Imidazo[1,5-d][1,2,4]triazines as potential antiasthma agents.
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.
Paul
R
R
Brockman
J A
JA
Hallett
W A
WA
Hanifin
J W
JW
Tarrant
M E
ME
Torley
L W
LW
Callahan
F M
FM
Fabio
P F
PF
Johnson
B D
BD
Lenhard
R H
RH
D000707:Anaphylaxis; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001491:Basophils / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D006967:Hypersensitivity / Q000097:blood; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*
D007093:Imidazoles; D014227:Triazines