ON THE QUESTION OF THE RELATIONSHIP BETWEEN CHEMICAL STRUCTURE AND ANTICONVULSANT ACTIVITY IN A SERIES OF UREA DERIVATIVES

N. S. DOBYCHINA, A. G. PECHENKIN

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

Among anticonvulsant drugs, the best known and most thoroughly studied are derivatives of barbituric acid and hydantoin.

Recently, new anticonvulsant drugs of acyclic structure have been obtained and have found application for the treatment of epilepsy, such as N-benzyl-β-chloropropionamide (chibicon) [1] and α-phenylacetylurea (phenurone) [1]. There are also data indicating that some other acyclic urea derivatives possess anticonvulsant action [2]. However, derivatives of this kind of urea have so far remained little studied with respect to their anticonvulsant activity; in particular, the influence of various radicals and groups introduced into urea has not been clarified at all.

Of a series of N,N′-benzylacyl derivatives of urea, synthesized by one of us jointly with the late L. P. Kulev [6], N,N′-benzylvaleryl-, N,N′-benzylisovaleryl-, and N,N′-benzylisonicotinoylurea hydrochloride showed considerable anticonvulsant activity in tests on guinea pigs. It was of interest to determine what significance the benzyl radical has in these derivatives and how the anticonvulsant activity of the latter would change when the benzyl radical is replaced by phenyl.

For this purpose we undertook the synthesis of N,N′-phenylacyl derivatives of urea, with phenyl- and benzylureas being acylated with acid chlorides of the same acids.

The compounds synthesized by us have the general formula:
C₆H₅ NHCO NHCO-R, where R is iso-C₃H₇, iso-C₄H₉, -C₄H₉, iso-C₅H₄N, -C₅H₄N. The last three compounds have not been described in the literature. All the preparations obtained are white crystalline products insoluble in water and soluble in hot alcohols: ethyl, propyl, and isopropyl.

According to pharmacological studies by E. M. Dumenova (Department of Pharmacology, Tomsk Medical Institute), the N,N′-phenylacylureas obtained by us did not show appreciable anticonvulsant activity against strychnine convulsions. It follows from this that replacement of the benzyl radical by phenyl in benzylacylureas leads to elimination of the anticonvulsant activity of the latter.

Experimental Part

Acylation of phenylurea (m.p. 148–149°C) was carried out with acid chlorides in molar ratios of phenylurea to acid chloride of 1 : 1.5. The latter were prepared by known methods [4, 5].

N,N′-Phenylisobutyrylurea (I). A mixture of 10 g of phenylurea and 11.4 ml of isobutyryl chloride is heated with stirring in an open round-bottom flask on a glycerol bath for 5 h at 120–130°C, until HCl has been completely removed.

After cooling, the reaction mass is dissolved in alcohol, water is added, and a crystalline product is isolated, namely N,N′-phenylisobutyrylurea. The latter, recrystallized from propanol, has m.p. 140–141°C, which agrees with the literature data [4].

Found, %: N 13.67; C 64.58; H 6.79. C₁₁H₁₄O₂N₂.
Calculated, %: N 13.65; C 64.07; H 7.14.

N,N′-Phenylisovalerylurea (II). Prepared analogously to (I) from 10 g of phenylurea and 13 ml of valeryl chloride. The product obtained is recrystallized from ethanol. M.p. 98–99°C, which agrees with the literature data [3].

Found, %: N 12.61.
Calculated, %: N 12.79. C₁₂H₁₆O₂N₂.

N,N′-Phenylvalerylurea (III). A mixture of 10 g of phenylurea and 13 ml of valeryl chloride is placed in a flask equipped with a reflux condenser and stirrer; 35 ml of benzene and 15 drops of hydrochloric acid (57% solution) are added. After the vigorous evolution of HCl has ceased, the reaction mass is heated for 1.5 h on a boiling water bath. After cooling of the reaction mass, the crystalline product is filtered off and recrystallized from alcohol, m.p. 108–109°C.

Found, %: N 12.67; C 65.97; H 7.64. C₁₂H₁₆O₂N₂.
Calculated, %: N 12.79; C 65.45; H 7.27.

N,N′-Phenylnicotinoylurea (IV). Prepared analogously to (III) from 20 g of phenylurea and 31.8 g of nicotinoyl chloride hydrochloride in the presence of 25 drops of hydrochloric acid, with heating for 4.5 h. The filtered precipitate is dissolved in boiling water, isolated by neutralization with soda, and recrystallized from propanol; a white crystalline product with m.p. 213–214°C is obtained.

Found, %: N 17.02; 17.34. C₁₃H₁₁O₂N₃.
Calculated, %: N 17.42.

N,N′-Phenylisonicotinoylurea (V). Prepared analogously to (IV) from 20 g of phenylurea and 31.8 g of isonicotinoyl chloride hydrochloride. The white crystalline product, recrystallized from ethanol, has m.p. 201–203°C.

Found, %: N 17.21; 17.64. C₁₃H₁₁O₂N₃.
Calculated, %: N 17.42.

Conclusions

1. Five N,N′-phenylacyl derivatives of urea have been synthesized; of these, three—N,N′-phenylvaleryl-, N,N′-phenylnicotinoyl-, and N,N′-phenylisonicotinoylureas—have not been described in the literature.

2. The N,N′-phenylacylureas obtained do not possess anticonvulsant activity.

References

1. R. Bartow. Introduction to Chemical Pharmacology, Inostrannaya literatura, 106, 1959.

2. Y. M. Beasley, Miss., V. Petrow, O. Stephanson. Certain 1-alkyl-3-aroylureas. J. Pharmacy and Pharmacol. 13, 694–697, No. 11, 1961.

3. Beilstein. Handbuchs organischen Chemie. Berlin, IV Aufl. 12, 356, 1925.

4. N. D. Pryanishnikov. Laboratory Manual in Organic Chemistry, Moscow, Goskhimizdat, 155, 1956.

5. F. Beilstein. Handbuchs organischen Chemie. Berlin, III Aufl. 4, 144, 1902.

6. L. P. Kulev, N. S. Dobychina. N,N′-benzylacyl derivatives of urea. ZhVKhO VIII, 701, 6, 1963.