Influence of substituents upon the basicity, spectral characteristics, and lipophilicity of a series of 3-aminopyridazines

Abstract

The protonation and partition thermodynamics of a series of substituted 3-aminopyridazines have been studied. The lead compound, 4-methyl-3-(2-morpholinoethylamino)-6-phenylpyridazine, minaprine, is a commercialized antidepressant drug.

The protonation constants were determined by potentiometric and/or spectrophotometric methods which also enabled us to calculate the electronic spectra of the different species. Although there are at least four potentially protonizable sites, only two constants could be determined, which correspond to the morpholino nitrogen (K₁) and to one of the nitrogen atoms of the amidino group (K₂)·log K₁(to a smaller extent) and especially log K₂ is shown to be linearly related to the classical Taft and Hammett electronic parameters for the different substituents. However, the correlation between partition coefficients (P) or distribution coefficients at physiological pH (P′) and lipophilic parameters such as those of Hansch, or the Rekker and Leo fragmental constants, is not as obvious.