GB1588157A - Prostanoic acid derivatives and processes for their preparation - Google Patents

Abstract

Novel prostane derivatives of the formula <IMAGE> in which the substituents are defined in Claim 1, are prepared. These compounds are obtained by reacting a corresponding prostane derivative, which has the carboxyl group in the 1 position, with an isocyanate, resulting in the introduction of the radical -NHR1. The compounds which are obtained can be used for the same pharmacological purposes as the natural prostaglandins.

Description

(54) PROSTANOIC ACID DERIVATIVES AND PROCESSES FOR THEIR PREPARATION (71) We, SCHERING AG., a body corporate organised according to the laws of the Federal Republic of Germany, of Berlin and Bergkamen, Federal Republic of Germany, 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 prostane derivatives.

It is known that the physiological action of prostaglandins is of short duration, both in the mammalian organism and also in vitro, as they are rapidly metabolised into a large number of pharmacologically inactive products. It is also known that the natural prostaglandins do not have the biological specificity necessary for a medicament.

It has therefore been desirable to develop prostaglandin analogues having a spectrum of action comparable with that of natural prostaglandins and to bring about structural alterations by means of which the duration and selectivity of activity are increased.

The present invention provides a compound of the general formula

in which R1 represents an acyl radical of a carboxylic or sulphonic acid which is aliphatic, aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic and which has from 1 to 10 carbon atoms, A represents a -CH2-CH2-, cis-CH=CH-, -trans-CH=CH- or -C-C- group, B represents a -CH2-CH2-, trans-CH=CH-, -C-C- or

group, wherein the methylene group may be in the a- or p-configuration, W represents a free, esterified or etherified hydroxymethylene group or a free, esterified or etherified

group, in which groups the hydroxy or etherified or esterified hydroxy group may be in the a- or p-configuration, or a carbonyl group or acetal thereof, 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, E represents an oxygen or sulphur atom or a direct bond, R3 represents an aliphatic hydrocarbon radical or a cycloalkyl or alkylsubstituted cycloalkyl group; an aryl group which is unsubstituted or substituted by I to 3 halogen atoms, a phenyl group, 1 to 3 alkyl groups each having 1 to 4 carbon atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, (C1-C4)-alkoxy or hydroxy group; or an aromatic heterocyclic group; an araliphatic group which is unsubstituted or substituted in the aryl moiety 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, carboxy, (C1-C4)-alkoxy or hydroxy group; or a benzodioxol - 2 - yl group; Z represents a carbonyl group or an acetal thereof or a free, esterified or etherified hydroxymethylene group in which the free, esterified or etherified hydroxy group may be in the a- or p-configuration, and R2 represents an alkyl or alkylthio group having from 1 to 5 carbon atoms, a -C=-N group, or an alkanoylthio group having 1 to 5 carbon atoms in the alkyl moiety.

We have found that such prostaglandin acid amide derivatives surprisingly possess an outstanding specificity of action and, in general, a longer duration of action than natural prostaglandins. The tissue specificity can be influenced by a suitable combination of substituents and modification of the side chain in the 12position. Thus, it is possible to obtain compounds which, for example, stimulate exclusively or preponderantly the non-striated muscular system of the uterus and thus have an anti-fertility action. Some of the compounds of the invention have a blood pressure lowering and diuretic action, while their influence on other organic systems is minimal.

Acyl radicals represented by R1 are those of carboxylic acids and sulphonic acids having 1 to 10 carbon atoms, belonging to the aliphatic, aromatic, aromaticaliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclicaliphatic series. These acids may be saturated or unsaturated, mono-, di- or polybasic, unsubstituted or substituted in the usual manner. As examples of substituents there may be mentioned halogen atoms and alkyl, hydroxy, carboxy, alkoxy, phenoxy, oxo and amino groups and amino groups substituted, for example, by alkyl groups or by an alkylene 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 an alkyl substituent by a halogen atom or atoms.

By way of example there may be mentioned the following carboxylic acids: acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, oenanthic acid, caprylic acid, trimethylacetic acid, diethylacetic acid, tert.-butylacetic acid, cyclopentaneacetic acid, cyclohexaneacetic acid, cyclopropanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, mono-, di- and tri-chloroacetic acid, glycine, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, benzoic acid, benzoic acids substituted by one or more substituents selected from halogen atoms and trifluoromethyl, hydroxy and carboxy groups, furan - 2 - carboxylic acid and cyclopentanepropionic acid. Especially favourable acyl radicals are those having up to 7 carbon atoms.

Suitable sulphonic acids are, for example, methanesulphonic acid, trifluoromethanesulphonic acid, ethanesulphonic acid, isopropylsulphonic acid, ss- chloroethanesulphonic acid, butanesulphonic acid, cyclopropanesulphonic acid, cyclopentanesulphonic acid, cyclohexanesulphonic acid, benzenesulphonic acid, para-toluenesulphonic acid, para - chlorobenzenesulphonic acid, para methoxybenzenesulphonic acid, N,N - dimethylaminosulphonic acid, N,N diethylaminosulphonic acid, N,N - bis - (ss - chloroethyl) - aminosulphonic acid, N,N - diisobutylaminosulphonic acid, N,N - dibutylaminosulphonic acid, l-pyrrolidinyl-, piperidino-, 1-piperazinyl-, 4-methyl-l-piperazinyl-, 2- or 3thiophene- and morpholinosulphonic acid.

An alkyl group represented by R2 may be straight or branched chain, and has from 1 to 5 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl and pentyl radicals. Especially preferred are the methyl and ethyl groups. Preferably, the alkyl moiety of an alkylthio or alkanoylthio group represented by R2 is as specified above for an alkyl group represented by R2.

A hydroxyl group present in the groups represented by W and Z may be, etherified or esterified, and the free esterified or etherified hydroxyl groups may be in the a- or p-configuration.

Suitable etherifiying and esterifying radicals are, for example, the radicals known in prostaglandin derivatives. Preferred are ether-forming radicals capable of being easily split off, such, for example, as the 2 - tetrahydropyranyl, 2 tetrahydrofuranyl, a - ethoxyethyl, trimethylsilyl, dimethyl, tert. - butylsilyl and tri - benzylsilyl radicals. Suitable esterifying radicals are, for example, those carboxylic and sulphonic acid radicals mentioned for R1; especially, for example, acetyl, propionyl, butyryl and benzoyl.

An acetal of the carbonyl group represented by W may for example be an acetal radical known in prostaglandin derivatives. Especially suitable are cyclic acetals prepared, for example, with ethylene glycol, 1,3 - propandiol, 2,2 - dimethyl - 1,3 - propandiol, 1,2 - cyclopentandiol or glycerine.

An unsubstituted or substituted aryl group represented by R3 or an aryl moiety 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 halogen atoms, a phenyl group, 1 to 3 alkyl groups each having 1 to 4 carbon atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, (C1-C4) - alkoxy or hydroxy group. Preferable substitution is in the 3- and 4 - position of the phenyl ring, for example by a fluorine or chlorine atom or an alkoxy or trifluoromethyl group or in the 4-position by a hydroxyl group.

An aliphatic group represented by R3 or an aliphatic moiety in a radical represented by R3 may be straight or branched chain, saturated or unsaturated, preferably saturated, preferably having from l to 10, and especially l to 6, carbon atoms; the aliphatic radical may be unsubstituted or substituted by an unsubstituted or substituted aryl group. By way of example there may be mentioned: methyl, ethyl, propyl, butyl, isobutyl, tert. - butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl and para - chlorobenzyl groups.

A cycloalkyl group represented by R3 preferably contains from 4 to 10, especially 5 to 6, ring carbon atoms. The ring or rings may be substituted by one or more alkyl groups each having 1 to 4 carbon atoms. By way of example there may be mentioned cyclopentyl, cyclohexyl methylcyclohexyl and adamantyl groups.

A heterocyclic group represented by R3 or a heterocyclic moiety in a radical represented by R3 comprises at least one heterocyclic ring, preferably a 5- or 6membered heterocycle having at least one heteroatom, 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.

An alkylene radical represented by D may be straight chained or branched.

D-E-R3 may, for example, represent an n-pentyl group, -CH(CH3)(CH3)3CH3, -C(CH3)2(CH2)3CH3, a phenethyl or phenoxymethyl group or a phenoxymethyl group in which the phenyl moiety is substituted by a chlorine or fluorine atom or by a trifluoromethyl group.

The following groups are especially preferred: R1: -COCH3 or -SO2CH3; A: -CH2-CH2- or -CH--CH-; B: -CH2-CH2- or -CH=CH-; W: -CO-, -CHOH-, -C(C113)OH- or a hydroxymethyl group in which the hydroxy group is etherified with a 2 - tetrahydropyranyl group or esterified with an acetyl group; D-E-R3: -CH2-O-C6H5, -CH(CH3)(CH2)3CH3, -C(CH3)2(CH2)3CH3 or, especially if W is l - hydroxy - 1 - methyl - methylene, -(CM2)4CH3; Z: -CO- or -CHOH-; R2: -CH3, -SCH3 or -CN, especially -CH3.

It will be understood that the structural formulae and written nomenclature of the compounds described and claimed herein include the optical antipodes and racemates of the compounds.

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

The invention also provides a process for the preparation of a compound of the general formula I or a salt of such a compound having a salt-forming group which comprises (a) reacting a compound of the general formula

in which A, B, W, D, E, Z, R2 and R3 have the meanings given above, with a compound of the general formula O=C=N-R1 III in which R1 has the meaning given above, (b) for those compounds in which A represents ci-CH=CH- reacting a lactol of the general formula

in which B, W, D, E, R2 and R3 have the meanings given above, with a Wittig reagent of the general formula

in which Ph represents a phenyl group and R1 has the meaning given above, or (c) hydrolysing a compound of the general formula

in which A, B, D, E, Z, R1, R2 and R3 have the meanings given above, and W' represents protected hydroxymethylene group or protected 1 - hydroxy - 1 methyl - methylene group, and, if desired, one or more of the following steps is carried out in any order: (i) an esterified or etherified hydroxy group is converted to a hydroxy group; (ii) a hydroxy group is esterified or etherified; (iii) a hydroxy group is oxidised; (iv) an acetal carbonyl group is converted to a carbonyl group; (v) a carbonyl group is converted to an acetal; (vi) a carbonyl group is reduced; (vii) a -C=C- group is hydrogenated; (viii) a compound of formula I having a salt-forming group is converted to a salt; (ix) a mixture of epimers is separated.

The reaction of a compound of the general formula II with an isocyanate of the general formula III may be carried out if desired in the presence of a tertiary amine such, for example, as triethylamine or pyridine. The reaction may be carried out without a solvent or in an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, N,N - dimethylacetamide, methylene chloride, diethyl ether, benzene, toluene or dimethyl sulphoxide, at a temperature above or below room temperature, for example from -80"C to 1000C, preferably from OOC to 30"C.

If the starting material contains one or more OH-groups in the prostane radical, these OH-groups also react. If the desired end product has a free hydroxyl group or groups, it is advantageous to use a starting material in which the hydroxyl, is protected by an ether-forming or acyl radical which is subsequently removed.

Preferably therefore, the ether-forming or acyl radical should be easy to split off.

Thus, after the reaction of compounds II and III, for example, optionally protected hydroxyl group(s) are liberated and/or free hydroxyl group(s) are esterified, etherified or oxidised and/or free oxo group(s) are acetalised or reduced and/or double bond(s) are hydrogenated, and optionally the epimers are separated.

The reaction of a lactol of the formula IV with a Wittig reagent of the formula V, which is prepared from the corresponding phosphonium bromide with sodium methyl - sulphinylmethide or potassium tert. - butoxide in dimethyl sulphoxide, may for example be carried out at a temperature of from 0 to 1000 C, preferably 20 to 800 C, in an aprotic solvent, preferably dimethyl sulphoxide or dimethylformamide.

After the reaction of compounds IV and V, for example, a 9 - hydroxyl group, optionally after intermediate protection of the 15 - hydroxyl group, is oxidised and/or a 9 - oxo group is reduced andlor optionally a protected hydroxyl group is liberated and/or free hydroxyl group(s) are esterified, etherified or oxidised and/or free oxo group(s) are acetalised and/or double bond(s) are hydrogenated, and optionally the epimers are separated.

The oxidation of a hydroxyl group may be carried out by methods known per se with the usual oxidising agents. For example, the oxidation of a 9 - hydroxyl group to ketone may be effected with Jones reagent (J. Chem. Soc. 1953, 2555) with intermediate protection of the 15 - hydroxyl group, if present, by silylation (Chem.

Comm. (1972), 1120). The operation may be carried out with an excess of the oxidising agent in an inert solvent, e.g. acetone, at a temperature of from -50 to 30"C, preferably at substantially -20"C. The reaction usually terminates after 5 to 30 minutes.

The acetalisation of a 9- and/or 15 - carbonyl group may be carried out in a manner known per se, for example by heating with ethylene glycol in the presence of an acid catalyst with the separation of water. Especially suitable as acid catalysts are para-toluenesulphonic acid and perchloric acid.

The reduction of a 9 - oxo group, for example in order to prepare the corresponding 9p - hydroxy compound, may be carried out with a reducing agent suitable for the reduction of ketones such, for example, as sodium borohydride.

The resulting epimeric mixture may be separated in the usual manner, for example by column or layer chromatography.

If one or more C=C-double bonds present in the product is to be reduced, the hydrogenation may be carried out by methods known per se.

Hydrogenation of the 5,6-double bond may be carried out in a manner known per se at a low temperature, preferably at substantially -20"C, in an atmosphere of hydrogen in the presence of a noble metal catalyst. As catalyst, for example, 10% palladium on carbon is suitable.

If both the 5,6- and also the 13,14 - double bond are to be hydrogenated, a higher temperature is used, preferably of substantially 200 C.

The liberation of an esterified or etherified hydroxyl group may be carried out by known methods. For example, an ether-protecting group, e.g. the 2 tetrahydropyranyl radical, may be split off by treatment with an aqueous solution of an organic acid such, for example, as oxalic acid, acetic acid or propionic acid, or with an aqueous solution of an inorganic acid, such, for example, as hydrochloric acid. In order to improve solubility it is advantageous to add an inert organic solvent miscible with water. 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. The splitting off is preferably carried out at temperatures of from 20"C to 800 C.

The hydrolysis of an acyl group may be carried out, for example, with an alkali metal or alkaline earth metal carbonate of hydroxide in an alcohol or in an aqueous solution of an alcohol. Suitable alcohols are; for example, aliphatic alcohols, for example methanol, ethanol, and butanol, preferably methanol. Suitable alkali metal carbonates and hydroxides are, for example, potassium and sodium compounds, but the potassium salts are preferred. Suitable alkaline earth metal carbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and barium carbonate. The reaction is preferably carried out at a temperature of from -l00C to +700 C, preferably at 250C.

A compound of the general formula II serving as starting material may be prepared, for example, in a manner known per se in which a prostaglandin-A derivative of the general formula

in which A, B, W, D, E and R3 have the meanings given above and R4 represents a hydrogen atom or a methyl group, is reacted, optionally after free hydroxyl groups have been protected by etherification or esterification, (a) saturating the 10,11 - double bond with the introduction of 11 - alkyl (R2=alkyl), by reaction with dialkyl - copper - lithium reagent in an inert solvent, for example diethyl ether or tetrahydrofuran, or (b) saturating the 10,11 - double bond with the introduction of an 11 - cyano or ll-alkylthio group (R2=-CN or-S-alkyl), by reaction with acetone cyanhydrin or an alkyl mercaptan in the presence of a base, for example sodium hydrogen carbonate or potassium carbonate, or (c) saturating the 10,11 - double bond with the introduction of an alkanoylthio group (R2=-S-CO-alkyl), by reaction with a thiocarboxylic acid, and optionally the 9 - oxo group is acetalised or the 1 - methyl ester is hydrolysed.

A lactol of the general formula IV used as starting material may be prepared by reacting an aldehyde of the general formula

(E. J. Corey et al. J. Org. Chem. 39, 256 (1974)) with a phosphorane or phosphonate in a Wittig reaction to form an z - unsaturated carbonyl compound of the general formula

in which B, D, E and R3 have the meanings given above, and in which the double bond in the 13,14 - position (PG - numbering) is optionally hydrogenated.

After reduction of the 15 - oxo group with zinc borohydride or reaction with an alkyl magnesium bromide or lithium alkyl to form the epimeric 1 5a- and 15p alcohols (PG - numbering), which may, if desired, be separated, and optionally introducing a hydroxyl-protecting group at the 15 - carbon atom, for example, with dihydropyran, there is obtained a compound of the general formula

The lactone so obtained may be reduced with diisobutyl - aluminium hydride to form the lactol of the general formula IV.

A starting material of the general formula VI may be obtained from a compound of the general formula X, in which W represents a free hydroxymethylene group or 1 - hydroxy - 1 - methyl - methylene group

by introducing a hydroxyl-protecting group at the 15-carbon atom, for example with dihydropyran, reducing the lactone with diisobutylaluminium hydride, subsequent reaction with a Wittig reagent of the general formula V and optionally oxidising the 9-hydroxyl group.

After the hydrolysis of a compound of formula VI, for example optionally a 9 oxo group is reduced and/or free hydroxyl group(s) are esterified, etherified or oxidised and/or free oxo group(s) are acetalised and/or double bond(s) are hydrogenated and optionally the epimers are separated.

A prostanoic acid amide of the general formula I is a useful pharmacological product, because, coupled with a similar spectrum of action, it has a considerably better (higher specificity), and above all considerably longer, action than the corresponding natural prostaglandin. As compared with PGE- and PGAderivatives, 11 - deoxyprostaglandins of the present invention are distinguished by a greater stability.

Some of the compounds of the invention have a strong antifertile activity. For inducing abortion, a considerably smaller quantity of the prostanoic acid amide is required than in the case of natural prostaglandins.

The recording of the isotonic contraction of the uterus in anaesthetised rats and in the uterus isolated from rats or guinea-pigs shows that the compounds of the invention are considerably more effective than, and their duration of action longer than that of, natural prostaglandins.

A few of the prostanoic acid amides of the invention are suitable, with a single intrauterine or vaginal application, for inducing menstruation or interrupting a pregnancy. Some of the compounds have a luteolytic action and are suitable for the synchronisation of the sexual cycle in female mammals, for example apes, horses, cattle and pigs.

The good tissue specificity of compounds of the invention having an antifertile or blood pressure lowering action is evident in the investigation of other unstriated organs such, for example, as the ileum of guinea-pigs or the isolated trachea of rabbits, where considerably less stimulation is observed than is the case with natural prostaglandins.

Many of the active substances of the invention exhibit on the isolated trachea of rabbits in vitro even a bronchodilatory action and strongly inhibit the secretion of gastric acid. The compounds having a blood pressure lowering and diuretic action also have a regulating effect on disturbances of cardiac rhythm.

For medicinal use the active substance may be converted into a form suitable for inhalation, for oral, parenteral or local (for example vaginal) application.

For inhalation it is advantageous to prepare aerosol solutions.

For oral application there may be used, for example, tablets, dragees or capsules.

For parenteral administration, there may be used sterile aqueous or oily solutions suitable for injection, for example an aqueous solution containing 0.01 to 10 Mg/ml.

For vaginal application, for example, suppositories are suitable and customary.

Accordingly, the invention also provides a pharmaceutical preparation comprising a compound of the general formula I or a physiologically tolerable salt of such a compound having a salt-forming group, in admixture or conjunction with a pharmaceutically suitable carrier. Preferably, the preparation is in dosage unit form.

The active substances of the invention may be used in combination with additives known and usual in galenical pharmacy, for example, for the production of preparations for inducing an abortion, for controlling menstruation, for inducing birth or for the treatment of hypertonia.

The following Examples illustrate the invention. In the Examples, ether denotes diethyl ether.

Comparative Example 1 (5Z, 1 3E)-( 1 SR)- 1 5-Hydroxy-N-mesyl-9-oxo- 16-phenoxy 17,18,19,20-tetranor-prosta-5,13-dienamide.

300 mg of (5Z,l3E) - (15R - N - mesyl - 9 - oxo - 15 - (tetrahydropyran - 2 yloxy) - 16 - phenoxy - 17,18,19,20 - tetranor - prosta - 5,13 - dienamide are stirred for 5 hours at 400C with 12 ml of a mixture of glacial acetic acid/water/tetrahydrofuran (65/35/10 v/v/v), the mixture is evaporated in vacuo, and the residue is purified by column chromatography over silica gel. With methylene chloride/isopropanol (9+1 by volume) there are obtained 210 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3590, 3400, 2940, 2860, 1736, 1720, 1600, 1340, 972 cm-'.

The starting material for the above compound is prepared as follows: (a) (lS,5R,6R) - 6 - [(E) - 3 - oxo - 4- phenoxy - 1 - butenyl] - 2 - oxabicyclo [3,3,0] - octan - 3 - one.

To a solution of 5.6 gms of dimethyl - (2 - oxo - 3 phenoxypropyl)phosphonate in 200 ml of ether are added dropwise 10 ml of a 2 molar solution of butyl lithium in hexane, the mixture is stirred for 15 minutes and there is then added dropwise to this mixture a solution of 2.6 gms of (1S,5R,6S) 6 - formyl - 2 - oxo - bicyclo - 3.3.0] - octan - 3 - one (E. J. Corey et al., J. Org.

Chem. 39, 256 (1974)) in 30 ml of ether. The whole is stirred for I hour at room temperature, neutralised with glacial acetic acid, diluted with ether, agitated with a solution of 5% sodium bicarbonate and with water, dried over magnesium sulphate and evaporated in vacuo. By filtration over silica gel there are obtained with ether/pentane (8+2 by volume) 2.8 gms of the title compound in the form of a colourless oil.

IR (CHCl3): 1770, 1695, 1670, 1653, 1600, 973 cm-1.

(b) (lS,5R,6R,3'R) - 6 - [(E) - 3 - Hydroxy - 4 - phenoxy - 1 - butenyl] - 2 oxo - bicyclo[3.3.0] - octan - 3 - one.

To a solution of 1.3 gms of the ketone obtained under (a) in 100 ml of 1,2 dimethoxyethane are added at 50C 100 ml of an ethereal solution of zinc borohydride (preparation: Neuere Methoden der praparativen organischen Chemie, Vol. 4, p. 241, Verlag Chemie), and the mixture is stirred for 5 hours at 5"C. After the cautious addition of water, the mixture is diluted with ether, agitated with brine, dried over magnesium sulphate and evaporated to dryness in vacuo. By column chromatography over silica gel (ether/hexane 8+2 by volume) there are eluted first 403 mg of the title compound (a-alcohol) and also 390 mg of the corresponding Alcohol (lS,5R,6R,3'S) - 6 [(E) - 3 - hydroxy - 4 - phenoxy 1 - butenyl] - 2 - oxabicyclo[3.3.0] - octan - 3 - one in the form of a colourless oil.

IR (CHCl3): 3590, 1770, 1600, 975 cm-l.

(c) (lS,5R,6R,3'R) - 6 - [(E) - 3 - (tetrahydropyran - 2 - yl - oxy) - 4 - phenoxy 1 - butenyli - 2 - oxo - bicyclo[3.3.0] - octan - 3 - one.

800 mg of the a - alcohol obtained under (b) are stirred with 0.7 ml of dihydropyran and 8 mg of para - toluene sulphonic acid in 30 ml of dried methylene chloride for 30 minutes at 50C under argon. After dilution with methylene chloride, the mixture is agitated with a saturated solution of sodium bicarbonate and water, dried over magnesium sulphate and evaporated in vacuo. By filtration of the residue over a small amount of silica gel there are obtained with ether/pentane (1+1 by volume) 840 mg of the title compound in the form of a colourless oil.

IR: 2940, 1770, 1600, 975 cm-l.

(d) (2RS,3aR,4R,6aS,3'R) - 4 - [(E) - 3 - (tetrahydropyran - 2 - yl - oxy) - 4 - phenoxy - I - butenyl] - 2 - hydroxy - perhydrocyclopenta[b] - furan.

To a solution, cooled to -650C, of 870 mg of the compound prepared

(f) (5Z,l3E) - (15R) - N- mesyl - 9 - oxo - 15 - (Tetrahydropyran - 2 - yl oxy) - 16 -phenoxy - 17,18,19,20 -tetranor -prosta -5,13 -dienamide.

To a solution of 400 mg of the compound obtained in accordance with Comparative Example l(e) in 10 ml of acetone is added at -200C 0.3 ml of Jones reagent (J. Chem. Soc. 1953, 2555), the mixture is stirred for 30 minutes at --200C, the excess of reagent is destroyed by the dropwise addition of 0.5 ml of isopropanol, 100 ml of water are added and extraction is carried out three times with 50 ml of ether each time. The organic extract is agitated three times with 30 ml of brine each time, dried over magnesium sulphate and evaporated in vacuo. By filtration over silica gel there are obtained with ether 350 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 1736, 1720, 1600, 975 cm~l.

Example 1 l l-Deoxy-2-decarboxy-2-methanesulphonamidocarbonyl- 11 a-methyl-prostaglandin-E2.

To a solution of 215 mg of 11 - deoxy - a - methylprostaglandin - E2 15 - (tetrahydropyran - 2 - yl) ether in 15 ml of tetrahydrofuran is added 0.8 ml of triethylamine, the mixture is stirred for 15 minutes at room temperature, then 5 ml of a solution of 60 mg of methanesulphonyl isocyanate in 5 ml of tetrahydrofuran are added dropwise and the whole is stirred for 6 hours at room temperature. The mixture is then neutralised with acetic acid, concentrated in vacuo, the residue is dissolved in 30 ml of methylene chloride, the solution is agitated with a saturated solution of sodium bicarbonate and with water, dried over magnesium sulphate and evaporated in vacuo. By chromatography of the residue over silica gel there are obtained with ether/pentane (8+2) 170 mg of 11 - deoxy - 2 - decarboxy - 2 methanesulphonamidocarbonyl - lla - methylprostaglandin - E2 15 (tetrahydropyran - 2 - yl) ether in the form of a colourless oil.

In order to split off the protecting group the sulphonamide obtained in this manner is stirred with 7 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10 v/v/v) for 5 hours at 400 C. By evaporation in vacuo and chromatography over silica gel with methylene chloride/isopropanol (9+1 by volume) there are obtained 110 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3600, 3400, 2945, 1735, 1720, 975 cm-l.

The starting material for the above title compound is prepared as follows: (a) 11 - Deoxy - 1 Ia - methylpropstaglandin - E2 15 - (tetrahydropyran - 2 - yl) ether methyl ester.

800 mg of 11 - deoxy - 1 l lia - methylprostaglandin - E2 methyl ester (Chemistry and Industry 1973, 635) are stirred with 0.6 ml of dihydropyran and 6 mg of para - toluenesulphonic acid in 30 ml of methylene chloride for 30 minutes at ice-bath temperature under argon. After dilution with methylene chloride, the mixture is agitated with a saturated solution of sodium bicarbonate and water, dried over magnesium sulphate and evaporated in vacuo. By filtration of the residue over a small amount of silica gel there are obtained with ether/pentane (1+1 by volume) 815 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3000, 2950, 1738, 1725, 975 cm-'.

(b) 11 - Deoxy - 11 a - methylprostaglandin - E2 15 - (tetrahydropyran - 2 - yl) ether.

A mixture of 530 mg of the compound prepared in accordance with Example l(a), 270 mg of the sodium hydroxide, 9 ml of methanol and 1.8 ml of water is stirred for 2 hours at room temperature under argon. The mixture is then concentrated in vacuo, diluted with 30 ml of water, acidified with 5% sulphuric acid to a pH of 6, extracted three times with 40 ml of ethyl acetate each time, the organic extract is agitated twice with 15 ml of brine each time, dried over magnesium sulphate and evaporated in vacuo. There are obtained 480 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3400 (wide), 2942, 2860, 1735, 1705, 975 cm- Example 2 (5Z,13E)-(11R,1 SRS)-N-mesyl- 11,15-dimethyl- 15-hydroxy- 9-oxo-prosta-5,13-dienamide.

From (5Z,13E) - (IIR,15RS) - 11,15 - dimethyl - 15 - hydroxy - 9 - oxo 5,13 - prosta - 5,13 - dienoic acid methyl ester (Chemistry and Industry 1973, 635) there is obtained in a manner analogous to that in Example 1 the title compound in the form of a colourless oil.

IR (CHCl3): 3600, 3400, 1735, 1720, 975 cm-1.

Comparative Example 2 I l-Deoxy-2-decarboxy-2-methanesulphonamidocarboxylprostaglandin-E2 To a solution of 380 mg of 11 - deoxyprostaglandin - E2 15 - acetate in 25 ml of tetrahydrofuran are added 1.5 ml of triethylamine, the mixture is stirred for 15 minutes at room temperature, then 10 ml of a solution of 120 mg of methanesulphonyl isocyanate in 10 ml of tetrahydrofuran are added dropwise and the whole is stirred for 6' hours at room temperature. The mixture is then neutralised with acetic acid, concentrated in vacuo, the residue is dissolved in 50 ml of methylene chloride, the solution is agitated with a saturated solution of sodium bicarbonate and with water, dried over magnesium sulphate and evaporated in vacuo. After filtering the crude product over silica gel there are obtained with ether 325 mg of 11 - deoxy - 2 - decarboxy - 2 - methanesulphonamido carbonylprostaglandin - E2 15 - acetate.

For splitting off the protecting group the 15 - acetate is stirred with 200 mg of anhydrous potassium carbonate in 15 ml of methanol for 4 hours at room temperature under argon. The mixture is neutralised with 0. IN hydrochloric acid, diluted with ether, agitated with brine and with water, dried over magnesium sulphate and evaporated in vacuo. By chromatography over silica gel there are obtained with methylene chloride/isopropanol (9+1 by volume) 240 mg of the title compound in the form of a. colourless oil.

IR (CHCl3): 3600, 3400, 1735, 1720, 975 cm-l.

The starting material for the above title compound is prepared as follows: (a) 11 - Desoxy - prostaglandin - E2 15 - acetate.

To a solution of 1 gm of 11 - desoxy - PGE2 (W. P. Schneider et al., J. Org.

Chem. 38, 951 (1973)) in 4 ml of pyridine is added 0.5 ml of acetic anhydride, and the mixture is allowed to stand at room temperature overnight and then evaporated in vacuo. By chromatography of the residue over silica gel there are obtained with ether 980 mg of the title compound in the form of a slightly yellow coloured oil.

IR (CHCl3): 3400 (wide), 1730, 975 cm-l.

Comparative Example 3 11 -Deoxy-2-decarboxy-2-acetylaminocarbonyl 16,16 dimethyl-prostaglandin-E2 450 mg of 11 - deoxy - 2 - decarboxy - 2 - acetylaminocarbonyl 16,16 dimethyl - prostaglandin - E2 15 - (tetrahydropyran - 2 - yl) ether are stirred for 16 hours at room temperature with 16 ml of a mixture of glacial acetic acid/water/tetrahydrofuran (65/35/10 by volume), evaporated in vacuo, and the residue is purified by column chromatography over silica gel. With methylene chloride/isopropanol (9+1 by volume) there are obtained 320 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3600, 3400, 2930, 2860, 1735, 1705, 1270, 972 cm The starting material for the above compound is prepared as follows: (a) (lS,5R,6R) - 6 - [(E) - 3 - oxo - 4,4 - dimethyl - i - octenyl] - 2 - oxa bicyclo[3.3.0] - octan - 3 - one.

To a mixture of 0.46 gm of sodium hydride suspension (50 /" in mineral oil) in 40 ml of 1,2 - dimethoxyethane is added dropwise at 200C under argon a solution of 2.75 gms of (3,3 - dimethyl - 2 - oxoheptyl)phosphonic acid dimethyl ester in 8 ml of 1,2 - dimethoxyethane, and the mixture is stirred for 2 hours at 200C. To this mixture is added dropwise a solution of 1.54 gms of(lS,5R,6S) - 6 - formyl - 2 oxabicyclo [3.3.0] - octan - 3 - one in 30 ml of tetrahydrofuran at --100C and stirred for 2 hours at 100 C. After neutralisation with glacial acetic acid, ether is added, and the mixture is agitated with a saturated solution of sodium bicarbonate and. with water, dried over magnesium sulphate and evaporated in vacuo. By chromatography of the residue over silica gel there are obtained with ether/pentane (8+2 by volume) 1.48 gms of the title compound in the form of a colourless oil.

IR (CHCl3): 1770, 1695, 1670, 1653, 975 cm-l.

(b) (1S,5R,6R,3'R)- 6 - [(E) - 3 - Hydroxy - 4,4 - dimethyl - I - octenyll - 2 oxabicyclo - [3.3.0] - octan - 3 - one.

To a solution of 1.5 gms of the ketone obtained in accordance with Comparative Example 3(a) in 100 ml of 1,2 - dimethoxyethane are added at icebath temperature 110 ml of an ethereal solution of zinc borohydride (see Comparative Example l(b)) and the whole is stirred for 4 hours at the ice-bath temperature. After the cautious addition of 2 ml of water, the mixture is stirred for 30 minutes, filtered, diluted with ether, and the filtrate is agitated with brine, dried over magnesium sulphate and evaporated in vacuo. By chromatography over silica gel (ether/pentane 8+2 by volume) there are eluted first 660 mg of the title compound (a-alcohol) and also 430 mg of the corresponding more polar alcohol (lS,5R,6R,3'S) - 6 - [(E) - 3 - hydroxy - 4,4 - dimethyl - I - octenyl] - 2 oxabicyclo - [3.3.0] - octan - 3 - one in the form of a colourless oil.

IR (CHCl3): 3600, 1770, 975 cm-1.

(c) (lS,5R,6R,3'R) - 6 - [(E) - 3 - (tetrahydropyran - 2 - yl - oxy) - 4,4 - dimethyl - I - octenyl] - 2 - oxa - bicyclo - [3.3.0] - octan - 3 - one.

600 mg of the a-alcohol obtained in accordance with Comparative Example 3(b) are stirred with 0.4 ml of dihydropyran (freshly distilled) and 5 mg of para toluenesulphonic acid in 25 ml of methylene chloride for 30 minutes at ice-bath temperature under argon. After dilution with methylene chloride, the mixture is agitated with a saturated solution of sodium bicarbonate and water, dried over magnesium sulphate and evaporated in vacuo. By filtration of the residue over a small amount of silica gel there are obtained with ether/pentane (1+1 by volume) 620 mg of the title compound in the form of a colourless oil.

IR (CHC13): 1770, 975 cm-l.

(d) (2RS,3aR,4R,6aS,3'R) - 4 - [(E) - 4,4 - dimethyl - 3 - (tetrahydropyran - 2 yl - oxy) - 1 - octenyl] - 2 - hydroxy - perhydrocyclopenta - [b] - furan.

To a solution, cooled to -650C., of 600 mg of the compound prepared in accordance with Comparative Example l(c) in 25 ml of dry toluene are added dropwise under argon 5 ml of a solution of 20% diisobutylaluminium hydride in toluene, the mixture is stirred for 30 minutes at -650C, and the reaction is terminated by the dropwise addition of isopropanol. 2 ml of water are added, and the mixture is allowed to rise to room temperature, stirred for 30 minutes, filtered and evaporated in vacuo. There are obtained 595 mg of the title compound in the form of a colourless oil.

IR (CHCI3): 3600, 2960, 972 cm-'.

(e) (5Z,13E)- (9S,l5R) - N - Acetyl- 9 - hydroxy - 16,16 - dimethyl - 15 (tetrahydropyran - 2 - yI - oxy) - prosta - 5,13 - dienamide.

To a solution of 4.9 gms of [4 - (acetylaminocarbonyl) - butyl] - triphenyl phosphonium bromide in 20 ml of dry DMSO are added dropwise at 150C 20 ml of a solution of sodium methylsulphinylmethide in dry DMSO (preparation: 1 gm of a suspension of 50 /" sodium hydride is dissolved in 20 ml of DMSO in the course of one hour at 700 C.) and the whole is stirred for 15 minutes at room temperature. To the red ylene solution is added dropwise a solution of 930 mg of the lactol obtained in accordance with Example 3(d) in 13 ml of DMSO, and the whole is stirred for 4 hours at 450C. The reaction mixture is poured into ice-water, acidified to a pH of 4-5 with a 10% citric acid solution, and extracted four times with 80 ml of a mixture of ether/pentane (1 + 1 by volume) each time. The organic phase is agitated with brine, dried over magnesium sulphate and evaporated in vacuo. By chromatography of the residue over silica gel there are obtained with methylene chloride/isopropanol (9+1 by volume) 720 mg of the title compound in the form of a colourless oil.

IR (CHCI3): 3400, 2940, 2860, 1733, 1705, 972 cm-'.

(f) 11 - Deoxy - 2 - decarboxy - 2 - acetylaminocarbonyl 16,16 - dimethyl prostaglandin - E2 15 - (tetrahydropyran - 2 - yl) ether.

To a solution of 500 mg of the compound obtained in accordance with Comparative Example 3(e) in 12 ml of acetone is added at -200C. 0.5 ml of Jones reagent (J. Chem. Soc. it53, 2555), stirred for 30 minutes at -200C, the excess of reagent is decomposed by the dropwise addition of 0.6 ml of isopropanol, 100 ml of water are added and extraction is carried out three times with 50 ml of ether each time. The organic extract is agitated three times with 40 ml of brine each time, dried over magnesium sulphate and evaporated in vacuo. By filtration over silica gel there are obtained with-ether 420 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3400, 2930, 2860, 1733, 1705, 972 cm-'.

Comparative Example 4 (5Z, I 3E)-(9S, 155)-9,1 5-Dihydroxy-N-mesyl 1 7-phenyl- 18,1 9,20-trinor-prosta-5, 1 3-dienamide.

To a solution of 2.6 gms of [4 - (methansulphonylaminocarbonyl) - butyl] triphenyl - phosphonium bromide in 10 ml of dry dimethyl sulphoxide are added dropwise at 150C. 10 ml of a'solution of sodium methylsulphinylmethide in DMSO (preparation: 0.5 gm of a suspension of 50 /n sodium hydride is dissolved in 10 ml of DMSO in the course of one hour at 700C), and the mixture is stirred for 15 minutes at room temperature. To the red ylid solution is added dropwise a solution of 355 mg of(2RS,3aR,4R,6aS,3'S) - 4 - [(E) - 3 - hydroxy - 5 - phenyl - I - pentenyl] 2 - hydroxyperhydrocyclopenta[b]furan in 7 ml of DMSO and the mixture is stirred for 4 hours at 450C. The reaction mixture is poured onto ice-water, acidified to a pH of 4-5 with a 10% citric acid solution, and extracted four times with 50 ml of a mixture of ether/pentane (1+1 by volume) each time. The organic phase is agitated with brine, dried over magnesium sulphate and evaporated in vacuo. By chromatography of the residue over silica gel there are obtained with methylene chloride/isopropanol (8+2 by volume) 310 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3600, 3400, 2940, 1720, 1600, 1585, 1345, 972 cm-'.

The starting material for the above compound is prepared as follows: (a) (lS,5R,6R) - 6 - [(E) - 3 - Oxo - 5 - phenyl - 1 - pentenyl] - 2 - oxabicyclo [3.3.0] - octan - 3 - one.

From 1.3 gms of (lS,5R,6S) - 6 - formyl - 2 - oxabicyclo - [3.3.0]octan - 3 one and 2.8 gms of dimethyl(2 - oxo - 4 - phenylbutyl)phosphonate there are obtained in a manner analogous to that in Comparative Example l(a) 1.35 gms of the title compound in the form of a colourless oil.

IR (CHCl3): 1770, 1695, 1670, 1655, 1600, 1585, 972 cm-'.

(b) (lS,5R,6R,3'S) - 6 - [(E) - 3 - Hydroxy - 5 - phenyl - 1 - pentenyl] - 2 - oxa bicyclo - [3.3.0] - octan - 3 - one.

From 1.2 gms of the ketone obtained in accordance with Comparative Example 4(a) there are obtained in a manner analogous to that in Comparative Example l(b) 410 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3600, 1770, 1600, 1585, 972 cm-'.

(c) (2RS,3aR,4R,6aS,3'S) - 4 - [(E) - 3 - Hydroxy - 5 - phenyl - I - pentenyl] 2 - hydroxyperhydrocyclopenta[b] - furan.

To a solution, cooled to -650C, of 400 mg of the compound prepared in accordance with Comparative Example 4(b) in 15 ml of dry toluene are added dropwise under argon 4 ml of a solution of 20% diisobutylaluminium hydride in toluene, the mixture is stirred for 30 minutes at -650C and the reaction is terminated by the dropwise addition of isopropanol. 1.5 ml of water are added, the temperature is allowed to rise to room temperature, the mixture is stirred for 30 minutes, filtered and evaporated in vacuo. 390 mg of the title compound are obtained in the form of a colourless oil.

IR: 3600, 1600, 1585, 972 cm-'.

Comparative Example 5 (5Z, 1 3E)-( 1 5S)- 1 5-Hydroxy-9-oxo-N-mesyl- 1 7-phenyl- 18,19,20-trinor-prosta-5.3 1 3-dienamide.

To a solution of 100 mg of the sulphonamide prepared in accordance with Comparative Example 4 in 4 ml of absolute acetone are added at -450C 1.2 ml of N,N - diethyltrimethylsilylamine and the whole is stirred for 6 hours at 40C C. It is then diluted with 40 ml of ether, which has previously been cooled to --700C, the mixture is agitated once with 5 ml of ice-cold sodium bicarbonate solution and twice with 5 ml of brine each time, dried with sodium sulphate and evaporated in vacuo. The 15 - (trimethylsilyl ether) obtained in this manner is dissolved in 15 ml of absolute methylene chloride and at +50C. there is added a solution of 700 mg of Collins reagent (prepared: see Org. Synthesis Vol. 52, 5), stirred for 10 minutes, diluted with 50 ml of ether, filtered and evaporated in vacuo. For splitting off the silyl ether protecting group the residue is stirred with a mixture of 9 ml of methanol, 0.9 ml of water and 0.45 ml of glacial acetic acid for 45 minutes at room temperature. The mixture is then diluted with 50 ml of ether, agitated with a saturated solution of sodium bicarbonate and twice with 10 ml of brine each time, dried over magnesium sulphate and evaporated in vacuo. After purification by preparative layer chromatography (methylene chloride/methanol 9+1 by volume as eluant) on silica gel plates there are obtained 33 mg of the title compound in the form of a weakly yellow coloured oil.

IR (CHCI3): 3600, 3400, 1735, 1720, 1600, 1585, 975 cm-'.

Comparative Example 6 I l-Deoxy-2-decarboxy-2-acetylaminocarbonyl-13,14-dihydro- 16,1 6-dimethyl-prostaglandin-E2 355 mg of 11 - deoxy - 2 - decarboxy - 2 - acetylaminocarbonyl 13,14 dihydro - 16,16 - dimethyl - prostaglandin - E2 15 - (tetrahydropyran - 2 - yl) ether are stirred for 4 hours at 500C with 12 ml of a mixture of a glacial acetic acid/water/tetrahydrofuran (65/35/10 v/v/v), evaporated in vacuo and the residue is purified by column chromatography over silica gel. With methylene chloride/isopropanol (9+1) 280 mg of the title compound are obtained in the form of a colourless oil.

IR (CHCl3): 3600, 3400, 1735, 1705, 1270 cm-'.

The starting material for the above title compound is prepared as follows: (a) (lS,5R,6R,3'R) - 6 - [4,4 - Dimethyl - 3 - (tetrahydropyran - 2 - yl - oxy) octyl] - 2 - oxabicyclo[3.3.0] - octan - 3 - one.

A solution of 1.1 gms of the compound prepared in accordance with Comparative Example 3(c) in 50 ml of ethyl acetate is agitated with the addition of 60 mg of palladium (10 /,, on carbon) for one hour under an atmosphere of hydrogen at room temperature. After filtration and evaporation of the solution, the residue is filtered over silica gel. With ether/pentane (8+2 by volume) there are obtained 1.05 gms of the title compound in the form of a colourless oil.

IR (CHCl3): 1770 cm-'.

(b) (2RS,3aR,4R,6aS,3'R) - 4 - [4,4 - Dimethyl 3 - (tetrahydropyran - 2 - yl oxy) - octyl] - 2 - hydroxyperhydrocyclopenta - [b] - furan.

From I gm of the compound prepared in Comparative Example 6(a) there is obtained in a manner analogous to that in Comparative Example 3(d) 1 gm of the title compound in the form of a colourless oil.

(c) (5Z) - (9S,l5R) - N - Acetyl - 9 - Hydroxy - 16,16 - dimethyl - 15 (tetrahydropyran - 2 - yl - oxy) - prost - 5 - enamide.

From I gm of the compound prepared in accordance with Comparative Example 6(b) there are obtained in a manner analogous to that in Comparative Example 3(e) 810 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3595, 3400, 2940, 2860, 1733, 1705 cm-'.

(d) 11 - Deoxy - 2 - decarboxy - 2 - acetylaminocarbonyl - 13,14 - dihydro 16,16 - dimethyl - prostaglandin - E2 15 - (tetrahydropyran - 2 - yl) ether.

From 0.8 gm of the compound prepared in Comparative Example 6(c) there is obtained in a manner analogous to that in Comparative Example 3(f) 0.68 gm of the title compound in the form of a colourless oil.

IR (CHCl3): 3400, 2930, 2860, 1733, 1705 cm-'.

Example 3 11 -Cyano-2-decarboxy-2-methanesulphonamidocarbonyl- I 1 -deoxy prostaglandin-E2.

From 240 mg of 11 - cyano - 11 - deoxy - prostaglandin - E2 15 - acetate there are obtained in a manner analogous to that in Comparative Example 1 130 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3600, 3400, 2240, 1735, 1720, 975 cm-'.

The starting material for the above title compound is prepared as follows: (a) 11 - Cyano - 11 - deoxy - prostaglandin - E2 15 - acetate.

From 300 mg of 11 - cyano - 11 - deoxy - prostaglandin - E2 (C. V.

Grudzinskas et al., Tetrahedron Letters 1973, 141) there are obtained in a manner analogous to that in Comparative Example 2(a) 280 mg of the title compound in the form of a colourless oil.

Example 4 Ila-methylthio-l -deoxy-2-decarboxy-2-methanesulphonamidocarbonyl- prostaglandin-E2 From 210 mg of ila - methylthio - 11 - deoxy - prostaglandin - E2 15 acetate there are obtained in the manner analogous to that in Comparative Example 2 85 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3600, 3400, 1735, 1220, 975 cm-'.

The starting material for the above title compound is prepared as follows: (a) llcg - Methylthio - 11 - deoxy - prostaglandin - E2 15 - acetate.

From 310 mg of lla - methylthio - 11 - deoxyprostaglandin - E2 (German Offenlegungsschrift No. 2,330,905) there are obtained in a manner analogous to that in Comparative Example 2(a) 220 mg of the title compound in the form of a colourless oil.

Comparative Example 7 (5Z, 1 3E)-( 1 5S)-N-Acetyl- 1 5-hydroxy- 1 5-methyl-9- oxoprosta-5, 13-dienamide.

To a solution of 430 mg of (5S,13E) - (l5S) - 15 - methyl 15(tetrahydropyran - 2 - yloxy) - 9 - oxoprosta - 5,13 - dienoic acid in 12.5 ml of acetonitrile are added 150 mg of triethylamine, the mixture is stirred for 15 minutes at room temperature, there are then added dropwise at OOC. 12.5 ml of a solution of 110 mg of acetyl isocyanate in 12.5 ml of acetonitrile, and the mixture is stirred for 2 hours at room temperature. The mixture is concentrated in vacuo, acidified to a pH of 6 with sulphuric acid of 5% strength, extracted three times with 50 ml of ether each time, the organic extract is agitated with brine, dried with magnesium sulphate and evaporated in vacuo. By filtration of the crude produce over silica gel there are obtained with ether 405 mg of (5Z,13E) - (155) - N - acetyl - 15 methyl - 9 - oxo - 15 - (tetrahydropyran - 2 - yl - oxy) - prosta - 5,13 dienamide in the form of a colourless oil.

In order to split off the protecting group the acetyl amide obtained in this manner is stirred with 16 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10 v/v/v) for 5 hours at 400 C. By evaporation in vacuo and chromatography over silica gel with methylene chloride/isopropanol (9+1 by volume) 325 mg ofthe title compound are obtained in the form of a colourless oil.

IR (CHCl3): 3600, 3400, 2935, 2860, 1735, 1705, 975 cm-'.

Example 5 11 -Deoxy-2-decarboxy-2-acetylaminocarbonyl 11 a methylprostaglandin-E2.

From 190 mg of the compound described in Example l(b) there are obtained in a manner analogous to that in Comparative Example 7 110 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3595, 3400, 1735, 1705, 975 cm-'.

Example 6 (5Z, 1 3E)-( 1 lR, 1 5RS)-N-Acetyl- 11,1 5-dimethyl- 1 5-hydroxy- 9-oxo-prosta-5, I 3-dienamide.

From the starting compound mentioned in Example 2 there is obtained in a manner analogous to that in Comparative Example 7 the title compound in the form of a colourless oil.

IR (CHCl3): 3600, 3400, 1735, 1705, 975 cm-'.

Comparative Example 8 (5Z, I 3E)-(9S, 1 5R)-9, 1 5-Dihydroxy-N-mesyl- 1 6-phenoxy- 17,18,1 9,20-tetranor-prosta-5, 13-dienamide.

200 mg of the compound prepared in accordance with Comparative Example l(e) are stirred for 5 hours at 450C with 8 ml of a mixture of glacial acetic acid/water/tetrahydrofuran (65/35/10 v/v/v), evaporated in vacuo and the residue is purified by column chromatography over silica gel. With chloroform/methanol (9+1 by volume) 140 mg of the title compound are obtained in the form of a colourless oil.

IR (CHCl3): 3600, 3400, 2940, 1720, 1600, 1340, 975 cm-'.

Example 7 By methods analogous to those in Comparative Examples 1, 3, 4, 5, 6 and 8 the following prostaglandins can be prepared: (5Z,l3E) - (1 lR,l5R) - 15 - Hydroxy N - mesyl - 11 - methyl - 9 - oxo - 16 - phenoxy - 17,18,19,20 - tetranor - prosta - 5,13 - dienamide. II - Deoxy - 2 - decarboxy - 2 methanesulphonamidocarbonyl - 1 la,l6,16 trimethyl - prostaglandin - E2.

11 - Deoxy - 2 - decarboxy - 2 - methanesulphonamidocarbonyl - 11a,16 dimethylprostaglandin - E2.

Comparative Example 9 (5Z, I 3E)-(9R, 1 5S)-9, 1 5-Dihydroxy-N-mesyl- 15-methyl prosta-5, 1 3-dienamide.

To a mixture of 250 mg of (5Z,13E) - (15S) - 15 - hydroxy - N - mesyl - 15 methyl - 9 - oxoprosta - 5,13 - dienamide, 3 ml of tetrahydrofuran and 3 ml of n propanol are added at 50C 25 mg of sodium

(13E) - (11R,15RS) - N - mesyl - 11,15 - dimethyl - 15 - hydroxy - 9 oxoprost - 13 - enamide.

11 - Deoxy - 2 - decarboxy - 2 - acetylaminocarbonyl - lIa methylprostaglandin - E,.

(13E) -(llR,l5RS) -N -Acetyl -11,15 dimethyl 15 -hydroxy - 9 - oxo prost - 13 - enamide.

Comparative Example 1! (1 5R)-15-Hydroxy-N-mesyl-9-oxo-16-phenoxy- 17,18,19,20-tetranor-prostanamide.

A solution of 150 mg of the compound prepared in accordance with Comparative Example 1 in' 15 ml of ethyl acetate is agitated with 15 mg of palladium (10% strength on carbon) for one hour under an atmosphere of hydrogen at room temperature. After filtration, there are obtained by chromatography of the evaporation residue over silica gel with chloroform/isopropanol (9+1 by volume) 95 mg of the title compound in the form of a colourless oil.

IR (CHCl3): 3600, 3400, 2940, 2860, 1735, 1720, 1600, 1340 cm-'.

The NMR-spectrum shows no olefinic protons.

Example 10 In a manner analogous to that in Comparative Example 11 there can be prepared from the corresponding prosta - 5,13 - dienamides the following prostanamides: 11 - Deoxy - 2 - decarboxy - 2 - methanesulphonamidocarbonyl - 13,14 dihydro - 11&alpha; - methylprostaglandin - E,.

(11R,15RS) - N- MesyI - 11,15 - dimethyl - 15 - hydroxy - 9 oxoprostanamide.

11 - Deoxy - 2 - decarboxy - 2 - acetylaminocarbonyl - 13,14,- dihydro lla- methylprostaglandin - E,.

(11R, 15RS)- N - Acetyl- 11,15 - dimethyl - 15 - hydroxy - 9 - oxo prostanamide.

WHAT WE CLAIM IS: 1. A compound of the general formula

in which R, represents an acyl radical of a carboxylic or sulphonic acid, which is aliphatic, aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic aliphatic, heterocyclic or heterocyclic-aliphatic and which has from 1 to 10 carbon atoms, A represents a -CH2-CH2-, ds-CH=CH-, -trans--CH=CH- or -C-C- group, B represents a -CH2-CH2-, trans-CH=CH-, -C=-C- or

group, wherein the methylene group may be in the a- or ss-configuration.

W represents a free, esterified or etherified hydroxymethylene group or a free, esterified or etherified

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

Claims (46)

**WARNING** start of CLMS field may overlap end of DESC **. (13E) - (11R,15RS) - N - mesyl - 11,15 - dimethyl - 15 - hydroxy - 9 oxoprost - 13 - enamide. 11 - Deoxy - 2 - decarboxy - 2 - acetylaminocarbonyl - lIa methylprostaglandin - E,. (13E) -(llR,l5RS) -N -Acetyl -11,15 dimethyl 15 -hydroxy - 9 - oxo prost - 13 - enamide. Comparative Example 1! (1 5R)-15-Hydroxy-N-mesyl-9-oxo-16-phenoxy- 17,18,19,20-tetranor-prostanamide. A solution of 150 mg of the compound prepared in accordance with Comparative Example 1 in' 15 ml of ethyl acetate is agitated with 15 mg of palladium (10% strength on carbon) for one hour under an atmosphere of hydrogen at room temperature. After filtration, there are obtained by chromatography of the evaporation residue over silica gel with chloroform/isopropanol (9+1 by volume) 95 mg of the title compound in the form of a colourless oil. IR (CHCl3): 3600, 3400, 2940, 2860, 1735, 1720, 1600, 1340 cm-'. The NMR-spectrum shows no olefinic protons. Example 10 In a manner analogous to that in Comparative Example 11 there can be prepared from the corresponding prosta - 5,13 - dienamides the following prostanamides: 11 - Deoxy - 2 - decarboxy - 2 - methanesulphonamidocarbonyl - 13,14 dihydro - 11&alpha; - methylprostaglandin - E,. (11R,15RS) - N- MesyI - 11,15 - dimethyl - 15 - hydroxy - 9 oxoprostanamide. 11 - Deoxy - 2 - decarboxy - 2 - acetylaminocarbonyl - 13,14,- dihydro lla- methylprostaglandin - E,. (11R, 15RS)- N - Acetyl- 11,15 - dimethyl - 15 - hydroxy - 9 - oxo prostanamide. WHAT WE CLAIM IS:

1. A compound of the general formula

in which R, represents an acyl radical of a carboxylic or sulphonic acid, which is aliphatic, aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic aliphatic, heterocyclic or heterocyclic-aliphatic and which has from 1 to 10 carbon atoms, A represents a -CH2-CH2-, ds-CH=CH-, -trans--CH=CH- or -C-C- group, B represents a -CH2-CH2-, trans-CH=CH-, -C=-C- or

group, wherein the methylene group may be in the a- or ss-configuration.

W represents a free, esterified or etherified hydroxymethylene group or a free, esterified or etherified

group in which groups the free, esterified or etherified hydroxy group may be in the a- or p-configuration, or a carbonyl group or an acetal thereof, D and E together represent a direct bond, or D represents an alkylene group having from I to 5 carbon atoms or a -C-C- group, E represents an oxygen or sulphur atom or a direct bond, R3 represents an aliphatic hydrocarbon radical or a cycloalkyl or alkyl substituted cycloalkyl group; an aryl group unsubstituted or substituted by 1 to 3 halogen atoms, by a phenyl group, by I to 3 alkyl groups each having 1 to 4 carbon atoms, or by a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, (C1-C4) - alkoxy or hydroxy group; or represents an aromatic heterocyclic group; an araliphatic group which is unsubstituted or substituted in the aryl moiety by 1 to 3 halogen atoms, by a phenyl group, by 1 to 3 alkyl groups each having I to 4 carbon atoms, or by a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, (CtC4) - alkoxy or hydroxy group; or represents a benzodioxol - 2 - yl group; Z represents a carbonyl group or an acetal thereof or a free, esterified or etherified hydroxymethylene group in which the free, esterified or etherified hydroxy group may be in the a- or p-configuration, and R2 represents an alkyl group having from 1 to 5 carbon atoms, a -C--N group, an alkylthio group having from I to 5 carbon atoms or alkanoylthio group having from 1 to 5 carbon atoms in the alkyl moiety.

2. A compound as claimed in claim 1, wherein the acyl radical represented by R, has from 1 to 7 carbon atoms.

3. A compound as claimed in claim 1 or claim 2, wherein the acyl radical represented by R, contains one or more of the same or different substituents selected from halogen atoms and alkyl, hydroxy, carboxy, alkoxy, phenoxy, oxo, amino, alkyl-substituted amino and alkyleneamino groups, alkyleneamino groups wherein the alkylene group is interrupted by a heteroatom, and halogen-substituted alkyl groups.

4. A compound as claimed in any one of claims 1 to 3, wherein R2 represents a methyl or ethyl group.

5. A compound as claimed in any one of claims 1 to 4, wherein R3 represents an alkyl having from 1 to 10 carbon atoms, a cycloalkyl group having from 4 to 10 ring carbon atoms and being unsubstituted or substituted by one or more alkyl groups each having from 1 to 4 carbon atoms, an aryl-substituted alkyl group in which the alkyl moiety has from 1 to 10 carbon atoms and the aryl moiety is unsubstituted or substituted as specified in claim 1, an unsubstituted or substituted aryl group as specified in claim 1 or a 2-furyl, 2-thienyl, 2-pyridyl, 3pyridyl or 4-pyridyl group.

6. A compound as claimed in claim 5, wherein R3 represents an alkyl group having from 1 to 6 carbon atoms, a cyclopentyl, cyclohexyl, methylcyclohexyl or adamantyl group, an aryl-substituted alkyl group in which the alkyl moiety has from 1 to 6 carbon atoms or an aryl group, the aryl moiety of an aryl-substituted alkyl group or the aryl group being a phenyl or naphthyl group which is unsubstituted or substituted as specified in claim 1.

7. A compound as claimed in claim 6, wherein R3 represents an aryl group substituted in the 3- or 4-position by a fluorine or chlorine atom or an alkoxy or trifluoromethyl group or in the 4-position by a hydroxy group.

8. A compound as claimed in any one of claims 1 to 4, wherein D-E-R3 represents CH2OC6Hs, (CH2)4CH3, CH(CH3)(CH2)3CH3 or C(CH3)2(CH2)3CH3.

9. A compound as claimed in any one of claims 1 to 8, wherein W and/or Z is a hydroxy group etherified by a 2 - tetrahydropyranyl, 2 - tetrahydrofuranyl, a ethoxyethyl, trimethylsilyl, dimethyl, tert. - butyl - silyl or tri - benzylsilyl radical or esterified by an acyl radical having up to 7 carbon atoms.

10. A compound as claimed in claim 9, wherein the acyl radical is an acetyl, propionyl, butyryl or benzoyl group.

11. A compound as claimed in any one of claims 1 to 10, wherein W and/or Z represents a carbonyl group acetalised with ethylene glycol, propane - 1,3 - diol, 2,2 - dimethyl - propane - 1,3 - diol, cyclopentane - 1,2 - diol or glycerine.

12. A compound as claimed in any one of claims 1 to 8, wherein W represents a carbonyl, hydroxymethylene or I - hydroxy - 1 - methyl - methylene group or a hydroxymethylene group in which the hydroxy group is etherified with a 2 tetrahydropyranyl group or esterified with an acetyl group and Z represents a carbonyl or hydroxymethylene group.

13. A salt of a compound as claimed in any one of claims I to 12 having a saltforming group.

14. A physiologically tolerable salt of a compound as claimed in any one of claims 1 to 12 having a salt-forming group.

15. 11 - Deoxy - 2 - decarboxy - 2 - methanesulphonamido - carbonyl 1 la - methyl - prostaglandin - E2.

16. (5Z,13E) - (11R,15RS) - 11,15 - Dimethyl - N - mesyl - 15 - hydroxy 9 - oxo - prosta - 5,13 - dienamide.

17. 11 - Cyano - 11 - deoxy - 2 - decarboxy - 2 methanesulphonamidocarbonyl - prostaglandin - E2.

18. 11&alpha; - Methylthio - 11 - deoxy - 2 - decarboxy - 2 - methane sulphonamidocarbonyl - prostaglandin - E2.

19. 11 - Deoxy - 2 - decarboxy - 2 - acetylaminocarbonyl - l la - methylprostaglandin - E2.

20. (5Z,13E) - (llR,l5RS) - N - Acetyl - 11,15 - dimethyl - 15 - hydroxy 9 - oxo - prosta - 5,13 - dienamide.

21. (5Z,13E) - (llR,15R) - 15 - Hydroxy - N - mesyl - 11 - methyl - 9 oxo - 16 - phenoxy - 17,18,19,20 - tetranorprosta - 5,13 - dienamide.

22. 11 - Deoxy - 2 - decarboxy - 2 - methanesulphonamidocarbonyl llct,16,16 - trimethylprostaglandin - E2.

23. 11 - Deoxy - 2 - decarboxy - 2 - methanesulphonamidocarbonyl 11&alpha;,16 - dimethylprostaglandin - E2.

24. (5Z,13E) - (9R,llR,l5RS) - 11,15 - Dimethyl - 9,15 - dihydroxy - N mesylprosta - 5,13 - dienamide.

25. (5Z,13E) - (9R,llR,l5RS) - N - Acetyl - 11,15 - dimethyl - 9,15 dihydroxy - prosta - 5,13 - dienamide.

26. 11 - Deoxy - 2 - decarboxy - 2 - methanesulphonamidocarbonyl - 11 a - methyl - prostaglandin - E,.

27. (13E) - (IIR,15RS) - 11,15 - Dimethyl - 15 - hydroxy - N - mesyl - 9 - oxo - prost - 13 - enamide.

28. 11 - Deoxy - 2 - decarboxy - 2 - acetylaminocarbonyl - Ila - methyl - prostaglandin - E,.

29. (13E) - (IIR,15RS) - N- Acetyl - 11,15 - dimethyl - 15 - hydroxy - 9 oxo - prost - 13 - enamide.

30. 11 - Deoxy - 2 -; decarboxy - 2 - methanesulphonamidocarbonyl 13,14 - dihydro - ll - methylprostaglandin - E,.

31. (IIR,15RS) - 11,15 - Dimethyl - 15 - hydroxy - N - mesyl - 9 oxoprostanamide.

32. 11 - Deoxy - 2 - decarboxy - 2 - acetylaminocarbonyl - 13,14 - dihydro 1 lea - methylprostaglandin - E,.

33. (IIR,15RS) - N - Acetyl - 11,15 - dimethyl - 15 - hydroxy - 9 - oxo prostanamide.

34. A process for the preparation of a compound claimed in claim 1 or a salt of such a compound having a salt-forming group, which comprises (a) reacting a compound of the general formula

in which A, B, W, D, E, Z, R2 and R3 have the meanings given in claim I, with a compound of the general formula O=C=N-R1 III in which R, has the meaning given in claim 1, (b) for those compounds in which A represents ds-CH=CH- reacting a lactol of the general formula

in which B, W, D, E, R2 and R3 have the meanings given above, with a Wittig reagent of the general formula

in which Ph represents a phenyl group and R1 has the meaning given in claim 1, or (c) hydrolysing a compound of the general formula

in which A, B, D, E, Z, R1, R2 and R3 have the meanings given in claim 1, and W' represents a protected hydroxymethylene group or protected I - hydroxy - 1 methyl - methylene group, and, if desired, one or more of the following steps are carried out in any order: (i) an esterified or etherified hydroxy group is converted to a free hydroxy group; (ii) a hydroxy group is esterified or etherified; (iii) a free hydroxy group is oxidised; (iv) an acetal group is converted to a carbonyl group; (v) a carbonyl group is converted to an acetal; (vi) a carbonyl group is reduced; (vii) a -C=C- group is hydrogenated; (viii) a compound of formula I having a salt-forming group is converted to a salt; (ix) a mixture of epimers is separated.

35. A process as claimed in claim 34, carried out substantially as described herein.

36. A process as claimed in claim 34, carried out substantially as described in any one of the Examples herein.

37. A compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 34 to 36.

38. A salt of a compound claimed in claim 1 having a salt-forming group whenever prepared by a process as claimed in claim 34 or claim 35.

39. A physiologically tolerable salt of a compound claimed in claim I having a salt-forming group, whenever prepared by a process as claimed in claim 34 or claim 35.

40. A pharmaceutical preparation which comprises a compound as claimed in any one of claims I to 12, 14 to 33, 37 and 39 in admixture or conjunction with a pharmaceutically suitable carrier.

41. A pharmaceutical preparation as claimed in claim 40, which is in dosage unit form.

42. A pharmaceutical preparation as claimed in claim 40, or claim 41, which is in a form suitable for oral administration.

43. A pharmaceutical preparation as claimed in claim 40 or claim 41, which is in the form of an injectable aqueous or oily solution.

44. A pharmaceutical preparation as claimed in claim 40 or claim 41, which is in a form suitable for inhalation.

45. A pharmaceutical preparation as claimed in claim 40 or claim 41, which is in a form suitable for local application.

46. A pharmaceutical preparation as claimed in claim 43, which contains from 0.01 to 10 g of active substance per ml of sterile aqueous solution.