Pharmaceutical Chemistry II Lectures 8 & 9 - NSAIDS Joseph O. Oweta | PHC 3201

Classes of NSAIDs - Recap 1.Salicylates 2. Propionic acids (Profens) 3. Aryl and heteroarylacetic acids 4. Anthranilates (Fenamates) 5.Oxicams (“Enol Acids”) 6.Phenylpyrazolones 7.Anilides.

Oxicams (“Enol Acids”) Oxicams (Piroxicam and Meloxicam) are characterized by the 4- hydroxybenzothiazine heterocycle. The acidity of the oxicams is attributed to the 4- OH with the enolate anion being stabilized by intramolecular hydrogen-bonding to the amide N-H group. These compounds are acidic (pKa = 6.3).

Oxicams (“Enol Acids”) The oxicams are primarily ionized at physiologic pH and acidity is required for COX inhibitory activity. Examples include Piroxicam and Meloxicam

Piroxicam

Meloxicam

Phenylpyrazolones Pyrazole Simply double unsaturated compound containing 2 N’s and 3 C’s in the ring with the nitrogen atoms neighboring

Phenylpyrazolones Pyrazole – Reduction products PyrazolinePyrazolidine

Pyrazoline Substitution Products 5 – Pyrazolone3,5-pyrazolidinedione

Phenylpyrazolones Phenylbutazone

Oxyphenbutazone

Silphinpyrazone

SAR’s Pharmacologic activity of the 3,5-pyrazolidinedione derivatives are closely related to their Acidity (the Acidic H at 4-position). The dicarbonyl functions at 3- and 5- positions enhance the acidity of the Hydrogen at the 4- position. Eliminating the acidic proton at the 4-position abolishes anti-inflammatory activity. Enhancing the acidity too much leads to a decrease in anti-inflammatory activity while other effects like uricosuric effects and sodium retention

SAR’s A single alkyl group at the 4-position enhances anti-inflammatory with the most activity being given by the n-butyl substituent. Substitution of the 2- phenylthioethyl group at the four position produces anti-gout drug sulphinpyrazone

Assignment Read and make notes about the synthesis of phenylbutazone from diethyl malonate

ANILIDES AND COX 2 INHIBITORS

Anilides [p-aminophenol Derivatives] Introduced as analgesics after the discovery of the powerful antipyretic activities of aniline The anilides are simple acetamides of aniline (Aminobenzene), which may or may not contain a 4-hydroxy or 4-alkoxy group. Anilides do not possess the carboxylic acid functionality and therefore they are classified as neutral drugs and possess little inhibitory activity against cyclooxygenase.

Anilides [p-aminophenol Derivatives] They are believed to act as scavengers of hydroperoxide radicals. Acetanilide was first introduced and was found to be too toxic causing jaundice. Phenacetin was withdrawn recently due to Nephrotoxicity. Paracetamol remains the only useful member of this group (introduced in1891)

SAR’s Esterification of the phenolic functional groups with methyl or propyl groups produce derivatives with greater side effects than the ethyl derivative. Substituents on the Nitrogen atom, which reduce the basicity, also reduce activity unless the substituent is metabolically labile e.g., acetyl. Amides derived from aromatic acid e.g. N-Phenyl benzamide's (Benzanilide) are less active or even inactive

Synthesis of Paracetamol Preparation of paracetamol involves treating an amine (p- aminophenol) with an acid anhydride (acetic anhydride) to form an amide (p-acetamidophenol).

Selective COX-2 Inhibitors Prostaglandins that mediate inflammation, fever and pain are produced solely COX-2 (Highly inducible by inflammation) Selective Cox – 2 inhibitors are devoid of side effects such as gastric ulcer and it does not affect the normal functioning of the platelet, uterus and renal system.

Celecoxib

Rofecoxib

Valdecoxib

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