| Abstract [eng] |
Nitrogen-containing heterocyclic compounds are found in pharmaceuticals, agrochemicals, and other functional substances. N-Heterocyclic compounds fused with a seven-membered 1,4-diazepine ring exhibit various biological activities: antiviral, anxiolytic, antibacterial, anticancer and antiparasitic. Intramolecular cyclisation of N-heterocyclic compounds containing ester and amino groups can be used for the synthesis of these compounds. In this master's final degree work, the synthesis of pyrazole and indole derivatives containing 1,4-diazepinone ring was performed. Firstly, ethyl-1H-pyrazole-3(5)-carboxylates were N-alkylated with 2-(chloromethyl)oxirane, as a result isomeric ethyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-3-carboxylates and ethyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylates were formed. Obtained ethyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylates were treated with aliphatic amines resulting in oxirane ring-opening and cyclisation affording the target tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine- 4-ones. It was determined that after the treatment of ethyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate with arylamines cyclisation does not occur and, for instance, after the reaction with aniline ethyl-1-(3-anilino-2-hydroxypropyl)-1H-pyrazole-5-carboxylate was obtained. Reaction of ethyl-1-(oxiran-2-ylmethyl)-1H-pyrazole-3-carboxylate with ammonia or benzylamine resulted in oxirane ring-opening without further cyclization. Synthesized tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-ones were treated with N-bromo-, N-chloro- and N-iodosuccinimides to obtain 2(3)-bromo-, 2(3)-chloro-, 2(3)-iodosubstituted fused compounds. An analogous two-step synthetic approach was applied to synthesize tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-ones from ethyl-1H-indole-2-carboxylates. Obtained 4-hydroxy-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one was treated with methyl iodide. Different ratios of N,O- and N-methylated products were formed depending on the amount of alkylating agent equivalents used. Anticancer activity of synthesized tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one and tetrahydro-1H-[1,4]diazepino[1,2-a]indol-1-one derivatives, and anthelmintic activity of brominated, chlorinated and iodinated tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one derivatives were performed by the researchers of prof. Vladimír Kryštof's group at the University of Palacky. After analyzing the obtained data, it was determined that none of the tested compounds had anticancer and anthelmintic activity within the tested concentration. |
