(f) with 5.1 grams of (4-carboxybutyl)-tri phenylphosphonium bromide and 22 ml of the sodium methylsulphlnylmethide solution described therein.

Yield: 480 mg. (e) The prostadienoic acid obtained as described under (d) was dissolved in methylene chloride and esterified with an ethereal solution of diazomethane. The evaporation residue was chromatographed over silica gel with hexane/50—95% by volume ethyl acetate as eluant. There was obtained the prostadienoic acid methyl ester identified in the heading of this Example.

Yield: 450 mg; {a)D23 = +51.2° (c-0.5; CHC13); IR: 3400 (wide), 1730, 1590, 1490, 980, 750 cm1.

Example 6 (5Z,13E)-(8R,9S,llR,12R,15S)-9,n,15-Trihydroxy-15-({2S}-l,3-benzodioxan15 2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester. General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y » CHZ—CH OH Rj β 0CH3, OH; Rz, R3, Ri, « H; the OH group at C-15 is in the ^configuration.

In the reduction of (lS,5R,6R,7R)-6-{(E)-3-oxo-3-{2S}-l,3-benzodioxan- 31 2-yl)-1-propenyl}-7-benzoyloxy-2-oxabicyclo{3,3,0}octan-3-one {the product of example 5(a)} with zinc borohydride described under Example 5(b) the S-alcohol vzas eluted as second product from the column: (a) (lS,5R,6R,7Rs3'S)-6-{(E)-3-Hydroxy-3-({2S}-l,3-benzodioxan-2-yl)-lpropenyl}-7-benzoyloxy-2-oxabicyclo{3,3,Q}octan-3-one.

Yield: 0.7 gram. (b) (2RS,3aR,4Rs5R,6aS,3'S)-4-{(E)-3-Hydroxy-3-({2S}-l,3-benzodioxan2-yl)-l-propenyl}-5-hydroxy-perhydrocyclopenta{b}furan-2-ol. General formula II: A = trans CH = CH; R2j R3, R4, R5, R6 = H; the OH group at C-3' is in the s-configuration. 600 mg of the S-alcohol obtained as described under 6(a) were reacted in a manner analogous to that described in Example 1(e) with diisobutylaluminium hydride. 470 mg of crude product were obtained. (c) (5Z, 13E)-{SR.9S S11R,12R#15S)-9 ,Π, 15-Tri hydroxy-15-({2S}-1,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid.

General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y = CH2—CH; OH Ri = OH; R2, R3j Ri* = H; the OH group at C-15 is in the s-configuration. The 470 mg of lactol obtained as described under (b) were reacted without further purification in a manner analogous to that described in Example 1(f) with 3.8 grams of (4-carboxylbutyl)-triphenylphosphonium bromide and 16.5 ml of the sodium methylsulphinylmethide solution described therein.

Yield: 330 mg. (d) The prostadienoic acid obtained as described under (c) was converted in a manner analogous to that described in Example 5(e) into the prostadienoic acid methyl ester identified in the heading of this Example.

Yield: 290 mg; {D23 = +S0° (c=0.5; CHC13); IR: 3400 (wide), 1730, 1590, 1490, 980, 750 cm-1.

Example 7 (5Z,l3E)-(8R,llR,l2R,l5R)-ll,l5-D1hydroxy-9-oxo-l5-({2RS}-l,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester.

General formula I: = A trans CH = CH; B = cis CH = CH; X ... Y = CH2—CH; OH Z d. C = 0; Ri = OCH3, OH; R2, R3, Ru = H; the OH group at C-15 is in the u-configurat1on. (a) (lS,5R,6R,7R,3'R)-6-{(E)-3-Hydroxy-3-({2RS}-l,3-benzodioxan-2-yl)-l20 propenyl}-7-hydroxy-2-oxabicyclo{3,3,0}octan-3-one.

A mixture of 1.97 grams of (lS,5R,6R,7R,3'‘R)-6-{(E)-3-hydroxy-3({2RS1-1,3-benzodi oxan-2-y1)-1-propenyl}-7-benzoyloxy-2-oxabi cyclo{3,3,0}octan-3-one {prepared according to the procedure described in Example 1(d)) and 622 mg of potassium carbonate (anhydrous) in 91 ml of methanol (absolute) was stirred for 2 hours at room temperature under argon. The mixture was then poured into 90 ml of O.lN-hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried with magnesium sulphate and evaporated in vacuo. After chromatography of the crude product over silica gel (ether/ethyl acetate = 7/3 v/v) 1.20 grams of a colourless oil were obtained. (b) (lS,5R,6R,7R,3'R)-6-{(E)-3-({2RS}-l,3-Benzodioxan-2-yl)-3-(2-tetrahydropyranyloxy)-1-propenyl}-7-(2-tetrahydropyranyloxy)-2-oxa0 bicyclo{3,3,0}-octan-3-one.

To a solution of 1.85 grams of the diol obtained as described under (a) in 50 ml of methylene chloride were added at ice-bath temperature 6.1 ml of dihydropyran (freshly distilled) and 15 mg of para-toluenesulphonic acid, and the mixture Was stirred at this temperature for 15 minutes, i diluted with methylene chloride and agitated with a solution of sodium carbonate. The organic phase was washed with water, dried with magnesium sulphate and evaporated in vacuo. By chromatography over silica gel (diethyl ether) there were obtained 2.2 grams of the bis-tetrahydropyranyl (THP) ether. (c) (2RS,3aR,4R,5R,6aS,3'R)-4-{(E)-3-({2RS}-l,3-Benzodioxan-2-yl)-3(2-tetrahydropyranyloxy)-l-propenyl}-5-(2-tetrahydropyranyloxy)perhydrocyclopenta(b}furan-2-ol.

General formula II: A = trans CH = CH; R2, R3, Rq - H; R5, R6 =. 2-THP; the 2-tetrahydropyranyloxy (OTHP) group at C-3' is 'n the «-configuration. - 34 434 53 To a solution cooled to -70°C of 2.2 grams of the lactone obtained as described under (b) in 85 ml of absolute toluene were added dropwise under argon 22 ml of a 20% w/v DIBAH solution in toluene. After 30 minutes the reaction was terminated by the dropwise addition of isopropanol, and stirred with the addition of 30 ml of water for 15 minutes at 0°C.

The mixture was then extracted with ethyl acetate, washed with brine, dried with magnesium sulphate and evaporated in vacuo. There were obtained 2.2 grams of the lactol in the form of a colourless oil. (d) (5Z,13E)-(8R,9S,llR,12R,15R)-9-Hydroxy-ll,15-bis-(2-tetrahydropyranyl10 oxy)-15-({2RS}-1,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid.

To a solution of 9.5 grams of (4-carboxybutyl)-triphenylphosphonium bromide in 40 ml of absolute dimethyl sulphoxide there were added dropwise 34.7 ml of a solution of sodium methylsulphinylmethide in absolute di15 methyl sulphoxide (preparation of the solution: 2.5 grams of a 50% w/v sodium hydride suspension in 50 ml of absolute dimethyl sulphoxide were stirred for 1 hour at 70°C), and the whole was stirred for 30 minutes at room temperature. This ylene-solution was then added dropwise at 15°C to a solution of 2.16 grams of the lactol obtained as described under (c) in 40 ml of absolute dimethyl sulphoxide in the course of 15 minutes, and the whole was stirred for 2 hours at 50°C. Most of the solvent was then distilled off at 45°C under the vacuum of an oil pump, and the residue was taken up in 80 ml of water and extracted three times with diethyl ether.

The organic extract was discarded. The aqueous phase was acidified to pH 4—5 with a solution of 10% w/v citric acid, and extracted four times with - 35 a mixture of hexane-diethyl ether 1/1 v/v. The diethyl ether/hexane extract was washed with brine, dried with magnesium sulphate and evaporated in vacuo. After chromatography of the evaporation residue over silica gel 2.48 grams of the acid were eluted with diethyl ether in the form of a colourless oil. (e) (5Z,13E)-(8R,nR,12R,15R)-9-0xo-n,15-bis-(2-tetrahydropyranyloxy)15-({2RST-1,3-benzodi oxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid.

To a solution of 2.35 grams of the alcohol obtained as described under 10 ’ (d) in 30 ml of acetone were added at -20°C 2.46 ml of Jones reagent (J. Chem. Soc. 1953, 2555), and the mixture was stirred for 30 minutes at -20°C. Then 3 ml of isopropyl alcohol were added dropwise, and the mixture was stirred for 10 minutes at -20°C, diluted with diethyl ether and extracted three times by agitation with water. The organic phase was dried with [5 magnesium sulphate and evaporated in vacuo. There were obtained 2.1 grams of the ketone in the form of a colourless oil. (f) (5Z,13E)-(8R,11R,12R,15R)-11,15-Dihydroxy-9-oxo-15-({2RS)-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid.

General formula I: A = trans CH = CH; B = cis CH = CH; X Y = CH2—CH; OH Z =/ C = 0; Rj = OH; R2, R3, R4 = H; the OH group at C-15 is in the a-configuration. 2.1 grams of the bis-tetrahydropyranyl ether obtained as described - 36 434S3 under (e) were stirred for 5 hours at 40°C in 42 ml of a mixture consisting of 65 parts by volume of glacial acetic acid, 35 parts by volume of water and 10 parts by volume of tetrahydrofuran. The mixture was then evaporated to dryness at 0.1 Torr, and the crude product was purified by column chromatography. With chloroform/ethanol (95/5 v/v) there were eluted 450 mg of the Ez-derivative in the form of a colourless oil. (g) To a solution of 130 mg of the acid obtained as described under (f) in 4 ml of methylene chloride were added dropwise at ice-bath temperature 7 ml of an ethereal solution of diazomethane, and the mixture was stirred for 2 minutes and then evaporated in vacuo. After chromatography of the crude product over silica gel (diethyl ether/dioxan 95/5 v/v) there were obtained, in addition to mixed fractions, 56 mg of the prostadienoic acid methyl ester identified in the heading of this Example in the form of an oil, which was homogeneous on thin-layer chromatography.

IR: 3400 (wide), 1740, 1730, 1590, 1490, 980, 750 cm-1.

Example 8 (5Z,13E)-(8R,HR,12R,155)-11,15-Dihydroxy-9»oxo-15-({2RS}-l ,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester.

General formula I: A « trans CH * CH; B - cis CH = CH; X ... Y = CH,—CH; OH Z 7. C » 0; Rj = OCH3, OH; R2, R3, Ri+ = H; the OH group at C-15 is in the B-configuration. (a) (lS,5R,6R,7R,3S)-6-{(E)-3-Hydroxy-3-({2RS}-l,3-benzodioxan-2-yl)-lpropenyl}-7-hydroxy-2-oxabicyclo{3,3,0}octan-3-one. 2.16 Grams of (IS^R^R^R^'Sj-S-ifEJ-a-hydroxy-S-tfaRSj-l.a-benzodi oxan-2-yl)-1-propeny1}-7-benzoyloxy-2-oxabi cyclo{3,3,0}cctan-3-one {pre5 pared as described in Example 2(a)} and 687 mg of anhydrous potassium carbonate were stirred for 2.5 hours in 99 ml of methanol at room temperature. There were then added 99 ml of O.lN-hydrochloric acid, the mixture was stirred for 15 minutes, and extracted with ethyl acetate, and the organic phase was agitated with brine, dried and evaporated in vacuo.

The crude product was chromatographed over silica gel. There were obtained 1.38 grams of the diol in the form of a colourless oil. (b) (lS,5R.6R,7R,3'S)-6-{(E)-3-({2RS}-l,3-Benzodioxart-2-yl)-3-(2-tetrahydropyranyloxy)-l-propenyl}-7-(2-tetrahydropyranyloxy)-2-oxabicyclo{3,3,0}-octan-3-one.

To a solution of 1.38 grams of the diol obtained as described under (a) in 30 ml of methylene chloride were added at ice-bath temperature 4.5 ml of dihydropyran (freshly distilled) and 10 mg of para-toluenesulphonic acid, and the mixture was stirred for 15 minutes at approximately 5°C, diluted with methylene chloride, agitated with a sodium bicarbonate solution and with brine, dried with magnesium sulphate and evaporated iin vacuo. After chromatography of the crude, product over silica gel (diethyl ether/hexane 8/2 v/v) there were obtained 1.91 grams of the bistetrahydropyranyl ether in the form of a colourless oil. (c) (2RS,3aR,4R,5R,6aS,3'S)-4-{(E)-3-({2RS}-l,3-Benzodioxan-2-yl)-3-(2i tetrahydropyrany1oxy)-l-propenyl)-5-(2-tetrahydropyranyloxy)-per- 38 43453 hydrocyclopenta{b}furan-2-ol.

General formula II: A = trans CH =CH; R2, R3, Ri, = H; Rs, R6 = 2-THP; the OTHP group at C-3' is in the β-configuration.

In a manner analogous to that described in Example 7(c) 1.91 grams of the lactone obtained as described under (b) in 75 ml of absolute toluene were reduced with 19 ml of diisobutylaluminium hydride (DIBAH) solution.

By working up in the usual manner there were obtained 1.93 grams of the lactol in the form of a colourless oil. (d) (5Z,13E)-(8R,9S,llR,12R,15S)-9-Hydroxy-ll,15-bis-(2-tetrahydropyranyloxy)-15-({2RS}-1,3-benzodioxan-2-yl)-15,17,18,19,20-pentanorprostadienoic acid.

In a manner analogous to that described in Example 7(d) 1.93 grams of the lactol obtained as described under (c) in 30 ml of absolute DMSO were reacted with an ylene-solution, which had been prepared from 8.47 grams of (4-earboxybuty1)-triphenylphosphonium bromide and 31 ml of sodium methylsulphinylmethide solution. After working up in the usual manner the crude product was purified by column chromatography. 2.1 Grams of the acid were eluted with ether in the form of a colourless oil. (e) (5Z,13E)-(8R,llR,12R,15S)-9-0xo-ll,15-bis-(2-tetrahydropyranyloxy)15-({2RS}-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid.

In a manner analogous to that described in Example 7(e) 2.05 grams of the alcohol obtained as described under (d) in 50 ml of acetone were oxidized with 2.14 ml of Jones reagent at -20°C, After working up, there was obtained 1.84 grams of the ketone in the form of a colourless oil. - 39 4 3 4 5 3 (f) {5Z,13E)-{8RsnR,12R,15S)-n,15-Dihydroxy-9-oxo-15-(i2RS}-l,3benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid.

General formula I: A = trans CH = CH; B = ris Cli =· CH; X ... Y = CK2—CH; OH Z => C = 0; Rj = OH; R2, R3, = H; the OH group at C-15 is in the ^-configuration.

In a manner analogous to that described in Example 7(f) 1.84 grams of the bistetrahydropyranyl ether obtained as described under (e) were stirred with 18 ml of an acetic acid/tetrahydrofuran mixture. By working up and chromatography over silica gel (chloroform/ethanol -95/5 v/v) there were obtained 528 mg of the E2-derivative in the form of a colourless oil. (g) 98 mg of the prostadienoic acid obtained as described under (f) were converted in a manner analogous to that described in Example 7(g) into the prostadienoic acid methyl ester.

Yield: 76 mg; IR: 3400 (wide), 1740, 1730, 1590, 1490, 980, 750 cm-1.

Example 9 (5Z,13E)-(8R,11R.12R,15R)-11,15-Dihydroxy-9-oxo-15-({2R}-1,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester.

General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y = CH2—CH; OH Z C = 0; Rj = 0CH3, OH; R2, R3, Ru = H; the OH group at C-15 is in the «-configuration. - 40 The preparation was carried out in a manner analogous to that described in Example 7(a)—(g) from the starting compound prepared as described in Example 3(b). The yield was 400 mg of the prostadienoic acid in the form of a colourless oil and 60 mg of the prostadienoic acid methyl ester (prepared from 130 mg of the acid).

IR (methyl ester): 3500—3400. 1740, 1730, 1590, 1490, 980, 750 cm1 Example 10 (5Z,13E)-(8R,11R,12R,15S)-11,15-Dihydroxy-9-oxo-15-({2R}-l,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester.

General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y = CH2—CH; OH Z =;c = 0; Rj = 0CH3, OH; R2, R3, Rt, = H; the OH group at C-15 is in the p-configuration.

The preparation was carried out in a manner analogous to that described in Example 8(a)—(g) from the starting compound prepared as described in Example 4(a).

Yield: 510 mg of the prostadienoic acid in the form of a colourless oil, and 70 mg of the prostadienoic acid methyl ester (from 100 mg of the acid); IR (methyl ester): 3500—3400, 1740, 1730, 1590, 1490, 980, 750 cm-1 Example 11 (5Z,13E)-(8R,11R,12R,15R)-11,15-Dihydroxy-9-oxo-15-({2RS}-l,3-benzodioxan· 2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl - 41 4 3 4 5 3 ester.

General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y = CH2—CH; OH Z =^- C = 0; = OCHj, OH; R2, R3, Rk = H; the OH group at C-15 is in the a-configuration.

The preparation was carried out in a manner analogous to that described in Example 7(a)—(g) from the starting compound prepared as described in Example 5(b).

Yield: 310 mg of the prostadienoic acid in the form of a colourless 0 oil, and 50 mg of the prostadienoic acid methyl ester (from 120 mg of the acid); IR (methyl ester): 3500—3400, 1740, 1730, 1590, 1490, 980, 750 cm-1. Example 12 (5Z,13E)-(8R,11R,12R,15S)-11,15-Dihydroxy-9-oxo-15-({2S}-l,3-benzodioxan5 2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl . ester.

General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y = CH-r-CH; OH Z =>C = 0; Ri = OCH3 , OH; R2, R3, Rq = H; the OH group at I C-15 is in the p-configuration.

The preparation was carried out in a manner analogous to that described in Example 8(a)—(g) from the starting compound prepared as - 42 43453 described in Example 6(a).

Yield: 410 mg of the prostadienoic acid, and 150 mg of the prostadienoic acid methyl ester (from 210 mg of the acid); IR (methyl ester): 3500—3400, 1740, 1730, 1590, 1490, 980, 750 cm1.

Example 13 (5Z)-(8R,9S,llR,12R,15R)-9,ll,15-Trihydroxy-15-({2RS}-l,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester. General formula I: A = CH2—CH2; B = cis CH = CH; X ... Y = CH2—CH; OH H Rj = 0CH3, OH; R2, R3, Ri* = H; the OH group at C-15 is in the «-configuration. (a) (lS,5R,6R,7R,3'R)-6-{3-Hydroxy-3-({2RS}-l,3-benzodioxan-2-yl)-115 propyl}-7-benzoyloxy-2-oxabicyclo{3,3,0}octan-3-one. 2.3 grams of the α-alcohol obtained as described in Example 1(d) and 230 mg of 10% palladium on carbon were agitated for 2 hours in 40 ml of ethyl acetate under an atmosphere of hydrogen. After filtering and evaporating there were obtained 2.3 grams of the above-mentioned alcohol in the form of a colourless oil.

IR: 3500, 1775, 1720, 1590, 1490, 770 cm1. - 43 43453 In the NMR-spectrum no olefinic protons were detected. (b) (lS,5R,6R,7R,3'R)-6-{3-Hydroxy-3-({2RS}-l,3-benzodioxan-2-yl)-lprupyl}-7-hydroxy-2-oxab i cyclo L 3,3,0}octan-3-one.

From 2.20 grams of the saturated alcohol obtained as described under 5 (a) there were obtained by hydrolysis in accordance with the procedure described in Example 7(a) 1.34 grams of the saturated diol in the form of a colourless oil.

IR: 3600 strong, 1775, 1590, 1490, 760 cm-1. (c) (1S,5R,6R,7R,3'R)-6-{3-({2RS}-l,3-Benzodioxan-2-yl)-3-(2-tetrahydro0 pyranyloxy)-l-propyl}-7-(2-tetrahydropyranyloxy)-2-oxabicyclo{3,3,01octan-3-one.

From 1.13 grams of the diol obtained as described under (b) there were obtained with dihydropyran in a manner analogous to that described in Example 7(b) 1.08 grams of the above-mentioned bis-(tetrahydropyranyl) ether in the form of a colourless oil.

IR: 1775, 1590, 1490, 1100, 760 cm’1. (d) (2RS,3aR,4R,5R,6aSs3'R)-4-{3-({2RS}-l,3-Benzodioxan-2-yl)-3-(2-tetrahydropyranyloxy)-l-propyll-5-(2-tetrahydropyranyloxy)-perhydrocyc1openta{b}-furan-2-ol.

General formula II: A = CH2—CH2; R2, R3, Ri, = H; R5, Rs = 2-THP, the OTHP group at C-3' is in the a-configuration.

In accordance with the procedure described in Example 7(c) there were obtained by the reduction of 1.08 grams of the bis-(tetrahydropyranyl)ether prepared as described under (c) 1.06 grams of the above-mentioned lacto! i in the form of a colourless oil. - 44 43453 IR: 3600, 1590, 1490, 1100, 760 cm1. (e) (5Z)-(8R,9S,llR,12R,15R)-9-Hydroxy-ll,15-bis-(2-tetrahydropyranyloxy)15-((2RS }-1,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostenoic acid. 1.06 grams of the lactol obtained as described under (d) were converted in accordance with the procedure described in Example 7(d) into 866 mg of the above-mentioned prostenoic acid.

IR: 3600—3400, 1710, 1590, 1490, 760 cm1. (f) (5Z)-(8R,9S,11R,12R,15R)-9,n ,15-Trihydroxy-15-({2RSI-1,3-benzodioxan2 - yl)-16,17,18,19,20-pentanorprostenoic acid. 310 mg of the compound obtained as described under (e) were stirred for 3 hours at 50°C in 9 ml of a mixture of acetic acid/water/tetrahydrofuran = 65/35/10 v/v/v. The mixture was evaporated to dryness in vacuo, and there were obtained by chromatography over 10 grams of silica gel (chloroform/ethanol 4/1 v/v) 211 mg of the above-mentioned compound in the form of a colourless oil.

IR: 3600—3300, 1710, 1590, 1490, 760 cmi. (g) To a solution of 130 mg of the acid obtained as described under (f) in 4 ml of methylene chloride were added dropwise at ice-bath temperature 7 ml of an ethereal solution of diazomethane, and the mixture was stirred for 15 minutes and then evaporated in vacuo. After chromatography of the crude product over silica gel (methylene chloride/3% by volume isopropanol) there were obtained 90 mg of the prostenoic acid methyl ester identified in the heading of this Example.

IR: 3600—3300, 1730, 1590, 1490 , 760 cm-1. - 45 43453 Example 14 (5Z)-(8R,9S,11R,12R,15S)-9,11,15-Trihydroxy-15-({2RS}-1,3-benzodioxan2 - yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

General formula I: A = CH2—CH2; B = cis CH = CH; X ... Y = CH2—CH , OH ,0H Z >H Rx = OCH3, OH; R2, R3, Rq = H; the OH group at C-15 is in the e-configuration. (a) (1S,5R,6R,7R,3'$)-6-{3-Hydroxy-3-({2RS}-1,3-benzodioxan-2-yl)-1propyl}-7-benzoyloxy-2-oxabi cyclo{3,3,0}octan-3-one.

In a manner analogous to that described in Example 13(a) 2.4 grams of the β-alcohol obtained as described in Example 2(a) were hydrogenated to form 2,4 grams of the above-mentioned saturated alcohol. A colourless oil was obtained.

IR; 3600, 1775, 1720, 1590, 1490, 770 cm’1 (b) (lS,5R,6R,7R,3'S)-6-{3-Hydroxy-3-({2RS}-l,3-benzodioxan-2-yl)-lpropyl}-7-hydroxy-2-oxabicyclo{3,3,01octan-3-one.

From 2.3 grams of the saturated alcohol obtained as described under 0 (a) there were obtained by hydrolysis with potassium carbonate in accordance with the procedure described in Example 7(a) 1.39 grams of the saturated diol in the form of a colourless oil. - 46 434S3 IR; 3600 (strong), 1775, 1590, 1490, 760 cm'1. (c) (lS,5R,6R,7R,3S)-6- 3-({2RSJ-1,3-Benzodioxan-2-yl)-3-(2-tetrahydropyranyloxy)-1-propyl )-7-(2-tetrahydropyranyloxy)-2-oxabi cyclοί 3,3,0) octan-3-one.

From 1.0 gram of the diol prepared as described under (b) there was obtained with dihydropyran in a manner analogous to that described in Example 7(b) 0.93 gram of the above-mentioned bis-(tetrahydropyranyl) ether in the form of a colourless oil.

IR: 1775, 1590, 1490, 1100, 760 cm-1. id) (2RS,3aR,4R,5R,6aS,3S)-4-{3-({2RS}-l,3-Benzodioxan-2-yl)-3-(2-tetrahydropyranyloxy)-1-propyl )-5-(2-tetrahydropyranyloxy)-perhydrocyclopenta{b)furan-2-o1.

In accordance with the procedure described under Example 7(c) there was obtained by the reduction of 0.74 gram of the bis-(tetrahydropyranyl) ether prepared as described under (c) 0.7 gram of the above-mentioned lactol in the form of a colourless oil.

IR: 3600, 1590, 1490, 1100, 760 cm1. (e) (5Z)-(8R,9S,llR,12R,15S)-9-Hydroxy-n ,15-bis-(2-tetrahydropyranyloxy)15-(ί2RSJ-1,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostenoic 20 acid. 0.7 gram of the lactol obtained as described under (d) was converted in accordance with the procedure described in Example 7(d) into 0.51 gram of the above-mentioned prostenoic acid.

IR: 3600-3400, 1710, 1590, 1490, 1100, 760 cm1. - 47 43453 (f) (5Z)-(8R,9S,Π R,12R,75S)-9,Π,15-Trihydroxy-15-({2RS}-1,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostenoic acid.

In a manner analogous to that described in Example 13(f) there were obtained from 345 mg of the trio! obtained es described under (e) 219 mg 5 of the above-mentioned compound in the form of a colourless oil.

IR: 3600—3300, 1710, 1590, 1490, 760 cm1. (g) By esterification in a manner analogous to that described in Example 13(g) there were obatained from 120 mg of the acid obtained as described under (f) 85 mg of the prostenoic acid methyl ester identified in the heading of this Example.

IR: 3600—3300, 1730, 1590, 1490, 755 cm1.

Example 15 (5Z)-(8R,9S,nR,12R,15R)-9,n,15-Trihydroxy-15-({2R}-l,3-benzodioxan-2y1)-!6,l7,l8,l9,20-pentanorprostenoic acid and its methyl ester.

General formula I: A = CH2—CH2; B = cis CH = CH; X ... Y = CH2—CH ; OH Ri = OCH3, OH; R2, R3, Rif = H; the OH group at C-15 is in the a-configuration. ίθ starting from the α-alcoho'l obtained as described in Example 3(b) the compounds identified in the heading were obtained by reaction stages analogous to those described in Example 13(a)—(g). - 48 IR (methyl ester): 3500-3300. 1730, 1590, 1490, 760 cm1.

Example 16 (5Z)-(8R,9S,llR,12R,15S)-9,11,15-Trihydroxy-15-({2R}-l,3-benzodioxan-2yl )-16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

General formula I: A = CH2—CH2; 8 = cis CH = CH; X ... Y = CH2—CH OH Ri - OCHj, OH; R2, R3j Ru = H; the OH group at C-15 is in the g-configuration.

Starting from the β-alcohol obtained as described in Example 4(a) the compounds identified in the heading were obtained by reaction stages analogous to those described in Example 14(a) to (g).

IR (methyl ester): 3400 (wide), 1730, 1590, 1490, 760 cm-1.

Example 17 (5Z)-(8R,9S,llR,l2R,l5R)-9,ll,15-Trihydroxy-l5-({2S}-1,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

General formula I: A = CH2—CH2; B = cis CH = CH; X ,,. Y = CH2~CH ; OH Rj - OCHj, OH; R2, R3, R,+ = H; the OH group at C-15 is in the - 49 ¢3453 «-configuration.

Starting from the «-alcohol obtained as described in Example 5(b) the compounds identified in the heading were obtained by reaction stages analogous to those described in Example 13(a)—(r).

IR (methyl ester): 3400 (wide), 1735, 1590, 1490, 760 cm'1.

Example 18 (5Z)-(8R,9S,11R,12R,15S)-9,11,15-Trihydroxy-15-({2S}-1,3-benzodioxan2-yT)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

General formula I: A = CHZ—CH2; B = cis CH = CH; X ... Y = CH2—CH; OH .cOH Z = C Rj = 0CH3, OH; Rz, R3, Ri* = H; the OH group at C-15 is in the S-configuration.

Starting from the β-alcohol obtained as described in Example 6(a) the compounds identified in the heading were obtained by reaction stages analogous to those described in Example 14(a)—(g).

IR (methyl ester): 3400 (wide), 1735, 1590, 1490, 760 cm'1.

Example 19 (5Z)-(8R,nR,12R,15R)-ll ,15-Dihydroxy-9-oxo-15-( {2RS1-1,3-benzodioxan0 2-yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

General formula I: A = CH2—CH2; B = cis CH = CH; X ... Y = CH2_CH ; OH - 50 43453 Z = ^. C = 0; Rj = 0CH3, OH; R2, R3, R4 = H; the OH group at C-15 is in the a-configuration. (a) (5Z)-(8R,11R,12R,I5R)-ll,15-Bis-(2-tetrahydropyranyloxy)-9-oxo-15({2RS}-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostenoic 5 acid. 300 mg of the compound obtained as described in Example 13(e) were converted by oxidation in a manner analogous to that described in Example 7(e) into the above-mentioned compound and 210 mg were obtained in the form of a colourless oil.

IR; 3600—3300, 1740, 1710, 1590, 1490, 760 cm-1. (b) (5Z)-(8R,HR,12R,15R)-ll,15-Dihydroxy-9-oxo-15-({2RS}-l,3-benzodi oxan-2-yl)-16,17,18,19,20-pentanorprostenoic acid.

In accordance with the procedure described in Example 7(f) there were obtained from 150 mg of the compound obtained as described under (a) 90 mg of the above-mentioned compound in the form of a colourless oil.

IR: 3600—3400, 1740, 1710, 1590, 1490, 760 cm’1 (c) In a manner analogous to that described in Example 7(g) there were obtained from 90 mg of the acid obtained as described under (b) 75 mg of the prostenoic acid methyl ester identified in the heading of this Example.

IP.; 3600—3400, 1740, 1730, 1590, 1490, 750 cm-1.

Example 20 (5Z)-(8R,11R,12R,15S)-11,15-Dihydroxy»9-oxo-15-({2RS}-l,3-benzodioxan2-y1)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

General formula 1: fi = CH2—CH2; 8 = cis CH = CH; - 51 43453 X ... Υ = CH2—CH ; OH I =S- C = 0; Rr = 0CH3, OH; R2, R3, Rt, = H; the OH group at C-15 is in the β-configuration. (a) (5Z)-(8R,11R,12R,15S;-11,15-Bis-(2-tetrahydropyranyloxy)-9-oxo-155 ({2RSI-1,3-benzodi oxan-2-yl)-16,17,18,19,20-pentanorprostenoic acid. 280 mg of the compound obtained as described in Example 14(e) were converted by oxidation in a manner analogous to that described in Example 7(e) into the above-mentioned compound. 180 mg were obtained in the form of a colourless oil.

IR: 3600—3300, 1740, 1710, 1590, 1490, 760 cm·1. (b) (5Z)-(8R,llR,12R,15S)-11,15-Dihydroxy-9-oxo-15-({2RS}-l,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostenoi c aci d.

In accordance with the procedure described in Example 7(f) 145 mg of 15 the compound obtained as described under (a) were reacted to form 80 mg of the above-mentioned diol.

IR: 3600—3400, 1740, 1710, 1590, 1490, 755 cm-1. (c) In a manner analogous to that described in Example 7(g) there were obtained from 80 mg of the acid obtained as described under (b) 56 mg of -0 the prostenoic acid methy! ester identified in the heading of this Example.

IR: 3600—3400, 1740, 1730, 1590, 1490 , 755 cm-1.

Example 21 (5Z)-(8R,llR,12R,15R)-n,15-Dihydroxy-9-oxo-15-(i2R)-l,3-benzodioxan-2-yl)- 52 43453 16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

General formula I: A = CHZ—CH?; B = cis CH = CH; X ... Y = CH2—CH ; OH Z =^- C = 0; Rj = 0CH3, OH; R2, R3, = H; the OH group at C-15 is in the a-configuration.

Starting from the derivative of Example 15 corresponding to the derivative obtained as described in Example 13(e) the compounds identified in the heading were obtained by reaction stages analogous to those described in Example 19(a)—(c).

IR (methyl ester): 3500—3400, 1740, 1730, 1590, 1490, 750 cm-1.

Example 22 (5Z)-(8R,1IR,12R,15S)~n,15-Dihydroxy-9-oxo-15-({2R}-l,3-benzodioxan-2yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

General formula I: A = CH2—CH2; B = cis CH = CH; X ... Y = CH2—CH ; OH Z C C = 0; Ri = OCH3, OH; R2, R3, R„ = H; the OH group at C-15 is in the 8-configuration.

Starting from the derivative of Example 16 corresponding to the derivative obtained as described in Example 14(e) the compounds identified in the heading were obtained by reaction stages analogous to those described in Example 19(a)—(c). - 53 43453 IR (methyl ester): 3600-3^-00. 1740, 1730, 1590, 1490, 755 cm-1.

Example 23 (5Z)-(8R,11R,12R,15R)-11,15-Dihydroxy-9-oxo-15-({2S}-l,3-benzodioxan-2yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

General formula I; A = CHZ—CH2; 5 - cis CH = CH; X ... Y = CH2—CH ; OH Z C = 0; Rj = 0CH3, OH; R2, R3, Rq = H; the OH group at C-15 is in the a-configuration.

Starting from the derivative of Example 17 corresponding to the deri10 vative obtained as described in Example 13(e) the compounds identified in the heading were prepared by reaction stages analogous to those described in Example 19(a)—(c).

IR (methyl ester): 3600—3400, 1740, 1730, 1590, 1490, 755 cm-1.

Example 24 (5Z)-(8R,llR,12R,15S)-n,15-Dihydroxy-9-oxo-l5-({2$}-l,3-benzodioxan-2yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

General formula I: A = CHZ—CH2; B = cis CH = CH; X ... Y = CH2—CH ; OH Z ¢: C = 0; Ri = 0CH3, OH; R2, R3, Rq = H; the OH group at C-15 0 is in the β-configuration.

Starting from the derivative of Example 18 corresponding to the derivative obtained as described in Example 14(e) the compounds identified in - 54 ¢3453 the heading were prepared by reaction stages analogous to those described in Example 19(a)—(c).

IR (methyl ester): 3500—3400, 1740, 1730, 1590, 1490, 750 cm-1.

Example 25 (5Z,10,13E)-(8R,12S,15R)-15~Hydroxy-9-oxo-15-({2RS}-l,3-benzodioxan-2-yl)16,17,18,19,20-pentanorprostatrienoic acid and its methyl ester.

General formula I: A = trans CH = CH; B = cis CH = CH; X...Y = CH = CH; Z / C = 0; Rx = 0CH3, OH; R2, R3, = H; the OH group at C-15 is in the «-configuration.

A solution of 88 mg of (5Z,13E)-(8R,llR,12R,15R)-ll,15-dihydroxy9-oxo-15-({2RS1-1,3-benzodioxan-2-y1)-16,17,18,19,20-pentanorprostadienoic acid {obtained as described in Example 7(f)} in 5 ml of 90% w/v acetic acid was stirred for 19 hours at 60°C and then evaporated in vacuo. After chromatography over silica gel (diethyl ether/3% by volume dioxan) the resulting prostatrienoic acid was esterified with an ethereal solution of diazomethane. There were obtained 45 mg of the methyl ester identified in the heading in the form of a pale yellow coloured oil.

IR (methyl ester): 3600—3300, 1730, 1700, 1590, 1490 , 980 , 760 cm-1 Example 26 (5Z,10,13E)-(8R,12S,15R)-15-Hydroxy-9-oxo-15-({2RS}-l,3-benzodioxan-2-yl)16,17,18,19,20-pentanorprostatrienoic acid and its methyl ester.

General formula 1: A = trans CH = CH; B = cis CH = CH; X...Y=CH=CH; Z =>C = 0; Rj = 0CH3, OH; R2, R3, R4 = H; the OH group at C-15 is in the s-configuration.

In a manner analogous to that described in Example 25 the compounds - 55 <3453 identified in the heading were prepared from the compound obtained as described in Example 8(f), IR (methyl ester): 3500—3300, 1730, 1705, 1590, 1490, 980, 760 cm-1 Example 27 (5Z,10,13E)-(8R,12S,15R)-15-Hydroxy-9-oxo-15-({2Rl-l,3-benzodioxan-2-yl)16,17,18,19,20-pentanorprostatrienoic acid and its methyl ester.

General formula I; A = trans CH = CH; B = cis CH = CH; X...Y=CH=CH; Z =>7 C = 0; Rj = 0CH3, OH; R2, R3, Ri, = H; the OH group at C-15 is in the a-configuration.

In a manner analogous to that described in Example 25 the compounds identified in the heading were prepared from the compound obtained as described in Example 9(f).

IR (methyl ester): 3600-3300, 1730, 1700, 1585, 1490, 980, 760 cm1 Example 28 (5Z,lO,l3E)-(8R,l2S,l5S)-l5-Hydroxy-9-oxo-l5-({2R}-l,3-benzodioxan-2-y1)16,17,18,19,20-pentanorprostatrienoic acid and its methyl ester.

General formula I: A = trans CH = CH; B = cis CH = CH; X...Y=CH=CH; Z =C? C = 0; R; = 0CH3, OH; R2, R3, Ri, = H; the OH group at C-15 is in the B-configuration, :0 In a manner analogous to that described in Example 25 the compounds identified in the heading were prepared from the compound obtained as described in Example 10(f).

IR (methyl ester): 3600—3300, 1730, 1700, 1590, 1490, 980, 760 cm1 Example 29 (5Z,l0,l3E)-(8R,12S,l5R)-15-Hydroxy-9-oxo-({2S}-l,3-benzodioxan-2-yl)- 56 16,17,18,19,20-pentanorprostatrienoic acid and its methyl ester.

General formula I: A = trans CH = CH; B = cis CH = CH; X...Y-CH-CH; Z -D C = 0; Rj - 0CH3, OH; R2, R3, R4 = H; the OH group at C-15 is in the a-configuration.

In an manner analogous to that described in Example 25 the compounds identified in the heading were prepared from the compound obtained as described in Example 11(f).

IR (methyl ester): 3500—3300, 1730, 1700, 1590, 1485, 980, 760 cm-1.

Example 30 (5Z,10,13E)-(8R,12S,15S)-15-Hydroxy-9-oxo-15-({2S}-l,3-benzodioxan-2-yl)16,17,18,19,20-pentanorprostatrienoic acid and its methyl ester. General formula I: A = trans CH = CH; B = cis CH = CH; X..,Y=CH=CH; Z -D C = 0; Ri = 0CH3, OH; R2, R3, Ru = H; the OH group at C-15 is in the e-configuration.

In a manner analogous to that described in Example 25 the compounds identified in the heading were prepared from the compound described in Example 12(f).

IR (methyl ester): 3600—3300, 1730, 1700, 1590, 1490, 980, 760 cm'1.

Example 31 (13E)-(8R,9S,llR,12R,15R)-9,11,15-Trihydroxy-15-({2RS}-1,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

General formula I: A = trans CH = CH; B = CH2—CH2; X ... Y = CH2—CH ; OH - 57 OH Ri = 0CH3, OH; R2, R3> Ri, = H; the OH group at C-15 is in the a-configuration. 150 mg of the compound obtained as described in Example 1(f) or 1(g) were mixed with 15 mg of 10% palladium on carbon, and stirred with 15 ml of ethyl acetate for 2 hours at -20°C under an atmosphere rf hydrogen.

After filtration, the mixture was evaporated to dryness in vacuo, and there were obtained the compounds identified in the heading, 140 mg of the ester being obtained in the form of a colourless oil.

IR (methyl ester): 3600-3300, 1730, 1590, 1490, 980, 750 cm-1.

The NMR-spectrum for the acid and for the methyl ester showed only two olefinic protons.

Example 32 From the corresponding starting compounds obtained as described in 15 Examples 2(d), 3(e), 4(d), 5(e) and 6(d) there can be prepared in a manner analogous to that described in Example 31: (13E)-(8R,9S,llR,12R,15S)-9,Π,15-Trihydroxy-15-((2RS}-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester, '0 (13E)-(8R,9S,llR,12R,15R)-9,ll,15-trihydroxy-15-({2R}-1,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester, (13E)-(8R,9S,llR,12R,15S)-9,ll,15-trihydroxy-15-({2R}-l,3-benzodioxan2-yl)-16,17,18,l9,20-pentanorprostenoic acid and its methyl ester, - 58 4345 (13E)-(8R,9S,11R,12R,15R)-9,11 ,15-trihydroxy-15-((2S}-l,3-benzodioxan2-yl)-16.17,18,19,20-pentanorprostenoic acid and its methyl ester and (13E)-(8R, 9S, HR, 12R,15S)-9,11,15-trihydroxy~15-({2S}-l,3-benzo5 dioxan-2-yl)~16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

Example 33 By interposing in the sequence of reactions leading to the compounds of Examples 7 to 12 a reduction of the compounds obtained as described in Examples 7(d), 8(d), 9(d), 10(d), 11(d) and 12(d) analogous to the process described in Example 31, the following compounds were obtained; (13E)-(8R,11R,12R,15R)-11,15-Dihydroxy-9-oxo-15-({2RS}~l,3-benzodi oxan-2-yl )-16, 17,18,19,20-pentanorprostenoic acid and its methyl ester, (13E)-(8R,llR,12R,15S)-ll,15-dihydroxy-9-oxo-15-({2RS}-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester, (13E)-(8R,UR,12R,15R)-ll,15-dihydroxy-9-oxo-15-({2R}-l,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester, (13E)-(8R,11R,12R,15S)-11,15-dihydroxy-9-oxo-15-({2R}-l,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester and (13E)-(8R,llR,12R,15R)-n,15-dihydroxy-9-oxo-15-({2S}-l,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester and - 59 43453 (13E)-(8R,nR,12R,15S)-ll,15-dihydroxy-9-oxo-15-({2Sl-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester.

Example 34 (8R,9S,llR,12R,15R)-9,ll,15-Trihydroxy-15-( General formula I: A = B = CH2—CH2; X ... Y = CH2—CH ; OH OH Ri = 0CH3, OH; R2, R3, Ri, = H; the OH group at C-15 is in the a-configuration. 432 mg of the acid or ester thereof obtained as described in Example 1, 45 mg of 10% palladium on carbon and 10 ml of ethyl acetate were agitated at room temperature in an atmosphere of hydrogen until 2 inmoles of hydrogen had been absorbed. After filtration and evaporation there were obtained the compounds identified in the heading, 420 mg of the ester being obtained in the form of a colourless oil.

IR (methyl ester): 3600—3400. 1730, 1590, 1490, 760 cm’1 Example 35 In a manner analogous to that described in Example 34 there were obtained with the products obtained as described in Examples 2 to 6 the following derivatives: - 60 43453 (8R,9S,lIR,12R,15S)-9,ll,15-Trihydroxy-15-({2RS}-l,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostenoic acid and its methyl ester, (8R,9S,llR,12R,15R)-9,ll,15-trihydroxy-15-({2R}-l,3-benzodioxan-2yl)-16,17,18,19,20-pentanorprostanoic acid and its methyl ester, (8R,9S,11R,12R,15S)-9,ll,15-trihydroxy-15-({2R}-l,3-benzodioxan-2yl)-16,17,18,19,20-pentanorprostanoic acid and its methyl ester, (8R,9S,11R,12R,15R)-9,11,15-trihydroxy-15-([2S1-1,3-benzodioxan-2yl)16,l7,18,19,20-pentanorprostanoic acid and its methyl ester and (8R,9S,11R,12R,15S)-9,ll,15-trihydroxy-15-({2S}-l,3-benzodioxan-2yl)-16,17,18,19,20-pentanorprostanoic acid and its methyl ester.

Example 36 (5Z,13E)-(8R,9S,l2R,l5R)-9,l5~Dihydroxy-l1-oxo-l5-({2RS}-l ,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester.

General formula I: A = trans CH = CH; 8 = cis CH = CH; X ... Y = CH220 \ ZH z = c /S Rj = 0CH3, OH; R2, R3, Ri, = H; the OH group at C-15 is in the a-configuration. (a) (lS,5R,6R,7R,3'R)-6-{(E)-3-(2-Tetrabydropyranyloxy)-3-(i2RS}-1.3- 61 43453 benzodi oxan-2-yl)-1-propenyl}-7-benzoyloxy-2-oxabi cyclo{3,3,0}octan-3-one.

To a solution of 2.4 grams of the α-alcohol obtained as described in Example 1(d) in 50 ml of methylene chloride were added at ice-bath tempera5 ture 3 ml of dihydropyran (freshly distilled) and 10 mg of para-toluenesulphonic acid, and the mixture was stirred for 15 minutes at that temperature, diluted with methylene chloride and agitated with a sodium bicarbonate solution. The organic phase was washed with water, dried with magnesium sulphate and evaporated in vacuo. There were obtained 2.8 grams of the above-mentioned compound. (b) (lS,5R,6R,7R,3'R)-6-{(E)~3-(2-Tetrahydropyranyloxy)-3-({2RS}-l,3benzodioxan-2-yl)~l-propenyl}-7-hydroxy-2-oxabicyc1o{3,3,0}octan-3-one.

A mixture of the 2.8 grams of the product obtained as described under (a) and 765 mg of potassium carbonate (anhydrous) in 110 ml of methanol (absolute) was stirred for 2 hours at room temperature under argon. The mixture was then diluted with ethyl acetate and washed until neutral with a saturated solution of sodium chloride. The organic phase was dried over magnesium sulphate and evaporated in vacuo. There were obtained . 1.85 grams of the above-mentioned compound. (c) (2RS,3aR,4R,5R,6aS,3‘'R)-4-{(E)-3-(2-Tetrahydropyranyloxy)-3-({2RS}l,3-benzodioxan-2-yl)-l-propenyl}-5-hydroxyperhydrocyclopenta{b}furan-2-ol.

To a solution, cooled to -70°C, of 1.85 grams of the lactone obtained l as described under (b) in 90 ml of absolute toluene were added dropwise - 62 a 3 4 5 3 under argon 22 ml of a 20% w/v DIBAH solution in toluene. After 30 minutes the reaction was terminated by the dropwise addition of isopropanol, and the whole was stirred at 0°C with the addition of 30 ml of water for 15 minutes. Then extraction with ethyl acetate, washing with brine, drying with magnesium sulphate and evaporating iri vacuo were carried out. There were obtained 1.8 grams of the above-mentioned compound in the form of a colourless oil. (d) (2RS,3aR,4R,5R,6aS,3''R)-4-{(E)-3-(2-Tetrahydropyranyloxy)-3-({2RSJ1.3- benzodi oxan-2-yl)-1-propenyl}-2,5-di acetoxyperhydrocyclopenta{b}furan. 1.8 Grams of the lactol obtained as described under (c) were stirred in a mixture of 10 ml of acetic anhydride and 25 ml of pyridine for 8 hours at room temperature. After removing the solvent in vacuo there were obtained 2.0 grams of the above-mentioned compound. (e) (2RS,3aR,4R,5R,6aS,3'R)-4-{(E)-3-(2-Tetrahydropyranyloxy)-3-({2RSl1.3- benzodioxan-2-yl)-l-propenyl}-5-acetoxyperhydrocyclopenta{b}furan-2-ol. 2.0 Grams of the diaeetate obtained as described under (d) were maintained in a mixture of 5 parts by volume of glacial acetic acid, 5 parts by volume of water and 1 part by volume of tetrahydrofuran for 15 minutes at 25°C, and the mixture was then stirred into a solution of sodium bicarbonate and washed until neutral. The organic phase was concentrated and the residue was purified by column chromatography over silica gel with diethyl ether/pentane = 1/1 v/v. 1.5 grams of the above-mentioned compound were obtained. - 63 43453 (f) (5Z,13E)-(8R,9S,llR,12R,15R)-9-Hydroxy-ll-acetoxy-15-(2-tetrahydropyranyloxy)-15-({2RS}-l,3-benzodioxan-2-yl)-16,17,18,19,20pentanorprostadienoic acid.

To a solution of 7.2 grants of (4-carboxybutyl)-triphenylphosphonium bromide in 30 ml of absolute diemthyl sulphoxide were added dropwise 26.3 ml of a solution of sodium methylsulphinylmethide in absolute DMSO (preparation of the solution: 2.5 grams of 50% w/v sodium hydride suspension in 50 ml of DMSO were stirred for one hour at 70°C), and the whole was stirred for 30 minutes at room temperature. This ylene-solution was then added dropwise at 15°C to a solution of 1.5 grams of the lactol obtained as described under (e) in 30 ml of absolute DMSO during the course of 15 minutes and the whole was stirred for 2 hours at 50°C. Most of the solvent v;as then distilled off at 45°C under the vacuum of an oil pump, and the residue was taken up in 70 ml of water and extracted three times with diethyl ether. The organic extract was discarded. The aqueous phase was acidified with a solution of 10% w/v citric acid to pH 4—5, and the mixture was extracted four times with a mixture of hexane/diethyl ether = 1/1 v/v. The diethyl ether/hexane extract was washed with brine, dried over magnesium sulphate and evaporated in vacuo. By chromatography of the residue over silica gel there were eluted with diethyl ether 1.1 grams of the above-mentioned compound in the form of a colourless oil. (g) (5Z,13E)-(8R,9S,nR,12R,15R)-9,15-Bis-(2-tetrahydropyranyloxy)-llacetoxy-15-({2RS}-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid. > To a methylene chloride solution of 1.1 grams of the compound obtained - 64 424X3 as described under (f) were added 2.2 ml of dihydropyran and 6 mg of para-toluenesulphonic acid at ice-bath temperature, and the whole was stirred for 15 minutes at that temperature. The mixture was then diluted with methylene chloride, and agitated with a sodium bicarbonate solution, and the organic phase was washed with water, dried over magnesium sulphate and concentrated. The residue was treated for 15 minutes at 25°C with a mixture of glacial acetic acid, water and tetrahydrofuran (5/5/1 v/v/v), and the mixture was then stirred into a solution of sodium bicarbonate and washed until neutral. After concentrating the organic phase there were obtained 1.2 grams of a colourless oil, (h) (5Z,13E)-(8R,9S,llR,12R,15R)-9,15-Bis-(2-tetrahydropyranyloxy)-llhydroxy-15-({2RS}-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid.

The 1.2 grams of product obtained as described under (g) were reacted in a manner analogous to that described under (b) with potassium carbonate and methanol. There was obtained 0.8 gram of the above-mentioned compound. (i) (5Z,13E)-(8R,9S,12R,15R)-9,15-Bis-(2-tetrahydropyranyloxy)-ll-oxo15-({2RS}-1,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid.

To a solution of 0.8 gram of the alcohol obtained as described under (h) in 10 ml of acetone was added at -20°C 0.84 ml of Jones reagent, and the mixture was stirred for 30 minutes at -20°C. 1 ml of isopropanol was then added dropwise, and the mixture was stirred for 10 minutes at -20°C, diluted with diethyl ether and extracted by agitation with water three times. The organic phase was dried over magnesium sulphate and evaporated - 65 43453 in vacuo. There were obtained 725 mg of the above-mentioned ketone in the form of a colourless oil. (j) (5Z,13E)-(8R,9S,12R,15R)-9,15-Dihydroxy-Il~oxo-15-({2RS}-1,3-benzodi oxan-2-yl)-16,17,18,19,20-pentanorpros tadi enoic aci d, 650 mg of the bis-tetrahydropyranyl ether prepared as described under (i) were stirred for 6 hours at 50°C in 15 ml of a mixture consisting of 65 parts by volume of glacial acetic acid, 35 parts by volume of water and 10 parts by volume of tetrahydrofuran. The mixture was then evaporated to dryness at 0.1 Torr, and the resulting crude product was purified by column chromatography. There were eluted with methylene chloride/5—8% by volume ethanol 280 mg of the above-mentioned compound. (k) To a solution of 140 mg of the acid obtained as described under (j) in 10 ml of methylene chloride were added dropwise at ice-bath temperature 7 ml of an ethereal solution of diazomethane, and the mixture was stirred for 10 minutes and then evaporated in vacuo. After chromatography of the crude product over silica gel with diethyl ether/dioxan = 95/5 v/v as eluant there were obtained 80 mg of the prostadienoic acid methyl ester identified in the heading of this Example.

IR: 3500—3300, 1740, 1730, 1590, 1485, 980, 760 cm1.

Example 37 In a manner analogous to that described in Example 36 there were obtained, starting from the compounds obtained as described in Examples 2(a), 3(b), 4(a), 5(b) and 6(a), the following derivatives: (5Z,13E)-(8R,9S,12R,15S)-9,15-Dihydroxy-ll-oxo-15-({2RS}-l,3-benzodioxan-2-y1)-l6,l7,l8,19,20-pentanorprostadienoic acid and its - 66 43453 methyl ester, (5Z, 13E)-(8R,9S,12R,15R)-9,15-dihyclroxy-n-oxo-15-({2R}-l ,3-benzodi oxan-2-y 1)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester. (5Z,13E)-(8R,9S,12R,15S)-9,15-dihydroxy-ll-oxo-15-({2R}-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester, (5Z,13E)-(8R,9S,12R,15R)-9,15-dihydroxy-ll-oxo-15-({2S}-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester and (5Z,13E)-(8R,9S,12R,15S)-9,15-dihydroxy-ll-oxo-I5-({2S}-l,3-benzodioxan-2-yl)-16,17,18,19,20-pentanorprostadienoic acid and its methyl ester.

Example 38 (5Z,13E)-(8R,9S,llR,12R,15R)-9,ll,15-Trihydroxy-15-({2RS}-6-bromo1,3-benzodioxan-2-yl)-16,17,18,l9,20-pentanorprostadienoic acid and its methyl ester.

General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y = CH2—CH ; OH \ c0H ZO Z = Z z S Rj = 0CH3,0H; R2, Ru = H; R3 = 6-Br; the OH group at C-15 is in the «-configuration. - 67 43453 (a) 5-Bromo-2-hydroxybenzyl alcohol.

To a suspension of 24.8 grams of saligenin and 24 grams of calcium carbonate in a solvent mixture of 200 ml of carbon tetrachloride and 220 ml of methylene chloride were added dropwise at 0—5°C 11.5 ml of bromine in 100 ml of carbon tetrachloride. The reaction mixture was stirred for 24 hours at room temperature, and then filtered, and the precipitate was washed with carbon tetrachloride. The CC1i,/CH2C12 phase was discarded.

The solid matter was taken up in ethyl acetate/water, and the organic phase was separated off, dried over magnesium sulphate and concentrated to dryness. The residue was recrystallized from methylene chloride.

There were obtained lamelliform, colourless crystals (24 grams).

Melting point: 107—109°C (methylene chloride). (b) 6-Bromo-l,3-benzodioxane-2-carboxylic acid methyl ester.

To 9.6 grams of a 50% sodium hydride suspension in 100 ml of dimethyl5 formamide was added dropwise while cooling with ice-water a solution of 20,3 grams of the 5-bromo-2-hydroxybenzyl alcohol obtained as described under (a) in 110 ml of dimethylformamide. The reaction mixture was stirred overnight at room temperature. There were then introduced dropwise 8.62 ml of dichloroacetic acid while cooling with ice in 100 ml of dimethyl) formamide. There were then added in portions 5.04 grams of 50% sodium hydride while cooling with ice. This sodium dichloracetate solution was stirred for 30 minutes at room temperature, and then introduced dropwise into the bromosaligenin-disodium solution first prepared. After the addition of 1.5 grams of sodium iodide the reaction mixture was stirred for 4.5 hours at 60°C. and during the last 2.5 hours the greater part of - 68 the dimethylformamide was distilled off in vacuo. After cooling, the residue was acidified to pH 3 with an aqueous solution of citric acid, saturated with sodium chloride, and extracted by agitation several times with methylene chloride. The organic phase was dried over magnesium sulphate, and concentrated in a rotary evaporator, and an ethereal solution of diazomethane was added at 0°C until the evolution of gas ceased and a yellow coloration of the reaction solution persisted. The solvent was removed together with the excess of diazomethane after stirring for J hour at room temperature in vacuo. The bright crystalline magma that remained behind was purified by column chromatography over silica gel with methylene chloride or hexane/10% by volume ethyl acetate as eluant.

Yield: 12.6 grams.

Melting point: 120°C (matted small needles from methylene chloride/ hexane). (c) {2-0xo-2-(6-bromo-l,3-benzodioxan-2-yl)-ethylidene}-triphenylphosphorane.

To a suspension of 13 grams of tri phenyl-methyl-phosphonium bromide (dried for 4 hours at 40°C under the reduced pressure of an oil pump) in 85 ml of absolute diethyl ether there were added dropwise, while cooling with ice and in an atmosphere of argon, 15.63 ml of a 2.15 m solution of butyl lithium in hexane, and then the whole was stirred for 15 hours at room temperature. To the yellow ylene-solution there were added dropwise 4,59 grams of the 6-bromo-l,3-benzodioxane-2-carboxylic acid methyl ester obtained as described under (b) in 75 ml of absolute benzene, the mixture was stirred for one hour at room temperature, and the white precipitate - 69 43453 was filtered off, dissolved in water and extracted with diethyl ether.

The organic phase was combined with the filtrate, washed with water, dried over magnesium sulphate and concentrated to dryness. The residue was purified by column chromatography over silica gel with hexane/20—100% by volume ethyl acetate.

Yield: 5.6 grams.

Melting point: 172°—174°C (ethyl acetate).

The further reaction stages were carried out in a manner analogous to that described in Example 1(c)—(g).

In an analogous manner all the other prostaglandin acids and esters thereof described in the present Examples can be converted into the derivatives corresponding to those described in Example 38.

Example 39 (5Z,13E)-(8R,9S,llR,12R,15R)-9,n ,15-Trihydroxy-15-({2RS 1-1,35 benzodi oxan-2-yl)-16,17,18,19,20-pentanorpros tadienoic acid 4-phenylphenacyl ester.

General formula I: A = trans CH = CH; B = cis CH = CH; X ... Y = CH2—CH ; OH \ l—\ Rj = O-CH2-U0-Q^-/Q^ R2>R3>&4 - H; the OH group as C-15 is in the «-configuration. mg of the prostadienoic acid obtained as described in Example 1(f) were stirred with 21 mg of triethyiamine and 53 mg of para-phenylphenacyl - 70 bromide in 4 ml of acetone for 12 hours at room temperature under argon. After dilution with water extraction with diethyl ether was carried out, and the ethereal extract was agitated with a sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The residue was filtered over 5 grams of silica gel with diethyl ether/dioxan mixtures.

After recrystallization from methylene chloride/hexane there were obtained 55 mg of the compound identified in the heading in the form of colourless crystals.

Melting point: 118°C.

IR: 3600, 1740, 1695, 1590, 1490, 980, 750 cm1.

In a manner analogous to that described in Example 39 all the other prostadienoic, prostenoic, prostatrienoic and prostanoic acids described in the foregoing Examples can be converted into the corresponding 4-phenylphenacyl esters.

Example 40 The tris-(hydroxymethyl)-aminomethane salt of (5Z,13E)-(8R,9S,11R,12R,15R)-9,11,15-trihydroxy-15-({2RSl-l,3-benzodioxan-2-yl)16,17,18,19,20-pentanorprostadienoic acid.

To a solution of 103 mg of the prostadienoic acid prepared as described 20 in Example 1(f) in 14 ml of acetonitrile was added at 60°C a solution of 32.9 mg of tris-(hydroxymethyl)-aminomethane in 0.1 ml of water, and the whole was allowed to stand for 14 hours at room temperature. There were obtained 76 mg of the above-mentioned salt in the form of colourless crystals In a manner analogous to that described in Example 40 all the other 25 prostadienoic, prostenoic, prostatrienoic and prostanoic acids described - 71 43453 in the foregoing Examples can be converted into the corresponding tris(hydroxymethyl)-aminomethane salts.

Example 41 (5Z,13E)-(8R,9S,11R,12R,15R)-9,11, 15-Tri hydroxy-15-({2S }-l ,3-benzodioxan5 2-yl)-16,17,18,19,20-pentanorprostadienoic acid 4-phenylphenacyl ester.

General formula I: A = trans CH = CH; 8 = cis CH = CH; X ... Y = CH2—CH ; OH ) R2,R3,Ri, = H; the OH group at C-15 is in the a-configuration. 130 mg of the prostadienoic acid obtained as described in Example 5(d) were reacted in a manner analogous to that described in Example 39, and there were obtained 85 mg of the compound identified in the heading in the form of colourless crystals.

Melting point: 79°C—80°C.

IR: 3430, 1745, 1695, 1585, 1225, 1030, 760, 750, 720 cm1.

Example 42 (5Z,13E)-(8R,9S,11R,12R,155)-9,11,15-Trihydroxy-15-({2S}-1,3-benzodioxan2-yl)-16,17,18,19,20-pentanorprostadienoic acid 4-phenylphenacyl ester.

General formula I: A = trans CH = CH; B = cis CH = CH; - 72 43453 X ... Y = CH2—C£ ; OH Rl = 0—CH2—Cl HpXo) Ry.R3.R1, = H; the OH group at C-15 is in the β-configuration. 100 mg of the prostadienoic acid prepared as described in Example 6(c) were reacted in a manner analogous to that described in Example 39, and there were obtained 115 mg of the compound identified in the heading in the form of colourless crystals.

Melting point: 60 C.

IR: 3440, 1740, 1700, 1590, 1240, 1030, 760, 725 cm-1. - 73 43453

Claims (1)

1. WHAT WE CLAIM IS:1. A 15-(1,3-benzodioxan- 2. -y1)-16,17,18,19,20-pentanorprostanoic acid derivative of the general formula I 5 in which Ri represents a hydroxyl group, an aliphatic hydrocarbonyloxy group containing 1 to 10 carbon atoms, a methanesulphonamido group, an unsubstituted or substituted aryloxy group or a group of the formula —0—CH?—U—V, in which U represents a direct bond, a 3. Carbonyl group or a carbonyloxy group (the carbonyl part of which is attached to the —CH 2 — group) and V represents a phenyl group substituted by one or more substituents selected from phenyl, methoxy, ethoxy, vinyloxy and ethynyloxy groups and halogen atoms, i A represents a —CH 2 —CH 2 — or a trans —CH = CH— group, B represents a —CH 2 —CH 2 — or a cis or trans —CH = CH— group, Z represents a hydroxymethylene or a carbonyl group, X ... Y, when Z represents a hydroxymethylene group, represents a - /4 43453 —CH2—CH— or —CH2—€— οΐ ° group and, when Z represents a carbonyl group, represents a —CH 2 —CH— OH or —CH = CH— group, 5 R 2 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms, and Rj and R, t each represents a hydrogen, fluorine, chlorine, bromine or iodine atom or a trifluoromethyi, methyl, methoxy, ethoxy, vinyloxy or ethynyloxy group, 10 2. A compound as claimed in claim 1, wherein R x represents an alkoxy group containing 1 to 6 carbon atoms. 3. A compound as claimed in claim 1, wherein V represents a phenyl group substituted by one or more bromine atoms. 4. An antipode of a compound of the general formula I given in claim 15 1, in which R l5 A, Β, Ζ, X . ,.Y, R 2 , R 3 and R u have the meanings given in claim 1. 5. A racemate of a compound of the general formula I given in claim 1, in which Rj, A, Β, Ζ, X ...Y, R 2 , R 3 and Ri, have the meanings given in claim 1. 20 6. A physiologically tolerable salt with a base of a compound as claimed in any one of claims 1 to 3 in which Ri represents a hydroxyl group. 7. A physiologically tolerable salt with a base of an antipode as - 75 claimed in claim 4 in which Rj represents a hydroxyl group. 8. A physiologically tolerable salt with a base of a racemate as claimed in claim 5 in which Rj represents a hydroxyl group. f. (5Z,13E) - (8R,9S,11R,12R,15R) - 9,11,15 - Trihydroxy - 15 5 ({2RSJ - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 10. (5Z,13E) - (8R,9S,11R,12R,15S) - 9,11,15 - Trihydroxy - 15 ({2RS} - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. ) 11. (5Z.13E) - (8R,9S,11R,12R,15R) - 9,11,15 - Trihydroxy - 15 ({2R1 - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 12. (5Z,13E) - (8R,9S,11R,12R,15S) - 9,11,15 - Trihydroxy - 15 ({2R1 - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 13. (5Z.13E) - (8R,9S,11R,12R,15R) - 9,11,15 - Trihydroxy - 15 ({2S1 - 1,3- benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 14. (5Z,13E) - (8R,9S,11R,12P.,15S) - 9,11,15 - Trihydroxy - 15 ({2S} - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 15. (5Z,13E) - (8R,11R,12R,15R) - 11,15 - Dihydroxy - 9 - oxo - 15 ({2RS1 -1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 16. (5Z,13E) - (8R,11R,12R,15S) - 11,15 - Dihydroxy - 9 - oxo - 15 - 76 (12RS} - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 17. (5Z,13E) - (8R,11R,12R,15R) - 11,15 - Dihydroxy - 9 - oxo - 15 (12R1 - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprosta5 dienoic acid. 18. (5Z,13E) - (8R,11R,12R,15S) - 11,15 - Dihydroxy - 9 - oxo - 15 (12R) - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 19. (5Z,13E) - (8R,11R,12R,15R) - 11,15 - Dihydroxy - 9 - oxo - 15 10 (l2Sl - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 20. (5Z,13E) - (8R,11R,12R,15S) - 11,15 - Dihydroxy - 9 - oxo - 15 (f2S) - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 15 21. (5Z) - (8R,9S,11R,12R,15R) - 9,11,15 - Trihydroxy - 15 - ({2RS} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 22. (5Z) - (8R,9S,11R,12R,15S) - 9,11,15 - Trihydroxy - 15 - ({2RSJ 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostenoic acid. 23. (5Z) - (8R,9S,11R,12R,15R) - 9,11,15 - Trihydroxy - 15 - (T2R1 20 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 24. (5Z) - (8R,9S,11R,12R,15S) - 9,11,15 - Trihydroxy - 15 - ({2R1 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 25. (5Z) - (8R,9S,11R,12R,15R) - 9,11,15 - Trihydroxy - 15 - ({2S} 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostenoic acid. 25 26. (5Z) - (8R,9S,11R,12R,15S) - 9,11,15 - Trihydroxy - 15 - (i2S) - 77 43453 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 27. (5Z) - 8R,11R,12R,15R) - 11,15 - Dihydroxy - 9 - oxo - 15 - ({2RSJ 1,3 - benzodioxan - 2 - yl) - 16,17,18,19,20 - pentanorprostenoic acid. 28. (5Z) - (8R,11R,12R,15S) - 11,15 - Dihydroxy - 9 - oxo - 15 5 ({2RS} - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 29. (5Z) - (8R,11R,12R,15R) - 11,15 - Dihydroxy - 9 - oxo - 15 (t2Rl - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 0 30. (5Z) - (8R,11R,12R,15S) - 11,15 - Dihydroxy - 9 - oxo - 15 (<2R> - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 31. (5Z) - (8R,11R,12R,15R) - 11,15 - Dihydroxy - 9 - oxo - 15 (12SJ - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic > acid. 32. (5Z) - (8R,11R,12R,15S) - 11,15 - Dihydroxy - 9 - oxo - 15 (t2Sl - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 33. (5Z,1O,13E) - (8R,12S,15R) - 15 - Hydroxy - 9 - oxo - 15 - ({2RSJ ι 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostatrienoic acid. 34. (5Z,10,13E) - (8R,12S,15S) - 15 - Hydroxy - 9 - oxo - 15 - ({2RS} 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostatrienoic acid. 35. (5Z,10,13E) - (8R,12S,15R) - 15 - Hydroxy - 9 - oxo - 15 - ({2R} 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostatrienoic acid. - 78 43453 36. (5Z.10.13E) - (8R.12S.15S) - 15 - Hydroxy - 9 - oxo - 15 - ({2R} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostatrienoic acid. 37. (5Z.10.13E) - (8R.12S.15R) - 15 - Hydroxy - 9 - oxo - 15 - ({2S} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostatrienoic acid. 38. (5Z,10,13E) - (8R,12S,15S) - 15 - Hydroxy - 9 - oxo - 15 - ({2S} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostatrienoic acid. 39. (13E) - (8R,9S,11R,12R,15R) - 9,11,15 - Trihydroxy - 15 - ({2RS} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 40. (13E) - (8R,9S,11R,12R,15S) - 9,11,15 - Trihydroxy - 15 - ({2RS} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 41. (I3E) - (8R,9S,11R,12R,15R) - 9,11,15 - Trihydroxy - 15 - ({2R} 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostenoic acid. 42. (13E) - (8R,9S,11R,12R,15S) - 9,11,15 - Trihydroxy - 15 - ({2RJ 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 43. (13E) - (8R,9S,11R,12R,15R) - 9,11,15 - Trihydroxy - 15 - ({2S} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 44. (13E) - (8R,9S,11R,12R,15S) - 9,11,15 - Trihydroxy - 15 - ({2S} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 45. (13E) - (8R,11R,12R,15R) - 11,15 - Dihydroxy - 9 - oxo - 15 ({2RS) - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 46. (13E) - (8R,11R,12R,15S) - 11,15 - Dihydroxy - 9 - oxo - 15 ({2RS} - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 47. (Ί3Ε) - (8R,11R,12R,15R) - 11,15 - Dihydroxy - 9 - oxo - 15 - 79 43453 ({2R1 - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 48. (13E) - (8R,11R,12R,15S) - 11,15 - Dihydroxy - 9 - oxo - 15 ({2R1 - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic 5 acid. 49. (13E) - (8R,11R,12R,15R) - 11,15 - Dihydroxy - 9 - oxo - 15 ((2SJ - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 50. (13E) - (8R,11R,12R,15S) - 11,15 - Dihydroxy - 9 - oxo - 15 0 (£2SJ - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. 51. (8R,9S,11R,12R,15R) - 9,11,15 - Trihydroxy - 15 - ({2RS} - 1,3 benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostanoic acid. 52. (8R,9S,11R,12R,15S) - 9,11,15 - Trihydroxy - 15 - ({2RST - 1,3 > benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostanoic acid. 53. (8R,9S,llR,12R,15R) - 9,11,15 - Trihydroxy - 15 - ({2R1 - 1,3 benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostanoic acid. 54. (8R,9S,11R,12R,15S) - 9,11,15 - Trihydroxy - 15 - ({2R} - 1,3 benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostanoic acid. ι 55. (8R,9S,11R,12R,15R) - 9,11,15 - Trihydroxy - 15 - ({2S} - 1,3 benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostanoic acid. 56. (8R,9S,11R,12R,15S) - 9,11,15 - Trihydroxy - 15 - ({2S} - 1,3 benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostanoic acid. 57. (5Z.13E) - (8R,9S,12R,15R) - 9,15 - Dihydroxy - 11 - oxo - 15 ({2RSJ - 1,3 - benzodioxan -2-yl) - 16,17,18,19 20 - pentanorprostadienoic acid. - 80 4 3 4 5 3 58. (5Z.13E) - (8R,9S,12R,15S) - 9,15 - Dihydroxy - 11 - oxo - 15 (I2RS1 - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 59. (5Z.13E) - (8R,9S,12R,15R) - 9,15 - Dihydroxy - 11 - oxo - 15 (i2R} - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 60. (5Z,13E) - (8R,9S,12R.15S) - 9,15 - Dihydroxy - 11 - oxo - 15 ((2Ri - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 61. (5Z.13E) - (8R,9S,12R,15R) - 9,15 - Dihydroxy - 11 - oxo - 15 ((2S) - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 62. (5Z.13E) - (8R,9S,12R,15S) - 9,15 - Dihydroxy - 11 - oxo - 15 (fZSi - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 63. (5Z.13E) - (8R,9S,11R,12R,15R) - 9,11,15 - Trihydroxy - 15 (i2RSl - 6 - bromo - 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 64. (5Z.13E) - (8R,9S,llR,12R,15R) - 9,11,15 - Trihydroxy - 15 (f2RSi - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid 4 - phenyl phenacyl ester. 65. The tris - (hydroxymethyl) - aminomethane salt of (5Z,13E) (8R,9S,11R,12R,15R) - 9,11,15 - trihydroxy - 15 - (T2RS) - 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostadienoic acid. 66. The tris-(hydroxymethyl)-aminomethane salt of the acid claimed - 81 4 3 4 5 3 in any one of claims 10 to 63. 67. (5Z,13E) - (SR.9S.nR.12R.15R) - 9,11.15 - Trihydroxy - 15 ({2S} - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid 4 - phenyl phenacyl ester. 68. (5Z.13E) - (8R,9S,11R,12R,15S) - 9,11,15 - Trihydroxy - 15 - ({2S> 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid 4 - phenyl phenacyl ester. 69. The methyl or 4 - phenyl phenacyl ester of (5Z,13E) - (8R,9S,11R,12R,15S) - 9,11,15 - trihydroxy - 15 - ({2RS} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. (5Z.13E) - (8R,9S,11R,12R,15R) - 9,11,15 - trihydroxy - 15 - (f2R} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. (5Z,13E) - (8R,9S,11R,12R,15S) - 9,11,15 - trihydroxy - 15 - (i2R) 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. (5Z.13E) - (SR.l1R.12R.15R) - 11,15 - dihydroxy - 9 - oxo - 15 (f2RSl - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. (5Z.13E) - (8R,11R,12R,15S) - 11,15 - dihydroxy - 9 - oxo - 15 (i2RSl - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. (5Z.13E) - (8R.11R.12R.15R) - 11,15 - dihydroxy - 9 - oxo - 15 - ({2R} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. - 82 4 3 4 5 3 (5Z,13E) - (8R,11R,12R,15S) - 11,15 - dihydroxy - 9 - oxo - 15 (12R1 - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. (5Z,13E) - (8R,11R,12R,15R) - 11,15 - dihydroxy - 9 - oxo - 15 ((2S1 - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. (5Z.13E) - (8R,11R,12R,15S) - 11,15 - dihydroxy - 9 - oxo - 15 ((2S) - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid. (5Z) - (8R,9S,11R,12R,15R) - 9,11,15 - trihydroxy - 15 - ({2RS} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. (5Z) - (8R,9S,11R,12R,15S) - 9,11,15 - trihydroxy - 15 - (|2RS} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid, (5Z) - (8R,9S,UR,12R,15R) - 9,11,15 - trihydroxy - 15 - ({2RJ 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid, (5Z) - (8R,9S,1lR,12R,15S) - 9,11,15 - trihydroxy - 15 - ({2R} - 1,3 benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid, (5Z) - (8R,9S,11R,12R,15R) - 9,11,15 - trihydroxy - 15 - ({2S} - 1,3 benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid, (5Z) - (8R,9S,11R,12R,15S) - 9,11,15 - trihydroxy - 15 - ({2SJ - 1,3 benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid. (5Z) - (8R,11R,12R,15R) - 11,15 - dihydroxy - 9 - oxo - 15 - ({2RS} 83 53453 1,3 - benzodioxan - 2 - yl) - 16,17,18,19,20 - pentanorprosten oic acid. (5Z) - (8R,11R,12R,15S) - 11,15 - dihydroxy - 9 - oxo - 15 - ({2RS} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprosten 5 oic acid, (5Z) - (8R,11R,12R,15R) - 11,15 - dihydroxy - 9 - oxo - 15 - ({2R} 1,3 - benzodioxan - 2- yl) 16,17,18,19,20 - pentanorprostenoic acid, (5Z) - (8R,11R,12R,15S) - 11,15 - dihydroxy - 9 - oxo - 15 - ((2R) 0 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprosten oic acid, (5Z) - (8R,11R,12R,15R) - 11,15 - dihydroxy - 9 - oxo - 15 - (¢25} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprosten oic acid, i (5Z) - (8R,11R,12R,15S) - 11,15 - dihydroxy - 9 -oxo - 15 - (¢25} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprosten oic acid, (5Z,10,13E) - (8R,12S,15R) - 15 - hydroxy - 9 - oxo - 15 - ({2RS} 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostatrienoic acid, (5Z,10,13E) - (8R,12S,15S) - 15 - hydroxy - 9 - oxo - 15 - (12RS} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostatrienoic acid, (5Z,10,13E) - (8R,12S,15R) - 15 - hydroxy - 9 - oxo - 15 - ({2R} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostatrienoic acid, - 84 4 34ί (5Z.10J3E) - (8R,12S,15S) - 15 - hydroxy - 9 - oxo - 15 - (12R) 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostatrienoic acid, (5Z,10,13E) - (8R,12S,15R) - 15 - hydroxy - 9 - oxo - 15 - ({2S} 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostatrienoic acid, (5Z,10,13E) - (8R,12S,15S) - 15 - hydroxy - 9 - oxo - 15 - ({2S} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostatrienoic acid, (13E) - (8R,9S,11R,15R) - 9,11,15 - trihydroxy - 15 - ((2RS) - 1,3benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid, (13E) - (8R,9S,11R,12R,15S) - 9,11,15 - trihydroxy - 15 - ({2RS} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid, (13E) - (8R,9S,11R,12R,15R) - 9,11,15 - trihydroxy - 15 - ({2R} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid, (13E) - (8R,9S,11R,12R,15S) - 9,11,15 - trihydroxy - 15 - ({2R} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid, (13E) - (8R,9S,11R,12R,15R) - 9,11,15 - trihydroxy - 15 - ({2S1 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostenoic acid, (13E) - (8R,9S,11R,12R,15S) - 9,11,15 - trihydroxy - 15 - ({2S} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid, - 85 4 3 4 S 3 (13E) - (8R,11R,12R,15R) - 11,15 - dihydroxy - 9 - oxo - 15 ((2RS} - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid, (13E) - (8R,11R,12R,15S) - 11,15 - dihydroxy - 9 - oxo - 15 - ({2RS} 5 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostenoic acid, (13E) - (8R,11R,12R,15R) -11,15 - dihydroxy - 9 - oxo - 15 - ({2R} 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostenoic acid, 10 (13E) - (8R,11R,12R,15S) -11,15 - dihydroxy - 9 - oxo - 15 - ({2R5 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostenoic acid, (Ί3Ε) - (8R,11R,12R,15R) - 11,15 - dihydroxy - 9 - oxo - 15 - ({2SJ 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprosten15 oic acid, (13E) - (8R,11R,12R,15S) - 11,15 - dihydroxy - 9 - oxo - 15 - ({25} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid, (8R,9S,11R,12R,15R) - 9,11,15 - trihydroxy - 15 - ({2RS} - 1,3 Ό benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostanoic acid (8R,9S,11R,12R,15S) - 9,11,15 - trihydroxy - 15 - (f2R?) - 1,3 benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostanoic acid, (8R,9S,11R,12R,15R) - 9,11,15 - trihydroxy - 15 - (t2RJ - 1,3 5 benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostanoic acid, - 86 434B3 (8R,9S,11R,12R,15S) - 9,11,15 - trihydroxy - 15 - ({2R} - 1,3 benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostanoic acid, (8R,9S,11R,12R,15R) - 9,11,15 - trihydroxy - 15 - ({2S} - 1,3 benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostanoic acid, 5 (8R,9S,11R,12R,15S) - 9,11,15 - trihydroxy - 15 - ({2S} - 1,3 benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostanoic acid, (5Z.13E) - (8R,9S,12R,15R) - 9,15 - dihydroxy - 11 - oxo - 15 - ({2RSJ 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid, 10 (5Z.13E) - (8R,9S,12R,15S) - 9,15 - dihydroxy - 11 - oxo - 15 ((2RS) - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostenoic acid, (5Z,13E) - (8R,9S,12R,15R) - 9,15 - dihydroxy - 11 - oxo - 15 - ({2R1 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostalb dienoit acid, (5Z,13E) - (8R,9S,12R,15S) - 9,15 - dihydroxy - 11 - oxo - 15 - ({2R1 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid, (5Z.13E) - (8R,9S,12R,15R) - 9,15 - dihydroxy - 11 - oxo - 15 - ({2S} 20 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid, (5Z.13E) - (8R,9S,12R,15S) - 9,15 - dihydroxy - 11 - oxo - 15 - ({2S1 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid, or 25 (5Z.13E) - (8R.9S,J1R,12R,15R) - 9,11,15 - trihydroxy - 15 - ({2RSJ - 87 13453 6. - bromo - 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 pentanorprostadienoic acid, or the methyl ester of (5Z.13E) - (8R,9S,11R,12R,15R) - 9,11,15 - trihydroxy - 15 - ({2RS} 5 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid, (5Z,13E) - (8R,9S,11R,12R,15R) - 9,11,15 - trihydroxy - 15 - ({2S} 1,3 - benzodioxan - 2- yl) - 16,17,18,19,20 - pentanorprostadienoic acid or 0 (5Z.13E) - (8R,9S,11R,12R,15S) - 9,11,15 - tri hydroxy - 15 - ({25} 1,3 - benzodioxan -2-yl) - 16,17,18,19,20 - pentanorprostadienoic acid, 70. A process for the manufacture of a compound as claimed in claim 1 or a physiologically tolerable salt With a base of such a compound in 5 which Rj represents a hydroxyl group, wherein a lactol of the general formula II in which R 2 , R 3 , and A have the meanings given in claim 1 and R5 and - 88 43453 R t each represents a hydrogen atom or a hydroxy1-protecting group, is reacted with a Wittig reagent of the general formula III Ph 3 P = CH—(CH 2 ) 3 —COR T (III) in which Ph represents a phenyl group and R x has the meaning given in 5 claim 1, to form a compound of the general formula in which Rj, R-,, R 3 , R„, R 5 , R c and A have the meanings given above and B represents a cis or trans —-CH = CH— group, and then, if desired after any oxidation, as defined below, in the 9 position, any hydroxyl10 protecting group in the Π-position is removed by hydrolysis and, if desired after any oxidation, as defined below, in the 9- and/or 11position(s), any hydroxyl-protect!ng group in the 15 position is removed by hydrolysis, and, if desired and in any desired sequence, any free 1carboxyl group is esterified or any esterified 1-carboxyl group is hydrolysed, 15 and/or the 5,6-double bond and, if desired, also any 13,14-double bond is/are hydrogenated, and/or either (a) the 9<»-hydroxyl group is oxidzed in the presence of protected hydroxyl groups in the 11- and 15-positions to - 89 ¢3453 form a 9-oxo group, which oxidation is, if desired, followed by removal of the hydroxyl-protect!ng group in the 11-position by hydrolysis and then dehydration with the elimination of the Π-hydroxyl group and the formation of the 10,11-double bond, or (b) the 9a-hydroxyl group is oxi5 dized in the presence of protected hydroxyl groups in the 11- and 15positions to form a 9-oxo group, which oxidation is followed by reduction to form a 9e-hydroxyl group, and/or if necessary after removal of any hydroxyl-prctectipg group in the 11-position by hydrolysis, the 11ahydroxyl group is oxidized after intermediate protection of the 9a- or 7. 10 9p-hydroxyl group and in the presence of a protected hydroxyl group in the 15-position to form an Π-oxo group, and/or any 1-carboxyl compound is converted into a physiologically tolerable salt thereof with a base and/or any racemate is resolved into its antipodes. 71. A process as claimed in claim 70, conducted substantially as 5 described herein. 72. A process for the manufacture of a compound as claimed in claim 1 or 6, conducted substantially as described in any one of Examples 1 to 40 herein. 73. A process for the manufacture of a compound as claimed in claim 3 1, conducted substantially as described in Example 41 or 42 herein. 74. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 1 to 5, in admixture or conjunction with a pharmaceutically suitable carrier. 75. A pharmaceutical preparation which comprises a salt as claimed i in any one of claims 6 to 8, in admixture or conjunction with a pharma- 90 42-253 ceutically suitable carrier. 76. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 9 to 69, in admixture or conjunction with a pharmaceutically suitable carrier. 5 77. A preparation as claimed in any one of claims 74 to 76, which is in the form of a sterile aqueous solution containing the active substance in an amount of 0.01 to- 10 μ grams per ml. · 78. A preparation as claimed in any one of claims 74 to 76, which is in a form suitable for inhalation. 10 79. A preparation as claimed in claim 78, which is in the form of an aerosol solution or a spray solution. 80. A preparation as claimed in any one of claims 74 to 76, which is in a form suitable for oral administration. 81. A preparation as claimed in claim 80, which is in the form of a 15 tablet, dragee or capsule. 82. A preparation as claimed in any one of claims 74 to 76, which is in a form suitable for parenteral administration. 83. A preparation as claimed in claim 82, which is in the form of a sterile aqueous or oily solution suitable for injection.