GB1569982A

GB1569982A - Pyrrolidones and process for their manufacture

Info

Publication number: GB1569982A
Application number: GB51912/76A
Authority: GB
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1975-12-13
Filing date: 1976-12-13
Publication date: 1980-06-25
Also published as: ZA767379B; LU76367A1; NL7613643A; JPS5273865A; CA1072108A; BE849346R; FR2334352A2; FR2334352B2; IL51090A0; DK554776A; SE7613948L; DE2556326A1; AU2047376A

Description

(54) PYRROLIDONES AND PROCESS FOR THEIR MANUFACTURE (71) We, HOECHST AKTIENGESELLSCHAFT, a body corporate organised according to the laws of the Federal Republic of Germany, of 6230 Frankfurt (Main) 80, Postfach 80 03 20, Federal Republic of Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to pyrrolidones and to a process for preparing them, and is an improvement in or modification of the invention claimed in our Co-pending application No.

26564/76 Serial No. 1553595.

Application No. 26564/76 Serial No. 1553595 describes and claims pyrrolidones which are analogues of prostaglandins and correspond to the general formula I

in which R1 represents a straight or branched chain, saturated or unsaturated, aliphatic hydrocarbon radical having up to 10 carbon atoms, or a cycloaliphatic hydrocarbon radical having 3 to 7 carbon atoms, which radicals may be unsubstituted or substituted by a) a straight or branched chain alkoxy, alkylthio, alkenyloxy or alkenylthio group of up to 5 carbon atoms, b) a phenoxy group which may carry one or two substituents selected from optionally halogenated alkyl groups of 1 to 3 carbon atoms, halogen atoms, optionally halogenated phenoxy groups, and alkoxy groups of 1 to 4 carbon atoms, c) a furyloxy, thienyloxy or benzyloxy group which may carry, on the nucleus, one or two substituents selected from optionally halogenated alkyl groups of 1 to 3 carbon atoms, halogen atoms, and alkoxy groups of 1 to 4 carbon atoms, d) a trifluoromethyl or pentafluoroethyl group, e) a cycloalkyl group of 3 to 7 carbon atoms, f) a phenyl, thienyl or furyl group which may carry one or two substituents selected from optionally halogenated alkyl groups of 1 to 3 carbon atoms, halogen atoms, and alkoxy groups of 1 to 4 carbon atoms, R2 represents a straight or branched chain, saturated or unsaturated, aliphatic or cycloaliphatic hydrocarbon radical having up to 6 carbon atoms; or an araliphatic hydrocarbon radical having 7 or 8 carbon atoms, and n represents the integer two, three or four, as well as the corresponding free acids and the salts, especially the physiologically acceptable e.g. metal or amine, salts thereof. If two or more substituents are present, they may be the same or differant.

There is also described and claimed a process for the manufacture of these pyrrolidones, wherein al) a pyrrolidone of the formula II

is protected at the nitrogen atom by introducing a protective group (R3), which can easily be split off, thus yielding a pyrrolidone of the formula III

a2) a pyrrolidone of the formula III

is oxidized to yield an aldehyde of the formula IV

a3) the so-obtained aldehyde of formula IV is reacted with a phosphonate of the formula V

in which R' is defined as above, and R4 represents an unbranched alkyl group of 1 to 4 carbon atoms, to yield a compound of the formula VI

a4) in the so-obtained compound of formula VI, the keto-carbonyl group is reduced to yield a compound of the formula VII

in which Rl is defined as above, a5) in the compound of formula VII, the protective group linked to the nitrogen atom is split off to yield a compound of the formula VIII

in which Rl is defined as above, or aS,) the pyrrolidone of formula II is oxidized to yield an aldehyde of the formula IX

a51 the protective group linked to the nitrogen atoms of the aldehyde of formula IV is a split off to give an aldehyde of formula IX, a52) the so-obtained aldehpde of formula IX is reacted with a phosphonate of formula V to yield a compound of the formula X

in which Rl is defined above, or a52,) in a compound of formula VI, the protective group linked to the nitrogen is split off to yield a compound of formula X, a53) in a compound of formula X, the ketocarbonyl group is reduced to yield a compound of formula VII a6) the alcohol function in a compound of formula VIII is protected with a group which can easily be split off under acid conditions, to yield a compound of the formula XI

in which R l is defined as above, and R5 represents a protective group, which can be easily split off under acid conditions, a7) the pyrrolidone of formula XI is deprotonized by means of a base at the nitrogen atom, and the thus-formed anion is reacted with a carboxylic acid derivative of the formula XII Y-CHI-CH = CH-(CH2)n-COOR2 XII in which R2 and n are defined as above, and Y represents a radical which can be substituted by a nucleophilic substitution reaction, to yield a compound of the formula XIII

in which R', R2 andn are defined as above, and R5 represents a protective group, which can easily be split off under acid conditions, the resulting ester is optionally hydrolyzed to yield the corresponding acid of formula XIII, in which R represents hydrogen, a8) the alcohol protective group R5 in the compound of formula XIII is split off to yield a compound of formula I, and optionally this compound is converted into the corresponding free acid or a salt thereof, or a8') the compound of formula VIII is deprotonized by means of a base, and the resulting anion is reacted with a carboxylic acid derivative of formula XII to yield a compound of formula I directly, or a7 i) the pyrrolidone of formula XI is deprotonized at the nitrogen atom by means of a base and the resulting anion is reacted with a carboxylic acid derivative of formula XII in which R1 represents hydrogen, to yield a compound of formula XIII in which R2 represents hydrogen, and the resulting acid is optionally converted into an ester of formula XIII, and step a8) is carried out, or a8,) the alcohol protective group in the compound of formula XIII in which R2 represents hydrogen, is split off to yield a compound of formula I, in which R2 represents hydrogen, and this acid is optionally converted into a salt or an ester thereof, or a8, ' ) the compound of formula VIII is deprotonized by means of a base, and the resulting anion is reacted with a carboxylic acid derivative of formula XII, in which R2 represents hydrogen, to yield directly a compound of formula I in which R2 represents hydrogen, or b,) into the pyrrolidone of formula II

an alcohol protective group R6, which can easily be split off under acid conditions, is introduced to yield a compound of the formula XIV

b2) the pyrrolidone of formula XIV is deprotonized at the nitrogen atom by means of a base, and the resulting anion is reacted with an allyl halide to yield a pyrrolidone of the formula XV

b3) the so-obtained pyrrolidone of formula XV is ozonolyzed to yield an aldehyde of the formula XVI

b4) the so-obtained aldehyde of formula XVI is reacted with an ylide of the formula XVII (R7)3P = CH(CH2)nCOOMe XVII in which n is defined as above, R7 represents identical or different groups selected from straight chain alkyl groups of l to 4 carbon atoms and phenyl groups, and Me represents an alkali metal atom, to yield a compound of the formula XVIII

and this compound is treated to set free the corresponding acid of the formula XIX

in which formulae n is defined as above, or b4' ) the protected pyrrolidone of formula XIV is deprotonized at the nitrogen atom by means of a base, and the resulting anion is reacted with a carboxylic acid derivative of formula XII, in which R2 represents hydrogen, to yield a compound of formula XIX, b5) the so-obtained compound of formula XIX is converted into the corresponding ester of the formula XX

in which R2 and n are defined as above, or b5') the protected pyrrolidone of the formula XIV is deprotonized at the nitrogen atom by means of a base, and the resulting anion is reacted with a carboxylic acid derivative of formula XII to yield the compound of formula XX directly, b6) the protective group R6 in the so-obtained compound of formula XX is split off under acid conditions to yield an alcohol of the formula XXI

in which R2 and n are defined as above, and then the corresponding acid may optionally be set free, or b6') esterification of a compound of formula XIX and splitting-off of the protective group R6 are carried out in a single step, or b6") the pyrrolidone of formula II is deprotonized at the nitrogen atom by means of a base, and the resulting anion is reacted with a carboxylic acid derivative of formula XII to yield a compound of formula XXI directly, or b61) the pyrrolidone of formula II is deprotonized at the nitrogen atom by means of a base, and the resulting anion is reacted with an allyl halide to yield a compound of the formula XXII

b62) The so-obtained compound of formula XXII is ozonolyzed to yield a compound of the formula XXIII and/or its cyclisized tautomer of the formula XXIV

or b62') the protective group R6 is split off from a compound of formula XVI also to yield the compound of formulae XXIII and/or XXIV, b63) the compound of formulae XXIII and/or XXIV is or are reacted with an ylide of formula XVII to yield a compound of the formula XXV

and the corresponding acid of the formula XXVI

is set free therefrom and optionally converted into an ester of formula XXI, in which formulae XXV and XXVI n is defined as above, or b63') the pyrrolidone of formula II is deprotonized at the nitrogen atom by means of a base, and the resulting anion is reacted with a carboxylic acid derivative of formula XII, in which R2 represents hydrogen, or b63gt) the protective group R is split off from a compound of formula XIX to yield a compound of formula XXVI, b7) the so-obtained alcohol of formula XXI is oxidized to yield an aldehyde of the formula XXVII

in which R2 and n are defined as above, and optionally the corresponding acid of formula XXVII (R2 = H) is set free therefrom, b8) the so-obtained aldehyde of formula XXVII is reacted with a phosphonate of formula V to yield a compound of the formula XXVIII

in which Rt, R2 and n are defined as above, or b8') a compound of formula X is deprotonized at the nitrogen atom by means of a base, and the resulting anion is reacted with a carboxylic acid derivative of formula XII to yield a compound of formula XXVIII directly, b9) in the so-obtained compound of formula XXVIII, the keto-carbonyl group is reduced to yield a compound of formula I, and this compound is optionally converted into the free acid or a salt thereof, or b71) a compound of formula XXVI is oxidized to yield an aldehyde of formula XXVII, in which R2 represents hydrogen, and this is optionally converted into an ester of formula XXVII, b81) an aldehyde of formula XXVII, in which R2 represents hydrogen, is reacted with a phosphonate of formula V to yield a compound of formula XXVIII, in which R2 represents hydrogen, and this is optionally converted into an ester of formula XXVIII, or b8l) a compound of formula X is deprotonized at the nitrogen atom b means of a base, and the resulting anion is reacted with a carboxylic acid derivative of formula XII, in which R2 represents hydrogen, directly to yield a compound of formula XXVIII, in which R2 represents hydrogen, 2 b91) in a compound of formula XXVIII, in which R2 represents hydrogen, the ketocarbonyl group is reduced, and the resulting compound of formula I, in which R2 represents hydrogen, is optionally converted into a salt or an ester thereof.

The present invention provides pyrrolidones which are also analogues of prostaglandins and have the formula I'

in which Rl, R2 and n are defined as in formula I and R8 represents a straight or branched chain alkyl radical having from 1 to 5 carbon atoms, an alkenyl or alkynyl radical having from 2 to 5 carbon atoms or an araliphatic hydrocarbon radical having 7 or 8 carbon atoms.

This invention also provides a process for preparing a pyrrolidone of the formula I', which comprises z) proceeding in the manner described in process steps b to b8 of claim 9 of our Patent Specification No. 1553595 (Application No. 26564/76), and reacting the resulting pyrrolidone of the formula XXVIII

in which Rl, R2 and n are as defined in formula I with an organometallic compound which comprises the radical R8 as defined as in formula I' above, to give a compound of formula I' and, if desired, converting the resulting compound of formula I into the free acid or a salt thereof, or yl) proceeding in the manner described in process steps al to a52' of claim 9 of our Patent Specification No. 1553595 (Application No. 26564/76), and reacting the resulting pyrrolidone of the formula X

in which Rl is defined as in formula I with an organometallic compound which comprises the radical R8 as defined in formula I', to give a compound of the formula XXIX

y2) protecting the hydroxy group in the pyrrolidone of formula XXIX by a group R9 which can easily be removed under acid conditions, thus forming a compound of the formula XXX

in which Rl is as defined in formula I and R8 is defined as in formula I', ys) deprotonizing the pyrrolidone of formula XXX at the nitrogen atom by means of a base and reacting the anion thus formed with a carboxylic acid derivative of the formula XXXI Y-CH2-CH = CH(CH2)nCOOR2 XXXI in which R2 andn are defined as in formula I and R2 may also represent a hydrogen atom, and Y represents a radical which may be substituted by a nucleophilic substitution reaction, to give a compound of the formula XXXII

y4) removing the hydroxy protective group R9 from the compound of the formula XXXII, thus forming a compound of formula I', and, if desired, converting that compound into the free acid, a salt, an ester or another ester thereof, as appropriate, or y41) deprotonizing the pyrrolidone of the formula XXIX at the nitrogen atom by means of a base, without introducing a protective group at the hydroxyl function, and reacting the anion formed with a carboxylic acid derivative of the formula XXXI to give a compound of the formula I' and, if desired, converting that compound into a free acid, a salt, an ester or another ester as appropriate. The preferred meanings for R1, R2 and n, are the preferred meansings given in Application No. 26564/76 Serial No. 1553595.

R8 preferably represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms, especially a methyl, ethyl, propyl or isopropyl group, an alkenyl or alkynyl group having from 2 to 4 carbon atoms, especially a vinyl, 1-propenyl, allyl or ethynyl group, or a benzyl group.

The organometallic compounds used for the processes z) and y) are preferably derived from metals of the first and second main groups of the Periodic Table of the Elements, i.e. the alkali and alkaline earth metals, and are in particular lithium- and magnesiumorganic compounds (Grignard compounds), which may be prepared according to any of the usual methods, for example, from a compound R8-X, in which R8 is defined as in formula I' and X is a halogen atom, for example a chlorine, bromine or iodine atom, and the corresponding metal, for example, Li or Mg.

The reaction of the pyrrolidone of formula XXVIII or X is generally carried out in a solvent which is inert under the reaction conditions, for example, a hydrocarbon or preferably an ether, for example, diethyl ether, tetrahydrofuran or 1 ,2-dimethoxyethane.

The reactions may be carried out at a temperature in the range of from -60 C to +30"C, preferably from -30 C to -OOC. The pyrrolidone XXVIII or X may be added to the organometallic compound or vice versa, but it is preferable to add the organometallic compound to the pyrrolidone in order to minimise side reactions. Subsequently, the reaction mixture may be mixed with water, a dilute mineral acid, or a solution of an ammonium salt, for example, ammonium chloride in water, and the product may then be isolated in the usual manner.

The hydroxy group in the compound of formula XXIX can generally be protected by any protective group that is easy to remove, but the preferred protective groups are those which are introduced by acid catalysis, predominantly by reaction with an enol ether. The enol ether is preferably 2,3-dihydropyran, ethyl vinyl ether or methyl isopropenyl ether, and the acid catalyst is preferably p-toluenesulphonic acid or sulphuric acid. The reaction is advantageously carried out in a solvent, for example, diethyl ether, dioxane or benzene, at temperatures of from -10 to + 600 C.

The pyrrolidone of formula XXX is alkylated by means of a carboxylic acid derivative of formula XXXI according to any of the usual methods, by deprotonizing the compound of formula XXX at the nitrogen atom by means of a suitable base, for example, sodium or potassium hydroxide, sodium or potassium amide, sodium hydride, potassium tert.-butoxide, lithium diisopropylamide or lithium cyclohexyl-isopropylamide, and then adding the alkylating agent per se or in solution in an ether, for example, tetrahydrofuran, dioxane or 1 ,2-dimethoxyethane, or in a dipolar aprotic solvent, for example, dimethyl sulphoxide or hexamethylphosphoric acid triamide.

The substituent Y in the compound of formula XXXI is preferably a methanesulphonyloxy, p-bromobenzenesulphonyloxy or p-toluenesulphonyloxy radical, or a chlorine, bromine or iodine atom, bromine and chlorine being of outstanding importance in this connection.

The reaction of a base with the compound of formula XXX is carried out with exclusion of air and moisture since the bases and resulting anion are sensitive to air and moisture. The solvent is especially an aprotic polar liquid which has a sufficient dissolving power at low temperatures and which is inert under the reaction conditions. Where required, a mixture of two or more solvents may be used to reduce the solidification point, preferably ethers, for example, dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1 ,2-dimethoxyethane, dimethylformamide, dimethyl sulphoxide or toluene.

The reaction temperatures generally range from -30 C to + 800 C, preferably from - 10 to + 500C, in particular from 0 C to room temperature. The reaction is generally carried out by adding a solution of the pyrrolidone of formula XXX with stirring to a frozen solution of the base in one of the said solvents, to maintain the temperature range desired for the reaction; the components may also be added to one another in the reverse order.

The alkenyl derivative XXXI is then preferably added to the solution obtained from the above reaction. The solution is preferably at or near freezing point, and the addition is made in such a manner that the temperature range of the reaction mixture does not substantially exceed the upper limits given above as a result of the reaction, which is exothermic. After the addition, the mixture is generally stirred for half an hour to 12 hours and then worked up, for example by adding a pre-determined amount of water to the reaction mixture, separating the organic phase, extracting the aqueous phase several times with an organic solvent, drying the united organic phases and concentrating them.

In a few cases, the residue can be purified by a high-vacuum distillation, in most cases only by column chromatography. In many cases, the products are obtained in such a pure state that further purification is unnecessary.

To remove the hydroxy protective group R9 to convert the compound of formula XXXII into a compound of formula I' or into the corresponding acid, the usual reactions and reaction conditions are used.

In a compound of formula XXXII, the hydroxy group is preferably protected by an acetal group which is split off, in the simplest case, by acid hydrolysis with dilute aqueous/alcoholic acid, preferably dilute aqueous-alcoholic oxalic acid, at 10 - 500C, or by heating it with 60 - 70% u/v acetic acid at 50 - 600C to yield the compound of formula I'.

Depending on the reaction conditions, the compound of formula I' or the corresponding acid is obtained, which may then, optionally, be converted as appropriate into further derivatives, for example, metal or amine salts, esters or other esters, as appropriate.

The alkylation reaction for the conversion of a compound of formula XXX into a compound of formula XXXII may also be carried out using the corresponding carboxylic acid of formula XXXI (R2 = H), and the resulting compounds of formula XXXII (R2 = H) may be converted into the corresponding compound of formula I' (R2 = H) by removing the hydroxy protective group by acid hydrolysis. In the same manner, the compounds of formula XXIX may be alkylated as above, optionally using both carboxylic acid ester derivatives of formula VI and carboxylic acid derivatives of formula VI (R2 = H). In this case, the compounds of formula I' are obtained in a single step.

The compounds of the invention have an activity which is spasmogenic on one hand and bronchodilatory on the other hand, furthermore, they have antihypertensive proper ties, they are able to inhibit the secretion of gastric juice and have abortive effects. They may therefore be used as drugs.

The pharmacological properties were tested on the following animals and/or organs: Spasmogenic effect: isolated rat stomach, isolated guinea-pig uterus Bronchodilatatory effect: guinea-pig 4 Antihypertensive effect: dog Secretion of gastric juice: rat Abortive effect: hamster.

The compounds of the invention may be employed in pharmaceutical preparations as free acids, in the form of the physiologically tolerable inorganic or organic salts thereof or as esters of aliphatic, cycloaliphatic or araliphatic alcohols, in admixture or conjunction with a pharmaceutically suitable carrier.

The inorganic salts are, for example, alkali metal salts, alkaline earth metal salts and ammonium salts; for formation of salts with organic bases, there may be used primary, secondary and tertiary amines which may contain further hydrophilic groups; for example salts with methyl-, triethyl-, benzyl-, phenylethyl-, allylamine or with piperidine, pyrrolidine, or morpholine, or with ethanolamine, triethanolamine, tris-(hydroxymethyl) aminomethane. The esters are preferably esters of lower aliphatic alcohols, for example, methyl, ethyl, propyl, butyl and hexyl esters, and benzyl esters.

The acids, salts or esters may be administered in the form of an aqueous solution or suspension thereof, or in solution or suspension in a pharmaceutically suitable organic solvent, for example, a mono- or polyhydric alcohol, for example, ethanol, ethylene glycol or glycerol; an oil, for example sunflower oil or castor oil; an ether, for example, diethylene glycol dimethyl ether, or a polyether, for example polyethylene glycol; or in the presence of a pharmaceutically suitable polymer carrier, for example, polyvinyl pyrrolidone.

The pharmaceutical preparations of the invention may be in a form suitable for injection or infusion, for oral administration, or for local administration, for example, in the form of a spray.

The compounds of the invention may be used in combination with other active ingredients, for example, hormones and compounds which influence the fertility, for example, LH-RH (inteinising hormone releasing hormone), FSH, estradiol and LH, diuretics, for example Furosemide, antihyperglycemics, for example, metformin, and agents acting on the circulation, for example cardio-vascular-dilatatory agents, for example, chromonar or prenylamine, antihypertensive agents, for example, reserpine, a-methyl dopa and clonidine [2-(2,6-dichloro-phenylamino)-2-imidazoline)], anti-arrhythmics, antihyperlipidemic agents and geriatric agents, and other compositions acting on the metabolism, psychopharmaceuticals, for example chlordiazepoxide, diazepam and meprobamate, as well as vitamins, other prostaglandins and prostaglandin-like compounds, and prostaglandin antagonists.

The preparations are preferably in unit dosage form, a unit dose preferably comprising from 5 ,ug to 5 mg, of the active substance, the daily dosage being from about 10 , lg to 20 mg.

The compounds of the formulae XXIX, XXX and XXXII are novel valuable intermediates for the manufacture of the compounds of formula I'.

The following Examples illustrate the invention. Solvent ratios are by volume.

EXAMPLE 1: I-(6-Merhoxycarbonyl- (Z) -2-hexenyl) -5-(3 -hydroxy-3 S-methyl-(E) -I-octenyl) -2- pyrrolidone A solution of 10 mmoles of 1-(6-methoxycarbonyl-(Z)-2-hexenyl)-5-(3-oxo-(E) -1-octenyl)- 2-pyrrolidine in 70 ml of diethyl ether was cooled to -150C under an argon atmosphere. Subsequently, 8 ml of a 1.5 molar solution (12 millimoles) of methylmagnesium iodide in ether was added dropwise, while stirring, the mixture was continued to be stirred for 30 minutes and was heated to room temperature. Afterwards about 1.5 ml of a saturated ammonium chloride solution was added at OOC, in which process a colorless precipitate was formed. After about 10 minutes, anhydrous magnesium sulfate was added, the product was suction-filtered, concentrated and chromatographed on silica gel (eluent: toluene/acetic ester/methanol 5:4:0.3).

EXAMPLE 2: 1-(6-Methoxycarbonyl- (Z) -2-hexenyl) -5-(3#-hydroxy-3-#-ethynyl-(E)-1 -octenyl)-2 -1-octenyl) -2 -pyrrolidone was prepared according to the method described in Example 1 from 1-(6methoxycarbonyl-(Z)-2-hexenyl)-5- (3-oxo-(E)- 1-octenyl) -2-pyrrolidone and lithium ethynyl.

Chromatography: toluene/acetic ester/methanol 5:4:0.1 NMR: 8 = 3.6 ppm (s) COOCH3 8 = 2.7 ppm (s) C#CH 8 = 5.4-5.6 ppm (m) CH=CH EXAMPLE 3: 1-(6- Methoxycarbonyl-(Z) -2- hexenyl) - 5- (3#-hydroxy-3#- allyl - (E) -1- octenyl) -2 -pyrrolidone was prepared according to the method described in Example 1 from 1-(6 methoxycarbonyl-(Z)- 2-hexenyl)-5-(3-oxo- (E)-1-octen-1-yl) -2-pyrrolidone and allyl magnesium bromide.

Chromatography: toluene/acetic ester/methanol 5:4:0.1 NMR: 8 = 3.7 ppm (s) COOCH3 8 = 5.2-5.7ppm(m) CH=CH and CH=CH2 (5 prot.) IR: 1735 cm mJ C=O 1685 cm-l lS 'J.C=O EXAMPLE 4: 1-(6-Methoxycarbonyl-(Z)-2-hexenyl) -5-(3 E,-hydroxy-3 t-methyl-5-ethoxy-4, 4-dimethyl (E)-l-pentenyl- 2-pyrrolidone was prepared according to the method described in Example 1 from 1 (6-methoxycarbonyl- (Z)-2-hexenyl)- 5- (3-oxo-5-ethoxy-4, 4-dimethyl-(E)- 1 pentenyl)-2-pyrrolidone and methylmagnesium iodide.

Chromatography: toluene/acetic ester/methanol 5:4:0.3 NMR: 8 = 0.95 ppm C(CH3)2 6 prot.

8 = 1.4 ppm C-CH3 8 = 3.65 ppm COOCH3 IR: 1685 cm-l u C=0 1735 cm-1 # C=0 EXAMPLE 5: 1 - (6-Methoxycarbonyl- (Z) -2-hexenyl-5- (3 #-hydroxy-3 (-benzyl- (E) -1-decenyl) - 2-pyrrolidone was prepared according to the method described in Example 1 from 1 (6-methoxycarbonyl-(Z) -2-hexenyl)-5-(3-oxo-(E) - 1-decen-1-yl) -2-pyrrolidone and benzylmagnesium chloride.

Chromatography: toluene/acetic ester/methanol 5:4:0.1 NMR: 8 = 3.7 ppm COOCH3 8 = 5.4 - 5.6 ppm CH=CH 8 = 7.1 - 7.3 pp

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

EXAMPLE 2: 1-(6-Methoxycarbonyl- (Z) -2-hexenyl) -5-(3#-hydroxy-3-#-ethynyl-(E)-1 -octenyl)-2 -1-octenyl) -2 -pyrrolidone was prepared according to the method described in Example 1 from 1-(6methoxycarbonyl-(Z)-2-hexenyl)-5- (3-oxo-(E)- 1-octenyl) -2-pyrrolidone and lithium ethynyl.

Chromatography: toluene/acetic ester/methanol 5:4:0.1 NMR: 8 = 3.6 ppm (s) COOCH3

8 = 2.7 ppm (s) C#CH

8 = 5.4-5.6 ppm (m) CH=CH EXAMPLE 3: 1-(6- Methoxycarbonyl-(Z) -2- hexenyl) - 5- (3#-hydroxy-3#- allyl - (E) -1- octenyl) -2 -pyrrolidone was prepared according to the method described in Example 1 from 1-(6 methoxycarbonyl-(Z)- 2-hexenyl)-5-(3-oxo- (E)-1-octen-1-yl) -2-pyrrolidone and allyl magnesium bromide.

Chromatography: toluene/acetic ester/methanol 5:4:0.1 NMR: 8 = 3.7 ppm (s) COOCH3

8 = 5.2-5.7ppm(m) CH=CH and CH=CH2 (5 prot.) IR: 1735 cm mJ C=O 1685 cm-l lS 'J.C=O EXAMPLE 4: 1-(6-Methoxycarbonyl-(Z)-2-hexenyl) -5-(3 E,-hydroxy-3 t-methyl-5-ethoxy-4, 4-dimethyl (E)-l-pentenyl- 2-pyrrolidone was prepared according to the method described in Example 1 from 1 (6-methoxycarbonyl- (Z)-2-hexenyl)- 5- (3-oxo-5-ethoxy-4, 4-dimethyl-(E)- 1 pentenyl)-2-pyrrolidone and methylmagnesium iodide.

Chromatography: toluene/acetic ester/methanol 5:4:0.3 NMR: 8 = 0.95 ppm C(CH3)2 6 prot.

8 = 1.4 ppm C-CH3

8 = 3.65 ppm COOCH3 IR: 1685 cm-l u C=0

1735 cm-1 # C=0 EXAMPLE 5: 1 - (6-Methoxycarbonyl- (Z) -2-hexenyl-5- (3 #-hydroxy-3 (-benzyl- (E) -1-decenyl) - 2-pyrrolidone was prepared according to the method described in Example 1 from 1 (6-methoxycarbonyl-(Z) -2-hexenyl)-5-(3-oxo-(E) - 1-decen-1-yl) -2-pyrrolidone and benzylmagnesium chloride.

Chromatography: toluene/acetic ester/methanol 5:4:0.1 NMR: 8 = 3.7 ppm COOCH3 8 = 5.4 - 5.6 ppm CH=CH

8 = 7.1 - 7.3 ppm C6H5 IR: l730cm-l u C=0 1680cm-1# C=0 WHAT WE CLAIM IS: 1. A compound of the formula I'

in which Rl represents a straight or branched chain, saturated or unsaturated, aliphatic hydrocarbon radical having up to 10 carbon atoms, or a cycloaliphatic hydrocarbon radical having 3 to 7 carbon atoms, which radicals may be unsubstituted or substituted by one or more of the followmg: a) a straight or branched chain alkoxy, alkylthio, alkenyloxy or alkenylthio group of up to 5 carbon atoms, b) a phenoxy group which may carry one or two substituents selected from optionally halogenated alkyl groups of 1 to 3 carbon atoms, halogen atoms, optionally halogenated phenoxy groups, and alkoxy groups of 1 to 4 carbon atoms, c) a furyloxy, thienyloxy or benzyloxy group which may carry, on the nucleus, one or two substituents selected from optionally halogenated alkyl groups of 1 to 3 carbon atoms, halogen atoms, and alkoxy groups of 1 to 4 carbon atoms, d a trifluoromethyl or pentafluoroethyl group, e a cycloalkyl group of 3 to 7 carbon atoms, f) a phenyl, thienyl or furyl group which may carry one or two substituents selected from optionally halogenated alkyl groups of 1 to 3 carbon atoms, halogen atoms, and alkoxy groups of 1 to 4 carbon atoms, R2 represents a straight or branched chain, saturated or unsaturated, aliphatic or cycloaliphatic hydrocarbon radical having up to 6 carbon atoms, or an araliphatic hydrocarbon radical having 7 or 8 carbon atoms, and n represents the integer two, three or four, and R8 represents a straight-chain or branched alkyl radical having from 1 to 5 carbon atoms, an alkenyl or alkynyl radical having from 2 to 5 carbon atoms or an araliphatic hydrocarbon radical having 7 or 8 carbon atoms, the free acid thereof, and salts of the free acid.
2. A compound as claimed in claim 1, wherein R8 represents a straight chain or branched alkyl radical having from 1 to 4 carbon atoms, an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, or a benzyl radical.
3. A compound as claimed in claim 1, substantially as described in any one of the Examples herein.
4. A physiologically tolerable salt of the free acid of a compound as claimed in any one of claims 1 to 3.
5. A process for the manufacture of a compound of formula I' as claimed in claim 1, which comprises z) proceeding in the manner described in process steps bl to b8 of claim 9 of our Patent Specification No. 1553595 (Application No. 26564/76), reacting the resulting pyrrolidone of the formula XXVIII

in which R1, R2 and n are as defined in claim I with an organometallic compound which comprises the radical R8 as defined in claim 1, to give a compound of formula I', and, if desired, converting the resulting compound of formula I into the free acid or a salt thereof, or yl) proceeding in the manner described in process steps al to a5 ' of claim 9 of our Patent Specification No. 1553595 (Application No. 26564/76), and reacting the resulting pyrrolidone of the formula X

in which Rl is defined as in claim I with an organometallic compound which comprises the radical R8 as defined in Claim I, to give a compound of the formula XXIX

wherein Rl and R8 are as defined in claim 1.

y2) protecting the hydroxy group in the pyrrolidone of formula XXIX by a group R9 which can easily be removed under acid conditions, thus forming a compound of the formula XXX

in which Rl and R8 are as defined in claim 1, and R9 is as defined above, ys) deprotonizing the pyrrolidone of formula XXX at the nitrogen atom by means of a base and reacting the anion thus formed with a carboxylic acid derivative of the formula XXXI Y - CH2 - CH = CH - (CH2)n - COOR2 XXXI in which R2 andn are defined as in claim 1 and R2 may also represent a hydrogen atom, and Y represents a radical which may be substituted by a nucleophilic substitution reac tion to give a compound of the formula XXXII

in which Rl, R2 R8 and n are as defined in claim 1, R2 may also represent a hydrogen atom, and R9 is defined as above, y4) removing the hydroxy protective group R9 from the compound of the formula XXXII by acid hydrolysis, thus forming a compound of formula I', and, if desired, converting that compound into the free acid, an ester or another ester thereof, as appropriate, or y4,) deprotonizing the pyrrolidone of the formula XXIX at the nitrogen atom without introducing a protective group at the hydroxyl function, and reacting the anion formed with a carboxylic acid derivative of the formula XXXI to give a compound of the formula I' and, if desired, converting that compound into a free acid, a salt, an ester or another ester as appropriate.
6. A process as claimed in claim 5, carried out substantially as described in any one of Examples herein.
7. A compound as claimed in claim 1, the free acid or a salt thereof, whenever prepared by a process as claimed in claim 6 or claim 6.
8. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 1 to 3 or claim 7, the free acid or a physiologically tolerable salt thereof as active substance, in admixture or conjunction with a pharmaceutically suitable carrier.
9. A pharmaceutical preparation as claimed in claim 8, in a form suitable for injection or infusion.
10. A pharmaceutical preparation as claimed in claim 8, in a form suitable for oral administration.
11. A pharmaceutical preparation as claimed in claim 21, in a form suitable for local administration.
12. A pharmaceutical preparation as claimed in claim 11, in the form of a spray.
13. A pharmaceutical preparation as claimed in any one of claims 9 to 12, in unit dosage form.
14. A pharmaceutical preparation as claimed in claim 13, which comprises from 5 ,ug to 5 mg of the active substance per unit dose.