DK151335B - METHOD OF ANALOGUE FOR THE PREPARATION OF (DL) - OR (L) -5-BENZOYL-1,2-DIHYDRO-3H-PYRROLO (1,2-A) PYRROL-1-CARBOXYLIC ACID ESTERS OR SALTS - Google Patents

Description

151335

The present invention relates to an analogous process for the preparation of novel (dl) or (l) -5-benzoyl-1 # 2- dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid esters or salts of the general formula in \ S-7 R l | 1 JL .COOK3. (XII)

• II I

3 represents hydrogen or an alkyl group of 1-4 carbon atoms, R1 represents hydrogen, an alkyl group of 1-4 carbon atoms, an alkoxy =

ISLAND

a group having 1-4 carbon atoms, chlorine, fluorine or bromine, and R is an alkyl group having 1-12 carbon atoms or a physiologically acceptable salt residue.

The method according to the invention is characterized by the characterizing part of the claim. The compounds of this invention exert anti-inflammatory, analgesic and antipyretic

Effect and thus are useful in the treatment of inflammation, pain and / or pyrexia in mammals, as described in more detail below. They are also smooth muscle relaxation eyes.

Typical alkyl groups R are, for example, methyl, ethylpropyl, isopropyl, butyl, t-butyl, isoamyl, pentyl, isopentyl, hexyl, octyl, nonyl, iso-decyl, 6-methyldecyl and dodecyl.

Salts derived from inorganic bases include sodium, potassium, lithium, 20 ammonium, calcium, magnesium, ferrous, zinc, copper, manganese, aluminum, ferric or manganese salts. The ammonium, potassium, sodium, calcium and magnesium salts are especially preferred. 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, triethylamine, diethylamine, triethylamine, triethylamine, , ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclo = hexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine -ethylpiperidine, polyamine resins and the like. Particularly preferred organic, non-toxic bases are iso = propylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicy = 35 clohexylamine, choline and caffeine *

The novel compounds of formula (XII] described below exist as pairs of optical isomers (or enantiomorphs), nozzles, a (dl1 mixture). However, the present invention relates, as is apparent to the preparation of The (1) form as (dl) -blan = things.

3 151335

The novel (dl) or (1) compounds of the present invention can be prepared by a process which can be illustrated by the following scheme of reaction: r "XcXX / cooh li I * ii io I_ o I____ (A ) (XII) dl or 1 dl or 1 1 3 where R, R and R have the meanings previously mentioned. In the process of the invention, the free acids of formula (A) can be converted to alkyl esters having from 1 to 12 carbon atoms by semen 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 (1) acid isomers can be converted to their alkyl = -u esters by the above-mentioned methods of (b) and (c).

The salt derivatives of the compounds of formula (A) and their (1) acid isomer 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, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, manganese hydroxide, aluminum hydroxide. droxide, ferric hydroxide, manganese hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline , glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N.ethylpiperidine or polyamine resins. The reaction through is carried out in water, alone or in combination with an inert, water miscible organic solvent at a temperature of approx. 0 ° C to approx. 100 ° C, preferably at room temperature. Typical inert, water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio of compounds of formula (A) or (1) acid isomers thereof to the base used is selected to provide the desired ratio for any particular salt. For manufacturing e.g. of the calcium salts or magnesium salts of the compounds of formula (A) or the (1) acid isomers thereof, the free acid starting material can be treated with at least in molar equivalent pharmaceutically acceptable base to produce a neutral salt. When the aluminum salts of the compounds of formula (A) or their (1) acid isomers are prepared, at least 1/3 molar equivalent of the pharmaceutically acceptable base is used if a neutral salt product is desired.

10

By the preferred method, the calcium salts and magnesium salts of the compounds of formula (A) and (l) acid isomers thereof can be prepared by treating the corresponding sodium or potassium salts thereof with at least · molar equivalent calcium chloride or magnesium = chloride in an aqueous solution, respectively or in combination with an inert, water-miscible organic solvent at a temperature of ca. 20 ° C to approx. 100 ° C. The aluminum salts of the compounds of this invention may preferably be prepared by treating the corresponding free acids with at least 1/3 molar equivalent of aluminum alkoxide, such as aluminum triethoxide or aluminum tripropoxide, in a hydrocarbon solvent such as benzene, xylene. or cyclohexane at a temperature of ca. 20 ° C to approx. 115 ° C. Similar methods can be used to prepare salts of inorganic bases which are not sufficiently soluble to readily react.

25

It is to be understood that the isolation of the compounds described herein may, if desired, be carried out by any suitable separation or purification method, such as e.g. extraction, filtration, evaporation, distillation, crystallization, thin layer chromatography or column chromatography, high pressure liquid chromatography (HPLC) or a combination of these methods. Examples illustrate suitable separation and isolation methods. Of course, other equivalents can also be used. separation or isolation methods. 1 2 3 4 5 6

Alkaline hydrolysis of the alkyl ester group in a compound of formula (XI) gives the corresponding free acid of formula (A). This hydro 3 lysis is carried out in the usual manner with an alkali metal hydroxide or 4 alkali metal carbonate, e.g. sodium hydroxide, potassium hydroxide, sodium = 5 carbonate or potassium carbonate in an aqueous lower aliphatic alcohol, e.g. methanol, ethanol and the like, at a temperature of approx.

5 to room temperature to reflux temperature from approx. 15 minutes to approx. 2 hours under an inactive atmosphere. In the preferred embodiments, this hydrolysis is carried out with aqueous methanolic potassium carbonate at the reflux temperature for approx. 30 minutes.

5 '

The compounds of formula (A) may be cleaved in accordance with known methods in the art to obtain the corresponding single isomers thereof.

10 (1) acid isomers and (d) acid isomers of the compounds of formula (A) can be obtained by applying the prior art high pressure liquid chromatography (HPLC) to α-phenethyl diastereoisomeric esters of the compounds of formula (A) followed by acid cleavage. Thus, the compounds of formula (A) wherein R and R 2 are both hydrogen can be e.g. 15 is subjected to further treatment according to the following diagram: * ·: -; ./ ·· Ox> c ^ 0k / doon · töl · '. · * - '· V. ·' '' y. * * several steps' · ..

* '· ** ··· ·. ···· *. '·. 4 ^. ·· ... / · '25 · - 1 *.

i (A) - (1) “isynoisomer-4 (1)” and “pbenethyl ester-)

'Mixture nf J ,. - C

/ (ΑΛ) - (ά) - acid isomer - '(i) -α-phenethyl ester j •. '.. ·' .separation below. ".

.. v · · .. '·.' use of 30; · ./ .. ··· · '; · '- High Pressure Liquid · - *' ·: Chromatography ·, '· • · (A ^) - (l) ~ .syseisomer- (l) -phenethyles.terr \' vy V · '(A) - (d) Acid isomer-d) -benzyl ester 1. ice/ . · In (A) - (1) acidomer. (A) - (d) acid isomer - 6151335

A more detailed description of this process can be found in the following Example 8. The starting materials of Formula A can be prepared according to the following reaction scheme: NH 2 COOCU 3 'cooch3 1 + f R = · H1 9H2 · COOCH- * P cooch3 in · 3 ( III)

• CH. 0. v V? Iin

'JL / \ 4 H «C ~ CH_' ° H ·. . (ID, 2 | 2 ·· '·'. '· Ί V® OH.' ^ (I) Ί · .- r '·' Poch3 '· ^ cooch3 ··. · -. *' L · ^ JJ ^ ^ cooch3 · "*;" J ^ J. ^^^ cooc ^ 'CH- \ i J 2. \ H2C-CH2 ch, (V) \. I (IV)! \.' 0H. f OS02CH3 R._C00CH3 * '^ cooch3' 1LHX / C00CH3 1 nX ^ C00C * 3

: '· ·. I · ·· .. I T

CH2. (will) • · · . I 2 (VI). .:. -,

IH2C

'R ^ CQQH · R ^^ JCOQH

. XjC> COOR2 “, /” · UycOOH

. . (IX) '; |: .. · (VIII): / Ί; i (X) · '(XI) "Vni

- ^ Xs ^ / COOH

'·. 11 r T

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

When the above process is carried out to prepare the compound of formula (IV) wherein R is hydrogen, equimolar amounts of ethanolamine (i) and dimethyl-1,3-acetone dicarboxylate (II) are reacted at a temperature of about 0 ° C to approx. room temperature to readily form a solution of the vinylamine of formula (III), which is then treated, preferably in situ, in a suitable inert organic solvent under anhydrous conditions with 2-bromoacetaldehyde or 2-chloroacetaldehyde at from ca. 40 ° C to approx. 100 ° C for a period of approx. 30 minutes to approx. Suitable solvents for this reaction are the aprotic solvents such as acetonitrile, tetrahydrofuran, dimeth = 15. oxyethane, chloroform, dichloromethane and the like. In the preferred embodiments, the reaction is carried out in acetonitrile solution at the reflux temperature of .ca. 1 hour. The 2-bromo (chloro) -acetaldehyde = reagents are known compounds or can be obtained by pyrolysis of the corresponding diethyl acetals in the presence of oxalic acid dihydrate.

20: ·.

To prepare the compounds of formula (IV) wherein R is a lower alkyl group, preferably straight chain, of 1-4 carbon atoms, treat an aqueous mixture of ethanolamine (I) and dimethyl-1,3-acetone = dicarboxylate (II) with a compound of formula 25 -

ISLAND

X II

R is -C-C 1 X, x wherein X is bromine or chlorine and R is a lower alkyl group, preferably straight chain, of 1-4 carbon atoms and best 1-bromoacetone, 1-bromo-2-3 butanone, 1-bromo-2 -pentanone and l-bromo-2-hexanone, at from ca. 40 ° C to approx. 100 ° C for a period of approx. 30 minutes to approx. 16 hours. In the preferred embodiment, the reaction is carried out at a temperature of approx. -10 ° C to about room temperature for from approx. 1 hour to approx. 6 hours.

The R-C-CEyi reagents are known compounds *

Eating the compound (IV) with methanesulfonyl chloride in the presence of a tertiary amine, i.e. triethylamine, pyridine and the like, optionally in the presence of a co-solvent such as dichloromethane at a temperature of about -10 ° C to about room temperature for approx. 10 minutes to approx. 2 hours form 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 the reflux temperature for from ca. 1 to approx. 10 hours.

By reaction of the iodoethyl compound of formula (VI) with sodium hydride in a suitable inert organic solvent such as dimethylformamide, dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7 is obtained. -dicarboxylai and the 6-alkyl-substituted derivatives thereof (VII). This ring closure is carried out under an inactive atmosphere, i.e. under argon or nitrogen atmosphere, at temperatures of the order of ca. 15 ° C to approx. 40 ° C for a period of approx. 15 minutes to approx. 4 hours. The best 15 results are obtained by conducting the reaction at room temperature for approx. 30 minutes when R is hydrogen.

% Alternatively, the compounds of formula (Vil) may be prepared by direct cyclization of the mesylate (V) with sodium hydride in dimethyl form = Λ A - amide solution at off. ca. -10 ° C to about room temperature for from approx. 30 minutes to approx. 2 hours.

Base hydrolysis of a compound of formula (VII) with an alkali metal = hydroxide or alkali metal carbonate, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, chlorium carbonate and the like in an aqueous lower aliphatic alcohol, e.g. methanol or ethanol, at a temperature between room temperature and the reflux temperature for from ca. 4 to approx. 24 hours, 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 derivative thereof. The hydrolysis is preferably carried out using aqueous methanolic potassium hydroxide at reflux temperature for about one hour. 10 hours.

The carboxylic acid group at the C-1 position of compound (VIII) is then selectively esterified by treatment with a lower aliphatic alcohol, e.g. methanol, ethanol, isopropanol, n-butanol and the like, in the presence of hydrogen chloride to prepare the corresponding alkyl-1,2-di = hydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid of formula 40 (IX). The reaction is carried out at a temperature of approx. 0 ° C to approx.

50 ° C for approx. 1 to approx. 4 hours.

151335 ίο

Decarboxylation of the mono-esterified compounds (IX) to the corresponding compounds of formula (X), the key intermediates of the process for the preparation of the compounds of the present invention, is achieved by heating (IX) at an elevated temperature 5 230 ° C to about-280 ° C for a time sufficient to complete the realization. The course of the reaction can be followed by the carbon dioxide development rate and thin layer chromatographic analysis, with decarboxylation usually completed in about 10 minutes. 45 to about 90 minutes. The reaction product, namely 10-alkyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and the 6-alkyl derivatives thereof (X), can be purified by chromatographic methods. Alternatively and especially for decarboxylating small portions of compound (IX), the reaction product (X) can be distilled directly from the reaction vessel.

15 '

Condensation of a compound (X) with an amide of the formula \ / y - CON (CH 3) 3, - · 20 - wherein R 1 is as defined above gives the corresponding alkyl-5-aroyl-1,2-dihydro-2 3H-pyrrolo [1,2-a] 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 from about 1 to about 175 hours under an inert atmosphere followed by further reflux in the presence of sodium acetate for about 5 hours. Instead of phosphorus oxychloride, other acid chlorides such as phosgene or oxyylchloride may be used alternatively.

In the preferred embodiments, this condensation is carried out by adding a solution of compound (X) in a suitable solvent to a previously refluxed mixture of 1.1-5 molar equivalents of both the desired amide and phosphorus oxychloride in the same solvent, refluxing it thus obtained reaction mixture for from ca. 6 to approx. 72 hours under an argon atmosphere and thereafter set from approx. 3 to about 10 molar equivalents of sodium acetate, followed by a further reflux period of from approx. 4 to approx. 6 hours.

40 151335.

11

Suitable solvents for this reaction are the halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like, dimethoxyethane and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane.

Examples of the Ν, Ν-dimethylarylamides that can be used are: N, N-dimethyl-o-toluamide, N, N-dimethyl-m-toluamide, N, N-dimethyl-p-toluamide, N, N-dimethyl -p-methoxy-benzamide, N, N-dimethyl-p-ethoxy-benzamide, N, N-dimethyl-o-chloro-benzamide, Ν, Ν-dimethyl-m-chloro-benzamide, N, N-dimethyl-1 p-chloro-benzamide, and N, N-dimethyl-p-fluoro-benzamide.

These amides are known, commercially available compounds or can be prepared in the usual manner from the corresponding acids, i.e. by conversion to the acid chlorides followed by treatment with dimethylamine

Although the (d) acid isomers are not used as medicine per se, they may, if desired, be converted to their pharmaceutically acceptable, non-toxic esters and salts thereof in accordance with the methods described for the conversion of (l) acid isomers to their pharmaceutically acceptable, non-toxic esters and salts thereof.

The (dl) and (1) compounds of formula (XII) are useful as anti-inflammatory agents, analgesics, platelet aggregation inhibitors, fibrinolytic agents and as smooth muscle relaxants. These compounds can be used both prophylactically and therapeutically. 1

Thus, the products containing these compounds are useful in the treatment and elimination of inflammation, such as inflammatory conditions in the muscular skeletal system, skeletal joints and other tissues, e.g.

12 151335 in the treatment of inflammatory conditions such as rheumatism, concussion, laceration, arthritis, fractures, post-traumatic conditions and arthritis. In cases where the above conditions include pain and pyrexia in connection with inflammation, the present compounds are useful in alleviating these conditions as well as the inflammation.

The preferred mode of administration for the conditions described above is the oral one, using an appropriate daily dose of dose that can be adjusted according to the nature and extent of the disorder. A daily dose of 25 mg to 500 mg of the active compound is used. Most disorders respond to a treatment comprising a dosage amount of the order of 0.5 mg to 6 mg kg body weight per day. day.

15

The compounds of the invention are also uterine muscle relaxants and thus useful as means of maintaining pregnancy in pregnant women and pregnant mammals for the benefit of the mother and / or fetus until termination of pregnancy from a medical point of view is found favorable or more favorable to the mother. and / or the fetus.

The following preparation methods and examples illustrate, respectively, the preparation of starting materials or intermediates of the starting materials for the process of the invention and the process of the invention. All mixing ratios used with regard to liquids refer to volume ratios. Where necessary, examples are repeated to prepare additional material for subsequent examples and unless otherwise stated, the reactions are carried out at room temperature (20-30 ° C).

Preparation method 1

A 250 ml 3-necked, round bottom flask containing a magnetic stir bar and fitted with calcium chloride-filled dryer pipes is connected directly (via one of the external necks) by means of a publishing beaker and a short (3 ") water cylinder to the acetal pyrolysis apparatus. consists of a 100 ml round bottom flask (pre-filled with 15.6 g of oxal = 151335 13 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 )) with a 6 "Vigreux column at the top provided with a thermometer connected to the above swallow.

The 3-neck flask is charged with 3.36 g of ethanolamine cooled in an ice bath to 0 ~ 10 ° C and treated dropwise with stirring with 8.7 g of dimethyl-1,3-acetonedicarboxylate. Methyl 3-carbomethoxymeth 3'1-3 (2, -hydroxyethyl) aminoacrylate (III) is formed immediately. After the addition is complete, remove the ice bath and add 100 ml of dry acetonitrile. The pyrolysis part of the apparatus is placed in an oil bath and the temperature of the bath is raised to 150-160 ° C. The bromoacetaldehyde solution formed is distilled (boiling point 80 ~ 83 ° C / 580 mm Hg) directly to the magnetically stirred solution of the vinylamine (III). When the distillation temperature drops below 80 ° C, the pyrolysis apparatus is switched off and a reflux condenser fitted with a calcium chloride drying tube is instead placed. The solution is heated to reflux for 1 hour, the solvent is removed under reduced pressure and then 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 top of a column of 200 g of silica gel packed in · 20 hexane. The column is then eluted with hexane / ethyl acetate (80:20; 500 mL) and hexane / ethyl acetate (1: 1; 9 x 500 mL). Fractions 2 and 3 contain minor polar impurities and dimethyl-1,3-acetone dicarboxylate. Fractions 4-8 give 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyr = rol-2-acetate (IV, R = H) which, after recrystallization from ether / hexane, has a melting point of 52 54 ° C.

Preparation Method 2

To a stirred solution of 4.1 g of methyl N- (2-hydroxyethyl) -3-carboxy methoxypyrrole-2-acetate in 35 ml of dry dichloromethane cooled to -10 ° C is added 2.65 ml of triethylamine, and then added dropwise 1 46 ml of methane = sulfonyl chloride, maintaining the temperature of the reaction mixture at -10 ° C to -5 ° C. The reaction is followed by a thin layer chromatographic analysis using chloroform / acetone (90:10). When the reaction is found to be complete (about 30 minutes after completion of the methanesulfonyl chloride addition), 10 ml of water is added slowly. The organic phase is separated, washed with water (3 x 30 ml), dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from dichloromethane / hexane gives 4.75 g (77.7%) of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H), m.p. ° C.

Provision in method of solution 3

A solution of 785 mg of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrol-2-aetate and 1.83 g of sodium iodide in 10 ml of acetonitrile reflux; for 1 hour. The cooled reaction mixture is evaporated to dryness under reduced pressure and the residue is decomposed with water. The insoluble food; The filtrate is separated by filtration and air dried. 840 mg (97%) of methyl N- (2-oodethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = mp 137-138 ° C) is obtained.

15

Preparation Method 4

A solution of 1 g of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate in 5 ml of dry dimethylformamide is stirred under an argon atmosphere with 2 ^ 137 mg of 50% sodium hydride in mineral oil. The reaction mixture is kept at room temperature for 30 minutes and then cooled rapidly with 100 ml of water. The product is extracted with ethyl acetate (3 x 50 ml), the combined extracts washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatography the residue on 20 g of silica gel using 25 des hexane / ethyl acetate (4: 1) as the eluant to give 500 mg (80%) of dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole -1,7-dicarboxylate (VII, R = H), m.p. 70-71 ° C.

A solution of 1.80 g of dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-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 refluxed for 6 hours. The cooled solution is evaporated to dryness and the residue is treated with 50 ml of saturated sodium chloride solution. The resulting solution is acidified with 6N hydrochloric acid and extracted with ethyl acetate (3 x 35 mL). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. There is thus obtained 1.51 g (95%) of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (VIII, R = H), m.p. 220 ° C during decomposition.

Preparation Method 5 A solution of 1.24 g of 1,2-dihydro-3H-pyrrolo [1,2-a] 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 to dryness under reduced pressure. 10 ml of 10 benzene is added to the residue and the solution is evaporated again under vacuum, repeating this process a total of three times to completely remove excess hydrogen chloride. Thus, 1.58 g (969b) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate ~ 7-carboxylic acid (IX, R = H, p R = iso C ^ HyH), which after recrystallization from methanol / ethyl acetate has a melting point of 144-145 ° C.

Preparation Method 6 1.054 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid is heated to 240-250 ° C in a dry 10 ml round bottom flask. , The reaction product being distilled directly from the reaction vessel.

In this way, 745 mg (87%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X, R = H, R2 = iso-C pale yellow oil with the following physical constants: UV : 215 nm (e 6020); I.R. : 1725 cm “1, · N.M.R. : 1.22 (d, J = 7Hz, 6H), 2.40-2.90 (m, 2H), 3.60-4.20 (m, 2H), 4.65-5.2 (m , 1H), 5.73-5.92 (m, 1H), 6.10 (t, J = 3Hz, 1H), 6.43-6.53 ppm / (m, 1H).

Preparation Method 7 2ø A 100 ml 3-necked, round bottom flask provided with a cooler, nitrogen supply tube and a gas bubbler is provided with 5.0 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 carboxylate-7-carboxylic acid. The apparatus is purged with nitrogen and the nitrogen flow is then stopped. The apparatus is immersed in an oil bath heated to 270 ° C and the reaction 35 is followed by the rate of carbon dioxide evolution (gas bubbles) and by thin layer chromatography on silica gel using benzene / di = oxane / acetic acid (90: 10: 1) as the developing agent. After 45 minutes, the reaction is almost complete. After 1 hour, the vessel is removed from the oil bath and the contents of the reaction flask are transferred to a round bottom flask with 500 ml of acetone. The solvent is removed under reduced pressure and the residue is purified by column chromatography on 100 g of silica gel. The fractions eluted with hexane / benzene (70: 30) and hexane / benzene (50:50) give 2.77 g (68%) of isopropyl-1,2-dihydro-β-3H-pyrrolo [1,2-a] pyrrole. 1-carboxylate (X, R = H, R = iso-C 2 Hy), an oil whose physical constants are identical to those obtained by Preparation Method 6.

Preparation Method 8

A solution of 179 mg of N, N-dimethyl-p-toluamide and 0.11 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is refluxed for 30 minutes. To this solution is added a solution of 193 mg of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 2 ml of 1,2-dichloroethane. The reaction mixture is refluxed under an argon atmosphere for 8 hours, treated with 405 mg of sodium acetate and refluxed for an additional 5 hours. The 2Q resulting mixture is then evaporated to dryness and the residue is chromatographed on 12 g of silica gel eluting with hexane / ethyl acetate (3: 1). Thus, 208 mg (66%) of isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI, R = H, R1 = p-CH , R2 = iso-C CH H), an oil having the following physical constants: UV 256, 312 nm, (e 8700, 19500); 1 · ^. : max 1735> 1620 160 1605 cm_li 6¾¾¾1> 25 ^ d J = 7Hz, 6H), 2.38 (s, ° 3H), 2.5-3.0 (m, 2H), 3.75 4.10 (m, 1H), 4.2-4.60 (m, 2H), 4.85-5.20 (m, 1H), 5.95 (d, J = 4Hz, 1H), 6, 70 (d, J = 4Hz, 1H), 7.10 (d, J = 8Hz, 2H), 7.60 ppm. (d, J = 8 Iiz, 2H).

Preparation Method 9

A solution of 336 mg of isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 10 ml of methanol is treated with a solution of 690 mg of potassium carbonate in 5 ml of water. . The reaction mixture is refluxed under a nitrogen atmosphere for 30 minutes, 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 with ethyl acetate (2 x 50 ml).

171335 17

The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate / hexane gives 238 mg (8950 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a) pyrrole-1-carboxylic acid [(A), R = H, R "1" = p-CH 2], mp 182-183 ° C.

Preparation Method 10

A solution of 250 mg of isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 8 ml of methanol is treated under a nitrogen atmosphere with a solution of 200 mg of sodium hydroxide in 1 ml of water, keeping the reaction mixture at room temperature for 1 1/2 hours. Me-10 thanol is removed under reduced pressure and the residual basic solution is diluted with 5 ml of water and extracted with ether to remove any unsaponifiable product. The aqueous solution is acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure and the residue is crystallized from ethyl acetate / hexane. There is thus obtained 5-p-toluyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid identical to the product obtained by Preparation Method 9.

Preparation Method 12 20-

Following the method of Preparation Method 8 using 1.1-5 molar equivalents 25 N, N-dimethylbenzamide, N, N-dimethyl-o-toluamide, N, N-dimethyl-m-toluamide, N, N-dimethyl1-p -methoxybenzamide, N, N-dimethyl-p-ethoxybenzamide, 30 N, N-dimethyl-o-chlorobenzamide, N, N-dimethyl-m-chlorobenzamide, and N, N-dimethyl-p-chlorobenzamide instead of N, N- dimethyl-p-toluamide and monitoring of the reaction process by thin layer chromatography are obtained, respectively: in isopropyl-5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, a pale yellow oil with the following physical constants: UV: 245, ΛΠΡΊ Ί HleUkb rViPl 311 nm (e 7230, 17800); 1 R -:% ax3 1735, 1620 cm 2 TMS 3 124 (d, 6H, (CH 3) 2 CH), 250-3.13 (m, 2H; H-2); 3.97 (dd, 1H, H1), 4.13-4.70 (m, 2H, H-3), 5.00 (sept, 1H, (CH 5) 2CH), 6.00 (d, IH, H-7), 6.86 (d, 1H, H-6), 7.10-7.90 ppm. (m, 5H, phenyl protons); MS: m / e 297 (M +), isopropyl-5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate an oil having the following physical constants: U.V. : 252, 303 nm 10 (- = 4460, 19100): I.R. : V ^ aks3 1735> 1620 cm_1; N * M * R ·: δ 18 (d, 6h, (OH) 2CH), 2.28 (s, 3H-, o -CH 3), 2.50-3.13 (m, 2H, H-2) ), 3.92 (dd, 1H, H1), 4.17-4.70 (m, 2H, H-3), 4.98 (sept. 1H, (CH 2 CH), 5.92 (d, 1H, H-7), 6.43 (d, 1H, H-6), 6.97-7.45 ppm (m, 4H, phenyl = protons), isopropyl-5-m-toluoyl-1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate an oil having the following physical constants: UV 250-251, 310-312 nm (e 6460, 17400); IR: yyyy 3 1735, 1620 cm -1: NMR: δ δ 813 1.25 (d, 6H, (CH 3) 2 CH), 2.27 (s, 3H, CH 3), 2.52-3.13 (m, 2H, H-2 ), Δ 3.92 2Q (dd, 1H, H1), 4.13-4.70 (m, 2H, H-3), 4.95 (Sept. 1H, (CH 3) 2CH), 5.95 ( d, 1H, H-7), 6.67 (d, 1H, H-6), 7.03-7.57 ppm (m, 4H; phenyl = protons), isopropyl-5-p-thioxybenzoyl -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate having the following physical constants: UV: 218, 270-25284 (shoulder), 314 nm (e 9780, 9320, 22400); IR: N> 8RC13 • 1730, 1605 cm @ -1; NMR: 3.24 (d, 6H, J = 6Hz; (CH2 CH2), 2.50-3.10 (m, 2H) ; H-2), 3.78 (s, 3H; CH 2 O), 3.93 (dd, 1H, = 6Hz JBX = 7Hz; H1), 4 , 13-4.60 (Μ, 2H; H-3), 4.95 (sept, 1H, J = 6Hz; 30 (CH 3) 2CH), 5.95 (s, 1H, J = 4Hz; H-7), 6.68 (d, 1H, J = 4Hz; H-6), 6.70-790 ppm. (m, 4H; phenyl protons); MS: m / e 327 (M +), isopropyl-5-ia-ethoxybenzoyl 1-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate / m.p. 50-51 ° C, isopropyl-5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 94-95 ° C, isopropyl-5 -o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, an oil having the following physical constants: UV: 251, 306 nm (e 5750, 16600); IR: + 3 1735, 1625 cm -1; Nm: 6 ^ 3.22 (d, 6h, (CH 3) 2 CH), 2.55-3.05 (m, 2H; H-2), 3, 97 (dd,

(1H, H1), 4.17-4.70 (m, 2H, H-3), 4.97 .. (Sept., 1H, (CH3) 2CH), C5.93 (d, 2 / 3H) , 6.00 (d, 1 / 3H) H-7], [6.42 (d, 2 / 3H), 6.67 (d, 1 / 3H), H-6], 7.07-7, 80 ppm. (m, 4H; phenyl protons), isopropyl-5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate, an oil having the following physical constants: UV: 241 , 3131 nm (e 6600, 15100); 1735, 1620, 1570'cm8 "1; N.M.R. : 1.27 (d, 6H, (CH 3) 2 CH), 2.50-3.18 (m, 2H, H-2), 3.93 (dd, 1H, H1), 4.10-4.63 (m, 2H, H-3), 4.98 (sept, 1H, (CH3) 2CH), 5.98 (d, 1H, H-7), 6.67 (d, 1H, H-6) ), 7.07-7.78 ppm.

(m, 4H, phenyl protons); MS: m / e 331-333 (M +), isopropyl-5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 80.5-81 ° C, isopropyl-5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 72-72.5 ° C, 20.

By hydrolysis of the isopropyl ester group according to the methods of Preparation Methods 9 or 10, the corresponding free acids are obtained, namely; 5-Benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 160-161 ° C, 5-o-toluoyl-1,2-dihydro-3H pyrrolo [1,2-a] pyrrole-1-carboxylic acid, an oil having the following physical constants: UV: AmoVc 253, 307 nm ρτ-γρί —i ρηρη §S (g 3310, 16980); I.R. : 1720> 1620 Cm 'n'M * R *: 6TMS 3 2'32 (s, 3H, CH 3), 2.53-3.03 (m, 2H, H-2), 3.97 (dd, 1H) , H1), 4.17-4.67 (m, 2H, H-3), 6.92 (d, 1H, H-7), 6.40 (d, 1H, H-6), 6.83 -7.37 (m, 4H, phenyl protons), 8.60 ppm. (b.s, 1H, COH), 5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, snap. 144-145 ° C, 5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 187-187.5 ° C, _____._________________________________________ -m-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 ~ Ccu: bo: xyl acid, syrup. 155-156 ° C, 5-p-Ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 169.5-170 ° C, 5-p-isopropoxybenzoyl -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 157-158 ° C, 5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid with the following physical constants: U.V. : 250, 307.5 nm (e 4360, 17400); IR: δ S3 1715s 1620 cm-5 N * M'R ·: 6¾¾¾ 2.60-3.15 (m, 5H); 4.02 (dd, 1H, JM = β,, JM = 7Hz; Η -Ϊ), 4.20-4.70 (m, 2H; H-3), 5.98 (d, 1H, J = 4Hz; H-7), 6.42 (d, 1H, J = 4Hz) ; H-6), 7.00-7.77 (m, 4H; phenyl protons), 8.67 ppm. (s, (br), 1H; COOH), 5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1-, 2-a] pyrrole-1-carboxylic acid, m.p. 180-181 ° C, 10 5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 201.5-202.5 ° C, 5-p-fluorobenzoyl-1,2-dihydro -3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 179.5-180.5 ° C.

For example, in method 13

A 250 ml 3-necked, round bottom flask with magnetic stir bar and fitted with a calcium chloride-filled drying tube is provided with 3.36 g of ethanolamine, cooled in an ice bath to 0-10 ° C and treated dropwise with stirring with 8.7 g of dimethyl-1,3-acetone dicarboxylate. Methyl 3-carbomethoxymethyl-3- (2'-hydroxyethyl) aminoacrylate (III) is formed immediately. After the addition is complete, remove the ice bath and add 80 ml of dry acetonitrile. The reaction mixture is then treated dropwise with 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile and then heated under 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 top of a column of 200 g of silica gel packed in hexane, eluting with 30 mixtures of hexane and ethyl acetate. The fractions eluted with hexane / ethyl acetate (1: 1) gave methyl N- (2-hydroxyethyl) -3-carbomethoxypyr = rci-2-acetate (IV, R = H) identical to the product obtained in Example 1 .

21

Preparation Method 14

To a solution of 6 ml of ethanolamine in 5 ml of water is added 1.74 g of dimethyl-1,3-acetone dicarboxylate. The resulting mixture is rapidly cooled to -10 ° C and treated dropwise over a period of 15 minutes with stirring with 1.67 ml of 1-bromoacetone while maintaining the reaction mixture temperature at a maximum of 40 ° C. After completion of the addition, the dark reaction 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 extracts are washed with cold water for neutral reaction, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography the residue on 30 g of silica gel using hexane: ethyl acetate (70:30) as eluant to give 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate as recrystallized from methylene chloride / hexane melts at 78 ° C and has the following analysis:

Calculated for C C-H- ^NO ^: C 56.45, H 6.71

Found: C 56.41, H 6.73.

Similarly, but using a stoichiometric equivalent amount of 1-bromo-2-butanone, instead of 1-bromoacetone, is obtained: 22 methyl-N- (2-hydroxyethyl) -3-cyanoethoxy-4 Ethylpyrrole-2-acetate, snip. 61-62 ° C, Preparation Method 15

Following the methods of manufacturing methods 2, 3, 4, 5 and 7, thyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R = O) successively to: 3 methyl-N- (2-mesyloxyethyl) -3-carbomethoxy-4-methylpyrrole -2-acetate, m.p. 81 ° C, methyl N- (2-iodoethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, m.p. 103 ° C, dimethyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate βφ. 71 ° Cf 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid, m.p. 200-2Q3 ° C, and isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid, m.p. 160 ° C.

Similarly, using methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate, methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrrole-2 is obtained. acetate and methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetate instead of methyl N- (2-hydroxy = 5 ethyl) -3-carbomethoxy-4-methylpyrrole 2-acetate respectively as final products: ·· '

Frews Addition 16 To the method of Preparation Method 8, iso = 10 propyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate is condensed with N, N-dimethyl p-toluamide to prepare isopropyl 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI, R = CH = p-CH 2, R 2 = iso-C 2 Hy) T mp, 72 ° C. Similarly, using the Ν, Ν-dimethylarylamides listed in Preparation Method 12 instead of N, N-dimethylamide. p-toluamide is obtained, respectively: isopropyl-5-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp 75 ° C nonhoxybenzoyl-1,2-dihydrp-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp, 89 ° C, isopropyl-5-p-chlorobenzoyl-1,2-dihydro-6- methyl 3H-pyrrolo [1,2-a] pyr = rol-1-carboxylate, mp 88 ° C, 25.

isopropyl 5-p-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate having the following physical constants: UV · 250> 315 ran (c 6170, 14100): 30 IR · axis 3 1734 · 16 ° 5. 1593 cm9393; ΓΠΠ N.M.R. 3 1.25 (d, 6H, J «6Hz; ester CH₂), 1.83 (s, 3H; ring CH3), 2.49-3.00 (m, 2H; CH₂), 3.90 (t, 1H, SJ = 7.4Hz; CHCO), 4.10-4.23 (m, 2H; N-CH 2), 4.93 (sept, 1H, J = 6Hz; ester CH), 5.84 (s, 1H, H-3) s 7.00 (t, 2H, Jortho = 8.4Hz, JHp = 8Hz; H-3 ', 51) / 7.55 (q, 2H, J-ortho = 8, 4Hz, JRF = 5.5Hz; H-2.6r); 23 M.S. m / e 1% 329 M + 242 100 M + -Cp2CH (CH3) 2 123 36 F-C6H4CO,

Preparation Method 17 A solution of 500 mg of isopropyl 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 15 ml of methanol is treated with a solution of 1.05 g of potassium carbonate in 8 ml of water. The reaction mixture is refluxed under a nitrogen atmosphere for 30 minutes and cooled and evaporated to dryness. The residue is taken up in 10 ml 10% aqueous hydrochloric acid and 10 50 ml water and the resulting mixture is extracted with ethyl acetate (3 x 50 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure to prepare 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid [. ( A), R = CH 2, R 1 = p-CH 2],. mp. 187 ° C, 15 Similarly or alternatively, by the hydrolysis method of Preparation Method 10, the remaining isopropyl ester compounds obtained by Preparation Method 16 are formed into the corresponding free acids, namely: 5-benzoyl-1,2-d 6-Mathyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 169 ° C ,.

5-p-methoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 182 ° C, 5-p-chlorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, m.p. 204 ° C, 5-p-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, m.p. 204 ° C,

Q

5-benzoyl-1,2-dihydro-6-ethyl'-3H --- pyrrolo [1,2-a] pyrrole carboxylic acid, m.p. 177 ° C and 5-p-fluorobenzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 196 ° C.

24

Preparation Method 18 710 mg of a 50% suspension of sodium hydride in mineral oil is washed with anhydrous hexane under a nitrogen atmosphere and then suspended in 50 ml of dimethylformamide. The suspension is cooled to -5 ° C and 4.5 g of methyl N- (2-mesyloxymethyl) -3-carbomethoxypyrrole-2-acetate are added, stirring the reaction mixture at -5 ° C - 0 ° C for 1 '. 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 to give dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-10 dicarboxylate (VII, R = H) identical to that of production method 4 product obtained.

Method of preparation 19

To a 250 ml 3-necked, round bottom flask provided with a nitrogen additive

J «J

and a discharge valve, a magnetic stir bar and a pressure equalized addition funnel containing 10.08 g of ethanolamine. while stirring, 26.1 g of dimethyl-1,3-acetone dicarboxylate is added dropwise over a period of 30 minutes while maintaining the temperature below 30 ° C. The resulting 20-methyl-3-carbomethoxymethyl-3- (2'-hydroxyethyl) aminoacrylate (III) 'is diluted with 20 ml of acetonitrile and chloroacetaldehyde, prepared by heating a mixture of 27.4g of chloroacetaldehyde diethylacetal with 46.8g. oxalic acid dihydrate at 150-160 ° C is added with stirring over a 2 minute period. The reaction mixture is refluxed for 5-10 minutes, after which the reaction by thin layer chromatographic analysis using acetone / chloroform (10:90) as the eluent is shown to be complete. The solvent is removed under reduced pressure, and to the residue are added 250 ml of benzene and 250 ml of heptane, and distillation is then carried out under reduced pressure. 2q The oily residue remaining after distillation is suspended in 50 ml of methylene chloride and to this is added 20 g of silica gel. The methylene chloride mixture is poured onto a column containing 200 g of silica gel made in ethyl acetate: hexane (20:80). The column is first eluted with 6 liters of ethyl acetate: hexane (20:80) and then with 4 liters of ethyl acetate: hexane 35 (50:50). The fractions eluted with ethyl acetate: hexane (50:50) are combined and concentrated to give 12.8 g of an oil which is decomposed with 20 ml of petroleum ether (30-60 ° C) followed by removal of the solvent under reduced pressure to Preparation of 11.89 g (32.9% of theory) of methyl N- (2, -hydroxyethyl) -3-carbomethoxy = 5 pyrrole-2-acetate (IV, R = H), m.p. 54 ° C, the same product obtained by Preparation Method 1.

Example 1 A solution of 200 mg of 5-benzoyl-1,2-dibydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ethereal diazorethane and the reaction mixture is kept at room temperature for 30 minutes. The solvents and reagent excess are removed under reduced pressure and the residue is crystallized ffa ethyl acetate / methanol. There is thus obtained methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = o oxylate, m.p. 86.5-88.5 ° C.

Similarly, but using diazoethane and diazopropane instead of diazomethane, ethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, respectively, is obtained, m.p. 67-68 ° C, and propyl 5-benzdyl-1,2-dihydro-3H-pyrrolo [2,2-a] pyrrole-1-carb, oxylate.

Similarly, the following compounds of formula A are prepared:

Xsopropyl 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, MeOH

an oil having the following physical constants: U.V .: '256, 312 nm, xs s in 1 max.

(ε 87QQ, 19500; IR; v 1 1735, 1620, 1605 cm; Nuclear Magnetic Resonance Spectrum; S 2 g ^ 1.23 (d, J = 7 Hz, 6H), 2.38 (s, 3H), 2.5 -3.0 (m, 2Hi, 3.75-4.10. (M, 1H), 4.2-4.60 (m, 2H), 4.85-5.20 3Q (m, 1H). , 5.95 (d, J = 4 Hz, 1H), 6.70 (d, J = 4 Hz, 1H), 7.10 (d, J = 8 Hz, 2Hl, 7.6Q ppm (d, J = 8 Hz, 2H) isopropyl-5-benzoyl-1,2-dihydro-2H-pyrrolo [1,2-a] pyrrole-1-carboxylate,

MeOH

a pale yellow oil with the following physical constants; U.V ,; λ 245, ρττρρ-ι _i max 35 311 nm (ε 7230, 178001; IR,: 3 1735, 1620 cm A, nuclear magnetic resonance; S ^ 13 1.24 [d, 6H, (CH 3 L 2 CH], 2.50 -3.13 (m, 2H; H-2I; 3.97 (dd, 1H, HI), 4-18-4.70 (m, 2H, H-3), 5.00. (CH 3 L 2 CH], 6.00 (d, 1H, H-7), 6.86 (d, 1H, H-6), 7.10-7.90 ppm Cm, 5H, phenyl protons); MS; m / m e 297 (m +); isopropyl-5-o-toluol-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = 40 26 151335

MeQH

oxylate, an oil having the following physical constants: U.V .: Amax 252, 303 nm (ε 4460, 19100); I. R .; 1735, 1620 cm -1; nuclear magnetic resonance: 1.18 [d, 6H, (CH 3) 2 CH], 2.28 (s, 3H-, O-CH 3), 2.50-3.13 (m, 2H , H-2), 3.92 (dd, 1H, H1], 4.17-4.70 (m, 2H, H-3), 4.98 [Sept. 1H, (CH 3) 2 CH], 5 , 92 (d, 1H, H-7), 6.43 (d, 1H, 4-6), 6.97-7.45 ppm (m, 4H, phenyl protons), isopropyl-5-m-toluoyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, an oil having the following physical constants; UV: 1mH x 250-251, 310-312 nm (ε 6.460, 17.400); IR: vmax13 1735, -1 CDC1 1620 cm, nuclear magnetic resonance: 5TMS 3.25 [d, 6H, (CH3) 2 CH], 2.27 (s, 3H, CH3), 2.52-3.13 (m, 2H, H-2)., 3.92 (dd, 1H, H1), 4.13-4.70 (m, 2H, H-3), 4.95 [Sept. 1H, (CH3) 2 CH], 5.95 (d, 1H, H-7), 6.67 (d, 1H, H-6), 7.03-7.57 ppm (m, 4H; phenyl protons); isopropyl-5 - (p-methoxybenzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate with the following physical constants UV; Imax 2.18, 27Q-284 (shoulder), 314 nm (ε 9780, 9320, 22400); 1.5, vmax 3 1730, -1 CDCl-3 1605 cm, nuclear magnetic resonance STMS J 1.24 [d, 6H, J = 6 Hz; (CH 3) 2 CH-], 2.50-3.10 (m, 2H; H-2), 3.78 (s, 3H); CH30), 3.93 (dd, 1H, = 6 Hz, JBX = 7 Hz; H1), 4.13-4.60 (m, 2H; H-3), 4.95 (sept, 1H, J = 6 Hz; (CH 3) 2 CH], 5.95 (s, 1H, J = 4 Hz; H-7), 6.68 (d, 1H, J = 4 Hz; H-6), 6, 70-7.90 ppm (m, 4H; phenyl = protons); M, S, m / e 327 (M +); isopropyl-5- (p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1 2-a] pyrrole-1-carboxylate, mp, 94-95 ° C; isopropyl-5- (o-chlorobenzoyl) -1,2-dihydro-3H-pyrrolo (1,2-a] pyrrole-1-carboxylate An oil having the following physical constants: UV: 30 λίη! ΧΗ 251, 306 nm (ε 5750, 16.6001; IR: vmax 3 1735, 1625 cm 1; CDCl 3 nuclear magnetic resonance; STMS 3 1.22 (d, 6H, CH3) 2 CH], 2.55-3.05 (m, 2H; H-2), 3.97 (dd, 1H, H1), 4.17-4.70 (m, 2H, H-3) , 4.97 [Sept., 1H (CH 3) 2 CH], [5.93 (d, 2 / 3H1, 6.00 (d, 1 / 3H) H-7], [6.42 (d, 2 / 3H), 6.67 (d, 1 / 3H1, H-6], 7.07-7.80 ppm (m, 4H; phenyl protons); isopropyl-5- (m-chlorobenzoyl) -1,2- dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, an oil having the following physical constants; UV,:

MeOH CHCl1 1 ′ λ max 241, 313 nm (ε 6600 ^ 15100); I, R ,; vmax 3 1735, 1620, 1570 cm χ, 40 nuclear magnetic resonance; STMS 3 1.27 [d, 6H, (CH 3) 2 CH], 2.50-3.18, 27.1335.

(m, 2H, H-2), 3.93 (dd, 1H, H1), 4.10-4.63 (m, 2H, H-3), 4.98 [sept., 1H, (CH3) 2 CH], 5.98 (d, 1H, H-7), 6.67 (d, 1H, H-6), 7.07-7.78 ppm (m, 4H, phenyl protons); MS; m / e 331-333 (M +); isopropyl-5- (p-chlorobenzoyl) -1,2-dihydro-3R-pyrrolo [1,2-a] pyrrole-5-1-carboxylate, mp 80.5-81 ° C isopropyl-5- (p-fluorobenzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp, 72-72.5 ° C isopropyl-5-p-toluoyl -6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp 72 ° C; isopropyl-5-benzoyl-6-methyl-1,2-dihydro-3H -pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p., 75 ° C; isopropyl-5- (p-methoxybenzoyl) -6-methyl-1,2-dihydro-3H-pyrrolo- [1 , 2-a] pyrrole-1-carboxylate, mp 89 ° C; isopropyl-5- (p-chloro-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo-20 [1,2-a]) pyrrole-1-carboxylate, mp 88 °; in sopropyl-5-p-toluoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp 72 ° C; dodecyl-5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp 33-34 ° C.

Example 2

A solution of 300 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylic acid in 5 ml of isoamyl alcohol is saturated with hydrogen chloride.

After 24 hours, the excess alcohol is distilled off in vacuo and the residue is purified by chromatography on alumina to prepare isoamyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Other esters, e.g. pentyl, hexyl, octyl, nonyl, dodecyl, and the like of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid using other alcohols, f. eg. pentyl, hexyl, octyl, nonyl, dodecyl alcohol and similar alcohols instead of iso-amyl alcohol.

151335 28

By the same method, the free acid compounds obtained by the preparation methods 12 and 17 are esterified with the appropriate alcohol, thus obtaining the corresponding esters, for example: isoamyl-5-benzoyl-1,2-dihydro-3 pyrrolo [1,2-a] pyrrole-1-carboxylate, 5-pentyl-5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, hexyl-5-p -ethylbenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxyl isoamyl-5-o-propylbenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate, octyl-3-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate, nonyl-5β-isopropoxybenzoyl-1 , 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, dodecyl-5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carb = oxylate, isoamyl-5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate, dodecyl-5-o-fluorobenzoyl-1,2 -dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = 20, oxylate, hexyl-5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxy = lat, nonyl-5-p-bromobenzoyl-1,2-dihydro-3H-pyrr olo [1,2-a] pyrrole-1-carboxylic acid is oamyl-5-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrroly-1-carboxylate, hexyl 5-p-ethylbenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-30'-1-carboxylate, nonyl-5-o-methoxybenzoyl-1,2-dihydro-1 6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, dodecyl-5-o-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylate, nonyl-5-benzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxy = lat, isoamyl-5-p-ethoxybenzoyl-1,2 -dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate) pentyl-5-p-fluorobenzoyl-1,2-dihydro-6-propyl-3H-pyrrolo [1,2] 2-a] pyrrole-1-carboxylate, hexyl-5-m-chlorobenzoyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and 5-dodecyl-5-p -bromobenzoyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, and octyl (dll-5-benzoyl-1,2-dihydro-3K - = - pyrrolo [ 1,2-ra] pyrrole-1-carb = oxyla.t, ': oil.

Example 2 To a solution of 200 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of potassium = hydroxide as a 0.1N solution. The solvent is stripped and the residue dissolved in 5 ml of water. The aqueous solution of potassium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate 15 thus obtained is added to a solution of 150 mg of cupronitrate trihydrate in 5 ml of water.

The formed precipitate is collected, washed with water and air dried. Thus, copper-5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxy = lat is obtained. · 20 Similarly, the free acid compounds obtained by the preparation methods 12 (and 8) and 17 can be converted to the corresponding copper salts'

Example 3 25

A solution of 200 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylic acid in 15 ml of hot benzene is treated with 60 mg of isopropyl = amine. The solution is allowed to cool to room temperature and the product is filtered off, washed with ether and dried. This gives the isopropyl = amine salt of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid.

Other amine salts, e.g. diethylamine, ethanolamine, piperidine, tro = methamine, choline and caffeine salts of 5-p-toluoyl-1,2-dihydro-3H-pyr = pyrrolo [1,2-a] pyrrole-1-carboxylic acid are also prepared by using each of the respective amines instead of isopropylamine.

Similarly, they obtained by the manufacturing methods 12 (and Ex. 8) and 17 obtained; free acid compounds are converted to the corresponding isopropylamine, di = ethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts, e.g. the tromethamine salt of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, sup. 162 ° C (decomp. In ng); NNR (300 MHz, DHSO) 2.54-2.66 (, 1H); 2.71-2.83 (m, 1H); 3.47 (s, 6H); 6.74-3.78 (dd, 1H, J = 8.8, 5.7 Hz); 4.20-4.44 (m, 2H); 6.01 (d, 1H, J = 3.9 Hz); 6.45 (bs, 6H); Δ 6 * 71 (d, 1H, J and 3.9 Hz); 7.46-7.60 (m, 3H); 7.73 (m, 2H).

Example 4

A solution of 770 mg of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylic acid in 10 ml of "benzene" is treated with 580 mg of dicyclohexyl = amine. The reaction mixture is stirred for 10 minutes and the solid formed is filtered off and washed with anhydrous ether. Thus, 965 mg of the dicyclohexylamine salt of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 20 Similarly, the residual free acid compounds obtained by Preparation Methods 12 (and Ex. 8) and the compounds of Preparation Methods 9 and 17 can be converted to the corresponding dicyclo = hexylamine salts, e.g. the dicyclohexylamine salt of 5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 173-175 ° C.

25

Example 5

To a solution of 300 mg of 5-henzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 25 ml of dry benzene is added 0.58 g of trifluoroacetic acid = 30 anhydride. The mixture is stirred at room temperature for 10 minutes and the resulting solution is cooled to 0-5 ° C and 1.4 g of dry triethyl amine is added, followed immediately by the addition of 0.5 g of (1) -α-phenyl = ethyl 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 followed by removal of the solvent and excess (1) -α-phenylethyl alcohol in vacuo. There is thus obtained 0.42 g of a mixture of (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (1) -α-phenethyl ester and (d) ) -5-Benzoyl-1,2-di = hydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (1) -a-phenethyl ester which is separated by high pressure liquid chromatography (using 4% EtOAc / hexane on an 11 mm x 50 cm 10 µm Lichrosord Sl-60 column) to produce 180 mg of a more polar ester (a ^ e ^ <^ 145.7 °) and 178 mg of a less polar ester (oc ^ e + + 128.6 °).

Dissolve 148 mg of the more polar ester in 8 ml of dry benzene. The solution is cooled to 15-20 ° C and 5 ml of trifluoroacetic acid is added and the solution is stirred at room temperature for 1 hour and 10 minutes. The reaction solution is poured into 60 ml of dry benzene and the solvents are removed under vacuum and at ambient temperature. Purification is carried out by high-pressure liquid chromatography (using a column 15 such as the one described above except that 35 $ EtOAc / hexane in 2-acetic acid is used instead of 4 $ EtOAc / hexane) to prepare 63 mg (1) -5-benzoyl -1,2-dihydro-3H-pyrrolo [1,2-a '] pyrrole-1-carboxylic acid with an £HCl13 = -155.7 ° C and a melting point of 153 ° 155 ° C.

Similarly, cleavage of the less polar ester according to the method described above for the cleavage of the more polar ester gives 85 mg (d) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a ] One pyrrole-1-carboxylic acid with an α ^ 3 = +155.1 C and a melting point of 154-156 ° C. The (d) acidomer thus obtained can be racemized (recycled) if desired, according to methods known in the art.

Similarly, other (dl) compounds can be converted to their respective (1) isomers and (d) isomers.

30

Biodata A. Test for analgesic (antidepressant) effect on mice.

Protocol: The material to be tested is orally administered by administration to an aqueous carrier at time 0 to 18-20 g male Swiss-Webster mice. 20 minutes later 0.25 ml of a 0.02 $ solution of phenylquinone is injected intraperitoneally. This solution produces distortion. The animals are then observed for the next 10 minutes with respect to torsion

End point: The total number of mice twisting and the average even number of turns per head. mouse.

Using the above protocol, it is determined that 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has an analgesic effect of about 430 times aspirin, and 5 (1) -5Hbenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has an analgesic effect of approx. 700 times aspirins.

(1) -6- (benzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has an analgesic effect of approx. 700 times aspi- rins; methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate has an analgesic effect of about 320 times «aspirin; octyl-5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate has an analgesic effect of approx. 200 times aspirin; dodecyl-5-benzoyl-1,2-dihydro-3M-pyrrolo [1,2-a] pyrrole-1-carboxylate has an analgesic effect of approx. 50 times the aspirin and the tromethamine salt of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has an analgesic effect in about 250 times aspirins.

In addition, the following strengths were determined: 5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. 5-p-isopropoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid ± 5-m-ethoxybenzoyl-1,2-dihydro-3K-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid β-5-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5-p -methylbenzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 250 5-p-methoxybenzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1 , 2-a] pyrrole-5 1-carboxylic acid 130 5-p-chlorobenzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole.

1-carboxylic acid 190 5-Benzoyl-6-ethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. 80 5- (4-Fluorobenzoyl) -6-ethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 130 B. Acute oral toxicity (LDcri) in mice.

15 50

Protocol: The material to be tested is suspended in an aqueous carboxymethyl cellulose suspending carrier. Concentrations are adjusted so that doses can be given in volumes of 10 ml / kg body weight. Five groups (consisting of six Swiss-Y / ebster male mice in each group) mice are used. A single oral dose of either 200 mg, 400 mg, 800 mg or 1200 mg of 5- (benzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid per day. kg of body weight is administered by stomach probe to the mice. ' (The fifth group is used as a control.) After administration, the mice are monitored for a 3-week period.

25

Using the above protocol, the acute oral LDβ value of 5- (benzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid is determined to be approx. 200 mg / kg.

2Q The corresponding values for 5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid and 5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [ 1,2-a] pyrrole-1-carboxylic acid is 606 mg / kg.

C. Test for anti-inflammatory action using carrageenin-induced rat protein inflammation in the rat.

34

Protocol: Simonsen female rats weighing 80-90 g were used. Test materials are administered orally at time 0 by administration in 1 ml of aqueous vehicle. One hour later, 0.05 ml of a 1% solution (in 0.9% NaCl) of carrageenin was injected into the right hind paw. This injection caused an inflammation of the paw. The rats were sacrificed 4 hours after time 0, at which time both hind legs were cut and weighed separately. ... v · - "

End point:% increase in paw size calculated as follows: 'weight of right paw' τ guard 'of left paw ^ qq weight of left paw

Using the above protocol, the following effects were determined (phenylbutazone = 1}: - "-: 5 ~ p -ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 5-p-isopropoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a} pyrrole-1-carboxylic acid 1 5- µm-ethoxybenzoyl-1,2-carboxylic acid 1-carboxylic acid 1,5-benzoyl-6-methyl-1,2-dihydro-3H-2-pyrrolo [1,2-a] pyrrole 1-carboxylic acid approx. 5-p-methylbenzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid about 5-p-methoxybenzoyl-6- methyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid about 45-5-p-chlorobenzoyl-6-methyl-1,2-di = hydro-3H-pyrrolo [1 , 2-a] pyrrole-1-carboxylic acid about 60 5-benzoyl-6-ethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

Claims (3)

5- (4-Fluorobenzoyl) -6-ethyl-12-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid Analogous process for preparing (dl) - or (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-aJ pyrrole-1-carboxylic acid esters or salts of the general formula; R 1 f ~ ^ l | ij R 1 represents hydrogen or an alkyl group of 1-4 carbon atoms, R · 1 · represents hydrogen, an alkyl group of 1-4 carbon atoms, an alk = 3 oxy group of 1-4 carbon atoms, chlorine, fluorine or bromine and R is an alkyl group of 1-12 carbon atoms or a physiologically acceptable salt residue, characterized by esterification of the corresponding free acid to form the esters thereof of formula (XII), or neutralization of the corresponding free acid to form the salts. 15 (of formula XII). thereof, optionally followed by cleavage of a (dl) ester or a (dl) salt (of formula XII) to the optically active enantiomers and isolation of the (11 ester (of formula XII) or (I) salt (of formula XII) .. 20