SEARCH FOR NEW ANTI-INFLAMMATORY AGENTS IN THE SERIES OF ACETYL DERIVATIVES OF ISOPROPYLAMINOANTIPYRINE

G. M. STEPNOVA, G. A. TERENT’EVA, V. M. STEPANENKO

(Presented by the scientific seminar of the Chemical-Technological Faculty)

Derivatives of 1-phenyl-3-methyl-5-pyrazolone are widely known in medical practice as effective antipyretic, anti-inflammatory, and analgesic agents. Thus, the methyl derivative of phenylmethylpyrazolone—antipyrine—has high antipyretic activity, but because of its toxicity it has not come into widespread use. Numerous modifications of the antipyrine structure have been associated with substitutions at the active 4-position.

Studies of monoalkyl derivatives of antipyrine have shown that few of them have any advantage over antipyrine itself [1]. The exception is isopropyl-antipyrine, which possesses a strong analgesic, antipyretic, and spasmolytic effect [2]. This drug, in combination with caffeine and phenacetin, is widely used in foreign medical practice.

High activity has been shown by preparations containing an alkylated amino group in the 4-position. Mono- and dialkylation of aminoantipyrine has led to the preparation of potent medicinal agents such as amidopyrine, analgin, and melubrin, which currently play a leading role in rheumatic therapy. Studies [3] have shown that introduction of an alkyl radical into the amino group of aminoantipyrine very strongly increases the analgesic effect. Thus, for example, isopropylaminoantipyrine, in analgesic activity, exceeds antipyrine and aminoantipyrine by more than a factor of two.

On the other hand, pharmacological tests of numerous acyl derivatives of aminoantipyrine have shown that the most characteristic properties for these compounds are anti-inflammatory and antipyretic properties; moreover, some of them surpass amidopyrine and butadione in specific activity, but all are inferior to amidopyrine and analgin in the strength of their analgesic action [4].

\[ \begin{array}{c} \mathrm{H_3C{-}C{=}C{-}N\langle^{CH(CH_3)_2}_{Ac}}\\ \quad | \qquad |\\ \mathrm{H_3C{-}N \quad C{=}O}\\ \quad \backslash \quad /\\ \mathrm{N}\\ |\\ \mathrm{C_6H_5} \end{array} \]

Therefore, it is of interest to synthesize derivatives of aminoantipyrine in which one hydrogen atom in the amino group is replaced by an isopropyl group, and the other by an acyl group:

Only two have been described in the literature.

acyl derivatives of isopropylaminoantipyrine—N-piperidyl-4-isopropylaminoantipyrine and N-methylpiperidyl-4-isopropylaminoantipyrine, which possess physiological activity [5].

The present work describes the synthesis of N-isopropylantipyrylamides of certain aromatic, fatty, and heterocyclic acids.

The synthesis of N-isopropylaminoantipyrine was carried out by reductive alkylation of aminoantipyrine with acetone and zinc amalgam in an acidic medium [6].

Acylation of isopropylaminoantipyrine was carried out both with carbonic acid chloranhydrides in an aqueous medium in the presence of potash, and with free acids in the presence of phosphorus trichloride in a benzene medium.

Reduction of para-nitrobenzoylisopropylaminoantipyrine was carried out with zinc dust in an acidic medium.

The acyl derivatives of N-isopropylaminoantipyrine are crystalline substances, insoluble in water and soluble in organic solvents. They were purified by recrystallization from alcohol.

The properties of the compounds obtained are given in the table.

Table

Acyl derivatives of N-isopropylaminoantipyrine

Experimental Part

N-Isopropylaminoantipyrine. To a solution of 20 g of aminoantipyrine in 120 ml of hydrochloric acid diluted with water in a 1:1 ratio are added 24 ml of acetone and 30 g of amalgamated zinc; the reaction mixture is boiled under a reflux condenser for 4 hours, then cooled to room temperature and neutralized with 20% sodium hydroxide solution to pH 8—10. The product is extracted with ether and recrystallized from ethyl acetate. Melting point 80°. Yield 80%.

N-Isopropylantipyrylamides of benzoic, para-nitrobenzoic, and para-methylbenzoic acids. To a 40% aqueous solution of 0.1 mol of isopropylaminoantipyrine, 0.5 mol of potash is added as a 10% aqueous solution, and 0.1 mol of the corresponding acid chloride is gradually added. The mixture is kept for 30 minutes at room tempera-

...temperature with vigorous stirring, after which the precipitated product is filtered off.

N-Isopropylantipyrilamides 1, 2, 3, 4, 5, 9, 11, 12, 13, 14, 15 (see table). To a solution of 0.1 mol of isopropylaminoantipyrine and 0.1 mol of the corresponding acid in 100 ml of dry benzene, heated to 70°, 0.05 mol of phosphorus trichloride dissolved in 10 ml of dry benzene is added dropwise. The mixture is heated on a water bath for 2 hours with vigorous stirring. After completion of the reaction the solvent is decanted, and the solid residue is removed from the flask and treated with a 10% aqueous solution of sodium carbonate, filtered, and washed with water.

p-Aminobenzoylisopropylaminoantipyrine. To a suspension of 0.1 mol of p-nitrobenzoylisopropylaminoantipyrine and 0.3 mol of zinc dust in 200 ml of water, 120 ml of concentrated hydrochloric acid is added with stirring. After 20 minutes the reaction mass becomes decolorized, indicating completion of the reduction. The excess zinc dust is filtered off, and the product is precipitated from the filtrate with a saturated aqueous solution of sodium acetate.

REFERENCES

1. Dyson G., May P. Chemistry of Synthetic Medicinal Substances. Moscow, “Mir,” 1964, 118–119.
2. Klosa I. Entwicklung und Chemie der Heilmittel, Vol. III, Berlin, 87–92, 1952.
3. Skita A., Keil F., Stuhmer W., Ber., 1942, 75, 1696.
4. Saratykov A. S., Stepnova G. M., et al. Izv. Sib. Otd. AN SSSR, No. 12, issue 84–90, 1965.
5. Herbert M. Swiss patent 433346 (1967); RZhKh, 1969, 1N335P.
6. Erlenbach M., Sieglitz A. British patent 693249 (1953), C. A. 49, 2521.