Summary
The initial rate of nitrosation of aminopyrine (AP, Pyramidon) to give dimethyl nitrosamine (DMN) showed maxima at pH 2.0 and 3.1. At pH 2, initial rate was proportional to nitrite concentration squared down to 6 mM, below which it decreased rapidly. The rate was independent of AP concentration at pH 2 but proportional to AP concentration at pH 0.5, indicating that nitrous anhydride formation was rate-limiting at pH 2. DMN was detected after 5 seconds reaction under “normal” conditions. The stoichiometric rate constant at pH 2 and 0° was 80 M−2 sec−1, higher than that for all secondary amines previously studied, except N-methylaniline. In addition to the “initial reaction”, a second slow reaction giving DMN was observed. When 20 mM AP was reacted for 1 hr with 25–100 μM nitrite at 37°, >90% of the nitrite reacted to give DMN. Ascorbate blocked DMN formation from AP efficiently under various conditions. We confirmed Bockmühl's finding that the other main product of AP nitrosation is 1-diketo-butyryl-1-phenyl-2-methyl-2-nitrosohydrazide hydrate (DPMN). The unusual ease of reaction is attributed to the enamine structure of AP. The possibility of intragastric nitrosation of AP is considered to present a hazard to people ingesting this analgesic drug, which is widely used in Europe.
Zusammenfassung
Die Anfangsgeschwindigkeit der Nitrosierung von Aminopyrin (AP, Pyramidon) zu Dimethylnitrosamin (DMN) zeigte Maxima bei pH 2,0 und 3,1. Bei pH 2 war die Anfangsgeschwindigkeit proportional zum Quadrat der Nitritkonzentration bis 6 mM, darunter nahm sie rasch ab. Die Geschwindigkeit war unabhängig von der AP-Konzentration bei pH 2 aber proportional zur AP-Konzentration bei pH 0,5. Daraus geht hervor, daß die Bildung von Salpetrigsäureanhydrid bei pH 2 geschwindigkeitsbestimmend ist. DMN wurde nach 5 Sekunden Reaktion unter „normalen“ Bedingungen nachgewiesen. Die stoichiometrische Geschwindigkeitskonstante bei pH 2 und 0° war 80 M−2 sec−1, also höher als für alle sekundären Amine, die früher untersucht wurden, außer N-Methylanilin. Zusätzlich zur „Anfangsreaktion“ wurde eine zweite langsame Reaktion beobachtet, die DMN ergab. Wenn 20 mM AP eine Stunde lang mit 25–100 μM Nitrit bei 37° umgesetzt wurden, so reagierten >90% des Nitrits zu DMN. Ascorbinsäure hemmte die DMN-Bildung aus AP unter verschiedenen Bedingungen wirkungsvoll. Wir bestätigten Bockmühl's Befund, daß das andere Hauptprodukt der AP-Nitrosierung das 1-Diketo-butyryl-1-phenyl-2-methyl-2-nitrosohydrazid-hydrat (DPMN) ist. Die ungewöhnliche Leichtigkeit der Reaktion wird der Enamin-Struktur von AP zugeschrieben. Die Möglichkeit der intragastralen Nitrosierung von AP wird als eine Gefahr für Menschen angesehen, die diese analgetische Substanz, deren Anwendung in Europa weit verbreitet ist, einnehmen.
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Supported by contract PH-43-68-959 from the US National Cancer Institute and grant BC-39A from the American Cancer Society.
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Mirvish, S.S., Gold, B., Eagen, M. et al. Kinetics of the nitrosation of aminopyrine to give dimethylnitrosamine. Z. Krebsforsch. 82, 259–268 (1974). https://doi.org/10.1007/BF00285560
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DOI: https://doi.org/10.1007/BF00285560