SYNTHESIS AND STUDY OF SOME UREIDO ACIDS AND THEIR DERIVATIVES

A. G. PECHENKIN, A. V. EVSEEVA, A. P. GILEV, T. V. MIKHAILOVA

(Submitted by the scientific-methodological seminar of the organic departments, KhTF)

It is known [1] that some arylalkylureas and their acyl derivatives possess high anticonvulsant activity.

At the same time, the literature contains data on the anticonvulsant action of a number of amino acids, especially γ-aminobutyric acid [2, 3].

It seemed of interest to obtain a series of compounds in which the basic structure of the active amino acid would be preserved, but a urea fragment would be introduced in place of the amino group, and thus to trace the influence of this fragment on the anticonvulsant activity of the compounds obtained.

Ureido acids were obtained by us by two known methods: by the reaction of amino acids with urea [4] and by the reaction of amino acids with sodium cyanate [5].

The results of the experiments show that the yields of purified reaction products in the interaction of amino acids with sodium cyanate are 40–67.1%, and in the reaction with urea, 43–61%; i.e., they are practically identical.

The preparation of ureido acids by interaction of amino acids with sodium cyanate, by boiling on a water bath for 4 hours in an aqueous medium, is preferable, since in this case purer products are obtained, requiring fewer recrystallizations.

The compounds obtained and some of their characteristics are given in Table 1.

All the ureido acids obtained are white crystalline substances, readily soluble in water and less readily soluble in alcohol.

Tests of the preparations (Table 2) showed that they do not possess anticonvulsant activity. Consequently, replacement of the amino group in an amino acid by urea removes the anticonvulsant activity of the starting amino acids.

Experimental Part

α-Ureidobutyric acid.
1. Obtained by heating for 15 hours under reflux on a boiling water bath 2.06 g (0.02 g-mol) of α-aminobutyric acid and 15.6 g (0.26 g-mol) of urea in 50 ml of water, followed by acidification of the reaction mixture with conc. HCl to a strongly pronounced acidic reaction. After recrystallization from a water–alcohol mixture (1:2), yield 1.28 g (44%).

Table 1

1. The same ureido acid was obtained by the reaction of 2.62 g of \(\alpha\)-aminobutyric acid and 1.3 g of sodium cyanate in 50 ml of water, after standing for 60 h in a closed vessel at room temperature, followed by acidification of the reaction mixture according to universal indicator paper. Yield of purified product, 1.48 g (40%); \(T_{\mathrm{m}}\) = 165—167°C after recrystallization from an alcohol:water mixture (5:1).

\(\gamma\)-Ureidobutyric acid.

1. Obtained from 2.06 g of \(\gamma\)-aminobutyric acid and 13.5 g of urea in 50 ml of water, acidified with 1.5 ml of conc. HCl to pH 3, by heating for 15 h on a boiling water bath. Yield, 1.69 g (59%) after two recrystallizations from an alcohol:water mixture (4:1).

2. The same ureido acid was obtained from 2.06 g of \(\gamma\)-aminobutyric acid and 1.3 g of sodium cyanate in 40 ml of water by heating for 4 h on a boiling water bath. Yield, 1.7 g (59.3%) after two recrystallizations from alcohol:water (5:1); m.p. 166.5—168°C.

Table 2

α-Ureido-n-valeric acid was obtained from 1.17 g of dl-norvaline and 0.65 g of sodium cyanate in 30 ml of water by keeping the mixture in a closed vessel at room temperature for 48 hours, followed by acidification of the reaction mixture with conc. HCl to a strongly acid reaction on universal indicator paper. After recrystallization from alcohol, the yield was 0.71 g (44.4%).

α-Ureidoisovaleric acid was obtained from 1.17 g of dl-valine and 0.65 g of sodium cyanate in 30 ml of water by standing in a closed vessel for 48 hours at room temperature and acidifying with conc. HCl to pH 2. Yield 0.60 g (40%) after two recrystallizations from alcohol.

α-Ureido-n-caproic acid was obtained from 2.72 g of dl-norleucine and 15.6 g of urea in a mixture of 100 ml of water and 20 ml of ethyl alcohol by heating for 15 hours on a boiling water bath, followed by acidification of the reaction mixture to an acidic medium. Yield 2.2 g (61%) after recrystallization from an alcohol:water mixture (5:1).

α-Ureidoisocaproic acid.
1. Obtained by heating a mixture of 1.31 g of dl-leucine and 12 g of urea in 50 ml of water for 15 hours on a boiling water bath, followed by acidification to pH 2. Yield 0.7 g (43%) after two recrystallizations, first from a water–alcohol mixture (4:1), and then from alcohol.

1. The same ureido acid was obtained from 1.31 g of dl-leucine and 1.3 g of sodium cyanate in 50 ml of water by standing at room temperature for 3 days, followed by acidification. Yield after recrystallization from alcohol 1.1 g (67.1%); however, the melting point of the substance, compared with that obtained by the first method, was 3°C higher and was 186–187°C.

β-Phenyl-β-ureidopropionic acid.
1. Obtained from 3.3 g of β-phenyl-β-alanine and 15.6 g of urea in 100 ml of water by heating on a boiling water bath for 15 hours and acidifying the reaction mixture. Yield 1.05 g (25%) after two recrystallizations from an alcohol:water mixture (4:1).

1. The same ureido acid was obtained from 3.3 g of β-phenyl-β-alanine and 1.3 g of sodium cyanate in 80 ml of water by heating for 4 hours on a boiling water bath and acidifying the reaction medium with conc. hydrochloric acid. Yield 2.5 g (60%) after recrystallization from alcohol; in this case the melting point was 2°C higher than that of the substance obtained by the first method.

The compounds described above were tested for anticonvulsant activity in the pharmacology laboratory of the Novokuznetsk Scientific Research Chemical-Pharmaceutical Institute by the electroshock test and by the corazole seizure threshold.

The data of the pharmacological tests are presented in Table 2 and show that the ureido acids are inactive.

Conclusions

1. On the basis of amino acids possessing anticonvulsant activity, seven ureido acids were synthesized.

2. The obtained preparations do not possess anticonvulsant activity; consequently, replacement of the amino group in an amino acid by urea abolishes their anticonvulsant action.

Literature

1. N. S. Dobychina, dissertation, Tomsk, 1966.
2. Kazumichi, Tsuchiya, Fuhuya Magashi. Nippon Seirigaki Zasshi, 22, 704 (1960); Ch. Abst., 54, 14478, i. (1960).
3. Merck SCO, Inc. Brit., 792, 576, April 2, (1958); Ch. Abst., 2108 i, 53, (1939).
4. N. G. Chernova, E. I. Rybkina, A. Ya. Berlin. ZhORKh, 1, 599 (1965).
5. I. Guben. Methods of Organic Chemistry. Goskhimizdat, IV, issue 1, second quarter, 923 (1948).