Starrett J E, Montzka T A, Crosswell A R, Cavanagh R L
Pharmaceutical Research and Development Division, Bristol-Myers Company, Wallingford, Connecticut 06492.
J Med Chem. 1989 Sep;32(9):2204-10. doi: 10.1021/jm00129a028.
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).
已合成了在3位被取代的新型咪唑并[1,2 - a]吡啶，作为潜在的抗分泌和具有细胞保护作用的抗溃疡药物。合成路线始于氨基吡啶5a,b与氯代酮6a,b的环化反应，得到咪唑并[1,2 - a]吡啶7 - 9。对3位的侧链进行修饰得到伯胺12a - c，将其分别用丁氧基氨基环丁烯二酮13或甲氧基氨基噻二唑1 - 氧化物(15)处理，分别得到14a,b和16a - c。噻二唑1 - 氧化物16a - c通过两步反应转化为噻二唑19a - c，该过程包括将16a - c中的亚砜挤出得到二亚胺酰胺17a - c，随后用硫代双邻苯二甲酰亚胺(18)处理。在胃瘘大鼠模型中，这些化合物均未表现出显著的抗分泌活性，但在乙醇和盐酸模型中，有几种化合物表现出良好的细胞保护特性。8 - (苄氧基)-3 - [1 - [[2 - [(4 - 氨基 - 1,2,5 - 噻二唑 - 3 - 基)氨基]乙基]硫代]乙基]-2 - 甲基咪唑并[1,2 - a]吡啶(19c)显示出与SCH - 28080(4)相当的细胞保护活性。
