Synthesis and Pharmacoclogical Activity of a Pyrido[3',4':5,4]pyrrolo[1,2-c][1,4]benzodiazepine-3,10-dione, a New Benzodiazepine-b-carboline Type Hybrid Molecule

Abstract

Diethyl 2.3-dihydro-6-azaindoline-2.5-dicarboxylate 9 was synthesized and used as starting material in the preparation of a novel benzodiazepine-p-carboline type hybrid molecule (3aR,S)-ethyl 3.10dioxo-2,3,3a,4-tetrahydr~-1OH-pyrido[3',4':5,4lpyrrolo[l,2-cl11,41b e n z o d i a z e p i n e -6 -c a h y l a t e z.The benzodiazepine receptor binding affinities of this compound and its precursors were found to be very modest & D. These results confirm our previously proposed model of the configuration of the benzodiazepine and 8-carboline binding sites on the receptor as represented by the configuration of these two moieties in the high affinity hybrid 1.This paper is dedicated to Professor Sir Derek Barton on the occasion of his 70th birthday.The benzodiazepine receptor of the m a l i a n central nervous system is known to mediate the anticonvulsant, anxiolytic and sedative properties of 1,4-ben~odiaze~ines (e.g.flunitrazeparn, la, Scheme 1 ) . -This receptor also binds compounds of the 3-cerboxy-0-carboline class (e.g.ethyl 0-carboline-3carboxylata or 0-CCE. 2 ) with high affinity.2Based on the hypothesis that 1.4-benzodiaeepines and 3-carboxy-0-carboline.occupy separate but adjacent (or partly overlapping) sites on the receptor protein, we have recently described the synthesis and high binding affinity of a hybrid molecule 2 which combines structural features of both and 2 in a single m~lecule.~This hybrid may thus presumably occupy simultaneously both types of sites on the receptor.In this paper, we present the synthesis and receptor affinity of another type of hybrid molecule in which the 1.4-beneodiazepinedione moiety (B) is this time fused to the 1.2 positions of 5-ethoxycarbonyl-6-amindoline (9).The latter constitutes the reduced form of the 6-azaindole h, the essential phamacophore of active 0-carbalines of type 2.The preparation of dicarboxylic 6-azaindolen of type 4 has not previously been described.Prydman et al.4 were able to synthesize 2-ethoxycarbonyl-5-rnethoxy-6-azaindole by condensation of diethyl oxalata with 2-methaxy-4-methyl-5-nitropyridine followed by reductive cyclizetion of the resulting pyruvatr.This methodology was adapted for the synthesis of starting from 2,4-lutidins @, Scheme 2 ) .