DE3106149A1 - (13E)-(8R, 11R, 12R, 15S, 16RS)-11,15-Dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid and its salts, processes for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

The invention relates to (13E)-(8R, 11R, 12R, 15S, 16RS)-11, 15-di-hydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid and its salts with physiologically tolerable bases, processes for their preparation and their use as abortion-inducing agents.

Description

fle spelling

The present invention relates to (13E) - (8R, 11R, 12R, 15S, 16RS) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid, their physiologically acceptable salts, processes for their preparation and these containing pharmaceutical compositions.

In the German Offenlegungsschrift 26 35 985 prostanoic acid derivatives of the general formula I are claimed, in the R1 one or Represents a group in which R6 represents a hydroxyl group, a straight or branched alkoxy group with 1-10 C atoms, a substituted or unsubstituted aryloxy group, an O-CH2-UV group, where U is a direct bond, a carbonyl or carbonyloxy group and V denotes a phenyl ring substituted by one or more phenyl groups, alkoxy groups with 1-2 C atoms or halogen atoms, preferably bromine atoms, or a -NER10 group, in which R10 is an alkyl or aryl group or an acid residue of an organic carboxylic or sulfonic acid with 1-15 carbon atoms, R7 and R8 represent hydrogen atoms or alkyl groups with 1-4 carbon atoms and R9 either an acid residue of an organic carboxylic or sulfonic acid with 1-15 carbon atoms or an inorganic acid or a Represent a group, where R10 has the meaning given above, A is a -CH2-CH2- or a cis- or trans-CH = CH- group, B is a -CE2-CH2-, a trans-CH = CH-, a - C = C group or a Group, where the methylene group can be in the α or ß position, means W is a free or functionally modified hydroxymethylene group, a free or functionally modified carbonyl group or a Group, where R11 1 is a hydrogen atom or an alkyl group with 1-5 C atoms and the OH group can be α or β and functionally modified, Z is a carbonyl or hydroxymethylene group which can be freely or functionally modified can, represents, X ... Y for or if Z is a free or functionally modified hydroxyme, ethylene group or is or -CH = CH-, when Z represents a free or functionally modified carbonyl group, where the radical R12 is a hydrogen atom, a methyl, a cyanide group or a free or functionally modified hydroxy group, R2 is a hydrogen atom or an alkyl group, R3 is Denotes hydrogen atom or an alkyl group, R4 = R5 denotes a methyl group or R4 denotes a chlorine atom when R denotes a methyl group 5 or R5 denotes a chlorine atom when R4 denotes a methyl group and, if R6 denotes a hydroxyl group, their physiologically compatible Mean salts with bases.

The compounds have valuable therapeutic properties and are distinguished in particular by the fact that they are applied after a single intrauterine application to induce menstruation or to interrupt a pregnancy. They are also suitable for synchronization of the sexual cycle in female mammals such as monkeys, cattle, pigs, sheep, etc. The prostaglandin derivatives from the DE-OS 26 35 985 have a strong uterine contracting and luteolytic effect, i. H. to trigger an abortion requires lower doses than the corresponding natural ones Prostaglandins. With the prostaglandins, the main effects desired are mostly accompanied by undesirable side effects that significantly reduce the quality of the main effect reduce.

Among the compounds claimed in DE-OS 2635 985 showed the compound (13E) - (8R, 11R, 12R, 15S, 16RS) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid as an abortive such outstanding properties that with it the dosage compared commercial preparations can be reduced many times over, whereby Of course, unwanted side effects are also suppressed even more. the Compound (13E) - (8R, 11R, 12R, 15S, 16RS) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid is not specifically described in DE-OS 26 35 985. Connections with A as' -CH2-CH 2 -group were compared to the other compounds in which A is a cis -CH = CH- group means not exposed.

The preparation of the compound 2- (1,4-dimethyl-3-pentenyl) -2-oxoethane phosphonic acid dimethyl ester takes place according to processes known per se, as described in DE-OS 26 35 985 have been.

All inorganic and organic bases are used for salt formation Question as known to those skilled in the art for the formation of physiologically compatible salts are.

Examples include alkali hydroxides, such as sodium or potassium hydroxide, Alkaline earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, Triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, etc.

The conversion of (8R, 9S111R, 12S) -9-benzoyloxy-13 oxo-11- (tetrahydropyran-2-yloxy) -14115,16117,18119,2O-heptanor-prostanoic acid methyl ester with 2- (1,4-dimethyl-3-pentenyl) -2-oxoäthanphosphonsäuredimethylester is in on in a known manner at temperatures from 0 oC to 100 oC, preferably at 20 oC up to 80 OC, carried out in an aprotic solvent, such as dimethyl sulfoxide, Dimethylformamide, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, Chloroform, methylene chloride, dimethoxyethane, etc.

The oxidation of the 9-hydroxy group is carried out according to methods known per se made with the usual oxidizing agents. For example, oxidation with intermediate protection of the 11- and 15-hydroxy groups, e.g.

by silylation (Chem. Comm. 1972, 1120) with Jones reagent.

The functionally modified hydroxyl groups are released according to known methods. For example, the elimination of hydroxyl protective groups, such as the tetrahydropyranyl radical, in an aqueous solution of an organic Acid such as oxalic acid, acetic acid, propionic acid and others, or in an aqueous solution of an inorganic acid such as hydrochloric acid. To improve the solubility, a water-miscible one is expediently used inert organic solvent added. Suitable organic solvents are for example alcohols such as methanol and ethanol, ethers such as dimethoxyethane, Dioxane and tetrahydrofuran and acetone. Tetrahydrofuran is preferred.

The cleavage is preferably at temperatures between 20 ° C and 80 ° C carried out.

-The saponification of the acyl groups takes place, for example, with alkali or alkaline earth carbonates or hydroxides in an alcohol or in the aqueous Solution of an alcohol. Aliphatic alcohols are suitable as alcohols, such as for example methanol, ethanol, butanol, etc., preferably methanol. As alkali carbonates and hydroxides are potassium and sodium salts, the potassium salts are preferred. Suitable alkaline earth carbonates and hydroxides are, for example, calcium carbonate, Calcium hydroxide and barium carbonate.

The reaction takes place at -10 ° C to +70 ° C, preferably at +25 ° C.

(13E) - (8R, 11R, 12R, 15S, 16RS) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadic acid can be neutralized with suitable amounts of the appropriate inorganic bases be converted into salts. For example, when the PG acid is dissolved in Water containing the stoichiometric amount of the base after evaporation of the water or after adding a water-miscible solvent, for example alcohol or acetone, the solid inorganic salt.

For the preparation of an amine salt, which takes place in the usual way, is the PG acid for example in a suitable solvent, for example methanol, Acetone, Diethyl ether or benzene dissolved and at least the stoichiometric Amount of amine added to this solution. The salt usually falls more solidly Form or is isolated in the customary manner after evaporation of the solvent.

The good dissociation of action of the substance according to the invention is shown when examining other smooth muscle organs, such as on the guinea pig ileum or on the isolated rabbit trachea, where one is essential Less stimulation can be observed than from the natural prostaglandins.

The active ingredient according to the invention shows on the isolated rabbit trachea in vitro bronchodilatory effect and strongly inhibits gastric acid secretion and has a regulating effect on cardiac arrhythmias. The new compound also lowers the Blood pressure and has a diuretic effect.

For medical use, the active ingredient can be converted into one for Inhalation, form suitable for oral or parenteral administration.

Aerosol or spray solutions are expediently used for inhalation manufactured.

For oral administration, for example, tablets, coated tablets or Suitable for capsules.

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

The invention thus also relates to medicaments based on the compound in claim 1 and customary auxiliaries and carriers.

The active ingredient according to the invention should be used in conjunction with those in galenics known and customary auxiliaries, for example for the production of preparations to trigger an abortion, to control the cycle or to initiate a birth to serve. For this purpose sterile, aqueous solutions containing 0.0001-10 ug / ml can be used containing the active compound should be administered as an intravenous solution for infusion. The acid and its salts are special for the preparation of aqueous isotonic solutions suitable. To increase solubility, alcohols1 such as ethanol and propylene glycol, to be added. Furthermore, suppositories for intravaginal application can easily be made produce.

Example 1: (13E) - (8R, 11R, 12R, 15S, 16RS) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid a) Ethoxycarbonyl-2,5-dimethyl-4-hexenoic acid ethyl ester 36.1 g of sodium (cut into small pieces) were placed in a three-necked flask equipped with a reflux condenser, dropping funnel and stirrer. For this purpose, 800 ml of abs. Ethanol was added dropwise so quickly that the solution remained in brisk boiling. 269.6 g of freshly distilled methylmalonic acid diethyl ester were added dropwise to the hot alcoholate solution, the mixture was stirred for 1/2 hour at 60 ° C. and then - likewise dropwise, 241.7 g of dimethylallyl bromide were added. After stirring for one hour with heating, the sodium bromide which had precipitated out was filtered off, the precipitate was washed and the filtrate was concentrated. The residue was taken up in ether, washed neutral with saturated sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. The evaporation residue was fractionated on the oil pump.

266 g of the title compound were obtained with a boiling point of 97-1120C.-IR (film) :, 1735, 1245, 1025, 860 / cm.

b) 2-carboxy-2,5-dimethyl-4-hexenoic acid 293.8 g of that obtained according to a) Diesters were together with 181 g of potassium hydroxide in 235 ml of water and 450 ml of ethanol heated under reflux for 4 hours.

The ethanol was then drawn off on a rotary evaporator, the residue was dissolved in 235 ml of water and treated with concentrated hydrochloric acid while cooling with ice added dropwise up to pH 1.

The precipitate (mp 162-166 ° C.) was collected and washed with water and used in the next stage without further purification.

IR (KBr) 1700, 1230, 840 / cm.

c) 2, 5-Dimethyl-4-oxenoic acid The obtained in the previous reaction stage Dicarboxylic acid was then in a distillation apparatus for 4 hours at normal pressure held at 21,000 for one hour at 75 torr. The product was then distilled in vacuo. 68 g of the title compound (boiling point = 98-106 ° C.; SPI = 67-700 ° C.) were obtained.

IR (film): 1705, 1220, 810 / cm.

d) 2,5-Dimethyl-4-hexenoic acid methyl ester According to the above procedure 68 g of carboxylic acid obtained were mixed with so much ethereal diazomethane solution that until no more nitrogen evolved when the reagent was added and the yellow color the reaction solution persisted. The solvent was then removed in vacuo and the residue is fractionated. 62.3 g of boiling point 356 = 32-35 ° C. were obtained.

IR (film): 1735, 1160, 1050, 820 / cm.

e) 2,5-Dimethyl-4-hexenoic acid ethyl ester 85.3 g of 2-ethoxycarbonyl-2,5-dimethyl-4-hexenoic acid ethyl ester were dissolved in 645 ml of dimethyl sulfoxide and successively with 29.7 g of lithium chloride and 6.3 ml of distilled water are added. After that, the reaction mixture became a whole 13 hours at 2000C heated and then -leave to cool down Poured 1 1 ice water. The aqueous phase was washed three times with 500 ml of methylene chloride each time extracted. The combined organic extracts were then washed twice with water washed, dried over magnesium sulfate, concentrated on a rotary evaporator and distilled in vacuo. 53.1 g of Kpl3 = 75-780C were isolated.

IR (film): 1735, 1160, 1050 / cm.

f) 2- (1,4-Dimethyl-3-pentenyl) -2-oxoethane phosphonic acid dimethyl ester To a solution of 59 g of dimethyl methanephosphonate in 400 ml of abs. Tetrahydrofuran 274.7 ml of a 1.61 M butyllithium solution in hexane were added dropwise under argon at -60 oC. After stirring for a further 15 minutes, a solution of 34.05 g of ethyl 2,5-dimethyl-4-hexenoate was obtained in 100 ml of absolute tetrahydrofuran added dropwise. The reaction mixture was left within of four hours to warm to room temperature and then stirred it 3 hours.

Then it was mixed with 26.5 ml of glacial acetic acid and concentrated in vacuo. The residue was taken up with ether / water, the aqueous phase with solid Sodium chloride added and extracted with ether. The combined organic phases were dried over magnesium sulfate and concentrated on a rotary evaporator.

The evaporation residue was purified by column chromatography on silica gel Purified with hexane / 50-100% ethyl acetate as a flow agent. 32 g of the desired product were obtained Link.

IR (film): 1710, 1260, 1030 / cm.

g) (1S, 5R, 6S, 7R) -6 - [(tert-butyl-dimethyl-silyloxy) -methyl] -7-benzoyloxy-2-oxabicyclo [3.3.0] octan-3-one To a solution of 13.8 g (1S, 5R, 6R, 7R) -6-hydroxymethyl-7-benzoyloxy-2-oxabicyclo (3.3) octan-3-one in 30 ml abs. Dimethylformamide was a solution of 9.9 g of dimethyl-tert-butyl-chlorosilane in 40 ml abs. Dimethylformamide and 9, 35 S imidazole given.

After stirring for two hours at room temperature and under an argon atmosphere analytical thin-layer chromatography indicated complete conversion.

The reaction mixture was diluted with 850 ml of ether, with about 60 ml of saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. The evaporation residue can optionally purified by column chromatography on silica gel with ether as the eluent. 17.8 g of the title compound were obtained (melting point 74-750 ° C. after crystallization from pentane / ether).

IR: 1775, 1715, 1600, 1580, 1275, 1255, 840, 790, 720 / cm.

h) (IS, 5R, 6S, 7R) -6-9 (tert-butyl-dimethylsilyloxy) -methyl] -7-hydroxy-2-oxabicyclo [3.3.0] octan-3-one A solution of 17.3 g of the benzoate obtained in the previous reaction stage in 200 ml abs. Methanol was added at room temperature along with 6.5 g of dry potassium carbonate stirred under argon. After two hours, the analytical thin layer chromatography showed full implementation. 500 ml of 0.1N hydrochloric acid were then added dropwise at 0 ° C. to the reaction mixture, stirred for 15 minutes at room temperature, concentrated in vacuo and extracted with ethyl acetate. The organic phase was saturated with sodium chloride solution washed and dried over magnesium sulfate. The evaporation residue was by column chromatography on silica gel with hexane / 50-100% ether as the eluent cleaned. 9.1 g of the desired compound (m.p .: 57-58.50C) were obtained.

IR (film): 1775, 1255, 840, 790 / cm.

i) (1S, 5R, 6S, 7R) -6 - [(tert -butyl-dimethylsilyloxy) -methyl] -7- (tetrahydroxypyran-2-yloxy) -2-oxabicyclo [3.3.0] octan-3-one A solution of 15.8 g of the obtained according to the above procedure Alcohol in 300 ml of distilled methylene chloride became fresh along with 7.5 ml Dihydropropane distilled over potassium hydroxide and 1.38 g of pyridine p-toluenesulfonate Stirred for 14 hours at room temperature. After concentrating the reaction solution at Room temperature was diluted with ether and half-saturated sodium chloride solution washed. The organic solution was then dried over magnesium sulfate and then concentrated to dryness. Optionally, the product can be purified by column chromatography be cleaned on silica gel with hexane / 20-50% ether as a flow agent. The yield was 20g.

IR (film): 1775, 1255, 1115, 1080, 1035, 835, 775 / cm.

j) (IS, 3RS, 5R, 6S, 7R) -3-hydroxy-6- (tert-butyI-dimet.hy1-silyloxy) methyl] -7- (tetranhydropyran-2-yloxy) -2-oxalicvclo /3.3.0j octane To a solution, cooled to -700C, of 5.4 g of the in the previous reaction stage obtained lactons in 200 ml of abs. Toluene were under argon within 15 minutes 20 ml of a 20% strength DIBAH solution in toluene were added dropwise. After stirring for about 5 minutes 1.2 ml of isopropanol were added dropwise at the same temperature until no foam formation occurred more. The reaction solution was allowed to warm to OOC, and 16 ml of water were added added, stirred for 10 minutes and filtered off through a frit. The precipitation was with Ethyl acetate washed out. The organic phase was three times washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. The product obtained (5.41g) was without further Purification used in the next reaction stage.

k) (5Z) - (8R, 9S, llR, 12S) -9-IIydroxy-ll- (tetrahydropyran-2-yloxy) -13- (tert-butyl-dimethyl-silyloxy) -14.15, 16,17,18,19,20-heptanor-5-prostenoic acid 104.6 ml of a solution of methanesulfinylmethyl sodium in abs. DMS0 (produced by dissolving 6g of 50% sodium hydride suspension in 120 ml of absolute dimethyl sulfoxide at a maximum of 700C) became a J, öseng at 1500 of 25, E7 g of 4-carboxybutyl-triphenylphosphonium bromide (previously at 70-80 C on the Oil pump dried) in 80 ml abs. Dimethyl sulfoxide was added dropwise. This ylene solution was Stirred for 30 minutes at room temperature and then to a solution with water cooling of 5.41 g of the lactol obtained in the previous reaction stage in 50 ml of abs. Dimethyl sulfoxide dripped within 15 minutes. The reaction mixture then became four Stirred under argon for hours at 35-40 ° C. (If necessary, 50-100 ml of abs.

Tetrahydrofuran to the reaction solution.

For work-up, the reaction mixture was poured onto ice / water, extracted three times with ether, the aqueous phase with 10% citric acid solution acidified to pH = 4 and extracted three times with a l / l mixture of ether / hexane. It was then extracted three times with methylene chloride. Because of the analytical Thin-layer chromatography, the methylene chloride phase was discarded, the two other organic phases, on the other hand, combined, dried over magnesium sulphate, filtered and on a rotary evaporator constricted. The residue was by column chromatography on silica gel with hexane / 70-100% ether as the flow agent justified.

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, 95,11R, 12S) -9-Hydroxy-II- (tetrahydropyran-2-yloxy) -13- (tert-butyl-dimethyl-silyloxy) -14,15,16, 17,18,19,20-heptanor-5-prostenic acid methyl ester Preparation with diazomethane: Die 4.32 g of carboxylic acid obtained after k) were dissolved in 20 ml of methylene chloride and So long mixed with ethereal diazomethane solution, until no more gas evolution occurred and the yellow color of the solution persisted. After peeling off the excess The reaction solution on a rotary evaporator was diazomethane in a water jet vacuum concentrated to dryness.

4.3 g of the desired methyl carboxylate were obtained.

Representation with iodomethane: To a solution of 32.5 g of the according to k) obtained carboxylic acid in 450 ml of acetonitrile was 75 ml of N-ethyldiisopropylamine at room temperature and 150 ml of iodomethane in 200 ml of acetonitrile were added dropwise over the course of 2 hours. It the mixture was subsequently stirred for one hour, then - after the TLC control had been carried out - the was sucked in Precipitate was washed off with ethyl acetate and the organic phase was shaken one after the other with sodium bisulphate, sodium hydrogen carbonate and sodium chloride solution.

After drying over magnesium sulfate, it was turned on a rotary evaporator Concentrated to dryness and the residue by column chromatography on silica gel cleaned with hexane / 50-100% ether as eluent. 32.3 g of the title compound were obtained.

IR (film): 3420 (hreit), 1740, 1255, 1120, 1030, 840, 70 / cm.

m) (5Z) - (8R, 9S, llR, 12S) -9-benzoyloxy-ll- (tetrahydropvran-2-yloxy) -13- (tert-butyl-dimethylsilyloxy) - 14,15, 16,17,18,19,20-heptanor-5-prostenoic acid methyl ester To a solution of 4.7 g of the 9-hydroxy compound obtained according to 1) in 70 ml of pyridine 2.32 ml of distilled benzoyl chloride were added dropwise with stirring at room temperature. After stirring for two hours under an argon atmosphere, the reaction solution became mixed with 1r8 ml of water, stirred for a further hour and then the oil pump concentrated at 30 0C and 1 Torr. The residue was in a two phase mixture Ether / water added, with sodium bicarbonate and saturated sodium chloride solution washed, dried over magnesium sulfate and concentrated to dryness in vacuo. After column chromatography of the evaporation residue on silica gel with hexane / 30-50% Ethyl acetate as a mobile phase gave 5.11 g of the title compound as a colorless one 01.

IR (film): 1745, 1720, 1605, 1590, 1280, 1260, 1120, 1030, 840, 780, 710 / cm.

n) (8R, 9S, llR, 12S) -9-Benzoyloxy-ll- (tetrahydropyran-2-yloxy) -13- (tert-butyl-dimethylsilyloxy) -14,15,16,17, 18,19,20-heptanor-prostanoic acid methyl ester A solution of 12.3 g of the obtained according to m) unsaturated compound in 160 ml of ethyl acetate was mixed with 1.23 g of 10 50% palladium-carbon added and in a shaker at room temperature and low hydrogen pressure hydrogenated. After uptake of 640 ml of hydrogen, the solvent was in vacuo removed, the residue taken up in 40 ml of ether, the organic phase with saturated Washed sodium chloride solution, dried over magnesium sulfate and on a rotary evaporator concentrated to dryness.

12.1 g of the title compound were obtained.

IR (film): 1740, 1720, 1600, 1580, 1275, 1255, 1115, 1070, 1025, 835, 780, 710 / cm.

o) (8R, 9S, 11R, 12S) -9-Benzoyloxy-11- (tetrahydroxypyran-2 yloxy-13-hydroxy-14,15,16,17,18,19,20-heptanorprostanoic acid methyl ester To a solution of 6.94 g of the compound obtained in the previous reaction stage in 110 ml-abs.

Tetrahydrofuran was added 16.11 ml of a 2M tetrabutylammonium fluoride solution while cooling with ice given in tetrahydrofuran. After stirring for 12 hours in an argon atmosphere the reaction mixture diluted with 1.3 liters of ether, with saturated sodium chloride solution washed neutral and the washing solution extracted twice with ether. The United organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was by column chromatography on silica gel with ethyl acetate as Purified superplasticizer. 5.54 g of the desired compound were found to be colorless Obtain oil.

IR (film): 3460 (broad), 1735, 1715, 1600, 1580, 1275, 1115, 1070, 1025, 710 / cm.

p) (8R, 9S, IIR, 12S) -9-Benzoyloxy-13-oxo-11- (tetrahydropyran-2-yloxy) -14,15,16,17,18,19,20-heptanorprostanoic acid methyl ester A solution of 5.54 g of the alcohol obtained according to the above procedure in 56 ml abs. Methylene chloride turned into a slurry within 20 minutes at 5-10 ° C of 18.7 g of Collins reagent in 170 ml of abs. Methylene chloride was added dropwise. After one hour After stirring in an argon atmosphere, the reaction mixture with 500 ml of a l / l mixture of ether and pentane added and decanted. The piston, piston was still washed twice with 500 each with the above mixture. The united organic Phases were then three times with 50 ml of 5% sodium carbonate solution each time, three times with 50 ml each of 5% Sulfuric acid shaken and then sent with saturated he sodium chloride solution washed neutral.

After drying over magnesium sulfate, the mixture was concentrated to dryness and the residue over a silica gel column (50 g; eluent: ethyl acetate / hexane = 2/8) filtered. 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, 11R, 12R, 16RS) -9-Benzoyloxy-16,19-dimethyl-15-oxo-11- (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid methyl ester To a suspension of 0.48 S 50% (suspended in 01) sodium hydride in 60 ml of dimethoxyethane freshly distilled over lithium aluminum hydride were added Argon dissolved at room temperature 2.48 g of the phosphonate obtained according to Example f) in 30 ml abs. Dimethoxyethane dripped. After adding 0.43 g (previously in a vacuum cabinet 2 hours at 50 ° C.) Lithium chloride, the reaction mixture was two hours stirred at room temperature. The suspension was then cooled to -200C and dropwise with 4.61 g of the aldehyde obtained according to p) dissolved in 90 ml of abs.

Dimethoxyethane, added. Then the temperature was left within from -20 'to OOC within 5 hours and further to 50C within 1.5 hours, in order to then stir the reaction solution for three hours at room temperature. at -10 ° C, 1 ml of glacial acetic acid and approx.

100 ml of water were added. The phases were separated and the aqueous five times with ether, combined the organic phases and washed them with 4% sodium bicarbonate and saturated sodium chloride solution. After drying over Magnesium sulfate was concentrated to dryness on a rotary evaporator. The residue was purified by column chromatography on silica gel using Subject to ethyl acetate / hexane = l / l as a flow agent. 5.78 g of the title compound were obtained.

IR (film): 170, 1720, 1695, 1670, 1625, 1600, 1580, 1270, 1105, 1060, 1025, 705 / cm.

r) (13E) - (8R, 9S, 11R, 12R, 15R, 16RS) -9-Benzoyloxy-16,19-dimethyl-15-hydroxy-11- (tetrahydropyran-2-yloxy) -13,19-methyl prostadiene ester To a solution, cooled to -400C, of 5.78 g of the in the previous reaction stage obtained ketone in 115 ml of abs. Methanol was added in portions, 2.37 g of sodium borohydride given. After stirring for one hour at -400C, the temperature-also at this temperature-5.09 ml of glacial acetic acid was added dropwise to the reaction solution. After removing the solvent on a rotary evaporator the residue was treated with methylene chloride / water, the separated water phase mixed with solid sodium chloride and extracted twice with methylene chloride. The combined organic phases were washed with saturated sodium chloride solution washed, dried over magnesium sulfate and concentrated in vacuo. The Isqmeren Separation carried out by repeated column chromatography on silica gel with hexane / 20-100% Ethyl acetate as a flow agent. 2.11 g of the title compound were obtained as the most unpolar product isolated.

IR (film): 3400 (broad), 1740, 1720, 1600, 1580, 1275, 1120, 1030, 1020, 710 / cm.

s), (13E) -8R, 9S, 11R, 12R, 15R, 16RS) -9-benzoyloxy-16,19-dimethyl-11,15-bis (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid methyl ester To a solution of 2.11 g of the obtained according to r) Alcohol in 60 ml abs. 0.49 ml of dihydropyran (fresh distilled over potassium hydroxide) and 9.7 mg of p-toluenesulfonic acid, stirred for 55 minutes at 0 ° C. and then extracted the reaction solution previously diluted with methylene chloride with saturated sodium hydrogen carbonate solution and water. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was by column chromatography on silica gel with ethyl acetate / hexane = 1/2 as the eluent cleaned. 2.3 g of the desired compound were obtained.

IR (film): 1740, 1720, 1605, 1585, 1275, 1115, 1080, 1025, 715 / cm.

t) (13E) - (8R, 9S, 11R, 12R, 15R, 16RS) -9-hydroxy-16,19-dimethyl-11,15-bis (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid A solution of 2.3 g of the benzoate obtained according to s) in 70 ml of methanol was with 20.6 ml of 2N potassium hydroxide solution are added and the mixture is stirred at room temperature for 31 hours. The reaction mixture was then concentrated on a rotary evaporator, the residue taken up in a little water and twice with 150 ml of an ether / pentane mixture each time extracted. The aqueous phase was acidified to pH 5 with citric acid and three times extracted with 150 ml of ethyl acetate each time. The combined organic phases were with saturated sodium chloride solution, washed neutral, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on Keisel Purified with hexane / 50-100% ethyl acetate all flow agents. There were 1.62 g of the title compound obtain.

IR (film): 3460, 2730, 2660, 1r30, 1710, 1130, purple, 1075, 1020, 810 / cm.

u) (13E) - (8R, 11R, 12R, 15R, 16RS) -9-Oxo-16,19-dimethyl-11, 15-bis- (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid To a solution, cooled to -200C, of 360 mg of the alcohol obtained in t) in 7 ml of acetone were added to 0.46 ml of Jones reagent and the mixture was stirred for 45 minutes at this temperature after. Then 0.6 ml of isopropanol was added and the mixture was stirred for a further 10 minutes, diluted with cold ether, washed three times with cold saturated sodium chloride solution, the organic phase was dried over magnesium sulfate and concentrated in vacuo. To Filtration through a Sep-Pack ready-to-use column gave 327 mg.

IR (film): 2730, 2660, 1740, 1710, 1110, 1075, 1025.

810 / cm.

v) (13E) - (8R, 11R, 12R, 15R, 15RS) -9-Oxo-11,15-dihydroxy-16,19-dimethyl-13,18-prostadienoic acid The 327 mg obtained according to the above procedure were in 26 hours 7 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10) at room temperature touched. It was then narrowed several times with benzene in an oil pump vacuum at room temperature a. The residue was purified by column chromatography on silica gel with ethyl acetate / 0-10% Purified methanol as a flow agent. 68 mS of the title compound were obtained.

IR (film): 3420, 2730, 2670, 1735, 1710, 1075, 975 / cm.

w) (13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -9-Benzoyloxy-16,19 dimethyl-15-hydroxy-11- (tetrahydropyran-2-yloxy) -13,18-prostandienoic acid methyl ester In the sodium borohydride reduction of the ketone according to r), in addition to the 2.11 g of alcohol and 0.27 g of a / ß mixture, 2.67 g of the title compound as polar product eluted from the column.

1k (movie): 3400 (wide), 1740, 1720, 1600, 1580, 1275, 1120, 1030, 1020, 710 / cm.

x) (13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -9-Benzoyloxy-16,19-dimethyl-11,15-bis- (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid methyl ester Analogously to the instructions given for the representation of the 15-β isomer in s) by reacting 2.67 g of the alcohol obtained in the previous reaction stage with 0.62 ml dihydropyran and 12.3 mg p-toluenesulfonic acid (reaction time: 75 minutes) after column chromatography on silica gel with ethyl acetate / IIexane = 1/3 as the eluent 2.96 g of the titre compound were obtained as a colorless oil.

IR (film): 1740, 1720, 1600, 1585, 1275, 1115, 1075, 1025, 715 / cm.

v) (13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -9-hydroxy-16,19-dimethyl-11,15-bis (tetrahydroxypyran-2-yloxy) -13,18-prostadienoic acid Analogously to the procedure given for the representation of the 15 [beta] isomer in t) by reacting 2.96 g of Example x) with 26.5 ml of 2N potassium hydroxide solution after column chromatography on silica gel with hexane / 50-100% ethyl acetate as the flow agent 2.22 g of the title compound were obtained.

IR (film): 3450, 2730, 2660, 1730, 1710, 1130, 1110, 1075, 1020, 810 / cm.

z) (13E) - (8R, 11R, 12R, 15S, 16RS) -9-Oxo-16,19-dimethyl-11,15-bis (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid , 360 mg of the alcohol obtained in the previous reaction stage were analogous to the for the representation of the corresponding 15β-isomers given in u) Regulation implemented. 326 mg of the title compound were obtained.

IR (film): 2730, 2770, 1740, 1710, 1105, 1070, 1020, 810 / cm.

(13E) - (8R, 11R, 12R, 15S, 16RS) -9-Oxo-11,15-dihydroxy-16,19-dimethyl-13,18-prostadic acid Analogously to the procedure given for the synthesis of the 15β-isomer in v) by reacting 326 mg of the compound obtained in the previous reaction step the title compound of Example 1) presented (54 mg).

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

Claims (3)

Claims 1.) (13E) - (8R, 11R, 12R, 15S, 16RS) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid and their salts with physiologically compatible bases. 2.) Process for the preparation of (13E) - (8R, 11R, 12R, 15S, 16RS) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid, characterized in that (8R, 9S, 11R, 12S) -9-benzoyl-13-oxo-11- (tetrahydropyran-2-yloxy) -14.15, 16,17,18, lq, 20-heptanor-prostanoic acid meth with 2- (1,4-dimethyl-3-pentenyl) -2-oxoethane phosphonic acid dimethyl ester converts and then reduces the 15fketo group and protects it with dihydropyran, the 9-hydroxyl group oxidizes after release, splits off existing protective groups and optionally converted into a physiologically acceptable salt. 3.) 'Pharmaceutical compositions, characterized in that they as the active ingredient (13E) - (8R, 11R, 12R, 15S, 16RS) -11,15-dihydroxy-16, lqoxo-13,18-prostadic acid together with one or more pharmaceutical carriers or diluents contain.