DK151337B - ANALOGY PROCEDURE FOR THE PREPARATION OF (DL) - OR (L) -5-BENZOYL-1,2-DIHYDRO-3H-PYRROLO (1,2-A) PYRROL-1-CARBOXYLIC ACID DERIVATIVES - Google Patents

Description

151337 \

The present invention relates to an analogous process for the preparation of novel (dl) or (l) -5-benzoyl-1,2-dihydro-3H-pyrrolori, 2-a] pyrrole-1-carboxylic acids of the general formula r L / coch (a)

H I

Or pharmaceutically acceptable salts thereof, wherein R represents hydrogen or an alkyl group of 1-4 carbon atoms and represents hydrogen, an alkyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon atoms, chlorine, fluorine or bromine, which The process is characterized by the characterizing part of the claim.

The compounds of the present invention, with the exception of the (d> acidomer) and its derivatives, exert anti-inflammatory, analgesic and antipyretic action and are thus useful in the treatment of inflammation, pain.

10 ° g / or pyrexia in mammals, as described in more detail below.

They are also smooth muscle relaxants.

The term "pharmaceutically acceptable salts" is used herein to refer to salts derived from pharmaceutically acceptable, inorganic and organic bases which may effect hydrolysis of the corresponding alkyl ester of the compounds of formula A.

Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, ferro, zinc, copper, manganese, 2Q 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, , ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine -ethylpiperidine or polyamine resins. Particularly preferred organic, non-toxic bases are iso = propylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicy = clohexylamine, choline and caffeine.

The novel compounds of formulas (A) and (XI) described below exist as pairs of optical isomers (or enantiomorphs), i.e. a (dl) mixture.

When the novel compounds prepared according to the invention are to be used to produce a physiological reaction (e.g., anti-inflammatory, analgesic or antipyretic), i.e. they are to be used as medicine, a preferred subgroup 5 is the group consisting of the compounds of formula (A) and (1) acid isomers thereof and the pharmaceutically acceptable salts thereof.

Yet another subset of compounds to be used as medicine are the compounds of formula (A) and (1) the acid isomer of formula (A) 10 and pharmaceutically acceptable salts thereof, wherein R and R 1 are both hydrogen.

The process of the present invention for the preparation of the present novel (dl) compounds can be illustrated by the following reaction: R.

R1 _.....]; Ί iXI> / i «i: / o ............ · 20 ./ 1 S '7: R ij ί! I. Wherein the compound of formula A may be either the free acid or a pharmaceutically acceptable salt thereof, obtained by the hydrolysis of the compound of formula XI. The resulting compounds of formula A can then be cleaved. The hydrolysis is carried out in a conventional manner with an alkali metal hydroxide or alkali metal carbonate, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate in an aqueous lower aliphatic alcohol, e.g. methanol or ethanol, at a temperature of approx. 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 min.

4 151337

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

(l) acid isomers and (d) acid isomers of the compounds of formula (A) 5 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, for example, the compounds of formula (A) wherein R and R 2 'are both hydrogen may be subjected to further treatment according to the following diagram: 1 °.

. * r COOII ^ - - 15 · '^ (A ^) · ·' · * '··. several steps'. .

. * Φ · -. ..

. 'F (A ^) - (1)'>> acid isomer- * (1) -cc-phenethyester ester 'Mixture -of f ,. . γ / (Aa) - (d) - Acidomeric * (1) -α-phenethyl ester j • ". · '- ['.

. ' · the use of ; ·. * .. ·· ·; .high pressure s fluid- *. .

· '. chromatography - (A ^) - (1) - ^ yire ^ oier- ^

(A1) - (d) - Acid isomer - (1) -phene thyl ester I

/ *. 1 (a) - (1) acid isomer. (A) - (d) acidomer - 35

A more detailed description of this method can be found in the following Example 4.

v * V »-ϊ πΛλΙ r« ηvn * a -P · ΡΛντη1 an YT tro · «Pv / - \ Mr * 4- ί 1 1« «Τ-» -4 -ν »1 * -» ^ 4? f / <1 5 151337. 'nh9 COOCH3 cooch3 1 + R * H (|? H2 I COOCH- * .P COOCH3 1 · 3.. {III) 1 7 H.C-CH, OH ·. . (II), 2, 2. . · ·. * OH. . - ·. * '(I) · !; ·.

r · Jr00CIi3 ^ cooch3 • 0Γ. cooch3 **; | M ^^ οοοοη3

; * i "- \ I

CH «\ I

I 2 \ H-C-CH- CH 2 (V) \ * I (IV).

I \ 0H.

r OS02CH3 R \ (__ ^ cooch3 * RVj _- ^ ooch3 U ^ cooch3 — iNJU-coocH3 .:? H2 ,, (VII) I (vi)., ih2c ···. ''. ··. "

R ^ COOH 'R XOOH

• X ^ JC_C00R2 XX / COOH

^^ (IX) I · (VIII); Wherein R, 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. - r

6 15133T

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 ca. 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 . 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 = 10% oxyethane, chloroform, dichloromethane and the like. In the preferred embodiments, the reaction is carried out in acetonitrile solution at the reflux temperature for about 3 hours. 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.

25 -

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) compound of formula 20 R3-C-CH2X, Z.

wherein X is bromine or chlorine and R is a lower alkyl group, preferably straight chain, having 1-4 carbon atoms and best 1-bromoacetone, 1-bromo-2-butanone, 1-bromo-2-pentanone and 1-bromo 2-hexanone, from about 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 30 o 3 "R-C-Cf x X 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 ca. -10 ° C to about room temperature for approx. 10 minutes to approx. 2 hours forms the corresponding mesylate of formula (V) which is converted to the corresponding γ- (2-iodoethyl) pyrrole of formula (Vi) war? r'fanlr'M nn mprl na + .r »i nminH i ri i nrifa + inm 'hrM T rml down in 7 151337

By reaction of the iodoethylfo / 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] pyrrol-1,7 dicarboxylate and the 6-alkyl-substituted derivatives thereof (VII). This ring closure 5 is conducted 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 results are obtained by conducting the reaction at room temperature for approx. 30 minutes when R is hydrogen.

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

30 minutes to approx. 2 hours.

15

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, potassium carbonate and the like in an aqueous lower aliphatic alcohol, e.g. methanol or ethanol, at a temperature 20 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 the 6-alkyl derivatives thereof. The hydrolysis is preferably carried out using aqueous methanolic potassium hydroxide at the reflux temperature for approx. 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 of hydrogen chloride to produce the corresponding alkyl-1,2-di-hydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid of formula (IX). The reaction is carried out at a temperature of approx. 0 ° C to approx.

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

Decarboxylation of the mono-esterified compounds (IX) to the corresponding compounds of formula (X), the key intermediates of the process for preparing the compounds of the present invention, is achieved by heating (IX) at an elevated temperature of the order of about 230 ° C to approx. 280 ° C for a time of 40. · Sufficient to complete the reaction. The course of the reaction can be sensed by the rate of carbon dioxide development and thin layer chromatographic analysis, since deciarboxylation is usually completed within about 10 minutes. 45 to approx. 90 minutes. The reaction product, namely alkyl-1,2-dihydro-5H-pyrrolo [1,2-a] pyrrole-1-carboxylate and its 6-alkyl derivatives (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.

Condensation of a compound (X) with an amide of formula 10 / - \ C y -con (ch 3) 3 wherein in the meaning given above gives the corresponding alkyl-5-aroyl-1,2-dihydro-3 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 ca. 1 to approx. 175 hours under an inert atmosphere followed by further reflux in the presence of sodium acetate 20 for from ca. 2 to approx. 10 hours. Alternatively, instead of phosphorus oxychloride, other acid chlorides such as phosgene or oxyethyl chloride may be used.

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 the reaction mixture thus obtained. i from approx. 6 to approx. 72 hours under an argon atmosphere and thereafter set from 30 approx. 3 to approx. 10 molar equivalents of sodium acetate followed by a further reflux period of from approx. 4 to approx. 6 hours.

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.

151337 9

Examples of the N, N-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-m-ethoxy-benzamide, N, N-dimethyl-p-ethoxy-benzamide, N, N-dimethyl-o-chloro-benzamide, N, N-dimethyl-m chloro-benzamide, N, N-dimethyl-p-chloro-benzamide, and N, N-dimethyl-p-fluoro-benzamide.

15

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.

20

The salt derivatives of the compounds of formula (A) and the (1) acid isomer thereof 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, aluminum hydroxide, ferric hydroxide, ferric hydroxide. dimethylamide noethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, or glucosamine, methylglucamine, τηβοΟΓΟιηϊη, purines, piperidine, piperidine, piperidine, piperidine polyamine resins. The reaction is conducted in water, alone or in combination with an inert, water miscible organic solvent at a temperature of about 0 ° C to 5 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 10 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% molar equivalent of 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 ribs of the pharmaceutically acceptable base are used if a neutral salt product is desired.

In the preferred method, the calcium salts and magnesium salts of the compounds of formula (A) and (1) acid isomers thereof can be prepared by treating the corresponding sodium or potassium salts thereof with at least 4 molar equivalent calcium chloride or magnesium = chloride in an aqueous solution, alone or · in combination with an inert water-miscible organic solvent at a temperature of about 25 ° C. 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, aluminum tripropoxide and the like, in a hydrocarbon solvent such as benzene, xylene, cyclohexane and the like. at a temperature of approx. 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.

It is to be understood that, if desired, the isolation of the compounds described herein can be accomplished 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 equivalent n 151337 may also be used

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

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. 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 20 which 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 of the formula (A) or (1) acid isomer thereof and the pharmaceutically acceptable, non-toxic salts thereof are used. Most disorders respond to a treatment comprising a dose amount of 25 of the order of 0.5 mg to 6 mg per day. kg body weight per day.

The compounds of formula (A,). and (1) the acid isomers thereof and the non-toxic, pharmaceutically acceptable salts thereof described above are also uterine muscle relaxants and thus useful as agents for maintaining pregnancy in pregnant women and pregnant mammals for the benefit of the mother and / or fetus. until the termination of pregnancy from a medical point of view is found favorable or more favorable to the mother and / or the fetus, 35 The following examples further illustrate the method of the invention. All mixing ratios used with regard to liquids refer to volume ratios. Where necessary, eczema pierces are repeated to prepare additional material for subsequent examples, and unless otherwise stated, the reactions are carried out at 40 room temperature (20-30 ° C, 12

Preparation method 1

A 250 ml 3-necked, round bottom flask containing a magnetic stir bar and fitted with calcium chloride-filled drying tube is connected directly (via one of the external necks) by means of a primer and a short 5 (3 ") water cooler to the acetal pyrolysis apparatus. steering wheel consists of a 100 ml round bottom flask (pre-loaded with 15.6 g oxal = acid dihydrate and 11.82 g bromoacetaldehyde diethyl acetal, prepared from vinyl acetate as described by PZ Bedoukian, J. Am. Chem. Soc. 66, 651 (1944)) with a 6U Vigreux column at the top equipped with a thermo - 0 meter 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-acetone dicarboxylate. Methyl 3-carbomethoxymethyl-3 (2'-hy = droxyethyl) 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 0 of the vinylamine (III). When the distillation temperature falls below 80 ° C, the pyrolysis apparatus is switched off and a reflux condenser containing calcium chloride is replaced instead. The solution is heated to reflux for 1 hour, the solvent is removed under reduced pressure, and then 200 ml of methanol 5 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. 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.

Method of production 2 5

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-mesyl = oxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H), m.p. 99-101 ° C.

10

Method of preparation 3

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

20

Preparation Method 4 - r

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 137 mg of 50% sodium hydride in mineral oil. The reaction mixture is kept for 25 minutes at room temperature 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 of the residue on 20 g of silica gel using hexane / ethyl acetate (4: 1) as the eluant gives 500 mg (80%) of diethyl-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 of 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 50ml). 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 1.34 g, 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 as the temperature of the reaction mixture kept below 50 ° C. The ice bath is then removed and the reaction is stirred for 1 1/2 hours at room temperature and evaporated to dryness under reduced pressure, 10 ml of benzene is added to the residue and the solution is again evaporated under vacuum, repeating this process three times to completely remove excess hydrogen chloride. Thus, 1.58 g (96%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid (IX, R = H, R C ^ Hy) which, after recrystallization from methanol / ethyl acetate, has a melting point of 144-145 ° C.

Similarly, but using methanol, ethanol, propanol and n-butanol instead of isopropanol in the above-mentioned process.

M U

are obtained, respectively: methyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid.

ethyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid, propyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid carboxylate-7-carboxylic acid and butyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid.

Preparation Method 6 to 1.054 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid are 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] is obtained.

ISLAND

5 pyrrole-1-carboxylate (X., R = H, R = iso-C- Hy), a pale yellow oil having the following physical constants: U.V. : 215 nm (e 6020); : ^ max ^ 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 151337

A 100 ml 3-necked round mouth flask is 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 germ blown with nitrogen and the nitrogen flow is then stopped.

The apparatus is immersed in an oil bath heated to 270 ° C and the reaction is monitored 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 500 ml acetone round bottom flask. 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 (6890 isopropyl-1,2-dihydro-p 3 H -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 in Preparation Method 6.

Method of preparation 8 20

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 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 3q [1,2-a] pyrrole-1-carboxylate (XI, R = H, R1 = p-CH Is an oil having the following physical constants: UV 256, 312 nm, (e 8700, 19500); : ^ max 1733 '1β20' 1605 cm ~ 1; : · Μ · Κ ·: ^ ΜίΡ3 1) 23 ^ d 'J = 7Hz, 6H), 2.38 (s, 3H), 2.5-3.0 (m, 2H), 3.75-4, (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, 35H), 7.10 (d, J = 8Hz, 2H), 7.60 ppm. (d, J = 8Hz, 2H).

Preparation Method 9 16 151337

Following the method of Preparation Method 8 using 1.1-5 molar equivalents N, N-dimethylbenzamide, 3 N, N-dimethyl-o-toluamide, N, N-dimethyl-m-toluamide, Ν, Ν-dimethyl p-methoxybenzamide, N, N-dimethyl-m-ethoxybenzamide,

LO

N, N-dimethyl-p-ethoxybenzamide, N, N-dimethyl-o-chlorobenzamide, N, N-dimethyl-m-chlorobenzamide, N, N-dimethyl-p-chlorobenzamide, L5 N, N-dimethyl-p-fluorobenzene amide, and N, N-dimethyl-o-bromobenzene amide »0 instead of N, N-dimethyl-p-toluamide and monitoring of the reaction by thin layer chromatography are obtained, respectively: isopropyl-5-benzoyl-1,2-dihydro-amine. 3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, a pale yellow oil with the following physical constants: UV : 311 nm (e 7230, 17800); IR ·: δ ax3 1735 ′ 1620 cm-1; · NMR: 124 (d, 6H, (CH3) ₂CH), 250-3.13 (m, 2H; H-2); 3.97 (dd, 1H, H1), 4.18-4.70 (m, 2H, H-3), 5.00 (sept., 1H, (CH 2 CH), 6.00 (d, 1H, H-7), 6.86 (d, 1H, H-6), 7.10-7.90 ppm (m, 5H, phenyl protons); MS: m / e 297 (M +), 0 isopropyl-5-o-toluoyl-1 , 2-Dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate an oil having the following physical constants: UV: 252, 303 nm (e 4460, 19100): IRV ^ aks3 1735 '1620 cnr1' N * M * R ·: 6TMSl3 1.18 (d, 6H, (CH3) 2CH), 2.28 (s, 3H-, o -CH2), 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: λ max 250-251, 310-312 nm (e 6460, 17400); -max3 1735, 1620 cm-1; N * M * R ·: 1> 25 (d, 6H, (CH 3) 2 CH), 2.27 (s, 3H, CH 2), 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, (CH 2 CH), 5.95 (d, 1H, H-7), 6.67 (d, 1H, H-6), 7.03-7.57 ppm. (m, 4H; phenyl = 0 protons), isopropyl-5-p-ethylbenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate, isopropyl-5-o-propylbenzoyl -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, 5-isopropyl-5-m-butylbenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carb = oxylate, isopropyl-5-o-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, 0-isopropyl-5-p-methoxybenzoyl-1,2-dihydro -3H-pyrrolo [1,2-a] pyrrole-1-carboxylate having the following physical constants: UV : R? 0- 284 (shoulder), 314 nm (e 9780, 9320, 22400); . . 1 R max: 171730, 1605 cm -1; NMR: 1.24 (d, 6H, J = 6Hz; (CH2 CH2), δ '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 (M, 2H; H-3 ), 4.95 (sept, 1H, J = 6Hz; (CH3) 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 +), O isopropyl-5-m-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1 , 2-a] pyrrole-1-carboxylate mp 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-p-isopropoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil is 151337-isopropyl-5-o-chlorobenzoyl-1,2 -dihydro-3H-pyrrolo [1,2-a] pyrrole-1-ΜθΟΗ carboxylate, an oil having the following physical constants: UV: λ 251, 306 nm (e 5750, 16600); IR: V a α 1735, 1625 cm -1: NMR: δ 3.22 (d, 6H, (CH 3) 2 CH), 2.55-3.05 (m, 2H; H-2), 3.97 (dd,

5H, H1), 4.17-4.70 (m, 2H, H-3), 4.97 (Sept., 1H, (CH2 CH), [5.93 (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, 313 nm (e 6600, 15100); IR: T> 173 → 1620, 1570 cm @ 1 NMR: δ 13 1.27 (d, 6H, (CH 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 +), 1 liter of isopropyl-5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 80.5-81 ° C , isopropyl-5-o-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrol-1-carboxylate, isopropyl-5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [ 1,2-a] pyrrole-1-carboxylate, m.p. 72-72.5 ° C, isopropyl-5-m-bromobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and isopropyl 5-p-bromobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Preparation Method 10

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 completion of the addition, the ice bath is removed and 80 ml of dry aceton-O C-tril is added. The reaction mixture is then treated dropwise with 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile and then refluxed 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 the column with mixtures of hexane and ethyl acetate. The hexane / ethyl acetate (1: 1) fractions eluted with methyl N- (2-hydroxyethyl) -3-carbomethoxypyr = rol-2-acetate (IV, R = H) identical to that of Preparative Example 1 product obtained, 5

Preparation Method 11

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 ml-10 'nuts with stirring with 1.67 ml of 1-bromoacetone while maintaining the temperature of the reaction mixture 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 the eluent to give 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate.

Which, after recrystallization from methylene chloride / hexane, melts at 78 ° C and has the following analysis:

Calcd for C 21 H 17 N 5: 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, there is obtained: 30-methyl-N- (2-hydroxyethyl) -3-carbanethoxy-4-ethylpyrrole-2-acetate / mp. 61-62 ° C,

Preparation Method 12 35 -

Following the methods of Examples 2, 3, 4, 5 and 7, methyl N- (2-hydroxyethyl) -3-carbomethoxy ~ 4-methylpyrrole-2-acetate (IV, R = CH 2) is successively converted to: 2o 151337

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, snro. q Dimethyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate, 71 C, 1,2-dihydro-6-ethyl-3H-pyrrolo [1, 2-a] pyrrole-1,7-dicarboxylic acid, m.p. 200-203 ° C, isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid, m.p. 160 ° C and isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X, R = CH3, R2 = iso-C3H7)? oil.

Similarly, using methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate, methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrrole-2-acetate is obtained. and methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-biitylpyrrole-2-acetate instead of methyl-N- (2-hydroxyethyl) -3-carhomethoxy-4-methylpyrrole-2-acetate, respectively, as final products: isopropyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, o] isopropyl-1,2-dihydro-6-propyl-3H-pyrrolo [ 1,2-a] pyrrole-1-carboxylate and isopropyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

20

Preparation Method 13 In accordance with the procedure of Example 8, iso = propyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate is condensed with 25 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 2, R 1 = p-CH 3, R 2 = iso-C 3 H 7) m.p. 72 ° C- Similarly, but using the 30 N, N-dimethylarylamides listed in Example 12 instead of N, N-dimethyl-p-toluamide are obtained respectively: isopropyl-5-benzoyl-1,2-dihydro-6 -methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 75 ° C, isopropyl 5-o-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 75 C, isopropyl-5-m-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, 2i isopropyl-5-p-ethylbenzoyl-1,2 -dihydro-6-methyl-3H-pyrrolo [1,2-a] pyr = -rol-1-carboxylate, isopropyl-5-o-propylbenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [ 1,2-a] pyr =, rol-1-carboxylate, isopropyl-5-m-butylbenzoyl-1,2-dibydro-6-methyl-3H-pyrrolo [1,2-a] pyr = rol-1-carboxylate , isopropyl-5-o-methoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5-p-methoxybenzoyl-1,2-dihydro-6 -methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, snip, 89 ° C, isopropyl-5-p-ethoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2 -a] pyrrole-1-carboxylate, 5-isopropyl-5-p-isopropoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5-o- chlorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylate, 0-isopropyl-5-m-chlorobenzoyl-1,2-dihydro-6-methyl-3H -pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5-p-chlorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1 -carboxy lat, m.p. 88 ° C isopropyl 5-o-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylate, isopropyl-5-p-fluorobenzoyl-1, 2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylate having the following physical constants: 3 µm * max · 25 ° 315 11111 (e 617 ° »14ιο °) ί IR Scissors 1734 '1β05' 1593 cm '1i N.M.R. 6¾¾ 1.23 ^ H, J = ^ Hz; Θ3ΪΘΓ CH ^) (s, 3H; ring CH3), 2.49-3.00 (m, 2H; CH₂), 3.90 (t, 1H, 5 EJ = 7.4Hz; CHCO), 4.10 -4.23 (m, 2H; N-CH 2), 4.98 (sept, 1H, J = 6Hz; ester CH), 5.84 (s, 1H, H-3), 7.00 (t, 2H, Jortho = 8.4Hz, JHp = 8Hz; H-3 ', 5'), 7.55 (q, 2H, J-ortho = 8.4Hz, = 5.5Hz; H-2.6 ·); 22 1 5 1 3 3 7 MS m / e 1% 329 M + 242 100 M + -CQ 2 CH (CH 3) 2 123 36 F-C6H4CO, isopropyl-5-ni-bromobenzoyl-1,2-dihydro-6-methyl-3H -pyrrolo [1,2-a] pyrrole 5 1-carboxylate and isopropyl-5-p-bromobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole 1-carboxylate.

The remaining final compounds obtained in Example 14 are also converted to the corresponding 5-aroyl substituted derivatives. Representative compounds obtained in this way are: isopropyl-5-benzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil, isopropyl-5-benzoyl-1 , 2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate ,. isopropyl-5-benzoyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5-p-toluoyl-1,2-dihydro-6-ethyl 3H-pyrrolo [1,2-a] pyrrole-1

Z U

carboxylate, isopropyl-5-p-ethylbenzoyl-1,2-dibydro-6-propyl-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylate, isopropyl-5-o-methoxybenzoyl-1,2- dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-5-p-ethoxybenzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a ] pyr = rol-1-carboxylate, isopropyl-5-o-chlorobenzoyl-1,2-dibydro-6-propyl-3H-pyrrolo [1,2-a] pyr = rol-1-carboxylate, isopropyl-5 m-chlorobenzoyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylate, isopropyl-5-o-fluorobenzoyl-1,2-dihydro-6-ethyl 3H-pyrrolo [1,2-a] pyr = pyrrol-1-carboxylate, isopropyl-5-p-fluorobenzoyl -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole 1-cdxboxylate, oil, isopropyl-5-p-fluorobenzoyl-1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a] pyrrolo-1-carboxylate and isopropyl-5-p bromobenzoyl-l, 2-dihydro-6-butyl-3H-pyrrolo [l, 2-a] pyrrole-1-carboxylate.

The feed flow method 14 710 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. .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-7-3 dicarboxylate (VII, R = H) identical to that of Preparation Example 4 obtained product,

For a 250 ml 3-necked, round-bottom flask equipped with a nitrogen add-on relief valve, a magnetic stir bar and a pressurized add-on 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 5-methyl-3-carbomethoxymethyl-3- (21-hydroxyethyl) aminoacrylate (III) is diluted with 20 ml of acetonitrile and chloroacetaldehyde, pre-prepared by heating a mixture of 27.4g of chloroacetaldehyde diethylacetal with 46.8g of oxalic acid dihydrate at 150 -60 ° 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 eluant 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.

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 li- -f-AT * P + lhvl ^ θη * ΡΠ \ r \ rr aq mother} / 1 1 i - {- or o -HlntrT or * o 4-q + * We above 151337 24 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 prepare 11.89 g (32.9% of theoretical yield) methyl N- (2, -hydroxyethyl) -3-carbomethoxy = 5 pyrrole-2-acetate (IV, R = H) having a melting point of 51-54 ° C, the same product obtained in Preparative Example 1.

Example 1

A solution of 336 mg of isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo 10 [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. water. The reaction mixture is left to cool 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). 15

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 (89%) of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a-pyrrole-1-carboxylic acid [(A), R = H = R-p-CH 2], mp 182-183 ° C, 20

Example 2

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. sodium hydroxide in 1 ml of water, 25. keeping the reaction mixture at room temperature for 1 1/2 hours. Methanol 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 in Preparative Example 1.

Example 3

By hydrolysis of the isopropyl ester group according to the procedures of Examples 1 or 2, the corresponding free acids are obtained, namely: 40.

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, one

Mpnu oil with the following physical constants: U.V. : V, 253, 307 nm (ε 3310, 16980); I.R .: 1720, 1620 cm; n.m.r. : Δ 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, ptienyl protons ), 8.60 ppm. (bs, 1H, C00H), 5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 144-145 ° C, 5-p-methoxybenzoyl-1 , 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 187-187.5 ° C, 5-m-ethoxybenzoyl-1,2-diliydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acid, m.p. 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: UV: 250, 307.5 nm (e 4360 , 17400); IR: δ = δ 1715> 1620 ° ”1 NMR: 2.60-3.15 (m, 2H; H-2), 4.02 (dd, 1H, = 6Hz, Jbx = 7Hz; H1) , 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; C00H), 5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 180-181 ° C, 5-p -chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 201.5-202.5 ° C, 5-o-fluorobenzoyl-1,2-dihydro-3H -pyrrolo [1,2-a] pyrrole-1-carboxylic acid, and 5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 179.5-180 , 5 ° C.

55 26 151337

Example 4

To a solution of 300 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 25 ml of dry benzene is added 0.58 g of trifluoroacetic acid 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-5 amine is added, followed immediately by the addition of 0.5 g of (1) -cc-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 solution 10. the agent and excess of (1) -oc-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) -cc-phenethylethyl ester and ( d) -5-Benzoyl-1,2-di = hydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (1) -α-phenethyl ester which is separated by high pressure liquid chromatography (using k% 15 EtOAc / hexane on an 11 mm x 50 cm 10 µm Lichrosord S1-60 column) to produce 180 mg of a more polar ester (a ^ e0H '* -145.7 °) and 178 mg of a less polar ester (oc H + 128.6 °), 148 mg of the more polar ester is dissolved 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 25 as described above except that 35% EtOAc / hexane in 1% 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 a Ct HCl = -153.7 ° 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 ] pyrrole-1-carboxylic acid with an oc 3 = +155.1 C and a melting point of 154-156 ° C. The (d) acidomer thus obtained can, if desired, be racemized (recycled) according to methods known in the art.

Similarly, other (dl) compounds can be converted to their fiTipTchi λγρ (l i «; ητηη * ηη no * (ri ^ -i. Qomprp 27 1513.37

Example 5

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 of 10% aqueous hydrochloric acid and 50 ml of 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-10-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid L ( A), R = CH 2, R 2 = p-CH 2] t mp 187 ° C. Similarly or alternatively, by the hydrolysis method of Example 2, other isopropyl ester compounds such as those obtained in Preparation Method 13 are converted. to the corresponding free acids, namely: 5-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 169 ° C, O Λ

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, mp 204 ° C, 5-benzoyl-1, 2-dihydro-6-phenyl-3H-pyrrolo [1,2-a] pyrrole carboxylic acid, m.p. 177 ° C, 5-β-fluorobenzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid, m.p. 196 ° C,

Biodata 35. a. Test for analgesic (anti-torsional) effect on mice.

Protocol: The compound 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.

28 1 5 1 3 3 7

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 (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has an analgesic effect of approx. 700 times aspirins.

In addition, the following strengths were determined relative to aspirin: 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 15-m-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxyl - acid 1 5-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxyl-SYXe 250 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-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 (LD ^ q) in mice.

Protocol: The compound to be tested is suspended in a monohydric 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-Webster male mice in each group) mice are used. A single oral dose of either 200 mg, 400 mg, 29 1 5 1 3 3 7 800 mg or 1200 mg of 5- (benzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 -carboxylic acid per kg of body weight is administered by the stomach probe to the mice. (The fifth group is used as a control.) After administration, the mice are monitored for a 3-week period.

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

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 effect using carageinin-induced po tein lamination in the rat.

0.5

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 causes 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. . ..u - ... l ... -

Endpoint; % increase in paw size calculated as follows: 15 '...........................

weight of right paw f weight of left 'paw weight of left paw

Using the above protocol, the following effects (phenylbutazone = 1] were determined: 10: 5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylic acid 30 -p-isopropoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 15-m-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2- a] pyrrole-1-carboxylic acid 15-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid approx.

Claims (1)

5-rp-methylbenzoyl-6-methyl-1,2,2-dihydro-3H-pyrrolo [1,2-a] pyrrole 1-carboxylic acid approx. 5-p-methoxybenzoyl-6-methyl-1H-2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. about 45 5-p-chlorobenzoyl-6-methyl "1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid about 60 5-benzoyl-6-ethyl-1, 2-dihydro-3H-2Q pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (4-fluorobenzoyl) -6-ethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole -1-carboxylic acid 38 Analogous process for the preparation of (dl) - or (1) - 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives of the general formula: ε1Η ^ 1 "l 3 L JL JL" JL. cooh ° 1_J (A) or pharmaceutically acceptable salts thereof, wherein R represents hydrogen or an alkyl group of 1-4 carbon atoms, represents hydrogen, an alkyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon atoms, chlorine, fluorine or bromine, characterized in that a corresponding alkyl ester is hydrolyzed to form the free acid or salt thereof of formula (A1, optionally followed by cleavage of the free acid of formula (A) in the optical acid isomers and isolation of (1) - the acidomer or salt thereof.