IE45606B1 - Prostanoic acid derivatives and processes for their preparation - Google Patents

Abstract

Novel prostane derivatives of the formula 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

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 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 I 4S606 in which Rj represents an acyl radical of a carboxylic or sulphonic acid which is aliphatic, aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or hetero5 cyclic-aliphatic and which has from 1 to 10 carbon atoms, A represents a -CH^-CHg-, w-CH=CH-, --t2?ar.j-CH=CH- or -C»C- group, B represents a -CHg-CH^-, trans-CH=CH-, -C»C- or CH-CH10 group, wherein the methylene group may be in the a- or B-confi gurati on, W represents a free, esterified or etherified hydroxymethylene group or a free, esterified or etherified -C0H group, in which groups the hydroxy or etherified or esterified hydroxy group may be in the a- or β-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 -CSC- group, 45603 i - 4 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 which is unsubstituted or substituted by 1 to 3 halogen atoms, a phenyl group, 1 to 3 alkyl groups each having 1 to carbon atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, (C^-C^)-aTkoxy or hydroxy group; or an aromatic heterocyclic group; an araliphatic group whieh 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, alfcoxy or hydroxy group; or a bertzodioxol - 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 ^-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 12-position. Thus, it is possible to obtain - 5 45606 compounds which, for example, stimulate exclusively or preponderantly the non-striated muscular system of the uterus and thus have an anti-ferti1ity 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 are those of carboxylic acids and sulphonic acids having 1 to 10 carbon atoms, belonging to the aliphatic, aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclicaliphatic series. These acids may be saturated or unsaturated, mono-, di- or poly-basic, 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, cyclohexane- 6 acetic acid, cyclopropanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, mono-, di- and trichloroacetic 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 aeid. Especially favourable acyl radicals, are those having up to 7 carbon atoms .10 Suitable sulphonic acids are, for example, methanesulphonic acid, trifluoromethanesulphonic acid, ethanesulphonic acid, isopropyl sul phonic acid, β-chloroethanesulphonic acid, butanesulphonic acid, cyclopropanesulphonic acid, cyclopentanesulphonic acid, cyclohexanesulphonic acid, benzenesulphonic acid, para15 toluenesulphonic acid, para-chlorobenzenesulphonic acid, pararoethoxybenzenesulphonic acid, Ν,Ν-dimethylaminosulphonic acid, Ν,Ν-diethylaminosulphonic acid, N,N-bis-(#-chloroethyl)aminosulphonic acid, N,N-diisObutylaminosuIphonic acid, N,Ntfi butyl ami nosjul phonic acid, 1-pyrrolidinyl-, piperidino-, 1-. piperazinyl-, 4-methyl-1-piperazinyl-, 2- or 3-thiophene- and morpholinosulphonic acid.

Art alkyl group represented by R2 may be straight or branched chain, andhas 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 456QG group represented by R2 is as specified above for an alkyl group represented by Rg.

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 ^-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, α-ethoxyethyl, trimethylsilyl, dimethyl, tert. - butylsilyl and tri - benzylsilyl radicals. Suitable esterifying radicals are, for example, those carboxylic and sulphonic acid radicals mentioned for Rp 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 Rg or an aryl moiety in a radical represented by Rg 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 8:-phenyl group, 1 to 3 alkyl groups each having 1 to 4 carbon atoms, a chloromethyl., fluoromethyl, tri fluoromethyl, carboxy, - 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 Rg or an aliphatic moiety in a radical represented by Rg may be straight or branched chain, saturated or uiisaturated, preferably saturated, preferably having from 1 to 10, and especially 1 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, tevt.-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl and parachlorobenzyl groups.

A cycloalkyl group represented by Rg 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. *» · - 9 A heterocyclic group represented by Rg 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, 2pyridyl, 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(CHg) (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: -COCHg or -SO2CH3; A: -CH2-CH2- or -CH=CH-; B: -CH2-CH2- or -CH=CH-; W: -CO-, -CHOH-, -C(CH3)0H- or a hydroxymethyl group in which the hydroxy group is etherified with a 2-tetrahydropyranyl group or esterified with an acetyl group; 4S606 -10D-E-R3: -CH2-0-CgH5, -CH(CH3)(CH2)3CH3, - C(CHg)2(CHg)3CH3 or, especially if W is 1 - hydroxy - 1 - methyl methylene, -(CHgJ^CHgj Z: -CO- or -CHOH-; R2;-CHg, -SCH^ or -CN, especially -CHg.

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 10 physiologically tolerable salt, of a compound of the general formula 1 having a salt-forming group.

The invention also provides a process for the preparation of a compound of the general formula 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, Ε, Z, R2 and Rg have the meanings given above, with a compound of the general formula 6 0 6 0=C=N-R III in which R^ has the meaning given above, (b) for those compounds in which A represents efs-CH=CHreacting a lacto! of the general formula W-D-E-R, IV in which B, W, D, E, Rg and Rg having the meanings given above, with a Wittig reagent of the general formula Ph3P=CK-(CHg)gN-R1 (-) in which Ph represents a phenyl group and Rj has the meaning given above, or 456 0 6 - 12 (c) hydrolysing a compound of the general formula in which A,B, D, ΐ, 7, Rp Rg and ^3· 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 1 having a salt-forming group is converted to a salt; - 13 45606 (xi) 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, Ν,Ν-dimethylacetamide, methylene chloride, diethyl ether, benzene, toluene or dimethyl sulphoxide, at a temperature above or below room temperature, for example from -80°C to 100°C, preferably from 0°C 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. 486 0 6 -14-.

The reaction of a lacto! of the formula IV with a Wittig reagent of the formula V, which is prepared from the corresponding phos'phon'ium bromide with sodium methyl - sulphinylmethide or potassium tert.. - butoxide in dimethyl sulphoxide, may for examples carried out at a temperature of from 0° to 1OO°C, preferably 20° to 80°C, in an aprotic solvent, preferably dimethyl sulphoxide or dimethylformamide.

After the reaction of compounds IV and V, for example, a 9 hydroxyl group, pptionally after intermediate protection of the - hydroxyl group, is oxidised and/or a 9 - oxo group is reduced and/or optionally a protected hydroxyl group is liberated and/or free hydroxy] 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 pep 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. 6 0 6 - 15 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 9(5-hydroxy compound, may be carried out with a reducing agent suitable for the reduction of ketones such, fcr 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-doub1e 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 20°C. 486 0 θ The liberation of an esterified or etherified hydroxyl group may be carried out by known methods'. For example, en etherprotecting 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 aeid, 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 80°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 alcbhol. 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 -10°C to +70°C, preferably at 25°C. - 17 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 Rg have the meanings given above and 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 Π-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 Π-cyano or Π-alkylthio group (Rg=-CN or -S15 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 4560® - 18 (c) saturating the 10, 11-double bond with the introduction of analkanoylthio group (R2=-S-C0—alkyl), by reaction with a thiocarboxylic acid, and optionally the 9 - oxo group is acetalised or the 1 - methyl 5 ester is hydro'lysed.

A lacto! of the general formula IV: used as starting material may be prepared by reacting an aldehyde of the general formula VIII or phosphonate in aWittig reaction to form an a,β-unsaturated ]θ carbonyl compound of the general formula 6 0 6 - 19 0 IX D-E-R, in which B, D, E and Rg 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 15a- and 155-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 B>'W-D-E-R. ‘3 The lactone so obtained may be reduced with di isobutyl-aluminium hydride to form the lacto! of the general formula IV. 456 0 6 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, CH OH by introducing a hydroxyl-protecting group at the 15-carbon atom, for example with'dihydropyran, reducing the lactone with diisobutylaluminum 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 - 21 natural prostaglandin. As compared with PGE- and PGAderivatives, Π - deoxyprostaglandins of the present invention are distinguished by a greater stability.

Some of the compounds of the invention have a strong antifertile in nonvhuman animals activity. For inducing abortioiV, 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 non*human 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. 6 0 6 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 pg/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 6 0 6 - 23 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,13E)-(15R)-15-Hydroxy-N-mesyl-9-oxo-16-phenoxy17,18,19,20-tetranor-prosta-5,13-dienamide. 300 mg of (5Z,13E)-(15R-N-mesyl-9-oxo-15-(tetrahydropyran-2yloxy)-16-phenoxy-17,18,19,20-tetranor-prosta-5,13-dienamide are stirred for 5 hours at 40°C with 12 ml of a mixture of glacial acetic acid/water/tetrahydrofuran (65/35/10 v/v/v), the mixture is evaporated in vaouo, 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 ihe form of a colourless oil.

IR (CHClg): 3590, 3400, 2940, 2860, 1736, 1720, 1600, 1340, 972 cm’1.

Is 6 Ο 6 The starting material for the above compound is prepared as follows: (a) (1S ,5R,6R)-6-]~(E)-3-oxo-4-phenoxy-1-butenyl[ -2-oxabicycloj3,3,0}-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 (1^5R,6S)-6-formyl-210 oxo-bicyclo-|3.3.oj-octan-3-one (E.J. Corey etal., J.Org.

Chem. 39, 256 (1974)) in 30 ml of ether. The whole is stirred for 1 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 obtaihed with ether/pentane (8+2 by volume) 2.8 gms of the title compound in.the form of a colourless oil.

IR (CHCI3): 1770, 1695, 1670, 1653, 1600, 973 cm1. (b) (1S,5R,6R,3‘R)-6- (E)“3-Hydroxy-4-phenoxy-l-butenylJ-220 oxo-bi cycl 0-/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 5°C 100 ml of an ethereal solution of zinc borohydride (preparation: Neuere Methoden der praparativen organischen Chemie, Vol.4, p. 241, - 25 48606 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 vaouo. By column chroro5 atography over silica gel (ether/hexane 8+2 by volume) there are eluted first 403 mg of the title compound (α-alcohol) and also 390 mg of the corresponding β-alcohol (IS, 5R,6R,3'S)6 -QE)-3-hydroxy-4-phenoxy-l-butenyf}-2-oxabicyclo [is.3.o]octan-3-one in the form of a colourless oil.

IR (CHCI3): 3590, 1770, 1600, 975 cm1. (c) (1S,5R,6R,3'R)-6- []e)-3-(tetrahydropyran-2-yl-oxy)-4phenoxy-1-butenyl] -2-oxo-bicyclo«]3_·3 ·-octan-3-one. 800 mg of the α-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 5°C 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 vaouo. 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 colour!ess oi1.

IR: 2940, 1770, 1600, 975 cm1. -26 (d) (2RS, 3aR, 4R, 6aS, 3'R)-4-£(E)-3-(tetrahydropyran-2-yToxy)-4-phenoxy-l-butenyT2-2-hydroxy-perhydrocyclopenta£bjj-furan. ' 1 To a solution, cooled to -65°C, of 870 mg of the compound prepared in accordance with Comparative Example 1 (cj in 30 ml of dry toluene are added dropwise under argon 7 ml of a solution of 20% diisobutylaluminium hydride in toluene, the mixture is stirred for 30 minutes at -65°C and the reaction is terminated by the dropwise addition of isopropanoT. 3 ml of water are added, the mixture is allowed to rise to room temperature, stirred for 30 minutes, filtered and evaporated in vaouo..865 mg of the title compound are obtained in the form of a colourless oil.

IR: 3600, 1600, 975 cm’1; (e) (5Z,13E)-(9S,15R)-9-Hydroxy-N-mesyl-l5-(tetrahydropyran15 2-yl-oxy)-16-phenoxy-17,18,19,20-tetranor-prosta-5,13-dienamide.

To a solution of 5.2 gms of £4-(methanesulphonyTaminocarbonyl)butylj-triphenyl-phosphonium bromide in 20 ml of dry dimethyl sulphoxide (DMSO) are added dropwise at 15°C 20 ml of a solution of sodium methylsulphonylmethide in dry DMSO (preparation: 1 gm of a suspension of 50% sodium hydride is dissolved in 20 SfJ of dry DMSO in the course of one hour at 70°C) and the solution is stirred for 15 minutes at room temperature. To the red yTid solution is added dropwise a solution of T.O gm of the lactol obtained in accordance with Example 1 (d) in 14 ml of DMSO, and - 27 the mixture is stirred for 3 hours at 45°C. The reaction mixture is poure'd on to ice-water, acidified to a pH of 4-5 with a solution of 10% citric acid, and extraction is carried four times with'70 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 vaouo.

By chromatography of the residue over silica gel there are obtained with methylene chioride/isopropanol (9+1 by volume) 950 mg of the title compound in the form of a colourless oil.

IR (CHClg): 3590, 3400, 2940, 1720, 1600, 1340, 975 cm'1. (f) (5Z,13E) -(15R)-N-mesyl-9-oxo-15-(Tetrahydropyran-2-yloxy)-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 1(e) in 10 ml of acetone is added at -20°C 0.3 ml of Jones reagent (J.Chem.Soc. 1953, 2555), the mixture is stirred for 30 minutes at -20°C, 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 vaouo. By filtration over silica gel there are obtained with ether 350 mg of the title compound in the form of a colourless oil. 4S606 - .28 -IR (CHClg): 1736, 1720, 1600, 975 cm'1.

Example 1 -Deoxy-2-decarboxy-Z-methanesulphonami docarbonylΠα-metbyl-prostaglandin-Eg.

To a solution of 215 mg of n-deoxy-lla-methylprostaglandinE215-(tetrahydropyran-2-yl) ether in 15 ml of tetrahydrofuran is added 0.8 ml of triethyl amine, the mixture is stirred for 15 minutes at room temperature, then 5 ml of a solution of 60 mg of methanesulphonyl isocyanate in 5ml 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 ll-deoxy-2-decarboxy-Z-methanesulphohamidocarbonyl-Πα-roethylprostag!andin-Eg 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 40°C. By evaporation in vacuo and chromatography over silica gel with methylene chloride/isopropanol (9+1 by volume) there 6 0 G - 29 are obtained 110 mg of the title compound in the form of a colourless oil.

IR (CHCI3): 3600, 3400, 2945, 1735, 1720, 975 cm-1.

The starting material for the above title compound is prepared 5 as follows: (a) ll-Deoxy-lla-methylprostaglandin-Eg 15-(tetrahydropyran2-yl) ether methyl ester. 800 mg of ll-deoxy-lla-methylprostaglandin-E^ 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 vaouo. 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 (CHCI3): 3000, 2950, 1738, 1725, 975 cm1. (b) 11-Deoxy-1la-methylprostaglandin-E2 15-(tetrahydropyran-2yl) ether. 6 Ο6 - 30 - . - ; A mixture of 530 mg of the compound prepared in accordance with ExampTe 1(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 vaouo. There are obtained 480 mg of the title compound in.the form of a colourless oil.

IR (CHClg): 3400 (wide), 2942, 2850, 1735, 1705, 975 cm1.

Example 2 (5Z, 13E)-(11R,15RS)-N-mesyl-11,15-dimethyl-15hydroxy-9-oxo-prosta-5,13-dienamide.

From (5Z,13E)-(11R, 15RSj-11,15-dimethyl-15-hydroxy-9-oxo-5,13prosta-5,1 3-dieiioic acid methyl ester (Chemistry and Industry 1973, 535) there is obtained in a manner analogous to that in Example 1 the title compound in the form of a colourless oil. IR. (CHClg): 3600, 3400, 1735, 1720, 975 cm-1. - 31 45606 Comparative Example 2 11-Deoxy-2-decarboxy-2-methanesulphon ami docarboxylprostaglandi n - Eg.

To a solution of 380 mg of Π-deoxyprostaglandin-E 15-acetate in 25 ml of tetrahydrofuran are added 1.5 ml of tri ethyl amine, the mixture is stirred for 15 minutes at room temperature, then 10 ml of a solution of 120 mg ofmethanesulphony! 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 productover silica gel there are obtained with ether 325 mg of Π-deoxy-2-decarboxy-2methanesulphonamido-carbonyl prostaglandi n-Eg 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 6 0 6 . - 32 - - -. (9+1 by volume) 240 mg of the title compound in the form of a colourless oil.

IR (CHClg): 3600, 3400, 1735, 1720, 975 cm1.

The starting material for the above title compound is prepared 5 as follows: (a) n-Desoxy-prostaglandin-Eg 15-acetate.

To a solution of 1 gm cf 11-desoxy-PGEg (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 vaeuo. 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 (CHClg): 3400 (wide), 1730, 975 cm'1. f 'Comparative Example 3 ll-Deoxy-2-decarboxy-2-acetylaminocarbonyl 16,16dimethyl-prostaglandin-Eg 450 mg of 11-deoxy-2-decarboxy-2-acetylami nocarbonyl 16,16-dimethylprostaglandin-EglS-ttetrahydropyran-B-yl) ether.are stirred for hours at room temperature with 16 ml of a mixture of glacial acetic acid/water/tetrahydrofuran (65/35/10 by volume), evaporated in vaeuo, and the residue is purified by column chromatography over silica gel. With methylene chloride/isopropanol (9+1 by volume) 6 0 6 - 33 there are obtained 320 mg of the title compound in the form of a colourless oil.

IR (CHCIg): 3600, 3400, 2930, 2860, 1735, 1705, 1270, 972 cm.

The starting material for the above compound is prepared as 5 follows: (a) (lS,5R,6R)-6 - JjE)-3-oxo-4,4-dimethyl-1-octenylj -2-oxabicyclo-j3.3.oj -octan-3-one.

Toamixture of 0.46 gm of sodium hydride suspension (50% in mineral oil) in 40 ml of 1,2-dimethoxyethane is added dropwise at 20°C under argon a solution of 2.75 gms of (3,3-dimethyl-2oxoheptyl)phosphonic acid dimethyl ester in 8 ml of 1,2dimethoxyethane, and the mixture is stirred for 2 hours at 20°C. To this mixture is added dropwise a solution of 1.54 gms of (1S,5R,6S)-6-formyl-2-oxabicyclo [T. 3.(T]-octan-3-one in 30 ml of tetrahydrofuran at -10°C and stirred for 2 hours at -10°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 vaouo. 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 (CHCIg); 1770, 1695, 1670, 1653, 975 cm1. 4Βϋυ υ - 34 (b) (IS,5R,6R,3'R)-6-j(E)-3-hydroxy-4,4-dimethyl-1-octenyTj2-oxabicyclo- -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 ice-bath temperature 110 ml of an ethereal solution «of zinc’iborohydride (see Comparative Example 1(b)) and the whole as 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 650 mg of the title compound (α-alcohol) and also 430 mg of the corresponding more polar β-alcohol (lS,5R,6R,3'S)-6-J(E)-3-hydroxy15 4,4-dimethyl-l-octenylJ -2-oxabicyclo-J/3.3.0 -octan-3-one in the form of a colourless oil.

IR (CHClg): 3600, 1770, 975 cm-1. (c) (lS,5R,6R,3'R)-6-^E)-3-(tetrahydropyran-2-yl-oxy)-4,4dimethyl-1-octenylj-2-oxa-bicyclo -octan-3-one. 600 mg of the α-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 - 35 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 (CHCIg): 1770, 975 cm'1. (d) (2RS,3aR,4R,6aS,3'R)-4-JjE)-4,4-dimethyl-3-(tetrahyciropyran2-yl-oxy )-1-octenyTj-2 - hydroxy-perhydrocyclopenta-£bj-furan.

To a solution, cooled to -65°C, of 600 mg of the compound prepared in accordance with Comparative Example 1(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 -65°C, 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'1. (e) (5Z,l3E)-(9.S,l5R)-N-Acetyl-9-hydroxy-l6,l6-d1methyl-15(tetrahydropyran-2-yl-oxy)-prosta-5,13-dienamide.

To a solution of 4.9 gms of £jl-(acety1aminocarbonyl)-butyTJtri phenyl-phosphonium bromide in 20 ml of dry DMSO are added 6 - 36 dropwise at 15°C 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 70°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 lacto! obtained in accordance with Example 3(d) in 13 ml of DMSO, and the whole is stirred for 4 hours at 45°C. The reaction mixture is poured into icewater, 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 vaouo.

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 (CHClg): 3400, 2940, 2860, 1733, 1705, 972 cm1\ (f) 11-Deoxy-2-decarboxy-2-acetylaminocarbonyl 16,16 -dimethylprostaglandiπ-Eg 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 -20°C. 0.5 ml of Jones reagent (J.Chem.Soc. 1953, 2555), stirred for 30 minutes at -20°C, 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 - 37 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 (CHCI3): 3400, 2930, 2860, 1733, 1705, 972 cm1.

Comparative Example 4 (5Z,13E)-(9S,15S)-9,15-Dihydroxy-N-mesyl-17phenyl-18,19,20-trinor-prosta-5,13-dienamide.

To a solution of 2.6 gms of Q-(methansulphonylaminocarbonyl)butyV}-triphenyl-phosphoniurn bromide in 10 ml of dry dimethyl sulphoxide are added dropwise at 15°C. 10 ml of a solution of sodium methylsulphinylmethide in DMSO (preparation: 0.5 gm of a suspension of 50% sodium hydride is dissolved in 10 ml of DMSO in the course of one hour at 70°C), 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-^JE)-3-hydroxy-5-phenyl-1-pentenylj-2hydroxyperhydrocyclopentajb^furan in 7 ml of DMSO and the mixture is stirred for 4 hours at 45°C. 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 - 38 chloride/isopropanol (8+2 by volume) 310 mg of the title compound in the form of a colourless oil.

IR (CHCIg): 3600, 3400, 2940, 1720, 1600, 1585, 1345, 972 cm'1.

The starting;material for the above compound is prepared as 5 follows: (a) (1S,5R,6R)-6- |7e )-3-0xo-5-pheny l-l~pentenyTj-2-oxabicyclo[j. 3.0] -octan-3-ooe.

From 1.3 gms of (lS,5R,6S)-6-formyl-2-oxabicyclo- 11-3.0] octan3-one and 2.8 gms of dimethyl (2-oxo-4-phenylbutyl) phosphonate there are obtained in a manner analogous to that in Comparative Example 1(a) T.35 gms of the title compound in the form of a colourless oil.

IR(CHCI3): 1770, 1695,, 1670,1655, 1600, 1585, 972 cm'1.

T5 (b) (IS,5R,6R,3'S)-6- |(E)-3-hydroxy-5-phenyl-l-pentenylJ-2oxa-bicyclo-jlL3.j)j-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 1(b) 410 mg of the title compound in the form of a colourless oil.

IR (CHCIg): 3600, 1770, 1600, 1585, 972 cm1. (c) (2RS,3aR,4R,6aS,3'S)-4 ^(E)-3-Hydroxy-5-phenyl -1 penteny lJ-2-hydroxyperhydrocyclopenta[bj-furan.

To a solution, cooled to -65°C, 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 -65°C 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 vaouo. 390 mg of the title compound are obtained in the form of a colourless oil.

IR: 3600, 1600, 1585, 972 cm’1.

Comparative Example 5 (5Z,13E)-(15S)-15-Hydroxy-9-oxo-N-mesyl-17phenyl-18,19,20-tri nor-prosta-5,13-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 -45°C 1.2 ml of N,N -diethyltrimethylsilylamine and the whole is stirred for 6 hours at -40°C. It is then diluted with 40 ml of ether, which has previously been cooled to -70°C, 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 vaouo. The -(trimethylsilyl ether) obtained in this manner is dissolved in 4B60G ' . : - - 40 “ ? ml of absolute methylene chloride and at- +5°C. there is added a solutionof 700 mg of Collins reagent (prepared: see Org. Synthesis Vol. 52. 5), stirred for 10minutes, diluted with 50 ml of’ether, filtered and evaporated in vaouo. For splitting off the silyl ether pr'otecting 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 vaouo. 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 (CHCIg): 3500, 3400, 1735, 1720, 1600, 1585, 975 cm'1.

Comparative Example 5 ll-Deoxy-.2-decarboxy-2-acetylaminocarbonyl-13,14dihydro-l6,16-dimethyl-prostaglandin-Eg 355 mg of ll-deoxy-2-decarboxy-2-acetylaminocarbonyl 13,14dihydro-16,16-di'methyl-prostag!andin-E2 I5-(tetrahydropyran-2yl) ether are stirred for 4 hours at 50°C with 12 ml of a mixture of a glacial acetic acit/Water/tetrahydrofuran (65/35/10 v/v/v), evaporated in vaouo 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 5606 the form of a colourless oil.

IR (CHClg): 3600, 3400, 1735, 1705, 1270 cm _1.

The starting material for the above title compound is prepared as follows: (a) (1S,5R,6R,3'R)-6-j£,4-Dimethyl-3-(tetrahydropyran-2-yl- 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 (CHClg): 1770 cm1. (b) (2RS,3aR,4R,6aS,3'R)-4-[*4,4-Di methyl-3-(tetrahydropyran-2- From 1 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. . 4S606 :: ? - 42 (c) (5Z)-(9S,15R)-N-Acetyl-9-Hydroxy-16,16-dimethy1-15(tef rahydropy ran-Z-yl-oxy)-pros t-5-enamide.

From 1 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 (CHCI3): 3595, 3400, 2940, 2860, 1733, 1705 cm'1: (d) 11-Deoxy-2-decarboxy-2-acety1aminocarbony1-13,14-dihydro16,16-dimethy1-prostag1andin-E2 15-(tetrahydropyran-2-y1) 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 (CHCIg): 3400, 2930, 2860, 1733, 1705 cm'1.

Example 3 n-Cyano-2-decarboxy-2-methanesu1phonamidocarbonyl-11deoxy-prostaglandin-Eg.

From 240 mg of 11-cyano-11-deoxy-prostaglandiπ-Eg 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.-4560 6 ___ - 43 - ..... IR (CHClg): 3600, 3400, 2240, 1735, 1720, 975 cm”1.

The starting material for the above title compound is prepared as follows: (a) ll-Cyano-ll-deoxy-prostaglandin-Eg 15-aeetate.

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

Grudzinskas et al., Tetrahedron Lettersl973, 141) there are obtained in a manner analogous to that in Comparative'Example2(a) 280 mg of the title compound in the form of a colourless oil.

Example 4 Πα-methylthi0-11-deoxy-2-decarboxy-2methanesulphonamidocarbonyl-pros tag!an din-Eg.

From 210 mg of lla-methylthio-ll-deoxy-prostaglandin-Eg 15acetate 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 (CHClg): 3600, 3400, 1735, 1220, 975 cm1.

The starting material for the above title compound is prepared as follows: a $0 s - 44 - / (a) Πα-methyl thio-Π-deoxy-prostaglandin-Eg 15-acetate.

From 310 mg of Ua-methylthio-lT-deoxyprostaglandin-Eg-(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,13E)-(T5S)-N-Acetyl-15-hydroxy-15-methyl-9oxoprosta-5,13-dienamide.

To a solution of 430 mg of (5S,13B)-(T5S)-15-methyl-15(tetra10 hydropyran-2-yloxy)-9-oxoprosta-5,13-dienoic acid in 12.5 ml 7 of acetonitrile are added 150 mg of triethylamine, the mixture is stirred for 15 minutes at room temperature, there are then added dropwise at 0°C. 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 (5Zs13E)-{15S)-N-acetyl-15-methyl-9-oxo-15(tetrahydropyran-2-yl-oxy)-prosta-5,13-dienamide in the form of a colourless oil. - 45 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 40°C. By evaporation in vacuo and chromatography over silica gel with methylene chloride/isopropanol (9+1 by volume) 325 mg of the title compound are obtained in the form of a colourless oil.

IR (CHClg): 3600, 3400, 2935, 2860, 1735, 1705, 975 cm'1.

Example 5 o 11-Deoxy-2-decarboxy-2-acetylami nocarbonyl-lidmethyl prostag 1andin-Eg.

From 190 mg of the compound described in Example 1(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 (CHCI3): 3595, 3400, 1735, 1705, 975 cm'1.

Example 6 (5Z-13E)-(llR,15RS)-N-Acetyl-n,15-dimethyl-15hydroxy-9-oxo-prosta-5,13-di enamide.

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 (CHClg): 3600, 3400, 1735, 1705, 975 cm'1. - 46 - . . ' Comparative Example 8 (52,13E) -(9S,15R)-9,15-di hydroxy-N-mesy!-T6-phenoxy- · 17,18,19,20-tetranor-prosta-5,13-dlenamidei 200 mg of the compound prepared in accordance with Comparative 5 Example 1(e) are stirred for 5 hours at’45°C with 8 ml of a mixture of glacial acetic acid/water/tetrahydrofuran (65/35/10 v/v/v), evaporated in vaouo and the residue is purified by .• ' - . - ’ column chromatography over silica gel. With chloroform/ methanol (9+l'by volume) 140 mg of the. title compound are obtained in the form of a colourless oil IR (CHCI3): 3600, 3400, 2940, 1720,.1600, 1340, 975 cm-1.

Example 7 By methods analogous to those in Comparative Examples 1, 3,-4, , 6 and 8 the following prostaglandins can be prepared: (5Z,13E) - (Ί 1R,15R)-15-Hydroxy-N-mesyl-11-methyl-9-oxo-16-phenoxy17,18,19,20-tetranor-prosta-5,13-dienami de. Π-Deoxy-2decarboxy-2-methanesulphonamidocarbonyl-llci,16,16ftrimethylprostaglandin-Eg. 11-Deoxy-2-decarboxy-2~methanesu1phonami docarbonyl-1la,1620 diraethylprostaglandin-Eg· Comparative Example. 9 (5Z,13E)-(9R,15S)-9,15-Dihydroxy-N-mesyl-15-methylprosta-5,13-dienamide. - 47 To a mixture of 250 mg of (5Z,13E)-(15S)-15-hydroxy-Nmesyl-15-methyl-9-oxoprosta-5,13-dienamide, 3 ml of tetrahydrofuran and 3 ml of n-propanol are added at 5°C 25 mg of sodium borohydride and the mixture is stirred for 60 minutes. The mixture is introduced into brine, adjusted to a pH value of 4 with citric acid and extracted several times with ether. The ether extract is washed with brine, dried over magnesium sulphate and evaporated in vacuo. The residue is chromatographed over silica gel (methylene chloride/isopropanol mixture). There are eluted in succession 75 mg of (5Z,13E)-(9S,15S)-9,15-dihydroxy-Nmesyl-15-methy1prosta-5,13-dienamide and as the more strongly polar compound 96 mg of the title compound in the form of a colourless oil.

IR (CHCI3): 3600, 3400, 1720, 975 cm-1.

Example 8 In a manner analogous to that in Comparative Example 9 there are obtained from the corresponding 9-oxo-compounds described in the foregoing Examples the following 95-hydroxy20 compounds: (5Ζ»13E)-(9R,11R,15RS)-11,15-Dimethyl-9,15-dihydroxy-Nmesyl-prosta-5,13-dienamide. (5Z,13E)-(9R,11R»1SRS)-N-Acetyl-11,15-dimethyl-9,15dihydroxy-prosta-5,13-dienamide. - 48 45606 Comparative Example 10 (13Ej-(l5R)-15-Hydroxy-9-oxo-N-mesyl-16-phenoxyT7,18,19,20-tetranorprost“l3-enamide.

A solution of '220 mg of the compound prepared in accordance 5 with Comparative Example 1 in 20 ml of ethyl acetate is agitated with 20 mg of palladium (10% strength on carbon)under an. atmosphere of hydrogen at -25°C, and the course of the hydrogenation is followed by thin layer chromatography. After 1.5 hours, rinsing with nitrogen, filtration and evaporation in vaouo are carried out. By chromatography with silica gel with methylene chloride/ispropanol (9+1 by volume) 153 mg of the title compound are obtained in the form of a colourless oil.

IR (CHCIg): 3595, 3400, 2940, 2860, 1735, 1720, 1600, 1340, 972 cm-1.

Example 9 In a manner analogous to that in Comparative Example 10 the following prostenamides can be prepared from the corresponding prosta-5,13-dienamides: Π-Deoxy-2-decarboxy-2-methanesulphonamidocarbonyi-Παmethyl-pros tag!andin-Ep 4SQ06 - 49 (13E)-(Π R,15RS)-N-mesy1-Π,15-di methyl-15-hydroxy-9oxoprost-13-enamide. 11-Deoxy-2-decarboxy-2-acetylaminocarbonyl-1 lamethyl pros tagl and i η-E -j. (13E)-(11R,15RS)-N-Acetyl-11,15-dimethyl-15-hydroxy-9oxo-prost-13-enamide, Comparative Example 11 (15R)-15-Hydroxy-N-mesyl-9-oxo-16-phenoxy17,18,19,20-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/ispropanol (9+1 by volume) 95 mg of the title compound in the form of a colourless oil.

IR (CHCIg): 3600, 3400, 2940, 2860, 1735, 1720, 1600, 1340 cm'1.

The NMR-spectrum shows no olefinic protons.

EXAMPLE 10 6Ο 6 - 50 In a manner analogous tothat inComparative Example 11 there can be prepared from the corresponding prosta-5,13dienamides the following prostanamides: Π-Deoxy-2-decarboxy-2-methanesulphonamidocarbonyl-13,145 dihydro-lla-methylprostaglahdin-E . (llR,15RS)-N-Mesyl-n,15-dimetbyl-T5-hydroxy-9oxoprostanamide. 11-Deoxy-2-decarboxy-2-acetyTaminocarbonyl-13,14-di hydroΠα-methylprostaglandin-Ep (11R,15RS)-N-Acetyl-11,15-di methyl-15-hydroxy-9-oxoprostanamide.

Claims (45)

1. WHAT WE CLAIM IS:1. A compound of the general formula in which Rj represents an.acyl radical of a carboxylic or sulphonic 5 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 -CHg-CHg-, 0is-CH=CH-, -irczMs-CH=CH- or -C=C- group, B represents a -CHg-CHg-, trans-CH=CH-, -C=C- or -CH-CHV CHg 4 S 6 0 G 7 - -- - 52 - . - 7 group, wherein the methylene group may be in the a- or β-configuration. W represents a free, esterffied or etherified hydroxymethylene group or a free, esterified or etherified 5 CH, . HZ. : -c- . . . J- ' OH . group in which groups the free, esterified or etherified hydroxy group may be in the a- or β-configuration, or a 10 carbonyl group or an acetal thereof, D and E together represent a direct bond, or 0 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, 15 Rg 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 1 to 3 alkyl groups each having 1 to 4 carbon atoms, or by a chloromethyl, fluoromethyl, tri20 fluoromethyl, carboxy, (C^-C^J-alkoxy or hydroxy group: or 4 5 6 0 6 - 53 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 1 to 4 carbon atoms, or by 5 a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, (C-j-C^-alkoxy or hydroxy group; or represents a benzodioxol2-yl group; Z represents a carbonyl group or an acetal thereof or a free, esterified or etherified hydroxymethylene group in which 10 the free, esterified or etherified hydroxy group may be in the ct- or β-configuration, and R 2 represents an alkyl group having from 1 to 5 carbon atoms, a -CSNgroup, an alkylthio group having from 1 to 5 carbon atoms or alkanoylthio group having from 1 to 15 5 carbon atoms in the alkyl moiety.

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

3. A compound as claimed in claimed 1 or claim 2, wherein the acyl radical represented by Rj contains one or more of 2o 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. 4560 - 54

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

5. A compound as claimed in any one of claims 1 to 4, wherein R g represents an alkyl having from 1 to 10 carbon 5 atoms, a cycloalkyl group having from 4 tb 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 10 unsubstituted or substituted as specified in claim.!, an unsubstituted or substituted aryl group as specified in claim 1 or a 2-furyl, 2-thienyl- 2-pyridyl, 3-pyridyl or 4-py.ridyl group.

6. A compound as claimed in claim 5, wherein R 3 represents 15 an alkyl group having from 1 to 6 carbon atoms, a cyclopentyl, cyclohexyl, methylcyclohexyl or adamantyl group, an arylsubstituted 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 groun or the aryl group being 20 a phenyl or naphthyl group which is unsubstituted or substituted as specified in claim 1. - 55

7. A compound as claimed in claim 6, wherein Rg 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. 5

8. A compound as claimed in any one of claims 1 to 4, wherein D - £ - Rg represents CHgOCgHg, (CHg-CHg, CH(CH 3 )(CH 2 ) 3 CH 3 or C(CH 3 ) 2 (CH 2 ) 3 CH 3<

9. A compound as claimed in any one of claims 1 to 8, wherein U and/or Z is a hydroxy group etherified by a 210 tetrahydropyranyl, 2-tetrahydrofuranyl, α-ethoxyethyl, trimethylsilyl, dimethyl, tert.-butyl-silyl or tribenzylsilyl 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 15 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-dimethylpropane-1,3-diol, cyclopentane-1,2-diol or glycerine. 20

12. A compound as claimed in any one of claims 1 to 8, wherein W represents a carbonyl, hydroxymethylene or 1-hydroxy4 5606 - 56 ί 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. 5

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

14. A physiologically tolerable salt of a compound as claimed in any one of claims 1 to 12 having a saltforming group. 10

15. lI-Deoxy-2-decarboxy-2-methanesulphonamido-carbonyl1 la-methyl-prostaglandin-Eg.

16. (5Z,13E)-(11R.15RS)-11,15-Dimethyl-N-mesyl-15-hydroxy9-oxo-prosta-5,13-dienamide.

17. 11-Cyano-11-deoxy-2-decarboxy-2-methanesul phonami do15 carbonyl-prostaglandin-Eg.

18. Πα-Methyl.thio-l 1 -deoxy-2-decarboxy-2-methanesulphonamidocarbonyl-prostaglandin-Eg.

19. 11-Deoxy-2-decarboxy-2-acetyl ami nocarbonyl -Παmethyl pros tag! andin-Eg. 4. $60S I

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

21. (5Z,13E)-(11R,15R)-15-Hydroxy-N-mesyl-ll-raethy1-9oxo-16-phenoxy-17,18,19 £0-tetranorprosta-5,13-dienamide.

5. 22. 11-Deoxy-2-decarboxy-2-methanesulphonamidocarbonyl~ 11 a,16,16-tri methylprostaglandin-Eg.

23. Π-Deoxy-2-decarboxy-2-methanesulphonamidocarbonylIla,16-dimethylprostag land in-Eg.

24. (5Z,13E)-(9R,llR,15RS)-n,15-dimethyl-9,15-dihydroxy10 N-mesy1prosta-5,13-dienamide.

25. (5Z,13E)-(9R,11R,15RS)-N-Acetyl-11,15-dimethyl-9,15di hydroxy-prosta-5,13-dienamide.

26. n-Deoxy-2-decarboxy-2-methanesulphonamidocarbonyl- Πα - methyl-prostaglandin “ Ep 15

27. (13e)-(11R,15RS)-11,15-Dimethyl-15-hydroxy-N-mesyl9-oxo-prost - 13-enamide.

28. 11-Deoxy-2-decarboxy-2-acetyl ami nocarbonyl-1 lamethyl -prostag! andin-E-j. - 58

29. (13E)-(llR,15RS)-N-Acetyl-ll,15-dimethyl-15-hydroxy9-oxo-prost-13-enamide.

30. 11-Deoxy-2-decarboxy-2-methanesulphonami docarbonyl13,14-dihydro-lla-methylprostaglandin-E^. 5

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

32. 11-Deoxy-2-decarbo xy-2-acetyl ami nocarbonyl-13,14dihydro-11 α-methylprostaglandin-E^.

33. (llR,15RS)-N-Acetyl-n,15-dimethyl-15-hydroxy-910 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 - 59 in which A, B, W, D, Ε, Z, Rg and R^ have the meanings given in claim 1, with a compound of the general formula O=C=N-R III in which R·] has the meaning given in claim 1, 5 (b) for those compounds in which A represents cis-CH=CHreacting a lacto! of the general formula IV W-D-E-R, in which B, W, D, E, Rg and R g have the meanings given above, with a Wittig reagent of the general formula Ph 3 P=CH-(CHg) 3 -C N-R (-) in which Ph represents a phenyl group and R 1 has the meaning given in claim 1, or - 60 (c) hydrolysing a compound of the general formula in which A, Β, Β, Ε, Z, Rp Rg and Rg have the meanings given in claim I, and W‘ represents a protected hydroxymethylene group or protected 1-hydroxy-1-methyl-methylene 5 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; 6. 10 (iii) a free hydroxy group is oxidised; · (iv) an acetal group is converted to a carbonyl group; s (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 1 having a salt-forming group 5 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 substan10 tially 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 saltforming group whenever prepared by a process as claimed in 7. 15 claim 34 or Claim 35.

39. A physiologically tolerable 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. 4360°

40. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 1 to 12, 14 to 33, 37 and 39 in admixture or conjunction with a pharmaceutically suitable carrier. 5

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

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

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

A pharmaceutical claim 41, which is preparation as in a form suitable claimed in claim for inhalation. 15 45. A pharmaceutical preparation as claimed in claim 40 or claim 41, which is in a form suitable for local application,

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