Lowering Lipophilicity by Adding Carbon: One-Carbon Bridges of Morpholines and Piperazines

In this article, we report our investigation
of a phenomenon by
which bridging morpholines across the ring with one-carbon tethers
leads to a counterintuitive reduction in lipophilicity. This effect
was also found to occur in piperazines and piperidines and lowered
the measured log D7.4 of the bridged molecules
by as much as −0.8 relative to their unbridged counterparts.
As lowering lipophilicity without introducing additional heteroatoms
can be desirable, we believe this potentially provides a useful tactic
to improve the drug-like properties of molecules containing morpholine-,
piperazine-, and piperidine-like motifs.