Synthesis of oxidative metabolites of K-115, a novel Rho-kinase inhibitor

In humans, oxidative metabolites 2-4 of (S)-4-fluoro-5-(2-methyl-1,4-diazepan-1-ylsulfonyl)-isoquinoline hydrochloride dihydrate (K-115, 1), a novel Rho-kinase inhibitor, are mainly formed by aldehyde oxidase and CYP3A4 / 3A5 in human liver S9 and hepatocytes. We synthesized the proposed compounds 2-4 and determined the metabolite structure by LC-MS/MS analysis. Metabolites 2-4 were synthesized by rearrangement of isoquinoline N-oxide and/or by using (S)-5-keto-2-methyl-1,4-diazepane moiety as a key structure, which in turn was prepared from (R)-3-amino-2-propanol and 3-amino-propionic acid through a Mitsunobu intramolecular cyclization reaction. (C) 2021 Elsevier Ltd. All rights reserved.