Pharmaceutical Chemistry II LectureS 6 & 7 - NSAIDS Joseph O. Oweta | PHC 3201

Classes of NSAIDs - Recap Salicylates Propionic acids (Profens) Aryl and heteroarylacetic acids Anthranilates (Fenamates) Oxicams (“Enol Acids”) Phenylpyrazolones Anilides.

Salicylates continued…. Acetylsalicylic acid Is an acetyl derivative of salicylic acid. Acetyl salicylic acid (aspirin) can be prepared by the reaction between salicylic acid and acetic anhydride. …the hydroxyl group on the benzene ring in salicylic acid reacts with acetic anhydride to form an ester functional group.

Acetyl Salicylic Acid Thus, the formation of acetyl salicylic acid is referred to as an esterification reaction. This reaction requires the presence of an acid catalyst.

Flufenisol acetyl-5-(4-fluorophenyl) salicyclic acid Flufenisol is more potent, long acting NSAID and produces less gastric irritation.

Proprionic Acid Derivatives (Profens)

Proprionic Acid Derivatives (Profens) …are often referred to as the “profens” based on the suffix of the prototype member, ibuprofen. Like the salicylates these agents are all strong organic acids(pKa = 3.0-5.0)and thus form water soluble salts with alkaline reagents. The arylpropionic acids are characterized by the general structure Ar—CH(CH3)—COOH which conforms to the required general structure. All of these compounds are predominantly ionized at physiologic pH and more lipophilic than acetyl salicylic acid or salicylic acid.

Proprionic Acid Derivatives (Profens) The α-CH3 substituent present in the profens increases cyclooxygenase inhibitory activity and reduces toxicity of the profens. The α-carbon in these compounds is chiral and the S-(+)-enantiomer of the profens is the more potent cyclooxygenase inhibitor. Sinister Vs Rectus whilts looking at enantiomers from via the chiral centre.

2-(4-(2-methylpropyl)phenyl)propanoic acid Ibuprofen 2-(4-(2-methylpropyl)phenyl)propanoic acid

Fenoprofen

Flurbiprofen Systematic Name?

Ketoprofen and Naproxen

Synthesis of Ibuprofen.

Two of the most popular ways to obtain ibuprofen are the Boot process and the Hoechst process. The Boot process is an older commercial process developed by the Boot Pure Drug Company, and the Hoechst process is a newer process developed by the Hoechst Company. Most of these routes to ibuprofen begin with isobutylbenzene and use Friedel-Craft’s acylation. The Boot process requires six steps, while the Hoechst process, with the assistance of catalysts, is completed in only three steps.

Assignment Draw the structure of Naproxen Give a systematic name for the structure above Describe the synthesis of Naproxen.

Aryl and Heteroarylacetic Acids Chemistry and General Structure These compounds are also derivatives of acetic acid, but in this case the substituent at the 2-position is a heterocycle or related carbocycle. This does not significantly effect the acidic properties of these compounds.

Aryl and Heteroarylacetic Acids Classification indene/indoles, pyrroles oxazoles

Indene and Indole Acetic Acids Indomethacin SAR’s and Structure 1 2 2 1. The carboxyl group is essential for anti-inflammatory activity. 2. Presence of methoxy (position 5) group on the ring (5 or 6), methyl (2), dimethylamino group (5) in indole moiety of indomethacin exhibit activity. 3. Presence of chlorine or fluorine or CF3 groups at para position of phenyl group also exhibits anti-inflammatory activity. 3

Synthesis of Indomethacin

Indene and Indole Acetic Acids Sulindac Structure

Indene and Indole Acetic Acids Sulindac Describe the synthesis of Sulindac Draw the structure of etodolac

Ketolorac Can you identify the chemical class of this drug molecule? Name and draw the structure of an oxazole acetic acid

Anthtranilates (fenamates) Actions. The anthranilates have primarily antiinflammatory with some analgesic and antipyretic activity and are non-COX selective. The anthranilates are used as mild analgesics and occasionally to treat inflammatory disorders. Diclofenac is used for rheumatoid arthritis, osteoarthritis and post-operative pain and mefenamic acid as an analgesic for dysmenorrhea. The utility of this class of agents is limited by a number of adverse reactions including nausea vomiting, diarrhoea, ulceration, headache, drowsiness and hematopoietic toxicity.

Mefenamic Acid

Meclofenamic Acid

Diclohlorophenyl Acetic Acid Draw the structure of diclofenac Describe the synthesis of diclofenac.

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