SE436877B - SET TO PREPARE LACTON DERIVATIVES OF CYCLOPENTANOL - Google Patents

Description

When A represents a single bond, the bond between the pentane ring and the oxygen atom is an α bond.

The invention relates in particular to a process for the preparation of novel lactone derivatives of cyclopentanol of the general formula I, in which the dashed line denotes a possible presence of a second bond, A denotes a single bond or a group - (CH2) 2 R represents a hydrogen atom or an unsaturated alkyl group having 2 to 4 carbon atoms, R1 represents a group OR ', wherein R' represents a hydrogen atom, a tetrahydropyranyl group, an acetyl group, a hemipthaloyl group or R and R1 together form a keto group, R 2 represents a group - (CH 2) m -CH 3, where m is an integer 3, 4 or 5, or R 1 and R 2 together form a group 4% \\ * (CH 2) n -CH 3, where n is an integer 2, 3 or 4, and the wave lines indicate that the bonds may exist in one or the other of the possible configurations, provided that when A represents a single bond, the bond between the pentane ring and the oxygen atom is an α bond. The substituent R may in particular represent a hydrogen atom, a vinyl, propenyl, butenyl, ethynyl or propargyl group.

The invention relates in particular to a process for the preparation of compounds of the general formula I, in which the dashed line indicates the presence of a second bond, A denotes a single bond or a group - (CH 2) 2 -, R denotes a hydrogen atom or an unsaturated alkyl group having 2 or 3 carbon atoms, R 1 represents a group OR ', where R' represents a hydrogen atom, a tetrahydropyranyl group, a hemipthaloyl group, R 2 represents a group - (CH 2) m -CH 3, where m is an integer 3, 4 or 5, or R1 and R2 together form a group f4% \\ ~ - (CH2) n-CH3, where n represents an integer 2, 3 or 4.

The invention relates in particular to a process for the preparation of compounds of the general formula I, in which the dashed line indicates the presence of a double bond, A represents a single bond, R represents a hydrogen atom or an unsaturated alkyl group having 2 or 3 carbon atoms , R 1 represents a group OR ', where R' represents a hydrogen atom, R 2 represents a group (CH 2) m -CH 3, where m represents an integer 4.

Among the compounds of the general formula I, mention may be made in particular of the compounds described in the following examples and in particular (1RS, 2SR, SRS, 3'SR) (1'E) -2-hydroxy-5- ( 3'-hydroxy--1'-octenyl) -cyclopentanecarboxylic acid lactone and (1RS, 2SR, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3'-hydroxy-1'-decenyl) -cyclopropanecarboxylic acid lacquer - tOn. The compounds of formula I according to the invention can be prepared by a) allowing a reactant to form functional acid derivatives to act on a compound of formula II II in which A, R, R 1 and R 2 represent the same as above or b) after preparing a compound of formula I according to a), wherein R 1 represents a tetrahydropyranyloxy group and R 2 represents a group (CH 2) m -CH 3 optionally exposing the compound to an acid hydrolyzing agent for the preparation of compounds of formula I , wherein R 1 represents a hydroxyl group.

The functional derivatives thus obtained are then reacted with the hydroxy group to form the lactone ring to give a compound of formula I.

In a preferred embodiment of the above method, the reactant for the formation of functional acid derivatives, with which the compound of formula II is reacted, is tosyl chloride to form a functional derivative which is a mixed anhydride.

It is preferred to work in the presence of triethylamine, but it is also possible to use another base, for example an alkali metal carbonate or an organic base, e.g. methylmorpholine, pyridine or trialkylamine.

You can also work in the presence of diazabicyclooctane.

One can also subject the compound of formula II to the action of other reactants to form mixed anhydrides.

Mention may be made, for example, of isobutyl chloroformate or other alkyl chloroformate. In this case, work in the presence of a basic agent, selected from the above groups. ? vo29oa-o Other reactants can also be used, e.g. dialkylcarbodiimides or dicycloalkylcarbodiimides, e.g. dicyclohexylcarbodiimide.

Finally, reactants can be used to form acid chlorides, e.g. thionyl chloride, in the presence of a basic agent, selected from the above group. The invention thus relates in particular to a process for the preparation of compounds of formula I, according to the process described above, which is characterized in that the reactant for the formation of functional acid derivatives is selected from the group of tosyl chloride, alkyl chloroformate, dicycloalkylcarbodiimides, dialkylcarbyl chloride and that the base optionally used is selected from the group consisting of alkali metal carbonate, triethylamine, methylmorphine, pyrimain and aiazabicyclooctane. The invention also relates to a process for preparing compounds of the general formula IB IB in which the dashed lines and the wavy lines, A and R; represents the same as above and corresponds to a compound of formula I, in which R1 represents a group OR ', where R' represents a hydrogen atom, and R2 represents a group - (CH2) m-CH3, characterized in that an acidic hydrolysing agents act on a compound of formula IA- (CH 2) m'CH 3 a. IA in 7702908-0 in which A, R and m represent the same as above, and correspondingly a compound of formula I, in which R1 represents a group OR ', where R' represents a tetrahydropyranyl group, and R2 represents a group - (cH2 m-cH3. The compounds of general formula IA used as starting compounds in the process can be prepared by the method described above, which consists in reacting a reactant to form functional acid derivatives with a compound of the formula in which A, R and m denotes the same as above.

In a preferred embodiment of the process for the preparation of the compounds of formula IB, the hydrolysis is carried out in the presence of acetic acid.

However, other organic and inorganic acids can be used, e.g. aqueous hydrochloric acid, sulfuric acid and trifluoroacetic acid.

When according to a) there are prepared compounds of the general formula IC (CH2) m-CH3 IC - 'Rn O = Ö in which A and R represent the same as above, R "represents a methyl, o-carboxyphenyl or a carboxyethyl group and m is 3, 4 or 5 and corresponds to a compound of formula I, in which R 1 represents a group OR ', where R' represents an acetyl, hemiftaloyl or hemisuccinyl group, and R 2 represents a group - (CH2) m-CH3, characterized in that with an acid of the formula R "CO2H or with an acid chloride of the formula R" COCl or with an acid anhydride of the formula (R "CO) 2O or with a mixed anhydride a compound of the above formula IB.

In a preferred embodiment of the above process, an anhydride of the formula (R "CO) is used.

However, an acid chloride of the formula R

One then works in the presence of an acceptor for hydrochloric acid, for example * an alkali metal carbonate or bicarbonate or a tertiary organic base, e.g. triethylamine, pyridine or an ocololine.

The invention also relates to a process for the preparation of compounds of the formula I'C (cH2) mA-CH3 - 'IC R ocR' '- cozn oi VilRGIIAOCh R represents the same as above, m is 3, 4, 5 or 6 and R "'represents an ethylene group, corresponding to a compound of formula I, in which R 2 represents a group - (CH 2) m CH 3, where m iver 3, 4, 5 or 6, and R 1 represents OR', where R 'is a hemisuccininyl group, characterized in that an anhydride of the formula (R "'CO) is treated with a compound of the formula I'B 9A yo, m -cH3 ~ IB R OH in the viüqnxde-stna fl æ fi b lines and wä fl injerna, lxochlšbeüa fl ußæ deuämua sumcß and m , 4, 5 or 6,: corresponding to a formula I, in which R 2 represents a group - (CH 2) m -CH 3 «where W is 3: 4f 5 or 5 '°° h R1 be' 7702908-0 represents a hydroxy group.

In a preferred embodiment of the above process, one works in the presence of a tertiary organic base, for example triethylamine, pyridine, dimethylaminopyridine, a picoline or a mixture of these bases.

The compounds of formula I'B can be prepared, for example, by the process described above starting from the corresponding compounds IIa or II with respect to the value of m.

The invention also relates to a process for the preparation of compounds of the general formula ID (cn fi n-cna ID in which A and R represent the same as above and n represents 2, 3 or 4, corresponding to a compound of formula I in which R1 and R 2 together form a group, 4¿š \ (CH 2) n -CH 3, wherein n is 2, 3 or 4, characterized in that a compound of the above formula IA or IB is treated with a dehydrating agent.

In a preferred embodiment of the above process, paratoluenesulfonic acid is used as the dehydrating agent, but other strong aqueous acids can also be used, e.g. conc. sulfuric acid, phosphoric acid and polyphosphoric acid.

The invention likewise relates to a process for the preparation of compounds of the general formula IE (CH2) m-CH3 IE in which A and m represent the same as above, corresponding to a compound of formula I in which R and R1 together form a keto group and R 2 represents a group - (CH 2) m -CH 3, wherein m is 3, 4 or 5, characterized in that an oxidizing agent is treated with a compound of the formula I - B (CH 2) m "CH 3 I IIIB in which A represents the same as above and m represents 3, 4 or 5, corresponding to a compound of formula I, in which R represents a hydrogen atom, RT represents a group OR ', where R" represents a hydrogen atom, and R 2 represents a group - (CH 2) m -CH 3, wherein m is 3, 4 or 5.

In a preferred embodiment of the above process, dichlorodicyanoquinone is used as the oxidizing agent, but silver silicate can also be used. The compounds of formula I 'B used as starting compounds in this process can be prepared from compounds of formula II using the method of the invention.

The invention also relates to processes for the preparation of compounds of formula IF IF in which A and m represent the same as above and m is -§, 4, 5 or 6, and RIV represents an alkyl group having 2-4 carbon atoms with a double bond, and each double bond carbon atom has at least one hydrogen atom, corresponding to a compound of formula I, in which R = RIV, R 1 represents a hydroxy group and R 2 represents a group - (CH 2) m -CH 3, where m is 3, 4, 5 or 6, characterized in that by means of hydrogen in the presence of a catalyst a compound of the formula IE 7702908-0 m 'is reduced in which RIIV represents an alkyl group having 2-4 carbon atoms and has a triple bond, corresponding to a compound with Formula I, in which R = R 1IV, R 1 represents a hydroxy group and R 2 represents a group - (CH 2) m -CH 3, wherein m is 3, 4, 5 or 6.

As the hydrogenation catalyst, palladium-on-barium sulfate is preferably used in the presence of traces of quinoline.

However, palladium-on-calcium carbonate can be used in the presence of lead acetate, palladium-on-carbon black in the presence of pyridine or Raney nickel.

The compounds of formula I'F, which were used as starting compounds in the above process, can be prepared, for example, by the methods described above starting from the corresponding compounds IIA or II, depending on the value of the m-r-wave lines present in most of the foregoing formulas, indicate different possible configurations of the substituents around the carbon atoms to which they are attached.

The components of the mixtures which may be formed by these different compounds can be separated by conventional physical methods, in particular by chromatography.

The compounds of formula I may exist in racemic or optically active forms. The active isomers can be separated by the commonly used methods.

These compounds show a hypotensive effect in pharmacology.

The pharmacological results obtained with the compounds of the invention will be found later in the experimental part.

The pharmacological properties of the compounds prepared by the method of the invention make them suitable for use as medicaments, in particular for the treatment of hypertension and circulatory diseases. Thus, the pharmaceutically acceptable compounds of formula I, as defined above, and in particular the compounds described in the examples, may be used as medicaments.

The pharmaceutically acceptable compounds of formula I can be used for the preparation of pharmaceutical compositions which contain as active substance at least one of these compounds.

The pharmaceutical compositions may be administered buccally, rectally, parenterally and topically.

They may be solids or liquids and be in pharmaceutical forms commonly used in human medicine, for example single or coated tablets, coated pills, granules, suppositories, injectables; They can be prepared by conventional methods. The active substance or substances can be introduced into the compositions together with excipients commonly used in these pharmaceutical compositions, e.g. talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter and aqueous or non-aqueous vehicles. The dose administered may be varied with respect to the disease being treated, the subject being treated, the mode of administration and the compounds concerned. For example, the dose may be between 0.5 and 20 mg of the compounds described in Examples 2 and 15, administered as injection, for example slow-acting perfusion, to humans.

The compounds of formula II, which are used as starting compounds in the process and where A represents a single bond, R1 and R2 can not together form a group 4% \ (CH2) n-CH3 and n is the number 4, can be prepared by that procedure as described in French Pat. No. 2,353,287.

This process is characterized in that either a compound of formula BU d 7702906-0 11 is treated in which R 4 represents an alkyl group having 1-12 carbon atoms and R 5 represents a hydrogen atom or a 2-tetrahydropyranyl group PP1 with an alkali metal hydride under mild conditions for to prepare a compound of the formula C COZRH, which compound is optionally treated a) either with hydrogen in the presence of a catalyst; to prepare a compound of formula D oH in co2Ru D 'ons ¶ b) or with an alkali metal base thereafter with an acid to prepare. a compound of the formula E on "_ COZH» I / E OR5 _ c) or, in the case where R5 represents a hydrogen atom of the formula C, with an oxidizing agent to produce a compound of the formula F OH in coz fi u '} - PO di 7702908-0 12 which is treated with an organometallic derivative of the formula R'2-MgX, wherein fR'2 represents a straight or a branched, saturated or unsaturated alkyl group having 1-H carbon atoms and X represents a halogen atom, to prepare a compound of formula G i or also treat a compound of formula B, in which R 5 represents a hydrogen atom, with diazomethane to produce a w compound of formula h - and which is treated with an oxidizing agent to prepare a compound of formula H 'ECH3 co R 2 u / I o which is treated with an organometallic or organometalloid derivative R'2MgX to produce a compound of the general formula J ocu a 3 coznu Tvozsoe-o 13 f' which is treated with an acid to prepare a compound of the formula K HO R 'which is treated d a mild conditioner to prepare a compound of the above formula G, or with 2,3-dihydropyran to prepare a compound but the formula K '/ i IK' which is treated with a mild conditioner to prepare a compound of the general formula T u H CC R and treating the compounds of formulas D, F, G, L with a base and then with an acid to produce acids included in formula II.

Examples for the preparation of these compounds of formula II are given below in the experimental part.

The compounds of formula II, wherein R 1 and R 2 together form a group 44fk \\ (CH 2) 3 -CH 3 and A represents a single bond, can be prepared by reacting 2,4-dinitrobenzenesulfinyl chloride with the compound of formula B, in which R 5 represents a 2-tetrahydropyranyl group. Q 'vvozsoe-o 14 f _ The compounds of formula II, wherein A represents a group - (CH2) 2, m represents the number 4 or R1 and R2 together represent a group ¿ç9 \\ (CH2) n-CH3 and n represents the number 3, can be prepared from a compound of the formula M - '._ \ / co2R, + with which one can carry out co-reactions such as those described above for the compound of formula B. "," The compound of formula M is prepared by bringing an alkyl acrylate to react with a compound of formula B, in which R 5 represents a 2-tetrahydropyranyl group, followed by an isomerization and then by a decarboxylation. An example of such a preparation is given in the following in the experimental part. The compounds of formula II, in which m represents the numbers 3 or 5 or n represents 2 or 4 can be prepared from compounds of formula B 'in which m' represents the numbers 3 or 5; The preparation methods are identical to those used starting from compounds of formula B. In particular, the compounds of formula II are prepared, in which A represents a group - (CH2 2- of compounds of formula M '' MI 7702908-0 as prepared of compounds of formula B 'according to the scheme given above.

Compounds of formula IIa 'IIa' (IIa, where R6 = ocoR "í, R7 = (CH2) m CH3) RO _53 .. in which R and m represent the same as above, m is 3, 4, 5 or 6 , R "represents an alkyl group having 2 carbon atoms substituted by a carboxyl group, and A represents a single bond, can be prepared as described below starting from a compound of the formula A 'OCH 3 CO 2 alk Of CHO carbon atoms.

The compound A 'itself can be prepared by the procedure described in French Pat. No. 2,332,971.

This process is characterized in reacting a compound of the formula HC CH-CH OH 2 (2) with the dihydropyran to prepare a compound of the formula H2CY-7CÉFCH2 -Ü- (j 0 which is treated with an alkyl acetyl acetate of the formula cH3cocH2c92a1k fvvozsos-o 16, _ in the presence of a strong base, for example a mixture of sodium hydride and butyllithium, to prepare a compound of the formula alkozc oH Û IO 0 O - which compound is treated with an oxidizing agent, for example pyridine chromic acid complex, to a compound of the formula alkozc o Û _ WOO 'O r which is treated with a base, eg potassium bicarbonate, to produce a compound of the formula alkoic CHfOÛ: fi ° O _ which is treated with hydrogen in the presence of a catalyst, eg palladium-on-carbon, to prepare a compound of the formula F, co alk JJ -2 '. 0D o. which is treated with an acid, e.g. ocalic acid, to prepare a compound of the formula 0 Ir, CO 2 alk-OH which is reacted with diazome to prepare a compound of formula 7702908 - 0 f 17 which is treated with an oxidizing agent, e.g., pyridine-chromium oxide complex, to prepare the desired compound of formula A 'AND 3 CO2alk Al CHO To prepare compounds with formula IIa ', the compound A' is brought to the presence in the presence of a strong base, e.g. sodium hydride, to react with dimethyl (2-oxononyl) phosphonate to prepare a compound of the formula AND (g which is treated with a reducing agent, eg zinc borohydride) to prepare a compound of the formula OCH of a mixture of its two components, which are separated into its two components, and wherein the hydroxyl function can be protected with a tetrahydropyranyl group and which is first treated with an acid, eg hydrochloric acid, and then with a reducing agent, e.g. L-selectride, and finally with a base, eg sodium hydroxide, optionally followed by an acidic treatment, for example with sodium monophosphate, to prepare a compound of formula B1 in which R3 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms Thus, the compounds of formula B2 (CH) ~, B 2 mACH3 are finally obtained in which mA denotes the same as above, by applying procedures analogous to those leading to compounds of formulas 31 and E. The compounds IIa ', where A represents a single bond, are then prepared by reacting compounds B2 either with an anhydride of the formula Ü O: / \: O \ Rnll or with an acid or a functional acid derivative of the formula Q, coz fl in R "O c followed by a possible hydrolysis under conditions identical to those given for the preparation of the compounds I'C and IG of compounds I'B. In the compounds of formula IIa '; where A represents a group _ (CH2) 2-, is prepared by reacting compounds B'2 OH 1- cozku ^ \\ /, / B '2 (cn2) mAcH3 _' on 7702903-o 19 with the same reactants as in the previous.

Finally, the compounds of formula II, which do not have a double bond, are prepared by hydrogenating the corresponding compounds which have a double bond.

The compounds of formula II, wherein m is 6 or wherein n is 5, can be prepared in the same manner as indicated above for the corresponding compounds of formula II, but by using as compound starting compound the compound of formula B as described above , or compounds of formula B'2, where m is the number 6, i.e. compounds of the formula OH COZR4 f '\ / OH The preparation procedures can be summarized as follows.

One can: either treat the compounds -B1 or B'2 with hydrogen in the presence of a catalyst to prepare compounds which do not have a double bond or treat the same compounds with an oxidizing agent to selectively oxidize allyl alcohol, thereby obtaining compounds, in wherein R and R 1 represent a keto group, then the compounds thus obtained are treated with an organometallic derivative to prepare compounds in which R represents an alkyl group, or treat compounds of formula B1 or B'2, wherein the ally hydroxyl function is protected with a tetrahydropyranyl group, by means of 2,4-dinitrobenzenesulfinyl chloride to produce compounds in which R1 and R2 represent a group «4'ß \\ (CH2) 5CH3-.

The acids corresponding to the esters prepared from the ester prepared in step A, 50 cm 3, are prepared by pre-digestion according to customary procedures. The following examples illustrate the invention without limiting it. Example 1 - (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'a-tetrahydropyranyloxy-1 ' -octenyl) cyclopentanecarboxylic acid lactone "A mixture of son mg (1 Rs, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'a) is added in about 2 hours at 20 ° C. -tetrahydropyranyloxy-1'-octenyl) cyclopentanecarboxylic acid, 12 cm 3 of anhydrous chloroform, 1 cm 3 of triethylamine and 402 mg of tosyl chloride. You then pour the mixture into one. solution of sodium hydrogen phosphate, decant, extract with methylene chloride and evaporate in vacuo to dryness. 700 mg of a product are obtained which are chromatographed on silica gel with a mixture of cyclohexane-ethyl acetate-triethylamine (75: 25: 0.1). 336 mg of the desired ß-lactone are obtained.- _ _ - - i. (1 RS, 2 SR, 5 RS, 5 'SR) G' E) -2-hydroxy-5- (3'a-tetrahydropyranyloxy-1'-octenyl) pentanecarboxylic acid, which was used as the starting compound in Example 1 , has been prepared as follows. "Step A: ethyl- (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'o-tetrahydropyranyloxy 1'- octenyl) cyclopentanecarboxylate A mixture of 14 g of ethyl 3- (3'-tetrahydropyranyloxy-trans-1'-octenyl) -2-cyclopentanone carboxylate, 200 cm 3 of isopropyl alcohol, 20 cm 3 of water and 5.6 g is stirred for 2 hours. sodium borohydride.

Then slowly add acetone to the mixture and pour it into a saturated aqueous solution of sodium monophosphate. Filter, evaporate the filtrate to dryness and take up the residue in ethyl acetate. Wash with water and dry, then evaporate the solvent.

Chromatograph the residue on silica eluting with a mixture of cyclohexane and ethyl acetate (8: 2) with 0.1% triethylamine to give 3.4 g of the desired α-OH (2 SR) -isomer.f W Step B : (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'a-tetrahydropyranyloxy-1'-octenyl) cyclopentanecarboxylic acid Stir for 3 hours at 20 ° C a mixture of 3.1 g of methanol and 8.15 cm3 of 2-normal sodium hydroxide solution. The solvents are then evaporated off at 35 DEG-3 DEG C., the residue is taken up in water, washed with ether, saturated with sodium chloride solution and then acidified with hydrochloric acid. Extract with ether, wash with water, dry and evaporate the solvent. 2.6 g of the desired compound are obtained. 7702908-0 21 Example Gel 2 (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-hydroxy-1'-octenyl) -cyclopentanecarboxylic acid lactone Dissolves 336 mg of the β-lactone prepared in Example 1 in 10 volumes of acetic acid with 20% water in the presence of 5 mg of sodium iodide.

The mixture is allowed to stand for 16 hours at 20 ° C, poured into water, extracted with methylene chloride, washed with sodium bisulfite and dried to give 280 mg of a product which is chromatographed on silica gel with a mixture of cyclohexane and ethyl acetate (75: 25). 160 mg of the desired compound are obtained. Exemgel 3 V (1 RS, 2 SR, 5 RS, 3 'SR) (1' B) -2-Hydroxy-5- (3'a-hemipthaloyloxy-1'-octenyl) cyclopentanecarboxylic acid lactone A mixture of 160 mg β-lactone prepared in exenmel 2, 1.6 cm3 py fi din and 200 mg phthalic anhydride stand 9 hours at room temperature. The mixture is then poured into ice-cold normal hydrochloric acid, extracted with ether, washed, the organic phases are extracted with 10% strength hydrogen carbonate solution, the ether phases are dried and evaporated to dryness in vacuo. The alkaline aqueous phases are acidified with normal hydrochloric acid. Extract with ether and evaporate in vacuo to dryness. He chromatographed the acidic fraction on silica gel with a mixture of cyclohexane and ethyl acetate (1: 1). 172 mg of the desired compound are obtained in the form of a colorless resin which crystallizes.

IR spectrum J) C = 0: 1828 cm-1 g 7 1811 cm-1) β-lactone 1725 cm-1) 1708 cm-1) ester + acid aromatic: 1603 cm-1 1583 if * 1491 cm-1 Exemgel H (1 RS, 2 SR, RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-hydroxy-3'-ethynyl-1'-octenyl) cyclopentanecarboxylic acid lactone A mixture of 530 mg (1 RS, 2 SR .5 RS, 3 'SR) <1' E) -2,3L Dihydroxy-5- (3'-ethynyl-1'-octenyl) cyclopentanecarboxylic acid, .3 cm3 chloroform, 0.78 cm3 triethylamine and 450 mg tosyl chloride for 30 minutes at 5 ° C, after which the temperature of the mixture is allowed to rise to ° C. The mixture is allowed to stand for 1 hour, after which it is poured into water added with sodium hydrogen phosphate, washed with water and extracted with methylene chloride. The extract is dried, chromatographed on silica gel with benzene-ethyl acetate (80:20) to give 106 mg of the desired compound. Rf = 0.4. Exemgel 5 U ii (1 RS, 2 SR, 5 RS, 3 'RS) (1' E) -2-hydroxy-5- (Sf-hydroxy-3'-ethynyl-1'-octenyl) cyclopentanecarboxylic acid lactone. about a mixture of 720 mg (1 RS, 2 SR, 5 RS, 3 'RS) (1' E) -2-hydroxy-5- (3'-hydroxy-3'-ethynyl-1'-octenyl) cyclopentanecarbon acid, 7.2 cm 3 of clone form, 1.44 cm 3 of triethylamine and 586 mg of tosyl chloride at 20 ° C under nitrogen. The mixture is poured into a mixture of water and sodium hydrogen phosphate. It is washed with water, extracted with methylene chloride, dried and evaporated to dryness to give about 1 g of product which is chromatographed on silica gel with a mixture of benzene and ethyl acetate (80:20). 128 mg of the desired compound are obtained.

Rf = 0.4. (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-hydroxy-3'-ethynyl-1'-octenyl) cyclopentanecarboxylic acid, which was used as starting compound of Example H, and (1 RS, 2 SR, 5 RS, 3 'RS) (1' E) -2-hydroxy-5- (3'-hydroxy-3'-ethynyl-1'-octenyl) Cyclopentanecarboxylic acid, which was used as a starting compound in Example 5, has been prepared in the following manner.

Step A: Ethyl (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-hydroxy-1'-octenyl) cyclopentanecarboxylate II 572 mg of ethyl 3- (3'a-hydroxy-trans-1'-octenyl) -2-cyclopentanone carboxylate, 23 cm 3 of ethanol, 2.3 cm 3 of water and 85 mg of sodium borohydride, stir the mixture for 2 hours at 5 ° C, add dropwise acetone and pour then the mixture in a saturated solution of monosodium phosphate. M Filter, evaporate the solvent, take up the residue in ethyl acetate, wash with water, dry and evaporate to dryness. 520 mg of a mixture of the 2α-OH and 2β-OH isomers are obtained, which is separated by chromatography on silica and eluting with methylene chloride with 2% methanol. 203 mg of the desired α-isomer are obtained. Step B: Ethyl (1 RS, = 2 SR, 5 RS) (1 'E) -2-hydroxy-5- (3'-oxo-1'-octenyl) -cyclopentanecarboxylate I' 1 g of the compound prepared in step A to cm 3 of dioxane and add 1.6 g of dichlorodicyanoquinone. The mixture is stirred for 20 hours at room temperature. You suck off and rinse 7702908 ~ 0 23 l thereafter. It is washed with ice-cold 10-normal sodium hydroxide solution to a pH value of 9. It is filtered, washed with water and dried, whereby 987 mg of crude product are obtained. It is chromatographed on silica and eluted with cyclohexane-ethyl acetate (1: 1). 930 mg of the desired compound are recovered.

Step C: Ethyl (1RS, 2 SR, 5 RS, 3 'SR and RS) (1' E) -2-hydroxy-5- (3'-hydroxy-3'-ethynyl-1'-octenyl) cyclopentanecarboxylate Man add 2.1 g of the compound prepared in step B to 2.1 cm 3 of tetrahydrofuran. The mixture is heated to 38 ° C and 45 cm3 of a normal solution of magnesium ethynyl bromide in tetrahydrofuran, which has been heated to 40 ° C, are rapidly introduced. Stir for 30 minutes at 38 ° C.

He then pours the mixture into a solution of ammonium chloride in ice-cold water, extracts with methylene chloride, washes with water, dries, filters and evaporates to dryness. Chromatography on silica to elute with a mixture of methylene chloride and ethyl acetate (85:15) gives 1.67 g of the desired compound.

Step D: (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-hydroxy-3'-ethynyl-1'-octenyl) cyclopentanecarboxylic acid and (1 RS , 2 SR, 5 RS, 3 'RS) (1' E) -2-hydroxy-5- (3'-hydroxy-3'-ethynyl-1'-octenyl) cyclopentanecarboxylic acid Stir for 2 hours at 20 ° C under nitrogen a mixture of normal 1.67 g of ester prepared in step C, 17 cm 3 of ethanol and 8.5 cm 3 of sodium hydroxide solution. It is then poured into water, extracted with ether, washed with N / 2 normal sodium hydroxide solution, then with water, dried and filtered to give 0.37 g of a fraction with impurities. The aqueous phases are combined, acidified with monosodium phosphate, extracted with ether, washed with water, dried and evaporated to give 1.33 g of product. The two isomers are separated by chromatography under pressure in isopropyl ether with 4% acetic acid. 530 mg of OHa (3 'SR) isomer are obtained, Rf = 0.15, and 720 mg of OHß (3' RS) isomer, Rf = 0.10.

Example 6 (1 RS, 2 SR, 5 RS) (1 'E, 3' E) -2-hydroxy-5- (1 ', 3'-octadienyl) cyclo-pentanecarboxylic acid lactone 150 mg of β-lactone prepared in Example 2 to 3 cm 3 of benzene and add 15 mg of paratoluenesulfonic acid and heat the mixture under nitrogen at HOOC for 3 hours. The mixture is neutralized with 150 mg of sodium carbonate, filtered and the solvent is evaporated.

139 mg of an oil are obtained which are chromatographed on silica (120 DEG-109 DEG C.) and eluted with cyclohexane-ethyl acetate (95: 5). 36 mg of pure compound are recovered. Rf = 0.25 (cyclohexane-ethyl acetate, 90:10).

IR spectrum (chloroform) 1;> c = 0 1830 cm -1 1816 cm -1 scholará \ a; ^ \ 4v \\ 993 cm -1 IR spectrum in ethanol Inflexion = 227 nm E 1 cm = 1310 cm T Maximum = 232 nm E 1% = 1110 cm'1 i = 31 000 Cm Infexion = 239 nm E 1% = 1onu cm "1 1 cm Example 7 (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-hydroxy-1'-octenyl) -cyclopentanepropionic acid lactone I 'is a mixture of 990-mg (1 Rs, 2 sR, s Rs, 3' sR) '(1' E ) -2-hydroxy-5- (3'-hydroxy-1'-octenyl) cyclopentanepropionic acid, 3 cm 3 anhydrous nitromethane, 0.3 cm 3 pyridine and 300 mg dicyclohexylcarbodiimide 16 hours at 20 ° C. You suck off, wash with ether and dry. 3 The organic phase is poured into water, decanted, extracted with ether, washed with water and evaporated to dryness. The residue is chromatographed on silica in cyclohexane-ethyl acetate (1: 1) to give 173 mg of homogeneous product.

Example gel 8 (1 RS, 2RS, _5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-hydroxy-1'-octenyl) -cyclopentanepropionic acid lactone I, 7, gu - Starting from H05 mg (1 RS, 2 RS, 5 RS, 3 'SR) (1' Ej-2-hydroxy-5- (3'-hydroxy-1'-octenyl) cyclopentanepropionic acid, 3 cm 3 nitromethane, 0.3 cm 3 pyridine and 300 mg of dicyclohexylcarbodiimide and proceed as in Example 7 to give 188 mg of pure compound. (1 RS, 2 SR, 5 RS, 3 'SR) (1' Ef-2-hydroxy-5- (3'-hydroxy) 1'-octenyl) cyclopentanepropionic acid and (1 RS, 2 RS, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-hydroxy-1'-octenyl) cyclopentanepropionic acid used as starting compounds in Examples 7 and 8, respectively, have been prepared as follows. "Step A: Ethyl (5 RS, 3 'SR) (1' E) -1-carboxylate-ethyl-2-oxo-5H (3'-α-tetrahydropyranyloxy) -1'-octenyl) cyclopentane propionate 1.113 g of methyl 3- (3'-α-tetrahydropyranyloxy-trans-1 '-octenyl) -2-cyclopentanone carboxylate are added to a nitrogen atmosphere to 3 cma 7702908-0 pzs [anhydrous ethanol. then add 0.23 cm 3 of a 0.22 normal sodium ylate solution in ethanol and then 303 mg of ethyl acrylate. The mixture is allowed to stand for 2 hours at 2500 and then for 1 hour at reflux. The mixture is cooled to 0 ° C and then poured into an ice-cold solution of monosodium phosphate. Extract with ether, wash with water, dry and evaporate the solvent in vacuo. The product obtained is chromatographed on silica and eluted with a mixture of cyclohexane, ethyl acetate and triethylamine (80: 20: 0.1). 1.13 g of the desired compound are obtained.

Step B: Ethyl (1 RS, 5 RS, 3 'SR) (1' E) -2-oxo-3-carbethoxy-5- (3'a-tetrahydropyranyloxy-1'-octenyl) cyclopentane propionate Add 2 , 1 cm 3 of a 1.02-normal solution of sodium ethylate in ethanol to 0.93 g of the compound prepared in step A. The mixture is heated for 2 hours at reflux, 10 cm3 of toluene are added and the ethanol is distilled off. The mixture is cooled to -20 ° C, precipitated in an ice-cold solution of monosodium phosphate, extracted with ether, washed with the organic phases with water and dried to give 9H0 mg of crude product which is purified on silica and eluted with cyclohexane. ethyl acetate (80:40). The desired pure compound is 680 mg.

Step C: Methyl (1 RS, 5 RS, 3 'SR) (1' E1-2-oxo-5- (3'a4trahydropyranyloxy-1'-octenyl) cyclopentane propionate '1.5 g of it are added to step B prepared the compound to cm 3 of methanol and adding 9.6 cm 3 of normal sodium hydroxide solution.

The mixture is allowed to stand at room temperature, after which it is heated for 12 hours at HOOC. The mixture is evaporated to dryness, the residue is taken up in a mixture of water and ethyl acetate, the mixture is cooled, acidified, extracted with ethyl acetate, washed with water and then evaporated to dryness to give 1.225 g of product, which is dissolved in cma benzene after which the mixture is heated for 1 hour at reflux to give 1.2 g of product which is taken up in methylene chloride with a drop of triethylamine and esterified with diazomethane.

An oil is obtained which is chromatographed on silica and eluted with a mixture of ethyl acetate and cyclohexane (50:50) - 852 mg of the desired compound are obtained. 1 * Step D: methyl (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'a-tetrahydropyranyloxy-1'-octenyl) cyclopentane propionate and methyl - (1 RS, 2 RS, RS, 3 'SR) (1' E) -2-hydroxy-5- (3'a-tetrahydropyranyloxy-1'-octenyl) -cyclopentane propionate 2.165 g of it are added under nitrogen to step C prepared 1vß2soa-Q 26 If the compound to 21 μg methanol. Add 220 mg of sodium borohydride at 0 ° C for 1 hour and stir the mixture for 1 hour. 30 cm 3 of water and 3 g of monosodium phosphate are then added, extracted with methylene chloride, washed with water and dried. 2.01 H g of product are obtained containing the two isomers, which are separated on silica by elution with a mixture of petrol G (boiling between and 70 ° C) and ether (50:50). 329 mg of 2 SR isomer and 1.103 g of 2 RS isomer are obtained. step E: methyl (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-hydroxy-1'-octenyl) cyclopentane propionate 7 A mixture of H58 mg of the 2 SR isomer prepared in step D, 4.6 cm 3 of methanol, 0.6 H6 cm 3 of water and 46 mg of oxalic acid for 4 hours at 40 ° C. If Step F: (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-hydroxy-1'-octenyl) cyclopentanepropionic acid _ '3' SA under nitrogen at 40 ° C 3 cm 3 of normal sodium hydroxide solution in the solution of 2 SR isomers obtained by the method in step E. The mixture is heated for 2 hours at 40 ° C. It is then poured into water containing monosodium phosphate, extracted with ethyl acetate, washed with water, dried, filtered and evaporated to give 390 mg of the desired crude product. 2 step-c; (1 Rs, 2 Rs, s Rs, a 'sRm' In-z-hydroxy-s- (sHhydroxine'-octenyl) cyclopentanepropionic acid å I A mixture of 479 mg of 2 RS isomer prepared in step D, 5 cm 3 methanol, 0.5 cm 3 of water and 50 mg of oxalic acid for 3 hours at HOOC and then add 3 cm 3 of normal sodium hydroxide solution and stir the mixture again for 3 hours at 40 ° C. Acidify with monosodium phosphate, extract with ethyl acetate, wash with water and drying to give HO5 mg of the desired compound; Example 9 4. I (1 RS, 2 SR, 5 RS) (1 'E) -2-hydroxy-5- (3'-oxo-1'-octenyl) cyclopentane Carboxylic acid lactone Under a stream of dry nitrogen, 15 cm3 of dry methylene chloride, 1.5 cm3 of anhydrous pyridine are mixed and 900 mg of chromium oxide are added slowly at cooling (C), the mixture is stirred for 15 minutes and then 358 mg (1 RS, 1) are added rapidly. 2 SR, 5 RS, 3 'SR) (1' E) - 2-hydroxy-5- (3'-α-hydroxy-1'-octenyl) cyclopentanecarboxylic acid lactone (prepared in Example 2) dissolved in 15 cm 3 of methylene chloride. Stir the mixture for 2 hours at 2 0 ° C and then add 4 g of Celite and 15 cm 3 of methylene chloride. It is filtered, the filtrate is evaporated in vacuo, the pyridine is removed by means of a stream of nitrogen, 375 mg of a brown oil are obtained. It is chromatographed on silica eluting with a mixture of cyclohexane and ethyl acetate (6: H). 329 mg of the desired compound are obtained. Rf = 0.45.

IR spectrum _> c = oß + 1akrøn 1a2s cm'1 conjugated system 44r \ jf ", 1696 cm_1 O 1674 cm_1 1eso cm" 1 Example 1Q (1 RS, 2 SR, 5 RS, 3 'SR) -2-hydroxy -5- (3'-hydroxy-octanyl) cyclopentanecarboxylic acid lactone 105 mg (1 RS, 2 SR, s Rs, 3 'sR) <1' E) -2-pydroxy-5- <3 'are placed in a hydrogenation apparatus. α-hydroxy-1'-octenyl] cycloperenran4l 3 ethyl acetate, carbonic acid lactone (prepared in Example 2) dissolved in 10 cm He adds 20 mg of 5% palladium on carbon, hydrogenates for 7 hours with an adsorption of 10, H cm 3 of hydrogen The catalyst is filtered off with suction, the filtrate is evaporated in vacuo and the remaining oil is chromatographed on silica, eluting with a mixture of cyanohexane and ethyl acetate (50:50).

The desired compound of 97 mg is obtained. Rf_ = 0.35.

IR spectrum C = 0 1800 cm-1 absence of C = C trans on ssoo em'1 (1 RS, 2 SR, 5 RS, 3 'RS) (1' E) -2-hydroxy-5- (3 ' hydroxy (3'-ethenyl-1'-octenyl) cyclopentanecarboxylic acid lactone - Saturate with hydrogen at atmospheric pressure H5 mg U, 75% palladium-on-barium sulphate in 5 cm 3 of ethyl acetate. 150 mg of (1RS, 2 SR, RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-hydroxy-3'-ethynyl-1'-octenyl) cyclopentanecarboxylic acid lactone (prepared in Example H), 10 mg quinoline and 1 cm 3 ethyl acetate. It is hydrogenated at 21 ° C. 14.3 cm 3 of hydrogen have been adsorbed after 30 minutes. The catalyst is filtered off, the solution is washed with 0.1% normal hydrochloric acid and then with brine. The organic phase is dried and evaporated to give 153 mg of crude product. The product is purified by chromatography on silica with a mixture of benzene and ethyl acetate (80:20) and then by preparative layer chromatography with the same eluent. 110 mg of pure compound are obtained. Rf = 0.41.

The IR spectrum shows the absence of CECH and the presence of β-lactone and of the groups ethenyl and hydroxyl, vvozsoa-o 28 NMR spectrum (CDCl 3 BOMH ) = 3.1 ppm (triple: J = s Hz) '(d): doublet 3.8.ppm J = -4 Hz (e): 5.16 to 6.2 ppm (f): 5 ppm (triplet J = 3 Hz) Example 12 (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-hydroxy-3'-ethenyl-1'-octenyl) cyclopentanecarboxylic acid lactone The procedure is exactly the same as Example 11 starting from 150 mg (1 RS, 2 SR, 5 RS, 3 'RS) (1' E) -2-hydroxy-5- (3 '~ hydroxy- 3'-ethynyl-1'-octenyl) cyclopentanecarboxylic acid lactone (prepared in Example 5).

127 mg of pure compound are obtained. The IR spectrum shows the absence of CEC and the presence of β-lactone and of the groups ethenyl and hydroxyl. NHR spectrum (CDCl 3, 60 MHz) (g) H 2; Sy 2 O 3 H (d) H (f); CH3 (a) (C) ~ § '_ (fm Ho \ (b) \ cH = cH (e) (eg (a): 0.88 ppm (b): 1.51 ppm (0): 3.1 ppm (d): doublet 3.8 ppm J = H Hz (e): 5.16 to 5.61 ppm (f): 5.16 to 8.2 ppm (3): 5 ppm (triplet) 7702903-o [Example 1§ <1 Rs, 2 SR, 5 Rs, 3'sR) (1 * B) -2-hydroxy-5- (3'-acetoxy-1'-octenyl) cyclopentanecarboxylic acid lactone Stirring at room temperature for 2 hours a mixture of 0.2 g (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-α-hydroxy-1'-octenyl) cyclopentanecarboxylic acid lactone (prepared in Example 2), 2 cm 3 of methylene chloride, 0.07 cm 3 of triethylamine and 0.091 cm 3 of acetic anhydride and a few grains of dimethylaminopyridine, 3 cm 3 of water are added, acidified to a pH of 5 with monosodium phosphate and extracted with methylene chloride. evaporate in vacuo to dryness to give 266 mg of a crude oil which is purified by chromatography on silica eluting with a mixture of cyclohexane and ethyl acetate (60:40) to give 211 mg of a pure compound. 5.

IR εSectrum> c = o complex 1808 to 1s2u cm -1 1 ester 1725 cm -1 NMR spectrum (60 MHz CDCl 3 / e) CH 3 (a) (a): 0.88 ppm (b): 2.03 ppm 1 (c): triplet centered at .33.08 ppm J = 5 Hz (d): doublet centered «, at δ 3.78 ppm J = 3.5 Hz (e): triplet centered at δ 5.01 ppm J = 5 Hz (f): 5.15 ppm Exemgel 14 (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (1'-octenyl-3'-hydroxy) cyclopentanecarboxylic acid lactis hemisuccinate 119 mg (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3'-α-hydroxy-1'-octenyl) cyclopentanecarboxylic acid lactone (prepared) in Example 2), 2 cm3 of anhydrous methylene chloride, 100 mg of succinic anhydride, 0.15 cm3 of pure triethylamine and 15 mg of H-dimethylaminopyridine, in which case the mixture is heated at reflux for 8 hours and the solvent is then evaporated to 2 cm3. ethanol and leave the mixture to stand for 1 hour at room temperature. The excess succinic anhydride in the form of ethyl hemisuccinate is removed. Evaporate in vacuo to give is 226 mg of crude product. This is chromatographed on silica with pure ethyl acetate, isolating 132 mg of pure product. Rf = 0.3. , NHR spectrum (CDCl 3 60 MHz) 0 (G) H ,,} k> ø * I I. 1H (°) H É (a> § HH - ° '§ H on ° e cb) (a): 0 , 88 ppm (b): 2.63 ppm (c): 3.08 ppm (d): 5.2 ppm (e): 5.0H ppm (f): 5.33 to 5.58 ppm Example 15 ( 1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5f (3'-hydroxy-1'-decenyl) cyclopentanecarboxylic acid alkaton - 0.15 g <1 Rs; 2 sR, s Rs, 3 'sR) (1' z) -2-hydroxy- (3'-hydroxy-1'-decenyl) cyclopentanecarboxylic acid to 4 cm 3 of chloroform, 0.315 g of triethylenediamine and 0.16 g of tosyl chloride. The reaction is instantaneous. The mixture is poured into water and extracted with ethyl acetate.

After working up, 183 mg of an oil are obtained, which are chromatographed on silica and eluted with a mixture of cyclohexane and ethyl acetate (60:40). 41 mg of pure compound are obtained. hf = 0.25.

IR spectrum> C = O complex 1808 vid182ü cmq; > C = C <973 cmq 7702908-0 31 NMR spectrum (CDCl 3 - 60 MHz) CH 3 (a) (a): 0.88 ppm (b): 1.3 ppm (c): 1.53 ppm (d ): 3.08 ppm (e): 3.78 ppm (doublet J (f): 4.05 ppm, (g): 5.47 ppm (doublet J = 5 Hz) (h): 5.01 ppm ( triplet) (1RS, 2 SR, 5 RS, 3 'SR) (1' E) 2-hydroxy-5- (3'-hydroxy-1'-decenyl) cyclopentanecarboxylic acid, which was used as a starting compound in Example 15, has been prepared a) 1,2-Epoxy-3-α-tetrahydropyranyloxypropane A solution of 3.9 g of glycidol (2,3-epoxy-1-propanol), 18.5 cms of dihydropyran and 150 mg p-toluenesulfonic acid.

After 30 minutes, an additional 150 mg of p-toluenesulfonic acid is added and then, after 15 minutes, the mixture is neutralized at room temperature by means of potassium carbonate. Filter, wash with ethyl acetate and remove the solvents in vacuo to give 8, H8 g (4 Hz) of the desired compound. R f = 0.6 (cyclohexane-ethyl acetate, 8: 2). b) Methyl 3-keto-6-hydroxy-7α-tetrahydropyranyloxyheptanoate A solution containing 8 cm 3 of methyl acetylacetate and 13 cm 3 of anhydrous tetrahydrofuran is added for 30 minutes to a suspension, maintained at 0 ° C, of 3,554 g of sodium hydride as 50 -% - suspension in oil in 16 cm3 of anhydrous tetrahydrofuran. 39 cm of butyllithium are added to the mixture for 30 minutes at 0 DEG C. The mixture is stirred for 1/2 hour, after which it is kept at -70 ° C. This solution is introduced for 45 minutes into a solution at 0 ° C containing 5.8 g of 1,2-epoxy-3a-tetrahydropyranyloxypropane, prepared in steps a), and 16 cm 3 of tetrahydrofuran. Stir the mixture for 3 1/2 hours. It is then poured into an excess of a concentrated and ice-cold solution of monosodium phosphate. The mixture is stirred for 10 minutes, then extracted with ethyl acetate and the extract is washed until neutral, 16.9 g of oil being obtained after evaporation of the solvent, which is then purified by chromatography on silica and eluting with cyclohexane-ethyl acetate (6: 4). 8.02 g of pure compound are recovered. Rf = 0.15. c) methyl 3,6-dioxo-7α-tetrahydropyranyloxyheptanoate Slowly introduce 6 g of chromic acid into a solution of 9.7 cm 3 of pyridine in 148 cm 3 of methylene chloride. Stir the mixture for 15 minutes.

1.1 g of the compound prepared in step b) dissolved in 10 cm 3 of methylene chloride are then added. After 15 minutes, 150 cm 3 of ether are added, the precipitate formed is filtered off, washed with ether and removed. evaporates the solvents. 1.3 g of crude product are obtained, which are purified by chromatography on silica / dioxide and eluting with methylene chloride-ethyl acetate (B: 2). H73 mg of pure compound is obtained. Rf = 0.45. d) 7-Methyl 2- (α-tetrahydropyranyloxymethyl) -5-oxo-1-cyclopentene carboxylate A mixture of 291 mg of potassium bicarbonate dissolved in 72 cma dist. water and 220 mg of crude product prepared in step c) dissolved in 2.4 cm 3 of methylene chloride. The mixture is acidified after 1/2 hour to a pH of 3 by means of oxalic acid, after which the mixture is saturated with sodium chloride and extracted with methylene chloride. After evaporation, 205 mg of the desired compound are obtained.) E) Methyl (1RS, 5 SR) -2-oxo-5- (α-tetrahydropyranyloxymethyl) cyclopentanecarboxylate a 2 A solution containing 215 mg of it in step is stirred under a hydrogen atmosphere. d) prepared compound, 10 cm 3 of methanol and 21 mg -% palladium on carbon. The theoretical volume has been adsorbed within 40 minutes. Filter, wash with ethyl acetate and evaporate the solvent to give 172 mg of an oil which is chromatographed on silica and eluted with cyclohexane-ethyl acetate (50:50). I 122 mg of the desired compound are obtained. f) Methyl (1 RS, 5 SR) -2-oxo-5-hydroxymethylcyclopentanecarboxylate A mixture of 43 g of the product prepared in step e) is heated at 60 ° C with stirring for 3 hours, and 860 cm methanol, 86 cm 3 of water and 127 g of oxalic acid. The mixture is evaporated in vacuo at 0 DEG C., the residue is taken up in chloroform, washed with water and dried. The solvent is evaporated to give 29.2 g of crude product, which is chromatographed on silica and eluted with cyclohexane-ethyl acetate (2: 8). 14 g of pure oil are recovered. vvozsoa-o 33 f) methyl- (5 RS) -2; mgt9xy-5-hydroxymethyl-1-cyclopentenecarboxylate A mixture of H of the β-keto ester prepared in step f), 10 cm 3 of methylene chloride, is stirred at room temperature for 4 hours. and 50 cm 3 of diazomethane dissolved in methylene chloride. The solvent and excess diazomethane are evaporated to give 4.3 g of a yellow oil which is used as crude product in the following reaction. h) Methyl (5 RS) -2-methoxy-5-formyl-1-cyclopentene carboxylate 25.5 g of chromium oxide are introduced in small fractions into a solution, kept at 15-20 ° C, of 41 cm 3 of pyridine in H cm3 of anhydrous methylene chloride.

Stir the mixture for 1 / H hour, cool the solution to -1500 and add 4.3 g of the product prepared in the previous step dissolved in cm 3 of methylene chloride. After 1 1/2 hours, add 50 g of Celite and 100 cm 3 of ether, filter, wash with ether and evaporate the solvents at 30 ° C. i) Methyl (5'R) (1'E) -2-methoxy-5- (3'-oxo-1'-decenyl) -1-cyclopentene carboxylate A solution of 9.675 g of dimethyl- (2-oxononyl) phosphonate in 20 cm 3 glyme in a 50% suspension of 1.85 g of sodium hydride in oil. After the mixture has solidified to mass, 5 g of the aldehyde prepared in step h) dissolved in 30 cm 3 of glyme are added over 20 minutes. The reaction is complete after 20 minutes. The mixture is then poured into a saturated solution of monosodium phosphate and extracted with ethyl acetate. 13.2 g of oil are obtained, which is purified by chromatography on silica, eluting with cyclohexane-ethyl acetate (60 DEG C.) and 1% of triethylamine. Thus, H, 652 g of pure oil are obtained. Rf = 0.25.

IR spectrum: C = O max: 1651 cm-2C = C <conjugated 1623 cm-1 j) methyl- (5 RS, 3 'SR) (1'E) -2-methoxy-5- (3'-hydroxy-1'- decenyl) -1-cyclopentene carboxylate and methyl (5 RS, 3 'RS) (1'E) -2-methoxy- (3'-hydroxy-1'-decenyl) -1-cyclopentene carboxylate Cool to 0 ° C 4 6 g of the ketone prepared in step i) dissolved in 100 cms of glyme distilled over sodium, after which 200 cma of a solution of 0.13 mol / liter of zinc borohydride in glyme are added over H5 minutes. The temperature is allowed to rise to room temperature and stirring is continued for hours. The mixture is then poured into a saturated solution of monosodium phosphate and extracted with ethyl acetate.

After reprocessing, 7.3 g of oil are obtained. Two successive chromatographs on silica are performed, eluting with a mixture of hydrogen sulfide and ethyl acetate (60:40) and 1% triethylamine. 901 mg of a (3 'RS) isomer and 810 mg of β (3' RS) isomer and 503 mg of the mixture are obtained. k) (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -Zhydroxy-5- (3'-hydroxy-1'f decenyl) cyclopentanecarboxylic acid1 a) Hydrolysis of the enol ether Stir for 15 hours at room temperature a solution of 8.49 mg of the 3 'SR isomer prepared in step j) in 3 cm 3 of methanol and 2 cm 3 of 0,1-normal hydrochloric acid. It is neutralized by means of 2 cm 3 of 0.1 normal sodium hydroxide solution and the aqueous phase is extracted with ether. 763 mg of an oil are obtained which are purified by chromatography. Rf_ = 0.32 (benzene-ethyl acetate, 80:40). 7 B) reduction of the ketone The above 763 mg is dissolved in 4 cm? tetrahydrofuran to 5.14 cm 3 of a molar solution of L selectride in tetrahydrofuran maintained at -6000. Stir the mixture for 2 1/2 hours at this temperature, then hydrolyze by pouring the mixture into a saturated solution of monosodium phosphate, and then extracting with ethyl acetate. 1.7 g of a crude oil are obtained, Rf = 0.25 (cyclohexane-ethyl acetate, 40:60). - Y) saponification _, The oil prepared above is stirred for 2 hours in the presence of 3 cm3 of ethanol and 2.4 cm3 of normal sodium hydroxide solution. The ethane is removed and extracted with ethyl acetate. The aqueous phase is acidified to a pH of 5 with monosodium phosphate and extracted with ethyl acetate. The organic phases are washed with water and dried. The solvent is evaporated off in vacuo, after which 365 mg of colorless oil are obtained which are purified by chromatography. Rf_ = between 0.1 and 0.36 (ethyl acetate). NMR spectrum (CDCl 3 60 MHz) CH 3 (a) 1, OH 7702908 "F (a): 0.88 ppm (b): two central doublets of 2.4 and 2.59 ppm (J = 5 Hz (c): 4.06 ppm * (d): 4.5 ppm Example 16 (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- (3 ' α-hydroxy-1'-octenyl) cyclopentanecarboxylic acid lactone.

Proceed in a manner analogous to that described in Example 1 but substitute triethylamine for diazabicyclooctane to give (1 RS, 2 SR, 5 RS, 3 'SR) (1' E) -2-hydroxy-5- ( 3'-α-tetrahydropyranyloxy-1'-octenyl) cyclopentanecarboxylic acid lactone, which is treated as in Example 2 to prepare the desired compound.

Paramacological experiments, This experiment indicates:. with compound A = <1 Rs, 2 sR, s Rs., s = SR) (1 'mz-hyamxy- - (3'-hydroxy-1'-octenyl) cyclopentanecarboxylic acid lactone. with compound B: (1 RS, 2 SR .5 RS, 3 'RS) (1' E) -2-hydroxy-5- (3'-hydroxy-3'-ethynyl-1'-octenyl) cyclopentanecarboxylic acid lactone, with compound C: (1 RS, 2 SR, 2 SR .5 RS, 3 'RS) (1' E) -2-hydroxy-5- (3'-hydroxy-3'-ethenyl-1'-octenyl) cyclopentanecarboxylic acid lactone, with compound D: (1 RS, 2 SR, 5 RS, 3'SR) (1 'E) -2-hydroxy-5- (3'-acetoxy-1'-octenyl) -cyclopentanecarboxylic acid lactone with compound E: (1 RS, 2 SR, 5 RS, 3' SR) (1 'E) -2-hydroxy-5- (3'-hydroxy-1'-decenyl) cyclopentanecarboxylic acid lactone 1) Hypotensive effect for anesthetized dog a) Methodology: The test is performed on adult dogs of mixed breeds from both sexes weighing 14- 20 kg with closed thorax. The animals are anesthetized with chloralose (125 mg / kg intravenously). The trachea is fitted with a tube and the animals are artificially inflated with a pump. The arterial pressure expressed in mm Hg is determined on the carotid artery by means of a pressure gauge pump. The cardiovascular effect on mean arterial pressure (diastolic pressure + 1/3 of the difference: systolic pressure - diastolic pressure) has been studied at doses of 10-1000 Y / kg intravenously for compound A and at 30-1000 Y / kg intravenously for compound B. The following table shows the maximum variations of the mean arterial pressure as well as the time required to return the pressure to the initial state. b) Result: "SEK 77629084) - 36 Dogapings Compound A Compound BT / kg intra- mean variance effect- Mean variance effect-" tion of mean time,. tion of mean time, venous arterial pressure,% min. 'arterial pressure, % min _ '-ui - 0 - - -05 5' o '- 100' -17 18 O - 300 _ -25 06,30 -8 8,30 1000 -a1 'of I' -17 20 The compounds show a significant hypotensive effect from the dose of 0.1 mg / kg for compound A and 1 mg / kg for compound B. A second experiment is performed on adult dogs of mixed breeds weighing 1H-20 kg with closed thorax. The trachea is fitted with a tube and the animals are artificially supplied with air by a pump.

The arterial pressure is determined on the fi pulse vein by means of a pressure gauge. Determine the dose which gives a reduction in mean arterial pressure of at least 20% for at least 20 minutes; The following results were obtained: Compound C: 0.5 mg / kg Compound ° D: 1 mg / kg Compound E: 1 mg / kg. 2) Hypotensive effect for rabbit The compounds were used dissolved in physiological serum with 10% ethanol. The solutions are administered intravenously to rabbits anesthetized with urethane and the pressure in the carotid artery is measured. The dosage which lowers this pressure by 30% has been found to be 20 pg / kg with the compound E and 50 pg / kg with the compound C.

Claims (5)

fvoæøoa-o '34 Patent Claims An analogous process for the preparation of compounds of general formula I in which the dashed line indicates the possible presence of a second bond, A represents a single bond or a group - (CH 2) 2 -, R represents a hydrogen atom or an unsaturated alkyl group having 2-4 carbon atoms, R 1 represents a group OR ', where R' represents a hydrogen atom, a tetrahydropyranyl, acetyl, hemiftaloyl or hemisuccinyl group, or R and R 1 together form a keto group, R 2 represents a group - (CH 2) m-CH3, where m is an integer 3, 4, 5 or 6, or R1 and R2 together form a group «4¿N \ (CH2) n-CH3, where n is an integer 2, 3, 4 or 5, the dashed lines indicate that the bonds may be present in one or the other possible configuration, with the proviso that when A represents a single bond, the bond between the pentane ring and the oxygen atom is an O 2 bond, characterized in that a) a reactant for the formation of functional oxygen derivatives affect a compound of formula II OH / ACOZH II in which A, R, R 1 and R 2 represent the same as above or in that b) after preparing a compound of formula I according to a), wherein R 1 represents a tetrahydropyranyloxy group and R 2 represents a group (CH 2) m - CH 3, optionally exposes the compound to an acidic hydrolyzing agent for the preparation of compounds of formula I, wherein R 1 represents a hydroxyl group - 7702908-0 32 2. -2. An analogous process according to claim 1, characterized in that the reactant for the formation of functional acid derivatives consists of tosyl chloride, alkyl chloroformate, dicycloalkylcarbodiimides, dialkylcarbodiimides or thionyl chloride. 3. An analogous process according to claim 1, characterized in that the reaction is carried out in the presence of a base which consists of alkali metal carbonate, triethylamine, methylmorpholine, pyridine or diazabicyclooctane. An analogous process according to claim 1, characterized in that (1RS, 2SR, SRS, 3'SR) (1'E) -2-hydroxy-5- (3'-hydroxy-1 ') is prepared. -decenyl) cyclopentanecarboxylic acid lactone. , An analogous process according to claim 1, characterized in that (1RS, 2SR, 5RS, 3'SR) (1'E) -2-hydroxy-5- (3'-hydroxy-1'-octenyl is prepared ) cyclopentanecarboxylic acid lactone.