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 wide 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, not 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 patently new class of NO donors based on N-trityl 3,6-dihydro-1,2-oxazines. We show that these molecules release nitric oxide when heated above 90 °C and that their release kinetics can be modified through variation of the substitution pattern on the oxazine ring. Amorphous solid dispersions of these molecules in porous polymers exhibit consistent, thermoresponsive gas flow nitric oxide release. Collectively, this work adds a new class of NO donor to the basis set of known NO-genic molecules and establishes a potential technological basis for a low-power, small-footprint iNO delivery system.