Paul R, Brockman J A, Hallett W A, Hanifin J W, Tarrant M E, Torley L W, Callahan F M, Fabio P F, Johnson B D, Lenhard R H
J Med Chem. 1985 Nov;28(11):1704-16. doi: 10.1021/jm00149a029.
By using inhibition of histamine release from antigen-challenged, sensitized human basophils as a means of identifying a potentially prophylactic drug for the treatment of asthma, a series of substituted imidazo[1,5-d][1,2,4]triazines were found, which were active. These compounds were prepared by treating imidazolecarboxaldehydes with excess Grignard agent and then oxidizing the resulting alcohols to ketones with Jones reagent. Pyrolysis of a mixture of ketone and methyl carbazate at 200 degrees C in diphenyl ether produced the desired imidazo[1,5-d][1,2,4]triazines. Those compounds with the greatest basophil activity were tested for in vivo activity in the mouse passive cutaneous anaphylaxis (PCA) and the guinea pig passive anaphylaxis tests. The best compounds, 1-ethyl-8-methyl-6-propylimidazo[1,5-d][1,2,4]triazin-4(3H)- one (4-17) and 1,8-dimethyl-6-propylimidazo[1,5-d][1,2,4]triazin-4-(3H)-one (4-16) were chosen for further study.
通过抑制抗原激发的致敏人嗜碱性粒细胞释放组胺，以此作为鉴定一种潜在的用于治疗哮喘的预防性药物的手段，发现了一系列具有活性的取代咪唑并[1,5-d][1,2,4]三嗪。这些化合物是通过用过量的格氏试剂处理咪唑甲醛，然后用琼斯试剂将所得的醇氧化为酮来制备的。在200℃下，将酮和氨基甲酸甲酯的混合物在二苯醚中热解，得到所需的咪唑并[1,5-d][1,2,4]三嗪。对那些具有最强嗜碱性粒细胞活性的化合物进行了小鼠被动皮肤过敏反应（PCA）和豚鼠被动过敏反应试验的体内活性测试。选择了最佳化合物1-乙基-8-甲基-6-丙基咪唑并[1,5-d][1,2,4]三嗪-4(3H)-酮（4-17）和1,8-二甲基-6-丙基咪唑并[1,5-d][1,2,4]三嗪-4-(3H)-酮（4-16）进行进一步研究。
