RU2437659C1 - Medication possessing antidepressive, anxiolytic and nootropic action - Google Patents

Abstract

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

Description

The invention relates to the pharmaceutical industry and medicine and relates to derivatives of 2-pyrrolidone, exhibiting antidepressant, anxiolytic and nootropic activity.

Derivatives of benzdiazepines are most often used as agents with anxiolytic and antidepressant effects. However, the presence of a large number of side effects in these agents limits their use, in particular for workers, children and the elderly.

Among the derivatives of 2-pyrrolidone, the most well-known drugs are piracetam (2-oxo-1-pyrrolidinacetamide) and phenotropyl or carphedone (N-carbamoylmethyl-4-phenyl-2-pyrrolidone). Piracetam is a nootropic drug that does not have anxiolytic and antidepressant activity. Phenotropil (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) has a wide spectrum of activity:

antihypertensive (SU No. 797219), antihypoxic activity (Yu.G. Bobkov and others. Pharmacological characteristics of the new phenyl analogue of piracetam - 4-phenylpiracetam // Bull. Expert. Biology and medicine. 1983. CSU. S.50-53), nootropic (RU No. 2050851), RU anti-ischemic (Evraz. Patent No. 002380), antidepressant (RU No. 2232578), neurotropic-neuromodulatory (RU No. 2229804). However, this medicine has a number of restrictions for use, in particular because of its ability to cause psychomotor agitation, agitation, and sleep disturbance (Phenotropil - instructions for use, http; www.rlsnet.ru).

The growth of neuropsychiatric diseases with an increasing share of borderline mental disorders, accompanied by cognitive deficits, anxiety-depressive symptoms, asthenoneurotic manifestations and decreased physical and mental performance, makes it relevant to search and develop new highly effective and low-toxic neuropsychotropic drugs with a wide spectrum of activity that allows for pharmacological correction symptoms of neuropsychiatric diseases without polypharmacy, safe for prolonged use, including by working people. It should be borne in mind that for modern medicines used in neurological practice, important criteria are:

- the effectiveness and breadth of the therapeutic spectrum (the possibility and feasibility of use in various forms of pathology);

- security;

- the breadth of the dose range, that is, the gap between the minimally therapeutic and minimally toxic doses.

It is known that one of the most productive ways to search for psychotropic substances is to modify the structure of already known drugs, which can increase efficiency, reduce toxicity, and expand the spectrum of pharmacological action.

N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone is described in a series of derivatives of 2-oxo-1-pyrrolidinylacetamides (Berestovitskaya V.M., Zobacheva M.M., Novikov B.M., Vasilieva O.S. , Usik N.V., Aleksandrova S.M., Tyurenkov I.N. 2-Oxo-1-pyrrolidinylacetamides: production methods and structure // Nitrous heterocycles and alkaloids. Materials of the international conference "Chemistry and Biological Activity of Nitrogen Heterocycles and Alkaloids ". Moscow. October 9-12, 2001, 229-233. / Edited by V. Kartsev, G. Tolstikov, Moscow." Iridium Press "). A preparative method for the preparation of this compound is not described. Its biological activity is not known.

The objective of the invention is to obtain a highly effective and low-toxic drug based on N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone, which has antidepressant, anxiolytic and nootropic activity, to expand the range of such agents.

The problem is realized by the use of a 2-pyrrolidone derivative - N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone of the following structural formula:

as an agent with antidepressant, anxiolytic and nootropic effects.

A drug based on N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone contains its effective dose, pharmacologically acceptable carriers and target additives.

The technical result of the invention is that the proposed tool has low toxicity and is capable of exhibiting a complex effect on the functional state of the central nervous system.

The invention is illustrated by the following examples:

Example 1

The preparation of N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone (CMPP) consists of two stages and consists in the reaction of 4- (n-methoxyphenyl) -2-pyrrolidone with ethyl chloroacetate and subsequent amination of the resulting product.

4- (n-Methoxyphenyl) -1-ethoxycarbonylmethyl-2-pyrrolidone. 4.45 ml of DMSO and 6.8 ml of benzene are added to a four-necked flask equipped with a stirrer, a Dean-Stark nozzle, a thermometer and a dropping funnel. With vigorous stirring, 1.34 g (0.007 mol) of 4- (n-methoxyphenyl) -2-pyrrolidone and 1.08 g (0.019 mol) of potassium hydroxide are added. The mixture is heated to 80-85 ° C, at this temperature the benzene ÷ water azeotrope is distilled off. Then the reaction mass is cooled to 70-75 ° C and 1.9 ml (0.018 mol) of freshly distilled ethyl monochloracetic acid ethyl ester are added in portions to the resulting potassium salt of 4- (n-methoxyphenyl) -2-pyrrolidone, maintaining the temperature of the reaction mass 90-95 ° C. After adding the entire amount of monochloracetate, the mixture is incubated for 2 hours at a temperature of 80-85 ° C. Then the reaction mass is cooled, a double volume of water is added (to the volume of the reaction mass), the organic layer is separated, the aqueous layer is extracted with benzene (3 × 20 ml). The organic layer and benzene extracts are combined, the solvent is evaporated under reduced pressure. 1.5 g (81%) of oily 4- (n-methoxyphenyl) -1-ethoxycarbonylmethyl-2-pyrrolidone are isolated.

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

N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone. Into a two-necked flask equipped with a stirrer, 0.83 g (0.003 mol) of 4- (n-methoxyphenyl) -1-ethoxycarbonylmethyl-2-pyrrolidone and 30 ml of 25% aqueous ammonia are added. Maintain the reaction mass with vigorous stirring for 20 hours. The crystalline product is filtered off and dried in air. Obtain 0.70 g (89%) of 1-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone with so pl. 117-118 ° C (from ethanol).

Found,%: C 59.29, 59.41; H 6.52, 6.51; N, 15.93.15 .94. C ₁₃ H ₁₇ N ₃ O ₃ . Calculated,%: C 59.30; H 6.51; N15.96.

¹ H NMR spectrum, CDCl ₃ . δ, ppm: 3.79, 6.88, 7.13 (n-methoxyphenyl); 2.57, 2.83 (C ³ H ₂ ); 3.49, 3.60 (C ⁵ 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 are examples illustrating the effectiveness of N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone (CMPP).

To study anxiolytic, antidepressant and nootropic activity (KMPP), methods for detecting animal behavioral activity are used, which are a set of psychopharmacological experimental standard tests:

- “open field” (OP) (Khaunina R.A., Lapin I.P. 1976, Voronina T.A. 1982; Gelman V.Ya., Kremenevskaya S.I., 1990);

- “elevated cruciform labyrinth” (PCL) (Pellow S. et al., 1985);

- “conditioned reflex of passive avoidance” (passive avoidance reaction) (Buresh Y., Bureshova O., Houston DP, 1991; Voronina T.A., Ostrovskaya R.U., 2005);

- “extrapolation deliverance” (TEI) (Bondarenko N.A. et al., 2003);

- “conflict situation technique” (Vogel version) (Voronina T.A., Seredenin SB, 2000);

- “hanging mice by the tail” (PMX) (Steru L. et al., 1985);

- “Porsolt forced swimming technique” (Porsolt R.D. et al., 1977).

Processing of the obtained data was carried out using statistical methods for evaluating the results of the study, which allow us to assess the degree of pharmacological effectiveness.

We used white outbred Wistar rats of both sexes weighing 180-220 g and white outbred mice, males weighing 20-25 g, kept in laboratory vivarium, for at least two weeks before the experiment, on a standard diet, with free access to water under natural light conditions. The experiments were carried out at the same time of day. The values of the indicators given in the tables represent the average statistical assessment of the measurement results of the parameters taking into account the accepted levels of reliability (p <0.05; p <0.01).

The acute toxicity of N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone, assessed by the survival of white mice 24 hours after intragastric administration of the drug, has the following average value of LD ₅₀ 2263.88 mg / kg (standard error LD ₅₀ 397 , 52). The substance is low toxic, which allows it to be classified as low hazard. By comparison, the acute toxicity of phenotropyl N-carbamoylmethyl-4-phenyl-2-pyrrolidone) is 800 mg / kg.

The study of antidepressant action

The effect of the substance on the severity of depressive behavior in animals was performed using two classic models of stress-induced depression: the “Test hanging mice by the tail” and the “Test of unavoidable forced swimming in Porsolt”.

The test "Hanging mice by the tail" (table 1)

The experiment was carried out in a chamber 60 × 20 × 20 cm in size, divided into two compartments. 45 minutes (the time of the peak of pharmacological activity development) before the experiment, the studied KMPP was administered to the animals. The mouse was suspended by the tail on a band-aid at a distance of 1.5 cm from the tip of the tail. The distance from the floor to the nose of the animal was 10 cm. Within 6 minutes, the total duration of immobilization (fixed hanging) was recorded simultaneously in two animals. Immobilization (an indicator of behavioral despair) is a clinical sign of depression. The decrease in the duration of immobilization in animals of the experimental groups compared with the control was regarded as the presence of antidepressant properties in the substance).

Forced Unavoidable Swimming Test (Table 2)

The experiment was carried out in a glass pool with a diameter of 32 cm and a height of 50 cm filled with water (temperature 21-24 ° C) to a level at which the animal cannot touch the bottom with its hind legs. Rats were placed in a pool for 15 minutes, then were placed in a heated cage for 30 minutes and returned to the vivarium. After 24 hours, 45 minutes before the start of the re-testing, the animals were injected with the studied KMPP and placed in a pool. The latent period of immobilization, the total time the rat was in the state of immobilization (the animal passively swims in the water with its head slightly raised), the duration of active swimming (the animal actively moves with all four limbs) and the number of jumps out of the water (the animal makes a jerk with its whole body) were recorded for 300 sec. trying to get out of the water). An increase in the latent period of immobilization, a decrease in its duration, an increase in the duration of active swimming and the number of jumps in animals of the experimental groups compared with the control indicates the presence of an antidepressant effect in the test substance.

The results of experiments performed on models of stress-induced depression showed that KMPP with a single administration to rats (both males and females) shows a pronounced antidepressant effect. Under the influence of KMPP in the tests of “unavoidable forced swimming in Porsolt” and “suspension of mice by the tail”, the latent period statistically significantly increased until the development of immobility and the total time of immobilization in animals decreased (Tables 1 and 2). In the test “unavoidable forced swimming but Porsolt” under the influence of the test substance, the number of jumps in animals and the total duration of active swimming statistically significantly increased (Table 2). In addition, the antidepressant effect of this substance is confirmed by the results of the extrapolation disposal test, in which, under the influence of CMP, the severity of the behavioral correlation of depression was statistically significantly reduced - the duration of immobilization in both male and female rats (Table 7). The antidepressant properties of KMPP exceed the similar effect of phenotropil.

The study of anxiolytic action

The study of anxiolytic activity was carried out using the tests “Open Field”, “Elevated Cruciform Maze”, as well as the model of “Conflict Situation by Vogel” caused by the collision of defensive and food reflexes.

Open Field Test (Table 3)

The open-field technique is used to study the effect of a substance on the indices of spontaneous individual behavior of animals (motor, orientational-research activity and emotional status) and to reveal anxiolytic properties.

The experiment was carried out in a square chamber measuring 80 × 80 cm and a height of 60 cm. The floor of the chamber is divided by black paint into 25 equal squares measuring 5 × 5 cm with the allocation of the central zone of the field. The chamber floor was equipped with 16 holes with a diameter and depth of 3 cm. The chamber was illuminated by a 90 Lx lamp located above the center of the field at a height of 150 cm. The rat was placed in the center of the chamber with its tail to the experimenter and its behavior was observed for 3 minutes. In the test were recorded: the number of crossed squares on the periphery, the number of crossed brightly lit squares, the number of vertical racks, the number of peeps into holes, the number of urinations and bowel movements, the number of acts and the total duration of grooming. The number of crossed squares characterizes the spontaneous locomotor activity of animals, the sum of the racks and peeping in the holes - the total tentative research activity. The number of visits to the central brightly lit area (aversive for burrowing rodents) indicates the level of anxiety of the animal (the less anxiety - the more, and vice versa). An increase in the number of such acts under the influence of the test substances indicates their anxiolytic activity. The behavior of the animal during washing and cleaning (grooming) reflects the degree of its emotional stress: frequent short-term (up to 5 sec) - anxiety state, rare and long-lasting - state of comfort. Vegetative indicators of stress (the number of boluses of bowel movements and urination) also characterize the emotional stress of animals (Table 3).

With a single administration of CMPF to animals before studying their individual behavior in the “open field” test, the number of crossed squares (motor activity), the number of racks and peeps in holes (tentatively research activity) statistically significantly increased in the group of test animals, which indicates the presence of substances activating effect comparable to the effect of phenotropil. In addition, when KMPP was administered to rats, the number of visits to the central brightly lit zone (aversive for burrowing rodents) statistically significantly increased, the number of acts of short-term (less than 5 sec) “disturbing” grooming decreased and its duration increased, which indicates a comfortable emotional state of the animals.

Thus, it was found that the KMPP compound (25 mg / kg) does not have a statistically significant effect on the indices of spontaneous individual behavior of both male and female rats in the “open field” test, which compares favorably with phenotropil, which causes psychomotor agitation. In addition, this substance, unlike diazepam, does not cause sedation in animals, which also expands the possibility of its clinical use (Table 3).

Test “Elevated Cruciform Maze” (Table 4)

The technique of the elevated cruciform labyrinth is used to study the effect of the substance on the severity of the emotional reaction of fear and anxiety in the test animals and the detection of anxiolytic activity. It is based on the preference by rodents of dark holes, the natural fear of being in open areas and falling from a height.

The experiment was carried out in a setup (labyrinth), consisting of a central platform 10 × 10 cm in size, from which four arms 50 × 10 cm each diverged crosswise at right angles. Two opposite sleeves are open, without walls and two closed, dark, limited to the sides by dark sides painted 40 cm high. The floor of the installation is painted white. The maze was raised above the floor by 80 cm. The test animal was placed on the central area of the maze with its muzzle facing the open sleeve and was monitored for 3 minutes. In the test were recorded: the time spent by animals on the central platform, in open and closed arms, the number of racks in closed and open arms, the number of hangings from open arms and the number of entries into the central zone, open and closed arms. The rat crossing the borders of any compartment with its hind legs was defined as the entry of the animal into the labyrinth compartment. An increase in the residence time in light arms, the number of entries in them, the uprights in open arms and hanging from them indicate the anxiolytic effect of the test substance. The length of stay at the central site allows you to evaluate the speed of decision making animals. Total motor activity is estimated by the total number of entries into open, closed arms and the center of the maze.

In the test, “elevated cruciform labyrinth” with a single injection of KMPF statistically significantly increases the length of stay in open arms in the test animals (both male and female rats), without having a statistically significant effect on the number of exits from them (Table 4). Thus, in the elevated cross-maze labyrinth test, the anxiolytic effect of the substance KMPP is comparable with the action of phenotropil.

Test “Conflict Technique” (Vogel option) (Table 5)

The technique of a conflict situation (Vogel variant) is used to study the effect of a substance on animal behavior on a model of creating a state of anxiety and fear in them using an electric stimulus that suppresses drinking reflexes.

The experiment was conducted in a chamber 27.5 × 27.5 × 45.0 cm in size, equipped with an electrode floor. On the wall of the chamber, at a height of 5 cm above the electrode floor there was a drinking bowl (vessel with a nipple). Before the test for 48 hours, the animals were not limited in feed intake and deprived of water intake. Then the animals developed the skill of taking water from the drinker: the rat was placed in the chamber for 10 minutes, where it found water and began to drink. The next day after learning the skill, 45 minutes (the time of the peak of their pharmacological activity) before the experiment, the test substances were administered to the animals. Then the rat was placed in the chamber for 10 minutes, and 10 seconds after the start of drinking, each water intake was punished with electric pain irritation (1 mA). In the test, the latent period of the first punishable approach to the drinker and the number of punishable water taken from the drinker were recorded. A decrease in the latent period and an increase in the number of punishable water intake indicates a suppression of feelings of anxiety and fear and indicates that the studied substance has an anxiolytic effect (Table 5).

In the conflict test (Vogel variant), with a single administration of KMPP, the number of punishable water withdrawals from the drinking bowl statistically significantly increased and the latent period decreased to the first punished water intake (Table 5). Thus, the tested KMPP has anxiolytic properties and the severity of the anxiolytic effect in the conflict test is statistically significantly higher than phenotropil (25 mg / kg), but inferior to the diazepam (1 mg / kg) benzodiazepine tranquilizer.

The study of nootropic action

Methods for developing a conditioned passive avoidance reflex (passive avoidance reaction) and extrapolation disposal (TEI) in animals allow us to quickly assess the effect of a substance on their learning ability, the formation and reproduction of a memorable trace in normal conditions and in conditions of its violation.

Test "Conditional reaction of passive avoidance" (passive avoidance reaction) (table 6)

The animals were trained in an installation consisting of two adjacent compartments, one of which is 60 × 40 × 40 cm in size, open from above and brightly lit (90 Lux). Another chamber with a smaller electrified floor (15 × 15 × 15 cm), darkened, closed on all sides and has an opening (8 × 8 cm) for communication with a large compartment. The experiment was carried out in two stages: the development of a conditioned reflex of passive avoidance in animals and the reproduction of a memorable trace in dynamics after 24 hours, 7 and 14 days.

During training, the test animal was placed in the middle of the illuminated compartment area, tail to the hole in the dark compartment. Within three minutes, the animal was visually observed. After each entry into the dark compartment, the animal was subjected to electric pain stimulation (40 V, 3 pulses of 1 sec, with an interval of 0.5 sec); animals not entering the dark chamber during this time were excluded from the experiment. At the stage of animal training, the following indicators were recorded: the time from the moment the animal was placed in the middle of the site until the first entry into the dark compartment (the latent period of the first entry) and the number of entries into it.

The experiment of reproducing the memorial trail was carried out as follows: the trained animal was placed in the middle of the illuminated compartment area, with its tail to the hole in the dark compartment, and visual observation of the animal was carried out for three minutes. After each entry into the dark compartment, the animal was not subjected to electric pain stimulation. At this stage, the following indicators were recorded: the latent period of the first entry, the number of entries into it and the total time the animal was in the dark compartment. In the experiment, the latent period of the first entry of animals into the dark compartment and the number of entries into it in the test of reproducing a commemorative trace with similar indicators during training were compared. An increase in the latent period and a decrease in the number of visits indicate that the animal is trained and that information about the aversivity of the dark compartment is preserved in memory (Buresh Y., Bureshova O., Houston DP, 1991). The total time spent in the dark compartment, recorded during the reproduction of the skill, also reflects the safety of the animal’s memorial trail - the less time the animal spends in the dark compartment, the better it remembers the electric pain irritation caused to it (Buresh Y., Bureshova O., Houston D .P., 1991).

With a single administration of KMPP before training in the group of test animals at all stages of reproduction of the avoidance skill (statistically significant after 7 and 14 days after training), an increase in the latent period of entry of animals into the dark compartment, a decrease in the number of entries into it and the time spent in it with respect to control (table 6). Such a positive effect of KMPP on learning and memory of animals, slowing down the extinction of the memorial trail in dynamics indicate the presence of a nootropic effect in the claimed substance.

Test "extrapolation deliverance" (table 7)

The animals were trained in a rectangular glass aquarium measuring 39 × 21 × 25 cm, filled with water with a temperature of 16-18 ° C by 17.5 cm. The aquarium contained a glass cylindrical cap with a diameter of 9 cm and a height of 18.5 cm, the edges of which were immersed in water 2.5 cm. The experiment was carried out in two stages: the development of a conditioned reflex response in animals and the preservation of the extrapolation deliverance skill in dynamics after 24 hours, 7 and 14 days.

During training, the test animal was placed in an aquarium under a cap. For three minutes he was visually observed. Animals dived under the edges of the cap and, thus, got rid of the aversive aquatic environment. Animals that did not solve the problem were excluded from the experiment. At the stage of animal training, the following indicators were recorded: the time from the moment the animal was immersed in water until the active swimming began (latent period of motor activity), immobilization time (the animal passively swims in the water with its head slightly raised, all four limbs are motionless), the number of jumps in the cap ( active attempts to jump out of the water) and the time from the moment the animal is immersed in water until diving under the edges of the cap (latent period of diving)

The experiment of reproducing the skill of extrapolation disposal in animals was performed as follows: the trained animal was placed in an aquarium under a cap. For three minutes he was visually observed. When evaluating cognitive functions, the most significant indicators were recorded: latent period of motor activity (characteristic of the speed of orientational reactions); latent diving period (an indicator of the ability to extrapolate, the lower the value of the indicator, the higher the speed of solving the extrapolation problem). The experiment compared the indicators that determine the degree of training of the animal and the state of memory: the latent period of diving of the animal during training and reproduction of the extrapolation ridding skill (the more it decreases during the reproduction of the skill, the greater the learning level of the animal and the memory footprint preserved).

When animals were once introduced before training in extrapolation disposal skills in the group of test animals, statistically significant at the stages of reproducing the skill 24 hours, 7 and 14 days after training, a decrease in the time to solve the extrapolation problem and the number of animals that did not find a way out of the aversive situation was observed (Table 7). In addition, when KMPP was administered to animals, the latent period of locomotor activity was statistically significantly reduced - an indicator that characterizes the rate of indicative reactions in animals (Table 7). Such a positive effect of KMPP on cognitive functions in animals suggests that it has nootropic properties. According to the severity of the nootropic effect, the proposed substance is statistically significantly inferior to phenotropyl.

Studies show that the derivative of 2-pyrrolidone-N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone has a pronounced antidepressant effect in combination with anxiolytic activity and nootropic properties. Antidepressant and anxiolytic effects are clearly manifested in the experiment already with a single use of KMPP, which distinguishes it from most known antidepressants, for the development of the effect of which requires at least a week's intake.

N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone has an original spectrum of pharmacological activity: a combination of pronounced antidepressant and anxiolytic effects with a nootropic effect determines its own niche of therapeutic use for certain groups of patients with anxiety-depressive disorders. An important advantage of the proposed tool over many of the antidepressants used today in medical practice is its ability to exert a clinically significant effect after a single use, while most known antidepressants require a course (at least two-week use) to develop the effect. In addition, N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone, unlike the number of antidepressants used (in particular, tricyclics), does not impair memory, attention, but, on the contrary, positively affects cognitive functions, which suggests the possibility of its application by employees. The anxiolytic effect of KMPP is not accompanied by hypnosedative phenomena, impaired memory and attention, decreased physical and mental performance, which distinguishes it from many tranquilizers, in particular the benzodiazepine series.

A drug containing N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone as an active ingredient, depending on the carriers and target additives selected, may be prepared in any solid or liquid dosage form.

Thus, the proposed tool exhibits a pronounced antidepressant effect in combination with anxiolytic activity and nootropic properties, it is safe, which suggests the possibility of prolonged use, in particular in working patients.

Table 1 Test "Hanging mice by the tail" Recorded Indicators Values of indicators M ± m The control phenotropil KMPP males females males females males females Latent period of immobilization, sec. 22 ± 1.81 - 52.3 ± 3.44 ** - 40.1 ± 2.43 ** - The total duration of immobilization, sec. 187.1 ± 5.71 - 136.2 ± 9.23 ** - 150.2 ± 11.64 ** - Designations: * - p <0.05; ** p <0.01 - significance of differences compared with the control group of animals; # - p <0.05;## - p <0,01 - significance of differences compared with the group of animals treated with phenotropil (Kruskal-Wallis rank one-way analysis, Dunn’s test for multiple comparisons; χ ² criterion).

table 2 Test "Technique of forced swimming in Porsolt" Recorded Indicators Values of indicators M ± m The control phenotropil KMPP males females males females males females Latent period of immobilization, sec 60 ± 3.64 52.2 ± 4.36 105 ± 9.22 * 21.4 ± 4.38 * 94.8 ± 10.29 * 86.2 ± 6.28 ** # The total duration of immobilization, sec 52.2 ± 5.34 84.6 ± 9.26 37 ± 3.9 * 46 ± 5,48 * 24.6 ± 2.32 ** # 29.2 ± 3.17 ** # The number of jumps from the water 4 ± 0.32 5.4 ± 1.2 10.2 ± 1.53 * 2.6 ± 0.75 8.6 ± 0.93 * 8 ± 1.3 # Total time of 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 * Total passive swimming time, 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 Designations: * - p <0.05; ** - p <0.01 - significance of differences compared with the control group of animals; # - p <0.05;## - p <0,01 - significance of differences compared with the group of animals treated with phenotropil (Kruskal-Wallis rank one-way analysis, Dunn’s test for multiple comparisons; χ ² criterion).

Table 3 Open Field Test Recorded Indicators Values of indicators M ± m The control phenotropil KMPP males Females males females males females The number of crossed squares 27.83 ± 2.21 25 ± 2.41 40.66 ± 3.24 * 40 ± 3.63 * 22.16 ± 2.52 # 19.6 ± 3.25 The sum of the uprights and peeping holes 12.83 ± 1.77 9.2 ± 0.73 21.23 ± 2.24 * 16.8 ± 1.32 * 10.66 ± 0.84 # 6.4 ± 1.99 # Visits to a brightly lit area 0.33 ± 0.21 0.4 ± 0.24 1.67 ± 0.42 * 1.2 ± 0.2 0.83 ± 0.3 0.6 ± 0.27 The number of fecal boluses 2.5 ± 0.56 3.6 ± 0.51 2.33 ± 0.42 1.8 ± 0.66 1 ± 0.37 3.4 ± 0.57 The number of acts of short-term grooming (<5 sec) 4.16 ± 0.94 4.6 ± 0.68 1.83 ± 0.6 2.6 ± 0.6 3 ± 0.68 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 # Designations: * - p <0.05; ** - p <0.01 - significance of differences compared with the control group of animals; # - p <0.05;## - p <0,01 - significance of differences compared with the group of animals treated with phenotropil (ranked one-way analysis of Kruskal-Wallis, Dunn's test for multiple comparisons; criterion χ ² ).

Table 4 Test "Elevated Cruciform Maze" Recorded Indicators Values of indicators M ± m The control phenotropil KMPP males females males females males females Number of entries in open sleeves 1.17 ± 0.17 1.2 ± 0.2 2.5 ± 0.43 * 3 ± 0.45 * 1.33 ± 0.21 1.4 ± 0.24 Time spent in open sleeves, sec 29.5 ± 2.79 24.6 ± 3.03 51 ± 5.65 * 39 ± 4.17 * 48.33 ± 4.08 * 39 ± 4.24 * Time spent in the central zone, sec 11.33 ± 1.74 20.4 ± 2.11 6.16 ± 0.87 * 7.6 ± 1.36 * 5.33 ± 1.15 * 16.6 ± 2.36 The number of uprights in open sleeves 0.33 ± 0.21 0.4 ± 0.24 0.5 ± 0.22 1 ± 0.45 0.66 ± 0.21 0.2 ± 0.2 Number of hangs in open sleeves 2 ± 0.82 0.6 ± 0.4 2.5 ± 0.67 1.8 ± 0.37 2.33 ± 0.49 1 ± 0.45 The total number of transitions between the arms of the maze 4.17 ± 0.48 5.2 ± 0.2 7 ± 0.45 * 9 ± 0.84 * 3.83 ± 0.4 6 ± 1.05 Designations: * - p <0.05; ** - p <0.01 - significance of differences compared with the group of animals; # - p <0.05;## - p <0,01 - significance of differences compared with the group of animals treated with phenotropil (ranked one-way analysis of Kruskal-Wallis, Dunn's test for multiple comparisons; criterion χ ² ).

Table 5 Test "Conflict Technique" (Vogel) Recorded Indicators Values of indicators M ± m The control phenotropil KMPP males Females males females males females Latent period of the first punished approach to the drinker, sec 25 ± 2.66 20 ± 2.88 12.8 ± 2.92 * 20.4 ± 3.08 2.4 ± 0.93 ** # 2.2 ± 0.58 ** ## Number of punishable drinking approaches 4.6 ± 1.63 5.6 ± 1.6 6.2 ± 1.16 7.8 ± 1.77 16.2 ± 2.35 * # 4.6 ± 1.21 Designations: * - p <0.05; ** - p <0.01 - significance of differences compared with the control group of animals; # - p <0.05;## - p <0,01 - significance of differences compared with the group of animals treated with phenotropil (ranked one-way analysis of Kruskal-Wallis, Dunn’s test for multiple comparisons; criterion χ ² ).

Table 6 Test "Conditional reaction of passive avoidance" (passive avoidance reaction) Recorded Indicators Values of indicators M ± m the control phenotropil KMPP males females males females males females Latent period of the first entry into the dark compartment, sec (training) 14.83 ± 2.83 14.4 ± 3.75 16 ± 2.87 12.4 ± 3.5 6.67 ± 1.05 * # 23.4 ± 2.77 The number of entries in the dark compartment (training) 1.17 ± 0.17 1.2 ± 0.2 1.17 ± 0.17 1.2 ± 0.2 1.17 ± 0.17 1.2 ± 0.2 Latent period of the first entry into the dark compartment, sec (playback after 24 hours) 134.83 ± 30 180 ± 0 180 ± 0 180 ± 0 165.83 ± 14.17 175.2 ± 4.8 The number of entries in the dark compartment (playback after 24 hours) 0.5 ± 0.34 0 0 0 0.17 ± 0.17 0.4 ± 0.24 Latent period of the first entry into the dark compartment, sec (playback after 7 days) 69.67 ± 22.6 113.2 ± 27.54 164.83 ± 15.17 * 147.6 ± 5.4 153.33 ± 17.06 * 162 ± 18 The number of entries in the dark compartment (playback after 7 days) 0.83 ± 0.17 1 ± 0.45 0.17 ± 0.17 0.2 ± 0.2 0.33 ± 0.21 0.4 ± 0.4 Latent period of the first entry into the dark compartment, sec (playback after 14 days) 40.33 ± 13.84 86 ± 27.79 144.83 ± 22.24 * 159.2 ± 12.8 129.33 ± 22.68 * 119.6 ± 37.18 The number of entries in the dark compartment (playback after 14 days) 1.33 ± 0.21 1.4 ± 0.6 0.33 ± 0.21 * 0.4 ± 0.24 0.5 ± 0.22 0.8 ± 0.49 Designations: * - p <0.05; ** - p <0.01 - significance of differences compared with the control group of animals; # - p <0.05;## - p <0,01 - significance of differences compared with the group of animals treated with phenotropil (Kruskal-Wallis rank one-way analysis, Dunn’s test for multiple comparisons; χ ² criterion).

Claims (1)

The use of N-carbamoylmethyl-4- (n-methoxyphenyl) -2-pyrrolidone with the following structural formula:

as an agent with antidepressant, anxiolytic and nootropic effects.