Alkyl Diethers of Prostaglandins

Synthesis of 11,15-bis(dimethyl' methoxy' methyloxy)-13-trans prostenoic acid, (11,15-bis diether of PGF.sub.2.alpha.). Finely powdered 5-triphenylphosphonio pentanoic acid, 1.20 m mol is heated to 75.degree. C in vacuo for 1 hr and is then placed under an argon atmosphere. Dry dimethyl sulfoxide, 0.8 ml, is added to dissolve the warm solid and the resulting solution is cooled to ambient temperature. Then, 2.30 m mol of 2 M sodio methylsulfinylcarbonide, in dimethyl sulfoxide is added with stirring. Crude hemi acetal, Formula 4, 0.48 m mol, ##STR19## in 0.50 ml of dry dimethyl sulfoxide is added after 5 minutes. The mixture is stirred at ambient temperature for 1.0 hr, the dimethyl sulfoxide is removed under pressure (0.1 mm) and the residue is diluted with distilled water. The pH of the aqueous phase is adjusted to 9-10 with potassium carbonate. The neutral components are extracted with ethylacetate:ether (1:1) and then the aqueous phase is acidified with oxalic acid to pH about 3. Extraction with 1:1 pentane:ether is followed by washing the extracts with saturated brine and then drying over anhydrous magensium sulfate. Concentration yields the desired product 11,15-bis diether of PGF.sub.2.alpha..

Synthesis of 11,15-bis(dimethyl' methoxy' methyloxy)-9-oxo-5-cis,13-trans-prostadienoic acid,(11,15-bis diether of PGE.sub.2). A mixture of the crude 11,15-bis diether of PGF.sub.2.alpha. (as prepared above), 0.135 m mol, and 1.34 ml of acetone is cooled to -10.degree. C. Then 59 .mu.1 (0.145 m mol) of Jones' Reagent is added over 5 minutes with stirring. After an additional 25 minutes at -10.degree. C, isopropyl alcohol, 59 .mu.1 is added and after 5 minutes the mixture is diluted with 10 ml of ethyl acetate. The organic phase is separated, washed with water and saturated brine, dried over magnesium sulfate and concentrated to yield the 11,15-bis diether of PGE.sub.2.

Synthesis of 11,15-bis(dimethyl' methoxy' methyloxy)-13-trans-prostenoic acid,(11,15-bis diether of PGF.sub.1.alpha.). A mixture of 0.076 m mol of 11,15-bis diether of PGF.sub.2.alpha. (as prepared in Example 1) and 9.6 mg of 5% Pd/C in 5.0 ml of methanol is hydrogenated at -20.degree. C to -20.degree. C at atmospheric pressure. After about 3 hours the mixture is filtered through Celite 545, a commercially available diatomaceous silica, and concentrated in vacuo to leave the desired product also containing small amounts of 13,14-dihydro-bis diether of PGF.sub.1.alpha..

Synthesis of 11,15-bis(dimethyl' methoxy' methyloxy)-9-oxo-13-trans-prostenoic acid,(11,15-bis diether of PGE.sub.1). To a solution, cooled to -10.degree. C, of PGF.sub.1.alpha. (prepared in Example 3) in 1.48 ml of acetone is added 59.5 .mu.1 (0.148 m mol) of Jones' Reagent. After stirring for 5 minutes at -10.degree. C, 59.5 .mu.1 of isopropyl alcohol is added and stirring is continued for 5 minutes at -10.degree. C. After dilution with ethyl acetate the organic phase is washed with water and saturated brine, dried over anhydrous magneisum sulfate and concentrated to yield the desired product.

To a solution of 50 mg of 9.alpha.,11.alpha.,15(S)-trihydroxy-13-transprostenoic acid, (PGF.sub.1.alpha.), in 10 ml of anhydrous dioxane there is added 10 ml, an excess of ethoxyisopropenyl ether, CH.sub.3 C(OC.sub.2 H.sub.5).dbd.CH.sub.2, boiling point 59.degree.-62.degree. C, and the solution is continually stirred to ensure a uniform mixture of the ingredients. To this mixture is next added about 5 mg of the acid catalyst, anhydrous p-toluenesulfonic acid, and the resulting reaction mixture is maintained with gentle stirring at ambient temperature for 72 hours. Next, the reaction mixture is washed with an aqueous 5% sodium carbonate and then with aliquots of water until a neutral pH is obtained for the mixture. The mixture is then dried over anhydrous sodium sulfate and evaporated to dryness. The dry residue obtained is dissolved in benzene-ethyl acetate and it is chromatographed through a colum of neutral alumina to give 9.alpha.,11.alpha.,15(S)-tris(dimethyl' ethoxy' methyloxy)-13-trans-prostenoic acid.

Repeating the procedure of Example 5 but replacing 9.alpha., 11.alpha., 15(S)-trihydroxy-13-trans-prostenoic acid with:

9.beta.,11.alpha.,15(S)-trihydroxy-13-trans-prostenoic acid, and,

9.beta.,11.alpha.,15(S)-trihydroxy-5-cis,13-trans-prostadienoic acid,

9.beta.,11.beta.,15(R)-trihydroxy-13-trans-prostenoic acid,

racemic 9.beta.,11.alpha.,15(R)-trihydroxy-5-cis,13-trans-prostadienoic acid,

9.alpha.,11.alpha.,15(S)-trihydroxy-5-cis,13-trans-prostadienoic acid, and,

9.alpha.,11.alpha.,15(S)-trihydroxy-5-cis,13-trans-17-cis-prostatrienoic acid,

the following ethers are formed:

9.beta.,11.alpha.,15(S)-tris-(dimethyl' ethoxy' methyloxy)-13-trans-prostenoic acid,

9.beta.,11.alpha.,15(S)-tris(dimethyl' ethoxy' methyloxy)-5-cis,13-trans-prostadienoic acid,

9.beta.,11.beta.,15(R)-tris(dimethyl' ethoxy' methyloxy)-13-trans-prostenoic acid,

racemic 9.beta.,11.beta.,15(R)-tris(dimethyl' ethoxy' methyloxy)-5-cis, 13-trans-prostadienoic acid,

9.alpha.,11.alpha.,15(S)-tris-(dimethyl' ethoxy' methyloxy)-5-cis,13-trans-prostadienoic acid, and,

9.alpha.,11.alpha.,15(S)-tris(dimethyl' ethoxy' methyloxy)-5-cis,13-trans, 17-cis-prostatrienoic acid.

To 50 mg of 15(S)-hydroxy-9-oxo-10,13-trans-prostadienoic and 20 ml of methylene chloride at 20.degree. C, there is added an excess of 5 ml of methoxyisopropenyl ether CH.sub.3 C(OCH.sub.3):CH.sub.2, boiling point about 38.degree. C, and 2 mg of anhydrous p-toluene-sulfonic acid catalyst, and the mixture is gently shaken for about 15 to 20 minutes. Next, the reaction mixture is diluted with about 25 ml of ether containing 10 mg pyridine and washed with 10 ml aliquots of 50l% brine and with 10 ml aliquots of saturated brine. Finally, the mixture is filtered, the residue is extracted with methylene chloride, freed of solvent and dried over anhydrous magnesium sulfate to give 15(S)-dimethyl' methoxy' methyloxy)-9-oxo-10,13-trans-prostadienoic acid.

Repeating the procedure of Example 7 but substituting for 15(S)-hydroxy-9-oxo-10,13-trans-prostadienoic acid the following:

15(S)-hydroxy-9-oxo-5-cis,10,13-trans-prostatrienoic acid, and,

15(S),19-dihydroxy-9-oxo-10,13-trans-prostadienoic acid, the following ethers are obtained:

15(S)-dimethyl' methoxy' methyloxy)-9-oxo-5-cis,10,13-trans-prostatrienoic acid, and,

15(S),19-bis(dimethyl' methoxy' methyloxy)-9-oxo-10,13-trans-prostadienoic acid.

To a 250 ml roundbottom borosilicate flask containing 0.4 g of 15(S)-hydroxy-9-oxo-8(12),13-trans-prostadienoic acid in 15 ml of methylene chloride is added 5 ml of isopropoxyisopropenyl ether and 0.01 ml of phosphorus oxychloride and the flask's contents allowed to react at 20.degree. C for 36 hours. Next, the reaction product is diluted with 25 ml of ether and washed with 50% brine and saturated brine until the solution is neutral. Next, the residue is extracted with methylene chloride, filtered, and freed of solvent under reduced pressure, dried over anhydrous magnesium sulfate, the give 15(S)-(dimethyl' isopropoxy' methyloxy)-9-oxo-8(12),13-trans-prostadienoic acid.

Following the procedure of Example 9, but replacing 15(S)-hydroxy-9-oxo-8(12),13-trans-prostadienoic acid with:

15(S)-hydroxy-9-oxo-5-cis,10,13-trans-prostatrienoic acid,

15(R)-9-oxo-10,13-trans-prostadienoic acid,

15(R)-hydroxy-9-oxo-5-cis,10,13-trans-prostatrienoic acid,

15(S),19-dihydroxy-9-oxo-10,13-trans-prostadienoic acid,

the following diethers are formed:

15(S)-(dimethyl' isopropoxy' methyloxy)-9-oxo-5-cis,10,13-trans-prostatrienoic acid,

15(R)-(dimethyl' isopropoxy' methyloxy)-9-oxo-10,13-trans-prostadienoic acid,

15(R)-(dimethyl' isopropoxy' methyloxy)-9-oxo-5-cis,10,13-trans-prostatrienoic acid, and,

15(S),19-bis(dimethyl' isopropoxy' methyloxy)-9-oxo-10,13-trans-prostadienoic acid.

To a freshly prepared solution of 0.5 g of 9.alpha.,11.alpha.15(S)-trihydroxy-13-trans-prostenoic acid in 30 ml of benzene is added 7.5 ml of butoxyisopropenyl ether and 0.01 g of anhydrous p-toluenesulfonic acid catalyst and the resulting mixture is allowed to stand at room temperature for about 48 hours. Following this reaction period, the mixture is washed with aliquots of 5% sodium carbonate solution and with distilled water until an essentially neutral pH is obtained for the aqueous phase. The mixture is then extracted with an organic solvent, dried over anhydrous sodium sulfate and then evaporated to dryness under in-house vacuum. The dry residue obtained is dissolved in hexane and chromatographed on a neutral alumina column to give 9.alpha.,11.alpha.,15(S)-tris(dimethyl' butoxy' methyloxy)-13-trans-prostenoic acid.

To 450 mg of 9-formamido,11.alpha.,15(S)-dihydroxy-13-trans-prostenonitrile, having the following structure, Formula 5, ##STR20## the prepared according to J. Am. Chem. Soc., Vol 90, pages 3245 to 3248, 1968, in 5 ml of methylene chloride there is added 5 ml of isopropenyl ether, CH.sub.3 C(OC.sub.3 H.sub.8).dbd.CH.sub.2, and 10 mg of anhydrous p-toluenesulfonic acid and the mixture shaken for 20 hours at ambient temperature. The reaction is quenched by the addition of pyridine and ether. The product is obtained from the ether solution after drying by evaporation of the solvent in vacuo. Next, the product 9-formamido,11.alpha., 15(S)-bis(dimethyl' isopropoxy' methyloxy)-13-trans-prostenonitrile, of the following structure, Formula 6, ##STR21## which is converted with the amino acid by the hydrolysis of the cyano group and deformylation with 4 chemical equivalents of KOH in MeOH--H.sub.2 O at 110.degree.-130.degree. C for 16 hours in a sealed tube. The amino acid product is isolated by extraction with dichloromethane after addition of water and excess solid carbon dioxide. The amino group at the 9-position is next converted to its N-bromo derivative with N-bromosuccinimide in dichloromethane; then base catalyzed dehydrobromination, using alkoxides or amidines hydrolysis in dilute aqueous acetic acid and chromatography on silica to give 11.alpha.,15(S)-bis(dimethyl' isopropoxy' methyloxy)-13-trans-prostenoic acid.

Following the procedure of Example 12, but replacing 9-formamido-11.alpha.,15(S)-dihydroxy-13-trans-prostenonitrile with:

racemic 9-formamido-11.beta.,15(S)-dihydroxy-13-trans-prostenonitrile,

racemic 9-formamido-11.alpha.,15(R)-dihydroxy-13-prostenonitrile,

racemic 9-formamido-11.beta.,15(R)-dihydroxy-13-trans-prostenonitrile, and

enantio 9-formamido-11.beta.,15(R)-dihydroxy-13-trans-prostenonitrile,

also prepared by the method outlined in J. Am. Chem. Soc., Vol 90, pages 3245 to 3248, 1968; the following ethers are formed:

racemic 11.beta.,15(S)-bis(dimethyl' isopropoxy' methyloxy)-9-oxo-13-trans-prostenoic acid,

racemic 11.alpha.,15(R)-bis(dimethyl' isopropoxy' methyloxy)-9-oxo-13-trans-prostenoic acid,

racemic 11.beta.,15(R)-bis(dimethyl' isopropoxy' methyloxy)-9-oxo-13-trans-prostenoic acid, and,

enantio 11.beta.,15(R)-bis(dimethyl' isopropoxy' methyloxy)-9-oxo-13-trans-prostenoic acid.

The compounds 9.alpha.-hydroxy,11.alpha.,15(S)-bis(lower dialkyl' methyloxy)-13-trans-prostenoic acid and 9.beta.-hydroxy-11.alpha.,15(S)-bis(lower dialkyl' methoxy)-13-trans-prostenoic acid are prepared by the reduction of 11.alpha.,15(S)-bis(lower dialkyl' methyloxy)-9-oxo-13-trans-prostenoic acid using NaB(R).sub.n H.sub.4-n wherein R is a lower alkyl of 1 to 4 carbons in an inert organic solvent at 0.degree. C to 30.degree. C for 15 minutes to 1 hour to give the set forth prostaglandins. For example, the reduction is carried out using sodium borohydride in methanol at 0.degree. C for 30 minutes followed by chromatographic separation to give the respective ether compounds.

the .alpha.-homo analogoues of 11,15-bis(lower dialkyl' methyloxy)-5-cis,13-trans-prostadienoic acid,(11,15-bis ether of PGF.sub.2.alpha.); of 11,15-bis(lower adialkyl' methyloxy)-9-oxo-5-cis,13-trans-prostadienoic acid,(11,15bis ether of PGE.sub.2); of 11,15-bis (lower dialkyl' methloxy)-13-trans-prostenoic acid,(11,15-bis ether of PGF.sub.1.alpha.); and of 11,15-bis(lower dialkyl' methyloxy)-9oxo-13-trans-prostenoic acid,(11,15-bis ether of PGE.sub.1) are prepared according to the procedure as set forth in Examples 1 to 4 inclusive, and all reaction conditions and reagents are as described except that 5-triphenylphosphonio hexanoic acid .phi..sub.3 P.sup.+ CH.sub.2 (CH.sub.2).sub.4 --CO.sub.2 H Br.sup.- (.phi.=phenyl) is used in place of .phi.P.sup.+ CH.sub.2 (CH.sub.2).sub.3 CO.sub.2 H Br.sup.- to give the desired compounds.

In this example, the 15-epimer of the lactone employed in Examples 15 to 18 inclusive, also prepared by the method set forth in J. Am. Chem. Soc., Vol 92, pages 2586 to 2587, 1970, and the references cited therein, and shown here as Formula 7, wherein R' is defined supra, and wherein ##STR22## the hemiacetal is in either this form, or as the enantiomer is reacted with .phi.P.sup.+ CH.sub.2 (CH.sub.2).sub.3 CO.sub.2 H Br.sup.- according to the method of Example 15 to 18 inclusive to produce the following ethers:

11.alpha.,15(R)-bis(lower dialkyl' methyloxy)-9.alpha.-hydroxy-5-cis, 13-trans-prostadienoic acid,

enantio 11.alpha.,15(R)-bis(lower dialkyl' methyloxy)-9.alpha.-hydroxy-5-cis,13-trans-prostadienoic acid,

11.alpha.,15(R)-bis(lower dialkyl' methyloxy)-9-oxo-5-cis,13-trans-prostadienoic acid, and,

enantio 11.alpha.,15(R)-bis(lower alkyl' methyloxy)-9-oxo-5-cis, 13-trans-prostadienonic acid.

Examples of additional (mono; or lower dialkyl' or alkoxy' methyloxy)-prostaglandins that are prepared in the mode and the manner of the present disclosure are as follows:

11.alpha.,15(S)-bis(methyl' methoxy' methyloxy)-9-oxo-5-cis,13-trans-prostadienoic acid,

11.alpha.,15(S)-bis-(ethyl' propoxy' methyloxy)-9-oxo-5-cis,13-trans,17-cis-prostatrienoic acid,

11.alpha.,15(S)-bis(ethyl' butyl' butoxy' methyloxy)-9-oxo-prostanoic aicd,

11.alpha.,15(S)-bis(diethyl' butoxy' methyloxy)-9-oxo-13-trans-8-iso-prostenoic acid,

11.alpha.,15(S)-bis(dimethyl' isopropoxy' methyloxy)-9-oxo-13-trans-.omega.-homo-prostenoic acid;

15(S)-(dipropyl' isopropoxy' methyloxy)-9-oxo-10,13-trans-prostadienoic acid,

15(S)-(isopropyl' methyl' isporopoxy' methyloxy)-9-oxo-5-cis, 10,13-trans-prostatrienoic acid,

9.beta.,11.alpha.,15(S)-tris-(dibutyl' butoxy' methyloxy)-13-trans-prostenoic acid,

9.alpha.,11.alpha.,15(S)-tris(dibutyl' methoxy' methyloxy)-5-cis,13-trans-prostadienoic acid,

15(S)-diamyl' isopropoxy' methyloxy)-9-oxo-8(12),13-trans-prostadienoic acid;

15(S),19-bis(diethyl' heptoxy' methyloxy)-9-oxo-10,13-transprostadienoic acid, and the like.

DESCRIPTION OF INVENTIVE APPLICATIONS

The novel prostaglandin ethers of the invention as embraced by Formula 1 possess valuable and useful properties. The prostaglandin ethers are inventively characterized by their ability to serve as a source of the parent prostaglandin following the metabolic hydrolysis of the prostaglandin from the diether moiety. For example, prostaglandin ethers with a C-9 keto group and one or both of the C-11 and C-15 positions substituted with a diether group on in vivo separation of the latter group and with the formation of hydroxyl groups make available prostaglandins that possess many pharmacological properties, including the ability to lower blood pressure and relieve asthma and nasal congestion. These parent prostaglandins are useful for the management of hypertension in avians, mammals, including humans and primates, farm animals and in laboratory animals. Also, following the liberation of the diether groups and with concomitant formation of hydroxyl groups in vivo, these will produce for example, 11.alpha.,15(S)-dihydroxy-9-oxo-5-cis,13-trans-prostadienoic acid; the latter compound when administered at the rate of 0.5 .mu.g/min intravenously, or 2mg/2hrs intravaginally, or 0.5 mg/2 hrs orally, is known to be effective in humans for the induction of labor. Representative prostaglandin ethers for obrtaining prostaglandins that possess the set forth pharmacological properties include 11.alpha.,15(S)-bis(lower alkyl' lower alkoxy', methyloxy)-9-oxo-13-trans-prostenoic acid;11.alpha.,15(S)-bis(lower alkyl' lower alkoxy' methyloxy)-9-oxo-5-cis,13-trans-prostadienoic acid; 11.alpha.,15(S)-bis(lower alkyl' lower alkoxy' methyloxy)-9oxo-5cis,13-trans,17-cis-prostatrienoic acid, and the like.

The prostaglandin ethers of the invention substituted at the C9, C-11 and C-15 positions with the diether group on liberation of the latter groups, and with concomitant in vivo formation of hydroxyl groups at the C-9,C-11 and C-15 positions, will produce prostaglandins possessing smooth muscle stimulating activity, for example, 9.alpha.,11.alpha.,15(S)-trihydroxy-13-trans-prostenoic acid; 9.alpha.,11.alpha.,15(S)-trihydroxy-5-cis,13-trans-prostadienoic acid, and the like, which latter compounds when administered intravenously(5 .mu.g/min) or intravaginally (25 mg/2 hrs) will induce labor in humans. Exemplary of prostaglandin ethers that furnish corresponding prostaglandins which latter prostaglandins possess smooth muscle activity are 9.alpha.,11.alpha.,15(S)-tris(lower alkyl' lower alkoxy'methyoxy)-13-trans-prostenoic acid; 9.alpha., 11.alpha.,15(S)-tris(lower alkyl' lower alkoxy' methyloxy)-5-cis,13-trans-prostadienoic acid; 9.alpha.,11.alpha.,15(S)-tris(lower alkyl' lower alkoxy' methyloxy)-5-cis,13-trans,17-cis-prostatrienoic acid; and the like.

The prostaglandin ethers of the invention that supply in vivo a physiologically active prostaglandin characterized by a C-9 keto group and (1)a C-11 and C-15 hydroxyl group or (2) a C-9, C-11 and C-15 hydroxyl group are physiologically useful for not only inducing labor but also menses and for the termination of pregnancy. Representative of prostaglandin ethers that can serve as an in vovo source of physiologically active prostaglandins when administered for example intravenously at the rate of 0.1 to 1.0 .mu.g/min, calculated as freed prostaglandins are ethers such as 9.alpha.,11.alpha.,15(S)-tris(lower alkyl' lower alkoxy' methyloxy)-13-trans-prostenoic acid; 9.alpha.,11.alpha.,15(S)-tris(lower alkyl' lower alkoxy' methyloxy)-5-cis,13-trans-prostadienoic acid; 9.alpha.,11.alpha.,15(S)-tris(lower alkyl' lower alkoxy'methyloxyl)-5-cis,13-trans,17-cis-prostatrienoic acid; 11.alpha.,15(S)-bis(lower alkyl' lower alkoxy' methyloxy)-9-oxo-5-cis,13-trans-prostadienoic acid; 11.alpha.,15(S)-bis(lower alkyl' lower alkoxy' methyloxy)-9oxo-13-trans-prostenoic acid; and the like.

The prostaglandin ethers can be used for the relief of asthma, nasal congestion and inhibition of lipolysis by supplying from prostaglandin ethers substituted with a C-9keto and a C-15 lower diether group or a prostaglandin ether substituted with a C-9 keto and at C-11 and C-15 a diether group the corresponding parent prostaglandins possessing the desired therapeutic utility. Exemplary of prostaglandin ethers of the invention for producing the corresponding prostaglandins include 15(S)-(lower alkyl' lower alkoxy' methyloxy)-9-oxo-10,13-trans-prostadienoic acid; 15(S)-(lower alkyl' lower alkoxy' methyloxy)-5-cis,10,13-trans-prostatrienoic acid; 11.alpha.,15(S)-bis(lower alkyl' lower alkoxy' methyloxy)-9-oxo-5-cis,13-trans-prostadienoic acid; and the like.

The prostaglandin ethers of the invention substituted with a C-9 keto group and additionally with a C-15 or C-11 and C-15 diether group are useful for the management of gastric secretions. These prostaglandin ethers release the natural anti-secretory prostaglandin in the stomach upon the acidic hydrolysis of the prostaglandin ether to free the prostaglandin group of the prostaglandin ether from the affixed ether moiety. The prostaglandin ether's ability to release free prostaglandin under gastric-like environmental conditions is demonstrated by standard in vitro experiments using an artificial gastric juice consisting essentially of mineral acid, hydrochloric, at varying pH from 1 to 4.5 at 37.degree. C. For example, 11.alpha.,15(S)-bis(dimethyl' isopropoxy' methyloxy)-9-oxo-5-cis,13-trans-prostadienoic acid releases 11.alpha.,15(S)-dihydroxy-9-oxo-5-cis, 13-trans-prostadienoic acid at pH 2 to 4 and at 37.degree. C. The immediately described prostaglandin ethers are therapeutically indicated for regulating gastric secretions, that is hyperacidity, because as the pH of the stomach reaches 4.5 to 5 the hydrolysis of the prostaglandin ether is essentially decreased, and, as the prostaglandin ether passes from the stomach into the intestine, the unwanted increased intestine peristalsis or increased intestinal motility with the accompanying bowel actions following administration of the natural form of the prostaglandins in the intestine are essentially absent for the prostaglandin ethers of the invention.

The prostaglandin ether's ability to release prostaglandin is determined by standard laboratory techniques, for example, by adding small amounts, 10 micrograms, 50 micrograms, etc., of the prostaglandin ether to hydrogen ion environments at varying pH and then detecting the presence of freed prostaglandin by conventional muscle bioassay. For example, the addition of 9.alpha.,11.alpha.,15(S)-tris(diamyl' isopropoxy' methyloxy)-5-cis,13-trans-prostadienoic acid, and for racemic 9.alpha.,11.alpha.,15(S)-tris(diethyl' ethoxy' methyloxy)-5-cis,13-trans-prostadienoic acid to a hydrogen ion environment, hydrochloric acid, indicated by rat bioassay, for example, contraction of isolated rat uterine or gerbil colon strips, that from about pH 1 to 4.5, hydrolysis of the ether linkage occurs to release the corresponding prostaglandin.

The prostaglandin ethers of the invention possess desirable partition coefficients between aqueous and lipid phases and they are therefore adaptable for administering for their physiological effects from drug delivery systems, such as intrauterine contraception devices, skin drug delivery bandages and the like, manufactured from naturally occurring and synthetic polymeric materials. This novel and useful property of the prostaglandin ethers make possible their diffusion at measurable controlled rates through polymeric materials such as polyvinylchloride, polyisoprene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, collagen, polydimethylsiloxane, hydrophilic hydrogels of esters of acrylic and methacrylic acids, polyvinyl acetates, propylene-vinyl acetate copolymers and the like.

The novel compounds of the invention can be used by the pharmaceutical and the veterinary arts in a variety of pharmaceutical preparations or veterinary preparations. In these preparations, the new compounds are administrable in the form of tablets, pills, powders, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix and in other suitable forms. The pharmaceutical or veterinary preparation which contains the compound is conventiently admixed with a non-toxic pharmaceutical organic carrier or a non-toxic pharmaceutical inorganic carrier. Typical of pharmaceutically acceptable carriers, are for example, water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly and other conventionally employed pharmaceutically acceptable carrier. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents and the like, as for example sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monopalmityl, dioctyl sodium sulfosuccinate, and the like.

Exemplary of a typical method for preparing a tablet containing the active ingredient is to first suitably comminute the active ingredient with a diluent such as starch, sucrose, kaolin or the like to form a powder mixture. Next, the just prepared mixture can be granulated by wetting with a non-toxic binder such as a solution of gelatin, acacia mucilage, corn syrup and the like and after mixing the composition is screened to any predetermined particle sieve size. As an alternative, if preferred to granulation, the just prepared mixture can be slugged through conventional tablet machines and the slugs comminuted before the fabrication of the tablets. The freshly prepared tablets can be coated or they can be left uncoated. Representative of suitable coatings are the non-toxic coatings including shellac, methylcellulose, carnauba wax, styrenemaleic acid copolymers and the like. For oral administration, compressed tablets containing 0.01 milligram, 5 milligrams 25 milligrams, 50 milligrams, etc., up to 1500 milligrams are manufactured in the light of the above disclosure and by art known fabrication techniques well known to the art and set forth in Remington's Pharmaceutical Science, Chapter 39, Mack Publishing Co., 1965. The pharmaceutical manufacture of a formulation is shown in Example 21:

To formulate the tablet, uniformly blend the prostaglandin ether, corn starch, lactose, and dicalcium phosphate in a V-blender until all the ingredients are uniformly mixed together. Next, the corn starch is prepared as a 10% aqueous paste and it is blended with the uniform mixture until a uniform mixture is obtained. Then, the wet granulation is passed through a standard eight mesh screen, dried and rescreened with a 12 mesh screen. The dry granules are next blended with calcium stearate and compressed into tablets. Other tablets containing 0.05, 0.25, 1.0, 5.0, 10.0 mgs, etc. are prepared in a like fashion.

The manufacture of capsules containing 0.1 milligram to 1500 milligrams for oral use consists essentially of mixing the active compound with a non-toxic carrier and enclosing the mixture in a gelatin sheath. The capsules can be in the art known soft form of a capsule made by enclosing the compound in intimate dispersion within an edible oil or the capsule can be a hard capsule consisting essentially of the novel compound mixed with a non-toxic solid such as talc, calcium stearate, calcium carbonate or the like. Exemplary of a typical use employing capsules containing 25 mg of 11.alpha.,15(S)-bis-(lower dialkyl' lower alkoxy' methyloxy)-9-oxo-13-trans-prostenoic acid is therapeutically indicated ad libitum for regulating gastric secretions with lesser amounts indicated as the pH of the stomach reaches 4 to 5.

The daily dose administered for the compounds will of course vary with the particular novel prostaglandin ether employed because of the varying potency of the compounds, the chosen route of administration and the size of the recipient. The dosage administered is not subject to definite bounds, but it will usually be an effective amount or the equivalent on a molar basis of the pharmacologically active free acid form produced upon the metabolic release of the prostaglandin to achieve the biological function of the prostaglandin. Representative of a typical method for administering the diethers of prostaglandin of the invention is by the injectable-type administration route. By this route, a sterile solution containing the compound is administered intravenously or subcutaneously at the rate of 0.01 microgram to 0.50 microgram per kilogram of body weight per minute by means of an infusion pump at the rate of 10 to 15 milliliters per hour. For example, the compound 9.alpha.,11.alpha.,15(S)-tris(dimethyl' methoxy' methyloxy)-13-trans-prostenoic acid can be administered by this route for producing stimulation of smooth muscles. The compound is administered by the injectable route in a form suited for injection, such as mixed with sterile physiological saline, or in aqueous solutions having incorporated therein an agent that delays absorption such as aluminum monostearate and the like.

Suitable topical preparations can easily be prepared by, for example, mixing 500 mg of the diethers prostaglandins with 15 g of cetyl alcohol, 1 g of sodium lauryl sulfate, 40 g of liquid silicone D.C. 200 sold by Dow Corning Co., Midland, Mich., 43 g of sterile water, 0.25 g of methylparaben and 0.15 g of propylparaben and warming the mixture with constant stirring to about 75.degree. C and then permitting the preparation to congeal. The preparation can be readily applied to the skin by inunction or it can be applied topically by dispensing the preparation from a conventional surgical gauze dispenser, and the like. The prostaglandin ethers penetrate the outermost layer of the skin, the stratum corneum, more readily than unetherified prostaglandins and as such the prostaglandin ethers lend themselves to topical administration. Suitable procedures for preparing topical applications are set forth in Remington's Pharmaceutical Science, Chapter 37, as cited supra.

The compounds of this invention can also be conveniently administered in aerosol dosage form. An aerosol form can be described as a self-contained sprayable product in which the propellant force is supplied by a liquified gas. For administering a self-propelled dosage form of about 25 mg to 150 mg that is used about 3 or 4 times daily for inhalation therapy, the bronchodialator 11.alpha.,15(S)-bis-(dimethyl' methoxy' methyloxy)-9-oxo-5-cis,13,-trans prostadienoic acid is suspended in an inert non-toxic propellant in a commercially available compressed-gas aerosol container. Suitable propellants include trichloromonofluoromethane, dichlorodifluoromethane, dichlorodifluoroethane, monochlorodifluoroethane and mixtures thereof. The inert gas can also be mixed with non-toxic cosolvents such as ethanol, if desired, to produce the aerosol form. If the compound is administered by oral inhalation employing conventional nebulizers, it is convenient to dilute in an aqueous solution about 1 part of the novel prostaglandin with about 1000 to 10,000 parts of solution, for administering 3 or 4 times per day.

For administering to valuable domestic household, sport or farm animals, such as sheep, goats, cattle, etc., or for administering to laboratory animals such as mice, rats, guinea pigs, monkeys, etc., for scientific studies, the compound is prepared in the form of a food premix, such as mixing with dried fish meal, outmeal, straw, hay, ground corn, mash, and the like, and then the prepared premix is added to the regular feed, thereby administering the compound to the domestic or laboratory animal in the form of feed. The prostaglandin ethers can also be administered in laboratory studies for determining the therapeutic utility of the prostaglandin ethers to mammals, including humans, avains and other valuable animals by other well known methods. For example, in laboratory studies with standard white laboratory rats, the compounds can be administered orally by perfusion in saline at the rate of 0.1 microgram to 1.0 microgram per minute across the mucosal surface of the stomach to study muscle stimulation properties of the compounds.

The above examples and disclosure are set forth merely for illustrating the mode and the manner of the invention and various modifications and embodiments can be made by those skilled in the art in the light of the invention without departing from the spirit of the invention.