LU83992A1 - NEW FLUORPROSTACYCLINE - Google Patents

Description

i i à F.Hoffmann-La Roche & Co.Aktiengesellschaft, Basel / Switzerland RAN 4303/11 5

A

10 New fluoroprostacyclins 15 The present invention relates to new fluoroprostacyclins, processes for their preparation, intermediates therefor and pharmaceutical preparations which contain these fluoroprostacyclins.

20 The new fluoroprostacyclins according to the invention hated the general formula

A

/ (ch2) 2C00r

(5 F

25 Ξ Ξ CT f -,, = ^ CH = CH-C-C- (CH „) _ CH0 -1 = i 233 30 R HÖ R21 where one of the dotted lines

Double bonds are present in the 4.5 or 5.6 position; R is hydrogen or lower alkyl; R is methyl, 2 35 is hydrogen or hydroxy; R is hydrogen, methyl or 21

Fluorine; and R is hydrogen, fluorine, trifluoromethyl Grn / 8.2.82 * il, * - 2 - 2 or methyl; where R is hydrogen or methyl, 21 when R is trifluoromethyl.

The invention further relates to pharmaceutically applicable salts, optical antipodes and racemates of the compounds of the formula I.

=> A preferred aspect of the present invention

meets the compounds of formula v = 10 O

II

^ CH-CH2-CH2-CH2-C-OR

15 ~ r —— ^ r21 I-A

L CH = CH-CH-C-CH2-CH2-CH2-CH3 OH £ 12 21 20 where R, R, R and R have the above meaning.

Another aspect of the present invention relates to compounds of the formula

O

25 ||

Hn ^^ - CH ^ H-CH ^ CH ^ C-OR

(5 I-B

Ξ_Ξ D 2i - · · I 1 i 30 L> ^ CHnCH-CH-C-CH2-CH2-CH2-CH3 '' 'OH k2 12 21 where R, R, R and R have the above meaning.

35 The term "lower alkali" used here refers to straight-chain and branched alkyl groups with 1-7 C atoms, such as methyl and ethyl. The expression "lower alkane carboxylic acids" encompasses alkane carboxylic acid with 1-7 C atoms

. * IW

- 3 - like formic acid and acetic acid. The term "halogen" or "halo" includes fluorine, chlorine, bromine and iodine unless otherwise specified. The term "alkali metal" includes all alkali metals such as lithium, sodium and potassium.

5

According to the invention, all compounds with one or more asymmetric carbon atoms can be prepared in the form / of racemates. These racemates can be cleaved at a suitable point in the production process in a manner known per se, whereupon the subsequent products can be obtained as optically pure enantiomers. On the other hand, optically active enantiomers or racemates of the formula I can be obtained depending on the optical form of the compound of the Ί5 formula II used as the starting material.

In the structural formulas given here, a wedge-shaped line means a substituent in the β position (above the molecular level), a broken line means a substituent in the α position (below the molecular level) and a wavy line means a substituent in either the a or β position has or mixture of these isomers. Only one form of the structural formulas is shown, but it is to be understood that it should also include other 25 forms including the enantiomers and racemates.

The term "aryl" as used herein denotes mononuclear aromatic hydrocarbon radicals such as phenyl, 30 and tolyl, which may be unsubstituted or substituted in one or more positions by lower alkylenedioxy, nitro, halo, lower alkyl or lower alkoxy; and multinuclear aryl groups such as naphthyl,

Anthryl, phenanthryl, azulyl which may also be unsubstituted or substituted by one of the aforementioned groups. Preferred aryl groups are substituted and unsubstituted mononuclear aryl groups, especially phenyl.

- * s - 4 -

The term "an ether protecting group removable by acid catalyzed cleavage" refers to any ether which provides a hydroxy group by acid catalyzed cleavage. A suitable ether protecting group is, for example, tetrahydropyranyl ether or 4-methyl-5,6-dihydro-2H-pyranyl ether.

- / Other protective groups are aryl methyl ethers such as benzyl,

Benzhydryl or trityl ether; or a-lower-alkoxy-lower-10 alkyl ether, for example methoxymethyl; or allylic ether or tri (lower alkyl) silyl ether such as trimethyl silyl ether or di-methyl tert-butyl silyl ether. Preferred are t-butyl, tetrahydropyranyl and tri (lower alkyl) silyl ether, especially dimethyl t-butyl ether. The Ί5 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. If an organic acid is used, it can serve as a solvent. In the case of a t ^ butyl group, the acid which forms the solvent is generally used.

In the case of tetrahydropyranyl ethers such as the cleavage, generally carried out in an aqueous medium. The temperature and pressure are not critical and the reaction can be carried out at room temperature and atmospheric pressure.

Of the compounds having the formula, those in which the 7-fluoro substituent has a β configuration are preferred. Of the 7-ß-fluorine compounds, the following 35 are preferred: - 5 -Ο ^ ch-ch9-ch9-ch.-c-or

"S'V

F- CH «

- I

CH = CH-CH -C -CH2-CH2-CH2-CH3 (¾ ÖH CH3 0 v ’^^ ch-ch2-ch2-ch2-Ö-or? - F hAii

CH-CH-CH-CH -CH9-CH -CH -CH ÖH ÔH

0

^ Cfl-CH2-CH2-CH2-ü-OE

j —— 1— »ÇH3 I — Aiii L J ^ | CH = CH-ÇH-C-CH -CH -CH -CH9CH__ - j ί L L à dk3 oh ch3

O

CH-CH2 "CH2-CH2-Ü-OR

I I I-Aiiii kv ^ -CH = CH-SH -CH-CH2-CH2-CH2-CH3

Sh3 0H F

- 6 -

If R in the formulas above is lower alkyl, methyl or ethyl radicals are preferred.

The process according to the invention for producing the 5 compounds I is characterized in that a compound of the general formula XII

f ff H X, CH -CH2-CH2-CH2-C-OK6

10 gV01 F

Μ B21 xn \ - U * CH-CH-gH -Ç -ch2 "CH2" CH2 ~ CH3 fl OH R2 15 6 “L 2 21

wherein X is halogen; R lower alkyl; and R, R and R

as in claim 1, dehydrohalogenated and, if desired, hydrolyzing an R ° ester group and / or converting a carboxylic acid 20 thus obtained into a pharmaceutically acceptable salt.

The compounds of the formula XII can be obtained from compounds of the formula 25 ^ O =; - - / R21 “30 \ -Lch - ch-çh-c-ch2-ch2-ch2-ch3 - ir I o R1 OH k 12 21 in which R, R and R have the meaning given above, or optical antipodes or racemates thereof about the 35 intermediates IV to XI are produced: -Ί Ο

A

Ω g IV

ι — ί r21 \ -Im CH = CH-ÇH -C -CH2 ~ CH2-CH2-CH3 5 A1 -4 ^ 2

R OR R

R5P

* <A,

/ R21 V

--L ^ ch = ch-ch -c -ch2-ch2-ch2-ch3 K11 OR ^ r2

15 X

/ '

20 \ I

CH = CH-CH -C -CH -CH -CH0-CH »

i "! A

O

25 F

7 * - ^ vu (L r.. Λ ^^ CH = CH-ÇH-C -CH-CH -CH -CH „* - - | L 2t 2 o M R ÖH R2

OH

35 / r21 VIII

= ^ CH = CH-CH -C -CH0-CH -CH-CH- Ä1 »4 l2 2 2 2 3

* OR4 R

- 8 -F

ho i

_ \\\\ CH -CH = CH-CH -CH -CH, -COOH

Ç R2i IX

V -U <CH = CH-CH -C-CH9-CH -CH -CH, î-> R «2

"* HO ^, (^ H-CH = CH-CH2-ch2-CH2-COOR

(X? 21 CH = CH-ÇH -C-'CH -CH.-CH -CH, "11 I 4 i2 2223

R OR R

X O

Hv ^ / CH-CH2-CH2-CH2-â-OR

_; ~ v ^ F

X3 f21 \ -W CH = CH-CH -C -CH0-CH, -CH, -CH, fil ot * ^ 2 2 2 3 „I5 S 6 H CH -CH2-CH2-CH2-C-OR6

1 F

M R21 V -U «CH-CH-ÇH -Ç -CH-CH -CH -CH,

- ~ I η "λ Z O

r! OH R

... / cii-ch? -ch2-ch2Xor6

F

f - T xiii

Cl, f ”\ = - W ^ CH ^ CH-C -CH, -CH-CH -CH, -i - | «À 2 3 tfl - - I 2

K OH R

- 9 -Ο s Η \ ^ ch = ch-ch2-ch2-I-or6

(f Vv F

. s ’7 T p21 XIV

\ I I

; 10 -U CH = CH -CH-C -CH2-CH2-CH2-CH3 Ξ, ~ .1.2

R1 OH R

0

CH-CH2-CH2-CH2 -! - OH

rj zVmf 15 = =

T T R21 'XV

V-U | CH = CH -ÇH-C -CH.-CH.-CH.-CH ,, - - j u L ù o r1 OH R2 2.0 0

H CH = CH-CH-CH2-â-OH

T R21 XVI

25 \ I

V - * ^ CH-CH -CH-C -CH2-CH2-CHa-CH

R1 OH R2 30 12 21

In the above formulas, R, R, R and R have the Il 4 meaning above; R is hydrogen, methyl or OR; 4th

OR is an ether-protecting group that can be split off by acid-catalyzed cleavage; R is lower alkyl; X is halogen; and R ^ is tri (lower alkyl) silyl "- 10 -

A compound of formula II can be converted into a compound of formula IV by conventional etherification in order to protect free hydroxyl groups in the compound of formula II. When R in the compound 5 of the formula II is hydroxy, the etherification converts the hydroxy group into an ether group of the compound IV. Preferred ethers for this purpose are tetrahydropyranyl and dimethyl-t-butylsilyl ether.

Any conventional method of etherifying the compound of Formula II can be used in this reaction.

If 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. 15 conventional 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 with a trialkyl-20 halosilane. The enolization can be carried out in a manner known per se. The compound of the formula IV is preferably treated with a non-aqueous alkali metal base. Preferred bases for this purpose are lithium diisopropylamide or sodium hexamethyldisilazane. When carrying out this reaction using the non-aqueous alkali metal bases, temperatures of -70 to -30 ° are generally preferred. The reaction is generally carried out in an inert organic solvent. Any conventional inert organic solvent that is liquid in the aforementioned 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 into a compound of formula V by treatment with a trialkylhalosilane, preferably trimethylchlorosilane. This reaction is usually carried out at the same temperatures and with the same solvent used in the formation of the enolate.

- 11 -

The compound of formula V is converted to a compound of formula VI by treatment with a fluorinating agent. Any conventional fluorinating agent can be used for this. 5 xenon difluoride and gaseous fluorine are preferred. In general, the reaction is carried out in the presence of an inert organic solvent. Any conventional inert. J 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, it is preferred to work at low temperatures, i.e. from 15 -10 to + 10 ° C.

In the conversion in the compound of the formula V into a compound of the formula VI, the compound of the formula VI is a mixture of the compounds of the formulas 20 A- »tl r £ = ^ * CH = CH-CH -C -Cfi-CH -CH -CHq "11 Ξ | 2 2 L i R - 4 * 2

OR R

30 and Λ-

7-R21 VI-B

35 / I

\ ^ CH = CH-CF -C -CH2-CH2-CH2-CH3 = ,, oa4 r2

R

- 12 - 11 2 21 where R, R and R have the meaning given above.

The compounds of the formulas VI-A and VI-B can be separated by 5 conventional means, such as chromatography. On the other hand, the compound of the formula VI can be used as a mixture of the compound of the formula VI-A and VI-B for the remaining reaction stages, or a separation can be carried out at a later stage to obtain a compound of the formula I with the desired fluorine orientation in 7 - Get position. When the compound of formula VI is separated into the compound of formula VI-A and VI-B, the configuration of the fluorine atom is maintained in the course of the usual reaction sequence. If 15 compound of the formula I with 7β-fluorine is desired, a compound of the formula VI-A is used to give the intermediates of the formula VII-XVI in which the fluorine atom has a β configuration. If a compound of the formula I with 7a-fluorine substitution is desired 2.0, a compound of the formula VI-B is assumed, the fluorine atom having the α configuration in the intermediates of the formula VIIXVI.

On the other hand, the compounds of the formula VI 25 can be used without separating them into the compound of the formula VI-A and VI-B. In this way, compounds of the formula I in which fluorine has both a and β configuration are prepared via the intermediates of the formula VII-XVI in which the fluorine atom occupies the same position.

When converting the compounds of formula II into the compound of formula VI, tri (lower alkyl) silyl ether is generally preferably used as the 35 hydroxyl protective group. When converting the compound of formula VI into a compound of formula I, it is generally preferred to protect one or more hydroxy groups as tetrahydropyranyl ether. On the other hand, silyl ether or any other conventional ether group can be used in the remaining process steps. According to the preferred embodiment, silyl ethers of the formula VI are hydrolyzed, giving compounds of the formula VII which are then esterified again and form compounds of the formula VI in which the ether groups are tetrahydropyranyl groups. For the hydrolysis - = 'of compounds of the formula VI to compounds of the formula

VII and the subsequent etherification of the compound of formula VII to a compound of formula VI

any conventional hydrolysis or etherification method can be used. If the protecting group in the compound of formula VI is tetrahydropyranyl, there is no need 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. Any conventional reducing agent which selectively reduces a keto group to the hydroxyl group is suitable for this. Preferred reducing agents are hydrides, preferably aluminum hydrides such as alkali metal aluminum hydrides and borohydrides such as alkali borohydrides, diisobutyl aluminum hydride being particularly preferred.

The reaction can also be carried out using di (branched-chain-lower-alkylene) boranes such as bis (3-methyl-2-butyl) borane. In this reaction, temperature and pressure are not critical, it is possible to work at room temperature and atmospheric pressure or at elevated or reduced temperatures and pressures. In general, it is preferable to carry out the reaction at a temperature 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. Any conventional inert organic solvent can be used. Preferred are - 14

Dimethoxyethylene glycol and ethers such as tetrahydrofuran, diethyl ether and dioxane.

Compounds of formula IX can be obtained from compounds 5 of formula VIII by reaction with a phosphonium salt of the formula

Rb O

. · ’R“ P-cHj-CHj-CH2 CH2-fa-OH

ic <+>,>

Yw 3. Id c where R, R, R is aryl or di (lower alkyl) amino and Y is halogen, can be obtained by a conventional Wittig reaction. The reaction conditions known per se for Wittig reactions can be used for this reaction.

The compound of formula IX can be converted to a compound 20 of formula X by esterification with diazomethane or a reactive derivative of a lower alkanol such as a lower alkyl halide. The usual reaction conditions for esterifications can be used for this.

25th

A compound of formula X can be converted to a compound of formula XI by treatment with a halogenating agent. Preferred halogenation agents are N-halosuccinimides, in particular N-iodosuccinimide.

30 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. Any conventional polar organic solvent can be used. The reaction temperatures can be 0-35 ° C. In general, it is preferred to work at room temperature.

I Λ - 15 -

A compound of formula XI is converted to a compound of formula XII by ether hydrolysis. Any conventional ether hydrolysis method can be used for this. In general, mild acidic hydrolysis, such as aqueous acetic acid, is used.

In the next reaction step, a compound of. V Formula XII treated with a dehydrohalogenating agent, whereby mixtures of compounds of formula XIII and XIV - 10 are obtained. The usual hydrohalogenation agents can be used for this reaction. Diazabicycloalkanes or alkenes such as 1,8-diazabi-cyclo [5.4.0] undec-7-ene and 1,4-diazabicyclo [2.2.2] octane are preferred. Furthermore, any other conventional organic base 15 used for dehydrohalogenation can be used in this reaction. The compound of formula XIII and formula XIV is obtained in a mixture. You can in a conventional manner such as be separated by chromatography.

20th

The compound of the formula XIII and the compound of the formula XIV are converted in the compound of the formula XV and XVI by hydrolysis. The usual ester hydrolysis methods can be used for this. 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 water -30 form salts with pharmaceutically usable

Bases. Preferred salts are alkali metal salts such as lithium, sodium and potassium, with sodium being particularly preferred. Other preferred salts are alkaline earth metal salts such as calcium and magnesium salts, salts with amines such as lower alkylamine, e.g. Aethylamine and hydroxy-substituted lower alkylamines and tris (hydroxymethyl) aminomethane, and ammonium salts. Further examples of salts are those with dibenzylamine, monoalkylamines, dialkylamines * 3 5 - 16 - and salts with amino acids such as arginine and glycine.

Preferred compounds of the formulas XIII and XV are 1 2 which are those where R and R are hydrogen.

5

The compounds of the formula I and their pharmaceutically acceptable salts and the optical antipodes and Race's mate thereof are active as antisecretory agents,

Antihypertensives, anti-ulcerogenic agents and can be used to combat gastro-hyperacidity and as agents for

Inhibition of platelet aggregation can be used.

The effectiveness of the prostacyclins of the formula I as an agent against platelet aggregation will follow from the test with the compound (5Z, 7β, 9a, lia, 13E, 15R) -7-fluoro-6,9-epoxy-ll, 15- Dihydroxy-16,16-dimethyl-prosta-5,13-diene-l-acidic acid methyl ester can be seen: 30 ml of blood from the jugular vein of awake beagle dogs were added to 3 ml of 3.8% sodium citrate solution in centrifuge tubes. The tubes were closed and the contents mixed gently. The citrated blood was centrifuged at 160 g for 15 minutes at 20 ° C. and the platelet-rich plasma (PRP) was carefully drawn off with a pipette 25 without stirring the leukocyte film and erythrocyte layers. The PRP was kept sealed in plastic tubes at 19-21 ° C. Preparations with a reddish tinge, which indicated hemolysis, were discarded. The remaining blood was centrifuged at 900 g for 10 minutes after removing the PRP to obtain platelet-poor plasma (PAP). The PRP was used immediately and the aggre-gatious study was carried out within 3 hours.

The platelet aggregation was carried out with a Payton two-channel aggregation module, which was connected to a recorder for the continuous * recording of the increase in light transmission due to the platelet clumping. A scale of 0-100% transmission was set with * »- 17 - PRP (0%) and PAP (100%). The temperature was kept at 37 ° C. and the mixture was stirred at 900 revolutions / minute. 0.45 ml PRP was placed in a cuvette with a Teflon stir bar and heated to 37 ° C in a water bath.

5 5 μΐ of different concentrations of (5Z, 73.9a, lia, 13E, 15R) -7-fluoro-6,9-epoxy-ll, 15-dihydroxy-16.16-dimethyl-prosta-5,13-diene- I-Acid methyl ester ge -4 V, which from a stock solution of 5 x 10 M in dimethyl sulfoxide with phosphate-buffered saline; 10 1 mg / ml bovine serum albumin, fraction V, was diluted. The whole was stirred for 1 minute. Then 50 μΐ arachidonic acid were added as an aggregation inducer, in concentrations which brought about 50-70% aggregation after 5 minutes. The table below shows the percentage inhibition calculated from the ratio of% aggregation with the test compound divided by the control value (vehicle) multiplied by 100.

20 concentration of (5Z, 7 (3.9a, lia, 13E, 15R) - 7-F J.uor-6,9-epoxy-ll, 15-dihydroxy- 16.16-dimethyl-prosta-5,13-diene- l-acid methyl ester__% inhibition 1 x 10-13M 14.2 2ö 3 x 10_13M 20.8 1 X 10_l2M 71.4 1 x 10 “nM 57.8 1 x 10“ 10M 20.8 30 The phosphate-buffered saline 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% (weight / volume) aqueous saline solution. The arachidonic acid solution was prepared from a · Stock solution containing 10 mg per ml in absolute methanol To prepare a 10 mM solution, 0.3 ml stock solution was evaporated almost to dryness under nitrogen and in 0.75 ml freshly prepared 0.02 Ammonium hydroxide and 0.2 ml PBS dissolved Further dilutions were made with a mixture of NH ^ OH and PBS.

5 The compounds of formula I and their pharmaceutically applicable salts can be used in a large number of pharmaceutical preparations. The new compounds can be administered in the form of tablets, pills,

Powders, capsules, solutions for injection, solutions, supplements, emulsions, dispersions and other suitable

To form. The pharmaceutical preparations are expediently prepared by admixing the active ingredient 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 can also contain non-toxic auxiliaries such as emulsifiers, preservatives and wetting agents, for example sorbitan monolaurate, triethanol-20 aminoleate, polyoxyethylene sorbitan, dioctyl sodium sulfosuccinate and the like.

The dosage of the new compounds depends on individual needs. In the case of oral administration, the compounds of the formula I can be administered, for example, in doses of 0.1 pg to 0.3 pg / day / kg of body weight.

The following examples further illustrate the invention. 30 The ether mentioned in the examples is diethyl ether.

All temperatures are in degrees Celsius. The petroleum ether has a melting point of 35-60 ° C.

35 -19 - * p

Example 1 502.2 mg [3aR- [3aa, 4α (iE, 3R *), 5β, 6aa]] - hexahydro-5-hydroxy-4- (3-hydroxy-4,4-dimethyl-l-octenyl) - 2H-cyclo-5 penta [b] furan-2-one was dissolved in 15 ml of dimethylformamide (reagent quality, dried over 3A molecular sieve) under argon. 1.045 g of t-butyldimethyl "chlorosilane (previously distilled) and 587.6 mg of imidazole (reagent quality) were added to the solution. The resulting mixture was stirred for 10 hours at room temperature, added to 60 ml of ice-cold 0.5N hydrochloric acid and three times with 60 ml of diethyl ether extracted. The extracts were washed with 60 ml of a mixture of saturated aqueous sodium bicarbonate solution, water and brine (1: 1: 2) and then with 60 ml of 15 brine. The extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. 1.25 g of a white semi-solid was obtained. The crude product was chromatographed on 75 g of silica gel, first with 1 1 of a mixture 20 of 10 vol.% Ether and 90 vol.% Petroleum ether and then with a mixture of 20 vol.% Ether and 80 vol.% Petroleum ether was eluted. 857.1 mg of C 3aR- [3aa, 4a (iE, 3R *), 5β, 6aa]] - hexahydro-5 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4 - [[ [3- (1,1-dimethylethyl} -25 dimethylsilyl] oxy] -4,4-dimethyl-l-octenyll-2H-cyclopenta- [b] furan-2-one as a white amorphous solid with a melting point of 67-68 °.

Example 2 30 579 μΐ diisopropylamine distilled over calcium hydride were dissolved in 15 ml tetrahydrofuran freshly distilled over lithium aluminum hydride. The mixture is cooled to + 3 ° under nitrogen and 2.5 ml of a 1.5N solution of n-butyl lithium in hexane are added dropwise at this temperature. After stirring for 5 minutes at the same temperature, the mixture was cooled to -40 ° and added dropwise with a solution of 1.757 g - * 4 -20- [3aR- [3aa, 4α (iE, 3R *), 5 (3.6aa] ] -Hexahydro-5 - [[(1,1-dimethylethyl) dimethylsilylyoxy] -4 - [[[3 - {1,1-dimethylathyl) dimethylsilyl] oxy] -4,4-dimethyl-l-octenyl ] -2H-cyclopenta [b] furan- 2-one in 6 ml of tetrahydrofuran. After 5 minutes of 5 stirring at -40 ° 570 μΐ trimethylchlorosilane were quickly added. After 2 minutes the cooling bath was removed and the mixture was allowed to warm up to + 15 ° over the course of 20 minutes *> '. The solvent was removed under reduced pressure at a temperature not above room temperature 10 and the residue was dried under high vacuum for 15 minutes. Then 10 ml of ether (freshly filtered over aluminum oxide, activity I) were added under argon and the mixture was filtered off. The white residue was washed three times with 3 ml of ether. The light yellow filtrate was concentrated under Ί5 reduced pressure and the oily residue was dried under high vacuum (room temperature) for 1 hour, where [3aR- [3aa, 4a (iE, 3R *), 5ß, 6aa]] - 4,5,6,6a -Tetrahydro-5 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4 - [[[3- (1, i-dimethylethyl) dimethylsilyl] oxy] -4,4-dimethyl-l-octenyl] -2- (tri-20 methylsilyl) oxy-3aH-cyclopenta [b] furan.

Example 3

The compound prepared in Example 2 was dissolved in 25 15 ml of methylene chloride (fresh over aluminum oxide, activity I) under argon. The mixture was cooled to + 2 ° and 680 mg of potassium bicarbonate (dried in a high vacuum for 3 hours over phosphorus pentoxide at 100 °) and 632.9 mg of xenon difluoride were added with stirring. In the first 30 30 seconds after the addition of the xenon difluoride, violent gas evolution started. The mixture was stirred at + 2 ° for 20 minutes, 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 35 sulfate and evaporated under reduced pressure. The residue was dried under high vacuum for 18 hours, leaving 1.92 g of a yellowish oil.

«« • - 21 -

The crude product was chromatographed on 200 g of silica gel (230-400 mesh) (plasma chromatography). 1 l of a solvent mixture of 5% by volume of ethyl acetate and 95% by volume of petroleum ether and then 5 petroleum ethers with 10% by volume of ethyl acetate were used as eluents. The following products were eluted in succession: 1.06 g (58%) [3S-C 3acx, 4ct (iE, 3 * R), 53.6aa]] - hexahydro-3-fluoro-5-5 [[(1, 1-dimethylethyl) dimethylsilyl] oxy] -4 - [[[3- (1,1-dimethylethyl) dimethylsilyl] oxy] -4,4-dimethyl-l-octenylΙ-ΙΟ 2H-cyclopenta [b] furan-2-one , white needles with a melting point of 49-51 °; 165.2 mg (9.4%) [3aR- [3aa, 4a (iE, 3 * R), 5β, 6aa]] - hexahydro-5 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4 - [[[3- (1,1-dimethylethyl) dimethylsilyl] oxy] -4,4-dimethyl-l-octenyl] -2H-cyclopenta [b] furan-l-one (starting material); Ί5 and 98.9 mg (5.4%) 3R- [3ß, 3aa, 4a (iE, 3 * R), 5b, 6aa] -hexahydro-3-fluoro-5 - [[(1,1-dimethylethyldimethylsilylloxy] -4 - [[[3- (1,1-dimethylethyl) dimethylsilyl] oxy] -4,4-dimethyl-l-octenyl] -2H-cyclopenta [b] furan-2-one, amorphous white solid with melting point 83- 85 °.

20th

Example 4 1.597 g [3S- [3aa, 4α (iE, 3 * R), 5ß, 6aa] -hexahydro-3-fluoro-5 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4 - [[ [3-25 (1,1-dimethylethyl) dimethylsilyl] oxy] -4,4-dimethyl-1-octenyl] -2H-cyclopenta [b] furan-2-one were dissolved in 60 ml acetic acid (reagent quality) and under argon heated to 55 °. 6 ml of water were then added with stirring. k 4 · After 7 hours, a further 4 ml of water were added and 3G was stirred for a further 64 hours (71 hours in total) at 55 ° * 4 '. After cooling to room temperature, the solvent was removed under reduced pressure at 25-30 °. The oily residue was at 2 hours. Dried room temperature in a high vacuum and then chromatographed on 200 g of silica gel (230-35 400 mes), solvent mixtures of ethyl acetate / petroleum ether (1: 1 parts by volume) to pure ethyl acetate being used as the eluent.

n - 22 -

# U

351.2 mg of the partially hydrolyzed material, which contained large amounts of impurities and 571.5 mg (62%) [3S- [3aa, 4a (iE, 3 * R), 53.6aa]] - hexahydro-3-fluoro- 5-hydroxy-4- (3-hydroxy-4,4-dimethyl-l-octenyl) -2H-cyclo-5 penta [b] furan-2-one (oil) was obtained. The partially hydrolyzed material (351.2 mg) was subjected to similar reaction conditions (acetic acid, water) for 42 hours. 'threw and delivered 39.6 mg (4.3%) of additional material so that the overall yield of [3S- [3a, 3aa, 4a (iE, 3 * R), 53, -10 6aa]] - hexahydro-3- fluoro-5-hydroxy-4- (3-hydroxy-4,4-dimethyl-l-octenyl) -2H-cyclopenta [b] furan-2-one, a clear oil, was 611.1 mg (66%).

Example 5 15 5 71.5 mg [3S- [3aa, 4a (iE, 3 * R), 53.6aot]] -hexahydro-3-fluoro-5-hydroxy-4- (3-hydroxy-4,4- dimethyl-l-octenyl) -2H-cyclopenta [b] furan-2-one were dissolved in 20 ml of methylene chloride (freshly filtered over aluminum oxide, activity I) under 20 argon. 2.0 ml of dihydropyran (freshly distilled over sodium) were added to the solution and then a crystal (9.7 mg) of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 30 minutes, then poured into 50 ml of saturated aqueous sodium bicarbonate solution and extracted three times with 30 ml of methylene chloride. The extracts were washed twice with 50 ml of brine, dried over magnesium sulfate and evaporated under reduced pressure. The crude product - '4 (oil, 1.14 g) was chromatographed on 100 g of silica gel with ether / petroleum 30 ether (1: 1) and gave 797 mg (91%)' * * [3S- [3a, 3aa, 4a (iE, 3 * R), 5β, 6aa]] - hexahydro-3-fluorine-5- · [(tetrahydro-2H-pyran-2-yl) oxy] -4- [3- (tetrahydro-2K ~ pyran- 2-yl) oxy] -4,4-dimethyl-l-octenyl] -2H ~ cyclopenta [b] furan- 2-one in the form of a clear oil (mixture of THP-diastereo-25 35 mers). [a] -32.46 ° in chloroform, c = 0.8780.

> ί - 23 -

Example 6 729.2 mg [3S- [3a, 3aa, 4a (iE, 3 * R), 53.6aa]] - hexahydro-3-fluoro-5 - [(tetrahydro-2H-pyran-2-yl) oxy ] -4- [3 - [(tetra-5 hydro-2H-pyran-2-yl) oxy] -4,4-dimethyl-l-octenyl] -2H-cyclopentaCb] furan-2-one were dissolved in 10 ml of toluene (distilled over calcium hydride) dissolved under argon. The Ge-s. ’Mix was cooled to about -70 ° and 1.25 ml of a 1.4M solution of diisobutylaluminum hydride - 10 in hexane was added dropwise. The mixture was stirred at -70 ° for 20 minutes, then 3 ml of aqueous ammonium chloride solution was added dropwise and the mixture was added to a separatory funnel with 20 ml of water and 50 ml of ethyl acetate. The very thick Sus-15 pension formed on shaking was filtered through a filter aid, the residue was washed thoroughly with 100 ml of ethyl acetate and the filtrate again with 60 ml of a mixture of concentrated saline and water (1: 1 parts by volume) and once with 100 ml Washed saline.

20 The washing solutions were re-extracted once with 80 ml of ethyl acetate. The organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on 200 g silica gel (230-400 mesh) of the crude product (oil, 806 mg) with ethyl acetate / 25 petroleum ether (4: 6) gave 661.5 mg (90%) [3S- [3a, 3aa, 4a- (iE, 3 * R), 53,6aa]] -Hexahydro-3-f luor-5- [(tetrahydro-2H-pyran-2-yl) oxy] -4- [3 - [(tetrahydro-2H-pyran -2-yl) oxy] ~ 4,4-dimethyl-l-octenyl] -2H-cyclopenta [b] furan-2-ol as amorphous • 25

Solids with melting point 58-66 °; [a] ^ -12.83 ° in chloro-30 form, c = 1.0290.

Example 7

20 ml of tetrahydrofuran (freshly distilled over lithium aluminum hydride) and 1.25 ml of hexa- to 1.24 g of (4-carboxybutyi) triphenylphpphosphonium bromide 35 (dried under high vacuum at 100 ° C. for 2 hours over phosphate pentoxide) and 1.275 g of sodium hexamethyldisilazane (distilled) under argon. Given -24- methylphosphoramide. The mixture was stirred at room temperature for 1 1/2 hours. The orange-red suspension was added dropwise with a solution of 560.5 mg [3S- [3a, -3aa, 4a (iE, 3 * R), 5ß, 6aa] -hexahydro-3-fluoro-5 - [(tetrahydro- 2H-5 pyran-2-yl) oxy] -4- [3 - [(tetrahydro-2H-pyran-2-yl) oxy] -4,4-dimethyl-l-octenyl] -2H-cyclopenta [b] furan -2-ol in 4 ml of tetrahydrofuran. The yellow-orange Ge--,. 'Mix was stirred for 4 hours at room temperature. The

The reaction was stopped by the dropwise addition of glacial acetic acid 10 (light yellow color). The majority of the solvent was evaporated under high vacuum at or below room temperature. The residue was transferred to a separatory funnel with 100 ml of ether and 100 ml of water. The aqueous phase was acidified to pH 3 with 13 ml 1N hydrochloric acid 15. 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 20 oily residue was dried under high vacuum for 1 1/2 hours, leaving 1.45 g of an oil. This crude acid was dissolved in 10 ml of methylene chloride (fresh over aluminum oxide, activity I) and esterified at room temperature with 15 ml of a 0.25N solution of diazomethane in ether.

The mixture was stirred at room temperature for 15 minutes, 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 sulfate and evaporated under reduced pressure. 1.24 g of a yellow oil were obtained. Chroma-f * 'tography on 100 g silica gel with ethyl acetate / petroleum ether (3: 7, 700 ml) and then ethyl acetate / petroleum ether (1: 1 parts by volume) gave 20.8 mg (3.7%) [3S ~ [3a, 3aa, -4a (iE, 3 * R), 5 (3,6aa] l-hexahydro-3-f luor-5-C (tetrahydro-2H ~ 35 pyran-2-yl) oxy] -4- [3- [(tetrahydro-2H-pyran-2-yl) oxy] -4,4-dimethyl-l-octenyl] -2H ~ cyclopenta [bjfuran-2-ol (starting material) and 496.3 mg (73%) ( 5Z, 7P, 9a, lia, 13Ef15R) -7-fluoro-11,15-di [(tetrahydro-2H-pyran-2-yl) oxy] -16,16- 9-25-dimethyl-9-hydroxy-prosta -5,13-diene-l-acidic acid methyl ester 25 (oil) as a mixture of diastereomers; [α] ^ + 2.74 ° in chloroform, c = 0.9116.

5 Example 3 246.9 mg (5Z, 7R, 9a, 11a, 13E, 15R) -7-fluoro-ll, 15-: di [(tetrahydro-2H-pyran-2-yl) oxy] -16, 16- dimethyl-9-hydroxy-prosta-5,13-diene-l-acidic acid methyl ester was dissolved in 10 ml of 10 acetonitrile (dried over 3A molecular sieve) under argon. Then 476.9 mg of N-iodosuccinimide were added with stirring, the reaction vessel was flushed with argon, sealed and protected from light with aluminum foil.

The mixture was stirred at room temperature for 27 hours, poured into 100 ml of a 10% by weight aqueous sodium thiosulfate solution and extracted three times with 100 ml of methylene chloride. The organic extracts were washed twice with 100 ml of brine, dried over magnesium sulfate and evaporated. 285.9 mg of an oily residue were obtained, which was chromatographed on 75 g of silica gel with ether / petroleum ether (1: 1 parts by volume) and 186.8 mg (62%) (7β, 9a, lia, 13E, 15R) -16 , 16-dimethyl-ll, 15-di [(tetra-hydro-2H-pyran-2-yl) oxy] -6,9-epoxy-7-fluoro-5-iodine prosta-13-en-1-acid methyl ester (oil) as a mixture of diastereomers 25.

Example 9 * '; 10.6 mg (7 (3.9dt, 11α, 13E, 15R) -16,16-dimethyl-ll, 15-30 di [(tetrahydro-2H-pyran-2-yl) oxy] -6,9-epoxy Methyl 7-fluoro-5-iodo-prosta-13-ene-l-acid 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 under argon. The mixture was heated to 40 and stirred for 35 hours, after cooling to room temperature the solvent was removed in a high vacuum at 25 ° C. Then 2 ml of toluene were added and the solvent was removed again in a high vacuum at 25 ° C. The oily residue * 26 - (11.2 mg) was chromatographed on thin layer chromatography plates with ether to give 6.3 mg (78%) (7ß, 9a, lia, 13E, 15R) -16,16-dimethyl-ll, 15-dihydroxy ~ 6 , 9-epoxy-7-fluoro-5-iodine-prosta-13-en-l-acidic acid methyl ester 5 (oil) as a mixture of isomers.

Example 10 6.3 mg of the isomer mixture 10 obtained in Example 9 was dissolved in 2.0 ml of toluene (distilled over calcium hydride) under argon. Then 20 μΐ 1,8-diazabicyclo- [5.4.0] undec-7-ene (distilled over calcium hydride) were added. The mixture was heated to 90 ° with stirring over 90 minutes and held at this temperature for 22 hours. After cooling to room temperature, the mixture was poured into 75 ml of semi-saturated saline and extracted three times with 20 ml of ether. The extracts were washed once with 20 ml of saline, dried over magnesium sulfate and evaporated. The remaining oil was dried in a high vacuum for 3 hours and the 6.2 mg of oil obtained were chromatographed on thin-layer chromatography plates with ethyl acetate. Two products were isolated: 3.0 mg (62%) (5Z, 73.9a, -lia, 13E, 15R) -7-fluoro-6,9-epoxy-ll, 15-dihydroxy-16,16-25 dimethyl -prosta-5,13-dien-l-acidic acid methyl ester (oil) and 1,1 mg (23%) (4E, 6a, 7ß, 9a, lia, 13E, 15R) -7-fluoro-6,9- epoxy-ll, 15-dihydroxy-16,16-dimethyl-prosta-4,13-diene-l-acidic acid methyl ester (oil).

Example 11 3 mg (5Z, 7ß, 9α, 11α, 13E, 15R5-7-fluoro-6,9-epoxy-ll, 15-dihydroxy-16,16-dimethyl ~ prosta ~ 5,13-diene ~ l-acid Methyl ester was dissolved in 0.5 ml of methanol and 0.5 ml of water under 3-5 argon, and 73 μl of 0.1N sodium hydroxide were added and the mixture was stirred at room temperature for 2 hours.

The methanol was removed under reduced pressure and the remaining aqueous solution was lyophilized, whereby -27- (5Ζ, 7β, 9α., 11α, 13Ε, ΐ5Ε) -7-fluoro-6,9-epoxy-ll, 15-dihydroxy- 16,16-dimethyl-prosta-5,13-dien-l-acid sodium salt as a white powder with a melting point of 48-51 °.

5 Example 12

In analogy to example 1, [3aR- [3aa, 4ot (iE, 3R *), -s 4R *), 6aa]] - hexahydro-4- [4-fluoro-3-hydroxy-l-octenyl) -2H- cyclopenta [b] furan-2-one in [3aR- [3aa, 4a (iE, 3R *, 4R *) 6aa]] - 10 hexahydro-4 - [[[3- (1,1-dimethylethyl) dimethylsilyl] oxy ] -4-fluoro-l-octenyl) -2H-cyclopenta [b] furan-2-one.

Example 13 15 In analogy to Examples 2 and 3, [3aR- [3aa, 4a- (IE, 3R *, 4R *) 6aa]] - hexahydro-4 - [[[3— (1,1-dimethylethyl) -dimethylsilyl ] oxy] -4-fluoro-l-octenyl] -2H-cyclopenta [b] -furan-2-one in [3aR- [3aa, 4oc (iE, 3R *, 4R *) 6aa] 3-hexahydro- 3- f] .uor-4- [[[3- (1, l-dimethylathyl) dimethylsilyl] oxy] -4-20 fluoro-l-octenyl] - 2H-cyclopenta [b] furan-2-one.

Example 14

In analogy to Example 4, [3aR- [3aa, 4a (iE, 3R * 25 4R *) 6aa]] - hexahydro-3-fluoro-4 - [[[3- (1,1-dimethylethyl) dimethylsilyl] oxy ] -4-fluoro-l-octenyl] -2H-cyclopenta [b] furan-2-one in [3aR- [3aa, 4a (iE, 3R *, 4R *) 6aa]] - hexahydro-3-fluoro- 4- (3-hydroxy-4-fluoro-l-octenyl] -2H-cyclopenta [b] - * 'furan-2-one converted.

30 5 ”'Example 15

Analogously to Example 5, [3aR- [3aa, 4a (iE, 3R * 4R *) 6aa]] -hexahydro-3-f] uor-4- (3-hydroxy-4-fluoro-1- · .35 octenyl ] -2H-cycl.openta [b] f urar.-2-one in [3a.R- [3aa, 4a (iE, -3R *, 4R *) 6aa]] - hexahydro-3-fluoro-4- [ 3 - [(tetrahydro-2H-pyran-2 ~ yl) oxy] -4-fluoro-l-octenyl'j-zH-cyclopentaiblfuran-Z-one converted.

- 28 -

Example 16

In analogy to Example 6, [3aR- [3act, 4ct (iE, 3R *, -4R *) 6aa]] - hexahydro-3-fluoro-4- [3 - [(tetrahydro-2H-pyran-2-5 yl ) oxy] -4-fluoro-l-octenyl] -2H-cyclopenta [b] furan-2-one in [3aR- [3aa, 4a (iE, 3R *, 4R *) 6aa]] - hexahydro-3-fluoro -4- [3 - [(tetrahydro-pyran-2-yl) oxy] -4-fluoro-l-octenyl] -2H-cyclo-, penta [b] furan-2-ol.

10 Example 17

In analogy to example 7, [3aR- [3aa, 4a (iE, 3R *, - 4R *) 6aa]] - hexahydro-3-fluoro-4- [3 - [(tetrahydro-2H-pyran-2-yl) oxy] -4-fluoro-l-octenyl] -2H-cyclopenta [b] furan-2-ol in 15 (5Z, 9α, 13E, 15R, 16R) -7,16-difluoro-15 - [(tetrahydro-2H -pyran- 2-yl) oxy] -9-hydroxy-prosta-5,13-diene - methyl l-acid ester.

Example 18? .0

In analogy to Example 8 (5Z, 9α, 13E, 15R, 16R) - 7.16-difluoro-15 - [(tetrahydro-2H-pyran-2-yl) oxy] -9-hydroxy-prosta-5,13-diene -l-Acid methyl ester in (9a, 13E, 15R, l6R) - 7.16-difluoro-15 - [(tetrahydro-2H-pyran-2-yl) oxy] -6.9-epoxy-25 5-iodine prosta-l3 -en-l-acidic acid methyl ester transferred.

Example 19 - “· In analogy to Example 9, (9α, 13E, 15R, 16R) -7.16-30 difluoro-l5 - [(tetrahydro-2H-pyran-2-yl) oxy] -6,9-epoxy -5- * '' iodine-prosta-13-en-l-acidic acid methyl ester in (9α, 13E, 15R, 16R) - 7.16- difluor-l5-hydroxy-6 ·, 9-epoxy-5-iodine prosta-13-en-l-acidic acid methyl ester transferred.

p: · Example 20

Analogously to Example 10, (9α, 13E, 15R, 16R) -7,16-pifluoro-15-hydroxy-6,9-epoxy-5-iodine prosta ~ 13-en-l-acid- * * - 29 - Methyl ester converted to (5Z, 9α, 13E, 15R, 16R) -7,16-difluoro-15-hydroxy-6,9-epoxy-prosta-5,13-diene-1-acidic acid methyl ester.

5 Example 21

Analogously to Example 11, (5Z, 9α, 13E, 15R, 16R) -, 7,16-difluoro-6,9-epoxy-l5-hydroxy-prosta-5,13-diene-l-acidic acid methyl ester in ( 5Z, 9α, 13E, 15R, 16R) -7,16-difluoro-6,9-10 epoxy-15-hydroxy-prosta-5,13-diene-l-acid sodium salt.

Example 22 15 In analogy to Example 10, (9α, 13E, 15R, 16R) - 7.16-difluoro-15-hydroxy-6,9-epoxy-5-iodo-prosta-13-en-l-acidic acid methyl ester in ( 4E, 9α, 13E, 15R, 16R) -7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-diene-l-acidic acid methyl ester.

ΓΌ

Example 23

Analogously to Example 11, (4E, 9α, 13E, 15R, 16R) - 7.16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-diene-1-25-acidic acid methyl ester is added to the sodium salt of (4E, 9α, 13E, 15R, -16R) -7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-diene-1-acid.

Example 24

Of '’’ ’To a solution of diisopropylamine in 9 ml tetrahydrofuran, 1.32 ml of a solution of 2.2M n-butyllithium in hexane was added dropwise at 0-5 °. The mixture was stirred for 5 minutes and cooled to -40 °. Thereafter, a solution of 1 g of 3.3aR, 4.5 (6.6aS “hexahydro-4R- [4,4-dimethyl-3R- (2-tetrahydropyranyloxy) -1-trans- octenyl] -5R-methyl-2H-cyclopenta [b] furan-2-one was added to 6 ml of tetrahydrofuran and - 30 - the reaction mixture was stirred at -45 ° for 5 minutes.

Then 4.26 ml of trimethylchlorosilane were added and the mixture was stirred at -45 ° for 5 minutes. The reaction mixture was then allowed to warm to 0 ° and the solvent was removed under high vacuum. 5 ml of diethyl ether were added to the residue and the cold mixture was filtered off. The solvent was removed under high vacuum (ice bath) and the residue was taken up in 10 ml of dichloromethane. The solution was then mixed at 0 ° with 530 mg 10 potassium bicarbonate and then with 429 mg xenondi fluoride. After the evolution of gas had ceased, 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 50 ml of brine. The 15 aqueous phase was separated and washed with 50 ml dichloromethane. The organic phases were combined, dried over magnesium sulfate and evaporated to give 0.95 g of crude product. Chromatography on 50 g of silica gel gave 300 mg of 3.3aS, 4,5,6,6aS-hexahydro-3-fluoro-4R- [4,4-? Q dimethyl-3R- (2-tetrahydropyranyloxy) -1-trans-octenylj -5R-methyl-2H-cyclopenta [b] furan-2-one.

Example 25 25 In analogy to example 6, 3.3aS, 4,5,6,6aS-hexahydro-3 ~ fluoro-4R- [4,4-dimethyl-3R- (2-tetrahydropyranyloxy) - 1-trans- octenyl] -5R-methyl-2H-cyclopenta [b] furan-2-one in 3,3aS, 4,5,6,6aS-hexahydro-3-fluoro-4R-C 4,4-dimethyl-3R- (2nd -tetrahydropyranyloxy) -1-trans-octenyl] -5R-methyl-2H-cyclo-SO penta [b] furan-2-ol.

Example 26

Analogously to Example 7, 3,3aS, 4,5,6,6aS-Hexa-35 hydro-3-fluoro-4R- [4,4-dimethyl-3R- (2-tetrahydropyranyloxy) -1-trans-octenyl] -5R-methyl-2H-cyclopenta [b] furan-2-ol in 11R, 16,16-trimethyl-7-fluoro-15R- (2-tetrahydropyranyloxy) -9S-hydroxyprosta-cis-5-trans-13-diene Acid-methyl ester transferred.

1 * - 31 -

Example 27

Analogously to Example 8, IIR, 16,16-trimethyl-7-fluoro-15R- (2-tetrahydropyranyloxy) -9S-hydroxyprosta-cis-5 5-trans-13-diene acid methyl ester is converted into (9S, IIR, 13E, 15R) - 11.16.16-Trimethyl-15- (2-tetrahydropyranyloxy) -6,9-epoxy-7-fluoro-5-iodine prosta-13-en-1-acidic acid methyl ester.

Example 28 10

In analogy to Example 9, (9S, IIR, 13E, 15R) - 11.16.16- trimethyl-15- (2-tetrahydropyranyloxy) -6,9-epoxy- 7-fluoro-5-iodine prosta-13-en- Methyl l-acid ester in (9S, llR, 13E, 15R) -ll, 16,16-trimethyl-15-hydroxy-6,9-epoxy-15 7-fluoro-5-iodine prosta-13-en-l Acid-methyl ester transferred.

Example 29

Analogously to Example 10, (9S, IIR, 13E, 15R) -20 11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-f luor-5-iodine prosta-13-ene -l-Acid-methyl ester in (5Z, 9SfllR, 13E, 15R) - 11.16.16- trimethyl-15-hydroxy-6,9-epoxy-7-fluor-prosta- -1 5.13- dien-l-acidic acid methyl ester , IR 3615, 1733, 1694 cm; Ultraviolet λ max 213 nm (ε = 12000) and (4E, 9S, IIR, 15R) - 25 11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-4,13-diene - l-Acid methyl ester, IR 3615, 1735, 1670 cm ^ transferred.

Example 30 30 In analogy to Example 11, (5Z, 9S, IIR, 13E, 15R) - 11.15.16-Trimethyl-15-hydroxy-6,9-epoxy-7-fluoroprosta-5.13-diene-l-acid -Methyl ester converted to (5Z, 9S, IIR, 13E, 15R) - 11.16.16- trimethyl-15-hydroxy-6,9-epoxy-7 ~ fluor-prosta- 5.13-diene-1-acid sodium salt.

35 '* - 32 -

Example 31

Analogously to Example 2 4, 3,3aR, 4,5,6,6aS-hexa-hydro-4R- [3S- (2-tetrahydropyranyloxy) -1-trans-octenyl] -5R-5 (2-tetrahydropyranyloxy) - 2H-cyclopenta [b] furan-2-one in 3,3aS, 4,5,6,6aS-hexahydro-3-fluoro-4R- [3S- (2-tetrahydropyr any1oxy) -1-tr ans-o ctenyl] -5R- (2-tetrahydr opyr any1oxy) - »'2H-cyclopenta [b] furan-2-one.

- 10 Example 32

In analogy to Example 6, 3,3aS, 4,5,6,6aS-Hexa-hydro-3-fluoro-4R- [3S- (2-tetrahydropyranyloxy) -1-trans-octenyl] -5R- (2-tetrahydropyranyloxy ) -2H-cyclopenta [b] furan-15 2-one in 3,3aS, 4,5,6,6aS-hexahydro-3-fluoro-4R- [3S- (2-tetra-hydropyranyloxy) -1-trans- octenyl] -5R- (2-tetrahydro-pyranyloxy) -2H-cyclopenta [b] furan-2-ol.

Example 33 20

Analogously to Example 7, 3,3aS, 4,5,6,6aS-hexa-hydro-3-fluoro-4R- [3S- (2-tetrahydropyranyloxy) -1-trans-octenyl] -5R- (2-tetrahydropyranyloxy ) -2H-cyclopenta [b] furan-2-ol in IIR, 15S-di- (2-tetrahydropyranyloxy) -7-fluoro-9S-25 hydroxy-prosta-cis-5-trans-13-diene acid methyl ester transferred.

Example 34

In analogy to example 8, IIR, 15R-di- (2-tetra-hydropyranyloxy) -7-fluoro-9S-hydroxy-prosta-cis-5-trans-13-dienoic acid methyl ester is converted into (9S, IIR, 13E, 15S ) -11,15-Di- (2-tetrahydropyranyloxy) -6,9-epoxy-7-fluoro-5-iodine prosta-13-en-l-säux'e-methyl ester.

* * - 33 -

Example 35

In analogy to Example 9, (9S, IIR, 13E, 15S) - 11.15-di- (2-tetrahydropyranyloxy) -6,9-epoxy-7-fluoro-5- 5 iodine prosta-13-en-1-acid -Methyl ester converted to (9S, IIR, 13E, 15S) - 11.15- dihydroxy-6,9-epoxy-7-fluoro-5-iodine prosta-13-en-1-acidic acid methyl ester.

Example 36 10

Analogously to Example 10, (9S, IIR, 13E, 15S) - 11.15-dihydroxy-6,9-epoxy-7-fluoro-5-iodine prosta-13-en-1-acidic acid methyl ester is converted into (5Z, 9S , IIR, 13E, 15S) -11.15-dihydroxy-6.9-epoxy-7-fluoro-prosta-5.13-diene-l-acidic acid methyl ester and 15 (4E, 9S, 11R, 15S) -11 , 15-Dihydroxy-6,9-epoxy-7-fluoro-4,13-diene-l-acidic acid methyl ester.

Example 37 20 In analogy to Example 11, (5Z, 9S, IIR, 13E, 15S) - ·

Dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13-diene-l-acidic acid methyl ester in (5Z, 9S, IIR, 13E, 15S) -11,15-dihydroxy-6,9-epoxy- 7-fluor-prosta-5,13-diene-l-acid sodium salt transferred.

25 ü'5 * «

- 34 - Example A

One tablet can be made as follows: 5 per tablet (5Z; 9cx; 13E, 15R, 16R) - 7,16-difluor-6,9-epoxy-15-hydroxy-prosta-5,13-dien-l- . acid-Na 25 mg

Dicalcium phosphate dihydrate, unground 175 mg "10 maize starch 24 mg

Magnesium stearate 1 mg

Total weight 225 mg

Active ingredient and corn starch are processed into a premix 15, which is mixed with the dicalcium phosphate and half the amount of magnesium stearate and granulated. The remaining magnesium stearate is mixed in and the mass is tabletted.

20 Example B

A capsule can be made as follows:

Parts by weight of 25 (5Z, 9a, 13E, 15R, 16R) -7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-diene-1-acid-Na 200

Dicalcium phosphate dihydrate, unground 235

Corn starch 70 3 'PD & C Yellow 45 - Aluminum Lake 25¾ 2 hydrogenated cottonseed oil (saturated) 25

Calcium stearate 3

All ingredients are mixed. The Sc powder obtained is filled into hard gelatin capsules (filling weight 350 mg).

Claims (17)

1. Compounds of the general formula 5 / (CH2) 2C00R (|. K2 m \ _ I £ - ^ CH = CH-C — C— (CH „) _CH0 - 1 - 1 2 3 3 R Ηδ k2i wherein one of the by Dashed lines indicated double bonds in the 4,5 or 5,6 position are present 15; R hydrogen or lower alkyl; R methyl, 2 hydrogen or hydroxy; R hydrogen, methyl or 21 fluorine; and R hydrogen, fluorine, trifluoromethyl 2 or Is methyl; where R is hydrogen or methyl, 21 when R is trifluoromethyl, 20 their pharmaceutically acceptable salts, optical antipodes and racemates. 2. Compounds according to claim 1 of the general formula 25.CH- (CH2) 3COOR H f 30 Ξ ^ CH = CH-C-C - (CH2) 3CH3 & Ηδ R21 12 21 wherein R, R, R and R have the meaning given in claim 1. 35 3. Compounds according to claims 1 or 2, in which the 7-fluorine substituent has a β configuration. * i » 36. DS 4303/11 4. Compounds according to claim 3, wherein r3 is hydroxy 2 21 2 or methyl and R and R are methyl or R are hydrogen and “21. . R are fluorine. 6 5. (5Z, 7ß, 9a, lia, 13E, 15R) -7-fluoro-6,9-epoxy-ll, 15-dihydroxy-16,16-dimethyl-prosta-5,13-diene-l-acid -Sodium salt. ç 6. (5Z, 73.9a, lia, 13E, 15R) -7-fluoro-6,9-epoxy-ll, 15-10 dihydroxy-16,16-dimethyl-prosta-5,13-diene-l- acid methyl ester. 7. (5Z, 9S, IIR, 13E, 15R) -11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-diene-l-acidic acid methyl ester. 15 8. Compounds according to claims 1-7 as pharmaceutical drugs. 9. A process for the preparation of compounds of the general formula I according to claim 1, characterized in that a compound of the general formula XI ß Hv ^ / CH- (CH2) 3C00R 25 <5 f-T f XI1 J ^ CH = CH-C- C- (CH2) 3CH3 Ξ1 ^ ^ 1 21 R1 HO R 30 6 12 21 where X is halogen; R lower alkyl; and R, R and R are as in claim 1, dehydrohalogenated and, if desired, hydrolyzing an ester group and / or converting a carboxylic acid thus obtained into a pharmaceutically acceptable salt. * - 37 - DS 4303/11 ί- 10. Pharmaceutical preparations containing a compound of formula I or a pharmaceutically acceptable salt thereof. 11. Compounds of the formula X 0 ch-ch2-ch2-ch2 - [!: - or6 10. P21 vL i ΞΙ "ch = ch-çh -c -ch0-ch0-ch" -chq -îl 1 j 2 2 2 3 OR -V 6 11 15 wherein R is lower alkyl; R is hydrogen, methyl or 5 2 21 -OR, R is methyl, hydrogen or fluorine; R fluorine, hydrogen, trifluoromethyl or methyl; X halogen; 41 and -OR represents hydroxy or a hydrolyzable ether protecting group; where R is hydrogen or 21 20 When R ^ is trifluoromethyl, methyl is optical antipodes and racemates thereof. 12. Compounds of formula 25. F O Hct i i 6 • ^, \\ \ \ CH-CH = CH-CH2-CH2-CH2-C-OR aR21 -,! CH = CH-CH -C -CH0-CH0-CH9-CH. * -; j ^ ll I | ù i ù o 5 2 OR R ^ 11 0 01 A1 wherein R, R, R ^, OR and R have the meaning given in claim 11 35. 38. DS 4303/11 ’i 13. Compounds of the formula rV Π f \ - ^ CH = CH2- £ H -c -ch2 ~ ch2 ~ ch2 ~ ch3 R11 æ41i2 10 XX 2 21 41 6 wherein R, R, R, OR and R are those specified in claim 11 Have meaning. 14. Compounds of formula 15 A-, 7-T r21 20. M | CH = CH-CH -C -CH0-CH0-CH0-CHo! | | Δ Δ Δ o R11 OR41 R2 on "11" 2 "21" "41," 6 Ί. , 25 wherein R, R, R, OR and R have the meaning given in claim 11. • kick 30 t 35