RU2547096C2 - N-[2-(adamant-2-yl)aminocarbonylmethyl]-n'-(dialkylamino)alkylnitrobenzamides possessing antiarhythmic activity - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new N-[2-(adamant-2-yl)aminocarbonylmethyl]-N'-(dialkylamino)alkylnitrobenzamide of general formula

and their physiologically acceptable salts, preferentially hydrochlorides, which possess antiarhythmic action. In formula I, R can be hydrogen, alkyl (C₁-C₆) or cycloalkyl; R¹ can be hydrogen or aliphatic residue (C₁-C₂); R² can be alkyl (C₁-C₂) or saturated heterocycle together with nitrogen with one or two heteroatoms, such as morpholine, pyrrolidine, piperidine; "n" can have a value of 2 or 3; a nitro group in benzamide can be found in any position of the cycle.

EFFECT: invention refers to a method for preparing the compounds of general formula I, specific compounds of formula I, as well as to using them antiarhythmic, particularly antifibrillation agents.

8 cl, 11 tbl, 5 ex

Description

The invention relates to the field of chemistry and relates to new biologically active compounds with antiarrhythmic activity, General formula I:

.where R is hydrogen, alkyl (C ₁ -C ₆ ) or cycloalkyl; R ¹ may be hydrogen or an aliphatic residue (C ₁ -C ₂ ); R ² may be alkyl (C ₁ -C ₂ ) or together with a nitrogen saturated heterocycle with one or two heteroatoms, such as, for example, morpholine, pyrrolidine, piperidine; "n" may be 2 or 3; the nitro group in benzamide can be in any (o-, m-, n-) position of the cycle and their physiologically acceptable salts with mineral and organic acids, preferably in the form of hydrochlorides of the formula

.

The inventive compounds exhibit high antiarrhythmic activity.

One of the urgent problems of pharmacology remains the search and study of the mechanism of action of effective antiarrhythmic drugs. This is due to the fact that arrhythmias often cause sudden death and cause dangerous complications from various body systems. Despite the fact that in recent years surgical methods have been proposed for the treatment of arrhythmias, implantation of pacemakers, the use of defibrillators, pharmacological correction remains the main approach in the treatment and prevention of arrhythmias, as well as the complications arising from this. It should be emphasized that in clinical practice in the treatment of cardiac arrhythmias, combination therapy is most often used, including antiarrhythmics of various classes [Nedostup A.V., Blagova O.V. The principles of combined antiarrhythmic therapy. Russian honey. Journal 2005, No. 11, pp. 767-774; Nedostup A.V. Issues of treatment strategy for cardiac arrhythmias. Russian honey. Journal of Cardiology, 2008, v.16, No. 6, pp. 431-435].

Treatment of arrhythmias is a very difficult task, often not having a unique solution. Existing antiarrhythmic drugs often have limited effectiveness and serious side effects, including proarrhythmogenic, which is especially dangerous for patients with existing cardiac pathology. The substances related to different classes of chemical compounds and various pharmacological groups have a normalizing effect on the disturbed rhythm of heart contractions.

Numerous studies in recent years have shown that, in some cases, class III drugs according to the classification of E.Vaughan-Williams are effective drugs for certain types of arrhythmias, such as atrial fibrillation. Currently, extensive clinical trials are being conducted on niferidil-antiarrhythmic class III - a structural analogue of nibentan [Glushkov R.G., Yuzhakov S.D., Lvov A.I. et al., Chemical and Pharmaceutical Journal, 2011, vol. 45, No. 2, pp. 3-12; Mironov N.Yu., Golitsyn S.P., Sokolov S.F. et al. Electrophysiological effects and antiarrhythmic activity of a new domestic antiarrhythmic drug of class III niferidil in patients with paroxysmal supraventricular tachycardia. Experiment and wedge. pharmacol., 2012, t. 75, No. 10, p. 78-83; Savelieva I. J. Camm. Europace, 2008, v. 10, No. 6, p. 646-665; Wulf H., Castle N.A., Pardo L.A. et al. Rev. Drug Discov., 2009, v. 8, No. 12, 982-1001].

However, existing drugs of this class, such as sotalol, amiodarone, nibentan, have a number of negative effects, including proarrhythmogenic [Mashkovsky M.D. Medicines, Moscow, New Wave Publishing House, 2000; Pollard S.E. et al. Br.J. Pharmacol., 2010, v. 159, N1, p.12-21]. In addition, class III antiarrhythmic drugs to one degree or another possess the properties of class I, II, and IV antiarrhythmics [Reznik A.V., Fedorov V.V., Rosenstrauh L.V., Kokoz Yu.M. and others. Ionic mechanisms of the cardiotropic action of the drug of class III RG-2. Cardiology, 2003, No. 10, p. 76-81; Mironov N.Yu., Golitsyn S.P., Sokolov S.F. et al. Electrophysiological effects and antiarrhythmic activity of a new domestic antiarrhythmic drug of class III niferidil in patients with paroxysmal supraventricular tachycardia. Experiment and wedge. pharmacol., 2012, t. 75, No. 10, p. 78-83; Moiseeva I.Ya., Kotlyarov A.A., Rodina O.P., Kustinova I.N. Fundamentals of clinical pharmacology of antiarrhythmic et al., 2006; Galenko-Yaroshevsky P.A., Sheikh-Zade Yu.R., Mikhin V.P., Bogus S.K. Antiarrhythmic drugs. Heart rhythm disturbance. "Enlightenment-South", 2012, p.17-42].

Therefore, the search for new chemical compounds exhibiting antiarrhythmic properties is highly relevant. The closest analogue of the claimed compounds in structure and action is N, N- (2-dicyclohexyl) aminocarbonylmethyl-N '- [3- (diethylamino) propyl] -4-nitro-benzamide hydrochloride (prototype), showing the properties of class III antiarrhythmics [Sauer V., Schindler R., Ruger K., Kaverina N.V., Seredenin S.B. and other Amides of aminocarboxylic acids, a method for their preparation and pharmaceutical composition. Pat. RF №2134683 (1994). Bull. 1999, No. 23]. The prototype also has the properties of antiarrhythmic drugs of I and IV classes [Kaverina N.V., Lyskovtsev V.V. et al. A new class III antiarrhythmic drug among aminocarboxylic acid dicyclohexylamides. Bulletin of RAMND998, No. 11, p. 42-46; Kaverina N.V., Lyskovtsev V.V., Sokolov S.F. et al. Al-275, a new class III antiarrhythmic drug. Pharmacological properties and features of the mechanism of action. Cardiology, 2000, No. 7, pp. 42-47]. In addition, the named compound also has a number of side effects and for this reason has not received practical use. It is known that the introduction into the molecule of a biologically active compound of an adamantyl substituent modifies its pharmacological effect and reduces toxicity [I. Kovalev. The biological activity of adamantane-containing substances. Chem. farm. Zh., 1977, v. 11, No. 3, pp. 19-27; Pandeya S.N. Indian J. Pharm., 1971, v33, p. 1].

The purpose of the invention is the synthesis of new compounds with high antiarrhythmic activity, low toxicity and a wide range of therapeutic effects, which is achieved by obtaining N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- (dialkylamino) alkylnitrobenzamides of the general formula I.

The inventive compounds of formula I of the present invention are not described in the special and patent literature.

Examples of compounds of formula I of the present invention can be the following compounds:

N- [2- (adamantan-2-yl) aminocarbonylmethyl] -N '- [2- (diethylamino) ethyl] -4-nitrobenzamide;

N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- [3- (diethylamino) propyl] -4-nitrobenzamide;

N, N- [2- (adamant-2-yl) -2-cyclohexylaminocarbonylmethyl] -N '- [2- (diethylamino) ethyl] -4-nitrobenzamide;

N, N- [2- (adamant-2-yl) -2-cyclohexylaminocarbonylmethyl] -N '- [3- (diethylamino) propyl] -4-nitrobenzamide;

N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- [3- (morpholino) propyl] -4-nitrobenzamide.

The goal is achieved according to the method for producing compounds of formula I, which consists in the fact that N- (adamant-2-yl) haloacetamides of the formula III

exposed to diamines of General formula IV

where R, R ¹ , n, R ² have the above meanings, Hal - chlorine or bromine.

The reaction is carried out in an inert solvent such as aromatic hydrocarbons, alcohols, ethers, polar aprotic solvents (dimethylformamide, dimethyl sulfoxide) or in excess of the starting diamine. The process is carried out in the presence of acceptors of hydrogen halides, which can be used alkali metal carbonates, tertiary amines or the starting diamine, at a temperature from room temperature to the boiling point of the starting diamine to obtain diaminoamides of the general formula V:

The compound of general formula V is acylated with the corresponding nitrobenzoyl halide in which the nitro group can be in any position of the phenyl ring. The reaction is carried out in inert solvents or in a two-phase system, for example, an organic solvent-water, in the presence of acceptors of hydrogen halides, with the release of the claimed compounds of General formula I. As solvents, toluene, xylene, benzene, chloroform, etc. can be used, and as acceptors tertiary amines (triethylamine, ethylmorpholine, pyridine, etc.), potassium, sodium carbonates (bicarbonates) or their aqueous solutions are applicable.

Amides of nitrobenzoic acids of the formula I are converted into physiologically acceptable salts of the formula II

the action of mineral or organic acids, preferably hydrochloric acid. Aromatic hydrocarbons, alcohols, ethers, acetone, chloroform, carbon tetrachloride can be used as solvents for the preparation of salts of general formula II.

The compounds of formula I are crystalline substances, insoluble in water, soluble in most organic solvents.

Hydrochlorides of the formula II are white or almost white crystalline substances, readily soluble in water, in alcohols, practically insoluble in ether, acetone, aromatic hydrocarbons.

The structure and purity of the claimed compounds are confirmed by the results of elemental analysis and ¹ H NMR spectra.

The invention is illustrated by the following examples.

Example 1: A mixture of 4.1 g (0.018 mol) of N- (adamant-2-yl) chloroacetamide, 5 g (6.1 ml; 0.043 mol) of 2-diethylaminoethylamine in 25 ml of toluene is heated to reflux and kept at reflux These conditions are 4-5 hours. At the end of the reaction, 15 ml of toluene are added to the cooled reaction mass and the resulting toluene solution is washed with 2 × 20 ml of water, the toluene is evaporated and 4.25 g (81% of theory) of the crude N- (adamant-2-yl) amide N'- (2-diethylamino) ethylaminoacetic acid.

To a solution of 4.2 g (0.013 mol) of N- (adamant-2-yl) amide N '- (2-diethylamino) ethylaminoacetic acid in 50 ml of benzene are added 3.2 g (0.03 mol) of sodium carbonate and 20 ml water. 3.2 g (0.0167 mol) of n-nitrobenzoic acid chloride are added in portions to the resulting mixture. The mixture is stirred at 20-25 ° C for 2 hours, and then 40 ml of water are added and the temperature in the reaction mass is raised to 50-55 ° C. Stirring is continued for another 2 hours. It is cooled, the benzene layer is separated, and the aqueous layer is further extracted with benzene. The combined benzene solution was washed with water, then the solvent was distilled off, and the residue was crystallized from aqueous ethanol. The resulting product is a white with a creamy tint crystalline powder with so pl. 155-157 ° C. The yield of N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- [2- (diethylamino) ethyl] -n-nitrobenzamide (Ia) 3.9 g (71% of theory).

Found,%: C 65.81; H 7.95; N12.52; C ₂₅ H ₃₆ N ₄ O ₄ .

Calculated,%: C 65.77; H 7.95; N, 12.27.

To a solution of 3.65 g (0.008 mol) of N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- [2- (diethylamino) ethyl] -n-nitrobenzamide in 50 ml of dry toluene, an alcohol solution is added with stirring hydrogen chloride to a pH of 2-3. The mixture is allowed to crystallize for 5-6 hours. The precipitate of N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- [2-diethylamino) ethyl] -n-nitrobenzamide (IIa) hydrochloride was filtered off, washed with acetone, dried, and then crystallized from propanol-2. White crystalline powder with so pl. 222-224 ° C. Yield 3.4 g (81%)

Found,%: C 61.20; H 7.68; C17.14; N, 11.24. C ₂₅ H ₃₇ Cl N ₄ O ₄ .

Calculated,%: C 60.90; H 7.56; Cl 7.19; N11.36.

¹ H NMR Spectrum (DMSO d ₆ , δ, ppm):

1.25 (6 H, t, N (CH ₂ CH ₃ ) ₂ ); 1.31-1.88 (14 N, m, AdH);

3.21 (4 H, q, N (CH ₂ CH ₃ ) ₂ ); 3.20 (2H, t, CH ₂ CH ₂ N); 3.78 (1H, d, AdH-2); 3.84 (2H, t, CONCH ₂ CH ₂ ); 4.07 (2H, s, -CH ₃ -CO-); 7.64 and 8.25 (4H, m, n-ArH); 7.94 (1H, d, -NH-).

Example 2. To a mixture of 5.7 g (0.025 mol) of N- (adamant-2-yl) chloroacetamide and 15 ml of toluene, 15 ml (12.3 g; 0.094 mol) of 3-diethylaminopropylamine are added. The reaction mass is boiled for 2 hours. It is cooled, 30 ml of water and 15 ml of toluene are added, the organic layer is separated, the aqueous layer is further extracted with toluene. The combined toluene solution is washed with water and then evaporated to dryness. 6.82 g (85%) of technical N- (adamant-2-yl) amide-N '- (3- (diethylamino) propylaminoacetic acid are obtained. The product is chromatographically pure.

To a stirred mixture of 6.0 g (0.0187 mol) of N- (adamant-2-yl) 3-diethylaminopropylaminoacetic acid amide and 4.2 g of potassium carbonate in 50 ml of toluene and 20 ml of water, 3.5 g (0, 0245 mol) of 4-nitrobenzoyl chloride at such a rate that the temperature in the reaction mixture does not exceed 25 ° C. Stirred for another 1.5 hours, and then add 50 ml of water, heated to 50-60 ° C and kept under stirring for 2 hours. It is cooled, the organic layer is separated, and the aqueous layer is further extracted with 25 ml of toluene. The combined toluene solution is washed with 25 ml of 10% ammonia solution and then with water. The solvent was distilled off in vacuo. 7.5 g of crude product are obtained, which crystallize from 70% aqueous ethanol. Light cream crystals with so pl. 119-121 ° C. The yield of N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- [3- (diethylamino) propyl] -4-nitrobenzamide (IB) 5.9 g (78% of theory).

Found,%: C 66.48; H 8.26; N, 11.87. C ₂₆ H ₃₈ N ₄ O ₄ .

Calculated,%: C 66.36; H 8.14; N, 11.90.

To a solution of 5.75 g of base 16 in 50 ml of acetone, a 25% alcohol solution of hydrogen chloride is added with stirring to a pH of 2-3. It is kept at 5-10 ° C for 2 hours, the precipitated precipitate of the target product is filtered off, washed with dry acetone. White crystalline powder with so pl. 199-200 ° C (iso-propanol). The yield of N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- [3- (diethylamino) propyl] -4-nitrobenzamide (IIb) hydrochloride was 5.72 g (81%).

Found,%: C 61.34; H 7.68; Cl 7.14; N, 10.94. C ₂₆ H ₃₉ Cl N ₄ O ₄ .

Calculated,%: C 61.56; H 7.75; Cl 6.99; N, 11.05.

¹ H NMR spectrum (DMSO d ₆ , δ, ppm): 1.14 and 1.23 (6H, t, N- (CH ₂ CH ₃ ) ₂ ; 1.30-1.86 (14H, m , AdH); 2.00 (2H, m, -CH ₂ CH ₂ N); 3.00 and 3.11 (6H, m, -CH ₂ CH ₃ ) ₂ and

- (CH ₂ CH ₂ N); 3.52 (2H, t, CO NCH ₂ , CH ₂ -); 3.77 and 3.89 (1H, d, AdH-2); 3.98 and 4.19 (2H, s, CH ₂ CO); 7.62 and 8.24; 7.67 and 8.31 (4H, m, n-Ar-H); 7.87 and 8.04 (1H, D, -NH).

Example 3. A solution of 6.2 g (0.02 mol) of N- (adamant-2-yl) -N-cyclohexylchloroacetamide and 7.79 g (9.5 ml; 0.067 mol) of diethylaminoethylamine in 15 ml of toluene are heated to 145 ° C and incubated for 4 hours. Excess amine and toluene are distilled off on a rotary evaporator. 25 ml of toluene and 20 ml of water are added to the residue. The layers are separated. The toluene solution is washed with water. The solvent was distilled off to obtain 7.25 g (92.9% of theory) of the crude N- (adamant-2-yl) -N-cyclohexylamide N ′ - (2-diethylamino) ethylaminoacetic acid.

To a stirred mixture of 7.22 g (0.018 mol) of N- (adamant-2-yl) -N-cyclohexylamide-N '- (2-diethylamino) ethylaminoacetic acid, 4.0 g (0.029 mol) of potassium carbonate and 30 ml of water in 65 ml of toluene, 4.12 g (0.022 mol) of 4-nitrobenzoyl chloride are added in portions. The reaction mass is stirred at room temperature for 1.5 hours, then 40 ml of water are added and the temperature in the mass is raised to 60 ° C. Stand under these conditions for 1 hour. It is cooled, the layers are separated, and water is additionally extracted with 20 ml of toluene. The toluene solution is washed with water and the solvent is distilled off, and the remaining 8.1 g is crystallized from propanol-2. Obtain 5.25 g (65%) of N, N- [2- (adamant-2-yl) -2-cyclohexylaminocarbonylmethyl] -N- [2- (diethylamino) ethyl] -4-nitrobenzamide (IIc). Light cream crystals with so pl. 198-199 ° C.

Found,%: C 68.90; H 8.90; N, 10.56; C ₃₁ H ₄₆ N ₄ O ₄ .

Calculated,%: C 69.11; H 8.61; N, 10.40.

To a solution of 5.1 g (0.01 mol) of base Ic in 50 ml of dry acetone, a solution of hydrogen chloride in ethanol is added with stirring to a pH of 2-3. The precipitate formed is filtered off, washed with acetone, dried and crystallized from absolute ethanol. Obtain 4.35 g (81.6%) of N, N- [2- (adamant-2-yl) -2-cyclohexylaminocarbonylmethyl] -N '- [2- (diethylamino) ethyl] -4-nitrobenzamide hydrochloride (IIc) . Mp 222-224 ° C (decomp.).

Found,%: C 64.91; H 8.24; Cl 6.38; N, 9.52. C ₃₁ H ₄₇ Cl N ₄ O ₄ .

Calculated,%: C 64.73; H 8.24; Cl 6.16; N, 9.74.

¹ H NMR Spectrum (DMSO d ₆ , δ, ppm): 1.25 (6H, t, -N- (CH ₂ CH ₃ ) ₂ ); 1.10-2.30 (24H, m, 14H AdH and 10H cyclohexyl); 3.24 (5H, m, 4H-N (CH ₂ CH ₃ ) ₂ and 1H cyclohexyl); 3.39 (3H, m, 2H, CH ₂ CH ₂ N and 1H Ad H-2); 3.83 (2H, t, CONCH ₂ CH ₂ ); 4.08 (2H, s, - COCH ₂ N-); 7.56 and 8.24 (4H, m, n-ArH).

Example 4. A mixture of 6.2 g (0.02 mol) of N- (adamant-2-yl) -N-cyclohexyl-chloroacetamide and 7.8 g (9.6 ml; 0.06 mol) of 3-diethylaminopropylamine in 20 ml of o-xylene is heated to a boil and incubated for 2 hours. Excess diamine and xylene are distilled off in vacuo. 40 ml of benzene are added to the residue. The resulting solution was washed with water, then the solvent was distilled off. Chromatographically pure N- (adamant-2-yl) -N-cyclohexylamide-N '- (3-diethylamino) propylaminoacetic acid was obtained in quantitative yield (8.1 g), which was used in the next step.

To a stirred mixture of 8.0 g (0.02 mol) N- (adamant-2-yl) -N-cyclohexylamide-N '- (3-diethylamino) propylaminoacetic acid, 3.65 g (0.035 mol) of sodium carbonate in 75 ml of toluene and 30 ml of water, 5.15 g (0.028 mol) of n-nitrobenzoyl chloride are slowly added. The reaction mixture is stirred at room temperature for 2 hours, then 45 ml of water are added, heated to 50-55 ° C and kept under these conditions for 2 hours. The mass is cooled, the toluene layer is separated, washed with water and the solvent is distilled off in vacuo. 9.75 g (89%) of N, N- [2- (adamant-2-yl) -2-cyclohexylaminocarbonylmethyl] -N '- [3- (diethylamino) propyl] -4-nitrobenzamide (1 g) (in form of oil), which is used in the next stage.

To a solution of 9.5 g of a base of 1 g in 75 ml of dry acetone, an ether solution of hydrogen chloride is added to pH 2-3 with stirring and cooling. The mixture is allowed to crystallize at 0 + 5 ° C for 2-3 hours. The precipitate is filtered off, dried and crystallized from absolute ethanol. 8.8 g (79.65%) of N, N- [2- (adamant-2-yl) -2-cyclohexylaminocarbonylmethyl] -N '- [3- (diethylamino) propyl] -n-nitrobenzamide hydrochloride are obtained (IIg ) White crystalline powder with so pl. 177-178 ° C.

Found,%: C 65.01; H 8.46; Cl 6.31; N, 9.76. C ₃₂ H ₄₉ Cl N ₄ O ₄ .

Calculated,%: C 65.23; H 8.38; Cl 6.02; N 9.51.

¹ H NMR spectrum (DMSOd ₆ - CF ₃ COOD, δ, m, d): 1.24 (6Н, t, -N (CH ₂ CH ₃ ) ₂ ; 1.10-2.30 (26Н, m, 14Н AdH, 10H cyclohexyl and 2H - CH ₂ CH ₂ N-); 3.11 (5H, m, 4H-N (CH ₂ CH ₃ ) ₂ and 1H-cyclohexyl); 3.14 (2H, t, CH ₂ CH ₂ N), 3.36 (1H, m, Ad H-2); 3.53 (2H, t, - CONCH ₂ CH ₂ ); 4.04 (2H, s, - COCH ₂ N-); 7, 55 and 8.24 (4H, m, n-ArH).

Example 5. A mixture of 4.1 g (0.018 mol) of N- (adamant-2-yl) chloroacetamide and 15 ml (14.8 g; 0.1 mol) of 3-morpholine propylamine is heated under reflux at 145-150 ° C in within 1 hour. The excess morpholinopropylamine is distilled off in vacuo, the residue is dissolved in 30 ml of toluene. The resulting solution was washed with water, and then toluene was distilled off. Obtain 4.7 g (77%) of crude N- (adamant-2-yl) amide-N '- (3-morpholino) propylaminoacetic acid.

To a stirred mixture of 4.7 g (0.014 mol) of N- (adamant-2-yl) amide N '- (3-morpholino) propylaminoacetic acid, 4.4 g (0.031 mol) of potassium carbonate in 50 ml of toluene and 20 ml of water 3.7 g (0.020 mol) of n-nitrobenzoyl chloride are added in portions. Upon completion of the addition, the mixture was stirred at room temperature for 2 hours, then 25 ml of water was added, heated to 60 ° C and held for another 1 hour. The mass is cooled, the toluene layer is separated, the aqueous layer is further extracted with 20 ml of toluene. The combined toluene solution is washed with 10% ammonia solution and water. The solvent was distilled off to obtain 5.8 g (85.8%) of non-crystallized N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- [3- (morpholino) propyl] -n-nitrobenzamide (Ie), which pass without purification to the next stage.

To a solution of 5.8 g of base Id in 50 ml of acetone is added diethyl ether saturated with hydrogen chloride to a pH of 2-3. The mixture is allowed to crystallize completely at + 5 ° C for 2 hours. The precipitate formed is filtered off and washed with ether. 4.75 g (76%) of N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- [3- (morpholino) propyl] -n-nitrobenzamide (IIe) hydrochloride are obtained. White crystals with so pl. 215-216 ° C (from abs. Ethanol).

Found,%: C 59.92; H 7.25; Cl 7.15; N, 10.91. C ₂₆ H ₃₇ ClN ₄ O ₄ .

Calculated,%: C 59.93; H 7.16; Cl 6.80; N, 10.75.

¹ H NMR Spectrum (DMSOd ₆ , δ, ppm): 1.30-2.10 (14H, m, AdH); 2.05; 3.18 and 3.50 (6H, three m, -CH ₂ CH ₂ CH ₂ -); 2.80-3.90 (8H, m, -morpholine); 3.90 and 4.13 (1H, m, AdH-2); 3.96 and 4.19 (2H, s, -N-CH ₂ CO-); 7.67; 8.24; 8.31 (4H, m, n-ArH); 7.88; 8.04 (1H, d, -NH-).

The study of the antarrhythmic activity of N - [(adamant-2-yl) aminocarbonylmethyl] -N '- (dialkylamino) alkylnitrobenzamides

A search was made for new antiarrhythmic drugs in the series N - [(adaman-2-yl) aminocarbonylmethyl] -N '- (3-dialkylamino) alkylnitrobenzamides using calcium chloride and aconitine arrhythmia models, as well as studying the acute toxicity of the studied compounds in accordance with the guidelines on preclinical study of drugs [Galenko-Yaroshevsky P.A., Kaverina N.V., Kamkin A.G., Turilova A.I., Bogus S.K., Sheikh-Zade Yu.R. Guidelines for the preclinical study of antiarrhythmic drugs. Guidelines for preclinical studies of drugs. Part one. - M.,: Grif and K, 2012b, p. 385-387 et al., 2012].

Research methods

The experiments were carried out on white nonlinear awake male rats weighing 200 g contained in standard vivarium conditions. Animals were received from the nursery: Stolbovaya branch of FSBI NTsBMT RAMS.

Two arrhythmia models were used in the work: aconitine and calcium chloride. Aconitine arrhythmia was caused by intravenous administration of aconitine hydrochloride at doses of 30-40 μg / kg. 1-3 minutes after the administration of aconitine, cardiac arrhythmias of a mixed atrioventricular type developed, which were diverse. The experiments used a dose of aconitine, which caused moderate heart rhythm disturbances (polytopic extrasystole). The ECG was recorded in the II standard lead using the Polyspectra-8 / B and a computer program 3, 5, 10, 15 and 20 minutes after the administration of aconitine. The criterion for the positive effect of the compound was the absence of arrhythmia caused by aconitine. The effective dose of ED ₅₀ and confidence limits were calculated by the method of Miller and Taint at a probability level p = 0.05. The therapeutic breadth of the drug was judged by the value of the antiarrhythmic index (AI), which is the ratio of the lethal dose of LD ₅₀ to effective ED ₅₀ .

Calcium chloride arrhythmia was caused by high doses of a 10% solution of calcium chloride (250-390 mg / kg). 1-2 minutes after the administration of calcium chloride, ventricular fibrillation occurs. At the beginning of the experiment, a dose of 10% calcium chloride solution was selected, causing lethal ventricular fibrillation. The test compounds were administered 1-2 minutes before the administration of calcium chloride. An ECG was recorded in a standard II lead every 5 minutes using Polyspectra-8 / B and a computer program. Antiarrhythmic effect was evaluated by reducing the number of cases of lethal ventricular fibrillation of the heart. The significance of the data was evaluated using the Fisher test.

Acute toxicity of the claimed compounds

The study began with a study of the acute toxicity of these substances in non-linear awake male rats weighing 200 g with intravenous administration. Pyrogen-free water for injection was used as a solvent. The study of acute toxicity was carried out on 6-8 animals using three or more doses. The results were evaluated 2 weeks after administration of the compounds. The effective dose — ED ₅₀ and the lethal dose — LD ₅₀ with confidence limits were calculated by the Miller and Taint method at a probability level of p = 0.05. The results of the experiments are presented in table 1. As a comparison substance, a prototype was used - the compound N, N- (2-dicyclohexyl) aminocarbonylmethyl-N '- [3- (diethylamino) propyl] -4-nitro-benzamide hydrochloride. Studies have shown that compound IIb turned out to be the least toxic, in which the toxicity was 2 times less than the prototype (Table 1).

Table 1 Acute toxicity of test compounds Compound LD ₅₀ mg / kg iv Prototype 40.0 (35.5 ÷ 44.5) IIa 45.0 (42.5 ÷ 47.5) IIb 81.0 (76.9 ÷ 85.1) IIc 47.0 (32.7 ÷ 61.3) IIg 16.0 (13.3 ÷ 18.7) IId 75.0 (70.8 ÷ 79.2)

The study of antiarrhythmic activity of the studied compounds in the conditions of calcium chloride model of arrhythmia

The study of each compound was carried out on 3-6 groups of animals depending on the number of doses studied. In the control there were 6 groups of 10 animals each. Experimental groups - 11 groups of 6 animals each; 6 groups of 8 animals; Group 1 - 5 animals.

The experiments showed that in the control, after the intravenous administration of a 10% solution of calcium chloride (250-390 mg / kg), 10 animals out of 10 died. The protective effect of the studied compounds was manifested in doses of 0.25-0.5-1.0 mg / kg when administered intravenously prior to the administration of calcium chloride (Tables 2, 3, 4, 5, 6, 7).

table 2 The influence of the prototype on the survival of animals in terms of calcium chloride model of arrhythmia (300 mg / kg, iv) Dose mg / kg iv Number of animals Dead Survivors % survivors The control 10 10 0 0 0.125 6 5 one 16.7 0.250 6 3 3 * 50 p≤0,036 0,500 6 6 0 * 100 p≤0,000

Table 3 The effect of compound IIa on the survival of animals in conditions of calcium chloride model of arrhythmia (350 mg / kg, iv) Dose mg / kg iv Number of animals Dead Survivors % survivors The control 10 10 0 0 0,062 7 6 one fourteen 0.125 8 four four * 50 p≤0.023 0.250 8 four four * 50 p≤0.023 0,500 8 3 5 * 62.5 p≤0.026 1,000 8 2 6 * 75 p≤0.007

Table 4 The effect of compound IIb on the survival of animals in the conditions of calcium chloride model of arrhythmia (300 mg / kg, iv) Dose mg / kg iv Number of animals Dead Survivors % survivors The control 10 10 0 0 0.125 7 6 one fourteen 0.250 8 four four * 50 p≤0.023 0,500 10 four 6 * 60 p≤0.01 1,000 8 one 7 * 88 p≤0,000

Table 5 The effect of compound IIc on the survival of animals in the conditions of calcium chloride model of arrhythmia (350 mg / kg, iv) Dose mg / kg iv Number of animals Dead Survivors % survivors The control 10 10 0 0 0.125 6 5 one 17 0.250 6 2 four * 67 p≤0.008 0,500 6 0 6 * 100 p≤0,000

Table 6 The effect of compound IIg on the survival of animals in the conditions of calcium chloride model of arrhythmia (350 mg / kg, iv) Dose mg / kg iv Number of animals Dead Survivors % survivors The control 10 10 0 0 0.125 6 four 2 33 0.250 6 2 four * 67 p≤0.008 0,500 6 one 5 * 83 p≤0.001

Table 7 The effect of compound IIe on the survival of animals in the conditions of calcium chloride model of arrhythmia (390 mg / kg, iv) Dose mg / kg, iv Number of animals Dead Survivors % survivors The control 10 10 0 0 0.125 5 2 3 60 0.250 6 2 four * 67 p≤0.008 0,500 6 3 3 * 50 p≤0,036

Summary data on the survival of animals under the influence of the studied compounds in the conditions of calcium chloride model of arrhythmia are presented in tables 8, 9.

Table 8 The influence of the prototype and the claimed compounds in a dose of 0.25 mg / kg when administered intravenously on the survival of animals in a model of heart rhythm disturbances caused by calcium chloride The control Prototype IIa IIb IIc IIg IId Vyzh. Pog. Vyzh. Pog. Vyzh. Pog. Vyzh. Pog. Vyzh. Pog. Vyzh. Pog. Vyzh. Pog. 0 10 3 3 four four four four four 2 four 2 four 2 p≤0,036 p≤0,023 p≤0,023 p≤0.008 p≤0.008 p≤0.008 Vyzh. - survived, pog. - died

Table 9 The influence of the prototype and the claimed compounds in a dose of 0.5 mg / kg when administered intravenously on the survival of animals in a model of heart rhythm disturbances caused by calcium chloride The control Prototype IIa IIb IIc IIg IId Vyzh. Pog. Vyzh. Pog. Vyzh. Pog. Vyzh. Pog. Vyzh. Pog. Vyzh. Pog. Vyzh. Pog. 0 10 6 0 5 3 6 four 6 0 5 one 3 3 p≤0,000 p≤0.01 p≤0,026 p≤0,000 p≤0.001 p≤0,036

All studied compounds under conditions of calcium chloride model of arrhythmia showed antiarrhythmic activity. Compound IIb was the least toxic compared to the prototype and compounds of the studied series. When determining the antiarrhythmic index of the claimed compounds and comparison drugs, it was found that compound IIb has the greatest breadth of therapeutic effect compared to the prototype, other compounds of this series and comparison drugs - lidocaine and verapamil (table 10).

Table 10 Antiarrhythmic activity of the studied compounds and comparison drugs in the conditions of calcium chloride model of arrhythmia Compound IU ₅₀ mg / kg iv LD ₅₀ mg / kg iv Antiarrhythmic index Prototype 0.27 (0.21 ÷ 0.33) 40.00 (35.50 ÷ 44.50) 148.10 IIa 0.5 (0.35 ÷ 0.65) 45.00 (42.50 ÷ 47.50) 128 IIb 0.34 (0.19 ÷ 0.49) 81.00 (76.90 ÷ 85.50) 238.20 IIc 0.26 (0.17 ÷ 0.35) 47.00 (32.70 ÷ 61.30) 90.00 IIg 0.30 (0.20 ÷ 0.40) 16.00 (13.30 ÷ 18.70) 53.30 IId 0.44 (0.4 ÷ 0.47) 75.00 (70.80 ÷ 79.20) 170 Lidocaine + 7.50 39.40 5.23 Verapamil + 1.10 17.00 15.45 + - Ninidze I.G., Turilova A.I., Berdyaev S.Yu. and others. "A new antiarrhythmic drug bonnecor." Proceedings, ed. N.V. Kaverina, G.G. Chichkanova, M., 1993, p. 124-127.

The study of the antiarrhythmic activity of the studied compounds in the conditions of the aconitine model of arrhythmia

Under the conditions of the aconitine model of arrhythmia, all compounds have antiarrhythmic activity. The most pronounced antiarrhythmic index was detected in compound IIb. This compound in terms of antiarrhythmic activity under the conditions of the aconitine model of arrhythmia is superior to the comparison drugs lidocaine and novocainamide (Table 11).

Table 11 Antiarrhythmic activity of the studied compounds and comparison drugs in the conditions of an aconitine model of arrhythmia Compound IU ₅₀ mg / kg iv LD ₅₀ mg / kg iv Antiarrhythmic index Prototype 0.24 (0.20 ÷ 0.28) 40.0 (35.5 ÷ 44.5) 166 IIa 0.35 (0.25 ÷ 0.45) 45.0 (42.5 ÷ 47.5) 128 IIb 0.3 (0.22 ÷ 0.38) 81.0 (76.9 ÷ 85.1) 270 Lidocaine + 7.8 (5.6 ÷ 10.6) 39,4 5,0 Etmozin 0.28 (0.17 ÷ 0.39) 16.4 (14.9 ÷ 17.8) 58 Novocainamide + 41 110 2.7 + - Turilova A.I., Berdyaev S.Yu., Gritsenko A.N., Senova Z.P. “The correlation between the chemical structure and antiarrhythmic action of etatsizin and its analogues. J. Pharmacol. and toxicol., 1990, No. 6, p.20-21. Berdyaev S.Yu., Turilova A.I., Senova Z.P. and others. "A new antiarrhythmic drug bonnecor." Proceedings, ed. N.V. Kaverina, G.G. Chichkanova. M, 1992, p.118-124.

Thus, the claimed compounds exhibit antiarrhythmic activity when studied under conditions of calcium chloride and aconitine models of arrhythmia. Compound IIb has a pronounced antiarrhythmic activity, the lowest toxicity and has the highest antiarrhythmic index, which exceeds 1.6 times the prototype.

Claims (8)

1. N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- (dialkylamino) alkyl nitrobenzamides having antiarrhythmic activity, of the general formula I:

,
where R is hydrogen, alkyl (C ₁ -C ₆ ) or cycloalkyl; R ¹ may be hydrogen or an aliphatic residue (C ₁ -C ₂ ); R ² may be alkyl (C ₁ -C ₂ ) or together with a nitrogen saturated heterocycle with one or two heteroatoms, such as, for example, morpholine, pyrrolidine, piperidine; “N” may be 2 or 3; the nitro group in benzamide can be in any (o-, m-, p-) position of the cycle, and their physiologically acceptable salts with mineral and organic acids, preferably in the form of hydrochlorides of the formula I · HCl (II). 2. Hydrochloride N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- [2- (diethylamino) ethyl] -4-nitrobenzamide, which has an antiarrhythmic effect. 3. Hydrochloride of N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- [3- (diethylamino) propyl] -4-nitrobenzamide, which has an antiarrhythmic effect. 4. N, N- [2- (adamant-2-yl) -2-cyclohexylaminocarbonylmethyl] -N '- [2- (diethylamino) ethyl] -4-nitrobenzamide hydrochloride having an antiarrhythmic effect. 5. Hydrochloride N, N- [2- (adamant-2-yl) -2-cyclohexylaminocarbonylmethyl] -N '- [3- (diethylamino) propyl] -4-nitrobenzamide, which has an antiarrhythmic effect. 6. Hydrochloride N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- [3- (morpholino) propyl] -4-nitrobenzamide, which has an antiarrhythmic effect. 7. The method of obtaining N- [2- (adamant-2-yl) aminocarbonylmethyl] -N '- (dialkylamino) alkylnitrobenzamides of the general formula I, where R, R ¹ , R ² and "n" have the above meanings, characterized in that N- (adamant-2-yl) haloacetamides of the general formula III:

,
where R is hydrogen, alkyl (C ₁ -C ₆ ) or cycloalkyl, Hal is chloro or bromo, are reacted with diamines of the general formula IV:

,
where R ² may be alkyl (C ₁ -C ₂ ) or together with a nitrogen saturated heterocycle with one or two heteroatoms, such as, for example, morpholine, pyrrolidine, piperidine, “n” may be 2 or 3, in inert solvents or an excess of starting diamine in the presence of acceptors of hydrogen halides with the release of the desired diaminoamides of the general formula V:

,
where R, R ¹ , R ² , n have the above meanings,
The resulting diaminoamides V are reacted with nitrobenzoic acid halides in inert organic solvents or mixed with water in the presence of hydrogen halide acceptors to isolate compounds of the general formula I, which are converted by the action of hydrogen chloride to the hydrochlorides of the general formula I · HCl (II). 8. The use of compounds according to claims 1-6 as antiarrhythmic, in particular anti-fibrillator agents.