SE453294B - PROSTACYCLINES, PROCEDURES FOR THEIR PRODUCTION AND PHARMACEUTICAL PREPARATIONS INCLUDING THE SUBSTANCES OF ANTISECRETORIC, ANTIUAL CEROGENE AND ANTI-PRESSURE-LOWERING EFFECTS - Google Patents

Description

O II CH-CH -CH 2 -CHz-C-OR 2 F IIHIO | HIHI;> \ E21 x-A I ~ cu: cngn-c-crxz-cuz-CHz-CHB = _ .; wherein R 1, R 1, R 2 and R 21 have the meanings given above.

In another aspect, the present invention relates to compounds of the formula “ï I VcrucH-cnz-c fi z-c-on _ s F l-ß Ü! than cli-.CH-CH-c-cu -cH -cu -ca - 2 E: lz 2 2 3 ål OH R wherein R, R1, R2 and R1z have the meaning given above.

The term "lower alkyl" as used herein refers to straight-chain and branched alkyl groups having 1-7 carbon atoms, such as methyl and ethyl. The term "lower alkane carboxylic acids" includes alkane carboxylic acids having 1 to 7 carbon atoms, such as formic acid and acetic acid. The term "halogen" or "haloh" includes, unless otherwise indicated, fluorine, chlorine, bromine and iodine.

The term "alkali metal" includes all alkali metals such as lithium, sodium and potassium. According to the invention, all compounds having one or more asymmetric carbon atoms can be prepared in the form of racemates. These racemates can be cleaved in a manner known per se at an appropriate time during the manufacturing process, whereby the following products can be obtained as optically pure enantiomers. Alternatively, optically active enantiomers or racemates of formula I may be obtained depending on the optical form of the compound of formula II used as starting material.

In the structural formulas set forth herein, a wedge-shaped line denotes a substituent in the β-position (above the molecular range), a dashed line denotes a substituent in the N-position (below the molecular range), and a wavy line denotes a substituent either in the Q- or in the ß- position or a mixture of these isomers. Of each structural formula, only one form is indicated, but this is also intended to include other forms including the enantiomers and racemates.

The term "aryl" as used herein refers to aromatic hydrocarbon groups having a core, such as phenyl and tolyl, which may be unsubstituted or substituted in one or more positions by lower alkylenedioxy, nitro, halogen, lower alkyl or lower alkoxy; and multi-core aryl groups such as naphthyl, anthryl, phenanthryl, azulyl, which may also be unsubstituted or substituted by one of the above groups. Preferred aryl groups are substituted and unsubstituted aryl groups having a core, especially phenyl.

The term "acid-catalyzed cleavage-removing ether protecting group" means any ether which, by acid-catalyzed cleavage, gives a hydroxy group. A suitable ether protecting group is, for example, tetrahydropyranyl ether or 4-methyl-S, 6-dihydro-2H-pyranyl ether.

Other protecting groups are arylmethyl ethers, such as benzyl, benzhydryl or trityl ethers; or d-lower alkoxy-lower alkyl ethers, for example methoxymethyl; or allylic ethers or tri3 (lower alkyl) silyl ethers, such as trimethylsilyl ether or dimethyl tert-butylsilyl ether. t-Butyl, tetrahydropyranyl and tri (lower alkyl) silyl ethers are preferred, especially dimethyl t-butylsilyl ether. The acid-catalyzed cleavage is carried out by treatment with a strong organic or inorganic acid.

Preferred inorganic acids are mineral acids such as sulfuric acid and hydrohalic acids. Preferred organic acids are lower alkane carboxylic acids, such as acetic acid, and p-toluenesulfonic acid.

The acid-catalyzed cleavage can be carried out in an aqueous medium or in an organic solvent. When an organic acid is used, it can serve as a solvent.

In the case of a t-butyl group, an acid is generally used which constitutes the solvent. In the case of tetrahydropyranyl ethers, the cleavage is generally carried out in an aqueous medium. Temperature and pressure are not critical and the reaction can be carried out at room temperature and atmospheric pressure.

Of the compounds of formula I, those in which the 7-fluoro substituent has a configuration are preferred. Of the 7-β-fluorine compounds, the following are preferred: cH-cnz-cnz-cuz-E-one /. (<1 F I-Ai CH I: s Ü fl cream-gu 41: -cnz-cnz-cxæz-cxi; _- 03 än C143 / c fl šrcnz-cuz-cnz-Å-on! _ UF An I canon-gwen - cuz-cxgfcxwcus 453 294 5 o Ä 'CH2 - (, H2-CH2- -OR _ F 5 _ i cna x-Aiii _ Qhcn-gu-lc-cuz-cxaz-cxag - cns' oucu C113 3 “ï ÅH -Cl 2 -C 12 -C 2 -Z-L-OR F Cppcu-g fl -CII-C 2 -Z 2 -CH 2 -Cl 2 -CH 2 -H 2 FA 3 H OH 3 _ OH F 3 If R in the above formulas represents lower alkyl, methyl or ethyl groups are preferred.

The process according to the invention for the preparation of the compounds I is characterized in that a compound of the general formula XII C} 1-CH2-CH2-CH2--OR is dehydrohalogenated in 6 F XII: R21 cn-cli-QH -c -cu - cn _ | 2 íCHíCHs ou a fill == § _ \ _ | ß | 453 294 wherein X is halogen; R 6 21 is lower alkyl; and R 1, R 2 and R have the meaning given in claim 1; and that, if desired, an ester group R 6 is hydrolyzed and / or a carboxylic acid thus obtained is converted into a pharmaceutically usable salt.

The compounds of the formula wherein R 1, R 2 and R XII can be prepared from compounds of III h ...

II IT21 cmcu-c -C-CH -cH -cH -cH-. _ I 2 2_ 2, Rz H H = | HH I- OH | 21 has the meaning given above, or of optical antipodes or racemates thereof over intermediates IV to XI: O JK Rzi <I Ln orken-gu -c -cnz-cnz-cnz-cns' z HHC | Hn 2 ÉJH F '' 0714 R RS \ í - »nn I orken-gu -c -cnz-cnz-cnz-cræz ii _ | 0114 112 yet! 453 294 RZJ.

I _ Cgpçypç fl -C -C fl z-CIIZ-CH -CH 2 Ill z 2 R 0114 R 0, F E21 I 5 CIFCH-gíl- (lï -CIå-CH2-CH2-CH3. "L" - '2 R on R RZJ .š- fl L fl cmcu-c fl -c -cufcnz-cxiz-cxx in 3114 IP 3 VI VII VIII 453 294 F uo 4 / uuäu-cn = cu-cn -cu -crlz-coou C 2 2 ¥ 2l Cgpcn- gu -ICI-CHZ-Cilz-Cííz-C fl a: lll :: 2 R 0114 RE \ _ _ _ H04: \\\\ c, ii-çu = cu-çnz Cllz CHZ COOR F21: CIFCH-CH -C-CH -CU -CH -CH “ll ä: 4 1., 2 2 2 3 R QR 11 * X 0 H ÉIH-CH -Cu -cn -ë-on 2 2 2 _'V \« ~ F _ lå Cllf- C11-CH -C -CH -CH -CH -CH E 54 | 2 2 2 2 3 R11 OR P. f I H fi cxxz-CHZ-c fl z-ï-ons F R2l I cn-c fl- c fl- - - - - _: çz caz C112 cuz C113 on R _ _ i 6 cncuz C112 crf -on 2 VF H2 l nlll ||||| |: _ - -C _, l CH CHÉH ïïz Hz-CHZ-C fl z Û fl a OHR ull Wo IX XI XII XIII 453 294 | ° - cmcn-cuz-cuz-rl-ons H fl rq / F z 7 xlv _ E21 l I çh = cu šrx-í; -c fl z-c fl z-c fl z-cna -T- 7: 1 2 n * on P- i ”I cH-cxxz-criz-clxz-Jï-oxl NA; Éfff \ R2l XV I Luca-een -çn-c -cnz-c fl -cn -cu, 2 2 J Lz wkHHR /: ï Ön o H CIPCH-czë-cnz-'É-øu _ s F i 'n; 1 xvx IE ~ ncn = czx -šu -Ic -cxxz-crzz-clag-c fl s ii ön nz In the formulas given above, R 1, R 1, R 2 and R 21 above have the meaning given above; R is hydrogen, methyl or OR; OR4 is an acid-catalyzed cleavable ether protecting group: β6 is lower alkyl; X is halogen; and R 5 is tri (lower alkyl) alkyl. A compound of formula II may be converted by ordinary etherification into a compound of formula IV for the purpose of protecting free hydroxy groups in the compound of formula II. If R1 in the compound of formula II is hydroxy, the hydroxy group is converted by this etherification to an ether group in compound IV.

Preferred ethers for this purpose are tetrahydropyranyl and dimethyl t-butylsilyl ether. In this reaction, any common method can be used to etherify the compound of formula II. When a tri (lower alkyl) silyl ether is desired, a tri (lower alkyl) chlorosilane is used as the etherifying agent in the presence of an organic base such as imidazole or pyridine.

Ordinary organic amine bases can also be used in this reaction.

A compound of formula IV is converted to a compound of formula V by first enolizing the compound of formula IV and then treating it with a trialkyl halosilane. The enolysis can take place in a manner known per se.

Preferably, the compound of formula IV is treated with a non-aqueous alkali metal base. Preferred bases for this purpose are lithium diisopropylamide or sodium hexamethyldisilazane. In carrying out this reaction using non-aqueous alkali metal bases, temperatures from -70 to -30 ° C are generally preferred. The reaction is generally carried out in an inert organic solvent. All common inert organic solvents which are liquid within the specified temperature range can be used. The preferred solvent is tetrahydrofuran. The enolate of the compound of formula IV can be converted as an alkali metal salt to a compound of formula V by treatment with a trialkyl halosilane, preferably trimethylchlorosilane. This reaction is usually carried out at the same temperatures and with the same solvent as used in the formation of the enolate.

The compound of formula V is converted to a compound of formula VI by treatment with a fluorinating agent. All common fluorinating agents can be used. Xenon difluoride J in 453 294 μl and gaseous fluorine are preferred. In general, the reaction is carried out in the presence of an inert organic solvent. All common inert organic solvents can be used.

Halogenated hydrocarbons such as methylene chloride or carbon tetrachloride are preferred. Temperature and pressure are not critical to the reaction and can be carried out at room temperature and atmospheric pressure. Although room temperature can be used, n -10 is preferably operated at lower temperatures, i.e. from + 10 ° C. in the conversion of the compound of formula V to a compound of formula VI, the compound of formula VI is obtained as a mixture of the compounds of the formulas 'Ü' vl-A R2l 5 cxhcn-g fl -c -CUZ-cnz-c fl z-cua RU 5 4 | 2 OP. R and § {lH \ Eg F 'i RZl Vl-B \\\ f.

Cypc fl- š fl -ïl -CH2-CH2-CPI2-CH3 than 018 * az R wherein R1, R2 and R1z have the meaning given above. The compounds of formulas VI-A and VI-B can be separated by common means, such as chromatography. Alternatively, the compound of formula VI may be used as a mixture of the compounds of formulas VI-A and VI-B for the remaining reaction steps, or a separation may be carried out at a later stage to obtain a compound of formula I with the desired fluorine orientation in 7- position. When the compound of formula VI is divided into the compounds of formulas VI-A and VI-B, the configuration of the fluorine atom is maintained during the course of the usual reaction sequence. Thus, if a compound of formula I with 7β-fluorine is desired, a compound of formula VI-A is used, whereby the intermediates of formulas VII-XVI are obtained, in which the fluorine atom has the β-configuration. If a compound of the formula I with 7d-fluoro-substitution is desired, the starting material is a compound of the formula VI-B, the fluorine atom of the intermediates of the formulas VII-XVI having a K-configuration.

Alternatively, the compounds of formula VI may be used without splitting into the compounds of formulas VI-A and VI-B. In this way, compounds of formula I, in which fluorine has both the M and ß configuration, are prepared over the intermediates of formulas VII-XVI, in which the fluorine atom has the same position.

In the conversion of the compounds of formula II to the compound of formula VI, tri (lower alkyl) silyl ether is generally preferably used as the hydroxy protecting group. In the conversion of the compound of formula VI to a compound of formula I, it is generally preferred to protect one or more hydroxy groups such as tetrahydropyranyl ether. Alternatively, silyl ethers or any other common ether group may be used in the remaining process steps. According to the preferred embodiment, silyl ethers of formula VI are hydrolyzed to give compounds of formula VII which are then re-etherified to give compounds of formula VI in which the ether group is a tetrahydropyranyl group. For the hydrolysis of compounds of formula VI to compounds of formula VII and the subsequent renewed etherification of the compound with. in formula VII, all common hydrolysis resp. etherification methods are used. If the protecting group of the compound of formula VI is tetrahydropyranyl, it is not necessary to hydrolyze the compound of formula VI to the compound of formula VII, since the compound of formula VIII can be obtained directly from the compound of formula VI.

A compound of formula VII is converted to a compound of formula VIII by treatment with a reducing agent. All common reducing agents are suitable for this purpose, which selectively reduce a keto group to the hydroxy group. Preferred reducing agents are hydrides, preferably aluminum hydrides, such as alkali metal aluminum hydrides, and borohydrides, such as alkali borohydrides, with diisobutylaluminum hydride being particularly preferred. The reaction can also be carried out using branched chain (lower alkyl) boranes, such as bis (3-methyl-2-butyl) borane. In this reaction, temperature and pressure are not critical and one can work at room temperature and atmospheric pressure or at elevated or lowered temperatures and pressures. In general, it is convenient to carry out the reaction at a temperature of from -80 ° C to the reflux temperature of the reaction mixture. The reduction can be carried out in the presence of an inert organic solvent.

All common inert organic solvents can be used. Dimethoxyethylene glycol and ethers such as tetrahydrofuran, diethyl ether and dioxane are preferred.

Compounds of formula IX may be prepared from compounds of formula VIII by reaction with a phosphonium salt of formula Rb o. I g 11-- P cu ~~ CHïcH¿-- CH - --OH <+> 2 2 Ås XX-A Y <-> 453 294 14 wherein Ra, Rb and Rc are aryl or di (lower alkyl) amino and Y are halogen, by a common Wittig reaction. For this reaction, the reaction conditions known per se for wittig reactions can be used.

The compound of formula IX may be converted into a compound having the derivative of a lower alkanol, such as a lower alkyl halide, as a derivative of a lower alkyl or a derivative of a lower alkanol.

In this case, the usual reaction conditions for esterifications can be used.

A compound of formula X can be converted to a compound of formula XI by treatment with a halogenating agent. Preferred halogenating agents are N-halosuccinimides, especially * N-iodosuccinimide. In general, this reaction is carried out in the presence of a polar solvent, such as acetonitrile or halogenated hydrocarbons, such as methylene chloride or ethylene chloride. All common polar organic solvents can be used. The reaction temperatures can be between 0 and 35 ° C. In general, it is advisable to work at room temperature.

A compound of formula XI is converted to a compound of formula XII by ether hydrolysis. All common ether hydrolysis methods can be used. Generally, mild acid hydrolysis, such as aqueous acetic acid, is used.

In the following reaction steps, a compound of formula XII is treated with a dehydrohalogenating agent to give mixtures of compounds of formulas XIII and XIV. Ordinary dehydrohalogenating agents can be used for this reaction. Preferably, diazabicycloalkanes or alkenes are used, such as 1,8-diazabicyclo-1.5.0.0 undec-7-ene and 1,4-diazabicyclo [2.2.2] octane. In addition, all other common organic bases used for dehydrohalogenations can be used in this reaction. The compounds of formulas XIII and XIV are obtained in admixture. They can be separated in a manner known per se, for example by chromatography.

The compound of formula XIII and the compound of formula XIV are converted into the compounds of formula XV and XVI by hydrolysis. Conventional ester hydrolysis methods were used. The compound of formula XIII or XIV is preferably treated with an alkali metal hydroxide. Preferred alkali metal hydroxides are sodium and potassium hydroxide.

The compounds of formula I, in which R is hydrogen, form salts with pharmaceutically useful bases. Preferred salts are alkali metal salts such as lithium, sodium and potassium, with sodium being particularly suitable. Other preferred salts are salts of alkaline earth metals, such as calcium and magnesium salts, salts with amines, such as lower alkylamines, e.g. ethylamine and hydroxy-substituted lower alkylamines and tris (hydroxymethyl) aminomethane, as well as ammonium salts.

Further examples of salts are those with dibenzylamine, monoalkylamines, dialkylamines and salts with amino acids such as arginine and glycine.

Preferred compounds of formulas XIII and XV are those in which a1 and R2 are hydrogen.

The compounds of formula I and their pharmaceutically usable salts as well as the optical antipodes and their racemates are active as antisecretory agents, antihypertensive and anti-ulcerogenic agents and can be used to control gastro-hyperacidity and as inhibitors of platelet aggregation.

The activity of the prostacyclin of formula I as an antiplatelet agent is shown by the following test with the compound (52, δ, 9d, 1h, 13E, ISR) -7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16 -dimethyl-prosta-5,3-diene-1-acid-methyl ester: 303 294 16 ml of blood from the jugular vein of awake Beagle dogs was added to 3 ml of 3.8% sodium citrate solution in small centrifuge tubes.

The tubes were sealed and the contents mixed gently. The citrated blood was centrifuged at 160 g for 15 minutes at 20 ° C and the high platelet (PRP) plasma was carefully removed with a pipette without stirring the leukocyte film and erythrocyte layers. PRP was stored in sealed plastic tubes at 19-21 ° C. Preparations with an attraction to red, which indicated hemolysis, were discarded. After PRP removal, the remaining blood was centrifuged for 10 minutes at 900 g to obtain low platelet (PAP) plasma. PRP was used immediately and the aggregation study was completed within 3 hours.

The platelet aggregation was performed with a Payton two-channel aggregation module, which was connected to a printer for continuous recording of increasing light transmission due to platelet aggregation. A scale of 0-100% transmission was determined with PRP (0%) and PAP (100%). The temperature was maintained at 37 ° C and stirred at 900 rpm. 0.45 ml of PRP was introduced into a cuvette with a Teflon stir bar and heated to 37 ° C in a water bath. 5 μl of different concentrations of (5Z, 7, 9, 11, 13E, 15R) -7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13- diene-1-acid methyl ester was added, which was diluted from a stock solution of 5-x 10 -4 M in dimethyl sulfoxide with phosphate buffered saline containing 1 mg / ml nut serum albumin, fraction V. The whole was stirred for 1 minute. Then, 50 μl of arachidonic acid was added as an aggregation inductor in concentrations which, after 5 minutes, gave 50-70% aggregation. The following table shows the percentage inhibition, which was calculated from the ratio% aggregation with the test compound, divided by the control value (vehicle), multiplied by 100. 453 294. Concentration of (5Z, Iß, 9d, 11u, 13E, 15R) 7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-S, 13-diene-1-acid methyl ester% Inhibition 1 x 1o'l3M 14.2 3 x 1o'l3m 20.8 1 x 1o'l2M 71.4 1 x 1o'11M 57.8 1 x 1o'l ° M 20.8 The phosphate buffered saline solution and the arachidonic acid solution was prepared as follows: buffered saline (PBS) was prepared by adding 1 mM sodium phosphate buffer pH 7.4 to 0.85% (w / v) aqueous saline.

The arachidonic acid solution was prepared from a stock solution containing 10 mg / ml in absolute methanol. To prepare a 10 mM solution, 0.3 ml of stock solution was evaporated almost to dryness under nitrogen and dissolved in 0.75 ml of freshly prepared 0.02 M ammonium hydroxide and 0.2 ml of PBS. Additional dilutions were prepared with a mixture of NH 4 OH and PBS.

The compounds of formula I and their pharmaceutically usable salts can be used in a variety of pharmaceutical preparations.

The new compounds can be administered in the form of tablets, pills, powders, capsules, solution for injection, solutions, suppositories, emulsions, dispersions and other suitable forms. The pharmaceutical preparations are conveniently prepared by mixing the active substance with a non-toxic pharmaceutical organic or inorganic carrier. Typical carriers are, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and petroleum jelly. The pharmaceutical preparations may also contain non-toxic excipients, such as emulsifiers, preservatives and wetting agents, for example sorbitan monolaurate, triethanolaminoleate, polyoxyethylene sorbitan, dioctyl sodium sulfosuccinate and the like. 453 294 18 \ ~ The dosage of the new compounds is adapted to individual needs. For oral administration, the compounds of formula I may, for example, be administered in doses ranging from 0.1 pg to 1 / / 0.3 pg / day / kg body weight.

The following examples further illustrate the invention. The ether mentioned in the examples is diethyl ether. All temperatures are given in degrees Celsius. The petroleum ether has a boiling point of 35-60 ° C.

Example 1 502.2 mg [3aR- [3aa, 4m (1E, 3Rx), SB, oem]] - Hexahydro-S-hydroxy-4- (3-hydroxy-4,4-dimethyl-1-octenyl) -ZH -cyclopenta [b] furan-2-one was dissolved in 15 ml of dimethylformamide (reagent grade, dried over SA molecular sieve fl under argon. The solution was added with 1.045 g of t-butyldimethylchlorosilane (previously distilled) and 587.6 mg of imidazole (reagent grade). The resulting mixture was stirred for 18 hours at room temperature, added to 60 ml of ice-cold, SN hydrochloric acid and extracted three times with 60 ml of diethyl ether.

The extracts were washed with 60 ml of a mixture of saturated aqueous sodium hydrogencarbonate solution water and brine (1: 1: 2) and subsequently with 60 ml of brine.

The extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. 1.25 g of a white semi-solid were obtained. The crude product was chromatographed on 75 g of silica gel, eluting first with one liter of a mixture of 10% by volume of ether and 90% by volume of petroleum ether, followed by a mixture of 20% by volume of ether and 80% by volume. petro- leumeter. There were thus obtained 857.1 mg of [3aR- [3a0g4a (1E, 3Rx), Sß, 6aæ]] - hexahydro-5 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4- [ff3- (1, 1-dimethylethyl) -dimethylsilylloxy] -4,4-dimethyl-1-octenyl] -2H-cyclopenta- [b] furan-2-one as a white amorphous solid with a melting point of 67-6 ° C.

Example 2 S79 μl of calcium hydride desfiltered diisopropylamine was dissolved in 15 ml of fresh lithium aluminum hydride distilled tetrahydrofuran. The mixture was cooled in a nitrogen atmosphere to + 3 ° and at this temperature was added dropwise with 2.5 ml of a 1, SN solution of n-butyllithium in hexane. After stirring for 5 minutes at the same temperature, the mixture was cooled to -40 ° C and added dropwise with a solution of 1.757 g [3aR- [3aa; 4m (1E, 3RxL SB, 6aa]] - hexahydro-S- [I (1) 1,1-dimethylethyl) dimethylsilyloxy] -4 - [[[s- (1,1-dimethylecyl) dimethylsilyl] oxy] -4,4-dimethyl-1-octenyl] -ZH-cyclopentafbifuran-2-one in 6 ml of tetrahydrofuran After stirring for 5 minutes at -40 DEG C., 570 .mu.l of trimethylchlorosilane were rapidly added. After two minutes, the cooling bath was removed and the mixture was allowed to warm to 20 DEG C. for 20 minutes. The solvent was removed under reduced pressure at a temperature = not above room temperature and the residue was dried for 15 minutes in a high vacuum, then 10 ml of ether (freshly filtered over alumina, activity I) were added under argon and the mixture was filtered off, the white residue was washed three times with 3m of ether and the pale yellow filtrate was evaporated under reduced pressure. The oily residue was dried for one hour in high vacuum (room temperature) to give (3aR-I 3aC§ 4 «(1E, 3Rx), 5B, 6aa] J-4, S, 6,6a-tetrahydro- [II (1,1-dimethylethyl) dimethylsilyl] oxy] -4-ICC3- (1,1-dimethylethyl) dimethylsilyloxyl -4,4-dimethyl-1-octenyl-2- (trimethylsilyl) oxy-3αH-cyclopentaflufuran.

Example 3 The compound prepared in Example 2 was dissolved in 15 ml of methylene chloride (freshly filtered over alumina, activity I) under argon. The mixture was cooled to + 2 ° and added sequentially with 680 mg of potassium bicarbonate (dried for 3 hours in high vacuum over phosphorus pentoxide at 100 °) and 632.9 mg of xenon difluoride with stirring. During the first 30 seconds after the addition of the xenon difluoride, a violent gas evolution occurred. The mixture was stirred for 20 minutes at + 2 °, poured into 150 ml of ice water and extracted three times with 150 ml of methylene chloride. The extracts were washed twice with 150 ml of brine, dried over magnesium sulphate and evaporated under reduced pressure.................................................. The residue was dried in high vacuum for 18 hours, leaving 1.92 g of a yellowish oil.

The crude product was chromatographed on 200 g of silica gel (230-400 mesh) (Flash chromatography). The eluent used is 1 l of a solvent mixture of 5% by volume of ethyl acetate and 95% by volume of petroleum ether and, in addition, petroleum ether of 10% by volume. -% ethyl acetate. The following proauk were eluted one after the other = 1.06 g (sas) / ss-¿äa «, 4 ~« 1ß, 3 * R), sß, eaq¿ / -hexahyarø- 3-fluoro-5-ÅZTI, 1 -dimethylethyl) dimethylsilyl] oxy] -4- [Y [3- (1,1-dimethylethyl) dimethylsilyl / oxy] -4,4-dimethyl-1-octenyl] -2H-cyclopenta [h] furan-2- on in the form of white needles, m.p. 49-510; 165.2 mg (9.4%) ŧaR- [§am, 4uJIE, 3 * R), 5ß.6a «Z / hexahydro-5-ÅZ11, 1-dimethylethyl) dimethylsilyl] oxy] -4- [Z [3- (1,1-dimethylethyl] -dimethylsilyl / oxy] 4,4-dimethyl-1-octenyl-2H-cyclopenta [h] furan-1-one (starting material), and 98.9 mg (5.4% ) 3R- [3ß, 3a «, mK (IE, 3, ÄL Sß, 6aq / -hexahydro-3-fluoro-S-1211, 1-dimethylethyl) dimethylsilyl] ° xi7-4-¿ZZ3- (1,1- dimethylethyl) dimethylsilyloxy / -4,4-dimethyl-1-octenyl] -23-cyclopenta [h] furan-2-one of an amorphous white solid, m.p. 83-850.

Example 4 1.591 g of za-α, 4a (1s, 3 * n), mp, sa- / hexahyaro-3-fluoro-s-1Zx1,1-dimethylethyl) dimethylsilylloxil-4- [YI3- (1, 1-dimethylethyl) dimethylsilyl] oxy] -4,4-dimethyl-1-octenyl] -2H-cyclopenta [h] furan-2-one was dissolved in 60 ml of acetic acid (reagent grade) and heated in argon to S50. Then 6 ml of water were added with stirring.

After seven hours, an additional 4 ml of water was added and the mixture was stirred for another 64 hours (71 hours in total) at 550. After cooling to room temperature, the solvent was removed under reduced pressure at 25-300. The oily residue was dried for two hours at rust temperature. in high vacuum and then chromatographed on 200 g of silica gel, (230 to 400 mesh), whereby as. eluents use solvent mixtures of ethyl acetate / petroleum ether (1.1 parts by volume) to pure ethyl acetate. 453 294 21 351.2 mg of partially hydrolysed material containing large amounts of impurities and 571.5 mg fšíš) [38- [ang 4%, (IE, 3 * R), åß, 6a1¿ / -hexahydro-3-fluor -5-hydroxy-4- (3-hydroxy-4,4-dimethyl-1-octenyl) -2H-cyclopentane] furan-2-one «oil was obtained. The partially hydrolyzed material (351.2 mg) was subjected for 42 hours to similar reaction conditions (acetic acid, water) to give 39.6 mg (4.3%) of additional material so that the total yield of [3S-] 3 ° C. 3a k, 4oL (1E, 3xR), Sfb, -Gagjj-hexahydro-β-fluoro-5-hydroxy-4- (3-hydroxy-4,4-dimethyl-1-octenyl) -2H-cyclopenta / hl furan- 2-one in the form of a clear oil amounted to 611.1 mg (66%).

Example gel S 571.5 mg δs-_73æ = «- 4æ (1E, 3 * R), sp, 6aæjj-nexanyarø-α-fluoro-s-hydroxy-4- (3-hydroxy-4,4-dimethyl-1- octenyl) -2H-cyclopentaylphuran-2-one was dissolved in 20 ml of methylene chloride (freshly filtered over alumina, activity 1) in argon. The solution was added with 2.0 ml of dihydropyran (distilled over sodium) and then with 9.7 mg of a crystalline toluenesulfonic acid monohydrate. The mixture was stirred for 30 minutes at room temperature and then poured into 50 ml of saturated aqueous sodium bicarbonate and extracted three times with 30 ml of methylene chloride. The extracts were washed twice with 50 ml of brine, dried over magnesium sulphate and evaporated under reduced pressure. The crude product (1.4 g of an oil) was chromatographed on 100 g of silica gel with ether / petroleum ether (1: 1) to give 797 mg (91%) of [3S- [3a, 3ad, 4K (1E, 3 *). R), αs, 6a & Z] -hexahydro-3-fluoro-5; [Ytetrahydro-2H-pyran-2-yl) oxy] -4- [3- (tetrahydro-2H-pyran-2-yl) oxy] -4 , 4-dimethyl-1-octenyl] -2H-cyclopentaphthuran-2-one in the form of a clear oil (mixture of the THP diastereomers (fl àzâ -32,460 in chloroform, c = 0.8780).

Example 6 729, 2 mg βs-α, saa, 4u. (1E, fn), s / b, sanf / -hexanyaro-s-fluoro-s- [Ttetrahydro-2H-pyran-2-yl) oxy] -4 -13- [Tetrehydro-2H-pyran-2-yl) oxy] -4,4-dimethyl-1-octenyl / -2H-cyclopentylfuran-2-one 453 294 22 was dissolved in 10 ml of toluene (distilled over calcium hydride) in argon The mixture was cooled to about -700 and added dropwise to 1.25 ml of a 1.4M solution of diisobutylaluminum hydride in hexane. The mixture was stirred for 20 minutes at -70 ° C and then 3 ml of aqueous ammonium chloride solution was added dropwise and the mixture was poured with 20 ml of water and 50 ml of ethyl acetate into a separatory funnel. The very thick suspension formed on shaking was filtered over a filtration aid, the residue was washed thoroughly with 100 ml of ethyl acetate and the filtrate was washed again once with 60 ml of a mixture of concentrated brine and water (1 part by volume) and once with 100 ml of saline solution. The wash solution was re-extracted once with 80 ml of ethyl acetate. The organic extracts were dried over magnesium sulphate and evaporated under reduced pressure.

Flash chromatography of the crude product (806 mg oil) on 200 g of silica gel (230-400 mesh) with ethyl acetate / petroleum ether (4: 6) gave 661.5 mg (sus) ßs-pm3ae4e (1s, 3 * 1z) ßßßaa / J-hexahyaro 3-Fluoro-5- [Ttetrahydro-2H-pyran-2-yl) oxy] -4- [3- [Y-tetrahydro-2H-pyran-2-yl) oxyH4,4-dimethyl-1-octenyl} 2H-cyclopentalhfuran 2-ol in the form of amorphous solid particles with a melting point of 58-600 (ayzâ -12, a3 ° in chloroform, c = 1.020

Example 7 1.54 g of (4-carboxybutyl) triphenylphosphonium bromide (dried in high vacuum at 100 ° for 2 hours over phosphorus pentoxide) and 1.275 g of sodium hexamethyldisilazane (distilled) were added to argon with 20 ml of tetrahydrofuran (freshly distilled over lithium aluminum hydride) and 1.25 ml of hexamethylphosphoramide. The mixture was stirred for one and a half hours at room temperature. The orange-red suspension was added dropwise with a solution of 560.5 mg / 35-β-§-3aog4odlE, 3 * R), SB, 6aq / -hexahydro-3-fluoro-5- / Ttetrahydro-28-pyran -2-yl) oxy [-4-13- [Ytetrahydro-2H-pyran-2-yl) oxy-4,4-dimethyl-1-; quenyl] -2H-cyclopentyl] furan-2-ol in 4 ml of tetrahydrofuran . The resulting yellow-orange mixture was stirred for 4 hours at room temperature. The reaction was terminated by dropwise addition of glacial acetic acid (light yellow color). The majority of the solvent was evaporated in high vacuum at or below room temperature. The residue was transferred with a 100 ml ether and 100 ml water to a separatory funnel. The aqueous phase was acidified with 13 ml of 1N hydrochloric acid to pH 3. After shaking and phase separation, the aqueous phase was re-extracted twice with 70 ml of ether. The organic extracts were washed twice with 70 ml of brine and dried over magnesium sulfate. After removal of the solvent, the oily residue was dried for 1 1/2 hours in a high vacuum to give 1.45 g of an oil.

The crude acid was dissolved in 10 ml of methylene chloride (freshly filtered over alumina, activity 1) and added at room temperature with 15 ml of a 0.25N solution of diazomethane in ether. The mixture was stirred for 15 minutes at room temperature and poured into 100 ml of semi-concentrated aqueous ammonium chloride solution and extracted three times with 100 ml of ether. The extracts were washed twice with 70 ml of brine, dried over magnesium sulphate and evaporated under reduced pressure. This gave 1.24 g of a yellow oil. Chromatography on 100 g of silica gel with ethyl acetate / petroleum ether (3: 7, 700 ml) and adjacent ethyl acetate / petroleum ether (1: 1 by volume) gave 20.8 mg (3.7%) of [35- [3ag3aa; - 4aJ1E, 3 * R), 58.6aqZ] -hexahydro-3-fluoro-5- [etetrahydro-28-pyran-2-yl) oxy] -4- [3- [Ktetrahydro-2H-pyran-2- yl) oxy] -4,4-dimethyl-1-octenyl] -2H-cyclopenta [h] furan-2-ol (starting material) and 496.3 mg (73%) (5Z, 7R, 9a, 11cpl3E 15R ) -7-fluoro-11,15-dilitetrahydro-2H-pyran-2-yl) oxy] -1,6,6-dimethyl-9-hydroxy-prosta-5,13-diene-1-acid methyl ester (oil) as a diastereomeric mixture; 125721: + 2.74 ° in claw form, c = 0.9116.

Example 8 246.9 mg (5Z, 7R, 9a; 11a, 13E, 15R) -7-fluoro-11,15-di [Ytetrahydro-2H-pyran-2-yl) oxy] -16,16-dimethyl-9 -hydroxyprosta-5,3-diene-1-acid-methyl ester was dissolved in 10 ml of acetonitrile (dried over 3A molecular sieve) in argon. Then 476.9 mg of N-iodosuccinimide were added with stirring, the reaction vessel was purged with argon, 453 294 24 was sealed and protected from light with aluminum foil. The mixture was stirred for 27 hours at room temperature, poured into 100 ml of a 10% strength by weight aqueous sodium thiosulfate solution and extracted 3 times with 100 ml of methylene chloride. The organic extracts were washed twice with 100 ml of brine, dried over magnesium sulphate and evaporated. This gave 285.9 mg of an oily residue, which was chromatographed on 75 g of silica gel with ether / petroleum ether (1.1 parts by volume) to give 186.8 mg (62%) (7B, 9a, 11Q, 13E, 15R) -16 1,6-dimethyl-11,15-dilietetrahydro-2H-pyran-2-yl) oxy] -6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-acid methyl ester (oil) as a diastereomeric mixture.

Example 9 10.6 mg (7B, 9a-, 11a; 13E, 15R) -16,16-dimethyl-11,15-di [(tetrahydron 2H-pyran-2-yl) oxy] -6,9-epoxy 7-Fluoro-5-iodo-prosta-13-ene-1-acid methyl ester was dissolved in a mixture of 3 ml of tetrahydrofuran (freshly distilled over lithium aluminum hydride), 6 ml of glacial acetic acid and 3 ml of water in argon. The mixture was heated to 400 and stirred for 19 hours. After cooling to room temperature, the solvent was removed in high vacuum at 250. Then 2 ml of toluene was added and the solvent was again removed in high vacuum at 250. The oily residue (11, 2 mg) was chromatographed on a thin layer chromatography plate with ether. There was obtained 6.3 mg (78%) of (7β, 9aql1a, 13E, 15R) -16,16-dimethyl-11,15-dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13- one-1-acid methyl ester (oil) as an isomer mixture.

Example 10 6.3 mg of the isomer mixture obtained in Example 9 were dissolved in 2.0 ml of toluene (distilled over calcium hydride) in argon. Then 20 μl of 1,8-diazabicyclo [É.4.Q / undec -7-ene (distilled over calcium hydride) was added. The mixture was heated with stirring over 90 minutes to 90 ° and kept at this temperature for 22 hours. After cooling to room temperature, the mixture was poured into 75 ml of half-saturated brine and extracted three times with 20 ml of ether. The extracts were washed once with 20 ml of brine and dried over magnesium sulphate and evaporated. The residual oil was dried for three hours in a high vacuum and the resulting 6.2 ml of oil was chromatographed on a thin layer chromatography plate with ethyl acetate. Two products are isolated: 3.0 mg (62%) (5Z, 7β, 9α, 11α, 13E, 15R) -7-fluo-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prostate -5,1-diene-1-acid methyl ester (oil) and 1.1 mg (23%) 4E, 6cc, 7ß, 9q, 11a, 13E, 15R) -7-fluoro-6,9-epoxy-11 , 15-dihydroxy-16,16-dimethyl-prosta-4,3-diene-1-acid-methyl ester (oil).

Example 11 3 mg (5Z, 7B, 9a, 11a, 13E, 15R) -7-fluoro-6,9-epoxy-11,15-dihydroxy-16,6-dimethyl-prosta-5,13-diene-1- acid methyl ester was dissolved in 0.5 ml of methanol and 0.5 ml of water in argon. After adding 73.111 10N sodium hydroxide, the mixture was stirred for 2 hours at room temperature. The methanol was removed under reduced pressure and the residual aqueous solution was lyophilized to give (5Z, 7B, 9 «, 11d, 13E, 15R) -7-fluoro-6,9-epoxy-11,15-dihydroxy- 16,16-dimethyl-prosta-5,13-diene-1-acid-sodium salt as white powder, m.p. 48-510.

Example 12 In analogy to Example 1, 13aR- [3aa, 4d (1E, 3R *), - 4R *), 6aaβL {-hexahydro-4- [U-fluoro-3-hydroxy-1-octenyl) -2H -cyclopenta [b] furan-z-one: 111/3 an-β-4 (1s, 31f. 413) α-acetyl-hexahydro-4- [3- (1,1-dimethylethyl) dimethylsily] oxy] -4-fluoro-1-octenyl ) -2H-cyclo-pentalh / furan-2-one.

Example 13 In analogy to Examples 2 and 3 (3aR- [3aa, 4,6aqZ] -hexahydro-4- [ZY3- (1,1-dimethylethyl) -dimethylsilyl / oxy] -4-fluoro-1-octenyl] -2H -cyclopenta [h] -furan-2-one to / äaR- / §aa, 4c1 un, 315, 415) saajj-nexanydro- à-flucr-- fi- / ZZB- (1,1-amethylethylene dimethylsilyl] oxy] -4-fluoro-1-octenyl] -2H-cyclopentane / furan-2-one 453 294 26 Example gel 14 In analogy to Example 4, / 3aR- / 3aa, 4a (1E, 3R *, - 4R *) 5aqZ2 -hexahydro -3-fluoro-4- [2Z3- (1,1-dimethylethyl) -dimethylsilyl] oxy] -4-fluoro-1-octenyl] -2H-cyclopenta [h] -furan-2-one ' 3R *, 4R *) 6aqZ] -hexahydro-3-fluoro-4- (3-hydroxy-4-fluoro-1-octenyl] -2H-cyclopenta [h] -furan-2-one. Example 15 I analogy to Example 5 is transferred [3aR- / 3aa, 4a1EE, 3R *; 4R *) 6aqZf -hexahydro-3-fluoro-4- (3-hydroxy-4-fluoro-1-octenyl / -2H-cyclopenta [b] furan -z-one: in [3aR- [3a «, 4a (n:, - 3n *, 41z *) saajj-nexa-hydro-3-fluoro-4- [3- [Ytetrahydro-2H-pyran-2-yl oxy [-4-fluoro-1-octenyl] -2H-cyclopenta [h] uran-2-one.

Example 16 In analogy to Example 6, [EaR- [3aa, 4a11B, 3R *, - 4R *) oaqzf -hexahydro-3-fluoro-4- [3- [Ytetrahydro-2R-pyran-2-yl / ox]] -4-Fluoro-1-octenyl-za-cyclopenta-fur-furan-z-one: in [an- [aaeaccuzyaa-6aqZ] -hexahydro-3-fluoro-4- [-[Ttetrahydro-pyran-2-yl) oxy] -4 fluoro-1-octenyl] -2H-cyclopentaethyl] furan-2-ol.

Example Gel 17 In analogy to Example 7, α 3aR- / 3a «, 4a (1E, 3R *, - 4R *) 6aqÅ / -hexahydro-3-fluoro-4- [3- [Y-tetrahydro-2H-pyran-2-yl ) oxy [-4-fluoro-1-octenyl] εZ-cyclopenta [h / faran-2-ol to (5Z, 9Q, 13E, 15R, 16R) * 7,15'FlF1U ° f'15 * ZYtetrahydro-2H-pyran- 2-yl) oxy] F9-hydroxy-prosta-5,3-diene-1-acid methyl ester. Example 18 In analogy to Example 8, (5Z, 9a, 13E, 15R, 16R) -7,16-difluoro-15- [Ktetrahydro-2H-pyran-2-yl) oxy] -9-hydroxy-prostate - S, 13-diene-1-acid methyl ester to (9d, 13E, 15R, 16R) -7,16-difluoro-151 [(tetrahydro-28-pyran-2-yl) oxy] -6,9-epoxy -5-iodo-prosta-13- and 1-acid-methyl ester.

Example 19 In analogy to Example 9, (9a, 13E, 15R, 16R 1-7, 16-difluoro-15- [Ytetrahydro-2H-pyran-2-yl) oxy] -6,9-epoxy-5-iodo- prosta-13--en-1-acid-methyl ester to (9a, 13E, 15R, 16R) -7,16-difluoro-15-hydroxy-6,9-epoxy-5-iodine-prosta-13-en-1 -acid-methyl ester.

Example 20 In analogy: with Example 10, (9a, 13E, 15R, 16R) -7,16-difluoro-15-hydroxy-6,9-epoxy-5-iodo-prostall 3 -ene-1-acid methyl ester is converted to ( 5Z, 9a, 13E, 15R, 16R) -7,16-difluoro-15-hydroxy-6,9-epoxy-prosta--5,13-diene-1-acid methyl ester.

Example 21 In analogy to Example 11, (5Z, 9a, 13E, 15R, 16R) -7,16-difluoro-6,9-epoxy-1S-hydroxy-prosta-5,13-diene-1-acid methyl ester is converted to (5Z, 9d, 13E, 15R, 16R) -7,16-difluoro-6,9-epoxy-1S-hydroxy-prostate-5,13-diene-1-acid-sodium salt.

Example 22 In analogy to Example 10, (9α, 13E, 15R, 16R) -7,16-difluoro-15-hydroxy-6,9-epoxy-5-iodo-prosta-13-ene-1-acid methyl ester to (4E, 9a, 13E, 15R, 16R) -7,16-difluoro-6,9-epoxy-15-hydroxy-prosta--4,13-diene-1-acid methyl ester. 453 294 28 Example 23 In analogy to Example 11, (4E, 9, 13E..5R, 16R) -7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-diene-1- acid methyl ester to the sodium salt of (4E, 9,13E, 15R, 16R) -7,16-difluoro-6,9-epoxy-1S-hydroxy-prosta-4,13-diene-1-acid.

Example 24 To a solution of diisopropylamine in 9 ml of tetrahydrofuran was added dropwise at 0 -So 1.32 ml of a solution of 2.2M n-butyllithium in hexane. The mixture was stirred for 5 minutes and cooled to -400.

Then, a solution of 1g of 3.3aR, 4,5,6,6aS-hexahydro-4R- [α, 4-dimethyl-3R- (2-tetrahydropyranyloxy) -1-trans-octenyl was added dropwise over 1 minute. ] -SR-methyl-2H-cyclopenta [E] furan-2-ene in 6 ml of tetrahydrofuran and the reaction mixture was stirred for 5 minutes at -450. Then 4.26 ml of trimethylchlorosilane was added and the mixture was stirred for 5 minutes at -450.

Then the reaction mixture was allowed to warm to 0 DEG and the solvent was removed in high vacuum. The residue was added with 5 ml of diethyl ether and the cold mixture was filtered off. The solvent was removed in high vacuum (ice bath) and the residue was taken up in 10 ml of dichloromethane. The solution was then charged at 0 DEG with 530 mg of potassium bicarbonate and subsequently with 429 mg of xenon difluoride. After the evolution of gas had stopped, the mixture was stirred for a further 15 minutes and diluted with 50 ml of dichloromethane. The solution was then washed with 50 ml of water and twice with 50 ml of brine. The aqueous phase was separated and washed with 50 ml of dichloromethane. The organic phases were combined, dried over magnesium sulphate and evaporated. to give 0.95 g of crude product. Chromatography on SO g of silica gel gave 300 mg of 3,3aS, 4,5,6,6aS-hexahydro-3-fluoro--4R- [α, 4-dimethyl-3R- (2-tetrahydropyranloxy) -1-trans-octenyl] SR-methyl-2H-cyclopenta [h] furan-2-one. in IM _, 453 294 29 Example 25 In analogy to Example 6, 3,3aS, 4,5,6,6aS-hexahydro-3-fluoro-4Rf [α, 4-dimethyl-3R- (2- (tetrahydropyranyloxy) - 1-trans-octenyl] -5R-methyl-2H-cyclopenta [b] furan-2-one to 3,3aS, 4,5,6,6aS-hexahydro-3-fluoro-4R- [α, 4-dimethyl-3R- (2-Tetrahydropyranyloxy) -1-trans-octenyl / -SR-methyl-2H-cyclopenta [N-furan-2-ol.

Example 26 In analogy to Example 7, 3,3aS, 4,5,6,6aS-hexahydro-3-fluoro-4R-11,4-dimethylα3R- (2-tetrahydropyranyloxy) -1-trans-octenyl / -SR are transferred -methyl-2H-cyclopentaylfuran-2-ol to 11R, 16,16-trimethyl-7-fluoro-1SR- (2-tetrahydropyranyloxy) -9S-hydroxyprosta-cis-5-trans-13-diene-acid-methyl ester.

Example 27 In analogy to Example 8, 11R, 16,16-trimethyl-7-fluoro-1SR (2-tetrahydropyranyloxy) -9S-hydroxyprosta-cis-5-trans-13-diene acid methyl ester is converted to (9S, 11R, 13E, 1SR) -11, 16, 16, -trimethyl-15- (2-tetrahydropyranyloxy) -6,9, -epoxy-7-fluoro-5-iodo-prosta-13-en-1-acid methyl ester.

Example 28 In analogy to Example 9, (9S, 11R, 13E, 15R) -1,16,16-trimethyl-15- (2-tetrahydropyranyloxy) -6,9-epoxy-7-fluoro-5-iodo-prostate 13-ene-1-acid methyl ester to (9S, 11R, 13E, 15R) -11.16, 16-trimethyl-15-hydroxy-6,9-epoxy-7-fluorine-5-iodine-prosta-13- and 1-acid methyl ester.

Example 29 In analogy to Example 10, (95, 11R, 13E, 15R) -11,6, 16,6-trimethyl-15-hydroxy-6,9, epoxy-7-fluoro-5-iodo-prosta-13-ene 1-acid methyl ester to (5Z, 9S, 11R, 13E, 15R) -11,16,6-trimethyl-1S-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-diene-1- acid methyl ester, In 3615, 1733, 1694 and others; ultraviolef-.A max 213 mn (»= 12000> and (4E, 9S, 11R, 15R) -11,6,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-4,13-diene -1-acid methyl ester, IR 3615, 1735, 1670 cm -1.

Example 30 In analogy to Example 11, (5Z, 9S, 11R, 13E, 15R) -11,6,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-diene is transferred -1-acid methyl ester to (5Z, 9S, 11R, 13E, 15R) -11,6,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prcsta-5,13-diene -1-acid-sodium salt.

Example 31 In analogy to Example 24, 3,3aR, 4,5,6,6aS-hexahydro-4R- [3S- (2-tetrahydropyranyloxy) -1-trans-octenyl] -SR- (2-tetrahydropyranyloxy) - 2H-cyclopenta [b / furan-2-one to 3,3aS, 4, S, 6,6aS-hexahydro-3-fluoro-4R- [3S- (2-tetrahydropyranyloxy) -1-trans-octenyl] -5R- (2-tetrahydropyranyloxy) -2H-cyclopenta [b] furan-2-one; Example 32 In analogy to Example 6, 3,3aS, 4,5,6,6aS-hexahydro-3-fluoro-4R- [3S- (2-tetrahydropyranyloxy) -1-trans-octenyl] -5R- (2-tetrahydropyranyloxy) are transferred ) -2H-cyclopenta [h / furan-2-one to 3,3aS, 4,5,6,6aS-hexahydro-3-fluoro-4R- [ES- (2-tetrahydropyranyloxy) -1-trans-octenyl] - 5R- (2-tetrahydropyranyloxy) -2H-cyclopenta [h7 furan-2-ol.

Example 33 In analogy to Example 7, 3,3aS, 4,5,6,6aS-hexahydro-3-fluoro-4R- [3S- (2-tetrahydropyranyloxy) -1-trans-oxcenyD-5R- (2-tetrahydropyranyloxy) are transferred -2H-cyclopentalhalofuran-2-ol to 11R, 15S-di- (2-tetrahydropyranyloxy) -7-fluoro-9S-hydroxy-prosta-cis-5-trans-13-diene-acid-methyl ester. 453 294 31 Example 34 In analogy to Example 8, 11R, 15R-di- (2-tetrahydropyranyloxy) -7-fluoro-9S-hydroxy-prosta-cis-5-trans-13-dienoic acid methyl ester are converted to (98,11R, 13E, 15S) -1,15-di- (2-tetrahydropyranyloxy) -6,9, -epoxy-7-fluoro-5-iodo-prosta-13-en-1-acid methyl ester.

Example 35 In an analogy to Example 9, (9S, 11R, 13E, 15S) -1,15-di- (2-tetrahydropyranyloxy) -6,9-epoxy-7-fluoro-5-iodo-prosta-13-ene 1-acid-methyl ester to (9S, 11R, 13E, 15S) -11,5-dihydroxy-6,9-epoxy-7-fluoro-5-iodine-prosta-13-en-1-acid-methyl ester.

Example 36 Analogy to Example 10 is transferred (9S, 11R, 13E, 15S) -1,15-dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-ene-1-acid methyl ester to (5Z, 9S, 11R, 13E, 158) -1,15-dihydroxy-5β-epoxy-7-fluoro-prostate-5,13-diene-1-acid methyl ester and (4E, 9S, 11R, 15S) -1,15-dihydroxy 6,9-epoxy-7-fluoro-4,3-diene-1-acid methyl ester.

Example 37 In analogy to Example 11, (5Z, 9S, 11R, 13E, 15S) -11,5-dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13-diene-1-acid methyl ester is converted to (5Z, 9S, 11R, 13E, 155) -1,15-dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13-diene-1-acid-sodium salt. 453 294 32 Example 38 (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-11,15-dihydroxyprosta-5,13-diene-1-acid methyl ester Using the procedure of Example 24 was converted to 3aR / 3alpha, 4alpha (1E, 3R) Sbeta, 6alpha // hexahydro-4- [3 / (tetrahydro-2H-pyran-2-yl) oxy] -4-fluoro-1-octenyl / -5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2H-cyclopenta [b] furan-2-one to / 3aR / 3aalfa, 4alfa- (1E, 3R), 5 beta, 6aalfa / / -hexahydro-3-fluoro-4- [3 - [(tetrahydro-2H-pyran-2-yl) oxy] -4-fluoro-1-octenyl] -5 - [(tetrahydro-2H-pyran-2-yl) ) - oxy / -2H-cyclopenta [b / furan-2-one, which in the procedure of Example 6 was converted to / 3aR / 3aalfa, 4alfa (1E, 3R), 5beta, 6a-alpha // hexahydro-3-fluoro -4-3 - [(tetrahydro-2H-pyran-2-yl) oxy] -4-fluoro-1-octenyl] -5- [(tetrahydro-2H-pyran-2-yl) oxy] -2H-cyclopenta / b / furan-2-ol, which in the procedure of Example 7 was converted to (SZ, 9alpha, 11alpha, 13E, 15R) -7,16-difluoro-11,15-bis - [(tetrahydro-2H-pyran) 2-yl) oxy [9-hydroxyprosta-5,13-diene-1-acid methyl ester, which in the process of Example 8 converted to (6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-5-iodo-11,15-bis / (tetrahydro-2H-pyran-2-yl) oxy-prost 13-ene-1-acid methyl ester, which in the process of Example 9 was converted to (Galpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-5-iodo-11, 15-Dihydroxyprost-13-ene-1-acid methyl ester, which in the procedure of Example 10 was converted to a mixture of (SZ, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro 11,15-dihydroxyprosta-5,13-diene-1-acid methyl ester and (4E, 6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-11,15-dihydroxyprosta-4 , 13-diene-1-acid methyl ester. This mixture was separated by silica gel chromatography and the components were converted according to the procedure of Example 11 to (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-11,15-dihydroxyprosta-5,13-diene -1-acid-sodium salt and (4E, 6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-11,15-dihydroxyprosta-4,13-diene-1-acid- sodium salt resp. In this example, the physical properties of (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-11,15-dihydroxyprosta-5,13-diene-1-acid methyl ester were a clear Oil ; NHR (CDCl 3, 200 HHz): 5.70 (m, 2H, CH =), 5.40 (dd, J = 58Hz, J = 8Hz, CHF), 4.63 (m, 28, = CH, CHO) , 4.50 (dm.

J = 48Hz, 1H, CHF), 4.22 (prod. J = 18Hz, C80), 3.97 (br, 1H, CHO), IIIIIIIIIIIIIIII ... IIIIIIIIIIIIIIIIIIIIIIIIIIInn: ---.! ...... ______lV 453 294 - 33 3.68 (5, 3H, COOCH3), 2.90-112 (m, 18H), 0.91 (t, J = 7Hz, H, ppm, CH3). ms; calculated for c 21 H 32 O 5 F 1 (n * - F) 3e3.2234; Found: 383.2l85; calculated for C 20 H 29 O 4 F 2 (M + - CHBO) 371, 2033; Found: 371, 1982 and (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-11,15-dihydroxyprosta-5,13-diene-1-acid sodium salt was a white powder, NMR (DMSO-d 6, 200 MHz): selected peaks: 5.60 e (M, ZH, CH = CH), 5.42 (dd, J = 57Hz, J = 8Hz, CHF), 4.48 ( m, 4H, = CH, CEO), 4.28 (dm, J = 48Hz, 1H, CHF), 3.98 (dm, J = 17Hz, 1H, cgo), 3.71 (q, J = 7nz, ln, cgo), 0.86 (t, J = 7Hz, 3H, CH3) ppm.

Example 39 (5Z, 9alpha, 13E, 15S) -6,9-epoxy-7-fluoro-15: hydroxyprosta-5,13-diene-1-acid methyl ester Using the procedure of Example 24, 3αR- / 3aalpha, 4alpha (1E) were converted. , 3S), 6aalfa // - hexahydro-4- [3 - [(tetrahydro-2H-pyran-2-yl) -oxy] -1-octenyl] -2H-cyclopenta [b] furan-2-one to / 3aR- [3aalfa, 4alfa (1E, 3S), 6aalfa // hexahydro-3-fluoro-4- [3- (tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -2H -cyclopenta [b / furan-2-one which was converted to / 3aR- - / 3aalfa, 4alfa (1E, 3S), 6aalfa // - hexahydro-3-fluoro-4- / 3- (tetra- hydro-2H-pyran-2-yl) oxy [-1-octenyl] -2H-cyclopenta [b] furan-2-ol which was converted to (5Z, 9alpha, 13E, 15S) -7-fluoro by the procedure of Example 7 15 - [(tetrahydro-2H-pyran-2-yl) oxy] -9-hydroxyprosta-5,13-diene-1-acid methyl ester, which was converted to (6alpha, 9alpha, 13E by the procedure of Example 8) 15S) -6,9--epoxy-7-fluoro-5-iodo-15 - [(tetrahydro-2H-pyran-2-yl) oxy-prost-13-en-1-acid methyl ester, which by the process according to Example 9 was converted to (6alpha, 9al fa, 13E, 15S) -6,9-epoxy-7-fluoro-5-iodo-15-hydroxyprost-13-en-1-acid methyl ester, which was converted to a mixture of (5Z) by the procedure of Example 10 9alpha, 13E, 15S) -6,9-epoxy-7-fluoro-15-hydroxyprosta-5,13-diene-1-acid methyl ester and (4E, 6alpha, 9alpha, 13E, 15S) -6.9 epoxy-7-fluoro-15-hydroxyprosta-4,13-diene-1-acid methyl ester.

This mixture was separated by silica gel chromatography and the components were converted by the method of Example 11 to (SZ, 9alpha, 13E, 15S) -6,9-epoxy-7-fluoro-1S-hydroxyprosta-5,13-diene-1-acid-sodium salt and . (4E, 6alpha, 9alpha, 13E, 15S) -6,9-epoxy-7-fluoro-15-hydroxyprosta-4,13-diene-1-acid-sodium salt. Example 40 (SZ, 9alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16,16-dimethyl-15-hydroxy-prosta-S, 13-Diene-1-acid methyl ester Using the procedure of Example 24, δ 3aR- / 3aalfa, 4alfa (1E, 3R), 6aalfa // hexahydro-4- / 4,4-dimethyl-3 - [(tetrahydro--2H-) pyran-2-yl) oxy [-1-octenyl] -2H-cyclopenta [b] furan-Zlon to / 3aR- / 3aalfa, 4alfa (1E, 3R), Gaalfa // hexahydro-3-fluoro-4- 4,4-dimethyl-3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -2H-cyclopenta [b] furan-2-one, which was converted to the procedure of Example 6 to 3aR- [3aalfa, 4alfa (1E, 3R), 6aalfa // hexahydro--3-fluoro-4- [4,4-dimethyl-3 - [(tetrahydro-2H-pyran-2-yl) oxy] - 1-octenyl / -2H-cyclopenta [b] furan-2-ol, which was converted to (5Z, 9alpha, 13E, 15R) -7-fluoro--16,16-dimethyl-15 - / (by the procedure of Example 7) tetrahydro-2H-pyran-2-yl) oxy [9-hydroxy-prosta-15,13-diene-1-acid methyl ester, which was converted to (6alpha, 9alpha, 13E, 15R) -6.9 by the procedure of Example 8 epoxy-7-fluoro-5-iodo-16,16-dimethyl-15β (tetrahydro-2 H-pyran-2-yl) oxy / -prost-13-ene-1-acid methyl ester, which was converted by the procedure of Example 9 to (6alpha, 9alpha, 13E, 15R) -6,9-epoxy-7-fluoro-S iodo-16,16-dimethyl-15-hydroxyprost-13-en-1-acid methyl ester, which was converted to a mixture of (5Z, 9alpha, 13E, 15R) -6,9-epoxy by the procedure of Example 10. -7-fluoro-16,16-dimethyl-15-hydroxyprosta-5,13-diene-1-acid methyl ester and (4E, 6alpha, 9alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16 1,6-dimethyl-15-hydroxyprosta-4,3-diene-1-acid methyl ester. This mixture was separated by silica gel chromatography and the components were converted by the method of Example 11 to (52.9 alpha, 13B, 15R) -6,9-epoxy-7-fluoro-16,16-dimethyl-15-hydroxyprost-5, 13-diene-1-acid-sodium salt and (4E, 6alpha, 9alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16,16-dimethyl-15-hydroxyprosta-4,13-diene- l-acid-sodium salt. Example 41 (5Z, 9alpha, 11alpha, 13E, 15S) -6,9-epoxy-7-fluoro-11-methyl-15-hydroxyprosta-5,13-diene-1-methyl ester The procedure of Example 24 was converted to 3aR [3] alpha, 4 alpha (1E, 3S), 5beta, Gaalpha // hexahydro-4- [3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -S-methyl-ZH -cyclopenta [b] -furan-2-453 294 35 on to / 3aR / 3aalfa, 4alfa (1E, 3S), 5beta, 6aalfa // - hexahydro-3-fluoro-4- / 3 - / (tetrahydro-2H- pyran-2-yl) oxy [-1-octenyl] -5-methyl-2H-cyclopenta [b] -furan-2-one, which was converted to 3aR / 3aalpha, 4alpha (1E, 3S) by the procedure of Example 6. ), 5beta, 6a alpha // hexahydro-3-fluoro-4- [3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -5-methyl-2H-cyclopenta [b] furan-2-ol, which was converted to (5Z, 9alpha, 11alpha, 13E, 15S) -7-fluoro-S-methyl-11 - [(tetrahydro-2H-pyran-2-yl) oxy] by the procedure of Example 7 N-9-hydroxyprosta-5,13-diene-1-acid methyl ester, which was converted by the procedure of Example 8 to (6alpha, 9alpha, 11alpha, 13E, 15S) -6,9-epoxy-7-fluoro-5 -Iodo-11-methyl-15 - [(tetrahydro-2H-pyran-2-yl) oxy] p rust-13-ene-1-acid methyl ester, which by the procedure of Example 9 was converted to (6alpha, 9alpha, 11alpha, 13E, 15S) -6,9-epoxy-7-fluoro-5-iodo-11-methyl-15- hydroxyprost-13-ene-1-acid methyl ester, which by the procedure of Example 10 was converted to a mixture of (5Z, 9alpha, 11alpha, 13E, 15S) -6,9-epoxy-7-fluoro-11-methyl-15 -hydroxyprost-13-ene--1-acid methyl ester and (4E, 6alpha, 9alpha, 11alpha, 13E, 15S) -6,9-epoxy-7-fluoro-11-methyl-15-hydroxyprosta-4,3-diene 1-acid methyl ester. This mixture was separated by silica gel chromatography and the components were converted by the method of Example 11 to (5Z, 9alpha, 11alpha, 13E, 15S) -6,9-epoxy-7-fluoro-11-methyl-15-hydroxyprost-13-en-1 -acid-sodium saltARXYD = + 114.63 (CHCl 3, c 1.051) and (4E, 6alpha, 9alpha, 11alpha, 13E, 158) -6,9-epoxy-7-fluoro-11-methyl-15-hydroxyprosta-4, l3-dien-1-acid-sodium salt.

Example 42 (SZ, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-11-methyl-15-hydroxyprosta-5,13-diene-1-acid methyl ester Using the procedure of Example 24, / 3aR / 3aalfa, 4alfa (1E, 3R), 5beta, 6aalfa // hexahydro-4- [4-fluoro-3 - [(tetrahydro-23-pyran-2-yl) oxy] -1-octenyl / -5-methylcyclopenta [b] furan-2-one to / 3aR / 3aalfa, 4alfa (1E, 3R), 5beta, 6aalfa // hexahydro--3-fluoro-4- / 4-fluoro-3 - / ( tetrahydro-28-pyran-2-yl) oxy [-1-octenyl] -5-methylcyclopenta [b] furan-2-one, which by the procedure of Example 6 was converted to / 3aR / 3aalfa, 4alpha (1E, 3R), Sbeta, 6aalpha // hexahydro-3-fluoro-4- [4-fluoro-3- [tetrahydro-2-pyran-2-yl) oxy] -1-octenyl] -5-methylcyclopenta [b] furan- 2-ol, which in the procedure of Example 7 was converted to (5Z, 9alpha, 11alpha, 13E, 15R) -7,16-difluoro-11-methyl-15 - [(tetrahydro-2H-pyran-2- yl) oxy / -9-hydroxyprosta-5,13-diene-1-acid methyl ester, which was converted to (6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro by the procedure of Example 8 -5-iodo-11-methyl-1 5 - [(tetrahydro-2H-pyran-2-yl) oxy] -prost-13-en-1-acid methyl ester, which by the procedure of Example 9 was converted to (6alpha, 9alpha, 11alpha, 13E, 15R) -6 .9-epoxy-7,16-didluoro-5-iodo-11-methyl-15-hydroxyprost-13-ene-1-acid methyl ester, which was converted to a mixture of (52,9alpha, 11alpha) by the procedure of Example 10 13E, 15R) -6,9-epoxy-7,16-difluoro-11-methyl-15-hydroxyprosta-5,13-diene-1-acid methyl ester and (4E, 6alpha, 9alpha, 11alpha, 13E, 15R) - 6,9-epoxy-7,16-difluoro-11-methyl-15-hydroxyprosta-4,3-diene-1-acid methyl ester.

This mixture was separated by silica gel chromatography and the components were converted by the method of Example 11 to (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-11-methyl-15-hydroxyprosta-5,13- diene-1-acid-sodium salt ÅKID + 19.18 ° (CHCl 3, c 1.014) and (4E, 6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-11-methyl -15-hydroxyprosta-4,3-diene--1-acid-sodium salt.

Example 43 (5Z, 9alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-trifluoromethyl-16-methyl-15-hydroxyprosta-5,13-diene-1-acid methyl ester Using the procedure of Example 24, 3aR / 3aalfa, 4alfa (1E, 3R), Gaalfa // hexahydro-4- [4-trifluoromethyl-4-methyl--3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl / -cyclopenta [b] furan-2-one to / 3aR / 3aalfa, 4alfa (1E, 3R), 6aalfa // hexahydro-3-fluoro-4/4-trifluoromethyl-4-methyl-3 - [(tetrahydro -2H-pyran-2-yl) oxy [-1-octenyl] -cyclopenta [b] furan-2-one, which by the procedure of Example 6 was converted to / 3aR / 3aalfa, 4alfa (1E, 3R), 6aalfa / / -hexahydro-3-fluoro-4- [4-trifluoromethyl--4-methyl-3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -cyclopenta [b] furan- 2-ol, which in the procedure of Example 7 was converted to (5Z, 9alpha, 13E, 15R) -7-fluoro-16-trifluoromethyl-16-methyl-15 - [(tetrahydro-2H-pyran-2-yl) oxy / -9-hydroxy-453 294 37 prostate-5,13-diene-1-acid methyl ester, which was converted to (5Z, 6alpha, 9alpha, 13E, 15R) by the method of Example 8 - -6,9-epoxy-5 -iodine-7 ~ fluoro- 16-Trifluoromethyl-16-methyl-15- [(tetrahydro-2H-pyran-2-yl) oxy] prost-13-ene-1-acid methyl ester, which was converted to (5Z, 6alpha, 9alpha, by the procedure of Example 9, 13E, 15R) -6,9-epoxy-5-iodo-7-fluoro-16-trifluoromethyl-16-methyl-15-hydroxyprost-13-en-1-acid methyl ester, which was converted by the procedure of Example 10 to a mixture of (5Z, 9alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-trifluoromethyl-16-methyl-15-hydroxyprosta-5,13-diene-1-acid methyl ester and (4E , 6alpha, 9alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-trifluoromethyl-16-methyl-15-hydroxyprosta-4,3-diene-1-acid methyl ester. This mixture was separated by silica gel chromatography, and the components were converted by the method of Example 11 to (5Z, 9alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-trifluoromethyl-16-methyl-15-hydroxyprosta-5 , l3-dien-1-acid-sodium salt resp. (4E, 6alpha, 9alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-trifluoromethyl-16-methyl-15-hydroxyprosta-4,3-diene-1-acid sodium salt.

Example 44 (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-methyl-11,15-dihydroxyprosta-5,13-diene-1-acid methyl ester Using the procedure of Example 24, 3aR / 3aalfa, 4alfa (1E, 3R), Sbeta, Gaalfa // hexahydro-4- [3 - [(tetrahydro-2H-pyran-2-yl) oxy] -4-methyl-1-octenyl / -5 - [(tetrahydro-2H-pyran-2-yl) -oxy] -2H-cyclopenta [b] furan-2-one to / 3aR / 3aalfa, 4alfa (1E, 3R), Sbeta, 6aalfa // - hexahydro -3-fluoro-4- [3 - [(tetrahydro-2H-pyran-2-yl) -oxy] -4-methyl-1-octenyl] -5-[(tetrahydro-2H-pyran-2-yl) oxy / -2H-cyclopenta [b] furan-2-one, which was converted to .beta. / 3aR / 3aalfa, 4alfa / IE, 3R), 5beta, 6aalfa // hexahydro-3-fluoro-4 - [3 - [(tetrahydro-2H-pyran-2-yl) -oxy-4-methyl-1-octenyl] -5 - [(tetrahydro-2H-pyran-2-yl) oxy-2H-cyclopenta / b / furan-2-ol, which in the procedure of Example 7 was converted to (5Z, 9alpha, 11alpha, 13E, 15R) -7-fluoro-16-methyl-11,15-bis - [(tetrahydro-2H- pyran-2-yl) oxy [9-hydroxy-prosta-S, 13-diene-1-acid methyl ester, which was converted by the method of Example 8 was added (6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-5-iodo-16-methyl-11,15-bis - [(tetrahydro-2H-pyran) -. _....-__. 453 294 β-yl) oxy / prost-13-en-1-acid methyl ester, which by the procedure of Example 9 was converted to (6alpha, 9alpha, 11alpha, 13E, 15R) -6, 9-epoxy-7-fluoro-5-iodo-16-methyl-11,15-dihydroxy-prost-13-ene-1-acid methyl ester, which by the procedure of Example 10 was converted to a mixture of (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-methyl-11,15-dihydroxyprosta-5,13-diene-1-acid methyl ester and (4E, 6alpha, 9alpha, 11alpha, 13E, 15R) - 6,9-epoxy-7-fluoro-16-methyl-11,15-dihydroxyprosta-4,3-diene-1-acid methyl ester. This mixture was separated by silica gel chromatography and the components were converted by the method of Example 11 to (SZ, 9alpha, 11alpha, 13E, 15R) - 6,9-epoxy-7-fluoro-16-methyl-11,15-dihydroxyprosta-5, l3-dien--1-acid-sodium salt resp. (4E, 6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-methyl-11,5-dihydroxyprosta-4,3-diene-1-acid-sodium salt.

Example 45 (5Z, 9alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-16-methyl-15-hydroxyprosta-5,13-diene-1-acid methyl ester Using the procedure of Example 24, 3aR- [3aalfa, 4alfa (1E, 3R), 6aalfa // hexahydro-4- [4-fluoro-4-methyl-3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1- octenyl / -2H-cyclopenta [b] furan-2-one to / 3aR- / 3aalfa, 4alfa (1E, 3R), 6aalfa // hexahydro-3-fluoro--4- / 4-fluoro-4-methyl- 3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -2H-cyclopenta [b] furan-2-one, which was converted to 3aR- / 3aalpha by the procedure of Example 6, 4alpha (1E, 3R), 6aalphaH-hexahydro-3-fluoro-4- [4-fluoro-4-methyl-3- [tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] - 2H-cyclopenta [b] furan-2-ol, which was converted by the procedure of Example 7 to (5Z, 9alpha, 13E, 15R) -7,16-difluoro-16-methyl-15 - [(tetrahydro-2H-pyran-2-ol). 2-yl) -oxy-9-hydroxyprosta-5,3-diene-1-methyl ester, which was converted to (6alpha, 9alpha, 13E, 15R) -6,9-epoxy-7 by the procedure of Example 8. 16-Difluoro-5-iodo-16-methyl-15 - [(tetrahydro-2H-pyran-2-yl) oxy] -prost-1 3-ene-1-acid methyl ester, which was converted to the method of Example 9 to (6alpha, 9alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-5-iodo-16-methyl-1S-hydroxy- prost-13-en-1-acid methyl ester, which by the procedure of Example 10 was converted to a mixture of (5Z, 9a1fa, 13E, 15R) - 453 294 39 6,9-epoxy-7,16-difluoro-16-methyl- 15-hydroxyprosta-5,13-diene-1-acid methyl ester and (4E, 6alpha, 9alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-16-methyl-15-hydroxyprosta-4,13- dien-1-acid methyl ester. This mixture was separated by silica gel chromatography and the components were converted by the method of Example 11 to (SZ, 9alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-16-methyl-1S-hydroxprosta-5,13- diene-1-acid sodium salt and (4E, 6alpha, 9alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-16-methyl-15-hydroxyprosta-4,13-diene-1-acid sodium salt.

Example 46 (5Z, 9alpha, 11alpha, 13e, 15R) -6,9-epoxy-7,16-difluoro-11,16-dimethyl-1S-hydroxyprosta-S, 11B-diene-1-acid methyl ester By the method according to Example 24 were converted to 3aR / 3aalfa, 4alfa (1B, 3R), Sbeta, Gaalfa // hexahydro-4/4-fluoro-4-methyl-3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl / -5-methylcyclopenta [b] furan-2-one to / 3aR / 3aalfa, 4alfa (1E, 3R), Sbeta, 6aalfa / hexahydro-3-fluoro-4 / 4- fluoro-4-methyl-3H (tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -5-methylcyclopenta [b] furan-2-one, which was converted to / 3aR / by the procedure of Example 6 3alpha, 4alpha (1E, 3R), Sbeta, 6aalpha // hexahydro-3-fluoro-4- [4-fluoro-4-methyl-3H- (tetrahydro-2H-pyran-2-yl) oxy] -1- octenyl / -5-methylcycolpenta [b / furan-2-ol, which was converted by the procedure of Example 7 to (SZ, 9alpha, 11alpha, 13B, 15R) -7,16-difluoro-11,16-dimethyl-15 / ( tetrahydro-2H-pyran-2-yl) oxy [9-hydroxyprosta-5,13-diene-1-acid methyl ester, which was converted to (6alpha, 9alpha, 11alpha, 13E, 15R) -6 by the procedure of Example 8. , 9-epoxy-7,16-difluoro- 5-iodo-11,16-dimethyl-15β- (tetrahydro-2H-pyran-2-yl) oxy / prost-13-en-1-acid methyl ester, which was converted to (α-alpha, 9-alpha, by the procedure of Example 9, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-5-iodo-11,16-dimethyl-15-hydroxyprost-13-en-1-acid methyl ester, which by the procedure of Example 10 was converted into a mixture of (SZ, 9alpha, 11alpha, 13E, 1SR) -6,9-epoxy-7,16-difluoro-11,16-dimethyl-15-hydroxyprosta-5,13-diene-1-acid methyl ester and (45, Galfa 9alpha, 11alpha, 13E, 1SR) -6,9-epoxy-7,16-difluoro-11,16-dimethyl-15-hydroxyprosta-4,13-diene-1-acid methyl ester. This mixture was separated by silica gel chromatography and the components were converted according to the procedure of Example 11 to (SZ, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-11,16-dimethyl-15 -hydroxyprosta-5,13-diene-1-acid sodium salt resp. (4E, 6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-11,16-dimethyl-15-hydroxyprosta-4,13-diene-1-acid sodium salt.

Example 47 (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16,16-trifluoro-11,15-dihydroxyprosta-5,13-diene-1-acid methyl ester Using the procedure of Example 24, 3aR / 3aalfa, 4beta (1E, 3R), Sbeta, 6aalfa // hexahydro-4- [4,4-difluoro-3- [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] - 5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2H-cyclopenta [b] furan-2-one to / 3aR / 3aalfa, 4beta (1E, 3R), Sbeta, 6aalfa // - hexahydro- 3-Fluoro-4- [4,4-difluoro-3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -5H (tetrahydro-2H-pyran-2-yl) -oxy / -2H-cyclopenta [b / furna-2-one, which was converted to / 3aR / 3aalfa, 4alfa (1E, 3R), 5beta, 6aalfa // hexahydro-3-fluoro-4 / by the procedure of Example 6 4,4-Difluoro-3- [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2H-cyclopenta [b] furan-2-ol, which was converted to (5Z, 9alpha, 11alpha, 13E, 15R) -7,16,16-trifluoro-11,15-bis - [(tetrahydro-2H-pyran) by the procedure of Example 7 -2-yl) oxy [9-hydroxyprosta-5,13-diene-1-acid methyl ester, which by the method of Example 8 was converted to (6alpha, 9alpha, 11alpha1.13E, 15R) -6,9-epoxy-7,16,16-trifluoro-5-iodo-11,15-bis- [(tetrahydro-2H-pyran-2-yl) ) oxy / prost-13-ene-1-acid methyl ester, which was converted to (6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16,16-trifluoro-5-iodo by the procedure of Example 9 11,15-dihydroxyprost-13-ene-1-acid methyl ester, which was converted by the procedure of Example 10 to a mixture of (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16,16- trifluoro-11,15-dihydroxyprosta-5,13-diene-1-acid methyl ester and (4E, fi alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16,16-trifluoro-11,15- dihydroxyprosta-4,13-diene-1-acid methyl ester. This mixture was separated by silica gel chromatography and the components were converted by the method of Example 11 to (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16,16-trifluoro-11,15-dihydroxy-prosta-S, l3-dien-l ~ acid sodium salt resp. (4E, 6alpha, 9alpha, 453 294 41 11alpha, 13E, 15R) -6,9-epoxy-7,16,16-trifluoro-11,15-dihydroxy-prosta-4,13-diene-1-acid sodium salt.

Example 48 (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-trifluoromethyl-11,6-dimethyl-15-hydroxyprosta-5,13-diene-1-acid methyl ester Using the procedure of Example 24 was converted to 3aR / 3aalfa, 4alpha (1E, 3R), Sbeta, 6aalfa // hexahydro-4- [4-trifluoromethyl-4-methyl-3- [tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl / -5-methyl-cyclopenta [b] furan-2-one to / 3aR / 3aalfa, 4alfa (1E, 3R), Sbeta, 6aa1fa // hexahydro-3-fluoro-4- / 4-trifluoromethyl -4-methyl-3- [(tetrahydro-2H-pyran-2-yl) oxy] -octenyl] -5-methylcyclopenta [b] furan-2-one, which with the preparation of Example 6 was converted to 3aR / 3aalpha , 4alpha (1B, 3R), 5beta, 6alpha // hexahydro-3-fluoro-4,4-trifluoromethyl-4-methyl-3H (tetrahydro-28-pyran-2-yl) oxy] -1-octenyl / -5-methylcyclopenta [b] furan-2-ol, which was converted to (SZ, 9alpha, 11alpha, 13E, 15R) -7-fluoro-16-trifluoromethyl-11,16-dimethyl-15 by the procedure of Example 7 - ((tetrahydro-2H-pyran-2-yl) oxy] -9-hydroxyprosta-5,13-diene-1-acid methyl ester, which was converted to (6alpha, 9 by the procedure of Example 8 alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-5-iodo-16-trifluoromethyl-11,16-dimethyl-15 - [(tetrahydro-2H-pyran-2-yl) oxy] - prost-13-ene-1-acid methyl ester which by the procedure of Example 9 was converted to (Qalpha, 9alpha, 11alpha, 13E, 1SR) -6,9-epoxy; 7-fluoro-5-iodo-16-trifluoromethyl-11, 16-dimethyl-15-hydroxyprost-13-en-1-acid methyl ester, which was converted by the procedure of Example 10 to a mixture of (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro 16-trifluoromethyl-11,6-dimethyl-15-hydroxyprosta-5,3-diene-1-acid methyl ester and (4E, 6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-lostrifluoromethyl -11,16-dimethyl-15-hydroxyprosta-4,13-diene-1-acid methyl ester. This mixture was separated by silica gel chromatography and the components were converted by the method of Example 11 to (SZ, 9alpha, 11alpha, 13E, 15R) - 6,9-epoxy-7-fluoro-16-trifluoromethyl-11,6-dimethyl-15R hydroxyprosta-5,13-diene-1-acid sodium salt resp. (4E, oleava, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-trifluoromethyl-11,6-dimethyl-15-hydroxyprosta-4,13-diene-1-acid sodium salt. Exemgel 49 / 3aR / 3aalfa, 4alfa (IE), Sbeta, 6aalfa // hexahydro-4- (4-fluoro-4-methyl-3-oxo-1-octenyl) -5 - [(phenylcarbonyl) oxy-2H-cyclopenta- [b] furan-2-one To a stirred mixture of 0.96 g of 50% sodium hydride dispersion in 140 ml of tetrahydrofuran under argon at 0 ° C was added a solution of 5.08 g dimethyl (3-fluoro-3-methyl-2-oxoheptyl) phosphonate in 100 ml of tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and after 2 hours it was cooled again to 0 ° C and a solution of 4.93 g / 3aR / 3aalfa, 4alfa, 5beta, 6aalfa // hexahydro-4-carboxaldehyde-5 / (phenylcarbonyl) oxy / -2H-cyclopentane-b-furan-2-one was added. After 6 hours, the reaction mixture was poured into 2M sodium hydrogen sulfate / ice. This mixture was extracted with ether and the combined extracts dried (Naz This material was chromatographed on silica gel using SO 4) and then evaporated to give a dark oil. ethyl acetate-hexane (1: 2) as eluent to give .beta. 5 - [(phenylcarbonyl) oxy-2H-cyclopenta [b] furan-2-one.

Exemgel 50 / 3aR / 3aalfa, 4alfa (1E, 3R), Sbeta, 6aalfa // hexahydro-é- (4-fluoro-4-methyl-3-hydroxy-1-octenyl) -5-hydroxy-2H-cyclopenta [ b / furan-2- 22.

To a solution of 1.56 g / 3aR / 3aalfa, 4alfa (IE), Sbeta, 6aalfa // -hexahydro-4- (4-fluoro-4-methyl-3-oxo-1-octenyl) -5 - / ( phenylcarbonyl) oxy-2H-cyclopenta [b / furan-2-one in 50 ml of methanol at -20 ° C was added 0.22 g of sodium borohydride. After 3 hours, 2.8 g of potassium carbonate were added and the reaction mixture was allowed to warm to room temperature. After 2.5 hours at room temperature, the reaction mixture was poured onto ice containing 21 ml of 2M sulfuric acid.

The mixture was mixed with sodium chloride and extracted with ethyl acetate. The combined extracts were dried (MgSO 4), concentrated and the residual material chromatographed on silica gel using ethyl acetate-hexane as eluent to give / 3aR / 3aa1fa, 4alpha (1E, 3R), 5bcta, Gaalfa // - hexahydro -4- (4-fluoro-4-methyl-3-hydroxy-1-octenyl) -53-hydroxy-2H-cyclopenta [b] furan-2-one.

. .... -FM __....._._...., ......, Exemgel 51 / 3aR / 3aalfa, 4alfa (lE, 3R), Sbeta, Gaalfa // - hexahydro-4 - (4-fluoro-4-methyl-3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -S - [(tetrahydro-2H-pyran-2-yl) oxy] -2H-cyclopenta [b] furan-2-one To a solution of 0.6 g / 3aR / 3aalfa, 4a1fa (1E, 3R), Sbeta, Gaalfa // hexahydro-4 (4-fluoro-4-methyl- 3-hydroxy-1-octenyl) -5-hydroxy-2H-cyclopent [b] furan-2-one in 30 ml of methylene chloride was added 1.2 ml of dihydropyran and 2 mg of p-toluenesulfonic acid. After 3 hours the mixture was washed with 5% sodium bicarbonate solution, dried (Na 2 SO 4) and evaporated to give a dark oil, this material was purified by silica gel chromatography using ethyl acetate-hexane as eluent to give fi e of / 3aR / 3alpha, 4alpha (5E, 3R) 6apha-alpha-hexahydro-4- [4-fluoro-4-methyl-3 - [(tetrahydro-2H-pyran-2-yl) -oxy] -1-octenyl] -5- [(tetrahydro-2H-pyran- 2-yl) oxy [-2H-cyclopenta [b] furan-2-one.

Example 52 (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-16-methyl-11,15-dihydroxyprosta-5,13-diene-1-acid methyl ester Using the procedure of Example 24 converted to 3aR / Baalpha, 4alpha (1E, 3R), Sbeta, 6aalpha // hexahydro-4/4-fluoro-4-methyl-3- [(tetrahydro-2H-pyran-2-yl) oxy] -1- octenyl / -5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2H-cyclopenta [b] furan-2-one to / 3aR / 3aalfa, 4alfa (1E, 3R), Sbeta, 6aalfa // - hexahydro-3-fluoro-4- [4-fluoro-4-methyl-3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -5- [(tetrahydro-2H-pyran -2-yl) oxy [2-ZH-cyclopenta [b] furan-2-one, which by the procedure of Example 6 was dehydrated to / BaB / Baalfa, 4alpha (1E, 3R), 5beta, Gaalfa // - hexahydro -3-fluoro-4- [4-fluoro-4-methyl-3 - [(tetrahydro-2H-pyran-2-yl) oxy] -ZH-cyclopenta [b] furan-2-ol, which by the procedure of Example 7 was converted to (5Z, 9alpha, 11alpha, 13E.1SR) -7,16-difluoro-16-methyl-11,15-bis- [(tetrahydro-2H-pyran-2-yl) oxy] -9-hydroxyprosta- 5,13-diene-1-acid methyl ester, which was converted to (6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-5-iodo-16-methyl-11,15-bis - [(tetrahydro-2H-pyran-2-yl) -453,294 44 oxy / prost-13-en-1-acid methyl ester, which was converted by the procedure of Example 9 to (6alpha, 9alpha, 11alpha, 13E, ISR), 6,9-epoxy-7,16-difluoro-5-iodo- 16-methyl-11,15-dihydroxy-prost-13-ene-1-acid methyl ester, which was converted by the procedure of Example 10 to a mixture of (5Z, 9alpha, 11alpha, 138, 15R) -6,9-epoxy-7 , 16-difluoro-16-methyl-11,15-dihydroxy-prosta-S, 13-diene-1-acid methyl ester and (4E, 6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16 -difluoro-16-methyl-11,15-dihydroxyprosta -4,13-diene-1-acid methyl ester. This mixture was separated by silica gel chromatography and the components were converted by the method of Example 11 to (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-16-methyl-11,15-dihydroxyprosta- 5,13-dien-1-acid sodium salt resp. (4E, 6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7,16-difluoro-16-methyl-11,15-dihydroxyprosta-4,3-diene-1-acid sodium salt.

Example 53 / 3aR / 3aalfa, 4alfa (1E, 3R), Sbeta, 6aalfa // hexahydro-4- [4-trifluoromethyl-47methyl-3 - [(tetrahydro-2H-pyran-2-yl) oxy] - 1-Octenyl [-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2H-cyclopenta [b] furan-2-one Using the procedure of Example 49, 3aR / 3aalfa, 4alfa, Sbeta, 6aalfa were converted. // - hexahydro-4-carboxaldehyde-5 - [(phenylcarbonyl) oxy] -2H-cyclopenta [b] furan-2-one to / 3aR / 3aalfa, 4alfa (1E), Sbeta, 6aalfa // - hexahydro- 4- [4-trifluoromethyl-4-methyl-3-oxo-1-octenyl] -5 - [(phenylcarbonyl) oxy] -2H-cyclopenta- [b] furan-2-one, which was converted by the method of Example 50 to / 3aR / 3aalfa, 4alfa (1E, 3R), 5beta, 6aalfa // hexahydro-4- [4-trifluoromethyl-4-methyl-3-hydroxy-1-octenyl] -5-hydroxycyclopenta [b / furan -2-one, which by the procedure of Example S1 was converted to / 3aR / 3aalfa, 4alfa (1E, 3R) Ääbeta, Gaalfa // - hexahydro-4- [4-trifluoromethyl-4-methyl-3 - / (tetrahydro-23 -pyran-2-yl) oxy [-1-octenyl] -5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2-cyclopenta [b] furan-2-one. 453 294 45 Example S4 (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-trifluoromethyl-16-methyl-11,15-dihydroxyprosta-S, 13-diene-1-acid methyl ester Using the procedure of Example 24, δ 3aR / 3aalfa, - 4alfa (1E, 3R), Sbeta, 6aalfa // - hexahydro-4- [4-trifluoromethyl-4-methyl-3] (tetrahydro-2H-pyran-2-yl) were converted. ) oxy-1-octenyl [-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2H-cyclopent [b] furan-2-one to / 3aR / 3alpha, 4alpha (1E, 3R) , Sbeta, 6aalpha // hexahydro-3-fluoro-4- [4-trifluoromethyl-4-methyl-3H (tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -5 - [( tetrahydro-2H-pyran-2-yl) oxy / 2H-cyclopenta [b] furan-2-one, which was converted to 3aR / 3aalfa, 4alfa (1E, 3R), 5beta, 6aalfa by the procedure of Example 6 // - hexahydro-3-fluoro-4- [4-trifluoromethyl-4-methyl-3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-octenyl] -5 - [(tetrahydro-2H-pyran -2-yl) -oxy-2H-cyclopenta [b] furan-2-ol, which was converted to (5Z, 9alpha, 11alpha, 13E, 15R) -7-fluoro-16-trifluoromethyl-16 by the procedure of Example 7 -methyl-11,15-bis - [(tetrahydro-2H-pyran-2-yl) oxy] -9-hyd roxiprosta-5,13-diene-1-acid methyl ester, which was converted to (α-alpha, 9-alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-5-iodo-16-trifluoro- methyl 16-methyl-11,15-bis - [(tetrahydro-2H-pyran-2-yl) oxy] -prost-13-ene-1-acid methyl ester, which was converted to (6alpha, 9alpha) by the procedure of Example 9 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-5-iodo-16-trifluoromethyl-16-methyl-11,15-dihydroxy-prost-13-ene-1-acid methyl ester, which by the method of Example 10 was converted to a mixture of (5Z, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-trifluoromethyl-16-methyl-11,15-dihydroxyprosta-5,13-diene-1 -acid methyl ester and (4E, 6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-trifluoromethyl-16-methyl-11,15-dihydroxyprosta-4,13-diene-1-acid methyl ester .

This mixture was separated by silica gel chromatography and the components were converted by the method of Example 11 to (SZ, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-trifluoromethyl-16-methyl-11,15- dihydroxyprosta-5,13-diene-1-acid sodium salt resp. (4E, 6alpha, 9alpha, 11alpha, 13E, 15R) -6,9-epoxy-7-fluoro-16-trifluoromethyl-16-methyl-11,15-dihydroxyprosta-4,13-diene-1-acid sodium salt. 453 294 46 Example gel A tablet can be prepared as follows: A tablet (5Z, 94,13E, 15R, 16R) -7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-diene -1-acid-Na 25 mg Dicalcium phosphate dihydrate, unmilled 175 mg Corn starch 24 mg Magnesium stearate 1 mg Total weight 225 mg The active substance and the corn starch were mixed into a premix. This was mixed with the dicalcium phosphate and half the amount of magnesium stearate and granulated. The residual magnesium stearate was mixed in and the mass was formed into tablets.

Example gel B A capsule can be prepared as follows: parts by weight (5Z, 9og13E, 1SR, 16R) -7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-diene-1-acid-Na 200 Dicalcium phosphate dihydrate, unmilled 235 Maize starch 70 FD and C Yellow 5 - aluminum Lake 25% 2 Boiled cotton seed oil (saturated) 25 Calcium stearate 3 All ingredients were mixed. The resulting powder was filled into hard gelatin capsules (fill weight 350 mg).

Claims (10)

453 294 47 PATENT REQUIREMENTS 1. l. Compounds of the general formula W ~ \ 4 /, / (cu2) 2cooR now m \ \ HIH M I! N 'Q Cli = Cli- - (CHZ) 3CH3 __ WHH ö | u \ n E W'-Û ”N P wherein one of the double bonds indicated by dashed lines is present in the 4.5 or 5.6 position; R is hydrogen or lower alkyl; R 1 is methyl, hydrogen or hydroxy; R 2 and R 21 are hydrogen, fluorine, trifluoromethyl is hydrogen, methyl or fluorine; or methyl; wherein R 2 is hydrogen or methyl, when R 21 is trifluoromethyl; their pharmaceutically usable salts, optical antipodes and feces. Compounds according to claim 1 having the general formula CH '(CH2) 3COOR š _ F Z lf IA 2 H1: = CH = CH-C- - Ii E? (CH2) 3CH3 R 'nö Rzl _ 1 2 21 _ _ wherein R, R, R and R have the meaning given in claim 1. Compounds according to claim 1 or 2, wherein the 7-fluoro substituent has a β-configuration. 453 294 48 Compounds according to claim 3, wherein R * is hydroxy or methyl and R 2 and R 21 are methyl or R 2 is hydrogen and R 21 is fluorine. A compound according to claim 1, (5Z, 6β, 9β, 11M, 13E, 15R) -7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13- dien-1-acid-sodium salt. A compound according to claim 1,5 (5Z, Zß, 9,11a, 135,15R) -7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13- dien-1-acid methyl ester. A compound according to claim 1, (S 2, 9S, 11R, 13E, 15R) -1,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-diene-1 -acid-methyl ester. Compounds according to any one of claims 1 to 7 for use as pharmaceuticals. 9. A process for the preparation of compounds of general formula I according to claim 1, characterized in that a compound of general formula is dehydrohalogenated x I 6 n cu- (cnz) 3coon 2 F 'I I R? -. xn a | _: _ czwca-lc-lc- (c fl z) 3CH3 _ = _ 21 Rl no R 6 1 2 21 wherein X is halogen; R is lower alkyl; and R, R and R have the meaning given in claim 1; and that, if desired, an ester group R6 is hydrolyzed and / or a carboxylic acid thus obtained is converted into a pharmaceutically useful salt. 10. Pharmaceutical preparations, characterized in that they contain as active ingredient a compound of the formula I or a pharmaceutically usable salt thereof.