FI83645B - Process for the preparation of therapeutically useful racemic or optically active 7-oxo-prostacyclin derivatives - Google Patents

Description

1 83645

Process for the preparation of therapeutically useful racemic or optically active 7-oxo-prostacyclin derivatives 5 Separated from patent application 85 0123

The invention relates to a process for the preparation of therapeutically useful racemic or optically active 7-oxo-prostacyclin derivatives of the formula I

--- Ί1 (I) C'Vn

OH

wherein R 1 represents hydrogen or a pharmacologically acceptable cation, A represents trans-vinylene or -C = C- and n may represent two or three.

If R1 represents a pharmacologically acceptable cation, it may represent all organic and inorganic cations which have no detrimental (toxic) effect in the dose range used; such inorganic cations may be, for example, alkali metals, such as sodium and potassium, or alkaline earth metals, such as calcium and magnesium ions. Unsubstituted ammonium ions or ammonium ions substituted by organic, preferably alkyl groups are also suitable. Substituted ammonium ions may have additional substituents, such as hydroxyl or amino groups, which favorably affect the solubility and crystallization properties of the salts. One such preferred cation 2,83645 is tris- (hydroxymethyl) -anunonium ion. Straight-chain and branched C 1-4 alkyl, as mentioned later herein, means methyl, ethyl, propyl or iso-propyl, preferably methyl. C 1-4 alkanoyl in the definition of R 2 may denote moieties derived from a C 1-4 alkanecarboxylic acid, such as formyl, propionyl or butyryl, preferably acetyl.

A compound of formula I may be prepared by:

A) oxidizing a compound of formula IV

OR3 0 COOR1 'if ^ «zo“ yV' "2 '" OR2 20 wherein R1' represents hydrogen, straight or branched C1-4 alkyl or a pharmacologically acceptable cation, R2 represents hydrogen or C1-4 alkanoyl, R3 represents hydrogen or straight chained or branched C 1-4 alkyl and .25 A and n have the same meaning as in formula I,

and heating the compound of formula II thus obtained

30 0R3 1 'V * (A' .. ·· 35 2 ''> A-f RO>

OR

li 3 83645 wherein R1 ', R2, R3, A and n have the same meaning as in formula IV, or

b) oxidizing the compound of formula III

5 ^ / N. 1 '

COOR

<Y y ~ 10 r-v, CH2'n r2o * a 'Y --- OR2 wherein R1', R2, A and n have the same meaning as in formula IV, and the alkanoyl group R2 and / or the alkyl group R1? and optionally converting the resulting compound to a salt.

The compounds of formula I are stable and selective, biologically active women of the prostacyclin derivative.

Prostacycline (PGI2), a metabolite of arachidonic acid that is widespread in mammals, was discovered in 1976. The substance has a variety of pharmaceutically valuable biological activities.

It inhibits platelet aggregation, has fibrinolytic activity, dilates airways and blood vessels, and reduces gastric acid secretion. It also has a so-called cytoprotective activity in various organs such as the stomach, liver, heart and kidneys; it eliminates or cures the destructive effects of the harmful effects on those organs.

There are two problems with the widespread use of PGI2. The second is chemical and biological instability, i.e., a very short biological half-life; thus, its 4,83645 administration can be performed only by special methods, e.g., it can be administered by infusion. Another problem is the occurrence of several side effects that can potentially be observed mainly as a desired effect due to the diverse biological spectrum of activity.

The preparation of 7-oxo-PGI2 derivatives, which are more stable than naturally occurring PGI2, was first disclosed in U.S. Patent 4,330,553. The disclosed compounds have better chemical stability - and their spectrum of activity is substantially the same as that of PGI2. spectrum [J. Med. Chem. 25, pp. 105 (1982)].

The preparation of similar 7-oxo-PGI2 derivatives is described in BE Patent 890,390. A common feature of the above-mentioned 7-oxo-PGI2 analogs is that, like the biological activity of PGI2, their biological activity is not selective.

The new 7-oxo-PGI2 derivatives prepared according to the invention have the same spectrum of activity as PGI2, but surprisingly a new compound has been found which is more bio-selective than the 7-oxo-PGI2 derivatives known from the early days of the study, although their shelf life is almost same.

The compounds of formula I are prepared as described above. The details of the embodiments of the above methods are as follows: a) The compound of formula IV is oxidized in an aqueous organic solvent, preferably dioxane or dimethoxyethane, using 1.1 to 10 equivalents, preferably 1.3 to 1.5 equivalents of selenium dioxide. 30 bonds at a temperature of 20 to 200 ° C, preferably 50 to 100 ° C. The compound of formula II thus obtained is then heated in the presence of an acid catalyst in organic solvents, preferably benzene or toluene, or in halogenated solvents such as chlorinated hydrocarbons, preferably chloroform, or dipolar aprotic solvents such as, for example, 5,83645 dimethyl sulfide. any solvent to give a compound of formula I. As the acid catalyst, p-toluenesulfonic acid or sulfuric acid are preferred. The compounds of formula II can be heated at 50 to 200 ° C, preferably at 60 to 90 ° C, with or without the separation of water. The preferred method is to carry out the heating in the presence of p-toluenesulfonic acid in benzene or toluene at 60 ° C while using a water separator.

The compounds of the formula IV are known from the literature or can be prepared by analogous methods (see, for example, HU patent application CI-1901).

b) According to another preferred process of the invention, a compound of formula III can be oxidized to a compound of formula I at 20 to 200 ° C with 1.1 to 10 equivalents of selenium oxide in an anhydrous organic solvent such as an ether type solvent, preferably dioxane. or dime-toxetane. The reaction is preferably carried out in dioxane-20 with 1.3 to 1.5 equivalents of selenium dioxide at 80 to 90 ° C.

The compounds of formula III are known in the art or can be prepared by uniform methods (R. F. Newton et al .; Synthesis 1984, p. 449).

The hydroxyl groups in positions 11 and 15 of the starting materials of formulas III and IV can be protected by various protecting acyl groups, trialkylsilyl groups, alkoxyalkyl groups and tetrahydropyranyl. The coupling of the protecting groups can be carried out by methods known per se, and this may be important for achieving a better yield. The above-mentioned protecting groups can be removed - if desired - from the compounds of the formula I by methods known per se. Alkoxyalkyl groups or tetrahydropyranyl groups can be removed with potassium fluoride or also in the presence of an acid. The acyl groups are hydrolyzed in a basic medium.

6 83645

In the salt formation of the compounds of formula I, the acids can be liberated from aqueous solutions of the salts by careful acidification, and said carboxylic acids can be dissolved in organic solvents and further converted into salts, e.g. trimetonium salts, by reaction of the corresponding acids with aliphatic and aromatic amines.

A typical representative of the compounds of formula I is 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-10β-PGI2.

The selective biological activity of these compounds can be studied by examining the inhibition of aggregation as well as the hypotensive activity simultaneously. Inhibition of aggregation activity was measured in vitro according to Born [Nature, 214, (1962), p. 927] with human plasma enriched in platelets and aggregated with 2 ADP, whereas hemodynamic activity was obtained with blood pressure. the reducing activity of the compound administered iv bolus injection-20 na to a cat that had been anesthetized and had its chest opened.

Aggre- Relative- Blood pressure- Relative- hVh2 gaation linen netta linen: .25 inhibition power lowering power IC50 H1 activity H2

Ed50 pg / kg 7-oxo-30 PGI2-Na 1 1 0.16 11 15 0.066 6.5 0.024 2.75 16,17,18,19,20-pentanor-15-35 cyclopentyl-7-oxo-PGI2- Na 1.6 0.625 21.2 0.0075 83.3 il 7 83645

It can be seen that the cyclopentyl analog is about 100-fold more selective than prostacyclin and is significantly more selective than the sodium salt of 7-oxo-PGI2 disclosed in U.S. Patent 4,330,533.

A particular advantage of the compounds of formula I is that they can also be administered orally.

Due to their biological activity, the compounds of the invention can be used as active ingredients in pharmaceutical compositions. Said-10 and compositions can be used to prevent or treat peripheral vascular diseases (artherosclero-sis obliterans, Burger's disease, diabetic angiopethia), to improve blood circulation in the limbs, to alleviate the severity of myocardial infarction and to reduce mortality.

The pharmaceutical compositions are suitable for alleviating the intensity and number of many types of heart attacks, as well as for the treatment of various other types of circulatory diseases, such as pulmonary hypertension and heart failure.

They can have a valuable effect in the prevention and treatment of cerebral anemia and can be used in the treatment of asthma, diseases of the gastrointestinal tract, such as gastric ulcer, etc., and liver and pancreatic diseases. The compositions are still suitable, alone or in combination with heparin, to prevent platelet loss in the case of extracorporeal circulation (renal chemodialysis, cardiopulmonary resuscitation). They are further used to inhibit metastasis in patients with tumors potevil-30a.

. . The pharmaceutical compositions may be administered intravenously, subcutaneously, intramuscularly or orally (ma-ha-intestinal tract) as well. The required amount is 0.0001 -10 mg / kg body weight. The exact dose depends on the Anka-35 disease, the rate at which the drug is delivered, the sensitivity of the organ or patient being treated, and the patient's ability to react.

8 83645

Anyone familiar with the subject can easily determine the best route of administration as well as the need for dosing.

In the preparation of pharmaceutical compositions, conventional excipients, diluents, substances which affect the moon and aroma, pH and osmotic pressure regulators, stabilizers, absorption enhancers, etc., and other excipients can be used. The compositions prepared may be solid (tablets, capsules, granules, powders, pills), liquids (infusion solutions, compression solutions, drug solutions, drops, etc.) or semi-solid liquids (creams, balms, suppositories, etc.).

The disclosed ingredients may be used alone or in combination with other active ingredients.

Example 1 6-Hydroxy-7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI, methyl ester 605 mg (1.25 mmol) of 6-methoxy The methyl esters of 11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI1 are dissolved in a mixture of 6 ml of dioxane and 0.5 ml of water. 210 mg (1.89 mmol) of selenium dioxide are added and the reaction mixture is stirred for 2 hours. When the reaction is complete, the mixture is filtered and the solvent is removed in vacuo. The residue is diluted with 50 mL of ethyl acetate, washed 2-5 with 2 x 10 mL of water, 5% sodium bicarbonate solution until pH 7.5-8, then washed with brine and dried over magnesium sulfate. The crude product thus obtained is chromatographed on 200 g of Reanal Kieselgel G absorbent and eluted by column chromatography on a short column with a 50% mixture of hexane and ethyl acetate. 380 g of methyl ester of 6-hydroxy-7-oxo-11,15-diacetyl-16,17,18,19,20-penta-nor-15-cyclopentyl-PGI1 are isolated in the form of a red oily substance. Thin layer chromatography: 35 Rf: 0.18 (hexane / ethyl acetate, 1: 1).

IR (cm-1, film): 3,400, 2,950, 1740 and 1,150.

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Example 2 Methyl ester of 7-oxo-11,15-dacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PG17 380 mg (0.79 mmol) of 6-hydroxy-7-oxo-11, The methyl ester of 15-diase-5-style-16,17,18,19,20-pentanor-15-cyclopentyl-PGI1 is dissolved in 30 ml of benzene, and 3 mg of p-toluenesulfonic acid is added to the solution, and the mixture is stirred at room temperature for 15 minutes. and at 60 ° C for 3 hours. During the heating, a total of 5 to 10 ml of benzene is distilled off in a water separator. When the reaction is complete, the reaction mixture is cooled to room temperature and stirred for 2 hours with 0.6 g of neutral alumina. The alumina is filtered off, the filtrate is partially evaporated and the substance is chromatographed on 20 g of Kieselgel 15 G adsorbent by column chromatography on a short column using a mixture of hexane and ethyl acetate (2: 1) as eluent. 199 mg of methyl ester of 7-oxo-11,15-diacetyl-16.17.18.19.20-pentanor-15-cyclopentyl-PGI2 are obtained in the form of a colorless oily substance.

Rf: 0.43 (hexane / ethyl acetate, 1: 1).

IR (cm -1, film): 2,950, 1,745, 1,715, 1,650 and 1,160.

UV λmax = 287 nm, 1 g ε = 3.96.

Example 3 7-Oxo-16,17,18,19,20-pentanor-15-cyclopentyl-25 PG17 methyl ester 198 mg (0.43 mmol) of 7-oxo-11,15-diacetyl-16.17.18.19.20 - the methyl ester of pentanor-15-cyclopentyl-PGI2 is dissolved in 30 ml of anhydrous methanol and 0.25 ml of a 1 M solution of sodium methoxide in methanol is added to the solution. The reaction mixture is stirred overnight at room temperature. The methanol is removed in vacuo at 0 ° C and the substance is dissolved in a mixture of 50 ml of ether and 7 ml of water at 0 ° C and, after separation of the layers, the ether solution is washed with 10 ml of saturated brine and stirred with 0.5 g. with neutral alumina and 0.2 g of activated carbon, filtered and finally dried over sodium sulfate in the presence of triethylamine. After evaporation, 135 g of pure 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2 methyl ester are obtained in the form of a colorless oily substance.

Rf: 0.36 (hexane / acetate, 1: 1).

UV Amak. = 267 nm, 1 g i = 3.856.

Example 4 Sodium salt of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI, 220 mg (0.63 mmol) of 7-oxo-16,17,18,19,20- The methyl ether of pentanor-15-cyclopentyl-PGI2 is dissolved in 10 ml of methanol, 2 ml of 1 M aqueous sodium hydroxide solution are added and the mixture is stirred at 40 ° C for 3 hours. The methanol is then removed in vacuo and the residue is dissolved in 15 ml of distilled water, the aqueous solution is shaken with 2x5 ml of ether and the aqueous layer is acidified to pH 60 by adding 1 N sodium hydrogen sulphate solution and extracted 2 x 10 ml: 11a ethyl acetate. The aqueous layer is further acidified with sodium hydrogen sulfate solution to pH 40 at 0 ° C and extracted again 2 x 20. . ml of ethyl acetate. All organic ethyl acetate layers are combined and washed with 2x5 mL of saturated brine. The solution is mixed with 0.6 g of neutral alumina and 0.2 g of activated carbon for 10 minutes and filtered. 20 ml of water are added to the solution and the pH of the solution is adjusted to 7.2 to 7.3 with 0.1 N sodium hydroxide solution. The two layers are separated and the organic layer is shaken with 10 ml of water. The combined aqueous layer is evaporated and dried to give 190 mg of the sodium salt of 7-oxo-16,17,18,19,20-pen-Tanor-15-cyclopentyl-PGI2.

- · When an aqueous solution of the title compound is intended to be used, the aqueous solution is not evaporated; the solution can be used directly.

and 83645

Thin layer chromatography: The substance is developed in the form of an acid.

Rf: 0.30 (benzene / dioxane / acetic acid, 20: 10: 1).

IR (cm-1, KBr): 3,500-3,200, 2,940, 2,850, 1,720, 1,650 and 1,615.

Example 5 Sodium salt of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI, 340 mg (0.74 mmol) of 7-oxo-16,17,18,19,20- The methyl ester of pentanor-15-cyclopentyl-PGI2 is dissolved in 50 ml of 10 methanol and 0.5 ml of 1M methanolic sodium methoxide solution is added to the solution. The reaction mixture is stirred for a further 10 hours at room temperature. After removal of the methanol portion (total volume about 20 ml), 5 ml of 1 N sodium hydroxide solution are added, and the solution is stirred for 3 hours at 40 ° C. The methanol is removed by distillation in vacuo. The reaction mixture is further treated as described in the previous example.

Example 6 Methyl ester of 7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-20-15-cyclohexyl-PGI?

To a solution of 1,010 mg (2.25 mmol) of 11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclohexyl-PGI2 in 20 mL of anhydrous dioxane is added 374 mg (3.4 mmol) of selenium dioxide. The reaction mixture is stirred for 2.5 hours at 85 ° C under argon. When the reaction is complete, 1 g of neutral alumina is added to the reaction mixture at room temperature and stirred for 15 minutes. After filtration, the mixture is partially evaporated and purified by column chromatography on a short column. 200 g of Kieselgel G are used as adsorbent 30 and a mixture of hexane and ethyl acetate (1: 1) is used as eluent. 200 g of the title product are isolated in the form of a colorless oily substance.

Rf: 0.40 (hexane / ethyl acetate, 1: 1).

35 IR (cm-1, film): 2,950, 2,860, 1,740, 1,715 and 1,650.

i2 83645

Example 7 Methyl ester of 7-oxo-16,17,18,19,20-pentanor-15-cyclohexyl-PGI,

To a solution of 220 mg (0.46 mmol) of 7-oxo-5,11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclohexyl-PGI2 methyl ester in 30 ml of anhydrous methanol, 0.25 ml of a 1 M solution of sodium methoxide in methanol is added. The reaction mixture is stirred at room temperature under argon overnight. The methanol is then removed in vacuo, the substance is dissolved at 0 ° C with a mixture of 50 ml of ether and 7 ml of water, the ether solution is washed with 10 ml of saturated brine after the layers have separated, and 0.5 g is stirred: with neutral alumina and 0.2 g of activated carbon for 10 minutes and finally dried over sodium sulfate. After evaporation, 148 mg of the title compound are obtained in the form of a colorless oily substance.

Rf: 0.34 (hexane / acetone, 1: 1).

UV A „ak. = 289 nm, 1 g E = 3.903.

Example 8 Tris- (hydroxymethyl) aminomethane salt of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI? 540 mg (1.35 mmol) of 7-oxo-16,17, The sodium salt of 18,19,20-pentanor-15-cyclopentyl-PGI2 is dissolved in 10 ml of water and the solution is acidified to pH 4 with 1 N sodium hydrogen sulphate and extracted with 2 x 20 ml of ethyl acetate. The combined organic layers are shaken with saturated brine and dried over sodium sulfate. The sodium sulfate is removed by filtration, and then 175 mg (1.45 mmol) of tris- (hydroxymethyl) aminomethane are added to the solution and stirred for 2 hours at 40 ° C and allowed to stand for 12 hours. The reaction mixture is then evaporated to dryness to give 510 mg of the title compound.

35 Thin layer chromatography: identical to the previous compounds in acid form.

UV; EtOH ληβΚβ = 288 nm, 1 g δ = 3.965.

ii i3 83645

Example 9 6-Hydroxy-7-oxo-11,15-diacetyl-13,14-didehydro-16,17,18,19,20-pentanor-15-cyclohexyl PGI, methyl Hester! 5,850 mg (3.76 mmol) of the methyl ester of 6-methoxy-11,15-diacetyl-13,14-didehydro-16,17,18,19,20-pentanor-15-cyclohexyl-PGI® are dissolved in 15 ml of: to dioxane and 2 ml of water, and 650 mg (5.86 mmol) of selenium dioxide are added to the solution, and the reaction mixture is stirred for 2 hours at 60 ° C. The reaction mixture is then filtered, the dioxane is removed under reduced pressure and the residue is diluted with 200 ml of ethyl acetate. The solution is washed successively with 2 x 50 ml of water, 5% sodium bicarbonate solution until pH 7.5-8, and saturated brine, and dried over magnesium sulfate. The product is isolated by column chromatography on a short column using 500 g of Kieselgel G silica gel and a mixture of hexane and ethyl acetate (1: 1) as eluent in an amount of 790 mg in the form of a red oily substance.

20 Thin layer chromatography:

Rf: 0.20 (hexane / ethyl acetate, 1: 1).

IR (cm-1, film): 3400, 2950, 2230, 1740 and 1160. Example 10 7-Oxo-11,15-diacetyl-13,14-didehydro-2 5,16,17,18 19,20-pentanor-15-cyclohexyl-PGI7 methyl ester 750 mg (1.52 mmol) of 6-hydroxy-7-oxo-11,15-diacetyl-13,14-didehydro-16,17,18, 19,20-Pentanor-15-cyclohexyl-PGI2 methyl ester is dissolved in 30 ml of benzene 30, and 5 mg of p-toluenesulfonic acid is added to the solution, followed by stirring for 15 minutes while distilling off the solvent water. During the reaction, about 10 ml of benzene are distilled off. The reaction mixture is then cooled to room temperature and stirred for 3 to 35 hours with 1 g of neutral alumina. The alumina is removed by filtration and the reaction mixture is purified by column chromatography on a short column (100 g of Kieselgel G silica gel; eluent: hexane / ethyl acetate, 2: 1). 286 mg of the title product are thus isolated in the form of a colorless oily substance.

5 Thin layer chromatography:

Rf: 0.56 (hexane / ethyl acetate, 1: 1).

UV; EtOH 4Mk8 = 285 nm, 1 g E = 4.01.

Example 11 7-Oxo-13,14-didehydro-16,17,18,19,20-pentanor-10-15-cyclohexyl-PGI7 methyl ester 250 mg (0.53 mmol) of 7-oxo-13,14-didehydro The methyl ester of -11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclohexyl-PGI2 is dissolved in 50 ml of anhydrous methanol and 1 ml (1 mmol) of a 1 M solution of sodium methoxide in methanol is added to the solution. . The reaction mixture is allowed to stand overnight and the solvent is removed under reduced pressure at 0 ° C. The residue is dissolved in a mixture of 50 ml of ether and 5 ml of water, the separated organic layer is washed with 10 ml of saturated brine, mixed with 0.5 g of neutral alumina and 0.5 g of activated carbon for 10 minutes. time, it is filtered and dried over sodium sulfate in the presence of triethylamine. After evaporation, 143 mg of the title compound are obtained in the form of a colorless oil.

.25 Thin layer chromatography:

Rf: 0.21 (hexane / ethyl acetate, 1: 1).

UV; EtOH Anaks = 287 nm, 1 g ε = 3.98.

Example 12 Sodium salt of 7-oxo-13,14-didehydro-16,17,18,19,20-pentanor-30 15-cyclohexyl-PGI7 113 mg (0.31 mmol) of 7-oxo-13,14-didehydro - 16,17,18,19,20-pentanor-15-cyclohexyl-PGI2 methyl ester is dissolved in 7 ml of methanol and 3 ml of water and 2 ml (2 mmol) of 1 M aqueous sodium hydroxide solution are added to the solution, and the solution stirred for 3 hours at room temperature. The methanol is then removed under reduced pressure 83645 and 10 ml of distilled water are added to the residue. The aqueous solution is washed with 2x5 ml of ether and cooled to 0 ° C and acidified to pH 5-6 by adding about 2 ml of cold 1 M aqueous sodium hydrogen sulphate solution, 5 and finally extracted with 2 x 10 ml of ethyl acetate.

The aqueous layer is further acidified with 0.1 M sodium hydrogen sulfate solution to pH 3-4, and washed with 2 x 20 mL of ethyl acetate. The combined ethyl acetate layers are washed with 2 x 10 mL of brine, stirred for 10 minutes with 0.5 g of neutral alumina and 0.2 g of activated carbon, and filtered. 20 ml of water are added to the filtrate and its pH is adjusted to 7.4 to 7.6 by adding 0.1 N sodium hydroxide solution. The organic layer is shaken with 10 ml of water and the combined aqueous layers are evaporated to give 78 mg of the title compound. Thin layer chromatography: the substance is developed in the form of an acid.

Rf: 0.30 (benzene / dioxane / acetic acid, 20: 10: 1).

IR (KBr, cm -1): 3,300, 2,950, 2,220, 1,720 and 1,645.

Claims (9)

A process for the preparation of therapeutically useful racemic or optically active 7-oxo-prostacyclin-5 derivatives of the formula I rCOOR1, HO'OH 15 wherein R1 represents hydrogen or a pharmacologically acceptable cation, A represents trans-vinylene or -CsC-: a and n can denote two or three, characterized in that a) a compound of formula IV OR3 I ^ V / ^ V ^ COOR1 '25 U / · is oxidized OR2 wherein R1 'is hydrogen, straight or branched C1-4alkyl or a pharmacologically acceptable cation, R2 is hydrogen or C1-4alkanoyl, R3 is hydrogen or straight or branched C1-4alkyl and A and n are as defined for I, II i7 83645 and heating the compound thus obtained of formula II OR3 χι C00R 0 ^, CH2> n 2 c '> Af WR 0 i 2 OR wherein R1 ', R2, R3, A and n are as defined in formula IV, or b) oxidizing a compound of formula III COOR1' r \ 111 W / - νΛ (ch „) 2 s ^ A 2 n R 1 O 2 OR 2 wherein R 1 ', R 2, A and n are as defined in formula IV, and the alkanoyl group R 2 and / or the alkyl group R 1' is removed and optionally the resulting compound is converted into a salt. Process according to Claim 1, characterized in that the sodium salt of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI 2 or 7-oxo-16,17,18,19 is prepared. , Tris- (hydroxymethyl) -aminomethane salt of 20-pentanor-15-cyclopentyl-PGI2. 18 83645 Process according to Claim 1, characterized in that the compound of the formula IV is oxidized with selenium dioxide in an aqueous solvent. Process according to variant a) of Claim 1, characterized in that the compound of the formula II is heated in a solvent in the presence or absence of an acid catalyst at a temperature of 50 to 200 ° C. Process according to variant b) of claim 1, characterized in that the compound of formula III is oxidized in anhydrous solution with selenium dioxide. Process according to Claim 1, variant a) or Claim 3, characterized in that the compound of the formula IV is oxidized with 1.1 to 10 equivalents of selenium dioxide at 20 to 200 ° C in aqueous dioxane or dimethoxyethane. Process according to Claim 1, variant a) or Claim 4, characterized in that the compound of the formula II is heated in an aromatic solvent or a halogenated and / or dipolar aprotic solvent in the presence of p-toluenesulfonic acid or sulfuric acid. Process according to Claim 1, variant a) or Claim 4, characterized in that the compound of the formula II is heated in benzene or toluene in the presence of a p-toluenesulfonic acid catalyst at 60 ° C. Process according to Claim 1, variant b) or Claim 5, characterized in that the oxidation is carried out in an ether-type solvent, preferably dioxane, with 1.1 to 10 equivalents, preferably 1.3 to 1.5 equivalents of selenium dioxide at 20 to 200 ° C. at a temperature of, preferably at 80-90 ° C. Il i9 83645