CS262697B2 - Process for preparing new racemic and optical active derivatives of interfuranylenprostacycline - Google Patents

Description

The process according to the invention is characterized in that the compound of the general formula V.

R‘O

Y or

0-R

3 in which

R ¹ represents hydrogen or alkyl with 1 to 4 carbon atoms or a branched chain, or the protonated form of an inorganic cation,

R ² represents hydrogen, alkanoyl having 1-4 carbon atoms or tetrahydropyranyl group,

R ³ represents an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 5 or 6 carbon atoms,

R ^2, R ^3, A and B have the abovementioned meaning, is reacted in the presence of a base with a compound of formula VI

262897

CG (knows) in which

R ¹ has the abovementioned meaning, and the resulting ketone compound of formula IV

-COOR

9-R ^;

0R ^? ~ in which

R ¹ , R ² , R ³ , A and B are as defined above, and

R ⁴ is hydrogen, heated in the presence of an acid catalyst either directly or optionally after conversion to a compound of formula IV wherein R ¹ , R ² , R ³ , A and B are as defined above and R ⁴ is an alkyl group having 1; to 4 carbon atoms, by reaction with an appropriate alcohol, and optionally removing the hydroxyl and / or carboxyl protecting groups and / or optionally converting the resulting compound into a salt thereof.

The compounds of formula (I) produced by the process of the invention can be regarded as analogs of prostacyclin (PGI 2), a physiologically important natural substance that is stable and exhibits a selective pharmacological effect.

Prostacyclin (PGI2), arachic acid metabilite widely used in mammalian organisms, was discovered in 1976. It has a number of therapeutically valuable effects: for example, it inhibits platelet aggregation, lowers blood pressure, expands the airways and reduces gastric secretion . In addition, prostacyclin has a cytoprotective effect in various organs, such as the stomach, liver, heart and kidney. This means that the destructive effects of various organ damages can be prevented or eliminated by the action of prostacyclin.

To date, a large number of papers on the above-mentioned beneficial pharmacological effects of prostacyclin have been published (see, for example, Flohé et al., Arzneimittelforschung 33, 1240 (1983), S. Moncada and JR Vane: J. Med. Chem. 23, 591). 1980), W. Bartman et al .: Angewandte Chemie, Int. Engl., 21, p. 751 (1982), RF Newton et al., Synthesia 1984, p. 449)].

Now, the beneficial pharmacological effects of prostacyclin have already been used in clinical treatment. Sodium salt was marketed by Wellcome under the name Flolan and Upjohn in 1983 under the name Cycloprostin [Drugs of Today, 19, p. 605 (1983)], with cardiopulmonary bypasses, perfusion during hepatic insufficiency and haemolysis as the indication areas. .

However, there are serious problems with the use of prostacyclin due to its extreme instability [A. J. Kresge et al., J. Chem. Soc. Chem. Comm. 1979, page 129].

The most sensitive part of the prostacyclin molecule is the ethanol ether function. The main principles of chemical and biological stabilization of the prostacyclin molecule are set forth in the above-cited articles.

The interfuranylene analogs of prostacyclin of formula (I), the method of manufacture of which is the subject of the present invention, are much more stable compounds than natural prostacyclin. The compounds of the invention are stabilized in a manner not previously described in the literature. The reason for their stability is their new chemical structure. The combustion ring of the compounds of the invention contains six members instead of five, thereby distinguishing them from the structure of natural prostacyclin. This circle. which is stabilized by an aromatic ring built into the combustion chain, is characterized by an unusual endocyclic enol ether structure. This aromatic ring exerts its effect by delocalizing the electron system.

Surprisingly, the compounds of formula (I) stabilized by this novel process exhibit a spectrum of activity characteristic of natural prostacyclin (PGI 2), in addition to a considerably higher stability and selective mode of action.

The process of the invention consists in reacting the lactone of formula V with a furan derivative of formula VI in a solvent, preferably of the ether type, such as diethyl ether and tetrahydrofuran, or in an aprotic polar solvent, such as hexamethylphosphoric triamide, or a mixture. of these solvents, in the presence of a base such as preferably alkyllithium, for example n-butyl or tert-butyllithium, or in the presence of an alkali metal hydride such as sodium hydride or sodium dimethyl sulfoxide, or lithium alkyl amide such as lithium diisopropylamide or a temperature in the range of -80 to +25 ° C, preferably at -78 ° C. In this reaction, 1 to 3 equivalents of base are used. Most preferably, 1 equivalent of n-butyllithium in tetrahydrofuran at -78 ° C is used.

The resulting ketone derivative of general vzor232697 ce IV is heated at a temperature ranging from 50 to 200 ° C, preferably 70-90 ^C C, in an organic solvent, preferably an aromatic solvent such as benzene, toluene or xylene, or a chlorinated solvent, as. is dichloromethane, chloroform or dichloroethane, optionally without solvent, in the presence of an organic acid catalyst, preferably in the presence of an aromatic sulfonic acid such as p-toluenesulfonic acid, or in the presence of an aromatic sulfonic acid salt with an organic base such as pyridinium tosylate. The water produced in this reaction is removed by means of a water trap. Interfuranylene propacycline analogs of formula (I) are obtained analogously. Most preferably, this reaction is carried out in benzene in the presence of pyridinium tosylate as a catalyst at a temperature in the range of 70 to 90 ° C.

The lactones of formula V used as starting materials in the process of the invention are known from the literature [see, for example, R. A. Johnson and E. G. Nidy: J. Org. Chem., 45, p. 3802 (198), or can be prepared by similar procedures.

The protecting groups R @ ¹ and R @ ² can optionally be cleaved from the compounds of the formula I prepared by methods known in the literature. Optionally, salts of the compounds of formula I may also be prepared.

The stability of the compounds of formula I produced by the process of the invention was compared with that of the prostacyclin PGI 2 sodium salt. The latter compound is fairly unstable with a half-life of 3-4 minutes at pH 7.4. The free acid (prostacyclin-2 PGI2J) cannot even be prepared due to its even greater volatility [RA Johnson et al., J. Am. Chem. Soc., 100, p. 7690 (1978)]. according to the invention is significantly greater. one of these, namely 2 '.. 5' -. interfuranylen-2,3,4-trinor-5,9a-epoxy-9-deoxy-5,6-didehydro-PGF _and, it can be stored as the free acid at pH 7.4 without any noticeable decomposition for 12 hours and stored at -20 ° C with less than 10% decomposition for at least one month. -interfuranylene-2,3,4-trmor-5,9a-epoxy-9-desoxy-5,6-didehydro-16,17,18,19,20-pentanor-15-cyclopeintyl-PGFi _K is approximately 3 hours at pH 3.

One of the pharmacologically most potent agents of the compounds of the invention is 2 2, 5‘-mterfuranylene-2,3,4-trinor-5,9a-epoxy-g-desoxy-S-didehydro-PGF 1α, the efficacy of which is characterized by the following data:

1)

Inhibition of platelet aggregation induced by 2 µmoles of adenosine diphosphate in platelet-enriched plasma:

[ID 50 - 20 ng.ml ^-1 (human plasma)];

ID 50 - 350 ng.ml ^-1 (rabbit plasma).

Other compounds of the invention inhibit adenosine diphosphate-induced platelet aggregation in human platelet-enriched plasma with the following ID50 values:

2 ', 5'-interfuranylene-2,3,4-trinor-5,9a-epoxy-9-desoxy-5,6-didehydro-16,17,18,19,20-pentanor-15-cyclopentyl- PGFia: 3'5 ng. ml ^-1 ;

2 ^', 5'-mterfu'ranylen-2,3,4-trinor-5,9a-epoxy-9-deoxy-5,6,13,14-tetrahydro-20-methyl-PGF _K: 40 ng. ml ^-1 .

2)

Hypotensive effect induced in anesthetized cat by intravenous administration of kaolin: ED 50 = 14 µg. kg ^-1 body weight.

Both the platelet aggregation inhibitory effect and the hypotensive properties exhibit at a concentration one order of magnitude higher than the respective effects of the reference PGI2 (prostacyclin-2).

In addition, the compounds of the invention exhibit a broad spectrum of cytoprotective activity, both on the myocardium and on the gastrointestinal tract, as well as in liver diseases. The compounds of the invention have other pharmacodynamic effects, namely a guinea pig trachea relaxation effect and an inhibitory effect on tumor metastasis induced in rats.

In view of the pharmacological effects described above, the compounds of the invention can be effectively used either alone or in combination with heparin to inhibit platelet aggregation without any loss in extracorporeal circulation (e.g., haemolysis, extracorporeal heart-lung circulation, etc.). The compounds of the invention may also be used to prevent or treat peripheral vascular diseases (etheroselerosis obliterans, Berger's disease, diabetic angiopathy, Raynaud's disease).

The dimensions of the areas affected by myocardial infarction as well as mortality are reduced by the use of the compounds of the invention. The number and severity of seizures of angina pectoris decrease in several types of angina pectoris. On. Due to their bronchodilator effect, the compounds of the invention can be advantageously used to reduce the number (frequency) of asthma attacks. Furthermore, these compounds can be advantageously used for the treatment of ulcer diseases due to their gastrointestinal cytoprotective effect. In addition, the use of the compounds of the invention can prevent the spread of tumors (after surgery).

An advantage in treatment with the compounds of the invention is that they can be administered by the gastrointestinal route, for example orally, in addition to intravenous, subcutaneous and intramuscular administration. A preferred dose of the compounds of the invention is from 1 ng.kg ^-1 body weight, to 10 ng. kg ¹ body weight. The appropriate dose depends on the type and severity of the disease, the rate at which the drug reaches the site of action, as well as the individual sensitivity of the patient or the organ in need of treatment and the response of the patient. Appropriate dosages and the most appropriate route of administration will be readily appreciated by those skilled in the art.

Commonly used fillers, diluents, flavoring agents, formulation aids, pH adjusting and osmotic pressure agents, and stabilizing and absorption enhancing agents can be used to prepare the pharmaceutical compositions. These pharmaceutical compositions may be solid (e.g. tablets, capsules, dragees, pills, etc.), liquid (e.g. drops, syrups, etc.) or semi-solid (creams, ointments, balms, suppositories and the like).

The compounds of the invention may be used in the pharmaceutical compositions as the sole active ingredients or in combination with other active ingredients.

The invention is illustrated by the following examples.

Example 1

Preparation of 2 ', 5'-interfuranylene-2,3,4-trinor-5α-epoxy-S-desoxyXe-didehydro-PGFβ (compound of formula I wherein R 1 = hydrogen, R ² = hydrogen, R ³ = - (CH 2) 4 CH 3, A = trans —CH — CH- and B - valency bond)

To a solution containing 400 mg (1.02 mmol of 2 ', 5'-interfuranylene-2,3,4-trinor-5,9a-epoxy-9-desoxy-5,6-didehydro-PGF _ff methyl ester (compound of formula I) wherein R ¹ = methyl, R ² = hydrogen, R ³ = = - (CH 2) 4 CH 3, A = trans —CH = CH- and B = valence bond) in 10 ml of methanol is added 5 ml (5 mmol of aq. After stirring at room temperature for 3 hours, the methanol was removed without heating under reduced pressure and the residue was extracted with solvents cooled to 5 DEG C. First, 25 ml of ether and 30 ml of water were added and the ether phase was separated. The aqueous phase is washed several times with 20 ml of ether, then acidified to pH 3-4 with about 8 ml of aqueous sodium hydrogen sulphate solution. The aqueous layer is extracted twice with 25 ml of ether each time, the organic phases are combined and washed twice with 10 ml of saturated sodium chloride solution. and dried over anhydrous magnesium sulfate 2 mg of pure title product as yellowish-white crystals, m.p. 108-110 ° C.

R _f = 0.30 (benzene-dioxane-acetic acid 20: 10: 1);

UV (C2H5OH):

Amax = 295 nm, log ε = 4.16 a

Λ max = 235 nm, log ε = 3.93.

Example 2

Preparation of l, 15-bis (tetrahydropyranyl j -2 ', 5'-interferon _{uranylen-2,3,4-trinor-5-oxo-PGF, and} (formula IV in which R ¹ = methyl, R ² - tetrahydropyranyl, R ³ = - (CH 2) ⁴ CH 3, R ⁴ = hydrogen, A - = trans —CPI — CH— and B = valence bond)

To a solution containing 300 mg (2.67 mmol) 2-furancarboxylic acid (compound of formula VI wherein R ¹ - = H) in 25 mL tetrahydrofuran at -78 ° C was added 2.2 ml of 2M solution of N- butyllithium (4.4 mmol in hexane) and the resulting mixture was stirred at this temperature for 40 min. A solution containing 303 mg (0.68 mmol of 3-οχο-7β- (3'-tetrahydropyranyloxy-1'-octene) was added dropwise at the same temperature. -1'-yl) -8a-tetrahydropyranyloxy-2-oxabicyclo [4.3.0] nonane (a compound of formula V wherein R ² = -tetrahydropyranyl, R ³ - -, (CH 2) 4 CH 3, A - trans (Clil = Cl and B = valence bond) in 14 ml of tetrahydrofuran, stirred for 30 minutes at this temperature, then gradually raised to 0 ° C and quenched by addition of 20 ml of water. the phases were washed with 20 ml of 0.1 M sodium hydroxide solution and then with 20 ml of water and the combined aqueous phases were acidified to pH 3-4 20 ml of sodium hydrogen sulphate solution, washed twice with 40 ml of ether each time and the organic phases are combined. After washing with 10 ml of water and 10 ml of saturated sodium chloride solution, 10 ml of ethereal diazomethane solution are added to the organic solution at 0 DEG C., the mixture is stirred for 5 minutes and then dried over anhydrous magnesium sulphate. Purification by short column chromatography (25 g of silica gel G, eluting with hexane / ethyl acetate 2: 1) afforded 69 mg of the title product as a colorless oil.

R _f = 0.40 (hexane-ethylacetátern 1: 1);

UV (C2H5OH):

Am _and x = 256 nm, log ε = 4 200.

Example 3

Preparation of 2 ', 5'-interfuranylene-2,3,4-trinor-5,9a-epoxy-9-desoxy-5-methoxy-PGFi methyl ester _a (compound of formula IV wherein R ¹ -methyl, R ² = hydrogen, R 3 - = - (CH 2) ⁴ CH 3, R ⁴ - methyl, A = trans —CH = CH- and B - valence bond)

Solution containing 328 mg (0.5-8 mmol)

6 2 6 9 Ί methyl ether 11,15-bis (tetrahydro-pyranyl) -2 ', 5'-interfuranylene-2,3,4-trinuoro-5-oxo-PGF _a (a compound of formula IV wherein R ¹ -methyl, R ² = tetrahydropyranyl, R ³ = = (GI-12) 4CH 3, R ⁴ = hydrogen, A = trans-CH ---- (C ¹ -I) and B = valence bond) and catalytic mo. ; of pyridinium t-butylate in 5 ml of methanol is stirred overnight, then 50 ml of ethyl acetate are added. The mixture was washed successively with 8 ml of water and 8 ml of saturated sodium chloride solution and dried over anhydrous magnesium sulfate in the presence of triethylamine. Purification by short column chromatography (20 g of SiGC G, eluting with hexane / acetone 1: 1) afforded 197 mg of the title compound as a colorless oil.

According to thin-layer chromatographic analysis, the obtained substance is a mixture of two isomers having R-values of 0.33 and 0.33, respectively. 0.27, obtained using a 1: 1 mixture of hexane and acetone as a detection reagent.

He attaches

Preparation of l, 15-diacetyl-2 ', 5'-interfuranylen-2,3,4-tri <) r 5; 9a-epoxy-9-deoxy-5-methoxy-PGF, _r (compound of formula IV, in which R ¹ '= methyl, R ² ----- acetyl, R-> - (Glycyl, R → methyl), Λ == trans -CH. G11- and B == valence bond)

To a solution containing 183 mg (0.43 millimoles) of 2 ', 5'-interfuranylene-2,3,4-trinor-5,9a-epoxy-9-desoxy-5-methoxy-PGF1' methyl ester (compound of formula IV, wherein R ¹ ----- methyl, R ² - = hydrogen, R ³ - = - (CH 2) ⁴ CH 3, R ⁴ methyl, A = trans —CH — CH— and B valence bond) in 10 ml of dichloromethane is added 1 ml of triethylamine and 0.2 ml (21 mmol) of acetic anhydride. The solution is left overnight at room temperature, 5 ml of water are added and the mixture is stirred vigorously for 15 minutes. After adding 50 roles of ethyl acetate. The organic layer is washed successively with 10 ml of sodium hydrogen sulphate solution, 10 ml of water, 10 ml of saturated sodium hydrogen carbonate solution, 10 ml of water and 10 ml of saturated sodium chloride solution, and then dried with perfect magnesium sulfate. Evaporation gave 193 mg of the title compound which could be further processed without purification.

R _; 21. (hexane / ethyl acetate 2: 1).

Example 5

Preparation of l, 15-diacetyl-2 ', 5'-interfuranylen-2,3,4-trinor-5,9a-epoxy-9-deoxy-5,6-PGF d.idehydro _and (formula I, where R ¹ = methyl, R ² = = acetyl, R ³ - (CH 2) 4 CH 3, A = trans —CH = CH— and B = valence bond)

To a solution of 11,15-diacetyl-2 ', 5'-interfuranylene-2,3,4-trinor-5,9a-epoxy-9 desoxy-5-methoxy-PGFi methyl ester (138 mg (0.27 milimo.lu) methyl ester) _K (compounds of formula IV wherein R ¹ - methyl, ^R2 = acetyl, ^R3 = - (CH2) 4CH3, R ⁴ - methyl, a = trans-CH = CH- and B = valence bond) in 15 5 ml (0.02 mmol) of pyrldinium tosylate was added to benzene (ml) and the mixture was heated to reflux for 30 minutes while the resulting water was removed, then 1 ml of triethylamine was added and the mixture was purified by short column chromatography (20 ml). g of silica gel G and a 2: 1 mixture of hexane and ethyl acetate as eluent to give the title compound as a colorless oil (53 mg).

Rf ₌ 0.28 (2: 1 hexane: ethyl acetate);

UV (C2H5OH):

A _n . ₁ , 237 nm, log ε 3,0 / and _i - 30.2 nm. log ε 4.16.

Example 6

Preparation of 2 ', 5Mnteríuranylen-2,3,4-trinor-5,9a-epoxy-9-deoxy-5,6-didehydro-PGF _and (formula I wherein R ¹ - = hydrogen, R ² = hydrogen, R ³ - (CH 2) 4 CH 3, A = trans - CH - CH - and B - valence bond)

A solution containing 105 mg (0.22 mmol) of 1,1,1-diacetyl-2 ', 5'-interfuranylene-2,3,4-trinor-5,9a-epoxy-9-desoxy-9,6-didehydro-PGFi methyl ester _and (a compound of formula I wherein R ¹ = = methyl, R ² = acetyl, R ³ = = - (CH 2) 4 CH 3, A = trans CH = CH- and B = valence bond) and 1 ml ( 1 mmol) of aqueous 1 M sodium hydroxide solution in 5 ml of methanol are left at room temperature for 2 days. The methanol was then removed at room temperature under reduced pressure and 20 ml of ether and 20 ml of water were added to the residue. Aqueous phase with zn; The reaction mixture was washed with 10 mL of ether and acidified to pH 3-4 with about 1.2 mL of sodium bisulfate solution. The aqueous layer was extracted twice with 25 ml of ether each time, the ether phases were combined and washed twice with 5 ml of saturated sodium chloride solution each time and dried over anhydrous magnesium sulfate. Evaporation gave 13 mg of the title product which did not require further purification. The physical properties of this product are. identical to the properties of the pc-product described in Example 1.

Example 7

Preparation of 2 ', 5'-interfuranylene-2,3,4-trinoro-5,9a-epoxy-9-desoxy-5,6-didehydro-PGF 10 methyl ester (compound of formula I wherein R ¹ -methyl, R ² = hydrogen, R ³ = = - (CH 2) 4 CH 3, A = trans - CH = CH - and B = valence bond j

282897

Solution containing 94 mg (0.020 mmol) of methyl 11,15-diacetyl-2 ', 5'-interfuranyl-Ζ^^ --ΐΓΐΓΐΓΐΓηfθ, βα-θροχγ-θ-άθΞοχγ-Ξ, β-γίάεhydro-PGFi _and (a compound of the general formula) formula I wherein R ¹ - methyl, R ² - acetyl, R ³ - = - (CH2) 4CH3, a = trans - CH = CH- and B = valence bond), 1 ml (1 mmol) of a methanol solution of 1 M of sodium methoxide in 3 ml of methanol was stirred at room temperature for 3 hours. After addition of 50 ml of ether, the mixture is washed with 8 ml of cold water and twice with 8 ml of saturated sodium chloride solution each time and dried over anhydrous magnesium sulfate. Purification on a short chromatography column (10 g silica gel, eluting with hexane / acetone 2: 1) gave 63 mg of the title compound, which showed the following data:

R ₍₌ 0.62 (hexane-acetone 1: 1) :; UV (C2H5OH)

Λ max = 326 nm, log ε = 3.93 a

Neither _ax - 301 nm, log ε - 4,14.

The melting point of the yellowish-white crystals is in the range 114-117 ° C.

Example 8

Preparation of 2 ', 5'-mterfuranylene-2,3,4-trifluoro-5,9'-epoxy-9-desoxy-5,6-didehydro-16,17,18,1920-pentanor-15-cyclopentyl- PGF _and (formula I wherein ^R1 = hydrogen, ^R2 = hydrogen, ^R3 = cyclopentyl, a = trans · -CH = CH- and B = valence bond)

A mixture of a solution containing 250 ml (0.64 mmol) of methyl 2 ', 5'-interfuranylene-3,4,5-trinor-5,9aepoxy-9-desoxy-5,6-didehydro-16,17,18,19, 20 pentanoir-15-cyclopentyl-PGF "(compound of formula I in which R ,. ¹ == methyl, ^R2 = hydrogen, R3 = cyclopentyl, a - trans -CH = CH- and B - valence bond) with 5 ml (5 mmole) of aqueous 1 M sodium hydroxide solution is left at room temperature for 3 hours, then evaporated to approximately half its volume and purified with cooled solvents, diluted with 25 ml of water and 25 ml of ether and the aqueous phase is acidified to pH 3-4 by addition of 1M sodium bisulfate solution The precipitated white precipitate is dissolved in 50 ml of ethyl acetate and the two phases are separated, the aqueous phase is washed again with 20 ml of ethyl acetate, the ethyl acetate phases are combined, washed twice with 10 ml of saturated solution each time. sodium chloride and dried over anhydrous magnesium sulphate of title product as white crystals, m.p. 157-160 ° C.

R t = 0.28 (20: 10: 1 benzene / dioxane / acetic acid)

Example 9

PREPARATION OF 2 ', 5'-interfuranylen-2,3,4-Trinar-5 ₍₉ "epoxy-9-deoxy-5 _R 6 H-didehydro-16,17,18-19,20-pentanor-15- PGF _and cyclopentyl (formula I wherein R ¹ = _y Ga. _2, ^R2 = hydrogen, ^R3 = cyclopentyl, a - trans -CH = CH- and B = valence bond]

A mixture of a solution containing 176 mg (0.45 mmol) of 2 ', 5'-interfuranylene-2,3,4-trinor-5,9a-epoxy-9-desoxy-5,6-didehydro-16,17,18 methyl ester, 19,20-Pentanor-15-cyclopentyl-PGF1 _K with 5 ml of 1 N sodium hydroxide solution in 10 ml of methanol is stirred at room temperature for 90 minutes, after which the methanol is distilled off under reduced pressure. After addition of 10 ml of water to the residue, the resulting solution is washed with 25 ml of ether, the aqueous phase is acidified to pH 4 by the addition of approximately 5 ml of 1M sodium hydrogen sulphate solution and extracted three times with cold 30 ml of ethyl acetate each time. The combined ethyl acetate solutions were washed with 10 mL of saturated sodium chloride solution. After evaporation, the residue was dissolved in 10 ml of tetrahydrofuran and 30 mg was added after 3 ml of water. (0.53 mmol) of calcium oxide. The resulting cloudy solution was stirred overnight, then filtered, the filtrate was evaporated to dryness and after the addition of benzene, the residue was evaporated again to dryness. The residue was evaporated. The mixture is stirred for 20 minutes with 20 ml of ethanol and then filtered. Evaporation of the filtrate gave the title compound as a white solid, m.p. 130 DEG-155 DEG C. (dec.).

Rf ₌ 0-, 2 & (benzene / dioxane / acetic acid 20: 10: 1)].

The calcium content of the compound can be determined by conductametric titration using an acid. In this particular case, the calcium content of the sample of 15 mg compound is 0.785 mg.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of novel racemic and optically active interfuranyleneprostacycline derivatives of the general formula I in which: R ¹ is as defined above, α and the resulting ketone derivative of the general formula IV (i) in which R ¹ represents hydrogen or a C 1 -C 4 alkyl group, straight or branched chain, or a protonated form of inorganic cations, R ² represents hydrogen, alkanoyl having 1-4 carbon atoms or tetrahydropyranyl group, R ³ represents an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 5 or 6 carbon atoms, A represents a group - CH - CH - or - C C, a B represents a chemical bond or a group --CH2 -, characterized in that the compound of the general formula V JI / X R ³ (as in which R ^2, R ^3, A and B have the abovementioned meaning, is reacted in the presence of a base with a compound of formula VI yi '. (IV) wherein R ¹ , R ² , R ³ , A and B are as defined above and a R ⁴ is hydrogen, heated at 50 to 200 ° C in the presence of an acid catalyst either directly or optionally after conversion to a compound of formula IV wherein R ¹ , R ² , R ³ A and B are as defined above, and R 4 ⁴ represents an alkyl group having 1 to 4 carbon atoms, by reaction with an appropriate alcohol, and optionally removing the hydroxyl and / or carboxyl protecting groups, and / or optionally converting the resulting compound into its salt. 2. The method according to claim 1, characterized by. 2-furancarboxylic acid is used as the compound of formula VI. 3. A process according to claim 1, wherein an alkali metal lithium compound, preferably lithium diisopropylamide or butyllithium is used as the base in which the compound of formula V is reacted with a compound of formula VI, and ether type solvents are used as solvents. , preferably tetrahydrofuran, and / or an aprotic polar solvent, preferably hexamethylphosphoric triamide, and / or mixtures thereof. 4. Process according to claim 1, characterized in that a strong mineral acid or a strong organic acid, preferably p-toluene, lionic acid, is used as the acid catalyst in the presence of which the compound of the formula IV is heated. at a temperature of 50 to 200 ° C, preferably at a temperature of 70 to 90 ° C.