IE45965B1 - P-biphenylyl estern of 15-heteroaryl-16,17,18,19,20,-petanorprostaglandins - Google Patents

Abstract

Heterocyclo-omega- dioxopolyazamacrocycle to aryl. [FR2362848A1]

Description

This invention relates to certain novel analogs of the naturally occurring prostaglandins and to various novel intermediates and reagents useful in their preparation. In particular it relates to novel aryl heterocyclic-u*-pentanorprostaglandins.

: The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. Each of the known, naturally occurring prostaglandins is derived from prostanoic acid which has the structure and position numbering: Ό00Η /Bergstrom, et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein_J7 A systematic name for prostanoic acid.is 7-Z[2|B-octyl)-cyclopent-la-ylTheptanoic acid.

PGAg has the structure: COOH H OH 4596 PGBg has the structure: PGEg has the structure: Each of the PG^ prostaglandins, PGEj_, PGFj_a, PGFj^, PGAj and PGB]_, has a structure the same as the corresponding PG2 compound except that the cis double bond between C-5 and C-6 is replaced by a single bond. For example, PGA^ has the structure 43965 The PGq compounds are those in which there are ho double bonds in either side chain. For instance, PGEq has the structure Broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring.

The side-chain hydroxy at C-15 in the above formulas is in S configuration·. /See, Nature, 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins_j7 Molecules of the known prostaglandins each have several centers of asymmetry, and can exist in racemic (optically inactive} form and in eithercf the two enantiomeric (optically active) forms, i.e. the dextrorotatory and levorotatory forms. As drawn above, each structure represents the particular optically active 'form of the prostaglandin which is obtained from certain mammalian tissues, for example, sheep vesicular glands, swine lung, or human seminal plasma, or by carbonyl and/or double bond reduction of that prostaglandin. /Bergstrom et al., cited above/7 The mirror image or optical antipode of each of the above structures represents the other enantiomer of that prostaglandin. - 4 I For instance, the optical antipode of Ρ0?2α (ent-PGFgq) is drawn a^ OH COOH HO The racemic form of a prostaglandin contains equal numbers of a particular stereoisomer and its mirror image. When reference to a prostaglandin racemate is intended, the symbols rac or dl will precede the prostaglandin name. Two structures are needed to represent a racemate. For instance, the structure of dl-PGF2a is properly represented as an equimolar mixture of PGF2a and ent-PGFgq. The terms PGBj, PGEg, PGF^q and the like as used herein will mean that stereoisomer with the same absolute configuration as the corresponding prostaglandin found in mammalian tissue.

In an optical antipode, the absolute configuration at all ol the above-mentioned centers of asymmetry is inverted. In an epimer, the configuration is inverted at one or more but not all of the centers. For Instance, the absolute configuration of the 15-hydroxy group In 15-epi-PGFgq is the 11 configuration and is shown as OH HO HO H 4S965 It will be noted that only the configuration at the 15-position is inverted and that at the other centers of asymmetry, namely the 8-, 9-, 11- and 12-positions, the absolute’configuration is the same as that in the naturally-occurring mammalian PGPga* Racemic mixtures of epimers may also exis% for instance, if 15-. oxo »PGF2a is reduced with zinc borohydride or a hindered alkyl borohydride, the resulting product is a racemic mixture of 15a-hydroxy and 150-hydroxy-PGF2a· PGEg_, PGEp, and the corresponding PGFa, PGF^, PGA, and PGB compounds, and many of their derivatives such as the esters, acylates, and pharmacologically acceptable salts, are extremely potent inducers of various biological responses. These compounds are, therefore, potentially useful for pharmacological purposes. /Bergstrom et al., cited abovej/. A few of those biological responses are systemic arterial blood pressure lowering in the cas^ of the PGFp, PGE and PGA compounds as shown in cardiac cannulated rats or dogs; pressor activity for the PGFa compounds; stimulation of smooth muscle as shorn by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potential, on of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization cf free fatty acids or inhibition of the spontaneous release of glycerol, from isolated rat fat pads; inhibition of gastric secretion in the case of the PGE and PGA compounds as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; controlling spasm and facilitating breathing in asthmatic conditions; decrease of blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet - 6 // 45065 aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury; in the case of the PGE and PGB compounds, stimulation of epidermal proliferation and keratinization as shown when applied in culture to embryonic chick and rat skin segments; and in the case of PGFg and PGE compounds luteolytic activity as shown in hamster? and rats.

Prostaglandins are useful to prevent, control, or alleviate a wide variety of diseases and undesirable physiological condition^ in avians and mammals, Including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.

For example, these compounds, especially those of the E series, are useful in mammals, including man, as bronchodilators /Cuthbert, Brit. Med. J., 4:723-726, 1969/. As nasal deconges15 tants, the compounds are used in a dose range of about 10 pg. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

The PGE compounds are useful in the treatment of asthma because of their activity as bronchodilators and/ or as inhibitors of mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex.

Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes, these compounds are administered in a variety of routes in a number of dosage forms, e.g,, orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenterally with intravenous administration being preferred in emergency situations; by inhalation In the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder. Doses in the range of 0.01 to 5 mg. per kg, of body weight are used 1 to 4 times a day. These prostaglandins can also be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (Iso5 proterenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline and aminophyllin); and corticosteroids (ACTH and prednisolone). Regarding use of these compounds see South African Patent No. 68/1055.

The PGE and PGA compounds are useful in mammals, including 10 · man and animals to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. /Shaw and Ramwell, In; Worchester Symposium on Prostaglandins, Wiley (New York, 196θ), pp. 55-64/ For this purpose, the compounds are administered parenterally by Injection or intravenous infusion in an infusion dose range of 0.1 p.g. to 500 jig. per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range of 0.1 to 20 mg. per kg.. of body weight per day. 2C The PGE compounds are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. /Emmons et al., Brit. Med. J., 2:468-472, 1967// These compounds are, for example, useful in the treatment and prevention of mycardial infacts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood - 8 48866 clotting defects such as lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range of o.oos to 20 mg. per '.kg. of body weight per day are used.

The PGE compounds are especially useful as additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extracorporeal circulation and perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to the new body.

Under such conditions, aggregated platelets tend to block the blood I vessels and portions of the circulation apparatus. Such aggregation is inhibited by the presence of a prostaglandin. For this purpose, the compound is added gradually or in single or multiple portions to the ciruclating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of .001, to 10 mg. per liter'or circulating fluid.· PGE and PGFg compounds are extremely potent in causing stimulation of smooth muscle, and are also highly active in potentiating other known smooth muscle stimulators. Therefore, PGEg, for example, is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for exampl^, to relieve the symptoms of paralytic ileus, or to control or prevedt atonic uterine bleeding after abortion or delivery, to aid in -·, expulsion of the placenta,' and during the puerperium. For the latter purpose, the PGE compound is administered intravenously immediately after abortion or delivery at a dose in the range of O.O1 to 50 ug. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given parenterally during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day.

The PGE, PGA and PGFp compounds are useful as hypotensive agents and vasodilators /Bergstrom et al., Acta Physiol. Scand., 64:332-333, 1965; - Life Sci., 6:449-455, 196/7 in mammals, including 1 man. To lower systemic arterial blood pressure, the compounds are administered by intravenous infusion at the rate of 0.01 to 50 ug. per kg. of body weight per minute, or in single or multiple doses of 25 to 500 jug. per kg. of body weight total per day. /Weeks and King, Federation 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. 75:161-169, 1969.J The PGA compounds and derivatives and salts thereof increasl the flow of blood in the mammalian kidney, thereby increasing volume and electrolyte content of the urine. For that reason, PGA compounds are useful in managing cases of renal disfunction, especially in cases of severely impaired renal blood flow, for example, the hepatorenal syndrome and early kidney transplant ’ ·. t rejection. In casescf excessive or inappropriate ADH (antidiuretii - 10 45965 hormone; vasopressin) secretion, the diuretic effect of these compounds is even greater. In anephretic states, the vasopressin action of these compounds is especially useful. Illustratively, the PGA compounds are useful in alleviating and correcting cases of edema resulting from massive surface burns in the management of shock, etc. For these purposes, the PGA compounds are preferably first administered by intravenous injection at a dose in the range 10 to 1000 pg. per kg. of body weight or by intravenous infusion at a dose in the range 0.1 to 20 y,g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses a-e given by intravenous, intramuscular, or subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of body weight per day.

The PGE compounds, especially PGE^, are useful in the treatment of psoriasis (Fiboh, et al., Nature, 254, 351 (1975))· For this purpose, the compound is administered topically at a dose of 1-500 |ig. 1 to 4 times daily until the desired effect is obtained.

The PGE, especially PGEg, PGFa, and PGFp compounds are 2C useful in the induction of labor in pregnant female animals, including man, cows, sheep, and pigs, at or near term ^Carim, et al., J. Obstet. Gyna'ec. Brit. Cwlth., 77:200-210, 19707 or in the ~ πΠηοη-human animals induction of therapeutic abortion/,/Bygdeman et al.. Contraception, 4, 293 (1971)/. For this purpose, the compound is infused inBra25 venously at a dose of 0.01 to 50 μg. per kg. of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds are especially useful when the female 'is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started. Alternative routes of administration are oral, extraammiotic or intraammiotic.

The PGE, PGFa, and PGFo compounds ape useful for fertility nop-human animals control in female mammals //Karim, Contraception, 3., 173 (1971)/ juid- rmimnls such as monkeys, rats, rabbits, dogs, cattle. By the term ovulating female mammals is meant animals which are mature enough to ovulate but not so old that regular ovulation has ceased. For that purpose, PGF2tt, for example, is administered systemically at a dose level in the range 0.01 mg. to -20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Intravaginal and intrauterine are alternative routes of administration. Additionally, non-human animals expulsion of an embryo or a foetus As accomplished by similar administration of- the compound during the first third of the normal mammalian gestation period.

Patents have been obtained for several prostaglandins of th^ E and F series as inducers of labor in mammals (Belgian Patent 754,153 and West German Patent 2,034,641), and on PGE]., F2 and Fg for control of the reproductive cycle (South African Patent 69/608^ 453 65 It has been shown that luteolysis can take place as a result of administration of PGF2q //abhsetwar, Nature, 230, 528 (1971)/ and hence prostaglandins have utidt; for fertility control by a process in which smooth muscle stimulation is not necessary.

The PGE and PGFg compounds are useful as antiarrhythmic agents (Forster, et al., Prostaglandins, 3, θ95 (1973)). For this purpose the compound is infused intravenously at a dose range of 0.5-500 ug/kg/minute until the desired effect is obtained.

As mentioned above, the PGE compounds are potent antagonist^ 10 of epinephrine-induced mobilization of free fatty acids. For this reason, these compounds are ua=ful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats, intended to lead to the understanding, prevention, symptom alleviation, and cure of diseases Involving abnormal lipid mobilization and high free fatty acid levels, e.g., diabetes mellitus, vascular diseases, and hyperthyroidism.

The PGE and PGB compounds promote and accelerate the growth of epidermal cells and keratin in animals, including humans, .- 13 45965 . useful domestic animals, pets, zoological specimens, and laboratory animals. For that reason, these compounds are useful in promoting healing of skin which has been damaged, for example, by burns, wounds, and abrasions, surgery, etc. These compounds are also useful in promoting adherence and growth of skin autografts, especially small, deep (Davis) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and to retard rejectioncf homografts.

To promote the growth of epidermal cells, these compounds . ,10 are preferably administered topically at or near the site where cell growth and keratin formation is desired, advantageously as an aerosol liquid or micronized powder spray, as an isotonic aqueous solution in the case of wet dressings, or as a lotion, cream, or ointment in combination with the usual pharmaceutically . ,15 acceptable diluents. In some instances, such as when there is substantial fluid loss as in the case of extensive burns or skin loss due to other causes, systemic administration is advantageous. Especially in topical applications, these prostaglandins may be advantageously combined with antibiotics such as gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, tetracycline and oxytetracyclinej with other antibacterials such as mafenide hydrochloride; sulfadiazine, furazolium chloride, and nitrofurazone; and with corticosteroids such as hydrocortisone, prednisolone, methylprednisolone, and fluprednisolone, each being used in the combination at the usual concentration suitable for its use alone.

In the preparation of synthetic pharmaceutical agents, amon^ the principal objects is the development of analogs of naturally occurring compounds which are highly selective in their physiological activity and which have an increased duration of activity.

In a series of compounds like the naturally-occurring prostaglandins which has an extremely broad activity spectrum, increasing the selectivity of a single compound usually involves the enhancement of one physiological effect and the diminution of the others. By increasing the selectivity, one would, in the case of the natural prostaglandins, expect to alleviate the severe side . effects, particularly the gastrointestinal one frequently observed following systemic administration of the natural prostaglandins.

In order to achieve increased selectivity and duration of action in the prostaglandin series, many researchers have concen15 trated on the molecular modification of the last five carbons of the methyl-terminated side chain. One modification consists of removing one to four carbon atoms from the end of the lower side chain and terminating the chain with an aryloxy or heteroaryloxy group. Compounds cf this type are described, for instance, in Patent No. 37602 > the published Dutch Patent Application No. 73/06462 and Belgian Patent No. 8θ6,995. , 45965 The 11-deoxy analogs of the natural prostaglandins have also been described, for instance, in the published Dutch patent publication No. 16,804, Belgian Patent No. 766, 521 and the West German Offenlegungsschrift No. 2,103,005.

The analogs described below have been found to be more potent, longer acting, and more selective and possess unanticipated activities when compared to the prior art.

The present state of the art of knowledge about structureactivity correlations in the prostaglandins does not, however, permit one to explain the observed enchancement of selectivity in the compounds of the present invention.

Patent Specification No. 39569 discloses prostaglandins similar to those of the present application but without the added advantages offered by esterification with p-phenylphenol.

The present invention comprises the C-j_ £-biphenylyl esters of 16, 17, 16, 19, 20-pentanorprostaglandins, having at the 15-position one substituent of the formula: CH5 wherein R is hydrogen, chlorine, fluorine, methyl, trifluoromethyl, or methoxy; and n is 1 or 2; and either an oxo group, or a hydrogen atom and a hydroxy group. 965 A preferred group of compounds include the C-j. jo-biphenyiyl esters of 16, 17, 18, 19, 20 ω-pentanorprostaglandins of the Δ, E, or P aeries, having at the 15-position one substituent of the formula: wherein r and n are as defined above and either an Oxo group or a hydrogen atom and hydroxy group.

Such compounds' are of the formula: wherein Rand n are as defined above; R* is £- biphenylyl; 459 65 W is a single bond or cis double bond; Z is single bond or trans double bond; L is a single or double bond M and are oxo N is hydrogen or α-hydroxyl; with the proviso that when L is a double bond N is hydrogen.

Especially preferred among these are compounds of the formulae: (iaaoo and the Cg epimers of compound of the formulae XI and VI, wherein R, R', M, W, Z and n are as defined above.

Certain novel intermediates are involved in the synthesis of the novel prostaglandins of this invention and they constitute a further aspect of the invention.

Such intermediates are of the formulae: 45S65 and the epimers thereof, wherein R, R', W, Z and n are as defined above; THP is 2-tetrahydropyranyl and Q is hydrogen or 2-tetrahydropyranyloxy.

It is noted that the substituent attached to the 15-position contains a chiral carbon. Consequently, this substituent may be prepared in the + or configurations. It is obvious that the substituent may also be prepared in the racemic or + form and it is intended that all three possibilities fall within the scope of this invention.

In this Specification the substituent attached, to the 15position wherein n=l is named either 2-coumaryl or 2,3-dihydrobenzoKlfur-2-yl while wherein n=2 is named either 2-chromanyl or 3,4-dihydrobenzo[j5pyran-2-yl. The configuration of these substituents is noted by the prefix +, or + which refers to the sign of optical rotation of the starting acids.

Especially preferred novel compounds of the present invention include: -[(-)-2-coumaryl]-16,17,18,13,20-pentanor-PGE2 £-biphenylyl ester; -[(-)-2-coumaryl]-16,17,18,19,20-pentanor-PGF2a £-biphenylyl ester; -E£i-[(-)-2-coumaryl]-16,17,18,19,20-pentanor-PGF2a £biphenylyl ester; -[(+)-2-coumaryl]-16,17,18,19,20-pentanor-PGE2 £-biphenylyl ester; -[(+)-2-coumaryl] -16,17,18,19,20-pentanor-PGF2a £-biphenylyl 10 ester; -Epi-15-t(-)-2-coumaryl]-16,17,18,19,2O-pentanOr-PGE2 £biphenylyl ester; -[(+)-2-chromanyl] -16,17,18,19,20-pentanor-PGF2a £biphenylyl ester; -E£i-15-[.(+)-2-chromanyl]-16,17,18,19,20-pentanor-PGF2a £biphenylyl ester; -[(-)-2-chromanyl] -16,17,18,19,20-pentanor-PGF2a £biphenylyl ester; -Epi-15-[(-)-2-chromanyl]-16,17,18,19,20-pentanor-PGF2a £20 biphenylyl ester; -[(+)-2-chromanyl]-16,17,18,19,20-pentanor-PGE2 £-biphenylyl ester; -Epl-15-[(+)-2-chromanyl]-16,17,18,19,20-pentanor-PGE2 £biphenylyl ester; -[(-)-2-chromanyl]-16,17,18,19,20-pentanor-PGE2 £-biphenyly1 ester; and -Epi-15-[(-)-2-chromanyl]-16,17,18,19,20-pentanor-PGE2 £biphenylyl ester.

The starting material for the various novel compounds of this invention are available commercially or are made by methods well known to those skilled in the art. For example, < to make dimethyl 2-oxo-2-(+2,3-dihydrobenzo/*b_/fur-2-yl)ethylphosphonate, a solution of dimethyl methylphosphonate (Aldrich) in dry tetrahydrofuran is cooled to -78¾ 'in an inert atmosphere^ especially a dry nitrogen atmosphere. To the stirred phosphonate solution is added n-butyllithium in hexane solution (Alfa Inorganics, Inc.) at such a rate that the reaction temperature never rises above -65°. After an additional stirring at -78°, methyl 2,3-dihydrocoumarilate is added dropwise at a rate that keeps the reaction temperature lower than -70°, The reaction mixture is neutralized with organic acid, especially acetic acid, and allowed to warm to ambient temperature, and is then rotary evaporated (in vacuo, water aspirator) to a white gel. The gelatinous material is taken up in water, the aqueous phase is extracted with ethyl ether (3x), the organics are washed with water, and concentrated (water aspirator) to give dimethyl 2-oxo2-(±2,3-dihydrobenzo/-b_J7fur-2-yl)ethylphosphonate. ’ In a similar manner, the phosphonates 2a-2d, are. prepared using the esters shown as starting material. -254 5935 Ester TABLE I Phosphonate C02CH3 c-ch2-: '-(och3)2 la 2a co2ch3 +\-C-CH2-P(0CH3)2 >-(och3)2 '-(och3)2 ld 2d -2645965 Such phosphonates are then employed as reagents for the preparation of intermediates according to Reaction Scheme A. -2745965 In 2—>2. 4he OX(>phosphonate 2 is reacted with the known /Corey et al., J. Am. Chem. Soc,, 93, 1491 (1971)/ aldehyde H to produce,-after chromatography, or crystallization, the enone 3. 1 The enone 3 can he reduced with zinc borohydride or with trialkylborohydrides, such as lithium triethylborohydride, to a mixture of aLcohols, 4 and 5. which can be separated by column chromatography. In this reaction ethers such as tetrahydrofuran or 1,2-dimethoxyethane are usually employed as solvents.

Further transformations of 4 are shown on Scheme B: .—>6 is a base catalyzed hydrolysis in which the £~phenyl -benzoyl protecting group is removed.

This is most conveniently conducted with potassium carbonate in methanol or methanol-tetrahydrofuran solvent. 6—>7 involves the protection of the two free hydroxyl groups with an acidlabile protecting group. Any sufficiently acid-labile group is satisfactory; however, the most usual one is 2-tetrahydropyranyl, which can be incorporated in the molecule by treatment with dihydropyran and an acid cataLyst in an anhydrous medium. The ' catalyst is usually p-toluenesulfonic acid. -2848965 Scheme B -29f—>8 is a reduction of the lactone 7 to the hemiacetal 3 using'diisobutylaluminium hydride in an inert solvent.

Low reaction temperatures are preferred and -60° to -70°C are usual. However, higher temperature may be employed if over-reduction does not occur. 8 is purified, if desired, ’ by column chromatography. —> £ is a Wittig condensation in which hemiacetal 8 is reacted with (4-carbohydroxy butyl )triphenylphosphonium bromide in dimethyl sulfoxide, in the presence of sodium methylsulfinylmethide 9 is purified as above.

The conversion 9.—>12 is an acidic hydrolysis of the tetrahydropyranyl groups. Any acid may be used which does not cause destruction of the molecule in the course of the removal of the protecting group; however, this is accomplished 'most often by use of 65% W/v , aqueous acetic acid. The product is purified as above. £—>10 is an oxidation of the secondary alcohol £ to the ketone 10. This may be accomplished using any oxidizing agent which does not attack double bonds; however, the Jones reagent is usually preferred. The product is purified as above. — >11 is carried out in the same manner as £ 12.

The product is purified as above. 11— >15 is an acid-catalyzed dehydration. Any acid ;may be used for the process which does not cause extensive decomposition of the product, but the most usual procedure consists of heating 11 to 70°C in an excess of glacial acetic acid -30· Scheme C Scheme D 3145965 followed by concentration, dilution with ice water and extraction of the product after the starting material has been consumed.

The product is purified as above. 11—924 is a reduction of the ketone 11 to the alcohol 24. g This may be accomplished using any reducing agent which does not attack double bonds or carboxylic acid groups; however, sodium borohydride in ethanol is usually preferred.

As is illustrated in scheme C, £ may be substituted for £ in scheme B to provide prostaglandin derivatives 11', 12',15', and 24'.

Scheme D illustrates the synthesis of precursors to the 13, 14-dihydro-15-substituted-16, 17, 18, 19,20-pentanorprostaglandins.

In 3—919 + 19' the enone 3 is reduced to the tetrahydro compound through the use of any of the complex metal hydride reducing agents, LiAlH , NaBH , KBH , LiBH and Zn(BH ),. 4 4 4 4 z Especially preferred is NaBH^. The products, 19 and 19/, are separated from each other by column chromatography.

Furthermore, the compounds £ and 5 of Scheme A can be 20 reduced catalytically with hydrogen to 19 and 19 1 respectively.

The stage at which the double bond is reduced is not critical, and hydrogenation of £ or 2'of scheme B will also afford useful intermediates for the 13, 14-dihydroprostaglandin analogs of the present invention. This reduction may be achieved with either a homogenous catalyst such as tris(triphenylphosphine)chlororhodium, or with a heterogeneous catalyst such as platinum, palladium, or rhodium. The 43965 conversion of 19 and 19' to their respective prostaglandins follows the route shown in scheme B when 4 is replaced by 19 and 191 to yield the 13,l4-dihydro-PGE2,-PGAo and PGF2 series of prostaglandin derivatives.

Scheme E illustrates the preparation of the various reduced prostaglandin precursors: —»22 is carried out as illustrated on Scheme B for 5.—22 can be used as both a precursor to a 13 Ί-series. 22—>23 is carried out by catalytic hydrogenation using the catalyst described for the reduction of 4 —>19 of Scheme D, Intermediates of the type 21 are prepared by selective reduction of the 5,6-cls double bond of intermediates of the type £ at low temperature using catalysts such as those described for 4 —>lg and 17 —>23. Especially preferred for this reduction Is the use of palladium on carbon as a catalyst and a reaction temperature of -20° c. Intermediates of the type 21 are not only precursors to prostaglandins of the l-series though the route 2—»15 and g4 of scheme B, but also a precursor to compounds of the type 23 through the route already discussed for .22->23. -3345868 Scheme Ε -3445965 Furthermore, the prostaglandins of the Ep and Fqa series may be obtained directly from -the corresponding prostaglandin analog of the 2-series by first protecting the hydroxyl by introducing dimethyl Isopropylsilyl groups, reducing selectively the cis double bond, and removing the protecting group.

The introduction of the protecting group is usually accomplished by treatment of the prostaglandin analog with dimethylisopropyl chlorosilane and triethylamine, the reduction is accomplished as discussed above for £) —} 21 and removal of the protecting group is accomplished by contacting the'reduced protected compound with 3:1 v/ν acetic acid water for 10 minutes or until reaction is substantially complete.

The C15 epimers of 21, 22 and 23 can be used as precursors to the 15-epi series of prostaglandin derivatives described above. -354 5965 The 11-deoxy intermediate compounds are prepared J according to Reaction Scheme F. In the first step of this sequence the ketophosphonate 2 is reacted with the known /Corey and Ravindranathan, Tetrahedron Letters, 4-753 (1971)/ aldehyde H' to produce after chromatography the enone 3/.

The enone 3' can he reduced as described above for —>4 + 5. to provide a mixture of alcohols 4* and 5' which may be ‘ separated by column chromatography. Conversion of the alcohols 4' and 5' into ll-deoxyprostaglandins 10 follows the procedures described above for the conversion of . 4 and 5 into 11,'12, 15, 24, 11', 12', 15', 24', 22, 21 and 23. -3645965 CHO Η' 4' The 15-oxo intermediates are prepared as outlined on Scheme G. To prepare 15-ketoprostaglandins cf the 2- and 1- series, the 6x5 alcohols 25-28 are oxidized by an appropriate oxidizing agent. Although any oxidant may be used which will selectively oxidize allylic alcohols, activated .manganese dioxide or 2,3-dichloro-5,6-dicycano-l,4-benzoquinone are preferred.

To prepare 15-ketoprostaglandins of the O-series, the 15- oxoprostaglandins of the 1- or-2- series may be reduced as described for 5.—> 19 above.

To prepare 15- oxoprostaglandins of the 13, l4-dihydro-2• series, 15- oxo analogs of the 2-series such as 29 and 30 are treated with lithium and ammonia at -780 in an inert solvent 3uch as tetrahydrofuran. -38Scheme G 4S965 -394596S Scheme H shows three different routes to the ester E.

In each case the p-biphenylyl group is introduced by an esterification reaction which may be conducted by contacting the appropriate prostaglandin analog or its precursor with g-phenylphenol in the presence of a dehydrating agent such as dicyclohexylcarbodiimid. Any prostaglandin analog may be used as a substrate for the above esterification reaction, and additionally precursors' to such prostaglandins or prostaglandin analogs may also be used ajs illustrated in Scheme H. For example, £ may be converted to !9E by the esterification reaction alluded to above and 9B may then be converted to 10E and 12E by the same methods used to convert to 10 and 12 as previously discussed. Compound 10E may be converted to HE by reactions described for the conversion of to 11.

As is obvious from the above, the esters such as 9S, Ί0Ε, 11E and 12E may be used as substrates for the various reductive or oxidative schemes previously described for the production of the prostaglandin analogs of the one and zero series and -keto prostaglandins. -4o45965 Scheme Η Φ Ε 0Η OH -4l45963 In the foregoing procedures, where purification by chromatography is desired, appropriate chromatographic supports include neutral alumina’ and silica gel and 60-200 mesh silica gel is generally preferred. The chromatography is suitably conducted in reaction-inert solvents such as diethyl, ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane, as further illustrated in the appended examples.

It will be seen that the foregoing formulae depict optically active compounds. It will be clear, however, that the corresponding racemates will exhibit valuable biological activity by virtue of their content of the above-mentioned biologically active optical isomer, and it is intended that such racemates also be embraced by the foregoing formulae herein and.in the appended claims. The racemic mixtures are readily prepared by the same methods employed herein to synthesize the optically active species, by mere substitution of corresponding racemic precursors in place of optically active starting materials. -4245965 In numerous in vivo and in vitro tests we have demonstrated that the new prostaglandin analogs possess physiological activities comparable to those exhibited by the natural prostaglandins. These tests include, among others, a test for effect on isolated smooth muscle from guinea pig uterus and rat uterus, inhibitation of histamine-induced bronchospasm in the guinea pig, effect on dog blood pressure, inhibition of stressinduced ulceration in rats, inhibition of gastric acid secretion in rats, diarrheal activity in mice, and abortifacient activity in rats and guinea pigs.

The physiological responces observed in these tests are useful in determining the utility of the test substance for the treatment of various natural and pathological conditions. Such determined utilities include: antihypertensive activity, bronchodilator activity, antiulcer activity, smooth muscle activity [useful i. for the induction of labor, in non-human animals as an anti-fertility agent and and/as an abortifacient], and anti-fertility activity through a mechanism not affecting smooth muscle, for example, luteolytic mechanisms, and the synchronization of the eostrous cycle in farm animals.

The novel compounds of this invention possess more selective activity profiles than the corresponding naturally occuring prostaglandins, and in many cases, are also more potent. For example, the p-biphenylyl ester of 15-((+)-2-chromanyl)-16,17,18,19, 20-pentanorprostaglandins-E2 which exhibit guinea pig uterine smooth muscle stimulating activity greater than PGE2, is inactive in inhibition of histamine-induced bronchospasms in guinea pigs. Furthermore, the threshold dose of hypotensive response of the ^-biphenylyl ester of 15-((+)-2-chromanyl)-16,17,18,19,20-pentanor PGE2 in dogs is higher than that of PGE2· ¢5935 As another example, the £-biphenylyl ester of 15-epi-15((-)-2-coumaryl)-16,17,18,19,20-pentanorprostaglandin-F2a, which exhibits antifertility activity in vivo in the rat 30-100 times greater than PGF2r, possesses less smooth muscle and diarrheal activity.

As another example the £-biphenylyl ester of 15-epi-15-((-) 2-coumaryl)-16,17,18,19,20-pentanorprostaglandin-E2,which possesses antisecretory activity in vivo in the rat greater than PGE.,,exhibits less smooth muscle activity, for the induction of labour and in non-human animals and abortion Particularly useful/for fertility control are the £-biphenylyl esters of the 15-substituted16.17.18.19.20- pentanorprostaglandins of the E2 and F2(x series based on especially outstanding smooth muscle stimulating activity, and at the same time reduced blood pressure of diarrheal effects.

Similarly, the £-biphenylyl esters of the substituted-16,17,18,19, -pentanorprostaglandins of the PGE^,PGE ,F ,F. , 13,14-dihydro for the induction of labour an? in°non-numan animals PGE2 and F2a and 11-deoxy PGE series are usetul/for fertility control including abortion on the basis of their smooth muscle stimulant activity.

Also particularly useful fertility control by a non-smooth muscle mechanism and synchronization of the estrous cycle in farm animals are the £-biphenylyl esters of the 15-substituted-16,17,18, 19.20- pentanorprostaglandins of the E2 and F2a series based on especially outstanding in vivo antifertility activity in rats and at the same time reduced smooth muscle, blood pressure, or diarrheal effects. Similarly, the £-biphenylyl ester of the substituted 16.17.18.19.20- pentanorprostaglandins of the PGE1,PGE0,Foa.Fla, 13,14-dihydro PGE2 and F2cj and 11-deoxy PGE series are useful for fertility control including abortion and induction of labor on the basis of their smooth muscle stimulant activity.

The nev; compounds of this invention can be used in a variety of pharmaceutical formulations which contain the compound, and they may be administered in the same manner as natural prostaglandins by a variety of routes, such as intravenous oral, intravaginal, intramuscular, intra- and extra-amniotic, among others.

For induction of abortion, tablets of an aqueous suspension or alcoholic solution of the novel p-biphenylyl ester prostaglandins of the E and F series would appropriately be administered at oral doses of 0.1-20 mg., with 1-7 doses per day being employed. For intravaginal administration a suitable formulation would be lactose tablets or an impregnated tampon of the same agent. For such treatments suitable doses would be from 0.1-20 mg/dose with 1-7 doses being employed. For intra-amniotic administration a suitable formulation would be aqueous solution containing 0.05-10 mg/dose with 1-7 doses being employed. For extra-amniotic administration a suitable formulation would be an aqueous solution containing 0.005-1 mg/dose with 1-5 doses being employed. Alternatively, the novel prostaglandins of the E and F series of this invention can be infused intravenously for induction of abortion at doses of 0.05-50 pg/minute for a period of from 1-24 hours.

Another use for the novel p-biphenylyl ester of prostaglandins of the E and F series of this invention is as an inducer of labor. For this purpose an ethanol-saline solution is employed as an intravenous infusion in the amount of from 0.110 pg/kg/min for from 1-24 hours.

Another use for the novel £-bipheny]yl esters of prostaglandins of the E and F series of this invention is for fertility control. For this purpose a tablet is employed for intravaginal or oral administration containing 0.1-20 mg of prostaglandin per dose with 1-7 doses being employed at or following the expected day of menstruation. For synchronization of the estrous cycle in pigs, sheep, cows or horses, a solution or suspension containing 0.03-30 mg/dose of novel, p-biphenylyl ester of 15-substituted-16,17,18,19,20-tetranorprostaglandin of the E and F series is administered intramuscularly frcm 1-4 days.

The novel jo-biphenylyl ester prostaglandins of- the 11-deoxy PGE and 5 PGF series of this invention are useful as gastric antisecretory and antiulcer agents. ’ To prepare any of the above dosage forms or any of the numerous other forms possible, various reaction-inert diluents, excipients or carriers may be employed. Such substances include, 'for example, water, ethanol, gelatins, lactose, starches, magnesiuto stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylenb ~ ' glycols, petroleum Jelly, cholesterol, and other known carriers •for medicaments. If desired, these pharmaceutical compositions •may contain auxiliary substances such as preserving agents, wetting agents, stabilizing agents, or other therapeutic agents such as antihbtics.

The p-biphenylyl esters are prepared in. the Examples by simply adding p-phenylphenol to the prostaglandin in methylene chloride in the presence of a dehydrating agent, for example, dicyclohexylcarbodlimide,' and stirring overnight. Althou^li not more potent in in vitro smooth muscle tests, abortifacient evaluation of certain £-biphenylyl esters of this invention demonstrated that these p-biphenylyl-esters possess physiological activities in vivo markedly greater than those of the free acids.

In addition, many of the £-biphenylyi esters of this invention have the advantage of being crystalline.

The following non-limiting Examples XVII and XVIII illustrate the invention. In the Examples it will be appreciated that all temperatures are expressed in Centigrade, all melting and boiling . points are uncorraoted. -46I ! 43965 c-ch2-p-(och3)2 ί ο ιι EXAMPLE I Dimethyl. 2-0xo-2~ (±2,3-dihydrobenzo/“b 7fur-2-yl) ethylphosphonate (I A solution of 25.6 g (206 mmoles) dimethyl methylphosphonate (Aldrich) in 250 ml dry tetrahydrofuran was cooled to -78° in a I dry.nitrogen atmosphere. To the stirred phosphonate solution was added 107 ml of 2,0 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 30 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 18.3 g (103 mmole) methyl 2,3-dihydrocoumarilate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 0.5 hours at -78° the.reaction mixture was neutralized with 35 ml acetic acid and allowed to warm to ambient temperature, and rotary evaporated (in vacuo, water aspirator) to a white gel. The gelatonous material was taken up in 100 ml water,. the aqueous phase extracted with 200 ml portions of ethyl ether (3x), the organics washed with water, and concentrated (water aspirator) to give 18,3 g (66$) dimethyl 2-oxo-2-(±2,3-dihydrobenzo/“‘b_/fur-2-j yl)ethylphosphonate (2).

*The ± refers to the origin of the dihydrobenzfuryl portion of the molecule originating from ± 2,3-dihydrobenzo!uran”2~ carboxylic acid.

In a simlar manner, the phosphonates 2a-2d were prepared 5 (Table I). i TABLE I co a) N G H G a> N CM CU CO G CO P CD • P JSf •N CM CO i—1 CO »N i r4 + o 11 IO > 1, G in II in II Jh M d H VO co H O W co Q co n o in • H VO co r-i VO a co W • o -G* in n + L·- 11 H U in vo ‘KJ” in in M3 II cm m . h £! '9 in o o (1) The product phosphonates were purified hy column chromatography using silica gel (Baker, 60-200 mesh) and benzene/chloroform as eluting solvents. (2) Prepared from the (-)amphetamine salt of (-)hydrocoumarilic acid substituting methanol for ethanol following the procedure of D. M. Bowen, J. I. Degraw, V. R. Shah, and W. A. Bonner, J. Med, Chem., 6, 315 (1963). (3) Prepared from the (+)amphetamine salt of (+)hydrocoumarilic acid by the method of reference (2). (4) Prepared from the (-)amphetamine salt of (-)chroman-2p carboxylic acid. (5) Prepared from the (+)amphetamine salt of (+)chroman-22 carboxylic acid.

EXAMPLE II 2-/3a-2-Phenyrbenzoyloxy-5a-hydroxy-2/3-(3-oxo-3-(±2,3-dihydrobenzo-l /b_7fur-2-yl)-trans-l-propen-l-yl)-cyclopent-la-yl7Acefic Acid, γ-lactone (3_): Dimethyl 2-oxo-&(±2,3-dihydrobenzo/K_7fur-2-yl)ethylphosphonatt (2) (8.48 g, 31.4 mmole) In 50 ml anhydrous THF was added dropwise to 1333 mg (31.4 mmole) 575^ sodium hydride in 300 ml dry THF in a dry nitrogen atmosphere at room temperature. After 60 min. of stirring, 10.0 g (28.6 mmole) 2-/Ja-£-phenylbenzoyloxy-5“-hydroxy10 2£-formyleyclopentan- la-yl/acetic acid, γ-lactone was added in 459 85 one portion followed by 50 ml anhydrous THF. After 60 minutes the reaction mixture was quenched with 3 ml glacial acetic acid, filtered, evaporated, diluted with 350 ml ethyl acetate and washed successively with 100 ml saturated sodium bicarbonate solution (2x), 100 ml water (2x), 100 ml saturated brine (lx), dried (NagSOZj.) and evaporated to yield 9.8 g (69$) 2“/Ja-]3-phenylbenzoyloxy-5a-hydroxy-20-(3-oxo-3-(12,3-dihydrobenzo7b_7fur-2-yl) trans-l-propen-l-yl)cyclopent-la-yl7acetic acid, γ-lactone (3) as a foam after column chromatography.

The ir spectrum (KBr^) of the product 3. exhibited absorption bands at 1775 cm-1· (strong), 1715 cm-1 (strong), 1675 cm1 (medium) and 1630 cm1 (medium) attributable to the carbonyl groups and at 970 cm·'· (medium) for the trans double bond.

Similarly, the enones 3a-3d were prepared (Table II). 4S965 EXAMPLE III 2-/3a-E-Phenylbenzoyloxy-5a-hydroxy-2p- (3a-hydroxy-3- (±2,3 -dihydro Denzo/b_7fur-2-yl)-trans-l-propen-l-yl)cyclopent-la-yl7acetic acid γ-lactone (5): To a solution of 12.0 g (24.3 mmole) 2-/Ja-]o-phenylbenzoyloxy5a-hydroxy-2/3- (3-oxo-3-(±2,3-dihydrobenzo/b 7fur-2-yl)-trans-l!propen-l-yl)cyclopent-la-yj[7acetic acid, γ-lactone (3) in 150 ml dry THF in a dry nitrogen atmosphere at -780 was added dropwise 62.4 ml (25.8 mmole) of a 0.413 M lithium tri-sec-butylborohydride solution. After stirring at -780 and 0.5 hours the reaction was quenched with 54 ml of acetic acid/water (4θ:6θν/ν). The reaction \ mixture was allowed to warm' to room temperature and then combined with 200 ml water and 300 ml methylene chloride. The methylene chloride layer was separated and the aqueous layer further extracted with methylene chloride (1 x 300 ml). After washing · the combined organic with brine (2 x 150 ml), drying (MgSO^) and concentrating (water aspirator) the resultant residue was purified by column chromatography on silica gel (Baker Analyzed Reagent 60-200 mesh) using percentages benzene ethyl acetate as eluents. After elution of less polar impurities fractions containing 1.8 g 2-/Ja-io-phenylbenz oyloxy-5a-hyd roxy--(3 a-hydroxy-3-(±2,3dihydrobenzo/“b_7’fur-2-yl)-trans-l-propen-l-yl)cyclopent-la-yl/acetic acid, γ-lactone (5.), 1.5 g mixed 4 and 5 and 1.9 g 2-/Ja£-phenylbenzoyloxy-5a-hydroxy-2/3- (3/3-hydroxy-3 - (±2,3-dihydrobenzo/b_7-fur-2-yl)-trans-l-propen-l-yl)cyclopent-la-yl/acetic acid, γ-lactone (4) were obtained.

The ir spectra (KBrg) of 4 and 5. had strong carbonyl adsorbtions at 1770 and 1715 cm1 and an adsorbtion at 970 cm-1 for the trans double bond. The mass spectrum of 5 exhibited characteristic parent peak, m/e = 496.

Similarly, the alcohols 4a-4d and 5a-5d were prepared (Table III). 45933 co o CO -Sibbco H I vo OvVO • σ\ =t · t-in 1 I O W bCM CM • Ch in · b-rn t i o w co p-l B o co O W o o CM o -=t vo p4 vo σ\ co m • * CO a H o .xj· t-l 00 J=f m CJ CM m 1 H 1 1 ll in cm p r-n tJ II u vo in in in comvo CM PCM -cfCM CO vo in in in comvo CMQCM ^fCM CO r—» Γ-’ r~i * * * I O O CM mm H H I o .=± vo coco Η H I o b-CT> mm rirl - 57 48965 CO rJ w o co r-I w o o o o • o H . H KO o r-I o r-I b- KO co co H • • • l·- KO • KO Γ-t O •=t CO b“ fc- CO GJ -=t KO r-I co 1 < 1 I 1 r I II· II* II II II II KO in KO in Lf\ ιηοηιηκο in in co in Ko Cu pcu-3- cm cn GJ pGJ-=tGI σ J—‘1 Γ—1 i—i Γ“» 1—1 r-I a & 3) w tS •6 EXAMPLE IV 2-/3α,5c-Dihydroxy-2B-(3a-hydroxy-3-(i2,3-dihydrobenzo/b/fur-2-yl)- trans-l-propen-l-yl)cyclopent-la-yl7acetic acid, γ-lactone (6): A heterogeneous mixture of 1.8 g (3.6 mmole) of 2-/3a~£-phenyl-, benzoyloxy-5a-hydroxy-2j3-(3a-hydroxy-3- (±2,3-dihydrobenzo/b/fur-2yl)-trans-l-propen-l-yl)cyclopent-la-yl7acetlc acid, γ-lactone (5), 20 ml of absolute methanol, 15 ml THF and 502 mg of finely powdere^, anhydrous potassium carbonate was stirred at room temperature for 1.5 hours, then cooled to 0°. To the cooled solution was added 7.26 ml (14.52 mmole) of 1.0N aqueous hydrochloric acid. After stirring at 0° for an additional 10 minutes, 35 ®1. of water was added with concomitant formation of methyl p-phenylbenzoate which was collected by filtration. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (2 x 100 ml.), the combined organic extracts were washed with saturated sodium bicarbonate (2 x 75 ml.), brine (50 ml) and dried (MgSOij.) 4S96S and concentrated to give 1.2 g (100$) of viscous, oil 2-7?α,5adihydroxy-2/3- (3a-hydroxy-3{±2,3-dihydrobenzo/~b 7-2-fur-yl) -transl-propen-l-yljcyclopent-la-yl/aeetic acid, γ-lactone (6).

The ir spectrum (CHgClg) exhibited a strong adsorption 5 at 1775 cm-'· for the lactone carbonyl and medium adsorption at 970 cm”1 for the trans-double bond.

In a similar manner, the' following diols (6a-6d) were prepared from their corresponding ester-alcohols (5a-5d). 6c 6d EXAMPLE V 2-/3α, 5g-Dihydroxy-2p-(3P-hydroxy-3^i2,3-dihydrobenzo^~b_7fur-2-yli trans-l-propen-l-yl)cyclopent-la-yl7acetic acid, γ-lactone (16): A heterogeneous mixture of L9 g (3.θ2 mmole) of 2-(/Ja-£-phenyl5 3enzoyloxy-5a-hydroxy-2j3-(3jS-hydroxy-3-(±2,3-dihydrobenzoz^~'b_J7fur-2.yl)-trans-l-propen-l-yl)cyclopent-la-yl7acetic acid, γ-lactone (4), 20 ml, of absolute methanol, 7 ml. THP and 529 mg of finely powdered, anhydrous potassium carbonate was stirred at room temperature for 1.5 hours, then cooled to 0°. To the cooled solution was added 7.64 ml (15.28 mmole) of 1.0N aqueous hydrochlor acid. After stirring at 0° for an additional 10 minutes, 30 ml. of water was added with concomitant formation of methyl p-phenylbenzoate which was collected by filtration. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (2 x 100 ml), the combined organic extracts were washed with saturated sodium bicarbonate (2 x 75 ml), brine (150 ml) and dried (MgSOi).) and concentrated to give 1.2 g (1OC$ of viscous, oily 2-/3a, 5a-dihydroxy-2p-(3j8-hydroxy-3*(±2,3-dihydrobenzo/’b_7fur-2-yltrans -1-propen-l-yl)cyclopent-la-yl7acetic acid, γ-lactone (16). - 61 -. The ir spectrum (CHgClg) exhibited a strong adsorption at 1775 cml for the lactone carbonyl aid medium adsorption at 97° cm-1 for the trans double bond.

In a similar manner, the following diols (16a, 16c, l6d) were prepared from their corresponding ester-alcohols (4a, 4c, 4d) EXAMPLE VI 2-/5a-Hydroxy-3a- (tetrahydropyran-2-yloxy) -2β- (3a-/tetrahydropyran-< —— ...........— - — “ Γ 2-yloxj7-3-(-2,3-dihyd:rcpen2o/b_7fur-5-yl)-trans-l-propen-l-yl)cyclopent-la-yl7acetic acid, γ-lactone (7): To a solution of 1.2 g (3.84 mmole) 2~/Ja, 5a-dihydroxy~2/3(3a-hydroxy-3X±2,3-dihydrobenzo/”b_/fur-2-yl)-trans-l-propen-yl)cyclopent-la-yl/acetic acid, γ-lactone (6) in 24 ml anhydrous methylene chloride and 2,l4 ml of 2,3-dihydropyran at 0° in a dry nitrogen atmosphere was added 16 mg p-toluenesulfonic acid, monohydrate. After stirring for 30.minutes, the reaction mixture was combined with 150 ml diethyl ether, the ether solution washed wiph saturated sodium bicarbonate (2 x 75 ml) then saturated brine (1 x 100 ml), dried (MgSO/j) and concentrated to yield 1.9 g of 2-/5<2“hydroxy-3a-(tetrahydropyran-2-yloxy)-2P-(3a-/tetrahydro15 pyran-2-ylox^3-(+2,3-dihydrobenzo/b_7fur-2-yl)-trans-l-propen-lyl)cyclopent-la-yl7acetic acid, γ-lactone (7).

The ir (CHgClg) spectrum had a medium adsorption at 970 cm-1 for the trans double bond and a strong adsorption at 1775 cm·'' for the lactone carbonyl. <55SQa In a similar manner, the diols (6a-6d) were converted into their corresponding THP derivatives (7a-7d). 7a 7b 7c 7d - 64 45965 EXAMPLE VII 2-/Ja-Hydroxy-3g-(tetrahydropyran-2-yloxy)-2iS-(3)S-/tetrahydropyran* 2-yloxy7-3-(^2,3-dihydrobenzo/b_7-fur-2-yl)-trans-l-propen-l-yl)cyelopent-la-yl7acetic acid, γ-lactone (17): To a solution of 1.12 g (3.55 nmole) 2-/^a, 5a-dihydroxy-2j3-(3jS-, hydroxy-3- (±2,3-dihydrobenzo/-b_7fur-2-yl)-trans-l-propen-l-yl) eyclopent-la-yl/aeetic acid, γ-lactone (l6) in 22 ml anhydrous methylene chloride and 1.975 ml of 2,3-dihydropyran at 0° in a dry nitrogen atmosphere was added 14.8 mg p-toluenesulfonic acid, •10 monohydrate. After stirring for 30 minutes, the reaction mixture . was combined with 150 ml diethyl ether, the ether solution v/ashed wi^h saturated sodium bicarbonate (2 x 75 ml) then saturated brine (1 x 100 ml), dried (MgSOij.) and concentrated to yield l68o mg of 2-1/5a“hydroxy-3a-(tetrahydropyran-2-yloxy)-2^-(3a-/tetrahydro15 pyran-2-yloxy7-3-(+2.3-dihydrobenzo/~b 7fur-2-yl)-trans-l-propen-lyl )cyclopent-la-yl7acetic acid, γ-lactone (17) after column chromatography.

The ir (CHgClg) spectrum had a medium adsorption at 970 cm1 for the trans-double bond and a strong adsorption at 1775 cm-·'- for the lactone carbonyl.

In a similar manner, the diols (l6a, 16c, l6d) were converted into their corresponding THP derivatives (17a, 17c, 17d) 17a 4S9 65 2-/5d~Hyaroxy-3ct-(tetrahydropyran-2-yloxy) -2β- (3g-/tetrahydropyran-j 2-ylo^7-3-(±2j3-dihydrobenzo/b_7fur-2-yi)4;rans-l-propen-l-yl)cyclo-j pent-la-yl7acetaldehyde, γ-hemiaeetal (8): A solution of 1.86 g (3.84 mmole) of 2-/5a-hydroxy-3a-(tetra. hydropyran-2-yloxy)-2^-^a-/tetrahydropyran-2-ylox^7-3- (±2,3dlhydrobenzo/~b 7fnr-2-yl)-trans-l-propen-l-yl)cyclopent-la-yl7 acetic acid, γ-lactone (7) in 20 ml dry toluene was cooled to -78° in a dry nitrogen atmosphere. To this cooled solution was added 5· 25 ml of 20$ diisobutylaluminium hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the Internal temperatu^i never rose above -65° (20 minutes). After an additional 30 minutes of stirring at -78°, methanol was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 150 ml diethyl ether, washed With 50% sodium potassium tartrate solution (3 x 60 ml) brine (1 x 75 ml), dried (Ha2S0i|) and concentrated to yield 1467 mg 2-/5a-hydroxy-3a(tetrahydropyran-2-yloxy)-2j3-(3a-/tetrahydropyran-2-ylox2/7-3- (±2,3-, dlhydrobenzo/b 7fur-g-yl)-trans-l-propen-l-yl)cyelopent-l-yl767 45963 acetaldehyde, γ-hemiacetal (8) after column chromatography. The ir spectrum exhibited a medium adsorption at 970 cm-1 for the brans double bond.

In a similar manner, the following hemiacetals (8a-8d) were 5 prepared from their corresponding THP derivatives (7a-7d). 8a 8b 8c 8d EXAMPLE IX 2-/^a-Hydroxy-3a(tetrahydropyran-2-yloxy)-2jS-(3jS-/tetrahydropyran-^yloxy7-3- (+2,3-dihydrobenzo/b_7fur-2~yl)-trans-l-propen-l-yl) cyclopent-la-yl7acetaldehyde, γ-hemiacetal (18): A solution of 1.68 g (3.47 mmole) 2-/5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-20-(3j3-/tetrahydropyran-2-ylox27-3-(±2,3dihydrobenzo/b Tfur-2-yl)-trans-l-propen-l-yl)cyclopent-la-yl7acetic acid, γ-lactone (17) in 20 ml dry toluene was cooled to -78° in a dry nitrogen atmosphere. To this cooled solution was added 4.75 ml of 20% diisobutylaluminiumhydrid'e in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal temperature never rose above -65° (20 minutes). After an additional 30 minutesj of stirring at -78°, methanol was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was contained with 150 ml diethyl, ether, washed, with 50?, sodium potassium tartrate solution (3 x 60 ml), brine (1 x 75 ml), dried (NagSOij.) and concentrated to yield 1513 mg 2-/5a-hydroxy-3a-(tetrahydropyranl2-yloxy)-2/3-(3(3-/tetrahydropyran-2-yloxy73~(±2/3-dihydrobenzo/b_7fur-2-yl)-trans-l-propen-l-yl)cyclopent-l-yl7acetaldehyde, γ20 hemiacetal (17) after column chromatography. The ir spectrum exhibited a medium adsorption at 970 cm-·*' for the trans double bone In a similar manner, the following hemiacetals (l8a, 18c, l8dj were prepared from their corresponding THP derivatives (17a, 17c, 17d). . 43965 C02H EXAMPLE X 9a-Hydroxy-lla,15a-bis-(tetrahydropyran-2-yloxy)-15-(±2,3-dihydrobenzo/~’b_7'fur-2-yl) -cis-5-trans-13—16,17,18,19,20-pentanor-prostadienoic acid (J); To a solution of 3.3 g (7.4 mmole) (4-carboxybutyl) trlphenylphosphonium bromide in a dry nitrogen atmosphere in 10 ml dry dimethyl sulfoxide was added 8.05 ml (16.9 mmole) of a 21M solution of sodium methylsulfinylmethide in dimethyl sulfoxide.

To this red ylide solution was added dropwise a solution of 1467 mg (3.04 mmole) 2-/5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2)3· (3a-/tetrahydr°pyran-2-yl0X27-3- (+2,3-dihydrobenzo/b_7fur-2-yl)trans-l-propen-l-yl) cyclopent-la-yl/acetaldehyde, γ-hemiacetal (8) in 15.0 ml dry dimethyl sulfoxide over a period of 20 minutes. After an additional 20 hr stirring at room temperature, the reaction mixture was poured onto ice water, 10# HC1 (60 ml), and ethyl acetate (100 ml). The acidic solution was extracted with ethyl acetate (2 x 100 ml) and the combined organic extracts washed with water (1 x 100 ml), brine (100 ml), dried (MgSO/j.) and evaporated to a residue. The residue was purified by column chromatography on silica gel (Baker Analyzed Reagent 60-200 mesh) using chloroform and ethyl acetate as eluents. After ' removal of high Rf impurities, 658 mg of 9a-hydroxy-lla,15a-t>is(tetrahydropyran.-2-yloxy) -15-(±2,3-dihydrobenzo/b_7fur-2-yl)5 cis-5-trans-13~16, 17', 18, 19, 20-pentanorprostadienoic acid was collected. 43965 EXAMPLE XI 9a-Hydroxy-lla,15/3-bis-(tetrahydropyran-2-yloxy)-15-(±2,3dlhydrobenzo/b_7fur-S-yl)-cis-5-j;rans-13-16,17,18,I9,20-pentanorprostadienoic acid (9a): ' To a solution of 3440 mg (7.85 mmole) (4-carboxybutyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 10 ml dry dimethyl sulfoxide was added 8.15 ml (17.1 mmole) of a 2.1M solution of sodium methylsulfinylmethide in dimethyl sulfoxid£. To this red ylide solution was added dropwise a solution of 1513 mg (1.34 mmole) 2-/?a-hydroxy-3a-(tetrahydropyran~2-yloxy)-2£(3|S“/tetrahydropyran-2-ylox^7-3-(±2,3-dihydrobenzo/b_7-fur-2-yl)trans-propen-l-yl)cyclopent-la-yl7acetaldehyde, γ-hemiacetal (8a) in 15 ml dry dimethyl sulfoxide over a period of 20 minutes.

After an additional 24 hours stirring at room temperature, the reaction mixture was poured onto ice water, 10$ HC1 (60 ml) and ethyl acetate (100 ml). The acidic solution was extracted with ethyl acetate (2 x 100 ml) and the combined organic extracts washed once with water (100 ml), brine (100 ml), dried (MgSOj^) and evaporated to a residue. The residue was purified by column chromatography on silica gel (Baker Analyzed Reagent 60-200 mesh using chloroform and ethyl acetate as eluents. After removal of high Rf impurities, 5βθ mg of 9a-hydroxy-lla, 15jB-bis-(tetrahydropyran-2-yloxy) -15- (±2,3-dihydrobenzo/b_7fur-2-yl)-cis-5-transl· 13 ‘16,17,18,19,20-pentanorprostadienoic acid was collected.

In similar manner, the hemiacetals (8a-8d) were converted into the prostanoic derivatives (9a-9d).

AR= 19ο 19<3 ί 35S6g EXAMPLE XII 9α, 11α, 15a-Trihydroxy-15- (+2,3-dihyarobenzo/b_7fur-2-yl)-cis-5trans-13-16,17,18,19,20-pentanorprostadienoic acid (12): A solution of 577 mg 9a-hydroxy-lla, 15a-bis- (tetrahydropyran-2·» yloxy) -15- (±2,3-dihydrobenzo/b_7f ur-2-yl)-cis-5-trans-13-i6,17,18, .19,20-pentanorp’rostadienoic acid (_9) in 5.8 ml of a 65:35 v/v mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 16 hours then was concentrated by rotary evaporation. The 1 resultant crude oil was purified by column chromatography on 10 silica gel (Mallinckrodt (Registered Trade Mark) 00-77 using chloroform and ethyl acetate as eluents. After elution of less polar impurities the desired 9a, 11a, 15a-trihydroxy-15-(-2,3-dihydrobenzofbJfur-2-yl)-cis-5-trans-13-16,17,18,19,20-pentanorprostadienoic acid (12) wieghing 168 mg was collected.

In a similar manner, the 1·'2α 15-cubsLitubed 16,17,18,l9,20-pentanor4 prostaglandins (12a-12g) were prepared. Table summarizes the chiral optical properties of these compounds.

Compound Solvent 12a +10.6 (0.76) CH3OH 12b +Ϊ2.9 (1.23) CH3OH 12c +3,.3 (1.02) chci3 12d +54.3 (1.16) CHCI3 12e +22.5 (0.54) CHgOH 12f -21.5 (1.33) chci3 12g +40.2 (1.28) CHCI3 The following spectral data for 12f was typical: IR (CHCI3): A broad adsorption centered at 3400 cm-1 for the hydroxyls; a strong adsorption at 1712 cm-1 for the carboxylic acid carbonyl and a medium adsorption at 975 cm·'· ftr the -double bond.

NMR (CDCI3): A multiplet (6.65-7.22$) for the aromatic 15 protons (4h); multiplets between 5.11$ and 5·9θ$ tor the cts and trans olefinic protons (4H) and for the variable hydroxyl protons (4h); multiplet between 3.78$ and 4.58$ for the -0-C-H protons (4H); and a multiplet between l.l/ and 3.04/ for , the remainder of the protons (16H).

EXAMPLE XIII 9-0xo-llct, lSa-bls- (-tEbrahydropyran-2-yloxy) -15-(±2,3-dihydrobenzo(bJfur-2-yl)-ci.s-5—hrans-13- 16,17,18,19,20-pentanoigrostadienoic acid (10): To a solution cooled to -10° under nitrogen of 658 mg 5 (1.15 mmole) 9a-hydroxy~lla, 15a-bis-(tetrahydropyran-2-yloxy)15(+2,3-dlhydrobenz o/~b_J7f ur- 2-yl)-cls-5-trans-13-16,17,18,19,20-pentanofprostadienoic acid (£) In 10 ml. reagent grade acetone was added dropwise to 0.51 ml of Jones' reagent. After 5 minutes at -10°, 1.0 ml 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 100 ml ethyl acetate, washed with water (3x50 ml), brine (1 x 50 ml), dried (MgSO^) and concentrated to give 514 mg of 9-oxo-lla,15a-bls-(tetrahydropyran-2-yloxy)-15-(±2,3-dihydrobenzo/~b_7fur-2-yl)-cis-5-trans-13-16,17,18,19,20-pentanorprosta15 dienoic acid (10). nil OTHP COgH OTHP 100 EXAMPLE XIV ' 9-0xo-lla, 15|3-bis.-(tetrahydropyran-2-yloxy)-15-(i2,3-dihydrobenzo ffiJ-fur-2-yl)-cis-5-tyans-13-16,17,18,19,20-gentanorpro5tadienoic acid (10a)t To a solution cooled to -10° under nitrogen of 560 mg 5 (Ο.98 mmole) 9a-hydroxy-lla, 15/3-bis-(tetrahydropyran-2-yloxy)-15(±2,3 -dihydr obenzo^b^Tf ur- 2-yl )-5-trans-13~16,17,18,19, 2O-pentanorprostadienoic acid (9a) in 10 ml. reagent grade acetone was added dropwise to 0.44 ml. of Jones' reagent. After 5 minutes at -10° 1.0 ml. 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 100 ml. ethyl acetate, washed with water (3 x 50 ml.), brine (1 x 50 ml.), dried (MgSOjj.) and concentrated to give 392 mg. of 9-oxo-lla,15ft-bis-(tetrahydropyran-2-yloxy)15- (+2j 3“dihydrobenzo/~b_7-fur-2-yl) -eis-5-trans-13-*16,17,18,19, 20-pentanorprostadienoic acid (10a). - 80 In a similar manner, the protected were uaxuj the protected PGE2 derivatives (lOa-d, lOOa-c). jtu J. Il Cv Ο-Οχο-ΙΙα,15a-dihydroxy-15-(±2,3-dihydrobenzo/ b /fur-2-yl)-cis-5trans-13·-; 16,17,18,19,20-pentanogprostadienoic acid (11): A solution of 514 mg. 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy) 15-(+ 2,3-dihydrQbenzo [blftu>2-yl-cis-5-trans-13-16,17,18,19,20-pentanorprostad ietoic acid (10) in 5.2 ml. of a 65:35 v/v mixture of glacial acetic acid: water was stirred under nitrogen at 25° for 18 hours then was con1 jcentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7) 'using chloroform and ethyl acetate as eluents. After elution of less polar impurities the desired 9-oxo-lla,15a-dihydroxy-15-(±2,3dihydrobenzoJVj fur-2-yl) -cis-5-trans-13-16,17,18,1.9,20-pentanorprostadienoic acid (l·!) weighing 150 mg. was collected. The ir spectrum .(CHC1-) exhibited a broad hydroxyl adsorbtion (3200-3650 cm ^strong 3 -1 -1 15 carbonyl adsorbtions at 1740 cm (Ketone) and 1710 cm (acid) 'and a medium absorbtion at 970 cm 1 for the trans double bond. 4596s 100 110 EXAMPLE XVI 9-0χο-11α,15£-dihydroxy-15-(±2,3-dihydrobenzo/~h_7fur-2-yl)-cis5-trans-13-16,17,18,19,20-pentatiorprostadlenoic acid (110): A solution of 492 mg. 9-oxo-lla,153-bis-(tetrahydropyran-25 yloxy)-15-(+2,3-dihydrcbenzo/b)fur-2-yl)-cis-5-trans-13-16,17,18,19,2O-pentanorprostadienoic acid (100) in 4.9 ml. of a 65:35 v/v mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 18 hours then was concentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7) using chloroform and ethyl acetate as eluents. After elution of less polar impurities the desired 9-oxo-lla, 15β-dihydroxy-15-(±2,3-dihydrohenzo/E_7fur-2~yl)'^· cis-5-trans-13-16 ,17,18,19,20-pentanorprostadienoic acid (110) weighing 219 mg. was collected. 459 35 X5965 The following spectral data for lid was typical: IR (CHClg): Broad hydroxyl region centered at 3375 cm“l; strong carbonyl adsorptions at 1740 cml (ketone) and 1710 cm~l (acid)j medium adsorption at 970 cra~l (trans double bond), NMR (CDClg): A multiplet, 665-7·2li, for the aromatic . protons (4H); multiplets centered at 6.05/, 5.79/, 5.38/ for the hydroxyl (-0-H, 3H), trans (2H) and cis (2H) protons, respectively; a broad multiplet, 3.79^-4.42^, for the ether protons (-O-C-H, 3H); and multiplets from 11/-3.0^ for the ' remainder (ίδΗ) of the protons. - 86 1 -€Μ2>“365 EXAMPLE XVII g-Biphenylyl 9-oxo-lla, 15 a-dihydroxy-15- (±2, 3-dihydrobenso/~b_7~ fur-g-yl)-cis-5-trans-13-16,17,18,19,20-pentanorprostadienoate (13): To a solution of 70 mg, (0,17 mmole) of 9-oxo-lla,15a5 dihydroxy-15-(±2,3-dihydrobenzo/-bJ7fur-2-yl)-cis-5-trans-13-16, 17,18,19,20-rentonorprostadienoic acid (11) 330 mg. (1.94 rrmole) of n-phenylphenol in 10 ml. of dry methylene chloride was added 2.44 ml. (0.24 mmole) of 0.1M dicyclohexylcarbodiimide in methylene chloride and the solution stirred overnight at room temperature. After concentration, the crude product was purified by silica gel chromatography to give the desired p-biphenylyl ester (13), m.p. 97-104° (45 mg.).

In a similar manner, lla-g, were converted into the p-bijhenylyl esters, 13a-g .

Compound 13 a 46-48° 5 13b 103-104' 13c 75-78° 13d 88-90° 13 e <30° - - .91-92° 10 13£ <30° EXAMPLE XVIII ! p-Biphenylyl 9α, 11α, 15a-Trihydroxy-15- (±2,3-dihydrobenzo/“b_7lfur-2yl)-cis-5-trans-l3 - 16,17,18,19,20-pentanorprostadienoate (14): To a solution of 120 mg. (0.29 mmole) of 11a, 15a-Trihydroxyf 5 15-(i2,3-dihydrobenzo £bjfur-2-yl)-cis-5-trans-13-16,17,18,19,2O-pentanorprostadienoic aoid (12) and 571 mg. (3.36 mmole) of £-phenylphenol in 10 ml. of dry methylene chloride was added 4.23 ml. (.42 mmole) of 0.1M dicyclohexylcarbodiimide in methylene chloride and the solution stirred overnight at room temperature.

After concentration, the crude product was purified by silica gel chromatography to give the desired £-biphenylyl ester (14), m.p. 147-148° (42 mg.). - 89 · In a similar manner, the free acids 12a-g were converted into the g^biphenylyl esters l4a-g.

Compound ajsx 14a 106-8° 14¾ 146-8° 14c 74-76° l4d oil --- -l4e 105-7° l4f oil l4g ' oil EXAMPLE XIX 9a-Hydroxy-lla, 15g-bis-(tetrahydropyran-2-yloxy)-15-/”(+)-3,4dihydrcbenzo^/3yran-2-yl7-16,17,lS,19,2O-eentanorpi«stanoic acid (36d): A mixture of 190 mg (0.33 mmole) 9a-hydroxy-lla,lgct-bis5 (tetrahydropyran-2-yloxy) -15-/7+)-3,4-dihydrobenzo/“b_7pyran-2-yl7 cis-5-trans-13-16,17,18,19.20-pentanorprostadienoic acid, 5¾ palladium on carbon (150 mg) in ethyl acetate (10 ml) is stirred under an atmosphere of hydrogen for 60 hours at room temperature. The 1 mixture is filtered and concentrated to give 9a-hydroxy-lia,15a10 bis-(tetrahydropyran-2-yloxy)-15-/(+)-3,4-dihydrobenzo/“b_7pyran-2-yl7 - 16,17,18,19,20-pentanorprostanoic acid (36d). i >1 - 91 45965 9α, 11α, 15a-Trihydroxy-15-/T+) -3,4-dihydrobenzo/7b_7pyran-2-yl716,17,18,19,20-penfcanoi-prostanoic acid (37d): Hydrolysis cf 20 mg 9a-hydroxy-lla,15a-bis-(tetrahydro5 pyran-2-yloxy) -3,4-dihydcobsnzo/3/pyran-2-ylJ-16,17,18,19,20-pentanor prostanoic (36d) acid is carried out with acetic acid (0.5 ml) I and water (0.3 ml) under nitrogen at room temperature for 20 hours Purification as described in Example XII affords pure 9a, 11a,15atrihydroxy-15-/T+) -3,4-dihydrobenz offb_7pyran-2-ylZi6,17,18,19,201θ pantanorprostanoic acid (37d) EXAMPLE XXI 9-0χο-11α, 15a-dihydroxy-15-/7+)-3,4-άίΗγ(3ϊ·οΐ3Θηζο/~ΐ)_7ρ7ΓΕη-2-7ΐ716,17,18,19,20-pentanorprostanoic acid 39d): A solution of l86 mg. of the product of Example -xrxin 3 ml acetone is oxidized with 0.2 ml of Jones' reagent as described in Example XIII. Isolation of the product and hydrolysis with acetic acid and water at room temperature and purification as described in Example XV gises pure 9-oxo-lla, 15a-dihydroxy15-/X+ )-3,4-dihydrobenzo7^_7pyran-2-yl7-16'17/13'91'20Pentanorprostarioic acid (39d). lid 12d 4ld EXAMPLE XXII 9ft, 11α, 15a-Trihydroxy-15-/~(+)-3,4-dihydrobenzo /~b_7pyran-2-yl7, 5-CiS,13-trans- 16,17,18,19,20-pentanorprostadienoic acid (41d) : To a solution of 50 mg of 9-oxo-lla, 15a-dihydroxy5 _314-dihydrdbenz(/bypyraft-2-yj^-cis-5rtrans-13-16,17,18,19,20-pentanorprostadienoic acid (lid) in 2.5 ml absolute methanol cooled to 0° is added dropwise a solution of 25 mg of sodium borohydride in 1 ml absolute methanol. The reaction mixture is stirred under nitrogen at 0° for 2 hours and then concentrated. The residue is dissolved in methylene chloride, washed with brine, dried (NagSOk), and is concentrated. Purification of the crude product : by silica gel chromatography affords 15-/7(+)-3,4-dihydrobenzo/~b_/~ Oyran-2-ylJ-lS,17,18,19,20-pentanor-PGF2ci (13d) and the desired 9ft-lla,15a-triliydrojy-15- ^/7+) -3,4-dih.ydrobenzoJbj pyran-2-yl^-5-cis, 13-trans-16,17,18,19,2015 pentanorprostadienoic acid (41d).

EXAMPLE XXIII 2-/3~a-hydroxy-5a-hydroxy-23- (3α-hydroxy-3-/[+)-3,4-dihydrobenzo/~b_7 pyran-2-yl7prop-l~yl)cyclopent-la-yl7acetic acid, γ-lactone: A heterogenous solution of 2.5 g of 2-/3a-hydroxy-5a5 hydroxy-23- (3 a-hyd r oxy-3-/(+ )-3,4-dihydrobenzo/-b__7pyrsn-2-yl7trans-l-propen-l-yl)cyclopent-la~yl7acetic acid, γ-lactone and 0.25 g of 5$ palladium on charcoal in 30 ml of ethyl acetate is stirred under 1 atmosphere of hydrogen for 4 hours. The.mixture is then filtered and concentrated to afford 2-/~3α-hydroxy-5a10 hydroxy-23- (3-oxo-3-/T+ )-3,4-dihydrobenzo/73_J7pyran-2-yl7-prop-l-y 1' cyclopent-la-yl7acetic acid, γ-lactone.

This is converted to the 13, l4-dihydro-E2 and- *2α compounds using methods employed in Examples VI to XVIII. 43935 43d EXAMPLE XXIV 9a-Hydyoxy-lla,15a-bis-(tetrahydropyran-2-yloxy)-15-/(+)-3,4_dihydrcbanzc/b/pyran.-2-y]7-13-jxans-16,17,18,19,20-pentanorprostenoic acid: A heterogeneous mixture of 800 mg of 9a-hydroxy-lla, 15a5 bis- (tetrahydropyran-2-yloxy) -15-/(+) -3,4-dihydrobenzo/“b_7pyran2-yl7~cls-5-trans-13-16,17,18,19,20-tetranorprostadienoic acid and 8Qmg of 5¾ palladium on charcoal in 10 ml of absolute methanol is stirred under 1 atmosphere of hydrogen, at -22° for 5 hours. The mixture Is then filtered and the filtrate is concentrated and purified by column chromatography to afford 9a-hydroxy-lla, 15aII bis-(tetrahydropyran-2-yloxy) -15-/(+)-3,4-dihydrobenzo/“b_7pyr an2-yl7-13-trans-16,17,18,19 ,20-pentanoqorostenoic acid.

Hydrolysis and purification as described in Example XII , affords 15-/(+)-3,4-dihydrobenzo/b_7pyran-2-yl7“l6,17,18,19, -pentanor PGF^% 48065 Oh Ο Ο COgH OH OH lid 44d EXAMPLE XXV 9-oxo-lla, 15a-dihydroxy-15-/f+ )-3,4-dihydrobenzo/“h_7pyran-2-yl7~ ____ A solution of 72 mg 9-oxo-lla, 15a-dihydroxy-15-/f+ )-3,45 dihydrohenzo/b 7pyran-2-yl7-cls-5-trans-13-i6,17,lS,19,20 pentanorprosb adienoic acid in 5 ml of anhydrous diethyl ether is treated with 450 mg dimethylisopropyl chlorosilane and 36 mg of triethylamine at room temperature under nitrogen for 48 hours. The reaction mixture is cooled to 0°, methanol is added, and the resulting solution is washed with water, dried (NagSO^), and is concentrated) The residue is dissolved in methanol (6 ml) and 30 mg of 5$ ! palladium on charcoal is added. The resulting mixture is stirred at -22° under 1 atmosphere of hydrogen for 4 hours. After filtration and concentration of the filtrate, the residue is stirred with a 65:35v/V mixture of acetic acid: water for 10 minutes at room temperature. The mixture is diluted with water, extracted with ethyl acetate, dried (NagSOii.) and concentrated to afford, after purification by silica gel chromatography, 9-°χ°-11α,15αdihydroxy-15-/r+)-3,4-dihydrobenzo/~b_7pyran-2-yl7-13-trans-16,17, : IS,19,20-pentanorprostenoic acid.

Zi59 6 5 CHO 49d EXAMPLE XXVI (rac.) - 2-)5ct-Hydroxy- 2 g- (3-oxo-3- /(+) - 3,4-dihydrobenzo pyran2-yjJ—fcrans.-1-propen-l-yl)-cyclopent-la-yJ Acetic Acid, γ-lactone (A94) Dimethyl 2-oxo-3-[j+)-3,4-dihydrobenzo[b]pyran -2-ylJethylphosphonate {2) (28.6 mmole) in 420 ml anhydrous THE is treated with 1.21 g (28.6 mmole) 57% sodium hydride in a dry nitrogen atmosphere at room temperature. After 60 min. of stirring (rac.) -2-f~5oi-hydroxy-28-formylcyclopentan-loi-yi~l acetic acid, γlactone in 50 ml anhydrous THF is added. After 95 minutes the reaction mixture is quenched with 4.2 ml glacial acetic acid, filtered, evaporated and combined with 250 ml ethyl acetate which is washed successively with 100 ml saturated sodium bicarbonate solution (2X), 150 ml water (IX), 150 ml saturated brine (IX), dried (Na SO ) and evaporated to afford (hat.)-2-/5ot-hydroxy2 4 —28-(3-oxo-3-/7+)-3,4-dihydrobenzorb]pyran-2-yl~]-trans-l-propen1-yl)cyclopent-la-yljacetic acid, γ-lactone. 49d may be converted to the ll-deoxy-16,17,18,19,20-pentanorprostaglandins by Examples III and VI through XXV. 43965 j OH 50d EXAMPLE XXVII 9-0xo-15tx-hydroxy-15- [ (+) -3,4-dihydrobenzo [b] -fur-2yl~}-cls-5,10,trans-13-16,17,18,19,20-pentanorprostatrienoic acid (50d) : A mixture of 68 mg 9-oxo-lla,15a-dihydroxy-15-f(+)-3,4dihydrobenzofb]-fur-2-vl*1-cls-5—trans-13-16,17,18,19,20-tetranorprostadienoic acid and 6 ml acetic acid is stirred overnight at 70° After concentration, the reaction mixture is combined with 50 ml ethyl acetate, washed with water (3 x 25 ml), dried (Na2S04) and concentrated to give the desired 9-oxo-15a-hydroxy-15- 0+)-3,4dlhydrobenzorb~|-fur-2-yri-cis~5,10,trans-13-16,17,18,19,20-tetranor prostatrienoic acid. Similarly, the other E prostaglandins are converted to their corresponding A prostaglandin derivatives.

Claims (5)

1. The £-biphenylyl estersof 16,17,18,19,20-pentanorprostaglandins, having at the 15-position one substituent of the formula: 5 wherein R is hydrogen, chlorine, fluorine, methyl, trifluoro methyl,or methoxy; and n is 1 or 2; and either an oxo group or a hydrogen atom and hydroxy group.

2. The £-biphenylyl esters of 16,17,18,19,20-pentanoroprostaglandins of the A,E, or F series, having at the 1510 position one substituent of the formula: wherein R and n are as defined in claim 1, and either an oxo group or a hydrogen atom and a hydroxy group.

3. A compound of the structure: R and n are as defined in claim 1; R' is £-biphenylyl; W is a single bond or cis double bond; 20 Z is a single bond or trans double bond; L is a single or double bond; and M are oxo 100 45 965 OH N is hydrogen or α-hydroxyl; with the proviso that when L is a double bond N is hydrogen.

4. A compound of the structure: wherein R, R', M, W, Z and n are as defined in claim 3.

5. The C g epimer of the compound of Claim 4 6. A compound of the structure: III wherein R, R', M, W, Z, and n are as defined in claim 3 101 7. A compound of the structure: W COR' wherein R, R', M, W, Z and n are as defined in claim 3. 102 8. A compound of the structure: wherein R, n, W, Z, M and R' are defined in claim 3. 9. A compound of the structure: wherein R, n, W, Z, M and R' are as defined in claim 3. 103 and the Cg and C^^ epimers thereof, wherein R, R', W, Z and n are as defined in claim 3, THP is 2-tetrahydropyranyl; and Q is hydrogen or 2-tetrahydropyranyloxy. wherein R, R', W, Z and n are as defined in claim 3 and THP and Q are as defined in claim 10. 12. A compound of Claim 3 wherein n is 1 13. A compound of Claim 3 wherein n is 2. 14. A compound of Claim 12 wherein the chiral carbon atom of said substituent at the 15-position has the (+)configuration. 15. A compound of Claim 12 wherein the chiral carbon atom of said substituent at the 15-position has the (-) configuration. 16. A compound of Claim 13 wherein the chiral carbon atom of said substituent at the 15-position has the (+) configuration. 17. A compound of Claim 13 wherein the chiral carbon atom of said substituent at the 15-position has the (-) configuration. 18. 15- jj-)-2-coumaryl“[ -16,17,18,19,20-pentanor-PGE 2a “£“ biphenylyl ester. 19. 15- j2(-)-2-coumarylJ-16,17,18,19,20-pentanor-PGF 2a -£-biphenyl yl ester. 20. 15-Epi-Q-)-2-coumarylj-16,17,18,19,20-pentanor-PGF 2a -£biphenylyl ester. 104 4 5965 21. 15-[(+)-2-coumaryl]-16,17,18,19,20-pentanor-PGE 2 £biphenylyl ester. 22. 15-β+)-2-coumarylJ-16,17,18,19,20-pentanor-PGF 2a £biphenylyl ester. 5 23. 15-Epi-15- β-)-2-coumarylJ-16,17,18,19,20-pentanor-PGE 2 £-biphenylyl ester. 24. 15-jj+)-2-chromanylJ-16,17,18,19,20-pentanor-PGF 2a £biphenylyl ester. 2 5. 15-Epi-15 - [(+)-2- chromany l] -16,17,-18,19,20-pentanor-PGE 2 10. £-biphenylyl ester. 26. 15- |/-)-2-chromanylJ-16,17,18,19,20-pentanor-PGF 2a £biphenylyl ester. 27. 15~Epi-15-/(-)-2-chromanyl/-16,17,18,19,20-pentanor-PGF 2ci pbiphenylyl ester. 28. 15-/(+)-2-chromany]/-16,17,l8,19,20-pentanor-PGE 2 biphenylyl ester. 29. 15-Epi-15 -/7+) -2-chroiaanyl.7-l 6,17,18,19,20-pentanor-PGE 2 ρ-biphenylyl ester. 30. 15-f(-)-2-chromanyl7-16,17,18,19,20-pentanor-PGE 2 p20 biphenylyl ester. 31. 15-Epi-15-/(-)-2-chromanyl7-16,17,18,19,20-pentanor-PGE 2 £-biphenylyl ester.