A series of new sympathomimetic amines containing an 8-hydroxycarbostyril moiety was synthesized. These compounds probably exist as resonance hybrids having two acidic hydrogen atoms in locations approximating to those of the hydroxyl groups of catechol-containing adrenergic agents. In an in vitro test, many of these compounds showed potent activity for relaxation of guinea pig tracheal smooth muscle. One of the compounds was 24 000 times more potent than isoproterenol. Their actions on cardiac muscle were also examined in vitro by measuring increase in the beating rate of the right atria of guinea pigs. Several of the compounds appeared to be beta-selective. Some of the compounds seem suitable for use as bronchodilators. The structure-activity relationships of these compounds were discussed in comparison with those of catecholamines.
Die vier Stereoisomeren (Ia)‐(Id) werden synthetisiert und a) in die jeweiligen Acetate (IIa) sowie b) in die jeweiligen Propionate (IIb) übergeführt, die auf ihre Pheromonaktivität (Kiefem‐Sägewespe (Hymenoptera: Diprionidae)) getestet werden sollen: 1. Ausgehend von der D‐Weinsäure (IIIa) wird über die Stufen (IIIb), (IVa) (bekannte Reaktionen), (IVb)‐(IVe), (V) und (VI) das Epoxid (VII) dargestellt.
The isomers of erythro-5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril (1), a new potent and beta2-selective bronchodilator, were synthesized by optical resolution of compound 1 and inversion of the erythro to the threo isomers. The isomers were tested for activities to inhibit histamine-induced bronchospasm and to increase the heart rate of anesthetized dogs. Racemic and (-)-erythro-1 showed potent and beta2-selective bronchodilater activities. Among the isomers, (-)-erythro-1 showed the highest activities and (+)-erythro-1 showed the lowest.
Key Words: OPC-13340-€alcium antagonist-Hypertension-EDRF-Cerebral blood flow.OPC-13340 is a new dihydropyridine calcium antagonist that is now under clinical trials as a long-acting antihypertensive and an antianginal agent. OPC-13340 was found to have the most potent and the longest hypotensive action among six compounds (OPC-13340, nifedipine, nitrendipine, nisoldipine, nicardipine, and diltiazem) tested in various hypertensive rat and dog models. Its hypotensive action is more specific for hypertensive than for normotensive animals. In normotensive conscious rats, OPC-13340 increased cerebral blood flow more than nicardipine or nimodipine. Also, in the aged spontaneously hypertensive rat (SHR) model, OPC-13340 did not decrease cerebral blood flow during severe hypotension. OPC-13340 has a unique action on endothelium-dependent relaxation in isolated rat aorta, namely it prolongs the duration of endothelium-dependent relaxation, while other calcium antagonists tested did not have such an effect at a clinically relevant concentration range. The following review summarizes preclinical and clinical experience with this compound to date.
CHEMISTRY
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