Antiulcer agents. 3. Structure-activity-toxicity relationships of substituted imidazo[1,2-a]pyridines and a related imidazo[1,2-a]pyrazine

Abstract

Investigation of the interrelationship between structure, antiulcer activity, and toxicology screening data derived from a series of compounds selected from structure-activity studies directed toward identifying a successor to 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, Sch 28080 (1), has identified 3-(cyanomethyl)-2,7-dimethyl-8-(phenylmethoxy)imidazo[1,2 -a]pyridine (5), 3-amino-2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine (6), and 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyrazine (7). These analogues exhibit a combination of antisecretory and cytoprotective activity in animal models, while eliminating the adverse effects of the prototype 1. One of these, 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyrazine, Sch 32651 (7), has a profile meeting all criteria.

Tandem Amination/Cycloisomerization of Aryl Propargylic Alcohols with 2‐Aminopyridines as an Expedient Route to Imidazo[1,2‐a]pyridines

“…The possible Meyer-Schuster rearrangement was also ruled out because the reaction of 5 with 2a did not provide 4a under the reaction conditions. Although 2-aminopyridine has two potential nucleophilic N atoms, [16] the propargylic cation IA should be attacked by the NH 2 group to give propargylic amine 3a instead of IIB. This was strongly supported by the fact that neither IIB nor its cycloisomerized product 8 [17] were detected.…”

Catalyst‐Free, Glycerol‐Assisted Facile Approach to Imidazole‐Fused Nitrogen‐Bridgehead Heterocycles

“…For example the drugs KDU691 and KAI407, have recently been reported as potent antimalarials. Imidazopyrazine based molecules have also been used as anti‐inflammatory, antihypertensive, antiulcerative, antibronchospastic, and as antiproliferative agents. [31]…”

Insights on the Chemical Behavior of Ethyl Cyanoformate: Dipolarophile, Cyano or Ethoxycarbonyl Source

“…Imidazo[1,2‐ a ]pyridine (azaindolizine) ring proved to be an attractive scaffold found in the structure of molecules displaying a wide range of applications in medicinal chemistry including antiviral, anticancer, antifungal, anti‐inflammatory and antiulcer activities with several candidates attending clinical trials . For example, “azaindolizines” are known as retinoic acid receptor‐related orphan receptor gamma (RORγ or RORc) inverse agonists ( e. g .…”