Bioaktive und Heterocyclische Sulfondiimine und Sulfonimidamide

  • Bioactive and Heterocyclic Sulfondiimines and Sulfonimidamides

Schöbel, Jan-Hendrik; Bolm, Carsten (Thesis advisor); Albrecht, Markus (Thesis advisor)

Aachen : RTWH Aachen University (2021)
Dissertation / PhD Thesis

Dissertation, RTWH Aachen University, 2021

Abstract

Sulfonamides are among the most important compound classes in the pharmaceutical industry. Despite their promising pharmalogical profile, their aza-analogues, known as sulfonimidamides and sulfondiimines, are much less explored. Just recently, bioisosteric replacement of sulfonamides and related organosulfur compounds with sulfonimidamides and sulfondiimines have more frequently been included in drug development programs of the pharmaceutical industry with the goal to fine-tune pharmacological or physicochemical parameters of drug candidates in lead optimization processes. Besides their interesting bioactivities, sulfonimidamides and sulfondiimines have proven to be versatile building blocks for the synthesis of sulfur- and nitrogen-containing heterocycles. In the first part of the presented thesis, the bioisosteric replacement of the sulfonamide with a sulfonimidamide or sulfondiimine in PFIZER's anti-cancer drug candidate PFI-1 is described. These modifications allow for variation of the nitrogen substituents, which could act as an additional anchor for three-dimensional functionalizations. Moreover, a stereogenic center at sulfur is generated. A successful synthesis of the target compounds was achieved by cross-coupling reactions. The biological activity against various leukemia cell lines was confirmed in cooperation with the University Hospital Aachen. The second part of the presented thesis describes synthetic methods for unprecedented sulfur-nitrogen heterocycles from sulfonimidamides or sulfondiimines. The synthesis of 1,2,6-thiadiazine-1-oxides was achieved by reacting N-unsubstituted sulfonimidamides and propargyl ketones or enones and can be carried out either in solvent-phase or under mechanochemical solvent-free conditions in a ball mill reactor. S-Aryl-substituted sulfonimidamides or sulfondiimines were converted into 1,2-benzothiazine derivatives by regioselective metal-catalyzed C-H-bond functionalization followed by cyclization. In addition, methods for the synthesis of 1,2-dibenzothiazine derivatives are presented. These tricyclic heterocycles can either be obtained by an one-pot inter- and intramolecular imination sequence starting from biaryl-sulfides, or by metal-catalyzed annulation of sulfondiimines and arynes.

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