Antihypertensive ureidopiperidines

Abstract

The synthesis of a series of 1-aralkyl-4-ureidopiperidines is reported. These compounds are related to the benzamidopiperidines exemplified by indoramin. Some of the ureidopiperidines are more potent antihypertensive agents than their benzamidopiperidine counterparts. Two examples, 1-(2-thenoyl)-3-[1-[2-(3-indolyl)ethyl]piperid-4-yl]urea and 1-(2-thenoyl)-3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperid-4-yl]urea (19 and 58), emerged as the most potent antihypertensive agents in this series.

Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

“…In route i, reductive amination of a boc-protected 4-amino piperidine ( 2 ) yielded a common protected amine ( 3 ) with good yield (70–99%). Subsequent acid-mediated deprotection and condensation of the resulting amine with isocyanates furnished the desired disubstituted urea analogues ( 4 ) in moderate yields over the two steps (40–75%). − Synthesis of the trisubstituted ureas utilized two separate routes (ii and iii) that permitted the late-stage introduction of either the Ile or the hinge pocket substitutions. Starting from 4-piperidone ( 5 ), alkylation to give 6 and reductive amination afforded an amine common intermediate 7 that was coupled with isocyanates to give alkylurea analogues targeting the hinge pocket 8 .…”

Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

“…Reductive amination of 14 with benzylamine furnished the secondary amine 15 Tables and ). − Given the wider availability of anilines, we used the CDI-mediated reaction for our parallel chemistry. For this reaction, it was critical to allow CDI to react with the aniline prior to addition of the secondary amine 15 .…”