RU2414893C1 - Quaternary ammonium derivative of novocain, which possesses anti-arrhythmic activity, and method of its obtaining - Google Patents

Abstract

FIELD: medicine, pharmaceutics. ^ SUBSTANCE: invention relates to pharmacology and organic chemistry and deals with novel quaternary ammonium derivative of Novocain of formula which possesses anti-arrhythmic activity, and method of its obtaining by interaction of Novocain base with bromide allyl in medium of isopropyl alcohol at temperature 57-63C, holding at said temperature during 5-6 hours with following cooling of reaction mixture to room temperature and separation of N-allyl-N-(2-oxiethylcarboxy-4-aminophenyl)-diethylamine of bromide. ^ EFFECT: compound possesses useful biological properties. ^ 2 cl, 2 tbl

Description

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

A compound of β-diethylaminoethylamide of para-aminobenzoic acid hydrochloride is known under the name novocainamide, which exhibits an antiarrhythmic effect in life-threatening heart rhythm disturbances (Mashkovsky MD Medicines. Ed. 14, revised, corrected and supplemented. M: "New Wave", 2002 - S.365).

A disadvantage of the known solution is its low antiarrhythmic activity and a small breadth of therapeutic action - it is effective mainly in atrial rhythm disturbances.

The technical result consists in increasing the pharmacological antiarrhythmic activity and increasing the breadth of the therapeutic effect.

The invention is achieved in that the quaternary ammonium derivative of novocaine - N-allyl-N- (2-hydroxyethylcarboxy-4-aminophenyl) diethylamine bromide of the formula (1):

possesses antiarrhythmic activity. The method of obtaining the compounds of formula (1) is that the novocaine base is reacted with allyl bromide in isopropyl alcohol at a temperature of 57-63 ° C, at which it is kept for 5-6 hours, followed by cooling of the reaction mixture to room temperature and isolation N-allyl-N- (2-hydroxyethylcarboxy-4-aminophenyl) diethylamine bromide.

The method is illustrated by the following example.

Example. Synthesis of N-allyl-N- (2-hydroxyethylcarboxy-4-aminophenyl) diethylamine bromide.

150 ml of isopropyl alcohol are added to 100 g of novocaine base, 65 ml of allyl bromide are gradually added to the resulting solution. The resulting mixture is heated to a temperature of 57-63 ° C and incubated for 5-6 hours. Part of the solvent is removed by distillation, and the target product is isolated by adding 50 ml of water, followed by cooling and filtering the precipitate. Obtain 105.8 g of technical product (70.0%) which is purified by recrystallization from isopropyl alcohol with the addition of activated carbon. 86.7 g of a yellow crystalline powder (99.4% of the basic substance) are obtained, odorless, insoluble in water, easily soluble in ethanol, ethyl acetate, chloroform. _Mp = 123-125 ° C.

Found%: C 53.72; H 7.15; N, 7.86; O 8.94; Br 22.31.

Calculated,%: C 53.78; H 7.05; N, 7.84; O 8.96; Br 22.36.

C ₁₆ H ₂₅ N ₂ O ₂ Br, m.m. 357.28.

A study of the pharmacological activity of the compounds of formula (1).

Example 1. Antiarrhythmic activity of a compound of formula (1), a structural precursor and the closest analogue in ventricular arrhythmias in cats, caused by high ligation of the coronary artery and its subsequent reperfusion.

Currently, to evaluate the effectiveness of therapy in conditions of transient ischemic and reperfusion arrhythmogenesis, the method described by B. Storozhuk is used. Antifibrillator activity of some antiarrhythmic drugs with the highest possible ligation of the coronary artery and its reperfusion in cats // Farmakol. and toxicol. -1985. - Number 3. - S. 47-49 and Manning G.A.S., Grome R., Istcol K. et al. Reperfiision induced ventricular fibrillation. Modification by pharmacological agents // Adv. Myocardiol. - Vol. 6. - New York, London, 1985 .-- P.515-522.

The results of the study of the claimed compounds, analogs and precursors are given in table 1.

The study of the compounds of formula (1). The introduction of a compound of formula (1) at a dose of 3.2 mg / kg allowed to suppress ischemic and reperfusion ventricular fibrillation in 100% of experiments (significantly when compared with control at p <0.05) and significantly reduce the risk of ventricular arrhythmia: ischemic - to 33 %, reperfusion - up to 50%.

Thus, in strength and duration of the antiarrhythmic effect, 1 is superior to its structural predecessor novocaine and its closest analogue, novocainamide.

Example 2. The activity of the compounds of formula (1), procainamide and procaine on the model of aconitine arrhythmia in rats and mice

Arrhythmia was reproduced according to the method of Yu.I. Vikhlyaev and N.V. Kaverina (Prince Kaverina N.V., Berdyaev S.Yu., Kushchuk E.P., Paschina O.E. Methodological instructions for studying the antiarrhythmic activity of new pharmacological substances // Guidance on 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 2.

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 the compound of formula (1) effectively relieves atrial arrhythmia caused by intravenous administration of aconitine nitrate. Moreover, the value of the antiarrhythmic index calculated for the compound of formula (1) is much higher than those of novocaine and novocainamide, therefore, 1 has a greater breadth of therapeutic effect than the compared analogues, which indicates its greater safety with equivalent activity.

The data presented indicate that N-allyl-N- (2-hydroxyethylcarboxy-4-aminophenyl) diethylamine bromide (1) exhibits pronounced antiarrhythmic properties in models of ventricular and atrioventricular aconitine arrhythmias that are superior to the antiarrhythmic properties of the structural precursor, novocaine, and the analogue is Novokainamide.

The duration of the antiarrhythmic effect 1 significantly exceeds the duration of the effect of novocaine and novocainamide. An important advantage of the claimed compound is its large breadth of therapeutic effect on the aconitine model of arrhythmias compared with the closest analogue and predecessor.

Thus, the modification of novocaine by attaching an allyl group to the nitrogen atom (synthesis of N-allyl-N- (2-hydroxyethylcarboxy-4-aminophenyl) diethylamine bromide) allows one to obtain a more effective and safe compound for the treatment of heart rhythm disturbances than its structural predecessor and closest analogue.

Table 1 Antiarrhythmic properties of N-allyl-N- (2-hydroxyethylcarboxy-4-aminophenyl) diethylamine bromide, the closest analogue and structural precursor on the model of acute occlusal and reperfusion arrhythmias in cats Substance Dose ^a , mg / kg Number of animals Number of animals in experience with occlusal in experience with reperfusion arrhythmia VF arrhythmia VF The control - 31 31 (100%) 9 (29%) 23 23 (100%) 15 (65%) Novocainamide 20,0 6 4 (67%) * 0 (0%) 6 3 (50%) * 2 (33%) * Novocaine 10.5 6 4 (67%) * 1 (17%) 5 5 (100%) 3 (60%) The compound of formula (1) 3.2 6 0 (0) ^a 0 (0%) 6 2 (33%) * 0 (0%) ^a Notes: ^a - the presented doses are 5% of the LD ₅₀ for mice with intraperitoneal administration; VF - ventricular fibrillation; * - differences from the corresponding control value are significant at p <0.05; ^a - differences from novocaine and novocainamide are significant at p <0.05.

table 2 Antiarrhythmic effect of N-allyl-N- (2-hydroxyethylcarboxy-4-aminophenyl) diethylamine bromide, procaine and procainamide upon intravenous administration of aconitine nitrate Test compound (drug) In experience Dose mg / kg The number of animals with arrhythmia ED ₅₀ , mg / kg AI The control 19 - 19 - 6 2.5 6 9 5,0 four Novocaine 8.5 ± 1.9 23.5 9 10.0 3 9 15.0 0 6 10.3 6 6 20.6 5 Novocainamide 6 41.2 four 49.4 ± 5.6 8.4 6 51.5 2 5 61.8 0 The compound of formula (1) 6 0.5 6 6 1,5 2 1.23 ± 0.18 47.2 6 2.9 2 6 5.8 0 Note: AI - antiarrhythmic index; ED ₅₀ - the average therapeutic dose.

Claims (2)

1. The quaternary ammonium derivative of novocaine of the formula (1):

possessing antiarrhythmic activity. 2. A method of obtaining a quaternary ammonium derivative of novocaine of the formula (1), which consists in the fact that the novocaine base is reacted with allyl bromide in isopropyl alcohol at a temperature of 57-63 ° C, at which it is kept for 5-6 hours, followed by cooling the reaction mixture to room temperature and the isolation of N-allyl-N- (2-hydroxyethylcarboxy-4-aminophenyl) diethylamine bromide.