6-Benzoxazinylpyridazin-3-ones: potent, long-acting positive inotrope and peripheral vasodilator agents

Abstract

A series of 6-benzoxazinylpyridazin-3-ones was prepared and evaluated for inhibition of cardiac phosphodiesterase (PDE) fraction III in vitro and for positive inotropic activity in vivo. 6-[3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl]-2,3,4,5-tetrahydro-5 - methylpyridazin-3-one (bemoradan) was found to be an extremely potent and selective inhibitor of canine PDE fraction III and a long-acting, potent, orally active inotropic vasodilator agent in various canine models. Additional benzoxazin-6-yl and -8-yl compounds were also prepared. Altering the pyridazinone substitution from the 6-position to the 7-position produced a 14-fold increase in the iv cardiotonic potency (ED50) from 77 to 5.4 micrograms/kg while substitution at the 8-position reduced potency. Methyl substitution at various sites in the molecule was also examined. Positive inotropic activity was maintained for between 8 and 24 h after a single oral dose (100 micrograms/kg) of bemoradan in dogs, thus making it one of the most potent and long-acting orally effective inotropes yet described. Bemoradan is currently under development as a cardiotonic agent for use in the management of congestive heart failure.

Synthesis of 2,3‐dihydro‐6H‐1‐oxa‐3a‐aza‐phenalene and its benzo/hetero‐fused analog

“…The first step employed was the N-alkylation of benzoxaxine 1 with 3-bromo-propionic acid benzyl ester in presence of K 2 CO 3 to obtain 3-(6,7-Dialkyl-2,3-dihydro-benzo [1,4]oxazin-4-yl)-propionic acid benzyl ester 2a-j. 2a-j when subjected to reduction and subsequent cyclization using trifluoroacetic anhydride in dichloromethane at room temperature yielded the desired products 3a-j (Scheme 1).…”

“…2,3,4,6-Tetrahydro-6H-oxa-3a-aza-phenalene (3a 3-(2,3-Dihydro-benzo [1,4]oxazin-4-yl)-3-methylsulfanyl-1-phenyl-propenone (5a). To a solution of 3,4-dihydro-2H-1,4-benzoxazines (7 mmol) in dry THF (30 mL) was added n-BuLi (9 mmol) drop wise under nitrogen atmosphere at À78 C, it was then allowed to attain room temperature and further stirred for 30 min.…”

“…They have shown to be long-acting positive inotropes and peripheral vasodilator [1] with potential intracellular calcium activity [2]. Tricyclic analogs with a fused additional ring on the nitrogen atom of the benzoxazine moiety have been prepared and evaluated for their cardiovascular effects and as potential antihypertensive agents.…”

Design, synthesis and antihypertensive screening of novel pyridazine substituted s-triazin-2-imine/one/thione derivatives

“…Pyridazines are important biologically active scaffolds, possessing antihypertensive 4 , cardiotonic 5 , analgesic 6 , anti-inflammatory 7 , antidepressant 8 , antibacterial 9 , anticancer 10 , nephrotopic drugs 11 , antithrombic 12 , diuretic 13 and anti-HIV 14 activities. Some pyridazine derivatives, such as bemoradan 15 , indolidan 16 , levosimendan 17 , pimobendan 18 , zardaverine 19 and imazodan 20 , have already appeared in the clinical market. Nitrogen containing heterocycles play an important role not only for life science industry but also in many other industrial fields related to special and fine chemistry.…”

Synthesis, Characterization and Antihypertensive Activity of Some New Substituted Pyridazine Derivatives

“…Pyridazine derivatives, a class of compounds containing the N-N bond, exhibit a wide range of pharmacological activities such as antidepressant 4 , antihypertensive [5][6][7][8] , antithrombotic 9 , anticonvulsant 10 , cardiotonic 11 , antibacterial 12 , diuretics 13 , antiHIV 14 and anticancer 15 . Some pyridazinone derivatives like indolidan 16 , bemoradan 17 , primobendan 18 , levosimendan 19 (antihypertensive), already approved in the clinical market. The current work describes the synthesis of some new substituted pyridazine derivatives with encouraging antihypertensive activity by non-invasive method using Tail Cuff method.…”