SYNTHESIS, STRUCTURE AND AFFINITY TO CNS RECEPTORS 8-BROM-11-METHYL-6-PHENYL-11-PYRIMIDO[4,5-B][1,4]BENZO¬DIAZEPINE

Abstract

The purpose of this work is the synthesis of an annelated with pyrimidine system at position 2–3 of  the diazepine cycle and the study of the affinity of the synthesized compound for the central  benzodiazepine receptors (CBDR) and peripheral  benzodiazepine receptors (PBDR) of the CNS, as well as, in the future, the study of pharmacological  properties. The synthesis of 8-bromo‑11-methyl‑6-phenyl‑11-pyrimido[4,5-b][1,4]benzodiazepine II was carried out by heating 7-bromo‑1-methyl‑5-phenyl‑1,3-dihydro‑2Н‑1,4-benzodiazepin‑2-one I with formamide in a solution of phosphorus  oxychloride. The structure of compound II was  confirmed by mass spectrometry and 1H NMR spectroscopy, as well as by X‑ray diffraction analysis.  1Н NMR spectrum was recorded in ~2% solution of the compound in CDCl3 on the Bruker (300 MHz),  internal standard TMS. Mass spectrum of the  compound was obtained by electron impact on an  mass spectrometer, “MX‑1321”, ionizing voltage 70  eV, ionizationchamber temperature 220 °C. The X‑ray diffraction study of the single crystal was carried out on a KUMA‑4CCD diffractometer using MoKa –  radiation with ω-scanning at 100 K. The affinity of compound II to the central and peripheral  benzodiazepine receptors of the CNS was studied by radioligand analysis. The experiment was carried out on nonpedigreed male rats with mass 180–220 g. The following radioligands were used: [3H]flumazenil (CBDR) and [3H]RK 11195 (PBDR). As a result of  radioligand studies, it was found that compound II at a concentration of 1 10–6 M inhibits the specific  binding of the radioligand [3H]flumazenil to CBDR by 43.7%, which indicates the presence of a moderate affinity for CBDR. It was also found that compound II  at a concentration of 1 10–6 M inhibits the specific binding of the radioligand [3H]RK 11195 with PBDR  by 3.7%, which indicates the practical absence of  affinity for PBDR. The presence of a moderate affinity of compound II for CBDR and the selectivity of the  binding of this compound to CBDR with respect to  PBDR is of interest for further studies of this class of compounds as potential anxiolytics of a new type.