Synthesis and antihypertensive activity of a series of spiro[1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine-2,5'-oxazolidin-2'-one]s.
The 2R*,11bS* and 2S*,11bS* diastereoisomers of the spiro[1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine-2, 5'-oxazolidin-2'-one] system were prepared by stereoselective methods. Evaluation of these compounds for antihypertensive activity by oral administration to the spontaneously hypertensive rat showed the 2S*,11bS* series was the more potent. Within that series it was found that small alkyl substituents at positions 3 and 4' enhanced antihypertensive activity and that methoxyl substitution at positions 9 and 10 was optimal. (2S,3S,11bS)-Spiro-[2-ethyl-9,10-dimethoxy-1,3,4,6,7, 11b-hexahydro-2H-benzo[a]quinolizine-2,5'-oxazolidin-2'-one] [(-)-9e] was one of the most efficacious compounds of this series, while its antipode, (+)-9e, was inactive. Selected compounds in this series were shown to be alpha-adrenoceptor antagonists.
D012369:2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy- / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000633:toxicity; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D001011:Aorta / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis* / Q000633:toxicity; D011807:Quinolizines / Q000138:chemical synthesis*; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D010080:Oxazoles; D011807:Quinolizines; D011942:Receptors, Adrenergic, alpha; D012369:2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-; D009638:Norepinephrine