Synthesis of Heterocyclic Compounds Isosterically Related to Pyrazolo[4,3-c]quinolines as Benzodiazepine Receptor Ligands

Abstract

Fused pyridine and pyrimidine derivatives have been synthesized which are isosterically related to pyrawlo[4,3-clquinolines with the high affinity ta the henwdiazepine receptor.Benzodiazepines are important therapeutic agents which have been extensively studied.1 Recently, a number of synthetic compounds with a diverse ring system have been found to have an affinity to the benzodiazepine receptors.2PThese non-benzndiazepines serve as important tools for studying the physiological properties and structural requirements of the recognition site of the receptor itself.Representative of the non-henzodiazepines is the series of pyrazolo[4,3-clquinoline derivatives such as CGS 8216 and CGS 9896, which have very high affinity for receptors and different intrinsic activities.3We have reported that thienylpyrazolo[4,3-clquinolines 6a and Bb, having the high affinity for the receptors, exhibit inverse agonist and agonist activities, re~~eetively.4In addition, 6a was shown to enhance performance in learning and memory tasks in animal models.5These findings led us to synthesize other heterocyclic compounds with analogous ring systems and screen them for benwdiazepine binding affinity.Here we report the synthesis and the binding affinity of fused pyridine and pyrimidine derivatives which contain at least two nitrogen atoms and one phenyl suhstituent corresponding to those of 2-substituted pyrazolo[4,3-cl-C 0 2 E 1 ~) ~a ~/ ~~~-~~~ sealed, llO'C 2) XQNCO, room temp.