New imidazo[1,2-a]pyridines substituted at the 3-position have been synthesized as potential antisecretory and cytoprotective antiulcer agents. The synthetic routes began with cyclization of aminopyridines 5a,b and chloro ketones 6a,b to give imidazo[1,2-a]pyridines 7-9. The side chain at the 3-position was elaborated to give primary amines 12a-c, which were treated with either butoxyaminocyclobutenedione 13 or methoxyaminothiadiazole 1-oxide (15) to give 14a,b and 16a-c, respectively. Thiadiazole 1-oxides 16a-c were converted to thiadiazoles 19a-c in a two-step process which involved extrusion of the sulfoxide in 16a-c to afford diimidamides 17a-c, which were subsequently treated with thiobisphthalimide (18). None of the compounds displayed significant antisecretory activity in the gastric fistula rat model, but several demonstrated good cytoprotective properties in both the EtOH and HCl models. 8-(Benzyloxy)-3-[1-[[2-[(4-amino-1,2,5-thiadiazol-3- yl)amino]ethyl]thio]ethyl]-2-methylimidazo[1,2-a]pyridine (19c) showed comparable cytoprotective activity to SCH-28080 (4).
Carboxylate anions are more basic on the syn side because carboxylic acids are more stable with the proton syn to the carbonyl oxygen than anti. This led Gandour to propose that carboxylic anions should act as catalytic bases, as in enzymes, better on the syn side than the anti. However, numerous experimental tests have failed to reveal a strong preference. We resolve this problem by showing, on the basis of Linnett structures and MO calculations, that as a proton gradually departs from its firm syn position in the un-ionized COOH group, its preference for syn over anti diminishes rapidly, crossing over to a preference for anti before the midpoint of the reaction coordinate has been reached. Therefore in catalytic events, where the proton is partially transferred, the preference could favor either syn or anti and is small.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.