PL124445B1 - Process for preparing novel derivatives of pyrrole-1-carboxylic acid - Google Patents

Description

The invention relates in particular to a method for preparing new 5-arylcarbonyl-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylic acids of the formula I, wherein R is a hydrogen atom or a lower alkyl radical with 1-4 carbon atoms, R1 is a hydrogen atom, a lower alkyl radical with 1-4 carbon atoms, a lower alkoxy group with 1-4 carbon atoms or a chlorine, fluorine or bromine atom, substituted in the ortho, meta or para position of the arylcarbonyl ring substituent, and their isomers (1) and (d) as well as their pharmacologically non-toxic salts and new intermediates in their synthesis. The new compounds, with the exception of the (d) acid isomer and related compounds, possess anti-inflammatory, sedative, and antipyretic properties and are therefore useful in the treatment of inflammatory, painful, and febrile conditions in mammals, as described in detail below. They also have utility as smooth muscle relaxants. The term "pharmacologically acceptable, non-toxic esters and salts" in this specification means "alkyl esters"—branched-chain or straight-chain hydrocarbon derivatives of 1-12 carbon atoms and salts of pharmaceutically acceptable, non-toxic inorganic or organic bases. Typical alkyl esters are, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isoamyl, pentyl, isopenyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl and dodecyl esters. Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, ferrous, manganous and the like salts. Ammonium, potassium, sodium, calcium and magnesium salts are particularly preferred. Salts derived from pharmaceutically acceptable, non-toxic organic bases include salts of primary, secondary, and tertiary substituted amines, including naturally occurring compounds, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylamine, tri(hydroxymethyl)aminomethane, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- -ethylpiperidine, polyamine resins and the like. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tris(hydroxymethyl)aminomethane, dicyclohexylamine, choline and caffeine. The new compounds of formula I exist in the form of pairs of optical isomers (or enantiomers), i.e. mixtures (dl). However, each optically active isomer as well as mixtures (dl) thereof are within the scope of the invention. Due to their physiological properties, i.e. anti-inflammatory, soothing and antipyretic, a preferred subgroup consists of compounds of formula I and their isomers (l), their pharmacologically acceptable esters and salts. A particularly preferred subgroup within this group consists of acids, esters and salts in which R and R 1 are both hydrogen atoms. The (d) isomers of the acids of formula I and their pharmacologically acceptable esters and salts are useful as intermediates in the synthesis of racemic mixtures of acids (dl) of formula I, which are described in more detail below. The new compounds (dl) are prepared by the process according to the invention by hydrolysis of the ester of formula Il. In formulas I-10 appearing in this scheme, R and R 1 have the meanings given above, and R 2 is a lower alkyl radical having 1-4 carbon atoms, e.g., methyl, ethyl, isopropyl or n-butyl, or a hydrogen atom. The starting materials used in the process according to The invention is prepared by the reactions shown in Scheme 1 to obtain the final product. In these reactions, ethanolamine is first treated with equimolar amounts of acetonedicarboxylic acid-1,2-dimethyl ester of formula II, to obtain a solution of vinylamine of formula III, which is preferably treated, without isolation from the reaction mixture, with 2-bromoacetaldehyde or 2-chloroacetaldehyde in an inert solvent under anhydrous conditions to obtain a compound of formula IV, wherein R is hydrogen. Compounds of formula IV, wherein R is a lower alkyl radical, are prepared by treating an aqueous mixture of ethanolamine and acetonedicarboxylic acid-1,3-dimethyl ester with the known compound of formula R3COCH2X, wherein X is bromine or chlorine and R3 is a lower alkyl radical. The compound of formula 4 is then esterified with methanesulfonyl chloride in the presence of a tertiary amine and optionally a cosolvent, e.g., dichloromethane, to give the mesylate of formula 5, which is converted to the corresponding N-(2-iodoethyl)-pyrrole of formula 6 by treatment with sodium iodide in acetonitrile at reflux. Treatment of the compound of formula 6 with sodium hydride in an inert solvent gives compounds of formula 7. Alternatively, compounds of formula 7 can be obtained by direct cyclization of the mesylate of formula 5 with sodium hydride in dimethylformamide. Basic hydrolysis of the compound of formula 7 by alkali metal hydroxide or carbonate in an aqueous lower aliphatic alcohol gives the diacid of formula 8 or its 6-? The carboxyl group at C-1 of the compound of formula 8 is then selectively esterified by treatment with a lower aliphatic alcohol in the presence of hydrogen chloride to give the corresponding 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-7-alkoxycarbonyl acid of formula 9. Decarboxylation of the monoester of formula 9 to the corresponding compound of formula 10, i.e. the key starting material in the synthesis according to the invention, is carried out by heating the compound of formula 9 at a temperature of 230-280°C for a time sufficient for the complete reaction to take about 45-90 minutes. Condensation of the compound of formula 10 with the amide of formula 12, in which R1 has a higher The above-mentioned meaning gives the corresponding 5-arylcarbonyl-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylic acid alkyl ester of formula XI, wherein R* denotes a lower alkyl group. These reactions are carried out in an inert, protic, organic solvent, in the presence of phosphorus oxychloride, at the reflux temperature of the reaction mixture for about 1-175 hours in an inert atmosphere, followed by heating for about 2-10 hours at reflux in the presence of sodium acetate. Alternatively, another acid chloride such as phosgene or oxalyl chloride may be used instead of phosphorus oxychloride. In a preferred embodiment, the above condensation is carried out by adding a solution of the compound of formula (XI) in a suitable solvent to a refluxing mixture of 1.1 to 5 molar equivalents of the amide and phosphorus oxychloride in the same solvent. The resulting mixture is heated under reflux for about 6-72 hours under argon, then 3-10 molar equivalents of sodium acetate are added and reflux is continued for another 4-6 hours. Suitable solvents for this reaction include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, and the like, dimethoxyethane, and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane. Suitable N,N-dimethylarylamides are, for example, N,N-dimethylbenzamide, N,N-dimethyl-o-toluamide, N,N-dimethyl-m-toluamide, N,N-dimethyl-p-toluamide, N,N-dimethyl-p-ethylbenzamide, N,N-dimethyl-o-propylbenzamide, N,N-dimethyl-m-butylbenzamide, N,N-dimethyl-o-methoxybenzamide, N,N-dimethyl-m-methoxybenzamide, N,N-dimethyl-p-ethoxybenzamide, N,N-dimethyl-55 -p-isopropoxybenzamide, N,N-dimethyl-o-chlorobenzamide, N,N-dimethyl-m-chlorobenzamide, N,N-dimethyl-p-chlorobenzamide, N,N-dimethyl-o-fluorobenzamide, N,N-dimethyl-p-fluorobenzamide N,N-dimethyl-m-bromobenzamide and N,N-dimethyl-60 lo-p-bromobenzamide. The above amides are known compounds, commercially available or obtainable by conventional methods from the corresponding acids, e.g. by conversion of the acid to an acid chloride and subsequent treatment with dimethylamine. Base hydrolysis of the ester group of the new compound of formula (XI) gives the corresponding free acid of formula (I). The above hydrolysis is carried out by conventional methods, using an alkali metal hydroxide or carbonate, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and the like, in an aqueous lower aliphatic alcohol, e.g. methanol, ethanol, and the like, at room temperature to reflux temperature. The reaction is carried out for about 15 minutes to about 2 hours in an inert atmosphere. Hydrolysis is preferably carried out with an aqueous methanolic solution of potassium carbonate at reflux temperature for about 30 minutes. Compounds of formula 1 can be separated into their individual optical isomers by known methods. Isomers of acid (1) and acid (d) of formula 1 can be obtained by known high-pressure liquid chromatography (HPLC) techniques and their diastereomeric α-phenethyl esters, followed by acidic cleavage. For example, compounds of formula 1 in which R and R* are hydrogen atoms can be further processed according to Scheme 2. The free acids of formula 1 can be converted into other alkyl esters with an alkyl radical of 1-12 carbon atoms. Conventional methods are used for this purpose, e.g. (a) treatment with an alcohol corresponding to the desired ester in the presence of a strong mineral acid, (b) treatment with an ethereal solution of a diazoalkane, or (c) treatment with an alkyl iodide in the presence of lithium carbonate. The isomers of acids (1) can be converted into alkyl esters by methods (b) and (c) as defined above. Salts of compounds of formula I and their acid isomers (1) are obtained by treating the free acids with a suitable amount of a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, ammonium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, manganous hydroxide, aluminum hydroxide, ferric hydroxide, manganous hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tri-(hydroxymethyl)aminomethane, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, Betaine, ethylenediamine, glucosamine, methylglucamine, theobramine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. The reactions are carried out in water, neat or mixed with an inert, water-miscible organic solvent, at a temperature of about 0°C to 100°C, preferably at room temperature. Typical water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane, and tetrahydrofuran. The molar ratio of the compound of formula 1 or its acid isomer (1) to the base is selected to obtain a value corresponding to the proportion of both components in the desired salt. In order to obtain, for example, the calcium or magnesium salt of the compound of formula 1 or its acid isomers (1), the starting material in the form of the free acid is treated with at least half a molar equivalent of a pharmaceutically acceptable base, thus obtaining a neutral salt. In order to obtain a neutral aluminum salt, the starting acid is treated with at least one-third of a molar equivalent of a pharmaceutically acceptable base. In a preferred embodiment of the process according to the invention, magnesium or calcium salts of the compounds of formula I or their isomers of acid (1) are obtained by treating the corresponding sodium or potassium salts of these compounds with at least one-half of a molar equivalent of magnesium chloride or calcium chloride in aqueous solution or in a mixture of water with a neutral, water-miscible organic solvent at a temperature of about 20°C to 100°C. The aluminum salts are obtained by sieving. preferably by treating the corresponding free acid with at least one-third molar equivalent of an aluminum alkoxide, such as aluminum triethanolate, aluminum tripropoxide, and the like, in a hydrocarbon solvent such as benzene, xylene, cyclohexane, and the like, at a temperature of about 2°C to 115°C. Salts of inorganic bases of limited solubility can be prepared by similar methods. Isolation of the described compounds can be accomplished by any suitable method, e.g., extraction, filtration, evaporation, distillation, crystallization, thin layer chromatography, column chromatography, high pressure liquid chromatography (HPLC), or combinations thereof. Methods of isolation are described in the examples below. In addition to those described, other equivalent isolation methods can, of course, be used. The isomers of acids (d) are not used as drugs per se. However, they can be converted into pharmaceutically acceptable, non-toxic esters and salts by the methods described for the isomers of acids (1). The compounds of formula 1, the isomers of acid (1), and their pharmacologically acceptable, non-toxic esters and salts of these acids are useful as anti-inflammatory, soothing, platelet aggregation-inhibiting, and fibrinolytic agents, and as smooth muscle relaxants. They can be used prophylactically and therapeutically. Compositions containing the above compounds are useful in the treatment and relief of inflammation, such as inflammation of the musculoskeletal system, skeletal joints and other tissues, for example in the treatment of inflammatory conditions such as rheumatoid arthritis, shock, cuts, arthritis, bone fractures, post-traumatic conditions, and gout. In cases where the above conditions are accompanied by pain and fever combined with inflammation, the compounds in question are useful in the relief of both these conditions and the inflammation. Active compounds of formula 1 or their acid isomers (1) and their pharmacologically acceptable, non-toxic esters and salts. In a suitable pharmaceutical composition, the active substances can be introduced in any way accepted for introducing agents treating inflammation, pain or fever or for prophylactic purposes. Thus, they can be introduced orally, parenterally or topically, in the form of solid, semi-solid or liquid dosage forms, e.g. tablets, suppositories, pills, capsules, powders, solutions, suspensions, emulsions, creams, lotions, ointments and the like, preferably in unit dose form enabling simple administration of a specific amount of the active ingredient. The compositions comprise a conventional pharmaceutical carrier or filler and an active compound of formula I or its acid isomer (1) and a pharmacologically acceptable, non-toxic ester or salt and optionally another therapeutic agent, pharmaceutical agent, additional carriers, adjuvants, etc. A preferred method of using the compounds for the above-described conditions is oral administration at a convenient daily schedule, adapted to the degree of the condition. As a rule, a daily dose of 25-500 mg of the active compound of formula I or its acid isomer (1) and a pharmacologically acceptable, non-toxic ester or salt thereof is used. In most cases, a suitable dose is 0.5-6 mg/kg of body weight per day. For oral administration, a pharmaceutically acceptable, non-toxic composition is prepared with a conventional carrier such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate, etc. Such compositions may take the form of solutions, suspensions, tablets, pills, capsules, powders, time-release formulations, and the like. The active compounds of formula (I) or their acid isomers (I) and their pharmacologically acceptable, non-toxic esters and salts may be formulated as suppositories using polyalkylene glycols such as polypropylene glycol as the carrier. Liquid pharmaceutical compositions can be prepared, for example, by dissolving or suspending an active compound such as that described above and, optionally, a pharmaceutical adjuvant in a carrier such as water, saline solution, glucose solution, glycerin, ethanol, etc. If desired, the pharmaceutical compositions may also contain non-toxic auxiliary substances such as wetting or emulsifying agents, buffers, etc., e.g., sodium acetate, sorbitan monolaurate, triethylamine oleate, etc. Methods for preparing such pharmaceutical forms are known to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, Meck Publishing Company, Easton, Pennsylvania, 14th Edition, 1970. In each case, the suspension compositions to be administered are preferably administered in a liquid form. The active ingredient is administered in an amount effective for the condition in question, in accordance with the instructions given in this specification. The compounds of formula 1 and their isomers of acid (1) and their pharmacologically acceptable non-toxic esters and salts have a relaxing effect on the smooth muscles of the uterus and are therefore useful as agents maintaining pregnancy in mammals, to the benefit of the mother and/or the fetus, until termination of pregnancy is favorable or more favorable from a medical point of view for the mother and/or the fetus. It should be understood, however, that in certain cases, e.g. when labor has already begun (when the mother experiences uterine contractions, especially when the term of pregnancy is approaching), administration of the described compounds may not maintain the pregnancy indefinitely. In these cases, pregnancy will most likely be somewhat "prolonged", which may be beneficial for the mother and/or the fetus. In particular, the compounds of formula 1 and their acid isomers (1) and their pharmacologically acceptable non-toxic esters and salts are used especially as agents delaying the onset of labor. In the present description, this term means the delay of labor induced by the administration of compounds of formula 1 or their acid isomers (1) and their pharmacologically acceptable esters or salts at any time before the onset of uterine contractions. Thus, it applies both to the prevention of miscarriage in the early stages of pregnancy (i.e. before the fetus becomes viable) and to the delay of the onset of premature labor pains later in pregnancy, when the fetus is already viable. In each of these cases, the compounds obtained by the method according to the invention are administered prophylactically to prevent premature labor. Administration of the compounds is particularly advisable in the case of women who have had a history of spontaneous abortion or premature labor (i.e. before the full term of pregnancy has elapsed). It is also recommended in those clinical cases when there are indications that pregnancy may be terminated prematurely and its prolongation is beneficial for the mother and/or the fetus. In animals, the administration of the described compounds can be used to synchronize parturition in a group of pregnant animals, in order to carry them out at the same time or at a desired time and/or place when the parturition is easier to achieve. The expression "postponement of parturition" in the present description means the postponement induced by the administration of compounds of formula 1 or their acid isomers (1) and their pharmacologically acceptable, non-toxic esters or salts, before the onset of uterine muscle contractions. The results of their use are influenced by the condition of the patient, also during the period of pregnancy in which contractions occur, the intensity of contractions and their duration. For example, this may result in a reduction in the intensity and/or duration of contractions ("prolongation" of the actual time of labor) or in a complete cessation of contractions. In each of these cases, the effect is to prolong the period of pregnancy, although, depending on the condition of the patient, as described above, the effect may be weak or, under appropriate circumstances, slightly greater. Such administration may prevent spontaneous abortion, facilitate labor and/or make it less painful for the mother, or cause labor to occur at a more appropriate time and/or place. / In each case, administration of compounds of formula 1 or their acid isomers (1) and their 10 15 20 25 30 35 40 45 50 55 60124 445 9 pharmacologically acceptable, non-toxic esters or salts, for the purposes indicated above, should be in accordance with best and/or accepted medical (or veterinary) practice to achieve the greatest benefit to the mother and/or fetus. For example, pregnancy should not be prolonged to the point of fetal death in utero. A therapeutically effective dose of the compound of formula 1 or its acid isomer (1) and the pharmacologically acceptable, non-toxic ester or salt and pharmaceutical compositions containing them are administered to the pregnant mammal by any usual and accepted method. These compounds may be administered singly or in combination with another compound or compounds as hereinbefore indicated or with other pharmaceutical agents, carriers, adjuvants, etc. Such compound(s) or compositions may be administered orally or parenterally, in solid, semi-solid, or liquid form. Typically, pharmaceutical compositions are employed which comprise the active compound and one or more pharmaceutical carriers or adjuvants. The pharmaceutical compositions may be in the form of oral tablets, vaginal or intrauterine tablets or suppositories, pills, capsules, liquid solutions, suspensions, or the like, preferably in unit dosage forms, enabling simple dosing of predetermined amounts of the active compound. As conventional non-toxic solid carriers there are used, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. The active compound as described above may be formed into suppositories using, for example, polypropylene glycol as a carrier. Liquid pharmaceutical compositions may be prepared, for example, by dissolving, suspending, etc., the active compound as described above and, optionally, a pharmaceutical adjuvant in a carrier such as water, saline, aqueous glucose, glycerin, ethanol and the like. If desired, the pharmaceutical composition may also contain a minor amount of a non-toxic auxiliary substance such as a wetting agent or emulsifying agent, pH buffering agent, and the like, e.g., sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. Methods for preparing such unit doses are known, see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing, Company, Paston, Pennsylvania, 14th edition 1970. The compositions or preparations contain the active compound(s) in an amount effective to delay the onset of labor or to be sufficient to induce labor if uterine contractions have already begun. A daily dose of about 0.5-25 mg of active compound per kilogram of body weight is usually used, administered as a single dose or divided into 3 or 4 smaller doses administered regularly throughout the day. The amount of active compound administered depends, of course, on its relative activity. Tests illustrating the properties of the compounds produced by the method of the invention are presented below. Male Swiss-Webster mice weighing 18-20 g are administered the test material orally in an aqueous vehicle at time 0. After 20 minutes, 0.25 ml of a 0.02% phenylquinone solution is injected intraperitoneally, which causes the animals to writhe in pain (spasms). The animals are observed for the next 10 minutes. The number of mice undergoing spasms and the average number of spasms per mouse are recorded. In the above test, the analogous activity of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid exceeds the analgesic activity of aspirin by about 430 times, and the analgesic activity of (1)5-benzoyl-1,2-dihydro-3H-pyrrolo{1,2-a]pyrrole-1-carboxylic acid is greater than the analgesic activity of aspirin by about 700 times. B. Acute toxicity by oral administration to mice (LD50). The test material is suspended in an aqueous solution of carboxymethylcellulose. Concentrations are selected so that the intended doses can be administered in a volume of 10 ml/body weight. Five groups of male Swiss-Webster mice, 6 animals per group (one group serves as a control), are used. Single oral doses of 200, 400, 800 or 1200 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid per kg of body weight are administered via a stomach tube. The LD50 value of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid determined in the above manner is approximately 200 mg/kg. The subject of the invention is illustrated by the examples below. The abbreviation t.l.c. denotes thin-layer chromatography, and the composition of liquid mixtures is given in volume proportions. Unless otherwise stated, reactions were carried out at room temperature (20-30°C). Example 1. A solution of 336 mg of 5-p-toluyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid isopropyl ester in 10 ml of methanol was treated with a solution of 690 mg of potassium carbonate in 5 ml of water. The reaction mixture, maintained under a nitrogen atmosphere, was heated to reflux for 30 minutes, cooled, and evaporated to dryness. The residue was dissolved in 10 ml of 10% aqueous hydrochloric acid and 50 ml of water, and the resulting mixture was extracted with ethyl acetate (2 x 50 ml). The combined extracts were dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate-hexane gave 238 mg (89%) of 5-p-toluyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (compound of formula (1, R = H, R1 = p-CH3), melting at 182-183°C. Example 2. A solution of 250 mg of 5-p-toluyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid isopropyl ester in 8 ml of methanol, maintained under nitrogen, was treated with a solution of 200 mg of sodium hydroxide in 1 ml of water, maintaining the reaction mixture for 1.5 minutes. hours at room temperature. The methanol was removed under reduced pressure, and the remaining basic solution was diluted with 5 ml of water and extracted with ether to remove the unsaponifiable product. The aqueous solution was acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts were dried and evaporated under reduced pressure to dryness, and the residue was recrystallized from ethyl acetate-hexane to obtain 5-p-toluyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, identical to the product obtained according to Example I. Example III. After hydrolytic cleavage By removing the isopropyl ester group, the corresponding free acids are obtained by the methods of Examples 1 or 2, namely: 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, melting point 160-161°C, 5-o-toluyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, in the form of an oil with the following physical constants: UV spectrum (MeOH): Amax 253, 307 nm (e 3310, 16980), IR spectrum (CHCl3): vmax 1720, 1620 cm-1, nuclear magnetic resonance spectrum (CDCl3, TMS): 6 2.32 (d. 3H, CH3), 2.53—3.03 (m, 2H, H-2), 3.97 (dd, 1H, H-l), 4.17^1.67 (s, 2H, H-3), 6.92 (d, 1H, H-7), 6.40 (d, 1H, H-#, 6.83—7.37 (m, 4H, phenyl protons), 8.60 (broad s, 1H, COOH), ppm 5-m-toluyl-1,2-dihydro-3H-pyrrolo-1, 5-p-ethylbenzoyl-1,2-dihydro-3H-pyrrole acid. [1,2-a]pyrrolocarboxylic acid-1, acid 5-o-propylbenzoyl-1,2-dihydrogen-3H-pyrrolo[1,2-a]pyrrolocarboxylic-1, 5-m-butylbenzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrolocarboxylic acid-1, 5-o-methoxybenzoyl-1 ,2-dihydrogen-3H-pyrrolo[l,2-a]pyrrolocarboxylic-1, 5-p-methoxybenzoyl-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrolocarboxylic-1, melting point 187-187.5°C, acid 5-p-ethoxybenzoyl-1,2-dihydro-3H-pyro- lo-[l,2-a]pyrrolecarboxyl-l with a melting point of 169.5-170°C. 5-p-isopropyxybenzoyl-1,2-dihydro-3H-pyrrolo[l,2-a]pyrrolocarboxylic acid, 5-o-chlorobenzoyl-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrolocarboxylic acid with the following physical constants: ultraviolet spectrum (MeOH): ^inax 250, 307.5 nm (e 4300, 17400), infrared spectrum (CHCl3) vmax 1715, 1620 cm-1, nuclear magnetic resonance spectrum (CDC13, TMS): <5 2.60—3.15 (m, 2H, H-2), 4.02 (dd, 1H, JAX = 6 Hz, JBi = 7 Hz, H-l), 4.20^.70 (m, 2H, H-3), 5.98 (d, 1H, J = 4 Hz* H-7), $.42 (d, 1H, J = '( Hz, H-6), 7.00—7.77 (m, 4H phenyl protons), 8.67 (s, (broad), 1H, COOH). 5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrole-[1,2-a]pyrrolecarboxylic acid, m.p. 180-181°C. 5-p-chlorobenzoyl-1,2-dihydro-3H-pyro- 1-[1,2-a]pyrrole-1-carboxylic acid, melting point 201.5-202.5°C, 5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid, melting point 179.5-180.5°C. Example 4. A solution of 500 mg of 5-p-toluyl-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid isopropyl ester 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 boiled under reflux for 30 minutes. The mixture was cooled under reflux under nitrogen and evaporated to dryness. The residue was dissolved in 10 ml of 10% aqueous hydrochloric acid and 50 ml of water and the resulting mixture was extracted with ethyl acetate (3 x 50 ml). The combined extracts were dried over magnesium sulfate and evaporated under reduced pressure to dryness, yielding 5-p-toluyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrolecarboxylic acid (compound of formula I, R = CH3, R1 = p-CH3). In a similar manner to that described above, or alternatively by the hydrolysis described in Example II, other isopropyl esters were converted to the corresponding free acids, i.e. 5-benzoyl-1,2- -dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, melting point 169°C, 5-p-methoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, melting point 182°C, 5-p-chlorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, melting point 204°C, 5-p-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, melting point 204°C, 5-(4-fluorobenzoyl)-1,2-dihydro-6-ethyl-3H-pyrrolo[17-a]pyrrole-1-carboxylic acid, melting point 196°C. Example 5. To a solution of 300 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 25 ml of dry benzene is added 0.58 g of trifluoroacetic anhydride. The mixture is stirred for 10 minutes at room temperature. The resulting solution is cooled to 0-5°C and immediately 1.4 g of dry triethylamine is added, followed immediately by 0.5 g of α-phenylethyl alcohol. The solution thus obtained The reaction mixture was stirred for 15 minutes at room temperature and poured into 20 ml of water containing 1 ml of triethylamine, then extracted with ethyl acetate. The extract was dried over sodium sulfate and the solvent and excess (1)-α-phenylethyl alcohol were removed under reduced pressure, to obtain 0.42 g of a mixture of (1)-α-phenethyl esters (1) and (d)-5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-α]pyrrole-1-carboxylic acid. The mixture was separated by high-pressure liquid chromatography (using 4% EtOAc) on a Lichrosord S1-60 column, 11 mm X 50 cm, 10 µm. 180 mg of the more polar ester (α⋅EOH -145.7°C) and 178 mg of the less polar ester (α⋅EOH +128.6°C) were obtained. 148 mg of the more polar ester were dissolved in 8 ml of dry benzene. The solution was cooled to 15-20°C, 5 ml of trifluoroacetic acid was added and the solution was stirred at room temperature for 70 minutes. The solution was then poured into 60 ml of dry benzene and the solvents were removed under reduced pressure at room temperature. Purification was carried out by high-pressure liquid chromatography (using the column as described above and replacing 4% EtOAc (hexane) with 0.5% acetic acid). 13, 63 mg of L-5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrolecarboxylic acid, having a D s of -153.7° and a melting point of 153-155°C, is obtained. Cleavage of the less polar ester, carried out in a similar manner, gives 85 mg of (d)-5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrolecarboxylic acid, having a D s of +153.7° and a melting point of 153-155°C. The isomer of acid (d) thus obtained can, if desired, be racemized and recycled by known methods. In a similar manner, mixtures (dl) of other isomers can be separated into pure isomers 1 and d. 1. A method for the preparation of new pyrrolecarboxylic acid derivatives of the formula 1, wherein R is a hydrogen atom or a lower alkyl radical with 1-4 carbon atoms, R1 is a hydrogen atom or a lower alkyl radical with 1-4 carbon atoms, a lower alkoxy group with 1-4 carbon atoms or a chlorine, fluorine or bromine atom substituted in the ortho, meta or para position of the arylcarbonyl ring substituent, and their pharmacologically non-toxic salts, characterized in that the new ester of the formula 11, wherein R1 and R have the above-mentioned meaning and R2 is a lower alkyl group with 1-4 carbon atoms, is subjected to hydrolysis and the resulting compound of the formula 1, wherein R and R1 have the above-mentioned meaning, is converted into a pharmacologically non-toxic salt. 2. A method for preparing new derivatives of pyrrolecarboxylic acid-1 of the formula 1, wherein R is a hydrogen atom or a lower alkyl radical with 1-4 carbon atoms, R1 is a hydrogen atom or a lower alkyl radical with 1-4 carbon atoms, a lower alkoxy group with 1-4 carbon atoms, or a chlorine, fluorine or bromine atom substituted in the ortho, meta or 'para' position of the arylcarbonyl ring substituent, and their pharmacologically non-toxic salts, characterized in that the new ester of the formula 11, wherein R11 and R2 have the above-mentioned meaning, and R2 is a lower alkyl group with 1-4 carbon atoms, is subjected to hydrolysis and the resulting acid is separated into corresponding isomers, racemizes the acid isomer (d) and optionally converts the product to a pharmacologically acceptable salt.124 445 R 1/£CON(CH32 FORMULA 12 COOCH NH2CH2CH2OH COOCH: CT^ HN I FORMULA 2 HoC-CH7 zl z OH 3 COOCH3 R=H (^ COOCH: R CCOCH-; c^O000^ - CH2 CH2 6SO2CH3 R FORMULA 5 COOCH3 COOCH3 CH2 JH2C FORMULA 3 COOCH3 ^1OCOOCH3 FORMULA U R FORMULA 6 SCHEME 1m JPOOCH3 FT COOCHo FORMULA 7124 445 R^ COOH R COOH FORMULA 9 R FORMULA 8 R *no. YT COOR2 r~E 1„ X1L COOR2 II l 0 FORMULA 10 FORMULA 17 Ol,xi C^N O COOH FORMULA 13 several operations R II I I o FORMULA 1A SCHEME 1r?i (isomer of (L)-α-tetraethyl ester (I) of formula 13 mixture) /isomer of (6)-α-tetraethyl ester (I) of formula 13 separation by HPLC technique isomer of (L)-α-tetraethyl ester (I) of formula 13 isomer of (d)-α-tetraethyl ester (I) of formula 13 and isomer of acid (I) of formula 13 isomer of acid (d) of formula 13 SCHEME 2 PL PL PL PL PL

Claims (1)

1.