RU2436772C2 - 4[(4'-nicotinoylamino)butyroylamino]butanoic acid, exhibiting nootropic activity, and method of producing said compound - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound and specifically 4[(4'-nicotinoylamino)butyroylamino]butanoic acid of formula (I)

, as well as a method of producing said compound.

EFFECT: novel compound is obtained and described, which exhibits high nootropic activity and has low toxicity.

2 cl, 1 ex, 1 tbl

Description

The invention relates to the field of medicine and organic chemistry and relates to a new biologically active chemical compound, specifically 4 [(4'-nicotinoylamino) butyroylamino] butanoic acid of the formula (I)

showing nootropic activity. The specified compound and its properties are not described in the literature.

Known nootropic drugs of various chemical structures and mechanisms of action: pyrrolidone derivatives; pyridoxine derivatives; derivatives of gamma-aminobutyric acid (GABA); cerebrovascular agents; diethylaminoethanol derivatives; neuropeptides and their analogues; antioxidants; different substances with a component of nootropic action [1].

Currently, the issue of expanding the range of nootropic drugs is extremely relevant, which determines the demand for their development and production. These drugs are used in narcology, psychiatry, preventive medicine, to stimulate the processes of memory, learning, and also to increase physical and mental performance. Most used nootropic drugs have serious drawbacks.

The closest in properties to the described compound is nicotinoyl gamma-aminobutyric acid, hopantenic acid, piracetam [2]. However, these drugs exhibit not high enough nootropic activity.

The problem to which the present invention is directed, is to search for new compounds with increased nootropic activity.

In accordance with the invention describes a new chemical compound 4 [(4'-nicotinoylamino) butyroylamino] butanoic acid of the formula (I)

showing nootropic activity.

Also described is a method for producing 4 [(4'-nicotinoylamino) butyroylamino] butanoic acid of the formula (I)

by reacting ethyl ester of N (4-nicotinoylamino) butanoic acid with the sodium salt of gamma-aminobutyric acid in an organic solvent.

The acute toxicity of compound (I) was determined on outbred white rats weighing 150-160 g with intravenous administration. It has been established that compound (I) is a low-toxic substance. LD ₅₀ is 6500 mg / kg.

The compound of formula I was studied in studies on white rats weighing 190-210 g. To evaluate the nootropic effect, the conditional passive avoidance reaction (passive avoidance reaction) was used, followed by the use of an electric shock as an amnesating factor:

- the animal was placed in the light compartment of the two-chamber installation and the latent time of entry into the dark compartment of the chamber was recorded, where the rat received electric shock through the electrode floor (training).

30 and 90 minutes before training, the experimental groups of animals received twice the orally studied drugs - compound (I) at a dose of 10 mg / kg, nicotinoyl gamma-aminobutyric acid - 50 mg / kg, hopantenic acid - 200 mg / kg in terms of the content of active ingredients.

After training, amnesia was induced by electric shock (115 V, 50 Hz, 500 mA). The reproduction of the reflex was maintained 24 hours after training.

Studies have shown that electroshock causes forgetting skill in animals when reproducing passive avoidance reaction 24 hours after training. The preliminary administration of compound (I) to experimental animals at a dose of 10 mg / kg, nicotinoyl gamma-aminobutyric acid - 50 mg / kg, hopantenic acid - 200 mg / kg and the subsequent use of amnestic factors caused a significant increase in the latency of the reflex, i.e. preservation of learning skills compared to control animals.

The most effective was the preliminary administration of compound (I) - an almost 4-fold increase in the retention time of the skill when inducing amnesia by electric shock (see table).

The duration of the latent period of maintaining the habit of habituation (h) Mouse number Compound (I)
10 mg / kg Nicotinoyl gamma-aminobutyric
acid 50 mg / kg Hopantenic acid 200 mg / kg The control one 98 62 49 28 8 95 55 48 21 9 94 56 fifty 22 four 91 53 fifty 23 3 95 54 46 24 10 92 59 45 25 5 88 59 43 26 2 90 55 51 27 6 93 60 51 21 7 95 62 46 29th Average value 93.1 57.5 47.9 24.6

The results shown in the Table show that the described new low-toxic compound - 4 [(4'-nicotinoylamino) butyroylamino] butanoic acid of formula (I) has high nootropic activity and can be used in the treatment of various forms of ischemic diseases, as well as in the field of narcology, psychiatry, preventive medicine, to stimulate the processes of memory, learning, and also to increase physical and mental performance

The invention is illustrated by the following example.

Example

Synthesis of compound (I) - 4 [(4'-nicotinoylamino) butyroylamino] butanoic acid

HCL was passed through a solution of 10 g of N (4-nicotinoylamino) butanoic acid in 100 ml of ethanol. The reaction mass is kept for 1 h, poured onto ice and extracted with toluene. A solution of the obtained N (4-nicotinoylamino) -butanoic acid ethyl ester was added to a suspension of gamma-aminobutyric acid sodium salt in toluene. The solvent is distilled off, the residue is dissolved in water and, upon acidification, 8 g of the expected product is isolated in the form of a white crystalline powder with a _mp = 151-153 ° C.

Below are the results of elemental analysis obtained using the CHNSO element analyzer Euro Vector EA3000, and the PMR spectrum (drawing), which confirm the structure of the obtained compound.

Elemental analysis

Calculated for C ₁₄ H ₁₉ N ₃ O ₄ : C 57.326; H 6.529; N, 14.327; O 21.818;

Found: C 57.2; H 6.6; N, 14.3; About 21.9.

Bibliography

1. Voronina T.A. Experimental psychopharmacology of nootropics. // In the book. "The pharmacology of nootropics (experimental and clinical study)." - M., 1989. - S.8-20.

2. M.D. Mashkovsky. Medicines 14th ed. 2001 year

Claims (2)

1. 4 [(4'-Nicotinoylamino) butyroylamino] butanoic acid of the formula (I)

showing nootropic activity. 2. The method for producing 4 [(4'-nicotinoylamino) butyroylamino] butanoic acid according to claim 1, wherein the ethyl ester of N (4-nicotinoylamino) butanoic acid is reacted with the sodium salt of gamma-aminobutyric acid in an organic solvent.

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