RU2398761C2 - Anxiolytics - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to new amino acid derivatives of 3,4-dimethoxyphenylethylamine 1-4 exhibiting anxiolytic activity and described by general formula

(1-4). In the formula, R represents

NH represents (COOH)₂ (1-4); Y = 1 (1, 2); Y = 3 (3); Y = 0 (4).

EFFECT: preparation of an anxiolytic compound.

2 cl, 6 tbl, 2 ex

Description

The invention relates to medicine, namely to pharmacological preparations intended for the treatment of various neurotic and borderline conditions, accompanied by an increased level of anxiety. It is an amino acid derivative of 3,4-dimethoxidopamine with anxiolytic activity. Preparations of synthetic origin, previously not used for these purposes, can find application in the treatment and / or prevention of anxiety conditions.

Currently, in the market for neurotropic drugs, there are a huge number of types of drugs used to treat affective disorders, accompanied by fear and anxiety. Most of these drugs are derivatives of benzodiazepine and have a number of side effects and contraindications. The preparations synthesized according to the invention are not such derivatives and exhibit a more pronounced anxiolytic effect. They can significantly expand the range of anxiolytic drugs.

For the synthesis, a methylated form of dopamine, 3,4-dimethoxyphenylethylamine, was used.

It is known that dopamine in its pure form does not penetrate the blood-brain barrier. To date, dopamine is used for cardiovascular failure (with cardiogenic shock), nephrosclerosis, acute renal failure, poisoning with barbiturates (Gromova E.G. Medication Guide with a Prescription, St. Petersburg, 2002, p.190-191).

It is well known that for the treatment of various neuroses, neurotic conditions accompanied by anxiety and anxiety, chlozepide (elenium) is used - a benzadiazepine derivative. However, its prolonged use can cause drug dependence, allergic reactions, as well as impaired liver and kidney function. In addition, Elenium can not be assigned to persons who in the process of work require precise coordination of movements, quick reaction (Mashkovsky M.D. Medicines, vol. 1, M., 2002, p. 74-87).

Meprotan (a derivative of the carbamic ester of substituted propanediol) is also currently used in medical practice, the activity of which is slightly lower than that of benzodiazepines. And it has the same contraindications and side effects as Elenium (Mashkovsky M.D. Medicines, Volume 1, M., 2002, p. 74-87).

Among atypical benzodiazepines, tofisopam (grandaxin) is of particular interest. This drug does not cause drowsiness and does not have muscle relaxant and anti-road effects. The absence of a sedative effect allows you to use the drug during the day. However, there is evidence of a possible development of addiction, allergic reactions, and dyspeptic disorders. For drivers and persons whose work requires a quick mental and physical reaction, grandaxin is prescribed with caution (Mashkovsky M.D. Medicines, Volume 1, M., 2002, p. 74-87). The authors selected this pharmacological drug for the prototype.

The objective of the invention was the creation of a drug with pronounced anxiolytic properties and not addictive and drowsiness, as well as with the absence of unwanted adverse reactions of the body.

The goal was achieved with the help of synthetic preparations based on 3,4-dimethoxyphenylethylamine (3,4-dimethoxydofamine) and a number of amino acids.

Five preparations were synthesized and studied, of which the most active are the oxalates of N-L-alanyl-3,4-dimethoxyphenylethylamine monohydrate (1) and N-L-tyrosyl-3,4-dimethoxyphenylethylamine monohydrate (2).

The following new amino acid derivatives of dopamine were synthesized: NL-alanyl-3,4-dimethoxyphenylethylamine (1), NL-tyrosyl-3,4-dimethoxyphenylethylamine (2), NL-tryptophanyl-3,4-dimethoxyphenylethylamine (3), N-β -alanyl-3,4-dimethoxyphenylethylamine (4) and N-glycyl-3,4-dimethoxyphenylethylamine (5). They were isolated: 1 and 2 in the form of monohydrate oxalates, 3 in the form of trihydrate oxalate, 4 in the form of oxalate and 5 in the form of hydrochloride. The structure of the obtained compounds is presented below.

General formula of substances:

where R:

HX: (COOH) ₂ (1, 2, 3,4),

Y = 1 (1.2);

Y = 3 (3);

Y = 0 (4, 5).

These substances were prepared by reacting activated esters of (n-nitrophenyl or TV-hydroxysuccinimide) N-substituted amino acids with 3,4-dimethoxyphenylethylamine hydrochloride in the presence of a base (triethylamine) at a temperature of 17-21 ° C for 5-24 hours. Isolation and purification of the reaction product, deprotection and conversion to salt (oxalate or hydrochloride) were carried out according to well-known standard methods: unreacted components were removed by washing ethyl acetate solutions with aqueous solutions of sodium chloride, sodium bicarbonate, sulfuric acid; recrystallized from a suitable solvent. Protective groups were removed by hydrogenation on palladium catalyst on activated carbon (Gershkovich A.A., Kibirev V.K. Synthesis of peptides. Reagents and methods, Kiev, 1987, 264 p.). The identity of the reaction products was confirmed by thin layer chromatography in the chloroform-methanol system (9: 1). Characteristics of the compounds obtained are shown in table 1.

For synthesized compounds, LD ₅₀ was determined with acute administration. The calculation was performed using the Pershin method: LD ₅₀ = Σ (a + b) · (mn) / 200.

Thus, with an average therapeutic dose of 1.0 mg / kg, the therapeutic index is 153.0 (1, 2, 3, 4) and 760.0 (5), which indicates a low toxicity of the compounds.

Subsequently, the anxiolytic and anticonvulsant effects of the synthesized compounds were evaluated.

As a result of the evaluation of the anxiolytic effect of the substances, it was found that, with intraperitoneal (ip) administration in different doses, the preparations exhibit biological activity. So, compound 1 (1.0 mg / kg, ip, once), 2 (0.1 mg / kg, ip, chronically), 3 (1.0 mg / kg, ip, chronically) , 4 (1.0 mg / kg, ip, chronically), 5 (10.0 mg / kg, ip, once) increase the time spent by animals in the open arms of the labyrinth compared to control animals that received saline and with the comparison drug grandaxin (0.04 mg / kg), which confirms the presence of substances 1, 2, 3, 4, 5 with an anxiolytic effect exceeding the effect of grandaxin (table 3, table 4).

Assessment of the level of anxiety of animals against the background of the introduction of the studied compounds and grandaxin (comparison drug) was carried out according to the severity of horizontal, vertical and research activity, as well as the emotional response in rats in the test "open field", when animals after administration of the drug are placed in the center of the illuminated area at 3 minutes and automatically using the hardware-software complex fix the parameters characterizing the behavior of the rat. The substance was found to be 1 (1.0 mg / kg, ip, once), 2 (0.1 mg / kg, ip, chronically), 3 (1.0 mg / kg, ip, chronically ), 4 (1.0 mg / kg, ip, chronically), 5 (10.0 mg / kg, ip, once) significantly reduce the horizontal, vertical activity and severity of the emotional component compared to grandaxin (0, 04 mg / kg), which indicates a more pronounced decrease in the level of anxiety in rats compared with protopip (table 5, table 6).

Examples of the invention.

Example I. Synthesis of N, L-tyrosyl-3,4-dimethoxyphenylethylamine oxalate (2).

a) A mixture of 3.07 g (7.04 mmol) of N-benzyloxycarbonyl-O-benzyl-L-tyrosine n-nitrophenyl ester, 1.53 g (7.01 mmol) of 3,4-dimethoxy-phenylethylamine hydrochloride and 0.99 ml triethylamine in 10 ml of dimethylformamide was stirred for 5 hours at a temperature of 18-20 ° C and left overnight at the same temperature. The mass was diluted with ethyl acetate (100 ml) and water (20 ml), the layers were separated, and the organic layer was washed successively with saturated sodium chloride solution (2 × 20 ml), 1M sulfuric acid solution (3 × 20 ml), saturated sodium chloride solution (2 × 20 ml), saturated sodium bicarbonate solution (3 × 20 ml), saturated sodium chloride solution (3 × 20 ml), dried with sodium sulfate and evaporated. The residue was treated with ethanol, the crystals were filtered off, washed with ethanol and dried. After recrystallization from ethanol, 2.6 g (77.4% of theory) of N- (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl) -3,4-dimethoxyphenylethylamine, m.p. 160-162 ° C. The product is individual in the chloroform-methanol system (9: 1).

b) To a suspension of 1.7 g (3.56 mmol) of N- (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl) -3,4-dimethoxyphenylethylamine in 25 ml of ethanol was added 0.2 g of catalyst (palladium on activated carbon ) and with stirring a stream of hydrogen was passed for 7 hours. The catalyst was filtered off, 0.46 g of oxalic acid dihydrate was added to the solution, and the solvent was distilled off in vacuo. The residue was recrystallized twice from acetonitrile. Yield 0.72 g (57.7% of theory). The product is individual in the chloroform-methanol system (9: 1). Mp and elemental analysis are presented in table 2.

Analogously to example I, compounds 1, 3, 4, 5 were obtained.

Example II Preclinical studies were carried out in accordance with the Guidelines for the experimental (preclinical) study of new pharmacological substances (edited by V. Fisenko, 2000, 398 pp.). All animals were divided into groups of 10 animals each. The test substances were administered intraperitoneally at doses of 0.1 mg / kg, 1.0 mg / kg and 10.0 mg / kg. The control group of animals received physiological saline in an equivalent volume. The comparison drug grandaxin was administered intraperitoneally at a dose of 0.04 mg / kg All drugs were administered once and chronically for 10 days. Testing was carried out in the first half of the day (10-13 hours).

Acute toxicity determination

To determine acute toxicity, pharmacological compounds were tested in the following doses: 50.0, 100.0, 200.0, 500.0, 700.0, 1000.0 mg / kg. The drugs were administered intraperitoneally in a volume of 0.1-0.5 ml at a rate of 0.1 ml / sec. Assessment of the physiological state of animals was carried out within 48 hours. At the end of the testing time, the percentage of dead animals was determined.

Processing of the results was carried out using the Pershin calculation method according to the formula: LD ₅₀ = Σ (a + b) · (mn) / 200, where a, b are the values of adjacent doses; m, n - the frequencies of the lethal effect corresponding to these doses (Sernov L.N., Gatsura V.V. Elements of experimental pharmacology. M., 2000, 352 pp.).

The test the raised "cruciform" labyrinth

The level of anxiety in animals was determined using the generally accepted test of an elevated “cruciform” labyrinth (Guide to the experimental (preclinical) study of new pharmacological substances, under the editorship of Fisenko V.P. M., 2000, pp. 126-130). The labyrinth consisted of two open and two closed sleeves located crosswise and raised 50 cm above the floor. The width of the sleeves was 10 cm with a length of 45 cm, the height of the walls in the closed sleeves was 45 cm. From above, all the sleeves were open. At the perpendicular intersection of the arms, there was a 10 × 10 cm platform on which the test rat was planted. The behavior of the animals was recorded for 5 min and the following parameters were evaluated: time spent in open and closed arms, number of entries in open and closed arms.

Open Field Test

Placing an animal in a new environment (a brightly lit area, which is much larger than the cage in which the rat lives) leads to changes in the nature of behavior (Y. Buresh et al. Methods and basic experiments to study the brain and behavior. M., 1991 , 339 p.).

The behavior of animals in the test "open field" was studied by a modified method of ES Petrova et al (1982). The "open field" was a square area measuring 80 cm × 80 cm and side walls 36 cm high. The floor of the area was divided into 16 equal squares measuring 19.5 cm × 19.5 cm. The area was uniformly illuminated by a light source. The animal was placed in the center of the "open field" for 3 minutes Changes in animal behavior were controlled automatically using the Open Field Biological Installation software and hardware complex (D.I.Ulyanov State Electrotechnical University, St. Petersburg). The following parameters were recorded: horizontal motor activity ("movement") and vertical motor activity ("rising"); research activity (rat study of round through holes located on the floor); grooming reactions (combing, licking, washing e and others); emotional reactions (defecation and urination).

The test results of the synthesized amino acid derivatives of dopamine are presented in tables 1, 2, 3, 4, 5, 6.

Table 1. The obtained experimental data allow us to conclude that the toxicity of compounds 1, 2, 3, 4, 5 is low.

Table 3. From tests of compounds 1, 2, 3, 4, 5 and the comparison drug, it can be seen that with a single administration, substances 1 and 5 have the most pronounced anxiolytic effect.

Table 4. The test results of substances 1, 2, 3, 4, 5 and the prototype indicate that in a chronic experiment, compounds 2, 3, 4 have a more pronounced anti-anxiety effect.

Table 5. From tests of compounds 1, 2, 3, 4, 5 and the comparison drug, it can be seen that substances 1, 3, 4, 5 have an advantage in a single administration.

Table 6. Experimental data indicate that, with chronic administration, substances 2, 3, 4, 5 have an advantage.

Table 2. Characteristics of oxalates of NL-alanyl-3,4-dimethoxyphenylethylamine (1), NL-tyrosyl-3,4-dimethoxyphenylethylamine (2), NL-tri-xyphenylethylamine (3), N-β-alanyl-3,4-dimethoxyphenylethylamine (4) and N-glycyl-3,4-dimethoxyphenylethyl hydrochloride. Compound Mp (from acetonitrile), ° С Calculated% Gross formula Found,% C H N C H N one 97-100 49.99 7.77 6.71 C ₁₅ H ₂₂ N ₂ O ₇ H ₂ O 49.96
50.38 7.76
8.02 6.56
6.65 2 100-102 55.75 6.24 6.19 C ₂₁ H ₂₆ N ₂ O ₈ H ₂ O 55.88
56.00 5.98
6.08 6.43
6.45 3 136-139 54.00 6.50 8.20 C ₂₃ H ₂₇ N ₃ O ₇ · 3H ₂ O 54.21
54.69 5.85
6.03 8.02
8.10 four 142-144 52.62 6.48 8.18 C ₁₅ H ₂₂ N ₂ O ₇ 51.82
51.81 6.90
6.75 7.63
7.61 5 146-148 52,46 6.97 10,20 C ₁₀ H ₁₈ N ₂ O ₃ · HCl 52.61
52.61 7.07
7.07 9.66
9.69

Table 3. The effect of a single administration of oxalates of NL-alanyl-3,4-dimethoxyphenylethylamine monohydrate (1), NL-tyrosyl-3,4-dimethoxyphenylethylamine monohydrate (2), NL-tryptophanyl-3,4-dimethoxyphenylethylamine trihydrate (3), N-β -alanyl-3,4-dimethoxyphenylethylamine (4) and N-glycyl-3,4-dimethoxyphenylethylamine hydrochloride (5) on the anxiety level of male rats in the test, an elevated “cross-shaped” maze Groups of animals (n = 10) Open sleeve time, sec Time in a closed sleeve, sec The number of entries in the open sleeve, times The number of entries in the closed sleeve, times intact 70.0 ± 2.4 230.0 ± 2.4 1.2 ± 0.4 2.8 ± 0.2 grandaxin 90.0 ± 3.6 * 210.0 ± 3.6 * 4.2 ± 0.8 * 3.2 ± 0.8 0.1 mg / kg one 90.0 ± 4.4 * 210.0 ± 2.4 * 3.0 ± 0.4 * 1.5 ± 0.2 * # 2 60.0 ± 2.4 # 240.0 ± 2.4 * # 1.2 ± 0.2 # 3.7 ± 0.2 * 3 31.0 ± 2.4 * # 269.0 ± 2.4 * # 1.2 ± 0.2 # 2.0 ± 0.2 four 65.0 ± 2.4 # 235.0 ± 2.4 # 1.2 ± 0.2 # 2.2 ± 0.2 5 120.0 ± 4.5 * # 180.0 ± 4.5 * # 1.8 ± 0.2 # 2.6 ± 0.2 1.0 mg / kg one 157.0 ± 4.6 * # 143.0 ± 4.2 * # 4.5 ± 0.4 * 2.0 ± 0.4 2 45.0 ± 2.6 * # 255.0 ± 4.2 * # 1.3 ± 0.2 # 2.0 ± 0.4 3 57.0 ± 2.6 # 243.0 ± 4.2 * # 1.9 ± 0.2 # 3.5 ± 0.3 four 71.0 ± 2.6 # 229.0 ± 4.2 # 1.6 ± 0.2 # 3.0 ± 0.3 5 46.0 ± 2.9 * # 254.0 ± 2.9 * # 2.4 ± 0.2 * # 2.4 ± 0.2 10.0 mg / kg one 120.0 ± 6.4 * # 180.0 ± 2.2 * # 2.5 ± 0.4 * # 2.5 ± 0.2 2 40.0 ± 2.4 * # 260.0 ± 2.2 * # 1.5 ± 0.4 # 3.5 ± 0.2 * 3 94.0 ± 2.4 * 206.0 ± 2.2 * 4.5 ± 0.4 * 1.5 ± 0.2 * # four 78.0 ± 2.6 # 222.0 ± 4.2 1.4 ± 0.2 # 3.0 ± 0.3 5 131.0 ± 8.9 * # 169.0 ± 8.9 * # 1.6 ± 0.4 # 1.2 ± 0.2 * # * - differences are significant relative to intact animals at p≤0.05 # - differences are significant relative to grandaxin (0.04 mg / kg) at p≤0.05

Table 4. The effect of chronic administration of oxalates of NL-alanyl-3,4-dimethoxyphenylethylamine monohydrate (1), NL-tyrosyl-3,4-dimethoxyphenylethylamine monohydrate (2), NL-tryptophanyl-3,4-dimethoxyphenylethylamine trihydrate (3), N-β- alanyl-3,4-dimethoxyphenylethylamine (4) and N-glycyl-3,4-dimethoxyphenylethylamine hydrochloride (5) to the level of anxiety of male rats in the test an elevated "cross-shaped" maze. Groups of animals (n = 10) Open sleeve time, sec Time in a closed sleeve, sec The number of entries in the open sleeve, times The number of entries in the closed sleeve, times intact 70.0 ± 2.4 230.0 ± 2.4 1.2 ± 0.4 2.8 ± 0.2 grandaxin 96.0 ± 3.0 * 204.0 ± 3.0 * 3.5 ± 0.8 * 3.8 ± 0.8 0.1 mg / kg one 37.0 ± 4.1 * # 263.0 ± 4.1 * # 1.8 ± 0.4 # 4.6 ± 0.7 * 2 134.0 ± 4.3 * # 166.0 ± 4.3 * 3.6 ± 0.4 * 3.2 ± 0.2 3 134.0 ± 11.9 * # 166.0 ± 6.8 * 3.4 ± 0.2 * 3.2 ± 0.4 four 76.0 ± 5.0 # 224.0 ± 5.1 4.2 ± 0.4 * 4.0 ± 0.4 * 5 63.0 ± 5.4 # 237.0 ± 5.4 # 4.4 ± 0.2 * 4.6 ± 0.2 * 1.0 mg / kg one 67.4 ± 13.8 # 232.6 ± 13.8 # 4.2 ± 0.4 * 5.8 ± 0.4 * # 2 90.6 ± 5.6 * 209.4 ± 5.6 * 3.0 ± 0.1 * 3.2 ± 0.2 3 156.0 ± 7.6 * # 144.0 ± 7.6 * # 3.0 ± 0.1 * 2.6 ± 0.2 # four 97.5 ± 6.3 * 202.5 ± 5.1 * 3.4 ± 0.2 * 3.0 ± 0.5 5 68.0 ± 2.5 # 232.0 ± 2.5 # 2.0 ± 0.3 3.0 ± 0.4 10.0 mg / kg one 32.0 ± 2.5 * # 268.0 ± 2.5 * # 2.2 ± 0.4 * 3.2 ± 0.7 2 60.0 ± 8.8 # 240.0 ± 8.8 # 2.2 ± 0.4 * 3.2 ± 0.5 3 90.0 ± 7.4 * 210.0 ± 8.4 * 3.2 ± 0.4 * 2.6 ± 0.2 four 70.0 ± 9.5 # 230.0 ± 9.5 # 2.6 ± 0.2 * 3.4 ± 0.2 5 65.0 ± 5.0 # 235.0 ± 5.0 # 1.8 ± 0.4 # 4.4 ± 0.2 * * - differences are significant relative to intact animals at p≤0.05 # - differences are significant relative to grandaxin (0.04 mg / kg) at p≤0.05

Table 5. The effect of a single injection of compounds 1, 2, 3, 4, 5 on the behavior of male rats in the test "open field" for 180 sec Groups of animals (n = 10) Options Physical activity Research activity Emotionality Moving Rising Grooming Defecation intact 62.7 ± 6.9 13.2 ± 3.2 3.0 ± 0.5 3.2 ± 0.4 2.4 ± 0.2 grandaxin 27.8 ± 1.6 * 8.5 ± 0.9 26.7 ± 2.4 * 1.6 ± 0.3 * 1.0 ± 0.3 * 0.1 mg / kg one 66.3 ± 4.9 # 20.2 ± 2.6 # 40.3 ± 3.5 * # 12.1 ± 1.4 * # 1.0 ± 0.2 * 2 50.3 ± 4.9 # 2.3 ± 0.6 * # 35.3 ± 3.5 * 6.5 ± 0.4 * # 1.2 ± 0.2 * 3 18.4 ± 2.7 * # 3.8 ± 0.5 * # 2.0 ± 0.4 # 2.8 ± 0.2 1.2 ± 0.2 * four 13.8 ± 1.2 * # 6.4 ± 0.9 * 2.2 ± 0.8 # 5.6 ± 0.7 * # 1.6 ± 0.2 * 5 18.3 ± 0.8 * # 5.3 ± 0.7 * # 3.5 ± 0.8 # 0 1.0 ± 0.3 * 1.0 mg / kg one 25.7 ± 2.8 * 4.7 ± 0.8 * # 23.0 ± 2.8 * 10.7 ± 0.8 * # 1.3 ± 0.2 * 2 44.7 ± 7.8 # 5.7 ± 0.8 * 29.0 ± 2.8 * 5.7 ± 0.8 # 0.8 ± 0.2 * 3 25.4 ± 3.4 * 15.8 ± 1.4 # 2.2 ± 0.8 # 3.6 ± 0.6 # 1.0 ± 0.1 * four 29.8 ± 2.2 * 18.0 ± 2.5 # 1.6 ± 0.4 * # 8.8 ± 0.4 * # 1.6 ± 0.4 5 19.5 ± 1.2 * # 6.7 ± 0.9 * 4.7 ± 0.5 * # 1.2 ± 0.3 * 1.4 ± 0.4 * 10.0 mg / kg one 55.8 ± 3.5 # 6.7 ± 0.8 * 35.0 ± 4.6 * 4.8 ± 0.4 # 2.7 ± 0.2 # 2 56.8 ± 3.5 # 7.3 ± 0.8 * 37.0 ± 4.6 * 3.8 ± 0.4 1.2 ± 0.2 * 3 16.2 ± 1.4 * # 12.2 ± 0.9 # 2.0 ± 0.3 # 2.2 ± 0.7 1.6 ± 0.2 * four 30.6 ± 4.7 * 16.2 ± 0.9 # 2.0 ± 0.3 # 5.8 ± 0.5 * 2.0 ± 0.3 5 20.7 ± 2.1 * # 6.0 ± 0.7 * # 5.5 ± 0.8 * # 1.4 ± 0.4 * 1.4 ± 0.4 * * - differences are significant relative to intact animals at p≤0.05 # - differences are significant relative to grandaxin (0.04 mg / kg) at p≤0.05

Table 6. The effect of chronic administration of compounds 1, 2, 3, 4, 5 on the behavior of male rats in the test "open field" for 180 sec Groups of animals (n = 10) Options Physical activity Research activity Emotionality Moving Rising Grooming Defecation intact 62.7 ± 6.9 13.2 ± 3.2 3.0 ± 0.5 3.2 ± 0.4 2.4 ± 0.2 grandaxin 21.0 ± 1.5 * 0 14.0 ± 3.0 * 0 0 0.1 mg / kg one 45.5 ± 1.6 # 11.8 ± 3.1 # 2.4 ± 0.5 # 3.0 ± 0.5 # 2.7 ± 0.3 # 2 18.2 ± 1.0 * 8.0 ± 1.0 * # 2.4 ± 0.5 # 2.0 ± 0.3 * # 2.0 ± 0.4 # 3 24.6 ± 1.4 * 8.8 ± 0.7 # 2.4 ± 0.5 # 1.4 ± 0.4 * # 0.8 ± 0.2 * four 27.8 ± 2.2 * # 5.6 ± 0.8 * # 3.0 ± 0.7 # 1.2 ± 0.2 * # 2.4 ± 0.7 # 5 17.0 ± 0.6 * # 6.4 ± 0.5 * # 1.0 ± 0.2 * # 0 1.8 ± 0.2 1.0 mg / kg one 58.5 ± 2, b # 9.8 ± 2.3 # 2.4 ± 0.5 # 1.4 ± 0.3 * # 2.4 ± 0.2 # 2 19.0 ± 2.1 * 12.4 ± 0.8 # 1.2 ± 0.4 * # 2.4 ± 0.5 # 1.8 ± 0.4 # 3 17.0 ± 2.4 * 5.4 ± 0.9 * # 1.0 ± 0.6 * # 1.4 ± 0.5 * # 1.6 ± 0.5 # four 14.0 ± 1.4 * # 3.0 ± 0.8 * # 0 0 0.8 ± 0.2 * # 5 16.2 ± 2.1 * 6.8 ± 0.5 * # 1.2 ± 0.7 # 0 1.6 ± 0.2 * # 10.0 mg / kg one 71.0 ± 3.8 * # 19.7 ± 1.2 * # 1.2 ± 0.2 * # 4.9 ± 0.3 * # 4.0 ± 0.2 * # 2 27.0 ± 2.3 * 11.2 ± 1.6 # 2.0 ± 0.8 # 1.0 ± 0.3 * # 2.6 ± 0.4 # 3 27.0 ± 2.8 * 9.2 ± 0.8 # 1.0 ± 0.4 * # 0.6 ± 0.2 * # 1.6 ± 0.4 # four 18.8 ± 1.3 * 3.2 ± 0.4 * # 1.0 ± 0.4 * # 1.0 ± 0.5 * # 1.2 ± 0.4 * # 5 27.2 ± 2.1 * # 5.6 ± 0.5 * # 0 1.4 ± 0.4 * # 1.6 ± 0.2 * # * - differences are significant relative to intact animals at p≤0.05 # - differences are significant relative to grandaxin (0.04 mg / kg) at p≤0.05

Claims (2)

1. Amino acid derivatives of 3,4-dimethoxyphenylethylamine 1-4 of the General formula

where R:

HX: (COOH) ₂ (1, 2, 3, 4);
Y = 1 (1, 2); Y = 3 (3); Y = 0 (4). 2. Amino acid derivatives according to claim 1, characterized in that they have anxiolytic activity.