CS221269B2 - Method of preparation of new 1,5-disubstituted 2-pyrrolidone compounds - Google Patents

Description

The present invention relates to a new series of 1,5-disubstituted-2-pyrrolidones having a chemical structure and biological character similar to prostaglandins, to a process for the preparation of these 2-pyrrolidones and to synthetic intermediates in these processes.

C20 unsaturated fatty acids, known as prostaglandins, form a large group of naturally occurring compounds. These molecules can have up to 5 asymmetric centers and elicit a response in various biological tissues.

As an example of a particular type of prostaglandin E, PGE2 of the following formula is defined as a bond originating from the plane of the paper toward the reader. Similarly, the dotted or dashed line represents the α-configuration, which is defined as the binding going beyond the plane of the paper in the direction away from the reader. Thus, the prostaglandin E2 configuration depicted by the above formula includes the α-configuration at carbon 8 and the β-configuration at carbon 12. [S. Bestr. Et al., Acta Chem. Scand. 16, 501 (1962)].

By the same convention, the wavy line represents a mixture of both a & β. 2-pyrrolidone with structure

prostaglandin E2

According to the notation commonly used to describe the stereochemistry of prostaglandins, it represents a thick solid line / J-confguration, which is thus a mixture of epimers А а В

Stereochemistry at positions 12 and 15 is the same for both types but at position 8 is different between the groups of compounds falling within the scope of the pyrrolidone of structure V on one side and prostaglandin E G on the other side (see above formulas). The configuration of the C8-C7 bond of prostaglandin E is α-, but the configuration of the N8-C7 bond is in the plane of the paper as shown above. Another way to illustrate the two examples above, which provides a better understanding of the configuration difference is the "side" representation where the single bond between C2 ‘and 03‘ is replaced by a double bond. The corresponding 8-aza-11-desoxy PGEo compound has the structure:

0 II 0 1 X X. Чк A ' Ί L · X * В i H prostaglandin E pynrolidone where А а В pose two side chains

of the above compounds.

The illustration shows the alignment of the A-0'8 bond with the C12-H bond and the alignment of the 012-V bond with the 08-H bond in the case of prostaglandin E and the bisecting position of the A-N8 bond relative to the dihedral angle formed by pyrrolidone. This conformation difference is due to the planar arrangement provided by the amide group of the pyrrolidone. [Basic Principles of Organic Chemistry, J. D. Roberts and M. C. Caserio, W. A. Benjamin, New York, 1965, p. 674.]

Systematic name for 1,5-disubstituted-2-pyrrolidone structures:

is 1- (6‘-carboxyhexyl) -5D- (3'-hydroxy-oct-1'-phenyl) -2-pyrrolidone. The compound may also be referred to as 11-desoxyprostaglandin E1 derivative; i.e., 8-aza-11-desoxy PGE 1.

The corresponding 8-aza-11-desoxy PGE2 compound has the structure:

where the double bond between C1 "and 02" is replaced by a single bond.

Said pyrrolidones have several centers of asymmetry and can occur in racemic (optically inactive) form and in both enantiomeric (optically active) forms, ie dextrorotatory (D) and left-handed (L) forms. As shown above, each pyrrolidone structure represents a certain optically active form or enantiomer, which may be partially derived from D-glutamic acid. The mirror image, or optical antipode, of each of the above structures represents the second enantiomer of pyrrolidone, which may be partially derived from L-glutamic acid.

For example, the optical antipode of 1- (6'-carboxyhexyl) -5- (3 'α-hydroxyoct-1'-phenyl) -2-pyrrolidone is shown as

and is referred to as 1- (6'-carboxyhexyl) -5- (3'-p-hydroxyoct-1'-phenyl) -2-pyrrolidone.

The racemic form of the above pyrrolidone contains an equal amount of a particular enantiomer and its mirror image. When it is intended to indicate in the following that it is a racemate of the compound, the symbol rac is preceded by the name of the compound. This designation means that it is an equimolar mixture of the D and L enantiomeric forms.

The pair of optical isomers that are optical antipodes, or enantiomers, differ from each other in that the individual antipodes have an inverted absolute configuration at all centers of asymmetry. On the other hand, if one isomer has an inverted configuration in one or more but at all centers of asymmetry, these isomers form a pair of epimers or diastereomers. So ^{EXAMPLE IKL d} and l- ⁽⁶ '- ^{k y} arbox ^yl hex-5 J / J (J' h ^{y y} o -hydroxy ^TTL "-en ^yl) -2- ^{pyrrol about} one and 1- ( 6 ^ - ^{k y} arbox hex ^y1) -5a- (^ "^ al l-drOXýoM" -en ^yl) -2-p ^y rrk1idkn diasteromers are ^{diisocyanates} having ^facing Onii ^g uracil at the C5 atom. They can be represented by these formulas

Chemical experiments with either enantiomer from an enantiomeric pair or with a mixture of both enantiomers result ^{in the} same results.

As mentioned above, the replacement of carbon atom of the 8 ^d US ^{CART em} toamatickou causes a change in the. the three-dimensional conformation of the resulting prostene. Because the structure is related to biological activity and often has little structural change, such as. a conformational change, a profound influence on the biological .aktivitu were recently studied modifications Metelka Lande ^g devoid ^of lie in the ^B tutions heteroatoms. Most of these modified compounds studied. it contains heteratomic substituents at position 09 and C11 of prostaglandin. For example, 9-oxaprosta ^g landines [I. Vlattas, Tetrahedron Let., 4455 (1974)], 11-oxaprosta ^g Landine [A. Fougerousse, Tetrahedron Let., 3983 ( ¹⁹⁷⁴ ) 1 and S. Hanessian and Datet ^ trahedron Let., 3983 (1974) and ^ thiaprostaglandins [ I. In ^one aιttá's ^{T h} Etra Leu edron ^{4459 (19} 74)].

In the literature also describes two 8-aza-l-E desoxyrrkttag1andiny natural ω-postonmm zcem ^{of RET,} i. Composites with aza-substitution at position C8 1.l1de'SOk prrkэtaglandinu ^y Ei and E2 · [G. Bol-liger and JM Muchowski, Tetrahedron Leu 2 ⁹³¹ ( ¹⁹⁷ 5) sr ^p en (1 · 9 ⁷⁵ ) ^, and J. ^W. Bruin date and Tetra ^h ^ ^L eu edron ^{4599 (1975)} ·]. These Imada ^ ^ rrohdinových compounds are outside the scope of the invention, projecting into the cavity ^kt pose a number ^p ^ ej ^ vo® intervention, and variation of the molecule at the Cl position of the prostaglandin and the w-chain postrannta ^{p kl} of manufacture with ad ^y! Ou ^No. enyne from Zn ^and Me hteratures have been reported ^to have relatively little biological activity and thus contrast with the more molecularly more complex novel compounds of the invention.

Natural prostaglandins and many derivatives thereof, such as esters, acylates and pharmaceutically acceptable salts, are substances that produce a high biological response with different biological responses [DE Wilson, Arch. Intern. Med., 133 (^ L (Wd)] in Teano formed ^hl ad ^to YM muscle, such as tissues of the cardiovascular, pulmonary, GA ^ t ^ t ^ OLntest ^-abdominal and reproductive system, the · cell tissues such as tissues of the central nervous hematological, reproductive, gattrintintestinal, pulmonary, nephritic, epidermal, cardiovascular and adipidial systems, as well as homeostasis, due to such a large spectrum of biological response, it is clear that prostaglandins are involved in the underlying biological processes in the cell This basic role of prostaglandins is supported by the fact that they can be found in the cellular tissue of almost all animal organisms.

At the cell level, the effect of closely related natural prostaglandins may be reversed. The ^PGE 2 ^to najDřMad ^PU with U is ^b · u ^HDS YC ^h stimulate platelet aggregation, inhibiting aggregation while PGE.

Such contrast effects can also be seen at the tissue level. For example, the effect of PGE2 in vivo on the mammalian cardiovascular system is shown to be a hypotensive effect, while the effect of PGF2 in vivo is shown to be a hypertensive effect. [JB Lee Arch. Intern. Copper. 133, 56 (1974)]. However, these comparisons do not currently allow predicting the biological effect of the tractagandan tnd. ^T and ^the napHMad zatrnco ^is i ^for FA stated, the cardiovascular effects of PGE2 and PGF2 opposite their effect in vivo or in vitro into the uterine smooth muscle of mammals is the same stimulating (causing contractions [HR ... Behrman et al, Arch. Intern Med., 133, 77 (1974)].

In the preparation of synthetic pharmaceutical compositions, one of the main objects of interest is the development of compounds which are highly selective in their pharmacological action and which. they have a prolonged effect compared to similar naturally occurring substances. ·^IN Serum compounds that are similar to naturally occurring rectaglandins represent an increase in the telectivity of one compound usually enhancing one physiological effect characteristic of prostaglandins and attenuating the others. By increasing the selectivity, it would be possible to mitigate the sharp side effects that are often observed^y after^pO^dárn ^ rodmch^rrosta^g1an^din^atfor example, in the case of the desired bronchodilator^dLej^š gastrointestinal effect^y diarrhea and emesis or ve^dLej^{ší k}araovascular^účin^ky.^Ned^anddevelopment^, for measured to increase^withem WotegteW telektiv^{you too,}includes 11-desoxyprossaglandins [N. H.

Anderson, Arch. Intern. Med., 133, 30 (1974) Review], 11-desoxy-15-subs-substituted-1-pentanorprostaglanid (MR Johnson et al., U.S. Pat. No. 3,932,389), in which certain modifications are characterized as leading modifications for the selective vasodilator, ulcer, anti-fertility, sert-dilatation and hypertensive effects, as well as 16-phenoxy-16-ω-tetranorprostaglandins which have an anti-fertility effect (Sritis Patent No. 1,350,971) and 1-imld and prostaglandin 1-sulfonimide (U.S. Patent No. 3,954,741).

This invention relates to novel compounds podoSných Rosia ^{g p} lan ^{d s} in ^{m, to} ter selektivtá ^E have a strong biological effect. The object is cut by multiplying ^{L PU} with ^{S p y at} pH rav new computer-disutetituovanýc ^h 1,5 ^{h 2} - ^p yrrolidonových skžernn oSecného formula I

and their Cs epimers, wherein

Q is -COOH or SO-COOR, wherein R is C 1 -C 5 alkyl,

W represents a single ne cis cis double bond,

Z represents a single non-trans double ligament,

M represents a group of formula and / or 1 AH oh H Nina ^S ecného formula I ^kt ER ^E M Q ^instance represents a group of formula COOR, and R, W, · Z, M and R 'have the previously listed ^d Eny ^{importance hyd} ro ^ly controlled at pyrrolidone compound oSecného formula I wherein Q is COOH and ^{W, Z,} m and R 'owner ^I above defined, bear the obtained pyrrolidone compound oSecného formula I wherein Q is COOH and W ^Z, M and R 'maps previously listed ^d Eny ^importance esteeiftouje give ^py rrolidonov ^Star composites oSecného formula I in which Q' represents a group of formula COOR oSecného and ^{R, W,} ZM and R ^d maj defined above.

Reduction and optionally bearing acidic alkaline hydrolysis of 2-p ^y rrolidonové oSecného compound of Formula II is obtained several final products of the invention. The reduction is preferably ^p Rovai ^says nthiumtriethYlžroh ^{yd chloride,} however. ^d is equally navbox Mze použft and other selective reducing agents which reduce the keto group, but no other groups, e.g., zinc Sorohydridu bear sodium oroh ^{S y} Dr. ^ID hi. As usual. Oust extended ^{p of p} ou REL ^{from an} IV ^and extend ^{ed p} el Oust ethereal ριρ ^ j and ^k is the ^y dro tetrahydro ^furan and diethyl ether. Vols temperature depends on the activity of the reducing ^NO Reagents and ^possibly in windy and ^dU is expedient OUZ ^{e p s} l vat ^and Zn ^of that dry ^{eh d} u le of acetone.

For OSV ^y klých reaction conditions, reduction SuliΓ'ten-3 '-one nominal ^{y h} o p ^y array oSecného pyrrolidone · II · grow two oSecného pyrrolidone compounds of formula I, which are diastereomers.

3 ^"and -h ^yd rox ^y ene compound ^{No. i} to ^{R f} represents ^{a straight} l- ^y en ^S a non ^phenoxy SKU ^{y P} inu.

^2PU with ^{S p} about le ^d to ^{L y} in the ^y-sectional značuje t ^ in the pyrrolidone The intermediate compound of formula II oSecného

where

Q, W, ^Z and ^R 'owner ^s sliora hereinbefore ^defined, by reduction converted into a 15-oxo group on the alpha-hydroxysteroid ^to UPRN not ^with the β-h ^yd rox ^y s ^k u ^{p flax,} then ^p o ^{p at} pH ad ^e zístoná ^py rrolidonová slouče-

3 ^"/ 3h ^{y y} -hydroxy compound ^with mountains ^{p p} o Sanyo ^PU with ^S em te ^dy prepared these two compounds, which can be divided žžnými izolačrtmi the t ^ m ^ as ^y-pressure chromatography. If these compounds are not separated, a mixture of two diastereomers is obtained. which can be expressed by the crop formula

The individual symbols in this formula as well as in the dlastereomeric samples have the meaning given above.

After isolation of the product from the reduction mixture, the group Q of the resulting compounds may optionally be modified. For example, when Q is an alkyl ester group and the free acid is to be prepared, the carboxylic acid can be prepared by simple alkaline hydrolysis with one equivalent of a base at ambient temperature to the boiling point of the solvent, usually overnight and subsequent neutralization.

The ester products of the present invention, i.e. compounds of formula I wherein Q is C 2 -C 6 alkoxycarbonyl, can be prepared from the corresponding acidic products of the invention, i.e. compounds of formula I wherein Q is carboxy, by well-known esterification methods . Such methods include reaction with diazoalkanes containing 1 to 5 carbon atoms.

Numerous "in vivo" and "in vitro" assays have shown that new prostaglandin analogs have an effect characterized by higher selectivity, potency and duration than natural prostaglandins. The tests included, but not limited to, the guinea pig isolated uterine smooth muscle effect test, guinea pig histamine-induced bronchospasm inhibition test, dog blood pressure test, stress-induced ulcer test in rats, diarrheal effect test in mice, and stimulated gastric secretion inhibition test. acid in rats and dogs.

The physiological response observed in these assays is useful for determining the utility of a test substance in the treatment of various natural and pathological conditions. The compounds of the invention have been found to have the following useful effect: vasodilating effect, antihypertensive effect, bronchodilator effect, anti-fertility effect and anti-ulcer effect.

The novel 8-aza-11-desoxyprostaglandins obtainable by the process of the invention have a highly selective effect compared to the corresponding naturally occurring prostaglandins and in many cases exhibit a longer duration of action. For example, the novel prostamimetic pyrrolidones obtainable according to the invention, which contain a phenyl group as a substituent R 1 and a carboxy group or a carboxylic ester group as a Q group, have a useful vasodilating effect. With regard to the therapeutic importance of the reasons can be lism of pyrrolidone compounds of Formula I 1- ⁽⁴ -karboxyhexyl 6) -5- / 3- (3-hydroxy-4 ^{t 4} "phenylbut-l 'enyl] -2-pyrrolidinone and 1- (6'-carboxyhexyl) -5- (3'-hydroxy-4'-phenylbut-1'-phenyl) -2-pyrrolidone, which exhibit a hypotensive effect of similar intensity to that of PGE alone when administered intravenously to anesthetized dogs using the procedure described in U.S. Patent No. 3,956,284, while significantly reducing other effects compared to PGE2, such as bronchodilator and anti-ulcer activity (also measured by the procedure described in U.S. Patent No. 3,956,284).

Another excellent example of the therapeutic importance of the pyrrolidone compounds obtainable according to the invention is the selective anti-ulcer effect of compounds containing a R-phenoxy substituent as a substituent and a carboxy or carboxylic ester ester group as a Q substituent. For example, 1- (6'-carboxyhexyl) -5- (3'-hydroxy-4'-phenoxybut-1'-phenyl) -2-pyrrolidone exhibits an excellent and selective anti-secretion effect when administered orally to dogs.

The novel compounds obtainable by the process of the invention can be used in various pharmaceutical preparations containing the active compound or a pharmaceutically acceptable salt thereof. They can be administered in various ways depending on the type of disease and the condition of the patient.

The 8-aza-11-desoxy-16-aryl-ω-tetranorprostaglandin compounds of the invention and their epimers are useful vasodilating agents. For the treatment of hypertension, the drugs may conveniently be administered intravenously at a dose of from about 0.5 to 10 mg / kg or preferably in the form of capsules or tablets at a dose of from 0.005 to 0.5 mg / kg / day.

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

Particularly suitable metal cations are those derived from alkali metals such as lithium, sodium and potassium and from alkaline earth metals such as magnesium and calcium, although salts with other metal cations such as aluminum, zinc and iron are also included.

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines. Examples of suitable amines include methylamine, dimethylamine, triethylamine, ethylamine, dibutylamine, trusopropylamine, N-methylhexylamine, decvlamm, dodecylamine, allylamine, crotylamine, cyclopontylamine, dicyclohexylamine, benzylamine and dibenzylethylamine. Z-phenylethylamine, ethylenediamine, diethylenetriamine, and other aliphatic, cycloaliphatic and araliphatic amines containing up to about 18 carbon atoms and heterocyclic amines, for example piperidine, morpholine, pyrrolidine, piperazine and their lower alkyl derivatives, for example 1-η · ΐθΠ ^^ ΐΊΌ1ίάί , 1,4-dimethylpiperazine, 2-methylpiperazine and the like, and amines containing water-solubility-mediating or hydrophilic groups such as mono-, di- and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol. 2-amino-2 - eth ^y l, 3-propanediol, 2-amino-2-methyl-l-propanol, tris (hydroxymtthyljaminomethan N ^{l-phenylethane amine, N} - (p-terc.amylfenyl) dtethanol · amine, galaktamin, methylgiukamin N, N-meth ^{yl l} u g ^{to axes} -ί-τίτί п ^ ^ · ·· -й epinephrine, procaine and the like.

Examples of ^the pharmacologically acceptable ammonium vartérmch kattontů to indicate the tetramethylammonium, tetraethylammonium, benz ^y ltrimtthylamoniový, fenyltriethylamonidvý cation like.

To prepare any of the many possible for ^p ar ^{sulfates from} his e ^p ou ^IT excitation cutting ents or ^pi - carriers which do not react with the compounds of the invention and are thus inert. Such materials are e.g. water, ethanol, gelatin, lactose, starches, magnesium stearate, talc, rosibnim oil microcapsules, more of alcohol tenzv ^ ^k1 ovatin ^y, polyalkylene glycols, petroleum jelly, cholesterol and other known carriers of medicinal -látek. If desired, these pharmaceutical preparations may contain adjuvants such as preservatives tet ^ smáMdla stabilizers ^b not on JINR tečivé agents such as antibiotics.

The following examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way. Spectral data were obtained using a Varian T-60 or A-60 NMR (NMR spectra), Perkin-Elmer Grating (Infared Spectrometer (with ^p ektrum infrared) spectrometer and m.ass LKB-9000 Spectrometer (MS). Infrared Data are plotted in cm ^-1 and ^d ata NMR are ^given in ^pp m using t-tramethylsilane - (TMS) - as standard.

Unless the reaction temperature is specified in the examples, it is understood that the reaction was carried out at ambient temperature, i.e. room temperature, which varied from 15 to 30 ° C.

The reaction time described in the examples was determined by monitoring the reaction mixture by thin layer chromatography (TLC) unless otherwise indicated. Usually used TLC system consisted of a silica glass (silica gel plates producer E. Merck, Darmstadt (FRG ^ Systemia from benzene / ether or methanol / ^h1 oro c ^f orm ^as elučnfch agent from the system and vanillin / ethanol or iodine as generants (Introduction to Chromatography) JM В ^ ЬЫ ^ AE Schwarting RJ (Jritter, Van Nostran ^d- Reinho ^ld , NY 19681. The fact that the TLC spot of the critical starting material was considered as a rule to determine that the reaction was essentially complete. disappeared or changed.

EXAMPLE 1 ^{5 /} 3- (tetra ^{hyd ro-pyran-2'-yl} tex ^y meth ^yl) -2-pyrrolidone (Compound 1)

To a flame dried flask under nitrogen was charged with 2.54 g (22.1 mMol) 5- ^D -hydroxy ^<y ymeth only 2- ^{d p} yrro1i ^one, prepared according to the method described by V. Bruckntr et al, Acta Chim. Hung. Tomus, 21, 106 (1959), and 50 mL of methylene chloride. To this solution was added 3.72 g (44.2 mmol) of undistilled dihydropyran and 0.2 g of p-toluenesulfonic acid at 0-5 ^° C. The solution was allowed to warm to room temperature and was stirred overnight. ^p zředěrt a reaction mixture of 20 ml of ethyl acetate, the solution is extracted with 2x5 ml - saturated sodium bicarbonate solution and 1 x 10 mL. saturated sodium chloride solution. The organic layer was dried over ořečnatým ^h, the odfiterujt sušiiho and extended on ^p Oust ^EDL under vacuum from ^p and ^r i. 4.1 g of a yellow oil are obtained. This oil was chromatographed on a 50 g gauge silica gel column containing chloroform as the mobile phase. Elution with one liter of chloroform removes the less polar readers. ^p and will burst ETEC 2% methanol in chloroform collecting 10 ml fractions. The fractions containing purified product were combined and evaporated therefrom in vacuo solvents: a ^{poorly soluble in water. Hexaneether} typist ^3.95 g Ti compound 1 as žteteho oil microcapsules (HE ^EZ eq of 90%). N ^M R T-60 (DCC13) bs δ 6.60 ppm (1H), m-δ 4.60 ppm (1H), m δ 4.05 - 3.25 ppm (5H), m δ 2 , 50-2.10 ppm, m δ 2.00-1.40 ppm (10H). IR (CHC13 solution) 3425, 2980, 2930, 2850, 1680, 1250-1200, 1025 cm ^1st

It may also be used dimtthyl triphenyl tertbutyl-t-protecting group - instead of tetrahydropyran-2-yl group, wherein aplikuj- ^procedure response to the letters ^{P E.} J. Corey et ^al ., J. Am. Chem. Soc., 94, 6190- (1974) to 5-D-hydroxymethylene-2-pyrrolidone.

Example 2

1- (7'-TT ^hyl 'htptanato) -5- / 3- (tetrahydro ^y dr r op ^{y n} - ² "- ^y lox ^y metih ^yl) - ^ pyrrolidinone (Compound 2)

To a flame-dried flask, under a nitrogen atmosphere, was added 0.725 g (18.7 mmol) of 62% dispersion of sodium hydroxide in mineral oil and 10 ml of dry tetrahydrofuran (THF). To this mechanically stirred suspension is then slowly added dropwise 3.74 g (18.7 mmol) of 5-D- (2-tetrahydropyran-2-yloxymethylJ pyrrolj-DON (compound 1) in the 10th it ^é mg dry THF. ^P o Almost all of the thick slurry was stirred for 30 minutes until hydrogen evolution ceased.

The sodium salt is then alkylated:

K obtained. suspension at ^the inclu ^PRIK and ^p is ^5, 3 ⁽⁴ g, ^22.5 mMol) eth ^yl-7-bromo

221289 heptanoate in 15 mL of dry dimethylformamide (DMF). After the prid ^ a ^ as ^well as ^'15', are sus ^{p p} Enzo extended orifice and slowly begins to precipitate from the solution sodium bromide. The reaction mixture was stirred overnight, then filtered and the solvent was evaporated from the filtrate in vacuo. Ethyl acetate (100 ml) was added to the residue and the resulting organic solution was extracted with water (2 x 20 ml). After drying the organic layer ^Ké Shane ^y · ^h o ^R e ^{v y} has NAT filtering off the drying agent the solvent was evaporated in vacuo from jfiltrátu. A yellow oil is obtained which is chromatographed on a Merek silica gel column (120 g) in chloroform. Elution is performed with a) 250 ml of chloroform, B] 500 mL of 5% et ^hyl acetate, ^and the chloroform c) ¹⁰⁰⁰ m ^l of 10% ethyl acetate in ^hyl chforoformu. 10 ml fractions are automatically collected to allow separation and purification of the product. Fractions containing product were drawbar with ^{p s} and the solvent evaporated. The title compound 2 was obtained as a colorless oil. Weight 3.39 ^g of frames, yield off ^from the EC ^51%.

NMR T-60 (DCCl 3): δ 4.60 ppm (1H). q, <5 4.17 ppm, Ji = 8 Hz, m δ 4.00 - 2.70 ppm [9H], m δ 2.6 - 1.4 ppm, t δ 1.3 ppm, Ji = 8 Hz, (23 H).

IR ^(HCC1 the solution, ^{r _3): 2975,} 2840. 29 ^ ^1720, 1665, 1450, 1250-1200, 1025 cm-1 ^first

Mass Spec. - Heated Input ^(m / e -% ⁾ 256-1 °% 255-3 °% 310-17 °% 240-100 °% 194-83%.

The above procedure may be adapted to prepare the pyrrolidones of the structure described below by using a suitable alkylating agent instead of ethyl 7-bromoheptanoate and optionally by using the dimethyl-t-butylsilylanalog pyrrolidone 1.

X = —CO2C6H5 —CO2H5,

N- ^{(tetrahydrofuranyl} rop ^y methyltetrahydrofuran-2-yl) -5 ^t etrazo ^l-yl, N- (acetyloxy) tetrazol-5-yl,

A = single or cis double bond,

T = tetrahydropyranyl or dimethyl-t-butylsilyl.

How it was written. ^^ ubstituované] - ^5/3 - ^{(tetrahydrofuranyl} rop ^{y u} ran-2 - ^y lox ^y meth ^y l ^y Шmeth or 1-t-but ^yl Isílox Metti ^{y y} I) · ^py -2- pyrrolidone may ^p H ^p Ravita so that a suitable reagent in place alkyalčního eth I ^{yl-7-bromoheptanoate.} For example, if a prepare l- ^(6'-b ar ^to ox2n-eth ^yl niex- ² '-en21) -5 / M ^ ro ^ fotrah healing - ^ - yloxyinetov ¹⁾ ^ -pyrrohcfon is used as alkylating ^ o ^ nthis ^{methylthiophenyl} l17- ^b rhmhept-5-enoate. If it is desired to prepare 1- (6 ^L -Γ '1acet ^y1 hx ^y meth ^y l ^t e ^t razhl15 ^"i - ^y lhex ^yl) -5- / 3- (tetrahydro ^yd RH ^py ran1 ^{2" 1-yl} methyl-hy ^y - pyriolídon, is used as the ^¹H alkylač14 n ^or n and ^IDL (1-- ^{r-acetyloxy-1-ethyl} ltetrazol S ^ HE ^ ibn anus.

¹ - ^(2, 2-market by x e ^{y e} hy ¹⁾ -5 / 3- (tetrahydro ^yd r opy ^r an- ² "- ^{y 1} lhУ ^yl methyl) pyrrol ^ ^ omo compound 3 M ^for the rovitož prepared by the same procedure using 2- romacetaldeh ^{b y} · ddiethyl1 acetal as the alkylating agent.

Pnprava 6- roim ^{b - l} tetrazh ^-5'-yl -N Heyan m is ^already prov e ^^ tf ^ADETO up followed by:

^S '· month ^2.98 g ^(23.5 mmoln) ⁷ - ^hyd rox ^YH e ^p tannitrilu, 1.60 g (30.0 mol-) chloride am ^on the LV ^{eh, 0.032} g ^(0.76 mmol) of ИНтё ^ ^(1.91 g, ^29.3 mmol) and ⁵⁰ ml natriumazfou dimethylphenylsulfanyl ^{l FHI} mэm u ^id was heated at 120 ° C under nitrogen with stirring for 18 hours or until the reaction is substantially complete. The dimethylformamide is then removed in vacuo and the resulting residue is purified by one or two methods, such as chromatography or extraction. This product, 6 ^ 1 ^ ^^^ DLI hyy-1L1 (ttJα zϋ ^. ^ - ^ 51 ^yl] LT-Aan, is ^{running in} uso ^p bromHem fosfority- vhodnýc ^h under conditions to form 6- ^ROM-b l- (tetrazhl-5 - ^yl) hexane. ⁴ N 1acetyloyymet ^HYL skupma may be connected using the method described WV Daehne et al in the above cited work. N-tetrahydro dIhpyran ^y-2-yl group is attached by the method of Example 1.

^Of Work ^{& 7} mm - (DRH tetIah ^{y py} Ian1 ²ⁱ - ^y loyy) HEP - ^^ iinnttrilu same as the above method gave the 6- ^{(tetrahydropyran-2} '- ^y tox ^y) of 4- ^(t etrazhl15'1 ^yl jhex ^ -in This material can then be converted to the 6-bromo-l- (tetrazokS lhex ^ é-en-z ^ manner described in DOS 2 121 361 (OA 76: 24 712d). the starting-hept-5-Шп гП can of course also to be hydrogenated based oils before the nitrile is converted to the tetrazole by operating in substantial same postopem. ^1, in this case the protective groups are acidic hydrogen tetrazol-S-yl group can be connected by the above methods.

Example 3

1- ⁽⁷ '-methyl- ^would lheptanato) -5 / yddo хуте -h ^ ^y ук -2-1t rrhlidhπ (Compound 4)

To a solution of 200 ml of methanol and 3.99 g p ^y THP belched ^id -one (Compound ^No. enyne ^{y 2) at} d ^{and 7} 9 mg tosyl-oic acid · solution overnight reflux. After working up as described below, the NMR spectrum of the reaction mixture showed 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 toluenesulfonic acid was added and the reaction mixture was refluxed overnight. The solvent is removed in vacuo, the yellow oil obtained is dissolved in ethyl acetate and extracted with 1 x 10 mL of saturated sodium bicarbonate solution and half saturated Rochelle's salt 1: 2 solution. The organic phase is dried over magnesium sulfate, filtered, and concentrated. the solvent was evaporated. The title compound 4 was obtained as a clear yellow oil. Yield 2.528 ^g (88%).

NMR. A-60 (DCCls) s δ 3.86 ppm, m δ 4.00 - 3.33 ppm, m δ 3.20 - 2.70 ppm (13H), m / 1 ^2.50 - ^{2 00 pp m,} m. ^{5 1.90 to 1.20} ppm (10H), partial spectrum.

IC (HCCl 3 solution): 3550-3100, 2980, 2910, 2840, 1720, 1650, 1540, 1425, 1410, 1250 to 1190 µm -1.

MS LKB 9000 stationary inlet (m / ^{e -%) 0} 70 eV 226-26% 194 ^{- 19.8% 74-100%} 13 ° V ^{e 257-3,} 3% ^0% 226 to 100 ° 168- 24 6%.

Alternatively IWE tetrahydro ^yd rop ^y ran-2 '"- YLS ^k u ^p INA oďstějpit h ^yd roiýzou ^p dip ^{at 65:} 35 mixture of glacial acetic acid and water, wherein the reaction is carried out for about 18 hours essentially as described in Example fourteenth

In this case the pyrrolidone 2 ethyl ester group remains intact.

The above procedure, hydrolysis with acetic acid and water may also be ^p ou ^Gd t ^p ro about ^ds t ^'EP em tetra ^hyd ro ^{pyran s} hunting ^s protective groups from other pyrrclidonových ^p genus ^KTU from ^comm la ^d u ^{2; Price} em ^f to ^p and ^to provide the corresponding 1- (substituted) -5- (3-hydroxymethyl-2- pyrrolidone ^{py y.} However, when the oc ^h wound group of alkyl groups tetrazoh5- ^yl tetrahydropyran-2-yl, then it is advisable to use as a group T This silyl group can be selectively cleaved by tetra-n-butylammonium fluoride in the manner described by Corey in the above cited work.

When the process is applied to acetic acid l- (2,2-diethoxy-ethylj ^yl 5- (tetrahydro ^yd ro-healing - ^^ ^ lo ^ pyrroMon methylpropyl 3 of Example 2 is accompanied by cleavage of the tetrahydropyranyl group by cleavage of the acetal and cyclization. In this case, the product mixture obtained by the equilibrium of the open mold and 4- aza -2-hydroxy ^gamma -L-oxabicyclo [3.4.0] nonan-5-one fifth

(5)

The equilibrium mixture containing the compound ⁵ was ^already e m ^BC ev ^E ST to 1- (su ^b st ⁱ tuovaný) -5-hydroxymethyl-2-pyrrolidone as follows.

^{To a} solution of ^{23.04 g (52.0} mmol) of 5-phenyl ^{trifluroacetic} acid · fosfoniopentanové (bromide) in 46 ml of dry dimethyl sulfoxide was added dropwise 49.3 ml (98.6 mmol) of 2.0 N solution of sodium. methylsulfinylmethide in dimethylsulfoxide. To the resulting. The red solution is then added over 1.0 h to 3.27 g. (20.8 mmol) ^4- aza-2-hyd ^; roxy-1-oxabicyclo [3.4.0] nonan-5-ene 5 in dry dimethylsulfoxide (63 mL). The mixture was stirred for an additional 30 minutes or until the reaction was substantially ^no ENA ^thee demise. ^ akčrá mixture of 6M vhje ^d m ¹ of ice water and then extracted with 2 x 300 ml ethyl acetate. The cold aqueous layer was covered with ethyl acetate and acidified to a pH of about 3 with 10% hydrochloric acid. ^p and the aqueous layer extracted with 2 x 200 mL ethyl acetate. The combined organic extracts were washed with water then brine, and the organic layer was dried over anhydrous sodium sulfate. The filtered organic layer was concentrated to give crude 1- ⁽⁶ '- ^b ar ^{to oxyhex-2'-enyl)} - ⁵ /J-hydroxymethyl-2-pyrrolid.on which is then chromatographed. The acid can then be esterified with diazomethane.

This Ostu ^{p p} u m is equal to ^{E of} the f ^p ou ^IT for the preparation of 1- (substituted) -5-hydroxymethyl% ^y -pyrroBdonů structures.

where

X has the same ^meaning s ^comm I ^to ice for ^2, so that a suitable phosphonium salt in place of 5-trifenylfosfonopentanové acid and then with an acidic hydrogen of N-acyloxymethyl protected using the procedure described in PR ^{and W.} C. Daehne and others cited above by N-tetrahydroxypyran-2-yl as described in Example 1 or by esterification for a carboxylic acid.

Example 4 ^l- (7'-meth ^yl lhep yes ^t) - ⁵ / ^S- ofmy ^l l2-pyrrolo ^d one (Compound 6)

To a flame dried flask containing ^d ears ^to be ^straight and ^can 0Д286 ^g (0. ⁵ mmol) of l- ⁽⁷ '-methylheptanato) -5 / 3--1у meebyl Hydroxy-2-pyrroMonu ⁴ in 5 ml of benzene Suc ^HEH . To this solution was added all 0.1286 g (1.5 mmol ^L u) ^ dtoet laminopropyíethyllkarbodiimféhydrochloridu (DAPC), and 0.142 ml (2 mmol) of dimethylsulfoxide and ^the PA after 5 minutes ^{0.108 g (0.55} mmol) ^{of p} yr ^id iniumtrifluorace - ^melt in. ^R eakční mixture of ^p mícM ^dd US ^CART verifies atmosphere at room te ^pl OFE ^1/75 hour, then benzene delkantuje and second viscous phase formed on the bottom of the flask was washed with 3 x 5 ml of benzene. The benzene solutions were combined and the solvent was evaporated in vacuo. ^September twisted in Titus ^{0.152 g} of compound 6 as a clear žfétého oféje. Arového ^p roducts was used immediately without further purification in the next reaction.

NMR T-60 (DCCl 3), d <3 9.72 ppm, J 1 = 3 Hz (1H), m δ 4.37-4 ^, ° 7 ppm (1H), s δ 3.70 ppm (3H) ), partial spectrum.

The above procedure can also be used for the oxidation of other 1- (substituted) -5 / hydroxymethyl-2-pyrrolidones of ^{the example,} about 3 to ^dp ovídající l- (substituted) -5 / -formel-2- ^p · yrrolidond

Example 5

1- (7‘-roeth.)^dlhe^ptanato) -5β- (4 “-^F en^ylbut -rhenf-4-onyl-4-p-monon (compound 7)

To a flame dried flask PPD nitrogen was added 0.1188 g (2.97 mmol) of 60% ^D is ^p ^ ersion natriumh RWU mineral oil and 5 ml of THF · To the suspension was added a solution of 0.7815 g (3.24 mmol ) dimethdl-3 - ^{(phenylpropan-2-yl)} fosÍOnátu in 5 mL of THF · after the evolution of hydrogen appears white suspension which was stirred for 15 minutes · to this slurry was added 0.6894 g (2.70 mmol) of l- (7'-methyl ^yy l ^{p h} e tannate) - ^{5 ₍₃} -form ^yl-2- pyrrolidone ^py 6 in 10 ml of THF within 1 min · within 5 minutes, the reaction mixture clears to a clear yellow solution which was stirred for further 2 hours of reaction the mixture is neutralized with glacial to ^y bismethylenesalicylic acid to pH ⁵ · dissolve was removed in vacuo and the residue was taken up in 100 ml ethyl acetate · the organic solution was extracted with 2 x ^10ml sat ^y price ^eh about Voth ^ o ^ ogenuhličitanu the solution, 3 x 10 mL water and 1 x 10 mL sat ^{y s} prices it with clilonclu solution ^with copper. the organic layer was dried over magnesium sulfate, filtered and the solvent poorly soluble in water under vacuum by ^dp and ^RI. hexaneether ^ Å žlutěo ^1,141 g of oil. The crude product was chromatographed on a column of silica Merck-Nagel of 35 g of ethyl acetate. Purification of the product was accomplished by elution with ethyl acetate, automatically collecting 10 ml fractions. The product fractions were collected and the solvent was removed in vacuo. There were obtained 0.614 g of the title compound ^Y 7 ^f Orme bezharvěo toeje ^(61% yield based on starting alcohol).

NMR T-60 (DCCl 3) δ 7.33 ppm (5H), dofd · δ 6.73 ppm, J 1 = 7 Hz, J = 16 Hz, d δ 6.60 ppm, J = 16 Hz ( Δ 3.73 (2H), δ 3.73 ppm (3H), partial spectrum.

IR (CHC13 A solution) ^{2980, 2900,} 28 ^{4 0, 1725,} 1685 (FL i ^{n e} x ^{e), 1675, 1625,} 1250-1200 ст ^'first

Mass ektrum ^{E P} L ^A B ⁹⁰⁰ 0 (m / e%) ^e 70% at 372 to 20 ° from ³⁷¹ to 82 °% 252 to 96% ²²⁶ to 24%, from 194 to 35 °% 1.2 eV 372-18% ^, 371-100%, 252-24 °% 226-39%.

Also ostatmch l- ^{(substituted-t} oovancyh 53fformylf2fpyrrolironovýcУ compound of Example 4 was ^already m e s ^h at Ora Uve en ^{d s} m ^p rocedure pyrrolidone used instead of 6 to give ^and d from ^{d p} OVI ající l- {subst formula --NR ^{IT s)} -53 (4 "ffen ^y lbut-l" fenf3 "fon ^yl) -2-p ^y yy olidenov ^E compound. In addition, a phosphonate of the formula (MeO 2 -CH 2 C 2 CH 2, II II) can be used wherein

Z represents the group —CsHáCHs (m) —a-thiend — C6H4OCH3 (p) —СбНг — СбШ (m) —C6H4CF3 (p) —C6H4Cl (o), instead of rimetУdlf (3-phenylpϋϋpan-2-one ^y ) phosphonate , to afford the corresponding 1- (siJbsthuované) - ^3.5 (4 "-substituted BUB) - ^ - ^y pyrroHctanové compounds. ^Vp ec ^h n ^y t ^y that p rгo ^{d -} i ^{d r} on the ^No. Men Etne ^ ^ The S are referred to as 1- (subst.řuovaím) -53- (^ '- substituted but-l "-en-З ^í 'Oil ^d l-2-p ^d g ^- iclon ^d .

Example 6

1- (7'-meth l ^{d h} eptanato) -50- (3 "-hydroxy -У ^{d d} - ^ - ^ ίΈηνΡινΓ η} /].) -2-pyrrolidone (compound 8)

To ptemenem in ^y su ^with EN ^{é b} and ^y in ^ňky Baven magnetic stir bar, thermometer, containing a nitrogen atmosphere. was added ^0.5784 g ^(1.5 6 mmoles) of l - ^ - methyl ^ toeptanato) - ⁵ 3- ^ "- ^ ténYtoubr ene-N -only] -2-pyrrolidinone in 20 m ^l of Suc ^{HEH T} HF. The clear colorless solution was cooled to -78 ° C and injection sínkac ^^ at which the ^p-RIP evněna Jeb through rubber stopper within 15 minutes at ^the APE ^1.56 m ^{l (1.5} mMol 6] htoiumtriettytaorotytotáu. ^P 1 ^h o ^d u Ina azuje ^to thin layer chromatography (TLC), it is no longer present in the starting enone and therefore the reaction is stopped and the excess hydride was quenched by the addition of glacial acetic acid to pH 5. the solvent was removed in vacuo, the residue dissolved in 50 ml of ethyl acetate and the resulting organic solution was extracted with 1 x 10 ml of half-saturated aqueous sodium hydrogencarbonate, 4 x 10 ml of water and 1 x 10 ml of saturated sodium chloride solution, and the organic layer was dried over magnesium sulfate. The mixture was filtered and the solvent was removed in vacuo to give 700 mg of a crude product which was chromatographed on a 9 g silica gel column containing ethyl acetate as the mobile phase. 5 ml fractions are collected automatically by pooling the fractions containing the product and vacuum removal. the solvent afforded 0.298 g of the title compound 8 as a ^B arv ^eh of oil microcapsules ^(51% yield ^EZ eq).

NMR T-60 (DCCl 3) δ 7.37 ppm (5H), δ 5.72 ppm, δ = 7 Hz, δ 5.62, δ = 7 Hz (2H), m δ 4 Δ 4.30 - 3.83 ppm (2H), δ 3.73 ppm (3H), d δ 2.90 ppm, J = 6 Hz (2H), partial spectrum.

IR (HCC- ^s solution) 3450-3200, ^{2975, 2900,} 283 ^{0, 1725, 1665,} 1250-1200 cm ^-1.

Other 1- (su ^b The substituted ^s) -53- ^{(4 "b} The substituted sulphonyl ЫИ-Теп-Э-оп ^) ^ -pyrrohdonové compound of Example 5 can also be

and converted to the corresponding 1- (substituted) -5 / 3- (4'-substituted) by the above procedure^E-3-hydroxybutyl-phenyl) p^yrrolido new compounds.

Case 7

I v

1- (6'-carboxy ^YH exyl) -5- (3- (3 '-h ^yd rox ^y - ⁴ "-f ^ ui phenyl-R-phenyl) -2-pyrrolidone olidon (Compound 9)

To a solution of 69 mg (0.185 mmol) of l- (7-inethylheptanato) -5 / 3- (3-hydroxy-4-phenyl-but-enyl) -2-pyrrolidone 8 in 3 ml methanol was ^{added 0.185} п ^{1 (0.185} Me ^{k) 1} N H ^y DROXI ^id u n ^d of about ^eh. Rakííiu mites ^{k p} and ^{k BC} overnight reflux, and then neutralized to pH 4 with glacial acetic acid. The solvent was removed in vacuo and the oily residue was dissolved in 15 mL of ethyl acetate. The organic solution is extracted with 2x2 ml water and 1 x 2 ml of saturated sodium chloride solution, dried over magnesium sulfate to give the title compound 9 as a yellow oil microcapsules of ^eh. Yield ^Ez ek ^59, 4 mg, 8 ^9%.

NMR, T-60, DCCl 3, s δ 7.33 ppm (5H), bs δ 6.30 ppm center (1H), d δ 5.73 ppm, J 1 = 7 'Hz, d 5, 6 ppm, Jt = 7 Hz (2H), m δ 4.6-3.2 ppm (4H), d δ 2.93 ppm, J = 7 Hz (2H), partial spectrum.

IG HCC13 solution, 3500-3100, 2980, 2920, 1700, 1600, 1250-1200 cm ^-1 .

Using other-substituted) -5 / A-H ^{yy yy} гox ^-buten-yl L2 ^y p rrol ^and DON ⁱⁿ place of the Example 6 pyrrolidone 8 occurs during the above procedure for cleavage of methyl or acyloxymethyl protecting groups and generate the following 8-aza- -11-deshydroxyprostaglandins Ei and Ez. (N-tetrahydropyran-2-yl protective group, if it is lo b ^y m e ^been removed with ^PU em ^b described in Example 3 or 14).

= —CO2H-tetrazol-5-yl, = —CeHeCH5 — α-thlenyl — СбШОСНз —C6H4 — C6H5 —C6H4CF3 —C1H.

EXAMPLE l - ^ - ^ e ^ meth anatomical) - ^{5- (3-} (4 "-phenoxy ^but-y ^ r ^^ onYH en-IL-pyrrolidone (compound 10)

A flame-dried flask containing a nitrogen atmosphere was charged with 22 mg (0.55 mmol) of the sodium hydride dispersion in mineral oil and 5 mL of THF. To this suspension ^{1 when the} mites can 0Д ^{549 g (0,} 6 mmol) dimethyl- (3-phenoxy-pr -propan-2-ones i) phosphonate in 5 ml of THF. When hydrogen evolution ceased, the reaction mixture was a clear light yellow solution, which was stirred for 15 minutes. To this solution was added 0.1277 g (0.5 mmol) of 1- (7'-meth ^yl heptanato 1) - ^{5 (3-formyl-yl-2-p} · ^y 6 pyrrolidone in 5 ml THF '1 minute The reaction mixture is clarified to a clear yellow solution over 5 minutes, stirred for a further 2 hours, acidified to pH 5 with glacial acetic acid, the solvent is evaporated off under vacuum and the residue is taken up in 50 ml of ethyl acetate. x 5 mL of saturated aqueous sodium bicarbonate, 2 x 5 ml water and 1 x 5 ml brine. the organic layer was dried over ^{hořečnalým,} přeflhruje and expand ^p ou ^{te d} lo was removed in vacuo. to give 0.231 g of yellow oil . This crude product was chroniritografuje on a column of Merck silica gel with a weight of 25 g of cyclohexane as the mobile phase. Purification of the producer ^to have the ^p rove ^d e eluting with 50% chloroform in cyclohexane, whereby to automatically collecting 10 ml fractions. fractions containing product were combined and solvent carrier lo is removed under vacuum. There were obtained 53.6 mg of the title compound 10 ^(the GET ² 8 θθ based on se ^h · Oz all alcohol).

NMR T-60 (DCCl 3), δ 7.40 - 6.70 ppm (5H), δ 6.7 - 6.33 ppm (2H), δ 4.67 ppm (2H), m . δ 4.40 to 3.97 ppm (1H), p. δ ³ 6 ⁷ ppm (3H). Partial with ^p ektrum.

^O with TATE 1- (substituted) - ^5/3 f ^orm-yl -2-pyrrolidone compound of Example 4 may also be used in the above procedure instead of 6 pyrrolidone, whereby are obtained ^by 1- (was substituted) - ^ 3- ( ⁴ "-O ENOX ^yb ut-l" -en-3 '-one ^yl) -2- ^{py y} rrolidonové compounds. In addition, the phosphonate U of the formula (MeO) 2 PCH 2 CCH 2 -O-V,

Where

V = —CeHCHb (p) —C6H4CF3 (m).

-C6H4- C6H4 (p) -CCH4OCH3 (p) Cl-cutaway (O) -C6H5 instead of dimethyl (3-phenoxy ^{yl propan-2-yl)} phosphonate to give the corresponding 2-pyrrolido221269 novel compounds.

Example 1 9

1- (7‘-Methylheptanato) -4- (3'-hydroxy-4'-phenoxybut-1-enyl) -2-pyrroleidone (compound 11)

To a flame dried Uaňky vyUavené magnetic stirring bar, thermometer, and nitrogen atmosphere oUsahující předtoč 0Д046 ^g (O, ²⁷ mmol) l- (7'-methyl ^"p tannate HE ^hyl) -5- ⁽⁴ '- ^{phenoxy y} but-l "-en-3 ^'-one-yl) - ^2-pyrrolidin one ^{people 10} in 5 m ^l Suc ^HEH of THF. The clear, colorless solution was cooled to -78 ° C and 0.27 ml (0.27 mmol) of lithium triethytoorohydride was added dropwise through the rubber stopper over the course of 15 minutes via syringe to which the needle was attached. After Todini 1 shows thin layer chromatography (TLC), that can not longer ^p řítomen výcliozí eno ^ and therefore the reaction is stopped and přeUytek hydride was quenched by the addition of glacial acetic acid to pH 5. The solvent was removed under vacuum, zUytek was dissolved in 25 ml ethyl acetate and ^ORG the organic solution was extratoje ¹ x 5 ml half-saturated aqueous sodium hydrogenuhhčitanu, 1 x 10 ml water. and 1 x 10 mL saturated sodium chloride solution. The organic layer was dried over magnesium ^{sulfate, filtered,} and the extended ^p Oust the ^EDL for ^the va ua removed. 101 mg of crude product are obtained. This product was chromatographed on silica and ^{the g} Knife hundredth or ^p is weight of ^{25 g.} o ^U reaching as mobile phase of Uenzen. The product was purified from impurities by elution with ethyl acetate, automatically collecting 5 ml fractions. Two epimers in ^width and ^to this způsotom insoluble eh ^d. FRA ^to CE ^U sahuj ^{ic p} ro ^d u ^KT with ^p drawbar and the solvent removed under vacuum. There were obtained ^{85 g of} 6 m titulrn compound ^{11 (82%} yield).

NMR T-60 (DCCl 3) δ 7.54-6.82 ppm (5H), δ 5.94-5.73 ppm (2H), δ 4.79-4.43 ppm (1H ) m. δ 4.33 to 3.94 ppm (s 3HH. δ ^{3 7} 0 ppm (3H). Partial with ^p ektrum.

IR ^{(CHC1 3} the solution, ^r) 36 (0 ^ 3 ^ ^2980, 29 ^ ^1730, 167 ^{0, 1600,} 1200-1250 cm ^-1..

In the above uvedenrnn ^p rocedure m is ^already used also other e-ssubstKuovaných l - ^ - (f enoxyUutenoyl) -2- ^p yrroliclonových compounds of pnMaáu place pyrroliéonu 8 and ¹⁰ correspond to získap ^ (substitimvaíp

-5j3- (4 '- ^phenoxy) 3' -h ^yd roxybu ^t -l ^{'enyl) -2} -pyrrolidonové compound.

Example 10

1- ^(6'к AR ⁱⁿ ox ^y hex ^yl) -5β- ⁽³ '- ^{hydroxy -} 4'-phenoxy-but ^y l ") ^en-yl) -2-pyrrolidone (compound 12)

К rozto^tou 50 mg (^0,128 mmole) th^ylhE^ptanato) -5 (3- (1-hydroxy-phenoxy) Uuttl '-en^yl) -²-^pyrro^1idonu¹¹ in³ m¹ of methanol^exand^{gives 0.128} ml (^0,128 1)^N sodium hydroxide. The reaction solution was then refluxed overnight and then neutralized to pH 4 by addition of ice^kyslm · vinegar. It was for you^toThe oily residue is dissolved in 15 ml of ethyl acetate. The organic solution was extracted with 2 x 2 mL water and 1 x 2 mL saturated solution^touch^yňs^toe solt v^ysu^š sulfate^hbryophyte and filtered. The solvent was evaporated in vacuo to give the title compound 12 as a yellow oil. Yield 48.0 mg (% of theory).

NMR T-60 · (DCCl 3) m δ 7.40 - 6.82 ppm (5H), m δ 6.73 - 6.17 ppm (2H), m δ 5.87 - 5.70 ppm ( 2H, m δ 4.7 - 4.4 ppm (1H), m ^{δ 4.23} - ^{3.88 pp} m (3H).

IC (HCCl 3 solution) 3600-2900, 2920, 1700, 1670^, 160^0, 1200^, 1250 cm^OFand use other Msuíituovar ^ ch] -^5/3- (h^ydrox^yfenox^ybutene^yl) -2-pyrrolido of the novel compounds of Example 9 instead of pyrrolidone;^{11 d}oj^de above^den^Em postu^pat^{k odš}t^RepNot metoyestester^ATo ac^y1ox^ym^Ethytov^E oc^hmorning sku^pin^y and the following 8-aza-11-dehydroxypoosaaglandins E 1 and E 2 are formed. (N-Thetaahydroiryran-2-yl protecting group)^and with^toat^pina^{, p}O^toat^d j^{í Uy1}O^použito^, pull^alreadye removed from^pSat^ATem^pO^psalým v pří-

X = -CO 2 H -tetrazol-5-yl,

V = · —C6H4CH3 (p) —C6H4CF3 (m) —O6H4 — C6H4 (p) —C6H4OCH3 (£) · —CsHa — Cl (o)

Ex AD 11 ¹ - ^ pCmeťhytoe Anat.) ^{(3 '-tetrahydro-pyran-2-ro'} "- ox ^{y y1} -4" phen ^y 1 ^U ut-1-enу1) -2-pyrrolidone (compound 13)

^U and ^{ňky characterized} dried under Dusl píneneni ^é ·

221 mg of 1- (7‘-methylheptanato) -5 / 3- (3'-hydroxy-4'-phenylbut-1-enyl) -2-pyrrolidone 9 and 5 ml of methylene chloride are introduced under an atmosphere of nitrogen. 0.062 ml (0.684 mmol) of redistilled dihydropyran and 3 mg of p-toluenesulfonic acid are added to this solution at 0-5 ° C. The solution was allowed to warm to room temperature and stirred overnight. After diluting the reaction mixture with 10 mL of ethyl acetate, the solution was extracted with 2 x 2 mL of saturated sodium bicarbonate solution and 1 x 5 mL of saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered to dryness, and the solvent was evaporated in vacuo. 0.135 g of a yellow oil is obtained. The oil is chromatographed on a 15 g Merck silica gel column containing chloroform as the mobile phase. Elution with one liter of chloroform removes less polar impurities. Elution with 2% methanol in chloroform was then carried out and 10 ml fractions were collected. The fractions containing the purified product were combined and the solvent was evaporated under vacuum. 0.1756 g of the title compound 13 is obtained as a yellow oil.

NMR T-60 (DCCl 3) δ 6.34 ppm (5H), δ 5.77-5.37 ppm (2H), δ 5.13-4.80 ppm (1H), s. Δ 3.7 ppm (3H), partial spectrum.

In addition, the 1- (substituted) -5 / 3- (4'-substituted-3'-hydrobut-1'-phenyl) -2-pyrrolidones of Examples 6, 7, 9 and 5 can also be used to prepare the corresponding tetrahydropyranyl derivatives by the same procedure. 10.

Example 12

1- (7‘-Methylheptanato) -5 / 3- (3'-tetrahydropyran-2'-yloxy-4'-phenylbutyl) -2-pyrrolidone (compound 14)

To a solution of 156.5 mg (0.342 mmol) of 1- (7'-methylheptanato) -5 / 3- (3'-tetrahydropyran-2''-yloxy-4'-phenylbut-1-enyl) -2-pyrrolidone 13 in 10 ml of ethyl acetate was added with 31 mg of 10% palladium on charcoal and the resulting mixture was placed in a Parr hydrogenation reactor and shaken for 4 hours under 50 psi of hydrogen. Then the suspension is filtered through celite to remove the catalyst and the solvent is removed from the filtrate. 158.2 mg of the title compound 14 are obtained.

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

Other tetrahydropyranyl derivatives of Example 11 in which A represents a single bond can also be used to prepare the corresponding hydrogenated derivatives by this process.

Example 13

1- (6'-Carboxyhexyl) -5 / 3- (3'-tetrahydropyran-2'-yloxyphenylbutyl) -2-pyrrolidone 15

To a solution of 1582 mg (0.342 mmol) of 1- (7'-methylheptanato) -5 / 3- (3'-tetrahydropyran-2''-yloxy-4'-phenylbutyl) -2-pyrrolidone 14 in 5 ml of methanol is added 0.342 ml (0.342 mmol) of 1 N sodium hydroxide. The reaction solution was then refluxed overnight and then neutralized to pH 4 by the addition of glacial acetic acid. 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 1 x 2 mL of saturated brine, dried over magnesium sulfate and filtered. The solvent was evaporated in vacuo to give the title compound 15 as a yellow oil, 134.2 mg (89% yield).

NMR T-60 (DCCl 3, δ 7.37 ppm (5H, m δ 4.4-3.2 ppm, m δ 2.92 ppm (2H)).

Other hydrogenated derivatives of Example 12 may also be used in this procedure. The corresponding 6‘-carboxylic acids and 6‘-tetrazol-5-yl compounds are obtained.

EXAMPLE 14 1- (6'-Carboxyhexyl) -5 / 3- (3'-hydroxy-4-phenylbutyl) -2-pyrrolidone (compound 16) (8-aza-11-deshydroxy-16-phenyl) -16-to-tetranor PGEo 16)

A solution of 134.2 mg (0.3 mmol) of 15 was stirred in 5 mL of a 65:35 mixture of acetic acid and water overnight under nitrogen at ambient temperature. The solvent was then evaporated in an oil pump vacuum and the residue dried azeotropically by distillation with benzene. The crude product is then chromatographed on 15 g of ARCC7 silica gel. Elution with 2% methanol in chloroform gave 82 mg of the title compound 16.

NMR T-60 (DCCl 3) δ δ 7.17 ppm (5H), m δ 3.2-4.0 ppm (3H), d <5 2.77 ppm, J _H equals 7 Hz (2H ). Partial spectrum.

IR (HCCH solution) 3600-3100, 2930, 2860, 1700, 1660, 1250, 1200, 710 cm ^1st

This process can also be used to cleave the tetrahydropyranyl protecting group from the 6'-carboxy and 6'-tetrazol-5-yl derivatives of Example 13 and the hydrogenated derivatives of Example 12.

Example 1 a d 15

1- (6‘-N-phenylimidohexyl) -5 / 3- (3'-hydroxy-4'-phenylbut-1-enyl) -2-pyrrolidine

To a solution of 64 mg (0.171 mmol) of 1- (6'-carboxyhexyl) -5 / 3- (4'-phenyl-3'-tetrahydro-pyran-2''-yloxybut-1'-phenyl) -2-pyrrolidone, prepared as described in Example 11, in 10 ml of dry tetrahydrofuran was added 25.16 mg (0.171 mmol) of benzoyl isocyanate prepared according to the procedure described by AJ Speziale, J. Org. Chem., 27, 3742 (1962), in 5 mL of dry THF. The mixture was refluxed overnight.

212'69

The solvent was removed under vacuum and the reaction product is freed ^and protective group (THP group) as described in Example - 14th · yield the title compound.

Kd ^Y Z is ^p oužije ostatrnch ^{suitably protected} NYCHA carboxamide ^{s-target alkyl} Selin z · ^AMPLE la ^d of 7, 10 and 14 may be ^p o ^d a ^b Nym ^PU with ^b em pnpravit follow im ^id b ^s deilváty :

OH where

Im =

By long NHCPh

O

II NHCCH3,

Z has the meaning given in Example 7,

The RD is defined as ^EXAMPLE la ^{DE 10,}

A is a single or cis double bond, B is a single or ^b double bond ^b a.

rcan ^Py-2 '' - yloxy ^y bu ^t -l ^"-en-yl) - ^ pyrrolidomL prepared as described in Example 11, in 10 ml of dry THF was added 20.7 mg (0.171 mmol) methylsulfonylisokyanátu (AJ Speziale, see Example 16). in 5 mL of dry benzene at rt pulse ^{l e} o ^to OH. ^MES weights overnight under ^P from Etna condenser, the solvent was removed under vacuum and the reaction product is freed from the protective group (THP group) as described in Example 14. yielding the title compound.

When used fenylsulfonylisokyanátu mfeto ^{methanesulfonyl} onyhso ^to yanátu jrnak and proceed as described above, there are obtained the corresponding fenylsulfoximidové derivatives.

Using other suitably protected ^to arbox ^yl ovýc ^h cr ^alkyl Selin ^Rik la ^Importan Ί, ¹⁰ and ^14, the following sulfonimides.

Example 16

1- (6'-N-methylsulfonim ^id o ^h exyl] -5β- (3 '-h ^yd rox ^y-4 "-phenyl ^b ut-l' enyl) -2-p ^y RRO ^people he

To mites in ^the 64 mg ^(0, Γ71 mmol) of l- (6'-Carboxyhexyl) -5 / 3- ⁽⁴ '- ^{phenoxy-l- yl 3} "-tetrah ^yd roSuf = NHSO2CH3

NHSOa »h,

V has the meaning given in Example 10,

Z is as defined in Example 7, ^A is a ^d or ^d bond or a cds double bond, B is a single or trans double bond.

Claims (1)

SUBJECT OF THE INVENTION ^1. preparation of new computer PTis ^{b h} ^ S-disubstituted 2-pyrrolidone compounds of formula I and epimers ^of C jejmh ^wherein Q is -COOH or -COOR slrupinu, wherein R is ^alkyl al lskupinu having 1-5 carbon atoms; W represents a single or cis double bond, Z represents simple. or a trans double bond, M represents a group of the formula or / AH OH OH H R‘ represents a phenyl- or phenoxy group, characterized in that, in a pyrrolidone Intermediate Compound of formula (II): Q, W, Z and R 'are as defined above, by conversion of the 15-oxo group to the α-hydroxy or β-hydroxy group, followed by the optionally obtained pyrrolidone compound of formula I wherein Q is COOR and R, W, Z, M and R 'are as defined above, hydrolyzed to a pyrrolidone compound of formula I wherein Q is COOH and W, Z, M and R * are as defined above, or the obtained pyrrolidone compound of formula I wherein Q is COOH and W, Z, M and R 'are as defined above, esterifying to give a pyrrolidone compound of formula I wherein Q is COOR and R, W, Z, M and R * are as defined above.