Vìsnik Odesʹkogo Nacìonalʹnogo Unìversitetu: Hìmìâ (Dec 2019)
SYNTHESIS OF NOVEL 1-METHOXYCARBONYLMETHYL-7-BROMO-5-PHENYL-3-ARYLIDENE-1,2-DIHYDRO-3H-1,4-BENZODIAZEPIN-2-ONES
Abstract
It is known that 1,4-benzodiazepines have neurotropic properties. Relatively recently, we have shown that 2-arylidenesubstituted 1,4-benzodiazepines demonstrate pronounced analgesic properties. In this regard, the aim of this work is the synthesis of potential analgesics. In this article, the synthesis under conditions of interphase catalysis and the analgesic activity of 1-methoxycarbonylmethyl-7-bromo-5-phenyl-3-arylidene-1,2-dihydro-3H-1,4-benzodiazepin-2-ones not previously described in the literature are described. It was shown that the application of the method using a saturated aqueous solution of potassium carbonate as the base and the use of tetrabutylammonium bromide (TBAB) as the phase transfer catalyst provides high yields of the expected products at an acceptable reaction rate. Our earlier attempt to use sodium methylate as the base in anhydrous aprotonic solvents leads to the formation of a large number of by-products, which subsequently made it difficult to process the reaction mixture and isolate the target compounds. The structure of the synthesized compounds was confirmed by mass spectrometry and 1H NMR spectroscopy. It was found that all compounds, tested for the presence of analgesic activity in in vivo experiments in mice, possess the analgesic activities which exceed the activity of the standard preparation «diclofenac – sodium». For the most active compounds, ED50 values were found for analgesic activity. These values were approximately 10 times higher than the value obtained for the standard preparation. It was found that in the synthesized series, the most active is compound 20 (ED50 = 0.60 ± 0,20 mg/kg), which contains a methoxy group in the arylidene fragment, a bromine atom is in the seventh position, and a phenyl substituent is in the fifth position.
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