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

Description

The subject of the invention is a process for the preparation of new derivatives of pyrrolecarboxylic acid-1. The invention relates in particular to a process for the preparation of new 5-arylcarbonyl-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrolecarboxylic acids - Formula I, wherein R is hydrogen or a lower alkyl radical of 1-4 carbon atoms, R 1 is a hydrogen atom, a lower alkyl radical of 1-4 carbon atoms, a lower alkoxy group of 1-4 carbon atoms or a chlorine atom, Fluorine or bromide substituted in the ortho, meta or para position of the arylcarbonyl substituent and their isomers (1) and (d) as well as their pharmacologically non-toxic salts and new intermediates in their synthesis. The novel compounds, with the exception of the (d) isomer and the related compounds, have anti-inflammatory, irritating and antipyretic properties and are therefore useful in the treatment of inflammation, pain and fever in mammals, as described below in detail . They also find use as smooth muscle relaxants. The term "pharmacologically acceptable non-toxic esters and salts" in this specification means "alkyl esters" - derivatives of branched or straight chain hydrocarbons with 1 to 12 carbon atoms and salts acceptable in pharmaceuticals, non-toxic, inorganic or organic bases. Typical esters of the alkyl group are, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isoamyl, pentyl, isopenyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl and dodecyl esters. derived from inorganic bases are the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, iron, manganese, and the like salts. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable, non-toxic organic bases include salts of primary, secondary, and tertiary substituted amines including naturally derived compounds, ring amines, and basic ionic resins such as isopropylamine, trimethylamine. , diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethyl aminceano, tri (hydroxymethyl) aminomethane, dicyclohexylamine, lysine, arginine, histidithia, co-phein, procaine, hydrabaine, choline, bethenedamine, choline, , glucosamine, methylglucamine, purine theobromine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine, ethanolamine, piperidine, trioxymethyl / amine, chyclohexylamine, cyclohexylamine, cyclohexylamine, and the like. New compounds with formulas 1 appear in the form! 25 30 124 445 124 445 3 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. In view of their physiological properties, ie anti-inflammatory, calming and anti-pyretic properties, a preferred subgroup is the compounds of formula I and their isomers (1), their pharmacologically acceptable esters and salts. A particularly preferred subgroup of this group are acids, esters and salts in which both R and R 1 are hydrogen. Isomers (d) of the acids of formula I and their pharmacologically acceptable esters and salts are useful as compounds, intermediate in the synthesis of racemic mixtures of acids (dl) of formula I, which will be described in more detail below. The new compounds (dl) are prepared according to the invention by hydrolyzing an ester of formula 11. In the formulas 1-10, R in this scheme, and R 1 are as defined above, and R 2 is a lower alkyl radical with 1 to 4 carbon atoms, for example methyl, ethyl, isopropyl or n-butyl, or hydrogen. The substrates used in the process of the invention are prepared by by the reactions outlined in Scheme 1 to give the end product. In these reactions, the ethanolamine is first treated with equimolar amounts of 1,2-acetone-dicarboxylic acid dimethyl ester of the formula II to give a vinylamine solution of the formula III, which is preferably subjected to treatment without isolation from the reaction mixture. 2-bromoacetaldehyde or 2-chloroacetaldehyde in an inert solvent under anhydrous conditions to give the compound of formula IV, where R is hydrogen. Compounds of formula IV, where R is a lower alkyl radical, are prepared by treating the aqueous mixture with ethanolamine and 1,3-acetone dicarboxylic acid dimethyl ether by treatment with a 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 an adjuvant solvent, e.g., dichloromethane, to provide the mesylate of formula 5, which is converted to the corresponding N- (2-iodoethyl) -pyrrole of formula VI, treatment with sodium iodide in acetonitrile under reflux conditions. Treatment of a compound of formula VI with sodium hydride in an inert solvent gives compounds of formula 7. Alternatively, the compounds are of formula VII can be obtained by direct cyclization of the mesylate of formula V with sodium hydride in dimethylformamide. Basic hydrolysis of a compound of formula VII with an alkali metal hydroxide or carbonate in an aqueous lower aliphatic alcohol gives a diacid of Formula 8 or its 6-alkyl derivative. Thereafter, the carboxyl group in the Cl position of the compound of Formula 8 is selectively esterified by treatment with a lower aliphatic alcohol in the presence of hydrogen chloride, keeping the appropriate alkoxycarbonyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrocarboxylic acid-7 of formula 9. Decarboxylation of the monoester of formula 9 to the corresponding compound of formula 10, i.e. In the synthesis of the present invention, the compound of formula 9 is heated at 230 ° -280 ° C. for a time sufficient to complete this reaction for about 45-90 minutes. Condensation of the compound of formula 10 with the amide of formula 12, wherein R1 is as defined above, gives the corresponding 5- -arylcarbonyl-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrolecarboxylic-1 alkyl ester of Formula 11 wherein R * is lower * alkyl group. These reactions are carried out in an inert, proton-free organic solvent in the presence of phosphorus oxychloride at the boiling point of the reaction mixture under reflux for about 1-175 hours, in an inert atmosphere, followed by heating over a period of time. about 2 to 10 hours under reflux in the presence of sodium acetate. Alternatively, another acid chloride, such as phosgene or oxalyl chloride, may be used in place of phosphorus oxychloride. In a preferred embodiment, the above condensation is performed by adding a solution of the compound of Formula 10 in a suitable solvent to keep it at boiling under pressure. reflux of a mixture of 1.1 to 5 molar equivalents of amide and phosphorus oxychloride in the same solvent. The mixture obtained is refluxed for about 6 to 72 hours under argon, then 3 to 10 molar equivalents of sodium acetate are added and heating is continued under reflux for a further 4 to 6 hours. . Suitable solvents for this reaction are 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-methoxy-benzamide, N, N-dimethyl-m-methoxybenzamide, N, N-dimethyl-p-ethoxybenzamide, N, N-dimethyl-55-p-isopropoxybenzamide, N, N-dimethyl-8-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-p-bromobenzamide. The above amides are known compounds, commercially available or obtainable by conventional methods from suitable acids, e.g. by conversion of the acid into an acid chloride followed by treatment with dimethylamine. 124 445 5 6 After basic hydrolysis of the ester group. the compound of formula 11 gives the corresponding free acid of formula 1. The above hydrolysis is carried out in a conventional manner with the aid of an alkali metal hydroxide or carbonate, for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like. in aqueous lower aliphatic alcohol, such as methanol, ethanol and the like, at room temperature to reflux temperature. Reactions are carried out for about 15 minutes to about 2 hours in an inert atmosphere. The hydrolysis is preferably carried out with an aqueous methanolic solution of potassium carbonate at the boiling point under reflux for about 30 minutes. The compounds of formula I can be separated into the individual optical isomers by known methods. The acid (1) and acid isomers (d) of the formula I can be obtained by the known technique of high pressure liquid chromatography (HPLC) and their diastereoisomeric β-phenethyl esters followed by acidic cleavage. For example, compounds of formula I, in which R and R * are hydrogen, can be further processed according to Scheme 2. The free acids of formula I can be converted to other alkyl esters with an alkyl radical of 1-12 carbon atoms. . Conventional methods are employed for this purpose, for example (a) treatment with an alcohol corresponding to the desired ester in the presence of a strong mineral acid, (b) treatment with an ethereal diazoalkane solution or (c) treatment with an alkyl iodide in the presence of lithium carbonate. The acid isomers (1) can be converted into alkyl esters by the methods (b) and (c) described above. The salts of the compounds of formula I and their acid isomers (1) are obtained by treating the free acids with an appropriate pharmaceutically acceptable amount. bases, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, ammonium hydroxide, iron hydroxide, zinc hydroxide, copper hydroxide, manganese hydroxide, aluminum hydroxide, iron hydroxide, manganese hydroxide , isopropylamine, trimethylamine, diethylamine, triethylamine, triethylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trihydroxymethylaminomethane, lysine, arginine, histidine, caffeine, hydrocaine, choline, , betaine, ethylenediamine, glucosamine, methylglucamine, theobramine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. The reactions are carried out in water, either pure or mixed with an inert, water-miscible organic solvent, at a temperature of about 0 ° 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 I or its acid isomer <1) to the base is selected so as to obtain a value corresponding to the proportion of both components in the additional salt. For example, to obtain a calcium or magnesium salt of a compound of formula I or its acid isomers (1) the free acid starting material is treated with at least half the mole equivalent of a pharmaceutically acceptable base, yielding neutral salt. To obtain the neutral aluminum salt, the starting acid is treated with at least 1/3 the mole equivalent of a pharmaceutically acceptable base. In a preferred embodiment of the invention, the magnesium or calcium salts of the compounds of formula I or their acid isomers (1) are are obtained by treating the corresponding sodium or potassium salts of these compounds with at least half the molar equivalent of magnesium chloride or calcium chloride, in an aqueous solution or in a mixture of water with an inert, water-miscible organic solvent at a temperature of about 20 —100 ° C. Aluminum salts are replaced by a sieve. preferably by treating the appropriate free acid with at least 1/3 mole of an equivalent of an aluminum alcoholate 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. 115 ° C. Inorganic base salts with limited solubility can be obtained by similar methods. The isolation of the compounds described can be completed by a suitable method, e.g. extraction, filtration, evaporation, distillation, crystallization, thin-layer chromatography, column chromatography. , high pressure liquid chromatography (HPLC) or combinations of these methods. The isolation methods are described in the examples below. In addition to those described, other equivalent isolation methods may of course be used. The acid isomers (d) are not used as such as medicaments. They can, however, be converted into pharmaceutically acceptable non-toxic esters and salts by the methods described for the acid isomers (1). The compounds of formula I, acid isomers (1) and their pharmacologically acceptable non-toxic esters and salts of these acids are useful as anti-inflammatory, calming, anti-clumping 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 of skeletal joints and other tissues, for example in the treatment of inflammatory conditions such as voice, 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 relieving both these conditions and inflammation. The active compounds of the formula I or the acid isomers thereof (1) and their pharmacologically acceptable, non-toxic esters and salts. Any route adopted for the introduction of agents to treat inflammation, pain or fever, or for prophylaxis may be introduced in a suitable pharmaceutical formulation, 50 55 60 124 445 7 8. orally, parenterally or topically, in 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 the form of a unit dose, enabling simple administration of a specific amount of the active ingredient. The compositions contain a conventional pharmaceutical carrier or filler and an active compound of formula I or an acid isomer (1) thereof, and a pharmacologically acceptable, non-toxic ester or salt and possibly another therapeutic agent, pharmaceutical agent, additional carriers, adjuvants and the like. A preferred method of using the compounds in the above-described conditions is by oral administration on a convenient daily schedule according to the severity of the disease. As a rule, a daily dose of 25 to 500 mg of the active compound of formula I or its acid isomer (1) and its pharmacologically acceptable non-toxic ester or salt is used. In most cases, 0.5 to 6 mg / kg by weight is suitable. body a day. For oral administration, a pharmaceutically acceptable, non-toxic composition is formulated with a commonly used carrier such as a pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, etc. sucrose, magnesium carbonate and the like. Such compositions may take the form of solutions, suspensions, tablets, pills, capsules, powders, delayed release preparations, etc. The active compounds of the formula I or their acid isomers (1) and their pharmacologically acceptable, not toxic esters and salts can be formed into a suppository using polyalkylene glycols such as polypropylene glycol as a carrier. Liquid pharmaceutical compositions can be prepared, for example, by dissolving or suspending the active compound such as that described above and optionally a pharmaceutical adjuvant in a carrier such as water, saline solution, glucose solution, glycerin, ethanol and the like. If desired, the pharmaceutical compositions may also contain non-toxic excipients such as wetting or emulsifying agents, buffers and the like, e.g. sodium acetate, sorbitan monolaurate, triethylamine oleate, etc. Methods for the preparation of such pharmaceutical forms are known in the art. for those skilled in the art, see, for example, Remington's Pharmaceutical Sciences, Meck Publishing Company, Easton, Pensylvania, 14th Edition, 1970. In each case, the administered compositions contain an amount of active ingredient that is effective for the condition in question, in accordance with the directions given. The compounds of formula I and their isomers of acid (1) and their pharmacologically acceptable non-toxic esters and salts act to decompose attaching to the smooth muscles of the uterus and are therefore useful as maintenance factors for the pregnancy of mammals, for the benefit of the mother and / or the fetus, until termination of pregnancy is favorable or more medically advantageous for However, it should be understood that in certain cases, such as when labor has already begun (when the mother experiences uterine contractions, especially when the pregnancy is nearing its end), the administration of these compounds may not be maintain pregnancy condition indefinitely. In these cases, the pregnancy will most likely be somewhat "prolonged" which may be beneficial for the mother and / or the fetus. In particular, the compounds of formula I and their acid isomers (1) and their pharmacologically acceptable non-toxic esters and salts are used especially as Delayed Beginning of Labor As used herein, this term means a delay in labor induced by the administration of the compounds of formula I or their isomers of acids (1) and their pharmacologically acceptable esters or salts at any time prior to the commencement of uterine contractions. So it concerns both preventing miscarriage in the early stages of pregnancy (i.e. before the fetus becomes viable) and delaying the onset of premature labor pains later in pregnancy, when the fetus is already viable. In the case of cases, the compounds according to the invention are administered prophylactically to prevent premature onset of labor. relationship is especially appropriate for women who have had a history of spontaneous abortion or preterm labor (i.e. before the end of your pregnancy). It is also recommended in those clinical cases, when there are indications that the pregnancy may be terminated prematurely and its prolongation is beneficial for the mother and / or the fetus. In animals, administration of the described compounds can be used to synchronize deliveries in the group. pregnant animals, in order to undergo them at the same or desired time and / or place when childbirth is easier to deliver. The term "postponement of labor" is used herein to mean the delay induced by the administration of compounds of formula I or their of acid isomers (1) and their pharmacologically acceptable non-toxic esters or salts before the onset of uterine contractions.The results of their use are influenced by the condition of the patient, also during the period of pregnancy when contractions, severity of contractions and their duration. For example, this may result in a reduction in the intensity and / or duration of contractions ("lengthening" of the actual time of labor), or the complete cessation of contractions In each of these cases, the effect is an extension of the gestation period, although, depending on the patient's condition, as described above, the effect may be weak or, where appropriate, slightly greater. Such administration may prevent a spontaneous abortion, ease the delivery and / or make it less painful for the mother or cause delivery to occur at an appropriate time and / or place. / In each case, the administration of the compounds of formula I or their isomers of acid (1) and them. 10 15 20 25 30 35 40 45 50 55 60 124 445 9 pharmacologically, non-toxic esters or salts, for the above-mentioned purposes, should be in accordance with the best and / or accepted medical (or veterinary) practice, for the greatest benefit to the mother and / or fetus. For example, pregnancy should not be prolonged until fetal death in the uterus. A therapeutically effective dose of a compound of formula I or its acid isomer (1) and a pharmacologically acceptable non-toxic ester or salt containing them is administered to the pregnant mammal by any conventional and customary method. . These compounds may be administered singly or in conjunction with another compound or compounds such as those listed above, or with other pharmaceutical agents, carriers, adjuvants, etc. The compound (s) or compositions may be administered orally or parenterally, in solid, semi-solid form, Typically, pharmaceutical compositions are used containing the active compound and one or more pharmaceutical carriers or adjuvants. The pharmaceutical compositions may be oral tablets, tablets, vaginal or intrauterine suppositories, pills, capsules, liquid solutions, suspensions or the like, preferably unit doses, allowing simple dosing of specified amounts of active compound. As conventional non-toxic carriers, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like are used continuously. be formed into suppositories using, for example, polypropylene glycol as a carrier. Fluid pharmaceutical compositions can be prepared, for example, by dissolving, suspending, etc. the active compound as described above and, optionally, a pharmaceutical adjuvant in the carrier, such as water, saline, aqueous glucose, glycerol, ethanol, and the like. If desired, the pharmaceutical composition may also contain minor amounts of non-toxic excipients such as a wetting or emulsifying agent, pH buffering agent, and the like. for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and the like. The methods for formulating such dosage units are known, see, for example, Remingto. n's Pharmaceutical Sciences, Mack Publishing, Company, Paston, Pennsylvania, 14th edition 1970. The compositions or preparations shall contain an active compound (s) in an amount effective to delay the onset of labor or sufficient labor to be delivered when uterine contractions have already begun. Usually, a daily dose of about 0.5-25 mg of active compound per kilogram of body weight will be used, administered at once, 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 according to the invention are presented below. Male Swiss-Webster mice weighing 18-20 g are administered the test material orally in an aqueous carrier. , at time 0. After 20 minutes, 0.25 ml of a 0.02% phenylquinone solution is injected intraperitoneally, which causes the animals to squirm with pain (spasms). The animals are observed over the next 10 minutes. The number of mice undergoing spasms and the average number of spasms in one mouse are recorded. 10 In the above test, the analogous activity of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-carboxylic acid-1 exceeds the analgesic activity of aspirin by about 430 times, and the analgesic activity of the acid (1 ) 5-benzoyl-1,2-dihydro-3H-pyrrole (1,2-a] pyrrolecarboxylic-1 is approximately 700 times greater than the analgesic activity of aspirin. B. Acute toxicity when administered orally in mice (LD50). A suspension of the test material is made in an aqueous solution of carboxymethylcellulose. The concentrations are selected so as to be able to use the stipulated doses of 10 ml / body weight. Five groups of male Swiss-Webster mice are used, each with 6 animals per group (one group being controls). Single oral doses of 200, 400, 800 or 1200 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolecarboxylic acid-1 per kg of body weight, a probe is inserted The LD50 value of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolecarboxylic acid-1 as determined as above is about 200 mg / kg. The subject of the invention is illustrated by the following examples . Abbreviation t.l.c. stands for thin layer chromatography and the composition of liquid mixtures is given in volumetric proportions. Unless otherwise specified, the reaction was carried out at room temperature (20-30 ° C.). EXAMPLE I. A solution of 336 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrole isopropyl ester. The lo [1,2-a] pyrrolecarboxylic-1-carboxylic acid in 10 ml of methanol is mixed with a solution of 690 mg of potassium carbonate in 5 ml of water. The reaction mixture was heated under nitrogen for 30 minutes under reflux, 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 are dried over magnesium sulphate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate-hexane gives 238 mg (89%) of 5-p-toluyl-1,2-dihydrogen-3H-pyrrolo [1,2-a] pyrrolecarboxylic acid-1 (compound of formula (1, R = H, Ri = p-CH3) with a melting point of 182-183 ° C. Example 2 A solution of 250 mg of 5-p-toluyl-1 acid isopropyl ester kept under nitrogen atmosphere The 2-dihydro-3H-pyrrolo [1,2-a] pyrrolocarboxylic-1-1 in 8 ml of methanol is mixed with a solution of 200 mg of sodium hydroxide in 1 ml of water, maintaining the reaction mixture for 1.5 hours at room temperature, the methanol is stripped off under reduced pressure, the remaining basic solution is diluted with 5 ml of water and extracted with ether to remove the unsaponifiable product. The aqueous solution is acidified with 10% hydrochloric acid and extracted three times. ethyl acetate. The combined extracts are dried and evaporated to dryness in vacuo and the residue "recrystallized from ethyl acetate-hexane to give acid 5. -p-toluyl-1,2-dihydrogen-3H-pyrrolo [1,2-a] pyrrolecarboxylic-1 identical to the product obtained according to example I. Example III. After the hydrolytic cleavage of the isopropyl ester group by the methods of Examples I or II, the corresponding free acids are obtained, namely: 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolecarboxylic-1, m.p. 160 ° -161 ° C, 5-o-toluyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolecarboxylic acid-1, in the form of an oil with the following solid physical constants: ultraviolet spectrum (MeOH): Amax 253, 307 nm (e 3310, 16980), infrared spectrum (CHCl 3): vmax 1720, 1620 cm-1, nuclear magnetic resonance spectrum (CDCl 3, TMS): 6 2.32 (d, 3H, CH3), 2.53-3.03 (m, 2H, H-2), 3.97 (dd, 1H, Hl), 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 propones), 8.60 (broad s , 1H, COOH), ppm. 5-m-toluyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolecarboxylic acid-1,2-dihydrogen acid. 3H-pyrrole [1,2-a] pyrrolecarboxylic acid-1,2, 5-o-propylbenzoyl-1,2-dihydro-3H-pyrrole [1,2-a] pyrrolecarboxylic-1,2-m- acid butyl obenzoyl-1,2-dihydro-3H-pyrrole [1,2-a] pyrrolecarboxylic-1,2-a-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolecarboxylic acid -1, 5-p-methoxybenzoyl-1,2-dihydrogen-3H-pyrrolo [1,2-a] pyrrolocarboxylic-1, melting point 187-187.5 ° C, 5-p-ethoxybenzoyl acid -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolecarboxylic-1, mp 169.5-170 ° C. 5-p-isopropybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolecarboxylic acid-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolecarboxylic acid -a] pyrrolecarboxylic-1 with the following physical constants: ultraviolet spectrum (MeOH): nax 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, Hl) , 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). Acid 5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo - [1,2-a] pyrrolocarboxylic-1 with a melting point of 180-181 ° C, 5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrol- [1,2-a] pyrrolecarboxylic acid- 1, mp 201.5-202.5 ° C, 5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrol- [1,2-a] pyrrolecarboxylic acid-1 with a melting point of 179.5-180.5 ° C. EXAMPLE 4 Solution of 500 mg of isopropyl acid ester 5-p-toluyl-1,2-dihydro-6-methyl-1H-pyrrolo [1,2-a] pyrrolecarboxylic-1 in 15 ml of methanol is mixed with a solution of 1.05 g of potassium carbonate in 8 ml of water. The reaction mixture is refluxed for 30 minutes under a nitrogen atmosphere, 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 (3 x 50 ml). The combined extracts are dried over magnesium sulphate and evaporated to dryness in vacuo to give 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 manner similar to that described above, or alternatively the hydrolysis described in Example 2, the other isopropyl esters are converted to the corresponding free acids, i.e. 5-benzoyl acid. -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrolocarboxylic-1, m.p. 169 ° C, 5-p-methoxybenzoyl-1,2-dihydro-6- methyl-3H-pyrrolo [1,2-a] -pyrrolecarboxylic-1, mp 182 ° C, 5-para-chiorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [ 1,2-a] pyrrolecarboxylic-1, m.p. 204 ° C, 5-p-fluoro-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid , mp 204 ° C, 5- (4-fluorobenzoyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [172-a] pyrrolecarboxylic acid-1 with a melting point of 196 ° C. Example 5 To a solution of 300 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo (1,2-a] pyrrolecarboxylic acid-1 in 25 ml of dry benzene, 0.58 g of trifluoroacetic anhydride is added. All are mixed for 10 minutes at room temperature. The solution obtained is cooled to 0 ° -5 ° C. and 1.4 g of dry triethylamine are added, followed immediately by 0.5 g of (1) α-phenylethyl alcohol. The reaction solution thus obtained was stirred for 15 minutes at room temperature, poured into 20 ml of water containing 1 ml of triethylamine, then extracted with ethyl acetate. The extract was dried over sodium sulphate and stripped of the solvent and excess alcohol under reduced pressure ( l) -a-phenylethyl, obtained 0.42 g of a mixture of (l) -t-phenylethyl esters (l) and (d) -5-benzoyl-l, 2-dihydrogen-3H-pyrrolo [l, 2- a] pyrrolocarboxylic-1. The mixture is separated by high pressure liquid chromatography (using 4% EtOAc) hexane on a Lichrosord SL-60 column, 11 mm X 50 cm, 10 µm). 180 mg of the more polar ester are obtained (A [theta] * eOH —145.7 ° and 178 mg of the less polar ester (a ^ eOH + 128.6 ° C). 55,148 mg of the more polar ester are dissolved in 8 ml of dry benzene. to 15-20 ° C, 5 ml of trifluoroacetic acid are added, and the solution is stirred at room temperature for 70 minutes. The 60 ml solution is then poured into 60 ml of dry benzene and under reduced pressure at room temperature. Purification was carried out by high pressure liquid chromatography (using a column as described above and replacing 4% EtOAc (hexane) with 0.5% acetic acid.) 63 mg of L-5 acid was removed. benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolecarboxylic-1 o D s -153.7 ° and melting point 153-155 ° C. Similarly carried out, less polar cleavage of the ester yields 85 mg of (d) -5-5 benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolecarboxylic acid-1aHCl8 + 155.1 ° and a melting point of 154 ° C. 156 ° C. The acid isomer (d) obtained in this way can, if desired, be racemized and recycled by known methods. Similarly, it is possible to separate pure isomers 1 and a mixture (dl) of other compounds. of the pyrrolecarboxylic acid derivatives of formula I, in which R is a hydrogen atom or a lower alkyl radical of 1-4 carbon atoms, R1 is a hydrogen atom or a lower alkyl radical of 1-4 carbon atoms, the lower alkoxy group of 1-4 carbon atoms or chlorine, fluorine or bromine substituted in the ortho, meta or paired ring position of the arylcarbonyl substituent and their pharmacologically non-toxic salts, characterized in that the novel ester of formula 11 wherein R1 and R are as defined above, and R2 is lower alkyl group with 1-4 carbon atoms, is subjected to hydrolysis and the optionally obtained compound of formula I, wherein R and R1 are as defined above, is converted into a pharmacologically non-toxic and salt. 2. Process for the preparation of new pyrrolecarboxylic acid derivatives of formula I, in which R represents a hydrogen atom or a lower alkyl radical with 1 to 4 carbon atoms, R 1 is a hydrogen atom or a lower alkyl radical with 1 to 4 atoms. carbon, lower alkoxy of 1-4 carbon atoms or chlorine, fluorine or bromine substituted in the ortho, meta or paired position of the arylcarbonyl substituent and their pharmacologically non-toxic salts, characterized in that the new ester of formula 11, in which R1 and R are as defined above, and R2 is a lower alkyl group with 1-4 carbon atoms, are hydrolyzed and the acid formed is separated into the corresponding isomers, the acid isomer (d) is racemized and the product is optionally converted in a pharmacologically acceptable salt. 124 445 R 1 / CON (CH32 FORMULA 12 COOCH NH2CH2CH2OH COOCH: CT ^ HN AND FORMULA 2 HoC-CH7 zl with OH 3 COOCH3 R = H (^ COOCH: R CCOCH-; c ^ O000 ^ - CH2 CH2 6so2ch3 R MODEL 5 COOCH3 COOCH3 CH2 JH2C MODEL 3 COOCH3 ^ lOCOOCH3 MODEL UR MODEL 6 SCHEME 1m JPOOCH3 FT COOCHo MODEL 7124 445 R ^ COOH R COOH MODEL 9 R MODEL 8 R * no. YT COOR2 r ~ E 1 "X1L COOR2 II l 0 MODEL 10 MODEL 17 Ol, xi C ^ NO COOH MODEL 13 several operations R II II o FORMULA 1A SCHEME 1r 'i ((L) -oC-tenethyl acid ester isomer (I) of formula 13 mixture) / (8) - * C-tenethyl acid ester isomer (I) of formula 13 separation by HPLC isomer of ester (l) -oE-tenethyl acid (For formula 13 isomer of (d) -cC-th ester of netetic acid (l) in formula 13 and isomer of acid (l) of formula 13 isomer of acid (d) of formula 13 SCHEME 2 EN

Claims (2)

Claims 10.15. 1. A method for the preparation of new pyrrolecarboxylic acid derivatives of formula I, wherein R is hydrogen or a lower alkyl radical of 1-4 carbon atoms, R1 is hydrogen or a lower alkyl radical of 1-4 carbon, lower alkoxy with 1-4 carbon atoms or a chlorine, fluorine or bromine atom substituted in the ortho, meta or ring position of the arylcarbonyl substituent and their pharmacologically non-toxic salts, characterized in that the new ester of formula 11, in which R1 and R are as defined above, and R2 is lower alkyl group with 1-4 carbon atoms, are subjected to hydrolysis, and the optionally obtained compound of formula I, in which R and R1 are as defined above, is carried out by transform into a pharmacologically non-toxic salt. 2. Process for the preparation of new pyrrolecarboxylic acid derivatives of formula I, in which R represents a hydrogen atom or a lower alkyl radical with 1 to 4 carbon atoms, R 1 is a hydrogen atom or a lower alkyl radical with 1 to 4 atoms. carbon, lower alkoxy of 1-4 carbon atoms or chlorine, fluorine or bromine substituted in the ortho, meta or paired position of the arylcarbonyl substituent and their pharmacologically non-toxic salts, characterized in that the new ester of formula 11, in which R1 and R are as defined above, and R2 is a lower alkyl group with 1-4 carbon atoms, are hydrolyzed and the acid formed is separated into the corresponding isomers, the acid isomer (d) is racemized and the product is optionally converted in a pharmacologically acceptable salt. 124 445 R 1 / CON (CH32 FORMULA 12 COOCH NH2CH2CH2OH COOCH: CT ^ HN AND FORMULA 2 HoC-CH7 zl with OH 3 COOCH3 R = H (^ COOCH: R CCOCH-; c ^ O000 ^ - CH2 CH2 6so2ch3 R MODEL 5 COOCH3 COOCH3 CH2 JH2C MODEL 3 COOCH3 ^ lOCOOCH3 MODEL UR MODEL 6 SCHEME 1m JPOOCH3 FT COOCHo MODEL 7124 445 R ^ COOH R COOH MODEL 9 R MODEL 8 R * no. YT COOR2 r ~ E 1 "X1L COOR2 II l 0 MODEL 10 MODEL 17 Ol, xi C ^ NO COOH MODEL 13 several operations R II II o FORMULA 1A SCHEME 1r 'i ((L) -oC-tenethyl acid ester isomer (I) of formula 13 mixture) / (8) - * C-tenethyl acid ester isomer (I) of formula 13 separation by HPLC isomer of ester (l) -oE-tenethyl acid (For formula 13 isomer of (d) -cC-th ester of netetic acid (l) in formula 13 and isomer of acid (l) of formula 13 isomer of acid (d) of formula 13 SCHEME 2 EN