Azomethine Derivatives of 4-Aminoantipyrine and Their Anti-Inflammatory Activity
Abstract Generated abstract
Nine azomethine derivatives of 4-aminoantipyrine were synthesized by condensation with substituted benzaldehydes, including five compounds not previously described, and characterized by yield, melting point, empirical formula, and nitrogen analysis. Their anti-inflammatory activity was evaluated in rats using a polyglucin-induced paw edema model, with intraperitoneal administration of test compounds and comparison to butadione. The study found that activity depended on the aldehyde substituent: unsubstituted, halogenated, and nitro derivatives were weak or inactive, while electron-donor substituted derivatives showed anti-edematous effects. The salicylidene and 4-diethylaminobenzylidene derivatives produced comparatively stronger inhibition of edema and were identified as candidates for further pharmacological study.
Full Text
AZOMETHINE DERIVATIVES OF 4-AMINOANTIPYRINE AND THEIR ANTI-INFLAMMATORY ACTIVITY
E. V. Shmidt, T. P. Prishchep, N. A. Chernova
(Presented by the Scientific-Methodological Seminar of the Faculty of Chemical Technology)
Previously we studied the relationship between structure and pharmacological activity in a series of acyl derivatives of 4-aminoantipyrine [1, 2]. The present work is a continuation of these studies. Azomethine derivatives of 4-aminoantipyrine were chosen as the object of study. Benzaldehydes with various substituents in the 2- and 4-positions of the benzene ring were used as the carbonyl-containing component.
Some azomethines based on 4-aminoantipyrine have previously been described in the literature [3–5]; there is fragmentary information about their pharmacological properties [5–6]; azomethine derivatives of 4-aminoantipyrine have not been tested for anti-inflammatory activity.
We were interested in what change in anti-inflammatory activity would result from the transition from amides to azomethines, as well as in the influence of the structure of the aldehyde component in azomethines on anti-inflammatory properties.
The azomethines were obtained by condensation of 4-aminoantipyrine with aldehydes in ethanolic or 2-propanolic solution. The condensation procedure was as follows: a solution of 0.025 g mole of aldehyde in 20 ml of hot solvent was added dropwise with stirring to 20 ml of a hot solution of 0.025 g mole of 4-aminoantipyrine in the same solvent. The mixture was stirred for 10–15 min while heating and then cooled. After cooling, a crystalline precipitate formed, which was filtered off, washed with water, alcohol, and ether, and recrystallized. The azomethines obtained are needle-like yellow crystals, insoluble in water and ether, and soluble on heating in alcohols and acetic acid.
The characteristics of the compounds obtained are presented in Table 2.
The anti-inflammatory activity of the synthesized azomethine derivatives of 4-aminoantipyrine was studied. The experiments were carried out on 110 rats of both sexes, weighing 90–120 g. Inflammation was induced by introducing 0.05 ml of polyglucin under the plantar aponeurosis of the right hind paw. The criterion for the intensity of the edema that developed was the increase in the volume of the inflamed paw compared with the initial value, expressed as a percentage. The volume of the limb was measured 15, 30, and 45 min, and 1.5, 3, 6, and 8 hours after administration of the phlogogenic agent. The test preparations were administered intraperitoneally at a dose of 50 mg/kg 3 hours 30 min before and 30 min after injection of the irritant; in control experiments the animals received potato-starch mucilage.
The magnitude of the edema was measured using a mercury oncometer; the hind paw was immersed in mercury up to the level of the ankle joint, three measurements were made each time, and the mean value was taken. In comparison
Table 2
| No. | Compound name | Yield, % | M.p., °C | Nitrogen analysis, %, found | Empirical formula | Nitrogen analysis, %, calculated |
|---|---|---|---|---|---|---|
| 1 | *) 4-Benzylideneaminoantipyrine | 95 | 173–174 (ethanol) | 14.30 | $C_{18}H_{17}ON_3$ | 14.43 |
| 2 | 4-(4′-Chlorobenzylidene)-aminoantipyrine | 94 | 253–254 (ethanol) | 13.21 | $C_{18}H_{16}ON_3Cl$ | 12.90 |
| 3 | 4-(4′-Bromobenzylidene)-aminoantipyrine | 93 | 253–254 (ethanol) | 11.70 | $C_{18}H_{16}ON_3Br$ | 11.35 |
| 4 | 4-(4′-Nitrobenzylidene)-aminoantipyrine | 94 | 256–257 (ethanol + acetic acid) | 16.76 | $C_{18}H_{16}O_3N_4$ | 16.66 |
| 5 | *) 4-(4′-Methoxybenzylidene)-aminoantipyrine | 91 | 168–169 (ethanol) | 13.38 | $C_{19}H_{19}O_2N_3$ | 13.08 |
| 6 | 4-(2′-Methoxybenzylidene)-aminoantipyrine | 91.5 | 213–214 (2-propanol) | 13.41 | $C_{19}H_{19}O_2N_3$ | 13.08 |
| 7 | *) 4-(2-Oxybenzylidene)-aminoantipyrine | 95 | 196–197 (ethanol) | 13.85 | $C_{18}H_{17}O_2N_3$ | 13.68 |
| 8 | *) 4-(4′-Dimethylaminobenzylidene)-aminoantipyrine | 90 | 213–214 (ethanol) | 17.22 | $C_{20}H_{22}ON_4$ | 16.77 |
| 9 | 4-(4′-Diethylaminobenzylidene)-aminoantipyrine | 90 | 220–220.5 (2-propanol) | 15.84 | $C_{22}H_{26}ON_4$ | 15.47 |
*) Azomethines described previously in the literature.
with butadione, the pharmacological activity of the compounds studied was judged. The results of the experiments are presented in Table 1.
In the control group of animals, 30 min after administration of polyglucin the paw volume increased one and a half times and remained at this level for one hour. The maximum increase in limb volume occurred after 45 min; the excess over the initial level at this time was \(157.8 \pm 12.5\%\). After 3 h the edema began to decrease; by the time of the subsequent measurements the magnitude of the inflammatory edema was decreasing intensively.
Butadione, administered to the next group of animals, reduced the magnitude of dextran edema during the period of intensive development of inflammation (30, 45 min, 1.5 and 3 h after injection of the irritant), but this decrease was not significant in relation to the control.
It is evident from Table 1 that there is a definite relationship between the structure of the azomethines and their anti-inflammatory activity. As in the series of acyl derivatives of 4-aminoantipyrine (1–2), in the series of its azomethines anti-inflammatory properties are not manifested by all compounds. The transition from amides to azomethines led to a sharper differentiation of the compounds by the magnitude of the effect; the nature of the aldehyde component of the azomethines affects the antiphlogistic properties of the preparations more clearly than the nature of the acid group in the series of acyl derivatives of 4-aminoantipyrine.
The antiexudative effect is extremely weak throughout the entire observation period in 4-benzylideneaminoantipyrine unsubstituted in the ring. Introduction into its molecule of electron-acceptor substituents—halogens and a nitro group—led to loss by the azomethines of the ability to attenuate inflammation, and introduction of chlorine even led to aggravation of the edema.
Azomethines with electron-donor substituents in the benzene ring—a methoxy group in the 2- and 4-positions and a dimethylamino group in the 4-position—exhibit an anti-edematous action analogous to that of butadione. Two compounds—a derivative of salicylaldehyde and of 4-diethylaminobenzaldehyde—showed, in comparison with butadione, a more pronounced anti-inflammatory action; for 3 h after injection of the irritant they significantly (in comparison with the control) delayed the development of dextran inflammation. Both preparations are of interest for more detailed pharmacological study.
Conclusions
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Nine azomethine derivatives of 4-aminoantipyrine have been synthesized, 5 of which had not previously been described in the literature.
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The anti-inflammatory activity of these compounds has been studied and the relationship between the structure of the azomethines and their antiphlogistic action has been discussed.
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4-Salicylideneaminoantipyrine and 4-(4′-diethylaminobenzylidene)aminoantipyrine are of interest for further pharmacological investigation.
LITERATURE
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T. P. Prishchep, “Farmakologiya i toksikologiya,” No. 1, 55, 1962.
-
A. S. Saratnikov, G. M. Stepnova, E. V. Shmidt, L. A. Shabrova, L. N. Lavrent’eva, T. P. Prishchep. Izv. Sib. otd. AN SSSR, ser. biol.-med., 3, 12, 84, 1965.
-
Knorr L., Stolz F. Annalen der Chemie, 293, 58, 1896.
-
Tiffeneau M., C, 1368, 1914, 1.
-
Oohashi Tomij, Matsamara Gisashi. RZh Biokhimiya 20, 29275, 1960.
-
I. Ivanov, D. Popov. Nauchnye trudy Vysshego veterinarno-med. in-ta, 17, 189, 1966 (Bulg.); RZh Khim. 9 zh., 260, 1968.