52322-17-5Relevant academic research and scientific papers
Structure-property relationships in the basicity and lipophilicity of arylalkylamine oxides
Caron, Giulia,Ermondi, Giuseppe,Boschi, Donatella,Carrupt, Pierre-Alain,Fruttero, Roberta,Testa, Bernard,Gasco, Alberto
, p. 1630 - 1639 (1999)
Homologous N,N-dimethyl-phenylalkylamine oxides and N,N-dimethyl- diphenylalkylamine oxides were prepared. Their basicity and lipophilicity (octan-1-ol/H2O) were compared to those of the parent amines. In contrast to the amines, the basicity of all N,N-dimethyl-arylalkylamine oxides showed very limited pK(a) variations (range 4.65-5.01) with increasing chain length and number of Ph groups. The N-oxides in their neutral form had a log p(N) value lower by 2.77 ± 0.34 (n = 9) units than that of the parent amine. The log P(C) of the cationic N,N-dimethyl-diphenylalkylamines was lower than that of their neutral form, with a decrement diff(log P(N-C)) that increased from 3.25 to 4.21 in the homologous series. Unexpectedly, the decrement diff(log P(N-C)) for the N-oxides was much smaller than for the tertiary amines, being 0.23 for the aliphatic N,N-dimethyl-pentylamine oxide, 0.47 ± 0.13 for the phenylalkylamine oxides, and 0.80 ± 0.07 for the diphenylalkylamine oxides. In fact, the protonated N-oxides had log P(C) values that were quite comparable to those of the protonated parent amines. Because of the differences in basicity, the difference in distribution coefficients at physiological pH (log D7.4) between a tertiary arylalkylamine and its N- oxide was 0.82 ± 0.66 (n = 9). The pharmacokinetic implication is that N- oxygenation may have a smaller effect on the urinary excretion of tertiary amines than usually assumed.
