Di-N-substituted 2-Halogenoethylamines. Part VI.¹ NN-Dialkyl(or N-Alkyl)-2-alkyl(or aryl or arylalkyl) Derivatives: Synthesis, Reactivity, and Pharmacology

The preparation is described of a series of compounds Ar·CHX· CH₂NRR, HX with X = Cl, Br, or, rarely, I, Ar = phenyl or substituted phenyl, R = alkyl or hydrogen, and R' = alkyl; and of a second series CH ₃·CHX·CH₂·NR₂.HX, with X = Cl or Br, and R = alkyl. Where necessary the corresponding alcohols have been unambiguously synthesised by reduction of the related ketone of definite structure, but usually interaction of an amine and an epoxide has been used to obtain the alcohols. These have been converted into the corresponding halogeno-compounds by standard methods. In some cases the products of solvolysis of the halogeno-amines in 1 : 1 aqueous acetone have been characterised; and in suitable cases rate coefficients and Arrhenius parameters for the solvolysis in 1 : 1 aqueous acetone of the related ethyleniminium ions have been determined, and the proportions of three possible products calculated. The anti-adrenaline and anti-noradrenaline activities of many of the compounds are reported : this series includes some of the most potent known substances of this kind. Their pharmacological activity, however, differs in important respects from that of the "Dibenamine" group of compounds, particularly as to their briefer action. In this series also some secondary alkylamino-compounds with significant activity have been discovered. Structure-action relationships are discussed and the relevance of the results to Belleau's theory of anti-adrenaline activity is considered. The relation of the structure of the substituted 2-halogenoethylarnine molecule to its rate of cyclisation is discussed in terms of an internal 5_N2 mechanism (involving neighbouring-group participation). Also the orientation and rate of solvolysis of the ethyleniminium ions formed in this process are discussed by citing analogies with the corresponding reaction of epoxides, mainly in terms of the steric and polar influences of the various dialkylamino-groups present in the compounds studied.