NO147563B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 5- (2-FUROYL, 5- (2-TENOYL) -, 5- (3-FUROYL) - AND 5- (3-TENOYL) -1,2-DIHYDRO-3H-PYRROLO ( 1,2-A) pyrrole-1-carboxylic acid derivatives - Google Patents

Description

The present invention relates to the production of new, therapeutically effective pyrrole-1-carboxylic acid derivatives, and more particularly new 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids which are substituted in the C-5 position with a 2-furoyl, 2-thenoyl, 3-furoyl or 3-thenoyl group, and having the formula: or

or their individual (l)-acid and (d)-acid isomers and their lower alkyl esters of 1-3 carbon atoms or ct-phenyl ethyl esters, as well as pharmaceutical non-toxic salts thereof, where X is oxygen or sulphur, R is hydrogen or lower alkyl of 1-4 carbon atoms and R"<*>" is hydrogen, methyl or chlorine.

The compounds in question which are described in more detail below, apart from their (d)-acid isomers and derivatives, have anti-inflammatory, analgesic and antipyretic effects and are therefore suitable in 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 derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganese, aluminum, ferric, manganese salts and the like. Particularly preferred salts are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutical organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine . , polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, pyeridine, tromethamine, choline and caffeine.

The new compounds of formula (A) and (B), as well as the compounds of formula (XI) and (XII) below, exist as pairs of optical isomers (or enantiomorphs), i.e. as a (dl) mixture. However, all optical isomers and (dl) mixtures are covered by the present invention.

When the new substances are to be used to induce a physiological reaction (e.g. anti-inflammatory, analgesic or anti-pyretic effect), a preferred subgroup will be compounds of formula (A) and (B) as well as their (1)- acid isomers, and further mentioned esters and pharmaceutical salts thereof.

A further group are compounds of formula (A) and (1)-acid isomers of formula (A) as well as their aforementioned esters and pharmaceutical salts, and this subgroup can be further divided into two divisions which are constituted by (a) the compound of formula ( A), i.e. the (dl) compound, where R and R both represent hydrogen and X is sulfur and (b) the (1)-acid isomer of formula (B), where R and R1 both represent hydrogen and X represents sulfur , as well as their aforementioned esters and pharmaceutical salts.

The (d)-acid isomer of formula (A) and (B) and their aforementioned esters and pharmaceutical salts are suitable as intermediates for the preparation of (dl)-acids of formula (A) and

(B) as described later.

The compounds (A) and (B.) are produced according to the present invention by one or more of the following steps: a) condensation of a compound with the following: where R has the meaning given above and R 2 is a lower alkyl group with 1-3 carbon atoms or a-phenylethyl ester group, with an amide selected from where R"*" and X have the meanings given above, which gives the corresponding compounds of formula: or

where R and R 2 have the meanings given above,

b) hydrolysis of an alkyl ester group giving the free acid of compounds of formula (A) or (B), c) separation of the free acids of formula (A) or (B) into their corresponding respective (1)-acid isomers and (d)-acid isomers,

d) racemization of (d)-acid isomers or their salts,

to the corresponding respective compounds of formula (A)

or (B),

e) esterification of the carboxylic acid group in compounds of formula (A) or (B) or the (1)-acid isomers or (d)-acid isomers thereof, or converting these into their pharmaceutically acceptable, non-toxic salts , f) conversion of salts of formula (A) or (B) or their individual isomers into the corresponding free acids.

The production of the compounds (A) and (B) can be illustrated with the following reaction core:

1 2

where X, R, R and R have the indicated meaning.

When carrying out 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 approx. 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 30 minutes to 16 hours. Suitable solvents for this reaction are aprotic solvents such as acetonitrile, tetrahydrofuran, dimethoxyethane, chloroform, dichloromethane and the like. In a preferred embodiment, the reaction is carried out in acetonitrile, at reflux temperature and during approx. 1 hour. 2-Bromo-(chloro)-acetalde-hydrogens are known compounds or can be prepared by pyrolysis of the corresponding diethyl acetals in the presence of oxalic acid dihydrate.

For the preparation of compounds of formula (IV) where R denotes lower alkyl with 1-4 C atoms, an aqueous mixture of the ethanolamine (I) and dimethyl-13,3y-acetone dicarboxylate (II) is treated with a compound of formula R -C-CH„Z, where Z denotes bromine or chlorine and R <3> denotes lower alkyl, preferably straight chain and with 1-4 C atoms, and preferably 1-bromoacetone, l-bromo-2-butanone, l-bromo- 2-pentanone or l-bromo-2-hexanone, at 40 - 100°C and during 30 minutes to 16 hours. The reaction temperature is preferably -10°C to room temperature and the time 1-6 hours. The reagents R 3 -C0-CI^Z are known compounds.

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

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

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

Base hydrolysis of a compound of formula (VII) with an alkali metal hydroxide or alkali metal carbonate such as 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 the reflux temperature and over 4-24 hours, it forms the corresponding free diacid of formula (VIII), i.e. 1,2-dihydro-3H-pyrrolot1,2 -a]pyrrole-1,7-dicarboxylic acid and its 6-alkyl derivatives. The hydrolysis is advantageously carried out with methanolic aqueous potassium hydroxide at reflux temperature and above approx. 10 hours.

The carboxylic acid group in the C-1 position in the compound (VIII) is then selectively esterified by treatment with a low aliphatic alcohol such as methanol, ethanol, isopropanol, n-butanol and the like. in the presence of hydrogen chloride, and 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 approx.

0 - approx. 50°C over 1-4 hours.

Decarboxylation of the monoesterified compound (IX) to the corresponding compound of formula (X), which are the crucial intermediates in the present process, is achieved by heating (IX) to an elevated temperature in the range of 230 - 280°C, for a sufficiently long time to complete the reaction. The course of the reaction can be followed by the development of carbon dioxide and thin-layer chromatographic analysis (TLC), as the decarboxylation is usually completed within 45 - 90 minutes. The reaction product, namely alkyl-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylate and its 6-alkyl derivatives (X) can be purified by chromatographic techniques. Optionally, and particularly for the decarboxylation of small amounts of the compound (IX), the reaction product (X) can be distilled directly from the reaction vessel.

Condensation of a compound (X) with an amide formula

where X and R have the indicated meaning, gives the corresponding alkyl-5-substituted-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylate of formula (XI) or (XII), respectively. This reaction is carried out in an inert organic aprotic solvent and in the presence of phosphorus oxychloride at reflux temperature and over 1-72 hours, under an inert atmosphere, followed by further refluxing in 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 pre-boiling mixture of 1.1 - 2 molar equivalents of both the desired amide and phosphorus oxychloride in the same solvent, refluxing this reaction mixture for 2 -30 hours under an argon atmosphere and then add 3-10 molar equivalents of sodium acetate followed by further reflux 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 best solvent is 1,2-dichloroethane.

Representatives of applicable N,N-dimethylamides

is e.g. :

N,N-dimethylfuran-2-carboxamide,

N,N-dimethyl-3-methylthiophene-2-carboxamide, N,N-dimethyl-4-chlorothiophene-2-carboxamide, N,N-dimethylthiophene-3-carboxamide and N,N-dimethylfuran-3-carboxamide.

These amides can be prepared in a known manner from the corresponding thiophene- or furan-2-(3)-carboxylic acids, i.e. by conversion to acid chlorides followed by treatment with dimethylamine.

By alkaline hydrolysis of the alkyl ester group in a compound of formula (XI) or (XII), the corresponding free acids of formula (A) or (B) are obtained, respectively. The hydrolysis is carried out in a known manner with an alkali metal hydroxide ^HÉjfijB^rlkali metal carbonate -such as na^j^^flflHj^HH^^H^^^unhydrok-s^d/ - sodium carbonate, potassium carb^^^^^^^^HHlH^Bi ^aqueous low aliphatic alcohol such as methanol, ethanol dTx., at a temperature of approx. room temperature to the reflux temperature and within 30 minutes - 4 hours under inert atmosphere. In a preferred embodiment, the hydrolysis is carried out with aqueous methanolic potassium hydroxide, at reflux temperature and above approx. 2 hours.

Compounds of formula (A) and (B) can be dissolved according to known methods into the individual isomers. E.g. compounds of formula (A) where R and R"*" both denote hydrogen and X denotes sulfur can undergo further treatment according to the following diagram:

A more detailed description of this procedure can be found in example 2.-

Alternatively, (1)-acid isomers and (d)-acid isomers of compounds of formula (A) and (B) can be obtained by using the known method of high pressure liquid chromatography (HPLC) on a -phenethyl diastereomeric esters of compounds of formula (A) and (B) followed by acid cleavage. E.g. can compounds with formula

(A) where R and R both denote hydrogen and X denotes sulfur undergo further processing according to the following scheme:

A more detailed description of this method can be found in the later example 3.

The free acids of formula (A) and (B) can be converted into the appropriate mentioned esters according to known methods, e.g. by treatment with a) an alcohol corresponding to the desired ester, in the presence of a strong mineral acid, b) ethereal diazoalkane or c) the desired alkyl iodide in the presence of lithium carbonate. (1)-Acid isomers can be converted to their alkyl esters by methods b) and c) above.

Salt derivatives of compounds of formula (A) and (B) and their (1)-acid isomers are prepared by treating these free acids with a suitable amount of pharmaceutically usable base. Examples of pharmaceutical bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferrohydroxide, 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, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. The reaction is carried out in water, alone or in combination with an inert, water-miscible organic solvent, at a temperature of 0 - 100°C, and preferably at room temperature. Typical inert, water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio between compounds of formula (A) or (B) or their (1)-acid isomers and base is chosen so that the desired ratio is obtained for a particular salt E.g. in the preparation of calcium salts or magnesium salts of compounds of formula (A) or (B) or their (1) acid isomers, the free acid may be treated with at least half a molar equivalent of a pharmaceutically acceptable base to form a neutral salt. When the aluminum salt of compounds of formula (A) or (B) or their (1) acid isomers is desired, at least one third molar equivalent of pharmaceutically acceptable base is used if a neutral salt product is desired.

Calcium salts and magnesium salts of compounds of formula (A) and (B) and their (1)-acid isomers can preferably 13

are prepared by treating the corresponding potassium or sodium salts with at least half a molar equivalent of calcium chloride or magnesium chloride, respectively, in aqueous solution, alone or together with an unreactive but water-miscible organic solvent at a temperature of 20 - 100°C. Preferably, aluminum salts of these compounds can be prepared by treating the free acids with at least one-third molar equivalent of aluminum alkoxide such as aluminum trietoxide, aluminum tripropoxide, etc., in a hydrocarbon such as benzene, xylene, cyclohexane, etc. at a temperature of 20 - 115°C. Similar procedures can be used to make salts of inorganic bases which are not sufficiently soluble to give a simple reaction.

It will be understood that isolation of the described compounds can be carried out by any suitable separation or purification method, e.g. by extraction, filtration, evaporation, distillation, crystallization, thin layer chromatography or column chromatography, high pressure liquid chromatography (HPLC) or a combination of two or more of these methods. Examples of suitable separation and isolation processes will appear in the later examples. Other and equivalent separation or isolation methods could also, of course, have been used.

While the (d)-acid isomers are not used as drugs as such, they can, if desired, be converted to pharmaceutical, non-toxic esters and salts in the same manner as described for the (1)-acid isomers.

Compounds of formula (A) and (B) and their (1)-acid isomers as well as pharmaceutical, non-toxic esters and salts, are suitable as anti-inflammatory, analgesic agents, inhibitors of bioplate aggregation, fibrinolytic agents and de- relaxants for the smooth muscle tissue. The compounds can be used both preventively and therapeutically.

Preparations containing these compounds are therefore suitable for the treatment and elimination of inflammation in e.g. the musculoskeletal system, joint tissue, impact wounds, open wounds, arthritis, broken bones, post-traumatic conditions and rheumatic fever. In cases where the above conditions are associated with pain and fever as well as inflammation, the compounds are suitable for removing these conditions and the inflammation.

Administration of the active substances with formula (A) or (B) or their (1)-acid isomers as well as said pharmaceutical, non-toxic esters and salts in suitable pharmaceutical preparations can take place in accepted ways for the treatment of inflammation, pain or fever , or prevention of these.

Compounds of formula (A) and their (1)-acid isomers as well as non-toxic, pharmaceutical mentioned esters and salts described above also act as muscle relaxants for uterine smooth muscle tissue and are therefore suitable agents for helping the mother to retain the foetus, for the benefit of 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 fetus.

In particular, compounds of formula (A) and their (1)-acid isomers as well as pharmaceutical, non-toxic esters and salts mentioned above 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 said esters and salts at any time before the 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 when treating women with previous spontaneous abortions, miscarriages or premature births on the 15th

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

With regard to animals, the treatment can also be used for

to synchronize 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.

With expressions such as "delayed" or "delayed" birth, one means here a delayed birth due to the administration of compounds of formula (A) or their (1)-acid isomers or non-toxic said esters and salts after muscle contractions in the uterus have begun. The patient's condition, i.a. 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 of the intensity and/or duration of the contractions (the actual birth is "prolonged"), or the contractions are stopped completely.■ In all cases, the effect will be to extend the gestation period even if, depending on the above conditions, the effect may be small or, under other conditions, somewhat stronger. The preparations can therefore be used 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 administrations of compounds of formula (A) or their (1)-acid isomers or pharmaceutical, non-toxic said esters and salts for this stated purpose should follow the best and/or accepted medical (veterinary) practice so that achieves 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 relevant compounds can be administered to a pregnant mammal in any known and customary manner. The compounds can be given separately or in combination with other compounds as previously mentioned or other pharmaceutical carrier media etc. Such compounds or preparations can be given orally, parenterally, either in the form of solid, semi-solid or liquid forms.

The following examples illustrate the invention. The abbreviation T.S.K. refers to thin-layer chromatography, and all mixing ratios with respect to liquids apply to volume ratios. Where necessary, examples are repeated to form material for subsequent examples, and where nothing else is indicated, the reactions are carried out at room temperature (20 - 30°C). Preparation of starting materials:

Production 1

A mixture of 23 g of 4-chlorothiophene-2-carboxylic acid

(J. Iriarte et al., J. Heterocyclic Chem. 13, 393) and 80 ml of thionyl chloride are heated to reflux under anhydrous conditions for 4 hours. The excess of thionyl chloride is removed and the residue is distilled under reduced pressure (60°C/2 mm), which yields 18 g of 4-chlorothiophene-2-carboxylic acid chloride.

A solution of 10.5 g of 4-chlorothiophene-2-carboxylic acid chloride in 500 ml of anhydrous benzene is cooled in ice water and dimethylamine is slowly bubbled through for 30 minutes. The ice water is removed and the flow of dimethylamine is continued for 15 minutes. The reaction mixture is diluted with 100 ml of 10% sodium chloride solution and stirred for 5 minutes at room temperature, the organic phase is separated, washed with 10% hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride, dried over sodium sulfate and evaporated to dryness under reduced pressure , giving N,N-dimethyl-4-chlorothiophene-2-carboxamide.

In a similar manner, the thiophene and furan-2-carboxylic acids below under I are converted to the N,N-dimethylamides listed under II:

Manufacturing 2

A 250 mL 3-neck round-bottomed flask with magnetic stirrer is fitted with a calcium chloride drying tube and connected directly (through one of the other bottle necks) to the acetal pyrolysis apparatus via a short (7.5 cm) water cooler. The pyrolysis apparatus consists of a 100 ml round flask (filled with 15.6 g of oxalic acid dihydrate and 11.82 g of bromoacetaldehyde diethyl acetal prepared from vinyl acetate as described by P.Z. Bedoukian, J. Am. Chem. Soc. 66, 651 (1944)), fitted with a 12, 5 cm Vigreux column, fitted with a thermometer, connected to the above condenser.

The three-necked 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)amino-acrylate (III) is immediately formed. After the addition is complete, 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 the temperature is increased to 150 - 160°C. The bromoacetaldehyde solution that forms is distilled off directly (bp. 80 - 83°C/580 mm) into the magnetically stirred solution of the vinylamine (III). When the distillation temperature falls below 80°C, the pyrolysis apparatus is disconnected and replaced with a reflux cooler equipped with a drying tube containing calcium chloride. The solution is heated at reflux temperature for 1 hour, the solvent is removed under reduced pressure and then 200 ml of methanol and 20 g of silicon dioxide gel are added to the residue. The mixture is evaporated to dryness in vacuo and placed on top of a column of 200 g of silica gel in 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 impurities and dimethyl-1,3-acetone dicarboxylate, fractions 4-8 give 4.1 g of methyl-N-(2-hydroxyethyl)-3-carbomethoxypyrrole-2-acetate (IV, R = H),

which on recrystallization from ether-hexane has a melting point equal to 52 - 54°C.

Manufacturing 3

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 while keeping the temperature of the reaction mixture at -10 - -5°C. The course of the reaction is followed by a T.S.K. analysis with chloroform:acetone (90:10). When the reaction appears to have ended (approx. 30 minutes after the addition of the methanesulfonyl chloride), 10 ml of water is slowly added. 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%) methyl-N-(2-mesyloxyethyl)-3-carbomethoxypyrrole-2-acetate (V, R = H), melting point 99 - 101°C .

Manufacturing 4

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 rubbed off with water. The insoluble substance is separated by filtration and dried in air to give 840 mg (97%) of methyl-N-(2-iodoethyl)-3-carbomethoxypyrrole-2-acetate (VI, R = H), melting point 137 - 138°C .

Manufacturing 5

A solution of 1 g of methyl-N-(2-iodoethyl)-3-carbo-methoxypyrrole-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 quenched with 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 evaporation residue on silica gel (20 g) with hexane:ethyl acetate (4:1) as eluent gives 500 mg (80%) of dimethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7 -dikar-

boxylate (VII, R = H), melting point 70 - 71°C.

A solution of 1.80 g of dimethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate in 20 ml of methanol is treated with a solution of 4.48 g of potassium hydroxide in 20 ml of water and the reaction mixture is refluxed for 6 hours. The cooled solution is concentrated 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, yielding 1.51 g (95%) of 1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1,7-dicarboxylic acid (VIII , R = H), melting point 220°C, decomp.

Production 6

A solution of 1.34 g of 1,2-dihydroT3H-pyrrolo-[1,2-a]pyrrole-1,7-dicarboxylic acid in 50 ml of isopropanol, cooled in an ice bath, is saturated with gaseous hydrogen chloride while 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, and concentrated to dryness under reduced pressure, 10

ml of benzene is added and the solution is evaporated again under vacuum, this procedure is repeated a total of three times to completely remove the excess of hydrogen chloride and 1.58 g (96%) of isopropyl-1,2-dihydro-3H-pyrrolo[1, 2-a]pyrrole-1-carboxylate-7-carboxylic acid (IX, R = H, R 2 = iC^H^), which upon crystallization from methanol-ethyl acetate has a melting point of 144 - 145 C. Preparation 7

1.054 g of isopropyl-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylate-7-carboxylic acid is heated to 240 - 250°C

in a dry 10 ml round bottom flask while distilling the reaction product directly from the container. In this way, 745 mg (87%) of isopropyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (X, R = H, R 2 = iC-jH^ ), a pale yellow oil which has the following physical constants: U.V.: A Me°H = 215 nm (e 6020); ■

max

I. R.: u c^^3 = 1725 cm ;

max

CDC1 N.M.R.: 6 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 = 3 Hz, 1H),

6.43-6.53 (m, 1H).

Manufacturing 8

5.0 g of isopropyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate-7-carboxylic acid are added to a 100 ml three-neck round-bottomed flask equipped with a condenser, nitrogen intake tube and gas bubbles. 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 T.S.K, on silicon dioxide gel with benzene:dioxane:acetic acid (90:10:1) as developing agent. After 45 minutes, the reaction is almost complete. After 1 hour, the container is removed from the oil bath and the contents are transferred to a round bottom flask with 500 ml of acetone. The solvent is removed under reduced pressure and the evaporation 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- l-carboxylate (X, R = H, R 2 = iC^I^), which is an oil whose physical constants are identical to those during preparation 7.

Production 9

710 mg of a 50% suspension of sodium hydride in mineral oil is washed with anhydrous hexane under a nitrogen atmosphere and suspended in 50 ml of dimethylformamide. The suspension is cooled to -5°C and 4.5 g of methyl-N-(2-mesyloxymethyl)-3-carbomethoxypyrrole-2-acetate are added while stirring the reaction mixture at -5-0°C for 1 hour. It is then poured into ice-cooled sodium chloride solution and extracted several times with benzene. The combined extracts are washed with water, dried and evaporated to dryness under reduced pressure. The solid residue is crystallized from ether and gives dimethyl-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1,7-dicarboxylate (VII, R = H) identical to the product from preparation 5.

Production 10

A 250 ml three-necked round flask fitted with a magnetic stirrer and a calcium chloride-filled drying tube 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 addition is complete, the ice bath is removed and 80 ml of dry acetonitrile is added. The reaction mixture is treated dropwise with 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile bg then it is heated at reflux temperature for 2 hours. The solvent is evaporated under reduced pressure and 200 ml of methanol and 20 g of silicon dioxide gel are added to the residue. This mixture is evaporated to dryness in vacuo and filled to the top of a column containing 200 g of silica gel in hexane, after which the column is eluted with hexane:ethyl acetate. The fractions eluted with hexane:ethyl acetate (1:1) give methyl-N-(2-hydroxyethyl)-3-carbomethoxypyrrole-2-acetate (IV, R = H) identical to the product from preparation 2.

Production 11

1.74 g of dimethyl-1,3-acetone dicarboxylate is added to a solution of 6 ml of ethanolamine in 5 ml of water. This mixture is rapidly cooled to -10°C and treated dropwise over 15 minutes with stirring with 1.67 ml of 1-bromoacetone, the reaction mixture not exceeding 40°C. After the addition is complete, the dark reaction mixture is stirred for a further 1 hour at room temperature and poured into a mixture of hydrochloric acid ice, saturated with solid sodium chloride and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts are washed with cold water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography of the residue on 30 g of silica gel with hexane:ethyl acetate (70:30) as eluent gives 890 mg of crystalline methyl-N-(2-hydroxyethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate which on recrystallization from methylene chloride -hexane melts at 78°C and has the following analytical values:

Preparation 12 -'<*>

The procedure from preparation 3 is followed and methyl-N-(2-hydroxyethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R = CH3) is converted into methyl-N-(2-mesyloxyethyl)- 3-carbo-methoxy-4-methylpyrrole-2-acetate which is cyclized with sodium hydride in dimethylformamide according to preparation 9 and gives dimethyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole- 1,7-dicarboxylate.

By hydrolysis of the latter with potassium hydroxide as indicated in preparation. 5, followed by selective esterification at C-1 and decarboxylation at C-1 according to preparations 6 and 8 respectively, 1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]yrrole-1 is eventually obtained ,7-dicarboxylic acid, isopropyl-1,2-dihydro-6-methyl-3H-<p>yrrolo[1,2-a]pyrrole-1-carboxylate-7-carboxylic acid and isopropyl-1,2-dihydro-6- methyl 3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (X, R = CH3, R<2> = 1C3H7).

Production 13

According to the procedure from example 1, isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate is condensed with N,N-dimethylthiophene-2-carboxamide under the synthesis of isopropyl 5-(2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrro-lo[1,2-a]pyrrole-1-carboxylate (XI, R = CH3, R<1> = H, R<2> = iC-jH^, X = S) , which has a melting point of 102.5°C.

The following examples illustrate the present invention with the production of relevant final products.

Example 1

a) A solution of 232.5 mg of N,N-dimethylthiophene-2-carboxamide and 0.15 g of phosphorus oxychloride in 2 ml of 1,2-dichloroethane

boil at reflux for 30 minutes. A solution of 181 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 in an argon atmosphere for 8 hours, treated with 450 mg of sodium acetate and further refluxed for 5 hours. The mixture is evaporated to dryness and the residue is chromatographed on 12 g of silica gel, eluting with hexane:ethyl acetate (3:1), which gives isopropyl-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1, 2-α]pyrrole-1-carboxylate (XI, R

and R<1> = H, R<2> = iC3H7, X = S).

b) A solution of 300 mg of isopropyl-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 30 ml of 50%

aqueous methanol containing 1% potassium hydroxide is refluxed under a nitrogen atmosphere for 2 hours. The methanol is evaporated under reduced pressure and the remaining basic solution is diluted with water and extracted with chloroform to remove unsaponifiable products. The aqueous alkaline phase is acidified with 20% hydrochloric acid and extracted three times with ethyl acetate.

The combined extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure, which gives 250 mg of crude 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid [( A), R

and R<1> = H, X = S], with melting point 145 - 148°C, which upon crystallization from ethyl acetate melts at 152 - 153°C.

■-•410 mg .5-(2-thenoyl)-1, 2-dihydro-3H-pyrrolo[1, 2-a]-pyrrole-1-carboxylic acid and 212.3 mg (d)-amphetamine are dissolved in 15 ml of absolute methanol and heated at reflux for 15 minutes, after which the methanol is evaporated in vacuo. The resulting diastereomeric (d)-amphetamine salt mixture (612.3 mg) is dissolved in a minimal volume of hot acetone (55°C), cooled to room temperature, filtered and washed with 2 ml of cold acetone (-10°C). This recrystallization process was repeated three times to give 247 mg of (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carbox- syllic acid-(d)-amphetamine salt with aD 3 = -181.3° and melting point 168 - 170°C. The (1)-acid isomer (d)-amphetamine salt prepared above is added to 30 ml of methylene chloride and shaken three times with 10 ml of 0.1N aqueous hydrochloric acid. The methylene chloride solution is washed three times with 15 ml saturated sodium chloride/water (2:1/V:V) and dried over anhydrous sodium sulfate. Filtration and removal of the organic solvent in vacuo gives 90 mg of (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid having ctQ<HC1 >3 = -177° and melting point 134 - 135.5°C.

The acetone mother liquor from this separation (ie, crystallization process) of the diastereomeric (d)-amphetamine salt mixture described above is pooled and transferred by

using the hydrochloric acid cleavage method described above,

to 245 mg of a mixture enriched in (d)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid and containing

dende (1)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid. The mixture is racemized (recycled) back to a 1:1 mixture of (d)- and (1)-isomers of 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a] pyrrole-l-carboxylic acid as follows: 245 mg of the mixture enriched in (d)-isomer and containing (l)-isomer, described above, is dissolved in 15 ml of methanol. 1.5 ml of methanol and 350 mg of sodium hydroxide are added and the mixture is heated at reflux under nitrogen for 1

hour. The methanol is removed in vacuo, 2.5 ml of water is added, and the solution is acidified to pH 2 with 10% hydrochloric acid. The mixture is extrahSSS^^mi# Sphere 10 ml portions with tylenk ^"^'^^ S^^^^^ itM^^' 9^^-~'~ the chloride extracts are combined and washed to r^ytrality (pH-jf , dried over anhydrous sodium sulfate and concentrated in vacuo to 230 mg of crude crystalline product which, on recrystallization from ethyl acetate-hexane, gives 180 mg of 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole- 1-carboxylic acid with a^<e0H> = 0.0° and melting point 152 - 154°C.

Example 3

To a solution of 118 mg of 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 8 ml of dry benzene, 0.234 g of trifluoroacetic anhydride is added. mix-

none is stirred at room temperature for 10 minutes and the solution is cooled to 0 - 5°C where 0.55 g of dry triethylamine is added followed immediately by 0.2 g of (1)-a-phenylethyl alcohol. The reaction 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 sulfate, after which the solvent is removed as well as the excess of (1)-α-phenylethyl alcohol under vacuum, which gives 0.166 g of a mixture of (1)-5-(2-thenoyl)-1,2-dihydro -3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid-(1)-a-phenethyl ester and (d)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1, 2-α]pyrrole-1-carboxylic acid-(1)-α-phenethyl ester which is separated by high pressure liquid chromatography (with 4% EtOAc/hexane on a 11 mm x 50 cm column

10 pm "Lichrosorb Sl-60") which gives 68 mg of the most polar ester (apSOH = -149.1°) and 73 mg of a less polar

, , MeOH , _ r „o.

ester (ctD = +105.2 ) .

6 2.1 mg of the most polar ester is dissolved in

3 ml of dry benzene. The solution is cooled to 15 - 20°C and 2.5 ml of trifluoroacetic acid is added, after which the solution is stirred at room temperature for 1 hour and 40 minutes. The reaction solution is poured into 60 ml of dry benzene and the solvents are removed in vacuo and at room temperature. Purification is by high pressure liquid chromatography (with the above column, except that 35% EtOAc/hexane in 3% acetic acid is used instead of 4% EtOAc/hexane) and this gives 41 mg of (1)-5-(2-thenoyl)- 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid with a^<eOH> = -144° and melting point 130 - 132°C.

Similarly, cleavage of the less polar ester according to the above method for cleavage of the most polar ester will give (d)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a ]pyrrole-1-carboxylic acid with a^<e0H> = +142.4° and melting point 127 - 129°C. The produced (d)-acid isomer can, if desired, be racemized (and returned), according to known methods.

Example 4

A solution of 336 mg of isopropyl-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 10 ml of methanol is treated with a solution of 6 90 mg of potassium carbonate in 5 ml of water. The reaction mixture is refluxed under a nitrogen atmosphere for 2 hours, cooled and evaporated to dryness. The residue is taken up in 10 ml of 10% aqueous hydrochloric acid and 50 ml of water and the resulting mixture is extracted with ethyl acetate (2 x 50 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate gives 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylic acid which is identical to the product from Example 1.

Example 5

By following the procedures from preparation 7 or 8, ethyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid-7-carboxylic acid (obtained in example 4) is converted into: ethyl-1 ,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.

Condensation of this compound with N,N-dimethylthiophene-2-carboxamide according to the procedure in example 1 gives: ethyl-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2 -α]-pyrrole-1-carboxylate, Δ 265, 328 nm (e 7580, 17780).

Example 6

Following the procedure described in example 1, one obtains by using 1.1-2 molar equivalents of

N,N-dimethylfuran-2-carboxamide,

N,N-Dimethyl-5-methylthiophene-2-carboxamide, N,N-Dimethyl-4-chlorothiophene-2-carboxamide, N,N-Dimethylthiophene-2-carboxamide and

N,N-dimethylfuran-3-carboxamide,

instead of N-N-dimethylthiophene-2-carboxamide, and by following the course of the reaction by thin-layer chromatography, respectively the following compounds: isopropyl-5-(2-furoyl)-1,2-dihydro-3H-pyrrolo-[1,2- a]pyrrole-1-carboxylate, an oil with the following physical data:

MeOH

UV \ mak, p275, 332.5 nm (e 8900, 17800), I.R. u ™£g3 1735 , 1685 , 1605 cm"<1>,

CDC1

N.M.R. 6 TMS 3 1>23 6H)J = 6 Hz; (Ch ) 2 CH], 2.60-3.00

(m, 2H), 3.90 (dd, 1H, JAX = 6 Hz; JBX = 7 Hz;

H-l), 4.10-4.67 (m, 2H), 4.95 [sept., 1H, J = 6 Hz; (CH3)2CH], 6.00 (d, 1H, J = 4 Hz; H-7), 6.40 (m, 1H), 7.10 (m, 1H), 7.23 (d, 1H, J = 4 Hz;

H-6), 7.43 ppm (m, 1H),

M.S. m/e 287 (M<+>),

isopropyl 5-(i 5-methyl-2-thenoyl)-1,2-dihydro-3H-pyrro-lo[1,2-a]pyrrole-1-carboxylate, with melting point 82 - 82.5°C,

isopropyl 5-(4-chloro-2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylate, oil,

isopropyl 5-(3-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylate, melting point 67 - 68°C, and

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

By hydrolysis of the isopropyl ester group according to the methods in example 1b) or 4, the corresponding free acids are obtained, namely: 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1 -carboxylic acid, melting point 184 - 184.5°C,

5-(5-methyl-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylic acid, with melting point 169 - 170°C,

5-(4-chloro-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylic acid, melting point 169 - 169.5°C,

5-(3-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylic acid, melting point 166 - 167°C, 5-(3-furoyl)-1,2- dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylic acid, melting point 156°C.

Example 7

A solution of 500 mg of isopropyl-5-(2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 15 ml of methanol is treated with a solution of 1 .05 g of potassium carbonate in 8 ml of water. The reaction mixture is refluxed under a nitrogen atmosphere for 3 hours, 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 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-(2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (( A), R = CH3, R1 = H, X = S), with melting point 166°C.

Example 8

A solution of 232.5 mg of N,N-dimethylthiophene-3-carboxamide and 0.15 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is refluxed for 30 minutes. A solution of 181 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 mixture is refluxed under an argon atmosphere for 8 hours, treated with 50 mg of sodium acetate and refluxed for a further 5 hours. The mixture is evaporated to dryness and the residue is chromatographed on 12 g of silica gel eluted with hexane:ethyl acetate (3:1), which thereby gives isopropyl-5-(3-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2- a]pyrrole-1-carboxylate

(XII, R = H, R<2> = iC3H?, X = S), melting point 67 - 68°C.

By the same procedure, by using N,N-dimethylfuran-3-carboxamide instead of N,N-dimethylthiophene-3-carboxamide, the corresponding 5-(3-furoyl)-derivatives are obtained, namely: isopropyl-5-(3- furoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylate, an oil, with the following physical data:

UV A M1 p, OH222, 244-277 (shoulder), 314 nm

max

(e6750, 4250, 14800), I.R. u ^ks3 1730, 1610, 1560 cm"<1>,

min

N.M.R. 6 ym<s> 3 1.23 l-d' 6H' J = 6 Hz? (CH 3 ) 2 CH], 2.50-3.00

(m, 2H), 3.92 (dd, 2H, JAX = 6Hz, JBX = 7 Hz; H-l), 4.10-4.60 (m, 2H), 4.95 [sept., 1H, J = 6 Hz;

(CH3)2CH], 5.95 (d, 1H, J = 4 Hz; H-7), 6.78 (m, 1H), 6.83 (d, 1H, J = 4 Hz; H-6) , 7.30 (m, 1H), 7.83

ppm (m, 1H),

M.S. m/e 270 (M<+>).

Example 9

A solution of 300 mg of isopropyl-5-(3-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 30 ml of 50% aqueous methanol containing 1% potassium hydroxide is boiled under reflux and nitrogen atmosphere for 2 hours. The methanol is evaporated under reduced pressure and the basic solution that remains is diluted with water and extracted with chloroform to remove unsaponifiable products. The aqueous alkaline phase is acidified with 20% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure, and this yields 250 mg of crude 5-(3-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid ( B), R = H, X = S, melting point 166 - 167.5°C.

By the same procedure, isopropyl 5-(3-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (obtained in Example 8) is converted to free acid, namely: 5- (3-Furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, melting point 156°C.

Example 10

A solution of 200 mg of 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ethereal diazomethane and the reaction mixture is kept at room temperature for 30 minutes. The solvents and excess reagent are removed under reduced pressure and the evaporation residue is crystallized from ethyl acetate-methanol, which gives methyl-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole -1-carboxylate, 265, 328 nm (e 7580, 17780).

Biological data

A. _ Search for the cause of pain_with_mouse_^Antiv

Procedure: The test compound is given orally by gavage in an aqueous 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 resolution induces pain twisting. The animals are then observed during the next 10 minutes for painful writhing.

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

According to the above method, it is determined that 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid has about 350 times the analgesic effect of aspirin and (1)-5 (2-Thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid has about 670 times the analgesic effect of aspirin.

B. Experiments to determine the anti-inflammatory effect of. h jelp__av_ca r rageen-induced^

Method: Female rats of the Simonsen strain weighing 80 - 90 g were used. The test compound is given at time 0 orally by forced feeding in 1 ml of aqueous medium. After 1 hour, 0.05 ml of a 1% solution (in 0.9% NaCl) of carrageenan is injected into the right hind paw. The injection causes inflammation in the paw. The rats are killed at hour 4, after which both hind paws are removed and weighed separately.

End point: % increase in paw size calculated

as follows:

Weight of right hind paw - weight of left paw Weight of left paw Following the above procedure, it is found that 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid has 48 times (95% confidence limits: 32-72) the anti-inflammatory effect of phenylbutazone.

C^__Attempt_for_measurement_of_f eberstillende_virkninc[

Method: Female rats of the Simonsen strain with weight

90 - 100 g was used. The "normal" rectal temperature of the rats is measured at time 0 followed by injection of 2 ml of yeast suspension subcutaneously (1 ml dorsally, 1 ml ventrally). The injection points are massaged to spread the suspension out under the skin. The yeast injection causes an elevated temperature (fever). At time 17 hours, the animals are massaged again to stimulate a further increase in body temperature. At hour 18, the second rectal temperature is measured, after which the test compound is administered orally by force-feeding in 1 ml of aqueous medium. The third rectal temperature is measured 2 hours after administration of the test compound.

End point: The decrease in temperature (°C) that takes place from the second to the third temperature reading.

Following the above procedure, it is found that 5-(1-tenoy)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid has 17 times as much antipyretic activity as aspirin.

D. Acute oral toxicity in mice (LD_.)

you_

Method: The test compound is suspended in 2% aqueous starch. The concentrations are adjusted so that doses can be given in volumes of 0.1 ml per 10 g body weight. Six groups (consisting of 6 female Swiss Webster mice in each group) are used. A single oral dose through stomach tube per kg body weight of either 50 mg, 100 mg, 200 mg, 400 mg, 800 mg or 1600 mg of 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo 1,2-a pyrrole-1-carboxylic acid is administered. After the administration, the mice are observed over a 2-week period.

According to the above method, acute oral LD3 ,-U-for 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo 1,2-a pyrrole-1-carboxylic acid is found to be 631 mg/kg with 95% confidence limit on

404 - 991 mg/kg.

Claims (1)

Analogous method for the preparation of therapeutically active compounds of the formula: or or their individual (l)-acid and (d)-acid isomers <q>g their lower alkyl esters of 1-3 carbon atoms or ct-phenylethyl esters, as well as pharmaceutical non-toxic salts thereof, where X is oxygen or sulphur, R is hydrogen or lower alkyl with 1-4 carbon atoms and R"*" is hydrogen, methyl or chlorine, characterized by one or more of the following steps: a) condensation of a compound with the formula: where R has the meaning given above and R 2 is a lower alkyl group with 1-3 carbon atoms or a-phenylethyl ester group, with an amide selected from where R^" and X have the meanings given above, which gives the corresponding compounds of formula: or where R and R 2 have the meanings given above, b) hydrolysis of an alkyl ester group which gives the free acid of compounds of formula (A) or (B), c) separation of the free acids of formula (A) or (B) in their corresponding respective (1)-acid isomers and (d)-acid isomers, d) racemization of (d)-acid isomers or their salts, to the corresponding respective compounds of formula (A) or (B), e) esterification of the carboxylic acid group in compounds of formula (A) or (B) or the (1)-acid isomers or (d)-acid isomers thereof, or conversion of these into their pharmaceutical acceptable, non-toxic salts, f) conversion of salts of formula (A) or (B) or their individual isomers into the corresponding free acids.