DK144247B - 16-PHENOXY-OMEGA-TETRANOR PROSTAGLANDINES OF E-OR F-SERIES FOR USE AS FERTILITY CONTROLS - Google Patents

Description

(19) DENMARK

02) PRESENTATION WRITING ου 1 kk2kl B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 6010/73 (51) Int.CI.3 C 07 C 177/00 (22) Filing Day 7. November 1973 C 07 0 257/04 (24) Race day 7 · Nov. 1973 (41) Aim. available May 9, 1974 (44) Posted Jan 25 1 982 (86) International application no. - (86) International filing day - (85) Transfer day - (62) Master application no. -

(30) Priority Nov. 8 1972, 304813, US

(71) Applicant PFIZER INC., New York, US.

(72) Inventor Jasjit Singh Bindra, US: Michael Ross Johnson, US.

(74) Associate Engineer Hofman-Bang & Boutard.

(54) 1 6-Phenoxy-omega-tetranorprostaglan = E or F-series diner for use as a fertility control agent.

BACKGROUND OF THE INVENTION The present invention relates to novel 16-phenoxy-tetra-tetranorprostaglandins for use as fertility control agents, which are characterized in that they have the general formula I as set forth in the claim,

The prostaglandins are unsaturated C20 fatty acids which exhibit different physiological effects. For example, the prostaglandins' of the E and A series are potent vasodilators (Bergstrom et al., Acta J Physiol. Scand. 64: 332-33, 1965 and Bergstrom et al., Life Sci.

£ 6: 449-455, 1967) and lowers systemic arterial blood pressure (vasodepressure) by intravenous administration (Weeks and King. Federation * 2 144247

Proc. 23: 327, 1964; Bergstrom et al., 1965, op. cit .; Carlson et al., Acta Med. Scand. 183: 423-430, 1968; and Carlson et al.,

Acta Physiol. Scand. 75: 161-189, 1969). Another known physiological effect of PGE 2 and PGE 2 is as a bronchodilator (Cuthbert,

Brit. With. J. 4: 723-726, 1969).

Yet another important physiological role is played by the natural prostaglandins associated with reproduction. It is known that PGEg has the ability to induce labor (Karim et al., J. Obstet Gynaec, Brit. Gwlth. 77: 200-210, 1970), to induce therapeutic abortion (Bygdeman et al., Contraception, 4, 293 (1971)) and to be useful for controlling fertility (Karim, Contraception, 3, 1973 (1971)). Patents have been issued on several pro-staglandins of the E and F series as mammalian web developers (Belgian Patent No. 754,158 and West German Patent No. 2,034,641) and on PGF. ,, 1 * 2 ° S ^ 3 1 -1-1 control of reproduction (South African Patent No. 69/6089).

Further known physiological activities of PGE1 include inhibition of gastric acid secretion (Shaw and Ramwell, in: Worcester

Symp. on Prostaglandins, New York, Wiley, 1968, pages 55-64) and also of platelet aggregation (Emmons et al., Brit. Med. J. 2: 468-472, 1967).

It is now known that such physiological effects in vivo will only be produced for a short time after the administration of a prostaglandin. Extensive experience suggests that the reason for this rapid cessation of activity is that the natural prostaglandins are metabolically and rapidly deactivated by β-oxidation of the carboxylic acid side chain and by oxidation of the 15α-hydroxy group (Anggard et al., Acta. Physiol. Scand., 81 (396 (1971) and references cited therein).

Therefore, it was considered desirable to provide analogous compounds to the prostaglandins which had physiological activities equivalent to the physiological activities of the natural compounds, but in which the selectivity of the action and duration of activity would be increased. An increased selectivity of the effect would be expected to mitigate the serious side effects, especially the gastrointestinal side effects, which are frequently observed after systemic administration of the natural prostaglandins (see Lancet, 536, 1971).

Danish Patent Application No. 2362/72 discloses prostaglandin analogous compounds of the general formula 2 * 5 / A-CH-X-Y-R4 HO *

OH

wherein R 1 is hydroxymethyl, carboxy, alkoxycarbonyl of up to 11 carbon atoms, or 5- or J-substituted alkoxycarbonyl of 2 or 3 carbon atoms, wherein the substituent is dialkylamino, each alkyl group having 1-4 carbon atoms, pyrrolidino, piper 2 or morpholmo, R represents hydroxy or alkanoyloxy zp ^ having 1-4 carbon atoms and R R hydrogen, or R and R · together form an oxo group, A means ethylene or vinylene, X means alkylene having 1-3 carbon atoms optionally substituted, Y means O, S, SO or> N-alkyl having up to 4 carbon atoms, and R 4 means aryl, benzyl or furfuryl optionally substituted with halogen atoms or hydroxy, nitro or phenyl groups or alkyl, alkenyl, haloalkyl, , alkoxy, alkenyloxy or acylamino groups having 1-4 carbon atoms or dialkyl amino groups wherein each alkyl group has 1-3 carbon atoms, which compounds may optionally further have an alkyl group of up to 4 carbon atoms at the carbon atoms of 2-, 3- or 4-position, as well as pharmaceutically acceptable salts of the compounds wherein R R is carboxy. For these compounds are indicated activity as luteolytic agents, as stimulating agents for the uterine smooth muscle, as hypotensive agents or for relieving bronchospasm; therefore, they are believed to be useful as fermentation control agents.

The prostaglandin analogous compounds of the invention have been found to be more potent and more selective as fertility control agents than both PGE 1 and PGE 2 as well as the related compounds known from Danish Patent Application No. 2362/72.

4 144247

Preferred compounds of the invention are those of Formula I wherein R is hydrogen and the prostaglandin is PGEg, or PGFgp.

Further preferred compounds of the invention are those of Formula I wherein R is hydrogen, H is H or

"ΌΗ"% E

that line is an additional bond and X is -CONHR "where R" is methylsulfonyl.

Further preferred compounds of the invention are those of formula I wherein M is as defined in the claim, R is hydrogen, the dotted line is an additional bond, and X is tetrazolyl or -CONHR "where R" is acetyl or methylsulfonyl.

More preferred compounds are 1-phenoxy-β-tetranor-PGE 2 -β-biphenyl ester, 16-phenoxy-1β-tetranor-PGFβ-β-biphenyl ester and 16-phenoxy-1β-tetranor-PGF 2β-β biphenylester.

The starting materials for the preparation of the 16-phenoxy-β-tetranor-prostaglandins of the invention are available commercially or are prepared by methods well known to those skilled in the art. To prepare dimethyl 2-oxo-3-phenoxypropyl phosphonate, which is one of these starting materials, cf. Scheme A, a solution of dimethyl methyl phosphonate in tetrahydrofuran is cooled to -78 ° C in a dry nitrogen atmosphere and then added dropwise to butyllithium in hexane. After stirring, methyl 2-phenoxyacetate is added dropwise. After 3-4 hours at -78 ° C, the reaction mixture is warmed to room temperature, neutralized with acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in water, the aqueous phase is extracted in chloroform and the combined organic extracts are washed, dried and concentrated to give the desired product.

For the preparation of substituted compounds in the phenoxy group, correspondingly substituted phenoxyacetic acids are prepared which are prepared by condensing a corresponding substituted phenol with a haloacetic acid or haloacetic acid ester in the presence of base as described by J.M. Petersen, Acta Chem. Scandinavica, 5 ^ 519 (1951) or M. Beroza, Agri. Food Chem., 4, 49 (1956).

Thus, condensation of bromomethyl acetate with p-chlorophenol in the presence of sodium methoxide gives p-chlorophenoxyacetic acid.

These acids are converted to esters by the usual method and then to phosphonates as described above for the unsubstituted phenoxy starting compound.

6 U4247

SCHEDULE. A

^ 0-CH2C00CH3 -> ^ -CH2i-CH2i-0CH3 3 .Ι Ο '^ «3 β 4 / Ρί 5 7 144247

As shown in Scheme A, the first step in the complete synthesis (1 - 2) is the condensation of the corresponding ester of phenoxyacetic acid with a dialkyl methyl phosphonate to prepare the ketophosphonate 2. These esters are prepared as described above.

In 2-3, the ketophosphonate 2 is reacted with the known / Corey et al., J. Am. Chem. Soc., 93, 1491 (1971)] aldehyde H to prepare the enone 3 after chromatography or crystallization.

The enon 3 is reduced e.g. with zinc borohydride or with a trialkyl borohydride, such as lithium triethylborohydride, for a mixture of alcohols, 4 and 5, which is separated by column chromatography. In this reaction, ethers such as tetrahydrofuran or 1,2-dimethoxyethane are usually used as solvents, although methanol is sometimes preferred to ensure specificity of the reduction. Further conversion of 4 is shown in Scheme B.

4 -> 6 is a base catalyzed deesterification, thereby removing the protective p-biphenylcarbonyl group. This is conveniently carried out with potassium carbonate in methanol or a mixture of methanol and tetrahydrofuran. 6 -> 7 involves the protection of the two free hydroxy groups with an acid labile protecting group. Any sufficiently acid-labile group is satisfactory, but the most common is tetrahydropyranyl, which can be introduced into the molecule by treatment with dihydropyran and an acidic catalyst in anhydrous medium. The catalyst is usually p-toluenesulfonic acid.

8 U4247

SCHEME B

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8 is a reduction of lactone 7 to hemiacetal 8 using diisobutylaluminum hydride in an inert solvent, low reaction temperatures are preferred and temperatures from -60 to -70 ° C are usual. However, higher temperatures can be used if there is no over-reduction. The compound 8 is purified, if desired, by column chromatography.

8 - * 9 is a Wittig condensation whereby the hemiacetal 8 is reacted with (4-X-n-butyl) triphenylphosphonium bromide in dimethylsulfoxide in the presence of sodium methylsulfinylmethyl. Compound 9 is purified as above.

Conversion 9 -> 12 is an acidic hydrolysis of the tetrahydropyranyl groups. Any acid which does not cause degradation of the molecule during the removal of the protecting group may be used, but this is most often accomplished using 65 l of aqueous acetic acid. The product is purified as above.

9 - "10 is an oxidation of the secondary alcohol 9 to the ketone 10. This can be accomplished using any oxidizing agent which does not attack double bonds, but usually Jones' reagent is preferred. The product is purified as above. 1 -> 11 is carried out in the same way as 9 -> 12. The product is purified as above.

10 144247

Scheme C shows the preparation of precursors for reduced 16-phenoxy-Ul-tetranorprostaglandins.

Intermediates of type 21 are prepared by selectively reducing the 5,6-cis double bond at low temperature using either a homogeneous catalyst such as tris (triphenylphosphite) chloroform, or a heterogeneous catalyst such as platinum, palladium or rhodium. Particularly preferred for this reduction is the use of palladium-on-coal as a catalyst and a reaction temperature of -20 ° C. Intermediates of type 21 are precursors to 16-phenoxy-W-tetranor prostaglandins of the "1-row" along route 9 - * 12 of Scheme B.

SCHEME C

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THPO Η OTHP

21 i?

In addition, the 16-phenoxy-β-1 tranorpr ost aglandins of the E - and F - ^ series can be prepared directly from the corresponding prostaglandin analog of the "2-row" by first protecting the hydroxy group by introducing the dimethylisopropylsilyl groups, then selectively reducing the cis double bond and finally removing the protecting group.

The introduction of the protecting group is usually carried out by treating the prostaglandin analogue with dimethylisopropyl chlorosilane and triethylamine, the reduction is carried out as mentioned above for 9 - 21, and the removal of the protecting group is carried out by bringing the reduced protected compound into contact. U4247 with a mixture of acetic acid and water in a volume ratio of 5: 1 for 10 minutes, or until the reaction is substantially complete.

Where in the foregoing procedures purification is desired by chromatography, as appropriate chromatographic carriers may be mentioned neutral alumina and silica gel, and usually silica gel having a particle size of 0.074 - 0.250 mm is preferred. The chromatography is conveniently carried out in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane, as further elucidated in the following examples.

It will be seen that the above formulas depict optically active compounds. However, it will be appreciated that the corresponding racemates will exhibit valuable biological activity because of their content of the above biologically active optical isomer, and such racemates should be considered as encompassed by the formulas set forth in this specification and in the claims. The racemic mixtures are readily prepared by the same methods used to synthesize the optically active compounds simply by using corresponding racemic precursors instead of the optically active starting materials.

Numerous tests in vivo and in vitro have shown that the novel prostaglandin analogs have physiological activities comparable to those of the natural prostaglandins. These tests include, among others, a test for effect on isolated smooth muscle of guinea pig and rat uterus, guinea pig bronchospasm histamine-induced and effect on canine blood pressure, stress-induced ulceration in rats, inhibition of gastric acid and pepsin secretion, and rat secretion of collagen- or ADP-induced platelet aggregation and abortion-inducing activity in rats and guinea pigs by luteolytic and non-luteolytic mechanisms.

12 144247

The physiological responses observed in these tests are valuable in determining the utility of the test compound in treating various natural and pathological conditions. Such established uses include: smooth muscle activity (useful as antifertility agent, to induce labor and as an abortion inducer), and antifertility activity by a mechanism which does not affect smooth muscle, e.g. luteolytic mechanisms, and synchronization of the estrus cycle in farm animals.

The novel compounds of the invention have more selective activity profiles than the corresponding naturally occurring prostaglandins, and in many cases exhibit a longer duration of action. For example, 16-phenoxy-ii; -tetranorprostaglandin-E2, which exhibits a smooth muscle stimulating activity comparable to the activity of inactive to inhibit histamine-induced bronchospasm in guinea pigs. The 16-Phenoxy ->> tetranor prostaglandins PGE 1 and F 2 series exhibit similar smooth muscle stimulating activity. "Particularly useful for fertility control and abortion induction are the 16-phenoxy-U1-tetranorprostaglandins of the ^ 2 ~ r ^ 2p ~ series, based on particularly excellent smooth muscle stimulating activity and at the same time reduced blood pressure effects. Similarly, 16-phenoxy-1 'tetranorprostaglandins of the PGE 2 and PGF 2 series are useful for fertility control, including abortion on the basis of their smooth muscle stimulating activity.

In the following Tables I, II and III, the biological activity of the novel compounds of the invention is compared with the activity of the known naturally occurring PGE2 and some compounds known from Danish Patent Application No. 2362/72.

The biological tests used for the comparisons are as follows: 13 U4247 A. Spasmogenic effect on isolated guinea pig (relative strength), PGE2 / PGF2a = 100) - a test for antifertility / abortion-inducing activity.

B. Determination of the effect on anesthetized dogs blood pressure (threshold in pg / kg i.v.) - a test for a rare side effect of prostaglandins.

C. Determination of diarrhea-inducing activity in mice in vitro (relative potency, PGE2 = 100) - a test for a frequent side effect of prostaglandins.

D. Determination of abortion-inducing activity in rats (in Table I in vivo, indicated as minimal effective dose in mg / kg sc, and in Table II in vitro, expressed as relative potency relative to PG® + = 100) - a test for antifertility / abortion-inducing activity by a non-smooth muscle mechanism. This model, in which PGF2 is more potent than PGE2, acts by a luteolytic mechanism, and active compounds are expected to be antifertility / abortifacients by this mechanism as well as agents for synchronizing estrus in domestic animals such as horses and cattle.

E. Determination of abortion-inducing activity on guinea pigs (in Table I in vivo, given as minimal effective dose in mg / kg sc, and in Table III in vitro, expressed as relative potency relative to PGE2 = 100) - a test for antifertility / abortion-inducing activity by a smooth muscle mechanism (i.e., uterine stimulation).

14 144247

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Compared to the known compounds, a number of the compounds of the invention are distinguished by being readily purified crystalline substances and all have a more selective and, for the most part, more potent antifertility effect.

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The above Table II shows that the compounds of the invention are 3 - 1000 times more potent than PGFg (compound # 1) in terms of abortifacient activity in rats by the luteolytic mechanism. In addition, compound # 5 exhibits significantly less (10-fold) effect on canine blood pressure and is therefore expected to have less of this side effect. Furthermore, Compounds # 2 and 3 have a much more favorable therapeutic index with respect to the common diarrhea-causing side effect than PGF2.

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The above, Table III, clearly shows that the compounds of the invention (Nos. 2 - 21) are more potent and more selective than both PGE2 (Nos. 1) and the compound of Danish Patent Application no.

2362/72 (No. 22). Thus, the compounds of the invention are expected to be better antifertility agents and abortifacients than the known compounds.

More specifically, changes in blood pressure are a side effect that is sometimes observed when administering PGE2 to humans. Since the prostaglandin analogs at issue here exhibit 40-7,200 times less blood pressure effects than PGE2 and 4-720 times less than the compound of Application No. 2362/72, they should be expected to exert much less of this side effect.

Diarrhea is perhaps the most common side effect observed with the administration of prostaglandins to humans. However, although the compounds of this invention exhibit a diarrhea-inducing activity comparable to the known compounds, they exhibit many times greater abortion-inducing effects than PGE2 (10 - 300 times) or the compound of Application No. 2362/72 (3 - 100 times ). Thus, the therapeutic index of the compounds of this invention is 20 to 1875 times greater than that of PGE2 and 10 to 937 times greater than that of the compound of Application No. 2362/72.

The novel compounds of the invention can be used in a wide variety of pharmaceutical compositions containing the compound and can be administered in the same way as natural prostaglandins by a variety of routes such as intravenous, oral, intra-vaginal, intra- and extra-amniotic, etc.

For inducing abortion, 16-phenoxy-ii'-tetranorprostaglandin in tablets or an aqueous suspension or alcoholic solution will usually be administered in oral doses of from about 0.1 to about 20 mg, using 1-7 doses per day. day. For intravaginal administration, a suitable composition would be lactose tablets or an impregnated tampon with the same agent. For such treatments, suitable dosages will be from about 0.1 to about 20 mg / dose, using 1-7 doses. For intramuscular administration, a suitable composition will be an aqueous solution containing 0.05 - 10 mg / dose, using 1-7 doses. For extra-amniotic administration, a suitable composition will be an aqueous solution containing 0.005 - 1 mg / dose, using 1 -5 doses per day. day. Alternatively, the 16-phenoxy-β-tetranorprostaglandins can be infused intravenously to induce abortion at doses of 0.05 - 50 µg / minute for a period of from about 1 to about 24 hours. To synchronize the oestrus cycle in pigs, sheep, cows or horses, a solution or suspension containing 16-phenoxy-to-tetranorprostaglandin is administered in an amount of 0.03 - 30 mg / day subcutaneously for from 1 to 14 days.

To prepare any of the above dosage forms or any of the numerous other possible forms, various reaction-inert diluents, excipients or carriers may be used. Such substances include, for example, water, ethanol, gelatins, lactose, starch, magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum vaseline, cholesterol and other known carriers. If desired, these compositions may contain adjuvants such as preservatives, wetting agents, stabilizers or therapeutic agents such as antibiotics.

A particularly useful ester is the β-biphenyl ester. Such esters are prepared in the following examples by simply adding p-phenylphenol to the prostaglandin in methylene chloride in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide and stir overnight. Although not more potent in smooth muscle tests in vitro, abortion induction assessment of 16-phenoxy-V-tetranor-PGE

The following examples serve to illustrate in detail the preparation of the 16-phenoxy-1β-tetranorprostaglandins of the invention. In these examples, all melting and boiling points are uncorrected.

EXAMPLE 1

Dimeth2l-2-oxo-3- henox £ £ £ E £ 02ylEhos honat

A solution of 33.2 g (268 mmol) of dimethyl methyl phosphonate in 360 ml of dry tetrahydrofuran was cooled to -78 ° C under a dry nitrogen atmosphere. To the stirred phosphonate solution, 118 ml of 2.34 M n-butyllithium in hexane solution was added dropwise over 18 minutes at such a rate that the reaction temperature never rose above -65 ° C. After a further 5 minutes of stirring at -78 ° 0, 22, 2 g (134 mmol) of methyl 2-phenoxyacetate dropwise at a rate such that the reaction temperature was kept below -70 ° C (20 minutes). After 3.5 hours at -78 ° C, the reaction mixture was allowed to warm to room temperature, neutralized with 14 ml of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 175 ml of water, the aqueous phase was extracted with 100 ml portions of chloroform (3 times), the combined organic extracts were washed back (50 ml of H 2 O), dried over magnesium sulfate and concentrated (water pump) to a crude residue. and distilled, b.p. 172 - 175 ° C / 0.5mmHg to give 24.6 g of dimethyl 2-oxo-3-pbenoxypropyl phosphonate.

The NMR spectrum (CDCl3) showed: 0

A doublet centered at 3.75 δ (J = 11.5 cps, 6H) for (CH₂O) -P-, a singlet at 4.7 δ (2H) for CgH ^O-CHg-CO-, Q

a doublet centered at 3.24 δ (J = 23 cps, 2H) for -C-CHg-P- and a multiple at 6.8 - 7.5 δ (5H) for the aromatic protons.

2- [3oc-p-phenylbenzoyloxy-5α-hydroxy-20- (3-oxo-4-phenoxy-trans-1- 5.4 g (21 mmol) dimethyl-2-oxo-3-phenoxypropylphosphonate in 200 ml anhydrous ether) was treated with 7.9 ml (19 mmol) of 2.5 M n-butyllithium in n-hexane under a dry nitrogen atmosphere at room temperature, After 5 minutes of stirring, an additional 400 ml of anhydrous ether was added followed by 6.0 g (17 mmol) 2 - [3a-p-phenyl-26 U * 2 * 7 benzoyloxy-SiVhydroxy-Z 2 -formylcyclopentane - ^ - yl / acetic acid - ^ - lactone in one portion and 50 ml of anhydrous ether. After 35 minutes the reaction mixture was quenched with 5 ml glacial acetic acid and washed with 100 ml of saturated sodium bicarbonate solution (4 times), 100 ml of water (2 times), 100 ml of saturated saline (1 time), dried over magnesium sulfate and evaporated to give 5.2 g of 2/3 (β-phenoxybenzoyloxy-5β-hydroxy-2β) - (3-oxo-4-phenoxy-trans-1-buten-1-yl) cyclopent-1β-yl-acetic acid-1β, lactone as a solid after column chromatography on silica gel (particle size 0.074 - 0.250 mm); mp 112 - 114 ° C after crystallization from methylene chloride / hexane.

The IR spectrum (KBr) of the product exhibited absorption bands at 1775 cm 2 (strong), 1715 cm 2 (strong), 1675 cm 2 (medium) and 1630 cm 2 (medium) attributable to the carbonyl groups, and at 970 cm 2 for trans. -double bond.

2- [3α-β-phenylbenzoyloxy-5α-hydroxy-2β- (3α-hydroxy-4-ph and oxy-______)

To a solution of 5.1 g (10.5 mmol) of 2- [3a-p-phenylbenzoyloxy-5a-hydroxy-2β- (3-oxo-4-phenoxy-trans-1-buten-1-yl) cyclopentene 1a-yl] acetic acid-y-lactone in 30 ml of dry 1,2-dimethoxyethane under a dry nitrogen atmosphere at room temperature was added dropwise 11 ml (5.5 mmol) of 0.5 M zinc borohydride solution. After stirring at room temperature for 2 hours, a saturated sodium hydrogen tartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was stirred for 5 minutes, adding 250 ml of dry methylene chloride. After drying over magnesium sulfate and concentration (water pump), the resulting semi-solid was purified by column chromatography on silica gel (particle size 0.074 - 0.250 mm) using ether as eluant.

After eluting minor polar impurities, a fraction containing 896 mg of 2- / 3β-phenylbenzoyloxy-5β-hydroxy-2β- (3β-hydroxy-4-phenoxy-trans-1-butene-1) was collected. -yl) cyclopent-1c-6-yl-acetic acid-Vlactone (4), a fraction containing 600 mg of mixed (4) and (5) and finally a fraction containing 1.5 g of 2- / 3dL-p-phenylbenzoyloxy-50t -hydroxy-2β- (3β-hydroxy-4-phenoxy-trans-1-buten-1-yl) cyclopentyl-1β-yl7e (acetic acid-1β-lactone (5)).

The IR spectrum (01101-,) of (4) had strong carbonyl absorptions at −1 171 1770 and 1715 cm og and an absorption at 970 cm "for the trans double bond.

2- [3a, 5a-dihydroxy-2β- (3a-hydroxy-4-phenoxy-trans-1-buten-1-yl) - 222 ^ 2222 ^: 12: 2 ^ 12 ^^ 22215: 2 :: 2: : 1221: 22 _____________________________

A heterogeneous mixture of 846 mg (1.7 mmol) of 2- [3α-p-phenylbenzoyl-oxy-5α-hydroxy-2β- (3α-hydroxy-4-phenoxy-trans-1-buten-1-yl) -cyclopent -1α-yl] acetic acid-y-lactone, 10 ml of absolute methanol and 120 mg of finely powdered anhydrous potassium carbonate were stirred at room temperature for 20 hours and then cooled to 0 ° C. To the cooled solution was added 1.75 ml of 1.0 K hydrochloric acid. After stirring at 0 ° C for a further 10 minutes, 10 ml of water was added with the accompanying precipitation of methyl-p-phenylbenzoate, which was collected by filtration. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (4 x 10 ml), the combined organic extracts washed with saturated sodium hydrogen carbonate (10 ml), dried over magnesium sulfate and concentrated to give 445 mg of viscous oily 2- [3α, 5α-dihydroxy-2β- (3α-hydroxy-4-phenoxy-trans-1-buten-1-yl) cyclopent-1α-yl] -acetic acid γ-lactone.

The IR spectrum (CHCl3) showed a strong absorption at 1772 cm -1 for the lactone carbonyl and mean absorption at 965 cm -1 for the double-double bond.

2- [5 α-Hydroxy-3α- (tetrahydropyran-2-yloxy) -2 # - (3β-tetrahydropyran-2-yloxy-4-phenoxy-trans-1-buten-1-yl) cyclopentene 1α-yl] acetic acid, y-lactone ____________

To a solution of 445 mg (1.46 mmol) of 2- [3α, 5α-dihydroxy-2β- (3α-hydroxy-4-phenoxy-trans-1-buten-yl) cyclopent-1α-γ1] acetic acid re-γ-lactone in 5 ml of anhydrous methylene chloride and 0.4 ml of 2.3 dihydropyran at 0 ° C in a dry nitrogen atmosphere was added 5 mg of p-toluenesulfonic acid monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 100 ml of ether, the ether solution washed with saturated sodium bicarbonate solution (1 x 15 ml) and then with saturated brine (1 x 15 ml), dried over magnesium sulfate and concentrated to give 752 mg ( $ 100) crude 2- [5 <λτ hydroxy-3oC- (tetrahydropyran-2-yloxy) -2β- (3c-tetrahydropyran-2-yloxy-4-phenoxy-trans-1-buten-loC-yl) cyclopent -ia-yl] acetic acid -1 acton.

The IR spectrum (CHCl3) had an average adsorption at 970 cm 2 for the trans double bond and at 1770 cm 2 for the lactone carbonyl.

2- [5α-hydroxy-3α (t etrahydropyran-2-yloxy) -2β- (3α-tetrahydropyran-2-yloxy-4-phenoxy-trans-1-buten-1-yl) cyclopene t-1α yl] acetaldehyde-γ-hemiacetal _______ _ _

A solution of 690 mg (1.46 mmol) of 2- [5α-hydroxy-3α- (tetrahydro-pyran-2-yloxy) -2β- (3α-tetrahydropyran-2-yloxy-4-phenoxy-trans-1-butene) -1-yl) cyclopent-1α-yl] acetic acid γ-lactone in 8 ml of dry toluene was cooled to -78 ° C under a dry nitrogen atmosphere. To this cooled solution, 2.0 ml of 20 diisobutyl aluminum hydride in n-hexane was added dropwise at such a rate that the internal temperature never rose above -65 ° C (15 minutes). After a further 45 minutes of stirring at -78 ° C, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 100 ml of ether, washed with 50 $ sodium potassium tartrate solution (4 x 20 ml), dried over sodium sulfate and concentrated to give 613 mg of 2- [5α-hydroxy-3α (tetrahydropyran-2-yl-oxy) -2β- (3α-tetrahydropyran-2-yloxy-4-phenoxy-trans-1-buten-1-yl) cyclopent-1-yl] acetaldehyde-ί'-hemiacetal.

9A-hydroxy-llø (, 15rt-bis- (tetrahydropyran-2-yloxy) phenoxy -l6 5-2i§ll3 tr§ns ^ V-tetranor-prostadienoic = ____

To a solution of 1.6 g (3 »6 mmol) of (4-carboxy-n-butyl)-triphenylphosphonium bromide under a dry nitrogen atmosphere in 6.0 ml of dry dimethyl sulfoxide was added 3.24 ml (6.5 mmol) of a 2.0 M solution of sodium methylsulfinylmethide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 613 mg (1.29 mmol) of 2- [5d - hydroxy-3 <t- (tetrahydropyran-2-yloxy) -2ji- (3oi · tetrahydropyran-2-yloxy) -4-phenoxy-trans-1-buten-1-yl) cyclopent-1c (-yl7acetaldehyde - ^ - hemiacetal in 5.0 ml of dry dimethylsulfoxide in 29 minutes over 20 minutes. After a further 2 hours stirring at room temperature, the reaction mixture was The basic aqueous solution was washed twice with ethyl acetate (20 ml) and acidified to pH 3 with 10% aqueous hydrochloric acid. The acid solution was extracted with ethyl acetate (3 x 20 ml) and the combined organic extracts washed once with water (10 ml), dried over magnesium sulfate and evaporated to give a solid residue.

The solid residue was triturated with ethyl acetate and the filtrate concentrated to give 75 µmg of 9 <X-hydroxy-IIl, lixibis (tetrahydropyran-2-yloxy) -1,6-phenoxy-5-cis-13 trans-'W / tetra-norprostadiensyre.

IR spectrum (CHCl3) showed a strong band at 1720 cm @ -1 for the carboxyl group.

9-oxo-11o, 15a-bis (tetrahydropyran-2-yloxy) -16-phenoxy-5-cis-13-trans-cu-tetranor-prostadic acid _____ _ ____

To a solution of 754 mg (1.3 mmol) of 9α-hydroxy-11α, 15α-bis (tetrahydropyran-2-yloxy) -16-phenoxy-5-cis-13-trans-cu-tetranor-propane Stage acid in 13 ml of reagent pure acetone cooled to -10 ° C under nitrogen was added dropwise 0.56 ml (1.41 mmol) of Jones' reagent.

After 20 minutes at -10 ° C, 0.260 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes, then combined with 75 ml of ethyl acetate, washed with water (3 x 10 ml), dried over magnesium sulfate and concentrated to give was obtained 752 mg of 9-oxo-11a, 15a-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-5-cis-13-trans -ethetranor-prostadioic acid which was chromatographed on silica gel using ethyl acetate as eluent to give 505 mg of pure substance.

9-oxo-L1A, 15a-dihydroxy-16-phenoxy-5-cis-13-trans-w-tetranor-prostadienoic _______________________________________________

A solution of 505 mg (0.9 mmol) of 9-oxo-11α, 15α-bis- (tetrahydro-pyran-2-yloxy) -1β-phenoxy-5-cis-1S-trans-β-tetranor.-process -acid in 6.3 ml of a 65:35 volume acetic acid-water mixture was stirred under nitrogen at 25 ° for 18 hours and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (particle size 0.074 - 0.149 mm) using ethyl acetate as eluant. After eluting minor polar impurities, the oily 9-oxo-11 &apos; 15 <l -dihydroxy-16-phenoxy-5-cis-13-trans-V-tetranor-prostadioic acid, weighing 210 mg, was collected.

IR · (CHCl3) exhibited a broad band at 1725 cm -1 for acarbonyl absorptions and a band at 970 οπΤ1 for the 13,14-trans double bond.

p-biphenyl-9-oxo-11a, 15a-dihydroxy-16-phenoxy-5-cis-13-trans-tetranor-pro-state

To a solution of 50 mg (0.13 mmol) of 9-oxo-11α, 15α-dihydroxy-16-phenoxy-5-cis-13-trans-m-tetranor-prostadioic acid and 63 mg (0.4 mmol) phenylphenol in 10 ml of dry methylene chloride was added 825 mg (0.4 mmol) of dicyclohexylcarbodiimide and the solution was stirred overnight at room temperature. After concentration, the crude product was purified by silica gel chromatography to give the desired p-biphenyl ester, m.p. 100-102 ° 0.

Analysis:

Calculated for C CjH₂OO: 0 75.55 - H 6.71 Bound: 0 75.65 - H 6.83.

EXAMPLE 2 9a, 11a, 15a-Trihydroxy-16-phenoxy-5-cis-13-trans-hydrogen tetranor-pro-sti assure ____________________________________________

A mixture of 375 mg (0.65 mmol) of 9α-hydroxy-11α, 15α-bis (tetrahydropyran-2-yloxy) -16-phenoxy-5-cis-13-trans-β-tetranor-prostate diacetic acid, 6.5 ml of acetic acid and 3.5 ml of water were stirred under nitrogen at room temperature for 20 hours. Bone resulting clear solution was concentrated under reduced pressure and the residue (380 mg) dissolved in ethyl acetate. The ethyl acetate solution was washed with brine (20 ml), dried over sodium sulfate and concentrated to a clear oil. Chromatography on silica gel using chloroform and then ethyl acetate as eluent gave the desired product, 9'L, 11l, 15o <-trihydroxy-l6-phenoxy-5-cis-13 ~ trans-ll-tetranor-prostadienic acid , as a colorless oil weighing 98 mg.

p-biphenyl-9oc, 11α, 15α-trihydroxy-16-phenoxy-5-cis-13-trans-ιυ-tetranor-prostadienoate

To a solution of 106 mg of 9a, 11a, 15α-trihydroxy-16-phenoxy-5-cis-13-trans-m-tetranor-prostadioic acid and 189 mg of p-phenylphenol in 30 ml of dry methylene chloride was added 600 mg of dicyclohexylcarbo-diimide and the solution was stirred overnight at room temperature. After concentration, the crude product was purified by silica gel chromatography to give 80 mg of pure p-biphenyl ester, m.p. 101-103 ° C.

Analysis:

Calculated for C CH ^ gOg: C 75.25 - H 7.06 Bound: 0 75.38 - H 7.30.

Example, g of N-methanesulfonyl-9-oxo-11α, 15α-bis (tetrahydropyran-2-yloxy) - 7β-tetranor-prostadienamide

To a solution of 400 mg of N-methanesulfonyl-9α-hydroxy-11α, 15α-bis (tetrahydropyran-2-yloxy) -16-phenoxy-5-cis-13-trans-α-tetra-nor-prostadienamide in 8 ml reagent pure acetone, cooled to -10 ° C under nitrogen, was added dropwise to 0.4 ml Jones' reagent. After 30 minutes at -10 ° C, 0.4 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes, then combined with 60 ml of ethyl acetate, washed with water (; x 10 ml), dried over sodium sulfate and concentrated. to obtain 380 mg of colorless oily N-methanesulfonyl-9-oxo-11a, 15oc-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-5-cis-13-trans -w-tetra-nor-prostadienamide.

N-Methanesulfonyl-9-oxo-11 α, 15α-dihydroxy-16-phenoxy-5-cis-13-trans-to-tetranor-prostadienamide

A solution of 260 mg of N-methanesulfonyl-9-oxo-11a, 15a-bis (tetrahydropyran-2-yloxy) -16-phenoxy-5-cis-13-trans-α-tetranor-prosta-dienamide in 6 ml of a glacial acetic acid-water mixture 65:35 by volume was stirred under nitrogen at 25 ° for 20 hours and then concentrated to a crude oil which was purified by column chromatography on silica gel (particle size 0.074 - 0.149 mm) using mixtures of chloroform and ethyl acetate as eluant. After elution of less polar impurities, 130 mg of colorless N-methanesulfonyl-9-oxo-11lot, 15d.-dihydroxy-16-phenoxy-5-cis-13-trans-tetranor-prostadienamide was collected. The product crystallized from ether as colorless crystals, m.p. 76 ° C.