1-(2,4,6-trimetilfenil)-2-[(2`-hydroxy-3`-phenyloxy)-n - substituted-aminol tyl]-pyrrole and their salts, possess antiarrhythmic and antiischemic activity

 

The invention relates to a new group of pyrrole, in particular 1-(2,4,6-trimetilfenil)-2-[(2-hydroxy-3-phenyloxy)-N-substituted-aminomethyl]pyrrole General formula

where VI, R=-H, VIa R=-C(O)H, VII R=-C(O)CH3, VIIIa R=-CH3, VIII R=-C2H5and their pharmaceutically acceptable salts of dicarboxylic acids, which have anti-arrhythmic and anti-ischemic activity and intensity of effect exceeds applicable in the clinic verapamil, amiodarone and lidocaine. 7 table.

The invention relates to the field of biologically active compounds, specifically to a new group of pyrrole and their salts of the General formula I

where R=hydrogen, alkyl, acyl,

possessing antiarrhythmic and antiischemic activity.

The claimed compounds in the experiment have a pronounced antiarrhythmic activity and intensity of effect exceeds applicable in the clinic verapamil, amiodarone and lidocaine.

These compounds I, their properties and the method of obtaining not described in literature. The closest prototype of the chemical structure are 1,2-substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine is.Peresada, A. M. Lihosherstov, M. N. Vitanov, N. In.Kaverin, K. M. Reznikov, N. With. Nikita // Application N200011081070 (008638) from 04.04.2000]. The previously described compounds differ from the claimed structure and pharmacological properties.

The aim of the invention is the synthesis of new derivatives of pyrrole with antiarrhythmic and antiischemic action, based on the ability of these compounds to affect the transmembrane ionic currents and to increase the stability of the membranes of cardiomyocytes to ischemic stress.

1-(2,4,6-Trimetilfenil)-2-[(2’-hydroxy-3’-phenyloxy)-N-substituted-aminomethyl]pyrrole and get their salts according to the following scheme:

When boiling 1-(2,4,6-trimetilfenil)-2-formylphenol (II) with 2-hydroxy-3-vinyloxy-1-Propylamine (III) in toluene receive a corresponding Schiff base (IV), which without isolation in pure form restores 1-(2,4,6-trimetilfenil)-2-(2’-hydroxy-3’-vinyloxymethyl)pyrrole (V), which was isolated in the form of hydrosylate (VI), and in the acylation of amine (V) with ethyl formate (R’=-H, R’=-C2H5) or acetic anhydride (R’=-CH3, R’=-CO-CH3) were obtained corresponding acyl compound (VII). When restoring acyl compounds (VII) AIII) is a white crystalline substance, soluble in water and aqueous alcohol, insoluble in ether. The structure of the obtained compounds are confirmed by the data of elemental analysis and spectral data.

N-Acyl compounds (VII) are crystalline substances, soluble in methanol, insoluble in ether.

Experimental chemical

Example 1

Hydrosylate 1-(2,4,6-trimetilfenil)-2-(2’-hydroxy-3’-phenoxypropylamine)pyrrole (VI)

A solution of 5.84 g (0,0275 mol) of 1-(2,4,6-trimetilfenil)-2-formylindole and 5.6 g (0,0275 mol) of 2-hydroxy-3-vinyloxy-1-Propylamine in 50 ml of toluene was boiled with water separator 7 hours. Toluene drove away, the residue was dissolved in 50 ml of methanol and was first made with stirring over 0.6 g of palladium on coal (10% Pd) at room temperature. theoretical amount of hydrogen was absorbed in 3 hours. The catalyst was filtered, the methanol drove away. The residue was dissolved in 25 ml of isopropyl alcohol and the resulting solution was added a solution of 3.6 g (0.03 mol) of succinic acid in 25 ml of isopropanol. Isopropanol drove away, the residue was dissolved in ether and the resulting solution ostavlali to stand until crystallization. The precipitate was filtered and recrystallized from isopropanol. The output of 5.1 g (37.9% of theory), so pl. 120-121the emer 2

1-(2,4,6-Trimetilfenil)-2-N-(formyl-N-(2’-hydroxy-3’-phenoxypropan)aminomethyl)pyrrole (VIIa)

of 3.97 g (to 0.011 mol) of 1-(2,4,6-trimetilfenil)-2-(2-hydroxy-3-phenoxypropylamine)of pyrrole in 10 ml of ethylformate boiled under reflux for 7 hours. The reaction mixture was evaporated to dryness, the residue was added 30 ml of ether and left to stand until the end of crystallization. The precipitate was filtered, washed with ether, and dried. Yield 3.2 g (74.1% of theory), so pl. 112-113C.

Found, %: C 73,70, N 7,22, N 7,31. C24H28N2O3.

Calculated, %: C 73,45, N 7,19, N 7,13.

Example 3

1-(2,4,6-Trimetilfenil)-2-(N-acetyl-N-(2’-hydroxy-3’-phenoxypropan)aminomethyl)pyrrole (VII)

A solution of 6 g (0,0166 mol) of 1-(2,4,6-trimetilfenil)-2-(2-hydroxy-3-phenoxypropylamine)of pyrrole and to 12.52 g (0,025 mol) of acetic anhydride in 40 ml of dry benzene was boiled under reflux for 24 hours. To the reaction mixture were added 20 ml of a 5% solution of potash, and the mixture was stirred 2 hours at room temperature. To the reaction mixture were added 60 ml of water, the benzene solution was separated, washed with water and benzene were released. To the residue was added 30 ml of ether and left to stand until the end of crystallization. The precipitate was filtered and dried. Output 1-(2,4,6-trimetilfenil)-2-(N-methyl-N-(2’-hydroxy-3’-phenoxypropan)aminomethyl)pyrrole (VIIIa)

To a suspension from 0.76 g (0.02 mol) of lithium aluminum hydride in 60 ml of dry ether was added with stirring in portions to 3.92 g (0.01 mol) of 1-(2,4,6-trimetilfenil)-2-(N-formyl-N-(2-hydroxy-3-phenoxypropan)aminomethyl)pyrrole. The reaction mixture with stirring and boiled under reflux for 5 hours. To the reaction mixture were added 10 ml of water. The ether solution decantation, and the residue was extracted with ether. After drying the ethereal solution of magnesium sulfate the ether drove away. The residue was dissolved in 10 ml of ether to the resulting solution was added a solution of 1.18 g (0.01 mol) of fumaric acid in 12 ml of isopropanol and left before the end of crystallization. The precipitate was filtered and recrystallized from isopropanol. Yield 2.8 g (56% of theory), so pl. 153-154C.

Found, %: C 67,98, N? 7.04 Baby Mortality, N 5,72. With28H34N2About6.

Calculated, %: C 67,99, N 6,93, N 5,66.

Example 5

Gidrofumarat 1-(2,4,6-trimetilfenil)-2-(N-ethyl-N-(2’-hydroxy-3’-phenoxypropan)aminomethyl)pyrrole (VIII)

To a suspension from 0.76 g (0.02 mol) of lithium aluminum hydride in 60 ml of dry ether was bury with stirring, a solution of 6.75 g (0,0166 mol) of 1-(2,4,6-trimetilfenil)-2-(N-acetyl-N-(2-hydroxy-3-phenoxypropan)aminomethyl)of pyrrole in 15 ml of dry benzene. The reaction mixture with premesis actor decantation and the residue was extracted with ether. After drying benzoline-ether solution of magnesium sulfate, the solvent drove away. The residue was dissolved in 15 ml of isopropanol and left before the end of crystallization. The precipitate was filtered and recrystallized from a mixture of isopropyl alcohol and ether. Yield 3.8 g (45% of theory), so pl. 108-109C.

Found, %: C 68,17, N 7,07, N The Ceiling Of 5.60. With29H36N2O6.

Calculated, %: C 68,48, N 7,13, N 5,51.

Pharmacological

Example 1

Study of acute toxicity of the inventive compounds

Studies of acute toxicity of compounds VI, VIIIa and VIII were performed on white mice of both sexes weighing 18-20 g, divided into groups of 10 animals [Belenky, M. L. elements of a quantitative evaluation of the pharmacological effect. - Riga, 1959. - 113 C.]. Substances introduced vnutribruchinno in the liquid volume of 0.5 ml/10, the Results are presented in table 1. In the study of acute toxicity of the compounds VI found that the introduction of a substance at a dose of 50 μmol/kg and less visual signs of the effect of compound no. When the connection is used at a dose of 300 and 500 µmol/kg over 5 minutes after injection, mice inhibited, do not respond to tactile and painful stimuli. Within 10-15 minutes the motor comes the ez 20 minutes the convulsions gradually cease, the breath goes in the breath of Kussmaul, gradually ceased. All the animals die within the hour, autopsy signs of the effect of compound no. When the connection is used in a dose of 100, 150, 200 and 250 µmol/kg the animals are killed with a clinical picture similar to animals that received the compound at a dose of 1000 µmol/kg, part survives, having the characteristic symptoms of the activity of a compound, slightly differing in the degree of severity of cramps and the length of inhibition. All surviving animals (all groups) when monitoring for 2 weeks had a normal appetite, the dynamics of weight was missing. Animal behavior corresponded to the control group. Animals slaughtered by an overdose of ether anesthesia; at the opening of the signs of the activity of a compound was not detected.

Picture of intoxication with the introduction of compounds VIIIa and VIII had no fundamental differences from the observed for compounds VI. The number of dead animals, depending on the dose given in table 1.

Thus, as can be seen from table 1, the least toxic of issledovanij compounds was substance VI.

Example 2

A comparative study of the antiarrhythmic activity of the inventive compounds on the model HLV S. Yu, Kischuk E. P., Pashina O. E. Experimental study of new antiarrhythmic drugs //Vedomosti of the Pharmacological Committee. - 1998. - N2. - S. 11-19]. The substance was compared with the standard means of complications (propranolol, amiodarone, verapamil).

The results obtained are presented in table 2.

On the model of potassium chloride arrhythmia activity of the compounds decreases in the order: verapamil > VI > amiodarone > VIII > VIIIa > VIIa > propranolol. For the most active compound (VI) was determined dose of the ED50that is 5,561,29 mmol/kg (p=97,77%). When comparing antiarrhythmic and antifibrillatory effects of equimolar doses of the compounds detected that VI potency superior to amiodarone and propranolol - reference antiarrhythmic agent.

Example 3

A comparative study of the antiarrhythmic activity of the inventive compounds on the model of gloriamarie fibrillation

Gloriamarie fibrillation reproduced by a standard method by the introduction of barium chloride at a dose of 35 mg/kg intravenously to rats in a series of 6-12 animals [Mironova M. I. Antiarrhythmic properties of some classes of sulfur-containing organic compounds: author. Dr. med. Sciences. -M., 1986. - 4 what KMOL/kg for acid intravenously. As comparative drugs were used classic antiarrhythmic agent - propranolol, verapamil. The results are presented in table 3.

In the series of the studied compounds, the activity decreased in the order: verapamil > VI > VIII. Substance VIIa did not affect the course of gloriamarie arrhythmias, a VIIIa and propranolol worsened during arrhythmias, increasing the number of dead animals.

Example 4

A comparative study of the antiarrhythmic activity of the inventive compounds on the model of aconitine arrhythmia

Continuou arrhythmia caused by the standard method [Kaverin N.In., Berdyaev, S. Y., Kischuk E. P., Pashina O. E. Experimental study of new antiarrhythmic drugs //Vedomosti of the Pharmacological Committee. - 1998. - N 2. - S. 11-19]. The results obtained are presented in table 4.

Antiarrhythmic activity in this model, decreased in number VI>lidocaine>VIII=amiodarone. Thus, VI was superior to anti-arrhythmic action of the reference drugs. In this model, the ED50for VI amounted to 3 µmol/kg

Example 5

The effect of the inventive compounds for arrhythmias caused by strophanthin

Modeling glycosidic arrhythmias were performed by standard m funds //Vedomosti of the Pharmacological Committee. - 1998. - N 2. - S. 11-19.]. As follows from the data in table 4, compound VIIIa significantly increases the life expectancy of animals, and VII has a pronounced tendency to lengthen the life of Guinea pigs.

Example 6

Study of the effect of the inventive compounds for izadrin-pituitrin myocardial ischemia.

Izadrin-pituitrin ischemia of the myocardium (ipim) evoked outbred white rats weighing 180-220 g according to the method Reznikov K. M. et al. (A. S. No. 1019482). The investigated compound was administered twice for 15 min to even injections izadrina dose of 3 mmol/kg of myocardial damage was confirmed by morphological examination of the myocardium with staining hematoxylin-eosin. Animals recorded ECG in the second abstraction, in the plasma was determined by the concentration of protein biuret method, the activity of alanine aminotransferase (ALAT), aspartate aminotransferase (AST) and their ratio - De Ritis coefficient. Also recorded coagulation tests investigated the aggregation activity of platelets, did complete blood count was determined leukocyte formula to the calculation of the leukocyte index of intoxication (LII), investigated the amount of water in the lungs.

Histological examination found that when EPIM morphological cart unevenly colored, transverse striation is missing. Areas of intense staining along the beams alternate with more pale, which often breaks the muscle fibers. Glycogen in the cytoplasm occurs in the form of individual granules, pale colored area visible granules of glycogen, freely located in the interstitium. Most of the cores myocardiocytes in karyopyknosis and karyorhexis. Over the entire area of the slice, there are numerous areas of non-nuclear myocardiocytes, around which are visible focal infiltrates of leukocytes, marked interstitial edema. In vessels stasis of red blood cells, thickening of the wall, loosening, razvlechenie intima around some diabetes erythrocytes. In the result we can conclude that there is a small acute myocardial infarction, predominantly intramural.

When using compounds VI morphological picture is similar in all samples, only slightly varying in degrees of severity. Diffuse interstitial edema moderate in all departments of the myocardium. On the whole thickness of the myocardium there are numerous areas peresobrany muscle fibers alternating with lots of breaks myofibrils, which are visible fragments of surcolombiana setoptions not detected. Transverse striation visible not always stored partially in subepicardial zone, where contractions are relatively rare. There are few petechial interstitial hemorrhage. Vessel walls thickened, friable, intima looks corrugated, in the lumen of the isolated red blood cells.

Thus, on a background of application of the compounds of ischemic damage to the myocardium is observed to a lesser extent than in the control.

These laboratory analyses are presented in table 6.

During the development of ipim an increase in the amount of water in the lungs. Compound VI was eliminated this manifestation of IPEM, reducing the degree of pulmonary edema and circulatory failure on a small circle.

On the background of ipim there was no change in the number of red blood cells, but there were some changes in the formula blood: moderate leukocytosis, neutrophilia with left shift formula, relative lymphocytopenia; accordingly significantly increased LII (694% of normal).

On the background of the application VI the number of erythrocytes was higher than the values in untreated animals (154%, p <0,05), but from control values did not differ significantly. The number of cells was also increased (149% from the group with Petelino, as neutrophilia when THEY are associated with the resorption of necrotic tissue, the use of compound VI was reduced myocardial necrosis.

Development ipim accompanied by hypoproteinemia (89,4% of normal, p<0,05). The number of MSM also sharply increased (3-fold), which may indicate, first, about the increase in the number of decay products of high molecular weight peptides, and, secondly, an increase in blood stress-limiting oligopeptides as a compensatory response to myocardial injury. Substance VI tended to increase the concentration of protein in the blood, however, without changing the number of MSM. Thus, on the background of decreasing necrosis was observed tension stress-limiting systems of the body.

The study of aminotransferases in EPIM showed that the concentration of ALT in the background ipim not change and the concentration of AST increased by 33%. The use of the compounds significantly reduced the amount of AST, accompanied by increased De Ritis coefficient, which confirms the reduction of cytolysis under the influence of substances.

When determining the number of platelets in EPIM showed reduced to 47.7% of normal (p<0,05) with a simultaneous decrease in the rate and degree of their agreg the society VI confirms a lesser degree of blood clots, and heart damage. However, the reduction of platelet aggregation (reduction of a General change in extinction), observed as a compensatory reaction in EPIM, against the use of compound VI was significantly lower than values obtained for untreated ipim, 4 times. Thus, the use of compounds VI resulted in a decrease of the aggregation properties of platelets, which lowers blood viscosity and may serve as a subsequent prevention of thrombosis and reinfarction. In the study of coagulation established that when modeling ipim observed increase in time to begin phasing in 2 times (p<0.05), and 2.3 times increases the start time of fibrinolysis, and in 50% of cases fibrinolysis is not. Fibrinolytic potential, thus, reduced 4.5 times (p<0.01) and the degree of fibrinolysis - 2 times. 3.5-fold increased hemostatic potential of 2.5 times the lifetime of a dense clot. There is a tendency to decrease clotting activity of the blood (15%). Thus, on the background of ipim there is a decrease in the intensity of the phase 1 of coagulation with a moderate increase in clotting activity of the blood and the sharp decline in the activity of fibrinolysis.

When using compounds VI in the background ipim were observed normalization time of the beginning of the fibrinolysis was not observed, the start time of fibrinolysis was close to normal. Hemostatic potential was decreased compared to untreated animals 6 times, fibrinolytic potential was increased 5-fold (p<0.01), and the degree of fibrinolysis 6 times (p<0.01), and coagulating activity was decreased compared to the norm of 18%. Thus, the substance not only reduces platelet aggregation, but also intensifies the fibrinolysis in EPIM, at the same time normalizing the action of the humoral coagulation factors.

Example 7

The definition of the breadth of therapeutic action of the compounds VI

Based on the data obtained in examples 1, 2 and 4, the toxicity of these compounds and their antiarrhythmic activity models chloralkali and aconitine arrhythmia, it is possible to determine therapeutic index (the ratio LD50/ED50for the antiarrhythmic activity of substances VI. For arrhythmia caused by aconitine T=39 s.ed., for chloralkali 22,5 srvc. units (see table 7).

Therefore, as can be seen from examples 1-7, the claimed compounds are characterized by high antiarrhythmic activity, surpassing traditionally used in the clinic compound, and having a wide spectrum of action. Also in substance VI well expressed to antisemitist, the pyrrole and their salts possess antiarrhythmic and antiischemic properties. The greatest interest represents the connection VI.

Claims

1-(2,4,6-Trimetilfenil)-2-[(2’-hydroxy-3’-phenyloxy)-N-substituted-aminomethyl]-pyrrole General formula

where VI, R=H; VIa; VII; VIIIa R=-CH3; VIII R=-C2H5,

and their pharmaceutically acceptable salts of dicarboxylic acids having anti-arrhythmic and anti-ischemic activity.

 

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