DD201884A5 - PROCESS FOR THE PREPARATION OF CARBACYCLINE DERIVATIVES - Google Patents

Abstract

1. Claims for the contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Carbacyclin derivatives of the general formula I see diagramm : EP0057660,P15,F5 wherein R1 is the group OR2 , where R2 is hydrogen or alkyl of 1-4 carbon atoms, or the group NHR3 , where R3 is acetyl, methanesulfonyl or hydrogen, W is a hydroxymethylene group or a see diagramm : EP0057660,P15,F6 group, in which the OH is in the alpha- or beta-configuration, D is a straight or branched chain alkylene group of 1-5 carbon atoms, R4 is alkyl of 1-7 carbon atoms, and when R2 is hydrogen, salts of these compounds with physiologically acceptable bases. 1. Claim for the contracting State : AT Process for the preparation of the carbacyclin derivatives of the general formula I see diagramm : EP0057660,P17,F1 wherein R1 is the group OR2 , where R2 is hydrogen or alkyl of 1-4 carbon atoms, or the group NHR3 , where R3 is acetyl, methanesulfonyl or hydrogen, W is a hydroxymethylene group or a see diagramm : EP0057660,P17,F2 group, in which the OH is in the alpha- or beta-configuration, D is a straight or branched chain alkylene group of 1-5 carbon atoms, R4 is alkyl of 1-7 carbon atoms, and when R2 is hydrogen, salts of these compounds with physiologically acceptable bases, characterised in that a double bond is introduced in known manner in the 2-position into a compound of general formula II see diagramm : EP0057660,P17,F3 by reacting it with a lithium alkylamine of general formula III see diagramm : EP0057660,P18,F1 wherein R8 and R9 are alkyl of 1-10 carbon atoms, cycloalkyl of 3-6 carbon atoms or a trialkylsilyl group in which the alkyl is of 1-4 carbon atoms, treating it with a phenyl compound of general formula IV see diagramm : EP0057660,P18,F2 in which R10 is the group see diagramm : EP0057660,P18,F3 see diagramm : EP0057660,P18,F4 or -Se-Br and oxidising it, and then optionally, and in an arbitrary sequence separating the isomers, and/or freeing protected hydroxy groups, and/or esterifying or etherifying free hydroxy groups, and/or esterifying a free carboxyl group and/or saponifying an esterified carboxyl group or converting a carboxyl group into a -CONHR3 group or into a salt with a physiologically acceptable base.

Description

AP A 61 K / 237 115/4 60 314/12

Process for the preparation of carbacyclene derivatives Field of application of the invention

The invention relates to the preparation of novel prostacyclin derivatives which can be used as medicaments with different directions of action,

Cha ^ akteristi kd he _m knownη tec h nasche n ^ j-solun en

In DE-OS'28 45 770, 290O 352/29 02 442, 29 04 655, 29 09 08S and 29 12 409 (5H) - and (5Z) ~ 6a-carba ~ prostaglandin -! "- analogues are described , The nomenclature of the compounds according to the invention is based on a proposal by Hort on and Brokovv (D. Org, Chem. 44, 2880 (1979)). The synthesis of these compounds always produces two double-bond isomers, which are characterized by the addition of (5E) or (5Z). The two isomers of this prototype are illustrated by the following structural formulas:

COOH COOH

OH

OH

OH

OH

(5E) -5a-Carbaprostagland In-I ₉ (OZJ-ea-Carbaprostaglandin-Io

Y / I

4,5,1982

AP ^Α 61 Κ / 237 116/4

60 314/12

From the?, Much more extensive. Matter hereof technology o'er ¹ prostacyclins and their analogs white man. That this class is suitable due to their biological and pharmacological properties for treating mammals, including humans. Their use as a drug, however, often encounters difficulties because they have a too short duration of action for therapeutic purposes.

Aim of the E rfin du ng

All structural changes have the goal to increase the duration of action as well as the selectivity of the efficacy,

Presentation of the VVeSe ₁ PS _{1 of} the invention

The invention has for its object to provide processes for the preparation of new Carbacyclinderivate *

It has now been found that by introducing a double bond into the 2,3-position of the carbacycline a longer duration of action, greater selectivity and better efficacy can be achieved. The compounds according to the invention have an antihypertensive and bronchodilating effect. They are also suitable for the inhibition of platelet aggregation, vasodilation and inhibition of gastric acid secretion.

The new Carbacyclinderivate correspond to the general formula I.

05/04/1982

AP A 61 K / 237 116/4

60 314/12

R _{1 is} the radical OR_, where R _{2 can} denote hydrogen, alkyl, cycloalkyl, aryl or a heterocyclic radical, or the radical NHR_ with R 1 in the meaning of an acid radical or hydrogen atom,

A represents a -CFU-CH-, tränS-CH = CH- or -CsC group,

1 6

W is a free or functionally modified hydroxymethylene group or a free or functionally modified

-C group, where the OH group may be α or β-one, OH

a straight-chain or branched, saturated ^^ tess © g & s & alkylene group having 1-10 C atoms, which may optionally be substituted by fluoro atoms ^ Y,

E is a -C = C bond or a -CRg = CR group, where Rg and S ₇ are different and denote a hydrogen atom or an alkyl group having 1-5 C atoms,

R is an alkyl, cycloalkyl, or an optionally substituted aryl or a heterocyclic group,

c is a free or functionally modified hydroxy group, and, if IL has the meaning of a hydrogen atom, their salts with physiologically acceptable bases.

The compounds of formula I represent both (5E) and (5Z) isomers.

As alkyl groups R _? are geraji- or branched-chain alkyl groups having 1-10 C atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, eexyl, decyl.

The alkyl groups R 1 - may optionally be monosubstituted to polysubstituted by halogen atoms, C ₁ -C 4 alkoxy groups, optionally substituted C 1 -C 4 -aryl groups, di-C ₁ -C 4 -alkylamines and tri-C ₁ -C -alkylammonium , Preferred are those alkyl groups which are monosubstituted.

Examples of suitable substituents are fluorine, chlorine or bromine atoms, phenyl, dimethylamines, diethylamino, methoxy, xthosy.

Preferred alkyl groups R 1 are those having 1 k carbon atoms, such as, for example, methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, butyl. Suitable aryl groups B- include both substituted and unsubstituted aryl groups, for example phenyl, 1-naphthyl and 2-naphthyl, each of which may be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each having 1 -A C atoms, a · Chiormethyl-, fluoromethyl, trifluoromethyl, carboxyl, hydroxyl or alkoxy group with 1-k C atoms. Preferably, the substituents in the 3- and ^ -position on the phenyl ring, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in ^ f-position by hydroxy. The cycloalkyl group R - may contain in the Jf-IO, preferably 5 and 6 carbon atoms. The hinges may be substituted by alkyl groups of ± k carbon atoms. Examples which may be mentioned are cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl. Suitable heterocyclic groups Bp are 5- and 6-membered heterocycles which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples which may be mentioned are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, k- pyridyl and others

Physiologically acceptable acid residues come in as hemmercest R_, question. Preferred acids are organic carboxylic acids and sulfonic acids having 1-15 carbon atoms which belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic and heterocyclic series. These acids can be saturated, un ~. saturated and / or polybasic and / or substituted in the usual way. As examples of the substituents there may be mentioned C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, oxo or amino groups or halogen atoms (F, Cl, Br).

Examples which may be mentioned are the following carboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, ollanic acid, capric acid, pelargonic acid, capric acid, undecynic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid.

16

acid,. fcert.-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid; Phenylacetic acid, phenoxyacetic acid .; Methoxylic acid, ethoxyacetic acid, mono-, di- and trichloroacetic acid, arainoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acids substituted by halogen, trifluoromethyl, hydroxy, alkoxy or carboxy groups, nicotinic acid , Isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid AIs particularly preferred acyl radicals are considered to be those having up to 10 carbon atoms. As sulfonic acids for example methanesulfonic come ο acid tert. acid, ethanesulfonic acid, Isopropansulf oic acid, ß-Chloräthansulfonsäure, butanesulfonic acid, Cyclopentansulfonsäure cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, N, N-Dimethylaminosulfonsäure, N ₁ N-Diäthylaminosulfonsäure, Ν, Ν-bis- (.beta.-chloroethyl) -aminosulfonic acid, N, N-diisobutylaminosulfonic acid, N, N-dibutylaminosulfonic acid, pyrrolidino, piperidino, piperazine, N-methylpiperazino and Morpholinosulfonsäure in question.

The hydroxy groups R_ and in W may be functionally modified, for example by etherification or esterification, wherein the free or modified hydroxy groups in W cc- or may be dentate, wherein free hydroxy groups are preferred.

Suitable ether and acyl radicals are the radicals known to the person skilled in the art. Preference is given to easily removable ether radicals such as, for example, the tetrahydropyranyl, tetrahydrofuranyl, .alpha.-ethoxyethyl, triaethylsilyl, dimethyl-tert-butyl-silyl and tri-i-benzylsilyl radicals. As acyl radicals, the same v / ie for R, called in question; By way of example, mention may be made, for example, of acetyl, propionyl, butyryl, benzoyl. ·

As the alkyl group R ^ are straight and branched chain, saturated and unsaturated alkyl radicals, preferably saturated, having 1-10, in particular 1-7 C atoms, in question, optionally by

f-

optionally substituted aryl may be substituted. Examples which may be mentioned are methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, hexenyl , Benzyl and p-chlorobenzyl.

The cycloalkyl group E may contain in the ring ¹ I-IQ, preferably 5 and 6 carbon atoms. The rings may be substituted by alkyl groups having 1-k carbon atoms. Examples which may be mentioned are cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl.

As substituted or unsubstituted aryl groups S, are, for example: phenyl, 1-naphthyl and 2-N.aphthyl which may be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each containing ^l-2 * C -Atomen, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C 1 -C 4 alkoxy or hydroxy groups The substitution in the 3 and 3 position on the phenyl ring for the example by fluorine, chlorine, C-- is preferred. C, alkoxy or trifluoromethyl. or in the α-position by hydroxy. Suitable heterocyclic groups Rr are 5-membered 6-membered heterocycles which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples which may be mentioned are 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, k ~ pyridyl, 3-furyl, 3-thienyl and others

As alkylene group D are straight-chain or branched-chain, saturated srais ^ ipsESSgösfi ^^? Alkylenr este, preferably saturated with 1-10, in particular _l-5 C-atoms, in question, which may optionally be substituted by fluorine atoms ^. Examples which may be mentioned are: methylene, fluoromethylene, ethylene, 1,2-propylene, A'thyläthylen, trimethylene, tetramethylene, pentamethylene, 1-methyltetramethylene, 1-methyl-trimethylene.

• For salt formation with the free acids (R ^ = H), inorganic and organic bases are suitable, such as. they are known in the art for the formation of physiologically acceptable salts. For example

may be mentioned: alkali hydroxides, such as sodium and potassium hydroxide, Erdulkaiihydroxide 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 novel priester derivatives of the general formula I, which comprises reacting, in a manner known per se, in a compound of the general formula II,

COH ₁

GH

(II)

y "^ A-W-D-E-B ,,

introduces a double bond in the 2-position by reacting with a Lithiumdialkylamid of the general formula HJ,

^fi 8

N-Li (III),

wherein Rn and R _{q represent} an alkyl group having 1-10 carbon atoms or a cycloalkyl group having 3-6 carbon atoms or trialkylsilyl group with alkyl as meaning C -C, alkyl, with a phenyl compound of the general formula

(IV),

3 xt

in which H _{10 represents} the radicals -Se-Se-ZCo, -SS-ZqS or -Se-Br, treated umd oxidized and optionally subsequently in any order isomers, separates and / or releases protected hydroxy groups and / or esterified free hydroxy groups, etherified and / or esterifying a free carboxyl group and / or saponifying an esterified carboxyl group. or a carboxyl group in an amide or with a physiologically acceptable base in a salt.

Suitable alkyl groups Rg. And B "are all the groups mentioned for R_. The same groups should also be preferred. As cycloalkyl groups Rn and R _q with 3-6 C atoms are meant: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The reaction of the compounds of the general formula II with a lithium amide compound of the general formula II, preferably lithium diisopropylamide, is carried out in a manner known per se in an inert solvent or solvent mixture, such as e.g. Tetrahydrofuran, diethyl ether, Hexamethylphosphorsäurearnid, dimethoxyethane, etc., preferably tetrahydrofuran. The reaction is carried out at temperatures between -100 and 0 C, preferably -80 C to -50 C. The reaction with diphenyldiselenide, diphenyldisulphide or phenylselenylbromide takes place at temperatures between -100 C and + 30 C, preferably -70 C and 0 C. The oxidation of the resulting selenium compound is carried out with hydrogen peroxide in an inert solvent or solvent mixture such. Tetrahydrofuran, ethyl acetate, methyl acetate, methanol, ethanol, isopropanol, etc. at temperatures between -20 C and +60 C, preferably 0 C -30 C, wherein already decomposes the intermediate selenium oxide compound to form the Δ double bond.

The oxidation of the resulting sulfur compound is conveniently carried out with sodium periodate in the presence of an alcohol, such as methanol, Äthanol with the addition of water at temperatures between OC and 60 C, preferably 10 C to 30 C.

carried out. The decomposition of the sulfoxide formed in the Δ compound of general formula I is carried out at temperatures between JQ'Z and 120 C with the addition of a small amount of calcium carbonate in an inert solvent such as toluene, xylene, carbon tetrachloride, etc.

The saponification of the prostaglandin esters is carried out by the methods known to those skilled in the art, such as with basic catalysts.

The introduction of the ester group -OK for R ,, in which R- represents an alkyl group having 1-10 C atoms, is carried out by the methods known to those skilled in the art. The carboxy compounds are reacted, for example, with diazohydrocarbons in a manner known per se. The esterification with diazohydrocarbons 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 another inert solvent such as methylene chloride. After completion of the reaction in 1 to 30 minutes, the solvent is removed and the ester purified in a conventional manner. Diazoalkanes are either known or can be prepared by known methods. Theory Reactions Bd-- _8_, p. 389-39 ^ · (95 ^J +) 7

The introduction of the ester group -OR for R ₁ , in which R _? represents a substituted or unsubstituted aryl group, is carried out according to the methods known 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 pyridine or triethylamine, in an inert solvent. Suitable solvents are methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform, in question. The reaction is carried out at temperatures between -30 ⁰ C and + 50 ⁰ C, preferably at +10 C.

The prostaglandin derivatives of general formula I R a in the meaning of a hydroxy group can be converted into salts with suitable amounts of the corresponding inorganic bases with neutralization. For example, in dissolving the corresponding PG acids in water containing the stoichiometric amount of the base, after evaporation of the water or after addition of a water-impartable solvent, for example, alcohol or acetone, the solid inorganic salt is obtained.

The preparation of the amine salts is carried out in the usual manner. For this purpose, 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 is added to this solution. The salt usually accumulates in solid form or is isolated by evaporation of the solvent in a conventional manner. "

The functional modification of the free OH group is carried out by the methods known to the person skilled in the art. For the introduction of ether protecting groups, for example, is reacted with dihydropyran in methylene chloride or chloroform using an acid condensing agent such as p-toluenesulfonic acid. The dihydropyran is used in the upper part, preferably in h ~ to 10 times the theoretical requirement. The reaction is usually complete at 0 C - 0 C after 15-30 minutes.

The introduction of the acyl protecting groups is accomplished by reacting a compound of general formula I in a manner known per se with a carboxylic acid derivative such as acid chloride, acid anhydride and the like.

The release of a functionally modified OH group to the compounds of general formula I is carried out by known methods. For example, the removal of ether protecting groups in an aqueous solution of an organic acid, such as

2371 1 6 L,

for example, acetic acid, propionic acid, and the like. or in an aqueous solution of an inorganic acid, such as, for example, hydrochloric acid .. To improve the permeability, a water-miscible inert organic solvent is expediently added, for example alcohols, such as methanol and Ethanol, and ethers, such as dimethoxyethyldioxane and tetrahydrofuran.Tetrahydrofuran is preferably used.The cleavage is preferably carried out at temperatures between 20 ° C and 80 ° C.

The splitting off of the silyl ether protective groups takes place, for example, with tetrabutylammonium fluoride. Suitable solvents are, for example tetrahydrofuran, diethyl ether, dioxane, methylene chloride, etc. The cleavage 'is preferably carried out at temperatures between 0 C and 80 C.

The saponification of the acyl groups is carried out, for example, with alkali or alkaline earth carbonates or hydroxides in an alcohol or the aqueous solution of an alcohol. Suitable alcohols are aliphatic alcohols, such as, for example, methanol, ethanol, butanol, etc., preferably methanol. As alkali metal carbonates and hydroxides potassium and sodium salts may be mentioned, but are preferably the potassium salts. Examples of suitable alkaline earth metal carbonates and hydroxides are calcium carbonate, calcium hydroxide and barium carbonate. The reaction takes place at -1O ⁰ C to 70 C, preferably at 25 C.

The introduction of the amide group NUR-, for H-. takes place according to the methods known to those skilled in the art. The carboxylic acids of general formula I (R_ = H) are first converted in the presence of a tertiary amine, such as triethylamine, with isobutyl chloroformate in the mixed anhydride. The reaction of the mixed anhydride with the alkali metal salt of the corresponding amide or with ammonia (S 1 = H) is carried out in an inert solvent or solvent mixture, such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric acid.

• - / 3

retriamid, at temperatures between -30 C and +60 C _1, preferably at 0 C to 30 C.

A further possibility for the introduction of the amide groups NHR-, for R, consists in the reaction of a 1-carboxylic acid of the general formula I (R - = H), in which free hydroxyl groups are optionally intermediately protected, with compounds of the general formula V,

O = C = NR "V ₁ where R is as defined above.

The reaction of the compound of general formula I (H ₁ = OH) with an isocyanate of general formula V is optionally carried out with the addition of a tertiary amine, such as triethylamine or pyridine. The reaction can be carried out without solvent or in one. inert solvents, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetaraid, methylene chloride, diethyl ether, toluene, at temperatures between -80 ° C to 100 ⁰ C ₁ preferably bsi 0 ⁰ C to 30 C, made.

If the starting product contains OH groups in the prostane radical, these OH groups are also reacted. If end products are ultimately desired which contain free hydroxyl groups in the prostane radical, it is expedient to start from starting materials in which these are protected as intermediates by preferably easily cleavable A'ther or Aoylreste.

The compounds of the general formula II which serve as starting material can be prepared, for example, by reacting, in a manner known per se, an-Xeton of the formula VI

(VI)

wherein R, R_, A, W, D and Ξ have the meanings given above, optionally after protection of present free hydroxy groups with a Wit tig reagent of the general, - formula VII

and optionally subsequently esterifying the free carboxyl group. The reaction of the compound of general formula VI with the Wittig reagent of general formula VII, which is prepared from the corresponding Fhosponiumsalz with Methansulxinylmethylnatrium or Methansulfinylmethylkalium or potassium 1ert.-butoxide in dimethyl sulfoxide, at temperatures of 0 C to 100 C, preferably at 20 C to 80 ° C, in an aprotic solvent, preferably dimethyl sulfoxide or dimethylformamide made. The separation of the Z- and S-configured olefins thus obtained is carried out in the usual way, for example by column or layer chromatography.

The compounds of this invention have hypotensive and bronchodilatory effects. They are also suitable for inhibiting platelet aggregation. Consequently, the new prostacyclin derivatives of the formula I are valuable pharmaceutical active ingredients. In addition, they have a similar specific spectrum of action, compared with corresponding prostaglandins, a higher specificity and above all a significantly longer efficacy. Compared to PGI, they are characterized by greater stability

yf ··

- out. The high tissue specificity of the new prostaglandins is demonstrated by examination on smooth muscle organs, e.g. on the guinea pig ileum or on the isolated rabbit, where a much lower stimulation is observed than with the application of natural prostaglandins of the Ξ, A or F type. '

The new prostaglandin analogues have the properties typical of prostacyclin, such as lowering of peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and dissolution of platelet thrombi, myocardial cytoprotection and thus lowering of systemic blood pressure without simultaneously reducing stroke volume and coronary blood flow; Treatment of stroke, prophylaxis and therapy of coronary heart disease, coronary thrombosis, myocardial infarction, peripheral arterial diseases. Arteriosclerosis and thrombosis, therapy of shock, Inhibierur.g bronchoconstruction, inhibition of Mage.nsäure secretion cytoprotection of the gastric and intestinal mucosa \ antiallergic properties, lowering of the pulmonary vascular. Resistance and

- Pulmonary blood pressure, promotion of Kierendurchblutu_ng, instead of heparin or as adjuvant in the hemofiltration dialysis, preservation of Blutplasmakonser'wen, especially of platelet preserves, inhibition of labor pains, treatment of pregnancy toxikose, increase the

"ir

cerebral circulation, etc. In addition, the new prostaglandin analogs possess antiproliferative properties.

The dose of the compounds is 150 μg / kg / day when administered to the human patient The unit dose for the pharmaceutically acceptable carrier is 0.01-100 mg.

When administered intravenously to conscious, hypertonic subjects at doses of 5i 20 and 100 μg / kg body weight, the compounds of the invention show a greater hypotensive and long a n-P

S Prophylaxis and treatment of ischemic attacks of the CITS system. Cytoprotection in the liver and pancreas. The prostacyclins of the invention may also be used in combination, e.g. with: ß-blockers or diuretics are applied.

2371 16 4

holding effect as PGE and PGA without causing PGS ₂ diarrhea o.dez PGAp cardiac arrhythmias.

Upon intravenous injection to anesthetized rabbits pointer. the compounds of the present invention, in comparison to PGE and PGA, have a stronger and significantly longer lasting blood pressure effect without affecting other smooth muscle organs or organ functions.

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

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

The active compounds according to the invention are intended to be used in conjunction with the auxiliaries known and customary in galenics, e.g. serve for the production of hypotensives.

example 1

(2E, 5E) - (16RS) -2,3-didehydro-16-methyl-18, 18,19,19 · tetradehydro-oa-carba-prostaglandin-L-methyl ester

To a solution of 0.215 ml of diisopropylamine in 5 ml of tetrahydrofuran is added dropwise at -70 ° C 1.01 ml of a 1.3 molar butyllithium solution in hexane and stirred for 30 minutes at -75 ° C under argon. In this solution is added dropwise at -70 ° C, a solution of 0.48 g (5E) -

Prostaglandin ~ I ₇ -methylester-ll, 15-bis-tetrahydropyran-2-yl-ether) in 6 ml of tetrahydrofuran, stirred for 25 minutes at -70 ° C and then added dropwise a solution of 420 mg of diphenyldiselenide in 7 ml of tetrahydrofuran. The reaction mixture is stirred at -70 ° C. for 30 minutes, at 0 ° C. for 30 minutes, acidified to pH 6 with 3% sulfuric acid, extracted three times with ether, washed neutral with water, dried over magnesium sulfate and evaporated Vacuum. The residue is filtered with ether / hexane (1 + 1) over silica gel. This gives 0.4 g of the selenium compound as a yellowish oil.

For oxidation, a solution of 0.4 g of the selenium compound prepared above in 5 ml of ethyl acetate and 5 ml of tetrahydrofuran with 0.4 ml 30 foiger hydrogen peroxide solution and stirred for 4 hours at 25 ° E. Then diluted with ethyl acetate, once with 5 oiger sodium bicarbonate solution, washes

237116 4

neutral with water, dried over magnesium sulfate and evaporated in vacuo. This gives the bis-tetrahydropyranyl ether of the title compound as Ql, which is then stirred for 16 hours with 10 ml of a mixture of acetic acid, water / THF (65 + 35 + 10) at 20 ° C.

It is evaporated in vacuo and the residue is purified by preparative layer chromatography. With ether / dioxane (9 + 1) as eluant, 180 mg of the title compound are obtained.

as a colorless oil.

IR (CH 2 Cl 2): 3,600, 3,420 (wide), 2940,2865, 1720, 1660, 1604, 973 / cm.

The starting material for the above title compound is prepared as follows:

Example 1 a

(5E) - (16RS) -16-methyl 1-18,18,19,19-tetradehydro-6a-carba prostaglandin I_-11,15-bis (tetrahydropyran-2-yl ether)

To a solution of 30.4 g of 4-carboxybutyltripheny1-phosphonium bromide in 60 ml of absolute dimethyl sulfoxide (DMSO) is added dropwise at 15 ° C under argon 120 ml of a 1.04 molar solution of Methylsulfinylmethylnatrium in DMSO and stirred for 30 minutes at 20 ° C Red solution is added dropwise to a solution of 5 g (IR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3S, 4RS) -4-methyl-3- ( tetrahydropyran-2-yloxy) -oct-1-en-6-ynyl] -bicyclo [3.3, Q] -octan-3-one in 30 ml of absolute DMSO and stirred for 4 hours at 45 ° C. The reaction mixture is poured into ice-water , acidified to pH 4-5 with 10% citric acid solution and extracted three times with methylene chloride. The organic phase is shaken with brine, transferred

Dried magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel, with ether / hexane (1 + 1), 1.2 g of (5Z) - (16RS) -16-methyl-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I are initially obtained. 11,15-bis- (tetrahydropyran-2-yl-ether) as the polar component 2, 5 g of the title compound as a colorless oil.

IR: 3510 (wide), 2960, 2870, 1712, 973 / cm. Example 1 b

(5E) - (16R5) -16-M ethyl -18,18,19,19-tetradehydro-6acarba-prostaglandin-1 "-methylester-II, 15-bis- (tetrahydroxy)

hydropyran-2-yläther)

A solution of 0.5 g of the acid prepared according to Example 1 a in 25 ml of methylene chloride is added dropwise with stirring at 0 ° C with an ethereal Diazomethanlosung until permanent yellowing. After evaporation of the solvent, the residue is purified by chromatography on silica gel with hexane / ether (3 + 2) to give 0.48 g of the title compound as an oil.

IR: 1735, 975 / cm

Example 2

(2 £, 5E) - ( 16RS) -2,3-didehydro-16-methyl-18,18,19,19-tetradehydro-oa-carba-prostaglandin-I

110 mg of the methyl ester prepared according to Example 1 is stirred for 2.5 hours at 20 ° C with 3 ml of a solution

VP

237

of potassium hydroxide in ethyl alcohol and water (Her-.

Position: Dissolve 2 g of potassium hydroxide in 75 ml of ethanol and 25 ml of water. The mixture is then acidified to pH 4 with 10% citric acid solution, extracted three times with methylene chloride, and the organic extract is washed once with brine, dried over magnesium sulfate and concentrated by evaporation in a vacuum. Chromatography of the residue on silica gel with methylene chloride / isopropanol (9 + 1) as eluent gives 65 mg of the title compound as a colorless oil.

IR: 3600, 3400 (wide), 2930, 2870, 1705, '1655,1604,970 / cm ¹ ,

Example 3

(2 £, 5Z) - (16RS) -2,3-didehydro -16-methyl-18,18,19,19- tetradehydra-oa-carba-prostaglandin-1 "-methyl ester

In analogy to Example 1, from 0.62 g (5Z) - (IoRS) -

I-methyl ester-II, 15-bis- (tetrahydropyran-2-yl-ether) (prepared from the corresponding acid at 0 ° C with ethereal diazomethane solution according to Example 1 b) 0.28 g of the title compound as a colorless oil.

IR: 3600, 3400 (wide), 2940, 2865, 1720, 1662, 1605,972 / cm. Example 4

(2E, 5Z) - (16RS) -2,3-didehydro-16-methyl-18,18,19,19- tetradehydro-oa-carba-prostaglandin-1

In analogy to Example 2 is obtained from 150 mg of the methyl ester prepared according to Example 3 78 mg of

Title compound as a colorless oil.

IR: 3600, 3410 (wide), 2932, 2870, 1704, 1654, 1604.971 / cm.

Example 5 «

(2E, 5E) - (16RS) -2,3- dide-hydroxy-16,20-diniethyl-1 8,18,19,19-tetradehydro-6a-carba-prostaglandin- 1 -methylester

In analogy to Example 1, 1 g of (5E) - (16RS) -16,20-dimethyl-18,18,19,19-tefcradehydro-6a-carba-prostaglandin-I is obtained _. methyl ester II, 15-bis- (tetrahydropyran-2-yl-ether) 390 mg of the title compound as a colorless Q1.

IR: 3610, 3400 (wide), 2940, 2863, 1721,1660,1603,972 / cm.

The starting material for the title compound above is prepared as follows:

Example 5 a

(5E) - (16RS) -16,2Q-dimethyl-18,18,19,19-tetradehydro- 6a-carba-prostaglandin- III , 15-bis- (tetrahydropyran-

'.. ι ι ι ι ι ι ι. Ii _w

2-yläther)

To a solution of 15.2 g of 4-carboxybutyltriphenylphosphonium bromide in 30 ml of dimethyl sulfoxide (DMSO) is added dropwise at 15 ° C under argon 60 ml of a 1.04 molar solution of Methansulfinylmethylnatrium in DMSQ and stirred for 30 minutes at room temperature. A solution of '2.5 g (IR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [(E) - (3S, 4RS) -3- (tetrahydropyran) is added dropwise to the red solution of Ylen -

237116 4

2-yloxy) -4-methyl-non-1-en-6-ynyl] bicyclo [3,3,0] octan-3-one in 15 ml of DMSO and stirred for 4 hours at 45 ° C The reaction mixture is poured into ice-water, acidified to pH 4-5 with 10% citric acid solution and extracted three times with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel ^ is obtained with ether / hexane '; λ (1 + 1), first 590 mg (5Z) - (16RS) -16.20-Dimethyl-18, 18 ^ 19 ^ - tetradehydro- oa-carba-prostaglandin-1-11,15-bis- (tetrahydropyran-2-yl-ether) and, as a more polar component, 1.29 g of the title compound as a colorless oil.

IR: 35QO (br eit), 2960, 2870-, 1710, 972 / cm.

Example 5. b ^:

(5E) - (16RS) -16,20-dimethyl-18,18,19,19-tetradehydro-6a- carba-prostaglandin-I ₇ -methylester-II, 15-bis- (tetra- hydrazine)

hydropyran-2-ylather)

In analogy to Example 1b, 0.9 g of the acid prepared according to Example 5a give 0.85 g of the title compound as an oil.

IR: 2960, 1733, 974 / cm

Example 6

(2E, 5E) - (16RS) -2,3-didehydro-16,2-dimethyl-18,18,19,19- tetradehydro-oa-carba-prostaglandin-1

In analogy to Example 2 is obtained from 0.4 g of

237 1.1 6 A

according to Example 5 produced methyl ester 0.21 g of the title compound as a colorless oil.

IR: 3605, 3400 (wide), 2930, 2870, 1705, 1653, 1603, 970 / cm.

Example 7

(2E, 5Z) - (16RS) -2,3-didehydro-16,20-dimethy 1-18,18,19,19- tetradehydro-oa-carba-prastaglandin-1'-methyl ester

By analogy with Example! Obtained. 0.8 g of (5Z) - (16RS) -16,20-dimethy 1-18,18,19,19-tetradehydro-6a-carbaprostagandin-I "-methylester-ll, 15 -bis (tetrahydropyran-2-yl ether) (prepared from the corresponding acid with diazomethane ether solution according to Example 1 b) 0.38 g of the title compound as a colorless Ql.

IR: 3600, 3410 (wide), 2942, 2866, 1721, 1662.1605, 971 / cm Example 8

(2E _< 5Z) - (16RS) -2,3-didehydro-16,20-dimethyl-18,18,19,19- tetradehydro-6a-carba-prostaglandin-I ₂

In analogy to Example 2, from 0.18 g of the methyl ester prepared according to Example 7, 73 mg of the title compound are obtained as a colorless oil.

IR: 3600, 3400 (wide), 2930, 2870, 1705, 1654, 1603, 970 / cm.

2371 16 % '

Example 9

(2E, 5E) - (l6RS) -2,3-Didehydro-l6,2o-dimethyl-19,19,20,20-tetrade- hydro-6a-carba-prostaglandin-lp-methyl ester In analogy to Example 1 is obtained from 0.6g (5E) - (16S) -16,20-dimethyl-19,19,20 ^ O-tetradehydro-oa-carba-prostaglandin-1pmethyl ester-11,15-bis (tetrahydroprano-2-yl-ether) 250mg the title compound as a colorless oil

 IS: 3600, 3 ^ 00 (wide), 2935, 2860, 1720, 1662, 1660, 972 / cm.

The source material for the above title connection is made as follows:

Example 9a

(5E) - (L65S) -l6,20-dimethyl-19,19,20,20-tetradehydro-6a-carbaldestaglandin -Ip-11,15-bis- (tetrahydropyran-2-yl-ether) The procedure is analogous to that of Example 1a 3g of (IS, 5S, βΗ, 7 ^ 0-7- (tetrahydropyran-2-yloxy) -6 - / (S) - (3S, ^4-i HS) -3- (tetrahydropyran-2-yloxy) - ⁱ i-ethyl-non-1-en-7-ynyl / bicyclo / 3x3 oyoctan-3-one 650 rag (5Z) - (l6HS) -l6,2O-dimethyl-19,19,20, 20-tetradehydro-6a-carbaprostaglandin-Ip-11,15-bis- (tetrahydropyran-2-yl ether) and, as a more polar component, 1.6 g of the title compound as a colorless oil: IH: 35IO (broad), 296Ο, 287Ο, 1708, 97l / cm.

Example 9b

(5E) - (l6RS) -l6,2O-dimethyl-19,19,20,20-tetradehydro-6a-carba prostaglandin-1'-methyl ester-11,15-bis (tetrahydropyran-2- yl ether )

In analogy to Example Ib is obtained from 1.6 g of the acid prepared according to Example 9a 1, ^ 5 g of the methyl ester as a colorless oil.

IE: 296Ο, 173 ¹ +, 973 / cm.

2371 16 4 if

Example 10

(2E, 5E) - (l6BS) -2,3-didehydro-l6 ₁ -20-diethyl-19,19,20,20-tetra- dehydro-öa-carba-prostaglandin-I,

In analogy to Example 2 is obtained from 0.2 g of the methyl ester prepared according to Example 9 0.12 g of the title compound as a colorless oil

 IB: 3600, 3 * f00 (wide), 2932, 2868, 1704, I652, l602, 972 / cm.

Example 11

(2E, 5Z) - (l6-RS) -2,3 "di- dehydro-l6,20-dimethyl -19,19,20,20-tetra- dehydro-6a-carba-prostaglandin-1-methyl ester

Analogously to Example 1, 0.95 g of (5Z) -166-dimethyl-19,19,20,20-1-etradehydro-öa-carba-prostaglandin-1-methyl ester 11,15 are obtained -bis (tetrahydropyran-2-yiether) (prepared from the corresponding acid with ethereal Diazoraethanlösung according to Example Ib) 0, k g of the title compound as a colorless oil. IB: 3600, 3 ^ 00 (broad), 29 ^ 0, 2865, 1721, I663, 10O5, 971 / cm.

Example 12

(2E, 5Z) - (l6RS) -2,3-didehydro-l6,20-dimethyl-19a9, 20,2Q-tetrade hydro-6a-prostaglandin-ip

In analogy to Example 2, nanoparaffin obtained from 0.3 g of the methyl ester prepared according to Example 11 gives 0.18 g of the title compound as a colorless oil

 IB: 3600, 3 ^ 10 (broad), 2903, 287I, 1704, 1653, - 16O3, 97l / cm.

Example 13

(2E ₁ 5E) - (l5B5) -2 ₁ 3-didehydro-l5-methyl-i8, l8, 19a-tetra- dehydro-6a-carba-prostaglandin-12-methyl ester In analogy to Example 1, from 0.5 g (5S) - (15RS) -15-methyl-l, 18, 19, 19-tetradeh. Hydro-6a-carba-prostaglandin-1-methyl-ethyl-ll, 15-bis (tetrahydropyran-2-yl) -ether 2 ^ 5 mg of the title compound as a colorless oil.

237116 A

Z6 IS: 3600, 3 ^ 05, 295 ^, 2858, I72O, 1660, 1600, 978 / cm.

The starting material for the above title compound is prepared as follows: Example 13a

' (5E) - (l5RS) -l5-methyl-l8 ₁ l8, l9il9-tetradehydrQ-6a-carba prostaglandin-l2-ll, 15-bis (tetrahydropyran-2-yl) ether

In analogy to Example 1a, 2.5 g of (IR, 5H, 6R, 7H) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3BS) -3- (tetrahydropyran- 2-yloxy) -oct-1-en-6-ynyl / bicyclo / 3 "3-Q / octan-3-one ~~ 0 mg (5Z) - (15fiS) -15-methyl-18, 18,19 lS-tetradehydro-oa-carba-prostaglandin-II, 15-bis (tetrahydrop2-rran-2-yl) -ether and, as a more polar component, 1.2 g of the title compound as a colorless oil, IE: 3580, 2965, 1710, 978 / cm.

Example 15b

(5E) - (L55S) -15-meth-1-18, l8,19,19-tetradehydro-6a-carba- prostaglandin-1-methyl ester-11,15-bis- (tetrahydropyran-€-yl) -ether

In analogy to Example Ib is obtained from 1.2 g of Example I33. 1.05 g of the methyl ester as a colorless oil

 IH: 2953, 2862, 1735, 976 / cm.

example

(2S ₁ 55) - (15S) -2,3-didehydro-15-methyl-18 ₁ l8, 19, 19-tetra-dehydro- 6a-carba-prostaglandin-I_

In analogy to Example 2, from 120 mg of the methyl ester prepared according to Example 13, 80 mg of the title compound are obtained as a colorless oil

IR: 3605, 3 ¹ HDO (wide), 29 ^ 8, 2862, 17ΟΟ, 165O ₁ 1602, 976 / cm.

Example 15

(2E, 5E) -2,3-didehydro-1,88,19,19-tetradehydro-6a-carba- prostaglandin-1-n-butyl ester

In analogy to Example 1 is obtained from 800 mg (5E) -l8,18,19,19-Te tradehydro-6a-carba-prostaglandin-1 _? -n-butyl ester -11,15-bis (tetrahydropyran-2-yl) -ether 370 mg of the title compound as a colorless oil

IH: 3600, 3 ¹ HO, 2960, 2852, 1722, 1662, 1602, 976 / cm.

The starting material for the above titanium compound is prepared as follows:

Example 15a

(5E) -18, l8,19, lg-tetradehydro-öa-carba-prostaglandin-lp-l, 15- bis- (tetrahydropyran-2-yl) ether ·· In analogy to Example la is obtained from 2, ^ 5 g (IR, 5S, 6H, 7H) -7- (tetrahydro-opyran-2-yloxy) -6 - / (E) - - (3S) -3- (tetrahydro-pyra-2-yl)

«- fr: '

yloxy) -oct-1-en-6-ynyl / bicyclo / 3 "3" 0 "" _{J "} octan-3-one" ¹ -OO; ng (5Z) -l8,18,19, lg-tetradehydro-toa- carba-prostaglandin-Ip-II, 15-bis (tetrahydropyran-2-yl) ether and, as a more polar component, 1.21 g of the title compound as a colorless oil

IH: 3585, 3 ^ 0O ₁ 296O, 285 ^, 1710, 976 / cm.

Example 15b

(5S) -l8,18,19,1-Tetradehydro-öa-carba-prostaglandin-1- butyl ester-11,15-bis- (tetrahydropyran-2-yl) ether. To a solution of Ig prepared according to Example 15a Acid in 30 ml of ether is added dropwise at 0 G an IM ethereal solution of diazobutane and the reaction is monitored by thin layer chromatography (silica gel plates with ethyl acetate / hexane / 3 + 7J " as eluent.) After complete reaction, evaporated in vacuo and the residue is purified by column chromatography on silica gel, using hexane with increasing ethyl acetate gradient, giving 0.91 g of the title compound as a pale yellow oil

 IR: 2962, 286O, 17 ^ 0, 978 / cm.

2371

Example 16

(2E, gE) -2,3-didehydro-l8,18,19,19-tetradehydro-6a-carba prostaglandin-ip

In analogy to Example 2, 250 mg of the butyl ester prepared according to Example 15 give 100 mg of the title compound as an oil

 IH: -3605, 3 ^ 10, 2952, 2860, 1702, 1652, 1602, 976 / cra.

At sOJel 17

(2E _r 5E) - (l6aS) -2,3-Didehydro-l6,19-dimethyl-l8,19-didehydro- 6a-carba-prostaglandin-1-methylester In analogy to Example 1, from Ig (5S) - (l62S) -l6,19-Dimethyl-l8,19-didehydro-6a-carba-prostaglanain-1-methyl ester-11,15-bis- (tetrahydropyran-2-yl) -ether. V30 mg of the title compound as a colorless oil

12: 36O5, 3 ^ 10 (broad) -, 2950, 2862, I718, I66O, 16O2, 97-k / cm.

The starting material for the above title compound is prepared as follows: Example 17a

(5E) - (l65S) -l6,19-dimethyl-l8,19-didehydro-6a-carba-prostaglan din-I ^ -ll, 15 ^Å bis- (tetrahydropyran-2-yl) ether In analogy to Example la is obtained from 3.5 S (1B, 5S> 6S, 7H) -7- (tetrahydropyran-2-yloxy) -6 - / '(S) - (3S, IFSS) -if, 7-dimethyl-3- ( tetrahydropyran-2-yloxy) octa-l, 6-dien-1-yl-7-bicyclo / "3" 3-0_7-octan-3-one 700 mg (^ Z) - (l6RS) -16,19-dimethyl- l8,19-didehydro-6acarba-prostaglandin-I-II, 15-bis- (tetrahydropyran-2-yl) -ether and, as more polar component, 1.8 g of the title compound as a colorless oil

 IB: 3600, 3 ^ 10, 2952, 28 ^ 8, 178, 978 / cm.

Example Γ / b

(5E) - (l6HS) -16,19-Dimethyl-1,88-didehydro. ~ 6 a-carba-pr ostaglan · - din-1 "-methyl ester 11,15-bis- (tetrahydropyran-2-yl) -ether

In analogy to Example Ib is obtained from 1.5 S of the acid obtained according to Example 17a l, k g of the title compound as an oil. IH: 2960, 28 ^ 2, 1738, -976 / cm.

Example 18

(2S, 5E) ~ (l6HS) -2 ₁ 3-Dideh y _dro-1 l6 19-dimethyl-l8,19-didehydro-6a-carba-prostaglandin-Ip

In analogy to Example 2 is obtained from 8OO mg of the methyl ester prepared according to Example 17, 550 mg of titanium compound as an oil

IE: 36ΟΟ, 3 * H0 (wide), 2958, 285 ^, 1700, 165O ₁ 1602, 978 / cm.

Example 19

(2E, 5E) - (l6RS) _-2-T 3 didehydro-l6-methyl-l8, l8,19,19-th tradehydro- 'öa-carba-prostaglandin-Ip-N-methanesulfonyl-carboxamide

A solution of 358 mg (2E, 5E) - (lions) -2,3-didehydro-l6-methyll8, l8, 19, ^ -tetradehydro-öa-carba-prostaglandin-I, in 8 al dimethylformamide is added at 0 ° C with I60 mg of isobutyl chloroformate and 120 mg of triethylamine. After 30 minutes, * f80 mg of the sodium salt of methanesulfonamide (prepared from methanesulfonamide and sodium methylate) and 2 ml of hexamethylphosphoric triamide are added and stirred at 25 C for 3 hours. The reaction mixture is then added to citrate buffer (pH 5)> extracted several times with ethyl acetate, the organic phase is washed with brine, dried over magnesium sulfate and concentrated by evaporation in a vacuum. Chromatography of the residue on silica gel with methylene chloride / isopropanol (9 + 1) gives 210 mg of the title compound as an oil

 IR: 3600, 3 ^ 50, I705, 16 ^ 5, 976 / ca-

237 1 1 6 ". Λ

Example 20

(2E ₁ 5E) - (l6aS) -2,3-didehydro-l6-methyl-l8, l8,19,19-tetradehydro- 6s-C3.I * b?. ~ PrOSt 3.τΐ3-ΠίϋΠ-I. ~ Ν- 3. C et """! - 9.SÜX d

To a solution of 2 ^ 8 mg (2E, 5E) - (16S) -2,3-didehydro-l6-methyl · 18, 18, 19, ^ -tetradehydro-öa-carba-prostaglandin-Ip-II, 15- bis- (tetrahydropyran-2-yl) ether in 8 ml of acetonitrile is added at 25 C 65 mg of triethylamine, then cooled to 0 C and added dropwise a solution of k-2 rag acetyl isocyanate in k ml of acetonitrile. The mixture is then stirred for 2 hours at 5 ° C engen concentrated in vacuo, diluted with 50 ml of water, acidified by adding IN sulfuric acid to pH k , extracted with ether, the organic phase is washed with brine, dried over magnesium sulfate and evaporated in vacuo , For deprotection the residue with 7 ml of glacial acetic acid / water / tetrahydrofuran is stirred (65/35 / IO) overnight at 3O ⁰ C and evaporated in a vacuum. The residue is chromatographed on silica gel with methylene chloride / 5/3 isopropanol. You get. 150 mg of the title compound as an oil

 IE: "36ΟΟ, 3VrO, 1β98, 16 ^ 5, 976 / cm.

Example 21

(2S, 5E) - (l6BS) -2,3-didehydro-l6-fflethyl-l8 ₁ l8,19,19-tetradehydro oa-carba-prostaglandin-Ip-carboxamide

Dissolve 398 mg (2E, 5E) - (L6SS) -2,3-didehydro-16-methyl-1,88,19,19-tetradehydro-6a-carba-prostaglandin-I in 5 ml of tetrahydrofuran and add ΐβΟ mg of triethylamine , and I80 mg of chloroamiser. acid isobutyl ester and allowed to stand at 0 G for one hour. Then ammonia gas is introduced for 10 minutes at 0 C and then left at 25 C for one hour. For working up, it is diluted with 100 ml of water, extracted several times with methylene chloride, the combined extracts are shaken with brine, dried over magnesium sulfate and evaporated in vacuo. It is purified by chromatography on silica gel with chloroform / ethyl acetate (8 + 2) and receives JiQQ mg of the title compound as an oil. IE: 36ΟΟ, 3510, 3IfIO ₁ 2958 ,. 2862, 1655, 976 / cm.

711 6

Example 22

(2E, 5E) - (i6RS -) - 2, 3-didehydro-l6-methyl-18, 18, 19, 1 9-tetradehydro-6a ~ carba-t; rostar], anda-1, -tri sin vdroxvTnethvl> arainoraet hansalz

To a solution of 100 mg (2E, 5S) - (l6HS) -2,3-dihydroxy-l6-methyll8,18,19) 19-tetradehydro-6a-carba-prostaglandin-I ₂ in 8 ml acetonitrile is added at 65 C, a solution of JO mg tris (hydroxymethyl) aminomethane in 0.1 ml of water. The mixture is allowed to cool with stirring, decanted after l6 hours from the solvent and the residue is dried in vacuo. 80 mg of the title compound are obtained as a viscous oil. , ,

Claims (1)

4.5,1982 AP A 61 K / 237 116/4 - ΊΑ - 60 314/12 Erf, and υ pci sanRo ruch ^ Process for the preparation of carbacyclene derivatives of general formula I COR
I ^X
CH CH ₂ CD. CH ^R 5 R is the radical OR ₂ , where Rp can denote hydrogen, alkyl, cycloalkyl, aryl or a heterocyclic radical, or the radical NHR with R-. in the meaning of an acid residue or hydrogen atom, A is a -CH ₂ -CH ₂ -, trans -CH = CH- or -CHC- group,. VV a free or functionally modified hydroxymethylene ^1, group or a free 'or functionally modified CH,
5 3 -C group, where the OH group can be i- or β-permanently OH, D is a straight-chain or branched, saturated or unsaturated alkylene group having 1 to 10 C atoms, which may optionally be substituted by fluorine atoms, 4 * 5 * 1982 AP A 61 K / 237 116/4 60 314/12 E represents a -C = C ~ bond or a CR "= CR_ group, where R, _ and R- are different and a hydrogen 6 7 atom or an alkyl group having 1 to 5 carbon atoms, R. "is an alkyl, cycloalkyl or an optionally substituted aryl or a heterocyclic group, R_ is a free or functionally modified hydroxy group, and, if R _{1 is} the meaning of a hydrogen atom_ has, their salts with physiologically acceptable bases, characterized in that, in a conventional manner in. A compound of general formula II COR (Cl-U) - CH A-W-D-E-R introduces a double bond in the 2-position by reacting with a Lithiuradialkylamid of the general formula III N-Li 4,5.1982 ^ u AP A 61 K / 237 116/4 237116 4 - ^ ~ ^{S0 3} wherein R _p and R _{0 is} an alkyl group having 1 to 10 Kohlenötü.r Γα tuiiidri or a Cycloaikylg group having 3 to 6 'carbon atoms or trialkylsilyl group with alkyl in the meaning C -C alkyl, is reacted with a Phenylverßindung the general Formula IV wherein R _{10 represents} the radicals' -Se-Se-ZO / * ~ S ~ S- / O or -Se-Br , treated and oxidized and optionally subsequently in any order isomers isomers and / or releases protected hydroxy groups and / or free Esterified hydroxy groups, etherified and / or e-ine free carboxyl group esterified and / or saponified an esterified carboxyl group or converted a carboxyl group into an amide or with a physiologically acceptable base in a salt.