On-Demand Nitric Oxide Generation via Thermal Decomposition of N-Trityl Dihydro-1,2-Oxazines

Inhaled nitric oxide (iNO) is a promising therapy for a variety of pulmonary conditions but is limited by the cost, portability, and safety limitations of the compressed gas cylinders used in conventional iNO delivery systems. On-demand generation of iNO via thermally controlled decomposition of an NO-genic precursor is an attractive alternative to systems based on compressed gas cylinders. However, most NO-releasing materials, which would form the basis of such a system, are designed for in vivo applications, but not for gas flow release at elevated temperatures. Novel NO donors with tunable kinetics suited for simple thermal generation are needed to realize such iNO delivery systems. Here we report the development of a new class of NO donors based on N-trityl 3,6-dihydro-1,2-oxazines. We show that amorphous solid dispersions of these molecules in porous polymers exhibit consistent, thermoresponsive NO release in good yields when heated above 90 °C in the presence of a carrier gas. We further demonstrate that these donors undergo NO release in aqueous media at 37 °C. Collectively, this work adds a new class of NO donor to the basis set of known NO-genic molecules and establishes a potential chemical basis for a low-power, small-footprint iNO delivery system.