Studies on Agents with Vasodilator and .BETA.-Blocking Activities. V. Synthesis and Pharmacological Activity of the Optical Isomers of TZC-5665.

Seki, Toshimi; Kanada, Arihiro; Nakao, Tomio; Shiraiwa, M.; Asano, Hajime; Miyazawa, Kazuhiro; Ishimori, Tsutomu; Minami, Nobuyoshi; Shibata, Kenyu; Yasuda, Kikuo

doi:10.1248/cpb.46.84

Cited by 6 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2-Unsubstituted -NH signal was observed at d 10.41 ppm in the case of 10 and 11 while it was absent in the case of 2-substituted derivatives 2-4 and 7-9. The ratio of two enantiomers in 5-methyl derivative 11 could not be determined using proton NMR spectroscopy since all the protons resonate at the same position in both isomers (12). The racemic mixture obtained was used as such for further studies.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of 2-substituted-6-phenyl-4,5-dihydropyridazin-3(2H)-ones as potent inodilators

Kumar¹,

Carrón²,

Calle³

et al. 2008

Acta Pharmaceutica

View full text Add to dashboard Cite

The inotropic and vasodilatory properties of 4,5-dihydro-6-phenylpyridazin--3(2H)-ones are well documented in literature (1-3). Pyridazinone derivatives like SK&F--93741, its nor-methyl derivative and levosimendan ( Fig. 1) possess a substituted amino group at para-position of 6-phenyl ring and have emerged as potent cardiotonic agents with dual inotropic and vasodilatory properties in higher animals (4-6). These pyridazinone-based cardiotonics have shown good promise in the treatment of congestive heart failure; however, species differences in inotropic response to these agents have been observed (7). It is also evident from literature reports that the most dramatic alterations in the potency of pyridazinone based cardiotonics result from varying para-substituents of the phenyl ring attached to 4-position of pyridazinone nucleus. However, position 2 of the pyridazinone ring remains relatively unexplored. Pyridazin-3(2H)-ones further drew our attention because of their easy functionalization at various ring positions (1), which makes them attractive synthetic building blocks for designing and development of novel pyridazinone based cardiotonic agents. The present study describes the synthesis and pharmacological evaluation of 2-substituted-6-(4-acylaminophenyl)-4,5-dihydropyridazin-3(2H)-ones as potent inodilating agents. The synthesis of target compounds 2-4 and 7-11 was achieved by Friedel-Crafts acylation of appropriate anilide derivative with succinic anhydride or methylsuccinic anhydride and subsequent cyclization of intermediary keto acids with various hydrazine derivatives. The newly synthesized pyridazinone derivatives were evaluated for cardiotonic activity using isolated rat atria and for vasorelaxant activity using descending thoracic aortic rings of Wistar rats precontracted with phenylephrine (10 -6 mol L -1 ). 6-(4-Methanesulfonamidophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one (7) exhibited significant inodilatory properties and showed vasorelaxant activity in a nanomolar range (IC 50 = 0.08 ± 0.01 mmol L -1 ).

show abstract

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of 2-substituted-6-phenyl-4,5-dihydropyridazin-3(2H)-ones as potent inodilators

Kumar¹,

Carrón²,

Calle³

et al. 2008

Acta Pharmaceutica

View full text Add to dashboard Cite

show abstract

“…The title compound, (I), is a key intermediate in the synthesis of cardiotonic agents that have long-acting effects on hypertensives and platelet aggregation (McEvoy & Allen, 1974;Seki et al, 1998, Jiang & Sun, 1990, Dong et al, 2005, such as amipizone (Thyes et al, 1983) and levosimendan (Zhang et al, 2004). However, the crystal structure has not been determined previously.…”

Section: Commentmentioning

confidence: 99%