IE45505B1 - 1,5-disubstituted-2-pyrrolidones - Google Patents

Abstract

A series of 1,5-disubstitued-2-pyrrolidones which are prostaglandin-like in character and the processes for making them are disclosed. [CA1077948A]

Description

This invention relates to a novel series of l,5-disubstitu.ted-2pyrrolidones which are prostaglandin-like in chemical structure and biological character, and synthetic intermediates employed in these processes.

The Cjq unsaturated fatty acids, known as prostaglandins, form a large family of .naturally-occurring compounds. These molecules may have as many as five asymmetric centers and are present in and evoke response from a diversity of biological tissues. An example of a particular species of the prostaglandin E genera is PGEg pictured below.

According to the notation usually employed to describe the stereochemistry of prostaglandins, a heavy solid line represents the β configuration which is defined as a bond coming up out of the plane of the paper and toward the reader. In a like manner, a dotted or hashed line represents the a configuration which is defined as a bond going behind the plane of the paper and away from the reader. Thus, the configuration of the prostaglandin Eg, P^c~ tured above, is a at carbon atom 8 and β at carbon atom 12. [S. BergstrBm, et al., Acta. Chem. Scand.( 16, 501 (1962)]. - 2 45505 By the same terminology, a wavy line represents a mixture of the two forms a and B. Thus, a 2-pyrrolidone of the structure: - 3 By reference to the pyrrolidone of structure II and prostaglandin E„ ’ i. shown above, a stereochemical comparison can be made between the two sets of compounds. The stereochemistry at positions 12 and 15 is the same in both types but that at position 8 is different. That is, the configuration of the C8-C7 bond of the prostaglandin E is a, but that of the N8-C7 bond is in the plane of the paper according to the representation of the drawing above. Another way to represent the above two examples which will develop a better appreciation of this difference in configuration is the edge-on drawing below: pyrrolidone where A and B stand for the two side chains of the examples. Here the illus10 tration depicts the eclipsing of the A-C8 bond with the C12-H bond and the eclipsing of the C12-B bond with the 08-H bond in the ease of the prostaglandin E and the bisecting position of the A-N8 bond with respect to the dihedral angle formed by B-C12-H in the case of the pyrrolidone. This difference In conformation is a result of the planarity generated by the amide moiety of the pyrrolidone. (Basic Principles of Organic Chemistry, J. D. Roberts and M. C. Caserio, W. A. Benjamin, New York, 1985, p. 874] A systematic name for a l,5-disubstituted-2-pyrrolidone of the structure: - 4 4S50S is l-(6'-carboxyhexyl)-58-(3a-hydroxyoct-l-enyl)-2~pyrrolidone and it also can ba named as a derivative of 11-desoxyprostaglandin E^{ that is, 8-aza-ll· desoxy PGE^.

The corresponding 8-aza-ll-desoxy PGE^ compound has the structure: where the single bond between C2’ and C3' has been replaced by a double bond. The corresponding 8-aza-ll-desoxy PGEq compound has the structure: where the double bond between Cl and C2 has been replaced by a single bond. - 5 45505 The above pyrrolidones have several centers of asymmetry, and can exist is the racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e. the dextrorotatory (D) and levorotatory (L) forms. As drawn above, each pyrrolidone structure represents the particular optically active form or enantiomer which is derivable in part from D -glutamic acid. The mirror image or optical antipode of each of the above structures represents the other enantiomer of that pyrrolidone and is derivable in part from L -glutamic acid.

For instance, the optical antipode of l-(6'-carboxyhexyl)-56-(3a10 hydroxyOct-l-enyl)-2-pyrrolidone is drawn as: and is called l-(6'-carboxyhexyl)-5a-(3i3-hydroxyact-l-enyl)-2-pyrrolidone.

The racemic form of the above pyrrolidone contains equal numbers of a particular enantiomer and its mirror image. When reference to the racemate of a compound contained herein is intended, the symbol rac will precede the compound's name. This term will then mean and is properly represented by an equimolar mixture of the D and the 1 or enantiomeric forms.

A pair of optical isomers which are optical antipodes or enantiomers are related through inversion of the absolute configuration at all of their centers of asymmetry. Contrastingly, when the relationship is an inversion of absolute configuration at one ox more but not all of the centers of asymmetry, che pair of isomers are epimers or diastereomers. For instance, 1—(6 carboxyhexyl)-5(S- (3e-hydrexyoct-l .-enyl) -2-pyrrolidone and 1- (6 ’-carboxy- 6 45S05 hexyl)-5a-(3a-hydroxyOct-l-enyl)-2-pyrrolidone are diastereomers related by an inversion of configuration about the C5 atom and are shown respectively as: It is a fact that chemical experimentation on either member of an 5 enantiomeric pair or upon a mixture of the two will produce the same and identical results.

As pointed out earlier, substitution of a nitrogen for the carbon at C8 causes a dramatic change in the three dimensional conformation o'f the resultant prostaglandin. Because structure is related to biological activity and often a subtle change in structure such as a conformational change will have a profound effect upon the biological activity, such molecular modification of prostaglandins by substitution of heteroatoms has been investigated recently. Most compounds are attempts at investigation of heteroatom substitutions at the C9 and Cll prostaglandin positions and include such examples as 9-oxaprostaglandins (I. Vlattas, Tetrahedron Let.,4455 (1974)]; ll-oxtyrostaglandins £a. Fougerousse Tetrahedron Let., 3983 (1974)] and S. Hanessian et al., Tetrahedron Let., 3983 (1974) and 9-thiaprostaglandins [I. Vlattas, Tetrahedron Let,, 4459 (1974)]..

Two 8-aza-ll-desOxy prostaglandin E’s with the natural ut-side chain, that is, compounds with the aza substitution at C8 of ll-desoxy pros20 taglandin Eg and Eg have also been reported in the literature (G. Bolliger and J. M. Muchowski, Tetrahedron Let., 2931 (1975) (Aug. 1975); and J. W.

Bruin, et al., Tetrahedron Let., 4599 (1975)). These examples of pyrrolidone - 7 43303 compounds are outside of the scope of the present invention which presents a higher order of complexity and molecular variation at the Cl prostaglandin position and in the ω-side chain. Relatively little-biological activity is reported for these literature examples and they can be contrasted in form and in molecular complexity with the novel compounds of the present invention.

The natural prostaglandins and many of their derivatives such as the esters, acylates, and pharmacologically acceptable salts, are extremely potent inducers’ of'various biological responses [D. E. Wilson, Arch. Intern.

Med.,133 (29) (1974)] in tissues composed of smooth muscle such as those of the cardiovascular, pulmonary, gastrointestinal and reproductive systems, in cellular tissues such as those of the central nervous, hematologic, reproductive, gastrointestinal, pulmonary, nephritic, epidermal, cardiovascular and adipose systems and also operate as mediators in the process of homeostasis. With such a wide range of responses, it is apparent that the prostaglandins are involved in basic biological processes of the cell. Indeed, this basic implication of prostaglandins is supported by the fact that they can be found in cellular tissue of almost all animal organisms.

Often on such a cellular level the actions of closely related natural prostaglandins may be opposite. For instance, the effect of FGEj on humanplatelets is enhancement of aggregation while that of PGE^ is inhibition of aggregation.

Such contrasting effects may also be observed at the tissue level.

For instance, in vivo PGEj action on the cardiovascular system of mammals manifests itself by causing hypotension while the in vivo action of PGEja hypertension [J. B. Lee, Arch. Intern. Med., 133 56 (1974)]. However, the ability to predict the biological action of prostaglandin classes based upon such observations is largely illusory at present. For instance, while the cardiovascular actionsof PGE2 and PGF2aare °PP°site as described above, their in vivo or in vitro action on mammalian uterine smooth muscle is the same and is stimulatory (causes contraction) [H. R. Behrman, et al., Arch. Intern. Med., 133 77 (1974)] - 8 4550 5 In the preparation of synthetic pharmaceutical agents, among the principal objects is the development of compounds which are highly selective in their pharmacological activity and which have an increased duration of activity over their naturally occurring relatives. In a series of compounds which is similar to the naturally-occurring prostaglandins, increasing selectivity of a single compound usually Involves the enhancement of one prostaglandin-like physiological effect and the diminution of the others. By Increasing the selectivity, one would alleviate the severe side effects frequently observed following administration of the natural prostaglandins; for example, those gastrointestinal side effects of diarrhea and emesis or cardiovascular side effects when bronchodilator effects are desired. Recent developments directed toward an increase of biological selectivity include the 11-desoxy prostaglandins [Ν. H. Anderson, Arch. Intern. Med., 133, 30 (1974) Review], 2-decarboxy2-(tetrazol-5-yl)-ll-desoxy-15-substituted-m-pentanorprostaglandins (M. R.

Johnson et al., U.S. 3,932,389) where certain modifications are cited as producing selective vasodilator, antiulcer, antifertility, bronchodilator and antihypertensive properties, 16-phenoxy-16-m~tetranor prostaglandins having antifertility activity Patent Specification No. 37602 and l-imide and l-sulfonimide prostaglandins (U.S. 3,954,741). - 9 4 5 S I) S The present invention comprises novel prostaglandin-like compounds which have selective and potent biological activity and which have the structure: and the C5 epimer thereof wherein: ft Q is -COR3, tetrazol-5-yl or II -CNHRZ[; A is a single or cis double bond; B is a single or trans double bond; U is or ; R2 is a-thienyl, phenyl, phenoxy, monosubstituted phenyl and monosubstituted phenoxy, said substituents being chloro, fluoro, phenyl, methoxy, trifluoromethyl or alkyl having from one to three carbon atoms; Rj is hydrogen, alkyl having from one to five carbon atoms, phenyl and £-biphenyl; I? R^ is -CR5 or “SOjRg, said Rg being phenyl or alkyl having from one to five carbon atoms; and the alkali rtetal alkaline earth metal and ammonium salts of those confounds having a carboxylate or betrazol-5-yl group. - 10 4 5 5 0 5 In addition the present invention comprises intermediates which will allow the preparation of the final products above and which have the structure: and the C5 epimer thereof wherein W is -COR^, tetrazol-5-yl, N-(acyloxymethyl,tetrazol-5-yl having from two to five carbon atoms in the acyloxy group, N-(phthalidyl)tetrazol-5-yl and N-(tetrahydropyran-2-yl)tetrazol-5-yl, and A, B, R2 and R3 are each defined as above.

Other intermediates used in the preparation of the compounds of the present invention are described in Patent Specification No. and have the structure: and the C5 epimer thereof wherein W and A are defined as above. - 11 45505 Of interest as agents having selective prostaglandin-like biological activity is the series of pyrrolidones having the structure: cor3 wherein A; B; U; R2 and Of interest also having tie structures: are defined as above and the C5 epimer thereof, in this connection are the series of pyrrolidones wherein A; B; U,‘ Rj and R^ are defined as above and the 05 epimers thereof. 4550S Of special interest in the above connection is the series of compounds represented by the structure wherein A: B,‘ ϋ and R are defined as above, and the 05 epimer thereof.

Another especially'interesting series of compounds which have selective biological activity is represented by the structure: wherein A,’ Β,* V and R2 are defined as above, and the C5 epimer thereof. - 13 45505 Especially preferred for their selective biological activity are: l-(6’-carboxyhexyl)-5B-(3a-hydroxy-4-phenylbut-l-enyl)-2-pyrrolidone and the methyl ester and 5a- epimer thereof/ 1-(6'-carboxy-hex-2'-enyl)-5 B-(3a-hydroxy -4-phenylbut-l-enyl)-2 pyrrolidone and the 5a epimer thereof, 1- (61 -carboxyhexyl)-5S - (3 α-hydroxy-4 -phenylbutyl) -2-pyrrolidone and the 5a epimer thereof, l-C6'-carboxyhexyl)-5B-(3',a-hydroxy-4-phenoxybut-l-enyl)-2-pyrrol idane and the 5a epimer thereof, 1-(6'-carboxyhex-2'-enyl)-56-(3a-hydroxy-4-phenoxybut-l-enyl)-2pyrrolidone and the 5a epimer thereof, l-(6'-carboxyhexyl)-5B“(3a-hydroxy-4-phenoxybutyl)-2-pyrrolidone and the 5a epimer thereof, the compounds wherein 6'-(tetrazol-5-yl) replaces the 6'-carboxy lSf group of each of the above especially preferred compounds, and the compounds wherein a 3B-hydroxy replaces the 3a-hydroxy group of each of the above 6'-carboxy and 6*-(tetrazol-5-yl) compounds.

The pyrrolidone compounds of the present invention of prostamimetics are prepared in an optically active form by six step sequence which attaches the two side chains, the a or top side chain and the m or bottom side chain, to the pyrrolidone ring and starts with a resolved amino acid, D- or L-glutamic acid. It is noted that the choice of the route starting from D- or L-glutamic acid establishes the absolute confirmation of C5 of the 2-pyrrolidone ring and pre-empts the necessity of resolving this position at the end of the synthesis. In the examples and discussion to follow, the D-configuration is shown. The Lconfiguration compounds are prepared by the same sequence from L-glutamic acid.

The synthetic sequence shown by Scheme A illustrates the methods by which the a chain is attached to the 2-pyrrolidone nucleus. It will be noted that the methods prepare in each instance a pyrrolidone intermediate 19 differing only at the C2'-C3' bond. The final products of the present invention are then synthesized from intermediate 19 according to the methods presented in Schemes B, C and D. - 15 15 5 0 5 SCHEME A - a CHAIN ATTACHMENT 45303 A brief summary of the steps in Scheme A is as follows. The first step, marked (a), illustrating the cyclization of D-glutamic acid to methyl Dpyroglutamate and the reduction of the pyroglutamate to 5-D-hydroxy-2-pyrrolidone is known [V. Bruckner et al.. Acta. Chim. Hung. Tomus, 21, 106 (1959)].

The second step (b) is the protection of the hydroxymethyl group with protecting agent T which can be any group suitable for the protection of the hydroxy] against alkylation; for instance, benzyl, dimethyl-t-butyl silyl, acetyl, 1ethoxyethyl, or especially tetrahydropyranyl. Steps (c) and (e) illustrate th' alkylation of the sodium or lithium salt of pyrrolidone 1 by alkylating agents of the formula or XCH^CHCOY)^, respectively, wherein X is Cl, I, or especially Br; W is CO^Ry N-acyloxymethyl)tetrazol-5-yl having from two to five carbon atoms in the acyloxy group, N-(phthalidyl)tetrazol-5-yl, N-(tetrahydropyran-2-yl)tetrazol-5-yl or tetrazol-5-yl; Y is alkyl having from one to three carbon atoms,and A and are defined as above. Step (d) is the removal of protecting group T.the method of which will depend upon the identity of T. Step (f) is the deprotection of the pyrrolidone compound 18 to produce in situ l-(ethan-2'-al)-5~hydroxymetiiyl2-pyrrolidone which can exist in intimate equilibrium with the hemi-acetal compound 5,. Step (g) is a Wittig reaction of the equilibrium mixture contain20 ing bicycloI4,3,0]nonan-5-one 5, with a phosphorane of the structure Ph^P·* CHCCHgJjW wherein W, defined above, is unprotected to produce the corresponding 2-pyrrolidone compound 19 wherein A is a double bond.

The reactions necessary to produce the products of the invention are arranged in order so that no epimerization of the optically active center at C5 will occur. Therefore, by starting with either of the two enantiomers of glutamic acid, the same configuration at the asymmetric centers is preserved in the products. Also by starting with racemic glutamic acid, the racemic or rac products are produced.

The C5 position of the intermediates and products of the present invention will be drawn in the β configuration but the a configuration at the C5 position is applicable also, provided that the starting glutamic acid has the proper configuration.

The first two steps of the reaction sequence are the condensation and esterification of D-glutamic acid to produce the corresponding Dmethyl pyroglutamate of the structure: [E. Hardegger, et al., Helv. Chem. Acta., 38, 312 (1955); E. Segel, J. Am. Chem If Soc., 74, 851 (1952)].

The third, and known, step of the sequence shown in Scheme A as step (a) Is the reduction of the 5-carboxymethyl group of D-methylpyroglutamate to produce 5-D-hydroxymethyl-2-pyrrolidone. This reaction is most conveniently conducted by employing a variation of the method reported by V. Bruckner, et al.[Acta. Chem. Hung. Tomus, 21, 106 (1959)].

The D-methyl pyroglutamate is stirred with lithium borohydride in dry tetrahydrofuran or other ethereal solvent until the reduction is substantially complete. Isolation of the product in the reported manner gives 5-D-hydroxymethyl· 2-pyrrolidone of the structure: Γ ?*CH20H In order to alkylate the amide nitrogen of 5-D-hydroxymethyl-2pyrrolidone, it is appropriate to protect the labile 5-hydroxymethyl hydrogen with the known tetrahydropyranyl group. This protection (Scheme A, step (b)) is most conveniently accomplished by contacting 5-D-hydroxymethyl-2-pyrrolidone with dihydropyran in the presence of an organic acid such as jj-toluene sulfonic acid and in an inert solvent such as methylene chloride, chloroform, tetrahydrofuran or diethoxy ethane. The appropriate temperature range for this reaction is from that of an ice bath to that of refluxing solvent and preferably ambient. After the formation of 5-D-(tetrahydropyran-2'-yloxymethyl)-2-pyrrolidone JL is substantially complete, usually overnight, it is isolated by first removing the organic acid by basic extraction and removing the solvent and any excess dihydrojpyran by vacuum evaporation techniques. The product is most commonly purified f>y column chromatography.

Other protecting agents that can be employed with equal facility include any which will protect the hydroxyl from alkylation. Some examples are benzyl, acetyl, dimethyl-_t-butyl silyl and 1-ethoxyethyl. These protecting agents are readily available and can be attached to the 5-hydroxymethyl group by known methods. Their selection for synthetic purposes will depend upon the protecting group at C7'. For instance, if it is desired to employ N-tetrahydro pyran-2-yl as a protecting group for the acidic hydrogen of a C7’ tetrazol-5yl (W), appropriate C3 hydroxyl protecting groups (T) would be acetyl or dime thy 1-t-butyl silyl. 5 0 5 The l-(alkylated)-2-pyrrolidone compounds (17 and 18 Scheme A) are prepared by a combination of two reactions which are performed upon 5-D-(tetrahydropyran-2'-yloxymethyl)~2-pyrrolidone 2 or any °f its T group analogs. First the sodium or lithium salt of pyrrolidone j. is prepared by contacting a solu5 tion of compound JL in an inert organic solvent such as tetrahydrofuran, diethoxyethane or dioxane with a base such as n-butyl' lithium, phenyl lithium or especially sodium hydride. The appropriate temperature range for this salt formation is ambient to that of refluxing solvent and preferably ambient. All base must be reacted before starting the alkylation which usually requires times of 1 to 4 hours. Then, the desired l-(alkylated)-2-pyrrolidone compounds 17 and 18 are respectively formed by contacting the above prepared lithium or sodium salt of 2-pyrrolidone compound .1 with an alkylating agent of the structure: X W or XCH2CH(0Y)2 wherein X is Cl, X and especially Br, W and A are each defined as above and Y is alkyl having from one to three^carbon atoms. This second part of the alkylation procedure Is usually conducted by addition of a mixture of the alkylating agent in the inert organic solvent previously defined or especially by addition of a mixture of the alkylating.agent in a polar aprotic organic solvent such as dimethylformamide or dimethylacetamide to the above formed mix20 ture of the sodium or lithium salt of pyrrolidone .1 in an inert organic solvent and then by allowing contact between the mixture of alkylating agent and 2pyrrolidone sodium or lithium salt at temperatures of ambient to solvent reflux .τ'» until the alkylation is substantially complete, usually overnight.

Of course, the alkylated 2-pyrrolidone resulting from use of XCH2CH25 (0Y)2can a^so be prepared by. employing XCH2C02Et as the alkylating agent followed by selective conversion of the ester group of the resultant l-(2’-ethyl acetate)-5-(substituted)-2-pyrrolidone to aldehyde. 45503 When there is the possibility of having an acidic’ hydrogen present ίτ W, the alkylation procedure is most conveniently executed by protecting or otherwise removing that acidic hydrogen,. For example, in the case where R^ is hydrogen, the best method is employment of an ester derivative which can then be removed by alkaline hydrolysis at the end of the synthetic sequence. In the case where W is tetrazol-5-yl, the best method 'is replacement of the acidic hydrogen by an acyloxymethyl as defined above, a phthalidyl group (W. v.Daehne J_. Med. Chem., 13, 607 (1970); I. lsaka, et al., Chem. fharm. Bull., 24, 102. (1976)] or a tetrahydropyran-2-yl group. The first two groups for tetrazol-5yl protection will also be removed by alkaline hydrolysis at the end of the synthesis (Scheme B) but the THP group will be removed by acidic hydrolysis.

It will be assumed in the ensuing discussion that the acidic hydrogen of the W group has been protected unless otherwise stated.

The character of the C2'-C3' bond of the 2-pyrrolidone compound 17 obtained from the alkylation step is determined by the nature of A in the alkylating agent The selection of A will also determine the unsaturated or saturated character of the α-side chain of the final product of the synthesis; that is, whether the. final product will be an 8-aza-ll-desoxy FCE^ or an 8-aza-desoxy FGEj.

Obviously, the selection of A only causes a difference in the character of the C2'“C3' bond of the a-side chain and in fact, conversion from pyrrolidone compounds where A is a double bond to those where A is a single bond is possible at the pyrrolidone compound 17 stage of the synthesis. For instance, the 2-pyrrolidone compound 17 with the double bond at A may be converted to the 2-pyrrolidone compound 17 with the single bond at A by hydrogenation over a noble metal catalyst such as palladium on carbon at ambient temperature until 1 equivalent of hydrogen is absorbed. - 22 *5505 Compound 17 A “ double bond Compound 17 A “ single bond In either case, the protecting group T is removed (step d, Scheme A) by methods known to those familiar with the art in anticipation of the formation of the ω-side chain. The resulting 2-pyrrolidone compounds of the structure: Compound 19 wherein tf and A are each defined as above, are then'carried through Schemes B, C and D to produce the novel final products of the present invention. The above 2-pyrrolidone compound 19 can also be prepared by contact ing the hydrolyzed form of the 2-pyrrolidone of the structure: wherein Y and T are defined as above with a phosphorane of the structure: Ph3P-CH(CH2)3W wherein W, defined as above, is unprotected, e.g. C02H or tetrazol-5-yl. The synthesis of the tetrazol-5-yl phosphorane will be found in U.S. 3,953,466.

This subset of reactions, illustrated by steps (f) and (g) of Scheme A, can be executed in the follcwing manner. If the preferred T protecting group, tetrahydropyran-2-yl, is used in compound 18, then acid hydrolysis of compound 18, according to the usual method for acetal re5 moval such as acetic acid in water at ca, 40°C. will cleave both the tetrahydropyran-2-yl and the acetal to form l-(ethan-2'-al)58-hydrctrethyl2-pyrrolidone which can exist in intimate equilibrium with 4-aza-2-hyaroxyl-oxa-bicyclo[4,3,0]nonan-5-one 5.

Nonancne 5 The equilibrium mixture containing hemiaoetal 5 can then be contacted with about 2 equivalents of phosphorane as defined above in a polar aprotic solvent such as dimethylsulfoxide or a mixture of an ethereal and polar aprotic solvent such as tetrahydrofuran and dinethylsulfoxide at tenperatures of 0°C. to 60°, usually overnight, to produce 2-pyrrolidone 19 wherein A is a double bond.

It will be noted that the acidic hydrogen or group W can then be protected as an ester in the case of the carboxylic acid or as an N-acyloxymathyl, N-phthalidyl or N-tetrahydropyran-2-yl group in the case of tetrazol20 5-yl. This 2-pyrrolidone 19 with A as a double bond can, if desired, be converted to 2-pyrrolidone 19 wherein A is a single bond by the hydrogenation method described above.

Several of the final products of the present invention, the 2pyrrolidone ccnpounds 22, carb, and tet., are prepared ty oxidation of the 58-hydroxymethyl group of 2-pyrrolidone 19 and Homer-Wittig reaction of the thus - 24 45505 formed 56-formyl-2-pyrrolidone compound 20 with the sodium or lithium salt of ? 7 a phosphonate of the structure (MeOJ^PCH^CCH^R^ wherein R^ is defined as above followed by reduction of the thus formed 5-(4-substituted-but~l-en-3-onyl) moiety of 2-pyrrolidone 21.

Scheme B illustrates this outlined process, the method of which attaches the ω-chain.

SCHEME Β ω-CHAIN ATTACHMENT oxidation 0 II I (MeO)PCHCCHR2 I reduction 4 5505 The aldehyde 20 is obtained from the 5g-hydroxymethyl-2-pyrrolidone compound 19 by a modification of the Pfitzner Moffatt oxidation [K. E. Pfitzner and Μ. E. Moffatt, J.Am. Chem. Soc.. 87, 5661 (1965)] which avoids contact of the 58-formyl compound 20 with water. For example, stirring a slurry of l-(7'methylheptanato )-5g-hydroxymethyl-2-pyrrolidone or other appropriate 5g-hydrox> methyl-2-pyrrolidone in an inert, hydrocarbon solvent such as toluene, xylene or especially benzene with dimethyl sulfoxide, a weak acid such as acetic acid or especially pyridinium trifluoroacetate and a water soluble diimide such as diethyl carbodiimide or especially dimethylaminopropylethylcarbodiiraide or, if desired, its hydrochloride salt, at temperatures of.O’C. to ambient for 1 to 4 hours, will oxidize the primary alcohol 19 to aldehyde 20.· Alternate methods to achieve oxidation include the usual Pfitzner-Moffatt reaction and oxidation with chromium trioxide-pyridine complex [R. Ratcliffe, et.al., J. Org. Chem.·, 35, 4000 (1970)] although the method of choice is the reaction described above.

The 58-(4-substituted but-1- n-3-onyl)-2-pyrrolidone compound 21 is prepared by contacting the 5g-formyl-ί-pyrrolidone compound 20 with the sodium or lithium salt of a phosphonate of the structure! p » ,,11 (MeOjjPCHjCCHjRj wherein Rj is defined as above in a solution or slurry with an ethereal solvent such as tetrahydrofuran, dimethoxyethane or dioxane at temperatures from 0’ to 50°C. until the reaction is essentially complete, a’s determined by reaction monitoring methods. The isolation of product from this Horner-Wittig reaction, the method of which is known to those familiar with the art, Is accomplished in the usual‘fashion by chromatography. .OtneMmethods include high, pressure liquid chromatography and in some cases fractional recrystallizatidn. The method for the preparation of the phosphonates will be found in U.S. 3,932,389.

AS505 Reduction and, if desired, alkaline or acidic hydrolysis of the 2pyrrolidone compound 21 produces several of the final products of the invention , wherein Q is CO^ or tetrazol-5-yl. The reagent of choice for conducting the reduction is lithium triethylborohydride, but other selective reduction reagents . i which will reduce the ketone but no other groups, e.g. zinc borohydride or sodium borohydride, can be employed with equal facility.. The usual solvents employed ' are ethereal in nature such as tetrahydrofuran and diethyl ether. The temperature selection will he based upon the Activity of the reducing agent and in most cases it is convenient to employ a dry ice/aeetone bath.

Under the usual reaction conditions, the reduction of the but-l-en3-onyl moiety of the pyrrolidone 21 will actually produce'two 2-pyrrolidone compounds 22, which are diastereomers. 3B-hydroxy compound 22b 3a-hydroxy compound 22a Thus, these two compounds, which are separable by the common isolation technique; 15 such as high pressure liquid chromatography, are both prepared by the described manner; and it is assumed that both are indicated even though the o isomer is shown throughout. If the separation of the two diastereomers is not done, then a mixture of the two compounds will result and is indicated as! and is taken to mean a mixture of the a epimer and the S epimec - 28 45505 After isolation of the product of the above reduction reaction in the usual manner, the protecting group on the acidic position of the C7 group W, cai be removed, if'desired, using conditions common for the removal of such groups. For instance, if an alkyl ester was selected as K and the acid is desired, simple alkaline hydrolysis with one equivalent of base at ambient temperature to that of refluxing solvent, usually overnight,· will yield after neutralization the carboxylic acid. In a like manner, the phthalidyl and acyloxymethyl groups can be removed,’but the tetrahydropyran-2-yl (THP) group will be removed with acid such as acetic acid in water or ^-toluene sulfonic acid in methanol at am10 bient temperature to 50° usually overnight.

The products of the present invention wherein A and B are each single bonds, e.g. compound 23 carb, and tet., are prepared by catalytic reduction of the 3-tetrahydropyran-2'-yloxy derivative of 2-pyrrolidone 22 wherein A is a single bond. That sequence is outlined in Scheme C.

Alternatively, the pyrrolidone compounds 23 can be produced by catalytic reduction of the 3’-tetrahydropyran-2'-yloxy derivative of 2-pyrrolidone 22 wherein A is a double bond. In this case, A and B will be reduced to single bonds at the same time. £5505 SCHEME C OH OH carb. tec. 4S505 The tetrahydropyran-2'-yloxy derivative of compound 22 wherein A is a single bond is formed in the sane manner as that described for 5-D-(tetrahydropyran-2-yloxymethyi)-2-pyrrolidone 3.· Then,'hydrogenation over noble metal catalysts such as palladium on carbon or platinum oxide in solvents such as ethyl acetate, methanol or ethanol at ambient to reflux temperatures until 1 equivalent of hydrogen is absorbed followed by.removal of the tetrahydropyran-2-yl group and, if desired, the W protecting group by the usual methods will allow the preparation of the 8-aza-ll-desoxy prostaglandin Εθ compounds 23.

The products of the present invention wherein Q is SnHR^ are prepared 10 from the tetrahydropyran-2'-yloxy derivatives of compounds 22 and 23 having a COgH group at W. That synthetic sequence is outlined in Scheme D wherein Rj is defined as above. These acid derivatives, compounds 24 and 25, are formed according to well-known methods described for imide and sulfonimide preparations from carboxylic acids. The preferred method is that according to the procedure of Speziale and Hurd where the acyl or sulfonyl isocyanate is contacted with the above cited derivatives of compounds 22 and 23 in an inert solvent such as ether or tetrahydrofuran at temperatures of ambient to solvent reflux, usually overnight. See the following: [A. J. Speziale, et.al., J. Org. Chem., 30, 4306 (.1965), C. D. Hurd and A. G. Prapas, J. Org. Chem., 24, 388 (1959); reactions of isocyanates with carboxylic acids in Survey of Organic Synthesis, C. A.Beuhler D. E. Pearson, Wiley Interscience, New York, 1970, N-acylation of amides and imides, J. March, Advanced Organic Chemistry: Reactions, Mechanism and Structure, McGraw-Hill, New York, 1968, p. 340].

There are also several other methods to prepare the products of the present invention wherein Q is CONHR^. The first alternate route comprises treating the 5 -(4-substitutedbut-l-en-3-onyl)-2-pyrrolidone compound 21 wherein W is COOH with an acyl or sulfonyl isocyanate under the conditions described above for the procedure of Speziale and Hurd. The C-15 keto group of resulting aminated or sulfonaminated pyrrolidone intermediate is then reduced to an hydroxyl group using the procedure described for the reduction of pyrrolidone compound 21fP pyrrolidone compound 22.

The second alternate route comprises condensing nonanone compound 5 with a phosphorane of the structure Ph^ P « CONHR^ using the procedure described for the analogous preparation of pyrrolidone 19 from nonanone 5. After optional hydrogena15 tion of the resulting C5-C6 double bond, this route produces a pyrrolidone intermediate of the structure The above pyrrolidone carboxamide intermediate is analogous to pyrrolidone compound 17 and can become carried through the subsequent steps illustrated in Scheme B to prepare the compounds of the present invention wherein Q is CONHR^. '1 S 5 Ο 5 The ester products of the present invention wherein Q is earboalkoxy, earbophenoxy and carbo-para-biphenoxy can be prepared from the corresponding acid products of the present invention wherein Q is COOH by well-known methods of esterifi5 cation including reaction with diazoalkanes of from one to five :arbon atoms, and the reaction of phenol or 2-biphenol with the acid and dicyclohexylcarbodiimide. 505 SCHEME D - IMIDE AND SULFOHIMIDE DERIVATIVES - 34 -53505 In numerous in vivo and in vitro tests it has been demonstrated that the new prostaglandin analogs possess physiological activities of greater selectivity, potency, and duration of action than those exhibited by the natural prostaglandins. These tests include, among others, a test for effect on isolated smooth muscle from guinea pig uterus, inhibition of histamine-induced bronchospasm in the guinea pig, effect on dog blood pressure, inhibition of stressinduced ulceration in the rat, diarrheal effect in the mouse, and inhibition of stimulated gastric acid secretion in rats and dogs.

The physiological responses observed in these tests are useful in determining the utility of the test substance for the treatment of various natural and pathological conditions. Such determined utilities include: vasodilator activity, antihypertensive activity, bronchodilator activity, antifertility activity and antiulcer activity.

The novel 8-aza-ll-desoxy prostaglandins of the instant invention posses highly selective activity profiles compared with the corresponding naturally-occurring prostaglandins and, in many cases, exhibit a longer duration of action. For instance, the novel prostamimetic pyrrolidones of the present invention having the substitutions of aryl (including phenyl, substituted phenyl and β-thienyl) at Jt, and carboxylic acid, carboxylic ester or tetrazol-5-yl at Q possess useful vasodilator activity. Prime examples of the therapeutic importance of these pyrrolidone compounds are the efficacies of 1-® carboxyhexyl)-56-(3-hydroxy-4-phenylbut-l-enyl)-2-pyrrolidone and 1-(6'-carboxyhexyl)-5a-(3-hydroxy-4-phenylbut-l-enyl)-2-pyrrolidone which exhibit hypotensive activity of a similar potency compared with PGE^ itself when administered intravenously to anesthetized dogs according to the procedure of U.S. 3,956,284 At the same time, other activities such as bronchodilation and antiulceration ire greatly diminisned ccnpared to PGEg as measured by the procedure descrioed. in U.S. 3,956,284.

Another outstanding instance of the therapeutic importance of pyrrolidones of the instant invention is the selective anti-ulcer activity of compounds having the substitutions of aryloxy (including ph'enOiy and substituted phenoxy) at and carboxylic acid, carboxylic ester or imide, tetrazol-5-yl or sulfonimide at Q. For example, l-(6'-carboxyhexyl)-56-(3-hydroxy-4-phenoxy but-l-enyl)-2-pyrrolidone displays outstanding .and· selective antisecretory activity when administered orally to dogs.

The new compounds of this invention can be used in a variety of pharmaceutical preparations which contain the compound or a pharmaceutically acceptable salt thereof. They may be administered by a variety of routes which will depend upon the type of ailment and the condition of the individual.

The 8-aza-ll-desoxy-16-aryl-ui-tetranorprostaglandin compounds of the present invention and the epimers thereof are useful vasodilator agents. For treatment of hypertension, these drugs can appropriately be administered as an intravenous injection at doses of about 0.5-10 mg./kg. or preferably in the form of capsules or tablets at doses of 0.005 to 0.5 mg./kg./day.

The 8-aza-ll-desoxy-16-aryloxy~(u-tetranor prostaglandin compounds of the present invention and the epimers thereof are useful anti-ulcer agents: For treatment of peptic ulcer, these drugs may be administered in the form of capsules or tablets at doses of 0.005 to 0.5 mg./kg./day.

Pharmacologically acceptable salts useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

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

Pharmacologically acceptable amine cations are those derived from primary, secondary, or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, triethylamine, ethylamine, dibutylamine, triisopropylanine N-methylhexylaraine, decylamine, dodeeylainine, allylamine, erotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine, 8-phenylethylamine, ethylenediamine, diethylenetriamine, and other aliphatic, cycloaliphatic, and araliphatic amines Containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., 1-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-l-butano], 2-amino-2-ethy 1-1,3-propanediol, 2-amino-2-methyl-l-pr£>panol, tris (hydroxymethyl) aminomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine, N-methylglucamine, M-methylglucosamine, ephedrine, phenylephrine, epinephrine, or procaine.

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

To prepare any of the numerous formulations possible,' various reactioninert diluents, excipients or carriers may be employed. Such substances include for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol and other known carriers for medicaments. If desired, these pharmaceutical compositions may contain auxiliary substances such as preserving agents, wetting agents, stabilizing agents, or other therapeutic agents such as antibiotics.

The following examples are merely illustrative, and in no way limit the scope of the appended claims. The spectral data were obtained on a Varian [Registered Trade Mark) T-60 or an A-6O-NMR, a Perkin-Elmer Grating Infrared Spectrometer and an EKB-9OOO mass spectrometer. The infrared data are given in reciprocal centimeters and the MIR data are given in 6 parts per million using TMS as a standard.

In general, the temperatures of the reactionsdescribed in the exanples When unspecified, will be taken to mean anbient or room temperature which varied frcm 15° to 30°C. - 38 45505 The time requirement of the reactions described in the examples, unless otherwise stated, was determined by monitoring with thin layer chromatography (TLC). The usual TLC system was silica'gel-on glass ( E. Merck Silica Gel plates, E. Merck Dormstadt, W. Germany) with benzene/ether or methanol/' chloroform as eluants and vanillin/ethanol or iodine as developers. [Introduction to Chromatography J. M. Bobbitt, A. E. Schwarting, R. J. Gritter, Van Nostrand-Reinhold, N.Y. 1968]. As a general rule, the reaction in question was deemed essentially complete when the TLC spot representing the critical starting material had disappeared or had quit changing.

The ccmpounds of the present invention will new be described with reference to Examples 5 to 10 and 14 to 16. -The remaining .Examples describe intermediates in the preparation of the ccmpounds of this invention. 45bOS EXAMPLE 1 β- (Tetrahydropyran-2'-yloxymethyl)-2-pyrrolidone 1 Into a flame dried flask under a nitrogen atmosphere was put 2.54 g. (22.1 mmoles) 5-D-hydroxymethylene-2-pyrrolidone, prepared according to the method of V. Bruckner et. al., Acta Chim. Hung. Tomus, 21, 106 (1959), and 50 ml. methylene chloride. To this solution at 0°C to· 5° C was then added 3.72 g. (44.2 mmoles) redistilled dihydropyran and 0.2 g. p-toluenesulfonic (tosic)acid. The solution was then allowed to warm to room temperature and to stir overnight. After dilution of the reaction with 20 ml. ethyl acetate, the solution was extracted with 2x5 ml. saturated sodium bicarbonate solution and 1 x 10 ml. saturated brine. The organic layer was dried with magnesium sulfate, filtered to remove the drying agent, and the solvent was removed in vacuo to give 4.1 g. yellow oil. This oil was chromatographed on a 50 g. column of Merck silica gel packed in chloroform. Elution with IL. chloroform removed less polar impurities. Elution with 22 methanol in chloroform and collection of 10 ml. fractions separated and purified the product. Combination of product fractions and removal of solvent in vacuo gave 3.95 g. of the title compound 1 as a yellow oil, 902 yield. NMR T-60(bCCl3>b.s. 66.60 ppm (IH), m. 64.60 ppm (IH), m. 64,05 20 ’3.25 ppm (5H), m. 62.50 -62.10 ppm, a. 62.00 - 61.40 ppm (10H).

IR(CHC13 solution)3425 , 2980 , 2930 , 2850, 1680, 1250-1200, 1025 nT1 Additionally, the dimethyl-jt-butyl silyl protecting group can he employed in place of the tetrahydropyran-2-yl group by applying the procedure of E. J. Corey, et. al..J, Am. Chem. Soc., 94, 6190 (1974) to 5-D-hydroxymethylene-2-pyrrolidone. - 40 4 55 0 5 EXAMPLE 2 1- (7'_(Ethylheptanato)-58-(tetrahydropyran-2”-yloxymethyi)-2-pyrrolidone 2, Into a flame dried flask containing a nitrogen atmosphere was put 0.725 g. (18.7 mmoles) of 62% sodium hydride dispersion in mineral oil and 10 ml. dry THF. To this mechanically stirred slurry was then slowly added dropwise 3.74 g. (18.7 mmoles) of 5-D-(tetrahydropyran-2-yloxymethyl)-2pyrrolidone 1 in 10 ml. dry THF. After the addition was complete, the thick slurry was stirred for 30 minutes until all hydrogen evolution had ceased.

The alkylation of the sodium salt was then performed.

To this slurry at room temperature was then added dropwise 5.34 g. (22.5 mmoles) of ethyl-7-bromoheptanoate in 15 ml. dry DMF. At the completio of the addition, ca. 15 minutes, the slurry had dissolved and sodium bromide slowly started to precipitate from the solution. The' reaction was stirred overnight, then filtered, and the solvent was removed in vacuo from the filtrate. To the residue was then added 100 ml. ethyl acetate and this organic solution was extracted with 2 x 20 ml. water. After drying the organic layer with magnesium sulfate and filtering it to remove the drying agent, the solvent was removed in vacuo from the filtrate to give a yellow oil which was chromatographed on a 120 g. column of Merck silica gel packed in chloroform. Elution with: (a) 250 ml. of chloroform; (b) 500 ml. ethyl acetate in chloroform; (c) IL. 102 ethyl acetate in chloroform; and automatic collection of 10 ml. fractions allowed the separation and purification of the product. The product fractions were combined and stripped of solvent to yield the title conpound 2 as a colorless oil 3.39 g. 51% yield.

NMR Ϊ-60 (DCClj):M 64.60 ppm (IH), q. 64.17 ppm J “ 8 hz., m, 64.00 - 2.70 ppm (9H), m, 62.6 - 1.4 ppm, t. 61.3 ppm » 8 hz. (23H) IR (HCClj) solution) 2975, 2915, 1840, 1720, 1665, 1450, 1250-1200, 1125, 1025 cm-1.

MS-heated inlet (m/e-2) 356-12, 355-32, 310-172, 240-1002, 194-832.

The foregoing procedure can be adapted to the preparation of pyrrolidones of the structure below by substitution of the appropriate alkylating agent for ethyl-7-bromoheptanoate and optionally by employment of the dimethylt.-butyl silyl analog of pyrrolidone 1. x - -co2c6h5 -c°2ch3 N- (tctrahydropyran-2-yl)tetrazol-5-yl N-(acetyloxymethyl)tetrazol-5-yl A “ single or cis double'bond.

T - THP or dimethyl-jt-butyl silyl 4 5 5 0 5 As stated the l-(substitu:ed)-5£-(tetrahydropyran“2“yloxymethyl or dimethyl-ty butyl siloxy methyl)-2-pyrrolidones can be prepared by substitution of the appro· priate alkylating agent for the ethyl-7-bromoheptanoate. For instance, if 1-(61 carboxymethylhex-2'-enyl)-58-(tetrahydropyran-2-yloxymethyl)-2-pyrrolidone is to be prepare^,the alkylating agent will be methy1-7-bromohept-5-enoate. If 1-(61 1!’'-acetyloxymethyltetrazol-5‘'’-ylhexyl)-56-(tetrahydropyraa-2-yloxynethyl)2-pyrrolidone is to be prepared, the alkylating agent will be 6-bromo-l-(!'acetyloxymethyltetrazol-5'-yl)-n-hexane. l-(2,2-Diethoxyethyl)-56-(tetrahydropyran-2-yloxymethyl)-2pyrrolidone 3. can also be prepared by the same procedure by employing 2-bromoacetaldehyde diethyl acetal as the alkylating agent.

The preparation of 6-bromo-l-tetrazol“5'-yl-n-hexane can be accomplished by the following method, A mixture of 2.98 g. (23.5 mmoles) 7-hydroxyheptanenitrile, 1.60 g. (30.0 mmoles) ammonium chloride, 0.032 g, (0.76 mmole) lithium chloride, 1.91 g. (29.3 mmoles) sodium a2ide and 50 ml. dimethyl fermaaide can be heated to 120’ under nitrogen with stirring for 18 hours or until the reaction is essentially complete. The dimethyl formamide can then be removed in vacuo and the resulting residue can be purified by one of several methods such as chromatography or extraction. This product, 6-hydroxy-l-(tettazol-5-yl)hexane, can then be treated with phosphorus tribromide under appropriate conditions to produce 6-bromo-l-(tetrazol-5-yl)hexane. The N'-aeetyloxymethyl group can be attached by employing the method of W. V. Daehne et. al. opt, cit. while the N-tetrahydropyran-2-yl group can be attached according to the method of Example 1.

Treatment of 7-(tetrahydropyran-2’-yloxy)hept-5-ynenitrile in the same manner as above will allow preparation of 6-(tetrahydropyran-2'-yloxy)1-(tetrazol-5'-yl)hex-4-yne. This material can then be converted into 6-bromo1-(tetrazol-5'-yl)hex-4-ene according to the procedure of Ger. Offen. 2,121,361 (C.A. 76r24712d). Of course, the starting hept-5-ynenitrile can also be hydrogenated to'the olefin before converting the nitrile to the tetrazole, essentially by following the same procedure. Again the protecting groups for the acidic hydrogen of the tetrazol-5-yl can be attached by the above methods.

EXAMPLE 3 l-(7'-Methylheptanato)“56-hydroxymethyl-2-pyrrolidone 4 To a solution of 200 ml. methanol and 3.99 g. THP-pyrrolidone 2_ was added 79 mg p-toluene sulfonic (tosic) acid and the solution was refluxed overnight. After work up as described below, an NMR spectrum of the reaction mixture revealed the presence of a small amount of starting ethyl ester. Therefore, the reaction mixture was redissolved in 160 ml. methanol, .080 g. tosic acid added, and the reaction again refluxed overnight. Removal of the solvent in vacuo from the reaction gave a yellow oil which was dissolved in ethyl acetate and extracted with 1 x 10 ml. of a 1:2 mixture of saturated sodium bicarbonate and half saturated Rochelle's salt solution. The organic phase was dried over magnesium sulfate, filtered and the solvent evaporated to give the title compound 4 as a clear yellow oil. 2.528 g (88%)..

NMR A-60 (DCC13) s. ¢3.86 ppm, m. ¢4.00 - 3.33 ppm, m. ¢3.20¢2.70 ppm (13H), m. ¢2.50 - ¢2.00 ppm, an ¢1.90 - ¢1.20 ppm (10H), partial spectrum.

IR (HCC13 solution) 3550-3100, 2980, 2910, 2840, 1720, 1650, 1450, 1425, 1410, 1250-1190 cm-1.

MS, LKB 9000, solid inlet (m/e-%)70eV 226-26%, 194-19.8% 74-100% 13eV 257-3.3%, 226-100% 168-24.6%.

Alternatively the tetrahydropyran-2'-yl group can be removed by hydrolysis In a 65:35 mixture of glacial acetic acid:water for ca. 18 hours essentially according to the procedure of Example 14.

In this case, the ethyl ester group of pyrrolidone 2. will be kept intact. 550 5 The foregoing acetic acid, water hydrolysis procedure can also be used to remove the tetrahydropyranyl protecting group from the other pyrrolidone products of Example 2 whieh then will produce the corresponding l-(substituted)-5f!-hydroxymethyl-2-pyrrolidones. However, if the tetrazol-5-yl protecting group is tetrahydropyran-2-yl, then it will be appropriate to , employ the dimethyl-jt-butyl silyl group as T. This silyl group can be selectively removed with tetra n-butyl ammonium fluoride according to the method of Corey, opt, cit, On application of the acetic acid procedure to l-(2,2-diethoxyethyl)10 5“(tetrahydropyran-2-yloxymethyl)-2-pyrrolidone 2 of Example 2, removal of the tetrahydropyranyl group will be accompanied by cleavage of the acetal and cycli zation, to yield as product an equilibrium mixture of the open form and 4-aza2-hydroxy-l-oxa-bicyclo [3,4,0]nonan-5-one 5..

OH Ihe equilibrium mixture containing compound 5. can be converted to l-(substi15 tuted)-5B-hydroxymethyl-2-pyrrolidones by the following procedure. - 46 4 5 5 Ο 5 To a solution of 23.04 g. (52.0 mmoles) of 5-triphenylphosphoniopentanoic acid (bromide salt) in 46 ml. dry dimethyl sulfoxide can be added dropwise 49.3 ml. (95.6 mmoles) of a 2.ON solution of sodium methylsulfinylmethide in dimethyl sulfoxide. To the resultant red solution can then be added over the course of 1.0 hour 3.27 g. (20.8 mmoles) of 4-aza-2-hydroxy-l-oxa-bicyclo[3,4,0]nonan-5-one 5. in dry dimethyl sulfoxide (63 ml.). After being stirred for an additional half hour or until substantially complete, the reaction can be poured into 600 ml. of Ice-water and then can be extracted with 2 x 300 ml. of ethyl acetate. The cold aqueous layer can be covered with ethyl acetate and acidified to pIM wi’Ji 102 hydrochloric acid after which the aqueous layer can be extracted with 2 x 200 ml. of ethyl acetate. The combined organic extracts are washed with water, followed by brine, and the organic layer can be dried over anhydrous sodium sulfate. Concentrating the filtered organic layer will afford crude 1-(6 ’-carboxyhex-2 '-enyl)-5 This procedure can also be used to prepare 1-(substituted)58-hydroxymethyl-2-pyrrolidones of the structure, wherein X is the same as that of Example 2, by substituting the appropriate 20 phosphonium salt for 5-triphenylphosphonopentanoic acid and then protecting the acidic hydrogen with an N-acyloxymethyl- group according to the procedure described by W. V, Daehne et.. al.,. op. cit.. with an N-tetrahydropyran-2yl group according to the procedure of Example 1 or by esterifying in the Case of carboxy acid. 43505 EXAMPLE 4 l-Q'-Methylheptanatoj-SS-formyl-Z-pyrrolidone 6 To a flame dried flask containing a nitrogen atmosphere was added 0.1286 g. (0.5 mmoles) 1-(7'-methylheptanato)-5B-hydroxymethyl-2-pyrrolidone £ in 5 ml. dry benzene. To this solution 0.1286 g. (1.5 mmoles) dimethylaminepropylethylcarbodiimide hydrochloride (DAPC) and 0.142 ml. (2 mmoles) dimethyl· sulfoxide were added followed after five minutes by 0.108 g. (0.55 mmoles) of pyridinium trifluoroacetate. The reaction was stirred under a nitrogen atmosphere at room temperature for 1.75 hours, then the benzene was decanted and the viscous second phase which had formed at the bottom of the flask was washed with 3 x 5 ml. benzene. The benzene solutions were combined and the solvent was removed in vacuo to give 0.132 g. of the title compound j5 as-a clear yellow oil. The crude product was used immediately and without further purification in the next reaction.

NMR T-60 (DCCl^, d. 69.72ppm J^hz(3H), m, 64.37 - 64.07ppm (IH), s. 63.70ppm (3H) - partial spectrum The foregoing procedure can also be used'to oxidize the other lr (substituted)-5S-hydroxymethyl-2-pyrrolidones of Example 3 to the corresponding l-(substituted)-5B-formyl-2-pyrrolidones.

EXAMPLE 5 l-(7l-Methylheptanato.)-53-(4-phenylbut-l-en-3-onyl)-2-pyrrolidones 7 Into a flame dried flask containing a nitrogen atmosphere was put 0.1188 g. (2.97 mmoles) of a 60% sodium hydride mineral oil dispersion and 5 THF. To this slurry was added a solution of 0.7815 g. (3.24 mmoles) of dimethyl(3-phenylpropan-2-onyl)phosphonate in 5 ml. THF. After the evolution of hydrogen ceased, a white suspension occurred which wa3 stirred for fifteen minutes. To this suspension was added 0.6894 g. (2.70 mmoles) of l-(7’methylheptanato)-53-formyl-2-pyrrolidone 6. in 10 ml. THF over a period of 1 minute. Within five minutes, the reaction became a clear yellow solution and was stirred for an additional two hours. The reaction was quenched with glacial acetic acid to pH 5. The solvent was rciroved in vacuo and the residue was taken up in 100 ml. ethyl acetate. The organic solution was extracted with 2 x 10 ml. saturated aqueous sodium bicarbonate, 3 x 10 ml.water and 1x10 ml saturated brine. The organic layer was dried over magnesium sulfate filtered and the solvent removed in vacuo to give 1.141 g, yellow oil. This crude product was chromatographed on a 35 g. column of E. Merck silica gel packed in ethyl acetate. Elution with ethyl acetate and automatic collection of 10 ml fractions allowed the purification of the product. The product fractions were combined and the solvent removed in vacuo to give 0.614 g. of the title compound T_ as a colorless oil (61% yield from the starting alcohol).

NMR T-60 OJCClj)s. 57.33ppm (5H), dofd. 66.73ppm J^«7hz ^“Ιβίιζ, d. 66.60ppm J2-16hz (2H), m. 64.27ppm center (IH), s. 63.93 (2H), s. 63.73ppm (3H) partial spectrum.

IR(CHC13 solution) 2980, 2900, 2840, 1725, 1685(sh), 1675, 1625, 1250-1200 cm-1 MS.LKB9000 (m/e %)70eV 372-20%, 371-82%, 252-96%, 226-24%, 194-35%, 12eV 372-18%, 371-100%, 252-24%, 226-39%. 43505 The other l-(substituted)-5S-formyl-2-pyrrolidone compounds of Example 4 can be employed in the foregoing procedure in place of pyrrolidone 6. to make the corresponding l-(substituted)-56-(4-phenylbut-len-3-onyl)*-2pyrrolidone compounds. In addition, phosphorates of the structure: (MeO).PCH CH22 Z -CgH4CH3 (m) -a-thienyl -C6H4OCH3 Φ -C6H4-C6H3 Φ -C6H4CF3 <£> -C6H4C1 (o) can be substituted for dimethyl(3-phenylpropan-2-onyl)phosphorate to make the corresponding l-(substituted)-$B-(4-substituted but-l-en-3-onyl)-2-pyrrolidone compounds. Hereafter, all pyrrolidones including the 4-phenyl compounds shall be known as l-(substituted)-50-(4-substituted but-l-en-3-onyl)-2pyrrolidones. -1 5 5 0 S EXAMPLE 6 . 1-(7'-Me thylhe? tanato)-5 8-(3-hydroxy-4-phenylbut-l-enyl)2-pyrrolidone 8 To a flame dried flask equipped with a magnetic scirring bar, thermometer and containing a nitrogen atmosphere was added 0.5784 g. (1.56 mmoles) l-(7'-methylheptanato)-58- (4-phenylbut-l-en-3-onyl)-2-pyrrolidone T_ in . 20 ml. dry THF, The clear, colorless solution was cooled to -78®C. and 1.56.ml (1.56 mmoles) lithium triethyl borohydride was added dropwise via syringe, needle and serum cap over a 15 minute period. After 1 hour, a TLC showed the absence oi starting enone so the reaction was quenched with glacial acetic acid to pH 5 which was followed by removal of the solvent in vacuo. The residue was dissolved in 50 ml. ethyl acetate and this organic solution was then extracted with 1 x 10 ml. half saturated aqueous sodium bicarbonate, 4 x 10 ml· water and 1 x 10 ml. saturated brine. The organic layer was dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give 700 mg. crude product. This product was chromatographed on a 9 g, silica gel column packed in ethyl acetate. Elution with ethyl acetate and automatic colles tion of 5 ml. fractions separated the product from impurities · Combination of product fractions and removal of solvent in vacuo-gave 0.298 g. of the title compound 3 as a colorless oil (5IS yield)ι NMR T-60 0CClj)s. 57.37 ppm (5H), d. 65.72 ppm - 7 hz, d. 65.62 Jx - 7 hz (2H), m. 44.67-64.33 ppm, m. 44.30-43.83 ppm (2H), s. 43.73 ppm(3H) d. 42.90 ppm J2 - 6 hz (2H). partial spectrum .

IR (HCClg solution)3450-3200, 2975, 2900, 2830, 1725, 1665, 12501200 cm”1.

The other l-(substituted)-58-(4-substituted but-1 -en-3-oy.l)>-2pyrrolidone compounds of Example 5 can be used in the foregoing procedure to prepare the corresponding l-(substituted)-5S-(4-substituted-3,,-hydroxybut-lenyl)pyrrolidone compounds. - 51 455θδ EXAMPLE 7 l-(6'-Carboxyhexyl)-5 S-(3-hydroxy-4-phenylbut-l-enyl)-2-pyrrolidone 9 To a solution of 69 mg. (0.185 mmoles) l-(7-methylheptanat0)-58-(35 hydroxy-4-phenylbut-l-enyl)-2-pyrrolidone 2 in 3 ml. methanol was added 0.185 ml. (0.185 meq) IN sodium hydroxide. The reaction solution was then refluxed overnight and then neutralized to pH 4 by addition of glacial acetic acid.

The solvent was removed in vacuo and the oily residue was dissolved in 15 ml. ethyl acetate. The organic solution was extracted with 2x2 ml. water snd 1 x2 ml. saturated brine, dried with magnesium sulfate and filtered. The solvent was removed in vacuo to give the title compound 9 as a yellow oil; 59.4 mg., 89Z yield.

NMR, 1-60,.DCClj, s. 87.33 ppm (5B), b.s. 86.30 ppm center &H), d. 85.73 ppm · 7 hz, d. 85.6' ppm 7 hz (2H), m. 84.6 - 83.2 ppm (4H), d. 82.93 ppm J2 ” 7 hz (2H). (partial spectrum).

IR,HCC13 solution, 3500-3100, 2980, 2920, 1700, 1600, 1250-1200 cm-1. Employment of the other 1-(substituted)-58-hydroxybutenyl-2-pyrrolidones of Example 6 in place of pyrrolidone 2 ttle foregoing procedure will allow cleavage of the methyl ester or the acyloxymethyl protecting groups and will allow the preparation of the following 8-aza-ll-deshydroxy prostaglandin Εχ and E2 compounds.. The N-tetrahydropyran-2-yl protecting group ii one was employed, can be removed by the method of Example 3 or!4. •4550« X « -C02H -tetrazol-5-yl 2 - -WH3 -α-thienyl -c6h4°ch3 “C6H4_C6HS -We3 -CgH^ EXAMPLE 8 1-(7'-Methylheptanato)-5 β-(4-phenoxybut-l-en-3-onyl)-2;pyrrolidone 10 Into a flame dried flask containing· a nitrogen atmosphere was put 5 22 mg. (0.55 mmoles) of a sodium hydride dispersion in mineral oil and 5 ml.

THF. To this slurry was added a solution of 0.1549 g. (0.6 mmoles) dimethyl(3-phenoxypropan“2-onyl)phosphonate in 5 ml. THF. After the evolution of hydrogen ceased, there was a clear, pale yellow solution which was stirred for fifteen minutes. To this solution was added 0.1277 g. (0.5 mmoles) l-(7'10 methylheptanato)-5-6-formyl-2-pyrrolidone 6, in 5 ml. THF over a period of 1 minute. Within five minutes, the reaction had become a clear yellow solution and was stirred for an additional two hours. The reaction was quenched with glacial acetic acid to pH 5. The solvent was removed in vacuo and the residue was taken up in 50 ml. ethyl acetate. The organic solution was extracted with 2x5 ml. saturated aqueous sodium bicarbonate, 2x5 ml. water and 1 x 5 ml. saturated brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to give 0.231 g. yellow oil. This crude product was chromatographed on a 25.g. column of E. Merck silica gel packed in cyclohexane. Elution with 502 chloroform in cyclohexane and auto20 matic collection of 10 ml. fractions allowed the purification of the product. The product fractions were combined and the solvent removed in vacuo to give 53.6 mg. of the title compound 10 (282 from the starting alcohol). .

NMR T-60 (DCC13), m. 67.40-6.70 ppm (58), a. 66.7-6.33 ppm (2H) s. 64.67 ppm (2H), m, 64.40-3.97 ppm (IH), s. 63.67 ppm (3H). partial spectrum The other l-(substituted)~56-formyl-2-pyrrolidone compounds of Example 4 can be used in the foregoing procedure in place of pyrrolidone 6. to make the corresponding l-(substituted)-5S-(4-phenoxybut-l-en~3-onyl)~2pyrrolidone compounds. In addition, phosphonates of the structure: (MeO)2)JCH2CCH2-O-V '0 0 v - -c6h4ch3 (£) -C6H4CF3 (m) -C6H4-C6B4 -c6h4och3 (£) -C6H4-C1 (o) -C6H5 can be substituted for dimethyl(3-phenoxypropan-2-onyl)phosphonate to make those corresponding 2-pyrrolidone compounds.

EXAMPLE 9 l-(7'-Methylheptanato)-5 e-(3-hydroxy-4-phenoxybut-f-enyl)2-pyrrolidone 11 To a flame dried flask equipped with a magnetic stirring bar, thermometer and containing a nitrogen atmosphere was added 0.1046 g. (0.27 mmoles) 1- (7' -methylheptanato’.)—5- (4-phenoxybut-l-en-3-onyl)-2-pyrrolidoae 10 in 5 ml. dry THE. The dear, colorless solution was cooled to -78’ C. and 0.27 ml. (0.27 mmoles) lithium triethyl borohydride was added dropwise via syringe, needle and serum cap over a 15 minute period. After 1 hour, a TLC showed the absence of starting enone so the reaction was quenched with glacial acetic acid to pH 5 which was followed by removal of solvent in vacuo. The residue was dissolved in 25 ml. ethyl acetate and this organic solution was then extracted with 1x5 ml. half saturated aqueous sodium bicarbonate, 1 x 10 nl. water and 1 x 10 ml. saturated brine. The organic layer was dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give 101 mg. crude product. This product was chromatographed on a 25 g. silica gel column packed in benzene. Elution with ethyl acetate and automatic collection of 5 ml. fractions separated the product from impurities but did not separate the two epimers. Combination of product fractions and removal of solvent in vacuo gave 85.6 ng. of the title compound 11 (822! yield).

NMR T-60 (DCC13) tt. 67.54-6.82 ppm (5H), a. 65.94-5.73 ppm (2H), a. 64.79-4.43 ppm (IH), m, 64.33-3.94 ppm (3H), s. 63.70 ppm (3H). partial spectrum.

IR (CHC13 solution) 3600-3100, 2980, 2920, 1730, 1670, 1600, 120025 1250 cm-1 The other l-(substituted)-58-(phenoxybutenoyl)-2-pyrrolidone compounds of Example 8 can be substituted for pyrrolidone 10 in the foregoing procedure and will produce the corresponding l-(substituted5-56-(4~phenoxy3-hydroxybut-l-enyl)-2-pyrrolidone compounds.

EXAMPLE 10 1- (6'-Carboxyhexyl)-5 8-(3-hydroxy-41-phenoxybut-l-enyl)-2pyrrolidone 12 To a solution of 50 ng. (0.128 mmoles) l-(7'-methylheptanato)-56-(3 5 hydroxy-4-phenoxybut-l’'-enyl)-2-pyrrolidone 11 in 3 ml. methanol was added 0.128 ml. (0.128 mmoles) of IN sodium hydroxide. The reaction solution was refluxed overnight and then neutralized to pH 4 by addition of glacial acetic acid. The solvent was removed In vacuo and the oily residue was dissolved in 15 ml. ethyl acetate. The organic solution was extracted with 2x2 ml. water and 1x2 ml. saturated brine, dried with magnesium sulfate and filtered. The solvent was removed In vacuo to give the title compound 12 as a yellow oil; 48.0 mg. (99Z yield).

NMR T-60 (DCC13) m. 67.40-6.82 ppm (5H), m. 66.73-6.17 ppm (2H), m. 65.87-5.70 ppm (2H), m. 64.7-4.4 ppm (IH), a. 64.23-3.88 ppm -(3H). partial spectrum. 1R(HCC13 solution) 3600-2900, 2920, 1700, 1670, 1600, 1200, 1250 cm1 Employment of the other l-(substituted)-58-(hydroxyphenoxybutenyl)~ 2-pyrrolidone compounds of Example 9 in place of pyrrolidone 11 in the foregoing procedure will allow cleavage of the methyl ester or the acyloxymethyl groups and allow the preparation of the following 8-aza-ll-deshydroxy prostaglandin E^ and E2 compounds. The N-THJ? protecting group can be cleaved according to the procedure of Exanple 14.

X - -C02H -cetrazol-5-yl v - -c6h4ch3 (£) -c6h4Cf3 (m) -C6H4C6H4 <£> -c6h4och3 (£) -CgH^-Cl (0) “C6H5 ^5505 EXAMPLE 11 l-:(7'-Methylheptanato)-5B-(3-tetrahydropyran-2,yloxy-4phenylbut-l-enyl)-2-pyrrolidone 13 Into a flame dried flask under a nitrogen atmosphere was put 128 ng. 5 CO.342 mmoles) of l-(7'-methylheptanato)—5B-(3-hydroxy-4phenylbut-i-enyl)2-pyrrolidone 4 and 5 ml. methylene chloride. To this solution at 0° C. to 5“ C. was then added 0.062 ml. (0.684 mmoles) redistilled dihydropyran and 3 mg. tosic acid. The solution was then allowed to warm to room temperature and to stir overnight. The reaction was worked up by dilution with 10 ml. ethyl acetate, extraction with 2 x 2 ml. saturated sodium bicarbonate solution and 1 x 5 ml. saturated brine. The organic layer was dried with magnesium sulfate filtered and the solvent was removed in vacuo to give 0.135 g. yellow oil.

This was chromatographed on a 15 g. column of Merck silica gel packed in chloroform. Elution with 1 1. chloroform removed less polar impurities.

Elution with 2% methanol in chloroform and automatic collection of 10 ml. free tions separated and purified the product. Combination of product fractions and removal of solvent in vacuo gave 0.1756 g. of the title compound 13 as a yellow oil.

NMR T-60 ilCClj) s. ¢6.34 ppm (5H), m. ¢5.77-5.37 ppm (2H), m. ¢5.1320 4.80 ppm (1H), s. ¢3.7 ppm (3H). partial spectrum.

In addition, the l-(substituted)-58-(4-substituted-3-hydroxybut-l enyl)-2“pyrrolidones of Example 6, 7, 9 and 10 can be employed in thi6 procedure to prepare the corresponding THP derivatives. 45S0S EXAMPLE 12 1-(7'-Mathylheptanato)-5 8-(3-tetrahydropyran-2'-yloxy-4phenylbutanyl)-2-pyrrolldone 14 To a solution of 156.5 mg. (0.342 mmoles) of l-(7’-methylheptanato) 5 58-(3-tetrahydropyran-2.'-yloxy-4-phenylbut-l-enyl)-2-pyrrolidone 13 in 10 ml. ethyl acetate was added 31 mg. of 102 palladium on charcoal and the entire mixture placed on a Parr hydrogen reduction apparatus and shaken under a pressure of 50 lb. hydrogen for 4 hours. The slurry was then filtered through Celite (Registered Trade Mark) to remove the catalyst and the solvent was removed frcm the filtrate to give 158.2 mg. of the title ccnpound 14.

NMR T-60 (DCClj ) s. 67.33 ppm (5H), m. 65.13-4.67 ppm (1H), m. 64.57 4.33 ppm OH), s. 63,73 ppm (3H). partial spectrum.

In addition, the other THP derivatives of Example 11 wherein A is a single bond can be 'employed in this procedure to prepare the corresponding 15 hydrogenated derivatives. - 60 45505 EXAMPLE 13 1- (6 ,-Carboxyhexyl)-5g-(3,’-tetrahydropyran-2' -yloxy-phenylbutanyl)-2-pyrrolidone 15 To a solution of 1582 og. (0.342 mmoles) of 1-(7’-methylheptanato)5 $-(3-tetrahydropyran-2'-yloxy-4-phenylbutanyl)-2-pyrrolidone 14 in 5 ml.· methanol was added 0.342 ml. (0.342nmoles)of IN sodium hydroxide. The reactioi solution was refluxed overnight and then neutralized to pH 4 by addition of glacial acetic acid. The solvent was removed in vacuo aad the oily residue was dissolved In 15 ml. ethyl acetate. The organic solution was extracted with 2 x 2 ml. water and 1 x 2 ml. saturated brine, dried with magnesium sulfate and filtered. The solvent was removed in vacuo to give the title compound 15 as a yellow oil; 134.2 mg. (89Z yield).

NMR T-60 3) s. 67.37 ppm (5H), m. 64.4-3.2 ppm, a. 62.92 (2H). partial spectrum.

IS In addition, the other hydrogenated derivatives of Example 12 can be employed in this procedure to prepare the corresponding 6’-carboxylic acid and 6’-tetrazol-5-yl compounds. - 61 45505 EXAMPLE 1« β l-(6’-Carboxyhexyl)-5 6-(3-hydroxy-4_-phenylbutanyl)-2-pyrrolidone 16 (8-aza-ll-deshydroxy-16-phenyl-16-aj-tetranor PGEg 16) A solution of 134.2 mg. (0.3 mmoles) of compound 15 was stirred in 5 5 ml. of a 65:35 mixture of acetic acid:water overnight under nitrogen at ambient temperature. Ihe solvent was then removed hy vacuum evaporation using an oil vacuum pump and the residue azeotroped with benzene. Ihe crude product was then chromatographed on 15 g. of ARCC7 silica gel by eluting with 2X methanol in chloroform to give 82 mg. of the title compound 16.

NMR. T-60 (DCClj) s. 67.17 ppm (5H), m. 63.2-4.0 ppm (3H) , d. 62.77 ρρή Jjj « 7hz (2H). partial spectrum.

IR (HCC13 solution) 3600-3100, 2930, 2860, 1700, 1660, 1250, 1200, 710 cm-1.

In addition, this procedure can be employed to remove the THF pro15 tecting group from the 6’-carboxylic acid and 6’-tetrazol-5-yl derivatives of Example 13 and the hydrogenated derivatives of Example 12.

EXAMPLE 15 l-(6'-(N-benzqyl)carbanKylhexy])-5g-(3-hydTOxy-4-phgnylbut-l-enyl)-2-pyrroj.idone To a solution of 64 mg. (0.171 mmoles) l-(6'-earbexyhexyl)-56-(4phenyl-3~tetrahydropyran-2'-yloxybut-l-enyl)-2-pyrrolidone prepared according to the procedure of Example 11 in 10 ml. of dry tetrahydrofuran can be added .16 mg. (0.171 mmoles) of benzoyl isocyanate prepared according to the procedure of A. J. Speziale, J_. Org. Chem., 27, 3742 (1962) in 5 ml. of dry THE. After refluxing overnight, the solvent can be removed in vacuo and the reaction material deprotected (THP group removed) according to the procedure of Example 14 to give the title compound. carbamoyl In a similar fashion, the following / derivatives can be made; by substituting the other appropriately protected carboxylic acids of Examples 7, 10 and 14.

Ia - NHCPh X, Z is defined in Example 7 V is defined in Example 10 A is a single or cis double bond B is a single or trans double bond EXAMPLE 16 l-(6'- (tF-methylsulfonyl)carhamoylhexy'l) -5B-(3-hydroxy-4phenylbut-l-enyl)-2-pyrrolldone To a solution of 64 mg. (0.171 mmoles) 1-(6’-carboxyhexyl)-56-(45 phenyl-3-tetrahydropyran-2' ’ ’-yloxybut-l-enyl)-2-pyrrolidone prepared according to the procedure of Example 11 in 10 ml. dry benzene can be added .7 mg. (0.171 mmoles) of methyl sulfonyl isocyanate (A. J. Speziale see Example 16) in 5 ml. dry benzene at ambient temperature. After refluxing overnight, the solvent can then be removed in vacuo and the resulting residue deprotected (THP group removed) according to the procedure of Example 14 to. give the title compound.

By substituting phenyl sulfonyl isocyanate for methane sulfonyl carbamoyl isocyanate in this procedure, the corresponding phenyl sulphonyl/ derivatives can also be made. carbamoyls In addition the following sulphonyl/ can be prepared by substituting the other appropriately protected carboxylic adds of Examples 7, and 14.. suf » nhso2ch3 NHSOjPh V is defined in Exanple 10.

Z is defined in Example 7 A is a single or cis double bond B is a single or trans double bond.

Claims (20)

1. CLAIMS :1. A compound of the structure and the C5 epimer thereof wherein: 0 0 I I Q is -CORg, tetrazol-5-yl or -CNHR^j A is a single or cis double bond; B is a single or trans double bond; U is OH or Rg is α-thienyl, phenyl, phenoxy, monosubstituted phenyl or monosubstituted phenoxy, said substituents being chloro, fluoro, phenyl, methoxy, trifluoromethyl or alkyl having from one to three carbon atoms; is hydrogen, alkyl having from one to five carbon atoms, phenyl or £-biphenyl; R 4 is -CR S or -SO 2 R 5 , and Rg being phenyl or alkyl having from one to five carbon atoms, 2. O and the alkali metal, alkaline earth metal and ammonium salts of those compounds having a carboxylate or tetrazol5-yl group.

2. A compound of claim 1 wherein Rg is phenyl, substituted phenyl or a-thienyl. 65 45505

3. A compound of claim 1 wherein R 2 is phenoxy or substituted phenoxy.

4. A compound of claim 2 wherein Q is I -COR,.

5. A compound of claim 2 wherein Q is tetrazol-5-yl,

6. A compound of claim 2 Wherein Q is II -CNHR 4 .

7. A compound of claim 3 wherein Q is Ϊ -COR 3 .

8. A compound of claim 3 wherein Q is tetrazol-5-yl.

9. A compound of claim 3 wherein Q is -cnhr 4 .

10. A compound of claim 4 wherein R 2 is phenyl.

11. A compound of claim 7 wherein R 2 is phenoxy.

12. A compound of claim 5 wherein R 2 is phenyl.

13. A compound of claim 8 wherein R 2 is phenoxy.

14. The compound of claim 10 wherein A is a single bond, B is a trans double bond, Rg is hydrogen, 0 is H OH and C5 is β.

15. The C5 epimer of the compound of claim 14.

16. , The compound of claim 10 wherein A is a single bond, B is a single bond, Rg is hydrogen, 0 is OH and C5 is β. 66 4C505

17. The C5 epimer of the compound of claim 16.

18. The compound of claim 11 wherein A Is a single bond, B is a trans double bond, is hydrogen, ϋ is H OH 5 and C5 is β. 19. The C5 epimer of the compound of claim 18 20. A compound of the structure: and the C5 epimer thereof wherein: 10 W is 0 II -COR 3 , tetrazol-5-yl N-(acyloxymethyl)tetrazol-5-yl having from two to five carbon atoms in the acyloxy group, N-(phthalidyl)tetrazol 5-yl, or N-(tetrahydropyran-2-yl)-tetrazol-5-yl; 15 A is a single or cis double bond; B is a single or trans double bond; R 2 is α-thienyl, phenyl, phenoxy, monosubstituted phenyl or monosubstituted phenoxy, said substitutes being chloro, fluoro, phenyl, methoxy, trifluorcinethyl or alkyl having from

19. 20 one to three carbon atoms: R 3 is hydrogen, alkyl having from one to five carbon atoms, phenyl or p-biphenyl; and the alkali metal, alkaline earth metal and ammonium salts of those compounds having a carboxylate or

20. 25 tetrazol-5-yl group. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.