A number of human diseases such as depression and neurodegenerative diseases are connected to the action of Monoamine Oxidases (MAOs). Tranylcypromine (trans-2-phenylcyclopropylamine) is a MAO inhibitor used for treatment of serious depression. Unfortunately, this drug is unselective having a number of side effects. Therefore, more selective derivatives are desirable. We prepared a series of analogs of this compound and investigated the role of fluorine attached to the cyclopropane ring and that of various substituents at the phenyl moiety (Scheme 1). Substituted styrenes and α-fluorostyrenes were transformed to the diastereoisomeric 2-phenyl-cyclopropane carboxylates by either Cu(I)-catalyzed reactions with diazoacetates [1] or by Fe(III)-porphyrine-catalyzed reactions with ethyl glycinate according to a protocol by Carreira et al. [2]. In case of the fluorinated cyclopropane carboxylates 1:1 mixtures were formed, while the nonfluorinated parents were formed with diastereoselectivity of about 3:1 in favor of the trans-isomers. The products were separated by column chromatography. The carboxylic acids formed by hydrolysis were converted to the amines using Curtius degradation. Depending on the stereochemistry of fluorine and amino group at the cyclopropane ring and the nature of the aryl substituents, the pKa-values of these compounds are up to two orders of magnitude lower compared to tranylcypromine. All compounds are potent MAO A and/or MAO B inhibitors with IC50 values down to 70 nM. [18F]-Radiolabeling of the cis-compound with X = H and Y = OEtF (IC50 = 0.9 μM for MAO A and 19 μM for MAO B) provided a suitable tracer for Positron-Emission-Tomography (PET).

2-Aryl-2-fluoro-cyclopropylamines: Synthesis, physicochemical properties and monoamine oxidase inhibitor potencies

253rd National Meeting (2017)

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