IL42373A

IL42373A - Oxaprostagliandins and their preparation

Info

Publication number: IL42373A
Application number: IL42373A
Authority: IL
Original assignee: Pfizer
Priority date: 1972-06-02
Filing date: 1973-05-28
Publication date: 1977-08-31
Also published as: JPS5239629A; DK143498C; LU67738A1; SE7608221L; FI55995B; JPS4954349A; JPS5231054A; GB1440602A; FI55995C; DE2344839B2; NL7307740A; ES441003A1; SE415756B; DE2344838A1; CH586716A5; CA1095034A; PH11300A; AU5639373A; CH589074A5; AR199300A1

Description

42373/2 PFIZE 0· 4 42373/3 This invention relates to certain novel analogs of the naturally occurring prostaglandins. In particular, it relates to novel 18-oxa, 19-oxa, 20-oxa, and 19-oxa-lJ-homo-prostaglandins , and various novel intermediates, useful in their preparation.

The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. For instance, the prostaglandins of the E and A series are potent vasodilators (Bergstrom, et al . , Acta Physiol. Scand. 64:332-33, 1965 and Bergstrom, et al. , Life Sci. 6:449-455, 1967) and lower systemic arterial blood pressure (vasodepression) on intravenous administration (Weeks and King, Federation Proc . 23:327, 1 64; Bergstrom, et al.., 196 , op_. cit . ; Carlson, et al. , Acta..Med. Scand. 183:423-430, 1968; and Carlson, et al., Acta Physiol. Scand. 75:l6l-l69, 1969). Another well known physiological action for PGE^ and PGE2 is as a bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969).

Still another important physiological role for the natural prostaglandins is in connection with the reproductive cycle. PGE2 is known to possess the ability to induce labor (Karim, et al. , J. Obstet Gynaec ♦ Brit. Cwlth. 77:200-210, 1970), to induce therapeutic abortion (Bygdeman, et al . , Contraception, 4, 293 (1971) and to be useful for control of fertility (Karim, Contraception. 3, 173 (1971))· Patents have been obtained for several prostaglandins of the E and F series as inducers of labor in mammals (Belgian Patent Λ 754,158 and Israel Patent 34793), and on PGF1 , and F2 , for control of the reproductive cycle (Israel Patent 32893) .

Still other known physiological activities for PGEj are in the ihhibition of gastric acid secretion (Shaw and Ramwell, In: Worcester Symp . on Prostaglandins , New York, Wiley, 1968 , p. 55-64 ) and also of platelet aggregation (Emmons, et al. , Brit. Med. J. 2 : 468-472 , 1967 ) .

It is now known that such physiological effects will be produced in vivo for only a short period, following the administration of a prostaglandin. A substantial body of evidence indicates that the reason for this rapid cessation of activity is that the natural prostaglandins are quickly and efficiently metabolically deactivated by ^-oxidation of the carboxylic acid side-chain and by oxidation of the 15c -hydroxyl. group (Anggard, et al. , Acta . Physiol . Scand . , 81 , 396 ( 1971 ) and references cited therein).

It was, of course, considered desirable to create analogs of the prostaglandins which would have physiological activities equivalent to the natural compounds, but in which the selectivity of action and the duration of the activity would be increased. Increased selectivity of action would be expected to alleviate the severe side effects, particularly gastrointestinal side effects, frequently observed following systemic administration of the natural prostaglandins (see Lancet, 536 , 1971 ) · The novel compounds of the present invention, the j -trisnorprostaglandins having at the 17-position two hydrogen atoms and one substituent of the formula: (CH2)n-0-(CH2)mCH3 wherein n is an integer of from 0 to 2, m is an integer of from 0 to 4 uniquely satisfy the above mentioned requirements. That is, they possess activity profiles comparable to the parent prostaglandins, although they are more tissue selective in their action and they exhibit a longer duration of action than the parent prostaglandins.

Especially preferred are U-trisnorprostaglandins of the A, E, or P series having at the 17-position two hydrogen atoms and one substituent of the formula: (CH2)n-0-(CH2)mCH3 wherein n is an integer of from 0 to 2 , m is 0 or 1.

The present invention comprises novel prostaglandins, and novel intermediates of the formulae: XV XIX wherein - W is a single bond or a, cis double bond; Z is a . single bond or a trans double bond; R3 is hydrogen or 2-tetrahydropyranyl M is keto, <, , or ''<0Ή '"Ή ' .·' N and L when taken together form a single bond, or N is 0L-OR2 when L is hydrogen; n is an integer of from 0 to 2 and m is 0 or 1 and wherein L, M, and N are so selected as to complete the structure of a prostaglandin of the A, E, or F series, and the C9, C]_]_ and C15 esters thereof, v.-hevem the ester group is formyl, alkanoyl of 2 to 5 carbon atoms or benzoyl; and the pharmaceutically acceptable salts . thereof , or their THP ethers. · .

Especially preferred novel prostaglandins of this invention are: 15 9-o o-llPf ,l¾X-dihydroxy-19-oxa-cis-5-trans-13 " prostadienoic acid; ' ■ 9-0 0-11 °^ , 15^-dihydroxy÷ii9--oxa-cis-- 5--trans-13- U -homoprostadlenoic acid; * Ί 9-oxo-ll< , 15°- homoprostadienoic acid; 25 9< ,Hc< > 15c s.— trihydroxy-l8-oxa-cJ^-5-trans-13- prostadienoic acid. ''<■ Other novel and useful oxaprostaglandin analogs are the Cg, C-Q, and C-^ esters wherein said esterifying group is formyl, alkanoyl having from 2 to 5 carbon atoms, or ben An aspect of the invention resides in a process for preparing a compound of the structure: wherein m, n, Z, N, L, M and W are as defined above and wherein L, M, and N are so selected as to complete the structure of a prostaglandin of the A, E, or P series, and the Cg, C11 and esters thereof, wherein the ester group is formyl, alkanoyl of 2 to 5 carbon atoms or benzoyl; characterized by the fact that a) when N is o -hydroxy and L is hydrogen, and n, m, M, w and Z are as defined above, ; said compound is prepared by treating the 11- and 15- tetra-hydropyranyl ethers of a compound of Formula I, above, with aqueous acetic acid; ) when N and L, when taken together, form a single bond, M is keto, and n, m, W and Z are as defined above, said compound is prepared by reacting a compound of Formula I, above, wherein N is « -hydroxy and L is hydrogen, M is keto and n, m, W and Z are as defined above, with formic acid: c) when N is c -hydroxy and L is hydrogen; and n, m, R, W and Z are as defined above, said compound is prepared by reacting a compound of the Formula I, above, wherein N is ^-hydroxy and L is hydrogen M is keto; n, m, W and Z are as defined above, with sodium borohydride and, if desired, separating the 9- ζ- and 9-β- hydroxy isomers, and, when required forming the formyl, alkanoyl or benzoyl esters of any free 9» 11 or 15 hydroxy groups by reacting said compounds with the appropriate acylating agent.

Another aspect of the invention resides in a process for preparing compound of the structure: ...IA wherein m, n, Z and W are as defined above; and the Cg , and C15 esters thereof, wherein the este. group is formyl, alkanoyl of 2 to 5 carbon atoms a benzoyl, characterized by the fact that a) the 11- and 15- tetrahydropyranyl ethers of a compound of Formula I, above, is treated with aqueous acetic acid; b) by reducing a compound of the formula wherein n, m, W and Z are as defined above with sodium borohydride and then separating the 9-o(- and S-β- isomers; and, when required, forming the formyl, alkanoyl or benzoyl esters of the free 9-, 11- and 15- hydroxy groups, by reacting said compounds with the appropriate acylating agents.

A further aspect of the invention resides in a process of preparing a compound of the structure: wherein m, n, Z and W are as defined above; and the and esters thereof, wherein the ester. roup is formyl, alkanoyl of 2 to 5 carbon atoms or benzoyl, characterized by the fact that the 11- and 15- tetrahydropyranyl ether derivative of the above compound is treated with aqueous acetic acid, and, when required, forming the formyl, alkanoyl or benzoyl esters of the free 11- and 15- hydroxy groups, by reacting said compounds with the appropriate acylating agents.

An additional aspect of the invention resides in a process for preparing a compound of the structure: ...IC wherein m, n, Z and W are as defined above; and the C 15 esters thereof wherein the ester group is formyl, alkanoyl of 2 to 5 carbon atoms or benzoyl; characterized by the fact that a compound of Formula IB ...IB wherein n, m, W and Z are as defined above is treated with formic acid, and, when required, forming the formyl, alkanoyl or benzoyl esters of the free C^- hydroxy group by reacting said compound with the appropriate acylating agents.

The invention also concerns itself with a process for preparing compound of the structure: II wherein m, n, Z, M and W are as defined above; and HP is 2-tetrahydropyranyl; characterized by the fact that when M is keto and n, m, w and Z are as defined above said compound is prepared by oxidation of a compound of the formula OH wherein n, m, W and Z are as defined above with chromic acid, aqueous sulfuric acid and acetone, when M is W is a cis double bond and m, n and Z are as defined above by reacting a compound of the formula with an ylide of the Formula (C6H5)3P=CH-CH2CH2CH2-COOH and, when required, subsequently reducing the product thus formed to afford a compound wherein n, m and Z are as defined above and W is a single 42373/3 bond when n, m and M are as defined above and W and Z are single bonds by reducing a compound of the Formula IIA wherein n, m and M are as defined above > W is < double bond and Z is a trans double bond; when M is n and m are as defined above is a single bond and Z is a trans double bond; v by selective reduction of a compound of Formula IIA, as 1 defined above.

Oxaprostaglandin F lot' and A- 13 ^-dihydro-oxaprostaglandin Fi^» > and REACTION SCHEME B XII F2(7 , Eg, and A≥ 42373/3 As shown in Reaction Scheme A VIII ^ IX is brought about by reaction with ( 4-carbohydroxy-n-butyl) -triphenylphosphonium bromide and methylsulfinylmethide in dimethyl sulfoxide at room temperature for at least 2 hours. The mixture is then acidified with, for example, aqueous hydrochloric acid, and then is extracted with ethyl acetate, evaporated, and concentrated.

IX-—^Oxaprostaglandin F2 involves hydrolysis with aqueous acetic acid, concentration, and purification by column chromatography .

IX Oxaprostaglandin E2 requires treatment with Jones' reagent for about 20 minutes at -10°C. to form a second intermediate before the acid treatment and purification as above.

Oxaprostaglandin A2 is obtained by treating oxaprostaglandin ∑2 with formic acid, concentration, and purification by column chromatography.

IX* Oxaprostaglandihv F requires a reduction with palladium-on-carbon and methanol to produce X which may then be hydrolyzed with aqueous acetic acid, and purified as above.

X ^Oxaprostaglandin E-j_ > Oxaprostaglandin Αχ follows exactly the same method as outlined for the PGE2-PGA2 series above.

IX 13,14-dihydro-oxaprostaglandin F1¾ requires a reduction with palladium-on-carbon and methanol to produce XI which is then hydrolyzed with aqueous acetic acid, and i purified as above. '· To produce the other 13 , 14-dihydro derivatives one follows the procedures outlined above. 42373/3 Referring now to Reaction Scheme B XIII XIV is analogous to VIII- IX of Reaction Scheme A.

XIV 13>l -dihydro-oxaprostaglandin involves hydrolysis with aqueous acetic acid, concentration, and purification by column chromatography.

XIV 13, l^-dihydro-oxaprostaglandin E2 requires treatment with Jones' reagent for about 20 minutes at -10°C. to form a second intermediate before acid treatment and purification as above. 13, l^-dihydro-oxaprostaglandin A2 is obtained by treating 13 , 14-dihydro-oxaprostaglandin E2 with formic acid, concentrating, and purifying by column chromatography.

The novel alkanoates, formates, and benzoates of the E, P and A series of oxaprostaglandins are prepared by reaction of the appropriate prostaglandins with an acid chloride. For example, 19-oxa PGE2 when reacted with benzoyl chloride, in the presence of a tertiary amine in a reaction-inert solvent, will yield 11, 15-dibenzdyl-19-oxa PGE2 and, in the same way, 18-oxa PGF2o<^ when reacted with pivaloyl chloride will yield 9,ll,15-tripivaloyl-l8-oxa PGF2o< .

As the literature cited establishes, the natural prostaglandins are known to exhibit a spectrum of physiological activities. In numerous in vivo and in vitro tests we have demonstrated that the oxaprostaglandin analogs have the same physiological activities as exhibited by the natural prostaglandins. These tests include, among others, a test for effect on isolated smooth muscle from guinea pig ileum and rat uterus, a test for effect on histamine induced broncho-spasm in guinea pig, a test for effects on dog blood pressure, a test for Induction of diarrhea in mice, and a test for the induction of abortion in early pregnant rats.

Results on these various physiological tests are shown in Table I below. It will be noted that not only do these oxaprostaglandin analogs possess comparable action quantitatively to the natural prostaglandin, but they also possess the advantage of tissue selectivity, particularly 19-oxaprostaglandin On the basis of the difference seen in the rat uterus and guinea pig ileum tests with 19-oxaprostaglandin ∑2 > one would expect to have a reduction of the unpleasant gastrointestinal side effect's which were encountered when natural PGE2 was employed as an abortion inducer (Lancet , 536, 1971). This important advantage has been amply verified by the fact that 19-oxaprostaglandin has now been found to be only 10% as effective as natural PGEg in inducing diarrhea in mice in vivo, while it is as effective as natural PGE? in inducing abortion in the early pregnant rat. Furthermore, as can be seen from Table I, l8-oxa PGE2 is particularly^ selective with regard to its blood pressure effects, while 19-oxa- J -homo PGE2 is a more selective bronchodilator than natural PGE .

TABLE I Dog Blood Histamine Rat Ute Prostaglandin Pressure (a) Aerosol (¾) ng/m 19-oxa PGE2 20 19% 50-100 19-oxa- -homo-PGEg 38% 100 l8-oxa PGE2 2 3% 100-300 19-oxa PGF^ - - 100-500 19-oxa-w -homo-PGF^,- - - 60-300 l8-oxa PFg^ - - 300-600 PGE2 1 75% 10-30 Relative dose at which oxaprostaglandin derivative has similar action to anesthetized dog blood pressure.

Per cent protection by 100jig/ml. aeroSol dose for histamine induced bronc Threshold dose for spasmogenic effect on estrogenized rat uterus in vitro . Threshold dose for spasmogenic effect on guinea pig ileum in vitro .

Inhibition constant for norepinephrine stimulated lipolysis.

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, bronchodllator activity, antlthrombogenlc activity, antiulcer activity, smooth muscle activity [useful as anti-fertility agent, for the induction of labor, and as an aborti-facient], and anti-fertility activity through a mechanism not affecting smooth muscle, for example, luteolytic mechanisms.

The novel compounds of this invention possess more selective activity profiles than the corresponding naturally occurring prostaglandins and, in many cases, exhibit a longer duration of action. For example, if an intravaginal treatment for abortion induction is desired, a suitable vehicle is a tampon impregnated with 19-oxa-U -homoprostaglandln F2< or lactose tablets of the same agent. In such treatments a suitable dose would be about 100 mg. with 1 or 2 doses being employed .

In cases where a midterm abortion is necessary, an effective agent would be physiological NaCl solution of 19-oxa-PGE2 administered as an intravenous infusion. A suitable dosage could be from about 5 to 100 administered for a period of from about 2 to 10 hours.

Another use for the oxaprostaglandins is as an inducer of labor. For this purpose a physiological NaCl solution of 18-oxa PGp2< is emPl°veci as an Intravenous infusion in the amount of from about 5 to 100 jig/kg/min for from about 1 to 10 hours, or 18-oxa ls administered orally at doses of 5 to 100 mg. every 2 hours.

Still other applications for the oxaprostaglandins are to produce bronchodilation or to increase nasal patency . An appropriate dosage form for this use is an ethanplic solution of 1 employed as an aerosol using fluorinated hydrocarbons as propellant in the amount of from about 50-500 ig/dos.

Oxaprostaglandins of the A series are useful hypotensive agents, as are those of the E series. For treatment of hypertension these compounds are administered as intravenous injections at doses of about 0.5-10 ug/kg or preferably orally in the form of capsules or tablets at doses of 0.005 to 0.5 mg/kg/day.

The prostaglandin analogs which have a beta hydroxyl atC^5 have action which is similar to their epimers. In some eases, however, the selectivity of these compounds display exceeds that of the epimeric compounds. Furthermore, the prostaglandins of the PGF series have substantially the same activities as prostaglandins ofthe PGFt.. series as do the Cg, C-j^, and C^,. esters of all the novel prostaglandins of this invention. The latter are especially appropriate for oral dosage preparations.

The new compounds of this invention can be u in a variety of pharmaceutical preparations which contain the compound or a pharmaceutically acceptable salt thereof, and they may be administered in the same manner as natural prostaglandins by a variety of routes, such as intravenous, oral and topical, including aerosol, intravaginal, and intranasal, among others. Pharmaceutically acceptable salts include salts of pharmaceutically acceptable bases such as alkali and alkaline earth metals, ammonia, and amines.

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 examples are merely illustrative, ί and in no way limit the scope of the' appended claims.

EXAMPLE I (Starting Material) A solution of 310 mg. (0.71 mmole) 2-[5 o-hydroxy-30 -(tetrahydropyran-2-yloxy)-2p -3o-[tetrahydropyran-2-yloxy 1-7-oxa-trans-l-octen-l-yl)cyclopent-lo^-yl» acetic acid, ^-lactone as prepared in Example V in 5 ml. dry toluene was cooled to -78° in a dry nitrogen atmosphere. To this cooled solution was added 1.5 ml. of 20% diisobutylaluminum hydride in n-hexane dropwise at such a rate so that the interna] temperature never rose about - 65° ( 15 minutes). After an additional 45 minutes of stirring at -78° , anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 100 ml. ether, washed with 50% sodium potassium tartrate solution ( 4 x 20 ml.), dried (MgSOjj) and concentrated to yield 290 mg. (93?) 2- [ 5c/.-hydroxy-3 o^-(tetra-hydropyran- 2-yloxy ) - 2j2> -(3 ^- [tetrahydropyran- 2-yloxy ] - 7-oxa-trans-l-octen-l-yl ) eyelopent-l-yl]acetaldehyde , -hemiacetal .

EXAMPLE II ~ To a solution of 870 mg. ( 2 . 0 mmole) ( 4-!carboxy n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 5 . 0 ml. dry dimethyl sulfoxide was added 2 . 0 ml. t )l )l '-.nnl ^, A -F* ^ Ό o 1 - - *- ■» - ■- <■ c -— ~ "> - " " 1 4' * f -in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 290 mg. ( 0 . 66 mmole) 2-[ c ~hydroxv"" 3c^-(tetrahydropyran- 2-yloxy ) - 2 |2>-(3 C^-Ctetrahydropyran-2-yloxy ]- 7-oxa-trans- 1-octen-l-yl) eyelopent-1 ^-yl ]acetaldehyde, ""^-hemiacetal as prepared in Example ϊ in 3.0 ml. dry dimethyl sulfoxide over a period of 20 minutes. After an additional 2 hours stirring at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was washed twice with ethyl acetate ( 20 ml.) and acidified to pH Λ-' 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 20 ml.) and the combined organic extracts washed once with water ( 10 ml.), dried (MgSO^) and evaporated to a solid residue weighing 784 mg. This solid residue was triturated with column chromatography on silica gel (Baker "Analyzed" Reagent 60-200 mesh) using ethyl acetate as eluen . After removal of high Rf impurities, 225 mg. (66%) of 9 bis- (tetrahydropyran-2-yloxy )-19-oxa-cis-5-trans-13-prosta-dlenoic acid was collected.

The nmr spectrum (CDCl^) exhibited a multlplet (variable) at 5-84-6.38J~ (2H) for the -OH protons, a multlplet at 5.27- .68^ (4H) for the olefinic protons, a multlplet at 4.52-4.84 ¾Γ (2H) for the acetal protons, a singlet at 3.34 (3H) for the methyl ether protons and multiplets at 3· 25- 4.3 J~ (9H) and 1.20-2.72 (28H) for the remaining protons.

EXAMPLE VIII To a solution cooled to -10° under nitrogen of 190 mg. (Ο.356 mmole) 9 o^-hydroxy-11 <-^, 15 o^-bis- (tetrahydropyran-2-yloxy )-19-oxa-cis-5-trans-13-prostadienoic acid as prepared in Example VII, in 5 ml. reagent grade acetone was added drop-wise 0.143 ml. (Ο.356 mmole) of Jones' reagent. After 20 minutes at -10°, 0.140 ml. 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 40 ml. ethyl acetate, washed with water (3 x ml.), dried (MgSO^) and concentrated to give 174 mg. of 9-oxo-llo ,15r7(-bis-(tetrahydropyran-2-yloxy )-19-oxa-cis-5-trans-13-prostadienoic acid.

EXAMPLE IX A solution of 174 mg. (0.334 mmole) 9-oxo-ll^, 15 G^-bis-tetrahydropyran-2-yloxy )-19-oxa-cis-5-trans-13-prosta-dienoic acid as prepared in Example VIII in 3-0 ml. of a 65:35 mixture of glacial acetic acid: water was stirred under nitrogen at 40° for 5 hours then was concentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Malllnckrodt CC-4 100-200 mesh) using ethyl acetate as eluent. After elution of less polar impurities the semisolid 9-οχο-11θ , 15 C^-dihydroxy-19-oxa-cis-5-trans-13-prostadienoic acid weighing 33 mg. was collected. This product is 19-oxaprostaglandin E2> m.p. 58-9° (ethyl acetate, cyclohexane ) .

Analysis: Calc'd for C - 64.39; H - 8.53 Pound . C - 64.30; H - 8.28 [o ]25 s -71.2° (C = 1.0, methanol) D The ir spectrum (CHCl^) of the product exhibited a strong adsorption at 1715 cm-1 for the carbonyls and a medium band at 965 cm-1 for the trans double bond. The uv spectrum in methanol with added potassium hydroxide solution exhibited a " ø max27'8 ■mu and an £>- max 28,>000.

If the corresponding 19-oxaprostaglandin A2 is desired, the above 19-oxoprostaglandin E2 may be treated with formic acid, and the product then purified by column chromatography .

EXAMPLE V A solution of 2 mg. (0.10 mmole) 9<5^\-hydroxy- 11 , 15o(-bis_- (tetrahydropyran-2-yloxy )-19-oxa-cis- -trans-13-prostadienoic acid as prepared in Example VII, in 3.0 ml. of a 65:35 mixture of glacial acetic acid: water was stirred under nitrogen at 40° for 5 hours then was concentrated by rotary evaporation. The resultant crude oil was purified on silica gel (Malllnckrodt CC-4 100-200 mesh) using ethyl then methanol as eluents. After elution of less polar impurities the oily 9 , 11 , 15 -trihydroxy-19-oxa-cis-5-trans-13-prosta-dienoic acid weighing 15 mg. was collected. This product is 19-oxaprostaglandin ^2a' EXAMPLE VI (Starting Material) A solution of 575 mg. (1.28 mmole) crude 2- acetic acid, a-lactone in 5.75 ml. dry toluene was cooled to -78° in a dry nitrogen atmosphere.

To this cooled solution was added 1.8 ml . of 20% diisobutyl-aluminum hydride in n-hexane dropwise at such a rate so that the internal temperature never rose above -65° (15 minutes). After an additional 1 hour of stirring at -78°, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 50 ml. ether, washed with 505? sodium potassium tartrate solution (4 x 10 ml.), dried (MgSOjj) and concentrated to yield 458 mg. (80%) 2-[5o^-hydroxy-3 C- (tetra-hydropyran-2-yloxy )-2j¾ - ( 3 ^-[tetrahydropyran-2-yloxy]-7-oxa- trans-l-nonen-l-yl)cyclopent-l-yl]acetaldehyde , .

EXAMPLE VII To a solution of 1330 mg. (3-0 mmole) ( 4-carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmo-sphere in 6 ml. dry dimethyl sulfoxide was added 3· 4 ml. (6.8 mmole) of a 2.0 M solution of sodium methylsulfinylmethlde in dimethyl sulfoxide. To this red ylide solution was added drop-wise a solution of 4 mg. (1.0 mmole) crude 2-[5 c^-hydroxy-3 ^-(tetrahydropyran-2-yloxy ) -2jB -(3©^-[tetrahydropyran-2-yloxy]-7-oxa-trans-1-nonen-l-yl)cyclopent-lo^-yl]acetaldehyde, ^f-hemiacetal in 3.0 ml. dry dimethyl sulfoxide over a period of 20 minutes. After 2 hours stirring at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was washed twice with ethyl acetate (30 ml.) and acidified to 3 with 10$ aqueous hydrochloric acid. The acidic solution was extracted evaporated to a solid residue weighing 900 mg. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" Reagent 60-200 mesh) using ethyl acetate as eluent. After removal of high Rf impurities, 290 mg. ( 54 ) of 9 C^-hydroxy-llo >15c^-bis-(tetrahydropyran-2-yloxy )-19-oxa-cis-5-trans-13-^j-homo-prostadlenoic acid was collected.

The nmr spectrum (CDCl^) exhibited a multiplet (variable) at 6.2-6.6 ^ (2H) for the -OH protons, a multiplet at 5.3-5-7 W~ (4H) for the olefinlc protons, a multiplet at 4.6-4.9 J~ (2H) for the acetal protons, a quartet at 3 · 5 (2H) for the ethyl ether protons and multlplets at 3·3-* ·* (9H) and 1.0-2.6 (31H) for the remaining protons.

EXAMPLE VIII To a solution cooled to -10° under nitrogen of 290 mg.

(O.5 0 mmole) 9 o(-hydroxy-ll o, 15 G^-bis-(tetrahydropyran-2-yloxy )-19-oxa-cis- -trans-13- -homo-prostadienoic acid in 5.4 ml. reagent grade acetone was added dropwise 0.226 ml. (0.600 mmole) of 2.67 M Jones' re-agent. After 5 minutes at -10°, 0.230 ml. 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 30 ml. ethyl acetate, washed with water (3 x 5 ml.), dried (MgSOij), concentrated, and chromatographed (Baker 60-200 mesh silica gel, CH2C12 eluent) to give l80 mg. of 9-oxo-llo(,15c7i-bis-(tetrahydropyran-2-yloxy )-19-oxa-cis-5-trans-13-^0-homo-prostadienoic acid.

EXAMPLE IX A solution of 129 mg. (0.240 mmole) 9-oxo-ll (,15 If 19-oxa-u)-homoprostaglandin A2 is desired, the procedure outlined in Example IV may be followed.

If 19-oxa-u)-homoprostaglandin P2c-^ls desired, the procedure outlined in Example v ma be followed, using the product of Exarriple VIII as a starting material.

EXAMPLE X (Starting Material) .A'solution of 880 mg. (2.01 mmole) crude 2-C5 o(-hydroxy-3o-tetrahydropyran-2-yloxy )-2p -(3 To this cooled solution was added 3 ml. of 20% di- isobutylaluminum hydride in n-hexane dropwise at such a rate so that the internal temperature never rose about -65° (15 minutes). After an additional 30 minutes of stirring at -78°, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 100 ml. ether, washed with 50% sodium potassium tartrate solution (4 x 10 ml.), dried (MgSC/j) and concentrated to yield 65» mg* 2-[5c -hydroxy-3 (-(tetrahydropyran-2-yloxy)-2¾ -(3o(-[tetrahydro-pyran-2-yloxy]-6-oxa-trans-l-octen-l-yl)cyclopent-l-yl]-acetaldehyde, -hemiacetal .

EXAMPLE XI : ■' To a solution of 2600 mg. (6.0 mmole) ( — carboxy—n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 6 ml. dry dimethyl sulfoxide was added 6.0 ml. (12.0 mmole) of a 2.0 M solution of sodium methyl-sulfinylmethide in dimethyl sulfoxide. To this red ylide solu tion was added dropwise a solution of 660 mg. (1.5 mmole) crude 2-[5 o(-hydroxy-3 (^- (tetrahydropyran-2-yloxy )-2|3 -(3o - [tetrahydropyran-2-yloxy ]-6-oxa-trans-l-octen-l-yl)cyclopent-lo(-yl]acetaldehyde, (if-hemiacetal , in 5.0 ml. dry dimethyl sulfoxide over a period of 20 minutes. After an additional 2 hours stirring at room tempera ture, the reaction mixture was poured onto ice water. The basic aqueous solution was washed twice with ethyl acetate (100 ml.) and acidified to pH A^ 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 100 ml.) and the combined organic extracts washed once with water (25 ml.), dried (MgSO^) and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" Reagent 60-200 mesh) using ethyl acetate as eluent . After removal of high Rf impurities, 550 mg. (70%) of 9o(-h.ydroxy-llo( , 15p(-bis-(tetrahydropyran-2-yloxy )-l8-oxa-cis-5-trans-13-prostadienoic acid was collected.

The nmr spectrum (CDCl^) exhibited a multiplet (variable) at 6.2-6.6 T (2H) for the -OH protons, a multiplet at 5-3-5-7 ( H) for the olefinic protons, a multi-plet at 4.6-4.9 *z~ (2H) for the acetal protons, a quartet at 3-5^T (2H) for the ethyl protons and multiplets at 3-3-4.Ί (9H) and 1.0-2.6 v$~ (31H) for the remaining protons.

EXAMPLE XII To a solution cooled to -10° under nitrogen of 400 mg. (Ο.765 mmole) 9o -hydroxy-ll<^ , 1 ( -bis- ( tetrahydro- pyran-2-yloxy )-l8-oxa-cis-5-trans-13-prostadienoic - i acid in 8 ml. reagent grade acetons was added dropwise 0.338 ml. (0.900 mmole) of 2.67 Jones' reagent. After 5 minutes at -10°, 0.350 ml. 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 60 ml. ethyl acetate, washed with water (3 x 5 ml.), dried (MgSO^), and concentrated to give 280 mg. of 9-oxo-llo ,15(-bis-(tetrahydropyran-2-yloxy )-l8-oxa-c is-5-trans-13-prostadienolc acid.

EXAMPLE XIII A solution of 280 mg. (0.240 mmole) 9-oxo-ll o , 15 (?-bis-tetrahydropyran-2-yloxy )-l8-oxa-cis-5-trans-13-prosta-dienoic acid in 4.0 ml of a 65:35 mixture i of glacial acetic acid .water was stirred under nitrogen at 40° for 2.5 hours then was concentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-4 100-200 mesh) using ethyl acetate as eluent . After., elution of less polar impurities the oily 9-oxo-llo(,15 C>^-dihydroxy-l8-oxa-cis-5-trans-13-prostadienoic acid weighing '66 mg. was collected. This product is 18-oxaprostaglandin Ε2· The uv spectrum in methanol with added potassium hydroxide solution exhibited a max 23,800 to 25,600.

If the corresponding l8-oxaprostagla.ndin A^ is desired, the procedures of Example IV may be carried out.

EXAMPLE XIV A solution of 75 mg. (0.10 mmole) 9oC~hydroxy-llo^, 15 o(-bis- (tetrahydropyran-2-yloxy )-18-oxa-cis-5-trans- 13-prostadienoic acid in 3.0 ml. of a 65:35 of glacial acetic acid .water was stirred under nitrogen at 40° for 5 hours then was concentrated by rotary evaporation. The resultant crude oil was purified on silica gel (Mallinckrodt CC-4 100-200 mesh) using ethyl then methanol as eluents. After elution of less polar impurities the oily 9 o(, 11 ri , 15 o(-trlhydroxy-l8-oxa-cis-5-trans-13-prosta-dlenoic acid weighing 20 mg. was collected. This product is ΐδ-oxaprostaglandin EXAMPLE XV (Starting Material) acetaldehyde, ^-hemiacetal (8a): A solution of 900 mg. ( 2 . 0 mmole) 2- [5c?^-hydroxy- (tetrahydropyran-2-yloxy ) -2 - ( 3 -[tetrahydropyran-2-yloxy]-8-oxa-trans-l-nonen-l-yl)cyclopent-lP(-yl]acetic acid, <]f-lactone (7_a) in 15 ml. dry toluene was cooled to -78° in a dry nitrogen atmosphere. To this cooled solution was added 2.7 ml. of 20$ diisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal tem-perature never rose above -65° ( 15 minutes). After an additional 45 minutes of stirring at -78°, anhydrous acetic acid was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 60 ml. toluene, washed with 0$ sodium potassium tartrate solution ( 1 x 25 ml.), dried ( a2S0|) and concentrated to yield 5 4 mg. 2- [ 5(^-hydroxy-3<7^-(tetrahydro-pyran-2-yloxy ) -2 ¾ - ( 3^ - [tetrahydropyran-2-yloxy ]-8-oxa-trans-l-nonen-l-yl)cyclopent-l-yl]acetaldehyde, ^-hemiacetal (8a), after chromatography.

EXAMPLE . VI (Starting 'Material) " 2-[5o-Hydroxy-3o-(tetrahydropyran-2-yloxy )-2 > - ( 3o -[tetra-hydropyran-2-yloxy]-8-oxa-trans-l-nonen-l-yl)cycloyent-li7-yllacetaldehyde , ^"-hemiacetal ($) A solution of 3-5 g. (7-75 mmole) 2-[5 -( tetrahydro-pyran-2-yloxy)-2|3-(3 c^- (tetrahydropyran-2-yloxy ]-8-oxa-trans-l-nonen-l-yl)cyclopent-l-yl]acetaldehyde, (8) after chromatography.

EXAMPLE II - 9C^-Hydroxy-ll 15 c?(-bis-(tetrahydropyran-2-yloxy )-20-oxa-cis-5-trans-13-(/ -homo-prostadlenoic acid ( ) : To a solution of 7 · 65 g. (17.25 mmole) (4-carboxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 20 ml. dry dimethyl sulfoxide was added 15.3 nil. (32.2 mmole) of a 2.1 M solution of sodium methylsulfinyl- added dropwise a solution of 2.6 g. (5.76 mmole) 2-[5^-hydroxy-3c^-(tetrahydropyran-2-yloxy )-2^ -(3c-[tetrahydro-pyran-2-yloxy ]-8-oxa-trans-l-nonen-l-yl )cyclopent-lo(-yl]-acetaldehyde, "-hemiacetal (8) in 15.0 ml. dry. dimethyl sulfoxide over a period of 20 minutes. After an additional 2 hours stirring at room temperature, the reaction mixture was poured onto ice water (60 mis.), 250 ml. ethyl acetate and 35 ml. IN HC1. The acidic solution was further extracted with ethyl acetate (2 x 120 ml.) and the combined organic extracts washed once with water (60 ml.), dried (MgSO^) and evaporated to a residue. The residue was purified by column chromatography on silica gel (Baker "Analyzed" Reagent 60-200 mesh) using ethyl acetate as eluent . After removal of high Rf impurities, 3.1 g. of 9 o(-hydroxy-ll o315c -bis- (tetrahydro Ti an-?-ylox ) -20-ova -r. i.s-5- rJ?ns-i 3- iA^- omn-n-rnstsiierioic acid was collected.

EXAMPLE .XVIII 9o(-Hydroxy-llo( , 15 >-bis- ( tetrahydropyran-2-yloxy ) -20-oxa- To a solution of 2120 mg. (5.0 mmole) (4-carboxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 8.0 ml. dry dimethyl sulfoxide was added 5·02 ml. (9·3 mmole) of a I.85 M solution of sodium methylsulfinyl-methide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 564 mg. (1.22 mmole) 2-(5o^~ was poured onto ice water. The basic aqueous solution was extracted with ethyl acetate (2 x 100 ml.) and the combined organic extracts washed once with water (40 ml.), dried (MgSO^) and evaporated to a residue. This residue was purified by column chromatography on silica gel (Baker "Analyzed" Reagent 60-200 mesh) using chloroform ethyl acetate as eluents. After removal of high Rf impurities, 642 mg. of 9c ~nvcroxy- 11 o(t 15p -bis-(tetrahydropyran-2-yloxy )-20-oxa-cis-5-trans- 13- U-homo-prostadienoic acid was collected.

EXAMPLE XLI 15β -bis- (tetrahydropyran-2-yloxy )-20-oxa-cis-5- trans-13-^-homo-prostadienoic acid (10a) · To a solution cooled to -10° under nitrogen of 642 mg. (1.19 mmole) 9 -hydroxy-ll^( , 15 -bis- (tetrahydropyran-2-yloxy)-20-oxa-cis-5-trans-13- ^-homo-prostadienolc acid (9a) in 20 ml. reagent grade acetone was added dropwise to 0.59 nil. (I.58 mmole) of Jones' reagent. After 20 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 80 ml. ethyl acetate, washed with water (3 x 15 ml.), dried (MgS0j) and concentrated to give 578 mg. of 9-oxo-llo^ , 15 -bis-(tetrahydropyran-2-yloxy )-20-oxa-cis-5- acid (10) .

EXAMPLE XLII 9-Oxo-ll0{ , 15o -bis-(tetrahydropyran-2-yloxy )-20-oxa-cis-5-trans-13- U/-homo-prostadienoic acid (10): To a solution cooled to -15° under nitrogen of 2000 mg. (3.72 mmole) pyran-2-yloxy )-20-oxa-cis-5-trans-13- U homo-prostadienoic acid in 0 ml. rea ent rade acetone was added dropwis to I.85 ml. (Ο.655 mmole) of Jones' reagent. After 20 minutes at -10°, I.8 ml. 2-propanol was added and the reaction mixture was allowed to stir an additional minutes at which time it was combined with 125 ml. ethyl acetate, washed with water (3 x 25 ml.), dried (MgSO^) and concentrated to give 2.1 g. of trans-13-IA)-tetranorprostadienoic acid ( 10 ) .

EXAMPLE XLIII 9-Oxo-ll < fl5 c^-dihydroxy-20-oxa-cis-5-trans-13~U^-homo-prostadienoic acid ( 11 ) : A solution of 2100 mg. (3.29 mmole) 9-oxo-llo ,15 c^-bis-tetrahydropyran-2-yloxy )-20-oxa-cis-5-trans-13-^-homo-prostadienoic acid (10) in 21 ml. of a 65:35 mixture of glacial acetic acid: water was stirred under nitrogen at room temperature for 16.5 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 oily 9-oxo-ll EXAMPLE XLIV 9-OxO-llo ,15^-dihydroxy-20-oxa-cis-5-trans-13-^-homo-prostadienoic acid ( 11a) : A solution of 578 mg. (1.08 mmole) 9-oxo-ll o{, 15p-bis-tetrahydropyran-2-yloxy )-20-oxa-cls-5~trans-13- -homo-prostadienoic acid (10a) in 3.0 ml. of a 65:35 mixture of glacial acetic acid: water was stirred under nitrogen at 25° for 24 hours then was concentrated by rotary evaporation.

The resultant crude oil was purified by column chromatography on silica gel (Malllnckrodt CC-7) using chloroform and ethyl acetate as eluents. After elution of less polar impurities the semisolid 9-oxo-H 15|3-dlhydroxy-20-oxa-cis-5-trans-13-UJ-homo-prostadienoic acid (11A) weighing 131 mg. was collected.

EXAMPLE XLV 9 O(J 11 cjj 15o(-trihydroxy-20-oxa-cls-5-trans-13- - oxao-prostadienoic acid (12_) : A solution of 800 mg. (1.49 mmole) 9o(-hydroxy-HIT ,15g(.-bis-tetrahydropyran-2-yloxy )-20-oxa-cis-5-trans- 13- j-homo-prostadienoic acid (9) in 3·0 ml. of a 65:35 mixture of glacial acetic acldrwater was stirred under nitrogen at 25° for 16 hours then was concentrated by rotary evaporation. The resultant crude oil was purified by column chroma-tography on silica gel (Malllnckrodt CC-7) using ethyl acetate and ethyl acetate/methanol as eluents. After elution of less polar impurities the oil 9θ , 11 c^, 15 ^-trihydroxy-20-oxa-c_is-5-trans_-13-i -homo-prostadienoic acid (12) weighing 33 mg. was collected.

EXAMPLE XLVI To a solution of 76 mg. of 19-oxa-PGF2^ in 1.0 ml. of pyridine is added 120 mg. (1.0 mmole) of pivaloyl chloride. The solution is stirred for hours at 45° under nitrogen then is cooled to room temperature. To the solution is then added 36 mg. (2.0 mmoles) of water. The solution is then stirred at room temperature for 2.0 hours, then is diluted with ethyl acetate. The diluted solution is washed with 0.1 N hydrochloric acid (3x), with water (lx), and with saturated brine (lx), is dried (anhydrous magnesium sulfate), and is concen-trated. Purification of the crude residue by silica gel chromatography provides the desired 9 ctl^- t15/^-tris-pivaloyloxy 19-oxa PGP2^.

EXAMPLE XXV To a solution of 37 mg. of 19-oxa GA2 in 0.5 ml. of dry tetrahydrofuran is added 29 mg. (0.33 mmole) of formic acetic anhydride and 35 mg. (0.33 mmoles) of 2 , 6-lutidine .

The solution is stirred for 4 hours under nitrogen at room temperature then 36 mg. (2.0 mmoles) of water is added. The mixture is stirred at room temperature for an additional 1.0 hour then is diluted with ethyl acetate. The diluted solution is washed with 0.1 N hydrochloric acid (lx), with water (lx), and with saturated brine (lx), is dried (anhydrous magnesium sulfate), and is concentrated, Purification of the crude residue by silica gel chromatography affords the 15 o^formyloxy-19-oxa PGA2- EXAMPLE XXVI To a solution, cooled in ice under nitrogen, of 75 mg. of 19-oxa- (xAhomo PGE2~ in 1.5 ml. of methylene chloride is added 350 μΐ of pivaloyl chloride" followed by 450 μΐ. of tr'iethylamine . After being stirred 'at room temperature for 5 hours the mixture is poured onto a mixture of ethyl acetate/-ice. The aqueous layer is extracted with ethyl acetate; the combined organic extracts are washed with 10$ hydrochloric acid, with saturated bicarbonate, with water, is dried (an-hydrous magnesium sulfate), and is concentrated. Purification of the crude product by chromatography provides the desired 11 o(, 1 o^-bis-pivaloyloxy 19-oxa-U -homo-PGE2 · .

EXAMPLE XXVII To a solution, cooled in ice under nitrogen, of 125 mg. of l8-oxa-PGEp in 2.5 ml. of methylene chloride is added 0.50 ml. of benzoyl chloride followed by 0.625 ml. of triethylamine . After being stirred at room temperature for 5 hours, the mixture is poured onto a mixture of ethyl acetate rice water. The aqueous layer is further extracted with ethyl acetate; the combined organic extracts are washed with 10% hydrochloric acid and with water, is dried (anhydrous magnesium sulfate), and is concentrated. Purification of the : crude products by chromatography provides the desired ll^,1 o^-di-benzoyloxy-18-oxa PGE2 and 15c^-benzoyloxy-l8-oxa-PGA2 · EXAMPLE L To a solution, cooled in ice, of 35 mg. of 19-oxa-PG∑2 prepared in Example IX in 7 ml. of absolute methanol is added an ice-chilled solution of 105 mg. of sodium boro-hydride in 12 ml. of absolute methanol. The solution is stirred under nitrogen for 20 minutes at 0-5° then for 1.0 hour at room temperature. The reaction mixture is then cooled in ice, 2 ml. of water is added, and the resultant solution is concentrated. The concentrated mixture is overlaid with ethyl acetate, acidified with 10% hydrochloric acid, and the acidi-fied aqueous layer is extracted with ethyl acetate (4 x 5 ml.).

The combined extracts are washed with water and saturated brine, dried (anhydrous magnesium sulfate), and concentrated. The crude residue is purified by column chromatography (Mallinckrodt CC-7) using mixtures of methanol in methylene chloride as eluents to afford 19-oxa PGF2c^and 19-oxa PGF2p .

EXAMPLE LI 9 - ^-Hydroxy-11p(,15 (-bis- (Tetrahydropyran-2-yloxy )-19-oxa-prostanolc acid: A heterogenous solution of 9 ^hydroxy-ll^,1 ^-bis-(Tetra-hydropyran-2-yloxy )-cis-5-trans-13-19-oxaprostadienoic acid and 5% palladium on carbon In methanol is hydrogenated at 0° for 2 hours (1 atm.). The reaction mixture is filtered and evaporated to yield the desired product.

EXAMPLE LII 9 O^-Hydroxy-llc^, 15 g^-bis- (Tetrahydropyran-2-yloxy )-13-trans-19-oxaprostenoic acid: A heterogeneous solution of 9 p(j-hydroxy-ll p( , 15o^-bls-(Tetrahydropyran-2-yloxy )-cis-5-trans-13-19-oxaprostadienolc acid and $ palladium on carbon in methanol is hydrogenated at -22° for 4 hours (1 atm.). The reaction mixture is filtered and chromatographed to yield the desired product.

Claims

CLAIMS : 1.
A compound of the structure; and its Cj5 earners wherein W is a single bond or a cis double bond; Z is a single bond or a trans double bond; R3 is hydrogen or 2-tetrahydropyran l; H M is keto, ,f , or '-OH N and L when taken together form a single bond, or N is ot-OR3 when L is hydrogen; n is an integer of from 0 to 2 and m -is 0 or 1 and wherein L, M, and N are so selected as to complete the structure of a prostaglandin of the A, E» or F series, and the C9, Cn and C15 esters thereof, wherein the ester group is formyl, alkanoyl of 2 to 5 carbon atoms or benzoyl; and the pharmaceutically acceptable salts thereof, or their THP ethers. wherein m, n, Z and W are as defined above.
3. A compound of the structure: wherein m, n, Z and W are as defined above
4. A compound of the structure: wherein m, n, Z and W are as defined above.
5. A compound of the structure: wherein m, n, Z and are as defined above and THP is 2-tetrahydropyrany1.
6. 9-Oxo-ll^ 15¾(-dih.ydroxy-19-oxa-cis-5-trans-1.3-prostadienoic acid.
7. 9-Oxo-ll^,15. -dihydroxy-19-oxa-cis-5-trans-13-U-homoprostadienoic acid.
8. 9-0xo-ll° 9.
9^, 11°< ,15^-Trihydroxy-19-oxa-cis- 5-trans-13-prosta-dienoic acid.
10. 9*,ll«,15^<-Trihydroxy-19-oxa-cis-5-trans-13-aJ-homoprostadienoic acid.
11. 9
12. A process for preparing a compound of the structure: and its C15 epimers wherein W, M, L, N, Z, n and m are as defined in claim 1, and the C9 , C±i and C15 esters thereof, wherein the ester group is formyl, alkanoyl of 2 to 5 carbon atoms or benzoyl; characterized by the fact that a) when N is o-hydroxy and L is hydrogen, and n, m, R, M, and Z are as defined above; said compound is prepared by treating the 11- and 15-tetrahydro-pyranyl ethers of a compound of Formula I, above, with aqueous acetic acid; b) when 42373/2 N and L, when taken together, form a single bond; M is keto, and n, m, R, W and Z are as defined above; said compound is prepared by reacting a compound of Formula I, above, wherein N is oi -hydroxy and L is hydrogen, M is keto and n, m, R, and Z are as defined above, with formic acid; c) when N is o[-hydroxy and L is hydrogen; M is or and n, m, R, and Z are as defined ^OH above ; said compound is prepared by reacting a compound of the Formula I, above, wherein N is of-hydroxy and L is hydrogen; M is keto; n, m, R, W and Z are as defined above, with sodium bOi iiyui-J- It: and, LZ feS j-'fcu. , Se ra in Llic 3-^i— dUu ^(^~ hydroxy isomers ; and, when required forming the formyl, alkanoyl or benzoyl esters of any free 9, 11 or 15-hydroxy groups by reacting said compounds with the appropriate acylating agent.
13. A process for preparing a compound of the structure wherein m, n, M, z and W are as defined in claim 1; and THP is 2-tetrahydropyranyl; characterized by the fact that a) when is keto and n, m, R, W and Z are. as defined above 42373/2 wherein n, m, W and Z are as defined above with chromic acid, aqueous sulfuric acid and acetone, b) when H M is >. , W is a cis double bond and m, n, R and Z '"OH are as defined above by reacting a compound of the formula with an ylide of the formula and, when required, subsequently reducing the product thus formed to afford a compound wherein n, m, R and Z are as defined above and is a single bond; c) when n, m, R and M are as defined above and W and Z are single bonds by reducing a compound of the formula 42373/2 wherein , m, R and M are as defined above, W is a cis double bond and Z is a trans double bond; d) when M is , n, m and R are as defined above; W is a single bond and Z is a trans double bond; by selective reduction of a compound of Formula IIA as defined above. For th Applicant