Synthesis and properties of the sulfonyl analogs of 4(5)-aminoimidazole-5(4)-carboxamide, 4(5)-(formylamino)imidazole-5(4)-carboxamide, guanine, and xanthine

Abstract

Reduction of 4(5)-nitroimidazole-5(4)-sulfonamide afforded the sulfonamide analogue of 4(5)-aminoimidazole-5(4)-carboxamide (AICA). This was formylated to afford the sulfonamide analogue of formyl-AICA and was ring closed to the unsubstituted 6-sulfonyl analogue of guanine, 3-aminoimidazo[4,5-e]-1,2,4-thiadizine 1,1-dioxide. Diazotiz ation of the latter afforded the corresponding 6-sulfonyl analogue of xanthine. None of the imidazole-sulfonamides or the purine 6-sulfonyl analogues inhibited the growth of L1210 cells in culture nor were they substrates for or significant inhibitors of human hypoxanthine--guanine phosphoribosyltransferase or milk xanthine oxidase.

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease

“…This process generated the protected β-amino sulfonamide 39 in 75% yield and high diastereomeric ratio (dr 98:2). , The tert- butylsulfinamide group was cleaved upon treatment of adduct 39 with hydrogen chloride, and the p -methoxy benzyl (PMB) group was subsequently removed using TFA to afford β-amino sulfonamide 40 . The iminothiadiazinane dioxide core was then formed in high yield using a three step protocol . First, treatment of amine 40 with benzoylisothiocyanate was followed by cleavage of the benzoyl group to provide an intermediate thiourea.…”

“…The iminothiadiazinane dioxide core was then formed in high yield using a three step protocol. 49 First, treatment of amine 40 with benzoylisothiocyanate was followed Scheme 2 describes the preparation of the iminopyrimidinone amides 21−25. The iminopyrimidinone core was prepared in a similar fashion to our previously described chemistry.…”

“…The crude residue was purified by HPLC (C 18 ; gradient elution 10−45% MeCN:water with 0.1% TFA) to afford 9 (80 mg, 82% yield) as the TFA salt. 1 (49). To a flame-dried round-bottom flask containing a solution of 38 (60.0 g, 262 mmol) in THF (750 mL) at −75 °C under an atmosphere of nitrogen was added over 10 min a solution of n-BuLi (1.6 M in hexanes, 165 mL, 262 mmol), and the mixture was stirred for 30 min.…”