Synthesis and biological activity of 3-substituted imidazo[1,2-a]pyridines as antiulcer agents.
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).
Starrett
J E
JE
Pharmaceutical Research and Development Division, Bristol-Myers Company, Wallingford, Connecticut 06492.
Montzka
T A
TA
Crosswell
A R
AR
Cavanagh
R L
RL
D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D000431:Ethanol; D005744:Gastric Acid / Q000378:metabolism; D005747:Gastric Fistula / Q000188:drug therapy / Q000503:physiopathology; D006851:Hydrochloric Acid; D007093:Imidazoles / Q000138:chemical synthesis* / Q000627:therapeutic use; D010437:Peptic Ulcer / Q000503:physiopathology / Q000517:prevention & control*; D011725:Pyridines / Q000138:chemical synthesis* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
D000897:Anti-Ulcer Agents; D007093:Imidazoles; D011725:Pyridines; C035235:Sch 28080; D000431:Ethanol; D006851:Hydrochloric Acid