GB2158822A

GB2158822A - Intermediates for the preparation of fluoro-prostacyclins

Info

Publication number: GB2158822A
Application number: GB08426077A
Authority: GB
Inventors: George William Holland; Hans Maag; Perry Rosen
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1981-03-11
Filing date: 1984-10-16
Publication date: 1985-11-20
Also published as: SE8201506L; FR2515650A1; CA1208634A; SE8703023D0; FR2515650B1; NL8200992A; FR2515644A1; AU576441B2; LU83992A1; SE453294B; IL65177A; IL65177A0; DE3208880A1; NO154494C; NO820779L; PH18584A; IT8219966A0; IE52388B1; NO154494B; NZ199912A

Abstract

The present invention relates to compounds of the general formula <IMAGE> wherein: R<6> is lower alkyl; R<11> is hydrogen, methyl or OR<41>; R<2> is methyl, hydrogen or fluoro; R<21> is fluoro, hydrogen, trifluoromethyl or methyl; X is halogen; and OR<41> is hydroxy or forms a hydrolyzable ether protecting group, with the proviso that when R<21> is trifluoromethyl, R<2> is hydrogen or methyl, and to their optical antipodes and racemates. These compounds are useful intermediates for the preparation of novel fluoro-prostacyclins of the general formula I. These compounds are useful in the preparation of the novel fluoro-prostacyclins disclosed in our copending application No. 8207004.

Description

1 GB 2 158 822 A 1

SPECIFICATION

Intermediates for the preparation of fluoro-prostacyclins The present application is divided out of our co-pending application No. 8207044 filed on 10 March 1982. 5 The present invention relates to compounds of the general formula X 1 11 6 H % CH-CH 2 -CH 2 -CH 2 -C-OR > 10 0 IF 0 C1 Rl 1 H=CH-CH -C -CH2-CH2 -C 112 -CH3 R11 1 41 1 2 OR R wherein:

R6 is lower alky]; W' is hydrogen, methyl or OR 41; R 2 is methyl, hydrogen or fluoro; R 21 is fluoro, hydrogen, trifluoromethyl or methyl; X is halogen; and OR 41 is hydroxy orforms a hydrolyzable ether protecting group, with the proviso that when R 21 is trifluoromethyl, R 2 is hydrogen or methyl, and to their optical antipodes and racemates.

These compounds are useful intermediates for the preparation of novel fluoro-prostacyclins of the general formula 1.

(CH) COOR 30 4 2 2 35 R 21 (H=CH-'-rl-' 1 - "-"2 3C113 2 HO R 40 wherein oneof thedouble bonds indicated by broken lines ispresentin 4, 5or5,6 position; R is hydrogen or lower alkyl; R' is methyl, hydrogen, or hydroxy; R 2 is hydrogen, methyl or fluoro; and R 21 is hydrogen, fluoro, trifluoromethyl or methyl; with the proviso that when R 21 is trifluo ro methyl. R2 is hydrogen or methyl. 45 Our copending application No. 8207044 relates to these novel fluoro-prostacyclins and their pharmaceutic- 45 ally acceptable salts, optical antipodes or racemates. Preferred compounds of the formula 1 are those of formula I-A.

0 11 50 H-CH,-CH -CH -C-OR 2 2 21 1-A R 55 1 CH=CH-CH-C-CH 1 2-CH 2-CH2-CH 3 SH R 60 wherein R, W, R 2 and R 21 are as above.

In another aspect, the present parent application is concerned with compounds of the formula]-B.

2 GB 2 158 822 A 2 0 11 H CH CH-CH 2 CH 2-C-OR 5:≥ 1-13 5 R 21 CH 2-CH2-CH2- 3 OH 10 wherein R, R1, R 2 and R 21 are as above.

As used throughout this application, the term "lower alkyl" refers to both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms such as methyl and ethyl. As also used herein, the term "lower alkanoic acids" refers to alkanoic acids of 1 to 7 carbon atoms, such asformic acid and acetic acid. As 15 further used herein, the term "halogen" or "halo", unless otherwise stated, refers to fluorine, chlorine, bromine or iodine. Alkali metal refers to all alkali metals such as lithium, sodium and potassium.

All compounds according to the present invention having one or more asymmetric carbon atoms can be produced as racemic mixtures. These racemic mixtures which are obtained can be resolved by methods well known in the art whereupon subsequent products may be obtained as the corresponding optically pure enantiomers.

In the pictorial representation of the compounds given throughout this application, a thickened taper line M indicates a substituent which is in the beta-orientation (above the plane of the molecule), a dotted line indicated a substituent which is in the alpha-orientation (below the plane of the molecule) and a wavy line indicates a substituent which is in either the alpha- or beta- orientation or mixtures of these isomers. It is to be understood that the pictorial representations of the compounds given throughout the specification are setforth for convenience and are to be construed as inclusive of otherforms including enantiomers and racernates and are not to be construed as limited to the particular form shown.

As also used herein, the term "aryl- signifies mononuclear aromatic hydrocarbon groups, which can be unsubstituted or substituted in one or more positions with a lower alkylenedioxy, nitro, halo, a lower alkyl or 30 a lower alkoxy substituent, such as phenyl and tolyl and polynuclear aryl groups such as naphthyl, anthryl, phenanthryl and azulyl, which can be unsubstituted or substituted with one or more of the aforementioned groups. The preferred aryl groups are substituted and unsubstituted mononuclear aryl groups, particularly phenyl. The term" ether protecting group removable by acid catalyzed cleavage" designates any ether which, upon acid catalyzed cleavage yields the hydroxy group. A suitable ether protecting group is, for example, the tetrahydropyranyl ether, or 4-methyl-5,6-dihydro-2H-pyranyl ether. Others are arylmethyl ethers such as benzyl, benzylhydryl, or trityl ethers or alpha-lower alkoxy lower alkyl ether, for example, methoxymethyl or allylic ethers, ortriflower alkyl) silyl ethers such as trimethyl silyl ether or dimethyl-tert butyl silyl ethers. The preferred ethers which are removed by acid catalyzed cleavage are t-butyl and tetrahydropyranyl and the tri(lower alkyl) silyl ethers, particularly dimethyl-tert-butyl ethers. Acid catalyzed 40 cleavage is carried out by treatment with a strong organic or inorganic acid. Among the preferred inorganic acids are the mineral acids such as sulfuric acid, and hydrohalic acids. Among the preferred organic acids are lower alkanoic acids such as acetic acid and para-toluene sulfonic acid. The acid catalyzed cleavage can be carried out in an aqueous medium or in an organic solvent medium. Where an organic acid is utilized, the organic acid can be the solvent medium. In the case of t-butyl, an organic acid is general lyptilized with the acid forming the solvent medium. In the case of tetrahydropyranyl ethers, the cleavage is generally carried out in an aqueous medium. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure.

3 Among the preferred compounds of formula GB 2 158 822 A 1 are those compounds where the 7-fluoro substituent is in the beta configuration. Among the 7-beta fluoro compounds, the following are preferred:

v OH CH-CH 2 -CH 2 -CH2-C-OR F CH 3 1 1:L.4 CH=CH-CH -c --CH -CH -CH -CH 1 2 2 2 3 CYH ";n3 0 CH-CH 11 2-CH2-CH2-C-OR CH=CH-CH-CH -CH 2-CH2-CH2-CH3 F -6 H 'UR 0 0"",e CH-CH -CH -CH 11 ', F 2 2 2-C-OR F-]_ CH 3 CR=CH-CIP, 1 ---CH-CH -CH = 1 2 2 23 CH 3 OH CH 3 0 11 CH-CH2-CH 2 -CH2-C-OR F H=CH-QH-CH-CH -CH -CH.-CH [:;)-c = 1 2 2 3 EH 3 OH F 1-Ai 1-AH I-All! 1-Aiiii When R is lower alkyl in the compound of formulae 1-Ai, 1-Aii, 1-Aiii and 1-Aiiii, R is preferably methyl or 45 ethyl.

The compounds of formula 1 are prepared from a compound of formula 0 C.4CH=CH-12 -CH -CH =1 = 12 2 2 3 R 6H R jel 1 3 it 4 GB 2 158 822 A wherein W, R 2 and R 21 are as above, or optical antipodes or racemates thereof, XII:

0 "-k D z:

R21 C1 CH-Un-CH -% -CH -CH -CH -CH ill R5 CH=CH-1-11 -CH -CH2-CH2-CH3 2 11 Ik iR4 fL2 p (1 - = 4 12 2 2 2 3 WR R R21 R 21 -CH- -C -,R -CH -CH -CH QH 1 Pzil.q CH- 2 P=.

12 & A 3 jg4 R 0 R21 1 (:1..4 CH=CH-Cm-C -c %-CH 2 -CH 2 -CH 3 11 = 12 OH R OH 0--'F n R21 1 CH=CH-CH -C -CH 2-CH2-CH2-CHS 014 A2 F HO TlitH-CH=CH-CH -CH -CH -COOR 2 1 R CH=CH-CH -C#-CH2-CH2-CH2-CH3 1 1 2 R OR 4 R HO, 5H-CH=CH-CH -CH -CH -COOR i c CH=CH-CH -C-CH 2 -CH 2-CH 2 -CH 3 = 1 1 4 R12 it, OR 2 2 2 p21 via the intermediates W to IV v V1 YN YM IIX X 4 GB 2 158 822 A X i 0 H>CH-CH 2 -CH 2 -CH 2_ 8 -OR F R21 " CH=CH-CH -C -CH -CH -CH -CH Ril E4 'R 2 2 2 2 3- OR ?'- 6 H 9H -CH2-CH 2-CH 2-C OR F R 21 1 C:I.itCH=CH-CH -C -CH -CH -CH -CH 12 2 2 2 3 OH R ji 0 11 CH-CH 2-CH2-CH2 -C-OR6 F R 21 (:1CH=CH-CH-C H -CH -CH -CH = 1 2 2 2 3 2 Ifi OH R 0 H CH=CH-CH -CH -OR <, 2 2-C > F R21 1 (!L CH----CH -CH-C -CH -CH -CH -CH - 12 2 2 2 3 OH R Ri -1 R 0 11 CH-CH2-CH 2-C'H2-C-'JH R21 1 (-LCH---CH -CH-C -CH -CH -CH -CH = 12 2 2 23 UH 0 11 H='--CH-C%-CH2C-OH F R21 1 (:1.0CH--CH-CH-C -CH -CH -CH -CH 2 2 2 3 = 12 OH R xi xii xiii xiv XY xm 6 GB 2158822 A 6 wherein R, W, R' and R 21 are as above, R' l is hydrogen, methyl or OR'; - OR 4 forms an ether protecting group removable by an acid catalyzed cleavage; R' is lower alkyl; X is halogen; and R' is tri(lower alkyl) sily].

The compound of formula 11 is converted to the compound of formula IV by conventional etherification in order to protect any free hydroxy groups in the compound of formula It. Where R' is hydroxy in the compound of formula 11, this etherification converts the hydroxy group to the protected ether in the compound of formula IV. The preferred ethers for use in this reaction are tetrahydropyranyl and dimethyl-t-butyl silyl ether. In carrying out this reaction, any conventional method of etherifying the compound of formula 11 can be utilized in forming the compound of formula IV. When a tri (lower alkyl) silyl ether is desired, a tri (lower alkyl) chlorosilane is utilized as the etherifying agent in the presence of an organic base such as imidazol or pyridine. Any conventional organic amine base can be utilized in carrying 10 out this reaction.

The compound of formula W is converted to the compound of formula V by first enolizing the compound of formula IV and then treating the compound of formula IV with a trialkyl halosilane. Any conventional method of enolizing can be utilized to carry out this reaction. Among the preferred methods is by treating the compound of formula IV with a non-aqueous alkali metal base. The preferred base for use in this reaction is 15 lithium diisopropyl amide or sodium hexamethyidisilazane. In carrying out the reaction utilizing the non-aqueous alkali metal base, temperatures of -70 to -300 are generally preferred. Generally, this reaction is carried out in an inert organic solvent. Any conventional inert organic solvent which is a liquid atthe aforementioned temperatures can be utilized. Among the preferred solvents is tetrahydrofuran. The enolate of the compound of formula IV in the form of its alkali metal salt is converted to the compound of formula V 20 by treating the compound of formula V with a trialkyl halosilane, preferably trimethylchlorosilane. Generally, this reaction is carried out at the same temperatures and in the same solvent utilized to form the enolate.

The compound of-formula V is converted to the compound of formula V1 by treating the compound of formula V with a fluorinating agent. Any conventional fluorinating agent can be utilized in carrying out this reaction. Among the preferred flubrinating agent are xenon difluoride and fluorine gas. Generally, this reaction is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized in carrying out this reaction. Among the preferred solvents are halogenated hydrocarbons such as methylene chloride and carbon tetrachloride. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. While room temperature can be utilized, it is preferred to carry out this reaction at low temperatures, i.e. from -10% to 30 + 1 OOC.

In converting the compound of formula V to the compound of formula VI, the compound of formula V1 is produced as a mixture of the following compounds:

35 F VI-A R21 40 Q= 1 - CH=CH-CH -C -CH -CH -CH -CH 11 2 2 2 3 R 4 12 OR R and 45 _611 F R 21 1 H=CH-CH -C -CH -CH -CII -CH C:LC - 1 12 2 2 2 3 OW R - 11 R VI-B wherein C, R2 and R 21 are as above.

The compounds of formulae VI-A and VI-B can be separated by conventional methods such as chromatography. On the other hand, the compound of formula V] as a mixture of the compounds of formulae VI-A and VI-B can be utilized throughoutthe rest of the reaction or, if desired, separated at some GO later state in the reaction scheme to produce the compound of formula 1 having the desired fluoro orientation m at the 7-position. If the compound of formula VI is separated into the compounds of formulae VI-A and V1-13, the same configuration of the fluorine atom is carried on throughout the rest of the reaction. Therefore, if the compounds of formula 1 wherein the fluorine atom is atthe 7-beta position, are desired, the compound of formula VI-A is utilized in the rest of the reaction scheme producing compounds of the formulae V11 through XVI wherein the fluorine atom set forth in these formulae is in the beta position. If the compounds formula 1 5 7 GB 2 158 822 A 7 are desired wherein the fluorine is in the 7-alpha position, then the compound of formula VI-B is utilized in the reaction scheme to produce the compounds of formulae Vif through XVI wherein the fluorine atom shown in these formulae is in the alpha position.

On the other hand, the compound of formula VI can be utilized without separating it into the compounds of formulae VI-A and VI-B. In this manner, the compounds of formula I wherein the fluorine is in both of the 5 alpha and beta positions is produced via intermediates of the formulae Vil through XVI having the fluoro group in the same position as shown.

In converting the compounds of formula 11 to the compound of formula VI, it is generally preferred to utilize the tri (lower alkyl) silyl ethers as the hydroxy protecting group. In the conversion of the compounds of formula V1 to the compounds of formula I it is generally preferred to protect one or more of the hydroxy 10 groups with a tetra hyd ropyranyl ether. On the other hand, the silyl ethers or any other conventional ethers can be utilized in the rest of this process. However, it is preferred that the silyl ethers of formula V1 are hydrolyzed to produce the compound of formula VII which is then reetherified to produce the compound of formula V1 wherein the ether group is tetra hydropyranyl. Any conventional method of hydrolyzing ethers can be utilized to carry out the conversion of the compounds of formula V1 to the compounds of formula VII 15 and any conventional method of etherification can be utilized to carry out the reconversion of the compounds of formula VII to the compounds of formula VI. With tetra hydrophyra nyl as the protecting group in the compound of formula VI, there is no need to hydrolyze the compound of formula VI to the compound of formula VII since the compound of formula Vill can be produced directly from the compound of formula VI.

The compound of formula VII is converted to the compound of formula Vill by treating the compound of formula Vil with a reducing agent. In carrying out this reaction, any conventional reducing agent which will selectively reduce a keto-group to a hydroxy-group can be utilized. Preferred reducing agents are the hydrides, particularly the aluminum hydrides such as alkali metal aluminum hydride, and the borohydrides such as alkali metal borohydriides, with diisobutyl aluminum hydride being particularly preferred. Also, this 25 reaction can be carried out utilizing di (branched chain lower alkyl) boranes such as bis (3-methyl-2-butyl) borane. In carrying out this reaction, temperature and pressure are not critical and the reaction can be carried out at room temperature and atmospheric pressure or at elevated or reduced temperatures and pressures.

Generally, it is preferred to carry out this reaction at a temperature of from -800C to the reflux temperature of the reaction mixture. This reduction reaction can be carried out in the presence of an inert organic solvent. 30 Any conventional inert organic solvents can be utilized in carrying out this reaction. Among the preferred solvents are dimethoxy ethylene glycol, and the ethers such as tetrahydrofuran, diethyl ether and dioxane.

The compound of formula IX is obtained from the compound of formula Vill by reacting the compound of formula Vill with phosphonium salts of the formula:

0 a 1 1 P -CH-CH- - R 2 2 CH 2 CHi-A-0H XX-A Y0 40 wherein each of R', R b, Rc is either aryl or di (lower alkyl) amino, and Y is halogen, via a conventional Wittig type reaction. Any of the conventional conditions in Wittig reactions can be utilized in carrying out this reaction.

The compound of formula IX can be converted to a compound of the formula X by esterification with diazomethane or a reactive derivative of a lower alkanol such as a lower alkyl halide. Any conventional conditions utilizing in these esterifying reactions can be utilized to form the compound of formula X from the compound of formula IX The compound of formula X is converted to the compound of formula XI by treating the compound of formula X with a halogenating agent. Among the preferred halogenating agents are included N halosuccini m ides, particularly N-iodosuccinimide. Generally, this reaction is carried out in the presence of a polar solvent such as acetonitrile and halogenated hydrocarbons such as methylene chloride, ethylene chloride, etc. In fact, any conventional polar organic solvent can be utilized. In carrying out this reaction, temperatures of from 0 to 35'C can be utilized. Generally, it is preferred to carry out this reaction at room temperature.

The compound of formula X1 is converted to the compound of formula X11 by ether hydrolysis. Any conventional method of ether hydrolysis can be utilized to carry out this reaction. Generally, it is preferred to utilize mild acid hydrolysis such as aqueous acetic acid.

In the next step, the compound of formula XII is treated with a dehydrohalogenating agent to produce the 60 compounds of formulae XIII and XIV in admixture. In carrying out this reaction, any conventional dehydrohalogenating agent can be utilized. Among the preferred dehydrohalogenating agents are the diazabicycloalkanes or alkenes such as 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane.

Furthermore, any other conventional organic base utilized for dehydrohalogenation can be utilized in carrying out this reaction. This reaction produces the compounds of formula XIII and the compounds of 8 GB 2 158 822 A 8 formula XIV in admixture. The compounds of formula X111 can be separated from the compounds of formula XIV by any conventional procedure such as chromatography.

The compound of formula X111 is converted to the compound of formula XV and the compound of formula XIV is converted to the compound of formula XVI by hydrolysis. Any conventional method of ester hydrolysis can be utilized in carrying outthese reactions. Among the preferred method of ester hydrolysis is eithertreating the compound of formula X111 orthe compound of formula XIV with a alkali metal hydroxide.

Among the preferred alkali metal hydroxides for use in this reaction are sodium and potassium hydroxides.

The present invention relates to compounds of the formulae X1 and X11 given above.

The compounds of formula I their pharmaceutically acceptable salts as well as optical antipodes and racernates thereof are useful as anti-secretory agents, anti hypertensives, antiucerogenic agents, and for combating gastro-hyperacidity and for antiblood platelet aggregating agents.

Any pharmaceutically acceptable basic salt of the compound of formula I where R is hydrogen can be utilized. Among the preferred pharmeutically acceptable basic salts are included the alkali metal salts such as lithium, sodium, and potassium, with sodium being especially preferred. Other salts which are also preferred are the alkaline earth metal salts such as calcium and magnesium, amine salts such as the lower 15 alkyl amines, e.g. ethylamine and the hydroxy-substituted lower alkyl amine salts and tris (hydroxymethyl) aminomethane. Also preferred are the ammonium salts. Among the other salts are dibenzylamine, monoalkylamines or dialkylamine and salts with amino acids (i.e. salts with arginine and glycine).

Thatthe prostacyclins of formula I are active as anti-blood platelet aggregating agents can be seen from the administration of (5Z,7p,9(x, 11(x, 13E, 15R)-7-fluoro-6,9-epoxy-11, 15-dihydroxy-16,16-dimethyl-prosta20 5,13-dien-l-oic acid methyl ester by the following test.

ml of blood was drawn from the jugular vein of a conscious beagle using two 15 ml Vacutainer tubes, with no additive, connected to a 20 g 1 inch multiple sample needle. The blood was immediately transferred to a 50 ml conicalplastic centrifuge tube containing 3 ml of 3.8% sodium citrate (3.8 grams of sodium citrate crystal, Na3C6H5O7.2H2O, in 100 ml of distilled water), capped and gently mixed. The citrated blood was centrifuged at 160 g for 15 minutes at 20'C. The platelet rich plasma (PRP) was carefully withdrawn with a pipette, without disturbing the buffy coat and erythrocyte layers. The PRP was placed in 16 x 125 mm plastic tubes, capped and stored at room temperature 19-210C. PRP preparations showing a tinge of redness, indicative of hemolysis, were discarded. The remaining blood, afterthe removal of PRP, was recentrifuged at higher speed, 900 g for 10 minutes, to yield platelet poor plasma (PPP). The PRP was used immediately and 30 the aggregation study completed within three hours after preparation.

Platelet aggregation was measured with a Payton dual channel aggregation module connected to a dual pen recorder for the continuous recording of the increase in light transmission due to clumping of platelets.

The 0-100% transmission scale was set with PRP (0% and PPP (100%). The temperature was set at 370 and the stirring speed at 900 rpm. 0.45 ml of PRP was added to a cuvette containing a Teflon @ coated stirring bar and prewarmed at 37' in a water bath. 5 Rl of various concentrations of (5Z,7P,9a,-1 1 a,1 3E,1 5R)-7-fluoro-6,9 epoxy-1 1,1 5-dihydroxy-1 6,16-dimethyl-prosta-5,13-dien-1 -oic acid methyl ester, diluted from a stock solu tion of 5 x 10-4 M in DMSO (dimethylsulfoxide) with phosphate buffered saline containing 1 mg/ml of bovine serum albumin, fraction V, was added and stirred for 1 minute. The inducer of aggregation,, arachidonic acid, at a concentration which will cause 50-70% aggregation after 5 minutes, was then added in 40 [tl of solution. The % inhibition, setforth in the following Table, was calculated from the ratio of the % aggregation with (5Z,5P,9a,1 la,13E,15R)-7-fluoro-6,9-epoxy-1 1,15dihydroxy- 16,16-dimethyl-prosta-5,13 dien-l-oic acid methyl ester over that with the vehicle x 100.

Concentration of (5Z, 7p, Ax, 1 let, 13E, 15R)- 45 7fluoro-6,9-epoxy- 11, 15-dih ydroxy- 16,16 -dimethyl-prosta-5,13-dien- 1-oic acid methyl ester % Inhibition 1 X 10-13m 14.2 3 X 10-13M 20.8 50 1 X 10-12M 71.4 1 - 10-11M 57.8 1 X 10-10M 20.8 The preparation of phosphate buffered saline and arachidonic acid solution used above is as follows: Phosphate buffered saline PBS) was prepared by adding 1 mM solution of sodium phosphate aqueous buffer, pH 7. 4 to 0.85% by weight/volume of an aqueous sodium chloride solution. Arachidonic acid solution was prepared as follows: A stock solution of 10 mg per ml in absolute ETOH was prepared and stored in freezer. To make a 10 mM solution, 0.3 ml of the stock solution was evaporated to near dryness under nitrogen and redissolved in 0.75 ml of 0. 02 NH40H (freshly prepared) and 0.2 ml of PBS. Further dilutions of achidonic acid were made with NH40H and PBS mixture.

i 9 _ GB 2 158 822 A i 9 The compounds of formula I or their pharmaceutically acceptable salts can be used in a variety of pharmaceutical preparations. In these preparations, the new compounds are administerable in the form of tablets, pills, powders, capsules, injectables, solutions, suppositorien, emulsions, dispersions, and in other suitable forms. The pharmaceutical preparations which contain the compounds of formula I are conveniently formed by admixing with a non-toxic pharmaceutical organic carrier or a non-toxic pharmaceutical inorganic carrier. Typical of pharmaceutically acceptable carriers are, for example, water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly and other conventionally employed pharmaceutically acceptable carriers. The pharmaceutical preparations may also contain non-toxic auxiliary substances such as emulsifying, preserving and wetting agents as for example, sorbitan monolaurate, triethanol amine oleate, polyoxyethylene sorbitan, and dioctyl sodium sulfosuccinate.

The daily dose administered for the compounds will, of course, vary with the particular novel compound employed because of the very potency of the compounds, the chosen route of administration and the size of the recipient. The dosage administered is not subject to definite bounds but it will usually be in effective amounts of the pharmacologically function of the prostacyclin. Representative of a typical method for administering the prostacyclin compounds of formula I is by oral administration. By this route, the prostacyclins of formula I can be administered at a dosage of 0.1 micrograms to 0.30 micrograms per day per kilogram of body weight.

The following Examples are illustrative but not limitative of the invention. In the Examples, the ether utilized was diethyl ether. All temperatures are in degrees Centigrade. The petroleum ether utilized in the Examples had a boiling point of from 350 to 600C. In the Examples, "h" indicates hours.

The Examples show the preparation of the compounds of the present invention and their use in the preparation of the novel fluoro prostacyclins of our copencling application.

Example 1 [3aR-[3a(x,4(x(1E,3R), 5P,6aoL]I-Hexahydro-5-[[(1,1-dimethylethyl) dimethylsiIy1oxy1-4-[[[3-(1,1dimethylethyl)-dimethylsilylloxyl(-4,4dimethy1 -1-octenyll-2H-cyclopenta[b]furan-2-one 502.2mg (1.69 mmol) of [3aR-[3aa,4a(1 E,3R), 5P,6aotll-hexahydro-5hydroxy-4-(3-hydroxy-4,4-dimethyl1-octenyl)-2H-cyclopenta[b]furan-2-one, was dissolved in 15 ml of climethy1formamide (reagent grade, dried over3A molecular sieves) under a positive argon pressure. 1.045 g (6.93 mmol = 4. 09 eq.) of t-butyldimethy[chlorosilane (dist. before use) and 587.6 mg (8.63 mmol = 5.09 eq.) of imiclazole (reagent grade) were added. The resulting mixture was stirred at room temperature for 18 h, poured into 60 ml ice cold 0.5 N aqueous HCI and extracted three times with 60 mi of cliethylether. The extracts were washed with 60ml of a mixture of sat. aqueous NaHC03/H20/brine = 1:11:2 followed by washing with 60 ml brine. The extracts were combined, dried over MgS04 and concentrated at reduced pressure. 1.25 g of a white semi-solid remained. The crude product was chromatographed on a 75 g silica gel column with 10% by volume ether/90% by volume petroleum ether (first 1 1t) followed by 20% by volume ether/80% by volume petroleum ether. 857.1 mg (1.63 mmol, 96.46) of[3aR-[3aa,4a-(l E,3R), 5P,6a(x1J- hexahydro-5-[[(1, 1 dimethylethyl)dimethylsilylloxyl-4-[[[3-(1,1dimethylethyl)-dimethylsilyllox y]-4,4-dimethyl-1 -octenyl]-2Hcyclopenta[blfuran-2-one as a white amorphous solid was obtained; mp P7-68.

Example 2 [3all-PaotAx(l E,3R),5p,6aa]1-4,5,6,6a-Tetrahydro-5-[[1,1 dimethylethyl)dimethylsilylloxyl-4-[[[3-(1,1 dimethylethyl)dimethylsilylloxy]-4,4-dimethyl-1 -octenyll-2(trimethylsilyl)oxy-3aH-cyclopenta[b]furan 570[LI(4.07 mmol) of diisopropylamine (dist. from Cal-12) was dissolved in 15 ml of tetrahydrofuran (freshly dist. f rom LAH). The mixture was cooled to +30C under a positive argon pressure. 2.5 ml (3.75 mmol) of 1.5 N 45 n-butyllithium in hexane was added dropwise at +3'C. After stirring at + 3'C for 5 min, the mixture was cooled to -40C with a dry ice/acetone bath. 1.757 g (3.35 mmol) of [3aR- [3aa,4u_(1 E,313),513,6aall hexahydro-5-[[(1,1 -dimethylethyl)dimethylsilylloyl-4-[[[3-(1,1dimethylethyl)-dimethylsilyloxy l-4,4dimethyl-l-octenyll-2H-cyclopenta-[blfuran-2-one dissolved in 6 ml THIP was added dropwise to the lithium diisopropylamide solution at -40'C. After stirring at -40'C for an additional 5 min, 570 lil (4.49 mmol) of trimethyichlorosilane (dist.) was added rapidly. Two min after the addition, the cooling bath was removed and the mixture was allowed to warm to + 1 5'C over a 20 min period. The solvent was removed under vaccum (ca.0.2 MMHG) at or below room temperature and the residue was dried at high vacuum for 15 min.

mi of ether (freshly filtered through aluminum oxide, activity 1) was added under argon and the mixture was filtered through a sintered glass funnel. The white residue was washed three times with 3 ml of ether.

The slightly yellow filtrate was concentrated under vacuum and the oily residue was dried at hig h vacuum (room temperature) for 1 h producing [3aR[3aa,4a(1 E,3R),5p,6aa.]]-4,5,6, 6a-tetrahydro5-[[(1,1 dimethylethyl)dimethylsilylloxy]4-[[[3(1,1 -dimethylethyl)dimethylsilylloxyl-4,4-dimethyl-1 -octenyll-2 (trimethylsilyl)oxy-3aH-cyclopenta[blfuran.

GB 2 158 822 A Example 3 13S-13a,3act,4a(lE,3R),5p,6a(xll-Hexahydro-3-fluoro-5[[(1,1 - dim ethylethyi)dim ethylsilyl loxy]-4-[[[3(1,1 - dimethylethyi)dimethyisilylloxy]-4,4-dimethyl-1 -octenyll-2H- cyclopenta[blfu ran-2-one The compound [3aR-[3au-,4ct(l E,3R),5p,6a&-11-4, 5,6,6a-tetrahydro-5-[[1,1 -dimethylethyl)dimethyisilylloxy]-4-[-[[3-(1,1-dimethylethyi)-dimethyisilylloxy]-4,4dimeth yl-2-octenyll-2-(trimethyisiiyi)oxy-3aH-cyciopenta[blfuran was dissolved in 15 ml of methylene chloride (freshly filtered through aluminum oxide, activity 1) under argon. The mixture was cooled to +20C with an icelwater bath. 680 mg (6.8 mmol) of potassium bicarbonate (dried at high vacuum at 10Wover P205 for 3 h) followed by 632.9 mg (3.73 mmol) of xenon difluoride were added under stirring. An immediate reaction ensued as judged by the vigorous gas evolution in the first 30 sec. after the addition of XeF2. The mixture was stirred at +2'C for 20 min, poured into 150 mi of ice cold water and extracted three times with 150 rril of methylene chloride. The extracts were washed twice with 150 mi of brine, combined, dried over M9S04 and concentrated at reduced pressure. The residue was dried at high vacuum for 18 h leaving 1.92 g of a yellowish oil.

The crude product was chromatographed on 200 g of silica gel (230-400 mesh) using the flash chromatography technique. 5% by volume ethyl acetate/95% by volume petroleum ether (1 It) followed by 15 10% ethyl acetatelpetroleum ether (1 It) followed by 10% ethyl acetatelpetroleum ether were used as eluting solvents. The following products were obtained in order of elution: 1.06 g (1.95 mmol) 58% of [3S- [3a,3aot,4u-(1 E,3R),5p,6aa-11-hexahydro-3-fluoro-5-[[(1,1dimethylethyl)dimethyisilylloxy]-4-[[[3-(1,1dimethylethyl)dimethyisilylloxy]-4,4-dimethyl-l-octenyll-2H-cyclopenta[blfu ran-2-one; white needles 20 formed on standing, m.p. 49-51'; 165.2 mg (0.315 mmol) 9.4% of [3aR;-[; 3aot,40t(l E,3R),5P,6aallhexahydro-5[[(1,1dimethylethyi)dimethyisilylloxy]-4-[[[3-(1, ldimethylethyi)dimethyisilylloxy]-4,4dimethy]-1-octenyll-2H-cyciopenta[blfuran-2-one, starting material; and 98.9 mg (0.182 mmol) 5.4% of 3R[3p,3acc,4u-(1 E,3R),5P,6aal-hexahyd ro-341 uo ro-5-[[(1,1 -di methyl ethyl)dimethyisitylloxy]-4-[[[3(1,1-dimethyl-ethyl)dimethyisilyll-oxy]-4, 4-dimethyl-l-octenyll-2H-cyclopent a[b]furan-2-one;amorphous white solid; m.p. 83-85'.

Example 4 [3S-[3ot,3aa_AY0 E,3R),5p,6au-11-Hexahydro-3-fluoro-5-hydroxy-4-(3hydroxy-4,4-dimethyl-l-oc tenyl)-2H- cyclopenta-[blfuran-2-one 1.597 g (2.94 mmol) of the fluoro lactone [3S-[a,-3a(x,4(y(lE,3R),5p, 6a(xlhexahydro-3- fluoro-5-[[(1,1 -dimethylethyl)dimethylsilylloxy]4-[[[3-(1,1 dimethylethyl)dimethylsilylloxyl- 4,4-dimethyl-1 -octenyll-2H-cyclopenta[b]-furan-2-one was dissolved in 60 ml of acetic acid (reagent grade) and the mixture was warmed to 55'C under a positive argon pressure. 6 ml of water was added with stirring at 55'C. After 7 h, an additional 4 ml of water was added and stirring at 55'C was continued for 64 h (71 h total). After cooling to room temperature, the solvent was removed under vacuum(ca.0.2 Torr) at 25-30'C. 35 The oily residue was dried at high vacuum for 2 hat room temperature, followed by chromatography on 200 g of silica gel (230-400 mesh) using solvent mixtures ranging from ethyl acetate/petroleum ether 1:1 parts by volume to pure ethyl acetate for elution.

351.2 mg of partially hydrolyzed material containing large amounts of impurities and 571.5 mg (1.82 mmole, 62%) of [3S-[3(x,3aa,4(x(1 E,3R),5p,6a(x]]-hexahydro-3-fluoro-5- hydroxy-4-(3-hydroxy-4,4dimethyl-l-octenyl)-2H-cyclo-penta[b]furan-2-one (oil) were obtained. Resubjecting the 351.2 mg of partially hydrolyzed material to similar reaction conditions (HOAc, H20) for 42 h resulted in the formation of 39.6 mg (0.126 mmole) 4.3% of additional [3S-[3a_,3aa,4cL(1 E,3R),6p, 6aotll-hexahydro-3-fluoro-5- hydroxy-4-(3-hydroxy-4,4-dimethyl-1 -octenyl)-2H-cyclopenta[b]furan-2-one. Total yield of [3S-[3a,3au.,4a (lE,3R),5p,-6aall-hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4,4-dimethyll-o ctenyl)-2H-cyclopenta[bl- 45 furan-2-one was 611.1 mg (1.94 mmol) 66%, oil, clear.

Example 5 [3S-[3(x,3aa,4a-(1E,3R),SP,6actIl-Hexahydro-3-fluoro-5-[(tetrahydro-2Hpyra n2-yi)oxy]-4-[3-tetrahydro- 2H-pyran-2yl)oxyll-4,4-dimethyi-l-octenyil-2H-cyclopenta[blfuran-2-one 571.5 mg (1.83 mmol) of [3S-[3a,3au-,4et(1E,3R),5p,6aall-Hexahydro-3fluoro-5-hydroxy- 4-(3-hydroxy-4-4-dimethy]-1 -octenyi)-2H-cyclopenta[blfuran-2-one was dissolved in 20 mi of methylene chloride (freshly filtered through aluminum oxide, activity 1) under a positive argon pressure. 2.0 mi (21.9 mmol) of dihydropran (freshly dist. from sodium) was added under stirring followed by a crystal of p-toluenesulfonic acid monohydrate (9.7 mg; 0.05 mmol). The mixture was stirred at room temperature for 55 min, poured into 50 m[ of sat. aqueous sodium bicarbonate and extracted three times with 30 mi of methylene chloride. The extracts were washed twice with 50 mi of brine, combined, dried over M9S04 and concentrated at reduced pressure. The crude product (1.14 g, oil) was chromatographed on a 100 g silica gel column with etherlpetroieum ether (1: 1) yielding 797 mg (1.65 mmol) 91% of [3S-[3ct,3act,4(x(l E,3R), 5P,6aall-hexahydro-3-fluoro-5[(tetrahydro-2H-pyran-2-yi)oxyll-4[3- (tetrahydro-2H-pyran-2-yl)oxy]-4,4dimethy]-1-octenyll-2H-cyclopenta[blfuran-2-one as a clear oil (mixture of THP-diastereomers).

[,125 -32.4Win CHCL3, c = 0.8780.

D 11 GB 2 158 822 -A 11 Example 6 [3S-[3(Y,3aa-,4u-(1E,3R),5p,6a(xl]-Hexahydro-3-fluoro-5[(tetrahydro-2Hpyra n-2-yi)oxy]-4-[3-(tetrahydre:2H-pyra n-2-yl) oxy]-4.4di methyl -1 -octenyl 1-21-1-cycl o penta [blfu ra n-2-ol After dissolving 729.2 mg (1.51 mmol) [3S-[3a,3aa.,4u-(1 E,3R),5p,6aocllhexahydro-3-fluoro-5- [(tetra hyd ro-2H-pyran-2-yi)oxy]-4-[3-[(tetra hyd ro-21-1-pyra n-2- y1)oxy]-4,4-d i methyl-1 -octenyl 1-21-1cyclopenta[b]furan-2-one in 10 mi of toluene (dist. from CaH2) under argon,the mixture was cooled to approx. -700C with a dry icelacetone bath. 1.25 mi (1.75 mmol) of a 1.4M solution of diisobutylalyminum hydride in hexane was added dropwise at - 70'C. The mixture was stirred at -700C for 20 min. 3 mi of a saturated aqueous ammonium chloride solution was added dropwise at -70C and the resulting mixture was transferred with 20 mi of water and 50 m[ of ethyl acetate into a separatory funnel. Shaking caused a 10 very thick suspension to form, which was filtered through Celite @ The residue was washed throughly with 100 mi of ethyl acetate. The filtrate was again transferred into a separatory funnel and washed once with 60 mi of brine/water (1: 1 parts by volume) and once with 100 mi brine. The aqueous washings were reextracted once with 80 m] of ethyl acetate. The organic extracts were combined, dried over M9S04 and concentrated at reduced pressure. Flash chromatography on 200 g of silica gel (230-400 mesh) of the crude product (806 mg; 15 oil) with ethyl acetatelpetroleum ether (4:6) gave 661.5 mg (1.36 mmol) 90% of [3S-[3a.,3aa,4(x(l E,311), 5P,6act]l-hexahydro-3-fluoro-5[(tetrahydro-2H-pyran-2-yi)oxy]-4-[3-[(tetrah ydro-2H-pyran-2-yi)oxy]-4, 4dimethyi-l-octenyll-2H-cyclopenta-fblfuran-2-ol as an amorphous solid, m. p. 58-66'C; [Cj25= -12.830 D in CHC13, C 1.0290.

Example 7 (5Z,7R,9a,l (M 3E,l 511)-7-Fluoro-l 1,1 5-di[(tetrahydro-2H-pyran-2- yi)oxy]-1 6,16-dimethyl-g-hydroxy prosta-5,13-dien-l-oic acid methyl ester 1,54 9 (3.47 m mol) of (4-carboxybutyi)triphenylphosphonium bromide (dried at high vacuum at 100 over P205 for 2 h) and 1.275 g (6-95 mmol) of sodium hexamethyidisilazane (dist.) were placed into a three neck 25 flask under argon. 20 mi of tetrahydrofuran (freshly dist. from LAH) and 1.25 mi (7.18 mmol) of hexa methyl phosph oramide (dist.) were added. This mixture was stirred at room temperature for 1 112 h. To the orange red suspension was added dropwise a solution of 560.5 mg (1.16 mmol) of [3S-[3ot,3aa,4a (1 E,3R),5p,6aa-11-hexahydro-3-fluoro-5-[(tetrahydro-2Hpyran-2-yi)oxy]-41[3-[ (tetrahydro-2H-pyran-2-yi)- oxy]-4,4-dimethyl 1 -octenyll-2H-cyclopenta [blfu ran-2-ol in 4 m] of tetrahydrofu ran. The resulting yellow orange mixture was stirred at room temperature for 4 h. The reaction was quenched by the dropwise addition of glacial acedic acid (faint yellow color). Most of the solvent was evaporated under high vacuum at or below room temperature. The residue was transferred with 100 mi of ether and 100 mi of water into a separatory funnel. The aqueous phase was acidified to pH 3 with 13 mi of 1 N HCL After shaking and separation of the two phases, the aqueous phase was reextracted twice with 70 mI of ether. The organic extracts were washed twice with 70 m] of ether. The organic extracts were washed twice with 70 mi of brine, combined and dried over M9S04. After removal of the solvent, the oily residue was dried at high vacuum for 1 112 h, leaving 1.45 g of an oil. This crude acid was dissolved in 10 mf of methylene chloride (freshly filtered through aluminum oxide, activity 1) and exterified at room temperature by the addition of 15 mf (3.75 mmol) of a =.25N solution of diazomethane in ether. After removal of the solvent at aspirator pressure, the remaining oil (1.27 9) was dissolved in 10 m] of tetrahydrofuran and 2.8 mi (2.8 mmol) of a 1.OM solution of tetra-n-butylammonium fluoride in tetrahydrofuran was added. The mixture was stirred at room temperature for 15 min, poured into 100 mi of a half concentrated aqueous ammonium chloride solution and extracted three times with 100 mi of ether. The extracts were washed twice with 70 mi of brine, combined, dried over M9S04 and concentrated at reduced pressure. 1.24 9 of a yellow oil was obtained.

Chromatography on 100 g of silica gel with ethyl acetate/petroleum ether (3:7) (700 m[) followed by ethyl acetatelpetroleum ether (1:1 parts by volume) gave 20.8 mg (3.7%) of[3S- [3a,3aoc,4(x(1E,3R),5p,6aetl]hexahydro-3-fluoro-5-[(tetrahydro-2H-pyran-2-yi)oxy]-4-[3-[(tetrahydro-2Hpy ran-2-yi)oxy]-4,4dimethyi-l-octenyll-2H-cyciopenta[blfuran-2-oi-(starting material) and 496.3 mg (0.85 mmol) 73% of (5Z,7R,ga,llu-,13E,15R)-7-fluoro-11,15-dif(tetrahydro-2H-pyran-2-yi)oxy]16, 16-dimethyi-9-hydroxy- prosta-5,13-dien-l-oic acid methylester (oil), as a mixture of diastereomers; ['125= +2.7,V in CHC13, D c= 0.9116.

12 GB 2 158 822 A 12 Example 8 (7p,g(x,l let,13E,15R)-1 6,16-Dimethy]-1 1,1 5-di [(tetra hyd ro-2H-pyra n-2-yi)oxy]-6,9-epoxy-7-fi uo ro 5-iodo-prosta-1 3-en-1 -oic acid methyl ester 246.9 mg (0.424 mmol) of (5Z,7R,9a,l 1(x,13E,15R)-7-fluoro-1 1,1 5-di [(tetra hyd ro-2H-pyra n-2-yi)oxy]-1 6,16 dimethyl-9hydroxy-prosta-5,13-dien-l-oic acid methyl ester was dissolved in 10 m] of acetonitrile (dried over 5 3A molecular sieves) under a positive argon pressure. 476.9 mg (2.12 mmol, 5 eq.) of Modo succinimide was added under stirring, the flask was flushed with argon, closed with a stopper and wrapped in aluminum foil to protect the reaction mixture from light. The mixture was stirred at room temperature for 27 h, poured into 100 mi of a 10% weight by volume solution of sodium thiosulfate in water and extracted three times with 100 mI of methylene chloride. The organic extracts were washed twice with 100 mi of brine, combined, dried 10 over M9S04 and concentrated at aspirator pressure. 285.9 mg of an oily residue was obtained.

Chromatography on 75 g of silica gel with etherlpetroleum ether 0:1 parts of volume) gave 186.8 mg (0.263 mmoi)62%of(7p,gp,ll(x,13E,15R)-16,16-dimethyi-11,15-di[(tetrahydro-2Hpyran-2 -y1)oxy]-6,9-epoxy-7- fluoro-5-iodo-prosta-13-en-l-oic acid methyl ester (oil) as a mixture of diastereomers.

is Example 9 (7p,got,l 1 et,13E,1 5R)-1 6,16-Dimethyl-l 1,1 5-dihydroxy-6,9-epoxy-7- fluoro-5-iodo-prosta-1 3-en-1 -oic acid methyl ester 10.6 mg (15 limol) of (7p,9ct,l let,13E,15R)-16,16-dimethyi-l 1,15di[(tetrahydro-2H-pyran-2-yi)oxy]- 6,9-epoxy-7-fluro-5-iodo-prosta-1 3-en-1 -oic acid methyl ester was dissolved in a mixture of 3 mi of 20 tetrahydrofuran (freshly dist. from LAH). 6 mI of glacial acetic acid and 3 mI of water under a positive argon pressure. The mixture was heated in an oil bath at 4M and stirred for 19 h. After cooling to room temperature, the solvent was removed at high vacuum at 250.2 mi of toluene was added and the solvent was again removed at high vacuum at 25'. The oily residue (11.2 mg) was chromatographed on a thin layer silica gel plate with ether giving 6.3 mg (11.65 mol, 78%) of (7p,9(x,l la,13E,l 5R)-16,16-dimethyl-l 1,15-dihydroxy- 25 6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-l-oic acid methyl ester (oil) as a mixture of isomers.

Example 10 (5Z,7p,9a,ll(x,13E,15R)-7-fluoro-6,9-epoxy-1 1,15-dihydroxy-16,16- dimethyi-prosta-5,1-3-dien-l-oic acid methyl ester 6.3mg(11.66limoi)of(7p,9oL,11(x,13E,15R)-16,16-dimethyi-11,15-dihydroxy-6, 9-e poxy-7-fluro-5-iodo- prosta-13-en-l-oic acid methyl ester (mixture of isomers) was dissolved in 2.0 m[ of toluene (dist. from CaH2) under a positive argon pressure. 20gi (134 gmot) of 1,8-diazabicyclo[5.4. Olundec-7-ene (dist. from CaH2) was added. With stirring, the mixture was slowly heated to 90'C (over 90 min) and kept at 900C for 22h. After cooling to room temperature, the mixture was poured into 75 mI of half saturated brine and extracted three 35 times with 20 mi of ether. The extracts were washed once with 20 mi of brine, combined, dried over M9S04 and concentrated at aspirator pressure. The remaining oil was dried at high vacuum for 3 h and the 6.2 mg of residual oil was chromatographed on a thin layer silica gel plate with ethyl acetate. Two products were isolated: 3.0 mg (7.27 [Lmol) 62% of (5Z,7P,9a,l 1(x,13E,1 5R)-7-fluoro-6, 9-epoxy-1 1,1 5-dihydroxy-1 6,16 dimethyi-prosta-5,13-dien-l-oic acid methyl ester (oil) and 1.1 mg (2.66 Kmol) 23% of (4E,6(x,7p,9ct,l la,13E,15R)-7-fluoro-6,9-epoxy-1 1,15-dihydroxy-16,16dimethyi-prosta-4,13-dien-l-oic acid methyl ester (oil).

Example 11 (5Z,70,gct,llot,13E,15R)-7-Fluoro-6,9-epoxy-11,15-dihydroxy-16,16dimethyl-p rosta-5,13-dien-l-oic acid 45 sodium salt 3.0 mg (7.27 1Lmole) of (5Z,70,9a,l leL,13E,15R)-7-Fluoro-6,9-epoxy-1 1, 15-dihydroxy-16,16-dimethyl-prosta- 5,13-dien-l-oic acid methyl ester was dissolved in 0.5 mi methanol and 0. 5 mi water under argon. 731A (7.3 [Lmole = 1 eq.) 0.1 N sodium hydroxide was added and the mixture was stirred at room temperature for2 hr.

The methanol was removed at reduced pressure and the remaining aqueous solution was lyophilized to give 50 (5Z,7P,9a,l 1 et,13E,1 5R)-7-Fluoro-6,9-epoxy-1 1,1 5-dihydroxy-1 6,16dimethyi-prosta-5,13-dien-l-oic acid sodium salt as a white powder; m.p. 48-51'C.

Example 12 [3aR-[3aa,4a-(1E,3R,4R)6aa.11-Hexahydro-4-[[[3-(1,1dimethylethyl)dimethyi siiylloxy]-4-fluoro-l-octenyi]2H-cyclopentafblfuran-2-one Bythe procedureof Example 1[3aR-[3au-,4eL(1E,3R,-4R)6a(x]l-hexahydro-4-[4- fluoro-3-hydroxy-ioctenyi)-2H-cyclopenta[blfuran-2-one was converted to [3aR-[3aoL,4a(l E, 3R,4R)6aa-1]-hexahydro-4 [[[3-(1,1 di methyl ethyl)-dimethylsi ly] loxy]-4-fi uoro-1 -octenyi)-2H- eyclo penta [b]fu ran-2-one.

13 GB 2 158 822 A - 13 Example 13 [3aR-[3aoc,4oi(1E,3R,4 R)6acLI1-Hexahydro-3-fluoro-4-[[[3-(1,1dimethylethyl)-dimethyisilylloxy]-4 -fluoro1-octenyll-2H-eyclopenta[blfuran-2-one Bythe procedure of Examples 2 and 3,[3aR-[3au.,4(Y.(1E,3R,4R)6act]]- hexahydro-4-[[[3-(1,1 dimethyiethyi)dimethyisilylloxy]-4-fluoro-l-octenyll-2H-cyclopenta[blfuran-2 -one was converted to [3aR- 5 [3aa,4a(1E,3R,4R)6aotll-Hexahydro-3-fluoro-4-[[[3-(1,1dimethylethyl)dimet hyisilylloxy]-4-fluoro-l- octenyll-2H-furan-2-one.

Example 14 [3aR-[3act,4a-(1 E,3R,4R)6a(xl]-Hexahydro-3-fluoro-4-(3-hydroxy-4-fluoro- loctenyll-2H-cyciopentafblfuran-2-one Bythe procedure of Example 4 [3aR-[3act,4a(l E,3R,4R)6actIl-Hexahydro-3- fluoro-4-[[[3-(1,1dimethylethyl)dimethyisilylloxy]-4-fluoro-l-octenyll-2H-cyclopenta[b]furan-2 -one was converted to [3aR-[3aot,4ct(1E,3R,4R)6a(xl]-hexahydro-3-fluoro-4-(3-hydroxyfluoro-loct enyll-2H-cyclopenta[b]- furan-2-one.

Example 15 [3aR-[3aa,4a-(1E,3R,4R)6acLI1-Hexahydro-3-fluoro-4-[3-[(tetrahydro2Hpyran -2-yi)oxy]-4-fluoro-l-octenyll- 2H-cyclopenta[b]-2-one By the procedure of Example 5 [3aR-[3a(x,4eL(1 E,3R,-4R)6act]l-hexahydro3fluoro-4-(3-hydroxy-4-fluoro- 20 1-octenyll-2H-cyclopenta[blfuran-2-one was converted to [3aR-[3act,4,a(1E, 3R,4R)6a(xll-hexahydro-3fluoro-4[3-[(tetrahydro-2H-pyran-2-yi)oxyll-4-fluoro-l-octenyll-2Hcyclopen ta[blfuran-2-one.

Example 16 [3aR-[3act,4a(1E,3R,4R)6a(xl]-Hexahydro-3-fluoro-4-[3-[(tetrahydro-2Hpyra n-2-yl)oxyll-4-fluoro-l-octenyll- 25 2H-eyclopenta[blfuran-2-ol By the procedure of Example 6[3aR-[3act,4(x(l E,3R,4R(6aall-Hexahydro-3fluoro-4-[3-[- (tetra hyd ro-21-1-pyra n-2-y1)oxyl 1-4-fluoro-l -octenyll-2H-cycl openta[blfu ra n2-one was converted to [3aR[3au,4u-(1 E,3R,4R)6aa.1]-hexahydro3-fluoro-4-[3[(tetrahydro-pyran-2yi)oxy]-4-fluoro -1 -octenyl]-2H cyclopenta[blfuran-2-ol.

Example 17 (5Z,9u-,13E,15R,16R)-7,16-Difluoro-15-[(tetrahydro-2H-pyran-2-yi)oxyll-ghyd roxy-5,13-dien-l-oic acid methyl ester By the procedure of Example 7 [3aR-[3act,4a(1E,3R;,4R)6actIl-hexahydro-3- fluoro-4-[3- [(tetra hyd ro-2H-pyran-2-yi)oxy]-4-fi u o ro-l-octenyll-2H- eyclopentafbjfuran-2-ol was converted to (5Z,9(x,l M-A 5RA 6R)-7,16-difluoro-1 5-[(tetrahydro-2H-pyran-2-yi)oxy]-9- hydroxy-prosta-5,13-dien ester.

Example 18 (9a,13E,15R,16R)-7,16-Difluoro-15-[(tetrahydro-2H-pyran-2-yi)oxy]-6,9epoxy-5 -iodo-prosta-13-en-l-oic acid methyl ester Bythe procedure of Example 8,(5Z,goL,13E,15R,16R)-7,16-difluoro-15- [(tetrahydro-2H-pyran-2yi)oxy]-9-hydroxylprosta-5,13-dien-l-oic acid methyl ester was converted to (9(x,13E,15R,16R)-7,16-difluoro15-[(tetrahydro-2H-pyran-2-yi)oxy]-6,9-epoxy-5-iodo-prosta-13-en-l-oic acid methyl ester.

Example 19 (9cL,13E,15R,16R)-7,16-Difluoro-15-hydroxy-6,9-epoxy-5-iodo-prosta-13-enl-o ic acid methyl ester Bythe procedureof Example 9, (9(x,13E,15R,16R)-7,16-difluoro-15- [(tetrahydro-2H-puran-2-yl)oxyll-6,950 epoxy-5-iodo-prosta-13-en-l-oic acid methyl ester was converted to (9a, 13E,15R,16R)-7,16-difluoro-15- hydroxy-6,9-epoxy-5-iodo-prosta-13-en-l-oic acid methyl ester.

Example 20 (5Z,9a,l 3E,l 5R,l 6R)-7,16-Difluoro-6,9-epoxy-1 5-hydroxy-prosta-5,13- dien-1 -oic acid methyl ester By the procedure of Example 10 (ga,l 3E,1 5R,l 613)-7,16-difluoro-l 5hydroxy-6,9-epoxy-5-iodo-prosta-1 3 en-1 -oic acid methyl ester was converted to (5Z,9ot,l 3E,l 5R,l 6R)-7,16- difluoro-1 5-hydroxy-6,9-epoxy-prosta 5,13-dien-l-oic acid methyl ester.

Example 21 (5Z,g(x,13E,15R,16R)-7,16-Difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-dienl-o ic acid sodium salt By the procedure of Example 11, (5Z,9et,13E,15R,16R)-7,16-difluoro-6,9- epoxy-15-hydroxy-prosta-5,13dien-l-oic acid methyl ester was converted to (5Z,9a,13E,l 5R,l 6R)-7,16difluoro-6,9-epoxy-1 5-hydroxy prosta-5,13-dien-1 -oic acid sodium salt.

1 14 GB 2 158 822 A Example22 (4E,9(x,13E,15R,16R)-7,16-Difluoro-6,9-epoxy-15-hydroxy prosta4,13-dienl-oic acid methyl ester By the procedure of Example 10, (get,13E, 15R,16R)-7,16-difluoro-15-hydroxy-6,9-epoxy-5-iodo-prosta-13- en-l-oic acid methyl ester was converted to (4E,got,13E,15R,16R)-7,16difluoro-6,9-epoxy-15-hydroxy-prosta5 4,13-dien-1 -ole acid methyl ester.

Example 23 By the proced u re of Exa m p le 11, (4E,9(x,l 3E, 1 5R,l 6R)7,16-difi uoro-6,9-epoxy-1 5-hydroxy-prosta-4,13- dien-1 -oic acid methyl ester was converted to the sodiu m salt of (4E,9a, l 3E,l 5R,l 6R)-7,16-difluoro-6,9jo epoxy-15-hydroxy-prosta-4,13-dien-l- oic acid.

Example 24

14 A tablet was found containing:

(SZ,ga,13E,15R,16R)-7,16-Difluoro-6,9- Per tablet 15 epoxy-1 5-hydroxy-prosta-5,13-dien-1 -oic acid sodium salt 25 mg Dicalcium phosphate dihydrate, unmilled 175 mg Corn Starch 24 mg 20 Magnesium stearate 1 mg Total Weight 225 mg The active ingredient and corn starch were mixed together and passed through a #00 screen in Model "X' Fitzmill with hammers forward. This premix was then mixed with dicalcium phosphate and one-half of the 25 magnesium stearate, passed through a #1Z screen in Model "J" Fitzmill with kniver forward, and slugged.

The slugs were passed through a #2A plate in a Model "D" Fitzmill at slow speed with knives forward and the remaining magnesium stearate was added. The mixture was mixed and compressed.

Example 25

A tablet was formulated in the same manner as in Example 24 except that (4E,ga,l 3E,l 5R,l 6R)-7,16difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-l-oic acid methyl ester was the active ingredient.

Example 26

A capsule was prepared containing the following ingredients:

Per tablet (5Z,9a,l 3E,1 5R,1 6R)-7,16-difluoro-6,9 epoxy-1 5,-hydroxy-prosta-5,13-dien-1 -oic acid sodium salt 200 mg 40 Dicalcium phosphate dihydrate, unmilled 235 mg Corn Starch 70 mg FD & C Yellow Y15 Aluminum Lake 25% 2 mg Durkee Duratex 25 mg Calcium Stearate 3 mg 45 535 mg Hydrogenated cotton seed oil (fully saturated) All of the above ingredients were mixed until thoroughly blended in a suitable size container. The powder was filled in to #2, two-piece, hard-shell gelatin capsules to an approximately fill weight of 350 mg using a 50 capsulating machine.

Example27

Acapsulewas prepared bythe procedure of example 24 exceptthat (4E,9ot,13E, 15R,16R)-7,16-difluoro-6,9- epoxy-1 5-hydroxy-prosta-4,13-dien-l-oic acid methyl ester was the active ingredient.

--- GB 2 158 822 A - is Example 28

3,3aS,4,5,6,6aS-Hexahydro-3-fl uoro-4R-[4,4-dimethyl-3R-(2tetrahydropyranyloxy)-1 trans-octenyl]-5R methyl-21-1-cyclopenta [b1fu ran-2-one To a solution of diisopropyla mine in 9 ml of THF (tetrahydrofuran) cooled to 00-50C, was added dropwise 1.32 ml of a 2.2M solution of n-butyl lithium in hexane. The mixture was stirred for 5 min and cooled to -40'C 5 with a dry ice acetone bath. A solution of 1 g of 3,3aR,4,5,6,-6aS- hexahydro-4R-[4,4-dimethyl-3R(2-tetrahydropyranyloxy)-itrans-octenyl]-5R-methyl-2H-cyclopenta[b]furan2-o ne in 6 ml of THF (tetrahydro furna) was added ropwise over 1 minute and stirred at -45for 5 min. Trimethylchlorosilane (4.26 ml) was then added and the mixture stirred at -40'C for 5 min. The mixture was then allowed to warm to O'C and the solvent removed under high vacuum. Diethyl ether (5 ml) was added to the residue and the cold mixture filtered through a sintered glass funnel. The solvent was then removed under high vacuum (ice bath) and the residue dissolved in 10 ml of CH2CI2. To the solution at OOC was then added 530 mg of potassium bicarbonate followed by 429 mg of xenon difluoride. After the gas evolution ceased, the mixture was stirred for an additional 15 min and diluted with 50 ml of CH2CI2. The solution was then washed with 50 ml of H20 +2 x 50 ml of brine. The aqueous phase was separated and back washed with 50 ml of CH202. The organic layers were combined, dried (MgS04) and the solvents removed under reduced pressure to give 0.95 g of crude product. chromatography on 50 g of silica gel afforded 300 mg of 3,3aS,4, 5,6,6aS-hexahydro-3-fluoro-4R-[4,- 4-dimethyl-3R-(2-tetrahydropyranyloxy)1 -trans-octenyll-5R-methyl-2H- cyclopenta[b]furan.

Example 29

3,3aS,4,5,6,6aS-Hexahydro-3-fluoro-4R-[4,4-dimethyi-3R-(2tetrahydropyranylo xy)-1-trans-octenyll5R-methyi-2H-eyclopenta[blfuran-2-ol By the procedure of Example 6,3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[4,4- dimethy]-3R-(2tetrahydropyranyioxy)-1-trans-octenyll-5R-methyl-2H-cyclopenta[blfuran-2one was converted to 3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[4,4-dimethyi-3R-(2tetrahydropyranylo xy)-1-trans-octenyll5R-methyl-2H-cyclopenta[blfuran-2-ol.

Example 30

1111,16,1 6-Tri methyl-7-fi u oro-1 5R-(2-tetra hyd ropyranyloxy)-9S-hyd roxyprosta-cis-5-trans-1 3-dienoic acid methyl ester By the procedure of Example 7,3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[4,4dimethyl-3R-(2-tetra- hyd ropyranyloxy)-1 -tra ns-octenyl]5R-methy]-2H-eyclopenta [fu ra n-2-ol was converted to 11 R,1 6,16 trimethyl-741 uo ro-1 5R-(2-tetra-hyd ro pyranyl oxy)-9S-hyd roxyprosta- cis-5-trans-l 3-dienoic acid methyl ester.

Example 31 (9S,l 113,1 3E,l 5R)-1 1,1 6,16-Trimethyl-l 5-(2-tetrahydro-pyranyloxy)-6, 9-epoxy-7fluoro-5-iodo-prosta-1 3 en-1 -oic acid methyl ester By the procedure of Example 8,11 R,1 6,16-trimethyi-7-fluoro-1 5R-(2- tetrahydropyranyloxy)-9S hydroxyprosta-cis-5-trans-13-dienoic acid methyl ester was converted to (9S,l 1R,13E,15R)-1 1,16,16trimethyi-15-(2-tetrahydro-pyranyloxy)-6,9-epoxy-7-fluoro-5-lodo-prosta13-e n-l-ioc Example 32 (9S.1 1 R,1 3E,l 5R)-1 1,1 6,16-Trimethyl-l 5-hydroxy-6,9-epoxy-7-fluoro- 5-iodo-prosta-1 3-en-1 -oic acid methyl ester Bythe procedureof Example 9,(9S,11R,13E,15R)-11,16,16-trimethyl-15-(2- tetrahydropyranyioxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-l-oic acid methyl ester was converted to (9S,11R,13E,15R) 11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-loic acid methyl ester.

16 GB 2 158 822 A 16 Example 33 (5Z,9S,l 1 R,1 3E,l 513)-11,1 6,16-trimethyl-l 5-hydroxy-6,9-epoxy- 7fluoro-prosta-5,13-dien-1 -oic acid methyl es ter and (4E,9S,l 1 R,1 5R)-1 1,1 6,16-trimethyi-l 5-hydroxy-6,9-epoxy-7- fi uoro-4,13-dien-1 -oic acid methyl ester By the procedure of Example 10 (9S,l 1 R,1 3E,l 5R)-1 1,1 6,16-trimethyl- l 5-hydroxy-6,9-epoxy 7-fluoro-5-iodo-prosta-1 3-en-1 -oic acid methyl ester was converted to a mixture which was separated by the 5 procedure of Example 10 to (5Z,9S,l 1 R,1 3E,l 5R)-1 1,1 6,16-trimethyl-l 5-hydroxy-6,9-epoxy-7-fi uoro-prosta 5,13-dien-1 -oic acid methyl ester.

Calc. for C24H39F04 C 70.21, H 9.57, F 4.63 Found C 70.00, H 9.44, F 4.49 10 ir 3615,1733,1694 cm-l; ultraviolet X. max 213 nm ( E= 12000) and (4E,9S, l 1 R,1 511)-11,1 6,16-trimethyi-l 5-hydroxy-6,9-epoxy-7-fluoro-4,13-dien- 1 -oic acid methyl ester, Calc. C 70.21, H 9.57, F 4.63 15 Found C70.19, H 9.52, F 4.85 ir 3615,1735,1670 cm -1.

Example 34 (5Z, 9S,l 1 11,13E,l 5R)-1 1,1 6,16-Trimethyl-l 5-hydroxy-6,9-epoxy-7- fluoro-prosta-5,13-dien-l-oic acid sodium salt By the procedure of Example 11, (5Z,9S,l 1 IR,13E,l 511)-11,1 6,16trimethyl-l 5-hydroxy-6,9-epoxy-7-fluoro prosta-5,13-dien-1 -oic acid methyl ester was converted to (R,9S,l 1 RJ3E, l 5R)-1 1,16,16-trimethyl-l 5 hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-l-oic acid sodium salt.

Example 35

3,3aS,4,5,6,6aS-Hexahydr'o-3-fluoro-4R-[3S-(2-tetrahydro-pyranyloxy)-1trans -octenyll-5R-(2-tetrahydro- pyranyloxy)-2H-cyclopenta[b]furan-2-one By the procedure of Example 28,3,3aR,4,5,6,6aS-hexahydro-4R-[3S-(2tetrahydropyranyloxy)-1-transoctenyll-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[blfuran-2-one was converted to 3,3aS,4,5,6,6aS hexahydro-3-fluoro-4R-[3S-(2-tetrahydropyranyloxy)l-trans-octenyll-5R-(2tet rahydropyranyloxy)-2H- cyclopenta[blfuran-2-one.

Example 36

3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[3S-(2-tetrahydropyranyloxy)-ltrans-o cetenyll-5R-(2-tetrahydro- pyranyloxy)-2H-cyclopenta[b]furan-2-one By the procedure of Example 6,3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[3S(2tetrahydro- pyranyloxy)-1-trans-octenyll-5R-(2-tetrahydropyranyloxy)-2Hcyclopenta[blfur oro-2-one was con vertedto3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[3S-(2tetrahydropyranyioxy)-1 -trans-octenyll-5R-(2tetrahydropyranyloxy)-2H-cyclopenta[blfuran-2-ol.

Example 37

11R,15S-Di-(2-tetrahydropyranyloxy)-7-fluoro-9S-hydroxy-prosta-cis-5trans-1 3-dienoic acid methyl ester By the procedure of Example 7, 3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[3S- (2-tetrahydropyranyloxy)-1-transoctenyll-5R-(2-tetrahydropyranyloxy)-2Hcyclopenta[b lfuran-2-of was converted to 11R,15S-di-(2-tetrahydropyranyloxy)-7-fluoro-9S-hydroxy-prosta-cis-5trans-1 3-dienoic acid methyl ester.

Example 38 (9SA 1RA3EA5SM 1,15-Di-(2-tetrahydropyranyloxy)-6,9-epoxy-7-fluoro-5-iodoprosta-13-en-l-io c acid 50 methyl ester Bythe procedure of Example 8, 11 R,15R-di-(2-tetrahydropyranytoxy)-7- fluoro-9S-hydroxyprosta-cis-5trans-13-dienolc acid methyl ester was converted to (9S,l 1 R,-13E,15S)-1 1,15-di-(2-tetrahydropyranyloxy)- 6,9-epoxy-7-fluoro-5-iodo-prosta-1 3-en-1 -oic acid methyl ester.

Example 39 (9S,l 1 R,1 3E,l 5S)-1 1,1 5-Dihydroxy-6,9-epoxy-7-fi uoro-5-iodo-prosta- 1 3-en-1 -oic acid methyl ester By the procedu re of Exa mple 9, (9S,l 1 R, 1 3E,l 5S)-1 1,1 5-di-(2- tetrahydropyra nyloxy)-6,9-epoxy-7-fi uoro-5 -Ci iodo-prosta-13-en-l-oic acid methyl ester was converted to (9S,l 1 RJ3E,l 5S)-1 1,1 5-dihydroxy-6,9-epoxy-76(.) fiuoro-5-iodo-prosta-1 3-en-1 -oic acid methyl ester. 17 - GB 2 158 822 A 17 Example 40 (5Z,9S,l 1 R,1 3E,l 5S)-1 1,1

5-Dihydroxy-6,9-epoxy-7-fluoro- prosta-5,13-dien-1 -oic acid methyl ester and (4E,9S,l 1 R,1 511)-11,1 5- dihydroxy-6,9-epoxy-7-fluoro-4,13-dien-1 -oic acid methyl ester By the procedure of Example 10 (9S,l 1 R,1 3E,l 5S)-1 1,1 5-dihydroxy-6,9- epoxy-7-fluoro-5-iodo-prosta-1 3- en-1 -oic acid methyl ester was converted to a mixture which was separated in accordance with the procedure of Example 10 to produce (5Z, 9S,l 1 R,1 3E,l 5S)-1 1,1 5-dihyd roxy-6,9-epoxy-7-fluoro-prosta-5,13dien- 1 -oic acid methyl ester and (4E,9S,l 113,1 5S)-1 1,1 5-dihydroxy-6,9epoxy-7-fluoro-4,13-dien-1 -oic acid methyl ester.

Example41 (5Z,9S,11R,13E,15S)-1 1,15-Dihydroxy-6,9-epoxy-7-fluoro-prosta5,13-dien-l-oic acid sodium salt By the procedure of Example 11, (5Z,9S,l 1 R,13E,15S)-dihydroxy-6,9-epoxy- 7-fluoro-prosta-5,13-dien-l-oic acid methyl ester was converted to (5Z,9S, l 1 R,13E,l 5S)-1 1,1 5-dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13dien-l- oic acid sodium salt.

@) indicates a registered Trade Mark.

Claims

CLAIM

1. Compounds of the formula 20 0 H 9I-I,.CH.-CH -CH -OEt CJ 2 2 25 rc _ -7 --1 H=CH-CH -C -CH 2-C"2-CI"2-'CH3 R-11 1 1 OR 41 a2 30 wherein R % lower alkyl; R" is hydrogen, methyl or -OR 41, R2 is methyl, hydrogen or fluoro; R 21 is fluoro, hydrogen, trifluoromethyl or methyl; and X is halogen; -OR 41 is hydroxy or forms a hydrolyzable ether protecting group with the proviso that when R 21 is trifluoromethyl; R 2 is hydrogen or methyl; their optical 35 antipodes and racemates.

Printed in the UK for HMSO, D8818935, 9185, 7102. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.