Abstract
(3S)-2-[N-Substituted N-(2-carboxyethyl)carbamoyl]-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid derivatives (V) were synthesized by condensation of (3S)-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylates (III), 3-alkylaminopropionates (II), and phosgene, followed by cleavage of ester groups. The in vitro angiotensin converting enzyme (ACE) inhibitory activities of these dicarboxylic acid derivatives (V) were evaluated. Among them, N-ethyl (13) and N-isopropyl (14) derivatives showed high inhibitory activities with IC50 values of 1.1×10-8 and 7.7×10-8M, respectively. These compounds showed only weak inhibition of the pressor response to angiotensin I after oral administration in normotensive rats. Thus, in order to derive orally active inhibitors, the ester derivatives (IV, VI, and VII) were prepared as prodrugs of the dicarboxylic acids (V). Of these esters, the monoester compounds (VI) having the ester function at the side chain were found to be orally active. In particular, (3S)-2-[N-ethyl-N-(2-butoxycarbonylethyl)carbamoyl]-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid (20) inhibited the pressor response to angiotensin I by up to 82% at an oral dose of 1.0 mg/kg.
