IE41407B1 - Analogues of prostanoic acids and process for preparing them - Google Patents

Abstract

Novel analogues of prostanoic acids, which have the accompanying formula I, in which the symbols R1 to R3 have the meaning given in Patent Claim 1, are prepared by removing the tetrahydropyranyl ether protective group and the ketal grouping simultaneously or successively from an appropriately substituted 3-tetrahydropyranyloxy- 1,5-dioxaspiro compound. The corresponding compounds in which, instead of the keto group in the cyclopentyl radical, hydrogen and a hydroxy group are present, are obtained by reduction with a complex metal hydride. The compounds can then be converted into their physiologically tolerable salts or esters. The compounds are distinguished, even in the form of their epimer mixtures, by a good general spasmolytic, in particular bronchodilatory, action. They additionally have a hypotensive action and can also be employed in some cases in gastrointestinal disorders.

Description

This invention relates to prostanoic acid analogues and to a process for their manufacture.

Prostaglandins are a group of natural substances that can be isolated from various animal tissues. In mammals, they are responsible for a number of physiological activities. These natural prostaglandins have a carbon skeleton containing, in general, 20 carbon atoms and they are distinguished from each other essentially by a higher or lower content of hydroxyl groups and/or double bonds, in the cyclopentane ring or in the side chains. (For the structure and activity of prostaglandins, c.f., among others, M. F. Cuthbert The Prostaglandins, Pharmacological and Therapeutic Advances, William Heinemann Medical Books Ltd., London 1973).

The present invention provides an analogue of prostanoic acid of the formula I wherein R^ and R2 together represent an oxygen atom or one represents a hydrogen and the other represents a hydroxy 4140? group, R3 represents a straight or branched chain alkyl group of 1 to 10 carbon atoms, which itself may be substituted by a straight or branched chain alkoxy group of 1 to 5 c-atoms, by an aryloxy group, by a furyloxy group or by a benzyloxy group, which themselves may be substituted by one or more substituents selected from halogen atoms, trifluoromethyl groups, alkyl groups of 1 to 3 carbon atoms, and phenoxy groups which may carry one or more halogen atoms, or represents a saturated cycloalkyl group of 3 to 7 ring members, an aryl or a furyl group, which radicals may be substituted by one or more alkyl groups of 1 to 3 carbon atoms, with the proviso that Rg may not represent an unsubstituted alkyl group branched at the α-carbon atom and having up to 7 carbon atoms in the chain from the α-carbon atom to the cu-carbon atom inclusive and salts thereof, especially the physiologically tolerable salts, with organic and inorganic bases and esters thereof with aliphatic, cycloaliphatic or araliphatie alcohols having up to 8 carbon atoms.

The present invention also provides a process for preparing a prostanoic acid analogue of the general formula I, which comprises a) reacting an acetal or dithioacetal of the formula II CH. '2 CH.

CH-CH2-CH2-CN II in which X represents an oxygen or sulphur atom, and Y represents a —CH2— or 41401? group or a direct bond, with a Grignard compound of the formula III Hal-Mg-CH2-CH2-CH2-CH2-O-CH2 III, in which Hal represents a chlorine or bromine atom, or with another organo-metallic compound which contains the 4-henzyloxybutyl radical, to give a ketone of the formula IV CH -X / 2 \ r \ Z ch2-x in which X and Y have the meanings given for formula II, b) removing the acetal or dithioacetal group from the ketone of the formula IV to give an aldehyde-ketone of the formula V β 0HC-CH2-CH2-C-CH2-CH2-CH2-CH2-O-CH2 c) subjecting the aldehyde-ketone of the formula V to an aldol/condensation under acid or alkaline conditions, to give an unsaturated ketone of the formula VI d) reacting the resulting unsaturated ketone of the formula VI under alkaline conditions with cyanide ions to give a cyano-ketone of the formula VII VII e) converting the resulting cyano-ketone of the formula VII with an anhydrous alcoholic solution of an inorganic acid to an imino-ether salt of the formula Vila Vila in which HA represents an inorganic acid, and represents an alkyl group of 1 to 5 carbon atoms, and subsequently hydrolysing the compound of the formula villa to give an ester of the formula VIII Ο VIII in which R^ has the meaning given for formula Vila, f) catalytically hydrogenating the ester of the formula VIII to give an alcohol of the formula IX in which R^ has the meaning given for formula VIII, g) oxidizing the alcohol of the formula IX to an aldehyde of the formula X in which R^ has the meaning given for formula VIII, h) reacting the aldehyde of the formula X with a dithiol of the formula XI HS—CH2——CH2—SH XI 4140? in which Y^ represents a —CH^— group or a —CCCH^)™ group or a direct bond, in the presence of an acid catalyst to give a dithioacetal of the formula XII XII in which R^ has the meaning given for has the meaning given for formula XI, formula X and Y' i) reacting the dithioacetal of the formula XII in the presence of an acid catalyst with a glycol of the formula XIII HO—CH2——CH2—OH XIII in which Y2 has the meaning given for Y in formula XII to give a compound of the formula XIV XIV in which Y^ and Y2 may be identical or different and have the meanings given for formulae XI and XIII, and R^ has the meaning given for formula X, j) reducing the compound of the formula XIV with a complex metal hydride in an aprotic solvent to an aldehyde of the formula XV in which Y^ and Y^ have the meanings given for formula XIV, k) reacting the aldehyde of the formula XI with a phosphonate of the formula XVI CH,0 0 0 3 \f 1 P—CH —Cr / 2CH3° XVI in which R^ has the meaning given for formula I except that it is not subject to the proviso, to give an unsaturated ketone of the formula XVII /\ CH„ CH„ H 0 XVII 414 0? in which Y. and Y have the meanings given for formula X * XIV, and R^ has the meaning given for formula XVX, 1) reducing the ketone of the formula XVII with a complex metal hydride to the epimeric mixture of alcohols of the formula xvill z 2\ CHL CH_ XVIII in which Y^ and Y^ and R3 have the meanings given for formula XVII, m) reacting the alcohols of the formula XVIII in 10 the form of the epimeric mixture or after separation of the epimers, with 2,3-dihydropyran in the presence of an acid catalyst to give a tetrahydropyrahyl ether of the formula XIX 2.407 z*2 CH„ CH_ in which and Y2 and R3 have the meanings given for formula XVII, n) heating the ether of the formula XIX with a 5 —C^-alkyl iodide in a polar aprotic solvent in the presence of an acid acceptor to give an aldehyde of the formula XX /X CH„ CH. in which Y2and Rj have the meanings given for formula XVII, o) reacting the aldehyde of the formula XX with 5 the ylide derived from (3-carboxypropyl)-tripheny1/phosphonium bromide in a solution of sodium hydride in dimethyl/sulphoxide to give an acid of the formula XXI a 4 ο ? χΧ ?2 X in which Υ2 and R3 have the meanings given for formula XVII, p) eliminating the 2-tetrahydropyranol group from 5 the compound of the formula XXI by mild acid hydrolysis whereupon an alcohol of the formula XXII X’\ CH_ CH_ 0 HO - 13 in which Y2 and R^ have the meanings given for formula XVII, is obtained and g) removing the cyclic acetal group from the alcohol of the formula XXII either by mild acid-catalyzed hydrolysis or by transacetalization by reacting the compound of formula XXII with a large excess of a ketone, or eliminating both protective groups in one step by mild acid hydrolysis, and optionally reducing the resulting compound obtained of the formula I in which R^ and R2 together represent an oxygen atom to the corresponding compound of the formula I in which R^ or R2 represents a hydrogen atom and the other represents a hydroxyl group, by means of a complex metal hydride, and, if desired, converting the resulting compound of the formula I into a salt thereof, especially a physiologically tolerable salt, or into an ester.

Among the groups mentioned for substituent R^, there are preferred alkyl groups of 3 to 8 carbon atoms, cycloalkyl groups of 3 to 7 carbon atoms, and phenyl radicals, and phenyl radicals substituted by one or more methyl groups. Furthermore, there are preferred, for R,, groups of the formula —C(R'),—(CH ) —O—R, in which each radical R' represents a hydrogen atom or an alkyl group of 1 to 3 carbon atoms, in particular a methyl group, the two radicals R1 being identical or different, and in which n is zero or 1 and R represents an alkyl group of 1 to 5 carbon atoms, a phenyl or benzyl group which may be substituted one or more times in the nucleus by substituents selected from halogen atoms, in particular chlorine atoms, trifluoromethyl groups, and alkyl groups of 1 to 3 carbon atoms. 407 - 14 or represents a phenoxyphenyl group, in which the phenoxy radical may be substituted by one or more substituents selected from halogen, in particular chlorine atoms, trifluoromethyl groups and alkyl groups of 1 to 3 carbon atoms. Particularly preferred as R^ are groups of the formula —C(R')2—(CH,,)n—0—R in which n is zero and R represents a phenyl radical which is monosubstituted by a chlorine atom or a trifluoromethyl group, or represents a phenoxyphenyl group in which the phenoxy radical is mono-substituted by a chlorine atom.

The process of the invention starts with synthesis of a ketone from a nitrile of the general formula II.

Such nitriles may be obtained, for example by converting 2-(1,3-dioxolan-2-yl)-ethyl bromide obtainable according to G. Bilchi and H. Wuest, J. Org. Chem. 34, (1969), page 112, by reaction with KCN to 2-(1,3-dioxolan-2-yl)-ethyl cyanide. This nitrile of the general formula II may be converted by acid-catalyzed transacetalization with a thiol of the general formula XI into the sulphur analogues (X=S) of the general formula II.

In the first step, the nitrile of the general formula II (x = 0 or S) is reacted with a Grignard compound of the general formula III, whereupon a ketone of the general formula IV is obtained by mild acid hydrolysis. The Grignard compounds of the general formula III may be obtained in the usual manner from 4-benzyloxybutyl chloride or bromide in one of the usual solvents, for example diethyl ether or tetrahydrofuran.

In principle, any other organo-metallic compounds containing the 4-benzylbutyl group, for example, 4-benzyloxybutyllithium, may be used.

The donponenta II and III are preferably allowed to react for a period of from 2 to 20 hours in the presence of an inert gas. The reaction is preferably carried out in a solvent, advantageously diethyl ether or tetrahydrofuran, the preferred temperatures are in the range of from 30° to 70°C, and reaction times in the range of from 12 to 15 hours are generally suitable. The reaction product is hydrolyzed under mild acid conditions and the resulting ketone of the general formula IV may be isolated in pure form by distillation or column chromatography. However, the products of the general formula IV may be used directly without further purification in the next synthesis step, the splitting off of the acetal or dithioacetal protective group.

In order to obtain the aldehyde-ketone of the formula V, the acid ketal group is split off in the usual manner. In the case of an oxygen-containing acetal of the formula IV (X represents oxygen atoms), a particularly mild and therefore especially suitable method of carrying out this step of the process of the invention comprises thoroughly mixing a solution of the compound of the general formula IV in which X =0 in an ether, for example diisopropyl ether, at 40° to 80°C, in the presence of inert gas, for 3 to 6 hours, with aqueous oxalic acid and, after washing until neutral, removing the solvent by distillation. To split off a dithioacetal group from the compound of the general formula IV (X represents sulphur atoms), any of the methods described in literature, for example, those described by Hsin-Lan Wang Chan, Tetrahydron Lett. 1972, pages 1989—1990, may be used. A preferred method com prises splitting off the group using CuCl2 and CuO as described in the Bll. Chem. Soc. Jap. 45, (1972), page 3724.

The resulting aldehyde of the formula V can be purified by chromatography or distillation; however, it is advantageous to use it directly without purification in the following reaction, the more so since it is obtained in high purity if the above-mentioned CuCl^— CuO method is used.

The aldehyde of the formula V is subsequently subjected to an aldol condensation under acid, or preferably alkaline conditions, whereby the unsaturated ketone of the formula VI is formed. A preferred, particularly mild form of the aldol condensation comprises heating, while stirring thoroughly, with exclusion of oxygen, a two-phase system at 40° to 6O°C, one phase being a solution of the aldehyde of the general formula V in a non20 hydrolyzable, water-immiscible solvent, for example, diisopropyl ether or benzene, and the other phase consisting of aqueous ΙΝ-sodium or potassium hydroxide solution. The resulting unsaturated ketone of the formula VI can be purified, as already mentioned, by chromatography or distillation It is, however, also possible to use the raw product in the next reaction.

Then,the ketone of the formula VI is reacted with cyanide ions in order to obtain a cyanorketone of the formula VII, this reaction being preferably carried out with acetocyanohydrin in a methanolic alkaline solution or with KCN in a mixture of methanol and water at room temperature. In general, the formation of cis-trans isomers must be expected in this reaction step. However, in view of the investigations carried out by D. Varoeh et al., Bull. Soc. Chim. 6, 1622 (1965), the most stable trans-configuration will generally be formed under alkaline conditions.

The cyano-ketone of the general formula VII is then reacted with an alcoholic solution of an inorganic acid, preferably with ethanolie hydrochloric acid, to give an ester of the general formula VIII via the iminoether hydrochloride Vila.

In this step, for example, the imino-ether hydrochloride Vila is obtained, after evaporation of the excess alcohol, in the form of an oil and can be freed from byproducts by extraction with a weakly polar solvent, for example, pentane or diethyl ether. Preferably the compounds of the general formulae V, VI and VII, are reacted each time as a crude product, and the by-products are removed by purification of the compounds Vila by the above extraction.

The imino-ether hydrochloride Vila is then hydrolyzed in the usual manner to give an ester of the general formula VIII, preferably by covering the aqueous solution with a layer of diethyl ether and stirring the mixture at room temperature.

The ethereal solution then contains the estar of the general formula VIII which may be purified in the usual way by distillation or by chromatographic techniques.

Prom the ester of the general formula VIII, an ester alcohol of the general formula IX is obtained by - 18 splitting off the benzyl-ether grouping by hydrogenation, preferably in the presence of a noble metal catalyst, for example 10% of palladium on animal charcoal.

The oxidation of the ester-alcohol of the general formula IX to an aldehyde of the general formula X may be carried out according to any one of the methods usually used for the oxidation of a primary alcohol to an aldehyde. A preferred method is the oxidation with chromic anhydride in the presence of pyridine, optionally in the presence of methylene chloride as solvent, as described by Collins in Tetrahedron Lett., 3363 (1968). Another preferred method is the oxidation with chlorine in the presence of thioanisole (Corey and Kinn, J. Org. Chem 38 (1973) 1233).

The aldehyde of the formula X may be converted in the usual manner in its pure form, but it is advantageous to react it in its crude form in the presence of an acid catalyst in an inert solvent with a dithiol of the general formula XI to give a dithioacetal of the general formula XII.

Preferably the aldehyde of the general formula X, which is generally obtained with a purity of about 90%, is reacted with an equimolar quantity of a dithiol of the general formula XI, for example ethylene dithioglycol, in the presence of an acid catalyst, preferably boron trifluoride etherate in the presence of an oxygen-free, inert gas, for example, nitrogen or argon in an aprotic solvent, for example, benzene or toluene, for a period of from 30 minutes to 5 hours at a temperature within the range of from 15°C to 50°C. In this step. 4140? - 19 the aldehyde group in the compound of the general formula XII is protected selectively.

The oxo group in the dithioacetal of the general formula XII is then protected by acetalization with a glycol of the general formula XIII in an aprotic solvent in the presence of an acid catalyst whereby a compound of the general formula XIV is obtained. It is particularly preferred to carry out the acetalization of the compound of formula XII with a glycol of the general formula XIII, for example, ethylene/glycol or 2,2-dimethyl-1,3-propanediol by heating the reaction components for 3 to 5 hours in benzene or toluene on a water-separator, with continuous removal of the water formed, whereby the compound of the general formula XIV is obtained.

The compounds of the formulae IX, X, XII and XIV may be purified; however, in the process of the invention it is advantageous to react the compounds of the general formulae IX, X and XII, which are obtained in high yields in the respective reaction steps as crude products and to purify only the resulting compound of the general formula XIV in the usual manner, preferably by column chromatography.

The ester group of the compound of the general formula XIV is reduced with a complex metal hydride, preferably diisobutylaluminium hydride, generally in an inert solvent, for example, toluene, at a temperature of 0°C or less, preferably at —40° to -80°C, to the corresponding aldehyde of the general formula XV.

The aldehyde of the general formula XV is then reacted according to the method of Horner, Emmons and Wittig with a phosphonic acid ester of the general formula XVI to give an unsaturated ketone of the general 40? formula XVII, preferably by preparing the sodium salt of the phosphonic acid ester of the general formula XVI with sodium hydride in the 1,2-dimethoxyethane and subsequently adding the aldehyde of the general formula XV and allowing the mixture to react for 2 to 6 hours. A phosphonic acid ester of the general formula XVI may be prepared according to any of the known methods (c.f. for example Corey, J. Am. Chem. Soc. 88, 5654 (1966).

An alcohol of the general formula XVIII is obtained in the form of its epimeric mixture, by reducing the ketone of the general formula XVII with a complex metal hydride, preferably an alkali metal borohydride. The epimer mixture of alcohols of the general formula XVIII may be separated, but the subsequent reaction may be carried out with the epimeric mixture and the separation of the epimers may be effected at the stage of the final products.

The etherification with dihydropyran to give the tetrahydropyranyl ether of the general formula XI is generally carried out in an ether or benzene solution of the alcohol of the general formula XVIII, in the presence of an acid catalyst, for example p-toluenesulphonic acid. In general, it is advantageous to purify the resulting tetrahydropyranyl ether of the general formula XVIII at this stage by chromatography.

Owing to the preparative difficulties involved, the liberation of an aldehyde or ketone from a dithioacetal has been the subject of many publications (c.f. among others Chang in Tetrahydron Letters No. 19, page 1989 (1972). In particular, the preparation of a relatively sensitive aliphatic aldehyde is very difficult, the more so if a particularly unstable protective group, for example, a tetrahydropyranyl ether group, is present in the same molecule. It is surprising that upon addition of an acid binding agent, preferably calcium carbonate, to a solution of the dithioacetal of the general formula XIX in a polar aprotic solvent, preferably dimethylformamide or acetone, an aldehyde of the general formula XX, which retains the tetrahydropyranyl group, is formed in practically quantititative yield after heating, for example, for 1 to 5 hours to a temperature in the range of from 30° to 70°C, preferably 50°C, with a —C^alkyl iodide, preferably methyl iodide.

The resulting aldehyde ether of the general formula XX may be reacted without purification to give a carboxylic acid of the general formula XXI. Preferably the Wittig reaction is effected in accordance with the method described in J. Org. Chem. 28, 1128 (1963).

The tetrahydropyranyl protective group is split off by mild acid catalysed hydrolysis, preferably in a 2% w/v O 0 aqueous alcoholic solution of oxalic acid at 20 C to 50 C, or by heating at 20° to 50°c for 1 to 2 hours in 60 to 70% v/v acetic acid, whereupon a carboxylic acid of the general formula XXII is obtained.

The last step of the synthesis of this invention comprises the mild acid catalysed hydrolysis of the acetal group of the compound of the formulaXXir to give a compound of the general formula I in which R^ and R2 together represent an oxygen atom. Another method for removal of the acetal group comprises the trans-acetalization of the compound of formula XXII to a compound Of formula I in which R^ and R2 together represent an oxygen atom by reacting the compound of formula XXII with a. large excess of a ketone, preferably acetone, generally in the presence of an acid catalyst, for example, £toluenesulphonic acid.

However, in a preferred method of the process of the invention, both protective groups in the carboxylic acid of the formula XXI may be split off in one step by mild acid hydrolysis, for which purpose 10% w/v aqueous oxalic acid has proved particularly advantageous. Thereby, a compound of the general formula I in which R^ and together represent an oxygen atom is obtained directlyo The reduction to the corresponding compound of the formula I in which R^ or R^ represents a hydrogen atom and the other a hydroxyl group is carried out with a complex metal hydride, preferably with a metal borohydride, for example, sodium borohydride, generally in an aqueous15 alcoholic solution. A mixture of the 9a, β-epimeric alcohols is obtained. The epimers can be separated in the usual manner, for example, by thin-layer chromatography or by partition chromatography.

If no separation of the epimers at the stage of the alcohols of the general formula XVIII has been effected, it is possible to separate resulting mixture of epimers of the general formula I in which R^ and S.% together represent an oxygen atom, (the compound being epimeric at the 15-position).

Furthermore, a racemate may be resolved at the stage of the acids of the general formula XXI or of the formula I in the usual manner by salt formation with an optically active base.

The compounds of the formulae IV, V, VI, VII, VIII, IX, X, XII, XIV, XV, XVII, VIII, xrx, XX, XXI and XXII are valuable intermediate products for the synthesis of the 43407 compounds of the formula I, and the compounds of formulae XXI and XXII are themselves part of the invention.

The compounds of formula I are distinguished by spasmogenic as well as spasmolytic, in particular bronchodilating and blood-pressure lowering properties. They are, furthermore, therapeutically active in the case of gastro-intestinal disorders and have an antifertility action. In comparison to the natural prostaglandins E, P and A, they are more stable. They may, therefore, be used as medicaments. In this respect it is surprising that the compounds of the formula I..which are epimeric with regard to the 15-0H group possess the pharmacological properties in about the same degree.

The invention therefore provides a pharmaceutical preparation which comprises a compound of formula I in the form of the free acid, a physiologically tolerable salt or an ester with an aliphatic, cycloaliphatic or araliphatic alcohol having up to 8 carbon atoms, or a mixture of the epimers of such a compound that is epime20 ric at the 15-OH group as active ingredient, in admixture or conjunction with a pharmaceutically suitable carrier.

As the salt, there may be used, for example, a benzylammonium, triethanolammonium or morpholine salt, in particular a tris-(hydroxymethyl)-aminomethane salt, or an alkali metal salt, for example, a Na- and K-salfc.

As the aster there is preferably used an ester with a lower saturated aliphatic alcohol, for example, a methyl, ethyl, propyl, isopropyl, butyl or pentyl ester, or a benzyl ester.

The pharmaceutical preparation may comprise the active substance in the form of an aqueous solution or suspension or even a solution in a pharmaceutically suit able organic solvent,-for example, a mono- or polyhydric alcohol, dimethy1/sulphoxide or dimethylformamide, or it may be in admixture with a pharmaceutically suitable polymeric carrier substance, for example, polyvinylpyrrolidone .

The pharmaceutical preparations may be in the form of infusion or injection solutions, or may be in a form suitable for oral administration, for example, capsules or tablets; preferably, however, they are locally applicable preparations, for example, creams, emulsions, suppositories, sprays, or aerosols.

The preparations may also comprise other pharmacologically active substances, for example, diuretic agents or anti-diabetic agents.

A pharmaceutical preparation with a surprisingly strong bronchodilating action may be obtained by mixing the two epimers of 7-Γ2Β-(2£-hvdroxy-trans-l-octenvl)5-oxo-la-cyclopentyl] -cis-4-heptenoic acid, (epimeric with regard to the 15-OH group,) either in the form of the free acid or in the form of a physiologically tolerable inorganic or organic salt or of an ester with an aliphatic, cycloaliphatic or araliphatie alcohol having up to 8 carbon atoms, in a weight ratio of from 0.75 to 1 to 1.25 to 1; such mixtures have the greatest activity when in the form of an aerosol.

Surprisingly, such mixtures show an activity which is several times higher than the activities of the individual isomers. Particularly advantageous is a mixture of the isomers in a weight ratio of 1:1.

The epimers and isomers may also be used in the 414©? form of physiologically tolerable salts or esters in pharmaceutical preparations, as described above. Particularly preferred are mixtures of the isomeric free acids and of the methyl, ethyl, propyl and isopropyl esters of the mentioned acids.

For administration in aerosol form, a compound or a mixture of compounds of formula I may be dissolved in a physiologically tolerable solvent which is not irritating with regard to taste, for example, water or ethanol, or suspended, for example, in a lower alkyl ester of a higher fatty acid, for example, myristic acid isopropyl ester, if desired with the addition of a surface-active agent as stabilizer, for example, a sorbitan or pentaerythirtol fatty acid ester, and filled, together with an inert propellant gas into an aerosol container. However, a pharmaceutical preparation may also be administered by means of an atomizer with the aid of compressed air.

The following dosage units or daily doses may be administered for the various indications: Bronchodilating action (as aerosol): Dosage unit: 0.1—1000 |ig preferred: 1 — 200 |ig (per single spray output) Daily dose: 0.1— 10 mg Blood-pressure-lowerincr action: Dosage unit: 1—1000 |j,g preferred: 1— 100 (ig parenterally (i.v.) Daily dose: 1— 10 mg Dosage unit: 0.5—1000 p,g preferred: 1 — 500 |ig orally Daily dose: 1 mg— 10 mg The doses to be administered in the treatment of gastro intestinal disorders correspond to those indicated for administration as blood-pressure-lowering agents.

The invention therefore also provides a method of 5 treating bronchiospasms and/or gastro-intestinal disorders and/or high blood pressure, which comprises administering to a commercially reared animal a compound of formula I, a physiologically tolerable salt or ester thereof, or a mixture of epimers of such a compound that is epimeric at the 15-OH group. The invention also provides a method of controlling fertility, which comprises administering to a mammal an active substance as defined in the above method.

The compound or mixture is preferably administered in the dosages specified above and is advantageously in the form of a pharmaceutical preparation of the invention.

The following Examples illustrate the invention.

In the Examples, ratios of solvents for chromato20 graphy are by volume.

Preparation of Starting materials: 2-(2-bromoethyl)-1,3-dioxolane was prepared according to G. Buchi and H. Wuest (J. Org. Chem. 34. (1969) page 1122) and heated in a manner analogous to that described by Wohl, (Chem. Ber. 39 1906), page 1952, for 3 hours under reflux in a mixture of 60 parts of ethyl alcohol and 40 parts of H^O with 2 molar equivalents of KCN in the presence of catalytical amounts of potassium iodide. The resulting 2-(2-cyanoethyl)-1,3-dioxolane (Β.ρ.θ g mm 68°—69°C) was heated under reflux in benzene 414 0 7 with ethylene dithioglycol in the presence of boron trifluoride etherate, whereupon, after the usual working up 2-(2-cyanoethyl)-1,3 -dithiolane having a B.p. _ mm U· o of 124°—-26°C was obtained. 4-Benzyloxybutanol was obtained according to the method described by Butler, Reufrew and Clapp (Am. Soc. (1938) 1472) and transformed according to Bennett and Hock, J. Chem. Soc. (Lond.) 1927, page 476, into the 4benzyloxybutyl chloride.

EXAMPLE 1. 2-(7-Benzyloxy-3-oxoheptyl)-l,3-dithiolane The Grignard compound was prepared by heating 2.5 g (0.103 g atoms) of Mg and 20 g (0.101 mole) of 4-bensyloi^butyl chloride in 50 ml of diethyl ether for 5 hours.

To this Grignard solution, there was added drOpwise the solution of 12 g [0.076 mole] of 2-(2-cyanoethyl)1,3-dithiolane in 50 ml of diethyl ether and the mixture was retti&.e4 for IS hours under argon. After cooling, 200 ml of methylene chloride and ice water were added, the mixture was acidified to pH 1 by means of HC1 and stirred for 15 minutes. The organic phase was separated, washed with water and concentrated. The residue was dissolved in 200 ml of acetone and 50 ml of methanol and stirred with 25 ml of 2n—HCl for 4 hours at room temperature.

The solvent was evaporated off under reduced pressure, the residue was dissolved in methylene chloride, washed once with a 2N sodium carbonate solution and twice with water, dried over Mg SO and evaporated to dryness. The 4 residue was distilled under reduced pressure. Β.ρ.θ ^mm 205—207°C.

EXAMPLE 2. 8-Benzyloxy-4-oxooctanal 0.135 mole (44 g) of 2 (7-benzyloxy-3-oxoheptyl)1,3-dithiolane in 1 litre of acetone were refluxed for 1 hour under nitrogen with 47 g [0.275 mole] of CuCl^ .

H^O and 44 g [0.57 mole] of CuO, the copper salts were filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether, washed twice with 2N—HC1 and thrice with water, dried and the solvent was removed by distillation under reduced pressure. The residue was distilled under, reduced pressure. Β.ρ.θ 5 mm 185°—192°C.

' EXAMPLE 3. 2-(3-Benzyloxypropyl)-2-cyclopenten-l-one .8 g of crude 8-benzyloxy-4-oxooctanal were dissolved in 100 ml of di-isopropyl ether and well mixed with 500 ml of ΙΝ-sodium hydroxide solution at 50°C under nitrogen with the aid of a vibromixer. The organic phase was separated, the aqueous phase was extracted with 200 ml of diethyl ether and the combined ethereal extracts were washed with water, dried, concentrated and distilled under reduced pressure. Β.ρ.θ 5 η™ 175—180°C.

EXAMPLE 4. 2a-(3-Benzyloxypropyl)-3p-cyanocyclopentanone 47.8 g [0.208 mole] of 2-(3-benzyloxypropyl)-2cyclopenten-l-one were dissolved in 200 ml of methanol, 41.5 g [0.64 mole] of KCN were added and then 15 g [0.25 mole] of glacial acetic acid in 25 ml of methanol were added dropwise within one hour. After having stirred - 29 4 2 4 0? for 1 hour, 4 g [0.066 mole] of glacial acetic acid were again added and the mixture was stirred for a further hour. After this time, no starting material could be detected in the thin-layer chromatogram. 100 ml of 2N— HaOH and 900 ml of ice-water were added and the mixture was extracted thrice with 200 ml of diethyl ether each time, the combined ether extracts were washed until neutral, dried and the solvent was removed by distillation under reduced pressure. The residue was distilled.

B.p. _ mm 210°—215°C. 0.5 EXAMPLE 5. 3^-EthoXycarbonyl-2ct-(3-benzyloxypropyl)-cyclopentanone .1 g [0.02 mole] of 2a-(3-benzyloxypropyl)-3βcyanocyclopentanone were dissolved in 25 ml of absolute benzene and 1 g [0.022 mole] of absolute ethyl alcohol, and then HCl gas was bubbled through slowly for 4 hours.

The reaction mixture was allowed to stand for 16 hours at room temperature. The solvent was removed under reduced pressure and the residue was stirred thrice, each tirao with 75 ml of absolute diethyl ether, and these ether extracts were rejected.

The oily residue was dissolved in 20 ml of water, 100 ml of diethyl ether was added, and the mixture was stirred for 30 minutes at room temperature, the organic phase was separated and the aqueous phase was extracted with 200 ml of diethyl ether. The combined ether extracts were washed with 2N sodium carbonate solution and water, dried, and the solvent was removed under reduced pressure. An oil was obtained. An analytically pure sample was obtained by chromatography on silica gel using a mixture of cyclohexane and glacial acetic acid in a proportion of 9:1 as eluant. The sample showed the - 30 following spectroscopic data: N.M.R 7.3 ppm singulett 5 H,/4.2 (c) ppm 4,4 ppm singulett 2 H,/quartett 2H.

EXAMPLE 6. 3p-Ethoxycarbonyl-2a-(3-hydroxypropyl)-cyclopentanone g of 33-ethoxycarbonyl-2a-(3-benayloxypropyl)cyclopentanone were hydrogenated in 50 ml of 80% acetic acid with 1 g of palladium black at room temperature and a pressure of 50 atmospheres gauge. The reaction mixture was mixed with 100 ml of water and 100 ml of methylene chloride, the catalyst was filtered off, the filtrate was mixed with an aqueous caustic soda solution to give a pH of 8 to 9, the methylene chloride was removed, the remainder was washed, dried and distilled under reduced pres15 sure. The oily residue was heated for 1 hour at 50°C at 0.02 mm Hg.

I.R. 3500 cm-1.

EXAMPLE 7. 3-(2p-Ethoxycarbonyl 5-oxo-la-cyclopentyl)-propionaldehyde 3.07 g [0.014 mole] of 30-ethoxycarbonyl-2a-(3hydroxypropyl)-cyclopentanone were dissolved in 3 ml of methylene chloride and added dropwise to 11.95 g of CrO3 and 19.15 g of pyridine in 300 ml of methylene chloride at 0°C. After stirring for 35 minutes at 0°C, 61.8 g of solid sodium bisulfate/monohydrate were added and the mixture was further stirred for 30 minutes at 0°C. The suspension was filtered through a clarifying filter and the filter residue was washed six times, each time with 50 ml of methylene chloride. The combined methylene chlo30 ride filtrates were dried over MgSO^ and concentrated.

An oil was obtained.

X.R. no OH-band at 3500 cm '', wide carbonyl band at 1730—1740 cm .

EXAMPLE 8. 3-(2 β-Ethoxycarbony1-5-oxo-1α-cyclopentyl)-propionaIdehyde ethylene dithioacetal g (0.014 mole) of oily 3-(23-ethoxycarbonyl-5oxo-Ια-cyclopentyl)-propionaldehyde were stirred for 3 hours at room temperature with 1.29 g (0.0137 mole) of ethylene dithioglyeol, 0.5 ml of boron trifluoride etherate and 50 ml of anhydrous bensene, diluted with 150 ml of diethyl ether and washed with ice-cold IN—HaOH and water. The mixture was dried over sodium sulfate and the solvent was evaporated under reduced pressure. An oil was obtained.

I R.= 1740 cm'1.

EXAMPLE 9a 7a - [2- (1,3 - dithiolan - 2 - yl)ethyl] - 3,3 -dimethyl - 1,5 - dioxaspiro[5,4]dec - 8β - ylcarboxylic acid ethyl ester 3.35 g (0.0116 mole) of 3—(2p-ethoxycarbonyl-5-oxoΙα-cyclopentyl)-propionaldehyde ethylene dithioacetal ware heated for 3 hours on a water separator under reflux with 2.1 g [0.02 mole] of 2,2-dimethyl-l,3-propanediol, 0.2 g of g-toluenesulfonie acid and 50 ml of benzene. After cooling, the reaction mixture was diluted with ether, washed with ice-cold 2N sodium carbonate solution, dried over Ha^O^ and concentrated. Prom the oil that had formed, there was obtained an analytically pure product by chromatography on silica gel and elution with oyclohexane/ethyl acetate in a ratio of 95:5 v/v.

N.M.R. 4.2 ppm (o)-quartett 2H 3 5 ppm (singulett 4H. 407 EXAMPLE 9b.

In a manner analogous to that described above, there was obtained with ethylene glycol the Sa-[2-(l,3dithiolan-2-yl)ethyl]-l,4-dioxaspiro[4,4]ηοη-7β-γ1carboxylic acid ethyl ester N.M.R. 3.8—45 ppm singulett + multiplett 7H 3.2 ppm singulett 4H.

EXAMPLE 10. 7a - [2 - (1,3 - dithiolan - 2 - yl)ethyl]- 3,3 - dimethyl - 1,5 - dioxaspiro[5,4] - 8β - decane carbaldehyde 1.3 g [3.5 mmoles] of 7a-[2-(1,3-dithiolan-2-yl)ethyl] -3,3-dimethyl-l,5-dioxaspiro[5,4] dec-3p-ylcarboxylic acid ethyl ester were dissolved in 50 ml of absolute toluene, then 0.7 ml [3.85 mmoles] of diisobutylaluminium hydride in 10 ml of absolute toluene were added dropwise within 20 minutes at -70°C and the mixture was stirred for 2 hours at -70°C. 1 ml of methanol and 0.5 ml of glacial acetic acid were added dropwise, then 20 ml of water were added and finally 50 ml of diethyl ether were added. The turbid solution was filtered through a clarifying filter and the residue was washed with diethyl ether. The ethereal phase was washed with a solution of sodium bicarbonate, dried and concentrated under reduced pressure.

The oil that had formed showed the following spectral data: N.M.R. 9.35 4.4 3.5 3.2 ppm dubleft 1H ppm triplett 1H ppm singulett 4 H ppm singulett 4H EXAMPLE 11a. 7α - [2 - (1,3 - dithiolan - 2 - yl)ethyl] - 3,3 - dimethyl— 8β - (3 - oxo - trans - 1 - octenyl) - 1,5dioxaspiro[5,4]decane 0.1 g [3 3 mmoles) of 80% sodium hydride were stirred for 15 minutes at room temperature in 25 ml of 1,2dimethoxyethane and then 0.89 g [4 mmoles] of dimethyl 2-oxoheptylphosphonate were added dropwise. After a 25 minutes' stirring, a white emulsion had formed. To this emulsion, a solution of 1.06 g [3.2 mmoles] of 7a - [2(1,3 - dithiolan - 2 - yl)ethyl] - 3,3 - dimethyl - 1,5dioxaspiro[5,4] - 8β - decane - carbaldehyde was added dropwise and the mixture was stirred for 2 1/2 hours at room temperature After this time, the solution was only weakly turbid. Some drops of glacial acetic acid and 2 spatula points of charcoal were added and the whole was filtered. The filtrate was concentrated under reduced pressure, whereupon a light oil was obtained. Chromatography on silica gel and elution with cyclohexane/ethyl acetate 95:5 and 90:10 yielded the analytically pure sample.

N.M.R. 5.8—6.8 ppm multiplett 2H 4.4 ppm triplett 1 H 3.5 ppm singulett 4 H 3.2 ppm singulett 4 H EXAMPLE lib.

In analogous manner, there was prepared by the reaction with dimethyl 2-oxo - nonylphosphonate, 7a - [2(1,3 - dithiolan - 2 - yl) - ethyl] - 3,3 - dimethyl8β r (3 - oxo - trans - 1 - decenyl) - 1,5 - dioxaspiro [ 5,4] decane.

EXAMPLE 11c.

In analogous manner, there was prepared by the reaction with dimethyl (2 - cyclohexyl - 2 - oxoethyl) phosphonate, 7a - [2 - (1,3 - dithiolan - 2 - yl) ethyl] - 8β - (3 - cyclohexyl - 3 - oxo - trans - 1propenyl) - 3,3 - dimethyl - 1,5 - dioxaspiro[5,4] decane.

EXAMPLE lid.

In analogous manner, there was prepared by the reaction with dimethyl (3,3 — dimethyl - 4 -- ethoxy2 - oxobutyl)phosphonate, 7a - [2 - (1,3 - dithiolan-2yl) - ethyl] - 3,3 - dimethyl - 8β - (4,4 - dimethyl 5 - ethoxy - 3 - oxo - trans - 1 - pentenyl) - 1,5dioxaspiro[5,4]decane.

EXAMPLE lie.

In analogous manner, there was prepared by the reaction with dimethyl (2 - cycloheptyl - 2 - oxoethyl) phosphonate, 7a - [2 - (1,3 - dithiolan - 2 - yl)ethyl] - 3,3 - dimethyl - 8β - (3 - cycloheptyl - 2oxo - trans - 1 - propenyl) - 1,5 - dioxaspiro[5,4]decane.

N.M.R. 5.8—6.8 ppm multiplett 2H EXAMPLE Ilf.

In analogous manner, there was prepared by the reaction with dimethyl 2-oxopentylphosphonate, 7a[2 - (1,3 - dithiolan - 2 - yl) - ethyl] - 3,3 - dimethyl - 8β - (3 - oxo - trans - 1 - hexenyl) - 1,5dioxaspiro[5,4] decane.

N.M.R. 5.8—6.8 ppm multiplett 2 H EXAMPLE llg.

In analogous manner, there was prepared by the reaction between dimethyl [3 - £ - (£- chlorophenoxy)phenoxy - 2 - oxobutyl] phosphonate and 6a - [2 - (1,3dithiolan - 2 - yl)ethyl] - 1,4 - dioxaspiro[4,4] - 7βnonaneearbaldehyde, 7β - [4 - p_ - (£ - chlorophenoxy)phenoxy - 3 - oxo - trans - 1 - pentenyl] - 9a - [2(1,3— dithiolan - 2 - yl) ethyl] - 1,4 - dixoaspiro[4,4]nonane.

N.M.R 6.3—7,4 ppm multiplett 10 H 4.5 ppm (c) 1 H 3.9 ppm singulett 4 H 3.15 ppm singulett 4 H EXAMPLE llh.

In analogous manner to Example llg, there was prepared by the reaction with dimethyl [3 - (£- (£chlorophenoxy)phenoxy - 3 - methyl - 2 - oxobutyl)phosphonate, 7β - [4 - £ - (p - chlorophenoxy)phenoxy4 - methyl - 3 - oxo - trans - 1 - pentenyl] - 6a - [2(1,3 - dithiolan - 2 - yl)ethyl] - 1,4 - dioxaspiro[4,4]nonane.

W.M.R. 6.8— 7.4 ppm multiplett 10 H 4.5 ppm 1 H 3.9 ppm singulett 4 H 3.15 ppm singulett EXAMPLE Hi. 4 H In analogous manner to Example llg. there was prepared by the reaction with dimethyl (3 - phenoxy- 2 - oxopropyl)phosphonate, 6a - [2 - (1,3 - dithiolan· - yl) - ethyl] - 7β - (4 - phenoxy - 3 - oxo - trans1 - butenyl) - 1,4 - dioxaspiro[4,4]nonane. 40? N.M.R. 6.8—7.5 ppm multiplett 5H EXAMPLE 11 j.

In analogous manner to Example llg, there was prepa red by the reaction with dimethyl [3 » (4 - fluorophenoxy) - 2 - oxopropyl)phosphonate, 7β - [4 - (4fluorophenoxy) - 3 - oxo - trans - 1 - butenyl] - 6 a[2 - (1,3 - dithiolan - 2 - yl) - ethyl] - 1,4 - dioxaspiro[4,4]nonane.

N.M.R. 6.9—7.3 ppm multiplett 4 H EXAMPLE Ilk.

In analogous manner to Example llg, there was prepared by the reaction with dimethyl [3 - (3 - chlorophenoxy) - 2 - oxopropyl]phosphonate, 7β - [4 - (3chlorophenoxy) - 3 - oxo - trans - 1 - butenyl] - 6a[2 - (1,3 - dithiolan - 2 - yl) - ethyl] - 1,4 - dioxaspiro[4,4] - nonane.

N.M.R. 6.7—7.5 ppm multiplett 4H EXAMPLE 111.

In analogous manner to Example llg, there was prepared by the reaction with dimethyl [3 - (3 - trifluoromethylphenoxy) - 2 - oxopropyl]phosphonate, 7β[4-(3- trifluoromethylphenoxy) - 3 - oxo - trans - 1butenyl] - 6a - [2 - (1,3 - dithiolan - 2 - yl)ethyl]1,4 - dioxaspiro[4,4]nonane.

N.M.R. 7.0—7.6 ppm multiplett 4 H EXAMPLE 11m.

In analogous manner to Example llg, there was prepared by the reaction with dimethyl (4 - methyl - 2oxopentyl)phosphonate, 7β - (5 - methyl - 3 - oxotrans - 1 - hexenyl) - 6a - [2 - (1,3 - dithiolan - 2yl)ethyl] - 1,4 - dioxaspiro[4,4]nonane. 414 0? N. M.R. 5.9—7 ppm multiplett 2 H 4.5 ppm multiplett 1 H 3.95 ppm singulett 4 H 3.2 ppm singulett 4 H EXAMPLE lln.

In analogous manner to Example llg, there was prepared by the reaction with dimethyl - (3,3 - dimethyl - 2 - oxoheptyl)phosphonate, 7β - (4,4 - dimethyl - 3 - oxo - trans-i-octenyl) - 6a - [2 - (1,3dithiolan - 2 - yl)ethyl] - 1,4 - dioxaspiro[4,4]nonane.

EXAMPLE 12a. 7a - [2 - (1,3 - dithiolan - 2 - yl)ethyl] - 3,3 - dimethyl - 8β - (3ξ - hydroxy - trans - 1 - octenyl)1,5 - dioxaspiro[5,4]decane O. 12 g of NaBH^ [3.2 mmoles] were dissolved in 1 ml of HjO + 10 ml of CH^OH, cooled to 0°C and 1.29 g (3 mmoles) of the product of Example 11a in 15 ml of methanol were added dropwise,- the whole was stirred for 1 hour at room temperature. The solution was neutralised with glacial acetic acid, concentrated under reduced pressure and the residue was dissolved in diethyl ether and washed with water. After removal of the ether by evaporation, an oil remained which showed the following spectra data: I.R. 3500 cm ; no carbonyl band N.M.R. 5.3—5.7 ppm multiplett 2 H EXAMPLE 12b.

In analogous manner there was prepared from the product of Example life , 7a- [2 - (1,3 - dithiolan - 2yl)ethyl] - 3,3 - dimethyl - 8β - (3ξ - hydroxy - trans1 - decenyl) - 1,5 - dioxaspiro[5,4]decane.

I.R. 3500 cm N.M.R. 5.3—5.7 ppm multiplett 2 H EXAMPLE 12c.

Analogously, from the product of Example 11c, 7a[2 - (1,3 - dithiolan - 2 - yl)ethyl] - 3,3 - dimethyl8β - (3ξ - cyclohexyl - 3ξ - hydroxy - trans - 1propenyl) - 1,5 - dioxaspiro[5,4] decane.

I.R. 3500 cm-1 N.M.R. 5.3—5.7 ppm multiplett 2 H EXAMPLE 12d.

Prom the product of Example lid, 8β - (4,4 - dimethyl - 5 - ethoxy - 3ξ - hydroxy - trans - 1pentenyl) - 7a - [2 - (1,3 - dithiolan - 2 - yl)ethyl]3,3 - dimethyl - 1,5 - dioxaspiro[5,4] decane.

I.R. 3500 cm1 N.M.R. 5.3—5.7 ppm multiplett 2 H EXAMPLE 12e.

From the product of Example lie, 8β - (3ξ - cycloheptyl - 3ξ - hydroxy - trans - 1 - propenyl) — 7a - [2(1,3 - dithiolan - 2 = yl) - ethyl] - 3,3 - dimethyl1,5 - dioxaspiro[5,4]decane.

I.R. 3500 cm 1 N.M.R. 5.3—5.7 ppm multiplett 2 H EXAMPLE 12f.

In a manner analogous to that described in Example 12a, there was prepared from the product of Example Ilf, 8β - (3ξ - hydroxy - trans - 1 - hexenyl) - 7β - [2(1,3 - dithiolan - 2 - yl) - ethyl] - 3,3 - dimethyl1,5 - dioxaspiro[5,4]decane.

I.R. 3500 cm-1 N.M.R. 5.3—5.7 ppm multiplett 2 H 407 EXAMPLE 12g.

In a manner analogous to that described in Example 12a, there was prepared from the product of Example llg, 7 β - [4 - £ - (£-- chlorophenoxy)phenoxy3ξ - hydroxy - trans - 1 - pentenyl] - 6a - [2 - (1,3dithiolan - 2 - yl) - ethyl] - 1,4 - dioxaspiro[4,4]nonane.

I.R. 3500 cm1.

N.M.R. 5.3—5.7 ppm multiplett 2 H EXAMPLE 12h.

In a manner analogous to that described in Example 12a, there was prepared from the product of Example llh, 7(3 - [4 - £ - (£- chlorophenoxy)phenoxy - 3ξ - hydroxy4 - methyl - trans - 1 - pentenyl] - 6a - [2 - (1,3ditholan - 2 - yl) - ethyl] - 1,4 - dioxaspiro[4,4]nonane.

I.R. 3500 cm N.M.R. 5.3—5.7 ppm multiplett 2 H EXAMPLE 12i.

In a manner analogous to that described in Example 12a, there was prepared from the product of Example Hi, 6a - [2 - (1,3 - dithiolan - 2 — yl) - ethyl] - 7β - (3ξhydroxy - 4 - phenoxy - trans - 1 - butenyl) - 1,4dioxaspiro[4,4]nonane.

I.R. 3500 cm-1 N.M.R. 5.3—5.7 ppm multiplett 2 H EXAMPLE 12j.

In a manner analogous to that described in Example 12a, there was prepared from the product of Example 11j, 6a - [2 - (1,3 - dithiolan- 2 - yl) - ethyl] - 7β - [4(4 - fluorophenoxy) - 3ξ - hydroxy ~ trans - 1 - butenyl] 41407 - 40 1,4 - dioxaspiro[4,4]nonane.

I.R. 3500 cm1 N.M.R. 5.3—5.7 ppm multiplett 2 H EXAMPLE 12k.

In a manner analogous to that described in Example 12a, there was prepared from the product of Example Ilk, 7β - [4 - (3 - chlorophenoxy) - 3ξ - hydroxy - trans1 - butenyl] - 6a- [2 - (1,3 - dithiolan - 2 - yl)ethyl] - 1,4 - dioxaspiro[4,4]nonane.

I.R. 3500 cm1 N.M.R. 5.3—5.7 ppm multiplett 2 H EXAMPLE 121.

In a manner analogous to that described in Example 12a, there was prepared from the product of Example 111, 7β - [3ξ - hydroxy - 4 - (3 - trifluoromethylphenoxy)trans - 1 - butenyl] - 6a - [2 - (1,3 - dithiolan - 2yl)ethyl] - 1,4 - dioxaspiro[4,4] nonane.

I.R. 3500 cm 1 N.M.R. 5.3—5.7 ppm multiplett 2 H EXAMPLE 12m.

In a manner analogous to that described in Example 12a, there was prepared from the product of Example 11m, 6a - [2 - (1,3 - dithiolan - 2 - yl)ethyl] - 7β - (3ξhydroxy— 5 — methyl - trans - 1 - hexenyl) - 1,425 dioxaspiro[4,4]nonane.

I.R. 3500 cm 1 N.M.R. multiplett 2 H EXAMPLE 12n. ύ In a manner analogous to that described in Example 12a, there was prepared from the product of Example lln. 4140^ - 41 6α - [2 - (1,3 - dithiolan - 2 - yl)ethyl] - 7β - (3ξ~ hydroxy - 4,4 - dimethyl - trans - 1 - octenyl) - 1,4dioxaspiro[4,4]nonane.

I.R. 3500 cm-1 N.M.R. 5.3—5.7 ppm multiplett 2 H EXAMPLE 13a. 7a - [2 - (1,3 - dithiolan - 2 - yl)ethyl] - 3,3 - dimethyl - 8β - [3ξ - (2 - tetrahydropyranyloxy)trans - 1 - octenyl] - 1,5 - dioxaspiro[5,4] decane 1.1 g [2.5 mmoles] of the product of Example 12a were dissolved in 20 ml of absolute diethyl ether, 20 mg Of £-toluenesulphonic acid were added, 1.2 ml [13 mmoles] of dihydropyran in 10 ml of absolute diethyl ether were added dropwise and the mixture was stirred for 4 hours at room temperature. 0.2 ml of dihydropyran were added. The reaction mixture was allowed to stand overnight and was then stirred for 30 minutes with 0.5 g of solid Na2CO3· The suspension was filtered, the filtrate was concentrated under reduced pres20 sure and the oil that had formed was eluted with cyclohexane-ethyl acetate (9:1) over a silica gel column.

In the infrared spectrum, the analytically pure -1 sample showed no OH-band at 3500 cm .

Thin-layer chromatography iC = 0.64 on silica gel in cyclohexane/ether 4:6.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

In analogous manner, there were prepared from the above-described alcohols the following tetrahydropyranyl ethers: EXAMPLE 13b. 7a- [2 - (1,3 - Dithiolan - 2 - yl)ethyl] - 3,30 7 dimethyl - 8β - [3ξ - (2 - tetrahydropyranyloxy)trans - 1 - decenyl] - 1,5 — dioxaspiro[5,4] - decane.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

EXAMPLE 13c. 7a - [2 - (1,3 - Dithiolan - 2 - yl)ethyl] - 8β[3ξ - cyclohexyl - 3ξ - (2 - tetrahydropyranyloxy)trans - 1 - propenyl] - 3,3 - dimethyl - 1,5 - dioxaspiro[5,4]decane.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

EXAMPLE 13d. 8β - [4,4 - dimethyl - 5 - ethoxy - 3ξ - (2tetrahydropyranyloxy) - trans - 1 - pentenyl] -7 a[2 - (1,3 - dithiolan - 2 - yl)ethyl] - 3,3 - dimethyl1,5 - dioxaspiro[5,4]decane.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

EXAMPLE 13e. 8β - [3ξ - cycloheptyl - 3ξ - (2 - tetrahydropyranyloxy) - trans - 1 - propenyl] - 7a - [2 - (1,3 dithiolan - 2 - yl)ethyl] - 3,3 - dimethyl - 1,5dioxaspiro[5,4]decane.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

EXAMPLE 13f. 8β - [3ξ -(2- tetrahydropyranyloxy) - trans1 - hexenylj/- 7a - [2 - (1,3 - dithiolan - 2 - yl)ethyl] - 3,3 - dimethyl-a 1,5 - dioxaspiro[5,4]decane.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

EXAMPLE 13g.

Prom the products of Example 12g, 7β - [4 - £ (£ - chlorophenoxy)phenoxy - 3ξ - (2 - tetrahydro- 43 pyranyloxy) - trans - 1 -pentenyl/ - 6α - [2 - (1,3dithiolan - 2 - yl)ethyl] - 1,4 - dioxaspiro[4,4] nonane.

N.M.R. 4.1—5.0 ppm broad multiplet 4 H.

EXAMPLE 13h.

Prom the alcohol of Example 12h, there was obtained in a manner analogous to that of Example 13a, 7β - [42, - (£ - ohlorophenoxy)phenoxy - 4 - methyl - 3ξ - (2tetrahydropyranyloxy) - trans - 1 - pentenyl] - 6a - [2(1,3 - dithiolan - 2 - yl) - ethyl] - 1,4 - dioxaspiro[4,4]nonane.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

EXAMPLE 13i.

Prom the alcohol of Example 12i, there was prepared in a manner analogous to that of Example 13a, 7β[4 - phenoxy - 3ξ - (2 - tetrahydropyranyloxy) - trans1 - butenyl] - 6a - [2 - (1,3 - dithiolan - 2 - yl)ethyl] - 1,4 - dioxaspiro[4,4] nonane.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

EXAMPLE 13j.

Prom the alcohol of Example 12j, there was prepared in a manner analogous to that of Example 13a, 7(3[4 -(4- fluorophonoxy) - 3ξ -(2- tetrahydropyranyloxy) - trans - 1 - butenyl] - 6a - [2 - (1,3 - dithiolan - 2 - yl)ethyl] - 1,4 - dioxaspiro[4,4]nonane.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

EXAMPLE 13k.

Prom the alcohol of Example 12k, there was prepared in a manner analogous to that of Example 13a, 7β[4 - (3 - ohlorophenoxy) - 3ξ - (2 - tetrahydropyranyloxy) - trans - 1 - butenyl] - 6a - [2 - (1,3 - dithio4240? - 44 lan. - 2 - yl)ethyl - 1,4 - dioxaspiro[4,4]nonane.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

EXAMPLE 131.

Prom the alcohol of Example 121, there was prepa5 red in a manner analogous to that of Example 13a, 7β[4 - (3 - trifluoromethylphenoxy) - 3ξ - (2 - tetrahydropyranyloxy) - trans - 1 - butenyl] - 6a - [2(1,3 - dithiolan - 2 - yl)ethyl] - 1,4 - dioxaspiro[4,4]nonane.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

EXAMPLE 13m.

From the alcohol of Example 12m, there was obtained in a manner analogous to that of Example 13a, 7β[5 - methyl - 3ξ - (2 - tetrahydropyranyloxy) - trans15 1 - hexenyl] - 6a - [2 - (1,3 - dithiolan - 2 - yl)ethyl] 1,4 - dioxaspiro[4,4]nonane.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

EXAMPLE 13n.

From the alcohol of Example 12n, there was prepa20 red in a manner analogous to that of Example 13a, 7β [4,4 - dimethyl — 3ξ - (2 - tetrahydropyranyloxy)trans - 1 - octenyl] - 6a - [2 - (1,3 - dithiolan - 2yl)ethyl] - 1,4 - dioxaspiro[4,4]nonane.

N.M.R. 4.5—4.8 ppm multiplett 2 H.

EXAMPLE 14a. - [3,3 - Dimethyl - 8β - [3ξ --(2- tetrahydropyranyloxy) - trans - 1 - octenyl] - 1,5 - dioxaspiro[5,4]dec - 7a - yl] - propionaldehyde 1.05 g [2.05 mmoles] of the product of Example 13a 30 was stirred for 2 hours at 50°C in 100 ml of DMF with 0.7 ml (10,3 mmoles) of methyl iodide, 1.4 g (14 moles) 414 0 7 of CaC0_ and 0.4 ml of H^O. The solution vss cooled, combined with 50 ml of acetone, suction-filtered to remove the precipitate and the filtrate was evaporated to dryness at 0.1 mm Hg. The residue was dissolved in diethyl ether, washed with ^0, dried over MgSO^ and the solvent was removed by distillation under reduced pressure. The oily residue, which was not further purified showed in the infrared spectrum a strong carbonyl band at 1730 cm \ Thin-layer chromatography value 0.51 on silica gel in cyclohexane/ether 4:S.

In analogous manner, there was obtained from the thioacetals 13b—13n, the following propionaldehydes of the general formula XX: EXAMPLE 14b. - [3,3 - dimethyl - 8β - [3ξ -(2- tetrahydropyranyloxy) - trans - 1 - decenyl] - 1,5 - dioxaspiro [5,4]dec - 7a - yl] - propionaldehyde.

I.R. 1730 cm-1 EXAMPLE 14c. - [3,3 - Dimethyl - 8β - [3ξ - cyclohexyl - 3ξ(2 - tetrahydropyranyloxy) - trans - 1 - propenyl] · 1,5 - dioxaspiro[5,4] dec - 7a - yl] - propionaldehyde.

I.R. 1730 cm-1 EXAMPLE 14d - [3,3 - Dimethyl - 8β - [4,4 - dimethyl - 5ethoxy - 3ξ - (2 - tetrahydropyranyloxy) - transl-pentenyl/- 1,5 - dioxaspiro[5,4]dec - 7a - yl] propionaldehyde.

I.R. 1730 cm a 4 Ο 7 EXAMPLE 14e.

In a manner analogous to that described in Example 14a, there was prepared from the tetrahydropyranyl ether of Example 13e, 3 - [3,3 - dimethyl - 8β-’ (3ξ - cycloheptyl - 3ξ - (2 - tetrahydropyranyloxy)trans - 1 - propenyl) - 1,5 - dioxaspiro[5,4] dec - 7ayl] - propionaldehyde.

I.R. 1730 cm-1 EXAMPLE 14f. in a manner analogous to that described in Example 14a, there was prepared from the tetrahydropyranyl ether of Example 13f, 3 - { 3,3 - dimethyl - 8β[3ξ - (2 - tetrahydropyranyloxy) - trans - 1 - hexenyl] 1,5 - dioxaspiro[5,4]dec - 7a - yl} - propionaldehyde.

I.R. 1730 cm1 EXAMPLE 14g.

In a manner analogous to that described in Example 14a, there was prepared from the tetrahydropyranyl ether of Example 13g, the 3 - { 7β - [3ξ - (220 tetrahydropyranyloxy) - ' 4 - £ - (£ - chlorophenoxy) - phenoxy - trans - 1 - pentenyl] - 1,4dioxaspiro[4,4]non - 6a - yl } - propionaldehyde.

I.R. 1730 cm-1 EXAMPLE 14h.

In a manner analogous to that described in Example 14a, there was prepared from the tetrahydropyranyl ether of Example 13h,3—{7β-£3ξ -(2- tetrahydropyranyloxy)] 4 - £ - (£- chlorophenoxy) - phenoxy - 4 - methyltrans - 1 - pentenyl] - 1,4 - dioxaspiro[4,4] 30 6a - yl } - propionaldehyde. non- 47 414 0 7 I.R. 1730 cm EXAMPLE 14i.

In a manner analgous to that described in Example 14a, there was prepared from the tetrahydropyranyl ether of Example 13i, 3-{7β-[3ξ- (2- tetrahydropyranyloxy) - 4 - phenoxy - trans — 1 - butenyl] - 1,4 - dioxaspiro[4,4]non - 6a - yl} - propionaldehyde.

EXAMPLE 14j.

In a manner analogous to that described in Example 14a, there was prepared from the tetrahydropyranyl ether of Example 13j, 3 - {7β - [3ξ - (2 - tetrahydropyranyloxy) - 4 - (4 - fluorophenoxy) - trans - 1 - butenyl]1,4 - dioxaspiro[4,4] - non - δα - yl} - propionaldehyde.

I.R. 1730 cm-1 EXAMPLE 14k.

In a manner analogous to that described in Example 14a, there was prepared from the tetrahydropyranyl ether of Example 13k, 3 - { 7β - [3ξ - (2 - tetrahydropyranyloxy) -4-(3- chlorophenoxy) - trans - 1 - butenyl)1,4 - dioxaspiro[4,4]non - δα - yl} - propionaldehyde. _l I.R. 1730 cm EXAMPLE 141.

In s manner analogous to that described in Example 14a, there t-zas prepared from the tetrahydropyranyl other of Example 131, 3 - {7β - [3ξ -(2- tetrahydropyranyloxy) - 4 - (3 - trifluoromethylphenoxy) - trans - 1butenyl] - 1,4 - dioxaspiro[4,4]non - 6a - yl}propionaldehyde.

I.R. 1730 cm 40? EXAMPLE 14m.

In a manner analogous to that described in Example 14a, there was prepared from the tetrahydropyranyl ether of Example 13m, 3 - {7β - [3ξ -(2- tetrahydro5 pyranyloxy) - 5 - methyl - trans - 1 - hexenyl] - 1,4dioxaspiro[4,4]non - 6a - yl} - propionaldehyde.

I.R. 1730 cm-1 EXAMPLE 14n.

In a manner analogous to that described in Example 10 14a, there was prepared from the tetrahydropyranyl ether of Example 13n, 3 - { 7β - [3ξ -(2- tetrahydropyranyloxy) - 4,4 - dimethyl - trans - 1 - octenyl] - 1,4dioxaspiro[4,4] non - 7a - yl} - propionaldehyde.

I.R. 1730 cm 1 EXAMPLE 15a. - {3,3 - Dimethyl - 8β - [3ξ - (2 - tetrahydropyranyloxy) - trans - 1 - octenyl) - 1,5 - dioxaspiro[5,4]dec - 7a - yl'} - cis - 4 - heptenoic acid 0.3 g [10 moles] of 80% sodium hydride were heated 20 for 1 hour under argon to 60—65°C in 3 ml of absolute dimethyl sulfoxide and then 2.15 g (5 moles) of (3carboxypropyl)triphenylphosphonium bromide in 12 ml of DMSO were added. The solution whose colour had changed to red was stirred for 40 minutes at room temperature, and then 0.88 g of 3 -{ 3,3 - dimethyl - 8β - [3ξ — (2tetrahydropyranyloxy) - trans - 1 - octenyl] - 1, 5dioxaspiro[5,4]dec - 7a - yl} - propionaldehyde in 5 ml of DMSO was added dropwise. The solution was stirred for 16 hours at room temperature. It was diluted at 0°C with 50 ml of diethyl ether, acidified to pH 1—2 with 5% NaHSO^ solution, the organic phase was separated and the aqueous phase was extracted thrice with d a 4 © 7 each time 75 ml of diethyl ether. The combined ethereal extracts were washed with water, dried over MgSO. and 4 concentrated under reduced pressure.

The oil that had formed was chromatographed on silica gel and an analytically pure substance was obtained by elution with cyclohexane/ethyl acetate in a ratio of 8:2.

N.M.R. 8.5 ppm broad signal 1 H .3—5.7 ppm broad signal 4 H 4.7 ppm broad signal 1 H 3.5 ppm duplett 4 H EXAMPLE 15b.

In analogous manner, there were obtained from the aldehydes of the general formula XX described in Examples 14b—14n, the following acids: - { 3,3 - dimethyl - 8β - [3ξ -(2- tetrahydropyranyloxy) - trans. - 1 - decenyl] - 1,5 - dioxaspiro[5,4]dec - 7a - yl} - cis - 4 - heptenoic acid.

N.M.R. 5.3—5.7 ppm broad signal 4 H EXAMPLE 15c. -{ 3,3 - Dimethyl - 8β - [3ξ - cyclohexyl - 35(2 - tetrahydropyranyloxy) - trans - 1 - propenyl]1,5 - dioxaspiro[5,4]dec - 7a - yl} - cis - 4 - heptenoic acid.

N.M.R. 5.3—5.7 ppm broad signal 4 H EXAMPLE 15d. - {3,3 - Dimethyl - 8β - [4,4 - dimethyl - 5ethoxy - 3ξ - (2 - tetrahydropyranyloxy) - trans - 1pentenyi7 - 1,5 - dioxaspiro[5,4]dec - 7a - yl} - cis4 - heptenoic acid. 42.40? - 50 EXAMPLE 15e.

In a manner analogous to that described in Example 15a, there was obtained from the propionaldehye of Example 14e, the 7 - {3,3 - dimethyl - 8β - [3ξ- cycloheptyl - 3ξ - (2 - tetrahydropyranyloxy) - trans - 1 propenyl] - 1,5 - dioxaspiro[5,4] - dec - 7a - yl} cis - 4 - heptenoic acid.

N.M.R. 5.3—S.7 ppm broad signal 4 H EXAMPLE 15f.

In a manner analgous to that described in Example 15a, there was prepared from the propionaldehyde of Example 14f, the 7 - {3,3 - dimethyl - 8β - [3ξ - (2tetrahydropyranyloxy) - trans - 1 - hexenyl] - 1,5dioxaspiro[5,4]dec - 7a - yl} - cis - 4 - heptenoic acid.

N.M.R. 5.3 ppm broad signal 4 H.

EXAMPLE 15g.

In a manner analgous to that described in Example 15a, there was obtained from the propionaldehyde of Example 14g, 7 - {7β - [3ξ - {2 - tetrahydropyranylossy)4 - £ - (£- chlorophenoxy) - phenoxy - trans - 1pentenyl] - 1,4 - dioxaspiro[4,4] - non - 6a - yl} cis - 4 - heptenoic acid.

N.M.R. 5.3—5.7 ppm broad signal 4 H EXAMPLE 15h.

In a manner analogous to that described ih Example 15a, there was obtained from the propionaldehyde of Example 14h, 7 -{ 7β = [3ξ - (2 - tetrahydropyranyloxy)4 - methyl - 4 - £ - (£ - chlorophenoxy) - phenoxytrans - 1 - pentenyl] - 1,4 - dioxaspiro[4,4]non - 6ayl} - cis - 4 - heptenoic acid. 4 Ο 7 N.M.R. 5.3—5.7 ppm broad signal 4 H EXAMPLE 15i In a manner analogous to that described in Example 15a, there was prepared from the propionaldehyde of Example 14ί,7-(7β·[3ξ -(2- tetrahydropyranyloxy) - 4phenoxy - trans - 1 - butenyl] - 1,4 - dioxaspiro[4,4]non - 6a - yl} - cis - 4 - heptenoic acid.

N.M.R. 5.3—5.7 ppm broad signal 4 H EXAMPLE 15j.

IO In a manner analogous to that described in Example 15a, there was prepared from the propionaldehyde of Example 14j, 7-{7β-[3ξ-(2- tetrahydropyranyloxy)4-(4- fluorophenoxy) - trans - 1 - butenyl] - 1,4dioxaspiro[4,4]non - 6a - yl} - cis - 4 - heptenoic acid.

N.M.R. 5.3—5 7 ppm broad signal 4 H EXAMPLE 15k.

In a manner analogous to that described in Example 15a, there was prepared from the propionaldehyde of Example 14k, 7-{7β- [3ξ -(2- tetrahydropyranyloxy)20 4-(3- chlorophenoxy) - trans - 1 - butenyl] — 1,4— dioxaspiro[4,4]non - 6a - yl} - cis - 4 - heptenoic acid.

N.M.R. 5.3—5.7 ppm broad signal 4 H EXAMPLE 151.

In a manner analogous to that described in Example 15a, there was prepared from the propionaldehyde of Example 141, 7 - { 7β - [3ξ -(2- tetrahydropyranyloxy)4-(3- trifluoromethylphenoxy) - trans - 1 - butenyl]1,4 - dioxaspiro[4,4] non - 6a - yl} - cis - 430 heptenoic acid. 3.407 N.M.R. 5.3—5.7 ppm broad signal 4 H EXAMPLE 15m.

In a manner analogous to that described in Example 15a, there was prepared from the propionaldehyde of Example 14m, 7 ~ { 7β - [3ξ -(2- tetrahydropyranyloxy)5 - methyl - trans - 1 - hexenyl] - 1,4 - dioxaspiro[4,4]non - 6a - yl} - cis - 4 - heptenoic acid.

N. M.R. 5.3—5.7 ppm broad signal 4 H EXAMPLE 15n.

In a manner analogous to that described in Example 15a, there was prepared from the propionaldehyde of Example 14n, 7 - {7β - [3ξ -(2- tetrahydropyranyloxy)4.4 - dimethyl - trans - 1 - octenyl] - 1,4 - dioxaspiro[4,4]non - 6a - yl } - cis - 4 - heptenoic acid.

N.M.R. 5.3—5.7 ppm broad signal 4 H EXAMPLE 16a. — [2β - (3ξ - Hydroxy - trans - 1 - octenyl) - 5 - oxola - cyclopentyl] - cis - 4 - heptenoic acid O. 41 g [1 mmole] of 7 - {3„3 - dimethyl - 8β20 [3ξ - (2 - tetrahydropyranyloxy) - trans - 1 - octenyl]1.5 - dioxaspiro[5,4]dec - 7a - yl} - cis - 4 - heptenoic acid was dissolved in 25 ml of ethyl alcohol and stirred with 5 ml of 2% aqueous oxalic acid solution for 20 hours at room temperature under nitrogen. The solvent was partially removed by distillation under reduced pressure, the residue was combined with 20 ml of a satura ted NaCl solution and extracted twice with 100 ml of diethyl ether. The combined ethereal extracts were washed thrice with each time 20 ml of H20, dried and concentrated. 337 mg of a light oil were obtained.- 7 - [3,3dimethyl - 8β - 3ξ - hydroxy - trans - 1 - octenyl)] 1,5 - dioxaspiro[5,4] dec - 7a - yl) - cis - 4 -heptenoic acid.

These 337 mg from the first stage were stirred in 30 ml of acetone with 20 mg of £-toluenesulfonic acid monohydrate for 5 hours at 50°C under nitrogen and allowed to stand overnight at room temperature. The mixture was then concentrated, the residue was dissolved in diethyl ether, washed with water and concentrated. The residue was chromatographed on silica gel and the analytically pure substances were obtained by elution with a solvent mixture of 80 parts of cyclohexane, 20 parts of ethyl acetate and 1 part of glacial acetic acid. 2 Isomers were isolated which were found to distinguish in their Rf-values on silica gel (of Messrs. Merck) in the solvent mixture cyclohexane/ethylacetate/glacial acetic acid 80/ 20/1 as follows: isomer B 0.41 isomer A 0.36.

After HD exchange, the N.M.R. spectrum of both isomers was practically identical.

Before HD exchange: .2- ^6.0 ppm broad signal 6 H 4.05 ppm broad signal 1 H After HD exchange: .2— 5.4 ppm broad signal 2 H .5—5.7 ppm broad signal 2 H 4.05 ppm broad signal 1 H.

In analogous manner, there were prepared from com07 pounds of the general formula XXI, as those described in Example 15b—15n, the following carboxylic acids of the general formula I, in which and together repre sent oxygen: EXAMPLE 16b. - [2β - (3ξ - hydroxy - trans - 1 - decenyl) - 5 oxo - la - cyclopentyl] - cis - 4 - heptenoic acid.

N.M.R. 5.2—6.0 ppm bread signal 6 H EXAMPLE 16c. - [2β - (3ξ - Hydroxy - 3ξ - cyclohexyl - trans1 - propenyl) - 5 - oxo - la - cyclopentyl] - cis - 4heptenoic acid.

N.M.R. 5.2—6.5 ppm broad signal 6 H EXAMPLE 16d. - [2β - (3ξ - Hydroxy - 4,4 - dimethyl - 5ethoxy - trans - 1 - pentenyl) - 5 - oxo - la - cyclopentyl] - cis - 4 - heptenoic acid.

N.M.R. 5.2—6.0 ppm broad signal 6 H EXAMPLE 16e.

In a manner analogous to that described in Example 16a, there was prepared from the heptenoic acid of Example 15e, 7 - [2β - (3ξ - hydroxy - 3ξ - cyeloheptyltrans — 1 - propenyl) - 5 - oxo - la - cyclopentyl]cis - 4 - heptenoic acid.

N.M.R. 5.2—6.2 ppm broad signal 6 H EXAMPLE 16f.

In a manner analogous to that described in Example 16a, there was prepared from the heptenoic acid of Example 15e, 7 - [2β - (3ξ - hydroxy - trans - 1hexenyl) - 5 - oxo - la - cyclopentyl] - cis - 4414 0 7 heptenoic acid.

N.M.R. 5.2—6.0 ppm broad signal.

EXAMPLE 16g.

In a manner analogous to that described in Example 16a, there was prepared from the heptenoic acid of Example 15g, 7 - [2β - (3ξ - hydroxy - 4 - £ - (£chlorophenoxy) - phenoxy - trans - 1 - pentenyl] - 5oxo - Ice - cyclopentyl] - cis - 4 - heptenoic acid.

N.M.R. 5.2—6.1 ppm broad signal 6 H EXAMPLE ISh.

In a manner analogous to that described in Example 16a, there was prepared from the heptenoic acid of Example 15h, 7 - [2β - (3F, - hydroxy - 4 - methyl - 4£ - (p - chlorophenoxy) - phenoxy - trans - 1 - pentenyl5 - oxo - la - cyclopentyl] - cis - 4 - heptenoic acid.

N.M.R. 5.2—6.0 ppm broad signal.

EXAMPLE 16i.

In a manner analogous to that described in Example 16a, there was prepared from the heptenoic acid of Example 15i, 7 - [2β - (3ξ - hydroxy - 4 - phenoxyfcrans - 1 - butenyl) - 5 - oxo - la - cyclopentyl]cis - 4 - heptenoic acid.

N.M.R. 5.2—6.1 ppm broad signal 6 H EXAMPLE 16j.

In a manner analogous to that described in Example 16a, there was prepared from the heptenoic acid of Example 15j, 7 - [2β - (3ξ - hydroxy - 4 - (4 - fluorophenoxy) - trans - 1 - butenyl] - 5 - oxo - la - cyclopentyl] - cis - 4 - heptenoic acid.

N.M.R. 5.2—6.5 ppm broad signal 6 H EXAMPLE 16k.

In a manner analogous to that described in Example 16a, there was prepared from the heptenoic acid of Example 15k, 7 - [2β - [3ξ - hydroxy - 4 - (3 - chloro5 phenoxy) - trans - 1 - butenyl] - 5 - oxo - la - cyclopentyl] - cis - 4 - heptenoic acid.

N.M.R. 5.2—6.0 ppm broad signal 6 H EXAMPLE 161.

In a manner analogous to that described in Example 10 16a, -there was prepared from the heptenoic acid of Example 151, 7 - [2β - [3ξ - hydroxy - 4 - (3 - trifluoro · methylphenoxy) - trans - 1 - butenyl] - 5 - oxo - lacyclopentyl] - cis - 4 - heptenoic acid.

-----N.M.R. ,5.2—6.3 ppm . ' / - - \ EXAMPLE 16m. <·.

K. A In a manner analogous to that described in Example 16a, there was prepared from the heptenoiG'acid of Example 15m, 7 - [2β - (3ξ - hydroxy - 5 - methyl - trans - 1hexenyl) - 5/- oxo - la - cyclopentyl] - cis --’Φ- 1 heptenoic acid.

N.M.R. 5.2—6.1 ppm broad .signal EXAMPLE Ιδη.

In a manner analogous to that described in Example 16a, there was prepared from the heptenoic acid of Example 15n, 7 - [2β - (3ξ - hydroxy - 4,4 - dimethyltrans - 1 - octenyl) - 5 - oxo - la - cyclopentyl] cis - 4 - heptenoic acid.

N.M.R. 5.2—6.5 ppm broad signal 6 H A, ??« .fe: '< 3 414 0 7 EXAMPLE 17a. - [2β - (3ξ - Hydroxy - trans - 1 - octenyl) - 5ξhydroxy - la — cyclopentyl] - cis - 4 - heptenoic acid. 150 mg of 7 - [2β - (3ζ - hydroxy - trans - 1octenyl) - 5 - oxo - la - cyclopentyl] - cis - 4heptenoic acid were dissolved in 20 ml of methanol and three times each time 150 mg of NaBH^ were added within the course 1 1/2 hours. The reaction solution was adjusted to pH 7 by means of glacial acetic acid, the solvent was removed by distillation under reduced pressure, the residue was acidified with 2N—HCl to pH 1 and extracted thrice with 150 ml of ether. After washing, the organic phase was concentrated.

I.R. 3500 cm 1 1720—1700 cm1 In analogous manner, there were prepared from the carboxylic acids of the general formula I, in which R^ and R2 together represent oxygen and which are described in Examples 16b—16d, carboxylic acids of the general formula I, in which and R2 each represent hydrogen or the hydroxyl group: EXAMPLE 17b - [2β - (35. - Hydroxy - trans - 1 - decenyl)55. - hydroxy - la - cyclopentyl] - cis - 4 - heptenoic acid.

I.R. 3500 cm1 1720—1700 cm”1 EXAMPLE 17c. - [2β - (3ξ - Hydroxy - 3ξ - cyclohexyl - trans1 - propenyl) - 5ξ - hydroxy - la - cyclopentyl) - cis4 - heptenoic acid.

I.R. 3500 cm1 1720—1700 cm-1 .407 EXAMPLE 17d. - [2β - 3ξ - Hydroxy — 4,4 - dimethyl - 5 ethoxy - trans - 1 - pentenyl] - 5ξ -hydroxy - lacyclopentyl] - cis - 4 heptenoic acid.

I.R. 3500 cm 1 1720—1700 cm1 EXAMPLE 17e - [2β - (3ξ - Hydroxy - 3ξ— cycloheptyl - trans 1 - propenyl) - 5ξ - hydroxy - la - cyclopentyl] - cis 4 - heptenoic acid.

I.R. 3500 cm 1 1720—1700 cm-1 EXAMPLE 17f. - [2β - (3ξ - Hydroxy - trans - 1 - hexenyl)15 5ξ - hydroxy - la - cyclopentyl] - cis - 4 - heptenoic acid.

I.R. 3500 cm1 1720—1700 cm EXAMPLE 17g. 7 - {2β - [3ξ - Hydroxy - 4 - £ - (p - chloro phenoxy) - phenoxy - trans - 1 - pentenyl] - 5ξ hydroxy - la - cyclopentyl } - cis - 4 - heptenoic acid.

I.R. 3500 cm-1 1720—1700 cm1 EXAMPLE 17h. - { 2β - [3ξ - Hydroxy - 4 - methyl - 4 - £ - (jo chlorophenoxy) - phenoxy - trails - 1 - pentenyl] - 5ξhydroxy - la - cyclopentyl} - cis - 4 - heptenoic acid.

I.R. 3500 cm 1720—1700 cm1 414 0 7 - 59 EXAMPLE 17i. - [2β - (3ξ - Hydroxy - 4 - phenoxy - trans - 1hutenyl) - 5ζ - hydroxy - la - cyclopentyl] - cis 4 - heptenoic acid.

I.R. 3500 cm 1 1720—1700 cm EXAMPLE 17 j. - { 2ξ - [3β - Hydroxy - 4 - (4 - fluorophenoxy)trans - 1 - butenyl] - 5ξ - hydroxy - la - cyclopentyl}cis - 4 - heptenoic acid.

I.R. 3500 cm 1 1720—1700 cm”1 EXAMPLE 17k. - {2β - [3ξ - Hydroxy - 4 — (3 - chlorophenoxy)trans - 1 - butenyl] - 5ξ - hydroxy - la - cyclopentyl}cis - 4 - heptenoic acid.

I.R. 3500 cm 1720—1700 cm_1 EXAMPLE 171. - { 2β - [3ξ - Hydroxy - 4 - (3 - trifluoromethylphenoxy) - trans - 1 - butenyl] - 5ζ - hydroxy - lacyclopentyl} - cis - 4 - heptenoic acid.

I.R. 3500 cm 1 1720—1700 cm1 EXAMPLE 17m. - {2β - [35, - Hydroxy - 5 - methyl - trans - 1hexenyl] - 5ζ - hydroxy - la - cyclopentyl} - cis - 4heptenoic acid.

I.R. 3500 cm 1 1720—1700 cm”1 - 60 EXAMPLE 17n. - [2β - [3ξ - Hydroxy - 4,4 - dimethyl - trans1 - octenyl] - 5ξ - hydroxy - la - cyclopentyl] - cis 4 - heptenoic acid.

I.R. 3500 cm-1 1720—1700 cm_1 EXAMPLE 18.

The isomer A and the isomer B of 7 - [2β - (3ξhydroxy - trans - 1 - octenyl) - 5 - oxo - la - cyclopentyl] - cis - 4 - heptenoic acid (Example 16a) were mixed in a weight proportion of 1:1, dissolved in ethyl alcohol, diluted with distilled water and atomized at a total volume of 0.02 ml per minute in an uultrasonic atomizer.

For testing the broncho-spasmolytic activity, the measurement of the breath volume according to Konzett and Rossler (Arch. exp. Path. Pharmakol. 195, 71 (1940)) was used. As test animals, male white Guinea pigs having a weight of 400—500 g were used which had been anesthetized with 10 mg/kg i.p. of Evipan and 200 mg/kg i.p. of urethane.

As asthmogenic substance, histamine-dihydrochloride in a dose of 1—5 pg/kg was administered. The experimental data were subjected to a regression analysis and the equation of the regression line Y=A+B:1 g (X) was calculated. Therewith, also the average inhibition dose (ED,_0) as the dose which inhibits the asthmogenic action by 50% of its initial value, could be determined.

Results - [2β - (3ξ - Hydroxy - trans - 1 - octenyl) - 5oxo - la - cyclopentyl] - cis - 4 - heptenoic acid.

Average inhibition dose i.v. (u-g/kg) Aerosol (^g/animal) Isomer A 0.08 0.01 Isomer B 0.1 0.1 Mixture A + B (1:1) 0.1 0.002

Claims (56)

1. CLAIMS:- HO wherein 5 R^ and R 2 together represent an oxygen atom or one represents a hydrogen and the other represents a hydroxy group, R 3 represents a straight or branched chain alltyl group of 1 to 10 carbon atoms, which itself may be sub10 stituted by a straight or branched chain alkojy group of 1 to 5 alkyl C-atoms, or an aryloxy group, by a furyloxy group or by a benzyloxy group, which themselves may be substituted by one or more substituents selected frcm halogen atoms, trifluoromethyl groups, alkyl groups of 15 1 to 3 carbon atoms, and phenoxy groups which may carry one or more halogen atoms, or represents a saturated cycloalkyl group of 3 to 7 ring members, an aryl or a furyl group, which radicals may be substituted by one or more alkyl groups of 1 to 3 carbon atoms, with the proviso 20 that R 3 may not represent an unsubstituted alkyl group branched at the α-carbon atom and having up to 7 carbon atoms in the chain from the α-carbon atom to the ωcarbon atom inclusive.

2. A compound as claimed in claim 1 and which is 25 described in any one of the Examples 16a to I7n herein. 414 0 7 - 63

3. A salt of a compound as claimed in claim 1 or claim 2.

4. A physiologically tolerable salt of a compound as claimed in claim 1 or claim 2.

5. 5. An ester of a compound as claimed in claim 1 or claim 2 with an aliphatic, cycloaliphatic or araliphatic alcohol having up to 8 carbon atoms.

6. A process for preparing a compound as claimed in claim 1, except that is not subject to the proviso 10 given therein, which comprises either first splitting off the 2-tetrahydropyranyl ether protective group from a compound of the formula XXI /\ CH. CH. in which represents a —CH^— or a —CCCH^)^—' group 15 or a direct bond and R 3 is as defined in claim 1, except that it is not subject to the proviso given therein, by mild acid hydrolysis, whereby an alcohol of the formula ΧΧΠ XXII Ο Ο ,CH 2 -CH 2 -CH=CH-CH 2 -CH 2 -cooh HO' R. is obtained, in which Y 2 and R 3 are as defined in formula XXI, and then removing the acetal grouping from the alcohol of the formula XXII by mild acid-catalysed hydrolysis 5 or by trans-acetalization by reacting the compound of formula XXII with a large excess of a ketone, or eliminating both protective groups in one step by mild acid hydrolysis, and if desired reducing with a complex metal hydride the resulting compound of formula I in which R^ 10 and R 2 together represent an oxygen atom to the corresponding compound of the formula I in which either R^ or R 2 represents a hydrogen atom and the other represents a hydroxyl group.

7. A process as claimed in claim 6, wherein a re15 suiting compound of formula I is converted into a salt thereof.

8. A process as claimed in claim 7, wherein the salt is a physiologically tolerable salt.

9. A process as claimed in claim 6, wherein a 20 resulting compound of formula I is esterified with an aliphatic, cycloaliphatic or araliphatic alcohol having up to 8 carbon atoms.

10. A process as claimed in claim 6, conducted substantially as described in any one of Examples 16a to 17n herein.

11. A process as claimed in claim 6, wherein 5 the compound of formula XXI is obtained by reacting a compound of formula XX /X in which Y 2 an< ^ R 3 have the meanings given in claim 6 with the ylide derived from (3-carboxypropyl)triphenyl10 phosphonium bromide in a solution of sodium hydride in dimethyl sulphoxide.

12. A process as claimed in claim 11, wherein the compound of formula XX is produced by heating a compound of formula XIX /X Η„ CH, in which Y^ represents a —cl·^— group or a —CiCH^)^ group or a direct bond and ΐ^ and R 3 have the meanings given in claim 6, with a -alkyl iodide in a polar 5 aprotic solvent in the presence of an acid acceptor.

13. A process as claimed in claim 12, wherein the compound of formula XIX is obtained by reacting an alcohol of the formula XVIII in the form of the epimer mixture or after separation of the epimers. X 2 CH„ CH„ in which Y^ and Y 2 and R^ have the meanings given for formula XIX with 2,3-dihydropyran in the presence of an acid catalyst.

14. A process as claimed in claim 13, wherein the 5 epimeric mixture of alcohols of formula XVIII is obtained by reducing a ketone of the formula XVII /X CH_ CH. in which R^, Y^ and Y 2 have the meanings given for formula XIX, with a complex metal hydride. 10 15. A process as claimed in claim 14, wherein the compound of formula XVII is obtained by reacting a compound of formula XV in which Y and Y 2 have the meanings given for formula

15. XIX, with a phosphonate of the formula XVI CH.O Ο Ο 3 \ΐ 11 Ε-CH_-C—R„ / 2 3 CH 3 0 in which has the meaning given in claim 6.

16. A process as claimed in claim 15,wherein the compound of formula XV is obtained by reducing a compound 5 of the formula XIV 10 a complex metal hydride in an aprotio solvent.

17. A process as claimed in claim 16, wherein the compound of formula XIV is obtained by reacting a compound of formula XII 15 in which R^ has the meaning given for formula XIV, in the presence of an acid catalyst with a glycol of the formula XIII HO—CH 2 —Y—CH 2 —OH in which Y 2 has the meaning given in formula XIX. 5

18. A process as claimed in claim 17, in which the compound of formula XII is obtained by reacting a compound of formula X in which R, has the meaning given for formula XIV, selec4 10 tively with a dithiol of the formula XI HS—CH 2 —Y —CH 2 —SH in which Y is as defined for formula XIX, in the presence of an acid catalyst.

19. A process as claimed in claim 18, wherein the 15 compound of formula X is obtained by oxidizing an alcohol of formula IX in which has the meaning given for formula XIV.

42.407 70 20. A process as claimed in claim 19, wherein the compound of formula IX is obtained by catalytically hydrogenating an ester of formula VIII 5 in which R^ has the meaning given for formula XIV.

21. A process as claimed in claim 20, wherein the compound of formula VIII is obtained by converting a compound of formula VII 10 with an anhydrous alcoholic solution of an inorganic acid to an imino-ether salt of the formula Vila 0 in which HA represents an inorganic acid, and R^ is as defined for formula XIV, and subsequently hydrolysing 15 the compound of formula Vila. 414 0 7

22. A process as claimed in claim 21, in which the compound of formula VII is obtained by reacting a compound of formula VI 5 under alkaline conditions with cyanide ions.

23. A process as claimed in claim 22, wherein the compound of formula VI is obtained by subjecting a compound of formula V o y-v OHC-CH 2 -CH 2 -C-CH 2 -CH 2 -CH 2 -CH 2 -O-CH 2 10 to an aldol condensation under acid or alkaline conditions

24. A process as claimed in claim 23, wherein the compound of formula V is obtained by removing the acetal or dithioacetal group from a compound of formula IV ch-ch 2 -ch 2 -c-ch 2 -ch 2 -ch 2 -ch 2 -o-ch 2 · CH„ in which X represents an oxygen or sulphur atom and. Y represents a —c:h 2 or —C(CH 3 ) 2 — group or a direct bond.

25. A process as claimed in claim 24, wherein the compound of formula IV is obtained by reacting an acetal or dithioacetal of the formula II 72 CH_-X 2 \ CH-CH--CH--CN in which X and Y are as defined for formula IV, with a Grignard compound of the formula III Ha1-Mg-CH 2 -ch 2 -ch 2 -ch 2 -o-ch 2 5 in which Hal represents a chlorine or bromine atom, or with another organo-metallic compound which contains the 4-benzyloxybutyl radical.

26. A process as claimed in any one of claims 11 to 25, carried out substantially as described in any one of 10 Examples 1 to 17n herein.

27. A compound as claimed in claim 1, except that is not subject to the proviso given therein, or a salt or ester thereof whenever produced by a process as claimed in any of claims 6 to 26. 15

28. A pharmaceutical preparation which comprises a compound as claimed in claim 1, claim 2, claim 4, claim 5 or claim 27 or a mixture of epimers of such a compound that is epimeric at the 15—OH group as active ingredient, in admixture or conjunction with a pharmaceutically suit20 able carrier.

29. claim 28, A pharmaceutical preparation as claimed in in a form suitable for oral administration.

30. A pharmaceutical preparation as claimed in claim 28, in a form suitable for parenteral administration. - 73 41407

31. claim 30, A pharmaceutical preparation as claimed in in a form suitable for topical administration.

32. A pharmaceutical preparation as claimed in claim 31, in the form of a cream, emulsion or suppository.

33. claim 31, A pharmaceutical preparation as claimed in in the form of an aerosol or spray.

34. A pharmaceutical preparation as claimed in any one of claims 2Θ to 32, wherein the active ingredient is a mixture of the two 15—OH epimers of 7 - [2β - (3ξhydroxy - trans - 1 - octenyl) - 5 - oxo - la - cyclopentyl) - cis 4 - heptenoic acid each being in the form of the free acid, physiologically tolerable salt or ester with an aliphatic cycloaliphatic or araliphatic alcohol having up to 8 carbon atoms.

35. A pharmaceutical preparation as claimed in claim 34, wherein the two epimers are in a ratio of from 0.75:1 to 1.25:1 by weight.

36. A pharmaceutical preparation as claimed in claim 35, wherein the two epimers are in a ratio of 1:1 by weight.

37. A pharmaceutical preparation as claimed in claim 28, in unit dosage form.

38. A pharmaceutical preparation as claimed in claim 37, wherein the unit dose comprises from 0.5 to 1000 μ-g of the active ingredient.

39. A pharmacaxtical preparation as claimed in claim 38, wherein the unit dose comprises from 1 to 500 p,g of the active ingredient. 74

40. A pharmaceutical preparation as claimed in claim 30, in a form suitable for administration by injec tion and in unit dosage form.

41. A pharmaceutical preparation as claimed in 5 claim 40, which comprises from 1 to 1000 ^g of the active ingredient per unit dose.

42. A pharmaceutical preparation as claimed in claim 41, which comprises from 1 to 100 ^g of the active ingredient per unit dose. 10

43. A pharmaceutical preparation as claimed in claim 33 or any one of claims 34 to 36 when appended to claim 33, wherein the spray output is regulated.

44. A pharmaceutical preparation as claimed in claim 43, which comprises from 0.1 to 1000 μg of the 15 active ingredient per single spray output.

45. A pharmaceutical preparation as claimed in claim 30, which comprises from 1 to 200 μg of the active ingredient per single spray output.

46. A method of treating bronchiospasms, which 20 comprises administering to a commercially reared animal a compound as claimed in claim 1, claim 2, claim 4, claim 5 or claim 26 or a mixture of the epimers of such a compound that is epimeric at the 15—OH group.

47. A method as claimed in claim 46, wherein the 25 mixture is a mixture of the two 15—OH epimers of 7 - [2(3 - hydrcxy - 3 — pentyl - trans - 1 - propenyl) - 5oxo - cyclopentyl] - cis - 4 - heptenoic acid.

48. A method as claimed in claim 47, wherein the two epimers are in a weight proportion of from 0.75:1 to 30 1.25:1. 414 0 7

49. A method as claimed in claim 48, wherein the weight proportion is 1:1.

50. A method as claimed in any one of claims 46 to 49, wherein the compound or mixture is in the form 5 of an aerosol spray.

51. A method as claimed in claim 50, which comprises administering from 0.1 to 10 mg of the compound or mixture per day.

52. A method of lowering the blood pressure and/or 10 treating gastro-intestinal disorders, which comprises administering to a commercially reared animal a compound as claimed in claim 1, claim 2, claim 4 or claim 5 or a mixture of epimers of such a compound that is epimeric at the 15—OH group. 15

53. A method as claimed in claim 52, which comprises administering from 1 to 10 mg of the compound or mixture per day.

54. A method of controlling fertility, which comprises administering to a subject a compound as claimed 20. In claim 1, claim 2, claim 4, claim 5 or a mixture of the epimers of such a compound that is epimeric at the 15—OH group.

55. A compound of the formula XXI 42 407 /X ? H 2 ? H 2 in which R^ is as defined in claim 6 and represents a —CH 2 — or —C(CH 3 ) group or a direct bond.

56. Compounds of the formula XXII γ / 2 \ CH. CH„ in which R 3 is as defined in claim 6 and Y 2 is as defined in claim 55.