IE831630L

IE831630L - Carbacyclin derivatives

Info

Publication number: IE831630L
Application number: IE831630A
Authority: IE
Original assignee: Schering Ag
Priority date: 1982-07-13
Filing date: 1983-07-13
Publication date: 1984-01-13
Also published as: FI832557A0; CS235329B2; IL69199A0; HU191057B; EP0099538B1; PH25119A; DK163579C; DE3226550A1; DE3382408D1; DK321283A; AU1671883A; ATE67182T1; DD210027B3; EP0099538A1; ES524058A0; IL69199A; DD210027A5; JPH0324457B2; ES8403865A1; AU571841B2

Abstract

Carbacylin derivatives of the general formula I <IMAGE> in which R1 denotes a hydrogen atom or the radical OR2, in which R2 can denote hydrogen, alkyl, cycloalkyl, aryl, the radical <IMAGE> 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 <IMAGE> group, in which the OH group can be in the alpha or beta position, D denotes the group <IMAGE> 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

The invention relates to carbacyclin derivatives, a process for their manufacture and their use as medicaments.

German Offenlegungsschriften DE-OS 28 45 770, 29 CO 352, 29 02 442, 29 C4 S55, 29 09 088, 30 48 906 and 29 12 409 describe (5E)- and S£)-6a-carbaprosta-glandin-Ij analogues. The nomenclature of the compounds according to the invention is based on a proposal by Morton and Brokow (J. Org. Chem., 44, 2280 id="p-1979" id="p-1979" id="p-1979"

[1979]). The synthesis of these compounds always produces two double bond isomers which are characterised by the affix (5£) or (5Z). The two isomers of this prototype are illustrated by the following structural formulae: Ho OB HO OH (SB)-6a-carbaprostaglan-din-I2 (5Z)-6a~carbaprostagla» din-I- 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.

It has now been found that by homologis ing the upper chain of the-3-oxa-carbacyclins a longer duration of action, greater selectivity and an improved activity can be achieved. The compounds according to the invention have a hypotensive and broncho dilative action. They are also suitable for vasodilation and for inhibiting thrombocyte aggregation and gastric acid secretion.

The invention relates to carbacyclin derivatives of the general formula I 0 , t I D-E-R, OH in which Rj_ represents hydrogen or 0Hf X represents a hydrogen atom or a fluorine atom A represents a trans-CH=*CH- or -Csq- group/ W represents a hydroxynethylene group wherein the OH group nay be in the a- or fl-conf iguration, D represents the group -C-CHj-* -CH(CH3)-CH2- or -C(CH3)2-CH2-, E represents a -e=C- group, R4 represents methyl or ethyl and, if Ri represents an OH group, the salts thereof with physiologically tolerable bases.

The invention relates furthermore to the following compounds: (5fi)-(16BS)-la,lb-dihoao-16-methyl-3-oxa-18,18,19,19- tetradehydro-6a-carbaprostaglandin-l2-methyl ester -\ (5B)-(16BS)-l®f lb-dihomo-l6-methyl-3-oxa-l8,18,19,19- tetradehydro-6a-carbaprostaglandin-I2-carboxamide 1 (5Z)-(16BSL)-la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2-(2,3-dihydroxypropyl)-amide (5£) - (16BS)-la, lb-dihoao- 5-£ luoro-16-aethy1 - 3 -oxa- 18,18,19,19 -1 etradehydro-6 a-carbaprqs t agl andin-* 12 - (4-pheny1)-phenacyl ester.

Suitable for salt-formation with the free acids (Rj[ - OH) are inorganic and organic bases, such as those known to the person skilled in the art for the formation of physiologically tolerable salts. There may be mentioned, for example: alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc..

The invention relates also to a process for the manufacture of the carbacyclin derivatives of the general formula I according to the invention, characterised in that, in a manner known per se. a compound of the general formula IX wherein X, R4, A, W, D and E have the meanings given above, is etherified in the presence of a base, optionally after protecting any free hydroxy groups present.

CK.OH CX OH with a haloketal of the general formula III y°H Hai-(CH2)3 ' xOR9 (III) wherein Hal represents a chlorine, bromine or iodine atom, each of R8 and R9 represents an alkyl group having from 1 to 10 carbon atoms, or Rg and R9 together represent a ring-forming group having from 2 to 10 carbon atoms, the ketal is split with acid, and optionally then, in any sequence, isomers are separated and/or protected hydroxy groups are freed and/or free hydroxy groups are esterified or etherified and/or the aldehyde group is oxidised and/or the resulting free car boxy group is esterified and/or an esterified carboxy group is hydrolysed or a carboxy group is converted into an amide or is converted into a salt with a physiologically tolerable base.

The reaction of the compound of the general formula II with a haloketal of the general formula III is carried out at. temperatures of from o"C to 100*C, preferably from 10"C to 80*C, in an aprotic solvent or mixture of solvents, for example dimethyl sulphoxide, diaethyl-formamide, tetrahydrofuran, etc.. As bases there come into consideration the bases known to the person skilled in the art for etherification reactions, for example sodium hydride, potassium tert.-butoxide, butyllithium etc..

The splitting of the ketal to form compounds of the general formula I after the etherification reaction is carried out according to known methods. For example, the splitting of the ketal is carried out in an aqueous solution of an organic acid, such as, for example, acetic acid or propionic acid inter aliaf or in an aqueous solution of an inorganic acid, such as, for example, hydrochloric acid. To improve solubility, advantageously a water-aiscible inert organic solvent is added.

Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, and ethers, such as dinethoxyethane, dioxane and tetrahydrofuran. Preferably tetrahydrofuran is used. The splitting of the ketal is preferably carried out at temperatures between 20 "C and 80 "C.

The oxidation of the aldehyde group is carried out according to methods known to the person skilled in the art. There may be used as oxidising agents, for example: pyridinium dichromate (Tetrahedron Letters, 1979. 399), Jones reagent (J. Chem. Soc. 1953. 2555) or platinua/-oxygen (Adv. in Carbohydrate Chem. 12, 169 (1962)).

Oxidation with pyridinium dichromate is carried out at temperatures 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 dimethylfornamide.

Oxidation with Jones reagent is carried out at temperatures of from -40"C to +40*C, preferably from o'c to 30*C, using acetone as solvent. Oxidation with platinum/oxygen is carried out at temperatures of from o'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 acetate.

The hydrolysis of the carbacyclin esters is carried out according to methods known to the person skilled in the art, such as, for example, using basic catalysts.

The introduction of the ester group with OCH3 for R^ is carried out according to methods known to the person skilled in the art. The carboxy compounds are reacted, for example, with diazomethane in a manner known per s£. The esterification with diazomethane is carried out, for example, by mixing a solution of the diazomethane 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. in from 1 to 30 minutes, the solvent is removed and the ester is purified in customary manner. Diazomethane is known and can be manufactured according to known methods [Org. Reactions, Vol. £, pages 389-394 (1954)].

The introduction of the ester group with o for can also be carried out by reacting the carboxy late anion with the corresponding alkyl halide or 0 1 W -haloketone (Hal-CH2-C-Ar in which Ar represents diphenyl).

The carbacyclin derivatives of the general formula I in which Rj_ represents a hydroxy group cam be converted into salts by neutralisation using suitable aaounts of the corresponding inorganic bases. The solid inorganic salt is obtained, for exaaple, by dissolving the corresponding acids in water that contains the stoichiometric aaount of the base and then evaporating off the water or adding a water-aiscible solvent, for exaaple an alcohol or acetone.

The manufacture of the aaine salts is carried out in custoaary Banner. For this purpose, the carbacyclin acid is dissolved, for exaaple, in a suitable solvent, such as ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric aaount of the aaine is added to this solution. The salt is generally obtained in solid fora or is isolated in customary Banner after evaporation of the solvent.

The functional modification of the free OH groups is carried out according to methods known to the person skilled in the art. For the introduction of the ether protecting groups, reaction is carried out, for exaaple, with dihydropyran in methylene chloride or chloroform using an acid condensation agent, such as, for exaitple, p-toluenesulphonic acid. The dihydropyran is used i in excess, preferably in from 4 to 10 times the amount theoretically required. At from 0°C to 30°C the reaction is normally complete after from 15 to 30 minutes.

The introduction of the acyl protecting groups is carried out by reacting a compound of the general formula I in a manner known per se with a carboxy lie acid derivative, such as, for example, inter alia, an acid chloride or acid anhydride.

The liberation of a functionally modified OB group to form the compounds of the general formula I is carried out according to known methods. For example, ether protecting groups are split off in an aqueous solution of an organic acid, such as, for example, inter alia, 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. Splitting off is preferably carried out at temperatures of between 20°C and 80°C.

Silyl ether protecting groups are split off, for exaaple, with tetrabutylammonium fluoride. Suitable solvents are, for example, tetrahydrofuran, diethyl ether, dioxane, methylene chloride, etc.. Splitting off is preferably carried out at temperatures of between 0°C and 80"C.

The hydrolysis of acyl groups is carried out, for example, with alkali metal or alkaline earth metal carbonates or hydroxides in an alcohol or the aqueous solution of an alcohol. As alcohols there come into consideration aliphatic alcohols, such as, for example, methanol., ethanol, butanol, etc., preferably methanol. As alkali metal carbonates and hydroxides there may be mentioned potassium and sodium salts, but the potassium salts are preferred. Suitable alkaline earth metal carbonates and hydroxides are, for exaaple, calcium carbonate, calcium hydroxide and barium carbonate. The reaction takes place at from -10"c to 70"C, preferably at 25*C.

The introduction of the amide group with NHj or MHCHjCHCaB) CH2CH for is effected according to methods known to the person skilled in the art. The carboxy lie acids of the general formula I are first converted into the mixed anhydride using chloroformic acid isobutyl ester in the presence of a tertiary amine, such as, for exaaple, triethylamine. The reaction of the mixed anhydride with the alkali metal salt of the corresponding 11 amine or with aaaonia is carried out in an inert solvent or mixture of solvents, such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide or hexamethyl-phosphoric acid triamide, at temperatures of between ~30"c and +60*C, preferably at o'c to 30*c.

Xf the starting material contains OH groups in the prostane radical, then these OH groups are also reacted. If the ultimate aim is to produce end products that contain free hydroxy groups in the prostane radical, it is advantageous to use starting materials in which these hydroxy groups are intermediately protected by ether or acyl radicals that preferably can readily be split off.

The compounds of the general formula XX which serve as starting materials can be manufactured, for example, by, in a manner known par sg, reacting an aldehyde of the formula V (DE-OS 28 45 770) with a phosphonate of the general formula VI ch3o CH^O 0 \H p / - CH„ - 0 II c - D - E - R (VI) in which D, E and R4 have the meanings given above, in the presence of a deprotonating agent, such as, for example, sodium hydride or potassium tert.-butoxide, to form .a ketone of the general formula VII (Z « H), or additionally in the presence of a brominating agent, such as, for example, N-bromosuccinimide, to form a ketone of the general formula VII (Z ■ Br) 1 0 'CH-CZ —C -D —E — OCOPh 0 (VII).

Reduction of the keto group with zinc borohydride or sodium borohydride or reaction with alkylmagnesiua bromide or alkyllithium and subsequent separation of the epimers yields compounds of the general formula VIII 13 ch«cz-w~d-e-r4 6co Y7\ (VIII) 5 10 Hydrolysis of the ester group, for example with .0 potassium carbonate in methanol, and optional hydro-genation of the double bond or optional etherification 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, tot example by etherification with dihydropyran, yields the ketone of the general formula DC 0 A-W-D-e-R 4 (IX) OH i An olefination reaction with phosphonoacetic acid trie thy 1 ester or phosphonoacetic acid trixnethyl ester or with phosphonofluoroacetic acid triethyl ester or phosphonof luoroacetic acid trimethyl ester and subsequent reduction with lithium aluminium hydride yields the compounds of the general formula IZ which are isomeric at the double bond and can optionally be separated.

The phosphonates of the general formula VI are manufactured in a manner known per se by reacting the anion of methylphosphonic acid dimethyl eater with an ester of the general formula X in which D, E and have the meanings given above and R,0 represents an alkyl group having from 1 to 5 carbon atoms and which may optionally be obtained from the corresponding malonic acid ester by alkylation with the halide (X) Hal - E - R4 (XI) of the general fornula XI in which Hal represents chlorine or bromine and subsequent decarboxylation. The ester of the general fornula X can optionally be obtained also from the carboxylic acid of the general fornula XII 0 HO - C - D (XII) in which D has the meaning given above, by alkylation with the halide of the general foraula XX and subsequent esterification.

The compounds of the general fornula IIX which serve as starting materials can be manufactured# for example, by, in a manner known per se. reducing a 0-halocarboxylic acid ester of the general formula XIII Hal~(CH2)3-COOR10 (XIII) in which Hal has the meaning given above and Rio represents an alkyl group having from 1 to 5 carbon atoms, with diisobutylaluminium hydride to form the correspond'" ing aldehyde and subsequently ketalising with an alcohol in known manner.

The compounds of this invention have a hypotensive and broxtchodi lat ive action. They are also suitable for the inhibition of thrombocyte aggregation.

Consequently, the new carbacyclin derivatives of the formula I are valuable pharmaceutical active substances. Furthermore, whilst having a similar spectrum of action, conpared with corresponding prostaglandins, they exhibit higher specificity and, especially, substantially longer activity. In conparison with POI2 they are distinguished by greater stability. The high tissue specificity of the new prostaglandins is apparent in studies on smooth-muscle organs, such as, for example, the ileum of guinea pigs or the isolated .trachea of rabbits, 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 new carbacyclin analogues possess properties typical of prostacyclins, such as, for exaaple, reduction of the peripheral arterial and coronary vascular resistance, inhibition of thrombocyte aggregation and breaking up of platelet thrombi, myocardial cyto-protection and, therewith, lowering of the systemic blood pressure without simultaneously reducing cardiac output and coronary blood flow; treatment of stroke, prophylaxis and therapy of coronary heart diseases, coronary thrombosis, cardiac infarct, peripheral artery diseases, arteriosclerosis and thrombosis, prophylaxis and therapy of ischaemic attacks of the central nervous system, therapy of shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion and cytoprotection of the gastric and intestinal mucosa, cytoprotection in the liver and pancreas* anti-allergic properties, reduction of pulmonary vascular resistance and of pulmonary blood pressure# stimulation of the blood flow through the kidneys, use instead of heparin or as adjuvant in the dialysis of haemofiltration, preservation of blood plasma supplies, especially blood platelet supplies, inhibition of labour pains, treatment of toxaemia in pregnancy, increase in cerebral blood flow -etc.. In addition, the novel carbacyclin derivatives have anti-proliferative and anti-diarrhoeal properties. The carbacyclins of this invention can be used also in combination, for example, with 0-blockers or diuretics.

, The dosage of the compounds is from 1 to 1500 iig/kg/day when administered to human patients. The unit dose for the pharmaceutically acceptable carrier is from 0.01 to 100 mg.

In the case of intravenous injection to conscious hypertensive rats in doses of 5, 20 and 100 (ig/)cg body weight, the compounds according to the invention have a greater auod longer lasting hypotensive action than do PGE2 and PGA^, without causing diarrhoea, as does or cardiac'arrhythmia, as does PGA2a In the case of intravenous injection to narcotised rabbits, the conqpounds according to the invention cause - 18 - a greater and considerably longer-lasting decrease in blood pressure compared with PGEj and PGA2, without other smooth-muscle organs or organ functions being influenced.

For parenteral administration, sterile, injectable 5 aqueous or oily solutions are used. For oral administra tion, tablets, dragges or capsules, for example, are suitable.

The invention also relates, therefore, to oedica-aents based on compounds of the general formula I and 10 customary adjuncts and carriers.

The active substances according to the invention are to be used, in combination with the adjuncts known and customary in galenical pharmacy, for example for the manufacture of hypotensive agents. - 19 - Exaeale 1 (SE)-(16RS }-2-decarboxy-la, lb-dihoxno~2-£ormyl--16-EDiethyl-3- 0 oxa-lS, 18,19 • 19-tetradehydro-6a-carbaproataglandia~I2 u 77 ng of 55 % sodium hydride suspension in mineral 5 oil is added at 0°C to a solution of 7oo ng of 2-£(E)- y (IS, 5S, 6R, 7R)-7-( tetrahydropyran-2-yloxy )-6-[ (E)-(3S, 4RS )-4-methyl-3~( tetrahydropyran-2-yloxy )-oct-l-en- 6-yny 1 ] -bicyelo [ 3 - 3. o]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-brozaopropyl)-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 2 5 with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. Chromatography of the residue over silica gel with hexaae/ether (7-4-3) yields 4-80 mg of the oxa compound which is stirred with 40 ml of a mixture of acetic acid/water/tetrahydrofuran O * 20 (65+35+10) for 16 hours at 24 C. The whole is subsequently concentrated by evaporation in vacuo and the ^ residue is chromatographed over silica gel. Using ethyl acetate/hexane (4+1)# 270 ng of. the title cone-pound in the form of a. colourless oil are obtained. 25 ZR (CH&3): 3600, 3420 (broad). 2970, 2862, 2730. 1725, 1603, 970/em. 20 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 5 -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 10 ml of isqpropyl alcohol and 25 ml of water are added dropwise thereto. The whole is stirred for 2 hours at room temperature and 10 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 100 mg of g-toluenesulphonic acid are added and the whole is refluxed for 6 hours using a water 15 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 20 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-raethyl-3-oxa-18,18,19,19-2 5 tetradehydro-6a-carbaprostaglaadin- l2 2 ml of acetic anhydride are added to a solution of 500 sag of the aldehyde manufactured according to Exanple 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 rimes with water, dried over 10 magnesium sulphate and concentrated by evaporation { in vacuo. Chromatography of the residue over silica ! j gel with hexane/ethyl acetate (1+1) yields 410 mg of (5E)-( 16RS )-la, lb-dihomo-16-raethyl-3-oxa~18,18,19,19-tetradehydro-6a-carbaprostaglandin-11,15-diacetate i 15 in the form of a colourless oil.

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

To split off the protecting groups, 410 mg of the 11,15-diacetate in 20 xnl of methanol are stirred j with 520 mg of potassium carbonate for 16 hours at 20 24°C. The whole is subsequently concentrated in vacuo, j 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.

IRs 3590, 3420 (broad). 2960, 2930, 2865, 1720, 1600. 970/cm. - 22 Example 3 (5Z)- (16RS )-2-decarboxy-la, lb-d£homo-2-f onnyl-16-methyl 3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin~I2 Analogously to Example 1, 125 mg of the title compound are obtained in the form of a colourless oil from 320 mg of 2-|(Z)-(lSf5Si,6R,7R)-7~(tetrahydropyran-2-yloxy)-6-[ (E)-(3S, 4RS)-4-methyl-3-( tetrahydropyran-2-yloxy)-oct-l-eri-6-ynyl ] -bicyclo [3.3.0] oct an- 3-ylideneJ -ethan-l-ol.

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

Example A (52)-(16R5 )-la, lb-aihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 Analogously to Example 2. 90 mg of (5Z)-(16R5)-la, lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 11,15-diacetate are obtained from 125 mg of the aldehyde manufactured according to Example 3. After splitting off the protecting groups, 57 mg of the title compound are obtained in the form of a colourless oil.

IRs 3600, 3410 (broad), 2960, 2866, 1718, 1600, 968/cm. - 23 - Example 5 ( 5E)-(16RS)-2-deearboxy-la. lb-dihomo-16,20-dimethyl-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a~carbaprosta-glandin~I2 5 Analogously to Example 1. 610 mg of the title compound are obtained in the form of a colourless oil from 1.35 g of 2-£(E)-(lS,5S,6R,7R)-7-(tetrahydropyran-2-yloxy )-6-[ (E)-(3S, 4RS ) - 4—methyl-3- (tetrahydrqpyran-2- i —Trj yloxy) -non-l-en- 6-ynyl ] -bicyclo [3.3.0] oct an- 3-y lidenej -10 ethan-l-ol.

ZR: 3600. 3410 (broad). 2967, 2862. 2731. 1725, 1601. 970/cra.

The starting material for the above title compound is manufactured as follows: 15 5a) (1R, 5S, 6R, 7R)-3,3-ethylenedioxy-7-benzoyloxy-6~ [ (E)- (3S, 4RS) - 3 -hydroxy- 4-me thy lnon- 1-en- 6~yny 1 ] -» 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-20 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 (lR,5£,6R,7R)-3.3- ethylenedioxy- 7-benzoyloxy-6~fozniyl-bicyclo [3.3. O ] octane « 25 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 xnl - 24 - of saturated anmoniua 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, 0-unsaturated ketone in the form of an oil. 5.2 g of sodium borohydride are added in portions at -40°C to a solution of 9.1 g of the ketone in 300 al 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: 15ec-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. 20 5b) (1R, 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]oetan-3~one A mixture of 3.6 g of the a-alcohol manufactured according to Example 5 a 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 - 25 - 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/tetrahvdrofuran (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.

IRs 2960, 2865, 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.o]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 -26 - in 170 ml of tetrahydrofuran, the whole is stirred for 10 minutes, a solution of 9 g of the ketone manufactured according to Exaaple 5b in 90 ml of toluene is added and stirring is carried out for 16 hours at room 5 tenperature 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 fcr 30 minuses 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. *Hie residue is chromatographed 20 over silica gel with ether/hexane (3+2). 2.8 g of 2-£(Z)-( IS, 5S, 6R. 7R) - 7 - (t et r ahydr opy r an- 2-y loxy)-6-[ (E)-( 3S, 4RS )-4-methyl-3-( tetrahydropyran-2-yloxy)-non-l-en-6-yny 1 ] -bicyclo [3.3.0] octan-3-ylidenej -ethan-l-ol are obtained as the less polar compound 25 awri 4.2 g of the title compound in the form of a colourless oil.

ZR: 3600, 3430, 2942, 2863, 1600, 972/csu, 27 " Example 6 ( 5E)-(16RS)-la, lb-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglaadin-I2 Analogously to Example 2, 305 mg of (5E)-(16RS)-5 la, lb-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetr ade-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, ib-dihomo-2-foncyl-20-methyl-3-oxa-15 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)-(IS,5S,6R,7R)-7-(tetrahydro-2 0 pyran- 2-yloxy )-6- [ (E)- (3R )-3- (t et r ahydr opyr an- 2-y loxy ) -4,4-1 r imethy lenenon- l-en-6-ynyl ] -bicyclo [3.3.0]octan-3-ylidenej-ethan-l-ol (manufactured according to Example 5a-c from 2-oxa-3,3-trimethylenenon-5-ynphosphonic acid dimethyl ester). 25 IR: 3610, 3400 (broad), 2968, 2864, 2730, 1725, 1602, 970/cm. - 28 - The starting material for the above title compound is manufactured as follows: Analogously to Example 5c, there are obtained from 3 g of (1R,5S, 6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[ (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 ag 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 compound and 690 mg of the title compound in the form of a colourless 15 oil.

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

Example 8 (5£)-la, lb-dihomo-20-methyl-3-oxa-16,16-trimethylene-18,18,19,19-tetradehydro-6a-carbaprostaglandin-X2 20 Analogously to Example 2, 295 mg of (5E)-la,lb- dihorao- 20-methyl-3-oxa-16,16-tr imethylene-18,18,19,19-tetradehydro-6a-carbaprostaglandin-X2 11»15-diacetate are obtained from 400 mg of the aldehyde manufactured according to Example 7. 25 After splitting off the protecting groups, 220 sag 7a) 2- £(E)—(IS, 5S, 6R, 7R)-7-( tetrahydrqpyran-2-yloxy-4,4-trimethylenenon-l-en-6-ynyl]-bicyclo[3.3.0]- 5 - 29 - of the title compound are obtained in the form of a colourless oil.

IR: 3610, 3400 (broad), 2960 , 2864, 1721, 1602 , 970/cm. Example 9 5 (5E)-2-dec arboxy-1 a, lb-dihomo-16,16-dimethyl-2-f ormyl- 3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin~I2 Analogously to Examples 1 and 5, 0.28 g of the title compound is obtained in the form of a colourless oil from 0.5 g of 2-£(E)-(lS,5S,6R,7R)-7-(tetrahydro-1° pyran-2-yloxy)-6-[ (E)-(3R)-4,4-diaethyl-3~ (tetrahydro-pyran- 2-yloxy) -oct-l-en-6-ynyl ] -bicyclo [3.3.0] octan-3-ylidene^-ethan-l-ol.

IR: 3600, 3400 (broad), 2965, 2732, 1724, 1600, 970/cm. 15 Example 10 (5E )-la, lb-dihomo-16,16-aimethyl-3-oxa-18,18,19,19~ tetradehydro-6a-carbaprostaglandin-I2 Analogously to Example 2, 180 mg of (5E)-la, lb-dihomo-16 , 16-dimethyl-3-oxa-18,18.19,19-tetradehydro-20 6a-carbaprostaglandin-X2 11,15-diacetate are obtained from 0.27 g of the aldehyde manufactured according to Exanple 9.

After splitting off the protecting groups, 120 mg & of the title compound are obtained in the form of a 25 colourless oil.

IR: 3600, 3400 (broad), 2962, 2865, 1720, 1600. 971/cm. 30 Examplell (5E)-2-decarboxy-la,lb-dihomo-2-formyl-3-oxa-16, 16,20-trimethyl-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 5 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)-(lS,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;-1 a, 1 b-dihomc-2-cxa-i6,15,20-triaiethy 1 -18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 15 Analogously to Example 2, 0.3 g of (5E)-la,lb- dihomo-3-oxa-16,16,23-trimeuhyl-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 11,15-diacetate is obtained from 0.4 g of the aldehyde manufactured according to Example 11. 20 After splitting off the protecting groups, 0.22 g of the title compound is obtained in the form of a colourless oil.

IR: 3610, 3400 (broad), 2964, 2864, 1721, 1600, 972/cm. - 31 - Example 15 (5E)-( 16RS)-2-decarboxy-13,14-diaehydro-la, lb-dihomo-2-formyl-16-methyl-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 5 Analogously to Examples 1 and 5, 0.29 g of the title compound is obtained in the form of a colourless oil from 0.6 g of 2-£(E)-(lS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[ (3S,4RS)-4-.methyl-3-(tetrahyaropyran-2-yloxy)-octa-1, 6-diynyl 3-bicyclo! 3.3.0 ]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, 65, 7R)-7-(tetrahydropyran-2-yloxy)-15 6-[ (3S, 4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)- 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 (lR,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 2-j(Z)-(IS, 5S, 6S, 7R)-7-(tetrahydrcpyran-2-yloxy)-6-[ (3S,4RS)-4-methy 1- 3- (tetrahydropyran-2 -yloxy) -octa-1,6-diynyl J -25 bicyclo[ 3.3.0 ]octan-3-ylidene] -ethan-l-ol as the less _ 32 _ 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 5 (5E)-( 16RS) — 13,14-didehydro-la, lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetraaehydro-6a-carbaprostaglandin-l2 Analogously to Example 2, 0.21 g of (5E)-(16RS)-13,14-didehydro-la,lb-dihomo-16-methyl-3-oxa-l 8,18,19,19-tetrahydro-ea-carbaprostaglandin-Ij 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 cbrair.ed in the form of a colourless oil. 15 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 20 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)-(lS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[ (3S, 4RS)-4-methyl-3-(tetrahydropyran- 33 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)-(1S,5S,6S,7R)-7-(tetrahydropyran-2-y loxy) -6 - (3S, 4RS) -4-me thy 1-3- (tetrahydropyr an-2-yloxy) - ethan-l-ol Analogously to Example 5c, there are obtained from 2.1 g of (lR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S, 4RS) - 4-methy 1 - 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, 7H )-7-(tetrahydrcpyran-2-yloxy )-6-[(3S,4^)-4-msthyl-(te'trahydropyran-2-y loxy) -nona-1,6-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-16,2 0-dime thy 1-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin~l2 nona-1,6-diynyl]-bicyclo[3.3.0]octan-3 Analogously to Example 2, 340 mg of (5E)-(16RS)- _ 34 _ 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. 5 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 10 (5E)-2-decarboxy-13,14-didehydro-la,lb-dihomo-2-formyl-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethyl-ene-Sa-carbaprostaglandin-Ij Analogously to Examples I 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-(tetrahydro-pyran-2-yloxy)-6-[(3S)-(tetrahydropyran-2-yloxy)-4,4-trimethylenenona-1,6-diynyl]-bicyclo [3.3.0]octan-3-yliaenej-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: 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 (lR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-3-{tetrahydropyran-2-yloxy)-4,4-trimethylene-nona-1,6-diynyl]-bicyclof 3.3.0]octan-3-one, after separation of the isomers by chromatography, 890 mg of 2-^(_Z)-(IS,5S,6S,7R)-7-(tetrahydropyran-2-y 1 oxy) - 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 fern of an oil.

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

Example 20 (5EJ-13,14-aidehyaro-ia,lb-dihomo-20-methyl-3-oxa-18,18,19,19-tetradehyaro-16,16-trimethylene-6a-carba-prostaglandin-I2 Analogously to Example 2, 0.32 g of (5E)-13,14-didehydro-la , lb-dihomo-2 0-methyl-3-oxa-18, 18,19,19-tetrade-hydro-16,16-trimethylene-6a-carbaprostaglandin-l2 II,15-diacetate is obtained from 0.42 g of the aldehyde manufactured according to Example 19. _ 36 _ 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. 5 Example 21 (5E)-2-decarboxy-13,14-didehydro-la,lb-dihomo-16,16-dimethyl-2-formyl-3-oxa-18,18,19,19-tetradehvdro-6a-carbaprostaglandin-I2 Analogously to Examples 1 and 5, 0.47 g of the 10 title compound is obtained in the form of a colourless oil from 0.9 g of 2-£(E)-(lS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy )-6-[ (3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy) -o.cza-1,6-diynyl ] -bicyclo[ 3.3.0 ]octan-3-ylidene| ethan-l-ol.. 15 IR: 3600, 3410 (broad), 2966, 2730, 2225, 1725/cm.

The starting material for the above title compound is manufactured as follows: 21a) 2(E) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6-[(3S)-4,4-dimethyl-3- (tetrahydropyran-2-yloxy)-20 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 -1 (3 S) -4,4-dimethy 1-3- (tetrahydropyran-2-y loxy) -octa- 37 - 1,6-diynyl]-bicyclo[3.3.0]octan-3-one, after separation of the isomers by chromatography, 625 mg of 2-£(Z>)-(IS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-4,4-dimethy1-3-{tetrahydropyran-2-yloxy)-octa-1,6-diynyl ] -5 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 10 (5EJ-13,14-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-dicehyarc-ia,lb-dihomo-16,I6-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 11,15-diacetate 15 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. 20 IR: 3600, 3410 (broad), 2964, 2865, 2225, 1720/cm. - 38 - Example 23 (5E)-2^decarboxy-13,14-didehydro-la, lb-dihomo-2-formyl-3-oxa-:18,18,19,19-tetradehydro-16,16-20-trimethyl-6a-carbaprostaglandin-Ij 5 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)-(lS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(3S)-4,4-dimethyl-3- (tetrahydropyran-2-yloxy)-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-{ terranvdropyran-2-yloxy )-15 6-[ (3S )-4, 4-dimethyl-3-(tetrahydropyran-2-yloxv)- 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 (lR,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-I(3 S) -4,4 -dimethyl-3- (tetrahydropyran-2-yloxy) -nona-1,6-diynyl ] -25 bicycio[3.3.0]octan-3-ylidene^-ethan-l-ol as the less - 39 - polar compound and 430 mg of the title compound in the form of an oil.

IR: 3610,3400 (broad), 2945, 2865, 2225/cm. 1 Example 24 5 (5E)-13,14-didehydro-1a,1b-dihomo-3-oxa-18,18,19,19-* tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin-l2 Analogously to Example 2, 0.1 g of (5E)-13,14-didehydro-la, lb-dihomo- 3-oxa-l 8 , 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. 15 IR:- 3600, 3400 (broad), 2965, 2864, 2224, 1718/cm.

Example 25 (5£)-(16RS )-2-decarboxy-la,lb-dihomo-5-fluoro-2-formyl-16-methy 1-3-oxa-l 8,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 20 42 mg of 55 % sodium hydride suspension in mineral oil are added at 0°C to a solution of 420 mg of 2-|(Z.)-(lS,5S,6R,7R)-7—(tetrahydropyranr2-yloxy)-6-l(E)-(3S, 4RS) -4-methyl-3- (tetrahydropyran-2-yloxy) -oct-l-en- - 40 6-ynyl ] -bicyclo! 3.3.0] octan-3-ylidenej -2-f luoroethan-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)-l,3-dioxolane in 8 ml 5 of tetrahydrofuran is subsequently added and the whole is refluxed for 20 hours under argon. The 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 24eC. The whole is subsequently concentrated by evaporation in vacuo and 15 the residue is chrcmatographea 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 26 (5Z )-(16RS)-la, lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 Analogously to Example 2, 110 mg of (5Z)-(16RS)-25 la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19- - 41 - tetradehydro-6a-carbaprostaglandin-I- 11,15-diacetate I 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-fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-10 carbaprostaglandin-12 Analogously to Example 25, 370 mg of the title i compound are obtained in the form of a colourless oil from 610 mg of (E)-1, lS,5S,6R,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[ (3S,4RS)-4-methyl-3-(tetrahydropyran-15 2-yloxy) -non-l-en-6-yny 1 ] -bicyclo! 3.3.0 ]octan-3-ylidene 2-fluoroethan-l-oi.

IR: 3610, 3400 (broad), 2963, 2930, 2868, 2731, 163Q, 1602, 971/cm.

Example 28 20 (52) - (16RS) - la, lb-dihomo-16,2 0-dimethyl-5-f luoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 Analogously to Example 2, 125 mg of (5£)-(16RS)-la, lb-dihomo-16,20-dimethyl-5-f luoro-3-oxa-18,18,19,19- - 42 - tetradehydro-6a-carbaprostaglandin-I2 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, 970/cm.

Example 29 10 (5Z)-2-decarboxy-la,lb-dihomo-5-fluoro-2-formyl-20- methy 1 - 3-oxa-l 8,18,19,19-tetradehydro-l 6,16-trimethy 1 ene-6a-carbaprostaglancin-l2 Analogously tc Example 25, 165 mg of the title compound are obtained in the form of a colourless i5 oil from 390 mg of ?-£(£)-(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-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-18,18,19,19-tetradehydro-16,16-trimethy lene-6a-carbaprostaglandin-I2 Analogously to Example 2, 105 mg of (5,Z)-la,lb- - A3 - . dihomo-5-fluoro-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carbaprostaglandin-I2 11,15-diacetate are obtained from 190 mg of the aldehyde manufactured according to Example 29. 5 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. 10 Example 31 (5 2) - 2 -decarboxy-1 a, lb-dihomo-16,16 -dime thy 1 - 5 - f 1 uoro- 2 -formyl-3-oxa-l 8, 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 • % 4 oil from 0.6 g of 2-^( 3Z)-(1S, 5S,6R, 7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl-3-(tetrahydro-pyran-2-yloxy)-oct-l-en-6-ynyl ] -bicyclo [3.3.0] octan-3-ylidenej-2-fluoroethan-l-ol. 20 IR: 3610, 3420 (broad), 2966, 2930, 2868, 2732, 1730, 1602, 971/cm.

Example 32 (52 )-!-la,lb-dihomo-16,16-dimethyL-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 25 Analogously to Example 2, 120 mg of (52)~la,lb - 44 dihomo-16,16-dimethyl-5-f luoro-3-oxa-l 8,18,19,19-tetra dehydro-6a-carbaprostaglandin-I2 11,15-diacetate are obtained from 220 mg of the aldehyde manufactured according to Example 31. of the title compound are obtained in the form of a colourless oil.

IR: 3600/ 3410 (broad), 2964, 2931, 2870, 1720, 1601, 10 Example 33 (5Z) -2-dfecarboxy-la, lb-dihomo-5-f luoro-2-f ormyl-3-oxa-18,18,19,19-tetradehydro-l 6,16,20i-trimethyl-6a-carba-prostagianain-I2 Analogously to Example 25, 0.38 g of the title 15 compound is obtained in the form of a colourless oil from 0.7 g of 2-|(Z)-(lS,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- 20 IR: 3610, 3400 (broad), 2965, 2930, 2870, 2730, 1730, 1601, 970/cm. 5 After splitting off the protecting groups, 92 mg 971/cm - 45 - 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-18,18,19,19-tetradehydro-l 6,16,20-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 35 (5Z) - (16RS )-2-decarboxy-13,14-didehydro-la,lb-dihomo-5-15 f luoro-2-forxnyl-16-methyl-3-oxa-18,18,19,19-tetrade-hydro-6a-carbaprostaglandin-I2 Analogously to Example 25, 0.2 g of the title compound is obtained in the form of a colourless r oil from 0.41 g of 2-[(Z)-(lS,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. - 46 - Example 36 (5Z)-(16RS) -13,14-didehydro-la, lb-dihomo-5-fluoro-16-methyl-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 5 Analogously to Example 2, 0.1 g of (5Z)-(16RS)- 13.14-didehydro-la, lb-dihomo-5-f luoro-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. 10 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 15 (5Z)-(16RS) -2-decarboxy-13,14-didehydro-la, lb-dihomo-16,20-dimethyl-5-f luoro-2-f ormyl-3-oxa-l 8,18,19,19-tetradehydro-6a-carbaprostaglandin-i2 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>)-(lS,5S,6S,7R)-7-(tetrahydro-py r an- 2-yloxy)-6-[(3S,4RS) -4 -methyl - 3 -1 e t r ahy dropy ran-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. - hi - Example 38 (5Z)r(16RS)-13,14 -didehydro-1 a, lb-dihomo-16,20 -dime thy 1 ~ 5-f luoro-3-oxa-l 8,18,19,19-tetradehydro-6a-carbaprosta-glandin-Ij 5 Analogously to Example 2, 0.18 g of (5Z)-(16RS)- 13.14-didehydro-la, lb-dihomo-16,20-dimethyl-5-f luoro-3- oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 « 11.15-diacetats is otbainad from 0.35 g cf the aldehyde manufactured according to Example 37. 10 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 39 15 (5Z)-2-decarboxy-13,14-didehydro-la, lb-dihomo-5-f 1 uoro-2-f ormyl-20-methyl-3-oxa-18,18,19,19-tetradehydro- 16.16-trimethylene-6a-carbaprostaglandin-I2 Analogously to Example 25, 0.7 g of the title compound is obtained in the form of a colourless 20 oil from 1.2 g of 2-[(Z)-(lS,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. - 48 - Example 40 (5Z)-13,14-didehydro-1a,lb-dihomo-5-f1uoro-2 0-methy1- 3 -oxa-18,18,19,19-tetradehydro-l 6,16-trimethylene-6a->> carbaprostaglandin-I2 ■v. 5 Analogously to Example 2, 0.31 g of (5Z)-13,14- didehydro-1 a, lb-dihomo- 5 -f luoro-20 -methyl - 3 -oxa-18,18,19,19-tetradehydro-l 6,16-trimethylene-6a-carba-prostaglandin-I2 11,15-diacetate is obtained from 0.6 g of the aldehyde manufactured according to Example 39. 10 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 15 (5Z)-2-decarboxy-13,14-diaehydro-1 a, lb-dihomo-16,16-dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetra-dehydro-6a-carbaprostaglandin-I2 Analogously to Example 25, 0.65 g of the title compound is obtained in the form of a colourless 20 oil from 1.4 g of 2-[(Z)-(lS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(3S)-4,4-dimethyl-3- (tetrahydro^yran-2-y1oxy)-octa-1,6-diynyl]-bicyclol 3.3.0]octan-3-ylidene^-2-fluoroethan-l-ol.

IR: 3600, 3420 (broad), 2970, 2930, 2865, 2730 2225, 25 1730/cm. - 49 - Example 42 (5Z)—13,14-didehydro-la, lb-dihomo-16,16-diznethyl-5- f luoro-3-oxa-l 8,18,19,19-tetradehydro-6a-carbaprosta- glandin-Ij ^ 5 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. 10 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 43 15 (5Z*)-2-decarboxy-13,14-didehydro-la, lb-dihamo-5-f luoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-l6,16,20-trimethyl-r6a-carbaprostaglandin-I2 Analogously to Example 25, 0.3 g of the title f compound is obtained in the form of a colourless 20 oil from 0.7 g of 2-| (Zi)-(lS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy) —6—[ (3S)-4,4-dimethyl-3 -(tetrahydropyran-2-yloxy)-nona-1,6-diynyl]-bicyclol3.3.0loctan-3-ylideneJ-2-fluoroethan-l-ol.

IR: 3600, 3420 (broad), 2968, 2932, 2864, 2730# 2225, 25 1730/cm.

Example 44 (52) -13,14-didehydro-la, lb-dihomo-5-f 1 uoro-3-oxa-18/18,19,19-tetradehydro-l 6,16,20-tr imethy 1 -6a-carba-prostaglandin-I2 5 Analogously to Example 2, 0.14 g of (5Z)-13,14- didehydro-^la, lb-dihomo-5-f luoro-3-oxa-18,18,19,19-tetradehydro-16,16-20-trimethyl-6a-carbaprostaglandin-l2 11,15-diacetate is obtained from 0.3 g of the aldehyde manufactured according to Example 43. 10 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 45 15 (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)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a- 20 carbaprostaglandin-Ij in 10 ml of dichloroxnethane 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 -51 - of the title compound are obtained in the form of a colourless oil.

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

Example 46 5 (5E)-( 16RS)-la, lb-dihomo-16-methyl-3-oxa-l 8,18,19,19-tetradehydro-6a-carbaprostaglandin-I, carboxamide 105 mg of (5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin*-l2 are dissolved in 3 .ml of tetrahydrofuran; 40 mg 10 of triethylamine and 45 mg of chlorofonaic 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 three times with 30 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/isopropancl (9+1) yields 78 mg of the title compound in the form of an oil.

ZR: 3610, 3540, 3400 (broad), 2960, 1670, 975/ca. - 52 - Example 47 (5 Z J - (16RS) -1 a, 1 b-dihomo-5 «*f 1 uoro-16-methyl -3-oxa- 18,18,19,19-tetraaehydro-6a-carbaprostaglandin-I2 (2 , 3-dihydroxypropyl) -amide 5 195 mg (5Z)-(16RS)-la,lb-dihomo-5-fluoro-16-methyl 3-oxa-l 8,18, 19,19-tetradehydro-6a-carbaprostaglandin-I2 are dissolved in 5 ml of acetone; 60 mg of triethyl- aimine and 75 mg of chloroformic acid isobutyl ester are added at 0°C. After 20 minutes, a solution of 10 260 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 15 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.

IBs 3600, 3400 (broad), 2935, 1645, 974/ca. 20 Example 48 (5Z)-(16RS )-la, lb-dihomo-5-f luoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2 (4-phenyl)-phenacyl ester 120 mg of (5Z)-(16RS)-la,lb-dihomo-5-f 1 uoro-16- 53 methyl ^-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 are dissolved in 3 ml of acetone; 90 mg of »-bromo-4-phenylacetophenone and 1 ml of tri ethyl amine are added and stirring is carried out overnight at r 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 49 (5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-l8,18,19,19-15 tetradehydro-6a-carbaprostaglandin-I2 tris-(hydroxy-methyl)-aminomethane salt A solution of 60 mg of tris-(hydroxymethyl )-amino-methane 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-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 i 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. - 54 -

Claims

1. CLAIMS 1. Carbacyclin derivatives of the formula 'CM,l.-C-R , z 3 1 0 JjHa (I) 1 2 GX A • ! j—( &*U-D-C*C-R^ U in which 5 Rx represents hydrogen or hydroxy, X represents hydrogen or fluorine, A represents a trans-CH = CH- or -CSC- group, W represents a hydroxymethylene group wherein the OH group may be in the a- or R- configuration, 10 D represents the group -CH(CHj)-CHz- or -C (CHS) 2-CHz-, R4 represents methyl or ethyl and, if Rt represents a hydroxy group, the salts thereof with physiologically tolerable bases. 15 2. (5E.)-(16RS)-la,lb-Dihomo-16-methyl-3-oxa-18,l8,19,19-tetradehydro-6a-carbaprostaglandin-I2-m©thyl ester. - 55 - (5fi) - (16RS) - la, lb-Dihomo-16 -methyl - 3 -oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2-carboxamide. (5jS.) - (16RS) -la, lb-Dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2- (2,3-dihydroxypropyl)-amide. (5Z.) - (16RS) -la, lb-Dihomo-5-f luoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2- (4-phenyl)-phenacyl ester. Process for the manufacture of carbacyclin derivatives according to claims 1 to 5, wherein a compound of formula II wherein X, R4/ A, W and D have the meanings given in claim 1, is etherified in the presence of a base, optionally after protecting any free hydroxy groups present, with a haloketal of formula III CX OH (III) wherein Hal represents a chlorine, bromine or iodine atom, each of R8 and R« represents an alkyl group having from 1 to 10 carbon atoms, or R« and R» together represent - 56 - a ring-forming group having from 2 to 10 carbon atoms, the ketal is split with acid, protected hydroxy groups are freed and the aldehyde group is oxidised, and optionally then, in any sequence, isomers are separated 5 and/or the resulting free carboxy group is esterified and/or an esterified carboxy group is hydolysed or a carboxy group is converted into an amide or is converted into a salt with a physiologically tolerable base. 7. Medicament comprising one or more compounds of claims 1 10 to 5 and customary adjuncts and carriers. 8. (5JE)-( 16RS)-la, lb-Dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 • 9 . (5E)-(16RS)-13,14-Didehydro-la,lb-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-l2. 15 10. (5j5)-(16RS)-13,14-Didehydro-la, lb-dihomo-16,20-dimethyl-5-fluoro-3-oxa-l8,18,19,19-tetradehydro-6a-carbaprostaglandin-I2. 11. A compound substantially as hereinbefore described with reference to the examples. 20 12. A process substantially as hereinbefore described with reference to the examples. 13. A mediceunent substantially as hereinbefore described with reference to the examples. Dated this 13th day of July, 1983 CRUICKSHANK & CO. Agents for the Applicant 1 Holies Street Dublin 2 MM\A.-RTB\raS2.0GC