FI70009B - FRAMEWORK FOR THE FRAMEWORK OF NYA 1,5-DISUBSTITUERAD-2-PYRROLIDONFOERENINGAR VILKA HAR PROSTAGLANDINLIKNANDE BIOLOGISKA EGENSKAPER - Google Patents

Description

Ιν Τ ^ · | ΓΒ1 m, NOTICE.SU 70009 11 UTLÄGGNINGSSKRIFT fUUU? • C (45) Pentent myCaactty

Patn-t .-, .2 2.1 ols 113 CO 10CG

(51) Kv.lk//lnt.CI/ C 07 D 207/26 FINLAND —FINLAND (21) Patent application - Patentansökning 772376 (22) Application date - Ansökningsdag 05.08.77 (23) Starting date - Giltighetsdag 05.08.77 (41) Tullut to the public - Blivit offentllg gy g £ yg

National Board of Patents and Registration ...., .... .. ... ... .....

* (44) Date of display and of publication. - -1 n 1

Patent and Registration Office '' Ansökan utlagd och Utl.skriften published 5 1 · u 1 · 00 (32) (33) (31) Privilege requested — Begärd priorltet 06.08.76 USA (US) 712362 (71) Pfizer Inc., 235 East 42nd Street, New York, New York, USA (US) (72) Albin James Nelson, Croton-on-Hudson, New York, USA (US) (7 * 0 Oy Kolster Ab (5 * 0 Method for new 1, For the preparation of 5 "disubstituted-2-pyrrolidone compounds having prostaglandin-like biological properties - For the preparation of prostaglandin-like biological agents 1 and av, 1, 5-disubstituted-2-pyrrolidone-like biological agents

The invention relates to a process for the preparation of novel 1,5-disubstituted-2-pyrrolidone compounds of the formula (I) and their C5 epimers having prostaglandin-like biological properties,

M

wherein Q is -COOR, wherein R is hydrogen or alkyl of 1 to 5 carbon atoms, Z is a single bond or a trans double bond, 270009. (fif / M is H OH or HO H, and R 'is phenyl or phenoxy.

C 1-4 unsaturated fatty acids, known as prostaglandins, form a broad class of naturally occurring compounds. These molecules can have up to five centers of asymmetry and are present and act in a variety of biological tissues. As an example of a specific prostaglandin E genus species, PGE2 e co5h J-1 prostaglandin E2 is described below.

According to the notation commonly used to describe the stereochemistry of prostaglandins, the thick solid line corresponds to the β-configuration, which is defined as a bond that rises from the plane of the paper and per reader. Similarly, a dotted or dashed line corresponds to an oi configuration, defined as a bond that goes behind the paper and away from the reader. Thus, the configuration of prostaglandin E2, pictured above, corresponds to the β-form at carbon atom 8 and the β-form at carbon atom 12. / S. Bergström et al., Acta Chem. Scand., 16, 501 (1962) 7 ·

Using the same terminology, the wavy line corresponds to a mixture of θ {and 7-5 forms. Thus, a 2-pyrrolidone having the structural formula Λη corresponds to a mixture A of epimers A and B. ' ..........

r '<0H and 3 70009.-k

“OH

With reference to the pyrrolidone and prostaglandin E 1 corresponding to structure B above, a stereochemical comparison can be made between the two sets of compounds. For stations 12 and 15, the stereochemistry of both types is the same, but for station 8 it is different. Thus, the C8-C7 bond of prostaglandin E corresponds to the configuration, but the N8-C7 bond is in the plane of the paper as shown in the above drawing. Another way to present the above two examples, which gives a better picture of this configuration difference, is the side sectional drawing below.

Λ A

> -0H] /

A

prostaglandin E pyrrolidone where A and B correspond to the two side chains of the examples. In this case, the drawing illustrates the eclipse of the A-C8 bond with the C12-H bond and the eclipse of the C12-B bond with the C8-H bond in the case of prostaglandin E, and the bisecting position of the A-N8 bond to form B-C12-H. With respect to the V-shaped angle in the case of pyrrolidone.

This structural difference is due to the planarity caused by the amide group of pyrrolidone. / "Basic Principles of Organic Chemistry", J. D. Roberts and M. C. Caserio, W. A. Benjamin, New York, 1965, p. 6747.

1,5-disubstituted-2-pyrrolidone having the structural formula

o cQ H

—-1 MOli \ /

H + 0H

70009 is systematically designated 1- (6'-carboxyhexyl) -5H- (3 "- (.beta.-hydroxy-oct-1" -enyl) -2-pyrrolidone and may also be referred to as 11-deoxyprostaglandin E . designated 8-aza-11-deoxy-PGE 2.

The structural formula of the corresponding 8-aza-11-deoxy-PGE2 compound is: 0

H OH

2 *.

wherein the single bond between C and C3 'is replaced by a double bond. The structural formula of the corresponding 8-aza-11-deoxy-PGEg compound is: 0

H OH

wherein the double bond between ClH and C2 "is replaced by a single bond.

The pyrrolidones described above have several centers of asymmetry and may exist in racemic (optically inactive) form and in both enantiomeric forms (optically active form), i. in a right-turning (D) and left-turning (L) form. As described above, each pyrrolidone structure corresponds to a particular optically active form or enantiomer that is partially derivatizable from D-glutamic acid. The mirror image or optical antipode of each of the above structures corresponds to the second enantiomer of that pyrrolidone and is derived in part from L-glutamic acid.

For example, the optical antipode of 1- (6'-carboxyhexyl) -5H-3- (3 "(hydroxyethoct-1" -enyl) -2-pyrrolidone is described as follows: 5 70009 cfCQCC?

HO H

and is referred to as 1- (6'-carboxyhexyl) -5® {- (3'-3-hydroxyoct-1 "-enyl) -2-pyrrolidone.

The racemic form of the pyrrolidone described above has a corresponding number of individual enantiomers and mirror images thereof. When referring to the racemate of a related compound, the name of the compound is preceded by the symbol "rac". This term then means and corresponds to an equimolar mixture of D and L forms or enantiomeric forms.

The isomers of an optical isomer pair, which are optical antipodes or or enantiomers, are uniform for all of their centers of asymmetry as inversion forms of absolute configuration.

Conversely, when there is consistency between the inversion forms of the absolute configuration for one or more but not all centers of asymmetry, the isomers of the isomer pair are epimers or diastereomers. For example, 1- (6'-carboxyhexyl) -N- (3 ", =? - (c-hydroxyoct-1H-enyl) -2-pyrrolidone and 1- (6'-carboxyhexyl) -5H- (3" N-hydroxyoct-1 "-enyl) -2-pyrrolidone are diastereomers with the inversion of the configuration at the C5 atom and are shown

O

respectively by the formula: CO H

L-ίccoc

Η ^ 'ΟΗ H' OH

The fact is that when chemical experiments are performed with either member of a pair of enantiomers or a mixture of the two, the same and identical results are obtained.

6 70009

As previously noted, replacing the carbon at the C8 site with nitrogen results in a dramatic change in the three-dimensional structure of the resulting prostaglandin. Because structure is related to biological activity and often a slight change in structure, such as a conformational change, has a profound effect on biological activity, such modification of the prostaglandin molecule by replacing carbon atoms with heteroatoms has recently been investigated. For most compounds, there is the substitution of carbon atoms by heteroatoms at the C9 and C11 positions of prostaglandins, with 9-oxa-prostaglandins being exemplified (see Vlattas, Tetrahedron Let., 44-55 (1974) 7; 11-oxaprostane). glandins (see Fougerousse, Tetrahedron Let., 3983 (1974) 7 and S. Hanessian et al., Tetrahedron Let., 3983 (1974) and 9-thiaprostaglandins il. Vlattas, Tetrahedron Let., 4459 (1974)).

There have also been reports in the literature of two 8-aza-11-deoxy-prostaglandin Es having a natural product β-side chain, i.e., compounds with an aza substitution for 11-deoxy-prostaglandin E1 and -E-β. (G. Bolliger and JM Muchowski, Tetrahedron Let., 2931 (1975) (Aug. 1975); and JW Bruin et al., Tetrahedron Let., 4599 (1975)). · These examples of pyrrolidone compounds are not within the scope of this invention. which offers more demanding complexity and the possibility of molecular variation at the C1 position and side chain of prostaglandin These exemplified compounds reported in the literature are reported to have relatively low biological activity and can be considered as opposites to the novel compounds of this invention in form and molecular complexity.

Naturally occurring prostaglandins and many of their derivatives such as esters, acylates, and pharmacologically acceptable salts are highly effective stimulators of various biological reactions. Wilson, Arch. Intern. Med., 133 (29) (1974) 7 in smooth muscle tissues such as the cardiovascular, pulmonary, gastrointestinal and reproductive systems, in cellular tissues such as the central nervous system, haematological, reproductive, gastrointestinal, pulmonary, renal, epidermal - and liposuction systems and also act as mediators in the homeostasis process. With such a variety of reactions, it is apparent that prostaglandins are involved in the basic biological processes of the cell. Indeed, the coupling of prostaglandins to these basic processes is supported by the fact that they can be found in almost all cellular tissues of animal organisms.

At this cellular level, the effects of naturally occurring Prosta glandins that are close to each other may be reversed. For example, PGE2 promotes human platelet aggregation while PGE2 inhibits aggregation.

Such opposite effects can also be observed at the tissue level. For example, when administered in vivo, the effect of PGE2 on the cardiovascular system of mammals is manifested by its hypotension, whereas when administered in vivo, PGFβ causes hypertension. Lee, Arch. Intern. Med., 133 56 (1974), 7. However, the possibility of predicting the biological effect of prostaglandin types based on such observations is now largely apparent. For example, when the effects of PGE1 and PGF2 on cardiovascular vessels are opposite, as described above, their effect when administered in vivo or in vitro to mammalian uterine smooth muscle is the same and the effect is stimulatory (causes contraction). Behrman et al., Arch. Intern. Med., 133 77 (1974), 7.

In the manufacture of synthetic pharmaceuticals, the main focus is on the development of compounds which have a highly selective pharmacological action and a longer duration of action than their naturally occurring relatives. An increase in the selectivity of a private compound in a series of compounds similar to naturally occurring prostaglandins is associated with an increase in some prostaglandin-like physiological effect and a decrease in others. By increasing selectivity, severe side effects commonly observed after administration of natural Prosta glandins can be alleviated; for example, diarrhea and vomiting or cardiovascular side effects include gastrointestinal side effects, with the desirability of bronchodilating effects. Recently developed products that have sought to increase biological selectivity include 11-deoxy-prostaglandins. Anderson, Arch. Intern. Med., 133, 30 (1974) Rev., 1,2-Descarboxy-2- (tetrazol-5-yl) -11-deoxy-15-substituted-GXpentanorprostaglandins (MR Johnson et al., U.S. Pat. No. 3,932,389), some variants of which is said to selectively exert vasodilatory, antiulcer, antiprotective, bronchodilator and antihypertensive properties, with 16-phenoxy-16-CO-tetranorprosta-glandins having anti-fertilizing effect (GB-1) and 1-sulfonimide prostaglandins (U.S. Patent 3,954,741).

Of the corresponding compounds of formula (I) according to the invention, the following are particularly preferred because of their selective biological activity: 1- (5'-carboxyhexyl) -5/3 - (3 "α-hydroxy-4" -phenylbut-1 "-enyl) - 2-pyrrolidone and its methyl ester and 5 C ("epimer, 1- (6'-carboxyhex-2'-enyl) -5H- [3- (3" (N-hydroxy-4 "-phenylbut-1" -enyl) ) -2-pyrrolidone and its 5 0 (-imimer, 1- (6'-carboxyhexyl) -5- (3 "N-hydroxy-4" -phenylbutanyl) -2-pyrrolidone and its 5-epimer, 1- (6'-carboxyhexyl) -5/3-hydroxy-4 "-phenoxy but-1" -enyl) -2-pyrrolidone and its 5 & L epimer, 1- (6 * -carboxyhex-2'-enyl ) -5β- [3- (3 "-hydroxy-4" -phenoxybut-1 "-enyl) -2-pyrrolidone and its 5β-epimer, 1- (6 * -carboxyhexyl) -5- (3" -hydroxy-4 "-phenoxybutanyl) -2-pyrrolidone and its 5 IA epimer, and compounds in which the 3", Ά, -hydroxy group of each of the above 6'-carboxy compounds is replaced by a 3 ", β-hydroxy group.

Compounds of formula (I) are prepared by reduction of a pyrrolidone intermediate of formula (II) wherein Q, Z and R 1 are as defined above to convert a 3 "oxo group to an alpha-hydroxy or beta-hydroxy group, and optionally esterifying a compound of formula (I) ) wherein Q is carboalkoxy, or optionally hydrolyzing a pyrrolidone compound of formula (I) wherein Q is carboalkoxy to give a compound of formula (I) wherein Q is -C00H.

9 70009

In the preparation of the starting compound of formula (II), two side chains are attached to the pyrrolidone ring, q (- the upper side chain and cu - i.e. the lower side chain, and the starting material is an amino acid decomposed into enantiomers, D- or L-glutamic acid. or L-glutamic acid, the absolute correct structure of the 2-pyrrolidone ring is confirmed at C5 and this position does not need to be cleaved at the end of the synthesis.The D-configuration is shown in the following examples and in the context of the present case: Compounds corresponding to the L-configuration are prepared using the same reaction sequence. acid.

The synthetic sequence shown in Scheme A describes methods for attaching a chain to a 2-pyrrolidone ring.

10 70009

Diagram Δ - g »C-chain connection 0 V" 2

H CO2H

(a) vo

CH 2 OH

<b> p

(c) CH 2 OX

N. XCH2CH (OY) 2

If X (c) \ Λ ^ <° Υ

11 Q 1- ^ OY

ch20T (f) I

\ Λ ^ οπο ^ Λν-τοη \ I-I-1 ^ 0 (d) \ /

\ (g) / Ph3P = CH (CH2) 3Q

1, - 1_oh 70009

A brief summary of the steps in Scheme A is as follows. The first step, denoted by (a): 11a, which describes the cyclization of D-glutamic acid from the reduction of methyl D-pyroglutamate to 5-D-hydroxy-2-pyrrolidone, is known. Bruckner et al., Acta. Chim. Hung. Tomus, 21, 106 (1959). The second step (b) is to protect the hydroxymethyl group with a protecting group T, which may be any group suitable for protecting the hydroxyl group against alkylation; examples are benzyl, dimethyl-t-butylsilyl, acetyl, 1-ethoxyethyl, or especially tetrahydropyranyl. Steps (c) and (e) illustrate the alkylation of the sodium or lithium salt of pyrrolidone 1 with alkylating agents of the formula or, respectively, with a compound XC 1 CH 2 O 2, wherein X is Cl, J or especially Br; Q is COOR, wherein R is as defined above; Y is alkyl of one to three carbon atoms, and A is a single bond or a double bond. Step (d) is the removal of the protecting group T, which method depends on the protecting group used. Step (f) is deprotection of the pyrrolidone compound (18) to produce in situ 1- (ethane-2'-aal) -5-hydroxymethyl-2-pyrrolidone, which may be in equilibrium with the hemiacetal compound 5. Step (g) is a Wittig reaction which takes place in an equilibrium mixture of bicyclo [4.3.0] nonan-5-one (5) with phosphorane of the formula PHgP as defined above is unprotected to give the corresponding 2-pyrrolidone compound (19) wherein A is a double bond.

The reactions required for the preparation of the products of the invention are arranged in such an order that no epimerization occurs at the optically active center at C5. Therefore, by using as starting material one of the two enantiomers of glutamic acid, the same configuration at the centers of asymmetry can be ensured in the products as well. Racemic or racemic products can also be prepared using isemic glutamic acid as the starting material.

12 70009

The C5 position of the compounds and intermediates of formula (I) is plotted in the β-configuration, but the C5 position may also be in the Tucone iguration, provided that the configuration of the starting glutamic acid is suitable.

The first two steps of the reaction sequence are the condensation and esterification of D-glutamic acid to give the corresponding D-methyl pyroglutamate having the structural formula Λ 3 ΧΝ-Η

u .A

^ CO2Me / E. Hardegger et al., Helv. Chem. Acta, 38, 312 (1955); E. Segel, J. Am. Chem. Soc., 74, 851 (1952) 7.

The third, and known step in the series, shown in Scheme A as step (a), is the reduction of the 5-carboxymethyl group of D-methylpyroglutamate to give 5-D-hydroxymethyl-2-pyrrolidone. This reaction is most conveniently performed using a variation of the method described by V. Brucker et al., / Acta.

Chem. Hung. Tomus, 21, 106 (1959) 7 · D-methylpyroglutamate is mixed with lithium basohydride in dry tetrahydrofuran or other ether solvent until the reduction is substantially complete. Isolation of the product as described gives 5-D-hydroxymethyl-2-pyrrolidone having the structural formula: For the alkylation of the amide nitrogen of 5-D-hydroxymethyl-2-pyrrolidone, labile 5-hydroxymethyl hydrogen is preferred. protected with a known tetrahydropyranyl group. This protection (Scheme A, step (b) is most conveniently performed by contacting 5-D-hydroxymethyl-2-pyrrolidone with dihydropyran in the presence of an organic acid such as p-toluenesulfonic acid and in a neutral solvent such as methylene chloride, chloroform, tetrahydrofuran or die. the appropriate temperature range required for the reaction is the temperature range between the ice bath and the boiling solvent, with room temperature being preferred, after the formation of 5-D- (tetrahydropyran-2'-yloxymethyl) -2-pyrrolidone 1 is substantially complete, usually overnight, it is isolated by removal first by extracting the organic acid with a base and removing the solvent and any excess dihydropyran using a vacuum exchange technique.The product is usually purified by column chromatography.

Other equally useful preservatives are any hydroxyl group protecting agents against alkylation. Some examples are benzyl, acetyl, dimethyl-t-butylsilyl and 1-ethoxyethyl. These preservatives are readily available and can be attached to the 5-hydroxymethyl group by known methods. Their choice for synthetic purposes depends on the group to be protected at position C7 '.

The 1- (alkylated) -2-pyrrolidone compounds (17 and 18 in Scheme A) are prepared by a combination of two reactions performed using 5-D- (tetrahydropyran-2'-yloxymethyl) -2-pyrrolidone 1 or any of its T groups -analogue. First, the sodium or lithium salt of pyrrolidone 1 is prepared by contacting a solution of Compound 1 in a neutral organic solvent such as tetrahydrofuran, diethoxyethane or dioxane with a base such as n-butyllithium, phenyllithium or especially sodium hydride. A suitable temperature for the formation of this salt is between room temperature and the boiling point of the solvent, mainly room temperature. The entire amount of base must be complete before alkylation is initiated, which usually takes 1 to H hours. The desired 1- (alkylated) -2-pyrrolidone compounds 17 and 18, respectively, are then formed by contacting the lithium or sodium salt of the 2-pyrrolidone compound 1 prepared above with an alkylating agent having the structural formula or XCH 2 CH (YO) 2 wherein X and Cl, J and especially Br, 14 70009 Q and A are each as defined above and Y is alkyl having one to three carbon atoms. This second part of the alkylation process is usually carried out by adding a mixture of an alkylating agent in a previously defined neutral organic solvent or, in particular, adding a mixture of an alkylating agent in a polar aprotic organic solvent such as dimethylformamide or dimethylacetamide to a mixture of n-pyrrole formed above: a lithium salt in a neutral organic solvent, and then allowing the mixture of alkylating agent and the sodium or lithium salt of 2-pyrrolidone to contact each other at a temperature between room temperature and the boiling point of the solvent until the alkylation is substantially complete, usually overnight.

The alkylated 2-pyrrolidone formed by the use of XCl (CHCOY) ^ can of course also be prepared by using XCH ^ CO4 Et as the alkylating agent, followed by the ester group of 1- (2'-ethyl acetate) -5- (substituted) -2-pyrrolidone obtained selective conversion to aldehyde. If the group Q contains acidic hydrogen, the alkylation process is most conveniently performed by protection, or other removal of acidic hydrogen. For example, when R is hydrogen, the best method is to use an ester derivative which can then be removed at the end of the synthesis by hydrolysis with alkali. Continuing the treatment, it is assumed that the acidic hydrogen of the Q group is protected unless otherwise stated.

The nature of the C2 * to C3 * bond of the 2-pyrrolidone compound 17 obtained in the alkylation step is determined by the nature of the alkylating agent A.

The choice of A also determines the unsaturation or saturated nature of the ol side chain of the final product obtained in the synthesis; that is, whether the choice of 8-aza-11-deoxy-PGE 2 or S-aza-deoxy-PGE 2 70009 A appears to cause a difference only in the nature of the C2'-C3 'bond of the «^ side chain and pyrrolidone The conversion of compounds in which A is a double bond to compounds in which A is a single bond is indeed possible in step 17 of the synthesis of the pyrrolidone compound. For example, 2-pyrrolidone compound 17 with a double bond at A can be converted to 2-pyrrolidone compound 17 with a single bond at A by hydrogenation over a noble metal catalyst such as palladium on carbon at room temperature until 1 equivalent of hydrogen is absorbed. .

I a-L.> R ^ q

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 familiar to those skilled in the art in predicting to-side chain formation. Obtained 2-pyrrolidone compounds having the structural formula:

Compound 19 wherein Q and A are each as defined above is then further treated according to Schemes B, C and D to provide novel end products of this invention.

The above compound 19 can also be prepared by reacting a hydrolyzed form of 2-pyrrolidone having the formula:

An ^ / ° Y

- in which Y and T have the meanings defined above, for contact with phosphorane of the formula: 16 70009

Ph 3 P = CH (CH 2) 3Q

wherein Q as defined above is unprotected, e.g. CO 2 H.

This part of the reaction sequence, illustrated in steps (f) and (g) of Scheme A, can be carried out as follows. If the primary T-protecting group, tetrahydropyran-2-yl, is used in compound 18, hydrolysis of compound 18 with an acid by a conventional acetal removal method, such as acetic acid in water at about 40 ° C, cleaves both tetrahydropyran-2-yl and acetal to form 1- ( ethane-2'-allyl-5β-hydroxymethyl-2-pyrrolidone, which may be in equilibrium with 4-aza-2-hydroxy-1-oxa-bicyclo- (4,3,0) nonan-5-one.

- nonanones 5

The equilibrium mixture containing the hemiacetal 5 can then be contacted with about 2 equivalents of phosphophane as defined above in a polar aprotic solvent such as dimethyl sulfoxide or in a mixture of ether and a polar aprotic solvent such as tetrahydrofuran and dimethyl sulfoxide at temperatures between 0 ° C and 60 ° C. to give 2-pyrrolidone 19, where A is a double bond. It should be noted that the acidic hydrogen or group Q can then be protected as an ester in the case of a carboxylic acid.

This 2-pyrrolidone 19, A being a double bond, can be converted to 2-pyrrolidone 19, where A is a single bond, by the hydrogenation method described above.

70009

The final products of formula (I) are obtained by oxidizing the 5H-hydroxymethyl group of 2-pyrrolidone (19) and treating the 5H-p-phenyl-2-pyrrolidone compound (20) thus formed according to the Horner-Wittig reaction with sodium or lithium phosphonate. with a salt of the formula O 0 (MeO) 2PCH2CCH2R 'wherein R' is as defined above, followed by the 5- (4 "-substituted-but-1" -en-3 "- 2-pyrrolidone (21) thus formed reduction of the onyl) group.

Scheme B illustrates this method described above for performing chain coupling.

18 70009

Scheme B

Connecting the ίύ chain 0 A

N ^ t) H

Ai oxidation

L-V

B

20 0 0 Il # (MeO) 2POT2CCH2R '

0 A

21 0 reduction r '22 ·

- H OH

i9 70009

Aldehyde 20 is obtained from 5β-hydroxymethyl-2-pyrrolidone compound 19 by a modified Pfitzner Moffatt oxidation method (KE Pfitzner and ME Moffatt, J. Am. Chem. Soc., 87, 5661 (1965) 7, which avoids 5β- contact of the formyl compound 20 with water, for example by stirring a slurry of 1- (7'-methylheptanate) -5,3-hydroxymethyl-2-pyrrolidone or other suitable hydroxymethyl-2-pyrrolidone in a neutral hydrocarbon solvent such as toluene , in xylene or especially in benzene with dimethyl sulfoxide, a weak acid such as acetic acid or especially pyridinium trifluoroacetate and a water-soluble diimide such as diethylcarbodiimide or especially dimethylaminopropylethylcarbodiimide or, if desired, its hydrochloride salt between 0 ° C and room temperature at 1-4 hours, the primary alcohol 19 is oxidized to the aldehyde 20. Alternative oxidation methods are the standard Pfitzner-Moffatt reaction and oxidation with chromium trioxide-pyridine complex ^ R. Ratcliffe, et al., J. Org. Chem., 35, 4000 (1970) 7, although the best method is the reaction described above.

5- (4 "-Substituted-but-1" -en-3 "-onyl) -2-pyrrolidone compound 21 is prepared by contacting 5/2'-formyl-2-pyrrolidone compound 20 with sodium or lithium phosphonate. with a salt of the formula O 0 (MeO) 2 PCH2 CCH2 R 'wherein R' is as defined above, as a solution or slurry of an ether solvent such as tetrahydrofuran, dimethoxyethane or dioxane, at temperatures between 0 and 50 ° C until the reaction The isolation of the product from this Horner-Wittig reaction mixture, which is known to those skilled in the art, is carried out in the usual manner by chromatography, Other methods include high pressure liquid chromatography and, in some cases, fractional crystallization. patent 3,932,389.

Reduction, and if desired, hydrolysis of 2-pyrrolidone with alkali or acid affords several final products of the invention wherein Q is -C00R.

20 70009

The best reagent for the reduction is lithium triethyl borohydride, but it is equally easy to use other selective reduction reagents which reduce the ketone but not other groups, e.g. zinc borohydride or sodium borohydride. Commonly used solvents are of the ether type such as tetrahydrofuran and diethyl ether. The choice of temperature depends on the activity of the reducing agent and in most cases it is most convenient to use a dry ice / acetone bath.

Under conventional reaction conditions, reduction of the but-1 "-en-3" -onyl group of pyrrolidone 21 actually results in the formation of two 2-pyrrolidone compounds 22, which are diastereomers.

£ rr— "·· r 'H H' ° v»

H H OH 0H

3 "othydroxy compound 22a 3β / 3-hydroxy compound 22b Thus, these two compounds, which can be separated by common isolation methods such as high pressure liquid chromatography, are each prepared as described; and it is assumed that both, although only the o (-isomer) are shown completely. Unless diastereomers are isolated, a mixture of the two compounds is formed and is shown as follows: 0 R.

H OH

and by this is meant a mixture of O 2 -imimer and γ-epimer.

After the product obtained in the above reduction reaction is isolated in the usual manner, the protecting group of the group q in the acidic C7 position can be removed, if desired, using general methods for removing such groups. For example, if an alkyl ester is selected as Q and an acid is desired, a simple alkaline hydrolysis is performed with one equivalent of base at a temperature between room temperature 2170009 and the boiling point of the solvent, usually overnight to give the carboxylic acid after neutralization. The phthalidyl and acyloxymethyl groups can be removed in the same manner, but the tetrahydropyran-2-yl (THP) group is removed with an acid such as acetic acid in water or p-toluenesulfonic acid in methanol, usually by overnight treatment at room temperature to 50 ° C.

The products of this invention wherein A and Z are each single bonds, e.g., compound 23, are prepared by catalytic reduction of a 3-"-tetrahydro-pyran-2-yloxy derivative of 2-pyrrolidone 22 wherein A is a single bond.

This reaction sequence is described in Scheme C.

Alternatively, pyrrolidone compounds 23 can be prepared by catalytic reduction of a 3 "'- tetrahydropyran-2"' - yloxy derivative of 2-pyrrolidone 22 wherein A is a double bond. In this case, A and Z are simultaneously reduced to simple bonds.

22 70009

Scheme C

A = simple 22 h R

There was a bond of dihydropyran o sr

11 ^ OTllP H2, Pd / C

0 7

OTHP

h3o ® 7 C ° 2R '

H "oH

23 23 70009

The tetrahydropyran-2 "'- yloxy derivative of 22, wherein A is a single bond, is formed in the same manner as described for 5-D- (tetrahydropyran-2-yloxymethyl) -2-pyrrolidone 1. Then, by hydrogenation over a noble metal catalyst such as palladium on carbon. with a carbon catalyst or platinum oxide in solvents such as ethyl acetate, methanol or ethanol at temperatures between room temperature and boiling point until 1 equivalent of hydrogen is absorbed and then removing the tetrahydropyran-2 "-yl group and, if desired, the Q-protecting group by conventional methods, -11-deoxy-prostaglandin EQ compounds 23.

Esters of formula (I) wherein Q is carboalkoxy can be prepared from the corresponding acids of formula (I) wherein Q is COOH by well known esterification methods, including reaction with diazoalkanes having one to five carbon atoms.

Numerous in vivo and in vitro experiments have shown that new prostaglandin analogues have a more selective, potent and long-lasting physiological effect than naturally occurring prostaglandins. These experiments include, but are not limited to, the effect on guinea pig uterine smooth muscle, the inhibitory effect on guinea pig histamine-induced bronchospasm, the effect on canine blood pressure, the preventive effect against exercise-induced ulceration in rats, the effect on diarrhea in mice and the inhibitory effect on stimulation.

The physiological reactions observed in these experiments are useful in determining the usefulness of a test substance for the treatment of various congenital and pathological conditions. Such defined beneficial effects include: vasodilating effect, antihypertensive effect, bronchodilator effect, fertility inhibitory effect, and ulcer formation inhibiting effect.

The 8-aza-11-deoxy-prostaglandins of formula (I) have highly selective action profiles compared to the corresponding properties of naturally occurring prostaglandins and in many cases have a longer duration of action. For example, the novel prostamimetic pyrrolidones of this 70009 invention wherein R 'is phenyl have a useful vasodilating effect. The best examples of the therapeutic significance of these pyrrolidone compounds are the compounds 1- (6 · -carboxyhexyl) -5- (o-hydroxy-4 "-phenylbut-1" -enyl) -2-pyrrolidone and 1- (61-carboxyhexyl) The efficacies of -5 - (- (3 "-hydroxy-1 +" - phenylbut-1 "-enyl) -2-pyrrolidone, the antihypertensive activity of which is comparable to that of PGE1 itself when administered intravenously to anesthetized dogs in accordance with U.S. Pat. At the same time, other effects, such as bronchodilator and antiulcer effect, are greatly attenuated by the effect of PEG2 as measured by the method described in U.S. Patent 3,956,284.

Another excellent example of the therapeutic relevance of the pyrrolidones of this invention is the selective antiulcer effect of compounds in which R 'is a phenoxy group. For example, 1- (6'-carboxyhexyl) -5/9- (3 "-hydroxy-4" -phenoxy-but-1 "-enyl) -2-pyrrolidone has an excellent and selective antacid isolation effect when administered orally to dogs.

The compounds of formula (I) may be used in a variety of pharmaceutical preparations containing the compound or a pharmaceutically acceptable salt thereof. They can be given in different ways, depending on the type of disease and the individual condition of the patient.

The 8-aza-11-deoxy-16-aryl-to-tetranorprog taglandin compounds of this invention and their epimers are useful vasodilators. For the treatment of hypertension, these drugs may conveniently be administered by intravenous injection at doses of about 0.5 to 10 mg / kg, or preferably in capsules or tablets, at doses of 0.005 to 0.5 mg / kg per day.

The 8-aza-11-deoxy-16-aryloxy-Co-tetranor-prostaglandin compounds of this invention and their epimers are useful antiulcer agents. For the treatment of indigestion, these drugs can be administered as capsules or tablets at doses of 0.005 to 0.5 mg / kg / day.

Pharmacologically acceptable salts suitable for use for the purposes described above include salts with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Particularly preferred metal cations are cations of alkali metals, e.g. lithium, sodium and potassium, and cations of alkaline earth metals, e.g. magnesium and calcium, although cationic forms of other metals, e.g. aluminum, zinc and iron are included within the scope of this invention.

Pharmacologically acceptable amine cations are cations of primary, secondary or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, triethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, dicyclohexylamine, diethylenetriamine, and other aliphatic, cycloaliphatic, and araliphatic amines having up to about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and their lower alkyl derivatives, e.g., 1-methyl-pyrrolidine, e.g. , 2-methylpiperidine, and the like amines, as well as amines having water-solubilizing or hydrophilic groups, e.g. mono-, di- and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol , 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-prop panol i, tris- (hydroxymethyl) aminomethane, N-phenylethanolamine, N- (p-tert-amylphenyl) diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and amines such as these.

Examples of suitable pharmacologically acceptable quaternary ammonium cations include tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.

Various reaction-neutral diluents, excipients or carriers may be used in the preparation of any of a number of possible formulation compositions. Such substances include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, resins, polyalkylene glycols, petrolatum gel, cholesterol, and other known drug carriers. If desired, these pharmaceutical compositions may contain adjuvants such as preservatives, wetting agents, stabilizers, or other therapeutic agents such as antibiotics.

The following examples are illustrative only and in no way limit the scope of the appended claims. Spectral values were obtained on a Varian T-60 or Δ-60 NMR, a Perkin-Elmer IR spectrometer and an LKB-9000 mass spectrometer. Infrared values are reported as 1 / cm and NMR values are reported as ^ -ppm using standard TMS.

The reaction temperatures described in the examples, unless specified, are considered to mean ambient or room temperatures ranging from 15 to 30 ° C.

The reaction times required for the reactions described in the examples were determined, unless otherwise indicated, by monitoring the progress of the reaction by flash chromatography (TLC). A common TLC system was silica gel on glass (E. Merck Silica Gel plates, E. Merck Darmstadt, West Germany) with benzene / ether or methanol / chloroform mixtures as eluents and vanillin / ethanol or iodine color developers. ^ 'Introduction to Chromatography ", J.M. Bobbitt, A.E. Schwarting, R. J. Gritter, Van Nostrand-Reinhold, N.Y. 1968Λ As a general rule, this reaction was considered to be substantially complete when the TDC spot corresponding to the starting material had disappeared or completely faded.

Example 1 5 - [- (Tetrahydropyran-2'-yloxymethyl) -2-pyrrolidone (1)

2.54 g (22.1 mmol) of 5-D-hydroxymethylene-2-pyrrolidone, prepared by the method of V. Bruckner et al., Acta Chim, were placed in a flame-dried flask under nitrogen. Hung. Tomus, 21, 106 (1959), and 50 ml of methylene chloride. To this solution were then added 3.72 g (44.2 mmol) of freshly distilled dihydropyran and 0.2 g of p-toluenesulfonic acid at 0-5 ° C. The solution was then allowed to warm to room temperature and stirred overnight. After diluting the reaction mixture with 20 ml of ethyl acetate, the solution was extracted with 2x5 ml of saturated sodium hydrogencarbonate solution and once with 10 ml of saturated brine. The organic layer was dried over magnesium sulfate, filtered to remove the desiccant, and the solvent was removed in vacuo to give 4.1 g of a yellow oil. This oil was chromatographed on a column of 50 g of Merck silica gel packed in chloroform. Elution with 27 L of 0 7 9 chloroform removed e.i-polar impurities. The product was isolated and purified by eluting with 2% methanol in chloroform and collecting in 10 ml fractions. Combining the product fractions and removing the solvent in vacuo gave 3.95 g of the title compound (I) as a yellow oil in 90% yield.

NMR T-6 O (DCCl 3) b. s. ci 6 6.60 ppm (1H), mj 4.60 ppm (1H), m cf 4.0 5- <£ 3.2 ppm (5 H), mc £ 2.50 - <= f 2.10 ppm m / z 2.00 - ς $ 1.4 0 ppm (10H).

IR (CHCl 3 solution) 3 * 4 2 5, 2980, 2930, 2850, 1680, 1250-1200, 1025 cm -1.

In addition, instead of tetrahydropyran-2-yl, a dimethyl-t-butylsilyl protecting group can be used by applying E.J.

The method of Corey et al., J. Am. Chem. Soc. 94, 6190 (1974) for the preparation of 5-hydroxymethylene-2-pyrrolidone.

Example 2 1- (71- (ethylheptanate) -5A- (tetrahydropyran-2H-oxymethyl) -2-pyrrolidone (2_)

To a flame-dried flask filled with nitrogen was charged 0.725 g (18.7 mmol) of a 62% mineral oil dispersion of sodium hydride and 10 mL of dry tetrahydrofuran. To this mechanically stirred slurry was then slowly added dropwise 3.74 g (18.7 mmol) of S-D- (tetrahydropyran-2-yloxymethyl) -2-pyrrolidone 1 dissolved in 10 ml of dry tetrahydrofuran. At the end of the addition, the thick slurry was stirred for 30 minutes until hydrogen evolution had completely ceased. Alkylation of the sodium salt was then performed.

To this slurry was then added dropwise 5.34 g (22.5 mmol) of ethyl 7-bromoheptanoate in 15 mL of dry DMF at room temperature. At the end of the addition, after about 15 minutes, the slurry had dissolved and sodium bromide began to precipitate slowly from the solution. The reaction mixture was stirred overnight, then filtered and the solvent removed from the filtrate in vacuo. To the residue was then added 100 ml of ethyl acetate and this organic solution was extracted with 2 x 20 ml of water. After the organic layer was dried over magnesium sulfate and filtered to remove the desiccant, the solvent was removed from the filtrate in vacuo to give a yellow oil which was chromatographed on a column of 120 g of Merck silica gel in chloroform. Eluting with: (a) 250 ml of chloroform; (b) 500 ml of 5% chloroform solution of ethyl acetate; (c) per liter of 10% chloroform solution of ethyl acetate, 70009 and by automatically collecting 10 ml fractions, the product could be isolated and purified. The product fractions were combined and the solvent removed to give the title compound {2} as a colorless oil, 3.3 g, 51% yield.

NMR T-60 (DCCl 3): M + 4.60 ppm (1H), q. af4.17 ppm J ± = 8 ppm, m, -4.00-2.7 ppm (9H), m, 2.6-1.4 ppm, t, S1.3 ppm = 8 Hz. (2 3 H).

IR (HCCl 3 solution) 2975, 2915, 2840, 1720, 1665, 1450, 1250-1200, 1125, 1025 cm -1.

MS heated input (w / w%) 356-1%, 355-3%, 310-17%, 240-100%, 194-83%.

Example 3 1- (7'-methylheptanate) -5 {h-hydroxymethyl-2-pyrrolidone (4),

To a solution of 200 ml of methanol and 3.99 g of THP-pyrrolidone (2) were added 79 mg of p-toluenesulfonic acid, and the solution was boiled overnight. After further work-up as described below, the NMR spectrum of the reaction mixture revealed the presence of a small amount of the starting ethyl ester. Therefore, the reaction mixture was redissolved in 160 ml of methanol, 0.080 g of p-toluenesulfonic acid was added, and the reaction mixture was boiled again overnight. Removal of the solvent from the reaction mixture in vacuo gave a yellow oil which was dissolved in ethyl acetate and extracted once with 10 ml of a 1: 2 mixture of saturated sodium hydrogen carbonate and half-saturated Rochelle's salt solution. The organic phase was dried over magnesium sulphate, filtered and the solvent evaporated to give the title compound (4) as a clear yellow oil, 2.528 g (88%).

NMR δ-6 O (DCCl 3) s. CT "3.86 ppm, m. (F 4.0 0-3.33 ppm, m <f 3.2 0-2.70 ppm (13H), m. CT 2.50-ci * 2.00 ppm, m cf 1.90-S 1.20 ppm (10H), partial spectrum.

IR (HCCl 3 solution) 3550-3100, 2980, 2910, 2840, 1720, 1650, 1450, 1425, 1410, 1250-1190 cm -1.

MS, LKB 9000, solid input (m / e-%) 70eV 226-26%, 194-19.8%, 74-1009, 13eV 257-3.3%, 226-100%, 168-24.6% .

29 70009

Example 4 1- (7'-Methylheptano) -5H-formyl-2-pyrrolidone (6)

To a flame-dried flask filled with nitrogen gas was added 0.1286 g (0.5 mmol) of 1- (7β-methylheptane) -5- (N-hydroxymethyl-2-pyrrolidone (4) in 5 mL of dry benzene. To this solution were added 0.1286 g (1.5 mmol) of dimethylaminopropylethylcarbodiimide hydrochloride (DAPC) and 0.142 ml (2 mmol) of dimethyl sulfoxide, followed after 5 minutes by the addition of 0.108 g (0.55 mmol) of pyridinium trifluoroacetate. The mixture was stirred under nitrogen at room temperature for 1.75 hours, after which the benzene was decanted off and the viscous second phase formed on the bottom of the flask was washed with 3x5 ml of benzene The benzene solutions were combined and the solvent removed in vacuo to give 0.152 g of the title compound (6). as a yellow oil The crude product was used immediately and without further purification in the next reaction.

NMR T-60 (DCCl 3), d. cf 9.72 ppm J = 3 Hz (1H), m cf 4.37 - 4.07 ppm (1H), m.p. 3.70 ppm (3H), partial spectrum.

Example 5 1- (71-Methylheptanate) -5O * - (4 "-phenylbut-1" -en-3 "-onyl) -2-pyrrolidones (7)

A flame-dried, nitrogen-filled flask was charged with 0.1188 g (2.97 mmol) of a 60% sodium hydride mineral oil dispersion and 5 mL of THF. To this slurry was added a solution of 0.7815 g (3.24 mmol) of dimethyl (3-phenylpropan-2-onyl) phosphonate in 5 mL of THF. When hydrogen evolution ceased, a white suspension formed which was stirred for twelve minutes. To this suspension was added 0.6894 g (2.70 mmol) of 1-7'-methylheptanate) -5/3-formyl-2-pyrrolidone (6) in 10 mL of THF over 1 minute. Within 5 minutes, the reaction mixture turned into a bright yellow solution and was stirred for another two hours. The pH of the reaction mixture was adjusted to 5 with glacial acetic acid. The solvent was removed in vacuo and the residue was dissolved in 100% ethyl acetate. The organic solution was extracted with 2 x 10 mL of saturated aqueous sodium bicarbonate, 3 x 10 mL of water and once with 10 mL of saturated brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to give 1.142 as a yellow oil. This crude product was chromatographed on a column of 35 g of E. Merck silica gel packed with ethyl acetate. By eluting with ethyl acetate and automatically collecting 10 ml fractions, the product could be purified.

The product fractions were combined and the solvent removed in vacuo to give 0.614 g of the title compound (7) as a colorless oil (yield from the starting alcohol 61%).

NMR T-60 (DCCl 3) δ cT 7.33 ppm (5H), dofd. cT 6.73 ppm J = 7h

O .1 Z

J2 = 16hz, d. 6.60 ppm J 2 = 16Hz (2H), m.p. = 4.27 ppm center (1H), mp cT3.93 (2H), m.p. 3.73 ppm (3H), partial spectrum.

IR (CHCl 3 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%.

Example 6 1- (7'-Methylheptanate) -5H - (3'1-hydroxy-4 "-phenylbut-11'-enyl) -2-pyrrolidone (8)

To a flame-dried flask equipped with a magnetic stirrer, thermometer and filled with nitrogen was added 0.5784 g (1.56 mmol) of 1- (7'-methylheptanate) -5- (4 "-phenyl-but-1'-en- 3 "-onyl) -2-pyrrolidone (7) in 20 mL of dry THF. The clear colorless solution was cooled to -78 ° C and 1.56 mL (1.56 mmol) of lithium triethyl borohydride was added dropwise over 15 minutes. After 1 hour, TLC analysis showed no starting material enone, so the reaction was quenched by the addition of glacial acetic acid until pH 5. This was followed by removal of the solvent in vacuo, the residue was dissolved in 50 mL of ethyl acetate and this organic solution was extracted. then once with 10 ml of half-saturated aqueous sodium hydrogen carbonate solution, 4x10 ml of water and once with 10 ml of saturated brine The organic layer was dried over magnesium sulphate, filtered and the solvent removed in vacuo to give 700 mg of crude product. This product 70009 was chromatographed on a column of 9 g of silica gel in ethyl acetate. By eluting with ethyl acetate and automatically collecting 5 ml fractions, the product was separated from the impurities. Combining the product fractions and removing the solvent in vacuo gave 0.298 g of the title compound (8) as a colorless oil (yield 51%).

NMR T-60 (DCCl 3) δ cf 7.37 ppm (5H), d. cf 5.72 ppm J = 7 Hz, d. cf 5.62 ppm = 7 Hz (2H), m 4.67 - cf * 4.33 ppm, m. "4.30 - <P 3.83 ppm (2H), s. << 3.73 ppm (3H), d.c. 2.90 ppm Jj = 6 Hz (2H), partial spectrum.

IR (HCCl 3 solution) 3450-3200, 2975, 2900, 2830, 1725, 1665, 1250-1200 cm -1.

Example 7 1- (61-Carboxyhexyl) -5H- (3''-hydroxy-4 "-phenylbut-1" -enyl) -2-pyrrolidone (9)

To a solution of 69 mg (0.185 mmol) of 1- (7-methylheptanoate) -5%% (3-hydroxy-4-phenylbut-1-enyl) -2-pyrrolidone (8) in 3 ml of methanol was added. 0.185 mL (0.185 meq) of 1-norm. sodium hydroxide. The reaction solution was then boiled overnight and then neutralized by the addition of glacial acetic acid until the pH was 4. The solvent was removed in vacuo and the oily residue was dissolved in 15 ml of ethyl acetate. The organic solution was extracted with 2 x 2 mL of water and once with 2 mL of brine, dried over magnesium sulfate and filtered. The solvent was removed in vacuo to give the title compound (9) as a yellow oil; 59.4 mg, yield 89%.

NMR T-60, DCCl 3, m.p. 7.33 ppm (5H), b.s. <f 6.30 ppm center (1H), d. cf 5.73 ppm ~ 7 Hz, d. cf * 5.6 ppm = 7 Hz (2H), m. <f * 4.6 - cf 3.2 ppm (4H), d. cf 2.93 ppm = 7 Hz (2H), (partial spectrum).

IR, HCCl solution, 3500-3100, 2980, 2920, 1700, 1600, 1250-1200 -1 d cm

Example 8 32 70009 1- (71-Methylheptanate) -5H- (4N-phenoxybut-11, -en-3 "-onyl) -2-pyrrolidone (10)

A flame-dried flask filled with nitrogen was charged with 22 mg (0.55 mmol) of a mineral oil dispersion of sodium hydride and 5 mL of THF. To this slurry was added a solution of 1549 g (0.6 mmol) of dimethyl (3-phenoxypropan-2-onyl) phosphonate in 5 mL of THF. After the evolution of hydrogen ceased, a clear, pale yellow solution remained, which was stirred for fifteen minutes. To this solution was added 0.1277 g (0.5 mmol) of 1-7'-methylheptanate) -5-formyl-2-pyrrolidone (6) in 5 mL of THF over one minute. Within five minutes, the reaction mixture had become a clear yellow solution and was stirred for another two hours. The reaction was quenched by the addition of glacial acetic acid until the pH was 5. The solvent was removed in vacuo and the residue was dissolved in 50 mL of ethyl acetate. The organic solution was extracted with .2x5 ml of saturated aqueous sodium hydrogen carbonate solution, 2x5 ml of water and once with 5 ml of saturated brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to give 0.231 g of a yellow oil. This crude product was chromatographed on a column of 25 g of E. Merck silica gel in cyclohexane. By eluting with 50% chloroform in cyclohexane and collecting 10 ml fractions, the product was purified. The product fractions were combined and the solvent removed in vacuo to give 53.6 g of the title compound (10) (28% based on the starting alcohol).

NMR T-60 (DCCl 3), m <7.40-6.70 ppm (5H), m c 6.7 - 6.33 ppm (2H), m.p. 4.67 ppm (2H), mp ci 4.40-3.97 ppm (1H), m.p. 3.67 ppm (3H), partial spectrum.

Example 9 70009 1- (71-Methylheptanate) -5- (3 "-hydroxy-4" -phenoxybut-1-enyl) -2-pyrrolidone (11)

To a flame-dried flask equipped with a magnetic stirrer thermometer and filled with nitrogen was added 0.1046 g (0.27 mmol) of 1-7'-methylheptanate) -5- (4 "-phenoxybut-1" -en-3 "-onyl) -2-pyrrolidone (10) in 5 mL of dry THF. The clear colorless solution was cooled to -78 ° C and 0.27 mL (0.27 mmol) of lithium triethylborohydride was added dropwise over 15 minutes using TLC analysis showed that the starting enone disappeared after 1 hour, so the reaction was quenched by the addition of glacial acetic acid until the pH was 5, followed by removal of the solvent in vacuo, the residue was dissolved in 25 ml of ethyl acetate and this organic solution was then extracted once. 5 ml of half-saturated aqueous sodium hydrogen carbonate solution, once 10 ml of water and once 10 ml of saturated brine The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to give 101 mg. raw product. This product was chromatographed on a column of 25 g of silica gel in benzene. By eluting with ethyl acetate and automatically collecting 5 ml fractions, the product was purified from impurities, but the epimers did not separate. Combining the product fractions and removing the solvent in vacuo gave 85.6 mg of the title compound (11) (yield 8 2%).

NMR T-60 (DCCl 3) δ cd 7.54 - 6.82 ppm (5H), m cT 5.94 - 5.73 ppM (2H), m cf δ 4.79 - 4.43 ppm (1H ), mp 4.33 - 3.94 ppm (3H), m.p. 3.70 ppm (3H), partial spectrum.

IR (CHCl 3 solution) 3600-3100, 2980, 2920, 1730, 1670, 1600, 1200-1250 cm -1.

Example 10 34 70009 1- (61-carboxyhexyl) -5,3 "-hydroxy-4 * -phenoxybut-1" -enyl) -2-pyrrolidone (12)

To a solution of 50 mg (0.128 mmol) of 1- (7'-methylheptanoate) -5 / 3- (3 "-hydroxy-4" -phenoxybut-1 "-enyl) -2-pyrrolidone (11) in 3 mL 0.128 ml (0.128 mmol) of 1N sodium hydroxide were added in methanol, the reaction solution was boiled overnight and then neutralized by the addition of glacial acetic acid to pH 4. The solvent was removed in vacuo and the oily residue was dissolved in 15 ml of ethyl acetate. 11a of water and once 2 ml of saturated brine, dried over magnesium sulfate and filtered, the solvent was removed in vacuo to give the title compound (12) as a yellow oil, 48.0 mg (99% yield).

NMR T-60 (DCCl 3) δ cf 7.40 - 6.82 ppm (5H), m cf 6.73 - 6.17 ppm (2H), m d> 5.87 - 5.7 ppm (2H), m.c. 4.7-4.4 ppm (1H), mf ~ 4.23-3.88 ppm (3H), partial spectrum.

IR (HCCl 3 solution) 3,600-2900, 2920, 1700, 1670, 1600, 1200, 1250 cm -1.

Example 11 1- (7 * -methylheptanate) -5 / 3- (3''-tetrahydropyran-2 "'-yloxy-4" -phenylbut-1-enyl) -2-pyrrolidone (13)

To a flame-dried, nitrogen-filled flask was charged 128 mg (0.342 mmol) of 1- (7'-methylheptanate) -5β- (3 "-hydroxy-4" -phenylbut-1-enyl) -2-pyrrolidone (9) and 5 ml of methylene chloride. To this solution at 0 ° C to 5 ° C were then added 0.062 ml (0.684 mmol) of redistilled dihydropyran and 3 mg of p-toluenesulfonic acid. The solution was then allowed to warm to room temperature and stirred overnight. The reaction mixture was further treated by diluting with 10 ml of ethyl acetate, extracted with 2 x 2 ml of saturated aqueous sodium hydrogencarbonate solution and once with 5 ml of saturated brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to give 0.135 g of a yellow oil. This was chromatographed on a column using 15 g of Merck silica gel in chloroform. Elution with one liter of chloroform removed non-polar impurities. Eluting with 2% methanol in chloroform and automatically collecting 10 mL fractions, the product was isolated and purified. Combining the product fractions and removing the solvent in vacuo gave 0.1756 g of the title compound (13) as a yellow oil.

NMR T-60 (DCCl 3) δ δ 6.3 6 4 ppm (5H), m cT 5.7 δ 5.37 ppm (2H), m δ 5.11 - 4.80 ppm (1H), s. d "3.7 ppm (3 H), partial spectrum.

Example 12 1- (7,1-Methylheptanate) -5β- (3,11-tetrahydropyran-2 '-1-yloxy-4,11-phenylbutyl) -2-pyrrolidone (14)

To a solution of 156.5 mg (0.342 mmol) of 1- (7'-methylheptanoate) -5- (3 "-tetrahydropyran-2" '- yloxy-4 "-phenylbut-1-enyl) 2-pyrrolidone (13) in 10 mL of ethyl acetate, 31 mg of 10% palladium on carbon catalyst was added, and the entire mixture was placed in a Parr hydrogen reduction apparatus and shaken under 50 lb (23 kg) of hydrogen for 4 hours. then the slurry was filtered through Celite to remove the catalyst and the solvent was removed from the filtrate to give 158.2 mg of the title compound (14).

NMR T-60 (DCCl 3) δ cT 7.33 ppm (5H), m cf 5.13 - 4.67 ppm (1H), m cf 4,5 4.57 - 4.33 ppm (1H), s. cT "3.73 ppm (3H), partial spectrum.

Example 13 1- (6'-Carboxyhexyl) -5- (3 "-tetrahydropyran-2" 1-yloxyphenylbutyl) -2-pyrrolidone (15) -

To a solution of 1582 mg (0.342 mmol) of 1- (7'-methylheptanate) -5 '(3 "-tetrahydropyran-2"' - yloxy-4 "-phenylbutyl) -2-pyrrolidone (14) in 5 ml: 0.342 ml (0.342 mmol) of 1N sodium hydroxide were added, the reaction solution was boiled overnight and then neutralized by the addition of glacial acetic acid to pH 4. The solvent was removed in vacuo and the oily residue was dissolved in 15 ml of ethyl acetate. ml of water and once 2 ml of saturated brine, dried over magnesium sulfate and filtered, and the solvent was removed in vacuo to give the title compound (15) as a yellow oil: 134.2 mg (yield 89%).

NMR T-60 (DCCl 3) δ g 7.37 ppm (5H), m d 4 4.4 - 3.2 ppm, m.

<5.92 (2H), partial spectrum.

Example 14 1- (6'-Carboxyhexyl) -5,3- (3, '- hydroxy-3-phenylbutanilyl) -2-pyrrolidone (16) (8-aza-11-deshydroxy-16-phenyl-16-yl) J-tetranor-PGE 16).

A solution of 134.2 mg (0.3 mmol) of compound (15) was stirred overnight under nitrogen at room temperature in 5 ml of a 65:35 mixture of acetic acid and water. The solvent was then removed in vacuo by evaporation using an oil vacuum pump, and the residue was azeotroped with benzene. The crude product was then chromatographed on 15 g of ARCC7 silica gel and eluted with 2% methanol in chloroform to give 82 mg of the title compound (16).

NMR T-60 (DCCl 3) δ <5 "7.17 ppm (5H), m. D ~ 3.2 - 4.0 ppm (3H), d. Cf 2.77 ppm, = 7 Hz (2H) , partial spectrum.

IR (HCCl 3 solution) 3600-3100, 2930, 2860, 1700, 1660, 1250, 1200, 710 cm -1.

Claims (1)

37 70009 A process for the preparation of novel 1,5-disubstituted-2-pyrrolidone compounds of formula (I) and their C5 epimers having prostaglandin-like biological properties? R 2 is R 'M wherein Q is -COOK, wherein R is hydrogen or alkyl of 1 to 5 carbon atoms, Z is a single bond or a trans double bond, M is Η ^ ,, ν0Η or H (XH, and R' is phenyl or phenoxy, characterized in that the pyrrolidone intermediate kaν / \ - (II) "ΜΎ" '· of formula (II) is reduced in which Q, Z and Rf have the same meaning as above, in order to change the 3 "oxo group to an alpha-hydroxy or to a beta-hydroxy group, and optionally esterifying a pyrrolidone compound of formula (I) wherein Q is carboalkoxy, or optionally hydrolyzing a pyrrolidone compound of formula (I) wherein Q is carboalkoxy to give a compound of formula (I) wherein Q is - C00H.