Aniline derivatives acetaminophen

Aniline derivatives (para-aminophenol derivative were, historically, also introduced in the last century. The original member used extensively in medicine was phenacetin, but this has been replaced by paracetamol (acetaminophen,... 

Paracetamol (known as acetaminophen in the USA) is N-acetyl-para-aminophenol (Figure 25.11). It has the same detoxification pathways as phenol and also carries the risk of inducing methemoglobinemia. To be on the safe side, it should not be used as an intravenous analgesic during a full-face phenol peel, so as not to saturate the detoxification pathways. Paracetamol is also an intermediate in the pathway for detoxification of aniline derivatives, before hepatic glucuronide and sulfate conjugation allow them to... 

B. Aniline Derivatives - A structure-activity study of a new series of alkoxyaniline derivatives has been reported along with a detailed workup of one of them . This compound (XII) appears to have good analgesic and anti-inflammatory activity, associated with some CNS depressant effects. An antidiuretic effect was described for acetaminophen 9 a d it was suggested that this drug might be a useful substitute for vasopressin in certain patients with diabetes insipidus. Evidence was also presented to show that acetophenetidin has antipyretic activity which is not dependent on metabolism to N-acetyl-p-aminophenol. 

The structure-activity relationships of p-aminophenol derivatives have been widely studied. Based on the comparative toxicity of acetanilide and acetaminophen, aminophenols are less toxic than the corresponding aniline derivatives, although p-aminophenol itself is too toxic for therapeutic purposes. Etherification of the phenolic function with methyl or propyl groups produces derivatives with greater side effects than with ethyl groups. Substituents on the nitrogen atom that reduce basicity reduce activity unless that substituent is metabolically labile (e.g., acetyl). Amides derived from aromatic acids (e.g., N-phenylbenzamide) are less active or inactive. 

Both phenacetin and the newer replacement acetaminophen are derivatives of p-aminophenol. Although these latter two are analgesics and antipyretics, the aniline-phenol derivatives show little if any antiinflammatory activity. p-Aminophenol itself is toxic, but acylation of the amino group makes it a convenient drug. 

---