Some Complex Compounds of the Acridine Series and Their Therapeutic Activity

A. G. Pechenin

(Presented by Professor, Doctor of Chemical Sciences L. P. Kulev)

In the treatment of certain skin diseases, lotions prepared from solutions of bactericidal dyes and ointments whose active principle consists of various salts of mercury, silver, and other metals are widely used. Thus, trypaflavine, rivanol, and silver nitrate are widely used for the treatment of infected wounds and trophic and varicose ulcers. Mercury salts also have a beneficial effect in psoriasis [1].

However, the external application of mercury salts—for example, in the treatment of psoriasis—is always limited to only small areas of affected skin, since their considerable absorbability and high toxicity make these compounds unsuitable for treating large affected surfaces.

It is known that, as a result of complex-formation reactions, compounds are often obtained that are considerably less toxic than the starting components [2].

It therefore seemed of interest to obtain complex compounds consisting of two active components and to test them in the treatment of certain skin diseases.

As the first component of the complexes, dyes of the acridine series—trypaflavine and rivanol—were selected, and as the second component, mercury rhodanide potassium and silver rhodanide potassium.

In pharmacological tests of the complex compounds obtained by us, it was established that their toxicity for guinea pigs is 5–10 times lower than the toxicity of the original organic component. Such a decrease in toxicity is apparently explained by the fact that the indicated complex compounds possess a low degree of dissociation and high hydrolytic stability. Although the absolute value of the degree of dissociation was not determined for the complexes obtained, the value of the specific electrical conductivity of these compounds, measured by Kohlrausch’s method at a temperature of 80°C, averaged \(3.79 \cdot 10^{-5}\) reciprocal ohm. This order of magnitude of the specific electrical conductivity indicates an insignificant degree of dissociation of the substances tested. After a 6-hour exposure at 80°, the electrical conductivity of the solutions of the indicated complex compounds increased by only 0.5%, i.e., under these conditions the complexes practically did not undergo hydrolysis, which testifies to their fairly high stability. In clinical testing of the complex compounds of trypaflavine with mercury rhodanide potassium (preparation No. 57) and rivanol with mercury rhodanide potassium (preparation No. 71), no noticeable difference was found in their action in treating patients with psoriasis.

Of 60 patients with squamous lichen treated with preparations No. 57 and No. 71, in most cases a therapeutic effect was obtained. The preparations were used in the form of two- and five-percent ointments on small and large areas of affected skin; at the same time, no complications of any kind were noted in any of the patients.

The complex compounds of trypaflavine with silver rhodanide potassi-

with it (preparation No. 24) and rivanol with potassium silver rhodanide (preparation No. 24A) were tested in 28 patients in the treatment of trophic, varicose, and pyogenic ulcers. No appreciable difference in the action of these preparations was found either. Complete healing was noted in 18 patients, considerable improvement in four, improvement in three patients, no effect in three patients (2 pyogenic and 1 trophic ulcer), and recurrences were observed in five patients with varicose ulcers.

Preparations No. 24 and 24A were used as lotions from solutions of 1:5000 and 1:10 000.

All the indicated preparations were tested in the Clinic of Skin and Venereal Diseases of the Tomsk Medical Institute under the direction of Professor I. S. Beirakh.

Experimental Part

I. Preparation of the complex compound of trypaflavine with potassium mercuric rhodanide.

3.16 g of mercuric rhodanide are added to a solution of 3 g of potassium rhodanide in 20 ml of water. The resulting clear, colorless solution of potassium mercuric rhodanide is gradually added to a solution of 2.6 g of 10-chloromethyl-3,6-diaminoacridine (trypaflavine) in 100 ml of water. The yellow-orange precipitate formed is filtered off, thoroughly washed with warm water, and dried. The yield is quantitative. Melting point 175–178°. A yellow powder with an orange tint, poorly soluble in water and alcohol.

Found: mercury—29.32%; tested under No. 57.

II. Preparation of the complex compound of rivanol with potassium mercuric rhodanide.

The preparation was obtained analogously to I from a solution of 6.16 g of potassium mercuric rhodanide in 20 ml of water and a solution of 3.43 g of rivanol. The yield is quantitative. Melting point 160–163°. A yellow powder, poorly soluble in water and alcohol.

Found: mercury—29.53%. Tested under No. 71.

III. Preparation of the complex compound of trypaflavine with potassium silver rhodanide.

To a solution of 2 g of potassium rhodanide in 10 ml of water, 1.65 g of freshly prepared silver rhodanide is added in small portions. The resulting solution is poured in a thin stream, with vigorous stirring, into a solution of 5 g of trypaflavine in 100 ml of water. The complex compound immediately precipitates in the form of orange crystals.

After recrystallization from hot water, the product has a melting point of 135°. Yield 4.7 g (90%).

Found: silver—13.78%. Tested under No. 24.

IV. Preparation of the complex compound of rivanol with potassium silver rhodanide.

Preparation No. 24A was obtained analogously to III from a solution of 3.65 g of potassium silver rhodanide in 15 ml of water and a solution of 6.9 g of rivanol in 200 ml of water. After recrystallization from hot water, the product had a melting point of 167°. Yield 83%. Found: silver—13.16%.

Conclusions

1. Complex compounds of trypaflavine and rivanol with potassium mercuric rhodanide and with potassium silver rhodanide have been obtained.

2. Preliminary pharmacological and clinical data show that the complex compounds obtained have lower toxicity than the starting products and exert a therapeutic effect in the treatment of psoriasis and trophic and varicose ulcers.

References

1. Selisskii, A. B. Treatment of Skin Diseases and Prescription Writing. Academy of Sciences of the BSSR. Minsk, 1955.

2. Lepetit, S. Methods for preparing salts of p-aminobenzoic acid with alkylamines and aminopyridines. RZhKh, 8440, 1955.