SE455093B - N NIKOTINOYLAMINOSYROR - Google Patents

Description

455 093 A medicinal product under the name pyritinol (encephatol manufactured by the West German company "Merch") (Bis- [hydroxy-4-hydroxymethyl-2-methylpyrid-5-yl) methyl] -disulfide dihydrochloride monohydrate has the following structure cnzon c fi zone H _l OH C32 _ S _ S 'CHz-LO, 2 Hcl H20 N / v H3 l CHB Pyritinol was used in disorders of blood supply and metabolism in the brain.

The compounds proposed according to the present invention are new and have not been described in the literature.

The main object of the present invention is to provide new compounds which exhibit high antihypoxic and anti-human activity as well as low toxicity.

This object is achieved according to the present invention by proposing new compounds, namely N-nicotinoylamino acids of the general formula R "coR 'ON where R" is OH, Br if R' represents L - NH - CH (CH 2) 2 COOH in COOH R "consists of OH if R 'represents DL - NH - CH (CH 2) 2 COOH I COOH R" consists of OH if R' is NH (CH COOH. z) 3 The compounds proposed according to the present invention consist of crystalline substances which are sparingly soluble in cold water, are moderately soluble in hot water, are sparingly soluble in methanol, ethyl and isopropyl alcohol, dissolve practically not at all in benzene, chloroform, ethyl acetate and other organic solvents, are soluble in dimethyl sulfoxide and dimethylformamide and in dilute solutions of 455,093 acids and alkalis. The structure of the substances has been confirmed by data from IR, UV and PMR spectra, while the substances' so-called individuality has been determined by elemental analysis and thin layer chromatography on so-called silufol (in a system consisting of chloroform, MeOH and NH 4 OH in a mutual mixing ratio of 2.5: 7.5: 0.01).

The compounds of the present invention exert a pronounced anti-hypoxic and anti-amnesic effect with the least possible side effects.

In animal experiments the activity of the following compounds proposed according to the present invention has been investigated: N- (5-hydroxynicotinoyl) -L-glutamic acid (Compound I) N- (5-hydroxynicotinoyl) -DL-glutamic acid (Compound II) N - (5-hydroxynicotinoyl) -1-aminobutyric acid (Compound III) N- (5-bromonicotinoyl) -L-glutamic acid (Compound IV).

The antihypoxic activity of the compounds of the present invention has been investigated, compared with pyritinol, on two hypoxic models, namely of hypercapnic and a hemic one, which are commonly used for the evaluation of so-called antihypoxants (compare, for example, E. van Lier, K. Stickney "Hypoxi", Moscow, publisher "Meditsina", 1967). The studies were performed on white raceless male mice with a body weight of between 18 and 20 g (with a body weight of 25-28 g in so-called hypobaric hypoxia) Each dose of the substance in question was tested on 10 animals, the substances being introduced intra-abdominally 40 minutes before the start of the experiment.

The hypercapnic hypoxin was administered in tightly closable 200 cm 3 vials, while the hemic hypoxin was examined by subcutaneous injection of a sodium nitrate solution at a dose of between 200 and 300 mg / kg of body weight.

In the examination of the antihypoxic activity, it has been found that all the compounds proposed according to the present invention have the ability to increase the lifespan of mice under conditions of acute oxygen insufficiency.

Injection of the compounds of the present invention at a dose of 100 mg / kg of body weight resulted in an increase in the lifespan of mice under conditions of hypoxia with hypercapnia in a hermetically sealed volume of 20-70%. brought with reference mice. In hypoxia of this type, nootropyl exerted a similar effect at a significantly higher dose (500 mg / kg body weight).

Under conditions of "hard" hemic (methemoglobin-like) hypoxia, the substances of the present invention also proved to be effective, while nootropyl in this type of hypoxia, regardless of the dose variation, showed no activity.

The test results are reported in Table 1.

Table 1 Antihypoxic activity Percentage duration of survival of mice, compared to the 100% life expectancy of reference mice Dose in Hypoxia with Hemic Compound mg / kg hypercapnia hypoxia Nootropyl 250 - 98 in 7.8 Nootropyl soo 130 ï 30.2. 1o3 i 9.6 Compound I - + + @nl. ref.) 50 105 - 11,8 120 - 21,6 1oo 121 i 6,6 127 116,1 zoo 134 ï 13,6 142 ï14,7 Förening II + (enl.uppf.) 100 130 - 13,1 Förening III + (according to invention) 50 127.5 ~ 17.7 100 125 in 10.9 134 and 19.9 Compound IV + (according to invention) 50 114 - 8.4 The anti-compounds of the compounds proposed according to the present invention amnesic effect (anti-amnesic effect) was examined on white raceless male mice with a body weight of 17-20 g by one of Bures et al. proposed method for passive avoidance in a modified embodiment (cf. for example Bures JI, Buresova O, Huston G. "Techniques and Basic Experiments for the Study of Brain and Behavior", Elsevier / 455 093 North-Holland Biomedical Press, year 1976 ). An experimental facility consisted of two chambers, namely a dark (small) chamber with so-called electrode floor and an illuminated (large) chamber, in which the animal in question was placed. The residence time of the animal in the illuminated chamber and in the dark chamber (dark chamber) was recorded over a time interval of 2 minutes. In the dark chamber, the animal then received a one-time electric shock by means of electric current with a current of 0.4 mA via the electrode floor (inertia). For initiation of amnesia, a maximum, by means of so-called electrical convulsion (convulsions generated by electric current) caused seizures (a maximum electric shock, 50 Hz, 0.2 s). By generating the electric shock immediately after learning, the memory slot is erased. The reproduction test was performed 24 hours after the learning by placing the animal in question in the illuminated chamber and the residence time of the animal in the dark and the illuminated chamber - even in the case described above - was recorded over a time interval of 2 minutes. When a reflex for passive avoidance was reproduced without generating any electric shock, the reference animals preferred to be in the illuminated chamber for most of the two minute period. The electric shock caused amnesia of the conditioned reflex in the animals, so the animals with a short latency period entered the dark chamber and stayed in it for most of the time. The substances were introduced intraabdominally for 40 minutes. before learning began, each dose being tested on six animals. Data on the anti-amnesia effect are reported in Table 2.

Table 2 Effect of the compounds I-IV and nootropyl proposed by the present invention on amnesia caused by an electric shock when reproducing memory traces in mice after 24 hours.

The time (in p.) That mice spent during the reproduction test Förening. in the illuminated in the dark Nr. mg / kg chamber chamber 1 2 3 4 1 Reference test without amnesia 112.8 (108-120) 7.2 (5-12) 2 Reference test with amnesia 74.3 (55-85) 45.7 (30-75) 455 093 1 2 3 4 3 Nootropyl 300 81.8 (61-93) 38.2 (27-49) 4 Compound I (according to invention) 94.4 (75-110) 25.6 (15-36) 106 50.6 (95-120) 13.4 (5-25) 6 Compound II (according to reference) 50 101.4 (93.8-109) 18.6 (10.6-28.6) Compound III (acc.) 82.3 (63.5-101.1) 37.7 (18.9-56.5) 8 Compound IV (acc.) 50 91.3 (80.1 102.5) 28.7 (16.7-40.7) Table 2 shows that the compounds proposed according to the present invention show an anti-amnesic effect, which in other words means that they can eliminate the adverse effect of the electric shock on the memory, why the residence time of the experimental animals in the illuminated chamber was significantly increased (compared with the reference animals) and in the dark chamber, on the other hand, it was reduced. The effect of the compounds was dose dependent. By comparing the action of the compounds of the present invention with the action of nootropyl with respect to the test for the entry and residence of the animals in the dark chamber (the main criterion for the experiment in question), it has been found that the memory trace is better maintained after administering the compounds of the present invention. invention than after the introduction of nootropyl.

The other positive feature of the compounds proposed according to the present invention is that they show higher dose-dependent activity, namely that the antiamnesic effect of these compounds is manifested in doses which are 6 times lower than the respective dose of nootropyl.

The side effects and acute toxicity of the compounds proposed according to the present invention were investigated on white raceless male mice (with a body weight of 17-20 g) upon intra-abdominal introduction of the substances in successively increasing doses: 25 - 100 - 400 - 800 - 1200 mg / kg. The myorelaxant effect of the compounds (due to possible coordination disorders in the movements of the experimental animals on a rotating rod) and the lethality of the animals were estimated. The acute toxicity of the compounds was examined in individually maintained animals, which had continuous access to water and food, at the constant temperature of the surrounding medium of 22 ° C. For this purpose, mice were placed in cell-shaped cages with the dimensions 8 x 8 x 8 cm (one animal in each cage). The deaths of the animals were recorded 24 hours after introduction of the substance, calculating the number of dead and surviving mice. The survey results are reported in Table 3.

Table 3 Side effects and toxicity Movement coordination disorder Daily toxicity Substances ED50, mg / kg LD50, mg / kg Compound I (according to invention) 800 2200 (2000-2420) Compound II (according to invention) 700 2000 Compound III (according to Compound IV 500 (Compound IV) 500 1500 Based on the experimental results, it has been found that injection of the substances proposed according to the present invention into the animals at doses of between 25 and 200 mg / kg does not cause any appreciable changes in the condition and behavior of the animals. The introduction of the compounds proposed according to the present invention in these doses and in higher doses did not cause a myorelaxant effect and did not disturb the movement coordination, whereby toxic effects in the animals were found starting from doses of between 800 and 900 mg / kg. Upon introduction of the compounds at doses of between 1000 and 1300 mg / kg, the animals partially died.

The compounds proposed according to the present invention can thus - in animal experiments - protect animals (mice) from death in acute oxygen deficiency, in partial oxygen deficiency and hypoxia in meta-hemoglobin form. The compounds of the present invention also exhibit activity with respect to the retention of short-term memory, namely that they exhibit anti-amnesic effect. Compared to the known drug preparation under the name nootropyl, the compounds of the present invention show considerable advantages, since they exceed nootropyl both in terms of the types and quantitative parameters of the antihypoxic action and in terms of the "depth" (intensity) of the antiamnesic effect. .

The most active of all these compounds of the present invention is N- (5-hydroxynicotinoyl) -L-glutamic acid (Compound I). The association's anti-amnesic effect was tested on different amnesic models for a conditioned reflex (reflex phenomenon) for passive avoidance when using several animal species and different modes of administration compared to reference preparations, for example nootropyl, pyritinol, centrophenoxin, cleregyl.

In experiments with rats, it has been found that the maximum electroshock in a reference group of animals, which learned a conditioned reflex for passive avoidance (obtaining a pain relief in the dark chamber), causes amnesia of the habit, (finished why the time the animals spend in the darkroom increases considerably. After the compound I proposed according to the present invention has been introduced orally or intra-abdominally before or after the maximum electric shock is generated, maintenance of the memory lane is found. The animals maintain the habit of passive avoidance. The latency time for the reflex for entering the darkroom increases considerably. The compound I proposed according to the present invention is effective in doses of 10, 20 and 50 mg / kg. The test results are reported in Table 4.

Nootropyl can only prevent amnesia of the conditioned reflex for passive avoidance, when administered at a dose of 300 mg / kg. The test results are reported in Table 5.

The compound I of the present invention proposed in doses of between 50 and 100 mg / kg also eliminated the amnesia of the conditioned passive avoidance reflex caused by the maximal electric shock in mice.

The efficacy of Nootropyl for this test was only established when introduced at a dose of 300 mg / kg. 455 093 Centrophenoxine as well as pyritinol exerted an antiamnesic effect at a dose of 50 mg / kg. The test results are reported in Table 6.

Table 4 The anti-amnesic effect of the compound proposed according to the present invention on a model of the amnesia of a conditioned reflex for passive avoidance caused by the maximum electric shock in rats Experimental conditions ïïdsinterval Infönellan Introducing di- Administ- introductory rect ef- eration- it and before inter- learning- Dose in pre-learning- learning and Nr. Substances mg / kg erande ningen shock 1 2 3 4 5 6 7 1 Reference experiment Physio- Intra- without amnesic logical abdominal solution nalt 2 Reference experiment with the amnesia, which is caused by the maximum electric shock "" 3 Compound I (acc. ) 10 "30 min. + 4 Reference experiments Physiotherapy without amnesia logical solution 5 Reference experiments with the amnesia caused by the maximum electric shock" per os 6 Compound I Intra- (according to inventor) 20 abdominal 7 Compound I (according to ref.) 20 per os 30 min. + 8 Reference experiments Physio- Intra- without amnesia logical abdominal solution nalt 9 Reference experiments with the amnesia caused by the'- maximum electric shock "" 10 Compound I (according to inventor) 50 "45 min. + 455 093 10 Table 4 , cont.

Learning, maximum electric shock Reproduction after 24 hours.

Latency intact animals before learning is the tinga- Time in s, which spend ref- Time in s. SOm _ Iaterxs- gats in the lexen spent 1 time: fær PBS 'for the The s1vt_ The __ s.k. ref- illuminated Mörker- ur fi vßan- illuminated Morker- Nr. lexen, i s. kammaren kammaren de, i S- ka fl mafe-n kanma-fen 1 s 9 10 11 12 13 -1 4, aï1,9 z0ï3, s 100ï3, e a2, sï2s, 4 94ï23, s 2e, oï23, e 2 1, aïo.5s 14,2ïs, 04 1os, sïs, 0 1, sï0,5s 11,5ïs, s 10e, 5ï53 3 2, sï0,3 22, sïs, s 97.2ïs, s 39, eï9, 1 s4,0ï2,0 seï20, s 4 9,6ï6,4 27ï7 93ï7 120 120 0 5 4, eï19,5 19, sïs, 1 10010 ,? s, 1ï1,9 s, 7ï1,9 114, zï1,9 6 11ï4,3s 21,2ïs, 1 9s, sï5,1 37,7ï17, a 49, sï17, s 70,5ï17, s 7 10ïs, 3 2e, 7ï7, z 93,3ï7, z 49,2ï1s, 3 s3,0ï15,3 e7,0ï15,3 sa, sï2,4 40, zïs, 5 79, sïe, s a3, sï19,4 s3,3ï19,4 36, 7ï19.4 9 2.0ï0, s 2s, 3ï4.2 93.7ï4.2 2s, 1ï20, s 29.1ï20, s 90.9ï20, s 10 7.7ï10.9 12.7ï1o, 9 107.3i10.9 5s, 7ï30, a 5a, 7ï30, s es, 3ï3o, a 455 095 11 Éabell 5 Nootropyl's antiamnesic effect on a model of the amnesia of the conditioned reflex for passive avoidance, caused by the maximum electric shock in rats Nr. Subject Test conditions Introduction Immediately after learning Time interval between introduction and learning Introduction before learning Administration procedure and in mg / kq rande shock 3 4 5 6 7 10 11 12 Reference experiment with anlnesi Reference experiment with the emesis caused by the maximum electric shock Nootropyl Reference experiment with arnnesi Reference experiment with the armesis, sun caused by the maximum electric shock Nootmpyl Reference experiment with amnesia Reference experiment with the amnesia, which causes the maximum Reference experiment with amnesia Reference experiment with the amnesia, which is caused by the maximum electric shock Nootropyl 200 IntraabP dominant 50 nun. + 300 Intraab- dominant 50 min. + 300 Intraab- clomjnalt 400 Intraab- 60 min. + dominant 455 D93 l2 Table 5, cont.

Learning, maximum electric shock Reproduction after 24 hours.

Lñtênå '1 tia Intact animals before learning for the conditional- Time in s, which spend ref- Time in s, which Laten- gats in the lacen spent in time- for pas- for the The sivt The so-called. ref- illuminated Dark- avoid- illuminated Dark- Nr. lexen, i s. kammaren kanmaren de, i s. kantnaren kanmaren 1 8 9 10 11 12 13 1 s, oï4,4s 14,7ï1,9 1os, 3ï1,9 1os, 3ï1e, s 1os, oï16, a s5ï1s, s 4 '2 11, oï5, o 17, sïs, o 1o2,4ïs, o 7, sïs, o 19,3ï5, o 100,7-s, o 3 9,4ï5,1 14, sï4,7 1o5,4ï4, 7 2o, sï12, e 23, sï11,1 9s, 2ï11,1 4 4, sï1,9 2o, oï3,6 1oo, oï3,6 s2,5ïzs, 4 94, oï23, ß 26, oï23, s 5 1, eïo, 6 14,2ïs, o 1o5, sï5, o 1, sïo, 6 11,5ï5,3 1o8, sï5,3 6 3,2ïo, 7 1sïo, 9 1o5ïo, 9 2s, eï2o, a 34,4ï19,9 ss, 6ï19, s 7 s, 5ïs, o 24,2ï7, o 9s, sï7, o 120 _ 120 0 8 s, sïs, 4 3o, 3ï1o, o s9,7ï1o, o 23,3ï21.3 zs, oï21, 3 92ï21.3 9 1o, 3ï7, s 22.6ï7.8 97.4ï7, a 6o, 7ï17.3 s5, oï17.3 35, oï17.3 10 s, aï2.4 4o, 2ïe, 5 79, sïs, 5 s3,3ï19,4 s3,3ï19,4 3a, 7ï19,4 11 z, oïo, s 2s, 3ï4,2 93,7ï4,2 zs, 1ï2o, s 29,1ï2o, s 9o, 9ï2o, e 12 aï3, 3 z1.2ïs, 39s, sïe, 3 2a, 2ï7, e 2a, eï1,9 91.4ï7,9 13 Table 6 455 095 Effect of compound I according to the invention on the amnesia of the conditioned reflex for passive avoidance, which is caused of the maximum electric shock in mice Åuugbn gen ngenldaabetügade reflex for passive avoid- Dose, mg / kg cand e (reflex latency- no. Substances (intra-abdominal) time in p.) 1 2 3 4 1 Reference experiment Physiological solution 87.08 in 10.5 without amesia Compound I + (according to invention) 25 70 - 20.2 4 so 78.5 i 25.7 s Nostmpyl 1oo 26.3 ï 3.1 s soo so f 13.9 7 centrofermxin zs 39 ï 3.4 s so 68.4 in 8.4 9 Pyrite fi mi 25 31 ï 5.4 10 so 98 in 7.7 The compound of the present invention proposed in a dose of 100 mg / kg of body weight prevents - as well as nootropyl in a dose of 800 mg / kg of body weight - development of the amnesia of the conditioned reflex for passive avoidance, caused by intra-abdominal injection of scopolamine at a dose of 2.5 mg / kg before learning begins, test results are reported in Table 7. 455 093 14 Table 7 Impact of the substances on the amnesia of the conditioned reflex for passive avoidance in mice, caused by the introduction of scopolamine (scopolamine is introduced intraabdominally at a dose of 2.5 c mg / kg before learning start) Reproduction of the conditioned reflex for passive avoidance Dose, mg / kg Time in S, SOm to- (intraab- Reflex brought in the Nr. Substances dominant) latency, p. Illuminated chamber 1 2 3 4 5 1 Reference experiments + + without amnesia - 91.5 - 12.4 110 - 5.2 2 Reference experiments with amnesia + + (scopolamine) ~~ 17.2 - 1, 6 27.2 - 4.3 3 Compound I + + (according to invention) 100 51.9 - 11.4 56.9 - 10.8 Nootrapyl 400 26 ï_ 9.2 35 i 9.7 Noatropyl soo 60, 5 f 11 69.5 ï 11.4 Amnesia of the conditioned reflex for passive avoidance was also caused by so-called deprivation (deprivation) of the paradoxical phase of sleep through the so-called The Jouvet method (compare, for example, Jouvet M., Physiol. Revs, 1967, volume 47, no. 2, p. 117). For this purpose, rats were placed - immediately after learning the conditioned reflex for passive avoidance - in a water-filled pool for a period of 24 hours, the rats being on bearing surfaces measuring 4.5 x 4.5. cm, which protruded a distance of 1 cm above the water surface. The electrophysiological analysis shows that a percentage of the paradoxical phase of sleep under these conditions decreases from 13% (under normal conditions) to 1%.

The retention of the conditioned reflex for passive avoidance was estimated depending on the latency of the rats' entry into the dark section of the chamber, where they are exposed to an electric shock during learning. The reproduction results of the conditioned reflex for passive avoidance after deprivation of the paradoxical phase of sleep have shown that the rats practically completely lose the acquired habit. 455 093 The compound I proposed according to the present invention helps to restore the disturbed reaction by 40%, when introduced intraabdominally at a dose of 25 mg / kg, the compound is started, which shows that the compound I exert anti-human effect on the model in question. Nootropyl (at a dose of 400 mg / kg) restores the reaction under similar conditions by only 10%, while centrophenoxine restores the reaction by 74%. The test results are reported in Table 8.

Table 8 Antiamnesic effect of nootropic substances on a model of the amnesia of the conditioned reflex for passive avoidance, caused by so-called deprivation of the paradoxical phase of sleep Latency time for the animals' inclusion in the chamber's Nr. Substances dark section 1 2 3 1 Reference experiments without deprivation + of the paradoxical phase of sleep 102.4 - 34.25 2 Reference experiments with deprivation + of the paradoxical phase of sleep 2.6 - 0.7 3 Compound I (according to invention) + (25 mg / kg) 42 - 15.2 Nootropyl (400 mg / kg) 10.6 ï 2.65 Centrophenoxin (50 mg / kg) 74.3 É 15.42 The anti-hypoxic effect of the compound of the present invention was tested in experiments with mice on three hypoxia models, namely a hypobaric, a hemic model and a model of hypoxia with hypercapnia in a hermetically tightly closed volume.

For estimation of acute hypobaric hypoxia, a pressure chamber (barometric chamber) of the flow-through and extraction type was used, in which the pressure and the lifting speed were registered. The animals were conditionally lifted at a speed of 50 m / s to an "altitude" of 10.5 - 11 km. The duration of the animals' survival (the so-called reserve period) and the percentage of the surviving animals were recorded. When compound I of the present invention was used at a dose of 50 and especially 100 and 400 mg / kg, it exerted a pronounced antihypoxic effect, thereby helping to statically increase the reserve time and the percentage of surviving animals.

At the same time, none of the known nootropic drugs nootropyl, centrophenoxin and pyritinol had a similar effect. The test results are reported in Table 9.

The efficacy of compound I of the invention was also found in a model of hypoxia with hypercapnia in a tightly closed volume. This hypoxia model was simulated by inserting mice into cans with a volume of 200 cm 3 with tightly closable lids. Reliable differences in the duration of survival of animals in the experimental and reference group were observed when compound I of the present invention was used at a dose of between 100 and 200 mg / kg.

No similar effect was observed with pyritinol, centrophenoxin, cleregyl and nootropyl when these preparations were introduced at a dose of between 50 and 500 mg / kg. The test results are reported in Table 10.

The hemic hypoxia caused in mice by subcutaneous injection of sodium nitrite at a dose of 300 mg / kg was attenuated by the introduction of compound I according to the invention at a dose of 100 and 200 mg / kg, increasing the lifespan of the animals by 1.38 resp. 1.48 times.

The similar effect was detected for pyritinol and nootropyl, when these preparations were introduced at a dose of 200 mg / kg resp. 1000 mg / kg.

The test results are reported in Table 11. 17 Table 9 455 093 Antihypoxic effect of compound I according to the present invention compared with substances with nootropic type effect on a model of hypobaric hypoxia in experiments on mice Number Dose, Reserve time, survivor No., Substance mg / kg min. animals,% 1 2 3 4 5 1 Reference (physiological + + solution) - 9.4 ~ 1 22 2 Compound I + (according to invention) 50 12.6 -, 33 3 "100 15.7 3 5, 6 50 Reference - 11.2 ï 5.3 16.6 5 Compound I + (according to invention) 400 20.9 - 5.12 66.6 Reference - 9.7 in 1 22 Nootropyl 300 10.1 - 1 , 2 22 8 Reference -, É 22 9 Centrofenoxin 100, i 3,5 22 10 Reference - 6,05 1 2,7 16,6 11 Centrofenoxin 200 11,1 É 3,4 33,3 12 Reference - 9,7 ï 1 22 13 Pyritinel 1oo 6.3 ï 3.5 o 14 Reference - 5.75 I 2.7 11.1 15 Pyritinel zoo 8.9 ï 3.5 22.2 455 093 18 Table 1 0 Antihypoxic effect of the compound I according to the present invention compared to known nootropic preparations on a model of hypoxia with hypercapnia in a tightly closed volume Dose, Lifespan, Effect, No. Substance mg / kg min.% 1 2 3 4 5 1 Reference (physiological + logical solution) - 25.1 - 1.2 100 2 Compound I + (acc.) 50 26.6 - 2, 105 Reference - 20.3 in 2.7 100 Compound I + (acc. 100 100 24 , 5 - 3.2 120.7 5 »" 200 27.1 i 5.4 133.5 Reference I - 29.3 1 3.6 100 Neotropyl 500 29.2 i 5.9 9 3 s Reference - 30.2 i 3.18 100 cenerofenexin 50 32.7 ï 2.2 108 10 Reference - 30.2 f 3.18 100 11 Rleregyl 200 35.7 1 4.5 111 12 Reference - 25.9 i 4.1 100 13 Ryrieinei 100 29.5 1 5.5 _ 114 14 Reference - 26.22 ï 4.3 100 + 15 Pyritinol 200 30.96 4.5 118 455 093 19 Table 11 Antihypoxic effect of compound I according to present invention on a model of hemic hypoxia caused by subcutaneous insertion of sodium nitrite, NaNO2 at a dose of 300 mg / kg Dose, Lifespan, End of effect. Substance mg / kg min. ring,% 1 Reference (physiological + logical solution) - 14.5 - 2.7 100 2 Compound I + (according to inventor) 50 16.5 - 3.2 113.8 Reference - 13.2 3 2 , 7 100 Compound I + (according to invention) 100 17.5 ~ 4.5 132.6 5 "zoo 19.6 1 7.3 148.5 Reference - 20.4 ï 2.2 100 Neorrepyl soo 23, 5 I 2,6 115 a Reference - 18,2 i 4,4 1oo Nootropyl 1000 26,1 i 4,7 143 10 Reference - 17,6 1 2,2 1oo 11 Pyririnel 100 19,6 1 2,2 111 12 Reference - 16.53 ï 2 1oo 13 Pyritinel zoo 24.04 1 144 Unlike nootropyl, pyritinol, centrophenoxin and other nootropic drug preparations, whose antihypoxic effect only appears on individual hypoxic models and at significantly increased doses, the compound I thus participates according to the present invention to increase the lifespan of the animals under conditions of all used hypoxia models, i.e. a hemic hypoxia model, a hypobaric hypoxia model and a model of hypoxia with hypercapnia in a tightly closed volume.

The effect of compound I according to the present invention on the learning of conditioned reflexes has been investigated. Compound I of the invention at doses of 10, 20, 50, 100 and 200 mg / kg had no effect on the development of a conditioned reflex for passive avoidance in mice and rats. When compound I of the invention was administered for a long time at a dose of 70 mg / kg, it did not change the rate of (time for) preparation of a conditioned drinking reflex in a T-shaped labyrinth. The test results are reported in Tables 4 and 12.

The effect of compound I according to the present invention on the reflex reproduction in mice was examined on a model of conditioned reflex for passive avoidance 24 hours, 7 days and 14 days after learning. The majority of animals (58%) in the reference group forgot the situation and did not produce the reflex after a period of 2 weeks, while the administration of compound I according to the invention for a period of 2 weeks resulted in a percentage of the animals with disturbed conditional reflex for passive avoidance was only 15%.

The other mice (85%) remembered the situation and spent most of the time in the illuminated chamber.

In experimental rats, the effect of the long-term administration of the preparation on the reproduction and extinction of the reflex for passive avoidance was examined under conditions for a method for conflict situation (compare, for example, TA Klygoulj, VA Krivopalov "Pharmacology and Toxicology", 1966, no. 2, p. 241). The conflict was caused by a collision (coincidence) of drinking and defense motivations at the time when the animal took water from a watering device, which was followed by an electric shock. The time was recorded when the animal first approached the watering device and took water from it for the first time.

When the conditioned passive reflex reflex was reproduced 24 hours after learning, the reference rats remembered the situation and did not take the water. When the reflex was returned after a period of 2 weeks, it gradually went out, with most animals ingesting the water. The long-term introduction of the compound I of the present invention and other drug preparations (nootropyl, cleregyl) had no effect on the learning and reproduction of the conditioned reflex for passive avoidance under the conditions of the conflict situation after a period of 24 hours. However, two weeks after learning, when most of the animals in the reference group forgot the situation and the reflex time (time for ingestion of the water) of said animals was reduced by at least half, the memory trace of the rats given compound I according to the invention was almost 455 093 21 constantly, which is why the reflex time (the time for ingesting the water) was practically not changed. The similar effect was observed for nootropyl at a dose of 300 mg / kg, while kleregyl to a lesser extent promoted reproduction sv the memory trace. The test results are reported in Table 13.

Table 12 Effect of compound I according to the invention on rats' learning of a conditioned reflex in a T-shaped labyrinth Reflex time, p.

Learning Compound I, 50 mg / kg, sessions Reference intra-abdominal 1 2 3 Before the introduction of the substance 54.61 (48.42-60.8) 48.57 (42.5 ~ 54.57) 1 79.2 (68 , 72-89.68) 53.7 143.5-63.9) 2 53.4 (42.92-63.88) 71.2 (60.4-82) 3 74.0 (63.52- 84.48) 65.0 (54.8-75.2) 4 59.4 (48.92 - 69.88) 74.5 163.8-85.2) 5 79.7 (68.74 ~ 90 , 66) 62.6 152.4-72.8) 6 68.0 (57.04-78.96) 49.06 (38.8-59.2) 7 77.7 (67.22-88, 18) 54.3 142.1-64.5) 8 52.7 (42.22-63.18) 70.3 (61.0 ~ 79.6) 9 62.9 (51.94-73.86 ) 66.4 (57.1-75.7) 10 76.9 (66.42-87.38) 34.0 (23.3-44.7) 11 49.1 (40.05 ~ 58.15 ) 24.0 (13.1-34.9) 12 37.4 (28.16-46.64) 24.5 (13.6-35.4) 13 29.4 (24.16-34.64 ) 18.4 (12.2-24.6) 14 30.0 (23.71-36.29) 31.8 (20.9-42.7) 15 31.1 (24.81-37.39 ) 23.8 116.7-30.9) 16 18.5 (15.07-21.93) 19.9 (11.8-28.0) 17 47.3 (39.7-54.9) 22.2 (16.9-28.1) 18 36.0 (30.29-41.71) 26.9 (21.6-32.2) 19 40.2 (31_44-48.96) 17, 7 (13.3-22.1) 20 12.9 (3.52_17.23) 10.7 (7.3-14.1) 21 18.6 (12.22-24.98) 6.4 ( 4.8-8.0) 455 093 22 In investigating the effect of the compound I enli In accordance with the present invention on the extinction of the conditioned reflex for passive avoidance without renewed reflex reproduction under conditions of conflict situation, it has been found that all the animals in the reference group of rats take the water for 12 minutes. after the test has been presented. It has been found that the memory track is extinguished more gradually (more evenly) under the influence of compound I according to the invention, whereby only half the number of animals in the group took the water from the irrigation device for 12 minutes. after the animals have been inserted into the device for producing the reflex. At the same time, there was a significant increase in the time interval after which the experimental animals first approached the irrigation device, and in particular in the time interval after which the experimental animals took the water for the first time, compared with the reference animals. In animals in the experimental group, a noticeable variation (spread) was also detected in the time interval between the time when the animals first approached the irrigation device and the time when the animals took the water. The test results are reported in Tables 14 and 15.

Table 13 Effect of long-term administration of medicinal products on the reproduction of a reflex for passive avoidance in rats under conditions of conflict situation The time interval The interval, interval, after which the animal for the first gait gaxgàïñæm gaxfäfen Attempted - for irrigation- first el- Nr. Preparation conditions of the device, p. Shock, p. 1 2 3 4 5 Reference physiological solution soï41, p soï41, p. 2 "Refhee reproduction 24 + thn. After learning 181-0.06 300 3" Reflex reproduction 14 + + days after learning 149, 29-44.4 149.57-44.5 Compound of the invention + + (50 mg / kg) Disposable injection 31.5-14.3 31.5-14.3 Compound I Introduction under a + + (according to Rev.) time of 18 days 35.29- 12.2 35.29-10.2 (50 mg / kg) 455 093 23 3 4 Compound I (according to Rev.) (50 mg / kg) Reflex reproduction 24 hours after learning 4300 Reflex reproduction 14 days after learning (introducing for a period of 32 days) 2o9,29ï43, p 273, s7ï44, s Nootropyl (300 HIQ / kg) Electrical input injection + 1 3-4, 2 9 13ï4,29 Introduction for a period of 21 days 3sï2o, 4 3si2o, 4 10 Reflex reproduction after a period of 24 hours 2s2ïs3, ß 11 Reflex reproduction 14 days after learning (introduction for a period of 35 eyes) 191, sï71, 3 2s1ïsa, 3 12 Kieregyl (150 mig / kg) Elngângsinj icering 30:24, 2 3of24,2 13 Reflex reproduction 24 h. Learning 300 14 Reflex reproduction 14 days after learning (insertion over a period of 35 days) 143i11s, 5 2ooï94, a 455 093 24 Table 14 Effect of compound I according to the present invention (in a dose of 50 mg / kg, intraabdominal, insertion during a ti on the extinction of a reflex for passive avoidance under conditions of conflict situation Number of animals (%), who remembered the situation and did not go to the irrigation device for a period of 12 min.

Iid interval in min. d of 14 days) e in rats Fbpart time interval, after which the animal proceeded.to watering- Nr. Topics 1-2 3-4 5-6 7-8 9-10 11-12 device, p. 1 2 3 4 5 6 7 8 9 1 Reference (physiological + logical solution) 42.6 42.6 28.4 28.4 14.2 0 231.3 ~ 64.5 2 Föna I ng I, + (according to inventor) 71 71 42.6 28.4 28.4 28.4 340.7-277.5 Table 15 Number of animals (%), who did not take the water net from the irrigation device during the average reflex time one of mln '(downtime interval in min. meadow after which No. Substances 1-2 3-4 5-6 7-6 9-10 11-12 the water taken), s- 1 2 3 4 5 6 7 8 9 1 Reference substance + (physiological solution.) 42.6 42.6 28.4 28.4 14.2 0 235.3-79 2 Phoenix I + (acc. invention) 100 85.2 56.8 56.8 56.8 56.8 513.6-189.8 The effect of compound I according to the present invention on induced so-called transcollasal potential.

Experiments were performed on non-anesthetized and non-immobilized rabbits, the potential being recorded with (stimulation parameters: ch by myorelaxants n induced transcollasal part a neurodator-based analyzer 25-3SV, 0.1 - 1 s.) Was brought to an average value (starting from 20 experimental measurements) and were analyzed for a period of 200 ms after the induction was initiated. In experiments to investigate the action of substances with nootropic type action, it has been found that the compound I according to the present invention acts on the induced transcollacial potential in the same way as the preparations nootropyl, pyritinol and cleregyl. Compound I according to the invention contributes to increasing the amplitude of the positive primary component P1 and negative primary component N1 of the induced transcolasal potential without the compound I according to the invention simultaneously changing the latency periods of these components. The effect of compound I of the present invention on the induced transcollacial potential compared to the nootropic-type preparations (with nootropic action) is characterized by the fact that compound I does not affect the positive secondary component P2 of this potential, which is generated by stimulation not via the cerebral cortex. but via the reticular formation of the midbrain.

Compound I according to the present invention thus - like other preparations with nootropic action - has a relieving effect on the transfer process between the brain halves. The test results are reported in Table 16.

The anticonvulsant (antispasmodic) effect of the compound proposed according to the invention was estimated depending on the ability of the substance to prevent mice from having seizures and dying under the influence of anticonvulsants: pentylenetetrazole (140 mg / kg, subcutaneous); thio-semicarbazide (28 mg / kg, intra-abdominal); bicuculline (2 mg / kg, subcutaneous) and maximal electric shock. ..a 455 093 26 Table 16 Effect of preparations with nootropic type effect (with nootropic effect) on the various components of the induced transcollasal potential Positive Negative POSitiV Substance compound comma dose P1 + N1 comgosant dose (mg / kg) 1 1 2 1 2 3 4 5 Nootropyl (300-500) ++ ++ ++ ++ Pyritinol (100-150) + + + + Kleregyl + (25-50) ++ - ++ ~ Compound I (according to invention) (25-50) + + + 0 Note: ++ denotes an increase of the component by at least 50% + increase of at most 50% - decrease 0 effect missing The anti-convulsive effect of compound I according to the present invention with respect to all the tests used was shown only in a dose of 200 mg / kg and was found in 30% of the animals. Compound I according to the invention in a dose of 100 mg / kg also helped to increase the latency after which bicuculline-induced seizures began to occur. When the dose of compound I according to the invention was increased to 400 mg / kg, the anti-convulsant effect of the substance disappeared (the test results are reported in Tables 17, 18, 19 and 20). When compound I of the invention was administered at doses of 25, 50 and 100 mg / kg, no effect of compound I on tremor caused by arecholine (26 mg / kg, subcutaneous) was detected. The administration of the compound I of the invention at a dose of 100 and 200 mg / kg greatly contributed to the prevention of hyperkinesis in mice (shaking of the head) caused by 5-hydroxytryptophan (200 mg / kg, intra-abdominal). The test results are reported in Tables 21 and 22.

The anti-aggressive effect of compound I according to the invention 455 093 '27 was detected on a model by experimental electrical pain induction (at an electrical current of 0.45 mA) via an electrode floor for a pair of mice, when compound I was administered in a dose of 200 and 400 mg / kg. A decrease in the number of fights (fights) between the mice in the pair was observed by 1.5 - 2 times.

The test results are reported in Table 23.

Compound I according to the invention did not - when administered at a dose of between 50 and 400 mg / kg - have any appreciable effect on the so-called the orientation and examination behavior in a test with climbing up into a net. Nor did it cause any disturbance in the coordination of movements during a test with a rotating rod. The test results are reported in Tables 24 and 25.

Thus, in animal experiments, Compound I of the present invention has a number of advantages over the nootropic drug nootropyl used as an antiamnesic and antihypoxic drug preparation. Compound I of the invention significantly exceeds nootropyl in terms of activity and exhibits a broader therapeutic spectrum of action. Compound I according to the invention exceeds nootropyl by dose by 6-10 times with respect to the anti-amnesic effect depending on the type of amnesia (shock or scopolamine-induced amnesia, amnesia caused by deprivation of the paradoxical phase of sleep and by isolation) and contributes to that the memory track is maintained for a longer period of time.

Compound I of the invention not only exceeds nootropyl in terms of antihypoxic activity (by 5-10 times) but also exhibits a broader spectrum of activity, promoting survival for a longer period of time under conditions of hypobaric hypoxia (during which nootropyl is insufficiently active) , hypoxia with hypercapnia and hemic hypoxia. Compound I according to the invention shows low toxicity and does not give any side effects of a myorelaxant nature. 455 093 28 Table 17 Effect of compound I according to the invention on seizures caused by pentylenetetrazole (140 mg / kg, subcutaneous) at pre- ". Ns ° k Pa moss Tonic extension and D ° 5 of fo? animal death gene I according to the invention in mg / kg Absolute Percent- Preparation (intra-abdominal) value value 1 2 3 4 Pentylentetrazole 9/10 90 Compound I according to the invention + pentylentetrazole '50 5/6 83 "200 4/6 66" 400 6/6 100 Table 18 Effect of compound I according to the invention on seizures caused by the maximum electric shock in mice Protective effect Dose, mg / kg Tonic extension Animal death (intraab- Absolute- Percent- Absolute »Percent- Preparation dominant) value value value value 1 2 3 4 5 6 Compound I according to the invention + maximum electric shock 50 0/6 0 0/6 0 "200 2/6 33 4/6 66" 400 0/6 0 2/6 33 455 095 29 Table 19 Effect of compound I according to the invention on seizures caused by thiosemicarbazide (28 mg / kg, intra-abdominal) in experiments on mice Dose of the compound I according to uPpfin_ Animal mortality in mg / kg in absolute- in percent- Preparations (intravenous) values values 1 2 3 4 Thiosemicarbazide 1Û / 10 100 Compound I acc. invention + thiosemicarbazide 7 7/10 70 "50 7/10 70" 100 7/10 70 Table 20 Effect of compound I according to the invention on seizures caused by bicuculline (2 mg / kg, subcutaneous) in experiments on mice Dose of the compound - Latency _ U gen I according to after want The death of the animals want the invention in ken hug- in ab- mg / kg (intra- pâ- solut- Preparations abdominal) begin values in% 1 2 3 4 5 Bikukullin 2, sïo, 97 10 / 90 90.9 Compound I acc. invention + + bicuculline 100 11.9-2.93 7/10 70 455 093 ~ 30 Table 21 Effect of compound I according to the invention on the tremor caused by subcutaneous injection of arecholine in a dose of 26 mg / kg in mice Dose of compound I according to the invention Tremorens ningen in mg / kg duration, Preparation (intra-abdominal) min. 1 2 3 Arekolin 12, 3315 Compound I according to the invention + arecholine 25 15.77-5 "so 9,4ï4,1" 1oo 13, o4ï3,1a Table 22 Combined effect of compound I according to the invention on 5-hydro- oxytryptophan (200 mg / kg, intra-abdominal) in a head shake test in experimental mice Dosage of compound I according to the invention in mg / kg (intra-boon-Number Effect-end Preparation minalt) shaking ring degree 1 7 2 3 4 5-hydroxy-tryptophan 26 1 Compound I acc. invention + 5-hydroxytryptophan 50 28 1.07 "100 16 0.57 5-hydroxytryptophan 28 1 Compound I according to the invention + 5-hydroxytryptophan 200 11 0.39 455 095 31 Table 23 Effect of compound I according to the invention on the aggression caused by experiments in mice Number of fights between a pair of mice over a period of time Preparation Dose, mg / kg of 2 min.

Reference - 11.6 in 3.2 Compound I + according to the invention 50 10.8 - 4.2 "100 9.6 in 3.4 - 'zoo 7.4 in 3.4" 4oo si 1.5 Table 24 Impact of the compound I according to the invention in the so-called orientation and examination behavior in mice (test with climbing up into a net) Effect Substance Dose, mg / gg 'in absolute values in% Compound I according to ref. 50 0/10 0 "100 2/10 20" 200 2/16 12.6 "400 3/16 18.9 Eabell 25 Effect of compound I according to the invention on the movement coordination in a test with a rotating bar in mice Dose, Effect Substance mg / kg in absolute values in% Compound I according to the invention 50 0/10 O "100 O / 10 O" 200 O / 10 O "400 O / 10 0 455 095 _ 32 The compounds of the present invention proposed by (namely) N The nicotinoylamino acids are prepared according to the following reaction scheme: = R '112114 H 2 O RÛCQNHHHZ Nanoa Ûcooczus N Hcl NR coN _ O 3 Lmacr fl c fl gzcoo fl NR, R 0 CONHCHCHZCHQCOOH "fi I.

N R 'where R represents OH, Br and R' is H, COOH. Starting ethyl ethers of 5-bromonicotinic or 5-hydroxynitotinic acids are reacted with hydrazine hydrate in an aqueous or alcoholic medium. The resulting 5-bromonicotinic acid or hydroxynicotinic acid hydrazides are converted to acid azides by reacting with sodium nitrite in the presence of aqueous hydrochloric acid. The acid azides are then prepared from the final products by reacting the acid azides with L- and DL-glutamic acids and aminobutyric acid in an aqueous and alkali-containing medium with a pH of between 8 and 10.

The invention is further illustrated below by means of the following working examples of the preparation of the new compounds, namely the N-nicotinoyl acids.

Example 1 16.7 g (0.1 mol) of 5-hydroxynicotinic acid ethyl ester are mixed with 100 ml of 50% aqueous hydrazine hydrate and boiled for 1 hour. The dark solution is evaporated to dryness and the solid phase residue is recrystallized from dimethylformamide. The yield of the 5-hydroxynicotinic acid hydrazide is 11 g (72%). The hydrazide has a decomposition temperature of 26100. 455 093 33 Analysis for C 6 H 7 N 3 O 2: Found: C 46.91 H 4.50 N 27.67% Calculated: C 47.06 H 4.57 N 27.45% 11 g (0.072 mol) 5-Hydroxynicotinic acid hydrazide is dissolved in a mixture of 17 ml of concentrated hydrochloric acid (d = 1,19) and 20 ml of water and cooled to a temperature of between 0 ° C - 5 ° C, after which the solution thus obtained is stirred very slowly with simultaneous stirring. temperature dropwise add a solution of 11.7 g (0.1 mol) of sodium nitrite in 20 ml of water. At the same time as the reaction is carried out, a white so-called volume precipitate precipitates as the sodium nitrate solution is added. After the addition of the sodium nitrite solution is complete, the mixture is stirred for a further 0.5 hour at a temperature of 0 DEG C., after which the precipitate is filtered off. The mother liquor is added with a cold saturated solution of sodium hydrocarbonate until the precipitation of the precipitate ceases.

The precipitates are combined and air dried. The yield of the 5-hydroxynicotinic acid azide is 11.5 g (97%). The azide has a decomposition temperature of about 138 ° C. 1.47 g (0.01 mol) of L-glutamic acid are dissolved in 10 ml of a 1N solution of sodium hydroxide. While stirring the resulting solution, 1.64 g (0.01 mol) of 5-hydroxynicotinic azide are added portionwise, the pH of the reaction solution being controlled within the range of between 9 and 9.5 by periodically (batchwise) adding an SN solution of sodium hydroxide. . After the azide is completely dissolved, the solution is mixed for a further 1 hour at room temperature. The solution is then acidified with concentrated hydrochloric acid to a pH of between 4 and 4.5. The precipitated product is filtered off and recrystallized from water. 1.83-2 g of N- (5-hydroxynicotinoyl) -L-glutamic acid (Compound I) are obtained (68-75%).

This acid has a decomposition temperature of 222-223 ° C. Åäjšo -14,80 (C 5,8% hydrochloric acid).

Analysis for C 11 H 12 N 2 O 6: Found: C 49.37 H 4.59 N 10.25% Calculated: C 49.20 H 4.48 N 10.48%: R-spectrum (mar), etc.; 3278 (ommn, 1719 (coon), 1655 (Conn) .455 093 34 UV spectrum (water 1: Åmax = 289 nm.

MR spectrum (CD 3 OD-D 2 SO 4, internal standard hexamethyldisilazane): δ 2.0 - 2.7 (4H, m, CH 2 CH 2 COOH), 4.60 (LH, m, NCH (COOHD, 8.52 (1H, g, 2) -H in pyridine), 8.40 (1H, k, 4-H in pyridine), 8.80 (1H, g, 6-H in pyridine).

Example Gel 2 In analogy to that described in Example 1, 5-hydroxynicotinic acid azide is prepared. From 1.47 g (0.01 mol) of DL-glutanimic acid in 10 ml of a 1N sodium hydroxide solution and 1.64 g (0.01 mol) of 5-hydroxynicotinic acid azide are then prepared - under the process conditions analogous to the process conditions described in Example 1 - N- (5-hydroxynico / tinoyl) -DL-glutamic acid (Compound II), the yield of which is 2 g (75%). The final product has a decomposition temperature of 219-220 ° C (from water).

Found: C 49.28 H 4.36 N 10.19%.

Example Gel 3 In analogy to that described in Example 1, 5-hydroxynicotinic acid azide is prepared. 1.03 g (0.01 mol) of 1'-aminobutyric acid in 10 ml of a 1N sodium hydroxide solution and 1.64 g (0.01 mol) of 5-hydroxynicotinic acid azide are then prepared - analogously to that described in Example 1- N- (5-Hydroxyquinotinoyl) -aminobutyric acid (Compound III), the yield of which is 1.98 g (89%). The final product has a decomposition temperature of 220-221 ° C (from water).

Analysis for C 10 H 12 N 2 C 4: Found: C 53.50 H 5.39 N 12.18% Calculated: C 53.57 H 5.36 N 12.50%.

IR spectrum (KBr1 = cm -1; 3304 (cn, NH), 1639 (cows).

UV spectrum (water):), max = 288 nm.

PMR spectrum (CD 3 OD-D 2 SO 4, internal standard hexamethyldisilazane): 61.95 (za,: It / b-cnz), 2.40 (2H, m, Ncnz (j j cnzn, 3.43 (zu, m, CH 2 COOH), 8.52 (1H, g, 2-H pyridine), 8.40 (1H, k, 4-H in pyridine), 8.78 (1H, g, 6-H in pyridine) 455 093 Example 4 g-5-bromonicotinic acid ethyl ester is mixed with 50 mg of hydrazine hydrate and boiled for 1 hour After cooling, the precipitated precipitate is filtered off and recrystallized from water to give 4.05 g (90%) of 5-bromonicotinic acid hydrazide, m.p. 1a4 ° c.

Analysis for C 6 H 6 BrN 3 O: Found: H 19.23 Br 37.41% Calculated: N 19.44 Br 37.00%. 4.5 g (0.021 mol) of 5-bromonicotinic acid hydrazide are dissolved in a mixture of 7 ml of concentrated hydrochloric acid and 3 ml of water and cooled to a temperature of between 0 ° C - 5 ° C, after which a solution of 5.3 g (0.077 mol) of sodium nitrite in 7 ml of water is added dropwise to the reaction solution. After completion of the addition of sodium nitrite, the reaction mass is kept at a temperature of 0 DEG C. for a period of 0.5 hour. The precipitated volume precipitate is filtered off, while the mother solution is treated with a cold saturated solution of sodium hydrogen carbonate until the precipitation ceases to precipitate. The precipitates are combined, washed with ice water and air dried. The yield of the 5-bromonicotinic acid azide is 4.1 g (88%), while the decomposition temperature of the azide is about 87 ° C.

A solution of 1.47 g (0.01 mol) of L-glutamic acid in 10 ml of a 1N sodium hydroxide solution is treated (in small portions) with 2.27 g (0.01 mol) of 5-bromonicotinic acid azide at a pH of between 9 and 9.5. The final product is isolated analogously to that described in Example 1. 2.42 g (73%) of compound IV with a melting point of 185-186 ° C (from water) are obtained. Å š lšo -8.60 (c 5; 8% hydrochloric acid).

Analysis for C 11 H 11 BrN 2 O 5: Found: C 39.71 H 3.11 N 8.23 Br 24.36% Calculated: C 39.89 H 3.32 N 8.46 Br 24.15%.

IR spectrum (kar), cm -1 = 3372 (NH), 1714 (coon), 1646 (conn).

UV spectrum (water): Å5max = 276 nm. 4555 (193 36 PMR spectrum (CD 3 OD-D 2 SO 4, internal standard hexamethyldisilazane): δ 2.0 - 2.7 (4H, m, cnzcnzcoon), 4.60 (1H, m, NcH (cooH), 9.04 UH , q, 2-H pyridine), 8.78 (1H, k, 4-11 pyridine), 9.00 (m, q, 6-H in pyridine).

Comparison between the HNA-10 compound and the compounds mentioned in the Table article in Khim.-Farm. Zh, 1980, 9, p. 49 HNA-10 Known compounds 20-10O compounds 200- Effects ng / kg 600 mg / kg 1. Anti-amnesty effect shock + W scopolamine + - DPPS + - 2. Facilities learning, memory t - reproduction of memory rudiment + - 3. Antihypoxic effect hypobaric hypoxia + - hemic hypoxia + - hypercapnia + + 4. Potentiation of transcolasal induced potential + - 5. Effect on energy spectrum + - 6. Effect on age-related pathology + - 7. Anxiety effect - - 8. Antispasmodic effect (corasol) - + 9. Anti-aggressive effect - - 10. Intensification of emotional reaction during prolonged application + - 11. Open field ~ - 12. Potentiation of barbiturates 0 + 13. Myorelaxative effect - - 14. Toxicity, mg / kg, LD50 3000 1500 n)

Claims (1)

Claims N-nicotinoylamino acids of the general formula R "\ ¶Éšâ] / CCR 'where R" is OH, Br, if R' represents L-NH-? H (CH2) 2COOH; COOH R "is OH , if R 'represents DL-NH-αH (CH 2) 2 COOH; COOH and R "are OH, respectively, if R 'represents NH (CH2) 3COOH.