RU2629022C1 - 11-(4-TRET-BUTYLBENZYL) - AND PHENACYLREPLACED 2,3,4,5-TETRAHYDRO [1,3] DIAZEPINO [1,2-a] BENZIMIDAZOLE WITH ANXIOLYTIC ACTIVITY - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention relates to the new derivatives in the 2,3,4,5-tetrahydro[1,3]diazepino [1,2-a]benzimidazole, with general formula 1:

.

The new hydrobromides 11-(4-t-butylbenzyl) - and 11-phenacyl substituted 2,3,4,5-tetrahydro[1,3]diazepino[1,2-A]benzimidazoles with anxiolytic activity are obtained.

EFFECT: improved compounds properties.

4 cl, 2 tbl, 3 ex

Description

The invention relates to new derivatives in the series 2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazole, namely to the previously undescribed 11- (4-tert-butylbenzyl) and 1-phenacyl substituted 2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazole of the general formula 1:

where n = 0.1; R = H, Br; R ₁ = 4- (CH ₃ ) ₃ SS ₆ H ₄ , 4-FC ₆ H ₄ CO, 3,4- (OH) ₂ C ₆ H ₃ CO;

including when

n is 1; R = H, R ₁ = 4- (CH ₃ ) ₃ CC ₆ H ₄ (a); R = H, R ₁ = 4-FC ₆ H ₄ CO (b);

n is 0; R = Br, R ₁ = 3.4- (OH) ₂ C ₆ H ₃ CO (c),

possessing anxiolytic activity.

Neurotic disorders are currently one of the leading medical and social problems. Their prevalence among the population of developed countries is extremely high (10-20%), and the average annual growth rate of their prevalence in the world exceeds 10%. Therefore, the problem of effective diagnosis and treatment of neurotic disorders goes today to one of the leading places in medicine and pharmacology. One of the most characteristic clinical manifestations of neurosis (primarily neurasthenia), as well as psychoemotional disorders in the framework of psychosomatic diseases are anxiety disorders [1]. Modern medicine has a large variety of drugs for the prevention and treatment of neuropsychiatric diseases: agonists of benzodiazepine receptors (diazepam, phenazepam, etc.); serotonin receptor agonists (buspirone); substances of various types of action (benactisine, etc.) [2]. Most drugs have adverse side effects of CNS depression: daytime drowsiness, lethargy, muscle weakness, dull emotions, headache, dizziness, ataxia, etc. Cognitive function impairment is possible, and with prolonged use, addiction, drug dependence [3 ]. In this regard, the search for new effective tranquilizers, which against the background of high biological activity would not have a toxic effect and had minimal side effects, is relevant [4].

In early studies, psychotropic activity was found in benzimidazole derivatives, which also had a low risk of adverse effects. Experimental studies previously conducted at the Volgograd State Medical University, revealed anxiolytic activity in benzimidazole derivatives. In this regard, it is promising to study the combination of two privileged structures - derivatives of diazepine and benzimidazole - diazepinobenzimidazole, which are highly effective and have a low risk of adverse reactions.

In the series 2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazole, the hydrochlorides of 11-phenacyl derivatives of 2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazole with antihypertensive properties [5].

The closest in structure are the 11-phenoxyethyl- and benzyl-substituted 2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazole hydrohalides having antiplatelet activity [6].

In the series 2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazole, compounds exhibiting anxiolytic activity are not known.

The technical result of the invention is new compounds in the series 2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazole, exhibiting quite effective and unknown for this series anxiolytic activity that does not cause muscle relaxation and hypnogenic effect.

The technical result is achieved by compounds 1.

The synthesis of compounds at n = 1, including 1a, b, consists in the alkylation of 2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazole (2) similarly to the procedure [7] 2- ( 4-tert-butylbenzyl) bromide or 4-fluorophenacyl bromide when boiled in nitromethane or acetonitrile:

1a R ₁ = 4- (CH ₃ ) ₃ SS ₆ H ₄ ; 1b R ₁ = 4-FC ₆ H ₄ CO

The synthesis of compounds at n = 0, including 1c, is carried out in 2 stages. First, diazepinobenzimidazole 2 is alkylated with 3,4-dimethoxyphenacyl bromide in nitromethane, and then the phenacyl derivative 3 formed is introduced into the hydrolysis reaction with hydrobromic acid, which is accompanied by bromination of the methylene group of the phenacyl fragment.

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

Example 1. Hydrobromide 11- (2- (4-tert-butylbenzyl) -2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazole (1a).

A mixture of 1.87 g (10 mmol) of 2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazole (2), 2.27 g (10 mmol), 2- (4-tert-butylbenzyl bromide and 10 ml of nitromethane was boiled for 5 hours. Then the mixture was cooled, 3.72 g (90%) of 11- [2- (4-tert-butylbenzyl) -2,3,4,5-tetrahydro [1,3] diazepino [ 1,2- a ] benzimidazole (1a). Colorless crystals with mp 249-251 ° C (from isopropanol).

¹ H NMR spectrum, (300 MHz), δ, ppm (DMSO-d ₆ ): 1-20 (s, 9H, C (CH ₃ ) ₃ ), 1.97-2.10 (m, 4H, 2H (3), 2H (4)); 3.57-3.58 (m, 2H, C (5) H ₂ ); 4.35-4.36 (m, 2H, C (2) H ₂ ); 5.46 (s, 2H, CH2 Ar); 7.22-7.39 (m, 6H, H (8), H (9), H (2 '), H (3'), H (5 '), H (6')) ¹ ( ¹ Hereinafter, the numbers with the prime indicates the protons of the aryl substituent at position 11 of diazepinobenzimidazole 1); 7.48 (d, 1H, H (10) or H (7), J = 7.6 Hz), 7.71 (d, 1H, H (7) or H (10)); 9.05 (s, 1H, ⁺ NH).

Found, (%): C 63.52; H 6.95; Br 19.07; N 10.20. C ₂₂ H ₂₇ N ₃ ⋅HBr. Calculated, (%): C 63.77; H 6.81; Br 19.28; N 10.14.

Example 2. Hydrobromide 1- (4-fluorophenyl) -2- (2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazol-11-yl) ethanone (1b).

A solution of 0.37 g (2 mmol) of 2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazole and 0.44 g (2 mmol) of 4-fluorophenacyl bromide in 10 ml of acetonitrile was boiled for 12 hours. The precipitate formed after cooling, it was filtered off, washed with acetone. Yield 0.68 g (84%). Colorless crystals with so pl. 246-247 ° C (from ethanol).

¹ H NMR spectrum, (600 MHz), δ, ppm (DMSO-d ₆ ): 1.95-2.11 (m, 4H, C (3) H ₂ , C (4) H ₂ ); 3.47-3.48 (m, 2H, C (5) H ₂ ); 4.37-4.38 (m, 2H, C (2) H ₂ ); 5.99 (s, 2H, CH2 Ar); 7.32 (t, 1H, H (8) or H (9), J = 7.6 Hz); 7.38 (t, 1H, H (9) or H (8), J = 1.1 Hz); 7.49 (t, 2H, H (3 '), H (5'), J = 8.8 Hz); 7.62 (d, 1H, H (7) or H (10), J = 7.9 Hz); 7.72 (d, 1H, H (10) or H (7), J = 8.1 Hz); 8.18 (dd, 2H, H (2 '), H (6'), J ¹ = 8.8, J ² = 5.4 Hz); 8.83 (s, 1H, ⁺ NH).

Found, (%): N 10.25. C ₁₉ H ₁₈ FN ₃ O⋅HBr. Calculated, (%): N 10.39

Example 3. 2-Bromo-1- (3,4-dihydroxyphenyl) -2- (2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazol-11-yl) ethanone ( 1c).

Stage 1. Hydrobromide of 1- (3,4-dimethoxyphenyl) -2- (2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazol-11-yl) ethanone (3). A solution of 0.37 g (2 mmol) of diazepinobenzimidazole 2 and 0.52 g (2 mmol) of 3,4-dimethoxyphenacyl bromide in 5 ml of nitromethane was boiled for 6 hours. It was cooled, 15 ml of acetone was added and the precipitate formed was filtered off. Yield 0.80 g (90%). Colorless crystals with so pl. 233-234 ° C (from ethanol). ¹ H NMR spectrum, (300 MHz), δ, ppm (DMSO-d ₆ ): 1.95-2.10 (m, 4H, C (3) H ₂ , C (4) H ₂ ); 3.47-3.48 (m, 2H, C (5) H ₂ ); 3.84 (s, 3H, OCH ₃ ); 3.89 (s, OCH ₃ ); 4.37 (t, 2 N, C (2) H ₂ , J = 5.1 Hz); 5.95 (s, 2H, CH2 Ar); 7.20 (d, 1H, H (5 '), J = 8.7 Hz); 7.28-7.41 (m, 2H, H (8), H (9)); 7.51 (d, 1H, H (2 '), J = 1.8 Hz); 7.59 (d, 1H, H (7) or H (10), J = 1.5 Hz); 7.73 (d, 1H, H (10) or H (7), J = 8.4 Hz); 7.78-7.81 (dd, 1H, H (6 '), J ¹ = 8.4, J ² = 1.8 Hz); 8.81 (broad s., ⁺ NH).

Found, (%): C 56.37; H 5.21; Br 17.74; N, 9.62. C ₂₁ H ₂₃ N ₃ O ₃ ⋅HBr. Calculated, (%): C 56.51; H 5.42; Br 17.90; N 9.41.

Stage 2. 2-Bromo-1- (3,4-dihydroxyphenyl) -2- (2,3,4,5-tetrahydro [1,3] diazepino [1,2- a ] benzimidazol-11-yl) ethanone ( 1c). A solution of 0.45 g (1 mmol) of dimethoxy derivative (3) in 5 ml of 48% HBr was boiled for 4 hours. After cooling, the precipitate that formed was filtered off, washed with 10 ml of ice water. Yield 0.35 g (84%), mp> 305 ° С (decomp., From water). ¹ H NMR spectrum, (600 MHz), δ, ppm (DMSO-d ₆ ): 2.23-2.32 (m, 4H, C (3) H ₂ , C (4) H ₂ ); 4.07 (t, 2H, C (5) H ₂ , J = 5.2 Hz); 4.30 (t, 2H, C (2) H ₂ , J = 5.2 Hz); 6.89-6.97 (m, 3H, H (2 '), H (5'), H (6 ')); 7.52 (t, 1H, H (8) or H (9); J = 7.6 Hz); 7.60 (t, 1H, H (9) or H (8); J = 7.6 Hz); 7.89 (d, 1H, H (10) or H (7), J = 8.2 Hz); 8.08 (d, 1H, H (7) or H (10), J = 8.1 Hz); 8.28 (s, 1H, CHBr); 9.34 (s, 1H, OH); 9.54 (s, 1H, OH). ¹³ C NMR spectrum, (150 MHz), δ, ppm (DMSO-d ₆ ): 25.02, 25.03, 46.60, 48.60, 106.0, 112.44, 112.59, 115.98, 116.77, 117.02, 121.01, 123.12, 123.55, 125.51, 134.63, 135.35, 142.81, 145.68, 147.32.

Found, (%): C 54.90; H 4.18; Br 19.03; N 10.17. C ₁₉ H ₁₈ BrN ₃ O ₃ . Calculated, (%): C 54.82; H 4.36; Br 19.19; N 10.09.

Study of anxiolytic activity.

Materials and methods.

The experiments were carried out on adult male mice weighing 18-23 g. Animals were kept in vivarium with natural light on a standard diet of laboratory animals, without restricting access to food and water (GOST R 50258-92) in compliance with the International recommendations for the protection of vertebrate animals used in experimental studies (1997). The animals were divided into groups of 10 animals each.

The studied substances in equimolar doses (diazepam 2 mg / kg) were administered 30 minutes before the test. The animals of the experimental groups were injected intraperitoneally with the test substance or comparison preparations. Control groups of rats were injected with isotonic sodium chloride solution. The reference drug was diazepam at a dose of 2 mg / kg [9, 10].

The method of studying anxiolytic activity in the “elevated cruciform labyrinth” test was based on the natural preference of dark holes by rodents, as well as on the fear of being in open areas and falling from a height [8].

The animals were placed in an elevated cruciform labyrinth and the following indicators of anxiolytic activity were recorded for 3 minutes: latent period before reaching the open sleeve (sec); number of exits to the open sleeve; total time spent in the open arms of the maze (sec); total number of transitions from sleeve to sleeve (indicating the transitions of sleeve types); number of hangs; reactivity, time of leaving the center (sec); total time spent in the center (sec); the number of peeps from the closed sleeve; number of boluses.

To study the locomotor activity of animals, they were placed in an Activity cage 7401 actometer (Ugo Basil), in the chamber of which there are sensors recording the horizontal activity of the animal [9, 10].

Thermal sensors (AnD DT-623) were used to determine rectal temperature. The temperature is determined by immersing the electrode to a depth of 1.5-1.8 cm [11].

Evaluation of the progipogenic effect was carried out using the hexenal sleep test. The level of antipsychotic action was judged by the change in the duration of sleep in the experimental groups compared to the control. Recorded the time of falling asleep (the adoption of "lateral position") and the end of sleep (the appearance of the first signs of activity, exit from the lateral position). The absence of the effect of the studied substance on the duration of hexenal sleep suggests that it has no inhibitory effect on the microsomal systems of the liver metabolizing barbiturates. The comparison drug is diazepam at a dose of 2.0 mg / kg [9-11].

Statistical processing of the research results was carried out using the Wilcoxon test, the Kruskal-Wallis test with post-processing the Dunn test, or using one-way analysis of variance and the Newman-Keuls test, in the case of a normal distribution of data. The calculation is implemented in the program GraphPad Prism 5.0.

Results and discussions

The level of tranquilizing effect was judged by the change in the fixed parameters in the experimental groups compared to the control.

According to the results of the study of anxiolytic activity in the elevated cruciform labyrinth (Table 1), it was shown that compounds 1a, 1b, 1c reduce emotional anxiety, exceeding the efficacy (time spent in the light sleeve) of the diazepam comparison drug by 40%, 35%, and 22% , respectively. In all animals, experimental groups, the number of transitions increased statistically significantly compared to the control group and relative to the diazepam comparison drug, which indicates an increase in research and search activity. The number of exits to the light sleeve also increased, which indicates a decrease in fear and suppression of natural stress.

Upon further study, it was found that compounds 1a and 1b do not affect locomotor activity, animal body temperature, and sleep duration, that is, they do not have hypnogenic and muscle relaxant effects, in contrast to the diazepam comparison drug (Table 2).

Compound 1c significantly reduced the motor activity of animals in the actometer, but did not affect the animal's body temperature and duration of sleep. Thus, compound 1c has a muscle relaxant effect, characteristic of benzodiazepines, but, in contrast, does not exhibit a hypnogenic effect.

Thus, compounds 1a and 1b have a pronounced anxiolytic effect that is superior to diazepam in comparison with efficacy and does not cause muscle relaxation and hypnogenic effect. Compound 1c in anxiolytic activity is superior to the diazepam comparison drug, does not affect the duration of sleep, and has a muscle relaxant effect.

Literature

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2. Reference radar drugs.

3. Gurovich I.Ya., Shmukler A.B. Cupping therapy with atypical antipsychotics of patients with newly emerged psychotic conditions // Social and Clinical Psychiatry. 2011, T. 21, No. 4, p. 51-57.

4. Fattakhov Sh.A. Directed synthesis of N-containing derivatives of phosphoryl acetic acids with biological activity: abstract. dis. Cand. Chem. sciences / Sh.A. Fattahov. - Kazan: KSTU, 2010.

5. Anisimova VA, Osipova M.M., Kuzmenko T.A., Caignard D.-H., Renard P., Manechez D. // Nouveaux derives tricycliques de benzimidazoles, leur precede de preparation et les compositions pharma-ceutiques qui les contiennent. Fr Pat. 2765 223, C07D 487/04, 1998, WO / 1999/000390.

6. Divaeva L.N., Kuzmenko T.A., Spasov A.A., Morkovnik A.S., Anisimova V.A., Kucheryavenko A.F., Sirotenko B.C. RF patent No. 2582618, C07D 487/04, 2016.

7. Anisimova V.A., Kuzmenko V.V., Kuzmenko T.A., Morkovnik A.S. Izv. AN Ser. Chem., 2007, p. 2237.

8. Voronina T.A., Seredenin SB. Guidelines for the study of the tranquilizing (anxiolytic) action of pharmacological substances. Guidelines for the experimental (preclinical) study of new pharmacological substances. M .: Remedium, 2000. 126-136.

9. Yakovlev D., Kolobrodova N., Spasov A., Anisimova V. Anxiolytic profile of 5-HT3-antagonist RU 1204 versus tropisetron and diazepam / European neuropsychopharmacology / 21 No. S2 2011.

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11. Mironov A.H. Guidelines for preclinical studies of drugs. Part one. - M.: Grif and K, 2012, p. 944.

Claims (6)

1. 11- (4-tert-butylbenzyl) - and 11-phenacyl substituted 2,3,4,5-tetrahydro [1,3] diazepino [1,2-a] benzimidazole general formula 1:

where n = 0.1; R = H, Br; R ₁ = 4- (CH ₃ ) ₃ SS ₆ H ₄ , 4-FC ₆ H ₄ CO, 3,4- (OH) ₂ C ₆ H ₃ CO. 2. 11- (4-tert-butylbenzyl) - and 11-phenacyl substituted 2,3,4,5-tetrahydro [1,3] diazepino [1,2-a] benzimidazole according to claim 1, where n = 1, R = H, R ₁ = 4- (CH ₃ ) ₃ SS ₆ H ₄ . 3. 11- (4-tert-butylbenzyl) - and 11-phenacyl substituted 2,3,4,5-tetrahydro [1,3] diazepino [1,2-a] benzimidazole according to claim 1, where n = 1, R = H, R ₁ = 4-FC ₆ H ₄ CO. 4. 11- (4-tert-butylbenzyl) - and 11-phenacyl substituted 2,3,4,5-tetrahydro [1,3] diazepino [1,2-a] benzimidazole according to claim 1, where n = 0, R = Br, R ₁ = 3.4- (OH) ₂ C ₆ H ₃ CO.