Hydrochloride 3-(2-hydroxyethyl)-1,5-dinitro-3 - azabicyclo[3.3.1]non-6-ene showing antiarrhythmic activity

 

(57) Abstract:

The invention relates to chemical-pharmacological industry and relates to new biologically active chemical compounds of the hydrochloride of 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene of formula (1) with high antiarrhythmic activity and low toxicity. 1 PL.

The invention relates to new biologically active chemical compound, specifically to the hydrochloride of 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene (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 closest to C the objective antiarrhythmic agent in 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 new chemical compound is the hydrochloride of 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene (I), possess antiarrhythmic activity.

Acute toxicity of the compound (I) was determined on white outbred rats weighing 150-160 g intravenously according to the method of Litchfield-Wilcoxon signed. Studies have shown that the compound (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 arrhythmia sardinnya studies have shown, the compound (I) possesses 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 is compared with allapinina more antiarrhythmic index (the ratio of lethal dose to effective LD50/ED50). The target compound (I) according to the intensity of anti-arrhythmic action and good endurance surpasses most of the known antiarrhythmic drugs, 44 times less toxic than VFS.

Synthesis of compound (I) was performed by the interaction of 1,3-dinitrobenzene with sodium borohydride, followed by the condensation of aqueous solutions of formaldehyde and monoethanolamine and processing of the obtained 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene 5% aqueous solution of hydrochloric acid.

Thus, the inventive compound (I) is low toxic compound and has a pronounced anti-arrhythmic activity in the treatment of various forms of arrhythmias.

The invention is illustrated by the following examples.

EXAMPLE 1. Sine 0-10 ° C to a solution of 6.00 g (29 mmol) of 1,3-dinitrobenzene in 18 ml of THF, 12 ml of formamide and 36 ml tO added in small portions over 0.5 h 4.20 g (111 mmol) NaBH4. Then the reaction mass was diluted with 100 ml of ice water and was added a mixture of 32 ml of 33% formalin and 26 ml of ethanolamine, then added 32 ml of ice Asón and were extracted l3(3100 ml). The extract was washed with water (340 ml), dried over Na2SO4and evaporated the solvent in vacuo. The residue was recrystallize sequentially from the Meon and tO, got 5.20 g (56%) of white crystals of 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene, (Alufol, Rf0.8, l3- Meon, 2:3), so pl. 106-S. Found (%): At 46.75; H 5.85; N, 16.37. C10H15N3O5. Calculated (%): 46.69; N, 5.83; N, 16.34. Mass spectrum: m/z 257 [M]+IR-spectrum /cm-1: 3436 (OH); 1545 (NO2); 1378 (NO); 1054 (C-O); 754 (CH=CH). An NMR spectrum1H (CDCl3, , M. D. J/Hz): 2.21 (t, 1H, HE, J=5.5); 2.65 (d, 1H, Hand(2),2J=10.6); 2.68-2.80 (m, 6N, N2WITH(8), N(9), Nand(4), N2With(10)); 2.9 (D. T., 1H, H/(9),2J=11.4,4J=2.1; 2.1); 3.17 (D. D., 1H, He(2),2J=10.6,4Ja2a4=1.8; 2.1); 3.38 (D. D., 1H, He(4),2J=15.6, 4Ja2a4=1.8; 2.1); 3.65 (m, 2H, H(11)); 6.04 (m, 2H, 1H, H(6) N(7)). An NMR spectrum13With (, m D.): at 35.58 (t, C(9)); 37.68 (t, C(8)); 57.85 (t, C(10)); 57.87 (t, C(2)); 58.23 (t, C(11)); 61.99 (t, C(4)); 84.32 (s, s(1)); 86.83 (s, C(5)); 125.86 (d, C(7)); 130.07 (d,3.9 mmole) of 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene 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 was recrystallize from acetone, got 1.05 g (92%) of compound I. Found (%): 40.80; N, 5.55; N, 14.37; Cl 11.99. C10H16N3O5Cl. Calculated (%): 40.89; N, 5.49; N, 14.31; Cl 12.07. IR-spectrum /cm-1: 3064 (HE); 1552 (NO2); 1342 (NO); 1066 (C-O); 760 (CH=CH). An NMR spectrum1N (D2O , M. D., J/Hz): 3.06-3.37 (m, 4H, H2WITH(8), N2With(9)); 3.51-3.78 (m, 3H, HE, Hand(4), Nand(2)); 3.91-4.01 (m, 2H, H2With(11)); 4.12 (m, 2H, H2C(10)); 4.23 (d, 1H, He(2)); 4.32 (d, 1H, He(4); 6.24 (d, 1H, HC(6)); 6.36-6.47 (m, 1H, HC(7)). An NMR spectrum13With (, m D.); 37.05 (t, C(9)); 37.47 (t, C(8)); 55.57 (t, C(10)); 57.02 (t, C(2)); 59.12 (t, C(11)); 61.98 (t, C(4)); 84.13 (C, C(1)); 84.45 (s, C(5)); 124.62 (d, C(7)); 134.45 (D. C(6)).

EXAMPLE 2. Determination of acute toxicity of the compound (I)

Acute toxicity hydrochloride 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene was determined on white outbred 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 265 mg/kg (see table). The compound (I) is low toxic substance.

EXAMPLE 3. The study of antiarrhythmic activity the tail 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 rhythm mixed atrio-ventricular type. The compound (I) was administered prophylactically for 1-2 minutes until the introduction of aconitine. The electrocardiogram (ECG) were recorded in II standard lead 3, 5, 10, 15, 20, etc. minutes for 2 hours. The activity of compound (I) was evaluated by its ability to prevent the development of cardiac arrhythmias under the influence of aconitine.

The compound (I) prevented the development of arrhythmia mixed type with the introduction of aconitine. Effective dose (ED50) the compound (I) intravenously on aconitine model is equal to 0.30 mg/kg of the studies are summarized in the table.

EXAMPLE 4. The study of the antiarrhythmic activity of the compounds (I) on chloralkali model

Chloralkali (ventricular) arrhythmias caused nonlinear anesthetized rats weighing 150-160 g introduction into the tail vein of 250 mg/kg of calcium chloride in the form of a 10% solution. In most cases, ventricular fibrillation occurs for 1-2 minutes. The compound (I) 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. Effective dose of the analyte (U50) was determined by the Litchfield-Wilcoxon.

On chloralkali model arrhythmia compound (I) in a dose of 0.11 mg/kg completely prevented the death of animals. When administered intravenously, the compounds (I) decreased the number of deaths fibrillation, caused by the introduction of high doses of calcium chloride.

Research shows that the hydrochloride of 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene (I) has a high anti-arrhythmic effect in models of experimental arrhythmias and less toxic compared with known drugs that have anti-arrhythmic action.

Bibliography

1. Mashkovsky M. D. Medicines. - M.: Medicine.-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. H. a comparative Study of antiarrhythmic efficacy alapini the ptx2">

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.

Hydrochloride 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene of the formula

showing antiarrhythmic activity.

 

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