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The N-isopropyl- and N-t-butyl-substituted 1-[o-(3-amino-2-hydroxypropoxy)benzylideneaminoxy]-3-amino-2-propa nols (7a,b) and their meta (8a,b) and para (9a,b) isomers, in which a single aromatic ring is substituted both by the oxypropanolaminic chain of (aryloxy)propanolaminic beta-adrenergic antagonists (AOPAs) and the [(methyleneamino)oxy]propanolaminic chain of [(methyleneamino)oxy]-propanolaminic beta-blocking drugs (MAOPAs), were synthesized and assayed for their beta-adrenergic activity by functional tests on isolated preparations. Compounds 7-9 represent a new type of molecular duplication of beta-adrenergic drugs, formally deriving from the sharing of the aromatic portions of two different pharmacophoric subunits, namely the (aryloxy)propanolaminic portion of AOPAs and the [(benzylideneamino)oxy]propanolaminic portion of aryl-substituted MAOPAs. The pharmacological results showed that the beta-blocking activity of compounds 7-9 is closely related to the way in which the two subunits are linked by the aromatic nucleus: the activity decreases on passing from the ortho-compounds (7a,b) to the meta (8a,b) and then to the para (9a,b) isomers. A comparison of this activity trend with those found for series of both beta-blocking AOPAs and aryl-substituted MAOPAs seems to indicate that compounds 7-9 can be considered more as AOPAs substituted on the phenyl ring by a [(methyleneamino)oxy]propanolaminic chain rather than as aromatic MAOPAs substituted on the same phenyl moiety by an oxypropanolaminic portion.

In a previous paper, it had been found that completely aliphatic 3-(methylene aminoxy)propanolamine derivatives showed a good beta-blocking adrenergic activity directed prevalently towards beta 2-tracheal receptors. In an attempt to change the beta-adrenergic properties of these compounds from antagonist to agonist, while still retaining the beta 2-selectivity, a series of new completely aliphatic 3-(methyleneaminoxy)propanolamine derivatives were designed in which either a hydroxylic or a methoxylic group was present on the aliphatic portion linked to the oximic carbon. The synthesis of the new compounds and their beta-adrenergic activity, evaluated by means of functional tests on isolated preparations, are described and discussed; the results obtained are then rationalised on the basis of their conformational and reactivity characteristics, determined by means of theoretical methods.

Hemodynamic activity of cadralazine (ethyl-2-[6-(2-hydroxypropyl)-ethylaminol-3-pyridazinyl hydrazine carboxylate), a new, long-acting antihypertensive agent, was evaluated on systemic and regional circulation in conscious dogs. Cadralazine given i.v. (1 mg/kg) caused a sustained fall in total peripheral vascular resistances and mean blood pressure (from 103 to 90 mmHg) and an increase in heart rate (from 97 to 161 beats/min). Heart rate variations paralleled the drop in peripheral resistances. Cadralazine produced a consistent increase in cardiac output, and this effect was related to the increase in heart rate. No significant change in myocardial contractility was observed. Blood flow was increased and vascular resistances decreased in coronary, iliac and mostly in renal vascular beds, whereas the variations in the mesenteric district were not significant. This hemodynamic pattern characterizes cadralazine as a vasodilator. Changes in hemodynamic responses to epinephrine (1 microgram/kg i.v.) after cadralazine treatment were also evaluated. Cadralazine reduced hypertension and bradycardia effects, increased hypotension and tachycardia responses, and caused a further increase in cardiac output and coronary blood flow. These effects of cadralazine are not due to alpha-blocking or to beta-stimulating properties.

The synthesis and some pharmacological properties of five 2,3-dihydro-3-phenyl-1,4-behzodioxin derivatives (II d-h) are reported. The new compounds generally result more active as local anaesthetics, but less effective as anti-arrhythmic agents than the corresponding 1,3-benzodioxole derivatives.

A series of omega-amino-2-hydroxy-p-fluorobutyrophenones have been synthesized to evaluate the influence exerted by a hydroxyl group in alpha-position to the carbonyl on the persistence of their neuroleptic and collateral properties. The new compounds generally did not show any neuroleptic activity while some of them were still hypotensive; this last effect, however, did not seem to be related to their alpha-adrenolytic properties.

Seven 1,3-benzodioxole derivatives have been found to be effective against certain types of experimentally induced arrhythmias. Among them, 2-[2-(5-chloro-2-methyl-1, 3-benzodioxol-2-yl)ethoxy]-N, N-diethyl-ethanamine (LR 529) showed to be the most active. LR 529 prevented arrhythmias induced by CaCl2 intoxication in anaesthetized and conscious rats, by benzene-epinephrine in anaesthetized guinea-pigs, and by direct electrical stimulation either at increasing intensity of the ventricles of anaesthetized cats or at increasing frequency of the rabbit isolated atria. The new compound reversed to sinus rhythm the arrhythmias provoked by intoxication with aconitine and ouabain respectively in anaesthetized rats and dogs. LR 529 (and the other 1,3-benzodioxoles as well) showed scant local anaesthetic activity, short-lasting hypotensive effects, not accompanied by any change in heart rate, and discrete anti-aggregating activity on rabbit platelets "in vitro". In general, the new compounds showed weak or no effect on autonomic and central nervous systems, neither influenced other pharmacological parameters (at least within the range of doses active on experimental arrhythmias). Acute toxicity studies have indicated that even if some of the 1,3-benzodioxoles were more toxic than quinidine and procainamide, their anti-arrhythmic indexes (especially those of LR 529) were greater than those of the two reference drugs.

A few analogs of the isoxsuprine drug with the phenoxyethyl group incorporated into the heterocyclic 2,3-dihydro-1,4-benzodioxin or 1,3-benzodioxol ring have been synthesized. Among these compounds, the benzodioxol derivative (I e) has been found to possess hypotensive activity in rats in the same range as isoxsuprine, with no alpha-adrenolytic and central sedative properties. Cardiovascular studies in dogs have shown that (I e) is less potent than isoxsuprine, although its activity is longer-lasting at an equally hypotensive dose.

The synthesis of a new series of 1-alkoxybenzyl-4-(2-pyrimidyl)piperazines 2-methyl or 2,6-dimethyl substituted, related to piribedil, is described. Besides compounds (IV)-(IX a, b), the isomer (XI) of (V) was also prepared. Central dopaminergic and alpha-blocking activities both in vitro and in vivo were determined for all compounds. Derivatives (IV), (VII), (XI) were also studied for peripheral vasodilator and sympatholytic activities.

Four new esters (1 b-e) involving the phenolic group of isoxsuprine have been prepared. Preliminary pharmacological evaluation showed that the pivaloyl ester (1 e) (LR693) lowers blood pressure values more gradually than isoxsuprine with a longer-lasting effect. This compound was selected for further assessment as a long-acting peripheral vasodilator.