Studies of cardiotonic agents. 8. Synthesis and biological activities of optically active 6-(4-(benzylamino)-7-quinazolinyl)-4,5-dihydro-5-methyl-3(2H)- pyridazinone (KF15232).
We previously reported that (+/-)-6-(4-(benzylamino)-7-quinazolinyl)-4,5- dihydro-5-methyl-3(2H)-pyridazinone (+/-)-1, KF15232) showed potent cardiotonic activity with a strong myofibrillar Ca(2+)-sensitizing effect. As an extension of our work, we attempted to synthesize optically active 1. (+/-)-4-(4-(Benzylamino)-7-quinazolinyl)-3-methyl-4-oxobutyric acid (-)-menthyl ester (6) was separated into both diastereoisomers, and each was converted to optically pure 1 (> 99% ee) in an enantioselective manner. In order to determine the absolute configuration of the isomers, an alternative synthesis of optically active 1 was employed. The precursor of (-)-1 ((+)-9) was obtained by enantioselective synthesis from (R)-D-alanine. Consequently, we concluded that the absolute configuration of (-)-1 at the 5-position of the pyridazinone ring was R. The cardiotonic effects and inhibitory activities to PDE III and V of racemic 1 and (-)-1 were more potent than those of (+)-1. These compounds also demonstrated greater vasorelaxant effects in guinea pig aorta. In contrast, (+)-1 showed only weak cardiotonic and vasodilating effects, although the compound displayed potent Ca(2+)-sensitizing activity. Racemic and (-)-1 attracted our interest for the treatment of congestive heart failure.
Nomoto
Y
Y
Pharmaceutical Research Laboratories, Fuji, Kyowa Hakka Co., Ltd., Shizuoka, Japan.
Takai
H
H
Ohno
T
T
Nagashima
K
K
Yao
K
K
Yamada
K
K
Kubo
K
K
Ichimura
M
M
Mihara
A
A
Kase
H
H
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D004285:Dogs; D006168:Guinea Pigs; D006333:Heart Failure / Q000188:drug therapy; D066298:In Vitro Techniques; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects; D009712:Nucleotides, Cyclic / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D014268:Trifluoperazine / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017725:Ventricular Pressure / Q000187:drug effects
D002316:Cardiotonic Agents; D009712:Nucleotides, Cyclic; D010726:Phosphodiesterase Inhibitors; D011799:Quinazolines; D014665:Vasodilator Agents; C070673:KF 15232; D014268:Trifluoperazine; D002118:Calcium