SYNTHESIS OF \(N\)-ARYLALKYL-\(N'\)-ACYL DERIVATIVES OF UREA AND THEIR PHARMACOLOGICAL ACTIVITY

Communication 2

A. G. PECHENKIN, L. G. TIGNIBIDINA

(Presented by the Scientific-Methodological Seminar of the Faculty of Chemical Technology)

We previously described syntheses [1] of urea derivatives substituted in the \(N\)-position by the benzhydryl radical \((\mathrm{C_6H_5})_2\mathrm{CH}-\) and in the \(N'\)-position by acyl residues of fatty acids from \(\mathrm{C_2}\) to \(\mathrm{C_5}\), which differ from benzylacyl derivatives of urea—compounds that showed significant anticonvulsant activity—in that the hydrogen atom in the \((\mathrm{CH_2})\) group of the benzyl radical is replaced by a phenyl radical.

Some derivatives of \(N\)-benzhydrylurea also showed high activity against seizures induced by electroshock.

As is known [2], introduction of a second phenyl radical into the 5-position of the luminal and hydantoin molecule increases their anticonvulsant action to a lesser degree than introduction into the same position, instead of a phenyl radical, of an alkyl group with a small number of carbon atoms.

The aim of the present work is the synthesis and study of the anticonvulsant activity of urea derivatives in which branched arylalkyl radicals are contained in the \(N\)-position and acyl residues of carboxylic acids in the \(N'\)-position:

\[ \begin{array}{c} \mathrm{R}\backslash \\ \quad \mathrm{CH{-}HN{-}C{-}NH{-}CO{-}R} \\ \mathrm{C_6H_5}/ \qquad \| \\ \qquad\qquad \mathrm{O} \end{array} \]

The synthesis of the indicated derivatives was carried out by condensation of the corresponding amine with nitrourea and subsequent acylation of the resulting \(N,N'\)-arylalkylureas with fatty acids. In this way the following were obtained:

1) \(\alpha\)-phenylethylurea,
2) \(\alpha\)-phenylethylacetylurea,
3) \(\alpha\)-phenylethylpropionylurea,
4) \(\alpha\)-phenylethylvalerylurea,
5) \(\alpha\)-phenylethylbutyrylurea,
6) \(\alpha\)-phenylethylisovalerylurea.

When tested for anticonvulsant activity, all the derivatives obtained showed high activity against electroshock seizures in mice.

Experimental Part

α-Phenylethylurea [1]. 50 g of nitrourea is dissolved in 1000 ml of water, 48 ml of α-phenylethylamine is added, and the mixture is heated for 0.5 h at 50°C in a water bath. After standing for 48 h at room temperature, a white precipitate of α-phenylethylurea separates from the solution. The precipitate is filtered off, the filtrate is evaporated on a water bath, and an additional amount of α-phenylethylurea is obtained; this is combined with the first portion and washed with ether. After two recrystallizations from water, the yield of the final product is 54.6 g (90% of theory), mp 138°C.

Found, %: N — 17.47; calculated, %: N — 17.07.

Acylation of (I) was carried out with acids in the presence of PCl₃ in benzene according to the method described [3]. The resulting N-α-phenylethyl-N′-acylureas are white crystalline products.

N,N′-α-Phenylethylacetylurea (II) was obtained from 10 g of (I), 3.4 ml of PCl₃, and 7 ml of glacial acetic acid. Yield of the technical product: 12.1 g (97% of theory); yield of the purified product: 7.2 g (57.6% of theory), mp 70–71°C. Recrystallization is carried out from an alcohol–water mixture, 1:1.

Found, %: C — 64.42, H — 6.92; calculated, %: C — 64.08, H — 6.79.

N,N′-α-Phenylethylpropionylurea (III) was obtained from 15 g of (I), 5.4 ml of PCl₃, and 13.7 ml of propionic acid. Yield of the technical product: 13.4 g (67% of theory); yield of the purified product after 4 recrystallizations from an alcohol–water mixture, 2:1: 7 g (34.8% of theory), mp 99–100°C.

Found, %: C — 65.8, H — 7.4; calculated, %: C — 65.45, H — 7.27.

N,N′-α-Phenylethylvalerylurea (IV) was obtained from 8 g of (I), 2.9 ml of PCl₃, and 10.6 ml of valeric acid. Yield of the technical product: 10.2 g (90% of theory); yield of the purified product: 8 g (66% of theory), mp 37–38°C. Recrystallization is carried out from an alcohol–water mixture, 2:1.

Found, %: N — 11.41; calculated, %: N — 11.29.

Similarly obtained were: N,N′-α-phenylethylbutyrylurea, mp 35°C (nitrogen found 12.5%, calculated 11.96); N,N′-α-phenylethylisovalerylurea — an oil (nitrogen found 11.02%, calculated 11.29%); N,N′-α-phenylethylbenzoylurea, mp 136°C (nitrogen found 10.62%, calculated 10.44%).

References

1. A. G. Pechenkin, L. G. Tignibidina, N. S. Dobychina, L. I. Vodopyanova, see the present collection.
2. R. Barlow. Introduction to Chemical Pharmacology. Moscow, IL, 523, 1949.
3. N. S. Dobychina, A. G. Pechenkin, L. G. Tignibidina. Author’s Certificate No. 188957 of December 29, 1965.