Antipyrine discovery

Knorr reported the first pyrazole derivative in 1883. The reaction of phenyl hydrazine and ethylacetoacetate resulted in a novel stmcture identified in 1887 as l-phenyl-3-methy 1-5-pyrazolone 9. His interest in antipyretic compounds led him to test these derivatives for antipyretic activity which led to the discovery of antipyrine 10. He introduced the name pyrazole for these compounds to denote that the nucleus was derived from the pyrrole by replacement of a carbon with a nitrogen. He subsequnently prepared many pyrazole analogs, particularly compounds derived from the readily available phenyl hydrazine. The unsubstituted pyrazole wasn t prepared until 1889 by decarboxylation of liT-pyrazole-3,4,5-tricarboxylic acid. ... 

The birth of drug discovery is closely connected to the study of plant natural products and was shaped by two seminal events, the isolation of morphine 1 from opium by the pharmacist Serturner in 18171 and the introduction in the clinics of Antipyrin 6 (phenazone) 70 years later, in 1887.2 The obtaining of a pure compound responsible for the medicinal properties of a crude drug marked the beginning of medicinal chemistry, triggering the transition from botanical extracts to pure molecules and eventually leading to the isolation of the active principle of most heroic drugs. 

Scheme 5.1 The serendipitous discovery of antipyrine 6, an alleged morphine 1/ quinine 8 mimic.

After discovery of a COX-1 variant in some regions of the brain, it was suggested that acetaminophen, a weak inhibitor of COX-1 and COX-2, acts by inhibiting this variant, termed COX-3. Discovered in 2002, encoded by the COX-1 gene and with an intron not retained in COX-1, COX-3 was shown to be inhibited by acetaminophen, phenacetin, metamizole (dipy-rone), antipyrine, and some NSAIDs in rodent experiments. It turned out, however, that results with canine COX-3 were not applicable to mouse... 

The release of ASA into the market played an important role in the discovery of new anti-inflammatory thugs. At the University of Erlangen, the chemist Knorr successfully sjmthesised phenazones, and their antipyretic and analgesic activities were proven by the pharmacologist Filehne. The phenazone, Antipyrine (Fig. 14.5) was patented in 1884 and was produced by a small chemical firm (Farbwerke, vorm. Meister, Lucius und Bmning) near Frankfurt. Later Hochst bought the increasing production of Antipyrine , which later made the company a world renowned pharmaceutical firm. 

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