Octahydropyrazino[2',3':3,4]pyrido[1,2-a]indoles. A new class of potent antihypertensive agents.
Simplifications and modifications of the vincamine molecule led to the discovery of antihypertensive 1,2,3,4,4a,5,6,12b-octahydro-12-methylpyrazino[2',3':3,4]pyr ido[1,2-a] indoles. Stereoselective syntheses of both 4a,12b-cis and 4a,12b-trans isomers represent new annulation strategies for the construction of fused piperazines. Compounds of the trans series were at least 10 times more potent than the corresponding cis isomers. Antihypertensive activity and alpha 1-adrenoceptor blocking properties peaked with a simultaneous introduction of 4-methylethyl and 1-alkyl substituents. Compound 15j (AY-28,228; atiprosin), (4a, 12b-trans)-1-ethyl-1,2,3,4,4a,5,6, 12b-octahydro-12-methyl-4-(1-methylethyl)pyrazino[2',3':3,4]pyrido [1,2-a]indole, was chosen for a detailed preclinical evaluation.
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D001794:Blood Pressure / Q000187:drug effects*; D004837:Epinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013053:Spectrophotometry; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D007202:Indicators and Reagents; D007211:Indoles; D011719:Pyrazines; D011725:Pyridines; D004837:Epinephrine