IL43571A - Omega-pentanorprostaglandins and their preparation - Google Patents

Description

onJ an i o» i » a >a 00 noi l a ROa a- ^ CA -Pentanorprostaglandins and their preparation PFIZER INC.

C. 41703 P.O. 5k6/$Uk6A This invention relates to certain novel analogs of the naturally occurring prostaglandins. In particular, it relates to novel 15-substituted-o5-pentanorprostaglandins and various novel intermediates useful in their preparation. j. The prostaglandins are C-20 unsaturated fatty acids which Iexhibit diverse physiological effects.' For instance, the prosta-'glandins of the E and A series are potent vasodilators (Bergstrom, let al., Acta Physiol. Scand. 64:332-33, 1 65 and Bergstrom et al., jLife Sci. 6:4 9- 55, 19 7) and lower systemic arterial blood pressure (vasodepression) on 'intravenous administration (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:l6l-l69, 1969).. Another jjwell known physiological action for PGE^ and PGE2 is as a bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969) . natural 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, , 173 (1971) ) . Patent., have been obtained for several prostaglandins of the E and F series as inducers of labor in mammals (Belgian Patent 75 , 158 and West German Patent 2, 034,64-1 ) , and ton PGF^, F2, and F3 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 PGF^^La hsetwa , ature 30J5 8 (1971j7 and hence prostaglandins have utility for fertility control by a process in which smooth muscle stimulation is not necessary.

Still other known physiological activities for PGE-^ are in the inhibition 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. 2:468r472, 1 67) .

It IB 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 netabolically deactivated by β-oxidation of the carboxylic acid side-chain and by oxidation of the 15a-hydroxyl group (Anggard, et al., Acta. Physiol. Scand. , 8l, 36 (1971) and references cited therein). It has been shown that placin a 15-alkyl group in the prostaglandins has the effect of increasing the duration of action possibly by preventing the oxidation of the C15-hydroxyl Yankee and Bundy, JACS, 9k, 3651 (I97 )J > Kirton and Forbes. Prostaglandins, 1, 31 (197¾.

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 (Lancet, 536/1971). 43571/3 The present invention comprises novel tJ-pentanor prostaglandins, and intermediates for the preparation of the formula and its C^5 epimer; . wherein A is 1-adamantyl, 2- (1 , 2, 3 , 4-tetrahydronaphthyl) wherein said group is racemic or optically active, 2-indanyl or substituted 2-indanyl wherein said substituent is lower alkoxy; R3 is hydrogen or THP; R is hydrogen or lower alkyl; n is an integer from 0 to 5; W is a single bond or cis double bond; Z is a single bond or trans double bond; M is keto, or ; 'OH ''Ή N and L, when taken together form a single bond, or N is < -0R3 when L is hydrogen; THP is 2-tetrahydropyranyl 0 II X is selected from a first sub-group comprising -C-O-R' wherein R1 is hydrogen, alkyl of from 1-10 carbon atoms; aralkyl of from 7 to 9 carbon atoms; cycloalkyl of from 3 to 8 carbon atoms; monosubstituted phenyl, wherein said substituent is halo, lower alkyl, lower alkoxy or phenyl; a second sub-group comprising 5-tetrazolyl; or 43571/2 Preferred compounds of formula 1 are prostaglandins of the E series, compounds of formula 1 wherein said prostaglandins aije of the Fa series, compounds of formula 1 wherein said prostaglandins are of the F^ series, compounds of formula 1 wherein said prostaglandins are of the A series, compounds of formula 1 wherein n is 0, compounds of formula 1 wherein n is 1, compounds of formula 1 wherein n is 2, compounds of formula 1 wherein n is 3, compounds of formula 1 wherein n is 4, compounds of formula 1 wherein n is 5, compounds of formula 1 wherein n is 0 and said prostaglandin is of the E series, compounds of formula 1 wherein n is 0 and said prostaglandin is of the F series, compounds of formula 1 wherein n is 1 and said prostaglandin is of the E series, compounds of formula 1 wherein n is 1 and said prostaglandin is of the F series, compounds of formula 1 wherein n is 2 and said prostaglandin is of the E series, compounds of formula 1 wherein n is 2 and said prostaglandin is of the F series,- - compounds of formula 1 wherein A is 2-norooruyl, compounds of formula 1 wherein A is 1-adamantyl, compounds of formula 1 wherein A is 2 indanyl or substituted 2-indanyl wherein said substituent is halo, trifluoromethyl, lower alkyl or lower alkoxyl, compounds of formula] 1 wherein A is 2- (5 , 6-dimethoxy indanyl) , a compound of formula 1 wherein W is a a compound of formula 1 wherein X is selected from the first subgroup, 15- (2-indanyl) -ω-pentanor-prostaglandin E^, 1?- (2-indanyl) - -pentanorprostaglandin F2a, - 2.- (5, 6-dimethcxy indanyl_),-u-pentanorprostaglandin ∑2> 6-dimethoxy indanyl_)7-/-pentanorprostaglandin F2c_' 17-(i-adamarityl)-UAtrinorprostaglandin F2a.

Novel intermediates of the formulae "below are also a feature of this invention.

A compound of the structure OH and and the and Cj^ epimers thereof wherein X, W, Z, R, THP , n and A are as defined above. 43571/2 It will be understood that as herein used, the expression "prostaglandin of the .'zero' series," for example PGE( refers to prostaglandin in which the 5-6 and 13-14 double bonds have been saturated, i.e.: PGEQ' is 5,6-13,14 - tetrahydro PGE2. jln addition, the phrases "one series" or "two series" as herein jemployed refer to the degree of unsaturation in the side chains, e_.g., PGE , PGA2 and P.GF2£, are prostaglandins of the "two series" whereas PGE^, PGF]_ and PGA]_ are prostaglandins of the "one series". As used herein and in the claims, the term prostaglandin is understood to embrace both epimers at C]_^. Furthermore as herein employed the phrase lower "alkyl group refers to alkyl groups containing from 1 to.4 carbon atoms.

The novel compounds according to the invention can be pre ared as shown in the following Reaction Scheme A which, , i by way of illustration, depicts only one of the two possible configurations at C-^-. , it being understood that the other epimers of the 15-epi series can also be prepared in the same manner. i i 3571/2 It will be understood by those skilled in the art that in structure 8 depicting a hemiacetal, no sterochemistry is implied at the lactol carbon.

As shown in Scheme A The C15 epiitiers of 9, 10_, 11, 12 and 15. of the 15-epi series of prostaglandin derivatives described above, and 15-lower-alky1-15-substituted-liJ-pentanorprostaglandins reduced at the 5-6 position and/or the 13-14 position and their C^5 epimers can be prepared from the appropriately substituted analogs of 9 whose syntheses follow those of Scheme A and B.

Thus, the novel 5-6-dihydro derivatives of the " 1-series" can be prepared in a manner similar to the route 9_—»15 in "Scheme A" above, by substituting the intermediate 9_ with its 5-6 dihydro analogue, prepared by selective reduction of the 5-6 cis double bond. This reduction may be achieved by catalytic hydrogenation at low temperature using either a homogeneous catalyst such as tris-tri-phenylphosphine-chlororhodium (I), or a heterogeneous catalyst such as platinum, palladium or rhodium. Especially preferred for this reduction is the use of palladium on carbon as a catalyst and a reaction temperature of -20°C.

Furthermore, 13 , 14-dihydro-15-lower alkyl-15-substituted-UJ-norprostaglandins are available from the appropriately substituted precursors corresponding to formula 8 wherein the trans double bond is replaced by a single bond.

The novel esters of this invention can be prepared in several different ways. These differ from one another in that the esterifying group is attached to the prostaglandin or its precursor at different stages of its synthesis.

' For example Scheme F shows three different routes to the ester "E". ■ / In each case the esterifying group is introduced by an ester ification reaction which may be conducted by contacting the appropriate prostaglandin analog or its precursor with the alcoho or phenol in the presence of a catalyst. Alternatively, the prostaglandin or its precursor may be treated with a diazo alkane or cycloalkane in reactions inert solvent to provide the desired ester. Any prostaglandin analog may be used as a substrate for the above esterification reactions, and additionally precursors to such prostaglandins or prostaglandin analogs may also be used as illustrated in Scheme F." For example, 9, may. be converted to 9E by the esterification reaction alluded to above and _9E may the be converted to lOE and 12E by the same methods used to convert J9 to 10 and 12 as previously discussed. Compound 10E may be converted to HE by reactions described for the conversion of 10 to 11.

As is obvious from the above, the esters such as.9E, 10E, llE and 12E may be used as substrates for the various reductive schemes previously described for the production of the prostaglandin analogs of the "one" and "zero" series.

The prostaglandin analogs of this invention and their esters which are acylated at Cn and C .5 are readily prepared from the corresponding parent by acyla.tion which is usually carried out using carboxylic acid anhydride or carboxylic acid chloride as the acylation agents .

To prepare formyloxy derivatives the mixed anhydrides (e.g. formic-} acetic anhydride) is employed. The C9, Cn and C15 acyloxy prostaglandin analogs and their esters -are. prepared in the same way from the- desired PGF precursor.

Various modifications are possible on the upper side chain of the prostaglandins of this invention. A 5-tetrazoyl moiety may be placed at the position as described in Israel Patent Specification No. ,40183, and in the appended examples. For example, compound 8.may be caused to react with the ylide generated, from (4- (tetrazol-5-yl) -n-butyl) triphenylphosphonium bromide and sodium methylsulfinylmethide to [provide the C_ tetrazole-substituted compound 9· Conversion of 9 into the corresponding prostaglandins proceeds as described above. Another upper side chain modification which may be made in the prostaglandins of this invention is substituition of the I carboxylate moiety at the C^ position by a carboxamide or carbox-Isulfonamide moiety. The methods for preparing these compounds are disclosed in Israel Patent Specification No. 42385 and in the appended examples . For example 8 may be caused to react with the ylide generated from (methane sulfonylaminocarbonyl-n-butyl) triphenylphosphonium bromide and sodium methylsulfinylmethide to afford the Ci N-methanesulfonyl carboxamide substituted compound 9. Conversion of 9 into the corresponding prostaglandins proceeds as described above. 43571/2 Alternatively, the novel compounds of this invention 0 where X is CNHR" , and wherein R" is as previously defined, can be prepared, for example, from compound.' 10 of Scheme A by reaction with appropriate acyl-or sulfonyl These tests include, among others; a test for effect on isolated^' smooth muscle 'from guinea pig uterus, guinea pig ileum and rat uterus, stimulation of diarrhea in mice, inhibition of histamine-induced bronchospasm in the guinea pig, effect on dog blood pressure, inhibition of stress-induced ulceration in the rat, inhibition of gastric acid secretion in the rat and dog, inhibition of lipolysis antiarrhythmic activity, cardiac stimulant activity, inhibition of collagen or ADP-induced blood platelet aggregation and abortifacient activity in rats and guinea pigs by luteolytic and non-luteolytic mechanisms.

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, broncho-dilator activity, antithrombogenic activity, antiulcer activity, smooth muscle activity /useful as an anti-fertility agent, for the induction of labor, and as an abortifacient/ and anti-fertilit activity through a mechanism not affecting smooth muscle, for example, luteolytic mechanisms, and the synchronization of the estrous 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 more potent and exhibit a longer duration of action. For example, 15- (2-indanyl) -c -pentanor-prostaglandin F2a which exhibits guinea pig uterine, smooth muscle stimulating activity comparable to PGF2a, has only 8 the guinea pig ileum stimulating activity, and is at least 30 times more potent then PGF2a in abortifacient activity in rats.

The 15-substituted-W-pentanorprostaglandins of the PGFla, PGFQa and 13, l -dihydro PGF2a are similarly selective regarding smooth muscle stimulant activity.

The various modifications of the upper si-de chain of the prostaglandins of this invention as a rule do not alter the basic biological activity, although they may increase selectivity and duration of action further and reduce toxicity.

Particularly useful for fertility control, abortion and induction of labor are the 15- (2-indanyl)-i0-pentanorprostaglandins, the 15- (1,2, 3> -tetrahydronaphthyl) -t-pentanorprostaglandins, the 15- (2- (5, 6-dimethylindanyl) ) -y-pentanorprostaglandins, 17- (1-adamantyl) -{ji-trisnorprostagjaadin, and l6~(l-adamantyl) -6)-tetranor-prostaglandins of the E2 and F2a series based on potent smooth muscle stimulating activity, and abortifacient activity in rats and at the same time reduced blood pressure and diarrhocal effects. Similarly, the substituted-w-pentanorprostaglandins of the PGE^,. PGF0a, PGFl , and 13, l -dihydro PGF2a series are useful for fertility control including abortion and induction of labor on the basis of their selective smooth muscle stimulant activity. The novel prostaglandins with a β-ΟΗ at the 15-position are in general less potent, although frequently more selective than the correspond! -hydroxyl epimers. Additionally, the prostaglandins having a β-hydroxyl at C-15 are valuable intermediates to prostaglandins having a a-hydroxyl at C-15 through a recycling process involving an oxidation and reduction at C-15. The novel prostaglandin analo of this invention wherein said prostaglandins are of the A, E, or F series have useful antifertility properties and are further useful synchronization of the estrous cycle in animals.

A solution of 20.4 g (164 mmoles) dimethyl ethylpliosphonate (Aid rich) in 200 ml dry tetrahydrofuran was coded to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 82.6 ml of 2.25M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 20 minutes at such a rate that the reaction temperature never rose above -65°.

After an additional 5 minutes stirring at -78°, 14.0 g (73.5 mmole) ftiethyi indane-2-carboxylate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 20 ml acetic acid and rotary evaporated to a white gel. The . gelatinous material was taken up in 50 ml water, the aqueous phase extracted with 75 ml portions of methylene chloride (4x) , the combined organic extracts were back-washed (75 ml H^O) , dried (MgSO^) , and concentrated (water aspirator) to a crude residue and distilled, b.p. 150-160° (0.1 mm) to give 17.0 g (86.4%) dimethyl 2-oxo-2-(2-indanyl)^ethylphosphonate.

The. nmr spectrum (CDCl^) of the distilled product exhibited a singlet at 7.15 δ for the aromatic protons, a doublet at 3.76 6 (J = 11 cps) for the OCK a singlet at 3.25 <5 for the behzylic protons, a doublet at 3.18 δ (J = 23 cps) for the PC]l , and a deformed triplet at 3.13 6 (J = 2 cps) for the C C0. distinct resonances 2-r3g-£-Phenvlbenzoyloxy-5a-hydroxy-2S-(3-oxo-3-(2-indanyl)-trans-l-propen-l-yl)- cyclopent-la-yl ]acetlc acid, γ-lactone; To a solution, cooled in ice under nitrogen, of 17.2 ml (32.6 mmoles) of a 1.90 solution of n-butyllithium in hexane in 150 ml of dry l,2-dimfc* -/ e ktnt. was added dropwise 9.2 g (34.5 mmoles) of dimethyl-2-oxo-2-(2-indanyl)ethyl- phosphonate. The solution was stirred in the cold for 10 minutes then 11.9 g (33.5 mmoles) of the known 2-[3a-£-phenylbenzoyloxy-5a-hydroxy-23-formyl- cyclopent-la-yl]acetic acid, γ-lactone was added. The ice bath was removed; the mixture was stirred for 1.0 hour then was quenched by the addition of glacial acetic acid (pH ¾5) . The mixture was concentrated and the resultant mixture was dissolved in methylene chloride (300 ml) . The organic layer was washed with water (100 ml) , saturated sodium bicarbonate (50 ml) , and saturated brine (50 ml), was dried (anhydrous magnesium sulfate), and was concentrated to a semi-solid. Recrys allization of the crude product from isopropyl alcohol rmethylene chloride afforded the desired 2-[3ct-p_- phenylbenzoyloxy-5a-hydroxy-26- (3-ΟΧΟ-3- (2-indanyl) -trans-l-propen-l-yl) cyclopent-l -yl]acetic acid, δ-lactone as white feathers melting at 170- 172° and weighing 6.85 g. (42.8%) .

The ir spectrum (CHCl^) of the product exhibited absorptions at 1775 cm ^ for the lactone carbonyl, at 1710 cm for the ester carbonyl, 1670 and 1625 cm ^ for the ketone carbonyl, and at 975 cm ^ for the trans double bond.

EXAMPLE 6 2- [5a-Hydroxy-3a- ( tc trahydropyran-2-yloxy) -22- (3a- [ te trahyd ropyran-2-yloxy] - 3-(2-indanyl)-trans-l-propen-l-yl) cyclopent-la-yl]acetaldehyde, γ-hemiacetal : A solution of 1.39 g (2.9 mmole) 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)- 2B-(3a-[tetrahydropyran-2- loxy]-3-(2-indanyl)-trans-l-propen-l-yl)cyclo- pent-la-yl]acetic acid, γ-lactone in 20 ml dry toluene was cooled to -78° , in a dry nitrogen atmosphere. To this cooled solution was added 4.2 ml of 20% diisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal temperature never rose above -65° (15 minutes). After an additional 30 minutes of stirring at -78e, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature and was concentrated by rotary evapora- tion. The resultant oil was slurried in methanol then was filtered to remove aluminum salts. Concentration of the filtrate afforded the crude product which was purified by silica gel . Baker "Analyzed" 60-200 mesh) column chromatography using mixtures of benzene :ethyl acetate as elements. After removal of less polar impurities the desired 2- [Sa-hydroxy-Sci-Ctetrahydro- pyran-^-yloxy) -23- (3a-[tetrahydropyran-2-yloxy] -3- (2-indanyl)-trans-l-propen- l-yl)cyclopent-la-yl]acetaldehyde, γ-hemiacetal as a viscous oil weighing 1.17 g (84.3%). , " ' The ir spectrum (CHCl^) of the purified product exhibited a medium absorption at 975 cm for the trans double bond and n_o carbonyl absorption.

Additional compounds of the structure (Starting Materials) OTHP A n Hc( IR Data (cm 2-indanyl 0 MP 975 2- (5 , 6-dimethoxyindanyl) 0 LP 970 1-adanantyl 1 LP 975 1-adamantyl 1 MP 975 1-adamantyl 2 LP 975 1-adamantyl 2 MP 975 (a) Thin layer chromatographic mobility of ester-alcohol. LP less polar, MP= more polar.

-Hydroxy-lla .15a-bis-(tetrahydropyran-2-yloxy)-15"(2-indanyl)-cis-5-trans 13-o)-pentanor prostadienoic acid: To a solution of 3.21 g (7.24 mraole) (4-carbohydroxy-n-butyl) triphenylphos-phonium bromide in a dry nitrogen atmosphere in 6.0 ml dry dimethyl sulfoxide was added 6.96 ml (14.0 ramole) of a 2.01M solution of sodium methylsulfinyl-methide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 1.16 g (2.41 mmole) 2-[5a-hydroxy-3ct-(tetrahydropyran-2-yloxy)-2B-(3a-[tetrahydropyran-2-yloxy]-3-(2-indanyl)-trans-l-propen-l-yl)^cyclo-pent-la-yl]acetaldehyde, γ-hemiacetal in 2.0 ml dry dimethyl sulfoxide over a period of 20 minutes. After an additional 2.0 hours stirring at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was acidfied to pH ¾3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3x) and the combined organic extracts washed with water (2x) , dried (MgSO^) and evaporated to a solid residue. This solid residue was triturated with ether and filtered. The filtrate was concentrated to provide, 1.99 g (>100%) of 9a-hydroxy-lla, 15a —-bis- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis-5-trans-13---pentanor -prostadienoic acid which was used without further purification. ' ' ' i The ir spectrum (CHCl^) of the purified product exhibited a strong absorption at 1710 cm ^ for the acid carbonyl and a medium absorption at 970 cm ^ ,for the trans double bond.

Additional compounds of the structure OH HC( 2- indanyl 0 MP 2-(5,6-dimethoxyindanyl) 0 LP 1-adamantyl 1 LP 1-adamantyl 1 MP 1-adamantyl 2 LP 1-adamantyl 2 MP (a) Thin layer chromatographic mobility of ester-alcohol. LP= less polar, MP 9a,lla,15a-trihydroxy-15-(2-indanyl)-cis-5-trans-13-hJ-pentnnorprostadienoic acid: A solution of 602 mg 93-hydroxy~lla,15a-bis-(tetrahydropyran-2-yloxy)-15~ (2-indanyl)-c^-5-_t ans_-13-u-pentanorprostadienoic acid in 10 ml of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at; room temperature for 18 hours then was concentrated by rotary evaporation.

The resultant crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7 100-22 mesh) using mixtures of chloroform: ethyl acetate as eluents. After elution of less polar impurities the 9a,lla,15a-trihydroxy^ 15- ^- ' dtntj / ) cis-5-trans-13-m-trinorprostadienoic acid was collected as a white solid weighing 156 mg (39%) and melting at 114-115° rora ethyl acetate) .

The ir spectrum (KBr ) of the product exhibited a strong absorption at 5.77 "p for the acid carbonyl and a medium absorption at 10.25 y for the trans double bond.

Additional compounds of the structure A n He (a) ΠΚ . 2-indanyl 0 MP oil 2- (5 ,6-dime hoxyindanyl) 0 LP 90-9 1-adamantyl 1 LP 133. 1-adamantyl i MP · oil 1-adamantyl 2 LP 167. 1-adamantyl 2 MP oil Thin layer chromatographic mobility of ester-alcohol LP= less polaar 9-Oxo-llg>15a-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans -13-to-pentanorprostadienoic acid: To a solution cooled to -10° under nitrogen of 1.32 g (2.34 mmole) 9o- hydroxy-lla.l5a-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans 13-u)-pentanorprostadienoic acid in 15 ml reagent grade acetone was added' dropwise to 1.17 ml of Jones' reagent. After 15 minutes at -10°, 1.17 ml 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at vhich time it was combined with ethyl acetate, washed with water (2x), dried (MgSO^) and concentrated to give 1.11 g (84.2%) of 9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans- 13-u)-pentanorprostadienoic acid which was used without purification.

Additional compounds of the structure n TLC(a) 2-indanyl 0 MP 2- (5 , 6-dimethoxyindanyl) 0 LP 1-adamantyl 1 LP 1-adamantyl 1 MP 1-adamantyl 2 LP 1-adamantyl 2 MP (a) Thin layer chromatographic mobility of ester-alcohol. LP= less polar, MP 9-Oxo-lla,15a-dihydroxy-15-(2-indanyl)-cis-5-trans-13-g)-pentanorprostadienoic acid: A solution of 1.11 g 9-oxo-llo>15a-bis~(tetrahydropyran-2-yloxy)-15-(2-indanyl) cis-5-trans-13-m-pentanorprostadienoic acid in 15 ml of a 65:35 mixture of glacial acetic acid: water was stirred under nitrogen at room temperature for 18 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 mixtures of chloroform: ethyl acetate as eluents.

After elution of less polar impurities the 9-oxo-lla,15a-dihydroxy-15-(2- lndanyl)-cis-5-trans-13-(ij-pentanorprostadienoic acid was collected as a vhite solid weighing 288 mg (37%) and melting at 110-112° (from ethyl acetate :hexane) .

The ir spectrum (KBr ) of the product exhibited strong absorptions at 5.68 μ for the ketone carbonyl and at 5.84 JJ for the acid carbonyl and a medium absorption at 10.25 y for the trans double bond.

Additional compounds of the structure A n '. He(a) m . p · 2-indanyl 0 MP oil 2-(5,6-dimethoxy) 0 LP 125-1 1-adamantyl 1 LP oil 1-adamantyl 1 MP oil 1-adamantyl 2 LP oil 1-adamantyl 2 MP oil (a) Thin layer chromatographic mobility of ester-alcohol. LP= less polar, MP= P"Biphenyl-9-oxo-llg,15a-dihydroxy-15-(2-indanyl)-cis-5-trans 13-to-pentanor- prostadienoate : To a mixture of 60 mg (0.15 mmole) of 9-oxo-lla,15a-dihydroxy-15-(2-indanyl)-cls-5-trans-13-(.)-pentanorprostadienoic acid a d 255 mg (1.5 mmoles) of p_-phenyl-phenol in 6 ml of dry methylene chloride was added 1.65 ml of a O.lM solution of dicyclohexylcarbodiimide in methylene chloride. The mixture was stirred at room temperature for 16 hours under nitrogen then was concentrated. The solid residue was purified by silica gel (Baker "Analyzed" 60-200 mesh) chromatography using mixtures of chloroform:ethyl acetate as eluents. After removal of less polar impurities the solid p_-biphenyl 9-oxo-lla,15ct-dihydroxy-15-(2-indanyl)-cis-5-trans-13-.o-pentanorprostadienoate was collected weighing 43 mg and melting at 103-104.5° (from methylene chloride :hexane) .

The ir spectrum ( Br) of the product exhibited strong adsorptions at 5.65 μ for the ketone carbonyl and 5.70 u for the ester carbonyl and a medium absorption at 10.35 u for the trans double bond.

£-Biphenyl 9-οχο-11α,156-dihydroxy-15-(2-indanyl)-cis-5-trans-13-m-pentanor- prostadienoate : To a mixture of 60 mg (0.15 mmole) of 9-oxo-lla,15S-dihydroxy-15-(2-indanyl)- cis-5-trans-13-u)-pentanorprostadienoate and 255 mg (1.5 mmoles) of £_-phenyl- phenol in 6 ml of dry methylene chlroide was added 1.65 ml of a 0.1M solution of dicyclohexylcarbodiimide in methylene chloride. The mixture was stirred for 16 hours at room temperature under nitrogen then was concentrated. Purification of the solid residue by silica gel (Baker "Analyzed" 60-200 mesh) chromatography using mixtures of chloroform:ethyl acetate as elements after removal of less polar impurities the solid £-biphenyl 9-oxo-lla,15S-dihydroxy- -15-(2-indanyl)-cis-5-trans-13-a)-pentanorprostadienoate weighing 34 mg and melting at 98-100° (from methylene chloride :hexane) .

The ir spectrum (KBr) of the product exhibited strong absorptions at 5.66 μ for the ketone carbonyl and 5.77 u for the ester carbonyl and a medium absorption at 10.35 y for the trans double bond.

EXAMPLE 13 p_-Biphenyl 9 , 11α , 15ot-trihydroxy-15- (2-indanyl)-cis-5-trans-13-o.'-pentanor- prostadienoate; ' To a mixture of 60 mg (0.15 mmole) of 9a,llct,15a-trihydroxy-15-(2-indanyl)- cis-5-trans-13-a)-pentanorprostadienoate and 255 mg (1.5 mmoles) of £-phenyl- phenol in 6 ml of dry methylene chloride was added 1.65 ml of a 0.1M solution of dicyclohexylcarbodiimide in methylene chloride. The mixture was stirred for 16 hours at room temperature under nitrogen then was concentrated Purification of the solid residue by silica gel (Baker "Analyzed" 60-200 mesh) chromatography using mixtures of chloroform: ethyl acetate as elements after removal of less polar impurities the solid £-biphenyl 9a,lla,15o-trihydroxy- 15-(2-indanyl)-cis-5-trans-13-G.-pentanorprostadienoate weighing Al mg and melting at 134-135° (from methylene chloride :hexane) .

The ir spectrum (KBr) of the product exhibited a strong absorption at 5.68 μ for the ester carbonyl and a medium absorption at 10.35 y for the trans double bond.

£-Biphenyl 9a,11a, 15β-trihydroxy-15- (2-indanyl) -cis-5-trans-13-ω- To a mixture of 60 mg (0.15 mmole) of 9a,11a,15a-trihydroxy-15- (2-indanyl)- cis-5-trans-13-uj-pentanorprostadienoate and 255 mg (1.5 nnioles) of p_- phenylphenol in 6 ml of dry methylene chloride was added 1.65 ml of 0.1M solution of dicyclohexylcarbodiimide in methylene chloride. The mixture was stirred for 16 hours at room temperature under nitrogen then was concentrated. Purification of the solid residue by silica gel (Baker "Analyzed" 60-200 mesh) chromatography using mixtures of chloroform:ethyl acetate as elements after removal of less polar impurities the solid -biphenyl 9a,lla,156-trihydroxy- -15-(2-indanyl)-cis-5-trans-13-(j-pentanorprostadignoate weighing 40 mg and melting at 98-100° (from methylenechloride rhexane) .

The ir spectrum ( Br) of the product exhibited a strong absorption at 5.65 y for the ester carbonyl and a medium: absorption at 10.20 μ for the trans double bond.

Ethyl 5 , 6-dimethoxyindan-2-carboxylate ; A 46.8 g (159 ramole) portion of 2-carboethoxy-5 ,6-dimethoxy-indan-2-carboxyli acid was heated (oil bath 200-210°) under reduced pressure (oil pump). The desired ethyl 5 ,6-dimethoxyindan-2-carboxylate was collected by distillation weighing 29.6 g (74.6%); b.p. 170-176° at 1.0 mm; m.p. 46-48°. , The ir spectrum (KBr) of the products exhibited a string absorption at 5.75 u for the ester carbonyl.

EXAMPLE l8 cis-5-trans-13-a)-pentanorprostadlenamide : To a solution of 2.37 g (A.56 mmole) (methanesulfonylaminocarbonyl-t-butyl) triphenylphosphonium bromide in a dry nitrogen atmosphere in 5.0 ml dry dimethyl sulfoxide was added 4.50 ml (8.62 mmole) of a 1.90M solution of sodjum methylsufinylmethide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 735 mg (1.52 mmole) 2-[5ct-hydroxy-3a-(tetrahydro- pyran-2-yloxy) -26- (3α-[ tetrahydropyran-2-yloxy] -3-(2-indanyl) -trans-l-propen- l-yl)cyclopent-la-yl]acetaldehyde, γ-hemiacetal in 6.0 ml dry dimethyl sulfoxide. After an additional 1 hour stirring at room temperature, the « reaction mixture was poured onto ice water. The basic aqueous solution was acidified to pH ^3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3x) and the combined organic extracts washed once with water (10 ml) , dried (MgSO^) and evaporated to a solid residue. The crude product was purified by column chromatography on silica gel (Baker "Analyzed" Reagent 60-200 mesh) using mixtures of chloroform: ethyl acetate as eluents. After removal of high Rf impurities, 899 mg (81.5%) of N-methAnesulfonyl 9a-hydroxy-llct,15a-bis-(tetrahydropyran-2-yloxy)-15-(2- indanyl)-cis-5-trans-13-t-)-pentanor^prostadienamide was collected.

The ir spectrum (CHCl^) of the product exhibited medium absorptions at 1710 cm for the carbonyl group and at 970 cm ^ for the trans double bond.

Treatment of above hemiacetal with the ylide from (4- (tetrazol-5-yl) -n-butyl) triphenylphosphonium bromide provide a product which may be converted into 2- descarboxy-2-(tetrazol-5-yl)prostaglandins as described in Examples 19-21.

Additional compounds of the structure OH OTHP n He(a) 2-indanyl 0 . N-N - H LP TJ-N H 2- (5 , 6-dimethoxyindanyl) CONHS02CH3 LP 2- (5 , 6-dimethoxyindanyl) (a) Thin layer chromatographic mobility of ester-alcohol. LP= less polar, MP= N-MethAnesulfonyl gg.lla.lSci-trihydroxy-lS- -indany^-cis-S-trans-lS-ui-- pentanorprostadienanvi.de: A solution of 500 mg N-methcujesulfonyl 9a-hydroxy-lla,15a-bis-{tetra.hydro- pyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13^-pentanorprostadienamide in 10 ml of 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at room temperature for 18 hours then was concentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Mallinckrodt CC7 100-200 mesh) using mixtures of chloroform: ethyl acetate as eluents. After elution of less polar impurities the N-methlne- sulfonyl 9a la»15a-trihydroxy-15-(2-indanyl)-cis-5-trans-13--o-pentanorprosta- dienamide was collected as a viscous oil weighing 257 mg (69.6%).

The ir spectrum (CHCl^) of the product exhibited a strong absorption at 1705 cm for the carbonyl group and a medium absorption at 965 cm ^ for the trans double bond. j Additional compounds of the structure A n He (a) 2-indanyl 0 2-(5,6-dimethoxy.ndanyl) 0 CONHSC^CH LP - 2- (5 , 6-dimethoxyindanyl) LP (a) Thin layer chromatographic mobility of jBster-alcohol. LP= less polar, MP= more N-Methinesulfonyl 9-oxo-lla,15a-b_is-(tetrahydropyran-2-yloxy)-15-(2-indanyl) cls-5-trans-13 -pentariorprostadienamide; To a solution cooled to -10° under nitrogen of 399 mg (0.62 mmole) N-methane- sulfonyl 9a-hydroxy-lla , 15a-bis_- (tetrahydropyran-2-yloxy) -15- (2-indanyl) -cis_- 5-trans-13-u-pentanorprostadienamide in 15 ml reagent grade acetone was , added dropwise to 0.31 ml of Jones* reagent. After 15 minutes at -10°, 0.31 ml 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with ethyl acetate, washed with water (2x) , dried (HgSO^) and concentrated to give 371 mg (93%). N- methinesulfonyl 9-oxo-lla,15 -bis-(tetrahydropyran-2-yloxy) -15- (2-indanyl) - cis-5-trans-13-(d-pentanorprostadienamide which was used without purification.

Additional compounds of the structure n He(a) -indanyl 0 N- LP Thin layer chromatographic mobility of ester-alcohol. polar, MP=more pol N-Methanesulfonyl 9-oxo-lla ,15a-dihydroxy-15- (2-indanyl) -c^-5- rans_-13-w- · pentanorprostadienami'de ; A solution of 371 mg N-me h.vnesulfonyl 9-oxo-lla, 15o-bis-(tetrahydropyran^2-» yloxy) -15- (2-indanyl) -cis-5-trans-13^-pentanorprostadienamide in 10 ml of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at; room temperature for 16 hours 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 chloroform: ethyl acetate as eluents. After elution of less polar impurities the N-methajiesulfonyl St oxo-lla.l5a-dihydroxy-15-(2-indanyl)-cis-5^trans-13-^-pentanorprostadienamlde was collected as a viscous oil weighing 65 rag C23.8%).

The ir spectrum (CHCl^) of the product exhibited strong absorptions at 1740 cm for the ketone carbonyl, 172Q cm"*^ for the sulfoniraide carbonyl, and at 970 cm for the trans double bond. / Additional compounds of the structure Thin layer chromatographic mobility of ester-alcohol LP= less polar, MP= more -EXAMPLE 26 Dimethyl 2-oxo-7-cyclopentylheptylphosphonate : . >J, A solution of 20.4 g. (l64 mmoles) dimethyl methylphos-phonate (Aldrich) in 200 ml. dr -tetrahydrofuran is cooled to -780 in' a dry nitrogen atmosphere. To the stirred phosphonate solution is added 82.6 ml. of 2.25M n-butyllithium in hexane solution (Alfa Inorganics, Inc. ) dropwise over a period of 20 minutes at such a rate that the reaction temperature never rises above -65°. After an additional 5 minutes stirring at -780 , 14.5 g. (73.5 mmole) methyl 6-cyclopentylhexanoate is added dropwise at a rate that keeps the reaction temperature less than -70° (20 minutes). After'1.0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 20 ml. acetic acid and rotary evaporated to a white gel. The gelatinous material is. taken up in 50 ml. water, the aqueous phase extracted with 75 ml. portions of methylene chloride (4x), the combined organic extracts are backwashed (75 ml. H20), dried (MgS0]|), and concentrated (water aspirator) to a crude residue and distilled to give dimethy. 2-oxo-7-cyclopentylheptylphosphonate.

The product of this reaction is the starting material for the synthesis of 20-cyclopentyl-vA-tetranorprostaglandins of the A, E, or F series via the procedures of Examples 2-10, 18-21, 29, and 40-48. Other precursors required for the synthesis of 15 •through 19 substituted prostaglandin analogs of this invention are prepared in the same way from the appropriate methyl esters.

EXAMPLE 27 Dimethyl 2-oxo-2-cyclodecylethylphosphonate ; A solution of 20.4 g. (164 mmoles) dimethyl methylphos-phonate (Aldrich) in 200 ml. dry tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere. ' To the stirred phosphonate solution is added 82.6 ml. of 2. 25M n-butyllithium in hexane solution (Alfa Inorganics, Inc. ) dropwise over a period of 20 minutes at such a rate that the reaction temperature never rises above -65°. After an additional minutes stirring at -78° , l4.5 g. (73.5 mmole) methyl cyclodecancarboxylate is added dropwise at a rate that kept the reaction temperature less than -70° ( 20 minutes). After 1. 0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 20 ml.' acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 50 ml. water, the aqueous phase extracted with 75 ml. portions of methylene chloride (4x), the combined, organic extracts are backwashed (75 ml. H^O), dried (MgSO^), and concentrated (water aspirator) to a crude residue and distilled to give dimethy! 2-oxo-2-cyclodecylethylphosphonate.

The product of this reaction is the starting material for the. synthesis of 15-cyclodecyl-^-tetranorprostaglandins of the A, E, or F series via the procedures of Examples 2-10, 18-21, 29, and 40-48. Other precursors required for the synthesis of ΐβ through 20 substituted prostaglandin analogs of this invention are prepared in the same way from the appropriate methyl esters..

EXAMPLE 28 Dimethyl 2-oxo-6-cyclopropylhexylphosphonate : A solution of 20.4 g. (164 mmoles) dimethyl methylphosphonat (Aldrich) in 200 ml. dry tetrahydrofuran is cooled to -780 in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 82.6 ml. of 2.25M n-butyllithium in hexane solution (Alfa Inorganics, Inc. ) dropwise over a period of 20 minutes at such a rate that the reaction temperature never rises above -65°. After an additional 5 minutes stirring at -78° , 11.5 g.. (73.5 mmole) methyl 5-cyclopropylvalerate is added dropwise at a rate that keep the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture is allowed to warm to ambien temperature, neutralized with 20 ml. acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 0 ml. water, the aqueous phase extracted with 75 nil. portions of methylene chloride (4x), the combined organic extracts are back-washed (75 ml. H20), dried (MgS0_), and concentrated (water aspirator) to a crude residue and distilled to- give dimethyl 2-oxo-6-cyclopropylhexylphosphonate .

The produd of this reaction is the starting material for the synthesis of 19-cyclopropyl-^-tetranorprostaglandins of the A, E or F series via the procedures of Examples 2-10, l8-21, 29, and o-48. Other precursors required for the synthesis of 15 through l8 and 20 substituted prostaglandin analogs of this invention are prepared in the same way from the appropriate methyl esters. , l6- ( l-Adaman by1) -^ -tcl.ranorp.roo baglrmdin- F.

To a solution under nibrogcm cooled in ice of 100 mg (0.233 mmole ) of l6- ( 1-adama:ityl)- LO- tetranorprostaglandin Ep in 10 ml of -absolute methanol was added an ice-cooled solution of 300 mg of sodium borohydride in methanol. The solution was stirred at o 0 for 20 minutes. then at room temperatur for 1.0 hour. The solution was then quenched by the addition of 2.0 ml of water and the methanol was removed by rotary evaporation. The resultan aqueous solution was overlaid with ethyl acetate (10 ml), was acidified by the addition of 10 hydrochloric acid, and was extracted with ethyl acetate (4 x 5 ml) . The combined organic extracts were washed with water (5 ml) and saturated brine (5 ml), was dried (anhydrous magnesium sulfate), and was concentrated. . Purification of the crude residue by silica gel chromatography using mixtures of methylene chlorid : methanol as eluent provided l6- (l-adaman.tyl)-i -tetranorprostaglandin F r, (^9 II!S) a>d l6- (l-adatnantyl)- ) -tetranorprostaglandin F 2β The other prostaglandin F^ analogs of the present invention are similarly prepared from the corresponding E precursors. •Ί-7- ( .-adaman l l) - ) - trisnor rostaglandi n Fgfi :" .

To a solution under nitrogen cooled in ice of 100 mg (0.225 , minolc) of 17- (1-adamantyl) - -trisnorprostaglandin in 10 ml of. absolute methanol was added an ice-cooled solution of 300 mg · of sodium borohydride in methanol. The solution was stirred at 0° for 20 minutes then room temperature for 1.0 hour. The solution was then quenched by the addition of 2.0 ml of water and the methanol was removed by rotary evaporation. The resultan aqueous solution was overlaid with ethyl acetate (10 ml), was acidified by the addition of '10$ hydrochloric acid, and was extracted with ethyl acetate x 5 ml) . The combined organic extraots were washed with water (5 ml) and saturated brine (5 ml) was dried (anhydrous magnesium sulfate), and was concentrated. Purification of the crude residue by silica gel chromatography using mixtures of methylene chloridejmethanol as eluent provided 17- ( 1-adamantyl) -L.J -trisnorprostaglandin ϊ'2α (28 mg) and 17- (1~ ada!nant.yl)~ ^-trisnorprostagland.i.n Ι^ (28 rag).. present invention I precursors.

EXAMPLE 31 Cyclooctyl 9α, 11α, 15a-trihydroxy-17-(l-adamantyl)-5-cis-13-trans-^-trisnorprostadienoate : To a solution of 130 mg. (0.30 mmole) of 9a, 11a, 15a-tri-hydroxy-17- (1-adamantyl) -5-cls-13-trans-^-trlsnorprostadlenoic acid in 7 ml. of dry methylene chloride is added 33 mg. (0.33 mmole) of triethyl amine. The mixture is stirred for 5 minutes then 36 mg. (0.33 mmole) of pivaloyl chloride is added. The solution is stirred for 45 minutes at room temperature under nitrogen then 192 mg. (1.5 mmole) of cyclooctyl alcohol and 225 μΐ of pyridine are added. The mixture is stirred at room temperature for an additional 2.0 hours then is diluted with ethyl acetate. The diluted solution is washed with water (2x) and saturated brine (lx), is dried (anhydrous magnesium sulfate), and is concentrated. Purification of the crude residue by silica gel chromatography provides the cyclooctyl 9a, 11a, 15a-trihydroxy-17-( 1-adamantyl) -5-cis-13-trans-^-trisnorprostadienoate.

The other prostaglandin cyclooctyl esters of the present invention are similarly prepared from the correspondin E, A, or F precursors.

EXAMPLE 32 15-epi-l6- (1-adamantyl) -tA>-tetranorprostaglanclin E2 ethyl ester: To a solution of 15-epi-l6- (1-adamantyl) -tJ-tetranorprosta-glandin E2 (25 mg) in 5 ml of ether was added a solution of diazo-ethane in ether until the reaction mixture remained yellow for 5 minutes. Concentration of the reaction mixture followed by silica gel column chromatography of the residue using chloroform as eluent afforded the desired 15-epi-l6- (1-adamantyl) -ω-tetranorprosta-glandin E2 ethyl ester weighing 22 mg.

The other prostaglandin ethyl esters of the present invention are similarly prepared from the corresponding E, A or F precursors.

EXAMPLE 33 Methyl 9 ·, I a, 15a-trihydroxy-l6- ( 2-indanyl) -5-cis-1 -trans-k>' tetr.anorprostadienoate To a solution of 75 mg of 9a, Ha, 15ct-trihydroxy-l6- (2-indanyl) 5-cis-13-trans- )-tetranorprostadienoic acid in 10 ml of ether is added a yellow solution of diazomethane in ether (prepared from N-methyi-N'nitro-N-nitrosoguanidine) dropwise until the yellow color persists for 5 minutes. Concentration of the solution and silica gel chromatographic purification of the crude residue affords methyl S , Ha, 15a-trihydroxy-l6- ( 2-indanyl) -5-cis-13-trans-U-tetranorprostadienoate .

The other prostaglandin methyl esters of the present invention are similarly prepared from the corresponding E, A or F precursors.

EXAMPLE 36 Cyclopropyl 9α, 11α, 15a-trihydroxy-15- (2- (1, 2, 3, -tetrahydronaphthyl| 13-trans- -pentanorprostadienoate To a solution of 82. mg (0.20 mmole) of 9a, 11a, 15a-trihydroxy-15-(2-(l,2, 3, 4-tetrahydronaphthyl) ) -5-cis-13-trans- -pentanorprosta dienoic acid (12a) in 5 ml of dry methylene chloride is added 22 mg (0.22 mmole) of triethylamine . The mixture is stirred for 5 minute then 24 mg (0.22 mmole) of pivaloyl chloride is added. The solutio is stirred for 45 minutes at room temperature under nitrogen then 58 mg (1.0 mmole) of cyclopropyl alcohol and 150 μΐ of pyridine are added. The mixture is stirred at room temperature for an additional 2.0 hours then is diluted with ethyl acetate. The diluted solution is washed with water (2x) and saturated brine (lx) is dried (anhydrous magnesium sulfate), and is concentrated.

Purification of the crude residue by silica gel chromatography provides the cyclopropyl 9a, 11a, 15a-trihydroxy-15- (2- (1, 2, 3, 4-tetraj hydronaphthyl) ) -5-cisr-13-trans- -pentanorprostadienoate.

The other prostaglandin cyclopropyl esters of the present invention are similarly prepared from the corresponding E, A or F precursors. ':' . l.'l a, lifo-T ifoydvojy-l?- (l--adamanbyl ) -5-c.l ,- t rang- t.j - To a -solution of 31 ng (0.70 imaole) of 9/3, 11α, 15a- rihydroxy-17- ( l-adavaan t l ) -5- is-13- trans ·- lJ -trisnorprosta- dienoic acid (12b) in 35 ml of "dry ace'tonitrile, heated at 8o°, is added v/ith vigorous stirring a solution of 86 mg (0.68 mrnole) of t ris-hydroxyme th la iio tae hane in 0.15 ml of water. The mixture is allov/ed to cool at room temperature and the 9 , 11α, 15 - 1 ihy d roxy- 17- ( 1 -adaman tyl ) - 5- c i s - 13- 1 rans ■ -trisnorprostadienoic acid t r i s -hyd roxyine hylamino methane salt is collected.

EXAMPLE 3 N-methanesulf,onyl 9α, 11^, 15/3-trihydroxy~15- (2- (5, 6-dimethoxy-indanyl) ) -13-trans- -pentanorprostenamide A solution of 58 mg N-methanesulfonyl a, 11a, 15 - rihydroxy-15-(2-(5,6-dimethoxyindanyl) ) -5-cis-13-trans- -pentanorprosta-dienamide in 6 ml of anhydrous ether is treated with 448 mg (3.6 mmole) dimethyl isopropyl chlorosilane and 36.0 mg (3.6 mmoles) triethylamine at 25° for 48 hours. The reaction mixture is cooled to ύ°, methanol is added and the resulting solution is washed with water, is dried (anhydrous magnesium sulfate), and is concentrated. The residue is dissolved in methanol (6 ml), 5$ palladium in carbor (30 mg) is added, and the resultant slurry is hydrogenated for 4 hours at -22°. After filtration (Celite) and concentration of the filtrate, the product is hydrolyzed in 2 ml of a 65:35 mixture of acetic acid: water for 10 minutes, is diluted with water, and is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (anhydrous magnesium sulfate), and concentrated to afford N-methanesulfonyl 9a, 11a, 15β-trihydroxy-15-(2- (5, 6-dimethoxyindanyl) ) -13-trans- -pentanorprostenoic acid after purification by silica gel chromatography.

The other prostaglandin Fia or F^ analogs of the present invention are similarly prepared from the corresponding F2a or F; precursors. 3.7- ( l-Adamantvl ) - ij -trinnorpros l-.f.v.',lanc n p(7: ■ Λ mixture of 447 mg (1.0 mrr.ole) of 15-epi-17-(l~a-da atvtyl) ~ J.~ Irisnornrotttaglandin !·' t and .5 g of activated manganese dioxide in 5 ml of dry me thyleneehloride is stirred overnight at room temperature, -filtered, and concentrated to afford 15-keto-17-(l- damantyl)-L To a solution, cooled in ice, of 223 ™ (0-50 mmole) of 15-keto-17- (1-adamaatyl)- cJ-trisnorprostaglandin F2a in 22 ml of absolute methanol is added an ice-cooled solution of 66 nig of sodium borohydride in 85 ml of absolute methanol. After being o stirred for 20 minutes at 0 and 1.0 hour at room temperature, the reaction is quenched by the addition of 6.6 ml of water. The methanol is removed by rotary evaporation and the resultant . aqueous solution is overlaid with -ethyl acetate, is acidified wit 10 hydrochloric acid, and is further extracted with .ethyl acetat The combined organic extracts are washed with water and with saturated brine, are dried, (anhydrous magnesium sulfate), and are concentr ted. Purification of the crude residue by silica ge chromatography affords 17- ( i-adamanty.l.) -io -trisnorprostaglandin ^2u an'-l 15-epi-17- (1-adamantyl) - iJ -trisnorprostaglandin F2a The other 15 epi prostaglandins of this invention having no D ower a k l group at C-,<- j.j may be similarly converted to their C,15_ epimers by the process above.

EXAMPLE -5 2-Descarboxy-2-(tetrazol-5-yl)-9-oxo-ll , 15a-dihydroxy-l6- (2-indany! - -tetranorprostanoic acid: A heterogeneous mixture of 120 mg 2-descarboxy-2- ( tetrazol-5-yl)-9-oxo-lla, 15 -dihydroxy-l6- (2-indanyl) -5-cis-13-trans- -tetra-norprostadienoic acid and 12 mg of 5$ palladium on carbon in 12 ml of absolute methanol is stirred under 1 atmosphere of hydrogen at 0° for 3 hours. The reaction mixture is filtered (Celite) and concentrated. The crude residue is purified by silica gel chromatography to provide 2-descarboxy-2- (tetrazol-5-yl)-9-oxo-lla, 15a-dihydroxy-l6- (2-indanyl)- -tetranorprostanoic acid.

By the above procedure the other prostaglandin analogs of this invention of the E", Pa or Έβ type of the one, two or 13, 14-dihydro two series may be converted to the corresponding analog of the "zero" series. j EXAMPLE 46 (1-adamantyl)- -tetranorprostanoic acid: A heterogeneous mixture of 150 mg 9-oxo-lla, 15 -dihydroxy-l6-(1-adamantyl)-5-cis-13-trans-13- -tetranorprostadienoic acid (11a) and 15 mg of 5$ palladium on carbon in 15 ml of absolute methanol is stirred under 1 atmosphere of hydrogen at 0° for 3 hours. The reaction mixture is filtered (Celite) and concentrated. The crude product is purified by silica gel chromatography to provide 9-oxo-lla, 15 -dihydroxy-l6- (1-adamantyl) - -tetranorprostanoic acid.

By the above procedure the other prostaglandin analogs of this invention of the E, Fa or type of the one, two, or 13,14-dihydro-two series may be converted to the corresponding analogs of the zero series.

EXAMPLE 29 N-methanesulfonyl 9a~hydroxy-lla, 15 -bis-(tetrahy.dropyran-2-yloxy) -15- (2-(l, 2, 3, -tetrahydronaphthyl) ) -ι^-pentanorprostanamide : A heterogeneous mixture" of 1.52 g of the N-methanesulfonyl '9a hydroxy-lla, 15a-bis- ( tetrahydropyran-2-yloxy) -5-cis-13-trans-15-(2- (1, 2, 3^-tetrahydronaphthyl) ^ω-pentanorprostadienamide and 152 mg of 0 palladium on carbon in 15 ml of absolute methanol is stirred under 1 atmosphere of hydrogen at 0° for hours. The reaction mixture is filtered (Celite) and concentrated to provide N-methanesulfonyl 9a-hydroxy-lla, 15 - is- ( tetrahydropyran-2-yloxy) -15- (2- (1, 2, 3> -tetrahydronaphthyl) ) -L-pentanorprostanamide .

The product is transformed into N-methanesulfonyl 15- (2- ( 1, 2, 3, -tetrahydronaphthyl) )-)-pentanorprostaglandins of the A, E or F series via the procedures of examples 11-15. - 58 - EXAMPLE 5 2~/3α, 5cr.-Dihydroxy-2/3- ( 3 -hydroxy-3~ ( 2-indanyl)-trans-I-prope.n-l-yl)cyclopent~lot-yl7acetaldehyde, γ-hemiacetal:.

To a solution, cooled to -78° , of 750 mg (1.5 mmole) of the 2-/ α-£-phenylbenzoyloxy-5 -h droxy-2β- ( 3a-hydroxy-3- ( 2-indanyl)-trans~l-propen-l-yl)cyclopent-lq-yl/acetic acid, γ-lactone in 15 ml of toluene is added 7. 5 nil of a 20% solution of diisobutylaluminuni •hydride in hexane (Alfa). The reaction mixture is stirred in the cold for 1. 0 hour, then is quenched by the addition of methanol until gas evolution ceases. The quenched mixture is let warm to .» room temperature then is concentrated. The residue is stirred with methanol ( 3x ) and is concentrated. Purification of the crude product by silica gel chromatography affords the desired 2-/3a, 5a-dihydroxy~2 - ( 3g~hydroxy~3- ( 2-indanyl)-trans-l~propen-l-yl)cyclo-pent-la-yl. 'acetaldehyde, γ-hemiacetal.

The above product may be converted into the 15- (2-indanyl) - -pentanor FGF^a analogs of t this invention. By the above procedure the other prostaglandin analogs of the F-type of this invention may be prepared.

Claims (12)

1. 43571/4 CLAIMS : 1. A compound of the structure: and its 0^5 epimer; wherein A is 1-adamantyl, 2-norbornyl, 2- (1,2,3,4- November 5, tetrahydronaphthyl) wherein said group is racemic or optically 1973 except compounds of active, 2-indanyl or substituted 2-indanyl wherein said sub-claim 2 stituent is lower alkoxy; R3 is hydrogen or THP; R is hydrogen or lower alkyl; n is an integer from 0 to 5; W is a single bond or cis double bond; Z is a single bond or trans double bond; M is keto, N and L, when taken together form a single bond, or N is «<-0R3 when L is hydrogen; THP is 2-tetrahydropyranyl 0 X is selected from a first sub-group comprising II -C-O-R' wherein R' is hydrogen, alkyl of from 1-10 carbon atoms"; aralkyl of from 7 to 9 carbon atoms; cycloalkyl of from 3 to 8 carbon atoms; monosubstituted phenyl, wherein said substituent is halo, lower alkyl, lower alkoxy or phenyl; a second sub-group comprising 5-tetrazolv^l ; or II a third sub-group comprising -CNHR" wherein R" is alkanoyl having from 2-10 carbon atoms or cycloalkanoyl having from 4 to 8 carbon atoms; aroyl or substituted aroyl of from 43571/4 7 to 11 carbon atoms wherein said substituent is methyl, halogen or methoxy; alkylsulfonyl of from 1 to 7 carbon atoms; arylsulfonyl or substituted arylsulfonyl wherein said substituent is methyl, halogen or methoxy; 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 lower alkanoyl, formyl or benozyl esters of any feee hydroxyl groups at the C9-, C^- and C^s-positions and the pharmaceutically acceptable salts of those compounds where X is COOH.

2. A compound of Formula i', according to claim 1 wherein W, N, L, N, Z and R are as defined above A is 1-adamantyl, 2-indanyl and 2-norbornyl and X is -CC^R1 wherein R1 is 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 F series; the lower alkanoyl, formyl or benozyl esters of any free hydroxyl groups at the Cg-, C^- and C]_5-positions and the pharmaceutically acceptable salts of those compounds where X is COOH.

3. A compound according to claim 1 or 2, of the structure: OH and its Cj_5 epimer. ,0H

4. The compound of claim 1 or 2 , wherein M is/ , L is a single bond, and N is ^-hydrox 1.

5. A compound according to claim 1 or 2, of the structure and its epimer

6. A compound according to claim 1 or 2, of the structure and its C epimer. 15

7. A compound of claim 1 or 2, wherein n is 0.

8. A compound of claim 1 or 2, wherein n is 1.

9. A compound of claim 1 or 2, wherein n is 2.

10. A compound of claim 1 or 2 , wherein n is 3.

11. A compound of claim 1 or 2 , wherein n is 4.

12. A compound of claim 1 or 2 , wherein n is 5. 43571/3 s is of the F series. 15. A compound of claim 8, wherein said prostaglandin is of the E series. 16. A compound of claim 8, wherein said prostaglandin is of the F series. 17. A compound of claim 9, wherein said prostaglandin is of the E series. 18. A compound of claim 9, wherein said prostaglandin is of the F series. 19. A compound of claim 1 or 2, wherein A is 1-adamantyl. vember 5, 20. A compound of claim 1 or 2, wherein A is 2-indanyl or 973 except rnpounds of substituted 2-indanyl said substituent is lower alkoxy. laim 2 vmeber 5, 21. A compound of claim 20, wherein A is 2- (5, 6-dimethoxyindany 1973 22. A compound of claim 1 or 2 , wherein is a cis double bond and Z is a trans double bond. 23. A compound of claim 1 or 2 , wherein is a cis double bond and Z is a single bond. 24. A compound of claim 1 or 2, wherein W is a single bond and Z is a single bond. 25. A compound of claim 13, wherein A is 2-indanyl and the prostaglandin is PGE2« 26. A compound of claim 14, wherein A is 2-indanyl and the prostaglandin is PGF2¾<. November 5, 27. A compound of claim 13, wherein A is 2- (5 , 6-dimethoxy- 1973 indanyl) and the prostaglandin is PGE2 · 28. A compound of claim 14, wherein A is 2- (5, 6-dimethoxy- 1973 indanyl) and the prostaglandin is PGF2°(. 29. A compound of claim 17, wherein A is 1-adamantyl and the prostaglandin is PGE2 · the prostaglandin is PGF2a^ Novmeber 31. A compound of claim 26, wherein X is selected from the 5, 1973 second sub-group, and R is hydrogen. November 32. A compound of claim 26, wherein X is selected from the 5, 1973 third sub-group, R" is methyl sulfonyl, and R is hydrogen. 33. A compound of claim 1 or 2, wherein X is selected from the first sub-group. 34. A compound of claim 25, wherein X is selected from the first sub-group, R and R' are each hydrogen. 35. A compound of claim 26, wherein X is selected from the first sub-group, R and R' are each hydrogen. 36. A compound of claim 30, wherein X is selected from the first sub-group, R and R' are each hydrogen. ^OH 37. A compound according to claim 1 wherein M is , H ' is OR3 and R3 is THP and the Cg and C15 epimers thereof. 38. A compound according to claim 1 wherein M is οχό, Ν' is OR3 and R^ is THP and the C15 epimer thereof. November 39. A process for preparing a compound of the structure: and its C-^^ epimer; wherein A, n, R, Z, N, L, M, W and X are as defined in claim 1, characterized by the fact that a) when N is cK-hydroxy and L is hydrogen, and A, n, M, R, W, X and Z are as defined above, said compound is prepared by treating 43571/3 the 11-, and 11- and 15-tetrahydropyranyl ethers of a compound of Formula I, above, with a suitable acid; b) when N and L, when taken together form a single bond, M is keto and A, n, R, W, X 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 A, n, R, W, X and Z are as defined above', with a suitable dehydrating agent; c) when N is -hydroxy and L is hydrogen, M is / ^OH ✓OH or £ and A, n, R, W, X and Z are as defined above, said 'Ή compound is prepared by reacting a compound of the Formula I, above, wherein N is °<-hydroxy and L is hydrogen, M is keto, A,, n, R, W, X and Z are as defined above, with a suitable reducing agent, and, if desired, separating the 9°<- and 9^'-isomers ; d) when N is o< -hydroxy, L is hydrogen, A, R, n, M and X are as defined above, and and Z are single bond, said compound is prepared by catalytic reduction of a compound of Formula I, above wherein A, R, n, M and X are as defined above, W is a single bond or cis double bond when Z is a trans double bond and Z is a single bond when W is a cis double bond; e) when N is o^-hydroxy, L is hydrogen, A, R, n, M and X are as defined above, W is a single bond:, and Z is a trans double bond said compound is prepared by selective reduction of a compound of Formula I, above, wherein A, R, n, M and X are as defined above, 43571/3 and, when required, converting those compounds of Formula I, wherein X is COOR* wherein R1 is hydrogen to their esters and substituted amides, as defined above, by reaction with suitable esterifying and amidating agents, respectively; and, if desired, preparing the 9^-, IK- and 15=-lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups by reacting said compounds with the appropriate acylating agents and, if desired, preparing the pharmaceutically acceptable salts of these compounds wherein X is COOH. 40. A process according to claim 39 wherein X, W, M, L, N, Z, R, n and A are as defined in claim 2.