With the use of the human basophil histamine release assay, 5-aryl-2-amino1,2,4triazolo1,5-cpyrimidines were found to be active as mediator release inhibitors. These compounds were prepared by ...reacting arylamidines with sodium ethyl formylacetate or with ethyl propiolate to give pyrimidinones. Treatment with phosphorus oxychloride gave a chloropyrimidine, which was converted to a hydrazinopyrimidine with hydrazine. Cyclization, using cyanogen bromide, gave the triazolo1,5-cpyrimidines, after a Dimroth rearrangement. Following a structure-activity evaluation, the 5-3-(trifluoromethyl)phenyl-2-amino (8-10), 5-(3-bromophenyl)-2-amino (8-13), 5-3-(difluoromethoxy)-phenyl-2-amino (8-11), and 5-(4-pyridinyl)-2-amino (6-7) compounds were found to have the best activity. They were chosen for further pharmacological and toxicological study.
The role of immunologically released mediators, such as histamine, leukotrienes, and platelet-activating factor, is well-established for asthma and other allergic disorders. Developing therapeutic ...agents which would block mediator release from mast cells and other relevant cell types would provide a rational approach to asthma therapy. Using human basophil as a screen, a series of 4-aryl-2-(phenylamino)pyrimidines was found which inhibited mediator release. These compounds were prepared by condensing acetyl heterocycles with dimethylformamide dimethyl acetal to form enaminones which are cyclized with aryl guanidines to give pyrimidines. After examining a large number of analogs, N-3-(1H-imidazol-1-yl)phenyl-4-(2-pyridinyl)-2- pyrimidinamine (1-27) was chosen for toxicological evaluation.
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 imidazo1,5-d1,2,4triazines 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 imidazo1,5-d1,2,4triazines. 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-propylimidazo1,5-d1,2,4triazin-4(3H)- one (4-17) and 1,8-dimethyl-6-propylimidazo1,5-d1,2,4triazin-4-(3H)-one (4-16) were chosen for further study.
