FI63406C - FRUIT PROTECTION FOR THERAPEUTIC USE OF THERAPEUTIC 5-ENTSOYL-1,2-DIHYDRO-3H-PYRROLO (1,2-A) PYRROL-1-CARBOXYLSYR ADRIVATE - Google Patents

Description

I> —---- ra1 ANNOUNCEMENT, -, A n, W (11) UTLÄGGNINGSSKRIFT 63406 C Pc ten'll elyl'nnetty 10 C6 1933 (45) Patent uecdclat ^ T ^ (51) Kv.ik? / Int. a.3 C 07 D 4-87 / 04- FINLAND I — FIN LAND (21) P »^ lh« k * imi «-P» Mnt «n« elB * .f 772153 (22) HakemltpUvt - Anaeknlnpdtg 11.07 * 77 ^ ^ (23) Alkuptlvi — GlMghutsdag 11.07.77 (41) Tullut lulkbuksi - BlhrH offwitHg 15.01. 78 tantti, and the Board of the NihtMtoipwon. month »taun pvm.-

Patent- och registerstyrelsan '7 Amekan uti * jd oeh utUkriftM pubUcund 28.02.83 (32) (33) (31) ivmuttjr utuolkuut —Buflrd priorltut ll *. 07.76 23.02.77 USA 70 ^ 909, 771286 (71) Syntex (USA) Inc., 3 ^ 01 Hillview Avenue, Palo Alto, California 9 ^ 301 +, USA (72) Joseph M. Muchowski, Mexico, Mexico-Mexico (MX),

Arthur F. Kluge, Los Altos, California, USA (USM) 7M Oy Kolster Ah (5M Process for the preparation of therapeutically useful 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives - For the preparation of therapeutically active compounds, 5-hentoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives

The invention relates to a process for the treatment of a therapeutically useful formula

LL Jl / COOM A

for the preparation of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives or optical isomers thereof, especially (1) -acid isomers, wherein R is hydrogen or C 1 -C 4 alkyl according to , R 3 - is hydrogen, C 1 -C 4 alkyl, lower C 1 -C 4 alkoxy, chlorine, fluorine or bromine, and M is hydrogen, C 1 -C 4 alkyl or a pharmaceutically acceptable, non-toxic cation, wherein the R 1 substituent is in the ortho, meta or para position of the benzoyl group.

The process according to the invention is characterized in that one or more of the following reaction steps are carried out: a) condensing of the formula (X) 'N-o

ö Ji / COOR2 X

LJ

2

wherein R is as defined above and R is C 1 -C 4 alkyl of formula XIII

CON (CH3) 2 XIII

with an amide of formula (XI) wherein R1 is as defined above, β \ jl of formula (XI)

COOR2 XI

5 M

1. 2, wherein R, R and R are as defined above? b) hydrolyzing a compound of formula (XI) to a compound of formula (A) wherein M is hydrogen: c) preparing a pharmaceutically acceptable salt of an acid of formula (A) by treating the free acid of formula (A) with an equivalent amount of a pharmaceutically acceptable base; d) the carboxylic acid function of the acid of formula (A) or of its (1) or (d) -isomer is esterified with a C 1 -C 4 alkanol, the corresponding diazoalkane or a C 1 -C 4 alkyl iodide to the corresponding C 1 -C 4 alkyl ester of formula (A); e) inorganic or organic salts of an acid of formula (A) or its individual isomers are converted to the corresponding acids by reaction with an organic or inorganic acid having a pK value of less than 3; f) the acid of formula (A) is divided into optical isomers in a manner known per se; g) The (d) -acid isomer or a salt thereof is racemized to the corresponding acid of formula (A).

3 63406

The compounds of the invention described above and discussed in more detail below, with the exception of the (d) -acid isomer and its derivatives, have anti-inflammatory, analgesic and antipyretic activity and are thus useful in the treatment of inflammation, pain and / or fever in mammals, as described below. They are also smooth muscle relaxants.

The term "pharmaceutically acceptable, non-toxic esters and salts" as used herein means "alkyl esters" derived from branched or straight chain hydrocarbons having from 1 to 4 carbon atoms and salts derived from pharmaceutically acceptable, non-toxic inorganic or organic bases.

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

Salts derived from inorganic bases include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, ferro, zinc, copper, manganese, aluminum, ferric, manganese salts, etc. Ammonium salts are particularly preferred. , potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic, non-toxic bases include, for example, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchangers such as isopropylamine, dimethylamine, trimethylamine, trimethylamine, trimethylamine -lamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanolitromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin salts, etc. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexyl.

The novel compounds described by formulas (XII) and (XI) below exist as pairs of optical isomers (i.e. enantiomorphs), i. (dl) are within the scope of this invention.

When the compounds of the invention are to be used to produce a physiological effect (e.g. an anti-inflammatory, analgesic or antipyretic effect), i.e. when used as medicaments, the preferred subgroup of compounds of formula (XII) 634 0 6 are the compounds of formula (XII) and their (1) -acid isomers and their esters and pharmaceutically acceptable salts.

Another subgroup of compounds to be used as medicaments are those compounds of formula (XII) and (1) -acid isomers and their esters and pharmaceutically acceptable salts, wherein R and R 1 are each hydrogen.

The (d) -isoisomers of formula (XII) and their esters and pharmaceutically acceptable salts are useful intermediates in the preparation of (dl) -acids of formula (A), as described in more detail below.

The novel (dl) compounds of the invention can be prepared by the method described in the reaction scheme on page 5: (See Scheme Page 5 of the Explanatory Memorandum) 1 2 wherein R and F. are as defined above and R is lower alkyl of 1-4 carbon atoms, e.g. methyl, ethyl , isopropyl or n-butyl.

In the reaction scheme shown on page 5, to prepare a compound of formula (IV) wherein R is hydrogen, equimolar amounts of ethanolamine (I) and dimethyl-1,3-acetonedicarboxylate (II) are reacted with each other at a temperature from about 0 ° to about room temperature to readily a solution of vinylamine (III) is formed, which is then treated, preferably in situ, in a suitable inert organic solvent under anhydrous conditions with 2-bromoacetaldehyde or 2-chloroacetaldehyde at about 40 to about 100 ° C for about 0.5 to 16 hours. Suitable solvents for this reaction include aprotic solvents such as acetonitrile, tetrahydrofuran, dimethoxyethane, chloroform, dichloromethane, etc. Preferably, the reaction is carried out in acetonitrile solution at reflux temperature for about one hour. The 2-bromo (chloro) acetaldehyde reagents are known compounds or can be prepared by pyrolysis of the corresponding diethyl acetals in the presence of oxalic acid dihydrate.

In the preparation of compounds of formula (IV) wherein R is lower alkyl, preferably a straight chain mixture of ethanolamine (I) having 1 to 4 carbon atoms and dimethyl 1,3-acetonedicarboxylate (II) in water,

, 2 XIV

with a compound of formula r-3-c-ch2x wherein X is bromine or chlorine, and • 63406 5 NH2 COOClI3 COOCH3 L + IR - H (|, 2 coocn, ** [I COOCII, I 3 (III) CH, O HN ^

I 2 'N. * r »I

'\ V * H-C-CH-0H <”> \ V. 2 I 2

X OH

(I) · COOCH3 \ R COOCH3 \ ^ ΐ ^ / 00ε: Η3 ^ QOcCOCH3

ch2 \ I

I & \ h2c-ch ch2 (V) \ I (IV)

I 2 \ 0H

»0SO2CH3 \ _cooch3 X _ ^, cooch3 v 1nA ^ cooch3? 2 (VI)! VII)

IH2C

r '

R ^ COOH R ^ ^ COOH

T ^ Xx00R2 "\ NX ^ -C00K

LJ 1_J '(IX) (VIII) r An R ^ <X) {XI) rU ^ n N-, X A. coon <XII> II, NI o I- 6 63406 is lower alkyl, preferably straight chain, 1-4 carbon-containing, and most preferably 1-bromoacetone, 1-bromo-2-butanone, 1-benz-2-pentanone or 1-bromo-2-hexanone, at about 40 to about 100 ° C for about 0.5 to about 16 hours I drive. In the preferred method, the reaction is carried out at a temperature between about -10 ° C and room temperature for about 1-6 hours. The triggered reagents of formula (XIV) are known compounds.

Esterification of compound (IV) with methanesulfonyl chloride affords a tertiary amine, i. in the presence of triethylamine, pyridine, etc., optionally in the presence of an additional solvent such as dichloromethane at temperatures from about -10 ° C to about room temperature for a period of about 10 minutes to about 2 hours to give the corresponding mesylate (V), which is converted to N- (2) -iodoethyl) pyrrole in reaction with sodium iodide in acetonitrile solution at reflux for about 1 to about 10 hours.

Reaction of an iodoethyl compound of formula (VI) with sodium hydride in a suitable inert organic solvent such as dimethylformamide gives dimethyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate and its 6-alkyl substituted derivatives. (VII). This cyclization is carried out in an inert atmosphere, for example argon or nitrogen, at a temperature in the range of about 15 to about 40 ° C for a period of about 15 minutes to about 4 hours. When R is hydrogen, the best results are obtained when the reaction is carried out at room temperature for about 30 minutes.

Alternatively, compounds of formula (VII) may be prepared by direct cyclization of the mesylate (V) with sodium hydride in dimethylformamide solution at a temperature in the range of about -10 ° C to about room temperature for about 0.5 to about 2 hours.

Alkaline hydrolysis of a compound of formula (VII) with an alkali metal hydroxide or alkali metal carbonate, for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like in an aqueous aliphatic alcohol, for example methanol or ethanol, at reflux for about 24 hours (VIII), i.e. 1,2-Dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and its 6-alkyl derivatives. The hydrolysis is preferably performed with a solution of potassium hydroxide in aqueous methanol at reflux temperature for about 10 hours.

The C1-Carboxylic acid group of compound (VIII) is then selectively esterified by treatment with a lower aliphatic alcohol, e.g. methanol, ethanol, isopropanol, n-butanol, etc., in the presence of hydrogen chloride to give the corresponding compound of formula (IX). alkyl-1,2-dihydro-3H-pyrrolo / 1,2-a / 'pyrrole-l-carboxylate-7-carboxylic acid. The reaction is carried out at about 0 ° to about 50 ° C for about 1 to about 4 hours.

Decarboxylation of the monoesterified compound (IX) to the corresponding compound of formula (X), which is the main starting material in the process of the invention, is carried out by heating compound (IX) at an elevated temperature of about 230 to about 280 ° C for a sufficient time to complete the reaction. The progress of the reaction can be monitored by the rate of carbon dioxide evolution and by thin layer chromatography. Decarboxylation is generally complete in about 45 to about 90 minutes. The reaction product, i.e. The alkyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and its 6-alkyl derivatives (X) can be purified by chromatography. Alternatively, especially when decarboxylating small batches of compound (IX), the reaction product (X) can be distilled directly from the reaction vessel.

Condensation of compound (X) and an amide of formula JQ)-CON (CH3> 2 XI11, wherein R "*" is as defined above, gives the corresponding alkyl-5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2 α / pyrrole-1-carboxylate (XI) This reaction is carried out in an inert, aprotic organic solvent in the presence of phosphorus oxychloride at reflux for about 1 to about 175 hours under an inert atmosphere, followed by further refluxing with sodium acetate for about 2 to about 10 hours Instead of phosphorus oxychloride, other acid chlorides such as phosgene or oxalyl chloride can also be used.

In a preferred embodiment, this condensation is performed by adding a solution of compound (X) in a suitable solvent to a refluxed mixture of 1.1 to 5 molar equivalents of both the desired amide and phosphorus oxychloride in the same solvent, boiling the resulting reaction mixture for about 6 to about 72 hours under argon. then adding about 3 to about 10 molar equivalents of sodium acetate and further refluxing for about 4 to about 6 hours.

8 '63406

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

Examples of suitable N, N-dimethylbenzamides include: N, N-dimethylbenzamide, N, N> -dimethyl-o-toluamide, N, N-dimethyl-m-toluamide, W, H-dimethyl-p-toluamide -toluamide N, N-dimethyl-p-ethylbenzamide, N, N-dimethyl-o-propylbenzamide, N, N-dimethyl-m-butylbenzamide, N, N-dimethyl-o-methoxybenzamide, Ν, Ν-dimethyl-m- methoxybenzamide, N, N-dimethyl-p-ethoxybenzamide, N, N-dimethyl-p-iropropoxybenzamide, N, N-dimethyl-p-chlorobenzamide, N, N-dimethyl-m-chlorobenzamide, N, N-dimethyl-p-chlorobenzamide chlorobenzamide N, N-dimethyl-p-fluorobenzamide, N, N-dimethyl-p-fluorobenzamide,

N, N-dimethyl-m-bromobenzamide and N, N-dimethyl-p-bromobenzamide A

These amides are known, commercially available compounds which can be prepared by conventional methods from the corresponding acids, i. converting these to acid chlorides, and treating with acid chloride and dimethylamine.

Alkaline hydrolysis of the alkyl ester group of the compound of formula (XI) gives the free acid of formula (XII). This hydrolysis is carried out in the usual manner with an alkali metal hydroxide or alkali metal carbonate, for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. in an aqueous lower aliphatic alcohol at reflux at room temperature for about about 15 minutes to about 2 hours. Preferably, this hydrolysis is performed in an aqueous-methanolic solution of potassium carbonate at reflux temperature for about 30 minutes.

9 63406

The compound of formula (XII) can be divided into the corresponding different isomers by methods known per se.

The (1) acid isomers and (d) acid isomers of the compounds of formula (XII) can be obtained by applying a known high pressure liquid chromatography (HPLC) method to the phenylethyl diastereoisomeric esters of the compounds of formula (XII) and then carrying out the acid liberation. Compounds of formula (XII) in which R and R 1 are both hydrogen can thus be further treated according to the following reaction scheme: <--— (xii) several reaction steps Φ (XII) ~ (1) - acid isomer- (1) - < Separation of * ~ phenethyl ester and \ (XII) - (d) -acid isomeric CD-oT-phenethyl ester) by high performance liquid chromatography (XII) * "(1)" acid anomer ^ (XII) ~ (d) - acid isomer - (l) -phenylethyl ester Ί ". 'b (XII) - (1) - acid isomer (XII) - (_ acid isomer _______ A detailed description of this method is given in Example 5 below.

10 63406

The free acids of formula (XII) may be converted to other alkyl esters having 1 to 4 carbon atoms in the alkyl by conventional methods, for example by treating (a) the desired ester with the corresponding alcohol in the presence of a strong mineral acid, (b) an ethereal solution of diazoalkane or (c) the desired alkyl iodide . The (1) -acid isomers can be converted to their alkyl esters by the above methods (b) and (c).

Salts of the compounds of formula (XII) and their (1) acid isomers are prepared by treating these free acids with a suitable amount of a pharmaceutically acceptable base. Examples of pharmaceutically acceptable bases include sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, isopropylamine, diethylamine, ethanolamine, piperidine, etc. 100 ° C, preferably at room temperature. Typical inert, water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane and tetrahydrofuran. The molar ratio of the acid isomer of formula (XII) or its (1) to the base is chosen to correspond to the desired salt in each case. For example, in the preparation of calcium or magnesium salts of compound (XII) or its (1) acid isomer, the starting free acid can be treated with at least half a molar equivalent of a pharmaceutically acceptable base to obtain a neutral salt. In the preparation of aluminum salts of the compounds of formula (XII) or of their (1) acid isomers, at least 1/3 molar equivalent of a pharmaceutically acceptable base is used to obtain neutral salts.

In a preferred process, the calcium and magnesium salts of the compounds of formula (XII) and their (1) acid isomers are prepared by treating the corresponding sodium or potassium salts with at least half a molar equivalent of calcium or magnesium chloride in an aqueous solution which may contain an inert, water-miscible organic solvent at about 20- about 100 ° C. The corresponding aluminum salts are preferably prepared by treating the free acids with 1/3 molar equivalent of aluminum alkoxide such as aluminum trioxide, aluminum tripropoxide and the like in a hydrocarbon solvent such as benzene, xylene, cyclohexane, etc. at temperatures of about 20 to 115 ° C. Similar methods can be used to prepare salts of inorganic bases which are not sufficiently soluble for easy reaction.

11 63406 The isolation of the compounds described herein may, if desired, be carried out by any suitable separation or purification method, such as extraction, filtration, evaporation, distillation, crystallization, thin layer chromatography or column chromatography, high performance liquid chromatography (HPLC) or combinations of these methods. eristysmenetel-groups. However, other suitable separation and isolation methods can also be used.

Although (d) -acid isomers are not used as drugs, they can be converted to pharmaceutically acceptable, non-toxic esters and salts, if desired, by methods similar to those described above for the conversion of (1) -acid isomers to pharmaceutically acceptable, non-toxic esters and salts.

Biological tests A, Mouse analgesia test (anti-falsification)

Experimental procedure: At the beginning of the experiment, the test compound is administered orally by forced feeding in aqueous medium to male Swiss-Webster mice weighing 18-20 g. After 20 minutes, mice are injected intraperitoneally with 0.25 ml of a 0.02% phenylquinone solution. This solution causes warping. The writhing of the animals is then observed for the next 10 minutes.

Evaluation of results: The total number of twisting mice and the average number of twists per mouse are determined.

The above experiment showed that 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (doses 0.001, 0.003, 0.01 and 0.03 mg) to acetylsalicylic acid (doses 0 , 33, 1 and 3 mg) compared to about U30-fold analgesic activity, and (1) -5- (benzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (doses of 0.001, 0.003, 0.01 and 0.03 mg) has approximately 700-fold analgesic activity compared to acetylsalicylic acid (doses of 0.33 L and 3 mg).

In addition, values were obtained for the analgesic activity of the following compounds: 5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid-5-p-isopropoxybenzyl-1,2-dihydro- 3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, __ 1 '5-m-ethoxybenzoyl-1,2-dihydro-3n-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 12 63406 250 5-benzoyl -6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 250 5-p-methylbenzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 130 5-p-methoxybenzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 190 5-p-chlorobenzoyl-6-methyl- 1,2-Dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 80 5-Benzoyl-6-ethyl-1,2-dihydro-3H-pyrrolo - [[2-a] pyrrole-1-carboxylic acid 130 5- (4-fluorobenzoyl) -6-ethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

B. Acute oral toxicity (LD ^ q) in mice.

Test procedure: The test compound is suspended in aqueous carboxymethylcellulose. Concentrations of the compound are selected so that the doses are 10 ml / kg body weight. 5 groups of mice are used, each with a Swiss-Webster male mouse. Mice are given a single oral dose via stomach using 5- (benzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid at a dose of 200, 400, 800 or 1,200 mg. The fifth group is the control group. After administration of the compound, the hiite is monitored for 3 weeks.

The above test procedure gave an acute oral toxicity of 5- (benzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid of about 200 mg / kg.

In addition, the following values were obtained: 606 mg / kg 5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid "5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo 1,2-α-pyrrole-1-carboxylic acid.

C. Anti-inflammatory activity in a test using carrageenan-induced inflammation in the rat foot.

Female Simonsen rats (80-90 g) were used in the experiment. the test compound was administered orally to rats in 1 ml of aqueous medium at time 0. After 1 hour, 0.05 ml of a 1% carrageenan solution in 0.9% NaCl solution was injected into the right hind leg of each rat. The injection caused inflammation of the foot. 4 hours after the time of departure, the 0 rats were sacrificed and both hind legs were weighed separately. The weight gain of the inflamed foot in% is calculated as follows: weight of the right foot - weight of the left foot χ weight of the left foot 13 63406 This method gave the following relative anti-inflammatory activities (the activity of phenylbutazone is denoted 1): 30 5-p-ethoxybenzoyl-1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 1,5-p-isopropoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 1,5 -m-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid about 5-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole- 1-25 carboxylic acid about 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 [7,2-a] 45 pyrrole-1-carboxylic acid about 5-p-chlorobenzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] 60 Pyrrole-1-carboxylic acid 25 5-benzoyl-6-ethyl-1,2-dihydro-3H-pyrrolo [7,2-a] pyrrole-1-carboxylic acid 38 5- (4-fluoro oribenzoyl) -6-ethyl-1,2-dihydro-3H-pyrrolo [7,2-a] pyrrole-1-carboxylic acid.

The compounds of formula (A) and their (1) acid isomers are thus useful as anti-inflammatory, analgesic, antiplatelet, fibrinolytic and smooth muscle relaxants. These compounds can be used for both prophylaxis and treatment.

Compositions containing these compounds can thus be used to treat and ameliorate inflammations, such as inflammatory conditions of the musculoskeletal system, joints and other tissues of the body, such as rheumatism, concussions, tears, arthritis, bone fractures, accidental conditions and gout. In cases where the above conditions are associated with pain and fever, the compounds are also useful for relieving these in addition to inflammation.

The following examples illustrate the invention.

Abbreviation t.l.c. means thin layer chromatography, and all liquid mixture ratios refer to volume ratios. If necessary, the examples are also repeated to prepare additional material for the following examples. Unless otherwise stated, the reactions are performed at room temperature (20-30 ° C).

lit

Preparation 1 63406

Dimethyl 1,3-acetonodicarboxylate A 250 ml 3-neck round bottom flask equipped with a magnetic stir bar and a CaCl2-filled drying tube is connected (via one neck) directly via a receiving adapter and a short (7.5 cm) water separator to the acetal pyrolysis. This apparatus comprises a 100 ml round bottom flask previously charged with 15.6 g of oxalic acid dihydrate and 11.82 g of bromoacetaldehyde diethyl acetal prepared from vinyl acetate according to P.Z.Bedoukian, J. Am. Chem. Soc. 66, 651 (1944), an on-board 15 an Vigreux column with a thermometer connected to the above-mentioned water separator-cooler.

Preparation 2

Methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate 3.36 g of ice-cooled (0-10 ° C) ethanolamine are introduced into a 3-necked flask, to which 8.7 g of dimethyl-1 are added dropwise with stirring, 3-acetyl-nidikarboksylaattia. In this case, methyl 3-carbomethoxymethyl 3- (2, -hydroxyethyl) aminoacrylate (III) is immediately formed. At the end of the addition, the ice bath is removed and 100 ml of dry acetonitrile are added to the mixture. The pyrolysis part of the apparatus is placed in an oil bath and the temperature is raised to 150-160 ° C. The bromoacetaldehyde formed (b.p. 80-83 ° C / 580 nm) is distilled directly into a solution of vinylamine (III) stirred with a magnetic stirrer. When the distillation temperature drops below 80 ° C, the pyrolysis apparatus is removed and replaced with a reflux condenser equipped with a CaO 2 drying tube. The solution is heated under reflux for 1 hour, the solvent is removed under reduced pressure, and 200 ml of methanol and 20 g of silica gel are added to the residue. This mixture is evaporated to dryness in vacuo and the residue is applied to the top of a column packed with 200 g of silica gel in hexane. This 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 have less polar impurities and dimethyl 1,3-acetonedicarboxylate; Fractions 4-8 give 4.1 g of methyl N- (2-hydroxyethyl-3-carbomethoxypyrrole-2-acetate (IV, R = H) which, recrystallized from ether / hexane, has a mp of 52-54 ° C. .

Preparation 3

Methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole acetate is placed in a 250 ml 3-neck round bottom flask equipped with a magnetic stir bar and a Cad® drying tube, 3.36 g of ethanolamine and the reaction vessel is cooled in an ice bath to 0-10 ° C. and 8.7 g of dimethyl 1,3-acetonedicarboxylate are added dropwise while stirring. In this case, 3-carboxymethyl-3- (2'-hydroxyethyl) -630406 aminoacrylate crystals (III) are immediately formed. At the end of the addition, the ice bath is removed and 80 ml of dry acetonitrile are added to the mixture. 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile are then added dropwise to the reaction mixture, and the mixture is heated under reflux for 2 hours. The solvent is removed under reduced pressure, and 200 ml of methanol and 20 g of silica gel are added to the residue. The mixture is evaporated to dryness in vacuo and applied to the top of a column containing 200 g of silica gel in hexane, and the column is eluted with hexane / ethyl acetate mixtures. Fractions eluted with hexane / ethyl acetate (1; 1) give methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole acetate (IV, R = H), which is identical to the compound obtained in Preparation 2.

Preparation 4

Methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate

To a solution of 6 ml of ethanolamine in 5 ml of water is added 1.74 g of dimethyl 1,3-acetonedicarboxylate. The resulting mixture is rapidly cooled to -10 ° C and 1.67 ml of 1-bromoacetone are added dropwise over 15 minutes with stirring, so that the temperature of the reaction mixture does not rise above 40 ° C. At the end of the addition, the dark reaction mixture is stirred for a further hour at room temperature, then the mixture is poured into a mixture of hydrochloric acid / ice saturated with solid sodium chloride and the mixture is extracted with ethyl acetate (3 x 100 ml). The combined organic extracts are washed neutral with cold water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed on 30 g of silica gel eluting with hexane / ethyl acetate (70:30) to give 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (IV), which, recrystallized from methylene chloride / hexane melts at 78 ° C and has an analysis.

Preparation 5

Methyl N- (2-hydroxyethyl-3-carbomethoxypyrrole-2-acetate; to a 250 ml 3-neck round bottom flask containing 10.08 g of ethanolamine, equipped with a dry nitrogen flow inlet and outlet valve, a magnetic stir bar, and a pressure-controlled addition funnel 26.1 g of dimethyl 1,3-acetonedicarboxylate are added dropwise with stirring over a period of 30 minutes, the temperature of which must not rise above 30 [deg.] C. The methyl 3-carbomethoxymethyl-3- (2'-hydroxyethyl) aminoacrylate formed ( III) is diluted with 20 ml of acetonitrile and chloroacetaldehyde, prepared by heating at 150-160 ° C a mixture of 27.4 g of chloroacetaldehyde ethyl acetal and 46.8 g of oxalic acid dihydrate, is added to the solution with stirring over 2 minutes. The reaction mixture is refluxed for 5-10 minutes, after which time the reaction is complete, as can be seen by tlc analysis using acetone / chloroform (10:90) as eluent. and 250 ml of benzene and 250 ml of heptane are added to the residue, followed by distillation under reduced pressure. The oily residue obtained as a distillation residue is suspended in 50 ml of methylene chloride and 20 g of silica gel are added to the suspension. The methylene chloride mixture is poured onto a column containing 200 g of silica gel in ethyl acetate / hexane (20:80). The column is eluted first with 6 liters of ethyl acetate / hexane (20:80) and then with 4 liters of ethyl acetate / hexane (50:50). The fractions eluted with ethyl acetate / hexane (50:50) are combined and evaporated to give 12.8 g of an oil which is triturated in 20 ml of petroleum ether (30-60 ° C). Removal of the solvent under reduced pressure gives 11.89 g (32.9% of theory) of methyl N- (21-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H), m.p. 51-54 ° C, which is the same as the compound obtained in Preparation 2.

Preparation 6

Methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate

To a stirred solution, cooled to -10 ° C, of 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate in 35 ml of dry dichloromethane is added 2.65 ml of triethylamine and then dropwise and maintaining the temperature of the mixture at -10 to 5 ° C with 1.46 mL of methanesulfonyl chloride. The progress of the reaction is monitored by tlc analysis using chloroform / acetone (90:10). After completion of the reaction (about 30 minutes after the addition of methanesulfonyl chloride), 10 ml of water are slowly added to the mixture. The organic phase is separated, washed with water (3 x 30 ml), dried over sodium sulphate and evaporated under reduced pressure. The residue is crystallized from dichloromethane / hexane to give 4.75 g (77.7%) of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate (R = H), 99-101 ° C.

Preparation 7

Methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate

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 triturated with water. Insoluble nine is filtered off and filtered to give 840 mg (97%) of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = H), m.p. 137-138 ° C.

Preparation 8

A solution of 1 g of methyl N- (2-iodoethyl) -3-carbomethoxy-pyrrole-2-acetate in 5 ml of dry dimethylformamide is stirred under an argon atmosphere together with a 50% sodium hydride mineral oil suspension (137 mg). The reaction mixture was allowed to stand at room temperature for 30 minutes, then it was poured into 100 any water. The product is extracted with ethyl acetate (3 x 50 ml), the combined extracts are washed with water, dried over magnesium melt and evaporated to dryness. Chromatography of the residue on 20 g of silica gel using hexane / ethyl acetate (4: 1) as eluent gives 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.

Preparation 9

Dimethyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate A 10% suspension of 710 mg of sodium hydride in mineral oil is washed with anhydrous hexane under nitrogen and then suspended in any dimethylformamide. The suspension is cooled to -5 ° C and 4.5 g of methyl N- (2-mesyloxymethyl) -3-carbomethoxypyrrole-2-acetate are added over a period of -5 ° C at -0 ° C with stirring. poured into a mixture of NaCl solution and extracted several times with benzene, the combined extracts are washed with water, dried and evaporated to dryness under reduced pressure, and the solid residue is crystallized from ether to give dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1. , 7-dicarboxylate (VII, R = H), which is identical to the product of Preparation 8.

Preparation 10 1,2-Dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid

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 potassium hydroxide (4.48 g) in water (20 ml). ml) by refluxing the reaction mixture for 6 hours. The cooled solution is evaporated to dryness and the residue is taken up in 50 ml of saturated sodium chloride solution. The resulting solution is acidified with 6N hydrochloric acid and extracted with ethyl acetate (3 x 50 mL). The combined extracts are dried over magnesium sulphate and evaporated to dryness under reduced pressure to give 1.51 g (95%) of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (VIII, R = H). , sp. 220 ° C, decomposes.

18 63406

Preparation 11

Isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid Solution cooled in an ice bath containing 1.34 g of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole -1,7-dicarboxylic acid in 50 ml of isopropanol is saturated with hydrogen chloride gas, keeping the temperature of the reaction mixture below 50 ° C. The ice bath is removed and the reaction mixture is stirred for 1.5 hours at room temperature, evaporated to dryness under reduced pressure, 10 ml of benzene are added to the residue and the solution is again evaporated to dryness in vacuo. This is repeated a total of 3 times to completely remove excess hydrogen chloride.

1.58 g (96%) of isopropyl-1,2-dihydro-3H-pyrrolo

- - O

[1,2-a] pyrrole-1-carboxylate-7-carboxylic acid (IX, R = H, R = IC3H2) which, crystallized from methanol / ethyl acetate, has m.p. 144-145 ° C.

In a similar manner, however, using methanol instead of the isopropanol used in the above process, methyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid is obtained.

Preparation 12

Isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate 1.054 g of isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid is heated at 240-250 ° C in a dry 10 ml round bottom flask and the reaction product is 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, R1 = iC2H2) are obtained in the form of a pale yellow oil having the following physical constants: \ MepH CHCl 3, UV: λ max 215 nm (c 6 020); I.R.:Y max 1 725 cm; , CDC1,

N.M.R .: O TMS

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 = 3 Hz, 1H), 6.43-6.53 ppm. (m, 1 H).

Preparation 13

Isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate is introduced into a 100 ml 3-necked flask equipped with a condenser, a nitrogen inlet tube and a wash flask through which the exhaust gas bubbles. 0 g of isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid. The apparatus is thoroughly purged with nitrogen, then the nitrogen flow is stopped. The apparatus is immersed in an oil bath at 19 63406 270 ° C and the progress of the reaction is monitored by monitoring the rate of CO 2 evolution (wash flask) and tlc analysis on silica gel using benzene / dioxane / acetic acid (90: 10: 1) for evolution. After 45 minutes, the reaction is almost complete. After one hour, the reaction vessel is removed from the oil bath and the contents of the vessel are transferred to a round bottom flask containing 500 ml of acetone. The solvent is removed under reduced pressure and the residue is purified by chromatography on a column of 100 g of silica gel. Fractions eluted with hexane / benzene (70:30) and hexane / benzene (50:50) give 2.77 g (68%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1. carboxylate (X, R = 2 H, R = iC 3 H 2) as an oil having the same physical constants as the compound obtained in preparation.

Preparation 14

Ethyl-1,2-dihydro-3H-pyrrolo / l, 2-a7pyrroli-l-carboxylate

Following the procedure of Preparation 12 or 13, the methyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid obtained in Preparation 11 is converted to the title compound as an oil.

Preparation 15

Following the procedures of Preparations 6-8, 11 and 13, N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R = CH 2) is sequentially converted to the following compounds: methyl N- (2 -mesyloxyethyl) -3-carbomethoxy-4-methyl-pyrrole-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-d] pyrrole-1,7-dicarboxylate, m.p. 71 ° C, 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid, m.p. 200-230 ° 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 = iC3H7), oil.

In a similar manner, using methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate instead of methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, isopropyl 1,2-Dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil.

20 63406

Example 1

Isopropyl 5-O-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate

A solution of 179 mg of Ν, Ν-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 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 argon for 8 hours, 405 mg of sodium acetate are added and refluxing is continued for a further 5 hours. The resulting mixture was evaporated to dryness and the residue was chromatographed on 12 g of silica gel eluting with hexane / ethyl acetate (3: 1) to give 208 mg (66%) of isopropyl-5-o-toluoyl-1,2-dihydro-3H-pyrrolo / 1 , 1,2-α-pyrrole-1-carboxylate (XI, R = H, R1 = p-CH2, R2 = iC2H2) as an oil having the following physical constants: t 8,700, 19,500); I.R .: max 1735,, r CDCl 3.

1,620, 1,605 cm; N.M.R .: O TMS

1.23 (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 = 4 Hz, 1H), 6.70 (d, J = 8 Hz) , 2H), 7.10 (d, J = 8 Hz, 2H), 7.60 ppm (d, J = 3 Hz, 2H).

Condensation of the compound obtained in Preparation 14 with N, N-dimethyl-p-toluamide by the above method affords methyl 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate, respectively. methacrylate.

Following the above procedure and using 1.1 to 5 molar equivalents of N, N-dimethylbenzamide, N, N-dimethyl-o-toluamide, N, Nd sucking-m-toluamide, N, N-dimethyl-p-methoxybenzamide, N, N-dimethyl-p-ethoxybenzamide, N, N-dimethyl-ipropoxybenzamide, N, N-dimethyl-o-chlorobenzamide, N, N-dimethyl-m-H4oorbenzeamide, w, N-dimethyl -p-chlorobenzeamide and N, N-dimethyl-pf-fluorobenzamide ·.

Instead of N, N-dimethyl-p-toluamide and following the reaction procedure, isopropyl-5-benzoyl-1,2-dihydro-3H-2R 6 34 0 6 pyrrolo [1,2-a] pyrrole-1- Carboxylate as a pale yellow oil with the following physical constants:

MeOH CHCl 3 max 245, 311 nm (λ 7 230, 17 800); I.R. L max J 1 735, -1 i CDCl 3

1,620 cm; N.M.R. : o TMS J

1.24 / d, 6H, (CH 3) 2 Cl 2, 2.50-3.13 (m, 2H; H-2) 3/97 (dd, 1H, .H1), 4.18-4.70 (m , 2H, H-3), 5.00 (sept., 1H, (CH3) 2CH), 6.00 (d, 1H, H-7), 6.86 (d, 1H, H-7), 6 , 86 (d, 1H, H-6), 7.10-7, 90 ppm phenyl proton); MS: m / e 297 (M +), isopropyl 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate as an oil having the following physical constants: i MeOH CHCl3- .

U.V.: λ max 252, 303 nm (£ 4,460, 19,100); I.R.rV'max 1735, -1 (CDCl3

1,620 cm; N.M.R.:o TMS

1.18 / d, 6H, (CH 3) 2 CH 7, 2.28 (s, 3H-, o-CH 3), 2.50-3.13 (m, 2H, H-2), 3.92 (dd, 1H, H1), 4.17-4.70 self, 2H, H-3), 4, J98 ^ sept. 1H, (CH3) 2CH7, 5.92 1H, H-7), 6.43 (d, 1H, H-6), 6.97-7.45 ppm (m, 4H, phenyl protonite).

Isopropyl 5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate as an oil having the following physical constants:

MeOH in CHCl 3: λ max 250-251, 310-312 nm (£ 6,460, 17,400); I.R.:/max. . CDC1-

1735, 1620 Cm "; N.M.R.; δ TMS J

1.25 (d, 6H, (CH 3) 2 CH), 2.27 (s, 3H CH 3), 2.52-3.13 (m, 2H / H-2) γ 3.92 (dd, 1H, H1), , 13-4 / 70 in, 2H, H-3), 4.95 / eq. 1H, (CH3) 2CH2, 5.95 (d, 1H, H-7), 6.67 (d, 1H, H-6), 7.03-7.57 ppm. (m, 4H; phenyl protonite).

Isopropyl 5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo, 1,2-a-pyrrole-1-carboxylate having the following physical constants:

, MeOH

U. V. λ max 218, 270-284 (olka), 314 nm (ε9,780, 9,320, 22,400): chc13. . CDClo

I.R.Y max 1,730, 1,605 cm; N.M.R.ö TMS

1.24 6H, J = 6 Hz; (CH 3) 2 CH 2 -, 2.50-3.10 (m, 2H; H-2), 3.78 (s, 3H; CH, O), 3.93 (dd, 1H ·, i 6 Hz, JBX 7 Iis; H1), 4.13-4.60 (m, 2H; H-3), 4.95 / sept. , 1H, J = 6 Hz; (0¾) jCg /, 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 protonite); , M. S. m / e 327 (M &lt; + &gt;). Isopropyl 5-m-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [2H-α] -1-carboxylate, m.p. 50-51 ° C> 22 63406 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, isopropyl-5-o-chlorobenzoyl-1,2-dihydro -3H-pyrrolo [1,2-b]. α7-pyrrole-1-carboxylate as an oil having the following physical constants:, MeOH-CHCl-U.V .: Λ max 251, 306 ran (t 5 750, 16 600); I.R .: max J 1 735,, r cdc1t

1625 cm N.M.R.tö TMS

1.22 / d, 6H, (CH 3) 2 CH 7, 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 2 Cl 2), / 5.93 (d, 2 / 3H) 6.00 (d, 1 / 3H) Hrl 2, 42 (d, 2 / 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-carboxylate as an oil having the following physical constants:, MeOH, CHCl3 UViAmax 241, 313 nm (C 6,600, 15,100); I.R.:Ymax J 1735, -1 {CDCl3

1,620, 1,570 cm x; N .M. R .: <>) TMS

1.27 / d, 6H, (CH 3) 2 CH 7, 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, (CH 3) 2 CH / 5.98 (d, 1H, H-7), 6.67 (d, 1H, H-6), 7.07- 7.78 ppm. (m, 4H, phenyl protonite); M.S .: m / 3333-333 (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 to 72.5 ° C.

Hydrolysis of the isopropyl ester group by the method described in Example 2 or 3 below gives the corresponding free acids: 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 160-161 ° C, 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid as an oil having the following physical constants:

MeOH CHCl 3, U.V .: max 253, 307 nm (3,310, 16,980); I.R .: max 1720, i CDCl3

1620 cm -1; N.M.R .: TMS

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, li, H-6), 6.83-7.37 (m, 4H, phenyl protons), 8.60 ppm ( bs, 1H, COOH), 5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 144-145 ° C, 23 63406 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-dihydro-3H-pyrrolo-1-carboxylic acid> m.p. 155-156 ° C, 5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 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 having the following physical constants:. MeOH CHCl 1-5 U.V.A max 250, 307.5 nra (t 4,360, 17,400); I.R.V max 1 715, -1 i cdc13

1 620 cm? N.M.R.Ö TMS

2.60-3.15 (m, 2H; H-2), 4.02 (dd, 1H, J = 6 Hz, 77 Hz? H1), 4.20-4.70 (m, 2H; H-3), 5.98 (d, 1H, J = 4 Hz - H-7), 6.42 (d, 1H, J = 4 Hz - H-6), 7.00-7.77 (m, 4H? Phenyl proton), 8.6 7 ppm [s, (br), 1H? C00H7,5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolol [1,2-a] pyrrole-1-carboxylic acid, m.p. 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-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo, 1,2-a-pyrrole-1-carboxylic acid, m.p. 179.5 to 180.5 ° C.

By the method of Example 1, isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate is condensed with N, N-dimethyl-p-toluamide to give isopropyl-5-p-toluoyl. -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI, R = CH3, R1 = p-CH3, R2 = iC3H7), m.p. At 72 ° C.

In a similar manner but using the Ν, Ν-dimethylarylamides listed in Example 1 instead of N, N-dimethyl-p-toluamide, the following are obtained, respectively: isopropyl-5-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-b] α-pyrrole-1-carboxylate, m.p. 75 ° C, isopropyl 5-o-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl 5-m-toluoyl-1,2-dihydro -6-methyl-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate, isopropyl-5-p-methoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1 carboxylate, m.p. 89 ° C, isopropyl 5-p-ethoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, 24 63406 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- α7-pyrrole-1-carboxylate, 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, 1H-2-pyrrole-1-carboxylate, m.p. 88 ° C, isopropyl 5-p-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate having the following physical constants: CHCl U.V. Λ max 250, 315 nm (£ 6,170, 14,100); I.R. ^ max 3 1 734,, e CDCl1,

1,605, 1,593 cm; N.M.R.6 TMS

1.25 (d, 6H, J = 6 Hz; ester CH 2), 1.83 (ε, 3H; ring CH 2), 2.49-3.00 (m, 2H; CH 2), 3.90 ( t, 1H, J = 7.4 Hz (CHOO), 4.10-4.23 m, 2H; N-CH 2), 4.98 (sept., 1H, J = 6 Hz; ester CH), 7.00 (t, 2H, J ortho = 8.4 Hz, JHp = 8 Hz; H-3 ', 5' ), 7.55 (q, 2H, J ortho = 8.4 Hz, = 5.5 Hz; H-2.6 '); M.S. m / e 1% 329 25 M + 242 100 M + -CO 2 CH (CH 3) 2 123 36 F-C 6 H 4 CO.

In a similar manner, the other compounds obtained in Preparation 15 are converted to the corresponding 5-aroyl-substituted derivatives. For example, the following compounds are obtained: isopropyl 5-benzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil.

Example 2 5-p-Toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

To 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 added 690 mg of potassium carbonate in 5 ml of water. . The reaction mixture is refluxed under nitrogen for 30 minutes, cooled and evaporated to dryness. To the residue is added 10 ml of 10% hydrochloric acid, and the resulting mixture is extracted with ethyl acetate (2 x 50 ml).

The combined extracts are dried over magnesium sulphate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate / hexane gives 238 mg (89%) of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylic acid / (A), R = H, R1 * P-CH3 /, m.p. 182-183 ° C.

63406 25 isopropyl 5-β-J: lucribenzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil.

Example 3 5-p-Toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

To a solution of 250 mg of isopropyl 5-p-toluoyl-1,2-dihydro-5H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 8 ml of methanol is added 200 mg of sodium hydroxide in 1 ml under nitrogen: in water, and the reaction mixture is allowed to stand at room temperature for 1.5 hours. The methanol is then removed under reduced pressure and the basic solution is diluted with 5 ml of water and extracted with ether to remove unsaponifiable matter. The aqueous solution is acidified with 10% hydrochloric acid and extracted 3 times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure. The residue is crystallized from ethyl acetate / hexane to give 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, which is identical to the compound obtained in Example 2.

In a similar manner or alternatively, by the hydrolysis method of Example 3, the other isopropyl ester compounds of Example 1 are converted to the corresponding free acids: 5-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid , sp. 169 ° C;

Example 4

To 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 added 1.05 g potassium carbonate in 8 ml of water. The reaction mixture is refluxed under nitrogen for 30 minutes, cooled and evaporated to dryness. To the residue are added 10 ml of 10% hydrochloric acid in water 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 sulphate and evaporated to dryness under reduced pressure to give 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid / (A), R = CH3, R1 = p-CH2-, m.p. 187 ° C.

In a similar manner or alternatively, by the hydrolysis method of Example 3, the other isopropyl ester compounds of Example 1 are converted to the corresponding free acids: 5-benzoyl-1,2-dihydro-6-methyl-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-carbocryl hop, m.p. 182 ° C, 26 6 3 4 0 6 5-p-chlorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-b] pyrrole-1-carboxylic acid, m.p. 204 ° C, 5-p-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 204 ° C, 5-benzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 177 ° C, 5-p-fluorobenzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 196 ° C.

Example 5 (1) -5-Benzoyl-1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylic acid

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 anhydride. The mixture is stirred at room temperature for 10 minutes, the resulting solution is cooled to 0-5 ° C, 1.4 g of dry triethylamine are added, followed immediately by 0.5 g of (1) -N-phenylethyl alcohol. The resulting reaction solution is stirred at room temperature for 15 minutes, then the solution is poured into any water containing 1 ml of triethylamine, and the mixture is extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate, the solvent and excess (1) -o-phenylethyl alcohol are evaporated in vacuo to give 0.42 g 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-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylic acid (1) - oC-phenethyl ester mixture separated by high performance liquid chromatography 4% ethyl acetate / hexane, 11 mm x 50 cm column, 10

um Lichrosord S1-60) to give 180 mg of the more polar ester MeOH MeCH

(D = 145.7 ° C) and 178 mg subtract the polar ester (D + 128.6 ° C).

148 mg of the more polar ester are dissolved in 8 dry Bent * mushrooms. The solution is cooled to 15-20 ° C, and 5 ml of trifluoroacetic acid are added, and the solution is stirred at room temperature for 70 minutes. The reaction solution is poured into 60% dry benzene and the solvents are evaporated off under vacuum at room temperature. Purification by high performance liquid chromatography (same column as above, use of 35% ethyl acetate / hexane in 0.5% acetic acid instead of 4% ethyl acetate / hexane) to give 63 mg of (1) -5-benzoyl-1 , 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid having? HCl3 - 153.7 ° C and m.p. 153-155 ° C.

Similarly, decomposition of the less polar ester is performed to give 85 mg of (d) -5-benzoyl-1,2-dihydro-3H-27 6 34 0 6

pyrrolo [1,2-a] pyrrole-1-carboxylic acid having? 3 + 155.1 C

and m.p. 154-156 ° C. The (d) -acid isomer thus obtained can, if desired, be racemized (and re-reacted) in a manner known per se.

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

Example 6

Ethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2- a] pyrrole-1-carboxylate

To a solution of 200 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-carboxylic acid in 5 ml of dichloromethane is added an excess of ethereal diazomethane and the reaction mixture is allowed to stand. at room temperature for 30 minutes. The solvents and excess reagent are removed under reduced pressure, and the residue is crystallized from ethyl acetate / methanol to give methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

In a similar manner, using diazoethane and diazopropane instead of diazomethane gives ethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and propyl 5-benzoyl-1,2- dihydro-3H-pyrrolo / l, 2-a7pyrroli-l-carboxylate.

In a similar manner, the other free acids obtained in Examples 1, 4 and 5 are converted to esters. Examples of these are: isopropyl 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil.

I tflaOH film U.V. : λ max 256, 312 nm, (£ 8,700, 19,500); I.R .: max 1 735, r CDCl 3

1,620, 1,605 cm -1; N.M.R .: O TMS

1.23 (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 = 4 Hz, 1H), 6.70 (d / J = 4 Hz, 1H), 7.10 (d, J = 8 Hz, 2H), 7.60 ppm (d, J = 8 Hz, 2 «).

isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil.

MeOH CHCl 3, max 245, 311 nm (j \ 7 230, 17 800); I.R. L max 3 1 735,, CDC1-

1,620 cm; N.M.R .: δ TMS J

1.24 / d, 6H, (CH 3) 2 CH 7, 2.50-3.13 (m, 211; H-2) 3/97 (dd, 1H, Π-1), 4.18-4.70 (m, 2H, H-3), 5.00 (sept., 1H, '(Q? 3)? Ol) t 6.00 (d, 1H, M-7), 6.86. (D, 1H, H -7), 6.86 (d, 1H, H-6), 7.10-7.90 ppm (m, 5H, phenyl protons); M.S .: m / e 297 (M +), isopropyl 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-28-63406 li-1-carboxylate, oil.

* MeOH CHCl 3, U.V .: λ max 252, 303 nm (£ 4,460, 19,100); I.R.:Vmax 1735, ...- 1 cCDC13

1,620 cm; N.M.R. : 0 TMS

1.18 / d, 6H, (CH 3) 2 CH 7, 2.28 (s, 3H-, o-CH 3), 2.50-3.13 (m, 2R, H-2), 3.92 (dd, 1H, H1), 4.17-4.70 (m, 2H, H-3), 4.98 / Sep. 1H, (CH3) 2GH7, 5.92 (d '1H' H-7) '6.43 (d, 1H, H-6), 6.97-7.45 ppm (m, 4H, phenyl protonite).

isopropyl 5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil.

, MeOH ... CHCl 3 0. V,: λ max 250-251, 310-312 nm (ε 6,460, 17,400); t.r.;? £ max, t CDCl 3, 1735, 1620 cm -1; NMR: TMS δ 1.25 (d, 6H, (CH 3) 2 CH], 2.27 (s, 3H Cl 13), 2.52-3.13 (m, 2H, H-2), 3.92 (dd, 1H, H1), 4.13-4.70 (2H, H-3), 4.95 / sept. 1H, (CH3) 2CH2, 5.95 (d, 1H, H-7), 6.67 (d, 1H, H-6), 7.03-7.57 ppm. (m, 4H; phenyl protonite).

isopropyl 5- (p-methoxybenzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate,

, MeOH

u; v./i max 218, 270-284 (ole) 314 nm (ε 9,780, 9,320, 22,400): CHCl CDCl 1 IRVmax 3 1730, 1 605 cm -1; NMRS TMS 3 1 24/3, 6H, J = 6 Hz; (CH 3) 2 CH-; 7, 2.50-3.10 (m, 2H; H-2), 3.78 (s, 3H; CH 3 O), 3.93 (dd, 1H, JAX = 6 Hz, JBX = 7 Hz; H1), 4.13-4.60 (m, 2Ϊ1; H-3), 4.95 / sept., 1H, J = 6 IIz; (CH 3) 2 qi /, 5.95 (s, 111, J = 4 Hz; H-7), 6.68 (d, 1H, J b 4 Hz; II-6), 6.70-7.90 ppm (m, 4Π; phenyl protonite); MS m / e 327 (M +).

isopropyl 5-p-ethoxybenzoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate [mp] 94-95 ° C; i $ opropyyli-5- (o-kloorobentsoyyli) -1,2-dihydro-3H-pyrrolo / 1,2-a / pyrrole-l-carboxylate.

. MeOH r CHCl 3 U.V.: Amax 251, 306 nm (C 5 750, 16 600); I.R .: max 1 735,. f cdci3

1625 cm -1; N.M.R.: <-> TMS

1.22 / d, 6H, (CH 3) 2 CH 7, 2.55-3; .05 (m, 2H; H-2) 3.97 (dd, HI, H1), 4.17-4.70 (m , 2H, H-3), 4.97 / sept. , ITT, (CH3) 2Ch7, / 5.93 (d, 2/311) 6.00 (d, 1/311) 11- / 7 6¾ / 42 (d, 2 / 3H), 6.67 (d, 1 / 3H, 11-6 /, 7.07-7.80 ppm (m, 411; phenyl protons).

29 63406 Isopropyl 5- (p-chlorobenzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, i MeOH r, CHCl3 U.V. : Λ max 241, 313 nm (C 6 600, 15 100); I.R.sYmax 1 735, - _i, cdci3

1,620, 1,570 cm -1 N.M.R .: ^ TMS

1.27 / d, 6H, (CH 3) 2 CH 7, 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, (CH 3) 2 CH 3 7.98 (d, 1H, H-7), 6.67 (d, 1H, H-6), 7.07 -7.78 ppm. (m, 4H, phenyl protons); M.S .: mp 331-333 (M), isopropyl 5- (p-chlorobenzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 80.5 to 81 ° C; isopropyl 5- (p-fluorophenyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 72 to 72.5 ° C; isopropyl 5-p-toluoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 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, m.p. 89 ° C, isopropyl 5- (p-chlorobenzoyl) -6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 88 ° C, isopropyl 5-p-toluoyl-6-methyl-1,2-dibydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 72 ° C, isopropyl 5-benzoyl-6-ethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil, isopropyl- (p-fluorobenzoyl) -6-ethyl -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil.

Example 7

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

A solution of 300 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-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 give isoamyl 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Similarly, other esters of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid are obtained, for example pentyl, hexyl, octyl, nonyl, dodecyl etc. ethers using other alcohols instead of isoamyl alcohol, for example pontyvinyl, hexyl, octyl, nonyl, dodecyl alcohol, etc.

Example 8

Sodium o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate

To a solution of 300 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 sodium hydroxide as a 0.1 N solution. The solvent is then evaporated off under reduced pressure, 2 ml of methanol are added to the residue, followed by addition of ether to precipitate crude sodium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, which can be crystallized from ethyl acetate. /heksaanista.·

Similarly, other salts are prepared, for example, the ammonium and potassium salts of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, using ammonium hydroxide and potassium hydroxide instead of sodium hydroxide.

In a similar manner, the 5-substituted 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid compounds prepared in Examples 1, 4 and 5 can be converted to the corresponding sodium, potassium and ammonium salts. Examples of compounds thus prepared are: sodium 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, sodium 5-benzoyl-1,2-dihydro-3H-pyrroloZ. 12-α-pyrrole-1-carboxylate, sodium (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate, potassium 5-p-ethylbenzoyl-1,2-ol dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, potassium 5-o-butylbenzoyl-1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate, sodium 5-p- methoxybenzoyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, ammonium 5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole -1-carboxylate, ammonium 5-o-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [2,3-b] pyrrole-1-carboxylate, potassium 5-p-bromobenzoyl-1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-1-carboxylate, sodium 5-benzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, potassium 5- Toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] o'-ol-1-carboxylate - xionic ammonium-5-o-meth oxybenzoyl 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, sodium 5-p-fluorobenzoyl-1,2-dihydro-6-propyl-3H-pyrrole 10/1,2-α-pyrrole-1-carboxylate and potassium 5-m-chlorobenzoyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Example 9

Calcium-5-p-toluoyl-l, 2-dihydro-3H-pyrrolo / l, 2-a7pyrroli-l-carboxylate

To a solution of 175 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 0.1 N solution, to give a solution containing potassium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate. Solution containing 40 mg of calcium carbonate

dissolved in a quantity of 1N hydrochloric acid which still dissolves the calcium carbonate, is buffered by adding 100 mg of solid ammonium chloride, then a further 5 ml of water are added. This is how I

i

the resulting buffered calcium solution is then added to potassium 5-p-toluoyl

In a solution of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, the precipitate formed is filtered, washed with water and air-dried to give calcium 5-p-toluoyl-1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-1-carboxylate.

In a similar manner, magnesium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate is prepared using magnesium carbonate instead of calcium carbonate.

Similarly, using instead of 5-toluoyl-1,2-dihydro-3H-pyrrolo-4H-2-a-pyrrole-1-carboxylic acid: 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5-p-chlorobenzoyl-1,2-dihydro-3H- pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5-o-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, i; 5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole | 1-carboxylic acid, 5-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid and 5-o-fluorobenzoyl-1,2-dihydro-6-ethyl-3H- pyrrolo [1,2-a] pyrrole-1-carboxylic acid, the corresponding calcium and magnesium salts are obtained j - - · - ---—-—— ~ - -: r: - - - '- -' -ί 63406 32

Example 10

Copper 5-b-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate

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 in 0.1 ml. in solution. An aqueous solution of potassium 5-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate thus obtained is added to a solution of 150 mg of cuprin nitrate trihydrate in 5 ml of water. The precipitate formed is collected, washed with water and air dried to give copper 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-IX, 2-α-pyrrole-1-carboxylate.

In a similar manner, the free acids obtained in Examples 1, 4 and 5 can be converted into their copper salts, respectively.

Example 11

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

A solution of 200 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-IX, 2-α-pyrrole-1-carboxylic acid in 15 ml of hot benzene is treated with 60 mg of isopropylamine. The solution is allowed to cool to room temperature, the product is filtered, washed with ether and dried to give 5-p-toluoyl-1,2-dihydro-3H-pyrrolo, 1,2-a-pyrrole-1-carboxylic acid isopropylamine salt.

Other amine salts of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid are prepared in a similar manner, for example, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts. , using the corresponding amine instead of isopropylamine.

In a similar manner, the free acids obtained in Examples 1, 4 and 5 can be converted to the corresponding isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts.

Example 12 Dicyclohexylamine salt of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

A solution of 770 mg of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo-IX, 2-g7-pyrrole-1-carboxylic acid in 10 ml of benzene is treated with 580 mg of dicyclohexylamine. The reaction mixture is stirred for 10 minutes, then the solid formed is filtered and washed with anhydrous ether to give 965 mg of the dicyclohexyl-amine salt of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp. 161-163 ° C.

Similarly, the other free acids of Examples 1, 4 and 5 can be converted to the corresponding dicyclohexylamine salts, for example 5-o-chlorobenzoyl-1 / 2-3H-pyrrolo [1/2-a] pyrrole-1-carboxylic acid dicyclohexylamine salt, m.p. 173-175 ° C.

Example 13 5-Benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 100 mg of sodium 5-benzoyl-1,2 / dihydro-3H-pyrrolo [1,2-b] The N-pyrrole-1-carboxylate is dissolved in 50 ml of water. 10 ml of concentrated hydrochloric acid are added to the solution at room temperature with stirring. The aqueous solution is extracted with ethyl acetate (2 x 50 ml), the extracts are dried and evaporated. The product, 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, is crystallized from ethanol / ether, m.p. 160-161 ° C.

In a similar manner, the other salts prepared in Examples 8-12 are hydrolyzed to acids: 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 182-183 ° C, 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, oil, 5- (4-methoxybenzoyl) -1,2-dihydro- 3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 187-187.5 ° C, 5- (4-ethoxybenzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 169.5-170 ° C, 5- (3-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 180-181 ° C, 5- (4-chlorobenzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 201.5-202.5 ° C, 5- (4-fluorobenzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 179.5-180.5 ° C, 5-p-toluoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 187 ° C, 5-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 169 ° C, 5 - (4-methoxybenzoyl) -6-methyl-1,2-dihydro-3H-pyrrolo [2,2-a] pyrrole-1-carboxylic acid, mp 182 ° C, 5- (4-chlorobenzoyl) -6-methyl- 1,2-Dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 204 ° C, 6-propyl-6-methyl-1,2-dihydro-3H-pyrrolo [2,2-a] pyrrole- 1-carboxylic acid, mp 172 ° C and 34 6 34 0 6 5- (4-fluorobenzoyl) -6-ethyl-1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylic acid, mp 196 ° C.

Example 14 Racemization of d-5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-chloroacetic acid d-5-benzoyl-1,2-dihydro-3H-pyrrolo] To a boiling solution of 1,2-α-pyrrole-1-carboxylic acid (200 mg) in ethanol / water (50 ml) is added 2 ml of concentrated hydrochloric acid, and the mixture is refluxed for 30 minutes. The obtained (dl) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (m.p. 160-161 ° C) is isolated in the usual manner.

Accordingly, other d-carboxylic acids prepared according to the invention are converted to dl compounds. Examples which may be mentioned are the following dl compounds of the formula A: '5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 182-183 ° C, 5-o-toluoyl-1,2-dihydro-3-H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, oil, 5- (4-methoxybenzoyl) -1,2- dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 187-187.5 ° C, 5- (4-ethoxybenzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 169.5-170 ° C, 5- (3-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 180-181 ° C, 5- (4-chlorobenzoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 201.5-202.5 ° C, 5- (4-fluorobenzoyl) -1,2-dihydro -3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 179.5-180.5 ° C, 5-p-toluoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-b] α-pyrrole-1-carboxylic acid, mp 187 ° C, 5-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 169 ° C, 5- (4-methoxybenzoyl) -6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 182 ° C, 5- (4-chlorobenzoyl) -6 -methyl-1,2-dihydro-3H-pyrrolo-71,2-a7pyrrole-1-carboxylic acid, mp 204 ° C, 6-propyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-d] α-pyrrole-1-carboxylic acid, mp 172 ° C and 5- (4-fluorobenzoyl) -6-ethyl-1,2-dihydro-3H-pyrrolo [7,2-a] pyrrole-1-carboxylic acid, mp 196 ° C .

Claims (1)

A process for the preparation of therapeutically useful 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-b] 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2- for the preparation of pyrrole-1-carboxylic acid derivatives or (1) -acid isomers thereof, wherein R is hydrogen or C 1 -C 4 alkyl, R 1 is hydrogen, (C 1 -C 4 alkyl, C 1 -C 4 alkyl) -alkoxy, chlorine, fluorine or bromine, and M is hydrogen, C 1 -C 4 alkyl or a pharmaceutically acceptable, non-toxic cation, wherein the R 1 substituent is in the ortho, meta or para position of the benzoyl group, characterized in that that one or more of the following reaction steps are performed: a) condensing a compound of formula (X) OL w YY (x) 2, wherein R is as defined above and R is C 1 -C 4 alkyl, of formula (XIII) 1 with an amide of formula (XI) 63406 36 ^>, \ t.ANx) \ / C00R <XI) ö [__ To a compound according to 12, wherein R, R and R are as defined above; b) hydrolyzing a compound of formula (XI) to a compound of formula (A) wherein M is hydrogen; c) preparing a pharmaceutically acceptable salt of an acid of formula (A) by treating the free acid of formula (A) with an equivalent amount of a pharmaceutically acceptable base; d) the carboxylic acid function of the acid of formula (A) or of its (1) or (d) -isomer is esterified with a C 1 -C 4 alkanol, the corresponding diazoalkane or a C 1 -C 4 alkyl iodide to give the corresponding C 1 -C 4 alkyl iodide of formula (A) alkyl ester; e) inorganic or organic salts of an acid of formula (A) or its individual isomers are converted to the corresponding acids by reaction with an organic or inorganic acid having a pK value of less than 3; f) the acid of formula (A) is divided into optical isomers in a manner known per se; g) The (d) -isoisomer or a salt thereof is racemized to the corresponding compound of formula (A). 63406 For the preparation of therapeutically active 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives of the form R'1-jl (A) (A) or the (1) -isra isomer , i and the formula R 1 is a substituent or C 1 -C 4 alkyl, R 1 is a C 1 -C 4 alkyl, C 1 -C 4 alkoxy, chloro, fluoro or Bromo, and M is in the case of C 1 -C 4 -alkyl or in the form of a pharmaceutical moiety, a cation, a variety of substituents R or a benzoyl group in the ortho-, meta- or para-positioning, the addition of a compound, a) a condenser: for compounds of formula (X) V_ See coor2 I_J (x) 2 color R har ovan nämnda betydelse, och R är en C 1 -C 4 -alkyl, with amides of formula (XIII) L · "y-CON (CHo) 2 R! (ΙΙιΙΙ) Väri R "* · har ovan nämnda betydelse, account en förening med formeln (XI)