RU2290404C1 - 9-SUBSTITUTED 2-HALOGENPHENYLIMIDAZO[1,2-a]BENZIMIDAZOLE SALTS AND 1-SUBSTITUTED 3-HALOGENPHENACYL-2-AMINOBENZIMIDAZOLIUM HALIDES POSSESSING HEMORHEOLOGICAL PROPERTIES - Google Patents

Abstract

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel salts in order of 9-substituted 2-halogenphenylimidazo[1,2-a]benzimidazoles of the general formula (I):

wherein R means (C₁-C₆)-alkyl, allyl, benzyl and substituted benzyl-, dialkylamino-alkyl; X means fluorine (F), chlorine (Cl), bromine (Br) atoms in ortho-, meta- and para-positions of phenyl ring, dihalides in 3,4-, 2,4-, 3,5- and in other position of phenyl ring; Y means Cl, Br, -NO₃, -SO₄, -(COOH)₂, -(CH₂COOH)₂, -CH₃-C₆H₄-SO₃H and other pharmaceutically acceptable acid residues; n = 0-2 (with exception for compounds wherein R means -(CH₂)₂-NEt_2; X means Br or Cl; Y means Cl; n = 2; R means -(CH₂)₂-NMe₂; X = Y mean Cl; n = 2), and to intermediate compounds of their synthesis, namely to 1-substituted 3-halogenphenacyl-2-aminobenzimidazolium halides of the general formula (II):

, wherein R means (C₁-C₆)-alkyl, allyl, benzyl and substituted benzyl-, dialkylamino-alkyl; X means F, Cl, Br at ortho-, meta- and para-positions of phenyl ring, dihalides at 3,4-, 2,4-, 3,5- and at other positions of phenyl ring; Y means Cl, Br, J (with exception for compounds wherein R means -(CH)₂-NEt₂; X means Br or Cl; Y means Br; R means -(CH₂)₂-NMe₂; X means Cl; Y means Br) possessing hemorheological properties. Invention provides synthesis of novel biologically active compounds possessing hemorheological properties.

EFFECT: valuable medicinal properties of compounds.

2 cl, 3 tbl, 31 ex

Description

The invention relates to new derivatives in the series of 2,9-disubstituted imidazo [1,2-a] benzimidazoles, namely to the salts of 9-substituted 2-halogenphenylimidazo [1,2-a] benzimidazoles of the general formula

where R = C ₁ -C ₆ -alkyl-, allyl-, benzyl- and substituted benzyl-, dialkylamino-alkyl; X = F, Cl, Br at the o-, m-, p-positions of the phenyl core, dihalogens at 3,4-, 2,4-, 3,5- and other positions of the phenyl core; Y = Cl, Br, NO ₃ , SO ₄ , (COOH) ₂ , (CH ₂ COOH) ₂ , CH ₃ C ₆ H ₄ SO ₃ H and other pharmaceutically acceptable acid residues, n = 0-2 (except for compounds with R = (CH ₂ ) ₂ NEt ₂ , X-Br or Cl, Y = Cl, n = 2; R = (CH ₂ ) ₂ NMe ₂ , X = Y = Cl, n = 2), and their intermediate products synthesis, namely, halides of 1-substituted 3-halogenophenacyl-2-aminobenzimidazolium of the general formula II

where R = C ₁ -C ₆ -alkyl-, allyl-, benzyl- and substituted benzyl-, dialkylamino-alkyl; X = F, Cl, Br at the o-, m-, p-positions of the phenyl core, dihalogens at 3,4-, 2,4-, 3,5- and other positions of the phenyl core; Y = Cl, Br, I (excluding compounds with R = (CH ₂ ) ₂ Net ₂ , X = Br or Cl, Y = Br; R = (CH ₂ ) ₂ NMe ₂ , X = Cl, Y = Br) possessing hemorheological properties.

The drug Pentoxifylline occupies a leading position as a means of pharmacological correction of blood rheology disorders (Russian Drug Register. Drug Encyclopedia. Radar Patent, 2005, p. 691-692; N. Hikiami, H. Goto, N. Sekiya et al. Phytomedicine, 2003, v.10, No. 6-7, p. 459-466; A.M. Zudin, G.S. Krotovsky, A.E. Kotov et al., Violation of the rheological properties of blood and their correction in post-thrombophlebic syndrome, Surgery , 2004, No. 2, p. 33-36). The drug inhibits the activity of phosphodiesterase (leading to an increase in the intracellular concentration of ATP and cAMP) and enhances the activity of the magnesium-dependent protein kinase (N. Hikiami, N. Goto, N. Sekiya, N. Hattori, I. Sakakibara, Y.Shimada, K. Terasawa, Comparative efficacy of Keishi-bukuryo-gan and pentoxifylline on RBC deformability in patients with "oketsu" syndrome, Phytomedicine, 2003, No. 10, p. 459-466). These effects are manifested in the form of improved deformability and a decrease in red blood cell aggregation, relaxation of vascular smooth muscle cells (moderate vasodilation) and a decrease in platelet aggregation (AS Dukhanin, FR Gubaeva. Pharmacological regulation of platelet activity. Experiment. And wedge. Pharmacology, 1998 No. 4, p. 66-71). However, pronounced side effects - impaired consciousness, convulsions, visual disturbances, arrhythmias, intestinal atony, cholestatic hepatitis, intestinal bleeding, skin hemorrhages, leukopenia, thrombocytopenia, hypofibrinogenemia - limit the use of this drug in clinical practice (Russian Drug Register. Encyclopedia of drugs. Radar Patent 2005, p.691-692; DLDawson, Q. Zheng, SAWorthy, B. Charles, DV Bradley, Failure of pentoxifylline or cilostazol to improve blood and plasma viscosity, fibrinogen, and erythrocyte deformability in claudication, Angiology , 2002, No. 53, p.509-520).

A more effective analogue of pentoxifylline, propentophylline, has also been developed, which affects several rheological parameters - improved deformability of red blood cells (selective inhibition of phosphodiesterases I, II, IV, increased intracellular cAMP), as well as inhibition of platelet aggregation (L. Rossignol, M. Plantavid, H. Chap, L. Douste-Blazy, Effect of pentoxifylline and propentofylline on the turnover of poliphosphoinositides of the erythrocyte membrane and on the metabolism of arachidonic acid on platelets, Pathol. Biol., 1988, No. 36, p. 1073-1075) . However, clinical trials showed a high level of toxicity of propentophylline in 2000. The European Committee on Patented Medical Products revoked the license of the drug from manufacturers (V.P. Fisenko, A.P. Drozhzhin, M.T. Abidov. Analysis of the most promising studies on the creation of new drugs. Scientific Center for Expertise and State Control of Medicines Ministry of Health of Russia, 2000, 48 p.).

In the series of 2,9-disubstituted imidazo [1,2-a] benzimidazole, the di- hydrochloride of 2- (4-bromophenyl) -9-diethylaminoethylimidazo [1,2-a] benzimidazole, which exhibits antihypertensive and anti-inflammatory properties (Simonov A. Kovalev G.V., Anisimova V.A. et al., Auth. Certificate No. 566588 (USSR), M.cl ^2. A 61 K 31/475; Bull. Inventory, 1977, No. 28; Kovalev G. V., Anisimova V.A., Simonov A.M. et al., Chemical-Pharmaceutical Journal, 1979, v.13, No. 8, pp. 57-62).

In the series of 2,9-disubstituted imidazo [1,2-a] benzimidazole and intermediate halides of 1-substituted 3-phenacyl-2-aminobenzimidazole, compounds exhibiting hemorheological properties are unknown.

The technical result of the invention is new compounds in the series of 2,9-disubstituted imidazo [1,2-a] benzimidazoles, as well as in the series of intermediate products of their synthesis, exhibiting a hemorheological effect unknown for these classes of compounds, more effective than the leading action in this form activity of the known drug "pentoxifylline".

The technical result is achieved by compounds of formulas I and II, the synthesis of which consists in the interaction of 1-substituted 2-aminobenzimidazoles with Bz-halogen-substituted phenacyl halides and further cyclization of the intermediate-formed halides of 1-substituted 3-halogen-phenacyl-2-aminobenzimidazolium II to 2-halogeno-phenylimide -a] -benzimidazoles and the translation of tricyclic bases into pharmaceutically acceptable salts I.

where R, X, Y, n take the values indicated above.

The structure of all synthesized compounds was proved by elemental analysis, IR and ¹ H NMR spectra. In the IR spectra of salts II, taken in liquid paraffin, there are absorption bands of the carbonyl group in the region of 1700-1710 cm ^-1 , as well as two bands of stretching vibrations of the primary amino group in the region of 3150-3350 cm ^-1 , which indicates the existence of these compounds in crystalline state in the form of salts of 2-aminobenzimidazolium. In the ¹ H NMR spectra of these salts, two-proton singlet signals (δ 6.0-6.2) are observed, which correspond to the absorption of methylene protons of benzoylmethyl radicals. The signals of the protons of the amino group (2H) appear in the form of narrow singlets with δ 8.50-9.50. The listed signals are absent in the spectra of tricyclic bases I.

The following are examples of methods for the synthesis of the proposed compounds.

Example 1. Step 1. 2-amino-3- (4-bromophenacyl) -1- (2-di-ethylaminoethyl) benzimidazolium bromide (IIa). 2.78 g (10 mmol) of 4-bromophenacyl bromide are added to a hot solution of 2.32 g (10 mmol) of 2-amino-1- (2-diethylaminoethyl) benzimidazole in 50 ml of acetone. The mixture is stirred until the latter is dissolved, heated until precipitation begins and left to stand at room temperature for 4-6 hours. Then the precipitate is filtered off, washed thoroughly with acetone. Yield 4.82 g (94.5%), mp. 224 ° C (decomp.). Lit. so pl. 224 ° C. Found,%: C 49.44; H 5.09; Br 31.40; N, 11.04. C ₂₁ H ₂₆ Br ₂ N ₄ O. Calculated,%: C 49.43; H 5.14; Br 31.32; N, 10.98.

Using this technique, other Quaternary salts II were synthesized based on 1-substituted 2-aminobenzimidazoles and Bz-halogen-substituted phenacyl bromides. These salts are generally chromatographically pure and are introduced into the cyclization reaction without further purification.

Stage 2. Dihydrobromide 2- (4-bromophenyl) -9- (2-diethylaminoethyl) imidazo [1,2-a] benzimidazole (Ia). Boil 5 mmol of bromide IIa in 100 ml of water until the reaction is complete (3-5 hours, control - TLC). Then the solution was alkalinized to pH 8-9 and the precipitated base was extracted with chloroform. The extract is passed through a layer of Al ₂ O ₃ (eluent is CHCl ₃ ). The residue after evaporation of CHCl ₃ from the eluate is dissolved in acetone and the solution conc. HBr to pH 1-2. The yield of 91.3%, so pl. 263-264 ° C (decomp., EtOH). ¹ H NMR spectrum, δ, ppm: 1.35 (6H, t, 2CH ₃ ); 3.32 (4H, q, N (CH ₂ ) ₂ ); 3.63 (2H, t, N (CH ₂ ) ₂ ); 5.14 (2H, t, NCH ₂ ); 7.47 (2H, dt, 2 ', 6'-H); 7.62 (2H, d, 3 ', 5'-H); 7.85-8.24 (4H, m, arom. H); 8.60 (1H, s, 3-H); 11.77 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 44.07; H 4.35; Br 41.71; N, 9.90. C ₂₁ H ₂₃ BrN ₄ · 2HBr. Calculated,%: C 44.00; H 4.40; Br 41.82; N, 9.78.

Example 2. Step 1. 2-amino-3- (4-bromophenacyl) -1- (2-piperidinoethyl) benzimidazolium bromide (IIb). Obtained from 2-amino-1- (2-piperidinoethyl) benzimidazole and 4-bromophenacyl bromide. Yield 96.05%, mp. 204 ° C (decomp.). Found,%: C 50.48; H 4.92; Br 30.70; N, 10.87. C ₂₂ H ₂₆ Br ₂ N ₄ O. Calculated,%: C 50.59; H 5.02; Br 30.60; N, 10.73.

Stage 2. Dinitrate of 2- (4-bromophenyl) -9- (2-piperidinoethyl) imidazo [1,2-a] benzimidazole (Ib). It was synthesized by boiling IIb bromide in water (see example 1, stage 2), isolating a cyclic base and obtaining dinitrate 16 by acidifying the acetone solution of the base with an acetone solution of NHO ₃ . Yield 78.6%, mp. 176-177 ° C (decomp., 2-RgON). ¹ H NMR spectrum, δ, ppm: 1.35-2.14 (6H, m, - (CH ₂ ) ₃ -); 2.82-3.07 (4H, m, N (CH ₂ ) ₂ ); 3.53 (2H, t, NCH ₂ ); 5.17 (2H, t, NCH ₂ ); 7.44 (2H, dt, 2 ', 6'-H); 7.60 (2H, d, 3 ', 5'-H); 7.81-8.19 (4H, m, arom. H); 8.55 (1H, s, 3-H); 11.84 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 48.31; H 4.55; Br 14.60; N, 15.33. C ₂₂ H ₂₃ BrH ₄ · 2HNO ₃ . Calculated,%: C 48.10; H 4.59; Br 14.54; N, 15.30.

Example 3. Step 1. 2-amino-1- (2-diethylaminoethyl) -3- (3-bromophenacyl) benzimidazolium bromide (IIc). Obtained analogously to bromide 1a starting from 2-amino-1- (2-diethylaminoethyl) benzimidazole and 3-bromophenacyl bromide. Yield 89.25%. Mp 186-188 ° C (decomp.). Found,%: C 49.35; H 5.19; Br 31.19; N, 11.21. C ₂₁ H ₂₆ Br ₂ N ₄ O. Calculated,%: C 49.43; H 5.14; Br 31.32; N, 10.98.

Stage 2. Dihydrochloride of 2- (3-bromophenyl) -9- (2-diethylaminoethyl) imidazo [1,2-a] benzimidazole (Ic). Obtained by acidification of an acetone solution isolated as a result of cyclization of the base I conc. HCl to pH 2-3. Yield 89.6%, mp. 269-271 ° C (decomp., EtOH-H ₂ O). ¹ H NMR spectrum, δ, ppm: 1.33 (6H, t, 2CH ₃ ); 3.25 (4H, q, N (CH ₂ ) ₂ ); 3.60 (2H, t, NCH ₂ ); 5.07 (2H, t, NCH ₂ ); 7.11-8.17 (8H, m, arom. H); 8.52 (1H, s, 3-H); 11.45 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 52.05; H 5.18; Br 16.55; Cl 14.68; N, 11.54. C ₂₁ H ₂₃ BrN ₄ · 2HCl. Calculated,%: C 52.09; H 5.20; Br 16.50; Cl 14.64; N, 11.57.

Example 4. Step 1. 2-amino-1- (2-dimethylaminoethyl) -3- (4-chlorophenacyl) benzimidazolium bromide (IIg). Synthesized based on 2-amino-1- (2-dimethylaminoethyl) benzimidazole and 4-chlorophenacyl bromide. Yield 88.64%, mp. tech. Sample 187-189 ° C (decomp.). Lit. so pl. 219 ° C (decomp.). Found,%: C 52.10; H 5.17; Br 18.20; Cl 8.17; N, 12.74. C ₁₉ H ₂₂ BrClN ₄ O. Calculated,%: C 52.13; H 5.07; Br 18.25; Cl 8.10; N, 12.80.

Stage 2. 9- (2-Dimethylaminoethyl) -2- (4-chlorophenyl) imidazo [1,2-a] benzimidazole dinitrate (Ig). Obtained by acidification of an acetone solution of cyclic base I, isolated after boiling bromide IIg in water, with a solution of HNO ₃ in acetone. Yield 86.8%, mp. 164-165 ° C (decomp., CH ₃ CN). ¹ H NMR spectrum, δ, ppm: 3.04 (6H, s, N (CH ₃ ) ₂ ); 3.75 (2H, t, CH ₃ ); 5.18 (2H, t, CH ₂ ); 7.25 (2H, t, 3 ', 5'-H); 7.53 (2H, dt, 2 ', 6'-H); 7.93-8.20 (4H, m, arom. H); 8.61 (1H, s, 3-H); 11.85 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 49.23; H 4.64; Cl 7.45; N, 18.32. C ₁₉ H ₁₉ ClN ₄ · 2HNO ₃ . Calculated,%: C 49.13; H 4.56; Cl 7.53; N, 18.10.

Example 5. Step 1. 2-amino-1- (2-diethylaminoethyl) -3- (4-chlorophenacyl) benzimidazolium bromide (IIe). Obtained from 2-amino-1- (2-di-ethylaminoethyl) benzimidazole and 4-chlorophenacyl bromide. Yield 90.32%, mp. 196-198 ° C (decomp.). Lit. so pl. 196-197 ° C (decomp.). Found,%: C 54.11; H, 5.69; Br 17.23; Cl 7.68; N, 12.09. C ₂₁ H ₂₆ BrClN ₄ O. Calculated,%: C 54.15; H 5.63; Br 17.15; Cl 7.61; N, 12.03.

Stage 2. Dinitrate of 9- (2-diethylaminoethyl) -2- (4-chlorophenyl) imidazo [1,2-a] benzimidazole (Ie). Synthesized analogously to dinitrate Ig. The yield of 88.4%, so pl. 169-171 ° C (decomp., CH ₃ CN). ¹ H NMR spectrum, δ, ppm: 1.37 (6H, t, 2CH ₃ ); 3.31 (4H, q, N (CH ₂ ) ₂ ); 3.64 (2H, t, NCH ₂ ); 5.17 (2H, t, NCH ₂ ); 7.32-8.24 (8H, m, arom. H); 8.60 (1H, s, 3-H); 11.78 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 51.34; H 5.19; Cl 7.04; N, 17.32. C ₂₁ H ₂₃ ClN ₄ · 2HNO ₃ . Calculated,%: C 51.17; H, 5.11; Cl 7.19; N, 17.05.

Example 6. Step 1. 2-amino-1- (2-piperidinoethyl) -3- (4-chlorophenacyl) benzimidazolium bromide (IIe). Obtained by standard procedures from 2-amino-1- (2-piperidinoethyl) benzimidazole and 4-chlorophenacyl bromide. Yield 95.8%, mp. 194-195 ° C (decomp.). Found,%: C 55.25; H 5.48; Br 16.77; Cl 7.50; N, 11.78. C ₂₂ H ₂₆ BrClN ₄ O. Calculated,%: C 55.30; H 5.55; Br 16.72; Cl 7.42; N, 17.73.

Step 2. 9- (2-Piperidinoethyl) -2- (4-chlorophenyl) imidazo [1,2-a] benzimidazole dihydrochloride (Ie). Dihydrochloride was isolated as a result of acidification of a solution of a cyclic base (mp 112-113 ° С) in alcohol conc. HCl. Yield 92.6%, mp. 285-286 ° C (decomp., 60% EtOH). ¹ H NMR spectrum, δ, ppm: 1.36-2.00 (6H, m, - (CH ₂ ) ₃ -); 3.11-3.54 (4H, m, N (CH ₂ ) ₂ ); 3.64 (2H, t, NCH ₂ ); 4.97 (2H, t, NCH ₂ ); 7.24-8.10 (8H, m, arom. H); 8.50 (1H, s, 3-H); 11.08 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 58.54; H 5.50; Cl 23.48; N, 12.48. C ₂₂ H ₂₃ ClN ₄ · 2HCl. Calculated,%: C 58.48; H 5.58; C 123.54; N, 12.40.

Example 7. Step 1. 1-Allyl-2-amino-3- (4-chlorophenacyl) benzimidazolium bromide (IIg). Obtained in 96.3% yield by reaction of equimolar amounts of 1-allyl-2-aminobenzimidazole and 4-chlorophenacyl bromide in acetone. Mp 247-248 ° C (decomp., EtOH). Found,%: C 53.17; H 4.23; Br 19.67; Cl 8.77; N, 10.33. C ₁₈ H ₁₇ BrClN ₃ O. Calculated,%: C 53.16; H, 4.21; Br 19.65; Cl 8.72; N, 10.33.

Stage 2. Hydrobromide 9-allyl-2- (4-chlorophenyl) imidazo [1,2-a] benzimidazole (IIg). 0.01 mol of bromide IIzh in 30 ml conc. HCl for 1.5-2 hours. After cooling the reaction mass, the precipitate is filtered off, washed with a small amount of ice water and acetone. Then the resulting salt is suspended in 20 ml of water, heated and made basic with an ammonia solution. It is cooled, the precipitate of 9-allyl-2- (4-chlorophenyl) imidazo [1,2-a] benzimidazole is filtered off, dried in air. The yield is 86.6%. Mp 134-135 ° C (2-PrOH). Found,%: C 70.21; H 5.01; Cl 11.50; N, 13.68. C ₁₈ H ₁₄ ClN ₃ . Calculated,%: C 70.25; H 4.58; Cl 11.52; N, 13.65.

Hydrobromide Izh obtained by the action of conc. HBr on the obtained base in alcohol. Yield 89.7%. Mp 249-250 ° C (decomp., EtOH). ¹ H NMR spectrum, ppm: 4.91 (2H, d, NCH ₂ ); 5.18-5.59 (2H, dd, CH ₂ ); 5.97-6.15 (1H, m, CH); 6.93-8.25 (8H, m, arom. H); 8.55 (1H, s, 3-H); H ⁺ in exchange. Found,%: C 55.59; H 3.92; Br 20.60; Cl 9.07; N, 10.82. C ₁₈ H ₁₄ ClN ₃ · HBr. Calculated,%: C 55.62; H 3.89; Br 20.56; Cl 9.12; N, 10.81.

Example 8. Step 1. 2-amino-1- (2-diethylaminoethyl) -3- (2-chlorophenacyl) benzimidazolium bromide (IIc). Yield 84.2%. Mp 174-175 ° C (decomp.). Found,%: C 54.04; H 5.74; Br 17.5; Cl 7.54; N, 12.23. C ₂₁ H ₂₆ BrClN ₄ O. Calculated,%: c 54.15; H 5.63; Br 17.15; Cl 7.61; N, 12.03.

Stage 2. Toluene sulfonate 9- (2-diethylaminoethyl) -2- (2-chlorophenyl) imidazo [1,2-a] benzimidazole monohydrate (Iz). The cyclization of salt is carried out by boiling in water. Toluene sulfonate is prepared by mixing equivalent amounts of saturated acetone solutions of the base of 2-chlorophenylimidazo [1,2-a] benzimidazole and 4-toluenesulfonic acid. Yield 77.5%, mp. 120-121 ° C (CH ₃ CN). ¹ H NMR spectrum, δ, ppm: 1.33 (6H, t, 2CH ₃ ); 2.55 (3H, s, CH ₃ ); 3.23 (4H, q, N (CH ₂ ) ₂ ); 3.51 (2H, t, NCH ₂ ); 4.95 (2H, t, NCH ₂ ); 7.21-8.43 (12H, m, arom. H); H ⁺ in exchange. Found,%: C 60.21; H, 6.07; Cl 6.45; N, 10.20; S 5.63. С ₂₁ Н ₂₃ ClN ₄ · С ₇ Н ₈ O ₃ S · Н ₂ O. Calculated,%: С 60.37; H 5.97; Cl 6.36; N, 10.06; S 5.75.

Example 9. Step 1. 2-amino-1-methyl-3- (4-fluorophenacyl) benzimidazolium (IIi) bromide was prepared by reacting equimolar amounts of 2-amino-1-methylbenzimidazole and 4-fluorophenacyl bromide. Yield 97.5%, mp. 319-320 ° C (decomp.). Found,%: C 52.79; H 4.20; Br 21.86; F 5.20; N, 11.44. C ₁₆ H ₁₅ BrFN ₃ O. Calculated,%: C 52.76; H 4.15; Br 21.94; F 5.22; N, 11.54.

Stage 2. Hydrochloride of 9-methyl-2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole (Ii). A mixture of 3.64 g (10 mmol) of 1-methyl-3- (4-fluorophenacyl) benzimidazolium bromide, 2 g of finely ground Na ₂ CO ₃ , 100 ml of EtOH and 20 ml of H ₂ O is heated to complete the reaction (15-20 hours) , control - TLC). Then the alcohol is evaporated, 30 ml of water are added to the residue, the precipitate is filtered off, washed with water and dried in air. The resulting base is purified from impurities sitting at the start using column chromatography (γ-Al ₂ O ₃ , eluent - CHCl ₃ ). The residue (chromatographically pure base, mp 126-127 ° C) after evaporation of CHCl ₃ from the eluate is dissolved in acetone and a salt is obtained by acidification of an acetone solution conc. HCl. Yield 87.9%, mp. 240-241 ° C (EtOH-H ₂ O). Nuclear Magnetic Resonance Spectrum ¹ H δ, ppm: 4.06 (3H, s, CH ₃ ); 7.33 (2H, t, 3 ', 5'-H); 7.41-7.64 (2H, m, 2 ', 6'-H); 7.73-8.11 (4H, m, arom. H); 8.58 (1H, s, 3-H); H ⁺ in exchange. Found,%: C 63.55; H 4.44; Cl 11.86; F 6.32; N, 13.83. C ₁₆ H ₁₂ FN ₃ · HCl Calculated,%: C 63.69; H 4.34; Cl 11.75; F, 6.30; N 13.92.

Example 10. Stage I. 2-amino-1-butyl-3- (4-fluorophenacyl) benzimidazolium bromide (IIk). Obtained by the interaction of equimolar amounts of 2-amino-1-butylbenzimidazole and 4-fluorophenacyl bromide in acetone. Yield 96.06%, mp. 231-232 ° C (decomp.). Found,%: C 56.25; H 5.17; Br 19.77; F 4.62; N, 10.38. C ₁₉ H ₂₁ BrFN ₃ O. Calculated,%: C 56.17; H, 5.21; Br 19.67; F 4.68; N, 10.34.

Stage 2. The hydrochloride of 9-butyl-2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole (Ic) was synthesized by boiling IIk bromide in an aqueous-alcoholic solution in the presence of Na ₂ CO ₃ and the subsequent conversion of the obtained cyclic base to hydrochloride using conc. HCl. Yield 84.0% mp. 234-235 ° C (EtOH). ¹ H NMR spectrum, δ, ppm: 0.98 (3H, t, CH ₃ ); 1.47 (2H, sext, CH ₂ ); 1.91 (2H, q, CH ₂ ); 4.67 (2H, t, NCH;); 7.26 (2H, t, 3 ', 7'-H); 7.48 (2H, dt, 2 ', 6'-H); 7.72-8.20 (4H, m, arom. H); 8.60 (1H, s, 3-H); H ⁺ in exchange. Found,%: C 66.45; H 5.50; Cl 10.11; F 5.59; N, 12.25. C ₁₉ H ₁₈ FN ₃ · HCl. Calculated,%: C 66.37; H 5.57; Cl 10.21; F 5.53; N, 12.22.

Example 11. Step 1. 1-Allyl-2-amino-3- (4-fluorophenacyl) benzimidazolium chloride (IIL). A mixture of 0.69 g (4 mmol) of 1-allyl-2-aminobenzimidazole and 0.70 g (4 mmol) of ω-chloro-4-fluoroacetophenone in 15 ml of CH ₃ CN is boiled until the reaction is complete (8 h, control - TLC ) It is cooled, the precipitate is filtered off, washed with acetonitrile. Yield 1.30 g (93.3%), mp. 254 ° C. Found,%: C 65.47; H 5.07; Cl 10.21; F 5.55; N, 12.13. C ₁₈ H ₁₇ ClFN ₃ O. Calculated,%: C 65.52; H 4.96; Cl 10.25; F 5.49; N, 12.15.

Step 2. 9-Allyl-2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole hydrochloride (Il). The resulting chloride IIl is treated with a solution of 22% NH ₄ OH at room temperature. After 3-4 hours, the modified precipitate is filtered off, washed with water, and dried in air. The yield of 1-allyl-2-imino-3- (4-fluorophenacyl) benzimidazoline is quantitative, so pl. 157-158 ° C. In an open tube, the resulting base is heated to a temperature of 170 ° C and maintained until the cyclization reaction is complete (15-20 min). After cooling, the melt is dissolved in a minimum amount of CHCl ₃ , the solution is passed through an Al ₂ O ₃ layer, eluting with a chloroform final tricycle. The eluate was evaporated to a small volume and acidified with a solution of HCl in 2-PrOH. The precipitated hydrochloride salt Il is filtered off, washed with acetone. Yield 89.7%, mp. 245-246 ° C (decomp., EtOH-H ₂ O). ¹ H NMR spectrum, δ, ppm: 4.87 (2H, d, NCH ₂ ); 5.16-5.61 (2H, dd, CH ₂ ); 5.94-6.17 (1H, m, CH); 6.90-8.14 (8H, m, arom. H); 8.48 (1H, s, 3-H); H ⁺ in exchange. Found,%: C 66.00; H 4.53; Cl 10.75; F 5.87; N, 12.85. C ₁₈ H ₁₄ FN ₃ · HCl. Calculated,%: C 66.04; H 4.62; Cl 10.69; F 5.81; N, 12.84.

Example 12. Step 1. 2-amino-1-benzyl-3- (4-fluorophenacyl) benzimidazolium bromide (IIm) was prepared from 2-amino-1-benzylbenzimidazole and 4-fluorophenacyl bromide. Yield 95.0% mp. 293-295 ° C (decomp.). Found,%: C 60.00; H 4.44; Br 18.25; F 4.37; N, 9.48. C ₂₂ H ₁₉ BrFN ₃ O. Calculated,%: C 60.01; H 4.35; Br 18.18; F 4.31; N, 9.54.

Stage 2. The hydrochloride of 9-benzyl-2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole (Im) is synthesized by boiling IIm bromide in an aqueous-alcoholic solution in the presence of Na ₂ CO ₃ and then converting the resulting cyclic base to hydrochloride Im Yield 92.8%, mp. 248-250 ° C (EtOH-H ₂ O). ¹ H NMR spectrum, δ, ppm: 5.78 (2H, s, CH ₂ ); 7.21-8.13 (13H, m, arom. H); 8.50 (1H, s, 3-H); H ⁺ in exchange. Found,%: C 69.89; H 4.59; Cl 9.31; F, 5.11; N, 11.10. C ₂₂ H ₁₆ FN ₃ · HCl Calculated,%: C 69.93; H 4.53; Cl 9.38; F 5.03; N, 11.13.

Example 13. Step 1. 2-amino-1- (4-methylbenzyl) -3- (4-fluoro-phenacyl) benzimidazolium (IIH) bromide was obtained by reacting 2-amino-1- (4-methylbenzyl) benzimidazole and 4 -fluorophenacyl bromide in acetone. Yield 88.1%, mp. > 245 ° C (decomp.). Found,%: C 60.70; H 4.69; Br 17.65; F 4.16; N, 9.31. C ₂₃ H ₂₁ BrFN ₃ O. Calculated,%: C 60.80; H 4.66; Br 17.59; F 4.18; N, 9.25.

Stage 2. The nitrate 9- (4-methylbenzyl) -2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole (In) was synthesized by boiling IIn bromide in an aqueous-alcoholic solution in the presence of Na ₂ CO ₃ . The resulting base is crystallized from acetonitrile to isolate 9- (4-methylbenzyl) -2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole. Yield 94.8%, mp. 171-172 ° C (CH ₃ CN). ¹ H NMR spectrum, δ, ppm: 2.24 (ЗН, s, СН ₃ ); 5.39 (2H, s, CH ₂ ); 7.08-7.37 (4H, m, arom. H); 7.64 (2H, dd, 6.7-H); 7.89 (2H, t, 5.8-H); 8.16 (1H, s, 3-H). Found,%: C 77.70; H 5.05; F 4.41; N, 11.84. C ₂₃ H ₁₈ FN ₃ . Calculated,%: C 77.73; H 5.10; F 4.35; N, 11.82. The base is dissolved in EtOH and acidified with a solution of HNO ₃ in EtOH. Yield 92.4%, mp 170-171 ° C (decomp.). Found,%: C 66.00; H 4.54; F 4.50; N, 13.43. C ₂₃ H ₁₈ FN ₃ · HNO ₃ . Calculated,%: C 66.02; H 4.58; F 4.54; N, 13.39.

Example 14. Step I. 2-amino-1- (4-tert-butylbenzyl) -3- (4-fluorophenacyl) benzimidazolium (IIo) bromide is prepared from 2-amino-1- (4-tert-butylbenzyl) benzimidazole and 4-fluorophenacyl bromide. Yield 93.5%, mp. 272-273 ° C (decomp.). Found,%: C 62.87; H 5.55; Br 16.11; F 3.85; N, 8.42. C ₂₆ H ₂₇ BrFN ₃ O. Calculated,%: C 62.91; H 5.48; Br 16.10; F 3.83; N, 8.46.

Stage 2. Hydrobromide 9- (4-tert-butylbenzyl) -2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole (Io). IIo bromide is cyclized in an aqueous-alcoholic solution in the presence of Na ₂ CO ₃ to the base of 9- (4-tert-butylbenzyl) -2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole. Yield 92.7%, mp. 165-166 ° C (CH ₃ CN). ¹ H NMR spectrum, δ, ppm: 1.22 (9H, s, C (CH ₃ ) ₃ ); 5.40 (2H, s, CH ₂ ); 7.14-7.42 (4H, s, arom. H); 7.64 (2H, dd, 6.7-H); 7.90 (2H, t, 5.8-H); 8.17 (1H, s, 3-H). Found,%: C 78.50; H, 6.11; F 4.81; N, 10.58. C ₂₆ H ₂₄ FN ₃ . Calculated,%: C 78.56; H 6.09; F 4.78; N, 10.57. The base is dissolved in EtOH and acidified with concentrated HBr. Yield 91.8%, mp. 269-270 ° C (decomp., EtOH). Found,%: C 65.33; H 5.24; Br 16.63; F 4.02; N, 8.78. C ₂₆ H ₂₄ FN ₃ · HBr. Calculated,%: C 65.28; H 5.27; Br 16.70; F 3.97; N, 8.78.

Example 15. Step 1. 2-amino-3- (4-fluorophenacyl) -1- (4-chloro-benzyl) benzimidazolium (IIp) bromide was prepared according to standard procedures from equimolar amounts of 2-amino-1- (4-chlorobenzyl) benzimidazole and 4-fluorophenacyl bromide in acetone. Yield 92.4%, mp. > 285 ° C (decomp.). Found,%: C 55.58; H 3.80; Br 16.88; Cl 7.52; F 4.02; N, 8.80. C ₂₂ H ₁₈ BrClFN ₃ O. Calculated,%: C 55.66; H 3.82; Br 16.83; Cl 7.47; F 4.00; N, 8.85.

Stage 2. 9- (4-Chlorobenzyl) -2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole hydrochloride (Ip). The cyclization of bromide IIn is carried out in an aqueous-alcoholic solution in the presence of Na ₂ CO ₃ . The base yield of 9- (4-chlorobenzyl) -2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole is 87.9%, so pl. 187-188 ° C (EtOH). ¹ H NMR spectrum, δ, ppm: 5.45 (2H, s, CH ₂ ); 7.12-7.50 (4H, m, arom. H); 7.66 (2H, dd, 6.7-H); 7.88 (2H, t, 5.8-H); 8.17 (1H, s, 3-H). Found,%: C 70.29; H 4.05; Cl 9.39; F, 5.11; N, 11.16. C ₂₂ H ₁₅ ClFN ₃ . Calculated,%: C 70.31; H 4.02; Cl 9.43; F 5.06; N, 11.18. The base is dissolved in EUN and acidified with concentrated HCl. Yield 94.3%, mp 266-268 ° C (decomp., EtOH). Found,%: C 64.05; H 3.85; Cl 17.27; F 4.62; N, 10.21. C ₂₂ H ₁₅ ClFN ₃ · HCl. Calculated,%: C 64.09; H 3.91; Cl 17.20; F 4.61; N, 10.19.

Example 16. Step 1. 2-Amino (2-dimethylaminoethyl) -3- (4-fluorophenacyl) benzimidazolium bromide (IIp). Obtained from 2-amino-1- (2-dimethylaminoethyl) benzimidazole and 4-fluorophenapyl bromide. Yield 80.95%, mp. 207-208 ° C (decomp.). Found,%: C 54.10; H 5.31; Br 18.81; F 4.55; N, 13.25. C ₁₉ H ₂₂ BrFN ₄ O. Calculated,%: C 54.17; H 5.26; Br 18.97; F 4.51; N, 13.30.

Step 2. 9- (2-Dimethylaminoethyl) -2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole dihydrochloride (Ip). It was synthesized by boiling IIp bromide in water, isolating a cyclic base and converting it to dihydrochloride. The yield of 63.3%, so pl. 236-237 ° C (EtOH). ¹ H NMR spectrum, δ, ppm: 2.96 (6H, s, N (CH ₃ ) ₂ ); 3.68 (2H, t, CH ₂ ); 5.11 (2H, t, CH ₂ ); 7.28 (2H, t, 3 ', 5'-H); 7.49 (2H, dt, 2 ', 6'-H); 7.91-8.17 (4H, m, arom. H); 8.58 (1H, s, 3-H); 11.52 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 57.59; H 5.42; Cl 17.88; F 4.90; N, 14.20. C ₁₉ H ₁₉ FN ₄ · 2HCl. Calculated,%: C 57.73; H 5.35; Cl 17.94; F 4.81; N, 14.17.

Example 17. Stage 1. Chloride of 2-amino-1-diethylaminoethyl-3- (4-fluorophenacyl) benzimidazolium (IIc). Obtained analogously to IIl chloride from 2-amino-1-diethylaminoethylbenzimidazole and ω-chloro-4-fluoroacetophenone in CH ₃ CN. Yield 95.6%, mp. 194 ° C. Found,%: C 62.33; H 6.51; Cl 8.70; F 4.75; N, 13.77. C ₂₁ H ₂₆ ClFN ₄ O. Calculated,%: C 62.29; H, 6.47; Cl 8.76; F 4.69; N 13.84.

Step 2. 9-Diethylaminoethyl-2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole dihydrochloride (Ic). 0.81 g (2 mmol) of IIc salt is boiled in 50 ml of water until the reaction is complete (3-5 hours, control by TLC). Then the solution is alkalinized and the precipitated base is extracted with chloroform. The extract is passed through a layer of Al ₂ O ₃ (eluent is CHCl ₃ ). The residue after evaporation of CHCl ₃ from the eluate was dissolved in acetone and acidified with a solution of HCl in 2-PrOH to give Ic dihydrochloride. Yield 0.66 g (78.3%), mp. 239-240 ° C (2-PrOH-EtOH, 4: 1). ¹ H NMR spectrum, δ, ppm: 1.28 (6H, t, 2CH ₃ ); 3.32 (4H, q, N (CH ₂ ) ₂ ); 3.67 (2H, t, NCH ₂ ); 5.04 (2H, t, NCH ₂ ); 7.23-8.15 (8H, m, arom. H); 8.55 (1H, s, 3-H); 11.12 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 59.56; H, 6.00; Cl 16.80; F 4.41; N, 13.23. C ₂₁ H ₂₃ FN ₄ · 2HCl. Calculated,%: C 59.58; H 5.95; Cl 16.75; F 4.49; N, 13.23.

Example 18. Step 1. 2-amino-1- (2-diethylaminoethyl) -3- (4-fluorophenacyl) benzimidazolium bromide (IIt). Obtained from 2-amino-1- (2-diethylaminoethyl) benzimidazole and 4-fluorophenacyl bromide. Yield 91.76%, mp. 187-188 ° C. Found,%: C 56.19; H 5.88; Br 17.90; F 4.27; N, 12.44. C ₂₁ H ₂₆ BrFN ₄ O. Calculated,%: C 56.13; H 5.83; Br 17.78; F 4.23; N, 12.47.

Stage 2. Dihydrobromide 9- (2-diethylaminoethyl) -2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole (It). The cyclic base isolated after boiling IIt bromide in water is converted into dihydrochloride using a solution of HCl in 2-RgOH. Yield 91.8%, mp. 265-267 ° C (decomp., EtOH). ¹ H NMR spectrum, ppm: 1.31 (6H, t, 2CH ₃ ); 3.35 (4H, q, N (CH ₂ ) ₂ ); 3.70 (2H, t, NCH ₂ ); 5.09 (2H, t, NCH ₂ ); 7.19-8.10 (8H, m, arom. H); 8.71 (1H, s, 3-H); 11.53 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 49.22; H 4.97; Br 31.18; F 3.76; N, 10.87. C ₂₁ H ₂₃ FN ₄ · 2HBr. Calculated,%: C 49.23; H 4.92; Br 31.20; F 3.71; N, 10.94.

Example 19. Step 1. 2-amino-1- (2-pyrrolidinoethyl) -3- (4-fluorophenacyl) benzimidazolium bromide (IIy). Obtained in the usual way from 2-amino-1- (2-pyrrolidinoethyl) benzimidazole and 4-fluorophenacyl bromide in acetone. Yield 88.8%, mp. 179-180 ° C. Found,%: C 56.34; H 5.45; Br 17.68; F 4.36; N, 12.56. C ₂₁ H ₂₄ BrFN ₄ O. Calculated,%: C 56.38; H 5.41; Br 17.86; F 4.25; N, 12.52.

Step 2. 9- (2-Pyrrolidinoethyl) -2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole dihydrochloride (Iu). Synthesized similarly to dihydrochloride It. Yield 81.63%, mp. 257-258 ° C (decomp., 2-RgON). ¹ H NMR spectrum, δ, ppm: 2.08 (4H, q, - (CH ₃ ) ₂ -); 3.31 (2H, t, NCH ₂ ); 3.64 (2H, t, NCH ₂ ); 3.76 (2H, t, NCH ₂ ); 5.17 (2H, t, NCH ₂ ); 7.21 (2H, t, 3 ', 5'-H); 7.47 (2H, dt, 2 ', 6'-H); 7.86-8.20 (4H, m, arom. H); 8.48 (1H, s, 3-H); 12.40 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 59.79; H 5.60; Cl 16.78; F 4.44; N, 13.39. C ₂₁ H ₂₁ FN ₄ · 2HCl Calculated,%: C 59.86; H 5.50; Cl 16.83; F 4.51; N, 13.30.

Example 20. Step I. 2-amino-1- (2-piperidinoethyl) -3- (4-fluorophenacyl) benzimidazolium (IIp) bromide was prepared by reacting 2-amino-1- (2-piperidinoethyl) benzimidazole and 4-fluorophenacyl bromide in acetone. Yield 92.7%, mp. 185-186 ° C. Found,%: C 57.30; H 5.68; Br 17.25; F 4.06; N, 12.25. C ₂₂ H ₂₆ BrFN ₄ O. Calculated,%: C 57.27; H 5.68; Br 17.32; F 4.12; N, 12.14.

Step 2. 9- (2-Piperidinoethyl) -2- (4-fluorophenyl) imidazo [1,2-a] benzimidazole (Iph) dihydrochloride is synthesized in a similar manner to the It salt. The yield of 90.6%, so pl. 260-262 ° C (EtOH). ¹ H NMR spectrum, ppm: 1.38-2.18 (6H, m, - (CH ₂ ) ₃ -); 2.87-3.17 (4H, m, N (CH ₂ ) ₂ ); 3.59 (2H, t, NCH ₂ ); 5.22 (2H, t, NCH ₂ ); 7.24 (2H, t, 3 ', 5'-H); 7.48 (2H, dt, 2 ', 6'-H); 7.86-8.32 (4H, m, arom. H); 8.53 (1H, s, 3-H); 11.92 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 60.73; H 5.73; Cl 16.37; F 4.33; N, 12.84. C ₂₂ H ₂₃ FN ₄ · 2HCl. Calculated,%: C 60.69; H 5.79; Cl 16.29; F 4.36; N, 12.87.

Example 21. Step 1. 2-amino-1-dimethylaminoethyl-3- (3,4-dichlorophenacyl) benzimidazolium bromide (IIx). Obtained from 2-amino-1- (2-di-methylaminoethyl) benzimidazole and 3,4-dichlorophenacyl bromide in acetone. The yield of 83.2%, so pl. 187-188 ° C (decomp.). Found,%: C 48.45; H 4.52; Br 16.78; Cl 14.95; N, 11.91. C ₁₉ H ₂₁ BrCl ₂ N ₄ O. Calculated,%: C 48.33; H 4.48; Br 16.92; Cl 15.02; N, 11.86.

Step 2. 9- (2-Dimethylaminoethyl) -2- (3,4-dichlorophenyl) -imidazo [1,2-a] benzimidazole dihydrochloride (Ix). 0.81 g (2 mmol) of IIx salt is boiled in 50 ml of water until the reaction is complete (1.5-2 hours, control by TLC). Then the solution is alkalinized and the precipitated base is extracted with chloroform. The extract is passed through a layer of Al ₂ O ₃ (eluent is CHCl ₃ ). The base after evaporation of CHCl ₃ from the eluate is crystallized from isooctane to give 9-dimethylaminoethyl-2- (3,4-dichlorophenyl) imidazo [1,2-a] benzimidazole. The yield of 90.8%, so pl. 130 ° C. ¹ H NMR spectrum, ppm: 3.02 (6H, s, N (CH ₃ ) ₂ ); 3.75 (2H, t, CH ₂ ); 5.17 (2H, t, CH ₂ ); 7.49 (2H, dt, 5 ', 6'-H); 7.68 (1H, d, 2'-H); 7.94 (1H, q, 8-H); 8.14 (2H, dd, 6.7-H); 8.28 (1H, t, 5-H); 8.67 (1H, s, 3-H); 12.04 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 61.17; H 4.80; Cl 14.24; N, 16.89. C ₁₉ H ₁₈ Cl ₂ N ₄ . Calculated,%: C 61.13; H 4.86; Cl 14.27; N, 16.83. The resulting base is dissolved in acetone and the solution conc. HCl. Yield 86.75%. Mp 254-256 ° C (EtOH-H ₂ O). Found,%: C 50.90; H 4.96; Cl 31.60; N, 12.54. C ₁₉ H ₂₀ Cl ₂ N ₄ · 2HCl Calculated,%: C 50.91; H 4.95; Cl 31.64; N, 12.50.

Example 22. Step 1. 2-amino-3- (3,4-dichlorophenacyl) -1- (2-diethylaminoethyl) benzimidazolium (IIc) bromide was prepared starting from 2-amino-1- (2-diethylaminoethyl) benzimidazole and 3, 4-dichlorophenacyl bromide. Yield 95.0% mp. 190 ° C. Found,%: C 50.44; H 5.14; Br 15.85; Cl 14.21; N, 11.24. C ₂₁ H ₂₅ BrCl ₂ N ₄ O. Calculated,%: C 50.42; H 5.04; Br 15.97; Cl 14.17; N, 11.20.

Stage 2. The dihydrochloride of 2- (3,4-dichlorophenyl) -9- (2-diethylaminoethyl) imidazo [1,2-a] benzimidazole (Ic) was synthesized by boiling IIc bromide in water, isolating the cyclic base and converting it to dihydrochloride. The yield of 83.4%, so pl. 254-256 ° C (decomp., EtOH). Nuclear Magnetic Resonance Spectrum ¹ H δ, ppm: 1.36 (6H, t, 2CH ₃ ); 3.33 (4H, q, N (CH ₂ ) ₂ ); 3.64 (2H, t, NCH ₂ ); 5.17 (2H, t, NCH ₂ ); 7.47 (2H, dt, 5 ', 6'-H); 7.67 (1H, d, 2'-H); 7.91 (1H, q, 8-H); 8.10 (2H, dd, 6.7-H); 8.25 (1H, t, 5-H); 8.65 (1H, s, 3-H); 11.98 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 53.23; H 5.02; Cl 29.98; N, 11.77. C ₂₁ H ₂₂ Cl ₂ N ₄ · 2HCl Calculated,%: C 53.18; H 5.10; Cl 29.90; N, 11.82.

Example 23. Step 1. 2-Amino-3- (3,4-dichlorophenacyl) -1- (2-pyrrodinoethyl) benzimidazolium bromide (IIh) was prepared by reacting equimolar amounts of 2-amino-1- (2-pyrrolidinoethyl) benzimidazole and 3 , 4-dichlorophenacyl bromide in acetone. Yield 86.5%, mp. 187-188 ° C. Found,%: C 50.67; H 4.53; Br 16.11; Cl 14.24; N, 11.22. C ₂₁ H ₂₃ BrCl ₂ N ₄ O. Calculated,%: C 50.62; H 4.65; Br 16.04; Cl 14.23; N, 11.24.

Stage 2. The dihydrochloride of 2- (3,4-dichlorophenyl) -9- (2-pyrrolidinoethyl) imidazo [1,2-a] benzimidazole (Ih) was synthesized in the same way as the dihydrochloride It. Yield 78.6%, mp. 227-228 ° C (CH ₃ CN). ¹ H NMR spectrum, δ, ppm: 2.14 (4H, q, - (CH ₂ ) ₂ -); 3.37 (2H, t, NCH ₂ ); 3.68 (2H, t, NCH ₂ ); 3.80 (2H, t, NCH ₂ ); 5.15 (2H, t, NCH ₂ ); 7.45 (2H, dt, 5 ', 6'-H); 7.64 (1H, d, 2'-H); 7.89 (1H, q, 8-H); 8.12 (2H, dd, 6.7-H); 8.28 (1H, t, 5-H); 8.71 (1H, s, 3-H); 12.03 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 53.34; H 4.77; Cl 30.40; N, 11.79. C ₂₁ H ₂₀ Cl ₂ N ₄ · 2HCl. Calculated,%: C 53.41; H 4.70; Cl 30.33; N, 11.86.

Example 24. Step I. 2-amino-3- (3,4-dichlorophenacyl) -1- (2-piperidinoethyl) benzimidazolium (IIш) bromide is prepared from 2-amino-1- (2-piperidinoethyl) benzimidazole and 3, 4-dichlorophenacyl bromide. Yield 89.84%, mp. 190-191 ° C. Found,%: C 51.20; H 4.99; Br 15.54; Cl 13.84; N, 11.00. C ₂₂ H ₂₅ BrCl ₂ N ₄ O Calculated,%: C 51.28; H 4.92; Br 15.60; Cl 13.84; N, 10.94.

Stage 2. The dihydrochloride of 2- (3,4-dichlorophenyl) -9- (2-piperidinoethyl) imidazo [1,2-a] benzimidazole (Is) is synthesized similarly to the dihydrochloride It. The yield of 74.7%, so pl. 227-228 ° C (EtOH). ¹ H NMR spectrum, δ, ppm: 1.30-1.98 (6H, m, - (CH ₂ ) ₃ -); 2.85-3.45 (4H, m, N (CH ₂ ) ₂ ); 3.62 (2H, t, NCH ₂ ); 5.05 (2H, t, NCH ₂ ); 7.40 (2H, dt, 5 ', 6'-H); 7.65-7.98 (4H, m, arom. H); 8.17 (1H, s, 8-H); 8.52 (1H, s, 3-H); 10.87 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 54.28; H 4.89; Cl 29.20; N, 11.52. C ₂₂ H ₂₂ Cl ₂ N ₄ · 2HCl. Calculated,%: C 54.24; H 4.97; Cl 29.16; N, 11.52.

Example 25. Step 1. 2-amino-3- (2,4-Dichlorophenacyl) -1- (2-diethylaminoethyl) benzimidazolium bromide (II) is prepared in the usual way from 2-amino-1- (2-diethylaminoethyl) benzimidazole and 2 , 4-dichlorophenacyl bromide in acetone. Yield 87.2%, mp. 196-197 ° C (decomp.). Found,%: C 50.44; H 5.14; Br 15.85; Cl 14.21; N, 11.24. C ₂₁ H ₂₅ BrCl ₂ N ₄ O. Calculated,%: C 50.42; H 5.04; Br 15.97; Cl 14.17; N, 11.20.

Stage 2. Hydrobromide 2- (2,4-dichlorophenyl) -9- (2-diethylaminoethyl) imidazo [1,2-a] benzimidazole (Is). 1.00 g (2 mmol) of IIsc bromide is boiled in 50 ml of water until the reaction is complete (3-5 hours, control by TLC). The reaction mixture is cooled, the precipitate formed is filtered off, washed with cold water and air dried. Yield 0.94 g (97.5%), mp. 221-222 ° C (EtOH). ¹ H NMR spectrum, δ, ppm: 1.29 (6H, t, 2CH ₃ ); 3.21 (4H, q, N (CH ₂ ) ₂ ); 3.51 (2H, t, NCH ₂ ); 5.11 (2H, t, NCH ₂ ); 7.10-8.40 (8H, m, arom. H); H ⁺ in exchange. Found,%: C 50.40; H 5.10; Br 16.00; Cl 14.13; N, 11.17. C ₂₁ H ₂₃ Cl ₂ N ₄ · HBr. Calculated,%: C 50.42; H 5.04; Br 15.97; Cl 14.17; N, 11.20.

Example 26. Oxalate 9- (2-piperidinoethyl) -2- (4-chlorophenyl) imidazo [1,2-a] benzimidazole (Ië). Isolated under the action of an alcohol solution of an equivalent amount of oxalic acid on an acetone solution of base Ie (see example 6, stage 2). Yield 89.11%. Mp 233-234 ° C (EtOH). ¹ H NMR spectrum, δ, ppm: 1.40-2.05 (6H, m, - (CH ₂ ) ₃ -); 3.10-3.51 (4H, m, N (CH ₂ ) ₂ ); 3.59 (2H, t, NCH ₂ ); 5.07 (2H, t, NCH ₂ ); 7.27-8.14 (8H, m, arom. H); 8.55 (1H, s, 3-H); 11.25 (1H, broad s, N ⁺ H); H ⁺ in exchange. Found,%: C 61.50; H 5.33; Cl 7.61; N, 11.90. C ₂₂ H ₂₃ ClN ₄ · (COOH) ₂ . Calculated,%: C 61.47; H 5.37; Cl 7.56; N, 11.95.

Example 27. Succinate 9- (2-piperidinoethyl) -2- (4-chlorophenyl) imidazo [1,2-a] benzimidazole (Iy). An equivalent amount of succinic acid was obtained by mixing an acetone solution isolated from cyclization of Ie base with an alcohol solution. Yield 84.2%. Mp 195-196 ° C (CH ₃ CN-2-PrOH). Nuclear Magnetic Resonance Spectrum ¹ H δ, ppm: 1.38-2.11 (6H, m, - (CH ₂ ) ₃ -); 2.81-3.50 (8H, m, N (CH ₂ ) ₂ + (CH ₂ COO) ₂ ); 3.65 (2H, t, NCH ₂ ); 4.88 (2H, t, NCH ₂ ); 7.19-8.00 (8H, m, arom. H); 8.34 (1H, s, 3-H); H ⁺ in exchange. Found,%: C 62.75; H 5.80; Cl 7.20; N, 11.42. C ₂₂ H ₂₃ ClN ₄ · C ₄ H ₆ O ₄ . Calculated,%: C 62.84; H 5.88; Cl 7.13; N, 11.27.

Example 28. Step 1. 2-Amino-3- (2,4-dichlorophenacyl) -1- (2-piperidinoethyl) benzimidazolium bromide (IIe). Obtained by the interaction of equimolar amounts of 2-amino-1- (2-piperidinoethyl) benzimidazole and 2,4-dichlorophenacyl bromide in acetone. Yield 88.7%, mp. 207-208 ° C (decomp.). Found,%: C 50.44; H 5.14; Br 15.85; Cl 14.21; N, 11.24. C ₂₁ H ₂₅ BrCl ₂ N ₄ O. Calculated,%: C 50.42; H 5.04; Br 15.97; Cl 14.17; N, 11.20.

Stage 2. Hydrobromide 2- (2,4-dichlorophenyl) -9- (2-piperidinoethyl) imidazo [1,2-a] benzimidazole (Ie). Isolated as a result of boiling IIe bromide in water until complete cyclization and cooling of the reaction mass. Yield 98.1%, mp. 275-276 ° C (decomp., EtOH). Nuclear Magnetic Resonance Spectrum ¹ H δ, ppm: 1.14-1.79 (6H, m, -CH ₂ ) ₃ ); 2.18-3.05 (6H, m, N (CH ₂ ) ₃ ); 4.36 (2H, t, NCH ₂ ); 7.11-8.32 (8H, m, arom. H); H ⁺ in exchange. Found,%: C 53.40; H 4.75; Br 16.20; Cl 14.29; N, 11.36. C ₂₂ H ₂₃ Cl ₂ N ₄ · HBr. Calculated,%: C 53.46; H 4.69; Br 16.16; Cl 14.35; N, 11.34.

Example 29. Step 1. 2-amino-3- (2,4-Dichlorophenacyl) -1- (2-piperidinoethyl) benzimidazolium chloride (IIu) was obtained by boiling equimolar amounts of 2-amino-1-piperidinoethylbenzimidazole and ω, 2,4 trichloroacetophenone in CH ₃ CN. The yield of 83.9%, so pl. 266-267 ° C (decomp.). Found,%: C 56.44; H 5.37; Cl 22.66; N, 12.00. C ₂₂ H ₂₅ Cl ₃ N ₄ O. Calculated,%: C 56.48; H 5.39; Cl 22.73; N, 11.98.

Stage 2. Dihydrochloride of 2- (2,4-dichlorophenyl) -1-piperidinoethylimidazo [1,2-a] benzimidazole (Iu). The cyclization of chloride II is carried out in boiling water, the isolated tricyclic base using conc. HCl is converted to dihydrochloride Iu. Yield 92.7%. Mp 283-284 ° C (decomp., 90% EtOH). ¹ H NMR spectrum, δ, ppm: 1.17-1.84 (6H, m, - (CH ₂ ) ₃ -); 2.21-3.21 (6H, m, (CH ₂ ) ₃ ); 4.40 (2H, t, NCH ₂ ); 7.15-8.36 (8H, m, arom. H); H ⁺ in exchange. Found,%: C 54.30; H 5.03; Cl 29.12; N, 11.55. C ₂₂ H ₂₂ ClN ₄ · HCl. Calculated,%: C 54.34; H 4.97; Cl29.16; N, 11.53.

Example 30. Sulfate 9- (2-diethylaminoethyl) -2- (4-chlorophenyl) imidazo [1,2-a] benzimidazole (Ia). The alcoholic solution of base Id (mp. 86-87 ° C) described in Example 5 is acidified to pH 1-2 with a dilute acetone solution of H ₂ SO ₄ . The precipitate was separated and washed thoroughly with acetone. Yield 99.4%. Mp 230-232 ° C (decomp., EtOH-H ₂ O). Found,%: C 54.22; H 5.47; Cl 7.60; N, 12.00; S 6.94. C ₂₁ H ₂₃ ClN ₄ · H ₂ SO ₄ . Calculated,%: C 54.25; H 5.42; Cl 7.62; N, 12.05; S 6.90.

Example 31. The study of hemorheological properties.

Research Methods. The syndrome of increased blood viscosity was simulated using hyperthermia (Plotnikov MB, Koltunov AA, Aliev OI, Bull. Exp. Biol. And honey., 1996, No. 9, p.274-275), using blood of rabbits. For this, samples in a volume of 1 ml were placed in a thermostat and incubated for 1 hour at a temperature of 42.5 ° C. Blood was taken from the ear vein of the rabbit in plastic tubes with 3.8% sodium citrate in a ratio of 1: 9. The hematocrit value was determined by the standard method for centrifuging capillaries with blood samples on an MGC-8 microhemocentrifuge (8000 rpm, 3 minutes) as the ratio of the length in the centrifuge capillary of a red blood cell column to a plasma column. Blood samples were standardized to a single hematocrit of 45% by adding or removing the required amount of plasma. Pentoxifylline (Aventis, Germany) was chosen as a comparison drug, which has been used in the clinic for a long time as a corrector of rheological disorders. The test substances and pentoxifylline at concentrations of 10, 50, 100, 500 μmol / L were added to blood samples 15 minutes before the start of incubation. 10 μl of warm (37 ° C) physiological saline (0.89% sodium chloride solution) was added to control samples. The viscosity of blood samples was measured before and after incubation.

Blood viscosity was measured on an AKP-2 viscometer (Rus-Can Research Ltd., Russia), the principle of operation of which is based on the method of rotational viscometry with a freely floating rotor cylinder ((N.A.Dobrovolsky, Yu.M. Lopukhin, A. S. Parfyonov et al. Rheological studies in medicine: Collection of scientific papers, M .: NIH RAMS, 1998, p. 45-51.) To determine the viscosity of a blood sample in a volume of 0.84 ml with a dosing pipette, it was transferred to a measuring a kyuvezu, a rotor-float was placed in the same place, and the kyuvezu was installed for 10 minutes in the device thermostat block. A rezu was transferred to a measuring cell and after the readings were established (unchanged value within 45 seconds after its last change), the analysis result was read from a digital display, and blood viscosity was studied at the following shear rates of 300, 200, 100, 50, 30, 20, 10, 5 , 3 s ^-1 (reverse seconds), simulating different blood flow intensities in blood vessels. Blood viscosity was measured in centipoise (cP). Blood viscosity in total reflects the red blood cell deformability, the state of aggregation of red blood cells and blood fibrinogen content (Roitman E.V., Gema Tology and Transfusiology, 1996, No. 3, p. 36-40). The effect of substances on erythrocyte aggregation was evaluated by the aggregation index, calculated as the ratio of blood viscosity at a shear rate of 3 reverse seconds (s ^-1 ) to blood viscosity at 100 s ^-1 (Dintenfass L., Aging, 1989, No. 1, p.99- 125).

Calculation of the inhibitory effect of the compound on red blood cell aggregation was carried out according to the formula: InAE = 100- (B / A) × 100%; Where:

A - the degree of aggregation of red blood cells without the studied compounds;

B - the degree of aggregation of red blood cells after incubation of the suspension with the studied compounds.

For some active compounds and a comparison drug - pentoxifylline - the concentration dependences of the effect were studied and non-linear regression analysis was used to calculate the concentrations that cause a decrease in the red blood cell aggregation index by 20% - EC ₂₀ (Dukhanin A.S., Gubaeva F.R., Experiment. and Clinical Pharmacology, 1998, No. 4, pp. 66-71).

The acute toxicity of the test compound was studied on white outbred male mice weighing 18-22 g with intraperitoneal administration. The death of animals was recorded within two weeks. The calculation of the LD ₅₀ value was carried out according to the method of Prozorovsky (Prozorovsky VB et al., Pharmacol. And Toxicol, 1978, No. 4, pp. 497-502). As an objective indicator of the conditional breadth of the therapeutic effect, the conditional therapeutic index of the compounds was used, which was determined by dividing the acute toxicity index LD ₅₀ by the effective concentration of the EC ₂₀ compound.

Statistical data processing was performed using the t-paired student criterion and ANOVA (Newman-Keuls post-hoc test) in the Statistica 5.0 software.

Test results. Thermostating of blood samples led to pronounced rheological abnormalities and a clear change in viscosity indicators: at a shear rate of 300 s ^-1, blood viscosity increased by 17.3%, at a shear rate of 3 s ^-1 - 28.5% compared with blood samples, not exposed to hyperthermia, and the increase in the aggregation index of heated red blood cells was reliably 20.74%.

Under the influence of the studied substances (Ich, Ip, It, Iu, Ii, Ik, Im), a significant decrease in blood viscosity was observed at a shear rate of 300 s ^-1 (Table 1), which indicates an improvement in the deformability of red blood cells under the influence of these substances.

At a low shear rate of 3 s ^-1, most of the compounds studied also had a significant effect on blood viscosity in the direction of its decrease. Thus, for 9-substituted 2-halogenophenylimidazo [1,2-a] benzimidazoles, an antiplatelet effect on erythrocytes was established, while the compounds Ich, Ip, It, Iu significantly exceeded the comparison drug pentoxifylline in terms of activity.

Table 1
The effect of 2-halogenophenyl substituted imidazobenzimidazole derivatives (at a concentration of 100 μmol / L) on the viscosity characteristics of blood samples of rabbits with experimental in vitro syndrome of increased blood viscosity (M ± m). Blood samples Blood viscosity IAE, cu 300 s ^-1 30 s ^-1 3 s - ¹ The control 4.45 ± 0.16 7.15 ± 0.25 9.62 ± 0.15 2.17 ± 0.07 Ia 4.12 ± 0.07 6.47 ± 0.20 8.19 ± 0.32 * 1.82 ± 0.08 * Ib 4.00 ± 0.04 6.25 ± 0.02 * 8.16 ± 0.08 * 1.82 ± 0.03 * Ie 4.07 ± 0.11 6.35 ± 0.12 * 8.17 ± 0.20 * 1.84 ± 0.04 * Ig 4.26 ± 0.14 6.51 ± 0.20 8.32 ± 0.40 * 1.84 ± 0.09 Id 4.24 ± 0.13 6.44 ± 0.14 8.30 ± 0.32 * 1.84 ± 0.06 * Ic 3.86 ± 0.07 5.96 ± 0.13 7.83 ± 0.37 * 1.73 ± 0.07 * Ic 3.43 ± 0.03 * 4.57 ± 0.08 * 6.08 ± 0.34 * 1.37 ± 0.10 * Ish 3.99 ± 0.08 6.18 ± 0.10 7.96 ± 0.06 * 1.77 ± 0.03 * IIt 4.00 ± 0.15 6.23 ± 0.31 8.31 ± 0.35 * 1.87 ± 0.08 * Ip 3.45 ± 0.07 * 4.85 ± 0.13 * 6.65 ± 0.36 * 1.52 ± 0.12 * It 3.85 ± 0.03 * 5.42 ± 0.12 * 7.08 ± 0.10 * 1.60 ± 0.05 * Iu 3.42 ± 0.04 * 4.73 ± 0.08 * 6.48 ± 0.29 * 1.48 ± 0.11 * If 4.09 ± 0.08 6.43 ± 0.08 8.59 ± 0.14 * 1.91 ± 0.03 * Ii 4.17 ± 0.08 * 6.23 ± 0.16 * 8.47 ± 0.22 * 1.91 ± 0.09 * Ik 3.83 ± 0.11 * 5.58 ± 0.20 * 7.72 ± 0.21 * 1.76 ± 0.10 * Im 3.93 ± 0.13 * 5.68 ± 0.23 * 7.87 ± 0.15 * 1.77 ± 0.04 * Pentoxifylline 4.07 ± 0.04 6.51 ± 0.10 8.27 ± 0.29 * 1.84 ± 0.06 * * - the data are reliable in relation to the control (p <0.05), paired student criterion.

table 2
Concentration dependence of hemorheological activity of some studied compounds Connection cipher The concentration of the substance, µmol / l The value of the hemorheological effect,% Ic 10
fifty
500 15,2
20.78
34.02 Ic 10
fifty
500 17.46
25.74
38.48 It 10
fifty
500 13.59
23.16
49.90 IIt 10
fifty
500 14.61
22.86
28.34 Ip 10
fifty
500 18.8
28.07
43.61 Iy 10
fifty
500 19.56
32.33
47.03 Pentoxifylline 10
fifty
500 4,58
10.49
28.13

Table 3
Indicators of acute toxicity, effective concentration and conditional therapeutic index of 2-halogenophenyl substituted imidazobenzimidazole. Connection cipher Sharp Accuracy LD ₅₀ Effective concentration of EC ₂₀ compound (mmol / L) Conventional Therapeutic Index (UTI) LD ₅₀ / EC ₂₀ mmol / kg mg / kg Ic 0.395 187.21 0,033 12.09 Ic 0.505 238.38 0.012 41.84 Ip 0.387 152.77 0.013 29.21 It 0.465 196.8 0,027 17.08 IIt 0.406 172.5 0,037 10.95 Iy 0.464 195.32 0.09 54.46 Pentoxifylline 1.010 289.7 0.197 5.12

The concentration dependences of the activity of some compounds were studied (Table 2). As can be seen from the table, the level of hemorheological activity of the investigated substances significantly exceeds that of the comparison drug. In this case, there is a clear dependence of the magnitude of the effect of the compounds on their concentration in the samples.

In the experimental determination of EC _{20 it was} found that the compounds Ic, Ich, Ip, It, IIt, Iy exceeded pentoxifylline in the level of hemorheological activity of 6.05; 16.35; 14.91; 7.25; 5.33; 23.17 times, respectively (Table 3).

Indicators of acute toxicity (LD ₅₀ ) for mice with intraperitoneal administration of these compounds and the calculated indices of relative safety indices (conditional therapeutic index) for the studied compounds are also shown in Table 3. According to the last value of the substance, Ic, Ih, Ip, It, IIt, Iy exceeded the reference drug in 2.37; 8.18; 5.71; 3.34; 2.14; 10.65 times, respectively.

Thus, the level of hemorheological activity of salts of 9-substituted 2-halogenphenylimidazo [1,2-a] benzimidazoles and intermediate products of their synthesis significantly exceeds the activity of pentoxifylline. In this case, a clear dependence of the magnitude of the effect on concentration is observed.

Claims (2)

1. Salts of 9-substituted 2-halo-phenylimidazo [1,2-a] benzimidazoles of the general formula

where R is C ₁ -C ₆ alkyl-, allyl-, benzyl- and substituted benzyl-, dialkylamino-alkyl; X is F, Cl, Br at the o-, m-, p-positions of the phenyl core, dihalogens at 3,4-, 2,4-, 3,5- and other positions of the phenyl core; Y is Cl, Br, NO ₃ , SO ₄ , (COOH) ₂ , (CH ₂ COOH) ₂ , CH ₃ C ₆ H ₄ SO ₃ H and other pharmaceutically acceptable acid residues; n = 0-2 (except for compounds with R - (CH ₂ ) ₂ NEt ₂ ; X - Br or Cl; Y - Cl; n = 2; R - (CH ₂ ) ₂ NMe ₂ ; X - Y = Cl, n = 2), possessing hemorheological properties. 2. Halides of 1-substituted 3-halogenophenacyl-2-aminobenzimidazolium of the general formula

where R is C ₁ -C ₆ alkyl-, allyl-, benzyl- and substituted benzyl-, dialkylamino-alkyl; X is F, Cl, Br at the o-, m-, p-positions of the phenyl core, dihalogens at 3,4-, 2,4-, 3,5- and other positions of the phenyl core; Y - Cl, Br, I (except for compounds with R - (CH ₂ ) ₂ NEt ₂ ; X - Br or Cl; Y - Br; R - (CH ₂ ) ₂ NMe ₂ ; X - Cl; Y - Br) possessing hemorheological properties.