HU183292B - Process for producing pyrrol-derivatives of myocardium-protecting, antiarrhythmic and thromaocite-aggregation-inhibiting activity and pharmaceutical compositions containing them as active agents - Google Patents

Abstract

The present invention relates to pyrrole derivatives of the formula I wherein R1 is hydrogen, C1-6alkyl, phenyl or pyridyl, R2 is hydrogen or C1-C4 alkyl, R1 and R4, which may be the same or different. C 6 -C 6 alkyl, C 5-7 cycloalkyl, or R 3 and R 4 together with the adjacent nitrogen atom are 2,6-dimethylpiperidino, morpholino, or 1,4-diazabicyclo [4.3.0] nonyl, n is 2 or 3, and mineral or acid addition salts with organic acids. The novel compounds may be prepared by reacting a compound of formula (II) with a diketone or a 2,5-dimethoxy tetrahydrofuran. The new pyrrole derivatives have anti-cardiac aggregation inhibiting and antiarrhythmic effects and can therefore be used as active ingredients in pharmaceutical formulations. The invention also relates to the preparation of pharmaceutical compositions. (CH2) n R 1 N - C -P I A -1-

Description

The present invention relates to novel pyrrole derivatives of the formula I which possess antiarrhythmic and platelet aggregation inhibiting properties.

In the general formula (I)

R 1 is hydrogen, C 1-6 alkyl, phenyl or pyridyl,

R ₂ is hydrogen or C 1-4 alkyl,

R ₃ and R 4 may be the same or different,

C 1-6 alkyl, C 5-7 cycloalkyl, or R ₃ and R _{4 taken} together with the adjacent nitrogen atom are 2,6-dimethylpiperidino, morpholine or 1,4-diazabicyclo [4.3.0] nonyl, n is 2 or 3.

The compounds of formula I form salts soluble in mineral or organic acids. Salts formed with pharmaceutically acceptable acids are also within the scope of the invention.

Of the known pyrrole derivatives, the compounds of the present invention are closest to those described in German Patent No. 2,647,368; this disclosure teaches the preparation of 3-phenoxybenzyl esters of α-1-pyrrolylcarboxylic acid.

The essence of the preparation of the novel pyrrole derivatives of formula I according to the invention consists essentially in the formation of the pyrrole ring; this is done essentially by reacting a compound of formula II with a diketone of formula III or 2,5-dimethoxytetrahydrofuran. In the formula (II), R ₁ is as defined, A is a C 2 -C 5 alkoxycarbonyl group or a derivative thereof, and P is a group of the type - (CH ₂ ) _n -NR ₃ R 4 or a group from which it can be directly produced.

The above general procedure may be carried out in different ways depending on the nature of the substituent R 1 in the compound of formula (II).

When Ri is hydrogen, formation of the pyrrole ring can be carried out according to the method _or the _second

Method A (method a).

Each step of the process is illustrated in Scheme A. In the following scheme, the compound of formula (1) may be prepared by alkylation of ethyl acetamido malonic acid in a known manner. Saponification of the compound of formula (1) in an alkaline medium gives the corresponding malonic acid which can be readily decarboxylated by heating in an acidic medium. Substituted butyric acid (2) thus obtained is converted to the methyl ester (3) by a known esterification process. The resulting methyl ester is converted to the amide of formula (4) by treatment with ammonia in a known manner, and the resulting amide is then heated, under heating in γ-diketone (II), to a compound of formula (I) wherein R1 is hydrogen.

In the case where R ₂ is also hydrogen, the compound of formula (I) is obtained by heating the compound of formula (4) with 2,5-dimethoxytetrahydrofuran in absolute alcohol in the presence of acetic acid.

The reaction illustrated in Scheme A1 may also be carried out by reacting the acid amide of formula (4) with γ-diketone of formula (III) while heating in acetic acid. This gives compounds of formula (I) wherein R 1 is hydrogen. This is called process b).

Method ₂ (variant c)

Each step of the process is illustrated in Scheme A ₂ . The hydrochloride of the 2-amino-4-bromobutyric acid methyl ester of formula (5) when n is 2 or the methyl ester of valeric acid if n is 3 (Tetrahedron, 25, 5971-81 (1969)) ) can be converted to a pyrrole derivative of the formula (II) by treatment with γ-diketone or 2,5-dimethoxyburane as described in Method A1.

Treatment of the compound of formula (6) with an amine of formula HNR3R4 in an inert solvent such as benzene or toluene yields a compound of formula (7) which is treated with ammonia to give a compound of formula (I): is hydrogen.

Method B (Procedure d))

When R1 is phenyl or 2-pyridyl, the compounds of formula (I) may be prepared from Scheme B starting material (8). In the compound of formula (8), R 1 is phenyl or 2-pyridyl and A is an acyl group such as a nitrile group or an ester of the formula -COO-Alk (Alk is methyl or ethyl).

Ai and _A2 similarly to the process of the amino compound (8) is converted by reaction with γ-diketone or 2,5-dimethoxy-tetrahydrofuran of the corresponding (9) pirollá formula.

Reaction of compound (9) in an inert solvent such as toluene with a base such as sodium hydride (IV) (in which Hal is a halogen) affords compound (10) in which the A group is converted to the amide. When A is cyano, it is hydrolysed in alcoholic solution by heating with sodium hydroxide. When A is an ester group, it is converted to the amide by treatment with ammonia or by reaction with a complex salt of aluminum hydride and ammonium in tetrahydrofuran.

Method C (method e).

When R 1 is alkyl, each step of the synthesis is illustrated in Scheme C.

The starting compound is the? -Isocyanoester of formula (11). Such compounds are known or can be prepared according to known methods, in particular by reaction of phosgene with the corresponding α-formylaminoester compounds.

The compound (11) is reacted with the compound (IV) in a suitable solvent and in the presence of an alkali to give the compound (12). This is treated with an acid in an organic solvent to give the amine (13) which is converted to the pyrrole (14) according to the above procedure.

Finally, the ester group is converted to the amide group by reaction with ammonia or a complex salt formed by reaction of lithium aluminum hydride with ammonia in tetrahydrofuran.

The following examples illustrate the preparation of compounds of formula I without limiting the scope of the invention.

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Example 1

Preparation of 2- (2,5-Dimethyl-1-pyrrolyl) -4-diisopropylaminobutyramide (Compound CM7753) according to Method A1

In the compound of formula I, R 1 is hydrogen, R ₂ is -CH ₃ , R ₃ and R ₄ are -CH (CH ₃ ) ₂ , n is 2.

Step 1: Preparation of 2-Amino-4-diisopropylaminobutyric acid

17.3 g of 2- (2-diisopropylaminoethyl) -acetamido-malonic acid ethyl ester and 4.4 g of sodium hydroxide in a mixture of 300 ml of water and 150 ml of ethanol are heated under reflux for three hours. The mixture was then evaporated to dryness and the residue taken up in 200 ml of 2N hydrochloric acid. The mixture was then refluxed for 5 hours.

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

The residue, which was a tan solid (11.3 g), was used in the next step.

Step 2: Preparation of 2-Amino-4-diisopropylamino-va) acid methyl ester

While cooling, 22 g of thionyl chloride are added to 30 ml of methanol while maintaining the temperature below -5 ° C. 37.7 g of the acid prepared above are then added in portions while maintaining the temperature below -5 ° C. After the addition was complete, the mixture was allowed to warm to room temperature and then held at 40 ° C for 2 hours. The methanol was evaporated and the residue taken up in a little water. 500 ml of ether are added with stirring and the aqueous phase is saturated with potassium carbonate. The ether phase is separated off and the aqueous phase is extracted again with ether. The ether extracts were collected, dried over sodium sulfate and evaporated to dryness.

g of a yellow liquid is used, which is used in the next step.

Step 3: Preparation of 2-Amino-4-diisopropylaminobutyramide

In an autoclave, cooled in an ice bath, 3 g of the ester prepared above were placed in 20 ml of anhydrous ethanol and bubbled with ammonia gas for 1 hour. The autoclave was then sealed and heated at 150 ° C for 36 hours.

The alcohol is evaporated and the residue is taken up in a mixture of water and chloroform. The organic layer was separated and washed with water. The aqueous phase is evaporated to dryness and the residue is extracted with chloroform. The combined chloroform extracts were dried over sodium sulfate and evaporated to dryness.

1.54 g of a colorless liquid are obtained, which product is used without further purification.

Step 4: Preparation of CM 7753

1.54 g of the oil from the previous step and 0.98 g of hexane-2,5-dione are dissolved in 40 ml of acetic acid and heated at 100 ° C for 3 hours. After evaporation of the solvent, the mixture is made basic with dilute sodium hydroxide solution. It is then extracted with ether, the ether phase is dried over sodium sulfate and evaporated to dryness. A black, viscous liquid is obtained, which is chromatographed on an alumina column, eluting with 70:30 hexane / ethyl acetate.

grams of a yellowish solid are obtained which are recrystallized from isopropyl ether. Colorless crystals are obtained, m.p. 71-72 ° C.

Example 2

Preparation of 2- (2,5-Dimethyl-1-pyrrolyl) -4- [4- (diaza-1,4-bicyclo [4.3.0] nonyl) butyramide (Compound CM 40018) according to rt ₂

In the compound of formula (I), R ₁ is hydrogen, R ₂ is methyl, -NR ₃ R ₄ is (15), n is 2.

Step 1: Preparation of 2- (2,5-Dimethyl-1-pyrrolyl) -4-bromobutyric acid methyl ester g of 2-amino-4-bromobutyric acid methyl ester hydrochloride, 17.7 g of 2,5-hexanedione, and Anhydrous sodium acetate (6 g) was dissolved in acetic acid (500 ml) and the solution heated at 100 ° C for 3 hours. The acetic acid is evaporated in vacuo and the residue is taken up in water and ether. The ethereal phase is separated off and washed successively with water, then with sodium bicarbonate solution and again with water. The solution was dried over sodium sulfate and evaporated to dryness.

The resulting residue was chromatographed on a silica gel column, eluting with 9: 1 v / v pentane: ethyl acetate. After evaporation, the resulting crystalline material is washed with petroleum ether. Weight 15.1 g, m.p. 79 ° C.

Step 2: Preparation of 2- (2,5-Dimethyl-1-pyrrolyl) -4- (4-diaza-1,4-bicyclo [4.3.0] nonyl) butyric acid methyl ester

11 g of the ester prepared according to the previous point are burned in 10.1 g of diaza-1,4-bicyclo [4.3.0] -nonane in 150 ml of toluene for 48 hours under reflux. After cooling, the organic solution was washed with water, dried over sodium sulfate and the solvent evaporated in vacuo.

The residue was chromatographed on an alumina column eluting with 95: 5 v / v pentane: ethyl acetate.

g of oil is obtained which is used in the next step.

Step 3: Preparation of CM 40018

1.71 g of lithium aluminum hydride are suspended in 100 ml of anhydrous tetrahydrofuran and bubbled through with ammonia until precipitation ceases. 3.19 g of the ester prepared above are dissolved in 40 ml of tetrahydrofuran and the solution is added with stirring, and the mixture is heated for 3 hours 30 minutes at 55-60 ° C. The mixture was then cooled in an ice bath and hydrolysed with 40% sodium hydroxide solution. After filtration, the solvent was evaporated. The resulting residue was taken up in chloroform and water. The organic layer was separated and the aqueous layer was re-extracted with chloroform. The organic extracts were combined and dried over sodium sulfate. Then evaporate to dryness.

The resulting solid residue (1.7 g) was recrystallized from ethyl acetate. 166-167 ° C.

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Example 3

Preparation of 2-Phenyl-2- (1-pyrrolyl) -4-diisopropylaminobutyramide (CM 7611) according to Method B

The compound of formula (I) R is phenyl, R is hydrogen, R 3 and R ₄ is -CH (CH _{3) 2,} n is the second

Step 1: Preparation of 2-Phenyl-2- (1-pyrrolyl) acetonitrile

16.85 g of 2-amino-2-phenylacetonitrile hydrochloride,

8.2 g of molten sodium acetate and 26.4 g of 2,5-dimethoxytetrahydrofuran in 200 ml of acetic acid are heated at 100 ° C for 2 hours. The acetic acid was then evaporated in vacuo and the residue taken up in ether. The precipitated solid is dried without heating and the ether solution is washed with water. The ethereal solution was dried over sodium sulfate and evaporated to dryness.

The residue, boiling at 108-112 ° C at 0.03 mm Hg, is distilled under high vacuum. The distillate crystallizes. The crystals were recrystallized from hexane. Weight 8 g, m.p. 51 ° C.

Step 2: Preparation of 2-Phenyl-2- (1-pyrrolyl] -4-diisopropylaminobutyronitrile

5.16 g of the nitrile prepared in the previous step,

1.3 g of sodium amide and 5.1 g of 1-chloro-2-diisopropylaminoethane in 150 ml of toluene are heated under reflux for 2 hours. After the solution has cooled, the organic phase is extracted with dilute hydrochloric acid. The acidic aqueous phase was separated, basified with sodium hydroxide and extracted with ether. The ethereal solution was dried and the solvent was evaporated. The residue was chromatographed on a silica gel column, eluting with 8: 2 hexane: ethyl acetate.

6.35 g of the expected product are obtained, which product is used without further purification.

Step 3: Preparation of CM 7611

6.07 g of nitrile prepared as above and 22.6 g of potassium sulfide in 180 ml of 96% ethanol and 45 ml of water are heated under reflux for 5 hours.

After evaporation of the alcohol, the residue is taken up in a mixture of water and chloroform. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on an alumina column. The impurities were eluted with hexane: ethyl acetate (8: 2) and the desired product was eluted with hexane: ethyl acetate (1: 1).

The product was recrystallized from isopropyl ether to give 4.5 g of colorless material. 103-104 ° C.

Example 4

Preparation of 2- (2-Pyridyl) -2- (1-pyrrolyl) -4-diisopropylaminobutyramide (Compound CM 7954) according to Method B

In the compound of formula I, R 1 is 2-pyridyl, R ₂ is hydrogen, R ₃ and R ₄ are -CH (CH ₃ ) ₂ .

Step 1: Preparation of 2- (2-Pyridyl) -α- (1-pyrrolyl) -acetic acid ethyl ester g of 2-amino-2- (2-pyridyl) -acetic acid ethyl ester and 32.3 g

A mixture of 2,5-dimethoxytetrahydrofuran in 300 ml of anhydrous ethanol and 150 ml of acetic acid was heated under reflux for 3 hours.

The solvent was then evaporated in vacuo and the residue taken up in aqueous sodium bicarbonate. The solution was extracted with ether and dried over sodium sulfate. The solvent was evaporated and the resulting residue, which had a boiling point of 0.01 Hgmm 115-122 ° C, was distilled off under reduced pressure.

The distillate recrystallizes and has a melting point of 75-75 ° C. Weight 11.3 g.

Step 2: Preparation of 2- (2-Pyridyl) -2- (1-pyrrolyl) -4-diisopropylamino-butyric acid ethyl ester

15.65 g of the ester prepared in the previous step, 3.57 g of sodium hydride and 12.5 g of 1-chloro-2-diisopropylaminoethane in 500 ml of anhydrous toluene under nitrogen at 100 ° C for 30 minutes. we heat up.

After cooling, the solution was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on an alumina column. Elution was carried out with 95: 5 v / v pentane: ethyl acetate. 17.8 g of the expected product are obtained, m.p. 45-47 ° C.

Step 3: Preparation of CM 7954 In anhydrous tetrahydrofuran, 1.14 lithium aluminum double hydride was suspended and anhydrous ammonia gas was bubbled through the suspension until precipitation ceased. The above ester (7.14 g) was dissolved in tetrahydrofuran (40 mL) and the mixture was stirred at room temperature for 24 hours.

The mixture was hydrolyzed by addition of 40% sodium hydroxide solution, the insoluble material was filtered off and the tetrahydrofuran was evaporated. The residue is taken up in ether, the organic solution is washed with water, dried over sodium sulfate and evaporated to dryness. The residue was recrystallized from isopropyl ether.

3.35 g of colorless crystals are obtained, m.p. 128-129 ° C.

Example 5

Preparation of 2-Methyl-2- (1-pyrrolyl) -4-diisopropylaminobutyramide (Compound CM 40019) according to Method C

In the compound of formula (I), R 1 is methyl, R ₂ is hydrogen, R ₃ and R ₄ are -CH (CH ₃ ) ₂ and n is 2.

Step 1: Preparation of 2-Isocyano-2-methyl-4-diisopropylamino-butyric acid ethyl ester

14.54 g of ethyl 2-isocyanopropionic acid and 19.75 g of 1-chloro-2-diisopropylaminoethane are dissolved in 300 ml of anhydrous ether and 120 ml of dimethylsulfoxide. The mixture was cooled in an ice bath and 5.73 g of 55-60% sodium hydride suspended in 90 ml of anhydrous ether was added portionwise. After the addition was complete, the mixture was heated under reflux for 2 hours. After cooling, the reaction mixture was poured into 300 ml of ice water.

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The organic phase is decanted and the aqueous phase is extracted three times with ether. The organic extracts were combined and washed with water. Dry over sodium sulfate and evaporate to dryness.

The residue, boiling at 0.7 mmHg at 5102-106 ° C, is distilled under reduced pressure to give a hanging product.

Step 2: Preparation of 2-Amino-2-methyl-4-diisopropylaminobutyric acid ethyl ester To 10 ml of absolute ethanol was added water (1.57 g) and hydrogen chloride gas was bubbled through the mixture until saturation.

The solution was cooled to below -10 ° C and 16 g of the isocyanate prepared according to the previous point dissolved in 18 ml of anhydrous ethanol were added. The mixture was gradually allowed to warm to ambient temperature and stored there for 20 hours. The solvent was evaporated in vacuo and the residue taken up in ether. The ethereal solution was washed with saturated aqueous potassium bicarbonate solution, the aqueous phase was separated and extracted with ether. The ether extracts were combined, dried over potassium carbonate and evaporated to dryness.

14.75 g of an oil are obtained which is used in the next step.

Step 3: Preparation of 2-Methyl-2- (1-pyrrolyl) -4-diisopropylamino-butyric acid ethyl ester in g of the amino ester prepared above and 2.17 g

2,5-Dimethoxy-tetrahydrofuran was dissolved in a mixture of 30 ml of anhydrous ethanol and 1 ml of acetic acid, and the solution was heated under reflux for 18 hours. It is then evaporated to dryness in vacuo and the residue is taken up in ether. The resulting solution was washed with water and then with aqueous sodium bicarbonate solution and again with water. The resulting material was dried over sodium sulfate and evaporated to dryness. The material was purified by chromatography on an alumina column. Elution was carried out with 98: 2 pentane: ethyl acetate. 1.1 g of the expected product are obtained.

Step 4: Preparation of CM 40019

The procedure was carried out according to Example 4, paragraph 3, using the ester prepared above, but reducing the reduction time to 1 hour instead of 24 hours.

In a similar manner, the desired amide is obtained in 60% yield. Melting point 79-80 ° C (recrystallized from petroleum spirit boiling at 40-65 ° C).

6-11. examples

1-5. Examples 1 to 8 can be used to prepare the products shown in Table 1 using the appropriate reagents.

The code number of the compounds of formula (I), the s / substituents, the method and finally the melting points after recrystallization are listed in Table I.

f. spreadsheet

Code number R r ₂ n Ra R ' process Melting point (° C) (solvent) 1 2 3 4 5 6 7 8 7640 phenyl -ch ₃ 2 -CH (CH ₃ ) ₂ -CH (CH ₃ ) ₂ B 106-107; (Petroleum ether) 40017 H -ch ₃ 2 A group of formula (16) a ₂ 124-125; (Ethyl acetate) 40002 H -ch ₃ 2 -C ₂ H ₅ -c ₂ h ₅ THE, 88-89; (Isopropyl ether) 7921 H H 2 -CH (CH,) j -CH (CH ₃ ) ₂ THE, 68-69; (Hexane) 40020 40021 H H _s 2 -CH (CH ₃ ) ₂ -CH (CH ₃ ) ₂ THE, 122-124, isolated as the hydrochloride; (Methyl ethyl ketone) CH, -CH (CH ₃ ) ₂ H 2 -CH (CH ₃ ) ₂ -CH (CH ₃ ) ₂ C isolated as hydrochloride 184-186; (Isopropanol) 40105 H -CH ₃ 2 A group of formula (17) THE, isolated as tosylate 110-112, (isopropanol) 40 169 H -ch ₃ 2 cyclohexyl -CH (CH ₃ ) ₂ THE, 165-166 isolated as fumarate; (Ethanol) 40 176 H -ch ₃ 2 -ch ₂ ch ₂ ch ₃ -CHjCHjCH, THE, 198-199, isolated as the hydrochloride; (Isopropanol) ch ₃ ch ₃ 40 178 H -ch ₃ 2 -ch-ch ₂ ch ₃ -CH-CH, ch ₃ THE, isolated as fumarate 147-147; (Acetone) CH ch ₃ 40 201 H -ch ₃ 3 CH -CH ^ THE, 80-81; (Isopropyl ether) ^x ch ₃ ch ₃ 40 261 II -ch ₃ 2 cyclohexyl cyclohexyl THE, 95-97; (Pentane)

The pharmacological properties of the compounds of the invention were tested in animal experiments.

Arrhythmic properties

The antiarrhythmic properties of the compounds of the invention were studied in ventricular arrhythmias of experimental animals.

Dogs were anesthetized and a metal spiral was injected into the coronary artery using a catheter. Simultaneously, a microwave frequency modulator was placed on the back of the animals and two preecordial electrodes were attached.

The animals were returned to their place; over time, advanced thrombosis of the aiterior intraventricular artery developed. Thus, a localized transmural myocardial infarction occurred, resulting in abnormal, repetitive electrical activity - ventricular s tachycardia.

In this condition, the test compounds were administered orally and monitored with arrhythmia over time using a measuring and control device.

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Sinus systolic complexes and pathological events were continuously counted by electrical equipment.

The method described was used to determine the extent and duration of action of the test compound.

Results

The results are shown in Table II. are shown in a table; the effect of the test compounds on ventricular tachycardia was characterized by either restoration of the sinus rhythm or improvement in the following ratio:

number of abnormal complexes number of sinusoidal complexes

II. spreadsheet

examined compound Dose (Mg / kg) Animals number Effect on ventricular tachycardia CM 7611 50 3 Recovery of sinus rhythm or improvement in rate of 70-90% for 3-4 hours CM 7753 50 4 Return of sinus rhythm or rate 90% improvement, 1.5 to 5 hours CM 7640 50 1 Return of sinus rhythm or rate 90% improvement, 90 minutes

Platelet aggregation inhibitory effect

The anti-aggregation activity was studied in vitro and in vivo using the Born's "turbidiuretic" method.

In vitro studies were performed on platelet-rich plasma prepared from human venous blood.

Different concentrations of the test compounds were always freshly prepared. Compounds ACM 7753, 7611, 7640, 7921, 7954, 40018 and 40020 marked prepared 2X 1CT ^2M solution in acetone were prepared and 2 x 1CT ^3M aqueous solutions of compounds 40,169 and 40,178 labeled CM.

2 μ 2 of acetone solutions and 40 μ 2 of aqueous solutions were incubated for 10 min at 37 ° C with 338 and 350 μ platelet-rich plasma, respectively. Then ΙΟμΙ of 40 µg / ml collagen solution was added; 2 μΐ acetone and 40 μΐ distilled water were used as controls.

In vivo studies were performed on baboons with CM 7753 at a daily dose of 50 mg / kg orally for 5 days.

Blood samples were taken to determine platelet aggregation 2 hours after compound administration (50 mg / kg on day 1) and

2 hours after the last administration on day 5.

Evaluation was done by graphically determining the maximum amplitude of aggregation. Results were expressed as the percentage reduction of this parameter, taking the control experiment as 100% aggregation.

Results

(a) In vitro tests

Two of the compounds tested were particularly effective in preventing collagen-induced platelet aggregation. These are the CM 7640 and

They were 7611 (IC _{50 at} about 30 μΜ).

CM 7753 and 7954 reduced aggregation to 50% in a solution of about 10μΜ. Compounds ACM 41018, 40020, 40169, 40178 and 7921 inhibited aggregation only to a lesser extent (20-30% inhibition at 100 μΜ).

(b) In vivo studies

CM 7753 was found to be particularly effective in inhibiting platelet aggregation induced by collagen.

In the 4 experimental baboons, 100% inhibition was observed after 5 daily treatments at 50 mg / kg. A lower anti-aggregation effect was observed against ADP.

The results show that the compounds of the present invention have a strong effect on experimental arrhythmia and have a remarkable antiplatelet effect. Therefore, the compounds of formula I can be used in human therapy as cardiomotor protective agents (myocardial protectors) for the correction of ischemic ventricular arrhythmias and for the treatment of platelet aggregation disorders.

The compounds may also be administered in the form of galenical formulations, orally (tablets, capsules, etc.) or parenterally (injections).

The dose required to inhibit platelet aggregation or restore sinus rhythm in humans is 50-150 mg / day for intravenous administration and 400-800 mg / day for oral administration.

As an example, the following Galenic preparation is described:

tablets

0 777 g of CM 7753

Microcrystalline cellulose 0.140 g

Lactose 0.140 g

Magnesium stearate 0.020 g

Claims (2)

Patent claims A process for the preparation of pyrrole derivatives of the formula I and their acid addition salts with mineral or organic acids - wherein: R 1 is hydrogen, C 1-6 alkyl, phenyl or pyridyl, R ₂ is hydrogen or C 1-4 alkyl, R ₃ and R ₄ may be the same or different, C 1-6 -alkyl, C 5-7 -cycloalkyl, or R ₃ and R _{4 taken} together with the adjacent nitrogen atom are 2,6-dimethylpiperidino, morpholino or 1,4-diazabicyclo [4.3.0] nonyl, n being 2 or 3, respectively that (a) treating a compound of formula (II) wherein R 1 is as defined herein, A is C 2 -C 5 alkoxycarbonyl, P is - (CH ₂ ) _n - NR ₃ R a - with ammonia, followed by treatment with a compound of formula (III). with a diketone of the formula wherein R ₂ is as defined herein, or with 2,5-dimethoxytetrahydrofuran, or b) for the preparation of pyrrole derivatives of the formula I in which R 1 is hydrogen, R ₂ , R ₃ , R ₄ and n are as defined in the general formula II; 182 292, wherein R 1 is hydrogen, A is -CONH ₂ , P is - (CH ₂ ) _n -NR 3 R ₄ - with a diketone of formula III wherein R ₂ is as defined in the preceding claims, or 2 With 5-dimethoxytetrahydrofuran, or c) for the preparation of compounds of the general formula (I) in which R 1 is hydrogen, R ₂ , R ₃ , R 4 and n are as defined above, a compound of the general formula (II) - wherein R 1 is hydrogen, A is a C 2 -C 5 alkoxycarbonyl group, and P is - (CH ₂ ) _n -Br - with a diketone of formula (III) wherein R ₂ is as defined herein or 2,5-dimethoxytetrahydrofuran, and Treating the compound thus obtained with an amine of formula HNR ₃ R ₄ and then with ammonia, or d) for the preparation of a compound of formula I wherein R 1 is phenyl or pyridyl, R ₂ , 20 R ₃ , R ₄ and n are as defined above, a compound of formula II wherein R 1 is phenyl or pyridyl, P is hydrogen, A is cyano or C 2 -C 5 alkoxycarbonyl, with a diketone of formula (III) wherein R ₂ is as defined herein or 2,5-dimethoxytetrahydrofuran, and then with a compound of formula IV: wherein Hal is halogen, n, R ₃ and R ₄ are as defined - treated and A is converted to - CO ₂ NH ₂ , or e) for the preparation of pyrrole derivatives of the formula I in which R 1 is a C 1 -C 6 alkyl group, R ₂ , R 3, R 4 and n are a compound of the formula II as defined above - wherein R 1 is C 1 -C 6 alkyl, A is C 2 -C 5 alkoxycarbonyl, P is - (CH ₂ ) _n -NR ₃ R ₄ - with a diketone of formula (III) - wherein R ₂ is as defined in the present specification. - obsession After reaction with 2,5-dimethoxytetrahydrofuran, the ester group of the resulting compound is converted to the -CONH ₂ group and, if desired, the compound (I) obtained by any of the processes a) to e) is converted into its acid addition salt with a mineral or organic acid. A process for the preparation of a cardiovascular protective, antiarrhythmic, and antiplatelet agent comprising the preparation of a compound of Formula I or a mineral or organic acid salt thereof according to any one of claims 1 to 4, wherein R R ₂ , R ₃ , R ₄ and n are as defined in the preamble of claim 1, which are mixed with pharmaceutically acceptable carriers and / or excipients, and the mixture is blinded to a pharmaceutical composition.