Complex Compounds of Uric Acid with Amines

L. I. Kulev, A. V. Boldyreva

The study of complex compounds of uric acid is not only of theoretical interest, but may also have great practical significance, since complex-formation reactions involving this acid may be used as the basis for the search for new anti-gout preparations.

Indeed, from the literature data it follows [1–5] that uric acid readily gives, with substances of a basic character, salt-like compounds which in most cases possess significantly better solubility in water than the acid itself. Organic bases deserve special attention here, since it is precisely among them that substances with valuable therapeutic properties may be found.

Taking into account that the question of the relationship between complex formation and the solubility of uric acid in solutions of organic substances is of undoubted interest and has been very little covered in the literature, we set ourselves the goal of studying the properties of salt-like compounds of this acid with certain amines and amino alcohols.

To assess the comparative complex-forming ability of substances and to determine the composition of the complexes formed, physicochemical methods of investigation were used (electrical conductivity, viscosity, and density), which have proved successful in a number of analogous cases [6].

According to the data obtained, uric acid forms complex compounds with aliphatic amines of composition 1:1, and with heterocyclic amines—1:2 [7]. Some of the complexes detected by physicochemical methods proved to be sufficiently stable and were isolated in the crystalline state from aqueous solutions of the initial substances. Analysis for nitrogen and decomposition with mineral acids and alkalis into the individual components confirmed the above-indicated composition of the complexes. All the complexes obtained by us are readily soluble in hot water and considerably less so in cold water; they dissolve in aqueous solutions of alcohol, acetone, dioxane, artificial serum, and are almost insoluble in ether, absolute alcohol, chloroform, and carbon tetrachloride.

The composition and properties of some of the complexes studied by us are presented in Table 1.

Complex compounds of uric acid

Table 1

It is evident from the table that the character of the amine has a substantial influence on the solubility of the complex in water; namely, primary and secondary amines have an undoubted advantage over tertiary amines, and the character of the hydrocarbon radicals at the nitrogen also plays a very substantial role. Thus amino compounds with ethyl groups impart to the complex a considerably better solubility than those with methyl groups, especially in the case of secondary aliphatic amines and amino alcohols (2 and 5, 9 and 10 in Table 1). An analogous phenomenon was observed by Greimor for compounds of uric acid with trimethyl- and triethyltrimethylenediamines [5]; however, its essence still remains unclear. A substantial difference is also observed with respect to the thermal stability of the complex compounds of uric acid with amines.

To determine the thermal stability of these compounds, we used the thermographic method of investigation, which only comparatively recently began to be applied to the study of organic systems [8].

The heating curves were recorded with an apparatus equipped with a self-recording SG-200 galvanometer, a differential copper–constantan thermocouple, and a GPZ-53 mirror galvanometer with visual readout [7]. Sodium chloride served as the standard; it gives no transformation points in the temperature interval of interest to us (from 20 to 400°C).

Horizontal portions on the differential curve indicate the absence of processes accompanied by thermal effects; a downward deviation of the curve indicates the presence of endothermic processes, and an upward deviation indicates exothermic processes in the substance being tested. Of the individual starting compounds, only uric acid itself and alpha-aminopyridine were studied, since all the other amino compounds are either gases or liquids, i.e., their presence in the complexes in free form is excluded.

The thermogram of uric acid is characterized by two minima (in the temperature regions 300–340° and 400–425°), of which the first is taken by us as the beginning of decomposition of this acid or of some other deep transformations connected with a change in the structure of the compound; the second corresponds to its complete decomposition (Fig. 1).

Fig. 1.
Heating curves of complex compounds of uric acid with amines.
1—uric acid, 2—uric acid–methylamine, 3—uric acid–dimethylamine, 4—uric acid–trimethylamine, 5—uric acid–ethylamine, 6—uric acid–diethylamine, 8—uric acid–butylamine, 9—uric acid–hydrazine hydrate, 10—uric acid–ethylenediamine, 11—uric acid–dimethylaminoethanol, 12—uric acid–diethylaminoethanol.

Comparison of the thermograms shows that complex compounds of uric acid with primary and secondary amines having identical radicals, and also with dialkylaminoethanols, as a rule are distinguished by higher thermal stability than the complexes of the same acid with tertiary amines.

Thus, the complex with trimethylamine begins to decompose already at \(100—110^\circ\), whereas the complex with dimethylamine only at \(240^\circ\); moreover, it is characterized by a more gradual decline of the curve. The latter circumstance indicates a small temperature coefficient of the rate of thermal decomposition, which is often observed for compounds with a coordination bond, for example, for crystalline hydrates [9]. It should also be noted that the curves of thermal decomposition of the complex compounds of uric acid with diethylamine and diethylaminoethanol are very similar to one another: both have three sharply expressed minima, which is not observed for the other complexes studied by us, including the complex with dimethylaminoethanol. Thus, the substantial difference in the solubility and thermal stability of the complex compounds studied indicates the different structure of these compounds, which may be represented on the basis of the following considerations.

Uric acid, reacting in its enol form, adds a molecule of amine by means of a hydrogen bond. The labile hydrogen atom of the nitrogen of uric acid, by its free electrons, attracts the covalently bound proton of the amine, as a result of which closure of a six-membered ring occurs.

\[ \begin{array}{c} \begin{array}{cccccc} \mathrm{HN} & \cdots & \mathrm{CO} \\ | && | \\ \mathrm{OC} && \mathrm{C}-\mathrm{NH} \\ | && \Vert & \backslash \\ \mathrm{HN} & - & \mathrm{C} & \cdots & \mathrm{N} & \displaystyle \genfrac{}{}{0pt}{}{\mathrm{C}-\mathrm{O}}{} \\ &&&& \cdots & \backslash \\ &&&& \mathrm{H}-\mathrm{N}-\mathrm{Alk} \\ &&&& | \\ &&&& \mathrm{Alk} \end{array} \end{array} \]

\[ \begin{array}{c} \begin{array}{cccccc} \mathrm{HN} & \cdots & \mathrm{CO} \\ | && | \\ \mathrm{OC} && \mathrm{C} & \mathrm{NH} \\ | && \Vert & \backslash \\ \mathrm{HN} & - & \mathrm{C} & - & \mathrm{N} \displaystyle \genfrac{}{}{0pt}{}{\mathrm{C}-\mathrm{OH}}{} \\ &&&&& \cdots \\ &&&& \mathrm{H}-\mathrm{N}-\mathrm{Alk} \\ &&&& | \\ &&&& \mathrm{Alk} \end{array} \end{array} \]

The formation of stable rings also explains the comparatively high thermal stability of complexes of uric acid with secondary amines; the complexes with primary aliphatic and certain heterocyclic amines, for example piperidine and piperazine, must have an analogous structure.

The complex of uric acid with piperazine was obtained by Maertens and Schmidt [2] and has a composition of 1:1, despite the fact that piperazine contains two equivalent imino groups.

In the case of tertiary amines that do not contain hydrogen atoms attached to nitrogen, a cyclic structure of the complex is excluded, i.e., the components constituting it are bound to one another by one secondary valence.

\[ \begin{array}{ccccc} \mathrm{HN}—\mathrm{CO} \\ \ \ | \qquad | \\ \mathrm{OC}\qquad \mathrm{C}—\mathrm{NH} \\ \ \ | \qquad \| \qquad \backslash \\ \mathrm{HN}—\mathrm{C}—\mathrm{N}=\mathrm{C}—\mathrm{OH}\ldots \mathrm{N}(\mathrm{Alk})_{3} \end{array} \]

The dependence between the complex-forming ability of substances and their solubility is confirmed in other cases as well.

Thus, the ability of benzene to dissolve in anhydrous hydrogen fluoride is explained by the possibility of formation of an electron-donor bond between these substances; alkanes and cycloalkanes, which show a lesser tendency toward complex formation, do not dissolve in anhydrous hydrogen fluoride [10]. By analogy with these data, the solubility of uric acid, which exhibits predominantly electron-acceptor functions, will also depend on the electron-donor properties of amines, in other words, on their complex-forming ability. According to Brown [11], the strongest electron-donor properties are possessed precisely by secondary aliphatic amines; after them come primary amines and, finally, tertiary amines, which is in good agreement with the results of our experiments on determining the solubility and thermal stability of the corresponding uric acid complexes.

In the case where the molecule of the amino compound contains several nitrogen atoms with different electron-donor ability, those most active among them should enter first into the complex-formation reaction. For example, of the three nitrogen atoms of guanidine, preference should be given to the nitrogen of the imino group as the carrier of the basic properties of this compound [12]. Therefore the complex of guanidine with uric acid must be constructed according to the type of complexes of secondary aliphatic amines, i.e., have a cyclic structure.

\[ \begin{array}{cccc} \mathrm{HN}—\mathrm{CO} \\ \ \ | \qquad | \\ \mathrm{OC}\qquad \mathrm{C}—\mathrm{NH} \\ \ \ | \qquad \| \qquad \backslash \\ \mathrm{HN}—\mathrm{C}—\mathrm{N}=\mathrm{C}—\mathrm{O}—\mathrm{H} \\ \qquad\qquad\qquad\quad \cdots \qquad \cdots \\ \qquad\qquad\qquad\quad \mathrm{H}—\mathrm{N} \\ \qquad\qquad\qquad\qquad | \\ \qquad\qquad\qquad \mathrm{H}_{2}\mathrm{N}—\mathrm{C}—\mathrm{NH}_{2} \end{array} \]

The verification we carried out confirmed this assumption: the complex of uric acid with guanidine has a composition of 1:1, possesses high thermal stability and considerable solubility in water. The fact that the complexes with dialkylaminoethanols are very close in their properties to the complexes of secondary amines argues for their structural similarity, although the aminospirits mentioned, like tertiary amines, do not contain unsubstituted hydrogen atoms attached to nitrogen.

It is possible that in this case there is formation of more complex multinuclear rings with a nonplanar configuration, in the forma-

in which the hydrogen of the hydroxyl group of the amino alcohol participates. However, additional investigations are necessary for a final resolution of this question.

Assessing the experimental data obtained by us from the point of view of their use in the search for new anti-gout agents, it may be said that, among the substances studied, diethylamine and diethylaminoethanol might be of the greatest interest in this respect. However, their use as medicinal preparations is precluded because of their comparatively high toxicity.

According to Leleti [13], the toxicity of alkylamines and amino alcohols is considerably reduced if they are used not in the free state, but in the form of salts—or, more precisely, complex compounds—with carboxylic acids, for example with p-aminobenzoic acid.

Taking into account that certain aromatic and heterocyclic carboxylic acids themselves exert a favorable action in the treatment of gout, we prepared a series of salts of aliphatic amines with salicylic acid and atophan (2-phenylquinoline-4-carboxylic acid). The properties of some of them are presented in Table 2.

Salts of salicylic acid and atophan with amines

Table 2

All the salts are readily water-soluble crystalline or syrup-like substances of neutral character. Experiments on the hydrolysis of salts of diethylamine with salicylic acid and atophan showed that the solubility of uric acid increases noticeably as they undergo hydrolytic cleavage. On this basis one may expect that, in the living organism as well, such salts will be subject to cleavage, liberating the amine and the acid; the former will give with uric acid a water-soluble complex, while the latter (salicylic acid or atophan), as is generally accepted [14, 15], will exert a stimulating action on the excretory system of the organism, promoting the elimination of endogenous uric acid. Apparently it is precisely such a mechanism of action that is possessed by dimonosalicylate piperazine, obtained by Bonelli [16] and tested under clinical conditions.

On the basis of our experiments with amino alcohols, among which diethylaminoethanol showed especially good results, one may expect that replacement of piperazine by its hydroxyethyl derivatives will contribute to an enhancement of the therapeutic action of such salts.

The preparation and comprehensive study of them will be the subject of our further work.

Conclusions

1. Sixteen complex compounds of uric acid with amines and amino alcohols have been isolated and studied. It has been established that the complexes of secondary aliphatic amines, as well as dialkylaminoethanols, are distinguished by considerably better solubility in water and higher thermal stability than the complexes of primary and especially tertiary amines.

2. Considerations are set forth concerning the structure of complex compounds of uric acid with amines and the avenues for searching for new antigout agents.

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