ACYL DERIVATIVES OF 4-AMINOANTIPYRINE

L. P. KULEV, G. M. STEPNOVA

Among the derivatives of 4-aminoantipyrine there are quite a number of representatives that have found application as medicinal agents with antipyretic and analgesic action. Long known, for example, are such derivatives of aminoantipyrine as pyramidon and analgin, which have not lost their importance up to the present time.

The acyl derivatives of aminoantipyrine have been studied comparatively little, although among them there are also representatives valuable from the therapeutic standpoint. Thus, isovaleryl-4-aminoantipyrine, α-bromisovaleryl-4-aminoantipyrine [1], and 2-hydroxybenzoyl-4-aminoantipyrine [2] may be noted; according to the authors’ data, they possess excellent medicinal properties.

Acyl derivatives of aminoantipyrine are of interest in another respect as well. The recently obtained 2-hydroxy-3,5-dibromobenzoylaminoantipyrine exhibited high activity as an insecticide, although information on the character of this activity is not given in the patent literature [3].

We set ourselves the goal of obtaining certain acyl derivatives of aminoantipyrine and determining the influence of acyl residues and of the position of substituents in them on the physiological activity of the compounds.

The synthesis of these compounds was based on the acylation reaction of aminoantipyrine hydrochloride with aromatic carboxylic acids in the presence of phosphorus trichloride according to the equation

\[ \begin{array}{c} \mathrm{CH_3{-}C{=}C{-}NH_2\cdot HCl} \\ \phantom{\mathrm{CH_3{-}}}\vert\quad\vert \\ \mathrm{CH_3{-}N\quad C{=}O} \\ \phantom{\mathrm{CH_3{-}}}\diagdown\ \diagup \\ \mathrm{N} \\ \vert \\ \mathrm{C_6H_5} \end{array} \;+\;3\mathrm{Ar{-}COOH}\;+\;2\mathrm{PCl_3} \;\to\; \mathrm{P_2O_3}\;+\;9\mathrm{HCl}\;+\;3 \begin{array}{c} \mathrm{CH_3{-}C{=}C{-}NH{-}CO{-}Ar} \\ \phantom{\mathrm{CH_3{-}}}\vert\quad\vert \\ \mathrm{CH_3{-}N\quad C{=}O} \\ \phantom{\mathrm{CH_3{-}}}\diagdown\ \diagup \\ \mathrm{N} \\ \vert \\ \mathrm{C_6H_5} \end{array} \]
.

The reaction was carried out with heating and stirring in an inert organic solvent medium (xylene). After completion of the reaction, the solvent was distilled off, and the solid residue was treated with a 10% solution of sodium carbonate and recrystallized from alcohol.

Amino-substituted acylaminoantipyrines were obtained by reduction of the corresponding nitro-substituted compounds with cast-iron turnings in the presence of an electrolyte.

Acyl derivatives of 4-aminobenzoylaminoantipyrine were synthesized according to the scheme

\[ \mathrm{ \begin{array}{c} \text{4-aminobenzoylaminoantipyrine hydrochloride} \end{array} + \mathrm{ClCOAr} \longrightarrow \begin{array}{c} \text{acyl derivative of 4-aminobenzoylaminoantipyrine} \end{array} + 2\mathrm{HCl}. \]

The antipyretic activity of some of the compounds obtained by us was determined in the pharmacological laboratory of the Tomsk Medical Institute under the direction of Prof. A. S. Saratkov. The fever-reducing action of the preparations was tested on rabbits, in which experimental fever was induced by subcutaneous administration of tetrahydro-β-naphthylamine hydrochloride.

The strongest antipyretic action was shown by 4-aminobenzoylaminoantipyrine, which considerably surpassed antipyrine in both strength and rapidity of action when administered into the animal organism per os in the same doses (50 mg/kg). The least active of all the compounds tested proved to be the benzoyl derivative of 4-aminobenzoylaminoantipyrine, as is shown by the graph (Fig. 1).

The curves in the graph show the rise in body temperature of the rabbit after prophylactic administration of:

I—4-aminobenzoylaminoantipyrine, II—cinnamoylaminoantipyrine, III—benzoylaminoantipyrine, IV—4-chlorobenzoylaminoantipyrine, V—benzoyl derivative of 4-aminobenzoylaminoantipyrine, VI—antipyrine, VII—upon administration of tetrahydro-β-naphthylamine (to create the background).

Fig. 1.

Experimental Part

I. Benzoyl-4-aminoantipyrine. To a suspension of 12 g of aminoantipyrine hydrochloride and 6.1 g of benzoic acid in 50 ml of dry xylene, 4.5 ml of phosphorus trichloride are added dropwise. The mixture is heated on a boiling water bath with constant stirring for 2 hours. The xylene is distilled off, and the solid residue is treated to neutral reaction with a 10% soda solution, thoroughly grinding the sticky lump in a mortar until it turns into a powder. The liquid is filtered off, and the precipitate is washed with water and dried. White crystals (from alcohol), m.p. 173°. Yield 14 g (90%). Found, %: N 13.18. \(\mathrm{C_{18}H_{17}O_2N_3}\). Calculated, %: N 13.67.

II. 4-Chlorobenzoyl-4-aminoantipyrine. Obtained analogously to I from 12 g of 4-aminoantipyrine hydrochloride, 7 g of 4-chlorobenzoic acid, and 4.5 ml of phosphorus trichloride. Reaction time 2 hours at 100°. Yield of substance with m.p. 223–224°: 9 g (90%). Colorless needles, m.p. 228° (from alcohol). Found, %: N 12.09. \(\mathrm{C_{18}H_{16}O_2N_3Cl}\). Calculated, %: N 12.29.

III. 3-Bromobenzoyl-4-aminoantipyrine. Obtained analogously to (I) from 12 g of 4-aminoantipyrine hydrochloride, 10.1 g of 3-bromobenzoic acid, and 4.5 ml of phosphorus trichloride (100°; 2 hours). Colorless needles, m.p. 117° (from alcohol). Found %: N 10.56. C₁₈H₁₆O₂N₃Br. Calculated %: N 10.86.

IV. 4-Nitrobenzoyl-4-aminoantipyrine. Obtained analogously to I from 12 g of 4-aminoantipyrine hydrochloride, 8.4 g of 4-nitrobenzoic acid, and 4.5 ml of phosphorus trichloride (100°; 1.5 h). Bright-yellow prisms, m.p. 210° (from alcohol). Found %: N 15.65. C₁₈H₁₆O₄N₄. Calculated %: N 15.90.

V. 2-Acetoxybenzoyl-4-aminoantipyrine. Obtained analogously to I from 12 g of 4-aminoantipyrine hydrochloride, 9 g of aspirin, and 4.5 ml of phosphorus trichloride (100°; 3 hours). Yield of substance with m.p. 210°: 15.1 g (82%). After recrystallization from alcohol—colorless needles, m.p. 216°. Found %: N 11.5. C₂₀H₁₉O₄N₃. Calculated %: N 11.5.

VI. 2-Nitrobenzoyl-4-aminoantipyrine. Obtained analogously to I from 12 g of 4-aminoantipyrine hydrochloride, 8.4 g of 2-nitrobenzoic acid, and 4.5 ml of phosphorus trichloride (100°; 1.5 hours). Yield of substance with m.p. 260°: 17.6 g (100%). After washing with hot alcohol—a pale-yellow powder, m.p. 263° (with decomposition); insoluble in the usual organic solvents and in water. Found %: N 15.51. C₁₈H₁₄O₄N₄. Calculated %: N 15.9.

VII. Cinnamoyl-4-aminoantipyrine. Obtained analogously to I from 12 g of 4-aminoantipyrine hydrochloride, 7.4 g of cinnamic acid, and 4.5 ml of phosphorus trichloride (100°; 3 hours). Yield of substance with m.p. 179°: 10.2 g (93%). After recrystallization from alcohol—colorless prisms, m.p. 183°. Found %: N 12.5. C₂₀H₁₉O₂N₃. Calculated %: N 12.61.

VIII. 4-Aminobenzoylaminoantipyrine. Obtained by reduction of 4-nitrobenzoylaminoantipyrine. To 200 ml of water are added 18 g of cast-iron turnings and 2 ml of concentrated hydrochloric acid. The mixture is heated with stirring on a water bath for 10–15 min, and 17.6 g of 4-nitrobenzoylaminoantipyrine is added in small portions. The reduction reaction is carried out for 3 hours. The reaction mass, cooled to 40–50°, is filtered; the precipitate is washed with water, dried, and 4-aminobenzoylaminoantipyrine is extracted with boiling alcohol. A white crystalline substance, m.p. 268°. Yield 14 g (90%). Found %: N 12.71. C₁₈H₁₈O₂N₄. Calculated %: N 13.04. The hydrochloride—pale-yellow crystals, m.p. 254°; soluble in water and alcohol.

IX. 3-Aminobenzoyl-4-aminoantipyrine. Obtained analogously to VIII from 17.6 g of 3-nitrobenzoyl-4-aminoantipyrine (100°; 3 hours). Yield of substance with m.p. 110°: 13.5 g (90%). After recrystallization from alcohol—white crystals, m.p. 112°. Found %: N 12.63. C₁₈H₁₈O₂N₄. Calculated %: N 13.04. The hydrochloride—white crystals, m.p. 116°, soluble in water.

X. 2-Aminobenzoyl-4-aminoantipyrine. Obtained analogously to VIII by reduction of 17.6 g of 2-nitrobenzoyl-4-aminoantipyrine (100°; 3 hours). Yield of substance with m.p. 216°: 13.4 g (90%). After recrystallization from alcohol—white crystals, m.p. 218°. Found %: N 12.70. C₁₈H₁₈O₂N₄. Calculated %: N 13.04. The hydrochloride—white crystals, m.p. 220°; sparingly soluble in water and alcohol.

XI. Benzoyl-4-aminobenzoyl-4-aminoantipyrine. 18 g of 4-aminobenzoylaminoantipyrine hydrochloride are suspended

in 50 ml of dry xylene, heated in an oil bath to 100°, and 7 g of benzoyl chloride are added dropwise with vigorous stirring. Heating at 130–140° is continued for 1.5 hours. The xylene is distilled off, the solid residue is treated with water, filtered, and the precipitate is washed thoroughly with a 10% solution of soda and with water. White, lustrous crystals with m.p. 245° (from alcohol). Sparingly soluble in hot alcohol, insoluble in water, acetone, ether, and benzene. Found, %: N 12.87. $\mathrm{C}_{25}\mathrm{H}_{22}\mathrm{O}_3\mathrm{N}_4$. Calculated, %: N 13.14.

XII. 4-Nitrobenzoyl-4-aminobenzoyl-4-aminoantipyrine. Obtained analogously to XI from 18 g of hydrochloride of 4-aminobenzoyl-4-aminoantipyrine and 9.3 g of 4-nitrobenzoyl chloride (120°; 1.5 hours). Yield of substance with m.p. 236°: 20 g (85%). After washing with boiling alcohol—white crystals with m.p. 240°; insoluble in water and in common organic solvents. Found, %: N 14.8. $\mathrm{C}_{25}\mathrm{H}_{21}\mathrm{O}_5\mathrm{N}_5$. Calculated, %: N 14.85.

XIII. 4-Chlorobenzoyl-4-aminobenzoyl-4-aminoantipyrine. Obtained analogously to XI from 18 g of hydrochloride of 4-aminobenzoyl-4-aminoantipyrine and 8.75 g of 4-chlorobenzoyl chloride (175°; 2.5 hours). Yield of substance with m.p. 244°: 20.7 g (90%). After washing with boiling alcohol—white plates with m.p. 248°; insoluble in water and in common organic solvents. Found, %: N 11.78. $\mathrm{C}_{25}\mathrm{H}_{21}\mathrm{O}_3\mathrm{N}_4\mathrm{Cl}$. Calculated, %: N 12.17.

Conclusions

1. A series of acyl derivatives of aminoantipyrine has been synthesized.
2. The antipyretic activity of the compounds obtained has been determined. It has been established that 4-aminobenzoylaminoantipyrine possesses the greatest fever-reducing action, and the benzoyl derivative of 4-aminobenzoylaminoantipyrine the least. The position of the primary amino group in the molecules of these compounds has no significant influence on their physiological activity.

Literature

1. Knoll, Chem. Zbl., II, 1346, 1910.
2. Stoll, Morf and Peyer, U.S. 2401522, 1946.
3. Morf, U.S. 2502528, 1950.