Synthesis and Evaluation of 7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines as Potassium-Competitive Acid Blockers

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• 作者：Andreas M. Palmer ; Burkhard Grobbel ; Cornelia Jecke ; Christof Brehm ; Peter J. Zimmermann ; Wilm Buhr ; Martin P. Feth ; Wolfgang-Alexander Simon ; Wolfgang Kromer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 29, 2007
• 年：2007
• 卷：50
• 期：24
• 页码：6240 - 6264
• 全文大小：408K
• 年卷期：v.50,no.24(November 29, 2007)
• ISSN：1520-4804

文摘

7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines with excellent physicochemical and pharmacologicalproperties were identified that represent interesting candidates for further development as potassium-competitive acid blockers (P-CABs). The title compounds were prepared following synthetic pathways thatrelied either on a Claisen rearrangement/cross-metathesis reaction or on the (asymmetric) reduction of prochiralketones. The influence of the character of the substituents R³, R⁶, and Ar on the biological activity and thephysicochemical properties of the target compounds was examined. In contrast to the parent system (R⁶ =H), compounds in which R⁶ represents a carboxamide residue generally show improved in vivo activity andfavorable pK_a/log D values. Whereas variation of R³ is useful to obtain target compounds with modifiedbasicity and lipophilicity, strong inhibition of the H⁺/K⁺-ATPase and potent in vivo activity is observed forR³ = methyl only. Small modifications of the aryl group, e.g., replacement of hydrogen versus a fluoroatom or a methyl group, are allowed. The (9S)-enantiomers are responsible for the gastric acid secretioninhibiting action, whereas the (9R)-enantiomers are virtually inactive.