Saccharin Aza Bioisosteres—Synthesis and Preclinical Property Comparisons

Abstract

Saccharin is a well-known scaffold in drug discovery. Herein, we report the synthesis and preclinical property comparisons of three bioisosteres of saccharin: aza-pseudosaccharins (cluster ), and two new types of aza-saccharins (clusters and ). We demonstrate a convenient protocol to selectively synthesize products in cluster or when primary amines are used. Preclinical characterization of selected matched-pair products is reported. Through comparison of two diastereomers, we highlight how stereochemistry affects the preclinical properties. Given that saccharin-based derivatives are widely used in many chemistry fields, we foresee that structures exemplified by clusters and offer new opportunities for novel drug design, creating a chiral center on the sulfur atom and the option of substitution at two different nitrogens.

Synthesis of 1λ6,2,4,6‐Thiatriazine‐1,3,5‐Trione Derivatives

“…In our previous work, pyridazine was preferably employed as a “magic” base for the mono N‐acylation of 4‐methylbenzene‐sulfonimidamide. [4b] Delightfully, this base also appeared effective for the selective formation of 3a . In entry 5, 6a was not found during the reaction course despite of 1.1 equiv.…”

“…The neutral form of 1 in the NMR study was from our previous work. [4a] Differently, CD 3 CN was used as the NMR solvent in this work. 1 H NMR (500 MHz, CD 3 CN) δ = 7.84–7.95 (m, 2H), 7.32–7.43 (m, 2H), 4.60 (s, 3H), 2.44 (s, 3H).…”

“…In the attempt of acylation of primary sulfonimidamides, the di‐acylated by‐products were formed as main products when common coupling reagents, such as TBTU, were applied at the presence of commonly used bases, such as DIPEA. [4b] This is not surprising because both nitrogen atoms, namely the amidic nitrogen (N) and the imidic nitrogen (N), in a primary sulfonimidamide are nucleophilic and basic (Figure a) . In terms of basicity of the imidic nitrogen, Grygorenko and co‐workers have recently reported the p Ka data of N‐dimethyl‐methanesulfonimidamide ( DM‐SIA ) (Figure b) .…”

“…Our research has been focusing on the synthesis and functionalization of sulfonimidamides . In the attempt of acylation of primary sulfonimidamides, the di‐acylated by‐products were formed as main products when common coupling reagents, such as TBTU, were applied at the presence of commonly used bases, such as DIPEA.…”

“…To tackle the selectivity issue, we applied a mixture of an acyl chloride and pyridazine as the acylating reagents to prepare N‐mono acylated products. [4b]…”