p-Amino phenol derivatives

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Chapter: Medicinal Chemistry : Analgesics, Antipyretics, and NSAIDs

i. Phenacetin (Acetophenetidin) ii. Paracetamol (Metacin, Tylenol, Tapar, Calpol) - SAR of p-amino Phenol Derivatives, Synthesis and Drug Profile


p-Amino phenol derivatives

These derivatives possess analgesic and antipyretic action, but lack anti-inflammatory effects. Acetanilide was introduced into the therapy in 1886 as an antipyretic–analgesic agent. However, it was subsequently found to be too toxic, having been associated with methemaglobinemia and jaundice.

Phenacetin was introduced in the following year and was widely used but was withdrawn recently because of its nephrotoxicity. Acetaminophen (paracetamol) was introduced in 1893 and it remains the only useful agent of this group used as an antipyretic and an analgesic agent.


Metabolism of para aminophenol derivatives: These drugs undergo hydrolysis to yield aniline derivatives that produce directly or through their conversion to hydroxylamine derivatives, such as Acetaminophen that undergoes rapid first pass metabolism in the GIT to o-sulphate conjugate. The N-hydroxylamine is then converted into a reactive toxic metabolite, acetiminoquinone, which produce toxicity to the kidney and liver in conjugation with hepatic glutathione to form mercapturic acid or cysteine conjugates.


 

SAR of p-amino Phenol Derivatives

1.           Etherification of the phenolic function with methyl or propyl groups produces derivatives with greater side effects than ethyl derivatives.

2.           Substituents of the nitrogen atom, which reduce the basicity, also reduce activity unless the substituent is metabolically labile. Example - acetyl groups.

3.           Amides derived from aromatic acid. Example - N-phenyl benzamides that are less active or inactive.

 

i. Phenacetin (Acetophenetidin)


Synthesis

Route I. From: p-nitro phenol


Route II. From: aniline


Route III. From: chlorobenzene


Properties and uses: It exists as a white glistering powder with a bitter taste, sparingly soluble in water and soluble in chloroform. It is an analgesic and an antipyretic with similar effectiveness as an aspirin. It has a greater potential for toxicity (hemolytic anaemia and methemoglobinaemia) than paracetamol.

Dose: Usual dose as oral for adults is 300 mg to 2 g per day.

 

ii. Paracetamol (Metacin, Tylenol, Tapar, Calpol)


Synthesis


Properties and uses: Paracetamols exist as white crystalline powder, sparingly soluble in water, soluble in alcohol, and very slightly soluble in methylene chloride. Paracetamols produce antipyresis by acting on the hypothalamic heat-regulating centre and analgesia by elevating the pain threshold. Hepatic necrosis and death have been observed following over dosage; hepatic damage is likely in an adult who takes more than 10 g in a single dose or if a 2-year old child takes more than 3 g.

Assay: Dissolve the sample in a mixture of water and dilute sulphuric acid (1:3), reflux, cool, and dilute with water. Add dilute hydrochloric acid and titrate against 0.1 M cerium sulphate using ferroin as an indicator until a greenish-yellow colour is obtained. Perform a blank titration.

Dose: Usual oral adult dose is 500 mg to 1 g for three or four times a day.

Dosage forms: Paracetamol tablets I.P, B.P., Paracetamol syrup I.P., Co-codamol tablets B.P., Effervescent Co-codamol tablets B.P., Co-dydramol tablets B.P., Co-proxamol tablets B.P., Paracetamol capsules B.P., Paediatric paracetamol oral solution B.P., Paracetamol oral suspension B.P., Paracetamol suppositories B.P., Dispersible paracetamol tablets B.P., soluble paracetamol tablets B.P.

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