IE46257B1 - 2-substituted-15-heteroaryl-16,17,18,19,20-pentanorprostaglandins - Google Patents

Abstract

Novel heterocyclo - omega - substituted in the 2 position to aryl . [FR2362849A1]

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 heterocyelie-zJ-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: /Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein// A systematic name for prostanoic acid is 7-/j(2|3-octyl)-cyclopent-la-yl7hePtanoie acid.

PGA2 has the structure: 6 2 3 PGBg has the structure: Each of the PG-j_ prostaglandins, PGEp PGFla, WFjfit PGA^, and PGBj, has a structure the same as the corresponding PGg 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 - 3 46257 The PGq compounds are those in which there are no double bonds in either side chain. For instance, PGEq has the structure HO H OH 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^/ Molecules of the known prostaglandins each have several centers of asymmetry’, and can exist in racemic (optically inactive) form and in either of 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.

For instance, the optical antipode of PGF2a (£S£.“PGF2a) is drawn as The racemic form of a prostaglandin contains equal numbers of a particular stereoisomer and its mirror image. When reference ·· to a prostaglandin paeemate 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-PGF^ is properly represented as an equimolar mixture of PGF2aan<^ eht-PGF2a. The terms PGEp PGEg, PGFla 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 of the above-mentioned centers of asymmetry is inverted. In an epimer, the cohfiguration 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-PGF2a is the R configuration and Is shown as r 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 PGF2a.

Racemic mixtures of epimers may also exist for instance, if 15-keto-PGF^^ is reduced with zinc borohydride or a hindered alkyl borohydride, the resulting product is a racemic mixture of lfja-hydroxy and 150-hydroxy-PGF2a· PGE-ρ PGE2, and the corresponding PGFa, PGF^, PGA, and PGB 10 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. /Sergstom et al., cited above^/ A few of those biological responses are systemic arterial blood pressure lowering in the case of the PGF^, PGE and PGA compounds as shown in cardiac cannulated rats or dogs; pressor activity for the PGFa compounds; stimulation of smooth muscle as shown by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization of 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; controlllin'g spasm and facilitating breathing in asthmatic conditions; decrease of blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and Inhibition of blood platelet 46S57 aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury; in the case of the PGE and PGB compounds, stumulation of epidermal proliferation and keratinization as shown when applied in culture to embryonic chick and rat skin segments; and in the case of PGPg and PGE compounds luteolytic activity as shown in hamsters and rats.

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

Por example, these compounds, especially those of the E series, are useful In mammals, including man, as bronchodilators /Guthbert, Brit. Med. J., 4: 723-726, 1969/. As nasal decongestants, the compounds are used in a dose range of about 10 p,g. 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 broncho.dilators 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. Por 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; - 7 or by insufflation in the form of powder. Doses in the range of O.O1 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 Ko. 68/1055· The PGE and PGA compounds are useful in mammals, Including . 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, 1968), pp. 55-64.J For this purpose, the compounds are administered parenterally by Injection or intravenous infusion in an Infusion dose range of 0.1 μg. to 5Q0 pg. per kg. of body weight per minutes, 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.

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, 1967/7 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 condition such as atherosclerosis, arteriosclerosis blood - 8 46257 clotting defects due to 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 situation, the intravenous route of administration is preferred. Doses in the range of ..0.005 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 artifical 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, br attached to the new body. Under such conditions, aggregated platelets tend to block the blood 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 circulating 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 of 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 exanple, have been used in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, br to control or prevent 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 pg. per kg. of body weight per minute until ' 5 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 PGF^ compounds are useful as hypotensive agents and vasodilators /Bergstrom et al., Acta Physiol. Scand., 64: 332-333, 1965; life Sci., 6:449-455, 1967/ in mammals, including man. To lower systemic arterial blood pressure, the compounds are administered by intravenous infusion at the rate of 0.01 to 50 pg. per kg. of body weight per minute, or in single or multiple doses of 25- to 500 pg. 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, I969J/ The PGA compounds and derivatives and salts thereof increase 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 ' rejection. In cases of excessive or inappropriate ADH (antidiuretic 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 injec5 tion at a dose in the range 10 td 1000 p,g. per kg. of body weight or by intravenous Infusion at a dose in the range of 0.1 to 20 ng. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are 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-ρ are useful in the treatment of psoriosis (Fiboh, et al., Nature, 254, 351 (1975)). For this purpose, the compound is administered topically at a dose of 1-500 hg. 1 to '4 times daily until the desired effect is obtained.

The PGE, especially PGEg, PGF^, and PGFp compounds have been used In the induction of labor in pregnant female animals, Including man, cows, sheep, and pigs, at or near term /“Karim et al., J. Obstet. Gynaec. Brit. Cwlth., 77:200-210, 197p/ or in the induction of therapeutic abortion /“Bygdeman et al., Contraception, 4, 293 (1971)_/· For this purpose, the compound is infused intravenously at a dose of 0.01 to 50 hg. 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. - 11 46257 The PGE, PGFa, and PGFp compounds have been used for fertility ' control in female mammals /TCarim, Contraception, 3, 173 (1971)7 including humans and animals such as monkeys, rats, rabbits, dogs, and 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, PGF2q, for example, has been 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 approxi10 mately 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, expulsion of an embryo or a foetus has been accomplished by similar administration of the compoud during the first third of the normal mammalian gestation period.

Patents have been obtained for several prostaglandins of the E and F series ad inducers of labor in mammals (Belgian Patent 754,158 and West German Patent 2,034,641), and on PGEi, Fg and F^ for control of the reproductive cycle (South African Patent 69/6089). It has been shown that luteolysis can take place as a result of administration of. PGF2a /7Labhsetwar, Nature, 230, 528 (1971)7 and hence prostaglandins have been used 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, 895 (1973))· For this purpose the compound is infused intravenously at a dose range of Ο.5-5ΟΟ hg/kg/minute until the desired effect is obtained. - ~ ! ! - 12 - ! J As mentioned above, the PGE compounds are potent antagoniota of epinephrine-induced mobilization of free fatty aclda^ For this reason, these compounds are useful 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. j The PGE and PGB compounds promote and accelerate the growth lo of epidermal cells and keratin in animals, Including humans, 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 rejection of homografts.

To promote the growth of epidermal cells, these compounds 2o are preferably administered topically at or near the si.te whefe cell growth and keratin formation is desired, advantageously,, as an aerosol liquid or micronized powder spray, as ah isotonic aqueous solution in the case of wet dressings, or as a lotion, cream, or ointment in combination with the usual pharmaceutically 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. - 13 46257 Especially in topical applications, these prostaglandins may be advantageously combined with antibiotics such as gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, tetracycline and oxytetracycline; with other antibacterials such as mafenide hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone; and with corticosteroids such as hydrocortisone, prednisolone, methylprednisolone, and flupredhisolone, each being used in the combination at the usual concentration suitable for its use alone. in the preparation of synthetic pharmaceutical agents, among 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 prosta15 glandins 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, except to alleviate the sever 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 concentrated 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 of this type are described, for instance, in Patent Specification No. 37602, the published Dutch Patent Appli30 cation No. 73/06462 and Belgian Patent No. 806,995. - 14 i 6 2 5 7 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 structure-activity correlations in the prostaglandins does not, however, permit one to explain the observed enhancement of selectivity in the compounds of this Invention. . - 15 4 6 2 57 The present invention provides 2-Decarboxy-16,17,18,19, 20-pentanorprostaglandins of the formulas - wherein 0 I! X ia 5-tetrazolyl or -CNHR' wherein R' is alkanoyl of from 2 to 5 carhon atoms; cycloalkanoyl of from 4 to 7 carbon atoms; benzoyl or monosubstituted benzoyl wherein said substituent is chlorine, fluorine, methyl, trifluoromethyl, methoxy or phenyl; alkylsulfonyl of from 1 to 4 carbon atoms; phenylsulfonyl or mono substituted phenylsulfonyl wherein said substituent is chlorine, fluorine, methyl, trifluoromethyl, methoxy or phenyl; W is a single bond or a cis double bond; L is a single or double bond; Z is a single bond or a trans double bond; • H OH -H and M are oxo -OH N is hydrogen or α-hydroxyl with the proviso that when L is a double bond, N Is hydrogen; R is hydrogen, chlorine, fluorine, methyl, trifluoromethyl or methoxy; n is 1 or 2; and the pharmaceutically acceptable acid addition salts thereof wherein the 2-position is substituted by a 5-tetrazolyl radical.

Especially preferred among these are compounds of the formulae: OH - 17 4 6 2 57 Where 5, M, W, X, and n are as defined above and the Cg epimer of compound of formula II. - 18 4 6 2 5 7 Certain novel intermediates are of the novel prostaglandins of this a further aspect of the Invention, of the formulae: involved in the synthesis Invention and they constitute Such'intermediates are wherein Q is hydrogen or 2-tetrahydropyranyloxy and all other substituents are as previously defined. rr It is noted that the substituent attached to the 15position contains a chiral carbon. Consequently, this substituent may be prepared in the + or configuration. 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 15-position wherein n = 1 is named either 2-coumaryl or 2,3dihydrobenzofb]fur-2-yl while wherein n = 2 is named either 2-chromanyl or 3,4-dihydrobenzofb]pyran-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: N-methanesulfonyl-15-[)(-)-2-coumaryl]-16,17,18,19,20pentanor-PGE2 amide; N-methanesulfonyl-15- [(-)-2-chromanyl] -16,17,18,19,20pentanor-PGE2 amide; N-methanesulfonyl-15- [(+)-2-chromanyl]-16,l7,18,19,20pentanor-PGE2 amide; N-methanesulfonyl-15-Q-)-2-chromanyl]-16,17,18,19,20pentanor-PGA2 amide; and 2-decarboxy-2-(tetrazol-5-yl)-15- [(-)-2-chromanyl]-16,17,18, 19,20-pentanor-PGE2 -.20 4 6 2 5 7 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/“bJ7fur-2-yl)ethyl5 'phosphonate, 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 ι 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 washed with water, and concentrated (water aspirator) to give dimethyl 2-oxo2- (±2,3-dlhydrobenzo/~b_7fur-2-yl) ethylphosphonate. in a similar manner, the phosphonates 2a-2d, are prepared using the esters shown as starting material. 6257 TABLE I Ester Phosphonateco2ch3 ° ° [Q)^Vc-ch2J-(och3)2 la 2a . [QT+>- c-ch2-p-(och3)2 lb , - 2b' ^00“ C02CH3 rcFY 8 «, / L^^O^Lc-CHg-P- ( och3 ) 2 '' lc Sc ^OC°2CH3· (Οζ+L i-CH2X(0CH3)2 Id 2d 4625 Such phosphonates are then employed as reagents for the novel prostaglandins of this Invention according to Reaction Scheme A. The symbol PBP indicates ^-biphenyl.

Scheme A In 2^—»3_ the oxophosphonate 2 is reacted with the known /Corey et al., J. Am, Chem. Soe.. 93, 1491 (1971/7 aldehyde H to produce, after chromatography or crystallization, the enone 3..

The enone 3. can he reduced with zinc borohydride or with trialkylborohydrides, such as lithium triethyIborohydride, 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 dimethoxy ethane are usually employed as solvents.

' Further transformations of 4 are shown on Scheme 33: —>6 is a base catalyzed hydrolysis in which the phenylbenzyl protecting group is removed. This is most conveniently conducted with potassium carbonate in methanol or methanol-tetrahydrofuran solvent. 6—>£ involves the protection of the two free liydroxyl groups with an acid-labile protecting group. Any sufficiently acid-labile group is satisfactory; however, the most usual one is 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. The symbol THP indicates 2-tetrahydropyranyl. if - 24 Scheme Β 7-—J-8 is a reduction of the lactone 7. to the hemiacetal 8 using diisobutyl aluminum 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.

The reagents thus prepared are reacted with substituted triphenylphosphonium bromide reagents to produce the novel prostaglandins of this invention. For example, when a compound of sub-group I I's desired, the known compound U-(tetrazol5-yl)-butyltriphenylphosphanium hranide will be employed. When a ccmpound in which X is CCNHR', when R' is as defined above is desired, a known compound such as /T-(methanesulfonylaminocarbonyl)hutyJ7’triphenylphosphonium bromide or /%-(acetamido carbonyl)butyl7triphenylphosphonium bromide will be employed; the reagent selected will of course reflect the end product desired. The preparation of these reagents may be found in British Patent Specification No. 1,3.73,463 and Patent Specification No. 38058.

In a typical example of the preparation of one of these reagents, /T-methanesulfonylaminocarbonyllbutyi/triphenylphosphonium bromide, a mixture of methanesulfonamide and 5-hromovaleric acid chloride Is heated on a steam bath until gas evolution ceases.

The mix is cooled and is dissolved in methylene chloride. The solution is filtered, diluted and cooled to form white, crystalline N-methanesulfonyl-5-bromvaleramide. 4 6 2 5? A solution of this latter compound is refluxed overnight with triphenylphosphine and· acetonitrile. The solution is concentrated by evaporation and triturated with hot benzene. The solid is recrystallized from absolute ethanol: diethyl ether to afford white, crystalline /f-(methanesulfonylaminocarbonyl)butyl7trlphenylpho’sphonlum bromide.

Once the two types of reagents are prepared, the first step in the preparation of the above named .prostaglandin analogs Is reacting the appropriate hemiacetal precursor with the disodlum salt of a substituted butyltriphenylphosphonium bromide in a molar ratio of from 1:2 to 1:5.

The intermediates produced in the first step, as described above, may be converted by published procedures (Corey, et al., J. Am. Chem. Soc., 93, ΐ4$)0 (1971)) to the analogs of any of the prostaglandins listed above. These procedures are further described in detail in the Examples and the steps entailed are summarized In the reaction schemes below, wherein all substituents have the significance previously described. 8—>2 a Wittig condensation in which hemiacetal ,8 is reacted with a triphenylphosphonium bromide reagent as described above in dimethyl sulfoxide, in the presence of sodium methylsulfinylmethide. j.g purified as above.

The conversion £—»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 - 27 Λ6257 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. • 9—> 10 is an oxidation of the secondary alcohol 2 to the 5 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 2—>12.

The product is purified as above. 11-—Is an acid-catalyzed dehydration. Any acid may be used for the process which does not caus.e extensive decomposition of the product, but the most usual procedure consists of heating 11 to 70°cin an excess of glacial acetic acid 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— >24 is a reduction of the ketone 11 to the alcohol 24. This may be accomplished using any reducing agent which does not attack double bonds ·, however sodium borohydride in ethanol is usually preferred.

As is illustrated in scheme C, 4 may be substituted for 5.

In scheme B to provide prostaglandin derivatives 11', 12', 15’ and 24'.

Scheme D illustrates the synthesis of precursors to the 13,14 25 -dihydro-15-substifcuted-16,17,IS,19,20-pentanorprostaglandins.

In 3—ί19 + 19' the enone 2 is reduced to the tetrahydro compound through the use of any of the complex metal hydride reducing aagents LiAlHij., NaBHjj., KBH^, ’.ΙΛΒΗψ and Zn(BHzj.)2.

Scheme C OH - 29 Especially preferred is NaBH^. The products, 19 and 19*, are separated from each other by column chromatography.

Furthermore, the compounds 4 and 5 of Scheme A can be reduced catalytically with hydrogen to 19 and 19' respectively, The stage at which the double bond is reduced is not critical, and- hydrogenation of 6 or 7 of. scheme B will also afford useful intermediates for the 13,14-dihydro prostaglandin analogs of the present invention. This reduction .may be achieved with either a homogenous catalyst such as tris(tri10 · phenylphosphine)chlororhodium, or with a heterogeneous catalyst such as platinum, palladium, or rhodium. The conversion of 19 and 19' to their respective prostaglandins follows the route shown in scheme B when 4 is replaced by 19 and 19' to yield the 13,14-dihydro-PGE2/-PGAg and-PGFg series of prostaglandin derivatives.

Scheme E illustrates the preparation of the various reduced prostaglandin precursors: 19—»22 is carried out as illustrated, on Scheme B for can be used as both a precursor to a 13,1420 dihydroprostaglandin of the 2-series or as an intermediate to 23, ‘a precursor to a 13,14-dihydroprostaglandin of the l-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-cis double bond of intermediates of the type £ at low temperature using catalysts such as those described for 4-»19 and 17-^23. Especially preferred for this reduction Y· - 30 4 6 2 5 7 Scheme Ε •f - 31 - ·· 4bat>7 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 1-series .through the route 9—and 24 of scheme B, but also as a' precursor to compounds of the type 23 through the route already discussed for 22—23. Furthermore, the prostaglandins of the E^ and Fj_a series may be obtained directly from the corresponding prostaglandin analog of the 2-series by first protecting the hydroxyl by introducing dimethylisopropylsilyl 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 acetic acid water for 10 minutes or until,reaction is substantially complete.

The C-j£ epimers of' 21, 22 and 23 can he used as precursors to the 15-epi series of prostaglandin derivatives described above.

The 11-deoxy analogs of this invention are prepared according to reaction Scheme F. In the first step of this sequence the oxophosphonate' 2 is reacted with the- known fGorey and Ravindranathaq, Tetrahedron Letters, 4753 (1971)7 aldehyde 11’ to produce after chromatography the enone 3’. 4 6 2 5 7 Scheme F S’ 4 6 2 5 7 The enone 3.' can be reduced as described above for 3_-> 4 and 2 to provide a mixture of alcohols 4' and 5.’ which may be separated by column chromatography. Conversion of the alcohols 4' and jj» into the 11- deoxyprostaglandins of this invention follows the procedures described 'above for the conversion of 4 and % into 11, 12, 15, 24, 11', 12», 15», '24!) 22, 21 and 23.

The 15- oxo compounds of this invention are prepared as outlined in Scheme G. To prepare 15-oxoprostaglandins of the 2- and 1- series, the 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-dioyaano-l,4-benzoguinine are preferred.

To prepare 15-keto prostaglandins of the 0- series, the 15- oxoprostaglandins, of the 1- or 2- series may be reduced as described for jj —>19 above. · J To prepare 15-oxoprostaglandins of the 13,l4-dihydro-2series, 15-oxoanalogs of the 2- series such as 29 and 30 are treated with lithium and ammonia at -780 in an inert solvent such as tetrahydrofuran.

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 ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane, as further illustrated in the Examples. - 34 Scheme G 7 “ 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.

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, inhibition of histamine-induced bronchospasm in the guinea pig, and 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 responses 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. Xn non-human mammels, the determined utilities include use as anti-fertility agent, for the induction of labor; and as an ’ abortifacient, and anti-fertility activity through a 6 8 5 7 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 occurring prostaglandins, and in many cases, are also more potent. For example, N-methanesulfonyl 15-((-)-2-chromanyl)-16,17,18,19, 20-pentanorprostaglandin E2 carboxamide which exhibits antifertility activity in the rat greater than PGE2, is inactive in inhibition of histamine-induced bronchospasms in guinea pigs. Furthermore, the threshold dose of hypotensive response of Nmethanesulfonyl 15-((-)-2-chromanyl)-16,17,18,19,20-pentanor PGE2 carboxamide in dogs is higher than that of PGEg.

Particularly useful for fertility control, abortion and induction of labor in nan-human manmels are the 15-substituted-16,17,18,19,20pentanorprostaglandins of the E2 and F series based on especially outstanding smooth muscle stimulating activity, and at the same time reduced blood pressure or diarrheal effects. Similarly, the substituted 16,17,18,19,20-pentanorprostaglandins of the PGE^, .PGEq, Fp^, ϊ*1α, 13 14-dihydro PGE2 and PGF2a,PGA and 11-deoxy series are useful for fertility control in non-human nammels including abortion and induction of labor on the basis of their smooth muscle stimulant activity.

Also particularly useful for fertility control by a nonsmooth muscle mechanism and synchronization of the eostrous cycle in farm animals are the 15-substituted-16,17,18,19,2Opentanorprostaglandins of the E2 and E2a series based on especially outstanding in vivo antifertility activity in rata and at the same time reduced smooth muscle, blood pressure, or diarrheal effects. Similarly, the - 37 ^6257 substituted-16,17,18,19,20-pentanorprostaglandins of the PGE. ,PGEn,F ,F.

L w (JOt XCt 13, 14-dihydro PGE2 and PGF2a,PGA and 11-deoxy series are useful for fertility control including abortion in non-human mammels and induction of labor on the basis 5 . of their smooth muscle stimulant activity.

The new 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 in non-human maranels, tablets or an aqueous suspension or alcoholic soluticti of the novel· prostaglandins of the E and F series of this invention 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 about 0.1-20 mg/dose with 1-7 doses being employed. For intra-amniotic administration a suitable formulation would be an 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 prostaglandins of the E and F series of this invention can be Infused intravenously for induction of abortion in non-human mammels at doses of 0.05:-50 pg/minute for a period of from about 1-24 hours. 6 2 5 7 Another use for the novel prostaglandins of the E and F series of this case is as an inducer of labor. For this purpose an ethanol-saline solution is employed as an' Intravenous Infusion in the amount of from 0.1-10 ug/kg/min for from 5 1-24 hours.

Another use for the novel prostaglandins of -the E and F series of this case is for fertility control in non-human mannels. 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 of suspension containing Ο.Ο3-3Ο mg/dose of prostaglandin of the E and F series of this case is administered intramuscularly from 1-4 days.

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, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene 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 antibiotics.

· The 'following non-limiting Examples illustrate the invention.

In the Examples and Preparations it will be appreciated that all ' temperatures are expressed in Centigrade, all melting and boiling points are uncorrected.

Dimethyl 2-0xo-2-(±2,3-dihydrobenzo/~,b_/fur-2-yl)ethylphoBphonate(2); A solution of 25.6 g (206 mmoles) dimethyl methylphosphonate (Aldrich) in 250 ml dry tetrahydrofuran wAs 'cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 107 ml of 2.0 M n-butyllithium in hexan'e solution (Alfa Inorganics, Inc.) dropwise over a period of 30 minutes at such a rate that the reaction temperature never rose above -650. 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 -7O0· (20 minutes). After 0.5 hours at -780 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 al 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 l8.3 g (66$) dimethyl 2-oxo-2-(±2,3-dihydrobenzo/~b_7fur-2yl)ethyIphosphonate (2_). 4625 *The ± refers to the origin of the dihydrobenzfuryl portion of the molecule originating from + 2,3-dihydrobenzo/~b_7' furan-2 carboxylic acid.

In a similar manner, the phosphonates 2a-2d were prepared 5 (Table I). flf - 41 ο CJ Θ CO Ν cu α co ω χί Ρ co * . I H H J m il wo , e kl w —s co cu W Φ cn p + ·, II o VD in ii w. o . K «I ϋ ki VD CO cn • tin ι II «η H O inol in vo·—· σι cn <1 • u £ B + ·> 11 H in vo ii· °Κ%| I <1 w cn - (1) The product phosphonates were purified by column chromatography using silica gel (Baker, 60-200 mesh) and benzene/chloroform as eluting solvents. (2) Prepared from the (-)amphetaraine 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, 3. Med. Chem., 6, 315 (1963). (3) Prepared from the (+)amphetamine salt of (+)hydrocoumarilic acid by the method of reference (2).

Prepared from the (-)amphetamine salt of (-)chroman-22 Carboxylic acid. (5) Prepared from the (+)amphetamine salt of (+)chroman-2carboxyllc acid.2 - 43 46257 0 LcHgJ-iOCHgJg 2-^ot-£-Phenylbenzoyloxy-5a-hydroxy-2P-(3-oxo-3-(±2,3-dihydrobenzo7~b 7fur-2-yl)-trans-1-propen-l-yl)-cyclope'nt-loi-yl7Aeetic Acid, V-lactone (3.): Dimethyl 2 -oxo-2{±2,3 -dihyd robenz o/-b_7fur-2 -y 1) ethylpho sphonat e (2.) (8.48 g, 31.4 mmole) In 50 ml anhydrous THF was added dropwise to 1333 mg (31.4 mmole) 57# 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-J/3a-2.-phenylbenzoyloxy-5a-hydroxy2j3-foimyl-cyclopentan-la-yl7acetlc acid, γ-lactone was added in one portion followed by 50 nil anhydrous THF. After 60 minutes the reaction mixture was quenched with 3 nil glacial acetic acid, filtered, evaporated, diluted with 35θ nil ethyl acetate and washed successively with 100 ml saturated sodium bicarbonate · solution (2x), 100 ml water (2x), 100 ml saturated brine (lx), dried '(NagSOi).) and evaporated to yield 9.8 g (69%) 2-^a-£-phenylbenzoyloxy-5a-hydroxy-2j3-(3-oxo-3“(±2,3-dihydrobenzo2^’_7fur-2-yl)trans-l-propen-l-yl)cyclopent-la-yl/acetic acid, γ-lactone (3,) ’rl I 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 cm-1 (medium) and I63O cm’· (medium) attributable to the carbonyl groups and at 970 cm-1 (medium) for the trans double bond.

Similarly, the enones 3&-3A were prepared (Table II). 4 6 2 S 7 »d d to 3 0 •rl rH τί a 5 o rH ώ U p d rH 0 ω cnst in in froscn «si in frol gi • GJ in · fr-in ι ι ow LO Gl Gl II tn XH. in in OSO inso rt rt Gl • Gl in ’ fr-in r i o w cn rH O •g· in o\ Vs Ci cn H o O rt II in m no l^s κ J LO CO I in tn m t-trt rt I o· c-o rtn I β Hm cuw rt rt PBPCOJ' PRBPRATION C 2-/3a-£-Phenylbenzoyl.oxy~5a-hydroxy-20-(3a-hydroxy-3-(±2,3-dihyd:ro< benzo/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-/3a-£-phenylbenzoyloxy5a-hydroxy-2|3-(3-οχο-3·(±2,3-dihydrobenzo/b 7fur-2-yl)-trans-l~ propen-l-yljcyclopent-la-yl/acetic acid, γ-lactone (3) in 150 ml dry THP in a dry nitrogen atmosphere at -78° was added dropwise 62.4 ml (25.8 mmole) of a 0.413 M lithium trl-sec-butyIborohydride solution. After stirring at -78° and 0.5 hours the reaction was quenched with 54 ml of acetic acid/water (40:60 v/w). The reaction - 47 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 cofitaining 1.8 g 2-2^a-£-phenylbenzoyloxy-5a-hydroxy-2p-(3a-hydroxy-3-(±2,3dihydrobenzo/~b 7fur-2-yl) -trans-1-propen-l-yl) cyclopent-ΐα-yl7acetic acid, γ-lactone (jj), 1.5 g mixed 4 and 5. and 1.9 S 2-/3a2,-pheny lb enz oyloxy-5a-hy dr οχγ-2β - (3β-hy droxy-3 - (±2,3-dihy drob enzo/b 7-fur-2-yl)-trans-l-propen-l-yl)eyclopent-la-yi7acetlc acid, γ-lactone (4) were obtained.

The ir spectra (KBr^) of 4 and £ had strong carbonyl • adsorbtions at 1770 and 1715 cm-·’· and an adsorbtion at 97° cm-^ 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). ‘ . ' 46237 CQ 0 •Wfr & CO rd t-in ι ι ow o oocv .•tiTt-tn ι i OW co OVD •V> it · c-in ι ι ow ra ow At^0· t-ir\ o w co OACO.

Jt'·0. c-in ι ι o w TABLE III - os t— CUCU «σ\ in · t-m I I os tn rt ϋ CO d g Α/ξ5 =-89.48 3.03 £fr3 H ί in o cu CO CO H co in ι \9 in β rt CU rt Τθιη^ι W ^±cu k .=} t£) O\ co rt CD CU o Jdin , cRm tn '^cu'D kl 1° H1 . <1 -° B » ll in m)8_ m ly^OcuSw I N, I 0 A}-\O corn Η H I 0 &—o\ in in rt rt I 0 O CU in in rlrl & 8! ep fh £1 o PU SP o in o fe W hi - 50 46257 ΓΌ Η ϋ Β (Ό Η <η • KO b; b- o ^- KO H KO r*! CO O CM -ΞΓ • 00 | I 1 1 Ψ 1 Η 11 II II II ιχ> ιη ιη ιη ιηιηΌ Χ'Χ'Α’ £ <1 ύ κο b<Ό I κο ΙΓ\ ΙΠ ΐί\<*ΛΠ κθ .8* .8 8 <1 <1 Μ I ο t~O ^Μη Η Η I ο b-cn ιηιη Η Η PREPARATION D 2-^α, Sa-Dihydroxy-aB-fSa-hydroxy-S-^jS-dihydrobenzo/FTfur-a-ylJtrans-l-propen-l-yllcyclopent-la-ylTacetic acid, γ-lactone (6): A heterogeneous mixture of 1.8 g (3.6 mmole) of 2-/Ta-jo-phenyl 5 benzoyloxy-5a-iiydroxy-2B-(3a-hydroxy-3/±2,3-dihydrobenzo/~b_7fur-2yl)-trans-l-propen-l-yl)cyclopent-la-yl7acetic.acid, γ-lactone (5.), 20- ml of absolute methanol, 15 ml THF and 5θ2 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 7.26 ml (14.52 mmole) of 1.ON aqueous·hydrochloric acid. After stirring at 0° for an additional 10 minutes, 35 ml. of water was added with concomitant formation of methyl p-phsnylbenzoate 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 (MgSO^) and concentrated to give 1.2' g (100$) of viscous, oil 2-/3α,5adihydroxy-2β-(3a-hydroxy-3r(±2,3 -dihydrobenzo/“b_7-2-fur-yl)-tran l-propen-l~yl)cyelopent-la-yl/acetic acid, γ-lac'tone (6).

The ir spectrum (CHgOlg) exhibited a strong adsorption 5 at 1775 cm”'1' 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). >46257 16 PREPARATION E • 2-/3α, 5a-Dihydroxy-20-(30-hydroxy-3-(±2,3-dihydrobenzo/b_7fur-2-yl)trans-l-propen-l-yl)cyclopent-la-yl7acetie acid, γ-lactone (16); A heterogeneous mixture of 1.9 g (3.82 mmole) of 2-/Ta-2.-phenyl5 benzoyloxy-5a-hydroxy-20-(30-hydroxy-3{±2,3-dihydrobenzo/-b_7’fur-2yl)-trans-l-propen-l-yl)cyclopent-la-yl7acetlc acid, γ-lactone (4), 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 7-6^· ml (15^28 mmole) of_ 1.ON aqueous hydrochloric 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 (MgSOjj.) and concentrated to give 1.2 g (100$) of viscous, oily 2 -gc, 5a -dihyd roxy-20 - (30-hyd roxy-3{ ±2,3 -dihyd r ob enz ur-2 -y 1trans-l-propen-l-yl)cyclopent-la-yl7acetic acid, γ-lactone (16). - 54 The ir spectrum (CHgClg) exhibited a strong adsorption at 1775 cm for the lactone carbonyl and medium adsorption at 970 cm for the trans double bond.

In a similar manner, the following d'iols (16a, 16c, l6d) were prepared from their corresponding ester-alcohols (4a, 4c, 4d).

PREPARATION F 2-,/5a-Hydroxy-3a- (tetrahydropyran-2-yloxy) -2β- (3a-/Fetrahydropyran2-yloxy7-3/±2,3-dihydrobenzo/b 7fur-2-yl)-trans-l-propen-l-yl)cyclopent-la-yl7acetic acid, γ-lactone (7): To a solution of 1.2 g (3.84 mmole) 2-/i3a,5a-dihydroxy-^(3a-hydroxy-3/ ±2,3 -dihyd robenzo/-b_7f ur-2-yl)-trans-1-propen-yl) • cyclopent-la-yl/acetie acid, γ-lactone (0 in 24 ml anhydrous methylene chloride and 2.14 ml of 2,3-dihydropyran at 9° 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 with saturated sodium bicarbonate (2 x 75 ml) then saturated brine (1 x 100 ml), dried (MgSOjj.) and concentrated to yield 1.9 g of 2-/53-hydroxy-3a-(tetrahydropyran-2-yloxy)-2B~(3a-7tetrahydro15 pyran-2-.vloxy7-3/±2.3-dihydrobenzo/~b 7fur-2-yl) -trans-l-propen-1yl)cyclopent-la-y!7acetic acid, γ-lactone (£).

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. - 56 4 6 2 5 7 In a similar manner, the diols (6a-6d)were converted into their corresponding THP derivatives (7a-7d). 7b 6 3 5 7 PREPARATION 6 2-/5a-Hydroxy-3a-(tetrahydropyran-2-yloxy) -2β- (3£-/tetrahydropyran• 2 “yloxy/-3 - (±2,3 -dihyd rob enz o/b_7-fur-2 -y 1)-trans-l-propen-l-yl) cyclopent-la-yl7acetic acid, γ-lactone (17): To a solution of 1.12 g (3.55 mmole) 2-/3a,5cc-dihydroxy-2£-(3£ hydroxy-3 - (±2,3-dihydrob enzo/“b_/fur-2-yl)-trans-l-propen-l-yl) cyclopent-la-yl7aeetie acid, γ-lactone (16)· 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, monohydrate. After stirring for 30 minutes, the reaction mixture was combined with Ί50 ml diethyl ether, the ether solution Washed with saturated sodium, bicarbonate (2 x 75' ml) then saturated brine (1 x 100 ml), dried (MgSO/j.) and concentrated to yield 1680 mg of 2-/5a-hydroxy-3ct-(tetrahydropyran-2-yloxy)-2/3-(3a-/tetrahydro15 pyran-2-yloxy/-3/±2,3'-dihydrobenzo/_b_7fur-2-yl) -trans-l-propen-lyl) eye lop ent-la-yl/acetic acid, γ-lactone (17 after column chromatography.

The ir (CH-C1 ). spectrum had a medium adsorption at 970 cm ά -1 for the trans-double bond and a' strong adsorption at 1775 cm for the lactone carbonyl. 4625? In a similar manner, the diols (16a, l6c, l6d) were. converted into their corresponding THP derivatives (17a, 17c, 17a) JZd PREPARATION Η 2-/5a-Hydroxy-3a- (tetrahydropyran-2-yloxy) -20- (3ct-/tetrahydropyran2-yloxy/-3-( ±2,3 -dihydrobenz o/b_7f ur-2 -yl) -trans-l-propen-l-yl-cyc lopent-la-yl7acetaldehyde, γ-hemiacetal (8): A solution of 1.86 g (3.84 mmole) of 2-/5a-hydroxy-3a-(tetrahydropyran-2 -yloxy) -2β ~/3a -/f-t rahydropyran-2 -yloxj/-3-( ±2,3dihydrobenzo/~b 7fur-2-yl)-trans-l-propen-l-yl)cyclopent-la-yi7 acetic acid, γ-lactone (7) in 20 ml dry toluene was cooled to -7θ° 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 temperature never rose above -650 (20 minutes). After an additional 30 minutes of stirring at -78°, methanol was'added and 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 (NagS0^) and concentrated to yield 1467 mg 2-/5a-hydroxy-3a(t etrahyd ropyran-2 -yloxy) -2β - (3α -/Jet rahydropyran-2 -y lox^7-3-( ±2,3 $ dihydrob enz o/b_7fur-2 -yl)-trans-1-p rop en-l-yl) eye lopent - 1-y 3/60 46257 acetaldehyde, γ-hemiacetal (8) after column chromatography. The ir spectrum exhibited a medium adsorption at 970 cm for the trans double bond. · In a similar manner, the following hemiacetals (8a-8d) were 5 prepared from their corresponding THP derivatives (7a-7d).

OH 8d ' ΤΗΡΟ .OH OTHP OTHP IL PREPARATION I 2-j/Ja-Hydroxy-3c>(tetrahydropyran-2-yloxy)-23-(33-/tetrahydropyran-2yloxy7-3(±2,3-dihydrobenzo/b 7fur-2-yl)-trans-l-propen-l-yl)cyclopent-la-yl7acetaldehyde, γ-hemiacetal (18): A solution-of 1.68 g (3.4-7 mmole) 2-/^a-hydroxy-3a-(tetrahydropyran-2-yloxy) -2(3-(3i3-7E’etrahydropyran-2-ylox27-3/±2,3dihydrobenzo/b 7fur-2-yl)-trans-l-propen-l-yl)cyclopent-la-yl7acfetic 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$ diisobutylaluminium hydride 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 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 (NagS0^) and concentrated to yield 1513 mg 2-/5a-hydroxy-3a-(tetrahydropyran~ 2-yloxy) -23 -(33 -/Eetrahydropyran-2-yloxy7-3 - (±2,3 -dihydrobenzo/b_7fur-2-yl)-trans-l-propen-l-yl)cyclopent-l-yl7acetaldehyde. γhemiacetal (17) after column chromatography. The ir spectrum exhibited a medium adsorption at 970 cm for the trans double bond.

In a similar manner, the following hemiacetals (l8a, l8e, l8d) were prepared from their corresponding THP derivatives (l£a, 17c, IB).

PREPARATION J 2-/3a-hyaroxy-5a-hydroxy-2ft- (3a-hydroxy-3-/(+ )-3,4-dihydrobenzo/b_7 pyran-2-yl7prop-l-yl)eyelopent-la-yl7acetic acid, γ-lactone: A heterogenous solution of 2.5 g of 2-/3ct-hydroxy-5a5 hydroxy-2j3-(3a-hydroxy-3-/f+)-3,4-dihydrobenzo/_b_7pyran-2-yl7trans-l-propen-l-yl)cyclopent-la-yl7acetic add, 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-^a-hydroxy-5a” hydroxy- 2/3 - (3-oxo-3-/(+ )-3,4-dihydrobenzo/7b_7pyran-2-yl7-propl-yl)cyclopent-la-yl7acetic acid, γ-lactone.

This is converted to the 13,14-dihydro Eg and Pgm compounds using methods employed in-Examples I to .Vi', VIII to ΧΪΙ and ZVI. ' CHO *9ά . PREPARATION Κ (rac. )-2-/^a-Hydroxy-20- (3-oxo-3-/{+ )-3 > 4-dihydrobenzo/“b_7pyran10 2-yl7-trans-l-propen -1-yl) -cyclopent-la-yl/Acetic Acid, γ-lactone 1 Dimethyl 2-oxo-3-/(+)-3,4-dihydrobenzo/“b_7pyran-2-y3^* D * 7 * * ac * * * * (Iethylphosphonate (_2) (28.6 mmole) in 420 ml anhydrous THP is treated with 1.21 g (28.6 nmole) 57$ sodium hydride in a dry nitrogen atmosphere at room temperature. After 60 min. of stirring, (rac. )-2-/5a-hydroxy-20-formylcyclopentan-la-yl7acetic acid, γ-lactone 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 (NagSOij.) and evaporated to afford (nat. )-2-/5a~ hydroxy- 2β - (3 - oxo-3 - /(+ )-3,4-dihydrobenz o/~b/7pyran- 2- yl/'-trans-1 propen-l-yl)cyclopent-la-ylJ7acetic acid, γ-lactone. 49a may be converted to the ll-deoxy-16,17,18,19,20-pentanorprostaglandins. - 65 i PREPARATION L (methanesulfonylaminocarbonyl)butyl7triphenylphosphonium bromide A mixture of 0.950 g (0.01 mole)'of methanesulfonamide and 1.80 g (0.01 mole) of 5-bromovaleric acid chloride was heated on a steam bath until gas evolution ceased (ca. 5 minutes). The brown reaction mixture was allowed to cool and was dissolved in methylene chloride. The methylene chloride solution was treated with D&rcp ( Trade Mark) ,was filtered,and was diluted with hexane with cooling to afford the white, crystalline N-methanesulfonyl-5-bromovaleramide wefehing 2.22 g. (86.0$ yield) which melted at 88-89°.

The nmr spectrum (CDCI3)' showed a broad singlet at 4.263.95^ for the N-H, a multiplet at 3.66-3.23 for the -CHgBr, a singlet at 3.31 (, for the SOg-CHg, a multiplet at 2,63-2.20 / for the -CHgCO, and a multiplet at 2.12-1.52 / for the CHg-CHg. The ir spectrum (CHCl^)-showed a strong absorption at 1720 cm“^ attributable to the carbonyl group.

A solution of 2.20 g. (8.57 mmoles) of the N-methanesulfonyl-5-bromovaleramide, prepared as above, 2.24 g. (8.57 mmoles) of triphenylphosphine, and 20 ml. of acetonitrile was heated to reflux under nitrogen overnight. The solution was then concentrated by rotary evaporation and the resultant solid was ‘ triturated with hot benzene (4X). The triturated solid was recrystallized from absolute ethanol:ether to afford the white, crystalline /K- (methanesulfonylaminocarbonylJbutyl/triphenylphosphonium bromide weighing 2.80 g. (63.7$ yield) melting at 190-191°. - 66 4 6 2 5 7 The ir spectrum (KBr) of the product exhibited a strong absorption at 5.85 μ attributable to the carbonyl group. The nmr spectrum (CDClg) exhibited a complex multiplet at 8.14-7.27 I for the aromatic protons, a multiplet at 4.00-3.30 £ for the -CHpP, a singlet at 3.12 ί for the -SOgCHg, a multiplet at 3.00-2.38 3 for the CHgCO, and a multiplet at 2.23-1.38 / for the CHgCHg. A titration of the solid product indicated the pKa 1/2 to be 5.25.

EXAMPLE I . j N-methanesulfonyl-9a-hydroxy-lla, 15a-bis_-(tetrahydropyran-2-yloxy)5-cis .-13-trans-15///2,4-dihydrobenzo/-b_7pyran-2-yl7-16,17,18,19,20pentanorprostadienamide (15c), To a solution of 2.78 g (5.35 mmole) //-(methanesulfonylaminocarbonylj-n-butyl/triphenylphosphonium bromide in a dry nitrogen atmosphere in 20 ml dry dimethyl sulfoxide was added 4.5 ml (10.43 mmole) ‘of a 2.3M solution of sodium methylsulfinylmfethide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 900 mg .(1.78 mmole) 2-/5a-hydroxy-3a(tetrahydropyran-2-yloxy) 2)3- (3a-/tetrahydropyran-2-ylox^r-3ΖΓ-)-3,4-dihydrobenzo/~b 7pyran-2-yl7-trans-l-propen-l-yl)cyclopentla-yl7&cetaldehyde, γ-hemiacetal (8c) in 5 ml dry dimethyl sulfoxide. After an additional 0.5 hour stirring at room tempera ture, the reaction mixture was poured onto a mixture of crushed Ice, ethyl acetate (150 ml) and 11 ml IN HCl. The acidic solution was further extracted with ethyl acetate (2 x 40 ml) and the combined organic extracts washed with water (2 x 40 ml.), brine (1 x 40), dried (NapSOlj.) and evaporated. The residue was purified by column * T - 68 46257 chromatography on silica gel (Balter Analyzed Reagent 60-200 mesh) using mixtures of chloroform:ethyl acetate as eluents. After removal of high Rf Impurities, the desired N-methanesulfonyl-9°> hydroxy-lla, 15cc-bis-(tetrahydropyran-2-yloxy)-5-cis-13-tTans15/(-)-3,4-dihydrobenzo/’”bJ7’pyran-2-yl/’-16,17,18,19,20pentanorprostadienamide (15c) was collected as a colorless oil weighing 400 mg. “ 69 - 26d EXAMPLE II N-methanesulf onyl-9-oxo-lla, 15a-bis (tetrahydropyran-2-yloxy) -5-eis13-trans-15-/C+)-3,4-dihyarobenzo/~bJ7,pyran-2-yl7-16,17,18,19,20pentanorprostadienamide (26d): To a solution cooled to -10° under nitrogen, of 800 mg (1.21 mmole) N-methanesulf onyl' 9“-hydroxy-lla, 15a-bis- (t'etrahydropyran- 2-yloxy) -5-cis, 13-trans-15-/(+) -3,4-dihydrobenzo/'b_7'pyran-2-yl7_16,17,18,19,20-pentanQEprostenamide(25d) in 30 ml reagent grade acetone was added dropwise to 0.8? ml. of Jones' reagent. After minutes at -10°, 1 ml. 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minies at which time it was combined with 70 ml. ethyl acetate, washed with water (2 x 20 ml.), brine (20 ml.), dried (MgSO/j.) and concentrated to give 8o4 mg. of the colorless, oily N-methanesulf onyl·-,9~οχο-11α, 15α· bis-(tetrahydropyran-2-yloxy)-5-cisJ13-trans.-15-/r+)-3,4-dihydrobenzo/7b_7pyran-2-yl7“l®' 17,18,19,20-pentanorprostadienamide (26d). ο 26a 27a EXAMPLE III N-methanesulfonyl-9-oxo-lla, l5g-dihydroxy-5-cis-13-trans-15-[(+) -3,4-dihydrobenzo (bJpyran-2-ylJ-16,17,18,19,20-pentanorprostadienamide (27d): A solution of 8o4 mg. N-methanesulfonyl 9-oxo-lla,15a5 bis-(tetrahydropyran-2-yloxy) -5-cls-13-trans-15-/I+)-3,4-dihydrobenzo/7b_J7pyran-2-yl7-i6,i7,i8,i9,20-pentanoxprostadienamide(26d)in 8 ml.of a 65.‘35 mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 16 hours then was concentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Mallinckrodt (registered Trade Mafk)CC-7 100-200 mesh)using mixtures of chloroform:ethyl acetate as eluents. After elution of less polar impurities N-methanesulfonyl-9~oxo-lla, 15a-dihydroxy5-cls-,· 13-trans-15 -/(+) -3,4-dihydrob enz o/JbJTpyran- 2-yl/- 16,17,18,19,20pentanorprostadienamide (27d) weighing 242 mg. was collected, m.p. 109-111°. - 71 PREPARATION m 4-(Tetrazol-5-yl butyltriphenylphosphonium bromide A mixture of 5-bromovaleronitrile (16.2 g., 0.10 mole), triphenylphosphine (26.2 g., 0.10 mole) and toluene (100 ml.) was heated to reflux with stirring under nitrogen for 16 hours. The resulting thick white suspension was cooled to room temperature and filtered. The residue was washed with benzene and air dried to give 33.0 g. of a white, crystalline solid, m.p. 230-232°, which was 4-cyanobutyltriphenylphosphonium bromide. 3.0 Anal. Calc'd for C^H^BrNP: C, 65.10; H, 5.47; N, 3.30.

Found: C, 65.01; H, 5.40; N, 3.19.

A mixture of the phosphonium salt above (10.0 g., 23.5 mmoles), ammonium chloride (1.60 g., 30.0 mmoles), lithium chloride (0.032 g., 0.76 mmole), sodium azide (1.91 g.} 29-3 mmoles), and dimethylformamide (50 ml.) was heated to 127° (oil bath) under nitrogen with stirring for 18 hours. . The resulting suspension was cooled and filtered. The residue was washed with dimethylformamide and the combined filtrate and washings were concentrated (aspirator pressure, ca. 45°). The oily residue was crystallized from water at 0° and air dried to give a white crystalline solid (8.11 g.), m.p. 100-102°. The product was recrystallized from methanol-ether to give white prisms (7.18 g.). m.p. 197-206°. An analytical sample was prepared by recrystallization from 2-propanol to give a white crystalline powder, m.p. 212-213°, which was 4-(tetrazol-5-yl) butyltriphenylphosphonium brcmide. - 72 · j OTHP 46357 28d EXAMPLE XV 1- (Tetrazol-5-yl) -9a-hydroxy-lla, lgabis-(tetrahydropyran-2-yloxy) 15-/(+)-3,4 -dihydrobenzo/~b_7pyran-2-yl7-cis-5, trans-13-2,, 16,17,18 It,20-hexanorprostadiene (28d): . To a solution of 4-(tetrazol-5-yl)butyltriphenylphosphonta bromide (2,97 g.) in a dry nitrogen atmosphere in 15 ml. dry DMSO was added 4.98 ml. of a 2.3M solution of sodium methylsulfinylmethide in DMSO. To this solution was added dropwise a solution of 1060 mg. 2-/5a-hydroxy-3a-(tetrahydropyran10 yloxy)-20-(3a-/tetrahydropyran~2-yloxy)-3— /T+)-3,4-dihydrobenzo/7b_7pyran-2-yl7-trans-l-prcpen -1-yl)cyclopent-la~yl7acetaldehyde, γ-hemiaeetal (8d) In 5·0 ml. dry DMSO over a period of 20 minutes. After an additional 1 hour stirring at room temperature, the reaction mixture was poured onto ice water'. The basic aqueous solution was aidified with 0.1N HCl and extracted with ethyl acetate. The residue obtained after evaporation of the solvent was chromatographed to give 756 mg. pure colorless oily l-(tetrazol-5-yl)-9a-hydroxy-lla, lga-bis- (tetrahydropyr an-2-yloxy) · 15-/(+)-3,4-dihydrobenzo/“b_7pyran-2-yl7-cis-5, trans-1320 16,17*18,19,20-hexanorprostadiene (28d). • i II Ν Ν II Ν 29ά EXAMPLE V 1- (Tetrazol-5-yl) -9-oxo-lla, lga-bis- (tetrahydropyran-2-yloxy) 15 -/(+ )-3,4- dihydrobenz ο/~b 7-pyran- 2-yl7-cis-5-trans-13 2,16,17,18,19,20-hexanorprostadiene (29d): To a solution cooled to -15° under nitrogen, of 756 mg. l-(tetrazol-5-yl)-9°-hydroxy-lla, 15a-bis-(-fetrahydropyran-2-yloxy)15“ZT+ )-3,4-dihyd robenzo/~b_7_pyran-2-yl/-cis-5; trans-13-2,16,17,18,19 20,hexanorprostadiene (28d) in 35 ml. reagent grade acetone was added dropwise 0,6 ml. of Jones' reagent. After 30 minutes at -10°, 0.6 ml. 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 150 ml.’ ethyl acetate, washed with water (2 x 50 ml.), dried (NagSO^) and concentrated to give the colorless, oily l-'(tetrazol5-yl) -9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-15-/(+)-3,415 dihydrobenzo/~b 7-pyran-2-yl7-cis-5-trans-13-2,16,17,18,19,20hexanorprostadiene (29d). tp·· - 74 46257 221 EXAMPLE VI . , 1- (Tetrazol-5-yl)-9-oxo-lla,15°t-dihydroxy-15-iZfi)-3,4-dihydrobenzo^Oj^JTpyran-g-ylZ-cls-S, trans-13-4fl6,17,18,19,20-hexanorpiX)stadiene (30d); A solution of 700 mg. l-(tetrazol-5-yl)-9-oxo-lla,15a5 bis- (tetrahydropyran- 2-yloxy)-15-/(+) -3,4-d±hydrobenzo/-’bJ7pyran~2yl7-cis-5rtrans-13-2,16,17,13,19,20-hexanorprosfcadiefte (29d) in 10 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 20 hours and then was concentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7 100-200 mesh) using mixtures of chloroforra:ethyl acetate as eluants. After elution of less polar impurities the colorless oily l-(tetrazol-5-yl)-9oxo-lla, 15a-dihydroxy-15-/f+) -3,4-dihydrobenzo7*’b_7pyran-2-yl7£11^5-^^5,13-2,16> 17, 18, 19,20 -hexanorprostaliene Weighing 277 mg. was obtained. The ir and nmr spectra were consistent with the product. j, - 75 46257 Ο EXAMPLE VU . . · N-Benzoyl-9-oxo-llQ) 15a-dihydroxy-5-cis-13-trans-15-/(+)-3,4dihydrobenzo/~b_7pyran-2-yl7-16,17,18,19,20-pentanorprostadienamlde: To 1.0 m mole of 9-oxo-lla,lga-bls-(tetrahydropyran-25 yloxy) -15-/(+) -3,4-dlhydrobenzo/bJ7pyran-2-yl7-clsg-tranB-13-16,17 18,19,20-pentanorprostadienoic acid in 40 ml. 1HF is added 2 ml. triethylamine. After 15 minutes of - stirring at room temperature 10.0 ml of 0.1 molar benzoyl isocyanate in THF is added. After a further hour of stirring, the reaction mixture is neutralized with acetic acid and the solvent removed by evaporation (in vacuo) The resultant residue is taken up in methylene chlorine and washed successively with water and sodium bicarborzte to yield, after drying and solvent evaporation, N-benzoyl-9-oxo-llffl,15a-bis(tetrahydropyran-2-yloxy) -15-/(+)-3,4-dihydrobenzo/-b_7pyran-2-yl7 cls-5· trans-13-16,17,18,19,20-pentanorprostadienamide. This intermediate is then hydrolized overnight with acetic acid/water and purified by column chromatography to give the desired N-benzoyl-9-oxo-lla, 15adIhydroxy-5-cisr13-trans-15-/(+ )-3,4-dihydrobenzo/”b_/pyran-2-yl7.16,17,18,19,20-pentanorprostadien.amide. - 76 46357 PREPARATION Ν A'solution of 50.5 g. (0.227 mole) of N-acetyl-5-bromovaleramide and 64.6 g. (0.274 mole) of triphenylphosphine iii 250 ml. of xylene was heated at reflux under nitrogen for 4 hours then was allaved to cool to rocm tanperature. The xylene was decanted from the resulting oil which was recrystallized from methylene chloride: ethyl acetate to afford colorless needles of ff-(acetylaminocarbonyl butyl/triphenylphosphonium bromide weighing 50.2 g. (45.7# yield) melting at 164-165°.

The ir spectrum (CHCl^) of the product exhibited absorption bands at 5.72 μ (moderately strong) and 5.80 μ (strong) attributable to-the carbonyl groups. The nmr spectrum (CDCI3) exhMted a multiplet at 3.42-3.98 I for the Ρ-CHo-, a multiplet 9 at 2.44-2.96 £ for the -CH2CNH-, a singlet at’2.23 £ for the CHgC, a multiplet at 1.48-2J3 for the CHgCHg, and a multiplet at 7.60-8.14 £ for the aromatic protons. - 77 46257 32d ' EXAMPLE VIII N-Acetyl-9a-hydroxy-lla 15«-bis-(tetrahydropyran-2-yloxy)-15-/(+)3,4-dihydrobenzo/b 7pyran-2-yl7-cls-5 Λϊ,&η5-13-·16,ΐ7,18,19,2οpentanorprostadienamide (32d) · · To a solution of 5*32 g /4-(acetamido carbonyljbutyl/triphenyl phosphonium bromide in a dry nitrogen atmosphere in 10 ml dry DMSO is added 17.7 ml of a. 2.0 M solution of sodium methylsulfinyl methide in DMSO. To this red ylid solution is added dropwise a solution of 1.1 mmoles 2-/5a-hydroxy-3«10 (tetrahydropyran-2-yloxy) -2β~ (3a- (tetrahydropyran-2-yloxy) -315-/(+) -3,4-dihydrobenzo/b_7pyran-2-yl7“trans-l-propeft-l-yl) cyclopen la-yl/acetaldehyde, γ-hemiacetal (8d) in 10 ml dry DMSO over a period of 20 minutes.- After an additional 2 hours stirring at room temperature, the reaction mixture is poured onto ice water.

The basic aqueous solution is washed twice with ethyl acetate (3 x 25 ml) and the combined organic extracts are washed once with water (10 ml), dried (NagSOij.) and evaporated. Chromatography ori silica gel affords N-acetyl-9a-hydroxy-lla, 15a-bis-(tetrahydropyran 2-yloxy)-15-/(+)-3,4-dihydrobenso/-b__7pyran-2-yl7-cis-5-?trans-13— 16,17,18,19,20-pentanorprostadieriamide (32d). - -78 4 6 357 23d · · EXAMPLE IX . .

N~Acetyl-9et, 11a, 15a-trihydroxy~15-/J+)-3,4-dihydrobenzo/~b_7pyran5 2»yl7-.cis-5, trans-13-16.17.IS. 19,20-pentanorprostadienamide (33d) A solution of 0.39 g of N-acetyl-9a-hydroxy-lla315a-bis(tetrahydropyran-2-yloxy) -15-/J+) ~3> 4-dihydrobenzo/7b__7pyran-2-yl7Cls-5-trans-13- 16,17,18,19,20-pentanorprostadienami.de(32d) in 5 ml of 65:35 v/v mixture of glacial acetic acid:water is stirred under nitrogen at 25° for 18 hours and then was concentrated· to a crude oil, which was purified by column chromatography· on silica gel (CC-7), using mixtures of chloroform:ethyl acetate as eluant. After elution of less polar impurities the desired N-acetyl-9a,lla,15a-trihydroxy15-/7+ )-3.4-dlhydrobenzo/~b 7nyrsn-2-yl7-cis-5 ,trans-13-16,17,18,19,2O15 pentanorprostadienamide (33d)is collected. f - 79 .46257 34a EXAMPLE X N-Acetyl-9-oxo-llct, 15a-bls- (tetrahydropyran-2-yloxy) -15-/(+ )-3,4dihydrobenzo/^J7pyran-2-y/7-cJs-5T trans-13-16,17,18,19,20-pentanorprostadienamide (34d): To a solution cooled to -10° under nitrogen, of 394 mg N-acetyl-9a-hydroxy-lla, 15ot-his-(tetrahydropyran-2-yloxy)15-/(+) -3,4-dihydr obenzo/“b_7pyran-2-yl7-cis.-5-trans-13 -16,17,18,19,20tetranorprostadienamide(32d)in 10 ml reagent-grade acetone is added dropwise 0.4 ml of Jones’ reagent. 'After 30 minutes at -10°, 0.4 ml 2-propanol is added and the reaction mixture is allowed to stir an additional 5 minutes at which time it is combined with 60 ml ethyl acetate, washed with water (3 x 10 ml), dried (Na2S0/|) and concentrated to afford N-acetyl-g-oxo-llaTlSa-bis-ftetrahydropyran-2-yloxy)-15-/(+)-3,4-dihydrobenzo/“b_7pyran-2-yl7£M“5 > .15 trans-13-16,17,18,19,20-pentaiiorprostadienamide (34d). 34a EXAMPLE Xl N-Aeetyl-9-oxo-lla? 15g-bis-dihydroxy-15-/(+) -3,4-dihydrobenzo/~b_7-. pyran-2-yl7-cis-5-trans-13-i6,17,18,19,2O-pen-tanorpro3tadlen:amide .(3M), A solution of 390 mg of CT-acetyl-9-oxo-lla, lga-bis5 (tetrahydropyran-2-yloxy) -15-/(+) -3,4-dihydrobenzo/b_7pyran-2-yl7-cls-5-trans-13-16,17,18,19,20-pentanorprostadienamlde (34d) in 8 ml of a 65:35 v/v mixture of glacial acetic acid:water Is stirred under nitrogen at 25° for 20 hours and then is concentrated to a crude oil which is purified by column chromatography on silica gel using mixtures of chloroform:ethyl acetate as eluants, to afford the desired N-acetyl-9-oxo-lla, 15a~biG-dihydroxy-15-/(+)-3,4dihydr obenzo/b_7pyr an- 2-yj7-cis-5 «trans-13 -16,17,18,19,20-pentanorJprostadienamide (35d). 40d EXAMPLE XII N-methanesulfonyl-9-Oxo-15a,hydroxy-15- £(+)-3,4-dihydrobenzo BJ fur-2-yl]-cis-5,10,trans-13-16,17,18,19,20-tetranorprostatrienamide (40d) s A mixture of 68 mg (0.138 mmole) N-methanesulfonyl-9-oxo11a ,15a-dihydroxy-15- /(+)-3,4-dihydrobenzo[b]-fur-2-yl]-cis-5trans-13-16,17,18,19,20-tetranorproBtadleamide and 6 ml acetic acid was stirred overnight at 70°. After concentration, the reaction mixture which was combined with 50 ml ethyl acetate, washed with water (3 x 25 ml), dried (Na2SO4) and concentrated to give 50 mg of the desired N-methanesulfonyl-9-oxo-15a-hydroxy-15- /(+)-3,4dihydrobenzo /bj-f ur-2-yl]-cis-5,10,trans-13rl6,17,18,19,20-tetranorprosta15 trienamide. The nmr spectrum (CDCl^) exhibited characteristic signals at 6.16 5(d of d, IS) and 7.53 (d of d, IH) for the a,β-unaaturated carbonyl system. 4 6 2 5 7 25d Id EXAMPLE XIII M-methane3ulfonyl-9g-Hydroxy-lla,15a -bis-(tetrahydropyran-2-yloxy)15- [(+)-3,4-dlhydrobenzo [bl pyran-2-yl] -16,17,18,19,20pentanorprostanamide (4Id): A mixture of 190 mg K-methanesulfonyl 9a-hydroxy-lla,15abis-(tetrahydropyran—2-yloxy)-15- [(+)-3,4-dihydroben2O [b]pyran-2-yljcls-5,trans-13,16,17,18,19,20-pentanorprostadienamide, 5% palladium on carbon (150 mg) in ethyl acetate (10 ml) is stirred under an atmosphere of hydrogen for 60 hours at room temperature. The mixture is filtered and concentrated to give N-methanesulfonyl9«-hydroxy-lla, 15a-bls-(tetrahydropyran-2-yloxy)-15- [(+)-3,4dihydrobenzo [b]-pyran-2-y1]-16,17,18,19,20-pentanorprostanamide (4Id).

EXAMPLE XIV N-methanesulfonyl-9a, Ha, 15a-TTlhydroxy-15-/(+ )-3,4-dihydrobenzo/b 7pyran-2-yl7-16,17,18,19,20-pentanorprostgnamide (42d): Hydrolysis of 20 mg N-methanesulfonyl-9a-hydroxy-lla, 15a5 bis- (tetrahydropyran-2-yloxy) -15-/(+) -3,4-dihydrobenzo/“b_7pyran2-y3716,17,18,19,20- pentanorprostanamide (41d) acid is carried out with acetic acid (0.5 ml) and water (0.3 ml) under nitrogen at room temperature for 20 hours. Purification as described in Example I affords pure N-methanesulfonyl 9a, Ila, 15a-trihydroxy10 15-/(+)-3,4-dihydrobenzo/~b_7pyran-2-yl7-’le'17'18'19'20“Psntsnorprostanamide (42d). · - 84 4 6 2 5 7 EXAMPLE XV M-Methanesulfonyl-9-oxo-lla,15a-dihydroxy-15-/T+)-3,4-dihydrobenzo/~b_7pyran-2-ylT^>]-7(18>19,2i>-pentanorpros-t:anaita.<3e (Met): A solution of l86 mg. of the product of Example XIII in 3 ml acetone is oxidized with 0.2 ml, of Jones' reagent as described in Example II. Isolation of the product and hydrolysis with acetic acid and water at room temperature and purification as described in Example hi gives pure N-methanesulfonyl~9-oxo~llajl5adihydroxy-15-/(+)-3,4-dihydrobenzo/_b_7pyran-2-yl7,i6,17,18,l9i2opentanoiprostanamide (44d). ^6357 46d EXAMPLE XVI N-methanesulf onyl-9/3, Ila, 15a-Trihydroxy-15-/(+)-3,4-dihydrobenzo[b]pyran-2-yf| -5-cis, 13-trans-16,17,18,19,20-pentanorpro3tadlenamide (46d): . To a solution of 50 mg of N-methanesulf onyl-9-oxo-llct. 15adihydroxy-15-/T+)-3.4-dihydrQbenzo/~b 7pyran-2-yl7-cis-5·,. trans-1316,17,18,19,20-pen.tanorprcstadienaud.de (27d) 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 (NagSOlj.), and is concentrated. Purification of the crude product by silica gel chromatography affords N-methanesulfonyl15-/f+)-3,4-dihydrobenzo/-lb_7’pyran-2-yl7£)G]i'2a amide (45d) and N-methanesulfonyl-9Bi Ha, 15a-trihydroxy-15-/J+ )-3,4-dihydrobenzo/~b 7pyran-2~yl7-5-cis, 13-trans-16,17,18,19,20-pentanorprostadienamide(46d), Similarly, the other E prostaglandins of this invention are converted to their corresponding Fa and Fp derivatives. - 86 4 6 2 5 7 OH i-NHSOgCttj OH OH R»Ntrstx,ait. »- 4 OH 27d 47d EXAMPLE ΧΓΙΙ N-Methane sulfonyl-9-oxo-lla,l5a-dihydroxy-15-/(+)-3,4~dihydrobenzo/~b_7pyran-2-yl/-13-trans-i6,17,18,19f20-p6ntanorprostenaniide (47dk A solution of 72 mg N-methanesulfonyl 9-οχο-11α,15αdihydroxy-15-/~(+)-3.4-aihydrobenzo/~b 7pyran-2-yl7-cis-5.,trans13,16,17,18,19,20-pentanorprostadienamide 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 (NagS0^), and is concentrated, Tlie 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 65:35 v/v mixture of acetic acid: water for 10 minutes at room temperature. The mixture is diluted with water, extracted with ethyl acette, dried (NagSO^) and concentrated to afford after purification by silica gel chromatography, N-methaneeulf onyl-9-oxo-lla, 15a-dihydroxy-15-/ (+)-3,4-dihydrobenzo/rb_7’pyran-2-yl7-13 -trans-16,17.18.19.20-pentanorprostenainide (47d).

Similarly, the Eg and Pg prostaglandins of this invention are converted to their Ej_ and Fj derivatives.

Claims (17)

1.

2. -Decarboxy-16,17,18,l9,20-pentanorprostaglandins of the formula:- wherein: 5 X is 5-tetrazolyl or -OnhR' wherein R’ is alkanoyl of from 2 to 5 carbon atoms; cycloalkanoyl of from 4 to 7 carbon atoms; benzoyl or monosubstituted benzoyl wherein said substituent is chlorine, fluorine, methyl, trifluoromethyl, methoxy or phenyl; alkylsulfonyl of frpm 1 to 4 carbon atoms; phenylsulfonyl or mono substituted phenylsulfonyl wherein said substituent is chlorine, fluorine, methyl, trifluoromethyl, methoxy or phenyl; j.5 W is a single bond or a cis double bond; L is a single or double bond; Z is a single bond or a trans double bond; H OH M. and M are oxo, , or ; 'oh h N is hydrogen or α-hydroxyl with the proviso that when L 20 is a double bond, N is hydrogen; R is hydrogen, chlorine, fluorine, methyl, trifluoromethyl or methoxy; 88 46257 n is 1 or 2 and the pharmaceutically acceptable acid addition salts, thereof wherein the 2-position is substituted by a 5tetrazolyl radical. 5 2. A compound according to claim i wherein X is a 5tetrazolyl group. II

3. A compound according to claim 1 wherein X is -CNHR 1 where R’ is as defined in claim 1.

4. A compound of the formula: and its epimers, wherein: Μ, X, W, Z, R and n are as defined in claim 1, and the pharmaceutically acceptable acid addition 15 salts thereof wherein X is 5-tetrazolyl.

5. The C-9 epimer of the compound of claim 4. wherein Μ, X, W, Z, R and n are as defined in claim 1 and the pharmaceutically acceptable acid addition salts - 89 4 6 2 T thereof wherein X is 5-tetrazolyl. wherein M, W, X p Z p R and n are as defined in claim 1; 5 and the pharmaceutically acceptable acid addition salts thereof wherein X is 5-tetrazolyl. wherein M, W, X, Z, R and n are as defined in claim 1; and the pharmaceutically acceptable acid addition salts 10 thereof wherein X is 5-tetrazolyl.

6. 9. A compound of the structure: wherein M p W, X, Z, R and n are as defined in claim 1; and the pharmaceutically acceptable acid addition salts 15 thereof wherein X is 5-tetrazolyl.

7. 10. A compound of the structure: -90 4625 and the Cg and C^^ epimers thereof, wherein X, W, Z, R and n are as defined in claim 1, Q is hydrogen or 2-tetrahydropyranyloxy; 5 THP is 2-tetrahydropyranyl; and the pharmaceutically acceptable acid addition salts thereof wherein X is 5-tetrazolyl radical.

8. 11. A compound of the structure: OH Q' R 10 the C^ epimer thereof, wherein X, W, Z, R and n are as defined in claim 1, Q and THP are as defined in claim 10; and the pharmaceutically acceptable acid addition thereof wherein X is tetrazolyl. 15

9. 12. A compound of claim 1 wherein the chiral carbon atom of said substituent at the 15-position has the (+) configura tion.

10. 13. A compound of claim 1 wherein the chiral carbon atom of said substituent at the 15-position has the (-) configura 20 tion. 4 6 2 5 7

11. 14. A compound of claim 1 wherein n is i.

12. 15. A compound of claim 1 wherein n is 2.

13. 16. M-methanesulfonyl-15-/(-)-2-coumaryl7-16,

14. 17,18,19,20pentanor-PGE2 amide. 5 17. N-methanesulfonyl-15-/{“)-2-chromanyl7“16,17,18,19,20 pentanor-PGE2 amide.

15. 18. N-methanesulfonyl-15-/(+)-2-chromanyl7-16,17,18,19,20 pentanor-PGE2 amide.

16. 19. N-methanesulfonyl-15“/(-)-2-chromanyl7-16,17,18,19,20 10 pentanor-PGE2 amide.

17. 20. 2-Decarboxy-2-(tetrazol-5-yl)-15-/(-)-2-chromanyl716,17,18,19,20-pentanor-PGE2.