CA1248525A

CA1248525A - Carbacyclins, process for their manufacture and their use as medicaments

Info

Publication number: CA1248525A
Application number: CA000432232A
Authority: CA
Inventors: Werner Skuballa; Bernd Raduchel; Helmut Vorbruggen; Jorge Casals-Stenzel; Gerda Mannesmann; Ekkehard Schillinger; Michael H. Town
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1982-07-13
Filing date: 1983-07-12
Publication date: 1989-01-10
Also published as: ATE67182T1; HU191057B; ES524058A0; IL69199A; DD210027B3; EP0099538A1; ZA835109B; DE3226550A1; IL69199A0; FI77645C; DK163579B; IE831630L; GR78873B; FI832557A0; DE3382408D1; NZ204875A; PH25119A; FI77645B; DK321283D0; DK321283A

Abstract

ABSTRACT OF THE DISCLOSURE

The present invention provides a carbacyclin derivative of the general formula (I), in which R1 represents either a radical of the general formula OR2 in which R2 represents a hydrogen atom or a C1-C4 alkyl radical or the radical or a radical of the general formula NHR3 in which R3 is hydrogen or 2,3-dihydroxypropyl, X represents a hydrogen atom or a fluoxine atom, A represents a trans-CH=CH- or-C?C-group, W represents a hydroxymethylene group where the OH
group may be in the .alpha. - or .beta. -configuration, D represents the group

Description

lZ~85Z5 NOVEL CARBACYCLI~S, PROCESS FO~ TE~EIR MANUFACTURE
AND THEIR USE AS MEDICAMENTS

The invention relates to carbacyclin derivatives, a process for their manufacture and their use as medicaments.
German Offenlegungsschriften DE-OS 28 45 770, 29 00 352, 29 02 442, 29 04 655, 29 09 088, 30 48 906 and 29 12 409 describe (5E)- and~5Z)-5a-carbaprosta-glandin-I2 analogues. The nomenclature of the compounds according to the invention is based on a proposal ~",t~ v by Morton and Brokow (J. Org. Chem., 44, 2000 [1979]).
The synthesis of these compounds always produces two double bond isomers which are characterised by the affix (5E) or (5Z). The two isomers of this prototype are illustrated by the following structural formulae:

~ C02H C02H

¢~ ~
HO OH HO OH

(5E)-6a-carbaprostaglan- (5Z)-6a-carbaprostaglan-din-I2 din-I2 lZ4~35,,'~

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 selectiv-ity and an improved activity.
The present invention provides carbacyclin derivatives of the general formula Il (CH2)n C R
o fH2 CX

~5 12485~5 in which ~1 represents either a radical of the general for-mula OR2 in which R2 represents a hydrogen a-tom or a Cl-C4 alkyl radical or a radical of the formula -CH2-C-or a radical of the general formula NIIR3 in which R3 is hydrogen or 2,3-dihydroxypropyl, X represents a hydrogen atom or a fluorine atom, A represents a trans-ClI=CH- or -C--C- group, W reprçsents a hydroxymethylene group, where the OII group may be in the ~- or ~-configuration, D
represeIlts the group -~-C~I2- or a straight-chain alklylene ~C~2 group with 1 to S carbon atoms or a branched chain alkylene group with 2 to 5 carbon atoms, E represerlts a -C-C group or 15 ~ ~ a ~ CII~CII3~ g~oup, R4 represents an alkyl radical with 1 to 7 carbon atoms and, when R2 is a hydrogen a-tom, salts with physiologically acceptable bases.

The present invention also provides salts of compounds of the general formula I, especially physiologi-cally tolerable salts thereof. When R2 represents a hydro-gen atom, for exarnple, salt formation with a base is possible.

The compounds according to the invention have a hypotensive and bronchodilative action. They are also suit-able for vasodilatation and for inhibiting thrombocyte aggregation and gastric acid secretion.

~ ~ ~ 3 -:12~85ZS

It will be understood that the structural formulae and written nomeclature of the compounds described and claimed herein include, unless otherwise stated, the indi-vidual 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 R2 are, for example, straight- and branched-chain alkyl radicals having from l to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, bu~tyl, isobutyl and tert.-bu-tyl.
A methyl group should especially be mentioned.

1,.~' \

, ~Z41~5Z5 R4 may be straight-chaln or branched alkyl radicals having 1 to 7 carbon atoms. Examples are methyl, ethyl, propyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl and heptyl. Alkyl radicals having 1 to 4 carb~n atoms are especially preferred.

D may represellt a straight-chain alkylene radical (i.e. saturated) having from 1 to 5 carbon atoms, or a branched-chain alkylene. There may be mentioned, for 10example: metnylene, ethylene, 1,2-propylene, ethylethylene, trirnethylene, tetramethylene, pentamethylene, l-methyl-tetramethylene, l-methyltrimethylene and l,l-trimethylene-ethylene.

15Thus, DER4 may represent, for example, lCl33 ICH3 -CH-CH2-C----C-CH3, -CH-CH2-C--C-CH2-CH3 , CH CH

-C-CH2-C--C-CH3, -Cl-CH2-C----C-CH2-CH3, , I
CH3 C~3 ICH3 ~CH3 -CH-CH2-CH=C ~ --C~ CH C~ -CH or CH

--~C~ CH2-C--C-CH2CH3 12'~352~

For formation of a salt of a compound of the general formula I which contains a COOII 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 ` 'B - 6 -12~85ZS

~3 -,,;~

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)-methylamine.
For salt formation with other salt forming groups in the compound of the general formula I, an appropriate reagent known to the expert may be used.
~ he invention also provides a process for the preparation of a carbacyclin derivative of the general formula I or a salt thereof, which comprises etherify-lS ing a compound of the general formula I

- O~ II

in which X, R4, R5, 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 present, with a haloketal of the general formula 124~5Z~

Hal-~CH2)3C~ \

ORg in which Hal represents a chlorine, bromine or iodine atom, each of R8 and Rg represents an alkyl group havlng from l to 10 carbon atoms or R8 and Rg together represent a ring-forming group having from 2 to 10 carbon atoms, 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 groups is esterified or etherified, the aldehyde group is oxidized., the resulting free carboxy group is esterified, an esterfied 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 ~E se, suitably, for example, at a temperature in the range . 30 ;~ 35 X

:`
~ , :

: -:
'~

~s ~

of from 0C to 100C, preferably from 10C to 80C, 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 20C to 80C.
The oxidation of the aldehyde group may be carried out according to methods known tc the person skilled in the art. Suitable oxidising agents are, lZ'~85ZS

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 0C to 100C, preferably from 20C
to 40C, in a solvent that is inert with respect to the oxidising agent, for example dimethyl-formamide.
Oxidation with Jones reagent may be carried out for example at a temperature in the range of from -40C to +40C, preferably from 0C to 30C, using acetone as solvent.
Oxidation with platinum/oxygen may be carried out for example at a temperature in the range of from 0C to 60C, preferably from 20C to 40C, in a solvent that is inert with respect to the oxidising agent, such as, for example, ethyl acetate.

~Z~5~5 ~j~.,, //
7 ~ ,,~

Hydrolysis of a carbacyclin ester may be carried out according to methods kn-own to the person skilled in the art, such as, for example, using a basic catalyst.
Introduction of an ester group -OR2 representing Rl, in which R2 represents an unsubstituted or substitu-ted alkyl radical (generally having from l to 10 carbon atoms in the alkyl moiety), may be carried out according to methods known to the person skilled in t~e art. The carboxy compound may be reacted, for example, with a diazo hydrocarbon in a manner known E~ 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 l to 30 minutes, the solvent may be removed and the ester purified in customary manner. The diazo-alkanes are known or may be manufactured accordingto known methods [Org. Reactions, Vol. 8, pages 389-394 (1954)].

.

, lZ4~5Z5 Introduction of an ester group -OR2 representing Rl, in which R2 repr-esents the diphenyl radical, may be carried out according to methods known to the person skilled in the art. For example, the carboxy compound and the cor-responding diphenylhydroxy compound may be reacted withdicyclohexyl carbodiimide in the presence of a suitable base, for exa~ple pyridine or triethylamine, in an inert solvent. Suitable solvenls are, for example, me-thylene chloride, ethylene chloride, chloroform, ethyl acetate and tetrahydrofuran, preferably chloroform. The reaction may be carried may be carried out, for example, at a temprature in the range of from -30C to +50C, preferably at +10C.

In-troduction of an ester group -OR2 representing Rl may also be carried out by reac-ting the carboxylate anion with an appropriate alkyl halide or haloketone (Hal-CH2-C-Ar in which Ar represents diphenyl).

A carbacyclin derivative of the general formula I
in which Rl represents a hydroxy group (R2=H) may be con-verted into a salt by neutralisation using a suitable amount of the corresponding inorganic base. The solid inorganic salt may be obtained, for ~ ie - 12 -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 S 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 advan-tageously used in excess, preferably in an amount that is from 4 to 10 times greater than the theoretical requirement. At from 0C to 30DC the reaction is normally complete after from 15 to 30 minutes.
Introduction of an acyl protecting group(s~
may be carried out by reacting a compound of the 1;248SZS

general formula I in a manner known per se witha carboxylic acid derivative, such as, for example, inter alia, an acid chloride or acid anhydride.
Liberation of a functionally modified OH group(s) 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 acid, such as, for example, hydrochloric acid.
To improve solubility, advantageously a water-miscibie 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 20C
to 80C.
A silyl ether protecting group(s) may be split 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 tempera-; ture in the range of from 0C to 80~C.

2~ Hydrolysis of an acyl groups(s) may be carried out, for example, with an alkali metal or alkaline , ~' 124~ 5 s~

earth metal carbonate or hydroxide in an alcoholor 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 -10C to 70C, preferably at 25C.
Introduction of an amide group NHR3 representing Rl 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 (R3=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 -30C to +60C, .
; ~ ~

~ .
: ~

i;Z48S25 preferably at 0C to 30C.
It is also possible to introduce the amide group NHR3 representing Rl by reacting a l-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 O = C = N - R3 IV

in which R3 has the meaning given above.
The reaction of the compound of the general formula I (Rl=OH~ 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 lS 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 -80C to 100C, preferably at from 0C
to 30C.
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, ~; .

12~8525 it is advantageous to use a starting material in which these hydroxy groupts) 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 ~ se, reacting an aldehyde of the formula V, ~ CHO

(DE-OS 28 45 770) in the presence of a deprotonating agent, such as, for example, sodium hydride or potassium tert.-butoxide, with a phosphonate of the general formula O O
CH30~

in which D, E and R4 have the meanings given above, to form a ketone of the general formula .
.

, .

lZ'~35'~5 o o X VII

O~CH=CZ-C-D-E-R4 O

(Z=H), or alternatively in the presenlce of a brominat-ing agent, such as, for example, N-bromosuccinimide, 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 O O
X VIIl ~J~CH=CZ_W_D_E_R4 OCO ~3 Hydrolysis of the ester group, for example with potassium carbonate in methanol, and optional .
~,; ' ` . , .

~ -: , , ~24~525 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 S with agueous 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 A~W-D-E-R4 IX

An olefination reaction with phosphonoacetic acid triethyl ester or phosphonoacetic 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 ~Z4~5~5 s~ ~

~ C - D - E - R X
Rl oO

in which D, E and R4 have the meanings given above and Rlo represents an alkyl radical having from 1 to 5 carbon atoms. This may if desired be obtained from the corresponding malonic acid ester by alk,yla-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 , 10 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, hy reducing an ~-halocarboxylic acid ester of the general formula "
, .Al -~.;
. .

12'~1~525 Hal-(CH2)3 -COORll XIII

in which Hal and a have the meanings given above and Rll represents an alkyl group having from l 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 inhibi-tlon of thrombocyte aggregation. Consequently, the carbacyclin derivatives of the formula I and their physiologically tolerable salts are useful pharmaceutical active substances.

, .

.

':

~z4~ilS~S

Furthermore, whilst having a similar spectrum of orostaq I c~?C~ S
action compared with corresponding ~ octac~clin~, they exhibit higher specificity and, above all, substantially longer activity. In comparison with 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, 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 proper'iés typical of prostacyclins, such 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 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 therapy of ischaemic attacks of the central nervous system, therapy of shock, inhibition of bronchocon-striction, inhibition of gastric acid secretion and : `

- ~24~5~S

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 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 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 ~-blockers or diuretics.
The dosage of the compounds is advantageously from 1 to 1500 ~g/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 hypertonic rats in doses of 5, 20 and 100 ~g/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.
In the case of intravenous injection to narcotised rabbits, the compounds according to the invention , `: :

.
.

12'~5~S

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 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 of the general formula I or a physiologically tolerable salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier. Suitably the preparation is in dosage unit form.
The following Examples illustrate the invention.
The 15-hydroxy group of the compounds in the Examples corresponds in configuration to the 15-hydroxy group ;~ in 6a-carbaprostaglandin-I2.

~24852S

l~xample (5E)-~16RS)-2-decarboxy-la, lb-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 77 mg of 55 % sodium hydride ~u~pension in mineral oil is added at 0C to a ~olution of 700 mg of 2-~(1_,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(E)-(3S,4RS~-~-methyl-3-(tetrahydropyran-2-yloxy)-oct-1-en-6-ynyl~-bicyclo[3.3.0~octan-3-ylidene~-ethan-1-ol in 15 ml of tetrahydrofuran and the whole is stirred for 30 minutes at 24 C under argon. A solution of 1.15 g of 2-(3-bromopropyl~-1,3-dioxolane in 7 ml of tetrahydrofuran is subsequently added dropwi~e thereto and the whole is refluxed for 21 hours under argon.
The solution is dil~ted with ether, washed until neutral with water, dried over magnesium sulphate and concen-trated 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 ~0 ml of a mixture of acetic acid/water/tetrahydrofuran (65~35+10) for 16 hours at 24C. The whole is subse-quently concentrated by evaporation in vacuo and the residue is chromatographed over silica gel. Using ethyl acetate~hexanc (4+1), 270 mg of the title com-pound in the form of a colourless oil are obtained.
IR (CHC13): 3600, 3420 (broad), 2970, 2862, 2730, 1725, 1603, 970/cm.

2~5~5 The 2-(3-bromopropyl~-1,3-dioxolane used for the above etherification reaction is manufactured as follows:
50 ml of a 1.2 molar solution of diisobutyl alu-minium hydride in toluene iq slowly added dropwise at -70C 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 -70C and then 10 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 25C. The residue i~
dissol~ed in 500 ml of toluene, 10 ml of ethylene glycol and 100 mg of ~-toluenesulphonic acid are added and the whole is refluxed for 6 hours using a water ~eparator. The mixture is subseguently diluted with 500 ml of ether, shaken once with a 5 % sodium bi-carbonate 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 - 45C yields 6.8 g of 2-(3-bromopropyl~-1,3-dioxol~ne in the form of a colourless liquid.

Ex~mDle 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 t:f- ~Z415 5Z5 .

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 _ 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 stirre~ for 30 minutes at 0C, 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 bylevaporation in vacuo. Chromatography of the residue over silica gel with hexane/ethyl acetate (1+1) yieldc 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, 12~5, 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 24C. The whole is subseguently 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 chromatsgraphed 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.

124~S2S

ExamDle 3 (5Z~-(16RS~-2-decarboxy-la,lb-dihomo-2-formyl-16-met~yl-

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)-(lS,55,6R,7R)-7-~tetrahydropyran-2-yloxy)-6-~(E)-(3S,4RS)-4-methyl-3-(tetra~ydropyran-2-yloxy~-oct-l-en-6-ynyl~-bicyclo[3.3.0]octan-3-ylidene~-ethan-l-ol.
IR: 3610, 3400 ~broad), 2965, 2860, 2730, 1726, 1602, 968/cm.

ExamDle 4 (5Z)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 Analosously to Example 2, 90 mg of (5Z~-(16RS)-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.
IR: 3600, 3410 (broad), 2960, 2866, 1718, 1600, 968/cm.

24~5Z5 Example 5 (5E)-(16RS)-2-decarboxy-la,lb-dihomo-16,20-dimethyl-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 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-(tetrahydropyran-2-yloxy)-non-l-en-6-ynyl~-bicyclo[3.3.0~octan-3-ylidene~-ethan-l-ol.
IR: 3600, 3410 (broad), 2967, 2862, 2731, 1725, 1601, 970/cm.
The starting material for the above title compound is manufactured 2S follows:

5a) (lR,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-~(E)-(3S,4RSj-3-hydroxy-4-methylnon-1-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 0C to a suspensionof 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,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo[3.3.0]octane in 130 ml of DME is then added at -20C and the whole is stirred for 1.5 hours at -20C, poured into 600 ml Z4~525 of saturated ammonium chloride solution and extracted three times with ether. The organic extract is washed until neutral with water, dried o~er magnesium sulphate and concentrated by evaporation in vacuo. Chromatography of the residue over silica gel with ether~hexane (1~1) yields 9.1 g of the a,~-unsaturated ketone in the form of an oil.
5.2 g of sodium borohydride are added in portions at -40C to a solution of 9.1 g of the ketone in 300 ml of methanol and stirring i~ 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:
15-hydroxy? and then 3.2 g of the isomeric 15~-hydroxy compound as the more polar component.
IR: 3600, 3400 (broad), 2942, 1711, 1603, 1588, 1276, 968, 947/cm.

5b) (lR,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-bonate in 120 ml of methanol is stirred for 16 hoursat room temperature ~nder argon. The mixture is , .

12~ 3525 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 S by evaporation is stirred with 75 ml of a mixture of acetic acid/water/tetrahydr~furan (65~35+10) for 16 hours at room temperature and subsequently concen-trated by evaporation in vacuo. Filtration of the residue over silica gel with ethyl acetate/hexane (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 ~-toluenesulphonic acid in 75 ml of methylene chloride is stirred for 30 minutes 15 at 0C. 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 whic~ is used without being purified.
IR: 2960, 2865, 1738, 970/cm.
5c) 2-~(E)-(lS,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-E(E)-(3S, 4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-non-l-en-6-ynyl]-bicyclo~3.3.0]octan-3-ylidene~-ethan-l-ol 3.5 g of potassium tert~-butoxide are added to a solution of 8.1 9 of phosphonoacetic acid triethyl ester .. --' .

~ 12~25 '~ 3~

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 5 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 22C, filtered and concentrated by evaporation in vacuo. The residue is chromatographed 20 over silica gel with ether/hexane 13+2). 2.8 9 of 2-~(Z)-(lS,5S,6R,7Rt-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-ylidene~-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.

~ `' ' .

.

` 12'~5;Z5 , ExamDle 6 (5E~-tl6RS~-la,lb-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-_ _ tetradehydro-6a-carbapro~taglandin-I2 Analogou~ly to Example 2, 305 mg of (5E)-(16RS~-la,lb-dihomo-16,20-dimethyl-3-oxa-18,18,1g,19-tetrade-hydro-6a-carbaprostaglandin-I2 11,15-diacetate are obtained from 380 mg of the aldehyde manufactured accord-ing to ~xample 5.
After splitting ~ff the protecting groups, 210 mg of the title compound are obtained in the form of a colourless oil.
IR: 3600, 3~00 (broad), 2962, 2865, 1720, 1601, 970/cm.

, Exam~le 7 (5E)-2-decarboxy-la,lb-dihomo-2-formyl-20-methyl-3-oxa-16~l6-trimethylene-l8~l8~l9~l9-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,55,6R,7R)-7-(tetrahydro-~; 20 pyran-2-yloxy)-6-[tE)-(3R)-3-(tetrahydropyran-2-yloxy~-; 4,4-trimethylenenon-1-en-6-ynyl~-bicyclo~3.3.0~octan-3-ylidene~-ethan-l-ol (manufactured according to Example 5a-c from 2-oxa-3,3-trimethylenenon-5-ynphosphonic acid dimethyl ester).

IR: 3610, 3400 (broad), 2968, 2864, 2730, 1725, 1602, 970jcm.

. ~ .
, :~
~ ~ .

24~5~S

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

7a~ 2-~(E~-~15,5S,6R,7R)-7-(tetrahydropyran-2-yloxy-

4,~-trimethylenenon-1-en-6-ynyl]-bicyclo[3.3.0]-octan-3-ylidene~-ethan-1-ol _ Analogously to Example 5c, there are obtained from 3 g of (lR,5S,6R,7R~-7-(tetrahydropyrzn-2 yloxy)-6-[(E~-(3R)-~-(tetrahydropyran-2-yloxy~-4,~-trimethylene-non-l-en-6-ynyl~-bicyclo[3.3.0~octan-3-one, after separation of the isomers by chromatography, 470 mg of 2-~(Z)-(lS,5S,6R,7R~-7-(tetrahydropyran-2-yloxy)-4,4-trimethylenenon-l-en-6-ynyl]-bicyclo~3.3.0~octan-3-ylidene~-ethan-l-ol as the less polar compound and 690 mg of the title compound in the form of a colourless oil.
IR: 3600, ~400 (broad), 2945, 2862, 1602, 972/cm.

ExamDle 8 (5E~-la,lb-dihomo 20-methyl-3-oxa-16,16-trimethylene-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 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-I2 11,15-diacetate are obtained from 400 mg o~ the aldehyde manufactured according to Example 7.
After splitting off the protecting groups, 220 mg 1ZL~85Z5 3~

of the title compound are obtained in the form of a colourleq~ 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-I2 Analogously to Examples 1 and 5, 0.28 g of the title compound is obtained in the form of a colourle~s oil from 0.5 g of 2-~(E)-(lS,5S,6R,7R)-7-(tetrahydro-pyran-2-yloxy)-6-~(E)-(3R)-4,4-dimethyl-3-(tetrahydro-pyran-2-yloxy)-oct-1-en-6-ynyl]-bicyclo[3.3.0]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-I2 Analogously to Exam~le 2, 180 mg of (5E)-la,lb-dihomo-16,16-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 11,15-diacetate are obtained from 0.27 g of the aldehyde manufactured according to Example 9.
After splitting off the protecting groups, 120 mg of the title compound are obtained in the form of a colourless oil.
IR: 3600, 3400 (broad), 2962, 2865, 1720, 1600, 971/cm.

1248~S

3~

ExamDl e 1 1 (5E)-2-decarboxy-la,lb-dihomo-2-formyl-3-oxa-16,16,20-trimethyl-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 ~nalogously 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,6_,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl-3-(tetrahydro-pyran-2-yloxy)-non-1-en-6-ynyl]-bicycl,ol3.3.0]octan-3-I0 ylidene}-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-I2 Analogously to Example 2, 0.3 g of (5E)-la,lb-dihomo-3-oxa-16,16,20-trimethyl-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.
After splitting off the pro.ecting groups, 0.22 g of the title compound is obtained in the form of a colourless oil.
Il`c: 3610 3400 ~broad), 2964, 2864, 1721, 1600, 972/cm.

.

i24~}525 ~L~I 3,~

Example 13 (5E)-(16RS)-2-decarboxy-18,19-didehydro-la,lb-dihomo-16,19-dimethyl-2-formyl-3-oxa-6a-carbaprostaglandin-I2 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-1,6-dienyl~-bicyclo[3.3.0]octan-3-ylidene}-ethan-l-ol. I
IR: 3600, 3400 (broad), 2966, 2732~ 1725, 1601, 972/cm.

Example 14 (5E)-la,lb-dihomo-16,19-dimethyl-18,19-didehydro-3-oxa-6a-carbaprostaglandin-I2 Analogously to Example 2, 0.14 g of (5E)-la,lb-15 dihomo-16,19-dimethyl-18,19-didehydro-3-oxa-6a-carba-prostaglandin-I2 11,15-diacetate is obtained from 0.2 g of the aldehyde manufactured according to Example 13.
After splitting off the protecting sroups, 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.

lZ~85~5 3~

ExamPle 15 (SE)-(16RS)-2-decarboxy-13,14-didehydro-la,lb-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 .
Analogously to Examples 1 and 5, 0.29 g o~ 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-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl]-bicyclo[3.3.0]octan-3rylidene}-ethan-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)-(lS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-

6-[(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl]-bicyclo-[3.3.0]octan-3-ylidene~-ethan-l-ol Ananogously to Example 5c, there are obtained from 1.8 g of (lR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-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-~(Z)-(lS,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene}-ethan-1-ol as the less 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-methyll-3-oxa-18,18,19,19-tetrahydro-6a-carbaprostaglandin-I2 11,15-diacetate is obtained from 0.4 g of ~he 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-lS,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)-(lS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[~35,4RS)-4-metbyl-3-(tetrahydropyran-~`

~ ' .

12~35:~5 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)-(lS,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-ylidene~-ethan-l-ol i Analogously to Example 5c, there are obtained from 2.1 g of (lR,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)-(lS,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-ylidene}-ethan-1-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-I2 Analogously to Example 2, 3qO mg of (SE)-(16RS)-; .

12~5~5 . ,~
.~ ~

13,14-didehydro-la,lb-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 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-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethyl-ene-6a-carbaprostaglandin-I2 . , .
Analogously to Examples 1 and 5, 0.18 g of the title compound is obtained in the form of a colourless oil from 0.41 g of 2-~(E)-(lS,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-ylidene}-ethan-l-ol.
IR: 3600, 3400 (broad), 2965, 2732, 2227, 1724/cm.
The starting material for the above title compound was manufactured as follows:

, lZ485Z5 ,4'9 -l9a) 2-~(E)-(15,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-1~3S)-3-(tetrahydropyran-2-yloxy)-4,4-trimethyl-enenona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene~-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-(t~trahydropyran-2-yloxy)-4,4-trimethylene-nona-1,6-diynyl]-bicyclo[3.3.0~octan-3-one, a~ter separation of the isomers by chromatography, 890 mg Of 2-~(Z)-(lS,5S,65,7R)-7-(tetrahydropyran-2-yloxy)-6-~(3RS)-3-(tetrahydropyran-2-yloxy)-4,4-trimethylenenona-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene~-ethan-1-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 20 (SE)-13,14-didehydro-la,lb-dihomo-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin-I2 Analogously to Example 2, 0.32 g of (5E)-13,14-didehydro-la,lb-dihomo-20-methyl-3-oxa-18,18,19,19-tetrade-hydro-16,16-trim~thylene-6a-carbaprostaglandin-I2 11,15-diacetate is obtained from 0.42 g of the aldehyde manufactured according to Example 19.

... . .

~Z4~5'~5 o 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-tetradehydro-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)-octa-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)-(lS,5S,65,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl]-bicyclo[3.3.0]octan-3-ylidene~-ethan-l-ol Analogously to Example 5c, there are obtained ~rom 2.5 g of (lR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa-. ' .

lZ~85~5 1,6-diynyl]-bicyclo[3.3.0]octan-3-one, after separation of the isomers by chromatography, 625 mg of 2-~(Z)-(lS,5S,6S,7R)-7-~tetrahydropyran-2-yloxy)-6-[~35)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl]-5 bicyclo[3.3.0]octan-3-ylidene3-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)-13,14-didehydro-la,lb-dihomo-16,16-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 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-I2 11,15-diacetate 5 i9 lobtainea 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.

:

, ~

~248SZ5 ,~

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-I2 -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.l0]octan-3-ylidene~-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)-(lS,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-ylidene}-ethan-l-ol Analogously to Example 5c, there are obtained from 1.3 g of (lR,5S,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-4,4-dimethyl-3-ttetrahydropyran-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)-tlS~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-1-ol as the less ~' , .
' ::

, ~:

lZ~ 5 ~.
~ ~3 -polar compound and 430 mg of the title compound in the form of an oil.
IR: 3610, 3400 (broad), 2945, 2865, 2225/cm.

Example 24 5 (5E)-13,14-didehydro-la,lb-dihomo-3-oxa-18,18,19,19-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 r l9-tetradehydro-16,16,20-trimethyl 6a-carbaprostaglandin-I2 11,15-10 diacetate is obtained from 0.16 g of the aldehydemanufactured 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 (SZ)-(16RS)-2-decarboxy-la,lb-dihomo-5-fluoro-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 42 mg of 55 % sodium hydride suspension in mineral oil are added at 0C to a solution of 420 mg of 2-~(Z)-(lS,5S,6R,7Rj-7-~tetrahydropyran-2-yloxy)-6-[(E)-(3S,4RS)-4-methyl-3-(tetrahydrop~-an-2-yloxy)-oct-1-en-~ 1248525 6-ynyl]-bicyclo[3.3.0]octan-3-ylidene~-2-fluoroethan-1-ol in 8 ml of tetrahydrofuran and stirring is carried out for 30 minutes at 24C 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 mixture is diluted with ether, washed until neutral with water, dried over magnesium sulphate and concentra-ted by evaporation ln 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 24C. The whole is sub-sequently concentrated by evaporation in vacuo and 15 the residue is chromatographed over silica gel.
~sinq 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, 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 (SZ)-(16RS)-25 la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-~æ4sszs ~ 5 -., tetradehydro-6a-carbaprostaglandin-I2 11,15-diacetate are obtained from 205 mg of the aldehyde manufactured according to Example 25.
After splitting off the protecting grou~s, 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 caxbaprostaglandin-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)-(lS,5S,6R,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-non-1-en-6-ynyl]-bicyclo[3.3.0]octan-3-ylidene~-2-fluoroethan-1-ol.
IR: 3610, 3400 (broad), 2963, 2930, 2868, 2731, 1630, 1602, 971/cm.

Example 28 2~ (5Z)-116RS)-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-18,18,19,19-:;
' lZ4~35;~5 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 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 t5Z)-2-decarboxy-la,lb-dihomo-5-fluoro-2-formyl-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-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)-(lS,5S,6R,7_)-7-(tetrahydro-pyran-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-1-ol.
IR: 3600, 3410 (broad), 2965, 2931, 2870, 2730, 1630, 1601, 970/cm.

ExamPle 30 (5Z)-la,lb-dihomo-5-fluoro-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carbaprostaglandin-I2 _ Analogously to Example 2, 105 mg of (5Z)-la,lb-i ...

124~5~ 5 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.
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 (5Z)-2-decarboxy-la,lb-dihomo-16,16-dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-T2 .
Analogously to Example 25, 0.27 9 of the title 15 compound is obtained in the form of a colourless oil from 0.6 g of 2-~(Z)-(lS,5S,6R,7R)-7-(tetrahydro-pyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl-3-(tetrahydro-pyran-2-yloxy)-oct-1-en-6-ynyl]-bicyclo[3.3.0]octan-3-ylidene~-2-fluoroethan-1-ol.
20 IR: 3610, 3420 (broad), 2966, 2930, 2868, 2732, 1730, 1602, 971/cm.

Example 32 (5Z)-la,lb-dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaslandin-I2 Analogously ,to Example 2, 120 mg of (5Z)-la,lb-'' ' 12~85:~5 ,,,~ ~ .

dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetra-dehydro-6a-carbaprostaglandin-I2 11,15-diacetate are obtained from 22Q 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 (5Z)-2-decarboxy-la,lb-dihomo-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carba-prostaglandin-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-1-en-5-ynyl]-bicyclol3.3.0~octan-3-ylidene¦-2-fluoroethan-1-ol.
20 IR: 3610, 3400 (broad), 2965, 2930, 2870, 2730, 1730, 1601, 970/cm.

., .

12~85~5 Example 34 (5_)-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-dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-16,16,20-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 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-fluoro-2-formyl-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 oil from 0.41 g of 2-~(Z)-(lS,5S,6S,7_)-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-1-ol.
IR: 3600, 3410 (broad), 2966, 2731, 2224, 1727/cm.

' ~ 12~ 5 -~r~ 0 Example 36 (5Z)-(16RS)-13,14-didehydro-la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetraaehydro-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 (5Z)-(16RS)-2-dec2rboxy-13,1g-didehydro-la,lb-dihomo-16,20-dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19,19-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-pyran-2-yloxy)-6-1(3S,4RS)-4-methyl-3-tetrahydropyran-2-yloxy)-nona-1,6-diynyl)-bicyclo[3.3.0]octan-3-ylidene3-2-fluoroethan-1-ol.

IR: 3600, 3400 (broad), 2968, 2730, 2225, 1728/cm.

iZ9~35~S

Example 38 (5Z)-(16RS)-13,14-didehydro-la,lb-dihomo-16,20-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 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-I2 11,15-diacetate is otbained from 0.35 g of the aldehyde manufactured according to Example 37. 1 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 (5Z)-2-decarboxy-13,14-didehydro-la,lb-dihomo-5-fluoro-2-formyl-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-l(3S)-3-(tetrahydropyran-2-yloxy)-4,4-trimethylenenona-1,6-diynyl]-bicyclo[3.3.0]octan-3-; ylidene3-2-fluoroethan-1-ol.
IR: 3620, 3420 (broad), 2970, 2731, 2224, 1730/cm.

, . .

.

, lZ48S25 ,~

Example 40 .

(SZ)-13,14-didehydro-la,lb-dihomo-5-fluoro-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-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-16,16-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.

Exam~le 41 (5Z)-2-decarboxy-13,14-didehydro-la,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 oil from 1.4 g of 2-~(Z)-(lS,5S,6S,7R)-7-(tetrahydro-pyran-2-yloxy)-6-1(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diynyl]-bicyclo[3.3.0]octa~-3-ylidene~-2-fluoroethan-1-ol.
IR: 3600, 3420 (broad), 2970, 2930, 2865, 2730 2225, ; 25 1730/cm.

lZ~8S~5 ~.

Example 42 (5Z)-13,14-didehydro-la,lb-dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2 -Analogously to Example 2, 0.22 g of (5Z)-13,19-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 43 (5Z)-2-decarboxy-13,14-didehydro-la,lb-dihomo-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro 16,16,20-trimethyl-6a-carbaprostaglandin-I2 Analogously to ExaTnple 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)-(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-ylidene~-2-fluoroethan-1-ol.
IR: 3600, 3420 (broad), 2968, 2932, 2864, 2730, 2225, 1730/cm.
.

.~ . .

i2485ZS
55~

Example 44 (5Z)-13,14 didehydro-la,lb-dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carba-prostaglandin-I2 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-I2 11,15-diacetate is obtained from 0.3 g of the aldehyde manufactured according to Example 43. 1 Arter 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 (5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 methyl ester An ethereal diazomethane solution is added dropwise at 0C to a solution of 60 mg of (5E)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-20 carbaprostaglandin-I2 in 10 ml o_ dichloromethane until a constant yellow colouring is obtained. After S minutes the whole is concentrated by evaporation in vacuo and the residue is chro~,atographed over silica gel. Vsing ethyl acetate~hexane (4~1), 40 mg ~'"`` '' .

.

~ 12~8525 of the title compound are obtained in the form of a colourless oil.
IR: 3600, 3400 (broad~, 2960, 1740, 974/cm.

Example 46 (SE)-(16RS)-la,lb-dihomo-16-methyl-3-oxa-18,18,19,19- -tetradehydro-6a-carbaprostaglandin-I2 carboxamide lOS 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; 40 mg 10 of triethylamine and 45 mg of chloroformic acid isobutyl ester are added at 0C. After 1 hour, ammonia gas is introduced at 0C for 10 minutes and then the whole is left to stand for 1 hour at 24C. 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. Chromato-graphy 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.

:' ...
`' ~"- . ..
:

12~ 5 Example 47 (5Z)-(16RS)-la,lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2(2,3-dihydroxypropyl)-amide 195 mg (5Z~-( 16RS ) -la, lb-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 are dlssolved in 5 ml of aceton; 60 mg of triethylamine and 75 mg of chloroformic acid isobutyl ester are added at 0C. After 20 minutes, a solution of 260 mg of 1-amino-2,3-dihydroxypropane in 8 ml of aceton and 8 ml of acetonitrile are added and stirring is carried out for 2 hours at 20C. The whole is concentrated in vacuo, diluted with methylene chlorlde, 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. IR: 3600,3400 (broad), 2935,1645,974/cm.
Exam~le 48 (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)-(l6Rs)-la~lb-dihomo-5-fluoro-l6 X

2~ 5 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 triethylamine are added and stirring is carried out overnight at 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 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-18,18,19,19-15 tetradehyd~o-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 70C 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 in 35 ml of acetonitrile. The whole is cooled while stirring, the solvent is decanted off after 16 hours and the residue is dried ln vacuo. 160 mg of the title compound are isolated in the form of a wax-like 25 substance.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A carbacyclin derivative of the general formula (I), In which R1 represents either a radical of the general formula OR2 in which R2 represents a hydrogen atom or a C1-C4 alkyl radical or the radical or a radical of the gen-eral formula NHR3 in which R3 Is hydrogen or 2,3-dihydroxypropyl, X represents a hydrogen atom or a fluorine atom, A represents a trans-CH=CH- or C=C- group, W represents a methylene group, where the OH group may be in the .alpha. - or .beta.-conflguration, D represents the group or a straight-chain alkylene group with 1 to 5 carbon atoms or a branched chain alicylene group with 2 to 5 car-bon atoms, E represents a -C?C- group or a -CH=C(CH3)- group, R4 represents an alkyl radical with 1 to 7 carbon atoms and, when R2 is a hydrogen atom, salts with physiologically acceptable bases.

2. A compound as claimed in claim 1, wherein R1 repre-sents a hydroxy group.

3. A compound as claimed in claim 1 or 2 wherein D
represents -CH(CH3)-CH2), -C(CH3)2-CH2- or wherein in each case the CH2 moiety is bonded to the radical rep-resented by E.

4. A compound as claimed In claim 1 or 2, wherein R4 represents a methyl, ethyl, propyl, butyl, isobutyl, tert.butyl, pentyl, hexyl or heptyl group.

5. A compound as claimed in claim 1 or 2, wherein R4 represents an alkyl radical having from 1 to 4 carbon atoms.

6. A compound as claimed in claim 1, 2 or 3, wherein DER4 represents

7. (5E)-(16RS)-1a,1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2.

8. (5Z)-(16RS)-1a,1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2.

9. (5E)-(16RS)-1a,1b-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2.

10. (5E)-1a,1b-dihomo-20methyl-3-oxa-16,16-trimethyl-ene-18,18,19,19-tetradehydro-6a-carbaprostaglandln-I2.

11. (5E)-1a,1b-dihomo-16,16-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2.

12. (5E)-1a,1b-dihomo-3-oxa-16,16-20-trimethyl-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2.

13. (5E)-1a,1b-dihomo-16,19-dimethyl-18,19-didehydro-3-oxa-6a-carbaprostaglandin-I2.

14. (5E)-(16RS)-13,14-didehydro-1a,1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2.

15. (5E)-(16RS)-13,14-dldehydro-1a,1b-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandln-I2.

16. (5E)-13,14-didehydro-1a,1b-dihomo-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carbaprostaglan-din-I2.

17. (5E)-13,14-didehydro-1a,1b-dihomo-16,16-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2.

18. (5E)-13,14-dihydro-1a,1b-dihomo-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin-I2.

19. (5Z)-(16RS)-1a,1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2.

20. (5Z)-(16RS)-1a,1b-dlhomo-16,20-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2.

21. (5Z)-1a,1b-dihomo-5-fluoro-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a-carbaprostaglan-din-I2.

22. (5Z)-1a,1b-dihomo-16,16-dimethyl-5- fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2.

23. (5Z)-1a,1b-dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin-I2.

24. (5Z)-(16RS)-13,14-didehydro-1a,1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2.

25. (5Z)-(16RS)-13,14-didehydro-1a,1b-dihomo-16,20-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprosta-glandin-I2.

26. (5Z)-13,14-dldehydro-1a,1b-dihomo-5-fluoro-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a-car-baprostaglandin-I2.

27. (5Z)-13,14-didehydro-1a,1b-dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2.

28. (5Z)-13,14-dldehydro-1a,1b-dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglan-din-I2.

29. (5E)-(16RS)-1a,1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 methyl ester.

30. (5E)-(16RS)-1a,1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 carboxamide.

31. (5Z)-(16RS)-1a,1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 (2,3-dihydroxypropyl)-amide.

32. (5Z)-(16RS)-1a,1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 (r-phenyl)-phenacyl ester.

33. A physiologically tolerable salt of compound as claimed in claim 7.

34. A salt of a compound as claimed in claim 7, with an alkali metal hydroxide, an alkaline earth metal hydroxide, ammonia, ethanolamine, diethanolamine, triethanolamlne, N-methylglucamine, morpholine or tris-(hydroxymethyl)-methyl-amine.

35. (5E)-(16RS)-1a,1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 tris-(hydroxymethyl)aminomethane salt.

36. A process for the preparation of compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, which comprises etherifying a compound of the general formula II

in which X, R4, 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 formula III

in which Hal represents a chlorine, bromine or iodine atom, each of R8 and R9, which may be the same or different, represents an alkyl radical having from 1 to 10 carbon atoms or R8 and R9 together represent a ring-forming group having from 2 to 10 car-bon atoms and splitting the resulting ketal, and, if desired, converting a compound of the general formula I or a salt thereof thus obtained into anothe compound of the general formula I or a salt thereof.

37. A process as claimed in claim 36, wherein after the splitting of the ketal one or more of the following reactions is carried out, where appropriate, In any desired sequence: iso-mers are separated, one ore more protected hydroxy groups is lib-erated, one ore more free hydroxy groups is esterified or etheri-fied, 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.