Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones

Abstract

Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.

Synthesis and Monkey-PET Study of (R)- and (S)-18F-Labeled 2-Arylbenzoheterocyclic Derivatives as Amyloid Probes with Distinctive in Vivo Kinetics

“…Traditionally, the racemates were resolved into their individual enantiomers by chiral separation using supercritical fluid chromatography (SFC) on a Chiralpak AD column . In this work, enantiopure ( R )-(−)-/( S )-(+)-epichlorohydrin and ( S )-(+)-/( R )-(−)-3-chloropropane-1,2-diol were employed as starting compounds to provide enantiopure final products as reported. − …”

4-Aryl-1-oxa-4,9-diazaspiro[5.5]undecane Derivatives as Dual μ-Opioid Receptor Agonists and σ1 Receptor Antagonists for the Treatment of Pain

“…This allowed diversification in substituents R 1 -R 2 (Scheme ) by building the spirobicyclic core following a similar strategy to that described in Scheme . The related spiro compound 20 was prepared from aminoalcohol 18 - 1 (where R 1 is H and n is 1) upon treatment with carbonyldiimidazole (CDI) …”

Readily Available Chiral Carbon Fragments and Their Use in Synthesis

“…These include practolol (899) (392) and 900 (393). One of the better approaches to such compounds is the opening of a chiral epoxide with an amine.…”