ABSTRACT
Several 1-acyl-4-[2-(1,4-benzodioxan-2-yl)-2-hydroxy-ethylamino]piperidine s were prepared and a number of the compounds showed antihypertensive activity in the spontaneously hypertensive rat (SHR). This activity was specific for the (2S, 2R) enantiomers. General pharmacological evaluation and ligand binding data on selected compounds indicated a moderate degree of alpha 1- and beta-antagonistic activity. The alpha 1 antagonism was probably not of sufficient magnitude to explain the blood pressure lowering activity in the SHR.
Subject(s)
Antihypertensive Agents/chemical synthesis , Piperidines/pharmacology , Animals , Chemical Phenomena , Chemistry, Physical , Piperidines/chemical synthesis , Rats , Rats, Inbred SHR , Receptors, Adrenergic, alpha/drug effects , Receptors, Adrenergic, beta/drug effectsABSTRACT
Forty-one 9-substituted 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones were prepared for antihypertensive screening in the spontaneously hypertensive rat (SHR). For the 9-(2-indol-3-ylethyl) series, the parent compound, 9-(2-indol-3-ylethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (21), was the most potent antihypertensive agent. Substitution of lower alkyl groups on the spirolactam ring gave compounds close in activity to 21, while substitution with large alkyl or aryl groups led to a significant decrease in activity. Ring-opened analogues of 21 that contained the same functionality were markedly less active. Several 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones substituted at the 9 position with 1,4-benzodioxan-2-ylmethyl, 1,4-benzodioxan-2-ylhydroxyethyl, and 2-phenylethyl groups also demonstrated significant activity. Compound 21 was chosen for a detailed pharmacological evaluation. Its antihypertensive activity appears to be predominantly due to peripheral alpha 1-adrenoceptor blockade.
Subject(s)
Antihypertensive Agents , Spiro Compounds/pharmacology , Adrenergic alpha-Antagonists/metabolism , Animals , Antihypertensive Agents/chemical synthesis , Binding, Competitive , Cerebral Cortex/metabolism , Norepinephrine/metabolism , Prazosin/metabolism , Rats , Spiro Compounds/chemical synthesis , Structure-Activity Relationship , Yohimbine/metabolismABSTRACT
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.
