Synthesis and antihypertensive activity of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones.
A series of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones was prepared and evaluated for antihypertensive activity in the spontaneously hypertensive rat (SHR). The basic ring system was prepared in one step by condensation of dilithiated (tert-butoxycarbonyl)aniline (3) with (tert-butoxycarbonyl)piperidinone. Deprotection afforded 6, which was condensed with expoxides or alkyl halides to furnish the title compounds. The most active compound was dl-erythro-4'-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]spiro [4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-one (9), and various modifications of this compound were made in order to elucidate the structure-activity relationships in the series. Preliminary indications are that 9 may act by both central and peripheral mechanisms.
D000818:Animals; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D010078:Oxazines / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D010881:Piperidones / Q000627:therapeutic use*; D051381:Rats; D013141:Spiro Compounds / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D013599:Systole / Q000187:drug effects
D010078:Oxazines; D010880:Piperidines; D010881:Piperidones; D013141:Spiro Compounds