Practical synthesis of potential endothelin receptor antagonists of 1,4-benzodiazepine-2,5-dione derivatives bearing substituents at the C3-, N1- and N4-positions.
The expedient synthesis of various 1,4-benzodiazepine-2,5-dione compounds, particularly those having substituents at the C3-, N1- and N4-positions is achieved. The important features in these synthetic strategies include: (i) using the coupling reaction of isatoic anhydride with alpha-amino ester for direct construction of the core structure of 1,4-benzodiazepine-2,5-dione; (ii) using potassium carbonate as the base of choice for selective alkylation at the N1-site, while using lithiated 2-ethylacetanilide as the required base to furnish the N4-alkylation; and (iii) using 2-nitrobenzoyl chloride as a synthetic equivalent of anthranilic acid to facilitate the polyethylene resin-bound liquid-phase combinatorial synthesis. The prepared 1,4-benzodiazepine-2,5-dione compounds are evaluated for endothelin receptor antagonism by a functional assay that measures the inhibitory activity against the change of intramolecular calcium ion concentration induced by endothelin-1. The preliminary results indicate that 1,4-benzodiazepine-2,5-diones bearing two flanked aryl substituents at the N1- and N4-sites show better inhibitory activity than the corresponding unalkylated and N-monoalkylated compounds. A promising candidate, 1-benzyl-7-chloro-3-isopropyl-4-(3-methoxybenzyl)-1,4-benzodiazepine-2,5-dione (17b), exhibits an IC50 value in low nM range.
Cheng
Ming-Fu
MF
Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan.
Yu
Hui-Ming
HM
Ko
Bor-Wen
BW
Chang
Yu
Y
Chen
Ming-Yi
MY
Ho
Tong-Ing
TI
Tsai
Yeun-Min
YM
Fang
Jim-Min
JM
D000818:Animals; D001570:Benzodiazepinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002244:Carbon / Q000737:chemistry*; D006224:Cricetinae; D065128:Endothelin Receptor Antagonists; D006801:Humans; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000378:metabolism; D013050:Spectrometry, Fluorescence
D001570:Benzodiazepinones; D065128:Endothelin Receptor Antagonists; D010455:Peptides; D017466:Receptors, Endothelin; D002244:Carbon; D009584:Nitrogen; D002118:Calcium