CH658247A5 - PROSTAGLANDIN ANALOGS SUBSTITUTED FOR 7-OXABICYCLOHEPTANE. - Google Patents

Description

The invention relates to prostaglandin 7-oxabicycloheptane analogs which are cardiovascular agents which can be used, for example, for the treatment of thromboses. These compounds have the following constitution formula:

CH, -A- (CH-) -COOR

where B is oxygen (—O—) or - S—

(OV

where n 'is 0 to 2, R is hydrogen, lower alkyl, alkali metal or trihydroxymethylaminomethane, R1 is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkynyl; A is —CH = CH— or - (CH2) 2—, n is 1 to 4, and m is 1 to 8, and include all of the stereoisomers thereof.

The term "lower alkyl" or "alkyl" as used herein encompasses both straight and branched chain radicals containing up to 12 carbons, preferably 1 to 8 carbons, such as methyl, ethyl, propyl, isopropyl, butyl , t-butyl, isobutyl, pentyl, hexvl, isohexyl, heptyle, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, various branched chain isomers thereof and the like , as well as groups comprising a halogen substituent, such as F, Br, Cl or I or CF3, an alkoxy substituent, a haloaryl substituent, a cycloalkyl substituent (i.e. cycloalkylalkyl) or an al-kylcycloalkyl substituent.

The terms "alkenyl" and "alkynyl" used herein include similar hydrocarbon groups bearing a carbon-carbon double or triple bond, such as, for example, 2-propenyl, 2-hexenyl, 3-hexenyl, 3 -hexynyl and, in the case of an aryl substituent or of a cycloalkyl substituent as defined below, the 3-phenyl-2-propenyl, 3-phenyl-2-propy-nyl, 3-cyclohexyl-2 groups -propenyl and 3-cyclohexyl-2-propynyl.

The term "cycloalkyl" embraces saturated cyclic hydrocarbon groups containing from 3 to 12 carbons, preferably from 3 to 8 carbons, including cyclopropyl, cyclobutyl, cy-clopentyl, cyclohexyl, cyeloheptyl, cyclodecyl, cyclooctyl and cy-clododecyl groups. one of these groups being able to be substituted with 1 or 2 halogens, 1 or 2 lower alkyl and / or lower alkoxy groups.

The term "aryl" or "Ar" as used herein refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the cyclic moiety, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl, where the substituent on phenyl or naphthyl can be lower alkyl, halogen (Cl, Br or F) or lower alkoxy.

The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" used herein refers to lower alkyl groups, as previously described, having an aryl substituent, such as benzyl.

The terms “(CII2) m” and “(CH2)„ ”include a straight or branched chain radical having from 1 to 8 carbons in the normal chain, in the case of“ (CH2) m ”, and from 1 to 4 carbons in the normal chain, in the case of “(CH2j„ ”and may contain one or more lower alkyl substituents. As examples of groups (CH2) m and (CH2)„, mention is made of the groups CH2, CH2CH2, (CH2) 3, (CH2) 4, (CH2) s, (CH2) 6, (CH2) 7, - (CH2) 2 — ÇH—,

ch3 ch3

[

-ch2-ch-, -ch2-ch-ch-ch2-,

I I!

ch3 ch3 ch3

-ch2-ch-ch, ~ ch-I "I ch3 ch3

and the like.

The compounds of formula I (where R is an alkyl) are prepared by etherification or thioetherrification of a compound of formula II:

CH.-A- (CH.) -CO alkyl with the desired groups R1 - OH or R1 - SH or their equivalents, according to conventional methods.

The synthesis of ethers and thioethers is based on the synthesis of Williamson [J. Chem. Soc., 4, 229 (1852)], where ethers (and subsequently, thioethers) were synthesized by alkylation of al-coxides using alkyl halides:

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658,247

R '(O or S) Na + R "X -> R' (O or S) R" + NaX

The modern version of this synthesis provides for the use of other remaining groups, in addition to halides. Thus, with regard to the abovementioned formula II, the etherification or thioetherification reaction comprises the reaction of a compound of formula Ha below:

CH -A- (CH.) -CO.alkyl 2 2 Q ■>

(CH.).-CH.X 2 n-1 2

(lia)

where X can be, in addition to a hydroxy, also - SH, or their sodium or potassium salts, chloro, bromo, iodo, and alkyl, aryl and aralkyl-sulfonyloxy groups, with a complementary compound R: X, to form the compounds of formula I of the following type:

(CH,) - A- (CH) -CO & lkyl to i m 2

(CH,) -O-R

â fì

CH -A- (CH.) CO, alkyl 2 2 Gl 2

(in)

(CH,) -S-R 2 n

(IV)

The thioethers of formula IV can then be oxidized to sulfinyl and sulfonyl derivatives (n '= 1 or 2 in formula I) having the formulas below:

CH2-A- (CH2) mC © 2alkyl

(CH) -S-R "

2 n n

O

CH -R- (CH) -COalkyl 2 2 m 2

(V)

(VI)

The compounds of formula I where R is an alkali metal or a hydrogen (free acid) can then be prepared from the abovementioned products, where R is an alkyl, by conventional base hydrolysis with sodium or potassium hydroxide, to form the sodium and potassium salts, this reaction being followed by acidification into free acid.

Etherification is usually carried out by reaction of a compound of formula II with a compound of formula R * X, where X is chloro, bromo or iodo or methylsulfonyloxy or toluenesulfon-yloxy, in the presence of a strong base, such than potassium or sodium hydroxide, in a suitable solvent. When the reaction is carried out, a molar excess of the reactant RJX is used, varying from 0.25 mol in excess to 5 mol in excess, using a solvent such as xylene, tetrahydrofuran, dimethylsulfoxide or di-5-methylformamide. In the case where X is a bromo or a chloro, a phase transfer etherification can be applied, in which case tetrahydrofuran is used as solvent, and a phase transfer reagent, such as Bu4NHS04 or (C6H5CH2) (CH3) 31SIHS04 . In the case where R1 is an aryl, it is advantageous to first react the alcohol group of the compound of formula II, with the triphenylphosphine and the diethylazodicarboxylate in solution, with an inert solvent, such as tetrahydrofuran, then with an RJ (aryl) alcohol such as a phenol. As is generally known in the art, the reaction sequence of the alcohol of formula II with the compound R'X to effect etherification can be reversed by converting the alcohol of formula II to a compound of formula II where the alcohol group has been replaced by another radical originating from group X, then reacting with an alcohol R1 or an alkoxide, to form the product of formula I.

The thioetherification is usually carried out by first converting the alcohol of formula II into another derivative of formula II-X, as indicated above, then by thioetherification with a mercaptan R'SH, in the presence of a base, or with an alkali metal salt thereof.

The oxidation of the sulphide product where n '= 0, to sulfinyl and sulphonyl analogs, where n' is equal to 1 or 2, is easily carried out by reaction with sodium periodate, in the presence of methanol and tetrahydrofuran, to form the sulfinyl and sulfonyl derivatives, which can then be separated by chromatography or other conventional separation method.

The starting materials of formula II, where n is equal to 1 (hydroxymethyl group) are known from United States Patent No. 4,143,054 and can be prepared as described in this patent. These compounds can be used to prepare the starting materials of formula II, where n is 2 to 4, by oxidation of the hydroxymethyl group to an aldehyde, by Collins oxidation, for example, by reacting compound II with chromium trioxide in pyridine, to form an intermediate product of formula:

CH.-A- (CH „) CO.alkyl

"<A CI 2

CHO

(VII)

45

The aldehyde of formula VII is subjected to a homologation sequence, by Wittig reaction, using (C6H5) 3P = CHOCH3, followed by hydrolysis (n - 1) times, then reduction of the aldehyde in alcohol, by using a reducing agent, such as sodium boro-50 hydride or sodium cyanoborohydride, in a solvent such as methanol, to form the starting product of formula II:

Wittig

- Cfü "

(QHs) 3P = CHOCH3

CH2 - A - (CH2) m - C02alkyl

H30 +

OCH,

. CH2 - A - (CH2) m — C02alkyl n

O

O

(repeat n - 1 time)

- (CH2) m — C02alkyl -CH2OH

The tris (hydroxymethyl) aminomethane salt of one of the acids of formula I of the present invention is formed by reacting a solution of such an acid in an inert solvent such as methanol, with the tris (hydroxymethyl) aminomethane, then removing the solvent by evaporation, leaving the desired salt.

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The compounds of the invention have four centers of asymmetry, as indicated by the asterisks in formula I. It is however understood that each of the previously indicated formulas, not comprising an asterisk, represents all the possible stereoisomers of compounds. All the various forms of stereoisomers fall within the scope of the invention.

The various stereoisomeric forms of the compounds of the invention, namely cis-exo, cis-endo and all the trans forms and the stereoisomeric pairs, can be prepared as indicated in the working examples which follow , with the use of the starting materials and in accordance with the procedures described in US Patent No. 4,143,054. Examples of such stereoisomers are given below:

ÇH, -A- (CH,) -CO, R

H

(cis-endo)

H

- -CH - A- (CH-} -CO, R

-B-R '

(cis-exo)

H

- - CH, -A- (CH-1 -CO, R

(trans)

CH, -A- (CH,) -CO, R

—-H

(trans)

For reasons of convenience, the nucleus, in each of the compounds of the invention, is represented as follows:

It should be noted that the nucleus, in the compounds of the invention, can be represented as follows:

The compounds of the invention are cardiovascular agents used as inhibitors of the aggregation of blood platelets, for example, for the treatment of thrombolytic diseases, such as coronary or cerebral thromboses. They also constitute selective thromboxane A2 receptor antagonists and synthetase inhibitors, for example, having a vasodilating effect for the treatment of ischemic myocardial diseases, such as angina pectoris. The compounds of the invention are also cyclooxygenase inhibitors of arachidonic acid. They can be administered orally or parenterally to various species of mammals known to be prone to such diseases, for example cats, dogs and the like, in an effective amount, the dosage being in a range between about I and 100 mg / kg, preferably between approximately 1 and 50 mg / kg, and more particularly between approximately 2 and approximately 25 mg / kg, for diet in a single dose or in doses distributed 2 to 4 times per day.

The active substance can be used in a composition in the form, for example, of tablets, capsules, solution or suspension containing approximately 5 to approximately 500 mg per dosage unit of a compound or of a mixture of compounds of formula I. These products can be mixed, in a conventional manner, with a physiologically acceptable vehicle or support, an excipient, a binder, a preservative, a stabilizer, a flavoring agent, etc., as required in pharmaceutical practice. approved. In addition, as indicated in the above description, certain compounds also serve as intermediates for other compounds of the group.

The following examples describe preferred embodiments of the invention.

Example 1

Acid [lß, 2a (5Z), 3a.4ß] -7- [3 - [(hexyloxyJmethyl] -7-oxabicyclo-

[2.2.1] hept-2-yl] -5-heptenoic, hexyl ester

A. Acid [lß, 2a (5Z), 3a, 4ßJ-7-f3 - [(hydroxymethylJ-7-oxabicyclo-

[2.2.1] hept-2-yl] -5-heptenoic, methyl ester

(a) A mixture of N-acetylpyridinium chloride is prepared by pouring dropwise 9.6 ml (136 mmol) of acetyl chloride into 56 ml of pyridine. To this mixture is added 5.0 g (27 mmol) of (exo) -3- (2-methoxy-ethenyl) -7-oxabicyclo [2.2.1] heptane-2-methanol dissolved in 5 ml of pyridine. The resulting mixture is stirred at room temperature for 1.5 hours and poured into brine. The product is extracted with ether (3 x 200 ml); the ethereal extracts are washed with 5% hydrochloric acid (2 x 400 ml) and brine (1 x

200 ml) and dried over sodium sulfate. By concentration, a yellow oil is obtained which is purified by passage over a short column of silica gel (150 ml) with dichloromethane: yield 4.42 g of oil.

(b) To a solution of 4.42 g (19.6 mmol) of the oil in 500 ml of tetrahydrofuran containing 50 ml of water, 31.1 g (97.8 mmol) of mercuric acetate are added. The yellow suspension which forms is stirred for 10 minutes, then the whole mixture is poured into a solution containing 200 g of potassium iodide in 21 of water. After stirring, the yellow color disappears, and the mixture is extracted with benzene (3 x 500 ml). The combined benzene extracts are washed with a solution of potassium iodide and brine and dried over sodium sulfate. By concentration, 3.7 g of a product are obtained, which crystallizes and is left to stand in a cooler.

(c) A Wittig reagent is prepared in dimethyl sulfoxide (dried over calcium hydride), by dropwise addition of a solution of sodium methylsulfinylmethylide (prepared by heating 300 mg of sodium hydride sodium in 60 ml of dimethyl sulfoxide at 75; C until cessation of the evolution of hydrogen), in a solution containing 5.32 g (12 mmol) of 4-carboxybutyl triphenylphosphonium bromide in 100 ml of dimethyl sulfoxide. After the first orange color has been maintained for more than 10 seconds, an equivalent amount of base is added to form the ylide. To this dark orange solution is added a solution of the product of part (b) in 20 ml of sulfoxide

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658,247

dimethyl, and the resulting mixture is stirred at room temperature for 45 minutes. The reaction is abruptly stopped by adding 24 mmol of acetic acid, then the mixture is poured into brine (300 ml) and extracted with ether (3 x 200 ml). By concentrating these extracts, an oil is obtained which is stirred with a saturated solution of sodium bicarbonate until formation, in the mixture, of crystallized triphenylphosphine oxide. This mixture is washed with benzene and acidified with 10% hydrochloric acid. The aqueous layer is saturated with salt and extracted with ether, which provides, after dehydration (sodium sulfate) and concentration, 2.43 g of crude product. The mixture is stirred for 24 hours with 10% aqueous sodium hydroxide and separated again by acidification and extraction with ether. The product is purified on 500 g of silica gel, using 50/50 ethyl acetate-hexane as eluent, which gives 600 mg of acid which crystallizes while leaving it to stand. This is recrystallized twice from ethyl acetate-cyclohexane to provide 320 mg of acid [1 ß, 2a (5Z), 3a, 4ß] -7- [3 - [(hydroxymethyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic, mp 59-63 ° C.

Analysis for ^ - "14 ^ 22 ^ 4 •

Calculated: C 66.11 H 8.72%

Found: C 66.06 H 8.79%

The acid is then transformed into the corresponding methyl ester by treatment with diazomethane.

B. Acid [1, 2a (5Z), 3a, 4ß] -7- [3 - [(hexyloxy) methyl] -7-oxabicyclo-

[2.2.1] hept-2-yl] -5-heptenoic, hexyl ester

A suspension of 0.56 g of KOH powder in 15 ml of anhydrous xylene is heated to reflux, and 7 ml of xylene is separated by distillation. To this mixture is added a solution of 300 mg (1.12 mmol) of alcohol ester from part A in 10 ml of anhydrous xylene. The resulting mixture is heated to reflux and 9 ml of xylene are separated by distillation. 1.0 g (5.6 mmol) of n-hexyl methanesulfonate is added to this mixture, and the resulting mixture is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature and diluted with CH2Cl2 (60 ml). The solution obtained is poured into 50 ml of saturated NaHCO3. The layers are separated, and the aqueous phase is extracted (2 x 60 ml) with CH2Cl2. The combined CH2Cl2 extracts are dried over MgSO4, then concentrated in vacuo to give 0.9 g of crude product. The crude product is chromographed on 33.4 g of silica gel 60 with hexane: ether (5: 1) to provide 390 mg (83%) of the hexyl ester indicated in the title.

Example 2

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [(hexyloxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-ylJ-5-heptenoic acid

To a stirred solution of 115 mg (0.27 mmol) of the hexyl ester of Example 1 in 12.0 ml of distilled THF and 1.60 ml of H2O, 2, is added under an argon atmosphere. 40 ml of an aqueous solution of IN lithium hydroxide. This mixture is purged with argon for 40 minutes and stirred at room temperature for 24 hours. At this time, a TLC analysis shows that the reaction is not complete, so that 1 ml of methanol and 1 ml of IN aqueous lithium hydroxide are added in addition. The reaction mixture is continued to stir for a further 4 hours, then it is acidified to pH 4 by addition of an aqueous solution of IN HCl. The solution obtained is poured into 25 ml of a saturated NaCl solution and is saturated with solid NaCl. The aqueous layer is extracted with EtOAc (4 x 40 ml). The combined EtOAc extracts are dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 124 mg of crude oil. This is chromatographed on 20.6 g of silica gel 60 using hexane: ether (2: 3) as eluent, which gives 102 mg of the desired product, contaminated with a small amount of hexyl alcohol. The mixture is placed under high vacuum overnight at room temperature, which provides 77 mg (84%) of the pure acid indicated in the title. TLC: silica gel, CH3OH / CH2Cl2 8%, Rf = 0.74, iodine.

Analysis for C20H34O4:

Calculated: C 70.97 H 10.12%

Found: C 70.60 H 9.89%

s 13CRNM (CDClj, 15.0 mHz) tau 33.4, 22.6, 24.6, 129.4, 130.1, 26.7, 46.4, 79.4, 29.5, 80.1 , 46.8, 71.3, 69.8, 31.7, 25.7, 29.7, 22.6,

14.0.

Example 3

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [(hexyloxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic, hexyl ester

Dissolve in 2.17 ml of tetrahydrofuran 503 mg (1.88 mmol) of acid [lß, 2a (5Z), 3a, 4ß] -7- [3 - [(hydroxynwthyl) -7-oxabicyclo [2.2.1 ] hept-2-yl] -5-heptenoic, methyl ester (prepared I5 as described in Example 1). Then 2.17 ml are added

(15.46 mmol) n-hexyl bromide, 173.4 mg (0.51 mmol) tetrabutylammonium bisulfate (Bu4NHS04) and 2.17 ml of 50% NaOH solution, and stirred vigorously mixing at room temperature. A slightly yellowish brown solution 2o is formed which, after stirring overnight, forms a white precipitate.

The reaction mixture is poured into 25 ml of saturated NaHCO3. The mixture is extracted with CH2Cl2 (4 x 25 ml). The combined CH2C12 extracts are dried (MgSO4), filtered and concentrated in vacuo to give the acid [1, 2a (5Z), 3a, 4ß] -7- [3 - [(hexyloxy) methyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] -5-heptenoic, hexyl ester (1272 mg). This is chromatographed on 40 g of silica gel using hexane: ether (4: 1) as eluent, which gives the final product.

Example 4

(Lß, 2a, 3a, 4ß) -7- [3 - [(hexyloxy) methyl] -7-oxabicyclo-30 [2.2.1] hept-2-yl] heptanoic, hexyl ester

A. (lß, 2a, 3a, 4fi) -7- [3 - [(hydroxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] heptanoic acid, methyl ester

At 800 mg (3.0 mmol) of acid [lß, 2a (5Z), 3a, 4ß] -7- [3- (hydroxy-3J methyl) -7-oxabicyclo [2.2.1] hept-2- yl] -5-heptenoic, methyl ester, prepared as in Example 1, dissolved in ethyl acetate, 160 mg of Pd 5% on carbon are added under an argon atmosphere. The argon atmosphere is replaced by a slightly positive pressure of hydrogen, and the reaction mixture is stirred for 40 8 hours at 25 ° C, filtered through a pad of celite and evaporated, which gives 730 mg (90%) of the compound indicated in title A.

B. (lß, 2a, 3a, 4ß) -7- [3- [(hexyloxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptanoic acid, hexyl ester

Following the procedure of Example 1, except that the alcohol ester of Example 1A is replaced with the alcohol ester from part A, the title product is obtained.

Example 5

(Lß, 2a, 3a, 4ß) -7- [3 - [(hexyloxy) methyl] -7-oxabicyclo-so [2.2.1] hept-2-yl] heptanoic

Following the procedure of Example 2, except that the hexyl ester of Example 1 is replaced by the hexyl ester of Example 4, the title acid is obtained in the form of a oil,

[a] g = -3.1 (c = 1.37, CHCl3); TLC (silica gel, 8% CH3OH) 55 CH2Cl2, Rf = 0.74.

Analysis for C20H36O4:

Calculated: C 70.55 H 10.66%

Found: C 70.30 H 10.70%

60 13CRNM (CDCI3, 15.0 mHz) tau 179.1, 33.9, 24.6, 27.6.29.2, 29.3, 29.0, 47.0, 79.1, 29.7 , 29.6, 80.1, 46.4, 71.2, 69.8, 29.3, 25.8, 31.6, 22.6, 14.0.

Example 6

65 Acid [1, 2a (5Z), 3ß, 4ß] -7- [3 - [(hexyloxy) methyl] -7-oxabicy clo- [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 3 and 2, except that the acid [1 ß, 2a (5Z), 3a, 4ß] -7- [3- (hydroxynMthyl) -7-oxabicy- is replaced.

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clo [2.2.1] hept-2-yl] -5-heptenoic, methyl ester with acid [lß, 2a (5Z), 3ß, 4ß] -7- [3- (hydroxymethyl) -7-oxabicyclo [2.2 .1] hept-2-yl] -5-heptenoic, methyl ester, the title compound is obtained in the form of an oil.

Analysis for C2oH3404:

Calculated: C 70.97 H 10.12%

Found: C 70.93 H 10.33%

13C RNM (CDC13.15.0 mHz) tau 178.7, 33.4, 24.6, 26.6, 128.7, 129.9, 32.6.47.9, 79.1, 29.5 , 23.8, 80.5.49.1, 71.7, 71.2, 31.6, 25.8, 29.9, 22.6, 13.9.

Example 7

[Lß, 2a (5Z), 3a, 4ß] -7- [3- (methyloxymethyl) -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 1 and 2, except that the n-hexyl methanesulfonate is replaced by methyl methanesulfonate, the title compound is obtained, in the form of an oil, [ag = +10.4 (C = 2.21, CHCI3).

Analysis for C! SH2404:

Calculated: C 67.14 H 9.01%

Found: C 67.03 H 9.14%

13C RNM (CDCI3, 15.0 mHz) tau 178.3, 33.2, 24.4, 25.5, 129.5, 129.8, 26.5, 46.5, 79.1, 29.3, 29 , 3, 79.9,46.2, 71.7, 58.6.

Example 8

[Lß, 2a (5Z), 3ß, 4ß] -7- [3 - [(propyloxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Example 6, except that the n-hexyl-bromide is replaced by n-propyl-bromide, the title compound is obtained.

Example 9

(1, 2a, 3a, 4ß) -7- [3 - [(butyloxyJmethyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -heptanoic acid

Following the procedure of Examples 4 and 5, except that the n-hexyl methanesulfonate is replaced by n-butyl methanesulfonate, the title compound is obtained.

Example 10

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [(octyloxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 1 and 2, except that the n-hexyl methanesulfonate is replaced by n-octyl methanesulfonate, the title compound is obtained.

Example 11

[Lß, 2a (5Z), 3a, 4ß] -7- [3- [(phenyloxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-iieptênoïque

(a) Phenol (1 mmol) is added to a solution of triphenylphosphine (1 mmol), diethylazodicarboxylate (1 mmol) and title A alcohol of Example 1 (1 mmol) in 25 ml of THF, and stirred under an argon atmosphere for 48 hours at 23 ° C. The reaction mixture is concentrated in vacuo. The residue is triturated with ether and the solids are removed. The filtrate is concentrated under vacuum and chromatographed on silica gel to give the acid [1, 2a- (5Z), 3a, 4P] -7- [3 - [(phenyloxy) methyl] -7-oxabicyclo [2.2.1 ] hept-2-yl] -5-heptenoic, methyl ester.

(b) Following the procedure described in Example 2, the ester of part (a) is transformed into the title compound.

Example 12

[Lß, 2a (5Z), 3ß, 4ß] -7- [3- [(phenyloxy methyl) -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid

(a) Add phenol (1 mmol) to a solution of triphenylphosphine (1 mmol), diisopropylazodicarboxylate (1 mmol) and title A alcohol of Example 1 (1 mmol) in 25 ml of THF, and stirred under an argon atmosphere for 48 hours at 23 ° C. The reaction mixture is concentrated in vacuo. The residue is triturated with ether, and the solids are removed. The filtrate is concentrated under vacuum and chromatographed on silica gel to give the acid [ip, 2a (5Z), 3P, 4p] -7- [3 - [(phenyloxy) methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic, methyl ester.

Following the procedure described in Example 2, the ester of part (a) is transformed into the title compound.

Example 13

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3 - [(ethyloxyJ methyl] -7-oxabicy clo- [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure described in Examples 3 and 2, except that the n-hexyl-bromide is replaced by ethyl bromide, the title compound is obtained.

Example 14

A cide [lß, 2a, 3a, 4ß7-7- / 3 - [(phenyloxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] heptanoïqae

Following the procedure of Example 11, except that the alcohol in part (a) of Example 11 is replaced by the acid (1 p, 2a, 3a, 4P) -7- [3- [(hydroxy) -methyl] -7-oxabicyclo [2.2. l] hept-2-yl] heptanoic, the title compound is obtained.

Example 15

[Lß, 2a (5Z), 3ß, 4ß] -7- [3 - [(benzyloxyjméthylJ-7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptènoique

Following the procedure of Example 6, except that the n-hexyl-bromide is replaced by benzyl bromide, the title compound is obtained.

Example 16

(1, 2a, 3a, 4ß) -7- [3 - [(benzyloxy) methyl] -7-oxabicy clo- [2.2.1] hept-2-yl] heptanoic acid

Following the procedure of Examples 4 and 5, except that the n-hexyl methanesulfonate is replaced by benzyl methanesulfonate, the title compound is obtained.

Example 17

A cide [1 ß, 2a (5Z), 3a, 4ß] - 7- [3- [(cyclohexyloxy) methyl] - 7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 1 and 2, except that the n-hexyl methanesulfonate is replaced by cyclohexyl methanesulfonate, the title compound is obtained.

Example 18

Acid [lß, 2a (5Z), 3ß, 4ß] -7- [3 - [(cyclopentyloxy) methyl] -7-oxabicy-clo [2.2.1] hept-2-vl] -5-heptenoic

Following the procedure of Examples 1 and 2, except that the n-hexyl methanesulfonate is replaced by cyclopentyl methanesulfonate, and that the acid [ip, 2a (5Z), 3a, 4p] -7- [ 3- (hydroxymé-thyl) -7-oxabicyclo [2.2.1] hept-2-yl] -5-hepténoïque, methyl ester by the acid [1 P, 2a (5Z), 3p, 4P] -7- [ 3- (hydroxymethyl) -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic, methyl ester (prepared as described in US Patent No. 4,143,054), the title compound is obtained.

Example 19

(Lß, 2a, 3a, 4ßl-7- [3 - [(cyclohexyloxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-ylJheptanoic acid

Following the procedure of Examples 4 and 5, except that the n-hexyl methanesulfonate is replaced by cyclohexyl methanesulfonate, the title compound is obtained.

Example 20

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [2- (hexyloxy) ethyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic

A. [1ß, 2a (5Z), 3a, 4fi] -7- [3 - [(2-oxo) ethyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid, methyl ester

5

10

15

20

25

30

35

40

45

50

55

60

65

7

658,247

12.9 g (37.7 mmol) of anhydrous methoxymethyltriphenylphosphonium chloride ((C6H5) 3PH — CH2OCH3Cr) and 235 ml of distilled toluene (stored on molecular sieves). The suspension obtained is stirred in an ice bath, under argon, until cooling, then a 1.55M solution of 18.3 ml (28.3 mmol) of potassium t-amylate in toluene is added dropwise. . A bright red solution is formed, which is stirred at 0 ° C for a further 35 minutes. Then adding, using a dropping funnel, operating over a period of 35 minutes, the ice bath remaining in place, a solution of 4.97 g (18.8 mmol) of acid [lß, 2a (5Z), 3a, 4ß] -7- [3-for-myl-7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic, methyl ester, in 60 ml of toluene. The reaction is then abruptly stopped by adding 2.3 g (39 mmol) of acetic acid in 5 ml of ether. The reaction mixture immediately turns pale yellow and is immediately poured into 200 ml of saturated NH4Cl, and extracted with ether (4 x 200 ml). The combined ethereal phases are washed with a saturated NaCl solution, dried (MgSO4) and concentrated, giving a yellow oil in a white crystalline solid (phosphine oxide). The white solid is triturated with EtOAc, and the mother liquor is purified by chromatography on a column of LPS-1 silica. The fractions obtained are: (A) acid [ip, 2a (5Z), 3a, 4p] -7- [3- (2-oxo) ethyl-7-oxabicyclo [2.2.1] hept-2-yl] -5 -heptenoic, methyl ester, (B) acid [ip, 2a (5Z), 3a, 4p] -7- [3 - [(2-methoxy) ethenediyl] -7-oxabicyclo- [2.2.1] hept-2- yl] -5-heptenoic, methyl ester, and (C) acid [ip, 2a- (5Z), 3a, 4P] -7- [3- (2,2-dimethoxy) ethyl-7-oxabicyclo [2.2.1 ] hept-2-yl] -5-heptenoic, methyl ester.

The compounds (B) and (C) are each treated with trifluoro-roacetic acid to be transformed each into compound (A).

B. [lß, 2a (5Zi, 3a., 4ß] -7- [3- (2-hydroxyithyl) -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid, methyl ester

The aldehyde (1.4 g, 5 mmol) from part A, in methanol (50 ml), is treated with NaBH4 (0.19 g, 5 mmol) in an argon atmosphere, at 0 ° C. After stirring at 0 ° C for 1 hour, the reaction is stopped by adding 2N HCl (at pH 2). The methanol is removed in vacuo, and the reaction mixture is taken up in ether. The ethereal solution is washed with saturated KHC03, saturated NaCl and dried (MgSO4). The ether is evaporated, giving the title compound B.

C. [1ß, 2a (5Z), 3a, 4ß] -7- [3- [2- (hexyloxy) ethyl] -7-oxabicy-clo [2.2.1 Jhept-2-yl] -5-heptenoic acid

Following the procedure of Examples 1 and 2, except that the alcohol used in Example 1 is replaced by the alcohol from part B above, the title compound is obtained.

Example 21

Acid [lß, 2a (5Z), 3ß, 4ß7-7- / 3- [2- (hexyloxy) ethyl] -7-oxabicy clo- [2.2.1 Jhept-2-ylJ-5-heptenoic

Following the procedure of Example 20, except that the acid [lß, 2a (5Z), 3a, 4ß] -7- [3-formyl-7-oxabicyclo- [2.2.1] hept- is replaced. 2-yl] -5-heptenoic acid methyl ester [1 P, 2a (5Z), 3 P, 4P] -7- [3-formyl-7-oxabicyclo [2.2.1] hept-2-yl ] -5-hepté-noïque, methyl ester, the title compound is obtained.

Example 22

Acid (lß, 2a, 3a, 4ß) -7- [3- [2- (hexyloxy) ethyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptanoic

Following the procedure of Example 21, except that the acid [ip, 2a (5Z), 3p, 4p] -7- [3-formyl-7-oxabicyclo- [2.2.1] hept- is replaced. 2-yl] -5-heptenoic acid methyl ester (ip, 2a, 3a, 4p) -7- [3-formyl-7-oxabicyclo [2.2. l] hept-2-yl] heptanoic, methyl ester, the title compound is obtained.

Example 23

[Lß, 2a (5Zj, 3ß, 4ß7-7- / 3- [2- (phenyloxy) ethyl] -7-oxabicyclo- [2.2.1 Jhept-2-ylJ-5-heptenoic acid

Following the procedure of Example 11, except that the acid [1 p, 2ct (5Z), 3a, 4p] -7- [3- (hydroxymethyl) -7-oxabicy-clo [2.2. 1] hept-2-yl] -5-heptenoic, methyl ester, with acid [ip, 2a- (5Z), 3a, 4P] -7- [3- [2- (hydroxy) ethyl] -7- oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic, methyl ester, the title compound is obtained.

5

Example 24

[1ß, 2a (5Z), 3fi, 4fi] -7- [3- [2- (phenyloxy) ethyl] -7-oxabicyclo- [2.2.1 [hept-2-yl] -5-heptenoic acid

Following the procedure of Example 12, except that io replaces the acid [ip, 2a (5Z), 3p, 4p] -7- [3- (hydroxymethyl) -7-oxabicy-clo [2.2. 1] hept-2-yl] -5-heptenoic, methyl ester, with acid [ip, 2a (5Z), 3p, 4P] -7- [3- [2- (hydroxy) ethyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic, methyl ester, the title compound is obtained.

I5 Example 25

(Lß, 2a, 3a, 4ß) -7- [3- [2- (phenyloxy) ethylj-7-oxabicyclo- [2.2.1] hept-2-yl] heptanoic acid

Following the procedure of Example 11, except that the acid [1 p, 2a (5Z), 3a, 4P] -7- [3- (hydroxymethyl) -7-oxabicy-20 clo [2.2] is replaced. .1] hept-2-yl] -5-heptenoic acid methyl ester (1 P, 2a, 3a, 4P) -7- [3- [2- (hydroxy) ethyl] -7-oxabicyclo [2.2 . l] hept-2-yljheptanoic, methyl ester, the title compound is obtained.

Example 26

25 Acid [1, 2a (5Z), 3a, 4fi] -7- [3- [2- (benzyloxy) ethyl] -7-oxabicyclo- [2.2.1 [hept-2-yl] -5-heptenoic

Following the procedure of Example 20, except that the n-hexyl methanesulfonate is replaced by benzyl methanesulfonate, the title compound is obtained.

30

Example 27

[Lß, 2a (5Z), 3ß, 4ß] -7- [3- [2- (benzyloxyJethyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Example 21, except that the n-hexyl methanesulfonate is replaced by benzyl methanesulfonate, the title compound is obtained.

Example 28

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [2- (cyclopentyloxy) ethyl] -7-oxabicy-40 clo [2.2.1 [hept-2-yl] -5-heptenoic

Following the procedure of Example 20, except that the n-hexyl methanesulfonate is replaced by cyclopentyl methanesulfonate, the title compound is obtained.

45 Example 29

Acid [1, 2a (5Z), 3a, 4ß] -7- [3- (cyclohexyloxy) ethyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Example 20, except that the n-hexyl methanesulfonate is replaced by cyclohexyl methanesul-50 fonate, the title compound is obtained.

Example 30

[Lß, 2a (5ZJ, 3a, 4ß] -7- [3- [4- (hexyloxyjbutyl] -7-oxabicyclo- [2.2.1 [hept-2-yl] -5-heptenoic acid 55 A. Acid [lß , 2a (5Z), 3a, 4ß] -7- [3- (3-oxo) propyl-7-oxabicyclo- [2.2.1] hept-2-yl [-5-heptenoic, methyl ester Following the procedure of example 20, part A, except that the acid [lß, 2a (5Z), 3a, 4ß] -7- [3-formyl-7-oxabicyclo- [2.2.1] hept-2- is replaced yl] -5-heptenoic, methyl ester, with acid [lß, 2ct-60 (5Z), 3a ^] - 7- [3- (2-oxo) ethyl-7-oxabicyclo [2.2.1] hept- 2-yl] -5-hepté-noïque, methyl ester, the title compound A is obtained

B. [1ß, 2a (5Z), 3a, 4ß] -7- [3- (4-oxo) butyl-7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid, methyl ester 65 Following the procedure of Example 20, part A, except that the acid [lß, 2a (5Z), 3a, 4ß] -7- [3-formyl-7-oxabicyclo- [2.2. 1] hept-2-yl] -5-heptenoic, methyl ester, with the aldehyde of part A above, the title aldehyde is obtained B.

658,247

8

C. [1, 2a (5Z), 3a, 4ß [-7- [3- (4-hydroxybutyl) -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid, methyl ester

Following the procedure of example 20, part B, except that the acid [lß, 2a (5Z), 3a, 4ß] -7- [3- (2-oxo ^ thyl-7-oxabi) is replaced -cyclo [2.2.1] hept-2-yl] -5-heptenoic, methyl ester, with the title B aldehyde, the title C alcohol is obtained

D. Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [4- (hexyloxy jbutyl] -7-oxabicy-clo [2.2.1 Jhept-2-yl] -5-heptênoïque

Following the procedure of Examples 1 and 2, except that the alcohol used in Example 1 is replaced by the alcohol from Part C above, the title compound is obtained.

Example 31

[Lß, 2a (5Z), 3a, 4ß] -7- [3- [4- (cyclohexyloxy) butyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Example 30, except that the n-hexyl methanesulfonate is replaced by cyclohexyl methanesulfonate, the title compound is obtained.

Example 32

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [4- (phenyloxyJbutyl] -7-oxabicy clo- [2.2.1 Jhept-2-yl] -5-heptenoic

Following the procedure of Example 11, except that the acid [1 ß, 2a (5Z), 3a, 4ß] -7- [3- (hydroxymethyl) -7-oxabicy-clo [2.2. 1] hept-2-yl] -5-heptenoic, methyl ester, by acid [lß, 2a- (5Z), 3a, 4ß] -7- [3- (4-hydroxybutyl) -7-oxabicyclo [2.2 .1] hept-2-yl] -5-heptenoic, methyl ester, the title compound is obtained.

Example 33

A cide [1 ß, 2a (5Z), 3a, 4ß] -7- [3- [4- (benzyloxy) butyl] -7-oxabicy clo- [2.2.1] hept-2-ylJ-5-heptenoic

Following the procedure of Example 30, except that the n-hexyl methanesulfonate is replaced by benzyl methanesulfonate, the title compound is obtained.

Example 34

Tris! Hydromethyl) aminométliane salt of the acid [lß, 2a (5Z) .3a, 4ßJ-7- [3- [(hexyloxy) methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5 -heptenoic

A solution of the compound formed in Example 2, in methanol, is treated with an equivalent amount of tris (hydromethyl) -aminomethane. The solvent is removed by evaporation to give the title compound, in the form of a solid, m.p. 68.5-70c C. TLC (silica gel, 8% CH3OH / CHXl2). Rf = 0.74.

Analysis for C24H4S07N:

Calculated: C 62.72 H 9.87 N 3.04%

Found: C 62.71 H 9.80 N3.10%

Example 35

Acid [1, 2a (5Z), 3a, 4ß] -7- [3- [2- (pentyloxy) ethyl] -7-oxabicyclo- [2.2.1 [hept-2-yl] -5-heptenoic

A. A cide [1 ß, 2a (5 ZJ, 3a, 4ß] -7- [3- [2- (pentyloxy) ethyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5 -heptenoic, pentyl ester A mixture of powdered KOH (0.36 g) in 15 ml of anhydrous xylene is heated to reflux, under an argon atmosphere, and 8 ml of xylene are removed by distillation. solution of 200 mg (0.71 mmol) of the methyl ester alcohol of example 20, part B, in 17 ml of anhydrous xylene The volume of the reaction mixture is reduced to 15 ml by removing the xylene by distillation. add to the reaction mixture a solution of 0.5 g (3.55 mmol) of pentyl mesylate in 10 ml of anhydrous xylene This mixture is heated at reflux for 2 hours and 30 minutes The cooled reaction mixture is diluted with 50 ml of saturated NaHCO3 solution and extracted with CH2Cl2 (3 x 60 ml). The combined extracts of CH2Cl2 are dried (MgSO4), filtered and concentrated in vacuo. Purification is carried out by instant chromatography on 33 g of silica gel 60 in u using hexane: ether (5: 1) as eluent. This makes it possible to obtain 238 mg of the title pentyl ester (83%), in the form of a colorless oil. TLC: silica gel, hexane: ether (1: 1).

B. [1ß, 2a (5Zj, 3a, 4ß [-7- [3- [2- (pentyloxy) ethyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid

To a stirred solution containing 238 mg (0.58 mmol) of pentyl ester from part A, 26 ml of distilled THF, 2.1 ml of CH3OH and 3.4 ml of H2O, under argon, 6.4 is added. ml of an aqueous solution of IN lithium hydroxide. This mixture is purged with argon vigorously for 30 minutes and stirred at room temperature for 7 hours. The reaction mixture is acidified to pH 3 by addition of an aqueous solution of IN HCl. The solution obtained is poured into 50 ml of a saturated NaCl solution and is saturated with solid NaCl. The aqueous layer is extracted with EtOAc (4 x 60 ml). The combined EtOAc extracts are dried (MgS04), filtered and concentrated in vacuo. The product is chromatographed on 24 g of silica gel 60 using 3% CH3OH in CH2Cl2 as eluent to give 181 mg (92%) of pure title acid. TLC: silica gel; CH3OH 4% / CH2Cl2. Rf = 0.30, vanillin.

Analysis for C20H34O4:

Calculated: C 70.97 H 10.12%

Analysis for C20H34O4 0.22 H20:

Calculated: C 70.16 H 10.14%

Found: C 70.16 H 9.87%

13 C RNM (CDC13, 15.0 mHz) tau 173.5, 33.8, 24.7, 26.7, 129.5, 25 130.1, 28.0, 43.8, 79.8, 29 , 5, 80.3, 47.3, 29.7, 71.0, 70.3, 28.7, 22.4, 28.3, 13.9, 64.3, 28.3, 22.2 , 28.3, 13.9.

Example 36

[Lß, 2a (5Z), 3a, 4ß] -7 - [(3-phenylpropoxy) methyl-7-oxabicyclo-30 [2.2.1 [hept-2-yl] -5-heptenoic

A. [1, 2a (5Z), 3a, 4ß] -7- [(3-phenylpropoxy) methyl-7-oxabi-cyclo [2.2.1] hept-2-yl] -5-heptenoic acid, phenylpropyl ester

A mixture of powdered KOH (0.59 g) in 16 ml of anhydrous xylene is heated to reflux, under an argon atmosphere, and 9 ml of xylene are removed by distillation. To this mixture is added a solution of 410 mg (1.53 mmol) of the methyl ester alcohol of Example 1, part A, in 10 ml of anhydrous xylene. The volume of the reaction mixture is reduced to 6 ml by removing the xylene by distillation. To the reaction mixture is added a solution of 1.66 g (7.58 mmol) of 3-phenylpropyl mesylate in 36 ml of anhydrous xylene. This mixture is heated at reflux for 1 hour. The cooled reaction mixture is diluted with 50 ml of saturated NaHCO3 solution and extracted with CH2Cl2 (3 x 50 ml). The combined CH2Cl2 extracts are dried (MgSO4), filtered and concentrated in vacuo. Purification is carried out by flash chromatography on 40 g of silica gel 60 using hexane: ether (3: 1) as eluent. This gives 0.61 g of the title phenylpropyl ester (81%), in the form of a colorless oil. TLC: silica gel 2% CH3OH / CH2Cl2; Rf: 0.60, iodine.

50

B. [1ß, 2a (5Z), 3a, 4ß] -7 - [(3-phenylpropoxy) methyl] -7-oxabicy clo [2.2.1] hept-2-yl] -5-heptenoic acid

To a stirred solution containing 610 mg (1.24 mmol) of the title A phenylpropyl ester, 55 ml of distilled THF, 4.40 ml of CH3OH and 55.30 ml of H2O, under argon, 13.7 ml are added. of an aqueous solution of lithium hydroxide IN. This mixture is vigorously purged with argon for 30 minutes and stirred at room temperature for 14 hours. The reaction mixture is diluted with 100 ml of an aqueous 0.1N lithium hydroxide solution and washed 60 times with 100 ml of hexane. The reaction mixture is acidified to pH 3 by addition of an aqueous solution of IN HCl and is poured into 100 ml of a saturated NaCl solution. The mixture obtained is saturated with solid NaCl and extracted with EtOAc (4 x 150 ml). The combined EtOAc extracts are dried (MgS04), filtered and con-65 centered in vacuo. The product is chromatographed on 44 g of silica gel 60 using 4% CH3OH in CH2Cl2 as eluent, to give 380 mg (82%) of pure title acid. TLC: silica gel, 4% CH3OH / CH2Cl2. Rf = 0.30, iodine.

20

9

658,247

Analysis for C23H304:

Calculated: C 74.16 H 8.66%

Analysis for C23H3204 0.35 H2O:

Calculated: C 72.94 H 8.70%

Found: C 72.94 H 8.49%

13C RNM (CDC13.15.0 mHz) tau 178.7, 33.4, 24.5, 25.7, 129.5, 130.1, 26.6, 46.3, 79.3, 29.5 , 80.1, 46.8, 70.2, 69.9, 31.2, 32.3, 141.9, 128.4, 128.4.

Example 37

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [(octyloxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid

A. [lß, 2a (5Z), 3a, 4ß] -7- [3 - [(octyloxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid, octyl ester

To a stirred solution of 508 mg (1.89 mmol) of the alcohol ester of Example 1, part A, in 2.69 ml of THF, is added, in order, 2.69 ml (15 , 6 mmol) of n-octyl bromide, 642 mg (1.89 mmol) of tetrabutylammonium hydrosulphate and 2.69 ml of a 50% aqueous solution of sodium hydroxide. This mixture is stirred at room temperature, in the dark, for 19 hours. The reaction mixture is poured into 25 ml of a saturated sodium bicarbonate solution and extracted with four 25 ml portions of CH2Cl2. The combined CH2Cl2 extracts are dried (MgSO4), filtered and concentrated in vacuo. Purification is carried out by flash chromatography on 39.6 g of silica gel 60 using hexane: ether (3: 1) as eluent, to give 333 mg (37%) of octyl ester and 250 mg of 'A mixed band of octyl ester and corresponding methyl ester. TLC: silica gel, 3% CH3OH / CH2Cl2, Rr: octyl ester, 0.85: methyl ester, 0.80, iodine.

B. [1ß, 2a (5Z), 3a, 4ß] -7- [3 - [(octyloxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid

To a stirred solution of 333 mg (0.70 mmol) of the octyl ester of part A, in 31 ml of distilled THF, 2.50 ml of CH3OH and 4.1 ml of H2O, under argon, 7 is added. , 70 ml of an aqueous solution of IN lithium hydroxide. This mixture is vigorously purged with argon for 60 minutes and stirred at room temperature for 16 hours and 30 minutes. The mixture of octyl ester and corresponding methyl ester is hydrolyzed in exactly the same way. To a stirred solution of this mixture (250 mg) in 29 ml of distilled THF, 2.40 ml of CH3OH and 3.9 ml of H2O, 7.30 ml of IN aqueous lithium hydroxide are added. This mixture is vigorously purged with argon for 20 minutes and stirred at room temperature for 16 hours and 30 minutes.

These two reaction mixtures are combined and diluted with a solution of 120 ml of 0.1N aqueous lithium hydroxide and 50 ml of H2O. The mixture obtained is extracted once with 220 ml of hexane. The aqueous layer is acidified to pH 3 by addition of an aqueous solution of IN HCl saturated with solid NaCl, and extracted with EtOAc (4 x 150 ml). The hexane extract and the EtOAc extracts (hexane extract containing the desired acid) are combined, dried (MgSO 4), filtered and concentrated in vacuo to give 0.53 g of crude product. The latter is chromatographed on 48 g of silica gel 60, using CH3OH 3% in CH2Cl2, to give 222 mg (45%) of the desired title acid. TLC: silica gel, CH3OH 4% / CH2Cl2, Rr = 0.40, vanillin.

Analysis for C22H3804:

Calculated: C 72.09 H 10.45%

Analysis for C22H380 4 0.24 H20:

Calculated: C 71.25 H 10.45%

Found: C 71.25 H 10.20%

13CRNM (CDC13, 15.0 mHz) tau 178.7, 33.8, 24.9, 26.2, 129.6, 130.0, 26.8, 46.5, 79.3, 29.5, 29.5, 80.1, 46.9, 71.2, 69.9, 31.7, 29.7, 29.2, 28.7, 25.9, 22.6, 14.0, 64, 4, 31.7, 29.7, 29.2, 28.2, 25.8, 22.6, 14.0.

Example 38

[1, 2a (5Z), 3a, 4ß] -7- [3- [(cyclohexylmethoxy) methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid

A. Acid [1, 2a (5Z), 3a, 4ß] -7- [3- (cyclohexylmethoxy) methyl-7-5 oxabicyclo [2.2.1 [hept-2-yl [-5-heptenoic, cyclohexylmethyl ester

A mixture of powdered KOH (0.56 g) in 15 ml of anhydrous xylene is heated to reflux, under an argon atmosphere, and 7 ml of xylene are removed by distillation. To this mixture is added a solution of 300 mg (1.12 mmol) of the methyl ester alcohol of Example 1, part A, in 10 ml of anhydrous xylene. The volume of the reaction mixture is reduced to 11 ml by removing the xylene by distillation. To the reaction mixture is added a solution of 2.47 g (12.9 mmol) of cyclohexylmethyl mesylate in 10 ml of anhydrous xylene. This mixture is heated at reflux for 5 hours. The cooled reaction mixture is diluted with 50 ml of saturated NaHCO3 solution and extracted with CH2Cl2 (3 x 50 ml). The combined CH2Cl2 extracts are dried (MgSO4), filtered and concentrated in vacuo. Purification is carried out by flash chromatography on 35 g of silica gel 60, using 1% CH3OH in CH2Cl2 as eluent. This makes it possible to obtain 0.46 g of the title hexyl ester (93%) in the form of a colorless oil. TLC: silica gel, 2% CH3OH / CH2Cl2, Rr = 0.80, iodine.

B. [1ß, 2a. (5Z), 3a, 4ß] -7- [3 - [(cyclohexylmethoxy) methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid To a solution stirred with 460 mg (1.03 mmol) of cyclohexylmethyl ester from part A, 45 ml of distilled THF, 3.80 ml of CH3OH and 6.10 ml of H2O, under argon, 11.4 ml of a solution

30 IN lithium hydroxide. This mixture is vigorously purged with argon for 20 minutes and stirred at room temperature for 16 hours. The reaction mixture is diluted with 83 ml of an aqueous 0.1N lithium hydroxide solution and washed once with 83 ml of hexane. The aqueous layer is acidified to pH 3, by addition of an aqueous solution of IN HCl and saturated with solid NaCl. The resulting aqueous layer is extracted with EtOAc (4 x 120 ml). The combined EtOAc extracts are dried (MgSO4), filtered and concentrated in vacuo to give 0.32 g of crude product. The latter is chromatographed on 34.6 g of 40 silica gel 60, using 3% CH3OH in CH2Cl2 as eluent, to give 278 mg (77%) of pure title acid. TLC: silica gel, CH3OH 4% / CH2Cl2, Rf = 0.28, iodine.

Analysis for C21H34:

45 Calculated: C 71.96 H 9.78%

Analysis for C21H3404 0.31 H2O:

Calculated: C 70.84 H 9.80%

Found: C 70.84 H 9.68%

n / a 13C RNM (CDC13, 15.0 mHz) tau 173,5,33,7,24,9,25,3, 129,5, 129,9, 26,0, 46,4, 79,2, 29, 6, 29.6, 79.2, 46.8, 70.0, 77.0, 37.9, 30.0, 26.7, 25.8, 26.7, 30.0, 69.3, 37.1, 29.1, 26.3, 25.6, 26.3, 29.1.

Example 39

55 Acid [la, 2ß (5Z), 3ß, 4a] -7- [3 - [[(1-methylhexyl) oxy] methylJ-7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 1 and 2, except that the n-hexylmethanesulfonate is replaced by 1-methylhexylmethane sulfonate, the title compound is obtained. TLC (silica gel, 60 CH3OH 4% / CH2Cl2), Rr = 0.47.

Analysis for C21H3604:

Calculated: C 71.55 H 10.29%

Found: C 71.73 H 10.21%

65

13C RNM (CDC13.15.0 mHz) tau 178.8, 33.4, 24.6, 25.7, 129.4, 130.2, 26.7, 46.4, 79.5, 29.5 , 80.1, 47.1, 67.5, 75.9, 36.7, 25.3, 31.9, 22.6, 14.0,19.7.

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Example 40

Acid [la, 2ß (Z), 3ß, 4a] -7- [3 - [(3-hexynyloxy) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic

Following the procedures of Examples 1 and 2, except that the preceding product is replaced by 3-hexynylmethanesulfonate, the title compound is obtained in the form of an oil; TLC (silica gel, CH3OH 4% / CH2Cl2) Rr = 0.32.

Analysis for C20H3004;

Calculated: C 71.82 H 9.04%

Found: C 71.66 H 9.21%

13C RNM (CDC13, 15.0 mHz) tau 178.9, 33.4, 22.0, 24.5, 129.5,

130.0, 26.7.46.4, 79.4, 29.4, 29.5, 80.0, 46.7, 69.0, 58.8, 76.1, 86.8, 22.0, 25.8, 13.4.

Example 41

[Lß, 2a (Z), 3a (Zj, 4ß] -7- [3 - [(3-hexenyloxy) methyl] -7-oxabi-cyclo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 1 and 2, except that the n-hexylmethanesulfonate is replaced by cis-3-hexene-1-mesylate, the title compound is obtained in the form of an oil. TLC (silica gel, CH3OH 4% / CH2Cl2) Rf = 0.3.

Analysis for C20H32O4:

Calculated: C 71.39 H 9.59%

Found: C 71.10 H 9.59%

13C RNM (CDC13, 15.0 mHz) tau 178.9, 33.4, 24.5, 25.6,129.5,

130.1, 27.7.46.3.79.3.29.4, 80.1.46.7, 70.7, 69.8.26.6,133.6,124.8, 20.6, 14.2.

Example 42

[1ß, 2a (ZJ, 3a (Z), 4ßJ-7- [3 - [(2-hexenyloxy) methyl] -7-oxabi-cyclo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 1 and 2, and replacing the n-hexylmethanesulfonate with 2-l-hex-2-enyl-mesylate, the title compound is prepared in the form of an oil; TLC (silica gel, 2% CH3OH / CH2Cl2) Rr = 0.22, vanillin.

Analysis for C20H32O4:

Calculated: C 71.39 H 9.59%

Found: C 70.97 H 9.64%

13C RNM (CDCI3.15.0 mHz) tau 178.8, 33.4.24.5, 25.8.129.5, 130.1, 26.7, 46.4, 79.5, 29.5.29 , 5, 80.1, 46.9, 69.3, 66.6, 133.5, 126.2, 29.5, 22.6, 13.6.

Example 43

[Iß, 2a (Z), 3a, 4a] -7- [3 - [(2-propenyloxy) methyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid, and methyl ester

To a stirred solution of 310 mg (1.16 mmol) of acid [lß, 2ct, - (5Z), 3a, 4p] -7 - [(3-hydroxymethyl) -7-oxabicyclo [2.2.1] hept- 2-yl] -5-heptenoic, methyl ester, in 1.34 ml of tetrahydrofuran, 1.34 ml of allyl bromide, 107 mg of tetrabutylammonium hydrogen sulphate and 1 are added, in order 34 ml of a 50% aqueous sodium hydroxide solution. The mixture is stirred at room temperature, in the dark, for 23 hours, then poured into 30 ml of a saturated sodium bicarbonate solution, and extracted twice with 30 ml portions of methylene chloride. The combined extracts are dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. Purification is carried out by flash chromatography on 35 g of silica gel 60, using hexane: ether (2: 1) as eluent, to give 220 mg of the methyl ester product; TLC {silica gel, hexane: ether (1: 1)] Rf = 0.4, iodine.

The ester is dissolved in 36 ml of tetrahydrofuran, with a small amount of hydroquinone, 6 ml of water and 7 ml of an IN aqueous solution of lithium hydroxide, and stirred at room temperature for 5.5 hours, after which the reaction mixture is poured into 80 ml of a saturated aqueous solution of sodium chloride and saturated with excess solid sodium chloride. The aqueous layer is extracted with 4 portions of ethyl acetate (125 ml each), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is chromatographed on 30 g of silica gel, using 4% CH3OH / CH2Cl2 as eluent, to give 190 mg of the acid product; TLC [silica gel, hexane: ether (1: 1)] Rf = 0.15.

Analysis for CnH2604:

Calculated: C 69.36 H 8.96%

Found: C 69.72 H 9.05%

13C RNM (CDC13, 15.0 mHz) tau 178.9, 33.4, 24.5, 25.7, 129.5, 130.0, 26.6, 46.3, 79.3, 29.4, 80 , 1.46.7, 69.3, 72.0, 134.7, 117.0.

Example 44

Acid [1, 2a (5Z), 3a, 4ß] -7- [3- [(hexylthio) methyl] -7-oxabicyclo-

[2.2.1] hept-2-yl] -5-heptenoic, methyl ester

A. Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- (hydroxymethyl) -7-oxabicyclo-

[2.2.1] hept-2-yl] -5-heptênoïque

(a) A mixture of N-acetylpyridinium chloride is prepared by adding dropwise 9.6 ml (136 mmol) of acetyl chloride to 56 ml of pyridine. To this mixture is added 5.0 g (27 mmol) of (exo) -3- (2-methoxy-ethenyl) -7-oxabicyclo [2.2.1] heptane-2-methanol dissolved in 5 ml of pyridine. The resulting mixture is stirred at room temperature for 1.5 hours and poured into brine. The product is extracted with ether (3 x 200 ml), the ether extracts are washed with 5% hydrochloric acid (2 x 400 ml) and with brine

(1 x 200 ml) and dried over sodium sulfate. By concentration, a yellow oil is obtained which is purified by passage over a short column of silica gel (150 ml) with dichloromethane; yield 4.42 g of oil.

(b) To a solution of 4.42 g (19.6 mmol) of oil in 500 ml of tetrahydrofuran containing 50 ml of water, 31.1 g are added

(97.8 mmol) mercuric acetate. The yellow suspension formed is stirred for 10 minutes, then the whole mixture is poured into a solution containing 200 g of potassium iodide in 21 of water. The yellow color disappears after stirring, and the mixture is extracted with benzene (3 x 500 ml). The combined benzene extracts are washed with potassium iodide solution and brine and dried over sodium sulfate. By concentration, 3.7 g of a product are obtained, which crystallizes and is left to stand in a cooler.

(c) A Wittig reagent is prepared in dimethyl sulfoxide (dried over calcium hydride), by adding dropwise a solution of sodium methylsulfinylmethylide (prepared by heating 300 mg of sodium hydride in 60 ml of dimethyl sulfoxide at 75: C until cessation of evolution of hydrogen) to a solution of 5.32 g (12 mmol) of 4-carboxybutyl triphenylphos-phonium bromide in 100 ml of dimethyl sulfoxide. After the first orange color remaining for more than 10 seconds has been formed, an equivalent amount of base is added to form the ylide. To this dark orange solution is added a solution of the product of part (b) in 20 ml of dimethyl sulfoxide, and the resulting mixture is stirred at room temperature for 45 minutes. The reaction is abruptly stopped by adding 24 mmol of acetic acid, and the mixture is poured into brine (300 ml) and extracted with ether (3 x 200 ml). By concentrating these extracts, an oil is obtained which is stirred with a saturated sodium bicarbonate solution until the crystallized triphenylphosphine oxide is formed in the mixture. This mixture is washed with benzene and acidified with 10% hydrochloric acid. The aqueous layer is saturated with salt and extracted with ether, which gives, on drying (sodium sulfate) and concentration, 2.43 g of crude product. The mixture is stirred for 24 hours with aqueous sodium hydroxide and isolated again by acidification and extraction with ether. The product is purified on 500 g of silica gel with ethyl acetate-hexane 50/50 as eluent, which gives 600 mg of acid which crystallizes leaving it to stand. This product is recrystallized twice from ethyl acetate-cyclohexane to give 320 mg of acid [lß, 2a (5Z), 3a, 4ß] -7- [3- (hydroxynwth-yl) -7-oxabicyclo [ 2.2.1] hept-2-yl] -5-heptenoic.

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B. Acid [1, 2a (5Z), 3a, 4fi] -7- [3- (p-toluenesulfonyloxymethyl) -7-oxabicyciò [2.2. l] hept-2-yl] -5-heptenoic, methyl ester

To a solution of 300 mg (1.12 mmol) of alcohol ester of part A in 4 ml of anhydrous pyridine, 427 mg (2.24 mmol) of tosyl chloride are added. The mixture is stirred at room temperature,

under an argon atmosphere, for 10 hours. The reaction mixture is diluted with 300 ml of ether, washed with an aqueous solution of IN HCl (3 × 100 ml) and an aqueous solution of 0.5N NaOH (3 × 100 ml). The ether layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification is carried out by flash chromatography on 30 g of silica gel 60, using 50% hexane in ether as eluent to give 450 mg of the title compound (95%). TLC: silica gel, CH3OH 4% in CH2C12, Rf = 0.80, iodine.

C. Acid [lß, 2a (5Z), 3a, 4ß] -7- [3 - [(hexylthio) t ^ thylJ-7-oxabicy-clo [2.2.1Jhept-2-yl] -5-heptenoic, methyl ester

To a solution of 132 mg (1.17 mmol) of potassium t-butoxide in 10 ml of anhydrous THF, under argon, 378 mg (3.21 mmol) of 1-hexanethiol is added. To this mixture is added a solution of 450 mg (1.07 mmol) of part B tosylate in 5 ml of THF. The reaction mixture is stirred at room temperature, under argon, for 2.5 hours, then heated to reflux for 5.5 hours. The cooled reaction mixture is diluted with 300 ml of ether and poured into 100 ml of a saturated NaHCO3 solution. The aqueous layer is extracted with ether (2 x 100 ml). The combined ethereal extracts (500 ml) are washed with 0.5N aqueous sodium hydroxide, brine (100 ml), then dried (MgSO4), filtered and concentrated in vacuo to give 0.55 g of crude oil . The purification is carried out by chromatography on 25.2 g of silica gel 60, using petroleum ether: ether 5: 1 as eluent, to give 328 mg of the title product, in the form of an oil ( 84%). TLC: silica gel, petroleum ether: 3: 2 ether, Rf = 0.55, iodine.

Example 45

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [(hexylthio) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid

To a stirred solution of 328 mg (0.89 mmol) of the methyl ester of Example 1 in 43.8 ml of THF and 6.67 ml of H2O, under argon, 8.40 ml of an aqueous solution is added IN lithium hydroxide. This mixture is vigorously purged with argon for 20 minutes and stirred at room temperature for 12.5 hours. The reaction mixture is acidified to pH 4 by addition of an aqueous solution of IN HCl and poured into 50 ml of a saturated NaCl solution. The solution obtained is saturated with solid NaCl and extracted with EtOAc (4 x 50 ml). The combined EtOAc extracts are dried (MgSO4), filtered and concentrated in vacuo to give 295 mg of crude acid. The purification is carried out by flash chromatography on 25 g of siliCAR CC-7 using petroleum ether: ether 2: 3 as eluent, to give the title product (250 mg, 79%) in the form of a oil. TLC: silica gel, petroleum ether: 2: 3 ether, Rr = 0.25, iodine.

Analysis for C20H34O3S:

Calculated: C 67.80 H 9.61 S 9.04%

Found: C 67.80 H 9.85 S 9.14%

13C RNM (CDC13, 15.0 mHz) tau 173.5, 33.1, 24.5, 25.6, 129.9, 128.8, 26.5.45.9, 79.9, 29.2 , 28.8, 78.3, 45.9, 69.5, 144.5, 129.7, 127.6, 132.1, 127.6, 129.7.21.3, 51.1.

Example 46

(Lß, 2a, 3a, 4ß) -7- [3- [fhexylthio) methyl [-7-oxabicyclo- [2.2.l] hept-2-yl] -5-heptenoic acid, methyl ester A. Acid (lß, 2a, 3a, 4ß) -7- [3- (hydroxyttäthyl) -7-oxabicyclo- [2.2.1] hept-2-yl] heptanoic, methyl ester 800 mg (3.0 mmol) of acid [lß , 2a (5Z), 3a, 4ß] -7- [3- (hydroxy-methyl) -7-oxabicyclo [2.2. l] hept-2-yl] -5-heptenoic, methyl ester, as prepared in example 1, dissolved in 120 ml of ethyl acetate, 160 mg of Pd 5 are added, under an argon atmosphere % on carbon. The argon atmosphere is replaced by a slight overpressure of hydrogen, and the reaction mixture is stirred for 8 hours at 25 ° C., filtered through a pad of celite and evaporated, which gives 5,730 mg (90%) of the compound. of title A.

B. Acid (lß, 2a, 3a, 4ß) -7- [3 - [(hexylthio) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] heptanoic, methyl ester Following the procedure of Example 1, except that the alcohol ester of Example 1A is replaced by the alcohol ester of part A, the title product is obtained.

Example 47

(Lß, 2a, 3a, 4ß) -7- [3 - [(hexylthiojmethylJ-7-oxabicyclo- [2.2.1] hept-2-yl] heptanoic Following the procedure of Example 45, except that 'the methyl ester of example 45 is replaced by the methyl ester of example 46, the title acid is obtained.

Example 48

20 Acid [1, 2a (5Z), 3a, 4ß] -7- [3 - [(pentyIthio) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic, methyl ester A [1, 2a (5Z), 3a, 4ß] -7- [3- (hydroxymethyl) -7-oxabicyclo- [2.2.l] hept-2-yl] -5-heptenoic acid, methyl ester To a solution containing 2.68 g of acid [lß, 2a (5Z), 3ct, 4ß] -7- [3-25 (hydroxymethyl) -7-oxabicyclo [2.2. l] hept-2-yl] -5-heptenoic in 175 ml of dimethylformamide, 13.16 g of pyridinium dichromate are added. This mixture is stirred at room temperature for 19 hours, after which an additional 8 g of pyridinium dichromate is added. This mixture is stirred for a further 24 hours. The reaction mixture is diluted with 500 ml of ether, and the resulting black gummy precipitate is separated by filtration on a pad of celite. The filtrate is concentrated in vacuo. The dark brown oil obtained is passed over 60 g of silica gel 60 and eluted with 5% MeOH / CH2Cl2 to give 1.86 g of a brown oil. The latter is purified by chromatography on 150 g of silica gel 60, using pentane: ether: acetic acid 1: 1: 0.01 as eluent. 0.63 g of acid are thus obtained [1 ß, 2a (5Z), 3a, 4ß] -7- [3- (carboxy) -7-oxabicyclo [2.2.1] hept-2-yl] -5- heptenoic, methyl ester, and 0.31 g of acid [lß, 2a (5Z), 3ß, 4ß] -7- [3- (carboxy) -7-oxabicy-40 clo [2.2.1] hept-2- yl] -5-heptenoic, methyl ester.

13C RNM (CDC13, 15.0 mHz) tau 177.0, 174.0, 130.6, 127.7, 81.5, 77.9, 54.7, 51.3, 46.2, 33.4 , 32.3, 29.2, 26.6, 25.8, 24.7.

A solution containing 350 mg of acid [lß, 2a (5Z), 3ß, 4ß] -7- [3-45 (carboxy) -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid, methyl ester, and 0.35 ml of triethylamine in 3.0 ml of anhydrous THF, under argon, is cooled to 0 ° C. To this stirred solution, 0.24 ml of ethyl chloroformate is added dropwise. The resulting mixture is stirred at 0 ° C for 50 minutes, then diluted with 20 ml of anhydrous ether 50. The mixture is filtered through an MgSO 4 buffer and concentrated in vacuo. The residue is dissolved in 2 ml of absolute EtOH and 3.3 ml of anhydrous THF. This solution is cooled in an ice bath, then 80 mg of NaBH4 is added. The mixture is stirred for 30 minutes at 0 ° C., then the ice bath is removed. After 15 minutes, the reaction mixture is poured into 25 ml of ice-cold IN HCl. The aqueous layer is extracted with three 25 ml portions of ether. The ethereal layers are combined, dried over MgSO4, filtered and concentrated in vacuo, which gives the crude product. The purification is carried out by flash chromatography of 22 g of silica gel, using 2% MeOH / CH2Cl2 as eluent. This provides 250 mg of acid [lß, 2a (5Z), 3ß, 4ß] -7- [3- (hydroxy-methyl) -7-oxabicyclo [2.2. l] hept-2-yl] -5-heptenoic, methyl ester.

I3C RNM (CDC13, 15.0 mHz) tau 174,1,130,0,128.5, 80.6, 78.7, 63.4, 51.7, 51.4, 47.8, 33.4, 32.7 , 29.8, 26.6, 24.7, 23.7.

65 B. Acid [1, 2a (5Z), 3ß, 4ß] -7- [3- (p-toluenesulfonyloxymethyl) -7-oxabicyclo [2.2. l] hept-2-yl] -5-heptenoic, methyl ester A solution containing 300 mg (1.12 mmol) of acid [lß, 2a (5Z), 3ß, 4ß] -7- [3- (hydroxynrethyl ) -7-oxabicyclo [2.2.1] hept-2-

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yl] -5-heptenoic, methyl ester, coming from part A, in 4 ml of anhydrous pyridine, 427 mg (2.24 mmol) of tosyl chloride are added. The mixture is stirred at room temperature, under an argon atmosphere, for 10 hours. The reaction mixture is diluted with 300 ml of ether, washed with an aqueous solution of IN HCl (3 × 100 ml) and an aqueous solution of 0.5N NaOH (3 × 100 ml). The ethereal layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. The purification is carried out by flash chromatography on 30 g of silica gel 60, using 50% hexane in ether, as eluent, which gives 450 mg of the title compound B.

C. [1ß, 2a (5Z), 3ß, 4ß] -7- [3 - [(pentylthio) methyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid, methyl ester To a solution containing 132 mg (1.17 mmol) of potassium t-butoxy in 10 ml of anhydrous THF, under argon, 378 mg (3.21 mmol) of 1-pentanethiol are added. To this mixture is added a solution of 450 mg (1.07 mmol) of part B tosylate in 5 ml of THF. The reaction mixture is stirred at room temperature, under argon, for 2.5 hours, then heated to reflux for 5.5 hours. The cooled reaction mixture is diluted with 300 ml of ether and poured into 100 ml of a saturated NaHCO3 solution. The aqueous layer is extracted with ether (2 x 100 ml). The combined ethereal extracts (500 ml) are washed with 0.5N aqueous sodium hydroxide (2 x 100 ml), brine (100 ml), then dried (MgS04), filtered and concentrated in vacuo to give 0 , 55 g of crude oil. Purification is carried out by chromatography on 25.2 g of silica gel 60, using petroleum ether: ether 5: 1 as eluent to give 328 mg of title compound.

Example 49

Acid [lß, 2a (5Z), 3ß, 4ß] -7- [3- [(pentylthio) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic

To an agitated solution containing 328 mg (0.89 mmol) of the methyl ester of Example 48, in 43.8 ml of THF and 6.67 ml of H2O, 8.40 ml of a IN aqueous lithium hydroxide solution. This mixture is vigorously purged with argon for 20 minutes and stirred at room temperature for 12.5 hours. The reaction mixture is acidified to pH 4 by addition of an aqueous solution of IN HCl and poured into 50 ml of a saturated NaCl solution. The solution obtained is saturated with solid NaCl and extracted with EtOAc (4 x 50 ml). The combined EtOAc extracts are dried (MgSO4), filtered and concentrated in vacuo to give 295 mg of crude acid. Purification is carried out by flash chromatography on 25 g of siliCAR CC-7, using petro-ether: ether 2: 3 as eluent to obtain the acid.

Example 50

Acid [1, 2a (5Z), 3a, 4ß7-7- / 3 - [(methylthio) methyl] -7-oxabicy clo- [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 44 and 45, except that 1-hexane-thiol is replaced by methyl mercaptan, the title compound is obtained.

Example 51

Acid [1ß, 2af5Z), 3ß, 4ß7-7- / 3- [(propylthio) methyl] -7-oxabicyclo- [2.2.1 Jhept-2-ylJ-5-heptenoic

Following the procedure of Examples 48 and 49, except that 1-pentanethiol is replaced by propylmercaptan, the title compound is obtained.

Example 52

(Lß, 2a, 3a, 4ß) -7- [3 - [(butylthio) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] heptanoic

Following the procedure of Examples 46 and 47, except that 1-hexanethiol is replaced by butylmercaptan, the title compound is obtained.

Example 53

Acid [lß, 2a (5Z), 3a, 4ß} -7- [3 - [(octylthiojmethylJ-7-oxabicyclo- [2.2.1 Jhept-2-yl] -5-heptenoic

Following the procedure of Examples 44 and 45, except that 1-hexanethiol is replaced by 1-octanethiol, the title compound is obtained.

Analysis for C22H3803S:

Calculated: C 69.06 H 10.01 S 8.38%

Found: C 69.08 H 9.75 S 8.20%

13C RNM (CDC13.15.0 mHz) tau 178.7, 32.6, 29.1, 29.4, 129.8, 129.8, 29.4, 46.9, 80.6, 29.7, 31 , 7, 80.4, 47.5, 33.4, 32.1, 29.1, 28.8, 26.7, 26.2, 24.5, 22.5, 13.9.

Example 54

Acid [1, 2a (5Z), 3a, 4ß] -7- [3 - [(phenylthio) methyl] -7-oxabicyclo- [2.2.1 Jhept-2-yI] -5-heptenoic

Following the procedure of Examples 44 and 45, except that 1-hexanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 55

(Lß, 2a, 3a, 4ß) -7- [3 - [(phenylthio) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] heptanoic

Following the procedure of Examples 46 and 47, except that 1-hexanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 56

[1ß, 2a (5Z), 3a, 4ß] -7- [3 - [(ethylthio) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl [-5-heptanoic

Following the procedure of Examples 44 and 45, except that 1-hexanethiol is replaced by ethylmercaptan, the title compound is obtained.

Example 57

[Lß, 2a (5Z), 3ß, 4ß] -7- [3- [(phenylthio) methyl] -7-oxabicy clo- [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 48 and 49, except that 1-pentane-thiol is replaced by phenylmercaptan, the title product is obtained.

Example 58

Acid [lß, 2a (5Z), 3ß, 4ß] -7- [3- [(benzylthio) methyl] -7-oxabicy clo- [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 48 and 49, except that 1-pentanethiol is replaced by benzylmercaptan, the title product is obtained.

Example 59

(1, 2a, 3a, -4ß) -7- [3 - [(benzylthio) methyl] -7-oxabicy clo- [2.2.1] hept-2-ylJheptanoic acid

Following the procedure of Examples 46 and 47, except that 1-hexanethiol is replaced by benzylmercaptan, the title product is obtained.

Example 60

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [(cyclohexylthio) methyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 44 and 45, except that 1-hexanethiol is replaced by cyclohexylmercaptan, the title product is obtained.

Example 61

[Lß, 2a (5Z), 3ß, 4ß] -7- [3 - [(cyclopentylthio) methyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 48 and 49, except that 1-pentanethiol is replaced by cyclopentylmercaptan, the title product is obtained.

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Example 62

(Lß, 2a, 3a, 4ß) -7- [3- [(cyclohexylthio j methyl] -7-oxàbicyclo- [2.2.1] hept-2-yl] heptanoic acid

Following the procedure of Examples 46 and 47, except that 1-hexanethiol is replaced by cyclohexylmercaptan, the title product is obtained.

Example 63

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [2- (hexylthio) ethyl] -7-oxabicyclo- [2.2.1 Jhept-2-yl] -5-heptenoic

A. Acid [1, 2a (5Z), 3a, 4fi [-7- [3- (2-oxo) ethyl-7-oxabicyclo- [2.2.1 Jhept-2-ylJ-5-heptenoic, methyl ester In a dry flask with three tubes, 100 ml, round bottom, containing a stirring bar, 12.9 g (37.7 mmol) of methoxymethyltriphenylphosphonium chloride ((C6H5) 3P + - CH2OCH3Cr) are added dry ml of distilled toluene (stored on molecular sieves). The resulting suspension is stirred in an ice bath, under argon, until cooling, then a 1.55 M solution of 18.3 ml (28.3 mmol) of potassium t-amylate in toluene is added dropwise. . The bright red solution formed is stirred at 0 ° C for a further 35 minutes. Then added, using a dropping funnel, over a period of 35 minutes, the ice bath being kept in place, a solution of 4.97 g (18.8 mmol) of acid [1, 2a ( 5Z), 3a, 4ß] -7- [3-formyl-7-oxabicyclo- [2.2.1] -hept-2-yl] -5-heptenoic, methyl ester, in 60 ml of toluene. The reaction is then stopped by adding 2.3 g (39 mmol) of acetic acid in 5 ml of ether. The reaction mixture immediately turns pale yellow and is immediately poured into 200 ml of saturated NH4Cl and extracted with ether (4 x 200 ml). The combined ethereal phases are washed with saturated NaCl solution, dried (MgSO4) and concentrated to give a yellow oil in a white crystalline solid (phosphine oxide). The white solid is triturated with EtOAc, and the mother liquor is purified by column chromatography on silica LPS-1. The fractions obtained are (A) acid [lß, 2a (5Z), 3a, 4ß] -7- [3- (2-oxo ^ thyl-7-oxabicyclo [2.2.1] hept-2-yl] -5- heptenoic, methyl ester, (B) acid [1, 2a (5Z), 3a, 4ß] -7- [3- (2-methoxy) -ethenediyl-7-oxabicyclo [2.2.1] hept-2-yl] - 5-heptenoic, methyl ester, and (C) acid [lß, 2a (5Z), 3a, 4ß] -7- [3- (2,2-dinwthoxy ^ -thyl-7-oxabicyclo [2.2.1] hept- 2-yl] -5-heptenoic, methyl ester.

The compounds (B) and (C) are each treated with trifluoro-roacetic acid, so as to be each transformed into compound (A).

B. [1ß, 2a (5Zj, 3a, 4ß] -7- [3- (2-hydroxyethyl) -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid, methyl ester

The aldehyde (1.4 g, 5 mmol) of part A, in methanol (50 ml), is treated with NaBH4 (0.19 g, 5 mmol), in an argon atmosphere, at 0 ° C. After stirring at 0 ° C for 1 hour, the reaction is stopped by adding 2N HCl (at pH 2). The methanol is removed in vacuo, and the reaction mixture is taken up in ether. The ethereal solution is washed with saturated KHC03, saturated NaCl and dried (MgS04). The ether is evaporated to give the title compound B.

C. [lß, 2a (5Z), 3a, 4ß] -7- [3- [2- (hexylthio) ethyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 44 and 45, except that the alcohol used in Example 44 is replaced by the alcohol from Part B above, the title compound is obtained.

Example 64

[Lß, 2a (5Z), 3ß, 4ß [-7- [3- [2- (hexylthio) ethyl] -7-oxabicyclo- [2.2.1 Jhept-2-yl] -5-heptenoic acid

Following the procedure of Example 63, except that the acid [lß, 2a (5Z), 3ß, 4ß] -7- [3-formyl-7-oxabicyclo- [2.2.1] hept- is replaced. 2-yl] -5-heptenoic acid methyl ester [lß, 2a- (5Z), 3a ^] - 7- [3-formyl-7-oxabicyclo [2.2.1] hept-2-yl] - 5-heptenoic, methyl ester, the title compound is obtained.

Example 65

Acid (lß, 2a, 3a, 4ß) -7- [3 - [- 2- (hexylthio) ethyl] -7-oxabicyclo- [2.2.1] hept-2-yl] heptanoic

Following the procedure of Example 64, except that the acid [lß, 2a (5Z), 3a, 4ß] -7- [3-formyl-7-oxabicyclo- [2.2.1] is replaced. -2-yl] -5-heptenoic acid methyl ester (lß, 2a, 3a, 4ß) -7- [3-formyl-7-oxabicyclo [2.2.1] hept-2-yl] heptanoi'que , methyl ester, the title compound is obtained.

io Example 66

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [2- (phenylthio) ethyl J-7-oxabicyclo- [2.2.1 Jhept-2-yl] -5-heptenoic

Following the procedure of Example 63, except that 1-hexanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 67

[Lß, 2a (5Z), 3ß, 4ß] -7- [3- [2- (phenylthio) ethyl] -7-oxabicy clo- ^ [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Example 64, except that 1-hexanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 68

25 (1 ß, 2a, 3a, 4ß) -7- [3- [2- (phenylthio) ethyl] -7-oxabicy clo- [2.2.1] hept-2-yl] heptanoic

Following the procedure of Example 65, except that 1-hexane-thiol is replaced by phenylmercaptan, the title compound is obtained.

30 ^

Example 69

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [2- (benzylthio) ethyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Example 63, except that 1-hexanethiol is replaced by benzylmercaptan, the title compound is obtained.

Example 70

Acid [lß, 2a (5Z), 3ß, 4ß] -7- [3- [2- (benzylthio) ethyl J-7-oxabicyclo-40 [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Example 64, except that 1-hexanethiol is replaced by benzylmercaptan, the title compound is obtained.

45 Example 71

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3 - [(2- (cyclopentyl) thiol) ethyl] -7-oxabicyclo [2.2.1 [hept-2-ylJheptenoic

Following the procedure of Example 63, except that 1-hexanethiol is replaced by cyclopentylmercaptan, the title compound is obtained.

Example 72

Acid [Iß, 2a (5Z), 3a, 4ß] -7- [3- [2- (cyclohexylthio) ethyl] -7-oxabicy-clo [2.2.1 [hept-2-yl] -5-heptenoic 55 En according to the procedure of Example 63, except that 1-hexanethiol is replaced by cyclohexylmercaptan, the title product is obtained.

Example 73

60 Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [4- (hexylthio) butyl] -7-oxabicyclo- [2.2.1 Jhept-2-ylJ-5-heptênoïque

A. Acid [1, 2a (5Z), 3a, 4ß] -7- [3- (3-oxo) propyl-7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic, methyl ester Following the procedure of example 63, part A, except that the acid [lß, 2a (5Z), 3a, 4ß] -7- [3-formyl-7-oxabicyclo- [2.2 .1] hept-2-yl] -5-heptenoic, methyl ester, with acid [lß, 2a- (5Z), 3a, 4p] -7- [3- (2-oxo) ethyl-7-oxabicyclo [2.2.1] hept-2-yl] -5-hepté-noïque, methyl ester, we obtain the title compound A.

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14

B. [1, 2a (5Z), 3a, 4ß [-7- [3- (4-oxo) butyl-7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid, methyl ester

Following the procedure of Example 63, part A, except that the acid [lß, 2ct (5Z), 3a, 4ß] -7- [3-formyl-7-oxabicyclo- [2.2.1] is replaced. ] hept-2-yl] -5-heptenoic, methyl ester with the aldehyde of part A above, the title aldehyde is obtained B.

C. Acid [1, 2a (5Z), 3a, 4ß] -7- [3- (4-hydroxybutyl) -7-oxabicyclo- [2.2. l] hept-2-yl] -5-heptenoic, methyl ester

Following the procedure of example 63, part B, except that the acid [lß, 2a (5Z), 3a, 4ß] -7- [3- (2-oxo ^ thyl-7-oxabi) is replaced. -cyclo [2.2.1] hept-2-yl] -5-heptenoic, methyl ester with the aldehyde of title B, the alcohol of title C is obtained

D. A cide [lß, 2a (5Z), 3a, 4ß] -7- [3- [4- (hexylthio) -butyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5 -heptenoic

Following the procedure of Examples 44 and 45, except that the alcohol used in Example 44 is replaced by the alcohol from Part C above, the title compound is obtained.

Example 74

Acid [1, 2a (5Z), 3a, 4ß] -7- [3- [4- (cyclohexylthio) butyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Example 73, except that 1-hexanethiol is replaced by cyclohexylmercaptan, the title compound is obtained.

Example 75

Acid [1, 2a (5Z), 3a, 4ß] -7- [3- [4- (phenylthio) butyl] -7-oxabicy clo- [2.2.1 Jhept-2-ylJ-5-heptenoic

Following the procedure of Example 73, except that 1-hexanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 76

[1 ß, 2a (5Z), 3a, 4ß] -7- [3- [4- (benzylthio) butyl] -7-oxabicyclo- [2.2.1] hept-2-yl] heptenoic acid

Following the procedure of Example 73, except that 1-hexanethiol is replaced by benzylmercaptan, the title compound is obtained.

Examples 77, 78 and 79

[Lß, 2a (5Zj, 3a, 4ß] -7- [3- [(hexylsulfinyl) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid, methyl ester (isomer to rapid displacement), acid [lß, 2a (5Z), 3a, 4ß] -7- [3 - [(hexylsulfinyl) methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic, methyl ester (slow-moving isomer) and acid [lß, 2a (5Z), 3a, 4ß] -7- [3 - [(hexylsulfonyl) -methyl] -7-oxabicyclo [2.2.1 [hept-2-yl] - 5-heptenoic, methyl ester A solution containing 634 mg (1.72 mmol) of acid [lß, 2a- (5Z), 3a, 4ß] -7- [3 - [(hexylthio) rKthyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic, methyl ester (prepared as described in Example 44) in 6.78 ml of methanol at 0 ° C., added dropwise over 4 minutes, 8.37 ml of a 0.5M aqueous sodium periodate solution. Tetrahydrofuran (2 ml) is added, and the resulting reaction mixture is stirred at room temperature for 15 hours. A white precipitate is separated by filtration and washed with ether (3 x 50 ml). The filtrate is washed with 60 ml of a saturated aqueous solution of NaHC03 and dried over anhydrous magnesium sulfate. By concentration under vacuum, 648 mg of an oily crude product is obtained. The latter is chromatographed on 54.16 g of silica gel 60, using 0.5-1% CH3OH in CH2Cl2 as eluent. This provides FMI sulfoxide (fast moving isomer) (example 77) (211 mg, 32%), SMI sulfoxide (slow moving isomer) (example 78) (142 mg, 21%) and sulfone (example 79) (165 mg, 24%). These products are oils which solidify by storage in the refrigerator. TLC: silica gel, 2% CH3OH / CH2Cl2, Rf: example 77 sulfoxide, 0.28; example 78 sulfoxide, 0.21; example 79 sulfone, 0.74; iodine.

Example 80

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [(hexylsulfonyl) methyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid

To a stirred solution containing 165 mg (0.41 mmol) of acid [1, 2a (5Z), 3a, 4ß] -7- [3 - [(hexylsulfonyl) nwthyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic, methyl ester (example 79) in 20.3 ml of THF and 3.09 ml of H2O, under argon, 3.90 ml of an aqueous solution of hydroxide are added lithium IN. This mixture is vigorously purged with argon for 10 minutes and stirred at room temperature for 6 hours. The reaction mixture is acidified to pH 4 by addition of an aqueous solution of IN HCl and poured into 30 ml of a saturated NaCl solution. The solution obtained is saturated with solid NaCl and extracted with EtOAc (4 x 50 ml). The combined EtOAc extracts are dried (MgSO4), filtered and concentrated in vacuo to give 165 mg of the crude acid. The purification is carried out by flash chromatography on 20 g of silica gel 60, using 3% CH3OH in CH2Cl2 as eluent. This provides the title acid (145 mg, 91%) which solidifies when stored in the refrigerator. TLC: silica gel, CH3OH 4% / CH2Cl2, Rf = 0.32, iodine.

Analysis for C20H34O5S:

Calculated: C 62.18 H 8.81 S 8.29%

Found: C 61.99 H 9.01 S 8.33%

13CNMR (CDC13, 15.0 mHz) tau 178.4, 33.1, 24.3, 26.7, 128.9, 130.3.28.0, 39.9.79.8, 31.1, 28.8, 80.9, 47.0, 54.1, 51.7, 29.4.27.1, 22.2.21.9, 13.7.

Example 81

[Lß, 2a (5Z), 3a, 4ß] -7- [3- [(hexylsulfinyl) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic (fast-moving isomer )

To a stirred solution containing 211 mg (0.55 mmol) of acid [1, 2a (5Z), 3a, 4ß] -7- [3 - [(hexylsulfinyl) nKthyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic, methyl ester (isomer with fast displacement) prepared in example 77 in 27,0 ml of THF and 4,11 ml of H2O, under argon, one adds 5,19 ml d '' an aqueous solution of lithium hydroxide IN. This mixture is vigorously purged with argon for 10 minutes and stirred at room temperature for 6 hours. The reaction mixture is acidified to pH 4 by addition of an aqueous solution of IN HCl and poured into 50 ml of a saturated NaCl solution. The solution obtained is saturated with solid NaCl and extracted with EtOAc (4 x 100 ml). The combined EtOAc extracts are dried (MgSO4), filtered and concentrated in vacuo to give 216 mg of crude acid. Purification is carried out by flash chromatography on 20.2 g of silica gel 60 using 3% CH3OH in CH2Cl2 as eluent to give the title acid (172 mg, 85%) as a white solid. TLC: silica gel, CH3OH 4% / CH, C12, Rr = 0.10, iodine.

Analysis for Q20H34O4S:

Calculated: C 64.83 H 9.25 S 8.65%

Found: C 64.71 H 9.17 S 8.55%

13C NMR (CDC13, 15.0 mHz) tau 176.8, 33.3, 24.5, 26.9, 129.0, 130.2, 28.4, 41.1, 80.1, 31.2 , 28.3, 80.4, 47.1, 52.7, 52.7, 29.6, 26.7, 22.6, 22.3, 13.8.

Example 82

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [(hexylsulfinyl) methyl] -7-oxabicyclo- [2.2.1 Jhept-2-yl] -5-heptenoic (slow-moving isomer)

To a stirred solution containing 142 mg (0.37 mmol) of acid [1, 2a (5Z), 3a, 4ß] -7- [3 - [(hexylsulfinyl) nrethyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic, methyl ester (slow-moving isomer) prepared as described in Example 78, in 18.2 ml of THF and 2.77 ml of H2O, under argon, 3 is added, 50 ml of an IN aqueous solution of lithium hydroxide. This mixture is vigorously purged with argon for 15 minutes and stirred at am5 temperature

10

15

20

25

30

35

40

45

50

55

60

65

15

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biante for 4 hours and 40. minutes. The reaction mixture is acidified to pH 4 by addition of an aqueous solution of IN HCl and poured into 30 ml of a saturated NaCl solution. The solution obtained is saturated with solid NaCl and extracted with EtOAc (3 x 70 ml). The combined EtOAc extracts are dried (MgSO4), filtered and concentrated in vacuo to give 152 mg of the crude acid. The purification is carried out by flash chromatography on 20.8 g of silica gel 60 using 4% CH3OH in CH2Cl2 as eluent to give the title acid (116 mg, 85%). TLC: silica gel, CH3OH 4% / CH2Cl2, Rf - 0.6, iodine.

Analysis for C20H34O4S:

Calculated: C 64.83 H 9.25 S 8.65%

Found: C 64.44 H 9.15 S 8.58%

13C NMR (CDC13.15.0 mHz) tau 33.4, 24.6, 26.7, 129.0, 130.3, 27.1, 41.8, 80.0, 31.3, 28.4, 81.7 , 47.3, 52.8, 52.8, 29.4, 27.1, 22.4, 22.4, 13.8.

Example 83

Acid [1, 2a (5Z), 3a, 4ß] -7- [3- [(methylsulfinyl) methyl] -7-oxabicy-clo [2.2. l] hept-2-yl] -5-heptenoic (fast-moving isomer)

Following the procedure of Examples 44, 77 and 81, except that 1-hexanethiol is replaced by methyl mercaptan, the title compound is obtained.

Example 84

[Lß, 2a (5Z), 3a, -4ß] -7- [3- [(octylsulfinyl) methyl] -7-oxabicy clo- [2.2.1] hept-2-yl] -5-heptenoic acid (isomer to slow moving)

Following the procedure of Examples 44, 77 and 82, except that 1-hexanethiol is replaced by 1-octanethiol, the title compound is obtained.

Example 85

[Lß, 2a (5Z), 3ß, 4ß] -7- [3 - [(phenylsulfinyl) methyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic (displacement isomer fast)

Following the procedure of Examples 48, 77 and 81, except that 1-pentanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 86

[Lß, 2a (5Z), 3a, 4ßJ-7- [3 - [(ethylsulfinyl) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid (slow-moving isomer)

Following the procedure of Examples 48,77 and 82, except that 1-pentanethiol is replaced by ethylmercaptan, the title compound is obtained.

Example 87

Acid (1 ß, 2a, 3a, 4ß) -7- [3 - [(heptylsulfinyl) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptanoic (fast-moving isomer)

Following the procedure of Examples 46, 77 and 81, except that 1-hexanethiol is replaced by 1-heptanethiol, the title compound is obtained.

Example 88

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [(benzylsulfinyl) methyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 44, 77 and 81, except that 1-hexanethiol is replaced by benzylmercaptan, the title compound is obtained.

Example 89

[Lß, 2a (5Z), 3ß, 4ß] -7- [3 - [(benzylsulfinyl) methyl] -7-oxabicy-clo [2.2.1] hept-2-ylJ -5-heptenoic (slow-moving isomer )

Following the procedure of Examples 48, 77 and 82, except that 1-pentanethiol is replaced by benzylmercaptan, the title compound is obtained.

Example 90

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [(cyclohexylsulfinyl) methyl] -7-oxabi-cyclo [2.2.1] hept-2-yl] -5-heptenoic (displacement isomer Slow) Following the procedure of Examples 44, 77 and 81, except that 1-hexanethiol is replaced by cyclohexylmercaptan, the title compound is obtained.

Example 91

[Lß, 2a (5Z), 3a, 4ß [-7- [3 - [(cyclopentylsulfinyl) methyl] -7-10 oxabicyclol2.2.1 Jhept-2-yl] -5-heptenoic (fast-moving isomer)

Following the procedure of Examples 44, 77 and 81, except that 1-hexanethiol is replaced by cyclopentylmercaptan, the title compound is obtained.

15

Example 92

[Lß, 2a (5Z), 3a, 4ß [-7- [3- [(octylsulfonyl) methyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 44, 77 and 80, except that 1-hexanethiol is replaced by octylmercaptan, the title compound is obtained.

Example 93

[1, 2a (5Z), 3a, 4ß] -7- [3 - [(propylsulfonyl) methyl] -7-oxabicy-25 clof2.2.1 Jhept-2-yl] -5-heptenoic

Following the procedure of Examples 44, 77 and 80, except that 1-hexanethiol is replaced by propylmercaptan, the title compound is obtained.

30 Example 94

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [(phenylsulfonyl) methyl] -7-oxabicyclol2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 44, 77 and 80, except that 1-hexanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 95

[Lß, 2a (5Z), 3a, 4ß] -7- [3- [(benzylsulfonyl) methyl] -7-oxabicy-clo [2.2.1 [hept-2-yl] -5-heptenoic 40 Following the procedure of Examples 44, 77 and 80, except that 1-hexanethiol is replaced by benzylmercaptan, the title compound is obtained.

Example 96

45 [1ß, 2a (5Z), 3a, 4ß] -7- [3 - [(cyclohexylsulfonylmethyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 44, 77 and 80, except that 1-hexanethiol is replaced by cyclohexylmercaptan, the title compound is obtained.

50

Example 97

[Lß, 2a (5Z), 3ß, 4ß] -7- [3- [(heptylsulfonyl) methyl] -7-oxabicy-clo [2.2.1 [hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 48, 77 and 80, except 55 that 1-pentanethiol is replaced by 1-heptanethiol, the title compound is obtained.

Example 98

[Lß, 2a (5Z), 3ß, 4ß] -7- [3 - [(benzylsulfonyl) methyl] -7-oxabicy-60 clo [2.2.1 [hept-2-yl] -5-heptenoic

Following the procedure of Examples 48, 77 and 80, except that 1-pentanethiol is replaced by benzylmercaptan, the title compound is obtained.

65 Example 99

[Lß, 2a (5Z), 3ß, 4ß] -7- [3 - [(cyclopentylsulfonyl) methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 48, 77 and 80, except

658,247

replacing 1-pentanethiol with cyclopentylmercaptan, the title compound is obtained.

Example 100

[Lß, 2a (5Z), 3ß, 4ß] -7- [3 - [(phenylsulfonyl) methyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 48, 77 and 80, except that 1-pentanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 101

(Lß, 2a, 3a, 4ßj-7- [3 - [(cyclopropylsulfinyl) methyl) -7-oxabicy-clo [2.2.1] hept-2-ylJ-5-heptanoic acid

Following the procedure of Examples 46, 77 and 80, except that 1-hexanethiol is replaced by cyclopropylmercaptan, the title compound is obtained.

Example 102

Acid (lß, 2a, 3a, 4ß) -7- [3- [fbenzylsulfinyl) methylJ-7-oxabicyclo- [2.2.1] hept-2-ylJ-5-heptanotque

Following the procedure of Examples 47, 77 and 81, except that 1-hexanethiol is replaced by benzylmercaptan, the title compound is obtained.

Example 103

[Lß, 2a (5Z), 3a, 4ß] -7- [3- [2- (pentylsulfinyl) ethylJ-7-oxabicy-clo [2.2.1] hept-2-ylJ-5-heptenoic acid

Following the procedure of Examples 63, 44, 77 and 81, except that 1-hexanethiol is replaced by 1-pentanethiol, the title compound is obtained.

Example 104

A cide [lß, 2a (5Z), 3a, 4ß] -7- [3- [2- (phenylsulfonylJ ethylJ-7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 63, 44, 77 and 80, except that 1-hexanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 105

A cide [lß, 2a (5Z), 3a, 4ß] -7- [3- [2- (cyclohexylsulfonyl) ethyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 63, 44, 77 and 80, except that 1-hexanethiol is replaced by cyclohexylmercaptan, the title compound is obtained.

Example 106

[Lß, 2a (5Z), 3a, 4ß] -7- [3- [2- (benzylsulfinyl) ethylJ-7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 63, 44, 77 and 81, except that 1-hexanethiol is replaced by benzylmercaptan, the title compound is obtained.

Example 107

[Lß, 2a (5Z), 3ß, 4ß] -7- [3- [2- (butylsulfonyl) ethyl] -7-oxabicy-clo [2.2.1Jhept-2-yl] -5-heptenoic acid

Following the procedure of Examples 63, 48, 77 and 80, except that 1-pentanethiol is replaced by butylmercaptan, the title compound is obtained.

Example 108

[Lß, 2a (5Z), 3ß, 4ß] -7- [3- [2- (phenylsulfinyl) ethyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 63, 48, 77 and 81, except that 1-pentanethiol is replaced by phenylmercaptan, the title compound is obtained.

16

Example 109

A cide [lß, 2a (5Z), 3ß, 4ßJ- 7- [3- [2- (benzylsulfinylJ ethyl] -7-oxabicy-clo [2.2.1 Jhept-2-yl] -5-heptenoic

Following the procedure of Examples 63, 48, 77 and 81, 5 except that 1-pentanethiol is replaced by benzylmercaptan, the title compound is obtained.

Example 110

A cide [lß, 2a (5Z), 3ß, 4ß] -7- [3- [2- (cycloheptylsulfonyl) ethyl] - 7-10 oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 63, 48, 77 and 80, except that 1-pentanethiol is replaced by cycloheptylmercap-tan, the title compound is obtained.

15 Example 111

Acid (lß, 2a, 3a, 4ß) -7- [3- [2- (pentylsulfonylJethyl] -7-oxabicyclo- [2.2.1 Jhept-2-ylJ-5-heptanotque

Following the procedure of Examples 63, 46, 77 and 80, except that 1-hexanethiol was replaced by 1-pentanethiol, the title compound was obtained.

Example 112

(Lß, 2a, 3a, 4ß) -7- [3- [2- (phenylsulfinyl) ethyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptanoic 25 Following the procedure examples 63, 46, 77 and 81, except that 1-hexanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 113

^ Acid (lß, 2a., 3o., 4ßj-7- [3- [2- (benzylsulfinyl) ethyl] -7-oxabicyclo- [2.2.1 Jhept-2-yl] -5-heptanoic

Following the procedure of Examples 63, 46, 77 and 81, except that 1-hexanethiol is replaced by benzylmercaptan, the title compound is obtained.

35 Example 114

(Lß, 2a, 3a, 4ß) -7- [3- [2- (cyclohexylsulfonyl) ethyl] -7-oxabicy-clo [2.2.1] hept-2-ylJ-5-heptanoic acid

Following the procedure of Examples 63, 48, 77 and 80, 40 except that 1-hexanethiol is replaced by cyclohexylmercaptan, the title compound is obtained.

Example 115

[Lß, 2a (5Z), 3a, 4ß] -7- [3- [4- (pentylsulfonyl) butyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid

45

Following the procedure of Examples 73, 63, 44, 77 and 80, except that 1-hexanethiol is replaced by pentylmercaptan, the title compound is obtained.

Example 116

50 Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [4- (cy clohexylsulfinyl) butylJ-7-oxabicyclof2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 73, 63, 44, 77 and 81, except that 1-hexanethiol is replaced by cyclohexylmercaptan, the title compound is obtained.

55

Example 117

Acid [lß, 2a (5Z), 3a, 4fiJ-7- [3- [4- (phenylsulfinyl) butylJ-7-oxabicy-clo [2.2.1 Jhept-2-ylJ-5-heptenoic

Following the procedure of Examples 73, 63, 44, 77 and 81, 60 except that 1-hexanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 118

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [4- (benzylsulfonyl) butyl] -7-oxabicy-65 clo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 73, 63, 44, 77 and 80, except that 1-hexanethiol is replaced by benzylmercaptan, the title compound is obtained.

17

658,247

Example 119

[Lß, 2a (5Z), 3ß, 4ß] -7- [3- [4- (cyclopentylsulfinyl) butyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 73, 63, 48, 77 and 81, except that 1-pentanethiol is replaced by cyclopentylmercaptan, the title compound is obtained.

Example 120

[Lß, 2a (5Z), 3ß, 4ß] -7- [3- [4- (benzylsulfinyl) butyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 73, 63, 48, 77 and 80, except that 1-pentanethiol is replaced by benzylmercaptan, the title compound is obtained.

Example 121

[Lß, 2a (5Z), 3ß, 4ß] - 7- [3- [4- (propylsulfinyl) butyl] -7-oxabicy-clo [2.2.1] hept-2-ylJ -5-heptênoïque

Following the procedure of Examples 73, 63, 48, 77 and 81, except that 1-pentanethiol is replaced by propylmercaptan, the title compound is obtained.

Example 122

Acid [lß, 2a (5Z), 3ß, 4ßJ-7-f 3- [4- (phenylsulfonyl) butyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 73, 63, 48, 78 and 80, except that 1-pentanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 123

(1, 2a, 3a, 4ß) -7- [3- [4- (nonylsulfinyl) butyl] -7-oxabicyclo- [2.2.1] hept-2-yl] -5-heptanoic acid

Following the procedure of Examples 73, 63, 46, 77 and 81, except that 1-hexanethiol is replaced by 1-nonanethiol, the title compound is obtained.

Example 124

Acid (lß, 2a, 3a, 4ß) -7- [3- [4- (pentylsulfonylj butyl] - 7-oxabicyclo- [2.2.1] hept-2-ylJ-5-heptanoïque

Following the procedure of Examples 73, 63, 46, 77 and 80, except that 1-hexanethiol is replaced by 1-pentanethiol, the title compound is obtained.

Example 125

Acid (lß, 2a, 3a, 4ß) -7- [3- [4- (phenylsulfinyl) butyl] -7-oxabicyclo- [2.2.1 Jhept-2-yl] -5-heptenoic

Following the procedure of Examples 73, 63, 46, 77 and 81, except that 1-hexanethiol is replaced by phenylmercaptan, the title compound is obtained.

Example 126

Acid (lß, 2a, 3a, 4ß) -7- [3- [4- (cyclohexylsulfonyl) butyl] -7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptanoic

Following the procedure of Examples 73, 63, 46, 77 and 80, except that 1-hexanethiol is replaced by cyclohexylmercaptan, the title compound is obtained.

Example 127

A cide [lß, 2a (5Z), 3a, 4ß] -7- [3 - [[(cyclohexylmethyl) thio [methyl] - 7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic A. [1ß, 2a (5Z), 3a, 4ß] -7- [3 - [[(cyclohexylmethyl] thio] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic, methyl ester To a solution containing 88 mg (0.78 mmol) of potassium t-butoxide in 5 ml of anhydrous THF, under argon, 277 mg (2.13 mmol) of cyclohexylmethanethiol (prepared from cyclohexylmethanol according to the Volante's method: Tetrahedron Letters 1981,22,3119). To this mixture is added a solution containing 300 mg (0.71 mmol) of acid [lß, 2a (5Z), 3a, 4ß] -7- [3- (p-tolu0nesulfo-nyloxymethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic, methyl ester, prepared as described in Example 44B, in 5.5 ml of anhydrous THF. The reaction mixture is heated at reflux for 7 hours, the cooled reaction mixture is diluted with 250 ml of ether and poured into 100 ml of saturated NaHCO 3 solution. The aqueous layer is extracted with ether (2 × 100 ml). . The combined ethereal extracts (450 ml) are washed with an aqueous solution of 0.5N sodium hydroxide (2 x 100 ml) and brine (100 ml). The ethereal extracts are dried over anhydrous MgSO4 and concentrated in vacuo to give an oily product. Purification is carried out by chromatography on 20.2 g of silica gel 60 using hexane: ether (3: 1) as eluent to give 253 mg of methyl ester of title A, in the form of a oil (94%). TLC: silica gel, petroleum ether: ether (3: 2), Rf = 0.70, iodine.

B. A cide [lß, 2a (5Z), 3a, 4ß] -7- [3 - [[(cyclohexylmethyl) thio] meth-15 yl] -7-oxabicyclo [2.2.1] hept-2-yl] - 5-heptenoic

To an agitated solution containing 243 mg (0.64 mmol) of the methyl ester of part A in 31.4 ml of THF and 4.80 ml of H2O, under argon, 6.00 ml of an aqueous solution of IN lithium hydroxide. This mixture is vigorously purged with argon for 20 minutes and stirred at room temperature for 16 hours. The reaction mixture is acidified to pH 5 by addition of an aqueous solution of IN HCl and poured into 40 ml of a saturated NaCl solution. The solution obtained is saturated with solid NaCl and extracted with EtOAc (4 x 50 ml). The combined EtOAc extracts are dried (MgSO4), filtered and concentrated in vacuo to give 253 mg of crude acid. Purification is carried out by flash chromatography on 20.6 g of silica gel 60 using petroleum ether: ether (2: 3) as eluent to give the pure title product (117 mg, 50%) at the same time than 108 mg (46%) of mixed fractions of which the title product is the main component. TLC: silica gel, petroleum ether: ether (2: 3), Rf = 0.32, iodine.

Analysis for C21H34O3S:

Calculated: C 68.85 H 9.29 S 8.74%

35 Found: C 68.90 H 9.43 S 8.66%

13C NMR (CDCI3, 15.0 mHz) tau 178.7, 32.9, 24.6, 26.1, 129.7, 129.9, 29.5.47.1, 80.4, 26.7, 26 , 3, 80.7, 47.6, 33.4, 40.4, 38.0, 32.9, 29.5, 26.1, 29.5, 32.9.

40 Example 128

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [[(2-phenylethyl) thio] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid

A. Acid [1, 2a (5Z), 3a, 4ß] -7- [3 - [[(2-phenylethyl) thio] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5- heptenoic, methyl ester

45

To a solution containing 55.7 mg (0.50 mmol) of potassium t-butoxide in 5 ml of anhydrous THF, under argon, 185 mg (1.35 mmol) of phenylethanethiol are added. To this mixture is added a solution containing 189 mg (0.45 mmol) of the acid [lß, 2a (5Z), 3a, 4ß] -7- [3- (p-toluenesulfonyloxymethyl) -7-oxabicyclo [2.2. 1] hept-2-yl] -5-50 heptenoic, methyl ester, prepared as described in Example 44B, in 6 ml of anhydrous THF. The reaction mixture is heated at reflux for 4 hours and 30 minutes. The cooled reaction mixture is diluted with 160 ml of ether and poured into 60 ml of a saturated NaHCO3 solution. The aqueous layer is extracted with ether 55 (2 x 60 ml). The combined ethereal extracts (280 ml) are washed with an aqueous solution of 0.5N sodium hydroxide (2 x 60 ml) and brine (75 ml). The ethereal extracts are dried over MgS04 and concentrated in vacuo to give an oily product. The purification is carried out by chromatography on 21.6 g of silica gel 60, 60 using petroleum ether: ether (5: 1) as eluent to give 157 mg of title compound A, in the form of a oil (90%). TLC: silica gel, petroleum ether: ether (2: 1), Rf = 0.60, iodine.

B. Acid [1, 2a (5Z), 3a, 4ß] -7- [3 - [[(2-phenylethyl) thio] methyl] -7-65 oxabicyclo [2.2.1] hept-2-yl] -5 -heptenoic

To a stirred solution containing 150 mg (0.39 mmol) of the methyl ester of part A in 19 ml of freshly distilled THF and 2.91 ml of H 2 O, under argon, 3.64 ml of a solution are added.

658,247

18

aqueous lithium hydroxide IN. This mixture is vigorously purged with argon for 25 minutes and stirred at room temperature for 6 hours. The reaction mixture is acidified to pH 5 by addition of an aqueous solution of IN HCl and poured into 40 ml of a saturated NaCl solution. The solution obtained is saturated with solid NaCl and extracted with EtOAc (4 x 60 ml). The combined EtOAc extracts are dried (MgSO4), filtered and concentrated in vacuo to give 147 mg of the crude acid. Purification is carried out by flash chromatography on 20 g of silica gel 60 using 2% CH3OH in CH2Cl2 as eluent to give the title product (122 mg, 84%) as an oil. TLC: silica gel, CH3OH 6% in CH2C12, Rf = 0.32, iodine.

Analysis for C22H30O3S:

Calculated: C 70.55 H 8.07 S 8.56%

Found: C 70.54 H 8.08 S 8.48%

13C NMR (CDC13.15.0 mHz) tau 179.0, 33.4, 24.5, 26.2, 129.9,

129.7, 26.7, 46.9, 80.4, 29.5, 80.6, 47.5, 32.3, 34.1, 36.4, 140.5, 128.4, 126.3, 128, 4, 128.4.

Example 129

Acid [1, 2a (5Z), 3a, 4ß] -7- [3- [[((3-phenylpropyl) thio Jmethyl J-7-oxabicyclo [2.2.1 Jhept-2-yl] -5-heptenoic

A. Acid [1, 2a. (5Z), 3a, 4ß] -7- [3- [f (3-phenylpropylJ thio Jmethyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic , methyl ester

To a solution containing 88 mg (0.78 mmol) of potassium t-butoxide in 5 ml of anhydrous THF, under argon, 324 mg (2.13 mmol) of 3-phenylpropylmercaptan is added. To this mixture is added a solution containing 300 mg (0.71 mmol) of acid [1, 2a- (5Z), 3a, 4P] -7- [3- (p-toluenesulfonyloxymethyl) -7-oxabicyclo- [2.2 .1 Jhept-2-yl] -5-heptenoic, methyl ester in 7 ml of anhydrous THF. The reaction mixture is heated at reflux for 6 hours and 30 minutes. The cooled reaction mixture is diluted with 250 ml of ether and poured into 100 ml of a saturated NaHCO3 solution. The aqueous layer is extracted with ether (2 x 100 ml). The combined ethereal extracts (450 ml) are washed with an aqueous 0.5N sodium hydroxide solution (2 x 100 ml) and with brine (100 ml). The ethereal extracts are dried over MgS04 and concentrated in vacuo to give an oily product. The purification is carried out by chromatography on 25 g of silica gel 60 using hexane: ether (3: 1) as eluent to give 280 mg of the title compound A, in the form of an oil (98%). TLC: silica gel, petroleum ether: ether (2: 1), Rf = 0.60, iodine.

B. A cide [lß, 2a (5Z), 3a, 4ß] -7- [3- [[(3-phenylpropyl) thioJmethyl] -7-oxabicyclo [2.2.1 Jhept-2-yl] -5-heptenoic

6.60 ml of a solution are added to a stirred solution containing 280 mg (0.70 mmol) of the methyl ester of part A in 34.4 ml of freshly distilled THF and 5.30 ml of H2O, under argon. aqueous lithium hydroxide IN. This mixture is purged with argon for 1 hour and stirred at room temperature for 3 hours. The reaction mixture is acidified to pH 5 by addition of an aqueous solution of IN HCl and poured into 50 ml of a saturated NaCl solution. The solution obtained is saturated with solid NaCl and extracted with EtOAc (4 x 60 ml). The combined EtOAc extracts are dried (MgSO4), filtered and concentrated in vacuo to give 280 mg of the crude acid. The purification is carried out by flash chromatography on 29 g of silica gel 60 using 2% CH3OH in CH2Cl2 as eluent to give the title product (205 mg, 76%). TLC: silica gel, 6% CH3OH / CH2Cl2, Rr = 0.34, iodine.

Analysis for C23H3203S:

Calculated: C 71.09 H 8.30 S 8.25%

Found: C 70.81 H 8.36 S 8.14%

13C NMR (CDC13.15.0 mHz) tau 179.0, 33.4, 24.7.26.7,129.7,

129.8, 29.5, 46.9, 80.4, 29.5, 80.6.47.5, 32.1, 31.9, 26.2, 34.7, 141.4, 128.4, 128.4, 125, 8, 128.4, 128.4.

Example 130

[Lß, 2a (5Z), 3ß, 4ß] -7- [3 - [[(cyclohexylmethyl) thio] methylJ-7-oxabicyclof 2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 48 and 49, except that 1-pentanethiol is replaced by cyclohexylmethanethiol, the title compound is obtained.

Example 131

[1, 2a (5Z), 3ß, 4ß] -7- [3 - [[((3-cyclohexylpropyl) thio] methyl] -7-oxabicyclo [2.2.1 Jhept-2-yl] -5-heptenoic

Following the procedure of Examples 48 and 49, except that 1-pentanethiol is replaced by 3-cyclohexylpropanethiol, the title compound is obtained.

Example 132

Acid (lß.2a, 3a..4ß) -7- [3 - [[f2-cyclohexylethyl) thio] methylJ-7-oxabicyclof2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 46 and 47, except that 1-hexanethiol is replaced by 2-cyclohexylethanethiol, the title compound is obtained.

Example 133

[Lß, 2a (5Z), 3ß, 4ß] -7- [3- [[((2-phenylethyl) thio JmethylJ-7-oxabicyclo [2.2.1 Jhept-2-yl] -5-heptenoic acid

Following the procedure of Examples 48 and 49, except that 1-pentanethiol is replaced by 2-phenylethanethiol, the title compound is obtained.

Example 134

[Lß, 2a (5Z), 3ß, 4ß] -7- [3 - [[(3-phenylpropyl) thio] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 48 and 49, except that 1-pentanethiol is replaced by 3-phenylpropanethiol, the title compound is obtained.

Example 135

(1, 2a, 3a, 4ß) -7- [3 - [[((2-phenylethyl) thio JmethylJ-7-oxabicy-clo [2.2.1] hept-2-yl] -5-heptanoic acid

Following the procedure of Examples 46 and 47, except that 1-hexanethiol is replaced by 2-phenylethanethiol, the title compound is obtained.

Example 136

Acid (lß, 2a, 3a, 4ß) -7- [3- [[((3-phenylpropyl) thio JmethylJ-7-oxabi-cyclof2.2.1 Jhept-2-yl] -5-heptenoic

Following the procedure of Examples 46 and 48, except that 1-hexanethiol is replaced by 3-phenylpropanethiol, the title compound is obtained.

Example 137

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3 - [[(cyclohexylmethyl) sulfinyljmêth-yl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic (isomer to slow moving)

Following the procedure of Examples 44, 77 and 81, except that 1-hexanethiol is replaced by cyclohexylmethanethiol, the title compound is obtained.

Example 138

Acid [lß, 2a (5Z), 3ß, 4ßJ-7- [3 - [[(cyclohexylmethyl) sul / inviJmêthylJ-7-oxabicyclo [2.2.1 Jhept-2-ylJ-5-heptenoic (fast-moving isomer)

Following the procedure of Examples 48, 77 and 81, except that 1-pentanethiol is replaced by cyclohexylmethanethiol, the title compound is obtained.

Example 139

[Lß, 2a (5Zj, 3ß, 4ßJ-7- [3 - [[(2-phenylethylJstdfinylJmethylJ-7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid (fast-moving isomer)

5

10

15

20

25

30

35

40

45

50

55

60

65

19

658247

Following the procedure of Examples 44, 77 and 81, except that 1-pentanethiol is replaced by 2-phenylethanethiol, the title compound is obtained.

Example 140

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [[(3-phenylpropyl) sulfinyl] methyl} -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic ( fast-moving isomer)

Following the procedure of Examples 48, 77 and 82, except that 1-pentanethiol is replaced by 3-phenylpropanethiol, the title compound is obtained.

Example 141

(Lß, 2a, 3a, 4ß) -7- [3 - [[(2-phenylethyl) sulfinyl] methyl] -7-oxabi-cyclo [2.2.1] hept-2-yl] -5-heptanoic (isomer fast moving) Following the procedure of Examples 46, 77 and 81, except that 1-hexanethiol is replaced by 2-phenylethanethiol, the title compound is obtained.

Example 142

[1ß, 2a (5Z), 3a, 4ß] -7- [3 - [((cyclohexylmethyl) suifonyl] meth-yl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 44, 77 and 80, except that 1-hexanethiol is replaced by cyclohexylmethanethiol, the title compound is obtained.

Example 143

[Lß, 2a (5Z), 3a, 4ß] -7- [3- [[(2-phenylethyl) tallow onyl] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 44,77 and 80, except that 1-hexanethiol is replaced by 2-phenylethanethiol, the title compound is obtained.

Example 144

[Lß, 2a (5Z), 3a, 4ß] -7- [3 - [[(3-phenylpropyl) sulfonyl] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 44, 77 and 80, except that 1-hexanethiol is replaced by 3-phenylpropanethiol, the title compound is obtained.

Example 145

A cide [lß, 2a (5Z), 3a, 4ß] -7- [3- [2 - [(cyclohexylmethyl) thio] ethyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 63 and 44, except that 1-hexanethiol is replaced by cyclohexylmethanethiol, the title compound is obtained.

Example 146

[1ß, 2a (5Z), 3a, 4ß] -7- [3- [2 - [(cyclohexylmethyl) sulfinyl] ethyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 63, 44, 77 and 81, except that 1-hexanethiol is replaced by cyclohexylmethanethiol, the title compound is obtained.

Example 147

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [2- [(cyclohexylmethyl) tallow onyl] -ethyl] -7-oxabicy clo [2.2.1] hept-2-yl] -5 -heptenoic

Following the procedure of Examples 63, 44, 77 and 80, except that 1-hexanethiol is replaced by cyclohexylmethanethiol, the title compound is obtained.

Example 148

[1, 2a (5Z), 3a, 4ß] -7- [3- [2 - [(2-phenylethyljthiolJethyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 63 and 44, except that 1-hexanethiol is replaced by 2-phenylethanethiol, the title compound is obtained.

Example 149

Acid [lß, 2a (5Z), 3ß, 4ß] -7- [3- [2 - [(2-phenylethyl) sulfinyl] ethyl] -7-oxabicyclof 2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 63, 44, 77 and 81, 5 except that 1-hexanethiol is replaced by 2-phenylethanethiol, the title compound is obtained.

Example 150

[Lß, 2a (5Z), 3a, 4ß] -7- [2- [(3-phenylpropyl) thio Jethyl] -7-îo oxabicyelo [2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 64 and 44, except that 1-hexanethiol is replaced by 3-phenylpropanethiol, the title compound is obtained.

15 Example 151

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [2 - [(3-phenylpropyl) sulfinylJethyl] -7-oxabicy clo [2.2.1 Jhept-2-yl] -5-heptenoic

Following the procedure of Examples 63, 44, 77 and 81, except that 1-hexanethiol is replaced by 3-phenylpropane-20 thiol, the title compound is obtained.

Example 152

[1, 2a (5Z), 3a, 4ß] -7- [3- [2 - [(2-phenylethyl) sulfonyl] ethyl] -7-oxabicycloj2.2.1] hept-2-yl] -5-heptenoic 25 Following the procedure of Examples 63, 44, 77 and 80, except that 1-hexanethiol is replaced by 2-phenylethanethiol, the title compound is obtained.

Example 153

Acid f lß, 2a (5Z), 3a, 4ß] -7- [3- [2- [(3-phenylpropyl) tallow onylJethyl] -30 7-oxabicyclof2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 63, 44, 77 and 80, except that 1-hexanethiol is replaced by 3-phenylpropane-thiol, the title compound is obtained.

35 Example 154

[Lß, 2a (5Z), 3a, -4ß] -7- [3- [4 - [(cyclohexylmethyl) thio] butyl] -7-oxabicycloj2.2.1] hept-2-yl] -5-heptenoic acid

Following the procedure of Examples 73, 63 and 44, except that 1-hexanethiol is replaced by cyclohexylmethanethiol, the title compound is obtained.

Example 155

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [4 - [(cyclohexylmethyl) sulfinyl] butyl] -7-oxabicy clo [2.2.1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 73, 63, 44, 77 and 81, except that 1-hexanethiol is replaced by cyclohexylmethanethiol, the title compound is obtained.

Example 156

50 Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [4 - [(cyclohexylmethyl) sulfonyljbuty-l] -7-oxabicy clo] 2.2.1] hept-2-yl] -5- heptenoic

Following the procedure of Examples 73, 63, 44, 77 and 80, except that 1-hexanethiol is replaced by cyclohexylmethanethiol, the title compound is obtained.

55

Example 157

Acid] lß, 2a (5Z), 3a, 4ß] -7- [3- [4 - [(2-phenylethyl) thio] butyl] -7-oxabicyclo] 2.2.1] hept-2-yl] -5- heptenoic

Following the procedure of Examples 73, 63 and 44, except that 60 which 1-hexanethiol is replaced by 2-phenylethanethiol, the title compound is obtained.

Example 158

Acid] lß, 2a (5Z), 3a, 4ß] -7- [3- [4 -] (2-phenylethyl) sulfinyl] butyl] -7-65 oxabicyclo [2.2.1] hept-2-yl] -5 -heptenoic

Following the procedure of Examples 73, 63, 44, 77 and 81, except that 1-hexanethiol is replaced by 2-phenylethanethiol, the title compound is obtained.

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20

Example 159

Acid [1, 2a (5Z), 3a, 4ß] -7- [3- [4- [(2-phenylethyl) sulfonyl] butyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5- heptenoic

Following the procedure of Examples 73, 63, 44, 77 and 80, except that 1-hexanethiol is replaced by 2-phenylethanethiol, the title compound is obtained.

Example 160

Acid [lß, 2a (5Z), 3a, 4ß] -7- [3- [2- fheptylthio) ethyl J-7-oxabicyclo- 10 [2.2.1] hept-2-yl] -5-heptenoic and methyl ester

By reacting [lp, 2a (5Z), 3a, 4P] -7- [3- (2-hydroxyethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid, methyl ester (see Example 20B) with tosyl chloride as in Example 44B, and with heptanethiol according to the method described in 44C, the title product is obtained, in the form of methyl ester, in colorless oil. TLC: silica gel, hexane: ether (2: 1), Rr = 0.45. By hydrolysis according to the method of Example 45, the free acid is obtained in the form of an oil; TLC: silica gel, 3% CH3OH / CH2Cl2, Rf =

Analysis for C22H3803S:

Calculated: C 69.06 H 10.01 S 8.38%

Found: C 68.80 H 9.99 S 8.24%

13C NMR (CDCI3, 15.0 mHz) tau 178.8, 33.4, 22.5, 24.5, 129.5, 130.1, 26.6.46.1, 80.1, 29.7, 29 , 7, 80.1, 47.3, 32.3, 31.7, 31.7, 29.5, 28.8, 32.3, 28.8, 26.6, 13.9.

Example 161

Acid [lß, 2a (5Z), 3a (E), 4ß] -7- [3 - [[((3-phenyl-2-propenyl) thio jmethyl] oxabicyclo [2.2.1] hept-2-yl] -5 -heptenoic and methyl ester

Following the procedure of Example 44 and replacing the 1-hexanethiol used in Example 44 (C) with 3-phenyl-2-propenylthiol, the title methyl ester is obtained; TLC: silica gel, hexane: ether (2: 1), Rf = 0.35; then proceeding to hydrolysis according to the method described in Example 45, the title free acid is obtained; TLC: silica gel, 3% CH3OH / CH2Cl2, Rf = 0.25.

Analysis C23H30O3S:

Calculated: C 71.46 H 7.82 S 8.30%

Found: C 71.31 H 7.87 S 8.26%

Claims (13)

658,247 2 CLAIMS 1. Compound having the following constitution formula: CH - A- {CH,) -CO_R and comprising all the stereoisomers thereof, wherein A represents - CH = CH— or - (CH2) 2 -; B is oxygen (—O—) or —S— II (0) n- or n 'is 0 to 2; m is 1 to 8; n is 1 to 4; R is hydrogen, alkyl, alkali metal or tris (hy-droxymethyl) aminomethane; and R1 is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkylalkynyl. 2. A compound according to claim 1, in which B is - O—. 3. The compound of claim 1, wherein B is - S—. 4. Compound according to claims 1 to 3, in which A is —CH = CH -. 5. Compound according to claims 1 to 3, in which R is H. 6. A compound according to claims 1 to 3, in which n is equal at 1. 7. A compound according to claims 1 to 3, in which n is equal to 2. 8. A compound according to claims 1 to 3, in which n is equal to 3 or 4. 9. A compound according to claims 1 to 3, in which A is —CH = CH—, m is 2 to 4, n is 1 or 2, R is H and R1 is lower alkyl or cycloalkyl. 10. A compound according to claims 1 to 3, in which A is —CH = CH—, m is equal to 3, n is equal to 1, R is H, CH3 or CöH13, and R1 is lower alkyl. 11. A compound according to claim 1, in which A is —CH = CH—, m is 3, n is 1, n 'is 1 and R1 is lower alkyl. 12. A compound according to claim 1, in which A is - CH = CH—, m is equal to 3, n is equal to 1, n 'is equal to 2 and R1 is lower alkyl. 13. Composition for inhibiting the aggregation of blood platelets and bronchoconstriction, comprising an effective amount of a compound according to claim 1 or of a pharmaceutically acceptable salt thereof, as well as a support pharmaceutically acceptable thereof.