IE48926B1 - N-alkanesulfonyl 16,16-dimethyl-17-oxaprostaglandin carboxamides - Google Patents

Description

The Cj0 unsaturated fatty acids, known as prostaglandins, form a large family of naturally-occurring compounds Their structure, biological activities and medicinal use have been variously described for example in O.S. 3,971,826, and 3,984,400.

One of the principal goals guiding the preparation of synthetic pharmaceutical agents is the development of compounds which are highly selective in their pharmacological activity and which have an increased duration of activity over their naturally-occurring congeners. In a series of compounds similar to the naturally-occurring prostaglandins, increasing selectivity of a single compound usually involves enhancement of one prostaglandin-like physiological effect and the diminution of the others. 4882b The potential benefits of this selectivity are manifold; e.g., a decrease in the severe side effects such as diarrhea and emesis which are frequently observed following administration of the natural prostaglandins. A separation of cardiovascular and bronchodllator activity which are both embraced hy natural prostaglandins also would have obvious medicinal potential.

Recent developments directed toward an increase of biological selectivity include the 16,16-dimethyl prostaglandins (B. J. Magerkln, et al., Prostaglandins, £, 143 (1973)), 17-oxaprostaglandin Fg (J. Bowler, et al., Prostaglandins, 9_, 391 (1975); 10, 5 (1975), 16,16-dialkyl (including diraethyl)-17, 18 or 19-oxaprostaglandin Eg, E^, Fg^ , F^ ; the 11, 15-bis-THP (tetrahydropyran-2-yl) ethers of those compounds (Belgian Patent 827,529); 16,16-dimethy1-17-oxaprostaglandin Eg, E^, Fg^ , F^and the 11,15-bis THP ethers of those compounds (Belgian Patent 832,479) and K-substituted prostaglandin carboxamides including N-alkanesulfonyl,' N-alkanoyl and N-benzoyl PGEg and PGFgO< carboxamides (U.S. Patent 3,954,741).

Although the compounds of the present invention are structurally close to those disclosed in BE-A-832479, they differ by the presence of the N-alkanesulfony1-substituted carboxamide function. The compounds of the present application differ from the prostaglandin disclosed in PROSTAGLANDINS, 15, 1st January, 1978, pages 161-167, in that they are 16,16-dimethyl-17-oxo-prostanoic acid derivatives instead of 16-phenoxy-17,18,19,20-tetranor-prostanoic acid derivatives. Moreover, the prostaglandin disclosed in this prior art document is primarily an abortifacient with uterine stimulant activity, whereas the compounds of the present invention are primarily gastric antisecretory agents. The compounds of the present application differ from those disclosed in FR-A-2356636 in that the latter do not possess an 11-hydroxy group. Moreover, although the compounds FR-A-2356636 are stated to have specifically abortive, hypotensive or diuretic action, there is no mention of their having specifically gastric antisecretory action. The compounds of the present invention differ from those disclosed in FR-A-2316924 in that the latter do not possess an 11-hydroxy group and are 16-aryloxy-17,18,19,20-tetranorprostanoic acid derivatives rather than 16,16-dimethyl-17-oxaprostanoic acid derivatives.

The present invention provides prostaglandin compounds which have selective and potent biological activity and includes the N-alkanesulfonyl carboxamides of 16,16-dimethyl-17-oxaprostaglandin E2 and 16,16-dimethyl-17-oxaprostaglandin E^, having from one to four carbon atoms in the alkanesulfonyl group and two to five carbon atoms in the alkanoyl group and the 15 isomers of these compounds.

In addition, the present application discloses as intermediates the bis-ll,15-THP ethers of the prostaglandin E compounds,as well as the corresponding F2e>< and FjO< compounds.

Of special interest as an agent which can be used for inhibition of gastric acid secretion is N-(methanesulfonyl)9-oxo-lla, 15a-dihydroxy-16,16-dimethyl-17-oxa-cis-5-trans-13prostadienamide, ie the N-(methanesulfonyl) derivative of 16,16-dimethyl-17-oxa-prostaglandin E2.

The 16,16-dimethyl-17-oxaprostaglandin compounds of the instant invention are prepared by a three-part sequence which is predicated upon the synthesis of the or bottom side chain, proceeds to the synthesis of the cU or top side chain and ends with the conversion of the synthesized PGF2e(_ intermediate into the array of final products. The sequence employs as a starting material the known compound 2-(3o<-£-phenylbenzoyloxy-5oi- hydroxy-2 p-formyl-cvclopentlc<-yl)acetic acid y-lactone (A) (E. J. Corey, et. al., J. Am. Chem. Soc., 93, 1491 (1971)).

With regard to the particular steps of the sequence, it is recognized that the chemical methods used herein are known to those familiar with the prostaglandin art. For instance, the reactions described herein as Wittig reactions, Jones oxidations, Wadsworth-Emmons reactions and Superhydride reductions are modeled after the methods of Corey and others (E. J. Corey, et al., J. Amer. Chem. Soc.,93, 1^91 (1971); E. J. Corey, et al., J. Amer. Chem. Soc. 92, 2586 (1970); U.S. Patent 3,883,513).

The synthetic sequence of Scheme (1)illustrates the synthesis of the Oand chains. The first step (a) unites the 2f-lactone A with Phosphonate B to complete the backbone of the Q-chain.

To prepare the novel phosphonate reagent B employed as one of the starting materials in reaction (a), the following reaction is completed: CH3CH2CH2OC (CH.j) 2COOCH3 + LiCHjPO (OCH3) 2 —> phosphonate B j contact of the lithium derivative of dimethylmethylphosphonate with methyl propoxyisobutyrate in solution with ethereal solvents such as tetrahydrofuran or ether at temperatures of -78° to -60“ and usually at the temperature of a dry ice/acetone bath for periods ranging from 30 minutes to 120 minutes will produce the phosphonate B. 8926 SCHEME (1) ( y -lactone D) A cc (R* = a mild-reagentlabile group) RXCO 0 (c,f (DiBal) ( y -lactol E) + PhjP = CKCH,CH,CH,COilR2Na (pfiosphorane F) f/o RX0 HO. (d) CONHR2 (prostadienamide G) R10 Rr0 It is purified from the above reaction mixture by neutralizing with an appropriate amount of an organic acid such as acetic acid, followed by the use of common techniques such as column chromatography or distillation.

After preparation of Phosphonate B, its salt ϊ,ξ combined with the lactone of formula A in a Wadsworth-Emmons fashion to prepare enone C; as illustrated in reaction (a). The method of that reaction is as follows. The.sodium or‘-lithium salt of Phosphonate B is prepared by contact with a base JO such as sodium hydride or n-butyl lithium in ethereal solvents such as tetrahydrofuran or dimethoxyethane at ambient temperature. Then the salt is contacted with the'^lactone, formula A, at temperatures 0° to 30° for about 30 to 90 minutes to form enone C. The reaction mixture is neutralized with an organic acid and the product is isolated by the usual technique of column chromatography.

The second part of Scheme (1), which is represented by step (b), consists of the following reactions: reduction of the enone fragment to an allyl alcohol fragment; transesteri20 fication of the £-biphenylcarboxyl group; and the formation of a mild-reagent-labile ether at each of the hydroxyl positions. The reduction of the enone fragment will be accomplished by any reducing agent, which attacks only the carbonyl of the enone fragment.

It is usual to employ a trialkylborohydride such as lithium tri-sec-butylborohydride in a stoichiometric ratio to the enone and the reaction is conducted at about dry ice temperature for 30 to 90 minutes in ethereal solvents followed by neutralization. The product can then be isolated by the usual purification techniques.

This reduction of the enone produces two compounds which are thecx* and p forms of the allyl alcohol. They are diasteromers and are separable by common techniques. Although only the^forra is shown, it is herein disclosed that the $ form is equally functionable in the processes cf the invention. Therefore, although Schemes (1),(2), -and (5, depict only theO^fonn, it is implied that the |3 form is included.

Transesterification of the p-biphenyl ester is accomplished in basic alcoholic media. Any weak base which is sufficient to hydrolyze esters will accomplish the -task and the usual reaction conditions are contact of the ester with potassium carbonate in methanol for about an hour, neutralization and isolation by the extraction. 489 26 Conversion of the hydroxyl functions at C-ll and C-15 to mild-reagent-labile ethers completes step (b) and produces the Jf -lactone of formula D.

Any group which will function as a mild-reagent-labile 5 protecting group can be employed as the moiety R3. Some groups are tetrahydropyran-2-yl and dimethy1-t-butyl silyl.

In the case wherein R1 is tetrahydropyran-2-yl the method of formation usually employs an excess of 2,3-dihydropyran in methylene chloride with ^-toluenesulfonic acid as a catalyst and reaction times of 30 to 90 minutes. In the case wherein R1 is dimethyl-tert-butylsilyl, the method of formation usually employs an excess of dimethyl-tert-butylsilyl chloride and a base such as imidazole in dimethylformamide at temperatures of 25-100 and reaction times of 3-24 hours. After following either of these procedures, the product y-lactone of formula D is isolated by basic extraction and column chromatography . 48826 Steps (c) and (d) of scheme (1) are the o< -chain synthesis which forms prostaglandins of formula G by combining the y -lactol of formula E with elements of the Phosphorane of formula P. The requisite methods of this 5 scheme follow those of Corey (og. cit.) and of U.S. Patent 3,954,741. Briefly, the 7$-lactone D is reduced to the 7/lactol E by diisobutylaluminumhydride (DiBal) at -78*C to -60*C in an inert solvent. The prostadienantide of formula G is then prepared in polar aprotic solvent at 10’ to 50’C by 10 a Wittig reaction of the 2f-lactol E with the sodium salt of 4-(N-alkanesulfonyl)-aminocarbonyl)-n-butyl triphenylphosphorane, Phosphorane F, the alkanesulfonyl group being one to four carbon atoms in length. The Phosphorane F is prepared in situ from the corresponding phosphonium bromide or chloride and the sodium salt of dimethyl sulfoxide immediately before the Wittig reaction. _ 48926 The reactions represented by Scheme (2) are those which convert prostadienamide G into some products of the present invention: prostadienamides of formulas H and K and the prostenamides of formulas J and L. In Scheme (2) step (e) consists of two reactions, the first of which is a Jones oxidation of the C9-hydroxyl to a keto group and the second of which is the cleavage of the mild-reagent-labile protecting group producing a hydroxyl group. Step (f) of Scheme (2) is a catalytic hydrogenation of the C5-C6 double bond to a single bond. The methods of these steps are known to those familiar with the art.

Briefly, the Jones oxidation contacts prostadienamide G or prostenamide I with Jones reagent (chromic acid in sulfuric acid and water) in acetone solution for about 5 minutes at -20cC to 0°C. followed by quenching with isopropanol.

(H) f (Jones oxidation + I (Rl - cleavage) HO HO, R1O HO (e) I (Jones oxidation + R1 - cleavage) CONHR* (J) HO HO 489 26 Cleavage of the mild reagent labile group, Rl, which produces compounds H, J, K and L, is accomplished by contacting the appropriate prostenamide or prostadienamide compound with a mixture of acetic 'acid and water for 5 to 24 hours at 20* to 40°C. or if desired in the silyl ether case, with the mild base tetra-alkylammonium fluoride having one to four carbons in each of the alkyl provided that the prostaglandin compound is other than a PGE.

Catalytic hydrogenation is accomplished by agitation of 10 prostadienamide G in methanol, ethanol or ethyl acetate solution with a noble metal catalyst such as palladium on carbon under one atmosphere of hydrogen at -20*C.

Alternatively, prostadienamide H and prostenamide J may be synthesized by the method illustrated by Scheme (3) The first step (g) of Scheme (3)which prepares prostadienoic acid is the attachment of the Oi -chain to the Tf -lactol of formula E. The attachment is achieved by a Wittig reaction of the y-lactol E with the sodium salt of (4-carboxy-nbutyl)triphenylphosphorane in a polar aprotic solvent at 10* to 50“C. In accord with most steps of the reaction sequence this step follows the method of Corey (op. cit.) and that described in U.S. 3,958,284.

SCHEME (3) CONHR Σ (Ο3) CONHR I (R1 - cleavage) | (Hr (J) \fC. S002A)·' In the optional second step of Scheme (3) the prostadienoic acid may be hydrogenated using the same conditions described for step (f) of Scheme (2) to produce the prostenoic acid of formula M .

In the third step of Scheme (3) the 9-hydroxy group 2 of the acid M or M is oxidized to a keto group using the Jones oxidation procedure described above and produces . 1 2 prostaglandin acid N or N .

In the fourth step (h) of Scheme (3) the prostaglandin 1 2 acid N and N is converted into an N-alkanesulfonyl 2 prostaglandin carboxamide 0 or 0 by reaction with sulfonyl isocyanate the method of which follows well-known art; (A. J.

Speziale, et al, J. Org. Chem., 30, 4305 (1965), C. O.

Hurd and A. G. Prapas, J. Org. Chem., 24, 388 (1959), reactions of isocyanates with carboxylic acids in Survey of Organic Synthesis, C. A. Beuhler, D. E. Pearson, Wiley Interscience, Hew York, 1970, N-acylation of amides and imides, J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, McGraw-Hill, New York, 1968, 2Q p. 3401. The preferred method is that of Speziale and Hurd where sulfonyl isocyanate is reacted with prostaglandin acid N1 or N3 in an inert solvent such as ether, tetrahydrofuran or methylene chloride using a weak base such as triethyl amine at temperatures ranging from ambient to reflux for 0·ι to 6 hours. 2 The prostaglandin carboxamide 0· or 0 is then deproteoted by cleaving the protecting group as described above and produces prostenamide H or prostadienamide 3.

In numerous in vivo and in vitro tests, it has been 5 established that the prostaglandin compounds of the present invention exhibit extreme selectivity. Their biological achievement is the diminuation of many of the physiologidal activities of the natural prostaglandins while maintaining activity in one area. The tests which allow such deter10 mination of selectivity include among others, a test for effect on isolated smooth muscle from guinea pig and rat uterus, inhibition of stimulated gastric acid secretion in the dog, effect on dog blood pressure, inhibition of cold stress-induced ulceration in the rat and diarrheal effect in the mouse.

After comparison to the responses by natural prostaglandins, the physiological responses observed in these tests are useful in determining the utility of the test substance for the treatment of natural and pathological conditions. Based upon such comparison, the determined utility of the prostaglandin compounds of the present invention is antisecretion. This selective utility is made apparent by the existence of oral gastric antisecretory activity in the prostaglandin compounds of the present invention which is much greater than that of the natural prostaglandins and the diminuation of such determined activities as hypotensive activity, diarrheal activity, uterine stimulant activity and bronchodilator activity.

A prime example of the therapeutic importance with respect to selectivity is N-methanesulfonyl 16,16dimethy 1-17-oxaprostaglandin Eg carboxamide.

The new compounds of this invention can be used in a variety of pharmaceutical formulations which contain one of the prostaglandin compounds or alternatively, a pharmaceutically acceptable salt. They may be administered in the same manner as natural prostaglandins by a variety of routes, such as intravenous and oral, among others, as anti-secretory agents for the control of and prophylaxis of peptic ulceration.

For pharmaceutical formulation and for solid compounding of the prostaglandin compounds of the present invention the useful pharmacological acceptable salts are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkali metal, e.g. lithium, sodium and potassium, and from the alkaline earth metals, e.g. magnesium and 2q calcium, although cationic forms of other metals, e.g. aluminium, zinc and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines.

Examples of suitable amines are methylamine, dimethylamine, triethylamine, ethylamine, benzylamine, -pheny1ethylamine, -phenylethylamine, as well as heterocyclic amines, e.g. piperidine, morpholine, pyrrolidine, and piperazine,as well as amines containing water-solubilising or hydrophilic groups, e.g. mono-, di-, and triethanolamine, ethyldiethanolamine, galactamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine and procaine.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium and phenyltrlethylammonium.

The new compounds of this invention can be used in a variety of pharmaceutical preparations which contain one of the prostaglandin compounds or a pharmaceutically acceptable salt thereof. They may be administered by several routes as described above.

Although the’ particular dose, formulation and route of administration are dependant upon each patient's unique 2o condition and the wisdom of his attending physician, the guidelines set forth infra for the 16,16-dimethyl-17oxaprostaglandin compounds describe their usefulness as peptic antisecretory agents. 489 26 For treatment of ulcers, these compounds may be orally administered in the form of capsules, or tablets at doses of 0.1 - 5 mg. of prostaglandin compound per dose.

To prepare any of the above dosage forms or any of 5 the numerous other forms possible, various reaction-inert diluents, excipients or carriers may be employed. Such substances include, for example, water, ethanol,λ gelatins, lactose, starches, magnesium stearate, tale, 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, and in no way limit the scope of the appended claims. The spectral data were obtained on a Varian T-60 or an A-60 NMR and a Perkin-Elmer Grating Infrared Spectrometer.

The infrared data are given in microns and the NMR data are given in parts per million using TMS as a standard. Melting points are uncorrected and are in °Centigrade.

In general, the temperatures of the reactions described in the examples, when unspecified, will be taken to mean ambient or room temperature which varies from ° to 30eC.

The time requirements of the reactions described in the examples, unless otherwise stated, were determined by monitoring with thin layer chromatography (TLC). The usual TLC system was silica-gel on glass (E. Merck-Silica Gel plates, E. Merck, Darmstadt, W. Germany) with benzene/ ether or methanol/chloroform as eluants and vanillin/ ethanol or iodine as developers. (Introduction to Chromatography J. M. Bobbitt, A. E. Sohwarting, R. J. Gritter, Van Nostrand-Reinhold, N.Y. 1968]. As a general rule, the reaction in question was deemed essentially complete when the TLC spot representing the critical starting material had disappeared or had quit changing in appearance.

Preparation A Dimethyl 2-Oxo-3,3-dimethyl-4-oxaheptylphosphonate (2): A solution of 73.0 g (568 mmoles) dimethyl raethylphosphonate in 600 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 294 ml of 2.0 M n-butyllithium in hexane solution dropwise over a period of 60 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 10 minutes stirring at -78°, 51.3 g (293 mmole) methyl propoxyisobutyrate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 0.5 hours at -78° the reaction mixture was allowed to warm to ambient tempera^ ture, neutralized with 35 ml acetic acid and rotary evapora15 ted to a white gel. The gelatinous material was taken up in 100 ml water, the aqueous phase extracted with 150 ml portions of methylene chloride (3x), and concentrated (water aspirator) to a crude residue and distilled, b.p. - 100° (0.6 mm) to give 60.3 g (93%) dimethyl 2-oxo20 3,3-dimethyl-4-oxa heptylphosphonate (2).

The n.m.r. spectrum (CDClj) showed a doublet centred at 3.81S (J = 11.5'cps, 6H) a triplet centred at a 3.29 (2H), a multiplet at 1.31 - 183S (2H), a doublet centred at 3.34 (J = 22 cps, 2H) a singlet at 1.30S (6H) and a triplet at 0.93S (3H).

EXAMPLE 1 2-[3oZ -p-Phenylbenzoyloxy-5c< -hydroxy-2 β -(3-oxo-4,4dimethyl-5-oxa-trans-l-octen-l-yl)-cyclopent-lo< -yl] Acetic Acid, y-lactone (3): Dimethyl 2-oxo-3,3-dimethyl-4-oxaheptylphosphonate (2) (3.48 g 15.7 nmole) In 10 ml anhydrous THF (tetrahydrofuran) was added dropwise to 660 mg (15.7 nmole) 57% sodium hydride in 220 ml dry THF in a dry nitrogen atmosphere at room temperature. After 40 minutes of stirring 5.0 g (14.3 mmole) 210 [3o<; -j>-phenylbenzoyloxy-5-phenylbenzoyloxy-5o4 -hydroxy-2 -(3-oxo-4,4-dimethyl5-oxa-trans-l-octen-1-yl)cyclopent-1£ -yl]acetic acid, -lactone (3) as a solid, m.p. 115 - 116’ (methylenechloride-hexane . Λ The i.r. spectrum (CHCl^) of the product £ exhibited absorption bands at 1775 cm 3 (strong), and 1630 3 (medium) . 489 26 The n.m.r. spectrum (CDClg) ’ exhibited a multiplet at 7.23 - 8.18 (9H), a doublet centred at 6.85S (2H), a multiplet from 4.9 - 5.68£ (2H), a triplet at 3.2 (2H), a multiplet from 1.3 - 1.8S (2H) a singlet at 1.285 (6H), a triplet at 0.87S > and a multiplet from 2.2 3.05 . C,H analysis, calculated for C2gH32°6: Calculated Found C - 73.1 73.0 H - 6.8 7.0 EXAMPLE 2 2-[3 04 -p-Phenylbenzoyloxy-5 oa -hydroxy-2 ^3-(3 p hydroxy-4,4-dimethyl-5-oxa-trans-l-octen-l-yl) cyclopent-1 ex -yl]acetic acid, y-lactone (4) and 2-[3 00-p-Phenylbenzoyloxy-5 ¢4-hydroxy-2 β -(3 ο*— hydroxy-4,4-dimethyl-5-oxa-trans-l-octen-l-yl) cyclopent-1 To a solution of 17.2 g (40.4 mmole) 2-[3 -y-lactone (3) in 200 ml dry THF/ether (4:1) in a dry nitrogen atmosphere at -78° was added dropwise 104 ml (43.0 mmole) of a 0.413 M lithium tri-sec-butylborohydride solution. After stirring at -78° and 0.5 hours the reaction was quenched with 91 ml of acetic acid/water (40:60). The reaction mixture was allowed to warm to room temperature and then combined with 300 ml water and 400 ml methylene chloride.

The methylene chloride layer was separated and the aqueous layer further extracted with methylene chloride (2 x ]00 ml). After washing the combined organic layers with brine (100 ml), drying (Na2SO4) and concentrating (water aspirator), the resultant residue'was purified by column chromatography on silica gel (Baker Analyzed* Reagent 60-200 mesh) using benzene/ethyl acetate (7:1 as eluant. After elution of less polar impurities a fraction containing 9.0 g 2--£-phenylbenzoyloxy-5cx -hydroxy-2 (β -(310 oxo-4,4-dimethyl-5-oxaoctan-l-yl)-cyclopent-lot -yl] acetic acid, Y-lactone (19), a fraction containing 3.7 g 2-[3o< -£-phenylbenzoyloxy-5 tu. -hydroxy-2 p -(3-hydroxy-4, 4- dimethy1-5-oxa-transl-octen-1-yl)cyclopent-1 ex-yl] acetic acid, Y-lactone (5), a 1.3 g fraction of mixed £' and 5 and finally a fraction (2.5 g) of 2-[3 -jo-phenylbenzoyloxy-5 ex·-hydroxy-2 p -(3- hydroxy-4,4-dimethyl5- oxa-trans-l-octen-l-yl)]cyclopent-1 ex -yl]acetic acid, Y-lactone (£) .

The i.r. spectra (CHClj) of £ and J5 had strong absorp20 tions at 1770 and 1715 cm^ and an absorption at 970 cm~^. 489 26 EXAMPLE 3 2-[3&Ζ ,5οέ -Dihydroxy-2 f? ~(3qg -hydroxy-4,4-dimethyl-5oxa-trans-l-octen-l-yUcyclopent-K^g -yl]acetic acid, •gf-lactone (6): A heterogeneous mixture of 3.7 g (7.8 mmole) of 2—[3— o< -g-phenylbenzoyloxy-5°< -hydroxy-2-^ - (3 O<-hydroxy-4,4 dimethy1-5-oxa-trans-l-octen-l-yl)cvclopent-1 c<-yl]acetic acid, ^-lactone (£), 50 of absolute methanol and 1070 mg of finely powdered, anhydrous potassium carbonate was stirred at room temperature for one hour, then cooled to 0 To the cooled solution was added 15.6 ml (15.6 mmole) of 1.0N aqueous hydrochloric acid. After stirring at 0“ for an additional 10 minutes, 50 ml of water was added with concomitant formation of methyl g-phenylbenzoate which was collected by filtration. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (3 x 150 ml), the combined organic extracts were washed with saturated sodium bicarbonate (50 ml), brine (50 ml) and dried (MgSO^) and concentrated to give 2.0 g (87¾) of viscous oily 2- [3Oi, 5 £% -dihydroxy-2 -(3 (X-hydroxy-4, 4-dimethy1-5-oxa-trans-l-octen-l-yl)cyclopent-loi -yl] acetic acid, Tf -lactone (£) .

The i.r. spectrum (CHClj) exhibited a strong absorption at 1770 cm-1 and medium absorption at 965 cm \ EXAMPLE 4 2-(3^ ,5 -Dihydroxy-2 p -(3 p -hydroxy-4,4-dimethy1-5oxa-trans-l-octen-l-yl)cyclopent-1-yl]acetic acid, y-lactone (6a): A heterogeneous mixture of 2'.5 g (5.25 mmole) of 25 [3cx -j>-phenylbenzoyloxy-5 <*<-hydroxy-2 p -(3 p -hydroxy-4, 4-dimethy1-5-oxa-trans-l-octen-yl)cyclopent-1oi-yX]acetic acid, y-lactone (£), 40 ml of absolute methanol and 720 mg of finely powdered, anhydrous potassium carbonate was stirred at room temperature for one hour, then cooled to 0®.

To the cooled solution was added 10.4 ml (10.4 mmole) of 1.0N aqueous hydrochloric acid. After stirring at 0“ for an additional 10 minutes, 40 ml of water was added with concomitant formation of methyl js-phenylbenzoate which was collected by filtration. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (3 x 100 ml), the combined organic extracts were washed with saturated sodium bicarbonate (40 ml), brine (40 ml) and dried (MgSO^) and concentrated to give 1.0 g (64%) of viscous, oily 2-[3e<,5 4-dimethyl-5-oxa-trans-l-octen-l-yl)cyclopent-lot-yl] acetic acid, y-lactone (6a).

The i.r. spectrum (CHC13) exhibited a strong absorption at 1770 cm-l and medium absorption at 965 cm \ EXAMPLE 5 2-[5 Of-Hydroxy-3 -(tetrahydropyran-2-yloxy)-2 ft-(3o<[tetrahydro-pyran-2-yloxy]-4,4-dimethyl-5-oxa-trans-locten-l-yl) cyclopent-1 c«5-yl] acetic acid, *ar-lactone (7) To a solution of 2.0 g (6.7 mmole) 2-[3O< ,5oc5 dihydroxy-2 ~(3o«i -hydroxy-4,4-dimethy 1-5-oxa-trans-locten-yl)cyclopent-1 c<-yl] acetic acid, 'δ'-lactone (6) in 40 ml anhydrous methylene chloride and 2 ml of 2,3-dihydro pyran at 0° in a dry nitrogen atmosphere was added 27 mg p-toluenesulfonic acid, monohydrate. After stirring for minutes, the reaction mixture was combined with 100 ml ether, the ether solution washed with saturated sodium bicarbonate (2 x 30 ml) then saturated brine (1 x 30 ml), dried (NajSO^) and concentrated to yield 2.5 g of 2-(5 The i.r. (CHClj) spectrum had a medium absorption at 970 cm-1.

EXAMPLE β 2-(5cc-Hydroxy-3 ex -(tetrahydropyran-2-yloxy)-2 p -(3 p [tetrahydropyran-2-yloxy]-4,4-dimethyl-5-oxa-trans-locten-l-yl)cyclopent-1 ex-yl]-acetic acid, y-lactone (7a): 5 To a solution of 1.0 g (3.36 mmole) 2-(3c<,5 rag £>-toluenesulfonic acid, monohydrate. After stirring for 30 minutes, the reaction mixture was combined with 100 ml ether, the ether solution washed with saturated sodium bicarbonate (1 x 15 ml) then saturated brine (1 x 15 ml), dried (MgSO^) and concentrated to yield 9]2 mg of 2-[5c^ -hydroxy-3- (tetrahydropyran-2-yloxy)-2 p-(3pEtetrahydropyran-2-yloxy]-4,4-dimethyl-5-oxa-trans-l-octenl-yl)oyclopent-l oi -yl]acetic acid, Tf-lactone (7a) after column chromatography.

The i.r. (CHC13) spectrum had a medium absorption at 970 cm”1.

EXAMPLE 7 2-[5 c< -Hydroxy-3 -(tetrahydropyran-2-yloxy)-2 β -(3 oc [tetrahydropyran-2-yloxy]-4,4-dimethyl-5-oxa-trans-locten-l-yllcyelopent-lcX -yl]acetaldehyde, X-hemiacetal 5 ου: A solution of 1.05 g (2.2 mmole) of 2-[5 -hydroxy3 oi - (tetrahydropyran-2-yloxy)-2 (S - [3 tx - (tetrahydropyran2-yloxy]-4,4-dimethyl-5-oxa-trans-l-octen-l-yl)cyolopent1 oC-yl]acetic acid, S'-lactone (7) in 20 ml dry toluene was cooled to -78° in a dry nitrogen atmosphere. To this cooled solution was added 3.0 ml of 20% diisobutylaluminium hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal temperature never rose above -65° (5 minutes). After an additional 30 minutes of stirring at -78°, 105 mg of acetic acid was added 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 (20 ml), dried (Na2SO^) and concentrated to yield 880 mg (2-[5-hydroxy20 3 oi -(tetrahydropyran-2-yloxy)-2 p -(3 o<-[tetrahydropyran2-yloxy]-4,4-dimethyl-5-oxa-trans-l-octen-l-yl)cyclopent-1yl]acetaldehyde, s'-hemiacetal (£) after column chromatography. The i.r. spectrum exhibited a medium absorption at 970 cm \ EXAMPLE 8 2-[5-Hydroxy-3 ex-(tetrahydropyran-2-yloxy)-2 p (3 p -(tetrahydropyran-2-yloxyl-4,4-dimethyl-5-oxatrans-l-octen-l-y1)cyclopent-1 -yl1 acetaldehyde, Y-hemiacetal (8a) ; A solution of 920 mg (1.92 mmole) 2-[5ex-hydroxy-3cx (tetrahydropyran-2-yloxy)-2 p> -(3 p -[tetrahydropyran-2yloxyl-4,4-dimethyl-5-oxa-l-trans-l-oeten-l-yl)cyclopentlo<-yl] acetic acid, Y-lactone (7a) in 20 ml dry toluene was cooled to -78’ in a dry nitrogen atmosphere. To this cooled solution was added 2.58 ml of 20% diisobutylaluminium hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal temperature never rose -65’ (15 minutes). After an additional 45 minutes of stirring at -78°, anhydrous acetic acid (80 mg) was added 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 (20 ml) , dried (Na2SO4) and concentrated to yield 645 mg 2-[5c>c20 hydroxy-3 ex - (tetrahydropyran-2-yloxy)-2 p -(3 p -[tetrahydropyran-2-yloxy)-4,4-dim&thyl-5-oxa-trans-l-octen-l-yl] cyclopent-1 ex-yllagetaldehyde, Y-hemiacetal (8a) after column chromatography. The i.r. spectrum exhibited a medium absorption at 970 cm \ „ 4.89 26 Example 9 o<-Hydroxy-11 ex ,15 CX-bis-(tetrahydropyran-2-yloxy)-16, •16-dimethyl-17-oxa-cis-5-trans-13-prostadienoic acid (9): To a solution of 4.04 g (9.1 mmole) (4-carbohydroxy5 n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 2.0 ml dry dimethyl sulfoxide was added 9.3 ml (16.7 mmole) of a 1.8M solution of sodium methylsulfinyl methide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 1453 mg (3.04 mmole) 210 [5 Reagent 60-200 mesh) using chloroform and ethyl acetate as eluants. After removal of high impurities, 1013 mg of 9 -hydroxy-llvx ,15 cX-bis- (tetrahydropyran-2-yloxy) -16,16-dimethy1-17-oxa-cis-5-trans-13-prostadienoic acid was collected.

EXAMPLE 10 -Hydroxy-11 a< ,15 p -bis-(tetrahydropyran-2-yloxy)-16, 16-dimethyl-17-oxa-cis-5-trans-13-prostadienoic acid (9a); To a solution of 1770 mg (4.0 mmole)(4-carbohydroxy5 n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 10 ml dry dimethyl sulfoxide was added 4.1 ml (7.35 mmole) of a 1.8M solution of sodium methylsulfinylmethide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 645 mg (1.34 mmole) 2-[5 -hydroxy10 3o<-(tetrahydropyran-2-yloxy)-2 p -(3 p -[tetrahydropyran2-yloxy]-4,4-dimethyl-5-oxa-trans-l-octen-l-yl)-cyclopentloi -yl]acetaldehyde, Zf -hemiacetal (8a) in 10 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 and 8 ml IN HCl. The acidic solution was extracted with ethyl acetate (3 x 150 ml) and the combined organic extracts washed once with water (2 x 30 ml), brine (30 ml), dried (MgSO4) and evaporated to a residue. The residue was purified by column chromato20 graphy on silica gel (Baker Analysed” Reagent 60-200 mesh) using chloroform and'ethyl acetate as eluents. After removal of high impurities, 694 mg of 9 -hydroxy-lloi , p -bis-(tetrahydropyran-2-yloxy)-16,16-dimethyl-17-oxacis-5-trans-13-prostadienoic acid was collected. 489 26 EXAMPLE 11 -Hydroxy-11oc , 15 c< -bis-(tetrahydropyran-2-yloxy)-16, 16-diniethyl-17-oxa-trans-13-prostenoic acid (10): A solution, cooled to -20°C, of 1.0 mmole of 5 hydroxy-11 ex ,15 ex—bis- (tetrahydropyran-2-yloxy)-16,16dimethyl-17-oxa-cis-5-trans-13-prostadienoic acid (9) in 50 ml methanol is hydrogenated on an atmospheric hydrogenation apparatus using 1 g of 10% palladium-on-carbon as a catalyst and a hydrogen atmosphere. After one equivalent of hydrogen is taken up, the catalyst can be filtered from the reaction mixture and the solvent can be removed in vacuo from the resultant filtrate. The residue can then be purified by the common techniques such as column or liquid high pressure chromatography to yield the title compound.

Using the same procedure, the prostadienoic acid (9a) of Example ]0 can be converted into the corresponding prostenoic acid.

EXAMPLE 12 9-Oxo-llox ,15 ex-bis-(tetrahydropyran-2-yloxy)-16,16dimethyl-17-oxa-cis-5-trans-13-prostadienoic acid (11): To a solution cooled to -10° under nitrogen of 526 mg (0.06 mmole) 9 cX-hydroxy-11 ex ,15 ex -bis-(tetrahvdropyran2-yloxy)-16,16-dimethyl-17-oxa-cis-5-trans-13-prostadienoic acid (£) in 30 ml reagent grade acetone was added dropwise 0.47 ml of Jones' reagent.

After 20 minutes at -lo”, 0.5 ml 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 100 ml ethyl acetate, washed with water (2 x 25 ml), dried (MgSC>4) and concentrated to give 443 mg of 9-oxo-llaX* ,15o«f -bis(tetrahydropyran-2-yloxy)-16,16-dimethyl-17-oxa-cis-5trans-13-prostadienoic acid (10).

Using the same procedure, the prostenoic acid compounds of Example 11 can be oxidised to the corresponding PGEj and 15-epi-PGE^ compounds, i.e. 9-oxo-ll<=x* ,15«»^ and 15 p bis-(THPO)-16,16-dimethyl-17-oxa-trans-13-prostenoic acids.

EXAMPLE 13 9-Oxo-ll&zi ,15 p -bis-(tetrahydropyran-2-yloxy)-16,16dimethyl-17-ox-cis-5-trans-13-prostadienoic acid (11a); To a solution cooled to -10° under nitrogen of 490 mg (0.80 mmole) 9 ex: -hydroxy-11®<. , 15 j3 -bis- (tetrahydropyran2-yloxy)-16,16-dimethyl-17-oxa-cis-5-trans-13-prostadienoic acid (9a) in 25 ml reagent grade acetone was added dropwise 0.43 ml of Jones' reagent. After 20 minutes at -10° 0.5 ml 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 75 ml ethyl acetate, washed with water (3 x 10 ml), dried (MgSO4) and concentrated to give 440 mg of 9-oxo11 ex , 15’ p -bis- (tetrahydropyran-2-yloxy) -16,16-dimethyl-17oxa-cis-5-trans-13-prostadienoic acid (11a).

EXAMPLE 14 N-Methanesulfonyl 9g-hydroxy-lla, 15g-bls-(tetrahydropyran-2-yloxy)-16,16-dimethyl-17-oxa-5-cis-13-transprostadienamide (14); To a solution of 2.76 g (5.3 mmole)/4-(methanesulfonylaminocarbonyl)-n-buty^triphenylphosphonium bromide in a dry nitrogen atmosphere in 5.0 ml dry dimethyl sulfoxide was added 4.5 ml (10.1 mmole) of a 2.2M solution of sodium methylsulfinylmethide in dimethyl sulfoxide.

To this ylide solution was added dropwise a solution of 829 mg (1.77 mmole) 2-[5o<-hydroxy-3 ex -(tetrahydropyran2-yloxy)-2 p - (3 oi.- [tetrahydropyran-2-yloxy] -4,4-dimethyl5-oxa-trans-l-octen-l-yl)cyclopent-1 o< -yl]-acetaldehyde, ^f'-hemiacetal (8) in 2.0 ml dry dimethyl sulfoxide over a period of 20 minutes. After an additional 45 minutes stirring at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was acidified to pHz<3 with l.N 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. This solid residue was triturated with ether and filtered. The filtate was purified by column chromatography on silica gel (Baker Analysed Reagent 60-200 mesh) using mixtures of chloroform:ethyl acetate as eluents. After removal of high Rf impurities, the desired N-methanesulfonyl 9 oc-hydroxy-11 ,15 —a -bis-(tetrahydropyran-2yloxy)-16,16-dimethyl-17-oxa-5-cis-13-trans-prostadienamide (14) was collected as a colourless oil weighing 405 mg.

In addition the other N-alkanesulfonyl 9a-hydroxy11a, 15a-(bls-THPO)-16,16-dimethyl-17-oxa-5-cis-13-transprostadienamide intermediates of the present invention can be synthesised by the method of Example 14 by substituting the appropriate N-alkanesulfonyl-(4-aminocarbonyl-n-butyl) 8926 triphenyl phosphonium salt for [4-(methanesulfonylaminocarbonyl)-n-butyl]triphenylphosphonium bromide in Example 14.

EXAMPLE 15 N-Methanesulfonyl 9-Hydroxy-11 «gf ,15 -bis-(tetrahydropyran-2-yloxy-16,16-dimethyl-17-oxa-trans-13prostenamide (18): A solution, cooled to -20°C, of 1.0 mmole of N-methane sulfonyl 9 -=-^ -hydroxy-11 ad , 15 ot -bis- (tetrahydropyran-210 yloxy)-16,16-dimethyl-17-oxa-trans-13-prostadienaroide (14) in 50 ml methanol is hydrogenated on an atmospheric hydrogenation apparatus using 1 g of 10% palladium-on-carbon as a catalyst and a hydrogen atmosphere. After one equivalent of hydrogen is taken up, the catalyst can be filtered from th reaction mixture and the solvent can be r enoved in vacuo from the resultant filtrate. The residue can then be purified by the common techniques such as column or liquid high pressure chromatography to yield the title compound.

In addition the other N-alkanesulfonyl 9a-hydroxy11,15a-bis-(THPO)-trans-13-prostenamlde intermediates of the present invention may be synthesised by the method of Example 15 by substituting the appropriate prostadienamide from Example 14 for prostadienamide (14) in Example 15. 48936 EXAMPLE 16 N-Methanesulfonyl 9 cxf , 11QC, 15 oc -trihydroxy-16,16dimethyl-17-oxa-5-cis-13-trans-prostadienamide (15): A solution of 400 mg N-methanesulfonyl 9=< -hydroxy5 11 oi., 15 ot -bis- (tetrahydropyran-2-yloxy) -16,16-dimethyl17-oxa-5-cis-13-trans-prostadienamide (14) in 10.0 ml of a 65:35 mixture of glacial acetic acid:water is stirred under nitrogen at 25® for 18 hours then is concentrated by rotary evaporation. The resultant crude product is puri10 fied by column chromatography on silica gel (Mallinckrodt CC-7 100-200 mesh) using mixtures of chloroform:ethyl acetate as eluent. After elution of less polar impurities the N-methanesulfonyl 9 ,11 cx.,15 tx-trihydroxy-16,16dimethyl-i7-oxa-5-cis-13-trans-prostadienamide (15) is collected.

In addition the other N-alkanesulfonyl PGF2q and PGFia carboxamides of the present invention may be synthesised according to the methods of Example 16 by substituting the appropriate 11,15-(bis-THP) PGF2£>£. intermediate from Example 14 for prostadienamide (14) in Example 16 or by substituting the appropriate 11, 15-bis-(THP) PGFjo< intermediate from Example 15 for prostadienamide (14) in Example 16.

EXAMPLE 17 N-Methanesulfonyl 9-oxo-ll ox,15ex -bis-(tetrahydropyran2-yloxy)-16,16-di»ethyl-17-oxa-5-cis-13-transprostadienamide (16): To a solution cooled to -15°. under nitrogen, of 400 mg (0.645 mmole) N-methanesulfonyl 9 ex-hydroxy-llo< ,15>c -bis- (tetrahydropyran-2-yloxy)-16,16-dimethyl-17-oxa-5cis-13-trans-prostadienamide (14) in 10 ml reagent grade acetone was added dropwise to 0.24 ml of Jones' reagent.

After 10 minutes at -10° 0.24 ml 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 75 ml ethyl acetate, washed with water (3 x 10 ml), dried (MgSO4) and concentrated to give 385 mg of the colourless, oily N15 methanesulf onyl 9-oxo-ll >=< ,15 oc-bis- (tetrahydropyrap-2yloxy)-16,16-dimethyl-17-oxa-5-cis-13-trans-prostadienamide (16).

EXAMPLE 18 N-Methanesulfonyl 9-oxo-llo< ,15 ox-dihydroxy-16,1620 dimethyl-17-oxa-5-cis-13-trans-prostadienamide (17): A solution of 385 mg N-methanesulfonyl 9-oxo-llo<; , 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 oily N-methanesulfonyl 9-oxo-ll ,15 oc -dihydroxy-16,16-dimethyl-17-oxa-5-cis-13trans-prostadienamide (17) weighing 134 mg was collected.

In addition the other N-alkanesulfonyl PGEg and PGE^ carboxamides of the present invention may be synthesised according to the methods of Examples 17 and 18 by substituting the appropriate 11,15-(bis-THP) PGFg-< intermediate from Example 14 for prostadienamide (14) in Example 17 or by substituting the appropriate 11,15bis- (THP) PGFj^ intermediate from Example 15 for prostadienamide (14) in Example 17.

Claims (3)

1. A cocpound having the structure: -CH 2 -A-CH 2 CH 2 CH 2 C0NHR CH=CHCH(Z)C(CH 3 ) 2 OCH 2 CH,CH 3 HO wherein A is ethylene or cis-vinylene; 5 R is alkanesulfonyl having one to four carbon atoms; Z is alpha-hydroxy or bete-hydroxy; and the pharmacologically acceptable salts thereof.

2. A compound of claim 1 wherein R is methanesulfonyl.

3. !(-(Methanesulfonyl)-9-oxo-ll OL ,15e< -dihydroxy-16,1610 dimethyl-17-oxa-cis-5-trans-13-prostadienamide.