DE3308561A1 - 19,20-Methyleneprostacyclin derivatives and a process for their preparation - Google Patents

Abstract

The invention relates to 19,20-methyleneprostacyclin derivatives of the general formula I <IMAGE> in which R1 represents the radical OR3, in which R3 may denote hydrogen, or alkyl having 1-10 C atoms and optionally substituted by halogen, phenyl, C1-C4-alkoxy or C1-C4-dialkylamino, or cycloalkyl, aryl or a heterocyclic radical, or the radical NHR4 where R4 denotes a hydrogen, alkyl, cycloalkyl or aryl, or an alkanoyl or alkanesulphonyl radical each having 1-10 C atoms, A denotes a -CH2-CH2-, trans-CH = CH- group or -C IDENTICAL C- group, W denotes a <IMAGE> or a <IMAGE> in which the OH group can in each case be esterified with a benzoyl or alkanoic acid radical having 1-4 C atoms or etherified with a tetrahydropyranyl, tetrohydrofuranyl, alkoxyalkyl or trialkylsilyl radical, it being possible for the free or esterified OH group to be in the alpha - or beta -position, D denotes a direct bond or a straight-chain or branched alkylene group having 1-10 C atoms, R2 denotes a hydroxyl group which can be esterified with an alkanoic acid radical having 1-4 C atoms or etherified with a tetrahydropyranyl, tetrahydrofuranyl, alkoxyalkyl or trialkylsilyl radical, X1 denotes the group CH2 or oxygen, X2 denotes the group CH2 or C=O and, if R3 represents hydrogen, their salts with physiologically tolerable bases, to a process for their preparation and to their use as hypotensive medicaments.

Description

19,20-methylene prostacyclin derivatives and Process for their manufacture

The invention relates to new 19 ^ ü-methylene prostacyclin derivatives, Process for their preparation as well as their conclusion as a medicine.

Prostacyclin (PGI "), one of the main factors in platelet aggregation, has a dilating effect on various blood vessels (Science 196 , 1072) and could therefore be considered as a means of lowering blood pressure. However, PG ^ does not have what is necessary for a medicinal product. Stability. Its half-life is only a few minutes at physiological pH values and at room temperature.

The compounds according to the invention have a hypotensive and bronchodilator effect. They are also suitable for inhibiting throinbocyte aggregation, vasodilation and gastric acid secretion and have a cytoprotective effect.

The invention relates to 19,20-methylene prostacyclins general formula I.

(CH ₂ ) ₃

R ₁ denotes the radical OR-, vi / obei R, hydrogen or optionally _{substituted by halogen, phenyl, C, -C -alkoxy or C 1} -C ^ -dialkylamino with 1-10 carbon atoms, cycloalkyl, aryl or a heterocyclic one May mean remainder, or the remainder NHR. with R ^ in the meaning of a hydrogen, alkyl, cycloalkyl or aryl or an alkanoyl or alkanesulfonyl radical with 1-10 carbon atoms each,

A is a -CH_-CH ₂ -, trans-CH = CH group or -CrC group,

H CH ₃

W is a -C- or a -C- group in which the OH group is OH OH

each esterified with a benzoyl or alkanoic acid residue with 1-4 carbon atoms or with a tetrahydropyranyl, Tetrahydrofuranyl, alkoxyalkyl or trialkylsilyl radical can be etherified, the free or esterified OH group can be in α or ß position,

D is a direct bond or a straight-chain or branched alkylene group with 1-10 C atoms,

R_ is a hydroxyl group with an alkanoic acid residue 1-4 carbon atoms esterified or with a tetrahydropyranyl, tetrahydrofuranyl, alkoxyalkyl or trialkylsilyl radical may be etherified, X, the group CH "or oxygen, X the group CH" or carbonyl and, if R, hydrogen represents, the salts of which with physiologically compatible bases mean.

_{In the case of X 1} = X ₂ = CH _{2, the} compounds of the formula I represent both (5E) and (5Z) isomers.

As the alkyl group R-, are straight or branched alkyl groups to be considered with 1-10 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, Heptyl, hexyl, decyl. The alkyl groups R 1 can optionally 1 to several times substituted by halogen atoms, Alkoxy groups with 1-4 carbon atoms, optionally substituted Aryl groups, dialkylamines and trialkylammonium with 1-4 carbon atoms. Preferred are those alkyl groups which are simply substituted. Examples of substituents are fluorine, chlorine or bromine atoms, phenyl, dimethylamine, Methoxy, ethoxy. Preferred alkyl groups R are those with 1-4 carbon atoms, such as methyl, ethyl, To mention propyl, dimethylaminopropyl, isobutyl and butyl.

As aryl groups R, both substituted and unsubstituted aryl groups into consideration, such as, for example, phenyl, 1-naphthyl and 2-naphthyl, which are each substituted can be through 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each with 1-4 carbon atoms, a Chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, Hydroxy or alkoxy group with 1-4 carbon atoms. The substituents in the 3- and 4-positions 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- can be in the 4-10 ring, preferably

Contain 5 and 6 carbon atoms. The rings can go through Alkyl groups may be substituted with 1-4 carbon atoms. Examples include cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl.

As heterocyclic groups R, there are 5- and 6-membered groups Heterocycles in question, of which those with a heteroatom, such as nitrogen, oxygen or sulfur in particular are preferred. Examples include: 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and others.

Physiologically acceptable acid residues come into consideration as the acid residue R. Preferred acids are organic carboxylic acids and sulfonic acids with 1-15 carbon atoms, those of the aliphatic, cyclo-aliphatic, aromatic, aromatic-aliphatic and heterocyclic series. These acids can be saturated, unsaturated and / or polybasic and / or be substituted in the usual way. Examples of the substituents are alkyl, hydroxy, Mentioned alkoxy, oxo or amino groups or halogen atoms.

The following carboxylic acids may be mentioned as examples: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, Valeric acid, isovaleric acid, caproic acid, enanthic acid, Caprylic acid, pelargonic acid, capric acid, undecylic acid, Lauric acid, tridecylic acid, myristic acid, pentadecylic acid, Trimethyl acetic acid, diethyl acetic acid, tert.-butyl acetic acid, Cyclopropyl acetic acid, cyclopentyl acetic acid, cyclohexyl acetic acid, Cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, Ethoxyacetic acid, mono-, di- and frichloroacetic acid, Aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, Morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, with halogen, trifluoromethyl,

Hydroxy, alkoxy or carboxy groups substituted benzoic acids, Nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. As particularly preferred acyl radicals those with up to 10 carbon atoms are considered. Examples of sulfonic acids are methanesulfonic acid, Ethanesulphonic acid, isopropanesulphonic acid, ß-chloroethanesulphonic acid, Butanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, Benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, N, N-dimethylaminosulphonic acid, N, N-diethylaminosulphonic acid, N, N-bis- (ß-chloroethyl) -aminosulphonic acid, N, N-diisobutylaminosulphonic acid, N, N-dibutylaminosulphonic acid, Pyrrolidino, piperidino, piperazino, N-methylpiperazino and morpholinosulfonic acid in question.

The hydroxyl groups R ₉ and in W can be functionally modified, for example by etherification or esterification, it being possible for the free or modified hydroxyl groups in W to be in the α or Q position, and free hydroxyl groups being preferred. The radicals known to the person skilled in the art are suitable as ether and acyl radicals. Easily split off ether residues, such as, for example, the tetrahydropyranyl, tetrahydrofuranyl, α-ethoxyethyl, trimethylsilyl, dimethyl-tert-butylsilyl and tribenzylsilyl radical, are preferred. Possible acyl radicals are C ₁ -C alkanoyl radicals, such as, for example, acetyl, propionyl, butyryl or benzoyl.

The alkylene group D is straight-chain or branched-chain Alkylene radicals with 1-10, in particular 1-5, carbon atoms, which are optionally replaced by fluorine atoms or C.-C.-alkyl can be substituted especially in the 1- or 2-position. Examples include: methylene, fluoromethylene, ethylene, 1,2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1-methyl-tetramethylene, 1-methyltrimethylene, 2-methyl-trimethylene, 2-methyl-tetramethylene.

For salt formation with the free acids (R ^ = H) are inorganic and organic bases suitable as they are to the person skilled in the art for the formation of physiologically compatible salts are known.

Examples include: alkali hydroxides, such as sodium and potassium hydroxide, alkaline earth 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 carbacycline derivatives of the general formula I _1, characterized in that a) a compound of the general formula II,

S-J

η ^(n> '

where R _? , W and D have the meanings given above, X ₁ and X _n denote a CH_ group and B denotes a trans double bond or a -CH = CBr group, optionally after protecting any free hydroxyl groups present with a Wittig reagent of the formula III

O
Ph ₃ P = CH- (CH ₂ ) -C ^ 0 III,

converts and then optionally separates isomers in any order and / or releases protected hydroxyl groups and / or reesterifies, etherifies and / or re-solidifies an esterified carboxy group or converts a carboxy group into an amide or with a physiologically compatible base into a salt, or b) a compound of the general formula IV

COR

IV,

\ A. B-W-D-

where R ₁ , R _? , B, W and D have the meanings given above and X oxygen:
oxidized with selenium dioxide.

have and X is oxygen and X is the group CH,

The reaction of the compound of the general formula II with the Wittig reagent of the formula III, which can be obtained from the corresponding Phosphonium salt with methanesulfinylmethylsodium or methanesulfinylpotassium or potassium terU-butylate in dimethylsulfoxide or diraethylsulfoxide-tetrahydrofuran mixtures is produced at temperatures from 0 C to 100 ° C, preferably 20 C to 00 C, in an aprotic solvent or Mixture of solvents, preferably dimethyl sulfoxide, dimethylformamide or tetrahydrofuran. The separation of the resulting Z- and Ε-configured olefins (5 »6-Poaition) takes place in the usual way, for example by column or layer chromatography. In the case of the above-described Wittig olefination occurs when B is a -CH = CBr group, at the same time, with elimination of hydrogen bromide, the formation of the 13,1 ^ -acetylene bond.

The saponification of the prostaglandin ester is after the Methods known to those skilled in the art are carried out, for example using basic catalysts.

The introduction of the group -OR, for R., in which ^H ^ represents an alkyl group with 1-10 carbon atoms, is carried out according to the methods known to the person skilled in the art. The carboxy compounds (, S ^ = H) 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 diazo hydrocarbon in an inert solvent, preferably in diethyl ether, with the carboxy compound in the same or in a different inert solvent, such as methylene chloride. After the reaction has ended in 1 to 3 minutes, the solvent is removed and the ester is purified in the usual way. Diazoalkanes are either known or can be prepared by known methods [org. Reactions Vol. JJ, pages 389-39 * +

The introduction of the group OH for R _{1, in which R 1 represents} a substituted or unsubstituted aryl group, takes place according to the methods known to the person skilled in the art. For example, the carboxy compounds are reacted with the corresponding arylhydroxy compounds with dicyclohexylcarbodiimide in the presence of a suitable base, for example fyridine 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 prostecyclin derivatives of the general formula I with R. in the meaning of a hydroxyl group can with suitable amounts of the appropriate inorganic bases with neutralization in Salts are transferred. For example, when the corresponding PG acids are dissolved in water, which has the stoichiometric Amount of base contains, after evaporating the water or after adding a water-miscible solvent, for example Alcohol or acetone, the solid inorganic salt.

The amine salts are produced in the usual way. In addition the PG 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 was added to this solution. The salt is usually obtained in solid form or is isolated in the customary manner after evaporation of the solvent.

The functional modification of the free ΟΠ groups takes place according to the methods known to the person skilled in the art. To introduce the xether protecting groups, reaction is carried out, for example, with dihydropyran in methylene chloride or chloroform using an acidic condensation agent such as, for example, p-toluenesulfonic acid. The dihydropyran is used in excess, preferably in k ~ to 10 times the amount required theoretically. The implementation is usually at 0 C - J50 C after 15 - J> 0 minutes

completed. *

The acyl protective groups are introduced by one Compound of general formula I in a manner known per se with a carboxylic acid derivative, such as acid chloride, Acid anhydride, etc., converts "

The release of a functionally modified OH group to the compounds of general formula I takes place according to known methods Acid such as hydrochloric acid. To improve the solubility, a water-miscible inert organic solvent is expediently added. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferred. The cleavage is preferably carried out at temperatures between 2O ° C and 8O ⁰ C.

The cleavage of the silyl ether protective groups takes place, for example, with tetrabutylamraonium fluoride. All solvents and, for example, suitable tetrahydrofuran, diethyl ether, dioxane, methylene chloride U3W. The cleavage is preferably carried out ⁰ C and 80 ° C at temperatures between O.

The saponification of the acyl groups takes place, for example, with alkali or alkaline earth carbonates or hydroxides in an alcohol or the aqueous solution of an alcohol. Aliphatic alcohols come into consideration as alcohols, such as, for example, methanol, ethanol, Butanol, etc., preferably methanol. Ala alkali carbonates and hydroxides, potassium and sodium salts may be mentioned and are preferred however the potassium salts. As alkaline earth carbonates and hydroxides are for example suitable calcium carbonate, calcium hydroxide and barium carbonate. The implementation takes place at -IU C to? 0 C, preferably at 25 C.

The amide group NHR ₄₊ for R. is introduced by the methods known to the person skilled in the art. The carboxylic acids of the general formula I (R -, = H) are first converted into the mixed anhydride in the presence of a tertiary amine, such as, for example, triethylamine, with isobutyl chloroformate. The reaction of the mixed anhydride with the alkali salt of the corresponding amide or with ammonia (R ^ = H) takes place in an inert solvent or Lösungsmifefeelgemisch, such as tetrahydrofuran, dimethoxyethane, dimethylformamide, Hexamethylphocphorsäuretriamid, at temperatures between -3O ° C and + 6O ⁰ C , Preferably at 0 ° C to 30 ⁰ C.

Another possibility for the introduction of the amide group NHPk for R ^ consists in the reaction of a 1-carboxylic acid of the general formula I (R - ^ - sIl), in which free hydroxyl groups may be present are intermediately protected, with compounds of the general formula V, - _

0 = C = N - R ^ 'V ₁ where R ₁ ^ has the meaning given above.

The reaction of the compound of the general formula I (B «OH) with an isocyanate of the general formula V is carried out with the addition of a tertiary amine, such as, for example, triethylamine or pyridine. The reaction can without solvent or in an inert solvent, preferably acetonitrile, tetrahydrofuran, "acetone, dimethylacetamide, methylene chloride, diethyl ether, toluene, at temperatures between -80 ° C to 100 ⁰ C, preferably from 0 ⁰ C to 30 ⁰ C, be made .

If the starting product contains OH groups in the prostane residue, then these OH groups also made to react. If end products are ultimately desired, the free hydroxyl groups in the Proetanreet contain, one expediently starts from Auegangsprodukte in which these are preferably easily split off ether or Aoylreete are intermediately protected *

The compounds of the general formula II which are used as starting material can be prepared, for example, by an aldehyde of the formula VI is used in a manner known per se

ι ι

O O

b-

VI,

HO

OCOPh

with a phosphonate of the general formula VII

CH, 0 0 0

^{> S} S Il Il

P-CH -C-D- ^ VII,

wherein D has the meaning given above, in the presence a Deprotonierungsmxttels, such as sodium hydride or potassium hydride and optionally (for B in the meaning of a -CH = CBr group) of a brominating agent such as N-bromosuccinimide, to a ketone of the general formula VIII.

0 0

VIII

OCOBh

After reduction of the keto group with sodium hormide and optionally epimer separation, saponification of the ester group, for example with potassium carbonate in methanol and Ketal cleavage with aqueous acetic acid and, if appropriate, epimer separation lead to the ketone of the general formula mel

CH - D - <I IX

The etherification of the hydroxyl groups with ζ. B. Dihydropyran in the presence of catalytic amounts of p-toluenesulfonic acid, the compounds of the general formula II are obtained.

The phosphonates of the general formula VII are prepared in a manner known per se by reacting an ester of the general formula X.
0

Kr L / * ~ Ο * ~ xJ ~ "^ T J Λ. Ι

where D has the meaning given above and E ₁ - denotes an alkyl group with 1-5 carbon atoms, with the anion of methylphosphonic acid dimethyl ester.

The esters of general formula X are prepared in a manner known per se by reacting a terminal = CHp-01efins provided with a nucleofugal leaving group (eg chlorine, bromine, iodine, tosylate) with the anion of the optionally substituted malonic acid diester, methylenation with diazomethane / palladium acetate and subsequent decarbalkoxylation with, for example, lithium chloride / dimethyl sulfoxide / water. The cyclopropanation of the terminal = CH group can also take place in all reaction stages of the reaction sequence (unsaturated alcohols to unsaturated phosphonate).

The compounds of general formula IV used as starting material can be prepared, for example, by a known prostaglandin F derivative of the general formula XI in a manner known per se

^0H . ^

'COB,

• B

XI,

with iodine in the presence of an alkyl hydrogen carbonate or alkali metal carbonate to the compounds of the general formula XII

XII,

R.

implemented / J. Tömöskäzi et al., Tetrahedronletters, 2627 (1977) 7 «

The reaction of the compounds of the general formula XII to the compounds of the general formula IV can, for example with!, S-diazabicycloC3,4, G] nonene-5 (DBN) or 1,5-diazabycyclo [5,4,0] -undecene-5 (DBU) in an inert solvent such as benzene, toluene, tetrahydrofuran, etc. or with Sodium methylate take place in methanol. The elimination of hydrogen halide is carried out at temperatures between 0 ° C and 120 ° C, preferably at 20-60 ° C.

If end products are ultimately desired which contain free hydroxyl groups in the prostane residue, it is expedient to do so from starting products, in which these are intermediates by ether or acyl residues that are preferably easily split off are protected.

Implementation of the compound of general formula IV with selenium dioxide is at temperatures of 20-140 ° C, preferably at 50-120 ° C, in an organic solvent, preferably dioxane or tert-butanol in 0.5-10 hours

The saponification of the 7-Oxoprostacyclinester is after methods known to those skilled in the art are carried out, for example with basic catalysts. The introduction of the ester group in which R is an alkyl group with 1-10 carbon atoms represents, takes place according to the methods known to the person skilled in the art. The carboxy compounds are, for example, with diazo hydrocarbons implemented in a known manner. Esterification with diazo hydrocarbons takes place, for example by having a solution of the diazo hydrocarbon in an inert solvent, preferably in Diethyl ether with the carboxy compound in the same or in a different inert solvent, such as, for example Methylene chloride, mixed. After the reaction has ended in 1 to 30 minutes, the solvent is removed and the ester purified in the usual way. Diazoalkanes are either known or can be prepared by known methods will [Org. Reactions Vol. 8, pp. 389-394 (1954)].

The introduction of the ester group OR, for R ,, in which R represents a substituted or unsubstituted aryl group, takes place according to the methods known to the person skilled in the art. For example, the carboxy compounds with the appropriate Aryl hydroxy compounds with dicyclohexylcarbodiimide in the presence of a suitable base, for example tyridine or triethylamine, in an inert solvent implemented. The solvents used are methylene chloride, ethylene chloride, Chloroform, ethyl acetate, tetrahydrofuran, preferably Chloroform, in question. The reaction is carried out at temperatures between -30 ° C and + 50 ° C, preferably at + 10 ° C, carried out.

The V-oxoprostacycline derivatives of the general formula I with R-, meaning a hydrogen atom, can with appropriate amounts of the corresponding inorganic bases converted into salts with neutralization «/ ground. For example when the corresponding PG acids are dissolved in water, the stoichiometric amount of the base is obtained contains, after evaporation of the water or after the addition of 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, the PG acid is, for example, in a suitable Solvents, for example ethanol, acetone, acetonitrile, diethyl ether or benzene, and at least the stoichiometric amount of the amine was added to this solution. The salt is usually obtained in solid form or is isolated in the usual way after evaporation of the solvent.

The functional modification of the free OH groups takes place according to the methods known to the person skilled in the art. To introduce the ether protection groups, for example, dihydropyran in methylene chloride, benzene or chloroform using an acidic catalyst such as POCl ,, p-toluenesulfonic acid or anhydrous mineral acids implemented. The dihydropyran is used in excess, preferably in 2 to 10 times the theoretical requirement. The reaction is usually at 0 ° C to 30 ° C after Finished 15-30 minutes.

The acyl protective groups are introduced by adding a compound of the general formula I in a manner known per se Way with a carboxylic acid derivative, such as acid chloride, Acid anhydride, among others, in the presence of a tertiary amine base, such as pyridine, dimethylaminopyridine, etc. .

The release of a functionally modified OH group to the compounds of general formula I takes place after known methods. For example, the splitting off of the ether protecting groups in an aqueous solution is an organic one Acid, such as acetic acid, propionic acid, etc. or in an aqueous solution of an inorganic one Acid, such as hydrochloric acid. To improve the solubility, a with is expediently Water-miscible inert organic solvent added. Suitable organic solvents are, for example Alcohols such as methanol and ethanol and ethers such as dimethoxyethane, dioxane and tetrahydrofuran. Is tetrahydrofuran preferably used. The cleavage is preferably carried out at temperatures between 20.degree. C. and 80.degree.

The cleavage of the silyl ether protective groups takes place, for example, with tetrabutylammonium fluoride. As a solvent are for example suitable tetrahydrofuran, diethyl ether, Dioxane, methylene chloride, etc. The cleavage is preferably carried out at temperatures between 0.degree. C. and 80.degree.

The saponification of the acyl groups takes place, for example, with alkali or alkaline earth carbonates or hydroxides in one Ai '<ohol or the aqueous solution of an alcohol. As alcohols Aliphatic alcohols such as methanol, ethanol, butanol, etc., are preferred Methanol. Potassium and sodium salts may be mentioned as alkali metal carbonates and hydroxides, but the potassium salts are preferred. Suitable alkaline earth carbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and barium hydroxide .

The compounds of this invention are blood-relieving, killing and bronchodilating. They are still suitable for
Inhibition of platelet aggregation. Consequently ask
the new prostacyclin derivatives of formula I valuable
pharmaceutical active ingredients. In addition, with a similar spectrum of activity, compared to corresponding prostaglandins, they have a higher specificity and, above all, a significantly longer effectiveness. Compared to
PGI they are characterized by greater stability. the

high tissue specificity of the new prostaglandins
when examining smooth-muscular organs, "such as, for example, the guinea pig ileum or the isolated rabbit trachea, where significantly less stimulation can be observed than when applying natural prgstaglandins of the E, A or F type.

The new prostacyclin analogs have those for prostate »
cycline-typical properties, such as lowering of the peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and dissolution of platelet thrombi, myocardial cytoprotection and so on
Lowering of systemic blood pressure without lowering stroke volume and coronary blood flow at the same time; treatment
of stroke, prophylaxis and therapy of coronary heart diseases, coronary thrombosis, myocardial infarction, peripheral artery diseases, arteriosclerosis and thrombosis, therapy of shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion and cytoprotection
the gastric and intestinal mucosa; antiallergic properties, lowering of pulmonary vascular resistance and des
pulmonary blood pressure, stimulation of kidney bleeding, use in place of heparin or as an adjuvant in dialysis of hemofiltration, preservation of blood plasma, especially blood platelet, inhibition

birth pains, treatment of toxicosis of pregnancy, Increase in cerebral blood flow etc. Also own the new prostacyclin analogs have antiproliferative properties

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

When injected intravenously into conscious, hypertensive rats in doses of 5, 20 and 100 μg / kg body weight, the Compounds according to the invention have a stronger antihypertensive and longer-lasting effect than PGE "and PGA", without like PGE "diarrhea" or PGA "cardiac arrhythmias trigger.

When injected intravenously into anesthetized rabbits, the compounds according to the invention show in comparison to PGE_ and PGA “a stronger and considerably longer lasting Lowering blood pressure without affecting other smooth muscle organs or organ functions.

For parenteral administration, sterile, injectable, aqueous or oily solutions are used. For the oral For example, tablets, coated tablets or capsules are suitable for application.

The invention thus also relates to medicaments based on German compounds of the general formula I and more commonly Auxiliary and carrier materials.

The inventive active ingredients should be used in conjunction with the auxiliaries known and customary in galenics, e.g. for the production of blood pressure lowering agents.

example 1

5- / ΓΕ ) - ( 1S , 5S, 6R ₁ 7R) -7-hydroxy-6- / CE ) - (3S, 4RS) -3-hydroxy 6-cyclopropyl-4-methyl-hex-1-enyl7-bicyclo /3.397octan-3 ylidenj-pentanoic acid

A solution of ikk mg 5- / CE) - (1S ₁ $ S , 6R, 7R) -7-Tetrahydropyran-2-yloxy) -6- / rE) - (3S, 4RS> -6 ^ cyclopropyl * 5ii t / fftfä- hydropyran ^ -yloxyJ - ^ - methyl-hex-i-eny ^ -bicyclo / Bo.O? octan-3-ylidenepentanoic acid in 3.2 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10) is stirred for 23 hours at room temperature. It is then evaporated several times on a rotary evaporator with the addition of toluene and the residue is purified by column chromatography on silica gel with ethyl acetate / 0-1 % methanol as the mobile phase. 76 mg of the title compound are obtained as a colorless oil. '

IR (film): 3360, 3075, 3000, 2950, 2930, 2870, 286Ο, 2650, 1710, 970 / cm

The starting material for the above Tite! Connection is manufactured as follows:

a) ^ -Butene-l-ol-jD-toluene sulfonate

A solution of 21.63 g of 3-buten-l-ol and 4? \ <o6 g ^ -Toluenesulfonylchlorid in 100 ml abs. Chloroform is cooled ayf 0 ^p and treated with ^ 0.36 ml of pyridine within 10 minutes. The mixture is stirred for 3.75 hours at Räumempeeatur under argon and then concentrated in a mixture consisting of 200 g of ice and 70 ml. Poured hydrochloric acid, the Ch.lgrpioPm _F phase is separated off, washed neutral with water _? ^ dried over sodium sulphate and concentrated in vacuo. Man. receives 52.82 g of the title compound. : ■: .-.

Ifi: 298Ο, 1640, I600, 136Ο, 1175, II90, 1100, "" 96P, 900 ", 770 and 660 / cm. ■ ■ '■■ ·;

b) Ethyl 2-carbethoxy-2-methyl-5-hexenoate

In a 500 ml three-necked flask equipped with a reflux condenser, dropping funnel and stirrer, 8.2 g of sodium in 182 ml of abs. .Ethanol dissolved under argon. 6l.2 g of methyl malonate are added dropwise to the hot alcoholate solution, and the mixture is stirred at 100 ° C. for 50 minutes. The solution is cooled to about ^ to ⁰ ° C. and 83.29 g of the tosylate prepared according to Example 1a are added dropwise over the course of 10 minutes. The mixture is refluxed for 5 hours at the boiling point and the white precipitate is then filtered off with suction and washed with ethanol. The filtrate is diluted with 900 ml of ether and washed neutral with saturated sodium chloride solution. The organic solution is dried over sodium sulfate, concentrated in vacuo and then distilled. Obtained ί + 0, ΐ6 of the title compound, bp. -66 ⁰ C ^ 6 g (l.5mbar).

c) ethyl 2-carbethoxy-2-methyl-5,6-methylenhexanoate

A solution of 20 g of the olefin prepared in Example Ib in 600 ml of ethereal diazomethane solution (corresponds to approx. 500 mmol of diazomethane) is mixed in portions with 1 ^ 6 mg of palladium acetate at room temperature under argon. After 3 hours, the mixture is treated with 100 ml of diazomethane solution and ** 9 mg of palladium acetate and stirred for a further 16 hours at room temperature. The reaction solution is then largely concentrated in vacuo. The residue is filtered and washed with ether. The filtrate is dried over sodium sulfate and concentrated in vacuo. The residue is purified by distillation in a bulb tube. This gives 21.30 g of the title compound, bp. 85-90 ⁰ C (U Torr).

d) ethyl 2-methyl-5,6-methylenhexanoate

A solution of 10.91 g of the diester described in Example Ic in 82.5 ml of DMSO is mixed with 3.78 g of lithium chloride and 0.8 ml of water and the mixture is heated under argon at reflux temperature for k hours. The solution is then cooled to room temperature, and 80 ml of ice water are added. The aqueous solution

is extracted several times with an ether-hexane 1: 1 mixture and the organic extracts are combined with water and then washed neutral with half-saturated sodium chloride solution, dried over sodium sulfate and im Reduced vacuum. The residue is by distillation in Kugelrohr cleaned up. 51 S of the title compound is obtained, Bp 70-75 ° C (12 torr).

e) 2- (3-Cyclopropyl-1-methyl-propyl) -2-oxoethane-phosphonic acid-j dimethyl ester

A solution of 19-62 g of dimethyl methanephosphonate i 2 ^ 2 ml of abs. Of tetrahydrofuran is cooled to -65 ⁰ C and treated with 9 ^, 8 ml of butyllithium solution (1.68 M in hexane) under argon within 10 minutes was added. The solution is stirred for 15 minutes at this temperature and then with a solution of 8.30 g of the ethyl ester described in Example Id in 20 ml of abs. Tetrahydrofuran added. After h hours the mixture is warmed to -10 ° C. and 8.35 ml of ice cream are added. The reaction solution is partitioned between ether and water, the organic phase is separated off, dried over magnesium sulfate and concentrated in vacuo. The residue is distilled in a bulb tube at 170 ° C. (1.5 torr). 11.55 g of the title compound are obtained.
IR: 2950, 1710, 1 ^ 60, I26O, II80, I030, 875 and 805 / cm.

f) (iR, 5S, 6R, 7R) -3.3-ethylenedioxy-7-benzoyloxy-6- / Te) - (4RS) -o-cyclopropyl - ^ - methyl-hex-1-enyl7-bicyclo / 3 · 3 « 07octane

To a suspension of 7 ^ 3 mg of sodium hydride (55 % suspension in oil) in 71 ml of abs. Dimethoxyethane (DME) is added dropwise at room temperature within 20 minutes a solution of ₁ 9 ^ S 2- (3-cyclo propyl-1-methyl-propyl) -2-oxoäthanphosphonsäure "dimethyl ester in 36 ml DME (abs.) And rüb, rt; 2 stun ^the at room temperature under argon. Then added dropwise this solution within at -20 ^0C. 3Q minutes

to a solution of 5.0 g (1R, 5s, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo / 3.3.07octane in 71 ml of DME (abs.) and stir for 2.25 hours at -20 to -10 C under argon. Thereafter, the reaction mixture Poured onto 400 ml of saturated ammonium chloride solution, extracted several times with ether and the organic phase washed neutral with three times 75 ml of water, dried over magnesium sulfate and in vacuo evaporated. The residue is cleaned with hexane 150-100% ethyl acetate as a mobile phase. You get 4.27 g of the title compound as a colorless oil. IR (film): 3O7O, 2990, 2955, 2915, 287O, 1720, 1695,

1668, 1625, 1275, 1115, 715 / cm

g) (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-

- (3S, 4RS) -6-cyclopropyl-3-hydroxy-4-methyl-hexbicyclo / ^ · 3'07octane

To a solution of 4.27 g of the ketone prepared according to Example 1 f) in 130 ml of methanol is added at -40 ⁰ C in portions 2.22 g of sodium borohydride and stirred for 2.25 hours at -40 ⁰ C under argon. It is then diluted with ether, washed neutral with saturated sodium chloride solution and water, dried over magnesium sulfate and evaporated in vacuo. Column chromatography on silica gel with hexane / 50-100 % ether gives 2.66 g of the title compound as a colorless oil. (The diastereomeric 15β-hydroxyl compound obtained as a more polar component in the reaction is largely converted into the desired title compound by oxidation of manganese dioxide to the ketone a) and subsequent renewed sodium borohydride reduction.

IR (film): 3400 (broad), 3O7O, 2990, 296O, 287O, 1720, 1275, 1115, 970, 715 / cm

h) (1H, 5S, OR, 7R) - 3,3-ethylenedioxy-7-hydroxy-6- / rE) - ( 3S, 'HlS) -ö-cyclopropyl-O-hydroxy - ^ - methyl-hex-i -enyl7-bicyclo / 3.3.07octane '"' -

A mixture of 2.66 g of the prepared according to Example 1g) α-alcohol and 1.67 g of potassium carbonate (anhydrous) in 185 ml of methanol are stirred for 26 hours Room temperature under argon. Then majn im Vacuum, dilute with 2 liters of ether and wash with 4t brine and water neutral. It is dried over magnesium sulfate and evaporated in vacuo. This gives 2.4 * 1 g of the Title compound which was used in the next reaction stage without further purification. IR (film): 3400 (broad), 3Ο7Ο, 2970, 2940, 2680, 1120, 975 / cm

i) (IR, 5S, 6R, 7R) -7-Hydroxy-6- / CE) - (3S, 4RS) -6-cyciQp ^ opj 3-hydroxy-4-methyl-hex-1-enyl7-bicyclp5- / 3 · 3..p7pctane

The 2.44 g obtained in the previous reaction stage

the mixture is stirred for 7 hours at room temperature with 73 ral one Mixture of acetic acid / tetrahydrofuran / V water (65 + IO + 35) · Then you steam with the addition of Toluene several times in vacuo, dissolve the residue in methylene chloride, shake with brine, dry over Magnesium sulfate and concentrated to dryness in a vacuum The residue is chromatographed on Kie.s'eJ | el with Ethyl acetate as a superplasticizer. This gives T, -74 g of the Title compound as a colorless oil.

IR (film): 3390 (wide), 3Ο7Ο, 2990, 2955 » ΜΛΡ, 287Ο, 1735, 968 / cm - -

j) (1R, 5S, OR, 7R) -7- (tetrahydropyran-2-yloxy) -6- / ΓΕ) - (3S, 4RS) -6-cyclopropyl-3- (tetrahydropyran-2-yloxy) - k - methyl-hex-1-enylZ-bicyclo / ^ 3 · θ7octan-3-one

A solution of 1.74 g of the prepared according to Example 1 i) Ketones, 2.2 ml of dihydropyran (freshly distilled over potassium hydroxide) and 19.3 mg of p-toluenesulfonic acid in 65 ml of methylene chloride, the mixture is stirred for 2 hours at OC. Then it is diluted with Ether, shake with 4% sodium bicarbonate solution, washes neutral with water, dries over magnesium sulfate and evaporates in vacuo. After column chromatography on silica gel with ethyl acetate / hexane (l / l) as the flow agent, 2.49 g of the title compound is obtained. IR (film): 3Ο7Ο, 2935, 2870, 2845, 1738, 1125, 1075, 1030, 970 / cm

k) 5- 16E) - (1S, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) -6- / Te) - (3S, 4RS) -ö-cyclopropyl-3- (tetrahydropyran2-yloxy) -4-methyl-hex-1-eny ^ -bicyclo / ^ -3 «07octan-3-ylidenepentanoic acid

To a solution of 4.06 g of Ί-carboxybutyltriphenylphosphonium bromide in 8.5 ml of dry dimethyl sulfoxide (DMSO) is added 2.06 g of potassium t-butoxide under argon at 8 ° C. and stirred for 45 minutes at 2 ° C. A solution of 0.7 g of the ketone obtained in the previous reaction stage in 1 ml of abs is then added to the red Ylene solution. Tetrahydrofuran (THF) and stir for 2.25 hours at 32 ° C. The reaction mixture is stirred into 100 ml of water, adjusted to pH 4.5 with 2.5 ml of 35% citric acid solution and extracted four times with 100 ml of methylene chloride each time. The combined organic phases are washed with brine and water, dried over magnesium sulfate and evaporated in vacuo. After column chromatography of the residue on silica gel with hexane / 20-100% ethyl acetate as the eluent

one next to 125 mg of the more non-polar, Z-configured in position 5 Isomers 4 1 5 mg of the desired olefination product.

IR (film): 3070, 2990, 2955, 2920, 287Ο, 265Ο, 1710, 1125, IO75, 1025, 97Ο / cm.

Example 2 '·.:;,

5 - {(E) - (1S, 5S, 6Κ, 7iO-7-hydroxy-6- / CE) - (35, 4rS) -3-hydroxy-6-cyclopropyl - ^ - methyl-hex-i -eny_l7 - * 'l> ieyc.l0- / 3-3 .07octan-3-ylidenj -pentanoic acid (^ -pheriylphenacyl) ester V. ■■ "., -"

97 mg of the carboxylic acid obtained according to Example Ik) are dissolved in 2.5 ml of acetone and stirred together with 20 mg of triethylamine and 52.6 mg of p-phenylphenacyl bromide for 22 hours at normal temperature under argon. Then the ^; Reaction solution diluted with 25Ο ml of ether, washed twice with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue is in b , k'2. ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10) and stirred for 23.5 hours at room temperature. Then it is evaporated several times on a rotary evaporator with the addition of toluene and the residue is purified by column chromatography on silica gel with hexane / 50-100% ethyl acetate as the mobile phase. 6O.5 mg of the title compound are obtained. Melting point 63 - 6-5 C. IH (KDr): 3 ^ 30 (broad), 3Ο75, 30000, 2930, 2875, 1690, 1605, 1240, 972, 765 / cm.

Example 3

5-ί (E) - (1 S, 5S, 611, 7R) -7-hydroxy-6- / ÜE) - (3S, '± RS) - 3-hydroxyo-cyclopropyl - ^ - methyl-hex-1 -enyl7-bicyclo- / 3 · 3-07octan-3-ylideni-pentanoic acid- (2,3-dihydroxypropyl) -amide

102.6 mg of the carboxylic acid obtained according to Example 1 k) are added to 1 ml of acetone and 22 mg of triethylamine and stirred for 5 minutes under argon at room temperature. After cooling to ice bath temperature, 29.6 mg of isobutyl chloroformate in 0.4t ml of acetone are added and the mixture is stirred at this temperature for 20 minutes. The suspension obtained in this way is added at room temperature to a solution of 171.3 mg of 1-aminopropane-2,3-diol in 3 ml of acetone and 3 ml of acetonitrile. A clear solution is obtained after 10 minutes and is stirred for 1.5 hours at room temperature. After concentration in vacuo, the residue is taken up in 25Ο ml of methylene chloride, washed four times with 50 ml of saturated sodium chloride solution each time and then washed neutral with water. The organic phase is dried over sodium sulfate and concentrated to dryness on a rotary evaporator. To split off the ether protective groups, the residue (14n mg) is treated for 18 hours with 2.25 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10) at room temperature. Then it is repeatedly evaporated on a rotary evaporator with the addition of toluene and the residue is purified by column chromatography on silica gel with methylene chloride / 0-20% isopropanol as the mobile phase. 72.3 mg of the title compound are obtained.

IR (film): 3350 (broad), 3075, 3000, 293Ο, 287Ο, 1555, IO75, 972 / cm.

Example 4

7-0xo-16-methyl-19,20-methylene-ll, 15-di- (2-0-tetrahydropyranyl) -prostacyclin-methylester

A solution of 490 mg of the 16-methy described in Example 4h 1-19,20-methylene-II, 15-di «< 2-0-tetrahydropyranyl) -prost acyclin-m.'ethyl ester in 18 ml of dioxane is mixed with 138 mg of selenium dioxide and 0.18 ml of hexanemethyldisilazane were added and the mixture was stirred at 100 ° under argon. The reaction solution is then poured into ice water stirred and extracted with ether several times, pie organic Phases are combined, washed with half-saturated sodium chloride solution, dried over magnesium sulfate and in vacuo constricted. The crude product (525 mg) is on silica gel in a Hexane / 25% ethyl acetate gradient chromatographed. Further cleanup this product is carried out by preparative thin layer chromatography in a hexane / ethyl acetate mixture (5:15) as the mobile phase. You get 12? mg of the title compound as an oil. IR: 2920, 1740, 1718, 1640, 1440, 1350, 1040 / cm.

The starting material for example 4) is prepared as follows: 4a) (lS, 5R, 6R, 7R) -7-Benzoyloxy-6 - / (4RS) - (lE) -3-oxo-4-methyl-6-cyclopropyl- l-hexenyl / -2-oxabicyclo / 3.3.Q7pctan-3-one To a suspension of 1.14 g of sodium hydride K5Q ^ suspension in oil) in 130 ml of abs. Dimethoxyethane is a solution of 6.4 g of the phosphonate prepared according to Example Ie) in 24 ml of abs. Dimethoxymethane was added dropwise and the mixture was stirred for 2 hours with argon. The solution is then cooled to -20 ° C. and a solution of 5.70 g (IS, 5R, 6R, 7R) -6-formyl-7-benzoyloxy-2-oxabicyclo _< /3.3-Q7octan-3-one / j. Am.Chem.Soc. , 96 , 5865 (1974) / in 74ml abs. Dimethoxymethane was added and the mixture was stirred at -10 ° C. for a further 2 hours. After the reaction has ended, 1.5 ml of glacial acetic acid are added to the solution and the mixture is partitioned between ether and water. The aqueous phase is extracted several times with ether and the ether extracts are then washed neutral with half-saturated sodium chloride solution. The ether solution is washed with 2% sodium bicarbonate solution and finally with half-saturated

ter N; triurnch] orid solution washer ;. The organic phase is dried over magnesium sulfate and concentrated in vacuo. 17 g of the title compound are obtained as an oil. IR ^{:; J9 r} -O, 1770, 1720, l? IO, 1d '.> 0,] Ί6θ, l? 80, 715 / cm.

kb) (lS, 5R, 6R, 7R) -7-Benzoyloxy-6- / OS, ^ RS) - (lE) -3-hydroxy - ^ - methyl-6-cyclopropyl-l-hexenyl / -2-oxabicyclo / 3.3 »Q / octan-3-one A solution of 6.16 g of the ketone prepared in example '+ a) in 200 ml of methanol is cooled to -kO C under argon and treated with 3.799 g of sodium borohydride. The mixture is stirred for 0.5 hours, 0.0 ml of glacial acetic acid is added and the mixture is poured into ice water. The product is extracted with chloroform and ethyl acetate, the organic phases are combined, washed with dilute sodium bicarbonate solution and then with half-saturated sodium chloride solution. The extract is dried over magnesium sulfate and concentrated in vacuo. 6.79 g of a crude product are obtained which, after chromatography over silica gel in a pentane / ether gradient, yields 3.72 g of the title compound and 2.57 of the epirenic 15β-alcohol.

kc) (IS, 5R, 6R, 7R) -7-hydroxy-6- £ {3S, 'lRS) - (IE) -3-hydroxy-'tmethyl-6-cyclopropyl-1-hexenyl] -2-oxabicyclo £ 3.3, octan-3-one.

A solution of 50.82 g of the alcohol described in Example kh in 52 ml of methanol is mixed with 78.1 mg of anhydrous potassium carbonate and the mixture is stirred continuously at room temperature under argon. The solution is cooled to OC and 0.79 ml of conc. Hydrochloric acid are slowly added dropwise. The mixture is stirred for a further 10 minutes and then concentrated in vacuo at room temperature. The residue is dissolved in methylene chloride, the solution is dried over magnesium sulfate and concentrated in vacuo. 5 »521 g of a crude product are obtained, which is chromatographed over silica gel in a methylene chloride / methanol gradient. After purification, 3ι3θ6 g of the title compound were obtained as an oil .

IR: 3350, 2900, I75O, 1440, 1410, I36O, 1280, II70, IO8O, 1030, 975, 905 / cm

Example 4d

(IS, 5R, OR, 7R) -7- (Tetrahydropyran-2-yloxy) -6- £ (3S, 4RS) -3- (tetrahydropyran-2-yloxy) - ^ - methyl-o-cyclopropyl-1-hexenyl ^ -2-oxabicyclo Γ 3 ι 30 "Ί octan-3-one.

A solution of 313 ^ 6 g of the diol prepared in Example 4c) in 76.4 ml of abs methylene chloride is mixed with 2.47 ml of dihydropyran and 18.3 mg of j> - toluenesulfonic acid and the mixture is stirred for 45 minutes at room temperature. The solution is washed with cold, dilute sodium bicarbonate solution and then with water. The organic phase is dried over magnesium sulfate and concentrated in vacuo
5.548 g of a crude product are obtained, which is chromatographed over silica gel in a hexane / acetone gradient. After purification, 4.729 g of the title compound were obtained as
Obtain oil.

IR: 2930, 1760, 1430, 1150, II30, IO7O, 1020, 970, 900, 87O, 810 / cm

Example 4e

(2RS, 3aR, 4R, 5R, 6aS) -4- £ (35.4RS) - (IE) - 3- (tetrahydropyran
-2-yloxy) -4-methyl-6-cyclopropyl-1.hexenyl J- -2-hydroxy-5- (tetrahydropyran-2-yloxy) -perhydrocyclopenta [Vjfuran.
To a solution of 4.699 g of the lactone prepared in Example 4d) in 130 ml of toluene, 18.2 ml of a 20 % DIBAH solution in toluene are added dropwise under argon at -70 ° C. and the solution is stirred for 30 minutes. After the reaction has ended
1. Oil ml of isopropanol and 91/2 ml of water are added to the solution. The cooling bath is then removed and that
Mixture stirred for 2 hours at room temperature. The White
Precipitate is filtered off with suction, the residue is washed with methylene chloride and the filtrate is concentrated in vacuo.

One obtains ^, 99 ** 5? of a crude product that, without further purification is used in the next stage. IR: 3 ^ 00, 2900, lOO, 13'tO, 1250, 1190, 1130, 1070, 1020, 975, 910, 870, 81.5.7 '/ cm.

Example 4b f

(5Z, 13E) - (8R, 9S, llR, 12R, 15S, 16RS) -r9-hydroxy ~ ll, 15- <1i- (tetrahydropyran-2-yloxy) -16-methyl-19,20-methylene-5 , 13-prostadienoic acid methyl ester.

A solution of 35 ml of hexamethyldisilazane in 120 ml of absolute tetrahydrofuran is treated with 1 ^ 7 ml of a 1, 1K M-butyllithiutn solution under argon at -10 ° C. over a period of 50 minutes. This solution of hexamethyldisilazane-lithium is added dropwise within 15 minutes to a suspension of 37 g of carboxybutyltriphenylphosphonium bromide in 300 ml of absolute tetrahydrofuran at room temperature and stirred for about 10 minutes.A solution of ^, 9 ^ 6 g of the lactol prepared in Example k e) in 100 ml of absolute tetrahydrofuran is added all at once to the dark red ylid solution and the mixture is immediately warmed to ^ OC. When the reaction has ended (approx. 90 minutes), the solution is cooled and stirred into Ί 1 of a 10% sodium chloride / ice-water mixture. This mixture is acidified with 10% citric acid solution (pH k ^ -k) and extracted k times with 300 ml of ether each time. The ether extracts are extracted k times with 20 ml each of a 0.1 η sodium hydroxide solution, the aqueous extracts are acidified with citric acid and extracted with ether. Both organic phases are dried separately from one another over magnesium sulfate and concentrated. 9.855 g of a neutral portion are obtained, which is discarded, and 5.639 g of a free carboxylic acid which is converted into the corresponding methyl ester by treatment with ethereal diazornotian solution. After purification; of the crude product over silica gel in an acetone / hexane gradient, 27 g of the title compound are obtained as an oil.

XR: 3 ^ 00.2 900, 17'1O ₁ 1440, 1350, 1190, 1130, 1070, Io30,975,900 870.810 / cm " ¹ .

Example 4 g

Methyl- (5RS) -5-iodine-5- {(2RS, 3aR, 4R, 5R, 6aS) -4 - / (3S, 4RS) - (E) 3, - (tetrahydropyran-2-yloxy) - ^/ i -methyl-6-cyclopropyl-1-hexenylJ'-5- (tetrahydropyran-2-yloxy) -perhydrocyclopenta / * b / furan-2-yl} pontanoate.

A solution of 4.156 g of iodine in 14l ml of ether becomes within 20 minutes under argon to form a mixture cooled to 0 ° C. consisting of 1.382 g of the olefin prepared in Example 4f in 9,314 ml of ether, 165 ml of water and 9,774 g of sodium bicarbonate added dropwise and the solution stirred at 0 C for 5 hours. The mixture is then rinsed into a separatory funnel which Phases are separated and the aqueous sodium bicarbonate layer is extracted three times with ether. The ether extracts are combined and washed free of iodine with 5% sodium thiosulfate solution. The ether phase is continued with water and then washed with half-saturated sodium chloride solution, dried over magnesium sulfate and concentrated. You get 5.50 g of a crude product which, by means of column chromatography over silica gel in a hexane / 20% strength ethyl acetate gradient is purified. 5 »215 g of the title compound were obtained .

IR: 2900.17 30.1430,1340,1190,1160,1120,1080,1020,970,900,87O, 815 cm - * ¹ .

Example 4 h

19,2O-methylene-16-methyl-ll, 15-di- (2-0-tetrahydropyranyl) -prostn ^ yclin-methyl ester.

Kino solution of 716 mg of the one described in Example 4 g) Jodiithors in fi ml of benzene is mixed with 1.2 ml of diazobicycloundecene vorsetzt and the mixture for 2 hours at 5Ο-6Ο C under argon

touched. After the reaction has ended, the solution is diluted with ethyl acetate and the organic phase with water several times washed. 590 mg of a crude product are obtained without further purification is used in the next stage.

IR: 2900.1720, 1680.1 / 4, 30.134O, I300, 1290.1230, II90, II60, II30, IO7O, 1020, 970, 920, 87O, 815 / cm.

Example 5

7-Oxo-19 »m ^20-i ethylene-l6-methylprostacyclin-rmethylester.

A solution of 100 mg of the prostacyclin derivative described in Example 4 is dissolved in 80 ml of a mixture consisting of acetic acid-tetrahydrofuran-water 35 * 10: 65 and 15 hours stirred at room temperature in vacuo under argon. The solution is then concentrated in vacuo at room temperature and the raw product on preparative thin-layer plates Purified in a chloroform / ether mixture (9 ^ 1) as the mobile phase . 97 mg of the title compound are obtained.

IR: 3350,2900,1720, 1640, 1430,1350,1250,1170, lo60,1010,965, 730

Example 6
7-0x0-19,20-methylene-16-methylprostacyclin-methyl ester.

A solution of 83.9 mg of the Methylesters described in Example 5 is dissolved in 3, S ml of methanol and 0.37 ml of an aqueous 10% potassium hydroxide was added. The mixture is stirred under argon for 21 hours and then concentrated in vacuo at room temperature. 10 ml of water are added to the residue and the solution is extracted with ether. The ether - '' has been discarded, the aqueous layer acidified with 10% citric acid solution and extracted with ether. The ether solution is dried over magnesium sulfate and concentrated. 66 mg of a crude product are obtained which, after purification over preparative thin-film plates in a chloroform / ethanol mixture (9: 1) as the mobile phase, yields 40 mg of the title compound.

IR: 3 ^ 00 (broad), 2930, 1740, 1710, 1670, 1430, 1370.970 / cm.

Claims (3)

Claims 19, 20-Methylenprostacyclinderiv / ate the general Formula I. COR ₁ (D, wherein R ₁ denotes the radical OR, and / or R, hydrogen or optionally _{substituted by halogen, phenyl, C 1} -C. -alkoxy or C 1 -C.-dialkylamino, alkyl having 1-10 carbon atoms, cycloalkyl, aryl or a heterocyclic one May mean remainder, or the remainder NHR. with R. represents a hydrogen, alkyl, cycloalkyl or aryl or an alkanoyl or alkanesulfonyl radical with 1-10 carbon atoms each, A is a -CH ₂ -CH ₂ -, trans-CH = CH group or -C = C group, H CH ₃ W is a - £ - or a -C- group in which the OH group is OH OH each with -iinem benzoyl or alkanoic acid radical with 1-4 C-atoms esterified or with a tetrahydropyranyl, tetrahydrofuranyl, alkoxyalkyl or trialkylsilyl radical can be etherified, u / whether the free or esterified OH group can be in the α or ß position, D a direct bond or a straight chain or branched alkylene group with 1-10 carbon atoms, R "is a hydroxy group which can be esterified with an alkanoic acid radical with 1-4 C atoms or etherified with a tetrahydropyranyl, tetrahydrofuranyl, alkoxyalkyl or trialkylsilyl radical, X" the group CH "or oxygen, X" the group CH or C = O
and, if R is hydrogen, their salts with physiologically compatible bases. 2. Medicines consisting of one or more compounds according to claim 1 and customary auxiliaries and carriers. 3. Process for the preparation of compounds of the formula I, characterized in that one a) a compound of the general formula II (II), ^R 2 wherein R ", W and D have the meanings given above have, X, and X "a CH" group and B a trans double bond or a -CH = CBr group, optionally after protection of any free hydroxyl groups present with a Wittig reagent of the formula III Ph, P = CH- (CH,), -C ^ © (III), converts and optionally then separates isomers and / or protected hydroxyl groups in any order releases and / or free hydroxy groups esterified, etherified and / or a carboxy group in an amide or with a physiologically acceptable base converted into a salt, or b) a compound of the general formula IV COR ₁
3 «1» 2 (IV), B-W-I where R ₁ , R ₇ , B, W and D have the meanings given above and X _{1 is} oxygen and X "is the group CH", oxidized with selenium dioxide.