Kyrychok O. Synthesis of new polyfunctional spirocyclic azetidines using the [2+2]cycloaddition method та their application in medicinal chemistry.

The dissertation is devoted to the development of preparative methods for the synthesis of new multifunctional spirocyclic azetidines by [2+2]cycloaddition and their application in drug discovery. The first chapter of the study describes the synthesis of 2-substituted azaspiro[3.3]heptanes as spirocyclic analogs of 2-substituted piperidines and their validation in drug discovery. A modification of the Staudinger reaction between ketenes and N-TMS-imines for NH-azetidinones was used for the synthesis of the target spirocycle. Commercially available cyclobutane carboxylic acid was readily converted to the corresponding chloro anhydride and then to the ketene by treatment with DIPEA. In turn, benzaldehyde was converted in situ to TMS-imine by LiN(TMS)2. A subsequent thermal Staudinger reaction between ketene and TMS-imine afforded the desired spirocyclic azetidinone (3-phenyl-2-azaspiro[3.3]heptan-1-one) in 81% yield. Further reduction of the amide group gave the desired amine (1-phenyl-2 azaspiro[3.3]heptane) in 76% yield. Both starting substances (cyclobutane carboxylic acid and benzaldehyde) are quite inexpensive and available reagents, which made it possible to scale up the reaction and obtain 50 g of the key amine in one synthetic run. Next, the scopes and limitations of the reaction were investigated, namely, the variation of the aldehyde component of the transformation was carried out: a number of aromatic, heteroatomic, and aliphatic aldehydes were successfully transformed into the corresponding spirocyclic derivatives. The structure of one of the obtained spirocyclic derivatives, 1-(pyridin-3- yl)-2-azaspiro[3.3]heptane, was confirmed by X-ray diffraction. Further, the physicochemical characteristics of the synthesized spirocyclic building blocks were investigated and the data obtained were compared with the data of the corresponding piperidine derivatives. All synthesized spirocyclic derivatives had appropriate physicochemical properties for use in drug discovery: they were chemically and metabolically stable in vitro, had appropriate lipophilicity and good solubility in water. To demonstrate the drug discovery potential of the synthesized spirocyclic analogs of 2-substituted piperidines, a spirocyclic analog of bupivacaine (an FDAapproved local anesthetic) with a 2-azaspiro[3.3]heptane residue instead of piperidine was synthesized. The spirocyclic derivative showed a similar duration, but at the same time a faster onset of action in vivo compared to bupivacaine. In addition, the spirocyclic compound showed a slightly lower level of toxicity in mice in vivo.