Ager I R, Barnes A C, Danswan G W, Hairsine P W, Kay D P, Kennewell P D, Matharu S S, Miller P, Robson P, Rowlands D A
Roussel Laboratories Ltd., Swindon, Wilts, United Kingdom.
J Med Chem. 1988 Jun;31(6):1098-115. doi: 10.1021/jm00401a009.
4H-Imidazo[2,1-c][1,4]benzoxazine-2-carboxylic acid (3) was found to possess potent activity in the IgE-induced rat passive cutaneous anaphylaxis model which may be predictive of clinical antiallergic activity. Compared to disodium cromoglycate (DSCG, 1), 3 was less active following iv administration but unlike DSCG showed very significant oral activity. To explore the structural requirements for this activity, a range of tricyclic compounds was prepared and their activities were measured. Individual 2-carboxylic acids derived from imidazo[1,2-a]quinolines, imidazo[1,2-a]quinoxalines, imidazo[1,2-a]quinoxalinones, pyrrolo[1,2-a]quinoxalinones, pyrrolo[2,3-a]quinoxalinones, and imidazo[2,1-b]benzothiazoles showed iv activities up to 10(3) times as potent as DSCG and many of them showed significant oral activity. From these, imidazo[1,2-a]quinoxaline-2-carboxylic acid 114 has been chosen for further development.
4H-咪唑并[2,1-c][1,4]苯并恶嗪-2-羧酸（3）在IgE诱导的大鼠被动皮肤过敏反应模型中显示出强效活性，这可能预示着其具有临床抗过敏活性。与色甘酸钠二钠（DSCG，1）相比，3静脉注射后的活性较低，但与DSCG不同的是，它显示出非常显著的口服活性。为了探索这种活性的结构要求，制备了一系列三环化合物并测定了它们的活性。源自咪唑并[1,2-a]喹啉、咪唑并[1,2-a]喹喔啉、咪唑并[1,2-a]喹喔啉酮、吡咯并[1,2-a]喹喔啉酮、吡咯并[2,3-a]喹喔啉酮和咪唑并[2,1-b]苯并噻唑的单个2-羧酸显示出高达DSCG活性10³倍的静脉注射活性，其中许多还显示出显著的口服活性。从中选择了咪唑并[1,2-a]喹喔啉-2-羧酸114进行进一步开发。
