| Abstract [eng] |
Since Leo Sternbach accidentally invented sedative Librium in 1956, benzodiazepines became one of the most studied heterocycles in medicinal chemistry. The abundance of benzodiazepine analogues confirms the importance of benzodiazepine backbone in medicinal chemistry. There is no doubt that ongoing exploration of variously substituted benzodiazepines and development of new drug delivery methods will unveil new pharmacological activities and possible disease treatments in the near future. The aim of current MSc thesis is to study the synthesis of variously substituted benzodiazepines that could be further modified through the linker and investigation of toxicity on mice in collaboration with UAB “Innovita Research”. It was found that the best thionation of 1a-d, 1a-cBn towards 2a-d, 2a-bBn performance was achieved by using P2S5Py2 complex in MeCN. In all cases isolated yields were above 63%. Moreover, it was observed that thioamides 2 react with amines without heavy metal catalysts to form amidines in moderate yields. In this work amidine derivatives 3, 4, 6a-d, 7a-f, 8, 9 were successfully synthesized and characterized. Surprisingly, thioamides 2a-b, 2aBn, 2cAc in the reaction with propargylamine gave unexpected imidazo derivatives 11a-d. The reaction proceeded smoothly without any catalyst added (isolated yields between 65-80 %). Unexpected benzodiazepine ring opening was observed during the reaction of 1a-bBn, 1d under known imidazo annulation conditions with potassium t-butoxide, diphenyl phosphoryl chloride and ethyl isocyanoacetate. Imidazo compounds 12a-b were obtained together with oxazole derivatives 13a, 13c-d. Interestingly, under the same reaction conditions benzodiazepine-2-thione 2bBn gave thiazole product 14 in moderate yield - 62 %. Starting compounds 2bAc and 2cAc after the reaction with acetylacetone gave different products 16 (pyrazole derivative) and 17 (1,2,4-triazole derivative). Last but not least, full assignment of H and C atoms in compounds 11b, 16, 17 was accomplished by the analysis of 1H, 13C, HSQC and HMBC spectra. Substances 6a, 6b, 7a-g, 8, 12a, 12b were selected for toxicity study on mice. In order to better evaluate synthesized benzodiazepines with linker groups several compounds without linkers 2bBnSMe, 3, 11b, 18 were selected together with acyclic – nonbenzodiazepine compounds 13a, 14. Saturated solutions of compounds in DMSO were mixed with saline solution 5%:95% (w/w). Final solutions were clear and no turbidity or deposits were observed. Unfortunately, compounds 6a, 11b, 7b, 7c, 8, 12a, 12b were not soluble enough in DMSO to perform toxicity testing. Substances 7d, 7e, and 3 are considered toxic due to the death of mice at 24h after their single subcutaneous injection. One-time administration of other tested substances did not evoke death, any visible signs of toxicity, or statistically significant changes in counts of blood cells. However, some tested substances could affect counts of RBC and connection parameters as well as immune cells and platelets. Further experiments on their toxicity of them are needed. |
