Azo Derivatives of Barbituric and Thiobarbituric Acids and Their Physiological Activity

L. P. Kulev, K. R. Voronova

Among medicinal preparations with hypnotic and anticonvulsant action, such derivatives of barbituric acid as veronal, luminal, barbamyl, hexenal, and others have long been in use.

The study of a large number of derivatives of barbituric acid has made it possible to establish a certain dependence between their structure and the character of their physiological action. Thus, for example, it has been shown that the introduction of two alkyl radicals at the carbon in the 5-position of barbituric acid imparts hypnotic action to the compound, whereas replacement of one alkyl radical in the same position by phenyl leads to the appearance of anticonvulsant properties. A rapidly developing, but short-lived, hypnotic effect is observed in barbiturates with an alkyl radical at nitrogen; an enhancement of anticonvulsant action occurs when this radical is replaced by an acyl residue [1]. Derivatives of thiobarbituric acid have been studied to a considerably lesser extent, especially with regard to their anticonvulsant action.

To clarify the relationship between the structure and physiological properties of barbiturates and thiobarbiturates, their azo derivatives may be of considerable interest, since by means of the readily effected coupling reaction it is possible to obtain azo compounds of varied structure.

In the patent literature, comparatively few azo dyes based on the above-mentioned acids have been described, and the authors provide no information on the physiological activity of the compounds obtained [2].

In order to determine the influence of substituents on the physiological activity of barbiturates and thiobarbiturates, we studied a large series of azo derivatives of barbituric and thiobarbituric acids. As azo components, both the acids themselves and some of their derivatives obtained by condensation of the corresponding esters with urea or thiourea were used; the diazo components were aromatic amines, aminocarboxylic acids, and aminosulfonic acids.

Pharmacological tests of the azo compounds obtained were carried out under the direction of Professor of the Tomsk Medical Institute E. M. Dumenova.

It should be noted that in a number of cases other regularities were observed than those which occur for derivatives of barbituric—

barbituric and thiobarbituric acids that do not contain an azo group. For example, 5-phenylbarbituric acid has no anticonvulsant action, whereas 5-phenylazobarbituric acid exhibits this action to a rather considerable degree, and it is intensified still further by introducing a second phenyl radical at C\(_5\) into the molecule of the same azo compound.

Carboxyl and sulfo groups exert a distinctive influence on the physiological properties of azo compounds. It is known that the introduction of these groups into the molecule of a hypnotic is usually accompanied by an increase in its solubility in water and by a marked weakening or complete disappearance of the soporific action. In a number of the azo derivatives studied by us, the opposite phenomenon is observed: with the introduction of a carboxyl group into the para position relative to the azo group in the benzene ring of the diazo component, the soporific action of the preparation is enhanced, whereas the anticonvulsant action, on the contrary, is almost completely lost. However, this influence of the carboxyl group does not extend to the ortho and meta isomers, which have the same properties as the azo derivatives of barbituric acid without a carboxyl group, i.e., clearly expressed anticonvulsant, but not soporific, properties. The position of acidic groups in the naphthalene ring of azo derivatives of barbituric acid has almost no effect: all of them, despite their considerable solubility in water, possess soporific action. In general, replacement of the carboxyl group by a sulfo group is in all cases accompanied by a decrease in the physiological activity of the azo derivatives.

A substantial difference in the properties of azo derivatives is also observed in other cases. Thus, whereas alkylation of the methylene radical of barbituric acid, as a rule, leads to an enhancement of the hypnotic effect, in azo derivatives it almost always has a negative influence on this effect. The weakening of soporific properties is also promoted by replacement of the carboxyl group by hydroxyl and by esterification of this group, irrespective of its position in the benzene ring of the diazo component. The nature of the azo component is only slightly reflected in the physiological activity of the preparations; however, the anticonvulsant properties are nevertheless more strongly expressed in the azo derivatives of barbituric acid, whereas the soporific properties are more strongly expressed in the azo derivatives of thiobarbituric acid. The most active of all the compounds tested in terms of anticonvulsant action proved to be

\[ \mathrm{I}\quad \begin{array}{c} \ce{O=C} \end{array} \begin{array}{c} \displaystyle \begin{matrix} & \ce{O} & \\ & \Vert & \\ \ce{NH}-\ce{C} & & \ce{C}(-\ce{C6H5})(-\ce{N=N}-\ce{C6H5})\\ \ce{NH}-\ce{C} & & \\ & \Vert & \\ & \ce{O} & \end{matrix} \end{array} , \]

\[ \mathrm{II}\quad \begin{array}{c} \ce{O=C} \end{array} \begin{array}{c} \displaystyle \begin{matrix} & \ce{O} & \\ & \Vert & \\ \ce{NH}-\ce{C} & & \ce{CH}-\ce{N=N}-\ce{C10H7}\\ \ce{NH}-\ce{C} & & \\ & \Vert & \\ & \ce{O} & \end{matrix} \end{array} , \]

and as a hypnotic

\[ \text{III.}\quad \begin{array}{c} \text{5-ethyl-5-(}p\text{-carboxyphenylazo)-2-thiobarbituric acid structure} \end{array} \]

Despite the comparatively high physiological activity of the indicated compounds, their use as medicinal preparations cannot be considered advisable because of the possible (especially for II) carcinogenic action.

All azo derivatives were obtained by known methods, by coupling diazotized amino compounds with barbituric and thiobarbituric acids. They are amorphous powders or fine crystals, ranging in color from yellow to dark brown. They are very slightly soluble in water and considerably more soluble in acetone, alcohol, and other common organic solvents. Azo compounds containing a sulfo group or a carboxyl group (in the diazo component) give alkali salts that are readily soluble in water.

The properties of the azo derivatives obtained are presented in the table.

Table

Azo derivatives of barbituric and thiobarbituric acids

\[ \begin{array}{c} \displaystyle \begin{matrix} & \mathrm{NH{-}CO} & \mathrm{R_1}\\[-2mm] \mathrm{X}=\mathrm{C} & & \mathrm{C}\\[-2mm] & \mathrm{NH{-}CO} & \mathrm{N{=}N{-}R_2} \end{matrix} \end{array} \]

Table (continued)

Table (continued)

Table (continued)

Conclusions

A series of azo derivatives of barbituric and thiobarbituric acids has been obtained. The relationship between the structure and the pharmacological properties of these derivatives has been studied. It has been found that the azo derivatives differ substantially in the character of their physiological action from the barbiturates and thiobarbiturates of analogous structure that do not contain an azo group.

LITERATURE

1. Henze H., Spurlock J. J. Am. Chem. Soc., 63, 3310, 1948.
2. U. S. 2140536, C. A. 1939, 33, 2725; AP 2140537, C. A. 33, U. S. 2140538, C. A. 1939, 33, 2725; U. S. 2121811, 1938, 32, 3163; Fr. 834538, C. A., 1939, 33, 4046; U. S. 2476259, C. A. 1949, 43, 9464.