LU85249A1 - SUBSTITUTED ANALOGS OF 7-OXABICYCLOHEPTANE-PROSTAGLANDIN - Google Patents

Description

Substituted analogs of 7-oxabicycloheptane-prostaglandin,

The present invention relates to analogs of 7-oxabicycloheptane-prostaglandin which are cardiovascular agents useful, for example, in the treatment of thrombolytic diseases. These compounds correspond to the structural formula: ch2-a- (¾) m ~ C00R 10 1 \ Jk \

ΐχΛ X (CH2> „- B-R

in which B represents an oxygen atom (—0-) '1 or -S- where n * represents a number from 0 to 2, R re- i ~. 15 (o), has a hydrogen atom, a lower alkyl group, an alkali metal or a trihydroxy- methylaminomethane group, R represents an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an aralkenyl group, an aralkynyl group, a cycloalkylalkyl group, a cycloalkylalkenyl group or a cycloalkynyl group, A represents -CH = CH- or -n represents a number from 1 to 4 and m represents a number from 1 to 8 , Including all stereoisomers of these compounds.

The terms "lower alkyl group" or "alkyl group" used in this specification include both straight chain and branched chain radicals containing up to 12 to 30 carbon atoms, preferably 1 to 8 carbon atoms. carbon, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, iso-butyl group, pentyl group, hexyl group, isohexyl group , heptyle group, 4 * 4- group

L

2 dimethylpentyl, octyl group, 2,2,4-? trimethylpentyl, the nonyl group, the decyl group, the undecyl group, the dodecyl group, their Hl- various branched chain isomers and the like, as well as those groups comprising a halo substituent such as F, Br, Cl or I or CF ^ 9 an alkoxy substituent, a haloaryl substituent, a cycloalkyl substituent (ie, a cycloalkyl-alkyl substituent) or an alkylcycloalkyl substituent.

The terms "alkenyl group" and "alkynyl group" used in this specification include groups of like hydrocarbons having a 5- carbon-carbon double or triple bond, for example, 2-propenyl group,> The 2-hexenyl group, the 3-hexenyl group, the 3-hexynyl group and, in the case of an aryl or td * substituent a cycloalkyl substituent as defined below, the 3-phenyl-2-propenyl group , 3-phenyl-2-propynyl group, 3-cyclohexyl-2-propenyl group and 3-cyclohexyl-2-propynyl group.

The term "cycloalkyl group" embraces saturated cyclic hydrocarbon groups containing 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, especially the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the cyclohexyl group, the cycloheptyl group, cyclo-octyl group, cyclodecyl group and cyclododecyl group, any of which may be substituted by one or two halogen atoms, Lm 30 as well as by one or two lower alkyl groups V. and / or lower alkoxy groups.

The expression "aryl group" or "Ar", used in the present specification, designates monocyclic or bicyelic aromatic groups containing 6 to 10 carbon atoms in the nucleus, per / h 3 for example, the phenyl group, the naphthyl group , the substituted phenyl group or the substituted naphthyl group in which the substituent of the phenyl group 5 or of the naphthyl group may be a lower 5 -alkyl group, a halogen atom (Cl, Br or F) or a lower alkoxy group.

The terms "aralkyl group", "aryl-alkyl group" or "aryl-lower alkyl group", used in the present specification, denote lower alkyl groups of the type indicated above having an aryl substituent such as group 6 benzyl .

The expressions "(CH2) m" and 11 (CH2) n "embrace a straight or branched chain radical containing 1 to 8 carbon atoms in the normal chain in the case of" (CH0) "and 1 with 4 carbon atoms in t m the normal chain in the case of "(CH0)" and this radi—> '<it π cal may contain one or more lower alkyl substituents. Among the groups (CEL) and (CH9 ).

<mm δ τι 20 there are, for example, the groups CH2, CK ^ CKU ,, (CE ^) ^, (ch2) 4, (ch2) 5, (ch2) 6, (ch2) 7, - (ch2 ) 2-ch-,

CH

çh3

-CH9-CH-, -CH9-CH - CH-CH „-, -CH0-CH-CH9-CH- and ana-1 I Δ I I L Z t ÎTT

25 ch3 ch3 ch3 ch3 ch3 = logues.

The compounds of formula I (in which R is an alkyl group) are prepared by etherification or thioetherification of a compound of formula II: Z. 30 ^^ - CH2-A- (CH2) m-C02 alkyl 35 0

/ U

4 with the desired R * -OH or R * SH groups or their - equivalents according to conventional methods.

The synthesis of ethers and thioethers is based on the synthesis of Williamson ("J, Chem.

5 Soc. ” 4 * 229 (1852)) in which ethers (and later thioethers) have been synthesized by alkylation of alkoxides with alkyl halides:

R * (0 or S) Na + R "X -» R * (0 or S) RH + NaX

In the modern version of this synthesis, consideration is given to the use of other groups which separate from one another, in addition to halides. This is so that with regard to formula XI above, the etherification reaction or of thioetherification includes the reaction of a compound of formula IIa: CH2-A- (CH2) m-CO2 alkyl \ Hj ^ CH2) n-rCH2X IIa 20 in which X can also represent, in addition to the hydroxy group, -SH or its sodium or potassium salts, a chlorine atom, a bromine atom, an iodine atom and an alkyl group, aryl- and aralkyl-sulfonyloxy groups with a complementary compound R ^ X to form the following compounds of the type of formula I: ^^^ (CH2) -A- (CH2) -C02alkyle • - ai

CH2) n-0-R

\

III

! U * 5 ___ ^ CH2-A- (CH2) mC02alkyl »\ ^ j '(CH2) n-S-Rl

IV

The thioethers of formula IV can then be oxidized to sulfinyl and sulfonyl derivatives 10 (n * = 1 or 2 in formula I) corresponding to the formulas: CH2-A- (CH2) mCO2alkyl 0 ^ (c "2) n-f-Ri

O

v CH2-A- (CH2) m-C02alkyle 20 \ JLA 0 V1 | X (CH2) n-S.R1 V 0

VI

The compounds of formula I in which R represents an alkali metal or a hydrogen atom (free acid) can then be prepared from the above products in which R is an alkyl group, by conventional basic hydrolysis with hy 30 sodium hydroxide or potassium hydroxide to form the sodium and potassium salts, while then carrying out an acidification into free acid.

Etherification is usually carried out by reacting the compound of formula II with a compound of formula R * X in which X is an atom

/ U

6 of chlorine, a bromine atom, an iodine atom, an i · methylsulfonyloxy group or a toluene-sulfonyloxy group, in the presence of a strong base such as; sodium hydroxide or potassium hydroxide, 5 in a suitable solvent. When the reaction is carried out, the reagent R * X is used in a molar excess varying between 0.25 mol and 5 mol using a solvent such as xylene, tetrahydro-furan, dimethylsulfoxide or dimethylformamide. When X is a bromine atom or a chlorine atom, a phase transfer etherification can be adopted, in which case tetrahydrofuran ** · is used as solvent and a phase transfer reagent such as Bu ^ NHSO ^ or ( C ^ Hj-CH ^) (CH ^) ^ NHS · When ^ 15 R * is an aryl group, the alcohol group of the compound of formula II should first be reacted with triphenylphosphine and diethyl azodicarboxylate in solution with an inert solvent such as tetrahydrofuran, then with an R ^ (aryl) alcohol such as phenol. As is generally known in the art, the reaction sequence of the alcohol of formula II with the compound RX to effect etherification can be reversed by converting the alcohol of formula II to a compound of Formula II in which the alcohol group has been replaced by another radical of group X, while then carrying out a reaction with an R 1 -alcohol or alkoxide to form the product of formula I.

Thxoetherification is usually carried out by first converting the alcohol of formula XI to another derivative of formula II-X as indicated above and then performing a thioetherification with a mercaptan RSH in the presence of a base or with one of its alkali metal salts.

L

7 The oxidation of the sulphide product in which * n1 = 0 into sulfinyl and sulphonyl analogs in which n * is equal to 1 or 2, is easily carried out by reaction with sodium periodate in the presence of methanol and tetrahydrofuran to forming the sulfinyl and sulfonyl derivatives which can then be separated by chromatography or by other conventional separation methods.

The starting materials of formula II in which n is 1 (hydroxymethyl group), are known from U.S. Patent No. 4,143,054 and can be prepared as described herein. patent. These compounds can be used .. to prepare starting materials of formula II

> 15 in which n is a number between 2 and 4d by oxidation of the hydroxymethyl group to an aldehyde by means of Collins oxidation, for example, by reacting compound IX with chromium trioxide in pyridine to form an inter- 20 medium of formula: ^ CH2-A- (CH2) mCO2alkyl

VII

25 \

The aldehyde of formula VII is subjected to a homologation sequence by means of a Wittig reaction using (C ^ Hj.) ^ P ^ HOCH ^ j this reaction being followed by hydrolysis (nl) times, then reduction of the aldehyde to alcohol using a reducing agent such as sodium borohydride or sodium cyanoborohydride in a solvent such as methanol to form the starting material of formula II

L

8 Λ

+ U

Ο Φ fl)

CO -p H

cd Ό ta> i ο * * · ή x

'0) I O H

Φ C C CM CÖ H ^ ci

I >> O

. x o a H I · "· 1 .........> I ° te I I S cq _ iS I I ^ a 0 φ ai I H Ο ή

S i >> ^ I

- ^ X IC

(M CO H <s- 'a a ce i <s * ο o cq, o <N a w ο ο Λ a o

„I / O // O

1 / (L · / \ S Ύ J \ _V- ° i W w ry

H

Λ A ο CO -ri

K -P

O O -fr! o c a a a ο 'Φ this feD he has a I - c -h a

o -P CO

• H -P - *

• p -H lO

o to this \ o

'D 0) O

| a a w_ |

! , L

9

The tris (hydroxymethyl) aminomethane salt of either of the acids of formula X of the present invention is formed by reacting a solution of this acid in an inert solvent such as methanol with the tris (hydroxymethyl) - aminomethane, then the solvent is removed by evaporation to obtain the desired salt *

The compounds of the present invention have four centers of asymmetry as indicated by the asterisks in formula I. However, it is evident that each of the formulas described above and which do not have an asterisk, always represents all the possible stereoisomers * All the different stereoisomeric forms fall into | - 15 the scope of the invention.

The various stereoisomeric forms of the compounds of the invention can be prepared, in particular the cis-exo, cis-endo forms, as well as all the trans forms and stereoisomeric pairs as described in the examples of implementation below, of same as * by using starting materials and by following the methods described in the patent of the United States of America 4 · 143 “054 · We will give below examples of these stereoisomers,

25 - CH9-A- (CH9) -C09R

2 'Z' m Z

\ J_ (CH?) -B-R1 \ Z Tl

Z. 30 \ H

^ (cis-endo)

L

10

H

---- CH2-A- (CH2) m-C02R

5 -H

\ (CH2) n-B-Rl (cis-exo)

10 a.m.

^ '^ CH9-A- (CH9) -C09R

^ / a ^ m a, vr ^ (cH2) n ”B" Ri

- 15 \ I

\ H

ν '- ** ^ (trans) CH9-A- (CH9) -co9r 2 v 2ym 2 20 ~~ h X ^' ^ T ~ h 25 "0 (CH2) nB-R1 (trans), For reasons of For convenience, the core of each of the compounds of the invention is represented as follows: L 30:.

L

/ - 11 it will also be understood that the nucleus of the compounds of the invention can be represented as follows:

The compounds of the present invention are cardiovascular agents useful as inhibitors of platelet agglomeration, for example, for the treatment of thrombolytic diseases such as coronary or cerebral thromboses. They can

"S

also be selective thromboxane k0 receptor antagonists and synthesase inhibitors exerting, for example, a vasodilatory effect for the treatment of ischemic myo-

V

cards such as angina. The compounds of the invention are also inhibitors of the arachidonic acid cyclooxygenase. 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 dosage. lying in the inter-valle ranging from about 1 to 100 mg / kg, preferably from about 1 to 50 mg / kg and, in particular, from about 2 to 25 mg / kg at a rate of single dose or two to four divided daily doses.

The active substance can be used in a composition such as a tablet, capsule, line solution or suspension containing from about 5 to about 500 mg (per dosage unit) of a compound or mixture of compounds of formula I. They can be combined in the usual way with a vehicle, a carrier, an excipient, a binding agent, an L · 12 t preservative (a stabilizer), a flavor, etc. physiologically acceptable as required by accepted pharmaceutical practice. Likewise, as - indicated in the description above, some mem-5 bres also act as intermediates for other members of the group.

The following examples illustrate preferred embodiments of the invention.

Example 1 10 Acid [1β, 2α (5Ζ), 3a, 4ß] -7- [3 - [(hexyloxy) nw5thyl] -7-oxabicyclo [2,2,1] hept-2-yl] —5-heptenoï que , hexyl ester.

A. Acid [1, 2a (5Z), 3a * 4ß] - * 7 ~ [3- (hydroxy-methyl) -7-oxabicyclo [2,2,1] hept-2-ylJ- - 15-heptenoic, methyl ester (a) A mixture of N-acetylpyridinium chloride was prepared by adding dropwise 9 * 6 if 'ml (136 millimoles) of acetyl chloride to 56 ml of

Ipyridine. To this mixture was added 5 g (27 milli-20 moles) of (exo) -3- (2-methoxyethenyl) -7-oxabicyclo [2,2,1] heptane-2-methanol dissolved in 5 ml of pyridine . The resulting mixture was stirred at room temperature for 1.5 hours and poured into brine. The product was extracted into ether (3 x 200 ml) 3 the ether extracts were washed with 5% hydrochloric acid (2 x 400 ml) and brine (1 x 200 ml) and dried them over sodium sulfate. By concentration, a yellow oil was obtained which was purified by passing it through a short column of silica gel (150 ml) with dichloromethane 3 yield: 4 * 42 g of an oil.

(b) To a solution of 4 * 42 g (19 * 6 millimol) of the oil in 500 ml of tetrahydrofuran 35 containing 50 ml of water, 31 * 1 g (97 * 8 milli-

U

13 moles) of mercuric acetate. The yellow suspension formed was stirred for 10 minutes, then the whole mixture was poured into a solution containing 200 g of potassium iodide in 2 liters of water.

Upon stirring, the yellow color disappeared and the mixture was extracted with benzene (3 x 500 ml). The combined benzene extracts were washed with potassium iodide solution and brine and dried over sodium sulfate. By concentration, 3 * 7 g of a material was obtained which crystallized when it was left to stand in a cooler.

(c) A Wittig reagent was prepared in dimethyl sulfoxide (dried over calium hydride) by adding dropwise a solution of sodium methylsulfinylmethide (prepared in heating 300 mg sodium hydride). sodium in 60 ml of dimethyl sulfoxide at 75 ° C, until the evolution of hydrogen stops) to a solution of 5.32 g (12 mil-20 limoles) of 4-carboxybutyl-triphenylphosphonium bromide in 100 ml of dimethyl sulfoxide. After the formation of the first orange color which lasted more than 10 seconds, an equivalent amount of a base was added to form the ylide. To this dark orange solution was added a solution of the product obtained sub (b) in 20 ml of dimethyl sulfoxide and the mixture obtained was stirred at room temperature for 45 minutes * The reaction was stopped suddenly by adding 24 * 30 millimoles of acetic acid and the mixture was poured into 300 ml of brine, then extracted with 1 * ether (3 x 200 ml). By concentrating these extracts, an oil was obtained which was stirred with saturated sodium bicarbonate solution until triphenylphosphine oxide formed

L

14 crystalline in the mixture. This mixture was washed z. with benzene and acidified with $ 10 hydrochloric acid. The aqueous layer was saturated with salt and extracted with ether to obtain 2.43 g of a crude product after drying (sodium sulfate) and concentration. The mixture was stirred for 24 hours with 10 $ aqueous sodium hydroxide and re-isolated by acidification and ether extraction. The product was purified on 500 g of silica gel with a 50/50 mixture of ethyl acetate and hexane as eluent for; get 600 mg of an acid that crystallized when left to stand. This acid was recrystallized twice from a mixture of ethyl acetate and cyclohexane to obtain 320 mg of the acid [1ß, 2a (5Z), 3α, 4ß] -7- [3- (hydroxymethyl) -7-oxabicy- '^ clo [2,2., L] hept-2-yl] -5-heptenoic; fis ion point: 59 -3 ° C.

Analysis for C ^ H ^ O ^ Calculated: C 66.11; H 8.72 Found: C 66.06 d H 8.79

The acid was then transformed into the corresponding methyl ester by treatment with dia zomethane.

25 B. Acid flß, 2q (5Z), 3 ^^ 1-7 ^ 3 - ^^ 3-- oxy) -methyl] -7-oxabicyclo [2,2,1] hept-2-yl “j -5 -hept enoic, is er hexyli that.

A suspension of 0.56 g of Κ0Η powder in 15 ml of dry xylene was heated to reflux and 7 ml of xylene was separated by distillation. To this mixture was added a solution of 300 mg (1.12 millimole) of the alcohol ester obtained under A in 10 ml of dry xylene. The resulting mixture was heated to reflux and 9 ml of xylene was separated by distillation. To this mixture was added 1 g (5 * 6 millimoles) of 15 methane-n-hexyl sulfonate and the resulting mixture was heated at reflux for 1.5 hours.

The reaction mixture was cooled to room temperature and diluted with 60 ml of CE ^ C ^. The solution obtained was poured into 50 ml of saturated NaHCO ^. The layers were separated and the aqueous phase (2 x 60 ml) was extracted with CE ^ C ^ The combined extracts of CILjC ^ were dried over MgS 0 ^, then concentrated in vacuo to obtain 0, 9 g of a pro-10 ends up raw. The crude product was subjected to chromatography on 33.4 g of silica gel 60 with a 50 ml mixture of hexane and ether to obtain 390 mg ($ 83) of the hexyl ester under the heading.

Example 2 o- Acβ, 2α (5Ζ), 3κ, 4ΒΊ-7- [3-Γ (hexyloxy) methyl1-7- oxabicyclor2, 2, llhept-2-yll-5-hepteno5! Acid, -

To a stirred solution of 115 mg (0.27 millimole) of the hexyl ester of Example 1 in 12 ml of distilled tetrahydrofuran and 1.60 ml of 20 ^ 0, under an atmosphere of argon, 2 , 40 ml of an aqueous solution of IN lithium hydroxide. This mixture was purged with argon for 40 minutes and stirred at room temperature for 24 hours. At that time, analysis by thin layer chromatography revealed that the reaction was not not completed, so an additional 1 ml of methanol and 1 ml of IN aqueous lithium hydroxide were added. The reaction mixture was kept under stirring for 4 v ~ 30 additional hours, then it was acidified to a pH of 4 by addition of an aqueous solution of IN HCl, The solution obtained was poured into 25 ml of a saturated NaCl solution and saturated with solid NaCl. The aqueous layer was extracted with EtOAc (4 x 40 ml). The combined extracts were dried

.U

16 d * BfcOAc over anhydrous MgSO 4, they were filtered and - they were concentrated under vacuum to obtain 124 mg of a crude oil. This oil was chromatographed on 20.6 g of silica gel 60 using a 2: 3 mixture of hexane and ether as eluent to obtain 102 mg of the desired product contaminated with a small amount of hexyl alcohol. The mixture was placed in a high vacuum overnight at room temperature to obtain 77 mg (8450 of the title acid in pure form. Thin layer chromatography: silica gel, 8% CH ^ OH / CH ^ C ^,; R. £ = 0.74, iodine.

Analysis: for C20H34 ° 4 Calculated: C 70.97 d H 10.12 c 15 Found: C 70.60; H 9.89.

ΙΟ

Nuclear magnetic resonance spectrum JC ^ (CDC13> 15 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.

20 Example 3

Acid [lß, 2g (5, Z,), 3 ", 4ßl-7-f 3-Γ (hexyloxy) methyl ~ 1-7-oxabicyclo [2, 2, l] hept-2-yl ~] -5- hepteno3! that, hexyl ester.

503 mg (1.88 millimole) of the methyl ester of acid [1β, 2α (5Ζ), 3α, 4β] -7- [3- (hydroxymethyl) -7-oxabicyclo [2.2, were dissolved 1] hept-2-yl] -5-heptenoi'que (prepared as described in Example 1) in 2.17 ml of tetrahydrofuran. Then, 2.17 ml (15.46 millimoles) of bromide> <30 n-hexyl, 173.4 mg (0.51 millimoles) of tetrabutylammonium bisulfate (Bu ^ NHSO ^) were added and 2 , 17 ml of a 50% NaOH solution, then the mixture was vigorously stirred at room temperature. A slightly yellowish brown solution formed which, when stirred overnight, formed a precipitate

L

17 white

The reaction mixture was poured into g-25 ml of saturated NaHCOg. The mixture was extracted with CH2Cl2 (4 x 25 ml). The combined extracts of CE ^ C ^ (MgSO ^) were dried, filtered and concentrated in vacuo to obtain 1.272 mg of the hexyl ester of acid [1β, 2α (5Ζ), 3α, 4β] -7 - * [3 ~ [(hexyloxy) methyl] -7-oxabicyclo [2,2,1] hept-2-yl] -5 “hepteno5! The latter was subjected to chromatography on 40 g of silica gel using a 4 * 1 mixture of hexane and ether as eluent to obtain the final product.

Example 4, Acid (lß, 2κ, 3 ", 4ß) -7- [3- [(hexyloxy) methyl ~ 1-7-oxa- i, · bicyclof2,2, llhept-2-yl] heptanoi, queÎ ester hexyl.

A. Acid (lß, 2q, 3a;, 4ß) -7- [3- [(hydroxy) - ^ methyl-7 "Qxabicyclor2, 2, 1 ~] hept-2-yl1- heptanoic, methyl ester A 800 mg ( 3 millimoles) of the methyl ester of acid [lß, 2a (5Z), 3a, 4ß] -7- [3- (hydroxyn ^ thyl) - 7-oxabicyclo [2,2, l] hept- 2-yl] -5-heptenoic acid prepared as described in Example 1 and dissolved in 120 ml of ethyl acetate, under an atmosphere of argon, 160 mg of 5% palladium on carbon were added, rem -25 placed the argon atmosphere by a slight positive pressure of hydrogen and the reaction mixture was stirred for 8 hours at 25 °, it was filtered through a celite plug and evaporated to obtain 730 mg (90%) of compound A under heading.

N 30 B. (ΐβ, 2α, 3α, 4β) -7- [3-Γ (hexyloxy) - methyll -7-oxabicyclo (~ 2, 2, 1 hept-2-yll - 5-heptanoic acid, hexyl ester according to the method of example 1, but by substituting the alcohol ester of part A for the al-35 cool ester of example IA, the product 18 was obtained under heading.

Example 5 -r Acid (18.2g, 3 ", 4-S'ί —7—f 3-Γ (hexyloxy) methyll-7-oxa- bicyclof2, 2, l] hept-2-yl] heptano3! Que 5 Following the process of Example 2, but substituting the hexyl ester of Example 4 for the hexyl ester of Example 1, the acid is obtained under heading in the form of an oil [a] DJ = -3 * 1 (c = 1.37, CHClg) J thin layer chromatography 10 (silica gel, 8% CH30H / CH2C12; Rf = 0.74.

Analysis: for C ^ H ^ O ^

Calculated: C 70.55 5 H 10.66 Found: c 70.30; H 10.70.

l

Nuclear magnetic resonance spectrum ° C

»S 15 (CDC13, 15 MHz) tau î 179.1, 33.9, 24.6, 27.6, 29.2, 29.3, 29.0, 47.0, 79.1, 29.7 , 29.6, 80.1, 7 46.4, 71.2, 69.8, 29.3, 25.8, 31.6, 22.6, 14.

Example 6

Acid [~ 1β, 2k (5Z), 36, 46l-7- [3- [(hexyloxy) méthyll-7-20 oxabicyclof ~ 2, 2, l1hept ~ 2-yl1 ~ 5 ~ heptenoxque «

Following the method of examples 3 e 2, but substituting the methyl ester of acid [1β, 2α (5Ζ), 3β, 4β] -7- [3- (hydroxymethyl) -7-oxabicy-clo [2, 2, 1] hept-2-yl] -5-heptenoic acid methyl ester [25, 2g (5Z), 3a, 4ß] -7- [3- (hydroxym6thyl) -7 “Oxabicyclo [2,2, 1] hept-2-yl] -5-heptenoic, the title compound is obtained in the form of an oil.

Analysis pour for * 30 Calculated: C 70.97; H 10.12

Found: c 70.93; H 10.33.

13

- C nuclear magnetic resonance spectrum

(CDC13, 15 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, 35 49.1, 71.7, 71.2, 31.6, 25.8, 29.9, 22.6, 13.9.

L19

Example 7

Acid Γ1Β "2tt (5Z), 3α, 48 ~ 1-7-Γ3-Γ (methyloxy) methyl'l-7- ^. oxabicyclof 2, 2, l] hept-2-yl ~ | -5-hepteno: Lque

By following the process of Examples 1 and 2, 5 but by substituting methyl methane sulfonate for n-hexyl methane sulfonate, the wedge is obtained! placed under heading in the form of an oil, [a] ^ = +10.4 (c = 2.21, CHC13).

Analysis: for î 10 Calculated: C 67.14> H 9.01

Found: C 67.03 J H 9.14.

13

Nuclear magnetic resonance spectrum C (CDC13, 15 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, 15 46 , 2, 71.7, 58.6.

Example 8

Acid ΓIB, 2q (5Z), 3B, 4Βΐ-7 ~ Γ3-Γ (propyloxy) methyll-7- oxabicyclof, 2, l1h.ept-2-yl ~ | -5-heptenoi‘que

Following the method of Example 6, but substituting n-propyl bromide for n-hexyl bromide, the title compound is obtained.

Example 9

(Ϊ́β, 2α, 3α * 4B) -7- [3- (butylQxy) methyl1-7-oxa-bicyclof, 2, l ~ | hept-2-yl] heptanoic acid 25 Following the procedure of Examples 4 and 5, but by substituting n-butyl methane sulfonate for n-hexyl methane sulfonate, the compound is obtained under heading.

Example 10 * 30 Acid fl B, 2q (5Z), 3α; , 4Bl-7 ~ [3 ~ | ~ (octyloxy) methyll-7- ^ oxabicyclo \ 2, 2.11 hept-2-yl] -5-hepténoi'que c Following the method of Examples 1 and 2, but in substituting n-octyl methane sulfonate for n-hexyl methane sulfonate, the com-35 is obtained under the heading.

U

20

Example 11 £ Acid flß, 2g (5Z), 3α, 4β1-7- [3 ~ Γ (phenyloxy) methyl1-7- oxabicyclc> r2, 2, l ~] hept-2-yl ~ l-5-heptenoic (a ) Phenol (1 mmol) is added to a solution of triphenylphosphine (1 mmol), diethyl azodicarboxylate (1 mmol) and the alcohol of paragraph A of Example 1 (1 mmol) in 25 ml of tetrahydrofuran and the mixture is 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 subjected to chromatography on silica gel to obtain the methyl ester of acid [1β, 2α (5Ζ), 3α, 4β] -7- [3-15 [(phenyloxy) methyl] -7-oxabicyclo [2,2, 1] hept-2-yl] -5- enoic hept.

(b) Following the process described in Example 2, the ester obtained sub (a) is transformed into the compound under heading.

20 _ Example 12

Acid flß, 2q (5Z), 36.4Β1-7-Γ3-Γ (phenyloxy) methyll-7-oxabicyclofZ, 2, l ~ 1hept-2-yll-5-hepténoi * as (a) Add phenol (l mmol ) to a solution of triphenylphosphine (1 mmol), of azis-25-diisopropylcarboxylate (1 mmol) and of the alcohol of paragraph A of Example 1 (1 mmol) in 25 ml of tetrahydrofuran and the mixture is stirred under an atmosphere of 'argon 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 in vacuo and subjected to one; chromatography on silica gel to obtain the methyl ester of acid [1β, 2α (5Ζ), 3β * 4β] -7 “[3 - [(phenyloxy) methyl] -7-oxabicyclo [2,2,1] hept-2-yl] -35 5-heptenoic.

AT

f 21 (b) Following the process described in Example 2, the ester obtained sub (a) is transformed into the compound under heading.

Example 13 5 acid riB.2g (5Z), 3a.4-61-7-Γ3-Γ (ethyloxy) methyll-7-oxabicyclof2, 2, 11hept-2-yl "] - 5-heptenoic

Following the procedure of Examples 3 and 2, but substituting ethyl bromide for n-hexyl bromide, the title compound is obtained, Example 14

Γΐβ, 2α, 3α, 4Β ’acid | —7— [3— [(phenyloxy) methyll-7-oxabicyclo f2,2,1] hept-2-yllheptanoïque

Following the method of Example 11, but substituting 1 * acid methyl ester (ΐβ, 2α, 3α, 4β) -15 7- [3 “[(hydroxy) methyl] -7-oxabicyclo [2,2 , l] hept-2-yl] ~ heptanoic to 1 * alcohol from paragraph (a) of 1 * example 11, the compound is obtained under heading.

Example 15

Acid ,26,2α (5ide), 3ß "46Ί-7-Γ3-Γ (benzyloxy) methyl ~ 1-7-20 oxabicyclo [2,2,1] hept-2-yl] -5-heptenoi that

Following the procedure of Example 6, but substituting benzyl bromide for n-hexyl bromide, the compound is obtained.

Example 16 25 (1 ß, 2q, 3α, 48) —7— [~ 3— Γ Çbenzyloxy) methyl ~ 1-7-oxabicyclof2, 2.1 ~] hept-2-yl] heptanoic

Following the procedure of Examples 4 and 5, but substituting benzyl methane sulfonate for n-hexyl methane sulfonate, the title compound is obtained.

Example 17? Acid f lß, 2q (5Z), 3a "4ß] -7- [3- [(cyclohexyloxy) methyll- 7-oxabicyclo f2, 2.11 hept-2-yll-5-heptenoxque

Following the process of Examples 1 and 2, but substituting the cyclo methane tallow onate

AT

22 hexyl with n-hexyl methane sulfonate, the compound is obtained under heading.

Example 18> Acid | ~ 16.2α (5Ζ) .36 »4ßl-7- (~ 3-f ~ (cyclopentyloxy) - 5 methyl] -7-oxabicyclof2 32 31 ~ | hept-2-yl] -5-heptenoic

Following the method of Examples 1 and 2, but substituting cyclo-pentyl methane sulfonate for n-hexyl methane sulfonate and substituting 1 * methyl ester of acid [1β, 2α (5Ζ), 3β, 4β ] -10 7- [3- (hydroxymethy3) -7-oxabicyclo [2,2, 1] hept-2-yl] - 5-heptenoic (prepared as described in US Patent No. 4 · 143 * 054) to the methyl ester of acid [1β, 2α (5Ζ), 3α, 4ß] -7- [3- (hydroxy-w methyl) -7-oxabicyclo [2,2,1] hept-2 -yl] -5-hepténoi'que,; The compound is obtained under heading.

Example 19 ^ (ΐβ, 2α, 3α, 43) -7 ~ Γ3-Γ (cyclohexyloxy) methyll-7-oxabicyclofZ a2 allhept-2-yl] heptanoic acid

Following the procedure of Examples 4 and 5 but substituting cyclohexyl methane sulfonate for n-hexyl methane sulfonate, the title compound is obtained.

Example 20

Acid [1β, 2α (5Ζ), 3α, 4ß] -7- [3- [2 .- (hexyloxy) ethyl] -7-25 oxabicyclo [2,2,11hept-2-yl] -5-heptenoic.

A. Acid | ~ 1β, 2 "(5Ζ), 3α, 4ΒΊ-7-Γ3- (2-οχο) -éthyll-7-oxabicyclof2, 2,1] hept-2-yl] -5-hepténoi'que, methyl ester. -ΐ

12.9 g (37 * 7 mmol) of methoxymethyl-triphenylphosphonium chloride (( ΟΗ ^ ΟΟΗ ^ ΟΙ ") and 235 ml of distilled toluene (stored on molecular sieves). The suspension obtained was stirred in an ice bath under an atmosphere of

U

j - 23 argon sphere until it is cold, then added drop by drop a 1.55M solution of 18.3 ml (28.3 mmol) of potassium t-amylate in toluene. A bright red solution formed which was stirred at 0 ° C for an additional 35 minutes. Then, using a tap funnel, over a period of 35 minutes, a solution of 4a97 g (18.8 mmol) of methyl acid ester [1β, 2α (5Ζ) was added, 3α, 4β] -7- [3-formyl-7-10 oxabicyclo [2,2, l] hept-2-yl] ~ 5-hepténo3! Only in 60 ml of toluene, the ice bath being always kept in place . Then, the reaction was abruptly stopped by adding 2.3 g (39 mmol) of acetic acid in 5 ml of ether. The reaction immediately turned pale yellow and was immediately poured into 200 ml of saturated NH 4 Cl, then extracted with ether (4 x 200 ml). The combined ether phases were washed with saturated NaCl solution and dried (MgSO 4) and concentrated to obtain a yellow oil in a white crystalline solid (phosphine oxide). The white solid was triturated with EfcOAc and the mother liquor was purified by chromatography on an LPS-1 silica column. The fractions obtained were: (A) the methyl ester of acid [lß ^ 2a (5Z), 3cc, 4ß] -7 ~ [3- (2-oxo) - ethyl-7-oxabicyclo [2,2, 1] hept-2-yl] -5-hepteno £, (B) the methyl ester of acid [1β, 2α (5Ζ), 3α, 4β] -7 ~ [3- (2-methoxy) é thene-diyl] - 7-oxabicyclo [2,2,1] hept-2 -yl] -5-heptenoid! and (C) the methyl ester of acid [1, 2a (5Z), 3a, 4ß ] -7- [3- (2,2-dim0thoxy) dthyl-7-oxa- bi cyclo [2,2,1] hept-2-yl] -5-heptenoic,

We treated each of the compounds (B) and (C) with trifluoroacetic acid to transform each of them into compound (A),

U

/ 24 B. Acid [Iß, 2g (5Z), 3a, 4Β ~ 1-7-Γ3- (2-Ιιν- - droxyethyl) -7-oxabicyclof2,2,1] hept-2-yl 1 -5-hept - noïque, methyl ester ". 1.4 g (5 mmol) of the aldehyde obtained sub A in 50 ml of methanol were treated with 0.19 g (5 nunoles) of NaBH 4 under an argon atmosphere at 0 ° C. After stirring at 0 ° for one hour, the reaction was abruptly stopped by the addition of 2N HCl (at a pH of 2). The methanol was removed in vacuo and the reaction mixture was taken up in ether. The ether solution was washed with saturated KHCO 4, saturated NaCl, then dried (MgSO 4). The ether was evaporated to give the compound for section B.

: 15 c. Γΐ6,2α (5Ζ), 3α, 4β] -7-Γ3-Γ2- (hexyloxy) ethyl] -7-oxabicyclor2,2, l] hept-2-yl] -5-heptenoiic acid

Following the process of Examples 1 and 2, but substituting the alcohol obtained in sub B above 20 for the alcohol used in Example 1, the compound is obtained under heading.

Example 21

[Υ3 ^ 2α4J3] -7-r_3-r2- (hexyloxy) ethyl] -7-oxabicyclof2, 2, l1hept-2-yl ~ | -5 "heptenoic acid 25“ Following the method of Example 20, but in substituting 1 * methyl ester of [1β, 2α (5Ζ), 3 β, 4β] -7- [3-formyl-7-oxabicyclo [2,2,1] hept-2-yl] -5-heptenoic to acid methyl ester [1β, 2α (5Z), 3α, 4ß] - * 7 “[3-f ormyl-7-oxabicyclo [2,2,1] hept-2-yl] -5-rj * . Λ · 9 30 heptenoxque, the compound is obtained under heading. ·;

Example 22 “·.

Acid (iß, 2a, 3a, 46) -7- [3- [2- (hexyloxy) ethyl] -7-oxa- ^ bicyclor2, 2, l] hept-2-yl] -5-h.eptano3!

Following the method of Example 21, but substituting the acid methyl ester (ΐβ, 2α, ->; '

L

25 3aa4ß) -7- [3-formyl-7-oxabicyclo [2,2,1] hept-2-yl] - ~ heptanoic with 1 * methyl ester of acid [1β, 2α (5Ζ), 3 β) 4β ] -7- [3-f ormyl-7-oxabi cyclo [2,2,1] hept-2-yl] -5- ^ heptenoic, the compound is obtained under heading.

5 Example 23

Γΐβ, 2α (5Ζ), 3ß.461-7-Γ3-Γ2- (phenyloxy) ethyl] - 7-oxabicyclor2, 2, l] hept-2-yl] -5-heptenoic acid

Following the method of 1 * example 11, but substituting 1 * methyl ester of acid 10 [1β * 2α (5Ζ), 3α, 4β] -7- [3- [2- (hydroxy) ethyl] -7-oxa - bicyclo [2,2,1] hept-2-yl] -5-heptenoic to 11 methyl ester of acid [1β, 2 <χ (5Ζ), 3α * 4ß] -7- [3- (hydroxy-methyl ) -7-oxabicyclo [2,2,1] hept-2-yl] -5-heptenoic, the compound is obtained under heading.

'15 Example 24

Acid [lß, 2g (5Z), 3ß * 46] -7- [3- [2- (phenyloxy) ethyl] - 7-oxabicyclo Γ2,2,1] hept-2-yl] -5-heptenoic

Following the procedure of Example 12, but substituting the methyl acid ester [1, 2a (5Z), 3ß, 4ß] —7— [3— [2— (hydroxy) 6thyl] -7-oxa— bicyclo [2,2,1] hept-2-yl] -5-heptenoic acid methyl ester [lß, 2a (5Z), 3ß, 4ß] -7- [3- (hydroxy-methyl) - 7-oxabi cyclo [2,2,1] hept-2-yl] -5-heptenoic, the compound is obtained under heading.

25 Example 25

(1β, 2g, 3α.4ß) -7-Γ 3-Γ 2- (phenyloxy) ethyl] -7-oxabicyclo [2,2,1] hept-2-yl] heptanoic acid

Following the method of Example 11, but substituting the methyl acid ester (ΐβ, 2α, ** 30 3oc, 4ß) —7— [3- [2— (hydroxy) ethyl] —7 — oxabicyclo [2, 2,1] - hept-2-yl] heptanoic acid methyl ester [lß, 2a (5Z), 3cc, 4ß] -7- [3- (hydroxymethyl) -7-oxabi-cyclo [2,2, l] hept-2-yl] -5-heptenoic, the compound is obtained under heading,

L

26

Example 26 * Acid | ~ 1β, 2α (5Ζ), 3a, 4B ~ 1-7-r3-r2- (benzyloxy) ethyn- 7-oxabicycloF2, 2, llhept-2-yl ~] -5-heptenoic

Following the procedure of Example 20, but substituting benzyl methane sulfonate for n-hexyl methane sulfonate, the compound is obtained under the heading.

Example 27

Acid ΓΐΒ, 2α: (5Ζ), 3B, 4-Bl-7-r2-f2- (benzyloxy) ethyll-10 7-oxabicyclor2,2, l] hept-2-yl1-5-heptenoic

Following the method of Example 21, but substituting benzyl methane sulfonate for n-hexyl methane sulfonate, the compound under heading is obtained, Example 28

Acid | ~ 16 "2oi (5Z), 3a, 4ß1-7-r3-r2- (cyclopentyloxy) -> ethyll -7-oxabicyclo f2, 2.11 hept-2-yl] -5-hepteno3Lque

Following the procedure of Example 20, but substituting the cyclo-pentyl methane sulfonate for n-hexyl methane sulfonate, the compound is obtained under heading.

Example 29

Acid | ~ 1β, 2κ (5Ζ) "3", 43l-7 ~ r3'-r2 "- (cyclohexyloxy) ethyl1-7-oxabicyclo f2, 2, l] hept-2-yll-5-hepténoi, that 25 En according to the method of Example 20, but by substituting cyclohexyl methane sulfonate for n-hexyl methane sulfonate, the compound is obtained under heading.

Example 30 * 30 Acid Γΐβ ^ 2α (5Ζ), 3oc "46l-7-r3-r4 ~ (hexyloxy) butyl ~ l-7- oxabicyelo [~ 2, 2, l] hept-2-yl ~] -5- heptenoic A. Acid Ι ~ 1β "2α (5Ζ), 3α" 46Ί ~ 7- [3- (3-οχο) - propyl-7-oxabi cyclo [2,2,1] hept-2-yl] -5- hept enoi'que, methyl ester

U

27

Following the procedure in part A of »Example 20, but substituting the methyl ester of [1β, 2α (5Z), 3α, 4β] -7" [3- (2-oxo) -ethyl -7-oxa-bicyclo [2,2, l] hept-2-yl] -5-heptenoic acid 5 methyl ester [1β, 2α (5Z), 3α, 4β] -7— [3- formyl- 7-oxabicyclo [2, 2,1] hept-2-yl] -5-heptenoic, the compound of heading A is obtained

B. Acid Γΐβ, 2α (5Ζ), 3α, 46 ~ 1-7-Γ3- (4-οχο) -butyl-7-oxabicyclof2, 2, l ~] hept-2-yl ~ l-5-hepteno5! , 10 methyl ester

Following the process of part A of example 20, but substituting the aldehyde of part A above for the methyl ester of acid [1β, 2α (5Ζ), 3α, 4β] -7- [3-formyl-7-oxabicyclo [2,2,1] -15 hept-2-yl] -5-heptenoic, the aldehyde is obtained from section B.

C. Acid [lß, 2_ (xl5ZL) 3aa4ß1 ~ 7 - r3- (4 ~ hydro- 'y xybutyl) -7-oxabicyclo [2, 2.11 hept-2-yl] - 5-hepteno3! methyl 20 Following the procedure in part B of Example 20, but substituting the aldehyde in heading B for the methyl ester of acid [1β, 2α (5Ζ), 3α, 4β] -7 “[ 3- (2-οχο) ethyl-7-oxabicyclo [2,2,1] hept-2-yl] -5-heptenoic, the alcohol is obtained from section 25 C. - D. Acid ri3,2g (5Z ), 3a., 4ß] -7- [3- [4- (hexyloxy) butyll-7-oxabicyclof2, 2, l] hept-2-yl] -5-heptenoic

By following the process of Examples 1 and 2, 30 but by substituting the alcohol of part C above for the alcohol used in Example 1, the compound is obtained under heading # L · 28

Example 31

Acid * Example 30, 5 but by substituting cyclohexyl methane sulfonate for n-hexyl methane sulfonate, the compound is obtained under heading.

Example 32

Acid flß, 2g (5Z), 3a <, 4B ~ l-7-r3-r4- (phenyloxy) butyl'1-10 7-oxabicyclor2, 2, l] hept-2-yl ~ | -5-heptenoic

Following the method of Example 11, but substituting the methyl acid ester ^ [lß, 2a (5Z), 3a, 4ß] -7- [3- (4-hydroxybutyl) -7-oxabi- cyclo [2,2, l] hept-2-yl] -5-heptenoic 1 * methyl ester of acid [lß, 2a (5Z), 3a, 4ß] -7- [3- (hydroxy-methyl) - 7-oxabicyclo [2,2, l] hept-2-yl] -5-heptenoic, the compound is obtained under heading.

Example 33

Acid [1βί2α (5Ζ), 3a, 4ßl-7-r3-r4- (benzyloxy) butyll-20 7-oxabicyclo [~ 2, 2, llhept-2-yl ~ | -5-hepténo3!

Following the procedure of Example 30, but substituting benzyl methane sulfonate for n-hexyl methane sulfonate, the compound is obtained under heading * Example 34

Tris (hydroxymethyl) aminomethane acid salt | ~ 1β, 2α (5Ζ), 3α »4βΊ-7- | ~ 3-Γ (hexyloxy) methyl] -7-oxa-bicyclofZ, 2, l] hept-2 -yl1-5-heptenoic

A solution of the compound formed in Example 2 in methanol is treated with an equivalent amount of tris (hydroxymethyl) aminomethane. The solvent is removed by evaporation to obtain the title compound as a solid; melting point: 68.5-70 ° C, thin layer chromatography (silica gel, 8% CH ^ OH / CH ^ Cl ^), L29

Rf = 0.74.

Analysis: for:

Calculated: C 62.72; H 9.87 5 N 3.04

Found: C 62.71; H 9.80; N 3.10.

5 Example 35

Acid [1β, 2g (5Z), 3a, AB ~ 1-7- [3- [2- (pentyloxy) ethyrj-7-oxabicyclo [2, 2, l ~ lhept-2-yl ~ l-5-heptenoic A Γΐβ, 2α (5Ζ), 3α, 4Βΐ-7-Γ3-Γ2- (pentyloxy) ethyl1-7-oxabicyclc> r2, 2, l] hept-2-yl ~ | -5-10 heptenoic acid

A mixture of 0.36 g of KOH powder in 15 ml of dry xylene was refluxed under an atmosphere of argon and 8 ml of xylene was removed by distillation. To this mixture was added a solution of 200 mg (0.71 mmol) of the methyl alcohol ester from Part B of Example 20 in 17 ml of dry xylene. The volume of the reaction mixture was reduced to 15 ml by removing the xylene by distillation. Then to the reaction mixture was added a solution of 0.5 g (3.55 mmol) of pentyl mesylate in 10 ml dry xylene. This mixture was heated at reflux for 2 hours, 30 minutes. The cooled reaction mixture was diluted with 50 ml of saturated NaHCO 4 solution and extracted with CI ^ C ^ (3 x 60 ml). The combined CH ^ C ^ extracts (MgSO ^) were dried, filtered and concentrated in vacuo. The purification was carried out by flash chromatography on 33 g of silica gel 60 using a 511 1: 1 mixture of hexane and ether as eluent. This resulted in 238 mg of the pentyl ester under the heading ($ 83) as a colorless oil. Thin layer chromatography with silica gel, 1: 1 mixture of hexane and ether.

U

30 B. Acid [16.2g (5Z), 3a.4.Bl »7-f3-f2- (pentyloxy) ethyl] ~ 7-oxat> icyclor2,2, l ~ | hept-2-yl ~ l- 5 -heptenoic A to a stirred solution of 238 mg (0.58 mmol) 5 of the pentyl ester of part A, 26 ml of distilled tetrahydrofuran, 2.1 ml of CHLOH and

O

3.4 ml of ^ 0, under an argon atmosphere, 6.4 ml of an aqueous solution of IN lithium hydroxide was added. This mixture was vigorously purged with argon for 30 minutes and stirred at room temperature for 7 hours * The reaction mixture was acidified to pH 3 by addition of an aqueous solution of IN HCl . The solution obtained was poured into 50 ml of a solution: saturated with NaCl and saturated with NaCl dissolved in. The aqueous layer was extracted with EfcOAc; ^ (4x60 ml) · The combined extracts I of EfcOAc (MgSO 4) were dried, filtered and concentrated in vacuo. Chromatography was then carried out on 24 g of silica gel 60 using 3% CH ^ OH in C ^ C ^ as eluent to obtain 18 mg ($ 92) of pure acid under the heading $ chromatography on thin layer: silica gel, 4% CHgOH / C ^ C ^, Rg = 0.30, vanillin.

25 Analysis i for C2 () H3404

Calculated: c 70.97 5 H 10.12 C2 () H3404 0.22 H20: C 70.16 5 H 10.14 Found: C 70.16 d H 9 * 87.

13

Nuclear magnetic resonance spectrum C 30 (CDC13, 15 MHz) tau î 173 * 5 * 33 * 8, 24 * 7 * 26.7, 129.5 130.1, 28.0, 43 * 8, 79.8, 29 * 5 * 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 * 13.9L · «31

Example 36

Acid flß "2α (5Ζ), 3α, 4Βΐ-7-Γ (3-phenylpropoxy) methyll-7-" oxabicyclo f2,2,1 ~ j hept-2 -yl1-5 -heptenoic, A. Acid riß, 2g ( 5Z), 3a, 4ß1-7-r (3-phenylpropoxy) methyl-7-oxabicyclo | ~ 2,2, l] hept-2-yl] -5- heptenoic, phenylpropyl ester

A mixture of 0.59 g of KOH powder in 16 ml of dry xylene was heated to reflux under an atmosphere of argon and 9 ml of xylene 10 was removed by distillation. To this mixture was added a solution of 410 mg (1.53 mmol) of the alcohol methyl ester from part A of Example 1 in 10 ml of dry xylene. The volume of the reaction mixture was reduced to 6 ml by removing the xylene by distillation. Then, to the reaction mixture was added a solution of 1.66 g (7 * 58 mmol) of mesylate of 3 -phenylpropyl in 36 ml of dry xylene.

This mixture was heated at reflux for one hour.

The cooled reaction mixture was diluted with 50 ml of saturated NaHCO 4 solution and extracted with CH 2 Cl 2 (3 x 50 ml). The combined CH2Cl2 extracts were dried (MgSO 4), filtered and concentrated in vacuo. The purification was carried out by flash chromatography on 40 g of silica gel 60 using a 3'1 mixture of hexane and ether as eluent. In this way, 0.61 g of the phenylpropyl ester was obtained under the heading ($ 81) in the form of a colorless oil. Thin layer chromatography: silica gel, 2% CH ^ OH / 30 CH2C12, Rf: 0.60, iodine, B. Acid f 1β * 2α (5Ζ), 3α, 4β ~ | -7 "Γ (3-phenyl -propoxy) methyl] -7-oxabicyclo f 2,2,1 ~ | hept-2-yl] -5-heptenoxque A stirred solution of 610 mg (1.24 35 mmol) of the phenylpropyl ester in section A , L, a 32 of 55 ml of distilled tetrahydrofuran, 4 * 40 ml of CH ^ OH and 7 * 30 ml of H ^ O, under an atmosphere of argon, 13 * 7 ml of a solution were added aqueous IN lithium hydroxide. This mixture was vigorously purged with argon for 30 minutes and stirred at room temperature for 14 hours. The reaction mixture was diluted with 100 ml of water. 0.1N aqueous lithium hydroxide solution and washed once with 100 ml hexane.

The reaction mixture was acidified to a pH of 3 by addition of an aqueous 1N HCl solution and poured into 100 ml of saturated NaCl solution, The resulting mixture was saturated with solid NaCl and * on Ha extracted with EfcOAc (4 x 150 ml). The combined extracts of EfcOAc (MgSO 4) were dried, filtered and concentrated in vacuo. Thereafter, chromatography was carried out on 44 g of silica gel 60 using 4% of CH ^ OH in C ^ Clg as eluent to obtain 380 mg ($ 82) of acid 20 under heading in the state pure. Thin layer chromatography: silica gel, \% CH ^ OH / C ^ C ^ *

Rf = 0.30, iodine.

Analysis for C ^ H ^ O ^: calculated: C 74 * 16; H 8.66 C23 H32 ° 4 °> 35 H2 ° * C 72i94 5 H 8> 7 ° 25 found · C 72.94 5 H 8.49 ·> .. 13

JC nuclear magnetic resonance spectrum

(CDC13, 15 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.

30

'U

5 33

Example 37

Γΐβ, 2α; (5Ζ), 3αa4ß1—7 — Γ3 — Γ (octyloxy) methylV7- acid. oxabicyclof ~ 2, 2, l ~ lhept-2-yl] -5-hepteno: £ than A. Acid f lß, 2a (5Z), 3 ", 4ßl-7-T3-Γ (octyl- 5 oxy) methyl] ~ 7 ~ oxabicyclor2, 2 jl ~ lhept-2-yl ~ |.-5-heptenoic, octyl ester To a stirred solution of 508 mg (1.89 mmol) of 1 * ester-alcohol of part A of l Example 1 in 2.69 ml of tetrahydrofuran was added, 10 in order, 2.69 ml (15 * 6 mmol) of n-octyl bromide, 642 mg (1.89 mmol) of hydrogen sulphate tetrabutylammonium and 2.69 ml of an aqueous sodium hydroxide solution at 50 $. This mixture was stirred at room temperature and in the dark for 19 hours. The reaction mixture was poured into 25 ml saturated sodium bicarbonate * solution and extracted with four 25 ml portions of CH2Cl2, The combined CH2Cl2 extracts (MgSO 4) were dried, filtered and concentrated under The purification was carried out by flash chromatography on 39 * 6 g of silica gel 60 using a 3 * 1 mixture of hexane and ether as eluan. t to obtain 333 mg ($ 37) of octyl ester and 250 mg of a mixed band of octyl ester and the corresponding methyl ester, thin layer chromatography: silica gel, $ 3 CH ^ OH / CH ^ C ^, * octyl ester, 0.85 * methyl ester, 0.80, iodine, B, Acid [lß, 2q (5Z), 3 ", 4ß] -7- [3" [(octyl-30 oxy) methyl] —7 — oxabicyclo [2,2,1] hept-2 — yl] —5 — hepté— noxque A stirred solution of 333 mg (0.70 mmol) of the octyl ester of part A in 31 ml distilled tetrahydrofuran, 2.50 ml CH 4 OH and 4.1 ml H2O, under an atmosphere of argon, was added

AT

34 T} 70 ml of an aqueous solution of 1N lithium hydroxide. This mixture was vigorously purged with argon for 20 minutes and stirred at room temperature for 16 hours 3 to 30 minutes, The mixture of the octyl ester and 1 * was hydrolyzed methyl ester corresponding exactly the same way * To a stirred solution of this mixture (250 mg) in 29 ml of distilled tetrahydrofurarm, 2.40 ml of CH 2 OH and 3 * 9 ml of H 2 O, 7 * 30 were added ml * aqueous lithium hydroxide IN *

This mixture was vigorously purged with 1 * argon for 20 minutes and stirred at room temperature for 16 hours, 30 minutes. These two reaction mixtures were combined and diluted with a solution. of 120 ml of an aqueous solution of lithium hydroxide 0.1N and 50! - ml of Β ^, Ο. The mixture obtained was extracted once with 220 ml of hexane. The aqueous layer was acidified to a pH of 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 EtOAc extracts were combined (the hexane extract contained the desired acid), dried (MgSO 4), filtered and very concentrated. under vacuum to obtain 0.53 g of a crude product. The latter was subjected to chromatography on 48 g of silica gel 60 using 3% CH 2 OH in CH 2 Cl 2 to obtain 222 mg ($ 45) of the desired acid under the heading. Thin layer chromatography - silica gel, 4 $ CH ^ OH / C ^ C ^, = 0.40, vanillin.

Analysis for C ^ H ^ gO ^: calculated; C 72 * 09 * H 10 * 45 C22H38 ° 4 ° î24 H20: C 71 * 25 5 H 10.45 found: C 71 * 25 5 H 10.20:

U

35

Nuclear magnetic resonance spectrum 5 (CDC13, 15 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, 5 22.6, 14.0 , 64.4, 31.7, 29.7, 29.2, 28.2, 25.8, 22.6, 14.0.

Example 38

Acid ßlß .2¾ (5Z), 3α, 431-7-Γ3 ~ (cyclohexylmethoxy) -methyll — 7 — oxabicyclo [2,2,11hept — 2 — yl] —5 — heptenoic acid 1. Acid f ~ lß.2q ( 5Z), 3a.46 1-7-Γ3- (cyclo hexylmethoxy) methyll -7-oxabi cyclo [2,2,11 h.ept-2-yl] - "5-heptenoic, cyclohexylmethyl ester

A mixture of 0.56 g v of KOH powder in 15 ml of dry xylene was heated to reflux under a? 15 argon atmosphere and 7 ml of xylene was removed by distillation. To this mixture was added a solution of 300 mg (1.12 mmol) of methyl alcohol test from Part A of Example 1 in; 10 ml of dry xylene. The volume of the reaction mixture was reduced to 11 ml by removing the xylene by distillation. Then, to the reaction mixture, a solution of 2.47 g (12.9 mmol) of cyclohexylmethyl mesylate in 10 ml of dry xylene was added. This mixture was heated at reflux for 5 hours. The cooled reaction mixture was diluted with 50 ml of saturated NaHCO 4 solution and extracted with CH2Cl2 (3 x 50 ml). The combined CH2Cl2 extracts were dried (MgSO 4), filtered and concentrated in vacuo. Purification was carried out by flash chromatography on 35 g of silica gel 60 using 1% CH 2 OH in CH 2 Cl 2 as eluent. 0.46 g of the hexyl ester was thus obtained under the heading ($ 93) in the form of a colorless oil. Thin layer chromatography: silica gel, 2% CH ^ OH / C ^ C ^, = 0.80,

Ls · —-V.

36 lode, B. Acid [1B, 2g (5Z), 3α, 461-7- · Γ 3- (cyclo-hexylmethoxy) methyll-7-oxabicyclo f2, 2.11 hept — 2-yl] - - 5-heptenoic 5 to a stirred solution of 460 mg (1.03 mmol) of the cyclohexylmethyl ester of part A, 45 ml of distilled tetrahydrofuran, 3 * 80 ml of CH 2 OH and 6.10 ml of H 2 O, under an argon atmosphere, 11.4 ml of an aqueous solution of IN lithium hydroxide was added. This mixture was vigorously purged with argon for 20 minutes - and stirred at room temperature for 16 hours. Was the reaction mixture diluted with * 83 ml of an aqueous solution of lithium hydroxide? 15 0.1N and washed once with 83 ml of hexane.

The aqueous layer was acidified to a pH of 3 by the addition of an aqueous 1N HCl solution and saturated with solid NaCl. The aqueous layer obtained was extracted with EtOAc (4 x 120 ml). The combined EtOAc extracts (MgSO 4) were dried, filtered and concentrated in vacuo to give 0.32 g of a crude product. The latter was subjected to chromatography on 34 * 6 g of silica gel 60 using 3% CH ^ OH in CH2Cl2 as eluent to obtain 278 mg ($ 77) of the acid under pure heading . Thin layer chromatography = silica gel, 4 $ CH30H / CH2C12, Rf = 0.28, iodine.

Analysis for ^ 21 ^ 34 ° 4 * ca - * - cu- ^: C 71 * 96; H 9 * 78 C21H34 ° 4 0.31 H2 °; C 70.84 5 H 9.80 30 found: C 70 * 84 * H 9 * 68.

13

Nuclear magnetic resonance spectrum C (CDC13, 15 MHz) tau s 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 * 35 30.0, 69 * 3 * 37 * 1 * 29 * 1 * 26.3 * 25.6, 26.3, 29.1.

u 37

Example 39

Fla acid, 2ß (Z), 36.4α ~ 1-7-Γ3-ΓΓ (l ~ methylhexyl) oxyl-i méthyll-7 ~ oxabicyclo f 2,2,11hept-2-yl] -5-heptenolque

By following the methods of Examples 1 and 5 2, but by substituting 1-methylhexyl methane-sulfonate for n-hexyl methane-sulfonate, the compound is obtained under heading, thin layer chromatography (silica gel, 4 $ CH -OH / CHLCln)

Rf "0.47.

10 Analysis: for ^ 21 ^ 36 ^ 4 calculated: C 71.55 S H 10.29 found: C 71.73 5 H 10.21.

JC nuclear magnetic resonance spectrum

(CDC13, 15 MHz) tau: 178.8, 33.4, 24.6, 25.7, 15 129.4, 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.

Example 40

Acid | ~ 1α, 2ß (z) "3B, 4α1-7-Γ3-Γ (3-hexynyloxy) methyll-7-oxabicyclo | ~ 2, 2,11hept-2-yll-5-heptenoic Following the methods of Examples 1 and 2, but by substituting 3-hexynyl methane sulfonate, the title compound is obtained in the form of an oil. Thin layer chromatography (silica gel, CH30H / CH2C12) Rf = 0.32.

Analysis: for c2oH30 ° 4 * calculated: C 71.82 5 H 9.04 found; C 71.66; H 9.21.

13

Nuclear magnetic resonance spectrum C (CDC13, 15 MHz) tau: 178.9, 33.4, 22.0, 24.5, 30 129.5, 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.

the 38

Example 41

Acid Γΐβ, 2α (Ζ), 3κ (Ζ), 4Βΐ-7-Γ3-Γ (3-hexenyloxy) -methyl] -7-oxabicyclo »2 »2» 11 hept-2 — yl ~] - 5 — heptenoic Next the process of Examples 1 and 2, 5 but by substituting cis-3-hexene-1-mesylate for n-hexyl methane sulfonate, the title compound is obtained as an oil. Thin layer chromatography (silica gel, 4% CH ^ OH / CH2Cl2) Rf = 0.3.

Analysis: for C20H32 ° 4 calculated: C 71.39 5 H 9.59 found: C 71.10; H 9.59

'' Nuclear magnetic resonance spectrum ° C

* (CDC13, 15 MHz) tau: 178.9, 33.4, 24.5, 25.6, 15 129.5, 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

Acid [~ lß »2q (z), 3 (x (Z), 43l" 7 * “f3 ~ r (2-hexenyloxy) -methyl] -7-oxabicyclo f2, 2, l1hept-2-yll-5-heptenoic Following the procedure of Examples 1 and 2, and substituting 2-1-hex-2-enyl mesylate for n-hexyl methane sulfonate, the title compound was prepared as an oil. thin layer (silica gel, 2% CH30H / CH2C12) 25 Rf = 0.22, vanillin.

Analysis ï for C20H32 ° 4 calculated: C 71.39 5 H 9.59 found: C 70.97 5 H 9.6413

Nuclear magnetic resonance spectrum C 30 (CDC13, 15 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.

U

39

Example 43

Acid [1Β.2α: (Ζ), 3cu4ff 1-7- [3-f2-propenyloxy) methyll-7-oxabicyclof2, 2, llhept-2-yll-5-heptenoxque and methyl ester 5 To a stirred solution of 310 mg (1.16 mmol) of the methyl ester of acid [1β, 2α (5Ζ), 3α, 4ß] ** 7 “[3- (hydroxym0thyl) -7-oxabicyclo [2,2, l] hept-2 -yl] -5-heptenoic acid in 1.34 ml of tetrahydrofuran, 1.34 ml of allyl bromide, 107 mg of tetrabutyl ammonium hydrogen sulfate and 1.34 were added in order ml 50% aqueous sodium hydroxide solution · The mixture was stirred at room temperature and in the dark for 23 hours, then poured into 30 ml of saturated bicarbonate solution of sodium and extracted twice with 30 ml portions of methylene chloride. The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. The purification was carried out by flash chromatography on 35 g of silica gel 60 using a 2: 1 mixture of hexane and ether as eluent to obtain 220 mg of the product in the form of the methyl ester $ chromatography on thin layer (silica gel, hexane-25 ether (l: l), = 0.4 * iodine).

The ester was dissolved in 36 ml of tetrahydrofuran together with a small amount of hydroquinone, 6 ml of water and 7 ml of a 1N aqueous solution of lithium hydroxide and stirred at room temperature for 5 * 5 hours, after which the reaction mixture was poured into 80 ml of a saturated aqueous solution of sodium chloride and saturated with an additional quantity of solid sodium chloride. The aqueous layer was extracted with four portions of ethyl acetate

U

$ 40 (125 ml each), it was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was subjected to chromatography on 30 g of silica gel using 4% CH ^ OH / 5 CH2Cl ^, as eluent to obtain 190 mg of the product in the form of the acid. Thin layer chromatography (silica gel, hexane-ether (1: 1)) = 0.15 ·

Analysis: for c1yH26 ° 4 calculated: C $ 69.36 H 8.96 10 found: C 69 * 72 5 H 9 * 0513

Nuclear magnetic resonance spectrum C (CDC13, 15 MHz) tau s 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.

15 Example 44

Acid [~ lß, 2q (5Z), 3 <x "4ß1" 7-f 3-Γ (hexylthio) methyl ~] -7 ~ oxabicyclo [2, 2 allhept-2-yl] -5-heptenofquea methyl ester A, Acid f Iß, 2q (5Z), 3a »4ßl-7-f3 - (20-hydroxy-methyl) -7-oxabicyclo \ 2, 2.1 lhept-2-yl] -5-heptenoid (a) On prepared a mixture of N-acetylpyridinium chloride by adding dropwise 9.6 ml (136 mmol) of acetyl chloride to 56 ml of pyridine * To this mixture was added 5 g (27 mmol) of ( exo) -3- (2-methoxy-ethenyl) -7-oxabicyclo [2,2, 1] -heptane-2-methanol dissolved in 5 ml of pyridine.

The third mixture obtained was stirred at room temperature for 1.5 hours and poured into brine. The product was extracted into ether (3 x 200 ml), the ether extracts were 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 was obtained which was purified by passing it through a short column of silica gel (150 ml) with

U

41 dichloromethane 3 yield: 4 * 42 g of an oil.

(b) To a solution of 4 * 42 g (19.6 mmol) of 1 * oil in 500 ml of tetrahydrofuran containing 50 ml of water, 31 * 1 g (97 * 8 mmol) of 5 * acetate was added mercuric. The yellow suspension formed was stirred for 10 minutes, then the whole mixture was poured into a solution containing 200 g of potassium iodide in 2 liters of water. Upon stirring, the yellow color disappeared and the mixture was extracted with benzene (3 x 500 ml).

The combined benzene extracts were washed with potassium iodide solution and brine and dried over sodium sulfate. By concentration, 3 * 7 g of a material was obtained which crystallized when it was left to stand in a cooler.

(c) A Wittig reagent was prepared in dimethylsulfoxide (dried over calcium hydride) by adding dropwise a solution of sodium methylsulfinylmethide (which is prepared by heating 300 mg of sodium hydride in 60 ml of dimethyl sulfoxide at 75 ° until the evolution of hydrogen stops) in a solution of 5 * 32 g (12 mmol) of 4-carboxybutyl -triphenylphosphonium bromide in 100 ml of dimethyl sulfoxide. After the first orange color had formed for more than 10 seconds, an equivalent amount of base was added to form the ylide. To this dark orange solution was added a solution of the product of part (b) in 20 ml of dimethyl sulfoxide and the resulting mixture was stirred at room temperature for 45 minutes. The reaction was quenched by the addition of 24 mmol of acetic acid and the mixture was poured into brine (300 ml), then extracted with ether (3 x 200 ml).

/ L ~ \ 42

By concentrating these extracts, an oil was obtained which was stirred with saturated sodium bicarbonate solution until crystalline triphenylphosphine oxide formed in the mixture. this mixture with benzene and it was acidified with hydrochloric acid at $ 10.

The aqueous layer was saturated with a salt and extracted with ether and then, after drying (sodium sulfate) and concentration, 2.43 g of a crude product was obtained. The mixture was stirred for 24 hours with 10% aqueous sodium hydroxide and again isolated by acidification and ether extraction. The product was purified on 500 g of silica gel with a 50:50 mixture of ethyl acetate and hexane as eluent to obtain 600 mg of an acid which crystallized when it was let ^ rest. This acid was recrystallized twice from a mixture of ethyl acetate and cyclohexane to obtain 320 mg of the acid [1β, 2α (5Ζ), 3ct, 4ß] “20 7- [3- (hydroxymethyl) - 7-oxabicyclo [2,2, l] hept-2-yl] - 5-heptenoic.

B. Acid (~ 1 ß, 2q (5Z), 3 ", 4ßl-7-f 3- (p-toluene-sulfonyloxymethyl) -7-oxabicyclor2" 2.1] hept-2-yl ~ | -5- heptenoi In addition, 427 mg (2.24 mmol) of chloride chloride were added to a solution of 300 mg (1.12 mmol) of the alcohol ester of part A in 4 ml of dry pyridine. The mixture was stirred at room temperature under an argon atmosphere for 10 hrs-30 hrs. The reaction mixture was diluted with 300 ml of ether, washed with 1N aqueous HCl solution ( 3 x 100 ml) and 0.5N aqueous NaOH solution (3 x 100 ml) The ether layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification was carried out by chro-

U

43 flash matography on 30 g of silica gel 60 using * using 50% of hexane in ether as eluent to obtain 450 mg of the title compound ($ 95) · Thin layer chromatography: 5 silica gel, 4 % CH ^ OH in CHL ^ C ^, R ^ = 0.80, iodine.

C. Acid [lß, 2q (5Z), 3α, 4ßl-7- [3 - [(hexyl-thio) méthyll-7-oxabicyclo [2, 2, l] hept-2-yl ~] -5-hepté nojque, methyl ester To a solution of 132 mg (1 * 17 mmol) of 10 t-potassium butoxide in 10 ml of dry tetrahydrofuran, under an atmosphere of argon, 378 mg (3 * 21 mmol) was added of 1-hexane-thiol. To this mixture was added a solution of 450 mg (1.07 ^ mmol) of the tosylate from part B in 5 ml of? 15 tetrahydrofuran. The reaction mixture was stirred at room temperature under an argon atmosphere for 2.5 hours, then heated to reflux for 5.5 hours. The cooled reaction mixture was diluted with 300 ml of ether and poured into 100 ml of saturated NaHCO 4 solution. "The aqueous layer was extracted with ether (2 x 100 ml) The combined ether extracts (500 ml) were washed with 0.5N aqueous sodium hydroxide (2 x 100 ml) and brine (100 ml), then dried (MgSO 4) , filtered and concentrated in vacuo to give 0.55 g of crude oil Purification was carried out by chromatography on 25.2 g of silica gel 60 using a 511 ether mixture petroleum and ether as eluent to obtain 328 mg of the product under title as an oil ($ 84) · Thin layer chromatography = silica gel, petroleum ether: ether = 3'2, = 0, 55, iodine.

U

44

Example 45

Acid [1β, 2g (5Z), 3α "4Βΐ-7- [~ 3-Γ (hexylthio) methyl 1--7-oxabicyclo f2, 2.11 hept-2-yl] -5-heptenoi'que A solution stirred 328 mg (0.89 mmol) 5 of 1 * methyl ester of 1 * example 1 in 43 * 8 ml of tetrahydrofuran and 6.67 ml of ΙΕ, Ο, under an atmosphere of argon, 8 was added, 40 ml of an aqueous solution of 1 IN lithium hydroxide. This mixture was vigorously purged with argon for 20 minutes and stirred at room temperature for 12.5 hours. The reaction mixture was acidified to a pH of 4 by addition of an aqueous 1N HCl solution and poured into 50 ml of saturated NaCl solution. The resulting solution was saturated with solid NaCl. and it was extracted with EtOAc (4 x 50 ml). The combined EtOAc extracts (MgSO 4) were dried, filtered and concentrated in vacuo to give 295 mg of crude acid.

Your purification was carried out by flash chromatography on 25 g of siliCAR CC-7 using a 2: 3 mixture of petroleum ether and ether as eluent to obtain the product under heading (250 mg, $ 79) under form of an oil. Thin layer chromatography: silica gel, petroleum ether: ether = ‘25 2: 3 5 Rf = 0.25, iodine.

Analysis: for C20H34 ° 3S

calculated · C 67.80; H 9.61; S 9.04 found: C 67.80; H 9.85; S 9.14 13

Nuclear magnetic resonance spectrum ° C * 30 (CDC13, 15 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 .

h 45

Example 46 i Acid (1B, 2g.3a:, A8) -7- [3 - [(hexylthio) methyl '| -7- oxabicyclo [2 »2,11 hept-2-yl] -5-heptenoic acid, ester * methyl.

5 A. (1, 2 ", 3α, 4β) -7- (3- (hydroxy-methyl) -7-oxabicyclo f2, 2.1] hept-2-yl ~] heptanoic acid, methyl ester.

At 800 mg (3 mmol) of 1 * methyl ester of acid [1, 2a (5Z), 3a, 4P] -7- [3- (hydroxymethyl) -7-10 oxabicyclo [2,2, l] hept- 2-yl] -5-hepteno £, prepared as described in Example 1 and dissolved in 120 ml cd * ethyl acetate, under an atmosphere of argon, 160 mg of 5% palladium on carbon were added. exchanged the argon atmosphere for a slight positive pressure of hydrogen and the reaction mixture was stirred for 8 hours at 25 °, filtered through a celite plug and evaporated to obtain 730 mg ($ 90) of the compound in section A, B. Acid (ΐβ "2α, 3α" 4β) -7-Γ3-Γ (hexylthio) -20 methyl * -7-oxabicyclo [2,2,1] hept-2-yl] -heptanoic, methyl ester

Following the method of Example 1, but substituting the alcohol ester of. Part A to the alcohol ester of Example IA, product 25 is obtained under the heading.

Example 47

Acid (1B, 2g, 3α, 4ß) -7- [3- [(hexyl thio) methyl ~ l -7-oxa-bicyclo [2, 2, l] hept-2-yl1 heptanoic

Following the procedure of Example 45, 30 but substituting the methyl ester of Example 46 for the methyl ester of Example 45, the acid is obtained under the heading.

AT

/ L - ’*’ 46

Example 48 f Acid [18% 2g (5Z) “3B, 4ΒΊ-7- [3- [(pentylthio) methyl] - 7-oxabicyclo [2, 2, llhept-2-yll-5-hepteno £ que, ester j methyligue "5 A · Acid ΓΐΒ, 2α (5Ζ), 3834ß1" 7-f3 - (hydroxy-methyl) —7 — oxabicyclo [2 "2 .llhept — 2-yl] - 5 — heptenoic acid, methyl ester To a solution 2.68 g of acid [1β, 2α (5Ζ), 3α, 4β] -7- [3- (hydroxymethyl) -7-oxabicyclo [2, 2,1] hept-10 2-yl] -5- heptenoic in 175 ml of dimethylformamide, 13.16 g of pyridinium dichromate was added, and this mixture was stirred at room temperature for 19 hours, after which an additional 8 g of c dichromate was added This mixture was stirred for an additional 24 hours, the reaction mixture was diluted with 500 ml of ether and the black gummy precipitate formed was removed by filtration through a pad of celite and the filtrate was concentrated in vacuo The dark brown oil obtained was passed through 60 g of silica gel 60 and eluted with S% MeOH / C ^ C ^ to obtain 1.86 g of a brown oil.

This oil was purified by chromatography on 150 g of silica gel 60 using a 1: 1: 0.01 mixture of pentane, ether and acetic acid as eluent. There was thus obtained 0.63 g of the methyl ester of acid [lß, 2a (5Z), 3a, 4ß] -7 “[3- (carboxy) -7-oxabicyclo [2,2, l] hept- 2-yl] -5-heptenoi * que and 0.31 g of the methyl ester of acid [1β, 2α (5Ζ), 3ß, 4ß] -7-30 [3- (carboxy) -7-oxabicyclo [ 2,2,1] hept-2-yl] -5-heptenoic.

1 o

> Nuclear magnetic resonance spectrum ° C

(CDC13, 15 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, 35 25.8, 24.7.

! t

L

47

Under a argon atmosphere, a solution of 350 mg of the methyl ester of acid [1, 2a (5Z), 3ß, 4ß] -7- [3- (carboxy) was cooled, to 0 ° C. ) -7-oxa-bicyclo [2,2, 1] hept-2-yl] -5-heptenoid! And 0.35 ml of triethylamine in 3 ml of dry tetrahydrofuran.

To this stirred solution was added dropwise 0.24 ml of ethyl chloroformate. The resulting mixture was stirred at 0 ° C for 50 minutes, then diluted with 20 ml of anhydrous ether. The mixture was filtered through an MgSO 4 pad and concentrated in vacuo. The residue was dissolved in 2 ml of absolute EbOH and 3 * 3 ml of dry tetrahydrofuran. This solution was cooled in an ice bath, then 80 mg of NaBH 4 was added. The mixture was stirred for 30 minutes at 0 ° C, then the ice bath was removed. After 15 minutes, the reaction mixture was poured into 25 ml of ice-cold IN HCl. It was extracted to the aqueous layer with three 25 ml portions of ether.

The ether layers were combined, dried over MgSO 4, filtered, and concentrated in vacuo to obtain the crude product. The purification was carried out by flash chromatography on 22 g of silica gel using 1% MeOH / CH ^ Cl ^ as eluent. 250 mg of the methyl ester of [1β, 2α (5Z), 3ß, 4ß] -7- [3- (hydroxy-methyl) -7-oxabicyclo [2,2,1] hept were thus obtained. -2-yl] -5-heptenoic.

10

Nuclear magnetic resonance spectrum ° C - (CDC13, 15 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, 30 23.7.

B. [1β, 2q (5Z), 3B, 4Bl-7- [3- (p-toluene-sulfonyloxymethyl) -7-oxabicyclo [2,2, l] hept-2-yl] —5-heptenoic acid, ester methyl.

To a solution of 300 mg (1 * 12 mmol) of the methyl ester of acid [1β, 2α (5Z), 3β * 4β] -7- [3-

JL

48 (hydroxymethyl) --7-oxabicyclo [2,2, l] hept-2-yl] -5-z heptenoxque obtained sub A in 4 ml of dry pyridine, 427 mg (2.24 mmol) of chloride are added tosyle. 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 x 100 ml) and an aqueous solution of 0.5N NaOH (3100 ml). The ether 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 ° of hexane in ether as eluent to obtain 450 mg of the compound of heading B. ~ 15 C. Acid ΓΐΒ , 2α (5Ζ), 36.4Β1-7-Γ3-Γ (pentylthio) méthyll-7-oxabicyclo f 2,2, llhept-Z-yll-j-hepté-noique, methyl ester A solution of 132 mg ( 1.17 mmol) of. potassium t-butoxide in 10 ml of dry tetrahydrofuran, under an argon atmosphere, 378 mg (3 * 21 mmol) of 1-pentane-thiol are added. To this mixture is added a solution of 450 mg (1.07 mmol) of tosylate, from part B in 5 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature under an argon atmosphere for 2.5 hours, then heated to reflux for 5 * 5 hours. The cooled reaction mixture is diluted with 300 ml of ether and dried. pour into 100 ml of saturated NaHCOg solution. The aqueous layer is extracted with ether (2 x 100 ml). The combined ether extracts (500 ml) are washed with 0.5N = aqueous sodium hydroxide. (2 x 100 ml) and brine (100 ml), then they are dried (MgSO 4), they are filtered and they are concentrated under vacuum to obtain 0.55 g of a crude oil.

The purification is carried out by chromatography on

AT

49 25.2 g of silica gel 60 using a c 5: 1 mixture of petroleum ether and ether as eluent to obtain 328 mg of the title compound.

Example 49 5 Γlß, 2α (5Ζ), 3β, 4β1-7-Γ3-Γ (pentylthio) methyll- 7-oxabicyclo [2,2,11hept-2-yl) -5-heptenoic acid To a stirred solution of 328 mg (0.89 mmol) of the methyl ester of Example 48 in 43.8 ml of tetrahydrofuran and 6.67 ml of 10%, under an atmosphere of argon, 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 1N HCl solution and poured into 50 ml of saturated NaCl solution. The solution obtained is saturated with> · solid NaCl and extracted with EtOAc (4 x 50 ml). The combined extracts of EtOAc (MgSO 4) are dried, filtered and concentrated in vacuo. to obtain s 295 mg of crude acid. The purification is carried out by flash chromatography on 25 g of siliCAR CC-7 using a 2: 3 mixture of petroleum ether and ether as eluent to obtain the acid.

25 “Example 50

Acid flß, 2 "(5Z), 3α, 4Βΐ-7-Γ3-Γ (methylthio) methyl] -7- oxabicyclo [2, 2, l ~ | hept-2-yl] -5-heptenoic ^. Following the procedure of Examples 44 and 45, but substituting methylmercaptan for 1-hexane- = 30 thiol, the title compound is obtained.

Example 51 ·

Acid f16,2q (gZ), 36,46ΐ-7 ~ [3-Γ (propylthio) méthyll-7-oxabicyclof 2,2 Îl ~] hept-2-yl ~ | -5-hepténo3!

Following the process of Examples 48 and 35 4-9f Métis by substituting propylmercaptan for 1-pentane-

AT

50 thiol, the compound is obtained under the heading, Example 52

Acid (lB.2a, 3a, 4B) -7-r34Îbutylthio) methyl] ~ 7-oxa- · bicyclo [~ 2, 2, llhept ^ -yll-heptanoique.

Following the procedure of Examples 46 and 47, but substituting butylmercaptan for 1-hexane-thiol, the title compound is obtained.

Example 53

Acid ΓΐΒ.2α (5ζ), 3α »4ß ~ 1-7- [3- [(octylthio) methyl ~ 1-7-10 oxabicyclor2, 2, llhept-2-yll-5-heptenoxque

Following the procedure of examples 44 and Λ 45, but substituting l-oetane-thiol for 1-

hexane-thiol, the compound is obtained under heading. Analysis î for C22H38 ^ 3S

“15 calculated: C 69.06; H 10.01; S 8.38 found: C 69.08 5 H $ 9.75 S 8.20 π

Nuclear magnetic resonance spectrum ° C (CDC13, 15 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, 20 33.4, 32.1, 29.1, 28.8, 26.7, 26.2, 24.5, 22.5, 13.9.

, Example 54

Acid flß, 2q (5Z), 3αι48ΐ-7-Γ3-Γ (phenylthio) methyll-7-oxabicyclor2, 2 "llhept - ^ - yll - ^ - hepténoi’que

By following the process of Examples 44 and ‘- 25 45, but substituting phenyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

Example 55

(Lß, 2α, 3α, 4ß) -7-f3- [~ (phenylthio) methyl1-7- oxabicyclo [232,1] hept-2-yl] -heptanoic ^ 30 Following the process of Examples 46 and 47, but by substituting phenyl-mercaptan for 1- „hexane-thiol, the compound is obtained under heading.

U

51

Example 56

Acid [ΐβ, 2α (ςζ) “3a, 4ßl-7-f3-Γ (ethylthio) methyl1-7 ~ oxabicyclo [2,2, l ~ | hept-2-yl] -5-heptanoic

Following the procedure of Examples 44 and 545, but substituting ethyl mercaptan for 1-hexane thiol, the title compound is obtained.

Example 57

Acid Γΐβ »2α (5Ζ), 3ß, 4Bl — 7 — Γ3 — Γ (phenylthio) methyll-7-oxabicyclo f 2, 2 a 1] hept — 2 — yl] —5 —heptenoic 10 Following the procedure of Examples 48 and 49, but by substituting phenyl-mercaptan for 1- „pentane-thiol, the product is obtained under heading.

Example 58

Acid Γΐ6.2α (5Ζ), 3ß, 4ßl-7-f3-Γ (benzylthio) methyll- "15 7-oxabicyclof2, 2.11 hept-2-yl ~ l-5-heptenoic

Following the procedure of Examples 48 and 49j but substituting benzyl-mercaptan for 1-pentane-thiol, the product is obtained under heading.

Example 59 20 (1 ß, 2g, 3a, 4ß) -7-f ~ 3- [(benzylthio) methyl ~] -7-s oxabicyclo f2, 2.1 ~ | hept-2-yl] -heptanoic

By following the process of Examples 46 and 47j but by substituting benzyl-mercaptan for 1-hexane-thiol, the product is obtained under heading.

25 Example 60

Γΐβ "2α (5Ζ), 3α, 4Bl-7- [3- [(cycloh.exylthio) methyl ~ 1-7-oxabicyclor2, 2,11hept-2-yl ~] -5-heptenoic acid

By following the process of Examples 44 and 45 3 but by substituting cyclohexyl-mercaptan for ~ 30 l-hexane-thiol, the product is obtained under heading.

Example 6l

Acid flß, 2g (5Z), 38,4β1-7-Γ3-Γ (cyclopentylthio) -methyll-7-oxabicyclo [2 * 2 * 1 Ihept — 2-yl ~ d -5-heptenoi'que Following the process of examples 48 and 35 49, but by substituting cyclopentyl-mercaptan for

, L

52 1-pentane-thiol, the product is obtained under heading · * Example 62

(1ß, 2g, 3a.4 B) -7- [3- [(cyclohexylthio) methyl] - ^ 7-oxabicyclo [2,2,1] hept-2-yl] -heptanoic acid 5 Following the method of the examples 46 and 47, but by substituting cyclohexyl-mercaptan for l-hexane ~ thiol, the product is obtained under heading.

Example 63

Acid [lB.2g (ÇZ) .3a, 46] -7- [3- [2- (hexylthio) ethyl1-10 7-oxabicyclo [2,2 · l] hept-2-yl ~ 1 -5-heptenoic.

A. Acid flß, 2g (5Z), 3a, 4Β ~ 1-7-Γ3- (2-οχο) - * ethyl-7-oxabicyclo [2,2,11 hept-2-yl] -5 — heptenoic, ester methyl.

12.9 g (37.7 mmol) of methoxymethyltriphenylphosphonium chloride ((OCH ^ Cl) and 235 were added to a dry, three-tube round bottom 100 ml flask containing a stir bar. ml distilled toluene (stored on molecular sieves) The suspension obtained was stirred in an ice bath under an argon atmosphere until it was cold, then solution 1 was added dropwise , 55M from 18.3 ml (28.3 mmol) of potassium t-amylate in toluene, a bright red solution formed which was stirred at 0 ° C for an additional 35 minutes. over a period of 35 minutes, using a tap funnel, a solution of 4.97 g- (18.8 mmol) of the acid methyl ester [1β, 2a (5Z) was added ), 3α, 4ß] -7- [3-formyl-7-oxabicyclo [2,2,1] -30 hept — 2-yl] -5-heptenoic in 60 ml of toluene, the ice bath being always maintained in Then the reaction was abruptly stopped by the addition of 2.3 g (39 mmol) acetic acid in 5 ml of ether. The reaction mixture immediately turned pale yellow, then poured immediately ---- V.

53 in 200 ml of saturated NH.Cl and extracted with 4 of 1 * ether (4 x 200 ml). The combined ether layers were washed with saturated NaCl solution, dried (MgSO 4) and concentrated to obtain a yellow oil in a solid white tall oil (phosphine oxide). The white solid was triturated with EtOAc and the mother liquor was purified by chromatography in a column of LPS-1 silica. The fractions obtained were: 10 (A) 1 * methyl ester of acid [1β, 2α (5Ζ ), 3 ", 4ß] -7- [3- (2-oxo) ethyl-7-oxabicyclo [2,2,1] hept-2-yl] -5-% heptenoic, (B) the methyl ester d acid [lß, 2oc (5Z), 3oc, 4ß] -7 “[3- (2-methoxy) ethene-diyl-7-oxabicyclo [2,2,1] hept-2-15 yl] -5-heptenoxque , and (C) the methyl ester of [ΐβ, 2α (5Ζ), 3α, 4β] -7 ~ [3- (2,2-dimethoxy) ethyl-7-oxabicyclo [2,2, l] hept -2-yl] -5-heptenoic.

Each of the compounds (B) and (C) was treated with trifluoroacetic acid to transform each of them into compound (A).

B. [1β, 2α (5Ζ), 3α.4ßl-7-f3- (2-hydro-xyethyl) -7-oxabicyclo [2,2,1] hept-2-yl] -5-heptenoic acid, methyl ester .

“1.4 g (5 mmol) of the aldehyde obtained sub A in 50 ml of methanol are treated with 0.19 g (5 mmol) of NaBH 4 under an argon atmosphere at 0 ° C. After stirring at 0 ° for one hour, the reaction is abruptly stopped by addition of 2N HCl '' 30 (at a pH of 2). The methanol is removed in vacuo and the reaction mixture is taken up in ether *.

* The ether solution is washed with saturated KHCO ^ and saturated NaCl, then dried (MgSO ^). The ether is evaporated to obtain the compound of heading B.

Αλ 54 C. Acid Γlß .2α (5Ζ), 3α, 4βΊ-7-Γ3-Γ2- (hexvl-_ thio) ethyll - 7-oxabicyclof2, 2, llhept-2 - yll —5 — heptenoxque,

By following the process of examples 44 and 45, but by substituting the alcohol of part B above 5 for the alcohol used in example 44, the compound set out under heading is obtained.

s · Example 64

Acid Γΐβ »2α (5Ζ)» 3ß * 4βΊ-7-Γ3-r2- (hexylthio) ethyl ~ | -7-oxabicyclofZ, 2, l ~] hept-2-yl] -5 ~ heptenoi, that.

10 Following the method of Example 63, but substituting the methyl ester of acid [1β, 2α (5Ζ), s 3ß * 4ß] -7- [3-formyl-7-oxabicyclo [2,2, l] hept-2-yl] -5- heptenoxque to the methyl ester of acid [lß, 2a (5Z), 3a, 4 ß] -7 “[3-formyl-7-oxabicyclo [2,2,1 ] hept-2-yl] -5-15 heptenoic, the compound is obtained under heading.

Example 65

Acid (lß, 2g, 3α, 46) -7-Γ3- [2- (hexylthio) ethyl1-7- U - oxabicyclofZ, 2, l ~ | hept-2-yllheptanoi * que

Following the method of Example 64j but substituting the methyl acid ester (ΐβ, 2α, 3α, 4ß) “7- [3-formyl-7-oxabicyclo [2,2, l] hept-2 -yl] hepta-noic acid methyl ester [1β, 2α (5Ζ), 3α, 4β] “7- [3-formyl-7-oxabicyclo [2,2,1] hept-2-yl] -5-heptenoï-que, the compound is obtained under heading.

25 Example 66

Γΐβ, 2α (5Ζ), 3α, 4Bl-7-r3-r2- (phenylthio) ethyl] -7-oxabicyclof2,2, l] hept — 2 — yl] —5 — heptenoxic acid

Following the method of Example 63, but substituting phenyl-mercaptan for 1-hexane-thiol, the title compound is obtained.

Example 67

Γlß acid, 2g (5Z), 36 ^ 4ß ~ 1—7 — Γ3 — Γ2- (phenylthio) ethyl] -7-oxabicyclo [2,2,1] hept-2-yll-5-heptenoic

Following the process of Example 64, but substituting phenyl-mercaptan for 1-hexane-thiol,

AT

55 the compound is obtained under heading.

Example 68

Acid (13,2a, 3a, 4.B) -7-r3-r2- (phenylthio) ethyl ~ |.-7-oxabicyclofZ, 2 "llhept ^ -yll-heptanoique.

Following the procedure of Example 65 * but substituting phenyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

Example 69

Acid ΓΐΒ <2α (5Ζ ~), 3a, 4Bl-7- [3- [2- (benzylthio) ethyll-10 7-oxabicyclof2, 2, ilhept-2-yl] -5-heptenoic

Following the procedure of Example 63> s but substituting benzyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

Example 70 15 Acid flß, 2g (5Z), 3ß .4-ß 1 —7— f3-Γ2- (benzylthio) ethyl ~ 1-7 ~ oxabicyclor2, 2, llhept ~ 2 <-yll-5-heptenoic

By following the procedure of Example 649 but substituting benzyl mercaptan for 1-hexane-thiol, the title compound is obtained.

20 Example 71

Acid Γΐβ »2α (5Ζ), 3¾, 461-7- ^ 3-Γ2- (cyclopentyl — thio) -ethyl] -7-oxabicyclo f2, 2,1] hept-2-yl] -heptenolque Following the process of Example 63f, but by substituting cyclopentyl-mercaptan for 1-25 hexane-thiol, the title compound is obtained.

Example 72

Acid Γ1β, 2α (5Ζ), 3α, 4ßl-7- [3- [2- (cyclohexylthio) -ethyl! —7-oxabicyclo f 2, 2.1] hept-2-yl] -5-heptenoxque Following the method of 1 * example 633 * 30 but substituting cyclohexyl-mercaptan for 1-hexane-thiol, the product under heading, / 56

Example 73% Acid flß, 2g (5Z), 3a, 4ßl-7- [3- [4- (hexylthio) butyri-7- oxabicyclo [2, 2, l ~ jhept-2-yl ~] -5-heptenolque.

A. Acid ΓΐΒ, 2α (5Ζ) .4β1-7-Γ3- (3-οχο) - s * 5 propyl-7-oxabicyclo [2,2, l] hept-2-yl] -5 — heptenoic, methyl ester "

Following the procedure in Part A of Example 63 * but substituting the methyl acid ester [1, 2a (5Z), 3cX; 4ß] “7- [3- (2-oxo) ethyl-7 -oxa- bicyclo [2,2, 1] hept-2 — yl] —5 — heptenoic acid methyl ester [1β32α (5Ζ), 3a, 4ß] -7 “[3-formyl-7- oxabicyclo [2i2il] hept-2-yl] -5-heptenoic3 the compound of heading A is obtained

B. Acid flß, 2g (5Z), 3oc, 4ßl-7-r3- (4-oxo) - butyl-7-oxabicyclof 2,2,1 ~ jhept-2-yl] - 5 - hepteno5! Que3, ester methyl.

Following the method of part A of example 63} but substituting the aldehyde of part A above for the methyl ester of acid 20 [lß, 2α (5Ζ), 3a? 4ß] -7 “[3-formyl-7-oxabicyclo [2i2il] - hept-2-yl] -5-heptenoic5 we obtain the aldehyde from section B, C. Acid Γΐβ, 2α (5Ζ), 3α, 43ΐ-7-Γ3 - (4-hydro-xybutyl) -7-oxabicyclo [2,2 ^ 1] hept-2-yl] - 5-hept enoi'que a 2S methyl ester.

Following the method of part B of Example 63; but by substituting the aldehyde in heading B for the methyl ester of acid [lß, 2a (5Z) a 3α; 4β] -7- [3 “(2-οχο) ethyl] -7-oxabicyclo [2 f291 ] hept-? ‘30 2-.yl] -5-heptenoxquej we obtain alcohol from ru brick C.

'/ ky 57 D. Acid Γΐβ * 2α (5Ζ), 3α, 4-ß1-7 "r3" f4- (hexyl-thio) butyll-7-oxabicyclor2, 2, l1hept-2-yl] -5-hepté noic.

By following the process of examples 44 © b 5 45t but by substituting the alcohol of part C above for the alcohol used in example 449, the title compound is obtained.

Example 74

Acid [ΐβ, 2α (5Ζ), 3α, 4ß1-7-r3- [~ 4- (cyclohexylthio) -10 butyll-7-oxabicyclo f2, 2, l1hept-2-yl ~ | ~ 5-hepbenoic

Following the method of Example 739. but by substituting cyclohexyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

Example 75 15 Acid Γΐ6,2α (5Ζ), 3cc, 46l-7 ~ [3- [4- (phenylthio) butyll-7-oxabicyclor2, 2, l] hept-2-yll-5-hepténo3!

By following the process of Example 733 but by substituting phenyl-mercaptan for 1-hexane-thiola, the compound is obtained under heading.

20 Example 76

Acid | ~ lß, 2q (5Z), 3a <4ßl-7- [3-f4 ~ (benzylthio) butyl1-7-oxabicyclo f2, 2.1 ~ | hept-2-yl] -heptenoic

Following the procedure of Example 73 "but substituting benzyl-mercaptan for 1-hexane-25 thiol} the compound is obtained under heading.

Examples 77, 78 and 79

Acid [lß, 2g (5Z), 3α, 4ß] -7- [3- [(hexylsulfinyl) methyl] -7-oxabicyclo [2, 2, l ~ jhept — 2 — yl ~] ~ 5 ~ hepteno3? methyl ester (rapidly moving isomer), c 30 acid [1β.2α (5Ζ) .3 ", 46] ~ 7- [3 - [(hexylsulfinyl) methyl] - 7-oxabicyclo [2, 2,1] hept- 2-yl] -5-heptenofüque, methyl ester (slowly moving isomer), and acid Γ1B, 2g (5Z), 3a ”43l-7 ~ [3 - [(hexylsulfonyl) methylhhΠ-7-oxabicyclof2, 2, l] hept-2-yl1-5-heptenoxque, methyl ester.

L · 58 To a solution of 634 mg (1.72 mmol) of s, 1 * methyl ester decides [lß, 2a (5Z) * 3ct * 4ß] -7 “[3- [(hexylthio) methyl] -7- oxabicyelo [2,2,1] hept-2-yl] -5-heptenoic (which is prepared as described in 5 1 * example 44) in 6.78 ml of methanol, at a temperature of 0 ° C, for 4 minutes, 8.37 ml of a 0.5M aqueous sodium periodate solution was added dropwise. Then, 2 ml of tetrahydrofuran was added and the reaction mixture obtained was stirred at room temperature for 15 hours. By filtration, a white precipitate was removed and washed with 1 * ether (3 x 50 ml).

The filtrate was washed with 60 ml of saturated aqueous NaHCO 4 solution and dried over anhydrous magnesium sulfate. By concentration in vacuo, 648 mg of an oily crude product was obtained. The latter was subjected to chromatography on 54 * 16 g of silica gel 60 using 0.5-1% CH ^ OH in CK ^ C ^ as eluent. 211 mg (32%) of sulfoxide (rapidly moving isomer) were thus obtained (Example 77) * 142 mg (21%) of sulfoxide (slowly moving isomer) (Example 78) and 165 mg (24%) of sulfone (Example 79) These products were oils which solidified when stored in the freezer. Thin layer chromatography = silica gel, 1% CHgOH / CH ^ C ^ *! sulfoxide of Example 77 · 0.28 \ sulfoxide of Example 78 ï 0.21; sulfone of example 79 î 0 * 74 * iodine, 5 '30 Example 80

Acid Γ 1Β, 2α (5Ζ), 3 "· 46ΐ-7-Γ3-Γ (hexylsulfonyl) methyl] -1 7-oxabicyclo [2.2.11 hept-2-yl] -5-hept enoic At a stirred solution of 165 mg (0.41 mmol) of the methyl ester of acid [lß, 2a (5Z) * 3ß * 4ß] “7- 35 [3- [(hexylsulfonyl) methyl] -7-oxabicyclo [2,2,1 ] hept-2-

AT

59 μl] -5-heptenoic (example 79) in 20.3 ml of t-trahydrofuran and 3.09 ml of H2O, under an atmosphere of argon, 3.90 ml of an aqueous hydroxide solution was added IN lithium. This mixture was purged vigorously with argon for 10 minutes and stirred at room temperature for 6 hours · The reaction mixture was acidified to pH 4 by addition of an aqueous solution of IN HCl and poured into 30 ml of saturated NaCl solution. The solution obtained was saturated with solid NaCl and extracted with EtOAc - (4 x 50 ml). The combined EtOAc extracts (MgSO 4) were dried, filtered and concentrated in vacuo to give 165 mg of crude acid.

The purification was carried out by flash chromatography on 20 g of silica gel 60 using 3% CH20H in CH2Cl2 as eluent. The resulting acid (145 mg, $ 91) was thus obtained which solidified when stored in the freezer.

Thin layer chromatography = silica gel, 4% CH30H / CH2Cl2, Rf 0.32, iodine.

Analysis for C ^ H ^ O ^ S

calculated: C 62.18 5 H 8.8l; S 8.29 found: C 61.99; H 9.01.5 S 8.33 · 25 Nuclear magnetic resonance spectrum ° C (CDClg, 15 MHz) tau î 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 8l v '30 Acid (~ lß, 2tt (5Z), 3α.481—7 ~ f3 - [(hexylsulfinyl) methyll- 7-oxabicyclo [2, 2,1] hept-2-yl ~ | -5-hepténoi 'that (rapidly moving isomer).

To a stirred solution of 211 mg (0.55 mmol) of the methyl ester of acid [1β, 2α (5Ζ), 3 <X, 35 4ß] “7- [3- [(hexylsulfinyl) methyl] -7 -oxabicyclo [2,2, lj-

: L

6θ hept-2-yl] -5-heptenoic (rapidly moving isomer), prepared as described in 11 Example 77, in 27 ml of tetrahydrofuran and 4.11 ml of ^ 0, under an atmosphere of argon, we added 5? 19 ml of an aqueous solution of 1N lithium hydroxide. This mixture was vigorously purged with argon for 10 minutes and stirred at room temperature for 6 hours. The reaction mixture was acidified to pH 4 by addition of an aqueous 1N HCl solution and poured into 50 ml of saturated NaCl solution. The solution obtained was saturated with solid NaCl and extracted with "f

EtOAc (4 x 100 ml). The combined extracts of EfcOAc (MgSO 4) were dried? they were filtered and concentrated in vacuo to obtain 216 mg of crude acid.

The purification was carried out by flash chromatography on 20.2 g of silica gel 60 using 2% CH g 0H in GHL ^ C ^ as eluent to obtain the acid under heading (172 mg, $ 85) in the form of * a 20 white solid. Thin layer chromatography = silica gel, 4 $ CHgOH / Œ ^ d ^, Rp ï 0.10, iodine.

Analysis: for C ^ qH ^^ O ^ S: calculated: C 64.83 J H 9.25; S 8.65 found î C 64.71 ï H 9.17 5 S 8.5513

25 Nuclear magnetic resonance spectrum C

(CDC13, 15 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 30 Acid flß, 2q (5Z), 3cx ^ 4ß1 ~ 7 "f3-r (hexylsulfinyl) methyll- 7-oxabicyclof2, 2, l | hept-2-yll-5 ~ heptenoi, that (slowly moving isomer ).

To a stirred solution of 142 mg (0.37 mmol) of 1 * methyl ester of acid [1β, 2α (5Ζ), 3κ, 4β] —7 * “35 [3 - [(hexylsulfinyl) methyl] -7” oxabicyclo [2,2, l] hept- 61 2-yl] -5 “heptenoic (isomer moving slowly), prepared as described in example 78, in 18.2 ml of Λ tetrahydrofuran and 2.77 ml of I ^ O, under an argon atmosphere, 3 * 50 ml of an aqueous solution of 1N lithium hydroxide was added. This mixture was vigorously purged with argon for 15 minutes and stirred at room temperature for 4 hours, 40 minutes. The reaction mixture was acidified to pH 4 by addition of an aqueous 1N HCl solution and poured into 30 ml of saturated NaCl solution. The resulting solution was saturated with solid NaCl. and treated with EbOAc (3 x 70 ml), The combined extracts of EfcOAc (MgSO 4) were dried, filtered and concentrated in vacuo to give 152 mg of acid gross. Purification was carried out by flash chromatography on 20.8 g of silica gel 60 using 4 $ CH ^ OH in QE ^ C ^ as eluent to obtain the acid under heading (116 mg, 85 $) · Chromatography on a thin layer: silica gel, 4% CH ^ OH / CH ^ Cl ^ y Rp: 0.6, iodine.

Analysis: for C2qH, ^ 0 ^ s calculated: c 64.83 J H 9.25; S 8.65 found: C 64.44; H 9.15> S 8.58.

1 7

25 Nuclear magnetic resonance spectrum ° C

(CDC13, 15 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 30 Acid [1Β, 2α (5Ζ), 3a, 4ßl-7- [3 - [(methylsulfinyl) methyll- 7-oxabicyclo [2,2, l1hept-2-yl] -5-heptenoxque (rapidly moving isomer ),

By following the process of Examples 44, 77 and 81, but substituting methyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading,

U

62

Example 84 * Acid 16.2g (5Z) .3 ", 46ΐ ~ 7-Γ3-Γ (octylsulfinyl) methyll- 7-oxabicyclo f 2,2,1 ~ 1hept-2-yl] -5-heptenoic (moving isomer ; slowly) .

Following the procedure of Examples 449 77 and 82, but substituting 1-octane-thiol for 1-hexane-thiol, the title compound is obtained.

Example 85

Acid | ~ IB, 2g (SZ), 3B, 4ßl-7- [3- [(phenylsulfinyl) methyl-10 7 ~ oxabicyclor2,2tl1hept> -2-yl] -5 ~ heptenoic (rapidly moving isomer).

Following the procedure of Examples 485 77 and 81, but substituting phenyl-mercaptan for 1-pentane-thiol, the compound is obtained under heading. 15 Example 86

Acid | ~ 1β, 2α (5Ζ), 3α, 4β1-7-Γ3-Γ (ethylsulfinyl) methyll-7-oxabicyclo [~ 2,2 .llhept - ^ - yll-S-heptenoic (slowly moving isomer).

Following the procedure of Examples 48, 77 and 82, but substituting ethyl mercaptan for 1-pentane-thiol, the compound is obtained under heading.

Example 87

(Ϊ́β, 2α "3α ,, 46) -7- [3- [~ (heptylsulfinyl) methyl] -7-oxabicyclo [2, 2, llhept-2-yll-5-heptanoic acid (fast-moving isomer 25).

By following the process of Examples 46, 77 and 81, but substituting 1-heptane-thiol for 1-hexane-thiol, the compound is obtained under heading.

Example 88 v_ 30 Acid Γΐ (3,2α (5Ζ), 3α, 4ß1-7-f3-f (benzylsulfinyllméthyll- 7-oxabicyclo | ~ 2, 2 .llhept-Z-yll-S-heptenoic

Following the procedure of Examples 44> 77 and 81, but substituting the benzyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

h 63

Example 89

Acid [lß, 2g (5Z) "3ß, 4ß] -7- [3- [(benzylsulfinyl) methyl ~ l-7-oxabicyclo [2,2,1 ~] hept-2-yl ~ l-5-heptenoic ( slowly moving isomer), 5 Following the procedure of Examples 48, 77 and 82, but substituting benzyl-mercaptan for 1-pentane-thiol, the title compound is obtained.

Example 90

Acid Γΐ6,2α (5Ζ), 3α, 4β ~ 1-7- [3 - [(cyclohexylsulfinyl) - 10 méthyll-7-oxabicycloΓ2, 2,1 ~ [hept-2-yl] -5-hepténoique3 (moving isomer quickly).

Following the procedure of Examples 44, 77 and 81, but substituting cyclohexyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

Example 91

Acid [lß, 2g (5Z) .3ou46] -7- [3 - [(cyclopentylsuli: inyl) -methyll "7 ~ Q3cabicyclor2, 2, l ~ lhept-2-yl ~ l-5-heptenoic (rapidly moving isomer ).

Following the procedure of Examples 44 * 77 and 81, but substituting cyclopentyl-mercaptan for 1-hexane-thiol, the title compound is obtained.

Example 92 ~ 25 Γΐβ, 2α (5Ζ), 3α, 4ß ~ d-7- [3 - [(octylsulfonyl) methyll- 7-oxabicyclo (2,2,1] hept-2-yll -S-heptenoiic acid)

Following the procedure of Examples 44, 77 and 80, but substituting 1 * octyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

* 30 Example 93

Acid flß, 2g (5Z), 3 ", 4ß1-7-f3-f (propylsulfonyl) -methyll-7-oxabicyclof2, 2.1 lhept-2-yl] -5-heptenoic.

Following the procedure of Examples 44 * 77 and 80, but substituting propyl-mercaptan for 1- 'r hexane-thiol, the title compound is obtained.

AT

64

Example 94

Acid Γΐ8 · .2α (5Ζ) «3α .4Β1-7-Γ3-Γ (phenylsulfonyl) - * methyl-7 ~ oxabicyclo f2,1,1] hept-2-yll-5-heptenoic

By following the process of Examples 44 * 77 5 and 8θ, but by substituting phenyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

Example 95

Acid [1Β, 2α (5Ζ), 3α, 4-ß 1—7 ~ -ff (benzylsulfonyl) -methyll-7-oxabicyclo [2,2,11hept-2-yl] ~ 5 ~ heptenoxque 10 Following the process of Examples 443 77 and 80, but by substituting benzylmercaptan for 1-hexane-thiol, the compound is obtained under the heading, “Example 96

[IB, 2α (5Ζ), 3a, 4Bl-7- [3 - [(cyclohexylsulfonyl) -15 méthyll-7-oxabicyclo [2,2, llhept-2-yl] -5-heptenoic acid Following the procedure of the examples 44> 77 and 80, but by substituting cyclohexyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

20 Example 97

Acid »β »2α (5Ζ), 3ß» 4Βΐ-7- [~ 3-Γ (heptylsulfonyl) -methyll-7-oxabicyclo [2,2,1lhept-2-yll-5-heptenolque Following the method of Examples 48, 77 and 80, but by substituting 1-heptane-thiol for 1-pentane-thiol, the title compound is obtained.

Example 98

Acid [lß, 2g (5Z), 33 * 4ß] -7- [3 - [(benzylsulfonyl) -methyll-7-oxabicyclo [2,2, llhept-2-yll-5-heptenoxque Following the procedure of Examples 489 77 30 and 80d but by substituting benzyl-mercaptan for 1-pentane-thiol3 the compound is obtained under heading.

U

65

Example 99 ï [1ß, 2ff (5Z), 3ß .481 - 7 — Γ3— [(cyclopentylsulfonyl) - methyll -7-oxabicyclo [2,2,1 lhept-2-yl] -5-heptenoic Following the process Examples 48, 77 and 80, but by substituting cyclopentyl-mercaptan for 1-pentane-thiol, the title compound is obtained.

Example 100

Acid rlß, 2k (5Z), 38 ·, 4-ß 1—7— Γ3— Γ (phenylsulfonyl) -10 méthyll-7-oxabicycloΓ2,2, l1hept-2 ~ yl] -5-hepténoi'que Following the process Examples 48, 77 and 80, but by substituting phenyl-mercaptan for T5 '1-pentane-thiol, the compound is obtained under heading.

Example 101 15 (18,20:, 3 ^ 348) -7- ^ 3-Γ (cyclopropylsulfinyl) - methyl] -7-oxabicyclof2, 2,11hept-2-yll-5-heptanoic acid Following the procedure of Examples 46 , 77 and 80, but by substituting cyclopropyl-mercaptan for 1-hexane-thiol, the compound is obtained under rubri-20.

Example 102

Acid (lß, 2g, .½, 48) -7- [3- [(benzylsulfinyl) methyll-7-oxabicyclo [~ 2,2,11 hept-2-yl] -5-heptanol‘que

Following the procedure of Examples 47 * 77 and 81, but substituting the benzyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

Example 103

Acid [lß, 2g (5Z), 3a, 4ßl-7- [3-r2- (benzylsulfinyl) -ethyll-7-oxabicyclo [2,2,1] hept-2-yll-5-heptenoic * 30 Following the The process of Examples 63 * 44 * 77 and 81, but by substituting 1-pentane-thiol for 1-hexane-thiol, the compound is obtained under heading.

Λ 66

Example 104 y Acid [~ lß, 2g (5Z), 3α »4βΊ-7 · -Γ3- [2— (phenylsulfonyl) - ethyl ~ l-7-oxabicyclor2,2,1lhept-2-yl] -5-heptenoic

Following the method of Examples 63 * 44 * 5 77 and 80 * but substituting phenylmercaptan for 1-hexane-thiol, the compound is obtained under heading.

Example 105

[Ίβ, 2α (5Ζ), 3α * 43l-7-T3- [2- (cyclohexylsulfonyl) -ethyl ~ 1-7 — oxabicyclof2, 2, llhept-2-yl ~] -5 — heptenoic 10 Following the process Examples 63 * 44 * 77 and 80, but by substituting cyclohexyl-mercaptan for 1-hexane-thiol, the compound is obtained under rubric.

Example 106 15 Acid [lß, 2g (5Z), 3α, 4ßl-7- [3- [2- (benzylsulfinyl) - ethyl] -7-oxabicyclo | ~ 2,2, l] hept-2-yll-5- heptenoic

By following the method of Examples 63 * 44 * 77 and 81j but by substituting benzyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

20 Example 107

Acid [lß, 2g (5Z), 3ß, 4ßl-7- [~ 3-l ~ 2- (butylsulfonyl) -ethyl ~ [-7-oxabicyclo [2, 2, l] hept-2-yll-5-heptenoic

Following the procedure of Examples 63 * 48 * 77 and 80, but substituting butyl-mercaptan for 1-pentane-thiol, the title compound is obtained.

Example 108

Acid flß, 2g (5Z), 33,431-7-Γ3-Γ2- (phenylsulfinyl) -ethyl] -7-oxabicyclo [~ 2 3 2,1 ~] hept-2-yl] -5-heptenoic

By following the process of Examples 63 * 48 * "30 77 and 81, but by substituting phenyl-mercaptan for 1-pentane-thiol, the compound is obtained under heading,

/ L

y '68

Example 114 * Acid (1B, 2g, 3a, 4ß) -7- [3- [2- (cyclohexvlsulfonyl ') - ethyl ~] -7-oxabicyclo [2, 2, llhept-2-yl] -, Î)> -heptanoxqüe

Following the procedure of Examples 63, 48, 77 and 80, but substituting cyclohexyl-mercaptan for 1-hexane-thiol, the title compound is obtained.

Example 115

Acid f ~ lß, 2g (5Z), 3a% 4ßl-7- [3- [4- (pentylsulfonyl) -10 butyll -7 ~ oxabicyclo f2,2, 1 lhept-2-yl ~ | -5-heptenoic

By following the procedure of Examples 73 * 63 * „44 * 77 and 80, but substituting pentyl mercaptant for 1-hexane-thiol, the title compound is obtained.

15 Example 116

Acid f ~ lß, 2g: (5Z), 3a, 4ß1-7- [3 - [4- (cyclohexylsulfinyl) -butyll-7 ~ oxabicyclo [2,2 "llhept ^ -yll-S-heptenoic

Following the procedure of Examples 73 * 63, 44 * 77 and 81, but substituting 20-cyclohexyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

Example 117

Acid [lß, 2g (5Z), 3a, 4ß ~ l-7- | ~ 3- [4 ~ (phenylsulfinyl) -butyll-7-oxabicyclo [~ 2, 2 "llhept ^ -yll ^ -heptenoic 25 process of Examples 73 * 63, 44 * 77 and 81, but by substituting phenyl-mercaptan for 1-hexane-thiol, the compound is obtained under heading.

Example 118 * '30 Acid | ~ lß, 2g (5Z), 3α, 4Βΐ · -7- · [3-r4- (benzylsulfonyl) - butyll -7-oxabicyclo [2,2,1] hept-2-yl] -5 "hepténoi'que

Following the procedure of Examples 73 * 63, 44 * 77 and 80, but substituting benzyl-mercap-tan for 1-hexane-thiol, the title compound is obtained.

AT

69

Example 119 * ·. Acid | ~ 16.2g (5Z), 33.4ßl-7- | ~ 3-Γ4- (cy dopant ylsulfi- nypbutyll -7-oxabicyclo f 2,2,11 hept-2-yl ~ l -5-hepté no. 5 Following the procedure of Examples 73, 63, 48, 77 and 81, but substituting cyclopentyl-mercaptan for 1-pentane-thiol, the title compound is obtained.

Example 120

Acid [lß, 2g (5Z), 3ß.4ß1-7- [3-r4- (benzylsulfinyl) -butyl] -7-oxabicyclo f2,2,1] hept-2-yl] -5-heptenoic% Following the process of Examples 73 * 63 * 48, 77 and 80, but by substituting benzyl-mercaptan for 1-pentane-thiol, the compound is obtained under rubric.

Example 121

Acid flß, 2g (5Z), 3ß.4ß1-7-r3-f4- (propylsulfinyl) -butyl] -7 ~ oxabicyclof2,2 ”1] hept — 2-yl] -5 — heptenoic

Following the procedure of Examples 73, 63, 48, 77 and 81, but substituting propyl-mercaptan for 1-pentane-thiol, the title compound is obtained.

Example 122

Flß acid, 2g (5Z), 33,46l-7-r3-f4- (phenylsulfonyl) -25 butyll -7 * joxabi cyclo [2,2,1] hept-2-yl] -5-heptenoic

Following the procedure of Examples 73 ”63” 14, 78 and 80, but substituting phenyl-mercaptan for 1-pentane-thiol, the compound is obtained under heading.

; · 30 Example 123

Acid (lß, 2g.3g, 4ß) ~ 7 -. ['3-. |' 4 -. (Nonylsulfinyl) butyl1-7-oxabicyclo f 2,2,1Ί hept-2 -yl] -5 -hept anoic

Following the procedure of Examples 73, 63, 46, 77 and 81, but substituting 1-nonane-thiol 35 for 1-hexane-thiol, the title compound is obtained.

L

70

Example 124

Acid (lB .2g: <3a <4-B) -7 "r ^ ~ ['4 -" - (pen-fcylsulfonyl) butyll ~ * 7-oxabicyclo [~ 2, 2 Îl] hept-2-yl' | ~ 5..heptanoic

Following the procedure of Examples 73 * 63 * 5 46, 77 and 80, but substituting 1-pentane-thiol for 1-hexane-thiol, the title compound is obtained.

Example 125

Acid (lß, 2g, 3a "4B) -7- [3- [4- (phenylsulfinyl) butyl1-10 7-oxabicyclo Γ2,2,1] hept-2-yll-5-heptenoic

Following the method of Examples 77j 63 * 46, 77 and 81, but substituting the phenyl-mercaptan. with 1-hexane-thiol, the compound is obtained under heading *

Example 126 15 Acid (1β, 2α, 3 ", 4ß) -7-r3-r4- (cycloh.exylsulfonyl) - ^ b utyl] -7-oxabicyclo [~ 2,2, 1 ~] hept-2-yl ~ ] -5-heptano £ that

Following the procedure of Examples 73 ”63 * 46 to 77 and 80, but substituting cyclohexyl-mercaptan for 1-hexane-thiol, compound 20 is obtained under heading.

Example 127

Acid [lß.2g (5Z), 3α "4ß] -7- [3 ~ [Γ (cyclohexylmethyl) - thio] methyl] -7-oxabicyclof2, 2,11hept-2-yl] -5-hepté-noique.

25 A. Acid [Ίβ, 2α (5Ζ), 3α, 4Βΐ-7-Γ3-ΓΓ (cyclohexylmethyl) thio1methyll-7-oxabicyclof2, 2, l ~ lhept — 2— yll-5-hepténoi'que, methyl ester .

To a solution of 88 mg (θ, 7β mmol) of potassium t-butoxide in 5 ml of dry tetrahydro- “· furan, under an atmosphere of argon, was added 277 mg (2.13 mmol) of cyclohexylmethane -thiol (prepared from cyclohexyl-methanol by the method of Volante î Tetrahedron Letters 1981, 22, 3119) · To this mixture was added a solution of 300 mg 35 (0.71 mmol) of l * acid methyl ester [1β, 2α (5Ζ), “71 3α, 4β] -7- [3- (p-toluene-sulfonyloxymethyl) -7-oxa-bicyclo [2,2, l] hept-2-yl ] -5-heptenofque, prepared as described in Example 44B, in 5 * 5 ml of tetra-; dry hydrofuran. The reaction mixture was heated to reflux for 7 hours. The cooled reaction mixture was diluted with 250 ml of ether and poured into 100 ml of saturated NaHCO 4 solution.

The aqueous layer was extracted with 1 * ether (2 x 100 ml). The combined ether extracts (450 ml) were washed with 0.5N aqueous sodium hydroxide solution (2 x 100 ml) and brine (100 ml). The ether extracts were dried over anhydrous MgSO 4 and concentrated in vacuo to obtain an oily product. The purification was carried out by chromatography on 20.2 g of silica gel 60 using a 3s1 mixture of hexane and ether as eluent to obtain 253 mg of the methyl ester of heading A as a oil ($ 94). Thin layer chromatography on silica gel, petroleum ether / ether (3: 2), = 0.70, iodine.

B. Acid [1, 2q (5Z), 3a "4Bl-7- [3- [f (cyclo-hexylmethyl) thiol methyll -7" Qxabi, cyclo f 2, 2 a 1] hept-2-yll -5- heptenoic acid 25 To a stirred solution of 243 mg (0.64 mmol) of the methyl ester of part A in 31.4 ml of tetrahydrofuran and 4 * 80 ml of 1 ^ 0, under an atmosphere of argon, we have 6 ml of a 1N aqueous solution of lithium hydroxide was added, This mixture was vigorously purged with argon for 25 minutes and stirred at room temperature for 16 hours. The reaction mixture was acidified at pH 5 by addition of an aqueous 1N HCl solution and poured into 40 ml of saturated NaCl solution. The solution was saturated

L

72 obtained with solid NaCl and extracted with EfcOAc (4 x 50 ml). The combined extracts of EtOAc (MgSO 4) were dried, filtered and concentrated in vacuo to obtain 253 mg of crude acid, purification was carried out by flash chromatography on 20.6 g of gel silica 60 using a 2: 3 mixture of petroleum ether and ether as eluent to obtain the product under heading in pure state (II7 mg, $ 50) together with 108 mg ($ 46) of 10 fractions mixed of which the product under heading was the main component. Thin layer chromatography: silica gel, petroleum ether / ether (2: 3),

Rp = 0.32, iodine.

Analysis: for COiH „.0_S

o 4 3 15 calculated: C 68.85 3 H 9.29; S 8.74 found: C 68.90; H 9.43 3 S 8.66.

Nuclear magnetic resonance spectrum ° C (CDC13, 15 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, 20 47.6, 33.4, 40.4, 38.0, 32.9, 29.5, 26.1, 29.5, 32.9.

Example 128

Acid [1β., 2α (5Ζ) “3“ .4β] -7- [3- [(2-phenylethvl) thio] - methyl: [- 7-oxabicyclo [2, 2, l] hept-2-yl ~ j -S-heptenolque. A. Acid ΓΐΒ, 2α (5Ζ), 3a.4Bl-7- [3-fΓ (2-25 phenylethyl) thio 1 methyll -7 ~ oxabicyclo | ~ 2,2,11 hept-2- yll-5-heptenoic, methyl ester.

To a solution of 55.7 mg (0.50 mmol) of potassium t-butoxide in 5 ml of dry tetrahydrofuran, under an atmosphere of argon, was added 3085 mg (1.35 mmol) of phenylethane-thiol, To this mixture was added a solution of 189 mg (0.45 mmol) of the methyl ester of acid [1β, 2α (5Ζ), 3α, 4β] -7- [3- (p-toluene -sulfonyloxymethyl) -7-oxabi-cyclo [2,2,1] hept-2-yl] -5-heptenoic, prepared as described in Example 44B, in 6 ml of tetrahydro—

U

73 dry furan * The reaction mixture was heated at reflux for 4 hours, 30 minutes # The cooled reaction mixture was diluted with 160 ml of ether and poured into 60 ml of saturated NaHCOg solution # The aqueous layer was extracted with 1 * ether (2 x 60 ml). The combined ether extracts (280 ml) were washed with 0.5N aqueous sodium hydroxide solution (2 x 60 ml) and brine (75 ml) · The ether extracts were dried over MgSO 4 and concentrated in vacuo to obtain an oily product # Purification was carried out by chromatography on 21.6 g of silica gel 60 using a 50 ml mixture of petroleum ether and ether as I eluent to obtain 157 mg of the compound of heading 15 A in the form of an oil (90%). Thin layer chromatography: silica gel, petroleum ether / ether (2: 1), Rp = 0.60, iodine # B. Γΐβ acid, 2α (5Ζ), 3 ", 4β1-7-Γ3-ΓΓ (2 -phenylethyl) thiolmethyll -7-oxabicyclof2, 2 »llhept-20 2-yll -5-heptenol'que # A a stirred solution of 150 mg (0.39 nrniole) of the methyl ester of part A in 19 ml of freshly distilled tetrahydrofuran and 2.91 ml of H 2 O, under an argon atmosphere, 3 * 64 ml of an aqueous solution of lithium hydroxide IN # 3 was added. This mixture was vigorously purged with argon for 25 minutes and stirred at room temperature for 6 hours # The reaction mixture was acidified to pH 5 by "= 30 addition of 1N aqueous HCl solution and poured into 40 ml saturated NaCl # solution

The solution obtained was saturated with solid NaCl and extracted with EtOAc (4 x 60 ml). The combined extracts of EfcOAc (MgSO 4) were dried, filtered and concentrated in vacuo to

U

74 obtain 147 mg of crude acid. The purification was carried out by flash chromatography on 20 g of silica gel 60 using 2% of CHjOH in CH2Cl2 as eluent to obtain the product under 5 heading (122 mg, 84 #) in the form of an oil.

Thin layer chromatography: silica gel, 6% CH30H in CH2C12, Rf = 0.32, iodine.

Analysis: for C22H30 ° 3S

calculated: C 70.55 3 H 8.07 5 S 8.56 10 found: C 70.54 5 H 8.08; S 8.48.

Nuclear magnetic resonance spectrum (CDC13, 15 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, 128.4-15 Example 129

Acid [lß, 2q (5Z), 3 <X, 4ß ~ l-7- [3- [Γ (3-phenylpropyl) thio ~ l-méthyll-7-oxabicyclo [2.2,11hept-2-yll-5-hepténoïaue .

A. Acid ΓΐΒ "2α (5Ζ), 3a, 4β ~ 1-7-Γ3" Γ r (3-phe-nylpropyl) thiolmethyll- • 7-oxabicyclo f2,2,11 hept-2 ~ 20 yll-5-heptenoic , methyl ester.

To a solution of 88 mg (0.78 mmol) of potassium t-butoxide in 5 ml of dry tetrahydrofuran, under an argon atmosphere, 324 mg (2.13 mmol) of 3-phenylpropyl-mercaptan was added. To this mixture was added a solution of 300 mg (0.71 mmol) of the methyl ester of acid [1, 2a (5Z), 3oc, 4ß] -7- [3- (p-toluene- sulfonyloxymethyl) -7-oxa-bicyclo [2,2, l] hept-2-yl] ~ 5-heptenoic in 7 ml of dry tetrahydrofuran. The reaction mixture was heated at reflux for 6 hours, 30 minutes # The cooled reaction mixture was diluted with 250 ml of ether and poured into 100 ml of saturated NaHCO3 solution # We extract the aqueous layer with ether (2 x 100 ml). The combined ether extracts (450 ml) were washed with 0.5N aqueous sodium hydroxide solution 75N (2 x 100 ml) and brine (100 ml). The extracts were dried. ether on MgSO 4 and concentrated in vacuo to obtain an oily product · Purification was carried out by chromatography on 25 g of silica gel 60 using a 3 * 1 mixture of hexane and ether as eluent to obtain 280 mg of the compound from section A as an oil ($ 98) · Thin layer chromatography: silica gel, 10 petroleum ether / ether (2: 1), = 0.60, iodine * B. Acid [1β, 2α (5Ζ), 3α, 4β1-7-Γ3 - ΓΓ (3-phenylpropyl) thiol methyll-7-oxabi cyclo f2, 2,1] hept-2-yl ~ | -5-heptenoic · To a stirred solution of 280 mg (0.70 15 mmol) of the methyl ester of part A in * 34j4 ml of freshly distilled tetrahydrofuran and 5.30 ml of H20, under an atmosphere of argon 6.60 ml of an aqueous solution of IN lithium lithium hydroxide were added. This mixture was purged with argon for one hour and stirred at room temperature for 3 hours. The reaction mixture was acidified to pH 5 by addition of an aqueous 1N HCl solution and poured into 50 ml of saturated NaCl solution. The solution obtained was saturated with solid NaCl and extracted with EtOAc (4 x 60 ml). The combined extracts of EtOAc (MgSO 4) were dried, filtered and concentrated under vacuum to obtain 280 mg of crude acid · Purification was carried out by _ · 30 flash chromatography on 29 g of silica gel 60 using 2% CH ^ OH in CH2Cl2 as eluent to obtain the product under heading (205 mg , $ 76) Thin layer chromatography: silica gel, 6% CH30H / CH2C12, Rf = 0.34, iodine ·

L

35 76

Analysis: for C ^ H ^ OgS

* calculated: C 71.09 3 H 8.30; S 8.25 found: C 70.81; H 8.36; S 8.14.

'' Nuclear magnetic resonance spectrum 5 (CDC13, 15 MHz) tau ï 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 10 Acid f lß, 2g (ζζ), 36 -46] -7- [3-Γ Γ (cyclohexylmethyl) -thiol —methyll -7-oxabicyclo [2,2,1] hept — 2-yl] -5 - heptenoic.

Following the procedure of Examples 48 and 49, but substituting cyclohexylmethane-thiol for 1-pentane-thiol, the title compound is obtained.

'Example 131

Acid flß, 2a; (5Z), 3ß "46Ί-7-Γ3-ΓΓ (3-cyclohexylpropyl) -thiolmethyl] -7-oxabicyclof2, 2.1 ~] hept-2-yl] -5-hepté-20 noique

By following the process of Examples 48 and 49, but by substituting 3-cyclohexylpropane-thiol for 1-pentane-thiol, the compound is obtained under heading.

25 Example 132

Acid (1β Ι | 2κ, 3α ^ 4β) -7 · - [3 "[Γ (2-çyclohexylethyl) thiol-methyll-7-oxabicyclo f2,2,1] hept-2 — yll — 5 — heptanoic Following the The process of Examples 46 and 47, but by substituting 2-cyclohexylethane-thiol for 1-hexane-thiol, the title compound is obtained.

fs 77

Example 133 ^ Acid Γ16.2g (5Z), 36.4Β1-7-Γ3-ΓΓ (2-phenylethyl) thio] - methyl] -7-oxabicyclo [2,2,1] hept-2-yl] -5 — heptenoic By following the procedure of Examples 48 and 549f but substituting 2-phenylethane-thiol for 1-pentane-thiol, the title compound is obtained.

Example 134

Acid flß, 2a (5Z), 3ß "48Ί-7-Γ3-Γ Γ (3-phenylpropyl) thio] -methyl] —7-oxabicyclo [2,2,1] hept-2-yl] —5 — heptenoic En according to the method of examples 48 and “49” but by substituting 3-phenylpropane-thiol for 1-pentane-thiol, the compound is obtained under heading.

-, Example 135 ^ * 5 Acid (lß, 2g, 3 <% "4β) -7- [3- * [Γ (2-phenylethyl) thio] - methyl] -7-oxabicyclor2,2, l] hept — 2 —Yl] -5 — heptanoic Following the procedure of Examples 46 and 47? but by substituting 2-phenylethane-thiol for 1-hexane-thiol, the title compound is obtained, Example 136

Acid (lß, 2α, 3 "" 4β) -7- [3- [Γ (3-phenylpropyl) thio1-methyl] -7-oxabicyclo [~ 2 SZ, 1] hept-2-yl] -5-heptenoic according to the method of examples 46 and 48, but by substituting 3-phenylpropane-thiol for 1-hexane-thiol, the compound is obtained under heading.

Example 137

Acid | "lßa2g (5Z), 3α" 4ß] -7 ~ [3- [(cyclohexylmethyl) -sulfinyllmethyl] -7-oxabicyclof2,2, l] hept-2-yl] -5-heptenoic (slowly moving isomer) Following the procedure of Examples 44, 77 and 81, but substituting cyclohexylmethane-thiol for 1-hexane-thiol, the title compound is obtained.

AT

/ 78

Example 138

Acid Γ1 ß, 2g (5Z), 36 »4ß 1 -7-Γ3-Γ Γ (cyclohexylmethyl) -suet inyll methyll -7-oxabicyclo f ~ 2.2.11 hept-2-yll -5-heptenoic (rapidly moving isomer ), 5 Following the procedure of Examples 4-8, 77 and 81, but substituting cyclohexylmethane-thiol for 1-pentane-thiol, the title compound is obtained.

Example 139 10 Acid ri6,2a (5Z) s36,48l-7-r3-rr (2-phenylethyl) .- sulfinyll méthyll -7-oxabicyclo [2, 2,1] hept-2-yll -5-heptenol'que (rapidly moving isomer),] v

Following the procedure of Examples 44, 77 and 81, but substituting 2-phenylethane-thiol | v | 15 with l-pentane-thiol, the compound is obtained under i heading.

Example 140

Acid Γ 1β, 2α (5Ζ), 3α »4β1-7-Γ3- | ~ Γ (3-phenylpropyl) -sulf inyll methyl] -7-oxabicyclo [~ 2, 2 to 11 hept-2-yll -5— 20 heptenoic (slowly moving isomer).

Following the procedure of Examples 48, 77 and 82 3 but substituting 3-phenylpropane-thiol for 1-pentane-thiol, the title compound is obtained, Example 141

Acid (Iß52g; a3u »4ß) ~ 7 ~ [3- [r (2-phenylethyl) tallow inyll -methyll -7-oxabicyclo [~ 2, 2, llhept — 2-yll-5-heptanoic (fast-moving isomer) .

Following the method of Examples 46, 77; T. 30 and 81, but by substituting 2-phenylethane-thiol for 1-hexane-thiol, the compound is obtained under heading, A, 79

Example 142

Acid r 16 (5Z) <4-ß 1—7— Γ3- [[(cyclohexylmethyl) - sulfonyl1methvll-7-oxabicyclo | ~ 2 .Z.llhept-Z-yll-S-heptenoic.

Following the procedure of Examples 44, 77 and 80, but substituting cyclohexylmethane-thiol for 1-hexane-thiol, the title compound is obtained.

Example 142 10 Acid [IB, 2g (5Z), 3a.48l-7- [3 - [[(2-phenylethyl) sulfonyl] methyl1-7-oxabicyclof2, 2, l] hept-2-yl] -5 -hept-noi'que.

Following the procedure of Examples 44 ”77 and 80, but substituting 2-phenylethane-thiol t 15 for 1-hexane-thiol, the title compound is obtained.

Example 144

Acid Γΐβ »2α (5Ζ), 3« »4β1 ~ 7-Γ3“ ΓΓ (3-phenylpropyl) -sulfonyl1methyll-7-oxabicyclor2,2, l ~ jhept-2-yl ~ l-5- 20 heptenoic.

Following the procedure of Examples 44 ”77 and 80, but substituting 3-phenylpropane-thiol for 1-hexane-thiol, the compound is obtained under heading.

25 Example 145

Acid [1β, 2g (5Z) §3α, 46ΐ-7- [3- [· 2- [(cyclohexylmethyl) -. thiolethyl] -7‘-oxabicyclo ['2, 2, l ~ | hept-2-yl ~ | -5-hepté-nolque.

By following the process of Examples 63 and 64, but substituting cyclohexylmethane-thiol for 1-hexane-thiol, the title compound is obtained.

AT

80

Example 146

Acid [18, 2g (5Z), 3a, 4ß] -7- [3- [2- [(cyclohexylmethyl) -sulfinyl] ethyll-7-oxabicyclo | ~ 2,2, l ~ lhept-2-yl ~ l- 5-c heptenoic.

Following the procedure of Examples 63 * 44 * 77 and 81, but substituting cyclohexylmethane-thiol for 1-hexane-thiol, the compound is obtained under heading.

Example 14-7 10 Acid [1β, 2α (5Ζ), 3α <4Bl ~ 7-f8- [2-r (cyclohexylmethyl) - sulfonyl1ethyl ~ l-7-oxabicyclo [2, 2, llhept-2-yl] -5 - hept enormous.

at*.

Following the procedure of Examples 63 * 44 * 77 and 80, but substituting cyclohexylmethane-15 thiol for 1-hexane-thiol, the compound is obtained under heading.

Example 148

Acid (~ 1B .20: (52), 3a, 4ß1-7- [3- [2- [(2-phenylethyl) -thio1ethyll-7-oxabicyclo ['2, 2, llhept-2-yl1-5-hepté -20 noic.

By following the process of Examples 63 and 44 * but by substituting 2-phenylethane-thiol for 1-hexane-thiol, the compound is obtained under heading.

Example 149 25 Acid [1β, 2α (5Ζ), 36.4p] -7- [3- [2 - [(2-phenylethyl) - sulfinyl] ethyl] -7 “Oxabicyclo [2,2,1] hept-2 -yl ~ d-5-heptenoic.

Following the procedure of Examples 63 * 44 * 77 and 81, but substituting 2-phenylethane-v, 30 thiol for 1-hexane-thiol, the compound is obtained under heading.

the 8ι

Example 150

Acid [lß, 2g (5Z), 3 "" 4Bl-7-f2- [(3-phenylpropyl) -thiolethyl ~ l-7-oxabicyclo [2, 2, l ~ lhept-2-yll-5-heptec . us.

5 By following the method of Examples 63 and 44a but by substituting 3-phenylpropane ~ thiol for 1-hexane-thiol, the compound is obtained under heading ·

Example 151

Acid [lß32g (5Z) a3tta43l-7 ~ f3 ~ Γ2 - [(3-pbenylpropyl) -10 sulfinyl1éthyll-7-oxabicyclo [~ 2, 2, llhept-2-yl "| -5-heptenoic.

Following the procedure of Examples 63a 44a 77 and 81, but substituting 3-phenylpropane-thiol for 1-hexane-thiol, the title compound is obtained.

Example 152

Acid [Ib.2g (5Z), 3a, 4Bl-7- [3- [2 - [(2-phenylethvl) -sulfonyl] ethyl] -7-oxabicyclo ['2,2, l1hept-2-yl ~] - 5-heptenoic.

Following the procedure of Examples 63a 44a 77 and 80, but substituting 2-phenylethane-thiol for 1-hexane-thiol, the title compound is obtained.

Example 153 25 Acid f 1β, 2α (5Ζ), 3α, 4ß ~ l-7-f3 ~ -Γ2- | ~ (3-phenylpropyl) - sulf onyll ethyll -7-oxabicyclo [~ 2, 2,1] hept- 2-yl] -5-heptenoic.

Following the procedure of Examples 63, 44a 77 and 80, but substituting 3-phenylpropane-w-thiol for 1-hexane-thiol, the title compound is obtained.

82

Example 154

Acid [18 <2g (5Z), 3 <% "4ß] -7- [3- [4- [(cyclohexylmethyl) -thio] butyl ~ | --7 ~ oxabicycloC2, 2, l] hept-2-yl ~ l-5-hepté-noi'que.

Following the procedure of Examples 73 # 63 and 44 # but substituting cyclohexylmethane-thiol for 1-hexane-thiol, the compound is obtained under heading.

Example 155 10 Acid [1 (3, 2g (5Z), 3a: .48] -7- [3- [4- [(cyclohexylmethyl) -sulfinyl '| butyll-7-oxabicyclo | ~ 2, 2, l "lhept -2-yl1-5-heptenoic.

By following the procedure of Examples 73 # 63 # 44 # 77 and 81 # but substituting cyclohexylmethane-thiol for 1-hexane-thiol, the compound is obtained.

v under heading.

Example 156

Acid | ~ 1β, 2α (5Ζ), 3α, 4ßl-7- [3- [4- [(cyclohexylmethyl) -sulfonyl1butyl1-7-oxabicyclo [2, 2, l ~ lhept-2-yl ~] -5-.

20 hepténoi'que.

Following the procedure of Examples 73 # 63 # 44 # 77 80, but substituting cyclohexylmethane-thiol for 1-hexane-thiol, the compound is obtained under heading.

25 - Example 157

Acid Γΐβ, 2α (5Ζ), 3α, 4ß1-7 “[3- [4 - [(2-phenylethyl) -thio1butyl1-7 ~ oxat> icycl ° r ^» 2 # l] hept-2-yl ~ | - 5-hepté-noi'que.

By following the process of Examples 73 # 63 30 and 44 # but by substituting 2-phenylethane-thiol for 1-hexane-thiol # the compound is obtained under heading.

83

Example 158

Acid [lB, 2g (5Z), 3a * 4B] -7-r3 - [4 - [(2-phenylethyl) -sulfinyl] butyl] -7 - oxabicyclor2, 2, l] hept-2 ~ yn- 5-Γ hepténoi'que.

Following the procedure of Examples 73 * 63, 44 * 77 and 81, but substituting 2-phenylethane-thiol for 1-hexane-thiol, the compound is obtained under heading.

Example 159 10 acid riB, 2tt (5Z), 3g, 4Bl-7-r3- [4 - [(2-phenylethyl) - sulfonyllbutyll-7 - oxabicyclo [2, 2, llhept-2-yll-5-hepténoi ' than.

Following the procedure of Examples 73 * 63 * - 447 77 and 80, but substituting 2-phenylethane-thiol for 1-hexane-thiol, the title compound is obtained.

Example l60

Acid [~ lß, 2q (5Z), 3cc, 4Bl-7- [3- [2- (heptylthio) ethyl ~ l-7-oxabicyclo [2, 2, l1hept-2-yll-5-hepténoi, que et son 20 methyl ester.

By reacting 1 * methyl ester of 1 * acid [1β, 2a (5 Z), 3α, 4ß] -7- [3- (2-hydroxyethyl) -7-oxabicyclo [2,2,1] hept-2- yl] -5-heptenoic (see Example 20B) with tosyl chloride as described - in Example 44B and with heptane-thiol according to the process of Example 440 * the product is obtained under heading in the form methyl ester and in the form of a colorless oil; thin layer chromatography (silica gel, hexane / 30 ether (2: 1)), Rf = 0.45. The hydrolysis carried out according to the method of Example 45 gives the free acid in the form of an oil 5 thin layer chromatography (silica gel, 3% CH ^ OH / CEL ^ C ^) *

Rf = 0.23.

AT

84

Analysis: for C22H38 ° 3S

calculated: C 69.06; H 10.01; S 8.38 found: C 68.80 d H 9j99 î S 8.24. C 5 nuclear magnetic resonance spectrum (CDC13, 15 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 16l 10 Acid [lß, 2g (5Z), 3a (E), 4ß1-7- [3 - [[(3 "Phenyl-2-propenyl) thio ~ | méthylloxabicyclo [2, 2, llhept-2-yl] - 5-heptenoic acid and its methyl ester.

VT

Following the procedure of Example 44 and substituting 3-phenyl-2-propenyl-thiol for the 1-15 hexane-thiol used in Example 44 (C), the methyl ester is obtained under the heading; thin layer chromatography (silica gel, hexane / ether (2: 1)), \

Rf = 0.35, while, continuing with the hydrolysis process described in Example 45, the free acid is obtained under heading j layer chromatography

thin (silica gel, 3% CH3OH / CH2Cl2), Rf = 0.25. Analysis: for C ^ H ^ O S

calculated: C 71.46 d H.7.82; S 8.30 found: C 71.31 i H 7.87 3 S 8.26.

25. AT\

Claims (28)

1. Compound corresponding to the structural formula: 'CH2-A- (CH2) m-C02R ce (CH2) nB-Rl 10. including all of its stereoisomers, formula in which A represents -CH = CH- or - (CH ^) ^ - 5 B represents an oxygen atom (-0-) or a group -S- r where. n 'is a number between 0 and 2; 15. is a number between 1 and 8; n is a number between 1 and 4 JR represents a hydrogen atom, an alkyl group, an alkali metal or a tris (hydroxy-methyl) aminomethane group and R * represents an alkyl group, an alkenyl group, an alkynyl group , an aryl group, an aralkyl group, an aralkenyl group, an aralkynyl group, a cycloalkyl group, a cycloalkylalkyl group, a cycloalkylalkenyl group or a cycloalkylalkynyl group. 2. A compound according to claim 1 in which B represents -0-. 3 · Compound according to claim 1 wherein B represents -S-. 4 · Compound according to any one of I _ 30 claims 1 to 3) in which A represents! -CH = CH-, 5 · Compound according to any one of claims 1 to 39 in which R represents H. 6. A compound according to any of claims 1 to 3, wherein n is 1. h 7. A compound according to any one of claims 1 to 3, in which n is equal to 2. & j 8, A compound according to any one of claims 1 to wherein n is 3 5 or 4 · 9 · Compound according to any one of Claims 1 to 3, in which A represents -CH = CH-, m is a number between 2 and 4j n is equal to 1 or 2, R represents H and R * represents 10 a a lower alkyl group or a cycloalkyl group. 10. Compound according to any one of claims 1 to 3j in which A represents w -CH = CH-, m is equal to 3} n is equal to 1, R represents r H, CH ^ or C ^ H ^ and R1 represents a lower alkyl group. ^. 11. Compound according to claim 1, * namely the acid [1β, 2α (5Ζ), 3oci4ß] “7“ [3 - [(hexyloxy) - methyl] -7-oxabicyclo [2,2,1] hept- 2-yl] -5-heptenoic or its hexyl ester. 12. Compound according to claim 1, namely the acid [Ιβ, 2α (5Z) 33α: fl4ß] -7- [3- [2- (pentyl-oxy) ethyl] -7-oxabicyclo [2,2,1 ] hept-2-yl] -5-heptenoic. 13 · Compound according to claim 1, namely the acid [1β, 2α (5Ζ), 3α, 4β] -7 - [(3-pbenyl-2 5 propoxy) methyl] -7-oxabicyclo [2,2,1 ] hept-2-yl] -5— heptenoic. 14 · Compound according to claim 1, namely the acid [1β, 2α (5Ζ), 3α, 4β] -7- [3 - [(octyloxy) -methyl] -7-oxabicyclo [2,2,1] hept -2-yl] -5-heptenoic. 30 15. A compound according to claim 1, namely the acid [lß, 2a (5Z), 3a, 4ß] -7- [3- (cyclohexyl-methoxy) methyl] -7-oxabicyclo [2,2, l] hept -2-yl] -5- „heptenoic. 16. The compound according to claim 1, wherein A represents -CH = CH-, m is equal to 35 U n is equal to 1, n * is equal to 1 and represents a lower alkyl group. 17. A compound according to claim 1,% in which A represents -CH = CH-, m is equal to 3.5, is equal to 1, n * is equal to 2 and R * represents a lower alkyl group. 18. A compound according to claim 1, namely the acid [1β, 2α (5Ζ), 3α> 4ß] -7- [3 - [(hexyl-thio) methyl] -7-oxabicyclo [2,2,1] hept-2-yl] -5-hepté-10 noique or its methyl ester. 19 · Compound according to claim 1, namely the acid [1β, 2α (5Z), 3α, 4β] -7- [3 - [(hexyl-sulfinyl) methyl] -7-oxabicyclo [2,2,1] hept-2-yl] -5-Γ heptenoic or its methyl ester. 20. Compound according to claim 1, ^ namely the acid [1β, 2α (5Ζ), 3α, 4β] -7- [3 - [(hexylsulfonyl) methyl] -7-oxabicyclo [2,2,1 ] hept-2-yl] -7 “heptenoic or its methyl ester. 21. Compound according to claim 1, 20. namely the acid [1β, 2α (5Ζ), 3α, 4β] -7- [3 - [[(cyclohexylmethyl) thio] methyl] -7-oxabicyclo [2, 2.1] hept-2-yl] -5-heptenoic or its methyl ester. 22. A compound according to claim 1, namely the acid [1β, 2α (5Z), 3α, 4β] -7- [3 - [[((2-phenyl-25 ethyl) thio] methyl] -7-oxabicyclo [ 2,2, l] hept-2-yl] -5-heptenoic or its methyl ester. 23. A compound according to claim 1, namely [ΐβ, 2α (5Ζ), 3α, 4β] -7- [3 - [[(3-phenylpropyl) thio] methyl] -7-oxabi cyclo acid [2, 2.1] hept- ^ 2-yl] -5-heptenoic or its methyl ester. 24. A method for inhibiting platelet agglomeration and bronchoconstrietion, characterized in that it consists in administering, to the circulatory system of a mammalian host, an effective amount of the following compound claim L 1 or a pharmaceutically acceptable salt thereof " 25. Composition for inhibiting platelet agglomeration and bronchoconstriction, characterized in that it comprises an effective amount of a compound according to claim 1 or of a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier for this compound or this salt, 26, A method for inhibiting the agglomeration of platelets, characterized in that it comprises administering to a mammalian host an effective amount of a compound according to claim. 1 or one of its pharmaceutically acceptable salts, - 27 "Method in view of inhibiting broncho- * v 15 constriction associated with asthma, characterized in that it consists in administering, to a mammalian host, an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof20 28, Method for inhibiting platelet agglomeration and bronchoconstriction by inhibiting the production of thromboxane A2 by blocking the action of thromboxane synthetase, characterized * in that it consists in administering to a mammalian host -25 fere, an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof,. UAXMq!