CH644862A5 - 5-(2- and 3-furoyl)- and 5-(2- and 3-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids and their salts and esters - Google Patents

Abstract

The compounds correspond to the formula <IMAGE> X represents oxygen or sulphur, R represents hydrogen or C1-C4-alkyl, R<1> represents hydrogen, methyl, chlorine or bromine and R<2> represents hydrogen, C1-C12-alkyl or a pharmaceutically acceptable cation. The compounds exhibit an anti inflammatory, analgesic and antipyretic action; they are suitable, in particular in the form of pharmaceutical preparations, for treating inflammations, pain and febrile conditions and as smooth-muscle relaxants.

Description

       

  
 

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

 or the / acid isomers of the formulas A and B or their pharmaceutically acceptable salts or their alkyl esters derived from unbranched or branched hydrocarbon radicals having 1 to 12 carbon atoms, where X is oxygen or sulfur, R is hydrogen or a lower alkyl group having 1 to 4 carbon atoms Rl is hydrogen, methyl, chlorine or bromine and any substituent R 'in the compounds of the formula A is in the 3-, 4- or 5-position of the furan or thiophene ring.



   34. Agent for administration to a pregnant woman or a pregnant mammal to delay the start of childbirth, characterized in that it consists of a pharmaceutically acceptable, non-toxic excipient and a therapeutically effective amount of a compound of the formula:
EMI2.1
 or the l-acid isomers of the formulas A and B or their pharmaceutically acceptable salts or their alkyl esters derived from unbranched or branched hydrocarbon radicals having 1 to 12 carbon atoms, where X is oxygen or sulfur, R is hydrogen or a lower alkyl group having 1 to 4 carbon atoms , R 'is hydrogen, methyl, chlorine or bromine and any substituent Rl in the compounds of the formula A is in the 3-4 or 5 position of the furan or

  Thiophene ring is located.



   The present invention relates to certain new pyrrole-1-carboxylic acid derivatives.



   In particular, the invention relates to new 1,2-di-hydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acids, which are in the 5-position by a 2-furoyl, 2-thenoyl , 3-furoyl or 3-thenoyl group and the formula:

  :
EMI2.2
 correspond to their individual l-acid isomers and d-acid isomers, their pharmaceutically acceptable salts and their alkyl esters derived from unbranched or branched hydrocarbon radicals having 1 to 12 carbon atoms, where X is oxygen or sulfur, R is hydrogen or a lower alkyl group having 1 to 4 carbon atoms, R 'is hydrogen, methyl, chlorine or bromine and any substituents Rl are present in the compounds of the formula A in the 3-, 4- or 5-position of the furan or thiophene ring.



   The compounds of the invention, with the exception of the d-acid isomers and the aforementioned salts and alkyl esters thereof, show an anti-inflammatory, analgesic and antipyretic effect and are therefore useful for the treatment of inflammation, pain and / or feverish conditions in humans and mammals, as follows is described in more detail. They are also smooth muscle relaxants.



   The term pharmaceutically acceptable salts, as used herein, refers to salts derived from pharmaceutically acceptable, non-toxic inorganic or organic bases.



   Typical alkyl esters are 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 sodium, potassium, lithium, ammonium, calcium, magnesium, ferro, zinc, copper, mangano, aluminum, ferric, manganese salts and the like. Particularly preferred become 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 naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procain, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylamine piperidine. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine.



   The new compounds of formulas A and B as well as formulas XI and XII below are present as pairs of optical isomers (or enantiomorphs), i.e. as dl mixtures. However, the present compound encompasses both the individual optical isomers and the dl mixtures thereof.



   If the new compounds according to the invention are to be used to induce a physiological reaction, e.g. an anti-inflammatory, analgesic or antipyretic effect, i.e. if they are to be used as medicaments, a preferred subgroup consists of the compounds of the formulas A and B and their l-acid isomers, as well as their C1-12 alkyl esters and pharmaceutically acceptable salts.



   Another subgroup of compounds used as medicaments comprises the compounds of the formula A.



  and the l-acid isomers of the formula A and their C1 12-alkyl esters and pharmaceutically acceptable salts; this subgroup can be divided into two further subgroups which (a) are the compounds of formula A, i.e. the dl compounds in which R 'is both hydrogen and X is sulfur, and (b) the I acid isomers of
Formula B, wherein R 'is both hydrogen and X is sulfur, and include their esters and pharmaceutically acceptable salts.



   The d-acid isomers of formulas A and B and their esters and pharmaceutically acceptable salts are useful as intermediates for the preparation of the dl acids of formulas A and B, as will be described in more detail below.



   The new dl relations according to the invention can be produced by means of a process which is explained by the following reaction scheme:
EMI3.1
  
EMI4.1
 (B) wherein X, R and Rl have the above meanings and R2 is a lower alkyl group with 1 to 4 carbon atoms, e.g.



  Methyl, ethyl, isopropyl or n-butyl means.



   In the practical implementation of the process outlined above, equimolar amounts of ethanolamine of the formulas and dimethyl 1,3-acetone dicarboxylate of the formula II are reacted at a temperature of from about 0 ° C. to about room temperature to prepare the compounds of the formula IV in which R is hydrogen , wherein a solution of the vinylamine of the formula III easily forms, which is then treated, preferably in situ, under anhydrous conditions in a suitable inert organic solvent with 2-bromoacetaldehyde or 2-chloroacetaldehyde, at about 40 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 and the like. According to a preferred embodiment, the reaction is carried out in solution in acetonitrile at the reflux temperature for about 1 hour. The 2-bromoacetaldehyde or 2-chloroacetaldehyde, which serve as reagents, are known compounds or can be obtained by pyrolysis of the corresponding diethylacetals in the presence of oxalic acid dihydrate.



   In order to prepare the compounds of the formula IV in which R is a lower alkyl group, which is preferably unbranched, having 1 to 4 carbon atoms, an aqueous mixture of ethanolamine of the formula 1 and 1,3-acetone dicarboxylic acid ester of the formula II with a compound of the formula :
EMI4.2
 wherein X is bromine or chlorine and R3 is a lower alkyl group, which is preferably unbranched, having 1 to 4 carbon atoms, in particular 1-bromoacetone, 1-bromo-2-butanone, 1-bromo-2-pentanone or 1-bromo-2 -hexanone, treated at about 40 to about 100 C for a period of about 30 minutes to about 16 hours. According to the preferred embodiment, the reaction is carried out at a temperature of about -10 C to about

  Room temperature carried out for about one to about 6 hours. The reagents of the formula:
EMI4.3
 are known connections.



   By esterification of the compound of formula IV with methanesulfonyl chloride in the presence of a tertiary amine, i.e. Triethylamine, pyridine and the like, optionally in the presence of a cosolvent, such as dichloromethane, at a temperature of about - 10 C to about room temperature for about 10 minutes to about 2 hours, the corresponding mesylate of formula V is obtained, which then is converted into the corresponding N- (2-iodoethyl) pyrrole of the formula VI by reaction with sodium iodide in solution in acetonitrile at the reflux temperature for about one to about 10 hours.

 

   By reacting the iodoethyl compounds of the formula VI with sodium hydride in a suitable inert organic solvent, such as dimethylformamide, 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1,7-dicarboxylic acid dimethyl ester and its Obtained in the 6-position alkyl-substituted derivatives of formula VII. This cyclization is carried out under an inert atmosphere, i.e. under an argon or nitrogen atmosphere, at temperatures of the order of about 15 to about 40 C for a period of about 15 minutes to about 4 hours. The best results are obtained when the reaction is carried out at room temperature for about 30 minutes when R is hydrogen.



   The compounds of formula VII can also be obtained by direct cyclization of the mesylate of formula V with sodium hydride in solution in dimethylformamide at from about -10 ° C. to about room temperature for about 30 minutes to about 2 hours.



   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 and the like in an aqueous lower aliphatic alcohol, e.g. Methanol or ethanol, at a temperature between room temperature and reflux temperature for about 4 to about 24 hours, provides the corresponding free diacid of formula VIII, i.e. 1, 2-Dihydro-3H-pyrrolo- [1,2-a] pyrrole-1,7-dicarboxylic acid and its 6-alkyl derivatives. The hydrolysis is preferably carried out using aqueous methanolic potassium hydroxide at the reflux temperature for about 10 hours.



   The carboxylic acid group on carbon atom 1 in the compound of formula VIII is then removed by treatment with a lower aliphatic alcohol, e.g. Methanol, ethanol, isopropanol, n-butanol and the like, selectively esterified in the presence of hydrogen chloride to give the corresponding 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid alkyl ester-7 to produce carboxylic acid of the formula IX. The reaction is carried out at a temperature of about 0 to about 50 C for about 1 to about 4 hours.



   The decarboxylation of the monoesterified compounds of the formula IX to the corresponding compounds of the formula X, the key intermediates in the process for the preparation of the compounds according to the invention, is achieved by the compound of the formula IX being raised to an elevated temperature in the mixture for a period of time sufficient to complete the reaction Order of magnitude of approx.



  230 to approx. 280 C heated. The course of the reaction can be followed on the basis of the rate of evolution of carbon dioxide and on thin layer chromatography, the decarboxylation generally being completed within about 45 to about 90 minutes. The reaction product, namely a 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid alkyl ester and its 6-alkyl derivatives of the formula X, can be purified by chromatographic methods. In particular in the decarboxylation of small batches of compounds of the formula IX, the reaction product of the formula X can also be distilled directly from the reaction vessel.



   The condensation of a compound of formula X with an amide of the formula:
EMI5.1
 where X and Rl have the above meanings, gives the corresponding 5-substituted 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid alkyl esters of the formula XI and XII.



   This reaction is carried out in an inert organic aprotic solvent and in the presence of phosphorus oxychloride at the reflux temperature for about 1 to about 72 hours under an inert atmosphere, after which it is refluxed for a further about 2 to about 10 hours in the presence of sodium acetate . Instead of phosphorus oxychloride, other acid chlorides, such as phosgene or oxalyl chloride, can also be used.



   According to the preferred embodiment, this condensation is carried out by adding a solution of the compound of formula X in a suitable solvent to a previously refluxed mixture of 1.1 to 2 molar equivalents of both the desired amide and phosphorus oxychloride in the same solvent , the reaction mixture thus obtained is refluxed for about 2 to about 30 hours under an argon atmosphere and then about 3 to about 10 molar equivalents of sodium acetate are added, whereupon the mixture is refluxed for a further about 4 to about 6 hours.



   Appropriate 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.



   Representative examples of N, N-dimethylamides which can be used are: N, N-dimethylthiophene-2-carboxamide, N, N-dimethylfuran-2-carboxamide, N, N-dimethyl-3-methylthiophene-2-carboxamide, N, N-dimethyl -4-methylthiophene-2-carboxamide, N, N-dimethyl-5-methylthiophene-2-carboxamide, N, N-dimethyl-4-chlorothiophene-2-carboxamide, N, N-dimethyl-5-chlorothiophene-2-carboxamide , N, N-dimethyl-3-bromothiophene-2-carboxamide, N, N-dimethyl-5-bromothiophene-2-carboxamide, N, N-dimethyl-3-methylfuran-2-carboxamide, N, N-dimethyl-4 -methylfuran-2-carboxamide, N, N-dimethyl-4-chlorofuran-2-carboxamide, N, N-dimethyl-5-chlorofuran-2-carboxamide, N, N-dimethyl-4-bromfuran-2-carboxamide, N , N-dimethyl-5-bromfuran-2-carboxamide, N, N-dimethylthiophene-3-carboxamide and N, N-dimethylfuran-3-carboxamide.



   These amides can be prepared in a conventional manner from the corresponding thiophene or furan-2- or -3-carboxylic acids, i.e. by conversion into the acid chlorides and subsequent treatment with dimethylamine.



   After alkaline hydrolysis of the alkyl ester group in a compound of the formula XI or XII, the corresponding free acids of the formula A or B are obtained. The hydrolysis is carried out in a conventional manner with an alkali metal hydroxide or alkali metal 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 a temperature from about room temperature to reflux temperature for about 30 minutes to about 4 hours under an inert atmosphere. According to a preferred embodiment, this hydrolysis is carried out with aqueous methanolic potassium hydroxide at the reflux temperature for about 2 hours.

 

   The compounds of the formulas A and B can be broken down by processes known to the person skilled in the art in order to obtain the corresponding individual isomers. For example,



  the compound of the formula A, in which R and Rl are both hydrogen and X is sulfur, are subjected to a further treatment in accordance with the following scheme:
EMI6.1


 <tb> <SEP> COOH
 <tb> <SEP> U <SEP> e.g. <SEP> COOH <SEP> <
 <tb> <SEP> split
 <tb> <SEP> (A1 <SEP>)
 <tb> d-amphetamine salt <SEP> des
 <tb> I acid isomers <SEP> the <SEP> formula <SEP> A '
 <tb> <SEP> mixture <SEP> from <SEP> d-amphetamine salt <SEP> des <SEP> d
 <tb> <SEP> acid isomers <SEP> the <SEP> formula <SEP> A ' <SEP> and <SEP> d
 <tb> <SEP> 15 <SEP>. <SEP> amphetamine salt <SEP> des <SEP> l-acid isomers <SEP> the
 <tb> <SEP> -aure isomer <SEP> formula <SEP> A '
 <tb> <SEP> the <SEP> formula <SEP> A ' <SEP> 25
 <tb>
A more detailed description of this procedure is given in Example 10 B-1.



   However, the l-acid isomers and d-acid isomers of the compounds of the formulas A and B can also be obtained by applying the known method of high pressure liquid chromatography (HPLC) to the diastereomeric a-phenylethyl esters of the compounds of the formulas A and B and then one Acid splitting. So you can e.g.



  subject the compound of the formula A, in which R and R 'are both hydrogen and X is sulfur, to a further treatment in accordance with the following scheme:
EMI6.2


 <tb> <SEP> II <SEP> II <SEP> C <SEP> COOII <SEP> COOII
 <tb> <SEP> g <SEP> I
 <tb> <SEP> (A1) <SEP>) <SEP> several
 <tb> <SEP> levels
 <tb> <SEP> I
 <tb> mixture <SEP> off <SEP> 1-a-phenyl ethyl ester <SEP> des <SEP> l-acid isomers <SEP> the
 <tb> formula <SEP> Al <SEP> and <SEP> l-a-phenyl ethyl ester <SEP> des <SEP> d-acid isomers <SEP> the
 <tb> formula <SEP> A '
 <tb> <SEP> separation <SEP> under
 <tb> <SEP> application <SEP> the <SEP> HPLC
 <tb> <SEP> train
 <tb> <SEP> 1-phenyl ethyl ester <SEP> 1-phenyl ethyl ester
 <tb> <SEP> des <SEP> l-acid isomers <SEP> des <SEP> d-acid isomers
 <tb> <SEP> the <SEP> formula <SEP> Al <SEP> the <SEP> formula <SEP> A '
 <tb> <SEP> l-acid isomer <SEP> d-acid isomer
 <tb> <SEP> the <SEP> formula

    <SEP> Al <SEP> the <SEP> formula <SEP> A
 <tb>
A more detailed description of this process is given in Example 10 B-2.



   The free acids of formula A and B can be converted to other alkyl esters of 1 to 12 carbon atoms by conventional methods, e.g. by treatment with (a) the alcohol corresponding to the desired ester in the presence of a strong mineral acid, (b) an ethereal diazoalkane or (c) the desired alkyl iodide in the presence of lithium carbonate. The l-acid isomers can be converted into their alkyl esters by processes (b) and (c) above.



   The salt derivatives of the compounds of the formulas A and B and their 1-acid isomers are prepared by treating these free acids with an appropriate amount of a pharmaceutically acceptable base. Representative pharmaceutically acceptable bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, manganese hydroxide, aluminum hydroxide, ferric hydroxide, manganese hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, dimethylamine, tripanolamine -Diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procain, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine,

   Piperidine, N-ethylpiperidine, polyamine resins and the like. The reaction is carried out in water alone or in combination with an inert, water-miscible organic solvent at a temperature of about 0 to about 100 C, preferably at room temperature. Typical inert, water-miscible organic solvents are methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio to be used of compounds of the formula A or B or their 1-acid isomers to base is chosen so that the ratio desired for any specific salt results.

  If you e.g. who wants to produce the calcium salts or magnesium salts of the compounds of the formulas A or B or of the 1-acid isomers thereof, the free acid which serves as the starting material can be treated with at least 0.5 molar equivalents of pharmaceutically acceptable base in order to produce a neutral salt. When the aluminum salts of the compounds of formula A or B or the 1-acid isomers thereof are prepared, at least 1/3 molar equivalent of the pharmaceutically acceptable base is used if one wishes to produce a neutral salt.



   According to the preferred process, the calcium salts and magnesium salts of the compounds of the formulas A and B and the l-acid isomers thereof can be prepared by mixing the corresponding sodium or potassium salts with at least 0.5 molar equivalents of calcium chloride or



  Magnesium chloride treated in an aqueous solution alone or in combination with an inert, water-miscible organic solvent at a temperature of about 20 to about 100 C. Preferably, the aluminum salts of the present compounds can be prepared by reacting the corresponding free acids with at least 1/3 molar equivalent of an aluminum alcoholate such as aluminum triethylate, aluminum tripropylate and the like in a hydrocarbon solvent such as benzene, xylene, cyclohexane and the like 2 at a temperature from approx. 20 to approx. 115 C. Similar processes can be used to prepare salts of inorganic bases that are not sufficiently soluble for easy implementation.



   It is understood that the isolation of the compounds described herein can, if desired, be accomplished using any suitable separation or purification method, such as extraction, filtration, evaporation, distillation, crystallization, thin layer chromatography, column chromatography, high pressure liquid chromatography (HPCL), or a combination of these practices. Explanations of suitable separation and isolation methods can be found in the following examples. However, other equivalent separation or isolation methods could of course also be used.



   Although the d-acid isomers are not in themselves used as medicinal agents, they can, if desired, be converted to their pharmaceutically acceptable, non-toxic esters and salts after those used to convert the l-acid isomers to their pharmaceutically acceptable, non-toxic Processes described esters and salts.



   The compounds of formulas A and B, l-acid isomers, their pharmaceutically acceptable salts and their C, l2-alkyl esters are useful as anti-inflammatory agents, analgesic agents, agglutination inhibitors, fibrinolytic agents, and smooth muscle relaxants.



  These compounds can be used both prophylactically and therapeutically.



   Agents containing these compounds are useful for the treatment and elimination of inflammation such as inflammatory conditions of the skeletal muscle system, the skeletal joints and other tissues, e.g. for the treatment of inflammatory conditions such as rheumatism, concussio, laceratio, arthritis, broken bones, post-traumatic conditions and gout. If the above conditions include pain and febrile conditions in combination with inflammation, the present compounds are useful for alleviating these conditions as well as inflammation.



   The administration of the active compounds of the formula A or B or their l-acid isomers and their pharmaceutically acceptable, nontoxic esters and salts in a suitable pharmaceutical preparation can, according to any accepted administration methods, for agents for the treatment of inflammation, pain or feverish conditions or for the Prophylaxis of the same. Thus, e.g. orally, parenterally or topically in the form of solid, semi-solid or liquid dosage forms, such as tablets, suppositories, pills, capsules, powders, solutions, suspensions, emulsions, creams, lotions, ointments or the like, preferably in the form of dosage units are suitable for the simple administration of precise doses.

  The preparations contain a conventional pharmaceutical carrier or a conventional pharmaceutical excipient and an active ingredient of the formula A or B or its l-acid isomers and its pharmaceutically acceptable, non-toxic esters and salts and can also other medical agents, pharmaceutical agents, carriers, excipients, etc. contain.



   The preferred mode of administration for the conditions indicated above is oral administration using an appropriate daily dosage which can be adjusted according to the degree of impairment. In general, a daily dosage of 25 to 500 mg of the active ingredient of the formula A or B or its 1-acid isomers and its pharmaceutically acceptable, non-toxic esters and salts is used. Most conditions respond to treatment using a dose on the order of 0.5 to 6 mg per kg body weight per day.

  For such oral administration, a pharmaceutically acceptable, non-toxic preparation is made by using any of the excipients normally used, e.g. pharmaceutical varieties of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. Such preparations can be in the form of solutions, suspensions, tablets, pills, capsules, powders, formulations for the protracted release and the like.



   The active compounds of the formula A or B or their I-acid isomers and their pharmaceutically acceptable, non-toxic esters and salts can be formulated into a suppository using, for example, polyalkylene glycols, such as polypropylene glycol, as carriers. Liquid, pharmaceutically administrable preparations can e.g.



  be prepared by dissolving, dispersing, etc. an active ingredient of the kind described above and any pharmaceutical excipients in a carrier such as water, physiological saline, aqueous dextrose, glycerin, ethanol and the like, thereby forming a solution or suspension . If desired, the pharmaceutical preparation to be administered can also contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.



   Methods for the production of such dosage forms are known or obvious to the person skilled in the art; see e.g. Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th edition, 1970. The preparation to be administered in any case contains a pharmaceutically effective amount of the active ingredient or ingredients which will alleviate the particular condition to be treated according to the teachings of the invention .



   The compounds of formula A and B and their 1-acid isomers and their non-toxic, pharmaceutically acceptable esters and salts, which have been described above, are also relaxants for the smooth muscles of the uterus and are therefore useful for maintaining the gravity of gravids Humans and mammals for the benefit of the mother and / or the fetus until the termination of pregnancy is considered to be beneficial or beneficial to the mother and / or the fetus from a medical point of view. However, it should be understood that in certain cases, e.g. if the birth has already started, i.e. if the mother experiences contractions of the uterus, especially near the date of birth, is unable to maintain the gravid state for an indefinite period.

  In such cases, pregnancy is likely to be lengthened instead; this factor can be beneficial for the mother and / or the fetus.



   In particular, the compounds of formula A and B and their 1-acid isomers and their pharmaceutically acceptable, non-toxic esters and salts are used as agents to delay the onset or postpone delivery. As used herein, the term delay in delivery is intended to include the delay in delivery caused by administration of the compound of Formula A or B or its l-acid isomers and their pharmaceutically acceptable, non-toxic esters and salts in any Time before the contractions of the uterine muscle begins.

  Thus, the term mentioned above is intended to prevent abortus in early stages of pregnancy, i.e. before the fetus is viable and include the delay in premature delivery, the latter term is sometimes used in relation to the premature labor that occurs in later stages of pregnancy when the fetus is considered viable. In any case, the agents are administered as prophylactic agents, since their administration can prevent the onset of childbirth. This administration is particularly useful in the treatment of
Women who already have spontaneous abortion, miscarriages or premature births, i.e. Have had births before the due date.

  Such administration is also useful when there is clinical evidence that pregnancy could end before this time and when administration is considered beneficial to the mother and / or the fetus.



   In animals, this treatment can also be used to synchronize births in a group of gravid animals so that they occur at the same time or approximately at the same time or at a desired time and / or at a desired location or in close to it when the births can be treated with greater ease.



   The term "postponing childbirth" as used here is intended to encompass the delay in childbirth which is caused by administration of the compounds of the formula A or B or their l-acid isomers and their pharmaceutically acceptable, non-toxic esters after the contractions of the Uterine muscle is caused. The
The patient's condition, including the time within the period of pregnancy in which the contractions started, the severity of the contractions, and the length of the contractions to date, affects the results obtained by the administration of the present compounds.

  The effect can e.g. consist in reducing the intensity and / or duration of the contractions (thereby lengthening the actual birth process) or ending the contractions at all. In any case, the effect is to increase the duration of pregnancy, although the effect can be either slight or, under appropriate circumstances, slightly greater depending on the patient's condition as described above. Such administration can serve to prevent spontaneous abortion, make birth easier and / or less painful for the mother, or the onset of the
Cause birth at a more convenient time and / or location.



   In all cases, the administration of the compounds of formula A or B or their l-acid isomers and their pharmaceutically acceptable, non-toxic esters and
Salts for the purposes set out above may be compatible with the best and / or accepted medical or veterinary practice to optimize benefits for the mother and fetus. E.g. administration should not continue beyond the date of birth until the fetus in the uterus dies.



   So it becomes a therapeutically effective amount of one
Compound of formula A or B or their 1-acid isomers and their pharmaceutically acceptable, non-toxic
Esters and salts, or a pharmaceutical preparation containing them, are administered to the gravid human or mammal by any of the usual and accepted known methods. The connections can be either individually or in
Combination with another compound or other compounds of the type defined above or with other pharmaceutical agents, carriers, excipients, etc. are administered. This connection or connections or
Preparations can be administered orally or parenterally in the form of solid, semi-solid or liquid dosage forms.

  In the typical case the administration takes place with
Help of a pharmaceutical preparation containing the pharmaceutically active compound and one or more pharmaceutical carriers or excipients.



   The administrable pharmaceutical preparations may be in the form of tablets for oral administration, tablets or suppositories for insertion into vagina or uterus, pills, capsules, liquid solutions, suspensions or the like, preferably in the form of dosage units which are simple Administration of precise doses. Conventional non-toxic solid carriers are e.g. pharmaceutical varieties of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. The active substances defined above can be formulated as suppositories by using, for example, polyalkylene glycols, such as polypropylene glycol, as carriers.

  Liquid, pharmaceutically administrable preparations can e.g. are prepared by dissolving, dispersing, etc. an active ingredient of the type defined above and any pharmaceutical excipients in a carrier such as water, physiological saline, aqueous dextrose, glycerin, ethanol and the like, to thereby form a solution or suspension . If desired, the pharmaceutical preparation to be administered can also contain small amounts of non-toxic auxiliary substances such as wetting agents or emulsifiers, pH buffering agents and the like, e.g. Sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. Methods for the production of such dosage forms are known or obvious to the person skilled in the art; see e.g.

  Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th edition, 1970. The preparation or formulation to be administered in any case contains an effective amount of the active ingredient or ingredients which delays the onset of birth or postpartum delivery pushes if the uterine contractions have already started. Generally, a daily dose of 0.5 to about 25 mg of the active ingredient is administered per kg of body weight, the administration being in the form of a single daily dose or in the form of up to three or four smaller doses, which are carried out at regular intervals during the day administered. The amount of active ingredient administered naturally depends on its relative activity.



   The following examples illustrate the invention. The abbreviation t.l.c. means thin layer chromatography, and all mixing ratios used with liquids are volume ratios. If necessary, examples are repeated to produce additional material for subsequent examples; unless otherwise stated, the reactions are carried out at room temperature (20 to 30 C).



  Preparation of the starting products a) A mixture of 23 g of 4-chlorothiophene-2-carboxylic acid (J. Iriarte et al., J. Heterocyclic Chem. 13, 393) and 80 ml of thionyl chloride is heated under reflux for 4 hours under anhydrous conditions. The excess thionyl chloride is removed and the residue is distilled under reduced pressure (60 C / 2 mm), 18 g of 4-chlorothiophene-2-carboxylic acid chloride being obtained.



   A solution of 10.5 g of 4-chlorothiophene-2-carboxylic acid chloride in 500 ml of anhydrous benzene is cooled in an ice water bath, after which dimethylamine is slowly bubbled through the solution for 30 minutes. The ice water bath is removed, maintaining the dimethylamine flow for an additional 15 minutes. The reaction mixture is then diluted with 100 ml of 10% sodium chloride solution and stirred for 5 minutes at room temperature. The organic phase is separated, washed with 10% hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure to produce N, N-dimethyl-4-chlorothiophene-2-carboxamide.



   In a similar manner, the thiophene and furan-2-carboxylic acids listed under I are converted into the N, N-dimethylamides listed under II: I II thiophene-2-carboxylic acid N, N-dimethylthiophene-2-carboxamide furan-2-carboxylic acid N , N-Dimethylfuran-2-carboxamide 3-methylthiophene-2-carboxylic acid N, N-dimethyl-3-methylthiophene-2-carboxamide 4-methylthiophene-2-carboxylic acid N, N-dimethyl-4-methylthiophene-2-carboxamide 5- Methylthiophene-2-carboxylic acid N, N-dimethyl-5-methylthiophene-2-carboxamide 5-chlorothiophene-2-carboxylic acid N, N-dimethyl-5-chlorothiophene-2-carboxamide 3-bromothiophene-2-carboxylic acid N, N-dimethyl -3-bromothiophene-2-carboxamide 4-bromothiophene-2-carboxylic acid N, N-dimethyl-4-bromothiophene-2-carboxamide 5-bromothiophene-2-carboxylic acid N, N-dimethyl-5-bromothiophene-2-carboxamide 3- Methylfuran-2-carboxylic acid N, N-dimethyl-3-methylfuran-2-carboxamide 4-methylfuran-2-carboxylic acid <RTI

    ID = 9.11> N, N-dimethyl-4-methylfuran-2-carboxamide 5-methylfuran-2-carboxylic acid N, N-dimethyl-5-methylfuran-2-carboxamide 3-chlorofuran-2-carboxylic acid N, N-dimethyl- 3-chlorofuran-2-carboxamide 4-chlorofuran-2-carboxylic acid N, N-dimethyl-4-chlorofuran-2-carboxamide 5-chlorofuran-2-carboxylic acid N, N-dimethyl-5-chlorofuran-2-carboxamide 4-bromofuran -2-carboxylic acid N, N-dimethyl-4-bromfuran-2-carboxamide 5-bromfuran-2-carboxylic acid N, N-dimethyl-5-bromfuran-2-carboxamide thiophene-3-carboxylic acid N, N-dimethylthiophene-3- carboxamide furan-3-carboxylic acid N, N-dimethylfuran-3-carboxamide b) A 250 ml three-necked round-bottomed flask, which contains a magnetic stir bar and is equipped with a drying tube filled with calcium chloride, is directly (via one of the outer necks) using a Connection piece for a template and a short water cooler (76.2 mm) connected to the acetal pyrolysis device.

  This latter device consists of a 100 ml round bottom flask previously loaded with 15.6 g of oxalic acid dihydrate and 11.82 g of bromoacetaldehyde diacetal [made from vinyl acetate as described by P.Z. Bedoukian, J.



  Am.Chem.Soc. 66, (1944) is loaded] and on which there is a 152.4 mm Vigreux column which carries a thermometer and is connected to the above-mentioned cooler.



   The three-necked flask is charged with 3.36 g of ethanolamine, which has been 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. 3-Car bomethoxymethyl-3- (2'-hydroxyethylamino) acrylic acid methyl ester of the formula III is formed immediately. When the addition is complete, the ice bath is removed and 100 ml of dry acetonitrile is added. The pyrolysis part of the apparatus is placed in an oil bath and its temperature is raised to 150 to 160 ° C. The bromoacetaldehyde solution (boiling point 80 to 83 C / 580 mm) that forms is distilled directly into the magnetically stirred solution of the vinylamine of the formula III.

  When the distillation temperature falls below 80 ° C, the pyrolysis device is removed and replaced by a reflux condenser which is provided with a drying tube which contains calcium chloride. The solution is heated to reflux for 1 hour. The solvent is removed under reduced pressure and 200 ml of methanol and 20 g of silica gel are added to the residue. This
The mixture is evaporated to dryness in vacuo and placed on a column with 200 g of silica gel which has been filled with hexane. The column is then eluted with a mixture of hexane and ethyl acetate (80:20, 500 ml) and a mixture of hexane and ethyl acetate (1: 1, 9 x 500 ml).

  Fractions 2 and 3 contain less polar impurities and 1, 3-acetone dicarboxylic acid dimethyl ester. Fractions 4 to
8 provide 4.1 g of N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetic acid methyl ester (formula IV, R = H), which after recrystallization from a mixture of ether and hexane
Has a melting point of 52 to 54 C.



   c) A solution of 4.1 g of N- (2-hydroxyethyl) -3-carbo methoxypyrrol-2-acetic acid methyl ester in 35 ml of dry
Dichloromethane, which is cooled to - 10 C, is stirred with 2.65 ml of triethylamine and then added dropwise
1.46 ml of methanesulfonyl chloride are added, the temperature of the reaction mixture being kept at -10 to -5 ° C. The
The course of the reaction is by thin layer chromatography using a mixture of chloroform and
Acetone (90:10) followed. When the reaction appears to have ended (about 30 minutes after the end of the methanesulfonyl chloride addition), 10 ml of water are slowly added.



   The organic phase is separated off, three times with 30 ml each
Washed water, dried over sodium sulfate and evaporated under reduced pressure. By crystallizing the
Residue from a mixture of dichloromethane and hexane gives 4.75 g (77.7%) of N- (2-mesyloxyethyl)
3-carbomethoxypyrrole-2-acetic acid methyl ester (formula V,
R = H) from melting point 99 to 101 C.



   d) A solution of 785 mg of N- (2-mesyloxyethyl) -3-car bomethoxypyrrol-2-acetic acid methyl ester and 1.83 g of sodium iodide in 10 ml of acetonitrile is added for one hour
Reflux heated. The cooled reaction mixture is evaporated to dryness under reduced pressure and the
Rub the residue with water. The insoluble material is separated off by filtration and air-dried, 840 mg (97%) of N- (2-iodoethyl) -3-carbomethoxy pyrrole-2-acetic acid methyl ester (formula VI, R = H) from
Melting point 137 to 138 C.



   e) A solution of 1 g of N- (2-iodoethyl) -3-carbomethoxy pyrrole-2-acetic acid methyl ester in 5 ml of dry dimethylformamide is under an argon atmosphere with 137 mg
50% sodium hydride stirred in mineral oil. The reaction mixture is kept at room temperature for 30 minutes and then quenched with 100 ml of water. The product is extracted three times with 50 ml of ethyl acetate. 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 (4: 1) as the eluent gives 500 mg (80%) of 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole- 1, 7-dicarboxylic acid dimethyl ester (formula VII, R = H) from melting point 70 to 71 C.



   A solution of 1.80 g of 1,2-dihydro-3H-pyrrolo- [1,2-a] - pyrrole-1,7-dicarboxylic acid dimethyl ester in 20 ml of methanol is mixed with a solution of 4.48 g of potassium hydroxide in 20 ml of water treated and the reaction mixture heated to reflux for 6 hours. The cooled solution is evaporated to dryness and the residue treated with 50 ml of saturated sodium chloride solution. The resulting solution is acidified with 6 normal hydrochloric acid and extracted three times with 50 ml of ethyl acetate. 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-dicarbon - Acid (Formula VIII, R = H) of melting point 220 C (with decomposition).



   f) A solution of 1.34 g of 1,2-dihydro-3H-pyrrolo- [1,2a] pyrrole-1,7-dicarboxylic acid in 50 ml of isopropanol, which is cooled in an ice bath, is saturated with gaseous hydrogen chloride , keeping the temperature of the reaction mixture below 50 C. The ice bath is then removed and the reaction mixture is stirred at room temperature for 1.5 hours and evaporated to dryness under reduced pressure. The residue is mixed with 10 ml of benzene and the solution is evaporated again in vacuo; this process is repeated three times in total to remove the excess hydrogen chloride.

  1.58 g (96%) of 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrol-1-carboxylic acid isopropyl ester-7-carboxylic acid (formula IX, R = H, R2 = iC3H7), which has a melting point of 144 to 145 C after crystallization from a mixture of methanol and ethyl acetate.



   If methanol, ethanol, propanol or n-butanol is used instead of isopropanol in the above process, the following is obtained in a similar manner: 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid methyl ester - 7-carboxylic acid, 1; 2-dihydro-3H-pyrrolo- [1, Za] -pyrrole-1-carboxylic acid, ethyl ester-7-carboxylic acid, 1, 2-dihydro-3H-pyrrolo- [1, 2-a] - pyrrole-l-carboxylic acid propyl ester-7-carboxylic acid and 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid butyl ester-7-carboxylic acid.



   g) 1.054 g of 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid isopropyl ester-7-carboxylic acid are heated to 240 to 250 ° C. in a dry 10 ml round-bottom flask, whereby the reaction product is distilled directly from the reaction vessel. In this way, 745 mg (87%) 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isopropyl ester (formula X, R = H, R2 = iC3H7), a pale yellow O1 , with the following physical constants:
MeOH U.V .: h 215 nm (E 6020); max CHCl I.R .:

   v 3 1725 cm-l; max CDCl N.M.R .: 8 3 1.22 (d, J = 7 Hz, 6H), 2.4C2.90 (m,
TMS 2H), 3.604.20 (m, 2H), 4.65-5.2 (M, 1H), 5.73-5.92 (m, lH), 6.10 (6, J = 3 Hz, lH), 6.43-6.53 (m, lH).

 

   h) A 100 ml three-necked round bottom flask equipped with a condenser, a nitrogen inlet tube and a bubble counter is charged with 5.0 g 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isopropyl ester-7 -carboxylic acid loaded. The device is purged thoroughly with nitrogen and the nitrogen flow is turned off. The device is immersed in an oil bath heated to 270 ° C and the reaction is followed by the rate of evolution of carbon dioxide (bubble counter) and by thin layer chromatography on silica gel using a mixture of benzene, dioxane and acetic acid (90: 10: 1) as a developing solvent. The reaction is almost complete after 45 minutes.

  After an hour, the vessel is removed from the oil bath, whereupon the contents of the reaction flask are placed in one
Round bottom flask is transferred with 500 ml acetone. The solvent is removed under reduced pressure and the
The residue was purified by column chromatography over 100 g of silica gel. The fractions eluted with a mixture of hexane and benzene (70:30) or hexane and benzene (50:50) yield 2.77 g (68%) of 1,2-dihydro-3H-pyrrolo- [1,2-a ] -pyrrole-l-carboxylic acid isopropyl ester (formula X, R = H, R2 = iC3H7), an oil whose physical constants are identical to those of the product of section (g).



   i) 710 mg of a 50% suspension of sodium hydride in mineral oil are washed with anhydrous hexane under a nitrogen atmosphere and then suspended in 50 ml of dimethyl formamide. The suspension is cooled to -5 C and mixed with 4.5 g of N- (2-mesyloxymethyl) -3-carbomethoxy-pyrrole-2-acetic acid methyl ester, the reaction mixture being stirred at -5 to 0 C for one hour. It is then poured into ice-cooled sodium chloride solution and extracted several times with benzene. The combined extracts are washed with water, dried and evaporated to dryness under reduced pressure.

  The solid residue is crystallized from ether, giving 1,2-dihydro 3H-pyrrolo- [1, 2-a] -pyrrole-1, 7-dicarboxylic acid dimethyl ester (formula VII, R = H), which with the in section ( e) product obtained is identical.



   j) A solution of 232.5 mg N, N-dimethylthiophene-2carboxamide and 0.15 ml phosphorus oxychloride in 2 ml
1,2-dichloroethane is heated to reflux for 30 minutes. This solution comes with a solution of 181 mg
Isopropyl 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate in 2 ml of 1,2-dichloroethane. The reaction mixture is heated to reflux under an argon atmosphere for 8 hours, treated with 450 mg of sodium acetate and refluxed for a further 5 hours.



  The resulting mixture is then evaporated to dryness and the residue is chromatographed on 12 g of silica gel, eluting with a mixture of hexane and ethyl acetate (3: 1); 5- (2-Theno yl) -1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid isopropyl ester (formula XI, R and Rl = H, R2 = iC3H7) is obtained in this way , X = 5).



     Example A
A solution of 300 mg of 5- (2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid isopropyl ester in 30 ml of 50% aqueous methanol, which contains 1% potassium hydroxide , is heated to reflux under a nitrogen atmosphere for 2 hours. The methanol is then removed under reduced pressure and the remaining basic solution is diluted with water and extracted with chloroform to remove any unsaponifiable product. The aqueous alkaline phase is acidified with 20% hydrochloric acid and extracted three times with ethyl acetate.

  The combined extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure; In this way, 250 mg of crude 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (formula A, round Rl = X = S) are obtained a melting point of 145 to 148 "C, which melts after recrystallization from ethyl acetate at 152 to 153 C with decomposition.



   Example 1 B-1
410 mg of 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [l, 2-a] - pyrrole-1-carboxylic acid and 212.3 mg of d-amphetamine are dissolved in 15 ml of absolute methanol and 15 Heated to reflux for minutes after which the methanol was removed in vacuo. The resulting diastereomeric mixture of d-amphetamine salts (612.3 mg) is dissolved in the smallest possible amount of hot (55 "C) acetone and cooled to room temperature, the precipitate is filtered off and washed with 2 ml of cold 10" C) acetone.

  This recrystallization process is repeated three more times, with 247 mg of l-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid d-amphetamine salt a CHCl3
D - 181.3 "and a melting point of 168 to 170 C.



   The d-amphetamine salt of the 1-acid isomer obtained immediately before is added to 30 ml of methylene chloride and shaken three times with 10 ml of 0.1 normal aqueous hydrochloric acid. The methylene chloride solution is washed three times with 15 ml of a mixture of saturated sodium chloride and water (volume ratio 2: 1) and dried over anhydrous sodium sulfate. Filtration and removal of the organic solvent in vacuo gives 90 mg of 1-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] -
CHCl3 pyrrole-l-carboxylic acid with a - 177 "and one
D melting point from 134 to 135.5 "C.



   The resulting from the split, i.e. the multiple crystallization resulting from acetone mother liquors of the diastereomeric mixture of d-amphetamine salts described above are combined and reacted using the hydrochloric acid cleavage procedure described above to give 245 mg of a mixture in which d-5- (2-The noyl) -l, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid is enriched and the l-5- (2-thenoyl) - 1, 2-dihydro-3H-pyr- contains rolo- [1,2-a] pyrrole-1-carboxylic acid.

  This mixture is racemized as follows to a mixture (1: 1) of the d and isomers of 5- (2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] pyrrole-1-carboxylic acid ( circulated): The 245 mg of the mixture in which the d-isomer is enriched and which contains the above-described l-isomer are dissolved in 15 ml of methanol. 1.5 ml of methanol and 350 mg of sodium hydroxide are added and the solution is refluxed under nitrogen for one hour. The methanol is removed in vacuo; 2.5 ml of water are added, and the solution is acidified to pH = 2 with 10% aqueous hydrochloric acid. The mixture is extracted three times with 10 ml of methylene chloride.

  The methylene chloride extracts are combined and washed neutral (pH = 7), dried over anhydrous sodium sulfate and concentrated in vacuo to give 230 mg of a crude crystalline product which, when recrystallized from a mixture of ethyl acetate and hexane, 180 mg of 5- (2 rhenoyl ) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carbon-
MeOH acid with a D 0.0 "and a melting point of 152 to
D 154 "delivers.

 

   In the same way, other optically active d-bases can be used in the above method instead of d-amphetamine. Particularly suitable are: d-p-bromo-a-phenylethylamine d-a-phenylethylamine d-a-1-naphthylethylamine and d-a-2-naphthylethylamine, with d-p-bromo-a-phenylethylamine being most preferred after d-amphetamine.



   Similarly, the d-acid isomers, e.g. d-5 (2-Thenoyl) -1, 2-dihydro-3H-pyrrolo- [1 2-al-pyrrole-1-carboxylic acid, obtained if the optically active bases are used instead of the optically active d-bases, e.g. I-amphetamine instead of d-amphetamine.



   Example 1 B-2
A solution of 118 mg of 5- (2-thenoyl) -1,2-dihydro-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid in 8 ml of dry benzene is mixed with 0.234 g of trifluoroacetic anhydride. The mixture is stirred at room temperature for 10 minutes; the resulting solution is cooled to 0 to 5 C and mixed with 0.55 g of dry triethylamine and immediately thereafter with 0.2 g of 1-a-phenylethyl alcohol. The reaction solution thus obtained is stirred at room temperature for 15 minutes and poured into 20 ml of water containing 1 ml of triethylamine, followed by extraction with ethyl acetate.

  The ethyl acetate extract is dried over sodium sulfate, whereupon the solvent and excess 1-a-phenyl-ethyl alcohol are removed in vacuo; 0.166 g of a mixture of 1-5- (2-thenoyl) -1,2-dihydro-3H-pyrro-1O- [1,2-a] -pyrrole-1-carboxylic acid, la-phenylethyl ester and d-5 is obtained (2-Thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid la-phenylethyl ester. This mixture is by high pressure liquid chromatography (using 4% ethyl acetate containing hexane on an 11 mm x
50 cm measuring column with 10 pm Lichrosorb S1-60) ge
MeOH separates, giving 68 mg of a more polar ester (? D
MeOH - 149.1 ') and 73 mg of a less polar ester (a D + 105.2 ").



   62.1 mg of the more polar ester are dissolved in 3 ml of dry benzene. The solution is cooled to 15 to 20 C and treated with 2.5 ml of trifluoroacetic acid, whereupon the solution
Stirred for 1 hour and 40 minutes at room temperature. The reaction solution is poured into 60 ml of dry benzene, after which the solvents are removed in vacuo and at ambient temperature. Purification is done by high pressure liquid chromatography (using a column of the type described above, but using hexane containing 35% ethyl acetate in 0.5% acetic acid instead of the hexane containing 4% ethyl acetate) and provides 41 mg 1-5- (2-Thenoyl) -1,2-dihydro-3H-pyr-
MeOH rolo- [1,2-a] pyrrole-1-carboxylic acid with a MeOH - 144 "and
D a melting point of 130 to 132 "C.



   Similarly, cleavage of the less polar ester after that provides for cleavage of the more polar
Ester's described method d-5- (2-thenoyl) - 1, 2-dihy-
MeOH dro-3H-pyrrolo- [l, 2-aj-pyrrole-1-carboxylic acid with a D + 142.4 and a melting point of 127 to 129 "C. The d-acid isomer thus obtained can, if desired, after the
Processes known to those skilled in the art are racemized (and circulated).



   Other dl compounds can be converted to the corresponding isomers and d-isomers in a similar manner.



   Example 2
A solution of 336 mg of 5- (2-thenoyl) -l, 2-dihydro-3H pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid isopropyl ester in 10 ml
Methanol is treated with a solution of 690 mg potassium carbonate in 5 ml water. The reaction mixture becomes 2
He heated to reflux for hours under a nitrogen atmosphere, cooled and evaporated to dryness. The residue is in 10 ml of 10% aqueous hydrochloric acid and 50 ml
Water taken up and the resulting mixture extracted twice with 50 ml of ethyl acetate. The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure.

  Crystallization of the residue from ethyl acetate gives 5- (2 thenoyl) -1, 2-dihydro-3H-pyrrolo- [1, 2-aj-pyrrole-1-carboxylic acid, which is identical to the product obtained in Example 1A.



  Preparation of starting materials (k) By following the procedures of section (g) or (h), the remaining compounds obtained in section (f) are converted into the following compounds:
1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid.



  methyl ester, 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid ethyl ester, 1,2-dihyGro-3H-pyrrolo- [1,2a] -pyrrole-1-carbon- acid propyl ester and 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid butyl ester.



   The following compounds are obtained by condensing these compounds with N, N-dimethylthiophene-2-carboxamide according to the procedure of Example 9: 5- (2-Thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2a] - methyl pyrrole-l-carboxylate, 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid ethyl ester, BmMaexoH 265.328 nm (g 7580, 17780), max. 5 - (2-Thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid propyl ester and 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [ 1,2-a] -pyrrole-1-carboxylic acid butyl ester.



      Example 'Example 3
Following the procedure in section (j), using 1.1 to 2 molar equivalents of N, N-dimethylfuran-2-carboxamide, N, N-dimethyl-3-methylthiophene-2-carboxamide, N, N-dimethyl 4-methylthiophene-2-carboxamide, N, N-dimethyl-5-methylthiophene-2-carboxamide, N, N-dimethyl-4-chiorthiophene-2-carboxamide, N, N-dimethyl-5-chlorothiophene-2-carboxamide, N, N-dimethyl-3-bromothiophene-2-carboxamide, N, N-dimethyl-4-bromothiophene-2-carboxamide, N, N-dimethyl-5-bromothiophene-2-carboxamide, N, N-dimethyl-3- methylfuran-2-carboxamide, N, N-dimethyl-4-methylfuran-2-carboxamide, N, N-dimethyl-5-methylfuran-2-carboxamide, N, N-dimethyl-3-chioffuran-2-carboxamide, N, N-dimethyl-4-chlorofuran-2-carboxamide, <RTI

    ID = 12.38> N, N-dimethyl-5-chlorofuran-2-carboxamide, N, N-dimethyl-4-bromfuran-2-carboxamide and N, N-dimethyl-5-bromfuran-2-carboxamide instead of N, N -Dimethylthiophene-2-carboxamide and while monitoring the course of the reaction by thin layer chromatography, the following compounds:
5- (2-Furoyl) - 1,2-dihydro-3H-pyrrolo- [l, -a] -pyrrole-1 - 1-carboxylic acid isopropyl ester, an oil with the following physical constants:
U.V .: MeOH275, 332.5 nm (± 8900, 17800); Max
I.R .:

  VCHC13 max 1735, 1685, 1605 cm-Ú; N.M.R .: # CDCl3
TMS 1.23 [d, 6H, J = 6Hz; (CH3) 2CH], 2.60-3.00 (m, 2H), 3.90 (dd, 1H, JAX = 6 Hz; JBX = 7Hz; H -1), 1H, J = 4 Hz; H-6), 7.43 ppm (m, 1H); 4.10-4.67 (m, 2H), 4.95 [sept., 1H, J = 6 Hz; (CH3) 2CH], 6.00 M.S. m / e: 287 (M +), (d, 1H, J = 4 Hz;

  H-7), 6.40 (m, lH), 7.10 (m, lH), 7.23 (d,
5- (3-methyl -2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid isopropyl ester,
5- (4-methyl -2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid isopropyl ester,
5- (5-methyl -2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid isopropyl ester, m.p.

   82-82.5 "C,
5- (4-chloro-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2a] -pyrrole-l-carboxylic acid isopropyl ester,
5- (5-chloro-2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-l-carboxylic acid isopropyl ester,
5- (3-bromo-2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid isopropyl ester,
5- (4-bromo-2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid isopropyl ester,
5- (5-bromo-2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isopropyl ester,
5- (3-methyl -2-furoyl) -1, 2-dihydro-3H-pyrrolo- [l, 2a] pyrrole-l-carboxylic acid isopropyl ester,
5- (4-methyl -2- furoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid isopropyl ester,
5- (5-methyl -2- <RTI

    ID = 13. 22> furoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid isopropyl ester,
5- (3-chloro-2-furoyl) - 1, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole l-carboxylic acid isopropyl ester,
5- (4-chloro-2-furoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid isopropyl ester,
5- (5-chloro-2-furoyl) - 1, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid isopropyl ester,
5- (4-bromo -2- furoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] pyrrole-1-carboxylic acid isopropyl ester or 



   5- (5-Bromo -2- furoyl) -1, 2-dihydro-3H-pyrrolo- [l, 2a] pyrrole-l-carboxylic acid isopropyl ester.    



   Upon hydrolysis of the isopropyl ester group by the processes of Example 1A or 2, the corresponding free acids are obtained, namely: 5- (2-furoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1 -carboxylic acid, mp. 184-184.5 oC,
5- (3-methyl -2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid,
5- (4-methyl -2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1, 2-a] pyrrole-1-carboxylic acid,
5- (5-methyl -2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid, m.p. 

   169-170 "C,
5- (4-chloro-2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-aj-pyrrole-1-carboxylic acid,
5- (5-chloro -2- thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid,
5- (3-bromo-2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,
5- (4-bromo-2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid,
5- (5-bromo-2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole- carboxylic acid,
5- (3-methyl -2- furoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid,
5- (4-methyl -2- furoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] pyrrole-1-carboxylic acid,
5- (5-Methyl -2- furoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1

   -carboxylic acid,
5- (3-chloro-2-furoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid,
5- (4-chloro-2-furoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid,
5- (5-chloro-2-furoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid,
5- (4-bromo -2- furoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] pyrrole-1-carboxylic acid and
5- (5-Bromo -2- furoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid.    



  Preparation of the starting products (1) A 250 ml three-necked round-bottomed flask, which contains a magnetic stirring rod 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, with stirring, 8 with drops , 7 g of 1,3-acetone dicarboxylic acid ester dimethyl ester treated.  3-Carbomethoxymethyl-3- (2'-hydroxyethylamino) acrylic acid methyl ester of the formula III is formed immediately.  When the addition is complete, the ice bath is removed and 80 ml of dry acetonitrile is added.  The reaction mixture is then treated dropwise with 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile and then heated to reflux for 2 hours. 



  The solvent is then removed under reduced pressure and 200 ml of methanol and 20 g of silica gel are added to the residue.  This mixture is evaporated to dryness in vacuo and placed on a column with 200 g of silica gel which has been filled in hexane, the column being eluted with mixtures of hexane and ethyl acetate.  The fractions, which were eluted with a mixture of hexane and ethyl acetate (1: 1), give N- (2-hydr oxyethyl) -3-carbomethoxypyrrole-2-acetic acid methyl ester (formula IV, R = H), which corresponds to that in Section (b) product obtained is identical. 



   (m) A solution of 6 ml of ethanolamine in 5 ml of water is mixed with 1.74 g of 1,3-acetone dicarboxylic acid dimethyl ester.  The resulting mixture is rapidly cooled to -10 ° C and treated dropwise with 1.67 ml of 1-bromoacetone with stirring over 15 minutes while maintaining the reaction mixture at a temperature of not more than 40 ° C.  When the addition is complete, the dark reaction mixture is stirred for a further hour at room temperature and then poured into a mixture of hydrochloric acid and ice saturated with solid sodium chloride and extracted three times with 100 ml of ethyl acetate each time.  

  The combined organic extracts are washed neutral with cold water, dried over 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 (70:30) as the eluent gives 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetic acid, which melts after recrystallization from a mixture of methylene chloride and hexane at 78 C and has the following analysis:
Analysis for C12H17NO5:
Calculated: C 56.45; H 6.71
Found: C 56.41; H 6.73. 



   In a similar manner, but using a stoichiometrically equivalent amount of l-bromo-2-butanone, l-bromo-2-pentanone or  l-Bromo-2-hexanone instead of l-bromoacetone gives: N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetic acid methyl ester, N- (2-hy & xyethyl) -3 -carbomethoxy-4-propylpyrrole-2-acetic acid methyl ester and
N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetic acid methyl ester. 



   (n) By following the procedure of section (c), N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrol-2-acetic acid methyl ester (formula IV, R = CH3) is converted into N- (2-mesyloxy ethyl) ) -3-carbomethoxy-4-methylpyrrole-2-acetic acid methyl ester, which is converted to 1,2-dihydro-6methyl-3H-pyrrolo- [1,2a] -pyrrole- in dimethylformamide with sodium hydride by the process of section (i) l, 7-dicarboxylic acid dimethyl ester is cyclized. 



   By hydrolysis of the last-mentioned compound with potassium hydroxide by the process in section (e) and subsequent selective esterification at carbon atom 1 and decarboxylation in carbon atom 7 by the process in sections (f) or  (h) is obtained one after the other
1,2-Dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylic acid, 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2 -a] -pyrrole-1-carboxylic acid isopropyl ester-7-carboxylic acid and 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isopropyl ester (formula X, R = CH3, R2 = iC3H7). 



   Similarly, using N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetic acid methyl ester, N- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrrole-2-acetic acid methyl ester and N - (2-Hydroxyethyl) -3 carbomethoxy-4-butylpyrrole-2-acetic acid methyl ester instead of N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetic acid methyl ester as end products: 1, 2-dihydro-6-ethyl-3H -pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isopropyl ester, 1,2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isopropyl ester or 



     
1,2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isopropyl ester. 



   (o) According to the procedure in section (1), 1,2-di hydro-6-methyl-3H-pyrrolo- [1,2a] pyrrole-1-carboxylic acid isopropyl ester with N, N-dimethylthiophene-2-carboxamide to 5- (2-thenoyl) - 1, 2-dihydro-6-methyl-3H-pyrrolo- [1, 2-a] -pyrrol-l-carboxylic acid isopropyl ester (formula XI, R = CH3, R '= H , R2 = iC3H7, X = S) with a melting point of 102.5 C. 



  In a similar way, but using the N, N-dimethylthiophene or  N, N-dimethylfuran -2-carboxamide instead of N, N-dimethylthiophene -2-carboxamide, the following compounds are obtained: 5- (2-furoyl) - 1, 2-dihydro-6-methyl-3H-pyrrolo- [1 , 2-a] pyrrole - 1 - carboxylic acid isopropyl ester, 5- (3-methyl -2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole -1- isopropyl carboxylate, 5- (4-methyl -2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole -1-isopropyl carboxylate, 5- (5-methyl -2 - thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole - 1-carboxylic acid isopropyl ester, 5- (4-chloro-2-thenoyl) - 1, 2-dihydro- 6-methyl-3H-pyrrolo- [1, 2-a] -pyrrole - 1-carboxylic acid isopropyl ester,

   5- (5-Chloro-2-thenoyl) - 1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole - 1 - carboxylic acid isopropyl ester, 5- (3-bromo-2-thenoyl ) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole -1-carboxylic acid isopropyl ester, 5- (4-bromo-2-thenoyl) - 1 2-dihydrn-6-methyl -3H-pyrrolo- [1, 2-a] pyrrole - 1 - carboxylic acid isopropyl ester, 5- (5-bromo-2-thenoyl) - 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2- a] -pyrrole - 1 - carboxylic acid isopropyl ester, 5- (3-methyl -2-furoyl) - 1, 2-dihydro-6-methyl-3H-pyrrolo- [1, 2-aj-pyrrole -1 - carboxylic acid isopropyl ester, 5- (4-methyl -2-furoyl) - 1,2-dihydrn-6-methyl-3H-pyrrolo- [1,2-a] pyrrole - 1-carboxylic acid isopropyl ester;

   5- (5-Methyl -2- furoyl) - 1, 2-dihydrn-6-methyl-3H-pyrrolo- [1, 2-a] -pyrrole - 1 - carboxylic acid isopropyl ester, 5- (3-chloro-2-furoyl ) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole - 1-carboxylic acid isopropyl ester, 5- (4-chloro -2-furoyl) -1,2-dihydro-6- methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid isopropyl ester, 5- (5-chloro-2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2 -a] -pyrrole-1-carboxylic acid isopropyl ester, 5- (4-bromo-2-furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2a] -pyrrole-1-carboxylic acid isopropyl ester or 



      5- (5-Bromo -2- furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole -1-carboxylic acid isopropyl ester. 



   The remaining end products obtained in section (s) are likewise converted into the corresponding 5-furoyl or 5-thenoyl derivatives.  Representative compounds obtained in this way are: 5- (2-thenoyl) -1,2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] pyrrole -1-carboxylic acid isopropyl ester, 5- (2- Furoyl) - 1, 2-dihydro-6-propyl-3H-pyrrolo- [1, 2-a] pyrrole - 1 - carboxylic acid isopropyl ester, 5- (3-methyl -2-thenoyl) -1,2-dihydro-6 -butyl-3H-pyrrolo- [1,2-a] pyrrole - 1-carboxylic acid isopropyl ester, 5- (4-chloro-2-thenoyl) - 1, 2-dihydro-6-ethyl-3H-pyrrolo- [1, 2-a] -pyrrole - 1 - carboxylic acid isopropyl ester, 5- (5-methyl -2-furoyl) - 1, 2-dihydro-6-propyl-3H-pyrrolo- [1, 2-a] -pyrrole - 1 - carboxylic acid isopropyl ester respectively. 



  5- (3-Chloro-2-furoyl) - 1, 2-dihydro-6-butyl-3H-pyrrolo- [1, 2-a] -pyrrole -1 - carboxylic acid isopropyl ester. 



   Example 4
A solution of 500 mg of 5- (2-thenoyl) -1,2-dihydro-6methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid isopropyl ester in 15 ml of methanol is mixed with a solution of 1.05 g of potassium carbonate treated in 8 ml of water.  The reaction mixture is heated to reflux under a nitrogen atmosphere for 3 hours, cooled and evaporated to dryness.  The residue is taken up in 10 ml of 10% aqueous hydrochloric acid 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- (2-thenoyl) - 1, 2-dihydro-6-methyl-3Hpyrrolo- [1,2-a] pyrrole -1-carboxylic acid (Formula A, R = CH3, Rl = H, X = S) with a melting point of 166 C. 



   The remaining isopropyl esters obtained in section (o) are converted into the corresponding free acids, namely: 5- (2-furoyl) -1, 2-dihydro-6-methyl-, in a similar manner or by the hydrolysis process of Example 1A. 3H-pyrrolo- [1,2-a] pyrrole -1-carboxylic acid, 5- (3-methyl-2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a ] -pyrrole-1-carboxylic acid, 5- (4-methyl-2-thenoyl) - 1 2-dihydro-6-methyl-3H-pyrrolo- [1, 2-a] -pyrrole - 1-carboxylic acid, 5- ( 5-methyl-24henoyl) - 1, 2-dihydro-6-methyl-3H-pyrrolo- [1, 2-aj-pyrrole - 1 - carboxylic acid, 5- (4-chloro-2-thenoyl) -1,2- dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole - 1-carboxylic acid, 5- (5-chloro-2-thenoyl) - 1,2-dihydro-6-methyl-3H-pyrrolo- [1, 2-a] pyrrole - 1 -

   carboxylic acid, 5- (3-bromo-2-thenoyl) - 1, 2-dihydro-6-methyl-3H-pyrrolo- [1, 2-a] pyrrole - 1 - carboxylic acid, 5- (4-bromo-2 -thenoyl) - 1, 2-dihydro-6-methyl-3H-pyrrolo- [1, 2-a] -pyrrole -1-carboxylic acid, 5- (5-bromo-2-thenoyl) - 1, 2-dihydro- 6-methyl-3H-pyrrolo- [1, 2-a] pyrrole - 1 - carboxylic acid, 5- (3-methyl-2-furoyl) - 1, 2-dihydro-6-methyl-3H-pyrrolo- [1 , 2-a] pyrrole - 1 - carboxylic acid, 5- (4-methyl-2-furoyl) - 1, 2-dihydro-6-methyte-3H-pyrrolo- [1, 2-a] pyrrole - 1 - carboxylic acid, 5- (5-methyl-2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole - 1-carboxylic acid, 5- (3-chloro-2 -furoyl) - 1, 2-dihydro-6-methyl-3H-pyrrolo- [1, 2-a] pyrrole - 1 - carboxylic acid,

   5- (4-Chloro-2-furoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylic acid, 5- (5-chloro-2-furoyl ) - 1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2a] pyrrole-l-carboxylic acid, 5- (4-bromo-2-furoyl) - 1, 2-dihydro-6-methyl- 3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylic acid, 5- (5-bromo-2-furoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [1, 2-a ] pyrrole -1 - carboxylic acid, 5- (2-thenoyl) - 1,2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] pyrrole - 1 - carboxylic acid, 5- (2-furoyl ) - 1, 2-dihydro-6-propyl-3H-pyrrolo- [1, 2-a] pyrrole -1 - carboxylic acid, 5- (3-methyl-2-thenoyl) -1,2-dihydro-6- butyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid, 5- (4-chloro-2-thenoyl) -1,2-dihydro-6-ethyl-3H-pyrrolo- [1,2 -a] -pyrrole-1-carboxylic acid,

   5- (5-methyl-2-furoyl) -1,2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] pyrrole -1-carboxylic acid or 



  5- (3-chloro-2-fluoryl) -1,2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid. 



  Preparation of the starting products (p) A solution of 232.5 mg of N, N-dimethylthiophene-3carboxamide and 0.15 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is heated to reflux for 30 minutes.  A solution of 181 mg of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid isopropyl ester in 2 ml of 1,2-dichloroethane is added to this solution.  The reaction mixture is heated to reflux under an argon atmosphere for 8 hours, treated with 450 mg of sodium acetate and refluxed for a further 5 hours. 



  The resulting mixture is then evaporated to dryness and the residue is chromatographed on 12 g of silica gel, eluting with a mixture of hexane and ethyl acetate (3: 1) and 5- (3-thenoyl) - 1, 2-dihydro-3H-pyrro - 1O- [1,2-a] pyrrole-1-carboxylic acid isopropyl ester (formula MI, R = H, R2 = iC3H7, X = S). 



   Similarly, 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isopropyl ester and 1,2-di hydro-6-propyl-3H-pyrrolo- [1 , 2-a] -pyrrole-1-carboxylic acid isopropyl ester in 5- (3-thenoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid isopropyl ester or .  5- (3-Theoyl) -l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2a] -pyrrole-l-carboxylic acid isopropyl ester. 



   The corresponding 5- (3-furoyl) derivatives, namely 5- (3-furoyl), are obtained using N, N-dimethylfuran-3-carboxamide instead of N, N-dimethylthiophene-3-carboxamide. 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid isopropyl ester, an oil with the following physical constants:
MeOH U. V. : X 222, 244-277 (shoulder), 314 nm max (86750.4250, 14800); CHCl3 I. R. : v 1730, 1610, 1560 cm- '; max CDC13 N. M. R. :

   6 TMS 1.23 [d, 6H, J = 6 Hz; (CH3) 2CH], 2.50-3.00 (m, 2H), 3.92 (dd, 2H, JAX = 6 Hz, JBX = 7 Hz; H-1), 4.104.60 (m, 2H) , 4.95 [sept. , 1H, J = 6 Hz; (CH3) 2CH], 5.95 (d, 1H, J = 4 Hz; H-7), 6.78 (m, 1H), 6.83 (d, 1H, J = 4 Hz; H-6) , 7.30 (m, 1H), 7.83 ppm (m, 1H);
M. S.  m / e: 270 (M +), 5- (3-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isopropyl ester and 5- (3- Furoyl) -1,2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid isopropyl ester. 



      Example 5
A solution of 300 mg of 5- (3-thenoyl) -1,2-dihydro-3H pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isopropyl ester in 30 ml of 50% aqueous methanol containing 1% potassium hydroxide , is heated to reflux under a nitrogen atmosphere for 2 hours.  The methanol is then removed under reduced pressure and the remaining basic solution is diluted with water and extracted with chloroform to remove any unsaponifiable product.  The aqueous alkaline phase is acidified with 20% hydrochloric acid and extracted three times with ethyl acetate. 

  The combined extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure, 250 mg of crude 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1- carboxylic acid (formula B, R = H, X = S) receives. 



   The remaining compounds obtained in section (p) are converted into the free acids by the same method, namely in: 5- (3-thenoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [1, 2 -a] -pyrrol-l-carboxylic acid, 5- (3-thenoyl) -1, 2-dihydro-6-propyl-3H-pyrrolo- [1, 2-a] -pyrrole-l-carboxylic acid, 5- (3-furoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid, m.p.  156 "C,
5- (3-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid and
5- (3-Furoyl) -1,2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid. 

 

   Example 6
A solution of 200 mg of 5- (2-furoyl) - 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 that Reaction mixture for 30 minutes
Kept at room temperature.  The solvents and the excess reagent are removed under reduced pressure and the residue is crystallized from a mixture of ethyl acetate and methanol, giving 5- (2-furoyl) - 1, 2-di-hydro-3H-pyrrolo- [1, 2- a] -pyrrole-1-carboxylic acid methyl ester. 



   In the same way, but using diazoethane and diazopropane instead of diazomethane, 5- (2-furoyl) - 1, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid ethyl ester or .  5- (2-Furoyl) - 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid propyl ester obtained. 



   Similarly, the remaining free acids obtained in Examples 1A, 1B-1, 1B-2 and 3 and the acids of Examples 4 and 5 are converted to the corresponding methyl, ethyl and propyl esters.  Representative compounds obtained in this way are: 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid methyl ester, 5- (2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole- 1-carbonic acid ethyl ester, 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [1, 2- a] -pyrrole- l-carboxylic acid propyl ester and the methyl, ethyl and propyl esters of 1-5- (2-thenoyl) -1,2- dihydro-3H-pyrrolo- [l, 2-a] -pyrrole- 1-carboxylic acid. 



   Example 7
A solution of 300 mg of 5- (2-thenoyl) -1, 2-dihydro-3H pyrrolo- [1,2-a] pyrrole-l-carboxylic acid in 5 ml 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 on aluminum oxide; 5- (2-Thenoyl) - 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid isoamyl ester is obtained.    



   In the same way, other esters, e.g. B.  Pentyl, hexyl, octyl, nonyl and dodecyl esters and the like. of 5- (2 Thenoyl) - 1,2-dihydro-3H-pyrrolo-l 1,2-a] -pyrrole-1-carboxylic acid, if other alcohols, e.g. B.  Pentyl, hexyl, octyl, nonyl and dodecyl alcohol and the like. , used instead of isoamyl alcohol. 



   Following the same procedure, the free acids obtained in Examples 1 B-1, 3, 4 and 5 are esterified with the corresponding alcohol to produce the corresponding esters, e.g. B. : 5- (2-Furoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isoamyl ester, 5- (4-methyl-2-thenoyl) -1,2 -dihydro-3H-pyrrolo- [1,2-a] -pyrrol- 1 -carboxylic acid pentyl ester, 5 (5-chloro-2-thenoyl) - 1,2-dihydro-3H-pyrrolo- [l, 2-a ] -pyrrole-1-carboxylic acid hexyl ester,

   5- (4-bromo-2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2a] pyrrole-1-carboxylic acid isoamyl ester, 5- (2-furoyl) -1, 2-dihydro-3H- pyrrolo- [1, 2-aj-pyrrole-1-carboxylic acid octyl ester, 5- (3-methyl-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1 -n-carboxylic acid esters, 5- (3-chloro-2-furoyl) - 1, 2-dihydro-3H-pyrrolo- [1,2a] -pyrrole-1-carboxylic acid dodecyl ester, 5- (4-chloro-2-thenoyl) -1 , 2-dihydro-6-methyl-3H-pyrrolo- [1,2- a] pyrrole-1-carboxylic acid hexyl ester, 5- (2-thenoyl) -1,2-dihydro-6-ethyl-3H-pyrrolo- [ 1,2-a] pyrrole-1-carboxylic acid isoamyl ester and 5- (3-furoyl) -1, 2-dihydro-3H-pyrrolo- [1, 2-a] pyrrole-1-carboxylic acid octyl ester. 



   Example 8
A solution of 300 mg of 5- (2-thenoyl) -1,2-dihydro-3H pyrmio- [1,2-a] pyrrole-1-carboxylic acid in 5 ml of methanol is mixed with 1 molar equivalent of sodium hydroxide in the form of a 1-normal solution.  The solvent is then evaporated under reduced pressure and the residue in
2 ml of methanol added; then it is precipitated with ether and crude sodium 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate is obtained, which can be crystallized from isopropanol. 



   In the same way, other salts, e.g. B.  Ammonium and potassium salts, of 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrpl-l-carboxylic acid prepared by using Am moniak or  Potassium hydroxide used instead of sodium hydroxide. 



   Similarly, the 5-substituted 1,2-di hydro-3H-pyrrolo- [1, 2-a] -pyrrole-1 - obtained in Examples 1 B1, 1 B-2, 3, 4 and 5 can carboxylic acids are converted into the corresponding sodium, potassium and ammonium salts. 



   Representative compounds obtained in this way are: sodium l-5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrol-l-carboxylate, sodium 5 - (2-furoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-
1-carboxylate, sodium 5- (4-methyl-2-thenoyl) -1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, potassium 5- (4-chloro- 2-thenoyl) - 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-I-carboxylate, potassium 5- (5-bromo-2-thenoyl) - 1,2-dihydro-3H -pyrrolo- [1,2- a] pyrrole-1 carboxylate, sodium 5- (3-methyl-2-furoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole - 1-carboxylate, ammonium 5- (2-furoyl) - 1, 2-dihydro-3H-pyrrolo- [1,2-a] - pyrrole-1-carboxylate, ammonium 5- (3-chloro-2- furoyl) - 1,2-

   dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, sodium 5- (4-methyl-2-thenoyl) -1, 2-dihydro-6-ethyl-3H pyrrolo- [1,2 -a] -pyrrole-1-carboxylate, potassium 5- (5-chloro-2-thenoyl) - 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2a] -pyrrole- l- carboxylate, ammonium 5- (3-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] - pyrrole-1-carboxylate and sodium 5- (3-furoyl) - 1,2- dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate. 



   Example 9
A solution of 237 mg of 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid in 8 ml of methanol is mixed with 1 molar equivalent of potassium hydroxide in the form of a 0 , 1-normal solution is added, a solution being obtained which contains potassium 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate.  A solution of 50 mg of calcium carbonate in the minimum amount of normal hydrochloric acid required to dissolve the calcium carbonate is buffered with 100 mg of solid ammonium chloride, after which 5 ml of water are added.  

  The buffered calcium solution thus obtained is then added to the solution of potassium 5- (2-theno yl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] pyrrole-1-carboxylate; the precipitate formed is isolated by filtration, washed with water and air-dried to give calcium 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole- l-carboxylate.    



   In the same way, magnesium 5- (2-thenoyl) -1,2-di hydro-3H-pyrrolo- [1, 2-aj-pyrrole-1-carboxylate is produced by using magnesium carbonate instead of calcium carbonate. 



   If 1-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2- a] pyrrole-1-carboxylic acid, 5- (2-furoyl) -1,2-dihydro- 3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid, 5- (4-chloro-2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1,2-a] - pyrrole-1-carboxylic acid, 5- (3-methyl-2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1, 2-a] pyrrole-1-carboxylic acid, 5- (5-bromo -2-furoyl) - 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid and 5- (3-chloro-2-furoyl) 1,2-dihydro -6-ethyl-3H-pyrrolo- [1, 2-a] - pyrrole-l-carboxylic acid instead of 5- (2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] - pyrrole-l-carboxylic acid used

   the corresponding calcium and magnesium salts are obtained in a similar manner. 



   Example 10
A solution of 237 mg of 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid in 8 ml of methanol is mixed with 1 molar equivalent of potassium hydroxide in the form of a 0 , 1-normal solution.  The solvent is driven off and the residue is dissolved in 5 ml of water.  The aqueous solution of potassium 5- (2-thenoyl) -1,2-di hydro-3H-pyrrolo- [l, 2a] -pyrrole-l-carboxylate thus obtained becomes a solution of 110 mg cuprinitrate trihydrate in 5 given ml of water.  The precipitate formed is isolated, washed with water and air-dried, whereby copper 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carb- receives oxylate. 



   In a similar manner, the free acids obtained in Examples 1 B-1, 1 B-2, 3, 4 and 5 can be converted into the corresponding copper salts. 



   Example 11
A solution of 237 mg of 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid in 15 ml of hot benzene is treated with 59 mg of isopropylamine.  The solution is allowed to cool to room temperature and the product is filtered off, washed with ether and dried, whereby the isopropylamine salt of 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo [1, 2-a] -pyrrole-1-carboxylic acid. 



   In the same way, other amine salts, e.g. B.  the diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1 -carboxylic acid prepared by using the amines in question instead of isopropylamine. 



   Similarly, the free acids obtained in Examples 1 B-1 or 1 B-2, 3, 4 and 5 can be converted to the corresponding isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts . 



   Example 12
Ingredients amount per
Tablet (mg) 5- (2-thenoyl) - 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 thoroughly and compressed into single scored tablets. 



   Example 13
Ingredients amount per
Tablet (mg)
5- (2-Thenoyl) - 1, 2-dihydro-
3H-pyrrolo- [1,2-a] -pyrrole-
1-carboxylic acid 200 corn starch 50 lactose 145 magnesium stearate 5
The above ingredients are mixed intimately and compressed into single-scored tablets. 



   100 mg of 1-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid are used in place of the 200 mg of the dl compound in the tablet above. 



   Example 14 Ingredients Amount Per
Capsule (mg) Potassium 5- (2-thenoyl) 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate 108 lactose 15 corn starch 25 magnesium stearate 2
The above ingredients are mixed and placed in a hard gelatin capsule. 



   Example 15 Ingredients Amount Per
Capsule (mg) calcium 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate 115 lactose 93 corn starch 40 magnesium stearate 2
The above ingredients are mixed and placed in a hard gelatin capsule. 



   Example 16 Ingredients Amount Per
Tablet (mg) isopropylammonium 5- (2 thenoyl) - 1,2-dihydro-3H pyrrolo- [1,2-a] pyrrole-1-carboxylate 245 corn starch 75 lactose 175 magnesium stearate 5
The above ingredients are mixed intimately and compressed into single-scored tablets. 



   Example 17 Ingredients Amount Per
Capsule (mg) 5- (2-Thenoyl) -l, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1-carboxylic acid methyl ester 25 lactose 125
The above ingredients are mixed and placed in a hard gelatin capsule no.  1 introduced.   



  (Continuation)
Example 18 Ingredients Amount Per
Tablet (mg) 5- (2-thenoyl) - 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole I-carboxylic acid 300 sucrose 300
The above ingredients are mixed thoroughly and made into single scored tablets; one tablet is given every 3 to 4 hours. 



   Example 19 Ingredients Amount Per
Tablet (mg) 5- (2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole l-carboxylic acid isoamyl ester 254 corn starch 50 lactose 190 magnesium stearate 6
The above ingredients are mixed intimately and compressed into single-scored tablets. 



   Example 20 Ingredients Amount Per
Capsule (mg) 5- (2-Thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole I -carboxylic acid 100 lactose 148 dextrose 2
The above ingredients are mixed and placed in a hard gelatin capsule. 



   50 mg of 1-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] - pyrrole-1-carboxylic acid are used in place of the 100 mg of the dl compound in the hard gelatin capsule above. 



   Example 21 Ingredients Amount Per
Capsule (mg) 5- (2-Thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrroll-carboxylic acid methyl ester 158 lactose 92
The above ingredients are mixed and placed in a hard gelatin capsule. 



   Example 22 Ingredients Amount Per
Tablet (mg) 5- (2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1 carboxylic acid isoamyl ester 127 lactose 91 corn starch 25 magnesium stearate 2 gelatin 5
The above ingredients are mixed and compressed into single scored tablets. 



   Example 23 Ingredients Amount per -TE tablet (mg) calcium 5- (2-thenoyl) -1,2 dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate 230 corn starch (paste) 40 corn starch 50 magnesium stearate 2 lactose 178
The above ingredients are mixed thoroughly and compressed into single scored tablets. 



   Example 24 Ingredients Amount Per
Tablet (mg) potassium 5- (2-thenoyl) - 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate 217 corn starch 50 magnesium stearate 2 gelatin 226 lactose 5
The above ingredients are mixed intimately and compressed into single-scored tablets. 

 

   Example 25 Ingredients Amount Per
Capsule (mg) isopropylammonium 5- (2 thenoyl) -1, 2-dihydro-3H-pyrrolo- [l, 2a] -pyrrole-l-carboxylate 122 corn starch 30 lactose 98
The above ingredients are mixed and placed in a hard gelatin capsule. 



   Example 26 Ingredients Amount Per
Capsule (mg) 5- (2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrole-1 - carboxylic acid isoamyl ester 32 lactose 101 corn starch 15 magnesium stearate 2
The above ingredients are mixed and placed in a hard gelatin capsule. 



   Example 27
An injectable preparation buffered to pH = 7 and having the following composition is prepared: 5- (2-Thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-aj-pyrrole-1-carboxylic acid 0.2 g K2HPO4 buffer (0.4 molar) 2 ml (continued) Ingredients Amount per
Capsule (mg) KOH (l-normal) to pH 7 water (distilled, sterile) to 20 ml
0.1 g of l-5- (2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrol-l-carboxylic acid is used instead of 0.2 g of the dl compound used in the above preparation. 



   Example 28
A total suppository weighing 2.8 g with the following composition is prepared: 5- (2-Thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid 25 mg Witepsol H -15 (Triglycerides of saturated vegetable fatty acids; a product of Riches-Nelson, Inc. , New York, N. Y. ) Rest
12.5 mg of l-5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1, 2-a] - pyrrole-l-carboxylic acid are substituted for the 25 mg of the dl compound in the suppository above used. 



   Example 29
An oral suspension for pediatric use is prepared with the following composition: l-5- (2-thenoyl) -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 flavors 0.035 ml coloring 0.5 mg distilled water per 100 ml
0.05 g of l-5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1, 2-a] - pyrrole-l-carboxylic acid are used instead of 0.1 g of the dl compound in the suspension used above. 



   Examples 30 and 31
Powder preparations for veterinary use with the following composition were produced:
Example 30 Example 31 5- (2-Thenoylj-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrol-l-carboxylic acid 0.1 g 1.2 g sucrose 5.7 g 3 , 7 g polyvinyl pyrrolidone 0.3 g 0.3 g
0.05 g of 1-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] - pyrrole-l-carboxylic acid are used instead of the 0.1 g of the dl compound the powder of Example 30 used. 



   0.6 g of l-5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1, 2-a] -pyrrol-l-carboxylic acid are used instead of the 1.2 g of the dl compound used in the powder of Example 31. 



  Biological data A. 



   Analgesia test (curvature test) on the mouse Protocol: The test material is administered orally by influences in an aqueous vehicle to male Swiss-Webster mice weighing 18 to 20 g at time 0.  20 minutes later, 0.25 ml of a 0.02% gene phenylquinone solution is injected intraperitoneally.  This solution creates curvatures.  The animals are then observed for curvatures for the next 10 minutes. 



   Endpoint: The total number of mice that curl and the average number of curvatures per mouse. 



   Using the above protocol, it is found that 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid has approximately 350 times the analgesic activity of aspirin and that l-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid has 670-fold analgesic activity of aspirin. 



   B.  Test for anti-inflammatory activity using carraghenin-induced paw inflammation in the rat. 



   Protocol: Simonsen female rats weighing 80 to 90 g are used.  The test materials are administered orally at 0 hours by pouring them into 1 ml of an aqueous vehicle.  At hour 1, 0.05 ml of a 1% solution of carraghenin in 0.9% saline solution is injected into the right hind paw.  This injection causes paw inflammation.  The rats are killed in hour 4; at this point both hind paws are removed and weighed separately. 



   Endpoint: The percentage increase in paw size is calculated by dividing the difference between the weight of the right hind paw and the weight of the left hind paw by the weight of the left hind paw and multiplying the result by 100. 



   Using the above protocol, it is determined that 5- (2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid is 48 times (95% confidence interval 32 to 72) has anti-inflammatory activity of phenylbutazone. 



   C.  Test for antipyretic activity
Protocol: Simonsen female rats weighing 90 to 100 g are used.  The normal rectal temperature of the rats is recorded at hour 0, after which 2 ml of a sea suspension are injected subcutaneously (1 ml dorsally, 1 ml ventrally).  The injection sites are massaged to spread the suspension below the skin.  The yeast injection causes an increased body temperature (fever).  At hour 17, the rats are massaged again to stimulate a further increase in body temperature.  At hour 18, the second rectal temperature is recorded, after which the test material is administered orally by exposure to 1 ml of an aqueous vehicle.  The third rectal temperature is measured 2 hours after the test material is administered. 

 

   End point: The temperature decrease (> C) from the second temperature reading to the third temperature reading. 



   Using the above protocol, it is found that 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid has 17 times the antipyretic activity of aspirin. 



   D.  Acute oral toxicity (LD50) in mice
Protocol: The test material is suspended in a 2% aqueous starch solution.  The concentrations are adjusted so that the doses can be administered in volumes of 0.1 ml / 10 g body weight.  6 groups of 6 female Swiss-Webster mice are used.  A single oral dose of either 50 mg or 100 mg or 200 mg or 400 mg or 800 mg or 1 600 mg 5- (2-Theno yl) - 1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrol-1-carboxylic acid per kg body weight is administered to the mice using a gastric tube.  After the administration, the mice are observed for two weeks. 

 

   Using the above protocol, the acute oral LD50 of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid is estimated to be 631 mg / kg, where the 95% confidence interval is 404 to 991 mg / kg.  


    

Claims (34)

 PATENT CLAIMS 1. Compound of the formula: EMI1.1  their individual l-acid isomers and d-acid isomers, their pharmaceutically acceptable salts and their alkyl esters derived from unbranched or branched hydrocarbon radicals having 1 to 12 carbon atoms, where X is oxygen or sulfur, R is hydrogen or a lower alkyl group having 1 to 4 carbon atoms, R 1 is hydrogen Is methyl, chlorine or bromine and any substituent R 'is present in the compounds of formula A in the 3-, 4- or 5-position of the furan or thiophene ring.  2. A compound according to claim 1, characterized in that X is oxygen.  3. A compound according to claim 1, characterized in that X is sulfur.  4. A compound according to claim 1, characterized in that R is hydrogen.  5. A compound according to claim 1, characterized in that R is methyl.  6. A compound according to claim 2 of formula A.  7. Carboxylic acid according to claim 6, wherein R and R 'are both hydrogen, namely 5- (2-furoyl) - 1, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole 1-carboxylic acid.  8. 5- (2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2a] -pyrrole-l-carboxylic acid isopropyl ester as a compound according to claim 2.  9. A compound according to claim 6, characterized in that R is hydrogen and Rl is methyl.  10. A compound according to claim 6, characterized in that R is hydrogen and R1 is chlorine.  11. A compound according to claim 6, characterized in that R is hydrogen and R1 is bromine.  12. A compound according to claim 3 of formula A.  13. A carboxylic acid according to claim 12, wherein R 'is both hydrogen, namely 5- (2-thenoyl) - 1, 2-di-hydro-3H-pyrrolo- [1,2-a] pyrrole-carboxylic acid.  14. 5- (2-Thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1, 2-aj-pyrrole-l-carboxylic acid ethyl ester as a compound according to claim 3.  15. A compound according to claim 12, characterized in that R is hydrogen and R 'is methyl.  16. A compound according to claim 12, characterized in that R is hydrogen and Rl is chlorine.  17. The carboxylic acid according to claim 12, wherein the substituent Rl is in the 4-position of the thiophene ring, namely 5- (4-chloro-2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [1,2 a] -pyrrole-1-carboxylic acid.     18.5- (4-chloro-2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid isopropyl ester as a compound according to claim 3.  19. The carboxylic acid of claim 16, wherein the substituent Rl is in the 5-position of the thiophene ring, namely 5- (5-chloro-2-thenoyl) - 1,2-dihydro-3H-pyrrolo- [1,2- a ] -pyrrole-1-carboxylic acid.  20. 5- (5-chloro-2-thenoyi) -1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isopropyl ester as a compound according to claim 3.  21. A compound according to claim 12, characterized in that R is hydrogen and Rl is bromine.  22. A compound according to claim 2 of formula B.  23. A carboxylic acid according to claim 22, wherein R is hydrogen, namely 5- (3-furoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole carboxylic acid.  24. A compound according to claim 3 of formula B.  25. The carboxylic acid of claim 24, wherein R is hydrogen, namely 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.  26. Sodium, potassium or calcium salt of a compound of formula A or B according to claim 1.  27. Potassium salt of a compound of formula A according to claim 26, wherein R is both hydrogen and X is sulfur, namely potassium-5- (2-thenoyl) - 1, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylate.    28. 1-acid isomer of the formula A or B according to claim 1.  29. A compound according to claim 28, characterized in that R 'both mean hydrogen.  30. A compound of formula A according to claim 29, wherein X is sulfur, namely 1-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1, 2-a] pyrrole-1-carboxylic acid.  31. Sodium, potassium or calcium salt of a [acid isomer of the formula A or B according to claim 1.  32. Potassium salt of formula A according to claim 31, wherein R and R1 both represent hydrogen and X represents sulfur, namely potassium-l-5- (2-thenoy1) - 1, 2-dihydro-3H-pyrrolo- [1, 2- a] -pyrrole-1-carboxylate.  33. Agent for the treatment of inflammation, pain or fever in humans or mammals, characterized in that it consists of a pharmaceutically acceptable, non-toxic excipient and a therapeutically effective amount of a compound of the formula: EMI1.2   or the / acid isomers of the formulas A and B or their pharmaceutically acceptable salts or their alkyl esters derived from unbranched or branched hydrocarbon radicals having 1 to 12 carbon atoms, where X is oxygen or sulfur, R is hydrogen or a lower alkyl group having 1 to 4 carbon atoms Rl is hydrogen, methyl, chlorine or bromine and any substituent R 'in the compounds of the formula A is in the 3-, 4- or 5-position of the furan or thiophene ring.  34. Agent for administration to a pregnant woman or a pregnant mammal to delay the start of childbirth, characterized in that it consists of a pharmaceutically acceptable, non-toxic excipient and a therapeutically effective amount of a compound of the formula: EMI2.1  or the l-acid isomers of the formulas A and B or their pharmaceutically acceptable salts or their alkyl esters derived from unbranched or branched hydrocarbon radicals having 1 to 12 carbon atoms, where X is oxygen or sulfur, R is hydrogen or a lower alkyl group having 1 to 4 carbon atoms , R 'is hydrogen, methyl, chlorine or bromine and any substituent Rl in the compounds of the formula A is in the 3-4 or 5 position of the furan or Thiophene ring is located.  The present invention relates to certain new pyrrole-1-carboxylic acid derivatives.  In particular, the invention relates to new 1,2-di-hydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acids, which are in the 5-position by a 2-furoyl, 2-thenoyl , 3-furoyl or 3-thenoyl group and the formula: : EMI2.2  correspond to their individual l-acid isomers and d-acid isomers, their pharmaceutically acceptable salts and their alkyl esters derived from unbranched or branched hydrocarbon radicals having 1 to 12 carbon atoms, where X is oxygen or sulfur, R is hydrogen or a lower alkyl group having 1 to 4 carbon atoms, R 'is hydrogen, methyl, chlorine or bromine and any substituents Rl are present in the compounds of the formula A in the 3-, 4- or 5-position of the furan or thiophene ring.  The compounds of the invention, with the exception of the d-acid isomers and the aforementioned salts and alkyl esters thereof, show an anti-inflammatory, analgesic and antipyretic effect and are therefore useful for the treatment of inflammation, pain and / or feverish conditions in humans and mammals, as follows is described in more detail. They are also smooth muscle relaxants.  The term pharmaceutically acceptable salts, as used herein, refers to salts derived from pharmaceutically acceptable, non-toxic inorganic or organic bases.  Typical alkyl esters are 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 sodium, potassium, lithium, ammonium, calcium, magnesium, ferro, zinc, copper, mangano, aluminum, ferric, manganese salts and the like. Particularly preferred become 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 naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procain, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylamine piperidine. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine.  The new compounds of formulas A and B as well as formulas XI and XII below are present as pairs of optical isomers (or enantiomorphs), i.e. as dl mixtures. However, the present compound encompasses both the individual optical isomers and the dl mixtures thereof.    If the new compounds according to the invention are to be used to induce a physiological reaction, e.g. an anti-inflammatory, analgesic or antipyretic effect, i.e. if they are to be used as medicaments, a preferred subgroup consists of the compounds of the formulas A and B and their l-acid isomers, as well as their C1-12 alkyl esters and pharmaceutically acceptable salts.  Another subgroup of compounds used as medicaments comprises the compounds of the formula A. ** WARNING ** End of CLMS field could overlap beginning of DESC **.