Structure-property relationships in the basicity and lipophilicity of arylalkylamine oxides

Citation
G. Caron et al., Structure-property relationships in the basicity and lipophilicity of arylalkylamine oxides, HELV CHIM A, 82(10), 1999, pp. 1630-1639
Citations number
19
Categorie Soggetti
Chemistry & Analysis",Chemistry
Journal title
HELVETICA CHIMICA ACTA
ISSN journal
0018019X → ACNP
Volume
82
Issue
10
Year of publication
1999
Pages
1630 - 1639
Database
ISI
SICI code
0018-019X(1999)82:10<1630:SRITBA>2.0.ZU;2-K
Abstract
Homologous N,N-dimethyl-phenylalkylamine oxides and N,N-dimethyl-diphenylal kylamine oxides were prepared. Their basicity and lipophilicity (octan-1-ol /H2O) were compared to those of the parent amines. In contrast to the amine s, the basicity of all N,N-dimethyl-arylalkylamine oxides showed very limit ed pK(a) variations (range 4.65-5.01) with increasing chain length and numb er of Ph groups. The N-oxides in their neutral form had a log P-N value low er 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 t heir neutral form, with a decrement diff(log PN-C) that increased from 3.25 to 4.21 in the homologous series. Unexpectedly. the decrement diff(log PN- 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 oxide s. In fact, the protonated N-oxides had log P-C values that were quite comp arable to those of the protonated parent amines. Because of the differences in basicity, the difference in distribution coefficients at physiological pH (log D-7.4) 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 usua lly assumed.