Glucuronide conjugates of Soraprazan (BY359), a new potassium-competitive acid blocker (P-CAB) for the treatment of acid-related diseases |
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Authors: | Jörg Senn-Bilfinger John R Ferguson Keith W Lumbard Karl Zech Peter J Zimmermann |
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Institution: | a ALTANA Pharma AG, Byk-Gulden-Str. 2, D-78467 Konstanz, Germany b Ultrafine UFC Ltd.†Ultrafine is now part of SAFC Pharma (Sigma-Aldrich Company Limited).†, Synergy House, Guildhall Close, Manchester Science Park, Manchester M15 6SY, UK |
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Abstract: | Glucuronide conjugates of Soraprazan (BY359), a potent novel anti-secretory drug (currently in Phase II clinical trials), were not directly accessible synthetically. This was due to the relative instability of Soraprazan under the harsh Lewis acid conditions employed in popular glucuronidation methodologies and a lack of reactivity under alternative, Koenigs-Knorr, coupling conditions. We have now devised a successful synthesis using the novel N-acetylated Soraprazan to access the required glucuronide metabolites on gram scale. Coupling of this novel aglycone with methyl 1-O-trichloroacetimidoyl-2,3,5-tri-O-isobutyryl-α-d-glucopyran-uronate in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) gave the protected glucuronide intermediates. A one-pot two-step deprotection involving hydrolysis of the ester functionalities and removal of the N-acetyl group with alkaline hydrazine delivered the title compounds in satisfactory yield. |
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Keywords: | Anti-ulcer Gastric anti-secretory Soraprazan Glucuronidation Imidazo-naphthyridine |
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