1,4:3,6-Dianhydrohexitol nitrate derivatives. I. Synthesis and antianginal activity of alkylpiperazine derivatives.
A series of 5-deoxy-5-(4-substituted piperazin-1-yl)-1,4: 3,6-dianhydro-L-iditol 2-nitrates was prepared and evaluated for oral anti-ischemic activities. Inhibition of lysine-vasopressin-induced T-wave elevation in the electrocardiogram (ECG) of rats (angina pectoris model) served as a primary assay. Optimum activity was observed for the compounds with the aryl-heteroatom (O,S, or N)-propyl group. Among them, the phenylthiopropyl-substituted compound 13 exhibited the most potent activity. Furthermore, intraduodenal administration (i.d.) of 13 tended to decrease left ventricular end-diastolic pressure (LVEDP) in a propranolol-induced heart failure model (dogs) and showed a potent protective effect against reperfusion arrhythmia in rats. Thus, 13 (KF 14124) is under further study as an orally active nitrate.
Hayashi
H
H
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Ikeda
J
J
Kuroda
T
T
Kubo
K
K
Sano
T
T
Suzuki
F
F
D000284:Administration, Oral; D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006333:Heart Failure / Q000188:drug therapy; D006339:Heart Rate / Q000187:drug effects; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D008236:Lypressin / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D011433:Propranolol / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents
D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D014665:Vasodilator Agents; C083109:KF 14124; D008236:Lypressin; D011433:Propranolol; D007548:Isosorbide Dinitrate