5-(2-pyrroyl)-1,2-dihydro-3h-pyrrolo(1,2-a)-pyrrole-1-car- boxylic acid derivatives

(54) Designation: Analogous process for the preparation of 5- (2-pyrroyl) -1,2-dihydro-3H-pyrroloyl 1,2-apyrrol-1-carboxylic acid derivative (56) Published publications: -

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The invention relates to an analogous process for the preparation of certain new pyrrole-1-carboxylic acid compounds, including anti-inflammatory, analgesic and antipyretic action.

More specifically, the invention relates to the preparation of

5- (2-pyrroyl) - and 5- (N-lower-alkyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo / 1,2-α- / pyrrole-1-carboxylic acids of the formula

<img file="SE436648B_D0001.tif" />

and the individual 1-acid isomers and d-acid isomers thereof and pharmaceutically acceptable, non-toxic esters and salts thereof, wherein each of R and R R independently represents hydrogen or a lower alkyl group of 1-4 carbon atoms, and

<img file="SE436648B_D0002.tif" />

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to a way of preparing these compounds.

R and R as alkyl groups preferably have straight chain, i.e. methyl, ethyl, n-propyl and n-butyl.

The compounds described in detail below, with the exception of the d-acid isomer and derivatives thereof, exhibit anti-inflammatory, analgesic and anti-pyretic action, and the compounds are thus useful for treating inflammation, pain and / or pyrexia in mammals, as described below. . The compounds are also relaxants for smooth muscles.

The term pharmaceutically acceptable, non-toxic esters and salts used herein refers to straight or branched chain alkyl esters of 1-12 carbon atoms and, respectively, salts derived from pharmaceutically acceptable, non-toxic inorganic and organic bases.

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

Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganese, aluminum, ferric and manganese salts etc. Particularly preferred are 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, e.g. isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic, non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexylamine, choline and caffeine.

The new compounds of formulas A and XI, which

7803549-0 is hereinafter set forth as pairs of optical isomers (or enantiomorphs), i.e., a dl mixture, and each optical isomer as well as the dl mixtures thereof are included within the present invention.

When the new compounds are used to elicit a physiological response (e.g., anti-inflammatory, analgesic or anti-pyretic action), i.e., the compounds are to be used as drugs, a preferred subgroup is the compounds of formula A and 1-acid isomers thereof and esters and pharmaceutically acceptable salts thereof.

A further subset of the compounds to be used as drugs are compounds of formula A and

1-acid isomers of formula A and esters and pharmaceutically acceptable salts thereof, wherein R is hydrogen and R R is methyl.

The d-acid isomer of formula A and esters and pharmaceutically acceptable salts thereof are useful as intermediates for the preparation of the d-acid of formula A, as described in detail below.

The novel dl compounds of the present invention can be prepared by a method illustrated by the following reaction sequence.

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2 where R and R are the same as above and R is a lower alkyl group of 1-4 carbon atoms, e.g. methyl, ethyl, isopropyl and n-butyl.

In carrying out the above process, equimolar amounts of ethanolamine (I) and dimethyl-1,3acetone dicarboxylate (II) are reacted at a temperature from about 0 ° C to about room temperature to readily form the vinylamine of formula III. To prepare the compound of formula IV, wherein R is hydrogen, a solution of compound III is treated in a suitable inert organic solvent under anhydrous conditions with 2-bromoacetaldehyde or 2-chloroacetaldehyde at a temperature of about 40 to about 100 ° C for a time period from about 30 minutes to about 16 hours. Suitable solvents for this reaction are aprotic solvents, e.g. acetonitrile, tetrahydrofuran, dimethoxyethane, chloroform, dichloromethane, etc. In the preferred embodiments, the reaction is carried out in acetonitrile solution at reflux temperature for about 1 hour. The 2-bromo (chloro) acetaldehyde reaction components are known compounds or can be prepared by pyrolysis of the corresponding diethyl acetals in the presence of oxalic acid dihydrate. To prepare the compounds of formula IV, wherein R represents a lower alkyl group, preferably a straight chain containing 1-4 carbon atoms, an aqueous mixture of ethanolamine (I) and dimethyl-1,3-acetone dicarboxylate (ΪΙ) is reacted with

O to a compound of formula R₃-C-CH₂x, where X represents bromine or chlorine and R 4 represents a lower alkyl group, preferably straight chain, of 1-4 carbon atoms and, in particular, 1-bromoacetone, 1-bromo-2-butanone, 1-bromo-2-pentanone and 1 -bromo-2hexanone, at a temperature of from about -20 to about 40 ° C for a period of time from about 30 minutes to about 16 hours. In the preferred embodiments, the reaction is carried out at about -10 ° C to room temperature for about 1 to about 6 hours. O

II

The R 2 -C 3 x reaction components are known compounds.

The esterification of a compound of formula IV with methanesulfonyl chloride in the presence of a tertiary amine, e.g. triethylamine, pyridine, etc., optionally in the presence of a co-solvent,

<img file="SE436648B_D0007.tif" />

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e.g. dichloromethane, at a temperature of from about -10 ° C to about room temperature for about 10 minutes to about 2 hours, produces the corresponding mesylate of formula V which is converted to the corresponding N- (2-iodoethyl) pyrrole of formula VI by reaction with sodium iodide in acetonitrile solution at reflux temperature for about 1 to about 10 hours.

It is obtained by reacting the iodine ethyl compounds of formula VI with sodium hydride in a suitable inert organic solvent, e.g. dimethylformamide, dimethylformamide

1,2-dihydro-3H-pyrrolo £ l, 2-a | pyrrole-1,7-dicarboxylate and

6-alkyl-substituted derivatives thereof (VII). This annealing is carried out under an inert atmosphere, i.e. under argon or nitrogen atmosphere, at temperatures of about 15 to about 40 ° C for a period of time of about 15 minutes to about 4 hours. The best results are obtained by performing the reaction at room temperature for about 30 minutes, when R is hydrogen.

Alternatively, the compounds of formula VII can be prepared by direct annealing of the mesylate of formula V by sodium hydride in dimethylformamide solution at about -10 ° C to about room temperature for about 30 minutes to about 2 hours.

Alkaline hydrolysis of a compound of formula VII with an alkali metal hydroxide or an alkali metal carbonate, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate etc., in an aqueous lower aliphatic alcohol, e.g. methanol or ethanol, at a temperature between room temperature and reflux temperature for about 4 to about 24 hours, gives the corresponding free diacid of formula VIII, i.e. 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7 dicarboxylic acid and 6-alkyl derivatives thereof.

The hydrolysis is preferably carried out using aqueous methanolic sodium hydroxide solution at reflux temperature for about 6 hours to about 10 hours.

The carboxylic acid group in the C-position of the compound of formula VIII is then selectively esterified by treating the compound with a lower aliphatic alcohol, e.g. methanol,

<img file="SE436648B_D0008.tif" />

7803549-0 ethanol, isopropanol, n-butanol, etc., in the presence of hydrogen chloride, to produce the corresponding alkyl-1,2-dihydro-3H-pyrrolo [1,2-a (pyrrole-1-carboxylate-7-carboxylic acid with The reaction is carried out at a temperature of from about 0 to about 50 ° C for about 1 to about 4 hours.

Decarboxylation of the mono-esterified compounds of formula IX to the corresponding compounds of formula X to complete the reaction. The course of the reaction can be followed by the degree of carbon dioxide evolution and thin layer chromatographic analysis. The decarboxylation is usually completed within about 45 to about 90 minutes. The reaction product, namely alkyl-1,2-dihydro-3H-pyrroloyl, 2-a-pyrrole1-carboxylate and 6-alkyl derivatives thereof of formula X, can be purified by chromatographic technique. Alternatively, and in particular for decarboxylating small batches of the compound (IX), the reaction product (X) can be distilled directly from the reaction vessel.

It is obtained by condensing a compound of formula X with an amide of formula

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in which R som represents the same as above, corresponding to alkyl-5 (2-pyrroyl) -1,2-dihydro-3H “pyrroloyl 1,2-aJ pyrrole-1-carboxylate (XI). This reaction is carried out in an inert organic aprotic solvent and in the presence of phosphorus oxychloride at reflux temperature for about 15 to about 70 hours and under an inert atmosphere, followed by further heating at reflux temperature in the presence of sodium acetate for about 20 minutes to about 1 hour. Alternatively, instead of phosphorus oxychloride, other acid chlorides may be used, e.g. phosgene or oxalyl chloride.

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In the preferred embodiments, this condensation is achieved 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. obtained the reaction mixture at reflux for about 17 to about 50 hours under an argon atmosphere and then adding about 3 to about 10 molar equivalents of sodium acetate, followed by a further reflux period of about 30 minutes.

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

Suitable amides are: N, N-dimethylpyrrole-2-carboxamide, N, N-dimethyl-1-methylpyrrole-2-carboxamide, N, N-dimethyl-1-ethylpyrrole-2-carboxamide, N, N-dimethyl-1- propylpyrrole-2-carboxamide and NN-dimethyl-1-butylpyrrole-2-carboxamide.

These amides can be prepared in a conventional manner by the corresponding pyrrole-2-carboxylic acids, e.g. by conversion to acid chlorides followed by treatment with dimethylamine. N-alkyl of pyrrole-2-carboxylic acids are known or can be prepared / corresponding to N-alkyl pyrrols by the method described by

A. Treibs et al., In Liebigs Ann. Chem. 721, 105 (1969).

It is obtained by alkaline hydrolysis of the alkyl ester group in a compound of formula XI corresponding to free acid of formula A. This hydrolysis is carried out in a conventional manner by an alkali metal hydroxide or an alkali metal carbonate, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate etc., in an aqueous lower aliphatic alcohol, e.g. methanol, ethanol, etc., at a temperature from about room temperature to reflux temperature for about 15 minutes to about 2 hours and under an inert atmosphere. In the preferred embodiments, the hydrolysis is carried out with aqueous methanolic potassium carbonate solution at reflux temperature for about 30 minutes.

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The compounds of formula A can be resolved by methods known in the art to obtain corresponding individual isomers.

The 1-acid isomers and d-acid isomers of the compounds of formula A can be prepared by conventional methods, for example, by applying known high pressure liquid chromatography (HPLC) techniques to (X-phenethyl-diastereoisomeric esters of the compounds of formula A, followed by acid cleavage. Thus, for example, compounds of formula A, wherein R represents hydrogen and R * represents methyl, may be subjected to further treatment according to standard procedures known in the art and in accordance with the following flow diagrams.

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Γ

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The α ^-1-acid isomer and A A-d-acid isomer listed above are 1-5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid and d-5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [2,2-a] pyrrole-1-carboxylic acid.

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

The salt derivatives of the compounds of formula A and the acid isomers thereof are prepared by reacting these free acids with a suitable amount of a pharmaceutically acceptable base. Representative pharmaceutically acceptable bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, manganohydroxid, aluminum hydroxide, ferric hydroxide, manganihydroxid, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol , trometamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. The reaction is carried out in water alone or in combination with an inert, water miscible organic solvent at a temperature of from about 0 to about 100 ° C, preferably at room temperature. Typical inert, water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane and tetrahydrofuran. The molar ratio of the compounds of formula A or the 1-acid isomers thereof to the base used is selected so as to achieve the desired ratio for each particular salt. For the preparation of, for example, calcium or magnesium salts of the compounds of formula A or the 1-acid isomers thereof, the starting compound, the free acid, can be treated with at least half a molar equivalent of pharmaceutically acceptable base to produce a neutral salt. When preparing aluminum salts of the compounds of formula A or the 1-acid isomers thereof, at least one-third of molecular equivalent of pharmaceutically acceptable base is used, if a neutral salt is desired.

In a preferred embodiment, calcium salts and magnesium salts of the compounds of formula A and 1-acid isomers thereof can be prepared by treating the corresponding sodium

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7803549-0 or potassium salts having at least half a molar equivalent of calcium chloride or magnesium chloride in an aqueous solution alone or in combination with an inert, water miscible organic solvent at a temperature of from about 20 to about 100 ° C. The aluminum salts of the compounds can preferably be prepared by treating the corresponding free acids with at least one third molar equivalent of an aluminum alkoxide, e.g. aluminum tri oxide, aluminum tripropoxide etc., in a hydrocarbon solvent, e.g. benzene, xylene, cyclohexane etc. at one temperature from about 20 to about 115 ° C. Similar procedures can be used to prepare inorganic base salts which are not sufficiently soluble to readily react.

It is to be understood that isolation of the compounds described herein may - if desired - be carried out by any suitable separation or purification process, e.g. extraction, filtration, evaporation, distillation, crystallization, thin layer chromatography or column chromatography. high-pressure liquid chromatography (HPLC) or a combination of these processes. Examples of suitable separation and isolation methods can be obtained with reference to the following examples. However, other equivalent separation and isolation methods can also be used.

Since the d-acid isomers are not used as drugs per se, they can, if desired, be converted to their pharmaceutically acceptable, non-toxic esters and salts according to the procedures described for converting the 1-acid isomers to their pharmaceutically acceptable, non-toxic. toxic esters and salts.

The compounds of formula A and the 1-acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof are useful as anti-inflammatory. substances, analgesic substances, platelet aggregation inhibitors, fibrinolytic substances and as smooth-muscle relaxants. These compounds can be used both prophylactically and therapeutically.

Thus, compositions containing these compounds are useful for treating and eliminating inflammation, e.g. inflammatory conditions in the muscular skeletal system,

7803549-0 skeletal joints and other tissues, e.g. for the treatment of inflammatory conditions, such as rheumatism, concussion, laceration, arthritis, bone fractures, post-traumatic conditions and gout. In those cases in which the above conditions include pain and pyrexia together with inflammation, the present compounds are useful for relieving these conditions as well as of the inflammation.

Administration of the active compounds of Formula A and the 1-acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof in a suitable pharmaceutical composition may be accomplished by any accepted mode of administration for substances for the treatment of inflammation, pain or pyrexia or for prophylaxis thereof. Thus, the administration may be, for example, orally, parenterally or topically in the form of solid, semi-solid or liquid dosage forms, for example tablets, suppositories, pills, capsules, powders, solutions, suspensions, emulsions, creams, lotions, ointments etc., preferably in unit dosage forms suitable for use. easy administration of exact dosages. The compositions include a conventional pharmaceutical carrier or excipient and an effective compound of formula A or acid isomers thereof and pharmaceutically acceptable non-toxic esters and salts thereof and may additionally include other drugs, pharmaceuticals, carriers, adjuvants, etc.

The preferred mode of administration for the conditions described above is oral administration using an appropriate daily dosing regimen which can be adjusted according to the degree of disease. A daily dose of 25 to 1000 mg of active substance of formula A or the 1-acid isomer thereof and pharmaceutically acceptable, non-toxic esters and salts thereof are usually used. Most conditions account for a treatment comprising a dosage level of the order of 0.5 to 15 mg / kg body weight per day. For such oral administration, a pharmaceutically acceptable, non-toxic composition is prepared by incorporating any of the commonly used excipients, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin,

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7803549-0 talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate etc. Such compositions may be in the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations etc.

The active compounds of the formula A or 1-acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof can be formulated into a suppository using, for example, polyalkylene glycols, e.g. polypropylene glycol, as carrier, Liquid, pharmaceutically administrable compositions may be prepared, for example, by dissolution, dispersion, etc. of an active compound as described above, and optional pharmaceutical aids in a carrier, e.g. water, brine, dextrose aqueous solution, glycerol, ethanol, etc., thereby obtaining a solution or suspension. The pharmaceutical composition to be administered may optionally also contain small amounts of non-toxic adjuvants, e.g. wetting or emulsifying agents, pH buffering agents etc., e.g. sodium acetate, sorbitan monolaurate, triethanolaminoleate, etc.

Correct processes for preparing such dosage forms are known or apparent to those skilled in the art, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th ed., 1970. In any case, the composition to be administered contains a quantity of the active compound (s) in a pharmaceutically effective amount to alleviate the particular condition to be treated in accordance with the meaning of the present invention.

The compounds of formula A and the 1-acid isomers thereof and the non-toxic, pharmaceutically acceptable esters and their salts are also uterine smooth muscle relaxants and are thus useful as substances for sustaining pregnancy in pregnant mammals in favor of the mother and / or fetus until the termination of pregnancy from a medical point of view is considered to be favorable or more favorable, for the mother and / or fetus. However, it should be realized that in some cases, for example when the birth has already begun (ie the mother has uterine contractions, especially near full time), administration of the

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7803549-0 disclosed herein do not maintain the pregnant condition for an indefinite period. In such cases, pregnancy is likely to be somewhat prolonged instead, a factor that may be beneficial to either the mother and / or the fetus.

The compounds of formula A and the 1-acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and salts thereof are used, in particular, as substances to delay the onset of, or to delay, delivery. The term for delaying the onset of delivery used herein is intended to cover the delay of delivery induced by administration of the compounds of formula A or 1-acid isomers thereof and pharmaceutically acceptable, non-toxic esters and salts thereof at any time prior to uterine muscle contractions. began. It is thus intended that said term covers the prevention of abortion early in pregnancy (ie before the fetus is alive) as well as a delay of premature birth, an expression sometimes used with reference to premature birth defects occurring later in pregnancy when the fetus is considered alive. In each case, the substances are administered as prophylactic agents in that such administration tends to prevent the onset of delivery. This administration is particularly useful for the treatment of women who have previously had spontaneous abortions, miscarriages or premature labor (ie, full-time childbirth). Such administration is also useful as clinical indications show that pregnancy can be terminated before this time and it is considered favorable for the mother and / or the fetus.

With regard to animals, this treatment can also be used to synchronize deliveries from a group of pregnant animals so that they occur at or around the same time or that they occur at or around a desired time and / or place, where the births can be managed with greater ease. .

The term postponed delivery used herein is intended to cover the delay of delivery induced by administration of the compounds of formula A or acid isomers thereof and pharmaceutically acceptable non-toxic

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7803549-0 esters and salts thereof after the onset of uterine muscle contractions. The patient's condition including cbn time in pregnancy when the contractions have begun, the severity of the contractions and how long the contractions have taken place affect the results achieved by administering the compounds. For example, the effect may be that the intensity and / or duration of the contractions decrease (the actual act of delivery is extended) or the effect may be that the contractions are completely stopped. In each case, the effect of extending the pregnancy period, although, depending on the conditions described above in the patient, the effect may be either minor or - under appropriate conditions - somewhat greater. Such administration may be intended to prevent spontaneous abortion or to make delivery easier and / or less painful for the mother or for the delivery to take place at a more convenient time and / or place.

Administration of the compounds of formula A or

The 1-acid isomers thereof and the pharmaceutically acceptable, non-toxic esters and their sites for the purposes stated above should in all cases be consistent with the best and / or accepted medical (or veterinary) practice so as to maximize the benefits for the mother and fetus. For example, administration should not be continued so long after full time that the fetus dies in the uterus.

In the practice of the methods of the present invention, a therapeutically effective amount of a compound of formula A or 1-acid isomers thereof and pharmaceutically acceptable, non-toxic esters and salts thereof or a pharmaceutical composition containing them is administered to the pregnant mammal by any of the common and acceptable procedures known in the art. The compound can be administered either alone or in combination with another compound or compounds as defined above, or other pharmaceutical substances, carriers, adjuvants etc. Such compound or compounds or compositions may be administered orally, parenterally, either in the form of solid, semi-solid, or liquid dosage forms. The administration is typically carried out with a pharmaceutical composition containing the pharmaceutically active compound and one or more pharmaceutical carriers or adjuvants.

The administrable pharmaceutical composition may be in the form of oral tablets, vaginal or uterine tablets or suppositories, pills, capsules, liquid solutions, suspensions, etc., preferably in unit dosage forms suitable for easy administration of precise dosages. Conventional, non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate, etc. The active compound may be formulated as suppositories using, for example, polyalkylene glycols. ex. propylene glycol, as carrier, Liquid pharmaceutically administrable compositions may be prepared, for example, by dissolution, dispersion, etc. of an active compound, as defined above, and optional pharmaceutical adjuvants in a carrier, e.g. water, brine, dextrose aqueous solution, glycerol, ethanol, etc., thereby obtaining a solution or suspension. The pharmaceutical composition to be administered may also possibly contain minor amounts of non-toxic adjuvants, e.g. wetting or emulsifying agents, pH buffering agents etc., e.g. sodium acetate, sorbitan monolaurate, triethanolaminoleate, etc. Correct procedures for preparing such dosage forms are known or apparent to those skilled in the art, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th ed., 1970. In any case, the composition or formulation to be administered contains a quantity of active compound or active compounds in an amount effective to delay the onset of delivery or to delay delivery if uterine contractions have already begun. A daily dose of 0.5 to about 25 mg of active compound per kg of body weight is usually administered, the administration being a single daily dose or up to 3 or 4 smaller doses given regularly throughout the day. The amount of active compound administered depends, of course, on its relative activity.

The following preparation and examples illustrate the invention POOR QUAL '^1TY

7803549-0 but does not intend to limit the scope of the invention. All mixing ratios used with respect to liquids relate to volume ratios. Examples are repeated, when necessary, to prepare additional materials for subsequent examples and unless otherwise indicated, the reactions are carried out at room temperature (20 - 30 ° C).

Production

A. A solution of 10 g of N-methylpyrrole-2-carboxylic acid in ml of anhydrous benzene is reacted with 11.5 ml of thionyl chloride and the reaction mixture is heated at reflux under anhydrous conditions for 16 hours. The benzene and excess thionyl chloride are distilled off and the residue distilled in vacuo to give 7.88 g of N-methylpyrrole-2-carbonyl chloride. Bp. 79.84 ° C / 5 mm.

B. Under argon atmosphere, 7.88 g of N-methylpyrroline are mixed.

2-carbonyl chloride and 400 ml of anhydrous benzene. The solution is cooled to 5 ° C in an ice-water bath and the anhydrous dimethylamine is slowly bubbled through the solution. The temperature of the reaction mixture is allowed to rise to room temperature and dimethylamine is bubbled through the mixture for an additional 5 minutes. The reaction mixture is then diluted with water, the organic phase is separated and washed with 50 ml of 10% hydrochloric acid, ml of a saturated sodium hydrogen carbonate solution and twice with 50 ml of saturated sodium chloride solution. The organic extract is dried over anhydrous sodium sulfate, decolorized with charcoal and evaporated to dryness in vacuo to give 8 g of N, N-dimethyl-1-methylpyrrole-2-carboxamide as an oil having the following physical constants: UV λ 221, 226 nm

CHC1 max CDCX (£ 6900, 9,300); IR V max³ 1610 cm¹; NMR STMS³ 3.08 (s, 6H), 3.70 (s, 3H), 5.87 - 6.05 (m, 1H), 6.17 - 6.35 (m, 1H), 6.47 - 6, 65 ppm (m, 1-H).

It is obtained by repeating the above procedures and using N-ethylpyrrole-2-carboxylic acid, N-propylpyrrole-2-carboxylic acid and Kf-butylpyrrole-2-carboxylic acid as starting compounds the following compounds: N, N-dimethyl-1-ethylpyrrole-2-carboxamide, N , N-dimethyl-1-propylpyrrole-2-carboxamide, respectively. N, N dimety1-1-butylpyrrole-2-carboxamide.

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N-propylpyrrole-2-carboxylic acid and N-butylpyrrole-2-carboxylic acid are prepared by reacting N-propylpyrrole and N-butylpyrrole with trichloroacetyl chloride to give the corresponding 2-trichloroacetylpyrrole, followed by a reaction with a base reaction. by A. Treibs et al., in Liebigs Ann. Chem. 721, 105 (1969).

Similarly, by the method of Part B of this preparation, pyrrole-2-carbonyl chloride, prepared as described by RJ Boatman et al., In J. Org. Chem. 41, 3050 (1976), to N, N-dimethylpyrrole-2-carboxamide. Mp: 100.5 - 102 ° C.

Example 1

A 250 ml three-necked round-bottom flask with a magnetic stirrer and fitted with a calcium chloride drying tube is connected directly (via one of the outer necks) by a receiver addition and a short (7.6 cm) water condenser to the acetal pyrolysis device. This device consists of a 100 ml round-bottom flask [in which 15.6 g of oxalic acid dihydrate and 11.82 g of bromoacetaldehyde diethyl acetal, prepared from vinyl acetate, as described by PZ Bedoukian, J. Am. Chem. Soc. 66, 651 (1944)} on the top provided with a 15.2 cm Vigreux column with a thermometer connected to the above-mentioned condenser.

Into the three-neck flask is introduced 3.36 g of ethanolamine, cooled in an ice bath at 0-10 ° C, and treated dropwise with stirring with 8.7 g of dimethyl-1,3-acetone dicarboxylate. Thereby, immediately methyl 3-carbomethoxymethyl-3- (2'-hydroxyethyl) aminoacrylate of formula III is formed. When the addition is complete, remove the ice bath and add 100 ml of dry acetonitrile. The pyrolysis part of the device is placed in an oil bath and its temperature is raised to 150 - 160 ° C. The bromoacetaldehyde solution formed is distilled (boiling 80 - 82 ° C / 580 mm) directly to the magnetically stirred solution of vinylamine (III). As the distillation temperature drops below 80 ° C, the pyrolysis device is disconnected and replaced with a reflux condenser provided with a drying tube containing calcium chloride. The solution is heated at reflux temperature for 1 hour. The solvent is removed in vacuo and 200 ml of methanol are then added to the residue

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7803549-0 and 20 g of silica gel. The mixture is evaporated in vacuo to dryness and applied on top of a column of 200 g of silica gel packed in hexane. The column is then eluted with 500 ml of hexane-ethyl acetate (80:20) and 9 x 500 ml of hexane-ethyl acetate (1: 1). Fractions 2 and 3 contain minor polar impurities and dimethyl-1,3acetone dicarboxylate, fractions 4-8 give 4.1 g of methyl N- (2hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H). Mp: 52-54 ° C (after recrystallization from ether-hexane).

Example 2

To a stirred solution of 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate in 35 ml of dry dichloromethane, cooled to -10 ° C, is added 2.65 ml of triethylamine and then dropwise 1, 46 ml of methanesulfonyl chloride, maintaining the reaction mixture temperature at -10 to -5 ° C. The reaction is followed by thin layer chromatographic analysis using chloroform-acetone (90:10). When the reaction appears to be complete (about 30 minutes after the addition of methanesulfonyl chloride is complete), 10 ml of water is slowly added. The organic phase is separated, washed with water (3 x 30 ml), dried over sodium sulfate and evaporated in vacuo. After crystallization of the residue from dichloromethane hexane, 4.75 g of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H) is obtained. Mp: 99 - 101 ° C

Example 3

A solution of 785 mg of methyl N- (2-mesyloxyethyl) -3carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodide. in 10 ml of acetonitrile is heated at reflux for 1 hour. The cooled reaction mixture is evaporated in vacuo to dryness and the residue is triturated with water. The undissolved material is filtered off and dried in the air to give 840 mg of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = H). Mp: 137 138 ° C.

Example 4

A solution of 1 g of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate in 5 ml of dry dimethylformamide is stirred under argon atmosphere with 137 mg of 50% sodium hydride in mineral oil. The reaction mixture is kept for 30 minutes at room temperature until the reaction is stopped by the addition of 100 ml of water. The car21

7803549-0 when the product is extracted with 3 x 50 ml of ethyl acetate. The combined extracts are washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatograph the residue on 20 g of silica gel and using hexane-ethyl acetate (4: 1) as the eluant, 500 mg of dimethyl-1,2-dihydro-3H-pyrrolo^_1,2-α / pyrrole-1,7-dicarboxylate (VII, R = H). Mp: 70-71 ° C.

A solution of 1.80 g of dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-1,7-dicarboxylate in 20 ml of methanol is treated with a solution of 4.48 g of potassium hydroxide in 20 ml water and the reaction mixture is heated at reflux for 6 hours. The cooled solution is evaporated to dryness and the residue is treated with 50 ml of a saturated sodium chloride solution. The resulting solution is acidified with 6-normal hydrochloric acid and extracted with 3 x 50 ml of ethyl acetate. The combined extracts are dried over magnesium sulfate and evaporated in vacuo to dryness to give 1.51 g

1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (VIII, R = H). Mp: 220 ° C (dec.).

Example 5

A solution of 1.34 g of 1,2-dihydro-3H-pyrrolo / 1,2-α-7-pyrrole-1,7-dicarboxylic acid in 50 ml of isopropanol, cooled in an ice bath, is saturated with hydrogen chloride gas, keeping the temperature of the reaction mixture below 50 ° C. The ice bath is then removed and the reaction mixture is stirred for 1 1/2 hours at room temperature and evaporated in vacuo to dryness. To the residue is added 10 ml of benzene and the solution is evaporated again in vacuo. This process is repeated a total of three times to completely remove the excess hydrogen chloride to give 1.58 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-1-carboxylate-7-carboxylic acid (IX , R = H, R² = iC ^ Hy). Mp: 144-145 ° C (crystallization from methanol-ethyl acetate).

Example 6

1.054 g of isopropyl-1,2-dihydro-3H-pyrrolo [^—1,2-α-7-pyrrole-1-carboxylate-7-carboxylic acid is heated to 240-250 ° C in a dry 10 ml round-bottom flask, directly distilling the reaction product from the reaction vessel. There is thus obtained 745 mg of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-1-carb2 oxylate (X, R = H, R = 1C 3 Hy) as a pale yellow oil with the following physical constants:

<img file="SE436648B_D0016.tif" />

78Ö3549-0

KL

CH₃OH CHCl3

UV: λ max 215 nm (ε 6020); IR: vmax cdci₃

1725 cm^-1; NMR: STMS 1.22 (d, J = 7 Hz, 6H), 2.40-2.90 (m, 2H), 3.6'0-4.20 (m, 2H), 4.65-5 , 2 (m, 1H), 5.73-5.92 (m, 1H), 6.10 (t, J = 3 Hz, 1H), 6.43-6.53 ppm (m, 1H).

Example 7

Into a 100 ml three-necked round bottom flask equipped with a condenser, nitrogen inlet tube and a gas bubbler are introduced 5.0 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] 7-pyrrole-1-carboxylate-7 carboxylic acid. The device is thoroughly flowed with nitrogen and then the nitrogen flow is stopped. The device is immersed in an oil bath heated to 270 ° C and the reaction is monitored by the degree of carbon dioxide evolution (gas bubbler) and by thin layer chromatography on silica gel using benzene dioxane acetic acid (90: 10: 1) as the developing solvent. The reaction is almost complete after 45 minutes. The reaction vessel is removed after 1 hour from the oil bath and the contents of the flask are transferred to a round flask with 500 ml of acetone. The solvent is removed in vacuo and the residue is purified by column chromatography on 100 g of silica gel. From the fractions eluted with hexane-benzene (70:30) and hexane-benzene (50:50), 2.77 g of isopropyl-1,2-dihydro-3H-pyrrolo / 1,2-a_ pyrrole-1-carboxylate (X) are obtained. , R = H, R = iC₃hrs_?) as an oil whose physical constants are identical to the constants obtained in Example 6.

Example 8

A solution of 204 mg of N, N-dimethyl-1-methylpyrrole-2-carboxamide is heated in 10 ml of anhydrous dichloromethane containing 307 mg of phosphorus oxychloride at reflux for 30 minutes under an argon atmosphere. To this solution is added a solution of 193 mg of isopropyl-1,2-dihydro-3H-pyrrolo / 1,2-a-7-pyrrol-1-carboxylate in 15 ml of 1,2-dichloroethane. The reaction mixture is heated at reflux under argon atmosphere for 50 hours, cooled to room temperature and treated with a solution of 1.36 g of sodium acetate dissolved in 15 ml of water. The resulting mixture is heated at reflux for 30 minutes and then cooled. The organic phase is separated and the aqueous phase is extracted with chloroform. The combined organic solutions are washed with a saturated sodium chloride solution (2x10 ml), dried over anhydrous sodium sulfate and evaporated in vacuo

<img file="SE436648B_D0017.tif" />

7803549-0 vacuum to dryness. The oily residue is purified by thin layer chromatography to give 253 mg of isopropyl acetate.

5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole

2 ^—

1-carboxylate (XI, R = H, R = CH 2, R = 1C, H_) as a light yellow t _CH QTT oil with the following physical constants: 3

UV Emax 260CHCl3

275 (shoulder), 330 nm (e 4790, 19500); IR umax 1735, cdci₃

1600 cm^-1; NMR 6TMS 1.27 (d, 6H J = 6 Hz), 2.50-3.10 (m, 2H), 3.85 (s, 3H), 3.92 (dd, 1H, J_EAR = 6 Hz, σ_βχ = 7 Hz; H-1), 4.17-4.60 (m, 2H), 4.95 (sept, 1H, J = 6 Hz), 5.856.20 (m, 2H), 6.60-7.87 ppm (m, 3H), MS m / e 300 (M⁺) .

Example 9

A mixture of 1.2 g of isopropyl-5- (N-methyl-2-pyrroyl) -

1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, 1.1 g of potassium carbonate and 25 ml of a mixture of methanol and water (4: 1) are heated at reflux for 30 minutes under a nitrogen atmosphere, cooled. and., evaporated to dryness. The residue is taken up in 50 ml of water and extracted with 3 x 10 ml of ethyl acetate. The aqueous solution is acidified with 10% hydrochloric acid and extracted with 10 x 15 ml of ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and evaporated in vacuo to dryness. After crystallization of the residue from methylene chloride-ether-hexane, 636 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro3H-pyrrolo-1,2-a-7-pyrrole-1-carboxylic acid (A, R = H, R 2 = CH 2). Mp: 161-161.5 ° C.

Example 10

Example 8 is repeated using 1.5 molar equivalents of N, N-dimethylpyrrole-2-carboxamide, instead of N, N-dimethyl-1-methylpyrrole-2-carboxamide to give isopropyl-5- (2-pyrroyl) 1,2-dihydro-3H-pyrrolo [1,2-a] 7-pyrrole-1-carboxylate, m.p. 131.5-132.5 ° C.

It is obtained by hydrolysis of the isopropyl ester group in accordance with the procedure of Example 9, corresponding to free acid

5- (2-Pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylic acid, m.p. 217-218 ° C.

POOR QUALITY

7803549-0

2i

Example 11

To a 250 ml three-necked round flask with magnetic stirrer and fitted with a calcium chloride drying tube is added 3.36 g of ethanolamine, cooled in an ice bath at 0 ° C, and to this is added dropwise with stirring 8.7 g of dimethyl-1,3-acetone dicarboxylate. . Thereby, immediately methyl 3-carbomethoxymethyl-3- (2'-hydroxyethyl) aminoacrylate (III) is formed. When the addition is complete, the ice bath is removed and 80 ml of dry acetonitrile is added. The mixture is then treated dropwise with 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile and then heated at reflux temperature for 2 hours. The solvent is then evaporated to the residue, 200 ml of methanol and 20 g of silica gel are added. The mixture is evaporated in vacuo to dryness and applied to the top of a column of 200 g of silica gel packed in hexane and the column eluted with mixtures of hexane and ethyl acetate. The fractions eluted with hexane-ethyl acetate (1: 1) give methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H), which is identical to the compound prepared in Example 1 .

Example 12

To a solution of 6 ml of ethanolamine in 5 ml of water is added in a portion 1.74 g of dimethyl-1,3-acetone dicarboxylate. The mixture is cooled to -10 ° C and then added dropwise over a period of 15 minutes with stirring 1.67 ml of 1-bromoacetone, all the time. keep the reaction mixture at a temperature not higher than 40 ° C. When the addition is complete, the dark mixture is stirred for an additional hour at room temperature and then poured into a mixture of hydrochloric acid and ice, saturated with solid sodium chloride and extracted with ethyl acetate (3 x 100 ml). The combined organic extract is washed neutral with cold water, dried with anhydrous sodium sulfate and evaporated in vacuo to dryness. Chromatograph the residue on 30 g of silica gel and using hexane-ethyl acetate (70:30) as the eluent, 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R = CH 2). Mp: 78 ° C (recrystallization from methylene chloride-hexane).

Example 13

To a redissolved solution of 7.7 g of methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate in 200 ml of dry di

Chloromethane cooled to 0 ° C is added 4.24 ml of triethylamine and 2.4 ml of methanesulfonyl chloride. The mixture is kept at room temperature for 15 minutes and then diluted with water. The organic phase is separated, washed with water (3 x 30 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. After crystallization of the residue from methanol, 9.04 g of methyl N- (2-mesyloxyethyl) -3-carbomethoxy-4-methylpyrrolide are obtained.

2- acetate (V, R = CH₃). Mp: 81 ° C.

To a solution of 9.067 g of methyl N- (2-mesyloxyethyl) -

3-carbomethoxy-4-methylpyrrole-2-acetate in 250 ml of dry acetonitrile is added 20.23 g of sodium iodide and the mixture is heated at reflux for 8 hours. Then, the mixture is evaporated in vacuo to dryness and the residue is taken up in 100 ml of dichloromethane. The organic solution is washed with water (2 x 40 ml), dried with anhydrous sodium sulfate and evaporated in vacuo to dryness. After crystallization of the solid residue from hexane ether, 9.13 g of methyl N- (2-iodoethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (VI, R = CH₃). Mp: 103 ° C.

Example 14

To a stirred suspension of 660 mg of sodium hydride in 250 ml of dry dimethylformamide, cooled to 0 ° C and held in a nitrogen atmosphere, is added 9.13 g of methyl N- (2-iodoethyl) -3-carbomethoxy-4-methylpyrrole-2 -acetate; The mixture is stirred for 3 hours at room temperature and the reaction is then quenched by the addition of 250 ml of water. The product is extracted with benzene (3 x 100 ml). The combined extracts are washed with water (2 x 100 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. Chromatograph the residue on 200 g of silica gel and using hexane-ethyl acetate (70:30) as the eluent, 4.56 g of dimethyl-1,2-dihydro-6-methyl3H-pyrrolo / 1,2-a pyrrole-1,7-dicarboxylate (VII, R = CH 2).

Mp: 71 ° C (recrystallization from ether-hexane).

To a solution of 3.81 g of dimethyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate in 30 ml of methanol is added a solution of 8.96 g of potassium hydroxide in 15 ml of water and the reaction mixture is heated at reflux for 8 hours. The methanol is then removed in vacuo, the aqueous solution is cooled to 0 ° C and acidified with 20% hydrochloric acid. The formed precipitate is filtered off, washed with water&gt; dried in an oven, and recrystallized from methanol to give 2.55 g of 1.2

<img file="SE436648B_D0018.tif" />

7803549-0 dihydro-G-methyl-SH-pyrrolo /^-1,2-α-7-pyrrole-1,7-dicarboxylic acid (VIII, R = CH 2). Mp: 200-230 ° C (dec.).

Example 15

A solution of 3.8 g of 1,2-dihydro-6-methyl-3H-pyrrolo-112-a-7-pyrrolo-1,7-dicarboxylic acid in 100 ml of freshly distilled isopropanol is cooled in an ice bath to -10 ° C and saturated with hydrogen chloride gas. The ice bath is then removed and the reaction mixture is stirred for 3 hours at room temperature and then evaporated in vacuo to dryness. The residue is dissolved in 100 ml of ethyl acetate and the solution is washed with a saturated sodium chloride solution (2 x 100 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. After crystallization of the residue from acetone water, 3.74 g of isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] 7-pyrrole-1-carboxylate-7-carboxylic acid (IX, R = CH₃, R² = iC₃hrs_?). Mp: 160 ° C.

g of isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo / 1,2-a-7-pyrrole-1-carboxylate-7-carboxylic acid is heated to 240 ° C for about 1 hour in a destination composition. A pale yellow oil distills everything as the decarboxylation proceeds to give 4.61 g of isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo / 1,2-a_ / pyrrole-1-carboxylate (X, R = CH₃, R² = iC-jH?). This substance is very unstable in air at room temperature and should be used immediately for the next step. The compound has the following physical constants:

CH₃OH

DV Ämax 226, 250 (shoulder) nm. (ε 4900, 2240); IR chci₃ CDCl₃ vmax 1717 cm^-1; NMR δTMS 1.22 (d, 6H, J = 6 Hz; ester CH₃), 2.03 (s, 3H; ring CH₃), 2.42-2.93 (m, 2H; CH₂), 3,554.17 (m, 3H, NCH)₂, CHCO), 4.92 (sept, 1H, J = 6 Hz; CH av

<td>ester), 5.66 (s,</td><td>1H; H-3), 6.25</td><td>(S,</td><td>1H; .H-5);</td>

<td>MS</td><td>m / e</td><td> 1%</td><td></td>

<td></td><td> 207</td><td> 18</td><td>M⁺</td>

<td></td><td> 120</td><td> 100</td><td>M⁺ -CO₂CH (CH₃)₂.</td>

<td>Example</td><td> 16</td><td></td><td></td>

<td colspan="2">In accordance with</td><td colspan="2">the method of Example 8</td>

isopropyl-1 is densified. , 2-dihydro-6-methyl-3H-pyrrolo / 1,2-α-7-pyrrole-1-carboxylate with N, N-dimethyl-1-methylpyrrole-2-carboxamide, to prepare isopropyl-5- (N-methyl -2-pyrroyl) -1,2-dihydro6-methyl-3H-pyrrolo-1,2-a-7-pyrrole-1-carboxylate (XI, R and R =

.. '-V u

7803549-0

CH₃, R² = iC₃hrs₇).

Example 17

To a solution of 500 mg of isopropyl 5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo / 1,2-a-7-pyrrol-1-carboxylate in 15 ml of methanol is added a solution of 1 05 g of potassium carbonate in 8 ml of water. The mixture is heated at reflux under a nitrogen atmosphere for 30 minutes, cooled and evaporated to dryness. The residue is taken up in 10 ml of 10% hydrochloric acid and 50 ml of water and the mixture is extracted with ethyl acetate (3 x 50 ml). The combined extracts are dried over magnesium sulfate and evaporated in vacuo to dryness to give 5- (N-methyl2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-11 carbonic acid (A, R and R = CH₃).

Example 18

A solution of 200 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrol-1-carboxylic acid in 5 ml of methylene chloride is reacted with an excess of an ether solution of diazomethane and the reaction mixture are kept at room temperature for 30 minutes. The solvents and excess reaction component are removed in vacuo and the residue is crystallized from ethyl acetate-methanol to give methyl 5- (N-methyl-2-pyrroyl) -1,2-dihydro-6-methyl-3H-pyrrolo.^_1,2-a_7pyrrol-1-carboxylate.

Example 19

A solution of 300 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro3H-pyrrolo7 1,2-a_ pyrrol-1-carboxylic acid in 5 ml of isoamyl alcohol is saturated with hydrogen chloride. the excess alcohol is distilled off in vacuo after 24 hours and the residue is purified by chromatography on alumina to give isoamyl-5- (N-methyl2-pyrroyl) -1,2-dihydro-3H-pyrrolo / 1,2-α 1-carboxylate.

Example 20

To a solution of 300 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo7 1,2-a-7-pyrrole-1-carboxylic acid in 5 ml of methanol is added 1 mole equivalent of sodium hydroxide in the form of a 0.1 -normal solution. Then, the solvent is removed in vacuo and the residue is taken up in 2 ml of methanol followed by precipitation with ether to give pure sodium 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo / 1.2 -a_7pyrrole-1-carboxylate, which can. is crystallized from ethyl acetate-hexane.

In the same way, other salts are prepared, e.g.

<img file="SE436648B_D0019.tif" />

7803549-0 as ammonium and potassium salt of 5- (N-methyl-2-pyrroyl) -1,2-dihydro3H-pyrrolo [1,2-a] 7-pyrrol-1-carboxylic acid by substituting sodium hydroxide with ammonium hydroxide and potassium hydroxide.

Similarly, the 5-substituted 1,2-dihydro-3H-pyrrolo / 1,2-a_7 prepared in Examples 11 and 20 can be convertedpyrrole-1-carboxylic acid compounds to the corresponding sodium, potassium and ammonium salts.

Example 21

To a solution of 175 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo / 1,2-α-7-pyrrolo-1-carboxylic acid in 5 ml of methanol is added 1 mole equivalent of potassium hydroxide in the form of a 0.1 -normal solution to obtain a solution containing potassium 5 (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo_J/ 1,2-α-7-pyrrole-1 carboxylate. A solution of 40 mg of calcium carbonate dissolved in the minimum amount of 1-normal hydrochloric acid necessary to effect dissolution of the calcium carbonate is buffered with 100 ml of solid ammonium chloride, followed by a further addition of 5 ml of water. The buffered calcium solution thus obtained is then added to the solution of potassium 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-1-carboxylate and the precipitate formed is filtered off , washed with water and dried in the air to give calcium 5- (N-methyl-2-pyrroyl) -1,2-dihydro3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Similarly, magnesium 5- (N-methyl2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] 7-pyrrole-1-carboxylate is prepared by replacing calcium carbonate with magnesium carbonate.

Example 22

To a solution of 200 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo / 1,2-a-7-pyrrole-1-carboxylic acid in 15 ml of hot benzene is added 60 mg of isopropylamine. The solution is allowed to cool to room temperature and the product is filtered off, washed with ether and dried to give the isopropylamine salt of 5- (N-methyl2-pyrroyl) -1,2-dihydro-3H-pyrrolo / 1,2-a-7-pyrrole-1-carboxylic acid.

Example 23

A solution of 770 mg of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo7 1,2-α-pyrrole-1-carboxylic acid in 10 nil benzene is reacted with 580 mg of dioyclohexylamine. The mixture is stirred for 10 minutes and the solid formed is filtered off and washed with anhydrous ether to give 965 mg of dicyclohexylamide salt of 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo [1,2] a_7 ~

7803549-0 pyrrole ~ 1-carboxylic acid.

Example 24

Biodata

A. Analgesic (anti-distortion) test

Methodology: The test material is orally administered by probe in an aqueous vehicle at time 0 to Swiss-Websterhan mice weighing 18-20 g. 20 minutes thereafter, intraperitoneally 0.25 ml of a 0.02% solution of phenylquinone is injected. This solution produces distortions. The animals are then observed for the following 10 minutes for distortions.

End point: The total number of mice distorted and the number of twists per mouse.

Using the above methodology, it was found that 5- (N-methyl-2-pyrroyl) -1,2-dihydro-3H-pyrrolo^-1,2-a_7pyrrol1-carboxylic acid has 120 times greater analgesic activity than aspirin.

B. Acute oral toxicity (LD_cn) in mice.

□ u

Methodology: The test material is suspended in an aqueous suspending vehicle of carboxymethyl cellulose. Concentrations are adjusted so that doses can be administered in volumes of 10 ml / kg body weight. Six groups (comprising six SwissWebster male mice in each group) mice were used. A single oral dose by gastric probe per kg body weight of either 75 mg, 150 mg, 300 mg, 600 mg or 1200 mg of 5- (N-methyl-2-pyrroyl) -

1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-1-carboxylic acid is administered to the mice. The sixth group serves as a control group. The mice are observed after administration for a period of 3 weeks.

Using the above methodology, the acute oral toxicity LD ^ for 5- (N-methyl-2-pyrroyl) -1,2-dihydro^—1,2-α / pyrrole-1-carboxylic acid about 900 mg / kg.

ρθθ · &amp;

7803549-0