RU2775616C2 - 2-(2-(dialkylamino polyethoxy))ethyl carboxylates and hydrochlorides thereof with antiarrhythmic activity and pharmaceutical compositions based thereon - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to the field of pharmacology and pertains to the creation of new medicinal products for preventing and treating cardiac arrhythmias. Invention relates to compounds exhibiting antiarrhythmic activity and represented by the general formula (I) wherein when n=1 and NR₂=NEt₂, then R’=Ph; PhCH₂; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂; when n=1 and NR₂=NC₅H₁₀, then R’=Ph; PhCH₂; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂; when n=1 and NR₂=NC₄H₈O, then R’=Ph; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂; when n=2 and NR ₂=NC₅H₁₀, then R’=Ph; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂; when n=2 and NR₂=N C₄H₈O, then R’=Ph; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂; when n=3 and NR₂=NC₅H₁₀, then R’= PhOCH₂; 2,4-Cl₂C₆H₃OCH₂ (wherein NC₄H₈O is morpholino and NC₅H₁₀ is piperidino). Invention also relates to a medicinal product and pharmaceutical composition including said compounds.

EFFECT: production of compounds applicable in preventing and treating cardiac arrhythmias.

(I)

3 cl, 3 dwg, 4 tbl, 30 ex

Description

The invention relates to the field of pharmacology, namely to compounds of the general formula indicated below, which exhibit antiarrhythmic activity.

Whenn=1, NR₂=NEt₂, then R^'=Ph; PhCH₂; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂;

Whenn = 1, NR₂=NC₅H_ten, then R^'= Ph; PhCH₂; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂;

Whenn=1, NR₂=NC_fourH_eightO, then R^'= Ph; PhCH₂; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂;

Whenn=2, NR₂=NC₅H_ten, then R^'=Ph; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂;

Whenn=2, NR₂=N C_fourH_eightO, then R^'=Ph; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂;

Whenn=3, NR₂=NC₅H_ten, then R^'= PhOCH₂; 2,4-Cl₂C₆H₃OCH₂,

(while NC ₅ H ₁₀ is piperidino, NC ₄ H ₈ O is morpholino).

The invention also relates to a medicament and a pharmaceutical composition which includes said compounds.

3 n.p. f-ly, 4 tab., 3 ill., 17 pr.

The invention relates to the field of pharmacology and relates to the creation of new drugs for the prevention and treatment of cardiac arrhythmias.

An analysis of the literature shows that compounds with the formulas similar in structure are known:

,

,

where D is a biologically active residue, n is an integer greater than 2, R'' is hydrogen or alkyl residues, including substituted [ patent US 2004/0152769 A1 publication date 05.08.2004 ] and

,

,

where R ₁ , R ₂ , R ₃ , R ₄ are alkyls, or their substituted or unsaturated derivatives, n = 1 - 10, X is an organic or inorganic anion [ patent US 2011/0097287 A1 publication date 04/28/2011 ].

In addition, a drug of similar structure Pentoxyverine, which has an antitussive effect, is widely used in different countries [ "Carbetapentane". drugs.com; Radar® Information and Reference System ].

However, all of the above compounds do not have antiarrhythmic properties.

The objective of the present invention was to synthesize the above compounds of general formula (I), which have high antiarrhythmic activity and are promising for the development of drugs based on them for the treatment of cardiac arrhythmias. The specified task and technical result are achieved by a new class of antiarrhythmic nitrogen-containing compounds - 2-(2-(Dialkylaminopolyethoxy))ethylcarboxylates and their hydrochlorides of the following formula:

Whenn = 1, NR₂=NEt₂, then R^'=Ph; PhCH₂; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂;

Whenn = 1, NR₂=NC₅H_ten, then R^'= Ph; PhCH₂; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂;

Whenn = 1, NR₂=NC_fourH_eightO, then R^'= Ph; PhCH₂; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂;

Whenn=2, NR₂=NC₅H_ten, then R^'=Ph; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂;

Whenn=2, NR₂=NC_fourH_eightO, then R^'=Ph; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂;

Whenn=3, NR₂=NC₅H_ten, then R^'= PhOCH₂; 2,4-Cl₂C₆H₃OCH₂;

(while NC ₅ H ₁₀ is piperidino, NC ₄ H ₈ O is morpholino).

The preparation of the claimed compounds of general formula (I) is shown in Scheme 1 and is described below:

Scheme 1

The quantitative composition of compounds 3-8 was confirmed by the results of mass spectroscopy, as well as on the basis of elemental analysis data. The structure of compounds 3-8 was confirmed by IR, NMR ¹ H-, ¹³ C-spectroscopy. Physico-chemical characteristics of these compounds are presented in tables 1-2.

Amino alcohols of the oxyethylene series 3a-i , necessary for the acylation reaction, were obtained from the corresponding chlorohydrins 2a-c by amination with a twofold excess of amine in a 5% aqueous solution of potassium carbonate by boiling the reaction mixture for 15 hours.

To obtain chlorohydrins 2a-c, the corresponding oligoethylene glycols 1a-c were used as starting compounds; which were subjected to interaction with thionyl chloride in a pyridine medium with vigorous stirring and cooling to 0-10°C, after which the reaction mass was boiled for 4-5 hours.

Synthesis of compounds 8a-y was carried out by acylation of the corresponding amino alcohols 3a-3d and an excess of acid chlorides 7a-d in benzene at a temperature of 10°C and stirring. In this case, amino esters are formed in the form of hydrochlorides 8a-y in 53-92% yields, which are white crystalline compounds, in some cases hygroscopic.

Example 1

To a mixture of 50.00 g (0.47 mol) of diethylene glycol and 18.63 g (0.235 mol) of pidine cooled to 0°C, 28.06 g (0.235 mol) of thionyl chloride are added slowly with stirring. The reaction mixture is kept for 1.5-2 hours at a temperature of 10-20°C, and then for 3 hours at a temperature of 100-106°C. After that, the solution is cooled and the product is extracted with diethyl ether, the solvent is evaporated, the residue is distilled under vacuum. 9.40 g (32%) of 2-(2-chloroethoxy)ethanol, _bp T was obtained. 79-81°C at 5mmHg Art., n _D ²⁰ 1.4520.

Example 2

To a solution of 45.00 g (0.30 mol) of triethylene glycol and 11.85 g (0.15 mol) of pyridine cooled to 0°C, 17.84 g (0.15 mol) of thionyl chloride are added in portions with stirring. The reaction mixture is kept for 1.5-2 hours at a temperature of 10-20°C, and then for 3 hours at a temperature of 100-106°C. After that, the solution is cooled and the product is extracted with diethyl ether, the solvent is evaporated, the residue is distilled under vacuum. 6.80 g (27%) of 2-[2-(2-chloroethoxy)ethoxy]ethanol _bp was obtained. 117-120°C at 5mmHg Art., n _D ²⁰ 1.4580.

Example 3

To a solution of 48.50 g (0.25 mol) of tetraethylene glycol and 9.875 g (0.125 mol) of pyridine, cooled to 0°C, 14.87 g (0.125 mol) of thionyl chloride are added in portions with stirring. The reaction mixture is kept for 1.5-2 hours at a temperature of 10-20°C, and then for 3 hours at a temperature of 100-106°C. After that, the solution is cooled and the product is extracted with diethyl ether, the solvent is evaporated, the residue is distilled under vacuum. 6.64 g (25%) of _bp 2-{2-[2-(2-chloroethoxy)ethoxy]ethoxy}ethanol were obtained. 136-139°C at 5mmHg Art., n _D ²⁰ 1.4568.

Example 4

A mixture of 9.97 g (0.08 mol) of 2-(2-chloroethoxy)ethanol and 11.68 g (0.16 mol) of diethylamine is boiled in 50 ml of 5% aqueous potassium hydroxide solution for 18 hours. Then, the reaction mass is cooled and the product is extracted with ethyl acetate. The extract is dried with sodium sulfate, the solvent is distilled off on a rotor, the residue is distilled under vacuum. 7.34 g (57%) of 2-(2 - N,N-diethylaminoethoxy)ethanol (3a) is thus obtained. Mass spectrum*, m/z (I _rel ;%): 162[M+1] ⁺ (2); 161[M] ⁺ (5); 160[M-1] ⁺ (3); 100(8); 86(100); 58(18); 45(13); 30(15).

Example 5

A mixture of 12.77 g (0.10 mol) of 2-(2-chloroethoxy)ethanol and 17.45 g (0.20 mol) of piperidine is boiled in 50 ml of a 5% aqueous potassium hydroxide solution for 10 hours. After that, the reaction mixture is cooled and the product is extracted with ethyl acetate. The extract is dried with sodium sulfate, the solvent is distilled off on a rotor, the residue is distilled under vacuum. As a result, 12.59 g (71%) of 2-(2-N-piperidinoethoxy)ethanol (3b) was obtained. Mass spectrum*, m/z (I _rel ;%): 174 [M+1] ⁺ (2); 173[M] ⁺ (5); 172[M-1] ⁺ (3); 112(10); 99(95); 60 (15).

Example 6

A mixture of 12.46 g (0.10 mol) of 2-(2-chloroethoxy)ethanol and 17.43 g (0.20 mol) of morpholine is boiled in 50 ml of a 5% aqueous potassium hydroxide solution for 12 hours. The mixture is then cooled and the product is extracted with ethyl acetate. The extract is dried with sodium sulfate, the solvent is distilled off on a rotor, the residue is distilled under vacuum. As a result, 10.51 g (60%) of 2-(2-N-morpholinoethoxy)ethanol (3c) was obtained. Mass spectrum*, m/z (I _rel ;%): 177[M+2] ⁺ (2); 176[M+1] ⁺ (9); 175[M] ⁺ (20); 144(16); 114 (37); 100(100); 75 (11).

Example 7

A mixture of 16.86 g (0.1 mol) of 2-[2-(2-chloroethoxy)ethoxy]ethanol and 14.62 g (0.2 mol) of diethylamine is boiled with 50 ml of 5% aqueous potassium hydroxide solution for 72 hours. Then the reaction mass is cooled, the product is extracted with ethyl acetate. The extracts are combined and dried over sodium sulfate, after which the solvent is distilled off on a rotor. The resulting residue is distilled under vacuum. As a result, 13.40 g (65%) of 2-[2-(2-N,N-diethylaminoethoxy)ethoxy]ethanol (3g) was obtained. Mass spectrum*, m/z (I _rel ;%): 206[M+1] ⁺ (4); 205[M] ⁺ (3); 204[M-1] ⁺ (2); 162(20); 146 (60); 100(14); 86(100); 58(12); 45(10).

Example 8

A mixture of 10.78 g (0.06 mol) of 2-[2-(2-chloroethoxy)ethoxy]ethanol and 10.89 g (0.13 mol) of piperidine is boiled in 50 ml of 5% aqueous potassium hydroxide solution for 60 hours . After which the mixture is cooled, the product is extracted with ethyl acetate. The extract is dried with sodium sulfate, the solvent is distilled off on a rotor, the residue is distilled under vacuum. This yielded 7.77 g (56%) of 2-[2-(2-N-piperidinoethoxy)ethoxy]ethanol (3e). Mass spectrum*, m/z (I _rel ;%): 218[M+1] ⁺ (3); 217[M] ⁺ (5); 216[M-1] ⁺ (2); 174(40); 144(35); 112(10); 99(95); 60 (15).

Example 9

A mixture of 8.43 g (0.05 mol) of 2-[2-(2-chloroethoxy)ethoxy]ethanol and 8.70 g (0.10 mol) of morpholine is boiled in 50 ml of a 5% aqueous solution of potassium hydroxide for 63 hours . The reaction mixture is cooled and the product is extracted with ethyl acetate. The extract is dried over sodium sulfate, the solvent is distilled off on a rotor, the residue is distilled under vacuum. 5.91 g (54%) of 2-[2-(2-N-morpholinoethoxy)ethoxy]ethanol (3e) is thus obtained. Mass spectrum*, m/z (I _rel ;%): 219 [M] ⁺ (7); 201(6); 158(15); 144(7); 131 (14); 114(46); 101 (49); 100(100); 86(23).

Example 10

A mixture of 12.76 g (0.06 mol) of 2-{2-[2-(2-chloroethoxy)ethoxy]ethoxy}ethanol and 8.78 g (0.12 mol) of diethylamine is boiled with 50 ml of a 5% aqueous solution of potassium hydroxide within 70 hours. The reaction mixture is cooled, the product is extracted with ethyl acetate. The extract is dried over sodium sulfate, after which the solvent is distilled off on a rotor, and the resulting residue is distilled under vacuum. As a result, 8.97 g (60%) of 2-[2-(2-(2-N,N-diethylaminoethoxy)ethoxy)ethoxy]ethanol (3g) was obtained. Mass spectrum*, m/z (I _rel ;%): 249[M ⁺ ] (3); 206(4); 205(3); 204(2); 162(20); 146(60); 100(14); 86(100); 58(12); 45(10).

Example 11.

A mixture of 8.50 g (0.04 mol) of 2-{2-[2-(2-chloroethoxy)ethoxy]ethoxy}ethanol and 6.80 g (0.08 mol) of piperidine is boiled in 50 ml of 5% aqueous hydroxide solution potassium for 75 hours. Then the reaction mass is cooled and the product is extracted with ethyl acetate. The extract is dried over sodium sulfate, the solvent is distilled off on a rotor, the residue is distilled under vacuum. As a result, 5.53 g (53%) of 2-{2-[2-(2-piperidinoethoxy)ethoxy]ethoxy}ethanol (3h) was obtained. Mass spectrum*, m/z (I _rel ;%): 261[M ⁺ ] (4); 218(3); 217(5); 216(2); 174(40); 144(35); 112(10); 99(95); 60 (15).

Example 12.

A mixture of 19.14 g (0.09 mol) of 2-{2-[2-(2-chloroethoxy)ethoxy]ethoxy}ethanol and 15.68 g (0.18 mol) of morpholine is boiled with 50 ml of a 5% aqueous solution of potassium hydroxide within 76 hours. Then the reaction mass is cooled, the product is extracted with ethyl acetate. The extract is dried over sodium sulfate, the solvent is distilled off on a rotor. The resulting residue is distilled under vacuum. Thus, 14.69 g (62%) of 2-[2-(2-(2-N-morpholinoethoxy)ethoxy)ethoxy]ethanol (3i) was obtained. Mass spectrum*, m/z (I _rel ;%): 263[M ⁺ ] (5); 219(7); 201(6); 158(15); 144(7); 131 (14); 114(46); 101 (49); 100(100); 86(23).

Example 13

1.36 g (8.47 mmol) of 2-(2-N ,N-diethylaminoethoxy)ethanol. The reaction mass is stirred on a magnetic stirrer at room temperature for 0.5 hours. The formed precipitate was filtered off, washed with dry ether, and recrystallized twice from dry acetone. As a result, 1.68 g (75%) of 2-(2-N,N-diethylaminoethoxy)ethylbenzoate hydrochloride (8a) was obtained. Mass spectrum*, m/z (I _rel ;%): 265[M ⁺ ] (9); 263[M-2] ⁺ (5); 248(15); 203 (57); 174 (43); 135(21); 112(65); 98 (100); 91(71); 77 (66). ¹ H NMR spectrum (300.13 MHz CDCl ₃ ;-*, ppm): 8.02 (m 2H); 7.59 (m. 1H); 7.46 (m. 2H); 4.38 (m. 2H); 3.64 (m. 2H); 3.58 (m. 2H); 2.94 (m. 2H); 2.64 (m. 4H); 0.96 (m. 6H). ¹³ C NMR spectrum (75.47 MHz; CDCl ₃ ;-*, ppm): 7.30 (2C); 47.53(2C); 57.14 (1C); 64.50 (1C); 66.09(1C); 70.69 (1C); 128.70 (2C); 129.28(2C); 133.40 (1C); 166.48(1C).

Example 14

To a solution of 1.23 g (7.96 mmol) of phenylacetic acid chloride and 5 ml of benzene cooled to 0 ° C, 1.16 g (7.23 mmol) of 2- (2-N, N-diethylaminoethoxy) ethanol are added with stirring . The solution is stirred on a magnetic stirrer, at room temperature, for 0.5 hours. After that, the formed precipitate is filtered off, washed with dry diethyl ether and recrystallized twice from dry acetone. Thus, 1.59 g (79%) of 2-(2-N,N-diethylaminoethoxy)ethylbenzylacetate hydrochloride (8b) was obtained. Mass spectrum*, m/z (I _rel ;%): 279[M ⁺ ] (5); 227 [M-2] ⁺ (3); 198(61); 154 (53); 112(13); 103(70); 98 (100); 74(78). ¹ H NMR spectrum (300.13 MHz CDCl ₃ ;-*, ppm): 7.95 (m 2H); 7.66 (m. 1H); 7.56 (m. 2H); 3.63-3.68 (m. 6H); 2.94 (m. 2H); 2.64 (m. 4H,); 0.96 (m. 6H). ¹³ C NMR spectrum (75.47 MHz; CDCl ₃ ;-*, ppm): 7.30 (2C); 47.53(2C); 57.14 (1C); 66.09(1C); 70.40 (1C); 70.84 (1C); 73.92 (1C); 127.05(2C); 128.28(2C); 133.37 (1C); 136.19 (1C); 194.23(1C).

Example 15

To a mixture of 1.05 g (4.40 mmol) of 2,4-dichlorophenoxyacetic acid chloride and 4 ml of dry benzene, cooled to 0°С, 0.69 g (4.00 mmol) of 2-(2-N,N-diethylaminoethoxy)ethanol was added portionwise with stirring. The reaction mass is stirred on a magnetic stirrer at room temperature for 0.5 hours. The resulting precipitate was filtered off, washed with dry ether, and recrystallized twice from dry acetone or ethanol. As a result, 0.98 g (61%) of 2-(2-N,N-diethylaminoethoxy)ethyl-2,4-dichlorophenoxyacetate hydrochloride (8c) was obtained. Mass spectrum*, m/z (I _rel ;%): 368[M+2] ⁺ (9); 366[M] ⁺ (7); 364[M-2] ⁺ (14); 223(38);145(56); 100 (41); 86 (100). ¹ H NMR spectrum (300.13 MHz CDCl ₃ ;-*, ppm): 7.78 (m 1H); 7.38 (m. 1H); 7.31 (m. 1H); 4.36 (m. 2H); 3.64 (m. 2H); 3.58 (m. 2H); 2.94 (m. 2H); 2.64 (m. 4H); 0.96 (m. 6H). ¹³ C NMR spectrum (75.47 MHz; CDCl ₃ ;-*, ppm): 7.30 (2C); 47.53(2C); 57.14 (1C); 64.50 (1C); 66.09(1C); 70.69 (1C); 127.11 (1C); 127.20 (1C); 131.11 (1C); 133.72 (1C); 137.48(1C); 164.86(1C).

Example 16

To a solution of 0.46 g (3.30 mmol) of benzoyl chloride and 3 ml of dry benzene, cooled to 0°С, 0.52 g (3.00 mmol) of 2-(2-N-piperidinoethoxy)ethanol is added with stirring. The reaction is carried out at room temperature and stirring for half an hour. The resulting product is separated from the reaction mass by filtration and washed with a small amount of dry diethyl ether, after which the resulting substance is recrystallized from dry acetone, and 0.81 g (85%) of 2-(2-N-piperidinoethoxy)ethylbenzoate hydrochloride (8 g) was obtained. Mass spectrum*, m/z (I _rel ;%): 277[M] ⁺ (5); 275[M-2] ⁺ (17); 156(61); 149 (53); 142(13); 105(70); 98 (100); 77 (71). ¹ H NMR spectrum (300.13 MHz CDCl ₃ ;-*, ppm): 12.04 (br.s. 1H); 7.99-7.96 (m. 2H); 7.55-7.49 (m. 1H); 7.42-7.37 (m. 2H); 4.46-4.42 (m. 2H); 4.04-4.02 (m. 2H); 3.78-3.76 (m. 2H); 3.53-3.49 (m. 2H); 3.15-3.12 (m. 2H); 2.71-2.60 (m. 2H); 2.16-2.07 (m. 2H); 1.77-1.61 (m. 3H); 1.30-1.14 (m. 1H). ¹³ C NMR spectrum (75.47 MHz; CDCl ₃ ;-*, ppm): 22.68 (1C); 23.54 (2C); 54.90 (2C); 57.73 (1C); 64.30 (2C); 66.69 (1C); 70.06 (1C); 129.40 (2C); 130.46 (2C); 130.69 (1C); 134.16 (1C); 167.22 (1C).

Example 17.

To a solution of 1.41 g (9.13 mmol) of phenylacetic acid chloride in acetone cooled to 0°C was added 1.44 g (8.30 mmol) of 2-(2-N-piperidinoethoxy)ethanol. The reaction is carried out with stirring for one and a half hours. The precipitate obtained is filtered off and washed with diethyl ether, then recrystallized from dry ethanol. As a result, 1.44 g (53%) of 2-(2-N-piperidinoethoxy)ethylbenzyl acetate hydrochloride (8e) was obtained. Mass spectrum*, m/z (I _rel ;%): 291[M] ⁺ (6); 289[M-2] ⁺ (15); 156 (57); 149 (43); 135(21); 112(65); 98 (100); 91(71); 77 (66). ¹ H NMR spectrum (300.13 MHz CDCl ₃ ;-*, ppm): 7.95 (m 2H); 7.66 (m. 1H); 7.56 (m. 2H); 4.43 (p. 2H); 3.63-3.68 (m. 4H); 3.64 (m. 2H); 2.98 (m. 4H); 2.78 (m. 2H); 1.88 (m. 4H). ¹³ C NMR spectrum (75.47 MHz; CDCl ₃ ;-*, ppm): 23.27 (2C); 54.45 (2C); 56.96 (1C); 66.32(1C); 70.40 (1C); 70.84 (1C); 73.93(1C); 127.05(2C); 128.28(2C); 133.37 (1C); 136.19 (1C); 194.23(1C).

Example 18.

A mixture of 1.07 g (6.30 mmol) of phenoxyacetic acid chloride and 3 ml of dry benzene is cooled to 0°C, and 1.00 g (5.70 mmol) of 2-(2-N-piperidinoethoxy)ethanol is added with vigorous stirring, stirring is continued for 0.5 hours. After that, the reaction mass is subjected to filtration, the resulting filtrate is washed with dry diethyl ether. As a result, 1.02 g (52%) of 2-(2-N-piperidinoethoxy)ethylphenoxyacetate hydrochloride (8f) was obtained. Mass spectrum*, m/z (I _rel ;%): 307[M] ⁺ (4); 305[M-2] ⁺ (21); 156 (67); 151(34); 112(47); 98 (100); 94 (33); 77 (52). ¹ H NMR spectrum (300.13 MHz CDCl ₃ ;-*, ppm): 7.32 (m 2H); 7.06 (m. 2H); 6.95 (m. 1H); 4.51 (p. 2H); 4.48 (m. 2H); 3.64 (m. 2H); 3.56 (m. 2H); 2.98 (m. 4H); 2.78 (m. 2H); 1.88 (m. 4H). ¹³ C NMR spectrum (75.47 MHz; CDCl ₃ ;-*, ppm): 23.27 (2C); 54.45 (2C); 56.96 (1C); 63.62 (1C); 65.52 (1C); 66.32(1C); 69.65 (1C); 114.63 (2C); 119.60 (1C); 129.50 (2C); 157.62 (1C); 168.73(1C).

Example 19.

In a benzene medium with a volume of 20 ml, cooled to 0°C, 10.53 g (44 mmol) of 2,4-dichlorophenoxyacetic acid chloride were dissolved. To the resulting solution, 7.20 g (40 mmol) of 2-(2-N-piperidinoethoxy)ethanol was added in portions with stirring and stirred for 0.5 hour, then the precipitate was filtered off. The resulting filtrate is washed with dry diethyl ether and then recrystallized from acetone. Thus, 14.16 g (83%) of 2-(2-N-piperidinoethoxy)ethyl-2,4-dichlorophenoxyacetate hydrochloride (8g) was obtained. Mass spectrum*, m/z (I _rel ;%): 375[M+1] ⁺ (6); 374[M] ⁺ (5); 220(14); 175(32);162(24); 156 (24); 145 (42); 112 (50). ¹ H NMR spectrum (300.13 MHz CDCl ₃ ; *, ppm): 12.10 (br.s. 1H); 7.35 (d. 1H); 7.18-7.13 (m. 1H); 4.72 (s. 2H); 4.34-4.31 (m. 2H); 4.02 (t. 2H, j=4.67); 3.69-3.66 (m. 2H); 3.56 (m. 2H); 2.70-2.60 (m. 2H); 2.28-2.13 (m. 2H); 1.93-1.75 (m. 4H); 1.41-1.33 (m. 1H). ¹³ C NMR spectrum (75.47 MHz; CDCl ₃ ;-*, ppm): 22.81 (1C); 23.57 (2C); 55.30(2C); 57.91 (1C); 64.88 (1C); 66.80 (1C); 67.34 (1C); 69.85 (1C); 115.96 (1C); 125.13(1C); 128.10 91C); 128.62 (1C); 131.23 (1C); 153.28 (1C); 168.94 (1C).

Example 20.

To a mixture of 1.38 g (9.81 mmol) of benzoyl chloride and 4 ml of dry benzene, cooled to 0°C, 1.56 g (8.91 mmol) of 2-(2-N-morpholinoethoxy)ethanol was slowly added with stirring . After that, the mixture is continued to stir on a magnetic stirrer at room temperature for 0.5 hours. The precipitate formed is separated by filtration. The filtrate is washed with dry diethyl ether and recrystallized twice from dry acetone. As a result, 2.11 g (85%) of 2-(2-N-morpholinoethoxy)ethylbenzoate hydrochloride (8h) was obtained. Mass spectrum*, m/z (I _rel ;%): 279[M] ⁺ (8); 277 [M-2] ⁺ (3); 254(17); 201(35); 182(23); 168 (72); 145(50); 114(15); 101 (38); 100(100); 86 (32). ¹ H NMR spectrum (300.13 MHz CDCl ₃ ; *, ppm): 8.02 (m 2H); 7.59 (m. 1H); 7.46 (m. 2H); 4.38 (m. 2H); 3.55-3.64 (m. 8H, 3.58); 2.83 (m. 2H); 2.46 (m. 4H). ¹³ C NMR spectrum (75.47 MHz; CDCl ₃ ;-*, ppm): 53.80 (2C); 57.36 (1C); 64.50 (1C); 66.33(1C); 67.02(2C); 70.69 (1C); 128.70 (2C); 129.02(1C); 129.28(2C); 133.40 (1C); 166.48(1C).

Example 21.

To a solution of 0.75 g (4.40 mmol) of phenoxyacetic acid chloride in 2 ml of dry benzene cooled to 0°C is added, with stirring, 0.70 g (4.00 mmol) of 2-(2-N-morpholinoethoxy)ethanol , then the mixture was stirred at room temperature for 0.5 hour. Then the reaction mass is subjected to filtration. The solid residue is washed with dry diethyl ether and recrystallized from dry acetone. As a result, 1.13 g (82%) of 2-(2-N-morpholinoethoxy)ethylphenoxyacetate hydrochloride with (8u) was obtained. Mass spectrum*, m/z (I _rel ;%): 310[M+3] ⁺ (2); 309[M+2] ⁺ (4); 308[M+1] ⁺ (8); 307[M] ⁺ (15); 179(20); 158 (35); 152(6); 135(5); 114(25); 107 (33); 100(100); 86 (24); 77 (35). 1H NMR spectrum ( ^250.13 MHz DMSO; *, ppm): 11.61 (br.s. 1H); 7.31 (t. 2H); 7.01-6.92 (m. 3H); 4.81 (s. 2H); 4.29 (p. 2H); 3.88 (t. 2H); 3.68 (t. 2H); 3.42-3.12 (m. 10H). ¹³ C NMR spectrum (75.47 MHz;-*, ppm): 53.77 (2C); 58.04 (1C); 64.46 (1C); 64.48 (2C); 66.21 (1C); 66.44 (1C); 69.84 (1C); 115.48 (2C); 122.73 (1C); 130.49 (2C); 158.56 (1C); 169.76 (1C).

Example 22.

1.50 g (6.30 mmol) of 2,4-dichlorophenoxyacetic acid chloride was dissolved in 3 ml of dry benzene, then the solution was cooled to 0°C. 1.00 g (5.70 mmol) of 2-(2-N-morpholinoethoxy)ethanol was added to the resulting solution with stirring, after which the reaction mass was stirred for 0.5 h at room temperature; at the end of the process, the separated precipitate was filtered off. The material thus obtained was washed with dry diethyl ether and recrystallized from dry acetone. As a result, 2.18 g (92%) of 2-(2-N-morpholinoethoxy)ethyl-2,4-dichlorophenoxyacetate hydrochloride (8 l) was obtained. Mass spectrum*, m/z (I _rel ;%): 379[M+2] ⁺ (2); 377[M] ⁺ (9); 375[M-2] ⁺ (12); 220(7); 175 (35); 162 (23); 158(72); 145 (50); 114(15); 101 (38); 100(100); 86 (32). 1H NMR spectrum ( ^250.13 MHz DMSO;-*, ppm): 11.53 (br. s. 1H); 7.59 (s. 1H); 7.37 (d. 1H); 7.13 (d. 1H); 4.98 (s. 2H); 4.29 (d. 2H); 3.90 (d. 2H); 3.69 (d. 2H); 3.12-3.43 (m. 10H). ¹³ C NMR spectrum (75.47 MHz;-*, ppm): 53.99 (2C); 58.22 (1C); 64.53 (2C); 64.74 (1C); 66.56 (1C); 67.29 (1C); 69.88 (1C); 115.84 (1C); 124.97 (1C); 128.01 (1C); 128.59 (1C); 131.18 (1C); 153.17 (1C); 168.92 (1C).

Example 23.

To a mixture consisting of 0.71 g (5.07 mmol) of benzoyl chloride and 3 ml of dry acetone, cooled to 0°C, 1.00 g (4.61 mmol) of 2-[2-(2-N-piperidinoethoxy)ethoxy]ethanol is added in portions with stirring , then the mixture is stirred for 0.5 hour at room temperature. After that, the precipitate formed during the reaction is filtered off and washed with dry diethyl ether. The resulting substance is recrystallized from dry acetone. Thus, 1.44 g (88%) of 2-[2-(2-N-piperidinoethoxy)ethoxy]ethylbenzoate hydrochloride (8m) was obtained. Mass spectrum*, m/z (I _rel ;%): 321[M] ⁺ (4); 319[M-2] ⁺ (14); 156(25); 149 (40); 122(22); 112(38); 105 (47); 98 (100); 77 (51). ¹ H NMR spectrum (250.13 MHz DMSO;-*, ppm): 8.02 (m. 2H); 7.59 (m.1H); 7.46 (m. 2H); 4.46 (m. 2H); 3.64 (m. 2H); 3.63-3.66 (m. 4H); 3.56 (m. 2H); 2.82 (m. 2H); 2.64 (m. 4H); 1.71 (m. 4H); 1.46 (m. 2H). ¹³ C NMR spectrum (75.47 MHz;-*, ppm): 23.84 (1C); 25.45 (2C); 54.89 (2C); 57.94 (1C); 64.78(1C); 66.32(1C); 69.93 (1C); 70.18(1C); 70.63(1C); 128.70 (2C); 129.02(1C); 129.28(2C); 133.40 (1C); 166.48(1C).

Example 24.

0.86 g (5.07 mmol) of phenoxyacetic acid chloride is dissolved in 3 ml of dry acetone and cooled to 0°C, then 1.00 g (4.61 mmol) of 2-[2-(2-N-piperidinoethoxy)ethoxy]ethanol is added slowly with stirring. The reaction mass is stirred for 0.5 hours at room temperature, then the mixture is filtered, the resulting filtrate is washed with dry diethyl ether and recrystallized from acetone. Thus, 1.34 g (75%) of 2-[2-(2-N-piperidinoethoxy)ethoxy]ethylphenoxyacetate hydrochloride (8n) was obtained. Mass spectrum*, m/z (I _rel ;%): 352[M+1] ⁺ (5); 351[M] ⁺ (25); 350[M-1] ⁺ (15); 349[M-2] ⁺ (28); 200(20); 156 (47); 151 (31); 112 (39); 98 (100); 94(32); 77(47). ¹ H NMR spectrum (250.13 MHz DMSO;-*, ppm): 7.32 (m 2H); 7.06 (m. 2H); 6.95 (m. 1H); 4.51 (p. 2H); 4.47 (m. 2H); 3.63-3.66 (m. 6H); 3.55 (m. 2H); 2.82 (m. 2H); 2.64 (m. 4H); 1.71 (m. 4H); 1.46 (m. 2H). ¹³ C NMR spectrum (75.47 MHz;-*, ppm): 23.84 (1C); 25.45 (2C); 54.89 (2C); 57.94 (1C); 63.91 (1C); 65.52 (1C); 66.32(1C); 68.89 (1C); 70.18(1C); 70.63(1C); 114.63 (2C); 119.60 (1C); 129.50 (2C); 157.62 (1C); 168.73(1C).

Example 25.

To a solution of 1.05 g (4.40 mmol) of 2,4-dichlorophenoxyacetic acid chloride in 3 ml of dry benzene, cooled to 0°C, with stirring, portionwise add 0.87 g (4.00 mmol) of 2-[2-(2-N-piperidinoethoxy) ethoxy]ethanol. The reaction mass is stirred for 0.5 hour at room temperature, then the precipitate formed is filtered off and washed with dry diethyl ether, after which it is recrystallized from dry acetone. As a result, 1.37 g (79%) of 2-[2-(2-N-piperidinoethoxy)ethoxy]ethyl-2,4-dichlorophenoxyacetate hydrochloride (8o) was obtained. Mass spectrum*, m/z (I _rel ;%): 422[M+2] ⁺ (3); 420[M+1] ⁺ (5); 420[M] ⁺ (23); 419[M-1] ⁺ (13); 418[M-2] ⁺ (28); 220 (33); 200(26); 156(44);); 112 (36); 98 (100). 1H NMR spectrum ( ^250.13 MHz DMSO;-*, ppm): 7.64 (m. 1H); 7.26 (m. 1H); 7.17 (m. 1H); 4.45-4.50 (m. 4H); 3.63-3.66 (m. 6H); 3.55 (m. 2H); 2.82 (m. 2H); 2.64 (m. 4H); 1.71 (m. 4H); 1.46 (m. 2H). ¹³ C NMR spectrum (75.47 MHz;-*, ppm): 23.84 (1C); 25.45 (2C); 54.89 (2C); 57.94 (1C); 63.91 (1C); 66.06(1C); 66.32(1C); 68.89 (1C); 70.18(1C); 70.63(1C); 115.43(1C); 122.40 (1C); 124.23 (1C); 127.39 (1C); 128.89 (1C); 152.08(1C); 168.73(1C).

Example 26.

A mixture of 1.45 g (6.60 mmol) of benzoyl chloride and 6 ml of dry acetone is cooled to 0°C and 0.84 g (6.00 mmol) of 2-[2-(2-N-morpholinoethoxy)ethoxy]ethanol is added slowly with stirring. Then the reaction mass is stirred at room temperature for 0.5 hours. The precipitate formed is separated by filtration and washed with dry diethyl ether, after which it is recrystallized from dry acetone. As a result, 1.57 g (73%) of 2-[2-(2-N-morpholinoethoxy)ethoxy]ethylbenzoate hydrochloride (8p) was obtained. Mass spectrum*, m/z (I _rel ;%): 323[M] ⁺ (3); 320[M-2] ⁺ (12); 158(18); 149 (36); 122(20); 114 (35); 105 (45); 100(100); 77(42). 1H NMR spectrum ( ^250.13 MHz DMSO;-*, ppm): 8.02 (m 2H); 7.59 (m. 1H); 7.46 (m. 2H); 4.46 (m. 2H); 3.61 (m. 2H); 3.53-3.66 (m. 10H); 2.83 (m. 2H); 2.46 (m. 4H). ¹³ C NMR spectrum (75.47 MHz;-*, ppm): 53.80 (2C); 57.36 (1C); 64.78(1C); 66.33(1C); 67.02(2C); 69.93 (1C); 70.18(1C); 70.63(1C); 128.70 (2C); 129.02(1C); 129.28(2C); 133.40 (1C); 166.48(1C).

Example 27.

To a solution of 0.75 g (4.40 mmol) of phenoxyacetic acid chloride in 3 ml of dry acetone at a temperature of 0°C, 0.88 g (4.00 mmol) of 2-[2-(2-N-morpholinoethoxy)ethoxy]ethanol is added in portions with stirring. Stirring is continued for 0.5 hours at room temperature. The reaction mass is filtered, the resulting precipitate is washed with dry diethyl ether and recrystallized from dry acetone. As a result, a hygroscopic compound, 2-[2-(2-N-morpholinoethoxy)ethoxy]ethylphenoxyacetate hydrochloride, weighing 1.22 g (78%) (8p), was obtained. Mass spectrum*, m/z (I _rel ;%): 354[M+1] ⁺ (5); 353 [M] ⁺ (22); 352[M-1] ⁺ (16); 351[M-2] ⁺ (30); 202(23); 158 (42); 152 (35); 114(42); 100(100); 94(32); 77(46). 1H NMR spectrum ⁽ 300 MHz DMSO;-*, ppm): 7.32 (m 2H); 7.06 (m. 2H); 6.95 (m. 1H); 4.51 (p. 2H); 4.47 (v. 2H); 3.55-3.66 (m. 10H); 3.55 (t. 2H); 2.83 (t. 2H); 2.46 (m. 4H). ¹³ C NMR spectrum (75.47 MHz;-*, ppm): 53.80 (2C); 57.36 (1C); 63.91 (1C); 65.52 (1C); 66.33(1C); 67.02(2C); 68.89 (1C); 70.18(1C); 70.63(1C); 114.63 (2C); 119.60 (1C); 129.50 (2C); 157.62 (1C); 168.73(1C).

Example 28.

0.88 g (4.00 mmol) ]ethanol, continuing stirring for 0.5 hour at room temperature. Then the reaction mass is filtered, separating the precipitate, which is washed with dry diethyl ether and recrystallized from dry acetone. Thus, 1.23 g (69%) of 2-[2-(2-N-morpholinoethoxy)ethoxy]ethyl-2,4-dichlorophenoxyacetate (8c) was obtained. Mass spectrum*, m/z (I _rel ;%): 424[M+2] ⁺ (2); 423[M+1] ⁺ (7); 427[M] ⁺ (27); 420[M-1] ⁺ (16); 419[M-2] ⁺ (30); 321(5); 277(2); 202 (21); 174(5); 158 (40); 149 (48); 105(60); 100 (100). 1H NMR spectrum (300 MHz DMSO;-*, ^ppm ): 7.64 (m. 1H); 7.26 (m. 1H), 7.17 (m. 1H), 4.45-4.50 (m. 4H); 3.55-3.66 (m. 10H); 3.55 (t. 2H,); 2.83 (t. 2H); 2.46 (m. 4H). ). ¹³ C NMR spectrum (75.47 MHz;-*, ppm): 53.80 (2C); 57.36 (1C); 63.91 (1C); 66.06(1C); 66.33(1C); 67.02(2C); 68.89 (1C); 70.18(1C); 70.63(1C); 115.43(1C); 122.40 (1C); 124.23 (1C); 127.39 (1C); 128.99 (1C); 152.08(1C); 168.73(1C).

Example 29.

Dissolve 0.36 g (2.14 mmol) of phenoxyacetic acid chloride in 2 ml of dry acetone and cool to 0°C, then slowly add 0.51 g (1.95 mmol) of 2-{2-[2-(2-N-piperidinoethoxy)ethoxy] with stirring ethoxy}ethanol, continuing stirring at room temperature for 0.5 hour. The precipitate formed during the reaction is filtered off and washed with dry diethyl ether, after which it is recrystallized from dry acetone. As a result, 0.59 g (70%) of 2-{2-[2-(2-N-piperidinoethoxy)ethoxy]ethoxy}ethylphenoxyacetate hydrochloride (8t) was obtained. Mass spectrum*, m/z (I _rel ;%): 396[M+1] ⁺ (6); 395[M] ⁺ (19); 394[M-1] ⁺ (10); 393[M-2] ⁺ (23); 244(7); 200 (17);186 (14); 156(32); 151(22);142(26); 112(21); 98 (100); 94(11); 77 (35). 1H NMR spectrum ⁽ 300 MHz DMSO;-*, ppm): 7.32 (m 2H); 7.06 (m. 2H); 6.95 (m. 1H); 4.51 (p. 2H); 4.47 (v. 2H); 3.63-3.66 (m. 10H); 3.55 (t. 2H); 2.82 (t. 2H); 2.64 (m. 4H); 1.71 (m. 4H); 1.46 (m. 2H). ¹³ C NMR spectrum (75.47 MHz; -*, ppm): 23.84 (1C); 25.45 (2C); 54.89 (2C); 57.94 (1C); 63.91 (1C); 65.52 (1C); 66.32(1C); 68.89 (1C); 70.18(1C); 70.23(1C); 70.48(1C); 70.63(1C); 114.63 (2C); 129.50 (2C); 157.62 (1C); 168.73(1C).

Example 30.

To a mixture of 1.09 g (4.55 mmol) of 2,4-dichlorophenoxyacetic acid chloride and 4 ml of dry acetone, while cooling to 0°C and stirring, add 1.08 g (4.14 mmol) )ethoxy]ethoxy}ethanol. The reaction mass is continued to stir at room temperature for 0.5 h, after which the precipitate formed is filtered off and washed with dry diethyl ether, and then recrystallized from dry acetone. As a result, 1.57 g (76%) of 2-{2-[2-(2-N-piperidinoethoxy)ethoxy]ethoxy}ethylphenoxyacetate hydrochloride (8y) was obtained. Mass spectrum*, m/z (I _rel ;%): 466[M+2] ⁺ (3); 465[M+1] ⁺ (6); 464[M] ⁺ (32); 463[M-1] ⁺ (13); 462[M-2] ⁺ (27); 321(6); 277(4); 244(5); 200 (21);186 (25); 156 (34); 142 (29); 112(33); 98(100). 1H NMR spectrum ⁽ 300 MHz DMSO;-*, ppm): 7.32 (m 2H); 7.06 (m. 2H); 6.95 (m. 1H); 4.51 (p. 2H); 4.47 (v. 2H); 3.63-3.66 (m. 10H); 3.55 (t. 2H); 2.82 (t. 2H); 2.64 (m. 4H); 1.71 (m. 4H); 1.46 (m. 2H). ¹³ C NMR spectrum (75.47 MHz;-*, ppm): 23.84 (1C); 25.45 (2C); 54.89 (2C); 57.94 (1C); 63.91 (1C); 65.52 (1C); 66.32(1C); 68.89 (1C); 70.18(1C); 70.23(1C); 70.48(1C); 114.63 (2C); 119.60 (1C); 129.50 (2C); 157.62 (1C); 168.73(1C).

Study of antiarrhythmic activity of compounds of formula (I)

The study of the antiarrhythmic properties of the studied compounds was carried out in accordance with the guidelines for conducting preclinical studies of drugs [ Guidelines for conducting preclinical studies of drugs. Part one. M: Grif and K, 2012. p. 944 ].

The antiarrhythmic properties of substances were evaluated in parallel on various models of cardiac arrhythmia, in which arrhythmias arise and are maintained by various mechanisms. As models, we used aconitine (aconitine hydrobromide at doses of 40–50 μg/kg), calcium chloride (CaCl₂ at a dose of 200-250 mg/kg) and barium chloride (BaCl₂ at a dose of 25 mg/kg) arrhythmias in Wistar rats (male and female, body weight 180-240 g). These models of arrhythmias simulate severe, in most cases life-threatening cardiac arrhythmias in humans, and are widely used in the search for antiarrhythmic drugs [Szekeres L. Experimental models for the study of antiarrhytmic agents / Progr. Pharmacol., 1979, V.2, No. 4, pp. 25-31]. The effectiveness of the antiarrhythmic action of the compounds is characterized by the ability to prevent the development of arrhythmias or stop already developed arrhythmias, facilitate their course and restore normal sinus rhythm.

Studies of the toxicity and antiarrhythmic activity of the claimed compounds were carried out on 250 Balb/c mice (males and females, body weight 18-20 g), 560 Wistar rats (males and females, body weight 180-240 g). Animals were kept in bioclinics Federal State Budgetary Institution "National Medical Research Center for Cardiology" of the Ministry of Health of the Russian Federation in accordance with the norms of group accommodation in natural light conditions with forced 16-fold ventilation at a temperature of 18-20 ° C and a relative humidity of 40-70%. The animals had free access to drinking water and standard (GOST R50258-92) PK 120-1 granular feed (OOO Laboratorsnab, Russia). The conditions for keeping animals complied with the order of the Ministry of Health of the Russian Federation No. 199n "On approval of the rules of good laboratory practice" dated 04/01/2016 and the ethical standards set forth in the Rules of Good Laboratory Practice (GLP) of the Declaration of Helsinki (2000). All work with animals was performed on the basis of standard operating procedures adopted by the National Medical Research Center for Cardiology of the Ministry of Health of the Russian Federation, which comply with the rules of the European Convention for the Protection of Vertebrate Animals Used for Scientific Purposes (ETS 123, Strasbourg, 1986).

Changes in the rhythm of cardiac activity using these models of arrhythmias in animals were recorded electrocardiographically in the II standard lead on a CARDIOVIT AT-1 VET "Schiller" electrocardiograph.

The study of the antiarrhythmic properties of newly synthesized compounds was preceded by a study of their " acute toxicity" in mice of the Balb/c line (males and females, body weight 18-22 g) with a single intraperitoneal injection. At stage I according to the method of Deichman, Le Blanc [ Deichman WB, Le Blanc TJ Determination of the approximate lethal dose with about six animals. J. Indust. Hyg. ToxicoL, 1943, 25, 9, 415-41 ] on a small number of animals (5-7) determined the approximate LD ₅₀ . Then put a detailed experiment on three groups of animals, 5-6 animals each, with doses equidistant from LD ₅₀ . The animals were observed for 14 days after the administration of the substances. Regularly recorded the general condition, behavior and motor activity, recorded the timing of the development of intoxication and death of animals. Indicators of "acute" toxicity LD ₁₀ , LD ₁₆ , LD ₅₀ ± _m , LD ₈₄ were determined using the method of probit analysis according to Litchfield and Wilcoxon [ Belenky M.L. Elements of quantitative assessment of the pharmacological effect. - L.: Medgiz, 1963. - 146 s ]. LD ₅₀ values for oxyethylene amino esters were 308-3900 mg/kg. Studies have shown that the claimed compounds proved to be of low toxicity after a single intraperitoneal injection to mice of the BALB/c line. The results of the experiments are presented in table 3.

As reference drugs, antiarrhythmic drugs known and widely used in medical practice were used - amiodarone (Cordaron "Sanofi-Aventis France"), propranolol (Anaprilin "Tatkhimfarmpreparaty"), verapamil (Alkaloid Republic of Macedonia), lidocaine ("Organika" Novokuznetsk Autonomous District), novocainamide (Organika, Novokuznetsk Autonomous District). The antiarrhythmic activity of the compounds was evaluated by the value of the average effective dose (ED ₅₀ ), preventing or relieving cardiac arrhythmias, antiarrhythmic index (AI) and the Schneider-Brock index (LD ₁₀ /ED ₉₀ ). The latter makes it possible to more accurately characterize the pharmacological activity of drugs, the therapeutic breadth and the prospects for creating drugs based on them [ Arzamastsev EV The safety of drugs at the stage of screening and preclinical toxicological studies. Lab. Zhyvotnye, 1991, Vol. 1, No. 2, 60-64 ]. These efficacy and toxicity parameters were determined by Litchfield and Wilcoxon probit analysis.

For the primary assessment of the antiarrhythmic properties of the compounds, an aconitine model of arrhythmia was used, the mechanisms of which are due to a change in the functional state of the fast sodium channels of the excitable membrane of cardiomyocytes and an increase in their conductivity [ Galenko-Yaroshevsky P.A. et al., Antiarrhythmic drugs: pharmacotherapeutic aspects, methods of search and preclinical study / Krasnodar: Education-South, 2012, 431 p. ]. This type of arrhythmia of the mixed atrioventricular type is close to heart rhythm disorders observed in the clinic with various myocardial lesions.

Anesthetized animals (Wistar rats, males and females weighing 180-240 g) (urethane 1100-1300 mg/kg, i.p.) were fixed in the supine position on the operating table, the femoral vein was catheterized for the administration of aconitine and the studied compounds. Before the start of the experiment, ECG was recorded in animals (standard lead II, calibration signal 10 mm/mV, recording speed 25 mm/sec). A CARDIOVIT AT-1 VET Schiller cardiograph (Switzerland) was used as a recorder. The claimed compounds in doses of 1/10-1/100 from LD ₅₀ (for mice with intravenous administration) and reference drugs were administered 2 minutes before the administration of aconitine. ECG registration was performed 3, 5, 10, 15 and 20 minutes after the administration of aconitine.

The effectiveness of the antiarrhythmic action of the claimed compounds was evaluated by the magnitude of the latent period of the onset of arrhythmia, by the duration of the arrhythmia or its prevention. At the end of the experiment, the average effective dose of the compound (ED ₅₀ ) was calculated by probit analysis according to Litchfield and Wilcoxon. To evaluate the effectiveness of the antiarrhythmic action of oxyethylene amino esters and reference drugs, the antiarrhythmic index (LD ₅₀ /ED ₅₀ ) and the Schneider-Brock index (LD ₁₀ /ED ₉₀ ) were used.

Based on several series of experiments in which the antiarrhythmic properties of various doses of the studied substances were studied, the doses that relieve arrhythmia in 50 and 90% of animals were determined by the Litchfield and Wilcoxon probit analysis.

The introduction of compounds in the range of tested doses of 1/100-1/10 from LD ₅₀ (for mice with intraperitoneal injection) led to 50-100% survival of animals in the model of aconitine arrhythmia. The claimed compounds in the tested doses increased the duration of the latent period of development of aconitine arrhythmia or completely prevented it. Cardiograms are presented in fig. 1-3.

The high antiarrhythmic activity of the claimed compounds is confirmed by another criterion used - the percentage of removed arrhythmias (table 4). The application of this criterion indicates the pronounced antiarrhythmic properties of the claimed compounds. On models of aconitine arrhythmia in rats, a number of the claimed compounds at doses up to 6 mg/kg (compounds 8g, 8i) relieve arrhythmias caused by the administration of aconitine hydrobromide in 50-100% of cases. Compounds 8l and 8g are characterized by the lowest average effective doses (ED ₅₀ ).

The most pronounced antiarrhythmic properties were shown by compound 8g, which exhibited an antiarrhythmic effect at a dose of 0.06 mg/kg (less than 1/500 LD ₅₀ for mice with i.p. administration). Next, in descending order, were the compounds 8s > 8u > 8p > 8n, which exceeded antiarrhythmic drugs (amiodarone, lidocaine, propranolol) taken as reference drugs in terms of antiarrhythmic index.

Pronounced antiarrhythmic properties of the claimed compounds, identified in the model of aconitine arrhythmia, were also confirmed in models of barium chloride and calcium chloride arrhythmia. Electrocardiograms are presented in fig. 2, 3. At the same time, well-known antiarrhythmics, which are widely used in clinical practice, were also used as reference drugs.

Cardiac arrhythmias induced by calcium chloride (200-250 mg/kg) were obtained with intravenous administration of it in the form of a 10% solution. In this case, after 30 seconds - 1 min, ventricular fibrillation of the heart occurred. The test compounds and the reference drug (verapamil) were administered intravenously 1-2 minutes before the administration of calcium chloride. ECG was recorded in standard lead II, starting from the 1st minute, and then 5, 10, 15, and 20 minutes after the administration of calcium chloride. The study of each compound was carried out on 3-6 groups of animals, depending on the number of doses studied. The antiarrhythmic effect was judged by a decrease in the number of cases of lethal ventricular fibrillation.

The barium chloride model of arrhythmia was induced by intravenous administration of barium chloride at a dose of 25 mg/kg to anesthetized rats (urethane 1100 mg/kg intraperitoneally). Barium chloride causes polytopic ventricular arrhythmia, caused by impaired automatism of the heart, changes in myocardial excitability and characterized by tachyarrhythmia and ventricular extrasystole. Arrhythmia occurs 10-15 seconds after the introduction of barium chloride and, according to electrocardiography, is noted for 42.7 ± 5.2 minutes, after which there is a restoration of sinus rhythm or death of animals in 85% of cases. The claimed compounds and reference preparations were administered intravenously 1-3 minutes before the administration of barium chloride.

As illustrations, the graphic images (Fig. 1-3) show electrocardiograms of rats with cardiac disorders caused by aconitine hydrobromide, barium chloride and calcium chloride.

The data obtained in the experiments indicate pronounced antiarrhythmic properties and noticeable advantages of the claimed compounds. Compared with known antiarrhythmics, the compounds have lower toxicity, high therapeutic indices (LD ₅₀ /ED ₅₀ and LD ₁₀ /ED ₉₀ ) - the most important indicators necessary to assess the feasibility of further study and the prospects of clinical trials and practical use as drugs for the prevention and treatment of cardiac arrhythmias.

Thus, the conducted studies have shown that the claimed aminoesters are low-toxic substances, have pronounced antiarrhythmic properties that are not inferior in effectiveness to the currently used known drugs amiodarone, verapamil and propranolol. The claimed compounds are substances with a combined mechanism of action and are promising for the development of new highly effective drugs based on them for the treatment and prevention of cardiac arrhythmias.

tables

Table 1

Yields and properties of hydrochloride of amino alcohols of the oxyethylene series 3а-i

Connection No. Exit,
% n NR _{2 Rf} * T _bale , ° С n _D ²⁰ IR spectrum, cm ^-1 ν _C-O
(on air) _νOH
(link) 3a 71 one NET ₂ 0.48 92-95
(7.0) 1.4457 1110 3325
1070 3b 63 one NC ₅ H ₁₀ 0.42 135-137
(18.0) 1.4761 1115 3320
1070 3v 53 one _{NC4H8O _} 0.40 149-154
(12.0) 1.4711 1115 3325
1070 3g 65 2 NET ₂ 0.40 123-128
(7.0) 1.4534 1110 3325
1070 3d 72 2 NC ₅ H ₁₀ 0.35 115-120
(1.5) 1.4720 1115 3320
1070 3rd 55 2 _{NC4H8O _} 0.36 138-140
(1.5) 1.4701 1115 3325
1070 3zh 60 3 NET ₂ 0.38 168-172
(7.0) 1.4537 1110 3325
1070 3h 67 3 NC ₅ H ₁₀ 0.35 132-136
(2.0) 1.4768 1115 3325
1070 3i 62 3 _{NC4H8O _} 0.35 149-154
(2.0) 1.4763 1115 3325
1070

*TLC system: methanol-chloroform (1:3)

table 2

Yields and properties of hydrochloride esters of oxyethylene series 8а-у

Comm. No. Solvent Exit, % n R' NR ₂ T _pl , °С IR spectrum, cm ^-1 ν _{C=O νNH} ⁺ _νCOC 8a benzene 75 one C ₆ H ₅ N(C ₂ H ₅ ) ₂ - 1735
1250 2625
2491 1100 8b benzene 79 one C ₆ H ₅ CH ₂ N(C ₂ H ₅ ) ₂ 149-150 1710
1280 2624 1100 8v benzene 61 one 2,4-Cl ₂ C ₆ H ₅ OCH ₂ N(C ₂ H ₅ ) ₂ 89-90 1762
1202 2587
2485 1091 8g benzene 85 one C ₆ H ₅ NC ₅ H ₁₀ 115-116 1708
1276 2620
2484 1112 8d acetone 53 one C ₆ H ₅ CH ₂ NC ₅ H ₁₀ 116-117 1730
1257 2615
2491 1126 8e benzene 52 one C ₆ H ₅ OCH ₂ NC ₅ H ₁₀ 117-118 1739
1212 2624
2456 1106 8g benzene 83 one 2,4-Cl ₂ C ₆ H ₅ OCH ₂ NC ₅ H ₁₀ 124-125 1752
1212 2628
2448 1088 8z benzene 85 one C ₆ H _{5 NC4H8O _} 142-144 1710
1280 2591
2452 1100 8i benzene 82 one C ₆ H ₅ OCH _{2 NC4H8O _} 109-110 1770
1209 2567
2448 1139 8l benzene 92 one 2,4-Cl ₂ C ₆ H ₅ OCH _{2 NC4H8O _} 133-134 1742
1212 2588
2376 1088 8m benzene 88 2 C ₆ H ₅ NC ₅ H ₁₀ 122-123 1728
1268 2634
2482 1096 8n acetone 75 2 C ₆ H ₅ OCH ₂ NC ₅ H ₁₀ hygrosk. 1748
1210 2606
2458 1114 8o benzene 79 2 2,4-Cl ₂ C ₆ H ₅ OCH ₂ NC ₅ H ₁₀ hygrosk. 1752
1211 2590
2467 1102 8p benzene 73 2 C ₆ H _{5 NC4H8O _} 119-120 1736
1264 2622
2434 1116 8r acetone 78 2 C ₆ H ₅ OCH _{2 NC4H8O _} hygrosk. 1746
1218 2615
2458 1106

Table 2 (continued)

8s benzene 69 2 2,4-Cl ₂ C ₆ H ₅ OCH _{2 NC4H8O _} hygrosk. 1759
1215 2591
2396 1115 8t acetone 70 3 C ₆ H ₅ OCH ₂ NC ₅ H ₁₀ oil 1731
1204 2630
2452 1118 8y acetone 76 3 2,4-Cl ₂ C ₆ H ₅ OCH ₂ NC ₅ H ₁₀ oil 1756
1216 2638
2486 1105

Table 3

Indicators of toxicity and effectiveness of antiarrhythmic action

hydrochlorides of aminoesters of the oxyethylene series and reference drugs

on various models of arrhythmias with intravenous administration

Cipher
connections Test Substances LD _ten i.p., mg/kg LD ₁₆ i.p., mg/kg LD ₅₀ ± _m
i.p., mg/kg LD ₈₄ i.p., mg/kg Arrhythmia patterns Aconitine hydrobromide,
50 mcg/kg CaCl ₂ ,
250 mcg/kg BaCl ₂ ,
25 mcg/kg R ^one n NR ₂ ED _fifty , mg/kg LD _fifty /ED _fifty ED _fifty , mg/kg LD _fifty /
ED _fifty ED _fifty , mg/kg LD _fifty /ED _fifty 8z C ₆ H ₅ one _{NC4H8O _} 2890 3415 3900±359 4635 3.3 80.6 11.5 23.13 99 2.7 8i C ₆ H ₅ OCH ₂ one _{NC4H8O _} 1170 1260 1610±203 2065 67.9 12.1 36 24.06 134 6.1 8r C ₆ H ₅ OCH ₂ 2 _{NC4H8O _} 1880 2080 2260±181 3245 four 35 5.8 24 5 28 8l 2,4-Cl ₂ C ₆ H ₃ OCH ₂ one _{NC4H8O _} 332 341 379±22 428 0.32 718 1.0 230 0.5 460 8g 2,4-Cl ₂ C ₆ H ₃ OCH ₂ one NC ₅ H ₁₀ 196 239 308±36 384 0.06 5133 12.9 21.24 38 7.21 Amiodarone 430 6.5 66 4.2 102.4 5 86 Verapamil 97 1.9 51 1.6 28 propranolol 85 3 28 4.5 19 Novocainamide 300 fourteen 21 13.3 22.5

Table 4

Antiarrhythmic properties of hydrochlorides of oxyethylene series amino esters and reference drugs on the model

aconitine arrhythmia in Wistar rats

Cipher
connections Toxicity, mg/kg Experiment conditions Research results LD _fifty ED _fifty ED _{9 0} LD _{5 0} /ED _fifty LD _ten /ED ₉₀ Tested doses, mg/kg Number of animals in the group removal of arrhythmias
% Arrhythmia prevention,% Arrhythmia duration, min surviving animals,
% 8z 3900 93.5 41.7 21 four 25 0 95.2±1.3 fifty 8i 1610 45.0 35.0 160
85
42
21
ten
one 2
one
5
5
5
5 0
0
60
80
100
100 0
0
0
0
twenty
twenty 38.6±11.3
42.0±13.8
83.3±6.6
80.4±7.5
77.2±16.8
62.2±8.6 0
0
80
100
80
100 8r 2260 142.0 15.9 175
110
one
0.5
0.25 5
eight
2
four
four 100
100
100
fifty
fifty 0
0
0
0
0 86.8±3.9
82.7±9.9
100.3±1.3
80.0±10.0
88.6±12.4 100
100
100
100
fifty 8l 379 50.0 7.6 35
twenty 5
eight 60
100 0
0 98.5±12.6
105.6±1.4 80
100 8g 308 0.06 0.45 5133.0 428.9 31
twenty
ten
5
2.5
one
0.5
0.25
0.125
0.06 2
four
four
6
5
3
2
2
5
7 0
100
25
67
100
100
100
100
100
100 0
0
0
17
60
0
0
0
40
fourteen 36.7±11.6
79.7±10.9
103.5±4.0
117.4±6.7
33.5±8.5
61.0±2.0
47.0±12.0
69.0±6.0
72.7±5.5
87.2±15.1 0
100
100
100
100
100
100
100
100
100 Amiodarone 430 6.5 13.4 66.0 21 four
5
7 four
5
5 75
100
100 0
60
40 48.0±7.8
31.0±5.9
53.0±14.4 100
100
100 Lidocaine 145 5.0 9.0 29.0 11.5 5
ten four
5 fifty
60 25
80 24.0±12.5
35.0±9.8 100
100 propranolol 85 3.0 7.2 28.0 7.8 2
6 6
5 66.7
80 fifty
40 36.0±8.4
47.0±15.2 100
100 Control - - - - - - 40 - - - twenty

Claims (11)

1. Compounds exhibiting antiarrhythmic activity and represented by the general formula:

, when n=1, NR ₂ =NEt ₂ then R'=Ph; PhCH ₂ ; PHOCH ₂ ; 2,4-Cl ₂ C ₆ H ₃ OCH ₂ ; when n=1,NR₂=NC₅H_ten, then R^'=Ph; PhCH₂; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂; when n=1,NR₂=NC_fourH_eightO, then R^'=Ph; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂; when n=2,NR₂=NC₅H_ten, then R^'=Ph; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂; when n=2,NR₂=N C_fourH_eightO, then R^'=Ph; PhOCH₂; 2,4-Cl₂C₆H₃OCH₂; when n=3, NR₂=NC₅H_ten, then R^'= PhOCH₂; 2,4-Cl₂C₆H₃OCH₂ (while NC ₄ H ₈ O is morpholino, NC ₅ H ₁₀ is piperidino). 2. A drug with antiarrhythmic activity, including compounds according to claim 1 as an active agent. 3. A pharmaceutical composition having antiarrhythmic activity, comprising, as an active agent, the compounds of claim 1 together with one or more pharmaceutically acceptable carriers or excipients.

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