GB1589200A - Prostaglandin derivatives - Google Patents

Description

(54) IMPROVEMENTS IN OR RELATING TO PROSTAGLANDIN DERIVATIVES (71) We, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT., a body corporate organised under the laws of Hungary, of 1-5 To utca, Budapest IV, Hungary, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to a process for the preparation of 5(Z)-9-deoxy-6,9,- epoxy-A5-PGF1a - termed hereinafter prostacyclin -- and certain compounds of analogous structure. These compounds can be represented by the following general formula I

wherein R1 is hydrogen, alkyl optionally substituted with aryl, amino, hydroxyl or halogen or a pharmaceutically acceptable organic or inorganic cation; R2 is hydrogen, hydroxyl or protected hydroxyl; R3 represents hydrogen or a lower alkyl; R4 is hydrogen or a hydroxyl protecting group; and R5 stands for a straight or branched chained alkyl group of which the carbon chain may optionally be interrupted by a hetero atom, or an aralkyl group of which the aryl moiety may optionally be substituted.

If R1 stands for an alkyl optionally substituted with aryl, amino, hydroxyl or halogen, it generally contains 1 to 10 carbon atoms in the alkyl chain. R1 alkyl preferably contains 1 to 6, more preferably 1 to 4 carbon atoms and may be straight or branched chained. Especially preferred R1 alkyls are the following: methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tertibutyl. The aryl substituents of these alkyl groups may be substituted or unsubstituted and preferably contain 6 to 10 carbon atoms. They are preferably unsubstituted. Some representatives of these groups are substituted and unsubstituted phenyl and 1- and 2-naphthyl.

The R1 alkyl groups, if desired, may bear one or more of the aryl groups defined above and/or amino and/or hydroxyl groups and/or halogens, in various positions.

To improve water-solubility it is advantageous if R1 stands for a pharmaceutically acceptable organic or inorganic cation. Pharmaceutically acceptable organic cations may be derived for example from primary, secondary, or tertiary amines, or quaternary ammonium hydroxides; while preferred inorganic cations are the alkali metal and alkaline earth metal cations. Typical cations used herein are: sodium, lithium, potassium, ammonium, tris(hydroxymethyl)methylammonium, piperidinium, pyrrolidinium and morpholinium cations.

The protecting group of the hydroxyl in the definition of R2 and the hydroxyl protecting group in the definition of R4 may be the same or different. It is preferred to choose the same groups. For this purpose all protecting groups conventional in the chemistry of prostaglandins may be used. Examples of such protecting groups are 2-tetrahydropyranyl: trialkylsilyl; alkanoyl, such as lower alkanoyl, e.g. acetyl; aroyl such as benzoyl, p-phenylbenzoyl; substituted carbamoyl, such as methylcarbamoyl, ethylcarbamoyl, phenylcartamoyl and p-phenylphenylcarbamoyl.

With regard to R3 the lower alkyls contain 1 to 6, preferably 1 to 4 carbon atoms, and may be straight or branched chained. Typical examples are methyl, ethyl, n- and isoWpropyl, n-, iso-, sec- and tert-butyl, pentyl and hexyl.

The straight or branched chained alkyl group optionally containing also a hetero atom in the definition of R2 contains e.g. 1 to 10, preferably 1 to 6 carbon atoms.

Examples of these alkyl groups are decyl, nonyl, heptyl, hexyl, pentyl, butyl and propyl, as well as methyl and ethyl. The optional heteroatom in the carbon chain preferably is oxygen or nitrogen (in form of an -NH-group). The aryl moieties of the R5 aralkyl groups preferably have 6 to 10 carbon atoms and are optionally substituted. It is preferred, however, that these aryls are unsubstituted. Typical examples are phenyl and 1- and 2-naphthyl. The optional substituents of the above aryl groups preferably are halogens and lower alkyl and/or alkoxy groups. A further preferred substituent is trifluoromethyl.

The compound of the general formula I in which R2 is hydroxyl, R3 and R4 are hydrogen and R2 is n-pentyl corresponds to PGX (or PGI2), if R1 is hydrogen, and to the lower alkyl esters and pharmaceutically acceptable salts of same, if R1 represents a lower alkyl group and a pharmaceutically acceptable cation, respectively.

The mode of action exerted by prostaglandins on the blood coagulation has only recently become known (Chemical and Engineering News, December 20, 1976, page 17) as a result or investigations of the various biochemical activities of prostaglandins.

It has been found that prostaglandin endoperoxide, which is a common precursor of the biosynthesis of various natural prostaglandins in mammalian tissues is subject to two different biochemical transformations. On the one hand it is transformed into a very active substance causing blood coagulation, called thromboxane A2 under the influence of an enzyme produced by thrombocytes; on the other hand it is transformed into another highly efficient substance inhibiting blood coagulation. The latter compound proved to be 5(Z)-9-deoxy-6,9,-epoxyia 5-PGF,. and received the name "prostacyclin" (PGX).

Prostacyclin has already been prepared by a biochemical synthesis by means of an enzyme system separated from mammalian aorta tissues and its biological activity has been proved also in vitro. It has been found that this compound prevents thrombocyte aggregation induced by adenosine diphosphate [Prostaglandins, Vol. 12., No. 5., 685 (1976)].

According to one aspect of the invention the compounds of the general formula I are prepared starting from a PGF2,l derivative having the general formula II

OH I I * 2 wherein p #ePI#;p5cooR8 (11) R3 and Rs are as defined above; 'OR8 R6 is hydrogen, alkyl optionally substituted with aryl, amino, hydroxyl or halogen, a pharmaceutically acceptable organic or inorganic cation or a hydroxyl protecting group; R7 is hydrogen, hydroxyl or protected hydroxyl; and RS stands for hydrogen or a hydroxyl protecting group.

The protecting group of the hydroxyl Rr and the hydroxyl protecting groups in the definition of R6 and RB may be one of the protecting groups defined with respect to R2 and R4.

The definition of R6 - except hydroxyl protecting group - is identical with the definition given for R1 hereinbefore.

Starting compounds of the general formula II are readily available. Compound, for instance, in which R3, R6 and R8 are hydrogen, R7 is hydroxyl and R" stands for an n-pentyl group (PGF,,) and the salts thereof are commercially available products and their esters (e.g. lower alkyl esters) may be prepared by numerous known methods.

According to the invention compounds having the general formula II are initially treated with brominating agents in an inert solvent or in the absence of any solvent.

In this reaction all suitable brominating agents known in the art may be employed.

Suitable brominating agents are for example bromine, or a complex thereof, preferably pyridinium hydrobromide perbromide, various known N-bromo reagents such as 1,3 diibromo-5,5-dimethylhydantoin, N-bromoacetamide, N-bro:nosuccinimide or the reagent systems supplying tribromide (Br,-) ions. The bromination may be performed in an acid and alkaline medium as well. Suitable solvents are all inert, protic or aprotic solvents generally used in organic chemistry. Typical examples of protic solvents are water, alkanols, organic acids; and suitable aprotic solvents include acetonitrile, dimethylformamide, dimethyl sulphoxide, different chlorinated hydro carbons and ether-type organic solvents.

The reaction can be carried out also in a mixture of the above solvents. Depending on the activity of the brominating agent employed, the reaction can be accomplished between - 780C and +100 C. It is preferred, however, if the reaction is performed at room temperature. The reaction may be monitored by thin layer chromatography.

The brominating agents listed above attack at the L cis-dourble bond of the compound of the general formula II treated regioselectively, when a corresponding bromonium ion is formed. The positive ions formed are stabilized with the active participation of the hydroxyl in the 9-position, when compounds having the general formula III

are obtained. In the general formula III R3, Ra, R6, K7 and R3 have the same meaning as defined above, and X stands for bromine.

The reaction of the compounds having the general formula II with brominating agents affords two isomeric compounds of the general formula III, which are epimers with respect to the configuration of the hydrogen in the 6-position, following the atom numbering of prostanoic acid (exouendo isomers). Depending on the brominating agent used and on the reaction conditions the molar ratio of the exo- and endo-compounds of the general formula III obtained may vary between 1:1 and 1:10. If desired, these isomers may be separated, for example by column chromatography on silica gel. Especially the esters of the compounds having the general formula III may be advantageously chromatographed, i.e. compounds in which R6 stands for an alkyl optionally substituted with aryl, amino, hydroxyl or halogen, or a hydroxyl protecting group.

If in the reaction according to the invention the PGF2a or its salts are used as starting compounds and subjected to bromination, the acid or salt having the general formula III obtained may be esterified by methods known per se. When a methyl ester having the general formula III (R6 = methyl) is desired, esterification is most advantageously accomplished by the interaction of the acid or salt and diazomethane in a diethyl ether solution.

Compounds of the general formula I are prepared from the compounds of the general formula III by the elimination of hydrogen bromide by a method known per se. This step alone forms another aspect of our invention. Dehydrobromination is advantageously carried out by treating the compounds having the general formula III with an inorganic or organic base, if desired with heating. According to a preferred embodiment of this reaction step compounds of the general formula Ill are reacted with alkali metal alkoxides in alkanols, or heated in the presence of tertiary aliphatic or aromatic nitrogen-containing bases, e.g. pyridine, collidine, picoline or triethylamine. Other bases suitable for the eliminaflon of hydrogen bromide, e.g. diazabicycloundecane (DBU), diazabicyclononane (DBN) may also be used in suitable solvents.

It has been found that it is especially preferred to perform the elimination with weaker bases such as potassium carbonate, in solvents such as alkanols, since the side-reactions can be in this way best avoided. The dehydrobromination is preferably carried out between room temperature and 200"C.

The velocity of the dehydrobromination of the endo-compound having the general formula IBI is considerably higher than that of the corresponding exo-compound, but the product obtained is in both cases the 5(Z)-isomenc compound encompassed by the general formula I.

The compounds having the general formula I obtained are isolated from the reaction mixture by conventional means. Since the products of the general formula I contain a very acid-labile enol-ether structure it is preferred to store them at low temperatures, after the addition of a small portion of a base, expediently sodium carbonate. When the product is a compound of general formula I wherein R1 and/or R4 is a protecting group and/or R2 is a protected hydroxyl group, said protecting groups) may be removed.

The new intermediates of the general formula III are also within the scope of this invention.

The compounds of the general formula I prepared according to the invention are useful to inhibit thrombocyte aggregation induced for example by adenosine diphosphate, and to remove or prevent the formation of thrombi in mammals, including man. Suitable concentration for this use is 0.2 to 20 ng/ml.

The aggregation inhibiting and thrombus removing effect of the compounds having the general formula I was demonstrated in the following test. Test compound: Compound of the general formula I, in which Ra and R4 are hydrogen, R2 is hydroxyl, R1 is methyl, R5 is n-pentyl [PGX (PGI2) methyl ester], prepared for example from PGF, methylester.

Tests were carried out on human plasma rich in thrombocytes (PRP). 1 ml. of the above plasma was tested in a Born aggregometer.

1) Aggregation in the control plasma was induced by 1 X 10-5 moles of adenosine diphosphate (ADP). The measured aggregation as a function of time is represented by the curve " so+" in Figure I of the accompanying drawings.

2) 5 to 20 ng of PGX methyl ester were dissolved in TRIS - hydrochloric acid buffer (pH = 7.5), 1 ml. of PRP are added and the mixture was incubated at room temperature for 1.5 minutes. The mixture was then poured into the aggregometer and aggregation induced with 1 X 10-5 moles of ADP. We found that aggregation was inhibited. The aggregation as a function of time is represented by the curve "x--xx--xx-x-x" in Figure I.

3) The aggregation induced by ADP could be reversed by the addition of 20 ng of PGX methylester to an extent of 50%. The results of this test are illustrated by the curve "X..X..X..X" in Figure I.

The invention is more fully illustrated in the following non-limiting Examples.

Example 1.

To the solution of 290 mg. (0.82 mmoles) of PGF, in 2 mi. of acetonitrile 140 mg. (0.32 moles) of 1,3-dibromo-5,5-dimethylhydantoin are added with stirring at 00E. The reaction terminates in 5 minutes. The molar ratio of the 6-endo-6,9a- epoxy-5α-bromo-11α,15α-dihydroxy-13(E)-prostenic acid to 6-exo-6,9α-epoxy-5α- bromo-11α,15α-dihydroxy-13(E)-prostenic acid in the obtained mixture is about 5:1 by weight, and the above main products are accompanied with minimum amounts of other impurities having either smaller or higher polarity. Thin layer chromatography carried out on silica gel with a 20: 10: 1 v/v/v mixture of benzene/dioxane/ acetic acid gave the following results: Rt for the endo-compound = 0.22; Rt for the exoWcompound = 0.27.

The solvent is evaporated and the crude product weighing 430 mg. is subjected to column chromatography using a 20:5:1 v/v/v mixture of chloroform/dioxane/ acetic acid and a silica gel column. The following products are obtained: 31.1 rug. of pure exo-compound, 94.5 mg. of a mixture of the pure exo- and endo-compounds, 102 mg. of the pure endo-c ompound.

Esterification of the pure isomers and the mixture thereof with diazomethane at 0 C in diethyl ether affords the corresponding methyl ester with an approximately quantitative yield.

Rt for the methyl ester of the endo-compound = 0.35; Rf for the methyl ester of the exocompound = 0.41.

Example 2.

To the solution of 175 mg. (0.49 moles) of PGF2, in 5 ml. of dichloromethane 141 rug. (0.55 mmoles) of N+bromocamphorimide are added at room temperature with stirring. The reaction terminates in 3 hours. The molar ratio of the 6-endo-6,9 epoxy-5α-bromo-11α,15α-dihydroxy-13(E)-prostenic acid to the 6-exo-6,9zz-epoxy-5e bromo-11α,15α-dihydroxy-13(E)-prostenic acid in the obtained mixture is about 2:1 by weight. The solvent is eliminated and 320 mg. of the crude product obtained is purified on a chroinatographic column as described in the Example 1. The following products are obtained: 45 mg. of the exocompound; 62 mg. of a mixture of the exo- and endo-compounds; 60 mg. of the endo-compound.

The Kf values for the above products are identical with the data given in the Example 1.

Example 3.

973 rug. (2.74 moles) of PGF2a are dissolved in 10 ml. of dichloromethane.

535 mg. (3.01 mmoles) of N bromosuccinimide in 5 ml. of dichloromethane are then added with stirring. The reaction terminates in 80 to 90 minutes. The molar ratio d the endo- and exocompounds in the reaction mixture obtained is about 4:1 by weight. Subjecting the mixture to column chromatography as described in the Example 1 the following products are obtained: 131 rug. of the exo-compound; 578 mg. of a mixture of the exo- and endo-compounds; 293 mg. of the endo-compound.

The Rt values of the above products are identical with the data given in the Example 1.

Example 4.

251 mg. of PGF2, are dissolved in a mixture of 10 ml. of acetic acid and 10 ml.

of water and a solution of 1 g. of potassium bromide in 5 ml. of water and thereafter 40 mg. of potassium bromate in 5 ml. of water are added with stirring. The reaction terminates in 3 to 4 hours.

The reaction mixture is shaken with 20 ml. of diethyl ether, the diethyl ether phase washed with 0.5 ml. of 10% w/v sodium thiosulphate solution and sus sequently with four 5-ml. portions of water and dried over magnesium sulphate at 0 C, in darkness. The diethyl ether phase is filtered off, evaporated and the residue relieved of the traces of acetic acid at a pressure of 1 mmHg. to constant weight.

342 rug. of a crude product are obtained, which is then purified as described in the Example 1 and subjected to column chromatography. The following fractions are obtained: 65 mg. of the exo-compound; 103 mg. of a mixture of the exo- and endocompound; 72 mg. of the endowcompound.

The Rt values for the above products are identical with the data given in the Example 1.

Example 5.

278 mg. (0.62 mmole) of 6,9α-epoxy-5-bromo-11α,15α-dihydroxy-13(E)-prostenic acid methyl ester are dissolved in 5 ml. of abs ethanol and 3 ml. of a 0.4 M/litre ethanolic potassium ethoxide solution are added. The solution obtained is stirred at 700C for 6 hours, the ethanol is eliminated, 50 ml. of diethyl ether and 20 ml.

of water are added to the residue at 0 C and the mixture is shaken. The diethyl ether phase is then separated and dried over anhydrous potassium carbonate. After evaporation of the ether 145 rug. (64%) of 5(Z)-9-deoxy-6,9α-epoxy-#5-PGF1a methyl ester (PGX methyl ester) are obtained as an oily residue.

NMR spectrum: 5.45 (2H, m); 4.55 (1H, m) ppm IR spectrum: Vmax = 1730 and 1765 curl.

Thin layer chromatography carried out on a silica gel plate pre-run with a triethyl amine/diethyl ether mixture, using 1:1 v/v mixture of acetone and ethyl acetate shows a spot corresponding to the product at RX = 0.58.

Example 6.

220 mg. (0.51 mmole) of 6,9epoxy5romo-11α,15α-dihydroxy-13(E)-prostenic acid methyl ester are dissolved in 10 ml. of abs. tert-butanol. Thereafter 340 mg.

(3.1 mmoles) of potassium tert-butoxide are added to the solution under argon atmosphere. The solution is stirred at 60 C for 4 hours and the reaction mixture is further treated as described in the Example 5. 141 mg. (75%) of PGX methyl ester are obtained. Physical characteristics of the product are identical with those of the product of the Example.

Example 7.

233 mg. (0.54 mmole) of 6,9α-epoxy-5-bromo-11α,15α-dihydroxy-13(E)-prostenic acid methyl ester are dissolved in 10 ml of abs. ethanol. 1 g. of anhydrous potassium carbonate is then added to the solution and the suspension formed is stirred at 700C for 2 hours. The reaction mixture is then treated as described in the Example 5.

137 mg. (72%) of PGX methyl ester are obtained. Physical characteristics of the product are identical with those of the product of the Example 5.

WHAT WE CLAIM IS: 1. Process for the preparation of compounds of the general formula I

wherein R1 is hydrogen, alkyl optionally substituted with aryl, amino, hydroxyl or halogen, or a pharmaceutically acceptable organic or inorganic cation; R2 is hydrogen, hydroxyl or protected hydroxyl; R3 represents hydrogen or a lower alkyl; R4 is hydrogen or a hydroxyl protecting group; and R5 stands for a straight or branched chained alkyl group of which the carbon chain may optionally be interrupted by a hetero atom, or an aralkyl group of which the aryl moiety may optionally be substituted, which comprises reacting a compound of the general formula II

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (20)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   Example 5.

   278 mg. (0.62 mmole) of 6,9α-epoxy-5-bromo-11α,15α-dihydroxy-13(E)-prostenic acid methyl ester are dissolved in 5 ml. of abs ethanol and 3 ml. of a 0.4 M/litre ethanolic potassium ethoxide solution are added. The solution obtained is stirred at 700C for 6 hours, the ethanol is eliminated, 50 ml. of diethyl ether and 20 ml.

   of water are added to the residue at 0 C and the mixture is shaken. The diethyl ether phase is then separated and dried over anhydrous potassium carbonate. After evaporation of the ether 145 rug. (64%) of 5(Z)-9-deoxy-6,9α-epoxy-#5-PGF1a methyl ester (PGX methyl ester) are obtained as an oily residue.

   NMR spectrum: 5.45 (2H, m); 4.55 (1H, m) ppm IR spectrum: Vmax = 1730 and 1765 curl.

   Thin layer chromatography carried out on a silica gel plate pre-run with a triethyl amine/diethyl ether mixture, using 1:1 v/v mixture of acetone and ethyl acetate shows a spot corresponding to the product at RX = 0.58.

   Example 6.

   220 mg. (0.51 mmole) of 6,9epoxy5romo-11α,15α-dihydroxy-13(E)-prostenic acid methyl ester are dissolved in 10 ml. of abs. tert-butanol. Thereafter 340 mg.

   (3.1 mmoles) of potassium tert-butoxide are added to the solution under argon atmosphere. The solution is stirred at 60 C for 4 hours and the reaction mixture is further treated as described in the Example 5. 141 mg. (75%) of PGX methyl ester are obtained. Physical characteristics of the product are identical with those of the product of the Example.

   Example 7.

   233 mg. (0.54 mmole) of 6,9α-epoxy-5-bromo-11α,15α-dihydroxy-13(E)-prostenic acid methyl ester are dissolved in 10 ml of abs. ethanol. 1 g. of anhydrous potassium carbonate is then added to the solution and the suspension formed is stirred at 700C for 2 hours. The reaction mixture is then treated as described in the Example 5.

   137 mg. (72%) of PGX methyl ester are obtained. Physical characteristics of the product are identical with those of the product of the Example 5.

   WHAT WE CLAIM IS: 1. Process for the preparation of compounds of the general formula I

   wherein R1 is hydrogen, alkyl optionally substituted with aryl, amino, hydroxyl or halogen, or a pharmaceutically acceptable organic or inorganic cation; R2 is hydrogen, hydroxyl or protected hydroxyl; R3 represents hydrogen or a lower alkyl; R4 is hydrogen or a hydroxyl protecting group; and R5 stands for a straight or branched chained alkyl group of which the carbon chain may optionally be interrupted by a hetero atom, or an aralkyl group of which the aryl moiety may optionally be substituted, which comprises reacting a compound of the general formula II

   wherein R3 and R5 are as defined above; Rg is hydrogen, alkyl optionally substituted with aryl, amino, hydroxyl or halogen, a pharmaceutically acceptable organic or inorganic cation or a hydroxyl protecting group; R7 is hydrogen, hydroxyl or protected hydroxyl; and R8 stands for hydrogen or a hydroxyl protecting group, with a brominating agent and eliminating hydrogen bromide by a method known per se from the compound of the general formula III so obtained.

   wherein R3, R5, R6, R7 and K8 are as defined above and X represents bromine.
2. 2. A process according to claim 1 wherein bromine, a bromine-containing plex, an Nwbromo reagent or reagents supplying tribromide (Br,-) ions are used as brominating agent.
3. 3. A process according to claim 2 wherein a pyridinium hydrobromide perbromide 1,3-dibromo-5,5 -dimethylhydantoin, N-bromoacetamide or N-bromosuccinimide is used as brominating agent.
4. 4. A process according to any of the preceding claims wherein bromination is performed in an inert solvent.
5. 5. A process for the preparation of compounds of the general formula I as defined in claim 1 which comprises eliminating hydrogen bromide by a method known per se from a compound of general formula III as defined in claim 1.
6. 6. A process according to any of the preceding claims wherein said hydrogen bromide is eliminated by reacting said comopund of general formula III with an organic or inorganic base.
7. 7. A process according to claim 6 wherein said compound of the general formula III is reacted with an alkali metal alhoxide in an alkanol, or with a tertiary aliphatic or aromatic nitrogen-containing base, optionally in the presence of a solvent.
8. 8. A process according to claim 7 wherein said nitrogen-containing base is pyridine, picoline, collidine or triethylamine.
9. 9. A process according to claim 6 wherein the elimination of hydrogen bromide is performed with an alkali metal carbonate in a solvent at a temperature between room temperature and 2000C.
10. 10. A process according to claim 9 wherein potassium carbonate in an alkanol is used to eliminate said hydrogen bromide.
11. 11. A process according to any of the preceding claims wherein, prior to elimina tion of hydrogen bromide from said compound of general formula III, isomers of said compound are separated.
12. 12. A process according to any of the preceding claims wherein the product is a compound of general formula I wherein R' and/or R4 is a protecting group and/or R2 is a protected hydroxyl group and wherein said protecting group(s) are removed.
13. 13. A process according to any of the preceding claims wherein the product of general formula I is transformed into another compound of general formula I wherein Ri is a pharmaceutically acceptable organic or inorganic cation or alkyl optionally substituted with aryl, amino, hydroxy or halogen, by methods known per se, or wherein an ester of general formula I is hydrolysed by methods known per se.
14. 14. A process according to any of the preceding claims wherein R1 is selected from hydrogen, alkyl of 16 carbon atoms or a pharmaceutically acceptable organic or inorganic cation, and R5 is alkyl of 1-6 carbon atoms.
15. 15. A process according to any of claims 1 to 13 in which compounds of the general formula I, wherein R3 and R4 are hydrogen, R is hydrogen or lower alkyl, R5 is npentyl and R2 is hydroxyl are prepared starting from PGF2a or from lower alkyl esters thereof.
16. 16. A process according to any of claims 1 to 13 or 15 in which compounds of the general formula I, wherein R1 is lower alkyl and R2, R3, R4 and Rs are as defined in claim 1, are prepared by esterifying the intermediate compounds of the general formula III obtained, in which R3, Rs, R7, K8 and X are as defined in claim 1, and R6 is hydrogen, with esterifying agents known per se, and separating the esters obtained beforc the hydrogen bromide elimination.
17. 17. A process according to claim 1, substantially as hereinbefore described with reference to the Examples.
18. 18. A process according to claim 5, substantially as hereinbefore described with reference to any of Examples 5-7.
19. 19. Compounds of the general formula III

    wherein R5, R3, R6, Rt, R8 and X are as defined in claim 1..
20. 20. 6,9a-Epoxy-5ebrom > 11e,15edihydroxy-13(E)-prostenic acid and pharmaceutically acceptable salts thereof.