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

Abstract

7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines with excellent physicochemical and pharmacological properties were identified that represent interesting candidates for further development as potassium-competitive acid blockers (P-CABs). The title compounds were prepared following synthetic pathways that relied either on a Claisen rearrangement/cross-metathesis reaction or on the (asymmetric) reduction of prochiral ketones. The influence of the character of the substituents R3, R6, and Ar on the biological activity and the physicochemical 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 and favorable pKa/log D values. Whereas variation of R3 is useful to obtain target compounds with modified basicity and lipophilicity, strong inhibition of the H+/K+-ATPase and potent in vivo activity is observed for R3 = methyl only. Small modifications of the aryl group, e.g., replacement of hydrogen versus a fluoro atom or a methyl group, are allowed. The (9S)-enantiomers are responsible for the gastric acid secretion inhibiting action, whereas the (9R)-enantiomers are virtually inactive.

Preparation of tricyclic imidazopyridines by asymmetric ketone hydrogenation in the presence of ruthenium phosphino-oxazoline catalyst

“…BYK 311319 1 was obtained from diol 3 by Mitsunobu cyclization as described previously. 8,9,21 3. Conclusion…”

“…[4][5][6][7] Over the course of our P-CAB led optimization program, we identified the tricyclic imidazo[1,2-a]pyridine BYK 311319 1 as a potent inhibitor of the H + /K + -ATPase showing promising pharmaceutical activity. 8,9 A key step in the synthesis of the enantiopure P-CAB 1 is the asymmetric reduction of ketone 2 and subsequent Mitsunobu cyclization of the resulting diol 3 (Scheme 1). 8,9 A variety of methods for the asymmetric reduction of ketones are currently available, including enzymatic transformations, 10 hydrosilylation, 11,12 hydroboration, [13][14][15][16] transfer hydrogenation, 17,18 and hydrogenation.…”

“…8,9 A key step in the synthesis of the enantiopure P-CAB 1 is the asymmetric reduction of ketone 2 and subsequent Mitsunobu cyclization of the resulting diol 3 (Scheme 1). 8,9 A variety of methods for the asymmetric reduction of ketones are currently available, including enzymatic transformations, 10 hydrosilylation, 11,12 hydroboration, [13][14][15][16] transfer hydrogenation, 17,18 and hydrogenation. 19,20 In the field of enantioselective homogeneous hydrogenation, the Noyori Ru-PP-NN systems of the type RuCl 2 [diphosphine][diamine] in the presence of base constitute the most prominent (pre)catalysts and excellent results have been published for aromatic ketone substrates in recent years.…”

“…Under optimized conditions and using an S/C ratio of 130:1, chiral alcohol 3 could be prepared with an enantiomeric purity of 85% ee. 8,9 While this result was encouraging, we were still aiming at the identification of an alternative, more selective system for the asymmetric reduction of ketone 2. Herein we report the preparation of alcohol 3 using the ruthenium POX (phosphino-oxazoline) catalyst system RuCl 2 (PPh 3 )(Ph 2 P-Fcoxa i Pr) 5 depicted in Figure 1.…”

6-Bromo-2-(4-chlorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine

“…Many imidazopyridines have a significant inhibitory effect on many target enzymes (Palmer et al 2007;Katritzky et al 2003), as well as anti-viral, antibacterial, anti-microbial and anti-cytokinin activity. Some of them can be used to treat peptic ulcers, diabetes and mental illness (Scribner et al 2007, Liang et al 2007.…”