IE45124B1

IE45124B1 - Cyclopentanol lactones

Info

Publication number: IE45124B1
Application number: IE601/77A
Authority: IE
Original assignee: Roussel Uclaf
Priority date: 1976-03-19
Filing date: 1977-03-21
Publication date: 1982-06-30
Also published as: FR2344285A1; BE852624A; SE436877B; DK119377A; ZA771654B; LU76976A1; DE2711950A1; NL7703056A; JPS52113956A; IL51690A0; CH620688A5; AU506760B2; CA1094569A; AT357275B; ES456999A1; SE7702908L; IL51690A; SU745366A3; HU178332B; AU2346677A

Abstract

The compounds of formula: are prepared from corresponding carboxylic acids of formula: by a reaction capable of converting the carboxyl group to a functional derivative. The meaning of the symbols is given in Claim 1. Of the compounds obtained, those which have a 15-tetrahydropyranyloxy group can be hydrolysed, those which have a hydroxyl group can be esterified, and those which have a secondary alcohol group in position 15 can be oxidised to the corresponding ketone or dehydrated in position 15, 16; finally, the double bond in position 13, 14 and the triple bond of an alkynyl group in position 15 can be hydrogenated. The compounds display a hypotensive activity; they can be employed in the treatment of hypertension (high blood pressure) and of circulatory disorders.

Description

This invention relates to new cyclopentanol lactone derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

According to one feature of the present invention there are provided compounds of general formula I, wherei?; A and B each represents a hydrogen atom or together represent a cerbon-=carbon bond; p is 0 or 2; and R represents a hydrogen atom or an aliphatic hydrocarbyl radical containing from 1 to 4 carbon atoms; represents a radical of formula -OR* [in which R’ - represents a hydrogen atom, a tetrahydropyranyl radical, an alkyl radical containing from 1 to 3 carbon atoms or a radical of formula -COR (in which R represents an alkyi radical containing from 1 to 3 carbon atoms optionally substituted by a carboxylic acid group or represents a - 2 phenyl radical optionally substituted by a carboxylic acid group, a hydroxyl radical or a protected hydroxyl radical j]; and Rg represents a radical of formula (in which m is 3, 4, 5 or 6; or R and together form an oxo group, Rg being as defined above; or R^ and Rg together form a radical of formula ^\(CHz)n-CH3 (in which n is 2, 3, 4 or 5), R being as defined above.

As used herein a wavy line ' indicates that the configuration of a substituent may be either «- or p-; however, in formula I when p is 0, the bond between the pentane ring and the oxygen atom is an a-bond.

A broken line attached to a cyclopentane ring indicates that the configuration of the substituent so attached is a. A wedge attached to a cyclopentane ring indicates that the configuration of the substituent is p.

The compounds of general formula I possess interesting pharmacological properties and in particular, in general, a hypotensive activity.

As will be appreciated, the compounds of general formula I may exist in a number of isomeric forms and it will be understood that all such forms, as well as mixtures thereof e.g. racemates, constitute features of the present invention.

In the compounds of general formula I R may, for example, represent a hydrogen atom or a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, vinyl, propenyl, butenyl, ethynyl or a propargyl radical.

R' or, when R8 represents a radical of formula -COR, R’8 may for example represent a methyl, ethyl, propyl or isopropyl radical. When R represents a phenyl radical substituted by a protected hydroxyl radical, the protecting group is one which may be removed by hydrolysis to regenerate the free hydroxyl radical, for example, an acyl radical containing from 2 to 4 carbon atoms, e.g. an acetyl, propionyl, n-butyryl or an isobutyryl radical.

Other protected hydroxyl radicals include, for example a tetrahydropyranyloxy and a tert.-butyl-dimethyl-silyloxy radical.

Preferred compounds according to the invention are those wherein A and B together represent a carbon-carbon bond; S represents a hydrogen atom or an unsaturated aliphatic hydrocarbyl radical containing 2 or 3 carbon atoms; and either S. represents a radical of formula -OR8 [in which R’ represents a hydrogen atom, a tetrahydropyranyl radical or a radical of formula -COR88 (in which R represents a phenyl radical substituted by a carboxylic acid group)] and Rg represents a radical of formula -(CHg^-CH^ (in which m is 3, 4 or 5) or R^ and Rg together represents a radical of formula >i>\( CHg )n-CH^ - 4 5 (in which n is 2, 3 or 4), especially those compounds wherein p is 0; R^ represents a radical of formula OR’ (in which R’ represents a hydrogen atom); and Rg represents a radical of formula -(CHg^-CHg (in which m is 4).

Particularly preferred compounds according to the invention are the following: (IRS,2SR,5RS,3’SR) (l’E)-2-hydroxy-5-(3’-α-hydroxyoct-l’-enyl)-cyclopentane-carboxylic acid lactone, (IRS,2SR,5RS,3'SR) (IsE)-2-hydroxy-5-(3’-hydroxydec-l*~enyl)-cyclopentane-carboxylic acid lactone and (IRS,2SR,5RS,3'SR) (1'E)-2-hydroxy-5-[3'-(2hydroxybenzoyloxy)-oct-l’-enyl]-cyclopentane-carboxylic acid lactone.

The compounds of general formula I may be prepared, for example, according to the following processes: A. Reaction of a compound of formula II, (^herein A, B, p, R, R^ and Rg are as hereinbefore defined) and an acid activating agent whereby the desired compound of formula I Is obtained.

The acid activating agent is preferably a mixed anhydride-forming agent, suitable agents including, for example, alkyl chloroformates' e.g. isobutyl chloroformate and, in particular, tosyl chloride. Other acid activating agents which may alternatively be used, if desired, include dialkylcarbodiimides and dicycloalkylcarbodiimides e.g. dicyclohexylcarbodiimide and acid chloride-forming agents such as, for example, thionyl chloride.

The reaction is preferably effected in the presence of a base such as, for example, an alkali metal carbonate, a trialkylamine e.g. triethylamine, methyImorpholine, pyridine or diasabicyclooctane.

B. For the preparation of compounds of general formula I wherein R^ represents a radical of formula -OR’ (in which R’ represents a hydrogen atom): Hydrolysis of a compound of formula I as hereinbefore defined [wherein R, represents a radical of formula -OR* (in which R’ represents a tetrahydropyranyl radical)] whereby the desired compound of formula I is obtained.

Hydrolysis is preferably effected by means of an β θ oa acid such as, for example, aqueous hydrochloric, sulfuric, trifluoroacetic or especially acetic acid.

C. For the preparation of compounds of general formula I wherein Rj represents a radical of formula -OR’ [in which R’ represents a radical of formula -COR (in which R is as hereinbefore defined)]; Reaction of a compound of formula I as hereinbefore defined [wherein Rj represents a radical of formula -OR’ (in which R’ represents a hydrogen atom)] with an acid of formula R'OOzH (wherein R is as hereinbefore defined) or an acid chloride, anhydride or mixed anhydride thereof.

The reaction is preferably effected using the anhydride of formula (R(CQ'/?O. When the reaction is effected using the acid chloride of formula RCOC1, it is preferably effected in the presence of a hydrochloric acid binding agent such as, for example, an alkaline carbonate or bicarbonate or a tertiary organic base e.g. triethylamine, pyridine or a picoline.

D« For the preparation of compounds of general formula I wherein Rj represents a radical of formula -OR’ [ln which R* represents a radical of formula -COR (in which R represents an alkyl radical containing from 1 to 3 carbon atoms substituted by a carboxylic acid group)]; Reaction of a compound of formula I as hereinbefore defined [wherein Rj represents a radical of formula -OR* (in which R*. represents a hydrogen atom)] with an GO anhydride of formula: (in which R ^G0Z represents an alkylene radical containing from 1 to 3 carbon atoms).

The reaction is preferably effected in the presence of a tertiary organic base such as, for example, triethyl· amine, pyridine, dimethylaminopyridine, a picoline or mixtures thereof.

E. For' the preparation of compounds of general formula I wherein and Rg together form a radical of formula (CHg^-GHg (in which n is as hereinbefore defined)s Removal of HOR1 from a compound of formula 1 as hereln- before defined [wherein R^ represents a radical of formula -0Rs (ia which R' represents a hydrogen atom or a tetrahydropyranyl radical)]. Removal may, for example, be effected by means of a strong aqueous acid such as, for example, concentrated sulphuric, phosphoric or polyphosphoric acid. The use of jo-toluenes.ulphonic acid is, however, preferred. - 8 4 31 ;> j F. For the preparation of compounds of general formula I wherein R and Rj together form an oxo group: Oxidation of a compound of formula I as hereinbefore defined [wherein R represents a hydrogen atom and Rj represents a radical of formula -OR’ (in which R’ represents a hydrogen atom)] whereby the desired compound of formula I is obtained.

Oxidation is preferably effected by means of dichlorodicyanoquinone but silver silicate may alternatively be used if desired, 0. For the preparation of compounds of general formula I wherein A and B each represents a hydrogen atom, R represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms and Rj represents a radical of formula -OR* (in which R’ is as hereinbefore defined): Catalytic hydrogenation of a compound of formula I as hereinbefore defined wherein A and B together represent a carbon-carbon bond and Rj represents a radical of formula -OR’ (in which R’ is as hereinbefore defined).

Hydrogenation is preferably effected in the presence of palladium on charcoal as catalyst but platinum or a platinum salt may alternatively be used as the catalyst if desired. Other catalyst supports such as, for example, barium sulphate may also alternatively be used.

H. For the preparation of compounds of general formula I wherein R^ represents a radical of formula -OR’ [in which Rf represents a radical of formula -COR (in which R represents a phenyl radical substituted by a hydroxyl or protected hydroxyl radical)]: Reaction of a compound of formula I as hereinbefore defined [wherein R^ represents a radical of formula -OR* (in which Rs represents a hydrogen atom)] with a reactive derivative of an acid of formula III, (III) (wherein Y represents a protected hydroxyl radical) and, if required, subsequent deprotection of the protected hydroxyl radical.

The reaction is preferably effected using the acid bromide or more preferably the acid chloride of the acid of formula. Ill, in which case it is desirable to effect the reaction in the presence of an appropriate hydrogen halide binding agent e.g. triethylamine or a picoline.

Alternatively, if desired, the reaction may be effected using a mixed anhydride of the acid of formula III, for example, the anhydride formed by reaction of the acid of formula III with oxalyl chloride, ethyl chloroformate or t isobutyl chloroformate. The reaction may also be effected using an activated ester, an azide or an amide of the acid of formula III.

In the compound of formula III, Y represents a protected hydroxyl radical e.g. an acyloxy radical containing from 2 to 4 carbon atoms. The compound of formula I obtained by reaction with the reactive derivative of the acid of formula III may if desired be subsequently deprotected hy hydrolysis. Thus an acyl radical may be removed by hydrolysis in the presence of a base to yield a compound of formula I wherein Rj represents a radical of formula -OR1 [_in which R1 represents a radical of formula -COR (in which R represents a phenyl radical substituted by a hydroxyl group)].

A preferred base for such a hydrolysis is sodium carbonate but other bases, e.g. sodium hydroxide or potash in ethanol or methanol may alternatively be used if desired.

When Y represents a protected hydroxyl radical in which the protecting group is removable by acid hydrolysis then preferably the acid is oxalic acid. Other acids, e.g. acetic or trifluoroacetic acid may, however, alternatively be used if desired.

I. For the preparation of compounds of general formula I wherein R represents an alkenyl radical containing from 2 to 4 carbon .atoms, each of the two carbon atoms which are double bonded having bonded thereto at least one hydrogen atom, and R^ represents a radical of formula -OR1 (in which R‘ represents a hydrogen atom): Catalytic hydrogenation of a compound of formula I as hereinbefore defined [wherein R represents an alkynyl radical containing from 2 to 4 carbon atoms and Rj represents a group of formula -OR' (in which R’ represents a hydrogen atom)] whereby the desired compound of formula I is obtained.

A preferred catalyst for use in the hydrogenation is palladium on barium sulphate in the presence of a trace of quinoline, but palladium on calcium carbonate in the presence of lead acetate, palladium on charcoal in the presence of pyridine or Raney nickel may alternatively be used if desired.

As indicated above, the compounds of general formula I may exist in a number of isomeric forms. As will be appreciated the above-described processes in general lead to the formation of isomeric mixtures of the compounds of general formula I. Such mixtures may, if desired, be separated into their individual isomers according to methods well known in the art such as, for example, chromatography and conventional resolution techniques.

The compounds of general formula II, wherein p is 0 and Rg represents a radical of formula -tay.-Os. (1 which m is 4), useful as starting materials in process A described above, may be prepared according to processes J1 J described in our Patent Specification No. 44292.

Thus compounds of general formula II wherein A and B each represents a hydrogen atom, p is 0, R represents a hydrogen atom, Rj represents a hydroxyl or a tetrahydropyran-2-yloxy radical and Rj represents a radical of forr.'.ula -(CHg^-CH^ (in which m is 4) may be obtained by treating a compound of formula IV, (wherein R^ represents an alkyl radical containing from 10 1 to 12 carbon atoms and R^ represents a hydrogen atom or a tetrahydrcpyran-2-yl radical) with a base and then with an acid.

The compound of formula IV may itself be obtained by catalytic hydrogenation of a compound of formula V, 4512-1 (wherein R and R_ are as hereinbefore defined). The compound of formula V may in turn be prepared by treating a compound of formula VI, (wherein R^ and Rg are as hereinbefore defined) with an alkaline hydride under mild conditions.

Compounds of general formula II wherein A and B together represent a carbon-carbon bond, p is 0, R represents a hydrogen atom, R^ represents a hydroxyl or a tetrahydropyran-2-yloxy radical and Rg represents a radical of formula -(CHg CHg (in which m is 4) may be obtained directly from a compound of formula V as hereinbefore defined by treatment with an alkali then with an acid. · The compounds of general formula V wherein Rg represents a hydrogen atom may be further used to form compounds of general formula II by oxidation to a compound of formula VII, £313 j (VII) (wherein R^ is as hereinbefore defined) which compound may be treated with a base then with an acid to give a compound of formula II wherein A and B together represent a carbon-carbon bond, p is 0, R and together represent an oxo group and R2 represents a radical of formula -(CHj^-CHg (in which m is 4). Alternatively, the compound of formula VII may be reacted with an organometallic reagent of formula VIII, RyMgX (VIII) (wherein Ry represents an aliphatic hydrocarbyl radical containing from 1 to 4 carbon atoms and X represents a halogen atom) to obtain a compound of formula IX, (wherein R^ and Ry are as hereinbefore defined) which compound may be treated first with an acid then with a base to give a compound of formula II in which A and B together form a carbon-carbon bond, p is 0, R represents an aliphatic hydrocarbyl radical containing from 1 to 4 carbon atoms, R1 represents a hydroxyl radical and Rg represents a radical of formula -(CHgJ^-CH^ (in which m is 4).

The compound of formula IX may alternatively be obtained by mild reduction of a compound of formula X, (wherein R^ and R·^ are as hereinbefore defined). The compound of.formula X may also be converted into other compounds of general formula II by reaction with dihydro2, 3-pyran to obtain a compound of formula XI, - 16 4 31 3-J (wherein R^ and R^ are as hereinbefore defined) which compound may then be reduced under mild conditions to give a compound of formula XII, (wherein R^ and R^ are as hereinbefore defined), said compound of formula XII being subsequently treated with a base then with an acid to give a compound of formula II wherein A and B together represent a carbon-carbon bond, p Is 0, R represents an aliphatic hydrocarbyl radical containing from 1 to 4 carbon atoms, Rj represents a tetrahydropyran-2-yloxy radical and Rg represents a radical of formula -(CHg^-CH^ (in which m is 4).

The compounds of general formula X may be obtained by treating a compound of formula XIII, - 17 '(XIII) (wherein R^ and R^ are as hereinbefore defined) with an acid.

The compound of formula XIII may in turn be 5 prepared by reacting a compound of formula XIV5 (wherein R^ is as hereinbefore defined) with an organometallic reagent of formula VIII as hereinbefore defined.

The compound of formula XIV may itself be formed 10 by oxidation of a compound of formula XV. (wherein R^ is as hereinbefore defined). Οΐίί3 4 The compound of formula XV may be obtained by reaction of a compound of formula VI as hereinbefore defined (wherein Rg represents a hydrogen atom) with diazomethane.

The above-described processes for the preparation of certain 5 of the compounds of general formula II as described in our Patent Specification No. 44292 are further illustrated hereinafter in the Examples.

Compounds of general formula II wherein A and B together represent a carbon-carbon bond, p is 0 and R^ and Rg together form a radical of formula ^^^(CHgjg-CH, may be prepared by reaction of a compound of formula Vl as hereinbefore defined (wherein Rg represents a tetrahydropyran-2-yI radical) with 2,4-dinitrobenzenesulphinyl chloride.

Compounds of general formula II wherein p is 2 and Rg represents a radical of formula -(CHg)4-CH3 or, together with Rp a radical of formuia (CHg)3-CH may be obtained from a compound of formula XVI, (XVI) (wherein R^ and Rg are as hereinbefore defined) by. processes analogous to those described in relation to compounds of general formula VI.

The compound of formula XVI may itself be prepared by reacting a compound of formula VI as hereinbefore defined (in which Rg represents a tetrahydropyran-2-yl radical) with an alkyl acrylate followed by an isomerisation and then a decarboxylation reaction. An illustration of such a process is given hereinafter in the Examples.

Compounds of general formula II wherein Rg represents a radical of formula -(CH„) -CH, (in which m is 3 or 5) £» El ύ or, together with Rp a radical of formula (CHg)n-CHg (in which n is 2 or 4) may also be prepared by processes analogous to those described in respect of compounds of general formula VI using a compound of formula XVII, 4513 4 Wm*' •CH_ (XVII) (wherein R^ and R^ are as hereinbefore defined and m* is 3 or 5).

The corresponding compounds of general formula II 5 wherein p is 2 may also be obtained analogously from the corresponding compound of formula XVIII, (wherein R^, R^ and m’ are as hereinbefore defined).

The compound of formula XVIII may be obtained from a compound of formula XVII by a process analogous to that described for the preparation of compounds of general formula XVI from a compound of formula VI.

Compounds of general formula II wherein R^ represents a radical of formula -OR* [in which R’ represents a radical of formula -COR (in which R represents an alkyl radical containing from 1 to 3 carbon atoms substituted by a carboxylic acid group or a phenyl radical substituted by a hydroxyl or protected hydroxyl radical)] may be prepared from a compound of formula XIX, och3 CO-alk \ Ύ (XIX) (wherein alk represents an alkyl radical containing from 1 fo 4 carbon atoms). Thus, the conpound of formula XVII is reacted with, for example, dimethyl (2-oxo-nonyl)phosphonate in the presence of a strong base e.g. sodium hydride to obtain a compound of formula XX, (XX$ (wherein alk is as hereinbefore defined) which is subsequently reduced, for example, with zinc borohydride, to obtain a compound of formula XXI, - 22 15 212 4 (wherein alk is as hereinbefore defined) in the form of an isomeric mixture which may then be separated. The free hydroxyl group may subsequently be protected e.g. with a tetrahydropyranyl group and the protected compound treated with an acid e.g. hydrochloric acid, then with a reducing agent, e.g. lithium tri-sec.-butyl-borohydride. The reduced compound thus obtained may then be treated with a base such as soda and finally, if required, with an acid e.g. monosodium phosphate to give a compound of formula XXII,.

OH (XXIIj (wherein R^ represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms). Compounds of formula XXIII, OH OH (XXIII) - 23 <ϊ> r> (wherein m is as hereinbefore defined) may be obtained by processes analogous to those describe in relation to the preparation of the compounds of general formula II wherein p is 0, A and B together represent a carbon-carbon bond, R^ represents a hydroxyl or tetrahydropyran-2-yloxy radical and Eg represents a radical of formula -(CHg^-CH^ and of compounds of general formula XXII.

Such compounds of general formula XXIII may then be converted into compounds of general formula II wherein p is 0, R^ represents a radical of formula -COR (in which R represents an alkyl radical containing from 1 to 3 carbon atoms substituted by a carboxylic acid group or a phenyl radical substituted by a hydroxyl or protected hydroxyl radical) by reaction with an anhydride of formula: R* ' XC0z (wherein R represents an alkylene radical containing from 1 to 3 carbon atoms) or with an acid of formula j // COgH - 24 (wherein Y represents a protected hydroxyl radical) or a reactive derivative thereof, followed if required, by hydrolysis under conditions identical to those described under processes D and H above.

Compounds of general formula II wherein p is 2, Rj represents a radical of formula -OR* [in which R’ represents a radical of formula -COR (in which R represents an alkyl radical containing from 1 to 3 carbon atoms substituted by a carboxylic acid group or a phenyl radical substituted by a hydroxyl or protected hydroxyl radical)] may be obtained by analogous processes using a compound of formula XXIV. (wherein m and R^ are as hereinbefore defined).

The compound of formula XIX may itself be obtained by the process described in our Patent Specification No. 44671 Thus, as described herein, a compound of formula: H,C — CH~CH,OH 2\ / 2 - 25 may be reacted with dihydropyran to obtain a compound of formula: K-CHg-0 which may subsequently be treated with an alkyl acetylacetate of formula: CHgCOCHgCOgalk (wherein alk is as hereinbefore defined), in the presence of a strong base, e.g. a mixture of sodium hydride and butyl lithium, to obtain a compound of formula: o (wherein alk is as hereinbefore defined) which compound may then be oxidised, e.g. with a chromic acid-pyridine complex, to give a compound of formula: (wherein alk is as hereinbefore defined) which, on treatment with a base such as, for example, potassium bicarbonate, yields a compound of formula: - 26 «3134 (wherein alk is as hereinbefore defined). The latter compound may be hydrogenated in tbe presence of a catalyst, e.g. palladium on charcoal, to give a compound of formula; (wherein alk is as hereinbefore defined) which, on treatment with an acid such as, for example, oxalic acid, yields a compound of formula; . CO-alk ώ 2 OH (wherein alk is as hereinbefore defined). Treatment of 10 this compound with diazomethane leads to a compound of (wherein alk is as hereinbefore defined) which, on oxidation, e.g. with a chromium trioxide-pyridine complex gives the 15 desired compounds of formula XIX.

The compounds of general.formula II wherein A and B each represents a hydrogen atom may be obtained by hydrogenation of a corresponding compound of formula II wherein A and B together represent a carbon-carbon bond. The acids of general formula II may also be obtained from their corresponding esters according to conventional methods.

As indicated hereinabove, the compounds of general formula I possess interesting pharmacological properties. Those compounds according to the invention which we have tested exhibit hypotensive activity. Such compounds 5 are thus useful in the treatment of hypertension and circulatory disorders.

According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of 1° formula I as hereinbefore defined in association with a pharmaceutical carrier or excipient.

For pharmaceutical administration the compounds of general formula I may be incorporated, in either solid or liquid form, into the conventional pharmaceutical preparations, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for oral, rectal or parenteral (including topical) administration. Preferred forms include, for example, tablets, coated tablets, capsules, granules, suppositories and solutions e.g. for injection. The active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. The dosage will vary according to the compound used, the subject treated and the complaint concerned, Thus, for example, the dosage for injection, e.g., by slow perfusion, may be from 0.5 to 200 mg for the products cf Examples 2 and 15 described hereinafter.

The following non-limiting Examples serve to illustrate the present invention.

AU 124 Example 1 (IRS,2SR,5RS.3 * SR) (1* E)-2hydroxy --5- (3' cc-tetrahydropyranyloxyocten-l’yl^cyclopentane-carboxylic· acid lactone 600 mg of (lRS,2SR,5RS,3sSR) (l'E)-2-hydroxy-5-(3'a5 tetrahydropyranyloxy-oCten-l ’ yl)-cyclopentane-carboxylic acid, 3 cm of anhydrous chloroform, 1 cm of triethylamine and 402 mg of tosyl chloride are introduced into a reaction vessel and the reaction mixture agitated for 4 hours at 20°C. A solution of sodium acid phosphate is added and the mixture decanted, extracted with methylene chloride and evaporated to dryness under vacuum. . 700 mg of product are obtained which are chromatographed on silica gel with a mixture of cyclohexane, ethyl acetate and triethylamine (75:25:0,1). 335 mg of β-lactone are obtained.

The (1RS,2SR,5RS,3’SR) (l'E)-2-hydroxy-5-(3'octetrahydropyranyloxy-octen-l-yl)-cyclopentane-carboxylic acid used as starting material in Example 1 is prepared as follows: Stage A: Ethyl (1RS.2SR ’17'-2-hydroxy-5-(3'a°-enyl)-cyclopentane-carboxylate A mixture of 14 g ethyl 3-(3’a-tetrahydropyranyloxy3 trans-oct-1’-enyl)-cyclopentanone-2-carboxylate, 200 cm 3 ' isopropyl alcohol, 20 cm water and 5.6 g sodium borohydride are shaken for two hours. Acetone is slowly added to the mixture which Is thes> poured into a saturated aqueous solution of monosodium phosphate.

The reaction mixture is filtered, taken to dryness'&k recrystallised from ethyl acetate. The product is washed with water, dried and the solvent evaporated. The residue is chromatographed on silica eluting with a mixture of cyclohexane: ethyl acetate (8:2) with 0.1% triethylamine. 3.4 g of the α-OH (2SR) isomer are obtained.

Stage B: (1RS.2SR.5RS,3*SR) (’’Ej •2“hydroxy-5-(3,K-tetrahydropyranyloxyoct-l’-enyp-cyclopentane-carboxylic acid A mixture of 3.1 g of the ester obtained in Stage A, 3 cm methanol and 8,15 cm 2N sodium hydroxide are shaken for three hours at 20°C. The solvents are evaporated off at 35-40°C and the residue taken up in water and washed with ether. The solution is saturated with sodium chloride, acidified with hydrochloric acid, extracted with ether, washed with water and dried and the solvent is evaporated. 2.6 grams of the desired product are obtained.

Example 2 (lRS^SR.SRS.S’SR) (l'E)-2-hydroxy-5-(3>-hydroxy-oct-l,enyl)~ cyclopentane-carboxylic acid lactone 336 mg of the β-lactone obtained in Example 1 are dissolved in 10 volumes of acetic acid containing 20% water in the presence of 5 mg of sodium iodide. The reaction mixture is left for 16 hours at 20°C, poured into water, extracted with·methylene chloride, washed with sodium bisulphate, and dried. 280 mg of product are obtained and chromatographed on silica gel with a mixture of cyclohexane; ethylacetate (75:25). 160 mg of desired product are obtained.

Example 3 oct-18-enyl)-cyclopentane-carboxylic acid lactone 160 mg of the β-lactone obtained in Example 2, 1.6 cm of pyridine and 200'mg of phthalic anhydride are introduced into a reaction vessel. The reaction mixture is left for 9 days at ambient temperature. The reaction mixture is then poured into iced N hydrochloric acid, extracted with ether and washed. The organic phases are-extracted-with 10% bicarbonate. The ' dhereeLphases are dried and evaporated to dryness under vacuum. The aqueous alkaline phases are acidified with N hydrochloric acid, extracted with ether and evaporated to dryness under vacuum.· , The acid fraction is chromatographed on silica gel with cyclohexane: ethyl acetate (1:1). 172 mg of the desired product are obtained in the form of a colourless resin which crystallises.

IR Spectrum : C = 0 : 1828 cm 1811 cm 1725 cm= 1708 cm β lactone aromatic : 1603 cm 1583 cm_ 1491 cm” acid lactone ’ , 43i 3-1 A mixture of 530 mg (1RS,2SR,5RS,3'SR) (l’E)-2,3'dihydroxy-5-(3’-ethynyl-oct-1’-enyl)-cyclopentane-carboxylic acid, 3 3 .3 cm chloroform, 0.78 cm triethylamine and 430 mg tosyl chloride are shaken at 5°G for 30 minutes and the temperature then allowed to rise to 20°C, The mixture is left for one hour, poured into water, sodium acid phosphate is added and the mixture washed with water, extracted with methylene chloride, dried and chromatographed on silica gel with benzene: ethyl acetate (80:20). 106 mg of desired product are obtained.

Rf « 0.4.

Example 5 (IRS, 5R. 5RS, 3°RS)-(l’R.)-2-hydroxy-5-(3*hydroxy-3,-ethynyloct-1'-enyl)-cyclopentane-carboxylic acid lactone A mixture of 720 mg (1RS,2SR,5RS,3’RS) (l’)-25 ' hydroxy-5-(3’-hydroxy-3'-ethynyl-oct-l’-enyl)-cyclopentane 3 carboxylic acid, 7.2 cm chloroform, 1.44 cm triethylamine and 586 mg tosyl chloride are shaken at 20°C under nitrogen. The reaction mixture is poured into a mixture of water and sodium acid phosphate, washed with water, extracted with methylene chloride, dried and evaporated to dryness.

About 1 g of products are obtained which are chromatographed ( on silica gel with a mixture of benzene:ethyl acetate (80:20).128 mg of desired product are obtained. R^ = 0.4.

(IRS,2SR,5RS,3’SR) (1’E)-2-hydroxy-5-(3’-hydroxy15 3’-ethynyl-oct“l’“enyl)cyclopentane-carboxylic acid used as starting material in Example 4 and (1RS,2SR,5RS,3’RS)“ (1’E)-2-hydroxy-5-(3’-hydroxy-3’-ethynyl-oct-1*-enyl)cyclopentane-carboxylic acid used as starting material in Example 5 are prepared as follows: Stage A Ethyl (1RS,2SR,5RS,3’SR) (l'E)-2-hydroxy-5-(3’hydroxy-oct-l’-enyl)-cyclopentane carboxylate A mixture of 572 mg ethyl 3-(3’-a-hydroxy-trans-octl’-enyl)-cyclopentanone-2-carboxylate, 23 cm ethanol, * a ι a i o 2.3 cm water and 85 mg sodium borohydride are shaken for two hours at 5°C. A few drops of acetone are added and the reaction mixture is then poured into a saturated solution of monosodium phosphate.

The reaction mixture is filtered and the solvent evaporated. Tha residue is taken up in ethyl acetate, washed with water, dried and evaporated to dryness. 520 mg of a mixture of 2a-0H and 2β-0Η isomers are obtained which are separated by chromatography on silica eluting with methylene chloride containing 2% methanol. 203 mg of the desired α-isomer are obtained.

Stage B Ethyl (1RS,2SR,5RS) (l,E)-2-hydroxy-5-(3,-oxo-oct1 *-enyl)-cyclopentane-carboxylate 1 g of the product obtained in Stage A is introduced into 20 cn dioxan and 1.6 g dichlorodicyanoquinone are added. The reaction mixture is shaken for 20 hours at ambient temperature, dried and rinsed. The reaction mixture is then washed with iced N/10 sodium hydroxide to pH 9, filtered, washed with water and dried. 987 mg of crude product are obtained which are chromatographed on silica with cyclohexane:ethyl acetate (1:1) as eluant whereupon 930 mg of the desired product are recovered.

S-4 Stage C ' Ethyl (1RS.2SR.5RS,3'SR and RS) (l,E)-2-hydroxy-5(3 *-hydroxy-38-ethynyl-oct-1'-enyl)-cyclopentane-carboxylate A mixture of 2.1 g of the product obtained in Stage B and 2.1 cm of tetrahydrofuran are warmed to 38°C and cm of a solution of ethynyl magnesium bromide in tetrahydrofuran warmed to 40°C are rapidly added. The reaction mixture is shaken for 30 minutes at 38°C then poured into a solution of ammonium chloride in iced water, extracted with methylene chloride, washed with water, dried, filtered and evaporated to dryness.

By chromatography on silica using as eluant methylene chloride:ethyl acetate (85:15) are obtained 1.67g of the desired product. nRS.PSR.B'SR) (l’E)~2-hydroxy-5-(3*-hydroxy-3 ethynyl-oct-l’-enyl^cyclopentane-carboxylic acid and' (1RS.2SR,5RS,38RS) (I'E^-hydroxy-S-Q'-hydroxy-S8ethynyl-oct-1'-enyl)-cyclopentane-carboxylie acid 1.67 g of the ester obtained-in Stage B, 17 cm 3 ethanol and 8.5 cm N sodium hydroxide are introduced into a reaction vessel under nitrogen. The reaction mixture is shaken for 2 hours at 20°C, poured into water, extracted with ether, 0.37 g of a fraction containing impurities are obtained.

The aqueous phases are combined, acidified with monosodium phosphate, extracted with ether, washed with water, dried and evaporated. 1,33 g product are obtained.

The two isomers are separated by chromatography under vacuum in diisopropyl ether containing 4% acetic acid. 530 mg α-OH isomer (3’SR) are obtained. 0.15. 720 mg β-Οίί isomer (3*RS) are obtained. R^ = 0.10.

I 1/ Example 6 (1RS,2SR,5SS) (l’E, 3*E)2-hydroxy-5-(octa-lt,3'-dienyl) cyclopentane-carboxylic acid lactone mg p-toluenesulphonic acid are added to 150 mg 3 of the β-laetone prepared in Example 2 in 3 cm benzene 15 and warmed under nitrogen to 40°C for 3 hours. The reaction mixture is neutralised with 150 mg sodium carbonate and filtered and the solvent evaporated. 139 mg of an oil are obtained which are chromatographed on silica with cyclohexane:ethyl acetate (95:5) as eluant. 36 mg of pure product are obtained. R^ = 0.25 (cyclohexane:ethyl acetate, 90:10). . Ο A ν' Υ <> G·» Infrared spectrum (chloroform) = 0 1830 cm1 1816 cm-*· shoulder 993 cm Ultraviolet spectrum (ethanol) % Inflection13 227 nm E Maximum a 232 nm E Inflection 239 nm E cm % cm 1 % = 1310 cm = 1410 cm ε = 31 000 cm Example 7 (lRS,2SR,5RSa3llSR) (l,E)-2-nydro: anyl)*-cyclopentane-propionic acid lactone 1044 cm hydroxy-oct-11-en A mixture of 390 mg (IRS,2SR,5RS,3’SR) (l’E)-2hydroxy-5-(3’-hydroxy-oct-1’-enyl)-cyclopentane-propionic 3 acid, 3 cm anhydrous nitromethane, 0.3 cm pyridine and 300 mg dicyclohexylcarbodiimide are shaken for 16 hours •at 20°Cj> dried, washed with ether and dried. The organic phase is poured into water and the resulting solution decanted, extracted with ether, washed with water and evaporated to dryness. Following chromatography on silica with cyclohexane:ethyl acetate (1:1), 173 mg of homogeneous product are obtained.

Example 8 (IRS,2RS,5RS,31SR) (l'E)-2-hydroxy-5-(3'-hydroxy-oct-Γ enyl)-cyclopentanepropionic acid lactone Startihg from 405 mg (1RS,2RS,5RS,3'SR) (l'E)-25 hydroxy-5-(3’-hydroxy-oct-1’-enyl)-cyclopentane-propionic 3 acid, 3 cm nitromethane, 0.3 cm pyridine and 300 mg dicyclohexylcarbodiimide and working in accordance with Example 7, 188 mg of pure product are obtained.

The (1SS,2SR,5RS,3'SR) (l'E)-2-hydroxy-5-(3'10 hydroxy-oct-l’-enyl)-cyclopentsne-propionic acid and (IRS,2RS,5RS,3’SR) (1’E)-2-hydroxy-5-(3’-hydroxy-oct-1*enyl)-cyclopentane-propitnic acid used as starting materials in Examples ? and 8 respectively are prepared as follows: - λ 2 A ς a * * Stage A: Ethyl (5RS.3*SR) (liE)-l-ethoxycarbonyl-2Oxo-5-(3l-o:tetrahydropyranyloxy-oct-1'-enyl)-cyclopentane-propionate 1.113 g ethyl 3-(3’-a-tetrahydropyranyloxy-trans-oct-l’-. enyl)-cyclopentanone -2-carboxylate and 3 cm anhydrous ethanol are introduced into a reaction vessel under a nitrogen atmosphere 0.23 cm sodium ethylate in ethanol (0.22 W) are added followed by 303 mg ethyl acrylate. The reaction mixture is allowed to stand for two hours at 25°G and then refl,uxed for one hour.

The reaction mixture is cooled to 0°C then poured onto an iced solution of monosodium phosphate. The mixture is extracted with ether, washed with water and dried and the solvent evaporated under vacuum. The product obtained is chromatogra on silica gel with an eluant consisting of cyclohexane, ethyl acetate and triethylamine (80:20:0.1), 1.13 g of desired product are obtained. tetrahydropyranylossy-oct-l8-enyl)-eyclopentane-propionate 3 2.1 cm of a solution of sodium ethylate (1.02 N) in ethanol are poured onto 0.93 g of the product prepared in Stage 3 A. The mixture is refluxed for four hours, 10 cm toluene are added and the ethanol distilled off. The reaction mixture is I refridgeratedto -20°C>added to an iced solution of mono sodium phosphate and extracted with ether. The organic phases are washed with water and dried. 940 mg of crude product are obtained which are purified on silica using an eluant consisting of cyclohexane: ethyl acetate (60:40). 680 rag of pure product are obtained.

Stage C: Methyl (1RS.5RS,3'SR) (llE)-2-oxo-5-(3>-a-tetrahydropyranyloxyoct-1'-enyl)-cyclopentane-proplonate A mixture of 1.5 g of the product prepared in Stage B, cm3 methanol and 9.6 cm3 N sodium hydroxide are allowed to stand at ambient temperature then warmed for 12 hours at 40°C. The mixture is concentrated to dryness, taken up in a mixture of water and ethyl acetate, iced, acidified, extracted with ethyl acetate, washed with water and concentrated to dryness. 1.225 g ·· 3 of product are obtained which are dissolved in 20 cm benzene then refluxed for one hour whereupon 1.2 g of -product are obtained which is taken up in methylene chloride with a drop of triethylamine and esterified by means of diazomethane. An oil is obtained which is chromatographed on silica with a mixture of ethyl acetate: cyclohexane (50:50) whereupon 852 mg of product are obtained.

Stage P: Methyl (IRS, 2SR.5RS.3,SR) (l,E)-2-hydroxy-5-(3t-atetrahydropyranyloxy-oct-11-enyl)-eyclopentane-propionate and methyl (IRS^RS.SRS.S'SR) (l*E)-2-hydroxy-5-(3t-gtetrahydropyranyloxy-oct-Γ -enyl)-cyclopentane-propionate 2.165 g of the product obtained in Stage C and 21 cm methanol are introduced into a reaction vessel under nitrogen. 220 mg sodium borohydride are added at 0°C over an hour and u 12 -I the reaction mixture is shaken for a further hour whereafter ' cm water and 3 g monosodium phosphate are added. The reaction mixture is extracted with methylene chloride, washed with water and dried. 2.014 g of product-are obtained, the product containing the two isomers which are seperated on silica eluting with a mixture .of petroleum ether (35°C-70°C): ether (50:50). 329 mg of the 2SR isomer and 1.143 g of the 2RS isomer are obtained.

Methyl (IRS.2SR.5RS.3’SR) (l*E)-22hydroxy-5-(3'-hydfoxyoct-l’-eny 458 mg of the 2SR isomer obtained in Stage D are warmed for 3 3 four hours to 40°C with 4.6 cm methanol, 0.45 cm water and 46 mg oxalic acid.

Stage Fs (1RS,2SR,5RS,38SR) (lcE)-2-hydroxy-5-( cyclopentane-propionic acid Z-oct-l'-enyl)2 • 3 cm N sodium hydroxide are introduced at 40°C under nitrogen into a solution of the 2SR isomer obtained according to the process described in Stage E. The reaction mixture is warmed for two hours at 40°C then poured into water containing monosodium phosphate, extracted with ethyl acetate, washed with water, dried, filtered and evaporated whereupon 390 mg of crude product are obtained.

Stage G: d ΰ i 2,j (IRS,2RS,5RS,3'SR) (l'E)-2-hydroxy-5-(3'-hydroxy-oct-1'-envl)cyclopentane-propionic acid 479 mg of the 2RS isomer obtained in Stage D, 5 cm 3 methanol, 0.5 cm water and 50 mg oxalic acid are shaken for 3 three hours at 40°C. 3 cm N sodium hydroxide are added and the reaction mixture shaken for a further three hours at 40°C, The reaction mixture is acidifed with monosodium phosphate, extracted with ethyl acetate, washed with water and dried. 405 mg product are obtained.

Example 9 (1RS.2SR.5RS) (l*E)-2-hydroxy-5-(3'-oxo-oct-1*-enyl)cyclopentane-carboxylic acid lactone 3 cm dry methylene choride and 1.5 cm anhydrous pyridine are placed in a reaction vessel under a current of 15 dry nitrogen and 900 mg chramijm trioxide (cooled) are added slowly at 20°C. The reaction mixture i.s shaken for 15 minutes and then 358 mg (1RS,2SR,5RS(3’SR) (1'>1- hydroxy-5-(3'-ochydroxy-oct-l'-enyly-cyclopentane-carboxylic acid lactone 3 (obtained in Example 2) dissolved in 15 cm methylene chloride 20 are added rapidly.

The reaction mixture is shaken for two hours at 20°C then 4 g *Celite and 15 em3 methylene chloride are added. The mixture is filtered and the filtrate concentrated under vacuum. The pyridine is removed by flushing with nitrogen whereupon 375 mg of a brown oil are obtained. This is chromatographed on silica ' with a mixture of cyclohexane: ethyl acetate (6:4) as eluant whereupon 329 mg product are obtained - R^ = 0.45.

*Celite is a Trade Mark /i /-Infrared spectrum 3XC=0p lactone 1826 cm conjugated system 1696 cm 1 1674 cm1 1630 cm1 Example 10 (lRS.2SR,5RSt3tSR)~2-hydroxy-5-(3,-hydroxy-octanyl)~ cyclopentane-carboxylic acid lactone 105 mg (1RS,2SR,5RS,3’SR) (l’E)-2-hydroxy-5-(3’5 a-hydroxy-oct-l’-enyl)-cyclopentane-carboxylic acid lactone (obtained in Example 2} dissolved in 10 cm ethyl acetate are placed in a hydrogenation apparatus. 20 mg 5% palladium on charcoal are added.

Hydrogenation is effected for 7 hours (absorption 10 10.4 cm' hydrogen). Tiie catalyst is filtered off and the filtrate concentrated under vacuum the residual oil being chromatographed on silica eluting with a mixture of cyclohexane and ethyl acetate (50:50).97 mg product are obtained Rf - 0.35.

Infrared spectrum C«0 1800 cm absence of trans OC OH 3600 cm1 Example 11 (IRS,2SR,5RS,3 * RS) (1'E)-2-hydroxy-5-(3'-hydroxy-3' -ethenyi 20 oct-1*-enyl)-cyclopentane-carboxylie acid lactone mg of 4.75% palladium on barium sulphate in 5 cm ethyl acetate are saturated with hydrogen at atmospheric pressure. (1RS,2SR,5RS,3’SR) (l’E)“2-hydroxy-5-(3'45 hydroxy-3’-ethynyl-oct-1*-enyl)-cyclopentane-carboxylic acid lactone (obtained in Example 4), 10 mg quinoline 3 and 1 cm ethyl acetate are added. Hydrogenation'is effected at 21°C. After 30 minutes, 14.3 cm hydrogen had been absorbed. The catalyst is filtered and the solution washed with 0.1 N hydrochloride acid then with saline water. The organic phase is dried and evaporated and 153 mg crude product are obtained.

The product is purified by chromatography on silica 10 with a mixture of bensene and ethyl acetate (80:20) then by preparative layer chromatography with the same eluant. 110 mg pure product are obtained, R^ = 0.41.

The infrared spectrum shows the absence of C=CH and the presence of a 6-lactone structure and ethenyl and hydroxyl groupings.

NMR spectrum (CDClg, 60 MHz) (a) : 0.88 ppm (b) : 1.51 ppm (c) : 3.1 ppm (triplet J = 5Hz) (d) : 3.8 ppm (doublet J =“ 4Hz) (e) : 5.16 to 6.2 ppm (f) : 5 ppm (triplet J = 3Hz) Example 12 (1RS,2SR,5RS,3’SR) (l'E)-2-hydroxy-5-(3'-hydroxy-3'- ethenyloct-l'-enyl)-cyclopentane-carbpxylic acid lactone.

Operating exactly as in Example 11 starting from 150 rag (1RS,2SR,5RS,3'RS) (l'E)~2-hydroxy~5-(3*-hydroxy3'-ethynyl-cct-l'-enyl)-cyclopentane-carboxylic acid lactone (obtained I:.; Example 5), are obtained 127 mg of pure product, The infrared spectrum shows the absence of C=C and the presence of β-lactone, ethenyl and hydroxyl.

NMR spectrum (CDC13, 50 MHz) (a) ; 0.88 ppm (b) : 1.51 ppm (c) : 3.1 ppm (d) s 3.8 ppm doublet (j = 4 Hz) (e) : 5.IS to 5.61 ppm (f) ; 5.16 to 6.2 ppm (g) : 5 ppm (triplet) Example 13 (IRS, 2SR,5SS.3’SR) (!'£)-2-hydroxy-5- (3 °-aeetoxy-oct-1 *10 enyl)-cyclopeAtane-carboxylic acid lactone A mixture of 0.2 g (1SS92SR,5RS,3’SR) (l’E)-2-hydroxy5-(3 ’“a=h.ydroxy»oct»l s“enyl)-cyclopentane-carboxylic acid 3 lactone, 2 cm methylene chloride, 0.47 cm triethylamine, 0.091 cm acetic anhydride and a few grains of dimethylamino pyridine are shaken at ambient temperature for 2 hours. . ’ 3 cm water are added and the reaction mixture acidified to pH 5 with monosodium phosphate and extracted with methylene chloride. The mixture is dried, evaporated to dryness under reduced pressure whereupon 266 mg of crude oil are obtained which are purified by chromatography on silica with a mixture of cyclohexane:ethyl acetate (60:40) as eluant. 211 mg of pure product are thus obtained. R^ = 0.5.

Infrared spectrum C = 0 complex 1808 to 1824 cm 1 ester 1725 cm”1 (a) : 0.83 ppm (fc) ; 2,03 pp® (c) : triplet centered at 3.08 ppm J “ 5 Hz (d) : doublet cent?·red at 3.78 ppm J » 3.5 Hz (e) ί triplet centered on 5.01 ppm J = 3 Hz (f) ; 5.15 ppm Example 14 (IRS,2 SK,5RS,3'SR) (1’E)-2-hydroxy-5-(oct-l,-enyl-3'hydroxy)-cyclopentang-carboxylic acid lactone hemisuccinate 119 mg (1RS,2SR,5RS,3'SR) (1Έ)-2-hydroxy-5-(3r-ahydroxy-oct-l’-enyl)-cyclopentane-carboxylic acid lactone 3 (obtained in Example 2), 2 cm methylene chloride (anhydrous), 3 100 mg succinic anhydride, 0.15 cm pure triethylamine and 15 mg 4-dimefchylaraino-pyridine are mixed.

The mixture is taken to reflux for 8 hours and the 3 solvents are then evaporated. 2 cm absolute ethanol are added .and-the reaction mixture left for 1 hour at ambient temperature. The excess succinic anhydride is 5 eliminated in the form of ethyl heraisuccinate. The resulting mixture Is evaporated under vacuum and 226 mg crude product are obtained which are chromatographed on silica using pure ethyl-acetate .132 mg pure product are isolated, = 0.3.

NMR spectrum (CCClg ‘60 MHz) (b) : 2.63 ppm (c) : 3,08 ppm (d) s 5.2 ppm (e) s 5.04 ppm (f) : 5.33 to 5.58 ppm Example 15 (IRS.2SR.5RS.3'SR) (11E)- 2-hydroxy-5-(3-hydroxy-dec-1*-enyl)cyclopentane— carboxylic acid lactone 0.15 g (1RS,2SR,5RS,2’SR) (l'E)-2-hydroxy-5-(3’-hydroxy3 dec-1’-enyl)- cyclopentane-carboxylic acid in 4 cm chloroform, 0.315 g triethylenediamine and 0.16 g tosyl chloride are placed in a reaction vessel. Reaction is instantaneous. The reaction mixture is poured int: water and extracted with ethyl acetate. After treatment, 183 mg of an oil are obtained which is chromatographed on silica with a mixture of cyclohexane: ethyl acetate (60:40) as eluant. 41 mg of pure product are obtained.

Rf - 0.25.

Infrared spectrum complex 1308 to 1824 cm1; J^C=(Z 973 cm' 15 NMR spectrum (CDGi^, 60 MHz.) (b) : 1,3 ppm (c) : 1.53 ppm (d) : 3.08 ppm (e) : 3.78 ppm (doublet J = 4Hz) (f) : 4.05 ppm (g) : 5.47 ppm (doublet J = 5Hz) (h) : 5,01 ppm (triplet) The (IRS,2SR,5RS,3'SR) (l’E)-2-hydroxy-5~(3’-hydroxydec-l,-enyl)-cyclopentane-carbo3^1ic acid used as starting material in Example 15 is prepared as follows: a) 1,2-epoxy-3-g-tetrahydropyranyloxy-propane A solution of 3.9 g glycidol (2,3-epoxy-propan-l-ol), 18.5 cm3 dihydropyran and 150 mg £-toluenesulphonic acid are warmed to AO°C.

After 30 minutes, 150 mg £-toluenesulphonic acid are added then, after 15 minutes, the reaction mixture is neutralised with potassium carbonate at ambient temperature. After filtration, washing with ethyl acetate and removal of the solvent under reduced pressure, 8.48 g product are obtained. &£·= 0.6 (cyclohexane; ethyl acetate, 8;2) b) Methyl 3<-kefo~6-hydroxy-7~K-tetrahydropropyranyloxyheptanoate To a solution ef 3.55A g sodium hydride (50% suspension 3 in oil) in 16 cm anhydrous tetrahydrofuran maintained at O’C are added over 30 minutes a solution containing 8 cm methyl 3 acetylacetate -and 16 cm anhydrous tetrahydrofuran. cm butyl lithium are introduced into the mixture over 30 minutes at O’C. The reaction mixture is shaken for half an hour then kept at -70°C.

The solution is introduced over A5 minutes into a solution (at O’C) containing 5.8 g l,2-epoxy-3-cctetrahydropropyanyloxy-propane (prepared in Stage A) and 16 3 cm tetrahydrofuran. The mixture is shaken for three and half hours then poured into an excess of a concentrated iced solution of monosodium phosphate, The mixture is shaken for 10 minutes then extracted with ethyl acetate and washed to neutrality. After evaporation of the solvent, 16.9 g of an oil are obtained which are purified on silica (cyclohexane: ethyl acetate, 6:4) whereupon 8,02 g of pure product are recovered. R^ = 0.15. c) Methyl 3.6-dioxo-7-g-tetrahvdropyranyloxy-heptanoate g chromic acid are slowly introduced into a solution 3 3 of 9.7 cm pyridine in 148 cm methylene chloride. The mixture is shaken for 15 minutes following which 1.1 g of the product obtained in Stage B in solution in 10 cm methylene chloride 3 are introduced. After 15 minutes, 150 cm ether are added.

The precipitate is filtered, wished in ether and the solvent evaporated. 1.3 g crude product are obtained which are purified by chromatography on silica (methylene chloride: ethyl acetate, 8:2). 473 mg pure prvj.net are obtained. R^ = 0.45. d) Methyl 2-( 291 mg potassium bicarbonate in solution in 72 cm 20 distilled water and 220 mg of the crude product obtained in Stage C in solution in 2.4 cm methylene chloride are vigorously shaken. After half an hour, the reaction mixture is acidified to pH 3 with oxalic acid then saturated with sodium chloride and extracted with methylene chloride. After evaporation, 205 mg product are obtained. e) Methyl (IRS, 5SR)-2-oxo-5-(cc-tetrahydropyranyloxy-methyl) cyclopentane-carboxylate A solution containing 215 mg of the product obtained in Stage d, 10 cm methanol and 21 mg 10% palladium on charcoal are shaken under an atmosphere of hydrogen. The theoretical volume is absorbed in 40 minutes following which the reaction mixture is filtered and washed with ethyl acetate. On evaporation of the solvent, 172 mg of an oil are obtained which are chromatographed on silica (cyclohexane: ethyl acetate, 50:50). 122 mg product are obtained. f ) Methyl (IBS.5SR)~2-oxO5-hvdroxymefchyi-cyclopentane— carboxylate A mixture of 43 g of the product obtained in Stage e, 860 eta'·5 methanol, 86 cm water and 12.7 g oxalic acid is shaken at 60°C for 3 hours. The reaction mixture is concentrated under reduced pressure at 40°G, taken up in chloroform, washed with water and dried. The solvent is evaporated and 29.2 g crude product are obtained whieh are chromatographed on silica (cyclohexane; ethyl acetate 2:8). 14 g pure oii are recovered, g) Methyl (5RS)-2-methoxy-5-hydroxymethyl-cyclopent-l-ehecarboxylate g of the β-keto ester obtained in Stage f, 10 cm. methylene chloride and 50 cm diazomethane in solution in methylene chloride are shaken at ambient temperature for 4 hours.

The solvent and excess diazomethane are evaporated where54 312 1 upon 4.3 g of a yellow oil are obtained which are used crude in the following reaction. h) Methyl (5RS)-2-methoxy-5-formyl-cyclopent-l-enecarboxylate .5 g chromium trioxide are introduced, in small portions, into a solution (maintained at 15-20°C) of 41 cm pyridine 3 in 400 cm' anhydrous methylene chloride. The reaction mixture is shaken for a quart-r of an hour then the solution obtained is refrigerated to -15°C whereupon 4,3 g of the product 3 obtained in the preceding stage, dissolved in 10 cm methylene 10 chloride, are added. After one and a half hours, 50 g celite and 100 cm ether are added and the mixture is filtered, washed with ether and tha solvent, evaporated at 30°C.

E5 O-l i) Methyl (5 RS)(I'E)-2-methoxy-5-(3'-oxo-dec-1*enyD-cyclopent-i-ene-carboxylate A solution of 9.674 g dimethyl (2-oxo-nonyl)3 phosphonate in 20 cm glyme is introduced over 10 minutes into a suspension of 1.85 g 50% sodium hydride in oil. After coagulation, 5 g of the aldehyde prepared in stage H in solution in 30 cm of glyme are added over 20 minutes. The reaction is completed after 20 minutes. The reaction mixture is then poured into a saturated solution of monosodium phosphate and extracted with ethyl acetate. 13.2 g of an oil are obtained xvhich are purified by silica chromatography with cyclohexane: ethyl acetate (60:40) and 17. triethylamine as eluant. 4.652 g of pure oil are thus obtained. R^ = 0.25. Infra-red spectrum 3-0=0 : max 1651 cm-~ >=C,E)-2-methoxy-5-(3l-hydroxy-clecl*-enyl)-cyclopent-l-ane-carboxylate and methyl (5RS, 3'RS)(1' E)-2-methoxy- 5- ( 3' -hydroxy-dec-111 -enyl)-cyclopent-l-eneearboxylate A solution of 4.6 g of the ketone obtained in stage i in 100 cm glyme distilled over sodium is cooled .to 0°C and 200 cm of a solution of 0.13M zinc borohydride in glyme are added over 45 minutes. The reaction mixture is allowed to return to ambient temperature and shaking is effected for 4 hours. The reaction mixture is poured into a saturated solution of monosodium phosphate and extracted with ethyl 4St%4 acetate. After treatment, 7.3 g of an oil are obtained.

Two successive chromatographic separations on silica are carried out, eluting with a mixture of benzene: ethyl acetate (60:40) and 1% triethylamine. There are obtained 901 mg of the a isomer (3*SR)‘, 810 mg of the β isomer (3’RS) and 503 mg of the mixture. k) (IRS. 2SR. 5 RS. 3'5R) (1'E)-2-hydroxy-5-(3’-hydroxydec-1 *-envl)~cyc.l.vpentane-carboxylic acid a) hydrolysis of the enol ether A solution of 8.49 mg of the 3’SR isomer prepared in 3 stage j in 3 em methanol and 2 cm 0,. IN hydrochloric acid • are shaken for 15 hours at ambient temperature. The reaction mixture is neutralised with 2 cm^ 0.1N sodium hydroxide and the aqueous phase extracted with ether, 763 mg of a pure oil are obtained after chromatography. = 0.32 (benzene: ethyl acetate, 60:40). β) reduction of the ketone The 763 mg of the preceding product in solution are added to 3 cm tetrahydrofuran and 5.14 cm of a molar solution of lithium tri-sen,-butyl-borohydride in tetrahydrofuran maintained at -60°C. · The reaction mixture is shaken for 2% hours at this temperature then hydrolysed by pouring into a saturated solution of monosodium phosphate following which the reaction mixture is extracted with ethyl acetate. 1,7 g crude oil are obtained, R^ = 0,25 (cyclohexane: ethyl acetate, 40:60) y) saponification The oil obtained above is shaken for 2 hours in the presence of 3 cm^ ethanol and 2.4 cf N sodium hydroxide. The ethanol is removed and the reaction mixture extracted with ethyl acetate. The aqueous phase is acidified to pH5 with monosodium phosphate and extracted with ethyl acetate. The organic phases are washed with water then dried. After removal of the solvent under reduced pressure, 365 mg pure colourless oil are obtained by chromatography. S„ - between 0.1 and 0.36 (ethyl acetate) (CDCl,,60 MHz) pj (b) ; two doublets centered on 2.4 and 2.59 ppm (J=5Hz) (c) : 4.06 ppm (d) s 4.5 ppm Example 16 iroxy-5-(3 * -q-hydroxy15 a-carboxylic acid lactone Working in a manner analagous to that described in Example 1 but replacing the triethylamine by diazabicyclooctane, there is obtained (1 RS, 2 SR, 5 SS, 3' SS) (l'E)2-hydroxy 5- (35 - a-tetrahydropyranyl oxy-oct-11 -eny 1) cyclopentane-carboxylic acid lactone which is.treated as in Example 2 in order to obtain the desired product.

Claims

1. CLAIMS « u 1 2 j 1, Compounds of general formula I, wherein 5 A and B each represents a hydrogen atom or together represent a carbon-carbon bond; p is 0 tr 2; and ’ R represents a cr.cgen atom or an aliphatic hydrocarbyl radica.·. containing from 1 to 4 carbon atoms; 10 Rj represents & radical cf formula -OR* [in which R* represents a hydrogen atom, a tetrahydropyranyl radical, an alkyl radical containing from 1 to 3 carbon atoms or a radical of formula -COR (in which R' represents an alkyl radical containing frcm 1 to 3 carbon atoms optionally 15 substituted by a carboxylic acid group or represents a phenyl radical optionally substituted by a carboxylic acid group, a hydroxyl radical or a protected hydroxyl radical)]; and Rg represents a radical of formula -(CHg^-CH^ (in Λ V> which m is 3, 4, 5 or 6) ; or R and R^ together form an oxo group, Rg being as defined above or and Rg together form a radical of formula (CHgj^-CHg (in which n is

2. , 3, 4 or 5), R being as defined above. 5 2. Compounds as claimed in claim 1 wherein R^ represents a radical of formula -O-COR in which R represents a phenyl radical substituted by an acyloxy radical containing from 2 to 4 carbon atoms.

3. Compounds as claimed in claim 1 wherein A and B 10 together represent a carbon-carbon bond; R represents a hydrogen atom or an unsaturated aliphatic hydrocarbyl radical containing 2 or 3 carbon atoms; and either R^ represents a radical of formula -OR’ [in which R’ represents a hydrogen atom, a tetrahydropyranyl radical or a radical ’ of formula -COR (in which R” represents a phenyl radical substituted by a carboxylic acid group)] and Rg represents a radical of formula -(CHg^-CHg (in which m is 3,

4. Or 5) or R, and Rg together represent a radical of formula (CHg^-CHg (in which n is 2, 3 or 4). 20 4. Compounds as claimed in claim 3 wherein p is 0; R^ represents a radical of formula OR’ (in which R’ represents a hydrogen atom); and Rg represents a radical of formula -(CHg^-CHg (in which m is 4). i

5. (1RS,2SR,5RS,3'SR) (l'E)-2-hydroxy-5-(3'-ahydroxy-oct-l'-enyl)-cyclopentanc-carboxylic acid lactone.

6. (1RS,2SR,5RS,3’SR) (l'E)-2-hydroxy-5-(3'-hydroxydec-1 ’-enyl )-cyclopentane-carboxylic acid lactone.

7. (1RS,2SR,5RS,3’SR) (l’E)-2-hydroxy-5-[3'-(2hydroxybenzoyl*;xy)«oct-l'-enylJ-cyclopentane-carboxylic acid lactone.

8. Compounds as claimed in claim 1 in the form of a single Isomer.

9. Compound* of general forruia I as defined in claim 1 wherein R represents a hydrogen atom or an aliphatic hydrocarbyl radical containing from 1 to 4 carbon atoms; R, represents a radical of formula -Oi* [in which R’ represents a hydrogen atom, a tetrafcyaropyranyi radical, an alkyl radical containing rrom 1 tc 3 carbon atoms or a radical of formula -COR” (in which 8 represents an alkyl radical containing from 1 to 3 carbon atoms or a phonyl radical optionally substituted by a carboxylic acid group)· and Rg represents a radical of formula -(Chg^-CHg (in which m is 3, 4 or 5); or R and Rj together form an oxo group, being as defined above; or Rg and Sj together form a radical of formula (CHg) -CH^ (in which n is 2, 3 or 4), R being as defined above. «Ό Λ·

10. Compounds as claimed in claim 1, other than those claimed in any of claims 5 to 7 as herein specifically disclosed in any of Examples 1 to Ifi.

11. Compounds as claimed in claim 9, other than those 5 claimed in claim 5 or claim 6. as herein specifically disclosed in any of Examples 1 to 8.

12. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula II, (wherein A, B, p, R, Rj and Rg are as defined in claim 1) with tn acid activating agent whereby the desired compound of formula I is obtained.

13. A process as claimed in claim 12 wherein the ]5 acid activating agent is a mixed anhydride-forming agent.

14. A process as claimed in claim 13 wherein the acid activating agent comprises tosyl chloride or an alkyl chloroformate.

15. A process as claimed in claim 14 wherein the ίί212·1 acid activating agent comprises isobutyl chloroformate.

16. A process as claimed in claim 12 wherein the acid activating agent is a dialkylcarbodiimide or a dicycloalkylcarbodiimide. 5

17. A process as claimed in claim 16 wherein the acid activating comprises dicyclohexylcarbodiimide.

18. A process as claimed in claim 12 wherein the acid activating agent is an acid chloride-forming agent.

19. A process as claimed in claim 13 wherein the •jq acid activating agsnt comprises thionyl chloride.

20. A process es claimed in any of claims 12 to 19 wherein the reaction is effected in the presence of a base.

21. A process as claimed in claim 20 wherein the base comprises an alkali metal carbonate, a trialkylamine, 15 methylmerpholine or pyridine.

22. A process as claimed in claim 21 wherein the base comprises triethylamine.

23. A process as claimed in claim 20 wherein the base comprises diazabicycloectane. 20

24. A process for the preparation of compounds of general formula 1 as defined in claim 1 wherein R^ represents a radical of formula -OR' (in which R’ represents a hydrogen atom) which comprises hydrolysing a compound of formula I as defined in claim 1 [wherein R^ represents a Λ* 4 radical of formula -OR* (in which R' represents a tetrahydropyranyl radical)] whereby the desired compound of formula I is obtained.

25. A process as claimed in claim 24 wherein hydrolysis 5 is effected by means of an acid.

26. A process as claimed in claim 25 wherein the acid comprises acetic, aqueous hydrochloric, sulfuric or trifluoroacetic acid.

27. A process as claimed in any of claims 12 .to 22 and

10. 24 to 26 for the preparation of compounds of general formula Σ as defined in claim 9.

28. A process for the preparation of compounds of general formula I as defined In claim 12 or claim 24 substantially as herein described.

11. 15 29. A process for the preparation of compounds of general formula I a& defined in claim 12 or claim 24 substantially as herein described in 'any of Examples 1 to 16.

30. Compounds of general formula I as defined in claim 1 whenever prepared by a process as claimed in any of

12. 20 claims 12 to 26, 28 and 29.

31. A process for the preparation of compounds of general formula Ί as defined in claim 9 substantially as herein described in any of Examples 1 to 8. -,3124

32. Compounds of general formula I as defined in ciaim 9 whenever prepared by a process as claimed in claim 27 or claim 31.

33. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula I as defined in claim 1 in association with 5 a pharmaceutical carrier or excipient.

34. Compositions as claimed in claim 33 in a form suitable for oral, rectal or parenteral administration.

35. Compositions as claimed in claim 33 cr claim 34 in the form of tablets, coated tablets, capsules, granules, suppositories and solutions. 10 35.

Compositions as claimed in any of claims 33 to 35 in the form of dosage units.

37. Compositions as claimed in any of claims 33 to 36 wherein the active ingredient comprises a compound as claimed in claim 5.

38. Compositions as claimed in any of claims 33 to 36 wherein the 15 active ingredient comprises a compound as claimed in claim 6.

39. Compositions as claimed in any of claims 33 to 36 wherein the active ingredient comprises a compound as claimed in claim 7.

40. Compositions as claimed in claim 33 wherein the active ingredient comprises a compound as claimed in claim 9. 20

41. Pharmaceutical compositions as claimed in claim 33 substantially as herein described.