A Convenient Synthesis of N-Substituted 2,3-Dihydro-3-oxoisothiazolo[5,4-b]pyridines in Acidic Condition

Nicotinamide Derivatives as a New Class of Gastric H+/K+-ATPase Inhibitors. 1. Synthesis and Structure−Activity Relationships of N-Substituted 2-(Benzhydryl- and benzylsulfinyl)nicotinamides

“…Accordingly, it appeared that replacement of the benzhydryl group by less hydrophobic benzyl groups was required to improve the bioavailability. Since 2-(benzylsulfinyl)- N -(4-pyridyl)nicotinamide is not readily converted into its active form, N -(4-pyridyl)-2,3-dihydro-3-oxoisothiazolo[5,4- b ]pyridine ( 5c ) (Table ), at room temperature under acidic conditions as reported previously, it was necessary to introduce an electron-donating alkoxy group into the ortho and/or para position(s) of the phenyl ring of the benzyl group to raise the conversion rate. The inhibitory activities against the AP accumulation in vitro and the histamine-induced gastric acid secretion in vivo as well as half-lives ( t 1/2 ) of conversion at pH 5.0, 3.0, and 1.0 for 8a − p are summarized in Table .…”

“…Procedure F. N -(4-Aminophenyl)-2-(benzhydrylsulfinyl)nicotinamide (7e). 2-(Benzhydrylthio)- N -(4-nitrophenyl)nicotinamide ( 29 ) was prepared from 2-(benzhydrylthio)nicotinic acid ( 10 ), which was chlorinated with oxalyl chloride followed by condensation with 4-nitroaniline in a manner similar to that described previously . The overall yield was 55%: mp 166−167 °C; 1 H NMR δ 6.44 (1H, s), 7.16−7.48 (10H, m), 8.28 (2H, m), 8.52 (1H, dd, J = 1.8, 4.8 Hz), 11.09 (1H, s); SIMS m / z 441 (M + ); IR (KBr) 1658 cm -1 (CO).…”

“…2-[[2-(2-Fluoroethoxy)-4-methoxybenzyl]sulfinyl]- N -(4-pyridyl)nicotinamide (8n). 2-[[2-(2-Fluoroethoxy)-4-methoxybenzyl]thio]- N -(4-pyridyl)nicotinamide was prepared starting from 2-[[2-(2-fluoroethoxy)-4-methoxybenzyl]thio]nicotinic acid ( 26 ), which was chlorinated with oxalyl chloride followed by condensation with 4-aminopyridine in a manner similar to that described previously …”

“…b A = CH 3 CN, B = CH 3 OH, C = acetone, D = H 2 O, E = CHCl 3 , F = toluene, G = (C 2 H 5 ) 2 O, H = C 2 H 5 OH, I = n -hexane, J = (iC 3 H 7 ) 2 O. c All compounds were analyzed for C, H, N, S, and halogen; analytical results were within ±0.4% of the theoretical values. d These compounds were previously prepared …”

“…Recently, we reported a convenient method for preparing 5 from 2-(benzhydrylsulfinyl)nicotinamides 7 or 2-(benzylsulfinyl)nicotinamides 8 substituted with alkoxy groups at the ortho and para positions of the benzyl group at room temperature in a diluted hydrochloric acid−methanol solution in high yields . We considered that the mechanism for the conversion of 7 and 8 might involve the sulfonium salt 9 as an intermediate followed by elimination of the leaving group R 1 , as shown in Scheme , and that the conversion rate might depend on the stability of the carbonium ion of the leaving group R 1 .…”