The hydrochloride of n-(beta-hydroxyethyl)tsitizina showing antiarrhythmic activity

 

(57) Abstract:

The invention relates to pharmaceutical industry and relates to new compounds of the hydrochloride of N-(-hydroxyethyl)tsitizina formula (I) exhibiting high antiarrhythmic activity and low toxicity. 1 PL.

The invention relates to new biologically active chemical compound, specifically to the hydrochloride of N-(-hydroxyethyl)tsitizina (I), formula

showing antiarrhythmic activity. The specified connection and its properties are not described in literature.

Currently in clinical practice in the treatment of various arrhythmias have found an extensive use drugs such as quinidine, procainamide, aymalin, ritilin, lidocaine, etmozin etc. However, these tools have a number of disadvantages, namely: low anti-arrhythmic activity in the various forms of arrhythmia, a relatively high toxicity, the presence of hypotensive and negative inotropic action, short duration antiarrhythmic effect [1]. The most important for drug, possess antiarrhythmic activity, is the breadth of his those used antiarrhythmic drugs have serious disadvantages. Therefore, the search of antiaritmikov remains an urgent task.

The closest properties to the proposed connection is VFS, clinical study which showed that he is a highly effective antiarrhythmic agent for various forms of arrhythmias and is especially effective in various forms of ventricular arrhythmias, proximale atrial fibrillation and chronic monotonously atrial tachycardia [2-4].

However, despite the high antiarrhythmic index allapinina active substance which is diterpenoid alkaloid lappaconitine, its high toxicity does not allow the clinic to show all its advantages over existing drugs similar type of action.

The task, which directed the claimed technical solution is to search for new compounds with high anti-arrhythmic activity in the various forms of arrhythmia.

In the claimed technical solution synthesized a new molecule hydrochloride N-(-hydroxyethyl)tsitizina (I) exhibiting anti-arrhythmic activity.

Acute toxicity of the compound (I) was determined on the white bespar the tion (I) is a low-toxic substance. The research results are summarized in the table.

Antiarrhythmic properties of compound (I) was studied on aconitine and chloride-calcium models of cardiac arrhythmia. As Comparators used VFS and the number of known antiarrhythmic drugs. Studies have shown that the compound (I) has a high antiarrhythmic activity models, reproducing various cardiac arrhythmias, including the most life-threatening - fibrillation. The research results are summarized in the table. The compound (I) exhibits a pronounced efficiency on both models arrhythmia and has the greatest antiarrhythmic index among the known antiarrhythmic drugs (the ratio of lethal dose to effective LD50/ED50). The hydrochloride of N-(-hydroxyethyl)tsitizina (I) according to the intensity of anti-arrhythmic action and good endurance surpasses most of the known antiarrhythmic drugs, 250 times less toxic than VFS (see table).

The compound (I) was obtained by treatment of 5% aqueous solution of hydrochloric acid N-(-hydroxyethyl)tsitizina obtained by the interaction tsitizina with ethylene oxide.

Thus, the proposed new small is encompassed in the treatment of various forms of arrhythmias.

The invention is illustrated by the following examples.

Example 1. Synthesis of compound (I)

1a. Synthesis of N-(-hydroxyethyl)tsitizina. To a solution of 1.0 g (5.3 mmol) tsitizina in 10 ml of methanol was added 0.3 g (8 mmol) of ethylene oxide. The reaction mass was kept for 3 days at a temperature of 0-5C. The solvent was distilled under vacuum, and the residue was recrystallized from methanol. Received 1.2 g (96%) N-(-hydroxyethyl)tsitizina, so pl. S. Found (percent): C, 66,71; N, The 7.65; N, 11,83; C13H18N2O2. Calculated (%): C, 66,64; N 7,74; N, 11,96. An NMR spectrum1H (CDCl3, , M. D.): 1,25 (OH); 1,82 d and was 1.94 (2HandFrom(11) and(13), J=12,85 Hz); 2,40-2,60 m (1H-C(9) 2N-C(8), 2HeFrom(11) and(13)); 3,00 t (2H-NH2, J=9,77 Hz); 3,50 t (2N-CH2O, J=5,34 Hz); a 3.87-3,93 D. D. (1HeFrom(10), J=8.30 and 7,44 Hz); 4,10 (1Ha-C(10), J=15,51 Hz); 6,00 d (1H-(5), J=6.75 Hz); 6,45 d (1H-C(3), J=9,07 Hz); 7.25 and 7,30 D. D. (1H-C(4), J=7,37-remaining 9.08 Hz). An NMR spectrum13With (, m D.): 25,40 t ((8)); 28,56 d ((9)); 34,97 d ((7)); 49,63 t ((10)); 57,67 t ((15)); 58,76 t ((11)); 59,76 t ((14)); 59,64 t ((13)); 104,67 d ((3)); 138,57 d (C(4)); 150,87 with (With(6)); 163,12 with (s(2)).

1B. Synthesis of hydrochloride of N-(-hydroxyethyl)tsitizina. To a solution of 1.0 g (4.3 mmole) N-(-hydroxyethyl)tsitizina in 10 ml of methanol was pricipally to the acid reaction of a 5% aqueous solution of Hcl. The solvent was distilled in vacuum, the residue Perekrest the UB>O2Cl. Calculated (%): C, 57,67; N 7,07; N, 10,35; Cl To 13.09. IR-spectrum /cm-1: 3600 (OH); 1644 (C-O); 636 (CH=CH). An NMR spectrum1N (D2O , M. D.): 1,90 (ush.S., 1 H, H2With(8)); 2,41-2,62 (m, 5 H, HC(9), N2WITH(11), N2With(13)); to 3.02 (t, 2 H, H2With(14), J=13,5); 3,22 (ush.S., 1 H, HC(7)); 3,63 (t, 2 H, H2With-IT, J=6,0); 3,90-of 4.05 (m, 2 H, H2With(10); 6,45-to 6.57 (m, 2 H, HC(3), HC(5)); to 7.61 (t, NS(4), J=7,9). An NMR spectrum13With (, m D.): 26,61 t ((8)); 29,16 d ((9)); 37,07 d ((7)); 52,60 t ((10)); 60,14 t ((15)); 61,38 t ((11)); 62,19 t ((14)); 62,20 t ((13)); 111,02 d ((3)); 143,25 d (C(4)); additional 154.36 (C(6)); 166,94 with (s(2)).

Example 2. Determination of acute toxicity

Acute toxicity hydrochloride N-(-hydroxyethyl)tsitizina was determined in anesthetized rats weighing 150-160 g according to the Litchfield-Wilcoxon signed with intravenous awake animals [5]. For the behavior and condition of the animals was observed within 24 h after drug administration. Lethal dose (LD50) this connection is 1500 mg/kg Studies have shown that the studied compound (I) is low toxic substance.

Example 3. The study of the antiarrhythmic activity of the hydrochloride of N-(-hydroxyethyl)tsitizina on aconitine model fibrillation

Continua model arrhythmia allows to study the influence of connections on a mixed form naru is Mostovoy vein at a dose of 50 mcg/kg anesthetized rats weighing 150-160 g Under the influence of aconitine after 1-3 min occurs polytopia premature beats, ventricular tachycardia and fibrillation, which can be associated with arrhythmia observed in clinical conditions. Registered arrhythmias atrioventricular type Compound (I) was administered prophylactically for 1-2 min before the introduction of aconitine. The electrocardiogram (ECG) were recorded in II standard lead 3, 5, 10, 15, 20, etc. minutes within 2 hours the activity of the compounds was assessed by its ability to prevent the development of cardiac arrhythmias under the influence of aconitine.

The compound (I) contributed to a more rapid recovery arrhythmia mixed type with the introduction of aconitine, reducing the duration of the arrhythmia at 304,2 min compared with the control. Effective dose (ED50) the compound (I) intravenously on aconitine model arrhythmia equal to 0.25 mg/kg of the studies are summarized in the table.

Example 4. The study of the antiarrhythmic activity of the hydrochloride of N-(-hydroxyethyl)tsitizina on chloralkali model fibrillation

Chloralkali (ventricular) arrhythmias caused nonlinear anesthetized rats weighing 150-160 g introduction into the tail vein of 250 mg/kg chlorine is aciu ventricular 1-2 minutes Some animals ventricular extrasystoles in combination with sinus bradycardia and block atrioventricular holding gave way to the emergence of short periods of ventricular tachycardia. The analyzed compound (I) was administered intravenously over 2 min before the introduction of aritmogeni. The electrocardiogram (ECG) were recorded in II standard lead. The criterion antiarrhythmic effect took the decrease in the percentage of fatal cases of atrial and percentage of prevention are studying the connection of the death of the animals. The effective dose of compound (I) (U50) was determined by the Litchfield-Wilcoxon signed.

On chloralkali fibrillation study the compound (I) at a dose of 0.14 mg/kg completely prevented the death of animals. This substance contributed to the reduced incidence of atrial induced lethal dose l2. The research results are summarized in the table.

The compound (I) contributed to a more rapid recovery arrhythmia mixed type with the introduction of aconitine, reduction of fatal cases of atrial caused by the introduction of high doses of calcium chloride. Thus, the hydrochloride of N-(-hydroxyethyl)tsitizina has a pronounced antiarrhythmic effect, prevastatin.-1986.

2. Kurbanov R. D., Abdullayev T. A. Pharmacodynamics and efficacy allapinina in patients with abnormal heart rhythm // Clinical medicine, 1988.- So 66.- No. 10.- S. 52-55.

3. Setnew A. S. Golitsyn, S. P., Levin, E. 3. A comparative study of antiarrhythmic efficacy allapinina, atalina and mexitil in patients with ventricular arrhythmias // Ter. arch.1988 at M.V.Lomonosov.- So 60.- No. 8.- S. 34-38.

4. Gasilin C. S. Dorofeev, E. C., N. Rozov.And. The experience of prolonged use allapinina in outpatient practice, Cardiology, 1990.- So 30.- No. 9.- C. 30-32.

5. Belenky, M. L. elements of a quantitative evaluation of the pharmacological effect. L., Medgiz.-1963.-S. 152.

The hydrochloride of N-(-hydroxyethyl)tsitizina formula

showing antiarrhythmic activity.

 

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