Quinazoline derivatives, possessing antidepressant, anxiolytic and nootropic activity. RU patent 2507199.

FIELD: chemistry.

SUBSTANCE: invention relates to novel medication possessing antidepressant, anxiolytic and nootropic activity, which represents compound of general formula where: X is NH or 1,4-piperasino; R¹=H or CH₃; R²=H, OCH₃ or N(CH₃)₂.

EFFECT: on experimental models in vivo compounds, possessing original spectrum of psychotropic action, exceed medications of different pharmacological groups - aphobazolum, melipramin, phenotropil, diazepam in complex of useful qualities, and can be applied in treatment of patients with anxiety and depressive disorders.

4 tbl, 8 ex

Derivative having antidepressant, anxiolytic and nootropic activity.

The invention relates to the field of organic chemistry and medicine, namely to new derivative , having expressed antidepressant, anxiolytic and nootropic activity, which can be used for the treatment of common neuropsychiatric diseases.

According to the world health organization, by 2025-2030 years in deaths from depression will be released on the 1st place in the world, ahead of other causes of mortality are cardiovascular, oncological and infectious diseases. Already, depression is a major health problem. In the modern world depression is becoming more common and increasingly long-current disorder. High rates of depression and their negative impact on quality of life demonstrated in patients with various pathologies, including cancer, HIV infection, viral hepatitis, skin diseases, rheumatoid arthritis, ulcers. Elderly patients are especially problematic is the combination of depression and physical illness. Finally, depression is one of the main causes of suicide [Wittchen H., F. Jacobi, Rehm J. The size and burden of mental disorders and other disorders of the brain in Europe 2010 // Eur. Neuropsychopharmacol. - 2011. - Vol.21. - No. 9. - P. 655-679].

Despite the fact that to date, created a wide range of psychoactive drugs of different chemical groups, the problem of pharmacotherapy of depression has not been solved yet. Many of the known tranquilizers, antidepressants and anxiolytics are different from or low therapeutic activity, or the presence of a significant number of unwanted side effects. For example, drugs benzodiazepinovogo a number of holding the dominant position among all the tranquilizers, have a number of disadvantages: cause psychomotor retardation, lethargy, miorelaksaciu, loss of coordination and cognitive functions, which reduces the quality of life of patients and limits the wider use of benzodiazepines. The appointment of the majority of modern antidepressants for course therapy in adequate therapeutic doses leads to the positive clinical effect only 65-75% of patients. The antidepressants also have a number of disadvantages: long latency period, lack of breadth and resistance therapeutic effect, the high probability of side effects, risk of toxic effects of overdose. In this regard remains relevant for the creation of psychotropic drugs with polyvalent the action of combining actually have antidepressant and anxiolytic activity with the ability to positively influence the intellectually-mnestic functions and mental state of the patient, having a short latent period and adequate therapeutic latitude, with a minimum of side effects.

Potential in terms of development of new highly effective, selective and safe psychotropic drugs are derived , structurally close to the endogenous pyrimidine bases and their derivatives, possessing wide spectrum of valuable psychotropic properties - nootropic, anxiolytic and antidepressant [ I.P. Molecular design and purposeful synthesis of N - substituted derivatives of 4-oxo-1,4- on the basis of brake neurotransmitters.// Chem. . Journe. - 2009. - 43. - №10. - C. 32-39].

Derivative widely distributed in nature, currently of lower fungi, bacteria and higher plants allocated about 150 alkaloids series, many of which have high pharmacological activity and found application in medical practice. The most famous alkaloid number is (Febrifugine), extracted from the leaves and roots of Chinese medicinal plant Dichroa febrifuga. -known anti-malarial drug, it is about 100 times more active compared with quinine, however, is more toxic. has also expressed action [Arora R., A., N.S. Gill, Rana A.C. Quinazolinone: an overview // Int. Res. J. Pharmacy. -2011. - Vol.2. -No.12. - P. 22-28].

A synthetic derivative of also have a broad spectrum of pharmacological activity, many of them have found application in medical practice as a safe and effective therapeutic and preventive products. One of the most known drugs number is methaqualone (Quaalude, Mandrax, Sopor), which in March 1966 . approved by the U.S. government as a sedative-hypnotic drug, a non-addictive:

In the future has been most effective analogs of methaqualone (, , , ) and the modern preparation - tranquilizer with anxiolytic and sedative activity. shows sleep disorders, anxiety, Autonomous manifestations, neurotic (TV) disorders. In the clinic for the treatment of alcoholism is used for the relief of alcohol withdrawal syndrome, as well as in the period of remission. Drug treatment helps to reduce fear, anxiety, irritability, normalization of sleep a night, elimination of vegeto-vascular manifestations. Elimination of psychopathological symptoms observed in patients with alcohol during remission, leads to the reduction of pathological attraction to alcohol [Medicines in the clinic alcoholism and drug addiction. A manual for doctors./ Under. amended ... - M: RSMU, 1999. -111 C.]:

Among other well-known drugs number should be mentioned specific antagonist of 5-HT 2 receptor ketanserin, a selective inhibitor of tyrosine kinase inhibitor reductase , diuretic , a 1-adrenergic antagonist prazosin, analgesic and anti-inflammatory , antifungal drug . However, all of these drugs and their numerous structural analogues not have antidepressant, anxiolytic or neuroprotective effect. Despite the rather wide spectrum of pharmacological activity of synthetic derivatives (, anti-inflammatory, antibacterial, antiviral, antitumoral, , antihypertensive, activity), information about their impact on the Central nervous system is rather poor. Known -derivative -4(3H)-she General formula:

where: R 1 and R 2 - aromatic substituents,

who have and anticonvulsant properties. According to the results of the swimming test antidepressant properties of these compounds are not found [Jatav V., P. Mishra, Kashaw S., Stables J.P. Synthesis and CNS depressant activity of some novel 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones // Eur. J. Med. Chem. - 2008. -Vol.43. -P. 135-141].

The closest chemical structure to the proposed connections is N-(2,6-dimetilfenil)-2-[4-oxo-3(4H)-]- formula:

This compound does not have antidepressant, and neuroprotective properties, on the contrary, in the spectrum of psychotropic properties of this substance is dominated by anxiety-phobic and effects [Tyurenkov I.N., Ozerov A.A., EA, Y. Glukhova .., E.N. Anomaly in a variety of pharmacological properties of -4(3H)-it with fragments of as alternate.// Vestnik . - 2012. - V.2. - P.66-68].

The aim of the invention is to obtain new derivatives with balanced complex of psycho-properties - antidepressant, anxiolytic and nootropics.

Summary of the invention consists in the synthesis of new derivatives of General formula:

where: X=NH or 1.4-piperazine derivatives;

R 1 =N or CH 3 ;

R 2 =N, cos 3 or N(CH 3 ) 2.

The proposed connection, combining in its structure the fragments -4(3H)-one and substituted , have expressed antidepressant, anxiolytic and nootropic activity in vivo, superior activity of reference preparations of various chemical and pharmacological groups.

The following examples illustrate the nature of the invention.

Example 1. N-(4-Methoxyphenyl)-2-[4-oxo-3(4H)-] (compound I).

A mixture of 2.0 g (13.7 per mmol) -4(3H)-she 4.0 g (28,9 mmol) of anhydrous potassium carbonate and 50 ml of dimethylformamide stirred at a temperature of 100-105 OC for 30 minutes, add 1.8 g (15,1 mmol) 2-chloro-N-(4-methoxyphenyl) and stirred at the same temperature within 1 H. is Cooled to room temperature, filtered, filtrate was evaporated in a vacuum residue add 50 ml of water is kept at a temperature 0-5 OC for 1 day, and the resulting the precipitate is filtered off, washed with water and dried in air. Is recrystallized from acetic acid and receive 2,60 g of compound I, exit 61%, So pl. 228-229°N

PMR spectrum (DMSO-D6 ), coth ppm: 3,72 with (3H, cos 3 ); 4,85 (2N, CH 3 ); 7,51 d (8 Hz, 2H, phenyl); 6,90 d (8 Hz, 2H, phenyl); 7,57 t (7 Hz, 1H, N 6 ); 7,73 d (8 Hz, 1H, N 8 ); 7,86 t (7 Hz, 1H, N 7 ); 8,16 d (8 Hz, 1H, N 5 ); 8,37 with (1H, N 2 ); 10,31 c (1H, NH).

Example 2. M-[4-(Dimethylamino)phenyl]-2-[4-oxo-3(4H)-] (connection II).

A mixture of 2.0 g (13.7 per mmol) -4(3H)-she 4.0 g (28,9 mmol) of anhydrous potassium carbonate and 50 ml of dimethylformamide stirred at a temperature of 100-105 OC for 30 minutes, add 3.2 g (15,1 mmol) 2-chloro-]-N-[4-(dimethylamino)phenyl] and stirred at the same temperature within 1 H. is Cooled to room temperature, filtered. The filtrate is kept at a temperature 0-5 C. during the day. The residue was filtered, washed with cold with DMF, water and air-dried. Is recrystallized from dimethylformamide and receive 2,95 g of compound II, exit 67%, So pl. 261-264°N

A mixture of 2.0 g (13.7 per mmol) -4(3H)-she 4.0 g (28,9 mmol) of anhydrous potassium carbonate and 50 ml of dimethylformamide stirred at a temperature of 100-105 OC for 30 minutes, add 3,96 g (15,1 mmol) 2-chloro-N-[4-(dimethylamino)phenyl] and stirred at the same temperature within 1 H. is Cooled to room temperature, filtered. Filtrate was evaporated in a vacuum residue add 50 ml of water is kept at a temperature 0-5 C. within 1 day, the precipitate is filtered off, washed with water and dried in air. Is recrystallized from ethanol and receive 2.94 g of compound III, exit 64%, that is square 231-233°N

PMR spectrum (DMSO-D6 ), coth ppm: 1,78 with (6N, 2CH 3 ); 2, 82 (3H, CH 3 ), 5,64 to (8 Hz, 1H, CH); 6,685 d (8 Hz, 2H, phenyl); 7,45 d (8 Hz, 2H, phenyl); 7,54 t (8 Hz, 1H, N 6 ); 7,72 d (8 Hz, 1H, N 8 ); 7,82 t (8 Hz, 1H, N 7 ); 8,18 d (8 Hz, 1H, N 5 ); 8,49 (1H, N 2 ); 10,10 with (1H, NH).

Example 4. 3 - [2-Oxo-2-(4-phenyl-1-piperazinil)ethyl]-4(3H)-one (compound IV).

A mixture of 2.0 g (13.7 per mmol) -4(3H)-she 4.0 g (28,9 mmol) of anhydrous potassium carbonate and 50 ml of dimethylformamide stirred at a temperature of 100-105 OC for 30 minutes, add 4.1 g (15,1 mmol) 1-chloroacetyl-4- and stirred at the same temperature within 1 H. is Cooled to room temperature, filtered, filtrate was evaporated in a vacuum residue add 50 ml of water is kept at a temperature 0-5 C. within 1 day, the precipitate is filtered off, washed with water and air-dried. Is recrystallized from a mixture of isopropyl alcohol - dimethylformamide (5: 1) and receive 3,47 g of compound IV, exit 73%, .. 222-224°N

PMR spectrum (DMSO-D6 ), coth ppm: 3,14-3,32 m (4H, piperazine); 3,62-3,78 m (4H, piperazine); 5,01 with (2H, CH 3 ); 6,96-7,01 m (2H, phenyl); 7,23-7,29 m (3H, phenyl); 7,55 tons (7.5 Hz, 1H, N 6 ); 7,71 d (8 Hz. 1H, N 8 ); 7,86 tons (7.5 Hz, 1H, N 7 ); 8,17 d (8 Hz, 1H, N 5 ); of 8.26 (1H, N 2 ).

Example 5. Study anxiolytic activity. The anxiolytic effects of substances studied using the classical model of anxiety in «high cross " labyrinth» and the model «the conflict Vogel, based on the collision of defensive and food reflexes. The studied substance is administered orally at a dose of 10 mg/kg, drugs comparison: afobazole - 10 mg/kg, diazepam -1 mg/kg

Test elevated plus maze (EPM) is aimed at revealing the investigated substances of possible anxiolytic activity through assess the severity of the emotional reaction of fear and anxiety under the action of the studied compounds compared with benchmarks. AWF is also used to detect the impact of studied substances on the locomotor activity, speed indicative reactions. The technique is based on the preference of rodents dark Nord, natural fear of finding the open areas and falling from a height. Installing the PCL consists of a cross diverging from the Central area (10 x 10 cm) perpendicular 4 sleeve dimensions of 50 x 10 cm each: two opposite, open, without walls and two closed, dark, bounded on the sides painted in dark colour boards in height 40 cm Floor installation is painted in white color. Labyrinth raised above the ground on 80 see The animal is placed in a PC on the Central platform of the head to the open sleeve and within 3 minutes record the time the pet is open, closed sleeves, and also at a Central location, number of logins open, closed sleeves and Central zone (as of call animal in any compartment of the maze regarded animal crossing borders compartment hind legs), the number of racks in the closed and open sleeves, the number of with open arms. To increase the time spent in the light sleeves, the number of visits in them, vertical racks in open sleeves and with them is estimated anxiolytic effect of substances. Duration of stay in the Central platform allows to estimate the speed of the decision. The total number of visits in the open, closed sleeves and center PC is estimated overall physical activity.

All new compounds I-IV are anxiolytic effects, increasing the number of outputs in the open arms of stay, the quantity of transitions between the arms and the number of with open sleeveless uplifted cruciform labyrinth (table 1). This behavior of the test animals in the model of situational anxiety in EPM indicates the ability of compounds suppress the anxiety, the fear of heights and brightly-lit open space, that is, to the anxiolytic effects.

In the test of «conflict Vogel» compounds I-IV statistically significantly increase the number of offences takes water from the trough in comparison with the control animals and animals getting afobazole, and reduce latency period before the first offence of taking of water (table 1). On severity of anxiolytics in «conflict Vogel» substance II-IV slightly inferior diazepam, but surpass afobazole.

Example 6. Study of the influence of the spontaneous individual behaviour in the «open field»test.

Test the «open field» (OP) is aimed at revealing the studied compounds ability to change spontaneous individual behaviour: motor and approximately research activity, emotional reactivity. Test OP allows to reveal or (sedative or anxiolytic action. Installation to test the open field is a square chamber (80 x 80 cm) with the walls with height of 60 see On camera sex with black paint is a grid that divides the field 25(5 x 5) equal squares with the release of the Central zone. The floor is equipped with a 16 holes diameter and a depth of 3 see Lighting lamp capacity is 90 LK located at a height of 150 cm above the centre of the field. The rat is placed in the center of the camera tail to the experimenter and observe its behavior within 3 minutes When testing is estimated spontaneous behaviour of animals, selection of standard indicators include: the number of crossing squares, the number of parietal («anxiety») and free («research») of the vertical posts, the number of surveyed holes-Minks, the number of visits allowed the Central zone with the frequency of acts and the total duration of grooming, the number of and defecation. The number of crossing squares treated as a spontaneous motor activity, the amount of racks and in the hole - the total of approximately research activity.

The number of visits to Central brightly lit area ( for burrowing rodents) characterizes the level of anxiety of the animal, the increase of such acts under the influence of pharmacological substances indicates their anxiolytic activity. Grooming (the behavior brushing) reflects the degree of emotional stress animal: frequent short-term (up to 5 s) grooming describes the behavior of an alarm, a rare and long - behavior comfort. Non-specific behavior of the animals - the number of boles defecation and - vegetative stress indicators - also to some extent characterize the emotional tension of the animals.

It is established, that connection I and IV statistically significantly increase the spontaneous individual motor activity and approximately exploratory behavior (table 2). A similar, but less pronounced effect exerted a comparator drug afobazole. Diazepam reduced horizontal movement and approximately exploratory behavior. In comparison with the studied substances diazepam animals have reduced the number of outputs in the center illuminated arena, the number of open and near-wall racks, indicating that it has expressed sedative action.

Animals receiving the new derivatives , do more outputs in the Central area of open fields, and in high cross " labyrinth more exits in open arms and longer were in them. In the test conflict situation, caused by the collision of defensive and food reflexes, animals of the control group carried out more punishable takes water than animals receiving the afobazole. Such data suggest that the substance I-IV have greater anxiolytic effects than afobazole.

Compounds I and IV increased the number crossing squares, gateways to Central, brightly lit area of open fields and the number of open racks, which indicates the presence of these substances in the anxiolytic and activates the action. Substance II additionally reduced the number of short-term grooming and acts of defecation, which also testifies about the decrease of evidence of vegetative correlates of anxiety.

Example 7. Study antidepressant activity. Antidepressant effect of new substances was studied in a test of forced swimming (swimming test ). In this test rats 15 min placed in a glass pool with a diameter of 32 cm and a height of 50 cm, filled with water 21-24 C till the level at which the animal can't touch the bottom of the hind legs. Then the animal seeded in a heated cage for 30 min and return in the vivarium. After 24 hours, the procedure was repeated, registering over 300 with latent period of immobilization, the total time spent rats in a state of immobilization (animal passively floating in the water with slightly raised head), the duration of active swimming (animal actively moves with all four limbs) and jumps out of the water (the animal makes a jerk all over, trying to get out of the water). The increase in the latent period of immobilization, reduction of the duration of the extension of active swimming and number of hops under the influence of the investigated compounds, as compared with the control group is regarded as having had antidepressant effect. The subjects of the substance was administered orally at a dose of 10 mg/kg to start testing again with regard to the peak of their actions. Drugs comparison: imipramine was administered at a dose of 15 mg/kg, afobazole - 10 mg/kg) and diazepam - 1 mg/kg

Compounds I-IV increased the latent period of immobilization and reduced the total time of immobilization (behavior despair, characterizing the depression), have increased the time of active swimming, significantly increased the number of hops (active behavior avoidance corresponding stress factor) compared with the control group and the group of animals receiving afobazole and, especially, diazepam (table 3).

Thus, the compounds I-IV are antidepressant effect, comparable to the effect of superior to such action. Diazepam antidepressant response is not provided.

Example 8. Study nootropic activity.

The solution is under the edge of the hood and deliverance, thus, from the aquatic environment. Registered indicators: the latent period (LP), physical activity (time of the moment of immersion in water to begin the active swimming), the immobilization time (animal passively floating in the water with slightly raised head, all four limbs immovable), number of hops in the bell (active attempts to jump out of the water), PL diving (the time from the moment of immersion of the animal in the water before diving under the edge of the hood). The experiment consists of two phases: training, skill development reflex deliverance) and its reproduction in 24 hours Animals, not the decisive task during the observation, at the stage of training are excluded from the experience. When assessing cognitive functions have the most value indicators, such as: PL motor activity, which characterizes the rate of the indicative reactions; PL diving - an indicator of the ability to extrapolate (the lower the number, the higher the speed of the decision tasks), comparison of the figure PL diving in learning and playing skill shows the degree of attainment of the animal and memory capacity (greater than it decreases when you play the test, the more training the animal and save the memorable trace). The test also provides an opportunity to assess the severity of animal behavioral depression and antidepressant effects of pharmacological substances by counting the number of hops (active attempts to get rid of impact) and time (signs of depression).

The studied substance I-IV (10 mg/kg), unlike diazepam (1 mg/kg), do not degrade the formation and preservation of traces in the passive avoidance reaction in the test and the test of deliverance» (table 4). These indicators were better than the control group animals and animals treated afobazole (10 mg/kg), not cede to parameters of treated animals (25 mg/kg).

Thus, the new derivatives I-IV have expressed anxiolytic, antifobicescoe, antidepressant and nootropic action. Unlike diazepam, they do not have a sedative action, do not reduce the behavioral activity in environment, do not impair learning and memory, that shall not reduce the reaction of a person in conditions of influence of aggressive factors. Simultaneously with this connection I-IV are antidepressant and nootropic properties comparable with , but surpassing the severity of the effects of Afobazol. Considering the totality of the obtained data, we can conclude that the new derivatives I-IV possess a complex of useful psychotropic properties, first of all expressed an anxiolytic and antidepressant effect, and do not reduce, but, on the contrary, increase cognitive and potential, which distinguishes them from diazepam. The studied substances have certain advantages over other representative anxiolytics - , surpassing him on the severity of anxiolytic, antidepressant and nootropic action. There are grounds to believe that drugs with different psychotropic will find wide application in treatment of patients with anxiety-depressive disorders.

Anxiolytic activity of new derivatives

Registered indicators

Values of parameters (Pitch t)

Afobazole

Effects of substances on the emotional the behavior of animals in test «uplifted cruciform labyrinth»

Number of outputs in the open arms

0,7±0,21

2,8±0,31 **Δ

1,9±0,24

2,3±0,21 **

2,2±0,31 **

1,8±0,22 **

1,5 ħ 0.33 *

The time spent in the open arms, with

11,2±1,49

51,5±2,74 **#

31,8±3,6 ***

29,7±1,50 *

29,8±2,50 **

27,2±3,4 **

50,4±4,7 ***

The number of transitions sleeves

3,0±0,45

6,0±0,52 ***

4,4±0,26

7,2±0,40 ***

9,0±0,37 ***#Δ

6,5±0,52 **

4,7±0,39 *

The number of racks in open arms

0,2±0,17

0,3±0,21

0,2±0,17

0,7±0,21 *

0,2±0,21

0,4±0,22

The number of with open sleeves

0,2±0,17

2,3±0,21 **

1,2±0,19 *

1,0±of 0.26 *

1,8±0,31 **

2,1±0,47 **

1,4±0,39 **

Effects of substances on anxiety behavior of animals in the test of «conflict Vogel»

The latent period of from 1 to 2 punishable taking water from the trough

21,9±4,3

9,5±2,78*

4,2±0,23 ***

5,7±0,42 ***

6,0±1,7 ***Δ

6,7±0,88"*

3,3±0,42 ***

The number of offences takes water from the trough

3,0±0,45

14,0±0,68 ***#

15,1±2,4 ***#

11,7±1,17 ***

16,5±0,92 ***#

9,7±0,90 **

18,5±0,22 ***#

Key: * - p<0.05; ** - p<0,01; *** - p<0,001 - reliability of differences compared with the control group of animals; # - the significance of differences compared with the group of animals treated with afobazole; Delta - reliability of differences in comparison with the group of animals treated with diazepam; (rank analysis of the Kruskal-Wallis test, the criterion Dunn for multiple comparisons, nonparametric U - test Mana-Whitney)

The impact of new derivatives on spontaneous individual behavior in the open field test»

Registered indicators

Values of parameters (Pitch t)

Afobazole

Physical activity

25,7±0,42

42,7±1,61 ***#

19.4 ħ 1,32 * Δ

29,8±l,25 #

42,8±l,19 ***#

34,1±4,2 *

17,0±1,54 *

Approximately research activity

14,3±0,49

19,2±0,31 *#

17,5±0,96#

18,5±0,22 *

19,5±0,56 *#

16,7±1,2

6,2±0,72 *

Number of outputs in the centre

0,2±0,17

0,94±0,17 *

0,6±0,12 *

0,92±0,17 *

1,2±0,22 ***#Δ

0,5±0,21

0,2±0,14

The number of open racks

0,2±0,17

and 1.7±0.33 ***#

0,8±0,21 *

0,7±0,21 *

0,8±0,17 **

1,3±0,19 **

0,6±0,20

The number of parietal racks

1,3±0,14

0,6±0,18 *

0,4±0,12 *

0,7±0,18

0,4±0,18 *

0,7±0,18

0,2±0,11

The number of acts of a long grooming

0,2±0,17

0,2±0,17

0,6±0,21

0,3±0,21

0,8±0,17 *

0,8±0,08

of 0.4±0.12

The number of acts of short-term grooming

2,0±0,37

1,8±0,31

0,5±0,19 * #Δ

1,3±0,21

1,2±0,17

1,6±0,22

1,8±0,16

The number of acts of defecation

3,5±0,34

3,3±0,49

0,6±0,18 *** #Δ

2,8±0,17

4,3±0,61*

3,0±0,42

2,6±0,58

Designations; * -p<0.05; ** -p<0,01; *** -p<0,005; **** -p<0,001 - reliability of differences compared with the control group of animals; # - reliability of differences in comparison with the group of animals treated with diazepam; Delta - reliability of differences in comparison with the group of animals treated with afobazole (rank analysis of the Kruskal-Wallis test, the criterion Dunn for multiple comparisons)

Antidepressant activity of new derivatives

Registered indicators

Values of parameters (Pitch m)

Imipramine

Afobazole

Total time active swimming, with

152,5±14.23 per

211,5±to 13.31 **#Δ

198,4±14,1

of 183.3±15,53 *#

205,5±16,19 **

236,3±15,55 ***#Δ

for 181.5 ą 12.5 *

138,6±14,9

The latent period of immobilization

69,2 ħ 4.9

88,3±16,1 #Δ

86,3±9,0 #Δ

96,0±12,3 *#Δ

81,6 ħ 9.3 #Δ

73,5±10,2 #Δ

66,3 ħ 7.0

52,3 ħ 3.8

The total duration of immobilization, with

45,5±2,40

21,1±0,65 ***#Δ

32,1±0,56 **#Δ

30,5±0,34 ***#Δ

26,3 ħ 3.3 ***#Δ

30,3±6.42 per ***#Δ

50,3±4,4

69,9 ħ 10.6 **

Number of hops

3,8±0,48

12,7±1,02 ***Δ

9,8±0,65 **

15,5±1,34 ***#Δ

14,3±0,42 ***#Δ

13,5±0,56 ***#

10,3±1,08

4,8±0,72

Marked: *-p<0.05; **-p<0,01; ***-p<0.001; - reliability of differences compared with control group of animals; #-p<0.05 significance of differences in comparison with the group of animals treated with diazepam; Delta - p<0.05 significance of differences in comparison with the group of animals treated with afobazole (rank analysis of the Kruskal-Wallis test, the criterion Dunn for multiple comparisons, nonparametric U - test Mana-Whitney)

Nootropic activity of new derivatives

Registered indicators

Values of parameters (Pitch PA)

Afobazole

Effects of substances on learning and memory in the test of «conditional reaction passive avoidance»

PL at training after the introduction of the connection

19,2±0,95

10,7±1,99 *

18,9±2,7

30,0±1,18 **

20,7±1,15

18,1±1,b

38,8±12,5

22,6±1,9

PL during playback over 24 h

137,7±22,08

153±15,8 #

160,0±10,4

to 150.2±to 21.77 #

167,0±16,94 #

19,2±12,7

71,6±14,1

of 148.6±13,4

PL playback after 7 days

77,7±27,36

111,8±17,03 #

137,0±7,7

126,3±15,04 #

138,5±11,23 #Δ

140.3kilometer±2B,0

59,3±11,6

100,4±9,9

PL during playback over 14 days

63,2±17,6

77,5±7,97 #

135,0±29,6

70,5±28,08 #

131,2±31,74 *#Δ

127,9±23,b

26,9±10,8

61,4±11,7

Effects of substances on the function and depressive behavior in “test” deliverance”

PL diving at training after the introduction of substances

35,0±1,15

32,0±1,57 #

32,2±2,2

21.3 ħ 1,15 **#

15,0±1,37 **#

31,3±2,36

B2,3±8,9

30,5±3,0

PL diving during playback over 24 h

26,0±0,73

7,5±0,22 *#Δ

14,1±0,9b

15,2±1,08 *#

14,7±0,61 **#

11,6±1,92 **

48,4±7,2

13,8 ħ 2.6

Key: *-p<0.05; **-p<0,01; ***-p<0,005; ****-p<0,001 - reliability of differences compared with the control group of animals; # - reliability of differences in comparison with the group of animals treated with diazepam; Delta - the significance of differences compared with the group of animals treated with afobazole (rank analysis of the Kruskal-Wallis test, the criterion Dunn for multiple comparisons)

Tool that has antidepressant, anxiolytic and nootropic activity, represents the connection of the General formula

where: X=NH or 1.4-piperazine derivatives; R 1 =H or CH 3 ; R 2 =H, cos 3 or N(CH 3 ) 2 .