IE46864B1

IE46864B1 - Esters of prostan-1-ol derivatives,methods for their preparation and compositions containing them

Info

Publication number: IE46864B1
Application number: IE671/78A
Authority: IE
Original assignee: Schering Ag
Priority date: 1977-04-05
Filing date: 1978-04-05
Publication date: 1983-10-19
Also published as: DE2715838A1; GB1601994A; FR2386523A1; FR2386523B1; CH638773A5; LU79369A1; IE780671L; IT7821951A0; NL7803415A; BE865705A; JPS53124238A; DK150778A; IT1093506B

Abstract

Prostane derivatives have the following formula in which the substituents are defined in Claim 1. The novel compounds are prepared by appropriately esterifying corresponding prostan-1-ols in which free OH groups, with the exception of the 1-OH group, have optional intermediate protection. A further process is based on the reaction of the prostan-1-ols with isocyanates or with carbamoyl chlorides. The novel prostane derivatives are used in medicaments. They can be used for inducing an abortion, for cycle control, for induction of labour or for the treatment of hypertension.

Description

This invention relates to prostane derivatives, a process for their production and their use as medicaments.

It is known from the very comprehensive prior art concerning prostaglandins and their analogues that, because of their biological and pharmacological properties, this class of substance is suitable for the treatment of mammals, including human beings. However, their use as medicaments is often faced with difficulties. Most natural prostaglandins have a duration of action which is too short for therapeutic purposes since they are decomposed metabolically too rapidly by various enzymatic processes. The production of derivatives of prostanoic acid has therefore gained great importance.

All structural alterations have aimed at increasing the duration of action and also the selectivity of effect!veness.

The present invention provides a prostane derivative of the general formula wherei η Rj represents an acyl radical of an organic carboxylic or sulphuric acid preferably having from 1 to 15 carbon atoms or a group obtainable from an oxygen-containing inorganic acid by removal of a hydroxy group or a -C-N \ R - 4 group, wherein U represents an oxygen or sulphur atom and each of and Rg which may be the same or different, represents a hydrogen atom, an unsubstituted or substituted alkyl, cycloaikyl, aryl or aromatic heterocyclic radical or an acyl radical or an organic carboxylic or sulphonic acid or R^ and Rg together with the nitrogen atom to which they are attached represent an aromatic or non-aromatic unsubstituted or substituted heterocyclic ring having from 4 to 7 ring members and containing, if desired, one or more additional hetero atoms, Rg represents a hydrogen atom or an alkyl group having from 3 to 5 carbon atoms, A represents a c£s-CH=CH-, *2’aws-CH=CH-or-C=C-group, B represents a -CHg-CHg-, £ra?2s-CH=CH-or-CsC-group, W represents a free, esterified or etherified hydroxymethylene group, wherein the hydroxy or esterified or etherified hydroxy group is in the a- or β-configuration, or a group of the formula -C- , s r7 6 8 6 4 - 5 in which R? represents a free, esterified or etherified hydroxy group which may be in the a- or β-configuration, or W represents a free or ketalised carbonyl group, D and E together represent a direct bond, or D represents an alkylene group having from 1 to 5 carbon atoms or a -C=C- group, and E represents an oxygen or sulphur atom or a direct bond, R3 represents an aliphatic hydrocarbon radical, preferably an alkyl group, which may be • unsubstituted or substituted by a cycloalkyl, alkylsubstituted cycloalkyl, unsubstituted or substituted aryl or heterocyclic group, a cycloalkyl or alkyl15 substituted cycloalkyl group, or an unsubstituted or substituted aryl or heterocyclic group, e.g. a benzodioxol-2-yl group, and Z represents a free or ketalised carbonyl group or a free esterified or etherified hydroxymothylene group in which the free esterified or etherified hydroxy group may be in the a- ore-configuration.

It will be understood that the structural formulae and - 6 written nomenclature of the compounds described and claimed herein include the optical antipodes and the racemates of the compounds, and where appropriate, geometrical isomeric forms.

The present invention also provides a salt of a compound of the general formula I, especially a physiologically tolerable salt.

Compounds of the general formula I and physiologically tolerable salts thereof have useful pharmacological properties.

An acyl radical represented by Rp or Rg or the group obtainable from an inorganic acid represented by is preferably a physiologically tolerable radical.

Preferred acids from which the acyl radicals are derived 15 are organic carboxylic acids and sulphonic acids having from 1 to 15 carbon atoms which belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclicaliphatic series. These acids may be saturated or unsaturated, mono, di- or poly-basic, unsubstituted or substituted. Examples of the substituents are halogen atoms and alkyl, hydroxy, carboxy, alkoxy, phenoxy, oxo and amino groups and amino groups substituted, for example, by one or two alkyl groups or by an alkylene - 7 group which may be interrupted by a hetero atom. One or more of the same or different substituents may be present in the acid and a substituent itself may be substituted, for example by an alkyl substituent or by a halogen atom or atoms.

The following carboxylic acids may be mentioned by way of example: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, oenanthic acid, caprylic acid, pelargonic acid, capric acid, undecyclic acid, lauric acid, tridecyclic acid, myristic acid, pentadecyclic acid, trimethylacetic acid, diethylacetic acid, iar*.butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid mono-, di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acids substituted by one or more halogen atoms or by one or more trifluoromethyl, hydroxy, alkoxy or carboxy groups, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid and cyclopentylpropionic acid.

Suitable sulphonic acids are, for example, methanesulphonic acid, ethanesulphonic acid, isopropanesulphonic acid, β-chloroethanesulphonic acid, - 8 butanesulphonic acid, cyclopentanesulphonic acid, cyclohexanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, p-chlorobenzenesulphonic acid, p-methoxybenzenesulphonic acid, N,N-dimethylaminosulphonic acid, Ν,Ν-diethylaminosulphonic acid, N,N-bis-(8-chloroethyl) - aminosulphonic acid, N,N - diisobutylaminosulphonic acid, N,N - dibutylaminosulphonic acid, and pyrrolidino-, piperidino, piperazino-, N-methylpiperazino-, thiophenoand morpholinosulphonic acid.

For Ry acyl radicals having up to 10 carbon atoms are especially preferred and for R^ or Rg acyl radicals having up to 6 carbon atoms are especially preferred.

Further, for derivation of radicals represented by Rj, the usual inorganic acids, for example sulphuric and phosphoric acid, are suitable.

The group represented by is an unsubstituted or substitued carbamoyl or thiocarbamoyl radical. The carbamoyl or the thiocarbamoyl group may be substituted at the nitrogen atom by an unsubstituted or substituted alkyl, cycloalkyl, aryl, aromatic heterocyclic or acyl radical of an organic carboxylic or sulphonic acid or by two such groups, R^ and Rg. Preferred C-N groups are unsubstituted and substituted carbamoyl groups.

Suitable alkyl groups represented by R^ and Rg are, for example, straight- and branched-chain alkyl groups having from 1 to 10 carbon atoms, e.g. methyl, ethyl, propyl, 6864 - 10 isopropyl, butyl, isobutyl, pentyl, heptyl, hexyl or decyl. Those having 1 to 5 carbon atoms are especially preferred.

A cycloaikyl group represented by R^ or Rg is, for example 5 a group having 3 to 8 ring carbon atoms, e.g. a cyclobutyl cyclopentyl, cycTohexyl, or, preferably, cyclopropyl group; such groups may be unsubstituted or substituted, e.g. by one or more alkyl groups.

An alkyl or cycloaikyl group represented by R^ or Rg may be unsubstituted or substituted by one or more of the same or different substituents selected, for example, from halogen atoms, alkoxy groups, unsubstituted and substituted aryl and aromatic heterocyclic groups, and dialkylamino and trialkylammonium groups in which the alkyl groups may be the same or different. An alkyl group represented by R^ or Rg may also be substituted by a cycloaikyl group, and a cycloaikyl group represented by R^ or Rg by one or more alkyl groups, for example by a substituted alkyl group.

Substituents that should especially be mentioned are, for example, bromine atoms and phenyl, dimethylamine, diethylamine, methoxy and ethoxy groups.

An aryl or aromatic heterocyclic group represented by R^ or Rg and an aryl or aromatic heterocyclic substituent - 11 of an alkyl group represented by or Rg may be unsubstituted or substituted. For example, there may be mentioned thienyl, furyl and pyridyl groups, and phenyl, 1-naphthyl and 2-naphthyl groups which may each be substituted by 1 to 3 of the same or different halogen atoms, by a phenyl group, by 1 to 3 of the same or different alkyl groups each having 1 to 4 carbon atoms, or by a chloromethyl, fluoromethyl, trifluoromethyl, or alkoxy group or by any combination of such substituents.

Fused rings should also be mentioned. Substitution in the 3-and/or 4-position at the phenyl ring is preferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl substi tuents.

If R^ and Rg form a ring together with the nitrogen atom to which they are attached, this ring may be unsubstituted or substituted, aromatic or non-aromatic, saturated or unsaturated, and may contain, if desired, one or more other hetero atoms. Examples are azetidine, pyrrolidine, piperidine, hexamethylenelmine, oxazolidine, morpholine and piperazine, and N-alkylpiperazine in which the alkyl group has 1 to 5 carbon atoms. Fused rings should also be mentioned.

As groups represented by Rp there should especially be mentioned -COCHgCHgCOOH, -C0CH3, -COCHgOCHp -CONHSOgCHg and -C0N(CH3)2 groups. Salts, preferably physiologically tolerable salts, of a compound in which R^ represents a - 12 -COCHgCHgCOOH group should also be mentioned.

An alkyl group represented by Rg is, for example, a straight-chained or branch-chained alkyl radical having 3 or 4 carbon atoms, e.g. the propyl, isopropyl, butyl, isobutyl or tert,-butyl group. There should especially be mentioned compounds in which Rg represents a hydrogen atom.

A hydroxy group in a group represented by W or Z may be functionally converted by etherification or esterification, the free or converted hydroxy groups being in either a- or^-configuration.

Suitable ether-forming and acyl radials are the radicals known to the man skilled in the art. Preferred are etherforming radicals that are easy to split off, such as, for example, a tetrahydropyranyl, tetrahydrofuranyl (usually 2-tetrahydropyranyl and 2-tetrahydrofuranyl), a-ethoxyethyl, trimethylsilyl, dimethyl-ieri.-butylsilyl and tribenzylsilyl radicals. Suitable acyl radicals are, for example those organic carboxylic and sulphonic acid acyl radicals mentioned for Rp R^ and Rg, e.g. acetyl, propionyl, butyryl and benzoyl.

A ketalised carbonyl group represented by W may be a group known to the man skilled in the art. Especially suitable are cyclic ketals having 1 to 3 carbon atoms in the ring, prepared, for example with ethylene glycol - 13 propane-1,3-diol, 2,2-dimethylpropane-1,3-diol, cyclopentane-1,2-diol or glycerine.

An aliphatic hydrocarbon group represented by R3 or an aliphatic moiety in a radical represented by R3 may be straight-chained or branched-chained, saturated or unsaturated, preferably saturated, preferably having 1 to 10, especially 1 to 6, carbon atoms; the aliphatic radical may be unsubstituted or substituted e.g. by an unsubstituted or substituted aryl group. Examples are methyl, ethyl, propyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, butenyi, isobutenyl, propenyl, pentenyl, benzyl and ρ-chlorobenzyl groups.

A cycloalkyl group represented by R3 or a cycloalkyl moiety in a radical represented by R3 preferably contains 4 to 10, especially 5 or 6, ring carbon atoms. The ring or rings may be substituted by one or more alkyl groups each having 1 to 4 carbon atoms. Examples are cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl groups.

An unsubstituted or substituted aryl group represented by R3 or an aryl moeity in a radical represented by R3 is, for example, a phenyl, 1-naphthyl or 2-naphthyl group, each of which may be unsubstituted or substituted by 1 to 3 of the same or different halogen atoms, a phenyl group, 1 to 3 of the same or different alkyl groups each having - 14 1 to 4 carbon atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, alkoxy or hydroxy group or by any combination of such substituents. Preferred is substitution in the 3- and 4-position of the phenyl ring, for example by fluorine, chlorine, alkoxy or trifluoromethyl substituents or in the 4-position by a hydroxy group.

A heterocyclic group represented by R3 or a heterocylic moeity in a radical represented by R3 comprises at least one heterocyclic ring, preferably a 5- or 6-membered heterocycle having at least 1 hetero atom, preferably a nitrogen, oxygen or sulphur atom. There may be mentioned, for example, the 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl radicals, and also the benzodioxol-2-yl group.

Alkylene groups represented by D may straight- or branchedchain. For example, DERg may represents the -CHgOCgHg group.

DER3 may also represent, for example, -(CH2),CH3> -CH(CHg)20 (CH2)3CH3, -C(CH3)2-(CH2)2CH3 or -CHgCgHg.

The present invention also provides a process for the preparation of a prostane derivative of the general formula I or a salt thereof, wherein a prostan-l-ol of the general formula 6 8 6 1 wherein A, B, 0, E, W, Z, Rg and R3 have the meanings given above and in which free hydroxy groups with the exception of the 1-hydroxy group may be free or protected is (a) esterified, or (b) reacted with a compound of the general formula u=c=n-r4 wherein U and R4 have the meanings given above, or (c) reacted with a carbamoyl chloride of the general formula . 16.

R4 wherein R^ and Rg have the meanings given above, and then, if desired, one or more of the following steps is carried out where appropriate in any desired order: (T) a protected hydroxy group is converted to a 5 free hydroxy group; (ii) a free hydroxy group is oxidised, esterified or etherified; (iii) a free carbonyl group is ketalised or reduced; (iv) a ketalised carbonyl group is converted to a 10 free oxo group; (v) a multiple bond is hydrogenated; - 17 (vi) a compound of the general formula I is converted into a salt thereof or a salt is converted into a free compound of the general formula I; (vii) a mixture of epimers is separated.

The alcohol of the general formula II may be esterified in a manner known per se. For example, esterification may be effected by reacting the alcohol with an acid derivative, preferably an acid halide or acid anhydride, in the presence of a base, for example sodium nydride, pyridine, triethylamine, tributylamine or 4-dimethylaminopyridine.

The reaction may be carried out without a solvent or in an inert solvent, preferably acetone, acetonitrile, dimethylacetamide or DMSO, at a temperature above or below room temperature, for example from -80 to 100°C, preferably at room temperature.

The alcohol of the general formula II may be reacted with a compound of the general formula III or IV in a manner known per se. For example, the reaction may be carried out in the presence of a tertiary amine, for example triethylamine or pyridine, and without a solvent or in an inert solvent, preferably acetone, acetonitrile, dietmylacetamide, methylene chloride, tetrahydrofuran, ether, benezene, toluene or DMSO, at a temperature above or below room temperature, for example from -80 to 100°C, preferably at 0 to 30°C.

If the starting material contains additional OH groups in -lain the prostane radical apart from the 1-positioned OH group, these OH groups are also esterified by the process. If the end product of formula I desired should have a free hydroxy group or groups, the corresponding group or groups in the starting material are preferably protected, preferably by formation of an easily-cleavable ether group or groups.

A functionally converted hydroxy group (esterified or etherified) in the product of formula I may be deprotected released according to known methods. For example, the hydroxy-protecting groups, such as, for example, the tetrahydropyranyl radical, may be cleaved in an aqueous solution of an organic acid, e.g. acetic acid or propionic acid, or in an aqueous solution of an inorganic acid, e.g. hydrochloric acid or tetrabutylammonium fluoride. A water-miscible inert organic solvent is advantageously added to improve the solubility. Suitable organic solvents are, for example, alcohols, e.g. methanol and ethanol, and ethers, e.g. 1,2-dimethoxyethane, dioxan and tetrahydrofuran. Tetrahydrofuran is preferably used.

Cleaving is preferably effected at a temperature of from 20 to 80°C.

A hydroxy group present may then be esterified or etherified or oxidised according to methods known per se with the usual esterification, etherification or oxidising agents. - 19 For example, the 9-hydroxy group may be oxidised to form the ketone with Jones reagent (J. Chem. Soc. 1953, 2555), the operation being effected with an excess of the oxidising agent in a suitable diluent, for example acetone, at a temperature of from 0 to - 50°C, preferably at substantially - 20°C. The reaction is generally complete after 5 to 30 minutes. Oxidation is preferably effected after the intermediate protection of the 15-hydroxy group by silylation. (Chem.Comm. 1972, 1120). Silylation may be effected, for example, with Ν,Ν-diethyltrimethylsilylamine in acetone at - 70 to +20°C, preferably at -40 to 0°C.

Other suitable oxidising agents are silver carbonate on Celite” (Trade Mark) or Collins reagent (Tetrahedron Letters 1968, 3363).

Ketalisation may be effected in a manner known per oe.

For example, the ketone may be heated with ethylene glycol in the presence of an acid catalyst with the separation of water. P-Toluenesulphonic acid and perchloric acid are particularly suitable as acid catalyst.

A 9-oxo group may be reduced using a conventional reducing agent, for example with sodium borohydride, lithium tritert.-butoxy aluminium hydride, zinc borohydride or aluminium isopropoxide in the presence of an alcohol, or potassium tri-sea.-butyl borohydride, preferably with sodium borohydride at a temperature of from -50 to +50°C, preferably 0 to 20°C. Suitable solvents for this .46864 reaction, depending on the reducing agent used, are methanol, ethanol, isopropanol, diethyl ether, dioxan and tetrahydrofuran. When reducing with sodium borohydride, methanol, ethanol· or isopropanol are preferably used. The resulting a- and β-ΟΗ-epimer mixture may be separated in the normal manner by column or layer chromatography.

Hydrogenation of a C=C double bond contained in the primary product, which may also be desired, may be effected according to a method known per se.

The alcohol of the general formula II used as the starting material for the above process may be produced, for example by reacting an aldehyde of the general formula / CHO - 2 1 {Ε. ύ. Corey et al., J. Org. Chem. 39, 256 (1974)3 with a phosphorane or phosphonate in a Wittig reaction to form an α,β-unsaturated or saturated carbonyl compound of the general formula VI wherein B, D, E and Rg have the meanings given above; the double bond in the 13,14-position (figures according to - 22 PG numbering) may then, if desired, be hydrogenated.

After reducing the 15-oxo group with zinc borohydride or adding an alkylmagnesiurn bromide or an alkyl lithium to form the epimeric 15a- and 15B-alcohols (PG numbering), which may be separated if desired, and optionally introducing a hydroxy-protecting group at the 15-C atom, e.g. with dihydropyran, a compound of the general formula VII wherein B, D, E, W and Rg have the meanings given above, is obtained. - 23 The lactone thus obtained may be reduced with diisobutylaluminium hydride to form the lactol of the general formula OH VIII B-W-D-E-R, wherein B, D, E, W and R3 have the meanings given above, which may be converted by a Wittig reaction with an ylene 5 of the general formula (c6h5)3p=ch-(ch2)3-coo® IX -24esterification, e.g. with CHgNg, and optional protection of the free hydroxy group by silylation to form a compound of the general formula in which A represents a CH=CH group The ester of the formula X in which Z is not a free carbonyl group may then be reduced to form an alcohol of the general formula II, preferably using LiAlH^.

An alcohol of the general formula II may be produced also 5 from a prostaglandin derivative of the general formula - 25 wherein A, B, D, E, W and Rg have the meanings given above and Rg represents a hydrogen atom or a methyl group, and in which free hydroxy groups are optionally protected by esterification or etherification, (i) to produce a compound in which R2 represents a hydrogen atom, by hydrogenating the 10, 11-double bond with NaBH^ in an alcohol, e.g. methanol or ethanol, and then, if desired, oxidising the 9-hydroxy group with Jones reagent, or (ii) to produce a compound in which R^ represents an alkyl group having 3 to 5 carbon atoms, by (a) reacting with a dialkyl copper lithium reagent in an inert solvent, e.g. diethyl ether or tetrahydrofuran,.which saturates the 10, 11-double bond and introduces an Π-alkyl group to form a compound of the general formula 6 8 6 1 - 27 (b) ketalising the 9-oxo group or reducing the oxo group with, for example, sodium borohydride or potassium selectride (Trade name for potassium ti - (sec. - butyl) - borohydride in tetrahydrofuran solution) and optionally protecting the free hydroxy group, e.g. by silylation, and (c) subsequently reducing with lithium aluminium hydride, Prostane derivatives of the general formula I and their physiologically tolerable salts are useful drugs since, with a comparable range of action, they have a considerably improved action (higher degree of specificity) and, above all, considerably longer-lasting action than the corresponding natural prostaglandins. In comparison to PGE and PGA derivatives the 11-deoxyprostaglandins of the invention are also distinguished by greater stability.

Furthermore, the compounds have an improved antiferti1ity activity. Considerably smaller quantities of the prostane derivatives are therefore necessary in comparison to the natural prostaglandins for inducing abortions in non-human animals When recording the isotonic contraction of the uterus of narcotised rats and of the isolated uterus of rats or guinea pigs the compounds of the invention proved to be - 28 considerably more effective and their effects were longerlasting than in the case of the natural prostaglandins.

In the case of some of the prostane derivatives of the invention a single intrauterinal or vaginal application indices menstruation or interrupts a pregnancy. In addition, some of the compounds have luteolytic action and are non-human suitable for synchronising the sexual cycle of/female mammals, e.g. apes, horses, cattle and pigs.

The good tissue specificity of the substances according to the invention having antifertile and hypotensive action is demonstrated in the investigation of other unstriated organs, such as, for example, the ileum of guinea pigs or the isolated rabbit trachea, where considerably less stimulation is to be observed than that caused by the natural prostaglandins.

Many of the active substances of the invention, when used on the isolated rabbit trachea in vitro, even have a bronchodilatory action and greatly inhibit the secretion of gastric acid. The compounds having diuretic and hypotensive action also have a regulating effect in cases of disturbances of the cardiac rhythm. In contrast, their effect on other organ systems is very slight.

Accordingly, the present invention provides a pharmaceutical preparation which comprises a compound of the general formula I or a physiologically tolerable salt thereof, in - 29 admixture or conjunction with a pharmaceutically suitable carrier.

The preparation may be in a form suitable for inhalation, oral, parenteral or local (for example vaginal) administration, and may, for example, be in dosage unit form containing, for example 0.01 to 25 mg of active ingredient per dosage unit.

For inhalation, aerosol solutions are preferably produced.

Tablets, dragees or capsules, for example, are suitable for oral administration.

Sterile, injectable, aqueous or oily solutions are used for parenteral administration.

Suppositories, for example, are suitable and customary for vaginal administration.

The active substance of the invention may be used together with the auxiliary substances which are known and conventional in galenical pharmacy, for example for the production of preparations for the inducement of abortions, for the control of the sexual cycle, for inducing birth or for the treatment of hypertension.

The following Examples illustrate the invention. Throughout - 3 0 the Examples of the term ether is used to denote diethyl ether.

Example 1 (5Z,13E)-(15R)-l-(3-Carboxypropiony1oxy)-15-hydroxy-16phenoxy-17,18,19,20-tetranor-5-13-prostadien-9-one.

A mixture of 1.3 gms of (5Z,13E) - (9S, 15R) - 9 tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) 16 - phenoxy - 17,18,19,20, - tetranor - 5, 13 - prostadien - 1 - ol, 0.19 gm of succinic anhydride and 2.3 ml of pyridine was stirred for 18 hours at room temperature under argon. The mixture then evaporated in vaouo, the crude product was purified by column chromatography over silica gel with pentate-ether (6+4), and 1.59 gms of (5Z, 13E) - (9S, 15R) -1-(3- carboxypropionyloxy) - 9 tribenzylsilyl - oxy - 15 - (tetrahydropyran - 2 - yloxy) - 16 - phenoxy - 17,18,19,20 - tetranor - 5,13 - prostadiene were obtained in the form of a colourless oil, IR: 1730, 1600, 1493, 975 cm-1 To 1.12 gms of the hemisuccinate so obtained in 32 ml of tetrahydrofuran was added a solution of 790 mg of tetrabutyl ammonium fluoride in 8 ml of tetrahydrofuran (THF) and the mixture was stirred for 5 hours at room temperature. The mixture was then diluted with water, acidified with a 10% w/v citric acid solution to pH4, extracted three times with ether, the organic phase was washed neutral with brine, dried over magnesium sulphate and evaporated in vaouo. By purification by chromatography over silica gel with ether there were obtained 513 mg of - 31 (5Z,13E)-(9S,15R)-1 -(3 - carboxyproplonyloxy) - 9 - hydroxy - 15 - (tetrahydropyran - 2 - yloxy) - 16 - phenoxy - 17,18,19,20 - tetranor - 5,13 - prostadiene in the form of a colourless oil.

IR: 3500, 2945, 1730, 1600, 1495, 978/cm.

The product was dissolved in 10 ml of acetone. To this solution was added at -20°C 0.60 ml of Jones reagent. After 40 minutes the excess of reagent was destroyed by the addition of isopropanol. The mixture was diluted with ether, agitated with brine until neutral, dried over magnesium sulphate and evaporated in vaouo. The residue was stirred for 16 hours at room temperature in 15 ml of a mixture of acetic acid/water/THF (65/35/10), evaporated in vacuo and chromatographed over silica gel with chloroform/5% methanol. 280 mg of the title compound were obtained in the form of a colourless oil.

IR: 3590, 3400, 2930, 2860, 1735 (wide), 1600, 1589) 1496, 973/cm.

The starting material for the title compound was prepared as follows: la) (5Z, 13E)-(9S, 15R) - 9 - Hydroxy - 15 (tetrahydropyran - 2 - yloxy) - 16 - phenoxy - 17,18, 19,20 tetranor - 5,13 - prostadienoic acid methyl ester.

To a solution of 11.51 gms of 4 - carboxybutyl triphenyl - 32 -phosphonium bromide in 60 ml of absolute dimethyl sulphoxide (DMSO) were added dropwise at 15°C 48.2 ml of a solution of sodium methanesulphinylmethylide in DMSO (preparation: 3 gms of a suspension of 50% sodium hydride were dissolved in 60 ml of absolute DMSO during one hour at 70°C), and the whole was stirred for 15 minutes at room temperature. To the red ylene solution was added dropwise a solution of 2.35 gms of (2RS, 3aR, 4R, 6aS, 31R) - 4 [(E) - 3 - (tetrahydropyran - 2 - yloxy) - 4 - phenoxy - 1 - butenylj - 2 - hydroxyperhydrocyclopenta - ^bj furan (German Offenlegungsschrift 26 29 834.0) in 45 ml of abolute DMSO and the whole was stirred for 2.5 hours at 50°C under argon. The reaction mixture was diluted with 300 ml of ice-water, and extracted three times with ether. The aqueous phase was then acidified with a 10% w/v citric acid solution to pH 5, extracted four times with a mixture of ethyl acetate/ether (1+1), the organic extract was agitated with brine three times, dried over magnesium sulphate and evaporated -in vacuo. The residue was purified by filtration over silica gel (pentane/ethyl acetate 3+7). 2.30 gms of the prostadienoic acid were obtained in the form of a pale yellow oil. For conversion into the methyl ester the latter acid was dissolved in 50 ml of methylene chloride and a small excess of an ethereal solution of diazomethane was added at 0°C. By evaporating the solvent 2.35 gms of the methyl ester were obtained in the form of a pale yellow oil.

IR: 3600, 3500, 2943, 1728, 1598, 1585, 1493, 975/cm. 468 64 - 33 lb) (5Z, 13E-(9S, 15R) - 9 - Tri benzyl silyloxy - 15 (tetrahydropyran - 2 - yloxy) - 16 - phenoxy - 17,18,19,20 - tetranor - 5,13 - prostadienoic acid methyl ester. gms of the methyl ester prepared in accordance with Example la, 2,4 gms of tribenzylsilyl chloride and 36 ml of pyridine were stirred for 6 hours at 45°C under argon, the mixture was evaporated in vacuo and the residue was filtered with ether/pentane (1+1) over silica gel. 3.35 gms of the tribenzylsilyl ether were obtained in the form of a colourless oil.

IR: 1732, 1600, 1495, 975/cm. lc) (5Z, 13E), - (9S, 15R) - 9 - Tribenzyl silyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 16 - phenoxy 17,18,19,20 - tetranor - 5,13 - prostadien - 1 - ol.

Into a solution of 3.3 gms of the silyl ether prepared in accordance with Example lb in 140 ml of ether 1 gm of lithium aluminium hydride was introduced in portions at room temperature while strring. Stirring was continued for 3 hours, the excess of reagent was destroyed by the cautious addition of ethyl acetate, 2.2 ml of water were added, and the mixture was stirred for 60 minutes at room temperature, filtered and evaporated in vacuo. By filtration over silica gel with pentane/ether (3+7)2.7 gms of the 1- alcohol were obtained in the form of a colourless oil.

IR: 3600, 3460, 2943, 1600, 1588, 1495, 978/cm. - 34 Example 2 (5Z, 13E)-(9S( 15R)-l-(3-Carboxypropionyloxy)-9-15dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13prostadiene. 500 mg of (5Z, 13E - (9S, 15R) -1-(3- carboxypropionyloxy) 5 - 9 - tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 16 - phenoxy - 17,18,19,20 - tetranor - 5,13 prostadiene were stirred for 16 hours in 10 ml of a mixture of acetic acid/water/THF(65/35/10) at room temperature, and the mixture was evaporated in vacuo and chromatographed over silica gel. With chloroform/ methanol (9+1) 130 mg of the title compound were obtained in the form of a colourless oil.

IR: 3590, 3400, 1730, 1600, 1493, 977/cm.

Example 3 (5Z, 13E)-(15R)-l-(3-Carboxypropionyloxy)-15-hydroxy16,16-dimethyl-5,13-prostadien-9-one.

A mixture of 1.58 gms of (5Z, 13E) - (9S, 15R)-16,16dimethyl - 9 - tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy - 5,13 - prostadien - 1 - ol, 270 mg of succinic anhydride and 5 ml of pyridine was stirred for 19 hours at room temperature under argon. The mixture was then evaporated in vaauo and the product was purified by column chromatography over silica gel. With ether there were obtained 1.44 gms of (5Z,13E) - (9S, 15R) - 1 -(3 25 carboxypropionyloxy) - 16,16 - dimethyl - 9 - tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 5,12 - prostadiene in the form of a colourless oil. - 35 IR: 2930, 1730, 1600, 1492, 980/cm.

To 1.42 gms of the hemisucciniate so obtained in 70 ml of THF is added a solution of 884 mg of tetrabutylammonium fluoride in 15 ml of THF and the whole was stirred for 5 hours at room temperature. The mixture was then diluted with water, extracted three times with ether, the organic phase was washed neutral with brine, dried over magnesium sulphate and evaporated in vaouo. After purification by chromatography over silica gel with ether 788 mg of (5Z, 13E) - (9S, 15R) -1-(3- carboxypropionyloxy) 16,16 - dimethyl - 9 - hydroxy - 15 - tetrahydropyran - 2 - yloxy) - 5,13 - prostadiene were obtained in the form of a colourless oil. 500 mg of this product were dissolved in 15 ml of acetone and 0.7 ml of Jones reagent was added at -30°C. After 30 minutes, the excess of reagent was destroyed by the addition of isopropanol, and the mixture was diluted with ether and washed neutral with brine. After being dried with magnesium sulphate, the evaporation residue was stirred with 12 ml of a mixture of acetic acid/water/THF (65/35/10) for 16 hours at room temperature. The mixture was evaporated in vaouo and the residue was chromatographed over silica gel with methylene chloride/5% methanol and 153 mg of the title compound were obtained in the form of a colourless oi1.

IR: 3600, 3500, 2930, 2858, 1732, 1600, 976/cm. - 36The starting material for the title compound was prepared as follows: 3a) (5Z, 13E)-(9S, 15R)-16,16 - dimethyl - 9 - hydroxy - 15 (tetrahydropyran - 2 - yloxy) - 5,13 - prostadienoic acid methyl ester.

To a solution of 3.55 gms of 4 - carboxybutyltriphenylphosphonium bromide in 18 ml of DMSO were added dropwise at 15°C, 15.3 ml of a solution of sodium methanesulphinylmethylide in DMSO (for the preparation see Example la) and the whole was stirred for 15 minutes at room temperature.

The the red ylene solution was added dropwise a solution of 0.73 gm of (2RS, 3aR, 4R, 6aS, 3'R) - 4 - [(E) - 4,4 dimethyl - 3 - tetrahydropyran - 2 - yloxy) - 1 - octenyij - 2 - hydroxyperhydrocyclopenta[bj furan (DOS 26 29 934.0) in 15 ml of DMSO and the whole was stirred for 2 hours at 50°C under argon. T50 ml of ice-water were added to the reaction mixture and the whole was extracted three times with a mixture of ether/ethyl acetate (1:1). The aqueous phase was acidified with a solution of 1051 w/v citric acid to pH 5, and the whole was extracted three times with a mixture of ether/pentane (1:1). The organic phase was washed neutral with water, dried over magnesium sulphate and evaporated to dryness in vacuo. By chromatographing the residue over silica gel with ether/pentane (8+2) 480 mg of the prostadienoic acid were obtained, which was converted with diazomethane into the oily methyl ester.

IR: 3600, 3500, 2940, 1730, 976/cm. - 37 3b) (5Z, Ί3Ε) - (9S, 15R) - 16,16 - Dimethyl - 9 tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 5,13 - prostadienoic acid methyl ester. 950 mg of the compound prepared in accordance with Example 5 3a, 130 gms of tri benzyl silyl chloride and 20 ml of pyridine were stirred for 24 hours at 50°C, the mixture was concentrated in vacuo and the residue was filtered over silica gel with ether/pentane (1:1). 1.50 gms of the tribenzylsilyl ether were obtained in the form of a colourless oil.

IR: 2958, 1731, 1600, 1495, 973/cm. 3c) (5Z, 13E) - (9S, 15R) - 16,16 - Dimethyl - 9 tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) 5,13 - prostadien - 1 - ol.

To a solution of 1.68 gms of the silyl ether prepared in accordance with Example 3b in 50 ml of ether were added at room temperature 310 mg of lithium aluminium hydride, the mixture was stirred for one hour at room temperature, ml of water were added dropwise, and the mixture was stirred for a further hour, filtered and evaporated in vaouo. The crude product was purified by chromatography over silica gel with ether/pentane (1:1). 1.59 gms of the 1-alcohol were obtained in the form of an oil.

IR: 3600, 3450, 2940, 1600, 1494, 978/cm. - 38 Example 4 (5Z, 13E)-(9S, 15R)-l-(3-Carboxypropionyloxy)-16,16dimethyl-9,15-dihydroxy-5,13-prostadiene, 600 mg of (5Z, 13E)-(9S, 15R)-l-(3-carboxypropionyloxy) 9 - tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 16,16 - dimethyl - 5,13 - prostadiene (prepared in accordance with Example 3) were stirred for 16 hours in 13 ml of a mixture of acetic acid/water/THF (65/35/10) at room temperature, and evaporation in vacuo and chromatography over silica gel were carried out. With chloroform/methanol (9+1) 160 mg of the title compound were obtained in the form of a colourless oil.

IR: 3590, 3350, 2940, 1730, 978/cm.

Example 5 (5Z, 13E)-(15S, 16RS)-l-(3-Carboxypropionyloxy)-15-hydroxy -16-methyl-5,13-prostadien-9-one.

Under the reaction conditions described in Example 3 there were obtained from 1.35 gms of (5Z, 13E) - (9S, 15S, 16RS) - 16 - methyl - 9 - tri benzyl silyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 5,13 - prostadien - 1 - ol and 220 mg of succinic anhydride in 4 ml of pyridine 1.40 gms of (5Z, 13E) - (9S, 15S, 16RS) -1-(3- carboxyproplonyloxy) - 16 - methyl - 9 - tribenzylsilyloxy - 15 (tetrahydropyran - 2 - yloxy) - 5,13 - prostadiene in the form of a colourless oil.

To 1.31 gms of the hemiscuccinate so obtained in 60 ml of - 39 THF was added a solution of 860 mg of tetrabutylammoniurn fluoride in 14 ml of THF, and the mixture was stirred for 5 hours at room temperature, diluted with water and extracted three times with ether. The organic phase was washed neutral, dried over magensium sulphate and evaporated in vacuo. After purification by chromatography over silica gel with ether 710 mg of (5Z, 13E)-(9S, 15S, 16RS) - 1 - (3 - carboxy-propionyloxy) - hydroxy - 16 - meth.vl - 15 10 (tetrahydropyran - 2 - yloxy) - 5,13 - prostadiene were obtained in the form of a colourless oil.

To 400 mg of this product in 15 ml of acetone were added at -30°C 0.5 ml of Jones reagent. After 30 minutes the excess of reagent was destroyed by the addition of isopropanol, the mixture was diluted with ether and washed neutral with brine, dried over magnesium sulphate, evaporated and the residue was stirred with 10 ml of a mixture of acetic acid/THF/water (65/10/35) for 16 hours at room temperature, evaporated in vacuo and the residue was chromatographed over silica gel with methylene chloride/5% methanol. 130 mg of the title compound were obtained in the form of a colourless oil.

IR: 3600, 3510, 2950, 1730, 1600, 970/cm.

The starting material for the title compound was prepared as follows:25 5a) (5Z, 13E) - (9S, 15S, 16RS) - 9 - Hydroxy - 16 - methyl - 15 - (tetrahydropyran - 2 yloxy) - 5,13 46864 - 40 prostadienoic acid methyl ester.

To a solution of 4.25 gms of 4-carboxybutyltriphenylphosphonium bromide in 22 ml of DMSO were added dropwise at 15°C 18.4 ml of a solution of sodium methanesulphinylmethylide in DMSO (for the preparation see Example la) and the mixture was stirred for 15 minutes at room temperature. To the red ylene solution was added dropwise a solution of 0.88 gm of (2RS, 3aR, 4R, 6aS, 3'S, 4* RS) - 4 - £(E)J - 4 - methyl - 3 - (tetrahydropyran - 2 yloxy - 1 - octenylj - 2 - hydroxyperhydrocyclopentafbjfuran (DOS 26 29 834.0) in 20 ml of DMSO and the mixture was stirred for 2 hours at 50°C under argon. To the reaction mixture were added 200 ml of ice-water and the whole was extracted three times with a mixture of ether/ethyl acetate (1:1). The aqueous phase was acidified to pH 5 with a 10% w/v solution of citric acid and extracted three times with a mixture of ether/pentane (1:1). The organic phase was washed neutral with water, dried over magnesium sulphate and evaporated in vaouo. After chromatographing the residue over silica gel with ether/pentane (8+2) 585 mg of prostadienoic acid were obtained, which was converted with diazomethane into the oily methyl ester.

IR: 3600, 3500, 2942, 1732, 978/cm. 5b) , (5Z, 15S, 16RS) - 16 - Methyl - 9 tribenzylsilyloxy - 15 (tetrahydropyran - 2 - yloxy) 5,13 - prostadienoic acid methyl ester. 6864 - 41 930 mg of the compound prepared in accordance with Example 5a, 1.25 gms of tribenzylsilyl chloride and 20 ml of pyridine were stirred for 16 hours at 50°C, the mixture was concentrated in vaouo and the residue was chromatographed over silica gel with ether/pentane (1:1). 1.4 gms of the tribenzyl ether were obtained in the form of a colourless oil.

IR: 2950, 1732, 1600, 1495, 975/cm. 5c) (5Z, 13E) - (9S, 15S, 16RS) - 16 - Methyl - 9 tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) 5,13 - prostadien - 1 - ol.

To a solution of 1.35 gms of the silyl ether prepared in accordance with Example 5b in 45 ml of ether were added 280 mg of lithium aluminium hydride, the mixture was stirred for one hour at room temperature, 1.7 ml of water were added dropwise, and the mixture was stirred for a further hour, filtered and evaporated in vaouo. After purification by chromatography over silica gel with pentane/ether (1:1) 1.21 gms of the 1-alcohol were obtained in the form of an oil.

IR: 3600, 3450, 2950, 1600, 1495, 978/cm.

Example 6 (5Z.13E) - (9S, 15S, 16RS) -1-(3- Carboxylpropionyloxy) - 9,15 - dihydroxy - 16 - methyl - 5,13 prostadiene. 500 mg of (5Z, 13E) - (9S, 15S, 16RS) -1-(346864 - 42 Carboxypropionyloxy) - 16 - methyl - 9 - tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 5,13 - prostadiene (prepared in accordance with Example 5) were stirred for 16 hours in 12 ml of a mixture of acetic acid/water/THF (65/35/10) at room temperature, evaporated in vaeuo and the residue was chromatographed with chloroform/ methanol (9+1) over silica gel. 135 mg of the title compound were obtained in the form of a colourless oil.

IR: 3600, 3300, 2945, 1730, 978/cm.

Example 7 (5Z, 13E)-(15S)-1-(3-Carboxypropionyloxy)-15-hydroxy -17-phenyl-18,19,20-trinor-5,13-prostadien-9-one.

A mixture of 1.4 gms of (5Z, 13E) - (9S, 15S) - 9 tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) 15 17 - phenyl - 18,19,20 - trinor - 5,13 - prostadien - 1 ol, 0.21 gm of succinic anhydride and 2.5 ml of pyridine was stirred for 18 hours at room temperature under argon. The mixture was then concentrated in vacuo and the crude product was purified by chromatography over silica gel.

With pentane/ether (1:1) 1.65 gms of(5Z, 13E) - (9S, 15S) -1-(3- carboxypropionyloxy) - 9 - tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 17 - plenyl 18,19,20 - trinor - 5,13 - prostadiene were obtained in the form of a colourless oil.

IR: 1730, 1598, 975/cm.

To 1.20 gms of the hemisuccinate so obtained in 35 ml of - 43 tetrahydrofuran was added a solution of 800 mg of tetrabutylammonium fluoride in 9 ml of THF and the whole was stirred for 6 hours at room temperature. The mixture was then diluted with water, acidified with a solution of % w/v citric acid to pH4, extracted with ether, and the organic phase was washed with brine, dried over magnesium sulphate and evaporated in vacuo. Purification by chromatography over silica gel with pentane/ether (1:1) gave 530 mg of (5Z, 13E) - (9S, IBS) -1-(310 carboxypropionyloxy) - 9 - hydroxy - 15 - (tetrahydropyran 2 - yloxy) - 17 - phenyl - 18,19,20 - trinor - 5,13 prostadiene in the form of a colourless oil.

IR: 3600, 3300, 2940, 1730, 1600, 977/cm.

This 9 - hydroxy - compound was dissolved in 10 ml of acetone and 0.6 ml of Jones reagent was added at -20°C.

After 40 minutes the excess of reagent was destroyed by the addition of isopropanol, and the mixture was diluted with ether and washed neutral with brine. After drying over magnesium sulphate, the evaporation residue was stirred in 15 ml of a mixture of acetic acid/water/THF (65/35/10) for 16 hours at room temperature, evaporated in vaouo and, after chromatography over silica gel with chloroform/ methanol (9+1),250 mg of the title compound were obtained in the form of a colourless oil.

IR: 3600, 3400, 2940, 2860, 1734 (wide), 1600, 975/cm.

The starting material for the title compound was prepared as follows: - 4 47a) (5Z, 13E) - (9S, 15S) - 9 - Hydroxy - 15 (tetrahydropyran - 2 - yloxy) - 17 - phenyl - 18,19,20 - trinor - 5,13 - prostadienoic acid methyl ester.

To a solution of 11.54 gms of 4 - carboxybutyltriphenyl5 phosphonium bromide in 60 ml of absolute DMSO were added dropwise at 15°C 48 ml of a solution of sodium methanesulphinylmethyl in DMSO (for preparation see Example la) and the mixture was stirred for 15 minutes at room temperature. To the red ylene solution was added dropwise a solution of 2.3 gms of (2RS, 3aR, 4R, 6aS, 3‘S) - 4 - [(E)J - 3 - (tetrahydropyran - 2 - yloxy) - 5 - phenyl - 1 - pentenyl] - 2 - hydroxyperhydrocyclopenta[bj furan (DOS 26 29 834.0) in 40 ml of DMSO and the mixture was stirred for 3 hours at 50°C. under argon. The reaction mixture was diluted with 300 ml of ice-water and the whole was extracted three times with a mixture of ether/ethyl acetate (1:1). The aqueous phase was then acidified with a solution of 10% w/v citric acid to fH4.5, the mixture was extracted four times with a mixture of ethyl acetate/ ether (1:1), this extract was agitated three times with brine, dried over magnesium sulphate and evaporated in vaouo. By chromatography of the residue over silica gel with pentane/ethyl acetate (3+7), 2.25 gms of the prostadienoic acid were obtained, which was converted in the usual manner with diazomethane into the oily methyl ester.

IR: 3600, 2945, 1730, 1600, 978/cm. - 45 7b) (5Z, 13E)-(9S, 15S) - 9 - Tri benzyl silyloxy - 15 (tetrahydropyran - 2 - yloxy) - 17 - phenyl - 18,19,20 trinor - 5,13 - prostadienoic acid methyl ester.

From 2 gms of the methyl ester prepared in accordance with Example 7a were obtained in a manner analogous to Example lb 3.4 gms of the 9-tribenzylsilyl ether in the form of a colourless oil.

IR: 1733, 1600, 978/cm. 7c) (5Z, 13E) - (9S, 15S) - 9 - Tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 17 - phenyl - 18,19,20 - trinor - 5,13 - prostadien - 1 - ol.

In a manner analogous to that in Example lc from 3.4 gms of the compound prepared in accordance with Example 7b were obtained 2.73 gms of the 1-alcohol in the form of a colourless oil.

IR: 3600, 3460, 2940, 1600, 978/cm.

Example 8 (5Z, 13E)-(9S, 15S)-l-(3-Carboxypropiony1oxy)-9,15di hydroxy-17-phenyl-18,19,20-tri nor-5,13-prostadiene.

From 600 mg of (5Z, 13E) - (9S, 15S) -1-(3carboxypropionyloxy) - 9 - tribenzysilyloxy - 15 (tetrahydropyran - 2 - yloxy) - 17 - phenyl - 18,19,20 trinor - 5,13 - prostadiene (prepared in Example 7) there were obtained in a manner analogous to that in Example 2 155 mg of the title compound in the form of a colourless oil. - 46 IR: 3600, 3400, 2940, 1730, 1600, 975/cm.

Example 9 (5Z, 13E)-(155)-1-(3-Carboxypropionyloxy)-15-hydroxy -15-methyl-5,13-prostadien-9-one. 210 mg of (5Z, 13E)-(15S)-9,9 - ethylenedioxy-15-methyl 15 - (tetrahydropyran - 2 - yloxy) - 5,13 - prostadien 1 - ol, 55 mg of succinic anhydride and 0.75 ml of pyridine were stirred for 24 hours at room temperature under argon.

The mixture was then evaporated in vaauo and purified by column chromatography over silica gel with ether/pentane (1:1). 155 mg of (5Z, 13E) - (15S) -1-(3carboxypropionyloxy) - 9,9 - ethylenedioxy - 15 - methyl 15 - (tetrahydropyran - 2 - yloxy) - 5,13 - prostadiene were obtained in the form of a colourless oil.

IR: 3630, 2950, 2920, 2355, 1725, 1600, 975/cm. 145 mg of the hemisuccinate so obtained were stirred for hours in 10 ml of a mixture of acetic acid/water/THF (65/35/10), then evaporated to dryness in vaouo and the residue was purified by filtration over silica gel with ether. 65 mg of the title compound wer obtained in the form of a colourless oil.

IR: 3590, 3300, 2928, 2858, 1728, 1600, 972/cm.

The starting material for the above title compound was prepared as follows: 9a) ll-deoxy-15-methyl-prostaglandin Eg 6 8 6 4 - 47 Into a solution of 800 mg of 15-methylprostaglandin-A2 methyl ester (E. W. Yankee et al. JACS 9β (18), 5865 (1974) in 15 ml of methanol was introdued dropwise at -20°C a solution of 900 mg of sodium borohydride in 14 ml of methanol and 1.5 ml of water, the mixture was stirred for 15 minutes at -20°C, neutralised with dilute acetic acid, concentrated in vaouo, water was added and extraction with methylene chloride was carried out three times. The organic extract was agitated with water, dried over magnesium sulphate and evaporated in vaouo. There were obtained 795 mg of the 9 - hydroxy - 10,11 - dihydro compound which was dissolved in 18 ml of acetone and treated at -30°C with 0.8 ml of Jones reagent. After 30 minutes at -20°C, the excess of reagent was destroyed with isopropanol, 120 ml of ether were added, the mixture was agitated three times with 10 ml of brine each time, dried over magnesium sulphate and evaporated in vaouo. By chromatography over silica gel there were obtained with ether 700 mg of the 10,11 -dihydro-compound in the form of a colourless oil.

IR: 3600, 2940, 1730, 976/cm. 9b) (5Z, 13E) - (15S) - 9,9 - Ethy1enedioxy - 15 - hydroxy - 15 methyl - 5,13 - prostadienoic acid methyl ester.

A mixture of 1.2 gms of the compound prepared according to Example 9a, 7 ml of orthoformic acid triethyl ester, 7 ml of ethylene glycol and 7 mg of para-toluenesulphonic acid - 48 was stirred for 48 hours at room temperature under argon.

The mixture was diluted with ether, agitated with a solution of 5% w/v sodium bicarbonate and brine, dried over magnesium sulphate and evaporated in vacuo. By chromatography over silica gel with ether 920 mg of the 9-ketal were obtained in the form of a colourless oil. 9c) (5Z, 13Έ) - (15S) - 9,9 - Ethylenedioxy - 15 - methyl - 15 - (tetrahydropyran - 2 - yloxy) - 5,13 prostadienoic acid methyl ester.

To a solution of 300 mg of the compound obtained in accordance with Example 9b in 7 ml of methylene chloride were added 85 mg of dihydropyran and 1 mg of paratoluenesulphonic acid at 0°C. After 15 minutes the mixture was diluted with ether, agitated with bicarbonate solution and brine, dried over magnesium sulphate and evaporated in vacuo. There were obtained 350 mg of the 15tetrahydropyranyl ether in the form of a colourless oil.

IR: 2940, 1725, 1600, 970, 948/cm. 9d) (5Z, 13E) - 9,9 - Ethylenedioxy - 15 - methyl - 15 - (tetrahydropyran - 2 - yloxy) - 5,13 - prostadien - 1 ol.

To a solution of 320 mg of the compound prepared in accordance with Example 9c in 8 ml of ether were added 280 mg of lithium aluminium hydride, the mixture was stirred - 49for 30 minutes at 25°C, 1 ml of ethyl acetate was cautiously added dropwise, 0.6 ml of water was added, and the mixture was stirred for 60 minutes, filtered and evaporated -in vacuo. By chromatography over silica gel with ether there-were obtained 250 mg of the 1-alcohol in the form of a colourless oil.

IR: 3630, 3450, 2938, 1600, 975, 948/cm.

Example 10 (5Z, 13E) -(15S) -1 - (3-Carboxy-propionyloxy)-1510 hydroxy-5,13-prostadien-9-one. 4.15 mg of (5Z, 13E)-(15S)-9,9-ethylenedioxy-15(tetrahydropyran - 2 - yloxy) - 5,13 - prostadien - 1 ol, 120 mg of succinic anhydride and 2 ml of pyridine were stirred for 24 hours at room temperature under argon. The mixture was then evaporated in vacuo, and purification was carried out by column chromatography over silica gel with ether/pentane (1+1). 375 mg of (5Z, 13E) - (15S) - 1 (3 - carboxypropionyloxy) - 9,9 - ethylenedioxyl - 15 (tetrahydropyran - 2 - yloxy) - 5,13 - prostadiene were obtained in the form of colourless oil.

IR: 3600, 2945, 1725, 1600, 975, 948/cm. 350 mg of the hemisuccinate so obtained were stirred for 16 hours in 16 ml of a mixture of acetic acid/water/THF (65+35+10) and evaporation in vacuo and purification of the residue by column chromatography over silica gel were carried out. With ether there were obtained 195 mg of the title compound in the form of a colourless oil. - 50 IR: 3600, 3320, 2935, 1730, 1600, 975/cm.

The starting material for the above title compound was prepared as follows: 10a) (5Z, 13E) - (15S) - 9,9 - Ethylenedioxy - 15 5 hydroxy - 5,13 - prostadienoic acid methyl ester.

A mixture of 2.3 gms of ll-deoxyprostaglandin-E2 methyl ester (prepared from 11-deoxyprostaglandin-E2 (W.P. Schneider et al., J. Org. Chem. 38,951 (1973) with diazomethane in the usual manner), 13 ml of orthoformic acid triethyl ester, 13 ml of ethylene glycol and 15 mg of para-toluenesulphonic acid was stirred for 48 hours at room temperature under argon, then diluted with ether, agitated with a 5% w/v sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated in vaeuo. By chromatography over silica gel there were obtained with ether 2.1 gms of the 9-ketal in the form of a colourless oil. 10b) (5Z, 13E)-(15S)-9,9-Ethylenedioxy - 15 (tetrahydropyran - 2 - yloxy) - 5,13 - prostadienoic acid methyl ester.

To a solution of 910 mg of the compound obtained in accordance with Example 10a in 20 ml of methylene chloride were added 270 mg of dihydropyran and 4 mg of para46864 - 51 toluene sulphonic acid at ice-bath temperature. After 30 minutes, the mixture was diluted with ether, agitated with a 5% w/v sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated in vaouo.

There were obtained 1.2 gms of the 15 - tetrahydropyranyl ether in the form of a colourless oil.

IR: 2935, 1726, 1600, 973, 948/cm. 10c) (5Z, 13E)-(15S)-9,9 - Ethylenedioxy - 15 (tetrahydropyran - 2 - yloxy) - 5,13 - prostadien - 1 - ol.

To a solution of 1.1 gms of the compound prepared in accordance with Example 10b in 30 ml of ether were added in portions 800 mg of lithium aluminium hydride, the mixture was stirred at room temperature for 45 minutes, the excess of reagent was destroyed by by the dropwise addition of ethyl acetate, 1.8 ml of water were added, the mixture was stirred for 60 minutes, filtered and evaporated in vaouo.

By chromatography over silica gel there were obtained with ether 810 mg of the 1-alcohol in the form of a colourless oil IR: 3600, 3400, 2940, 1600, 976, 948/cm.

Example 11 (5Z)-(15R, 16RS)-1-(3-Carboxypropi onyloxy)-15-hydroxy16-methyl-5-pros ten-9-one.

Under the reaction conditions given in Example 3 there were obtained from 1.3 gm of (5Z) - (9S, 15R, 16RS) - 16 - methyl - 9 - tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 5 - prosten - 1 - ol and 215 mg of succinic anhydride 46834 - 52 in 4 ml of pyridine 1.32 gm of (5Z) - (9S, 15R, 16RS) - 1 -(3- carboxypropionyloxy) - 16 - methyl --9tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 5 - prostene in the form of an oil.

To 1.4 gm of the hemisuccinate so obtained in 60 ml of THF was added a solution of 870 mg of tetrabutylammonium fluoride in 14 ml of THF, the mixture was stirred for 5 hours at room temperature, diluted with water and extracted three times with ether. The organic phase was washed neutral, dried over magnesium sulphate and evaporated in vaouo.

After purification by chromatography over silica gel with ether there were obtained 702 mg of (5Z) - (9S, 15R, 16RS) - 1 - (3-carboxypropionyloxy) - 9 - hydroxy - 16 - methyl - 15 - (tetrahydropyran - 2 - yloxy) - 5 - prostene in the form of an oil.

To 650 mg of this product in 20 ml of acetone were added at -20°C 0.7 ml of Jones reagent. After 30 minutes the excess of reagent was destroyed by the addition of isopropanol, the mixture was diluted with ether, washed neutral with brine, dried over magnesium sulphate and evaporated in vaouo.

The residue was stirred with 15 ml of a mixture of acetic acid/ water/THF (65/35/10) for 16 hours at room temperature, the mixture was evaporated in vaouo and the residue was chromatographed over silica gel. With methylene chloride/ % methanol 290 mg of the title compound were obtained in the form of a colourless oil. - 53 IR: 3600, 3450, 2940, 1730/cm.

The starting material for the above title compound was prepared as follows: Ila) (IS, 5R, 6R, 3'R, 4'RS - 6 - [3 - (tetrahydropyran - 2 - yloxy) - 4 - methyl - 1 - octylj - 2 - oxabicyclo [3.3.0] - octan - 3 - one. 2.8 gms of (IS, 5R, 6R, 3'S, 4'RS) - 6 - [(E) - 3 (tetrahydropyran - 2 - yloxy) - 4 - methyl - 1 - octenyl] 2 - oxabicyclo [3,3.(j) octan - 3 - one (German Offenlegungs10 schrift 26 29 834.0) and 200 mg of palladium (10% on carbon) in 50 ml of ethyl acetate were stirred for 3 hours at room temperature under an atmosphere of hydrogen, filtered and evaporated in vaouo. 2.8 gms of the hydrogenated compound were obtained in the form of an oil.

IR: 1770/cm. lib) (2RS, 3aR, 4R, 6aS, 3'R, 4'RS) -4-(4- methyl - 3 - (tetrahydropyran - 2 - yloxy) - 1 - octyl] -2hydroxyperhydrocyclopenta(b]furan.

To a solution, cooled to -65°C. of 2.8 gms of the compound prepared in accordance with Example Ila in 100 ml of absolute toluene were added dropwise under argon 25 ml of a 20% w/v solution of diisobutylaluminium hydride in toluene, the mixture was stirred for 30 minutes at -65°C, - 54 the excess of reagent was destroyed by the dropwise addition of isopropanol, 13 ml of water were added and the whole was stirred for 1 hour at room temperature, filtered and the precipitate was washed with methylene chloride and evaporated to dryness in vacuo. 2.65 gm of the lactol were obtained in the form of a colourless oil.

IR: 3600, 3400, 2945/cm. lie) (5Z)-(9s, 15R, 16RS) - 9 - Hydroxy - 16 - methyl - 15 - (tetrahydropyran - 2 - yloxy) - 5 - prostenoic acid 10 methyl ester.

By working in accordance with Example 5a, there are obtained 2.6 gms of the lactol prepared in accordance with Example 11b 2.5 gms of the methyl ester in the form of a colourless oil.

IR: 3600, 3500, 2940, 1735/cm. lid) (5Z) - (9S, 15R, 16RS) - 16 - methyl - 9 tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 5 - prostenoic acid methyl ester.

In a manner analogous to that in Example 5b there were 20 obtained from 1.6 gms of the methyl ester prepared in accordance with Example lie 1.95 gms of the tribenzylsilyl ether in the form of a colourless oil.

IR: 2945, 1732, 1495/cm. - 55 lie) (5Z) - (9S, 15R, 16RS) - 16 - Methyl - 9 tribenzylsilyloxy - - 15 - (tetrahydropyran - 2 - yloxy) - 5 - prosten - 1 - ol In a manner analogous to that in Example 5c there were 5 obtained from 1.8 gms of the compound prepared in accordance with Example lid 1.6 gms of the 1-alcohol in the form of an oi 1.

IR: 3600, 3400, 2945, 1495/cm.

Example 12 (5Z)-(15R)-l-(3-Carboxypropionyloxy-16,16-dimethyl15-hydroxy-5-prosten-9-one.

Under the reaction conditions given in Example 3 there are obtained from 2.1 gms of (5Z)-(&S, 15R)-16,16 - dimethyl - 9 - tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 5 - prosten - 1 - ol and 340 mg of succinic anhydride in ml of pyridine 2.15 gms of (5Z) - (9S, 15R) -1-(3carboxypropionyloxy) - 16,16 - dimethyl - 9 tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) 5 - prostene in the form of a colourless oil.

To 2.1 gms of the hemisuccinate so obtained in 80 ml of THF was added a solution of 1.3 gms of tetrabutyl ammonium fluoride in 18 ml of THF, and the mixture was stirred for hours at room temperature, diluted with water and extracted with ether. The organic phase was agitated three times with water, dried over magnesium sulphate and evaporated - 56 in vacua. By chromatography over silica gel there were obtained with ether 1.1 gms of (5Z) - (9S, 15R) -1-(3carboxypropionyloxy) - 16,16 - dimethyl - 9 - hydroxy - 15 - (tetrahydropyran - 2 - yloxy) - 5 - prostene in the form of an oil.

To 1 gm of this product in 24 ml of acetone there was added at -20°C 1 ml of Jones reagent the mixture was stirred for 30 minutes and the excess of reagent was destroyed with isopropanol. The mixture was diluted with ether, washed neutral with brine, dried over magnesium sulphate and evaporated in vacuo. The residue was stirred with 20 ml of a mixture of acetic acid/water/THF (65/35/10) for 18 hours at room temperature, the mixture was evaporated in vacuo and the residue was chromatographed over silica gel. With methylene chloride/5 methanol 560 mg of the title compound were obtained in the form of a colourless oi 1.

IR: 3600, 3400, 2940, 1730/cm.

The starting material for the above title compound was prepared as follows: 12a) (IS, 5R, 6R, 3'R) - 6 - [4,4 - Dimethyl - 3 (tetrahydropyran - 2 - yloxy) - 1 - octyl] - 2 oxabicyclo [3.3.o] octan - 3 - one.

In a manner analogous to that in Example Ila there were 48864 - 57 obtained from 3.6 gms of (IS, 5R, 6R, 3'R - 6 - [(E) - 3 - (tetrahydropyran - 2 - yloxy) - 4,4 - dimethyl - 1 octenylj - 2 - oxybicyclo[3.3.0) - octan - 3 - one (DOS 26 29 834.0) 3.6 gms of the hydrogenated compound in the form of an oil.

IR: 1770/cm. 12b) (2RS, 3aR, 4R, 6aS, 3'R) - 4 - ^4,4 - Dimethyl - 3 - (tetrahydropyran - 2 - yloxy) - 1 - octyl} -2hydroxyperhydrocyclopenta[b]furane.

In a manner analogous to that in Example lib there were obtained from 3.6 gm of the compound prepared in accordance with Example 12a 3.5 gms of the lacto! in the form of an oil.

IR: 3600, 3400, 2945/cm. 12c) (5Z) - (9S, 15R) - 9 - Hydroxy - 16,16 - dimethyl - 15 - (tetrahydropyran - 2 - yloxy) - 5 - prostenoic acid methyl ester.

In a manner analogous in that in Example 5a there were obtained from 3.3 gms of the lacto! prepared in accordance with Example 12b 3.2 gms of the methyl ester in the form of an oil.

IR: 3600, 3450, 2945, 1735/cm. 12d) (5Z) - (9S, 15R) - 16,16 - Dimethyl - 9 tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy) - 5 - prostenoic acid methyl ester. - 58 In manner analogous to that in Example 5b there were obtained from 3.2 gms of the methyl ester prepared in accordance with Example 12c 3.6 gms of the tribenzylsilyl ether in the form of an oil.

IR: 2940, 1732, 1495/cm. 12e) (5Z) - (9S, 15R) - 16,16 - Dimethyl - 9 tribenzylsilyoxy - 15 - tetrahydropyran - 2 - yloxy) - 5 - prosten - 1 - ol.

In a manner analogous to that in Example 5c there were 10 obtained from 3.4 gms of the compound prepared in accordance with Example 12d 3.3 gms of the 1-alcohol in the form of an oil IR: 3600, 3400, 2940, 1495/cm.

Example 13 (5Z, 13E)-(15R)-l-Acetoxy-15-hydroxy-16-phenoxy-17, 18,19,20-tetranor-5,13-prostadien-9-one.

A mixture of 1.5 gms of the 1-alcohol prepared in accordance with Example 1c, 6 ml of pyridine and 1 ml of acetic anhydride was allowed to stand for 16 hours at room temperature, evaporated in vaouo and filtered with pentane/ether (7+3) over silica gel. 1.55 gms of the 1 acetate were obtained in the form of a colourless oil.

IR: 2950, 1738, 1600, 1493, 1245, 978/cm.

To 1.2 gms of the 1-acetate so obtained in 30 ml of THF was added a solution of 800 mg of tetrabutylammonium fluoride - 59 in 8 ml of THF and the mixture was stirred for 5 hours at room temperature. The mixture was diluted with water, extracted with ether, the extract was washed with brine, dried over magnesium sulphate and evaporated in vacuo.

After purification by chromatography over silica gel there were obtained with ether/pentane (6+4) 510 mg of (5Z, 13E) - (9S, 15R) - 1 - acetoxy - 9 - hydroxy - 15 - (tetrahydropyran - 2 - yloxy) - 16 - phenoxy - 17,18,19,20 - tetranor - 5,13 - prostadiene in the form of an oil.

IR: 3600, 2940, 1737, 1600, 1495, 1245, 978/cm.

To a solution of 500 mg of this product in 10 ml of acetone there was added at -20°C 0.6 ml of Jones reagent, the mixture was stirred for 30 minutes at -20°C and the excess of reagent was destroyed by the addition of isopropanol. The mixture was diluted with ether, agitated neutral with brine, dried over magnesium sulphate and evaporated in vaouo. The residue was stirred for 16 hours at room temperature in 13 ml of a mixture of acetic acid/water/THF (65/35/10). The mixture was then evaporated in vaouo, chromatographed over silica gel with ether and 258 mg of the title compound were obtained in the form of a colourless oil.

IR: 3600, 3430, 2935, 2860, 1740, 1600, 1496, 1250, 976/cm.

Example 14 (5Z, 13E) - (9S, 15R) - 1 - Acetoxy - 9,15 46864 - 60 dihydroxy - 16 - phenoxy (5Z, 13E)-(9S, 15R)-1Acetoxy-9,15-dihydroxy-16-phenoxy- 17,18,19,20tetranor-5,13-prostadiene. 300 mg of (5Z, 13E) - (9S, 15R) - 1 - Acetoxy - 9 tribenzylsilyloxy - 15 - (tetrahydropyran - 2 - yloxy 16 - phenoxy - 17,18,19,20 - tetranor - 5,13 prostadiene (prepared in Example 13) were stirred for 16 hours in 8 ml of a mixture of acetic acid/water/THF (65/35/10) at room temperature, evaporated in vacuo and chromatographed over silica gel. With chloroform there were obtained 120 mg of the title compound in the form of a colourless oi1.

IR: 3600, 3400, 2940, 1735, 1600, 1496, 1250, 978/cm.

Example 15 (5Z, 13E)-(15R)-l-Acetoxy-16,16-dimethyl-15-hydroxy-5, 13-prostadien-9-one.

In a manner analogous to that in Example 13 there was obtained from the compound prepared in accordance with Example 3c the title compound in the form of a colourless oi 1.

IR: 3600, 3500, 2940, 2860, 1740, 1600, 1250, 978/cm.

Example 16 (5Z, 13E)-(15S, 16RS)-l-Acetoxy-15-hydroxy-16-methyl -5,T3-prostadien-9-one.

In a manner analogous to that in Example 13 there was obtained from the compound prepared in accordance with Example 5c the title compound in the form of an oil. - 61 IR: 3600, 3450, 2950, 1740, 1600, 1255, 975/cm.

Example 17 (5Z, 13E)-(15S)-l-Acetoxy-15-hydroxy-17-phenyl-18, 19,20-trinor-5,13-prostadien-9-one.

In a manner analogous to that in Example 13 there was obtained from the 1-alcohol prepared in accordance with Example 7c the title compound in the form of an oil.

IR: 3600, 3420, 2940, 2860, 1740, 1600, 1250, 975/cm.

Example 18 (5Z, 13E)-(15S)-l-Acetoxy-15-hydroxy-15-methyl-5,13prostadien-9-one, A mixture of 500 mg of (5Z, 13E) - (15S) - 9,9 ethylenedioxy - 15 - methyl - 15 - (tetrahydropyran - 2 yloxy) - 5,13 - prostadien - 1 - ol (prepared in accordance with Example 9d), 1 ml of pyridine and 0.5 ml of acetic anhydride was allowed to stand for 16 hours at room temperature, and then evaporated in vacuo.

The residue was stirred with 10 ml of a mixture of acetic acid/water/THF(65/35/10) for 16 hours, evaporated in vaauo and the residue was chromatographed over silica gel with ether. 250 mg of the title compound were obtained in the form of a colourless oil.

IR: 3600, 3300, 2930, 1740, 1600, 1245, 975/cm.

Example 19 (5Z, 13E)-(155)-1-Acetoxy-15-hydroxy-5,13-prostadien» - 62 -9-one.

In a manner analogous to that in Example 18 there was obtained from the 1-alcohol prepared in accordance with Example 10c the title compound in the form of a colourless oil.

IR: 3600, 3520, 2940, 1740, 1250, 975/cm.

Example 20 (5Z)-(15R, 16RS)-l-Acetoxy-15-hydroxy-16-methyl-5prosten-9-one.

In a manner analogous to that in Example 18 there was obtained from the compound prepared in Example 11 the title compound in the form of a colourless oil.

IR: 3600, 3450, 2945, 1740, 1255/cm.

Example 21 (5Z)-(15R)-l-Acetoxy-16,16-dimethyl-15-hydroxy-5prosten-9-one.

In a manner analogous to that in Example 18 there was obtained from the compound prepared in Example 12 the title compound in the form of a colourless oil.

IR: 3600, 3450, 2940, 1740, 1255/cm.

Example 22 -63(5Z,13E)-(15R-15-Hydroxy-l-methoxyacetoxy-16phenoxy-17,18,19,20-tetranor-5,13-prostadien-9-one A mixture of 800 mg of the compound prepared in accordance with Example 1c, 4 ml of pyridine and 1 ml of methoxyacetic acid chloride was stirred for 16 hours at room temperature under argon. The mixture was evaporated in vaouo and the residue was filtered with pentane/ether (7+3) over silica gel and 820 mg of the 1 - methoxyacetate were obtained in the form of a colourless oi1.

IR: 2945, 1736, 1600, 1493, 978/cm.

To 600 mg of the 1-methoxyacetate so obtained in 15 ml of THF was added a solution of 400 mg of tetrabutylammonium fluoride in 4 ml of THF and the mixture was stirred for 6 hours at room temperature. The mixture was diluted with water, extracted with ether, the Organic extract was washed with brine, dried over magnesium sulphate and evaporated in vaouo. After purification by chromatography over silica gel there were obtained with ether/pentane (6+4) 320 mg of (5Z, 13E) - (9S, 15R) - 9 hydroxy - 1 - methoxyacetoxy - 15 - (tetrahydropyran - 2 - yloxy) - 16 - phenoxy - 17,18,19,20 - tetranor -5,13 - prostadiene in the form of an oil.

IR: 3600,2940,1737,1600,1495,978/cm.

To a solution of 300 mg of this product in 8 ml of >46864 -64acetone there was added at -20°C 0.3 ml of Jones reagent, the mixture was stirred for 30 minutes at -20°C and the excess of reagent was destroyed by the addition of isopropanol. The mixture was diluted with ether, agitated with brine until neutral, dried over magnesium sulphate and evaporated in vacuo. The residue was stirred for 16 hours at room temperature in 7 ml of a mixture of acetic acid/water THF (65/35/10). The mixture was then evaporated in vaeuo, the residue was 1Q chromatographed over silica gel with ether and 120 mg of the title compound were obtained in the form of an oil IR: 3600,3400,2935,1740,1600,1496,976/cm.

Example 23 (5Z,13E)-(15R)-1-Methoxyacetoxy-15,16-dimethy1-15-hydroxy ,13-prostadien-9-one In a manner analogous to that in Example 22 there was obtained from the compound prepared in accordance with Example 3c the title compound in the form of an oil.

IR: 3600,3450,2940,1740,1600,978/cm.

Example 24 (5Z,13E)-(15S,16RS)-l-Methoxyacetoxy-15-hydroxy-16-methyl -13-prostadien-9-one In a manner analogous to that in Example 22 there was obtained from the compound prepared in accordance with 4686χ -65 Example 5c of the title compound in the form of an oil.

IR: 3600,3450,2945,1738,1600,978/cm.

Example 25 (5Z,13E)-(15S)-1-Methoxyacetoxy-15-hydroxy-l7-phenyl 5 18,19,20-trinor-5,13-prostadien-9-one.

In a manner analogous to that in Example 22 there was obtained from the compound prepared in accordance with Example 7c the title compound in the form of an oil.

IR:3600,3450,2940,2860,1740,1600,978/cm.

Example 26 (5Z,13E)-(15S)-15-Hydroxy-1-methoxyacetoxy-15-methyl5,13-prostadien-9-one A mixture of 500 mg of (5Z,13E)-(15S)-9,9-ethylenedioxy15-methyl-15-(tetrahydropyran-2-yloxy)-5,13-prostadien - 1 15 ol (prepared in accordance with Example 9d), 3 ml of pyridine and 0.6 ml of methoxyacetlc acid chloride was stirred for 16 hours at room temperature under argon. The mixture was evaporated in vaouo and the residue was stirred for 16 hours at room temperature with 10 ml of a mixture of acetic acid/water/THF (65/35/10), and the mixture was evaporated in vaouo and the residue was chromatographed over silica gel. With ether there were obtained 264 mg of the title compound in the form of a colourless oil. -66IR:3600,3400,2940,1740,1600,976/cm.

Example 27 (5Z)-(15R,16RS)-15-Hydroxy-16-methyl-1-methoxyacetoxy-5prosten-9-one.

In a manner analogous to that in Example 26 there was obtained from the compound prepared in Example lie the title compound in the form of an oil.

IR: 3600,3400,2940,1740/cm.

Example 28 (5Z-(15R)-16,16-Dimethy1-15-hydroxy-1-methoxyacetoxy15 5-prosten-9-one.

In a manner analogous to that in Example 26 there was obtained from the compound prepared in Example 12e the title compound in the form of an oil.

IR:3600,3400,2940,1738/cm.

Example 29 (5Z,13E)-(15R)-15-Hydroxy-1- [(N-methanesulphonyl)carbamoyloxyj 16-phenoxy-17,18,19,20-tetranor-5,13prostadien-9-one.

To a solution of 1 gm of the 1-alcohol prepared in accordance with Example lc in 12 ml of absolute toluene was added at 0°C a solution of 180 mg of methanesulphony! isocyanate in 12 ml of toluene and the mixture was stirred -67for 1 hour at 25°C. Water was then added, the mixture was extracted with ether, the organic extract was washed with water, dried over magnesium sulphate and evaporated in vacuo. After filtration of the residue over silica gel with methylene chloride there were obtained 945 mg of (5Z, 13E) - (9S,15R) - 1 - (N - methanesulphony!) carbamoyloxy - 9 - tribenzylsilyloxy - 15 (tetrahydropyran - 2 - yloxy) - 16 - phenoxy - 17,18, 19,20 - tetranor - 5,13 - prostadiene in the form TO of a colourless oil.

IR: 1720,1600,1493,975/cm.

To 900 mg of the compound so obtained in 25 ml of THF was added a solution of 600 mg of tetrabutyl ammonium fluoride in 6 ml of THF and the mixture was stirred for 6 hours at room temperature. The mixture was then diluted with water, extracted three times with ether, the organic phase was washed neutral with brine, dried over magnesium sulphate and evaporated in vacuo . By purification over silica gel with ether there was obtained 530 mg of the 9-hydroxy20 compound in the form of a colourless oil.

The product was dissolved in 10 ml of acetone and 0.6 ml of Jones reagent was added at -20°C. After 40 minutes, the excess of reagent was destroyed by the addition of isopropanol, the mixture was diluted with ether, washed neutral with brine, dried over magnesium sulphate and evaporated -68in vacuo. The residue was dissolved in 10 ml of a mixture of acetic acid/water/THF (65/35/10). After 16 hours, the mixture was evaporated in vacuo and the residue was chromatographed over silica gel with methylene chloride/1% methanol. 280 mg of the title compound were obtained in the form of a colourless oil.

IR: 3600,3380,1740,1600,1493,1345,976/cm.

Example 30 (5Z,13E)-(15R)-16,16-Dimethyl-15-hydroxy-l-£N-methanesulphonyl) carbamoyloxy] -5,13-prostadien-9-one.

In a manner analogous to that in Example 29 there was obtained from the compound prepared in Example 3c the title compound in the form of a colourless oil.

IR: 3600,3380,1738,1345,978/cm.

Example 31 (5Z,13E)-(15R)-15-Hydroxy-l-N,N-dimethylcarbamoyloxy-16phenoxy-17,18,19,20-tetranor-5,13-prostadien-9-one.

A solution of 1 gm of the compound prepared in accordance with Example lc in 5 ml of pyridine and 0.5 ml of N, Ndimethylcarbamoyl chloride was allowed to stand for 16 hours at room temperature, the mixture was diluted with ether and agitated in succession with dilute sulphuric acid, bicarbonate solution and brine, dried over magnesium sulphate, evaporated to dryness and chromatographed over -69silica gel with ether/pentane (1:1). There were obtained 850 mg of the urethane in the form of an oi 1.

IR: 2950,1700,1600,1495,976/cm.

To a solution of 600 mg of the urethane in 15 ml of THF were added a solution of 400 mg of tetrabutylammoniurn fluoride in 4 ml of THF and the mixture was stirred for 5 hours at room temperature. The mixture was diluted with water, extracted with ether, the extract was agitated with brine, dried over magnesium sulphate and evaporated in vacuo. After filtration over silica gel with ether there were obtained 380 mg of the 9-hydroxy-compound, which was dissolved in 5 ml of acetone and oxidised at -20°C with Jones reagent.

The crude product, without further purification, was stirred with 8 ml of a mixture of acetic acid/water/THF (65/35/10) for 16 hours at room temperature. The mixture was then evaporated in vacuo and the residue was purified by chromatography over silica gel with methylene chloride. There were obtained 190 mg of the title compound in the form of an oil.

IR: 3600,3450,2935,1740,1 702,1600,1495,978/cm.

Claims

1. WHAT WE CLAIM IS;1. A compound of the general formula wherein R-j represents an acyl radical of an organic carboxylic or sulphonic acid or a group obtainable from an oxygen-containing inorganic acid by the removal of a hydroxy group, or a group wherein U represents an oxygen or sulphur atom and R^ and Rg, which may be the same or different, each represents a hydrogen atom, an unsubstituted or substituted alkyl, cycloaikyl, aryl or aromatic heterocyclic radical or an acyl radical of an organic carboxylic or sulphonic acid or R^ and Rg together with the nitrogen atom to which they are -71attached represent an aromatic or non-aromatic unsubstituted or substituted heterocyclic ring having from 4 to 7 ring members, R 2 represents a hydrogen atom or an alkyl group having from 3 to 5 carbon atoms, A represents a ois - CH=CH-, trans- CH=CH- or -C=C - group, B represents a -CHg-CHg-, trans- CH=CH- or -CEC - group, W represents a free, esterified or etherified hydroxymethylene group, wherein the free, esterified or etherified hydroxy group is in the a- or g- configuration, or a group of the formula - C ί R 7 in which Ry represents a free, esterified or etherified hydroxy group in the a-or g- configuration or W represents a free or ketalised carbonyl group, D and E together represent a direct bond or Drepresents an alkylene group having from 1 to 5 carbon atoms or a -esc - group, E represents an oxygen or sulphur atom or a direct bond, R 3 represents an aliphatic hydrocarbon group which may be unsubstituted or substituted by a cycloalkyl, alkyl-substituted cycloalky, unsubstituted or substituted aryl or heterocyclic group, or represents a cycloalkyl or alkyl-substituted cycloalkyl group, or an unsubstituted or substituted aryl or heterocyclic group, and -72Z represents a free or ketalised carbonyl group or a free, esterified or etherified hydroxymethylene group in which the free, esterified or etherified hydroxy group may be in the a- or β- configuration. 5 2. A compound as claimed in claim 1, wherein R^ represents an acyl radical of a carboxylic or sulphonic acid having up to 10 carbon atoms or the group obtainable from a sulphuric acid or phosphoric acid by the removal of a hydroxy group. Ιθ 3. A compound as claimed in claim 2, wherein R^ represents C0CH 2 CH 2 C00H,C0CH 3 or COCHgOCHj. 4. A compound as claimed in claim 1, wherein R^ represents a group of the formula CU-NR^Rg, in which U, R^ and R g are as defined in claim 1. 15 5. A compound as claimed in claim 4, wherein each of R^ ana Rg represents an alkyl group which is unsubstitutea or substituted by one or more of the same or different substituents selected from halogen atoms and alkoxy, unsubstituted and substituted aryl and aromatic heterocyclic 20 groups and dialkylamino and tri alkyl ammonium groups in which the alkyl groups may be the same or different; or an unsubstituted cycloaikyl group having from 3 to 8 carbon atom an unsubstituted or substituted phenyl or naphthyl group; a thienyl, furyl or pyridyl group; or an acyl radical of -73an organic carboxylic or sulphonic acid having up to 6 carbon atoms; or and Rg together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine, hexamethyleneimine, oxazolidine, morpholine or 5 piperazine group or N-alkylpiperazine group in which the alkyl group has up to 5 carbon atoms. 6. A compound as claimed in claim 5, wherein an alkyl group represented by and/or Rg has up to 5 carbon atoms. 7. A compound as claimed in claim 5 or claim 6, wherein 10 a phenyl or naphthyl group represented by and/or R g is unsubstituted or substituted by 1 to 3 halogen atoms, a phenyl group, 1 to 3 alkyl groups each having 1 to 4 carbon atoms, a chloromethyl, fluoromethyl, trifluoromethyl or alkoxy group. 15 8. A compound as claimed in claim 7, wherein the phenyl group is substituted at the 3- and/or 4-position by fluorine, chlorine, alkoxy or trifluoromethyl substituents. 9. A compound as claimed in any one of claims 4 to 8, wherein U represents an oxygen atom. 20 1°· A compound as claimed in claim 4, wherein R-j represents C0NHS0 2 CH 3 or C0N(CH 3 ) 2 . 11. A compound as claimed in any one of claims 1 to 10, -74wherein an esterified or etherified hydroxy group in a group represented by Z and/or W is a hydroxy group esterified by an acyl radical of an organic carboxylic or sulphonic acid or etherified with a 2. -tetrahydropyranyl, 2-tetrahydrofuranyl, α-ethoxyethyl, trimethylsilyl, dimethyl-tert.-butylsilyl or tri-benzylsilyl radical. 12. A compound as claimed in claim 11, wherein the acyl group is an acetyl, propionyl, butyryl or benzoyl group. 13. A compound as claimed in any one of claims 1 to 12, wherein a ketalised carbonyl group represented by Z is a carbonyl group ketalised with ethylene glycol, propane-1, 3. -diol, 2,2-dimethylpropane-l, 3-diol, cyclopentane-1,2-diol or glycerine. 14. A compound as claimed in any one of claims 1 to 13, wherein Rg represents an alkyl group having from 1 to 6 carbon atoms and unsubstituted or substituted by an aryl group, or an aryl group, the aryl group or aryl substituent of an alkyl group being unsubstituted or substituted by 1 to 3 halogen atoms, a phenyl group, 1 to 3 alkyl groups each having 1 to 4. Carbon atoms, a chloromethyl, fluoromethyl, tri fluoromethyl, carboxy, alkoxy or hydroxy group, or Rg represents a cyclopentyl, cyclohexyl, methylcyclohexyl or adamantyl group or a 2-furyl, 2-thienyl or pyridyl or benzodioxol-2-yl group. -7515. A compound as claimed in any one of claims 1 to 13, wherein DER 3 represents CH^OCgHg, (CHgJ^CHg, CH(CH 3 )(CH 2 ) 3 CH 3 , C(CH 3 ) 2 - (CH 2 ) 2 CH 3 or CHgCgHg, 15. A salt of a compound as claimed in any one of claims 5 1 to 15. 17. A physiologically tolerable salt of a compound as claimed in any one of claims 1 to 15. 18. (5Z,13E)-(15R) -1-(3- Carboxypropionyloxy) - 15 hydroxy - 16 - phenoxy - 17,18,19,20 - tetranor - 5, 10 13 - prostadien - 9 - one. 19. (5Z.13E) - (9S, 15R) -1-(3- Carboxypropionyloxy) - 9,15 - dihydroxy - 16 - phenoxy - 17,18,19,20 - tetranor - 5,13 - prostadiene. 20. (5Z.13E) - (15R) -1-(3- Carboxypropionyloxy)- 15 - hydroxy jg 16,16 - dimethyl - 5,13 - prostadien - 9 - one. 21. (5Z.13E) - (9S.15R) -1-(3- Carboxypropionyloxy) - 16,16 - dimethyl - 9,15 - dihydroxy - 5,13 - prostadiene. 22. (5Z.13E) - (15S.16RS) -1-(3- Carboxypropionyloxy) 15 - hydroxy - 16 - methyl - 5,13 - prostadien - 9 - one. , 0 23. (5Z.13E) - (9S,15S,16RS) -1-(3- Carboxypropionyloxy) -76- 9, 15 - dihydroxy - 16 - methyl - 5, 13 - prostadiene. 24. (5Z,13E) - (15S) -1-(3- Carboxypropionyloxy) - 15 hydroxy - 17 - phenyl - 18,19,20 - trinor - 5,13 prostadien - 9 - one. 5. 25. (5Z.13E) - (9S,15S) - 1 -(3- Carboxypropionyloxy) 15 - dihydroxy - 17 - phenyl - 18,19,20 - trinor - 5, 13 - prostadiene. 26. (5S,13E) - (15S) - 1 -(3 - Carboxypropionyloxy) - 15 hydroxy - 15 - methyl - 5,13 - prostadien - 9 - one, 6. 10 27. (5Z,13E) - (15S) -1-(3- Carboxypropionyloxy) - 15 hydroxy - 5,13 - prostadien - 9 - one. 28. (5Z) - (15R.16RS) -1-(3- Carboxypropionyloxy) - 15 hydroxy - 16 - methyl - 5 - prosten - 9 - one. 29. (5Z) - (15R) -1-(3- Carboxypropionyloxy - 16,16 15 dimethyl - 15 - hydroxy - 5 - prosten - 9 - one. 30. (5Z.13E) - (15R) - 1 - Acetoxy - 15 - hydroxy - 16 phenoxy - 17,18,19,20 - tetranor - 5 - 13 - prostadien - 9 one. 31. (5Z,13E) - (9S.15R) - 1 - Actoxy - 9,15-dihydroxy 20 16 - phenoxy - 17,18,19,20 - tetranor - 5,13 - prostadiene. -7732. (5Z.13E) - (15R) - 1 - Acetoxy - 16, 16 - dimethyl - 15 - hydroxy - 5,13 - prostadien - 9 - one. 33. (5Z.13E) - (15S, 16RS) - 1 - Acetoxy - 15 - hydroxy - 16 - methyl - 5,13 - prostadien - 9 - one. 5 34. (5Z,13E) - (15S) - 1 - Acetoxy - 15 - hydroxy - 17 - phenyl - 18,19,20 - trinor - 5,13 - prostadien - 9 - one. 35. (5Z.13E) - (15S) - 1 - Acetoxy - 15 - hydroxy - 15 - methyl - 5,13 - prostadien - 9 - one. 10 36. (5Z.13E) - (15S) - 1 - Acetoxy - 15 - hydroxy - 5,13 - prostadien - 9 - one. 37. (5Z) - (15R, 16RS) - 1 - Acetoxy - 15 - hydroxy - 16 methyl - 5 - prosten - 9 - one. 38. (5Z) - (15R) - 1 - Acetoxy - 16,16 - dimethyl 15 - 15 - hydroxy - 5 - prosten - 9 - one. 39. (5Z.13E) - (15R) - 15 - Hydroxy - 1 - methoxyacetoxy - 16 - phenoxy - 17,18,19,20 - tetranor -5,13 - prostadien - 9 - one. 40. (5S,13E) - (15R) - 1 - Methoxyacetoxy - 16,16 20 dimethyl - 15 - hydroxy - 5,13 - prostadien - 9 - one. -7341. (5Z.13E) - (15SJ6RS) - 1 - Methoxyacetoxy - 15 hydroxy - 16 - methyl - 5,13 - prostadien - 9 - one. 42. (5Z,13E) - (15S) - 1 - Methoxyacetoxy - 15 - hydroxy - 17 - phenyl - 18,19,20 - trinor - 5,13 - prostadien 9 - one. 43. (5Z.T3E) - (15S) - 15 - Hydroxy - 1 - methoxyacetoxy 15 - methyl - 5,13 - prostadien - 9 - one. 44. (5Z) - (15R.16RS) - 15 - Hydroxy - 16 - methyl - 1 methoxyacetoxy - 5 - prosten - 9 - one. 10 45. (5Z) - (15R) - 16,16 - Dimethyl - 15 - hydroxy - 1 methoxyacetoxy - 5 - prosten - 9 - one. 46. (5Z,13E) - (15R) - 15 - Hydroxy - 1 -[(N - methanesulphonyl) - carbamoyloxy - 16 - phenoxy - 17,18,19,20 - tetranor - 5, 7. 13 - prostadien - 9 - one. 8. 15 47. (5Z.13E) - (15R) - 9. 16,16 - Dimethyl - 15 - hydroxy - 1 (N - methanesulphonyl)-carbamoyloxy -5,13 - prostadien - 9 one. 48. (5Z,13E) - (15R) - 15 - Hydroxy - 1 - N,N - dimethylcarbamoyloxy - 16 - phenoxy - 10. 17, 11. 18, 12. 19,20 - tetranor - 5, 13. 20 13 - prostadien - 9 - one. -7949. A compound as claimed in claim 1, which is specified in any one of the Examples 1,3,5,7,9 to 13, 22 and 29 herein, excepting those listed in claims 19, to 48. 50. A process for the preparation of a compound claimed in claim 1 or a salt thereof, wherein a compound of the general formula wherein A,B,D,EjW.Z.Rg and Rg have the meanings given in claim 1, or a salt thereof, is (a) esterified, or (b) reacted with a compound of the general formula u=c=n-r 4 III wherein U and R 4 have the meanings given in claim 1, or (c) reacted with a carbamoyl chloride of the general formula IV -80wherein Rg and R^ have the meanings given in claim 1, and then, if desired, one or more of the following steps is carried out where appropriate in any desired order: (i) a protected hydroxy group is converted to a free hydroxy 5 group; (ii) a free hydroxy group is oxided, or esterified or etherified. (iii) a free carbonyl group is ketalised or reduced; (iv) a ketalised carbonyl group is converted to a free oxo 10 group; (v) a multiple bond is hydrogenated; (vi) a free compound is converted to a salt thereof, or a salt into a free compound; (vii) a mixture of epimers is separated. 15 51. A process as claimed in claim 50, carried out substantially as described herein. 52. A process as claimed in claim 50, carried out substantially as described in any one of the Examples herein. 53. A compound as claimed in claim 1, whenever prepared 20 by a process as claimed in any one of claims 50 to 52. 54. A salt of a compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 50 to 52. -8155. A physiologically tolerable salt of a compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 50 to 52. 56. A pharmaceutical preparation which comprises a 5 compound as claimed in any one of claims 1 to 16,18 to 49, 53 to 55, in admixture or conjunction with a pharmaceutically suitable carrier. 57. A pharmaceutical preparation as claimed in claim 56 which is in dosage unit form.