RU2258700C1 - Quaternary ammonium derivative of lidocaine eliciting anti-arrhythmic activity and method for its preparing - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a new biologically active compound. Invention describes quaternary ammonium derivative of lidocaine of the formula:

eliciting anti-arrhythmic activity. Also, invention describes a method for preparing quaternary ammonium derivative of lidocaine of the formula (1). Method involves interaction of N-(2,6-dimethylphenylaminocarbonylmethyl)-morpholine with allyl bromide in isopropyl alcohol medium at temperature 58-62°C followed by cooling the reaction mixture to room temperature and isolation of N-allyl-(2,6-dimethylphenylaminocarbonylmethyl)-morpholinium bromide. Invention provides preparing new compound eliciting useful biological properties.

EFFECT: improved preparing method.

2 cl, 4 tbl, 4 ex

Description

The invention relates to medicine and may find application in medical practice for the correction of cardiac arrhythmias.

A compound N- (2,4,6-trimethylphenylcarbamoylmethyl) -N-allyl morpholinium bromide is known under the name quaternidine, which exhibits anti-ischemic and antiarrhythmic effects in coronary heart disease (RU 2105554, IPC 6 A 61 K 31/535, C 07 D 29/037 publ. 1997).

A disadvantage of the known solution is its high toxicity and low breadth of therapeutic effect.

The technical result consists in reducing acute toxicity, increasing the breadth of the therapeutic effect and reducing the mortality of laboratory animals with chronic stress.

The technical result is achieved by the quaternary ammonium derivative of lidocaine - N-allyl- (2,6-dimethylphenylaminocarbonylmethyl) morpholinium bromide of the formula (1):

possessing antiarrhythmic activity.

A method of obtaining a compound of formula (1) is that N- (2,6-dimethylphenylaminocarbonylmethyl) morpholine is reacted with allyl bromide in isopropyl alcohol at a temperature of 58-62 ° C, followed by cooling of the reaction mixture to room temperature and isolation of N- allyl- (2,6-dimethylphenylaminocarbonylmethyl) morpholinium bromide.

The method according to the invention is illustrated by the following example.

Example. Synthesis of N-allyl-N- (2,6-dimethylphenylaminocarbonylmethyl) morpholinium bromide

To 100 g of N- (2,6-dimethylphenylaminocarbonylmethyl) morpholine, 130 ml of isopropyl alcohol are poured, 49 ml of allyl bromide is gradually added to the solution. The mixture is heated to a temperature of 60 ° C, stirred for 5-6 hours, then cooled, the precipitated product is filtered off. 133.5 g of a technical substance (89.72%) are obtained, which is purified by recrystallization from isopropyl alcohol with the addition of activated carbon. Receive 109.5 g of a white crystalline powder readily soluble in alcohol, soluble in water, practically insoluble in ether and chloroform. T pl. 195-197 ° C.

Found%: C 55.12 H 6.71 N 7.42 O 8.53, Br 21.52

Calculated,%: С 55.29 Н 6.82 N 7.59 О 8.66, Br 21.64

C ₁₇ H ₂₅ N ₂ O ₂ Br, m.m. 369.29

IR, γ cm ^-1 : 1550 (NHCO), 1670 (C = O), 3280 (NH)

Study of pharmacological activity 1

In contrast to quaternidine 1, it is favorably characterized by lower toxicity with intraperitoneal, oral and intravenous routes of administration, as well as greater safety, as illustrated by example 1.

Example 1. Acute toxicity 1 and the closest analogues

Acute toxicity 1 was studied in experiments on mice (n = 440, m = 18-20 g) with intraperitoneal and oral methods of administration, on cats (n = 15, m = 1.5-4.8 kg) with intravenous administration.

The LD ₅₀ index was calculated by the Miller and Taint method (Prince M. Belenky. Elements of a quantitative assessment of the pharmacological effect. - Riga: Publishing House of the Academy of Sciences of the LSSR, 1963. - 130 pp.). To determine acute toxicity upon intravenous administration (LD ₁₀₀ ), solutions in an isotonic sodium chloride solution were administered to animals until cardiac arrest was stopped. The results of the study of the structural precursor of lidocaine, quaternidine, as well as 1 are presented in table 1.

From the data proposed in the table, it is clearly seen that the claimed compound is more toxic than the structural precursor lidocaine upon intraperitoneal administration and less toxic than the quaternary derivative of trimecaine - quaternidine. When administered orally, acute toxicity 1 was less than that of lidocaine and quaternidine. A lethal intravenous dose of 1 for cats is also lower than that of quaternidine and lidocaine.

Example 2. Antiarrhythmic activity of 1 and its closest analogues in ventricular arrhythmias in the late stage of experimental myocardial infarction in dogs

Ventricular arrhythmia in the late stage of experimental myocardial infarction was reproduced in mature dogs of both sexes weighing 7.0-15.0 kg. Violation of coronary blood flow in animals was caused by the method described in sources: Harris A.S. Delayed development of ventricular ectopic rhythm following experimental coronary occlusion. // Circulation Res. - 1950 .-- Vol. 1. - N6. - P.1318-1328 and Gendenstein E.I., Kostin Y.V. The antiarrhythmic effect of trimecaine with ventricular arrhythmias // Cardiology. - 1976. - No. 1. - S.128-131.

The test results of the claimed compounds and analogues are given in table.2.

Study 1. Introduction 1 at a dose of 4 mg / kg allowed to suppress arrhythmia in 100% of experiments. The duration of the antiarrhythmic effect was at least 500 minutes of observation. The complete antiarrhythmic effect developed on average 15 minutes after administration.

Thus, the strength and duration of the antiarrhythmic effect 1 is not inferior to quaternidine and lidocaine. Like the quaternary derivative of trimecaine (quaternidine) 1, the two-phase nature of the occurrence of antiarrhythmic action is characteristic.

Example 3. Activity 1 and quaternidine in aconitine arrhythmia model in rats and mice

Arrhythmia was reproduced according to the method of Yu.I. Vikhlyaev and N.V. Kaverina (1958) (Prince Kaverina N.V., Berdyaev S.Yu., Kushchuk E.P., Paschina O.E. Methodological guidelines for the study of antiarrhythmic activity new pharmacological substances // Guide to the experimental (preclinical) study of new pharmacological substances / Edited by V.P. Fisenko. - M., 2000. - P.210). Aconitine nitrate was administered to animals at a dose of 50 μg / kg. The research results are presented in table 3.

This model allows us to judge the breadth of the therapeutic effect of the presented compounds, its closest analogues and structural precursor. The breadth of the therapeutic effect was judged by the value of the antiarrhythmic index, defined as the ratio of LD ₅₀ with the intraperitoneal route of administration to ED ₅₀ on the aconitine model of arrhythmias.

The experiment shows that 1 effectively relieves atrial arrhythmia caused by intravenous administration of aconitine nitrate. Moreover, the value of the antiarrhythmic index calculated for 1 is much higher than those of quaternidine and lidocaine, therefore, 1 has a greater breadth of therapeutic effect than the compared analogues, which indicates its greater safety with equivalent activity.

Example 4. The study of the effect of 1, lidocaine and quaternidine on experimental mortality with prolonged administration to animals under stress

Currently, to evaluate the safety of long-term antiarrhythmic therapy, the method is used (Balashov V.P., Balykova L.A., Shuvalova E.N. et al. A new method for assessing the safety of potential antiarrhythmic drugs // Bull. Exp. Biol. And honey . - 2002. - T.133. - No. 5. - S.598-600) modeling of 6-hour immobilization stress in white mice daily for 6 weeks.

The results of study 1, lidocaine and quaternidine are presented in table 4. All compounds were administered at a dose of 5% of LD ₅₀ when administered intraperitoneally to mice. 1 - at a dose of 4 mg / kg ip, lidocaine - 10 mg / kg, quaternidine - 2 mg / kg.

In the control, immobilization led to the death of some animals, and mortality after 6 weeks was 30%. Lidocaine significantly increased the mortality of mice under stress. Quaternidine showed a tendency to its increase, and the percentage of death of animals with the introduction of 1 was the smallest of all considered substances.

The data presented indicate that N-allyl-N- (2,6-dimethylphenylaminocarbonylmethyl) morpholinium bromide (1) exhibits pronounced antiarrhythmic properties in models of ventricular and atrioventricular (aconitine) arrhythmias, comparable to those of the closest analogue (quaternidino) and superior properties of the structural precursor (lidocaine).

The duration of effect 1 corresponds to a similar indicator of quaternidine and significantly exceeds the duration of the effect of lidocaine. An important advantage of the claimed compound is its greater breadth of therapeutic effect compared with that of lidocaine and quaternidine. In addition, under conditions of prolonged immobilization stress with a 6-week administration, 1, unlike lidocaine, does not increase the mortality of experimental animals.

Thus, the modification of the morpholine analog of lidocaine by attaching an allyl group to the nitrogen atom (synthesis of N-allyl-N- (2,6-dimethylphenylaminocarbonylmethyl) morpholine bromide) allows one to obtain a more effective and safe compound for the treatment of heart rhythm disturbances than its structural predecessor and the closest analogue.

Table 1. Quaternary ammonium derivative of lidocaine with antiarrhythmic activity, and a method for its preparation The studied indicators Lidocaine Quaternidine 1 LD ₅₀ iv, mg / kg 200 ± 15 * ** 54 ± 4 ** 82 ± 5 * (M ± m) (173-227) (46-62) (76-94) Mice N = 80 n = 60 n = 100 LD ₅₀ per os, 297 ± 14 * ** 450 ± 26 ** 630 ± 26 * Mg / kg (271-324) (400-500) (578-689) (M ± m) Mice n = 80 n = 60 n = 60 LD ₁₀₀ iv, mg / kg 128 ± 7 * ** 47 ± 4 ** 90 ± 4 ^* (M ± m) cats n = 5 n = 6 n = 4 Note: * - differences when compared with quaternidine are significant at p <0.05; ** - differences when compared with lidocaine are significant at p <0.05.

Table 2. Quaternary ammonium derivative of lidocaine with antiarrhythmic activity, and a method for its preparation No. p / p Test compound The nature of the initial rhythm The nature of the rhythm after the introduction of the substance Number of animals The beginning of the effect, min The duration of the effect, min Arrhythmia Suppression,% Heart rate abbreviations Ectopic Contraction Rate Heart rate BSEC In experience With full effect (%) 1. Lidocaine 191 ± 9 143 ± 24 175 ± 3 0 6 2 (33) 1 4-6 61 ± 11 2. Quaternidine 206 ± 10 159 ± 25 188 ± 6 0 5 5 (100) 16 ± 4 536 ± 56 100 3. 1 191 ± 9 143 ± 24 175 ± 3 0 10 10 (100) 15 ± 5 500 minutes observed 100

Table 3. Quaternary ammonium derivative of lidocaine with antiarrhythmic activity, and a method for its preparation Test drug Dose mg / kg n With arrhythmia (%) Onset time, s HP duration, min ED ₅₀ , mg / kg AI The control - 19 19 31 ± 12 90.0 ± 8.0 - - Lidocaine 2,5 6 6 68 ± 22 67.0 ± 12.0 5 nine 4 135 ± 15 41.0 ± 6.0 8.47 ± 1.9 23.5 10 nine 3 186 ± 38 35.0 ± 6.0 fifteen nine 0 - - Quaternidine 0.5 5 5 100 ± 24 136.0 ± 26 1,5 6 4 140 ± 60 57.0 ± 8.0 2.09 ± 0.58 25.8 2.0 eleven 6 200 ± 35 64.0 ± 13.0 4.0 6 0 - - 1 0.5 nine 8 89 ± 21 100.0 ± 13 1,5 nine 6 96 ± 33 84.0 ± 18.0 2.0 ± 0.58 43.5 2.0 nine 3 154 ± 13 45.0 ± 13 4.0 nine 0 - - Note: ED ₅₀ - effective dose, HP - rhythm disturbances, AI - antiarrhythmic index.

Table 4. Quaternary ammonium derivative of lidocaine with antiarrhythmic activity, and a method for its preparation Group The number of dead animals Abs. % Without immobilization (n = 20) 0 0 Immobilization (control; n = 40) 12 30,0 +1 (n = 40) 14 35.0 + lidocaine (n = 40) 21 52.5 ^* + quaternidine (n = 40) 16 40,0 Note: ^* p <0.05 when compared with control.

Claims (2)

1. The Quaternary ammonium derivative of lidocaine of the formula (1)

possessing antiarrhythmic activity. 2. A method of producing a quaternary ammonium derivative of lidocaine of formula 1, characterized in that N- (2,6-dimethylphenylaminocarbonylmethyl) morpholine is reacted with allyl bromide in isopropyl alcohol at a temperature of 58-62 ° C, followed by cooling of the reaction mixture to room temperature and the isolation of N-allyl- (2,6-dimethylphenylaminocarbonylmethyl) morpholine bromide.