3, 5-Pyrazolidinediones

3, 5-Pyrazolidinediones

SAR of 3, 5-Pyrazolidinediones

·Replacement of one of the nitrogen atom in the pyrazolidinediones with an oxygen atom yields isoxazole analogues, which are as active as pyrazolidinediones derivatives.

·In 3, 5-pyrazolidinedione derivatives, pharmacological activities are closely related to their acidity, the dicarbonyl function at the 3rd and 5th positions enhance the acidity of hydrogen atom at the 4th position.

·Presence of a keto group in the γ-position of the butyl side chain produces the active compound.

·Decreasing or eliminating acidity by removing the acidic proton at 4th position (e.g. 4, 4-dialkyl derivatives) abolishes anti-inflammatory activity. Thus, if the hydrogen atom at the 4th position of phenyl butazone is replaced by substituents, such as a methyl group, antiinflammation activity is abolished.

·If acidity is enhanced too much, anti-inflammatory and sodium-retaining activities decrease while other properties, such as the uricosuric effect increases.

·Introduction of polar function in these alkyl groups give mixed results. The γ-hydroxy-n-butyl derivative posseses pronounced uricosuric activity, but give fewer anti-inflammatory effects.

·Substitution of 2-phenyl thio ethyl group at the 4th position produces antigout activity (sulphinpyrazone).

·Presence of both the phenyl groups is essential for neither anti-inflammatory nor analgesic activity.

·m-Substitution of aryl rings of the phenyl butazone gives uniformly inactive compounds. p-Substitution, such as methyl, chloro, nitro, or OH of one or both rings retains activity.

i. Phenylbutazone (Butazolidin, Busone)

Synthesis

Route I. From: Diethylmalonate

Route II. From: Diethyl-butyl malonate or butyl malonylchloride

Properties and uses: Phenylbutazone is a white crystalline powder, practically insoluble in water, sparingly soluble in alcohol, and soluble in alkaline solutions. It is a pyrazole derivative that has antipyretic, analgesic, and anti-inflammatory actions, because of its toxicity it is not used as a general antipyretic or analgesic. It is a usual practice reserved for use in the treatment of osteoarthrosis, ankylosing spondylitis, arthritis, acute superficial thrombophlebitis, painful shoulder, and Reiter’s disease, where less toxic drugs have failed.

Assay: Dissolve the sample in acetone and titrate against 0.1 M sodium hydroxide using bromothymol blue as indicator until a blue colour is obtained, which persists for few seconds. Perform a blank titration.

Dose: The usual dose is 100–600 mg per day.

ii. Oxyphenbutazone (Tandearil, Oxaril)

Synthesis

Route I. From aniline

Route II. From: Diethyl butyl malonate

Properties and uses: It exists as a white to yellowish white, odourless, crystalline powder, soluble in water, alcohol, chloroform, and ether. Used as an analgesic and in arthritis.

Dose: Usual oral adult dose for antirheumatic is 100 or 200 mg three times daily; for maintenance the dose is 100 mg one to four times a day; for the treatment of gout 400 mg initially as a loading dose, then 100 mg every 4 h.