GB2136428A - 7-Oxabicycloheptane Substituted Prostaglandin Analogs - Google Patents

7-Oxabicycloheptane Substituted Prostaglandin Analogs Download PDF

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GB2136428A
GB2136428A GB08406100A GB8406100A GB2136428A GB 2136428 A GB2136428 A GB 2136428A GB 08406100 A GB08406100 A GB 08406100A GB 8406100 A GB8406100 A GB 8406100A GB 2136428 A GB2136428 A GB 2136428A
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alpha
oxabicyclo
hept
heptenoic acid
methyl
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GB2136428B (en
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Steven E Hall
Martin F Haslanger
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0025—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing keto groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

7-Oxabicycloheptane substituted prostaglandin analogs are provided having the structural formula <IMAGE> wherein B is oxygen (-O-) or <IMAGE> wherein n' is 0 to 2, R is hydrogen, lower alkyl, alkali metal or trihydroxymethylaminomethane, R<1> is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkynyl. A is -CH=CH- or -(CH2)2-, n is 1 to 4, and m is 1 to 8, and including all stereoisomers thereof. The compounds are cardiovascular agents useful, for example, in the treatment of thrombolytic disease.

Description

SPECIFICATION 7-Oxabicycloheptane Substituted Prostaglandin Analogs The present invention relates to 7-oxabicycloheptane prostaglandin analogs which are cardiovascular agents useful, for example, in the treatment of thrombolytic disease. These compounds have the structural formula
wherein B is oxygen (0--0) or
wherein n' is 0 to 2, R is hydrogen, lower alkyl, alkali metal or trihydroxymethylaminomethane, R1 is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkynyl;; A is -cH=CH- or -(C2)2- n is 1 to 4, and m is 1 to 8, and including all stereoisomers thereof, The term "lower alkyl" or "alkyl" as employed herein includes both straight and branched chain radicals of up to 1 2 carbons, preferably 1 to 8 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, tbutyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including an halo-substituent, such as F, Br, Cl or I or CF3, an alkoxy substituent, a haloaryl substituent, a cycloalkyl substituent (that is, cycloalkylalkyl) or an alkylcycloalkyl substituent.
The terms "alkenyl" and "alkynyl" as used herein contemplate similar hydrocarbon groups bearing therein a carbon-carbon double or triple bond such as for example, 2-propenyl, 2-hexenyl, 3hexenyl, 3-hexynyl and in the case of an aryl substituent or cycloalkyl substituent as defined below, 3phenyl-2-propenyl, 3-phenyl-2-propynyl, 3-cyclohexyl-2-propenyl and 3-cyclohexyl-2-propynyl.
The term "cycloalkyl" includes saturated cyclic hydrocarbon groups containing 3 to 1 2 carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, any of which groups may be substituted with 1 or 2 halogen, 1 or 2 lower alkyl groups and/or lower alkoxy groups.
The term "aryl" or "Ar" as employed herein refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl wherein the substituent on either the phenyl or naphthyl may be lower alkyl, halogen (Cl, Br or F), or lower alkoxy.
The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used herein refers to lower alkyl groups as discussed above having an aryl substituent, such as benzyl.
The terms "(CH2)m" and "(CH2,n" includes a straight or branched chain radical having from 1 to 8 carbons in the normal chain in the case of "(CH2)m" and 1 to 4 carbons in the normal chain in the case of "(CH2)n" and may contain one or more lower alkyl substituents. Examples of (CH2)m and (CH2)n groups include CH3, CH 2CH2, (CH2)3, (CH2)4, (CH2)5, (CH2)6, (CH2)7
and the like.
The compounds of Formula I (wherein R is alkyl) are prepared by etherifying or thioetherifying a compound of the Formula II:
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 Williamson Synthesis (J. Chem. Soc. 4, 229 (1852)) wherein ethers (and later thioethers) were synthesized by alkylation of alkoxides with alkyl halides: R'(O or S)Na+R"XeR'(O or S)R"+NaX The modern version of this synthesis envisions use of other leaving groups in addition to halides.
Thus with respect to Formula II above, the etherification or thioetherification reaction comprehends reaction of a Formula la compound of the formula
wherein X in addition to hydroxy can also be -SH or their sodium or potassium salts, chloro, bromo, iodo and alkyl, aryl- and aralkyl-sulfonyloxy groups with a complementary R'X compound to form the following type compounds of Formula I:
The thioethers of Formula IV can then be oxidized to the sulfinyl and sulfonyl derivatives (n'=1 or 2 in Formula I) having the formulae::
The compounds of Formula I wherein R is an alkali metal or hydrogen (free acid) can then be prepared from the above products where R is alkyl by conventional basic hydrolysis with sodium or potassium hydroxide to form the sodium and potassium salts followed by acidification to the free acid.
Etherification is usually accomplished by reacting the Formula 11 compound with a compound of the formula R'X wherein X is chloro, bromo, or iodo or methylsulfonyloxy or toluenesulfonyloxy, in the presence of a strong base such as sodium or potassium hydroxide in an appropriate solvent. In carrying out the reaction a molar excess of the R'X reactant varying from .25 mole excess to a 5 mole excess is used employing a solvent such as xylene, tetrahydrofuran, dimethylsulfoxide or dimethylformamide. In the case where X is bromo or chloro, a phase transfer etherification can be employed in which case tetrahydrofuran is used as the solvent and a phase transfer reagent such as Bu4NHSO4 or (C6H5CH2)(CH3)3NHSO4 is employed.In the case wherein R' is aryl it is convenient to first react with the alcohol group of the Formula II compound with triphenylphosphine and diethylazodicarboxylate in solution with an inert solvent such as tetrahydrofuran and then with an R'(aryl) alcohol such as phenol.
As is generally known in the art, the sequence of reacting the Formula II alcohol with the R'X compound to achieve etherification can be reversed by converting the Formula II alcohol into a Formula II compound wherein the alcohol group has been replaced with another radical from the group X and then reacting with an R'-alcohol or alkoxide to form the Formula I product.
Thioetherification is usually accomplished by first converting the Formula II alcohol to another Formula lI-X derivative as indicated above and thioetherifying with an R'SH mercaptan in the presence of a base or with an alkali metal salt thereof.
Oxidation of the sulfide product where n'=O to the sulfinyl and sulfonyl analogs where n' is 1 or 2 is readily accomplished by reacting with sodium periodate in the presence of methanol and tetrahydrofuran to form the sulfinyl and sulfonyl derivatives which may then be separated by chromatography or other conventional separation procedures.
The starting materials of Formula II wherein n is 1 (hydroxymethyl group) are known from U.S.
Patent 4,143,054 and can be prepared as described therein. These compounds can be used to prepare starting materials of Formula II wherein n is 2 to 4 by oxidation of the hydroxymethyl group to an aldehyde by way of a Collins oxidation, for example, by reacting Compound II with chromium trioxide in pyridine, to form a intermediate of the formula
The Formula Vl.l aldehyde is subjected to a homologation sequence by way of a Wittig reaction using (C6H5)3P=CHOCH3 followed by hydrolysis (n1 ) times followed by reduction of the aldehyde to the alcohol employing a reducing agent such as sodium borohydride or sodium cyanoborohydride in a solvent such as methanol to form the Formula II starting material::
The tris(hydroxymethyl)aminomethane salt of any of the acids of formula I of the present invention is formed by reacting a solution-of such acid in an inert solvent such as methanol with tris (hydroxymethyl)aminomethane and thereafter the solvent is removed by evaporation to leave the desired salt.
The compounds of this invention have four centers of asymmetry as indicated by the asterisks in formula I. However, it will be apparent that each of the formulae set out above which do not include asterisks still represent all of the possible stereoisomers thereof. All of the various stereoisomeric forms are within the scope of the invention.
The various stereoisomeric forms of the compounds of the invention, namely, cis-exo, cis-endo and all transforms and stereoisomeric pairs may be prepared as shown in the working Examples which follow and by employing starting materials and following the procedures as outlined in U.S. Patent No.
4,143,054. Examples of such stereoisomers are set out below.
The nucleus in each of the compounds of the invention is depicted as
for matter of convenience; it will also be appreciated that the nucleus in the compounds of the invention may be depicted as
The compounds of this invention are cardiovascular agents useful as platelet aggregation inhibitors, e.g., for treatment of thrombolytic disease, such as coronary or cerebral thromboses. They are also selective thromboxane A2 receptor antagonists and synthetase inhibitors, e.g., having a vasodilatory effect for treatment of myocardial ischemic disease, such as angina pectoris. The compounds of the invention are also arachidonic acid cyclooxygenase inhibitors.They can be administered orally or parenterally to various mammalian species known to be subject to such maiadies, e.g., cats, dogs, and the like in an effective amount within the dosage range of about 1 to 100 mg/kg, preferably about 1 to 50 mg/kg and especially about 2 to 25 mg/kg on a regimen in single or 2 to 4 divided daily doses.
The active substance can be utilized in a composition such as tablet, capsule, solution or suspension containing about 5 to about 500 mg per unit of dosage of a compound or mixture of compounds of formula I. They may be compounded in conventional matter with a physiologically acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, etc. as called for by accepted pharmaceutical practice. Also as indicated in the discussion above, certain members additionally serve as intermediates for other members of the group.
The following Examples represent preferred embodiments of the invention.
EXAMPLE 1 [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Hexyloxy)methyl]-7-oxabicyclo[2.2 1 ]hept-2-yl]-5-heptenoic Acid, Hexyl Ester A. | 1}3,2 [1 ss,2&alpha;(5Z),3&alpha;4ss]-7-[3-(Hydroxymethyl)-7-oxabicyclo[2.2. 1 hept-2-yl]-5-heptenoic Acid, Methyl Ester (a) A mixture of N-acetylpyridinium chloride was prepared by adding 9.6 ml (136 mmole) of acetyl chloride dropwise to 56 ml of pyridine. To this was added 5.0 g (27 mmole) 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 (3x200 ml); the ether extracts were washed with 5% hydrochloric acid (2x400 ml) and brine (1 x200 ml) and dried over sodium sulfate.Concentration yielded a yellow oil which was purified by passage through a short column of silica gel (1 50 ml) with dichloromethane: yield 4.42 g of an oil.
(b) To a solution of 4.42 g (1 9.6 mmole) of the oil in 500 ml of tetrahydrofuran containing 50 ml of water was added 31.1 g (97.8 mmole) of mercuric acetate. The yellow suspension which formed was stirred for 10 minutes and then the entire mixture was poured into a solution containing 200 g of potassium iodide in 2 1. of water. Upon shaking, the yellow color disappeared and the mixture was extracted with benzene (3x500 ml). The combined benzene extracts were washed with potassium iodide solution and brine and dried over sodium sulfate. Concentration yielded 3.7 g of material which crystallized on standing in an ice box.
(c) A Wittig reagent was prepared in dimethyl sulfoxide (dried over calcium hydride) by adding a solution of sodium methylsulfinylmethide (prepared by heating 300 mg of sodium hydride in 60 ml of dimethyl sulfoxide at 750 until hydrogen evolution stops) dropwise to a solution of 5.32 g (12 mmole) of 4-carboxybutyl triphenylphosphonium bromide in 100 ml of dimethyl sulfoxide. After the first orange color lasting more than 10 seconds formed, an equivalent amount of base was added to form the ylide.
To this deep orange solution was added a solution of the product of part (b) in 20 ml of dimethyl sulfoxide and the resulting mixture stirred at room temperature for 45 minutes. The reaction was quenched by addition of 24 mmole of acetic acid and the mixture poured into brine (300 ml) and extracted with ether (3 x200 ml). Concentration of these extracts gives an oil which was stirred with saturated sodium bicarbonate solution until crystalline triphenylphosphine oxide formed in the mixture.
This mixture was washed with benzene and acidified with 10% hydrochloric acid. The aqueous layer was saturated with salt and extracted with ether which on drying (sodium sulfate) and concentration gave 2;43 g of crude product. The mixture was stirred 24 hours with 10% aqueous sodium hydroxide and reisolated by acidification and ether extraction. The product was purified on 500 g of silica gel with 50/50 ethyl acetate-hexane as the eluant which gave 600 mg of acid which crystallized on standing.
This was recrystallized twice from ethyl acetate-cyclohexane to yield 320 mg of [1 ss,2a(5Z),3a,4ss]-7- [3-(hydroxymethyl)-7-oxabicyclo[2.2. 1 ]hept-2-ylj-5-heptenoic acid, m.p. 59-63 0C.
Anal. Calc'd for C14H2204: C,66.11; H, 8.72 Found: C, 66.06; H, 8.79 The acid is then converted to the corresponding methyl ester by treating with diazomethane.
B. [1 ,2a(5Z),3or,4]-7-[3-[(Hexyloxy)-methylj-7-oxabicyclo[2.2. 1 Jhept-2-yl]-5-heptenoic Acid, Hexyl Ester A suspension of 0.56 g of powdered KOH in 1 5 ml of dry xylene was heated to reflux arid 7 ml of xylene was distilled off. To this mixture was added a solution of 300 mg (1.12 mmol) of alcohol ester from part A in 10 ml of dry xylene. The resulting mixture was heated to reflux and 9 my of xylene was distilled off. To this mixture was added 1.0 g (5.6 mmol) of n-hexylmethanesulfonate and the resulting mixture was heated at reflux for 1-1/2 hours. The reaction mixture was cooled to ambient temperature and diluted with CH2CI2 (60 ml). The resulting solution was poured into 50 ml saturated NaHCO3. The layers were separated and the aqueous phase was extracted (2x60 ml) with CH2CI2.The combined CH2CI2 extracts were dried over MgSO4, then concentrated in vacuo to yield 0.9 g of crude product. The crude product was chromatographed on 33.4 g of silica gel 60 with hexane:ether (5:1) to yield 390 mg (83%) of the title hexyl ester.
EXAMPLE 2 [1 ,2o(5Z),3a,4]'-7-[3-[(Hexyloxy)methyl]-7 -oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid To a stirred solution of 11 5 mg (0.27 mmol) of the Example 1 hexyl ester in 12.0 ml of distilled THF and 1.60 ml of H2O under argon was added 2.40 ml of 1 N aqueous lithium hydroxide solution.
This mixture was purged with argon for 40 minutes and stirred at room temperature for 24 hours. At this time, TLC analysis showed that the reaction was not complete so an additional 1 ml of methanol and 1 ml of 1 N aqueous lithium hydroxide was added. The reaction mixture was kept stirring for another 4 hours and then was acidified to pH 4 by the addition of 1 N aqueous HCI solution. The resulting solution was poured into 25 ml of saturated NaCI solution and was saturated with solid NaCI.
The aqueous layer was extracted with EtOAc (4x40 ml). The combined EtOAc extracts were dried over anhydrous MgS04, filtered and concentrated in vacuo to give 124 mg of crude oil. This was chromatographed on 20.6 g of silica gel 60 using hexane:ether (2:3) as eluant to give 102 mg of desired product contaminated with a small amount of hexyl alcohol. The mixture was put in high vacuum overnight at room temperature to give 77 mg (84%) of pure title acid. TLC: silica gel, 8% CH3OH/CH2Cl2, Rf=0.74, iodine.
Anal. Calc'dforC20H34O4: C, 70.97; H, 10.12 Found: C, 70.60; H, 9.89 C NMR (CDCl3, 1 5.0MHz)tau 33.4, 22.6, 24.6, 129.4, 130.1, 26.7,46.4, 79.4, 29.5, 80.1, 46.8, 71.3, 69.8,31.7, 25.7, 29.7, 22.6, 14.0.
EXAMPLE 3 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Hexyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Hexyl Ester 503 mg (1.88 mmol) of [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]- 5-heptenoic acid, methyl ester (prepared as described in Example 1) was dissolved in 2.17 ml tetrahydrofuran. Thereafter 2.17 ml (15.46 mmol) of n-hexyl bromide. 173.4 mg (0.51 mmol) tetrabutylammoniumbisulfate (Bu4NHSO4), and 2.17 ml of a 50% NaOH solution were added and the mixture vigorously stirred at room temperature. A slightly yellowish-brown solution formed which upon stirring overnight formed a white precipitate.
The reaction mixture was poured into 25 ml of saturated NaHCO3. The mixture was extracted with CH2CI2 (4x25 ml). The combined CH2CI2 extracts were dried (MgSO4), filtered and concentrated in vacuo to give [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(hexyloxy) methyl]-7-oxabicyclo[2.2. 1 ] hept-2-yl]-5-heptenoic acid, hexyl ester (1272 mg). This was chromatographed on 40 g silica gel using hexane:ether (4:1) as eluant to give final product.
EXAMPLE 4 (1 ss,2,3cr,4,B)-7-[3-[(Hexyloxy)methyl]-7-oxabicyclo[2.2. 1 ]hept-2-yl]heptanoic Acid, Hexyl Ester A. ( 1 jB,2hz,3cE,4,)-7-[3-[(Hydroxy)methyí]-7-oxabicyclo[2.2. 1 jhept-2-yljheptanoic Acid, Methyl Ester To 800 mg (3.0 mmoie) of the [1,ss,2(5Z),3cE,4,B]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]- hept-2-ylJ-5-heptenoic acid, methyl ester as prepared in Example 1, dissolved in 120 ml of ethyl acetate was added, under an argon atmosphere, 1 60 mg of 5% Pd on carbon. The argon atmosphere was exchanged for a slight positive pressure of hydrogen and the reaction was stirred for 8 hours at 250, filtered through a celite plug and evaporated to provide 730 mg (90%) of the title A compound.
B. (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[(Hexyloxy)methyl]-7-oxabicyclo[2.2. 1 ]hept-2-yl]-5-heptanoic Acid, Hexyl Ester Following the procedure of Example 1 except substituting the Part A alcohol-ester for the Example 1A alcohol ester, the title product is obtained.
EXAMPLE 5 (1 ss,2&alpha;,3&alpha;,4ss]-7-[3-[(Hexyloxy)methyl]-7-oxabicyclo[2.2. 1 ]hept-2-yl]heptanoic Acid Following the procedure of Example 2 except substituting the Example 4 hexyl ester for the Example 1 hexyl ester, the title acid is obtained as an oil [&alpha;]D25=-3.1(c=1.37, CDCl3); TLC(silica gel, 8% CH3OH)CH2Cl2, Rf=0.74 Anal.Calc'd for C20H36 4: C, 70.55; H, 10.66 Found: C, 70.30; H, 10.70 C NMR (CDCl3, 15.0MHz)tau 179.1 33.9, 24.6, 27.6, 29.2, 29.3, 29.0, 47.0, 79.1, 29.7, 29.6, 80.1, 46.4. 71.2, 69.8,29.3,25.8,31.6, 22.6, 14.0 EXAMPLE 6 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Hexyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 3 and 2 except substituting [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3- (hydroxymethyl)-7-oxabicyclo[2.2. 1 ]-hept-2-yl]-5-heptenoic acid, methyl ester for [1 ss,2&alpha;(5Z), 3&alpha;,4ss]- 7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1 ]-hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained as an oil.
Anal. Calc'd forC20H34O4: C, 70.97; H, 10.12 Found: C, 70.93; H, 10.33 13C NMR (CDCI3, 1 5.0MHz)tau 1 78.7, 33.4, 24.6, 26.6, 128.7, 129.9, 32.6,47.9, 79.1, 29.5, 23.8, 80.5, 49.1, 71.7. 7 1 .2, 3 1 .6, 25.8, 29.9, 22.6, 13.9 EXAMPLE 7 [1 -ss,2&alpha;(5Z),3&alpha;,4ss]-7 -[3-Methyloxy)methylj-7-xabicyclo[2.2. 1 ]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples T and 2 except substituting methyl methanesulfonate for nhexyl methanesulfonate, the title compound is obtained as an oil, [&alpha;]D25=+10.4 (C=2.21, CHCl3), Anal.Calc'd -for ClsH24 4 C, 67.14; H, 9.01 Found: C, 67.03; H, 9.14 '3C NMR (CDCl3, 15.0MHz) tau 178.3, 33.2, 24.4, 25.5, 129.5, 129.8, 26.5, 46.5, 79.1, 29.3, 29.3,79.9,46.2, 71.7, 58.6.
EXAMPLE 8 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Propyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 6, except substituting n-propylbromide for n-hexylbromide, the title compound is obtained.
EXAMPLE 9 (1ss,2&alpha;,3&alpha;,4ss)-7-[3-(Butyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]heptanoic Acid Following the procedure of Examples 4 and 5 except substituting n-butyl methanesulfonate for nhexyl methanesulfonate, the title compound is obtained.
EXAMPLE 10 [1 ss,2&alpha;(5Z), 3&alpha;,4ss]-7-[3-[(Octyloxy)methyl]-7-oxabicyclo[2.2. 1 ]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 1 and 2 except substituting n-octyl methanesulfonate for nhexyl methanesulfonate, the title compound is obtained.
EXAMPLE 11 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Phenyloxy)methyl]-k7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid (a) Phenol (1 mmol) is added to a solution of triphenylphosphine (1 mmol), diethylazodicarboxyiate (1 mmol) and title a alcohol from Example 1 (1 mmol) in 25 ml THF and is stirred under an argon atmosphere for 48 hours at 230 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 chromatographed on silica gel to give [1,B,2cE(5Z),3cg,4p]-7-[3-[(phenyloxy)methyl]-7-oxabicyclo- [2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester.
(b) Following the procedure asset out in Example 2, the ester from part (a) is converted to the title compound.
EXAMPLE 12 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Phenyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (a) Phenol (1 mmol) is added to a solution of triphenylphosphine (1 mmol), dilsopropylazodicarboxylate (1 mmol) and title A alcohol from Example 1 (1 mmol) in 25 ml THF and 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 in vacuo and chromatographed on sillca gel to give [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(phenyloxy)methyl]-7- oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic acid, methyl ester.
(b) Following the procedure as set out in Example 2, the ester from part (a) is converted to the title compound.
EXAMPLE 13 [1 ,2a(5Z),3,4]-7-[3-[(Ethyloxy)methyl]-7-oxabicyclo[2.2. 1 jhept-2-yl]-5-heptenoic Acid Following the procedure of Examples 3 and 2 except substituting ethylbromide for nhexylbromide, the title compound is obtained.
EXAMPLE 14 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[(Phenyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]heptanoic Acid Following the procedure of Example 11 except substituting (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[(hydroxy)- methyl]-7-oxabicyclo[2.2.1 ]hept-2-yl]heptanoic acid, methyl ester for the alcohol of part (a) of Example 11 , the title compound is obtained.
EXAMPLE 15 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3[(Benzyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 6 except substituting benzylbromide for n-hexylbromide, the title compound is obtained.
EXAMPLE 16 (1 2ez,3a,4)-7-[3-[(Benzyloxy)methylj-7-oxabicyclo[2.2. 1 ]hept-2-yljheptanoic Acid Following the procedure of Examples 4 and 5 except substituting benzyl methanesulfonate for nhexyl methanesulfonate, the title compound is obtained.
EXAMPLE 17 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Cyclohexyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 1 and 2 except substituting cyclohexyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained.
EXAMPLE 18 [1 P,2a(sZ).3P,4P]-7-[3-[(Cyclopentyloxy)me 1] hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 1 and 2 except substituting cyclopentyl methanesulfonate for n-hexyl methanesulfonate, and substituting [1 P,2 a( 5Z),3P.4P]-7-[3-(hydroxymethyl-7- oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (prepared as described in U.S. Patent No.
4,143,054) for [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-y 1 ]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained.
EXAMPLE 19 (1ss,2&alpha;,3&alpha;,4ss)-7-[3-[(Cyclohexyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]heptanoic Acid Following the procedure of Examples 4 and 5 except substituting cyclohexyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained.
EXAMPLE 20 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Hexyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid A. [1 }s,2cE(5Z),3a,4p]-7-[3-(2-Oxo)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Methyl Ester Into a dry 100 ml round bottom 3-necked flask containing a stir bar was added dried 12.9 g (37.7 mmoles) methoxymethyltriphenylphosphonium chloride ((C6Hs)3P+CH2OCH3CI-) and 235 ml distilled toluene (stored over molecular sieves). The resulting suspension was stirred in an ice-bath, under argon, until cold and then a 1.55 M solution of 18.3 ml (28.3 mmol) of potassium t-amylate in toluene was added dropwise. A bright red solution formed which was stirred at 0 C for an additional 35 minutes.Thereafter, a solution of 4.97 g (18.8 mmol) [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-formyl-7-oxabicyclo- [2.2.1 ]hept-2-yl]-5-heptenoic acid, methyl ester in 60 ml toluene was added by means of a dropping funnel over a 35 minute period with the ice-bath still in place. The reaction was then quenched by addition of 2.3 g (39 mmol) acetic acid in 5 ml ether. The reaction mixture immediately turned pale yellow and was immediately poured into 200 ml saturated NH4CI, and extracted with ether (4x200 ml). The combined ether phases were washed with NaCI saturated solution, and dried (MgSO4) and concentrated to yield a yellow oil in a white crystalline solid (phosphine oxide). The white solid was triturated with EtOAc and the mother liquor was purified by chromatography on an LPS-1 silica column.The fractions obtained were (A) [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(2-oxo)ethyl-7-oxabicyclo- [2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, (B) [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(2-methoxy)-ethendiyl]- 7-oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic acid, methyl ester, and (C) [1,B,2a:(5Z),3ex,4,B]-7-[3-(2,2- dimethoxy)ethyl-7-oxabicycio[2.2.1 ]hept-2-yl]-5-heptenoic acid, methyl ester.
Compounds (B) and (C) are each treated with trifluoroacetic acid to convert each to compound (A).
B. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(2-Hydroxyethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Methyl Ester The aldehyde (1.4 g, 5 mmol) from part A in methanol (50 ml) was treated with NaBH4 (0.19 g, 5 mmol) in an argon atmosphere at OOC. After stirring at 0 for 1 hour, the reaction was quenched by addition of 2N HCI (to pH 2). The methanol was removed in vacuo and the reaction mixture was taken up in ether. The ether solution was washed with saturated KHC03, saturated NaCI and dried (MgSO4).
The ether was evaporated to yield the title B compound.
C. [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Hexyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 1 and 2 except substituting the above part B alcohol for the alcohol used in Example 1, the title compound is obtained.
EXAMPLE 21 [1 a(5Z),3p,4p]-7-[3-[2-( Hexyloxy) ethyl]-7-oxabicyclo[2.2.1] 1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 20, except substituting [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-formyl-7- oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester for [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-formyl-7 oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained.
EXAMPLE 22 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[2-(Hexyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic Acid Following the procedure of Example 21 except substituting (1ss,2&alpha;,3&alpha;,4ss]-7-[3-formyl-7- oxabicyclo[2.2.1]hept-2-yl]heptanoic acid, methyl ester for [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-formyl-7- oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained.
EXAMPLE 23 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-()Phenyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 11 excepte substituting [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2- (hydroxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester for [1ss,2&alpha;(5Z),3&alpha;,4ss]-7- [3-(hydroxymethyl)-7-oxabicyclo[2.2. 1] hept-2-yl]-5-heptenoic acid, methyl-ester, the title compound is obtained.
EXAMPLE 24 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Phenyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 12 except substituting [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(hydroxy)- ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester for [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3- (hydroxymethyl)-7-oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained.
EXAMPLE 25 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[2-(Phenyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]heptanoic Acid Following the procedure of Example 11 except substituting (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[2-(hydroxy)- ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]heptanoic acid, methyl ester for [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3- (hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic acid, methyl ester, the title compound is obtained.
EXAMPLE 26 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Benzyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Example 20 except substituting benzyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained.
EXAMPLE 27 [1 ,2a(5Z),3ps,4p]-7-[3-[2-(Benzyloxy)ethyl]-7-oxabicyclo[221]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 21 except substituting benzyl methanesulfonate for nrhexyl methanesulfonate, the title compound is obtained.
EXAMPLE 28 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Cyclopentyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 20 except substituting cyclopentyl methanesulfonate for nhexyl methanesulfonate, the title compound is obtained.
EXAMPLE 29 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Cyclohexyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 20 except substituting cyclohexyl methanesulfonate for nhexyl methanesulfonate, the title compound is obtained.
EXAMPLE 30 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Hexyloxy)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid A. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(3-Oxo)propyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Methyl Ester Following the procedure of Example 20, part A except substituting [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(2- oxo)-ethyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester for [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3- formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title A compound is obtained.
B. [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(4-Oxo)butyl-7-oxabicyclo[2.2.1] hept-2-yl]-5-heptenoic Acid, Methyl Ester Following the procedure of Example 20, part A, except substituting the aldehyde from part A above, for [1,ss,2a(5Z),3Q,4ss]-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yí]-5-heptelloic acid, methyl ester, the title B aldehyde is obtained.
C. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(4-Hydroxybutyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Methyl Ester Following the procedure of Example 20. part B, except substituting the title B aldehyde for [1ss,2a(5Z),3Q,4ss]-7-[3-(2-oXo)ethyl-7-oxabicycio[2.2.1]hept-2-ylJ-5-heptenoic acid, methyl ester, the title C alcohol is obtained.
D. [1 ss,2a(5Z),3cg,4,a]-7-[3-[4-(HeXyloxy)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 1 and 2 except substituting the above part C alcohol for the alcohol used in Example 1, the title compound is obtained.
EXAMPLE 31 [1 2c'(5Z),3cz,4-7-[3-[4-(Cyclohexyloxy)bul]-7-oxabicyclo[2.2. 1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 30 except substituting cyclohexyl methanesulfonate for nhexyl methanesulfonate, the title compound is obtained.
EXAMPLE 32 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Phenyloxy)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 11 except substituting [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(4- hydroxybutyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid. methyl ester for [1ss,2&alpha;(5Z),3&alpha;,4ss]-7- [3-(hydroxymethyl-7-oxabicyclo[2.2. 1] hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained.
EXAMPLE 33 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Benzyloxy)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 30 except substituting benzyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained.
EXAMPLE 34 Tris(hydroxymethyl)aminomethane Salt of [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Hexyloxy)methyl]-7- oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic Acid A solution of the compound formed in Example 2 in methanol is treated with an equivalent amount of tris(hydromethyl)aminomethane. The solvent is removed by evaporation to yield the title compound as a solid, m.p. 68.5-70 C. TLC (silica gel, 8% CH3OH/CH2Cl2)Rf=0.74.
Anal. Calc'd for C24H4sO7N: C, 62.72; H, 9.87; N, 3.04 Found: C, 62.71; H, 9.80; N. 3.10 EXAMPLE 35 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Pentyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid A. [1/3,2a(5Z),3a,4X3]-7-[3-[2-(Pentyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl|-5-heptenoic Acid, Pentyl Ester A mixture of powdered KOH (0.36 g) in 15 ml of dry xyiene was heated to reflux under argon atmosphere and 8 ml of xylene was removed by distillation. To this mixture was added a solution of 200 mg (0.71 mmol) of Example 20, part B, alcohol methyl ester in 17 ml of dry xylene. The volume of the reaction mixture was reduced 1 5 ml by distillative removal of xylene.To the reaction mixture was then added a solution of 0.5 g (3.55 mmol) pentylmesylate in 10 ml of dry xylene. This mixture was refluxed for 2 hours and 30 minutes. The cooled reaction mixture was diluted with 50 ml of saturated NaHCO3 solution and extracted with CH2CI2 (3x60 rnl). The combined CH2CI2 extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was effected by flash chromatography on 33 g of silica gel 60 using hexane:ether (5:1) as eluant. This gave 238 mg of title pentyl ester (83%) as a colorless oil. TLC: silica gel, hexane:ether (1:1).
B. [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-Pentyloxy)ethyl]-7-oxabicyclo[2.2.1 jhept-2-ylj-5-heptenoic Acid To a stirred solution of 238 mg (0.58 mmol) of pentyl ester from Part A, 26 ml of distilled THF, 2.1 ml of CH30H and 3.4 ml of H2O under argon was added 6.4 ml of 1 N aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 30 minutes and stirred at room temperature for 7 hours. The reaction mixture was acidified to pH 3 by the addition of 1 N aqueous HCI solution. The resulting solution was poured into 50 ml of saturated NaCI solution and was saturated with solid NaCl. The aqueous layer was extracted with EtOAc (4x60 ml). The combined EtOAc extracts were dried (MgS04), filtered and concentrated in vacuo.This was chromatographed on 24 g of silica gel 60 using 3% CH30H in CH2CI2 as eluant to give 181 mg (92%) of title pure acid, TLC: silica gel, 4% CH3OH/CH2CI2, Rf=0.30, vanillin.
Anal. Calc'd for C20H3404: C, 70.97; H, 10.12 C20H34040.22 H2O: C, 70.16; H, 10.14 Found: C, 70.16; H, 9.87 3C NMR (CDCl3, 15.0MHz) tau 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, 13.9 EXAMPLE 36 [1ss,2&alpha;(5Z),3&alpha;;,4ss]-7-[(3-Phenylpropoxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid A. [1 ,2o(5Z),3o',4]-7-[(3-Phenylprnpoxy)methylj-7-oxabicyclo[2.2.1jhept-2-yl]-5-heptenoic Acid, Phenylpropyl Ester A mixture of powdered KOH (0.59 g) in 1 6 ml of dry xylene was heated to reflux under argon atmosphere and 9 ml of xylene was removed by distillation. To this mixture was added a solution of 410 mg (1.53 mmol) of Example 1, part A, alcohol methyl ester in 1.0 ml of dry xylene. The volume of the reaction mixture was reduced 6 ml by distillative removal of xylene. To the reaction mixture was then added a solution of 1.66 g (7.58 mmol) of 3-phenylpropylmesylate in 36 ml of dry xylene. This mixture was refluxed for 1 hour.The cooled reaction mixture was diluted with 50 ml of saturated NaHCO3 solution and extracted with CH2Cl2 (3x50 ml). The combined CH2Cl2 extracts were dried (MgS04), filtered, and concentrated in vacuo. Purification was effected by flash chromatography on 40 g of silica gel 60 using hexane:ether (3:1) as eluant. This gave 0.61 g of title phenylpropyl ester (81%) as a colourless oil. TLC: silica gel, 2% CH 30 H/CH2Cl2, Rf:.60, iodine.
B. [1,B,2a(5Z),3a,4,B]-7-[(3-P henylpropoxy)methyl]-7-oxabicyclo[2.2.1] hept-2-yl]-5-heptenoic Acid To a stirred solution of 610 mg (1.24 mmole) of title A phenylpropyl ester, 55 ml of distilled THF, 4.40 ml of CH30H and 7.30 ml of H20 under argon was added 13.7 ml of 1 N. aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 30 minutes and stirred at room temperature for 14 hours. The reaction mixture was diluted with 100 ml of 0.1 N aqueous lithium hydroxide solution and washed once with 100 ml of hexane. The reaction mixture was acidified to pH 3 by the addition of 1 N aqueous HCI solution and was poured into 100 ml of saturated NaCI solution. The resulting mixture was saturated with solid NaCI and extracted with EtOAc (4x 150 ml).The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo. This was chromatographed on 44 g of silica gel 60 using 4% CH30H in CH2CI2 as eluant to give 380 mg (82%) of pure title acid. TLC: silica gel,4% CH3OH/CH2Cl2, Rf=0.30, iodine.
Anal. Calc'd for C23H3204: C, 74.16; H, 8.66 C23H3204 0.35 H20: C, 72.94; H, 8.70 Found: C, 72.94; H, 8.49 13CNMR(CDCl3, 15.0 MHz)tau 178.7, 33.4, 24.5, 25.7, 129.5, 130.1,26.6, 46.3, 79.3. 29.5.
80.1,46.8, 70.2, 69.9, 31.2, 32.3, 141.9, 128.4, 128.4.
EXAMPLE 37 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Octyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid A. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Octyloxy)methyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Octyl Ester To a stirred solution of 508 mg (1.89 mmol) of Example 1, Part A, ester alcohol in 2.69 ml THF was added in order 2.69 ml (15.6 mmol) of n-octyl bromide, 642 mg (1.89 mmol) of tetrabutylammonium hydrogen sulfate and 2.69 ml of 50% aqueous sodium hydroxide solution. This mixture was stirred at room temperature in darkness for 19 hours. The reaction mixture was poured into 25 ml of saturated sodium bicarbonate solution and extracted with four 25 ml portions of CH2CI2. The combined CH2CI2 extracts were dried (MgS04), filtered and concentrated in vacuo.Purification was effected by flash chromatography on 39.6 g of silica gel 60 using hexane:ether (3:1) as eluant to give 333 rng (37%) of octyl ester and 250 mg of a mixed band of octyl ester and corresponding methyl ester. TLC: silica ge, 3% CH3OH/CH2Cl2, R,: octyl ester, 0.85; methyl ester, 0.80, iodine.
B. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Octyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid To a stirred solution of 333 mg (0.70 mmol) of Part A octyl ester in 31 ml of distilled THF, 2.50 ml of CH3OH and 4.1 ml of H20 under argon was added 7.70 ml of 1 N aqueous lithium hydroxide solution.
This mixture was purged with argon vigorously for 20 minutes and stirred at room temperature for 16 hours and 30 minutes. The mixture of octyl ester and corresponding methyl ester was hydrolyzed in the exact same manner. To a stirred solution of this mixture (250 mg) in 29 ml of distilled THF, 2.40 ml of CH30H and 3.9 ml of H20, was added 7.30 ml of 1 N aqueous lithium hydroxide. This mixture was purged with argon vigorously for 20 minutes and stirred at room temperature for 1 6 hours and 30 minutes.
These 2 reaction mixtures were combined and diluted with a solution of 120 ml of 0.1 N aqueous lithium hydroxide solution and 50 ml of H20. The resulting mixture was extracted once with 220 ml of hexane. The aqueous layer was acidified to pH 3 by the addition of 1 N aqueous HCI solution saturated with solid NaCI, and extracted with EtOAc (4x 150 ml). The hexane extract and EtOAc extracts (hexane extract contained the desired acid) were combined,'dried (MgS04), filtered and concentrated in vacuo to give 0.53 9 of crude product. This was chromatographed on 48 g of silica gel 60 using 3% CH3OH in CH2CI2 to give 222 mg (45%) of desired title acid.TLC: silica gel, 4% CH3OH/CH2Cl.Rf=0.40, vanillin Anal. Calc'd for C22H38O4: C, 72.09; H, 10.45 C22H3B040.24 H2O:' C, 71.25; H, 10.45 Found: C, 71.25; H, 10.20 13C NMR (CDCl3, 1 5.0mHz) tau 178.7, 33.8, 24.9, 26.2, 129.6, 130.0, 26.8, 46.5, 79.3, 29.5, 29.5, 80.1, 46.9, 71.2, 69.9, 31.7, 29.7, 29.2, 28.7, 25.9, 22.6, 14.0, 64.4, 31.7, 29.7, 29.2,28.2,25.8,22.6, 14.0.
EXAMPLE 38 [1 ,2a(5Z),3or,4-7-[3-(Cyclohexylmethoxy)-methyl]-7-oxabicyclo[2.2. 1 ]hept-2-yl]-5-heptenoic Acid A. [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Cyclohexylmethoxy)methyl]-7-oxabicyclo[2.2 1 hept-2-yl]-5-heptenoic Acid, Cyclohexylmethyl Ester A mixture of powdered KOH (0.56 g) in 1 5 ml of dry xylene was heated to reflux under 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 Example 1, Part A, alcohol methyl ester in 10 ml of dry xylene. The volume of the reaction mixture was reduced to 11 ml by distillative removal of xylene. To the reaction mixture was then added a solution of 2.47 g (12.9 mmol) cyclohexylmethylmesylate in- 10 ml of dry xylene: This mixture was refluxed for 5 hours.The cooled reaction mixture was diluted with 50 ml of saturated NaHCO3 solution and extracted with CH2CI2 (3x50 ml). The combined CH2CI2 extracts were dried (MgS04), filtered and concentrated in vacua. Purification was affected by flash chromatography on 35 9 of silica gel 60 using 1% CH3OH in CH2CI2 as eluant. This gave 0.46 g of title hexyl ester (93%) as a colorless oil. TLC: silica gel, 2% CH30H/CH2CI2, Rf=0.80, iodine.
B. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(Cyclohexymethoxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid To a stirred solution of 460 mg (1.03 mmol) of Part A cyclohexylmethyl ester, 45 ml of distilled THF, 3.80 ml of CH3OH and 6.10 ml of HzO under argon was added 1 1.4 ml of 1N aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 20 minutes and stirred at room temperature for 16 hours. The reaction mixture was diluted with 83 ml of 0.1 N aqueous lithium hydroxide solution and washed once with 83 ml of hexane. The aqueous layer was acidified to pH 3 by the addition of 1 N aqueous HCI solution and saturated with solid NaCI. The resulting aqueous layer was extracted with EtOAc (4x 120 ml).The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give 0.32 g of crude product. This was chromatographed on 34.6 g of silica gel 60 using 3% CH3OH in CH2CI2 as eluant to give 278 mg (77%) of pure title acid. TLC=silica gel, 4% CH3OH/CH2Cl, Rf=0.28, iodine.
Anal. Calc'd for C21H3404: C, 71.96; H, 9.78 C2,H34040.31 H20: C, 70.84 H, 9.80 Found: C, 70.84; H, 9.68 C NMR (CDCl3, 1 5.0MHz) tau 173.5 33.7, 24.9, 25.3, 129.5, 129.9, 26.0, 46.4, 79.2, 29.6, 29.6, 79.2, 46.8, 70.0, 77.0 37.9, 30.0, 26.7, 25,8, 26.7,-30.0, 69.3,37.1,29.1, 26.3, 25.6, 26.3, 29.1 EXAMPLE 39 1[&alpha;,2ss(Z),3&alpha;,4ss]-7-[3-[[(1-Methylhexyl)oxy]methyl]-7-oxobicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid By following the procedures of Examples 1 and 2 except substituting 1 -methylhexyl methane sulfonate for n-hexylmethanesulfonate, the titled compound is obtained, TLC (selica gel, 4% CH3OH/CH2Cl2) Rf=0.47, Anal.CaIc'dforC21H36O4: C, 71.55; H, 10.29 Found: C, 71.73; H, 10.21 '3C NMR (CDCí3, 15.0MHz) tau 178.8, 33.4, 24.6, 25.7, 129.4, 130.2, 26.7, 46.4, 79.5, 29.5, 80.1, 47.1, 67.5, 75.9, 36.7, 25.3, 31.9, 22.6, 14.0, 19.7 EXAMPLE 40 [1 a,2p(Z),3A,4hz]-7-[3-[(3-Hexynyíoxy)methyl-7-oxabicycío[2.2. 1] hept-2-yl]-5-heptenoic Acid By following the procedures of Examples 1 and 2 except substituting 3-hexynylmethane sulfate, the titled compound is obtained as an oil, TLC (silica gel, 4% CH30H/CH2Cl2) Rf 0.32 Anal. Calc'd for C20H3004: C, 71.82; H, 9.04 Found:C, 71.66; H, 9.21 C NMR (CDCl3, 15.0MHz) tau 178.9, 33.4, 22.0, 24.5, 129.5, 130.0, 26.7, 46.4, 79.4, 29.4, 29.5, 80.0, 46.7, 69.0, 58.8, 76.1, 86.8, 22.0, 25.8, 13.4 EXAMPLE 41 [1ss,2&alpha;(Z),3&alpha;(Z),4ss]-7-[3-[(3-Hexenyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid By following the procedure of Examples 1 and 2 except substiotuting cis-3-hexen-1-mesylate for the n-hexylmethanesulfonate, the titled compound is obtained as oil. TLC (silica gel, 4% CH30H/CH2CI2) Rf=0.3.
Anal. Calc'd for C20H,204: C, 71.39; H, 9.59 Found: C, 71.10; H, 9.59 '3C NMR (CDCl3, 1 5.0MHz) tau 1 78.9, 33.4, 24.5, 25.6, 129.5, 130.1, 27.7, 46.3, 79.3, 29.4, 80.1, 46.7, 70.7, 69.8, 26.6, 133.6, 124.8, 20.6, 14.2 EXAMPLE 42 [1 ,2ct(Z),3(Z),4fi]-7-[3-[(2-Hexenyloxy)methyl]-7-oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic Acid By following the procedure of Examples 1 and 2 andsubstituting 2-1-hex-2-enyl-mesylate for nhexylmethanesulfonate, the titled compound is prepared as an oil, TLC (silica gel, 2% CH3OH/CH2Cl2) Rf=0.22, vanillin.
Anal. CalE'd for C20H32O4: C, 71.39; H, 9.59 Found: C, 70.97; H, 9.64 C NMR (CDCl3, 15.0MHz) tau 178.3, 33.4, 24.5, 25.8, 129.5, 130.1, 26.7, 46.4, 79.5, 29.5, 29.5, 80.1, 46.9, 69.3, 66.6, 133.5, 126.2, 29.5, 22.6, 13.6 EXAMPLE 43 [1 ,2ar(Z),3o',4or]-7-[3-[2-Propenyloxy)methylj-7-oxabicyclo[2.2. 1] hept-2-yl]-5-heptenoic Acid, and Methyl Ester To a stirred solution of 310 mg (1.16 mmol) of [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(hydroxymethyl)-7- oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenolc acid, methyl ester in 1.34 ml of tetrahydrofuran was added in order, 1:34 ml of allyl bromide, 107 mg of tetrabutylammonium hydrogen sulfate and 1.34 ml of 50% aqueous sodium hydroxide solution.The mixture was stirred at room temperature in darkness for 23 hours and then poured into 30 ml of saturated sodium bicarbonate solution and extracted twice with 30 ml portions of methylene chloride. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. Purification was effected by flash chromatography on 35 g of silica gel 60 using hexane-ether (2:1) as eluant to give 220 mg of the methyl ester product, TLC (silica gel, hexane-ether (1:1 Rf=0.4, iodine.
The ester was dissolved in 36 ml of tetrahydrofuran along with a small amount of hydroquinone, 6 ml of water and 7 ml of 1 N aqueous lithium hydroxide solution and stirred at room temperature for 5.5 hours whereupon the reaction mixture was poured into 80 ml of saturated aqueous sodium chloride solution and was saturated with additional solid sodium chloride. The aqueous layer was extracted with 4 portions of ethyl acetate (125 ml each), dried over magnesium sulfate, filtered and concentrated In vacuo. The residue was chromatographed on 30 g of silica gel using 4% CH3OH/CH2Cl2 as eluant to give 190 mg of the acid product, TLC (silica gel, hexane-ether (1:1)) Rf=0.15.
Anal. Calc'd for C17H2604: C, 69.36; H, 8.96 Found: C, 69.72; H, 9.05 C NMR (CDCl3, 15.0MHz) tau 178.9, 33.4, 24.5, 25.7, 129.5, 130.0, 26.6, 46.3, 79.3, 29.4, 80.1, 46.7, 69.3, 72.0, 134.7, 117.0 EXAMPLE 44 [1A,2a(5Z),3t,4p]-7-[3-[(Hexylthio)methyl]-7-oxabicyclot2.2.1 ]hept-2-yl]-5-heptenoic Acid, Methyl Ester A. [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic Acid (a) A mixture of N-acetylpyridinium chloride was prepared by adding 9.6 ml (136 mmole) of acetyl chloride dropwise to 56 ml of pyridine. To this was added 5.0 g (27 mmole) of (exo)-3-(2methoxyethenyl)-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 (3x200 ml), the ether extracts were washed with 5% hydrochloric acid (2x400 ml) and brine (1x200 ml) and dried over sodium sulfate. Concentration yielded a yellow oil which was purified by passage through a short column of silica gel (150 ml) with dichloromethane, yield 4.42 g of an oil.
(b) To a solution of 4.42 g (19.6 mmole) of the oil in 500 ml of tetrahydrofuran containing 50 ml of water was added 31.1 g (97.8 mmole) of mercuric acetate. The yellow suspension which formed was stirred for 10 minutes and then the entire mixture was poured into a solution containing 200 g of potassium iodide in 2 í. of water. Upon shaking, the yellow color disappeared and the mixture was extracted with benzene (3x500 ml). The combined benzene extracts were washed with potassium iodide solution and brine and dried over sodium sulfate. Concentration yielded 3.7 g of material which crystallized on standing in an ice box.
(c) A Wittig reagent was prepared in dimethyl sulfoxide (dried over calcium hydride) by adding a solution of sodium methylsulfinylmethide (prepared by heating 300 mg of sodium hydride in 60 ml of dimethyl sulfoxide at 750 until hydrogen evolution stops) dropwise to a solution of 5.32 g (12 mmole) of 4-carboxybutyl triphenylphosphonium bromide in 100 ml of dimethyl sulfoxide. After the first orange color lasting more than 10 seconds formed, an equivalent amount of base was added to form the ylide.
To this deep orange solution was added a solution of the product of part (b) in 20 ml of dimethyl sulfoxide and the resulting mixture stirred at room temperature for 45 minutes. The reaction was quenched by addition of 24 mmole of acetic acid and the mixture poured into brine (300 ml) and extracted with ether (3 x200 ml). Concentration of these extracts gives an oil which was stirred with saturated sodium bicarbonate solution until crystalline triphenylphosphine oxide formed in the mixture.
This mixture was washed with benzene and acidified with 10% hydrochloric acid. The aqueous layer was saturated with salt and extracted with ether which on drying (sodium sulfate) and concentration gave 2.43 g of crude product. The mixture was stirred 24 hours with 1 0% aqueous sodium hydroxide and reisolated by acidification and ether extraction. The product was purified on 500 g of silica gel with 50/50 ethyl acetate-hexane as the eluant which gave 600 mg of acid which crystallized on standing.
This was recrystallized twice from ethyl acetate-cyclohexane to yield 320 mg of [1ss,2&alpha;(5Z),3&alpha;,4ss]-7- [3-(hydroxymethyl-7-oxabicyclo[2.2. 1 jhept-2-ylj-5-heptenoic acid.
B. [1 ,2a(5Z).3o'.4,3J-7-[3-(p-Toluenesulfonyloxymethyl-7-oxabicyclo[2.2. | hept-2-yl]-5-heptenoic Acid, Methyl Ester To a solution of 300 mg (1.12 mmol) of alcohol ester from Part A in 4 ml of dry pyridine was added 427 mg (2.24 mmol) of tosyl chloride. The mixture was stirred at room temperature under an argon atmosphere for 10 hours. The reaction mixture was diluted with 300 ml of ether, washed with 1N aqueous HCI solution (3x100 ml), and 0.5 N aqueous NaOH solution (3x100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification was effected by flash chromatography on 30 g of silica gel 60 using 50% hexane in ether as eluant to give 450 mg of title compound (95%).TLC: silica gel, 4% CH30H in CH2CI2, Rf=0.80, iodine.
C. [1 ,t,2o'(5Z),3or,4J3]-7-[3-[(Hexylthio)methyl-7-oxabicyclo[2.2. 1 jhept-2-yl]-5-heptenoic Acid, Methyl Ester To a solution of 132 mg (1.17 mmol) of potassium t-butoxide in 10 ml of dry THF under argon was added 378 mg (3.21 mmol) of 1 -hexanethiol. To this mixture was added a solution of 450 mg (1.07 mmol) of Part B tosylate in 5 ml of THF. The reaction mixture was stirred at room temperature under argon for 2.5 hours and then heated to reflux for 5.5 hours. The cooled reaction was diluted with 300 ml of ether and poured into 100 ml of saturated NaHCO3 solution. The aqueous layer was extracted with ether (2 xl 00 ml).The combined ether extracts (500 ml) were washed with 0.5N aqueous sodium hydroxide (2x 100 ml), brine (100 ml), and then dried (MgS04). filtered and concentrated in vacuo to give 0.55 g of crude oil. Purification was effected by chromatography on 25.2 g of silica gel 60 using 5:1 pet ether:ether as eluant to give 328 mg of title product as an oil (84%). TLC=silica gel, petroleum ether:ether 3:2, R,=0.55, iodine.
EXAMPLE 45 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Hexylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid To a stirred solution of 328 mg (0.89 mmol) of the Example 1 methyl ester in 43.8 ml of THF and 6.67 ml of H20 under argon was added 8.40 ml of 1 N aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 20 minutes and stirred at room temperature for 12.5 hours. The reaction mixture was acidified to pH 4 by the addition of 1 N aqueous HCI solution and poured into 50 ml of saturated NaCI solution. The resulting solution was saturated with solid NaCI and extracted with EtOAc (4x50 ml). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give 295 mg of crude acid.Purification was effected by flash chromatography on 25 g of siliCAR CC-7 using 2:3 petroleum ether:ether as eluant to give title product (250 mg, 79%) as an oil.
TLC: silica gel, 2:3 petroleum ether:ether, R,=0.25, iodine.
Anal. Calc'd for C20H34O3S: C, 67.80; H, 9.61; S. 9.04 Found: C, 67.80; H, 9.85; S,9.14 '3C NMR (CDCl3, 1 5.0MHz) tau 173.5, 33.1, 24.5, 25.6, 129.9, 128.8,26.5, 45.9, 79.9, 29.2, 28.8,78.3,45.9,69.5, 144.5, 129.7,127.6, 132.1,127.6,129.7.21.3, 51.1 EXAMPLE 46 (1ss,2&alpha;,3&alpha;;,4ss]-7-[3-[(Hexylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Methyl ester A. (1D,2a,3cE,4p)-7-[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-heptanoic Acid, Methyl Ester To 800 mg (3.0 mmole) of the [1 A,2(5Z),3,4p]-7-[3-(hydroxymethyi-7-oxabicycio[2.2.1]hept- 2-yl]-5-heptenoic acid, methyl ester as prepared in Example 1, dissolved in 120 ml of ethyl acetate was added, under an argon atmosphere, 160 mg of 5% Pd on carbon. The argon atmosphere was exchanged for a slight positive-pressure of hydrogen and the reaction was stirred for 8 hours at 250, filtered through a celite plug and evaporated to provide 730 mg (90%) of the title A compound.
B. (1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Hexylthio)methyl)-7-oxabicyclo[2.2.1]hept-2-yl]-heptanoic Acid, Methyl Ester Following the procedure of Example 1 except substituting the Part A alcohol-ester for the Example 1 A alcohol ester, the title product is obtained.
EXAMPLE 47 (1 ,2,3tz,4p)-7-[3-[(HeXylthio)methyl]-7-oxabicycio[2.2.1]hept-2-yl]-heptanoic Acid Following the procedure of Example 45 except substituting the Example 46 methyl ester for the Example 45 methyl ester, the title acid is obtained.
EXAMPLE 48 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Pentylthio)methyl]-7-oxabicyclo[2.2.1]lhept-2-yl]-5-heptenoic Acid, Methyl Ester [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-Hydromethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-hept-2-yl]-5-heptenoic Acid, Methyl Ester To a solution of 2.68 g of [1P.2a(5Z) ,3a,4P]-7-[3-( hydroxymethyl)-7 -oxabicyclo-[2.2.1] hept-2- yl]-5-heptenoic.'acid in 175 ml of dimethylformamide was added 13.16 g of pyridinium dichromate.
This mixture was stirred at room temperature for 19 hours as which time an additional 8 g of pyridinium dichromate was added. This mixture was allowed to stir an additional 24 hours. The reaction mixture was diluted with 500 ml of ether and the resultant black gummy precipitate was removed by filtration through a pad of Celite. The filtrate was concentrated in vacuo. The resulting dark brown oil was passed through 60 g of silica gel 60 and eluted with 5% MeOH/CH2CI2 to give 1.86 g of brown oil.
This was purified by chromatography on 150 g of silica gel 60 using 1:1:0.01 pentane-ether acetic acid as eluant. This gave 0.63 g of [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(carboxy)-7-oxabicyclo[2.2.1]hept- 2-yl]-5-heptenoic acid methyl ester and 0.31 g of [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(carboxy)-7-oxabicyclo- [2.2.1]hept-2-yl]-5-heptenoic acid methyl ester.
3C NMR (CDCl3,1 5.0MHz) tau 177.0, 174.0, 130.6, 127.7, 81.5, 77.9, 54.7, 51.3, 46.2, 33.4, 32.3, 29.2, 26.6, 25.8, 24.7.
A solution of 350 mg of [1,ss,2(5Z),3A,4,B]-7-[3-(carboxy)-7-oxabicycio[2.2.1]hept-2-yl]-5- heptenoic acid methyl ester and 0.35 ml of triethylamine in 3.0 ml of dry THF under argon was cooled to OOC. To this stirred soltuion was added dropwise 0.24 ml of ethylchloroformate. The resulting mixture was stirred at 00C for 50 minutes and then diluted with 20 ml of anhydrous ether. The mixture was filtered through a pad of MgS04 and concentrated in vacuo. The residue was dissolved in 2 ml of absolute EtOH and 3.3. ml of dry THF. This solution was cooled in an ice bath and then 80 mg of NaBH4 was added. The mixture was stirred for 30 min. at 0 C and then the ice bath was removed. After 15 minutes, the reaction mixture was poured into 25 ml of ice-cold 1N HCl. The aqueous layer was extracted with three 25 ml portions of ether.The ether layers were combined dried over MgSO4, filtred, and concentrated in vacuo to afford the crude product. Purification was effected by flash chromatography of 22 g of silica gel using 2% MeOH/CH2CI2 as eluant. This gave 250 mg of [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid methyl ester; '3C NMR (CDCl3, 15.0MHz) tau 174.1, 130.0, 128.5, 80.6, 78.7, 63.4, 51.7, 51.4, 47.8, 33.4, 32.7, 29.8, 26.6, 24.7, 23.7 B. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(p-Toluenesulfonyloxymethyl)-7-oxobicyclo[2.2.1]hept-2-yl-5-heptenoic Acid, Methyl Ester To a solution of 300 mg (1.12 mmol) of [1ss,2&alpha;(5Z),3&alpha; ;,4ss]-7-[3-(hydroxymethyl)-7-oxabicyclo [2.2.1 jhept-2-yl]-5-heptenoic acid, methyl ester from part A in 4 ml of dry pyridine is added 427 mg (2.24 mmol) of tosyl chloride. The mixture is stirred at room temperature under argon atmosphere for 10 hours. The reaction mixture is diluted with 300 ml of ether, washed with 1 N aqueous HCl solution (3 x 100 ml), and 0.5 N aqueous NaOH solution (3 x1 00 ml). The ether layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification is effected by flash chromatography on 30 g of silica gel 60 using 50% hexane in ether as eluant to give 450 mg of title B compound.
C. [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Pentylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Methyl Ester To a solution of 132 mg (1.17 mmol) of potassium t-butoxide in 10 ml of dry THF under argon is added 378 mg (3.21 mmol) of 1-pentanethiol. To this mixture is added a solution of 450 mg (1.07 mmol) of Part B tosylate in 5 ml of THF. The reaction mixture is stirred at room temperature under argon for 2.5 hours and then heated to reflux for 5.5 hours. The cooled reaction is diluted with 300 ml of ether and poured into 100 ml of saturated NaHCO3 solution. The aqueous layer is extracted with ether (2x 100 ml).The combined ether extracts (500 ml) are washed with 0.5 N aqueous sodium hydroxide (2:; 100 ml), brine (100 ml), and then dried (MgSO4), filtered and concentrated in vacuo to give 0.55 g of crude oil. Purification was effected by chromatography on 25.2 g of silica gel 60 using 5:1 pet. ether:ether as eluant to give 328 mg of title compound.
EXAMPLE 49 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Pentylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid To a stirred solution of 328 mg (0.89 mmol) of Example 48 methyl ester in 43.8 ml of THF and 6.67 ml of H20 under argon is added 8.40 ml of 1N aqueous lithium hydroxide solution. This mixture is purged with argon vigorously for 20 minutes and stirred at room temperature for 12.5 hours. The reaction mixture is acidified to pH 4 by the addition of 1 N aqueous HCI solution and poured into 50 ml of saturated NaCI solution. The resulting solution is saturated with solid NaCI and extracted with EtOAc (4x50 ml). The combined EtOAc extracts are dried (MgSO4), filtered and concentrated in vacuo to give 295 mg of crude acid.Purification is effected by flash chromatography on 25 g of siliCAR CC-7 using 2:3 petroleum ether:ether as eluant to give the acid.
EXAMPLE 50 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Methylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 44 and 45 except substituting methyl mercaptan for 1hexanethiol, the title compound is obtained.
EXAMPLE 51 [1 ,2a(5Z),3Aj-7-[3-[(Propylthio)methylJ-7-oxabicyclo[2.2. 1 Jhept-2-yl]-5-heptenoic Acid Following the procedure of Examples 48 and 49 except substituting propylmercaptan for 1pentanethiol, the title compound is obtained.
EXAMPLE 52 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-(Butylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]heptanoic Acid Following the procedure of Examples 46 and 47 except substituting butylmercaptan for 1hexanethiol, the title compound is obtained.
EXAMPLE 53 [1,B,2cY(5Z),3cE,4p]-7-[3-[(Octylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yí]-5-heptenoic Acid Following the procedure of Examples 44 and 45 except substituting 1-octanethiol for 1 hexanethiol, the title compound is obtained.
Anal. Calc'd for C22H3,03S: C, 69.06; H, 10.01; S. 8.38 Found: C, 69.08; H,.9.75; S, 8.20 '3C NMR (CDCl3, 15.0MHz) tau 178.7. 32.6, 29.1.29.4. 129.8, 129.8,29.4,46.9, 80.6,29.7, 31.7, 80.4, 47.5, 33.4, 32.1, 29.1, 28.8, 26.7,26.2. 24.5,22.5, 13.9 EXAMPLE 54 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Phenylthio)methyl]-7-oxabicyclop[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 44 and 45 except substituting phenylmercaptan for 1hexanethiol, the title compound is obtained.
EXAMPLE 55 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[(Phenylthio)methyl]-7-oxabicyclo[2.2.1-hept-2-yl]heptanoic Acid Following the procedure of Examples 46 and 47 except substituting phenylmercaptan for 1 hexanethiol, the title compound is obtained.
EXAMPLE 56 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Ethylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic Acid Following the procedure of Examples 44 and 45 except substituting ethylmercaptan for 1hexanethiol, the title compound is obtained.
EXAMPLE 57 [1ss,2cE(5Z),3ss,4/3]-7-[3-[(Phenylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 48 and 49 except substituting phenylmercaptan for 1 pentanethiol, the title product is obtained.
EXAMPLE 58 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Benzylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 48 and 49 except substituting benzylmercaptan for 1-pentanethiol, the title product is obtained.
EXAMPLE 59 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[(Benzylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]heptanoic Acid Following the procedure of Examples 46 and 47 except substituting benzylmercaptan for 1 hexanethiol, the title product is obtained.
EXAMPLE 60 [1 FB,2a(5Z),3a,4ss]-7-[3-[(CycíoheXylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 44 and 45 except substituting cyclohexylmercaptan for 1hexanethiol, the title product is obtained.
EXAMPLE 61 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Cyclopentylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 48 and 49 except substituting cyclopentylmercaptan for 1pentanethiol, the title product is obtained.
EXAMPLE 62 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[(Cyclohexylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]heptanoic Acid Following the procedure of Examples 46 and 47 except substituting cyclohexylmercaptan for 1 hexanethiol, the title product is obtained.
EXAMPLE 63 [113,2(5Z),3a,4ss]-7-[3-[2-(Hexylthio)ethyl]-7-oxabicyclof2.2.1 jhept-2-yl]-5-heptenoic Acid A. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(2-Oxo)ethyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Methyl Ester Into a dry 100 ml round bottom 3-necked flask containing a stir bar was added dried 12.9 g (37.7 mmoles) methoxymethyltriphenylphosphonium chloride ((C6H5)3P±CH2OCH3Cl-) and 235 ml distilled toluene (stored over molecular sieves). The resulting suspension was stirred in an ice-bath, under argon, until cold and then a 1.-55 M solution of 18.3 ml (28.3 mmol) of potassium t-amylate in toluene was added dropwise. A bright red solution formed which was stirred at 0 C for an additional 35 minutes.Thereafter, a solution of 4.97 g (18.8 mmol) [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-formyl-7-oxabicyclo- [2.2.1 ]-hept-2-yl]-5-heptenoic acid, methyl ester in 60 ml toluene was added by means of a dropping funnel over a 35 minute period with'the ice-bath still in place. The reaction was then quenched by addition of 2.3 g (39 mmol) acetic acid in 5 ml ether. The reaction mixture immediately turned pale yellow and was immediately poured into 200 ml saturated NH4CI, and extracted with ether (4x200 ml). The combined ether phases were washed with NaCI, saturated solution, and dried (MgS04) and concentrated to yield a yellow oil in a white crystalline solid (phosphine oxide).-The white solid was triturated with EtOAc and the mother liquor was purified by chromatography on an LPS-1 silica coumn.The fractions obtained were (A) [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(2-oxo)ethyl-7-oxabicyclo[2.2.1]hept- 2-yl]-5-heptenoic acid, methyl ester, (B) [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(2-methoxy)ethendiyl-7- oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, and (C) [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(2,2- dimethoxy)ethyl-7-oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic acid, methyl ester.
Compounds (B) and (C) are each treated with trifíuoroacetic acid to convert each to compound (A).
B. [1 ,2a(5Z),3aS,4XB]-7-[3-(2-Hydroxyethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Methyl Ester The aldehyde (1.4 g, 5 mmol) from part A in methanol (50 ml) is treated with NaBH4 (0.19 g, 5 mmol) in an argon atmosphere at OOC. After stirring at 0 for 1 hour, the reaction is quenched by addition of 2N HCI (to pH 2). The methanol is removed in vacuo and the reaction mixture is taken up in ether. The ether solution is washed with saturated KHC03, saturated NaCI and dried (MgSO4). The ether is evaporated to yield the title B compound.
C. [1 j3,2o'(5Z),3a,4]-7-[3-[2-(Hexylthio)ethyl]-7-oxabicyclo[2.2.1 jhept-2-yl]-5-heptenoic Acid Following the procedure of Examples 44 and 45 except substituting the above part B alcohol for the alcohol used in Example 44, the title compound is obtained.
EXAMPLE 64 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Hexylthio)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 63, except substituting [1 jB,2a:(5Z),3p,4,]-7-[3-formyl-7- oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester for [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-formyl-7 oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained.
EXAMPLE 65 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[2-(Hexylthio)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]heptanoic-Acid Following the procedure of Example 64 except substituting (1/S,2(x,3cx,4/s)-7-[3-formyl-7- oxabicyclo[2.2.1 ]hept-2-yl]heptanoic acid, methyl ester for [1 [;',2a'( 5Z),3&alpha;,4ss]-7-[3-formyl-7- oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained.
EXAMPLE 66 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Phenylthio)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 63 except substituting phenylmercaptan for 1-hexanethiol, the title compound is obtained.
EXAMPLE 67 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Phenylthio)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 64 except substituting phenylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 68 (1 ,2cr,3a.4)-7-[3-[2-(Phenylthio)ethyl]-7-oxabicyclo[2.2. 1 jhept-2-yl]heptanoic Acid Following the procedure of Example 65 except substituting phenylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 69 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Benzylthio)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 63 except substituting benzylmercaptan for 1-hexanethiol, the title compound is obtained.
EXAMPLE 70 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Benzylthio)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 64 except substituting benzylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 71 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Cyclopentyl)thio)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]heptenoic Acid Following the procedure of Example 63 except substituting cyclopentylmercaptan for 1hexanethiol, the title compound is obtained.
EXAMPLE 72 [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Cyclohexylthio)ethyl]-7-oxabicyclo[2.2. 1 jhept-2-ylj-5-heptenoic Acid Following the procedure of Example 63 except substituting cyclohexylmercaptan for 1hexanethiol, the title product is obtained.
EXAMPLE 73 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Hexylthio)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid A. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(3-Oxo)propyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Methyl Ester Following the procedure of Example 63, part A except substituting [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(2- oxo)-ethyl-7-oxabicyclo[2.2. 1 ]hept-2-yl]-5-heptenoic acid, methyl ester for [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3- formyl-7-oxabicyclo[2.2. 1 ]hept-2-yl]-5-heptenoic acid, methyl ester, the title A compound is obtained.
B. [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(4-Oxo)butyl-7-oxabicyclo[2.2. 1 J hept-2-yl]-5-heptenoic Acid, Methyl Ester Following the procedure of Example 63, part A, except substituting the aldehyde from part A above, for [1P,2( 5Z),3a,4pj-7-[3-formyl-7-oxabicyclo[2 .2.1] hept-2-yl]-5-heptenoic acid, methyl ester. the title B aldehyde is obtained.
C. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(4-Hydroxybutyl)-7-oxabicyclo[2.2.1]hept-2-yl]- 5-heptenoic acid, methyl ester Following the procedure of Example 63, part B, except substituting the title B aldehyde for [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(2-oxo)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title C alcohol is obtained.
D. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Hexylthio)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 44 and 45, except substituting the above part C alcohol for the alcohol used in Example 44, the title compound is obtained.
EXAMPLE 74 [1 ,2a(5Z),3cx,4p]-7-[3-[4-(Cycíohexylthio)butyí]-7-oxabicyclo[2.2. 1 ]hept-2-ylj-5-heptenoic Acid Following the procedure of Example 73 except substituting cyclohexylmercaptan for 1hexanethiol, the title compound is obtained.
EXAMPLE 75 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Phenylthio)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Example 73 except substituting phenylmercaptan for 1-hexanethiol, the title compound is obtained.
EXAMPLE 76 [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Benzylthio)butyl]-7-oxabicyclo[2.2. 1 ]hept-2-yl]heptenoic Acid Following the procedure of Examples 73 except substituting benzylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLES 77, 78 and 79 [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Hexylsulfinyl)methyl]-7-oxabicyclo[2.2. 1 ]hept-2-yl]-5-heptenoic Acid, Methyl Ester (Fast Moving Isomer), [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Hexylsulfinyl)methyl]-7- oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic Acid, Methyl Ester (Slow Moving Isomer and [1 ,2o( 5Z),3a&num;-7-[3-[(Hexylsulfonyl)methyl]-7-oxabicyclo[2.2. 1 jhept-2-ylj-5-heptenoic Acid, Methyl Ester To a solution of 634 mg (1.72 mmol of [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(hexylthio)methyl]-7- oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (prepared as described in Example 44) in 6.78 ml of methanol at 0 C was added dropwise over 4 minutes 8.37 ml of 0.5M aqueous sodium periodate solution.Tetrahydrofuran (2 ml) was then added and the resulting reaction mixture was stirred at room temperature for 1 5 hours. A white precipitate was removed by filtration and washed with ether (3x50 ml). The filtrate was washed with 60 ml of saturated aqueous NaHCO3 solution and dried over anhydrous magnesium sulfate. Concentration in vacuo afforded 648 mg of an oily crude product. This was chromatographed on 54.16 g of silica gel 60 using 0.5-1.0% CH3OH in CH2CI2 as eluent. This gave FMI (fast moving isomer) sulfoxide (Example 77) (211 mg, 32%), SMI (slow moving isomer) sulfoxide (Example 78) (142 mg, 21%) and sulfone (Example 79) (1 65 mg, 24%). These products were oils which solidified on storage in the freezer.TLC=silica gel, 2% (CH3OH/CH2Cl2, Rf: Example 77 sulfoxide, 0.28; Example 78 sulfoxide, 0.21; Example 79 sulfone, 0.74; iodine.
EXAMPLE 80 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Hexylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid To a stirred solution of 165 mg (0.41 mmol) of [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(hexylsulfonyl)methyl]-7 oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic acid, methyl ester (Example 79 in 20.3 ml of THF and 3.09 ml of H20 under argon was added 3.90 ml of 1 N aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 10 minutes and stirred at room temperature for 6 hours. The reaction mixture was acidified to pH 4 by addition of 1 N aqueous HCI solution and poured into 30 ml of saturated NaCI solution. The resulting solution was saturated with solid NaCI and extracted with EtOAc (4x50 ml).The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give 1 65 mg of crude acid. Purification was effected by flash chromatography on 20 g of silica gel 60 using 3% CH30H in CH2Cl2 as eluant. This afforded title acid (145 mg, 91 %) which solidified on storage in the freezer. TLC=silica gel, 4% CH30H/CH2Cl2, Rf 0.32. iodine.
Anal. Calc'd for C20H340 S: C, 62.18; H, 8.81; S, 8.29 Found: C, 61.99; H, 9.01; S, 8.33 C NMR (CDCl3, 15.0MHz) tau 178.4, 33.1, 24.3, 26.7, 128.9, 130.3, 28.0, 39.9, 79.8, 31.1, 28.8,80.9,47.0,54.1, 51.7, 29.4, 27.1, 22.2, 21.9, 13.7 EXAMPLE 81 [1,ss,2(x(5Z),3(x,4p]-7-[3-[(Hexylsulfinyl)methyl]-7-oxabicyclo[2.2.1 ]hept-2-yl)-5-heptenoic Acid (Fast Moving Isomer) To a stirred solution of 211 mg (0.55 mmol) of [1 ss,2&alpha;(5Z),3&alpha; ;,4ss]-7-[3-[(hexylsulfinyl)methyl]-7- oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (fast moving isomer) prepared in Example 77 in 27.0 ml of THF and 4.11 ml of H20 under argon was added 5.19 ml of 1 N aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for ten minutes and stirred at room temperature for 6 hours. The reaction mixture was acidified to pH 4 by addition of 1 N aqueous HCI solution and poured into 50 ml of saturated NaCl solution. The resulting solution was saturated with solid NaCI and extracted with EtOAc (4x 1 00 ml). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give 21 6 mg of crude acid.Purification was effected by flash chromatography on 20.2 g of silica gel 60 using 3% CH3OH in CH2Cl2 as eluant to give the title acid (172 mg, 85%) as a white solid. TLC=silica gel, 4% CH3OH/CH2Cl2, Rf 0.10, iodine.
Anal. Calc'd for C20H34O4S: C, 64.83; H, 9.25; S, 8.65 Found: C, 64.71; H, 9.17; S, 8.55 53C NMR (CDCI3, I 5.0MHz) 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 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Hexylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid (Slow Moving Isomer) To a stirred solution of 142 mg (0.37 mmol) of [1ss,2&alpha;(5Z),3&alpha;;,4ss]-7-[3-[(hexylsulfinyl)methyl]-7- oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic acid, methyl ester (slow moving isomer) prepared as described in Example 78 in 18.2 ml of THF and 2.77 ml of H20 under argon was added 3.50 ml of 1 N aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 1 5 minutes and stirred at room temperature for 4 hours and 40 minutes. The reaction mixture was acidified to pH 4 by addition of 1 N aqueous HCl solution and poured into 30 ml of saturated NaCI solution. The resulting solution was saturated with solid NaCI and extracted with EtOAc (3x70 ml). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give 1 52 mg of crude acid.
Purification was effected by flash chromatography on 20.8 g of silica gel 60 using 4% CH3OH in CH2CI2 as eluant to give title acid (11 6 mg, 85%). TLC: silica gel, 4% CH3OH/CH2Cl2, Rf 0.6, iodine.
Anal. Calc'd for C20H34O4S: C, 64.83; H, 9.25; S, 8.65 Found: C, 64.44; H, 9.1 5; S, 8.58 '3C NMR (CDCl, 15.0MHz) 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 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Methylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid (Fast Moving Isomer) Following the procedure of Examples 44, 77 and 81 except substituting methyl mercaptan for 1 hexanethiol, the title compound is obtained.
EXAMPLE 84 [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Octylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid (Slow Moving Isomer) Following the procedure of Examples 44, 77 and 82 except substituting 1-octanethiol for 1hexanethiol, the title compound is obtained.
EXAMPLE 85 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Phenylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid (Fast Moving Isomer) Following the procedure of Examples 48, 77 and 81 except substituting phenylmercaptan for 1pentanethiol, the title compound is obtained.
EXAMPLE 86 [1 ss,2a(5Z),3cE,4A]-7-[3-[(Ethylsulfinyl)methyl]-7-oxabicycío[2.2.1]hept-2-yí]-5-heptenoic Acid (Slow Moving Isomer) Following the procedure of Example 48,77 and 82 except substituting ethylmercaptan for 1pentanethiol, the title compound is obtained.
EXAMPLE 87 (1 ss,2&alpha;,3&alpha;,4ss]-7-[3-[(Heptylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid (Fast Moving Isomer) Following the procedure of Examples 46,77 and 81 except substituting 1-heptanethioí for 1hexanethiol, the title compound is obtained.
EXAMPLE 88 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Benzylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 44, 77 and 81 except substituting benzylmercaptan for 1 hexanethiol, the title compound is obtained.
EXAMPLE 89 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Benzylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid (Slow Moving Isomer) Following the procedure of Examples 48, 77 and 82 except substituting benzylmercaptan for 1pentanethiol, the title compound is obtained.
EXAMPLE 90 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Cyclohexylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid (Fast Moving Isomer) Following the procedure of Examples 44, 77 and 81 except substituting cyclohexylmercaptan for 1-hexanethiol, the title compound is obtained.
EXAMPLE 91 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Cyclopentylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid (Fast Moving Isomer) Following the procedure of Examples 44, 77 and 81 except substituting cyclopentylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 92 [1 ,2a(5Z),3a,4]-7-[3-[(0ctylsulfonyl) methyl]-7-oxabicyclo[2.2. 1 ]hept-2-ylj-5-heptenoic Acid Following the procedure of Examples 44, 77 and 80 except substituting octylmercaptan for 1hexanethiol, the title compound is obtained.
EXAMPLE 93 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Propylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 44, 77 and 80 except substituting propylmercaptan for 1hexanethiol, the title compound is obtained.
EXAMPLE 94 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Phenylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 44, 77 and 80 except substituting phenylmercaptan for 1hexanethiol, the title compound is obtained.
EXAMPLE 95 [1 ,2o(5Z),3o',4]-7-[3-[(Benzylsulfonyl)methyl]-7-oxabicyclo[2.2. 1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 44, 77 and 80 except substituting benzylmercaptan for 1hexanethiol, the title compound is obtained.
EXAMPLE 96 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Cyclohexylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 44, 77 and 80 except substituting cyclohexylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 97 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Heptylsulfonyl)methyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 48, 77 and 80 except substituting 1-heptenethiol for 1pentanethiol, the title compound is obtained.
EXAMPLE 98 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Benzylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 48, 77 and 80 except substituting benzylmercaptan for 1pentanethiol, the title compound is obtained.
EXAMPLE 99 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Cyclopentylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 48, 77 and 80 except substituting cyciopentylmercaptan for 1 -pentanethiol, the title compound is obtained.
EXAMPLE 100 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(Phenylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 48, 77 and 80 except substituting phenylmercaptan for 1pentanethiol, the title compound is obtained.
EXAMPLE 101 (1 B,2a,3a,4P)-7-[3-[(Cyclopropylsulfinyi) methyl]-7-oxabicyclo[2.2. 1 ]hept-2-yl]-5-heptanoic Acid Following the procedure of Examples 46, 77 and 80 except substituting cyclopropylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 102 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[(Benzylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic Acid Following the procedure of Examples 47, 77 and 81 except substituting benzylmercaptan for 1hexanethiol, the title compound is obtained.
EXAMPLE 103 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Pentylsulfinyl)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 63,44, 77 and 81 except substituting 1-pentanethiol for 1hexanethiol, the title compound is obtained.
EXAMPLE 104 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Phenylsulfonyl)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 63, 44, 77 and 80 except, substituting phenylmercaptan for 1-hexanethiol, the title compound is obtained.
EXAMPLE 105 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Cyclohexylsulfonyl)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 63, 44, 77 and 80 except substituting cyclohexylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 106 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Benzylsulfinyl)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 63, 44, 77 and 81 except substituting benzylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 107 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Butylsulfonyl)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 63, 48, 77 and 80 except substituting butylmercaptan for 1 -pentanethiol, the title compound is obtained.
EXAMPLE 108 [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Phenylsulfinyl)ethyl]-7 -oxabicyclo[2.2.1] hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 63,48, 77 and 81 except substituting phenylmercaptan for 1 -pentanethiol, the title compound is obtained.
EXAMPLE 109 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Benzylsulfinyl)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-hepten Following the procedure of Examples 63, 48, 77 and 81 except substituting bezyl 1-pentanethiol, the title compound is obtained.
EXAMPLE 110 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Cycloheptylsulfonyl)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5- Following the procedure of Examples 63, 48, 77 and 80 except substituting cycloheptylmercaptan for 1 -pentanethiol, the title compound is obtained.
EXAMPLE 111 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[2-(Pentylsulfonyl)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic Acid Following the procedure of Examples 63, 46, 77 and 80 except substituting 1-pentanethiol for 1hexanethiol, the title compound is obtained.
EXAMPLE 112 (1 -,2e,3a,4)-7-[3-[2-(Phenylsulfinyl)ethyl]-7-oxabicyclo[2.2. 1] hept-2-yl]-5-heptanoic Acid Following the procedure of Examples 63, 46, 77 and 81 except substituting phenylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 113 (1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Benzylsulfinyl)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic Acid Following the procedure of Examples 63,46, 77 and 81 except substituting benzylmercaptan for 1-hexanethiol, the title compound is obtained.
EXAMPLE 114 [1ss,2&alpha;,3&alpha;,4ss]-7-[3-[2-(Cyclohexylsulfonyl]ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic Acid Following the procedure of Examples 63, 48, 77 and 80 except substituting cyclohexylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 115 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Pentylsulfonyl)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 73, 63, 44, 77 and 80 except substituting pentylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 116 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-Cyclohexylsulfinyl)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 73, 63, 44, 77 and 81 except substituting cyclohexylmercaptan for 1 -hexanthiol, the title compound is obtained.
EXAMPLE 117 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Phenylsulfinyl)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 73, 63, 44, 77 and 81 except substituting phenylmercaptan for 1-hexanethiol, the title compound is obtained.
EXAMPLE 118 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Benzylsulfonyl)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 73, 63, 44, 77 and 80 except substituting benzylmercaptan for 1-hexanethiol, the title compound is obtained.
EXAMPLE 119 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Cyclopentylsulfinyl)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 73, 63,48, 77 and 81 except substituting cyclopentylmercaptan for 1-pentanethiol, the title compound is obtained.
EXAMPLE 120 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Benzylsulfinyl)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 73, 63, 48, 77 and 80 except substituting benzylmercaptan for 1-pentanethiol, the title compound is obtained.
EXAMPLE 121 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Propylsulfinyl)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 73, 63,48, 77 and 81 except substituting propylmercaptan for 1-pentanethiol, the title compound is obtained.
EXAMPLE 122 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-(Phenylsulfonyl)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 73, 63, 48, 78 and 80 except substituting phenylmercaptan for 1-pentanethiol, the title compound is obtained.
EXAMPLE 123 (1 2e,3a,4)-7-[3-[4-(NonyIsulfinyl)bul]-7-oxabicyclo[2.2. 1 ]hept-2-yl]-5-heptanoic Acid Following the procedure of Examples 73, 63, 46, 77 and 81 except substituting 1 -nonanethiol for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 124 (1 ss,2&alpha;,3&alpha;,4ss]-7-[3-[4-(Pentylsulfonyl)butyl]-7-oxabicyclo[2.2.1]hept-2 -yl]-5-heptanoic Acid Following the procedure of Examples 73, 63, 46, 77 and 80 except substituting 1 -pentanethiol for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 125 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[4-(Phenylsulfinyl)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 77, 63,46, 77 and 81 except substituting phenylmercaptan for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 126 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[4-(Cyclohexylsulfonyl)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic Acid Following the procedure of Examples 73, 63, 46, 77 and 80 except substituting cyclohexylmercaptan for 1-hexanethiol, the title compound is obtained.
EXAMPLE 127 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(Cyclohexylmethyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid A. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(Cyclohexylmethyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Methyl Ester To a solution of 88 mg (0.78 mmol) of potassium t-butoxide in 5 ml of dry THF under argon was added 277 mg (2,13 mmol) ofcyclohexylmethanethiol (prepared from cyclohexylmethanol by the method of Volante: Tetrahedron Letters 1981, 22, 311 9). To this mixture was added a solution of 300 mg (0.71 mmol) of [1 ,2o'( 5Z),3a,4/3])7-[3-(p-toluenesulfonyloxymethyl)-7 -oxabicyclo[2.2. 1 ]-hept-2- yl]-5-heptenoic acid, methyl ester, prepared as described in Example 44B, in 5.5 ml of dry THF.The reaction mixture was heated to reflux for 7 hours. The cooled reaction mixture was diluted with 250 ml ether and poured into 100 ml of saturated NaHCO3 solution. The aqueous layer was extracted with ether (2 x 100 ml). The combined ether extracts (450 ml) were washed with 0.5 N aqueous sodium hydroxide solution (2:; 100 ml) and brine (100 ml). The ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give an oily product. Purification was effected by chromatography on 20.2 g of silica gel 60 using hexane:ether (3:1) as eluant to give 253 mg of title A methyl ester as an oil (94%). TLC: silica gel, petroleum ether:ether (3:2), Rf=0.70, iodine.
B. [1 ,2a(5Z),3o',4]-7-[3-[[(Cyclohexylmethyl)thio]methyl]-7-oxabicyclo[2.2. 1]hept-2-yl]-5-heptenoic Acid To a stirred solution of 243 mg (0.64 mmol) of Part A methyl ester in 31.4 ml of THF and 4.80 ml of H20 under argon was added 6.00 ml of 1 N aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 25 minutes and stirred at room temperature for 16 hours. The reaction mixture was acidified to pH 5 by addition of 1 N aqueous HCl solution and poured into 40 ml of saturated NaCI solution. The resulting solution was saturated with solid NaCI and extracted with EtOAc (4x50 ml). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give 253 mg of crude acid.Purification was effected by flash chromatography on 20.6 g of silica gel 60 using petroleum-ether:ether (2:3) as eluant to give pure title product (117 mg, 50%) along with 108 mg (46%) of mixed fractions of which title product was the major component. TLC: silica gel, Petether:ether (2:3), Rf=0.32, iodine.
Anal. Calc'd for C2,H3403S: C, 68.85; H, 9.29; S, 8.74 Found: C, 68.90; H, 9.43; S, 8.66 13C NIMR (CDCl3, 15.0MHz) tau 178.7,32.9, 24.6,26.1, 129.7, 129.9,29.5,47.1, 80.4,26.7, 26.3, 80.7, 47.6, 33.4, 40.4. 38.0, 32.9, 29.5. 26.1.29.5, 32.9 EXAMPLE 128 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(2-Phenylethyl]thiolmethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid A. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(2-Phenylethyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid, Methyl Ester To a solution of 55.7 mg (0.50 mmol) of potassium t-butoxide in 5 ml of dry THF under argon was added 185 mg (1.35 mmol) of phenylethanethiol.To this mixture was added a soiution of 189 mg (0.45 mmol) of [[1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(p-toluenesulfonyloxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5- heptenoic acid, methyl ester, prepared as described in Example 44B, in 6 ml of dry THF. The reaction mixture was heated to reflux for 4 hours and 30 minutes. The cooled reaction mixture was diluted with 160 ml of ether and poured into 60 ml of saturated NaHCO3 solution. The aqueous layer was extracted with ether (2x60 ml). The combined ether extracts (280 ml) were washed with 0.5 N aqueous sodium hydroxide solution (2x60 ml) and brine (75 ml). The ether extracts were dried over MgS04 and concentrated in vacuo to give an oily product. Purification was effected by chromatography on 21.6 g of silica gel 60 using petroleum ether:ether (5:1) as eluant to give 1 57 mg of title A compound as an oil (90%).TLC: silica gel, petroleum ether:ether (2:1, Rf=0.60, iodine.
B. [1,B,2as(5Z),3a,4,5]-7-[3-[[(2-Phenylethyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid.
To a stirred solution of 1 50 mg (0.39 mmol) of Part A methyl ester in 1 9 ml of freshly distilled THF and 2.91 ml of H20 under argon was added 3.64 ml of 1 N aqueous lithium hydroxide solution.
This mixture was purged with argon vigorously for 25 minutes and stirred at room temperature for 6 hours. The reaction mixture was acidified to pH 5 by addition of 1 N aqueous HCl solution and poured into 40 mi of saturated NaCI solution. The resulting solution was saturated with solid NaCI and extracted with EtOAc (4x60 ml). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give 147 mg of crude acid. Purification was effected by flash chromatography on 20 g of silica gel 60 using 2% CH3OH in CH2Cl2 as eluant to give title product (122 mg, 84%) as an oil. TLC: silica gel, 6% CH30H in CH2Cl2, Rf=0.32, iodine.
Anal. Calc'd for C22H3003S: C, 70.55; H, 8.07; S, 8.56 Found: C, 70.54; H, 8.08; S, 8.48 '3C NMR (CDCI3, 1 5.0MHz) tau 179.0, 33.4, 24.5, 26.2, 129.9, 129.7, 26.7, 46.9, 80.4, 29.5, 80.6, 47.5, 32.3, 34.1, 36.4, 140.5, 128.4, 126.3, 128.4, 128.4 EXAMPLE 129 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(3-Phenylpropyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid A. [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(3-Phenylpropyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester To a solution of 88 mg (0.78 mmol) of potassium t-butoxide in 5 ml of dry THF under argon was added 324 mg (2.13 mmol) of 3-phenylpropylmercaptan.To this mixture was added a solution of 300 mg (0.71 mmol) of [1 ,2o'(5Z),3or,4-7-[3-(p-toluenesulfonyloxymethyl)-7-oxabicyclo[2.2.l ]hept-2- ylj-5-heptenoic acid, methyl ester in 7 ml of dry THF. The reaction mixture was heated to reflux for 6 hours and 30 minutes. The cooled reaction mixture was diluted with 250 ml of ether and poured into 100 ml of saturated NaHCO3 solution. The aqueous layer was extracted with ether (2 xl 00 ml). The combined ether extracts (450 ml) was washed with 0.5 N aqueous sodium hydroxide solution (2x100 ml) and brine (100 ml). The ether extracts were dried over MgSO4 and concentrated in vacuo to give an oily product.Purification was effected by chromatography on 25 g of silica gel 60 using hexane:ether (3:1) as eluant to give 280 mg of title A compound as an oil (98%). TLC: silica gel, petroleum ether:ether (2:1), Rf 0.60, iodine.
B. [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(3-Phenylpropyl)thio]methyl]-7-oxabicyclo[2.2. 1,] hept-2-yl]-5-heptenoic Acid To a stirred solution of 280 mg (0.70 mmol) of Part A methyl ester in 34.4 ml of freshly distilled THF and 5.30 ml of H20 under argon was added 6.60 ml of 1 N aqueous lithium hydroxide solution.
This mixture was purged with argon for an hour and stirred at room temperature for 3 hours. The reaction mixture was acidified to pH 5 by addition of 1 N aqueous HCl solution and poured into 50 ml of saturated NaCI solution. The resulting solution was saturated with solid NaCI and extracted with EtOAc (4x60 ml). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give 280 mg of crude acid. Purification was effected by flash chromatography on 29 g of silica gel 60 using 2% CK3OH in CH2CI2 eluant to give title product (205 mg, 76%). TLC: silica gel,. 6% CH3OH/CH2Cl2, Rf=0.34,lodine.
Anal. Calc'dforC23H32O3S: C, 71.09; H, 8.30; S, 8.25 Found: C, 70.81; H, 8.36; S, 8.14 '3C NMR (CDCl3, 1 5.0MHz) tau 179.0, 33.4, 24.7, 26.7, 129.7, 129.8, 29.5, 46.9, 80.4, 29.5, 80.6,47.5, 32.1, 31.9, 26.2, 34.7,141.4, 128.4, 28.4,125.8, 128.4, 128.4 EXAMPLE 130 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(Cyclohexylmethyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 48 and 49 except substituting cyclohexylmethanethiol for 1 -pentanethiol, the title compound is obtained.
EXAMPLE 131 [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(3-Cyclohexylpropyl)thiol] methyl]-7-oxabicyclo[2.2.1] hept-2 -yl]-5-heptenoic Acid Following the procedure of Examples 48 and 49 except substituting 3-cyclohexylpropanethiol for 1-pentanethiol, the title compound is obtained.
EXAMPLE 132 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[[(2-Cyclohexylethyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic Acid Following the procedure of Examples 46 and 47 except substituting 2-cyclohexylethanethiol for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 133 [1 ,2a(5Z),3p,4p]-7-[3-[[(2-Phenyíethyl)thio]methyl]-7-oxabicyclo[2.2.1]hept -2-ylJ-5-heptenoic Acid Following the procedure of Examples 48 and 49 except substituting 2-phenylethanethiol for 1pentanethiol, the title compound is obtained.
EXAMPLE 134 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(3-Phenylpropyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 48 and 49 except substituting 3-phenylpropane thiol for 1pentanethiol, the title compound is obtained.
EXAMPLE 135 (1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(2-Phenylethyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic Acid Following the procedure of Examples 46 and 47 except substituting 2-phenylethanethiol for 1 hexanethiol, the title compound is obtained.
EXAMPLE 136 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[[(3-Phenylpropyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 46 and 48 except substituting 3-phenylpropanethiol for 1'hexanethiol, the title compound is obtained.
EXAMPLE 137 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(Cyclohexylmethyl)sulfinyl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5- heptenoic Acid (Slow Moving Isomer) Following the procedure of Examples 44, 77 and 81 except substituting cyclohexylmethanethiol for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 138 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(Cyclohexylmethyl)sulfinyl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5- heptenoic Acid (Fast Moving Isomer) Following the procedure of Examples 48, 77 and 81 except substituting cyclohexylmethanethiol for 1 -pentanethiol, the title compound is obtained.
EXAMPLE 139 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(2-Phenylethyl)sulfinyl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid (Fast Moving Isomer) Following the procedure of Examples 44, 77 and 81 except substituting 2-phenylethanethiol for 1-pentanethiol, the title compound is obtained.
EXAMPLE 140 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(3-Phenylpropyl)sulfinyl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid (Slow Moving Isomer) Following the procedure of Examples 48, 77 and 82 except substituting 3-phenylpropane thiol for 1-pentanethiol, the tile compound is'obtained.
EXAMPLE 141 (1ss,2&alpha;,3&alpha;,4ss]-7-[3-[[(2-Phenylethyl)sulfinyl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic Acid (Fast Moving Isomer).
Following the procedure of Examples 46, 77 and 81 except substituting 2-phenylethanethiol for 1-hexanethiol, the title compound is obtained.
EXAMPLE 142 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(Cyclohexylmethyl)sulfonyl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5- heptenoic Acid Following the procedure of Examples 44, 77 and 80 except substituting cyclohexylmethanethiol for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 143 (1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(2-Phenylethyl)sulfonyl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 44, 77 and 80 except substituting 2-phenylethane thiol for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 144 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(3-Phenylpropyl)sulfonyl)methyl]-7-oxbicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 44, 77 and 80 except substituting 3-phenylpropanethiol for 1-hexanethiol, the tile compound is obtained.
EXAMPLE 145 [1 ,2a(5Z),3a,4/3]-7-[3-[2-[(Cyclohexylmethyl)thiojethylj-7-oxabicyclo[2.2. 1 Jhept-2-ylj-5-heptenoic Acid Following the procedure of Examples 63 and 44 except substituting cyclohexylmethanethiol for 1-hexanethiol, the title compound is obtained.
EXAMPLE 146 [(1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-[(Cyclohexylmethyl)sulfinyl]ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5- heptenoic Acid Following the procedure of Examples 63, 44, 77 and 81 except substituting cyclohexylmethanethiol for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 147 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-[(Cyclohexylmethyl)sulfonyl]ethyl]-7-oxablcyclo[2.2.1]hept-2-yl]-5 heptenoic Acid Following the procedure of Examples 63, 44,77 and 80 except substituting cyclohexylmethanethiol for 1-hexanethiol, the title compound is obtained.
EXAMPLE 148 [1,B,2a(5Z),3a,4,B]-7 -[3-[2-[(2-Phenylethyl)thio]ethylj-7-oxabicyclo[2.2. 1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 63 and 44 except substituting 2-phenylethanethiol for 1 hexanethiol, the title compound is obtained.
EXAMPLE 149 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-[(2-Phenylethyl)sulfinyl]ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 63, 44, 77 and 81 except subsfituting 2-phenylethanethiol for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 150 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[2-[(3-Phenylpropyl)thio]ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 63 and 44 except substituting 3-phenylpropanethiol for 1hexanethiol, the title compound is obtained.
EXAMPLE 151 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[2-[(3-Phenylpropyl)sulfinyl]ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63,44, 77 and 81 except substituting 3phenylpropanethiol for 1-hexanethiol, the title compound is obtained.
EXAMPLE 152 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-[(2-Phenylethyl)sulfonyl]ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of. Examples 63, 44, 77 and 80 except substituting 2-phenylethane thiol for 1-hexanethiol, the title compound is obtained.
EXAMPLE 153 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-[(3-Phenylpropyl)sulfonyl]ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of. Examples 63-44, 77 and 80 except substituting 3phenylpropanethiol for 1-hexanethiol. the title compound is obtained.
EXAMPLE 154 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-[(Cyclohexylmethyl)thio]butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 73, 63 and 44 except substituting cyclohexyl methanethiol for 1 -hexanethiol, the title compound is obtained.
EXAMPLE 155 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-[(Cyclohexylmethyl)sulfinyl]butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5- heptenoic Acid Following the procedure of Examples 73, 63,44, 77 and 81 except substituting cyclohexylmethanethiol for 1-hexanethiol, the title compound is obtained.
EXAMPLE 156 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-[(Cyclohexylmethyl)sulfonyl]butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5- heptenoic Acid Following the procedure of Examples 73, 63, 44, 77 and 80 except substituting cyclohexylmethanethiol for 1-hexanethiol, the title compound is obtained.
EXAMPLE 157 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4[(2-Phenylethyl)thio]butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 73, 63, and 44 except substituting 2-phenylethanethiol for 1-hexanethiol, the title compound is obtained.
EXAMPLE 158 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-[(2-Phenylethyl)sulfinyl]butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 73, 63,44, 77 and 81 except substituting 2phenylethanethiol for 1-hexanethiol, the title compound is obtained.
EXAMPLE 159 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[4-[(2-Phenylethyl)sulfonyl]butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid Following the procedure of Examples 73, 63,. 44, 77 and 80 except substituting 2phenylethanethiol for 1-hexanethiol, the title compound is obtained.
EXAMPLE 160 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[2-(Heptylthio)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic Acid and Methyl Ester By reacting [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(2-hydroxyethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (see example 20B) with tosyl chloride as per Example 44B and with heptanethiol according to the procedure of 44C, the titled product is obtained as the methyl ester as a colorless oil, TLC(sllica gel,-hexane:ether(2:1) Rf=0.45. Hydrolysis according to the procedure of example 45 affords the free acid as an oil, TLC(silica gel, 3% CH3OH/CH2Cl2) Rf=.23.
Anal. Calc'd for C22H3803S: C, 69.06; H, 10.01; S, 8.38 Found: C, 68.80; H, 9.99; S, 8.24 53C NMR (CDCI3, 15.0MHz) tau 178.8,33.4,22.5, 24.5, 129.5, 130.1,26.6,46.1, 80.1,29.7, 29.7, 80.1,47.3,32.3, 31.7, 31.7,29.5, 28.8, 32.3,28.8, 26.6, 13.9 EXAMPLE 161 [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(3-Phenyl-2-propenyl)thio]methyl]oxabicyclo[2.2.1]hept-2-yl]-5- heptenoic Acid and Methyl Ester' By following the procedure of example 44 and substituting 3-phenyl-2-propenylthiol for the 1 hexanethiol used in example 44(C), the titled methyl ester is obtained, TLC(silica gel, hexane:ether(2:1)) Rf=0.35; and continuing on which the hydrolysis procedure outlined in example 45 affords the titled free acid, TLC(silica gel, 3% CH30H/CH2Cl2), Rf=0.25 Anal. Calc'd for C23H30O3S: C, 71.46; H, 7.82; S, 8.30 Found: C,71.31; H, 7.87; S, 8.26

Claims (28)

1. A compound having the structural formula
and including all stereoisomers thereof, wherein A is -CH=CH- or -(CH2)2-; B is oxygen (-0-) or
wherein n' is 0 to 2; m is 1 to 8; n is 1 to 4; R is hydrogen, alkyl, alkali metal or tris(hydroxymethyl)aminomethane: and R1 is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylalkynyl.
2. A compound according to claim 1 wherein B is -O
3. A compound according to claim 1 wherein B is-S
4. The compound as defined in Claims 1-3 wherein A is -CH=CH-.
5. The compound as defined in Claims 1-3 wherein R is H.
6. The compound as defined in Claims 1-3 wherein n is 1.
7. The compound as defined in Claims 1-3 wherein n is 2.
8. The compound as defined in Claims 1-3 wherein n is 3 or 4.
9. The compound as defined in Claims 1-3 wherein A is -CH=CH-, m is 2 to 4, n is 1 or 2, R is H and R1 is lower alkyl or cycloalkyl.
10. The compound as defined in Claims 1-3 wherein A is -CH=CH-, m is 3, n is 1, R is H, CH3 orC6H13, and R1 is lower alkyl.
11. The compound as defined in Claim 1 having the name [[1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[(hexyloxy)- methyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or its hexyl ester.
12. The compound as defined in Claim 1 having the name [1 P,2a(5Z),3a,4P]-7-[3-[2- (pentyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.
13. The compound as defined in Claim 1 having the name [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[(3- phenylpropoxy)methyl]-7-oxabicyclo[2.2. 1 ]hept-2-yl]-5-heptenoic acid.
14. The compound as defined in Claim 1 having the name [lp,2a(5Z),3a,4P]-7-[3-[(octyloxy)- methyl]-7-oxabicyclo[2.2. 1 ]hept-2-yl]-5-heptenoic acid.
15. The compound as defined in Claim 1 having the name [1 ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-(cyclohexyl- methoxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.
16. The compound as defined in Claim 1 wherein A is -CH=CH-, m is 3, n is 1, n' is 1 and R' is lower alkyl.
17. The compound as defined in Claim 1 wherein A is -CH=CH-, m is 3, n is 1, n' is 2 and R' is loweralkyl.
18. The compound as defined in Claim 1 having the name [1,B,2a(5Z),3a,4/3]-7-[3-[(hexylthio)- methyl]-7-oxabicyclo[2.2. 1 ]hept-2-yl]-5-heptenoic acid or its methyl ester.
19. The compound as defined in Claim 1 having the name [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3- [(hexylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or its methyl ester.
20. The compound as defined in Claim 1 having the name [1,B,2a:(5Z),3a,423]-7-[3- [(hexylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-7-heptenoic acid or the methyl ester thereof.
21. The compound as defined in Claim 1 having the name [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(cyclohexyl- methyl)thio]methyl]-7-oxabicyclo[2.2.1 ]hept-2-yl]-5-heptenoic acid or the methyl ester thereof.
22. The compound as defined in Claim 1 having the name [1ss,2&alpha;(5Z),3&alpha;,4ss]-7-[3-[[(2- phenylethyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof
23. The compound as defined in Claim 1 having the name [1 ,2a(5Z),3a,4,B]-7-[3-[[(3- phenylpropyl)thio]methyl]-7-oxabicyclo[2 1 ]hept-2-yl]-5-heptenoic acid or the methyl ester thereof.
24. A method of inhibiting platelet aggregation and bronchoconstriction, which comprises administering to the circulatory system of a mammalian host an effective amount of a compound as defined in Claim 1 or a pharmaceutically acceptable salt thereof.
25. A composition for inhibiting platelet aggregation and bronchoconstriction comprising an effective amount of a compound as defined in Claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.
26. A method of inhibiting platelet aggregation which comprises administering to a mammalian host an effective amount of a compound as defined in Claim 1 or a pharmaceutically acceptable salt thereof.
27. A method of inhibiting bronchoconstriction associated with asthma, which comprises administering to a mammalian host an effective amount of a compound as defined in Claim 1 or a pharmaceutically acceptable salt thereof.
28. A method for inhibiting platelet aggregation and bronchoconstriction by inhibiting production of thromboxane A2 by blocking the action of thromboxane synthetase, which comprises administering to a mammalian host an effective amount of a compound as defined in Claim 1 or a pharmaceutically acceptable salt thereof.
GB08406100A 1983-03-14 1984-03-08 7-oxabicycloheptane substituted prostaglandin analogs Expired GB2136428B (en)

Applications Claiming Priority (2)

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US06/474,913 US4474803A (en) 1983-03-14 1983-03-14 7-Oxabicycloheptane substituted thio prostaglandin analogs useful in treating platelet aggregation and bronchoconstriction
US52332083A 1983-08-15 1983-08-15

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GB2136428A true GB2136428A (en) 1984-09-19
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Cited By (8)

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GB2153352A (en) * 1984-01-26 1985-08-21 Squibb & Sons Inc Prostaglandin analogs
GB2158064A (en) * 1984-04-27 1985-11-06 Squibb & Sons Inc 7-oxabicycloheptane substituted oxa prostaglandin analogs
EP0164075A2 (en) * 1984-06-04 1985-12-11 E.R. Squibb &amp; Sons, Inc. 7-Oxabicycloheptane substituted thio prostaglandin analogs
EP0183238A2 (en) * 1984-11-30 1986-06-04 E.R. Squibb &amp; Sons, Inc. 7-Oxabicycloheptane substituted oxa prostaglandin analogs
GB2169899A (en) * 1985-01-22 1986-07-23 Squibb & Sons Inc 7-oxabicycloheptane-substituted oxa prostaglandin analogs
FR2580651A1 (en) * 1985-04-22 1986-10-24 Squibb & Sons Inc THIO-PROSTAGLANDIN 7-OXABICYCLOHEPTANE-SUBSTITUTED ANALOGUES WITH THERAPEUTIC ACTION
FR2581066A1 (en) * 1985-04-26 1986-10-31 Squibb & Sons Inc 7-OXABICYCLOHEPTANE ETHERS, PROSTAGLANDIN ANALOGS, WITH THERAPEUTIC ACTION
FR2584074A1 (en) * 1985-06-28 1987-01-02 Squibb & Sons Inc 5,6-EPOXY-7-OXABICYCLOHEPTANE ETHERS USEFUL IN THE TREATMENT OF THROMBOSES

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US4513103A (en) * 1983-10-21 1985-04-23 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane ethers useful in the treatment of thrombolytic disease
US4654356A (en) * 1985-08-01 1987-03-31 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted diacid diamide prostaglandin analogs
US4673685A (en) * 1986-07-23 1987-06-16 E. R. Squibb & Sons, Inc. Hydroximic acids of 7-oxabicycloheptane substituted ethers and thioethers useful in the treatment of thrombotic disease

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US4143054A (en) * 1977-11-04 1979-03-06 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane- and 7-oxabicycloheptene compounds
ZA814307B (en) * 1980-07-01 1983-02-23 Nat Res Dev Prostaglandins
EP0082646B1 (en) * 1981-12-23 1989-11-15 National Research Development Corporation Prostaglandins
US4549030A (en) * 1982-12-13 1985-10-22 The Upjohn Company Organic compounds and process
US4526900A (en) * 1984-01-26 1985-07-02 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted oxa prostaglandin analogs and their use in the treatment of thrombolytic disease
US4542157A (en) * 1984-04-27 1985-09-17 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane substituted oxa prostaglandin analogs and their use in the treatment of thrombolytic disease

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2153352A (en) * 1984-01-26 1985-08-21 Squibb & Sons Inc Prostaglandin analogs
GB2158064A (en) * 1984-04-27 1985-11-06 Squibb & Sons Inc 7-oxabicycloheptane substituted oxa prostaglandin analogs
EP0164075A2 (en) * 1984-06-04 1985-12-11 E.R. Squibb &amp; Sons, Inc. 7-Oxabicycloheptane substituted thio prostaglandin analogs
EP0164075A3 (en) * 1984-06-04 1987-04-15 E.R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted thio prostaglandin analogs
EP0183238A2 (en) * 1984-11-30 1986-06-04 E.R. Squibb &amp; Sons, Inc. 7-Oxabicycloheptane substituted oxa prostaglandin analogs
EP0183238A3 (en) * 1984-11-30 1987-04-29 E.R. Squibb &amp; Sons, Inc. 7-oxabicycloheptane substituted oxa prostaglandin analogs
GB2169899A (en) * 1985-01-22 1986-07-23 Squibb & Sons Inc 7-oxabicycloheptane-substituted oxa prostaglandin analogs
FR2580651A1 (en) * 1985-04-22 1986-10-24 Squibb & Sons Inc THIO-PROSTAGLANDIN 7-OXABICYCLOHEPTANE-SUBSTITUTED ANALOGUES WITH THERAPEUTIC ACTION
FR2581066A1 (en) * 1985-04-26 1986-10-31 Squibb & Sons Inc 7-OXABICYCLOHEPTANE ETHERS, PROSTAGLANDIN ANALOGS, WITH THERAPEUTIC ACTION
FR2584074A1 (en) * 1985-06-28 1987-01-02 Squibb & Sons Inc 5,6-EPOXY-7-OXABICYCLOHEPTANE ETHERS USEFUL IN THE TREATMENT OF THROMBOSES

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GB8406100D0 (en) 1984-04-11
LU85249A1 (en) 1984-11-14
IL71184A0 (en) 1984-06-29
IE840525L (en) 1984-09-14
NO840960L (en) 1984-09-17
AU567919B2 (en) 1987-12-10
DD216932A5 (en) 1985-01-02
AT383600B (en) 1987-07-27
DE3409124A1 (en) 1984-09-27
ATA83484A (en) 1986-12-15
KR840009085A (en) 1984-12-24
HU190530B (en) 1986-09-29
GB2136428B (en) 1986-09-10
ES530548A0 (en) 1985-07-01
IE57027B1 (en) 1992-03-25
FI841008A (en) 1984-09-15
FI841008A0 (en) 1984-03-13
SE8401398L (en) 1984-09-15
IT1173442B (en) 1987-06-24
CH658247A5 (en) 1986-10-31
GR79881B (en) 1984-10-31
IT8420049A0 (en) 1984-03-14
AU2523584A (en) 1984-09-20
ES8506270A1 (en) 1985-07-01
HUT34179A (en) 1985-02-28
PT78242B (en) 1986-05-27
NL8400797A (en) 1984-10-01
CA1256887A (en) 1989-07-04
PL246663A1 (en) 1985-03-26
NZ207361A (en) 1986-12-05
DK155584A (en) 1984-09-15
FR2542743B1 (en) 1987-10-30
FR2542743A1 (en) 1984-09-21
SE8401398D0 (en) 1984-03-13
PT78242A (en) 1984-04-01
DK155584D0 (en) 1984-03-13

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