CH644861A5 - Process for the preparation of 5-(2-furoyl)-, 5-(2-thenoyl)-, 5-(3-furoyl)- and 5-(3-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid derivatives - Google Patents

Description

The present invention relates to a process for the preparation of 5- (2-furoyl) -, 5- (2-thenoyl) -, 5- (3-furoyl) - and 5- (3-thenoyl) -l, 2- dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid derivatives of the formula:.

where R 2 has the above meanings, with an amide of the formula:

'Jl or

"3'2

con (ch3j2

COOH

or

! 00h

30 (a>)

and the corresponding esters of the formula:

(b1)

wherein X and R1 have the above meanings, condensed.

2. The method according to claim 1, characterized in that one carries out the condensation in the presence of phosphorus oxychloride.

3. The method according to claim 1, characterized in that the amide used is N, N-dimethylthiophene-2-carboxamide.

4. The method according to claim 1, characterized in that the amide used is N, N-dimethylfuran-2-carboxamide.

5. The method according to claim 1, characterized in that the amide used is N, N-dimethyl-4-chlorothiophene-2-carboxamide.

6. The method according to claim 1, characterized in that the amide used is N, N-dimethyl-5-chlorothiophene-2-carboxamide.

7. The method according to claim 1, characterized in that the amide used is N, N-dimethylthiophene-3-carboxamide.

8. The method according to claim 1, characterized in that the amide used is N, N-dimethylfuran-3-carboxamide.

9. Process for the preparation of carboxylic acids of the formula:

35

: oor

40

45

50

or

OOH

(a>)

(b1)

wherein X, R and R1 have the meanings given in claim 1, or the pharmaceutically acceptable salts thereof, characterized in that a carboxylic acid ester of the formulas A and B defined in claim 1 is prepared by the process according to claim 1, the alkyl ester group is hydrolyzed and the carboxylic acid obtained optionally converted into a pharmaceutically acceptable salt.

10. The method according to claim 9 for the preparation of 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2 -] - pyrrole-l-carboxylic acid wherein X is oxygen or sulfur, R is hydrogen or a Is an alkyl group with 1 to 4 carbon atoms, R1 is hydrogen, methyl, chlorine or bromine and R2 is an alkyl group with 1 to 4 carbon atoms, any substituent R1 in the compounds of the formula A or A 'in the 3-, 4- or 5-position of the furan or thiophene ring. The compounds of the formula A 'or B' can be converted into their I-acid isomers and d-acid isomers and their pharmaceutically acceptable, non-toxic salts.

The compounds of the formulas A and B or A 'and B' described more fully above and below, with the exception of the d-acid isomers and the derivatives thereof, have an anti-inflammatory, analgesic and antipyretic action and are therefore useful for the treatment of inflammation, pain and / or febrile conditions in humans 55 and mammals, as described in more detail below. They are also relaxants for smooth muscles.

The term "pharmaceutically acceptable, non-toxic salts" as used herein refers to salts derived from pharmaceutically acceptable, non-toxic inorganic or 60 organic bases.

Typical alkyl groups with 1 to 4 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl and tert-butyl groups.

Salts derived from inorganic bases include 65 sodium, potassium, lithium, ammonium, calcium, magnesium, ferro, zinc, copper, mangano, aluminum, ferric, manganese salts and the like. Especially the ammonium, potassium, sodium, calcium and magnesium salts are preferred. To

644861

The salts derived from pharmaceutically acceptable organic, non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tri-propylamine, ethanolamine , 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosa-min, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylacine , Polyamine resins and the like. Particularly preferred organic, non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine.

The new compounds of the formulas A and B and A 'and B' exist as pairs of optical isomers (or enantiomer-phen), i. H. as dl mixtures. However, the present compound encompasses both the preparation of the individual optical isomers and the preparation of the dl mixtures thereof.

If the new compounds of formula A, A ', B and B' are to be used to induce a physiological response, e.g. B. an anti-inflammatory, analgesic or antipyretic effect, i.e. if they are to be used as medicaments, a preferred subgroup consists of the compounds of the formulas A 'and B' and their 1-acid isomers as well as their esters and pharmaceutically acceptable salts.

A further subgroup of compounds used as medicaments comprises the compounds of the formula A 'and the 1-acid isomers of the formula A' and their esters and pharmaceutically acceptable salts; this subgroup can be divided into two further subgroups, which (a) the compounds of formula A ', d. H. the dl compounds, in which R 1 is both hydrogen and X is sulfur, and (b) the 1-acid isomers of the formula B ', in which R and R 1 are both hydrogen and X is sulfur, and their esters and pharmaceutically acceptable salts.

The d-acid isomers of the formulas A 'and B' and their esters and pharmaceutically acceptable salts are useful as intermediates for the preparation of the dl acids of the formulas A 'and B', as will be described in more detail below.

The preparation of the starting compounds of the formula X for the preparation of the compounds A and B, from which the compounds of the formulas A 'and B' are prepared, is illustrated in the following reaction scheme:

nh,

I 2

CH,

i 2

cii,

i 2

oh jcooch3

(I)

\ ^. cooch.

X

10th

15

20th

'% kXxf-

5 LT

(a-)

(x)

cooh

30th

(b ')

wherein X, R, R1 and R2 have the above meanings, wherein R2 z. B. methyl, ethyl, isopropyl or n-butyl.

The process for the preparation of the compounds of formula X described in the above reaction scheme can be carried out as follows:

To prepare the compounds of the formula IV, in which R is hydrogen, equimolar amounts of ethanolamine of the formula I and 1,3-acetone dicarboxylic acid dimethyl ester of the formula II are reacted at a temperature of from about 0 ° C. to about room temperature, with easy reaction forms a solution of the vinylamine of the formula III, which is then treated, preferably in situ, under anhydrous conditions in a suitable inert organic solvent with 2-bromoacetaldehyde or 2-chloroacetal dehyde, at about 40 to about 100 ° C. over a period of about 30 minutes to about 16 hours. Suitable solvents for this reaction are aprotic solvents, such as acetonitrile, tetrahydrofuran, dimethoxyethane, chloroform, dichloromethane and the like. According to a preferred embodiment, the reaction is carried out in solution in acetonitrile at reflux temperature for about 1 hour. The 2-bromoacetaldehyde or 2-chloroacetaldehyde, which serve as reagents, are known compounds or can be obtained by pyrolysis of the corresponding diethylacetals in the presence of oxalic acid dihydrate.

55 In order to prepare the compounds of the formula IV in which R is a lower alkyl group, which is preferably unbranched, having 1 to 4 carbon atoms, an aqueous mixture of ethanolamine of the formula I and 1,3-acetone dicarboxylic acid ester of the formula II with a compound of the formula : 60

0

R3-H-CH2X

where X is bromine or chlorine and RJ is a lower alkyl 65 group, which is preferably unbranched, having 1 to 4 carbon atoms, in particular 1-bromoacetone, 1-bromo-2-butanone, 1-bromo-2-pentanone or 1- Bromine-2-hexanone, at about 40 to about 100 ° C for a period of about 30 minutes to about 16 hours

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treated. According to the preferred embodiment, the reaction is carried out at a temperature from about -10 ° C to about room temperature for about one to about 6 hours. The reagents of the formula:

• 0

3 "

Rj-C-CH2X

are known connections.

By esterifying the compound of formula IV with methanesulfonyl chloride in the presence of a tertiary amine, i.e. H. Triethylamine, pyridine and the like, optionally in the presence of a cosolvent such as dichloromethane, at a temperature of from about -10 ° C. to about room temperature for about 10 minutes to about 2 hours, the corresponding mesylate of the formula V is obtained then converted into the corresponding N- (2-iodoethyl) pyrrole of the formula VI by reaction with sodium iodide in solution in acetonitrile at reflux temperature for about one to about 10 hours.

By reacting the iodoethyl compounds of the formula VI with sodium hydride in a suitable inert organic solvent, such as dimethylformamide, 1,2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l, 7-dicarboxylic acid dimethyl ester and its in 6-position alkyl-substituted derivatives of the formula VII obtained. This cyclization is carried out under an inert atmosphere, i.e. H. under an argon or nitrogen atmosphere, at temperatures in the order of about 15 to about 40 ° C. for a period of about 15 minutes to about 4 hours. The best results are obtained when the reaction is carried out at room temperature for about 30 minutes when R is hydrogen.

The compounds of the formula VII can also be obtained by direct cyclization of the mesylate of the formula V with sodium hydride in solution in dimethylformamide at from about -10 ° C. to about room temperature for from about 30 minutes to about 2 hours.

Basic hydrolysis of a compound of formula VII with an alkali metal hydroxide or alkali metal carbonate, e.g. Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like, in an aqueous lower aliphatic alcohol, e.g. B. methanol or ethanol, at a temperature between room temperature and reflux temperature for about 4 to about 24 h provides the corresponding free diacid of formula VIII, d. H. 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylic acid and its 6-alkyl derivatives. The hydrolysis is preferably carried out using aqueous methanolic potassium hydroxide at the reflux temperature for about 10 hours.

The carboxylic acid group on carbon atom 1 in the compound of formula VIII is then treated with a lower aliphatic alcohol, e.g. B. methanol, ethanol, iso-propanol, n-butanol and the like. In the presence of hydrogen chloride selectively esterified to the corresponding 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid alkyl ester To produce -7-carboxylic acid of the formula IX. The reaction is carried out at a temperature of about 0 to about 50 ° C. for about 1 to about 4 hours.

The decarboxylation of the monoesterified compounds of the formula IX to the corresponding compounds of the formula X, the starting materials for the process according to the invention for the preparation of the compounds of the formulas A and B, is achieved by the compound of the formula IX for a period sufficient to terminate the reaction heated to an elevated temperature in the range of approximately 230 to approximately 280 ° C. The course of the reaction can be followed on the basis of the rate of evolution of carbon dioxide and on thin-layer chromatography, the decarboxylation generally being completed within about 45 to about 90 minutes. The reaction product, namely a 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid alkyl ester and its 6-

Alkyl derivatives of the formula X can be purified by chromatographic methods. In particular in the decarboxylation of small batches of compounds of the formula IX, the reaction product of the formula X can also be distilled directly from the reaction vessel.

The inventive condensation of a compound of formula X with an amide of the formula:

, f, 2

<* »« •

X CON (CH3) 2 x in which X and R1 have the meanings given above, gives the corresponding 1,2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid alkyl esters of the formula A which are substituted in the 5-position or B.

This reaction can be carried out in an inert organic aprotic solvent in the presence of phosphorus oxychloride at the reflux temperature for about 1 to about 72 hours under an inert atmosphere, after which the mixture is refluxed for a further about 2 to about 10 hours in the presence of sodium acetate can. Instead of phosphorus oxychloride, other acid chlorides, such as phosgene or oxalyl chloride, can also be used.

According to the preferred embodiment, this condensation is carried out by adding a solution of the compound of formula X in a suitable solvent to a previously refluxed mixture of 1.1 to 2 molar equivalents of both the desired amide and phosphorus oxychloride in the same solvent , the reaction mixture thus obtained is refluxed for about 2 to about 30 hours under an argon atmosphere and then about 3 to about 10 molar equivalents of sodium acetate are added, whereupon the mixture is refluxed for a further about 4 to about 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.

Representative examples of usable N, N-dimethylamine are:

N, N-dimethylthiophene-2-carboxamide,

N, N-dimethylfuran-2-carboxamide,

N, N-dimethyl-3-methylthiophene-2-carboxamide,

N, N-dimethyl-4-methylthiophene-2-carboxamide,

N, N-dimethyl-5-methylthiophene-2-carboxamide,

N, N-dimethyl-4-chlorothiophene-2-carboxamide,

N, N-dimethyl-5-chlorothiophene-2-carboxamide,

N, N-dimethyl-3-bromothiophene-2-carboxamide,

N, N-dimethyl-5-bromothiophene-2-carboxamide,

N, N-dimethyl-3-methylfuran-2-carboxamide,

N, N-dimethyl-4-methylfuran-2-carboxamide,

N, N-dimethyl-4-chlorofuran-2-carboxamide,

N, N-dimethyl-5-chlorofuran-2-carboxamide,

N, N-dimethyl-4-bromfuran-2-carboxamide,

N, N-dimethyl-5-bromfuran-2-carboxamide,

N, N-dimethylthiophene-3-carboxamide and

N, N-Dimethy] furan-3-carboxamide.

These amides can be prepared in a conventional manner from the corresponding thiophene or furan-2- or -3-carboxylic acids, i.e. H. by conversion into the acid chlorides and subsequent treatment with dimethylamine.

After preferably alkaline hydrolysis of the alkyl ester group in a compound of the formula À or B, the corresponding free acids of the formula A 'or B' are obtained. The hydrolysis can be carried out in a conventional manner with an alkali metal hydroxide or alkali metal carbonate, e.g. Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

644861

The like., in an aqueous lower aliphatic alcohol, for example methanol, ethanol and the like, at a temperature from about room temperature to reflux temperature for about 30 minutes to about 4 hours under an inert atmosphere. According to a preferred embodiment, this hydrolysis is carried out with aqueous methanolic potassium hydroxide at the reflux temperature for about 2 hours.

The compounds of the formulas A and B can be broken down by processes known to the person skilled in the art in order to obtain the corresponding individual isomers. For example, àie compound of formula A, wherein R and R1 are both hydrogen and X is sulfur, are subjected to a further treatment according to the following scheme:

COOH

(a1)

Splitting of the d-amphetamine salt of the J2 acid isomer of the formula A1

X-acid isomer of formula A1

V

"" Mixture of d-amphetamine salt of the d-acid isomer of the formula A * and d-amphetamine salt of the 4-acid isomer of the formula A1

A more detailed description of this procedure is given in Example 10 B-1.

However, the 1-acid isomers and d-acid isomers of the compounds of the formulas A and B can also be obtained by applying the known method of high pressure liquid chromatography (HPLC) to the diastereomeric a-phenylethyl esters of the compounds of the formulas A and B and then one Acid splitting. So you can e.g. subject the compound of the formula A ', in which R and R1 are both hydrogen and X is sulfur, to a further treatment in accordance with the following scheme:

coon

(a1)

several levels

Y

Mixture of / -a-phenylethyl ester of the <£ acid isomer of the formula A1 and ^ -a-phenylethyl ester of the d-acid isomer of the formula A-

Separation using HPLC

/ -Phenylethyl ester of the ^ acid isomer of the formula A *

^ -Phenylethyl ester of the d-acid isomer of the formula A *

4th

I.

/ Acid isomer of the formula A - * -

d-acid isomer of formula A ^

A detailed description of this process is given in Example 10 B-2.

The free acids of formula A 'and B' can be converted into other alkyl esters with 1 to 12 carbon-5 atoms by conventional methods, e.g. by treatment with (a) the alcohol corresponding to the desired ester in the presence of a strong mineral acid, (b) an ethereal diazo-alkane and (c) the desired alkyl iodide in the presence of lithium carbonate. The 1-acid isomers can be converted into their alkyl esters according to processes (b) and (c) above.

The salt derivatives of the compounds of the formula A 'and B' and their 1-acid isomers can be prepared by treating these free acids with an appropriate amount of a pharmaceutically acceptable base. Representative-15 pharmaceutically acceptable bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, manganese hydroxide, aluminum hydroxide, ferric hydroxide, manganese hydroxide, isopropylamine, trime-20 thylamine, diethylamine, triethylamine, triethylamine , 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydraba-min, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperine din, polyamine resins and the like. The reaction can be carried out in water alone or in combination with an inert, water-miscible organic solvent at a temperature of about 0 to about 100 ° C., preferably at room temperature. Typical inert, water-miscible organic solvents 30 are methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio to be used of compounds of the formula A 'or B' or their 1-acid isomer to base can be chosen so that the ratio desired for any specific salt results. If 35 If the calcium salts or magnesium salts of the compounds of the formula A 'or B' or the I-acid isomers thereof are to be prepared, the free acid serving as the starting material can be treated with at least 0.5 molar equivalents of pharmaceutically acceptable base in order to produce a neutral salt 40. When the aluminum salts of the compounds of formula A 'or B' or the 1-acid isomers thereof are prepared, at least 1/3 molar equivalent of the pharmaceutically acceptable base can be used if one wishes to produce a neutral salt.

45 According to the preferred method, the calcium salts and magnesium salts of the compounds of formula A 'and B' and the 1-acid isomers thereof can be prepared by combining the corresponding sodium or potassium salts with at least 0.5 molar equivalents of calcium chloride or. Magnesiumchlo-50 rid treated in an aqueous solution alone or in combination with an inert, water-miscible organic solvent at a temperature from about 20 to about 100 ° C. Preferably, the aluminum salts of the present compounds can be prepared by reacting the corresponding free acids with at least 1/3 molar equivalent of an aluminum alcoholate such as aluminum triethylate, aluminum tri-propylate and the like in a hydrocarbon solvent such as benzene, xylene, cyclohexane and Treated at a temperature of about 20 to about 115 ° C. Similar processes can be used to produce salts of inorganic bases that are not sufficiently soluble for easy implementation.

It is understood that the isolation of the compounds described herein can, if desired, be accomplished using any suitable separation or purification method, such as extraction, filtration, evaporation, distillation, crystallization, thin layer chromatography, column chromatography, high pressure liquid chromatography (HPCL), or one Combination of these procedures. Explanatory

The following examples provide formulations for suitable separation and isolation processes. Esters and salts can be formulated into a suppository. However, using, for example, polyalkylene glyco-

other equivalent separation or isolation processes, such as polypropylene glycol, as a carrier. Liquid, pharmaceutical

be applied. Table-top preparations can B. are produced

Although the d-acid isomers in and of themselves not as medicinal agents by using an active ingredient of the type described above and niche agents, they can, if desired, be converted into any pharmaceutical adjuvants in a carrier, such as

their pharmaceutically acceptable, non-toxic esters and for example water, physiological saline, aqueous

Salts are transferred, namely after those for the transfer dextrose, glycerol, ethanol and the like, dissolves, disperses, etc., in order to form the solution of the 1-acid isomers in their pharmaceutically unobjectionable solution or suspension. Desired-

non-toxic esters and salts described.10 if the pharmaceutical preparation to be administered can also

The compounds of the formulas A 'and B' and their 1- small amounts of non-toxic auxiliary substances, such as wetting agents

Acid isomers and their pharmaceutically acceptable, non- or emulsifiers, pH buffering agents and the like, such as toxic esters and salts, are useful as anti-inflammatory sodium acetate, sorbitan monolaurate, triethanolamine oleate,

agents, analgesic agents, agglutin inhibitors, etc. contain.

nation, fibrinolytic agents and relaxants for the smooth 15 process for the preparation of such dosage forms

Muscles. These compounds can either be known prophylactically or are obvious to the person skilled in the art; see e.g.

can also be used therapeutically. Remington's Pharmaceutical Sciences, Mack Publishing Com-

Agents containing these compounds are useful for pany, Easton, Pennsylvania, 14th edition, 1970. The

the treatment and elimination of inflammation, such as the corresponding preparation, can in any case be a pharmaceutically active

inflammatory conditions of the skeletal muscle system, the skeletal total amount of the active ingredient or the active ingredients that a steering and other tissues, eg. B. for the treatment of relieving the special condition to be treated according to inflammatory conditions, such as rheumatism, concussio, lacera- the teachings of the invention contain.

tio, arthritis, broken bones, post-traumatic conditions and The compounds of formula A 'and B' and their 1-acid iso-gout. If the above conditions include pain and febrile pain and their nontoxic, pharmaceutically acceptable conditions in combination with inflammation, esters and salts described above are also suitable, the present compounds for relieving these xants for the smooth muscle of the Uterus and are thus states as well as inflammation. useful for the maintenance of pregnancy gravidity. The administration of the active compounds of formula A 'or B' or humans and mammals for the benefit of the mother and / or of their I-acid isomers and their pharmaceutically acceptable fetus until the termination of pregnancy from the medical not Toxic esters and salts in a suitable pharma- ceutical position can be considered favorable or more favorable for the mother and / or table preparation after any accepted administration to the fetus. However, it is to be understood that the methods of treatment include agents for the treatment of inflammation, administration of the compounds described herein in pain or febrile conditions or for prophylaxis in certain cases, e.g. B. if the birth has already started, the same can take place. Thus the administration e.g. B. oral, i.e. if the mother experiences contractions of the uterus, in particular parenterally or topically in the form of solid, semi-solid or especially near the date of birth, the "gravid state of liquid dosage forms takes place, such as, for example, tablets, suppositories, pills, cannot be maintained for an indefinite period of time. Capsules, powders, solutions, mag. In such cases, the pregnancy is instead highly-suspensions, emulsions, creams, lotions, ointments and the like, probably somewhat "extended"; this factor can be preferred in the form of dosage units that are suitable for the mother and / or the fetus may be beneficial.

easy administration of exact doses. The 40 In particular, the compounds of the formula A 'and B'

Preparations contain e.g. B. a conventional pharmaceutical and their 1-acid isomers and their pharmaceutically acceptable

carrier or a conventional pharmaceutical excich, non-toxic esters and salts as an agent for delaying piens and an active ingredient of formula A 'or B' or its onset or postponement of delivery.

Acid isomers and its pharmaceutically acceptable, not. The term "to delay the onset of childbirth", such as toxic esters and salts and other medicinal products used herein, is intended to include any delay in childbirth, pharmaceuticals, carriers, excipients, etc., by administration contain the compound of formula. A or B or their 1-acid isomers and their pharmaceutical

The preferred mode of administration for the above-mentioned non-toxic esters and salts in a stressed condition is oral administration at the appropriate time prior to the start of the contraction of the uterine muscle at an appropriate daily dose, according to the degree. '50 is caused. Thus, the above mentioned expression that the impairment can be set. Generally prevention of abortus in early stages of pregnancy, i.e. H. a daily dosage of 25 to 500 mg of the active ingredient before the fetus is "viable" and include the delay of the formula A 'or B' or its 1-acid isomers and its premature birth; the latter term is applied to some pharmaceutically acceptable, non-toxic esters and salts times in relation to those premature contractions that are used. Most conditions respond to treatment 55 in later stages of pregnancy when the fetus is considered to be of the order of "viable" using a dosage. In any case, the means can be 0.5 to 6 mg per kg of body weight and per day. For being administered as a prophylactic agent by its perverted oral administration, a pharmaceutically inadmissible can prevent the onset of childbirth. This conceivable, nontoxic preparation made by administration is particularly useful in the treatment of any of the excipients normally used, such as e.g. 60 women who already have morbid abortion, miscarriages or early pharmaceutical varieties of mannitol, lactose, starch, magnetic births, d. H. Have births before the date of birth, experience sium stearate, sodium saccharin, talc, cellulose, glucose. Such administration is also useful when mixing gelatin, sucrose, magnesium carbonate and the like. There are clinical signs that pregnancy before this Such preparations can be terminated in the form of solutions, suspension time, and when administered, tablets, pills, capsules, powders, formulations for the 65 as favorable for the mother, and / or the fetus is viewed, protracted release and the like are present. This treatment can also be used on animals,

The active ingredients of formula A 'or B' or their 1-acid iso- to mere births in a group of gravid animals and to synchronize their pharmaceutically acceptable, non-toxic ones so that they are at the same time or approximately

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occur at the same time or occur at a desired time and / or in a desired location or in the vicinity thereof, if the births can be treated with greater ease.

The term "postponing childbirth" as used herein is intended to include the delay in childbirth caused by administration of the compounds of formula A 'or B' or their 1-acid isomers and their pharmaceutically acceptable, non-toxic esters after the contractions begin Uterine muscle is caused. The patient's condition, including the point in time within the period of pregnancy when the contractions started, the severity of the contractions, and the length of the contractions to date, affects the results obtained by the administration of the present compound. The effect can e.g. consist in reducing the intensity and / or duration of the contractions (thereby "prolonging" the actual birth process) or ending the contractions at all. In any case, the effect is to increase the duration of pregnancy, although the effect can be either slight or, under appropriate circumstances, slightly greater depending on the patient's condition as described above. Such administration can serve to prevent spontaneous abortion, make birth easier and / or less painful for the mother, or cause birth to occur at an appropriate time and / or location.

In all cases, the administration of the compounds of formula A 'or B' or their 1-acid isomers and their pharmaceutically acceptable, non-toxic esters and salts for the purposes set out above should be compatible with the best and / or accepted medical or veterinary practice optimize the benefits for the mother and the fetus. E.g. administration should not continue beyond the date of birth until the fetus in the uterus dies.

The administrable pharmaceutical preparations can be in the form of tablets or suppositories for insertion into the vagina or uterus, pills, capsules, liquid solutions, suspensions or the like, preferably in the form of dosage units which are suitable for the simple administration of precise dosages. Conventional, non-toxic solid carriers are e.g. pharmaceutical varieties of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. The active substances defined above can be formulated as suppositories by using, for example, polyalkylene glycols, such as polypropylene glycol, as carriers . Liquid, pharmaceutically administrable preparations can e.g. are prepared by dissolving, dispersing, etc. an active ingredient of the type defined above and any pharmaceutical excipients in a carrier such as water, physiological saline, aqueous dextrose, glycerin, ethanol and the like, thereby forming a solution or suspension .

If desired, the pharmaceutical preparation to be administered can also contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffering agents and the like, e.g. As sodium acetate, sorbitan monolaurate, triethanolamine oleate 5, etc. included. Methods for the production of such dosage forms are known or obvious to the person skilled in the art; see e.g. Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th edition, 1970. The preparation or formulation to be administered in any case contains an effective amount of the active ingredient or ingredients which delay the onset of childbirth or postpones delivery if the uterine contractions have already started. In general, a daily dose of 0.5 to about 25 mg of the active ingredient per kg of body weight 15 is administered, the administration in the form of a single daily dose or in the form of up to three or four smaller doses, which are taken at regular intervals during the Administered daily. The amount of active ingredient administered naturally depends on its relative activity. 20 The following preparation and the following examples illustrate the invention. The abbreviation «t.l.c.» means "thin layer chromatography" and all mixing ratios used in relation to liquids are volume ratios. If necessary, examples are repeated to produce additional material for subsequent examples; unless otherwise stated, the reactions are carried out at room temperature (20 to 30 ° CX).

30th

35

Preparation 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 is heated under reflux for 4 hours under anhydrous conditions. The excess thionyl chloride is removed and the residue is distilled under reduced pressure (60 ° C./2 mm), 18 g of 4-chlorothiophene-2-carboxylic acid chloride being obtained.

A solution of 10.5 g of 4-chlorothiophene-2-carboxylic acid chloride in 500 ml of anhydrous benzene is cooled in an ice water bath, and dimethylamine is then slowly bubbled through the solution for 30 minutes. The ice water bath is removed, maintaining the dimethylamine flow for an additional 15 minutes. The reaction mixture is then diluted with 100 ml of 10% sodium chloride solution and stirred for 5 minutes at room temperature. The organic phase is separated, washed with 4510% hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure to produce N, N-dimethyl-4-chlorothiophene-2-carboxamide.

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

Thiophene-2-carboxylic acid Furan-2-carboxylic acid

3-methylthiophene-2-carboxylic acid

4-methylthiophene-2-carboxylic acid

5-methylthiophene-2-carboxylic acid 5-chlorothiophene-2-carboxylic acid

3-bromothiophene-2-carboxylic acid

4-bromothiophene-2-carboxylic acid

5-bromothiophene-2-carboxylic acid

3-methylfuran-2-carboxylic acid

4-methylfuran-2-carboxylic acid

5-methylfuran-2-carboxylic acid 3-chlorofuran-2-carboxylic acid

II

N, N-dimethylthiophene-2-carboxamide

N, N-dimethylfuran-2-carboxamide

N, N-dimethyl-3-methylthiophene-2-carboxamide

N, N-dimethyl-4-methylthiophene-2-carboxamide

N, N-dimethyl-5-methylthiophene-2-carboxamide

N, N-dimethyl-5-chlorothiophene-2-carboxamide

N, N-dimethyl-3-bromothiophene-2-carboxamide

N, N-dimethyl-4-bromothiophene-2-carboxamide

N, N-dimethyl-5-bromothiophene-2-carboxamide

N, N-dimethyl-3-methylfuran-2-carboxamide

N, N-dimethyl-4-methylfuran-2-carboxamide

N, N-dimethyl-5-methylfuran-2-carboxamide

N, N-dimethyl-3-chlorofuran-2-carboxamide

644861

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I.

4-chlorofuran-2-carboxylic acid

5-chlorofuran-2-carboxylic acid

4-bromfuran-2-carboxylic acid

5-bromfuran-2-carboxylic acid thiophene-3-carboxylic acid furan-3-carboxylic acid

II

N, N-Dimethyl-4-chlorofuran-2-carboxamide

N, N-dimethyl-5-chlorofuran-2-carboxamide

N, N-dimethyl-4-bromfuran-2-carboxamide

N, N-dimethyl-5-bromfuran-2-carboxamide

N, N-dimethylthiophene-3-carboxamide

N, N-dimethylfuran-3-carboxamide

Manufacturing 2

A 250 ml three-necked round bottom flask, which contains a magnetic stir bar and is equipped with a drying tube filled with calcium chloride, is directly (via one of the outer necks) with the help of a connection piece for a template and a short water cooler (76.2 mm) to the acetal pyrolysis device connected. This latter device consists of a 100 ml round bottom flask previously charged with 15.6 g of oxalic acid dihydrate and 11.82 g of bromoacetaldehyde diacetal [made from vinyl acetate as described by P. Z. Bedoukian, J. Am. Chem. Soc. 66,651 (1944) has been charged] and on which there is a 152.4 mm Vigreux column which carries a thermometer and is connected to the above-mentioned cooler. - - -

The three-necked flask is charged with 3.36 g of ethanolamine, which has been cooled to 0 to 10 ° C. in an ice bath, and treated dropwise with 8.7 g of dimethyl 1,3-acetone dicarboxylate while stirring. It immediately forms 3-carbomethoxy-methyl-3- (2'-hydroxyethylamino) acrylic acid methyl ester of the formula III. When 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 thereof is raised to 150 to 160 ° C. The bromacta-dehyde solution (boiling point 80-83 ° C / 580 mm) that forms is distilled directly into the magnetically stirred solution of the vinylamine of formula III. When the distillation temperature falls below 80 ° C, the pyrolysis device is removed and replaced by a reflux condenser equipped with a drying tube containing calcium chloride. The solution is heated to reflux for 1 hour. The solvent is removed under reduced pressure and 200 ml of methanol and 20 g of silica gel are added to the residue. This mixture is evaporated to dryness in vacuo and placed on a column of 200 g of silica gel which has been filled in hexane. The column is then eluted with a mixture of hexane and ethyl acetate (80: 20,500 ml) and a mixture of hexane and ethyl acetate (1: 1.9 x 500 ml). Fractions 2 and 3 contain less polar impurities and 1,3-acetondi-carboxylic acid dimethyl ester. Fractions 4 to 8 yield 4.1 g of N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetic acid methyl ester (formula IV, R = H) which, after recrystallization from a mixture of ether and hexane, has a melting point of 52 to 54 ° C.

Manufacturing 3

A solution of 4.1g of N- (2-hydroxyethyl) -3-carbomethoxy-pryrrol-2-acetic acid methyl ester in 35 ml of dry dichloromethane, which is cooled to -10 ° C, is stirred with 2.65 ml of triethylamine and then dropwise 1.46 ml of methanesulfonyl chloride are added, the temperature being maintained at -10 to -5 ° C. from the reaction mixture. The course of the reaction is followed by thin layer chromatography using a mixture of chloroform and acetone (90:10). When the reaction appears to have ended (approx. 30 min after the end of the addition of the methanesulfonyl chloride), 10 ml of water are slowly added. The organic phase is separated off, washed three times with 30 ml of water each time, dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from a mixture of dichloromethane and hexane gives 4.75 g (77.7%) of N- (2-mesyloxyethyl) -3-

w carbomethoxypyrrol-2-acetic acid methyl ester (formula V, R = H) from melting point 99 to 101 ° C.

Manufacturing 4

A solution of 785 mg of N- (2-mesyloxyethyl) -3-carbometho-15 xypyrrol-2-acetic acid methyl ester and 1.83 g of sodium iodidine in 10 ml of acetonitrile is heated to reflux for one hour. The cooled reaction mixture is evaporated to dryness under reduced pressure and the residue is triturated with water. The insoluble material is separated off by filtration and air-dried, 840 mg (97%) of N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetic acid methyl ester (formula VI, R = H), melting point 137 to 138 ° C.

Manufacturing 5

25 A solution of 1 g of N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetic acid methyl ester 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 at room temperature for 30 minutes and then quenched with 100 ml of 30 water. The product is extracted three times with 50 ml of ethyl acetate each. The combined extracts are washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatography of the residue over 20 g of silica gel using a mixture of 35 hexane and ethyl acetate (4: 1) as the eluent gives 500 mg (80%) l, 2-dihydro-3H-pyrrolo- [l, 2-a] - pyrrole-l, 7-dicarboxylic acid dimethyl ester (formula VII, R = H) from melting point 70 to 71 ° C.

A solution of 1.80 g of 2-dihydro-3H-pyrròlo- [1,2-a] -pyr-40 rol-l, 7-dicarboxylic acid dimethyl ester in 20 ml of methanol is mixed with a solution of 4.48 g of potassium hydroxide in 20 ml of water treated and the reaction mixture heated to reflux for 6 h. The cooled solution is evaporated to dryness and the residue is treated with 50 ml of saturated sodium chloride solution 45. The resulting solution is acidified with 6 normal hydrochloric acid and extracted three times with 50 ml of ethyl acetate. The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, 1.51 g (95%) of 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-50 1,7- dicarboxylic acid (formula VIII, R = H) of melting point 220 ° C (with decomposition).

Manufacturing 6

A solution of 1.34 gl, 2-dihydro-3H-pyrrolo- [l, 2-a] pyr-55 rol-1,7-dicarboxylic acid in 50 ml isopropanol, which is cooled in an ice bath, is mixed with gaseous hydrogen chloride saturated, keeping the temperature of the reaction mixture below 50 ° C. The ice bath is then removed and the reaction mixture is stirred at room temperature for 1.5 h and evaporated to dryness under reduced pressure. The residue is mixed with 10 ml of benzene and the solution is evaporated again in vacuo; this process is repeated three times in total to remove the excess hydrogen chloride. In this way, 1.58 g (96%) of 1,2-dihydro-3H-pyrrolo- [1,2-a] -65 isopropyl pyrrole-1-carboxylate-7-carboxylic acid (formula IX, R = H, R2 = iC3H7) which after crystallization from a mixture of methanol and ethyl acetate has a melting point of 144 to 145 ° Chat.

644861

If methanol, ethanol, propanol or n-butanol is used instead of isopropanol in the above process, the following is obtained in a similar manner:

1,2-Dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid methyl-

ester-7-carboxylic acid, 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid ethyl

ester-7-carboxylic acid, 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid propyl-

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

Manufacturing 7

1,054 gl, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid-reisopropyl ester-7-carboxylic acid are heated to 240 to 250 ° C in a dry 10 ml round bottom flask, the reaction product being obtained directly distilled from the reaction vessel. In this way, 745 mg (87%) l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester (formula X, R =

H, R2 = iC3H7), a pale yellow oil, obtained with the following physical constants:

U.V .: X 215 nm (e 6020);

I.R .: Y ™ C13 1725 cm4;

NMR: ÔtmsC13 l, 22 (d, J = 7Hz, 6H), 2.40-2.90 (m, 2H), 3.604.20 (m, 2H), 4.65-5.2 (m, 1H) , 5.73-5.92 (m, 1H), 6.10 (6, J = 3 Hz, 1H), 6.43-6.53 (m, 1H).

Manufacturing 8

A 100 ml three-necked round bottom flask equipped with a condenser, a nitrogen inlet tube and a bubble counter is charged with 5.0 gl, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester- 7-carboxylic acid charged. The device is purged thoroughly with nitrogen and the nitrogen flow is turned off. The device is immersed in an oil bath heated to 270 ° C and the reaction is followed by the rate of evolution of carbon dioxide (bubble counter) and by thin layer chromatography on silica gel using a mixture of benzene, dioxane and acetic acid (90: 10: 1) as a developing solvent. The reaction is almost complete after 45 minutes. After an hour, the vessel is removed from the oil bath and the contents of the reaction flask are transferred to a round bottom flask containing 500 ml of acetone. The solvent is removed under reduced pressure and the residue is purified by column chromatography over 100 g of silica gel. The fractions eluted with a mixture of hexane and benzene (70:30) or hexane and benzene (50:50) yield 2.77 g (68%) l, 2-dihydro-3H-pyrrolo- [l, 2-a ] -pyrrole-l-carbonic acid isopropyl ester (formula X, R = H, R2, iC3H7), an oil,

whose physical constants are identical to those of the product of preparation 7.

Manufacturing 9

710 mg of a 50% suspension of sodium hydride in mineral oil are washed with anhydrous hexane under a nitrogen atmosphere and then suspended in 50 ml of dimethylformamide. The suspension is cooled to -5 ° C and 4.5 g of N- (2-mesyloxymethyl) -3-carbomethoxypyrrol-2-acetic acid remethyl ester is added, the reaction mixture being stirred at -5 to 0 ° C for one 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, giving 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l, 7-dicarboxylic acid dimethyl ester (formula VII, R = H) which is obtained with the products obtained in preparation 5 is identical.

example 1

A solution of 232.5 mg of N, N-dimethylthiophene-2-carboxamide and 0.15 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is heated to reflux for 30 minutes. This solution is mixed with 5 a solution of 181 mg 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid isopropyl ester in 2 ml 1,2-dichloroethane. The reaction mixture is heated to reflux under an argon atmosphere for 8 hours, treated with 450 mg of sodium acetate and heated to reflux for a further 5 hours. The resulting mixture is then evaporated to dryness and the residue is chromatographed over 12 g of silica gel, eluting with a mixture of hexane and ethyl acetate (3: 1); This gives 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid isopropyl ester (formula A, R and R1 15 = H, R2 = ÌC3H7 , X = S).

Example 2

A. A solution of 300 mg of 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester in 30 ml of 20 50% aqueous methanol containing 1% Containing potassium hydroxide is heated to reflux under a nitrogen atmosphere for 2 hours. The methanol is then removed under reduced pressure and the remaining basic solution is diluted with water and extracted with chloroform to remove any unsaponifiable product. 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; in this way, 250 mg of crude 5- (2-thenoyl) -30 l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid (formula A ', R and R1 = H , X = S) with a melting point of 145 to 148 ° C, which melts after recrystallization from ethyl acetate at 152 to 153 ° C with decomposition.

35 B. 410mg5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyr-rol-l-carboxylic acid and 212.3 mg of d-amphetamine are dissolved in 15 ml of absolute methanol dissolved and heated to reflux for 15 min, after which the methanol is removed in vacuo. The resulting diastereomeric mixture of d-amphetamine salts 40 (612.3 mg) is dissolved in the smallest possible amount of hot (55 ° C.) acetone and cooled to room temperature; the precipitate is filtered off and washed with 2 ml of cold (-10 ° C) acetone. This recrystallization process is repeated three more times, 247 mg of l-5- (2-thenoyl) -l, 2-dihy-45 dro-3H-pyrrolo- [i, 2-a] -pyrrole-l-carboxylic acid-d -amphetamine salt with (XdHCI3 -181.3 ° and a melting point of 168 to 170 ° C is obtained.

The d-amphetamine salt of the 1-acid isomer, which was obtained immediately beforehand, is added to 30 ml of methylene chloride and shaken three times with 10 ml of 0.1 normal aqueous hydrochloric acid. The methylene chloride solution is washed three times with 15 ml of a mixture of saturated sodium chloride and water (volume ratio 2: 1) and dried over anhydrous sodium sulfate. Filtration and removal of the organic solvent in vacuo gives 90 mg of l-5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid ciDHa3 -177 ° and a melting point of 134 to 135.5 ° C.

The resulting from the split, i.e. H. the multiple crystallization resulting from acetone mother liquors of the diastereomeric mixture of d-amphetamine salts described above are combined and reacted using the hydrochloric acid cleavage process described above to give 245 mg of a mixture in which d-5- (2- Thenoyl) -l, 2-dihy-dro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid is enriched 65 and the l-5- (2-thenoyl) -l, 2-dihydro-3H -pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid contains. This mixture again becomes a mixture (1: 1) of the d and 1 isomers of 5- (2-thenoyl) -! , 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid

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Racemized (circulated): The 245 mg of the mixture in which the d-isomer is enriched and which contains the 1-isomer described above are dissolved in 15 ml of methanol. 1.5 ml of methanol and 350 mg of sodium hydroxide are added and the solution is refluxed under nitrogen for one hour. The methanol is removed in vacuo; 2.5 ml of water are added, and the solution is acidified to pH = 2 with 10% aqueous hydrochloric acid. The mixture is extracted three times with 10 ml of methylene chloride. The methylene chloride extracts are combined and washed neutral (pH = 7), dried over anhydrous sodium sulfate and concentrated in vacuo to give 230 mg of a crude crystalline product which, when recrystallized from a mixture of ethyl acetate and hexane, 180 mg 5- (2- The-noyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid with aMe ° H q Qo uncj has a melting point of 152 to 154 ° C.

In the same way, other optically active d-bases can be used in the above method instead of d-amphetamine. The following are particularly suitable:

d-p-bromo-a-phenylethylamine d-a-phenylethylamine d-a-l-naphthylethylamine and d-a-2-naphthylethylamine,

with d-p-bromo-a-phenylethylamine being most preferred after d-amphetamine.

Similarly, the d-acid isomers, e.g. d-5- (2-Thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, obtained when the optically active 1-bases instead of the optically active d- Bases used, e.g. B. 1-amphetamine instead of d-amphetamine.

C. A solution of 118 mg5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid in 8 ml of dry benzene is mixed with 0.234 g of trifhioacetic anhydride. The mixture is stirred at room temperature for 10 minutes; the resulting solution is cooled to 0 to 5 ° C. and mixed with 0.55 g of dry triethylamine and immediately thereafter with 0.2 g of 1-a-phenylethyl alcohol. The reaction solution thus obtained is stirred at room temperature for 15 minutes and poured into 20 ml of water containing 1 ml of triethylamine, followed by extraction with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate, whereupon the solvent and excess 1-a-phenylethyl alcohol are removed in vacuo; 0.166 g of a mixture of l-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid-la-phe-nylethyl ester and d- 5- (2-Thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid la-phenyl ethyl ester. This mixture is separated by high pressure liquid chromatography (using 4% ethyl acetate-containing hexane on a 11 mm x 50 cm column of 10 [xm-Lichrosorb Sl-60) to give 68 mg of a polar ester (aut0H -149.1 °) and 73 mg of a less polar ester (aue0ïl + 105.2 °).

62.1 mg of the more polar ester are dissolved in 3 ml of dry benzene. The solution is cooled to 15 to 20 ° C and 2.5 ml of trifluoroacetic acid are added, whereupon the solution is stirred at room temperature for 1 h and 40 min. The reaction solution is poured into 60 ml of dry benzene, after which the solvents are removed in vacuo and at ambient temperature. Purification is carried out by high pressure liquid chromatography (using a column of the type described above, but using hexane containing 35% ethyl acetate in 0.5% acetic acid instead of the hexane containing 4% ethyl acetate) and provides 41 mg l-5 - (2-Thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid with anc0H -144 ° and a melting point of 130 to 132 ° C.

Similarly, cleavage of the less polar ester after that provides for cleavage of the polar ester

10th

described method d-5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid with a ^ eOH + 142.4 ° and a melting point of 127 to 129 ° C. The d-acid isomer obtained in this way can, if desired, be racemized (and recycled) by 5 methods known to those skilled in the art.

Other dl compounds can be converted in a similar manner into the corresponding 1-isomers and d-isomers.

Example 3

A solution of 336 mg of 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester in 10 ml of methanol is mixed with a solution of 690 mg of potassium carbonate in Treated 5 ml of water. The reaction mixture is heated to reflux under a nitrogen atmosphere for 2 h, 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 twice with 50 ml of ethyl acetate each time. The combined extracts are dried over magnesium sulfate 20 and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate gives 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyr-rol-l-carboxylic acid, with the products obtained in Example 2A is identical.

25 ". . ,, ~

Example 4

Following the procedures of Preparation 7 or 8, the remaining compounds obtained in Preparation 6 are converted to the following compounds: 30 1,2-Dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid methyl ester ,

1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid ethyl ester,

1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid propyl-

35

esters and

1,2-Dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid butyl ester

The following compounds are obtained by condensation of these compounds with N, N-dimethylthiophene-2-carboxamide by the method of Example 1: 40 5- (2-Thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carbonic acid methyl ester, 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrroI-l-carbon-

Acid ethyl ester, X ^ OH265.328 nm (e 7580.17780), 5- (2-Thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carbon-45 acid propyl ester and

5- (2-Thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carbonic acid butyl ester.

Example 5

Following the procedure of Example 1, using 1.1 to 2 molar equivalents of N, N-dimethylfuran-2-carboxamide, N, N-dimethyl-3-methylthiophene-2-carboxamide, N, N-dimethyl is obtained -4-methylthiophene-2-carboxamide, N, N-dimethyl-5-methylthiophene-2-carboxamide, 55 N, N-dimethyl-4-chlorothiophene-2-carboxamide, N, N-dimethyl-5-chlorothiophene-2- carboxamide, N, N-dimethyl-3-bromothiophene-2-carboxamide, N, N-dimethyl-4-bromothiophene-2-carboxamide, N, N-dimethyl-5-bromothiophene-2-carboxamide, 60 N, N-dimethyl -3-methylfuran-2-carboxamide, N, N-dimethyl-4-methylfuran-2-carboxamide, N, N-dimethyl-5-methylfuran-2-carboxamide, N, N-dimethyl-3-chlorofuran-2-carboxamide , N, N-Dimethyl-4-chlorofuran-2-carboxamide, 65 N, N-Dimethyl-5-chlorofuran-2-carboxamide, N, N-Dimethyl-4-bromfuran-2-carboxamide and N, N-Dimethyl- 5-bromfuran-2-carboxamide,

instead of N, N-dimethylthiophene-2-carboxamide and under

1.1

644861

Monitoring the course of the reaction by thin layer chromatography the following compounds:

5- (2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carbonic acid isopropyl ester, an oil with the following physical constants:

U.V .: I 275, 332.5 nm (s 8900.17800);

I.R .: y ™ CI3 1735.1685.1605 cm "1;

NMR: ÔtmsC13 l, 23 [d, 6HJ = 6Hz; (CH3) 2CH]; 2.60-3.00 (m, 2H), 3.90 (dd, 1H, Jax = 6 Hz; JBX = 7 Hz; Hl), 4, KM, 67 (m, 2H), 4.95 [sept., IH, J = 6 Hz; (CH3) 2CH], 6.00 (d, 1H, Ï = 4Hz; 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 (x \ f '), 5- (3-methyl-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-

1-carboxylic acid isopropyl ester,

5- (4-methyl-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-

1-carboxylic acid isopropyl ester, 5- (5-methyl-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-

1-carboxylic acid isopropyl ester, mp. 82-82.5 ° C, 5- (4-chloro-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-

carboxylic acid isopropyl ester, 5- (5-chloro-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-

carboxylic acid isopropyl ester,

5- (3-bromo-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-

carboxylic acid isopropyl ester,

5- (4-bromo-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-

carboxylic acid isopropyl ester, 5- (5-bromo-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-

carboxylic acid isopropyl ester, 5- (3-methyl-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-

carboxylic acid isopropyl ester, 5- (4-methyl-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-

carboxylic acid isopropyl ester, 5- (5-methyl-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-

carboxylic acid isopropyl ester, 5- (3-chloro-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-

carboxylic acid isopropyl ester,

5- (4-chloro-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l-

carboxylic acid isopropyl ester, 5- (5-chloro-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-

carboxylic acid isopropyl ester,

5- (4-bromo-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l-

isopropyl carboxylate or 5- (5-bromo-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester.

When the isopropyl ester group is hydrolysed by the processes of Example 2A or 3, the corresponding free acids are obtained, namely:

5- (2-furoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carbon-

acid, mp. 184-184.5 ° C,

5- (3-methyl-2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylic acid,

5- (4-methyl-2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylic acid,

5- (5-methyl-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-

1-carboxylic acid, mp. 169-170 ° C, 5- (4-chloro-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (5-chloro-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (3-bromo-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (4-bromo-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (5-bromo-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (3-methyl-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (4-methyl-2-furoyl) -l, 2-dihydro-3H-pyrroIo- [l, 2-a] pyrrole-l-carboxylic acid,

5- (5-methyl-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrroI-l-carboxylic acid,

5 5- (3-chloro-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (4-chloro-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (5-chloro-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-xo carboxylic acid,

5- (4-bromo-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (5-bromo-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l-

carboxylic acid.

15 Production 10 -

A 250 ml three-necked round-bottomed flask, which contains a magnetic stir bar and is equipped with a drying tube filled with calcium chloride, is charged with 3.36 g of ethanolamine, cooled in an ice bath to 0 to 10 ° C and, while stirring, with 8.7 g of 1 , 3-Acetondicarbonsäureesterdi-methyl ester treated. It immediately forms 3-carbomethoxy-methyl-3- (2'-hydroxyethylamino) acrylic acid methyl ester of the formula III. When the addition is complete, the ice bath is removed and 80 ml of dry acetonitrile is added. The reaction mixture is then treated dropwise with 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile and then heated to reflux for 2 hours. The solvent is then removed under reduced pressure and 200 ml of methanol and 20 g of 30 silica gel are added to the residue. This mixture is evaporated to dryness in vacuo and placed on a column of 200 g of silica gel which has been filled in hexane, eluting the column with mixtures of hexane and ethyl acetate. The fractions, which were eluted with a mixture of hexane and 35 ethyl acetate (1: 1), give N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetic acid methyl ester (formula

IV, R = H), which is identical to the product obtained in Preparation 2.

Manufacturing 11

40 A solution of 6 ml of ethanolamine in 5 ml of water is mixed with 1.74 g of 1,3-acetone dicarboxylic acid dimethyl ester. The resulting mixture is rapidly cooled to -10 ° C and treated dropwise with 1.67 ml of 1-bromoacetone with stirring over 15 minutes while maintaining the reaction mixture at a temperature of not more than 40 ° C. When the addition is complete, the dark reaction mixture is stirred for a further hour at room temperature and then poured into a mixture of hydrochloric acid and ice, which is saturated with solid sodium chloride, and extracted three times with 100 ml of ethyl acetate 50 each. The combined organic extracts are washed neutral with cold water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography of the residue over 30 g of silica gel using a mixture of hexane and 55 ethyl acetate (70:30) as the eluent gives 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetic acid which melts at 78 ° C after recrystallization from a mixture of methylene chloride and hexane and has the following analysis:

so analysis for CpHi7N05:

calc .: C56.45; H 6.71 Found: C 56.41; H 6.73

In a similar manner, but using a stoichiometric equivalent amount of l-bromo-2-butanone, l-bromo-2-pen-65 tanone or l-bromo-2-hexanone instead of l-bromoacetone, the following is obtained:

N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetic acid remethyl ester,

644861

12

N- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrrole-2-acetic acid

remethyl ester and N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetic acid remethyl ester.

Manufacturing 12

By following the procedure of Preparation 3, N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetic acid methyl ester (Formula IV, R = CH3) in N- (2-mesyloxyethyl) -3-carbomethoxy- 4-methylpyrrole-2-acetic acid methyl ester converted to 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1,7 by the method of preparation 9 in dimethylformamide with sodium hydride -Dicarbonsäuredimethylester is cyclized.

By hydrolysis of the last-mentioned compound with potassium hydroxide according to the process of preparation 5 and subsequent selective esterification at carbon atom 1 and decarboxylation at carbon atom 7 according to the processes of preparation 6 or 8, 1,2-dihydro-6-methyl-3H- pyrrolo- [l, 2-a] -pyrrole-l, 7-dicarboxylic acid, 1,2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester 7-carboxylic acid and 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid isopropyl ester (formula X, R = CH3, R2 = iC3H7).

Similarly, when using N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetic acid methyl ester, N- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrrole-2-acetic acid methyl ester and N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetic acid methyl ester instead of N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrol-2-acetic acid methyl ester as end products:

1,2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid isopropyl ester,

1,2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid rice propyl ester or

1,2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid isopropyl ester.

- Example 6

According to the procedure of Example 1, 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid isopropyl ester with N, N-dimethylthiophene-2-carboxamide is converted into 5- (2- Thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylic acid iso-propyl ester (formula A, R = CH3, R1 = H, R2 = ÌC3H7, X = S) condensed with a melting point of 102.5 ° C.

In a similar manner, but using the N, N-dimethylthiophene or N, N-dimethylfuran-2-carboxamides listed in Example 5 instead of N, N-dimethylthiophene-2-carboxamide, the following compounds are obtained: 5- (2-furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-

carboxylic acid isopropyl ester, 5- (3-methyl-2-thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-

a] -pyrrole-l-carboxylic acid isopropyl ester, 5- (4-methyl-2-thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-

a] -pyrrole-l-carboxylic acid isopropyl ester, 5- (5-methyl-2-thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-

a] -pyrrole-l-carboxylic acid isopropyl ester, 5- (4-chloro-2-thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid isopropyl ester,

5- (5-chloro-2-thenoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid isopropyl ester, 5- (3-bromo-2-thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid isopropyl ester, 5- (4-bromo-2-thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid isopropyl ester,

5- (5-bromo-2-thenoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid isopropyl ester,

5- (3-methyl-2-furoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -

pyrrole-l-carboxylic acid isopropyl ester,

5- (4-methyl-2-furoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid isopropyl ester;

5- (5-Methyl-2-furoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-aJ-

pyrrole-l-carboxylic acid isopropyl ester,

5- (3-chloro-2-furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester, 5 5- (4-chloro-2- furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester,

5- (5-chloro-2-furoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

isopropyl pyrrole-l-carboxylic acid, 5- (4-bromo-2-furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -10 isopropyl pyrrole-l-carboxylate or

5- (5-Bromo-2-furoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylic acid isopropyl ester.

The remaining end products obtained in Example 15 are likewise converted into the corresponding 5-furoyl or 5-thenoylderi-15ate. Representative compounds obtained in this way are:

5- (2-Thenoyl) -l, 2-dihydro-6-ethyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-

carboxylic acid isopropyl ester, 5- (2-furoyl) -l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-20 carboxylic acid isopropyl ester,

5- (3-methyl-2-thenoyl) -1, 2-dihydro-6-butyl-3H-pyrrolo- [l, 2-a] -

isopropyl pyrrole-l-carboxylic acid, 5- (4-chloro-2-thenoyl) -l, 2-dihydro-6-ethyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester, 25 5- ( 5-methyl-2-furoyl) -l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester or 5- (3-chloro-2-furoyl) - 1,2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid isopropyl ester.

30th

Example 7

A solution of 500 mg of 5- (2-thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester in 15 ml methanol is mixed with a solution of 1 , 05 g of potassium carbonate treated in 8 ml of water. The reaction mixture is heated to reflux under a nitrogen atmosphere for 3 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 three times with 50 ml of ethyl acetate. The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, giving 5- (2-thenoyl) -l, 2-dihydro-6-methyl3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid (Formula A, R = CH3, R1 = H, X = S) with a melting point of 166 ° C.

The remaining isopropyl esters obtained in Example 6 are converted into the corresponding free acids in a similar manner or by the hydrolysis process of Example 2A, namely:

5- (2-furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylic acid,

5- (3-methyl-2-thenoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-

a] -pyrrole-l-carboxylic acid,

5- (4-methyl-2-thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, 55 5- (5-methyl-2- thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, 5- (4-chloro-2-thenoyl) -l, 2-dihydro-6 -methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid,

5- (5-chloro-2-thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -60 pyrrole-l-carboxylic acid,

5- (3-bromo-2-thenoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid,

5- (4-bromo-2-thenoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylic acid, 65 5- (5-bromo-2- thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, 5- (3-methyl-2-furoyl) -l, 2-dihydro-6 -methyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid,

35

40

45

50

13

644861

5- (4-methyl-2-furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid, 5- (5-methyl-2-furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid, 5- (3-chloro-2-furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid, 5- (4-chloro-2-furoyl) -l, 2-dihydro-6-methy] -3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid, 5- (5-chloro-2-furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid,

5- (4-bromo-2-furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-1-carboxylic acid,

5- (5-bromo-2-furoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-1-carboxylic acid, 5- (2-thenoyl) -l, 2-dihydro-6-ethyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (2-furoyl) -l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (3-methyl-2-thenoyl) -1, 2-dihydro-6-butyl-3H-pyrrolo- [l, 2-a] -

pyrrole-1-carboxylic acid, 5- (4-chloro-2-thenoyl) -l, 2-dihydro-6-ethyl-3H-pyrrolo- [l, 2-a] -

pyrrole-1-carboxylic acid, 5- (5-methyl-2-furoyl) -l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid or 5- (3-chloro-l-fluroyl) -l, 2-dihydro-6-butyl-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylic acid.

Example 8

A solution of 232.5 mgN, N-dimethylthiophene-3-carboxamid and 0.15 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is refluxed for 30 minutes. This solution is mixed with a solution of 181 mg 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid isopropyl ester in 2 ml 1,2-dichloroethane. The reaction mixture is heated to reflux under an argon atmosphere for 8 hours, treated with 450 mg of sodium acetate and refluxed for a further 5 hours. The resulting mixture is then evaporated to dryness and the residue is chromatographed over 12 g of silica gel, eluting with a mixture of hexane and ethyl acetate (3: 1) and 5- (3-thenoyl) -1, 2-dihydro-3H-pyrrolo - [l, 2-a] pyrrole-l-carbonic acid isopropyl ester (formula B, R = H, R2 = iC3H7, X = S)

receives.

Similarly, 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid isopropyl ester and 1,2-dihydro-6-propyl-3H-pyrrolo- [1,2 -a] -pyrrole-l-carboxylic acid isopropyl ester in 5- (3-thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester or 5 - (3-Thenoyl) -l, 2-dihy-dro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester.

The corresponding 5- (3-furoyl) derivatives are obtained by the same method using N, N-dimethylfuran-3-carboxamide instead of N, N-dimethylthiophene-3-carboxamide, namely:

5- (3-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carbonic acid isopropyl ester, an oil with the following physical constants:

U.V .: X ^ 0H 222, 244-277 (shoulder), 314 nm (e 6750, 4250.14800);

LR .: y ™ a3 1730.1610.1560 cm "1;

NMR: Òtmsc13 l, 23 [d, 6H, J = 6Hz; (CH3) 2CH], 2.50-3.00 (m, 2H), 3.92 (dd, 2H, JAX = 6 Hz, JBX = 7Hz ; Hl), 4.10-4.60 (m, 2H), 4.95 [sept., IH, 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: (M +), 5- (3-furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester and

5- (3-Furoyl) -l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester.

5 Example 9

A solution of 300 mg of 5- (3-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid isopropyl ester in 30 ml of 50% aqueous methanol, the 1% potassium hydroxide included, heated to reflux under a nitrogen atmosphere for 2 h. The methanol is then removed under reduced pressure and the remaining basic solution is diluted with water and extracted with chloroform to remove any unsaponifiable product. 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, 250 mg of crude 5- (3-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l- carboxylic acid (formula B ', R = H, X = S).

20 Using the same process, the remaining compounds obtained in Example 8 are converted into the free acids, namely in:

5- (3-thenoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylic acid,

25 5- (3-thenoyl) -l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

5- (3-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carbon-

acid, mp. 156 ° C,

5- (3-furoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] pyrrole-l-30 carboxylic acid and

5- (3-furoyl) -l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylic acid.

Example 10

35 A solution of 300 mg of 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid in 5 ml of methanol is in the form with 1 molar equivalent of sodium hydroxide a 0.1 normal solution. The solvent is then evaporated under reduced pressure and the residue taken up in 2 ml of 40 methanol; then it is precipitated with ether and crude sodium 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate is obtained, which can be crystallized from isopropanol.

In the same way, other salts, e.g. B. ammonium and 45 potassium salts, of 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid prepared by ammonia or potassium hydroxide instead of Sodium hydroxide used.

Similarly, the 5-substituted 1,2-dihydro-3H-50 pyrrolo- [1,2-a] pyrrole-l-carboxylic acid obtained in Examples 2B, 2C, 5,7 and 9 can be converted into the corresponding sodium -, Potassium and ammonium salts are transferred.

Representative compounds obtained in this way are: sodium 1-5 (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

55 sodium 5- (2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Sodium-5- (4-methyl) -2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-

a] pyrrole-l-carboxylate,

Potassium 5- (4-chloro-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -60 pyrrole-l-carboxylate, potassium 5- (5-bromo-2- thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylate, sodium 5- (3-methyl-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate, 65 ammonium-5- ( 2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylate,

Ammonium 5- (3-chloro-2-furoyl) -l, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate,

644861

14

Sodium-5- (4-methyl-2-thenoyl) -l, 2-dihydro-6-ethyl-3H-pyr-

rolo- [l, 2-a] -pyrrole-l-carboxylate, potassium 5- (5-chloro-2-thenoyl) -l, 2-dihydro-6-methyl-3H-pyrrolo-

[1,2-a] pyrrole-l-carboxylate,

Ammonium-5- (3-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylate and sodium 5- (3-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate.

Example 11

A solution of 237 mg of 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid in 8 ml of methanol is in the form with 1 molar equivalent of potassium hydroxide a 0.1 normal solution is added to give a solution which contains potassium 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l- contains carboxylate. A solution of 50 mg of calcium carbonate in the minimum amount of 1-normal hydrochloric acid required to dissolve the calcium carbonate is buffered with 100 mg of solid ammonium chloride, after which 5 ml of water are added. The buffered calcium solution thus obtained is then added to the solution of potassium 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate; the precipitate formed is isolated by filtration, washed with water and air-dried and gives calcium-5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l- carboxylate.

In the same way, magnesium 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate is produced by using magnesium carbonate instead of calcium carbonate. If l-5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (2-furoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (4-chloro-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid,

5- (3-methyl-2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-

1-carboxylic acid, _

5- (5-bromo-2-furoyl) -1, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid and 5- (3-chloro-2-furoyl) -l, 2-dihydro-6-ethyl-3H-pyrrolo- [l, 2-a] -

pyrrole-l-carboxylic acid instead of 5- \ 2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyr-rol-l-carboxylic acid, the corresponding calcium is obtained in a similar manner - and magnesium salts.

Example 12

A solution of 237 mg of 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid in 8 ml of methanol is in the form with 1 molar equivalent of potassium hydroxide a 0.1 normal solution. The solvent is driven off and the residue is dissolved in 5 ml of water. The aqueous solution of potassium 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate thus obtained becomes a solution of 110 mg cuprinitrate trihydrate in Given 5 ml of water. The precipitate formed is isolated, washed with water and air-dried to give copper 5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylate receives.

In a similar manner, the free acids obtained in Examples 2B, 2C, 5,7 and 9 can be converted into the corresponding copper salts.

Example 13

A solution of 237 mg of 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid in 15 ml of hot benzene is treated with 59 mg of isopropylamine. The solution is allowed to cool to room temperature and the product is filtered off, washed with ether and dried, the isopropylamine salt of 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a ] -pyrrole-l-car-bonic acid.

In the same way, other amine salts, e.g. B. the diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts of 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l -carboxylic acid produced by using the amines in question instead of isopropylamine.

Similarly, the free acids obtained in Examples 2B or 2C, 5, 7 and 9 can be converted to the corresponding isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts.

10th

Biological data

A. Analgesia test (curvature test) on the mouse

Protocol: The test material is taken orally at time 0

Influenced in an aqueous vehicle administered to 15 male Swiss-Webster mice weighing 18 to 20 g. 20 minutes later, 0.25 ml of a 0.02% phenylquinone solution is intraperitoneally injected. This solution creates curvatures. The animals are then observed for curvatures for the next 10 minutes.

20 Endpoint: The total number of mice that curve and the average number of curves per mouse.

Using the above protocol, it is found that 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid is approximately 350 times the analgesic activity of Aspirin has and that l-5- (2-Thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid has 670-fold analgesic activity of aspirin.

B. Test for anti-inflammatory activity using carraghenin-induced paw inflammation in the rat.

Protocol: Simonsen female rats weighing 80 to 90 g are used. The test materials are administered orally at 0 hours by pouring them into 1 ml of an aqueous vehicle. At hour 1, 0.05 ml of a 1% solution of carraghenin in 0.9% saline solution is injected into the right hind paw. This injection causes paw inflammation. The rats are killed in hour 4; at this point both hind paws are removed and weighed separately.

Endpoint: The percentage increase in paw size is calculated by dividing the difference between the weight of the right hind paw and the weight of the left hind paw by the weight of the left hind paw and multiplying the result by 100.

Using the above protocol, it is found that 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid is 48 times (95% - Confidence interval 32 to 72) has anti-inflammatory activity of phenylbutazone.

C. Test for Antipyretic Activity Protocol: Simonsen female rats weighing 90 to 100 g are used. The "normal" rectal temperature of the rats is recorded at hour 0, after which 2 ml of a yeast suspension are injected subcutaneously (1 ml dorsally, 1 ml ventrally). The injection sites are massaged to spread the suspension below the skin. The yeast injection causes an increased body temperature (fever). At hour 17, the rats are massaged again to stimulate a further increase in body temperature. At hour 18, the second rectal temperature is recorded, after which the test material 60 is administered orally by infusion into 1 ml of an aqueous vehicle. The third rectal temperature is measured 2 hours after the test material is administered.

End point: The temperature decrease (° C) from the second temperature reading to the third temperature reading. 65 Using the above protocol, it is found that 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid has 17 times the antipyretic activity of Has aspirin.

D. Acute oral toxicity (LD50) in mice

25th

30th

35

40

45

50

Protocol: The test material is suspended in a 2% aqueous starch solution. The concentrations are adjusted so that the doses can be administered in volumes of 0.1 ml / 10 g body weight. 6 groups of 6 female Swiss-Webster mice are used. A single oral dose of either 50 mg or 100 mg or 200 mg or 400 mg or 800 mg or 1600 mg 5- (2-Thenoyl) -l, 2-dihydro-3H-pyr-

15 644861

rolo- [l, 2-a] -pyrrole-l-carboxylic acid per kg body weight is administered to the mice using a gastric tube. After the administration, the mice are observed for two weeks. Using the above protocol, the acute oral 5 LD5oVon5- (2-Thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid is estimated at 631 mg / kg, which is 95% confidence interval is 404 to 991 mg / kg. _

M

Claims (6)

644861 2nd PATENT CLAIMS 1. Process for the preparation of carboxylic acid esters of the formula: R. i COOR or R v! 7 t "Vrrf »I 12 I0 (B) where X is oxygen or sulfur, R is hydrogen or an alkyl group having 1 to 4 carbon atoms, R1 is hydrogen, methyl, chlorine or bromine and R2 is an alkyl group having 1 to 4 carbon atoms, with a possible substituent R1 in the compounds of the formula A is in the 3-, 4- or 5-filling of the furan or thiophene ring, characterized in that a compound of the formula: . _____ - 20 or l-5- (2-Thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid. 11. The method according to claim 9, characterized in that the carboxylic acid obtained is separated into the corresponding 1- and d-isomers. 12. The method according to claim 9 or 11, characterized in that a salt obtained of the formula A 'or B' or a single isomer thereof is converted into the corresponding free carboxylic acid. 13. A process according to claim 11, characterized in that the (d) -carboxylic acid or its salt obtained is racemized to the corresponding compound of the formula A 'or B'. 14. The method according to claim 9 for the preparation of the sodium salt of 5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid orl-5- (2-thenoyl) -l, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid.