RU2105554C1 - N-(2,4,6-trimethylphenylcarbamoylmethyl)-n-allylmorpholinium bromide showing antiischemic and antiarrhythmic effects at ischemic heart disease and a method of its synthesis - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: new chemical compound - N-(2,4,6-trimethylphenylcarbamoyl)-N-allylmorpholinium bromide of the formula (I)

. Method of synthesis of compound (I)

Description

 The invention relates to medicine, specifically to medicines used in the treatment of coronary heart disease, and arrhythmias that complicate it.

 The problem of prevention and treatment of coronary heart disease is very relevant, since the death of patients suffering from diseases of the cardiovascular system, ranks first in the world among deaths from other diseases.

 In addition, coronary heart disease is sometimes complicated by severe arrhythmia, and in the treatment of this disease it is necessary to use a combination of drugs with anti-ischemic and antiarrhythmic effects, which does not always give a positive result.

 The aim of the invention is the creation of a medicinal product for the treatment of coronary heart disease and its complicating arrhythmias, and the development of a method for its production in high yield.

Исследование фармакологической активности 1.The goal is achieved by N- (2,4,6-trimethylphenylcarbamoylmethyl) -N-allylmorpholinium bromide of the formula (1):

Study of pharmacological activity 1.

 1. Anti-ischemic activity 1.

 The indicated effect 1 was studied on white nonlinear rats weighing 250-300 g according to the known method, which allows us to evaluate the effect of the test substance on the sizes of ischemia and necrosis zones in the acute period of myocardial infarction. As a comparison drug, obzidan was used, the anti-ischemic effect of which is known (Mashkovsky M. D. Medicines. M. Medicine, 1993, part 1, p. 330-332).

 The results of the studies are presented in table 1.

 From the presented data it follows that 1 reduces the size of the necrosis zone in relation to the ischemic zone and this effect of the drug corresponds to the reference drug-obzidan.

 2. Effect 1 on coronary blood flow.

 Determination of the effect of 1 on coronary blood flow was carried out according to the well-known method of N. V. Kaverina on anesthetized with ethanol-sodium (50 mg / kg ip) cats transferred to controlled respiration. After opening the chest and cannulating the coronary sinus, the blood flow from it was sent to the jugular vein so that with the help of a tee, it was possible to draw venous blood from the coronary vessels into the measuring vessel at the right time. Each time, the collection of flowing blood was continued for 15 s. The collected amount of blood was multiplied by 4 and the volumetric blood flow velocity was obtained in 1 min. After administration of 1, a study of coronary blood flow was performed after 5, 15, 30, and 60 minutes.

 The results are presented in table.2.

 From the above data it can be seen that 1 at a dose of 1 mg / kg and even more at a dose of 2 mg / kg increases the volumetric velocity of coronary blood flow in the first 10 minutes of observation.

 3. Antiarrhythmic activity 1 in the acute phase of experimental myocardial infarction.

 Studies were conducted on outbred dogs weighing 8-25 kg and cats weighing 2-4 kg. Coronary circulation was impaired in animals anesthetized with hexenal (50 mg / kg intraperitoneally) by applying a ligature to the upper third of the descending branch of the left coronary artery.

 As a comparison drug used lidocaine, which is considered the drug of choice in the treatment of arrhythmias in the acute phase of myocardial infarction.

 The results of study 1 on cats are presented in table 3, on dogs in table 4.

 The results shown in Table 3 indicate that 1 is superior to lidocaine in antiarrhythmic activity in a model of ventricular arrhythmia in cats caused by coronary artery ligation, and in antifibrillator action 1 does not differ from the comparison drug.

 It is important to note that 1 not only prevents the onset of ventricular arrhythmia and ventricular fibrillation, but it is also able to stop arrhythmia that has already arisen. This is evidenced by the second series of experiments conducted with the drug, which was introduced against the background of arrhythmia that had already arisen (Table 3, series 2).

 The same data were obtained in the study of antiarrhythmic activity 1 in the acute period of coronary circulatory disorders in dogs (table 4). Intravenous administration of 1 after applying a ligature to the coronary vessel allows you to prevent the onset of arrhythmia in most animals for 10 hours

 The antiarrhythmic effect of lidocaine at a dose of 15 mg / kg under similar experimental conditions lasts less than 30 minutes. 1 also exerts a pronounced antiarrhythmic effect in the late stages after coronary circulatory disorders in dogs, restoring the sinus rhythm in all animals by 536 ± 56 min (Table 5). Under similar experimental conditions, the antiarrhythmic effect of lidocaine lasts 5-10 minutes.

 Thus, 1 has a pronounced antiarrhythmic activity in cases of cardiac arrhythmias resulting from myocardial ischemia. 1 compares favorably with lidocaine with greater activity and a longer antiarrhythmic effect.

 An important feature of 1 is the combination of antiarrhythmic and anti-ischemic action, which makes this drug the drug of choice in the treatment of arrhythmia in the acute phase of myocardial infarction.

 4. Antiarrhythmic activity 1 in patients with coronary heart disease.

 Antiarrhythmic activity 1 was investigated as an acute drug test. Evaluation of the antiarrhythmic action 1 was performed using the apparatus "Lenta-MT", which allowed for dynamic electrocardiography with subsequent analysis of the recording. Background Holter ECG monitoring was performed for patients who did not have indications for emergency relief of arrhythmia, and if any, the type and class of arrhythmia was determined by cardiomonitoring for 30-120 min or recording ECG-12.

 In the table. Figure 6 shows comparative data on the antiarrhythmic action of 1 and lidocaine in arrhythmias that complicate coronary artery disease.

 1 was used to relieve ventricular arrhythmias in 82 patients suffering from coronary heart disease, among them 40 patients had acute myocardial infarction.

 Intravenous administration of 1 caused a complete and stable suppression of ventricular arrhythmia in 39 patients with acute myocardial infarction, and in one patient there was a noticeable (more than 50%) decrease in the frequency of ventricular extrasystole. In the other 42 patients with coronary heart disease, the antiarrhythmic effect 1 was manifested in 38 patients. The data presented indicate a high antiarrhythmic activity 1 with ventricular arrhythmias of ischemic origin.

 Lidocaine, which is the antiarrhythmic of choice in the treatment of ischemic arrhythmias, especially in the acute phase of myocardial infarction, showed a complete antiarrhythmic effect in arrhythmias complicating the acute period of myocardial infarction in 10 out of 17 patients, which is significantly lower when compared with 1 (P <0.05) .

 In 73% of patients with coronary artery disease who had chest pains, the introduction of 1 was accompanied either by the complete disappearance of the pain syndrome, or by its noticeable decrease.

 5. Antianginal activity (AAA) 1.

 The study involved 11 men aged 30 to 60 years with angina of exertion of the II and III functional classes.

 To identify and objectify AAA 1 used the method of paired bicycle ergometry (VEM). Each patient underwent a diagnostic standard continuous stepwise increasing VEM. 1 hour before the second VEM, 1 was administered intravenously at a dose of 1.5 mg / kg. The load was stopped with depression of the ST segment by 1 mm or more at a distance of 0.08 s from point j in combination with an attack of angina pectoris. AAA criterion was considered to be an increase in the duration of the load against the background of the use of the drug by at least 2 minutes.

 Anti-ischemic effect 1 was recorded in 7 (64%) patients. And although the remaining patients 1 was ineffective according to accepted criteria, all showed an increase in exercise tolerance: an increase in time or load capacity and the total amount of work performed from 8 to 125% (in 40% average).

 Nitrosorbide, which is the standard preparation of these studies, at a dose of 10 mg is not inferior in severity of antianginal action 1. Only in one case 1 was more effective than nitrosorbide. It should be noted that in two patients both drugs in the studied doses were ineffective.

 From the results it follows that 1 has an anti-ischemic effect, approximately corresponding to nitrosorbide.

 The presented results convincingly indicate that 1 has anti-ischemic and antianginal activity. These effects 1, which have found experimental and clinical confirmation, are combined with pronounced antiarrhythmic activity, which, unlike lidocaine, lasts up to 10 hours. The most pronounced antiarrhythmic effect 1 manifests itself, both in the experiment and in the clinic, in the acute phase of myocardial infarction.

 The combination of the listed pharmacological properties 1 makes the drug very promising for improving the pharmacotherapy of the acute period of myocardial infarction.

The method of obtaining 1 consists in the interaction of N- (2,4,6-trimethylphenylcarbamoylmethyl) morpholine (II) with allyl (III) bromide in isopropyl alcohol at a molar ratio of II: III as 1: 1.4-1.6, respectively, at a temperature of 55-65 ^o C. The target product is isolated by filtration of precipitated 1 after cooling the reaction mass to room temperature. Get 1 in the form of an almost white crystalline powder with a yield of 90% counting on II, so pl. 172-176 ^o C (in the range of two degrees). After recrystallization from isopropyl alcohol, pharmacopoeial 1 is obtained.

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

Example. 400 ml of isopropyl alcohol, 100.3 g of 99.7%, 100 g (0.38 mol) of 100% II and 50 ml (0.58 mol) of III are mixed. The mixture was kept at 55-65 ^{° C.} for 7 hours, then cooled to room temperature. The precipitate 1 was filtered off, washed with isopropyl alcohol. Get 132.3 g of 99.4% or 131.5 g of 100% 1, which is 90.0 from theory, counting on II, so pl. 172-173.5 ^o C. After recrystallization from isopropyl alcohol receive pharmacopoeial 1.

 Compound I is readily soluble in water, insoluble in ether, chloroform.

 Found, N 7.6; Br 20.6.

C ₁₈ H ₂₇ N ₂ O ₂ Br.

 Calculated, N 7.31; Br 20.84.

 The purity and individuality of the reaction products is checked by thin-layer chromatography on Silufol UV-254 plates in a solvent system of chloroform ethanol 95% acetic acid 95 4.5 0.5 with a 3% potassium permanganate solution 15% developing in the chlorination chamber above the mixture - hydrochloric acid solution. After drying, the plate is sprayed with a solution of o-tolidine.

The PMR spectrum was recorded on a Hitachl Perkin elmer instrument, operating frequency 90 MHz, internal standard hexamethyldisiloxane, temperature 35 ^o С. Deuterated dimethyl sulfoxide and acetone solvent. Chemical shifts of protons (ppm) are given on a scale of δ. Proton Signals: 3.75-4.10 ppm M (CH ₂ ) ₄ 8H morpholine; 4.52 ppm (CH ₂ ) 2H allyl; 4.81 ppm c (CH ₂ ) -2H acetic acid; 5.56 5.91 ppm M (CH ₂ ) -2H allyl; 5.91 6.5 ppm M (CH) -1H allyl; 6.81 ppm s (2H) - 3.5H aromatics; 10.38 ppm s (NH).

 The parameters of the process of obtaining 1 indicated in the example are found experimentally and are optimal, which is confirmed by the experimental results shown in table. 7-9.

An important parameter of the process is the reaction temperature. As the experiment showed, the optimal temperature range is 55-65 ^o C. At lower temperatures, the reaction does not reach the end, the yield of the target product 1 decreases. At higher temperatures, the reaction mixture is ground, the target product 1 undergoes degradation to form the starting product II, in the result is the target product 1, not satisfying the requirements for color, extraneous impurities.

 As follows from table 8, the optimal molar ratio of reagents II: III during the reaction 1: 1.4-1.6, respectively. A decrease in the amount of III leads to a significant decrease in yield, and an increase in its quantity is unacceptable due to the deterioration of the quality of the target product 1.

As can be seen from table 9, the optimal temperature for the isolation of compound 1 is room temperature 18-25 ^o C. a decrease in temperature does not lead to any significant increase in output, at elevated temperatures, output losses are observed.

 In addition, in the process of obtaining 1, the use of other solvents was verified. In this case, output 1 was lower. than in the proposed method, and in some cases, lower quality 1.

Claims (2)

1. N- (2,4,6-Trimethylphenylcarbamoylmethyl) -N-allylmorpholinium bromide of the formula I

exhibiting anti-ischemic and antiarrhythmic effects in coronary heart disease. 2. A method of producing N- (2,4,6-trimethylphenylcarbamoylmethyl) -N-allylmorpholinium bromide of the formula I, characterized in that N- (2,4,6-trimethylphenylcarbamoylmethyl) morpholine is reacted with allyl bromide in isopropyl alcohol in molar the ratio of N- (2,4,6-trimethylphenyl carbamoylmethyl) morpholine and allyl bromide 1 1.4 1.6, respectively, and a temperature of 55 65 ^o With the subsequent cooling of the reaction mixture to room temperature and the allocation of N- (2,4,6- trimethylphenylcarbamoylmethyl) -N-allyl morpholinium bromide.

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