CH624934A5 - - Google Patents

Description

This invention relates to the preparation of a new series of 1,5-disubstituted 2-pyrrolidones whose chemical structure and biological character are of the prostaglandin type.

The unsaturated C20 fatty acids known as prostaglandins form a large family of natural compounds. These molecules can have as many as five asymmetric centers and are found in various biological tissues and cause reactions there. An example of a particular type of the genus Prostaglandins E is PGE2 described below.

60

x \

B ^ N H Prostaglandin E

/at.

Pyrrolidone where A and B denote the two side chains of the examples. Here the illustration represents the eclipsed position of link A-C8 and link C12-H and the eclipsed position of link C12-B and

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the C8-H bond in the case of prostaglandin E, and the bisector position of the A-N8 bond relative to the dihedral angle formed by B-C12-H in the case of pyrrolidone. This difference in conformation is due to the planar character generated by the amide part of the pyrrolidone. ["Basic Principles of Organic Chemistry", J.D. Roberts and M.C. Caserio, W.A. Benjamin, New York, 1965, p. 674.]

The systematic name of a 1,5-substituted 2-pyrrolidone of formula:

0

H OH

is 1 - (6'-carboxyhexyl) -5 ß- (3 '"a-hydroxyoct-1" -ény l) -2-pyrroli-done, and can also be named as a derivative of 11-deoxyprostaglandin Ei, c i.e. 8-aza-ll-deoxy-PGEi. The 8-aza-l 1-deoxy derivative PGE2 corresponding to the structure:

compound, the rac symbol will precede the compound name. This term will then mean and appropriately represent an equimolar mixture of the D and L forms or enantiomers.

A couple of optical isomers which are optical antipodes or enantiomers are linked by the inversion of the absolute configuration of all their centers of asymmetry. On the contrary, when the relation is the inversion of the absolute configuration to one or more but not to all the centers of asymmetry, the pair of isomers is made up of epimers or diastereoisomers. For example, 1- (6'-carboxyhexyl) -5p- (3 "a-hydroxyoct-l" -enyl) -2-pyrrolidone and 1- (6'-carboxyhexyl) -5oc- (3 "a- hydroxyoct-1 "-enyl) -2-pyrrolidone are diastereoisomers linked by the inversion of the configuration on the carbon atom C5 and are represented respectively by:

15 0

H OH

where the double bond between C2 'and C3' has been replaced by a double bond. The compound 8-aza-l 1-deoxy-PGEo corresponding to the structure:

where the double bond between Cl "and C2" has been replaced by a single bond.

The preceding pyrrolidones have several centers of asymmetry and can exist in racemic form (optically inactive) and in one or the other of the two enantiomeric forms (optically active), that is to say the dextrorotatory forms (D). and levorotatory (L). As indicated above, each pyrrolidone structure represents the optically active form or the particular enantiomother, which can be derived in part from D-glu-tamic acid. The image in a mirror or the optical antipode of each of the preceding structures represents the other enantiomer of this pyrrolidone and is partly derivable from L-gluta-mic acid.

For example, the optical antipode of 1- (6'-carboxyhexyl) -5ß- (3 "a-hydroxyoct-1" -enyl) -2-pyrrolidone is represented by:

0

HÜ H

and is called 1 - (6'-carboxyhexyl) -5oc- (3 "ß-hydroxyoct-1" -ény l) -2-pyrrolidone.

The racemic form of the preceding pyrrolidone contains equal amounts of a particular enantiomer and its optical inverse. When we wish to refer here to the racemic mixture of a

H OH

It is a fact that chemical experiments on one or the other of the elements of an enantiomeric couple or on a mixture of the two will give identical results.

As previously indicated, the replacement of the C8 carbon atom with a nitrogen atom introduces a significant change in the three-dimensional configuration of the resulting prostaglandin. As structure is related to biological activity and a subtle change in structure such as a change in conformation will often have a profound effect on biological activity, such molecular modification of prostaglandins by substitution of heteroatoms has been studied recently . Most of the compounds come from tests for substitution of heteroatoms at the C9 and Cl 1 positions of prostaglandin and include examples such as 9-oxaprostaglandins, [I. Vlattas, "Tetrahedron Let.", 4455 (1974)]; 11-oxaprostaglan-45 dines [A. Fougerousse, "Tetrahedron Let.", 3983 (1974)] and S. Hanessian et al., "Tetrahedron Let.", 3984, (1974)] and 9-thia-prostaglandins [I. Vlattas, "Tetrahedron Let.", 4459 (1974)].

Two 8-aza-1 1-deoxyprostaglandins E having the natural side-chain co, that is to say compounds having a substitution aza-C8 C8 of 11-deoxyprostaglandins Ei and E2 have also been described in the literature [ G. Bolliger and J.M. Muchowski, "Tetrahedron Let.", 2931 (1975) (August 1975); and J.W. Bruin et al., "Tetrahedron Let.", 4599 (1975)]. These examples of pyrrolidone derivatives are outside the field of the present invention, which presents a higher order of complexity and of molecular variation in the C1 position of the prostaglandin and in the side chain co. Relatively low biological activity is indicated for these examples from the literature, and can be distinguished by the shape and molecular complexity of the new compounds of the present invention.

Natural prostaglandins and many of their derivatives such as esters, acylates, and pharmacologically acceptable salts are extremely potent inducers of various biological reactions [D.E. Wilson, "Arch. 65 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 system, hematological, reproductive,

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gastrointestinal, pulmonary, nephritic, epidermal, cardiovascular and adipose, and act as mediators in the process of homeostasis. With such a wide reaction interval, it is obvious that prostaglandins are involved in the basic biological processes of the cell. In fact, this basic implication of prostaglandins is confirmed by the fact that they can be found in the cellular tissue of almost all animal organisms.

At such a cellular level, the actions of very close natural prostaglandins can often be opposed. For example, the effect of PGE2 on human blood platelets is the improvement of aggregation, while that of PGEi is the inhibition of this aggregation.

Such contrary effects can also be observed at the tissue level. For example, the action of PGE2 in vivo on the cardiovascular system of mammals manifests itself by causing hypotension while the in vivo action of PGF2a is hypertension [J.B. Lee, "Arch. Intern. Med. ”, 133, 56 (1974)]. However, the ability to predict the biological action of the categories of prostaglandins based on such observations is at present largely illusory. For example, while the cardiovascular actions of PGE2 and PGF2a are opposite as described above, their action in vivo or in vitro on the smooth muscle of the mammalian uterus is the same and is a stimulating action (causes the contraction) [H. R. Behrman et al., “Arch. Intern. Med. ”, 133, 77 (1974)].

In the preparation of synthetic pharmaceutical agents, among the main aims, one finds the development of compounds which have a very selective pharmacological activity and which have an increased duration of activity compared to the related natural compounds. In a series of compounds similar to natural prostaglandins, increasing the selectivity of a single compound generally includes improving a physiological effect of the prostaglandin type and decreasing the others. By increasing the selectivity, the important side effects commonly observed after the administration of natural prostaglandins would be relieved; for example gastrointestinal side effects of diarrhea and vomiting or cardiovascular side effects when you want broncho-dilation effects. Recent developments concerning an increase in biological selectivity have developed 11-deoxyprostaglandins [N. H. Anderson, “Arch. Intern. Med. ”, 133, 30 (1974) Review], 2-decarboxy-2- (tetrazol-5-yl) -1-deoxy-co-pentanorprostaglandins substituted in position 15 (US Patent No. 3,932,389, MR Johnson et al.) where certain modifications are cited as producing selective vasodilation, anti-ulcer, anti-fertility, bronchodilator, and anti-hypertensive properties, 16-phe-noxy-16-w-tetranorprostaglandins having anti-fertility activity (UK Patent No. 1350971) and 1-imide and 1-sulfonimide-prostaglandins (US Patent No. 3954741).

The present invention provides new prostaglandin-type compounds which have a selective and powerful biological activity and which have the structural formula:

o

1 /

and its epimer in C5, formula in which:

Q is a radical - COOH, - COOR, tetrazol-5-yl or —CONHR ",

R being a C 1 to C 5 alkyl, phenyl or p-biphenyl group and

R "a radical of formulas —COR '" or - so2r' "where R '" is a phenyl or C1-C5 alkyl group,

W is a single bond or an eis double bond;

Z is a single bond or a trans double bond;

5 H OH

/ /

M is a pair;

, and

OH

H

R 'is an α-thienyl, phenyl, phenoxy group; phenyl or phenoxy monosubstituted by chlorine or fluorine or a phenyl, methoxy, trifluoromethyl or C1-C1 alkyl group, and of alkali, alkaline earth metal and ammonium salts of the compounds having a carboxylic or tetrazol group -5-yle.

Intermediaries will be described below which allow the preparation of the above final products, and which have the formulas developed:

25

and its C5 epimer where Q 'is chosen from the group comprising the —COR groups; tetrazol-5-yl, N- (acyloxymethyl) tetra-zol-5-yl in which the acyloxy group has from 2 to 5 carbon atoms, N- (phthalidyl) tetrazol-5-yl and N- (tetrahydropyran-2-yl ) -30 tetrazol-5-yl, and W, Z, R 'and R are each defined as above; not

W

and its epimer at C5, where W and Q 'are as defined above; q

0

"I—

OH

45 H

and their epimers on C5 carbon.

Are interesting as agents having a selective biological activity of the prostaglandin type, the pyrrolidones of the series of compounds of structural formula:

in which W, Z, M, R 'and R are as defined above as well as their epimers on C5 carbon.

œ The pyrrolidones of developed formulas are also interesting in this respect:

0

W

5

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and

N — N II

N — N

in which W, Z, R ', M and R "are as defined above as well as their C5 epimers.

The compounds with the structural formula are particularly interesting for the above:

in which W, Z, M and R 'are as defined above and their C5 epimers.

Another series of particularly interesting compounds having a selective biological activity includes those of structural formula:

in which W, Z, M and R 'are as defined above and their C5 epimers.

The following compounds are particularly preferred for their selective biological activity:

1 - (6'-carboxyhexyl) -5 p- (3 "a-hydroxy-4" -phenylbut-1 "-enyl) -

2-pyrrolidone, its methyl ester and their epimers 5a,

1 - (6'-carboxy-hex-2'-enyl) -5p- (3 "a-hydroxy-4" -phenylbut-r-enyl) -2-pyrrolidone and its epimer 5a,

1 - (6'-carboxyhexyl) -5p- (3 "a-hydroxy-4" -phenylbutanyl) -2-5 pyrrolidone and its epimer 5a,

l- (6'-carboxyhexyl) -5p- (3 "a-hydroxy-4" -phenoxybut-l "-enyl) -2-pyrrolidone and its epimer 5a,

1 - (6'-carboxyhex-2'-enyl) -5p- (3 "a-hydroxy-4" -phenoxybut-l "-enyl) -2-pyrrolidone and its epimer 5a,

io la 1- (6'-carboxyhexyl) -5p- (3 "a-hydroxy-4" -phenoxybutanyl) -2-pyrrolidone and its epimer 5a,

compounds in which the 6 '- (tetrazol-5-yl) group replaces the 6'-carboxy group of each of the above particularly preferred compounds, and the compounds in which a 3 "ß-hydroxy group replaces the 3" group a -hydroxy of each of the above 6'-carboxy and 6 '- (tetrazol-5-yl) compounds.

The pyrrolidone derivatives of the present invention of the prostaglandin type (prostamimetics) are prepared in optically active form by a series of five steps which fix the two side chains, the side chain a or higher and the side chain <a or lower, on the pyrrolidone cycle, and which starts from a split amino acid, D- or L-glutamic acid. It will be noted that the choice of a synthesis route starting from D- or L-glutamic acid establishes the absolute configuration of the C5 carbon of the pyrrolidone 2-25 cycle and eliminates at the outset the need to split this position at the end of the synthesis. In the examples and the following discussion, the D configuration is represented. The L configuration compounds are prepared by the same series of reactions starting from L-glutamic acid.

The synthetic sequence shown in Scheme A illustrates the processes by which the α chain is attached to the 2-pyrroli-done nucleus. It will be noted that the methods in each case prepare 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 shown in Schemes B, C and D.

Diagram A: Attaching the chain at a

0

r \ „

V "2

H

(at)

C02H

XCH2CH (OY) 2

624934

17

ch2ot l l oy

(f) Y

ch2ot

Ph3P = CH (CH2) 3W

18

The steps in Scheme A can be briefly summarized as follows. The first step, marked (a), illustrates the cyclization of D-glutamide acid to methyl D-pyroglutamate and the reduction of 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 the protective agent T which may be any group suitable for the protection of the hydroxyl group against alkylation, for example a benzyl group, dimethyl-t -butylsilyl, acetyl, 1-hydroxyethyl or in particular tetrahydropyranyl. Steps (c) and (e) illustrate the alkylation of the sodium or lithium salt of pyrrolidone 1 by alkylating agents of formula:

w x

or XCH2CH (OY) 2 respectively, where X is Cl, I or in particular Br; Q 'is a group CO2R3, (N-acyloxymethyl-tetra-zol) 5-yl in which the acyloxy group has from 2 to 5 carbon atoms, N- (phthalidyl) -tetrazol-5-yl, N- (tetrahydropyran-2 -yl) tetra-zol-5-yl or tetrazol-5-yl; Y is an alkyl group having from 1 to 3 carbon atoms, and W and R3 are as defined above.

Step (d) is the elimination of the protective group T, the process of which depends on the identity of the group T. Step (f) is the deprotection of the pyrrolidone compound 18 to form in situ the l- (ethan- 2'-al-5-hydroxymethyl) 2-pyrrolidone which may exist in intimate equilibrium with the hemiacetal derivative 5. Step (g) is a Wittig reaction on the equilibrium mixture containing bicy-clo [4,3, 0] nonan-5-one-5, with a phosphorane of formula PI13P = CH (CH2) 3 Q 'where Q' defined above is unprotected, to form the corresponding 2-pyrrolidone derivative 19 where W is a double bond.

The reactions necessary to produce the compounds of the invention are carried out such that no epimerization of the optically active center at C5 will occur. Thus, starting from one or the other of the two enantiomers of glutamic acid, the products will have the same configuration with asymmetric centers. Starting from racemic glutamic acid, racemic compounds will be produced.

The C5 position of the intermediates and products of the present invention will be shown in the β configuration, but the a configuration in the C5 position can also be used, provided that the starting glutamide acid has the appropriate configuration.

The first two steps of the reaction sequence are the condensation and esterification of D-glutamic acid to form the corresponding methyl D-pyroglytamate of structural formula: q

C02Me

[E. Hargegger et al., "Helv. Chem. Acta. ”, 38, 312 (1955); E. Se-45 gel "J. Am. Chem. Soc. ”, 74, 851 (1952)].

The third known step in the sequence shown in Scheme 1 under the name of step (a) is the reduction of the 5-carboxymethyl group of methyl D-pyroglutamate to form 5-D-hydroxymethyl-2-pyrrolidone. This reaction is most commonly carried out using a variant of the method described by V. Bruckner et al. ["Acta. Chem. Hung. Tomus ”, 21, 106 (1959)].

The methyl D-pyroglutamate is stirred with lithium borohydride in dry tetrahydrofuran or other ethereal solvent until the reaction is substantially complete. Isolation of the product in the indicated manner gives 5-D-hydroxymethyl-2-pyrrolidone of structural formula:

0

A-h h

'ch2oh

To alkylate the nitrogen of the amide of 5-D-hydroxymethyl-2-pyrrolidone, it is suitable to protect the labile hydrogen from the 5-hydroxymethyl group by the known tetrahydropyranyl group. This protection (diagram A, step (b) is the most

7

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conveniently carried out by bringing 5-D-hydroxymethyl-2-pyr-rolidone into contact with dihydropyranne, in the presence of an organic acid such as p-toluenesulfonic acid and in an inert solvent such as methylene chloride, chloroform, tetrahydrofuran, or diethoxyethane. The appropriate temperature range for this reaction is from the temperature of the ice bath to that of the refluxing solvent, and is preferably room temperature. Once the formation of 5-D- (tetrahydropyran-2'-yloxymethyl) -2-pyrrolidone 1 is generally completed, generally overnight, the compound is isolated by first removing the organic acid by basic extraction, and by removing the solvent and any excess of dihydropyran by vacuum evaporation techniques. The product is most commonly purified by column chromatography.

Other protective agents, which can be used with equal ease, include any agent which will protect the hydroxyl group from alkylation. Examples are the benzyl, acetyl, dimethyl-t-butylsilyl, and 1-ethoxy-ethyl groups. These protective groups are readily available and can be attached to the 5-hydroxymethyl group by known methods. Their choice for the purpose of synthesis will depend on the protective group in CT. For example, if it is desired to use an N-tetrahydropyran-2-yl group as a protecting group for the acid hydrogen of a tetrazol-5-yl group in CT (Q ′), the appropriate protective groups for the hydroxyl group in C3 "(T) would be the acetyl or dimethyl-t-butylsilyl groups.

The 2-pyrrolidone derivatives alkylated in position 1 (compounds 17 and 18 of scheme A) are prepared by a combination of two reactions which are carried out on 5-D- (tetrahydropyran-2'-yloxy-methyl) -2 -pyrrolidone 1 whatever the group T. The sodium or lithium salts of pyrrolidone 1 are first prepared by bringing a solution of compound 1 into contact in an inert organic solvent, such as tetrahydrofuran, diethoxyethane or dioxane , with a base such as n-butyllithium, phenyl lithium and in particular sodium hydride. The appropriate temperature range for this salt formation is from room temperature to that of solvent reflux and is preferably room temperature. The entire base must have reacted before starting the alkylation, which generally requires periods of 1 to 4 hours. Thus, the desired 1-alkylated 2-pyrrolidone derivatives 17 and 18 are respectively formed by bringing the lithium or sodium salt prepared above of the 2-pyrrolidone-1 derivative into contact with an alkylating agent of formula:

Q 'or xch2ch (oy) 2

where X is CI, I and in particular Br, Q 'and W are as defined above and Y is an alkyl group having from 1 to 3 carbon atoms. This second part of the alkylation operation is generally carried out by adding a mixture of alkylating agent to the inert organic solvent defined above, or in particular by adding a mixture of alkylating agent to a polar aprotic organic solvent such as dimethylformamide or dimethylacetamide, to the mixture previously formed of the sodium or lithium salt of pyrrolidone 1 in an inert organic solvent, then allowing contact to take place between the mixture of alkylating agent and the sodium or lithium salt of 2-pyrrolidone, at temperatures ranging from room temperature to the reflux temperature of the solvent until the alkylation is essentially complete, usually overnight.

Obviously, it is also possible to prepare the alkylated 2-pyrrolidone resulting from the use of XCH2CH - (OY) 2 by using as alkylating agent XCH2CO2Et, then by selectively transforming the ester group of l- (2'-acetate) into an aldehyde. ethyl-2-pyrrolidone 5) resulting substituted.

When there is the possibility of having an acidic hydrogen present in Q ', the alkylation procedure is most conveniently carried out by protecting or otherwise eliminating this acidic hydrogen. For example, in the case where R3 is a hydrogen atom, the best method is to use an ester derivative which is then removed by alkaline hydrolysis at the end of the synthesis sequence. In the case where Q ′ is a tetra-zol-5-yl group, the best method is the replacement of acidic hydrogen with an acyloxymethyl group as defined above, a phthalidyl group [W. v. Daehme, "J. Med.

Chem. ”, 13.607 (1970); I. Isaka et al., “Chem. Pharm. Bull. ”, 24, 102 (1976)], or a tetrahydropyran-2-yl group. The first two groups for the protection of the tetrazol-5-yl group will also be eliminated by alkaline hydrolysis at the end of the synthesis (scheme B) but the THP group will be eliminated by acid hydrolysis. It will be assumed in the following discussion that the acid hydrogen of the group Q 'has been protected, unless otherwise indicated.

The character of the C2'-C3 'bond of the 2-pyrroli-20 done 17 derivative obtained in the alkylation step is determined by the nature of W in the alkylating agent

The choice of W will also determine the unsaturated or saturated character of the side chain α of the final product of the synthesis, that is to say that the final product will be a 9-aza-ll-deoxy PGEi or an 8- aza-l 1-deoxy PGE2.

Obviously, the choice of W only results in a difference in the character of the C2'-C3 'bond of the side chain in oc and in fact the transformation of the pyrrolidone derivatives where W is a double bond into those where W is a single bond is possible at the synthesis stage corresponding to the pyrrolidone 17 derivative. For example, the 2-pyrrolidone 17 derivative having a double W bond can be transformed into a 2-pyrrolidone 17 derivative with a single W bond, by hydrogenation on a catalyst which is a noble metal, such as palladium on carbon, at room temperature until an equivalent of hydrogen has been absorbed.

50 Compound 17 W = double bond. Compound 17 W = single bond.

In both cases, the protector T is removed (step (d), scheme A) by methods known to those skilled in the art, before the formation of the side chain in co. The resulting 2-pyrrolidone 55 derivatives of structural formula:

0

W

n ~

0 '

•Oh

Compound 19

where A and Q 'are as defined above, are then brought to the new final product of the present invention through the intermediary of reaction patterns B, C and D.

The preceding 2-pyrrolidone derivative 19 can also be prepared by putting the hydrolyzed form of 2-pyrrolidone of structural formula;

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8

Diagram B illustrates this process which aims to fix the chain in co.

Diagram B: Fixing the chain in cd

Compound 18

in which Y and T are as defined above, in contact with a phosphorane of structural formula:

Ph3P = CH (CH2) 3 Q '

in which Q ′, as defined above, is unprotected, for example a CO2H or tetrazol-5-yl group. The synthesis of tetrazol-5-yl-phosphorane is found in the U.S. Patent. No. 3953466.

This sub-series of reactions illustrated by steps (f) and (g) of scheme A can be carried out as follows: if the preferred protective group T is used, that is to say in compound 18 tetrahydropyran-2-yl, the acid hydrolysis of compound 18 according to the usual method for the elimination of the acetal group, like acetic acid in water at about 40 ° C, will then cut both the tetrahydropyran-2-yl group as the acetal group to form l- (ethan-2'-al) -5p-hydroxymethyl-2-pyrrolidone which can exist in intimate equilibrium with 4-aza-2-hydroxy-l-oxa-bicyclo [4,3 , 0] nonan-5-one-5.

30

Nonanone 5

The equilibrium mixture containing hemiacetal 5 can then be brought into contact with approximately 2 equivalents of phosphorane as defined above, in a polar aprotic solvent such as dimethyl sulfoxide or a mixture of a polar aprotic solvent and an ether solvent such as tetrahydrofuran or dimethyl sulfoxide, at temperatures from 0 ° C to 60 ° C, usually overnight, to form 2-pyrrolidone 19 in which W is a double bond. It will be noted that the acid hydrogen or the group Q ′ can then be protected in the form of an ester in the case of the carboxylic acid or in the form of an N-acyloxymethyl, N-phthalidyl or N-tetrahydropy-ran group. -2-yl in the case of the tetrazol-5-yl group. This 2-pyrrolidone 19 in which W is a double bond,

can, if desired, be transformed into 2-pyrrolidone 19 in which W is a single bond, by the hydrogenation process described above.

Several of the end products of the present invention, the pyrrolidone 22, carb derivatives. and tét., are prepared by oxidation of the 5p-hydroxymethyl group of 2-pyrrolidone 12 and the Honer-Wittig reaction of the 5ß-formyl-2-pyrrolidone derivative 20 thus formed with the sodium or lithium salt of a phosphonate of structural formula:

O 0

(MeO) 2PCH2CCH2R2

in which R2 is as defined above, then by reduction of the part 5- (but-1 "-en-3" -onyl substituted at 4 ") of the 2-pyr-rolidone 21 thus formed.

19

oxidation

H

20

(MeO) 2PCH

0

î'Œ2R2

reduction

-NOT

-NOT

22-tet.

H OH

The aldehyde 20 is obtained from the derivative of 5p-hydroxymé-thyl-2-pyrrolidone 19 by a modification of the oxidation Pfitz-ner-Moffatt [K.E. Pfitzner and M.E. Moffatt, "J. Am. Chem. Soc. ”, 87, 5661 (1965)] which avoids contact of the 5β-formylated compound 20 with water. For example, agitation of a suspension of 1- (7'-methylheptanato) -5P-hydroxymethyl-2-pyrrolidone or other suitable 5ß-hydroxyn "thyl-2-pyrrolidone in soil-

9

624,934

before inert hydrocarbon such as toluene, xylene or in particular benzene, with dimethyl sulfoxide, a weak acid such as acetic acid or in particular pyridinium trifluoroacetate, and a water-soluble diimide such as diethylcarbodimide or particularly dimethylaminopropylethylcarbo-diimide, or, if desired, its hydrochloride, at temperatures from 0 ° C to room temperature for 1 to 4 h, will oxidize primary alcohol 19 to aldehyde 20. Other processes for carrying out oxidation include the usual Pfitzner-Mof-fatt reaction and oxidation with the 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 5 [} - derivative (but-1 "-en-3" -onyl substituted at 4 ") - 2-pyrrolidone 21 is prepared by bringing the 5ß-formyl-2-pyrroli-done 20 derivative into contact with the sodium or lithium salt of a phos-phonate with structural formula:

0 0

N il il (MeO) 2PCH2CCH2R2

in which R2 is as defined above, in a solution or a suspension with an ethereal solvent such as tetrahydrofuran, dimethoxyethane or. dioxane, at temperatures from 0 ° C to 50 ° C until the reaction is essentially complete, as shown by the reaction control methods. Isolation of the product of this Horner-Wittig reaction,

whose method is known to those skilled in the art, is carried out in the usual way by chromatography. Other methods include high pressure liquid chromatography, and in some cases fractional crystallization. Found in the U.S. Patent No. 3932389 the process for the preparation of phosphonates.

The reduction and, if desired, the alkaline or acid hydrolysis of the 2-pyrrolidone derivative 21 provides several of the end products of the invention where Q is a CO2R3 or tetrazol-5-yl group. The reagent of choice for carrying out the reduction is lithium triethylborohydride, but other selective reducing agents which will reduce the ketone group but not other groups, for example zinc borohydride or sodium borohydride, may be used with equal ease. The usual solvents used have an ethereal nature, such as tetrahydrofuran, or diethyl ether. The choice of temperature will be based on the activity of the reducing agent and in most cases it is convenient to use a dry ice and acetone bath.

Under the usual reaction conditions, the reduction of the but-1 "-en-3" -onyl part of pyrrolidone 21 will in fact provide two derivatives of 2-pyrrolidone 22 which are diastereoisomers:

h h

Compound 3 "a-hydroxylated 22a and

Compound 3 "P-hydroxylated 22b

Thus, these two compounds which are separable by standard isolation techniques such as high pressure liquid chromatography, are both prepared as described and it is assumed that both are shown even if only the oc isomer is shown. If the separation of the two diastereoisomers is not made, then there will be a mixture of the two compounds which is indicated in the form:

0

and this formula denotes a mixture of the oc epimer and the β epi-mother.

After isolation of the product of the preceding reduction reaction, in the usual manner, the protecting group for the acid position of the group W at C7 can be removed if desired, using current conditions for the removal of such groups. . For example, if an alkyl ester is chosen as group Q ′ and the acid is desired, a simple alkaline hydrolysis with a base equivalent at a temperature between room temperature and that of reflux of the solvent, generally in one overnight will provide the carboxylic acid after neutralization. Similarly, the phthalidyl and acyloxymethyl groups can be eliminated, but the hydropy-ran-2-yl (THP) group will be eliminated by an acid such as acetic acid in water or p-toluenesulfonic acid in methanol, at a temperature between room temperature and 50 ° C, generally overnight.

The products of the present invention in which W and Z are each single bonds, for example the compound 23 carb. and tét., are prepared by catalytic reduction of the 3 "-tétra-hydropyran-2 '" - yIoxy derivative of 2-pyrrolidone 22 where W is a single bond. This reduction is described in diagram C.

Alternatively, the pyrrolidone 23 derivatives can be obtained by catalytic reduction of the 3 "'- tetrahydropyran-2"' - yloxy derivative of 2-pyrrolidone 22 where W is a double bond. In this case, W and Z will be reduced to single bonds at the same time.

40

Diagram C

Single link 22

oh dihydropyran

R "

h ^ 2

n othp

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10

23 carb.

The tetrahydropyran-2 "'- yloxy derivative of compound 22 where W is a single bond is formed in the same manner as that described for 5-D- (tetrahydropyran-2-yloxymethyl) -2-pyrrolidone 1. Then the hydrogenation on catalysts which are noble metals such as palladium on carbon, or platinum oxide, in solvents such as ethyl acetate, methanol or ethanol, at temperatures ranging from room temperature to the reflux temperature until an equivalent of hydrogen has been absorbed, then elimination of the tetrahydropyran-2 "-yle group and, if desired, elimination of the protective group Q" by conventional methods , will allow the preparation of derivatives 23 of 8-aza-l 1-deoxyprostaglandins Eo.

The products of the present invention are prepared in which

O

II

Q is a group cnhr4 from the tetrahydro-pyran-2 "'- yloxy derivatives of compounds 22 and 23 having a group co2h in Q'. This synthetic sequence is illustrated in scheme D where Rs is defined as above. these acid derivatives, compounds 24 and 25, according to well-known methods described for the preparation of imide and sulfonimide, from carboxylic acids. The preferred method is that carried out according to the procedure of Speziale and Hurd where an acyl or sulfonyl isocyanate is brought into contact with the previously described derivatives of compounds 22 and 23, in an inert solvent such as ether or tetrahydrofuran, at temperatures ranging from room temperature to the reflux temperature of the solvent, usually overnight See the following references: AJ Speziale et al., "J. Org. Chem.", 30, 4306 (1965); CD Hurd and AG Prapas, "J. Org. Chem.", 24 , 388 (1959); reactions of isocyanates with carboxylic acids in "Sur-vey 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 Mechanisms, and Structure", McGraw-Hill, New York, 1968, p. 340.

There are also several other methods of preparing the products of the present invention in which Q is conhr4. The first of these other routes consists in treating the derivative of 5- (but-1 "-en-3" -onyl substituted at 4) -2-pyrrolidone 21 where Q ′ is a COOH group, with an acyl isocyanate or sulfonyl under the conditions described above for the procedure of Speziale and Hurd. The ketone group in position Cl5 of the resulting intermediate amino or sulfoamine pyrrolidone is then reduced to a hydroxyl group using the procedure described for the reduction of the pyrrolidone derivative 21 to the pyrrolidone derivative 22. The second other possible route consists in condensing the derivative of nonanone 5 with a phosphorane of formula Ph3P = CH (CH2) 3CONHR4, using the procedure described for the analogous preparation of pyrrolidone 19 from nonanone 5. After optional hydrogenation of the resulting C5-C6 double bond, this h I

0 N — N

NOT -

Oh

23 tet.

synthetic route gives an intermediate pyrrolidone of structural formula:

The preceding intermediate pyrrolidone-carboxamide is analogous to the pyrrolidone derivative 17 and can undergo the subsequent steps shown in Scheme B to prepare the compounds of the present invention in which Q is conhr4.

The ester derivatives of the present invention in which Q is a carboalkoxy, carbophenoxy and carboparabi-phenoxy group, can be prepared from the corresponding acid products of the present invention in which Q is COOH, by well known methods of esterification, comprising the reaction with diazoalkanes having from 1 to 5 carbon atoms, and the reaction of phenol or p-biphenol with acid and dicy-clohexylcarbodiimide.

In addition to their formation as described in diagrams A to C, the 8-azaprostaglandins can be synthesized from intermediate 18 by initial fixation of the lower side chain then formation of the upper side chain. The reactions used for this reaction sequence are represented by scheme E. They have previously been described in detail in schemes A to C. Reaction 1 is the cleavage of the dimethyl-t-butylsilyl protecting group annotated by T in the scheme and is described on pp. 12, 16 and 36. Reaction 2 is the oxidation of the primary alcohol group to an aldehyde group which forms the site of attachment of the lower side chain. This reaction is described on p. 20, lines 1-19. Reaction 3 is the Horner-Wittig reaction described on p. 20, lines 20-37. It uses the same type of phosphonate as that used in the main synthesis. Reaction 4-1 is the reduction of the enone portion of the lower side chain to an allyl group. It is described on p. 20,

line 38 at p. 26, line 9. Reaction 4-2 is the protection of the hydroxyl function of the allyl part formed in reaction 4-1. It is described on p. 14. Reaction 5 is the deprotection of the acetal group which forms the binding site of the upper side chain. It is a simple hydrolysis and it is described on p. 35. Reaction 6 is the usual Wittig reaction used to form the upper chain of prostaglandins and is described on p. 17,

lines 22-30 and p. 37. Reaction 7 is again the deprotection reaction of the hydroxyl group and is analogous to reaction 1. The symbols Y, T, R 'and Q have the meanings given above.

20

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65

11

Scheme D: Imide and sulfonimide derivatives

624,934

22.23

H

, ©

H OTHP

\ K

COCNHCR ..

^ / Sthpr '

not

O 0

He II

CNHCR,

R S02NC0

Ii OTHP

-CO,

O V

0

, ©

C0CNHS02R5

CNHS02R

CNHSOZR5

H OH 25

Diagram E

Another possible reaction scheme for the synthesis of 8-aza-Prostaglandins: O

n-ch2 ~ ch (oy) 2

1.

Y-Mè, Et T ^ Siï ^ tBu n-Bu ^ NF (reactive)

O

I

n-ch2-ch (oy) 2

ch oh

624,934

12

I

DAPCO

n-iso

Oxidation reagent

O

N-CH2-CH (OY) 2

CHO

R.

OH

I ^ O ^ COCH P (o) (OMe) 2 / WaH

7.

N-CH2 ~ CH (OY) 2

4.

1. LiBet ^ H -78e

2. Me2t-BuSiCl

H 04-

3 t n-ch2_ch (oy) 2 ~ ►

n-BU / KF (reagent) 4

^ \ = / \ A

Fh ^ P = CH (G ^) (phosphorane)

In numerous in vivo and in vitro tests, it has been demonstrated that the new prostaglandin homologs have physiological activities having a selectivity, a potency and a duration of action greater than those presented by natural prostaglandins. These tests include, among others, a test of the effect on the isolated muscle of the guinea pig uterus, the inhibition of histamine-induced bronchial spasm in the guinea pig, and the effect on blood pressure in dogs , inhibition of stress-induced ulcerations in rats, the effect of diarrhea in mice, and inhibition of stimulated gastric acid secretion in rats and dogs.

The physiological reactions observed in these tests can be used to determine the usefulness of the test substance for the treatment of various natural hepatological conditions. These identified utilities include: vasodilatation activity, antihypertensive activity, bronchodilatation activity, antifertility activity and antiulcer activity.

The novel 8-aza-1 1-deoxyprostaglandins of the present invention have very selective activity profiles over the corresponding natural prostaglandins and in many cases have a longer duration of action. By

55

example, the new prostamimetic pyrrolidones of the present invention having aryl substitutions (phenyl, substituted phenyl, and a-thienyl) in R2 and carb-oxylic acid, carboxylic ester or tetrazol-5-yl substitutions in Q, have vaso activity - usable dilator. The first examples of the therapeutic importance of these pyrrolidone derivatives are the efficacies of l- (6'-carboxyhexyl) -5ß- (3 "-hydroxy-4" -phenylbut-l "-enyl) -2-pyrrolidone and 1 - (6'-carboxyhexyl) -5a- (3 "-hydr-oxy-4" -phenylbut-l "-enyl) -2-pyrrolidone, which exhibit hypotensive activity at a power similar to that of PGE2 itself, when administered intravenously to anesthetized dogs according to the operating procedure of the USA patent No. 3956284. Simultaneously, the other activities such as bronchodilatation and antiulcer activity are very markedly reduced compared to PGE2 when they are measured by the procedure described in the US patent. No. 3956284.

Another remarkable example of the therapeutic importance of the pyrrolidones of the present invention is the selective antiulcer activity of the compounds having aryloxy substitutions (including phenoxy, and substituted phenoxy) in R2 and carboxylic acid, carboxylic ester or imide, tetrazol-

13

624,934

5-yl or sulfonimide in Q. For example, l- (6'-carboxyhexyl) -5ß- (3 "-hydroxy-4" -ph6noxybut-l "-enyl) -2-pyrrolidone exhibits remarkable and selective antisecretion activity when given orally to dogs.

The novel compounds of this invention can be used in various pharmaceutical preparations which contain the compound or a pharmaceutically acceptable salt thereof. They can be administered by various routes depending on the type of disease and the condition of the individual.

The 8-aza-1-deoxy-16-aryl-cù-tetranorprostaglandins of the present invention and their epimers are useful vasodilators. For the treatment of hypertension, these drugs are appropriately administered as an intravenous injection in doses of about 0.5-10 mg / kg, or preferably in the form of capsules or tablets in doses from 0.005 to 0.5 mg / kg / day.

The 8-aza-1-deoxy-16-aryloxy-co-tetranorprostaglandins of the present invention and their epimers are useful antiulcer agents. For the treatment of peptic ulcers, these drugs can be used in the form of capsules or tablets in doses of 0.005 to 0.5 mg / kg / day.

The pharmacologically acceptable salts, which can be used for the purposes described above, are those formed with metal cations, ammonium, amine or quaternary ammonium, which are pharmacologically acceptable.

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

The pharmacologically acceptable amine cations are those originating from primary, secondary and tertiary amines. Examples of suitable amines are methylamine, dimethylamine, triethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, Pallylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine, p-phenylethylamine, ethylenediamine, diethylenetriamine, and other aliphatic, cycloaliphatic and aralyphatic amines, containing up to 18 carbon atoms, 18 being included, as well as heterocyclic amines, for example piperidine, morpholine, pyrrolidone, piperazine, and their lower alkyl substituted derivatives, for example 1-methylpyrrolidone, 1,4-dimethylpiperazine, 2-methylpiperidine, etc., as well as amines containing hydrophilic or water-solubilizing groups, for example mono-, di- and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethy ll, 3-propanediol, 2-amino-2-methyl-1-propanol, tris (hy-droxymethyl) -aminomethane, N-phenylethanolamine, N- (pt-amylphenyl) diethanolamine, galactamine, N- methylgluc-amine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, etc.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyl-trimethylammonium, phenyltriethylammonium, etc.

To prepare any of the many possible preparations, various diluents, excipients, or carriers inert to the reaction can be used. These substances include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petrolatum , cholesterol, and other known carriers for drugs. If desired, these pharmaceutical compositions can contain auxiliary substances such as preservatives, wetting agents, stabilizing agents or other therapeutic agents such as antibiotics.

The following examples are merely illustrative and do not limit the scope of the appended claims in any way. Spectral data is obtained on a Varian T-60 or A-60 NMR device, a Perkin-Elmer infrared spectrometer, and an LKB-9000 mass spectrometer. The infrared data are given in cm −1 and the NMR data are given in s parts per million using tetramethylsilane as a reference.

In general, the reaction temperatures described in the examples when they are not specified, are room temperature or room temperature, which varies from 15 ° C to 30 ° C.

The reaction time requirement described in the examples, unless otherwise indicated, was determined by control by thin layer chromatography (TLC). The usual TLC system is silica gel on glass (silica gel plate E. Merck, E. Merck Darmstadt, West Germany) with benzene / ether or methanol / chloroform as eluents, and vanillin / ethanol as development agents. ["Introduction to Chromatography", JM Bobbitt, AE Schwarting, RJ Gritter, Van Nostrand-Reinhold, NY, 1968], As a general rule, the reaction in question is considered to be essentially complete when the spot on TLC representing the starting substance in question has disappeared or has clearly changed.

Example 1:

5 \\ - (Tetrahydropyran-2'-yloxymethyl) -2-pyrrolidone 1

2.54 g (22.1 mmol) of 5-D-hydroxymethylene-2-pyrrolidone, prepared according to the method of Bruckner et al, "Acta Chim.", Is placed in a flame-dried flask under a nitrogen atmosphere. Hung Tomus ", 21, 106 (1959), and 50 ml of methylene chloride. To this solution at a temperature of 0-5 C, then added 3.72 g (44.2 mmol) of redistilled dihydropyran and 0.2 g of p-toluenesulfonic acid (tosic). Then the solution is allowed to warm to room temperature and stirred overnight. After diluting the reaction mixture with 20 ml of ethyl acetate, the solution is extracted with 2 times 5 ml of a saturated solution of sodium bicarbonate and once 10 ml of saturated brine. The organic layer is dried with magnesium sulfate, filtered to remove the drying agent, and the solvent is removed in vacuo to give 4.1 g of a yellow oil. This oil is chromatographed on a column of 50 g of Merck silica gel packed with chloroform. Elution with 1 l of chloroform removes less polar impurities. Elution with 2% methanol in chloroform and collection of 10 ml fractions separate and purify the product. The combination of the fractions containing the product and the removal of the solvent under vacuum gives 3.95 g of the title compound 1 in the form of a yellow oil, yield of 90%.

T-60 NMR (DCCI3) s. large, 86.60 ppm (1H), m. 64.60 ppm (1H), m. 54.05-53.25 ppm (5H), m. 52.50-52.10 ppm, m. 52.00-51.40 ppm (IOH).

IR (solution in CHCI3) 3425, 2980, 2930, 2850, 1680, 1250-1200,1025 cm-1.

In addition, the dimethyl-t-butylsilyl protecting group can be used 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-pyr-rolidone.

Example 2:

1- (7'-Ethylheptanato) -5ß- (tetrahydropyran-2 "-yloxymethyl) -2-

p-pyrrolidone 2

0.725 g (18.7 mmol) of a 62% dispersion of sodium hydride in mineral oil and 10 ml of dry THF are placed in a flame-dried flask containing a nitrogen atmosphere. To this mechanically stirred suspension, add

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624,934

14

then slowly drop by drop 3.74 g (18.7 mmol) of 5-D- (tetrahydropyran-2-yloxymethyl) -2-pyrrolidone 1 in 10 ml of dry THF. Once the addition is complete, the thick suspension is stirred for 30 min until all the evolution of hydrogen ceases.

The sodium salt is then alkylated.

5.34 g (22.5 mmol) of ethyl 7-bromoheptanoate in 15 ml of dry DMF are then added dropwise to this suspension at room temperature. At the end of the addition, approximately 15 minutes, the suspension has dissolved and sodium bromide slowly begins to precipitate in the solution. The reaction mixture is stirred overnight, then filtered and the solvent is removed from the filtrate in vacuo. 5 ml of ethyl acetate are then added to the residue and this organic solution is extracted with twice 20 ml of water. After the organic layer has dried over magnesium sulfate and filtered to remove the drying agent, the solvent is removed from the filtrate under vacuum and a yellow oil is obtained which is chromatographed on a column of 120 g of gel Merck silica, packed in chloroform. Elution with: (a) 250 ml of chloroform; (b) 500 ml of 5% ethyl acetate in chloroform; (c) 1 1 of 10% ethyl acetate in chloroform, and the automatic collection of 10 ml fractions allow the separation and the purification of the product. The fractions containing the product are combined and the solvent is removed, which gives the title compound 2 in the form of a colorless oil, 3.39 g, yield of 51%.

T-60 NMR (DCClj); M 54.60 ppm (1H), q. 54.17 ppm Ji = 8 Hz, m. 54.00-2.70 ppm (9H), m. 52.6-1.4 ppm, t. 51.3 ppm Ji = 8 Hz (23H).

IR (solution in CHCI3) 2975, 2915, 2840, 1720, 1665, 1450, 1250-1200, 1125-1025 cm- '.

SM (heated entry) (m / e-%) 356-1%, 355-3%, 310-17%, 240-100%, 194-83%.

The above procedure can be adapted to the preparation of pyrrolidones having the formula developed below, by substituting the appropriate alkylating agent for ethyl 7-bromoheptanoate and optionally using the dimethyl-t-butylsilylated homolog of the pyrrolidone 1.

0

x = -co2c6h5

-CO2CH3

N- (tetrahydropyran-2-yl) tetrazol-5-yl

N- (acetyloxymethyl) tetrazol-5-yl.

W = single bond or double bond eis.

T = THP or dimethyl-t-butylsilyl.

As indicated, the 5β- (tetrahydropyran-2 "-yloxymethyl or dimethyl-t-butylsiloxymethyl) -2-pyrrolidones substituted in position 1 can be prepared using the appropriate alkylating agent in place of ethyl 7-bromoheptanoate For example, if you want to prepare 1- (6'-carboxymethylhex-2'-enyl) -5p- (tetra-hydropyran-2 "-yloxymethyl) -2-pyrrolidone, the alkylating agent will be the Methyl 7-bromohept-5-enoate. If one wishes to prepare 1 - (6'-1 "'-acetyloxymethyltetrazol-5"' - ylhexyl) -5p- (tetra-hydropyran-2 "-yloxy-methyl) -2-pyrrolidone, the agent of alkylation will be 6-bromo-1- (r-acetyloxymethyltetrazol-5'-yl) -n-hexane.

The 1- (2,2-diethoxyethyl) -5P- (tetra-hydropyran-2 "-yloxymethyl) -2-pyrrolidone can also be prepared by the same procedure using the ethyl acetal of the diethyl acetal as alkylating agent. 2-bromoacetaldehyde.

The preparation of 6-bromo-1-tetrazol-5'-yl-n-hexane can be carried out in the following manner.

A mixture of 2.98 g (23.5 mmol) of 7-hydroxyheptanenitrile, 1.60 g (30 h) can be heated to 120 ° C. under nitrogen while stirring for 18 h, until the reaction is essentially complete. , 0 mmol) of ammonium chloride, 0.032 g (0.76 mmol) of lithium chloride, 1.91 g (29.3 mmol) of sodium azide and 50 ml of dimethylformamide. Dimethylformamide 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-1- (tetrazol-5-yl) -hexane, can then be treated with phosphorus tribromide under suitable conditions to form 6-bromo-1- (tetrazol-5-yl) hexane . The N'-acetyloxy-methyl group can be attached using the method of W. V. Daehne et al., Op. cit., while the N-tetrahydropyran-1-yl group can be fixed according to the method of Example 1.

Treatment of 7- (tetrahydropyran-2'-yloxy) hept-5-ynenitrile in the same manner as previously, will allow the preparation of 6- (tetrahydropyran-2'-yloxy) -l - (tetrazol-5'-yl) hex-4-yne. This substance can then be transformed into 6-bromo-1- (tetrazol-5'-yl) hex-4-ene according to the procedure of German patent No. 2121361, (C.A. 76: 24712d). Obviously, the starting hept-5-ynenitrile can also be hydrogenated to an olefin before the transformation of the nitrile into tetrazole, essentially by following the procedure. Again, protecting groups for the acidic hydrogen of the tetrazol-5-yl group can be attached by the foregoing methods.

Example 3:

1- (T-Methylheptonato) -5 $ -hydroxymethyl-2-pyrrolidone 4

To a solution of 200 ml of methanol and 3.99 g of THP-pyrrolidone 2, 79 mg of p-toluene sulfonic acid are added, and the solution is heated at reflux overnight. After treatment as described below, an NMR spectrum of the reaction mixture reveals the presence of a small amount of starting ethyl ester. The reaction mixture is therefore redissolved in 160 ml of methanol, 0.080 g of tosic acid is added and the reaction mixture is again heated at reflux overnight. Removal of the reaction solvent in vacuo gives a yellow oil which is dissolved in ethyl acetate and extracted with once 10 ml of a 1: 2 mixture of saturated sodium bicarbonate and of a semi-saturated solution of Rochelle salt. The organic phase is dried over magnesium sulfate, filtered and the solvent is evaporated, which gives the title compound 4 in the form of a light yellow oil, 2.528 g (88%).

NMR A-60 (DCCI3) s. 53.86 ppm, m. 54.00-3.33 ppm, m. 53.20-52.70 ppm (13H), m. 52.50-52.00 ppm, m. 51.90-1.20 ppm (10H) partial spectrum.

IR (solution in CHCI3) 3550-3100, 2980,2910, 2840,1720, 1650, 1450,1425, 1410, 1250-1190 cm "1.

SM, LKB 9000, solid input (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 and water for approximately 18 h, essentially according to the procedure of Example 14.

In this case, the ethyl ester group of pyrrolidone 2 will be kept intact.

The preceding procedure of hydrolysis with acetic acid and water can also be used to remove the tetrahydropyranyl protective group from the other pyrrolidone derivatives of Example 2 which will then give the 5 p-hydroxymethyl-2-pyrrolidones substituted in corresponding position 1. However, if the protecting group for the tetrazol-5-yl group is a tetrahydropyran-2-yl group, it will then be appropriate to use as group T a dimethyl-t-butylsilyl group. This silyl group can be selectively eliminated by tetra-n-butylammonium fluoride according to the method of Corey, op. cit.

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624,934

By applying the acetic acid procedure to 1- (2,2-diethoxyethyl) -5- (tetrahydropyran-2 "-yloxymethyl) -2-pyrro-lidone 3 of Example 2, elimination of the group tetra-hydropyranyl will be accompanied by acetal cleavage and cyclization, giving as product a balanced mixture of the open form and 4-aza-2-hydroxy-l-oxa-bicyclo [3,4, 0] -nonan-5-one 5.

5

CHO

The equilibrium mixture containing compound 5 can be transformed into 5p-hydroxymethyl-2-pyrrolidones substituted in position 1, by the following procedure.

To a solution of 23.04 g (52.0 mmol) of 5-triphenylphosphonio-pentanoic acid (in the form of bromide), in 46 ml of dry dimethylsulfoxide, 49.3 ml can be added dropwise (98 , 6 mmol) of a 2, ON solution of sodium methylsulfinylmethylide in dimethylsulfoxide. To the resulting red solution, 3.27 g (20.8 mmol) of 4-aza-2-hydroxy-1-oxabicyclo- [3,4,0] -nonan-5- can be added over 1.0 h. one 5 in dry dimethyl sulfoxide (63 ml). After an additional 1 h of stirring, or until the reaction is essentially complete, the reaction mixture is poured into 600 ml of ice water, then it can be extracted with twice 300 ml of acetate. ethyl. The cold aqueous layer can be covered with ethyl acetate and acidified to pH about 3 with 10% hydrochloric acid, after which the aqueous layer can be extracted with 2 times 200 ml of ethyl acetate . The combined organic extracts are washed with water and then with brine and the organic layer can be dried over anhydrous sodium sulfate. The concentration of the filtered organic layer will provide the crude 1 - (6'-carboxyhex-2'-enyl) -5p-hydroxymethyl-2-pyrrolidone which can be chromatographed. The acid can then be esterified with diazomethane.

This procedure can also be used to prepare the 5β-hydroxymethyl-2-pyrrolidones substituted in position 1 of the structural formula:

0

OH

in which X is the same as in Example 2, by substituting the appropriate phosphonium salt for 5-triphenylphosphono-pentanoic acid, then by protecting the acid hydrogen with an N-acyloxymethyl group according to the procedure described by WV Daehne et al., Op. cit., with an N-tetrahydropyran-2-yl group according to the procedure of Example 1, or esterifying it in the case of carboxylic acid.

Example 4:

1- (7'-Methylheptanato) -5 $ -formyl-2-pyrrolidone 6

0.1286 g (0.5 mmol) of 1- (7'-methylheptanato) -5p-hydroxymethyl-2-pyrrolidone 4 in 5 ml of dry benzene is placed in a flame-dried flask containing a nitrogen atmosphere. . To this solution is added 0.1286 g (1.5 mmol) of dimethylaminopropylethylcarbodiimide hydrochloride (DAPC) and 0.142 ml (2 mmol) of dimethyl sulfoxide, then after 5 min, 0.108 g (0.55 mmol) of pyridinium trifluoroacetate . The reaction mixture is stirred under a nitrogen atmosphere at room temperature for 1% h, then the benzene is decanted and the second viscous phase which has formed at the bottom of the flask is washed with three times 5 ml of benzene. The benzene solutions are combined and the solvent is removed in vacuo, which gives 0.152 g of the title compound 6 in the form of a clear yellow oil. The crude product is immediately used without further purification in the next reaction.

NMR T-60 (DCC13), d. 69.72 ppm Ji = 3 Hz (1H), m. 84.37-64.07 ppm (1H), s. 83.70 ppm (3H) partial spectrum.

One can also use the preceding procedure to oxidize the other 5p-hydroxymethyl-2-pyrrolidones substituted in position 1 of Example 3 into 5β-formyl-2-pyrrolidones substituted in position 1 corresponding.

Example 5:

l- (7'-Methylheptanato) -5ß- (4 "-phenylbuty-l" -ene-3 "-onyl) -2-

pyrrolidone 7

0.11188 g (2.97 mmol) of a dispersion of 60% sodium hydride in mineral oil and 5 ml of THF are placed in a flame-dried flask containing a nitrogen atmosphere. To this suspension is added a solution of 0.7815 g (3.24 mmol) of dimetyl (3-phenylpropan-2-onyl) phosphonate in 5 ml of THF. Once the evolution of hydrogen has ceased, a white suspension is obtained which is stirred for 15 min. To this suspension, 0.6894 g (2.70 mmol) of 1- (7'-methyl-heptanato) -5β-formyl-2-pyrrolidone 6 in 10 ml of THF is added over 1 min. In 5 min, the reaction mixture becomes a clear yellow solution and it is stirred for an additional 2 h. The reaction is stopped with glacial acetic acid until pH 5. The solvent is removed in vacuo and the residue is taken up in 100 ml of ethyl acetate. The organic solution is extracted with 2 times 10 ml of a saturated aqueous solution of sodium bicarbonate, 3 times 10 ml of water and once 10 ml of saturated brine. The organic layer is dried over magnesium sulfate, filtered and the solvent is removed in vacuo, giving 1.141 g of yellow oil. This crude product is chromatographed on a column of 35 g of E. Merck silica gel, packed with ethyl acetate. Elution with ethyl acetate and the automatic collection of 10 ml fractions allow the product to be purified. The product fractions are combined and the solvent is removed in vacuo, which gives 0.614 g of the title compound 7 in the form of a colorless oil (yield of 61% relative to the starting alcohol).

T-60 NMR (DCCI3) s. 87.33 ppm (5H), d of d, 86.73 ppm Ji = 7Hz, h = 16 Hz, d. 86.60 ppm J2 = 16 Hz (2H), 84.27 ppm (center) (1H), s. 63.93 (2H), s. 83.73 ppm (3H), partial spectrum.

IR (solution in CHCI3) 2980, 2900, 2840, 1725, 1685 (shoulder), 1675.1625, 1250-1200 cm-1.

SM, LKB 9000 (m / e-%) 70eV 372-20%, 371-82%, 252-96%, 226-24%, 194-35%, 12eV 372-18%, 371-100%, 252- 24%, 226-39%.

The other 5ß-formyl-2-pyrrolidones substituted in position 1 of Example 4 can be used in the preceding procedure in place of pyrrolidone 6 to prepare the 5ß- (4 "-phenylbut-1" -en-3). "-onyl) -2-pyrrolidones substituted in corresponding position 1. In addition, phosphonates of structural formula can be used:

(MeO) 2PCH2CCH2Z Il II O O

Z ~ - C6H4CH3 (m)

- oc-thienyl -CeH4OCH3 (p)

- C6H4-C6H5 (m)

-C6H4CF3 (p)

-C6H4C1 (o)

instead of dimethyl (3-phenylpropan-2-onyl) phosphonate to prepare the 5ß- (but-1 "-in-3" -onyl substituted in position 4 ") -

5

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Corresponding 2-pyrrolidones substituted in position 1. Hereinafter, all the pyrrolidones comprising the ^ '- phenyl compounds will be called 5p- (but-1 "-en-3" -onyl substituted at ^^ - pyrrolidones substituted in position 1.

Example 6:

1- (7'-Methylheptanato) -5 $ - (3 "-hydroxy-4" -phenylbut-l "-enyl) -

2-pyrrolidone 8

0.5784 g (1.56 mmol) of l- (7'-) is placed in a flame-dried flask equipped with a magnetic stir bar and a thermometer and containing a nitrogen atmosphere. methylheptanato) -5p- (4 "-phenylbut-1" -en-3 "-onyl) -2-pyrrolidone 7 in 20 ml of dry THF. The clear colorless solution is cooled to - 78 ° C and added dropwise 1.56 ml (1.56 mmol) of lithium triethylborohydride using a syringe, a needle and a serum cap, in 15 min. After 1 h, a TLC shows the absence of the starting enone, so that the reaction is stopped by adding glacial acetic acid to pH 5 and then the solvent is removed in vacuo The residue is dissolved in 50 ml of acetate of ethyl, then this organic solution is extracted with once 10 ml of a semi-saturated aqueous solution of sodium bicarbonate, four times 10 ml of water and once 10 ml of saturated brine. The organic layer is dried over magnesium sulfate, filtered and the solvent is removed under empty, which gives 700 mg of crude product. This product is chromatographed on a column of 9 g of silica gel packed in ethyl acetate. Elution with ethyl acetate and automatic collection of 5 ml fractions separate the product from impurities. The combination of the fractions containing the product and the removal of the solvent under vacuum gives 0.298 g of the title compound 8 in the form of a colorless oil (yield of 50%).

T-60 NMR (CDCI3) s. 57.37 ppm (5H), d. 55.72 ppm Ji = 7 Hz, d. 55.62 Ji = 7 Hz (2H), m. 54.67-54.33 ppm, m. 54.30-53.83 ppm (2H), s. 53.73 ppm (3H), d. 52.90 ppm J2 = 6 Hz (2H). Partial spectrum.

IR (solution in CHCI3) 3450-3200, 2975, 2900, 2830, 1725, 1665, 1250-1200 cm-1.

The other 5p- (but-1 "-en-3-onyl substituted at 4) -2-pyrrolidones substituted at 1 of Example 5 can be used in the preceding procedure to prepare the 5p- (3" -hydroxybut- l "-enyl substituted in position 4) -pyrrolidones substituted in position 1 corresponding.

Example 7:

1- (6 '-Carboxyhexyl J -5ß- (3 "-hydroxy-4" -phenylbut-l "-enyl) -2-

pyrrolidone 9

To a solution of 69 mg (0.185 mmol) of 1- (7-methyl-heptanato) -5p- (3-hydroxy-4-phenylbut-1-enyl) -2-pyrrolidone 8 in 3 ml of methanol, 0.185 is added ml (2.185 mEq) IN sodium hydroxide. The reaction solution is then heated at reflux overnight and neutralized to pH 4 by addition of glacial acetic acid. The solvent is removed in vacuo and the oily residue is dissolved in 15 ml of ethyl acetate. The organic solution is extracted with 2 times 2 ml of water and once 2 ml of saturated brine, it is dried with magnesium sulphate and filtered. The solvent is removed in vacuo, which gives the title compound 9 in the form of a yellow oil; 59.4 mg, 89% yield.

NMR T-60, DCCI3, s. 57.33 ppm (5H), s. large, 56.30 ppm (center) (1H), d. 55.73 ppm Ji = 7 Hz, d. 55.6 ppm Ji = 7 Hz, (2H), m. 54.6-53.2 ppm (4H), d. 52.93 ppm h = 7 Hz (2H)

partial september.

IR (solution in CHCI3) 3500-3100, 2980, 2920, 1700, 1600, 1250-1200 cm->.

The use of other 5P-hydroxybutenyl-2-pyrrolidones substituted in position 1 of Example 6 in place of pyrrolidone 8 in the preceding procedure, will allow the cleavage of the methyl ester or of the acyloxy-methyl protective groups. and will allow the preparation of the following 8-aza-l 1-dehydroxy-prostaglandins Ei and E2. The protective group N-tetrahydropyran-2-yl, if used, can be removed by the method of Examples 3 or 14.

0

OH

OH

—Tetrazol-5-yle z '= -c6h4ch3 - a-thienyl -C6H4OCH3 —C6H4-C6H5

-c6h4cf3 -c6h5

Example 8:

1- (7-Methylheptanato) -5p- (4 "-phenoxybut-l" -èn-3 "-onyl) -2-

pyrrolidone 10

22 mg (0.55 mmol) of a dispersion of sodium hydride in mineral oil and 5 ml of THF are placed in a flame-dried flask containing a nitrogen atmosphere. To this suspension, a solution of 0.1549 g (0.6 mmol) of dimethyl (3-phenoxy-propan-2-onyl) phosphonate in 5 ml of THF is added. Once the evolution of hydrogen has stopped, a clear pale yellow solution is obtained which is stirred for 15 min. To this solution is added 0.1277 g (0.5 mmol) of 1- (7'-methyl-heptanato) -5β-formyl-2-pyrrolidone 6 in 5 ml of THF over 1 min. In 5 min, the reaction mixture became a clear yellow solution and it was stirred for an additional 2 h. The reaction is stopped by adding glacial acetic acid to pH 5. The solvent is removed in vacuo and the residue is taken up in 50 ml of ethyl acetate. The organic solution is extracted with twice 5 ml of a saturated aqueous solution of sodium bicarbonate, 2 times 5 ml of water and 1 time 5 ml of saturated brine. The organic layer is dried over magnesium sulfate, filtered and the solvent is removed in vacuo, which gives 0.231 g of yellow oil. This crude product is chromatographed on a column of 25 g of E. Merck silica gel packed with cyclohexane. Elution with 50% chloroform in cyclohexane and the automatic collection of 10 ml fractions allow the purification of the product. The fractions containing the product are combined and the solvent is removed in vacuo, which gives 53.6 mg of the title compound 10 (28% relative to the starting alcohol).

T-60 NMR (DCCI3) m. 57.40-6.70 ppm (5H), m. 56.7-6.33 ppm (2H), s. 54.67 ppm (2H), m. 54.40-3.97 ppm (1H), s. 53.67 ppm (3H) partial spectrum.

The other 5ß-formyl-2-pyrrolidones substituted in position 1 of Example 4 can be used in the preceding procedure in place of pyrrolidone 6 to prepare the 5p- (4 "-phé-noxybut-l" -én -3 "-onyl) -2-pyrrolidones substituted in corresponding 1. In addition, phosphonates of structural formula can be used:

(MeO) oPCH_CCH - 0-V

2ll 2il 2

0 0

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624,934

V = -C6H4CH3 (p)

-C6H4CF3 (m)

-C6H4-C6H4 (p)

-c6h4och3 (p)

-C6H4-c1 (o)

-c6h5

in place of dimethyl (3-phenoxypropan-2-onyl) phosphonate to prepare the corresponding 2-pyrrolidone derivatives.

Example 9:

57'-Methylheptanato) -5 $ - (3 "-hydroxy-4" -phenoxybut-l-enyl) -

2-pyrrolidone 11

0.1046 g (0.27 mmol) of l- (7'-) are placed in a flame-dried flask equipped with a magnetic stir bar and a thermometer and containing a nitrogen atmosphere. methylheptanato) -5- (4 "-phenoxybut-l" -én-3 "-onyl) -2-pyrroli-done 10 in 5 ml of dry THF. The clear colorless solution is cooled to - 78 ° C and added drop 0.27 ml (0.27 mmol) of lithium triethylborohydride using a syringe, a needle and a serum stopper in 15 min. After 1 h, a TLC indicates l absence of the starting enone so that the reaction is stopped by adding acetic acid up to pH 5,

then removing the solvent under vacuum. The residue is dissolved in 25 ml of ethyl acetate and this organic solution is then extracted with once 5 ml of a semi-saturated aqueous solution of sodium bicarbonate, once 10 ml of water and one times 10 ml of saturated brine. The organic layer is dried over magnesium sulfate, filtered and the solvent is removed in vacuo, which gives 101 mg of crude product. This product is chromatographed on a column of 25 g of silica gel packed in benzene. Elution with ethyl acetate and the automatic collection of 5 ml fractions separate the product from the impurities but do not separate the two epimers. The combination of the fractions containing the product and the removal of the solvent under vacuum gives 85.6 mg of the title compound 11 (yield of 82%).

T-60 NMR (DCCI3) m. 57.54-6.82 ppm (5H), m. 55.94-5.73 ppm (2H), m. 54.79-4.43 ppm (1H), m. 54.33-3.94 ppm (3H), s. 53.70 ppm (3H) partial spectrum.

IR (CHC13) 3600-3100, 2980, 2920, 1730, 1670, 1600, 1200-1250 cm-1.

The other 5p- (phenoxybutenoyl) -2-pyrrolidones substituted in position 1 of Example 8 can be substituted for pyrrolidone 10 in the previous procedure and the 5p- (4 "-phenoxy-3" -hydroxybut will be obtained -l "-enyl) -2-pyrrolidones substituted in the corresponding position 1.

Example 10:

1- (6'-Carboxyhexyl) -5 $ - (3 "-hydroxy-4 '-phenoxybut-1" -ény l) -

2-pyrrolidone 12

To a solution of 50 mg (0.128 mmol) of 1- (7'-methylhepta-nato) -5p- (3 "-hydroxy-4" -phenoxybut-l "-enyl) -2-pyrrolidone 11 in 3 ml of methanol 0.128 ml (0.128 mmol) of sodium hydroxide IN is added. The reaction solution is heated at reflux overnight and then neutralized to pH 4 by addition of glacial acetic acid. The solvent is removed in vacuo and the oily residue is dissolved in 15 ml of ethyl acetate, the organic solution is extracted with twice 2 ml of water and once with 2 ml of saturated brine, dried over magnesium sulphate and filtered. The solvent is removed in vacuo, which gives the title compound 12 as a yellow oil; 48.0 mg (99% yield).

T-60 NMR (DCCI3) m. 57.40-6.82 ppm (5H), m. 56.73-6.17 ppm (2H), m. 55.87-5.70 ppm (2H), m. 54.7-4.4 ppm (1H), m. 54.23-3.88 ppm (3H) (partial spectrum).

IR (HCCL3) 3600-2900,2920,1700,1670,1600,1200, 1250 cm-1.

The use of the other 5P- (hydroxyphenoxybutenyl) -2-pyrroli-dones substituted in position 1 of Example 9 in place of pyrrolidone 11 in the previous procedure allows the methyl ester or the acyloxymethyl group to be cut off and allows the preparation of the following 8-aza-l 1-dehydroxyprostaglandins Ei and E2. The N-THP protective group can be cut according to the procedure of Example 14.

OV

OH

O

OV

OH

X = -CO2H

- tetrazol-5-yle v = -c6h4ch3 (p)

-C6H4CF3 (m)

-C6H4-C6H4 (p)

-C6H4OCH3 (p)

—C6H4-C1 (o)

-c6h5

Example 11:

1- (7'-Methylheptanato) -5ß- (3 "-tetrahydropyran-2 '" - yloxy-4 "-

phenylbut-1-enyl) -2-pyrrolidone 13

128 mg (0.342 mmol) of l- (7'-methyl-heptanato) -5p- (3 "-hydroxy-4" -phenylbut-l-enyl) are placed in a flame-dried flask under a nitrogen atmosphere. 2-pyrrolidone 9 and 5 ml of methylene chloride. To this solution, at a temperature of 0-5 ° C., 0.062 ml (0.684 mmol) of redistilled dihydropyran and 3 mg of tosic acid are then added. Then the solution is allowed to warm to room temperature and stirred overnight. The reaction mixture is treated by dilution with 10 ml of ethyl acetate, extraction with twice 2 ml of a saturated solution of sodium bicarbonate and once 5 ml of saturated brine. The organic layer is dried with magnesium sulfate, filtered and the solvent is removed in vacuo to give 0.135 g of a yellow oil. It is chromatographed on a column of 15 g of Merck silica gel packed with chloroform. Elution with 11 of chloroform removes less polar impurities. Elution with 2% methanol in chloroform and automatic collection of 10 ml fractions separate and purify the product. The combination of the product-containing fractions and the removal of the solvent in vacuo gives 0.1756 g of the title compound 13 as a yellow oil.

T-60 NMR (DCC13) s. 56.34 ppm (5H), m. 55.77-5.37 ppm (2H), m. 55.13-4.80 ppm (1H), s. 53.7 ppm (3H) (partial spectrum).

In addition, the 5p- (3 "-hydroxybut-1" -enyl 4-substituted) -2-pyrrolidones substituted in position 1 of Examples 6, 7, 9 and 10 can be used in the preceding procedure to prepare the derivatives of THP corresponding.

Example 12:

1- (7'-Methylheptanato) -5 $ - (3 "-tetrahydropyran-2" '-yloxy-4 "-

phenylbutanyl) -2-pyrrolidone 14

To a solution of 156.5 mg (0.342 mmol) of 1- (7'-methyl-heptanato) -5p- (3 "-tetrahydropyran 2" '- yloxy-4 "-phenylbut-1 -enyl) -

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624,934

18

2-pyrrolidone 13 in 10 ml of ethyl acetate, 31 mg of palladium on carbon at 10% are added and the whole mixture is placed in a hydrogen reduction apparatus of Parr and the mixture is stirred under a pressure of 3 , 5 kg / cm2 of hydrogen for 4 h. Then the mixture is filtered on Celite to remove the catalyst and the solvent is removed from the filtrate to obtain 158.2 mg of the title compound 14.

T-60 NMR (DCClj) s. 07.33 ppm (5H), m. 05.13-4.67 ppm (1H), m. 04.57-4.33 ppm (1H), s. 03.73 ppm (3H) (partial spectrum).

In addition, the other THP derivatives of Example 11 in which A is a single bond can be used in this procedure to prepare the corresponding hydrogenated derivatives.

Example 13:

l- (6'-Carboxyhexyl) -5ß- (3 "-tetrahydropyran-2" '- yloxy-phenyl-butanyl) -2-pyrrolidone 15

To a solution of 158.2 mg (0.342 mmol) of 1- (7'-. Methylheptanato) -5p- (3 "-tetrahydropyran-2" '- yloxy-4 "-phenyl-butanyl) -2-pyrrolidone 14 in 5 ml of methanol, 0.342 ml (0.342 mol) of sodium hydroxide IN is added. This reaction mixture is heated at reflux overnight then it is neutralized to pH 4 by the addition of glacial acetic acid. vacuum and the oily residue is dissolved in 15 ml of ethyl acetate, the organic solution is extracted with 2 times 2 ml of water and 1 time with 2 ml of saturated brine, dried over magnesium sulphate and filtered The solvent is removed in vacuo to give the title compound 15 as a yellow oil; 134.2 mg (89% yield).

T-60 NMR (DCCI3) s. 07.37 ppm (5H), m. 54.4-3.2 ppm, m. 62.92 (2H) (partial spectrum).

In addition, the other hydrogenated derivatives of Example 12 can be used in this procedure to prepare the corresponding 6 'carboxylic acid and 6' tetrazol-5-yl derivatives.

Example 14:

1- (6'-Carboxyhexyl) -5ß- (3 "-hydroxy-4-phenylbutanyl) -2-pyr-rolidone 16 (8-aza-1 l-dehydroxy- 16-phenyl-16-m ~ tetranor-PGEi, 16)

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

T-60 NMR (DCCI3) s. 57.17 ppm (5H), m. 53.2-4.0 ppm (3H), d. 62.77 ppm, Jh = 7 Hz (2H) (partial spectrum).

IR (HCCI3) 3600-3100, 2930, 2860, 1700, 1660, 1250, 1200, 710 cm- '.

In addition, this procedure can be used to remove the protective THP group from the derivatives containing a carboxylic group and tetrazol-5-yl in the 6 ′ position of Example 13 and the hydrogenated derivatives of Example 12.

Example 15:

1- (6'-Phénylimidohexyl) -5 $ - (3 "-hydroxy-4" -phenylbut-1 "-ènyl) -2-pyrrolidone

To a solution of 64 mg (0.171 mmol) of 1- (6'-carboxyhexyl) -5ß- (4 "-ph" nyl-3 "^ trahydropyran-2", - yloxybut-r-0nyl) -2-pyr- rolidone prepared according to the procedure of Example 11 in 10 ml of dry tetrahydrofuran, 25.16 mg (0.171 mmol) of benzoyl isoxyanate prepared according to the procedure of AJ Speziale, "J. Org. Chem. ", 27, 3742 (1962)

in 5 ml of dry THF. After heating at reflux overnight,

the solvent can be removed in vacuo and the reaction product deprotected (elimination of the THP group) according to the procedure of Example 14 to obtain the title compound.

Likewise, the following imide derivatives can be prepared using the other suitably protected carboxylic acids of Examples 7, 10 and 14.

C-Im

OH

OH O

not

Im = NHCPh 0

NHCCH3

Z 'is defined in Example 7.

V is defined in Example 10.

W is a single bond or an eis double bond.

Z is a single bond or a trans double bond.

Example 16:

l- (6'-N-Methylsulfonimidohexyl) -5ß- (3 "-hydroxy-4" -phenyl-

but-1 "-enyl) -2-pyrrolidone

To a solution of 64 mg (0.171 mmol) of 1- (6'-carboxyhexyl) -5p- (4K-phenyl-3 "-tetrahydropyran-2" '- yloxybut-r-enyl) -2-pyr-rolidone prepared according to the procedure of Example 11 in 10 ml of dry benzene, 20.7 mg (0.171 mmol) of methylsulfonyl iso-cyanate (AJ Speziale, see Example 16) are added in 5 ml of dry benzene at room temperature . After heating at reflux overnight, the solvent can be removed in vacuo and the protective group removed from the resulting residue (removal of THP) according to the procedure of Example 14 to obtain the title compound.

By using phenylsulfonyl isocyanate in place of methanesulfonyl iso-cyanate in the above procedure, the corresponding phenylsulfoximide derivatives can also be prepared.

In addition, the following sulfonimides can be prepared using the other suitably protected carboxylic acids of Examples 7, 10 and 14.

C-Suf

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624,934

Suf = nhso2ch3 nhso2pi1

V is defined in Example 10.

Z 'is defined in Example 7.

W is a single bond or an eis double bond.

Z is a single bond or a trans double bond.

R

Claims (3)

624,934 1. Process for the preparation of a pyrrolidone derivative corresponding to the formula: and its epimer on C5 carbon, formula in which: Q is a radical - COOH, - COOR, tetrazol-5-yl or - CONHR ", R being a C1-C5 alkyl, phenyl or p-biphene-nyl group and 20 R "a radical of formulas —COR '" or - SO2R "' where R '" is a phenyl or C1-C5 alkyl group, W is a single bond or an eis double bond; Z is a single bond or a trans double bond; HO * '' Prostaglandin E2 According to the notation generally used to describe the stereochemistry of prostaglandins, a bold line represents the configuration p which is defined as a bond coming above the plane of the paper and towards the reader. In the same way, a dotted or hatched line represents the configuration a which is defined as a connection going below the plane of the paper and away from the reader. Thus, the configuration of Prostaglandin E2, described above, is the configuration a on the carbon atom 8 and the configuration ß on the carbon atom 12 [S. Bergström et al., “Acta. Chem. Scand. ”, 16, 501 (1962)]. According to the same terminology, a wavy line represents a mixture of the two forms a and ß. Thus, a 2-pyrrolidone of formula: _ co7h / H M is a pair or noh / OH , and H R 'is an x-thienyl, phenyl, phenoxy group; phenyl or phenoxy monosubstituted by chlorine or fluorine or a phenyl, methoxy, trifluoromethyl or C1-C3 alkyl group, and of alkali metal, alkaline earth metal and ammonium salts of the compounds having a carboxylic or tetrazol group 5-yle, characterized in that a compound of formula is reduced: 30 represents a mixture of epimers: 35 (at) (B) 2. Method according to claim 1 for preparing a compound of formula I where Q is a group - COOH, characterized in that the compound obtained where Q = COOR is subjected to hydrolysis. 2 3. Method according to claim 1 for the preparation of a compound of formula I in which Q is a group - COOR, characterized in that an esterified compound is obtained where Q is a group - COOH. By referring to the Pyrrolidine of formula B and to the Prostaglandin E2 represented above, a stereoreochemical comparison can be made between the two series of compounds. The stereochemistry in position 12 and 15 is the same for the two types but is different in position 8. That is to say that the configuration of the C8-C7 double bond of prostaglandin E is the at configuration, but that of the N8-C7 link is in the plane of the paper according to the representation given above. Another way to represent the two previous examples which will allow a better appreciation of this difference in configuration is the side drawing below. below: _ 0 0