IE51010B1 - Derivatives of pyrrole for protecting the myocardium,having an anti-arrhythmic activity and an activity as blood platelet anti-aggregant process for preparation thereof and drugs containing same - Google Patents

Description

The present Invention relates to pyrrole derivatives, as well as to the methods for preparing them and application thereto in therapeutics.

The compounds according to the invention correspond 5 to the general formula: f1 cI CONH. -<CH2’n (I) in which: - represents an atom of hydrogen, an alkyl radical having from 1 to 6 carbon atoms, a phenyl radical or a 2-pyridyl radical, - Rz represents an having from 1 to atom of hydrogen or an alkyl radical 6 carbon atoms, - R3 and R4, which are identical or different, each represent an alkyl radical containing 1 to 6 carbon atoms or a cyclohexyl radical or the group ZR3 designates a pyrrolidinyl, piperidinyl, 2,6-dimethy1piperidinyl, morpholinyl or piperazinyl radical or a radical of the formula: -N • 51010 - 3 - n is equal to 2 or 3, or a salt thereof with an inorganic or organic acid.

The compounds (I) yield soluble salts with the inorganic or organic acids. These salts, with the pharmaceutically acceptable acids, form an integral part of the invention.

According to the nature of the substituent R^, the compounds (I) may be obtained by one of the following methods: When R3 designates hydrogen, the compounds (I) may be obtained according to two processes. - 4 SiOlO Method The different steps of the process are indicated in the following reaction diagram: COOC2H5 /r3 GH.CONH - C — (CH,) -N 3 \ Λ COOCjHj -> H,N — CH -(CH.) -N * ι ί n COOH ^3 0* H2N — CH — (CH2)n-N^ -> H2N — CH — COOCH.

CONH.

-R, /2 /*3 N — C —(cH2)n-N^ (I) (R1 = H) 2 °°™2 The compound 1_ is prepared by alkylation according to the known processes of ethyl acetajnidoraalonate. By saponification of the compound 1_ in an alkaline medium, the corresponding malonic acid is obtained which easily decarboxlates by heating in an acid medium to yield the substituted alkanoic acid 2. The latter esterified by a known process into methyl ester 3. The ester 3_ is converted into the corresponding amide _4 by action of ammonia according to a known process. Finally, the amide 4 is converted into compound (I) by heating with a Y -diketone R C-CH CH C-R in acetic acid. o o - 5 In the particular case of R2 = H, compound (I) may be obtained by heating the amide 4 with 2,5-dinethoxytetrahydrofuran in absolute alcohol in the presence oi acetic acid.

Method AThe different steps of the process are indicated in the following reaction diagram: Br —(CH,) -CH-COOCH,, HCl Z n , 3 NH, — C — (CH,) -Br ι Z n R.

N — C (, (CH ) -N^ ' n ft COOCH3k4 (CH,) -N. 2 n CONH, R, X 3 (I) (Κχ » H) The hydrochloride of methyl 2-aminow-bromoalkanoate (Ttetcahedrcn) 25. 5971-81, (1969) } is converted into corresponding pyrrole derivative b either by action of a y-diketone, or by action of the 2,5-dimethoxy tatrahydrofuran, as indicated in method 2^.

By action of an amine HN XR3 on 6 in solution in an inert solvent, euch as benzene or toluene, the compound 7 is obtained which, by amidification by ammonia, leads to the products (I), (R. = H).

Method B When Ri represents a phenyl group or a 2-pyridyl 1010 - 6 group, the compounds (I) are obtained according to the following reaction diagram from a product 8, R.CH-A, in which R. nh2 designates a phenyl or 2-pyri<3yl group and A designates a group derived from the acid function, namely a nitrile group -C =N or an ester group -COO-Alk (Alk represents a methyl (I) (R^ = phenyl or 2-pyridyl) As in the methods A^ and the amino compound & is converted into the corresponding pyrrole compound by action of a V-diketone or by action of the 2,5-dimethoxytetrahydrofuran.

R3\ The compound £ is alkylated by N-(CH7) -Hal V Z (Hal designating a halogen) in an inert solvent such as toluene and in the presence of a base such as sodium hydride and yields compound 10. In the latter, the group A is converted into an amide group. When A represents a nitrile group, the latter is hydrolysed for example by heating with sodium hydroxide in dilute alcoholic solution. When A designates an. ester group, the latter is converted into amide by action of ammonia or, in the case of voluminous amines, by action of the complex salt formed by the aluminium hydride and the ammonia in tetrahydrofuran. - 7 Method C When Is an alkyl group, the different steps of the synthesis are shown in the following reaction diagram: N=C=O Rx — CH —· COOC2H5 N=C=O -4 RjC-(CH2)n-N, COOC2h5 1¾ R, — C — 2)n-N .

COOC2H5 *1 N —C«3 (ch2)0-n^b — C — (CH,) -N t cooc2h5 CONHj The starting product 11. Is an -Isocyanatoester. The products of this type are known or may be prepared according to known processes, particularly by action of the phosgene on the corresponding «f-formylaminoester compounds.

Compound U is alkylated by Hal-(CH2)n-N in a suitable solvent and in the presence of an alkaline agent to lead to compound 12 . The latter treated by an acid in organic soluticn leads to the amine 13. The latter is ccnverted into pyrrole derivative 14, as has been indicated previously.

Finally, the ester function is converted into amide by action of ammonia or, preferably, by using the complex salt formed from lithiun-aluniniun hydride and anmonia in tetrahydrofuran. - 8 510 10 The following non-limiting examples are given byway of illustration for the preparation of the compounds (I). EXAMPLE 1 Method 2-(2,5-Dimethyl-l-pyrrolyl)-4-diiscprcpylaniinobutyramide (CM 7753)_&& _____ (I) Rj = H; R2 = CH3i R3 = R4 = -CH^ 3 ;n = 2 CIi3 1) 2-Amino-4-diisopropylamino butyric acid A mixture of 17. 3 g of ethyl 2“(2-d±iscpropylainino ethyl)-2-acetamidomalonate and 4. 4 g of sodium hydroxide in 300 ml of water and 150 ml of ethanol at 96° is refluxed for 3 hours. The mixture is evaporated to dryness and the residue is taken up in 200 ml of 2N hydrochloric acid; the mixture is refluxed for 5 hours.

After cooling, the mixture is neutralised to pH 7 by the addition of a solution of sodium hydroxide. The mixture is evaporated to dryness and the residue is taken up in chloroform. The insoluble sodium chloride is filtered, the solutionis dried over sodium sulfate and is evaporated to dryness.

The residue constituted by a brownish solid (11. 3 g) is used as such for the following operation. 2) Methyl 2-amino-4-aiisopropylajnino_butyrate g of thionyl chloride are added to 30 ml of methanol, with cooling, so as to maintain the temperature below 25 -5°C, then 37. 7 g of the acid obtained hereinabove are added in portions, always maintaining the temperature lower than -5°C. When the addition is finished, the temperature is allowed to return to ambient temperature, then the mixture is heat'ed for 2 hours at 40°C. The methanol is evaporated and the residue is taken up in the minimum of water; 500 ml of ether are added - 9 and, with stirring, the aqueous phase is saturated with potassium carbonate. The ethereal phase Is separated and the aqueous phase is re-extracted with ether. The ethereal extracts are combined, dried over sodium sulfate and evaporated to dryness.

A yellow liquid remains (13 g) used as such for the following operation, 3) 2ytoino-_4j^diisogropylamino__butyrarnide In an autoclave cooled by an ice bath, the solution of 3 g of the preceding ester is placed In 20 ml of absolute ethanol and a current of ammonia is bubbled therein for 1 hour.

The autoclave Is closed and heated at 150’C for 36 hours.

The alcohol Is evaporated and the residue is taken up in water and chloroform. The organic phase is separated and washed with water. The aqueous phases are evaporated to dryness and the residue is extracted with chloroform. The combined chloroform extracts are dried over sodium sulfate and evaporated to dryness.

A coloured liquid remains (1. 54 g) which is used without purification for the following operation. 4) CM_775_3_ The previously obtained oil (1. 54 g) and 0. 98 g of 2,5-hexanedicne is dissolved in 40 ml of acetic acid and the mixture is heated at 100’C for 3 hours. The solvent is evaporated then alkalinized with diluted sodium hydroxide. It is extracted with ether, the ethereal phase is dried over sodium sulfate and evaporated to dryness. A blackish, viscous liquid is obtained which is dircuBtographed over an alumina column, eluting by the 70:30 (vol/vol) mixture of hexane-ethyl acetate.

A yellowish solid (1 g) is obtained which is recrystal- 10 51610 Used in isopropyl ether. Finally, colourless crystals are obtained; m. p. 71-72°C.

EXAMPLE 2 Method A. 2 2-(2,5-Dimethyl Eyrrol-l-yl)-4-(l,4-diazabicyclo[4.3.0] non-4-yl) butyramide (CM 40018) (I, Rj = H; R2 = CH3; -N. '4 1) methyl 2-(2,5-dim£thyl-l-pyrrolyl)-4-broinobufcyrate A mixture of 30 g of hydrochloride of irethyl 210 amino-4-bromo butyrate, 17.7 g of 2,5-hexanedione and 10.6 g of anhydrous sodium acetate in 500 ml of acetic acid is heated at 100’C for 3 hours. The acetic acid is evaporated in vacuo, then the residue is taken up with water and ether. The ethereal layer is separated and washed successively with water, with a solution of sodium bicarbonate and again with water. The solution is dried over sodium sulfate, then the solvent is evaporated to dryness.

The residue is chromatographed over a silica colum eluting with the 9:1 (vol/vol) pentane-ethyl acetate mixture.

By evaporation, a '-rystallised solid is obtained which is washed with petroleum ether. Weight; 15.1 g; m.p. 79°C. 2) Methyl 2-(2,5-dinethyl-l-pyrrolyl)-4-(l,4-diazabicyclo[4.3.0] iicn-4-yl)butyrate A mixture of 11 g of the ester obtained hereinabove and 10,1 g of 1,4-diazabicyclo [4.3.O]ncnane in 150 ml of toluene is refluxed for 48 hours. After cooling, the organic solution is washed with water, dried over sodium sulfate and the solvent is evaporated to dryness in vacuo.

The residue is chromatographed over an alumina 30 column, eluting with the 95:5 (vol/vol) pentane-ethyl acetate mixture. - 11 An oil (9 g) is obtained, used as such for the following operation. 3) CM 40018 In a suspension of 1. 71 g of lithium-aluminium hydride in 100 ml of anhydrous tetrahydrofuran, a current of dry ammonia gas is bubbled until the end of precipitation. The solution of 3.19 g of the ester obtained in the preceding paragraph in 40 ml of tetrahydrofuran is then added with stirring, then the mixture is heated at 55-60'C for 3 hours 30 minutes.

The mixture is cooled by an ice bath and hydrolysed by a 40% sodium hydroxide solution. It is filtered and the solvent is evaporated to dryness. The residue is taken up in chloroform and water. The organic phase is separated and the aqueous phas& is again extracted with chloroform. The organic extracts are combined and dried over sodium sulfate. The solvent is evaporated to dryness.

The solid residue is recrystallised in ethyl acetate (1.7 g): m.p. 166-167‘C.

EXAMPLE 3 Method B 2-Phenyl-2-(1-pyrrolyl)-4-diisopropylamino butyramide (CM 7611) 1) 2-Phenyl-2-(l-jyrrolyl) acetonitrile A mixture of 16.85 g of 2-amino-2- phenyl acetonitrile hydrochloride, 8.2 g of molten sodium acetate and 26.4g of 2,5-dimethoxy tetrahydrofuran in 200 ml of acetic acid is heated at 100°C for 2 hours. The acetic acid is then evaporated in vacuo to dryness and the residue is taken up in ether. The precipitated solid is dried without heat, then the ethereal solu- 12 tion is washed with water. The ethereal solution is dried over sodium sulfate and the ether is evaporated to dryness.

The residue is distilled under a high vacuum,h. p/ 0. 03 mm of mercury; 108-112 °C. The distillate crystallises; it is recrystallised in hexane; weight: 8 g; m.p. 51°C. 2) 2-Phenyl-2-(pyrrolyl-l) - 4-diisopropylamino butyronitrile A mixture of 5.16 g of the nitrile obtained previously, 1. 3 g of sodium amide and 5.1 g of l-chloro-2-diisqpropylamino ethane in 150 ml of toluene is heated to reflux for 2 hours. After cooling, the organic solution is extracted with a dilute solution of hydrochloric acid. The acid aqueous phase is separated, alkalinised with sodium hydroxide and extracted with ether. The ethereal solution Is dried and the solvent is evaporated to dryness. The residue is chromatographed over a silica column, eluting by the 8:2 (vol/vol) hexane-ethyl acetate mixture. 6. 35 g of the expected product is obtained, and is used as such for the following operation. 3) CM 7611 The solution of 6. 07 g of the nitrile obtained previously and 22. 5 g of potash in 180 ml of 96¾ ethanol and 45 ml of water is heated to reflux for 5 hours.

After evaporation of the alcohol, the residue is taken up in water and chloroform. The organic phase is separated, is dried over sodium sulfate and the solvent is evaporated to dryness. The residue is chromatographed over an alumina column . By eluting with the 8-2 (vol/vol) hexane-ethyl acetate mixture, an impurity is eliminated then, with the 1:1 (vol/vol) mixture of hexane-ethyl acetate, the expected product is eluted. - 13 By «crystallisation in isopropyl ether, colourless crystals are obtained (4. Sg); m.p. 103-104’C.

EXAMPLE 4 Method-B. 2-(2-Pyridyl)-2-(1-pyrrolyl )-4-diisopropylamino butyramide(CM 7954) (ΌΙ4 < XCH N ; R2 = H; R3 = R4 = -CH^ 3 1) Ethyl 2-(2-βτί<^ρ-2-(>jyrro^l)acetate A mixture of 22 g of ethyl 2-amino-2-(2-pyridyl) acetate and 32.3 g of 2,5-dinethoxy tetrahydrofuran in 300 ml of absolute ethanol and 150 ml of acetic acid, is heated to reflux for 3 hours.

The solvents are evaporated to dryness in vacuo and the residue is taken up in an aqueous eolution of sodium bicarbonate. The solution is extracted with ether and is dried over sodium sulfate. The solvent is evaporated to dryness and the residue is distilled under reduced pressure;h..p/0. 01 mmHg: 115-122’C.

The distillate crystallises; m.p. 75-76’C; weight: 11. 3 g. 2) Ethyl 2- (2-pyridyl)-2-(l-pyrrolyl)-4-diiscprcpyl amino butyrate ___________ A mixture of 15. 65 g of the preceding ester, 3. 57 g of sodium hydride and 12. 4 g of l-chloro-2-diisopropylamino ethane in 500 ml of anhydrous toluene is heated at 100’C in an atmosphere of nitrogen, for 1 hour 30 minutes.

After cooling, the solution is washed with water, dried over sodium sulfate and the solvent is evaporated to dryness, Chromatography is carried out over an alumina column.

By eluting with 95:5 (vol/vol) pentane-ethyl acetate mixture, - 14 17. 8 g of the expected product is obtained; m.p. 45-47°C. 3) CM 7954 In a suspension of 1.14 g of lithiumaluminium hydride in 60 ml of anhydrous tetrahydrofuran, a stream of dry ammonia is bubbled until the complex has finished precipitating. The solution of 7.14 g of the ester obtained hereinabove is added in 40 ml of tetrahydrofuran and the mixture is left, with stirring, at ambient temperature for 24 hours.

Hydrolysis is carried out by addition of 40% solution of sodium hydroxide, the insoluble matter is filtered and the tetrahydrofuran is evaporated to dryness. The residue is taken up in ether, the organic solution is washed with water, dried over sodium sulfate and evaporated to dryness. The residue is recrystallised in isopropyl ether.

Colourless crystals are obtained (3. 35 g); m.p. 128129’C.

EXAMPLE 5 Method C 2-Methyl-2-(l-pyrroly])-4-diisopropyl20 amino butyranide (CM 40019)_ ZCH (I) R. = CH, ; R, = H; R, = R. = -CH ; n = 2 102 i 4 \CH^ 1) ethy1_ 214, 54 g of ethyl 2-isocyanato propionate and 19.75 g of l-chloro-2-diisopropylamino ethane are dissolved in 300 ml of anhydrous ether and 120 ml of dimethylsulfoxide. Cooling is effected with an ice bath and a suspension of 5. 73 g of 55-60% sodium hydride in 90 ml of anhydrous ether is added by fractions. The addition terminated, the mixture is refluxed for 2 hours. After cooling, the reaction mixture is poured in 300 ml of ided water. The organic phase is decanted and the aqueous phase is extracted three times with ether. The organic extracts - 15 are combined and washed with water. Drying is effected over sodium sulfate and the solvent Is evaporat ed to dryness.

The residue Is distilled under reduced pressure; B.p./ 0.7 mmHg: 102-106’C; weight: 16 g. 2) 1_ butyrate In 60 ml of absolute ethanol to which 1. 57 g of water is added, hydrogen chloride Is bubbled up to saturation.

The solution is cooled below -10°C and 16 g of the isocyanate obtained previously dissolved in 18 ml of absolute ethanol are added, then the temperature is allowed to rise progressively up to ambient temperature and the mixture is left to stand for 20 hours at this temperature. The solvent is evaporated to dryness in vacuo and the residue is taken up in ether. The ethereal solution is washed with a saturated solution of potassium bicarbonate in water. The aqueous phase is s eparated and extracted with ether. The ethereal extracts are combined, dried over potassium carbonate and the solvent is evaporated to dryness.

An oil remains (14. 75 g) used as such for the following operation. 3) EiW. 2-methy 1-2-(1-pyrrolyl) -4-dllaopropylaniino butyrate _ The mixture of 2 g of the aminoester obtained hereinabove and 2.17 g of 2,5-dimethoxy tetrahydrofuran in 30 ml of absolute ethanol and 15 ml of acetic acid is heated to reflux for 18 hours. The solvents are evaporated to dryness in vacuo and the residue is taken up in ether. The ethereal solution is washed with water, then with an aqueous solution of sodium bicarbonate and again with water. The substance is dried over sodium sulfate and the solvent is evaporated to dryness. Chromatography is carried out on an alumina column.

By eluting with 98:2 (vol/vol) pentane-ethyl acetate mix51010 - 16 ture, 1.1 g of the expected product is obtained. 4) CM 40019 The modus operandi is as indicated in Example 4, paragraph 3, using the ester prepared previously and reducing the duration of reaction to 1 hour instead of 24 hours.

By the same treatment, the expected amide is obtained With a yield of 60%;m. p. 79-80°C (petroleum ether (b.p. 40-65°C) ).

EXAMPLES 6 to 11 By operating according to Examples 1 to 5, but by varying the reagents, the products shown in Ihble I hereinbelow are obtained.

For each of the products (I), the code number, the nature of the substituents, the method of preparation used and finally the melting point and crystallisation solvent, are indicated.

TABLE I Code No.R1R2 nR3R4 ivfethod m.p°c (crystallisation solvent) 7640 -ch3 /CfI3 B 106-107 (pet- u 2 ‘chch3 -ch-ch3 roleum ether) 40017 H -ch3 2A2 124-125 (ethyl acetate) 40002 K -0Π3 2: -c2h5 -C2H5A1 88-89 (isopropyl ether) .CH, .CH, 7921 H H 2ch-ch3 -CH^ 3cikch3A1 68-69 (hexane) isolated in the form of 40020 H •C2H5 2 It IfA1 hydrochloride 122-124 (methyle thyJtatone - 17 TABLE X (cont.) Code No. 40021 S-CHj-CH; 'ch, 40105 40169 -CH, -CH, vfeahod m.p. ’C (crystallisation sol isolated In the form of hydrochloride 184-186 (isopropanol) Isolated in foe form of tosylate, 110-112 (isopropanol) isolated in the form of fumaiatei65-i66 (ethanol) 40176 H sP o 1 2 -CHjCHjCHj -CH2CH2CH,A1 Isolated in the form of hydrochloride 198-199 (iso- propanol)σ,3 CHj -CH-CH CH, 40178 H -CH.j 2 -CH-CH,CH, A. isolated in foe 2 3 2 3 1 form of fuma- rate, 147-148 (acetone) 40201 H -CH, 3 Λ -CH ^CH -CH JA1 80-81 (isopro· •5C«3 ch3 pyl ether) 40261 H -CH3 2 Ό 1 ΌA1 95-97 (pentane) The products of the invention have been studed in animal pharmacology and in particular with a view to demonstrating their properties.

Arrhythmic properties Protocol The anti-arrythmic power of these molecules was - 18 510 I® assessed on an animal model of ventricular arrythmia.

Mongrel dogs are anaesthesized then subjected to the positioning, by retrograde catheterism, of a metal spiro in the coronary bed. At the same time, a micro-emitter frequency modulator is fixed to the animal's back and connected to two precordial electrodes.

The animal returned to its box then shows a progressive thrombosis of the anterior interventricular artery.

Thus a localised, transmural myocardial infarction is consti10 tuted, generating an abnormal , but repetitive electrical activity: ventricular tachycardia.

In this state, the drugs are administered per os (P. O.) and the telemetered system enables the development of the arrythmia to be followed in real time.

The sinusal systolic complexes and pathologies are permanently counted by electronic processes.

Thus, the quality and duration of action of the product may be quantified.

Results The results concerning various products are shown in Table II hereinbelow.

The activity of the tested products on the ventricular tachycardia is expressed either by the re-establishment of the sinusal rhythm, or by a considerable improvement in the ratio: number of abnormal complexes number of sinusal complexes - 19 TABLE II Products CM No. Dose, mg/kg Number P, O. of animals Effect on the ventricu lar tachycardia CM 7611 50 3 Sinusal rhythm or improvement between 70-90% from 3 or 4 hours. CM 7753 50 4 Sinusal rhythm or 907« improvement from 1 1/2 hrs to 5 hours CM 7640 50 1 Sinusal rhythm or 90% improvement for 90 minutes Activity as blood platelet anti-aggregant Experimental protocol In vitro and ex vivo studies of the anti-aggregant activity were made according to Born's turbidiuretlc technique.

The in vitro studies were made on platelet-rich plasma (PRP) prepared from human venous blood.

The various solutions of the products to be tested were prepared extemporaneously. The CM 7753, 7611, 7640, 7921, 7954, 40018, 40020 were dissolved ac a concentration oi -2 x 10 M in acetone. _3 x 10 M aqueous solutions were prepared for the CM 40169, 40178, 2 of the acetone solutions of the products or 40 yUl of the aqueous solutions are incubated for 10 minutes at 37*C with, respectively, 388 and 350 jM. ot PRP, After this period of incubation, 10yul of the solution of collagen at 40^/ml are added. For controls, 2 jil oi acetone or 40 ju.1 ol distilled water are used. - 20 The ex vivo studies in the baboon were made solely on the anti-aggregant activity of the CM 7753. In this case, the CM 7753 is administered orally at a rate οί 50 mg/kg/day for a period of 5 days.

Blood samples for analysing the platelet aggregation were made before the product was administered, 2 hours after administration of 50 mg/kg on day 1 and 2 hours after the last administration of day 5.

Platelet aggregation was quantified by the graphic determination of the maximum amplitude of aggregation (MA).

The results are expressed in % of inhibition of this parameter calculated with respect to the control (100% aggregation).

Results In vitro study From the products studied, two proved particularly active with respect to the platelet aggregation induced by the collagen. These are CM 7640 and CM 7611 (IC50 approximately situated at 30 uM).

The products CM 7753 and 7954 Inhibit at 50% the platelet aggregation at a concentration close to 100Other products, CM 40018, 40020, 40169, 40178 and 7921 inhibit the phenomenon of aggregation less strongly (20 to 30% Inhibition at a concentration of 100 yvM).

Ex vivo study Studied under ex vivo conditions, the CM 7753 particularly inhibits the platelet aggregation induced by the collagen.

In four baboons used in the study, 100% of inhibition was obtained after 5 days of treatment at a dose of 50 mg/kg/ day. An anti-aggre.gant activity of lesser importance is also observed with respect to ADP.

These results show that the products according to the invention are endowed with a strong activity on expert 5 mental arrhythmia and present a considerable blood platelet anti-aggregant activity. Consequently, the products (I) may be used in human therapeutics as protectors of the myocardium for correcting disorders in the ventricular rhythm of ischaemic origin as well as disorders in platelet aggregation.

The products may be presented in galenic forms of administration to be taken orally (tablets, capsules, etc. . .) and parenterally (injectable ampoules).

The dose necessary for a platelet anti-aggregant activity or for restoring the sinusal rhythm in human beings is 15 ' between about 50 and 150 mg by the I. V. route and about 400 and 800 mg by the oral route, per day.

By way of example, the following galenic preparation is indicated: Tablets CM 7753 0.200 g Microcrystalline cellulose 0.140 g Lactose Magnesium stearate 0.140 g 0. 020 g

Claims (5)

CLAIMS :

1. A pyrrole derivative of fonnula R^ represents an atom of hydrogen, an alkyl radical having from 1 to 6 carbon atoms, a phenyl radical or a 2-pyridyl radical, - R 2 represents an atom of hydrogen or an alkyl radical having from 1 to 6 carbon atoms, 10 - R^ and R^, which are identical or different, each represent an alkyl radical containing 1 to 6 carbon atoms or a cyclohexyl radical,or the group / R 3 -N designates a pyrrolidinyl, piperidinyl, 2,6-dimethyl piperidinyl, morpholinyl, or piperazinyl radical or a 15 radical of the formula: - n is equal to 2 or 3, or a salt thereof with an inorganic or organic acid.

2. A pharmaceutical composition having antiarrhythmic 20 and blood platelet anti-aggregant properties, which comprises a pyrrole derivative of formula (I) given and defined in Claim 1, in association with a pharmacologically acceptable carrier or diluent therefor. - 23 3. A pharmaceutical composition according to Claim 2, which is prepared with a view to oral administration at a dose of 400 to 800 mg of the derivative of formula I per day.

3. 5 4. A pharmaceutical composition according to Claim 2, which is prepared with a view to parenteral administration at a dose of 50 to 150 mg of the derivative of formula I per day. 5. A process for preparing a pyrrole derivative of 10 formula I given and defined in Claim 1, or a salt thereof with an inorganic or organic acid, substantially as hereinbefore described with reference to the accompanying Examples.

4. 6. A pyrrole derivative of formula I given and defined 15 in Claim 1, or a salt thereof with an inorganic or organic acid, whenever prepared by a process claimed in Claim 5.

5. 7. A pharmaceutical composition according to any one of Claims 2-4, substantially as hereinbefore described.