Within the realm of proven pharmacophores, the sulfamide functional group (thiadiazine-1,1-dioxide) stands out as one of the most important structural motifs found in high affinity protein ligands and pharmaceutically useful agents. Indeed, a survey of the recent patent literature reveals several hundred proprietary compounds having an impressive and diverse array of biological activities wherein a sulfamide group is incorporated within a suitable scaffold, often cyclic. For examples of such compounds, see R. J. Cherney, et al., 2002, WO-2002028846; N.-Y. Shih, et al., 2001, WO-2001044200; G. M. Benson, et al., 2000, WO-2000076501; R. D. Tung, et al., 1999, U.S. Pat. No. 5,945,413; I. Mcdonald, et al., 1999, WO-9905141. Among the numerous applications of sulfamides, these agents have proven to be particularly effective as inhibitors of key enzymes including HIV protease (W. Schaal, et al., J. Med. Chem. 2001, 44, 155–169; Spaltenstein, A.; et al. Bioorg. Med. Chem. Lett. 2000, 10, 1159–1162; Bäckbro, K.; et al. J. Med. Chem. 1997, 40, 898–902; Hultén, J.; et al. J. Med. Chem. 1997, 40, 885–897) and serine protease (Kuang, R.; et al. Bioorg. Med. Chem. 2000, 8, 1005–1016; Kuang, R.; et al. J. Am. Chem. Soc. 1999, 121, 8128–8129; Groutas, W. C.; et al. Bioorg. Med. Chem. Lett. 1999, 9, 2199–2204; Groutas, W. C.; et al. Bioorg. Med. Chem. 1998, 6, 661–671), and have demonstrated utility as both agonists and antagonists of critical molecular receptors such as those used to regulate endogenous levels of seratonin (Castro, J. L.; et al. J. Med. Chem. 1994, 37, 3023–3032) and histamine (Tozer, M. J.; et al. Bioorg. Med. Chem. Lett. 1999, 9, 3103–3108). Beyond their obvious significance in the treatment of disease, cyclic sulfamides have also been employed with considerable success as chiral ligands and auxiliaries (Pansare, S. V.; et al. Synlett 1998, 623–624; Ahn, K. H.; et al. Tetrahedron Lett. 1992, 33, 6661–6664; Sartor, D.; et al. Tetrahedron: Asymmetry 1991, 2, 639–642; Oppolzer, W.; et al. Tetrahedron Lett. 1991, 32, 4893–4896; Oppolzer, W.; et al. Tetrahedron Lett. 1991, 32, 61–64), and constitute an increasingly popular set of building blocks within the field of supramolecular chemistry (Hof, F.; et al. Org. Lett. 2001, 3, 4247–4249; Hof, F.; et al. J. Am. Chem. Soc. 2000, 122, 10991–10996; Gong, B.; et al. J. Am. Chem. Soc. 1999, 121, 9766–9767 and references cited in each).
Despite the indisputable utility of these compounds, however, existing routes for their synthesis, particularly in a cyclic setting, are far from ideal. For example, typical procedures to fashion cyclosulfamides rely upon the reaction of a diamine with either SO2Cl2 or H2NSO2NH2 at elevated temperatures (Preiss, M. Chem. Ber. 1978, 111, 1915–1921; Rosenberg, S. H.; et al. J. Med. Chem. 1990, 33, 1582–1590; Dewynter, G.; et al. Tetrahedron Lett. 1991, 32, 6545–6548), conditions which often lead to a low yield of product due to the concomitant formation of polycondensation side-products. Equally problematic is the relative scarcity of suitable diamines for these reactions from commercial sources and the difficulties associated with their laboratory preparation. An online search of the available chemicals directory revealed just slightly more than 200 unsubstituted 1,2-diamine substrates. By contrast, there are over 3000 unsubstituted β-amino alcohols. While these issues have led to the development of several alternative protocols for sulfamide synthesis (Tozer, M. J.; et al. Bioorg. Med. Chem. Lett. 1999, 9, 3103–3108; Dougherty, J. M.; et al. Tetrahedron 2000, 56, 9781–9790; Dewynter, G.; et al. Tetrahedron Lett. 1997, 38, 8691–8694.), these additional synthetic technologies have proven amenable only to specific substrate classes and have not yet alleviated the need for multi-step protocols. Most significantly, none of these methods has enabled the efficient and selective synthesis of non-symmetrical N,N′-disubstituted cyclosulfamides (IV, FIG. 1), perhaps the most versatile class of these compounds for generating pharmaceutically-relevant molecular diversity.
What is needed is a general and widely applicable solution for the synthesis of these diverse classes of sulfamides for enabling the reliable and efficient formation of this highly desirable structural moiety (IV).
USPTO Backgrounds
USPTO Backgrounds