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The antihypertensive 5-methyl-6-p.cyanophenyl-4,5-dihydro-3(2H)-pyridazinone has been embodied in a rigid framework corresponding to a 4,4a-dihydro-5H-indeno[1,2-c]-3-pyridazinonic structure (II). The resulting 7-cyano derivative (IIc) was found to be devoid of antihypertensive activity. However this compound, as well as other members having structure (II), exhibited antiinflammatory properties.
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The binding of sulfamethoxypyridazine to human and bovine serum albumin was determined at eight constant molar drug/albumin ratios for seven different albumin concentrations ranging from 0.1% to 1.5%. The serum albumin concentration affects the determination of the albumin binding of the drug in two different ways. 1. The relative affinity of the albumins for the drug increases with increasing albumin concentrations, while the numbers of binding sites remain constant. 2. The association constants taken from Scatchard plots decrease with increasing albumin concentrations. It is concluded that a direct comparison of binding constants obtained with different albumin concentrations, as widely done, can lead to misinterpretations and should be avoided.
Derivatives of two new and unusual classes of heterocycles, possessing structural similarities to the broad spectrum antibiotic fervenulin, were synthesized and examined for in vitro antimicrobial activity. Only three of 17 mesoionic pyrimido[1,2-b]pyridazine-2,4-diones exhibited evidence of antimicrobial activity while seven of eight mesoionic pyridazino[2,3-a]-s-triazine-2,4-diones were active against one or more microorganisms. Susceptibility toward attack by nucleophiles of both mesoionic pyridazino[2,3-a]-s-triazine-2,4-diones and fervenulin was observed.
SC4453 is a digoxin analogue with a pyridazine instead of a lactone ring on C17 beta. SC4453 was compared with digoxin with respect to inhibition of (Na+ + K+)-ATPase prepared from human heart, guinea-pig heart and guinea-pig brain. SC4453 was slightly less potent than digoxin but showed a similar sensitivity to K+. As for cardenolides, species differences in sensitivity to SC4453 were accounted for by differences in the rate of dissociation from the receptors. These observations confirm that the human heart is one of the tissues most sensitive to cardiac glycosides.
56 moderate and severe hypertensive patients entered an open long-term trial aimed at evaluating the efficacy and tolerability of a combined treatment consisting of 3-hydrazino-6-[N,N-bis-(2-hydroxyethyl)amino]pyridazine (oxdralazine, L 6150), propranolol and chlorthalidone. The mean basal blood pressure was 186.9/111.8 mmHg: after one month of treatment, the mean value was 149.7/95.5 mmHg (p less than 0.01). The heart rate was practically unaffected by treatment, the mean value changing from 75.4 b.p.m. (basal) to 73.3 b.p.m. (one month). The significant reduction in the blood pressure observed at the end of the first month remained unchanged in the following months of therapy, and only minor variations occurred. The combined treatment was well tolerated. Five patients were withdrawn from the trial during the first month; three of them because of side-effects and two of them for personal reasons.
The synthesis of a series of 3-hydrazinopyridazines is described. Several of these compounds exhibited high antihypertensive activity in the rat. The most potent member of the series is l-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido-[4,3-c]pyridazine, compound 28 [1], which is now under clinical trial [2] under the clinical code number BQ 22-708 (endrazaline, Miretilan). It was possible to discover certain structure-activity relationships.