Morpholine

Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules, and is often employed in medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The combination of a weakly basic nitrogen and a ring oxygen at the para-position confers a lower pKa than piperidine or piperazine analogues, reducing the fraction of ionised species at physiological pH and improving passive permeability, while the ether oxygen simultaneously acts as a hydrogen bond acceptor. The presence of a weak basic nitrogen atom and an oxygen atom at the opposite position provides a peculiar pKa value and a flexible conformation to the ring, allowing it to take part in several lipophilic-hydrophilic interactions and to improve blood solubility and brain permeability of the overall structure.

In drug design, morpholine is deployed in three distinct roles: as a pharmacophore that directly engages the target active site, as a scaffold that positions pharmacophoric elements at the correct geometry, and as a peripheral solubilising group that modulates lipophilicity and metabolic clearance without substantially increasing molecular weight. Morpholine has long been a molecule of choice for medicinal chemists as it improves the aqueous solubility of lipophilic scaffolds, with many marketed drugs containing the morpholine moiety across a broad range of therapeutic areas including oncology, CNS, anti-infective, and cardiovascular programmes.

Examples of Morpholine in the clinic include: Gefitinib (Iressa, AstraZeneca), the first selective EGFR tyrosine kinase inhibitor approved for the treatment of non-small cell lung cancer, incorporates a morpholine ring attached to the quinazoline core via a propoxy tether, where the morpholine was specifically introduced during lead optimisation to enhance aqueous solubility whilst retaining EGFR potency. Rivaroxaban (Xarelto, Bayer), the first approved oral direct factor Xa inhibitor for the prevention of venous thromboembolism, utilises a morpholinone moiety that is sandwiched between Tyr99 and Phe174 within the S4 hydrophobic pocket of factor Xa, with this interaction central to the compound's potency and selectivity profile.

Our range of Morpholines features novel substitutions and the incorporation of synthetically tractable functional groups such as boronic acids and esters, amines, carboxylic acids, ketones, hydroxyls and halogens to enable expedient synthetic strategies.

Please examine a selection of Morpholines in our catalogue. The full range can be found using the substructure feature of our Search tools.