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

被引：1

作者：

Gomi, Noriaki ^{[1
]}

Shibuya, Kimiyuki ^{[1
]}

Kawamura, Kiyoshi ^{[1
]}

Kabeya, Mototsugu ^{[1
]}

机构：

[1] Kowa Co Ltd, Noguchicho Higashimurayama, Pharmaceut Div, 2-17-43 Noguchicho, Tokyo 1890022, Japan

来源：

TETRAHEDRON LETTERS | 2022年 / 91卷

关键词：

Rho-kinase inhibitor (K-115); Oxidative metabolites; Rearrangement of isoquinoline N-oxide; The combination of phase transfer catalyst and benzoyl chloride; PRACTICAL SYNTHESIS; ALDEHYDE OXIDASE; CONDENSING AGENT; DRUG; FASUDIL; MECHANISM; AMINES; ACID;

D O I：

10.1016/j.tetlet.2021.153589

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

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.

引用

页数：4

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