IE52600B1 - 9-oxo-13,18-prostadienoic acid derivatives and process for their preparation - Google Patents

Abstract

1. (13E)-(8R, 11R, 12R)-11,15-dihydroxy-16,19-dimethyl- -9-oxo-13,18-prostadienoic acids of the general formula I see diagramm : EP0058632,P15,F3 in which R represents hydrogen or a methyl group, or the physiologically tolerable salts thereof with bases.

Description

The present Invention relates to 9-oxo-13,18-prostadienoic acid derivatives, including the physiologically tolerable salts thereof, a process for their preparation and pharmaceutical compositions containing them.

German Offenlegungsschrift No. 26 35 985 describes and claims prostanoic acid derivatives of the general formula in which R^ represents a —C—Rg or ^C^ORg group in which Rg O Ry Rg represents a hydroxyl group, a straight-chain or branched alkoxy group having from 1 to 10 carbon atoms, a substituted or unsubstituted aryloxy group, a O-Ch2_O-V group wherein U represents a direct bond, a carbonyl group or a carbonyloxy group and V represents a phenyl ring substituted by one or more phenyl groups, alkoxy groups having 1 or 2 carbon atoms or halogen atoms, preferably bromine atoms, or represents a -NHR1Q group in which Rl0 represents an alkyl or aryl group or an acid radical of an organic carboxylic or sulphonic acid having from 1 to 15 carbon A B W Z X... - 3 atoms, R? and Rg represent hydrogen atoms or alkyl groups having from 1 to 4 carbon atoms and Rg either represents an acid radical of an organic carboxylic or sulphonic acid having from 1 to 15 carbon atoms or of an inorganic acid or represents a -C-NHRjq group wherein R1Q has the meaning given above, represents a -CH2-CH2 or a cis- or trans-GH=CHgroup, represents a -CH2-CH2-, a trans-CH=CH~,a -CSCgroup or a -CH-CH- group wherein the methylene ch2 group may be in the a- or β-position, represents a free or functionally modified hydroxy-methylene group, a free or functionally modified carbonylgroup or a Ri;l group wherein -σΙ OH Rjj represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms and the OH group may be in the a- or (5-position and may be functionally modified, represents a carbonyl or hydroxymethylene group that may be free or functionally modified, _Y represents -CH2-CH- or -CH2-C- if Z represents R12 0 a free or functionally modified hydroxymethylene group, ... or >·' . ή represents -CHj-CH- or -CH=CH- if Z represents _ Ri2 a free or functionally modified carbonyl group, w&erein 'the-ρώίαβΓ r12 represents a hydrogen atom*, a'methyl fyoupi-'-A cyanide group or a free or funj$4pneJ[Iy, modified hydroxy group, R2 represents a hydrogen atom or an alkyl group, r3 represents a hydrogen atom or an alkyl group, R4 and Rg'are thesame and each represents a methyl group or R4 represents a chlorine atom and Rg represents a methyl group or Rg represents a chlorine atom and R4 represents a methyl group, and if Rg represents a hydroxy group, the physiologically tolerable salts thereof with bases.

The compounds possess valuable therapeutic properties and are distinguished especially by the fact that they are capable of inducing menstruation or terminating a pregnancy after a single intrauterine administration. They are also suitable for synchronising the sexual cycle in female mammals such as apes, cattle, pigs, sheep etc.. The prostaglandin derivatives described in German Offenlegungsschrift No. 26 35 98 have a strongly contractive action on the uterus and also a luteolytic action, that is to say lower dosages are required to induce abortion than is the case with the corresponding natural prostaglandins. Also, with natural prostaglandins, the desired, main actions are usually accompanied by un5 desirable side effects which considerably diminish the quality of the main action.

Amongst the compounds claimed in German Offenlegungsschrift NO. 26 35985 there are (13E)-{8R,11R, 12R)-11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prost10 adienoic acids of general formula I COOH (X) where R represents a hydrogen or methyl group or their physiologically tolerable salts with bases.

We have found that these prostadienoic acids exhibit such outstanding properties as an abortifacient that, the dosage can be reduced by a multiple in comparison with customary commercial preparations (for example, sulproston), as a result of which undesirable side effects are, of course, even more strongly repressed. When compared with compounds, specifically described in German Offenlegungsschrift No, 26 35 985, we have found the compounds of the present invention to possess greater relative activity ranging, at least, between 10 and 100. - -6 * The hydroxy group' at the 15-position and the methyl group at the IgppoeltlOg.mayJjg in any suitable configuration, Preferably t{ie 15-hydroxy group has an s.7' • - ,·,· · configuration when tliei 16-methyl group has an BS’· . configuration. When, the compound is disubstituted in the 16-po'siti’on'W'a inefeH^fegF03pt':!l!lie 15-hydroxy group preferably U&i --··· < .,- . ,Jbe Provides a salt of a Ή compound 9|>the j; pepeoi»lly a physiologically tolerable salt Ihereqifj· and;JP particular a trisihydroxymethyl) amih0methahe>iijalt;ifchere'o£. The (13E) - (8R, HR, 12R) 11,15-dihydroxy-16,19-dimethyl-9-oxo-12(18-prostadienoic acids are not specifically described in German Offenlegungsschrift No. 26 35 985. Compounds in which A represents a -CHj-C^" 9rouP are not distinguished from the other compounds in which A represents a cis-CH=CHgroup in that document.

Thus, according to the invention there is provided (13E)-(8R,11R,12R)-11,15-dihydroxy-16,19-dimethyl-9-oxo20 13,18-prostadienoic acids of the general formula I in Which R represents hydrogen or a methyl group, or the physiologically tolerable salts thereof with bases.

The invention further provides a process for the preparation of a compound of general formula I, which comprises reacting (8R, 9S, HR,12S)-9-benzoyloxy-13-oxo-ll-(tetrahydropyran2-yloxy)-14,15,16,17,18,19,20-heptanorprostanoic acid methyl ester with 2-(1,4-dimethyl-3-pentenyl)-2-oxoethanephosphonic acid dimethyl esters of formula II CH3°\I I /CH3 P-CH,-C-C-CH,-CH=C / 2 it I 2 \ CH3° S iH3XcH3 (II) where R has the meaning given above, and where subsequently a 15-keto group is reduced and protected with dihydropyran, a 9-hydroxy group is oxidised after liberating it, present protecting groups are split off,'if R represents hydrogen, the compound is separated into stereo isomers and, if desired, is converted into a physiologically tolerable salt.

The preparation of 2-(l,4-dimethyl-3-pentenyl)-2oxoethanephosphonic acid dimethyl esters of formula II may be carried out according to methods known per se, as described in German Offenlegungsschrift No. 26 35 985. -8 Suitable for the salt formation are all inorganic and organic bases such as those known to the man skilled in the art for the formation of physiologically tolerable salts. There may be mentioned, by way of example, alkali metal hydroxides, such as sodium or potassium hydroxide, alkaline earth metal hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris(hydroxymethyl)-methylamine, etc.

The reaction of (8R-9S,llR,12S)-9-benzoyloxy-13oxo-11-(tetrahydropyran-2-yloxy)-14,15,16,17,18,19,20heptanorprostanoic acid methyl ester with compounds of formula IX may be carried out in a manner known per se at a temperature ranging from 0°C to 100°C, preferably from °C tO'.'80°C, in an aprotic solvent, such as, for example, dimethyl sulphoxide, dimethylformamide, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dioxan, chloroform methylene chloride,dimethoxyethane, etc.

The oxidation of the 9-hydroxy group may also be carried out according to methods known per se with the customary oxidising agents. For example, the oxidation can be carried out with the 11- and I5-hydroxy groups being temporarily protected, for example by silylation with Jones reagent (Chem. Comm. 1972, 1120}.

Freeing of functionally modified hydroxy groups is suitably carried out according to known methods. For example, the splitting off of hydroxy-protecting groups, - 9 such as, for example, the tetrahydropyranyl radical, may be carried out in an aqueous solution of an organic acid, such as, for example, oxalic acid, acetic acid and propionic acid inter alia, or in an aqueous solution of an inorganic acid, such as, for example hydrochloric acid. To improve solubility, a water-miscible inert organic solvent is advantageously added. Suitable organic solvents are, for example alcohols, such as methanol and ethanol, ethers, such as dimethoxyethcuie, dioxan and tetrahydrofuran, and acetone. Preferably tetrahydropyran is used. The splitting-off operation is preferably carried out at a temperature in the range of between 20°C and 80°C.

Hydrolysis of the acyl groups is carried out, for example with alkali metal carbonates or hydroxides or with alkaline earth metal carbonates or hydroxides in an alcohol or in an aqueous solution of an alcohol. Alcohols that come into consideration are aliphatic alcohols, such as, for example, methanol, ethanol, butanol, etc., preferably methanol. As alkali metal carbonates and hydroxides both potassium and sodium salts are suitable but potassium salts are preferred. Suitable alkaline earth metal carbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and barium carbonate.

The reaction is suitably carried out at a temperature in the range of between -l0°C to +70°C, preferably at +25°C.

The (13E)-(8r,HR,12R)-ll-15-dihydroxy-16,19- 10 dimethyl-9-oxo-13,18 prostadienoic acid$ may be converted Into salts with suitable amounts of the corresponding inorganic bases with neutralisation taking place. For example, upon dissolving the prostadienoic acid in water containing the stoichiometric amount of the base, after .- .· V. ' evaporating off the water or after adding a water-miscible solvent, for 'example· alcohol or acetone, a solid inorganic salt is obtained. .

For the preparation of an amine salt, which is suitably carried out in customary manner, the prostadienoic acid is, for‘;example, dissolved in a suitable solvent, for example ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine is added to that solution. In so doing, an amine salt is usually obtained in solid form or is isolated in customary manner after evaporation of the solvent.

The good dissociation of action of the compounds according to the invention may be demonstrated in tests on other non-striated organs, such as, for example, the ileum of guinea pigs or the isolated trachaea of rabbits, in which considerably lower stimulation than that produced by the natural prostaglandins has been observed by us.

The active substance of the invention has been found to exhibit a bronchodilative action on the isolated trachaea of rabbits in vitro and greatly inhibit gastric acid secretion and to have a regulatory action in the case 82600 - 11 of heart rhythm disorders. Ihe ccrtpounds of the Invention furthermore reduce blood pressure and have a diuretic action.

For medicinal use, the active substance may be converted into a form suitable for inhalation or for oral or parental administration.

Far inhalation, aerosol or spray solutions are advantageously used.

For oral administration, tablets, dragees or capsules far example, are suitable.

For parenteral administration, sterile, injectable, aqueous or oily solutions may be used.

Accordingly, the present invention provides a pharmaceutical preparation carprising a compound of the present invention, or a physiologically tolerable salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier.

Preferably the preparation is in unit dosage form. Depending upon the mode of administration, for example vaginal, extraannial, intranusoular or intravenous, the unit dosage is suitably in the range of from 0.25 pg to 50 mg.

The active substances of the invention may be used in combination with the auxiliaries known and customary in galenical pharmacy, for example for the production of preparations for inducing an abortion, for controlling the menstrual cycle or for inducing labour. For this purpose, sterile aqueous solutions containing in the range of fran 0.0001 to 10 ug/tal of the active canpound can be used in the form of an intravenous infusion solution. Par the preparation of aqueous isotonic solutions, the acid and salts axe especially suitable. To Increase solubility, alcohols, such as ethanol and propylene glycol, may be added. In addition, suppositories for intravaginal administration can readi ly be prepared.

The following Examples illustrate the invention, unless otherwise indicated, the percentages and proportions in the Examples are given on a volume basis. Ihe abbreviations DIBAH and TEC are used in the Exaiples to indicate diiscbutylaluminiun hydride and thin layer chromatography respectively. .53600 S ξί ·. i! ; 10 V·?-,-- : ‘ 1 *’-· -- · ? · :Λ,·· <7'· .. ' ·. .:- --/ -.12iW? IS, 1 g|, Jgs, 16SS)-J 1,15-dihydroxy-l 6,19-dimethyl0-ΟΣΟ» 15.18»woitadienoie acidi? . Of »odiuan (cut Jjtfp pmall piece·) «re placed ft» » libffc- ·wippadwit* '»·' »fl» condenser, dropping funneland stirrer. -800 ol of absolute ethanol vere added dropwise thereto rapidly- enough to keep the solution boiling briskly. 269.6 g of freshly distilled methylmalonic add diethyl ester «re added dropwise to the hot alcoholate eolation, the mixture vas stirred for 1/2 hoar at 60 C and then 241.7 g of dimethylallyl bromide vere added dropwise thereto. After stirring for one hoar vblle heating, the precipitated sodium bromide was-filtered off, the preci» pitate vas vashed and the filtrate concentrated. She residue vas taken up in ether, vashed neutral vith saturated sodloa chloride solution, dried over magnesium sulphate and concentrated in a rotary evaporator. She residue re«1n1ng after evaporation vas fractionated using an oil pump. 266 g of the title oompound {b.p.? = 97-112°c) vere obtained.

IE (film): 1735, 1245, 1025« 860/om. - 13 b) 2-earboxy-2.5-dlmethyl-4-hexenolc acid 223.8 g of the dieater obtained in a) were heated under refine for 4 hours together with 181 g of potassium hydroxide in 235 ml of water and 450 al of ethanol. The ethanol wae subsequently resowed In a rotary evaporator, the residue wae dissolved In 235 »1 of water and, while cooling with Ice, concentrated hydrochloric acid was added dropwiae until a pH of 1 was.reached. _ The precipitate, (m.p. 162-166°C) was collected, washed with water and used in the next step without further purification· IB (EBr): 1700, 1230, 840/cm. c) 2.5-dinethyl-4-hexenolc acid The dioarhoxylic acid obtained in the preceding reaction step was maintained at 210°C for 4 hours at normal pressure and then for one hour at 75 torr In a distillation apparatus. The product was then distilled in vacuo. 68 g of the-title compound (b.p.^- 98 - 106°C; b.p.^ 67 - 70°C) were obtained.

IB (film): 1705, 1220, 810/em. d) 2«5-dlmethTl-4-hexenoic acid methyl ester Ethereal diaEomethane was added to the 68 g of carboxylic acid obtained according to the method described above, until no more nitrogen was evolved upon adding the reagent and the yellow colour of the reaction solution remained unchanged. The solvent wae then removed in vacuo and the reeidue was fractionated. 62.3 β of the title - 14 Compound (b.p.g -g^g " 32 - 35°C) were obtained.

IB (film): 1735» 1160, 1050, 820/cm. e) 2>5-dlmothyl-4-hexonolc acid ethyl eater 85.3 g of 2-ethoxyearbonyl-2,5-dinethyl-4heienoio acid ethyl ester were dissolved in 645 al of dimethyl lulphoxide, and 29.7 g of lithium chloride and 6.3 al of distilled water were added in succession. She reaction mixture was then heated at 200°0 for a total of 13 hours and eubaequently, after being left to cool, was poured onto 1 litre of ice-water. She aqueous phase was extracted three timee with 500 al of methylene chloride mach time.

She combined organic extracts were then washed twiee with water, dried over magnesium sulphate, concentrated in a rotary evaporator and distilled in vacuo. 53· 1 g of 'the title compound (b.p.^g = 75 - 78°C) were isolated.

IB (film)j 1735, 1160, 1050/cm. f) 2-(1,4-dimethyl-3-pentenyl)-2-oxoethanephosphonic • dimethyl ester 274.7 ml of a 1.61M hutyllithium solution in hexane was added dropwlse under argon at -60°C to a solution of 59 g of methanephosphonic acid dimethyl ester in 400 ml of absolute tetrahydrofuran. After stirring for 15 minutes, a solution of 34·05 g of 2,5-dimethyl-4-hexenoic acid ethyl eeter in 100 ml of absolute tetrahydrofuran was added dropwlse She reaction mixture . waa left to warm to room temperature - 15 over a period of four hours and was then stirred for a further 3 hours. 26.5 ml of glacial acetic acid were then added and the mixture was concentrated in vacuo.

The residue was taken up in ether/water, solid sodium chloride was added to the aqueous phase and extraction with ether was carried out. The combined organic phases were dried over magnesium sulphate and concentrated in a rotary evaporator. The residue remaining after evaporation was purified by column chromatography over silica gel with hexane/50-10056 ethyl acetate as eluant. 32 g of the desired compound were obtained.

IR (film): 1710, 1260, 1030/cm. g) (l£r5B.65,7g)-6-[{tert.-butyldiinethylsilyloxy)methvll-7-benzoyloxy-2-oxabicyclor3.3,0loctan-3-one A solution of 9.9 g of diaethyl-tert.-butylchlorosilane in 40 ml of absolute dimethylformaaide and 9.35 g of imidazole were added to a solution of 13.8 g of (IS, 5R, 6R, 7R )-6-hydroxy-methyl-7-benzo.yioxy-2-oxafeicycl» [3.3.0]^octan-3-one in 30 ml of absolute dimethylformamide.

After stirring for 2 hours at room temperature and under an argon atmosphere, analytical thin-layer chromatography indicated complete reaction. The reaction mixture was - 16 diluted with 850 ml of ether, washed with approximately 60 ml of saturated sodium bicarbonate solution and saturated sodium chloride' solution and then dried over magnesium·sulphate. The residue remaining after concen5 tration by evaporation may, if desired, be purified hy column chromatography over silica gel with ether as eluant. 17.8 g of the titl· compound (m.p. « 74-75°C after crystallisation-from pentane/ether) were obtained.

XR: 1775, 173,¾ 16pQ, 1580, 1275, 1255 , 840, 790, 720/cm. h)' ' (is,5R,6S,7R)i6-[ (tert.-butyldimethy-lsilyloxy)-7. methvl‘1-7-hvdroxv-2-oxablcvclor3.3.0~loctan-3-one A solution of 17.3 g of the benzoate obtained in the preceding reaction step in 200 ml of absolute methanol was stirred with 6.5 g of dry potassium carbonate at room temperature under argon. After two hours, analytical thin-layer chromatography indicated complete reaction.Then, at 0°C, 500 ml of O.lN hydrochloric acid were added dropwise to the reaction mixture, the whole was stirred for 15 minutes at room temperature, concentrated in vacuo and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate. The residue remaining after concentration by evaporation was purified by column chromatography over silica gel with hexane/50-100% ether 25 as eluant. 9.1 g of the desired compound (m.p.: 57-58.5°C) were obtained. - 17 IR (film): 1775, 1255, 840, 790/em. i) (IS,5R,6S,7R)-6-[(tert,-butyldimethylsilyloxy)methyl]-7-(tetrahydropyran-2-yloxy)-2-axabicyclo • Γ 3.3.oloctan-3-one___________________ A solution of 15.8 g of alcohol obtained according to the method described above in 300 ml of distilled methylene chloride was stirred with 7.5 ml of dihydropyran freshly distilled using potassium hydroxide, and 1.38 g of pyridine-p-tolueneeulphonate for 14 hours at rocm tem10 perature. After concentrating the reaction solution at room temperature, it was diluted with ether and washed with semi-saturated sodium chloride solution. The organic solution was subsequently dried over magnesium sulphate and then concentrated to dryness. The product may, if desired, be purified by column chromatography over silica gel with hexane/20-50% ether as eluant. The yield was 20 g.

IR (film): 1775, 1255, 1115, 1080, 1035, 835, 775/cm. j) (IS,3RS,5R,6S,7R)-3-hydroxy-6-[fcert.-butyldimethylsilyloxy)-methyl]-7-(tetrahydropyran-2- 20 yloxv )-2-oxabicvclo Γ3.3.0 loctane· _______ ml of a 20% DIBAH solution in toluene were added dropwise under argon in the course of 15 minutes to ^600 - ·; v ·... :-4./ ID a solution, coole4 to-7O®C, of 514 g of the lactone obtained .'in bib preceding reaction step in 200 ml of ’ -for approximately 5 at the same |$|| fp^tipn of foam ceased. The reaction |ρ1^ίρη was left to warm to 0°c, 16 ml of water * - ... were 'added,'··and th» mixture was stirred for 10 minutes ' "i«h^';i|^|j^^-^l‘.’^|eipitate was washed phase w washed three fis^s'^^'lafu^^i^ 'iPdiW^lQpid·1 solution, dried over ^^SSiW^S^l^iafi^d'qPDtentrated. in a rotary evaporator. The resulting product (5.41 g) was used in the next reaction step without further purification. k) (5Z)-(8R,9S,llR,12S)-9-hydroxy-ll-(tetrahydro15 pyran-2-yloxy)-13-(tert.-butyldimethylsilylaxy}14.15,16,17,18,19-20-heptanor-5-prostenoic acid 104.6 ml of a solution of methanesulphinylmethyl sodium in absolute dimethyl sulphoxide (prepared by dissolving 6 g of 50% by weight sodium .hydride suspension in 1.20 ml of 20 absolute dimethyl sulphoxide at a maximum of 70*0 were added dropwise at 15°C to a solution of 25.67 g of 4-carboxyhutyltriphenylphosphonium bromide (previously dried at 7O-8O°C using an oil pump) in 80 ml of absolute dimethyl sulphoxide. This ylene solution was stirred for 30 minutes at roam 25 temperature and then, while cooling with water, added dropwise in the course of 15 minutes to a solution of - 19 5.41 g of the laetol obtained in the preceding reaction step in 50 ml of absolute dimethyl sulphoxide. The reaction mixture was then stirred for four hours at -4O°C under argon. (50-100 ml of absolute tetrahydrofuran may optionally be added to the reaction solution).

For working up, the reaction mixture was poured onto ice-water, extracted three times with ether, and the aqueous phase was acidified to pH 4 with 10% by weight citric add solution and extracted three times with a 1/1 mixture of ether/hexane. Extraction was then carried out another three times by shaking with methylene chloride. On the basis of analytical thin-layer chromatography , the methylene chloride phase was discarded, hut the other two organic phases were combined, dried over magnesium sulphate, filtered and concentrated in a rotary evaporator. The residue was purified by column chromatography'over silica gel with hexane/70-100% ether as eluant. 4.32 g of the carboxylic acid were obtained.

IR (film): 3440 (broad), 3200-2500, 1725, 1700, 1250, 1100, 1020, 830, 770/cm. 1) (5Z)-(8R,9S,11R,12S)-9-hydroxy-ll-(tetrahydropyran-2-yloxy)-13-(tert.-butyldimethylsilyloxy)-14,15,16,17,18,19,20-heptanor-5prostenoic acid methyl ester Preparation with diazomethane: The 4.32 g of carboxylic acid obtained in k) were - 20 dissolved in 20 ml of methylene chloride, and ethereal diazomethane solution was added until the evolution of gas had ceasgdsnd th# yellow colour of the solution remained W^>nge5.?>< After drawing off the excess diazomethane using a water- jet vacuum, the reaction solution was concentrated tp dryness in a rotary evaporator. 4.3 g of'the desired .Carboxylic acid methyl ester were . .·>. ·»λ· . - :. , . κ-Λ , Obtained. . .« ··.··< · 10 75 ml of fl-e-t^yldiisopropylamine and 150 ml of iqdometljane in 20p ml gf acetonitrile were added dropwlse at room temperature in the course of 2 hours to a solution of 32.5 g of the carboxylic acid obtained in k) in 450 ml of acetonitrile. Stirring was carried out fear one hour, then, after TLC examination, the precipitate was suctionfiltered and washed with ethyl acetate, and the organic phase was shaken in succession with sodium bisulphate, sodium bicarbonate and sodium chloride solutions. After drying over magnesium sulphate, the mixture was concentrated 20 to dryness in a rotary evaporator and the residue was purified by column chromatography over silica gel with hexane/50-100% ether as eluant. 32.3 g of the title eempound were obtained.

IR (film); 3420 (broad), 1740, 1255, 1120, 1030, 840, 780/cm, - 21 m) (5Z)-(8R,9S,llR,12S)-9-benzoyloxy~ll(tetrahydropyran-2-yloxy)-13-(tert.-butyldime thyleily loxy )-14,15,16,17,18,19,20hepfcanor-5-prostenoie acid methyl eater 2.32 ml of distilled benzoyl chloride were added dropwise while stirring at room temperature to a solution of 4.7 g of the 9-hydroxy compound obtained in 1) in 70 ml of pyridine. After stirring for two hours under an argon atmosphere, 1.8 ml of water were added to the reaction solution, the mixture was stirred for a further hour and then concentrated at 30°C and 1 torr using an oil pump. The residue was taken up in a two-phase mixture of ether/water, washed with sodium bicarbonate and saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness in vacuo. After column chromatography of the evaporation residue over silica gel with hexane/3O-50% ethyl acetate as eluant, 5.11 g of the title compound were obtained as a colourless oil.

IR (film): 1745, 1720, 1605, 1590, 1280, 1260, 1120, 1030, 840, 780, 710/cm. n) (8R,9S,11R,12S)-9-benzoyloxy-ll-(tetrahydropyran-2yloxy )-13- (tert .-butyldimethylsily loxy)-14,15, 16,17,18,19,20-heptanorprostanoic acid methyl ester 1.23 g of 10% by'weight palladium-on-carbon were added te Ρ'. 53600 ·· /X:ΐ· ·< .,,. .· · ·... . · a solution of 12,3 g of the unsaturated compound obtained in m) ‘in l6Q ml bi ethyl acetate and the mixture was h^rssgehstvS in ij .'sbaWihg apparatusatroom temperature 640 ml of >¥&90<ΜΜ!β b$«.<.$SSF&tfl, #»e solvent was removed in vacuo. the residue was taken up in 40 ml of ether, the brgwlS WMiH with-saturated sodium ehloride end concentrated to .*rypes|.;in r |v»poritot,:· 12.1 g of the title ίβ^ρβαηή;^?«. obtained, < lR(iil»U 1740, 1^,1600, 1580, 1275, 1255, 1115, 1070, 1025, 835, 780, 7l0/cm. o) (8R,9S,11R,12S)-9-benzoyloxy-ll-(tetrahydropyran-2 yloxy)-13-hydroxy-14,15,16,17,18,19,20heptanorprostanoic . acid methyl ester 16.11 ml of a 2M tetrabutylanmonium fluoride solution in tetrahydrofuran were added, while cooling with ice, to a solution of 6.94 g of the compound obtained in the preceding reaction step in 110 ml of absolute tetrahydrofuran. After stirring for 12 hours under an argon atmosphere, the reaction mixture was diluted with 1.3 litres of ether, washed neutral with saturated sodium chloride solution and the washing solution was subsequently extracted twice with ether. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography over 52800 - 23 silica gel with ethyl acetate as eluant. 5.54 g of the desired coinpound were obtained as a colourless oil.

IR (film)! 3460 (broad), 1735, 1715, 1600, 1580, 1275, 1115, 1070, 1025, 710/cm. p) (8R,9S,llR,12S)-9-benzoyloxy-13-oxo-ll- * (tetrahydropyran-2-yloxy)-14,15,16,17,18,19,20heptanorprostanoic acid methyl ester A solution of 5.54 g of the alcohol obtained according to the method described above in 56 ml of absolute methylene chloride was added dropwise at -lo°C in the course of 20 minutes to a suspension of 18.7 g of Collins reagent in 170 ml of absolute methylene chloride. After stirring the reaction mixture for one hour in an argon atmosphere, 500 ml of a 1/1 mixture of ether and pentane were added and decanting was carried out. The flask was washed two more times with 500 ml of the same mixture as mentioned above,each time. The combined organic phases were then shaken three times with 50 ml of 5% by weight sodium carbonate .solution each time and three times 20 with 50 ml of 5% sulphuric acid each time and were then washed neutral with saturated sodium chloride solution. After .drying over magnesium sulphate, the mixture was concentrated to dryness and the residue was filtered over a column of silica gel (50 g; eluant: ethyl acetate/hexane " 2/8). 4.6 g of the desired aldehyde were obtained.

IR (film): 2720, 1735, 1715, 1600, 1580, 1275, 1115, 1070, 1025, 715/cm. q) {13E)-(8R,9S,llR,12R,16RS)-9-benzoyloxy-16, 19-dimethyl-15-oxo-ll-(tetrahydropyran-2-yloxy)i3.1S-proatadienoic acid methyl eater 2.48 g'5 of the phosphonate obtained according to £), dissolved ip 30 φΐ of absolute dimethoxyethane', .were added dropwise at room temperature under, argon to a suspension of 0.48 g?pf 50% .hydride', (suspended: · in oil) > ffl pi gf dimethoxyethane freshly distilled using' lithium' alumin'iuro hydride. After the addition of 0,43 'g of lithium qhloride (previously dried in a vacuum cupboard for 2 hours'at 5O°C), the reaction mixture was stirred for 2 hours at room temperature. The suspension was subsequently cooled to -2O°C and 4.61 g of the aldehyde obtained according top), dissolved in 90 ml of absolute . dimethoxyethane, were added dropwise. The temperature was then allowed to increase from -2O°C to O°C in the course of 5 hours and to 5°C in the course of 1.5 hours in order then to stir the reaction solution for a further 3 hours at room temperature. At -1O°C, there were then added dropwise 1 ml of glacial acetic acid and approximately 100 ml of water. The phases were separated, the aqueous phase was extracted 5 times with ether, and the organic by weight phases were combined and washed with 4%/sodium bicarbonate and saturated sodium chloride solutions. After drying ever magnesium sulphate, the mixture was concentrated to dryness in a rotary evaporator. The residue was subjected to purification by column chromatography over silica gel 53600 - 25 with ethyl acetate/hexane - 1/1 as eluant. 5.78 g of the title compound were obtained.

IR (film); 1740, 1720, 1695, 1670, 1625, 1600, 1580, 1270, 1105, 1060, 1025, 705/cm. r) (13fi)-(8R,9S,11R,12R,15R,16RS)-9-benzoylaxy-16, 19-dimethyl-15-hydroxy-ll-(tetrahydropyran-2vloxy)-13,lfi-proatadienoie acid methyl eater 2.37 g of sodium borohydride were added in portions to a solution, cooled to -4o°C, of 5.78 g of the ketone obtained in the preceding reaction step in 115 ml of absolute methanol. After stirring for one hour at -40°C, 5.09 ml of glacial acetic acid were added dropwise to the reaction solution likewise at -40°C. After removing the solvent in a rotary evaporator, methylene chloride/ water were added to the residue, solid sodium chloride was added to the separated aqueous phase and the mixture was extracted twice with methylene chloride. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The isomers were separated by repeated column chromatography several times over silica gel with hexane/ 20-100% ethyl acetate aa eluant. 2.11 g of the title compound were isolated as the least polar product.

IR (film): 3400 (broad), 1740, 1720, 1600, 1580, 1275, 1120, 1030, 1020, 7l0/cm. ·!/ w " 26 β) i(}.35)"(8B,9S»llR,l2R,l5R,l6RS)-9-benzoyloxy-16,19 R ·· -ijimathyl-llr 15-bis (tetrahydropyran-2-yloxy)-13, t ^Bwggosiiitaisnoig scid^ methyl ester _ . ϊ·, 0.49 mJ.· of dihydropyran (freshly distilled using potfissiusV'l^^t^e^qnd^;? mg of p-toluenesulphonic acid were ,»44«4 »1s i,e«Bbath-ieipper^ure to a solution of 2,11 g Of the alcohol obtained according to r) in 60 ml Of absolute imst^ylsns^Shiori3e^:.tl»e ’mixture was stirred .«ii/llwwlng diluted the-reaction XR (film): 1740, 1720, 1605, 1585, 1275, 1115, 1080, 1025, 715/cm. t) (13E)-{SR,9S,12R,12R,15R,16RS)-9-hydroxy-16 , 19-dimethy1-11,15-bis (tetrahydropyran-2-yloxy )-13 18-prostadienoic acid .6 ml of 2H potassium hydroxide solution were added to a solution of 2.3 g of the benzoate obtained according to s) in 70 ml of methanol and the mixture was stirred for 31 hours at room temperature. The reaction mixture was subsequently concentrated in a rotary - 27 evaporator, and the residue was taken up in a little water and extracted twice with 150 ml of an ether/pentane mixture each time. The aqueous phase was acidified to a PH . pf 5 with citric acid and extracted three times with 150 ml of ethyl acetate each time. The combined organic phases were washed neutral with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography over silica gel with hexane/50-100% ethyl acetate as eluant. 1.62 g oC the title compound were obtained.

IR (film): 3460, 2730, 2660, 1730, 1710, 1130, 1110, 1075, 1020, 810/cm. . u) (13E)-(8R,llR,12R,15R,16RS)-9-oxo-16,19dimethyl-11,15- bis (tetrahydropyran-2-yloxy)-13, 18-prostadienoic acid 0.46 ml of Jones reagent was added to a solution, cooled to -2o°C, of 360 mg of the alcohol obtained according to t) in 7 ml of acetone and the mixture was stirred at that temperature for 45 minutes. 0.6 ml of isopropanol was then added, the mixture was stirred far a further 10 minutes, diluted with cold ether and washed three times with cold saturated sodium chloride solution, and the organic phase was dried over magnesium sulphate and concentrated in vacuo. After filtration over a Sep-Pack prepared column, 327 mg of the title, ccmpound were obtained. iR (film): 2730, 2660, 1740, 1710, 1110, 1075, 1025, 810/em. --28v) . (13E)-(8R,llR,12R,15R,16RS)-9-axo-ll,15dihvdroxv-16,19-dimethvl-13,18-prostadienoic acid ' · · ; ^,'X- - -W AV'' ?' y t-^be 327. mg obtained according to the method described .'^bove ‘ in μ) were stirred at room temperature-for 26 hours ip ? mi >!f a mixture of glacial acetic acid/water/ ,·/ --.'' . tstrahydrofusan (65/35/10). The whole was then concentrated seyeral^imeswith'benzene in an oil pump vacuum· at temperature. The residue was purified by column chromatography over silica gel with ethyl acetate/ 0-10% methanols· eluant. 68 mg of the title compound were obtained.

IR (film): 3420, 2730, 2670, 1735, 1710, 1075, 975/cm. w) (13£)- (8&, 9J5,11£,12R, 15S, 16RS )-9-benzoyloxy-16,19dimethy1-15-hydroxy-11-(tetrahydropyran-215 vloxy )-13,18-prostadienoic acid nethvi ester I In the sodium borohydride reduction of the ketone according to r), in addition to the 2.11 g of β-alcchol and 0.27 g of an ο/β mixture, 2.67 g of the title compound were eluted from the column as a more polar product.

IR (film):. 3400 (broad), 1740,· 1720, 1600, 1580, 1275, 1120, 1030, 1020, 710/cm. - 29 x) (13E_)—(8R,9S,11R,12R,15s,16RS)-9-benzoyloxy-16, 19-dimethyl-ll,15-bis(tetrahydropyran-2vloxv)-13,18-proatadienoic acid methyl ester Analogously to the method described in s) for the 5 preparation of the 15P-isomer, 2.96 g of the title compound were obtained, as a colourless oil by reacting 2.67 g of the alcohol obtained in the preceding reaction step with 0.62 ml of dihydropyran and 12.3 mg of p-toluenesulphonic acid (reaction time: 75 minutes) and after column chromatography over silica gel with ethyl acetate/hexane « 1/3 as eluant.

IR (film): 1740, 1720, 1600, 1585, 1275, 1115, 1075, 1025, 715/cm. . y) (13E.)-(8R, 9S, 11R, 12R, 15S, 16RS)-9-hydroxy-16, 19-dimethyl-ll,15-bis(tetrahydropyran-2-yloxy)-13, 18-prostadienolc acid Analogously to the method described for the preparation of the 15p-isomer in t), 2.22 g of the title compound were obtained by reacting 2.96 g of the; compound of x) with 26.5 ml of 2N potassium hydroxide solution and after column chromatography over silica gel with hexane/50-100% ethyl acetate as eluant.

IR (film): 3450, 2730, 2660, 1730, 1710, 1130, 1110, 1075, 1020, 810/cm. - 30 z) (13E.)-(8R,llR,12R,15S,16RS)-9-oxo-16,l9dimethyl-11,15-bis (tetrahydropyran-2vloxy)-13,18-orostadienoic acid 360 mg of the alcohol obtained in the preceding 5 reaction step were reacted analogously to the method described for the preparation of the corresponding ISp-isomer in u), 326 mg qf the title con^wund were obtained.' .' IR (film): 273Q, 2670, 1740, 1710. 1105, 1070, 1020, 810/en, · (13E)—(8R,31R,12R, 15S , 16RS )-9-oxo-ll, 15-dihydroxy-16, 19-dimethyl-13,18-prostadienoie acid Analogously to the method described for the synthesis of the iSP-isomer in v.), 54 mg of the title compound of Example 1) were obtained by reacting 326 mg of the compound obtained in the preceding reaction step. IR (£i3m)j 3400, 2730, 2660, 1740,-1710, 1075, 975/cm. - 31 Example 2 (13E)(8R,11R,12R,15R)-11,15-dihydroxy-16,16,19-trimethy19-oxo-1.3,18-prostadienoic acid a) 2,2,5-trlmethyl-4-hexenolc acid ethyl ester 610 ml of a 1.64N butyllithium solution in hexane were added dropwise under argon at -20 °C to a solution of 101.2 g of diisopropylamine in 125 ml of absolute tetrahydrofuran . The temperature was allowed to rise for a short time to approximately 0*C,in order then to add 116 g of iso10 butyric acid ethyl ester dropwise at from -50 to -60eC to the lithiumhiisopropylamide solution.The reaction solution was stirred for one hour at 0*C,then cooled to -40°C and subsequently added to a solution,maintained at -20°C, of 200 g of 4-bromo-2-methyl-2-butene (dimethylallyl bromide) in 60 ml of absolute dimethyl sulphoxide. While allowing the temperature to rise to room temperature, the reaction mixture was stirred for 60 hours and subsequently 250 ml of saturated sodium chloride solution were added. The organic phase was separated off and the aqueous phase was extracted five times with 200 ml each time of a 1/1 mixture consisting of’ether and hexane. The combined organic phases were washed neutral with 0.5N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulphate and concentrated in a rotary evaporator. The residue was distilled.in vacuo. 91.5. g of the desired ester were obtained ()..μ., ,,«7^(11(.'), IB J 1735, 1-^0, 1fi$0, 820/cm. •4/ ·/ b) 2j,2,5-trirnethyl-4-hexenolc acid methyl ester The tjtle compound was prepared according to the method deacribsdaboye for the pynthesis of the corresponding ethyl esfcor. wising' ippb^ysip sgi^inethyi ester.

M’lf. .. · ir («μ?ι)5 pas, i]eq? ioso, 820/cm, ? - ? - : ’ . '·. ··. ' ·' :. / ϊ ·,. ' ;i:. 4* e) '2,2,5»trlmethyl-4-hexenoie acid The title compound was prepared according to the method described in a) above using isobutyric acid as educt and 2 equivalents of lithium diisopropylamide. b.p.g 2-q 4 B 94-100"C.

IR (film): 1705, 1220, 820/cm. d) 2-(1,1,4-trimethyl-3-pentenyl)-2-oxoethanephosphonic acid dimethyl ester 49.5 ml of a 2.02N butyllithium solution in hexane were added dropwise under argon at -60°C to a solution of 13 g of methanephosphonic acid dimethyl ester in 160 ml of absolute tetrahydrofuran. After 15 minutes, a solution of 9.2 g of 2,2,5trimethyl-4-hexenoic acid ethyl ester in 25 ml of absolute tetrahydrofuran was added dropwise. After 2 hours at -60°C, the reaction mixture was left to warm to room temperature in the cours of one hour, 5.72 ml of glacial acetic acid were added and the mixture was then concentrated in vacuo. The residue, a white gel52600 - 33 like mass, was divided in a two-phase mixture consisting of 35 ml of water and 165 ml of ether. The organic phase was dried over magnesium sulphate and concentrated in a rotary evaporator. After the volatile side-products had been distilled off at 60*C and 0.1 torr, the residue was purified by column chromatography over silica gel with hexane/50-100% ethyl acetate as eluant. 8.6 g of the title compound were obtained.

IR (film): 1705, 1260, 1030, 820/cm. e) (13E)-(8R,9S,11R,12R)-9-benzoyloxy-16,16,19-trimethyl1S-oxo-11-(tetrahydropyran-2-yloxy) -/3,18-prostadienoic acid methyl ester 4.05 g of the phosphonate obtained according to d) dissolved in 45 ml of absolute dimethoxyethane, were added dropwise at room temperature under argon to a suspension of 0.74 g of 50« by weight sodium hydride (suspended in oil) in 90 ml of dimethoxyethane freshly distilled using lithium aluminium hydride. After the addition of 0.66 g of lithium chloride (previously dried in a vacuum cupboard for 2 hours at 50SC), the reaction mixture was stirred for 2 hours at room temperature. The suspension was subsequently cooled to -20°C and 7.11 g of the aldehyde obtained according to Example 1p) dissolved in 140 ml of absolute dimethoxyethane, were added dropwise. The temperature was then allowed to increase from -20°C to15°C in the course of 5 hours in order then to stir the reaction solution for a further 19 hours at room temperature. At -10°C, there were then added - 34 dropwise 1.6 ml of glacial acetic acid and approximately 100 ml of water. The phases were separated, the aqueous phase was extracted 5 times with ether, and the organic phases were then combined and washed with 4% by weight sodium bicarbonate and saturated sodium chloride solutions. After drying over magnesium sulphate, the mixture was concentrated to dryness in a rotary evaporator. The residue was subjected to purification by column chromatography over silica gel with hexane/150-100% ethyl acetate as eluant. 9.19 g of the title compound were obtained.

IR (film): 1740, 1720, 1695, 1670, 1625, 1600, 1580, 1270, 1105, 1060, 1030, 705/cm. f) {13E) -(8r,9S,11R,12R,15S)-9-benzoyloxy-16,16,19-trimethyl-15-hydroxy-11-(tetrahydropyran-2-yloxy)-13,18prostadlenoic acid methyl ester 3.68 g of sodium borohydride were added in portions to a solution, cooled to -40°C, of 9.19 g of the ketone obtained in the preceding reaction step in 180 ml of absolute methanol. After stirring for 3.5 hours at -40°C, 7.9 ml of glacial acetic acid were added dropwise to the reaction solution likewise at -40°C. After removing the solvent in a rotary evaporator, methylene chloride/water were added to the residue, solid sodium chloride was added to the separated aqueous phase and the mixture was extracted twice with methylene chloride. The combined organic phases were washed with saturated sodium chloride solution dried over magnesium sulphate and concentrated in vacuo. The - 35 isomers were separated by repeated column chromatography several times over silica gel with hexane/20-40« ethyl acetate as eluant. 2.02 g of the title compound were isolated as the less polar product.

IR (film): 3400 (broad), 1740, 1720, 1600, 1580, 1275, 1120, 1030, 1025, 710/cm. g) (13E)-(8R,9S,11R,12R,15S)-9-benzoyloxy-16,16,19trimethyl-11,15-bis(tetrahydropyran-2-yloxy)-13,18prostadlenolc acid methyl ester 0.45 ml of dihydropyran (freshly distilled using potassium hydroxide) and 9 mg of £-toluenesulphonic acid were added at ice-bath temperature to a solution of 2 g of the alcohol obtained according to f) in 60 ml of absolute methylene chloride, the mixture was stirred for 55 minutes at 0°C and, having diluted the reaction solution with methylene chloride, it was extracted with saturated sodium bicarbonate solution and water. The organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography over silica gel with ethyl acetate/hexane =1/2 as eluant. 2.12 g of the desired ‘compound were obtained.

IR (film): 1740, 1720, 1605, 1585, 1275, 1115, 1080, 1025, 715/cm. h) (13E)-(8R,9S,11R,12R,15S)-9-hydroxy-16,16,19-trimethyl11,15-bis(tetrahydropyran-2-yloxy)-13,18-prostadienoic acid 19 ml of 2N potassium hydroxide solution were added to a solution of 2.12 g of the benzoate obtained according to.g)in - 36 60 ml of methanol and the mixture was stirred for 26 hours at room temperature. The reaction mixture was subsequently concentrated’in a;rotary evaporator, and the residue was taken up |n a little water,and extracted twice with 150 ml of an ether/ pentane mixture each time. The aqueous phase was acidified to a pH of 5vith citiriq’acid and extracted three times with 150 ml of ethyl acetate-lijich'iiBie. Thecombined organic phases were washed 'neufcraliwith.saturated sodium chloride solution, dried over magnesium sulphate end concentrated in vacuo. The residue was'purified by fiolumtl chromatography over silica gel with hexane/ 50-100% .ethyl acetate as eluant. 1.43 g of the title compound were obtained.

IR (film): 3460, 2730, 2660, 1730, 1710, 1130, 1110, 1075, 1025, 810/cm. i) (13E)-(8R, HR,12R,15&)-9-0X0-16,16,19-trimethyl11,15-bis(tetrahydropyran-2-yloxy)-13,18prostadienolc acid0.63 ml of Jones reagent was added to a solution, cooled to -20°C, of 500 mg of the alcohol obtained according to h) in 10 ml of acetone and the mixture was stirred at that temperature for 45 minutes. 0.8 ml of isopropanol was then added, the mixture was stirred for a further 10 minutes, diluted with cold ether and washed three times with cold saturated sodium chloride solution, and the organic phase was dried over magnesium, sulphate and concentrated in vacuo. After filtration over a Sep-Pack prepared column, 442 mg of the title compound were obtained.

IR (film): 2730, 2660, 1740, 1710, 1105, 1070, 1025, 810/cm. j J (13E)-(8R,11R,12R,15S)-11,15-dihydroxy-16,16,19trlmethyl-9-oxo-13,18-proBtadlenolc acid The 442 mg obtained according to the method described above in 1) were stirred at room temperature for 24 hours in 9 ml of glacial acetic acid/water/tetrahydrofuran (65/35/10).

The whole was then concentrated several times with benzene in an oil pump vacuum at room temperature. The residue was purified by column chromatography over silica gel with ethyl acetate/ 0-10% methanol as eluant. 124 mg of the title compound were obtained.

IR (film): 3420, 2730, 2670,1740, 1710, 1075, 975/cm. k) (13E)-(8R,9S,11R,12R,15R)-9-benzoyloxy-16,16,1915 trimethyl-15-hydroxy-11-(tetrahydropyran-2-yloxy)13,18Tprostadienoic acid methyl ester In the sodium borohydride reduction of the ketone according to f), in addition to the 2.02 g of 8-alcohol and 0.7 g of an β/β mixture, 4.28 g of the title compound were eluted from the column as a less polar product.

IR (film): 3400 (broad), 1740, 1720, 1600, 1575, 1275, 1120, 1030, 1020·, 710/cm. *»·; · · Λ «1$ $3£··. · 4-' ·-!.·.'"·'?«·♦·· 3600 . & ί '4· 1) (13Ε)-(8R,9S,11R,12R,15R)-9-benzoyloxy-16,16,191#iftethyl-ii,15-bie(tetrahydropyran-2-yloxy)-13,18......., ΛΙίβι???!;^ 5§8steP with 0.96 ml of dihydropyran ;||| 11 of g^olugneeiilphonie acid (reaction time; 75:. p|putea);f |nd a$|er epilujpn' ghromatography over silica gel with IR (film): 1740, 1720, 1600, 1585, 1275, 1115, 1075, 1020, 715/cm. m) <13E) - (8R, 9S, 11 R,'12R, 15R) -9-hydroxy-16,16,19trimethyl-11,15-bis(tetrahydropyran-2-yloxy)-13,18prostadienoic acid Analogously to the method described for the preparation of the 15β-isomer in h), 2.8 g of the title compound were obtained by reacting 4.3 g of the compound obtained in 1) with 38.5 ml of 2N potassium hydroxide solution and after column chromatography over silica gel with hexane/50-100% ethyl acetate as eluant.

IR (film); 3450, 2730, 2660, 1730, 1710, 1130, 1110, 1075, 1025, 810/cm. n) (13E)-(8R,11R,12R,15R)-9-oxo-16,16,19-trimethyl11,15-bis(tetrahydropyran-2-yloxy,-13,18prostadlenoic acid 500 mg of the alcohol obtained in the preceding reaction - 39 step were reacted analogously to the method described for the preparation of the corresponding 150-isoroer in i). 410 mg of the title compound were obtained.

IR (film): 2730, 2670, 1740, 1710, 1110, 1075, 1020, 810/cm. o) (13£)-(8R,11R, 12R,15R)-ll,15-dihydroxy-16,16,19trimethyl-9-oxo-13,18-prostadienoie acid Analogously to the method described for the synthesis of the 15P-isomer in j), 110 mg of the title compound were obtained by reacting 410 mg of the compound obtained in the preceding reaction step.

IR (film): 3400, 2730, 2660, 1740, 1710, 1075, 975/cm.

Example 3 (13E)-(8R,11R,12R,15S,16RS)-11,15-dihydroxy-16,19-dimethyl9-oxo-13,18-prostadienoic acid, tris(hydroxymethyl)-aminomethane A solution of 32.9 mg of tris (hydroxymethyl)-aminomethane in 0.1 ml of water was added at 60°C to a solution of 94.5 mg of the compound obtained according to Example 1 in 14 ml of acetonitrile. The mixture was left to stand at room temperature for 14 hours. The yield was 63.5 mg.

Example 4 (13E)-(8R,11R,12R,15R)-11,15-dihydroxy-16,16,19-trimethyl-9oxo-13,18-prostadienoic acid, tris (hydroxymethyl )-amincmethane Analogously to the method described in Example 3, 68.5 mg of the title compound were obtained from 98 mg of the compound '' ·. :-ΐ For iieei' in parenteral >dinin4»tr8tion: ^>?feXl<«rtpg solution was WsMWg «$· fc|t« «mj^es^ .co8vej»tj.onsi. techniques.

'' OiT'^-ef'$}« ebjnpownd o||g^nt4'acgerding to Example 1, a,9 «g ©STwif» .- Sfc6ito>« pot ι$9ΐφ , .-- JBadt.wa fcp $$4 ; Ampoitlei egnjsgloW $· ??eording "" of Examples 2 to 4 were prepared in a similar manner. - 41 5 .2 6 Ο Ο CLAIMS

Claims (21)

1. (13Ε)-(8R,11R, 12R)-Η,15-dihydroxy-16,19dimethy 1-9-οχο-13,18-prostadienoic acids of the general in which R represents hydrogen or a methyl group, or the physiologically tolerable salts thereof with bases.

2. (13E)-(8R,HR,12R,15S,16RS)-11,15-dihydroxy10 16,19-dimethy1-9-oxo-13,18-prostadienoic acid.

3. (13E) - (8R, 11R, 12R, 15R) -Π, 15-dihydroxy-16,16, 19-trimethyl~9-oxo-13,18-prostadienoic acid.

4. A salt of a compound as claimed in any one of claims 1 to 3. 15

5. A physiologically tolerable salt of a compound as claimed in any one of claims 1 to 3.

6. A compound as claimed in claim 1 or claim 5, which is described in any one of Examples lv) , 2j), 3 and 4 herein. 20

7. (13E)-(

8. R,HR,12R,15S,16RS)-11,15-dihydroxy-16, 19-dimethy1-9-0X0-13,18-prostadienoic acid, tris(hydroxymethyl) aminomethane salt. 82600 0. 0 P-CH--C-C-CH, (II) - 42 8. (13E)-(8R,llR,12R,15R)-ll,15-dihydroxy-16,16, 19-trimethyl-9-oxo-13,18-prostadienoic acid, trie(hydroxymethyl) aminomethane salt.

9. A process for the manufacture of a compound of 5 the formula I as claimed in claim 1, in which (SR,9S,11R, 12S)-9-benzoyloxy-13-oxo-ll-(tetrahydropyran-2-yloxy)-14, 15,16,17.18-,19,2o-heptahorppoatanoic acid methyl ester is reacted with 2-(l,4-dimethyl-3-pentenyl)-2-oxoethanephosphonic acid dimethyl esters of the formula n / * » I * \ CHjO 0 CH 3 CH 3 in which R has the meaning given in claim 1, and subsequently the 15-keto group is reduced and protected with dihydropyran, the 9-hydroxy group is liberated and then oxidised, 15 protecting groups present are split off ? if R represents hydrogen the compound is separated into its stereoisomers, and, optionally, the compound is converted into a physiologically tolerable salt.

10. A process as claimed in claim 9, whenever 20 carried out substantially as described in Example 1 or Example 2 herein.

11. A compound as claimed in claim 1, whenever prepared by a process as claimed in claim 9 or claim 10. - 43

12. A salt as claimed in claim 4, whenever prepared by a process as claimed in claim 9 or claim 10.

13. A physiologically tolerable salt as claimed in claim 5, whenever prepared by a process as claimed in claim 9 or claim 10.

14. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 1 to 3, 5 to 8, 11 and 13 in admixture or conjunction with a pharmaceutically suitable carrier.

15. A pharmaceutical preparation as claimed in claim 14, which is in unit dosage form.

16. A pharmaceutical preparation as claimed in claim 14 or claim 15, which is in a form suitable for oral administration.

17. A pharmaceutical preparation as claimed in claim 14 or claim 15, which is in the form of a sterile injectable aqueous or oily solution.

18. A pharmaceutical preparation as claimed in claim 17 which contain^ in the range of from 0.0001 to 10 pg of active ingredient per ml of sterile aqueous solution.

19. A pharmaceutical preparation as claimed in claim 14 or claim 15, which is in a form suitable for inhalation.

20. A pharmaceutical preparation as claimed in claim 14 or claim 15, which is in a form suitable for vaginal administration. - 44

21. A pharmaceutical preparation as claimed in claim 14, which is substantially as described in Example 5 herein. Dated this 12th day of February 1982 CRUICKSHANK & CO. Agents for the Applicants,