RU2058314C1 - 2-(n-methyl piperazine)-5-aryl-6h-1,3,4-thiadiazine dihydrobromides having antiarrhythmic activity - Google Patents

Abstract

FIELD: pharmaceutical industry. SUBSTANCE: 2-(N-methyl piperazine)-5-(4-bromophenyl)-6H-1,3,4-thiazine dihydrobromide having essential formula C₁₄H₁₉N₄SBr₃ is prepared at yield 90 %. Its melting point is 254-256 C. 2-(N-methyl piperazine)-5-phenyl-6H-1,3,4-thiazine dihydrobromide having essential formula C₁₄H₂₀N₄SBr₂ is prepared at yield 81 %. Its melting point is 198-200 C. EFFECT: improves quality of desired product. 1 dwg, 2 tbl

Description

 The invention relates to the field of organic chemistry, in particular to the synthesis of drugs.

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Однако, наряду с высокой антиаритмической активностью эти препараты обладают ярко выраженным отрицательным инотропным действием, которое приводит к снижению сократительной функции сердца [1]
Известен ряд соединений класса тиадиазинов, которые обладают кардиоваскулярной активностью [2]
Известно близкое по структуре соединение 2-[4-(4-оксо-1,4- дигидропиридин-1-ил)-фенил] -4H, 6H-1,3,4-тиадиазин-5-он, обладающий инотропным, сосудо- и бронхорасширяющим действием и свойством ингибитора агрегации тромбоцитов [3]

Однако антиаритмического действия у представителей этого класса веществ не выявлено.Effective antiarrhythmic drugs of the phenothiazine series ethmosin and ethacyzin are known.

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However, along with high antiarrhythmic activity, these drugs have a pronounced negative inotropic effect, which leads to a decrease in the contractile function of the heart [1]
A number of compounds of the class of thiadiazines are known that have cardiovascular activity [2]
A compound 2- [4- (4-oxo-1,4-dihydropyridin-1-yl) phenyl] -4H, 6H-1,3,4-thiadiazin-5-one having an inotropic, vascular and bronchodilating effect and platelet aggregation inhibitor property [3]

However, no antiarrhythmic effect was found in representatives of this class of substances.

 The aim of the invention is the creation of a new cardiotropic drug that combines high antiarrhythmic activity with the absence of negative inotropy.

2HBr где 1: R=H;
2: R=Br.This goal is achieved by the synthesis of 2- (N-methylpiperazine) -5-phenyl-6H-1,3,4-thiadiazine dihydrobromide (1) and 2- (N-methylpiperazine) -5- (4-bromophenyl) -6H-1, 3,4-thiadiazine dihydrobromide (2) of the general formula

2HBr where 1: R = H;
2: R = Br.

 These drugs in an experiment on isolated papillary muscles and trabeculae of the ventricles of the hearts of laboratory animals (rats) possess the properties inherent in an antiarrhythmic drug, and, at the same time, do not have a negative inotropic effect on an isolated myocardium, which distinguishes them from such well-known domestic antiarrhythmics as ethmosin and etatsizin (test report attached). Effective drug concentrations [37 μM for (1) and 87 μM for (2)] at which the frequency of spontaneous muscle contractions is reduced by 2 times, slightly higher than that of ethmosin (28 μM) and ethacyzine (15 μM). However, the advantage of preparations 1 and 2 is that in a wide range of concentrations (up to 1 mM) they do not suppress the contractile response of an isolated muscle (inotropic action coefficient calculated as the ratio of muscle contraction force after drug exposure to control contraction force is approximately 1). Ethmosine and ethacycin have an inotropic coefficient of less than 0.5 (Table 2, graph) at concentrations below effective.

2HBr
Строение соединений подтверждено данными ПМР- и УФ-спектров: в ПМР-спектре 1 и 2 наблюдаются сигналы двух протонов метиленовой группы 1,3,4-тиадиазинового цикла (δ СН= 4,4 м.д.), уширенный синглет восьми протонов пиперазинового кольца (δ 3,6 м.д.), синглет трех протонов метильной группы в пиперазиновом кольце, а также для соединения 1-мультиплет пяти протонов фенильного ядра в области 7,4-8,1 м.д. а для соединения 2-дублет дублетов типа А₂В₂ от пара-замещенного бензольного кольца (δ 7,03; 7,8 м.д. I 9,1 Гц). В УФ-спектре два максимума поглощения ( λmax, lgE): 1:310 (3,98); 260 (3,95); 11:310 (4,1); 265 (4,1), характерные для 1,3,4-тиадиазинов [4]
ПМР-спектры записаны на приборе Perkin-Elmer-12 В (60 МГц) в ДМСО-d6.Compounds 1 and 2 were prepared by reacting equimolar amounts of W-bromoacetophenone (4-bromo-W-bromoacetophenone), respectively, and thiocarbazic acid N-methylpiperazinide by boiling in ethanol with the addition of HBr:

2HBr
The structure of the compounds was confirmed by the data of PMR and UV spectra: in the PMR spectrum 1 and 2, signals of two protons of the methylene group of the 1,3,4-thiadiazine ring (δ CH = 4.4 ppm), a broadened singlet of eight piperazine protons are observed rings (δ 3.6 ppm), a singlet of three protons of a methyl group in the piperazine ring, as well as for the connection 1-multiplet of five protons of the phenyl nucleus in the region of 7.4-8.1 ppm. and for the connection of a 2-doublet of doublets of type A ₂ B ₂ from a para-substituted benzene ring (δ 7.03; 7.8 ppm I 9.1 Hz). In the UV spectrum there are two absorption maxima (λmax, logE): 1: 310 (3.98); 260 (3.95); 11: 310 (4.1); 265 (4.1) characteristic of 1,3,4-thiadiazines [4]
PMR spectra were recorded on a Perkin-Elmer-12 V instrument (60 MHz) in DMSO-d6.

 Chemical shifts are given on a scale of δ relative to the internal TMS standard. The UV spectrum was recorded on a Specord UV VIS spectrometer in ethanol.

 The study of cardiotropic activity was carried out in experiments on isolated papillary muscles and trabeculae of the ventricles of the hearts of laboratory rats. Muscles were placed in baths perfused with nutrient solution and stimulated with superthreshold pulses using platinum electrodes with a frequency of 0.2 Hz.

 In order to evaluate the antiarrhythmic effect of the compounds in isolated muscles, adrenaline was used to induce sustained regular authoritarian activity. Then, the studied substances dissolved in physiological saline were introduced into the perfusate in gradually increasing concentrations from 1 μM to 1 mM. The frequency of spontaneous muscle contractions was recorded before and after the compounds were added to the perfusate. As follows from the data obtained, given in table 1, all compounds in a dose-dependent manner suppress autonomic muscle contractions.

 To assess the inotropic effects of substances, muscles were stimulated with a frequency of 0.2 Hz and the value of isometric contractions was recorded. The inotropic action coefficient of the studied compounds was calculated as the ratio of the amplitude of the isometric muscle contraction after the next portion of the substance was added to the perfusate to the amplitude of the control contraction, i.e. without pharmacological effects.

 The antiarrhythmic activity and inotropic effect of the antiarrhythmics of the phenothiazine series ethmosin and ethacyzine were evaluated in a similar manner. The data obtained are given in tables 1 and 2.

Example 1 2- (N-methylpiperazine) -5-phenyl-6H-1,3,4-thiadiazine dihydrobromide was obtained by heating in a water bath for 20 minutes. 2 g (0.01 mol) of bromoacetophenone and 1.74 g (0.01 mol) of thiocarbazinic acid N-methylpiperazinide in 30 ml of ethanol and 1.4 ml (0.01 mol) of HBr conc. The reaction mixture is cooled. The precipitated product is filtered off and crystallized from isopropyl alcohol with the addition of water (20: 1) and a few drops of HBr conc. The precipitate is filtered off, washed with isopropyl alcohol, and dried. A colorless crystalline product, soluble in water. Yield 3.5 g (81%). Mp 198-200 ^about S.

Calculated, C 38.7; H 4.5; N, 12.9; S 7.4;
C ₁₄ H ₂₀ N ₄ SBr ₂
Found C, 38.9; H 4.7; N, 12.9; S 7.4.

Example 2. 2- (N-methylpiperazine) -5- (4-bromophenyl) -6H-1,3,4-thiadiazine dihydrobromide was obtained by heating in a water bath for 10 min 2.8 g (0, 01 mol) 4-bromo-W-bromoacetophenone and 1.74 g (0.01 mol) of thiocarbazic acid N-methylpiperazinide in 30 ml of ethanol and 1.4 ml (0.01 mol) of HBr conc. A yellow precipitate is immediately observed, the reaction mass is cooled in an ice bath, filtered and crystallized from ethanol with the addition of water (10: 1) and a few drops of HBr. The precipitate was filtered off, washed with ethanol, and dried. A colorless crystalline product, soluble in water. Yield 4.6 g (90%). Mp 254-256 ^about S.

Calculated, C 32.7; H 3.7; N, 10.9; S 6.2
C ₁₄ H ₁₉ N ₄ SBr ₃
Found C 32.7; H 3.8; N 11.0; S 6.3.

Claims (1)

2- (N-Methylpiperazine) -5-aryl-6H-1,3,4-thiadiazines, dihydrobromides of the general formula

where IRH, II R Br, having antiarrhythmic activity.

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