Synthesis of 1,4-benzodiazepine-2,5-dione derivatives
Journal
Heterocycles
Journal Volume
57
Journal Issue
8
Pages
1501-1506
Date Issued
2002
Author(s)
Abstract
A synthesis of a series of 1,4-benzodiazepine-2,5-dione derivatives with a carboxy group at the 3-position is realized in good yields by using methyl malonylchloride as a key reagent and intramolecular nucleophilic substitution as ring closure reaction.1,4-Benzodiazepine-2,5-dione (BZD) and its derivatives whether it is natural 1,2 or synthetic 3,4,5 represent one of the most important bioactive molecules.The BZD systems exhibit bioactivities such as anticonvulsant, 3 anxiolytic, 4 antitumor 1,5 pain releasing, 6 platelet aggregation inhibiting 7,8 and even anti-AIDS activities. 9It was recently reported that 10,11 the human receptor ET A subtype is selective to endothelin-1 (ET-1), a 21 amino acid peptide.ET-1 exhibits profound endogenous vasoconstriction and mitogenic activities.Antagonism on the vasoconstrictor endothelin is a potential new approach to the treatment of a variety of human diseases including ischemia, hypertension, congestive heart failure, pulmonary hypertension and subarachnoid hemorrhage.In the process of searching for the non-peptide antagonists selective for ET A and ET B receptors, it was found by Elliott 12 that two phenyls on the indane derivative SB 209670 (Figure 1) are restricted dipeptide mimetic to Try-13 and Phe-14 of ET-1.By molecular modeling, we have found that the N-phenyl and N-benzyl group of the BZD ring can be a perfect match to the two phenyls of SB209670.Thus it is possible that compound (1) (Scheme 3) and its derivatives may serve as alternative candidates for the non-peptide antagonists of ET A .Many efforts have been devoted toward the synthesis of this bioactive BZD and its derivatives. 9,13-15For example, Keating and Armstrong recently published 3 a new synthetic method for BZD by using rearrangement (Scheme 1).In a primary attempt (Scheme 2), the N-benzylisatoic anhydride (2) was reacted with aniline to afford the amide (3).Then 3 was reacted with dimethyl chloromalonate to give 4.However, cyclization to seven membered ring by intramolecular amide formation to 5 from 4 was not successful.
Type
journal article