Octahydropyrazinopyridoindoles. A New Class of Potent Antihypertensive Agents

Article abstract of DOI:10.1021/jm00385a022

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>pyrido<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 α₁-adrenoceptor blocking properties peaked with a simulataneous 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.