Synthesis and Myelostimulatory Activity of β-Cyclodextrin Complexes of 3,7-Diazabicyclo[3.3.1]Nonan-9-One Derivatives

Abstract

Simultaneous Mannich condensation of 1-(3-methoxypropyl)piperidone-4 with paraformaldehyde and 1-(2-pyridinoethyl)amine yielded 3-(3methoxypropyl)-7-[2-(pyridin-2-yl)ethyl]-3,7-diazabicyclo[3.3.1]nonan-9-one, which was reduced to the corresponding bicyclic nonane under Huang—Minlon reaction conditions. The reaction of 3,7-diazabicyclo[3.3.1]nonan-9-one with hydroxylamine hydrochloride led to the corresponding oxime, subsequent acylation of which synthesized its O-benzoyloxime. Replacement of the morpholine or piperazine ring in 3-(3-ethoxy- or isopropoxypropyl)-7-[2-(N-morpholino- or N-piperazino) ethyl]-3,7-diazabicyclo[3.3.1]nonane by pyridine led to a loss of activity. However, 3-(3-methoxy- and isopropoxypropyl)-7-[2-(pyridin-2-yl- and N-piperazino)ethyl]-3,7-diazabicyclo[3.3.1]nonan-9-one O-benzoyloximes were myelostimulators although they differed in that the β-cyclodextrin complex of 3-(3-methoxypropyl)-7-[2-(pyridin-2-yl)ethyl]-3,7-diazabicyclo[3.3.1]nonan-9-one O-benzoyloxime stimulated both erythro- and leukopoiesis while its N-piperazine analog stimulated only leukopoiesis.