SYNTHESIS AND STUDY OF THE STRUCTURE AND PROPERTIES OF INDOLE-CONTAINING 1,4-BENZDIAZEPIN-2-ONE DERIVATIVES

Abstract

The successful method of synthesis of 3-indolylmethyl-1,2-dihydro-3H-1,4-benzdiazepinon-2-one derivatives was developed. As starting materials ethyl ester hydrochloride of tryptophan and the acid chloride of tryptophan hydrochloride were used to obtain derivatives of 3-indolylmethyl-1,4-benzodiazepin-2-one. The stoichiometry and structures of the synthesized compounds were confirmed by IR and UV spectroscopy, mass spectrometry, elemental analysis, polarographic reduction. To investigate the acid–base properties of 3-indolylmethyl derivatives, potentiometric titration of these compounds was carried out. Experimental results shown that the presence of an electron-withdrawing substituent at position 7 leads to a significant decrease in basicity, whereas the introduction of an electron-donating substituent (CH₃) results in its increase. A good correlation between the half-wave reduction potentials (E₁/₂) and basicity (pKВ) was observed. This was explained by the fact that both the ease of protonation and the process of electron addition during polarographic reduction ultimately depend on the magnitude of the negative charge at the nitrogen atom in position 4. All studied compounds exhibited anticonvulsant activity, expressed to varying degrees depending on their structure. A decrease in pharmacological activity observed for 7-substituted 1,2-dihydro-3H-1,4-benzodiazepines with increasing size of the substituent at position 7. This was explained by a reduced amount of the substance penetrating the histohematological barriers into the central nervous system. But the investigation of the distribution dynamics of 7-chloro-3-indolylmethyl-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one in the liver, blood, and brain of white mice indicated that the ability of 3-indolylmethyl-1,4-benzodiazepin-2-one derivatives to penetrate histohematological barriers into the central nervous system is not the determining factor of their biological activity. So pharmacological data obtained for representatives of the class of 3-indolylmethyl-1,2-dihydro-3H-1,4-benzodiazepin-2-ones indicated that these compounds are promising candidates in the search for new psychotropic agents.