1. Lowering LogD to increase water solubility
Changing the carbonyl group and kai-dimethyl in the molecule to oxetane can reduce LogD and increase water solubility . Introducing oxetane at different positions in the molecule has different effects on LogD and water solubility.
2. Effect on pKa
The polar nature of oxetane can be used to modulate the base of the proximal amine. pKa decreases depending on the topological distance between the two functional units. When the methylene unit is replaced by an oxetane unit, the amino group at the α-position shows the largest decrease in pKa (between -2.5 and -3.5).
3. Substitution of morpholine or other carbonyl-based structures in the block
The aqueous solubility of lipophilic scaffolds is often improved by the incorporation of morpholine structures, even though it is known that morpholine may be a target for oxidative metabolism. There are 17 commercially available APIs that contain a morpholine fraction. Metabolic data have been published for 13 of these compounds, and oxidative degradation of the morpholine peptide ring is the major metabolic pathway in eight of them. Spiro epoxetanes can be regarded as structural analogues of morpholine because of their ability to increase solubility while maintaining stability in oxidative metabolism. Thus, these oxetane derivatives are known as useful alternative building blocks to morpholine or other carbonyl-like structures through their unique polar spatial distribution.
4. Substitution of morpholine or other carbonyl-based structures in the block
The aqueous solubility of lipophilic scaffolds is often improved by the incorporation of morpholine structures, even though it is known that morpholine may be a target for oxidative metabolism. There are 17 commercially available APIs that contain a morpholine fraction. Metabolic data have been published for 13 of these compounds, and oxidative degradation of the morpholine peptide ring is the major metabolic pathway in eight of them. Spiro epoxetanes can be regarded as structural analogues of morpholine because of their ability to increase solubility while maintaining stability in oxidative metabolism. Thus, these oxetane derivatives are known as useful alternative building blocks to morpholine or other carbonyl-like structures through their unique polar spatial distribution.