NO147564B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 5-BENZYOL-1,2-DIHYDRO-3H-PYRROLO (1,2-A) PYRROL-1-CARBOXYLIC ACID DERIVATIVES - Google Patents

Description

The present invention relates to the preparation of certain new pyrrole-l-carboxylic acid compounds, and more particularly to

The invention enables the production of new 5-benzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylic acids with the formula:

or separate (1)-acid isomers or (d)-acid isomers and c^_4~

alkyl or a-phenylethyl ester thereof, as well as their pharma-

acetic, non-toxic salts, where R denotes hydrogen or lower alkyl of 1-4 carbon atoms, and R"*" denotes hydrogen, lower alkyl of 1-4 carbon atoms, lower alkoxy of 1-4 carbon atoms, chlorine, fluorine or bromine, and where the R - substituent is in the ortho, meta or para position on the benzoyl group.

The compounds of formula (A) except for the (d)-acid isomer

and its derivatives, exhibit anti-inflammatory, pain-

calming and antipyretic effects and are therefore useful for the treatment of inflammation, pain and/or fever in mammals as described in more detail later. They are also relaxants for the smooth muscle tissue.

Salts of inorganic bases are sodium, potassium, lithium,

ammonium, calcium, magnesium, ferrous, zinc, copper,

manganese, aluminium, ferric, manganese salts and the like.

Ammonium, potassium, sodium, calcium and magnesium salts are particularly preferred. Salts of pharmaceutical organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituents

amines, cyclic amines and basic ion exchange resins, for example isopropylamine, trimethylamine, diethylamine, triethyl-

amine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine,

arginine, histidine, caffeine, procaine, hydrabamine, choline,

betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexylamine, choline and caffeine.

New compounds of formula (A) and (XI) described below exist as pairs of optical isomers (or enantiomorphs), i.e. as a (dl) mixture. All optical isomers and (dl) mixtures are covered by the invention.

When the compound produced according to the invention is to be used to induce a physiological reaction (e.g. anti-inflammatory, analgesic or anti-pyretic effect), i.e. to be used as medicine, a preferred subgroup will be compounds of formula (A) and their (1)-acid isomers and the compounds' esters and pharmaceutical salts.

Yet another subgroup when the substances are to be used medicinally are compounds of formula (A) and (1)-acid isomers of formula (A), as well as their esters and pharmaceutical salts where R and R"<*>" both denote hydrogen.

According to the present invention, the above-mentioned compounds of formula (A) are prepared by following one or more of the following steps:

a) condenses a compound of formula:

where R has the meaning as previously indicated and R 2 denotes a

C^_4~alkyl or α-phenyl ester, with an amide of the formula: where R<1> has the meaning as previously indicated, for the preparation of corresponding compounds of the formula:

1 2

where R, R and R have meanings as previously indicated,

2 2

b) hydrolyzes the alkyl ester group COOR , where R has the above meaning, to form the free acid with

formula (A),

c) cleaves the free acids of formula (A) into the corresponding respective (1)-acid isomers and (d)-acid isomers, d) racemizes (d)-acid isomers or their salts to the corresponding respective compounds of formula (A), e ) optionally esterifies the carboxylic acid group to -COOR 2 , where R 2 has the above-mentioned meaning in compounds of formula (A) or in their (1)-acid isomers or (d)-acid isomers or converts each of them into pharmaceutical non-toxic salts, f) converts salts of formula (A) and separate isomers thereof into corresponding free acids. The (d)-acid isomer with formula (A) and the aforementioned esters and pharmaceutical salts are suitable as intermediates for the production of (dl)-acid with formula (A) as described in more detail below.

The preparation of the new (dl) compounds of formula (A) can be illustrated by means of the following reaction nucleus:

1 2

where R, R and R have the above meaning.

In the practical implementation of the specified method for the preparation of compounds of formula (IV) where R denotes hydrogen, equimolar amounts of ethanolamine (I) and dimethyl-1,3-acetone dicarboxylate (II) are reacted at a temperature of about 0°C to room temperature , and readily forms a solution of the vinylamine of formula (III), which is then treated, preferably in situ, in a suitable inert organic solvent and under anhydrous conditions, with 2-bromoacetaldehyde or 2-chloroacetaldehyde at 40-100°C during of a reaction time of 30 minutes to 16 hours. Suitable solvents

• are aprotic solvents such as acetonitrile, tetrahydrofuran, dimethoxyethane, chloroform, dichloromethane and the like. In preferred embodiments, the reaction is carried out in acetonitrile solution at reflux temperature for approx. 1 hour. 2-Bromo-(chloro)-acetaldehyde reagents are known compounds or can be prepared by pyrolysis of corresponding diethyl acetals in the presence of oxalic acid dihydrate. For the preparation of compounds of formula (IV) where R denotes alkyl with 1-4 C atoms, an aqueous mixture of ethanolamine (I) and dimethyl-1,3-acetone dicarboxylate (II) is treated with a compound of formula

where X denotes bromine or chlorine and R 3 is lower alkyl, preferably straight-chain alkyl with 1-4 C atoms, and preferably again 1-bromoacetone, l-bromo-2-butanone, l-bromo-2-pentanone and l-bromo -2-hexanone, at 40-100°C for 30 minutes to 16 hours. In a preferred embodiment, the reaction is carried out at between -10°C and room temperature over a reaction time of 1

hour to 6 hours.

O

The R 3 -C"-Cf^X reagents are known compounds.

Esterification of the compound (IV) with methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine, pyridine and the like, optionally in the presence of an auxiliary solvent such as dichloromethane, at approx. -10°C to room temperature, within 10 minutes to 2 hours, forms the corresponding mesylate of compound (V), which is converted to the corresponding N-(2-iodoethyl)pyrrole of formula (VI) by reaction with sodium iodide in acetonitrile - solution at reflux temperature over 1-10 hours.

By reacting iodomethyl compounds of formula (VI) with sodium hydride in a suitable organic solvent such as dimethylformamide, dimethyl-1,2-dihydro-3H-pyrrole(1,2-a)-pyrrole-1,7-dicarboxylate and their 6- alkyl substituted derivatives (VII). This ring closure is carried out under an inert atmosphere, e.g. argon or nitrogen, at 15-40° C over a reaction time of 15 minutes to 4 hours. The best results are obtained at room temperature, above approx. 30 minute reaction time and where R denotes hydrogen.

Alternatively, compounds of formula (VII) can be prepared by direct ring closure of the mesylate (V) with sodium hydride in dimethylformamide, at approx. -10°C to room temperature, over a reaction time of 30 minutes to 2 hours.

Base hydrolysis of a compound of formula (VII) with an alkali metal hydroxide or alkali metal carbonate, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like in an aqueous lower aliphatic alcohol such as methanol or ethanol, at a temperature between room temperature and reflux temperature, over a period of 4-24 hours, gives the corresponding free diacid of formula (VIII), i.e. 1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1,7-dicarboxylic acid, and their 6-alkyl derivatives. The hydrolysis is preferably carried out with aqueous methanolic potassium hydroxide at a reflux temperature above approx. 10 hours.

The carboxylic acid group in the C-1 position in compound (VIII) is then selectively esterified by treatment with a lower aliphatic alcohol of 1-4 carbon atoms, in the presence of hydrogen chloride, which gives the corresponding alkyl-1,2-dihydro-3H-pyrrolo(1, 2-a)-pyrrole-1-carboxylate-7-carboxylic acid of formula (IX). The reaction is carried out at 0-50°C within 1-4 hours.

Decarboxylation of the monoesterified compound (IX) to the corresponding compound of formula (X), which are the key intermediates for the preparation of compounds of formula (A), occurs by heating (IX) at an elevated temperature of 230-280°C in sufficient time to complete the reaction. The course of the reaction can be followed by the evolution of carbon dioxide and thin-layer chromatographic analysis, and the decarboxylation is usually completed within 45-90 minutes. The reaction product, namely C 4 -alkyl or α-phenylethyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylate and their 6-alkyl derivatives (X) can be purified by chromatographic techniques. Alternatively, and particularly for the decarboxylation of small amounts 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:

where R"<*>" has the previously stated meaning, gives the corresponding alkyl 5-aroyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylate (XI). This reaction is carried out in an inert aprotic solvent and in the presence of phosphorus oxychloride at reflux temperature and over 1-175 hours, under an inert atmosphere, followed by further refluxing in the presence of sodium acetate for 2-10 hours. Alternatively, other acid chlorides such as phosgene or oxalyl chloride can be used instead of phosphorus oxychloride.

This condensation is preferably carried out by adding a solution of the compound (X) in a suitable solvent to a refluxing mixture of 1.1-5 mol equivalents of both the desired amide and the phosphorus oxychloride in the same solvent, refluxing the reaction mixture for 6-72 hours under argon atmosphere and then add 3-10 mole equivalents of sodium acetate, followed by further refluxing for 4-6 hours.

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

Said amides are known available compounds or can be prepared in a known manner from the corresponding acids by conversion to acid chlorides and treatment with dimethylamine.

By alkaline hydrolysis of the alkyl ester group or the α-phenylethyl ester group in compounds of formula (XI), the corresponding free acid of formula (A) is obtained. The hydrolysis usually takes place with 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 such as methanol, ethanol and the like, at a temperature between room temperature and the reflux temperature over 15 minutes to 2 hours, under an inert atmosphere. In preferred embodiments, the hydrolysis takes place with aqueous methanolic potassium carbonate at reflux temperature over 30 minutes.

Compounds of formula (A) can be dissolved according to

known methods in the individual isomers.

The (1)-acid isomer and (d)-acid isomer of compound of formula (A) can be prepared by using known high pressure liquid chromatography (HPLC) on α-phenethyl diastereomeric esters of compounds of formula (A), followed by acid cleavage. Thus, e.g. compounds of formula (A) where R and R"<*>" both denote hydrogen undergo further processing according to the following summoning diagram:

A more detailed description of this procedure can be found in the later example 4.

<1> The free acids of formula (A) can be converted into alkyl esters with 1-4 C atoms or α-phenylethyl ester by known methods, e.g. treatment with (a) the alcohol corresponding to the desired ester, in the presence of a strong mineral acid, (b) ethereal diazo-alkane or (c) the desired alkyl iodide in the presence of lithium carbonate. The (1)-acid isomer can be converted to an alkyl ester

by treatment according to (b) and (c) above.

The derivative salts of compounds of formula (A) and their (1)-acid isomers are prepared by treating these free

acids with a suitable amount of pharmaceutical base. Representa-

tive pharmaceutical bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferric hydroxide, zinc hydroxide, copper hydroxide, manganese hydroxide, aluminum hydroxide, ferric hydroxide, manganese hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glycosamine, methylglucamine, theobrcmine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. The reaction is carried out in water, alone or in combination with an inert water-miscible organic solvent at 0-100°C, preferably at room temperature. Typical inert, water-miscible organic solvents are methanol,

ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio between the compound of formula (A) or the (1) acid isomer in relation to the base is chosen so that the desired ratio is obtained for a particular salt. Produced e.g. the calcium or magnesium salt of compounds of formula (A) or their (1)-acid isomers, the free acid starting material can be treated with at least half a molar equivalent of a pharmaceutically usable base to form a neutral salt. When aluminum salts of compounds of formula (A) or their (1)-acid isomers are prepared, at least one-third molar equivalent pharmaceutical base is used to prepare a neutral salt product.

In a preferred method, the calcium salt and the magnesium salt of compounds of formula (A) and their (1) acid isomers can be prepared by treating the corresponding sodium or potassium salts with at least half a mole equivalent of calcium chloride or magnesium chloride, respectively, in aqueous solution, alone or together with an inert, water-miscible organic solvent, at 20-100°C. Preferably, aluminum salts of the compounds can be prepared by treating the corresponding free acids with at least one-third mole equivalent of aluminum alkoxide, for example aluminum trioxide, aluminum triproxide and the like, in a hydrocarbon solvent such as benzene, xylene, cyclohexane and the like at a temperature of between 20 and 115°C. Similar methods can be used to prepare salts of inorganic bases which are not sufficiently soluble to readily react.

It is noted that isolation of the described compounds can take place if desired by any suitable separation or purification process such as e.g. extraction, filtration, evaporation, distillation, crystallization, thin layer chromatography or column chromatography, high pressure liquid chromatography or a combination of these processes. Illustrations of suitable separation and isolation processes will be the following examples. Other and equivalent separation and isolation methods could of course also have been used.

Although (d)-acid isomers are not used as drugs per se, they can, if desired, be converted to pharmaceutical, non-toxic esters and their salts according to the same methods described for the conversion of (1)-acid isomers to pharmaceutical non-toxic esters and salts.

Compounds of formula (A) and their (1) acid isomers, as well as pharmaceutical non-toxic esters and salts, are useful as anti-inflammatory and analgesic agents, antiplatelet agents, fibrinolytic agents and as smooth muscle relaxants. The compounds can be used both as preventive and curative agents.

Preparations containing these compounds are thus useful in the treatment of inflammation, e.g. in musculoskeletal systems, in joints and other tissues, e.g. in the treatment of inflammatory conditions such as rheumatism, shock, external wounds, joint inflammation, broken bones, post-rheumatic conditions and gouty fever. When the above-mentioned conditions are associated with pain and fever in connection with inflammation, the compounds produced are useful for eliminating these conditions, as well as the inflammation.

Compounds of formula (A) and their (1) acid isomers, as well as non-toxic pharmaceutical esters and salts described above, also act as muscle relaxants for the smooth muscle tissue of the uterus and are therefore suitable agents to help the mother retain the fetus, beneficial for the mother and/or the foetus, until the gestation period is deemed to be over from a medical point of view or is more favorable for the mother and/or the foetus. However, it is mentioned that in certain cases, e.g. where labor has already begun (where the mother is undergoing contractions of the uterus, especially close to full term), that administration of the compounds in question will possibly not maintain the pregnancy for a longer period of time. In these cases, the pregnancy will probably be extended somewhat instead, a factor that can be beneficial for the mother and/or the foetus.

In particular, compounds of formula (A) and their (1)-acid isomers, as well as the pharmaceutical, non-toxic esters and salts, are used as medicines for delaying the onset of labor or postponing labor. By such "delay" is meant such delay as is obtained by giving compounds of formula (A) or (1) acid isomers or pharmaceutical non-toxic esters and salts at any time before uterine muscle contractions have begun. The expressions used must therefore cover the prevention of abortion during early pregnancy (ie before the fetus is "viable"), as well as the postponement or delay of premature birth. In all cases, the appropriate means are given as preventive measures, as such administration will prevent the birth from occurring. Such administration is particularly useful in the treatment of women with previous spontaneous abortions, miscarriages or premature births. Administration of the compounds in question will also be appropriate when there are clinical indications that the pregnancy will be able to be terminated before full term and one pre-

otherwise it is assumed to be beneficial for the mother and/or the foetus.

With regard to animals, the treatment can also be used to synchronize the birth within a group of pregnant animals, so that birth will occur at or around the desired time and/or place, where the births can be handled more easily.

By expressions such as "delayed" or "delayed" birth is meant here a delayed birth due to the administration of compounds of formula (A) or their (1)-acid isomers or pharmaceutical, non-toxic esters and salts after muscle contractions in the uterus have begun . The patient's condition, including the time within the pregnancy when the contractions have begun, the degree of these contractions and how long the contractions have taken place will affect the results obtained by administration of the compounds in question. E.g. the effect may be a reduction in the intensity and/or duration of the contractions (the actual labor is "prolonged"), or the contractions stop altogether. In all cases, the effect will be to extend the pregnancy period, although, depending on the above-mentioned conditions, the effect may be small or, under other circumstances, somewhat greater. The preparations can therefore be given to prevent spontaneous abortion, to simplify the birth and make it less painful for the mother or for it to take place at a more suitable time or place.

In all cases, the administration of compounds of formula (A) or their (1)-acid isomers or pharmaceutical non-toxic esters and salts for the indicated purpose should follow best and/or accepted medical (veterinary) practice so as to achieve the best results for the mother and the fetus. E.g. you should not give the compounds in question for so long over full term that the fetus dies in the womb.

The following examples illustrate the invention. Abbreviation e.g. refers to thin-layer chromatography, and all mixing ratios with regard to liquids apply to volume ratios. Where nothing else is stated, the reactions are carried out at room temperature (20-30°C).

The following embodiments illustrate the production of output connections.

Production 1

A 250 ml 3-neck round-bottomed flask with a magnetic stirrer and fitted with a calcium chloride-filled drying tube is connected directly through a transition and a short water cooler (4.5 cm) to an acetal pyrolysis apparatus. This apparatus consists of a 100 ml round-bottom flask (charged with 15.6 g of oxalic acid dihydrate and 11.82 g of bromoacetal-hyddiethyl acetal, prepared from vinyl acetate as described by P.Z. Bedoukian, J. Am. Chem. Soc. 66, 651 (1944)) fitted with a 15 cm "Vigreux" column and provided with a thermometer, connected to the above cooler.

The 3-neck flask is filled with 3.36 g of ethanolamine cooled in an ice bath at 0-10°C and treated dropwise with stirring with 8.7 g of dimethyl 1,3-acetone dicarboxylate. Methyl 3-carbomethoxymethyl-3(2'-hydroxyethyl)aminoacrylate (III) is formed immediately. After the final addition, the ice bath is removed and 100 ml of dry acetonitrile is added. The pyrolysis part of the apparatus is placed in an oil bath and its temperature is increased to 150-160°C. The bromoacetaldehyde solution formed is distilled (bp. 80-83°C/580 mm) directly into the magnetically stirred solution of vinylamine (III). After the distillation temperature has fallen below 80°C, the pyrolysis apparatus is disconnected and replaced with a reflux cooler equipped with drying tubes filled with calcium chloride. The solution is heated at reflux temperature for 1 hour, the solvent is removed under reduced pressure and 200 ml of methanol and 20 g of silicon dioxide gel are added to the evaporation residue. The mixture is evaporated to dryness in vacuo and poured onto a column of 200 g of silica gel in equilibrium with hexane. The column is eluted with hexane:ethyl acetate (80:20, 500 ml) and hexane:ethyl acetate

(1:1, 9 x 500 ml). Fractions 2 and 3 contain less

polar pollutants and dimethyl 1,3-acetone dicarboxylate,

fractions 4-8 give 4.1 g of methyl N-(2-hydroxyethyl)-3-carbo--ethoxypyrrole-2-acetate (IV,' R=H), which upon recrystallization from ether-hexane has a melting point of 52-54° C.

Manufacturing 2

To a stirred solution of 4.1 g of methyl N-(2-hydroxyethyl)-3-carbomethoxypyrrole-2-acetate in 35 ml of dry dichloromethane cooled to -10°C is added 2.65 ml of triethylamine and then dropwise 1, 46 ml of methanesulfonyl chloride, keeping the temperature from -10°C to -5°C. The course of the reaction is followed by e.g. analysis with chloroform:acetone (90:10). After the reaction has ended (approx. 30 minutes after the finished addition of methanesulfonyl chloride), slowly add 10 ml of water. It

the organic phase is separated, washed with water (3 x 30 ml), dried over sodium sulphate and evaporated under reduced pressure.

Crystallization of the evaporation residue from dichloromethane hexane gives 4.75 g (77.7%) of methyl N-(2-mesyloxyethyl)-3-carbomethoxy-pyrrole-2-acetate (V, R=H), m.p. 99-101°C.

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

Manufacturing 4

) 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 with 137 mg of 50% sodium hydride in mineral oil. The reaction mixture is kept for 30 minutes at room temperature

and poured into 100 ml of water. The product is extracted with ethyl acetate (3 x 50 ml), the combined extracts are washed with water, dried over magnesium sulphate and evaporated to dryness. Chromatography of the residue on 20 g of silica gel with hexane:ethyl acetate (4:1) as eluent gives 500 mg (80%)

dimethyl 1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1,7-dicarboxylate (VII, R=H), m.p. 70-71°C.

A solution of 1.80 g of dimethyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1,7-dicarboxylate in 20 ml of methanol is treated with a solution of 4.48 g of potassium hydroxide in 20 ml water and the reaction mixture is refluxed for 6 hours. The cooled solution is evaporated to dryness and the residue is treated with 50 ml of saturated sodium chloride solution. The resulting solution is acidified with 6N hydrochloric acid and extracted with ethyl acetate

(3 x 50 ml). The combined extracts are dried over magnesium sulfate 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), m.p. 220°C (decomp.).

Manufacturing 5

A solution of 1.34 g of 1,2-dihydro-3H-pyrrolo-(1,2-a)-pyrrole-1,7-dicarboxylic acid in 50 ml of isopropanol, cooled in an ice bath, saturated with gaseous hydrogen chloride while maintaining 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 and evaporated to dryness under reduced pressure, 10 ml of benzene is added and the solution is evaporated again to vacuum, repeating the process three times in total to completely remove the excess of hydrogen chloride, this gives 1.58 g (96%) isopropyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrroic-1-carboxylate-7-carboxylic acid (IX, R=H, R 2 =iC^ Uj), which upon crystallization from methanol-ethyl acetate has a melting point of 144-145°C.

Manufacturing 6

1.054 g of isopropyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylate-7-carboxylic acid is heated to 240-250°C in a dry 10 ml round flask, distilling the reaction product directly from the flask. 745 mg (87°) of isopropyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylate (X, R=H, R 2 =±C^ ti^) are obtained, a pale yellow oil, with the following physical data: U.V.: xMe?H = 215 nm (e6020); I.R.: = 1725 cm 1; max. max.

mr in N.M.R.: 3 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).

Manufacturing 7

A 100 ml 3-necked round-bottomed flask equipped with a condenser, nitrogen introduction tube and glass bubbler tube is filled with 5.0 g of isopropyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylate-7-carbox- syllic acid. The apparatus is thoroughly flushed with nitrogen and the nitrogen flow is stopped. The apparatus is immersed in an oil bath at 270°C and the reaction is followed by the evolution of carbon dioxide (gas bubbles) and by thin-layer chromatogram on silica gel with benzene:dioxane:acetic acid (90:10:1) as eluent. After 45 minutes the reaction is almost complete. After 1 hour, the container is removed from the oil bath and the contents of the reaction container are transferred to a round-necked flask with 500 ml of acetone. The solvent is removed under reduced pressure and the residue is purified by column chromatography on 100 g of silica gel. The fractions eluted with hexane:benzene (70:30) and hexane:benzene (50:50) give 2.77 g (68%) of isopropyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole -1-carboxylate (X, R=H, R 2=iC3H7),

an oil whose physical constants are identical to the data given in preparation 5.

The following examples illustrate the invention.

Example 1

a) 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 boiled at

reflux for 30 minutes. A solution of 19 3 mg of isopropyl-1,2-dihydro-3H-pyrrolo-(1,2-a)-pyrrole-1-carboxylate in 2 ml of 1,2-dichloroethane is added to the solution. The reaction mixture is refluxed under an argon atmosphere for 8 hours, treated with 405 mg of sodium acetate and refluxed for 5 hours. The resulting mixture is evaporated to

dryness and the residue is chromatographed on 12 g of silica gel, eluting with hexane:ethyl acetate (3:1), and 208 mg (66%) of isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo(1, 2-a)-pyrrole-l-carboxylate (XI, R=H, R 1 =p-CH.j, R 2 =±0^^) , which is an oil with the following physical properties: U.V.: XMe?H 256 , 312 nm, (e 8700, 19500); I.R.: vfl.ch 1735, max. max.

-1 CDC1

1620, 1605 cm ; N.M.R.: ^MS 3 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=4Hz, 1H), 7.10 (d, J=8 Hz, 2H), 7 .60 ppm. (d, J=8 Hz, 2H).

Isopropyl 5-(-(p-ethoxybenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, m.p. 94-95°C,

isopropyl 5-(p-chlorobenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, m.p. 80.5-81°C,

isopropyl 5-(p-fluorobenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, m.p. 72-72.5°C,

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-dihydro-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.

b) 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

treated with a solution of 690 mg of potassium carbonate in 5 ml of water. The reaction mixture is boiled under reflux

nitrogen for 30 minutes, cool and evaporate to dryness. The evaporation residue is dissolved in 10 ml of 10% aqueous hydrochloric acid and

50 ml of water and the mixture is extracted with ethyl acetate (2 x

50 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the evaporation 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 , R1=p-CH3), m.p. 182-183°C.

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 of sodium hydroxide in 1 ml of water while keeping the reaction mixture at room temperature for 1.5 hours. The methanol is removed under reduced pressure and the remaining basic solution is diluted with 5 ml of water and extracted with ether to remove unsaponifiable products. 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, giving 5-p-toluoyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylic acid, identical with the product from example 1 above.

Example 3

The procedure from example 1 is repeated with 1.1 to 5 molar equivalents of N,N-dimethylbenzamide,

N,N-dimethyl-o-toluamide,

N,N-dimethyl-m-toluamide,

N,N-dimethyl-p-methoxybenzamide,

N,N-dimethyl-p-ethoxybenzamide,

N,N-dimethyl-o-chlorobenzamide,

N,N-dimethyl-m-chlorobenzamide,

N,N-dimethyl-p-chlorobenzamide,

N,N-dimethyl-o-fluorobenzamide,

N,N-dimethyl-p-fluorobenzamide,

N,N-dimethyl-m-bromobenzamide and

N,N-dimethyl-o-bromobenzamide,

instead of N,N-dimethyl-p-toluamide, and follows the course of the reaction at t.s.c., and then obtain respectively: isopropyl-5-benzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole- l-carboxylate, pale yellow oil, the following physical constants: U.V.: ^aks 245 , 311 nm (e 7230' 17800^ I«R- vmax3 1735' -1 CDC1 1620 cm ; N.M.R.: ^^MS 1.24 [d' 6H ' (CH 3 ) 2 CH]' 2'50-3'13 (m, 2H; H-2); 3.97 (dd, 1H, H-1), 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-6), 7.10-7.9 0 ppm (m, 5H, phenyl protons); MS.: m/e 297 (M<+>), isopropyl-5-o-toluoyl-1,2-dihydro-3H-pyrrolo(1,2-a) - pyrrole-1-carboxylate, an oil, with the following physical data: U.V.: ^aks 252, 303 nm (e 4460, 19100); I.R.: v^^3 173<5,>

1620 cm"<1>; N.M.R.: 6^3 [d' 6H' (CH3>2CH]' 2.28

(s, 3H-, o-ch3), 2.50-3.13 (m, 2H, H-2), 3.92 (dd, 1H, H-1), 4.17-4.70 (m, 2H , H-3), 4.98 [Sept. 1H, (CH 3 ) 2 CH], 5.92

(d, 1H, H-7), 6.43 (d, 1H, 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, with the following physical data:

MeOH

U.V.: \^ aks 250~251' 310-312 nm (e 6460, 17400); I.R.: vmax3 1735' 1620 cm<_1>; N.M.R.: ^MS<1>3 1/25 [d, 6H,

(CH3)2CH], 2.27 (s, 3H, CH3), 2.52-3.13 (m, 2H, H-2),

3.92 (dd, 1H, H-1), 4.13-4.70 (m, 2H, H-3), 4.95 [sept. 1H, (CH 3 ) 2 CH], 5.95 (d, 1H, H-7), 6.67 (d, 1H, H-6), 7.03-7.57 ppm. (m, 4H; phenyl protons),

isopropyl-5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylate with the following physical constants: U.V.: ^ax 218, 270-284 (shoulder), 314 nm (e 9780, 9320, 22400); I.R.: \^£s3 1730' 1605 cm~1 > N.M.R. ^g1^ 1.24 (d, 6H, J=6 Hz; (CH3)2CH-), 2.50-3.10 (m, 2H; H-2), 3.78 (s, 3H; CH3O) , 3.93 (dd, 1H, JAX=6 Hz, JgX<=7> Hz; H-l), 4.13-4.60 (m, 2H; H-3), 4.95 [Sept., 1H, J=6 Hz; (CH3)2CH], 5.95 (s, 1H, J=4 Hz; H-7), 6.68 (d, 1H, J=4 Hz; H-6), 6.70-7.90 ppm . (m, 4H; phenyl protons); M.S. m/e 327 (M<+>). isopropyl 5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylate, m.p. 94-95°C, isopropyl-5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylate, an oil, with the following physical constants: U.V.: xMe°H 251, 306 nm (e 5750, 16600); I.R.: vCH.C13 1735, . max. max.

-1 CDC1

1625 cm; N.M.R. : 6^ 3 1.22 [d, 6H, (CH 3 ) 2 CH] , 2.55-3.05

(m, 2H; H-2), 3.97 (dd, 1H, H-1), 4.17-4.70 (m, 2H, H-3), 4.97 [sept., 1H, (CH ) 2CH], [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-carboxylate, oil, with the following physical constants: U.V.: 241, 313 nm (e 6600, 15100) ; I.R.: v™£*3 1735 ,

-1 CDC]

1620, 1570 cm; N.M.R.: 3 1.27 [d, 6H, (CH3)2CH] ,

2.50-3.18 (m, 2H, H-2), 3.93 (dd, 1H, H-1), 4.10-4.63 (rn, 2H,

22

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); M.S.: m/e 331-333 (M<+>),

isopropyl 5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylate, m.p. 80.5-81°C,

isopropyl 5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylate, m.p. 72-72.5°C,

isopropyl-5-p-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo(1,2-a)pyrrole-1-carboxylate with the following physical constants: Amax. 250 , 315 nm (e 6170, 14.100); I.R. v^^3 1734,

1605, 1593 cm ; N.M.R. 3 1.25 (d, 6H, J=6 Hz; ester CH3), 1.83 (s, 3H; ring-CH3), 2.49-3.00 (m, 2H; CH2), 3.90 ( t, 1H, EJ=7.4 Hz; CHCO), 4.10-4.23 (m, 2H; N-CH2), 4.98 (sept. 1H, J=6 Hz; ester-CH), 5 .84 (s, 1H, H-3), 7.00 (h,

2H, JQrto=8.4 Hz, JHF=8 HZ; H-3',5'), 7.55 (q, 2H, Jorto<= >8.4 Hz, JHp=5.5 Hz; H-2.6<1>); M.S. w/e 1%

329 25 M+

242 100 M -CO 2 CH(CH 3 ) 2

123 .36 F-C,H,CO.

6 4

By hydrolysis of the isopropyl ester group according to example

1 or 2, the corresponding free acids are obtained, namely: 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, an oil, with the following physical properties: Amax. 253' 307 nm (£ 3310' 16980); J-R-: Vmax3 1720'

1620 cm"<1>; N.M.R. : 6^ 3 <2>'32 (s'3H' CH3> > 2.53-3.03

TMS

(m, 2H, H-2), 3.97 (dd, 1H, H-1), 4.17-4.67 (m, 2H, H-3), 6.92 (d, 1H, H-7) , 6.40 (d, 1H, H-6), 6.83-7.37 (m, 4H, phenyl protons), 8.60 ppm. (b.s., 1H, COOH),

5-p-Methoxybenzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 187-187.5°C,

5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 169.5-170°C,

5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrcl-1-carboxylic acid, with the following physical data: U.V.: 250, 307.5 nm (e 4360, 17400); I.R.: 1715,

-1 CDC1

1620 cm; N.M.R.: ^MS 3 2.60-3.15 (m, 2H; H-2), 4.02

(dd, 1H, JAX=6 Hz, JBX=7 Hz; H-1), 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 protons) , 8.67 ppm [s, (br), 1H; COOH],

5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 180-181°C,

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,

5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 179.5-180.5°C.

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, 0.58 g of trifluoroacetic anhydride is added. 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 triethylamine is added, followed immediately by 0.5 g of (1)-α-phenylethyl alcohol. The resulting solution 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 sulphate, after which the solvent and excess of (1)-α-phenylethyl alcohol are removed under vacuum to 0.42 g of a mixture of (1)-5-benzoyl-1,2-dihydro-3H-pyrrolo (1,2-a)pyrrole-l-carboxylic acid-(1)-a-phenethyl ester and (d)-5-benzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-l-car -carboxylic acid-(1)-a)-phenethyl ester which is separated by high pressure liquid chromatography (with 4% EtOAc/hexane on 11 mm x 50 cm 10 µm, "Lichrosord Sl-60" column) to give 180 mg of a more polar ester (α^<e0H> -145.7°) and 178 mg of a less polar ester (α^<e0H> + 128.6°).

148 mg of the higher ester are dissolved in 8 ml of dry benzene. The solution is cooled to 15-20°C and 5 ml of trifluoroacetic acid is added, after which the solution is stirred at room temperature for 1 hour and 10 minutes. The reaction mixture is poured into 60

ml of dry benzene and the solvents are removed in vacuo at room temperature. It is purified by high-pressure liquid chromatography (with the above column except that 35% EtOAc/hexane in 1/2% acetic acid is used instead of 4% EtOAc/hexane), which gives 63 mg of (1)-5-benzoyl-1,2- dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylic acid with α^^"^ -153.7°, and a melting point of 153-155°C.

Similarly, cleavage of the less polar ester according to the above method for cleavage of the highly polar ester gives 85 mg of (d)-5-benzoyl-1,2-dihydro-3H-pyrrolo-(1,2-a) pyrrole-l-carboxylic acid with a^<HC>''"3 + 155.1°, and melting point 154-156°C. The produced (d)-acid isomer can, if desired, be racemized (and recycled) according to known methods.

In a similar way, other (dl) compounds can be resolved into the respective (1) and (d) isomers.

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 nitrogen for 30 minutes, cooled and evaporated to dryness. The evaporation residue is dissolved 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 give 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo(1,2-a)pyrrole-1-carboxylic acid,

m.p. 187°C.

Example 6

A solution of 200 mg of 5-p-ethoxy-benzoyl-l,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-l-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ethereal diazoisopropane and. the reaction mixture is kept at room temperature for 30 minutes. Solvent and excess reagent are removed under reduced pressure and the evaporation residue is crystallized from ethyl acetate-methanol to give isopropyl-5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylate, m.p. 94-95°C.

Example 7

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 isopropyl alcohol is saturated with hydrogen chloride. After 24 hours, the excess alcohol is distilled off in vacuo and the evaporation residue is purified by chromatography on aluminum oxide to give isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylate.

26

Example 8

A solution of 770 mg of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylic acid in 10 ml of benzene is treated with 580 mg of dicyclohexylamine. The reaction mixture is stirred for 10 minutes and the solid formed is filtered off and washed with anhydrous ether, yielding 965 mg of the dicyclohexylamine salt of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole -1-carboxylic acid, m.p. 161-163°C.

In a similar way, the other free acids from example 3

(and 4) and the compounds from example 1b) and 5 are converted to the corresponding dicyclohexylamine salt, e.g. The dicyclohexylamine salt of 5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 173-175°C.

Example 9

A solution of 200 mg of d-5-benzoyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylic acid is dissolved in 50 ml of ethanol/water and brought to a boil. 2 ml of concentrated hydrochloric acid are then added and the mixture is refluxed for 30 minutes. The resulting (dl)-5-benzoyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylic acid, m.p. 160-161°C is isolated in the conventional way.

In the same way, other d-carboxylic acids are racemized so that the following dl-compounds with formula (A) are obtained: 5-p-toloyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylic acid, m.p. 182-183°C,

5-o-toloy1-1,2-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, m.p. 180-181°C,

5-(4-chlorobenzoyl)-1,2-dihydro-3H-pyrrolo(1,2-a)-

pyrrole-l-carboxylic acid, m.p. 201.5-202.5°C,

5-(4-fluorobenzoyl)-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 179.5-180.5°C,

5-p-toloyl-6-methyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 187°C,

5-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 169°C,

5-(4-Methoxybenzoyl)-6-methyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylic acid, m.p. 182°C,

5-(4-Chlorobenzoyl)-6-methyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylic acid, m.p. 204°C,

6-propyl-6-methyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 172°C, and

5-(4-Fluorobenzoyl)-6-ethyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylic acid, m.p. 196°C.

Example 10

Dissolve 100 mg of sodium 5-benzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylate in 50 ml of water. 10 ml of concentrated hydrochloric acid are added while stirring at room temperature. The aqueous solution is then extracted with 2 x 50 ml portions of ethyl acetate, the organic extracts are combined and dried and evaporated. The product, 5-benzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylic acid, is then recrystallized from ethanol ether, m.p. 160-161°C.

In a similar manner, other salts of compounds of formula

(A) is hydrolyzed to obtain the following: 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-3K-pyrrolo (1,2-a)-

pyrrole-l-carboxylic acid, m.p. 180-181°C,

5-(4-chlorobenzoyl)-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 201.5-202.5°C,

5-(4-Fluorobenzoyl)-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 179.5-180.5°C,

5-p-toluoyl-6-methyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 187°C,

5-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 169°C,

5-(4-Methoxybenzoyl)-6-methyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylic acid, m.p. 182°C,

5-(4-chlorobenzoyl)-6-methyl-1,2-dihydro~3H-pyrrolo-(1,2-a)pyrrole-1-carboxylic acid, m.p. 204°C,

6-propyl-6-methyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, m.p. 172°C, and

5-(4-Fluorobenzoyl)-6-ethyl-1,2-dihydro-3H-pyrrolo-(1,2-a)pyrrole-1-carboxylic acid, m.p. 196°C.

Biological data

A. Analgesic effect on mice (anti-pain writhing)

Procedure: The test compound is given orally by force-feeding in an aqueous mixing medium at time 0 to 18-20 g white male Webster mice. 20 minutes later, 0.25 ml of a 0.02% solution of phenylquinone is injected intraperitoneally. This solution induces pain twisting. The animals are observed during the next 10 minutes to find pain contractions.

End point: Total number of mice that have pain contortions and average number of such pain contortions per mouse.

Based on the above procedure, it is found that 5-benzoyl-1,2-dihydro-3H-pyrrolo (1,2-a)-pyrrole-1-carboxylic acid has about 430 times the pain-relieving effect of aspirin; and (1)-5-(benzoyl)-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylic acid has about 700 times the analgesic effect of aspirin.

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

Process: The test compound is suspended in aqueous carboxymethylcellulose as a carrier medium. The concentrations are set so that doses of 10 ml/kg body weight can be given

weight. Five groups (consisting of six white male Webster mice in each group) are used. A single oral dose of

200 mg, 400 mg, 800 mg, or 1200 mg 5-(benzoyl)-1,2-dihydro-3H-pyrrolo (1,2-a)pyrrole-1-carboxylic acid per kg body weight is given by gastric tube per animals. (The fifth group is used as a control group.) After administration, the mice are observed over three weeks. One determines the acute oral LDr, for

50 5-(benzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carboxylic acid and this turns out to be around 200 mg/kg.

Claims (1)

Analogous method for the preparation of therapeutically active compounds of the formula: or separate (1)-acid isomers or (d)-acid isomers and C1-4-alkyl or α-phenylethyl esters thereof, as well as their pharmaceutical, non-toxic salts, where R denotes hydrogen or lower alkyl with 1-4 carbon atoms, and R denotes hydrogen, lower alkyl with 1-4 carbon atoms, lower alkoxy with 1-4 carbon atoms, chlorine, fluorine or bromine, and where the R^" substituent is in the ortho-, meta- or para-position on the benzoyl group, characterized by follows one or more of the following steps: a) condenses a compound of formula: where R has the meaning as previously indicated and R 2 denotes a C^_^-alkyl or α-phenylethyl ester, with et. amide with the formula: where R<1> has the meaning as previously indicated, for the preparation of corresponding compounds with the formula: 1 2 where R, R and R have the meaning as previously indicated, 2 2 b) hydrolyzes the alkyl ester group -COOR, where R has the above meaning, to form the free acid with formula (A), c) cleaves the free acids with formula ( A) in the corresponding respective (1)-acid isomers and (d)-acid isomers, d) racemize (d)-acid isomers or their salts to the corresponding respective compounds of formula (A), e) optionally esterify the carboxylic acid group to -COOR 2, where R 2 has the above meaning in compounds of formula (A) or in their (1)-acid isomers or (d)-acid isomers or converts each of them into pharmaceutical non-toxic salts, f) converts salts of formula (A) qg separate isomers of these to corresponding free acids.