CH641461A5 - 5-Aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid derivatives - Google Patents

Abstract

The compounds correspond to the formula: <IMAGE> in which R denotes hydrogen or C1-C4-alkyl and R<1> denotes hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine or bromine; the pharmaceutically acceptable salts and esters of the carboxylic acids A also come within the scope of the invention. The compounds, their salts and esters can be used therapeutically, in particular in the form of pharmaceutical preparations, as anti-inflammatories, analgesics, fibrinolytics and muscle relaxants.

Description

** WARNING ** Beginning of DESC field could overlap end of CLMS **.

PATENT CLAIMS 1. Compounds of the general formula:

and the individual (0-acid isomers and (d) -acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof, wherein R is hydrogen or a lower alkyl radical having 1 to 4 carbon atoms and R is hydrogen atom, a lower alkyl radical having 1 to 4 carbon atoms, a lower alkoxy radical with 1 to 4 carbon atoms, the chlorine atom, fluorine atom or bromine atom.

2. Compounds according to claim 1, characterized in that R is the hydrogen atom.

3. Compounds according to claim 1, characterized in that R denotes the methyl radical.

4. As a compound according to claim 2, the 5-benzoyl-1,2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid.

5. As a compound according to claim 2, the isopropyl ester of 5-benzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid.

6. As a compound according to claim 2, the 5-o-toluoyl-1,2dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid.

7. As a compound according to claim 2, the isopropyl ester of 5-o-toluoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid.

8. As a compound according to claim 2, the 5-m-toluoyl-1,2 dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

9. As a compound according to claim 2, the isopropyl ester of 5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

10. As a compound according to claim 2, the 5-p-Toluoyl1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole- carboxylic acid.

11. As a compound according to claim 2, the isopropyl ester of 5-p-toluoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid.

12. As a compound according to claim 2, the 5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

13. As a compound according to claim 2, the isopropyl ester of 5-p-methoxybenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] -pyrrol-1-carboxylic acid.

14. As a compound according to claim 2, the 5-o-chlorobenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid.

15. As a compound according to claim 2, the isopropyl ester of 5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrol1-carboxylic acid.

16. As a compound according to claim 2, the 5-m-chlorobenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid.

17. As a compound according to claim 2, the isopropyl ester of 5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylic acid.

18. As a compound according to claim 2, the 5-p-chlorobenzoyl-1, 2-dihydro-3H-pyrrolo [l, 2-a] pyrrole-1-carboxylic acid.

19. As a compound according to claim 2, the isopropyl ester of 5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid.

20. As a compound according to claim 2, the 5-p-fluorobenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid.

21. As a compound according to claim 2, the isopropyl ester of 5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2a] pyrrole-l-carboxylic acid.

22. As a compound according to claim 2, the 5-o-fluorobenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid.

23. As a compound according to claim 2, the isopropyl ester of 5-o-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylic acid.

24. As a compound according to claim 2, the 5-p-ethoxybenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid.

25. As a compound according to claim 3, the 5-p-fluorobenzoyl-1, 2-dihydro-6-methyl-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid.

26. As salts according to claim 1, the sodium, potassium or calcium salts of the compounds of the formula A.

27. As the salt according to claim 26, the sodium salt of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

28. As the salt according to claim 26, the sodium salt of 5-p fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid.

29. The (I) acid isomers of the formula A according to claim 1.

30. As a compound according to claim 29, the (1) -5-benzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid.

31. As a compound according to claim 29, the (1) -5-p-fluoro benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1 - carboxylic acid.

32. As salts according to claim 1, the sodium, potassium or calcium salts of the (l) acid isomers of the formula A.

33. As the sodium salt according to claim 32, the sodium salt of (l) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

34. As the sodium salt according to claim 32, the sodium salt of (i) -5-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1 2- a] pyrrole-1-carboxylic acid.

35. As the salt according to claim 1, the dicyclohexylamine salt of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

36. As a salt according to claim 1, the dicyclohexylamine salt% of 5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid.

37. Preparation for the treatment of inflammation, pain or pyrexia in mammals and humans, characterized in that it consists essentially of a pharmaceutically acceptable, non-toxic drug carrier and a therapeutically effective amount of a compound of the formula A according to claim 1 or one (I) Acid isomer thereof or a pharmaceutically acceptable, non-toxic ester or salt thereof.

38. Preparation for administration to pregnant women and pregnant animals to delay labor, characterized in that it consists essentially of a pharmaceutically acceptable, non-toxic drug carrier and a therapeutically effective amount of a compound of the formula A according to claim 1, one of (I) - Acid isomer thereof or a pharmaceutically acceptable, non-toxic ester or salt thereof.

The present invention relates to new 5-aroyl 1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acids of the formula:

and the individual (l) acid isomers and the (d) acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts of these acids, where in the above formula R is the hydrogen atom or a lower alkyl radical with 1 to 4 Carbon atoms and Rl denotes the hydrogen atom, a lower alkyl group with 1 to 4 carbon atoms, a lower alkoxy group with 1 to 4 carbon atoms, the chlorine atom, the fluorine atom or the bromine atom.

The invention also relates to pharmaceutical preparations which contain one of the above-mentioned compounds as active ingredient.

The compounds of this invention described above and disclosed in greater detail below, with the exception of the (d) -acid isomers and derivatives thereof, 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 detailed below.

They are also excellent muscle relaxants.

The term pharmaceutically acceptable, non-toxic esters and salts, as used herein, preferably refers to alkyl esters derived from straight-chain or branched hydrocarbons containing 1 to 12 carbon atoms, while the salts are derived from pharmaceutically acceptable, non-toxic inorganic and derive organic bases.

Typical alkyl esters are, for example, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isoamyl, pentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl and dodecyl ester.

Salts derived from inorganic bases include the sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganese, 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 such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine , Ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperidine, theobromine, purinepiperidine etc.

Organic, non-toxic bases such as isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexylamine, choline and caffeine are particularly preferred.

The new compounds of formulas (A) and (XI) as disclosed below exist in the form of optical isomers or enantiomorphs, i. in the form of (dl) mixtures. Each optical isomeric compound as well as the (dl) mixtures thereof are encompassed by the present invention.

Should the new compounds according to the invention, because of their physiological responsiveness, e.g. their anti-inflammatory, analgesic or antipyretic effects, i.e. are used as medicaments, one will find a preferred subgroup in the compounds of the formula (A), the corresponding (i) -acid isomers thereof and their esters and pharmaceutically acceptable salts.

A further sub-grouping for compounds to be used as medicaments are the compounds of the formula (A) and the (I) -acid isomers of the formula (A) and their esters and their pharmaceutically acceptable salts, in which R and Rl each represent hydrogen atoms.

The (d) acid isomer of formula (A) and its esters and pharmaceutically acceptable salts are valuable as intermediates for the preparation of (d1) acids of formula (A), as will be described in more detail below.

The new (dl) compounds according to the invention can be prepared according to the following reaction scheme:

where R and Rl have the above meanings and R2 is a lower alkyl radical having 1 to 4 carbon atoms, e.g. denotes the methyl, ethyl, isopropyl or n-butyl radical.

When carrying out the present process in practice, equimolecular amounts of ethanolamine of formula I and dimethyl 1,3-acetonedicarboxylate of formula II are used for the preparation of the compound of formula IV in which R is the hydrogen atom at a temperature of about 0 ° C. to about React room temperature in order to get in this way easily to 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 at a temperature of about 40.degree treated to about 100 C for a period of 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 is carried out in acetonitrile solution at reflux temperature for about 1 hour. The compounds used as reactants, i.

2-bromoacetaldehyde and 2-chloroacetaldehyde are known Links. They can be obtained by pyrolysis of the corresponding diethyl acetals in the presence of oxalic acid dihydrate.

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

wherein X is bromine or chlorine and R3 is a lower alkyl radical having 1 to 4 carbon atoms, which is preferably a straight-chain radical, treated at about 40 to about 100 C for about 30 minutes to about 16 hours. Preferred compounds for this are l-bromoacetone, l-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 approximately -10 ° C. to approximately room temperature for approximately 1 hour to approximately 6 hours. The compounds of the formula:

are known.

The esterification of a compound of Formula IV with methanesulfonyl chloride in the presence of a tertiary amine, e.g. Triethylamine, pyridine or the like, is preferably carried out in the presence of a cosolvent, e.g. Dichloromethane at a temperature in the range from about -10 C to about room temperature for about 10 minutes to about 2 hours, resulting in a corresponding mesylate of the formula V, which is then obtained by reaction with sodium iodide in acetonitrile solution at reflux temperature for a period of about 1 Hour to about 10 hours is converted into a corresponding N- (2-iodine ethyl) pyrrole.

After the reaction of the iodomethyl compounds of the formula VI with sodium hydride in a suitable, inert, organic solvent, e.g. Dimethylformamide, a 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylic acid dimethyl ester and 6-position alkyl-substituted derivatives thereof of the formula VII are obtained. This cyclization takes place in an inert atmosphere , ie in an argon or nitrogen atmosphere, at temperatures ranging from about 15 C to about 40 C for a period of about 15 minutes to about 4 hours. The best results are achieved 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 the formula VII can also be obtained by direct cyclization of a mesylate of the formula V using sodium hydride in dimethylformamide solution at a temperature of approximately -10 ° C. to approximately room temperature for approximately 30 minutes to approximately 2 hours.

The basic hydrolysis of a compound of formula VII with an alkali metal hydroxide or alkali metal carbonate, e.g. Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., in an aqueous lower aliphatic alcohol, e.g. Methanol or ethanol, at a temperature between room temperature and reflux temperature for about 4 hours to about 24 hours results in a free diacid of formula VIII, i. 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 reflux temperature for about 10 hours.

The carboxylic acid group at the C-1 position in a compound of Formula VIII is then modified by treatment with a lower aliphatic alcohol, e.g. Methanol, ethanol, isopropanol, n-butanol or the like, selectively esterified in the presence of hydrogen chloride, using a 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-7-carboxylic acid 1- Carboxylic acid alkyl ester of the formula IX is obtained. 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 of the formula IX to corresponding compounds of the formula X, which are the key intermediates in the process for the preparation of the compounds 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 280 ° C. for sufficient time long period of time to cause full implementation. The course of the reaction can be determined by the extent of the evolution of carbon dioxide and by thin layer chromatography, the decarboxylation generally being complete within about 45 to about 90 minutes. The reaction products, namely the 1,2-dihydro-3H-pyrrolo- [1,2-aj-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 when decarboxylating 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:

where Rl has the above meaning, leads to corresponding 5-aroyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid alkyl esters of the formula XI. This reaction is 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, after which the mixture is refluxed in the presence of sodium acetate for about 2 to about 10 hours. Instead of phosphorus oxychloride, on the other hand, other acid chlorides, e.g. Use 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 previously refluxed mixture of 1.1 to 5 molar equivalents of both the desired amide and the phosphorus oxychloride in the same solvent, the resulting The reaction mixture is heated to boiling under reflux 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 refluxed again for about 4 to about 6 hours.

Appropriate solvents for this reaction are halogenated hydrocarbons, e.g. Dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, etc., also dimethoxyethane and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane.

Examples of suitable N, N-dimethylarylamides which can be used are: N, N-dimethyl-benzamide, N, N-dimethyl-o-toluamide, N, N-dimethyl-m-toluamide, N, N-dimethyl- p-toluamide, 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, N, N-dimethyl-p-ethoxy-benzamide, N, N-dimethyl-p-isopropoxy-benzamide, N, N-dimethyl-o-chlorobenzamide, N, N-dimethyl-m-chlorobenzamide, N, N-dimethyl-p-chlorobenzamide, N, N-dimethyl-o-fluoro-benzamide, N, N-dimethyl-p-fluoro-benzamide, N, N-dimethyl-m-bromo-benzamide and N, N-dimethyl-p-bromo-benzamide.

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

After the alkaline hydrolysis of the alkyl ester group in a compound of formula XI, the corresponding free acid of formula A is obtained. This hydrolysis is carried out in a manner known per se with an alkali metal hydroxide or alkali metal carbonate, e.g. Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate etc., in an aqueous, lower aliphatic alcohol, e.g. 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 takes place by means of aqueous, methanolic potassium carbonate at reflux temperature for approximately 30 minutes.

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

The (l) acid isomers and (d) acid 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 α-phenylethyl esters of the compounds of the formula A. and then causes the splitting by means of an acid.

For example, the compounds of the formula A in which R and R 'are each hydrogen atoms can be treated further in accordance with the following diagram:

of the (l) -a-phenylethyl ester of the (0-acid isomer of the formula (A) mixture of l (l) -a-phenylethyl ester of the (d) -acid isomer of the formula (A)

A more detailed description of this workflow can be found in Example 12B below.

The free acids of formula A can be converted into other alkyl esters having 1 to 12 carbon atoms in a manner known per se, e.g. by treatment with (a) the alcohol corresponding to the desired ester in the presence of a strong mineral acid, (b) with an ethereal diazoalkane or (c) the desired alkyl iodide in the presence of lithium carbonate. The (I) acid isomers can be converted into the corresponding alkyl esters by the methods according to (b) and (c).

The salt derivatives of the compounds of the formula A and the (I) acid isomers thereof 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, dimethylamine, ethylamine, triethylamine, dimethylamine, ethylamine, triethylamine, dimethylamine, ethylamine, 2-ethylamine, 2-ethylamine, 2-ethylamine, triethylamine, 2-ethylamine, 2-ethylamine -Diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, Methylglucamine, theobromine, purines, piperazine, piperidine, N-Ethylpiperidine, polyamine resins, etc. The reaction takes place in water alone or in conjunction with an inert, water-miscible, organic solvent in a Temperature from about 0 C to about 100 C and preferably at room temperature. Typical inert organic solvents which can be mixed with water are methanol, ethanol and isopropanol. Butanol, acetone, dioxane or tetrahydrofuran. The molar ratio of the compounds of the formula A or the (l) -acid isomers thereof, based on the base used, is selected so that the correct ratio is present depending on the salt used. For example, the calcium salts or magnesium salts of the compounds of the formula A. or the (1) acid isomers thereof, the free acid used as the starting material can be treated with at least 1/2 molar equivalent of a pharmaceutically acceptable base to obtain a neutral salt.

If the aluminum salts of the compounds of the formula A or the (l) -acid isomers thereof are to be prepared, at least 1/3 molar equivalent of the pharmaceutically acceptable base is used, if a neutral salt is desired.

According to the preferred embodiment, the calcium salts and magnesium salts of the compounds of the formula A and the (I) acid isomers thereof can be prepared by mixing the corresponding sodium or potassium salts thereof with at least 1/2 molar equivalent of calcium chloride or magnesium chloride in an aqueous solution alone or in combination with an inert, water-miscible organic solvent at a temperature of about 20 ° C to about 100 ° C. Preferably, the aluminum salts of such compounds can be prepared by treating the corresponding free acids with at least 1/3 molar equivalent of an aluminum alkoxide, e.g. Aluminum triethoxide, aluminum tripropoxide or the like, treated in a hydrocarbon solvent such as benzene, xylene, cyclohexane or the like at a temperature between about 20 ° C and about 115 ° C. Similar measures can be taken to prepare salts of inorganic bases which are not sufficiently soluble for easy conversion.

It will be understood that the isolation of the compounds described in the present patent can, if desired, be carried out using any suitable separation and purification process, e.g. Extraction, filtration, evaporation, distillation, allowing crystallization, thin layer chromatography or column chromatography, high pressure liquid chromatography (HPLC) or 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 pharmaceuticals as such, they can at least be converted into the corresponding, pharmaceutically acceptable, non-toxic esters and salts thereof, if desired, by following the methods for converting (l) - Acid isomers in the corresponding pharmaceutically acceptable, non-toxic esters and salts thereof.

The compounds of the formula A and the (I) -acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and 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 inflammations such as e.g. Inflammation of the skeletal muscles, joints and other tissues, for example in the treatment of Inflammations of this kind, e.g. Rheumatism, concus sio, laceratio, arthritis, bone fractures, post-traumatic conditions and gout. In those cases in which the above conditions cause pain and fever, paired with inflammation, the compounds 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 (l) -acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof in suitable pharmaceutical preparations can be used per se for the treatment of inflammation, pain or pyrexia or for prophylaxis suitable forms of administration for this are done. For example, administration can be carried out orally, parenterally or topically in the form of solid, semi-solid or liquid dosage forms, e.g. As tablets, suppositories, pills, capsules, powders, solutions, suspensions, emulsions, creams, lotions, ointments or the like, preferably in unit dosage forms which are suitable for easy administration of precise dosage amounts. The preparations contain conventional pharmaceutical carriers or Fillers and an active substance according to formula A or an (I) acid isomer thereof and / or pharmaceutically acceptable, non-toxic esters and 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 employed according to the degree of the disease. In general, a daily dosage of between 25 mg and 500 mg of active substance of the formula A or an (I) -acid isomer thereof or of pharmaceutically acceptable, non-toxic esters and salts thereof is administered. In most cases, the treatment is carried out with a dosage of 0.5 mg to 6 mg per kg of body weight per day. For such oral administrations, pharmaceutically acceptable, non-toxic preparations are formed by adding any desired active substance or substances to the active substance or substances. normally used excipients such as pharmaceutically acceptable mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like.

admits. Such preparations can be sold in the form of solutions, suspensions, tablets, pills, capsules, powders, sustained-release preparations, etc.

The active substances of the formula A, the (I) -acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof can be processed into a suppository using, for example, polyalkylene glycols such as polypropylene glycol as a carrier. Liquid, pharmaceutically administrable preparations can be prepared, for example, by dissolving, dispersing, etc., an active substance of the type described above and, if appropriate, pharmaceutical auxiliaries in a carrier such as e.g. Water, saline solution, aqueous dextrose, glycerin, ethanol and the like., 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. Wetting or emulsifying agents, pH buffering agents, etc. e.g.

Sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.

Methods for making such dosage forms are well known or readily available to those skilled in the art. In this context, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th Edition, 1970. The preparation to be administered will in all cases contain a certain amount of active substance or active substances in a pharmaceutically effective amount.

The compounds of the formula A, the (l) -acid isomers and their nontoxic, pharmaceutically acceptable esters and salts, as described above, are also relaxants for the uterine muscles and are therefore valuable as agents which both promote pregnancy Favorably influence the mother and / or the fetus up to the final stage of pregnancy. It should be noted that in certain cases, such as those in which labor has already started, i.e. In those cases in which the mother is already experiencing uterine contractions, which is particularly the case immediately before birth, the administration of the compounds described here cannot prolong the state of pregnancy indefinitely; in such cases, the pregnancy is most likely only slightly prolonged Factor which can be beneficial for the mother and / or the fetus.

In particular, the compounds of formula A, the (I) acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof are used as agents for delaying the onset or postponing labor. The term delay the onset of labor is intended to encompass that delay in labor which is achieved by the administration of compounds of formula A, of (I) acid isomers thereof and pharmaceutically acceptable, non-toxic esters and salts thereof at any time The beginning of uterine muscle contractions is caused. This designation is thus intended to prevent an abortion at the beginning of pregnancy, ie before the fetus is viable, as well as delaying premature labor, a term that is occasionally used with reference to premature labor, which experience has shown to occur later in pregnancy when the fetus is already said to be viable. In any event, the agents are used as prophylactic agents because such administration prevents the onset of labor. Administration is useful in the treatment of women with a history of spontaneous abortion, miscarriage or the possibility of premature birth, i.e. Delivery before the end of the full gestation period is 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 is particularly useful for the mother and / or the fetus could be beneficial.

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

In the present patent specification, the meaning postponement of labor is intended to include that delay in labor which is caused by the administration of compounds of formula A, of (I) -acid isomers thereof and pharmaceutically acceptable, non-toxic esters and salts thereof after the onset of Uterine muscle contractions.

The condition of the patient, including the duration within the gestational period in which the contractions began, the extent of the contractions, and the duration of the contractions will affect the results obtained from the administration of the compounds. For example, the effect can be that the intensity and / or duration of the contractions (whereby the actual labor act can be extended) or the contractions can be interrupted at all. In each case, the gestational period is prolonged, although depending on the patient's conditions the effect may be very weak or, in certain circumstances, somewhat greater; such administration may prevent spontaneous abortion, make labor easier for the mother and / or make it less painful or lead to the fact that the birth can be carried out at a more suitable time and / or in a more suitable place.

In all cases, administration of the compounds of formula A, the (I) acid isomers thereof, and the pharmaceutically acceptable, non-toxic esters and salts thereof, should with best and / or acceptable medical or veterinary practices in view of the above purposes be reconciled to maximize the benefits for the mother and fetus. For example, administration should not continue so long after the scheduled time that the fetus dies in the uterus.

In practice, a therapeutically effective amount of a compound of the formula A, an (I) -acid isomer thereof or a pharmaceutically acceptable, non-toxic ester or salt thereof or a pharmaceutical preparation containing such an active substance is added to the pregnant woman or the pregnant animal administered the previously known, customary and permissible methods. The compound can be administered either as such or in conjunction with another compound or with other compounds of the type defined above or with other pharmaceutical agents, carriers, excipients, etc.

Such a compound or compounds or preparations can be administered orally, parenterally in either solid, semi-solid, and liquid dosage forms.

In particular, the administration takes place with the aid of a pharmaceutical preparation which contains the pharmaceutically active compound and one or more pharmaceutical carriers or auxiliaries.

The administrable pharmaceutical preparation may be in the form of oral tablets, vaginal tablets or uterine tablets or suppositories, pills, capsules, liquid solutions, suspensions and the like, preferably in unit dosage forms suitable for easy administration of precise dosages. Usual, non-toxic, solid carriers include, for example, pharmaceutically acceptable mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate, etc. The active substance defined above can be in the form of suppositories using, for example, polyalkylene glycols such as Polypropylene glycol, present as a carrier. Liquid, pharmaceutically administrable preparations can be produced, for example, that an active substance of the type defined above and suitable, pharmaceutical additives in a carrier, such as Water, saline, aqueous dextrose, glycerin, ethanol, etc., dissolves, disperses, etc., so as to obtain a solution or suspension. If desired, the pharmaceutical preparation to be administered can also contain small amounts of non-toxic auxiliary substances, e.g. Wetting or emulsifying agents, pH buffering agents, etc. e.g. Sodium acetate, sorbitan monolaurate, triethanolamine, oleate etc. contain.

Methods of making such dosage forms are well known or readily available to those skilled in the art, with particular reference to Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th Edition, 1970. The preparation to be administered will in all cases contain such an amount of active substance or active substances which is sufficient to delay the onset of labor or to prolong labor when the uterine contractions have already started. In general, a daily dose of 0.5 mg to about 25 mg of active ingredient per kg of body weight will be administered, such administration being once daily or in smaller doses regularly three or four times per day. The amount of active ingredient to be administered depends of course on the respective effect of this active substance.

The following examples illustrate the present invention. The abbreviation t.l.c., if it occurs here, refers to thin layer chromatography, while all mixing ratios with regard to liquids represent volume ratios. If necessary, the examples are repeated to provide further material for the examples below. Unless otherwise stated, the reactions take place at room temperature, i.e. at temperatures ranging from 20 to 30 "C.

Example I. 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 a supply line and a short (7.6 cm) water condenser with the acetal pyrolysis device. This latter consists of a 100 ml round bottom flask which has previously been filled with 15.6 g of oxalic acid dihydrate and 11.82 g of bromoacetaldehyde diethylacetal, prepared from vinyl acetate, as has been described by P.Z. Bedoukian, J. Am. Chem. Soc. 66, 651 (1944), on this device a Vigreux column of 15.2 cm, which has a thermometer, is placed, 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. Methyl 3-carbomethoxymethyl 3- (2'-hydroxyethyl) aminoacrylate (III) is formed spontaneously.

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 150-160 ° 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 fallen 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 for 1 hour at reflux temperature, the solvent removed under reduced pressure and then the residue with 200 ml of methanol and 20 g of silica gel are added. The mixture is evaporated to dryness in vacuo and fed to a column which is charged with 200 g of silica gel and 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 fewer polar impurities and dimethyl 1,3-acetone dicarboxylate; Fractions 4 to 8 provide 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.

Example 2 2.65 ml of triethylamine are stirred into a solution of 4.1 g of methyl N- (2-hydroxyethyl) -3carbomethoxypyrrole-2-acetate in 35 ml of dry dichloromethane, cooled to -10 ° C., whereupon 1.46 ml of triethylamine are added dropwise ml of methanesulfonyl chloride is added while maintaining a temperature of the reaction mixture of -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 the 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. Letting the residue crystallize out from a mixture of dichloromethane and hexane gives 4.75 g (77.7%) of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H), melting point 99 to 101 "C.

Example 3 A solution of 785 mg of methyl N- (2-mesyloxyethyl) -3carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodide in 10 ml of acetonitrile is refluxed for 1 hour. The reaction mixture is then cooled and subsequently 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- (2iodoethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = H), mp.

137 to 138 C.

Example 4 A solution of 1 g of methyl N- (2-iodoethyl) -3-carbomethoxypryrrole-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 dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1,7-dicarboxylate (VII, R = H), m.p. 70 to 71 "C.

A solution of 1.80 g of dimethyl 1,2-dihydro-3H-pyrro- lo- [1,2a] -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 and the reaction mixture then heated to boiling under reflux for 6 hours. 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- [1,2-a-pyrrole-1,7-dicarboxylic acid (VIII, R = H), m.p. 220 C (decomposition) is obtained.

Example 5 A solution of 1.34 g of 1,2-dihydro-3H-pyrrolo- [1,2-a] - pyrrole-l, 7-dicarboxylic acid in 50 ml of isopropanol, cooled in an ice bath, is mixed with gaseous hydrogen chloride while maintaining a temperature of the reaction mixture of less than 50 ° C. is saturated. The ice bath is then removed and the reaction mixture is stirred for 11/2 hours 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, this procedure being repeated a total of three times to remove the excess hydrogen chloride. In this way 1.58 g (96%) of isopropyl-1,2-dihydro-3H-pyrolo are obtained - [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 being allowed to crystallize 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-1-carboxylate-7-carboxylic acid, ethyl-1,2-dihydro-3H-pyrrolo- [1,2-a] - pyrrole-1-carboxylate-7-carboxylic acid, Propyl 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate-7-carboxylic acid and Butyl 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate-7-carboxylic acid.

Example 6 1.054 g of isopropyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole 1-carboxylate-7-carboxylic acid are heated to 240 to 250 ° C. in a dry round-necked flask with a capacity of 10 ml, 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: UVXmMaxOH 215nm (# = 6020); I.R. # maxCHCl3 1725 cm-1; NMR: # CDCl3 1.22 (d TMS 22 (d, J = 7 Hz, 6H), 2.402.90 (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).

Example 7 A 100 ml three-necked round bottom flask, which is 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-1-carboxylate- 7-carboxylic acid charged. The device is thoroughly flushed out with nitrogen and then the nitrogen supply is stopped. The The device is then immersed in an oil bath heated to 270 ° C. and the reaction is observed on the basis of the evolution of carbon dioxide (gas inlet nozzle) and by thin layer chromatography over silica gel using a mixture of benzene, dioxane and acetic acid (mixing ratio 90: 10: 1) as the developer solvent.

After 45 minutes the reaction is practically complete. After The container is removed from the oil bath for 1 hour and the contents of the reaction flask are placed in 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 by means of 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-pyrro- lo- [1,2-al-pyrrole-1-carboxylate (X, R = H, R2 = iC3H7), an 01 whose physical constants are identical to those in Example 6.

Example 8 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-1-carboxylate in 2 ml of 1,2-dichloroethane is then added to this solution. The reaction mixture is then refluxed for 8 hours in an argon atmosphere, then treated with 405 mg of sodium acetate and then refluxed for a further 5 hours. The resulting mixture 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 is obtained -toluoyl-1,2-dihydro-3H-pyrro- lo- [1,2-a] -pyrrole-1-carboxylate (XI, R = H, Rl = p-CH3, R2 = iC3H7), an oil with the following physical constants: U.V .: #maxMeOH 256, 312nm (# = 8700, 19,500); I.R .: #maxfilm 1735, 1620, 1605 cm-1; N.MR.8DCD TMS 13 1.23 (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 = 4 Hz, 1H), 6.70 (d, J = 4 Hz, 1H), 7.10 (d, J = 8 Hz, 2H), 7.60 ppm. (d, J = 8 Hz, 2H).

Example 9 A solution of 336 mg isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate in 10 ml of methanol is mixed with a solution of 690 mg of potassium carbonate in Treated 5 ml of water. The reaction mixture is then refluxed for 30 minutes in a nitrogen atmosphere, 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. Recrystallization of the residue from a mixture of ethyl acetate and hexane gives 238 mg (89%) of 5-p-toluoyl-1,2-dihydro-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid [(A), R = H, Rl = p-CH3], m.p. 182 to 183 C.

Example 10 A solution of 250 mg isopropyl-5-p-toluoyl-1, 2-di-hydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate in 8 ml of methanol is in a nitrogen atmosphere with a solution of Treated 200 mg of sodium hydroxide in 1 ml of water, the reaction mixture being kept at room temperature for 1 1/2 hours. The methanol is then removed under reduced pressure and the remaining basic solution is diluted with 5 ml of water and extracted with ether in order to remove any unsaponified product. 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 made to crystallize out from a mixture of ethyl acetate and hexane, 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylic acid being obtained, which is obtained with the product according to example 9 is identical.

Example 11 When working according to the methods described in Examples 6 or 7, the compounds obtained according to Example 5 can be converted into: Methyl 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, ethyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1- carboxylate, Propyl 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate and Butyl 1,2-dihydro-3H-pyrrolo [1,2-a] -1-carboxylate.

After condensing this compound with N, N-dimethyl-p-toluamide according to the method of Example 8, the following compounds are obtained: Methyl 5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, ethyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole l-carboxylate, Propyl 5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate and Butyl 5-p -toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylate.

Example 12A The procedure is as in Example 8 using 1.1 to 5 molar equivalents of N, N-dimethyl-benzamide, N, N-dimethyl-o-toluamide, N, N-dimethyl-m-toluamide, 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-p-methoxy-benzamide, N, N-dimethyl-p-ethoxy-benzamide, N, N-dimethyl-p-isopropoxy-benzamide, N, N-dimethyl-o-chlorobenzamide, N, N-dimethyl-m-chlorobenzamide, N, N-dimethyl-p-chlorobenzamide, N, N-dimethyl-o-fluoro-benzamide, N, N-dimethyl-p-fluoro-benzamide, N, N-dimethyl-m-bromo-benzamide and N, N-dimethyl-o-bromobenzamide instead of N, N-dimethyl-p-toluamide and records the course of the reaction by thin-layer chromatography. The following compounds are obtained: Isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, light yellow oil with the following physical constants: U.V .: #maxMeOH 245.311 nm (# 7230, 17800); I.R.:#maxCHCl3 1735, 1620 cm-1; N.M.R.:#CDCl3 1.24 [d, 6H, (CH3) 2CH], 2.50-3.13 TMS (m, 2H; H-2); 3.97 (dd, 1H, H-1), 4.18-4.70 (m, 2H, H-3), 5.00 (sept, 1H, (CH3) 2CH), 6.00 (d, 1H, H-7), 6.86 (d, 1H, H-6), 7.10-7.90 ppm (m, 5H, phenyl protons); M.S .: m / e 297 (M +).

Isopropyl 5-o-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate, an oil having the following physical properties Constants: U.V .: #maxMeOH 252.303 nm (# 4460, 19,100); I.R .: # maxCHCl3 1735, 1620 cm-1; NMR: # TMSCDCl3 1.18 [d, 6H, (CH3) 2CH], 2.28 (s, 3H, o-CH3), 2.50-3.13 (m, 2H, H-2), 3, 92 (dd, 1H, H-1), 4.17-4.70 (m, 2H, H-3), 4.98 [sept. 1H, (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-1,2-dihydro-3H-pyrrolo- [1,2-a] - pyrrole-1-carboxylate, an oil with the following physical constants: UV: #maxMeOH 250-251, 310-312 nm (# 6460, 17,400); I.R .: # maxCHCl3 1735, 1620 cm-1; CDCl3 1.25 [d, 6H, (CH3) 2CHj, 2.27 (s, 3H, CH3), 2.52-3.13 (m, 2H, H-2), 3.92 (dd, 1H, H-1), 4.13-4.70 (m, 2H, H-3), 4.95 [sept. 1H, (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-1,2-dihydro-3H-pyrrolo- [1,2a] -pyrrole-1-carboxylate, Isopropyl 5-o-propylbenzoyl-1,2-dihydro-3H-pyrrolo [1,2-al-pyrrole-1-carboxylate, isopropyl-5-m-butylbenzoyl-1,2-dihydro-3H-pyrrolo [1, 2-a] -pyrrole-1-carboxylate, isopropyl-5-o-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate, isopropyl-5-p-methoxybenzoyl- 1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate with the following physical constants: UV:? MaxMeOH 218,270-284 (Schluter), 314, 314 nm (# 9780, 9320, 22 400); I.R .: # maxCHCl3 1730, 1605 cm-1; N.M.R .: # TMSCDCl3 1.24 [d, 6H, J = 6Hz; (CH3) 2CH-], 2.50-3.10 (m, 2H; H-2), 3.78 (s, 3H; CH3O), 3.93 (dd, 1H, JAX = 6 Hz, J8x = 7 Hz; H-1), 4.13-4.60 (m, 2H; H-3), 4.95 [sept, 1H, J = 6 Hz; (CH3) 2CH], 5.95 (s, 1H, J = 4 Hz; H-7), 6.68 (d, 1H, J = 4 Hz; H-6), 6.70-7.90 ppm (m, 4H; phenyl protons); M.S .: m / e 327 (M *).

Isopropyl 5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 94-95 C, Isopropyl 5-p-isopropoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate, isopropyl-5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo - [1,2a] -pyrrole-l-carboxylate, an oil with the following physical constants: U.V .: #maxMeOH 251.306 nm (# 5750, 16000); I.R .: # maxCHCl3 1735, 1625 cm-1; NMR: # TMSCSCl3 1.22 [d, 6H, (CH3) 2CH], 2.55-3.05 (m, 2H; H-2), 3.97 (dd, 1H, HI), 4.17- 4.70 (m, 2H, H-3), 4.97 [sept., 1H, (CH3) 2CH], [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-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate, an oil with the following physical constants: UV: # maxMeOH241.313 nm (# 6600, 15 100); I.R .: # maxCHCl3 1735, 1620, 1570 cm-1, NMR: 8CDCl3 1.27 [d, 6H, (CH3) 2CH], 2.50-3.18 TMS (m, 2H, H-2), 3.93 (dd, 1H, HI), 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); MS: m / e 331-333 (M +), isopropyl-5-p -chlorobenzoyl-1,2dihydro3H-pyrrolo [1,2- a] -pyrrole-1-carboxylate, m.p. 80.5-81 "C , Isopropyl 5-o-fluorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2- a] -pyrrole-1-carboxylate, isopropyl-5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo - [1,2- a] -pyrrole-1-carboxylate, m.p. 72-72.5 "C, isopropyl-5-m-bromobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] - pyrrole-1-carboxylate and Isopropyl 5-p-bromobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

By hydrolyzing the isopropyl ester group according to the methods mentioned in Examples 9 or 10, the corresponding free acids are obtained, namely: 5-Benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, m.p. 160-161 "C, 5-o-toluoyl-1,2-dihydro-3H -pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, an oil with the following physical constants: UV: h MeOH253, 307 nm (3310, 16,980); max IR: # maxCHCl3 1720, 1620 cm-1 ; NMR: # CDCl3 2.32 (@, 3 TMS 32 (s, 3H, CH3), 2.53-3.03 (m, 2H, H-2), 3.97 (dd, 1H, H-1), 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 (b.s., 1H, COOH).

5-m-Toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1 carboxylic acid, 5-p-Ethylbenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole 1 -carboxylic acid, 5-o-propylbenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyr- rol-1-carboxylic acid, 5-m-butylbenzoyl-1,2-dihydro-3H-pyrrolo- [l , 2-a] -pyrrole-1-carboxylic acid, 5-o-Methoxybenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid, 5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo- [1,2- a] - pyrrole-1-carboxylic acid, m.p. 187-187.5 C, 5-p-Ethoxybenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrol-1-carboxylic acid, m.p. 169.5-170 "C, 5-p-isopropoxybenzoyl-1,2 -dihydro-3H-pyrrolo- [1,2-a] pyrrole- 1 -carboxylic acid, 5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole 1-carboxylic acid, with the following physical constants: U.V .: # maxMeOH250, 307.5 nm (4360, 17 400); I.R .: # maxCHCl3 1715.1620 cm-1; NMR: # TMSCDCl3 2.60-3.15 (m, 2H; H-2), 4.02 (dd, 1H, JAX = 6 Hz, JBX = 7 Hz; HI), 4.20-4.70 ( m, 2H; H-3), 5.98 (d, 1H, 5 = 4 Hz; H-7), 6.42 (d, 1H, J Hz; H-6), 7.00-7.77 (m, 4H; phenyl protons), 8.67 ppm [s, (br), 1H; COOH].

5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, m.p. 180-181 C, 5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrol1-carboxylic acid, m.p. 201.5-202.5 C, 5-o-fluorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole 1 -carboxylic acid, 5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, m.p. 179-5-180.5 C, 5-m-bromobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid and 5-p-bromobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid.

Example 12B 0.58 g of trifluoroacetic anhydride are added to a solution of 300 mg of 5-benzoyl-1,2-dihydro-3Hpyrrolo- [1,2-a] -pyrrole-1-carboxylic acid in 25 ml of dry benzene. The mixture is then stirred for 10 minutes at room temperature and the resulting solution is cooled to 0 to 5 ° C. and 1.4 g of dry triethylamine and then immediately 0.5 g of (l) -a-phenylethyl alcohol are added. The reaction solution thus obtained is stirred for 15 minutes at room temperature 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 excess (1) -α-phenylethyl alcohol are removed in vacuo to give 0.42 g of a mixture of (1) -5-benzoyl-1,2-dihydro- 3H-pyrrolo- [1,2-a] -pyrrole-1carboxylic acid- (l) -a-phenylethyl ester and (d) -5-benzoyl1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole- 1-carboxylic acid (l) -a-phenylethyl ester, which is separated by high pressure liquid chromatography (using 4% EtOAc / hexane on a 11 mm x 50 cm, 10 to Lichrosord Sl-60 column), giving 180 mg of a more polar Ester [αDMeOH - 145.7] and 178 mg of a less polar ester [αDMeOH + 128.6].

148 mg of the more polar ester are dissolved in 8 ml of dry benzene. The solution is cooled to 15 to 20 ° C. and then 5 ml of trifluoroacetic acid are added. The solution is then stirred for 70 minutes at room temperature.

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 done by high pressure liquid chromatography (using a column as described above with the difference that 35% EtOAc / hexane in 1/2% acetic acid is used instead of 4% EtOAc / hexane), using 63 mg (l ) -5-Benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, [αDCHCl3 -153.7], m.p. 153-155 "C.

Similarly, the splitting of the less polar ester by the method described above for the splitting of the more polar ester leads to 85 mg of (d) -5-benzoyl-1,2-dihydro-3H-pyrrolo- [ 1,2-a] -pyrrole l-carboxylic acid, CHCl3 + 155.1], m.p. 154 to 156 "C.

LL) The (d) acid isomer thus obtained can, if desired, be racemized and recycled by methods known per se.

In a similar way, other (di) compounds can be converted into the corresponding (I) isomers and (d) isomers.

Example 13A A 250 ml three-necked round-bottomed 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, while stirring, with 8.7 g of dimethyl-1, Treated 3-acetone dicarboxylate, methyl 3-carbomethoxymethyl-3- (2'-hydroxyethyl) aminoacrylate (III) being obtained 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 refluxed for 2 hours. 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 of 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 provide methyl N- (2-hydroxyethyl) -3-carbomethoxy-pyrrole-2-acetate (IV, R = H), which with the according to Example 1 product obtained is identical.

Example 13B 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.degree. C. and then treated dropwise within 15 minutes with stirring with 1.67 ml of 1-bromoacetone, the reaction mixture being kept at a temperature not exceeding 40.degree.

After the addition is complete, the dark reaction mixture is stirred for a further 60 minutes at room temperature and then poured into a mixture of hydrochloric acid and ice, which is saturated with solid sodium chloride, 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 over 30 g of silica gel using a mixture of hexane and ethyl acetate in a mixing ratio of 70:30 as the eluent yields 890 mg of crystalline methyl N- (2-hydroxyethyl) -3carbomethoxy-4-methylpyrrole-2-acetate, which after after recrystallization from a mixture of methylene chloride and hexane melts at 78 C and gives the following analytical values: Calculated for C12H17NO5: C = 56.45; H = 6.71.

Found: C = 56.41; H = 6.73.

Similarly, using a stoichiometric equivalent amount of l-bromo-2-butanone, l-bromo-2-pentanone and l-bromo-2-hexanone instead of l-bromoacetone: Methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate, Methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrrole-2-acetate and Methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetate.

Example 14 If one works according to the methods according to Examples 2, 3, 4, 5 and 7, then methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R = CH3) is successively derin Methyl N- (2-mesyloxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, Methyl-N- (2iodoethyl) -3-carbomethoxy-4-methyl-pyrrole-2-acetate, dimethyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrol-1, 7-dicarboxylate, 1,2-Dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylic acid, Isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyr- rol- 1-carboxylate-7-carboxylic acid and isopropyl-1,2-dihydro-6-methyl-3H- pyrrolo- [1,2-a] -pyrrol-1-carboxylate (X, R = CH3, R2 = iC3H7) converted.

If you work in a similar way using methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate, Methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrrole-2-acetate and methyl N- (2-hydroxyethyl) -3carbomethoxy-4-butylpyrrole-2-acetate instead of Methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, isopropyl-1,2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a ] -pyrrole-1-carboxylate, isopropyl-1,2-dihydro-6-propyl-3H-pyrrolo- [1,2-al] -pyrrol-1-carboxylate or

Isopropyl 1,2-dihydro-6-butyl-3H-pyrroio- [1,2-a] -pyrrole-1-carboxylate.

Example 15 According to the information in Example 8, isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate is condensed with N, N-dimethyl-p-toluamide, with Isopropyl 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate (XI, R = CH3, R1 = p-CH3, R2 = iC3H7).

Using the N, N dimethylarylamides listed in Example 12A 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-1-carboxylate, isopropyl-5-o-toluoyl-1, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole- 1 - carboxylate, Isopropyl-5-m-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate, Isopropyl 5-p-ethylbenzoyl-1, 2-dihydro-6-methyl-3Hpyrrolo- [1, 2-a] -pyrrole-1-carboxylate, isopropyl-5-o-propylbenzoyl-1, 2-dihydro-6- methyl 3H pyrrolo- [1, 2-a] -pyrrole-1-carboxylate, Isopropyl-5-m-butylbenzoyl-1,2-dihydro-6-methyl-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylate, Isopropyl 5-o-methoxybenzoyl-1, 2-dihydro-6-methyl 3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylate, Isopropyl 5-p-methoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, isopropyl-5-p-ethoxybenzoyl-1,2-dihydro- 6-methyl-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylate, isopropyl-5-p-isopropoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1 -carboxylate, Isopropyl 5-o-chlorobenzoyl-1,2-dihydro-6-methyl-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylate, isopropyl 5-m-chlorobenzoyl-1,2-dihydro-6 -methyl-3H pyrrolo- [1, 2-a] -pyrrole-1-carboxylate, Isopropyl-5-p-chlorobenzoyl-1,2-dihydro-6-methyl-3Hpyrrolo- [1,2-a] -pyrrole-1-carboxylate, Isopropyl 5-o-fluorobenzoyl-1,2-dihydro-6-methyl-3H pyrrolo- [1,2-a] pyrrole-1-carboxylate, isopropyl 5-p-fluorobenzoyl-1,2-dihydro-6 -methyl-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylate, which has the following physical constants: UV: h ,,, 250, 315 nm (E 6170, 14 100); I.R .: # maxCHCl3 1734, 1605, 1593 cm-1; NMR: CDCl3 1.25 (d, 6H, J = 6 Hz; ester CH3), 1.83 TMS (s, 3H; ring CH3), 2.49-3.00 (m, 2H; CH2), 3.90 (t, 1H, #J = 7.4 Hz; CHCO), 4.10-4.23 (m, 2H; N-CH2), 4.98 (sept., 1H, J = 6 Hz; Ester CH), 5.84 (s, 1H, H-3), 7.00 (t, 2H, Jor tho = 8.4 Hz, JHF = 8 Hz; H-3 ', 5'), 7.55 (q, 2H, Jortho = 8.4 Hz, JHF = 5.5 Hz; H-2.6 '); M.S .: m / e 1% 32925M + 242 100 M ± CO2CH (CH3) 2 123 36 F-C6H4CO, Isopropyl 5-m-bromobenzoyl-1, 2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and Isopropyl 5-p-bromobenzoyl-1,2-dihydro-6-methyl-3H pyrrolo [1,2-a] pyrrole-1-carboxylate.

In a similar way, the end compounds obtained according to Example 14 can be converted into the corresponding ones Convert 5-aroyl-substituted derivatives. Examples of this are the following: Isopropyl 5-benzoyl-1, 2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, Isopropyl-5-benzoyl-1,2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, Isopropyl 5-benzoyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate, isopropyl-5-p-toluoyl-1,2-dihydro-6-ethyl -3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate, Isopropyl 5-p-ethylbenzoyl-1,2-dihydro-6-propyl-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylate, Isopropyl-5-o-methoxybenzoyl-1, 2-dihydro-6-butyl-3H pyrrolo- [1, 2-a] -pyrrole-1-carboxy lat, Isopropyl-5-p-ethoxybenzoyl-1,2-dihydro-6-ethyl-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylate, Isopropyl-5-o-chlorobenzoyl-1,2-dihydro-6-propyl-3Hpyrrolo- [1,2-a] -pyrrole-1-carboxylate, Isopropyl 5-m-chlorobenzoyl-1,2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, isopropyl 5-o-fluorobenzoyl-1,2-dihydro -6-ethyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, 3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, isopropyl-5-p-fluorobenzoyl - 1,2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate and isopropyl-5-p-bromobenzoyl-1,2-dihydro-6-butyl-3H-pyrrolo - [1, 2-a] pyrrole 1-carboxylate.

Example 16 A solution of 500 mg of isopropyl 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate in 15 ml of methanol is treated with a solution of 1.05 g of potassium carbonate in 8 ml of water. The reaction mixture is then heated to boiling under reflux for 30 minutes in a nitrogen atmosphere, 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, giving 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid [(A), R = CH3, R '= p-CH3] is obtained.

In a similar manner or according to the hydrolysis method of Example 10, the isopropyl ester compounds obtained according to Example 15 can be converted into the corresponding free acids, namely into the following free acids: 5-Benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1, 2-a] -pyr- rol- 1 -carboxylic acid, 5-o-Toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid, 5-m-toluoyl-1,2-dihydro-6-methyl-3H -pyrrolo- [1,2-al-pyrrole-carboxylic acid, 5-p-ethylbenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-al-pyrrole-1-carboxylic acid, 5-o Propylbenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, 5-m-butylbenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo - [1,2- a] -pyrrole-1-carboxylic acid, 5-o-methoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylic acid, 5-p-Methoxybenzoyl-1, 2-dihydro-6-methyl-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylic acid, 5-p-Ethoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylic acid, 5-p-Isopropoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, 5-o-chlorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2a] -pyrrole-1-carboxylic acid, 5-m-chlorobenzoyl-1,2-dihydro-6-methyl-3H- pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, 5-p-chlorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, 5-o-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, 5-p-fluorobenzoyl-1,2-dihydro-6-methyl- 3H-pyrrolo- [1,2 a] -pyrrole-1-carboxylic acid, m.p. 204 "C, 5-m-bromobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, 5-p-bromobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1 -carboxylic acid, 5-Benzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, 5-benzoyl-1,2-dihydro-6-propyl-3H-pyrrolo- [l , 2-a] -pyrrol- 1 -carboxylic acid, 5-benzoyl-1,2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] -pyrrol1-carboxylic acid, 5-p-Toluoyl-1,2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, 5-p-Ethylbenzoyl-1,2-dihydro-6-propyl-3H-pyrrolo- [1,2a] -pyrrole-1-carboxylic acid, 5-o-Methoxybenzoyl- 1, 2-dihydro-6-butyl-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid, 5-p-ethoxybenzoyl-1,2-dihydro-6-ethyl 3H-pyrrolo- [1,2- a] -pyrrole-1-carboxylic acid, 5-o-chlorobenzoyl-1,2-dihydro-6-propyl-3 H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, 5-m-chlorobenzoyl-1,2-dihydro-6-butyl -3H-pyrrolo- [1,2- a] -pyrrole-1-carboxylic acid, 5-o-fluorobenzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo- [1,2- a] -pyrrole-1 -carboxylic acid, 5-p-Fluorobenzoyl-1,2-dihydro-6-propyl-3H-pyrrolo- [1,2a] -pyrrole-1-carboxylic acid and 5-p-bromobenzoyl-1,2-dihydro-6-butyl-3H- pyrrolo- [1,2- a] pyrrole-1-carboxylic acid.

Example 17 710 mg of a 50% strength 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 4.5 g of methyl N- (2-mesyloxymethyl) -3-carbomethoxypyrrole-2-acetate are added, the reaction mixture being stirred at -5 ° C. to 0 ° C. for 1 hour .

The mixture is then poured into ice-cold 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 made to crystallize out of ether, dimethyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylate (VII, R = H) being obtained, which with the product obtained according to Example 4 is identical.

Example 18 A 250 ml, three-necked round bottom flask equipped with an inlet and outlet nozzle suitable for dry nitrogen, a magnetic stirring rod and a pressure equalization funnel containing 10.08 g of ethanol is added dropwise with stirring with 26.1 g of dimethyl-1, 3-acetone dicarboxylate is charged within 30 minutes, the temperature being kept at less than 30 ° C. The thereby gebil DeteMethyl-3-carbomethoxymethyl-3- (2'-hydroxyethyl) aminoacrylate (III) is with 20 ml of acetonitrile and chloroacetaldehyde, which was previously obtained by heating a mixture of 27.4 g of chloroacetaldehyde diethyl acetal with 46.8 g oxalic acid dihydrate was obtained at 150 to 160 ° C., added within 2 minutes with stirring. The reaction mixture is then heated to boiling under reflux for 5 to 10 minutes, whereupon the reaction can be regarded as complete, as indicated by thin layer chromatography analysis Use of a mixture of acetone and chloroform (mixing ratio 10:90) as eluent can be determined. The solvent is then removed under reduced pressure and 250 ml of benzene and 250 ml of heptane are added to the residue and the mixture is then distilled under reduced pressure. The oily residue obtained after distillation is suspended in 50 ml of methylene chloride and the suspension is treated with 20 g of silica gel. The methylene chloride mixture is poured into a column containing 200 g of silica gel and a mixture of ethyl acetate (mixing ratio 20:80) as the eluent. The column is first filled with 6 liters of a mixture of ethyl acetate and hexane (mixing ratio 20:80) and then with 4 liters of a Mixture of ethyl acetate and hexane (50:50) eluted. Those fractions eluted with a mixture of ethyl acetate and hexane in a mixing ratio of 50:50 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.) In this way 11.89 g (32.9% of theory) of methyl N- (2'-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H) with a melting point of 51 are obtained up to 54 "C. It is the same product as that obtained according to Example 1.

Example 19 A solution of 200 mg of 5-benzoyl-1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ethereal diazomethane and the reaction mixture during Maintained at room temperature for 30 minutes. The solvents and the excess reactant are eliminated under reduced pressure and the residue is made to crystallize out from a mixture of ethyl acetate and methanol.

In this way, methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate is obtained.

In a similar way, using diazoethane and diazopropane instead of diazomethane, the 5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid ethyl ester or 5-benzoyl-1, 2-dihydro-3H-pyrrolo- [1 2- a] -pyrrole-1-carboxylic acid propyl ester.

In a similar way, the free acids obtained according to Examples 12A and 12B and the acids according to Example 16 can be converted into the corresponding methyl, ethyl and propyl esters.

Example 20 A solution of 300 mg of 5-p-toluoyl-1,2-dihydro-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid in 5 ml of isoamyl alcohol is saturated with hydrogen chloride. After 24 hours the excess alcohol is distilled off in vacuo and the residue is purified by chromatography over aluminum oxide. In this way isoamyl 5-p-toluoyl 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate is obtained.

Similarly, other esters, e.g. the pentyl, hexyl, octyl, nonyl, dodecyl esters, etc. of 5-p toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, if instead of isoamyl alcohol other alcohols, e.g. the pentyl, hexyl, octyl, nonyl or dodecyl alcohol, etc. is used.

The free acid compounds as obtained in Examples 12A and 16 are esterified with the corresponding alcohols by the same method, the following esters being obtained, for example: isoamyl-5-benzoyl-1,2-dihydro-3H -pyrrolo- [1,2-a] -pyrrol-1-carboxylate, pentyl 5-m-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrol-1-carboxylate , Hexyl 5-p-ethylbenzoyl 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate, Isoamyl-5-o-propylbenzoyl-1,2-dihydro-3H-pyrrolo- [1,2- a] -pyrrole-1-carboxylate, Octyl 5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, nonyl-5-p-isopropoxybenzoyl-1,2-dihydro-3H-pyrrolo- [ 1,2-a] -pyrrole-1-carboxylate, dodecyl-5-o -chlorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2- a] -pyrrole-1-carboxylate, isoamyl-5-m -chlorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, dodecyl-5-o-fluorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2- a] pyrrole 1-carboxylate, Hexyl 5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] - pyrrole-1-carboxylate, Nonyl 5-p-bromobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-al-pyrrole-1-carboxylate, isoamyl-5-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo - [1,2-a] -pyrrole-1-carboxylate, hexyl-5-p-ethylbenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1 -carboxylate, Nonyl 5-o-methoxybenzoyl-1,2-dihydro-6-methyl-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylate, dodecyl-5-o-fluorobenzoyl-1,2-dihydro-6 -methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, nonyl-5-benzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a ] - pyrrole-1-carboxylate, isoamyl-5-p-ethoxybenzoyl-1,2-dihydro-6-ethyi-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate, Pentyl 5-p-fluorobenzoyl-1,2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, hexyl-5-m-chlorobenzoyl-1,2-dihydro -6-butyl-3H-pyrro lo- [1,2-a] -pyrrole-1-carboxylate and Dodecyl 5-p-bromobenzoyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Example 21 To a solution of 300 mg of 5-p-toluoyl-1,2-dihydro3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of sodium hydroxide in the form of a 0.1 N 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-1-carboxylate is obtained, which is made to crystallize from a mixture of ethyl acetate and hexane can.

Similarly, other salts, e.g. produce the ammonium and potassium salts of 5-p-toluoyl-1,2-dihydro-3Hpyrrolo- [1,2-a] -pyrrole-1-carboxylic acid if ammonium hydroxide or potassium hydroxide or potassium hydroxide are used instead of sodium hydroxide.

In a similar manner, the 5-substituted 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid compounds obtained according to Examples 12A and 12B can be converted into the corresponding sodium, potassium and Transfer ammonium salts.

Examples of such compounds are the following: Sodium 5-o-toluoyl 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyr- rol- I -carboxylate, sodium 5-benzoyl-1,2-dihydro-3H-pyrrolo- [l, 2a] pyrrole 1-carboxylate, sodium (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, potassium 5-p-ethylbenzoyl-1,2-dihydro-3H-pyrrolo- [1,2- a] -pyrrole- 1-carboxylate, potassium-5-o-butylbenzoyl-1,2dihydro3 H-pyrrolo- [l, 2- a] pyrrole 1-carboxylate, Sodium 5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate, ammonium-5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo- [ 1,2-a] pyrrole 1-carboxylate, Ammonium 5-o-fluorobenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] -pyrrole-1-carboxylate, potassium-so-bromobenzoyl-1, 2-dihydro-3H-pyrrolo- [l, 2- a] -pyrrole-1-carboxylate, sodium 5-benzoyi-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate, potassium 5-toluoyl -l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2- a] -pyrrole-1-carboxylate, Ammonium 5-o-methoxybenzoyl-1,2-dihydro-6-methyl 3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, Sodium 5-p-fluorobenzoyl-1,2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate and Potassium 5-m-chlorobenzoyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Example 22 To a solution of 175 mg of 5-p-toluoyl-l, 2dihydro-3H-pyrrolo- [l, Za] -pyrrole-l-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of potassium hydroxide in the form of a 0.1 N solution is added, a solution which contains potassium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [12-a] -pyrrole-1-carboxylate. A solution of 40 mg calcium carbonate, which has been dissolved in the smallest possible amount of 1N hydrochloric acid in order to be able to dissolve the calcium carbonate, is buffered with 100 mg solid ammonium chloride, after which 5 ml of water are added Calcium solution is then added in a solution of potassium 5-p-to luoyl-1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate and the precipitate formed is collected by filtration, with water washed and dried in the air, calcium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate being obtained.

Magnesium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate is obtained in a similar manner if magnesium carbonate is used instead of calcium carbonate.

In a similar way, the corresponding calcium and magnesium salts are obtained if one 5-Benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2 -a] -pyrrole-1-carboxylic acid, 5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2a] -pyrrole- l-carboxylic acid, 5-o-methoxybenzoyl-1,2-dihydro-3H- pyrrolo- [1,2-a] pyrrole-l-carboxylic acid, 5-p-Methoxybenzoyl-1, 2-dihydro-3H-pyrrolo- [1,2-a] - pyrrole-1-carboxylic acid, 5-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid and 5-o-fluorobenzoyl-1,2-dihydro-6-ethyl- 3H-pyrrolo- [1,2- a] -pyrrole-1-carboxylic acid instead of 5-p-Toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid was used.

Example 23 To a solution of 200 mg of 5-p-toluoyl-1,2-dihydro 3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of potassium hydroxide in the form of a 0.1N Solution. The solvent is removed and the residue is dissolved in 5 ml of water. The resulting aqueous solution of potassium 5-p-toluoyl-1,2-dihydro-3H-pyrrole- [1,2-a] -pyrrole-1-carboxylate is added to a solution of 150 mg cupric nitrate trihydrate in 5 ml water. The precipitate thus formed is collected, washed with water and air-dried to give copper 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate receives.

In a similar manner, the free acid compounds as obtained in Examples 12A and 12B and Example 16 can be converted into the corresponding copper salts.

Example 24 A solution of 200 mg of 5-p-toluoyl-1,2-dihydro-3H pyrrolo- [l, Za] -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, the isopropylamine salt of 5-p-toluoyl-1,2-dihydro 3H-pyrrolo- [1,2-a] -pyrrole-1 -carboxylic acid.

Similarly, other amine salts, e.g. the diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts of 5-p-toluoyl-1,2-dihydro-3H-pyrro-1O- [1,2-a] -pyrrole-1-carboxylic acid obtained if other corresponding amines are used instead of isopropylamine.

In a similar way, the free acid compounds, as obtained according to Examples 12A and 12B and Example 16, can be converted into the corresponding isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts.

Example 25 A solution of 770 mg of 5-o-toluoyl-1,2dihydro3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid in 10 ml of benzene is treated with 580 mg of dicyclohexylamine. The reaction mixture is then stirred for 10 minutes and the solid product formed is separated off by filtration and washed with anhydrous ether, 965 mg of the dicyclohexylamine salt of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2- a] -pyrrole-1-carboxylic acid, m.p. 161 to 163 "C, is obtained.

In a similar way, the free acid compounds obtained in this way, as described in Examples 12A and 12B and the compounds according to Examples 9 and 16, can be converted into the corresponding dicyclohexylamine salts, e.g. the dicyclohexylamine salt of 5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, melting point 173 to 175 "C, convert.

Example 26 Ingredients Amount per tablet, mg 5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid 25 corn starch 20 lactose (spray-dried) 153 magnesium stearate 2 The above ingredients are mixed together thoroughly and compressed into individual, grooved tablets.

Example 27 Ingredients Amount per tablet, mg 5-benzoyl-1, 2-dihydro-3H pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid 200 corn starch 50 lactose 145 magnesium stearate 5 The above ingredients are thoroughly mixed together and compressed into individual, grooved tablets.

100 mg of (a) -5-benzoyl-1, 2-dihydro-3H-pyrrolo- [1, 2-aj-pyrrole-1-carboxylic acid are used in place of 200 mg of the (da) compound of the above composition.

Example 28 Ingredients Amount per capsule, mg sodium 5-benzoyl-1, 2-dihydro-3H-pyrrolo- [1,2-al-pyrrole-1-carboxylate 108 Lactose 15 Corn starch 25 Magnesium stearate 2 The above ingredients are mixed together and placed in gelatin capsules with a hard shell.

Example 29 Ingredients Amount per capsule, mg calcium 5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate 115 Lactose 93 Cornstarch 40 Magnesium stearate 2 The above ingredients are mixed together and introduced into hard-walled gelatin capsules.

Example 30 Ingredients Amount per tablet, mg isopropylammonium-5-benzoyl 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate 245 corn starch 75 lactose 175 magnesium stearate 5 The above ingredients are intimately mixed with one another and pressed into individual, notched tablets.

Example 31 Ingredients Amount per capsule, mg 5-Benzoyl-1, 2-dihydro-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid methyl ester 25 Lactose 125 The above ingredients are mixed together and placed in a hard shell gelatin capsule labeled No. 1.

Example 32 Ingredients Amount per tablet, mg 5-Benzoyl-1, 2-dihydro-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid '300 Sucrose 300 The above ingredients are thoroughly mixed together and made into individual, grooved tablets.

Example 33 Ingredients Amount per tablet, mg isoamyl-5-benzoyl-1, 2-dihydro3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylate 254 Corn starch 50 Lactose 190 Magnesium stearate 6 The above ingredients are thoroughly mixed together and compressed into individual, grooved tablets.

Example 34 Ingredients Quantity per capsule, mg 5-Benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole 1 -carboxylic acid 100 Lactose 148 Dextrose 2 The above ingredients are mixed together thoroughly and introduced into hard shell gelatin capsules.

50 mg of (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrol-1-carboxylic acid are used instead of 100 mg of the (d0 compound of the above preparation added.

Example 35 Ingredients Amount per capsule, mg methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo- [l, 2a] -pyrrole-1-carboxylate 158 lactose 92 The above ingredients are mixed together and placed in hard shell gelatin capsules.

Example 36 Ingredients Quantity per tablet, mg isoamyl-5-benzoyl-1,2dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate 127 lactose 91 corn starch 25 Magnesium stearate 2 gelatin 5 The above-mentioned ingredients are mixed together and compressed into individual, notched tablets.

Example 37 Ingredients Amount per tablet, mg calcium 5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a-pyrrole-1 carboxylate 230 corn starch (paste) 40 corn starch 50 magnesium stearate 2 lactose 178 The above ingredients are thoroughly mixed together and compressed into individual, grooved tablets.

Example 38 Ingredients Amount per tablet, mg sodium 5-benzoyl-1, 2-dihydro-3H-pyrrolo- [1-pyrrole- 1-carboxylate 217 corn starch 50 magnesium stearate 2 gelatin 226 lactose 5 The above ingredients are thoroughly mixed together and compressed into individual, grooved tablets.

Example 39 Ingredients Amount per capsule, mg isopropylammonium-5-benzoyl 1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylate 122 Corn starch 30 Lactose 98 The above ingredients are mixed together and placed in hard shell gelatin capsules.

Example 40 Ingredients Amount per capsule, mg isoamyl-5-benzoyl-1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole 1-carboxylate 32 lactose 101 corn starch 15 magnesium stearate 2 The above ingredients are mixed together and placed in hard shell gelatin capsules.

Example 41 An injectable preparation of the following composition, buffered to a pH of 7, is prepared: 5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole 1-carboxylic acid 0.2 g of K2HPO4 buffer (0.4 molar solution) 2 ml 1 n-KOH q.s. up to pH 7 water (dist. sterile) q.s. Up to 20 ml 0.1 g (1) -5-benzoyl-1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyr- rol-1-carboxylic acid are used instead of 0.2 g of (dl ) Compound of the above composition is used.

Example 42 A total of 2.8 g of suppository is prepared with the following composition: 5-Benzoyl-1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid 25 mg Witepsol H-15 (triglycerides of saturated , vegetable fatty acids; product of Riches-Nelson, Inc., New York, NY) rest 12.5 mg of (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] - pyrrole-1-carboxylic acid is used in place of the 25 mg of the (dl) compound of the above composition .

Example 43 An oral suspension for pediatric use of the following composition is prepared: 5-Benzoyl-1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid 0.1 g fumaric acid 0.5 g sodium chloride 2, 0 g methyl paraben 0.1 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g taste-correcting agent 0.035 ml coloring agent 0.5 mg dist. Water q.s. up to 100 ml 0.05 g of (e) -5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] - pyrrole-1-carboxylic acid are used instead of 0.1 g of the (dA;) compound of Composition according to Example 44 used.

Examples 44 and 45 For veterinary use, the following powder is composed: Example 44 Example 45 5-Benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-carboxylic acid 0.1 g 1.2 g sucrose 5.7 g 3.7 g polyvinylpyrrolidone 0.3 g 0.3 g 0.05 g of (Q) -5-benzoyl-1, 2-dihydro-3H-pyrrolo- [1, 2-a] -1-carboxylic acid are used instead of 0.1 g of the (dS) compound of the composition according to the example 44 used.

0.6 g of (R) -5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrol-1-carboxylic acid are used instead of the 1.2 g of the (ddt) compound the composition of Example 45 was used.

Biological data A. Testing for analgesic effects (mouse; torso twist) Carrying out the test: The test material is administered orally in an aqueous vehicle by means of a gastric tube to male Swiss-Webster mice weighing 18 to 20 g.

After 20 minutes, 0.25 ml of a 0.02% solution of phenylquinone is injected intraperitoneally. The solution causes torso twisting or convulsions. The animals are observed for their contortions and twists for the next 10 minutes.

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

Using the above procedure, it is found that 5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid is approximately 430 times the analgesic effect of aspirin and () -5- ( Benzoyl) - 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrol-1-carboxylic acid have 700 times the analgesic effect of aspirin.

B. Acute oral toxicity test (LD50) on mice Procedure mode: The test material is suspended in a carrier containing aqueous carboxymethyl cellulose as a suspending agent. The concentrations are adjusted so that the dosages 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 a gastric tube in amounts of 200 mg, 400 mg, 800 mg or 1200 mg 5- (benzoyl) -1,2-dihydro-3H pyrrolo- [1,2-a] -pyrrole- 1 -carboxylic acid administered. The fifth group of mice is used as a control group. After the administration, the mice are observed for 3 weeks.

If one proceeds in the aforementioned manner, the acute, oral LD 50 value for 5- (benzoyl) -l, 2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylic acid is approximately 200 mg / kg.

Claims (38)

PATENT CLAIMS 1. Compounds of the general formula: and the individual (0-acid isomers and (d) -acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof, wherein R is hydrogen or a lower alkyl radical having 1 to 4 carbon atoms and R is hydrogen atom, a lower alkyl radical having 1 to 4 carbon atoms, a lower alkoxy radical with 1 to 4 carbon atoms, the chlorine atom, fluorine atom or bromine atom. 2. Compounds according to claim 1, characterized in that R is the hydrogen atom. 3. Compounds according to claim 1, characterized in that R denotes the methyl radical. 4. As a compound according to claim 2, the 5-benzoyl-1,2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid. 5. As a compound according to claim 2, the isopropyl ester of 5-benzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid. 6. As a compound according to claim 2, the 5-o-toluoyl-1,2dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid. 7. As a compound according to claim 2, the isopropyl ester of 5-o-toluoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid. 8. As a compound according to claim 2, the 5-m-toluoyl-1,2 dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. 9. As a compound according to claim 2, the isopropyl ester of 5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. 10. As a compound according to claim 2, the 5-p-Toluoyl1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole- carboxylic acid. 11. As a compound according to claim 2, the isopropyl ester of 5-p-toluoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid. 12. As a compound according to claim 2, the 5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. 13. As a compound according to claim 2, the isopropyl ester of 5-p-methoxybenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] -pyrrol-1-carboxylic acid. 14. As a compound according to claim 2, the 5-o-chlorobenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid. 15. As a compound according to claim 2, the isopropyl ester of 5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrol1-carboxylic acid. 16. As a compound according to claim 2, the 5-m-chlorobenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid. 17. As a compound according to claim 2, the isopropyl ester of 5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylic acid. 18. As a compound according to claim 2, the 5-p-chlorobenzoyl-1, 2-dihydro-3H-pyrrolo [l, 2-a] pyrrole-1-carboxylic acid. 19. As a compound according to claim 2, the isopropyl ester of 5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid. 20. As a compound according to claim 2, the 5-p-fluorobenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid. 21. As a compound according to claim 2, the isopropyl ester of 5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2a] pyrrole-l-carboxylic acid. 22. As a compound according to claim 2, the 5-o-fluorobenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid. 23. As a compound according to claim 2, the isopropyl ester of 5-o-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylic acid. 24. As a compound according to claim 2, the 5-p-ethoxybenzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid. 25. As a compound according to claim 3, the 5-p-fluorobenzoyl-1, 2-dihydro-6-methyl-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid. 26. As salts according to claim 1, the sodium, potassium or calcium salts of the compounds of the formula A. 27. As the salt according to claim 26, the sodium salt of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. 28. As the salt according to claim 26, the sodium salt of 5-p fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid. 29. The (I) acid isomers of the formula A according to claim 1. 30. As a compound according to claim 29, the (1) -5-benzoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid. 31. As a compound according to claim 29, the (1) -5-p-fluoro benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1 - carboxylic acid. 32. As salts according to claim 1, the sodium, potassium or calcium salts of the (l) acid isomers of the formula A. 33. As the sodium salt according to claim 32, the sodium salt of (l) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. 34. As the sodium salt according to claim 32, the sodium salt of (i) -5-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1 2- a] pyrrole-1-carboxylic acid. 35. As the salt according to claim 1, the dicyclohexylamine salt of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. 36. As a salt according to claim 1, the dicyclohexylamine salt% of 5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid. 37. Preparation for the treatment of inflammation, pain or pyrexia in mammals and humans, characterized in that it consists essentially of a pharmaceutically acceptable, non-toxic drug carrier and a therapeutically effective amount of a compound of the formula A according to claim 1 or one (I) Acid isomer thereof or a pharmaceutically acceptable, non-toxic ester or salt thereof. 38. Preparation for administration to pregnant women and pregnant animals to delay labor, characterized in that it consists essentially of a pharmaceutically acceptable, non-toxic drug carrier and a therapeutically effective amount of a compound of the formula A according to claim 1, one of (I) - Acid isomer thereof or a pharmaceutically acceptable, non-toxic ester or salt thereof. The present invention relates to new 5-aroyl 1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acids of the formula: ** WARNING ** End of CLMS field could overlap beginning of DESC **.