Lecture 16

Dr. Sana Shamim

ANALGESICS AND ANTIPYRETICS

LEARNING OBJECTIVES
At the end of this lecture students will be able to understand: Pyrazolone and pyrazolidineione derivatives Derivatives of 5-pyrazolone Derivatives of 3,5 pyrazolidinedione Their analogues Structure activity relationships Metabolism

PYRAZOLONE AND PYRAZOLIDINEIONE DERIVATIVES

The simple double unsaturated compound containing two nitrogen and three carbon atoms in the ring with the nitrogen atom neighboring is called as Pyrazole. The reduction products named as are other rings of 5 atoms are:

Pyrazoline Pyrazolidine

5 pyrazolone 3,5 pyrazolidinedione

Many of the pyrazoline derivatives used in medicines. Some are related to 5, pyrazolone 3,5 pyrazolidinedion

DERIVATIVES OF 5-PYRAZOLONE

In 1884, during the search of antipyretic agent, German scientist Ludwig Knorr attempted to synthesize quinolone derivatives as structural analogues of Quinine, whose structure was unresolved at that time. Indeed he obtained a pyrazole derivative ANTIPYRINE which was found to have marked antipyretic and analgesic activity.

There are three well known derivatives of 5pyrazolone

Antipyrene Aminopyrene

Dipyrone

Antipyrene and many related compounds were prepared by the condensation of hydrazine derivatives with various esters. Locally it posses the paralytic actions on sensory and motor nerves along with antiseptic and analgesic activity. Aminopyrene (4-dimethyl amino derivative) was found to be more potent but has slow onset of action than antipyrene. Both of these derivatives have analgesic, antipyretic and antirheumatic potencies similar to that of Aspirin, phenylbutazone and indomethacin. Later severe side effects were observed i.e; fatal agranulocytosis.

The antipyretic properties of antipyrene were so widely accepted that it was used in various OTC ophthalmic and analgesic preparations, which was seriously reviewed by FDA and now comes under non-OTC drugs.

Derivatives of 3,5 pyrazolidinedione:

In

mid 1940s in an effort to increae the analgesic properties of 5 pyrazolines a series of 3,5 pyrazilidinediones were synthesized.

1.Phenybutazone: It was shown to posses antipyretic and analgesic properties equipotent with antipyrine. It is acidic in nature and therefore could enhance the solubilization of other drugs. Its sodium salts were initially used as the solubilizing agent for aminopyrene Combination of both aminopyrene and phenylbutazone was found to be beneficial in patients with various rheumatic and anti-inflammatory activities. In 1952, after confirmation of the anti-inflammatory activity of the phenylbutazone, it was introduces as the anti-rheumatic agent.

Phenylbutazone posses three major pharmacological properties: Anti-inflammatory activity: which is greater than that of salicylates. Analgesic activity: however is less than salicylates and the routine use of phenylbutazone for this purpose is not recommended. Uricosuric activity: at relatively high doses it acts as agent.

Oxyphenebutazone:

It is synthesized by the hydroxylation of phenylbutazone at para position. It posses equipotent antiinflammatory activity and sodium retainig effects of phenylbutazone but has less GI irritations.
Sulfinpyrazone has uricosuric activity and is used in prepation for the treatment of Gout. It is a ketone derivative of phenylbutazone.

Sulfinpyrazone:

Ketobutazone:

SAR

The most striking clinical feature of 3,5 pyrazolididinediones is the fact that there acidity is equal to that of carboxylic acid and the pharmacological activity of 3,5 pyrazolididinediones is closely related to their acidity. The dicarbonyl function at 3rd and 5th position enhances the acidity of hydrogen atoms at the 4th position resulting in the following equilibrium. Decreasing or eliminating the acidity or replacing the H atom by a substituent such as CH3 group at the 4th position abolishes the anti-inflammatory activity.

Increase in acidic group will reduces its antiinflammatory and sodium retention abilities, presumably through the enhanced rate of excretion. Single alkyl group at position 4 enhances the antiinflammatory activity, although the n-butyl group enhances the activity whereas, propyl and allyl analogues also posses the anti-inflammatory activity. Introduction of polar functions in these alkyl groups gives mixed results. The g-hydroxy-n-butyl derivatives (metabolites of phenylbutazone) possess good uricosuric activity but has low anti-inflammatory activity.

METABOLISM

Phenylbutazone is metabolised into two metabolites slowly by aromatic hydroxylation via microsomal enzymes of liver.
Oxyphenbutazone:

pharmacologically active metabolite and is excreted through Oglucouroinde conjugation. Gamma-hydroxyphenylbutazone: Second most important metabolite and posses uricosuric activiy.

REFERENCES
Wilson and Gisvold, Text book of Organic medicinal and pharmaceutical chemistry 11th ed. chapter.22 .p.753-766. Foyes principle of medicinal Chemistry, sixth edition, section IV, Chapter 36, p. 954-1003.