Medication possessing antidepressive, anxiolytic and nootropic action. RU patent 2437659.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and medicine. Claimed is application of N-carbamoyl-4-(n-methoxyphenyl)-2-pyrrolidone of structural formula as means possessing antidepressive, anxiolytic and nootropic action. This low-toxic compound (LD₅₀ 2263.88 mg/kg) possesses high antidepressive, anxiolytic and nootropic activity, affect of which is not accompanied by hypnosedative phenomena, or reduction of mental and physical work ability.

EFFECT: demonstrated is antidepressive and anxiolytic action of compound already in its single application, which makes the medication different from most known antidepressants, requiring at least one-week long intake to develop their effect.

7 tbl

The invention relates to the pharmaceutical industry and medicine and concerns derivatives of 2- showing an antidepressant, anxiolytic and activity.

As a means possessing an anxiolytic and antidepressant effect, often use derivatives of benzodiazepine derivatives. However, the presence of these funds a large number of adverse effects limit their use, particularly among workers in children and elderly people.

Among the derivatives of 2- best known medicines piracetam (2-oxo-1-) and or (N--4-phenyl-2-pyrrolidone). Piracetam - nootropic tool that has no anxiolytic and antidepressant activity. (N--4-phenyl-2-pyrrolidone) has a wide spectrum of activity:

antihypertensive (SU # 797219), antihypoxic activity (..Б and other Pharmacological characterization of a new phenyl analogue of pyracetam - 4- // bul. Experts. Biology and medicine. 1983. HSU. P.50-53), nootropic (RU №2050851), EN (Evraz. patent №002380), antidepressant (RU №2232578), neurotropic- (RU №2329804). However, this medicine has a number of limitations to the application, in particular because of its ability to cause agitation, agitation, insomnia ( - instruction for use, http;www.rlsnet.ru).

The growth of psychoneurological diseases, with an increasing proportion of border mental disorders involving cognitive deficit, anxiety and depressive symptoms, manifestations and declining physical and mental health necessitates the search and development of new high-performance and low-toxic medicinal funds with a wide spectrum of activity, allowing to carry out the pharmacological correction range of symptoms neuropsychiatric diseases without , safe in long-term use, including working persons. It should be remembered that the modern medicinal tools used in neurological practice, important criteria are:

- efficiency and breadth of therapeutic range (possibility and expediency of application in various forms of pathology);

- security;

the latitude of the dose range, i.e. the gap between the minimum therapeutic and minimally toxic dose.

It is known that one of the most productive ways to search psychotropic substances is a modification of the structure already established tools, which allows to increase efficiency, reduce toxicity, to expand the spectrum of pharmacological action.

In the series of derivatives of 2-oxo-1- described N--4-(n-methoxyphenyl)-2- (Б V.M., M.M. Novikov BM, O. Vasilyeva, Usik N. Maximov, Aleksandrova S.M., Tyurenkov I.N. 2-Oxo-1-: the methods of obtaining and structure. // Nitrogenous heterocycles and alkaloids. Materials of the international conference «Chemistry and biological activity of nitrogen heterocycles and alkaloids». Moscow. 9-12 October 2001, 229-233. /Edited by V.G. Kartsev, Tolstikov G.A Moscow. «Iridium-Press»). Preparative method of obtaining this connection is not described. Biological activity it is not known.

Objective of the invention is to get high-efficient and low-emission medical product on the basis of N--4-(n-methoxyphenyl)-2- having the antidepressant, anxiolytic and nootropic activity, to expand the range of such tools.

A task is achieved by using derivative 2- - N--4-(n-methoxyphenyl)-2-pyrrolidone the following structural formula:

as a means of having the antidepressant, anxiolytic and nootropic effects.

Medical product on the basis of N--4-(n-methoxyphenyl)-2- contains its effective dose, pharmaceutically acceptable carriers and additives target.

The technical result of the invention consists in that the proposed remedy and can be a complex effect on the functional state of the Central nervous system.

The invention is illustrated by the following examples:

Example 1

Obtaining N--4-(n-methoxyphenyl)-2- () consists of two stages and is in the interaction between 4-(n-methoxyphenyl)-2- with and subsequent of the obtained product.

4-(n-Methoxyphenyl)-1--2-pyrrolidone. In flask, equipped with a mixer nozzle Dina-stark, a thermometer and a dropping funnel make 4.45 ml DMSO and 6.8 ml of benzene. At intensive hashing add 1.34 g (0.007 mol) 4-(n-methoxyphenyl)-2- and 1.08 g (0.019 mol) of potassium hydroxide. The mixture is heated up to 80-85 degrees, if this temperature is distilled azeotrope benzene to water. Then the reaction mass is cooled up to 70-75 OC and through the addition funnel to the resulting potassium salt of 4-(n-methoxyphenyl)-2- portions added 1.9 ml (0.018 mol) freshly distilled monochloracetic acid ethyl ester, keeping the temperature of the reaction mass 90-95°N After adding the total number of mixture is 2 hours at the temperature of 80-85°C. Then the reaction mass is cooled, add double (to the volume of the reaction mass) the amount of water, the organic layer is separated, water is extracted benzene (3 x 20 ml). The organic layer and benzene extraction unite, the solvent was evaporated under reduced pressure. Allocate 1.5 g (81%) oily 4-(n-methoxyphenyl)-1--2-.

Found, %: With 64.90, 64.91; N 6.91, 6.90; N 4.99, 4.98. C 15 H 19 NO 4 . Calculated, %64.97; N 6.91; N 5.05.

N--4-(n-methoxyphenyl)-2-pyrrolidone. In two-neck flask, equipped with a mixer, make 0.83 g (0.003 mol) 4-(n-methoxyphenyl)-1--2- and 30 ml of 25%aqueous ammonia. Withstand the reaction mass is under intensive stirring within 20 hours. Crystalline product, filtered and dried in air. Get 0.70 g (89%) 1--4-(n-methoxyphenyl)-2- with .. 117-118°(from ethanol).

Found, %: 59.29, 59.41; N 6.52, 6.51; N 15.93,15.94. C 13 17 H N 3 O 3 . Calculated, %: With 59.30; N 6.51; N15.96.

NMR-spectrum of 1 H, CDCl 3 . coth M.D.: 3.79, 6.88, 7.13 (n-methoxyphenyl); 2.57, 2.83 (C 3 H 2 ); 3.49, 3.60 (5 C H 2 ); 3.81 (C 4 H), 4.01 (NCH 2 ); 5.81, 6.32 (NH 2 ). IR-spectrum, KBr, v, cm -1 : 1695 (C=O); 3485,3415(NH 2 ).

The following examples illustrate the efficiency of the N--4-(n-methoxyphenyl)-2- ().

To study the anxiolytic, antidepressant and nootropic activity () applied methods of detecting behavioral activity of animals, which is a collection of psychopharmacological experimental standard tests:

- the «open field» (OP) ( R.A., Lapin I.P. 1976, Voronin T.A. 1982; Gelman YA., Kremenevskaya SR, 1990);

- elevated plus maze (EPM) (Pellow S. et al., 1985);

- «conditioned reflex passive avoidance» (passive avoidance reaction) (Б Ya, Burešová O., Houston D.P., 1991; Voronin T.A., Ostrovskaya .., 2005);

- « deliverance» (EMT) (Bondarenko N.A. and others, 2003);

- «methods of conflict situation» (optional Vogel) (Voronin T.A., S.B. Seredenin, 2000);

- «suspension of mice by the tail» (IMH) (Steru L. et al., 1985);

- «methods of forced swimming on » (Porsolt R.D. et al., 1977).

Data processing was performed using statistical methods to assess the results of the study allow us to estimate the degree of pharmacological efficiency.

In work were used white outbred rats of Wistar line of both sexes in weight 180-220 g and white outbred mouse males of 20-25 g, contained in conditions of the laboratory animal facility, for at least two weeks before the beginning of the experiment on a standard diet, with free access to water, with natural light mode. Experiments were carried out at the same time of day. Given in tables, the values of indicators represent the average assessment of the results of measurement of parameters with account of levels of assurance (p<0.05, p<0,01).

Acute toxicity N--4-(n-methoxyphenyl)-2-, measured by the survival rate of mice after 24 h after the intragastric administration of funds, has the following average value of the indicator LD 50 2263,88 mg/kg (standard error LD 50 397,52). Substance belongs to low-toxic, that allows to classify them as not dangerous. For comparison, acute toxicity N--4-phenyl-2-pyrrolidone) is 800 mg/kg

The study of antidepressant action

The influence of substances on the severity of depressive behavior of animals was performed using two classical models depression: «the Test suspension of mice by the tail» and «Test forced swimming on ».

Test «Suspension of mice by the tail» (table 1)

The experiment was conducted in a cell measuring 60 x 20 x 20 cm, which is divided into two compartments. 45 minutes (time of development peak pharmacological activity) prior to the experiment the animals entered the study . Mouse hung him up by the tail on the 1.5 cm from the tip of the tail. The distance from the floor to the nose of the animal was 10 see for 6 minutes recorded the total duration of immobilization (still hang) simultaneously two animals. Immobilization (figure behavioural despair) is a clinical sign of depression. Reduced duration of the immobilization of animals of experimental group compared to control was regarded as the presence of antidepressant properties of the matter).

Test «Forced navigation» (table 2)

The experiment was conducted in a glass pool with a diameter of 32 cm and a height of 50 cm, filled with water (temperature 21-24 OC) to a level where the animal can't touch the bottom of the hind legs. Rats 15 minutes were placed in a pool, then in a heated cage for 30 minutes and returned to the vivarium. After 24 hours, 45 minutes before the beginning of the repeated testing, the animals were injected analyzed and put them in the pool. Over 300 sec registered latent period of immobilization, the total time spent rats in a state of immobilization (animal passively floating in the water with slightly raised head), 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 in animals of experimental group compared with the control indicates the presence of the analyte antidepressant effect.

The results of investigations performed on models depression showed that after acute administration to rats (both males and females) is expressed antidepressant effect. Under the influence of in tests « forced swimming on » and «suspension of mice by the tail» statistically significantly increased the latency period to development and decreased total time immobilization in animals (Table 1 and 2). In the test of « forced swimming but » under the influence of the investigated substances statistically significantly increased the number of jumps from the animals and the total duration of the active swimming (table 2). In addition, the antidepressant effect of a given substance, confirm test results deliverance, which under the influence of statistically significantly decreased the severity of behavioral correlation depression - duration of immobilization as in male and female rats (table 7). Antidepressant properties exceed a similar effect .

The study anxiolytics

The study anxiolytic activity was performed using a test «open field», «Uplifted cruciform labyrinth», as well as models of «Conflict Vogel»caused by the collision of defensive and food reflexes.

Test the «open field» (table 3)

Methodology the open field is used to study the effects of substances on indicators of spontaneous individual behaviour of animals (motor, approximately-research activity and emotional status and identifying anxiolytic properties.

The experiment was conducted in a square cell measuring 80 x 80 cm and a height of 60 cm chamber Floor is divided in black paint on 25 equal squares of size 5 x 5 cm with the release of the Central zone of the field. The floor of the cell is equipped with a 16 holes diameter and a depth of 3, see Luggage covered lamp capacity of 90 LK located over the center of the field at a height of 150 see a Rat was put into the center of the camera tail to the experimenter and observe its behavior within 3 minutes. In the test are recorded: the number of crossing squares on the periphery, the number of crossed brightly lit squares, the number of vertical bars, the number of in the hole, the number of and defecation, the number of acts and the total duration of grooming. The number of crossing squares characterizes the spontaneous locomotor activity animals, the amount of racks and in holes - total approximately research activity. The number of visits to Central brightly lit area ( for burrowing rodents) indicates the level of anxiety animal (less anxiety - more, and Vice versa). The increase in the number of such acts under the influence of subjects of substances testifies to their anxiolytic activity. Animal behavior when washing and cleaning (grooming) reflects the degree of his emotional stress: frequent short-term (up to 5 seconds) - anxiety, rare and long - condition comfort. Autonomic stress indicators (number of boles defecation and ) also characterize the emotional strain of animals (table 3).

After acute administration animals before examining their individual behaviour in the test of «open field» in the group of test animals statistically significantly increase the number of crossing squares (physical activity), the number of racks and in the hole (approximately research activity), which indicates the presence of the proposed substances activating effect, comparable with the effect of . In addition, with the introduction of rats, a statistically significantly increased the number of visits to the Central brightly lit area ( for burrowing rodents), the decrease in the number of acts of short-term (less than 5 seconds) «alarming» grooming and increased its duration, which testifies the comfort of your emotional state the animals.

The experiment was carried out in the installation (labyrinth), consisting of a Central site of the size of 10 x 10 cm, which crosswise diverge at the right angle four sleeve dimensions of 50 x 10 cm each. Two opposite sleeves open, without walls and two closed, dark, bounded on the sides painted in dark colour boards in height 40 cm Floor installation painted white. Labyrinth elevated above the floor level 80 cm The animal was placed on the Central site of the maze muzzle to the open sleeve and within 3 minutes observed him. In the test were registered: the stay of animals at a Central location, in the open and closed sleeves, the number of racks in the closed and open sleeves, the number of with open arms and the number of visits to the Central zone, open and closed sleeves. Crossing the rat borders of any compartment hind legs was defined as the set of the animal in the compartment of the maze. Increase the time spent in the light sleeves, the number of visits in them, vertical racks in open sleeves and with them indicate the presence of the anxiolytic effect of the studied substance. Duration of stay in the Central platform allows to estimate the speed of the decision animals. Total physical activity is measured by the total number of visits in the open, closed sleeves and the center of the labyrinth.

In the test of «uplifted cruciform labyrinth» after acute administration statistically increases in test animals (both male and female rats) duration of stay in the open sleeves, without causing a statistically significant impact on the number of exits from them (table 4). Thus, in the test uplifted cruciform labyrinth anxiolytic effect of substances is comparable with the effect of .

Test Methodology the conflict situation» (optional Vogel) (table 5)

Methodology conflict situation (option Vogel) is used to study the effects of substances on the behavior of the animal model build a state of anxiety and fear with an electrical stimulus, the vast drinking reflexes.

The experiment was conducted in a cell measuring 27.5 x 27.5 x 45.0 cm, fitted with electrodes floors. On the wall of the chamber, at the height of 5 cm above the electrode floor was a drinker (vessel with the nipple). Before testing within 48 hours of animals are limited in the feed consumption and deprived of water. Then the animal produced the skill of taking water from the trough: rat was placed to a cell for 10 minutes, where she found the water and started to drink. The next day, after learning the skill, 45 minutes (time of development peak of their pharmacological activity) before the experiment, the animals were introduced investigated substances. Next rat was placed in the cell for 10 minutes and 10 seconds after the start drinking each take water punished irritation (1 mA). In the test recorded the latent period of the first punishable approach to a drinking bowl and the number of offences takes water from the trough. Reduction of latency period and the increase in the number of offences takes water points to the suppression of feelings of anxiety and fear, and shows that the studied substance has anksioliticski action (table 5).

In the test conflict situation (option Vogel) after acute administration statistically significantly increased the number of offences takes water from the trough and decreased latency period before the first offence of taking of water (table 5). Thus, the subject has properties and the expression of the anxiolytic effect in the test conflict situation connection statistically significantly superior to (25 mg/kg), but inferior to diazepam (1 mg/kg).

Study of nootropic action

Methods of production of the conditioned reflex of passive avoidance (passive avoidance reaction) and deliverance (EMT) in animals allow you to quickly assess the influence of substances on their trainability, formation and reproduction of traces in norm and in violation of it.

Test the Conditional reaction of passive avoidance» (passive avoidance reaction) (table 6)

Training of animals was carried out in the installation consisting of two adjacent bays, one of which measures 60 x 40 x 40 cm, an open top and brightly lit (90 LX). The other camera with electrified floor of a smaller size (15 x 15 x 15 cm), dark, closed on all sides and has a hole (8 x 8 cm) for emails with large compartment. The experiment was carried out in two stages: elaboration of animals conditional reflex passive avoidance and play traces the dynamics of 24 hours, 7 and 14 days.

During the training the animal was placed on the middle of the platform lit compartment tail to the hole in the dark compartment. Within three minutes after the animal was a visual observation. After each entry in the dark compartment animal inflicted irritation (40, 3 pulse 1 sec, at 0.5 sec); animals, not calling in a dark chamber during this time, from the experience of the excluded. During the training phase, animals were the following parameters: time from the date of placement of the animal in the middle of the platform to the first entry in the dark compartment (latent period of the first entry) and number of logins.

Experiment playback memorial trail ran as follows: my animal is placed in the middle of the platform lit compartment tail to the hole in the dark compartment and within three minutes led visual observation of the animals. After each entry in the dark compartment animal preserve stimulation. At this stage, recorded the following indicators: the latent period of the first approach, the number of visits in him and the total time the animal in the dark compartment. In the experiment compared the latent period of the first entry of animals into the dark compartment and number of logins him in the test playback traces with the same indicators for teaching. The increase in the latent period and the decrease in the number of visits indicate the training of the animal and the preservation of the memory of the information about the dark compartment (Б Ya, Burešová O., Houston D.P., 1991). Total time of staying in the black space, recognised when skill, but also reflects the preservation of traces of the animal - the less time the animal spends in the black space, the better it remembers about the damage to him here irritation (Б Ya, Burešová O., Houston D.P., 1991).

After acute administration before the training in a group of test animals at all stages of play skill avoidance (statistically significant after 7 and 14 days after training) were observed increase in the latent period of the call of the animals in the dark compartment, reducing the number of visits and time of stay in it compared to the control (table 6). Such a positive effect on learning and memory animals, slowing fading traces in the dynamics indicate the presence of nootropic action of the proposed substances.

Test of deliverance» (table 7)

Training of animals was carried out in a glass rectangular aquarium size 39 x 21 x 25 cm, filled with water, with a temperature 16-18°With 17.5 see Aquarium contained a glass cylindrical cap diameter of 9 cm and a height of 18.5 cm, the edges of which are immersed in water for 2,5 see The experiment was carried out in two stages: elaboration of animals conditioned reflex of deliverance, and the check of safety of skill deliverance in the dynamics of 24 hours, 7 and 14 days.

During the training the animal is placed in the aquarium under the hood. Within three minutes behind him was a visual observation. Animals under the edge of the hood and got rid of, so the aquatic environment. Not solved the task of animals from the experience excluded. During the training phase, animals were the following parameters: time from the moment of immersion animal in the water to start of active swimming (latent period of motor activity), 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) and the time from the date dive animal in the water before diving under the edge of the hood (latent period diving)

Experiment play skill deliverance of animals was performed in the following way: my animal is placed in the aquarium under the hood. Within three minutes behind him was a visual observation. When assessing cognitive functions recorded the most significant indicators: a latent period of physical activity (characteristic speed indicative reactions); the latent period diving (an indicator of the ability to extrapolate than lower the number, the higher the speed of decision tasks). In the experiment compared the indicators that determine the degree of attainment of the animal and memory status: a latent period of diving animal training and playing skill deliverance (than greater decreases when playing skill, the more training the animal and save the memorable trace).

After acute administration to animals before the training skill deliverance in the group of test animals statistically significant at the stages of play skill 24 hours, 7 and 14 days after the training, the decrease with time of the decision tasks and the number of animals, have not found the exit situation (table 7). In addition, with the introduction of animals statistically significantly decreased the latent period of impellent activity is a measure of the rate of the indicative reactions in animals (table 7). Such a positive effect on cognitive function in animals indicates that he has neuroprotective properties. On severity of nootropic effect of the proposed substance statistically significantly inferior .

Studies indicate that the derivative of 2--N--4-(n-methoxyphenyl)-2-pyrrolidone has a pronounced SSRIs antidepressant efficacy actions, combined with anxiolytic activity and neuroprotective properties. Antidepressant and anxiolytic actions are evident in the experiment already in a single application that distinguishes it from most of known antidepressants, for the development of the effect of which is required not less than a week reception.

N--4-(n-methoxyphenyl)-2-pyrrolidone has original spectrum of pharmacological activity: the combination expressed antidepressant and anxiolytic effects with nootropic action sets its own niche therapeutic use of certain groups of patients with anxiety-depressive disorders. An important advantage of this tool before many antidepressants, which are currently used in medical practice, is the ability of its clinically significant effect after a single use, while most known antidepressants for development effect require a course (minimum of two weeks of application). In addition, the N--4-(n-methoxyphenyl)-2-pyrrolidone in contrast to a number of applied antidepressants (in particular, tricyclic) does not violate the memory, attention, but on the contrary, a positive effect on cognitive function, which assumes the possibility of its application working persons. Anxiolytic effect not accompanied by phenomena, impaired memory and attention, declining physical and mental health, which distinguishes it from many tranquilizers, in particular benzodiazepinovogo series.

A medicine containing the active substance N--4-(n-methoxyphenyl)-2-pyrrolidone, depending on the selected media and special additives, can be made in any solid or liquid dosage form.

Thus, the proposed tool manifests expressed antidepressant activity, combined with anxiolytic activity and neuroprotective properties, it's safe, which implies the possibility of prolonged use, in particular and the working patients.

Test «Suspension of mice by the tail»

Registered indicators

The values of indicators Pitch m

The latent period of immobilization, sec.

52,3±3,44**

40,1±2,43**

Total the duration of immobilization, sec.

187,1±5,71

136,2±9,23**

to 150.2±11,64**

* - p<0.05; ** -p<0,01 - reliability of differences compared with the control group of animals;

# - p<0.05; ## - p<0,01 - reliability of differences in comparison with a group of animals receiving (rank analysis of the Kruskal-Wallis test, the criterion Dunn for multiple comparisons; criterion ^ 2 ).

Test Methodology of forced swimming on »

Registered indicators

The values of indicators Pitch m

The latent period of immobilization, sec

52,2±4,36

105±9,22*

21.4 ħ of 4.38*

94,8±10,29*

86,2±6,28**#

The total duration of immobilization, sec

52,2±5,34

84,6±9,26

46±5,48*

24,6±2,32**#

29,2±3,17**#

The number of hops from the water

10,2±1,53*

2,6±0,75

8,6±0,93*

Total time active swimming, sec

150,6±13,4

141,6±10,26

197±3,39**

174,6±12,84

206,8±13,42**

186,8±10,55*

The total time of passive swimming, sec

97,2±5,24

73,8±8,41

82,6±4,65

96,2±13,97

68,6±6,15*#

67,4±8,68

* - p<0.05; ** - p<0,01 - reliability of differences compared with the control group of animals;

# - p<0.05; ## - p<0,01 - reliability of differences in comparison with the group of animals treated with (rank analysis of the Kruskal-Wallis test, the criterion Dunn for multiple comparisons; criterion ^ 2 ).

Test the «open field»

Registered indicators

The values of indicators Pitch m

The number of crossing squares

27,83±2,21

40,66±3,24*

40±3,63*

22,16±2,52#

19,6±3,25

The amount of vertical columns and in the hole

12,83±1,77

9,2±0,73

21,23±2,24*

16,8±1,32*

10,66±0,84#

6,4±1,99#

Number visits brightly lit zone

0,33±0,21

0,4±0,24

1,67±0,42*

0,83±0,3

0,6±0,27

The number of faecal boles

2,5±0,56

3,6±0,51

2,33±0,42

1,8±0,66

3,4±0,57

The number of acts of short-term grooming (<5 seconds)

4,16±0,94

4,6±0,68

1,83±0,6

3,4±0,91

Duration of grooming, sec

7,5±2,59

11,8±1,66

9,16±1,01

18±1,58*

6,83±1,25

10,2±2,58#

* - p<0.05; ** - p<0,01 - reliability of differences compared with the control group of animals;

# - p<0.05; ## - p<0.01 - the significance of differences compared with the group of animals treated with (rank analysis of the Kruskal-Wallis test, the criterion Dunn for multiple comparisons; criterion ^ 2 ).

Test Methodology the conflict situation» (Vogel)

Registered indicators

The values of indicators Pitch m

The latent period of the first punishable approach to a drinking bowl, sec

12,8 + or-2,92*

20,4±3,08

2,4±0,93**#

2,2±0,58**##

Among the punishable approaches to drinking bowl

4,6±1,63

5,6 about 1.6

6,2±1,16

7.8 ħ 1,77

16,2±2,35*#

4,6±1,21

* - p<0.05; ** - p<0,01 - reliability of differences compared with the control group of animals;

# - p<0.05; ## - p<0,01 - reliability of differences in comparison with the group of animals treated with (rank analysis of the Kruskal-Wallis test, the criterion Dunn for multiple comparisons; criterion ^ 2 ).

Test the Conditional reaction of passive avoidance» (passive avoidance reaction)

Registered indicators

The values of indicators Pitch m

The latent period of the first entry in the dark compartment, sec (training)

14,83±2,83

14,4±3,75

12,4±3,5

6,67±1,05*#

23,4±2,77

Number calling in the dark compartment (training)

1,17±0,17

1,17±0,17

1,17±0,17

The latent period of the first entry in the dark compartment, sec (play 24 hours)

134,83 ą30

165,83±14,17

175,2±4,8

Number of visits in the dark compartment (play 24 hours)

0,5±0,34

0,17±0,17

0,4±0,24

The latent period of the first entry in the dark compartment, sec (playback after 7 days)

69,67±22,6

of 113.2±27,54

164,83±15,17*

147,6±5,4

153,33±17,06*

Number of visits in the dark compartment (playback after 7 days)

0,83±0,17

0,17±0,17

0,33±0,21

The latent period of the first entry in the dark compartment, sec (playback 14 days).

40,33±at 13.84

86±27,79

144,83±22,24*

159,2±12,8

129,33±22,68*

119,6±37,18

Number of visits in the dark compartment (reproduction of 14 days).

1,33±0,21

0,33±0,21*

0,4±0,24

0,5±0,22

0,8±0,49

* - p<0.05; ** - p<0,01 - reliability of differences compared with the control group of animals;

# - p<0.05; ## - p<0,01 - reliability of differences in comparison with a group of animals treated (rank analysis of the Kruskal-Wallis test, the criterion Dunn for multiple comparisons; criterion ^ 2 ).

Application of N--4-(n-methoxyphenyl)-2- the following structural formula:

as a means of having antidepressant, anxiolytic and nootropic effects.