Synthesis and oral antiallergic activity of carboxylic acids derived from imidazo[2,1-c][1,4]benzoxazines, 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.
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.
D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis; D004205:Cromolyn Sodium / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006967:Hypersensitivity / Q000188:drug therapy*; D007093:Imidazoles / Q000138:chemical synthesis*; D010078:Oxazines / Q000138:chemical synthesis; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis*; D011810:Quinoxalines / Q000138:chemical synthesis; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis
D002264:Carboxylic Acids; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D010078:Oxazines; D011758:Pyrroles; D011810:Quinoxalines; D013844:Thiazoles; C056037:imidazo(1,2-a)quinoxaline-2-carboxylic acid; D004205:Cromolyn Sodium