NZ204875A - 6alpha-carbaprostaglandin-i2 homologues and pharmaceutical compositions - Google Patents

Abstract

Carbacylin derivatives of the general formula I in which R1 denotes a hydrogen atom or the radical OR2, in which R2 can denote hydrogen, alkyl, cycloalkyl, aryl, the radical or a heterocyclic radical, or R1 can denote the radical NHR3 where R3 denotes an acid radical or the radical R2, n can denote the number 2, 3, 4 or 5, X denotes a hydrogen atom or a fluorine atom, A denotes a -CH2-CH2-, a trans -CH=CH- or -C IDENTICAL C- group, W denotes a free or functionally modified hydroxymethylene group or a free or functionally modified group, in which the OH group can be in the alpha or beta position, D denotes the group a straight-chain, saturated alkylene group having 1-5 C atoms, a branched saturated or a straight-chain or branched unsaturated alkylene group having 2-5 C atoms, which may be substituted by fluorine atoms, m can denote the number 1, 2 or 3, E represents a direct bond, a -C IDENTICAL C- group or a -CR6=CR7- group, in which R6 denotes a hydrogen atom or an alkyl group having 1-5 C atoms and R7 denotes a hydrogen atom, an alkyl group having 1-5 C atoms or a halogen atom, R4 denotes an alkyl, cycloalkyl or a substituted or unsubstituted aryl group or a heterocyclic group, R5 denotes a free or functionally modified hydroxyl group, and, if R2 denotes a hydrogen atom, the salts thereof with physiologically acceptable bases, a process for their preparation and their use as pharmaceuticals.

Description

New Zealand Paient Spedficaiion for Paient Number £04875 * 204875 / o ~f .

Priority Oate(s): ... .v *' Complete Specification Filed: ../.•••••■ Class: - * ft 2 NOV 1986 Publication Date: J2 P.O. Journal, No: .^/"""" & ^ 12 JUL1983^ $ NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION "NOVEL CARBACYCLINS, PROCESS FOR THEIR MANUFACTURE AND THEIR USE AS MEDICAMENTS." We, SCHERING AKTIENGESELLSCHAFT, a body corporate organized according to the laws of Germany, of 170-178 Mullerstrasse, D-1000 Berlin 65, Germany and Waldstrasse 14, 4619 Bergkamen, Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed to be particularly described in and by the follov.-ing statement:- - 1 204375 - ifl- NOVEL CARBACYCLINS, PROCESS FOR THEIR MANUFACTURE The invention relates to carbacyclin derivatives, a process for their manufacture and their use as medicaments. according to the invention is based on a proposal by Morton and Brokow (J. Org. Chem. , 4_4, 2880 [1979]). The synthesis of these compounds always produces two double bond isomers which are characterised by the affix (5E) or (52). The two isomers of this prototype are illustrated by the following structural formulae: AND THEIR USE AS MEDICAMENTS The nomenclature of the compounds / C02H C02h HO OH HO OH (5E)-6a-carbaprostaglan- (5Z)-6a-carbaprostaglan din-I2 din-I2 2048 2 It is known from the very comprehensive prior art on prostacyclins and their analogues that this class of substance is suitable by virtue of its biological and pharmacological properties for the treatment of mammals, including human beings. Their use as medicaments often encounters difficulties, however, since they have too short a duration of action for therapeutic purposes. All alterations of the structure have the aim of increasing the duration of action and the selectivity of action.

We have now found that 3-oxa-carbacyclins that are homologous with respect to the upper chain can produce a longer duration of action, greater selectivity and an improved activity.

The present invention provides carbacyclin derivatives of the general formula 0 II 0 CH 2 I CX 4 R 20487 in which represents (i) a hydrogen atom, (ii) a radical of the general formula OR2 in which R^ represents a hydrogen atom or an unsubstitu-ted or substituted alkyl, cycloalkyl, aryl or heterocyclic radical, or (iii) a radical of the general formula NHR^ in which R^ represents an acyl radical or has the meaning given for R2, n represents the number 2, 3, 4 or 5, X represents a hydrogen atom or a fluorine atom, A represents a , trans-CH=CH- or -CEC- group, W represents a free or functionally modified hydroxy-methylene group or a free or functionally modified CH, } 3 -C- group, 1>H wherein the OH group may be in the a- or 0-configuration, 2 0 D represents (i) the group -C-CH^- wherein m represents the z m number 1,2 or 3 and wherein the carbon atom of the ring is attached to the radical represented by W, or 204875 (ii) a straight-chain or branched aliphatic hydrocarbon radical having up to 5 carbon atoms, which is unsubstituted or substituted by one or more fluorine atcrns, or (iii ) - CH - CH - \ / CH2 E represents a direct bond, a -C=C- group or a -CR6=CR7~ group, wherein R& and R? are different and R^ represents a hydrogen or a halogen atom or an alkyl radical having from 1 to 5 carbon atoms, and Rg represents a hydrogen atom or an alkyl radical having from 1 to 5 carbon atoms, R^ represents an aliphatic hydrocarbon radical, a cycloalkyl or alkyl-substituted cycloalkyl radical, an unsubstituted or substituted aryl radical or heterocyclic radical or an araliphatic hydrocarbon radical which is unsubstituted or substituted in the aromatic moiety, and Rt- represents a free or functionally modified hydroxy group, As a substituted alkyl radical represented by R2, -CH2-C0-aryl should especially be mentioned.

The present invention also provides salts of compounds of the general formula I, especially physiologically tolerable salts thereof. When R2 represents a hydrogen atom, for example, salt formation with a base is possible.

The compounds according to the invention have a hypotensive and bronchodilative action. They are also suitable for vasodilatation and for inhibiting thrombocyte aggregation and gastric acid secretion. 204875 It will be understood that the structural formulae and written nomenclature of the compounds described and claimed herein include, unless otherwise stated, the individual isomers and the mixtures of the isomers.

Thus, for example, the compounds of the general formula I are both (5E)- and (5Z)-isomers.

Suitable alkyl radicals represented by are, for example, straight- and branched-chain alkyl radicals having from 1 to 10 carbon atoms, such 10 as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl and decyl. Preferred alkyl radicals are those having from 1 to 4 carbon atoms. A methyl group should especially be mentioned. 15 A cycloalkyl radical represented by R2 may, for example, contain from 3 to 10, more especially 5 or 6, ring carbon atoms.

An alkyl or cycloalkyl radical represented by R2 may be unsubstituted or substituted by one 20 or more of the same or different substituents selected for example, from halogen atoms, hydroxy groups, (C^-C^)-alkoxy radicals, unsubstituted and substituted (C^-C^q)-aryl and aromatic heterocyclic radicals and di-(C^-C^)-alkylamino and tri-(-C^)-alkylammonium 25 radicals in which the alkyl radicals may be the same or different. Those alkyl groups that are 2 048 75 mono-substituted are preferred. An alkyl radical may also be substituted by a cycloalkyl radical and a cycloalkyl radical by one or more of the same or different alkyl or alkylene groups, preferably 5 having up to 4 carbon atoms each and being themselves unsubstituted or substituted as specified above.

Substituents that should especially be mentioned are, for example, fluorine, chlorine and bromine atoms, phenyl, dimethylamino, diethylamino, methoxy 10 and ethoxy groups.

Thus J*2 may represent, for example, a methyl, ethyl, propyl, dimethylaminopropyl, isobutyl or butyl group or a cyclopentyl, cyclohexyl, methylcyclo-hexyl or adamantyl group.

An aryl radical represented by R2 is, for example, a phenyl, 1-naphthyl or 2-naphthyl group and a heterocyclic radical represented by R2 is, for example, a 5- or 6-membered heterocycle, preferably aromatic and containing at least 1 hetero atom, preferably 20 nitrogen, oxygen or sulphur. There may be mentioned, for example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.

An aryl or heterocyclic radical represented by R2 or as a substituent of an alkyl or cycloalkyl 25 radical represented by R2 may be unsubstituted or substituted, for example by 1 to 3 halogen atoms, 204875 a phenyl group, from 1 to 3 alkyl groups each having from 1 to 4 carbon atoms, or by a chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy group or )-alkoxy radicals or by any combination of such substituents. Salt formation is possible when a carboxy substituent is present for example.

Fused rings should also be mentioned. Preferably, the substituents are in the 3- and/or 4-positions on the phenyl ring and are, for example, fluorine, chlorine, alkoxy or trifluoromethyl or, in the 4-posi-tion, hydroxy.

The aryl radical in the -CH--C-aryl radical 2 ii O represented by R2 may be a phenyl, a- or P-naphthyl group which may be unsubstituted or substituted, for example, by from 1 to 3 (C^-C4)-alkoxy radicals; 1 to 3 halogen atoms (F, CI, Br); or by 1 to 3 phenyl groups (which, in their turn, may be unsubstituted or substituted by 1 to 3 halogen atoms, e.g. F, Cl or Br, or by from 1 to 3 (C^-C^)-alkoxy radicals); or by any combination of such substituents. Mono-substitutions with phenyl, (C^ or C2)-alkoxy, chlorine or bromine are preferred.

An acyl radical represented by R^ is preferably a physiologically tolerable acid radical.

Preferred acids are organic carboxylic acids 204875 and sulphonic acids having from 1 to 15 carbon atoms, which belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic, cycloali'phatic-aliphatic, heterocyclic and heterocyclic-aliphatic series. These 5 acids may be saturated or unsaturated, mono- di- or poly-basic, unsubstituted or substituted in usual manner. Examples of substituents are halogen atoms (F, CI, Br), (C^-C^)-alkyl and (C^-C^)-alkoxy radicals, hydroxy, carboxy, phenoxy, oxo and amino groups 10 and amino groups substituted, for example, by one or two alkyl radicals or by an alkylene radical which may be interrupted by a hetero atom.

The following carboxylic acids may be mentioned by way of example: formic acid, acetic acid, propionic 15 acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, oenanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, penta-decylic acid, trimethylacetic acid, diethylacetic 20 acid, tert.-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxy-acetic acid, ethoxyacetic acid, mono-, di- and tri-25 chloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, 204875 lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acid substituted by one or more of the same or different substituents selected from halogen atoms, trifluoromethyl, hydroxy, alkoxy 5 and carboxy groups, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid and cyclopentylpropionic acid.

Suitable sulphonic acids are, for example, methanesulphonic acid, ethanesulphonic acid, isopro-10 panesulphonic acid, f3-chloroethanesulphonic acid, butanesulphonic acid, cyclopentanesulphonic acid, cyclohexanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, p-chlorobenzenesulphonic acid, N,N-dimethylaminosulphonic acid, N,N-diethyl-15 aminosulphonic acid, N,N-bis~({3-chloroethyl)-amino-sulphonic acid, N,N-diisobutylaminosulphonic acid, N,N-dibutylaminosulphonic acid, pyrrolidino-, piperi-dino-, piperazino-, N-methylpiperazino- and morpholino-sulphonic acid.

Especially preferred acyl radicals are those having up to 10 carbon atoms.

If the acid is, for example, dibasic, the resulting compound of the general formula I may contain a free carboxy group or the acyl radical may 25 be the acyl radical derived from this compound of the general formula I having the free carboxy group. 2048 75 The hydroxy group represented by R5 and the hydroxy group in W may, independently of one another, be functionally modified, for example by etherification or esterification; free hydroxy groups being preferred. Free or modified hydroxy groups in W may be in the a- or p-configuration.

Suitable ether-forming and acyl radicals are the radicals known to the person skilled in the art. Preferred ether-forming radicals are those that can be readily split off, such as, for example, the tetrahydropyranyl, tetrahydrofuranyl, a-ethoxy-ethyl, trimethylsilyl, dimethyl-tert.-butyl-silyl and tribenzylsilyl radicals. Suitable acyl radicals are for example those carboxylic and sulphonic acid acyl radicals mentioned for R^, for example acetyl, propionyl, butyryl and benzoyl.

An aliphatic hydrocarbon radical represented by R^ or an aliphatic hydrocarbon moiety in a radical represented by R4 may be straight-chain or branched, saturated or unsaturated, preferably saturated, radicals preferably having 1 to 10, especially 1 to 7, carbon atoms; the aliphatic radical may be unsubstituted or substituted by an unsubstituted or substituted aryl radical. Examples are methyl, ethyl, propyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, 204875 \ t pentenyl, hexenyl, benzyl and g-chlorobenzyl groups. Alkyl radicals having 1 to 4 carbon atoms are especially preferred.

A cycloalkyl radical1 represented by R4 preferably 5 contains 3 to 10, more especially 3 to 6, ring carbon atoms. The ring or rings may be substituted by one or more of the same or different alkyl radicals each having 1 to 4 carbon atoms. Examples are cyclo- C and propyl, cyclobutyl, cyclopentyl, cyclohexyl.! methylcyc- I I lohexyl.

An unsubstituted or substituted aryl radical represented by R4 or an aryl moiety in a radical represented by R4 is, for example, a phenyl, 1-naphthyl or 2-naphthyl group, each of which is unsubstituted 15 or substituted, for example by 1 to 3 halogen atoms, a phenyl group, 1 to 3 alkyl groups each having 1 to 4 carbon atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, (C^-C^)-alkoxy or hydroxy group or by a combination of such substituents.

Salt formation is possible when a carboxy substituent is present for example. Preferably, the substituents are in the 3- and/or 4-position on the phenyl ring and are, for example, fluorine, chlorine, (C^-C^)-alkoxy or trifluoromethyl or, in the 4-position, 25 hydroxy.

A heterocyclic radical represented by R4 is, t eSEP19SG: 204875 for example, a 5- or 6-membered heterocycle, preferably aromatic and containing at least one hetero atom, such as, for example, oxygen, nitrogen or sulphur.

There may be mentioned, for example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl and 4-pyridyl groups.

An aliphatic hydrocarbon radical represented by D may be straight-chain or branched, unsaturated or saturated, for example an aliphatic hydrocarbon radical containing a double bond, or, preferably, an alkylene radical; such radicals have up to 10, especially up to 5, carbon atoms, and are unsubstituted or substituted by one or more fluorine atoms or, in the case of an ethylene radical, by methylene bonded to the carbon atoms in positions 1 and 2 or by a (C2 to C5)-alkylene radical bonded to the carbon atom in position 1 (where position 1 is the carbon atom bonded to W). Thus, for example, D may represent a straight-chain .alkylene radical (i.e. saturated) having from 1 to 5 carbon atoms, or a branchea-chain saturated, or straight-chain or branched unsaturated, aliphatic hydrocarbon radical having from 2 to 5 carbon atoms, each of which is unsubstituted or substituted by one or more fluorine atoms, or, in the case of an ethylene radical, by 1,2-methylene or 1,1 -trimsthylene. There may be mentioned, for example: methylene,fluoromethylene, ethylene, 1,2-propylene, ethylethylene, trimethylene., 204875 tetramethylene, pentamethylene, 1-methyltetramethylene, 1-methyltrimethylene and 1,1-trimethyleneethylene.

An alkyl radical represented by R, and/or R_ o 7 may be a straight-chain or branched group preferably 5 having from 1 to 4 carbon atoms, such as those already O"" mentioned for R2 and R^. A halogen atom represented by r? may be chlorine or bromine, preferably chlorine.

Thus, DER^ may represent, for example, ch, ch, | 3 | -ch-ch2-c=c-ch3 , -ch-ch2-c=c-ch2-ch3 , ch, ch, I 3 ! -c-ch2-c=c-ch3 , -c-ch2-c=c-ch2-ch3 , ch3 ch3 ch3 ch3 / -CH-CH_-CH=C , C CH--CHC-CH, or 2 \ / \ 2 3 ch3 c^2 /ch2 ch2 C CH„-CsC-CH_CH, / \ 2 2 3 ch2 ch2 ch2 For formation of a salt of a compound of the 15 general formula I which contains a COOH group (e.g. when R2 represents a hydrogen atom), any inorganic or organic base may be used, for example a base known to the person skilled in the art for the 204875 formation of physiologically tolerable salts. There may be mentioned, for example: alkali metal hydroxides, e.g. sodium or potassium hydroxide; alkaline earth metal hydroxides, e.g. calcium hydroxide; ammonia; and amines, e.g. ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine or tris-(hydroxymethyl)-methyl amine.

For salt formation with other salt forming groups in the compound of the general formula I, 10 an appropriate reagent known to the expert may be used.

The invention also provides a process for the preparation of a carbacyclin derivative of the general formula I or a salt thereof, which comprises etherify-15 ing a compound of the general formula CH-OH in which X, R4, A, W, D and E have the meanings given above, in the presence of a base, optionally after protecting one or more free hydroxy groups 20 present, with a haloketal of the general formula 204875 OR 8 Hal-(CH2)n- III OR 9 in which Hal represents a chlorine, bromine or iodine atom, each of Rg and Rg represents an alkyl group having from 1 to 10 carbon atcms or Rg and Rg together represent a divalent radical _ having from 2 to carbon atoms and n has the meaning given above, and splitting the ketal with acid, and, if desired, one or more of the following reactions is then carried out, where appropriate, in any desired sequence, isomers are separated, one or more protected hydroxy groups is liberated, one or more free hydroxy grous is esterified or etherified, the aldehyde group is oxidised, the resulting free carboxy group is esterified, an esterified carboxy group is hydrolysed, a carboxy group is converted into an amide or is converted into a salt.

The reaction of the compound of the general formula II with a haloketal of the general formula III may be carried out in a manner known per se, suitably, for example, at a temperature in the range on * 16 SEP 1986 204875 of from 0°C to 100°C, preferably from 10°C to 80°C, in an aprotic solvent or mixture of solvents, for example dimethyl sulphoxide, dimethylformamide or tetrahydrofuran. Suitable bases are, for example, those known to the person skilled in the art for etherification reactions, for example sodium hydride, potassium tert.-butoxide and butyllithium.

Splitting of the ketal to form a compound of the general formula I after the etherification reaction may be carried out according to known methods. For example, the splitting of the ketal may be carried out in an aqueous solution of an organic acid, such as, for example, acetic acid or propionic acid, or in an aqueous solution of an inorganic acid, such as, for example, hydrochloric acid. To improve solubility, advantageously a water-miscible inert organic solvent is added. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Preferably tetrahydrofuran is used. The splitting of the ketal is preferably carried out at a temperature in the range of from 20°C to 80°C.

The oxidation of the aldehyde group may be carried out according to methods known to the person skilled in the art. Suitable oxidising agents are, 204875 for example, pyridinium dichromate (Tetrahedron Letters, 1979, 399), Jones reagent (J. Chem. Soc. 1953, 2555) and platinum/oxygen (Adv. in Carbohydrate Chem. 17, 169 (1962)).

Oxidation with pyridinium dichromate may be carried out for example at a temperature in the range of from 0°C to 100°C, preferably from 20°C to 40°C, in a solvent that is inert with respect to the oxidising agent, for example dimethyl-10 formamide.

Oxidation with Jones reagent may be carried out for example at a temperature in the range of from -40°C to +40°C, preferably from 0°C to 30°C, using acetone as solvent.

Oxidation with platinum/oxygen may be carried out for example at a temperature in the range of from 0°C to 60°C, preferably from 20°C to 40°C, in a solvent that is inert with respect to the oxidising agent, such as, for example, ethyl 20 acetate. m 2048 7 5 Hydrolysis of a carbacyclin ester may be carried out according to methods known to the person skilled in the art, such as, for example, using a basic catalyst.

Introduction of an ester group -0R2 representing R^, in which R2 represents an unsubstituted or substituted alkyl radical (generally having from 1 to 10 carbon atoms in the alkyl moiety), may be carried out according to methods known to the person skilled in the art. The carboxy compound may be reacted, for example, with a diazo hydrocarbon in a manner known per se, 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 inert solvent or in a different inert solvent, such as, for example, methylene chloride. After the reaction is complete, i.e. usually in from 1 to 30 minutes, the solvent may be removed and the ester purified in customary manner. The diazo-alkanes are known or may be manufactured according to known methods [Org. Reactions, Vol. 8, pages 389-394 (1954)]. m 204875 Introduction of an ester group -0R2 representing R^, in which R2 represents a substituted or unsubstituted aryl radical, may be carried out according to methods known to the person skilled in the art.

For example, the carboxy compound and the corresponding arylhydroxy compound may be reacted with dicyclohexyl carbodiimide in the presence of a suitable base, for example pyridine or triethylamine, in an inert solvent. Suitable solvents are, for example, methylene 10 chloride, ethylene chloride, chloroform, ethyl acetate and tetrahydrofuran, preferably chloroform. The reaction may be carried out, for example, at a temperature in the range of from -30°C to +50oC, preferably at +10°C.

Introduction of an ester group -OR2 representing R^ may also be carried out by reacting the carboxylate anion with an appropriate alkyl halide or haloketone 0 ll (Hal-CH2~C-Ar in which Ar represents phenyl or diphenyl 20 each of which may be substituted, especially by (C^ or C2)-alkoxy or chlorine or bromine).

A carbacyclin derivative of the general formula I in which R^ represents a hydroxy group (R2=H) may be converted into a salt by neutralisation using 25 a suitable amount of the corresponding inorganic base. The solid inorganic salt may be obtained, for 2048 example, by dissolving the corresponding acid in water that contains the stoichiometric amount of the base and then evaporating off the water or adding a water-miscible solvent, for example an alcohol 5 or acetone. Preparation of an amine salt may be carried out in customary manner. For example, the carbacyclin acid is dissolved in a suitable solvent, such as ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine 10 is added to this solution. The salt generally forms in solid form or may be isolated in customary manner after evaporation of the solvent.

Functional modification of a free OH group(s) may be carried out according to methods known to 15 the person skilled in the art.

For the introduction of an ether protecting group(s), reaction is carried out, for example, with dihydropyran in methylene chloride or chloroform using an acid condensation agent, such as, for example, 20 p-toluenesulphonic acid. The dihydropyran is advantageously used in excess, preferably in an amount that is from 4 to 10 times greater than the theoretical requirement. At from 0°C to 30°C the reaction is normally complete after from 15 to 30 minutes. 25 Introduction of an acyl protecting group(s) may be carried out by reacting a compound of the i * 204875 general formula I in a manner known per se with a carboxylic acid derivative, such as, for example, inter alia, an acid chloride or acid anhydride.

Liberation of a functionally modified OH group(s) 5 may be carried out according to known methods.

For example, an ether protecting group(s) may be split off in an aqueous solution of an organic acid, such as, for example, acetic acid or propionic acid, or in an aqueous solution of an inorganic 10 acid, such as, for example, hydrochloric acid.

To improve solubility, advantageously a water-miscible inert organic solvent is added. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Preferably tetrahydro-furan is used. Splitting off is preferably carried out at a temperature in the range of from 20°C to 80°C.

A silyl ether protecting group(s) may be split 20 off, for example, with tetrabutylammonium fluoride.

Suitable solvents are, for example, tetrahydrofuran, diethyl ether, dioxane and methylene chloride.

Splitting off is perferably carried out at a temperature in the range of from 0°C to 80°C.

Hydrolysis of an acyl groups(s) may be carried out, for example, with an alkali metal or alkaline 204875 earth metal carbonate or hydroxide in an alcohol or the aqueous solution of an alcohol. Suitable alcohols are, for example, aliphatic alcohols, such as, for example, methanol, ethanol and butanol, preferably methanol. Suitable alkali metal carbonates and hydroxides are, for example, potassium and sodium compounds, the potassium compounds being preferred. Suitable alkaline earth metal carbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and barium carbonate. The reaction is generally carried out at a temperature in the range of from -10°C to 70°C, preferably at 25°C.

Introduction of an amide group NHR^ representing R^ may be effected according to methods known to the person skilled in the art. For example, the carboxylic acid of the general formula I (R2=H) may first be converted, in the presence of a tertiary amine, such as, for example, triethylamine, into the mixed anhydride using chloroformic acid isobutyl ester. The reaction of the mixed anhydride with the alkali metal salt of the corresponding amide or with ammonia (R^H) may be carried out in an inert solvent or mixture of solvents, such as, for example, tetrahydrofuran, dimethoxyethane, dimethyl-formamide or hexamethylphosphoric acid triamide, at a temperature in the range of from -30°C to +60°C, 2048 preferably at 0°C to 30°C.

It is also possible to introduce the amide group NHR3 representing Rx by reacting a 1-carboxylic acid of the general formula I (R2=H), in which one or more free hydroxy groups are, if desired, intermediately protected, with a compound of the general formula 0 = C = N - R^ IV in which R^ has the meaning given above.

The reaction of the compound of the general formula I (R^=0H) with an isocyanate of the general formula IV may be carried out optionally with the addition of a tertiary amine, such as, for example, triethylamine or pyridine. The reaction may be carried out without a solvent or in an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether or toluene, at a temperature in the range of from -80°C to 100°C, preferably at from 0°C to 30°C.

If the starting material contains one or more OH groups in the prostane radical, then these OH groups are also reacted. If the ultimate aim is to produce an end product that contains one or more free hydroxy groups in the prostane radical, 204875 \ \ it is advantageous to use a starting material in which these hydroxy group(s) are intermediately protected by an ether or acyl radical that can preferably be readily split off.

Compounds of the general formula II which serve as starting materials may be manufactured, for example, by, in a manner known per se, reacting an aldehyde of the formula u> >< v' dl m rCHO oco - ^ in the presence of a deprotonating agent, such as, for example, sodium hydride or potassium tert.-butoxide, with a phosphonate of the general formula ch3O.

^TP - CH2 - C- D- E-R4 VI CH3° in which D, E and J*4 have the meanings given above, to form a ketone of the general formula ,t6SEPV»^ 204875 / \ 0 0 X VII /^^\^CH=C Z-C-D-E- oco (Z=H), or alternatively in the presence of a brominat-ing agent, such as, for example, N-brornosuccinimide, to form a ketone of the general formula VII (Z=Br).

Reduction of the keto group with zinc borohydride or sodium borohydride or reaction with alkylmagnesium bromide or alkyllithium and subsequent separation of the epimers yields compounds of the general formula 0 o x VIII C>cH=c2-w-D-E-Ri L-0 Hydrolysis of the ester group, for example with potassium carbonate in methanol, and optional 20487 5 hydrogenation of the double bond or optional etheri-fication with dihydropyran and subsequent removal of hydrogen bromide using, for example, potassium tert.-butoxide in dimethyl sulphoxide, ketal-splitting with aqueous acetic acid and also optional functional modification of the free hydroxy groups, for example by etherification with dihydropyran, yields the ketone of the general formula 0 An olefination reaction with phosphonoacetic acid triethyl ester or phosphonoaceti-c acid trimethyl ester or with phosphonofluoroacetic acid triethyl ester or phosphonofluoroacetic acid trimethyl ester and subsequent reduction with lithium aluminium hydride yields compounds of the general formula II which are isomeric with respect to the double bond and which may, if desired, be separated.

A phosphonate of the general formula VI may be manufactured in a manner known per se by reacting the anion of methylphosphonic acid dimethyl ester with an ester of the general formula s \ **75 C - D - E - R. 4 R1T0° in which D, E and R^ have the meanings given above and R10 represents an alkyl radical having from 1 to 5 carbon atoms. This may if desired be obtained from the corresponding malonic acid ester by alkyla-tion with a halide of the general formula Hal - E - R4 XI (in which Hal represents chlorine or bromine) and subsequent decarbalkoxylation. The ester of the general formula X may if desired be obtained also from the carboxylic acid of the general formula HO - C - D XII in which D has the meaning given above, by alkylation with a halide of the general formula XI and subsequent esterification.

Compounds of the general formula III which serve as starting materials can be manufactured, for example, in a manner known per se, by reducing an o-halocarboxylic acid ester of the general formula * 1 6SEPWS6mji 204875 Hal - (CH.,) -COOR,, XIII z n 11 in which Hal and n have the meanings given above and R^ represents an alkyl group having from 1 to 5 carbon atoms, with diisobutyl aluminium hydride to form the corresponding aldehyde and subsequently, in a known manner, ketalising it with an alcohol.

The compounds of this invention have a hypotensive and bronchodilative action. They are also suitable for the inhibition of thrombocyte aggregation. Consequently, the carbacyclin derivatives of the formula I and their physiologically tolerable salts are useful pharmaceutical active substances.

\ J ^ + uf-- ..... m 204875" ' - 29 - V v Furthermore, whilst having a similar spectrum of action compared with corresponding prostaglandins, they exhibit higher specificity and, above all, substantially longer activity. In comparison with 5 PGI2 they are distinguished by greater stability.

The high tissue specificity of the prostaglandins of the invention is apparent in studies on smooth-muscle organs, such as, for example, the ileum of guinea pigs or the isolated trachea of rabbits, A where a substantially lower stimulation is to be observed than in the case of administering natural prostaglandins of the E, A or F type.

The carbacyclin analogues of the invention possess properties typical of prostacyclins, such 15 as, for example, reduction of the peripheral arterial and coronary vascular resistance, inhibition of thrombocyte aggregation and breaking up of platelet thrombi, myocardial cytoprotection and, therewith, lowering of the systemic blood pressure without S 20 simultaneously reducing cardiac output and coronary blood flow; treatment of stroke, prophylaxis and therapy of coronary heart diseases, coronary thrombo-sis, cardiac infarct, peripheral artery diseases, arteriosclerosis and thrombosis, prophylaxis and 25 therapy of ischaemic attacks of the central nervous system, therapy of shock, inhibition of bronchocon-striction, inhibition of gastric acid secretion and\t/f 16$EPl98$ vv£. n - ■ ■ f f' -\'V ._ ■ .......... --.* - •»* 204875 cytoprotection of the gastric and intestinal mucosa, cycoprotection in the liver and pancreas? anti-allergic properties, reduction of pulmonary vascular resistance and of pulmonary blood pressure, stimulation of 5 the blood flow through the kidneys, use instead of heparin or as adjuvant in the dialysis of haemo-filtration, preservation of blood plasma supplies, especially blood platelet supplies, inhibition of labour pains, treatment of toxaemia in pregnancy 10 and increase in cerebral blood flow. In addition, the carbacyclin derivatives of the invention have anti-proliferative and anti-diarrhoeal properties.

They may be used also in combination for example with 0-blockers or diuretics.

The dosage of the compounds is advantageously from 1 to 1500 (jg/kg/day when administered to human patients. Preferably the amount of active ingredient per unit dose is from 0.01 to 100 mg.

In the case of intravenous injection to conscious 20 hypertonic rats in doses of 5, 20 and 100 |jg/kg body weight, the compounds according to the invention have a greater hypotensive and longer-lasting action than do PGE2 and PGA2, without causing diarrhoea, as does PGE2, or cardiac arrhythmia, as does PGA2-25 In the case of intravenous injection to narcotised rabbits, the compounds according to the invention ■1 / 204875 cause a greater and considerably longer-lasting decrease in blood pressure compared with PGE2 and PGA2, without other smooth-muscle organs or organ functions being influenced.

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

The active substances according to the invention 10 may serve, in combination with the adjuncts known and customary in galenical pharmacy, for example, for the manufacture of hypotensive agents.

Accordingly, the present invention provides a pharmaceutical preparation which comprises a compound 15 of the general formula I or a physiologically tolerable salt thereof, in admixture or conjunction with a pharmaceutical^ suitable carrier. Suitably the preparation is in dosage unit f.orm.

The following Examples illustrate the invention. 20 The 15-hydroxy group of the compounds in the Examples corresponds in configuration to the 15-hydroxy group in 6a-carbaprostaglandin-I2.

J 204875 Example 1 (5E)-(16RS)-2-decarboxy-la, lb-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprost aglandin-I^ 77 mg of 55 % sodium hydride suspension in mineral 5 oil is added at 0°C to a solution of 700 mg of 2-£(E)-(ljS, 5S, 6R, 7R)-7-(tetrahydropyran-2-yloxy)-6-[ (E)-(3jS, 4RS)-4-methyl-3~(tetrahydropyran-2-yloxy)-oct-l-en-6-ynyl]-bicyclo[3. 3.0]octan-3-ylideneJ-ethan-l-ol in 15 ml of tetrahydrofuran and the whole is stirred 10 for 30 minutes at 24°C under argon. A solution of 1.15 g of 2-(3-bromopropyl)-l,3-dioxolane in 7 ml of tetrahydrofuran is subsequently added dropwise thereto and the whole is refluxed for 21 hours under argon. The solution is diluted with ether, washed until neutral 15 with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. Chromatography of the residue over silica gel with hexane/ether (7+3) yields 480 mg of the oxa compound which is stirred with 40 ml of a mixture of acetic acid/water/tetrahydrofuran 20 (65+35+10) for 16 hours at 24°C. The whole is subse-quently concentrated by evaporation in vacuo and the residue is chromatographed over silica gel. Using ethyl acetate/hexane (4+1), 270 mg of the title com-J pound in the form of a. colourless oil are obtained.

IR (CHC13): 3600, 3420 (broad), 2970, 2862, 2730, 1725, 1603, 970/cm. 204875 The 2-(3-bromopropyl)-l# 3-dioxolane used for the above etherification reaction is manufactured as follows: 50 ml of a 1.2 molar solution of diisobutyl aluminium hydride in toluene is slowly added dropwise at -70 C to a solution of 9.6 g of bromobutyric acid ethyl ester in 595 ml of toluene, the whole is stirred for 15 minutes at —70^C and then lO ml of isopropyl alcohol and 25 ml of water are added dropwise thereto. The whole is stirred for 2 hours at room temperature and filtered; the filtrate is dried using magnesium sulphate and concentrated in vacuo at 25°C. The residue is dissolved in 500 ml of toluene, 10 ml of ethylene glycol and lOO mg of p-toluenesulphonic acid are added and the whole is refluxed for 6 hours using a water separator. The mixture is subsequently diluted with 500 ml of ether, shaken once with a 5 % sodium bicarbonate solution and three times with water and the organic extract is dried using magnesium sulphate and concentrated in vacuo at 30°C. Distillation of the residue at 0.6 torr and 43° - 45°C yields 6.8 g of 2-(3-bromopropyl)-l,3-dioxolane in the form of a colourless liquid.

Example 2 (5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 2 ml of acetic anhydride are added to a solution 204S75 of 500 mg of the aldehyde manufactured according to Example 1 in 5 ml of pyridine and the whole is left to stand for 18 hours at room temperature. The solution is subsequently concentrated in vacuo and the resulting 5 11,15-diacetate is dissolved in 25 ml of acetone and 2.1 ml of Jones reagent are added dropwise at 0°C. ^ The whole is stirred for 30 minutes at 0°c, 2 ml of isopropyl alcohol are added and the whole is diluted with ether, shaken three times with water, dried over 10 magnesium sulphate and concentrated by evaporation in vacuo. Chromatography of the residue over silica gel with hexane/ethyl acetate (1+1) yields 410 mg of (5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 11,15-diacetate 15 in the form of a colourless oil.

IR: 3650, 3400 (broad), 2960, 1730, 1600, 1245, 968/cm.

To split off the protecting groups, 410 mg of the 11,15-diacetate in 20 ml of methanol are stirred with 520 mg of potassium carbonate for 16 hours at 20 24°C. The whole is subsequently concentrated in vacuo, ^ acidified to pH 4 with 10 % citric acid solution, extracted three times with methylene chloride, washed twice with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue 25 is chromatographed over silica gel with ethyl acetate/-acetic acid (99.5 + 0.5). 305 mg of the title compound are obtained in the form of a colourless oil.

IR: 3590, 3420 (broad), 2960, 2930, 2865, 1720, 1600, 970/cm. 2 048 75 Example 3 (5Z)~(16RS)-2-decarboxy-la,lb-dihorno-2-f ormyl—16-rnethyl- 3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 Analogously to Example 1, 125 rag of the title compound are obtained in the form of a colourless oil from 320 mg of 2- |(Z)-(1S, 5i5, 6R,7R)-7-( tetrahydropyran-2-yloxy)-6-[(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-oct-l-en-6-ynyl]-bicyclo[3.3.0]octan-3-ylideneJ -ethan-l-ol.

IR: 3610, 3400 (broad), 2965, 2860, 2730, 1726, 1602, 968/cm.

Example 4 (5Z)-(16RS)-la,lb-dihorao-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 Analogously to Example 2, 90 mg of (5jZ)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 11,15-diacetate are obtained from 125 mg of the aldehyde manufactured according to Exanple 3. After splitting off the protecting groups, 57 mg of the title compound are obtained in the form of a colourless oil.

IR: 3600, 3410 (broad), 2960, 2866, 1718, 1600, 968/cm. 204875 Example 5 (5E)-(16RS)-2-decarboxy-la,lb-dihomo-16,20-dimethyl-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I^ Analogously to Example 1, 610 mg of the title conqpound are obtained in the form of a colourless oil from 1.35 g of 2-£(E)-(IS,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(E ) - (3_S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-non-l-en-6-ynyl]-bicyclo[3.3.0]octan-3-ylideneJ -ethan-l-ol.

IR: 3600, 3410 (broad), 2967, 2862, 2731, 1725, 1601, 970/cm.

The starting material for the above title compound is manufactured as follows: 5a) (IR,5^,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6- [ (E)-(3S^, 4RS)-3-hydroxy-4-methylnon-l-en-6-ynyl]-bicyclo[3.3.0]octane.

A solution of 9.02 g of 3-methyl-2-oxo-oct-5-ynyl-phosphonic acid dimethyl ester in 67 ml of dimethoxy-ethan (DME) is added dropwise at 0°C to a suspension of 1.46 g of sodium hydride (55 % suspension in oil) in 130 ml of DME and the whole is stirred for 1 hour at 0°C. A solution of- 9.4 g of (IR,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo[3.3.0]octane in 130 ml of DME is then added at -20°C and the whole is stirred for 1.5 hours at -20°C, poured into 600 ml 204875 of saturated ammonium chloride solution and extracted three times with ether. The organic extract is washed until neutral with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. Chromatography 5 of the residue over silica gel with ether/hexane (1+1) yields 9.1 g of the a,p-unsaturated ketone in the form of an oil. .2 g of sodium borohydride are added in portions at -40°C to a solution of 9.1 g of the ketone in 300 ml 10 of methanol and stirring is carried out for 1 hour at -40°C. The whole is subsequently diluted with ether, washed until neutral with water, dried over magnesium sulphate and concentrated by evaporation in vacuo.

Column chromatography over silica gel with ether/hexane 15 yields first 3.9 g of the title compound (PG-nomenclature: 15a-hydroxy) and then 3.2 g of the isomeric 15p-hydroxy compound as the more polar component.

IR: 3600, 3400 (broad), 2942, 1711, 1603, 1588, 1276, 968, 947/cm. 5b) (IR,5S,6R, 7R)-7-(tetrahydropyran-2-yloxy)-6-[(E)—(3S,4RS)-3-(tetrahydropyran-2-yloxy)-4-methylnon-l-en-6-ynyl]-bicyclo[3. 3.0]octan-3-one A mixture of 3.6 g of the a-alcohol manufactured according to Example 5a and 1.4 g of potassium car— 25 bonate in 120 ml of methanol is stirred for 16 hours at room temperature under argon. The mixture is 204875 Vj J subsequently concentrated in vacuo, diluted with ether and washed until -neutral with brine. The whole is dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue from concentration 5 by evaporation is stirred with 75 ml of a mixture of acetic acid/water/tetrahydrofuran (65+35+10) for 16 hours at room temperature and subsequently concentrated by evaporation in vacuo. Filtration of the residue over silica gel with ethyl acetate/hexane 10 (7+3) yields 2.2 g of the ketone in the form of an oil.

A solution of 2.2 g of the ketone, 2.4 ml of dihydropyran and 23 mg of g-toluenesulphonic acid in 75 ml of methylene chloride is stirred for 30 minutes 15 at 0°C. The solution is subsequently diluted with ether, shaken with dilute sodium bicarbonate solution, washed until neutral with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. 3.4 g of the bis-tetrahydropyranyl ether are obtained 20 which is used without being purified.

IR: 2960, 2365, 1738, 970/cm. 5c) 2- £( E)-(IS,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy )-non-l-en-6-ynyl]-bicyclo[3.3.0]octan-3-25 ylidenej-ethan-l-ol 3.5 g of potassium tert.-butoxide are added to a solution of 8.1 g of phosphonoacetic acid triethyl ester 204875 • in 170 ml of tetrahydrofuran, the whole is stirred for 10 minutes, a solution of 9 g of the ketone manufactured according to Example 5b in 90 ml of toluene is added and stirring is carried out for 16 hours at room temperature under argon. The whole is diluted with 1000 ml of ether, shaken until neutral with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is filtered over silica gel with hexane/ether (3+2). 8.2 g of the unsaturated ester 10 are obtained in the form of a colourless oil.

IR: 2950, 2870, 1700, 1655, 968/cm. 2.2 g of lithium aluminium hydride are added in portions at 0°C to a stirred solution of 8 g of the ester manufactured above in 280 ml of ether and the 15 whole is stirred for 30 minutes at 0°C. Excess reagent is destroyed by the dropwise addition of ethyl acetate, 12 ml of water are added and the whole is stirred for 2 hours at 22°C, filtered and concentrated by evaporation in vacuo. The residue is chromatographed 2 0 over silica gel with ether/hexane (3+2). 2.8 g of 2- ^( Z)-(ljS, 5S, 6R, 7R)-7- (tetrahydropyran-2-yloxy )-6-[(E)- (3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-non-l-en-6-ynyl]-bicyclo[3. 3.o]octan-3-ylidenej-ethan-l-ol are obtained as the less polar compound 25 and 4.2 g of the title compound in the form of a colourless oil.

IR: 3600, 3430, .2942, 2863, 1600, 972/cm. 2048 75 Example 6 (5E)-(16RS)-la,lb-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 Analogously to Example 2, 305 mg of (5E)-(16RS)-la,lb-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetrade-hydro-6a-carbaprostaglandin-I2 11,15-diacetate are obtained from 380 mg of the aldehyde manufactured according to Example 5.

After splitting off the protecting groups, 210 mg of the title compound are obtained in the form of a colourless oil.

IR: 3600, 3400 (broad), 2962, 2865, 1720, 1601, 970/cm. Example 7 (5E)-2-decarboxy-la,lb-dihomo-2-formyl-20-methyl-3-oxa-16,16-trimethylene-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I2 Analogously to Examples 1 and 5, 0. 4 g of the title compound is obtained in the form of a colourless oil from 0.9 g of 2--£(E)-(lS,5S,6R,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(E)-(3R)-3-(tetrahydropyran-2-yloxy)-4,4-trimethylenenon-l-en-6-ynyl]-bicyclo[3.3.0]octan-3-ylidenej-ethan-l-ol (manufactured according to Exanple 5a-c from 2-oxa-3,3-trimethylenenon-5-ynphosphonic acid dimethyl ester).

IR: 3610, 3400 (broad), 2968, 2864, 2730, 1725, 1602, 970/cm. m The starting material for the above title corqpound is manufactured as follows: 7a) 2- £(E)- (is, 5£>, 6R, 7R)-7-(tetrahydropyran-2-yloxy-4,4-trimethylenenon-l-en-6-ynyl]-bicyclo[3.3.0]-5 octan-3-ylidenej-ethan-l-ol Analogously to Example 5c, there are obtained from 3 g of (IR,5S,6R,7R)-7-( tetrahydropyran^-yloxy^e-ll (E)- ( 3R)-3-(tetrahydropyran-2-yloxy)-4,4-trimethylene-non-l-en-6-ynyl]-bicyclo[3. 3.0]octan-3-one, after 10 separation of the isomers by chromatography, 470 mg of 2- £(Z)-<1S,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-4,4-trimethylenenon-l-en-6-ynyl]-bicyclo[3.3.0]octan-3-ylidenej-ethan-l-ol as the less polar conpound and 690 mg of the title compound in the form of a colourless 15 oil.

IR: 3600, 3400 (broad), 2945, 2862, 1602, 972/cm.

Example 8 (5E)-la,lb-dihomo-20-methyl-3-oxa-16,16-trimethylene-18,18,19,19-tetradehydro-6a-carbaprostaglcindin-l2 Analogously to Example 2, 295 mg of (5E)-la,lb- dihomo-20-methyl-3-oxa-16,16-trimethylene-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 11.15-diacetate are obtained from 400 mg of the aldehyde manufactured according to Example 7. 2 5 After splitting off the protecting groups, 220 mg 2048 75 of the title conpound are obtained in the form of a colourless oil.

IR: 3610, 3400 (broad), 2960, 2864, 1721, 1602, 970/cm. Example 9 (5E)-2-decarboxy-la,lb-dihomo-16,16-dimethyl-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 Analogously to Exanples 1 and 5, O.28 g of the title conpound is obtained in the form of a colourless oil from 0.5 g of 2-^(E)-(IS,5£,6R,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl-3-(tetrahydro-pyran-2-yloxy)-oct-l-en-6-ynyl]-bicyclo[3.3.O]octan-3-ylidene^-ethan-l-ol.

IR: 3600, 3400 (broad), 2965, 2732, 1724. 1600, 970/cm. Example 10 (5E)-la,lb-dihomo-16,16-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 Analogously to Example 2, 180 mg of (5E)-la,lb-dihomo-16, 16-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 11,15-diacetate are obtained from 0.27 g of the aldehyde manufactured according to Exarrple 9.

After splitting off the protecting groups, 120 mg of the title conpound are obtained in the form of a colourless oil.

IR: 3600, 3400 (broad), 2962, 2865, 1720, 1600, 971/cm. . .... y^.. 204875 Example 11 (5E)-2-decarboxy-la,lb-dihomo-2-formyl-3-oxa-l6 ,16,20-trimethyl-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-^ Analogously to Examples 1 and 5, 0.6 g of the title compound is obtained in the form of a colourless oil from 1.1 g of 2-|(E)-(IS,5S,6R,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(E)-(3R)-4, 4-dimethyl-3-(tetrahydro-pyran-2-yloxy)-non-l-en-6-ynyl]-bicyclo[3.3.0]octan-3-10 ylidenej-ethan-l-ol.

IR: 3610, 3420 (broad), 2964, 2730, 1725, 1602, 972/cm.

Example 12 (5E)-la,lb-dihomo-3-oxa-16,16,20-trimethyl-18,18,19,19- tetradehydro-6a-carbaprostaglandin-l2 « Analogously to Example 2, 0.3 g of (5E)-la,lb- dihomo-3-oxa-16,16,20-trimethyl-l8,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 11,15-diacetate is obtained from 0.4 g of the aldehyde manufactured according to Example 11.

After splitting off the protecting groups, 0.22 g of the title compound is obtained in the J form of a colourless oil.

IR: 3610, 3400 (-broad), 2964 , 2864, 1721 , 1600, 972/cm. i 204875 Example 13 (5E)-(16RS)-2-decarboxy-18,19-didehydro-la,lb-dihomo- 16,19-dimethyl-2-formyl-3-oxa-6a-carbaprostaglandin-l2 Analogously to Examples 1 and 5, 0.4 g of the 5 title compound is obtained in the form of a colourless oil from 0.7 g of 2-£(E)-(lS,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(E)-(3S,4RS)-4,7-dimethyl-3-(tetrahydropyran-2-yloxy)-oct-l,6-dienyl )-bicyclo[3.3.0]octan-3-ylidene|-ethan-l-ol.

IR: 3600, 3400 (broad), 2966, 2732, 1725, 1601, 972/cm.

Example 14 (5E)-la,lb-dihomo-16,19-dimethyl-l8,19-didehydro-3-oxa-6a-carbaprostaglandin-l2 Analogously to Example 2, 0.14 gof (5E)-la,lb-15 dihomo-16,19-dimethyl-l8,19-didehydro-3-oxa-6a-carba-prostaglandin-12 11,15-diacetate is obtained from 0.2 g of the aldehyde manufactured according to Example 13.

After splitting off the protecting groups, 90 mg 20 of the title compound are obtained in the form of a colourless oil.

IR: 3600, 3410 (broad), 2960, 2860, 1720, 1601, 972/cm. 204875 Example 15 (5E)-(16RS)-2-decarboxy-13,14-didehydro-la,lb-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I_ Analogously to Examples 1 and 5, 0.29 g of the title ccirpound is obtained in the form of a colourless oil from 0.6 g of 2-|(E)-(IS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl)-bicyclol3.3.0]octan-3-ylideneJ-ethan-10 l-ol.

IR: 3610, 3410 (broad), 2966, 2730, 2225, 1725/cm.

The starting material for the above title compound is manufactured as follows: 15a) 2-£(E)-(IS,5S,6S,7RJ-7-(tetrahydropyran-2-yloxy)-. 15 6-[(3'S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)- 4 octa-1,6-diynyl)-bicyclo-[3.3.0]octan-3-ylideneJ -ethan-l-ol Ananogously to Example 5c, there are obtained from 1.8 g of (IR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-20 6-[(3S,4RS)-4-methyl-3-tetrahydropyran-2-yloxy)-octa-1,6-diynyl]-bicyclo[3.3.0]octan-3-one, after separation of the isomers by chromatography, 380 mg of (IS,5Sr 6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-4-methyl-3- (tetrah'ydropyran-2-yloxy)-octa-1, 6-diynyl ]-25 bicyclo[3.3.0]octan-3-ylideneJ-ethan-l-ol as the less m 204875 polar compound and 610 mg of the title compound in » the form of an oil.

IR: 3600, 3400 (broad), 2945, 2860, 2225/cm.

Example 16 ( 5E) - (16RS)-13,14-didehydro-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 Analogously to Example 2, 0.21 g of (5E)-(16RS)-13,14-didehydro-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetrahydro-6a-carbaprostaglandin-I2 11,15-diacetate 10 is obtained from 0.4 g of the aldehyde manufactured according to example 15.

After splitting off the protecting groups, 150 mg of the title compound are obtained in the form of a colourless oil.

IR: 3600, 3410 (broad), 2960, 2864, 2226, 1718/cm.

Example 17 (5E)-(16RS)-2-decarboxy-13,14-didehydro-la, lb-dihomo-16,20-dimethyl-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 Analogously to Examples 1 and 5, 0.42 g of the title compound is obtained in the form of a colourless oil from 0.8 g of 2-£(E)-(IS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(3S,4RS)-4-methyl-3-(tetrahydropyran- 204875 2-yloxy)-nona-1,6-diynyl)-bicyclo[3.3.0]octan-3-ylidene-ethan-l-ol.

IR: 3600, 3400 (broad), 2965, 2732, 2227, 1724/cm.

The starting material for the above title compound is manufactured as follows: 17a) 2-^(E)-(IS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylideneJ -ethan-l-ol Analogously to Example 5c, there are obtained from 2.1 g of (IR,5S,6S,7R)—7—(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diynyl)-bicyclo[3.3.0]octan-3-one, after separation of the isomers by chromatography, 450 mg of 2-£(Z)-(IS, 5S, 6S, 7R)-7-(tetrahydropyran-2-yloxy )-6-[(3S,4RS)-4-methyl-3-(te'trahydropyran-2-yloxy)-nona-l,6-diynyl]-bicyclo[3.3.0]-octan-3-ylideneJ-ethan-l-ol as the less polar compound and 740 mg of the title compound in the form of a colourless oil.

IR: 3600, 3420 (broad), 2947, 2862, 2223/cm.

Example 18 (5E)—(16RS)-13,14-didehydro-la,lb-dihomo-16,20-dimethyl- 3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 Analogously to Example 2, 340 mg of (5E)-(16RS)- m 2048 75 13.14-didehydro-la,lb-dihomo-16,20-dimethyl-3-oxa- 18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 11.15-diacetate are obtained from 620 mg of the aldehyde manufactured according to Example 17.

After splitting off the protecting groups, 260 mg of the title compound are obtained in the form of a colourless oil.

IR: 3610, 3400 (broad), 2962, 2865, 2225, 1720/cm.

Example 19 (5E)-2-decarboxy-13,14-didehydro-la,lb-dihomo-2-formyl-2 0-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethyl-ene-6a-carbaprostaglandin-l2 Analogously to Examples 1 and 5, 0.18 g of the title compound is obtained in the form of a colourless 15 oil from 0.41 g of 2-^(E)-(IS,5S,6S,7R)-7-(tetrahydropyran- 2-yloxy)-6-[(3S)-(tetrahydropyran-2-yloxy)-4,4-trimethylenenona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidenej-ethan-l-ol.

IR: 3600, 3400 (broad), 2965, 2732, 2227, 1724/cm. 20 The starting material for the above title compound was manufactured as follows: 2048 75 19a) 2-^(E)-(IS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-3-(tetrahydropyran-2-yloxy)-4,4-trimethyl-enenona-1,6-diynyl)-bicyclo[3.3.0)octan-3-ylidenej-ethan-l-ol Analogously to Example 5c, there are obtained from 3.1 g of (IR,5S,6S,7R )-7-(tetrahydropyran-2-yloxy)-6-[(3S)—3-(tetrahydropyran-2-yloxy)-4,4-trimethylene-nona-1,6-diynyl]-bicyclo[3.3.0]octan-3-one, after separation of the isomers by chromatography, 890 mg of 2-^(Z)-(1S,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[ (3RS)-3-(tetrahydropyran-2-yloxy)-4,4-trimethylenenona- I,6-diynyl]-bicyclo[3.3.0]octan-3-ylidenej -ethan-l-ol as the less polar compound and 1.3 g of the title compound in the form of an oil.

IR: 3610, 3420 (broad), 2945, 2862, 2226/cm.

» Example 2 0 (5E)-13,14-didehydro-la,lb-dihomo-20-methyl-3-oxa-18,18,19,19-tetradehydro-l6,16-trimethylene-6a-carba-prostaglandin-l2 Analogously to Example 2, 0.32 g of (5E)-13,14-didehydro-la ,lb-dihomo-20-methyl-3-oxa-18,18,19,19-tetradehydro-l 6 ,16-trimethylene-6a-carbaprostaglandin-^ II,15-diacetate is obtained from 0.42 g of the aldehyde manufactured according to Example 19. 2048 After splitting off the protecting groups, 210 mg of the title compound are obtained in the form of a colourless oil.

IR: 3600, 3400 (broad), 2963, 2865, 2225, 1720/cm. Example 21 (5E)-2-decarboxy-13,14-didehydro-la,lb-dihomo-16,16-dimethyl-2-formyl-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprostaglandin-Ij Analogously to Examples 1 and 5, 0.47 g of the title compound is obtained in the form of a colourless oil from 0.9 g of 2-£(E)-(IS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy)-6-{(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa-l,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene ethan-l-ol.

IR: 3600, 3410 (broad), 2966, 2730, 2225, 1725/cm.

The starting material for the above title compound is manufactured as follows: 21a) 2-£(E )-(IS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidenej-ethan-l-ol Analogously to Example 5c, there are obtained from 2.5 g of (IR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy) 6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa- 204875 1,6-diynyl]-bicyclof3.3.0)octan-3-one, after separation of the isomers by chromatography, 625 mg of 2-^(2)-(IS, 5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S) — 4,4 — dimethyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl]-bicyclo[3.3.0)octan-3-ylideneJ-ethan-l-ol as the less polar compound and 1.1 g of the title compound in the form of an oil.

IR: 3600, 3400 (broad), 2946, 2865, 2225/cm.

Example 22 (5E)-l3,14-didehydro-la,lb-dihomo-16,16-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 Analogously to Example 2, 0.21 g of (5E)-13,14-didehydro-la , lb-dihomo-16,16-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 11,15-diacetate is obtained from 0.31 g of the aldehyde manufactured according to Example 21.

After splitting off the protecting groups 0.14 g of the title compound is obtained in the form of a colourless oil.

IR: 3600, 3410 (broad), 2964, 2865, 2225, 1720/cm. 204875 Example 2 3 ( 5E)-2-decarboxy-13,14-didehydro-la,lb-dihomo-2-formyl-3-oxa-l8,18,19,19-tetradehydro-16,16-20-trimethyl-6a-carbaprostaglandin-^ Analogously to Examples 1 and 5, 0.31 g of the title compound is obtained in the form of a colourless oil from 0.8 g of 2-^{E)—(IS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-2-y1oxy)-nona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylideneJ-10 ethan-l-ol.

IR: 3610, 3420 (broad), 2965, 2730, 2226, 1724/cm.

The starting material for the above title compound is manufactured as follows: 23a) 2- £(E)-(IS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-15 6-[(3S )-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)- nona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidenej -ethan-l-ol Analogously to Example 5c, there are obtained from 1.3 g of (IR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-20 6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diynyl]-bicyclo[3.3.0]octan-3-one, after separation of the isomers by chromatography, 300 mg of 2-^(Z)-(IS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-4 , 4-dimethyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diynyl]-25 bicyclo[3.3.0]octan-3-ylidene^-ethan-l-ol as the less 2048 75 polar compound and 4 30 mg of the title compound in the form of an oil.

IR: 3610, 3400 (broad), 2945, 2865, 2225/cm.

Example 24 (5E)-13,14-didehydro-la,lb-dihomo-3-oxa-l8,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin-I2 Analogously to Example 2, 0.1 g of (5E)-13,14-didehydro-la, lb-dihomo-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin-l2 11,15-10 diacetate is obtained from 0.16 g of the aldehyde manufactured according to Example 23.

After splitting off the protecting groups, 60 mg of the title compound are obtained in the form of a colourless oil.

IR:. 3600, 3400 (broad), 2965, 2864, 2224, 1718/cm.

Example 25 (5Z)-(16RS)-2-decarboxy-la,lb-dihomo-5-fluoro-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I^ 42 mg of 55 % sodium hydride suspension in mineral oil are added at 0°C to a solution of 420 mg of 2-|(Z)-(IS,5S,6R,7R)-7Htetrahydropyran-2-yloxy)-6-[(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-oct-l-en- 204875 6-ynyl]-bicyclo[3.3.0]octan-3-ylidene|-2-fluoroethan-l-ol in 8 ml of tetrahydrofuran and stirring is carried out for 30 minutes at 24°C under argon. A solution of 630 mg of 2-(3-bromopropyl)-1,3-dioxolane in 8 ml 5 of tetrahydrofuran is subsequently added and the whole is refluxed for 20 hours under argon. The I mixture is diluted with ether, washed until neutral with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. Chromatography of the 10 residue over silica gel with hexane/ether (3+2) yields 340 mg of the oxa compound which is stirred with 30 ml of a mixture of acetic acid/water/tetrahydrofuran (65+35+10) for 16 hours at 24°C. The whole is subsequently concentrated by evaporation in vacuo and 15 the residue is chromatographed over silica gel.

Using ethyl acetate/hexane (4+1), 280 mg of the title compound are obtained in the form of a colourless oil.

IR: 3600, 3420 (broad), 2960, 2930, 2870, 2730, 1730, 20 1603, 970/cm.

Example 2 6 (5Z)-(16RS)-la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 Analogously to Example 2, 110 mg of (5_Z )-(16RS)-la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19- m - 55 204875 tetradehydro-6a-carbaprostaglandin-I2 11f15-diacetate are obtained from 205 mg of the aldehyde manufactured according to Example 25.

After splitting off the protecting groups, 78 mg 5 of the title compound are obtained in the form of a colourless oil.

Example 27 (5Z)-(16RS ) -2-decarboxy-la,lb-dihomo-16,20-dimethyl-5-f1uoro-2-formy1-3-oxa-l8,18,19,19-tetradehydro-6a-10 carbaprostaglandin-I2 Analogously to Example 25, 370 mg of the title compound are obtained in the form of a colourless oil from 610 mg of 2-^(E)-(IS,5S, 6R,7R )-7-(tetrahydropyran-2-yloxy)-6-[ (3S,4RS)-4-methyl-3-(tetrahydropyran- 2-yloxy)-non-l-en-6-ynyl)-bicyclo[3.3.0]octan-3-2-fluoroethan-l-ol.

IR: 3610, 3400 (broad), 2963, 2930, 2868, 2731, 1630, Example 28 (SZ)-{16RS)-la,lb-dihomo-16,20-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 Analogously to Example 2, 125 mg of ( 5Z^)- (16RS)-la,lb-dihomo-16,20-dimethyl-5-fluoro-3-oxa-l8,18,19,19- 1602, 971/cm. 204875 tetradehydro-6a-carbaprostaglandin-l2 11,15-diacetate are obtained from 230 mg of the aldehyde manufactured according to Example 27.

After splitting off the protecting groups, 85 mg 5 of the title compound are obtained in the form of a colourless oil.

IR: 3600, 3410 (broad), 2965, 2930, 2870, 1720, 1602, 9 70/cm.

Example 29 (5Z)-2-decarboxy-la,lb-dihomo-5-fluoro-2-formyl-20- methyl-3-oxa-18,18,19,19-tetradehydro-l6,16-trimethylene-6a-carbaprostaglandin-I2 Analogously to Example 25, 165 mg of the title compound are obtained in the form of a colourless oil from 390 mg of 2-£ (.Z)-(IS, 5S, 6R, 7R)-7-(tetrahydropyran- 2-yloxy)-6-[(E)-(3R)-3-(tetrahydropyran-2-yloxy)-4,4-trimethylenenon-1-en-6-ynyl]-bicyclo[3.3.0]octan-3-ylidene^-2-fluoroethan-l-ol.

IR: 3600, 3410 (broad), 2965, 2931, 2870, 2730, 1630, 20 1601, 970/cm.

Example 30 (5Z)-la,lb-dihomo-5-fluoro-20-methyl-3-oxa-l8,18,19,19-tetradehydro-16,16-trimethylene-6a-carbaprostaglandin-I2 Analogously to Example 2, 105 mg of (5Z)-la,lb- 2 048 7 5 . dihomo-5-fluoro-20-methyl-3-oxa-l8,18/19,1 9-tetradehydro-16,16-trimethylene-6a-carbaprostaglandin-I2 11,15-diacetate are obtained from 190 mg of the aldehyde manufactured according to Example 29.

After splitting off the protecting groups, 70 mg of the title compound are obtained in the form of a colourless oil.

IR: 3600, 3400 (broad), 2965, 2930, 2870, 1718, 1602, 970/cm.

Example 31 (5£)-2-decarboxy-la,lb-dihomo-16,16-dimethyl-5-fluoro-2-formyl-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 Analogously to Example 25, 0.27 g of the title 15 compound is obtained in the form of a colourless oil from 0.6 g of 2-^(Z)-(IS,5S,6R,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl-3-(tetrahydropyran- 2-yloxy )-oct-l-en-6-ynyl ]-bicyclo[3.3.0]octan-3-ylidenej-2-fluoroethan-l-ol.

IR: 3610, 3420 (broad), 2966, 2930, 2868, 2732, 1730, 1602, 971/cm.

Example 32 ( 5Z )-la, lb-dihomo-16 ,16-dimethyl.-5-f luoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 Analogously to Example 2, 120 mg of (5JZ)-la,lb- fl 204875 dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetra-dehydro-6a-carbaprostaglandin-I2 11,15-diacetate are obtained from 220 mg of the aldehyde manufactured according to Example 31.

After splitting off the protecting groups, 92 mg of the title compound are obtained in the form of a colourless oil.

IR: 3600, 3410 (broad), 2964, 2931, 2870, 1720, 1601, 971/cm.

Example 33 (5:z )-2-decarboxy-la,lb-dihomo-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-l6,16,20-trimethyl~6a-carba-prostaglandin-I2 Analogously to Example 25, 0.38 g of the title compound is obtained in the form of a colourless oil from 0.7 g of 2-£ (JZ ) - (IS, 5S, 6R, 7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(E)-(3R)-4 ,4-dimethyl-3-(tetrahydro-pyran-2-yloxy)-non-l-en-6-yny1]-bicyclof 3.3.0]octan-3-ylidenej-2-fluoroethan-l-ol.

IR: 3610, 3400 (broad), 2965, 2930, 2870, 2730, 1730, 1601, 970/cm. ft 2t0 4 8 7 5 Example 34 ( 5Z)-la,lb-dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin-I2 Analogously to Example 2, 0.16 g of (5Z)-la,lb-5 dihomo-5-fluoro-3-oxa-l8,18,19,19-tetradehydro-l6,16,20-trimethyl-6a-carbaprostaglandin-I2 11,15-diacetate is obtained from 0.3 g of the aldehyde manufactured according to Example 33.

After splitting off the protecting groups, 0.12 g 10 of the title compound is obtained in the form of a colourless oil.

IR: 3610, 3400 (broad), 2965, 2868, 1720, 1602, 971/cm. Example 3 5 ( 5Z) -(16RS)-2-decarboxy-13,14-didehydro-la,lb-dihomo-5-15 fluoro-2-formyl-16-methyl-3-oxa-l8,18,19,19-tetradehydro-6a-car bapros tag landin-I2 Analogously to Example 25, 0.2 g of the title compound is obtained in the form of a colourless oil from 0.41 g of 2-[(Z)-(IS,5S,6S,7R)-7-(tetrahydro-20 pyran-2-yloxy)-6-[(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl ]-bicyclo[3.3.0]octan-3-ylidene| -5-fluoroethan-l-ol.

IR: 3600, 3410 (broad), 2966, 2731, 2224, 1727/cm. 2t0 4 8 7 5 Example 34 (5^) -1 a,lb-dihomo-5-f1uoro-3-oxa-l8,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin-l2 Analogously to Example 2, 0.16 g of (5Z)-la,lb-5 dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-l6,16,20-trimethyl-6a-carbaprostaglandin-l2 11/15-diacetate is obtained from 0.3 g of the aldehyde manufactured according to Example 33.

After splitting off the protecting groups, 0.12 g 10 of the title compound is obtained in the form of a colourless oil.

IR: 3610, 3400 (broad), 2965, 2868, 1720, 1602, 971/cm. Example 35 (5_Z ) — (16RS)-2-decarboxy-13,14-didehydro-la, lb-dihomo-5-15 f lu'oro-2-formyl-16-methyl-3-oxa-18,18,19,19-tetrade-hydro-6a-carbaprostaglandin-l2 Analogously to Example 25, 0.2 g of the title compound is obtained in the form of a colourless oil from 0.41 g of 2-[(Z )-(IS,5S,6S,7R)-7-(tetrahydro-20 pyran-2-yloxy)-6-[(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidenej-5-fluoroethan-l-ol.

IR: 3600, 3410 (broad), 2966, 2731, 2224, 1727/cm. 204875 Example 36 (5£)-(16RS)-13,14-didehydro-la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 Analogously to Example 2, 0.1 g of (5Z)-(16RS)- 13.14-didehydro-la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 11.15-diacetate is obtained from 0.2 g of the aldehyde manufactured according to Example 35.

After splitting off the protecting groups, 70 mg of the title compound are obtained in the form of a colourless oil.

IR: 3620, 3400 (broad), 2965, 2870, 2225, 1620/cm.

Example 37 ( 5J2 ) - {16RS)-2-decarboxy-13,14-didehydro-la,Ib-dihomo-16, 20-dimethyl-5-fluoro-2-forrny 1-3-oxa-18,18 ,19,19-tetradehydro-6a-carbaprostaglandin-l2 Analogously to Example 25, 0.38 g of the title compound is obtained in the form of a colourless 20 oil from 0.7 g of 2-^(Z)-(IS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy )-6-[(3S,4RS)-4-methyl-3-tetrahydropyran-2-yloxy)-nona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidenej-2-fluoroethan-l-ol.

IR: 3600, 3400 (broad), 2968, 2730, 2225, 1728/cm. 204875 Example 3 8 (5Z)-(16RS)—13,14-didehydro-la,lb-dihomo-16,20-dimethyl-5-f1uoro-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprosta-glandin-^ Analogously to Example 2, 0.18 g of (5Z)-(16RS)- 13.14-didehydro-la,lb-dihomo-16,20-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 11.15-diacetate is otbained from 0.35 g of the aldehyde manufactured according to Example 37.

After splitting off the protecting groups, 0.14 g of the title compound is obtained in the form of a colourless oil.

IR: 3600, 3420 (broad), 2966, 2870, 2226, 1718/cm. Example 3 9 (5£)-2-decarboxy-l3,14-didehydro-la,lb-dihomo-5-fluoro-2-formy1-20-methyl-3-oxa-l8,18,19,19-tetradehydro- 16.16-trimethylene-6a-carbaprostaglandin-l2 Analogously to Example 25, 0.7 g of the title compound is obtained in the form of a colourless oil from 1.2 g of 2-|(Z )-(IS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(3S)-3-(tetrahydropyran-2-yloxy)-4,4-trimethylenenona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidenej-2-fluoroethan-l-ol.

IR: 3620, 3420 (broad), 2970, 2731, 2224, 1730/cm. 2048 75 Example 40 (5 2)-l3,14-didehydro-la,lb-dihomo-5-fluoro-20-methyl-3-oxa-18, 18,19,19-tetradehydro-l6,16-trimethylene-6a-carbaprostaglandin-I2 Analogously to Example 2, 0.31 g of (5Z)-13,14-didehydro-la ,lb-dihomo-5-fluoro-20-methyl-3-oxa-18,18,19,19-tetradehydro-l6,16-trimethylene-6a-carba-prostaglandin-I2 11,15-diacetate is obtained from 0.6 g of the aldehyde manufactured according to Example 39.

After splitting off the protecting groups, 0.25 g of the title compound is obtained in the form of a colourless oil.

IR: 3620, 3425 (broad), 2968, 2870, 2225, 1720/cm.

Example 41 (5£)-2-decarboxy-13,14-didehydro-la,lb-dihomo-16,16-dimethyl-5-fluoro-2-formyl-3-oxa-l8,18,19,19-tetradehydro- 6a- carbaprosta gland in- I 2 Analogously to Example 25, 0.65 g of the title compound is obtained in the form of a colourless oil from 1.4 g of 2-£(Z)-(IS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa-l,6-diynylJ-bicyclo[3.3.0]octan-3-ylidene^-2-fluoroethan-l-ol.

IR: 3600, 3420 (broad), 2970, 2930, 2865, 2730 2225, 1730/cm. m 204875 Example 4 2 (5Z)-13,14-didehydro-la,lb-dihomo-16,16-dimethyl-5-fluoro-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprosta-glandin-^ Analogously to Example 2, 0.22 g of (5Z)-13,14- didehydro-la , lb-dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 11,15-diacetate is obtained from 0.4 g of the aldehyde manufactured according to Example 41.

After splitting off the protecting groups, 0.18 g of the title compound is obtained in the form of a colourless oil.

IR: 3600, 3420 (broad), 2970, 2870, 2224, 1718/cm. Example 4 3 (5Z)-2-decarboxy-13,14-didehydro-la,lb-dihomo-5-fluoro-2-formyl-3-oxa-l8,18,19,19-tetradehydro-l6,16,20-trimethyl-6a-carbaprostaglandin-l2 Analogously to Example 25, 0.3 g of the title compound is obtained in the form of a colourless 20 oil from 0.7 g of 2-^{Z)-(IS,5S,6S,7R)-7-(tetrahydropyran- 2-yloxy)-6-[(3S)—4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidenej-2-fluoroethan-l-ol.

IR: 3600, 3420 (broad), 2968, 2932, 2864, 2730, 2225, 25 1730/cm. 204 8 75 Example 4 4 ( 5_Z ) — 13 ,14 -didehydro-la, lb-dihomo-5-f luoro-3-oxa-18,18,19,19-tetradehydro-l6,16,20-trimethyl-6a-carba-prostaglandin-^ Analogously to Example 2, 0.14 g of (5Z)-13,14- didehydro-la, lb-dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-16,16-20-trimethyl-6a-carbaprostaglandin-^ 11,15-diacetate is obtained from 0.3 g of the aldehyde manufactured according to Example 43.

After splitting off the protecting groups, 0.1 g of the title compound is obtained in the form of a colourless oil.

IR: 3605, -3420 (broad), 2970, 2870, 2225, 1720/cm. Example 4 5 (5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 methyl ester An ethereal diazomethane solution is added dropwise at 0°C to a solution of 60 mg of (5E)-(16RS)-1 a,lb-dihomo-1 6-methyl-3-oxa-l8,18,19,19-tetraaehydro-6a- carbaprostaglandin-^ in 10 ml of dichloromethane until a constant yellow colouring is obtained. After 5 minutes the whole is concentrated by evaporation in vacuo and the residue is chromatographed over silica gel. Using ethyl acetate/hexane (4+1), 40 mg m -65 - 2 04 8 75 of the title compound are obtained in the form of a colourless oil.

IR: 3600, 3400 (broad), 2960, 1740, 974/cm.

Example 4 6 (5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 carboxamide 105 mg of (5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 are dissolved in 3 ml of tetrahydrofuran; 4 0 mg 10 of triethylamine and 4 5 mg of chloroformic acid isobutyl ester are added at 0°C. After 1 hour, ammonia gas is introduced at 0°C for 10 minutes and then the whole is left to stand for 1 hour at 24°C. The mixture is subsequently diluted with 30 ml of water, extracted 15 thr-ee times with 3 0 ml of methylene chloride each time, and the combined organic extracts are shaken with 20 ml of brine, dried over magnesium sulphate and concentrated by evaporation in vacuo. Chromatography of the residue over silica gel with methylene 20 chloride/isopropanol (9+1) yields 78 mg of the title compound in the form of an oil.

IR: 3610, 3540, 3400 (broad), 2960, 1670, 975/cm. 204875* Example 4 7 (5Z)-(16RS)-la,lb-dihomo-5-fluoro-16-methyl-3-oxa- 18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 (2,3-dihydroxypropy1)-amide 195 mg (5Z)-(16HS)-la,lb-dihomo-5-fluoro-16-methyl- 3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 are dissolved in 5 ml of acetone; 60 mg of triethyl- a:mine and 75 mg of chloroformic acid isobutyl ester are added at 0°C. After 20 minutes, a solution of 260 mg of l-amino-2,3-dihydroxypropane in 8 ml of acetone and 8 ml of acetonitrile are added and stirring is carried out for 2 hours at 20°C. The whole is concentrated in vacuo, diluted with methylene chloride, shaken with a little brine and the organic phase is dried over magnesium sulphate and concentrated by evaporation in vacuo. Chromatography of the residue over silica gel with methylene chloride/isopropanol (8+2) yields 160 mg of the title compound in the form of a colourless oil. /v IR: 3600, 3400(broad), 2935, 1645, 974/cm. 7 6S£PI986 Example 4 8 (5Z)-(16RS)-la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 (4-phenyl)-phenacyl ester 120 mg of (5Z)-(16RS)-la,lb-dihomo-5-f1uoro-16- 2 048 75 methyl-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 are dissolved in 3 ml of acetone; 90 mg of u-bromo-4-phenylacetophenone and 1 ml of triethylamine are added and stirring is carried out overnight at 5 room temperature. 100 ml of ether are added and the whole is shaken twice with 10 ml of water each time, dried over magnesium sulphate and concentrated by evaporation in vacuo. Purification is carried out by preparative thin-layer chromatography on silica 10 gel plates which are developed with ethyl acetate. 128 mg of the title compound are obtained.

IR: 3610, 2940, 1740, 1703, 1602, 974/cm.

Example 4 9 (5E )-(16RS)-la,lb-dihomo-16-methyl-3-oxa-l8,18,19,19-15 tetradehydro-6a-carbaprostaglandin-l2 tris-(hydroxy- 4 methyl)-aminomethane salt A solution of 6 0 mg of tris-(hydroxymethyl)-aminomethane in 0.2 ml of water is added at 70°C to a solution of 185 mg of (5E)-(16RS)-la,lb-dihomo-16-methyl-20 3-oxa-l8,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 in 35 ml of acetonitrile. The whole is cooled while stirring, the solvent is decanted off after 16 hours and the residue is dried in vacuo. 160 mg of the title compound are isolated in the form of a wax-like 25 substance. 2 048 75

Claims (1)

1. WHAT WE CLAIM IS: 1. A carbacyclin derivative of the general formula (CH,) -C-R, j 2 n 1 0 1 CH, I 2 CX A A-W-D-E-R 4 R5 5 in which R^ represents (i) a hydrogen atom, (ii) a radical of the general formula OR2 in which R2 represents a hydrogen atom or an unsubsti- 10 tuted or substituted alkyl, cycloalkyl, aryl or heterocyclic radical, or (iii) a radical of the general formula NHR^ in which R^ represents an acyl radical or has the meaning given for R2, 15 n represents the number 2, 3, 4 or 5, X represents a hydrogen atom or a fluorine atom, A represents a -CH2~CH2-, trans-CH=CH- or -C^C- group, - 69 - 2 048 75 represents a free or functionally modified hydroxy-methylene group or a free or functionally modified OH where the CM group may be in the a- or 3-configuration, represents (i) the group -C-CH2~ wherein m represents the number 1, 2 or 3 and wherein the carbon atom of the ring is attached to the radical represented by W, or (ii) a straight-chain or branched aliphatic hydrocarbon radical having up to 5 carbon atoms, which is unsubstituted or substituted by one or more fluorine atoms, or (iii) - CH - CH - , represents a direct bond, a -C=C- group or a -CRjp-CR^- group, wherein Rg and R^ are different and R^ represents a hydrogen or a halogen atom or an alkyl radical having from 1 to 5 carbon atoms, and Rg represents a hydrogen atom or an alkyl radical having from 1 to 5 carbon atoms, represents an aliphatic hydrocarbon radical, a cycloalkyl or alkyl-substituted cycloalkyl radical, an unsubstituted or substituted aryl radical or heterocyclic radical or an araliphatic -C- group, m o - 70 - 2048 75 hydrocarbon radical which is unsubstituted or substituted in the aromatic moiety, and represents a free or functionally modified hydroxy group. 5 2. A compound as claimed in claim 1, wherein R1 represents a radical of the general formula 0R2 in which represents -CHj-CO-aryl in which the aryl radical is unsubstituted or substituted. 3. A compound as claimed in claim 2, wherein 10 the aryl radical is unsubstituted or substituted by from 1 to 3 (C^-C4)-alkoxy radicals, 1 to 3 halogen atoms or 1 to 3 phenyl groups wherein these phenyl groups may, independently of one another, each be unsubstituted or substituted by 1 to 3 halogen atoms 15 or by 1 to 3 (C^-C^)-alkoxy radicals. 4. A compound as claimed in claim 3, wherein the aryl radical is a phenyl or naphthyl group which is unsubstituted or mono-substituted by a phenyl, (C^ or C2)-alkoxy, chlorine or bromine substituent. 20 5. A compound as claimed in claim 1, wherein represents a radical of the general formula 0R2 in which R2 represents an alkyl radical having from 1 to 10 carbon atoms which is unsubstituted or substituted by one or more of the same or different 25 substituents selected from halogen atomst (C^-C^)-alkoxy groups, hydroxy groups, unsubstituted and r o -c"\' 204875. - 71 - f substituted |aryl and aromatic heterocyclic groups and cycloalkyl, di-CC^-C^)-alkylamino and tri-tCj-C^)-alkylammonium groups; or in which R2 represents a cycloalkyl group having from 3 to 10 carbon atoms 5 which is unsubstituted or substituted by one or i in which R_ represents more alkyl and/or alkylene groups! orj~an aryl group which is unsubstituted or substituted by 1 to 3 halogen atoms, a phenyl group, 1 to 3 alkyl groups each having 1 to 4 carbon atoms, a chloromethyl, 10 fluoromethyl, trifluoromethyl, carboxy or hydroxy group or an alkoxy group having from 1 to 4 carbon atoms; or in which R2 represents a 5- or 6-membered aromatic heterocycle having one or more hetero atoms selected from nitrogen, oxygen and sulphur atoms. 15 6. A compound as claimed in claim 5, wherein R2 represents an alkyl group having from 1 to 4 carbon atoms which is unsubstituted or substituted by a fluorine, chlorine or bromine atom or by a •phenyl, dimethylamino, diethylamino, methoxy or 20 ethoxy group; or R2 represents a cyclopentyl, cyclo- hexyl,pnethylcyclohexyl group; or R2 represents a phenyl group which is unsubstituted or substituted in the 3- or 4-position by a fluorine, chlorine, (C^-C^)- alkoxy or trifluoromethyl substituent or in the 25 4-position by a hydroxy group; or R2 represents a 2-furyl, -thienyl or -pyridyl group or a 3-furyl I n 204875 - 72 - or -thienyl group or a 3- or 4-pyridyl group. 7. A compound as claimed in claim 1, wherein R^ represents a group of the general formula NHR^ in which R^ represents an acyl radical of a carboxylic 5 or sulphonic acid having from 1 to 15 carbon atoms. 8. A compound as claimed in claim 7, wherein the acyl radical has up to 10 carbon atoms. 9. A compound as claimed in claim 8, wherein ^ R^ represents a meth-anesulphonyl, isopropanosulphonyl 10 or acetyl group. 10. A compound as claimed in claim 1, wherein R^ represents a hydroxy group. 11. A compound as claimed in claim 1, wherein R^ represents a hydrogen atom. 15 12. A compound as claimed in any one of claims 1 to 11, wherein the radical represented by D is not substituted by fluorine. 13. A compound as claimed in claim 12. , wherein D represents -CHJCH^ , -CICH^ ^2~^2~ or 20 — C CH- wherein in each case the CH, moietv^™^, /\ 2 2 CH, /CH, A/ \? / 2 i'i CH2 \ 16SEP1986'; y is bonded to the radical represented by E. 14. A compound as claimed in any one of claims 1 to 13, wherein E represents -C=C- or -CR^-CR^- 15. A compound as claimed in claim 14t wherein \ \ - 73 - *04*75 Rg and R7 each represents a (C^-C^)-alkyl radical or Rg represents a (C^-C^jJ-alkyl radical and R^ represents a chlorine atcm. 16. A compound as claimed in any one of claims 1 to 15, wherein R^ represents an aliphatic hydrocarbon radical having from 1 to 10 carbon atoms; a cycloalkyl radical having from 3 to 10 ring carbon atoms which is unsubstituted or substituted by one or more alkyl radicals; an aryl or araliphatic hydrocarbon radical wherein the aliphatic moiety has 1 to 10 carbon atoms and wherein the aryl radical or aryl moiety of the araliphatic radical is unsubstituted or substituted by 1 to 3 halogen atoms, a phenyl group, 1 to 3 (C^-C^ )-alkyl radicals, a chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy group or by a (C^-C4)-alkoxy radical; or an aromatic heterocyclic radical having at least one heterocyclic atom selected from oxygen, nitrogen and sulphur. 17. a compound as claimed in claim 16, wherein R4 represents a methyl, ethyl, propyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, hexenyl, benzyl, £-chlorobenzyl, cyclopentyl, cyclohexyl, methylcyclo-hexyl,. 1-naphthyl or 2-naphthyl group; or a phenyl group which is unsubstituted or substituted in the 3- or 4-position by a fluorine or chlorine atom, a (C^-C^ )-alkoxy radical or a trif luoromethyl \ I - 74 - group or in the 4-position by a hydroxy group; or represents a 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl group. 18. A compound as claimed in claim 17, wherein R4 represents an alkyl radical having from 1 to 4 carbon atomsother than isopropyl. 19. A compound as claimed in any one of claims 1 to 11, wherein DER^ represents CH, CH, i i -CH-CH2-CSC-CH3 , -CH-CHj-CSC-CHJ-CH, , CH- CH, CH- I I / -C-CH2-C=C-CH3 , -CH-CH2-CH=C \. CHj ^CH3 CH2-C£C-CH3 or C CH2-C=C-CH2CH3 /\ ' /\ CH- CH- CH- CH- \ / \ / ch2 ch2 \fj8 SEP 1986 ' c p IV ~ k i ^ 20. A compound as claimed in any one of claims 1 to 19, wherein R^ represents a free hydroxy group. 21. A compound as claimed in any one of claims 1 to 20, wherein W represents a hydroxymethylene group or a -C(CH3)(OH)- group in which the hydroxy groups are free. 22. A compound as claimed in any one of claims f*5 . 75 . 204*75 1 to 19, wherein a functionally modified hydroxy group represented by R5 and/or in W is a hydroxy group etherified by a tetrahydropyranyl, tetrahydro-furanyl, oc-ethoxyethyl, trimethylsilyl, dimethyl-5 tert.-butylsilyl or tribenzylsilyl group or esterified by a (C^-C^)-alkanoyl radical or by a benzoyl group. 23 . A compound as claimed in any one of claims 1 to 22 , wherein the hydroxy or functionally modified hydroxy group in the radical represented by W is 10 in the a-configuration. 24. A compound as claimed in any one of claims 1 to 23, wherein n represents 3. 15 25. (5E)-(16RS)-2-decarboxy-la,lb-dihomo-2-formyl- 16-methyl-3-oxa-l8,18,19,19-tetradehydro-6a-carba-prostaglandin-l2. 26. (5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2. 20 27. (5£)-(16RS)-2-decarboxy-la,lb-dihomo-2-formyl- 16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-Ij. 28. (5Z)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2• 25 29. <5E)-(16RS)-2-decarboxy-la, lb-dihomo-16,20- dimethyl-2-formyl-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprostaglandin-l2. JtSEPms 204-875 - 76 - I 30. (5E)-(16R§) -1 a, 1 b-dihomo-16,20-dimethyl-3-oxa-18, 18,19,19-tetradehydro-6a-carbaprostaglandin-I2 • 31. (5E)-2-decarboxy-la,1b-dihomo-2-fonnyl-20-methyl-3-oxa-16,16-trimethylene-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I^ . 32. (5E)-la,1 b-dihomo-20-roethyl-3-oxa-16,16-trimethylene-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 . 33 . (5g)-2-decarboxy-1 a,lb-dihomo-16,16-dimethyl-2-forrnyl-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 . 34 . (5g)-1a,1 b-dihomo-16,16-dimethyl-3-oxa-l8,18,19, 19-tetradehydro-6a-carbaprostaglandin-I2 . 35 . (5E)-2-decarboxy-1a,1b-dihomo-2-formyl-3-oxa-16,16, 20-trixnethyl-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 . 36 . (5E)-la,1 b-dihomo-3-oxa-16,16,20-trimethyl-18,18, 19,19-tetradehydro-6a-carbaprostaglandin-I2 , 37. (5E)-(16RS)-2-decarboxy-18 #19-diaehydro-1 a,1b-dihomo-16,19-dimethyl-2-formyl-3-oxa-6a-carbaprostaglandin-I2. 38. (5E)-1 a,1 b-dihomo-16,19-dimethyl-18,19-didehydro-3-oxa-6a-carbaprostaglandin-I2' 3 9. (5E)-(16RS)-2-decarboxy-13,14-didehydro-1a,1b-dihomo-2-formyl-l6-methyl-3-oxa-18, 18 ,19,19-tetradehydro- 6a-carbaprostaglandin-I2 . 204675" - 77 - \ V 40. (5E)-(1 6R§ ) -1 3,14-didehydro-1 a, i b-dihorao-16-methyl— 3-oxa-l8,18,19 ,19-tetradehydro-6a-carbaprostaglandin-I2. 41. (5g)—(16Rg)-2-decarboxy-13,14—didehydro-1a,lb-dihomo-1 6,20-dimethyl-2-formyl-3-oxa-l8,18,19,19-tetra-dehydro-6a-carbaprostaglandin-I2. 42. (5E)-(16RS 3-13,14-didehydro-1 a,1b-dihomo-16,20-dime thyl-3-oxa-l8,18,19,19-tetradehydro-6a—carbaprosta-glandin-I2. 4 3. (5E)-2-decarboxy-13,14-didehydro-1 a,1 b-dihomo-2-£ orroyl-20-methyl-3-oxa-18,1 8,19,19-tetradehydro-l 6,16-trimethylene-6a-carbaprostaglandin-I2 . 44. (5E )-13,14-didehydro-1 a, Tb-dihomo- 20-methyl'- 3-oxa— 18,18,19,19-tetradehydro-l6,16-trimethylene-6a-carba-prostaglandin-I2 . 45 . (5E)-2-decarboxy-13,14-didehydro-1 a, lb-dihomo-16,16-dimethyl-2-formyl-3-oxa-18,18,19,1 9-tetradehydro-6a-carbaprostaglandin-l2 • 46. (5E)-l3,14-didehydro-1 a,1 b-dihomo-16,16-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 • 47 . (5E)-2-decarboxy-1 3 , 14-didehydro-1 a,1b-dihomo-2-formyl-3-oxa-18,i8,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin-I2 . ~-v\ 6SEP19&6.S- J/ WW. - «- jt.,- • >' • • 1 •• 20^875 - 78 - 48. (5E)-i3, 14-didehydro-ia, 1b-dihomo-3-oxa-l8,l8,i9,l9-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin-I2. 4 9. (5g)-(16gg)-2-decarboxy-ia,lb-dihomo-5—fluoro-2— formyl-16-methyl-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprostaglandin-I^. 50 . (52)-(i6RS)-1a,1b-dihorao-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2. 51. (5Z)-(16RS)-2-decarboxy-1 a,1b-dihomo-16,20-dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 . 52. (5Z)-(16RS)-1 a,1b-dihomo-16,20-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2. 53. (5Z)-2-decarboxy-1 a,1b-dihomo-5-fluoro-2-formyl-20-methyl-3-oxa-l8,18,19,19-tetradehydro-l6,16-trimethylene 6a-carbaprostaglandin-I2 • 54 . (5Z)-1a,lb-dihomo-5-fluoro-20-methyl-3-oxa-18,18,19, 1 9-tetradehydro-l6,16-trimethylene-6a-carbaprosta-glandin-I2. 55. (5z)-2-decarboxy-1 a,1b-dihomo-16,16-dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 , 56. (5Z)-1 a,1 b-dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-Iy/ ,r ■' '6Sfp/986 c 204875" - 79 - \ \ 57. (5Z)-2-decarboxy-1 a,1b-dihomo-5-fluoro-2-forroyl-3-oxa-18,18,19,19-tetradehydro-16,i6,20-trimethyl-6a-carbaprostaglandin-I^, 58. (52)-1 a,1 b-dihorao-5-fluoro-3-oxa-18,18,19,19-tetra-dehydro-l6, 1 6,20-trimethyl-6a-carbaprostaglandin-l2 . 59. (5Z)-(16RS)-2-decarboxy-13,14-didehydro-la,ib-dihomo-5-fluoro-2-formyl-i6-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2. 60. (5Z)-(16RS)-l3,14-didehydro-1 a,1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-^ . 61. (5Z)-(l6RS)-2-decarboxy-13,14-didehydro-1a,1b-dihomo-16,20-diinethyl-5-fluoro-2-formyl-3-oxa-l8,18,19, 19-tetradehydro-6a-carbaprostaglandin-l2 . 62. (5Z)-(16RS)-13,14-didehydro-1 a,lb-dihomo-16,20-dimethyl-5-fluoro-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprostaglandin-I2. 63. (5Z)-2-decarboxy-13,14-didehydro-1 a,1b-dihomo-5-fluoro-2-formyl-20-methyl-3-oxa-l8,18,19,19-tetra-dehydro-16,16-trimethylene-6a-carbaprostaglandin-l2. 64. (5Z)-i3,14-didehydro-1 a,1 b-dihomo-5-fluoro-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-triroethylene 6a-carbaprostaglandin-I _ . .-^£-7 - /''k *' h. /v as: 204875 - 80 - 65. (52)-2-d^carboxy-13,14-didehydro-ia,lb-dihomo-16,16~dirnethyl-5-f luoro-2-f orxnyl-3-oxa-l 8,18,19,19-tetradehydro-6a-carbaprostaglandin-I2, 66. (52)-13,14-didehydro-1a,1 b-dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 • 67. (52)-2-decarboxy-13,14-didehydro-1 a,1b-dihomo-5- fluoro-2-formyl-3-oxa-l8,18,19,19-tetradehydro-l6,16,20-^ trimethyl-6a-carbaprostaglandin-I2. 68. (5g)-l3,14-didehydro-1 a,lb-dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-l 6,16,20-trimethyl-6a-carba-prostaglandin-l2 - 69.. (5E)-(16RS )-1a, lb-dihomo-16-methyl-3-oxa-18,18,19, 19-tetradehydro-6a-carbaprostaglandin-I2 methyl ester. 70. (5E)-(16RS)-1a,ib-dihomo-i6-methyl-3-oxa-l8,18,19, 19-tetradehydro-6a-carbaprostaglandin-I2 carboxamide # 71. (52)-( 1 6RS )-1 a, 1 b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,1 9-tetradehydro-6a-carbaprostaglandin-I2 (2,3-dihydroxypropyl)-amide ♦ 72. (52)-(16RS)-1 a,1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandiu-I2 (4-phenyl)-phenacyl ester. r- \ «- .v' .*• A S // r,t6SEPI9, X ' i , 204*875" - 81 - 1 I 73. A salt of a compound as claimed in any one of claims 1 to 72. 74. A physiologically tolerable salt of a compound as claimed in any one of claims 1 to 72. 5 75. A salt of a compound as claimed in any r) one of claims 10, 12 to 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66 and 68, in which R^ represents a ^ hydroxy group, with an alkali metal hydroxide, 10 an alkaline earth metal hydroxide, ammonia, ethanol-amine, diethanolamine, triethanolamine, N-methylgluc-amine, morpholine or tris-(hydroxymethyl)-methylamine. 76. (5E ) -(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 15 tris-(hydroxymethyl)aminomethane salt. 77. A process for the preparation of a compound as claimed in claim 1 or a salt thereof, which comprises etherifying a compound of the general formula CH-OH I 2 CX V1 A 20 11 A-W-D-E-R. 4 S G? JV 1.A I 204875 - 82 - s in which X, R^, R^, A, W, D and E have the meanings given in claim 1, in the presence of a base, if desired after protecting one or more free hydroxy groups present, with a haloketal of the general 5 formula /0R8 Hal - (CH_ ) -CH^ hi 2 n N. 0Rg in which Hal represents a chlorine, bromine or iodine atom, each of Rg and Rg, which may be the same or different, represents an alkyl radical 10 having from 1 to 10 carbon atoms or Rg and R^ together represent a divalent radcal having from 2 to 10 carbon atoms and n has the meaning given in claim 1, and splitting the resulting ketal, and, if desired, converting a compound of the general 15 formula I or a salt thereof thus obtained into another compound of the general formula I or a salt thereof. 78. A process as claimed in claim 77, wherein after the splitting of the ketal one or more of 20 the following reactions is carried out, where appropriate, in any desired sequence: isomers are separated, one or more protected hydroxy groups is liberated£^ ft V* ~ ' ■ w ".V;j } 1986 ?■< //' i v £-5^' t - 83 - 204875 one or more free hydroxy groups is esterified or etherified, the aldehyde group is oxidised, the resulting free carboxy group is esterified, 5 an esterified carboxy group is hydrolysed, a carboxy group is converted into an amide or is converted into a salt. 79. A process as claimed in claim 77, carried out substantially as described in any one of the 10 Examples 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41 and 43 herein. 80. A process as claimed in claim 77, wherein the subsequent conversion is carried out substantially as described in any one of the Examples 15 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 45, 46, 47, 48 and 49 herein. 81. A compound as claimed in claim 1, whenever prepared by a process as claimed in any one of 20 claims 77 to 80. 82. A salt of a compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 77 to 80. \ 83. A physiologically tolerable salt of a 25 compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 77 to 80. o 'i - 84 - 2048 84. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 1 to 72, 74 to 76, 81 and 83, in admixture or conjunction with a pharmaceutically suitable carrier. 85. A pharmaceutical preparation as claimed in claim 84, which is in dosage unit form. 86. A pharmaceutical preparation as claimed in claim 85, wherein the amount of active ingredient per dosage unit is from 0.1 to 100 mg. SCHERING AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LIMITED By ■ §14