Synthesis and Benzodiazepine Receptor Binding Studies of Pyridazino[3, 4-b]indoles

Abstract

A series of methyl 9H-pyridazino[3,4-b]indole-3-carboxylates and related compounds were synthesized using a Diels-Alder reaction of methyl 3-(1H-indol-3-yl)-2-propenoates and dibenzyl azodicarboxylate. Several compounds were found to have high affinity for the benzodiazepine receptor. Their structure-activity relationships are discussed.

Construction of Unusual Indole-Based Heterocycles from Tetrahydro-1H-pyridazino[3,4-b]indoles

“…Given the intriguing structures and the medicinal importance of polycyclic indole-based molecules [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ], we envisioned that the amalgamation of the indole moiety [ 8 , 9 , 10 , 11 , 12 , 13 ] with the pyridazine ring [ 14 , 15 , 16 , 17 , 18 , 19 ] that potentially generates different isomeric scaffolds ( a – c ) would lead to entities endowed with either amplified or new biological activities ( Figure 1 ). A large number of reports dedicated to the synthesis of these appealing frameworks and studies on their pharmacologic activities appeared in the literature in the past few decades [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Among the heterocyclic architectures a – c , the tricyclic fused indole-pyridazine system c which can be considered to be aza-analogous (or bioisoster) of β-carboline, the unique tricyclic pyrido[3,4- b ]indole core amenable to an important family of bioactive natural products widely distributed in nature [ 30 ], has attracted our attention.…”

“…Although many of the above cited examples deal with 5 H -pyridazino[4,3- b ]indoles ( a ) [ 20 , 21 ] and 5 H -pyridazino[4,5- b ]indoles or 3 H -pyridazino[4,5- b ]indol-4(5 H )-ones ( b ) [ 22 , 23 , 24 , 25 , 26 ], the chemistry of 9 H -pyridazine[3,4- b ]indoles ( c ) [ 27 , 28 , 29 ] is much less known.…”

“…Specifically, in 1964, Kobayashi and Furukawa presented the synthesis of various 3-phenyl-9 H -pyridazine[3,4- b ]indoles by heating 3-phenacyl-oxindoles and hydrazine hydrate in acetic acid solution [ 27 ]. In 1992, Shimoji and co-workers synthesized a series of methyl 9 H -pyridazino[3,4- b ]indole-3-carboxylates and related compounds using a Diels-Alder reaction of 3-(1 H -indol-3-yl)-2-propenoates with dibenzyl dicarboxylate [ 28 ]. Several of these compounds were found to have high affinity for the benzodiazepine receptor.…”