Synthesis of functional derivatives of malonic acid as building blocks for elastase-inhibitors

Rheinische Friedrich-Wilhelms University Bonn The Faculty of Mathematics and Natural Sciences Pharmaceutical Institute, Pharmaceutical Chemistry I Diploma Thesis Synthesis of Functional Derivatives of Malonic Acid as Buildings Blocs for Elastase Inhibitors Marie Hrušková Human leukocyte elastase (HLE) is a serine protease, which plays an important role in inflammatory diseases. Low molecular weight inhibitors can be therapeutically used for example for the treatment of chronic obstructive pulmonary diseases. In this thesis, azetidin- 2,4-dione derivatives should be prepared as HLE inhibitors. In particular, 3- (benzyloxycarbonylamino)-3-ethyl-N-phenyl-azetidine-2,4-dione should be synthesized. The protected amino group was expected to increase the peptidic character of this molecule and thus, affinity to HLE. The starting compound was 2-aminomalonic acid diethylester hydrochlorid. The amino function was protected in the first step, followed by alkylation and then hydrolysis of 2- (benzyloxycarbonylamino)-2-ethylmalonic acid diethylester to 2-(benzyloxycarbonylamino)- 2-ethylmalonic acid. Both the ester of 2-(benzyloxycarbonylamino)malonic acid and the 2-(benzyloxycarbonyl-amino)ethylmalonic acid showed in their 1 H NMR spectra a multiplet in place of the expected quartet. This phenomenon was..