The purinergic P2X receptors are a family of cation-permeable ligand gated ion channels that open in response to the binding of extracellular adenosine 5'-triphosphate (ATP). This ionotropic receptor family contains seven subunits P2X1-7, and is involved in various physiological processes and associated with a variety of diseases including cancer, cardiovascular and neurological diseases. P2X4 is a predominant subtype expressed on immune and neural cells. The over expression of P2X4 is linked to neuroinflammation, which is an essential step in the progression of brain diseases. P2X4 has become a novel molecular target for treatment and PET imaging of neuroinflammation and associated brain diseases such as Alzheimer’s disease. Despite the therapeutic potential of P2X4 antagonists, only a very limited number of antagonists are known so far. However, potent and selective P2X4 antagonists are required as research tools for investigating the physiological functions of P2X4. 5-BDBD (5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1, 4]diazepin-2-one) is a specific P2X4 antagonist with an IC50 of 500 nM in Chinese hamster ovary cells (CHO). Here we report the design and synthesis of a series of 5-BDBD analogues as new potential P2X4 receptor antagonists. 5-(3-Substituted phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one analogues including 5-(3-fluorophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1, 4]diazepin-2-one (5a), 5-(3-chlorophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1, 4]diazepin-2-one (5b), 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1, 4]diazepin-2-one (5c), 5-(3-iodophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (5d), 5-(3-nitrophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (5e) and 5-(3-methoxyphenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (5f) were synthesized from commercially available 2-hydroxybenzonitrile with 3-substituted phenacyl bromides (1a-1f) in 3 steps with 36-80% overall chemical yield. Desmethylation of 5f gave 5-(3-hydroxyphenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (6) in 81% yield. O-alkylation of 6 with 2-fluoroethyl tosylate or 1,2-bis(tosyloxy)ethane afforded 5-(3-(2-fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (7) and 2-(3-(2-oxo-2,3-dihydro-1H-benzofuro[3,2-e][1,4]diazepin-5-yl)phenoxy)ethyl 4-methylbenzenesulfonate (8) in 65% and 43% yield, respectively.

Synthesis of 5-BDBD analogues as new potential P2X4 receptor antagonists

251st National Meeting (2016)

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