Synthesis and antihypertensive activity of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones

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Abstract
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 1 step by condensation of dilithiated (tert-butoxycarbonyl)aniline (3) with (tert-butoxycarbonyl)piperidinone. Deprotection afforded 6 [spiro[4H-3,1-benzoxazine-4,4''-piperidin]-2(1H)-one], 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. Compound 9 may act by both central and peripheral mechanisms.

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