Abstract

A study of the adrenergic blocking activity of 53 phenoxyethyl and closely related amines has revealed the following:

1. Secondary phenoxyethylamines and tertiary phenoxyethylamines which do not contain a β-haloalkyl grouping may exert an adrenergic blocking action which is relatively weak and of short duration. Phenoxyethyl-alkyl-β-haloalkyl-amines are somewhat more effective. Diphenoxyethyl- and phenoxyethyl-benzyl-β-haloalkylamines are very potent adrenergic blocking agents which produce a typical Dibenamine-type blockade.

2. Ortho-methyl substitution of the aromatic ring of phenoxyethylamines produces a considerable increase in activity while meta and para substitutions significantly reduce activity. Increasing the size of the alkyl substituent from methyl to isopropyl produces a progressive increase in activity, but n-amyl decreases activity. Compounds which include an α-methyl substituent on the oxyethyl chain are an exception to this rule in that unsubstituted or methyl-substituted derivatives exhibit maximal activity.

3. A definite potency relationship exists within each series of similarly substituted phenoxyethylamines, the phenoxyethyl-alkyl, diphenoxyethyl and phenoxyethyl-benzyl derivatives increasing in activity in that order. Several of the above phenoxyethyl-benzyl compounds are more potent adrenergic blocking agents than any β-haloalkylamines previously reported.

4. Irrespective of other substituents, replacement of a phenoxyethyl grouping by a phenylthioethyl causes a reduction in adrenergic blocking activity.

5. From a consideration of the structure-activity data presented, it is concluded that although the phenoxyethyl grouping is capable of influencing the adrenergic blocking activity of β-haloalkylamines by altering, through a resonance mechanism, the chemical properties of the active intermediates formed by members of this series, its primary contribution to the high activity of certain of the compounds reported here is steric. However, as in previous studies, prolonged effective adrenergic blocking activity was not observed in the absence of a structural configuration permitting the effects of an aromatic substituent to be exerted, perhaps by a process of hyperconjugation, on the ethylenimmonium intermediates.

6. The high adrenergic blocking activity and low toxicity of several of the reported diphenoxyethyl-β-chloroethylamines and particularly of the phenoxy-ethyl-benzyl-β-chloroethylamines suggest that these compounds may be significantly superior to the parent compound Dibenamine as agents for the production of an experimentally and clinically useful adrenergic blockade.