RU2712638C1 - N-(2-(2-(dialkylamino)ethoxy)ethyl)carboxamides and hydrochlorides thereof, having antiarrhythmic activity, and pharmaceutical compositions based thereon - Google Patents

Abstract

FIELD: medicine; pharmacology.SUBSTANCE: invention refers to pharmacology, namely to compounds of the following general formula, which exhibit antiarrhythmic activity. In said formula when R=CH, and n=0, then NR=NCHor NCHO; when R=CHOCH, and n=1, then NR=N(CH), NCH, NCHor NCHO; when R=CHOCH, and n=0, then NR=NCHor NCHO; when R=2,4-Cl-CHOCH, and n=1, then NR=N(CH), NCH, NCHor NCHO; when R=2,4-Cl-CHOCH, and n=0, then NR=NCHor NCHO, wherein NCHmeans pyrrolidino, NCH– piperidino, NCHO – morpholino. Invention also relates to a medicinal agent and a pharmaceutical composition, which include said compounds.EFFECT: disclosed are N-(2-(2-(dialkylamino)ethoxy)ethyl)carboxamides and hydrochlorides thereof, having antiarrhythmic activity, and pharmaceutical compositions based thereon.3 cl, 4 tbl, 3 dwg, 20 ex

Description

The invention relates to the field of pharmacology and relates to the creation of new drugs for the prevention and treatment of heart rhythm disorders.

Despite significant advances in medicine, the pathology of the cardiovascular system (coronary heart disease, arterial hypertension, atherosclerosis, acquired and congenital heart defects, myocardial diseases of inflammatory etiology) still occupy the first place among other somatic diseases of a person and are the main cause of death. Often diseases of the cardiovascular system are complicated by the development of cardiac arrhythmias of various origins [Guide to cardiac arrhythmias / Ed. E.I. Chazova, S.P. Golitsyna. - M.: GEOTAR-Media, 2010]. Arrhythmia and ventricular fibrillation are observed in 94% of cases in patients with myocardial infarction and, as a rule, are the direct cause of death. Despite the fact that in recent years, surgical methods and implantation of various technical devices for electropulse therapy have become widely used for treatment, pharmacotherapy remains the main method for the prevention and treatment of heart rhythm disturbances.

Currently, the clinic has a significant amount of antiarrhythmic drugs. However, most of them have serious drawbacks, the main of which is a small therapeutic breadth, as well as the presence of cardiac and extracardial side effects [Kaverina N.V. Modern aspects of the search and preclinical study of antiarrhythmic drugs / Cardiology, 1986, T. 26, No. 8, p. 59-63]. Moreover, as shown in the CAST I and CAST II studies, the use of highly effective IC group drugs in patients with coronary heart disease is accompanied by an increase in cases of sudden clinical death [The Cardiac Arrhythmia Suppression trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction / The New England Journal of Medicine, 1989, V. 321, N. 6, pp. 406-412].

In this regard, the development of effective therapy for heart rhythm disturbances and the search for new drugs with high antiarrhythmic activity and devoid of unwanted side effects are some of the most urgent problems of modern cardiopharmacology.

An analysis of the literature shows that from the prior art [patent US 9670242 B2, publication date 06/06/2017] compounds with the formula similar in structure are known:

R'C (O) NHCH ₂ CH ₂ OCH ₂ CH ₂ NR ₂

However, the above compounds do not have antiarrhythmic properties.

The objective of the present invention was the synthesis of compounds with high antiarrhythmic activity and promising for the development on their basis of drugs for the treatment of heart rhythm disorders.

The technical result of the present invention is to expand the arsenal of drugs with high antiarrhythmic activity and promising for the development of drugs based on them for the treatment of heart rhythm disorders.

The specified task and technical result is achieved by the fact that a new class of antiarrhythmic nitrogen-containing compounds is obtained, represented by the following general formula:

где

Where

(NC ₄ H ₈ - pyrrolidino, NC ₅ H ₁₀ - piperidino, NC ₄ H ₈ O - morpholino).

The inventive compounds were obtained according to the scheme:

Hydroxyethoxyethylamides (3a-c) were obtained by acylation of 2- (2-aminoethoxy) ethanol (1) with the corresponding carboxylic acid chlorides (2a-c) in methylene chloride under stirring at room temperature, followed by extraction and recrystallization, to obtain products (3a-c) with yields of 72-80%.

The tosyloxyethoxyethylamides (4a-c) required for the amidoethoxyethylation reaction were synthesized from the corresponding 2-hydroxyethoxyethylamides (3a-c) by reacting the latter in dry pyridine at -16 ° C for 15-17 hours with n-toluenesulfonyl chloride, followed by stirring in water for 1 hour before the formation of sediment. After filtration and drying, tosyloxyethoxyethylamides (4a-c) were obtained in 67-75% yields.

The amidoethoxyethylation of secondary amines (5a-f) with tosyloxyethoxyethylamides (4a-c) was carried out in boiling para-xylene (for monoamines) or acetonitrile in the presence of triethylamine (for diamines) with stirring for 20-70 hours, followed by precipitation of the hydrochlorides of the obtained products (6- 19) in diethyl ether using a solution of hydrogen chloride in dioxane to obtain N- (2- (2- (dialkylamino) ethoxy) ethyl) carboxamide hydrochlorides (6-19) in 43-78% yields.

The structure of compounds (3a-c), (4a-c), (6-19) was confirmed by IR, ¹ H-, ¹³ C-spectroscopy, as well as mass spectrometry, and the composition was determined by elemental analysis. Physico-chemical characteristics of the proposed compounds are presented in tables 1-2.

Example 1. A mixture of 2- (2-aminoethoxy) ethanol (1) (1.05 g, 0.01 mol) in 25 ml of methylene chloride and 8 ml of an aqueous solution of NaOH (10%) is cooled to -6 ÷ -4 ° C . To this intensively stirred solution, a solution of benzoic acid chloride (2a) (1.55 g, 0.011 mol) in 30 ml of methylene chloride is added dropwise. Then the mixture was stirred at room temperature for 10 hours. Leave for a day at room temperature. Add 15 ml of water and separate the organic layer. The aqueous layer was washed with methylene chloride (2 × 25 ml) and the combined organic extracts washed with hydrochloric acid solution (1: 1, 30 ml), saturated NaCl solution (30 ml) and dried over Na ₂ SO ₄ . After removal of the solvent, an oil is obtained which is recrystallized from diethyl ether. The yield of N- [2- (2-hydroxyethoxy) ethyl] benzamide (3a) was 1.51 g (72%). ¹ H NMR Spectrum (DMSO + CCl ₄ ): δ 7.7 (m, 2H); 7.35 (m, 3H); 6.90 (brd 1H); 3.60 (m, 8H); 2.8 (brd 1H). Mass spectrum, m / z: 210 (4), 164 (43), 148 (70), 134 (78), 105 (100), 77 (85).

Example 2. To a mixture of 1.17 g (0.011 mol) of 2- (2-aminoethoxy) ethanol (1) in 25 ml of methylene chloride and 8 ml of a 10% aqueous solution of NaOH, while cooling to 0 ° C, the solution is added dropwise with vigorous stirring 1.71 g (0.01 mol) of phenoxyacetyl chloride (2b) in 30 ml of methylene chloride. The reaction mixture was stirred at room temperature for two hours. Then 15 ml of water are added, the organic layer is separated, and the aqueous layer is washed with methylene chloride (2 × 25 ml). The combined organic extracts were washed with 30 ml of sodium chloride solution and dried over Na ₂ SO ₄ . After removing the solvent, a colorless oil is obtained, which is recrystallized from diethyl ether. 1.85 g (77%) of N- [2- (2-hydroxyethoxy) ethyl] phenoxyacetamide (3b) are obtained. ¹ H NMR Spectrum (DMSO + CCl ₄ ): δ 7.91 (brds, 1H, NH); 7.29 (t, 2H, H _m , Ph); 6.95 (brd, 1H, OH); 6.95 (t, 1H, H _p , Ph); 6.92 (d, 2H, H _o , Ph); 4.41 (s, 2H, CH ₂ CO); 3.50 (m, 2H, CH ₂ CH ₂ ); 3.48 (m, 2H, CH ₂ CH ₂ ); 3.32 (m, 2H, CH ₂ CH ₂ ); 3.23 (m, 2H, CH ₂ CH ₂ ). ¹³ C NMR spectrum: 167.52 (CO); 157.64 (C _i ); 129.25 (C _m ); 121.07 (s _p ); 114.64 (C _o ); 72.21 (CH ₂ CO); 68.97 (CH ₂ CH ₂ ); 66.91 (CH ₂ CH ₂ ); 60.37 (CH ₂ CH ₂ ); 38.98 (CH ₂ CH ₂ ). Mass spectrum, m / z: 239 (9), 194 (12), 177 (66), 151 (72), 107 (77), 93 (60).

Example 3. A solution of 2.39 g (0.01 mol) of 2,4-dichlorophenoxyacetyl chloride (2c) in 30 ml of methylene chloride was added dropwise while cooling to 0 ° C with vigorous stirring 1.17 g (0.011 mol) of 2 - (2-aminoethoxy) ethanol (1) in 25 ml of methylene chloride and 8 ml of a 10% aqueous solution of NaOH. The reaction mixture was stirred at room temperature for two hours. Then 15 ml of water are added, the organic layer is separated, and the aqueous layer is washed with methylene chloride (2 × 25 ml). The combined organic extracts were washed with 30 ml of sodium chloride solution and dried over sodium sulfate. After removal of solvent, diethyl ether was added. The precipitate formed is recrystallized from diethyl ether. 2.46 g (80%) of N- [2- (2-hydroxyethoxy) ethyl] -2,4-dichlorophenoxyacetamide (3c) are obtained. ¹ H NMR Spectrum (DMSO): δ 7.92 (brds, 1H, NH); 7.59 (s, 1H, H _m , Ph); 7.54 (d, 1H, H _m , Ph); 7.31 (d, 2H, H _o , Ph); 7.03 (brd, 1H, OH); 4.65 (s, 2H, CH ₂ CO); 3.50 (t, 2H, CH ₂ CH ₂ ); 3.48 (t, 2H, CH ₂ CH ₂ ); 3.35 (m, 2H, CH ₂ CH ₂ ); 3.30 (m, 2H, CH ₂ CH ₂ ). ¹³ C NMR Spectrum: 161.53 (CO); 148.34 (C _i ); 127.26, 126.09 (C _m ); 123.44 (C _p -Cl); 121.06 (C _o -Cl); 117.56 (C _o ); 75.12 (CH ₂ CO); 72.06 (CH ₂ CH ₂ ); 71.16 (CH ₂ CH ₂ ); 64.25 (CH ₂ CH ₂ ); 44.38 (CH ₂ CH ₂ ). Mass spectrum, m / z: 307 (5), 272 (100), 246 (31), 175 (65), 145 (40).

Example 4. To a solution of N- [2- (2-hydroxyethoxy) ethyl] benzamide (3a) (3.00 g, 0.0144 mol) in 15 ml of dry pyridine, cooled to 0 ° C, add a solution of n -toluenesulfonyl chloride (5.49 g, 0.0288 mol) in 15 ml of dry pyridine. The reaction mixture was kept at -18 ° C for 3 days. At the end of the reaction (TLC control, chloroform), the solution was carefully poured from crystals into ice water and stirred for 2 hours. The aqueous layer was washed with ether, the layers were separated, and the organic layer was washed with a hydrochloric acid solution (1: 1), 5% NaHCO ₃ solution and water. The organic layer was dried over Na ₂ SO ₄ . Removal of the solvent gave 3.87 g (74%) of N- [2- (2-n-toluenesulfonylethoxy) ethyl] benzamide (4a) as a pale yellow oil, which was recrystallized from diethyl ether. ¹ H NMR Spectrum (DMSO + CCl ₄ ): δ 8.35 (brds, 1H, NH); 7.85, 7.4 (m, 5H, Ph); 7.74 (d, 2H, PhTs); 7.45 (d, 2H, PhTs); 4.12 (t, 2H, CH ₂ CH ₂ ); 3.61 (t, 2H, CH ₂ CH ₂ ); 3.48 (m, 2H, CH ₂ CH ₂ ); 3.40 (m, 2H, CH ₂ CH ₂ ); 2.45 (s, 3H, CH ₃ Ts). ¹³ C NMR spectrum: 166.13 (CO); 154.95 (C _i ); 144.55 (C _i -T _s ); 130.74 (C _m ); 129.89 (C _m -T _s ); 127.90 (C _o -T _s ); 127.60 (C _p ); 127.25 (C _o ); 95.70 (C _i -T _s ); 69.48 (CH ₂ CH ₂ ); 69.13 (CH ₂ CH ₂ ); 67.76 (CH ₂ CH ₂ ); 38.72 (CH ₂ CH ₂ ); 21.25 (CH ₃ ). Mass spectrum, m / z: 363 (5), 199 (56), 164 (70), 155 (61), 148 (65), 134 (42), 105 (100), 91 (77), 77 ( 81).

Example 5. To a solution of N- [2- (2-hydroxyethoxy) ethyl] phenoxyacetamide (3b) (3.00 g, 0.0125 mol) in 15 ml of dry pyridine cooled to 0 ° C was added a solution of n -toluenesulfonyl chloride (4.77 g, 0.0251 mol) in 15 ml of dry pyridine. The reaction mixture is kept in the freezer for 2.5 days. At the end of the reaction (TLC control, chloroform), the solution was carefully poured from crystals into ice water and stirred for 2 hours. The aqueous layer was washed with ether, the layers were separated, and the organic layer was washed with a hydrochloric acid solution (1: 1), 5% NaHCO ₃ solution and water. The organic layer was dried over Na ₂ SO ₄ . Removal of the solvent gave 3.28 g (67%) of N- [2- (2-n-toluenesulfonylethoxy) ethyl] phenoxyacetamide (4b) as a pale yellow oil, which was recrystallized from diethyl ether. ¹ H NMR Spectrum (DMSO + CCl ₄ ): δ 7.89 (t, 1H, NH); 7.75 (d, 2H, PhTs); 7.45 (d, 2H, PhTs); 7.25.6.93 (m, 5H, Ph); 4.41 (s, 2H, CH ₂ CO); 4.10 (t, 2H, CH ₂ CH ₂ ); 3.60 (t, 2H, CH ₂ CH ₂ ); 3.45 (t, 2H, CH ₂ CH ₂ ); 3.30 (m, 2H, CH ₂ CH ₂ ); 2.45 (s, 3H, CH ₃ Ts). ¹³ C NMR spectrum: 167.44 (CO); 157.64 (C _i ); 144.51 (C _i -T _s ); 129.89 (C _m -T _s ); 129.26 (C _m ); 127.62 (C _o -T _s ); 121.04 (C _p ); 114.66 (C _o ); 95.70 (C _i -T _s ); 69.43 (CH ₂ CO); 68.97 (CH ₂ CH ₂ ); 67.72 (CH ₂ CH ₂ ); 66.94 (CH ₂ CH ₂ ); 38.08 (CH ₂ CH ₂ ); 21.25 (CH ₃ ). Mass spectrum, m / z: 393 (15), 199 (65), 155 (82), 91 (93).

Example 6. To a solution cooled to 0 ° C of N- [2- (2-hydroxyethoxy) ethyl] -2,4-dichlorophenoxyacetamide (3c) (3.08 g, 0.01 mol) in 15 ml of dry pyridine was added cooled to 0 ° C solution of n-toluenesulfonyl chloride (2.86 g, 0.015 mol) in 15 ml of dry pyridine. The reaction mixture is kept in the freezer for 2.5 days. At the end of the reaction (TLC control, chloroform), the solution was carefully poured from crystals into ice water and stirred for 2 hours. The aqueous layer was washed with ether, the layers were separated, and the organic layer was washed with a hydrochloric acid solution (1: 1), 5% NaHCO ₃ solution and water. The organic layer was dried over Na ₂ SO ₄ . Removal of the solvent gave 3.47 g (75%) of N- [2- (2-n-toluenesulfonylethoxy) ethyl] -2,4-dichlorophenoxyacetamide (4c) as white crystals. ¹ H NMR Spectrum (DMSO): δ 7.92 (brds, 1H, NH); 7.80 (d, 2H, PhTs); 7.59 (s, 1H, H _m , Ph); 7.49 (d, 2H, PhTs); 7.35 (d, 1H, H _m , Ph); 7.05 (d, 1H, H _o , Ph); 4.62 (s, 2H, CH ₂ CO); 4.11 (t, 2H, CH ₂ CH ₂ ); 3.60 (t, 2H, CH ₂ CH ₂ ); 3.40 (t, 2H, CH ₂ CH ₂ ); 3.25 (t, 2H, CH ₂ CH ₂ ); 2.4 (s, 3H, CH ₃ Ts). ¹³ C NMR Spectrum: 166.96 (CO); 152.50 (C _i ); 144.95 (C _i -T _s ); 130.18 (C _m -T _s ); 129.38, 128.06 (C _m ); 127.64 (C _o -T _s ); 125.23 (C _p -Cl); 122.63 (C _o -Cl); 115.51 (C _o ); 95.70 (C _i -T _s ); 72.19 (CH ₂ CO); 69.93 (CH ₂ CH ₂ ); 68.8 (CH ₂ CH ₂ ); 67.91 (CH ₂ CH ₂ ); 38.21 (CH ₂ CH ₂ ); 21.13 (CH ₃ ). Mass spectrum, m / z: 461 (1), 462 (100), 175 (33), 155 (70).

Example 7. N- [2- (2-n-toluenesulfonylethoxy) ethyl] benzamide (4a) (3.63 g, 0.01 mol) and piperidine (5a) (4.25 g, 0.05 mol) are boiled in 50 ml of xylene for 35 hours until the disappearance of the original tosyl derivative (TLC control, acetone). The solvent and the starting amine were distilled off in vacuo, the residue was dissolved in diethyl ether, and a 3N HCl / dioxane solution was added until a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 1.60 (51%) N- (2- (2-piperidinoethoxy) ethyl) benzamide hydrochloride is obtained (6). ¹ H NMR Spectrum (CDCl ₃ ): δ 10.85 (brd s, 1H, HCl); 7.77 (brd s, 1H, NH); 7.29 (t, 2H, H _m , Ph); 7.01 (t, 1H, H _p , Ph); 6.89 (d, 2H, H _o , Ph); 3.85-3.80 (m, 4H, CH ₂ CH ₂ ); 3.30-3.20 (m, 4H, CH ₂ CH ₂ ); 2.94 (m, 4H, NC ₅ H ₁₀ ); 1.97 (m, 4H, NC ₅ H ₁₀ ); 1.56 (m, 2H, NC ₅ H ₁₀ ). ¹³ C NMR Spectrum: 167.39 (CO); 149.09 (C _i ); 136.27 (C _m ); 124.56 (C _p ); 117.05 (C _o ); 73.11 (CH ₂ CH ₂ ); 69.05 (CH ₂ CH ₂ ); 61.73 (CH ₂ CH ₂ ); 56.18 (NC ₅ H ₁₀ ); 44.90 (CH ₂ CH ₂ ); 25.07 (NC ₅ H ₁₀ ); 19.70 (NC ₅ H ₁₀ ).

Example 8. N- [2- (2-n-toluenesulfonylethoxy) ethyl] benzamide (4a) (3.63 g, 0.01 mol) and morpholine (5b) (4.35 g, 0.05 mol) are boiled in 50 ml of xylene for 30 hours until the disappearance of the original tosyl derivative (TLC control, acetone). The solvent and the starting amine were distilled off in vacuo, the residue was dissolved in diethyl ether, and a 3N HCl / dioxane solution was added until a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. Obtain 1.76 (56%) of N- (2- (2-morpholinoethoxy) ethyl) benzamide hydrochloride (7). ¹ H NMR Spectrum (CDCl ₃ ): δ 10.93 (brds, 1H, HCl); 7.54 (brds, 1H, NH); 7.30 (t, 2H, H _m , C ₆ H ₅ ); 6.99 (t, 2H, H _p, C ₆ H _5); 6.83 (d, 2H, H _o , C ₆ H ₅ ); 3.84 (m, 4H, NC ₄ H ₈ O); 3.65 (m, 2H, CH ₂ CH ₂ ); 3.55 (m, 2H, CH ₂ CH ₂ ); 3.30 (m, 2H, CH ₂ CH ₂ ); 2.63 (m, 2H, CH ₂ CH ₂ ); 2.43 (m, 4H, NC ₄ H ₈ O). ¹³ C NMR spectrum: 169.37 (CO); 147.64 (C _i ); 135.12 (C _m ); 123.90 (s _p ); 121.07 (C _o ); 72.19 (NC ₄ H ₈ O); 70.56 (CH ₂ CH ₂ ); 70.08 (CH ₂ CH ₂ ); 69.72 (CH ₂ CH ₂ ); 62.80 (NC ₄ H ₈ O); 57.20 (CH ₂ CH ₂ ).

Example 9. A mixture of 0.76 g (3.69 mmol) of N-benzyl-2-diethylaminoethylamine (5c) and 1.44 g (3.66 mmol) of N- [2- (2-n-toluenesulfonylethoxy) ethyl] phenoxyacetamide (4b) in 35 ml of acetonitrile in the presence of 1.86 g (18.35 mmol) of triethylamine is heated at the boil of the solvent for 60 hours (control with TLC, ethanol). Then, the solvent and triethylamine were distilled off under vacuum, and a mixture of Et ₂ O / H ₂ O (1: 1, 40 ml) was added to the residue. The organic layer was separated. The aqueous layer was washed with diethyl ether (3 × 20 ml). The extracts are combined, washed with saturated NaCl (3 × 20 ml) and dried over Na ₂ SO ₄ . The solvent was rotated off, the residue was dissolved in diethyl ether (40 ml), and a 3N HCl / dioxane solution was added to a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 1.2 g (66%) of N- (2- (2- (benzyl (2- (diethylamino) ethyl) amino) ethoxy) ethyl) phenoxyacetamide dihydrochloride are obtained in powder form (8). ¹ H NMR spectrum (DMSO-d ₆ ), 300.13 MHz, δ (ppm), J (Hz): 1.22 (t, 6H, 2CH ₃ , J = 7.2); 3.11-3.24 (m, 4H, 2CH ₂ N); 3.34-3.80 (m, 12H, 2CH ₂ O + 4CH ₂ N); 4.45 (s, 2H, NCH ₂ Ph); 4.53 (s, 2H, CH ₂ O); 76.9 (m, 3H, Ar); 7.28 (m, 2H, Ar); 7.44 (m, 3H, Ar); 7.74 (m, 2H, Ar); 8.48 (t, 1H, NH, J = 5.2); 11.29 (s, 1H, HN +); 11.62 (s, 1H, HN +). ¹³ C NMR spectrum (DMSO-d ₆ ), 75 MHz, δ (ppm): 8.32 (2CH ₃ ); 38.07 (CH ₂ N); 44.70 (CH ₂ N); 46.61 (2CH ₂ N, NEt ₂ ); 46.88 (CH ₂ N); 50.76 (CH ₂ N); 57.20 (CH ₂ N); 63.96 (CH ₂ O); 66.71 (CH ₂ O); 69.18 (CH ₂ O); 114.64 (2CH, Ar); 121.07 (CH, Ar); 128.79 (2CH, Ar); 129.43 (C + 2CH, Ar); 129.55 (CH, Ar); 131.58 (2CH, Ar); 157.69 (C, Ar); 167.83 (C = O). HRMS, m / z: Found 428.2888 [M-2Cl-H] +. C ₂₅ H ₃₉ N ₃ O ₃ Cl ₂ . Calculated M-2Cl-H = 428.2913.

Example 10. A mixture of 0.280 g (1.38 mmol) of N-benzyl-2-pyrrolidinoethylamine (5d) and 0.54 g (1.38 mmol) of N- [2- (2-n-toluenesulfonylethoxy) ethyl] phenoxyacetamide (4b ) in 20 ml of acetonitrile in the presence of 0.7 g (6.9 mmol) of triethylamine is heated at the boil of the solvent for 60 hours (control with TLC, ethanol). Then, the solvent and triethylamine were distilled off under vacuum, and a mixture of Et ₂ O / H ₂ O (1: 1, 20 ml) was added to the residue. The organic layer is separated. The aqueous layer was washed with diethyl ether (3 × 10 ml). The extracts are combined, washed with saturated NaCl solution (3 × 10 ml) and dried over Na ₂ SO ₄ . The solvent was distilled off on a rotor, the residue was dissolved in diethyl ether (20 ml), and a 3N HCl / dioxane solution was added to a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 0.48 g (70%) of N- (2- (2- (benzyl (2- (N'-pyrrolidino) ethyl) amino) ethoxy) ethyl) phenoxyacetamide dihydrochloride is obtained in the form of a powder (9). ¹ H NMR spectrum (CDCl ₃ ), 300.13 MHz, δ (ppm): 2.02 (m, 4H, 2CH ₂ ); 2.82-3.65 (m, 16H, CH ₂ O + 7CH ₂ N); 4.55 (s, 4H, 2CH ₂ O); 6.98-7.04 (m, 3H, Ar); 7.22-7.39 (m, 5H, Ar); 7.74 (m, 2H, Ar); 8.03 (s, 1H, NH); 11.88 (s, 1H, NH +); 12.06 (s, 1H, NH +). ¹³ C NMR spectrum (CDCl ₃ ), 75.47 MHz, δ (ppm): 23.28 (2CH ₂ ); 38.83 (CH ₂ N); 49.42 (CH ₂ N); 50.37 (CH ₂ N); 51.76 (CH ₂ N); 54.50 (2CH ₂ N); 59.79 (CH ₂ N); 64.62 (CH ₂ O); 67.36 (CH ₂ O); 70.32 (CH ₂ O); 114.89 (2CH, Ar); 121.82 (CH, Ar); 128.33 (C, Ar); 129.45 (2CH, Ar); 129.65 (2CH, Ar); 130.33 (CH, Ar); 131.56 (2CH, Ar); 157.47 (C, Ar); 168.72 (C = O).

Example 11. A mixture of 0.6 g (2.75 mmol) of N-benzyl-2-piperidinoethylamine (5e) and 1.41 g (3.6 mmol) of N- [2- (2-n-toluenesulfonylethoxy) ethyl] phenoxyacetamide (4b) in 25 ml of acetonitrile in the presence of 1.39 g (13.76 mmol) of triethylamine is heated at the boil of the solvent for 60 hours (control with TLC, ethanol). Then, the solvent and triethylamine were distilled off under vacuum, and a mixture of Et ₂ O / H ₂ O (1: 1, 30 ml) was added to the residue. The organic layer is separated. The aqueous layer was washed with diethyl ether (3 × 15 ml). The extracts are combined, washed with a saturated solution of NaCl (3 × 15 ml) and dried over Na ₂ SO ₄ . The solvent was distilled off on a rotor, the residue was dissolved in diethyl ether (30 ml), and a 3N HCl / dioxane solution was added to a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 1.05 g (75%) of N- (2- (2- (benzyl (2- (N'-piperidino) ethyl) amino) ethoxy) ethyl) phenoxyacetamide dihydrochloride are obtained in the form of a powder (10). ¹ H NMR spectrum (DMSO-d ₆ ), 300.13 MHz, δ (ppm), J (Hz): 1.38-1.77 (m, 6H, H _β + H _γ , NC ₅ H ₁₀ ); 2.93 (s, 2H, CH ₂ N); 3.23 (s, 2H, CH ₂ N); 3.35-3.79 (m, 12H, 2CH ₂ O + 4CH ₂ N); 4.43 (s, 2H, NCH ₂ Ph); 4.53 (s, 2H, CH ₂ O); 6.95 (m, 3H, 133 Ar); 7.29 (t, 2H, Ar, J = 7.9); 7.44 (m, 3H, Ar); 7.72 (m, 2H, Ar); 8.44 (t, 1H, NH, J = 5.4); 11.07 (s, 1H, HN +); 11.40 (s, 1H, HN +). ¹³ C NMR spectrum (DMSO-d ₆ ), 75 MHz, δ (ppm): 21.09 (C _γ , NC ₅ H ₁₀ ); 22.22 (2C _β , NC ₅ H ₁₀ ); 38.08 (CH ₂ N); 46.83 (CH ₂ N); 49.58 (CH ₂ N); 50.52 (CH ₂ N); 52.36 (2C _α , NC ₅ H ₁₀ ); 52.36 (2C _α , NC ₅ H ₁₀ ); 57.22 (CH ₂ N); 64.05 (CH ₂ O); 66.75 (CH ₂ O); 69.18 (CH ₂ O); 114.66 (2CH, Ar); 121.09 (CH, Ar); 128.77 (2CH, Ar); 129.44 (C + 3CH, Ar); 129.52 (CH, Ar); 131.62 (2CH, Ar); 157.69 (C, Ar); 167.84 (C = O). HRMS, m / z: Found 440.2884 [M-2Cl-H] +. C ₂₆ H ₃₉ N ₃ O ₃ Cl ₂ . Calculated M-2Cl-H = 440.2913.

Example 12. A mixture of 0.64 g (2.9 mmol) of N-benzyl-2-morpholinoethylamine (5f) and 1.13 g (2.9 mmol) of N- [2- (2-n-toluenesulfonylethoxy) ethyl] phenoxyacetamide (4b) in 25 ml of acetonitrile in the presence of 1.47 g (14.56 mmol) of triethylamine is heated at the boil of the solvent for 60 hours (control with TLC, ethanol). Then, the solvent and triethylamine were distilled off under vacuum, and a mixture of Et ₂ O / H ₂ O (1: 1, 30 ml) was added to the residue. The organic layer is separated. The aqueous layer was washed with diethyl ether (3 × 15 ml). The extracts are combined, washed with a saturated solution of NaCl (3 × 15 ml) and dried over Na ₂ SO ₄ . The solvent was distilled off on a rotor, the residue was dissolved in diethyl ether (30 ml), and a 3N HCl / dioxane solution was added to a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 0.64 g (43%) of N- (2- (2- (benzyl (2-morpholinoethyl) amino) ethoxy) ethyl) phenoxyacetamide dihydrochloride are obtained in the form of a powder (11). ¹³ C NMR Spectrum (CDCl ₃ ), 75.47 MHz, δ (ppm): 38.66 (CH ₂ N); 48.08 (CH ₂ N); 51.12 (CH ₂ N); 51.90 (CH ₂ N); 52.24 (2CH ₂ N, NC ₄ H ₈ O); 59.32 (CH ₂ N); 63.48 (2CH ₂ O, NC ₄ H ₈ O); 64.54 (CH ₂ O); 67.12 (CH ₂ O); 70.07 (CH ₂ O); 114.26 (2CH, Ar); 121.80 (CH, Ar); 128.62 (C, Ar); 129.29 (2CH, Ar); 129.61 (2CH, Ar); 130.19 (CH, Ar); 131.50 (2CH, Ar); 157.33 (C, Ar); 168.80 (C = O).

Example 13. N- [2- (2-n-toluenesulfonylethoxy) ethyl] phenoxyacetamide (4b) (3.93 g, 0.01 mol) and piperidine (5a) (4.25 g, 0.05 mol) are boiled in 50 ml of xylene for 35 hours until the disappearance of the original tosyl derivative (TLC control, acetone). The solvent and the starting amine were distilled off in vacuo, the residue was dissolved in diethyl ether, and a 3N HCl / dioxane solution was added until a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 1.97 g (58%) of N- (2- (2-piperidinoethoxy) ethyl) phenoxyacetamide hydrochloride are obtained (12). ¹ H NMR Spectrum (CDCl ₃ ): δ 11.49 (brds, 1H, HCl); 7.81 (brds, 1H, NH); 7.21 (t, 2H, H _m , Ph); 6.83 (t, 1H, H _p , Ph); 6.80 (d, 2H, H _o , Ph); 4.45 (s, 2H, CH ₂ CO); 3.54 (m, 2H, CH ₂ CH ₂ ); 3.50 (m, 2H, CH ₂ CH ₂ ); 3.43 (m, 2H, CH ₂ CH ₂ ); 3.33 (m, 2H, CH ₂ CH ₂ ); 2.32 (m, 4H, NC ₅ H ₁₀ ); 1.80 (m, 2H, NC ₅ H ₁₀ ). ¹³ C NMR Spectrum: 175.90 (CO); 161.78 (C _i ); 133.19 (C _m ); 125.63 (C _p ); 118.97 (C _o ); 74.01 (CH ₂ CO); 73.25 (CH ₂ CH ₂ ); 71.89 (CH ₂ CH ₂ ); 71.03 (CH ₂ CH ₂ ); 62.80 (NC ₅ H ₁₀ ); 57.59 (CH ₂ CH ₂ ); 41.37 (NC ₅ H ₁₀ ); 23.07 (NC ₅ H ₁₀ ).

Example 14. N- [2- (2-n-toluenesulfonyl-ethoxy) ethyl] phenoxyacetamide (4b) (3.93 g, 0.01 mol) and morpholine (5b) (4.35 g, 0.05 mol) boil in 50 ml of xylene for 28 hours until the initial tosyl derivative disappears (TLC control, acetone). The solvent and the starting amine were distilled off in vacuo, the residue was dissolved in diethyl ether, and a 3N HCl / dioxane solution was added until a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 2.17 g (63%) of N- (2- (2-morpholinoethoxy) ethyl) phenoxyacetamide hydrochloride are obtained (13). ¹ H NMR Spectrum (CDCl ₃ ): δ 11.50 (br s, 1H, HCl); 7.84 (brd s, 1H, NH); 7.19 (t, 2H, H _m , Ph); 6.83 (m, 3H, H _p + H _o , Ph); 4.10 (s, 2H, CH ₂ CO); 3.55 (m, 2H, NC ₄ H ₈ O); 3.51 (m, 2H, CH ₂ CH ₂ ); 3.45 (m, 2H, CH ₂ CH ₂ ); 3.32 (m, 2H, CH ₂ CH ₂ ); 2.46 (m, 2H, CH ₂ CH ₂ ); 2.40 (m, 2H, NC ₄ H ₈ O). ¹³ C NMR Spectrum: 176.29 (CO); 164.10 (C _i ); 134.31 (C _m ); 124.97 (s _p ); 119.72 (C _o ); 73.89 (CH ₂ CO); 73.12 (NC ₄ H ₈ O); 72.58 (CH ₂ CH ₂ ); 71.78 (CH ₂ CH ₂ ); 71.43 (CH ₂ CH ₂ ); 62.84 (CH ₂ CH ₂ ); 58.93 (NC ₄ H ₈ O).

Example 15. A mixture of 0.76 g (3.69 mmol) of N-benzyl-N- (2-diethylaminoethyl) amine (5c) and 1.7 g (3.69 mmol) of N- [2- (2-n- toluene-sulfonylethoxy) ethyl] -2,4-dichlorophenoxyacetamide (4c) in 30 ml of acetonitrile in the presence of 1.87 g (18.5 mmol) of triethylamine is heated at the boiling point of the solvent for 60 hours (TLC control, ethanol). Then, the solvent and triethylamine were distilled off under vacuum, and a mixture of Et ₂ O / H ₂ O (1: 1, 40 ml) was added to the residue. The organic layer is separated. The aqueous layer was washed with diethyl ether (3 × 20 ml). The extracts are combined, washed with saturated NaCl (3 × 20 ml) and dried over Na ₂ SO ₄ . The solvent was rotated off, the residue was dissolved in diethyl ether (40 ml), and a 3N HCl / dioxane solution was added to a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 1.64 g (78%) of N- (2- (2- (benzyl (2- (diethylamino) ethyl) amino) ethoxy) ethyl) -2,4-dichlorophenoxyacetamide dihydrochloride are obtained in powder form (14). ¹ H NMR spectrum (CDCl ₃ ), 300.13 MHz, δ (ppm), J (Hz): 1.35 (t, 6H, 2CH ₃ , J = 5.4; 3.17 (m, 4H, 2CH ₂ N); 3.41 -3.80 (m, 12H, 2CH ₂ O + 4CH ₂ N); 4.56 (m, 2H, NCH ₂ Ph); 4.65 (s, 2H, CH ₂ O); 6.95 (d, 1H, H (6), Ar , 3 J = 8.6); 7.17 (dd, 1H, H (5), Ar, 4 J = 2.4, 3 J = 8.6); 7.32 (d, 1H, H (3), Ar, 4 J = 2.4); 7.75 (m, 2H, Ar); 7.40 (m, 3H, Ar); 7.86 (s, 1H, NH); 11.77 (s, 1H, HN +); 11.92 (s, 1H, HN +). ¹³ C NMR spectrum ( CDCl ₃ ), 75 MHz, δ (ppm): 8.74 (2CH ₃ ); 38.30 (CH ₂ N); 46.90 (2CH ₂ N, NEt ₂ ); 47.84 (CH ₂ N); 49.09 (CH ₂ N) ; 52.00 (CH ₂ N); 59.77 (CH ₂ N); 64.70 (CH ₂ O); 68.54 (CH ₂ O); 70.13 (CH ₂ O); 115.34 (CH, Ar); 123.57 (C-Cl, Ar ); 126.99 (C-Cl, Ar); 127.89 (CH, Ar); 129.38 (2CH, Ar); 129.89 (C + CH, Ar); 130.29 (CH, Ar); 131.47 (2CH, Ar); 152.10 ( C, Ar); 167.80 (C = O). HRMS, m / z: Found 496.2103 [M-2Cl-H] +. C ₂₅ H ₃₇ N ₃ O ₃ Cl _4. Calculated M-2Cl-H = 496.2134.

Example 16. A mixture of 1.8 g (8.82 mmol) of N-benzyl-N- (2-pyrrolidinoethyl) amine (5d) and 4.07 g (8.83 mmol) of N- [2- (2-n- toluene-sulfonylethoxy) ethyl] -2,4-dichlorophenoxyacetamide (4c) in 80 ml of acetonitrile in the presence of 4.46 g (44.15 mmol) of triethylamine is heated at the boiling point of the solvent for 60 hours (TLC control, ethanol). Then, the solvent and triethylamine were distilled off under vacuum, and a mixture of Et ₂ O / H ₂ O (1: 1, 80 ml) was added to the residue. The organic layer is separated. The aqueous layer was washed with diethyl ether (3 × 40 ml). The extracts are combined, washed with saturated NaCl (3 × 40 ml) and dried over Na ₂ SO ₄ . The solvent is rotated off, the residue is dissolved in diethyl ether (80 ml) and a 3N HCl / dioxane solution is added to a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 2.43 g (49%) of N- (2- (2- (benzyl (2-pyrrolidinoethyl) amino) ethoxy) ethyl) -2,4-dichlorophenoxyacetamide dihydrochloride are obtained in powder form (15). ¹ H NMR spectrum (DMSO-d ₆ ), 300.13 MHz, δ (ppm), J (Hz): 1.98 (m, 4H, 2CH ₂ , NC ₄ H ₈ ); 3.05 (m, 2H, CH ₂ N); 3.24 (m, 2H, CH ₂ N); 3.33-3.67 (m, 12H, 2CH ₂ O + 4CH ₂ N); 4.52 (m, 2H, NCH ₂ Ph); 4.72 (s, 2H, CH ₂ O); 7.08 (d, 1H, H (6), Ar, 3 J = 9); 7.36 (dd, 1H, H (5), Ar, 4 J = 2.6, 3 J = 9); 7.44 (m, 3H, Ar); 7.57 (d, 1H, H (3), Ar, 4 J = 2.6); 7.72 (m, 2H, Ar); 8.44 (t, 1H, NH, J = 5.1); 11.44 (s, 2H, 2HN +). ¹³ C NMR spectrum (DMSO-d ₆ ), 75 MHz, δ (ppm): 22.64 (2CH ₂ , NC ₄ H ₈ ); 38.21 (CH ₂ N); 47.39 (CH ₂ N); 47.97 (CH ₂ N); 50.76 (CH ₂ N); 53.05 (2CH ₂ N, NC ₄ H ₈ ); 57.19 (CH ₂ N); 64.00 (CH ₂ O); 67.63 (CH ₂ O); 69.16 (CH ₂ O); 115.31 (CH, Ar); 122.41 (C-Cl, Ar); 124.93 (C-Cl, Ar); 127.99 (CH, Ar); 128.79 (2CH, Ar); 129.29 (C + CH, Ar); 129.53 (CH, Ar); 131.55 (2CH, Ar); 152.55 (C, Ar); 167.03 (C = O). 135 HRMS, m / z: Found 494.1952 [M-2Cl-H] +. C ₂₅ H ₃₅ N ₃ O ₃ Cl ₄ . Calculated M-2Cl-H = 494.1977.

Example 17. A mixture of 0.7 g (3.2 mmol) of N-benzyl-N- (2-piperidinoethyl) amine (5e) and 1.48 g (3.2 mmol) of N- [2- (2-n- toluene-sulfonylethoxy) ethyl] -2,4-dichlorophenoxyacetamide (4c) in 25 ml of acetonitrile in the presence of 1.62 g (16.0 mmol) of triethylamine is heated at the boiling point of the solvent for 60 hours (control with TLC, ethanol). Then, the solvent and triethylamine were distilled off under vacuum, and a mixture of Et ₂ O / H ₂ O (1: 1, 30 ml) was added to the residue. The organic layer is separated. The aqueous layer was washed with diethyl ether (3 × 15 ml). The extracts are combined, washed with a saturated solution of NaCl (3 × 15 ml) and dried over Na ₂ SO ₄ . The solvent was distilled off on a rotor, the residue was dissolved in diethyl ether (30 ml), and a 3N HCl / dioxane solution was added to a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 1.3 g (70%) of N- (2- (2- (benzyl (2-piperidino) ethyl) amino) ethoxy) ethyl) -2,4-dichlorophenoxyacetamide dihydrochloride are obtained in powder form (16). NMR spectrum ^l H (CDCl ₃ ), 500 MHz, δ (ppm) J (Hz): 1.40-2.07 (m, 6H, H _β + H _γ , NC ₅ H ₁₀ ); 2.90 (br s, 2H, H _α , NC ₅ H ₁₀ ); 3.38-3.45 (m, 4H, 2H _α in NC ₅ H ₁₀ + CH ₂ N); 3.57-4.13 (s, 10H, 2CH ₂ O + 3CH ₂ N); 4.42-4.57 (m, 2H, CH ₂ Ph); 4.68 (d, 2H, CH ₂ CO); 6.98 (d, 1H, H (6), Ar, 3 J = 8.9), 7.20 (dd, 1H, H (5), Ar, 4 J = 2.5, 3 J = 8.9); 7.35 (d, 1H, H (3), Ar, 4 J = 2.5); 7.43 (m, 3H, Ar); 7.73 (m, 2H, Ar); 7.78 (s, 1H, NH); 11.78 (s, 1H, HN +); 12.01 (s, 1H, HN +). ¹³ C NMR spectrum (CDCl ₃ ), 125 MHz, δ (ppm): 23.08 (Cr, NC ₅ H ₁₀ ); 24.14 (2C _β , NC ₅ H ₁₀ ); 40.21 (CH ₂ N); 50.04 (CH ₂ N); 52.57 (CH ₂ N); 53.39 (CH ₂ N); 54.94 (2C _α , NC ₅ H ₁₀ ); 61.30 (CH ₂ Ph); 66.19 (CH ₂ O); 70.19 (CH ₂ O); 71.67 (CH ₂ O); 117.03 (CH, Ar); 125.21 (C-Cl, Ar); 128.64 (C-Cl, Ar); 129.42 (CH, Ar); 130.91 (2CH, Ar); 131.43 (C + CH, Ar); 131.81 (CH, Ar); 132.93 (2CH, Ar); 153.63 (C, Ar); 169.31 (CO). MS / MS, m / z: 509.08 (100) [M-2Cl] +, 207 (21), 134 (8), 112 (10).

Example 18. A mixture of 0.71 g (3.2 mmol) of N-benzyl-N- (2-morpholinoethyl) amine (5f) and 1.47 g (3.2 mmol) of N- [2- (2-n- toluene-sulfonylethoxy) ethyl] -2,4-dichlorophenoxyacetamide (4c) in 30 ml of acetonitrile in the presence of 1.62 g (16.0 mmol) of triethylamine is heated at the boiling point of the solvent for 60 hours (control with TLC, ethanol). Then, the solvent and triethylamine were distilled off under vacuum, and a mixture of Et ₂ O / H ₂ O (1: 1, 30 ml) was added to the residue. The organic layer is separated. The aqueous layer was washed with diethyl ether (3 × 15 ml). The extracts are combined, washed with a saturated solution of NaCl (3 × 15 ml) and dried over Na ₂ SO ₄ . The solvent was distilled off on a rotor, the residue was dissolved in diethyl ether (30 ml), and a 3N HCl / dioxane solution was added to a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 1.3 g (72%) of N- (2- (2- (benzyl (2-morpholino) ethyl) amino) ethoxy) ethyl) -2,4-dichlorophenoxyacetamide dihydrochloride are obtained in powder form (17). ¹ H NMR spectrum (CDCl ₃ ), 300.13 MHz, δ (ppm), J (Hz): 3.01-3.97 (m, 20H, 4CH ₂ O + 6CH ₂ N); 4.56 (d, 2H, NCH ₂ Ph); 4.63 (s, 2H, CH ₂ O); 6.93 (d, 3 J = 8.5, 136 1H, H (6), Ar); 7.18 (dd, 1H, H (5), Ar, 4 J = 2.15, 3 J = 8.5); 7.32 (d, 1H, H (3), Ar, 4 J = 2.1); 7.38 (m, 3H, Ar); 7.71 (m, 3H, NH + 2H (Ar)); 11.63 (s, 1H, HN +); 12.27 (s, 1H, HN +). ¹³ C NMR spectrum (CDCl ₃ ), 75 MHz, δ (ppm): 38.71 (CH ₂ N); 47.17 (CH ₂ N); 47.65 (CH ₂ N); 48.18 (CH ₂ N); 52.05 (2CH ₂ N, NC ₄ H ₈ O); 59.53 (CH ₂ N); 63.54 (2CH ₂ O, NC ₄ H ₈ O); 64.78 (CH ₂ O); 68.55 (CH ₂ O); 70.20 (CH ₂ O); 115.33 (CH, Ar); 123.56 (C-Cl, Ar); 127.12 (C-Cl, Ar); 127.96 (CH, Ar); 129.37 (2CH, Ar); 129.93 (C + CH, Ar); 130.27 (CH, Ar); 131.53 (2CH, Ar); 151.92 (C, Ar); 167.88 (C = O). HRMS, m / z: Found 510.1893 [M-2Cl-H] +. C ₂₅ H ₃₅ N ₃ O ₄ Cl ₄ . Calculated M-2Cl-H = 510.1926.

Example 19. N- [2- (2-n-toluenesulfonylethoxy) ethyl] -2,4-dichlorophenoxyacetamide (4c) (4.62 g, 0.01 mol) and piperidine (5a) (4.25 g, 0, 05 mol) is boiled in 50 ml of xylene for 25 hours until the initial tosyl derivative disappears (TLC control, acetone). The solvent and the starting amine were distilled off in vacuo, the residue was dissolved in diethyl ether, and a 3N HCl / dioxane solution was added until a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 2.42 g (59%) of N- (2- (2-piperidinoethoxy) ethyl) -2,4-dichlorophenoxyacetamide hydrochloride are obtained (18). ¹ H NMR Spectrum (DMSO + CCl ₄ ): δ 11.52 (brds, 1H, HCl); 7.75 (brds, 1H.NH); 7.41 (m, 1H, H _m Ph); 7.27 (m, 1H, H _m Ph); 7.05 (m, 1H, H _o Ph); 4.58 (s, 2H, CH ₂ CO); 3.53 (m, 2H, CH ₂ CH ₂ ); 3.50 (m, 2H, CH ₂ CH ₂ ); 3.48 (m, 2H, CH ₂ CH ₂ ); 3.35 (m, 2H, CH ₂ CH ₂ ); 2.45 (m, 4H, NC ₅ H ₁₀ ); 2.4 (m, 4H, NC ₅ H ₁₀ ); 1.56 (m, 2H, NC ₅ H ₁₀ ). ¹³ C NMR Spectrum: 166.48 (CO); 152.24 (C _i ); 129.22, 127.78 (C _m ); 125.50 (C _p -Cl); 122.80 (C _o -Cl); 115.31 (C _o ); 68.88 (CH ₂ CO); 68.21 (CH ₂ CH ₂ ); 67.91 (CH ₂ CH ₂ ); 58.00 (CH ₂ CH ₂ ); 54.51 (NC ₅ H ₁₀ ); 38.34 (CH ₂ CH ₂ ); 25.48,23.94 (NC ₅ H ₁₀ ).

Example 20. N- [2- (2-n-toluenesulfonylethoxy) ethyl] 2,4-dichlorophenoxyacetamide (4c) (4.62 g, 0.01 mol) and morpholine (5b) (4.35 g, 0.05 mol) is boiled in 50 ml of xylene for 37 hours until the initial tosyl derivative disappears (TLC control, acetone). The solvent and the starting amine were distilled off in vacuo, the residue was dissolved in diethyl ether, and a 3N HCl / dioxane solution was added until a constant pH = 2. The precipitate was washed with diethyl ether (3 × 10 ml) and dried in vacuo. 2.76 g (67%) of N- (2- (2-morpholinoethoxy) ethyl) -2,4-dichlorophenoxy-acetamide hydrochloride are obtained (19). ¹ H NMR Spectrum (DMSO + CCl ₄ ): δ 11.50 (br s, 1H, HCl); 7.73 (brs s, 1H, NH); 7.48 (s, 1H, H _m , Ph); 7.33 (d, 1H, H _m , Ph); 7.10 (d, 1H, H _o , Ph); 4.50 (s, 2H, CH ₂ CO); 3.60 (m, 2H, CH ₂ CH ₂ ); 3.50 (m, 2H, CH ₂ CH ₂ ); 3.47 (m, 2H, CH ₂ CH ₂ ); 3.30 (m, 2H, CH ₂ CH ₂ ); 2.56 (m, 4H, NC ₄ H ₈ O); 1.93 (m, 4H, NC ₄ H ₈ O). ¹³ C NMR Spectrum: 166.93 (CO); 152.48 (C _i ); 129.35, 127.84 (C _m ); 125.63 (C _p -Cl); 122.73 (C _o -Cl); 115.20 (C _o ); 71.04 (CH ₂ CO); 69.27 (NC ₄ H ₈ ); 68.51 (CH ₂ CH ₂ ); 67.23 (CH ₂ CH ₂ ); 65.48 (CH ₂ CH ₂ ); 38.34 (CH ₂ CH ₂ ); 34.25 (NC ₄ H ₈ O).

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

Antiarrhythmic properties of substances were evaluated in parallel on various models of heart rhythm disturbances, in which arrhythmias arise and are supported by various mechanisms. The models used were aconitine (aconitine hydrobromide at doses of 40-50 μg / kg), calcium chloride (CaCl ₂ at a dose of 200-250 mg / kg) and barium chloride (BaCl ₂ at a dose of 25 mg / kg) in Wistar rats (males and females, body weight 180-240 g). The effectiveness of the antiarrhythmic action of the compounds is characterized by the ability to prevent the development of arrhythmias or stop the already developed arrhythmias, facilitate their flow and restore normal sinus rhythm.

Studies of the toxicity and antiarrhythmic activity of the claimed compounds were performed on 380 Balb / c mice (males and females, body weight 18-20 g), 760 Wistar rats (males and females, body weight 180-240 g).

Animals were kept in accordance with the norms of group accommodation in natural light with forced 16-fold ventilation at a temperature of 18-20 ° C and relative humidity of 40-70%. Animals had free access to drinking water and standard (GOST R50258-92) granulated feed PK 120-1 (LLC Laboratsnab, Russia). The conditions of the animals were in accordance with the order of the Ministry of Health of the Russian Federation No. 199n “On the approval of the rules of good laboratory practice” dated 01.04.2016 and the ethical standards set forth in the Laboratory Practice Rules (GLP) of the Helsinki Declaration (2000). All research work with laboratory animals was carried out in accordance with generally accepted standards for the treatment of animals, which comply with the rules adopted by the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific purposes, Strasbourg, March 18, 1986].

The study of the antiarrhythmic properties of the first synthesized compounds was preceded by a study of their acute toxicity in Balb / c mice (males and females, body weight 18-22 g) with a single intraperitoneal administration. At stage I, according to the method of [Deichmann WB, LeBlanc TJ Determination of the approximate lethal dose with about six animals / Journal of Industrial Hygiene and Toxicology, 1943, V. 25, pp. 415-417] in a small number of animals (5-7), indicative LD ₅₀ values were determined. At the second stage, a detailed experiment established the exact value of toxicometry parameters using the Litchfield and Wilcoxon probit analysis method (detailed experiment on three groups of animals, 5-6 animals each, with doses above and below the established approximate LD ₅₀ ). Observation of animals was carried out for 14 days after administration of substances. Regularly fixed the general condition, behavior and motor activity, recorded the timing of the development of intoxication and death of animals. Acute toxicity indices LD ₁₀ , LD ₁₆ , LD _{50 ± m} , LD _{84 were} determined using the Litchfield and Wilcoxon probit analysis method [Litchfield J.T., Wilcoxon FA simplified method of evaluating dose-effect experiments / Journal of Pharmacology and Experimental Therapeutics, 1949, V. 96, N. 2, pp. 99-113; Belenky M.L. Elements of a quantitative assessment of the pharmacological effect / 2nd ed., Revised. and add. - Leningrad: Medgiz, 1963. - 146 p.]. As the studies showed, the studied compounds were found to be toxic with a single intraperitoneal injection of BALB / c mice. Moreover, the LD ₅₀ values were in the range of 104-822 mg / kg. The experimental results are presented in table 3.

Antiarrhythmic drugs known and widely used in medical practice were used as reference drugs: amiodarone (Kordaron Sanofi-Aventis France), propranolol (Anaprilin Tatkhimpharmpreparaty), verapamil (Alkaloid rep. Macedonia), novokainamide (Moskhimpharmpreparat N. . Semashko).

The antiarrhythmic activity of the compounds was evaluated by the value of the average effective dose (ED ₅₀ ), which prevents or removes heart rhythm disturbances, the antiarrhythmic index (AI) and the Schneider-Brock index (LD ₁₀ / ED ₉₀ ). The latter allows you to more accurately characterize the pharmacological activity of drugs, therapeutic breadth and prospects of creating drugs based on them [Arzamastsev E.V. The safety of drugs at the stage of screening and preclinical toxicological studies / Lab. Zhyvotnye, 1991, V. 1, N. 2, pp. 60-64]. The indicated parameters of efficacy and toxicity were established by the method of probit analysis according to the method of Litchfield and Wilcoxon [Litchfield J.T., Wilcoxon FA simplified method of evaluating dose-effect experiments / Journal of Pharmacology and Experimental Therapeutics, 1949, V. 96, N. 2, pp. 99-113].

Aconitine model of arrhythmia in Wistar rats. The experiments on the initial assessment of antiarrhythmic activity were performed on a model of aconitine arrhythmia in Wistar rats anesthetized with urethane (ip, 1300 mg / kg). Intravenous administration of aconitine hydrobromide at a dose of 40-50 μg / kg causes ventricular extrasystole, which quickly turns into tachysystole, flutter, flicker and fibrillation of the ventricles, leading to animal death in more than 90% of cases, and continues in the absence of ventricular fibrillation on average 49. 3 ± 10.4 minutes [Szekeres L. Experimental models for the study of antiarrhythmic agents / Progr. mPharmacol, 1979, V. 2, N. 4, pp. 25-31]. The electrocardiogram is shown in FIG. 1A.

Anesthetized animals (Wistar rats, males and females weighing 180-240 g) (urethane 1300 mg / kg, ip) were fixed in the supine position on the operating table, the femoral vein was catheterized for administration of aconitine and the studied compounds. Before the experiment, an ECG was recorded in animals (II standard lead, calibration signal 10 mm / mV, recording speed 25 mm / s). The cardiograph CARDIOVITAT-1 VETSchiller (Switzerland) was used as a registrar. Then, a dose of aconitine (n = 10, iv, bolus) was selected, which in all experiments within 1-2 minutes after the end of its administration causes polytopic atrial ventricular extrasystole. The studied compounds were administered in doses of 1 / 10-1 / 100 from LD ₅₀ for mice with intraperitoneal administration, comparison drugs in effective antiarrhythmic doses. ECG was recorded 3, 5, 10, 15, and 20 minutes after the administration of aconitine. Each dose of the test compounds was tested in 5-10 animals.

The effectiveness of the antiarrhythmic action of the compounds was evaluated by the latent period, by the duration of arrhythmia or its prevention. At the end of the experiment, the average effective dose of the compound — ED ₅₀ — was calculated by the Litchfield and Wilcoxon probit analysis method. To evaluate the effectiveness of the antiarrhythmic action of the studied compounds and comparison preparations, the antiarrhythmic index (LD ₅₀ / ED ₅₀ ) and the Schneider-Brock index (LD ₉₀ / ED ₉₀ ) were used. On the basis of 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 the studied compounds in the range of tested doses of 1 / 100-1 / 10 from LD ₅₀ (for mice with intraperitoneal administration) led to 30-100% survival of animals on the model of aconitine arrhythmia. The inventive compounds in the tested doses increased the duration of the latent period of development of aconitine arrhythmia or completely prevented it. Cardiograms are shown in FIG. 1-3.

The high antiarrhythmic activity of the claimed compounds is confirmed by another criterion used - the percentage of recorded arrhythmias (table 4). The use of this criterion indicates the pronounced antiarrhythmic properties of the claimed compounds. In rat aconitin arrhythmias, a number of the claimed compounds in doses up to 6 mg / kg (compounds (12), (6), (18)) in 50-100% of cases relieves arrhythmias caused by the introduction of aconitine hydrobromide. The lowest average effective doses (ED ₅₀ ) are characterized by compounds (12), (17), (18).

The pronounced antiarrhythmic properties of the claimed compounds, identified on the model of aconitine arrhythmia, were also confirmed on the models of barium chloride and calcium chloride arrhythmia. Electrocardiograms are shown in FIG. 2, 3.

Barium chloride model of arrhythmia in Wistar rats. Intravenous administration of barium chloride at a dose of 25 mg / kg to anesthetized rats (urethane 1300 mg / kg intraperitoneally) causes polytopic ventricular arrhythmia caused by impaired cardiac automatism, a change 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, it is observed for 42.7 ± 5.2 minutes, after which restoration of the sinus rhythm is observed or in 85% of cases the death of animals is noted. A typical electrocardiogram is shown in FIG. 2A.

Calcium chloride model of arrhythmia in Wistar rats. Calcium chloride induced heart rhythm disturbances (200-250 mg / kg) were obtained with iv in the form of a 10% solution. At the same time, after 30 sec - 1 min fibrillation of the ventricles of the heart occurred. The test compounds and the comparison drug (verapamil) were administered iv 1-2 minutes before the administration of calcium chloride. The ECG was recorded in the II standard lead, 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 latent period before the onset of arrhythmia is 7.5 ± 1.2 seconds, the duration of the arrhythmia is 18 ± 7 minutes. The antiarrhythmic effect was judged by a decrease in the number of cases of lethal ventricular fibrillation of the heart.

A typical electrocardiogram is shown in FIG. 3A.

Such an indicator as the antiarrhythmic index (LD ₅₀ / ED ₅₀ ratio), characterizing the breadth of the therapeutic effect of drugs, for a number of the claimed compounds exceeds 100 and amounts to 718 and 112 for compounds (12) and (17), respectively.

Electrocardiograms of rats with cardiac abnormalities caused by aconitine hydrobromide, barium chloride and calcium chloride are shown as illustrations in graphical images (Figs. 1-3).

The first synthesized N- (2- (2- (dialkylamino) ethoxy) ethyl) carboxamides and their hydrochlorides are low toxic compounds. The data obtained in the experiments indicate the pronounced antiarrhythmic properties and noticeable advantages of the claimed compounds. Compared with the known antiarrhythmics, the compounds have less toxicity, large therapeutic indices (LD ₅₀ / ED ₅₀ and LD ₁₀ / ED ₉₀ ) - the most important indicators necessary for further study and the prospects of clinical trials, and practical use as medicines for prevention and treatment heart rhythm disturbances.

Thus, the studies showed that the claimed aminoamides are low toxic substances, have pronounced antiarrhythmic properties, not inferior in terms of effectiveness to the currently used drugs amiodarone, verapamil and propranolol. The inventive compounds are drugs of combined action and are promising for the development on their basis of new highly effective and safe drugs for the treatment and prevention of heart rhythm disorders.

Claims (10)

1. Compounds exhibiting antiarrhythmic activity and represented by the General formula

where when R = C ₆ H ₅ and n = 0, then NR ¹ ₂ = NC ₅ H ₁₀ or NC ₄ H ₈ O; when R = C ₆ H ₅ OCH ₂ , an = 1, then NR ¹ ₂ = N (C ₂ H ₅ ) ₂ , NC ₄ H ₈ , NC ₅ H ₁₀ or NC ₄ H ₈ O; when R = C ₆ H ₅ OCH ₂ , an = 0, then NR ¹ ₂ = NC ₅ H ₁₀ or NC ₄ H ₈ O; when R = 2,4-Cl ₂ -C ₆ H ₃ OCH ₂ , and n = 1, then NR ¹ ₂ = N (C ₂ H ₅ ) ₂ , NC ₄ H ₈ , NC ₅ H ₁₀ or NC ₄ H ₈ O; when R = 2,4-Cl ₂ -C ₆ H ₃ OCH ₂ , and n = 0, then NR ¹ ₂ = NC ₅ H ₁₀ or NC ₄ H ₈ O, wherein NC ₄ H ₈ is pyrrolidino, NC ₅ H ₁₀ is piperidino, NC ₄ H ₈ O is morpholino. 2. A drug with antiarrhythmic activity, including as an active agent compounds according to claim 1. 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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