Σύνθεση και μελέτη δομής συμπυκνωμένων βενζοδιαζεπινικών παραγώγων με πιθανή βιολογική δράση

Abstract

In the present Thesis, the synthesis and chemical reactivity of 1,5-benzodiazepines and fused 1,5-benzodiazepines is studied. The one pot synthesis of arylodiazepinothiophenones 353, fused thiazolobenzo-diazepines 360, fused thiazolobenzimidazoles 362 and 1,5-benzodiazepines 39 was achieved by refluxing o-phenylenοdiamines with ketones and substituted mercapto-acids. Benzodiazepinothiophenones 353 and benzodiazepines 39 were also isolated from the reaction of o-phenylenodiamines with phorone and mercapto acids. The reactions of o-phenylenodiamine, substituted o-phenylenodiamines, naphtha­line- and pyridine-diamines with acetone, acetophenone, 2-butanone, 3-pentanone and several acides, as 3-mercapto, 2-mercapto-propionic acids, thiolactic acid and 2-mercapto-benzoic acid were studied. In addition, reactions of o-phenylenodiamines with 1,3-dicarbonyl compounds, such as acetyl acetone, acetylacetophenone, dibenzoylmethane and also 2-acetylcyclohexanone in the presence of acid under reflux or microwave irradiation conditions were examined. In the same chapter, the reductive reaction of 353a with LiAlH4 to 409 and with Raney-Ni to 410 were studied. The cycloadition reactions of 353a and 409 with dienes or dienophiles such as DMAD, 2,3-dimethyl-butadiene, ketenes and quinines, were investigated. The second goal of the reported work is the generation of the benzodiazepine o-quinodimethane 449a and its cycloaddition reactions with various dienophiles to produce polycyclic arylodiazepines 451-462. For this reason the 7,8-dimethyl-2,4-diphenyl-3H-1,5-benzodiazepine (429) was prepared in almost quantitative yield under microwave irradiation conditions. Radical photobromination of this 7,8-dimethyl derivative 429 was carried out using different stoichiometries of NBS. The mono-, di-, tri-, tetra- and hexabromo compounds 439, 440, 441, 442 and 444 were formed in good yields with a satisfactory degree of regioselectivity (~2:1). The pentabromode­rivative 443 was formed regiospecifically in excellent yield and was trapped by in situ reaction with dienophiles. The possibility of the formation of 2,3-dihydro-1H-1,5-benzodiazepine quino­dimethanes was also examined. The diazepine 463 was synthesized in solvent free conditions from o-phenylenediamines and ketones in the presence of catalytic amound of acetic acid, under microwave irradiation. However all attempts to obtain the bis-dibromo-derivative 466 failed. The reaction of 2,3-dihydro-1H-1,5-benzodiazepine 463 and 372 with anydrites and acid chlorides was also studied. A preliminary synthetic route for the preparation of 522 is also reported. Finally, the arylodiazepinothiophenones 353a, 353b, 353c1, 353d1, 353d2, 353e1, 353e2, 359, 364 και 383 were tested for their ability to interact with the stable radical 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and also for their inhibitory activity on aldose reductase and it was found that they are active antioxidants and some of them also inhibit the aldose reductanse enzyme.