IE45773B1 - 11-deoxy-11-oxaprostaglandin compounds - Google Patents

Abstract

PURPOSE: To miniaturize the work machine by using in common parts of a work machine moving mechanism by constituting the mechanism so that by an ascending/descending block being movable vertically, a machine supporting block can be subjected to reciprocating rotation at a prescribed angle in the horizontal direction, and a ball spline can turn the machine supporting block in the shaft rotating direction. CONSTITUTION: When a work machine 2 completes a work to a work 10, a third cylinder 9 allows an ascending/descending block 4 to descend to the lower limit. The work machine 2 separates from the work 10. A second cylinder 8 rotates a ball spline by a prescribed angle in the left direction. By this rotation, a machine supporting block 3 and the whole unit supported thereby are rotated and oscillated, and the work machine 2 is saved to a prescribed position separated enough from the work 10. Another work machine 11 moves to a work position in which the work 10 exists and executes a work. The work machine 2 can be miniaturized because a guide shaft for moving forward and backward and a rotation driving shaft are used in common by one piece of ball spline [JPS5337653A]

Description

This invention relates to certain new chemical compounds. More particularly it relates to certain chemical compounds which have valuable medicinal properties, and which are new members of the class of compounds known as the prostagland5 ins.

The prostaglandins are derivatives of the C-20 fatty acid 7-(2p~octylcyclopent-l XO Prostaglandins exist naturally and they have been isolated from a variety of mammalian sources. Natural prostaglandins of the so-called E-series have an oxo group at C-9, a hydroxy group at C-ll trans to the adjacent eight-carbon side chain at C-12, and an α-hydroxy group at C-15. Indiv15 idual members of the E-series of prostaglandins are further characterized by the number and location of double bonds 7 7 3 in the C-8 and. C-12 side chains. For example, prostaglandin has a 13-14 trans double bond, and prostaglandin Eg has a 13-14 trans double bond and a 5-6 cis double bond. Prostaglandin Eg is also named as 9-oxo-lla,15a-dihydroxycis—5-trans-l3-prostadienoic acid, and it has the following structure: COOH Natural prostaglandins of the E-series cause a wide variety of biological and phamacological responses, both in vitro and in vivo. For example, E series prostaglandins stimulate uterine smooth muscle, have hypotensive, diuretic, bronchodilatory and antilipolytic activities, and they also have effects on blood platelet aggregation and gastric acid secretion. (See further: Bergstrom et al., Pharmacological Reviews, 20, 1 (1968) and Caton, Progress in Medicinal Chemistry, Butterworths Publications, Ltd., London, 1971, Volume 8, page 317)· However, this diversity of pharmacological activities often limits the medicinal usefulness of E-series prostaglandins, since unwanted side effects are obtained when the compounds are being used to treat a particular clinical symptom or disease state. Accordingly, it is an object of the present invention to provide certain ll-deoxy-ll-oxa-17,18,19,20-tetranor derivatives of E-series prostaglandins, which have useful medicinal properties but which have a greater specificity of action than the natural compounds obtained from mammalian tissue. In particular, the present invention provides ll-deoxy-ll-oxa-17,18,19,20tetranor E-series prostaglandins, having a phenyl or substituted phenyl at C-16, which lower blood pressure in mammals, especially humans but have substantially reduced antifertility properties.

Although preparation of racemic 11-deoxy-ll-oxaprostaglandin E^, and its C-15 epimer, has been described (Tetrahedron letters, 32, 2733 [1974]), no hypotensive or antifertility properties were disclosed for these com5 pounds. They were reported to be only 0.05 to 0.005 times as effective as PGE2 in the in vivo gerbil colon assay for smooth muscle contracting activity. 11-Deoxy-11-oxaprostaglandin Eg, and its C-15 epimer, have been described by Hannessian et al., and by Vlattas /t al. (Tetrahedron l0 Letters, 46, 3983'[1974] and ibid, 5l/52 4451 [1974]); however no pharmacological properties were disclosed for these compounds. X0-Phenyl-17,18,19,20-tetranorprostaglandins of the E-series are disclosed, for example, in West German Offenlegungsschrift No. 2,154,3θ9· It is the principal object of this invention to provide novel prostaglandin compounds of the formula I (I) the pharmaceutically-acceptable salts thereof, the enantiomers thereof, ahd the pharmaceutically-acceptable salts of the enantiomers thereof; wherein one of R and R is hydrogen and the other one 1 2 of R and R is hydroxy; is carboxy,, the ester derivatives thereof or 5tetrazolyl; - 5 W represents a single bond or a cis double bond; Ζ ΓβρΓβθρηΐΒξ a single bond or a trans double bond; and R is hydrogen, fluorine, chlorine, methyl, methoxy or trifluoromethyl.

Also to be considered within the scope of this invention are esters of the compounds of the formula I and the enantiomers thereof, wherein 2 is carboxy. Typical examples of such esters are alkyl, having one to four carbon atoms, phenyl, substituted phenyl, benzyl, substituted benzyl, cyclopentyl a'nd cyclohexyl esters, especially alkyl esters having from one to four carbon atoms and 4-biphenylyl esters.

The compounds of this invention, are useful for lowering blood pressure in mammals, especially man.

As will be appreciated by one skilled in the art, the compounds of the formula I possess three centers of asymmetry (three asymmetrically-substituted carbon atoms). Throughout this specification, broken line attachment of a substituent to the tetra-hydrofuran ring of a compound of the formula I, and all other tetrahydrofuren derivatives, is intended to indicate that the substituent is below the plane of the tetrahydrofuran ring. Such attachment is also referred to as the α-configuration. Conversely, solid line attachment of a substituent to the tetrahydrofuran ring of the tetrahydrofuran compounds of this invention is intended to indicate attachment of that substituent above the plane of the 5-membered ring. This latter attachment is also known as the β-configuration. As written above, therefore, compounds of the formula I have the same absolute configurations at C-8 and C-12 as the naturally-occurring prostaglandins, and they are named as derivatives of prostanoic acid. Compounds of the formula X having absolute configurations at C-8 and C-12, both of which are the reverse of - 6 those found, in the naturally-occuring prostaglandins are named as derivatives of the enantiomer of prostanoic acid, which is called entprostanoic acid and is depicted as follows: In the compound of the formula I, wherein R1 is hydrogen 12 and R is hydroxy, the carbon atom to which R and R are attached has 'the ’same absolute configuration as found in naturally-occurring PGE^ and PGE2. In line with common IO prostaglandin stereochemical notation, such a compound is said to have (the jiydroxy group in the a-configuration.

In one method according to the invention, the compounds 12 3 of the formula I, wherein R , R , Q and R are as previously defined, W represents a cis double bond and Z represents a Ij trans double bond, are prepared by the method outlined in Scheme A. According to Scheme A, the compound of the formula II is< condensed with the anion of a phosphonate ester of the formula wherein R^ is as previously defined, to give the a,β-unsaturated ketone of the formula III. Reduction of the compound of the formula III with lithium triethylborohydride in tetrahydrofuran gives the compound of the formula IV, as a mixture of epimers. The compound of the formula IV is converted into the compound of the formula V, wherein R^ is a hydroxy protecting group which is easily removed under mildly acidic conditions (e.g. 2-tetrahydropyranyl, 2-tetrahydrofuranyl, l~ethoxyethyl or t-butyldi- Ί methylsilyl) and then the compound of the formula V is reduced with diisobutylaluminium hydride, to give the hemiacetal VI. Condensation of the hemiacetal VI with the ylid derived from the reaction of two molar equival5 ents of sodium methylsulfinylmethide and a phosphonium salt of the formula [(c6hs)3 - P- ch2 - CH2 - CH2 - ch2 - Q]+y- VIII IX 773 - 8 wherein Q is as previously defined and Ύ is chlorine or bromine, in dimethyl sulfoxide, affords the compound of the formula VII. The compound of the formula VII is then oxidized to the corresponding compound VIII. Although a variety of oxidizing agents known in the art for oxidizing secondary alcohols to ketones can be used, a particularly convenient reagent is chromic acid in acetone (Jones reagent ). In a typical procedure, a solution of the compound of the formula VII in acetone is treated with approximately the stoichiometric amount of the oxidant, at 0° to -20°C.

The reaction is complete within 5 minutes to 1 hour. Any excess oxidant is then decomposed, for example using isopropanol, and the product is isolated by the usual procedure of solvent extraction.

In the final step of Scheme A, the protecting group is removed by treatment of the compound of the formula VIII with acid, under mild conditions. A particularly convenient protecting group for R^ ie the 2-tetrahydropyranyl group, and its removal can be effected by treating the compound of the formula VIII with aqueous acetic acid at or about 25°C. The reaction usually takes several hours substantially to reach completion, e.g. from 10 to 40 hours.

As indicated hereinbefore, the reduction of the compound of the formula III to the compound of the formula IV produces a mixture of epimers at the carbon atom which ultimately becomes C-15 in the compound of the formula IX. Accordingly, operation of Scheme A as shown above produces *3 a mixture of a compound of the formula I,wherein 2 and R are as previously defined, W represents a cis double bond, 2 Z represents a trans double bond, R is hydrogen and R is hydroxy, and the corresponding compound wherein R1 is 2 hydroxy and. R is hydrogen. This mixture can be separated, and the pure isomers isolated, by chromatography on silica 1 2 gel. The isomer wherein R is hydroxy and R is hydrogen (i.e. C-15 hgs the (R)-configuration) is the less polar of the two isomers, and it is eluted from the column before 1 2 the isomer wherein R is hydrogen and R is hydroxy.

In an alternate procedure for obtaining the individual 5 epimers represented by the formula XX, the epimeric mixture IV can be separated into its individual components, and then each isomer is individually carried through the steps IV—^V, V-^VI, VI-J-V1I, VII-^VIII and of Scheme A.

As shown above, Scheme A depicts the preparation of the 12 3 compounds of the formula I, wherein R , R , 2 and R are as defined previously, W represnets a cis double bond and Z represents a trans double bond, having absolute configurations at C-8 and C-12 corresponding to those in the naturally occurring prostaglandins (i.e. derivatives of prostanoic acid). The enantiomers of these compounds (i.e. derivatives of ent-prostanoic acid) are prepared in an analogous fashion, but using the compound of the formula X (the enantiomer of II) as the starting material for Scheme A. 0—< a 'CHO In one method according to the invention, the compounds 3 of the formula I, wherein R , R , Q and R are as defined previously, W represents a single bond and Z represents a trans double bond, are prepared by the process outlined in Scheme B. - 10 Scheme Β Step 1 of Scheme B is a hydrogenation reaction, and it is usually carried out by stirring or shaking a solution of the compound of the formula VIII under an atmosphere of hydrogen, or hydrogen mixed with an inert diluent such as nitrogen or argon, in the presence of a catalytic amount of an appropriate metal catalyst. Typical metal catalysts which can be used are rhodium, palladium and platinum, with the preferred agent being palladium. Convenient solvents are lower alkanols such as methanol and ethanol, ethers such as diethyl ether and tetrahydrofuran and low molecular weight esters such as ethyl acetate and hutyl acetate. The hydrogenation is usually conducted at or about atmospheric pressure, and at or about -20&C. The palladium catalyst is conveniently used in the fprrn pf a 10% suspension on carbon and is usually present in an amount from 10 to SO weight-percent based on the compound of formula IX. As will be appreciated by one skilled in the art, Step 1 of Scheme B involves select20 ive reduction of the Cg-Cg double bond in the presence of the C13-Cu double bond. Accordingly, it is necessary to minitor the hydrogen uptake, and to interrupt the hydrogenation when approximately one molecular equivalent of hydrogen has been absorbed. Also it is advantageous to use a group 7 7 3 - 11 with large steric bulk for R4 in order to increase the selectivity. The hydrogenated product is usually recovered simply by removing the catalyst by filtration, and then removing the solvent by evaporation in vacuo. The product can be purified by chromatography using silica gel.

Step 2 of Scheme B involves removal of the hydroxy prottecting group R4, and it is carried out in the manner as described previously for conversion of a compound of the formula VIII into a compound of the formula IX.

As will be appreciated by one skilled in the art, Scheme B can be carried out using a starting material which is a mixture of epimers at C-15, or with either of the individual epimers. The configuration of C-15 will not change during either of the steps of Scheme B. Alternatively, if the com•5 pound of the formula XII, wherein R and 2 are as defined previously, is prepared as a mixture of epimers, this mixture can be separated into the individual isomers by chromatography using silica gel.

Additionally, if one carries out Scheme B, but one starts with the enantiomer of the compound of the formula VIII, this will produce the enantiomer of the compound of the formula XII.

In a variation of the method for preparing a compound of 12 3 the formula I, wherein R , R , Q and R are as defined previously, W represents a single bond and Z represents a trans double bond, a compound of the formula VTI can be selectively hydrogenated using the method described for Step 1 of Scheme B. The 9-hydroxy group in the product thus obtained is then oxidized to a 9-oxo group, and then the protecting group R4 is removed, using the techniques described earlier for the last two steps of Scheme A. This affords the desired compound of the formula I, wherein W represents a single bond and Z represents a trans double bond. - 12 Γη one method according to the invention, the compounds 12 3 of the formula I, wherein R , R , .Q and R are as defined previously, W represents a cis double bond and Z represents a single bond, are prepared by modification of Scheme A which involves adding an additional step to Scheme A. Said additional step involves hydrogenation of the double bond of a compound of the formula IV or V before converting that intermediate into the next compound as depicted in Scheme A. The hydrogenation is carried out in the same manner as described earlier for the hydrogenation of a compound of the formula VIII (Scheme B), except that the hydrogenation is preferably conducted at about 2S°C. When preparing a compound of the for12 3 mula I, wherein R , R , Q and R are as defined previously, W represents a cis double bond and Z represents a single bond, by the said modification of Scheme A, it is usually advantageous to separate the epimers at the carbon atom which becomes C-15 before carrying out the hydrogenation step.

Preparation of the compounds of the formula I, wherein 12 3 R , R , 2 and R are as defined previously and W and Z each represent a single bond are also prepared by addition of an additional step to Scheme A. In this case, both of the double bonds in a compound of the formula VII or VIII are hydrogenated before conversibn into a compound of the formula VIII or IX, respectively. Alternatively, both double bonds are hydrogen25 ated in the final product IX. The hydrogenation is conducted by the method previously described (Step 1 of Scheme B), except that two molar equivalents of hydrogen are required, and the hydrogenation is preferably conducted at about 25°C.

The starting materials for the preparation of the novel compounds of this invention are the compound of the formula IT and its enantiomer (X). The compound of the formula II is prepared by the published procedure. See: Lourens and Koekmer, Tetrahedron Letters, 43, 3719 (1975), and West German Offenlegungsschrift No. 2,436,332. The compound of formula X is prepared from the isopropylidene derivative of - 13 D-glyceraldehyde (XIII), by the method outlined in Scheme C.

Scheme C CH=CH-COOCH3 XIV s XCHO X Condensation of isopropylidene-D-glyceraldehyde with the anion of dimethyl methoxycarbonylmethylphosphonate affords the a,β-unsaturated ester XIV. The ester XIV is then reacted with lithium divinylcuprate, to give the vinylated derivative XV as a mixture of epimers at the newly-introduced asymmetric carbon atom (C-l of the propionate side chain). The compound of the formula XV is purified via hydrolysis with aqueous sodium hydroxide followed by reesterification using diazomethane, and then it is trated with aqueous acetic acid.

This causes removal of the isopropylidene protecting group, and recyclization, to give the lactone XVX, contaminated with the epimer having the reverse stereochemical configuration at C-3. Treatment of the crude lactone XVI with 3-chloroperbenzoic acid and a trace of trifluoroacetic acid, at -10°C, affords the bicyclic lactone XVII. Although the lactone XVII 7 7 3 - 14 is contaminated by the epimer having the reverse orientation of the hydroxy-mQthy], group at C-2, it is a single isomer at C-3 and C-4j with absolute stereochemistries as shown.

Finally, Pfitzer-Moffat oxidation of the hydroxymethyl com5 pound XVTI, affords the required lactone-aldehyde, X, contaminated by the epimer having the formyl group in the endo configuration. The lactone-aldehyde X so-produced is suitable for use in preparing the enantiomers of the compounds of the formula I, by the methods previously described.

As will be appreciated by one skilled in the art, use of the isopropylidene derivative of L-glyceraldehyde (the enantiomer of XIII) as the starting material for Scheme C leads to the preparation of the lactone-aldehyde II rather than the lactone-aldehyde X. , The phosphonate esters of the formula (ch3o)2-po-ch2-co-ch2and the phosphonium salts of the formula [(C6H5^3 “ P - CiI2 GH2 “ CH2 ~ CH2 * Q]+Y”’ wherein R , 2 and Y are as defined previously are either known compounds, which are prepared by the published procedures, or they are homologues or analogues of known compounds, which are prepared by analogous procedures. See further: West German Offenlegungsschrift No. 2,334,945: Journal of The American Chemical Society, 91. 5675 (1969); and United States Patent No. 3,953,466.' It has been explained hereinbefore that the compounds of 12 3 the formula I, wherein R , R , Q R , W and Z are as previously J defined are prepared from the lactone-aldehyde of the formula II. In like manner, the enantiomers of the compounds of the 4S773 - 15 12 3 formula I, wherein R , R , Q, R , W and Z are as previouslydefined, are prepared from the enantiomer of the lactonealdehyde of the formula II, i.e. the lactone-aldehyde of the formula X. As will be appreciated by one skilled in the art, it is alsp possible to operate the synthetic schemes outlined hereinbefore using an equimolar mixture of the compound of the formula II and the compound of the formula X (i.e. using racemic starting material). This leads to a racemic mixture of the compound of the formula I and its enantiomer.

By virtue of the acidic nature of the group Q, the compounds of the formula I and the enantiomers thereof will form salts with base, and all such pharmaceutically-acceptable salts are to be considered to be within the scope of this invention. Salts which are of particular value are alkali metal salts, alkaline earth metal salts, as well as salts formed from organic amines. Especially valuable salts are the sodium, potassium and magnesium salts.

The salts of the compound of the formula I and the enantiomers thereof are prepared by standard techniques for prostaglandin compounds. Such techniques include contacting the acidic and basic components, usually in a 1:1 molar ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. They are then recovered by filtrat25 ion, by precipitation followed by filtration, by evaporation of the solvent, or, in the case of squeous solutions, by lyophilization, as appropriate. Bases which are suitably employed in salt formation include ammonia, organic amines, alkali metal hydroxides, carbonates, biearbonates, hydroxides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxides. Representative examples of such bases are primary amines, such as n-propylamine, abutylamine, aniline, cyclohexylamine, benzylamine, p-toluidine and octylamirie; secondary amines, such as diethylamine, ΐ ί - 16 N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethylamine, Ν,Ν-dimethylaniline, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo [4-3.0]non-5-ene; hydroxides, such as sodium hydroxide, pot5 assium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides, such ps spdium ethoxide, potassium ethoxide and magnesium ethoxide; hydrides, such as calcium hydride and I sodium hydride; carbonates, such as potassium carbonate and sodium carbonate; and bicarbonates, such as sodium bicarbon10 ate and potassium bicarbonate.

Also embraced within the scope of this invention are esters of the compounds of the formula I, and the enantiomers thereof, wherein 2 is carboxy. Said esters can be prepared directly from the appropriate corresponding compound of the formula I, or its enantiomer, wherein 2 is carboxy, using standard methods for esterifying prostaglandin-type compounds. For example, alkyl (containing one to four carbon atoms) esters can be prepared using the appropriate diazoalkane, and phenyl or substituted phenyl esters can be prepared by coupling of the compound of the formula I, or its enantiomer, wherein 2 is carboxy, with the appropriate phenol in the presence of dicyclohexyl carbodiimide.

As indicated hereinbefore, the compounds of the formula I 12 3 and their enantiomers, wherein R , R , R , 2» W and Z are as defined previously, are useful as hypotensive agents for lowering blood pressure in mammals, especially humans.

When used as hypotensive agents, the compounds of this invention can be administered alone, or, preferably, in combination with pharmaceutically-acceptable carriers or dil30 uents, in accordance with standard pharmaceutical practice for the administration of prostaglanin-type compounds. For example, the compounds can be administered orally, rectally, - 17 intravaginally or parenterally. For oral use they are formulated, for example, as tablets, capsules, solutions or suspensions. For rectal or intravaginal use they are formulated as suppositories. For parenteral use, which includes intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredient are prepared, with the pH of the solution being adjusted and controlled by the addition of buffering agents.

When the compounds of this invention are used in humans, the dosage will be selected by the prescribing physician, and it will vary depending on the age, weight and response of the individual patient, as well as the particular use and the route of administration. However, the hypotensive agents of this invention will normally be administered at a dosage of 0.01 to 1.0 mg, per kilogram of body weight per day, in single or divided doses.

The following Examples and Preparations are provided solely for the purpose of further illustration. Infared (lR) spectra were measured on solutions in chloroform, and diagnostic absorption bands are reported in wave numbers (cm 1). Nuclear magnetic resonance spectra were measured at MHz for solutions in deutero-chloroform (CDCl^Jjand peak positions are expressed in parts per million (ppm) downfield from tetramethyl silane. The following abbreviations for peak shapes are used: s, singlet; d, doublet; t, triplet; q, quartet; and m, multiplet.

EXAMPLE 1 9-Oxo-15 ξ-hydroxy-l6-(3-tolyl)-ll-deoxy-ll-oxa-17,18,19) 20-tetranor-cis-5-6rans-l3-ent-prostadienoic Acid A solution of 150 mg. of 9-οχο-15ξ - (tetrahydropyran-2yloxy)-]6-(3-tolyl)-ll-deoxy-ll-oxa-17,18,19,20-tetranor-cis5-trans-l3-ent-prostadienoic acid in 15 ml. of 65:35 mixture of glacial acetic acid-water was stored at 25°C for 12 hours, - 18 and then it was evaporated in vacuo. The resultant oil was purified by column chromatography on silica gel using mixtures of diethyl ether and ethyl acetate as eluent. This afforded 25 mg. of 9-οχο-15ξ—hydroxy-l6-(3-tolyl)-ll-deoxyll-oxa-17,18,19 »20-tetranor-cis-5-trans-13-ent-prostadienOic acid.

The NMR spectrum of the product showed absorptions at 7.00 (s, 4H,) 5.83 (m,4H), 5.33 (m,2H), 3.95 (t, 1H) and 2.20 (s,3H) ppm.

J. EXAMPLE 2 The tetrahydropyranyl protecting group is removed from the ent-prostanoic acid derivatives, the prostanoic acid derivatives, the 2-decarboxy-2-(5-tetrazolyl)-ent- prostanoic acid derivatives and the 2-decarboxy-2-(5-tetrazolyl)prostanoic acid derivatives of Preparation l6 by acid-catalyzed hydrolysis, according to the procedure of Example 1. This affords: 9-ΟΧΟ-15 ξ-hydroxy-l6-phenyl-ll-deoxy-ll-oxa-17,18,19, 20-tetranor-cis-5-trans-13-ent-prostadienoic acid, 9-oxo-15 £-hydroxy-16-(2-chlorophenyl)-11-deoxy-11-oxa17,18,19,20-tetranor-cis-5-trans-l3-ent-prostadienoic acid, 9-0X0-15 5- hydroxy-16-(3-methoxyphenyl)-11-deoxy-l1oxa-17,18,19.20-tetranor-cis-5-trans-13-ent-prostadienoic acid, 9-oxo- Ι5ξ - hydroxy-l6-(4-trifluoromethylphenyl)-lldeoxy-ll-oxa-17, l8, IQ .20-tetranor-cj_s.-5-trans-13-entpropadienoic acid, - 19' 9-0X0-15 £-hydroxy-l6-phenyl-l1-deoxy-l1-oxa-17,18,19, 20tetr anor-cis-5-tr ans-13-prostadienoic acid, 9-OXO-15 έ -hydroxy-l6-(3-fluorophenyl)-ll-deoxy-ll-oxa17.18.19.20- tetranor-cis-5-trans-13-prostadienoic acid. 9-oxo-15^ -hydroxy-l6-(4-chlorophenyl)-ll-deoxy-ll-oxa17.18.19.20- tetranor-cis-5-trans-13-prostadienoic acid. 9-0x0-15 t,-hydroxy-16-(2-tolyl)-1l-deoxy-ll-oxa-17,18,19,20-tet ranor-cis-5-trans-13-prostadienoic acid, 9-0X0-15 £-hydroxy-l6-(4-methoxyphenyl)-ll-deoxy-ll-oxa1q 17.18.19.20-tetranor-cis-5-trans-13-prostadienoic acid, 9-0x0-15 I -hydroxy-l6-(3-trifluoromethylphenyl)-ll-deoxyll-oxa-17,18,19,20-tetranor-cis-.5-trans-13-prostadienoic acid, 9-0x0-15 £-hydroxy-2-(5-tetrazolyl)-16-(3-tolyl)-2-decar15 boxy-1l-deoxy-ll-oxa-17,18.19.20-tetranor-cis-5-trans13-ent-prostadienoic acid, 9-0X0-15 £ -hydroxy-2-(5-tetrazolyl)-l6-phenyl-2-decarboxy11-deoxy-ll-oxa-17,18,19,20-tetranor-cis-5-trans-l3ent-prostadienoic acid, 9-0X0-15 £-hydroxy-2-(5-tetrazolyl)-16-(2-chlorophenyl)2-decarboxy-11-deoxy-11-oxa-l6,18,19,20-tetranor-cis5-trans-13-ent-prostadienoic acid, 9-0X0-15 £-hydroxy-2-(5-tetrazolyl)-l6-phenyl-2-decarboxyll-deoxy-ll-oxa-17,l8,19,20-tetranor-cis-5-trans-1325 prostadienoic acid, 9-OXO-15 £-hydroxy-2-(5-tetrazolyl(-16-(3-fluorophenyl)-2decarboxy-11-deoxy-l1-oxa-l7,18,19120-tetranor-cis-5trans-13-prostadienoic acid, - 20 9-oxo-15 g-hydroxy-2-(5-tetrazolyl)-16-(2-tolyl)-2decarboxy-11-deoxy-11-oxa-17,18,19,20-tetranorcis-5-trans-13-prostadienoic acid, 9-oxo-15?-hydroxy-2-(5-tetrazolyl)-16-(4-mefchoxyphenyl)5 2-decarboxy-ll-deoxy-ll-oxa-17,18,19,20-tetranor-cis5-trans-l1-proafcadienoic acid and 9-0X0-15 5-hydroxy-2-(5-tefcrazolyl)-l6-(4“fcrifluoromethylphenyl)-2-decarboxy-l1-deoxy-ll-oxa-17,18,19,20-tetranorcis-5-trans-l3-prostadienoic acid, respectively.

EXAMPLE 3 9-0x0-15 ζ-hydroxy-16-(3-tolyl)-11-deoxy-ll-oxa-17,18,19,20-tetranor-trans-l3-ent-prostenoic Acid.

Acid-catalyzed hydrolysis of 9-oxo-15ξ-(tetΓahydropyΓan15 2-yloxy)-l6-(3-tolyl)-ll-deoxy-ll-oxa-17,l8,19,20-tetranortrans- 13-ent-prostenoic acid, using the procedure of Example 1 affords the title compound.

EXAMPLE 4 The products of Preparation l6 are hydrogenated using the 20 procedure of Preparation 17, and then they are hydrolyzed according to the procedure of Example 1. This affords: 9-oxo-15C-hydroxy-l6-phenyl-l1-deoxy-ll-oxa-17,18,19,20tetranor-trans-13-ent-prostenoic acid, 9-oxo-15 ξ-hydroxy-16-(2-chlorophenyl)-11-deoxy-11-oxa-17 25 18,19,20-tetranor-trans-l3-ent-prostenoic acid, 9-oxo-15 ξ-hydroxy-l6-(3-methoxyphenyl)-11-deoxy-11-oxa17,18,19,20-tetranor-trans-l3-ent-prostenoic acid, 57 7 3 - 21 9-oxo-15ξ-hydroxy-16-(4-trifluoromethylphenyl)-11deoxy-ll-oxa-17,l8,19,20-tetranor-trans-l3-entprostenoic acid, 9-0X0-15 ξ-hydroxy-l 6-phenyl-l 1-deoxy-Tl-OXa-l 718j19.20-tetranor-trans-l3-prostenoic acid, 9-oxo-15 ξ-hydroxy-l6-(3-fluorophenyl)-11-deoxy-1l-oxa17,18,19,20-tetranor-trans-l3-prostenoic acid, 9-oxo-15 ξ-hydroxy-16-(4-chlorophenyl)-11-deoxy-11-oxa17,18,19,20-tetranor-trans-l3-prostenoic acid, 9-oxo-15C-hydroxy-l6-(2-tolyl)-ll-deoxy-ll-oxa-17,18,19“ 20-tetranor-trans-l3-prostenoic acid, 9-oxo-l5 ξ-hydroxy-16-(4-methoxyphenyl)-11-deoxy-11-oxa17,18,19,20-tetranor-trans-l3-prostenoic acid, 9-0X0-15 ξ-hydroxy-l6-(3-trifluoromethylphenyl)-11deoxy-ll-oxa-17,18,19,20-tetranor-trans-l3-prostenoic acid, 9-oxo-15g-hydroxy-2-(5-tetrazolyl-l6-(3-tolyl)-2-decarboxy11-deoxy-11-oxa - 17.18,19,20-tetranor-trans-l3-entprostenoic acid, 9-oxo-l5 ?-hydroxy-2-(5-tetrazolyl)-16-phenyl-2-decarboxy-ll-deoxy-ll-oxa-17,18,19,20-tetranor-trans-l3-entprostenoic acid, 9-Oxo-l55-hydroxy-2-(5-tetrazolyl)-l6-(2-chlorophenyl)2-decarboxy-ll-deoxy-ll-oxa-17,18,19,20-tetranor-trans13-ent-prostenoic acid, 9-oxo-l5 £-hydroxy-2-(5-tetrazolyl)-l6-phenyl-2-decarboxy-lldeoxy-11-oxa-17,18,19,20-tetranor-trans-13-prostenoic acid, 3 7 7 3 - 22 9-oxo-15^ -hydroxy-2-(5-tetrazolyl)-16-(3-fluorophenyl)2-decarboxy-ll-deoxy-ll-oxa-17,18,19.20-tetranor-trans13-prostenoic acid, 9-0x0-15 ί -hydroxy-2-(5-tetrazolyl)-l6-(2-tolyl)-2-decar5 boxy-11-deoxy-11-oxa-17,18,19,20-tetranor-trans-13prostenoic acid, 9-oxo-157 -hydroxy-2-(5-tetrazolyl)-16-(4-methoxyphenyl)2-decarboxy-l1-deoxy-ll-oxa-17,18,19,20-tetranor-trans13-prostenoic acid and 9-0x0-15£-hydroxy-2-(5-tetrazolyl)-16-(4-trifluoromethylphenyl)-2-decarboxy-l1-deoxy-ll-oxa-17,18,19,20-tetranor trans-13-prostenoic acid, respectively.

EXAMPLE 5 9-Oxo-lS £ -hydroxy-l6-(3-tolyl)-ll-deoxy-ll-oxa-17,18,19,20-tetranor-cis-5-ent-prostenoic Acid. - (4P — Hydroxy - 2a - [3^ -fcetrahydropyran- 2 - yloxy) -4-(3- tolyl)but - 1 - yl]tetrahydrofuran - 3β - yl)acetic acid γ-lactone is carried through the following steps: (a) reduction with diisobutylaluminium hydride according to the procedure of Preparation 11; (b) condensation with ylid derived from (4-carboxybutyl)triphenylphosphonium bromide or (4-[5-tetrazolyl]-n-butyl)triphenylphosphonium bromide (as appropriate) according to the procedure of Preparation 13; (c) oxidation with chromic acid according to the procedure of Preparation 15; and (d) acid-catalyzed hydrolysis according to the procedure of Example 1. This produces the title compound.

In like manner, the 2-(4-hydroxy-2-[3£-^etrahydropyran-2- 23 45773 yloxy)-4-phenylbut-l-yl]tetrahydrofuran-3-yl)acetic acid γ-lactone and 2-(4-hydroxy-2-[3£-tetrahydropyran-2-yloxy4-(substituted phenyl)but-l-yl]tetrahydrofuran-3-yl)-acetic acid γ-lactone compounds of Preparation 19 are carried through steps (a), (b), (c) and (d) above. This produces the following compounds. 9-0X0-15 f-hydroxy-16-phenyl-l1-deoxy-ll-oxa-17,18,19,20-tetranor-cis-5-ent-prostenoic acid, 9-oxo-15 ft-hydroxy-16-(2-chlorophenyl)-11-deoxy-11-oxa17,18,19,20-tetranor-cis-5-ent-prostenoic acid, 9-0X0-15 ft-hydroxy-16-(3-methoxyphenyl(-11-deoxy-ll-oxa17.18.19.20- tetranor-cis~5-ent-protenoic acid, 9-oxo-lS £-hydroxy-l6-(4-trifluoromethylphenyl)-ll-deoxy11 -oxa-17,l8,19,20-tetranor-cis-5-ent-prostenoic acid 9-0x0-15 -hydroxy-l6-phenyl-ll-deoxy-ll-oxa-17,l8,19»20tetranor-cis-5-prostenoic acid, 9-0X0-15 ft -hydroxy-l6-(3-fluorophenyl)-ll-deoxy-ll-oxa17.18.19.20- tetranor-cis-5-prostenoic acid, 9-0X0-15 f-hydroxy-16-(4-chlorophenyl)-11-deoxy-11-oxa17, 18,19.20-tetranor-cis-5-prostenoic acid, 9-0X0-15 ft-hydroxy-16-(2-tolyl)-11-deoxy-l1-oxa-17>18,19, 20-tetranoll-cis-5-prostenoic acid, 9-0X0-15 ft -hydroxy-16-(4-methoxyphenyl)-11-deoxy-l1-oxaw-tetranor-cis-5-prosfenoic acid, 9-0X0-15 ft -hydroxy-16-(3-trifluoromethylphenyl)-11-deoxy11-oxa-17,18,19,20-tetranor-cis-5-prostenoic acid, 7 7 3 9-oxo-l5 -hydroxy-2-(5-tetrazolyl)-16-(3-tolyl)-2decarboxy-1l-deoxy-ll-oxa-17,18,19,20-tetranor-cis5-ent-prostenoic acid, 9-0X0-15 C -hydroxy-2-(5-tetrazolyl)-16-(phenyl-2-decar5 boxy-1l-deoxy-ll-oxa-17,18,19,20-tetranor-cis-5-entprostenoic acid, 9-0x0-15 I -hydroxy-2-(5-tetrazolyl)-l6-(2-chlorophenyl)2-decarboxy-ll-deoxy-ll-oxa-17,18,19,20-tetranor-cis5-ent-prostenoic acid, 9-0X0-15 /-hydroxy-2-(5-tetrazolyl)-l6-phenyl-2-decar~ boxy-1l-deoxy-ll-oxa-17,18,19,20-tetranor-cis-5-prostenoic acid, 9-0X0-15 / -hydroxy-2-(5-tetrazolyl)-16-(3-fluorophenyl)-2decarboxy-ll-deoxy-ll-oxa-17,18,19,20-tetranor-cis-515 prostenoic acid, 9-0X0-15 £-hydroxy-2-(5-tetrazolyl)-16-(2-tolyl)-2decarboxy-11-deoxy-11-oxa-17,18,19,20-tetranor-cis5-prostenoic acid, 9-0x0-15 £, -hydroxy-2-(5-tetrazolyl)-l6-(4-methoxhyphenyl)20 2-decarboxy-ll-deoxy-ll-oxa-17,18,19,20-tetranor-cis5-prostenoic acid, and 9-OXO-15 k-hydroxy-2-(5-tetrazolyl)-16-(4-trifluoromethylphenyl)-2-decarboxy-ll-deoxy-ll-oxa-17,18,19,20tetranor-cis-13-prostenoic acid, respectively.

EXAMPLE 6 9-0xo-15 /-hydroxy-16-(3-tolyl)-1l-deoxy-ll-oxa-17,18,19,20tetranor-ent-prostanoic Acid - 25 A suspension of 200 mg. of 10% palladium-on-carbon in 30 ml. of ethanol is stirred under an atmosphere of hydrogen, at atmospheric pressure and at 25°C., until hydrogen uptake ceases. A solution of 1.0 g. of 9-°x°-15^ -hydroxy-16-(3tolyl)-11-deoxy-11-oxa-17.18.19.20-tetranor-cis-5-ent-prostadienoic acid in 5 ml. of ethanol is added at 25°C. The hydrogenation is continued at 25°C. until two molar equivalents of hydrogen have been absorbed. The filtered reaction mixture is evaporated in vacuo, to give the title compound.

EXAMPLE 7 The products of Example 2 are hydrogenated according to the procedure of Example 6. This produces: 9-0X0-15 £-hydroxy-16-phenyl-l1-deoxy-ll-oxa-17,18,19,20tetranor-ent-prostanoic acid. 9-0X0-15 C-hydroxy-l6-(2-chlorophenyl)-11-deoxy-1l-oxa17, 18, 19.20-tetranor-ent-prostanoic acid, 9-0X0-15 I -hydroxy-16-(3-methoxyphenyl)-11-deoxy-l1-oxa17,18,19 j 20-tetranor-ent-prostanoic acid, 9-0x0-15 £ -hydroxy-16-(4-trifluoromethylphenyl)-ll-deoxy11-oxa-17.18.19.20-tetranor-ent-prostanoic acid, 9-0X0-15 £ -hydroxy-16-phenyl-l1-deoxy-ll-oxa-17,18,19,20tetranorprostanoic acid, 9-0X0-15 έ-hydroxy-l6-(3-fluorophenyl)-ll-deoxy-ll-oxa17j18,19,20-tetranor-prostanoic acid, 9-0X0-15 £-hydroxy-l6-(4-chlorophenyl)-ll-deoxy-ll-oxa17,18,19,20-tetranor-prostanoic acid, 43773 - 26 9-oxo1-15?-hydroxy-16-(2-tolyl)-11-deoxy-l1-oxa-17,18, l^,20-tetranorprostanoic acid, 9-0X0-15 £-hydroxy-l6-(4-methoxyphenyl)-ll-deoxy-ll-oxa17,18,19,20-tetranor-prostanoic acid, 9-oxo-15^ -hydroxy-l6-(3-trifluoromethylphenyl)-11-deoxy-l1oxa-17,18,19,20-tetranorprostanoic acid, 9-0X0-15 £-hydroxy-2-(5-tetrazolyl)-l6-(3-tolyl)-2dec arboxy-11-deoxy-11-oxa-17,18,19,2 O-tetranor-entprostanoic acid, 9-0X0-15 £-hydroxy-2-(5-tetrazolyl)-l6-phenyl-2-decarboxy11-deoxy-ll-oxa-17,18,19,20-tetranor-ent-prostanoic acid, 9-0x0-15 £-hydroxy-2-(5-tetrazolyl)-l6-(2-chlorophenyl)2-decarboxy-11-deoxy-11-oxa-17,18,19,20-tetranor-entprostanoic acid, 9-0X0-15 2 -hydroxy-2-(5-tetrazolyl)-l6-phenyl-2-decarboxy-11-deoxy-11-oxa-17,18,19,20-tetranorprostanoic . acid, 9-0x0-15 ( -hydroxy-2-(5-tetrazolyl)-16-(3-fluorophenyl)2-decarboxy-ll-deoxy-ll-oxa-17,18,19,20-tetranorprost20 anoic acid, 9-0X0-15? -hydroxy-2-(5-tetrazolyl)-16-(2-tolyl)-2decarboxy-ll-deoxy-ll-oxa-17,18,19,20-tetranorprostanoic acid, 9-0X0-15 £-hydroxy-2-(S-tetrazolyl)-l6-(4-methoxyphenyl)2 5 2-decarboxy-11-deoxy-1l-oxa-17,18,19,20-tetranorprostanoic acid, and 9-0X0-15 2-hydroxy-2-(5-tetrazolyl)—16—(4-trifluoromethylphenyl)-2-decarboxy-ll-deoxy-ll-oxa-17,18,19,20-tetran- 27 orprostarioic acid, respectively.

EXAMPLE 8 Sodium 9-0X0-15 £-hydroxy-l6-phenyl-ll-deoxy-ll~oxa5 17,18,19,20-tetranor-cis-5-trans-13-prostadienoate A solution of 3.58 g. (0.01 mole) of 9-oxo-15f-hydroxyl6-phenyl-ll-deoxy-11-oxa-17,18,19.20-tetranor-cis-5-trang13-prostadienoic acid in 50 ml. of methanol is mixed with a solution of 540 mg· (0.01 mole) of sodium methoxide in 10 ml. of methanol at 0°C. The mixture is allowed to warm to 25°C., and then the solvent is removed by evaporation in vacuo This affords fche title compound.

Preparation 1 Methyl 3-(2,2-Dimethyl-4-dioxolanyl)acrylate (XIV) To an ice-cold, vigorously stirred solution of 97.0 g. (0.370 mole) of l,2:5,6-diisopropylidene-D-mannitol in 800 ml. of ethyl acetate was added, in portions, lead tetraacetate until a solution gave a'blue color when tested with starch-iodine paper (163*0 g. of 90$ lead tetraacetate were required). The mixture was stirred for an additional 5 minutes, and then it was filtered. The filtrate was concentrated to a yellow oil which was distilled. The fraction boiling between 51 and 57°O· at ca. 10 mm of Hg pressure was collected. It weighed 71*7 g., and it contained 63 mole-percent of isopropyl25 idene-D-glyceraldehyde and 37 mole-percent of acetic acid as judged by NMR.

To a stirred suspension of 36.5 g (0.76 mole) of a 50$ dispersion of sodium hydride in mineral oil in 1,200 ml. of tetrahydrofuran, was added dropwise 138.Og (0.76 mole) of dimethyl methoxycarbonylmethylphosphonate. The resulting mixture was stirred for 60 minutes, and then the isopropylidene4 5'? 7 3 - 28 D-glyceraldehyde-acetic acid mixture prepared above was added dropwise. The reaction mixture was stirred an additional 25 minutes, and then 250 ml. of water were added. The bulk of the tetrahydrofuren was removed by evaporation under reduced pressure, and the residual aqueous phase was extracted with ethyl acetate. The combined extracts were dried (MgSO^), and concentrated to a yellow oil which was distilled. The fraction boiling between 67° and 70°C, (0.1 nun of Hg) was collected, affording 71·θ S· of the title compound as a clear, colorless liquid.

Preparation 2 Methyl 3-Vinyl-3-(2,2-Dimethyl-4-dioxolanyl)propionate (xv) To a solution stirred under nitrogen at 0°C. of 10.54 g. (l67 mmole) of diisopropylsulfide and 10.26 g. (53.6 mmole) of cuprous iodide in 40 ml. of dry diethyl ether,was added 43-0 ml. (IO3.4 mmole) of a 2.4 M solution of vinyllithium in diethyl ether. The rate of addition was controlled such that the reaction temperature did not exceed 30°C. The reaction mixture was stirred at 25°C. for 30 minutes, and then a solution of 5 g. (26.8 mmole) of methyl 3-(2,2-dimethyl 4-dioxolanyl)acrylate in 30 ml. of diethyl ether was added dropwise, below 45°C. The reaction mixture was stirred at. ca. 25°C. for 30 minutes, and then it was poured into 100 ml. of saturated ammonium chloride solution which had been buffered to pH 8 with ammonium hydroxide. Approximately 100 ml. of ethyl acetate were added and the two-phase system was filtered. The organic phase was removed, the aqueous phase was further extracted with ethyl acetate, and then the combined ethyl acetate phases were washed with a further quantity of saturated ammonium chloride buffered to pH 8 with ammonium hydroxide. Finally the ethyl acetate solution was dried, filtered and concentrated to give 13.4 g. of the title produce in crude form. - 29 Purification of the product: A solution of 6.08 g. of the methyl 3-vinyl-3-(2,2dimethyl-4-dioxolanyl)-propionate prepared as described above in 32.,2 mi. of 1.0N sodium hydroxide and l6 ml. of ethanol was stirred at room temperature for 17 hours, under nitrogen. At this point the solvents were removed by evaporation in vacuo, and the residue was washed several times with diethyl ether. The ether washings were combined and extracted with water. The aqueous extract was combined with the residue which had been washed with diethyl ether. To the aqueous solution thus obtained was added 50 ml. of ethyl acetate, and tjhe two-phase system was cooled to 0°C. The two-phase system was then acidified to pH 4·5 with 6N hydrochlric acid and stirred at pH 4·5 and 0°C. for an additional minutes. After the layers had been allowed to separate, the ethyl acetate was removed and the aqueous layer was extracted with further ethyl acetate. The combined ethyl acetate solutions were dried (MgSO^J and evaporated, giving 3-vinyl-3-(2,2-dimethyl-4-dioxolanyl)propionic acid as a yellow oil weighing 2.35 g.

The 2.35 g. of 3-vinyl-3-(2,2-dimethyl-4-dioxolanyl) propionic acid obtained above was dissolved in 10 ml. of diethyl ether, and the solution so obtained was added dropwise to a solution of 23.5 mmole of diazomethane in ether.

The reaction mixture was stirred for 10 minutes, and then glacial acetic acid was added dropwise until the evolution of nitrogen ceased. The resulting ethereal solution was washed with saturated sodium bicarbonate solution, dried (MgSO^) and concentrated. This afforded 2.30 g. of methyl 3-vinyl-3-(2,2-dimethyl-4-dioxolanyl)propionate as a yellow oil. 4S773 - 30 Preparation 3 ' cis-3-Vinyl-4-hydroxymethyl-γ-butyrolactone (XVI) A solution of 19.8 g. of methyl 3-vinyl-3-(2,2-dimethyl-4dimethyl-4-dioxolanyl)-propionate in 150 ml. of a 65:35 mix5 ture of glacial acetic apid-water was stirred at room temperature for 17 hours. The solution was then evaporated in vacuo. The residue was dissolved in benzene, which was then removed by evaporation. The process of gddipg benzene and removing it by evaporation was repeated several times in order to eliminate the last traces of acetic acid. This afforded a dark residue which was purified by column chromatography on 400 g. of silica gel, using mixtures of diehloromethane and ether as eluent. Concentration of the appropriate fractions afforded the title compound as clear, light yellow oil, weighing 8.10 g.

The product was analyzed by vapor phase chromatography.

This showed that the product consisted of 84$ of the compound of the formula XVI (Scheme C), and 16$ of the epimer in which the stereochemistry of the vinyl group at C-3 is reversed.

The two diastereomers were separated by chromatography, and their specific rotations at the D-line of sodium were measured. The compound of the formula XVI showed +77·3 (c=l; CHClj.); its C-3 epimer showed 5 (c=lj CHClj).

Preparation 4 2-(4p-Hydroxy-2-hydroxymethyltetrahydrofuran-3β-yljacetic Acid γ-Lactone (XVIl) A solution <£ 3.65 g. of the 84:16 mixture of isomers of 3-vinyl-4-hydroxy methyl γ-butyrolactone obtained in Preparation 3, 11.6 g. of 3-chloroperbenzoic acid and 0,12 ml. of trifluoroacetic acid, in 250 ml. of chloroform, was heated under reflux under nitrogen for 20 hours. At this point, the - 31 solvent was removed by evaporation and the residue was dissolved in 100 ml. of water. The aqueous solution was filtered, washed with diethyl ether and then evaporated in vacuo. The residue was purified by chromatography on 200 g. of silica gel, using diethyl ether and diethyl ether-ethyl acetate mixtures as eluent. Concentration of the appropriate fractions afforded the title product as a mixture of epimers at C-2. The yield was 2.62 g. (76%).

Preparation 5 2-(4.p-Hydroxy-2-formyltetrahydrofuran-3p-yl)acetic Acid γ-Lactone To a solution, stirred under nitrogen, of 3.0 g. of 2-(4βhydroxy-2-hydroxy-methyltetrahydrofuran-30-yl)acetic acid γlactone and 12.1 g. of dicyclohexylcarbodiimide in 100 ml. of benzene, containing 2.74 ml. of dimethyl sulfoxide, was added 4-03 g, of pyridinium trifluoroacetate. The mixture was stirred for one hour at room temperature, and then 100 ml. of ethyl acetate was added. The mixture was filtered, and the filtrate was concentrated in vacuo to a yellow oil which was extracted with water. The aqueous solution thus obtained was lyophilized, affording 2.03 g. of the title product, as its hydrate. The product is a mixture of epimers at C-2.

The NMR spectrum of the product showed absorptions at .10 (m, 2H), 4.00 (m, 5H), and 2.83 (m, 3H) ppm.

Preparation 6 2-(4fi-hydroxy-2q-r 3-oxo-4-(3-tolyl)-trans-l-buten-l-ylltetrahydrofuran-3p-yljacetic Acid γ-Lactone To 7·16 g. (28 mmole) of dimethyl 2-oxo-3-(3-tolyljpropyl phosphona te in 150 ml. of tetrahydrofuran was added 993 mg. (25.7 mmole) of sodium hydride, under nitrogen, at 25°C. - 32 After 50 minutes, a solution of 2.03 g. (ll.7 mmole) of 2-(4p-hydroxy-2a-formyltetrahydrofuran-3β-yl)acetic acid γ-lactone in 5 ml. of tetrahydrofuran was added dropwise during 10 minutes. After 30 minutes, the reaction mixture was acidified with 3 ml. of glacial acetic acid, and then diluted with an excess of ethyl acetate. The ethyl acetate solution was washed with 50 ml. of saturated sodium bicarbonate, followed by 50 ml. of brine, dried using anhydrous sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel, giving 470 mg. of 2-(4βhydroxy-2 a-[3-oxo-4-(3-tolyl)-trans-1-buten-1-yl]tetrahydrofuran-3-R-yl)aeetic acid γ-lactone.

The NMR spectrum of the product showed absorptions at 7.10 (m, 4H), 5.15 (m, IH), 4-40 (t, IH), 4.15 (d, 2H), 3-90 (2, 2H) and 2.43 (s, 3H) ppm. The IR spectrum of the product (CHClg solution) showed absorption bands at 1775, 1715, 1675 and I63O cm-1.

Preparation 7 Condensation of 2-(4P-hydroxy-2(j-formyltetrahydrofuran20 3p-yl)acetic acid γ-lactone with the anion derived from dimethyl 2-oxo-3-phenyl-propylphosphonate, or the appropriate dimethyl 2-oxo-3-(substituted phenyl)-propylphosphonate, according to the procedure of Preparation 6, affords the follow ing compounds: 2-(40-hydroxy-2a-[3-oxo-4-phenyl-trans-l-butyl-l-yl]tetrahydrofuran-3p-yl)acetic acid γ-lactone, 2- (4β-1ιγ0Γοχγ-2<ι-[ 3-oxo-4- (2-chlorophenyl )-trans-l-butenl-yl]tetrahydrofuran-3p-yl)acetic acid γ-lactone, 2-(4p-hydroxy-2a-[3-oxo-4-(3-methoxyphenyl )-trans-lbuten-l-yl]tetrahydrofuran-3-p-yl)acetic acid γlactone and - 33 2-(4P-hydr0xy-2a-[3-oxo-4-(4-trifluoromethylphenyl)-trans -1-buten-l-ylJ tetrahydrofuran-33~yl)acetic acid-y-lactone, respectively, Xn like manner, condensation of 2-(4a-hydroxy2p-formyltetrahydrofuran-3a-yl)acetic acid γ-lactone with the anion derived from dimethyl-2-oxo-3-phenyl-propylphosphonate or the appropriate dimethyl 2-ΟΧΟ-3-(substituted phenyl)propylphosphonate, according to the procedure of Preparation 6, affords the following compoundsi 2-(4a-hydroxy-2p-[3-oxo-4~phenyl-trans-l-buten~l-yl]tetrahydrofuran-3a-yl)acetic acid γ-lactone, 2-(4a-hydroxy-2 β-[3-oxo-4-(3-fluorophenyl)-trans-lbuten-l-yl]tetrahydrofuran-3a-yl)acetic acid γ-lactone, 2-(4a-hydroxy-2p-[3-oxo-4-(4-chlorophenyl)-trans-l-butenl-yl)tetrahydrofuran-3a-yl)acetic acid γ-lactone, 2-(4α-1ιγΰΓοχγ-2β-[3-oxo-4-(2-tolyl) -tr ans-1-buten-1-yl1tetrahydrofuran-3a-yl)acetic acid γ-lactone 2-(4a-hydroxy-2p-[3-oxo-4-(4-methoxyphenyl)-trans-1-butenl-yl]tetrahydrofuran-3a-yl)acetic acid γ-lactone and 2-(4a-hydroxy-2p-[3-oxo-4-(3-trifluoromethylphenyl)-trans 1-buten-1-yl]tetrahydrofuran-3a-yl)acetic acid γlactone, respectively.

Preparation 8 2-(4p-Hydroxy-2a-[3 / -hydroxy-4-(3-tolvl)-trans-l-butenl-yl]tetrahydrofuran-3p-yl)acetic Acid γ-Lactone To a solutionof 47θ mg. (1.64 mmole) of 2- (4(3-hydroxy-2a- 34 [3-oxo-4-(3-tolyl)-trans-1-buten-1-yll(.etrahydrofuran-3Byl)aeetic acid γ-lactone in 17 ml. of tetrahydrofuran, cooled to -78°C. and under a nitrogen atmosphere, was added 1.64 ml. (1.64 mmole) of a 1.0 M solution of lithium tri5 ethylborohydride in tetrahydrofuran. After stirring at -78°C. for 30 minutes, the reaction mixture was quenched with 2 ml. of a 9:1 mixture of water-acetic acid. The mixture thus obtained was evaporated in vacuo and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, following by brine, dried using anhydrous sodium sulfate, and then concentrated in vacuo. The residue was purified by column chromatography using 50 g. of silica gel and using dichloromethane-ethyl acetate (2:l) as eluent. This afforded 250 mg. of 2-(48~hydroxy-2a-(3£—hydroxy-415 (3-tolyl)-trans-l-buten-l-yl1-acetic acid γ-lactone.

The NMR spectrum of the product showed absorptions at 7.10 (m, 5H), 5-75 (m, 2H), 5.10 (q, IH), 4-15 (m, 3H) and 2.15 (s, 3H) ppm. The IR spectrum (CHC1„ solution) showed -1 3 absorption bands at 1770 and 970 cm • ί The product is a mixture of epimers at C-3 of the 3hydroxy-4-(3-tolyl)-trans-l-buten-1-yl side chain.

Preparation 9 ν 1 Reduction of each of the 2-(4-hydroxy-2-[3-oxo-4-phenyltrans-1-buten-1-yl1-tetrahydrofuran-3-vl)acetic acid γ25 lactone and 2-(4rhydroxy-2-[3-oxo-4-(substituted phenyl)trans-1-buten-1-yl]tetrahydrofuran-3-vllacetic acid γ-lactone compounds of Preparation 7 with lithium triethylborohydride in tetrahydrofuran, according to the procedure of Preparation 8, affords the following congeners: - 35 2-(4f!-hydroxy-2a-(3 7 -hvdroxv-4-phenyl-trans-1-buten-1yl]tetrahydrofuran-3p-yl)acetic acid γ-lactone, 2-(4p-hydroxy-2a-[3 2-hydroxy-4-(2-chlorophenyl-trans1-buten-1-yl]tetrahydrofuran-3β-ylJacetic acidy-lactone, 2-(4p-hydroxy-2a-[3 £ -hvdroxy-4-(3-methoxyphenyl)-transl-buten-l-yl]tetrahydrofuran-3p~yl)acetic acid γ-lactone and 2-(4p-hydroxy-2a-(3 % -hydroxy-4-(4-trifluoromethylphenyl)trans-buten-1-yl1-tetrahydrofuran-3β-yl)acetic acid γ-lactone, 2-(4«-hydroxy-2p-[3 Ϊ -hydroxy-4-phenyl-trans-1-buten-1yl]tetrahydrofuran-3a-yl)acetic acid γ-lactone, 2-(4a-hydroxy-2p-[3£ -hydroxy-4-fluorophenyl)-trans-lbuten-l-yl]tetrahydrofuran-3a-ylJacetic acid γ-lactone, 2-(4a-hydroxy-2β-[3 i -hydroxy-4-(4-chlorophenyl)-transl-buten-l-yl]tetrahydrofuran-3a-yl)acetic acid γ-lactone, 2-(4a-hydroxy-2p-[3 £ -hydroxy-4-(2-tolyl)-trans-l-butenl-yl]tetrahydrofuran~3a-yl)acetic acid γ-lactone, 2-(4a-hydroxy-2β-[3 £ -hydroxy-4-(4-methoxyphenyl)-transl-buten-l-yl]tetrahydrofuran-3a-yl)acetic acid γlactone and 2-(4a-hydroxy-2β-[3£ -hydroxy-4-(3-trifluoromethylphenyl)trans-l-buten-l-yl]tetrahydrofuran-3iY-yl)acetic acid γ-lactone, respectively. 7 7 3 - 36 Preparation 10 2-(4B-hydroxy-2a-[3$ -tetrahydropyran~2-yloxy)-4-(3tolyl )-trans-l-buten-l-yl1tetrahydrofuran-3β-yl)acetic Acid γ-Lactone To a solution of 250 mg. (0.868 mmole) of 2-(4β-hydroxy2a-[3 -hydroxy-4-(3-tolyl)-trans-l-buten-l-yl1tetrahydrofuran-3 β-yl )ace tic acid γ-lactone in S ml of diehloromethane, containing 0.125 ml. of dihydropyran, was added 5 mg. of 4toluenesulfonic acid. The solution was stirred at ca. 25°C. for 30 minutes, and then it was dilute with 50 ml. of ether. The ether solution was washed with sodium bicarbonate solution, followed by brine, dried (Na2S04) and concentrated in vacuo to yield the title compound.

The IR spectrum of the product showed absorption bands at 1770 and 970 cm-1.

Preparation 11 2-(4p-Hydroxy-2a-[31 ~(tetrahydropyran-2-yloxy)-4-(3tolyl)-trans-l-buten-l-yl1tetrahydrofuran-3e-vl)acetaldehyde γ-Hemiacetal To a solution of 456 mg. of 2-^-hydroxy-2a-[3 £-(tetrahydropyran-2-yloxy)-4-(3-tolyl-trans_-l-buten-l-yl]tetrahydrofuran-3 β-yl )acetic acid γ-lactone in 10 ml. of toluene, cooled to -78°C under an atmosphere of dry nitrogen, was added dropwise, 1.23 ml. of a 20% solution of diisobutylaluminium hydride in n-hexane. The reaction mixture was stirred at -78°C. for 45 minutes, and then anhydrous methanol was added until gas evolution ceased. The reaction mixture was allowed to warm to 25°C., diluted with an excess of diethyl ether and then it was washed with 50% sodium potassium tartrate. The - 37 4 5 7 73 dried ether solution was evaporated in vacuo giving 500 mg. of crude product. This crude product was purified by column chromatography on silica gel, eluting with diethyl etherethyl acetate (lsl). This afforded 250 mg. of the title compound.

Preparation 12 Each of the 2-(4-hydroxy-2-[3 -hvdroxv-4-phenyl-transl-buten-l-yl]tetrahydrofuran-3-ylAcetic acid γ-lactone and 2(4-hydroxy-2-[3f -hydroxy-4(substituted phenyl)-trans-l-buten10 l-yl]tetrahydrofuran-3-yl)acetic acid γ-lactone compounds of Preparation 9 is reacted with tetrahydropyran according to the procedure of Preparation 10, and then it is reduced with diisobutylaluminium hydride according to Preparation 11.

This affords:15 2-(40-hydroxy-2ot-[3 2-(tetrahydropyran-2-yloxy)-4-phenyltrans-l-buten-l-yl~1-tetrahydrofuran-3 β-ylAcetaldehyde γ-hemiacetal, 2-(4p-hydroxy~2a-[3^-(tetrahydropyran-2-yloxy)-4-(220 chlorophenyl)-trans-l-buten-l-yl) tetrahydrofuran-3βyl)acetaldehyde γ-hemiacetal, 2-(4 p-hydroxy-2«-[3 (tetrahydropyran-2-yloxy)-4-(3methoxyphenyl)-trans-1-buten-1-yl1tetrahydrofuran3β-ylAcetaldehyde γ-hemiacetal, 2-(40-hydroxy-2ct-[3 (tetrahydropyran-2-yloxy)-4-(4trifluoromethylphenyl-trans- buten-1-yl]tetrahydrofuran-3p-ylAcetaldehyde γ-hemiacetal, 2-(4a-hydroxy-2p-[3 (tetrahydropyran-2-yloxy)-4-phenyl4 3 7 7 3 -38trans-buten-l-ylj-fcetrahydrofuran-3a-ylJacetaldehyde γ-hemiacetal, 2-(4a-hydroxy-2p-[3(tetrahydropyran-2-yloxy)-4-(3fluorophenyl)-trans-buten-l-yl1tetrahydrofuran-3a-yl)5 acetaldehyde γ-hemiacetal, 2-(4a-hydroxy-2p-[3 £-(tetrahydropyran-2-yloxy)-4-(4chlorophenyl)-ty ans-buten-1-yl]tetrahydrofuran-3 π-yl)acetaldehyde γ-hemiacetal 2-(4a-hydroxy-2j3-[3 (tetrahydropyran-2yloxy)-4-(210 tolyl)-trans-buten-l-yl]-tetrahydrofuran-3a-yl)acetaldehyde γ-hemiacetal, 2- (4a-hydroxy-2p-[ 3I- (be.trahydropyran-2-yloxy)-4- (4methoxyphenyl)-trans-buten-l-yl1tebrahydrofuran-3aylJacetaldehyde γ-hemiacetal and 2-(4a-hydroxy-2p-[3 ζ-(tetrahydropyran-2-yloxy)-4-(3trifluoromethylphenyl)-trans-1-buten-1-yljtetrahydrofuran-3a-yl)acetaldehyde γ-hemiacetal, respectively.

Preparation 13 9p-Hydroxy-15-tetrahydropyran-2-yloxy-l6-(3-tolyl)-11deoxy-11-oxa-17,18,19,20-tetranor-cis-5-trans-13-entprostadienoic acid To a solution of 948 mg (2.13 mmole) of(4-carboxy-butyl) triphenylphosphonium bromide in 5 ml. of dimethyl sulfoxide, under dry nitrogen, was added 2.26 ml. (4.l8 mmole) of a 1.85 M solution of sodium methylsulfinylmethide in dimethyl sulfoxide. To this solution was then added, dropwise a solution of 260 mg. (0.695) mmole) of 2-(40-hydroxy-2aΓ 3$-(tetrahydropyran-2-yloxy)-4-(4-tolyl)-trans-l-buten-1- 39 yl]tetrahydrofuran-33-yl)acetaldehyde-Y-hemiacetal in 5 ml. of dimethyl sulfoxide. The reaction mixture was stirred for 24 hours and then it was poured onto an excess of icewater. The aqueous solution thus obtained was washed twice with ethyl acetate, and then it was acidified to pH 3 using 10$ hydrochloric acid. The acidic solution was extracted with ethyl acetate, and the combined extracts were washed with brine, dried (Na2S04) and evaporated in vacuo to a solid residue. The latter residue was purified by column chromatography on silica gel, using mixtures of diethyl ether and ethyl acetate as eluent. This afforded 330 mg. of the title compound.

The IR spectrum of the product (CHCl, solution) showed — 1 a strong absorption band at 1720 cm .

Preparation 14 Reaction of the appropriate 2-(4-hydroxy-2-[3^-tetrahydropyran-2-vloxv)-4-phenvl-trans-buten-1-yl]tetrahydrofuran-3yl)acetaldehyde γ-hemiacetal or 2-(4-hydroxy-2-[3^-(tetrahydropyran-2-yloxy)-4-(substituted phenyl)-trans-buten-lyl]tetrahydrofuran-3-yl)acetaldehyde γ-hemiacetal of Preparations 11 or 12, with the ylid from either (4-carboxybutyl)triphenylphosphonium bromide or (4-[.5-tetrazolyl]butyl)triphenylphosphonium bromide, according to the procedure of Preparation 13, affords: β-hydroxy-15^-(tetrahydropyran-2-yloxy)-16-phenyl11-deoxy-11-oxa-17,18,19.20-tetranor-cis-5-trans-l3ent-prostadienoic acid, 9β-hydroxy-15 ζ-(tetrahydropyran-2-yloxy)-16-(2-chlorophenyl )-11-deoxy-ll-oxa-17,18,19,20-tetranor-cis-5trans-13-ent-prostadienoic acid, 9p-hydroxy-l5^-(tetrahydropyran-2-yloxy)-l6-(3-methoxy4 5773 - 40 phenyl)-ll-deoxy-ll-oxa-17,18,19,20-tetranor-cis5-trans-13-ent-prostadienoic acid, β-hydroxy-15 <$-[tetrahydropyran-2-yloxy)-16-(4-trifluoromethylphenyl)-11-deoxy-ll-oxa-17,18,19,205 tetranor-cis-5-trans-13-ent-prostadienoic acid. 9a-hydroxy-15^- (tetrahydropyran-2-yloxy)-16-phenyl-11deoxy-1l-oxa-17,18,19,20-tetranor-cis-5-trans-13prostadienoic acid, 9a-hydroxy-15£-(tetrahydropyran-2-yloxy)-16-(3-flu.oro10 phenyl)-11-doexy-ll-oxa-17,18,19,20-tetranor-cis-5trans-13-prostadienoic acid, 9a-hydroxy-15^-(tetrahydropyran-2-yloxy)-16-(4-chlorophenyl )-11-deoxy-11-oxa-17,18,19,20-tetranor-cis-5-trans 13-prostadienoic acid, 9a-hydroxy-15^-(tetrahydropyran-2-yloxy)-l6-(2-tolyl)11-deoxy-l1-oxa-17,18,19 j20-tetranor-cis-5-trans-13 prostadienoic acid, 9a-hydroxy-15^-(tetrahydropyran-2-yloxy)-l6-(4-methoxyphenyl)-11-deoxy-l1-oxa-17,18,19,20-tetranor-cis-520 trans-13-prostadienoic acid, 9a-hydroxy-15i.-(tetrahydropyran-2-yloxy)-l6-(S-trifluoromethyl)-11-deoxy-11-oxa-17,18,19,20-tetranor-cis-5trans-13-prostadienoic acid, 9β-hydΓOxy-15(-(tetrahydropyran-2~yloxy)-2~(5-'tetra25 zolyl)-16-(3-tolyl)-2-decarboxy-l1-deoxy-ll-oxa-17,18, 19,20-tetranor-cis-5-trans-13-ent-prostadienoic acid 9β-1ινΰΓοχν-15ί-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl) -l6-phenyl-2-decarboxy-ll-deoxy-ll-oxa-17,18,19,20tetranor-cis-5-trans-13-ent-prostadienoic acid, 57 7 3 -419β-hydroxy-154-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl )-16-(2-chlorophenyl)-decarboxy-11-deoxy-ll-oxa17, l8, 19,20-tetranor-cis-5-trans-13-ent-prostadienoic acid, 9ct-hydroxy-l5i-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl )-16-phenyl-2-decarboxy-l1-deoxy-ll-oxa-17,18, 19.20-tetranor-cis-5-trans-13-prostadienoic acid, 9a-hydroxy-l5 ζ-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl )-)6-(3-fluorophenyl)-2-decarboxy-l1-deoxy-lΙΙΟ oxa-17,l8,19,20-tetranor-cis-5-trans-13-prostadien0ic acid, 9a-hydroxy-l5 i;-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl) -16-(2-tolyl)-2-decarboxy-l1-deoxy-ll-oxa-17,18,19,20tetranor-cis-5-trans-13-prostadienoic acid, 9a-hydroxy-15ii-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl)-16-(4-methoxyphenyl)-2-decarboxy-11-deoxy-11oxa-17 j18,19 < 20-tetranor-cis-5-trans-13-prostadienolc acid and 9a-hydroxy-l5^-(tetrzihydropyran-2-yloxy)-2-(5-tetrazol20 yl)-l6-(4-trifluoromethylphenyl)-2-decarboxy-ll-deoxy-1l-oxa-17,l8,19,20-tetranor-cis-5-trans-13-prostadienoic acid, respectively.

Preparation 15 9-Oxo-15^-(tetrahydropyran-2~yloxy)-l6-(3-tolyl)-lldeoxy-1l-oxa-17,18,19,20-tetranor-cis-5-trans-l3ent-nrostadienoic acid To a solution, cooled to -10°C., under nitrogen of 184 mg. (0.402 mmole) of 9β - hydroxy -15? - (tetrahydropyran 43773 - 42 2 - yloxy) - 16 - (3 - tolyl) - 11 - deoxy - 11 - oxa 17,18,19,20 - tetranor - cis - 5 - trans - 13 - ent prostadienoic acid in 6 ml. of acetone, is added dropwise 0.16 ml.'(0.442 mmole) of chromic acid. The reaction mix5 ture was stirred for 3 minutes at -10°C., 1 drop of isopropanol was added and stirring was continued for an additional 5 minutes at -40°C. At this point, the reaction mixture was diluted with 30 ml. of ethyl acetate, and the solution obtained was washed with water, dried (NagSO^) and concentrated in vacuo. This afforded 150 mg. of the title product, which was used without further purification.

The chromic acid used in this Preparation was prepared according to the method described by Djerassi, Journal of Organic Chemistry, 21. 1547 (1956).

Preparation 16 The 9β - hydroxy - 15 ^-(tetrahydropyran - 2 - yloxy) l6 - phenyl - 11 - deoxy - 11 - oxa - 17,18,19,20 tetranor - cis - 5 - trans - 13 - ent - prostadienoic acid, the 9β - hydroxy - 15 ij - (tetrahydropyran - 2 - yloxy) - 16 20 substituted phenyl) - 11 - deoxy - 11 - oxa - 17,18,19,20 tetranor - cis - 5 - trans - 13 - ent - prostadienoic acids, the 9a - hydroxy - 15 -trans-13-piOStadienoic acids of Preparation 14 are oxidized according to the procedure of Preparation 15· This affords: 9-0X0-15 k-(tetrahydropyran-2-yloxy)-l6-phenyl-ll-deoxy30 11-oxa-17,18,19,20-tetranor-cis-5-trans-13-ent-prostadienoic acid, 9-0X0-15 -(tetrahydropyran-2-yloxy)-l6-(2-chlorophenyl)- 43 11 - deoxy-1l-oxa-17.18,19,20-tetranor-cis-5-trans-13ent-prostadienoic acid, 9-0X0-15(tetrahydropyran-2-ylxoy)-l6-(3-methoxyphenyl)11-deoxy-ll-oxa-17,18,19,20-tetranor-cis-5-trans-13-entprostadienoic acid, 9-0X0-15 9-oxo-l5 %- (tetrahydropyran-2-yloxy)-l6-phenyl-l1-deoxy-l1oxa-17,18,19,20-tetranor-cis-5-trans-13-prostadienoic acid, 9-oxo-15^-(tetrahydropyran-2-yloxy)-16-(3-fluorophenyl)11-deoxy-ll-oxa-17,18,19,20-tetranor-cis-5-trans-13prostadienoic acid, 9-0X0-15 <;-(tetrahydropyran-2-yloxy)-l6-(4-chlorophenyl)11-deoxy-l1-oxa-17,18,19.20-tetranor-cis-5-trans-l3prostadienoic acid, 9-oxo-l5£-(tetrahydropyran-2~yloxy)-l6-(2-tolyl)-ll-deoxy11-oxa-17,18,19,20-tetranor-cis-5-trans-13-prostadienoic acid, 9-oxo-15^-(tetrahydrppyran-2-yloxy)-l6-(4-methoxyphenyl)11-deoxy-11-oxa-17,18,19,20-tetranor-cis-5-trans-13prostadienoic acid, and 9-oxo-l5^- (tetrahydropyran-2-yloxy)-16-(3-trifluoromethyl)-11-deoxy-ll-oxa-17,18,19,20-tetranor-cis-5-trans13-prostadienoic acid, respectively.

In like manner, the 5-tetrazolyl compounds of Preparation 14 are oxidized according to the procedure of Example 15, to - 44 give: 9-OXO-15 £-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl)16-(3-tolyl)-2-decarboxy-l1-deoxy-ll-oxa-17,18,19,20tetranor-cis-5-trans-l3-ent-prostadienoic acid, 9-0X0-15i v(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl)l6-phenyl-2-decarboxy-l1-deoxy-11-oxa-17,18,19,20tetranor-cis-5-tran.s-13-ent-prostadien.oic acid, 9-0X0-15 't,-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl)10- (2-chlorophenyl)-2-decarboxy-ll-deoxy-ll-oxa10 17,18,19,20-tetranor-cis-5-trans-l'3-ent-prostadienoic acid, 9-oxo-15^-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl)16-phenyl-2-dec arboxy-11-deoxy-11-oxa-17,18,19,2 0tetranor-cis-5-trans-13-prostadienoic acid, 9-oxo-15^-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl)16-(3-fluorophenyl)-2-decarboxy-l1-deoxy-l1-oxa-,17,18, 19,20-tetranor-cis-5-trans-13-prostadienoic acid, 9-0X0-15 4-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl)16-(2-tolyl)-2-decarboxy-l1-deoxy-l1-oxa-17,18,19,2020 tetranor-cis-5-trans-13-prostadienoic acid, 9-oxo-l5$-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl)l6~(4-methoxyphenyl)-2-decarboxy-l1-deoxy-ll-oxa17, l8,19,20—tetranor—cis—5—trans—13—prostadienoic acid, and 9-oxo-15^-(tetrahydropyran-2-yloxy)-2-(5-tetrazolyl)16-(4-trifluoromethylphenyl)-2-decarboxy-l1-deoxy11- oza-17,18,19,20-tetranor-cis-5-trans-l3-prostadienoic acid, respectively. - 45 Preparation 17 9-Oxo-15^- (tetrahydropyran-2-yloxy)-l6-(3-tolyl)-11deoxy-1l-oxa-17,18,19,20-tetranor-trans-13-entprostadienoic Acid A suspension of 200 mg. of 10$ palladium-on-carbon in ml. of ethanol is stirred under an atmosphere of hydrogen, at atmospheric pressure and at -20°C., until hydrogen uptake ceases. A solution of 1.0 g. of 9 - oxo - 15 \-(tetrahydropyran - 2 - yloxy) - 16 - (3 - tolyl) - 11 - deoxy - 11 10 oxa - 17,18,19,20- tetranor - cis - 5 - trans - 13 - ent prostadienoic acid in 5 ml. of ethanol is added at - 20°C.

The hydrogenation is continued at -20°C. until one molar equivalent of hydrogen has been absorbed, The filtered reaction mixture is evaporated in vacuo, to give the title compound.

Preparation 18 2-(4|3-Hydroxy-2a~[3 4- (tetr ahydropyr an-2-yloxy )-4- (3tolyl)but- 1 - yl]tetrahydrofuran-3p-yl)acetic Acid γ-Lactone - (4[3 - Hydroxy - 2a - [3&- (tetrahydropyran - 2 20 yloxy) - 4 - (3 - tolyl) - trans - 1 - buten - 1 - yljtetrahydrofuran - 3(3 - yl)acetic acid γ-lactone is hydrogenated according to the procedure of Preparation 17, except that the action is conducted at 25°C. This affords the title product.

Preparation 19 The 2-(4- hydroxy - 2 - [3$- hydroxy -4 - phenyl trans - 1 - buten - 1 - yljtetrahydrofuran - 3 - yl)acetic acid γ-lactone and the 2-(4- hydroxy - 2 - [3^- hydroxy4 - (substituted phenyl) - trans - 1 - buten - 1 - yljtetra- 46 hydrofuran - 3 - yl)acetic acid γ-lactones of Preparation 9 are reacted with dihydropyran, according to the procedure of Preparation 10, and then they are hydrogenated according to the procedure of Preparation 18. This affords: 2-(4p-hydroxy-2a-(3^-(tetrahydropyran·-2-yloxy)-4phenylbut-l-yl]tetrahydrofuran-3p-yl)acetic acid γ-lactone, 2-(4p-hydroxy-2oc-[3 (tetrahydropyran-2-yloxy)-4-(2chlorophenyl)but-l-yl]-tetrahydrofuran-3p-yl)acetic acid γ-lactone, 2-(4p-hydroxy-2a-[3 (tetrahydropyran-2-yloxy)-4-(3methoxyphenyl)but-l-yl]tetrahydrofuran-3 β-yl)acetic acid γ-lactone, 2-(4B-hydroxy-2a-[3 (tetrahydropyran-2-yloxy)-4-(4trifluoromethylphenyl)but-l-yl]tetrahydrofuran-3βyl)acetic acid γ-lactone 2- (4a-hydroxy-23~(3 ij- (tetrahydropyran-2-yloxy)-4phenylbut-J.-yl]tetrahydrofuran-3a-yl)acetic acid γlactone, 2- (4α-1ιγ<ΐΓοχν-2β-[3 £- (tetrahydropyran-2-yloxy )-4-(3fluorophenyl)but-l-yl]-tetrahydrofuran-3a-ylJacetic acid- γ-lactone, 2-(4a-hydroxy-2B-[3^-(tetrahydropyran-2-yloxy)-4-(4chlorophenyl)but-l-yl]-tetrahydrofuran-3a-yl)acetio acid γ-lactone, 2(4α“hydΓoxy-2β-[3 S- (tetrahydropyran-2-yloxy)-4-(2tolyl)but-l-yl]tetrahydrofuran-3a-yl)acetic aeid γlactone 2-(4α-1ινΰΓθχν-2β-[3 (tetrahydropyran-2-yloxy)-4-(4methoxyphenyl)but-l-yl]tetrahydrofuran-3ot-yl)acetic /73 - 47 acid γ-lactone and 2-(4a-hydroxy-2p-(3^-(tetrahydropyran-2-yloxy)-4-(3trifluoromethylphenyl)but-l-yl]tetrahydrofuran-3ayl)acetic acid γ-lactone, respectively. 7 7 3 — 48 —

Claims (27)

1. A compound of the formula ....(I) the pharmaceutically-acceptable salts thereof, the enantiomers thereof, and the pharmaceutically-acceptable salts of the enantiomers thereof; 1 2 wherein one of R and R is hydrogen and the other is hydroxy; R is hydrogen, fluorine, chlorine, methyl, methoxy or trifluoromethyl; Q is carboxy, the ester derivatives thereof or 5tetrazolyl; W represents a single bond or a cis double bond; ·» \ and Z represents a single bond or a trans double bond.

2. A compound of claim T having the formula z (I) 4 5 7 7 3 - 49 and the pharmaceutically accpetable salts thereof, where 12 3 R , R , R , 2, W and Z are defined in claim 1.

3. A compound according to claim 2, wherein Q is carboxy.

4. A compound according to claim 3, wherein R 1 is hydrogen 2 5. And R is hydroxy.

5. A compound according to claim 4, wherein W represents a cis double bond and Z represents a trans double bond.

6. The compound according to claim 5, wherein R is hydrogen. 10

7. · A compound according to claim 4, wherein W represents a single bond and Z represents a trans double bond.

8. The compound according to claim 7 > wherein R is hydrogen.

9. A compound according to claim 4, wherein W represents a cis double bond and Z represents a single bond. 15

10. The compound according to claim 9, wherein R is hydrogen.

11. A compound according to claim 2, wherein Q is 5-tetrazolyl.

12. A Compound according to claim 11, wherein R 1 is hydro2 20 gen and R is hydroxy.

13. A compound according to claim 12, wherein W represents a cis double bond and Z represents a trans double bond.

14. The compound according to claim 13, wherein R is hydrogen.

15. A compound according to claim 12, wherein W represents 25 4 5 7 7 3 - 50 a single bond and Z represents a trans double bond.

10. The compound according to claim 15, wherein R is hydrogen.

17. A compound according to claim 12, wherein W represents 5 a cis double bond and Z represents a single bond,

18. The compound according to claim 17, wherein R is hydrogen.

19. A compound of claim 1 having the formula 10 and the pharmaceutically-acceptable salts thereof, where R 4 , 2 1 R , R , 2, W and Z are as defined in claim 1.

20. A compound according to claim 19, wherein Q is carboxy.

21. A compound according to claim 20, wherein W represents 3 double bond and Z represents a trans double bond.

11. 15 22. A compound according to claim 20, wherein W represents a single bond and Z represents a trans double bond,

23. A compound according to claim 20, wherein W represents a cis double bond and Z represents .a single bond.

24. A compound according to claim 19, wherein 2 is 5-tetra20 zolyl.

25. A compound according to claim 24, wherein W represents 4 5 7 7 3 - 51 a C J- S double bond and Z represents a trans double bond.

26. A compound according to claim 24, wherein W represents a single bond and Z represents a trans double bond.

27. A compound according to claim 24, wherein W represents 5 a cis double bond and Z represents a single bond. F. R. KELLY & CO. AGENTS FOR THE APPLICANTS.