16-Aryloxy-17,18,19,20-tetranorprostanoic acids and derivatives

Abstract

This disclosure describes novel 16-aryloxy-17,18,19,20-tetranoprostanoic acids and derivatives thereof useful as bronchodilators and as hypotensive and contraceptive agents.

Description

BRIEF SUMMARY OF THE INVENTION

This invention relates to novel 16-aryloxy-17,18,19,20-tetranorprostanoic acids, their derivatives and intermediates for preparing same. More specifically the novel compounds of this invention can be represented by the following two general formulae wherein A has the same absolute configuration as is found in the naturally-occurring mammallian prostaglandins, and all the racemates, racemic mixtures and diasteromeric mixtures thereof. ##STR1## wherein R.sub.1 is hydroxy or an alkoxy group having from one to twelve carbon atoms; R.sub.2 is a phenyl, benzyl, naphthyl, or 5,6,7,8-tetrahydronaphthyl group optionally substituted with one or two of the following groups: halogen, lower alkyl, lower alkoxy, or trifluoromethyl radicals; n is an integer having the value 2 to 4, inclusive; Y is a divalent radical selected from the group consisting of ##STR2## X is a divalent radical selected from the group consisting of ##STR3## C.sub.5 -C.sub.6 is ethylene or cis-vinylene; C.sub.13 -C.sub.14 is ethylene or trans-vinylene; with the proviso that when C.sub.5 -C.sub.6 is cis-vinylene then C.sub.13 -C.sub.14 is trans-vinylene.

When X is ##STR4## it represents the 15.alpha.-hydroxy derivative, and the 15.beta.-hydroxy derivatives when it is ##STR5##

Suitable lower alkyl and lower alkoxy groups contemplated by the present invention are those having up to four carbon atoms such as, for example, methyl, propyl, iso-propyl, n-butyl, sec-butyl, methoxy, ethoxy, t-butoxy, etc.

Also embraced within the scope of the present invention are the non-toxic, pharmaceutically acceptable salts of the novel compounds of the present invention when R.sub.1 is hydroxy. The cations comprised in these salts include, for example, the non-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine cations such as the tri(lower alkyl)amine cations (e.g., triethylamine), procaine, and the like.

The novel compounds of the present invention are obtainable as yellow oils or crystalline solids having characteristics absorption spectra. They are relatively insoluble in water but are relatively soluble in common organic solvents such as ethanol, ethyl acetate, dimethylformamide, and the like. The cationic salts of the compounds when R.sub.1 is hydroxy are, in general, white to yellow crystalline solids having characteristic absorption spectra. They are relatively soluble in water, methanol and ethanol but are relatively insoluble in benzene, diethyl ether, and petroleum ether.

DETAILED DESCRIPTION OF THE INVENTION

The prostaglandins are a family of closely related compounds which have been obtained from various animal tissues, and which stimulate smooth muscle, lower arterial blood pressure, antagonize epinephrine-induced mobilization of free fatty acids, and have other pharmacological and autopharmacological effects in mammals. See Bergstom et al., J. Biol. Chem., 238, 3555 (1963) and Horton, Experienta, 21, 113 (1965) and references cited therein. All of the so-called natural prostaglandins are derivatives of prostanoic acid. ##STR6## The hydrogen atoms attached to C-8 and C-12 are in trans configuration. The natural prostaglandins represent only one of the possible optical isomers. The compounds of this convention include all possible optical isomers.

The novel compounds of this invention are prepared from the corresponding known 11.alpha.-hydroxy-9-oxo-5-cis,13-trans-prostadienoic acids (I) (Netherlands Patent No. 7,206,361; November 14, 1972) as illustrated in Flowsheet A which follows and in which n, R.sub.2 and C.sub.5 -C.sub.6 are as hereinabove defined and in which THP is the tetrahydropyranyl group. ##STR7##

According to Flowsheet A above, dehydration of (I) in the usual manner provides the 16-aryloxy-15.alpha.-hydroxy-9-oxo-17,20-tetranor-5-cis,10,13-trans-prostatrienoic acids (III) which upon treatment with dihydropyran and acid provide the bistetrahydropyranyl derivative (V). Upon treatment of (V) with sodium borohydride or sodium cyanoborohydride (pH 3-4), a mixture (VII) of 9.alpha.,15.alpha.-dihydroxy-16-aryloxy-9-oxo-17,20-tetranor-5-cis,13-trans-prostadienoic acid and the corresponding 9.alpha.-hydroxyl prostadienoic acid is obtained. Oxidation of the 9-hydroxy mixture (VII) provides, after acidic hydrolysis of the tetrahydropyranyl functions, the 16-aryloxy-15.alpha.-hydroxy-9-oxo-17,20-tetranor-5-cis,13-trans-prostadienoic acid (VIII), which upon hydrogenation provides the fully saturated 16-aryloxy-15.alpha.-hydroxy-9-oxo-17,20-tetranorprostanoic acids (IX).

Treatment of the 16-aryloxy-11.alpha.,15.alpha.-dihydroxy-17,20-tetranor-5-cis,13-trans-prostadienoic acids (I) with dihydropyran and an acid catalyst provides the tris-tetrahydropyranyl derivatives (II) which can be selectively reduced at the C.sub.5 -C.sub.6 cis double bond. Acid-catalyzed hydrolysis of the tetrahydropyranyl moieties then provides the 11.alpha.,15.alpha.-dihydroxy-9-oxo-16-aryloxy-17,20-tetranor-13-trans-prostenoic acids (IV), which when subjected to the steps as described above for I.fwdarw.III.fwdarw.V.fwdarw.VII.fwdarw.VIII provides the 15.alpha.-hydroxy-9-oxo-16-aryloxy-17,20-tetranor-13-trans-prostenoic acids of this invention.

The 9-hydroxy derivative of this invention can also be obtained by reduction of the corresponding 9-oxo derivative. When the reduction is carried out in the usual manner with sodium borohydride in ethanol as solvent, the product is a mixture of the 9.alpha.- and 9.beta.-hydroxy derivative (X) and (XI), respectively. These isomers are separable by chromatographic procedures. The stereoselective preparation of the 9.alpha.-hydroxy derivative (X) can be accomplished by reduction of the 9-oxo derivative with either lithium perhydro-9b-borophenalyl hydride [H. C. Brown and W. C. Dickason, Jour. Amer. Chem. Soc., 92, 709 (1970)] or with lithium tri-sec-butylborohydride. ##STR8##

The carboxylic acid esters (R.sub.1 =alkoxy) of this invention can be prepared by treating the corresponding carboxylic acid with the appropriate diazoalkane by the usual procedures well known to the art. An alternative procedure involves blocking the 15-hydroxy function with a tetrahydropyranyl group, conversion of the carboxylic acid to an acid chloride and reacting with the appropriate alcohol in the presence of an acid-acceptor and deblocking.

All of the compounds of this invention can be isolated and purified by conventional methods. Isolation can be accomplished, for example, by dilution of the reaction mixture with water, extraction with a water-immiscible solvent such as methylene chloride, ethyl acetate, benzene, cyclohexane, ether, toluene and the like, chromatography, adsorption on ion-exchange resins, distillation, or a combination of these. Purification of the compounds of this invention can be accomplished by means known in the art for the purification of prostaglandins and lipids, fatty acids, and fatty esters. For example, partition chromatography, reverse phase partition chromatography, countercurrent distribution, adsorption chromatography on acid washed Florisil.RTM. (synthetic magnesium silicate) and acid washed silica gel, dry column chromatography, preparative paper chromatography, preparative thin layer chromatography, chromatography over sili-ca loaded cation exchange resins, and combinations thereof can be used effectively to purify the compounds produced by the presence of this invention.

If a compound of this invention is prepared from a prostaglandin A (III, V, VI) which is in the optically active resolved from, then the product will also be in the resolved form. On the other hand, if the prostaglandin A is racemic, the product will be racemic.

In formulae XII-XXIII, which follow, R.sub.2, n, X, C.sub.5 -C.sub.6 and C.sub.13 -C.sub.14 are as hereinabove defined.

The racemic products and intermediates of this invention may be resolved into their optically active components by a number of methods of resolution well known in the art. For example, the free carboxylic acids can be treated with an optically active base such as cinchonine, quinine, brucine, d- or l-.alpha.-phenylethylamine and the like to produce diastereoisomeric salts which can be separated by crystallization. Alternatively, the acid may be esterified with an optically active alcohol, e.g., d- or l-menthol, estradiol 3-acetate, etc., and the diastereoisomeric esters then resolved.

Resolution of the racemic prostaglandin-like compounds of this invention may also be accomplished by reverse phase and absorption chromatography on an optically active support and adsorbent and by selective transformation of one isomer with a biologically-active prostaglanin transforming system. Such transformations can be carried out by incubation or perfusion, using methods well established in the art, followed by isolation and recovery of the isomer resistant to the metabolic transformation applied.

Additional procedures for effecting the resolution of the racemic products of this invention involve conversion of a 9.alpha.-hydroxy racemate (illustrated by XII and XIII below) to the corresponding hemiphthalate (e.g., XIV) and conversion of this diacid to a bis salt (e.g., XV) with an optically active amine (e.g., l-(-)-.alpha.-methylbenzylamine, d-(+)-.alpha.-methylbenzylamine, brucine, dehydroabietylamine, styrchnine, quinine, cinchonine, cinchonidine, quinidine, ephedrine, deoxyephedrine, amphetamine, (+)-2-amino-1-butanol (-)-2-amino-1-butanol and the like). The resulting diastereoisomers are then separated by fractional crystallization and the individual components are then converted by acidification and saponification to the individual optically active parent 9.alpha.-hydroxy enantiomers (XII) and (XIII), oxidation of which provides the corresponding individual 9-oxo enantiomers (XVI) and (XVII). ##STR9##

Another procedure involves conversion of the 9.alpha.-hydroxy racemate (as the 15-hydroxy blocked and then deblocked prostenoic acid ester) to the diastereomeric carbamates with an optically active isocyanate, e.g., (+)-1-phenylethylisocyanate and (-)-1-phenylethylisocyanate. Separation of the diastereomers, for example, (XVIII) and (XIX), can be accomplished by fractional crystallization or by the usual chromatographic procedures, or if necessary by high speed liquid chromatography involving, if required, recycling techniques [See G. Fallick, American Laboratory, 19-27 (August, 1973) as well as references cited therein. Additional information concerning high speed liquid chromatography and the instruments necessary for its application is available from Waters Associates, Inc., Maple St., Milford, Mass.] Base-treatment of the individual diastereomeric carbamates then affords the individual enantiomeric alcohols. ##STR10##

It is also possible to effect resolution of the 9.alpha.-hydroxy racemate, preferably as the prostenoate ester, by esterification of the 9.alpha.-hydroxy function (15-hydroxy function blocked as a tetrahydropyranyl ether or trimethylsilyl ester and then deblocked after 9.alpha.-hydroxyfunctionally action) with an optically active acid, via its acid chloride. Suitable optically active acids include .omega.camphoric acid, menthoxyacetic acid, 3.beta.-acetoxy-.DELTA..sup.5 -etianic acid, (-)-.alpha.-methoxy-S-trifluoromethylphenyl acetic acid and (+)-.alpha.-methoxy-.alpha.-trifluoromethylphenylacetic acid, and the like. The resulting diastereoisomeric esters, for example (XX) and (XXI) are then separated by fractional crystallization or by chromatographic techniques including if necessary, the use of high speed liquid chromatography. Saponification of the individual diastereoisomers then provides the individual 9.alpha.-hydroxyprostenoic acid enantiomers (XII) and (XIII). ##STR11##

Another resolution procedure involves derivatization of the keto function of the racemic 9-oxoprostenoic acid or ester with the usual type of ketone derivacizing agents bearing an optically active center. The resulting mixture of diastereomeric derivatives can then be separated by fractional crystallization or by chromatography or, if necessary, by high speed liquid chromatography. The individual diastereomeric keto derivatives, for example, (XXII) and (XXIII), are then convertable to the individual 9-oxo enantiomers (XVI) and (XVII) by any of the usual cleavage techniques. Ketone reduction of the 9-oxo-enantiomer as described hereinabove then provides the corresponding 9.alpha.-hydroxy or 9.beta.-hydroxy enantiomer. Among the optically active reagents useful for ketone derivatization are 1-.alpha.-aminoxy-.gamma.-methylpentanoic acid hydrochloride [E. Testa et al., Helv. Chimica Acta, 47 (3), 766 (1973), menthylhydrazine, and 4-.alpha.-methylbenzylisemicarbazide. ##STR12##

Other useful keto derivatizing agents are optically active 1,2-glycols, e.g., D(-)-2,3-butanediol, [for pertinent literature see, A. C. Neish, Can. Jour. Res. 23 sec. B, 10 (1945); G. E. Ward et al., Jour. Amer. Chem. Soc., 66, 541 (1944); J. Casanova, Jr. and E. J. Corey, Chem. and Ind. (London), 1961, 1664)] or optically active dithiols, e.g., L(+)-2,3-butanedithiol [see also E. J. Corey and R. B. Miha, Jour. Amer. Chem. Soc., 84, 2938 (1962)].

The novel compounds of this invention are useful as hypotensive agents (9-oxo-derivatives), bronchodilators for the treatment of asthma and as agents for the control of reproduction in females, in humans as well as in warm-blooded animals such as cattle, sheep, swine, horses, dogs and cats. Among the potential uses in domestic animals is the synchronization of oestrus in cattle and other domestic animals, and the induction of twinning.

In humans these compounds may have use as agents for the induction of labor at term, as abortifacients and as menses inducers.

There are several possibilities of contraceptive attack during the normal processes of mammalian female reproduction. These include any others ovulation blockage, interference with the fertilization of the ovum by sperm, interference with the normal transport of ova and or zygotes in the reproductive tract, prevention of embryo implantation, disruption of the maternal response to embryonic implantation, and maternal failure to support embryonic survival. While the exact mechanism or mechanisms which take place with the active ingredients in effecting contraception is not clear, the compounds of this invention may prevent conception by one or more of the above-mentioned occurrences. It is not intended, however, that the present invention be limited to any particular theory as to mechanism of contraception.

A major problem in the clinical use of prostaglandin E.sub.2 and prostaglandin F.sub.2 .alpha., and indeed of prostaglandins of the 11.alpha.-hydroxy series in general, is the often high incidence of gastrointestinal side-effects as manifested by nausea, vomiting and diarrhea. Presumably, these effects result from the stimulation of gastrointestinal smooth muscle by the administered prostaglandin. One important advantage of the compounds of this invention is that although they retain to a significant extent the antifertility pot-ency of the parent 11-hydroxy compounds they show a highly diminished ability to stimulate smooth muscle. This very significant and unanticipated separation of biological effects suggests that the compounds of this invention have the potential to be useful anti-fertility agents with a minimum of adverse side-effects. It is also conceivable that this separation will allow the use of higher relative doses of these compounds than hitherto possible with the established prostaglandins. This also denotes the possibilities of more effective application in the field of post-conception control, e.g. inducing menses during approximately the first two weeks following the first missed menstruation. For a discussion of these problems see Toppozada et al. "Prostaglandins in Fertility Control" 3, 108 (1973), Report from Meetings of the Prostaglandin Task Force Steering Committee sponsored by the World Health Organization; and Wiqvist et al., ibid. 3, 83 (1973).

The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1

Preparation of d,l-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis-13-trans-prostadienoic acid

A mixture of the 15 epimers of dl-16-phenoxy-9.alpha.,11.alpha.,-15-trihydroxy-17,20-tetranor-5-cis-13-trans-prostadienoic acid is prepared in accordance with Netherlands Patent No. 7,206,361, page 9, Example 1. The two epimers are separated by the procedure of Netherlands Patent No. 7,206,361, page 9, Example 1. The high Rf material is assigned the 15.beta. configuration and the low Rf material is assigned the 15.alpha.-configuration. dl-16-Phenoxy-9.alpha.,11.alpha.,15-trihydroxy-17,20-tetranor-5-cis-13-trans-prostadienoic acid (100 mg.) is dissolved in 2.0 ml. of dry acetone and stirred at -40.degree. C. under argon, N-trimethylsilyldimethylamine (3 ml.) is then added and after 1 hour the reaction is diluted with cold ether and extracted with 50% saturated aqueous sodium bicarbonate. Evaporation to dryness in vacuo yields as the major product: dl-11.alpha.,15.alpha.-bistrimethylsiloxy-9.alpha.-hydroxy-16-phenoxy-17,20-tetranor-5-cis-13-trans-prostadienoic acid trimethylsilyl ester.

The crude material is oxidized with Collins reagent (prepared in situ from 170 mg. of chromic anhydride and 275 ml. of pyridine in 4 ml. of methylene chloride) for 5 minutes at 25.degree. C. The reaction mixture is diluted with ether and extracted with 0.5 M hydrochloric acid washed with brine. The organic solution is dried with magnesium sulfate and concentrated in vacuo to give the crude dl-11.alpha.,15-bistrimethylsiloxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis-13-trans-prostadienoic acid trimethylsilyl ester.

The crude trimethylsilyl ester is dissolved in 5 ml. of methanol containing 0.5 ml. of water and 0.25 ml. of acetic acid and stirred at ambient temperature for 1 hour. The solution is diluted with 5 ml. of 30% aqueous potassium hydrogen phosphate and extracted twice with 10 ml. of ether. The ether is dried with magnesium sulfate and concentrated in vacuo to afford dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis-13-trans-prostatrienoic acid as an oil.

The crude oil is purified by dry column chromatography on silica gel to give dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis-13-trans-prostatrienoic acid.

EXAMPLES 2-57

Treatment of the compounds of the following table by the procedure of Example 1 is productive of the 9-oxo derivatives of the table.

__________________________________________________________________________Ex-ample Starting Compound 9-Oxo Product__________________________________________________________________________2 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-benzyloxy- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-benzylox y-17,20- 17,20-tetranor-5-cis,13-trans-prosta- tetranor-5-cis,13-trans-prostadienoic acid dienoic acid3 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(2-naph- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(2-napht hyloxy)- yloxy)-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic trans-prostadienoic acid acid4 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-p-chloro- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-p-chloro phenoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic trans-prostadienoic acid acid5 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-m-chloro- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-m-chloro phenoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic trans-prostadienoic acid acid6 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-o-chloro- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-o-chloro phenoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic trans-prostadienoic acid acid7 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(2,4- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(2,4-dic hloro- dichlorophenoxy)-17,20-tetranor- phenoxy)-17,20-tetranor-5-cis,13-trans-prosta- 5-cis,13-trans-prostadienoic dienoic acid acid8 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-p-bromo- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-p-bromop henoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic trans-prostadienoic acid acid9 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-p-fluoro- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-p-fluoro phenoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic trans-prostadienoic acid acid10 dl-9.alpha.,11.alpha.,15.alpha./.beta.-trihydroxy-16-p- dl-11.alpha.,15.alpha./.beta.-dihydroxy-9-oxo-16-p -methylphenoxy- methylphenoxy-17,20-tetranor-5- 17,20-tetranor-5-cis,13-trans-prostadienoic cis,13-trans-prostadienoic acid acid11 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-m- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-m-methyl phenoxy- methylphenoxy-17,20-tetranor-5- 17,20-tetranor-5-cis,13-trans-prostadienoic cis,13-trans-prostadienoic acid acid12 dl-9.alpha.,11.alpha.,15.alpha./.beta.-trihydroxy-16-p-t- dl-11.alpha.,15.alpha./.beta.-dihydroxy-9-oxo-16-p -t-butyl- butylphenoxy-17,20-tetranor-5- phenoxy-17,20-tetranor-5-cis,13-trans-prosta- cis,13-trans-prostadienoic acid dienoic acid13 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-p-tri- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-p-triflu oromethyl- fluoromethylphenoxy-17,20-tetranor- phenoxy-17,20-tetranor-5-cis,13-trans-prosta- 5-cis,13-trans-prostadienoic dienoic acid acid14 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-p- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-p-methox yphenoxy- methoxyphenoxy-17,20-tetranor- 17,20-tetranor-5-cis,13-trans-prostadienoic cis,13-trans-prostadienoic acid acid15 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-o- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-o-methox yphenoxy- methoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic trans-prostadienoic acid acid16 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-m-fluoro- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-m-fluoro phenoxy- phenoxy-17,20-tetranor-5-cis,13-trans- 17,20-tetranor-5-cis,13-trans-prostadienoic prostadienoic acid acid17 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-o-fluoro- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-o-fluoro phenoxy- phenoxy-17,20-tetranor-5-cis,13-trans- 17,20-tetranor-5-cis,13-trans-prostadienoic prostadienoic acid acid18 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(3,4- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(3,4-dic hloro- dichlorophenoxy)-17,20-tetranor- phenoxy)-17,20-tetranor-5-cis,13-trans-prosta- 5-cis,13-trans-prostadienoic acid dienoic acid19 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(2,5- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(2,5-dic hloro- dichlorophenoxy)-17,20-tetranor-5- phenoxy)-17,20-tetranor-5-cis,13-trans-prosta- cis,13-trans-prostadienoic acid dienoic acid20 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-o-methyl- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-o-methyl phenoxy- phenoxy-17,20-tetranor-5-cis,13-trans- 17,20-tetranor-5-cis,13-trans-prostadienoic acid prostadienoic acid21 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16(2,3-dime thyl- 16-(2,3-dimethylphenoxy)-17,20- phenoxy)-17,20-tetranor-5-cis,13-trans-prosta- tetranor-5-cis,13-trans-prosta- dienoic acid dienoic acid22 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(3,5- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(3,5-dim ethyl- dimethylphenoxy)-17,20-tetranor- phenoxy)-17,20-tetranor-5-cis,13-trans-prosta- 5-cis,13-trans-prostadienoic acid dienoic acid23 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(2-chloro- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(2-chlor o-4- 4-methylphenoxy)-17,20-tetranor-5- methylphenoxy)-17,20-tetranor-5-cis,13-trans- cis,13-trans-prostadienoic acid prostadienoic acid24 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-m-dimethyl- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-M-dimeth ylamino- aminophenoxy-17,20-tetranor-5-cis, phenoxy-17,20-tetranor-5-cis,13-trans-prosta- 13-trans-prostadienoic acid dienoic acid25 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(1- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(1-napht hyloxy)- naphthyloxy)-17,20-tetranor-5- 17,20-tetranor-5-cis,13-trans-prostadienoic cis,13-trans-prostadienoic acid acid26 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(4-chloro- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(4-chlor o-1- 1-naphthyloxy)-17,20-tetranor-5- naphthyloxy)-17,20-tetranor-5-cis,13-trans- cis,13-trans-prostadienoic acid prostadienoic acid27 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(6- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(6-methy l-2- methyl-2-naphthyloxy)-17,20-tetranor- naphthyloxy)-17,20-tetranor-5-cis,13-trans- 5-cis,13-trans-prostadienoic acid prostadienoic acid28 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(6- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(6-metho xy-2- methoxy-2-naphthyloxy)-17,20-tetra- napthyloxy)-17,20-tetranor-5-cis,13-trans- nor-5-cis,13-trans-prostadienoic prostadienoic acid acid29 dl-9.alpha.,11.alpha.,15-trihydroxy-16-(2,3-di- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(2,3-dic hloro- chloro)-17,20-tetranor-5-cis-13- phenoxy)-17,20-tetranor-5-cis,13-trans-prosta- trans-prostadienoic acid dienoic acid30 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(2,6-di- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(2,6-dic hloro- chlorophenoxy)-17,20-tetranor-5-cis, phenoxy)-17,20-tetranor-5-cis,13-trans-prosta- 13-trans-prostadienoic acid dienoic acid31 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(3,5- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(3,5-dic hloro- dichlorophenoxy)-17,20-tetranor- phenoxy)-17,20-tetranor-5-cis,13-trans-prosta- 5-cis,13-trans-prostadienoic acid dienoic acid32 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(4-chloro- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(4-chlor o-3-methyl- 3-methylphenoxy)-17,20-tetranor-5- phenoxy)-17,20-tetranor-5-cis,13-trans-prosta- cis,13-trans-prostadienoic acid dienoic acid33 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-m-methoxy- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-m-methox yphenoxy-17, phenoxy-17,20-tetranor-5-cis,13- 20-tetranor-5-cis,13-trans-prostadienoic acid trans-prostadienoic acid34 dl-9.alpha.,11.alpha.,15.alpha./.beta.-trihydroxy-16-(1- dl-11.alpha.,15.alpha./.beta.-dihydroxy-9-oxo-16-( 1-chloro-2- chloro-2-naphthyloxy)-17,20-tetra- naphthyloxy)-17,20-tetranor-5-cis,13-trans- nor-5-cis,13-trans-prostadienoic prostadienoic acid acid35 dl-9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-(5,6,7- dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(5,6,7,8 -tetra- 8-tetrahydro-2-naphthyloxy)-17,20- hydro-2-naphthyloxy)-17,20-tetranor-5-cis,13- tetranor-5-cis,13-trans-prosta- trans-prostadienoic acid dienoic acid36 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-benzyloxy- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-benzyloxy -17,20- 17,20-tetranor-5-cis,13-trans-prosta- tetranor-5-cis,13-trans-prostadienoic acid dienoic acid37 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-(2-naph- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-(2-naphth yloxy)- thyloxy)-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic trans-prostadienoic acid acid38 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-p-chloro- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-p-chlorop henoxy- phenoxy-17,20-tetranor-5-cis,13-trans- 17,20-tetranor-5-cis,13-trans-prostadienoic acid prostadienoic acid39 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-m-chloro- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-m-chlorop henoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic acid trans-prostadienoic acid40 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-o-chloro- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-o-chlorop henoxy- phenoxy-17,20-tetranor-5-cis,13-trans- 17,20-tetranor-5-cis,13-trans-prostadienoic acid prostadienoic acid41 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-(2,4- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-(2,4-dich loro- dichlorophenoxy)-17,20-tetranor- phenoxy-17,20-tetranor-5-cis,13-trans-prosta- 5-cis,13-trans-prostadienoic acid dienoic acid42 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-p-flouro- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-p-fluorop henoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic trans-prostadienoic acid acid43 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-m-methyl- dl-11.alpha.,15.beta.-trihydroxy-9-oxo-16-m-methyl phenoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic acid trans-prostadienoic acid44 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-p-tri- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-p-trifluo romethyl- fluoromethylphenoxy-17,20-tetranor- phenoxy-17,20-tetranor-5-cis,13-trans-prosta- 5-cis,13-trans-prostadienoic acid dienoic acid45 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-p-methoxy- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-p-methoxy phenoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic acid trans-prostadienoic acid46 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-o-methoxy- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-o-methoxy phenoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic acid trans-prostadienoic acid47 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-m-fluoro- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-m-fluorop henoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic acid trans-prostadienoic acid48 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-o-fluoro- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-o-fluorop henoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic acid trans-prostadienoic acid49 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-o-methyl- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-o-methylp henoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic acid trans-prostadienoic acid50 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-m-dimethyl- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-m-dimethy lamino- aminophenoxy-17,20-tetranor-5-cis,13- phenoxy-17,20-tetranor-5-cis,13-trans-prosta- trans-prostadienoic acid dienoic acid51 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-(1-naphth- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-(1-naphth yloxy)- yloxy)-17,20-tetranor-5-cis,13-trans- 17,20-tetranor-5-cis,13-trans-prostadienoic prostadienoic acid acid52 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-(6- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-(6-methox y-2- methoxy-2-naphthyloxy)-17,20-tetra- naphthyloxy)-17,20-tetranor-5-cis,13-trans- nor-5-cis,13-trans-prostadienoic prostadienoic acid acid53 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-(2,3-di- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-(2,3-dich loro- chlorophenoxy)-17,20-tetranor-5-cis, phenoxy-17,20-tetranor-5-cis,13-trans-prosta- 13-trans-prostadienoic acid54 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-(3,5- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-(3,5-dich loro- dichlorophenoxy)-17,20-tetranor-5- phenoxy)-17,20-tetranor-5-cis,13-trans-prosta- cis,13-trans-prostadienoic acid dienoic acid55 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-m-methoxy- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-m-methoxy phenoxy- phenoxy-17,20-tetranor-5-cis,13- 17,20-tetranor-5-cis,13-trans-prostadienoic acid trans-prostadienoic acid56 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-(5,6,7,8- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-(5,6,7,8- tetra- tetrahydro-2-naphthyloxy)-17,20- hydro-2-naphthyloxy)-17,20-tetranor-5-cis, tetranor-5-cis,13-trans-prostadienoic 13-trans-prostadienoic acid acid57 dl-9.alpha.,11.alpha.,15.beta.-trihydroxy-16-phenoxy- dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-phenoxy- 17,20-tetranor-5-cis,13-trans- 17,20-tetranor-5-cis,13-trans-prostadienoic prostadienoic acid acid__________________________________________________________________________

EXAMPLE 58

Preparation of dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-phenoxy-17,20-tetranor-13-trans-prostenoic acid by hydrogenation of dl-11.alpha.,15.alpha.-dihydro-9-oxo-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid (Example 1)

A solution of 110 mg. of dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid (Example 1) in 0.5 ml. acetone and 0.5 ml. benzene is purged with argon and 11 mg. of tris(triphenylphosphine)rhodium chloride is added. This mixture is stirred under hydrogen at 20-30 psi for 6 hours, or until a TLC (using silver nitrate impregnated silica plate) indicates the absence of any prostadienoic acid. The solvents are removed in vacuo and the oily residue is dissolved in 2 ml. methanol and poured into 10 ml. of 0.2 M sodium phosphate buffer. The mixture is extracted twice with toluene. The aqueous layers are acidified to pH 3 with 2 M citric acid, saturated with sodium chloride, and extracted twice with ether. The extracts are dried with magnesium sulfate and concentrated in vacuo to give 100 mg. of an oil.

This oil is chromatographed on acid washed silica gel to give 40 mg. of dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-phenoxy-17,20-tetranor-13-trans-prostenoic acid; .lambda.max. 3400, 1740-1710, 975 cm.sup.-1.

EXAMPLES 59-65

Treatment of the E.sub.2 compounds of the following table by the method of Example 58 is productive of the E.sub.1 compound of the table.

TABLE 2______________________________________Ex- E.sub.2ample Compound E.sub.1 Compound______________________________________59 Example 10 dl-11.alpha.,15.alpha./.beta.-dihydroxy-9-oxo-16-p-methyl- phenoxy-17,20-tetranor-13-trans-prostenoic acid60 Example 11 dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-m-methyl- phenoxy-17,20-tetranor-13-trans-prostenoic acid62 Example 22 dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-(3,5-di- methylphenoxy)-17,20-tetranor-13-trans- prostenoic acid62 Example 46 dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-o-methoxy- phenoxy-17,20-tetranor-13-trans-prostenoic acid63 Example 20 dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-o-methyl- phenoxy-17,20-tetranor-13-trans-prostenoic acid64 Example 45 dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-p-methoxy- phenoxy-17,20-tetranor-13-trans-prostenoic acid65 Example 50 dl-11.alpha.,15.beta.-dihydroxy-9-oxo-16-m-dimethyl- aminophenoxy-17,20-tetranor-13-trans- prostenoic acid______________________________________

EXAMPLE 66

Preparation of dl-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis-10,13-trans-prostatrienoic acid

A solution of 80 mg. of dl-11.alpha.,15.alpha.-dihydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis-13-trans-prostadienoic acid (Example 1) in 5 ml. of 0.5 N hydrochloric acid in 1:1 water-tetrahydrofuran for 60 hours at 25.degree. C.

The solution is diluted with 100 ml. of benzene and 50 ml. of brine is added. The organic solution is concentrated in vacuo to afford the oily product; .lambda.max: 3400, 1710, 975 cm.sup.-1, .lambda.max: 217 nm (.epsilon.=9000).

EXAMPLES 67-129

The prostaglandin E compound of the table, when submitted to the reaction conditions of Example 66 gives the prostaglandin A product of the table.

TABLE 3__________________________________________________________________________Example Starting E Compound Product A Compound__________________________________________________________________________67 Example 2 dl-15.alpha.-hydroxy-9-oxo-16-benzyloxy-17,20-tetranor- 5-cis,10,13-trans-prostatrienoic acid68 Example 3 dl-15.alpha.-hydroxy-9-oxo-16-(2-naphthyloxy)-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid69 Example 4 dl-15.alpha.-hydroxy-9-oxo-16-p-chlorophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid70 Example 5 dl-15.alpha.-hydroxy-9-oxo-16-o-chlorophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid71 Example 6 dl-15.alpha.-hydroxy-9-oxo-16-o-chlorophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid72 Example 7 dl-15.alpha.-hydroxy-9-oxo-16-(2,4-dichlorophenoxy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid73 Example 8 dl-15.alpha.-hydroxy-9-oxo-16-p-bromophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid74 Example 9 dl-15.alpha.-hydroxy-9-oxo-16-p-fluorophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid75 Example 10 dl-15.alpha./.beta.-hydroxy-9-oxo-16-p-methylphenoxy-17,20 - tetranor-5-cis,10,13-trans-prostatrienoic acid76 Example 11 dl-15.alpha.-hydroxy-9-oxo-16-m-methylphenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid77 Example 12 dl-15.alpha./.beta.-hydroxy-9-oxo-16-p-t-butylphenoxy-17,2 0- tetranor-5-cis,10,13-trans-prostatrienoic acid78 Example 13 dl-15.alpha.-hydroxy-9-oxo-16-p-trifluoromethylphenoxy- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid79 Example 14 dl-15.alpha.-hydroxy-9-oxo-16-p-methoxyphenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid80 Example 15 dl-15.alpha.-hydroxy-9-oxo-16-o-methoxyphenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid81 Example 16 dl-15.alpha.-hydroxy-9-oxo-16-m-fluorophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid82 Example 17 dl-15.alpha.-hydroxy-9-oxo-16-o-fluorophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid83 Example 18 dl-15.alpha.-hydroxy-9-oxo-16-(3,4-dichlorophenoxy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid84 Example 19 dl-15.alpha.-hydroxy-9-oxo-16-(2,5-dichlorophenoxy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid85 Example 20 dl-15.alpha.-hydroxy-9-oxo-16-o-methylphenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid86 Example 21 dl-15.alpha.-hydroxy-9-oxo-16-(2,3-dimethylphenoxy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid87 Example 22 dl-15.alpha.-hydroxy-9-oxo-16-(3,5-dimethylphenoxy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid88 Example 23 dl-15.alpha.-hydroxy-9-oxo-16-(2-chloro-4-methylphenoxy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid89 Example 24 dl-15.alpha.-hydroxy-9-oxo-16-m-dimethylaminophenoxy- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid90 Example 25 dl-15.alpha.-hydroxy-9-oxo-16-(1-naphthyloxy)-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid91 Example 26 dl-15.alpha.-hydroxy-9-oxo-16-(4-chloro-1-naphthyloxy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid92 Example 27 dl-15.alpha.-hydroxy-9-oxo-16-(6-methyl-2-naphthyloxy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid93 Example 28 dl-15.alpha.-hydroxy-9-oxo-16-(6-methoxy-2-naphthyloxy- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid94 Example 29 dl-15.alpha.-hydroxy-9-oxo-16-(2,3-dichlorophenoxy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid95 Example 30 dl-15.alpha.-hydroxy-9-oxo-16-(2,6-dichlorophenoxy)-17, 20-tetranor-5-cis,10,13-trans-prostatrienoic acid96 Example 31 dl-15.alpha.-hydroxy-9-oxo-16-(3,5-dichlorophenoxy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid97 Example 32 dl-15.alpha.-hydroxy-9-oxo-16-(4-chloro-3-methylphenoxy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid98 Example 33 dl-15.alpha.-hydroxy-9-oxo-16-m-methoxyphenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid99 Example 34 dl-15.alpha./.beta.-hydroxy-9-oxo-16-(1-chloro-2-naphthylo xy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid100 Example 35 dl-15.alpha.-hydroxy-9-oxo-16-(5,6,7,8-tetrahydro-2- naphthyloxy)-17,20-tetranor-5-cis,10,13-trans- prostatrienoic acid101 Example 36 dl-15.beta.-hydroxy-9-oxo-16-benzyloxy-17,20-tetranor- 5-cis,10,13-trans-prostatrienoic acid102 Example 37 dl-15.beta.-hydroxy-9-oxo-16-(2-naphthyloxy)-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid103 Example 38 dl-15.alpha.-hydroxy-9-oxo-16-p-chlorophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid104 Example 39 dl-15.beta.-hydroxy-9-oxo-16-m-chlorophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid105 Example 40 dl-15.beta.-hydroxy-9-oxo-16-o-chlorophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid106 Example 41 dl-15.beta.-hydroxy-9-oxo-16-(2,4-dichlorophenoxy)- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid107 Example 42 dl-15.beta.-hydroxy-9-oxo-16-p-fluorophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid108 Example 43 dl-15.beta.-hydroxy-9-oxo-16-m-methylphenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid109 Example 44 dl-15.beta.-hydroxy-9-oxo-16-p-trifluoromethylphenoxy- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid110 Example 45 dl-15.beta.-hydroxy-9-oxo-16-p-methoxyphenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid111 Example 46 dl-15.beta.-hydroxy-9-oxo-16-o-methoxyphenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid112 Example 47 dl-15.beta.-hydroxy-9-oxo-16-m-fluorophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid113 Example 48 dl-15.beta.-hydroxy-9-oxo-16-o-fluorophenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid114 Example 49 dl-15.beta.-hydroxy-9-oxo-16-o-methylphenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid115 Example 50 dl-15.beta.-hydroxy-9-oxo-16-m-dimethylaminophenoxy- 17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid116 Example 51 dl-15.beta.-hydroxy-9-oxo-16-(1-naphthyloxy)-17,20-tetra- nor-5-cis,10,13-trans-prostatrienoic acid117 Example 52 dl-15.beta.-hydroxy-9-oxo-16-(6-methoxy-2-naphthyloxy)-17, 20-tetranor-5-cis,10,13-trans-prostatrienoic acid118 Example 53 dl-15.beta.-hydroxy-9-oxo-16-(2,3-dichlorophenoxy)-17, 20-tetranor-5-cis,10,13-trans-prostatrienoic acid119 Example 54 dl-15.beta.-hydroxy-9-oxo-16-(3,5-dichlorophenoxy)-17, 20-tetranor-5-cis,10,13-trans-prostatrienoic acid120 Example 55 dl-15.beta.-hydroxy-9-oxo-16-m-methoxyphenoxy-17,20- tetranor-5-cis,10,13-trans-prostatrienoic acid121 Example 56 dl-15.beta.-hydroxy-9-oxo-16-(5,6,7,8-tetrahydro-2- naphthyloxy)-17,20-tetranor-5-cis,10,13-trans- prostatrienoic acid122 Example 57 dl-15.beta.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor- 5-cis,10,13-trans-prostatrienoic acid123 Example 58 dl-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor- 10,13-trans-prostadienoic acid124 Example 60 dl-15.alpha.-hydroxy-9-oxo-16-m-methylphenoxy-17,20- tetranor-10,13-trans-prostadienoic acid125 Example 61 dl-15.alpha.-hydroxy-9-oxo-16-(3,5-dimethylphenoxy)- 17,20-tetranor-10,13-trans-prostadienoic acid126 Example 62 dl-15.beta.-hydroxy-9-oxo-16-o-methoxyphenoxy-17,20- tetranor-10,13-trans-prostadienoic acid127 Example 63 dl-15.alpha.-hydroxy-9-oxo-16-o-methylphenoxy-17,20- tetranor-10,13-trans-prostadienoic acid128 Example 64 dl-15.beta.-hydroxy-9-oxo-16-p-methoxyphenoxy-17,20- tetranor-10,13-trans-prostadienoic acid129 Example 65 dl-15.beta.-hydroxy-9-oxo-16-m-dimethylaminophenoxy- 17,20-tetranor-10,13-trans-prostadienoic acid129a Example 59 dl-11.alpha.,15.alpha. /.beta.-dihydroxy-9-oxo-16-p-methy lphenoxy- 17,20-tetranor-10,13-trans-prostadienoic__________________________________________________________________________ acid

EXAMPLE 130

Preparation of dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid

150 mg. of dl-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid (Example 66) in 10 ml. of ether is esterified with excess diazomethane in ether. Evaporation of the ether gives dl-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid methyl ester.

The crude methyl ester is dissolved in 10 ml. of benzene and 7 ml. of a 1 N solution of acetic anhydride-pyridine in benzene is added. After 24 hours 5 ml. more of 1 N acetic anhydride-piperidine is added and stirred. After an additional 24 hours, 5 ml. more of 1 N acetic anhydride-pyridine is added and stirred 72 hours or until TLC indicates no starting material present. The volume of the reaction is reduced to 10 ml. in vacuo on a rotary evaporator. The reaction product is chromatographed on acid washed silica-gel with ethyl acetate-benzene to provide dl-15.alpha.-acetoxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,10,13-trans-prostatrienoic acid methyl ester as an oil.

The crude methyl ester is dissolved in 3 ml. of ethanol at 0.degree. C. and is treated dropwise with a cold solution of 230 mg. of sodium borohydride in 3 ml. of ethanol containing 0.3 ml. of water. After 15 minutes, 0.25 ml. of acetic acid and 10 ml. of water is added, and the mixture is extracted with 50 ml. of methylene chloride. The organic extract is washed with sodium bicarbonate, dried with magnesium sulfate, and concentrated in vacuo to give an oil.

The crude oil is dissolved in 8 ml. of acetone and cooled to -5.degree. C. Then 0.3 ml. of Jones chromic oxide mixture is added slowly and after 15 minutes 0.1 ml. of isopropanol is added.

After 5 minutes the solution is diluted with 25 ml. of methylene chloride and washed with 20 ml. of water. The methylene chloride is dried with magnesium sulfate and concentrated in vacuo to give the crude mixture as an oil.

The oil is purified on acid washed silica-gel using benzene-ethyl acetate to give dl-15.alpha.-acetoxy-11-deoxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid methyl ester as an oil.

To 50 mg. of the methyl ester in 2 ml. of methanol is added 1 ml. of 2.5 N aqueous sodium hydroxide. After stirring for 8 hours, the solution is acidified with 30% aqueous sodium dihydrogen phosphate, saturated with sodium chloride, and extracted with ether. The ether extracts are dried with magnesium sulfate and concentrated in vacuo to give dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid; 3400, 1735, 1710, 975 cm.sup.-1.

EXAMPLES 131-194

Treatment of the A type compounds of the table by the method of Example 130 is productive of the 11-deoxy compounds of the table.

TABLE 4__________________________________________________________________________ StartingExample Prostaglandin A 11-Deoxy Product__________________________________________________________________________131 Example 67 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-benzyloxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid132 Example 68 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(2-naphthyloxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid133 Example 69 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-p-chlorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid134 Example 70 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-m-chlorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid135 Example 71 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-o-chlorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid136 Example 72 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(2,4-dichlorophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid137 Example 73 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-p-bromophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid138 Example 74 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-p-fluorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid139 Example 75 dl-11-deoxy-15.alpha./.beta.-hydroxy-9-oxo-16-p-methylphenoxy - 17,20-tetranor-5-cis,13-trans-prostadienoic acid140 Example 76 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-m-methylphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid141 Example 77 dl-11-deoxy-15.alpha./.beta.-hydroxy-9-oxo-16-p-t-butylphenox y- 17,20-tetranor-5-cis,13-trans-prostadienoic acid142 Example 78 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-p-trifluoromethyl- phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid143 Example 79 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-p-methoxyphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid144 Example 80 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-o-methoxyphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid145 Example 81 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-m-fluorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid146 Example 82 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-o-fluorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid147 Example 83 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(3,4-dichlorophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid148 Example 84 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(2,5-dichlorophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid149 Example 85 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-o-methylphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid150 Example 86 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(2,3-dimethyl- phenoxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid151 Example 87 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(3,5-dimethyl- phenoxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid152 Example 88 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(2-chloro-4-methyl- phenoxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid153 Example 89 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-m-dimethylaminophenoxy - 17,20-tetranor-5-cis,13-trans-prostadienoic acid154 Example 90 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(1-naphthyloxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid155 Example 91 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(4-chloro-1-naphthylox y)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid156 Example 92 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(6-methyl-2-naphthylox y)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid157 Example 93 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(6-methoxy-2-naphth- yloxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid158 Example 94 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(2,3-dichlorophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid159 Example 95 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(2,6-dichlorophenoxy)- 7 17,20-tetranor-5-cis,13-trans-prostadienoic acid160 Example 96 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(3,5-dichlorophenoxy)- 1 17,20-tetranor-5-cis,13-trans-prostadienoic acid161 Example 97 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(4-chloro-3-methyl- phenoxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid162 Example 98 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-m-methoxyphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid163 Example 99 dl-11-deoxy-15.alpha./-hydroxy-9-oxo-16-(1-chloro-2-naphthyl- oxy)17,20-tetranor-5-cis,13-trans-prostadienoic acid164 Example 100 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(5,6,7,8-tetrahydro- 2-naphthyloxy)-17,20-tetranor-5-cis,13-trans-prosta- dienoic acid165 Example 101 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-benzyloxy-17,20-tetra- nor-5-cis,13-trans-prostadienoic acid166 Example 102 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-(2-naphthyloxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid167 Example 103 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-p-chlorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid168 Example 104 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-m-chlorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid169 Example 105 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-o-chlorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid170 Example 106 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-p-fluorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid172 Example 109 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-m-methylphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid173 Example 109 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-p-trifluoromethyl- phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid174 Example 110 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-p-methoxyphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid175 Example 111 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-m-methoxyphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid176 Example 112 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-m-fluorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid177 Example 113 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-o-fluorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid178 Example 114 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-o-methylphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid179 Example 115 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-m-dimethylaminophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid180 Example 116 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-(1-naphthyloxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid181 Example 117 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-(6-methoxy-2-naphthyl- oxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid182 Example 118 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-(2,3-dichlorophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid183 Example 119 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-(3,5-dichlorophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienic acid184 Example 120 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-m-methoxyphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid185 Example 121 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-(5,6,7,8-tetrahydro- 2-naphthyloxy)-17,20-tetranor-5-cis,13-trans- prostadienoic acid186 Example 122 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-phenoxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid187 Example 123 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20- tetranor-13-trans-prostenoic acid188 Example 129a dl-11-deoxy-15.alpha./.beta.-hydroxy-9-oxo-16-p-methylphenoxy - 17,20-tetranor-13-trans-prostenoic acid189 Example 124 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-m-methylphenoxy- 17,20-tetranor-13-trans-prostenoic acid190 Example 125 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(3,5-dimethylphenoxy)- O 17,20-tetranor-13-trans-prostenoic acid191 Example 126 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-o-methoxyphenoxy- 17,20-tetranor-13-trans-prostenoic acid192 Example 127 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-o-methylphenoxy- 17,20-tetranor-13-trans-prostenoic acid193 Example 128 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-p-methoxyphenoxy- 17,20-tetranor-13-trans-prostenoic acid194 Example 129 dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-m-dimethylamino- phenoxy-17,20-tetranor-13-trans-prostenoic__________________________________________________________________________ acid

EXAMPLE 195

Preparation of dl-11-deoxy-9-oxo-15.alpha.-hydroxy-16-phenoxy-17,20-tetranor-prostanoic acid

A solution of 900 mg. of dl-11-deoxy-9-oxo-15.alpha.-hydroxy-16-phenoxy-17,20-tetranor-13-trans-prostenoic acid (Example 187) in 1 ml. of acetone and 1 ml. of benzene was purged with nitrogen and 0.1 gm. of tris(triphenylphosphine)rhodium chloride is added. The mixture is shaken under 20-30 pounds of hydrogen for 12 hours. The mixture is diluted with 50 ml. of 5% aqueous sodium carbonate and extracted with 10 ml. of toluene. The aqueous solution is acidified to pH 4 with 2 N aqueous hydrochloric acid saturated with sodium chloride, and extracted twice with 50 ml. of ether. The ether is dried with magnesium sulfate and concentrated in vacuo to give dl-11-deoxy-9-oxo-16-phenoxy-17,20-tetranorprostanoic acid; max. 3400, 1735 cm.sup.-1.

EXAMPLES 196-202

Hydrogenation of the E.sub.1 compounds of the following table by the procedure of Example 195 is productive of the 13-dihydro compounds of the table.

TABLE 5______________________________________ Starting 13-trans-Ex- proste-ample noic acid Product Prostanoic Acid______________________________________196 Example dl-11-deoxy-15.alpha./.beta.-hydroxy-9-oxo-16-p-methyl- 188 phenoxy-17,20-tetranor-prostanoic acid197 Example dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-m-methyl- 189 phenoxy-17,20-tetranor-prostanoic acid198 Example dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-(3,5-di- 190 methylphenoxy)-17,20-tetranor-prostanoic acid199 Example dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-O--meth- 191 oxyphenoxy-17,20-tetranor-prostanoic acid200 Example dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-O--methyl- 192 phenoxy-17,20-tetranor-prostanoic acid201 Example dl-11-deoxy-15.beta. -hydroxy-9-oxo-16-p-methoxy- 193 phenoxy-17,20-tetranor-prostanoic acid202 Example dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-m-dimethyl- 194 aminophenoxy-17,20-tetranor-prostanoic acid

EXAMPLE 203

Preparation of dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid

To 5 ml. of a -78.degree. C. solution of 1 M lithium-tri-sec-butylborohydride in tetrahydrofuran is added slowly a cold solution of 600 mg. of dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid in 5 ml. of tetrahydrofuran. After 20 minutes at -78.degree. C., 2 ml. of 2.5 N aqueous sodium hydroxide is added and the solution is stirred in a 30.degree. C. bath for 40 minutes. The solution is diluted with 10 ml. of water and extracted three times with 20 ml. of ether.

The aqueous solution is acidified to pH 4 with 6 N hydrochloric acid, saturated with sodium chloride and extracted twice with 50 ml. of ether. The ether extracts are combined, dried with magnesium sulfate and concentrated in vacuo to give dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid; .lambda. max. 3400, 1710, 975 cm.sup.-1.

EXAMPLES 204-272

Treatment of the 9-oxo compounds of the following table by the method of Example 203 is productive of the 9.alpha.-hydroxy compounds of the table.

TABLE 6__________________________________________________________________________Example 9-Oxo Compound__________________________________________________________________________ 9.alpha.-Hydroxy Product204 Example 131 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-benzyl-17,20-tet ranor- 5-cis,13-trans-prostadienoic acid205 Example 132 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(2-naphthyloxy)- O 17,20-tetranor-5-cis,13-trans-prostadienoic acid206 Example 133 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-p-chlorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid207 Example 134 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-m-chlorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid208 Example 135 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-o-chlorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid209 Example 136 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(2,4-dichlorophe noxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid210 Example 137 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-p-bromophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid211 Example 138 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-p-fluorophenoxy- N 17,20-tetranor-5-cis,13-trans-prostadienoic acid212 Example 139 dl-11-deoxy-9.alpha.,15.alpha./.beta.-dihydroxy-16-p-methylp henoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid213 Example 140 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-m-methylphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid214 Example 141 dl-11-deoxy-9.alpha.,15.alpha./.beta.-dihydroxy-16-p-t-butyl phenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid215 Example 142 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-p-trifluoromethy l- phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid216 Example 143 dl-11-deoxy-9.alpha.,15.alpha.-dehydroxy-16-p-methoxyphenoxy - 17,20-tetranor-5-cis,13-trans-prostadienoic acid217 Example 144 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-o-methoxyphenoxy - 17,20-tetranor-5-cis,13-trans-prostadienoic acid218 Example 145 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-m-fluorophenoxy- N 17,20-tetranor-5-cis,13-trans-prostadienoic acid219 Example 146 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-o-fluorophenoxy- O 17,20-tetranor-5-cis,13-trans-prostadienoic acid220 Example 147 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(3,4-dichlorophe noxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid221 Example 148 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(2,5-dichlorophe noxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid222 Example 149 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-o-methylphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid223 Example 150 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(2,5-dimethylphe noxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid224 Example 151 dl-11-deoxy-11.alpha.,15.alpha.-dihydroxy-16-(3,5-dimethylph enoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid225 Example 152 dl-11-deoxy-11.alpha.,15.alpha.-dihydroxy-16-(2-chloro-4-met hyl- phenoxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid226 Example 153 dl-11-deoxy-11.alpha.,15.alpha.-dihydroxy-16-m-dimethylamino - phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid227 Example 154 dl-11-deoxy-11.alpha.,15.alpha.-dihydroxy-16-(1-naphthyloxy) -17, 20-tetranor-5-cis,13-trans-prostadienoic acid228 Example 155 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(4-chloro-1-naph thyl- oxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid229 Example 156 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(6-methyl-2-naph thyl- oxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid230 Example 157 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(6-methoxy-2-nap hthyl- oxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid231 Example 158 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(2,3-dichlorophe noxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid232 Example 159 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(2,6-dichlorophe noxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid 9.alpha.-Compound233 Example 160 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(3,5-dichlorophe noxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid234 Example 161 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(4-chloro-3-meth yl- phenoxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid235 Example 162 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-m-methoxyphenoxy -17,20- tetranor-5-cis,13-trans-prostadienoic acid236 Example 163 dl-11-deoxy-9.alpha.,15.alpha./.beta.-dihydroxy-16-(1-chloro -2-naphthyl- oxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid237 Example 164 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(5,6,7,8-tetrahy dro- 2-naphthyloxy)-17,20-tetranor-5-cis,13-trans-prosta- dienoic acid238 Example 165 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-benzyloxy-17,20-t etra- nor-5-cis,13-trans-prostadienoic acid239 Example 166 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-(2-naphthyloxy)-1 7,20- tetranor-5-cis,13-trans-prostadienoic acid240 Example 167 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-p-chlorophenoxy-1 7,20- tetranor-5-cis,13-trans-prostadienoic acid241 Example 168 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-m-chlorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid242 Example 169 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-o-chlorophenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid243 Example 170 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-(2,4-dichlorophen oxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid244 Example 171 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-p-fluorophenoxy- B 17,20-tetranor-5-cis,13-trans-prostadienoic acid245 Example 172 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-m-methylphenoxy- S 17,20-tetranor-5-cis,13-trans-prostadienoic acid246 Example 173 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-p-trifluoromethyl - phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid247 Example 174 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-p-methoxyphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid248 Example 175 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-o-methoxyphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid249 Example 176 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-m-fluorophenoxy-1 7,20- tetranor-5-cis,13-trans-prostadienoic acid250 Example 177 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-o-fluorophenoxy-1 7,20- tetranor-5-cis,13-trans-prostadienoic acid251 Example 178 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-o-methylphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid252 Example 179 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-m-dimethylamino- phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid253 Example 180 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-(1-naphthyloxy)-1 7,20- tetranor-5-cis,13-trans-prostadienoic acid254 Example 181 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-(6-methoxy-2-naph thyl- oxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid255 Example 182 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-(2,3-dichlorophen oxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid256 Example 183 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-(3,5-dichlorophen oxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid 257A Example 184 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-m-methoxyphenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid 257B Example 185 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-(5,6,7,8-tetrahyd ro- 2-naphthyloxy)-17,20-tetranor-5-cis,13-trans- prostadienoic acid 257C Example 186 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-phenoxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid258 Example 187 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-phenoxy-17,20- tetranor-13-trans-prostenoic acid259 Example 189 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-m-methylphenoxy- 17,20-tetranor-13-trans-prostenoic acid260 Example 190 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(3,5-dimethylphe noxy)- 17,20-tetranor-13-trans-prostenoic acid261 Example 191 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-o-methoxyphenoxy- 0 17,20-tetranor-13-trans-prostenoic acid262 Example 192 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-o-methylphenoxy- 0 17,20-tetranor-13-trans-prostenoic acid263 Example 193 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-p-methoxyphenoxy- 9 17,20-tetranor-13-trans-prostenoic acid264 Example 194 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-m-dimethylamino- phenoxy-17,20-tetranor-13-trans-prostenoic acid265 Example 195 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-phenoxy-17,20- tetranor-prostanoic acid266 Example 196 dl-11-deoxy-9.alpha.,15.alpha./.beta.-dihydroxy-16-p-methylp henoxy- 17,20-tetranor-13-trans-prostenoic acid267 Example 197 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-m-methylphenoxy- 17,20-tetranor-13-trans-prostenoic acid268 Example 198 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-(3,5-dimethylphe noxy)- 17,20-tetranor-13-trans-prostenoic acid269 Example 199 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-o-methoxyphenoxy- 17,20-tetranor-13-trans-prostenoic acid270 Example 200 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-o-methylphenoxy- 17,20-tetranor-13-trans-prostenoic acid271 Example 201 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-p-methoxyphenoxy- 17,20-tetranor-13-trans-prostenoic acid272 Example 202 dl-11-deoxy-9.alpha.,15.beta.-dihydroxy-16-m-dimethylaminoph enoxy- 17,20-tetranor-13-trans-prostenoic acid__________________________________________________________________________

EXAMPLE 273

Preparation of dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid and separation of the 9.alpha. and 9.beta. components

To a 0.degree. C. solution of 500 mg. of dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid in 10 ml. of ethanol is added 100 mg. of sodium borohydride. After 30 minutes the solution is diluted with 50 ml. of saturated aqueous ammonium chloride and extracted twice with 50 ml. of ether. The ether is dried with magnesium sulfate and concentrated in vacuo to give a nearly 1:1 mixture of the 9.alpha. and 9.beta. diols.

The diol mixture is placed onto a dry column of acid washed silica and developed with ethyl acetate-benzene.

The high Rf compound is isolated and is dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid. The lower Rf, more polar isomer, is dl-11-deoxy-9.beta.,15.alpha.-dihydroxy-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadiencic acid; the infrared spectrum of each is indentical: 3400, 1700, 975 cm.sup.-1.

EXAMPLES 274-345

Treatment of the 9-oxo compounds of the following table with sodium borohydride followed by separation by the method of Example 273 is productive of the separated 9,15-diols of the table.

TABLE 7__________________________________________________________________________Example 9-Oxo Compound Product 9,15-Diols__________________________________________________________________________274 Example 131 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-benzyloxy -17,20- tetranor-5-cis,13-trans-prostadienoic acid275 Example 132 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(2-naphth yloxy)-17,20- tetranor-5-cis,13-trans-prostadienoic acid276 Example 133 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-p-chlorop henoxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid277 Example 134 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-m-chlorop henoxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid278 Example 135 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-o-chlorop henoxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid279 Example 136 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(2,4-dich lorophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid280 Example 137 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-p-bromoph enoxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid281 Example 138 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-p-fluorop henoxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid282 Example 139 dl-11-deoxy-9.alpha./.beta.,15.alpha./.beta.-dihydroxy-16-p- methylphenoxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid283 Example 140 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-m-methylphenoxy- 17,20- tetranor-5-cis,13-trans-prostadienoic acid284 Example 141 dl-11-deoxy-9.alpha.,15.alpha./.beta.-dihydroxy-16-p-t-butyl phenoxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid285 Example 142 dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-p-trifluoromethy l- phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid286 Example 143 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-p-methoxy phenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid287 Example 144 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-o-methoxy phenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid288 Example 145 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-m-fluorop henoxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid289 Example 146 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-o-fluorop henoxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid290 Example 147 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(3,4-dich lorophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid291 Example 148 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(2,5-dich lorophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid292 Example 149 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-o-methylp henoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid293 Example 150 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(2,3-dime thylphenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid294 Example 151 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(3,5-dime thylphenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid295 Example 152 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(2-chloro -4-methyl- phenoxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid296 Example 153 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-m-dimethy lamino- phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid297 Example 154 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(1-naphth yloxy)-17,20- tetranor-5-cis,13-trans-prostadienoic acid298 Example 155 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(4-chloro -1-naphthyl- oxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid299 Example 156 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(6-methyl -2-naphthyl- oxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid300 Example 157 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(6-methox y-2-naphthyl- oxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid301 Example 158 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(2,3-dich lorophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid302 Example 159 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(2,6-dich lorophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid303 Example 160 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(3,5-dich lorophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid304 Example 161 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(4-chloro -3-methyl- phenoxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid305 Example 162 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-m-methoxy phenoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid306 Example 163 dl-11-deoxy-9.alpha./.beta.,15.alpha./.beta.-dihydroxy-16-(1 -chloro-2- naphthyloxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid307 Example 164 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(5,6,7,8- tetranor-2- naphthyloxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid308 Example 165 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-benzyloxy- 17,20-tetra- nor-5-cis,13-trans-prostadienoic acid309 Example 166 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-(2-naphthy loxy)-17,20- tetranor-5-cis,13-trans-prostadienoic acid310 Example 167 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-p-chloroph enoxy-17,20- tetranor-5-cis,13-trans-prostadienoic acid311 Example 168 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-m-chloroph enoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid312 Example 169 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-o-chloroph enoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid313 Example 170 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-(2,4-dichl orophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid314 Example 171 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-p-fluoroph enoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid315 Example 172 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-m-methylph enoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid316 Example 173 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-p-trifluor omethyl- phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid317 Example 174 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-p-methoxyp henoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid318 Example 175 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-o-methoxyp henoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid319 Example 176 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-m-fluoroph enoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid320 Example 177 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-o-fluoroph enoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid321 Example 178 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-o-methylph enoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid322 Example 179 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-m-dimethyl amino- phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid323 Example 180 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-(1-naphthy loxy)-17,20- tetranor-5-cis,13-trans-prostadienoic acid324 Example 181 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-(6-methoxy -2-naphthyl- oxy)-17,20-tetranor-5-cis,13-trans-prostadienoic acid325 Example 182 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-(2,3-dichl orophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid326 Example 183 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-(3,5-dichl orophenoxy)- 17,20-tetranor-5-cis,13-trans-prostadienoic acid327 Example 184 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-m-methoxyp henoxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid328 Example 185 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-(5,6,7,8-t etrahydro- 2-naphthyloxy-17,20-tetranor-5-cis,13-trans-prosta- dienoic acid329 Example 186 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-phenoxy-17 ,20- tetranor-5-cis,13-trans-prostadienoic acid330 Example 187 dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20- tetranor-13-trans-prostenoic acid331 Example 188 dl-11-deoxy-9.alpha./.beta.,15.alpha./.beta.-dihydroxy-16-p- methylphenoxy- 17,20-tetranor-13-trans-prostenoic acid332 Example 189 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-m-methylp henoxy- 17,20-tetranor-13-trans-prostenoic acid333 Example 190 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(3,5-dime thyl- phenoxy)-17,20-tetranor-13-trans-prostenoic acid334 Example 191 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-o-methoxyp henoxy- 17,20-tetranor-13-trans-prostenoic acid335 Example 192 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-o-methylp henoxy- 17,20-tetranor-13-trans-prostenoic acid336 Example 193 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-p-methoxyp henoxy- 17,20-tetranor-13-trans-prostenoic acid337 Example 194 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-m-dimethyl amino- phenoxy-17,20-tetranor-13-trans-prostenoic acid338 Example 195 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-phenoxy- 0 17,20-tetranor-prostanoic acid339 Example 196 dl-11-deoxy-9.alpha./.beta.,15.alpha./.beta.-dihydroxy-16-p- methylphenoxy- 17,20-tetranor-prostanoic acid340 Example 197 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-m-methylp henoxy- 17,20-tetranor-prostanoic acid341 Example 198 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-(3,5-dime thyl- phenoxy)-17,20-tetranor-prostanoic acid342 Example 199 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-o-methoxyp henoxy- 17,20-tetranor-prostanoic acid343 Example 200 dl-11-deoxy-9.alpha./.beta.,15.alpha.-dihydroxy-16-o-methylp henoxy- 17,20-tetranor-prostanoic acid344 Example 201 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-p-methoxyp henoxy- 17,20-tetranor-prostanoic acid345 Example 202 dl-11-deoxy-9.alpha./.beta.,15.beta.-dihydroxy-16-m-dimethyl amino- phenoxy-17,20-tetranor-prostanoic acid__________________________________________________________________________

EXAMPLE 346

Preparation of dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid methyl ester

150 mg. of dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid is dissolved in 10 ml. of ether, cooled to 0.degree. C. and an ethereal diazomethane solution is added until a persistant yellow color is observed. The excess diazomethane and solvent is removed under a stream of argon to provide the subject compound: .lambda. max. 3400, 1740, 975 cm.sup.-1.

EXAMPLES 347-356

The compounds of the following table when esterified with the appropriate diazoalkane by the procedure of Example 346 provide the product prostaglandin esters of the following table.

TABLE 8__________________________________________________________________________Example Starting acid Diazoalkane Product Prostaglandin Ester__________________________________________________________________________347 Example 131 diazoethane dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-benzyloxy- 17,20-tetranor-5-cis,13-trans-prostadienoic acid ethyl ester348 Example 134 diazopropane dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-m-chloro- phenoxy-17,20-tetranor-5-cis,13-trans-prosta- dienoic acid propyl ester349 Example 138 diazobutane dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-p-fluoro- phenoxy-17,20-tetranor-5-cis,13-trans-prosta- dienoic acid butyl ester350 Example 142 diazopentane dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-p-trifluoro- methylphenoxy-17,20-tetranor-5-cis,13-trans- prostadienoic acid pentyl ester351 Example 163 diazohexane dl-11-deoxy-15.alpha./.beta.-hydroxy-9-oxo-16-(1-chloro - 2-naphthyloxy)-17,20-tetranor-5-cis,13- trans-prostadienoic acid hexyl ester352 Example 172 diasoheptane dl-11-deoxy-15.beta.-hydroxy-9-oxo-16-m-methyl- phenoxy-17,20-tetranor-5-cis,13-trans-prosta- dienoic acid heptyl ester353 Example 188 diazooctane dl-11-deoxy-15.alpha./.beta.-hydroxy-9-oxo-16-p-methyl- O phenoxy-17,20-tetranor-13-trans-prostenoic acid octyl ester354 Example 202 diazononane dl-11-deoxy-9-oxo-15.alpha.-hydroxy-16-m-dinethyl- aminophenoxy-17,20-tetranor-prostanoic acid nonyl ester355 Example 207 diazodecane dl-11-deoxy-9.alpha.,15.alpha.-dihydroxy-16-m-chloro- phenoxy-17,20-tetranor-5-cis,13-trans-prosta- dienoic acid decyl ester356 Example 316 diazomethane dl-11-deoxy-9.beta.-15.beta.-dihydroxy-16-p-trifluoro- u methylphenoxy-17,20-tetranor-5-cis,13-trans- prostadienoic acid methyl ester__________________________________________________________________________

Claims

1. A compound selected from the group consisting of an optically active compound of the formula: ##STR13## and a racemic compound of that formula and the mirror image thereof; wherein R.sub.1 is hydroxy or alkoxy having from 1 to 12 carbon atoms; R.sub.2 is phenyl, naphthyl, 5,6,7,8-tetrahydronaphthyl, or 5,6,7,8-tetrahydronaphthyl substituted with one or two groups selected from the group consisting of halogen, lower alkyl, lower alkoxy and n is an integer from 2 to 4, inclusive; X is a divalent moiety selected from the group consisting of those of the formulae: ##STR14## Y is a divalent moiety of the formulae: ##STR15## the moiety of -C.sub.5 -C.sub.6 - is ethylene or cis-vinylene and the moiety -C.sub.13 -C.sub.14 - is ethylene or trans-vinylene with the proviso that when -C.sub.5 -C.sub.6 - is cis-vinylene then -C.sub.13 -C.sub.14 - must be trans-vinylene; and the non-toxic cationic salts thereof when R.sub.1 is hydroxy.

2. The enantiomer according to claim 1 wherein ##STR16## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is o-fluorophenoxy, and n is three; l-9-oxo-15.alpha.-hydroxy-16-o-fluorophenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

3. The racemate according to claim 1 wherein ##STR17## C.sub.5 -C.sub.6 l is cis-vinylene, C.sub.13 -C.sub.14 l is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is o-fluorophenoxy, and n is three; dl-9-oxo-15.alpha.-hydroxy-16-o-fluorophenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

4. The enantiomer according to claim 1 wherein ##STR18## C.sub.5 -C.sub.16 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is p-fluorophenoxy, and n is three, l-9-oxo-15.beta.-hydroxy-16-p-fluorophenoxy-17,20-5-cis,13-trans-tetranor-prostadienoic acid.

5. The racemate according to claim 1 wherein ##STR19## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is p-fluorophenoxy, and n is three, dl-9-oxo-15.beta.-hydroxy-16-p-fluorophenoxy-17,20-5-cis,13-trans-tetranor-prostadienoic acid.

6. The enantiomer according to claim 1 wherein ##STR20## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is n-butyl, R.sub.2 is p-fluorophenoxy, and n is three; l-butyl 9-oxo-15.alpha.-hydroxy-16-p-fluorophenoxy-17,20-tetranor-5-cis,13-trans-prostadienoate.

7. The racemate according to claim 1 wherein ##STR21## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is n-butyl, R.sub.2 is p-fluorophenoxy, and n is three; dl-butyl 9-oxo-15.alpha.-hydroxy-16-p-fluorophenoxy-17,20-tetranor-5-cis,13-trans-prostadienoate.

8. The enantiomer according to claim 1 wherein ##STR22## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is o-chlorophenoxy, and n is three; l-9-oxo-15.alpha.-hydroxy-16-o-chlorophenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

9. The racemate according to claim 1 wherein ##STR23## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is o-chlorophenoxy, and n is three; dl-9-oxo-15.alpha.-hydroxy-16-o-chlorophenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

10. The enantiomer according to claim 1 wherein ##STR24## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is m-chlorophenoxy, and n is three;l-9-oxo-15.alpha.-hydroxy-16-m-chlorophenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

11. The racemate according to claim 1 wherein ##STR25## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is m-chlorophenoxy, and n is three; dl-9-oxo-15.alpha.-hydroxy-16-m-chlorophenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

12. The enantiomer according to claim 1 wherein ##STR26## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is n-propoxy, R.sub.2 is m-chlorophenoxy, and n is three; l-propyl 9-oxo-15.alpha.-hydroxy-5-cis,13-trans-16-m-chlorophenoxy-17,20-tetranor-prostadienoate.

13. The racemate according to claim 1 wherein ##STR27## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is n-propoxy, R.sub.2 is m-chlorophenoxy, and n is three; dl-propyl 9-oxo-15.alpha.-hydroxy-5-cis,13-trans-16-m-chlorophenoxy-17,20-tetranor-prostadienoate.

14. The enantiomer according to claim 1 wherein ##STR28## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is m-chlorophenoxy, and n is three; l-9-oxo-15.beta.-hydroxy-16-m-chlorophenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

15. The racemate according to claim 1 wherein ##STR29## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is m-chlorophenoxy, and n is three; dl-9-oxo-15.beta.-hydroxy-16-m-chlorophenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

16. The enantiomer according to claim 1 wherein ##STR30## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is p-chlorophenoxy, and n is three; l-9-oxo-15.alpha.-hydroxy-16-p-chlorophenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

17. The racemate according to claim 1 wherein ##STR31## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is p-chlorophenoxy, and n is three; dl-9-oxo-15.alpha.-hydroxy-16-p-chlorophenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

18. The enantiomer according to claim 1 wherein ##STR32## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is p-trifluoromethylphenoxy, and n is three; l-9-oxo-15.alpha.-hydroxy-16-p-trifluoromethylphenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

19. The racemate according to claim 1 wherein ##STR33## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is p-trifluoromethylphenoxy, and n is three; dl-9-oxo-15.alpha.-hydroxy-16-p-trifluoromethylphenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

20. The enantiomer according to claim 1 wherein ##STR34## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is n-pentyloxy, R.sub.2 is p-trifluoromethylphenoxy, and n is three; l-pentyl 9-oxo-15.alpha.-hydroxy-16-p-trifluoromethylphenoxy-17,20-tetranor-5-cis,13-trans-prostadienoate.

21. The racemate according to claim 1 wherein ##STR35## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is n-pentyloxy, R.sub.2 is p-trifluoromethylphenoxy, and n is three; dl-pentyl 9-oxo-15.alpha.-hydroxy-16-p-trifluoromethylphenoxy-17,20-tetranor-5-cis,13-trans-prostadienoate.

22. The enantiomer according to claim 1 wherein ##STR36## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 is m-trifluoromethylphenoxy, and n is three; l-9-oxo-15.beta.-hydroxy-16-m-trifluoromethylphenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

23. The racemate according to claim 1 wherein ##STR37## C.sub.5 -C.sub.6 is cis-vinylene, C.sub.13 -C.sub.14 is trans-vinylene, R.sub.1 is hydroxy, R.sub.2 L is m-trifluoromethylphenoxy, and n is three; dl- 9-oxo-15.beta.-hydroxy-16-m-trifluoromethylphenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid.

24. The compound according to claim 1 wherein n is 3, C.sub.13 -C.sub.14 is trans-vinylene, and C.sub.6 -C.sub.5 is cis-vinylene.

25. The compound according to claim 24 wherein C.sub.6 -C.sub.5 is ethylene and C.sub.13 -C.sub.14 is trans-vinylene.

26. The compound according to claim 24 wherein C.sub.6 -C.sub.5 is cis-vinylene and C.sub.13 -C.sub.14 is trans-vinylene.

27. The compound according to claim 1 wherein R.sub.2 is phenyl substituted with one or two groups selected from the group consisting of halogen, lower alkyl and lower alkoxy.

28. The compound according to claim 27 wherein R.sub.1 is hydroxy.

29. The compound according to claim 27 wherein R.sub.1 is alkoxy having 1 to 12 carbon atoms.

30. The compound according to claim 1 wherein n is 3.

31. The compound according to claim 27 wherein n is 3.

32. The racemic compound according to claim 26, dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tretanor-5-cis,13-trans prostadienoic acid and the enantiomer l-11-deoxy-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,13-transprostadienoic acid.

33. The racemic compound according to claim 26, dl-11-deoxy-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid methyl ester, and the enantiomer l-11-deoxy-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-5-cis,13-trans-prostadienoic acid methyl ester.

34. A compound selected from the group consisting of an optically active compound of the formula ##STR38## and a racemic compound of that formula and the mirror image thereof, wherein R.sub.1 is hydroxy or alkoxy having from 1 to 12 carbon atoms; R.sub.2 is phenyl, benzyl, naphthyl, or 5,6,7,8-tetrahydronaphthyl or R.sub.2 is phenyl, benzyl, naphthyl or 5,6,7,8-tetrahydronaphthyl wherein each of said substituents includes one or more substituents selected from the group consisting of halogen, lower alkyl or lower alkoxy; n is an integer from 2 to 4, X is a divalent moiety selected from the group consisting of those of the formulae: ##STR39## C.sub.6 -C.sub.5 is ethylene or trans-vinylene and C.sub.13 -C.sub.14 is ethylene or trans-vinylene, with a proviso that when C.sub.6 -C.sub.5 is cis-vinylene then C.sub.13 -C.sub.14 must be trans-vinylene; and the non-toxic cationic salts thereof when R is hydroxy.

35. The compound according to claim 34 wherein R.sub.2 is selected from the group consisting of phenyl and phenyl substituted with one or two substituent groups selected from the group consisting of halogen, lower alkyl and lower alkoxy.

36. The compound according to claim 34 wherein R.sub.2 is phenyl.

37. The compound according to claims 35 or 36 wherein C.sub.6 -C.sub.5 is ethylene and C.sub.13 -C.sub.14 is trans-vinylene.

38. The compound according to claim 37 wherein n is 3.

39. The compound according to claim 34 wherein R.sub.2 is selected from the group consisting of p-methylphenyl, m-methylphenyl, 3,5-dimethylphenyl, o-methoxyphenoxy, o-methylphenyl, and o-ethylphenyl.

40. The racemate according to claim 37, dl-15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-13-trans-prostenoic acid or its mirror image.

41. The enantiomer according to claim 37, 15.alpha.-hydroxy-9-oxo-16-phenoxy-17,20-tetranor-13-trans-prostenoic acid or its mirror image.

42. The enantiomer according to claim 37, 15.alpha.-hydroxy-9-oxo-16-p-methylphenoxy-17,20-tetranor-13-trans-prostenoic acid or its mirror image.

43. The racemate according to claim 37, dl-15.alpha.-hydroxy-9-oxo-16-p-methylphenoxy-17,20-tetranor-13-trans-prostenoic acid.

44. The enantiomer according to claim 37, 15.alpha.-hydroxy-9-oxo-16-m-methylphenoxy-17,20-tetranor-13-trans-prostenoic acid or its mirror image.

45. The racemate according to claim 37, dl-15.alpha.-hydroxy-9-oxo-16-m-methylphenoxy-17,20-tetranor-13-trans-prostenoic acid.

46. The enantiomer according to claim 37, 15.alpha.-hydroxy-9-oxo-16-(3,5-dimethylphenoxy)-17,20-tetranor-13-trans-prostenoic acid or its mirror image.

47. The racemate according to claim 37, dl-15.alpha.-hydroxy-9-oxo-16-(3,5-dimethylphenoxy)-17,20-tetranor-13-trans-prostenoic acid.

48. The enantiomer according to claim 37, 15.beta.-hydroxy-9-oxo-16-o-methyoxyphenoxy-17,20-tetranor-13-trans-prostenoic acid or its mirror image.

49. The racemate according to claim 37, dl-15.beta.-hydroxy-9-oxo-16-o-methoxyphenoxy-17,20-tetranor-13-trans-prostenoic acid.

50. The enantiomer according to claim 37, 15.alpha.-hydroxy-9-oxo-16-o-methylphenoxy-17,20-tetranor-13-trans-acid or its mirror image.

51. The racemate according to claim 37, dl-15-.alpha.-hydroxy-9-oxo-16-o-ethylphenoxy-17,20-tetranor-13-trans-prostenoic acid.

52. The enantiomer according to claim 37, 15.beta.-hydroxy-9-oxo-16-p-methoxyphenoxy-17,20-tetranor-13-trans-prostenoic acid or its mirror image.

53. The racemate according to claim 37, dl-15.beta.-hydroxy-9-oxo-16-p-methoxyphenoxy-17,20-tetranor-13-trans-prostenoic acid.

54. The enantiomer according to claim 37, 15.beta.-hydroxy-9-oxo-16-m-dimethylamino-phenoxy-17,20-tetranor-13-trans-prostenoic acid or its mirror image.

55. The racemate according to claim 37, dl-15.beta.-hydroxy-9-oxo-16-m-dimethylamino-phenoxy-17,20-tetranor-13-trans-prostenoic acid.

56. The enantiomer according to claim 37, 15.alpha.-hydroxy-9-oxo-16-p-methylphenoxy-17,20-tetranor-13-trans-prostenoic acid octyl ester or its mirror image.

57. The racemate according to claim 37, dl-15.alpha.-hydroxy-9-oxo-16-p-methylphenoxy-17,20-tetranor-13-trans-prostenoic acid octyl ester.