RU2054938C1 - Agent showing antiarrhythmic activity - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: product: 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrochloride showing high antiarrhythmic effect and lowered toxicity with relation to contracting myocardium function as compared with known compounds. EFFECT: enhanced antiarrhythmic activity of agent proposed. 2 dwg, 2 tbl

Description

 The invention relates to biologically active compounds having antiarrhythmic activity, in particular to 2-morpholino-5-phenyl-6H-1,3,4-thiadisine hydrochloride, which can be used in medicine as the basis of an antiarrhythmic drug.

и 2-карбэтоксиамино-10-(3-диэтиламинопропионил)-фенотиазина гидрохлорид (этацизин) формулы

Известные этмозин и его диэтиламиновый аналог этацизин проявляют высокую антиаритмическую активность (Лысковцев В.В. Сенова З.П. Юравичус И.А. и др. Антиаритмические и электрофизиологические свойства этмозина и его диэтиламинового аналога (этацизина). Бюллетень экспериментальной биологии и медицины, 1979, т. 84, N 3, с. 243-247).Currently known compounds of the phenothiazine series, namely 2-carbethoxyamino-10- (3-morpholylpropionyl) -phenothiazine hydrochloride (ethmosine) of the formula

and 2-carbethoxyamino-10- (3-diethylaminopropionyl) phenothiazine hydrochloride (ethacyzine) of the formula

Known ethmosin and its diethylamine analog etatsizin exhibit high antiarrhythmic activity (Lyskovtsev V.V. Senova Z.P. Yuravichus I.A. et al. Antiarrhythmic and electrophysiological properties of ethmosin and its diethylamine analogue (etatsizin). Bulletin of Experimental Biology and Medicine, 1979 , T. 84, No. 3, pp. 243-247).

 However, along with high antiarrhythmic activity, the compounds have a pronounced negative inotropic effect, which leads to a decrease in the contractile function of the heart (Rosenstrauh L.V. Kaverina N.V. Anyukhovsky E.P. et al. Effect of ethmosine DAA on the myocardial functional state. Cardiology, 1982, v. 22, No. 6, pp. 72-74).

Соединение обладает высокой антиаритмической активностью, однако так же, как и указанные выше соединения, проявляет ярко выраженное отрицательное инотропное действие, которое приводит к снижению сократительной функции сердца (Sheu S. S. Lederer W.I. Lidocaines negative inotropic and antiarrhythmic actions, Circ. Res. 1985, v 57, N 4, р. 578-590).In addition, a compound of α-diethylamino-2,6-dimethylacetanilide hydrochloride (lidocaine) of the formula

The compound has a high antiarrhythmic activity, however, like the above compounds, it exhibits a pronounced negative inotropic effect, which leads to a decrease in cardiac contractile function (Sheu SS Lederer WI Lidocaines negative inotropic and antiarrhythmic actions, Circ. Res. 1985, v 57 N 4, p. 578-590).

 The objective of the invention is to obtain data regarding the antiarrhythmic activity of a biologically active compound, which along with antiarrhythmic properties would be less toxic with respect to the contractile function of the myocardium than known.

 The problem was solved by using 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrochloride as a compound exhibiting antiarrhythmic activity.

где Ph=

обладает интерес- ным сочетанием адрено-, холино- и серотонино-блокирующих свойств, что позволяет отнести его к веществам, обладающим нейропсихотропной активностью.It is now known that the compound 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrochloride of the general formula

where Ph =

It has an interesting combination of adreno-, choline- and serotonin-blocking properties, which allows it to be attributed to substances with neuropsychotropic activity.

 The use of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrochloride as a compound exhibiting antiarrhythmic activity was made possible after a series of in vivo and in vitro experiments were carried out, which made it possible to detect the presence of an antiarrhythmic property in the compound . It should be noted that the establishment of this property was possible only under the condition of special experiments with modeling of rhythm disturbances. The presence of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrochloride in the compound with the adreno-, choline- and serotonin-blocking properties previously identified does not in any way imply that it has an antiarrhythmic property, especially lack of negative inotropic action. Thus, experimental studies were needed to establish these properties.

 Biological tests of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrochloride for antiarrhythmic activity and inotropic effect were carried out at the Institute of Physiology, Ural Branch of the Russian Academy of Sciences.

 Testing Methodology.

 In vitro experiments were performed on isolated papillary muscles of the right ventricle of the rat heart and trabeculae of the atrial ears of patients with congenital heart defects obtained during heart surgery. Muscles were placed in the chamber of the experimental setup, perfused with nutrient solution, stimulated with superthreshold pulses with a frequency of 0.3 Hz using massive platinum electrodes (field stimulation). The force of contractions of myocardial preparations was recorded in isometric mode and the developed stress was calculated by recording mechanical activity.

 In a series of experiments, when authoritarian activity was caused, external stimulation was turned off and the natural frequency of spontaneous contractions was recorded.

The studied pharmacological compound was introduced into the perfusate in concentrations from 10 ^-7 to 10 ^-4 M.

 In addition, a series of in vivo experiments were performed on rats anesthetized with sodium thiopental.

 Study of the effect of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrochloride on the spontaneous contractile activity of an isolated muscle.

The antiarrhythmic effect of the compound was studied in vitro on isolated papillary muscles of the right ventricle of rats. One experimental group consisted of muscles in which autistic activity arose spontaneously. Another muscle perfused with a nutrient solution containing 10 ^-4 M adrenaline, as a result of which high-frequency autistic activity was established.

 The test substance was introduced into the perfusate in a gradually increasing concentration, and in both muscle groups, a dose-dependent decrease in the frequency of spontaneous contractions was observed, up to the complete disappearance of authoritarian activity. An example of an experimental recording is shown in FIG. 1, dots indicate the initiating pulse.

 To compare the effectiveness of the drugs with the well-known domestic antiarrhythmic drugs ethmosin and etacizin, a series of experiments was conducted on isolated trabeculae of the ears of the atria of patients extirpated during cardiac surgery. According to the described method (Mary-Rabine L. Hordof A. Danilo P. et.al. Mechanisms for impulse initiation in isolated human atrial fibers. Circ. Res. 1980, v. 47, No. 2, pp. 267-277) in trabeculae They evoked steady, authoritarian activity that could persist for a long time without an initiating impulse.

During perfusion of trabeculae with a solution containing the test compound at a concentration of 10 ^-4 M, a monotonic decrease in the frequency of spontaneous contractions occurred. For example, in one of the experiments a decrease in the repetition rate of authoristic contractions from 37.5 min (control) to 8.1 min was observed.

Compared with etatsizin, the test compound, like ethmosin, showed a slightly lower antiarrhythmic activity. For example, in order to reduce the frequency of spontaneous muscle contractions by 3-4 times, it is necessary to add 10 ^-4 M compounds to the perfusate, while the concentration of etazicin can be an order of magnitude lower. However, the current concentration of the proposed compounds is quite low. Numerical data on the change in the frequency of spontaneous contractions is given in table. one.

 Study of the effect of compounds on the activity of the sinus node.

To evaluate the chronotropic effect of the compound in vivo, experiments were performed on rats anesthetized with sodium thiopental (80 mg / kg). The test compound was administered to animals intraperitoneally at a dose of 0.2 LD ₅₀ . This dose, as established in previous experiments, is 73 mg / kg body weight.

 The spontaneous rhythm of the sinus node was recorded and evaluated by the duration of the R-R interval on the ECG. According to eight experiments, the R-R interval did not statistically significantly change when the drug was administered at a given concentration.

 Investigation of the antiarrhythmic effect of the compound on a barium arrhythmia model.

 The experiments were performed on rats anesthetized with sodium thiopental, weighing 200-250 g. Experimental rhythm disturbance was caused according to the generally accepted procedure with barium chloride (Terekhova L.A. which was administered intraperitoneally at a dose of 90 mg / kg. An ECG was recorded and the duration of the R-R interval was evaluated. It was shown that in one group of animals, 1-2 minutes after the introduction of barium chloride, the RR interval significantly increased (2-2.5 times), the appearance of single extrasystoles, periods of bigeminia, alternating with periods of asystole, ventricular fibrillation arose, and all without exception animals died on average after 15 minutes.

To another group of animals, initially, after anesthesia, the test compound was administered at a dose of 0.2 LD _-50 intraperitoneally. After 5 min, barium arrhythmia was created by the above method. It turned out that in these animals, as in the control group, the RR interval was prolonged (on average, 2 times). Single estrasystoles occurred approximately at the same time as in the control group. However, periods of rhythm disturbance gave way to periods when the sinus rhythm returned to normal. Ventricular fibrillation resulting in animal death occurred in five cases. At the same time, the duration of the survival period of animals increased by an average of 2.4 times (up to 37 minutes). One animal remained alive for at least another 2 hours.

 Study of the effect of compounds on the mechanical activity of an isolated muscle.

 It is known that most antiarrhythmic compounds have a pronounced negative inotropic effect. In all experiments on isolated heart muscles of rats and patients, the change in the value of isometric contractions was evaluated. It turned out that the test compound also has a negative inotropic effect, but to a much lesser extent than, for example, ethmosin and especially etacisin. In FIG. Figure 2 shows a dose-dependent decrease in the strength of isometric contractions under the influence of ethmosine (curve 2), ethacycin (curve 1) and the test compound (curve 3). In addition, in table. 2 shows comparative data taken from different sources, reflecting the severity of the negative inetropic effect of antiarrhythmic compounds.

 Thus, 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrochloride possesses the properties inherent in antiarrhythmic compounds. In experiments on isolated cardiac muscles, it suppresses induced authoristic activity, while in in vivo experiments, it prolongs the survival period of animals after modeling cardiac arrhythmia.

 In addition, it should be noted, firstly, a slight change in the intrinsic heart rhythm of experimental animals and, secondly, a weak negative inotropic effect of this compound, which allows us to expand the range of applied concentrations, this compares favorably with other well-known domestic ones (atmosin and etatsizin ) and foreign antiarrhythmics.

Claims (1)

 The use of 2-morpholino-5-phenyl-6H-1, 3,4-thiadiazine hydrochloride as a means of exhibiting antiarrhythmic activity.

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