3-Hydrazinopyridazines substituted in position 6 with a primary amine, secondary amine, or an alkoxy group were synthesized and screened for antihypertensive activity. In general, the 6-dialklamino derivatives are the most active; the (2-hydroxypropyl)methylamino chain provides the best combination of high antihypertensive activity and toxicity.

In Vitro. Rat brains (6 mg) were homogenized in distilled water in a Sorvall blender at maximum speed for 2 min, filtered through four layers of cheese cloth, and centrifuged at 100,000g for 1 hr. The supernatant, containing 23% of the total activity (specific activity 600 nmol/mg protein/hr), was used for assaying the reactivators. Bovine erythrocyte AChE (Sigma) was prepared by dissolving the enzyme powder into histidine buffer (10 mM) adjusted to pH 7.4 to an activity of 0.1-0.2 µ / .A standard assay was followed using 3.75 mM acetylthiocholine (Eastman re crystallized twice from ethanol) and 2.5 mM 5,5'-dithiobis(2-nitrobenzoic acid) in sodium phosphate buffer (0.1 M) at pH 8.21 The enzyme was inhibited with 1 pM paraoxon and excess inhibitor was removed by passing the enzyme mixture through a 1.2 by 12 cm Bio-gel column equilibrated in 10 mM histidine buffer (pH 7.4). The potential reactivator (1 mM in ethanol) or ethanol alone as control was then added to the inhibited enzyme and recovery monitored at room temperature.

metabolism in rat; TLC-MS analysis; GC-MS quantitation; synthesis of 3-pyrazolylpyridazine derivatives as standards. SUMMARYThe metabolism of cadralazine I was studied after oral administration to rat. Besides consistent amount of unchanged drug, three metabolites were separated in urine by TLC and GC and their structures elucidated by mass spectrometry in comparison with synthetie samples. A specific and sensitive method was developed to detect the decarbethoxylated metabolite III at nanogram levels.

Das Dichlor‐pyridazin (II) reagiert mit sekundären Aminen zu den Amino‐pyridazinen (III), mit Morpholin zum Bis‐morpholino‐pyridazin (I).

No abstract