ON THE DEPENDENCE OF THE PHYSIOLOGICAL ACTIVITY OF N-ACYL DERIVATIVES OF N′-BENZYLUREA ON THEIR HYDROLYSIS RATE

N. S. DOBYCHINA

(Presented by the scientific-methodological seminar of the Faculty of Chemical Technology)

Medicinal substances, upon entering a living organism, undergo more or less substantial changes there. The most probable transformation of an acyl derivative in the organism may be its hydrolytic cleavage.

In studying the dependence of the anticonvulsant action of N-acyl derivatives of barbituric acid on the rate of hydrolysis, V. G. Stolyarchuk [1] established that the greatest activity is exhibited by substances with moderate hydrolytic stability.

It seemed of interest to determine the dependence of anticonvulsant activity on the rate of hydrolysis in a series of acyl derivatives of urea. To study this dependence, we used a series of N,N′-benzylacyl derivatives of urea obtained earlier [2]. Upon hydrolysis of the latter, benzylurea and a carboxylic acid are formed. The products formed were quantitatively determined by the conductivity method (hydrolysis was carried out in an aqueous-alcoholic mixture at alcohol-to-water ratios of 1 : 3 and 1 : 1).

The experiments showed that the rate of hydrolysis of N-acyl derivatives of urea is inversely dependent on the dissociation constant of the acid entering into the molecule of the acyl derivative. Comparison of the rate of hydrolysis and anticonvulsant activity makes it possible to suppose that acyl derivatives of benzylurea having moderate hydrolytic stability also possess greater anticonvulsant activity.

Experimental Part

The substances taken for hydrolysis do not dissolve in water. Therefore, the weighed sample was dissolved in alcohol in a volumetric flask at 40°C in a thermostat; then, after cooling to 20°C, the solution was diluted twice with water redistilled over potassium permanganate to the volume of the volumetric flask (solution concentration 0.001 mole/l). The prepared solution was poured into a flask equipped with a reflux condenser, which was placed in a thermostat at a temperature of 99°C. Every hour, a 20 ml sample of the solution was taken from the flask; in this sample the content of the products formed was determined, for which purpose the vessel for determining conductivity by the compensation method was placed in a thermostat at a temperature of 40°C. The acid concentration was found from the conductivity with the aid of calibration curves, which had been constructed beforehand for each acyl derivative. The necessary standard-

solutions contained a mixture of the acyl derivative, the carboxylic acid, and benzylurea in amounts corresponding to various degrees of hydrolysis of the acyl derivative. For each solution tested, six standard solutions were prepared. A ZG-10 audio generator was used as the current source. As the instrument zero in the bridge diagonal—an EO-7 oscilloscope.

Fig. 1. Hydrolyzability of N,N′-acylbenzylurea derivatives: 1 — N,N′-propionylbenzylurea; 2 — N,N′-butyrylbenzylurea; 3 — N,N′-isobutyrylbenzylurea; 4 — N,N′-valerylbenzylurea; 5 — N,N′-isovalerylbenzylurea; 6 — N,N′-benzoylbenzylurea; 7 — N,N′-isonicotinoylbenzylurea.

The results of the experiments are presented in the figure.

Conclusions

1. By the electrical-conductivity method, the relative rate of hydrolysis was determined for N,N′-propionyl-, N,N′-butyryl-, N,N′-isobutyryl-, N,N′-valeryl-, N,N′-isovaleryl-, N,N′-benzoyl-, and N,N′-isonicotinoylbenzylurea.

2. It was established that the hydrolysis rate of these compounds is inversely dependent on the strength of the acid whose residue is incorporated into the molecule of the acyl derivative of urea.

3. It was found that the preparations with intermediate hydrolytic stability possess the strongest anticonvulsant action: N,N′-valeryl-, N,N′-isovaleryl-, and N,N′-isonicotinoylbenzylurea.

LITERATURE

1. V. G. Stolyarchuk. Dissertation, 178, Tomsk, 1952.

2. L. P. Kulev, N. S. Dobychina. Journal of the All-Union Chemical Society named after D. I. Mendeleev, VIII, 701, 6, (1963).