FI63407C - FORM OF THERAPEUTIC FRAME THERAPEUTIC 5-2-FUROYL) - 5- (2-TENOYL) - 5- (3-FUROYL) - OCH 5- (3-TENOYL) -21, DIHYDRO-3H-PYRROLO (1,2- A) pyrrole-1-KARBOXYLSYRADERIVAT - Google Patents

Description

G3P «1 m. HEARING JUICE £ -lAnn jm» lJ ** utlAogninosskrift 00407 C Patent granted 10 C6 1933 (45) Patent medcclnt ^ T ^ (51) K ».lk? / Lnta3 C 07 D 4-87 / 04- ENGLISH —FINLAND (21) PK «nulh * k * mit-Ptt« WHwekiWn | 772154 (22) Htk «mltpUvt —Ameknln | * d» g 11.07.77 ^ '(23) AlkupiWt — GlM | h «tsd * c ll.O7.77

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Patent- och refiatentyralMn AnaMun utltgd och utUkrtftM published 28.02.83 (32) (33) (31) Requested «tuolk * u * —B # ftrd prior ** 14.07.76 23.02.77 USA (US) 704857, 771283 (71) Syntex (USA) Inc., 3401 Hillview Avenue, Palo Alto, California 94304, USA (72) Joseph M. Muchovski, Echegaray, Mexico, Mexico-Mexico (MX),

Arthur F. Kluge, Los Altos, California, USA • (74) Oy Kolster Ah (54) Method for therapeutically useful 5- (2-furoyl) -, 5- (2-tenoyl) -, 5 ~ (3 for the preparation of 5-furoyl) and 5 '(3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives - For the preparation of 5- (2-furoyl) -royl) -, 5- (2-thenoyl) -5,5- (3-furoyl) - and 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole- l-karboxylsyraderivat

The invention relates to a process for the use of therapeutically useful formulas A and B R 7 e 7

r1 F I I j J00 * Il 1> C OOM

x'N (N) 0 3I-12 5- (2-furoyl) -, 5- (2-tenoyl) -, 5- (3-furoyl) - and 5- (3- tenoyl) 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole for the preparation of "1" carboxylic acid derivatives or (1) -acid isomers thereof, wherein X is oxygen or sulfur, R is hydrogen or C 1 -C 4 alkyl, R 1 is hydrogen, methyl, chlorine or bromine, and M is hydrogen C 1 -C 4 alkyl or a pharmaceutically acceptable, non-toxic cation, wherein the R 1 substituent of the compound of formula (A) is 3-, 4- or 5 of the furan or thiophene ring. -asemas-SA.

s 63407

The process according to the invention is characterized in that one or more of the following reaction steps are carried out: a) condensing of the formula (X) K._ | | A compound of COOR 2 (X) wherein R is as defined above and R 2 is C 1 -C 4 alkyl, with an amide of formula 14 CON (CH 3) 2 F "I 'or II (XVI) (XVII) X- ^ v ^ CON (CH3) 2 "'^ -X -'- ^ wherein X and R ^ - are as defined above, of the formulas R _

Rl — f-] | ί | COOR 2 as compounds of XOR 3 (COII) (XII), wherein R, R and X are as defined above; b) hydrolyzing a compound of formula (XII) or (XI) to a compound of formula (A) or (B) wherein M is hydrogen; c) preparing a pharmaceutically acceptable salt of an acid of formula (A) or (B) by treating the free acid of formula (A) or (B) with an equivalent amount of a pharmaceutically acceptable base; d) the carboxylic acid function of an acid of formula (A) or (B) or an isomer (1) or (d) thereof is esterified with a C 1 -C 4 alkanol, a corresponding diazoalkane or a C 1 -C 4 alkyl iodide corresponding to a compound of formula (A) or (B) ) to a C 1 -C 4 alkyl ester; e) inorganic or organic salts of an acid of formula (A) or (B) or their individual isomers are converted into the corresponding acids

V

by reaction with an inorganic or organic acid having a p 2 value of less than 3; f) the acid of formula (A) or (B) is divided into optical isomers in a manner known per se.

g) The (d) -acid isomer or a salt thereof is racemized to the corresponding compound of formula (A) or (B).

3 63407

Another subgroup of compounds for use in medicine are compounds of formula (XIII) and acid (1) isomers of formula (XEII) and their esters and pharmaceutically acceptable salts, which subgroup may be further subdivided into subgroup (a), i.e. (dl) compounds wherein R 1 is hydrogen and X is sulfur, and (b) (1) -acid isomers of formula (B) wherein R 1 is hydrogen and X is sulfur and esters and pharmaceutically acceptable salts thereof.

The (d) -isoisomers of formulas (XIII) and DpV) and their esters and pharmaceutically acceptable salts are useful intermediates in the preparation of (dl) -acids of formulas (A) and (B), as described below.

The novel (dl) compounds of the invention can be prepared by the method depicted in the following reaction scheme: i 4 63407 NHL / GOOCH, GOOCH., I + (CXXXH R- = H-> f f2 ^ ^ X ^ GOOCH, T2 m (ID * * V ** (III) OH (I) XX, 00 X, / COOCH3 _R. OOOCH3 L · J ^ axcHg ^ ^ nJJ \ ^ oooch3 p2 X. H2j: ^ CH2 CH, ,, 7> Xv CH (IV ) I 2 v OSO-CH, 4/2 3 Xg po ·.

T2 (VI) I (VII)

! H2c I

Rx. pOOOH / R OOCH

VNiJ ^ YOOOR2 ^ "(I j OOOH

L_j ^ X Jy FL. ° 00¾ —y r1 -FI "1 i] ooor2 / Vr"; χΛιΛνγ / (X) 0 (XI) CLL0 * "mu)

s J

V R OOOR2 R. _ F i _ ^ cJFjL / 00® (Xj a (XII) (XIV) 63407

1 2 wherein X, R and R are as defined above, and R

is lower alkyl having 1 to 4 carbon atoms, e.g. methyl, ethyl, isopropyl or n-butyl.

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

In the preparation of compounds of formula (IV) wherein R is lower alkyl, preferably a straight chain mixture of 1 to 4 carbon atoms, ethanol araine (I) and dimethyl 1,3-acetone dicarboxylate (II) in water is treated with a mixture of formula (XV)

O

II

R3 to C to CH2X (XV) wherein X is bromine or chlorine, and

O

R is lower alkyl, preferably straight chain, having 1 to 4 carbon atoms, and preferably 1-bromoacetone, 1-bromo-2-butanol, 1-bromo-2-pentanol or 1-bromo-2-hexanol, about 63407 6 about 40 ° to about 100 ° C for about 0.5 ° C to 16 hours. In a preferred process, the reaction is carried out at a temperature between about -10 ° C and room temperature for about 16 hours. The reagents of formula (XV) are known compounds.

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

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

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

By 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, aliphatic alcohol, e.g. during which the corresponding free diacid of formula (VIII) is obtained, i.e. 1,2-Dihydro-3H-pyrrolo [2,2-a] pyrrole-1,7-dicarboxylic acid and its 6-alkyl derivatives. The hydrolysis is preferably performed with a solution of potassium hydroxide in aqueous methanol at reflux temperature for about 10 hours.

The C1-carboxylic acid group of the compound (VIII) is then selectively esterified by treatment with a lower aliphatic alcohol, e.g., methanol, ethanol, isopropanol, n-butanol, etc., in the presence of hydrogen chloride to give the corresponding alkyl-1 , 2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate-7-carboxylic acid.

The reaction is carried out at about 0 ° to about 50 ° C for about 1 to about 4 hours.

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

By condensing the compound (X) of formula:

R1 —1— Jj or I I

with an amide of formula (XI) R (XII) (XVI) wherein X and R1 are as defined above, the corresponding alkyl-5-substituted-1,2-dihydro-alkyls of formula (XI) or (XII) are obtained. 3H-pyrrolo [1,2-a] -8 63407 pyrrole-1-carboxylates. This reaction is performed in an inert, organic aprotic solvent in the presence of phosphorus oxychloride at reflux for about 1 to about 72 hours under an inert atmosphere and then refluxing the reaction mixture with sodium acetate for about 2 to about 10 hours. Instead of phosphorus oxychloride, other acid chlorides, such as phosgene or oxalyl chloride, can also be used.

In a preferred embodiment, this condensation is accomplished by adding a solution of compound (X) in a suitable solvent to a refluxed cooled mixture of 1.1 to 2 molar equivalents of both the desired amide and phosphorus oxychloride in the same solvent, boiling the resulting reaction mixture for about 2 to about 30 hours under argon. then adding about 3 to about 10 molar equivalents of sodium acetate and further boiling for about 4 to about 6 hours under reflux.

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

Examples of suitable N, N-dimethylamides include: N, N-dimethylthiophene-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-bromofuran-2-carboxamide, N, N-dimethyl-5-bromofuran-2-carboxamide, N, N-dimethylthiophene-3-carboxamide and n, n-dimethyl-furan-3-carboxamide.

These amides can be prepared in the usual manner from the corresponding thiophene or furan-2- (3) -carboxylic acids, i. by converting these to acid chlorides, and treating the acid chlorides with dimethylamine.

Alkaline hydrolysis of the alkyl ester group of the compound of formula (XI) or (XII) gives the free acids (XIII) or (XIV), respectively. This hydrolysis is carried out in the usual manner with an alkali metal hydroxide or alkali metal carbonate, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, sodium carbonate. , in an aqueous lower aliphatic alcohol, e.g., methanol, ethanol, etc., in an inert atmosphere at a temperature ranging from about room temperature to reflux for about 0.5 to about H hours. Preferably, this hydrolysis is performed in an aqueous-methanolic solution of potassium hydroxide at reflux for about 2 hours.

The compounds of formulas (xiii) and (XIV) may be separated into their respective individual isomers by methods known per se. For example, a compound of formula (XIII) wherein R 1 is both hydrogen and X is sulfur can be further treated according to the following reaction scheme: Resolution 63407 10 (xiii)

(XIII) - (I) -acid isomer- (d) -amphetamine salt V

(XIII) - (1) -acid isomer. Λ

Mixture of (XIII) - (d) -acid isomer- (d) -amphetamine salt 3a 1 \ (XIII) - (1) -acid isomer- (d) -amphetamine salt

A detailed description of this method is given in Example 10B-1 below.

On the other hand, the (1) acid isomers and (d) acid isomers of the compounds of formula (xiii) and (Xiv) can be obtained by applying a known high pressure liquid chromatography (HPLC) method to diastereoisomeric oC-pheners of the compounds of formulas (XIII) and (xiv) 11 63407. and then releasing the acid. For example, compounds of formula CXIII) wherein R 1 is hydrogen and X is sulfur can be further treated according to the following reaction scheme: (XIII) several reaction steps

\ U

(XIII) - (1) -acid isomer- (1) -O <- phenethyl ester)

and L

Mixture of (XIII) - (d) -acid isomer- (1) -o-phenethyl ester

separation by high performance liquid chromatography HPLC

(XIII- (1) -Acoisomeric- (1) -phenethyl- \ ester \ (XIII) - (d) -Acetic Isomer- (1) -phenethyl ester Φ J.

(XIII) - (1) Acid Isomer (XIII) - (d) Acid Isomer This method is described in detail in the Examples.

12 63407

The free acids of formula (XXII) and (XIV) may be converted to other alkyl esters having 1 to 12 carbon atoms in the alkyl by conventional methods, e.g. by treating (a) the desired ester with the corresponding alcohol in the presence of a strong mineral acid, (b) an ethereal diazoalkane solution or (c) ) with the desired alkyl iodide in the presence of lithium carbonate. The (1) -acid isomers can be converted to their alkyl esters by the above methods (b) and (c).

Salts of the compounds of formulas (XIII) and (XIV) and their (I) -ac isomers are prepared by treating these free acids with an appropriate amount of a pharmaceutically acceptable base. Examples of pharmaceutically acceptable bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, anuno-hydroxide, calcium hydroxide, magnesium hydroxide, ferrohydrok-oxide, zinc hydroxide, copper hydroxide, manganohydroksidi, alumi-hydroxide, ferric hydroxide, manganihydroksidi, isopropyl amine, trimethyl amine, diethylamine, triethylamine, tri-n-propylamine , ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, piperidin, piperidin, theobromine, , polyamine resins, etc. The reaction is carried out in water, optionally with an added 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 include methanol, ethanol, isopropanol, butanol, acetone, dioxane and tetrahydrofuran. The molar ratio of the compound of the formula (xm) or (xrv) or of its (1) acid isomer to the base is chosen to correspond to the desired salt in each case. For example, in the preparation of calcium or magnesium salts of compound (xm) or (XIV) or their (1) acid isomers, the starting free acid can be treated with at least half a molar equivalent of a pharmaceutically acceptable base to obtain a neutral salt. In preparing aluminum salts of compound (xm) or (xrv) or their (I) acid isomers to give a neutral salt, the corresponding free acid is treated with at least 1/3 molar equivalent of a pharmaceutically acceptable base. In a preferred process, the calcium salts and magnesium salts of the compounds of formula (XIII) and formula (XIV) and their (1) acid isomers may be prepared by treating their respective sodium or potassium salts with at least half a molar equivalent of calcium chloride or magnesium chloride in aqueous, aqueous, organic and organic in a mixture of a miscible solvent at about 20 to about 100 ° C. The aluminum salts of these compounds are preferably prepared by treating the corresponding free acids with at least 1/3 molar equivalent of aluminum alkoxide such as aluminum trioxide, aluminum tripropoxide, etc. in a hydrocarbon solvent such as benzene, xylene, cyclohexane and the like at about 20 to about 115 ° C. Similar methods can be used to prepare salts of inorganic bases which are not sufficiently soluble to carry out the reaction.

The isolation of the compounds described herein may, if desired, be performed by any suitable separation and purification method, such as extraction, filtration, evaporation, distillation, crystallization, thin layer or column chromatography, high pressure liquid chromatography, or combinations of these methods. Suitable separation and isolation methods are described in the examples. However, other suitable separation and isolation methods can also be used.

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

The compounds of formulas (XIII) and (XIV), their (1) -acid isomers and their pharmaceutically acceptable non-toxic esters and salts are useful as anti-inflammatory, analgesic, antiplatelet, fibrinolytic agents and smooth muscle relaxants such as addressed.

Biological tests A. Mouse analgesia test (anti-twisting)

Execution of the test

The test compound (0.001, 0.0033 and 0.03 mg) or the reference compound (0.33, 1 and 3 mg of acetylsalicylic acid) is administered orally at the beginning of the experiment by forced feeding in aqueous medium to male Swiss-Webster mice weighing 18-20 g. After 20 minutes, mice are injected intraperitoneally with 0.25 ml of 0.02% phenylquinone solution. This solution causes warping. The writhing of the animals is then observed for the next 10 minutes.

14 63407

Evaluation of the results;

The total number of twisting mice and the average number of twists per mouse are noted.

The above test result showed that 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has about 350-fold analgesic activity compared to acetylsalicylic acid, and (1 ) -5- (2-thenovyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has about 670-fold analgesic activity compared to acetylsalicylic acid.

The analgesic activity of the following compounds was determined:

Activity 5- (5-methyl-2-thenoyl) -1,2-dihydro-3H-80 pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (3-furoyl) -1,2-dihydro-3H -pyrrolo-about 45 [1,2-a] pyrrole-1-carboxylic acid 5- (2-thenoyl) -6-methyl-1,2-dihydro-3H-about 200 pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (4-chloro-2-thenoyl) -1,2-dihydro-3H-about 130 pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo 160 / 5-, 2-α-pyrrole-1-carboxylic acid B. Anti-inflammatory activity test using carrageenan-induced inflammation of rat paws Test procedure: Female Simonsen rats weighing 80-90 g are used, Test compound (0.0033, 0.01, 0 , 09 and 0.27 mg) are given in 1 ml of aqueous medium at the beginning of the experiment by forced feeding. One hour later, 0.05 ml of a 1% (0.9% NaCl) carrageenan solution is injected into the right hind paw. This causes the paw to become inflamed.

4 hours after the start of the experiment, the rats are sacrificed, the hind legs are removed and weighed separately.

Evaluation of the results:

Paw size increase is calculated as a percentage as follows: right paw weight - left paw weight χ left paw weight 15 63407

The above experiment showed that (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (95% confidence limits: 32-72) has, compared to phenylbutazone 48-fold anti-inflammatory activity.

The anti-inflammatory activity of the following compounds was determined (comparison: phenylbutazone):

Activity 5- (5-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (3-furoyl) -1,2-dihydro-3H-pyrrolo 3,2-α-pyrrole-1-carboxylic acid 5- (2-thenoyl) -6-methyl-1,2-dihydro-3H-27 pyrrolo [1,2-b] pyrrole-1-carboxylic acid 5- (4-chloro -2-Tenoyl-1,2-dihydro-3H-19-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo-about 30 / 1,2- α-pyrrole-1-carboxylic acid dl-methyl-5- (2-thenoyl) -1,2-dihydro-60H-pyrrolo [1,2-a] pyrrole-1-carboxylate dl-octyl-5- (2-thenoyl) -1 1,2-dihydro-3H-pyrrolo [2,2-a] pyrrole carboxylate dl-dodecyl-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate dl Sodium 5- (5-methyl-2-thenoyl) -1,2-dihydro-10H-pyrrolo [1,2-a] pyrrole-1-carboxylate dl-sodium 5- (3-fyroyl) -1,2- dihydro-3H-3-pyrrolo [1H-pyrrole-1-carboxylate dl-sodium 5- (2-thenoyl-6-methyl-1,2-dihydro-27H-pyrrolo [1,2-a] pyrrole-1- carboxylate y C. Antipyretic activity test Test performance: Simonsen female rats weighing 90-100 g are used. The rats 'normal' rectal temperature is measured at the beginning of the test, and then they receive by subcutaneous injection of 2 ml of the yeast suspension (1 mL right and 1 mL to the left side). The sites of injection rubbed into the suspension to alleviate under the skin. Kiivainjektio cause hyperthermia (fever). 17 hours after the start of the experiment rats were rubbed again 18 hours after the start of the experiment, a second rectal temperature is measured, followed by the test compound (0.03, 0.09, 0.27 and 0.8 mg of the tenoyl compound or the reference compound (0.5, 1.5, 16 63407 and 4.5 mg of acetylsalicylic acid). ) is administered orally by gavage in 1 ml of aqueous medium. The third rectal temperature is measured 2 hours after administration of the test compound.

Evaluation of the results:

Calculate the temperature drop (° C) between the second and third measurements.

The above test result showed that 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has a 17-fold antipyretic activity compared to acetylsalicylic acid.

D. Acute oral toxicity (LD50) in mice.

Test performance:

The test compound is suspended in a 2% aqueous starch solution. Concentrations of the compound are selected so that the doses are 0.1 ml / 10 g body weight. 6 groups of mice are used, each with 6 female Swiss-Webster mice. Mice are administered a single oral dose of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid via gastric tube at a dose of 50, 100, 200 kg / kg body weight. 400, 800 or 1000 mg. The mice are then observed for 2 weeks.

In the above experimental run, the acute toxicity of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid LD50 was obtained at 631 mg / kg ha with 95% confidence limits of 404-991 mg / kg.

The compounds of formula (XIII) and (XIV) described above and their (1) acid isomers, as well as their non-toxic, pharmaceutically acceptable esters and salts, are also relaxants of uterine smooth muscle and are therefore suitable for use in the maintenance of maternal and / or fetal pregnancy. until, on medical grounds, termination of the pregnancy can be considered a viable or more advantageous option for the mother and / or the fetus. However, it is clear that in certain cases, e.g. after childbirth has already begun (i.e., the mother already has uterine contractions), especially near-end contractions), administration of the compounds described herein can induce pregnancy to last indefinitely. In such cases, the pregnancy is usually slightly prolonged, which may be beneficial for the mother and / or fetus.

Compounds of formula (XIII) and (XIV) and acid isomers of (1) and their pharmaceutically acceptable non-toxic esters 63407 and salts, in particular for retarding or delaying the onset of labor. As used herein, the term "delaying delivery" means delaying delivery due to administration of compounds of formula (XIII) or (XIV) or (1) acid isomers or pharmaceutically acceptable, non-toxic esters or salts thereof at any time prior to the onset of uterine muscle contractions. Thus, this term also includes the prevention of miscarriage in early pregnancy (i.e., before the fetus is viable) and the delay in preterm delivery, a term sometimes used for premature burns in later pregnancy, in which case the fetus is considered already viable. In both cases, drugs are administered as prophylactic drugs to prevent the onset of labor. Such drug administration is particularly useful for the treatment of women who have a history of spontaneous abortions or premature births (i.e., births before full pregnancy). Such administration is also preferred if there are symptoms that the pregnancy may end before its termination is considered beneficial to the mother and / or fetus.

In the case of animals, this treatment can be utilized to adjust the births of multiple pregnant animals to occur simultaneously or at a desired time (or near desired time) and at a desired location, at which point the births can then be more easily treated.

As used herein, the term "postpartum postponement" means postpartum postponement after the onset of uterine muscle contractions due to administration to a patient of a compound of formula (XIII) or (XIV) or an (1) acid isomer or pharmaceutically acceptable esters or salts thereof. The results obtained with the compounds of the invention are affected by the condition of the patient, including the duration of pregnancy at the onset of the contractions, the intensity of the contractions and how long the contractions have continued. The effect may also occur, for example, as a reduction in the intensity and / or duration of the contractions (thereby prolonging the duration of the birth event itself), or as a cessation of the contractions. In either case, the effect is to prolong the gestational age, although depending on the condition of the patient, as already described above, the effect may be mild or somewhat stronger under appropriate conditions. Such administration of a drug may be intended to prevent miscarriage, to facilitate the course of childbirth for the mother. and / or make them less painful or cause them to occur at a more convenient time and / or place.

In all cases, the administration of a compound of formula (A) or (B) or (1) acid isomers or pharmaceutically acceptable, non-toxic esters or salts thereof for the purposes set forth herein should be in accordance with best and / or acceptable medical (or veterinary) practice to maximize maternal benefit. and the fetus. For example, medication should not be continued after such a full waiting period that the fetus dies in the womb.

The following manufacturing examples and actual examples illustrate the invention. The abbreviation t.l.c, means thin layer chromatography, and all liquid mixture ratios are expressed as volume ratios. If necessary, the examples are also repeated to prepare additional material for the following examples. Unless otherwise stated, the reactions are performed at room temperature (20 ° to 30 ° C).

Preparation 1 N, N-Dimethyl-4-chlorothiophene-2-carboxamide

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 refluxed under anhydrous conditions for 4 hours. Excess thionyl chloride is removed and the residue is distilled under reduced pressure (60 ° C / 2 mm) to give 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 an ice-water bath, and dimethylamine is slowly passed through the solution for 30 minutes. The ice-water bath is removed and the dimethylamine is added for a further 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 10% hydrochloric acid, saturated sodium dicarbonate solution, dried over sodium sulphate and evaporated to dryness under reduced pressure. dimethyl-4-chloro-thiophene-2-carboxylic carboxamides.

Similarly, the thiophene and furan-2-carboxylic acids listed in column I below are converted to the N, N-dimethylamides listed in column II.

19 63407

I II

Thiophene-2-carboxylic acid N, N * -dimethylthio, phenene-2-carboxamide

Furan-2-carboxylic acid N, N, N-dimethylfuran-2-carboxamide 5-methylthiophene-2-carboxy-N, N, N-dimethyl-5-methylthiophene-2-silicic acid carboxylamide 3-methylfuran-2-carboxy Dimethyl-3-methylfuran-2-ylic acid carboxamide 4-methylfuran-2-carboxy-N, N4-dimethyl-4-methylfuran-2-silicic acid carboxamide Thiophene-3-carboxylic acid N, N-dimethylthiophene-3-carboxamide Furan-3- carboxylic acid N, N-dimethylfuran-3-carboxamide.

Preparation 2

Methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate A 250 ml 3-neck round bottom flask equipped with a magnetic stir bar and a CaCl 2 -filled drying tube is connected (via one neck) directly to the receiving adapter and a short ( 7.5 cm) via a water separator to an acetal pyrolysis apparatus. This apparatus comprises a 100 ml round bottom flask previously charged with 15.6 g of oxalic acid dihydrate and 11.82 g of bromoacetaldehyde diethyl acetal prepared from vinyl acetate P.Z. Bedoukian 1 in, J.Am.Chem.Soc. 66, 651 (1944) on a 15 cm Vigreux column with a thermometer connected to the above-mentioned water separator cooler.

3.36 g of ice-cooled (0 ° -10 ° C) ethanolamine are introduced into a 3-necked flask, to which 8.7 g of dimethyl 1,3-acetonedicarboxylate are added dropwise with stirring. In this case, methyl 3-carbomethoxymethyl- (2'-hydroxyethyl) aminoacrylate is immediately formed.

(III). At the end of the addition, the ice bath is removed and 100 ml of dry acetonitrile are added to the mixture. The pyrolysis part of the apparatus is placed in an oil bath and the temperature is raised to 150-160 ° C. The bromoacetaldehyde formed is distilled (b.p. 80-83 ° C / 580 mm) directly into a solution of vinylamine (III) stirred with a magnetic stirrer. When the distillation temperature drops below 80 ° C, the pyrolysis apparatus is removed and replaced by a reflux condenser equipped with a CaCl 2 drying tube. The solution is heated under reflux for 1 hour, the solvent is removed under reduced pressure, and 200 ml of methanol and 20 g of silica gel are added to the residue. This mixture is evaporated to dryness in vacuo and the residue is applied to the top of a column packed with 200 g of silica gel in hexane. This pad is then eluted with hexane / ethyl acetate (80; 20, 500ml) and hexane / ethyl acetate (1: lf9). x 500 ml). Fractions 2 and 3 have less polar impurities and dimethyl 1,3-acetonedicarboxylate; fractions 4-8 give 4.1 g of methyl N- (2-hydroxyethyl) -3-carbraethoxypyrrole-2-acetate (IV, R = H) which, recrystallized from ether / hexane has a m.p. 52-54 ° C.

Preparation 3

Methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate 3.36 g of ethanolamine are introduced into a 3-neck round bottom flask equipped with a 250 ml magnetic stirrer and a CaCl 2 drying tube, cooled in an ice bath to 0-10 ° C and then 8.7 g of dimethyl 1,3-acetonedicarboxylate are added dropwise with stirring. In this case, methyl 3-carbomethoxymethyl-3- (21-hydroxyethyl) aminoacrylate crystals (III) are immediately formed. At the end of the addition, the ice bath is removed and 80 ml of dry acetonitrile are added to the mixture. 6.75 g of bromoacetaldehyde in 20 ml are then added dropwise to the reaction mixture; in acetonitrile, and the mixture was heated to reflux for 2 hours. The solvent is evaporated off under reduced pressure, and 200 ml of methanol and 20 g of silica gel are added to the residue. This mixture is evaporated to dryness in vacuo and the residue is applied to the top of a silica gel column packed with hexane (200 g, silica gel) and eluted with hexane / ethyl acetate (1: 1) to give methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole. -acetate (IV, R = H), which is identical to the compound obtained in Preparation 2.

Preparation 4

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

To a solution of 6 ml of ethanolamine in 5 ml of water is added 1.74 g of dimethyl 1,3-acetonedicarboxylate. The resulting mixture is rapidly cooled to -10 ° C and 1.67 ml of dropwise is added dropwise with stirring over 15 minutes. 1-bromoacetone, in which case the temperature must not rise above 40 ° C during the addition. After the addition was complete, the dark reaction mixture was stirred for an additional hour at room temperature, then poured into hydrochloric acid / ice saturated with solid sodium chloride and extracted with ethyl acetate (3x100ml). The combined organic extracts were washed with cold water until neutral Chromatography of the residue on 30 g of silica gel, eluting with hexane / ethyl acetate (70:30), gives 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, which recrystallized from methyl chloride / hexane is m.p. 78 ° and the following analysis:

Calculated from C 56.45, H 6.71

Found: C 56.41, H 6.73

Preparation 5

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

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 at -10 ° C to -5 ° C 1.46 ml of methanesulfonyl chloride. The reaction is monitored by tlc analysis using chloroform / acetone (90:10). At the end of the reaction (about 30 minutes after the addition of methanesulfonyl chloride is complete), 10 ml of water are slowly added to the mixture. The organic phase is separated, washed with water (3x30ml), dried over sodium sulphate and evaporated under reduced pressure. The residue is crystallized from dichloromethane / hexane to give 4.75 g (77.7%) of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H), m.p. 99-101 ° C;

Preparation 6

Methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate A solution of 785 mg of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodide in 10 ml: in acetonitrile, reflux for one hour. The cooled reaction mixture is evaporated to dryness under reduced pressure and the residue is triturated with water. The insoluble matter is filtered off and air-dried to give 840 mg (97%) of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = H), m.p. 137-138 ° C.

Preparation 7 1,2-Dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid a) A solution of 1 g of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate In 5 ml of dry dimethylformamide, stirred under an argon atmosphere together with a 50% sodium hydride mineral oil suspension (137 mg). The reaction mixture is allowed to stand at room temperature for 30 minutes, then poured into 100 ml of water. The product is extracted with ethyl acetate (3Lx5Qro 1). The combined extracts are washed with water, dried over magnesium sulphate and evaporated to dryness. Chromatography of the residue on 20 g of silica gel using hexane / ethyl acetate (4: 1) as eluent gives 500 mg (80%) of dimethyl 1,2-dihydro-3H-pyrrolo-1,2-pyrrole-1,7'-dicarboxylate (VII , R = H), m.p. 70-71 ° C, b) A solution of 1.80 g of diraethyl 1,2-dihydro-3H-pyrrolo [1'-2-pyrrole-1,7-dicarboxylate in 20 ml of methanol is treated with potassium hydroxide (4.48 g) in water (20 ml) by refluxing the reaction mixture for 6 hours. The cooled solution is evaporated to dryness and the residue is taken up in 50 ml of saturated sodium chloride solution. The resulting solution is acidified with 6N hydrochloric acid and extracted with ethyl acetate (3x50ml). The combined extracts are dried over magnesium sulphate and evaporated to dryness under reduced pressure to give 1.51 g (95%) of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (VIII, R = H). , sp. 220 ° C, decomposes.

Preparation 8

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

Preparation 9

Isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid A solution cooled in an ice bath containing 1.34 g of 1,2-dihydro-3H-pyrrolo [1], 2-α7-Pyurol-1,7-dicarboxylic acid in 50 ml of isopropanol is saturated with hydrogen chloride gas, keeping the temperature of the reaction mixture below 50 ° C. The ice bath is removed and the reaction mixture is stirred for 1.5 hours at room temperature, the mixture is evaporated to dryness under reduced pressure, 10 ml of benzene are added to the residue and the solution is again evaporated to dryness in vacuo. This is repeated a total of 3 times to completely remove excess hydrogen chloride. There are thus obtained 1.58 g (96%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid 2 (IX, R = H, R = iC3H7), which crystallizes methanol / ethyl acetate is m.p. 144-145 ° C.

In a similar manner, however, using methanol instead of the isopropanol used in the above process is obtained;

Methyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Preparation 10

Isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole carboxylate 1.054 g of isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid are heated to 240- At 250 ° C in a dry 10 ml round bottom flask, and the reaction product is distilled directly from the reaction vessel. In this way, 745 g (87%) of isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X, R = H, R = iC2H2) are obtained in the form of a pale yellow oil having the following physical constants: ; U.V .: 215 nm (6020); IR: λmax 17 1725 cm -1. 1 H NMR,: 1.22 (d, J = 7 Hz, 6 H), 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, 1 H).

Preparation 11

Isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate is introduced into a 100 ml 3-necked flask equipped with a condenser, a nitrogen inlet tube and a wash flask through which the exhaust gas bubbles. 0.0 g of isopropyl, 1,2-dihydro-3H-pyrrolo [f] 2-pyrrole-1-carboxylate-7-carboxylic acid. The apparatus is thoroughly purged with nitrogen, then the nitrogen flow is stopped. The apparatus is immersed in a 270 ° C oil bath, and the reaction is monitored by monitoring the evolution of CCl 4 (wash flask) and tlc analysis on silica gel using benzene / dioxane / acetic acid (90: 10: 1) for evolution. After 45 minutes, the reaction is almost complete. After 1 hour, the reaction vessel is removed from the oil bath and the contents of vessel 24 6 3 4 0 7 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 K-chromatography on a 100 g silica gel column, Hexane / benzene (70; 30; ) and hexane / benzene (50; 50) eluted 2.77 g (68%) of isopropyl 1,2-dihydro-12H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X, R = H, R = iC ^ H ^) as an oil having the same physical constants as the compound obtained in Preparation 10.

Preparation 12

Following the procedure of Preparation 10 or 11, the compound obtained in Preparation 9 is converted to methyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, respectively.

Preparation 13

Isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate

Following the procedure of Preparation 5, methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R = CH 2) methyl-N- (2-mesyloxyethyl) -3-carbomethoxy-4- to methyl pyrrole-2-acetate, which is then cyclized with sodium hydride in dimethylformamide by the method of Preparation 8 to give dimethyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-d] pyrrole-1,7- dicarboxylate,

By hydrolysis of the latter compound with potassium hydroxide by the method of Preparation 7 and then selective esterification * | Cl position and decarboxylation at the C-7 position by the methods set forth in Preparations 9 and 11 sequentially affords 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-d] pyrrole-17-dicarboxylic acid, isopropyl-1,2-dihydro -6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid and isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-b] pyrrole 1-carboxylate (X, R = CH 2, R = iC 2 H 2).

Example 1

Isopropyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate

A solution of 232.5 mg of N, N-diraethylthiophene-2-carboxamide and 0.15 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is refluxed for 30 minutes. To this solution is added 181 mg of isopropyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 2 ml of 1,2-dichloroethane. The reaction mixture is refluxed under argon for 8 hours, 450 mg of sodium acetate are added, and the mixture is refluxed for a further 5 hours. The resulting mixture is then evaporated to dryness and the residue is chromatographed on 12 g of silica gel, eluting with hexane: ethyl acetate (3: 1) to give isopropyl-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1 , 2-pyrrole-1-carboxylate (X, R and R 1 HH, R 2 = IC 3 H 7, X = S).

Condensation of the compounds obtained in Preparation 10 with N, N-dimethylthiophene-2-carboxamide as described in Example 1 gives, respectively: ethyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-one. carboxylate MeOH 2,328,7580, 17780).

O IQcLX s

Following the procedure described in Example 1 and using 1.1 to 2 molar equivalents of the following compounds obtained in Preparation 1: N, N-dimethylfuran-2-carboxamide, N, N-dimethyl-5-methylthiophene-2-carboxamide N, N-dimethyl-4- chlorothiophene-2-carboxamide N, N-dimethylthiophene-3-carboxamide, N, N-dimethylfuran-3-carboxamide instead of Ν, Ν-dophenylthiophene carboxamide, and monitoring the reaction by thin layer chromatography gives the following compounds, respectively: isopropyl 2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-d] pyrrole-1-carboxylate, as an oil having the following physical constants: UV 275, 332.5 nm (8900, 17800): I.R. V ffi1 1735, 1685, 1605 cm -1; mp CDCl 3 Sms 1'23 {d '6H' J = 6 Hz? (Ch 3) 2ch), 2.60-3.00 (m, 2H), 3.90 (dd, 1H, 6 Hz; JBX = 7 Hz; H1), 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); MS m / e 287 (M +) 26 63407 isopropyl-5- (5-methyl-N, N-tenoyl) -R 2 "-dihydro-3H-pyrrole; "1,2-N-pyrrole-1-carboxylate having a m.p. 82 ° -82.5 ° C, isopropyl 5- (4-chloro-2-thenoyl-1,2-dihydro-3H-pyrrolo) T, 2- [a] pyrrole-1-carboxylate, oil, isopropyl-5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp 67-68 ° C, isopropyl -5- (3-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate, oil.

Hydrolysis of the isopropyl ester group according to Example 3 or 4 gives the corresponding free acids: 5- (2-fyroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid having m.p. 184 to 184.5 ° C.

5- (5-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 169-170 ° C.

5- (4-chloro-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 169.169-5 ° C, 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [2,2-a] pyrrole-1-carboxylic acid, m.p. 166-167.5 ° C, 5- (3-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 156 ° C.

Following the procedure of Example 1, isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate is condensed with N, N-dimethylthiophene-2-carboxamide to give isopropyl-5- ( 2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate (XI, R = CH2, R2 = H, R2 = IC = S) having m.p. 102 ° C;

Example 2

Isopropyl-5- (3-thenoyl-l, 2-dihydro-3H-pyrrolo / l, 2-a7pyrro-li-l-carboxylate

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. To this solution is added 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. The reaction mixture is refluxed under argon for 8 hours, then the solution is treated with 450 mg of sodium acetate and refluxed again for 5 hours. The resulting mixture is evaporated to dryness and the residue is chromatographed on 12 g of silica gel, eluting with hexane / ethyl acetate (3: 1) to give isopropyl-5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo / T, 2-α7-pyrrole-1-27 63407 carboxylate (XIf R = Hf R2 = iC3H7, X = S),

By the same procedure, using N, N-dimethylfuran-3-carboxamide instead of N, N-dimethylthiophene-3-carboxamide, the corresponding 5- (3-furoyl) derivative is obtained: isopropyl-5- (3-furoyl) -1,2- dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate, oil having the following physical constants: U, v · MeOH 222 244-277 (shoulder) 314 nm 'max r (6750, 4250, 14800) ? I.R. CHC1-.

VI3Q, 1610, 1560 cm-1; max N.M.R. CDCl3, STMS 1 * 23 (d '6H, J = 6 Hz? (CH) j 2CH).

2.50-3.00 (m, 2H), 3.92 (dd, 2H, = 6Hz, JBX = 7Hz; H1), 4.10-4.60 (m, 2H), 4.95 (sept., 1H, J = 6 Hz (CH3) 2CH), 5.95 (d, 1H, J = 4Hz; H-7), 6.78 (m, 1H) 6.83 (d, 1H, J = 4Hz) ? H-6), 7.30 (m, 1H), 7.83 ppm (m, 1H)? M.S. m / e 270 (M &lt; + &gt;),

Example 3 I% w n \% Ί 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate

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 a 50% water / methanol mixture which containing 1% potassium hydroxide, refluxed under nitrogen for 2 hours. The methanol is then removed under reduced pressure and the residual basic solution is diluted with water and extracted with chloroform to remove the unsaponifiable product. The alkaline aqueous phase is acidified with 20% hydrochloric acid and extracted 3 times with ethyl acetate. The combined extracts are dried over sodium sulphate and evaporated to dryness under reduced pressure to give 250 mg of crude 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid ((B), R = H, X = S).

28 63407

By the same procedure, 5- (3-furoyl) -1,2-dihydro-3H-pyrrolo [1,1'-pyrrole-1-carboxylic acid having a mp of 156 ° C is obtained from the corresponding isopropyl-5- (3-furoyl) compound.

Example 4 5- (2-Tenoyl) -1H-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

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% KOH, refluxed under nitrogen for 2 hours, the methanol is removed under reduced pressure, and the remaining basic solution is diluted with water and then extracted with chloroform to remove the unsaponifiable product. The alkaline aqueous phase is acidified with 20% hydrochloric acid and extracted 3 times with ethyl acetate. The combined extracts are dried over sodium sulphate and evaporated to dryness under reduced pressure to give 250 mg of crude 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid ((A), R and R1 = H, X = S) having m.p. 145-148 ° C, recrystallized from ethyl acetate, m.p. 152-153 ° C, dec.

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

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 690 mg of potassium carbonate. in ml of water. The reaction mixture is refluxed under nitrogen for 2 hours, cooled and evaporated to dryness. The residue is dissolved in 10 ml of 10% hydrochloric acid and 50 ml of water and the resulting mixture is extracted with ethyl acetate (2x50ml). The combined extracts are dried over magnesium sulphate 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 obtained in Example 4. Example 6

1 I «I I 1 · I I

5- (2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo £ T a7pyrro-2-yl-l-carboxylic acid

A solution of 500 mg of isopropyl 5- (2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate in 15 ml of methanol is treated with a solution of is 1.05 g of potassium carbonate in 8 ml of water. The reaction mixture is refluxed under nitrogen for 3 hours, cooled and evaporated to dryness. The residue is dissolved in 10 ml of 10% aqueous hydrochloric acid and 50 ml of water, and the resulting mixture is extracted with ethyl acetate (3 x 50 ml). The combined extracts are dried over magnesium sulphate 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 = CH 2, R 2 = H, X = S), m.p. 166 ° C.

Example 7 (1) -5- (2-Tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid 410 mg of 5- (2-thenoyl) -1,2-dihydro -3H-Pyrrolo [1,2-a] pyrrole-1-carboxylic acid and 212.3 mg of (d) -amphetamine are dissolved in 15 ml of absolute methanol, and the solution is refluxed for 15 minutes, after which the methanol is removed in vacuo. The resulting diastereoisomeric (d) -amphetamine salt mixture (612.3 mg) is dissolved in as little hot (55 ° C) acetone as possible, the solution is cooled to room temperature, filtered and washed with 2 ml of cold (-10 ° C) acetone. This crystallization procedure is repeated 3 more times to give 247 mg of (1) -5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (d) -amphetamine salt. with wCHCl, -181 ° and m.p. 168-170 ° C.

D J

The (1) -acid isomer1- (d) -araphetamine salt obtained above is added to 30 ml of methylene chloride and shaken with 0.1 N aqueous hydrogen chloride solution (3 x 10 ml). The methylene chloride solution is washed 3 times with 15 ml of saturated NaCl solution / water (2: 1 v / v) and dried over anhydrous sodium sulfate. Filtration and evaporation in vacuo give an organic solvent 90 mg of (1) -5- (2-thenoyl) -1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid with O2-CHCl3 -177 ° and m.p. 134 to 135.5 ° C.

D

The acetone mother liquors obtained from the resolution (i.e., multiple crystallization) of the diastereomeric (d) -amphetamine salt mixture described above are combined and converted to the mixture (245 mg) f enriched with (d) -5- (2-thenoy) using the HCl decomposition method described above. ) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid and containing (1) -5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo / 1,2-a / pyrrole-l-carboxylic acid. This mixture is racemized (recycled) as follows by recirculation of 5- (2-tetra-6H-4H-pyrrolo) [1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (d ) and (1) isomers; 245 mg of the mixture described above, in which the (d) -isomer is enriched and containing the (1) -isomer, are dissolved in 15 ml of methanol. To the solution are added 1.5 ml of methanol and 350 mg of sodium hydroxide and the mixture is refluxed under nitrogen for 1 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 HCl. 10 ml portions of methylene chloride, and the methylene chloride extracts are combined and washed to neutral (pH 7), dried over anhydrous sodium sulfate and evaporated in vacuo to give 230 mg of crude crystalline product, which is recrystallized from ethyl acetate / hexane-2-ol to give 180 mg of 5- (5) 1,2-dihydro-3H-pyrrolo / l, 2-§7-

pyrrole-1-carboxylic acid with fvMeOH

D 0.0 ° and m.p. 152-154 ° C;

Example 8 (1) -5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylic acid

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 is added 0.234 g of trifluoroacetic anhydride. at room temperature for 10 minutes, and the resulting solution is cooled to 0-5 ° C, and 0.55 g of dry triethylamine is added thereto, followed immediately by 0.2 g of (1) -C (1-C-phenylethyl) alcohol. at room temperature, and then the mixture is poured into 20 ml of water containing 1 ml of triethylamine, then extracted with ethyl acetate.The ethyl acetate extracts are dried over sodium sulfate, the solvent and excess (1) - (E-phenylethyl alcohol) are removed in vacuo to give 0.166 g (1) -5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (1) -OC-phenyl ester and (d) -5- (2-thenoyl) Mixture of 1,2-dihydro-3H-pyrrolo [1,2-d] pyrrole-1-carboxylic acid (1) - (X-phenyl ester) separated by high performance liquid chromatography (using 4% EtOAc / h). exane mixture, 11 mm x 50 cm column, 10 μm Lichro-sorb Sl-60) to give 68 mg of a more polar ester (c <_ 149 ° C) and 73 g of a less polar ester ((X ”eOH + 105.2 °) # 63407

62.1 g of the more polar ester are dissolved in 3 ml of dry benzene, the solution is cooled to 15-20 ° C and 2.5 ml of trifluoroacetic acid are added, and the solution is stirred at room temperature for 1 hour 40 minutes. The reaction solution is then poured into 60 ml of dry benzene and the solvents are evaporated off under vacuum at room temperature. Purification is performed by high performance liquid chromatography (using the same column as above, 4%; instead of EtOAc / hexane, a 35% solution of EtOAc / hexane in 0.5% acetic acid is used) to give 41 mg of (1) -5- (2- thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid with

- 144 ° and m.p. 130-132 ° C.

Similarly, the less polar ester is decomposed by the method described above to give (d) -5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid having +142.4 ° and m.p. 127-129 ° C. The (d) -acid isomer thus obtained can, if desired, be racemized (and reactivated) in a manner known per se.

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

Example 9

A solution of 300 mg of 4- (2-thenoyl) -1,2-dihydro-3H-pyrro-LoU, 2-ol-pyrrole-1-carboxylic acid in 5 ml of isoamyl alcohol is saturated with hydrogen chloride. After 24 hours, the excess alcohol is distilled off in vacuo and the residue is purified by chromatography on alumina to give isoamyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate ♦

Similarly, the use of other alcohols instead of isoamyl alcohol, e.g., benzyl, hexyl, octyl, nonyl, dodecyl alcohol, etc., gives the corresponding 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [T, 2 α-pyrrole-1-carboxylic acid esters, e.g. octyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate (oil) and dodecyl-5- ( 2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 48-50 ° C, etc.

Example 10

To a solution of 300 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of sodium hydroxide as a 0.1 N solution. .

32 6 3 4 0 7

The solvent is evaporated off under reduced pressure and the residue is dissolved in 2 ml of methanol. Precipitation with ether gives crude sodium (2-thenoyl) -1H-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, which can be crystallized isopropanol.

In a similar manner, other salts of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, e.g. ammonium and potassium salts, are prepared using ammonium or potassium hydroxide instead of sodium hydroxide.

Similarly, the other 5-substituted 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid compounds prepared above can be converted to the corresponding sodium, potassium and ammonium salts. Examples of these salts are: sodium (1) -5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, sodium 5- (2-furoyl) - 1,2-Dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, sodium 5- (4-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] p-pyrrole-1-carboxylate, potassium 5- (4-chloro-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-d] pyrrole-1-carboxylate, potassium 5- ( 5-bromo-2-thenoyl) -1,2-dihydro-5H-pyrrolo, 1H-2 (α-7-pyrrole-1-carboxylate, sodium 5- (3-methyl-2-furoyl) -1,2- dihydro-3H-pyrrolo [1,2-e] pyrrole-1-carboxylate, ammonium 5- (2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, ammonium-5 - (3-chloro-2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, sodium 5- (4-methyl-2-thenoyl) -1 , 2-dihydro-6-ethyl-3H-pyrrolo [2,2-b] pyrrole-1-carboxylate, potassium 5- (5-chloro-2-thenoyl) -1H-dihydro-6-methyl-3H-pyrrolo] HL, 2-pyrrole-1-carboxylate, ammonium 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate acetate and sodium 5- (3-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

33 63407

Example 11

To a solution of 237 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylic acid in 8 ml of roethanol is added 1 molar equivalent of potassium hydroxide as a 0.1 N solution, to give a solution containing potassium 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylate. 50 mg of calcium carbonate are dissolved in an amount of 1N hydrochloric acid which just causes the calcium carbonate to dissolve, the solution is buffered with 100 mg of solid ammonium chloride, then 5 ml of water are added to the solution. The buffered calcium solution thus obtained is added to a solution of potassium 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo, E, 1,2-α-pyrrole-1-carboxylate and the precipitate obtained is filtered, washed with water and air-dried. to give calcium 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Similarly, using magnesium carbonate instead of calcium carbonate gives magnesium 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

In a similar manner, using the following compounds instead of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid: (1) -5- (2-thenoyl) -1,2- dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylic acid, 5- (2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (4-chloro-2-thenoyl) -1,2-dihydro-3H-pyrrolo [2,2-b] pyrrole-1-carboxylic acid, 5- (3-methyl-2-thenoyl) -1,2-dihydro-3H -pyrrolo [1,2-a] pyrrole-1-carboxylic acid, 5- (5-bromo-2-furoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [2H-pyrrole-1-carboxylic acid and 5 - (3-Chloro-2-furoyl) -1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-b] pyrrole-1-carboxylic acid gives the corresponding calcium and magnesium salts.

Example 12

To a solution of 237 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 8 ml of methanol is added 1 molar equivalent of potassium hydroxide as a 0.1 N solution. The solvent is evaporated and the residue is dissolved in 5 ml of water. An aqueous solution of potassium 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [2H] pyrrole-1-carboxylate thus obtained is added to a solution of 110 mg of cuprin nitrate trihydrate in 5 ml of ye. The precipitate formed is filtered off, washed with water and air-dried to give copper (2-Teno-yl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-β-carboxylate,

Similarly, other free acids are converted to the corresponding copper salts.

Example 13

To a solution of 237 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 15 ml of hot benzene is added 59 mg of isopropylamine. The solution is allowed to cool to room temperature and the product is filtered, washed with ether and dried to give 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylic acid isopropylamine salt.

In a similar manner, other salts of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-b] pyrrole-1-carboxylic acid are prepared, e.g. diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts using the corresponding amines instead of isopropylamine.

In a similar manner, other free acids can be converted to the corresponding isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts.

Claims (1)

35 63407 A process for the preparation of 5- (2-furoyl) according to the therapeutically useful formulas 7 or R__ r1-i- 1 1 IL 500M rl il ^ co ° «'Il / ΓΊΤ Pä s L_T (A) 0 3 - 3 XJ (B) 5 '- (2 * -tenoyl) -, 5 "P-furoyl) - and 5- (3-thenoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole) - for the preparation of 1-carboxylic acid derivatives or their (1) ^ acid isomers in which X is oxygen or sulfur, R is hydrogen or C 1 -C 4 alkyl, R 1 is hydrogen, methyl, chlorine or bromine, and M is hydrogen, C 1 -C 4 alkyl or a pharmaceutically acceptable, non-toxic cation, wherein the R 1 substituent of the compound of formula (A) is in the 3-, 4- or 5-position of the furan or thiophene ring - characterized in that one or more of the following reaction steps: a) condensing a compound of formula (X) 1 -COOR 2 (X) 2 N '- 2, wherein R is as defined above and R is C 1 -C 4 alkyl, with an amide , of the formula _ __r ^ € ON (CH) .R1 -E ^ JLcON (ch, or IL * J (XVII) <XVI) where X and R ^ denote s as above, to compounds of formulas P H coor2 B ~ T I Joor2 trxs (XII) (XI) 1 2, wherein R, R, R and X are as defined above; B) hydrolyzing a compound of formula (XII) or (XI) to a compound of formula (A) or (B) wherein M is hydrogen; c) preparing a pharmaceutically acceptable salt of an acid of formula (A) or (B) by treating the free acid of formula (A) or (B) with an equivalent amount of a pharmaceutically acceptable base; d) the carboxylic acid function of the acid of formula (A) or (B) or of its (1) or (d) isomer is esterified with a C 1 -C 4 alkanol, the corresponding diazoalkane or a C 1 -C 4 alkyl iodide corresponding to the formula (A) or A C 1 -C 4 alkyl ester according to (B); e) inorganic or organic salts of an acid of formula (A) or (B) or their individual isomers are converted into the corresponding acids by reaction with an inorganic or organic acid having a p value of less than 3; f) the acid of formula (A) or (B) is divided into optical isomers in a manner known per se; g) the (d) -acid isomer or a salt thereof is racemized to the corresponding compound of formula (A) or (B), 37 Patentkr 63407 For the preparation of a therapeutic agent 5- (2-furoyl) -, 5 * · (2-tenoyl) * > r 5 ^ (3 ^ f uxoyl) ^ och 5 ^ (3 * 'tenoyl) "? 2'-dihydroOH-pyrrolo [T, 2-§7pyrrole-1'-carboxylic acid derivatized with the form r1 -1 * eiier n il qoom ΓίΤ — ΐΓ π 1 «A» ° ^ ° or a derivative (1) -syrisomer, in which form X is a substituent or a sva, R is a substituent or a C 1 -C 4 alkyl, a R 1 is a v chlorine or Bromine and M or, C 1 -C 4 -alkyl or a pharmaceutical moiety, a cation, or a substituent R in the case of black (A) and furan- or thiophenyls 3-, 4- or 5 (a) a condenser formed by the reaction of formula (X) R _ Ln -JL __- coor2 (X) I__ | 2 color R har ovan nämnda betydelse och R är en C ^ - C 1-6 alkyl with the formula ___CON (CH 2) 2 -1 -FI ΓΊ - X ----- "CON (CH 3) 2 or (XVI) (XVII) color X och har ovan nämnda betydelse. account for the formulation of the form ^ "'-ET3L * 1 i« * ·, - t OI 1 — JQ -1 U (XI) 1 2 color R, R, R and X are present in the letter; (b) Hydrolysis formulation with the form ( XII) or (XI) account for the formulation of formula (A) or (B), varo M är väte;