WO1984004307A1

WO1984004307A1 - 5-ethynyl-prostacyclyne, production process thereof and pharmaceutical utilisation thereof

Info

Publication number: WO1984004307A1
Application number: PCT/DE1984/000094
Authority: WO
Inventors: Helmut Vorbrueggen; Bernd Raduechel; Werner Skuballa; Claus-Steffen Stuerzebecher; Martin Haberey
Original assignee: Schering Ag
Priority date: 1983-04-20
Filing date: 1984-04-17
Publication date: 1984-11-08
Also published as: JPS60501106A; DE3314207A1; EP0139731A1

Abstract

Derivatives of 5-ethynyl-prostacyclyne having the formula (I) wherein R1 is hydrogen, alkyl, cycloalkyl, aryl, a heterocyclic rest or a group$(4,)$, R2 is a hydrogen atom in position alpha or beta or a methyl group in alpha or beta, R3 is an alkyl, cycloalkyl or aryl group optionally substituted, or a heterocyclic group, A is -CH2-CH2-, trans-CH=CH- or -C=C-group, B is a straight chain alkylen group comprising from 1 to 5 atoms of carbon, D and E form together a direct bond or D is a straight chain saturated alkylene group comprising from 1 to 5 atoms of carbon, a branched chain saturated alkylene group or an unsaturated straight chain alkylene group comprising from 2 to 5 atoms of carbon which may optionally be substituted by fluorine atoms, I is an oxygen atom, -C=C-group or CR5-group, wherein R4 and R5 are different from each other, may represent a hydrogen atom or an alkyl group comprising from 1 to 3 atoms of carbon and, if R1 is a hydrogen atom, they represent physiologically acceptable salts of said compounds with organic or inorganic bases; production process and pharmaceutical utilisation thereof.

Description

5-ethynyl prostacyclins, process for their preparation and their pharmaceutical use

Prostacyclin and its analogues are suitable for the treatment of mammals, including humans, due to their biological and pharmacological properties. However, their use encounters difficulties because they are chemically unstable and have a short duration of action for therapeutic purposes. All structural changes have the goal of increasing the duration of action and the selectivity.

It has now been found that the introduction of an ethynyl group in the 5-position of the prostacyclin causes greater selectivity and a longer duration of action and increases the stability of the compounds.

The compounds according to the invention have an antihypertensive and bronchodilatory effect. They are suitable for vasadilation, inhibition of platelet aggregation and gastric acid secretions, and for cytoprotection on the stomach, heart and liver.

The invention relates to prostacyclin derivatives of the general formula I.

where rin

R _{1 is} hydrogen, alkyl, cycloalkyl, aryl, a heterocyclic radical or a -CH ₂ - aryl group

R _{2 is} an α or β hydrogen atom or an α or β methyl group,

R _{3 is} an alkyl, cycloalkyl or an optionally substituted aryl group or a heterocyclic group,

A is a -CH ₂ -CH ₂ -, trans-CH = CH or -C≡C group,

B is a straight-chain alkylene group with 1-5 C atoms

D and E together have a direct bond or

D is a straight-chain, saturated alkylene group with 1 to 5 C atoms, a branched saturated or a straight-chain unsaturated alkylene group with 2 to 5 C atoms, which can optionally be substituted by fluorine atoms

E is an oxygen atom, a -C≡C group or a

-CR ₄ = CR ₅ group, where R ₄ and R ₅ differ and can mean a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and if

R _{1 has} the meaning of a hydrogen atom, the physiologically compatible salts of which mean with inorganic or organic bases.

As alkyl groups R ₁ straight or branched chain alkyl groups with 1 to 10 carbon atoms are to be considered, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. -Butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.

The alkyl groups R ₁ can optionally be substituted 1 to more times by halogen atoms, hydroxyl groups, C ₁ -C ₄ alkoxy groups, optionally substituted C6-C ₁₀ aryl groups, di-C ₁ -C ₄ alkylamines and tri-C ₁ -C ₄ alkylammonium. Preferably sinu. those alkyl groups which are monosubstituted.

Examples of substituents are fluorine, chlorine or eromatome, phenyl, dimethylamino, diethylamino, methoxy, ethoxy.

Preferred alkyl groups R ₁ are those with 1-4 C atoms, such as, for example, methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, butyl.

Aryl groups R ₁ are substituted as well as unsubstituted aryl groups in Eestracht, such as phenyl, 1-naphthyl and 2-naphthyl, which can each be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each with 1-4 C. -Atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxy or alkoxy group with 1-4 C-atoms. The substituents in the 3- and 4-position on the phenyl ring are preferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position by hydroxy.

The cycloalkyl group R ₁ can contain 3-10, preferably 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. Examples include cyclopentyl, cyclohexyl, methylclohexyl and adamantyl.

The aryl radical in the -CH ₂ - aryl group of R ₁ can be phenyl,

α- or ß-naphthyl, which are represented by 1-3-phenyl groups, which in turn are represented by 1-3 halogen atoms such as F, Cl or Br or 1-3 C ₁ -C ₄ alkoxy groups or 1-3 halogen atoms (F, Cl, Br ) may be substituted. Simple substitutions with phenyl, C ₁ -C ₂ alkoxy, chlorine or bromine are preferred. Suitable alkyl groups R ₃ are straight-chain and branched-chain, saturated and unsaturated alkyl radicals, preferably saturated, with 1-10, in particular 1-7, carbon atoms, which can optionally be substituted by optionally substituted aryl. Examples include methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutyl, propenyl, pentenyl, Hexenyl, benzyl and p-chlorobenzyl.

The cycloalkyl group R ₃ can contain 3-10, preferably 3-6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl.

Examples of suitable substituted or unsubstituted aryl groups R ₃ are: phenyl, 1-IIaphthyl and 2-naphthyl, which can each be substituted by 1-3 halogen atoms, one phenyl group, 1-3 alkyl groups, each with 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C ₁ -C ₄ alkoxy or hydroxyl group. The substitution in the 3- and 4-position on the phenyl ring is preferred, for example by fluorine, chlorine, C ₁ -C ₄ -alkoxy or trifluoromethyl or in the 4-position by hydroxy.

Suitable heterocyclic groups R ₃ are 5- and 6-membered heterocycles which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 2-thienyl, 2-pyridyl, 4-pyridyl, 3-furyl, 3-thienyl and others

Suitable alkylene groups D are straight-chain or branched-chain, saturated and unsaturated alkylene radicals, preferably saturated ones with 1-5 C atoms, which can optionally be substituted by fluorine atoms. Examples include: methylene, fluoromethylene, ethylene, 1,2-propylene, ethyl ethylene, trimethylene, tetramethylene, pentamethylene, 1-methyltetramethylene, 1-methyltrimethylene.

The alkyl groups R ₄ and R ₅ represent straight-chain or branched saturated alkyl groups with 1-3 C atoms.

For salt formation with the free acids (R ₁ = H), inorganic and organic bases are suitable, as are known to the person skilled in the art for the formation of physiologically compatible salts. Examples include: alkali metal hydroxides such as sodium and 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 invention further relates to a process for the preparation of the prostacyclin derivatives of the general formula I according to the invention, characterized in that a compound of the general formula II

wherein

R ₂ , R ₃ , A, B, D and E have the meaning given above, reacted with bromethylene triphenylphosphorane and the resulting

Bromolefin of the general formula III

treated with a base, such as, for example, potassium tert-butoxide, giving compounds of the general formula I. If appropriate, the carboxyl group can then be esterified or salts can be formed in the process products obtained. For more convenient purification, these products are optionally converted into an ester, preferably the methyl ester, purified by column chromatography or preparative thin-layer chromatography on silica gel, and the ester is then saponified.

The reaction of aldehydes of the general formula II with

Bromomethylene triphenylphosphorane is used at temperatures of

-100 ° C to + 20 ° C, preferably from -70 ° C to -20 ° C, in an aprotic solvent or solvent mixture, for example diethyl ether, tetrahydrofuran or dioxane in a mixture of diethyl ether or tetrahydrofuran.

The reaction of the bromoolefins of the general formula III to the products of the general formula I is carried out with bases, such as e.g. Potassium tert-butoxide, sodium ethylate, potassium butoxide, diazabicyclonones, diazabicycloundecene, diazabicyclooctane in solvent such as e.g. Tetrahydrofuran, toluene, xylene at temperatures between 0 ° C and 120 ° C. The reaction can also be achieved with alkali metal hydroxides, e.g. with potassium hydroxide in diethylene glycol dimethyl ether at 100 ° C. The preferred embodiment consists in the reaction with potassium tert-butoxide in tetrahydrofuran at + 20 ° C.

The esterification, in which R _{1 represents} an alkyl group with 1-10 C atoms, takes place according to methods known to the person skilled in the art. The carboxyl compounds are reacted, for example, with diazo hydrocarbons in a manner known per se. Esterification with diazo hydrocarbons is carried out, for example, by mixing a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether, with the carboxy compound in the same or in another inert solvent, such as, for example, methylene chloride. When the reaction has ended in 1 to 30 minutes, the solvent is removed and the ester is purified in the customary manner. Diazoalkanes are either known or can be prepared by known methods [Org.Reactions Vol. 8, pages 389-384 (1954)].

The esterification, in which R _{1 represents} a substituted or unsubstituted aryl group, is carried out by the methods known to the person skilled in the art. For example, the carboxy compounds and the corresponding arylhydroxy compounds are reacted with dicyclohexylcarbodiimide in the presence of a suitable base, for example pyridine or triethylamine, in an inert solvent. Suitable solvents are methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform. The reaction is carried out at temperatures between -30 ° C and + 50 ° C, preferably at + 10 ° C.

The esterification can also be carried out by reacting the carboxylate anion with the corresponding alkyl halide or ω-halo ketone (Hal-CH ₂ -

-Ar, where Ar is phenyl or diphenyl, which can be substituted by C ₁ -C ₂ alkoxy or chlorine or bromine).

The prostacyclin derivatives of the general formula I with -R ₁ in the meaning of a hydrogen atom can be converted into salts with suitable amounts of the corresponding inorganic bases with neutralization. For example, when the corresponding acids are dissolved in water which contains the stoichiometric amount of the base, the water is evaporated off or water is added miscible solvent, for example alcohol or acetone, the solid inorganic salt.

The amine salts are prepared in a conventional manner. For this purpose, the prostacyclic acid is dissolved, for example, in a suitable solvent, such as ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine is added to this solution. The salt is usually obtained in solid form or is isolated in a conventional manner after evaporation of the solvent.

The compounds of the general formula II are known (see German Offenlegungsschrift 28 09 733) or can be obtained from the compounds of the general formula IV

wherein R ₂ , R ₃ , A, B, D and E have the meaning described above, can be prepared by reduction with diisobuty aluminum hydride.

The preparation of compounds of the general formula IV is known and is described in the following publications:

1. European Patent 2,234

2. German Offenlegungsschrift 30 04 795

3. German Offenlegungsschrift 30 41 602. The new prostacyclin analogues have the properties typical of prostacyclins, such as a reduction in peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and dissolution of platelet thrombi, myocardial cytoprotection and thus a reduction in systemic blood pressure, without simultaneously reducing stroke volume and coronary blood flow; Treatment of stroke, prophylaxis and therapy of coronary heart diseases, coronary thrombosis, myocardial infarction, peripheral arterial diseases, arteriosclerosis and thrombosis, prophylaxis and therapy of ischemic attacks of the CNS system, therapy of shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion, gastric acid secretion inhibition Intestinal mucosa, cytoprotection in the liver and pancreas, anti-allergic properties, reduction of pulmonary vascular resistance and pulmonary blood pressure, promotion of renal blood flow, use in place of heparin or as an adjuvant in dialysis of hemofiltration, preservation of blood plasma preserves, especially of platelet preserves, especially blood platelets labor pains, treatment of pregnancy toxicosis, increased cerebral blood flow etc. In addition, the new carbacyclin derivatives have antiproliferative and antidiarrheal properties. The carbacyclins of this invention can also be used in combination, for example with β-blockers or diuretics.

The dose of the compounds is 1-1500μg / kg / day when administered to the human patient. The unit dose for the pharmaceutically acceptable carrier is 0.01-100 mg.

When intravenously injected into awake, hypertensive rats in doses of 5, 20 and 100 μg / kg body weight, the compounds according to the invention show a greater hypotensive and longer-lasting effect than PGE ₂ and PGA ₂ , without triggering cardiac arrhythmias like PGE ₂ or PGA ₂ .

When intravenously injected into anesthetized rabbits, the compounds according to the invention show, compared to PGE ₂ and PGA _2, a stronger and more prolonged drop in blood pressure without influencing other smooth-muscular organs or organ functions.

Sterile, injectable, aqueous or oily solutions are used for parenteral administration. Tablets, coated tablets or capsules, for example, are suitable for oral administration.

The invention thus also relates to medicaments based on the compounds of the general formula I and customary auxiliaries and carriers.

The active compounds according to the invention are to be used in conjunction with the auxiliaries known and customary in galenics, for example for the production of hypotensive agents. example 1

5-ethynyl prostacyclin

498 mg of potassium tert-butoxide are added to a suspension of 1.93 g of bromomethyltriphenylphosphonium bromide in 25 ml of tetrahydrofuran at -70 ° C. under argon and the mixture is stirred at -70 ° C. for 1 hour. 338 mg of 5-formyl prostacyclin dissolved in 5 ml of tetrahydrofuran are added to the yellow ylene solution thus obtained, and the mixture is stirred at -60 ° C. for 2 hours, at -40 ° C. for 3 hours and at -25 ° C. for 18 hours. It is diluted with 150 ml of water, adjusted to pH 9 by adding 5% sodium hydroxide solution and extracted twice with 50 ml of ether each time. This extract is discarded. The water phase is adjusted to pH 6.3 by adding citric acid at 0 ° C. and extracted three times with 20 ml of ethyl acetate each, the extract is shaken with 10 ml of brine, dried over magnesium sulfate and evaporated in vacuo. 150 mg of the bromoolefin (corresponds to the general formula III) are obtained as a brown oil.

To split off hydrogen bromide, the product is dissolved in 5 ml of tetrahydrofuran, 75 mg of potassium tert-butoxide are added and the mixture is stirred at 20 ° C. for 18 hours. The mixture is then cooled to 0 ° C., diluted with 10 ml of ice-cold 1 M citrate buffer (pH 6.2) and extracted three times with 15 ml of ethyl acetate each time, the extract is washed with 5 ml of brine, dried over magnesium sulfate and evaporated in vacuo. This gives 122 mg of a brown oil, which is dissolved in 10 ml of dichloromethane and an ethereal solution of diazomethane is added dropwise at 0 ° C., the course of the esterification being followed by thin-layer chromatography (silica gel plates, ethyl acetate-methanol 99/1). It is evaporated in vacuo and the residue is purified by rapid chromatography on silica gel with dichloromethane Ethyl acetate (1: 1) with the addition of 0.1% triethylamine. The fractions which are uniform by thin layer chromatography are combined. 55 mg of 5-ethynyl prostacyclin methyl ester are obtained as a colorless oil. For saponification, dissolve in 2 ml of a solution of 1 g of potassium hydroxide in 12 ml of water and 37 ml of ethanol, stir for four hours at room temperature, concentrate in vacuo, dilute with 20 ml of ice-cold 0.5 M citrate buffer (pH 6, 2) and extracted three times with 10 ml of ethyl acetate each. The extract is shaken with 5 ml brine, dried over magnesium sulfate and evaporated in vacuo at 25 ° C. 45 mg of the title compound are obtained as a colorless oil.

IR: 3600, 3400 br., 3305, 2931, 2859, 2088, 1710, 1632, 1180, 972 / cm.

Example 2

5-ethynyl-16-methyl-prostacyclin

Analogously to Example 1, 50 mg of the title compound is obtained as a colorless oil from 300 mg of 5-formyl-16-methyl-prostacyclin.

IR: 3600, 3400 br., 3305, 2935, 2863, 2090, 1711, 1630, 1177, 972 / cm.

Example 5

5-ethynyl-16,16-dimethyl-prostacyclin In analogy to Example 1, 58 mg of the title compound is obtained as a colorless oil from 350 mg of 16,16-dimethyl-5-formyl-prostacyclin.

IR: 3605, 3400 br., 3305, 2948, 2855, 2098, 1711, 1631, 1185, 976 / cm.

Example 4

5-ethynyl- (15RS) -15-methyl-prostacyclin In analogy to example 1, from 500 mg of 5-formyl- (15RS) -15-methyl-prostacyclin 95 mg of the title compound are obtained as a colorless oil.

IR: 3605, 3400 br., 3304, 2925, 2852, 2082, 1712, 1638, 1185, 972 / cm.

Example 5

5-ethynyl- (16RS) -16-methyl-18,18,19,19-tetradehydro-prostacyclin

Analogously to Example 1, 42 mg of the title compound are obtained as a colorless oil from 200 mg of 5-formyl- (16RS) -16-methyl-18, 18, 19, 19-tetradehydro-prostacyclin. IR: 3600, 3400 br., 3302, 2930, 2845, 2130, 2085, 1710, 1635, 1168, 976 / cm. The starting material for the above title compound is prepared as follows:

5a) 5-Cyano- (16R3) -16-methyl-18, 18, 19, 19-tetradehydro-prostacyclin-11, 15-bis (dimethyl-tert-butyl) -silyl ether

2.31 g of dimethyl-tert-butylsilyl- are added to a solution of 1.20 g of 5-cyano- (16RS) -16-methyl-18,18,19,19-tetradehydro-prostacyclin in 20 ml of dimethylformamide. chloride and 2.09 g imidazole, stirred for 18 hours at 20 ° C, diluted with 200 ml of water and extracted several times with hexane / ether (4: 1), the organic phase was washed with brine, dried over magnesium sulfate and evaporated in vacuo. 3.30 g of bis-silyl ether-silyl ester is obtained, which is stirred in 20 ml of tetrahydrofuran and 20 ml of water with 1.80 g of anhydrous potassium carbonate. After dilution with 100 ml of ice water and 100 ml of ether, the pH is adjusted to 4 with stirring by adding dilute sulfuric acid. It is then extracted with ether, the extract is washed with brine, dried over magnesium sulfate and evaporated in vacuo. 2.51 g of the title compound are obtained as a colorless oil.

IR: 3520, 2955, 2930, 2859, 2198, 1712, 1649, 1250, 972, 935, 908, 833 / cm.

b) 5-Formyl- (16RS) -16-methyl-18, 18, 19, 19-tetradehydro-prostacyclin methyl ester-11, 15-bis (dimethyl-tert-butyl) -silyl ether 15 ml of a 1.2 M solution of diisobutylaluminum hydride in toluene are added dropwise to a solution of 2.50 g of the silyl ether prepared according to Example 5a in 70 ml of toluene at −20 ° C. under argon within 5 minutes, and the mixture is stirred at −20 ° for 1 hour C, mixed with 7 ml of water and stirred for 30 minutes at + 20 ° C. 500 ml of ether are then added, the mixture is shaken with 50 ml of 10% sulfuric acid and four times with 50 ml of semi-concentrated brine each, dried over magnesium sulfate and evaporated in vacuo. 2.29 g of a yellow oil are obtained, which is converted into the methyl ester with ethereal diazomethane solution. The crude product is purified by chromatography on silica gel. Elution with hexane / ethyl acetate (7: 3) gives 1.15 g of the title compound as a light yellow oil.

IR: 2955, 2931, 2859, 1730, 1626, 1250, 972, 937, 908, 833 / cm.

5-formyl- (16RS) -16-methyl-18,18, 19, 19-tetradehydro-prostacyclin

A solution of 1.05 g of the formyl compound prepared according to Example 5b and 1.17 g of tetra-n-butylammonium fluoride trihydrate in 20 ml of tetrahydrofuran is left for 24 hours at 20 ° C., then diluted with water, extracted with ether, the extract is washed with brine, dries over magnesium sulfate and evaporates in vacuo. 520 g of an oily residue are obtained, which is stirred in 10 ml of a mixture of 1 g of potassium hydroxide, 12 ml of water and 37 ml of ethanol at 20 ° C. for 6 hours. After concentration in vacuo, it is diluted with water and extracted with hexane (this extract is ver the water phase is adjusted to pH 4 with citric acid and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel. Elution with ethyl acetate / 1% acetic acid gives 450 mg of the title compound as a colorless oil. IR: 3600, 3400 br., 2959, 2931, 2875, 2860, 1711, 1628, 972 / cm.

Example 6

5-ethynyl-16, 16-dimethyl-13, 18, 19, 19-tetradehydroprosta-cyclin

In analogy to Example 1, 55 mg of the title compound are obtained as a colorless oil from 300 mg of 16,16-dimethyl-5-formyl-18,18, 19,19-tetradehydroprostacyclin. IR: 3600, 3405 br., 3308, 2930, 2861, 2120, 2085, 1711, 1631, 1180, 976 / cm.

The starting material is obtained from 5-cyano-16,16-dimethyl-18,13,19,19-tetradehydro-prostacyclin in analogy to Example 5a - 5c.

Example 7

5-ethynyl- (16RS) -16, 20-dimethyl-18, 18,19,19-tetradehydro-prostacyclin

Analogously to Example 1, 35 mg of the title compound is obtained as a colorless oil from 200 mg (16RS) - 16,20-dimethyl-5-formyl-18,18,19,19-tetradehydro-prostacyclin. IR: 3600, 3400 br., 3305, 2930, 2861, 2120, 2088, 1710, 1635, 1185, 976 / cm.

The starting material is obtained from 5-cyano-16,20-dimethyl-18,18,19,19-tetradehydro-prostacyclin in analogy to Examples 5a - 5c.

Example 8

5-Ethyl- (16RS) -16 -methyl-18, 18,19,19-tetradehydro-prostacyclin methyl ester

An ethereal diazomethane solution is added dropwise at 0 ° C. to a solution of 30 mg of 5-ethynyl- (16RS) -16-methyl-18, 18,19,19-tetradehydroprostacyclin in 3 ml of dichloromethane until the color changes to yellow. After 5 minutes, the mixture is evaporated in vacuo and the crude product is purified by chromatography on silica gel. Elution with hexane / ethyl acetate (3: 7) with the addition of 0.1% triethylamine gives 21 mg of the title compound as a colorless oil. IR: 3600, 3305, 2942, 2840, 2125, 2082, 1731, 1635, 1185, 976 / cm. Example 9

5-ethynyl- (16RS) -16-methyl-18, 18, 19, 19-tetradehydro prostacyclin phenacyl ester

25 mg of 5-ethynyl- (16RS) -16-methyl-18, 13,19,19-tetradehydro-prostacyclin are dissolved in 1 ml of acetonitrile, 20 mg of ω-bromoacetophenone and 0.2 ml of triethylamine are added and the mixture is stirred for 24 hours 20 ° C. 20 ml of ether are added, each is shaken with 5 ml of water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by layer chromatography on a silica gel plate which is developed with dichloromethane-acetone (90:10). 20 mg of the title compound are obtained. IR: 3603, 3305, 3010, 2928, 2848, 2130, 2082, 1742, 1702, 1638, 1601, 1178, 976 / cm.

Claims

1. 5-ethynyl prostacyclin derivatives of the general formula I

(I)

wherein

R _{2 is} an α- or β-hydrogen atom or an α- or β-methyl group, R _{3 is} an alkyl, cycloalkyl or an optionally substituted aryl group or a heterαcyclic group, A is a -CH ₂ -CH ₂ -, trans- CH = CH or -C≡C group, B a straight-chain alkylene group with 1-5 C atoms D and E together a direct bond or D a straight-chain, saturated alkylene group with 1 to 5 C atoms, a branched saturated or one straight-chain unsaturated alkylene group with 2 to 5 carbon atoms, which may optionally be substituted by fluorine atoms E an oxygen atom, a -C≡C group or a

-CR ₄ = CR ₅ group, where R ₄ and R ₅ differ and are a hydrogen atom or an alkyl group having 1 to 3 carbon atoms can interpret and, if R _{1 has} the meaning of a Viassers toffatomes, mean their physiologically compatible salts with inorganic or organic bases.

2. A process for the preparation of the compounds of formula I, characterized in that a compound of general formula II

wherein

R ₁ , R ₃ , A, B, D and E have the meaning given above, reacted with bromomethylene triphenylphosphorane and the bromoolefin of the general formula III obtained

treated with a base, such as, for example, potassium tert-butoxide, and if appropriate subsequently esterifying the carboxyl group in the process products obtained or forming salts.

3. Medicament consisting of one or more compounds of claim 1 and customary auxiliaries and carriers

4. 5-ethynyl prostacyclin

5. 5-ethynyl-16-methyl-prostacyclin

6. 5-ethynyl-16,16-dimethyl-prostacyclin

7. 5-ethynyl- (15RS) -15-methyl-prostacyclin

8. 5-ethynyl- (16RS) -16-methyl-18,18,19,19-tetradehydroprostacyclin

9. 5-ethynyl-16,16-dimethyl-18,18,19,19-tetradehydroprostacyclin

10. 5-ethynyl- (16RS) -16,20-dimethyl-18,18,19,19-tetradehydroprostacyclin

11. 5-Ethynyl- (16RS) -16-methyl-18,18,19,19-tetradehydroprostacyclin methyl ester

12. 5-Ethynyl- (16RS) -16-methyl-18,18,19,19-tetradehydroprostacyclinphenacyl ester