CH646972A5 - Process for the preparation of new 5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids - Google Patents

Abstract

Novel carboxylic acids of the formula <IMAGE> as the racemate or in the (l) form are prepared by condensing an amide R<1>C6H4CON(CH3)2 with a corresponding (C1-C4)alkyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate and hydrolysing the resulting alkyl ester. R denotes hydrogen or C1-C4-alkyl and R<1> denotes hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine or bromine. The compounds and their pharmaceutically permissible salts can be used as antiphlogistics, analgesics, fibrinolytics and muscle relaxants in therapy.

Description

The present invention relates to a process for the preparation of new pyrrole-l-carboxylic acids, namely the (d, l) - and (l) -5-aroyl-1,2-dihydro-3H-pyrrolo- [l, 2-a ] -pyrrole-1-carbon-acids of the formula

COOH

(A)

in which R represents the hydrogen atom or an alkyl radical with 1 to

4 carbon atoms and R1 are the hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, an alkoxy radical with 1 to 4 carbon atoms or the chlorine atom, the fluorine atom or the bromine atom, the substituent R1 being in the o-, m- or p-position of the Aroylgruppe located, and their pharmaceutically acceptable salts.

The (d, l) and (l) forms of the compounds of formula A have anti-inflammatory, analgesic and antipyretic effects and are therefore valuable for the treatment of inflammation, pain and / or pyrexia in mammals and humans, as described in detail below becomes. They are also excellent muscle relaxants.

The salts of the compounds of formula A are derived from pharmaceutically acceptable, inorganic and organic bases.

Salts derived from inorganic bases include the sodium, potassium, lithium, ammonium, calcium, magnesium, ferro, zinc, copper, mangano, aluminum, ferric and manganese salts, etc. are particularly preferred the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable, organic, non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including the naturally occurring substituted amines, cycloamines and basic ion exchange resins, e.g. B. isopropylamine, trimethylamine, diethylamine, triethylamine, tri-propylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethain, ethain Glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred are organic, non-toxic bases, such as isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexylamine, choline and caffeine.

The new compounds of formulas (A) as disclosed below, consisting of optical isomers or enantiomorphs, i.e. H. in the form of (d, l) mixtures. The (l) compound as well as the (d, l) mixtures thereof are encompassed by the present invention.

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Should the new compounds because of their physiological responsiveness, eg. B. their anti-inflammatory, analgesic or antipyretic effect, d. H. used as medicaments, a preferred sub-group will be found among the (l) isomers thereof and their pharmaceutically acceptable salts.

Another subgroup for compounds to be used as medicaments are the compounds of the formula (A) and

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their pharmaceutically acceptable salts, in which R and R1 each represent a hydrogen atom.

The new (d, l) compounds can be prepared according to the following reaction scheme. The reaction sequence of 5 the compounds of formula (X) via the compounds of formula (XI) to the compounds of formula (A) represents the process according to the invention as defined in claim 1:

NH.

1 '

CH

I.

CH

I.

OH

COOCH

COOCH.

2 2

(I)

(III)

(VIII)

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COOR

COOR

(XI)

COOH

wherein R and R1 have the above meanings and R2 is a lower alkyl radical having ibis 4 carbon atoms, e.g. B. the methyl, ethyl, isopropyl or n-butyl radical means.

When carrying out the present process in practice, equimolecular amounts of ethanolamine of the formula I and dimethyl 1,3-acetonedicarbonate of the formula II are used at a temperature of approximately 0 ° for the preparation of the compound of the formula IV in which R is the hydrogen atom React C to about room temperature in order to easily obtain a solution of the vinylamine of the formula III, which is then preferably in situ in a suitable inert organic solvent under anhydrous conditions with 2-bromoacetaldehyde or 2-chloroacetaldehyde in one Treated temperature from about 40 ° C to about 100 ° C for a period from about 30 minutes to about 16 hours. Suitable solvents for this reaction are aprotic solvents, such as acetonitrile, tetrahydrofuran, dimethoxyethane, chloroform, dichloromethane, etc. In the preferred embodiments, the reaction in acetonitrile solution takes place at the reflux temperature for about 1 hour. The compounds used as reactants, i.e. H. 2-bromoacetaldehyde and 2-chloroacetaldehyde are known compounds. They can be obtained by pyrolysis of the corresponding diethylacetals in the presence of oxalic acid dihydrate.

To the compounds of formula IV, wherein R is a lower alkyl radical having 1 to 4 carbon atoms, which is preferably a straight-chain radical, is an aqueous mixture of ethanolamine of the formula I and 1,3-acetone dicarboxylic acid di-methyl ester of the formula II with a compound of the following formula Q

3 "

ft-c-ch2x wherein X is bromine or chlorine and R3 is a lower alkyl group of 1 to 4 carbon atoms, which is preferably a straight chain group, at about 40 to about 100 ° C for about 30 minutes to about 16 hours. Preferred compounds for this are 1-bromoacetone, 1-bromo-2-butanone, l-bromo-2-pentanone and l-bromo-2-hexanone. According to a preferred embodiment, the reaction takes place at a temperature of about -10 ° C. to about room temperature for about 1 hour to about 6 hours. The compounds of the formula q r3-c-ch2x are known.

Esterification of a compound of formula IV with methane sulfonyl chloride in the presence of a tertiary amine, e.g. Tri-ethylamine, pyridine or the like is preferably carried out in the presence

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a cosolvent such as e.g. Dichloromethane at a temperature in the range of about -10 ° C to about room 20 for about 10 minutes to about 2 hours to give a corresponding mesylate of Formula V which is then reacted with sodium iodide in acetonitrile solution at reflux temperature for one Time period from about 1 h to about 10 h is converted into a corresponding N- (2-iodoethyl) pyrrole.

After the reaction of the iodomethyl compounds of the formula VI with sodium hydride in a suitable, inert, organic solvent, such as. B. dimethylformamide, a 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l, 7-dicarboxylic acid di-methyl ester and derivatives thereof of the formula VII which are alkyl-substituted in the 6-position are obtained. This cyclization takes place in an inert atmosphere, d. H. my argon or nitrogen atmosphere, at temperatures in the range of about 15 ° C to about 40 ° C for a period of about 15 minutes to about 35 4 hours. The best results are obtained if the reaction is carried out at room temperature for about 30 minutes, provided that the radical R represents the hydrogen atom.

On the other hand, the compounds of Formula VII can also be obtained by directly cyclizing a mesylate of Formula V using sodium hydride in dimethylformamide solution at a temperature from about -10 ° C to about room temperature for about 30 minutes to about 2 hours.

The basic hydrolysis of a compound of formula VII with an alkali metal hydroxide or alkali metal carbonate, e.g. B. 45 sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., in an aqueous, low aliphatic alcohol, e.g. B. methanol or ethanol, at a temperature between room temperature and reflux temperature for about 4 h to about 24 h leads to a free diacid of 50 formula VIII, i.e. 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l, 7-dicarboxylic acid and 6-alkyl derivatives thereof. The hydrolysis is preferably carried out using aqueous methanolic potassium hydroxide at the reflux temperature for about 10 hours.

55 The carboxylic acid group at the C-1 position in a compound of formula VIII is thereupon treated by treatment with a lower aliphatic alcohol, e.g. B. methanol, ethanol, iso-propanol, n-butanol or the like, selectively esterified in the presence of hydrogen chloride, using a 1,2-dihydro-3H-60 pyrrolo- [1,2-a] pyrrole-7- carboxylic acid l-carboxylic acid alkyl ester of the formula IX. The reaction is carried out at a temperature between about 0 ° C and about 50 ° C for about 1 hour to about 4 hours.

The decarboxylation of the monoesterified compounds 65 of the formula IX to corresponding compounds of the formula X, which are the starting materials for the process according to the invention, is carried out by heating a compound of the formula IX to an elevated temperature of about 230 ° C. to about

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280 ° C for a sufficiently long period of time to effect complete conversion. The course of the reaction can be determined based on the extent of evolution of carbon dioxide and by thin layer chromatography, the decarboxylation generally being completed in about 45 to about 90 minutes. The reaction products, namely the 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid alkyl esters and the 6-alkyl derivatives thereof, which correspond to the formula X, can be purified by chromatographic methods. On the other hand, especially in the decarboxylation of small amounts of compounds of the formula IX, the reaction product of the formula X can be obtained directly from the reaction vessel by distillation.

The condensation of a compound of formula X with an amide of the following formula

,. © -CON '"• s12>

R

where R1 has the above meaning leads to corresponding 5-aroyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid alkyl esters of the formula XI. This reaction is advantageously carried out in an inert, organic, aprotic solvent and in the presence of phosphorus oxychloride at reflux temperature for about 1 hour to about 175 hours in an inert atmosphere, followed by refluxing in the presence of sodium acetate for about 2 to about 10 hours heated. Instead of phosphorus oxychloride, other acid chlorides, e.g. B. phosgene or oxalyl chloride.

According to preferred embodiments, this condensation is carried out by adding a solution of a compound of the formula X in a suitable solvent to a mixture of 1.1 to 5 molar equivalents of both the desired amide and the phosphorus oxychloride which has previously been heated under reflux in the same solvent, with the the resulting reaction mixture is refluxed for about 6 to about 72 hours in an argon atmosphere and then about 3 to about 10 molar equivalents of sodium acetate are added. The mixture is then heated to boiling under reflux for about 4 to about 6 hours.

Adequate solvents for this reaction are halogenated hydrocarbons, such as. B. dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, etc., also di-methoxyethane and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane.

Examples of suitable N, N-dimethylarylamides that can be used are:

N, N-dimethylbenzamide,

N, N-dimethyl-o-toluamide,

N, N-dimethyl-m-toluamide,

N, N-dimethyl-p-toluamide,

5 N, N-dimethyl-p-ethyl-benzamide, N, N-dimethyl-o-propyl-benzamide, N, N-dimethyl-m-butyl-benzamide, N, N-dimethyl-o-methoxy-benzamide, N , N-dimethyl-m-methoxy-benzamide, io N, N-dimethyl-p-ethoxy-benzamide, N, N-dimethyl-p-isopropoxy-benzamide, N, N-dimethyl-o-chloro-benzamide, N, N-dimethyl-m-chlorobenzamide, N, N-dimethyl-p-chlorobenzamide, 15 N, N-dimethyl-o-fluorobenzamide, N, N-dimethyl-p-fluorobenzamide, N, N -Dimethyl-m-bromo-benzamide and N, N-dimethyl-p-bromo-benzamide.

20 These amides are known, commercially available compounds. You can in the usual way from the corresponding acids, i.e. by conversion into the acid chlorides and by subsequent treatment with dimethylamine.

After the preferably alkaline hydrolysis of the alkyl ester group 25 in a compound of the formula XI, the corresponding free acid of the formula A is obtained. This hydrolysis is carried out in a manner known per se, preferably using an alkali metal hydroxide or alkali metal carbonate, e.g. As sodium hydroxide, potassium hydroxide, sodium carbonate, potassium 30 carbonate, etc., in an aqueous, lower aliphatic alcohol, e.g. As methanol, ethanol or the like., At a temperature in the range from about room temperature to reflux temperature for about 15 minutes to about 2 hours and this in an inert atmosphere. According to the preferred embodiments, this hydrolysis is carried out by means of aqueous, methanolic potassium carbonate at the reflux temperature for about 30 minutes.

The compounds of the formula A can be broken down by methods known per se for the preparation of the corresponding individual 40 isomers thereof.

The (l) acid isomers and (d) isomers of the compounds of the formula A can be obtained by using the known technique of high pressure liquid chromatography (HPLC) on the diastereoisomeric a-phenylethyl esters of the compounds of the formula A applies and then causes the splitting with an acid. For example, the compounds of the formula A, in which R and R1 are each hydrogen atoms, can be further treated according to the following diagram:

COOH

«

(A1)

several levels

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Mixture f (l) -a-phenylethyl ester of the (jl) acid isomer of the formula (A "'")' des / (l) -o ^ -enylethyl ester of the (d) acid isomer of the formula (A ^)

Separation using HPLC

(A) -C £) acid isomer (1) phenyl ethyl ester

(A) - (d) acid isomer (l) phenyl ethyl ester i

M /

(A) - (£) acid isomer

, L.

(A} - (d) acid isomer__

The salts of the compounds of formula A and their (1) isomers are obtained by treating these free acids with an appropriate amount of a pharmaceutically acceptable base. Suitable, pharmaceutically acceptable bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferro hydroxide, zinc hydroxide, copper hydroxide, manganese hydroxide, aluminum hydroxide, ferric hydroxide, manganese hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tri-propylamine, 2-ethylamine, ethylamine Dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procain, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylharpiperidine, etc. The reaction is carried out in water alone or in combination with an inert, water-miscible, organic solvent at a temperature from about 0 ° C. to about 100 ° C. and preferably at room temperature. Typical, inert, water-miscible, organic solvents are methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio of the compounds of formula A or the (1) acid isomers thereof, based on the base used, is selected so that the correct ratio is present depending on the salt used. For example, to prepare the calcium salts or magnesium salts of the compounds of formula A or the (I) acid isomers thereof, the free acid used as the starting material can be treated with at least Vi molar equivalent of pharmaceutically acceptable base to obtain a neutral salt. If the aluminum salts of the compounds of the formula A or the (I) acid isomers thereof are to be prepared, then at least 1 molar equivalent of the pharmaceutically acceptable base is used, if one wishes to obtain a neutral salt.

According to the preferred embodiment, the calcium salts and magnesium salts of the compounds of formula A and the (l) acid isomers thereof can be prepared by the corresponding sodium or potassium salts thereof with at least V2 molar equivalents of calcium chloride or magnesium chloride in an aqueous solution alone or treated in conjunction with an inert, water-miscible organic solvent at a temperature from about 20 ° C to about 40 100 ° C. The aluminum salts of such compounds can preferably be prepared by reacting the corresponding free acids with at least A molar equivalent of an aluminum alkoxide, e.g. As aluminum tri-oxide, aluminum tripropoxide or the like, in a hydrocarbon solvent, 45 such. Treated with benzene, xylene, cyclohexane or the like at a temperature between about 20 ° C and about 115 ° C. Similar measures can be taken to produce salts of inorganic bases which are not sufficiently soluble for easy implementation.

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Of course, the isolation of the compounds described in the present patent can, if desired, be carried out with the aid of any suitable separation and purification methods, such as e.g. B. extraction, filtration, evaporation, distillation-55 ren, crystallization, thin-layer chromatography or column chromatography, high pressure liquid chromatography (HPLC) or by a combination of these measures. Suitable separation and isolation methods can be found in the examples given below. Of course, other equivalent separation and isolation methods can also be used.

Although the (d) acid isomers are not used as drugs as such, they can, if desired, be converted to the corresponding pharmaceutically acceptable, non-toxic salts thereof by following the methods for the conversion of (l) - Served acid isomers in the corresponding pharmaceutically acceptable, non-toxic salts thereof.

The compounds of formula A and the (l) acid isomers thereof and the pharmaceutically acceptable, non-toxic salts thereof are valuable anti-inflammatory agents, analgesic agents, agglutination inhibitors, fibrinolytics and muscle relaxants. These compounds can be used both prophylactically and therapeutically.

The preparations containing these compounds are valuable for the treatment and healing of inflammation, e.g. Inflammation of the skeletal muscles, joints and other tissues, for example in the treatment of inflammations of this type, such as e.g. Rheumatism, concussio, laceratio, arthritis, bone fractures, post-traumatic conditions and gout. In those cases in which the above conditions bring with them pain and fever, coupled with inflammation, the compounds produced according to the invention are extremely valuable for eliminating these conditions and the inflammation.

The administration of the active compounds of the formula A or the (I) acid isomers thereof and the pharmaceutically permissible, non-toxic salts thereof in suitable pharmaceutical preparations can in itself be suitable for the treatment of inflammation, pain or pyrexia or for the prophylaxis therefor Forms of administration means happen. For example, administration can be administered orally, parenterally or topically in the form of solid, semi-solid or liquid dosage forms, e.g. B. as tablets, suppositories, pills, capsules, powders, solutions, suspensions, emulsions, creams, lotions, ointments or the like, preferably in unit dosage forms suitable for easy administration of precise dosage amounts. The preparations contain customary pharmaceutical carriers or fillers and an active substance according to formula A or a (l) acid isomer thereof and / or pharmaceutically acceptable, non-toxic salts thereof. They can also contain other drugs, pharmaceutical agents, carriers, excipients, etc.

The preferred mode of administration for the conditions detailed below is oral administration using an appropriate daily dosage amount, depending on the degree of the disease. In general, a daily dose of between 25 mg and 500 mg of active substance of the formula A or a (l) acid isomer thereof or of pharmaceutically acceptable, non-toxic salts thereof is administered. In most cases, the treatment is carried out with a dosage of 0.5 mg to 6 mg per kg body weight per day. For such oral administrations, pharmaceutically acceptable, non-toxic preparations will be formed by adding any of the normally used excipients, such as, for example, to the active substance or substances. B. Pharmaceutically acceptable mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. Such preparations can be marketed in the form of solutions, suspensions, tablets, pills, capsules, powders, prolonged-release preparations, etc.

The active substances of formula A, the (l) acid isomers thereof and the pharmaceutically acceptable, non-toxic salts thereof can be processed into a suppository using, for example, polyalkylene glycols, such as polypropylene glycol, as carriers. Liquid, pharmaceutically administrable preparations can, for example, by dissolving, dispersing, etc., an active substance of the type described above and optionally pharmaceutical excipients in a carrier such as. As water, saline, aqueous dextrose, glycerin, ethanol and the like., Are prepared, whereby a solution or suspension is obtained. If desired, the pharmaceutical preparation to be administered can also contain small amounts of non-toxic auxiliary substances, e.g. B. wetting or emulsifying agents, pH-buffering agents, etc.,

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e.g. As sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. included.

Methods for the preparation of such dosage forms are well known or readily available to the person skilled in the art. In this connection, reference is made, for example, to Reming-ton's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th edition, 1970. In all cases, the preparation to be administered will contain a certain amount of active substance or active substances in a pharmaceutically effective amount.

The compounds of formula A, the (l) acid isomers and their non-toxic, pharmaceutically acceptable esters and salts, as described above, are also relaxants for the uterine muscles and are therefore valuable as agents which help both pregnancy in favor of the mother and / or the fetus until the final stages of pregnancy. It should be noted that in those cases in which the contractions have already started, which is particularly the case immediately before birth, the administration of the compounds described here cannot prolong the pregnancy for an indefinite period. In such cases, the pregnancy is most likely only slightly “prolonged”, a factor that can be beneficial for the mother and / or the fetus.

In particular, the compounds of formula A and their (l) isomers can be used as agents for delaying the onset or for postponing labor. The term "delaying the onset of labor" should refer to any point in time before the start of uterine contractions. This expression is thus intended to prevent abortion at the beginning of pregnancy, i.e. H. before the fetus is viable, as well as delaying premature labor, a term that is sometimes used to refer to premature labor, which experience has shown to occur later in the pregnancy when the fetus is already considered viable. In any case, the agents are used as prophylactic agents because such administration prevents the onset of labor. Administration is in the treatment of women with a history of spontaneous abortion, miscarriage or preterm delivery, i.e. H. Delivery before the end of the entire gestation period, particularly valuable. Such administration is also valuable in those cases where there are clinical indications that the pregnancy should end prematurely, so that such administration could be particularly advantageous for the mother and / or the fetus.

As for animals, this treatment can also be used to synchronize the birth of a group of pregnant animals or to control such births at the desired time and / or location where such births can be performed with greater ease.

In the present specification, the term "labor shift" is intended to include the labor delay caused by the administration of compounds of Formula A, (l) acid isomers thereof, and pharmaceutically acceptable, non-toxic salts thereof Beginning of uterine muscle contractions. The patient's condition, including the length of time within the gestational period in which the contractions started, the extent of the contractions, and the duration of the contractions will affect the results achieved by the administration of the compounds. The effect can be, for example, that the intensity and / or the duration of the contractions (whereby the actual labor contraction becomes “extendable”) can be shortened or the contractions can be interrupted at all. In any case, an extension of the gestational

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period, although depending on the patient's conditions, the effect can either be very weak or, under certain circumstances, somewhat larger. Such administration can prevent spontaneous abortion, make the birth easier and / or less painful for the mother, or can lead to the fact that the birth can be carried out at a more suitable time and / or in a more suitable place.

In general, a daily dose of 0.5 mg to about 25 mg of active ingredient per kg of body weight will be administered, the administration being carried out once a day or in smaller doses regularly three or four times a day.

The following examples illustrate the present invention. The abbreviation t.l.c., if it occurs here, means thin layer chromatography, while all mixing ratios with respect to liquids represent volume ratios. Unless otherwise stated, the reaction takes place at room temperature, i.e. H. at temperatures in the range of 20 to 30 ° C.

Production of the starting products a) A 250 ml three-necked round bottom flask, which has a magnetic stirrer and is equipped with a drying tube filled with calcium chloride, is connected directly (via one of the outer openings) to the acetal pyrolysis device with a feed line and a short (3 ") water condenser. The latter consists of a 100 ml round-bottomed flask, which was previously treated with 15.6 g of oxalic acid dihydrate and II, 82 g of bromo-acetaldehyde diethyl acetal, prepared from vinyl acetate, as described by PZ Bedoukian, J. Am. Chem. Soc. 66, 651 (1944) , has been loaded, on this device a 6 "Vigreux column, which has a thermometer, is attached, which is connected to the aforementioned condenser.

The three-necked flask is charged with 3.36 g of ethanolamine, cooled to 0 ° to 10 ° C. in an ice bath, and treated dropwise with 8.7 g of dimethyl-1,3-acetone-dicarboxylate while stirring. This spontaneously forms methyl-3-carbomethoxymethyl-3- (2'-hydroxyethyl) aminoacrylate (III). When the addition is complete, the ice bath is removed and 100 ml of dry acetonitrile are added. The pyrolysis part of the device is placed in an oil bath and the temperature of the latter is allowed to rise to 150 to 160 ° C. The bromoacetaldehyde solution formed is distilled directly into the magnetically stirred solution of vinylamine III (boiling point 80 to 83 ° C./580 mm). As soon as the distillation temperature has dropped to less than 80 ° C., the pyrolysis device is interrupted and replaced by a reflux condenser equipped with a drying tube containing calcium chloride. The solution is then heated at reflux temperature for 1 h, the solvent is removed under reduced pressure and then the residue is mixed with 200 ml of methanol and 20 g of silica gel. The mixture is evaporated to dryness in vacuo and fed to a column filled with 200 g of silica gel, which contains hexane. The column is then eluted with a mixture of hexane and ethyl acetate (mixing ratio 80:20) (500 ml) and a mixture of hexane and ethyl acetate (mixing ratio 1: 1.9 x 500 ml). Fractions 2 and 3 contain less polar impurities and dimethyl 1,3-acetone dicarboxylate; fractions 4 to 8 yield 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H) which, after recrystallization from a mixture of ether and hexane, has a melting point of 52 to 54 ° C.

b) 2.65 ml of triethylamine are stirred into a solution of 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate in 35 ml of dry dichloromethane, cooled to -10 ° C., whereupon 1.46 ml of methanesulfonyl chloride is added dropwise while maintaining the reaction mixture at a temperature of from -10 ° C to -5 ° C. The course of the reaction is observed by thin layer chromatography analysis using a mixture of chloroform and acetone (mixing ratio 90:10). As soon as the reaction can be regarded as complete (30 minutes after the addition of methanesulfonyl chloride has ended), 10 ml of water are slowly added. The organic phase is separated off, washed three times with 30 ml of water each time, dried over sodium sulfate and evaporated to dryness under reduced pressure. By allowing the residue to crystallize out from a mixture of dichloromethane and hexane, 4.75 g (77.7%) of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H ), Mp. 99 to 101 ° C.

c) A solution of 785 mg of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodide in 10 ml of acetonitrile is heated to boiling under reflux for 1 h. The reaction mixture is then cooled and then evaporated to dryness under reduced pressure and the residue is triturated with water. The insoluble material is separated off by filtration and air-dried, 840 mg (97%) of methyl N- (2-iodoethyl) -3-carbomethoxy-pyrrole-2-acetate (VI, R = H), mp. Receives 137 to 138 ° C.

d) A solution of 1 g of methyl N- (2-iodoethyl) -3-carbo-methoxypyrrole-2-acetate in 5 ml of dry dimethylformamide is stirred in an argon atmosphere with 137 mg of 50% sodium hydride in mineral oil. The reaction mixture is then kept at room temperature for 30 minutes and then treated with 100 ml of water. The product is extracted three times with 50 ml of ethyl acetate each time and the combined extracts are washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatography of the residue over 20 g of silica gel using a mixture of hexane and ethyl acetate (mixing ratio 4: 1) as the eluent gives 500 mg (80%) of dirnethyl-1,2-dihydro-3H-pyrrolo- [1,2- a] -pyrrole-l, 7-dicarboxylate (VII, R = H), mp. 70 to 71 ° C.

A solution of 1.80 g of dimethyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l, 7-dicarboxylate in 20 ml of methanol is mixed with a solution of 4.48 g of potassium hydroxide in 20 ml of water are treated and the reaction mixture is then heated to boiling under reflux for 6 h. The cooled solution is evaporated to dryness and the residue is treated with 50 ml of saturated sodium chloride solution. The resulting solution is acidified with 6N hydrochloric acid and extracted three times with 50 ml of ethyl acetate each time. The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, giving 1.51 g (95%) of 1,2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l, 7-dicarboxylic acid (VIII, R = H), mp. 220 ° C (dec.).

e) A solution of 1.34 g of 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylic acid in 50 ml of isopropanol, cooled in an ice bath, is maintained with gaseous hydrogen chloride a temperature of the reaction mixture of less than 50 ° C saturated. The ice bath is then removed and the reaction mixture is stirred for 1 h at room temperature and evaporated to dryness under reduced pressure. Then the residue is mixed with 10 ml of benzene. The solution is then evaporated once more in vacuo, repeating this procedure three times in total to remove the excess hydrogen chloride. In this way, 1.58 g (96%) of isopropyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate-7-carboxylic acid (IX, R = H, R2 = iC3H7), which has a melting point of 144 to 145 ° C after crystallization from a mixture of methanol and ethyl acetate.

Similarly, when using methanol, ethanol, propanol and n-butanol instead of isopropanol, the following compounds are obtained:

Methyl 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate-7-carboxylic acid,

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Ethyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate-7-carboxylic acid,

Propyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate-7-carboxylic acid and

Butyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate-7-carboxylic acid.

f) 1.054 g of isopropyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate-7-carboxylic acid are heated to 240 to 250 ° C in a dry round-necked flask with a capacity of 10 ml , wherein the reaction product is distilled off directly from the reaction vessel. In this way, 745 mg (87%) of isopropyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate (X, R = H, R2 = iC3H7), pale yellow oil with the following physical constants:

U.V .: A. ^ ° H215 nm (e = 6020);

LR-: Y max'31725 cm "1;

N.M.R. : 1.22 (d, J = 7 Hz, 6H), 2.40-2.90 (m, 2H), 3.60-4.20 (m, 2H), 4.65-5.2 (m , 1H), 5.73-5.92 (m, 1H), 6.10 (t, J = 3 Hz, 1H), 6.43-6.53 ppm (m, 1H).

g) A 100 ml three-necked round bottom flask equipped with a condenser, a nitrogen inlet tube and a gas inlet tube is filled with 5.0 g of isopropyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole- l-carboxylate-7-carboxylic acid charged. The device is flushed out thoroughly with nitrogen and the nitrogen supply is then stopped. The device is then immersed in an oil bath heated to 270 ° C and the reaction observed due to the evolution of carbon dioxide (gas inlet port) and by thin layer chromatography on silica gel using a mixture of benzene, dioxane and acetic acid (mixing ratio 90: 10: 1) as developer solvent. The reaction is practically complete after 45 minutes. To

The container is removed from the oil bath for 1 h and the contents of the reaction flask are introduced into a round bottom flask which is provided with 500 ml of acetone. The solvent is removed under reduced pressure and the residue is purified by column chromatography over 100 g of silica gel. The fractions eluted using a mixture of hexane and benzene (mixing ratio 70:30) and a mixture of hexane and benzene (mixing ratio 50:50) yield 2.77 g (68%) isopropyl-1,2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate (X, R = H, R2 = ÌC3H7), an oil whose physical constants are identical to those according to section f).

example 1

A solution of 179 mg of N, N-dimethyl-p-toluamide and 0.11 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is heated to boiling under reflux for 30 minutes. A solution of 193 mg of isopropyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate in 2 ml of 1,2-dichloroethane is then added to this solution. The reaction mixture is then refluxed for 8 h in an argon atmosphere, then treated with 405 mg of sodium acetate and then refluxed for a further 5 h. The mixture obtained is then evaporated to dryness and the residue is chromatographed over 12 g of silica gel, eluting with a mixture of hexane and ethyl acetate (mixing ratio 3: 1). In this way, 208 mg (66%) of isopropyl-5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate (XI, R = H, R '= p-CH3, R2 = iC3H7), an oil with the following physical constants:

U.V .: X ^? H256, 312 nm (e = 8700.19500);

I.R .: YÏx 1735.1620.1605 cm "1;

N.M.R. : ô ^ fs'31.23 (d, J = 7 Hz, 6H), 2.38 (s, 3H), 2.5-3.0 (m, 2H), 3.75-4.10 (m , 1H), 4.2-4.60 (m, 2H), 4.85-5.20 (m, 1H), 5.95 (d, J = 4Hz, 1H), 6.70 (d, J = 4Hz, 1H), 7.10 (d, J = 8 Hz, 2H), 7.60 ppm (d, J = 8 Hz, 2H).

646 972

A solution of 336 mg of isopropyl-5-p-toIuoyI-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate in 10 ml of methanol is mixed with a solution of 690 mg of potassium carbonate in 5 ml of water treated. The reaction mixture is then heated to reflux in a nitrogen atmosphere for 30 minutes, cooled and evaporated to dryness. The residue is taken up in 10 ml of a 10% aqueous hydrochloric acid solution and 50 ml of water and the resulting mixture is extracted twice with 50 ml of ethyl acetate each time. The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. By allowing the residue to recrystallize from a mixture of ethyl acetate and hexane, 238 mg (89%) of 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid [ (À), R = H, R1 = p-CH3], mp. 182 to 183 ° C.

Example 2

A solution of 250 mg of isopropyl-5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate in 8 ml of methanol is dissolved in a nitrogen atmosphere with a solution of 200 mg Treated sodium hydroxide in 1 ml of water, keeping the reaction mixture at room temperature for 114 h. The methanol is then removed under reduced pressure and the remaining basic solution is diluted with 5 ml of water and extracted with ether to remove any unsaponified product which may be present. The aqueous solution is then acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure. The residue is crystallized from a mixture of ethyl acetate and hexane to give 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylic acid, which is obtained with the Product according to Example 1 is identical.

Example 3

When working in accordance with the methods described in sections (f) and (g), the compounds obtained in section (e) can be converted into:

Methyl 1,2-dihydro-3H-pyrrolo- [1,2-aJ-pyrrole-l-carboxylate,

Ethyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Propyl 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate and

Butyl 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate.

After the condensation of this compound with N, N-dimethyl-p-toluamide according to the method of Example 1, the following compounds are obtained:

Methy] -5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylate,

Ethyl 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Propyl-5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylate and

Butyl 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylate.

Example 4

The procedure of Example 1 is carried out using 1.1 to 5 molar equivalents

N, N-dimethylbenzamide,

N, N-dimethyl-o-toluamide,

N, N-dimethyl-m-toluamide,

N, N-dimethyl-p-ethylbenzamide,

N, N-dimethyl-o-propyl-benzamide,

N, N-dimethyl-m-butyl-benzamide,

N, N-dimethyl-o-methoxy-benzamide,

N, N-dimethyl-p-methoxy-benzamide,

N, N-dimethyl-p-ethoxy-benzamide,

N, N-dimethyl-p-isopropoxy-benzamide,

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N, N-dimethyl-o-chloro-benzamide,

N, N-dimethyl-m-chlorobenzamide,

N, N-dimethyl-p-chloro-benzamide,

N, N-dimethyl-o-fluoro-benzamide,

N, N-dimethyl-p-fluoro-benzamide,

N, N-dimethyl-m-bromo-benzamide and

N, N-dimethyl-o-bromo-benzamide instead of N, N-dimethyl-p-toluamide and registers the course of the reaction by thin layer chromatography.

The following connections are obtained:

Isopropyl-5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate, light yellow oil with the following physical constants:

U.V .: 245, 311 nm (e 7230.17800);

I.R .: Y ™ x'31735, 1620 cm "1;

N.M.R .: ô tms3 1.24 [d, 6H, (CH3) 2CH], 2.50-3.13 (m, 2H; H-2); 3.97 (dd, IH, Hl), 4.18-4.70 (m, 2H, H-3), 5.00 (sept., IH, (CH3) 2CH), 6.00 (d, IH , H-7), 6.86 (d, IH, H-6), 7.10-7.90 ppm (m, 5H, phenyl protons);

M.S .: m / e 297 (M +).

Isopropyl-5-o-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate, an oil with the following physical constants: UV: Xma? H252, 303 nm (e 4460 , 19100);

LR .: yS'3 1735, 1620 cm'1;

NMR: ôSms3 1.18 [d, 6H, (CH2) 2CH], 2.28 (s, 3H, o-CH3), 2.50-3.13 (m, 2H, H-2), 3.92 (dd, 1H, Hl), 4.17-4.70 (m, 2H, H-3), 4.98 [sept. IH, (CH3) 2CH], 5.92 (d, 1H, H-7), 6.43 (d, 1H, H-6), 6.97-7.45 ppm (m, 4H, phenyl protons).

Isopropyl-5-m-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate, an oil with the following physical constants: UV: O> H250-251, 310-312 nm (e 6460.17400); LR .: y ™? 1735, 1620 cm "1;

NMR: òSSfs31.25 [d, 6H, (CH3) oCH], 2.27 (s, 3H, CH3), 2.52-3.13 (m, 2H, H-2), 3.92 (dd, 1H, Hl), 4.13-4.70 (m, 2H, H-3), 4.95 [sept. IH, (CH3) 2CH], 5.95 (d, 1H, H-7), 6.67 (d, 1H, H-6), 7.03-7.57 ppm (m, 4H; phenyl protons).

Isopropyl-5-p-ethylbenzoyl-l, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate,

Isopropyl-5-o-propylbenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-m-butylbenzoyl-l, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

Isopropyl-5-o-methoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

Isopropyl-5-p-methoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate with the following physical constants:

U.V .: Xma ° H218,270-284 (shoulder), 314 nm (e9780,9320, 22400);

I.R .: Y max131730, 1605 cm "1;

N.M.R .: 1.24 [d, 6H, J = 6Hz; (CH3) 2CH], 2.50-3.10 (m, 2H; H-2), 3.78 (s, 3H; CH30), 3.93 (dd, 1H, JAX = 6 Hz, JBX = 7 Hz; Hl), 4.13-4.60 (m, 2H; H-3), 4.95 [sept., IH, J = 6 Hz; (CH3) 2CH], 5.95 (s, IH, J = 4 Hz; H-7), 6.68 (d, IH, J = 4 Hz; H-6), 6.70-7.90 ppm 4H ; Phenyl protons);

M.S .: m / e 327 (M +).

Isopropyl-5-p-ethoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate, mp. 94-95 ° C,

Isopropyl-5-p-isopropoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-o-chlorobenzoyl-l, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate, an oil with the following physical components:

U.V .: ^ ma? H251, 306 nm (e 5750, 16600);

I.R .: Y max'31735, 1625 cm "1;

NMR: ò? MSh 1.22 [d, 6H, (CH,), CH], 2.55-3.05 (m, 2H; H-2), 3.97 (dd, 1H, Hl), 4 , 17-4.70 m, 2H, H-3), 4.97 [sept., 1H,

(CH3), CH], [5.93 (d, 2 / 3H), 6.00 (d, 1 / 3H) H-7], [6.42 d, 2 / 3H), 6.67 (d , 1 / 3H), H-6], 7.07-7.80 ppm (m, 4H; phenyl protons).

Isopropyl-5-m-chlorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate, an oil with the following physical constants:

U.V .: ^? H241, 313 nm (e 6600.15100); I.R .: Y max'31735, 1620.1570 cm "1;

N.M.R .: ô ^ ms3 1.27 [d, 6H, (CH3) 2CH], 2.50-3.18 (m, 2H, H-2),

з, 93 (dd, 1H, Hl), 4.10-4.63 (m, 2H, H-3), 4.98 [sept., 1H, (CH3) 2CH], 5.98 (d, 1H , H-7), 6.67 (d, 1H, H-6), 7.07-7.78 ppm (m, 4H, phenyl protons);

M.S .: m / e 331-333 (M +),

Isopropyl-5-p-chlorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate, mp. 80.5-81 ° C,

Isopropyl-5-o-fluorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-p-fluorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate, mp 72-72.5 ° C,

Isopropyl-5-m-bromobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate and

Isopropyl-5-p-bromobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate.

The corresponding free acids are obtained by hydrolysis of the isopropyl ester group in accordance with the methods mentioned in Examples 1 and 2, namely:

5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, mp 160-161 ° C,

5-o-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, an oil with the following physical constants:

и.V .: C; ° H253, 307 nm (e 3310.16980);

I.R .: y ™ x'3 1720.1620 cm "1;

N.M.R .: 0 ^? 2.32 (s, 3H, CH3), 2.53-3.03 (m, 2H, H-2), 3.97 (dd, 1H, Hl), 4.17-4.67 (m, 2H) , H-3), 6.92 (d, 1H, H-7), 6.40 (d, 1H, H-6), 6.83-7.37 (m, 4H, phenyl protons), 8.60 ppm (bs, 1H, COOH).

5-m-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5-p-ethylbenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5-o-propylbenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5-m-butylbenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5-o-methoxybenzene-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5-p-methoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, mp. 187-187.5 ° C,

5-p-ethoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, mp. 169.5-170 ° C,

5-p-isopropoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5-o-chlorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, with the following physical constants: UV: ^ XOH250, 307.5 nm (e 4360.17400) ; I.R .: Y max'31715.1620 cm "1;

N.M.R .: ôS-m? 2.60-3.15 (m, 2H; H-2), 4.02 (dd, 1H, JAX = 6 Hz, JBX = 7 Hz; Hl), 4.20-4.70 (m, 2H; H-3), 5.98 (d, 1H, J = 4 Hz; H-7), 6.42 (d, 1H, J = 4 Hz; H-6), 7.00-7.77 (m, 4H; phenyl protons), 8.67 ppm [s, (br), 1H; COOH].

5-m-chlorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, mp. 180-181 ° C,

5-p-chlorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, mp. 201.5-202.5 ° C,

5-o-fluorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5-p-fluorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, mp. 179.5-180.5 ° C,

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5-m-bromobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid and

5-p-bromobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylic acid.

Example 5

0.58 g of trifluoroacetic anhydride are added to a solution of 300 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid in 25 ml of dry benzene. Then the mixture is stirred for 10 min at room temperature and the resulting solution is cooled to 0 to 5 ° C. and then 1.4 g of dry triethylamine and then immediately 0.5 g (l) -a-phenylethyl alcohol are added. The reaction solution thus obtained is stirred at room temperature for 15 minutes and then poured into 20 ml of water containing 1 ml of triethylamine and then extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate and the solvent and the excess (l) -cc-phenylethyl alcohol are removed in vacuo. In this way, 0.42 g of a mixture of (l) -5-benzoyl-l, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid- (l) -a- phenylethyl ester and (d) -5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-aj-pyrrole-l-carboxylic acid (l) -a-phenylethyl ester, which can be determined by high pressure liquid chromatography (under Using 4% EtOAc / hexane on an 11 mm x 50 cm, 10 µm Lichrosord S1-60 column), separating 180 mg of a polar ester Ke0H -145.7 °] and 178 mg of a less polar ester [c $ eOH + 128.6 °].

148 mg of the polar ester are dissolved in 8 ml of dry benzene. The solution is cooled to 15 to 20 ° C and then mixed with 5 ml of trifluoroacetic acid. The solution is then stirred at room temperature for 70 minutes. The reaction solution thus obtained is poured into 60 ml of dry benzene and the solvents are removed in vacuo and at room temperature. Purification is carried out by high pressure liquid chromatography (using a column as described above with the difference that 35% EtOAc / hexane in Vz% acetic acid is used instead of 4% EtOAc / hexane), whereby 63 mg (l ) -5-Benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, [an110'3 -153.7 °], mp. 153 to 155 ° C .

Similarly, the cleavage of the less polar ester by the method described above for the cleavage of the more polar ester leads to 85 mg (d) -5-benzoyl-l, 2-dihydro-3H-pyrrolo- [ l, 2-a] -pyrrole-1-carboxylic acid, [cïdHC | 3 + 155.1 °], mp. 154 to 156 ° C. The (d) acid isomer thus obtained can, if desired, be racemized and recycled by methods known per se.

Similarly, other (dl) compounds can be converted to the corresponding (l) isomers and (d) isomers.

Preparation of the starting products h) A 250 ml three-necked round-bottom flask, which contains a magnetic stirrer and is equipped with a drying tube filled with calcium chloride, is charged with 3.36 g of ethanolamine, cooled in an ice bath to 0 to 10 ° C. and added dropwise with stirring 8.7 g of dimethyl-1,3-acetone-dicarboxylate were treated to give methyl 3-carbomethoxymethyl-3- (2'-hydroxyethyl) aminoacrylate (III) spontaneously. When the addition is complete, the ice bath is removed and 80 ml of dry acetonitrile are added to the reaction mixture. The reaction mixture is then treated dropwise with 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile and then heated under reflux for 2 h. Then the solvent is removed under reduced pressure and 200 ml of methanol and 20 g of silica gel are added to the residue. The mixture is then evaporated to dryness in vacuo and introduced at the top into a column of 200 g of silica gel in hexane, the column being eluted with a mixture of hexane and ethyl acetate. The fractions eluted with the mixture of hexane and ethyl acetate in a mixing ratio of 1: 1 yield methyl-N- (2-hydroxyethyl) -3-carbomethoxy-pyrrole-2-acetate (IV, R = H), which corresponds to 5 according to section a) Product obtained is identical.

i) A solution of 6 ml of ethanolamine in 5 ml of water is mixed with 1.74 g of dimethyl-1,3-acetone dicarboxylate. The resulting mixture is rapidly cooled to -10 ° C and then treated dropwise over a 15 minute period with stirring 1.67 ml of 1-bromoacetone while maintaining the reaction mixture at a temperature not exceeding 40 ° C. After the addition has ended, the dark reaction mixture is stirred for a further 60 min at room temperature and then poured into a mixture of hydrochloric acid and ice saturated with solid sodium chloride 15 and then extracted three times with 100 ml of ethyl acetate each time. The combined organic extracts are washed neutral with cold water, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography of the residue 20 over 30 g of silica gel using a mixture of hexane and ethyl acetate in a mixing ratio of 70:30 as the eluent gives 890 mg of crystalline methyl-N- (2-hydroxy-ethyl) -3-carbomethoxy-4-methylpyrrole-2 acetate, which melts after recrystallization from a mixture of methylene chloride 25 and hexane at 78 ° C and provides the following analytical values:

Analysis for C12H17NO5:

calc.: C 56.45, H 6.71 found: C 56.41, H 6.73 30 Similarly, using a stoichiometric equivalent amount of l-bromo-2-butanone, l-bromo-2 -pentanone and l-bromo-2-hexanone instead of

1-bromoacetone: methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-

35 2-acetate,

Methy] -N- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrrole-

2-acetate and

Methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetate.

40 j) If you work according to the methods in sections b, c, d, e and g, then methyl N- (2-hydroxyethyl) -3-carbo-methoxy-4-methylpyrrole-2-acetate (IV, R = CH3) successively in methyl-N- (2-mesyloxyethyl) -3-carbomethoxy-4-methyl-pyrrole-2-acetate, 45 methyl-N- (2-iodoethyl) -3-carbomethoxy-4-methyl-pyrrole-2-acetate ,

Dimethyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylate, 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2 -a] -pyrrole-50 1,7-dicarboxylic acid,

Isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate-7-carboxylic acid and

Isopropyl-1,2-dihydro-6-methyl-3H-pyrroIo [1,2-a] pyrrole-l-carboxylate (X, R = CH3, R2 = iC3H7). 55 If one works in a similar manner using methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate,

Methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrrole-2-acetate and

60 methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetate instead of

Methyl N- (2-hydroxyethyI) -3-carbomethoxy-4-methylpyrrole-2-acetate,

the intermediate isopropyl-1,2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate is obtained as an intermediate,

Isopropyl-1,2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate or

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Isopropyl 1,2-dihydro-6-butyl3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate.

Example 6

According to the information in Example 1, isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate is condensed with N, N-dimethyl-p-toluamide, where isopropyl-5-p-to-luoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate (XI, R = CH3, R1 = p-CH3 , R2 = iC3H7).

Using the N, N-dimethylarylamides listed in Example 4 instead of N, N-dimethyl-p-toluamide, the following compounds are obtained in a similar manner: isopropyl-5-benzoyl-1,2-dihydro-6-methyl -3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

Isopropyl-5-o-toluoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

Isopropyl-5-m-toluoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

Isopropyl-5-p-ethylbenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-o-propylbenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-m-butylbenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-o-methoxybenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Isopropyl-5-p-methoxybenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-p-ethoxybenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-p-isopropoxybenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-o-chlorobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-m-chlorobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-p-chlorobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-o-fluorobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-p-fluorobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate, which has the following physical constants:

U.V .: ^ ° h250, 315 nm (e 6170.14100);

I.R .: y ™? 1734, 1605.1593 cm "1;

N.M.R. : Ôtms3 1.25 (d, 6H, J = 6 Hz; ester CH3), 1.83 (s, 3H; ring CH3), 2.49-3.00 (m, 2H; CH2), 3.90 (t , IH, 2J = 7.4 Hz; CHCO), 4.10-4.23 (m, 2H; N-CH2), 4.98 (sept., IH, J = 6 Hz; ester CH), 5, 84 (s, 1H, H-3), 7.00 (t, 2H, Jortho = 8.4Hz, Jhf = 8 Hz; H-3 ', 5'), 7.55 (q, 2H, Jortho = 8 , 4Hz, JHF = 5.5 Hz; H-2.6 '); M.S .: m / e 1%

329 25 M +

242 100 M + -C02CH (CH3) 2 123 36 F-QH4CO,

Isopropyl-5-m-bromobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate and

Isopropyl-5-p-bromobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate.

In a similar manner, the end compounds obtained in accordance with section j) can be converted into the corresponding 5-aroyl-substituted derivatives. Examples include the following:

Isopropyl-5-benzoyl-l, 2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

Isopropyl-5-benzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-benzoyl-l, 2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

Isopropyl-5-p-toluoyl-l, 2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

Isopropyl-5-p-ethylbenzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

Isopropyl-5-o-methoxybenzoyl-l, 2-dihydro-6-butyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate, 5 isopropyl-5-p-ethoxybenzoyl-l, 2-dihydro -6-ethyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate,

Isopropyl-5-o-chlorobenzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate, isopropyl-5-m-chlorobenzoyl-l, 2-dihydro- 6-butyl-3H-pyrrolo-10 [l, 2-a] pyrrole-l-carboxylate,

Isopropyl-5-o-fluorobenzoyl-l, 2-dihydro-6-ethyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-p-fluorobenzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate and 15 isopropyl-5-p-bromobenzoyl-l, 2-dihydro -6-butyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate.

Example 7

20 A solution of 500 mg isopropyl-5-toluoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate in 15 ml of methanol is mixed with a solution of 1.05 g of potassium carbonate treated in 8 ml of water. The reaction mixture is then heated to reflux for 30 min in a nitrogen atmosphere under reflux, cooled and evaporated to dryness. The residue is taken up in 10 ml of a 10% aqueous hydrochloric acid solution and 50 ml of water and the resulting mixture is extracted three times with 50 ml of ethyl acetate each time. The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, whereupon 5-p-toluene-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1- carboxylic acid [(A), R = CH3, R1 = p-CH3].

In a similar manner or according to the hydrolysis method of Example 2, the isopropyl-35 ester compounds obtained according to Example 6 can be converted into the corresponding free acids, namely into the following free acids:

5-benzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylic acid,

5-o-toluoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] pyrrole-40 1-carboxylic acid,

5-m-toluoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

5-p-ethylbenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

45 5-o-propylbenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5-m-butylbenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, 5-o-methoxybenzoyl-l, 2-dihydro-6-methyl- 3H-pyrrolo-50 [l, 2-a] pyrrole-l-carboxylic acid,

5-p-methoxybenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid,

5-p-ethoxybenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

55 5-p-isopropoxybenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid,

5-o-chlorobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, 5-m-chlorobenzoyl-l, 2-dihydro-6-methyl- 3H-pyrrolo-60 [l, 2-a] pyrrole-l-carboxylic acid,

5-p-chlorobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid,

5-o-fluorobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid,

65 5-p-fluorobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, mp. 204 ° C.,

5-m-bromobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid,

13

646 972

5-p-bromobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid,

5-ben2oyl-l, 2-dihydro-6-ethyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

5-benzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

5-benzoyl-l, 2-dihydro-6-butyl-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylic acid,

5-p-toluoyl-l, 2-dihydro-6-ethyl-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylic acid,

5-p-ethylbenzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid,

5-o-methoxybenzoyl-l, 2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid,

5-p-ethoxybenzoyl-l, 2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid,

5-o-chlorobenzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid,

5-m-chlorobenzoyl-l, 2-dihydro-6-butyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5-o-fluorobenzoyl-l, 2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid,

5-p-fluorobenzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid and

5-p-bromobenzoyl-l, 2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid.

Preparation of the starting products k) 710 mg of a 50% suspension of sodium hydride in mineral oil are washed with anhydrous hexane in a nitrogen atmosphere and then suspended in 50 ml of dimethylformamide. The suspension thus obtained is cooled to -5 ° C. and replaced with 4.5 g of methyl-N- (2-mesyloxymethyl) -3-carbomethoxy-pyrrole-2-acetate v, the reaction mixture being kept at -5 ° for 1 h C to 0 ° C stirred. The mixture is poured into ice-cooled sodium chloride solution and extracted several times with benzene. The combined extracts are washed with water, dried and evaporated to dryness under reduced pressure. The solid residue is crystallized from ether to give dimethyl-1,2-di-hydro-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylate (VII, R = H), that is identical to the product obtained according to section d).

1) A 250 ml three-necked round bottom flask, which is equipped with an inlet and outlet nozzle suitable for dry nitrogen, a magnetic stir bar and a funnel with pressure compensation, which contains 10.08 g of ethanol, is added dropwise with stirring with 26.1 g of dimethyl 1,3-acetone dicarboxylate charged within 30 minutes, keeping the temperature below 30 ° C. The methyl-3-carbo-methoxymethyl-3- (2'-hydroxyethyl) aminoacrylate (III) formed is treated with 20 ml of acetonitrile and chloroacetaldehyde, which was previously heated by heating a mixture of 27.4 g of chloroacetaldehyde diethyl acetal with 46 , 8 g of oxalic acid dihydrate was obtained at 150 to 160 ° C, added within 2 min with stirring. The reaction mixture is then heated to reflux for 5 to 10 minutes, after which the reaction can be regarded as complete, as can be determined by thin layer chromatography analysis using a mixture of acetone and chloroform (mixing ratio 10:90) as eluent. The solvent is removed under reduced pressure and the residue is mixed with 250 ml of benzene and 250 ml of heptane and then distilled under reduced pressure. The oily residue obtained after distillation is suspended in 50 ml of methylene chloride and 20 g of silica gel are added to the suspension. The methylene chloride mixture is poured into a column containing 200 g of silica gel and, as the eluent, a mixture of ethyl acetate (mixing ratio 20:80). The column is first filled with 61 a mixture of ethyl acetate and hexane (mixing ratio 20:80) and then with 41 a mixture of ethyl acetate and hexane (50:50)

eluted. The fractions eluted with the mixture of ethyl acetate and hexane in a 50:50 mixture ratio are combined and concentrated to give 12.8 g of an oil which is triturated with 20 ml of petroleum ether (30 to 60 ° C.). The solvent is then evaporated off under reduced pressure. In this way, 11.89 g (32.90% of theory) of methyl N- (2'-10 hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H) of melting point 51 to 54 ° C. It is the same product as is obtained according to section a).

Example 8

15 To a solution of 300 mg of 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid in 5 ml of methanol are added 1 mol equivalent of sodium hydroxide in the form of a 0, Add in solution. The solvent is then evaporated under reduced pressure and the residue is taken up in 2 ml of methanol and then precipitated with ether. In this way, sodium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylate is obtained, which can be crystallized from a mixture of ethyl acetate and hexane .

25 Other salts, e.g. B. the ammonium * and potassium salts of 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid produce, if one uses ammonium hydroxide or potassium hydroxide instead of sodium hydroxide.

30 Similarly, the 5-substituted 1,2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid compounds obtained according to Examples 4 and 5 can be converted into the corresponding sodium, potassium and Transfer ammonium salts. Examples of such compounds are the following: 35 sodium 5-o-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Sodium 5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

Sodium (l) -5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-401-carboxylate,

Potassium 5-p-ethylbenzoyl-l, 2-dihydro-3H-pyrrole [1,2-a] pyrrole-l-carboxylate,

Potassium 5-o-butylbenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

45 sodium 5-p-methoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

Ammonium-5-p-chlorobenzoyl-l, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate, ammonium-5-o-fluorobenzoyl-l, 2-dihydro-3H-pyrrolo- 50 [l, 2-a] pyrrole-l-carboxylate,

Potassium 5-o-bromobenzoyl-l, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

Sodium 5-benzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate, 55 potassium 5-toluoyl-1,2-dihydro-6-methyl -3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

Ammonium 5-o-methoxybenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Sodium 5-p-fluorobenzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo-60 [l, 2-a] pyrrole-l-carboxylate,

Potassium 5-m-chlorobenzoyl-l, 2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate,

65 Example 9

To a solution of 175 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid in 5 ml of methanol is added 1 mol equivalent of potassium hydroxide in the form of a 0.1 in solution

646 972

14

to give a solution which contains potassium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate. A solution of 40 mg calcium carbonate, which has been dissolved in the smallest possible amount in hydrochloric acid in order to be able to dissolve the calcium carbonate, is buffered with 100 mg solid ammonium chloride, after which 5 ml water is added. The buffered calcium solution thus obtained is then added in a solution of potassium 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate and the precipitate formed is filtered off collected, washed with water and air dried to give calcium 5-p-toIuoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate.

Similarly, magnesium 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate is obtained if magnesium carbonate is used instead of calcium carbonate.

Similarly, the corresponding calcium and magnesium salts are obtained when one

5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

(l) -5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylic acid,

5-p-chlorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

5-o-methoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

5-p-methoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

5-benzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylic acid and

5-o-fluorobenzoyl-l, 2-dihydro-6-ethyl-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylic acid instead of

5-p-Toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylic acid was used. ". . ,

Example 10

To a solution of 200 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid in 5 ml of methanol is added 1 mol equivalent of potassium hydroxide in the form of a 0.1 l Solution. The solvent is removed and the residue is dissolved in 5 ml of water. The aqueous solution of potassium 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate thus obtained is a solution of 150 mg of cuprinitrate trihydrate in 5 ml of water admitted. The precipitate thus formed is collected, washed with water and air-dried to give copper 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate .

The free acid compounds, as obtained in Examples 4 and 5 and Example 7, can be converted into the corresponding copper salts in a similar manner.

Example 11

A solution of 200 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid in 15 ml of hot benzene is treated with 60 mg of isopropylamine. The solution is then allowed to cool to room temperature and the product is filtered off, washed with ether and dried, whereby the isopropylamine salt of 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole- l-carboxylic acid is obtained.

Similarly, other amine salts, e.g. B. the diethylamine, ethanolamine, piperidine, tromethamine,

Chloin and caffeine salts of 5-p-To! Uoyl-l, 2-dihydro-3H-

pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid obtained if other corresponding amines are used instead of isopropylamine.

Similarly, the free acid compounds, such as 5 obtained from Examples 4 and 5 and Example 7, can be converted to the corresponding isopropylamine, diethylamine, ethanolamine *, piperidine, tromethamine, choline and caffeine salts.

Example 12

10 A solution of 770 mg 5-o-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid in 10 ml benzene is treated with 580 mg dicyclohexylamine. The reaction mixture is then stirred for 10 min and the solid product formed is separated off by filtration and washed with anhydrous ether, giving 965 mg of the dicyclohexylamine salt of 5-o-toluoyl-l, 2-dihydro-3H-pyrrolo- [l , 2-a] -pyrrole-1-carboxylic acid, mp. 161 to 163 ° C, is obtained.

Similarly, the free acid compounds thus obtained, as described in Examples 4 and 5 and the 20 compounds in Examples 1 and 7, can be converted into the corresponding dicyclohexylamine salts, e.g. B. the dicyclohexylamine salt of 5-o-chlorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, mp. 173 to 175 ° C, transfer.

25th

Biodata

A. Analgesic mouse test (action against torso twisting)

Carrying out the test: The test material is administered orally in an aqueous carrier by means of a gastric tube weighing 18 to 20 g 30 male Swiss-Webster mice. After 20 minutes, 0.25 ml of a 0.02% solution of phenylquinone is injected intraperitoneally. The solution causes torsion twists or convulsions. The animals are observed for their contortions 35 and twists during the next 10 minutes.

Final phase: total number of mice that squirm and average number of twists per mouse.

Using the above procedure, it is found that the 5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carbon-40 acid about 430 times the analgesic effect of aspirin and the (l) -5- (benzoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid have the 700-fold analgesic effect of aspirin.

45

B. Acute Oral Toxicity Test (LD50) in Mice Procedure: The test material is suspended in an aqueous carrier containing carboxymethyl cellulose as a suspending agent. The concentrations are adjusted so that the doses can be administered in volumes of 10 ml / kg body weight. Five groups of 6 male Swiss-Webster mice each are tested. The mice are given individual oral doses with the gastric tube in amounts of 200 mg, 400 mg, 800 mg and 1200 mg 5- (benzoyl) -55 1,2-dihydro-3H-pyrrolo- [l, 2-a] - pyrrole-1-carboxylic acid administered. The fifth group of mice is used as a control group. After administration, the mice are observed for 3 weeks.

If one proceeds in the aforementioned manner, the acute, 60 oral LD50 value for 5- (benzoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid is approximately 200 mg / kg.

M

Claims (9)

646 972 PATENT CLAIMS 1. Process for the preparation of (d, l) - or (l) -5-aroyl-1,2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acids of the formula COOH (A) in which R represents the hydrogen atom or an alkyl radical having 1 to 4 carbon atoms and R1 the hydrogen atom, an alkyl radical having 1 to 4 carbon atoms, an alkoxy radical having 1 to 4 carbon atoms or the chlorine, fluorine or bromine atom, the substituent R1 being ortho , Meta or para position of the aroyl group, and their pharmaceutically acceptable salts, characterized in that a corresponding compound of the formula: COOR ' wherein R has the above meaning and R2 represents an alkyl radical having 1 to 4 carbon atoms, with an amide of the formula Hi jCy ~ C0I, (CH3> 2 wherein R1 has the above meaning condensed in the resulting compound of the formula R .COOR (XI) the alkyl ester group is hydrolyzed and the carboxylic acid obtained is optionally converted into a pharmaceutically acceptable salt. 2. The method according to claim 1, characterized in that one carries out the condensation in the presence of phosphorus oxychloride. 3. The method according to claim 1, characterized in that one carries out an alkaline hydrolysis of the alkyl ester group, for example with an alkali metal hydroxide or carbonate in an aqueous, lower aliphatic alcohol. 4. The method according to claim 1, characterized in that one produces a compound of formula A, in which R and R1 each represent a hydrogen atom. 5. The method according to claim 1, characterized in that a resulting (d, l) carboxylic acid of the formula A is separated into the individual (d) and (l) isomers. 6. The method according to claim 1, characterized in that the carboxylic acid obtained is converted into a salt with an inorganic base, preferably an ammonium, potassium, sodium, calcium or magnesium salt. 7. The method according to claim 1, characterized in that the carboxylic acid obtained in a salt with an organic base, preferably an isopropylamine, diethylamine, ethanolamine, piperidine, 2-amino-2-hydroxymethyl-1,3 propanediol, choline or caffeine salt. 8. The process according to claim 7, characterized in that the dicyclohexylamine salt of 5-o-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylic acid is prepared. 9. The method according to claim 7, characterized in that the dicyclohexylamine salt of 5-o-chlorobenzoyl-l, 2-di-hydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid is prepared.