CS238382B2 - Pyrrole derivatives production method - Google Patents

Description

SOCIALIST RIPUBLIC («) DESCRIPTION OF THE INVENTION 238382 (11) (B2) (22) Registered 02 02 81 (21) (PV 7212-82) (51) Int. CIA C 07 D 207 / 32S C 07 D 207/327 // A 61 K 31/40 (40) Published 31 08 84 OftAO PRO VYNALttV A oejevY (45) Published 15 04 87 (72)

Author of the invention BERNHART CLAUDE ing., SAINT GELY DU FRESC, GAGNOL JEAN PIERRE, SAINT MARTIN DE LONDRES, GAUTIER PATRICE PHMR., COURNONTERRAL (France) (73)

Patent of SANOFI p. A., PARIZ (France) .54) Process for producing pyrrole derivatives

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of pyrrole derivatives having antiarrhythmic activity and anti-clotting effects of platelets as well as pharmaceutically acceptable salts thereof with mineral or organic acids.

The compounds of the invention can be described by the general formula (I)

(CHJn-N x CH 3 XH, CONH 2 CH 3)

CK

Cl-h

where J is a phenyl radical or a 2-pyridyl radical, R 2 is a hydrogen atom or a (C 1 -C 6) alkyl group in a straight or branched chain. With mineral or organic acids, the compounds of formula I provide soluble salts. The preparation of these salts with pharmaceutically acceptable acids is also within the scope of the invention.

The process according to the invention for the production of compounds of the formula I is characterized in that the compound of the formula I is present

R 1 -CH-NH 2 wherein R 1 is as defined above and A is a nitrile group-C = N or an ester group-COO-alkyl, is reacted with a compound of the group consisting of γ-diketone of the formula R 2 —C — CH 2 —CH 2 —C — R2

In which R 2 is as defined above, and 2,5-dimethoxytetrahydrofuran, whereupon the resulting product is reacted with an amine derivative of formula 238382 238382 ch 3 'CH,, αζ ch 3 2 in which hal represents a halogen atom, and then the residue A the starting compounds convert to the amide group either by hydrolysis in the case of a nitrile group, or by treatment with ammonia, or a complex salt formed by aluminum hydride and ammonia, in the case of the esters group, and the compound of formula I thus obtained is optionally converted into a pharmaceutically acceptable salt thereof with a mineral or organic acid.

The process of the invention can be represented by the following reaction scheme using the starting compound (8) of the formula

R1-CH-A NH2 wherein R1 and A are as defined above:

The amine compound (8) is converted into the pyrrole compound (9) by treatment with ω-diketone or by treatment with 2,5-dimethoxytetrahydrofuran.

The resulting compound (9) is alkylated with a compound of formula

(CH 3 J 2 CH-N (CH 2) 2 -halo

FROM

(CHACHCH where hal represents halogen, in an inert solvent such as toluene, and in the presence of a base such as sodium hydride to give compound (10) in which group A is converted into an amide group. When A is an ester group, it is converted into an amide group by the action of ammonia or, in the case of bulk amines, by the action of a complex salt, the latter is hydrolyzed, for example, by heating with sodium hydroxide in an aqueous alcoholic solution. of aluminum hydride and ammonia in intermediate tetrahydrofuran.

The invention is further illustrated by the following non-limiting examples. Example 1

2-phenyl-2- (pyrrol-1-yl) -4-diisopropylainobutyric acid amide (CM 7611) of the formula I wherein R 1 is phenyl, R 2 is hydrogen, each of them is R 3 and R 4, which are identical, isisopropyl and n is 2. 1. 2-Phenyl-2- (pyrrol-1-yl) acetonitrile

A mixture of 16.85 g of 2-amino-2-phenyl-acetonitrile hydrochloride, 8.2 g of molten sodium acetate and 26.4 g of 2,5-dimethoxytetrahydrofuran in 200 ml of acetic acid is heated to 2 ° C. hours at 100 ° C. The acetic acid is then evaporated to dryness under reduced pressure and the residue is dissolved in ether. The resulting solid was filtered off and the ether solution washed with water, dried over sodium sulfate and the ether evaporated to dryness.

The residue was distilled under high vacuum, boiling at 4 Pa in the range of 108-112 ° C. The distillate obtained crystallizes. Recrystallization from hexane gave 8 g of the title compound, m.p. 2-Phenyl-2- (pyrrol-1-yl) -4-diisopropyl-aminobutyronitrile

A mixture of 5.16 g of the nitrile obtained in paragraph 1, 1.3 g of sodium amide and 5.1 g of 1-chloro-2-diisopropylaminoethane is refluxed for 2 hours in 150 ml of toluene. After cooling, the organic solution is extracted with dilute hydrochloric acid solution. The acidic aqueous phase is separated, basified with sodium hydroxide and extracted with ether. The ether solution was dried and the solvent was evaporated to dryness. The residue was chromatographed on a silica column using hexane / ethyl acetate (8: 2 by volume) as eluent. 6.35 g of the title product are obtained, which product is used without further modification. 3. 2-Phenyl-2- (pyrrol-1-yl) -4-diisopropylaminobutyric acid amide (CM 7611)

A solution of 6.07 g of the nitrile obtained in paragraph 2. and 22.5 g of potassium hydroxide in 180 ml of 96% ethanol and 45 ml of water is heated under reflux for 5 hours.

After evaporation of the alcohol, the residue was dissolved in a mixture of water and chloroform. The organic phase is separated, dried over sodium sulfate and the solvent is evaporated to dryness. The residue was chromatographed on an alumina column. Elution with hexane-ethyl acetate (8: 2) eluted with hexane / ethyl acetate (1: 1 v / v) to elute the product. 4.5 g of colorless crystals with a temperature of 103-104 ° C are collected. Example 2

2- (pyridyl-2-yl) -2-pyrrol-1-yl) -4-diisopropylaminobutyric acid amide (CM 7954) of formula I wherein R 1 is 2-pyridyl, R 2 is hydrogen, R 3 is each and R 4, which is identical, is an isopropyl group and n is 2. Ethyl 2- (pyrid-2-yl) -2- (pyrrol-1-yl) acetic acid

A mixture of 22 g of 2-amino-2- (pyrid-2-yl) acetic acid ethyl ester, 32.3 g of 2,5-dimethoxytetrahydrofuran in 300 ml of anhydrous ethanol and 150 ml of acetic acid is heated under reflux for 3 hours. .

The solvent was evaporated to dryness under reduced pressure and the residue was dissolved in aqueous sodium bicarbonate solution. The resulting solution was extracted with ether and the extract dried over sodium sulfate. The solvent was evaporated to dryness and the residue was distilled under reduced pressure. The pressure pressure of 1.33 Pa is between 115 and 122 ° C. The distillate obtained crystallizes. 11.3 g of the title compound of melting point 75-76 ° C are obtained. 2. Ethyl 2- (pyrid-2-yl) -2- (pyrrol-1-yl) -4-diisopropylamino-butyric acid A mixture of 16.65 g of es is heated at 100 DEG C. for 1.5 hours under a nitrogen atmosphere. of the ether obtained according to paragraph 1., 3.57 g of sodium hydride and 12.4 g of 1-chloro-2-diisopropylaminoethane in 500 ml of anhydrous toluene.

After cooling, the resulting solution was washed with sodium sulfate, and the solvent was evaporated to dryness. The residue was chromatographed on an alumina column using a 95: 5 mixture of penta-ethyl acetate as eluent to give 17.8 g of the title compound, m.p. 45-47 ° C. 3. 2- (Pyrid-2-yl) -2- (pyrrol-1-yl) -4-diisopropylaminobutyric acid amide (CM 7954)

A suspension of 1.14 g of lithium aluminum hydride in 60 ml of anhydrous tetrahydrofuran is not bubbled through a stream of anhydrous ammonium until the precipitation of the complex is complete. A solution of 7.14 g of the ester obtained in accordance with paragraph 2 is then added in 40 ml of tetrahydrofuran and stirred at room temperature for 24 hours.

The mixture was hydrolyzed by the addition of 40% sodium hydroxide solution, insoluble matter was filtered off and tetrahydrofuran was

238382 evaporated to dryness. The residue was taken up in ether, the organic solution was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was recrystallized from isopropyl ether. 3.35 g of colorless crystals with a melting point of 128-129 DEG C. are obtained. Example 3

In particular, the compounds of formula (I) wherein R1 is phenyl, R2 is methyl, n is 2, R3 is isopropyl and, in particular, n is 2, R3 is an isopropyl radical, and the corresponding starting compounds can be prepared using the procedures described in the preceding examples. R4 is also an isopropyl radical (Compound No. 7640), melting point 106-107 ° C.

The compounds of the present invention were tested in veterinary pharmacology to demonstrate their advantageous properties.

Arytimcké vlastnosti

Procedure

The antiarrhythmic effect of these compounds was tested in the case of ventricular arrhythmias.

Dogs used as experimental animals are anesthetized and a spiral is introduced into the coronary circulatory system by back-catheterization. At the same time, the dog is on a suppressive microsensor, modulating the frequency, which is coupled to two precordial electrodes. In the dog again placed in the cubicle, there is a progressive thrombosis of the anterior interventricular artery. This will result in localized trans-mural myocardial infarction, which causes anomalous but recurrent electrical activity: ventricular tachycardia. In this state, the compounds under investigation are applied orally and the telemetry system allows for the progressive development of the dissection.

The electronic method enables the continuous measurement of sinusoidal systolic and histological complexes.

Thus, the degree and duration of action of the compound under investigation can be quantitatively evaluated. Results The results obtained with the application of the individual compounds produced by the process according to the invention are given in the following table. The effect of the compounds under investigation on ventricular tachycardia is expressed either by resuming the sinus rhythm or by significantly improving the ratio of the number of abnormal complexes of the sinusoidal complexes

TABLE

Compound Dose, Number of Attempts - Effect on Ventricular Tachycardia (code number) mg / kg of consecutive animals CM 7611 50 3 sinus rhythm or improvement between 70 and 90% for 3 or 4 hours CM 7640 50 1 sinus rhythm or 90% improvement lasting 90 minutes Effectiveness against clumping of blood platelets

Procedure

In vitro and ex vivo blood platelet aggregation efficacy assays were performed using the Boron turbidimetric method.

In vitro tests were performed with a blood plasma containing a large number of platelets prepared from venous human blood.

Solutions of the tested substances in acetone at a concentration of 2 x 10 -2 molar were prepared, especially solutions of the compounds code designation CM 7611 and 7640.

Blood samples for determining platelet aggregation were collected prior to administration of the test compound, then 2 hours after administration of 50 mg / kg on the first day and 2 hours after the last administration on the fifth day.

Platelet aggregation was quantified by a graph of maximum clustering. The results are expressed as% inhibition of this parameter, as determined by the control solutions (100% clustering).

In vitro tests

Of the compounds examined, two have proved particularly effective against collagen-induced platelet aggregation.

Claims (1)

238382 10 7640 and CM 7611 (IC 50 at approximately 30 μΐηοΐύ concentration). These results indicate that the compounds of the present invention exhibit significant efficacy in experimental disruption and have considerable platelet anti-slip effectiveness. Therefore, the compounds of the formula I can be used in human medicine for the protection of the myocardium, for the treatment of disorders of the ventricular rhythmisch origin, as well as for the correction of blood platelet aggregation. The compounds of the invention may be administered in galenic formulations for oral administration (tablets, pills, etc.) and proparental administration (injection solutions in vials). The daily dose required to produce an effect against platelet aggregation or recurrence of sinus rhythm in humans is between 50 and 150 mg at by intravenous administration and in the range from 400 to 800 mg by oral administration The process for the preparation of pyrrole derivatives of general formula I is reacted with a compound from the group comprising the ω-diketone of the formula I CONH / CH 3 CH 2 CH 3 R'2 - CH 2 CH 2 CH 2 R 2 wherein R 2 is as defined above, and 2,5-dimethoxytetrahydrofurane, whereupon the resulting product is reacted with an amine compound of formula IIIn in wherein R 1 is a phenyl radical or a 2-pyridyl radical, R 2 is a hydrogen atom or a C 1 -C 6 alkyl group in a straight or branched chain, as well as pharmaceutically acceptable salts thereof with mineral or organic acids, that the compound of the general formula R 1 -CH-A NH 2 in which R 1 is as defined above and A is nitrile or ester CH, CH 2 CH CH 3 H 7 Hat ch 3 wherein hal is halogen, and then residue A of the starting compound is changes in the amide group either by hydrolysis in the case of a nitrile group, or by treatment with ammonia or a complex salt formed from aluminum hydride and ammonia, in the case of an ester group, and the compound thus obtained in Optionally, the formula 1 is then converted into a pharmaceutically acceptable salt by mineral or organic acid.