RU2507198C1 - Quinazoline derivatives, possessing nootropic and antihypoxic activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel medication, possessing nootropic and antihypoxic activity, which represents arylamides of 2-[4-oxo-3(4H)quinazolinyl]acetic acid of general formula

where R=o-CH₃, n-CH₃ or 2,3-phenylene. Compounds demonstrated original spectrum of psychotropic action, exceeding in complex of useful properties medications of different pharmacological groups - piracetam, phenibut, phenotropil, mexidol, on experimental models in vivo.

EFFECT: compounds can be widely applied in treatment of patients with organic affection of brain.

3 tbl, 5 ex

Description

The invention relates to the field of organic chemistry and medicine, namely to new quinazoline derivatives having pronounced nootropic and antihypoxic activity, which can be used to treat widespread diseases of the central nervous system.

Currently, one of the most effective ways to prevent and treat neuropsychiatric disorders is psychopharmacotherapy. Medicines containing physiologically active compounds that affect the metabolism of neurotransmitters, synaptic transmission processes and metabolic reactions in neurons of the brain can significantly correct the mental and emotional state, which helps to strengthen adaptation to psycho-emotional stress, the scale of which is steadily progressing in modern industrial society. With the help of psychotropic drugs, in particular nootropics, the main characteristic of which is an activating effect on the integrative activity of the brain and the restoration of disorders of higher nervous activity, it is possible to increase a person's ability to learn, accelerate the pace of education, increase working capacity [Belenichev I.F., Cherniy V .I., Kolesnik Yu.M. Rational neuroprotection. - Donetsk: Ed. Zaslavsky A.Yu., 2009. - 262 p.]. In addition, with the advent of nootropics, the opportunity for a targeted pharmacological effect on cognitive functions (attention, memory, ability to assess and analyze the situation, make decisions) and the manifestation of mental and neurological deficits that form during organic brain damage has appeared for the first time. Nootropics facilitate the activity of brain cells during oxygen starvation, which can occur after a stroke, traumatic brain injury, infectious diseases, intoxications [Neznamov G. G., Teleshova E. S., Syunyakov S. A. A new peptide drug Noopept in patients with psycho-organic disorders // Spr. outpatient clinic. a doctor. - 2007. - T. 5. - No. 2. - S. 26-35]. Doctors recommend elderly people to take nootropic drugs constantly - they improve well-being, working capacity and mood. The extreme importance of drugs with a nootropic effect is evidenced by data on the widespread use of them - according to WHO statistics, a third of the adult population of Europe and Japan take nootropics, and they can rightfully be attributed to the group of vital drugs [Kosarev V.V., Babanov S. BUT. Clinical and pharmacological approaches to the use of nootropics in neurological diseases // Lectures for doctors. - 2010. - No. 2. - S. 4-8]. In this regard, the search for new, more effective and safe nootropic drugs with a balanced spectrum of psychopharmacological properties is an urgent problem of modern pharmacology and pharmacy.

Quinazoline derivatives structurally close to endogenous pyrimidine bases and their derivatives possessing a wide range of valuable psychotropic properties - nootropic, anxiolytic and antidepressant [Kodonidi I.P., are promising in terms of developing new highly effective, selective and safe psychotropic drugs. Molecular design and targeted synthesis of N-substituted 4-oxo-1,4-dihydropyrimidine derivatives based on inhibitory neurotransmitters // Chem. Pharmac journal - 2009. - T. 43. - No. 10. - S. 32-39].

Quinazoline derivatives are widely distributed in wildlife, at present, about 150 alkaloids of the quinazoline series, many of which have high pharmacological activity and are used in medical practice, have been isolated from lower fungi, bacteria, and higher plants. The most famous quinazoline alkaloid is febrifugine, isolated from the leaves and roots of the Chinese medicinal plant Dichroa febrifuga. Febrifugin is a well-known anti-malarial drug; it is approximately 100 times more active than quinine, but more toxic. Febrifugin also has a pronounced coccidostatic effect [Arora R., Karoor A., Gill N.S., Rana A.C. Quinazolinone: an overview // Int. Res. J. Pharmacy. - 2011. - Vol. 2. - No.12. - P. 22-28].

Synthetic derivatives of quinazoline also have a wide range of pharmacological activity, many of them have found application in medical practice as effective and safe therapeutic and prophylactic drugs. One of the most well-known quinazoline drugs is methaqualone (Quaalude, Mandrax, Sopor), which was approved by the US government in March 1966 as a non-addictive sedative-hypnotic drug:

In the future, more effective analogues of methaqualone (ethaqualone, meclocvalone, chloroqualone, nitromethaqualone) and the modern drug lonetil - a tranquilizer with anxiolytic and sedative activity were obtained. Lonetil is indicated for sleep disorders, anxiety, psycho-vegetative manifestations, neurotic (neurosis-like) disorders. In the clinic for the treatment of alcoholism, lonetil is used to relieve alcohol withdrawal symptoms, as well as during remission. Treatment with the drug helps to reduce fear, anxiety, irritability, normalize night sleep, and eliminate vegetative-vascular manifestations. The elimination of the psychopathological symptoms observed in patients with alcoholism during the period of remission leads to a decrease in the pathological craving for alcohol [Medicines in the clinic of alcoholism and drug addiction. Manual for Doctors / Ed. A.Yu. Magalifa. - M.: RSMU, 1999. - 111 p.]:

Other known drugs of the quinazoline series include the specific 5-HT2 receptor antagonist ketanserin, the selective tyrosine kinase inhibitor getifinib, the dihydrofolate reductase inhibitor trimethrixate, the diuretic quinetasone, the ai-adrenergic blocking agent prazosin, and the analgesic antagonistic antagonist drug and anti-inflammatory drug. However, all of these drugs and their numerous structural analogues do not have a nootropic or antihypoxic effect. Despite a fairly wide spectrum of pharmacological activity of synthetic quinazoline derivatives (analgesic, anti-inflammatory, antibacterial, antiviral, antitumor, antimalarial, antihypertensive, antidiabetic activity), information on their effect on the central nervous system is relatively scarce. Thiadiazolyl derivatives of quinazolin-4 (3H) -one of the general formula are known

where R ¹ and R ² are aromatic substituents,

which have psycho-suppressive and anticonvulsant properties [Jatav V., Mishra P., Kashaw S., Stables J.P. Synthesis and CNS depressant activity of some novel3- [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 compounds is N- (2,6-dimethylphenyl) -2- [4-oxo-3 (4H) -quinazolinyl] -acetamide of the formula:

The specified compound does not have nootropic and antihypoxic properties, anxiety-phobic and prodressive effects prevail in the spectrum of psychopharmacological properties of this substance [Tyurenkov I.N., Ozerov A.A., Solodunova E.A., Archakova Yu.V., Glukhova E. G., Shmatova E.N. Anomaly in the series of pharmacological properties of quinazolin-4 (3H) -one derivatives having acetanilide fragments as substituents // Bulletin of Volgograd State Medical University. - 2012. - Issue. 2. - S. 66-68].

The aim of the invention is to obtain new derivatives of quinazoline with a balanced complex of psychopharmacological properties - nootropic and antihypoxic.

The invention consists in the synthesis of new quinazoline derivatives of the general formula:

where R = o-CH ₃ , n-CH ₃ or 2,3-phenylene.

The proposed compounds, combining fragments of quinazolin-4 (3H) -one and substituted acetanilide in their structure, have pronounced nootropic and antihypoxic activity in vivo superior to the activity of reference drugs.

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

A mixture of 2.0 g (13.7 mmol) of quinazolin-4 (3H) -one, 4.0 g (28.9 mmol) of anhydrous potassium carbonate and 50 ml of dimethylformamide is stirred at a temperature of 100-105 ° C for 30 minutes, 2.8 g (15.1 mmol) of 2-chloro-N- (2-methylphenyl) acetamide are added and stirred at the same temperature for 1 hour. Cool to room temperature, filter, and the filtrate is kept at a temperature of 0-5 ° C. within 1 day, the precipitate formed is filtered off, washed with cold dimethylformamide, water and dried in air. Recrystallized from dimethylformamide to give 2.80 g of compound. I, yield 70%, mp. 266-268 ° C.

1 H-NMR spectrum (DMSO-d ₆ , δ, ppm: 2.19 s (3H, CH ₃ ); 4.86 s (2H, CH ₂ ); 7.02 t (7 Hz, 1H, H ⁶ ) ; 7.33-7.52 m (4H, phenyl); 7.66 d (8 Hz, 1H, H ⁸ ); 7.81 t (7.5 Hz, 1H, H ⁷ ); 8.11 d ( 7 Hz, 1H, H ⁵ ); 8.33 s (1H, H ² ); 9.77 s (1H, NH).

Example 2. N- (4-Methylphenyl) -2- [4-oxo-3 (4H) -quinazolinyl] acetamide (compound II).

A mixture of 2.0 g (13.7 mmol) of quinazolin-4 (3H) -one, 4.0 g (28.9 mmol) of anhydrous potassium carbonate and 50 ml of dimethylformamide is stirred at a temperature of 100-105 ° C for 30 minutes, 2.8 g (15.1 mmol) of 2-chloro-N- (4-methylphenyl) acetamide are added and the mixture is stirred at the same temperature for 1 hour. It is cooled to room temperature, filtered, the filtrate is evaporated in vacuo, 50 is added to the residue ml of water, maintained at a temperature of 0-5 ° C for 1 day, the precipitate formed is filtered off, washed with water and dried in air. Recrystallized from ethyl alcohol-dimethylformamide (3: 1) to give 2.29 g of the compound. II, yield 57%, mp. 256-258 ° C.

PMR spectrum (DMSO-d ₆ ), δ, ppm: 2.20 s (3H, CH ₃ ); 4.80 s (2H, CH ₂ ); 7.03 d (8 Hz, 2H, phenyl); 7.39 d (7 Hz, 2H, phenyl); 7.48 t (7.5 Hz, 1H, H ⁶ ); 7.63 d (8 Hz, 1H, H ⁸ ); 7.77 t (7.5 Hz, 1H, H ⁷ ); 8.07 d (7 Hz, 1H, H ⁵ ); 8.29 s (1H, H ² ); 10.31 s (1H, NH).

Example 3. N- (1-Naphthyl) -2- [4-oxo-3 (4H) -quinazolinyl] acetamide (compound III).

A mixture of 2.0 g (13.7 mmol) of quinazolin-4 (3H) -one, 4.0 g (28.9 mmol) of anhydrous potassium carbonate and 100 ml of dimethylformamide was stirred at a temperature of 100-105 ° C for 30 minutes, 3.3 g (15.1 mmol) of 2-chloro-N- (1-naphthyl) acetamide are added, the mixture is stirred at the same temperature for 1 hour. It is cooled to room temperature, filtered, and the filtrate is kept at 0-5 ° C in for 1 day, the precipitate formed is filtered off, washed with cold dimethylformamide, water and dried in air. Recrystallized from dimethylformamide to give 2.97 g of a compound. III, yield 66%, mp. 319-322 ° C.

PMR spectrum (DMSO-d ₆ ), δ, ppm: 5.02 s (2H, CH ₂ ), 7.44-7.86 m (9H, H ⁶ , H ⁸ , naphthyl), 7.91 t (7.5 Hz, 1H, H ⁷ ), 8.14 d (7.5 Hz, 1H, H ⁵ ), 8.4 s (1H, H ² ), 10.41 s (1H, NH).

Example 4. The study of nootropic activity

The nootropic properties of new quinazoline derivatives were studied using associative learning models based on the development of conditioned reflexes for avoiding the aversive factor: “conditional passive avoidance reaction” (passive avoidance reaction) and “extrapolation deliverance test” (TEI). In the first series of experiments, the effect of substances on the change in the memory trail in animals in dynamics was studied: each test was carried out in several stages - the first stage was to develop a reflex of avoiding the aversive factor, at the next stages an assessment was made of the training of animals and the safety of their memory. Passive avoidance reaction test was reproduced 24 hours, 3 and 7 days after training, TEI - after 24 hours.

The passive avoidance reaction test is traditionally used in psychopharmacology to identify specific nootropic activity of substances. The test allows you to evaluate the effect of substances on learning, the formation, preservation and reproduction of a memorable trace in normal conditions and in conditions of amnesia (often electroconvulsive or chemo-induced - scopolamine - origin), on different phases of memory with variations in the timing of the introduction of substances (the introduction to the development of the reflex characterizes memorization and learning , immediately after the elaboration of the reflex — consolidation of the memorable trace, before the reproduction of the reflex — extraction of information from the memory, repeated reproduction of the reflex through different time intervals - the dynamics of the forgetting process). The passive avoidance experiment setup consists of two adjacent compartments, one of which is large (60 × 40 × 40 cm), open from above and brightly lit (90 lux), the other is smaller (15 × 15 × 15 cm), darkened, closed with all sides, having a quadrangular hole (8 × 8 cm), for communication with a large compartment and electrode floor. The test is performed in two stages:

learning the skill of passive disposal and reproducing the dynamics of its preservation. During the experiment, the test animal is placed in the middle of the illuminated compartment area, tail to the hole in the dark compartment. Within 3 minutes, a visual observation is carried out on the experimental animals. When learning the skill, after each entry into the dark compartment, the animal is subjected to electric pain stimulation (40 V, 3 impulses of 1 s, with an interval of 0.5 s), animals not entering the dark chamber during this time are excluded from the experiment. At the training stage, indicators are recorded: the latent period of the first entry into the dark compartment (the time from the moment the animal was placed in the middle of the platform to the first entry into the dark compartment) and the number of entries into it. When checking the development of a reflex at the second stage of testing, the latent period of the first entry into the dark compartment and the number of entries into it are compared with the same indicators during training, an increase in the latent period and a decrease in the number of entries indicate the animal is trained, the information about the dark compartment aversivity is stored in memory. 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. Reproduction of the reflex is carried out in a similar way, however, the animal does not have electric pain stimulation, the latent period of the first entry into the dark compartment is recorded (the time from the moment the animal was placed in the middle of the platform to the first entry into the dark compartment), the number of entries into it, the total time the animal was in the dark and bright compartments. Verification of the passive avoidance reaction is carried out in dynamics after 24 hours, 7 and 14 days by re-placing the animal in the lit compartment. An increase in the latent period of entry into the dark compartment under the action of the compound, a decrease in the number of visits and the time spent in it relative to the control at all stages of the reproduction of the skill of avoidance is considered as a positive effect on the learning ability and memory of animals, the slowdown of the extinction of the memorial trail in dynamics and is regarded as the presence of nootropic actions.

The TEI test is also widely used to study the nootropic activity of pharmacological substances. Principle of the method: the test animal is placed in a rectangular glass aquarium measuring 39 × 21 × 25 cm, filled 17.5 cm with water, having a temperature of 16-18 ° C, under a glass cylindrical hood with a diameter of 9 cm and a height of 18.5 cm, edges which are immersed in water at 2.5 cm. For 3 minutes, a visual observation of the animal. The solution to the problem is to dive under the edges of the cap and, thus, getting rid of the aversive aquatic environment. Recorded indicators: latent period (PL) of motor activity (time about the moment of immersion in water before active swimming), immobilization time (animal passively swims in water with its head slightly raised, all four limbs are motionless), the number of jumps in the cap (active attempts to jump out from water), diving drugs (the time from the moment the animal is immersed in water to diving under the edges of the cap). The experiment consists of two stages: learning the skill (developing a reflex of deliverance) and reproducing it after 24 hours. Animals that do not solve the problem during the observation at the training stage are excluded from the experiment. When evaluating cognitive functions, the following indicators are of the greatest importance: drugs of motor activity, characterizing the speed of indicative reactions; Diving medication is an indicator of the ability to extrapolate (the lower the value of the indicator, the higher the speed of solving the extrapolation problem), a comparison of the diving medication during training and reproduction of a skill shows the degree of training of the animal and the state of memory (the more it decreases when playing the test, the more trained the animal is and more memorable trail). The test also makes it possible to assess the severity of behavioral depression in animals and the antidepressant effects of pharmacological substances by taking into account the number of jumps (active attempts to get rid of the aversive effect) and immobility time (a sign of depression). In this study, the development and preservation of the skill of extrapolation disposal was checked in dynamics - after 24 hours.

The experiments were performed on white outbred male rats (200-260 g), kept under standard vivarium conditions under natural light-dark mode, free access to water and full-grain granulated feed (GOST R 50258-92). The study was conducted in accordance with GOST 3 51000.3-96, GOST 3 51000.4-96 and Order of the Ministry of Health of the Russian Federation No. 267 dated 06/19/2003 “On approval of laboratory practice rules” (GLP). The test substances were administered 30 minutes prior to learning the passive avoidance reaction, orally at a dose of 10 mg / kg, comparison preparations: piracetam - 500 mg / kg, phenibut - 25 mg / kg, phenotropil - 25 mg / kg.

Compound III and to a greater extent I and II showed a pronounced nootropic effect comparable with phenotropyl and superior to phenibut and piracetam. In animals treated with compounds I-III, the passive avoidance reaction test showed a statistically significantly longer latent period of entry into the dark compartment than in animals of the control group and animals treated with piracetam and phenibut. In animals treated with the studied substances, a memorable trace of aversive effects was preserved to a greater extent, as evidenced by the longer latent period of entry into the dark compartment after 24 hours, but to an even greater extent after 3 and 7 days (Table 1).

When evaluating cognitive functions in TEI, it was found that compounds I-III, when developing the skill of extrapolation disposal at the stage of the first test, improved the rate of orientational reactions (reduced the latent diving period during training) in an unfamiliar aversive medium (cold water). When tested after 24 hours, animals that were administered compounds I-III, they solved the problem of extrapolation deliverance also faster than the animals of the control group and than the animals that were administered the comparison drugs: phenibut and piracetam.

To further confirm the presence of nootropic properties in the new quinazoline derivatives, an additional study was performed under the conditions of a chemo-inducing amnesic effect. On the model of scopolamine amnesia (scopolamine once, intraperitoneally at a dose of 15 mg / kg), nootropic (antiamnestic) properties were manifested to an even greater extent. So, the connections I-III in the group of animals with amnesia passive avoidance reaction statistically significantly increased the latent period of entry into the dark compartment, reduced the number of entries into it, thus showing an antiamnestic effect, indicating their nootropic activity (Table 2). In terms of the severity of the nootropic effect, the new compounds were statistically significantly superior to piracetam, phenibut, and were comparable to phenotropyl.

Example 5. The study of antihypoxic activity

The antihypoxic effect of new quinazoline derivatives and comparison drugs was studied on the models of "normobaric hypoxia with hypercapnia (" canned "hypoxia)" and "hemic hypoxia caused by nitrite intoxication."

"Normobaric hypoxia with hypercapnia" is used to evaluate the antihypoxic effect of pharmacologically active substances. The experiment is performed on mice. The technique consists in placing animals of the same weight (a spread of not more than 2 g per group), one at a time, in 200 ml sealed containers. The test substances are administered before the start of the experiment, taking into account the peak of their action. The time before apnea (standby time, life time under hypoxia) in the animal is recorded, which is recorded visually. After that, the animal is removed from the container and reanimated. An increase in the life span of animals under hypoxia (compared with the control) under the influence of the studied compounds indicates the presence of an antihypoxic effect.

“Hemic hypoxia caused by nitrite intoxication” is also used to evaluate the antihypoxic effect of the compounds. The test is carried out on mice. The experiment consists in a single subcutaneous injection of sodium nitrite in a toxic dose of 250 mg / kg to the animals in the cervical region of the back, followed by recording the animals' lifespan. The test substances are administered before the start of the experiment, taking into account the peak of their action. An increase in the life span of animals under hypoxia against the background of methemoglobinemia (compared with the control) under the influence of the studied compounds indicates the presence of antihypoxic activity.

Distinct antihypoxic properties were revealed in compounds I-III (10 mg / kg, orally 30 minutes before hypoxia), which are statistically significantly and comparable with mexidol (100 mg / kg) and more increase compared to piracetam (500 mg / kg) life expectancy of animals under conditions of normobaric hypoxia with hypercapnia and with hemic hypoxia caused by intoxication with sodium nitrite (Table 3).

Thus, new quinazoline derivatives combine high nootropic activity with a distinct antihypoxic effect. By the degree of nootropic and antiamnestic action, the new compounds used at significantly lower doses are superior to phenibut and, to an even greater extent, piracetam, and are comparable to phenotropyl. By the severity of the antihypoxic effect, they are statistically significantly superior to piracetam and not inferior to Mexidol.

The data presented suggest that drugs obtained on the basis of new quinazoline derivatives can replenish the arsenal of original nootropic drugs and are widely used in the treatment of organic brain lesions.

Table 1 Nootropic activity of new quinazoline derivatives Recorded Indicators Values of indicators (M ± m) The control I II III Phenotropil Phenibut Piracetam The effect of substances on learning and memory in the passive avoidance reaction test Drug training after drug administration 19.2 ± 0.95 24.0 ± 4.31 20.2 ± 0.60 13.7 ± 0.42 18.1 ± 1.6 24.2 ± 2.68 30.2 ± 2.84 PL when playing after 24 hours 127.7 ± 12.08 170.0 ± 10.0 ^{** # Δ} 176.3 ± 14.16 ^{** # Δ} 165.2 ± 27.25 169.2 ± 12.7 ^** 148.0 ± 9.4 ^* 140.4 ± 12.8 When playing after 3 days 77.7 ± 27.36 154.3 ± 21.8 ^*** 142.7 ± 16.27 ^*** 141.3 ± 14.4 ^* 140.3 ± 26.0 ^*** 132.4 ± 12.9 ^*** 118.0 ± 10.4 PL when reproduced after 7 days 53.2 ± 17.6 122.0 ± 34.22 ^** 129.2 ± 10.5 ^{*** Δ} 111 ± 14.21 ^{*** Δ} 127.9 ± 23.6 ^{*** Δ} 118.6 ± 13.1 ^{*** Δ} 92.6 ± 9.2 The effect of substances on mnestic function in TEI Diving medication during training after drug administration 35.0 ± 1.15 17.3 ± 0.92 ^{*** # Δ} 21.0 ± 0.77 ^*** 25.2 ± 1.87 ^** 22.4 ± 2.36 ^* 26.2 ± 4.0 ^* 31.5 ± 3.0 Diving when played after 24 hours 26.0 ± 0.73 7.0 ± 0.97 ^{*** # Δ} 10.7 ± 0.56 ^*** 13.2 ± 0.70 ^**** 11.6 ± 1.92 ^{*** Δ #} 17.4 ± 3.3 ^** 16.1 ± 1.1 ^** Designations: * - p <0.05; ** - p <0.01; *** - p <0.005; **** - p <0.001 - significance of differences compared with the control group of animals; # - significance of differences compared with animals receiving phenibut; Δ - significance of differences compared with animals treated with piracetam (Kruskal-Wallis rank one-way analysis, Dunn’s test for multiple comparisons)

table 2 The study of nootropic activity on the model of scopolamine amnesia Recorded Indicators Values of indicators (M ± m) Intact control Control + Amnesia I + amnesia II + amnesia III + amnesia Phenotropil + Amnesia Phenibut + Amnesia Piracetam + Amnesia Reflex stage LP of the first entry into the dark compartment 27.6 ± 2.4 26.0 ± 2.3 25.1 ± 3.6 30.7 ± 7.3 28.6 ± 6.9 32.4 ± 3.0 27.4 ± 9.6 34.3 ± 8.8 Number of visits 1.12 ± 0.13 1.12 ± 0.13 1.12 ± 0.13 1.12 ± 0.13 1,0 ± 0 1.12 ± 0.13 1.25 ± 0.2 1.25 ± 0.2 The stage of reproduction before the introduction of scopolamine LP of the first entry into the dark compartment 180 ± 0 180 ± 0 180 ± 0 180 ± 0 180 ± 0 180 ± 0 180 ± 0 180 ± 0 The number of visits, N / n (%) 0/8 (0) 0/8 (0) 0/8 (0) 0/8 (0) 0/8 (0) 0/8 (0) 0/8 (0) 0/8 (0) The stage of reproduction after the introduction of scopolamine LP of the first entry into the dark compartment 180 ± 0 ** 52.0 ± 8.1 158.5 ± 1.5 ^{*** # Δ} 135.4 ± 17.5 ^{** Δ} 157.9 ± 2.1 ^{*** # Δ} 147.0 ± 26.6 ^{*** # Δ} 122.1 ± 13.6 69.4 ± 11.2 The number of visits, N / n (%) 0/8 (0) 8/8 (100) 1/8 (12.5) ^{*** # Δ} 2/8 (25) ^{** Δ} 1/8; (12.5) ^{*** # Δ} 1/8 (12.5) ^{*** # Δ} 4/8 (50) 6/8 (75)

Table 3 Antihypoxic activity test Recorded Indicators Values of indicators (M ± m) The control I II III Piracetam Mexidol Normobaric hypoxia with hypercapnia The lifetime of animals, s 572.0 ± 18.5 749.1 ± 58 ^** 752.8 ± 45 ^** 827.8 ± 104 ^*** 728 ± 69 ^*** 800.1 ± 63.4 ^** % Change compared to control - +30.9 +31.6 +44.7 +27.4 +39.9 Hemic hypoxia The lifetime of animals, s 912 ± 62.1 1492 ± 165 ^{** #} 1419 ± 78 ^{** #} 1379 ± 152 1234 ± 88 ^** 1296 ± 134 ^* % Change compared to control - +41.7 +33.7 +51.2 +35.3 +42.1 Designations: * - p <0.05; ** - p <0.01; *** - p <0.005 - significance of differences compared with the control group of animals; # - significance of differences compared with animals treated with piracetam (Kruskal-Wallis rank one-way analysis, Dunn’s test for multiple comparisons)

Claims (1)

An agent having nootropic and antihypoxic activity, which is a compound of the general formula

where R = o-CH ₃ , n-CH ₃ or 2,3-phenylene.