Heteroatom analogs of bemoradan: chemistry and cardiotonic activity of 1,4-benzothiazinylpyridazinones

Abstract

A series of close analogues of the potent, long-acting cardiotonic bemoradan (2a) was synthesized and examined in both in vitro and in vivo test systems. Changing the oxygen heteroatom at the 1-position of the benzoxazine ring of bemoradan to sulfur gave 4a, a more potent enzyme inhibitor and in vivo cardiotonic compound by the iv route. Intraduodenal administration of bemoradan, however, showed a superior response compared to its sulfur analogue, possibly due to oxidation of sulfur followed by a facile Pummerer rearrangement. Model studies were performed to examine the effect of the oxidation state of sulfur. Lack of a heteroatom at the 1-position, 3a (Y-590), afforded a compound with activity and potency very similar to those of bemoradan while the 1-selena compound gave a much less potent analogue 5. Analogues having a methyl group on the 4-nitrogen (2b, 3b, and 4b) were less potent than the desmethyl compounds, but all of these compounds have potent PDE III inhibiting activity and the ability to increase cardiac force in an anesthetized dog preparation when given iv.

Chemistry of Biologically Important Synthetic Organoselenium Compounds

“…While selenium substitution in indolidan resulted in retention of cardiotonic activity, 510 similar substitution in bemoradan lowered the activity of the parent compound (Table 30). 509 The reduced potency of the selenium compound 652 at the enzymic level was reflected in the poor in vivo activity of this compound. It is still unclear whether the oxidation of the selenide 652 to the corresponding selenoxide would contribute to the reduced potency of the drug.…”

A Review on Pyridazinone Ring Containing Various Cardioactive Agents

“…The alteration of the substituent groups at position 5 of the 6-phenylpyridazinonesaffects variations in the antiplatelet activity. The compound (40) was showed the highest antiplatelet activity with IC50 value in the micromolar range (15 mM) [85]. The 6-[3, 4-dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl]-2, 3, 4, 5-tetrahydro-5-methylpyridazeone (41) was a potent and selective inhibitor of PDE fraction III and act as orally active potent inotropic and vasodilator agent [85].…”

“…The compound (40) was showed the highest antiplatelet activity with IC50 value in the micromolar range (15 mM) [85]. The 6-[3, 4-dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl]-2, 3, 4, 5-tetrahydro-5-methylpyridazeone (41) was a potent and selective inhibitor of PDE fraction III and act as orally active potent inotropic and vasodilator agent [85]. A pyridazinones as cardiotonic agents and have potent ionotropic and myofibrillar Ca 2+ sensitizing activity of (±)-6-(4-( benzyl amino)-7-quinazolinyl)-4, 5-dihydro-5-methylpyridazinone (42) [86].…”

Pyrazole Carbohydrazide Derivatives of Pharmaceutical Interest

“…A large number of heterocyclic carbohydrazides and their derivatives are reported to exhibit significant biological activities [1,2] and the carbohydrazide function represents an important pharmacophoric group in several classes of therapeutically useful substances [1,3,4,5,6,7,8]. In this paper, the authors will discuss the biological activity spectrum of various pyrazole derivatives containing carbohydrazide moieties.…”