N-(2,4,6-trimethylphenylsulfonyl)-n-allylnormorphine bromide, showing anti-ischemic and anti-arrhythmic effect in ischemic heart disease and method thereof

 

(57) Abstract:

A new chemical compound is N-(2,4,6-trimethylphenylsulfonyl)-N-allylnormorphine bromide formula 1 shows the experimental animals and in clinical conditions anti-ischemic and anti-arrhythmic effect in ischemic heart disease and can be used to create a promising drug for the treatment of coronary heart disease. A method of obtaining compound 1, which consists in the interaction of N-(2,4,6-trimethylphenylsulfonyl) research with methyl-allyl at a molar ratio of 1:1,4-1,6, respectively, in the environment of isopropyl alcohol at a temperature of 55-65oWith subsequent separation of the target product after cooling the reaction mass to room temperature. Yield 90%, the content of the basic substance is not less than 99%. 2 C. p. F.-ly, 9 PL.

The invention relates to medicine, specifically to medicines used in the treatment of ischemic heart disease, and arrhythmias complicating her.

The problem of prevention and treatment of coronary heart disease is very relevant, because the death of patients suffering from diseases of the cardiovascular system, occupies the first place in Loznitsa severe arrhythmia, in the treatment of this disease it is necessary to apply a combination of drugs with anti-ischemic and anti-arrhythmic effect, which does not always give a positive result.

The aim of the invention is the creation of medicines for the treatment of ischemic heart disease and arrhythmias complicating her, and the development of a method of obtaining high output.

This goal is achieved by N-(2,4,6-trimethylphenylsulfonyl)-N-allylnormorphine bromide of formula (1):

< / BR>
The study of pharmacological activity 1.

1. Anti-ischemic activity 1.

The effect of 1 was studied on white nonlinear rats weighing 250-300 g by well-known methods, which allows to estimate the influence of the test substance on the sizes of the zones of ischemia and necrosis in the acute period of myocardial infarction. As the comparison drug used obzidan, anti-ischemic effect of which is known (Mashkovsky M. D. Medicines. M. Medicine, 1993, H. 1, S. 330-332).

The results of these studies are presented in table.1.

From the presented data it follows that 1 reduces the size of the zone of necrosis in relation to the area of ischemia and the effect of the preparation according to the influence of 1 on coronary blood flow was performed by well-known methods N. C. Kaverina on narcotized eleminal-sodium (50 mg/kg intraperitoneally) cats, translated into controlled breath. After opening the chest and kanalirovaniya coronary sinus blood flow out of it was sent to the jugular vein so that with the tee at the right period of time it was possible to carry out the sampling of venous blood from the coronary vessels in a measuring Cup. Each time the fence flowing blood continued for 15 C. the amounts Collected blood was multiplied by 4 and got the volumetric rate of flow for 1 min After introduction 1 the study of coronary blood flow produced in 5, 15, 30 and 60 minutes

The results are presented in table.2.

The data show that 1 in a dose of 1 mg/kg and even more in the dose of 2 mg/kg increases the volumetric rate of coronary blood flow during the first 10 min of observation.

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

Research carried out on mongrel dogs weighing 8-25 kg and cats weighing 2-4 kg Violation of coronary circulation caused anesthetized with geksenal (50 mg/kg intraperitoneally) animals by applying ligatures on the upper third of the descending branch of the left crown of choice for treatment of arrhythmias in the acute phase of myocardial infarction.

The results of study 1 in cats is shown in table.3, the dogs table.4.

The results are shown in table.3, show that 1 is superior to lidocaine for antiarrhythmic activity on the model of ventricular arrhythmia in cats caused by ligation of the coronary artery, and protivopellargnoe step 1 does not differ from the comparison drug.

It is important to note that 1 not only prevents the onset of ventricular fibrillation and ventricular fibrillation, but it is able to remove an already existing arrhythmia. This is evidenced by the second series of experiments conducted with the drug that was introduced on the background of already existing arrhythmias (table.3,series 2).

The same data obtained in the study of antiarrhythmic activity 1 in acute disorders of the coronary circulation in dogs (table.4). Intravenous administration of 1 after applying ligatures on coronary vessel can prevent the onset of arrhythmia in most animals during the 10 o'clock

Antiarrhythmic effect of lidocaine at a dose of 15 mg/kg in the same experimental conditions is less than 30 minutes 1 also has a pronounced antiarrhythmic effect in later periods after nanosensornyh experimental conditions antiarrhythmic effect of lidocaine lasts 5-10 minutes

Thus, 1 has a pronounced antiarrhythmic activity in the cardiac arrhythmias resulting from myocardial ischemia. 1 differs from lidocaine higher activity and longer antiarrhythmic effect.

An important feature of 1 is the combination of antiarrhythmic and antiischemic action, what makes this tool the drug of choice for treatment of arrhythmias in the acute phase of myocardial infarction.

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

Antiarrhythmic activity of 1 was investigated in the form of acute drug test. Evaluation of antiarrhythmic action 1 was produced using the apparatus of the Ribbon-MT, which allows dynamic electrocardiography with subsequent analysis of the recording. Background Holter ECG monitoring was performed in patients in whom there were no indications for emergency relief of arrhythmia, and if any type and class of arrhythmia was determined by means of kardiomonitorami for 30-120 min or recording ECG-12.

In table. 6 shows comparative data antiarrhythmic actions 1 and lidocaine when arrhythmias complicating coronary artery disease.

Intravenous administration of 1 caused a complete and stable suppression of ventricular arrhythmias in 39 patients with acute myocardial infarction and one patient had a significant (more than 50%) reduction in the incidence of ventricular arrhythmia. The other 42 patients with ischemic heart disease antiarrhythmic effect 1 was observed in 38 patients. These data indicate high antiarrhythmic activity 1 with ventricular arrhythmias ischemic Genesis.

Lidocaine, which is antiaritmikom of choice for treatment of arrhythmias ischemic origin, especially in the acute phase of myocardial infarction, showed full antiarrhythmic effect in arrhythmias complicating acute myocardial infarction in 10 patients out of 17, which was significantly lower when compared with 1 (P < 0,05).

In 73% of patients with CHD who had chest pain introduction 1 was accompanied by either a complete disappearance of pain, or a noticeable reduction.

5. Antianginal activity (AAA) 1.

Surveyed 11 men aged 30 to 60 years with angina II and III functional classes.

To identify and objectification AAA 1 used the method of paired Bicycle exercise test (VEM). Cardamine second VEM intravenously was administered 1 dose of 1.5 mg/kg Loading was stopped when ST-segment depression of 1 mm or more at a distance of 0.08 to point j in combination with angina. Criterion AAA believed to increase the duration of the load on the background of the drug for at least 2 minutes

In 7 (64%) patients registered anti-ischemic effect 1. Although the remaining patients, 1 was ineffective on the adopted criteria, all of the observed increase in tolerance to physical activity: increase the time or power load and total work performed from 8 to 125% (average 40%).

Nitrosorbid, which is the reference drug of these studies, the dose of 10 mg is not inferior to the severity of antianginal action 1. In only one case 1 was more effective nitrosorbid. It should be noted that two patients both drugs in the tested doses were ineffective.

From these results, it follows that 1 has anti-ischemic effects, corresponds roughly to nitrosorbid.

The presented results strongly suggest that 1 has anti-ischemic and antianginal activity. These effects are 1, found experimental and clinical confirmation, combined with a pronounced is the rhythm action 1 is shown, as in experiment and clinic in the acute phase of myocardial infarction.

The combination of pharmacological properties listed 1 makes the product very promising to improve the pharmacotherapy of acute period of myocardial infarction.

The method of obtaining 1 lies in the interaction of N-(2,4,6-trimethylphenylsulfonyl)research (II) with methyl-allyl (III) in isopropyl alcohol at a molar ratio of II:III 1:1,4-1,6, respectively, at a temperature of 55-65oC. Target product are filtering dropped 1 after cooling the reaction mass to room temperature. Get 1 in the form of almost white crystalline powder with a yield of 90% counting on II, so pl. 172-176oWith (in the range of two degrees). After recrystallization from isopropyl alcohol get Pharmacopoeia 1.

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

Example. Mix 400 ml of isopropyl alcohol, to 100.3 g of 99.7%, 100 g (0.38 mol) of 100% II and 50 ml (0.58 mol) III. The mixture is maintained at 55-65oC for 7 h, then cooled to room temperature. The precipitation 1 is filtered off, washed with isopropyl alcohol. Get 132,3 g 99,4% or 131, 5mm g 100% 1 that ascout Pharmacopoeia 1.

The connection I easily soluble in water, insoluble in ether, chloroform.

Found, N 7,6; Br 20,6.

WITH18H27N2O2Br.

Calculated, N 7,31; VG 20,84.

The purity and identity of the products of the reaction is checked by thin-layer chromatography on plates "Silufol UV-254 in the solvent system chloroform ethanol 95% acetic acid, 95 4,5 0,5 with the manifestation of the camera to chlorine over a mixture of 3% solution of potassium permanganate 15% solution of hydrochloric acid. Plate after drying spray the solution on tolidine.

The PMR spectrum is cleared on the device Hitachl Perkin elmer, the operating frequency of 90 MHz, internal standard hexamethyldisiloxane, the temperature of the 35oC. the Solvent is deuterated dimethylsulfoxide and acetone. Chemical shifts of protons (M. D. ) is shown on the scale . The signals of protons: 3,75-4,10 m D. M(CH2)48H of the research; to 4.52 M. D. (CH2) 2N allyl; 4,81 m D. C (CH2)-2N acetic acid; 5,56 5,91 m D. M(CH2)-2H allyl; 5,91 6,5 m D. M(SN)-1H allyl; for 6.81 M. D. (2H)- 3.5 N aromatics; 10,38 M. D. (NH).

The following example parameters of the process of obtaining 1 was found experimentally and are optimal, as evidenced by the results is the atur reaction. The experiments showed that the optimum temperature range 55-65oC. At lower temperatures the reaction until the end comes, decreases the yield of the target product 1. At higher temperatures there is the resinification of the reaction mixture, the target material 1 is subjected to degradation with the formation of the original product II, the result is the target product 1, does not satisfy the requirements for color, extraneous impurities.

As follows from the table.8, the optimum molar ratio of the reactants II:III if the reaction 1:1,4-1,6, respectively. Reducing the number III leads to a significant reduction of output, and the increase is unacceptable because of the deteriorating quality of the target product 1.

As can be seen from the table.9, the optimal temperature selection connection 1 room temperature is 18-25oC. temperature Reduction does not lead to any significant increase in output, at elevated temperatures observed loss in output.

In addition, in the process of obtaining 1 has been tested using other solvents. The yield of 1 was lower. than in the proposed method, and in some cases lower quality 1.

1. N-(2,4,6-Trimetazidine action in ischemic heart disease.

2. The method of obtaining N-(2,4,6-trimethylphenylsulfonyl)-N-allylnormorphine bromide of the formula I, wherein N-(2,4,6-trimethylphenylsulfonyl)morpholine is subjected to interaction with methyl-allyl environment of isopropyl alcohol at a molar ratio of N-(2,4,6-trimetilfenil carbamoylmethyl)the research and allyl bromide 1 1,4 1,6 respectively, and a temperature of 55 to 65oC, followed by cooling the reaction mixture to room temperature and excretion of N-(2,4,6-trimethylphenylsulfonyl)-N-allylnormorphine bromide.

 

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EFFECT: valuable medicinal properties of compounds and drug.

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2 cl, 4 tbl, 4 ex

FIELD: chemistry of metalloorganic compounds, agriculture.

SUBSTANCE: invention describes derivatives of mepiquate borate of the general formula (I): wherein DMP means N,N-dimethylpiperidinium (mepiquate); M means metal cation acceptable for agriculture and chosen from a series comprising sodium, potassium, magnesium, calcium, zinc, manganese or copper, hydrogen atom or NH4+; O means oxygen atom; A means chelate of complex-forming fragment bound with one boron atom and representing (lower)-alkylglycols or sugars; n and m mean similar whole numbers in the range from 1 to 6; x means a whole or fraction number in the range from 0 to 10; y means a whole or fraction number in the range from 1 to 48; z means a whole or fraction number in the range from 0 to 48; v means a whole or fraction number in the range from 0 to 24, and w means a whole or fraction number in the range from 0 to 24. Also, invention describes methods for preparing compound of the formula (I) by interaction of N,N-dimethylpiperidinium hydroxide with boric acid and/or boron-containing oxides and optionally with metal hydroxides acceptable for agriculture indicated above or electrochemical method involving interaction of N,N-dimethylpiperidinium halide in the presence of water and boric acid and in the presence metal hydroxides acceptable for agriculture by bipolar electrodialysis. Invention describes electrochemical method for preparing N,N-dimethylpiperidinium hydroxide and a suspension concentrate possessing the plant growth-regulating effect prepared by mixing N,N-dimethylpiperidinium hydroxide, boron-containing compound chosen from boric acid and borate salt with a thickening agent and water, or by mixing compound of the formula (I) with Na2B8O13 x 4 H2O, a thickening agent and water. Prepared derivatives of mepiquate borate possess the improved indices of hygroscopicity and corrosion activity.

EFFECT: improved preparing methods, valuable properties of derivatives.

22 cl, 7 tbl, 16 ex

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