In an effort to develop antihypertensive agents with peripheral vasodilator activity, a series of 40 novel 3-hydrazino-5-phenyl-1,2,4-triazines (II) were synthesized and evaluated in the spontaneously hypertensive rat assay (SHR assay). Based on the performance of the structurally related standard, hydralazine (I), 15 triazines were active. Thirteen of these hypotensive triazines possessed LD50 values in the mouse greater than I (LD50 = 100 mg/kg); only one active triazine had an LD50 value greater than 300 mg/kg (11d). Four asymmetric triazines had moderate antihypertensive activity and LD50 values greater than 300 mg/kg (6b, 7c, 8f, and 9g). Based on the relationship between toxicity and antihypertensive activity, three triazines (8f, 9g, and 11d) were chosen for dose-responses studies in the SHR assay. None were as efficacious as I, but all three were less toxic, resulting in similar therapeutic indices relative to I.

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The synthesis of a series of 5,6-diarylpyridazinones is described. Some members of this series display an antihypertensive effect in both the spontaneously hypertensive rat (SHR) model and the deoxycorticosteroid (DOCA) model of hypertension. The most potent compounds in the series have halogen substituents on the 5,6-diphenyl rings, a beta-substituted alkyl group at the 2 position of the ring, and acetyl or cyano substituent at the 4 position.

From acid hydrolysates of amphomycin (+) 3-anteisotridecenoic acid, (+) 4-hydroxy-anteisotridecanoic acid lactone and 4-hydroxy-isododecanoic acid lactone were isolated. While the unsaturated acid is a genuine building component of the antibiotic, the lactones are formed from unsaturated acids during hydrolysis. * The authors express their gratitude to Mr. L. Szabo and H. Lundbeck & Co. of Copenhagen-Valby, Denmark, for the generous sample of amphomycin which made it possible to carry out such a detailed study. @@4OO @@THE JOURNAL OF ANTIBIOTICS SEPT 1969 @@4O2 @@THE JOURNAL OF ANTIBIOTICS SEPT.