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Triazoles of type (I)‐(III) are synthesized according to common procedures and compared with the antihypertensive agents clonidine (IV), nebidrazine (V), H 152/43 (VI) and hydralazine (VII).

Synthetic methods for the preparation of 3,4,5‐triamino‐4H‐1,2,4‐triazole (guanazine) and its 4‐arylidene‐amino derivatives are described. Guanazine, which can be used as an appropriate starting material in the syntheses of different bicyclic heterocycles, was readily obtained from thiosemicarbazide by treatment with mercuric oxide. Guanazine was also obtained from the S‐methylisothio ether of thiosemicarbazide via a pyrolytic reaction. The 4‐arylideneamino derivatives were either prepared by treatment of guanazine with an appropriate aromatic aldehyde, or by methods in which 1‐arylidene‐5‐thiocarbamoyldiaminoguanidines are used as starting materials.

The kinetics and dynamics of total and free (unbound) disopyramide (D) after dosing with D, 1.5 and 2 mg/kg iv, were compared with those of the dealkylated metabolite (MND) after dosing with MND, 0.5 and 1.5 mg/kg iv, in six healthy subjects. Dynamic parameters included ECG with measurement of the QT interval corrected for heart rate (QTc), systolic time intervals, vitamin C-stimulated saliva secretion, pupil size, and maximum accommodation capacity. Mean values of total clearance, apparent volume of distribution, and elimination t1/2 of MND were 5.9, 2.3, and 0.4 times those of total D, respectively. D significantly prolonged the QTc and systolic time intervals and induced transient inhibition of stimulated saliva secretion. In contrast, MND induced no substantial change in either the QTc or systolic time intervals, but did induce more persistent inhibition of salivary secretion. If anticholinergic potency is determined as the degree of inhibition of stimulated saliva flow per plasma concentration unit, MND was three times as potent as its parent when measured at maximum inhibition. There were no consistent drug effects on the ocular parameters. The effect of D on QTc correlated with both total and free plasma concentrations. Furthermore, its transient salivary inhibitory effect paralleled its initial rapid decline in plasma concentration. There was no relationship between the MND plasma concentration and its salivary inhibitory effect. We conclude that disopyramide significantly affected the QTc and systolic time intervals in healthy subjects, while MND in a similar dose had no such effects. MND more strongly inhibited stimulated saliva flow, indicating a more potent anticholinergic effect than D.

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