Phenothiazine Derivatives

Phenothiazine Derivatives

Phenothiazine (dibenz-1,4-thiazine) is a heterocyclic compound prepared by cyclization of diphenylamine with sulphur in the presence of iodine or aluminium chloride .

Phenothiazine is a yellow, crystalline compound in which the basic character of the nitrogen atom is so minimized that it forms no stable salts with acids. It is used in veterinary practice as an anthelmintic and certain of its derivatives, usually prepared by replacement of proton of nitrogen atom, are of medicinal importance.

The nature and the position of substituents on the phenothiazine nucleus strongly effect activity. The activity is increased, by replacing the hydrogen of C-2 by chlorine (chlorpromazine), trifluoromethyl (triflupromazine) or a dimethylsulphonamide group (thioperazine). Tranquillizing activity does not change due to substitution on C-2 such as thioalkyl (thioridazine, thioethylperazine) and octyl groups (butaperazine. acetophenazine. carphenazine). Tranquilizing activity is lost due to a ring substituent in positions l. 3, 4 or simultaneous substitution in both aromatic rings. Optimum tranquilizing activity is observed with the three-carbon side chain connecting the nitrogen of the phenothiazine ring and the more basic sidechain nitrogen. Compounds containing two-carbon side chains still possess a moderate central depressant activity, but these compounds have antihistaminic and antiparkinsonism effects. If length and polarity of the side chain is changed, tranquilizing effect is lost.

If a small group like methyl is substituted at the B-position of the side. chain, tranquilizing activity is reduced while antihistaminic and antipruritic effects are enhanced. Substitution on the side chain with a large or polar groups such as phenyl, dimethylamino or hydroxyl results in loss of tranquillizing activity. The laevo isomer of the side chain is more active than the dextro isomer for B-methyl analogues. Substitution of the piperazine group (prochlorperazine, trifluoperazine) in place of the terminal dimethylamino moiety on the side chain increases potency. Substitution of -CH, CHOH for the terminal methyl group on piperazine (perphenazine, fluphenazine) increases the potency. Dimethylamino compounds produce a parkinson-like syndrome (tremors, rigidity, salivation) while piperazine derivatives produce dyskinetic reactions. Dimethylamino and alkylpiperidyltype derivatives result in skin and liver disorders and blood dyscrasias Quaternary derivatives of the side chain nitrogen do not dissolve in lipids and their penetration in the central nervous system is lost.

he phenothiazines produce a lesser degree of central depression than the barbiturates or benzodiazepines. Adverse effects of phenothiazine therapy may include as dry mouth, constipation, urinary retention, mydriasis, agitation, tachycardia, electrocardiographic changes, postural hypotension, miosis, blurred vision, allergic reactions, jaundice, etc.