10-br-n(4)-propylamine bansilalpet with antiarrhythmic activity

 

(57) Abstract:

The proposed Quaternary derivative alkaloid of application-10-Br-N(4)-Propylamine benzoylphenyl, with pronounced antiarrhythmic activity, low toxicity, large breadth of therapeutic action. The specified connection may be of interest for practical health as antiarrhythmic and protivopellargnoe funds. Described compound synthesized from 10-Br-N(4)-Propylamine bromide ion exchange resin era elements-10P in the form of bansilalpet-ion battery. It is a white crystalline powder, odorless, it is difficult soluble in water and chloroform, slightly soluble in ethyl and methyl alcohols. MP 245-247oC (with decomp. ). Molecular weight 605. Brutto-formula C29H37N2O5SBr. []D20= + 72oC (1% solution in ethanol). Rf= 0,750,02 (in the system chloroform - acetone - diethylamine (5:4:1)); Rf= 0,220,02 ( in the system chloroform - methyl alcohol - ammonia(0,25%) (90:10:0,2)). 4 table.

The invention relates to new physiological means on the basis of 10-Br-N(4)-Propylamine of benzosulfimide formula I

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It is known that Quaternary about the ti used in medical practice for pharmacoprophylaxis and struggle with different types of cardiac arrhythmias, edema ventricular fibrillation. However, the quaternization of the application in the 4-position nitrogen atom of the molecule leads not only to increased biological activity, but also causes a significant increase in toxicity of the compounds. For example, N(4)-Propylamine roam on different models of arrhythmia was 5-10 times more active application and 4-10 times more toxic. So urgent is the problem of exploration of antiarrhythmic drugs based on Quaternary derivatives of application, which would have had a high specific activity, low toxicity, large therapeutic index.

Described is a new Quaternary derivative of application N(4)-Propylamine bansilalpet (laboratory designation s-1). This compound is a substance, the closest structure to the claimed connection (prototype), has a high antifibrillatory activity and solubility in water, allowing you to create injectable dosage form for emergency antiarrhythmic help.

Its disadvantages include a relatively low antiarrhythmic activity and small therapeutic index model aconitine arrhythmia, and increased toxicity compared with autotip on antiarrhythmic and protivopellargnoe activity and at the same time with less toxicity and greater breadth of therapeutic action (i.e., a large therapeutic index).

This object is achieved by the synthesis of new chemical compounds - 10-Br-N(4)-Propylamine of benzosulfimide formula I

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Connection l obtained from 10-Br-N(4)-Propylamine bromide ion exchange ion-exchange resin in the form of bansilalpet-ion battery. It is a white crystalline powder, odorless, it is difficult soluble in water and chloroform, slightly soluble in ethyl and methyl alcohols. The composition of the compounds proved the elemental analysis, the individual thin-layer chromatography, the structure of the IR, UV, PMR-spectra.

Example 1. 10 g of the resin era elements-10P in the form of bansilalpet-ion after swelling in water is placed in a column and washed with 50 ml of methyl alcohol. A solution of 1 g of 10-Br-N(4)-Propylamine bromide in 120 ml of methyl alcohol is passed through the column at a rate of 2 ml/min At the outlet from the column is collected solution C-2. Upon completion of the ion exchange column is washed with 20 ml of methyl alcohol to a negative reaction on the indole ring with concentrated nitric acid. The methanol mother liquor evaporated in vacuo to a minimum volume and videlicet powder, which is dried in vacuum for 3 h at 60oC. Yield 62% So pl. 245-247oC (decomposition).

Chromatographic purity of the compounds tested in the systems: 1) chloroform-acetone-diethylamine (5: 4: 1), Rf0,750,02; 2) chloroform-methyl alcohol-ammonia(0,25%) (90:10:0,2), Rf0,220,02.

Molecular weight 605. Brutto-formula C29H37BrN2O5S.

Found, C 57,7; H 6,3; N 4,5; S 5,5; Br 13,1.

Calculated C Of 57.5; H 6,1; N 4,6; S 5,3; Br 13,2. []D20+ 72 (1% solution in ethanol).

IR-spectrum (Krist. vaseline oil), maxcm-1: 630, 710 760, 1050 1250 (benzolsulfonate group), 1610 (aromatic ring of the alkaloid application), 3130 3330 (OH-group application).

UV-spectrum (0,001% solution in water)maxNM: 2061, 255)1, 2981.

TMR, M. D. (in SV3OD): 7,47 (multiplet), 7,33 (Quartet), 6,74 (doublet) (the protons of the indole fragment application), 7,85 (Quartet), 7,56 (doublet),7,45 (Quartet) (protons bansilalpet-anion).

Studies of acute toxicity.

They were carried out on 120 white mice weighing 18 to 20, the Test substance was administered in the form of a solution intraperitoneally in increasing amounts. Each test dose was administered group of mice, consisting of 8 to 10 individuals. Pogany in table. 1.

The study antiarrhythmic activity on aconitine model arrhythmia.

Rats weighing 150 to 200 g, anesthetized by intraperitoneal introduction Urena (800 mg/kg) caused an arrhythmia intravenous infusion of nitrate aconitine at a dose of 25 mg/kg of the Subjects of the substance was injected intravenously 5 min before the injection of nitrate aconitine. According to the data obtained after conducting 4 series of experiments, the calculated value of the ED50the tested compounds and antiarrhythmic index (the ratio LD50/ED50). The research results are summarized in table. 2.

Our data indicate that the toxicity of the compounds C-2 twice lower (p <0.05) than the toxicity of the prototype s-1.

The results of these studies indicate that the compound C-2 has a high antiarrhythmic activity on this arrhythmia and, apparently, more oppressing fast sodium current, than the prototype s-1. The breadth of therapeutic action C-2, judging by the amount of anti-arrhythmic index is considerably higher than that for C-1.

The study of antiarrhythmic and antifibrillatory actions proposed connection on the model of occlusion and reperfusion arrhythmias in rats.

the Ana (800 mg/ kg). Violation of coronary circulation caused by the descending branch of the left coronary artery during artificial ventilation of the lungs. Coronary blood flow was blocked and watched the heart rate within 5 min.

Compound was injected intravenously 5 min before occlusion. In the course of the experiment to evaluate the antiarrhythmic and antifibrillatory compounds S-2 and s-1 were recorded beginning occlusive arrhythmias, the average number of ventricular extrasystoles (GEN) per 1 animal and the frequency of occurrence of fibrillatio poly (FG). For statistical processing of the obtained results used the t-student test and Chi-square. The research results are reflected in table. 3.

As can be seen from the table. 3, the compounds C-1 and C-2 have a pronounced antiarrhythmic and antifibrillatory activities on the model of early occlusal arrhythmia in rats, and the claimed compound has a greater breadth of therapeutic action compared to the prototype. Compounds C-1 and C-2 is also effectively prevented the occurrence of ventricular fibrillation on the model of reperfusion arrhythmia in rats (table. 4).

It should be noted that the comparator drug s-1 BS="ptx2">

The research results presented in table. 4, indicate that the claimed connection-2 when expressed protivopellargnoe activity is more secure than the prototype s-1, as it has a large value of the ratio LD50to investigated the dose, i.e., a greater therapeutic index.

Thus, the research results prove that the new Quaternary derivative of application 10-Br-N(4)-Propylamine bansilalpet not inferior to antiarrhythmic and antifibrillatory activities to its prototype. The inventive compound is 2 times less toxic than the prototype, has more anti-arrhythmic activity on the model of aconitine arrhythmia in rats and greater breadth of therapeutic action.

Connection-2 10-Br-N(4)-Propylamine bansilalpet may be of interest for practical health as antiarrhythmic and protivopellargnoe funds.

10-Br-N(4)-Propylamine bansilalpet formula

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possess antiarrhythmic activity.

 

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