Novel bronchodilators: Synthesis, transamination reactions, and pharmacology of a series of pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides

The synthesis, pharmacological evaluation, and structure-activity relations hips of a new class of bronchodilator agents, derivatives of pyrazino[2,3-c ][1,2,6]thiadiazine 2,2-dioxides are described. The compounds were prepared by reaction of 3,4,5-triamino-1,2,6-thiadiazine 1,1-dioxide with suitable 1,2-dicarbonyl compounds or alpha -hydroxyiminoketones and subsequent N-alk ylation. A transamination procedure for synthesizing derivatives with diffe rent substituents at the 4-amino group is reported for the first time. The pyrazino[2,3-c][1,2,6]thiadiazine derivatives were screened for tracheal re laxing activity in vitro, and the active compounds were evaluated in vivo i n guinea pigs as bronchodilator agents in comparison to theophylline. Among the compounds studied, the most interesting properties were displayed by t he 4-aminol-ethyl-6-methyl derivative (21). The toxicological evaluation of this derivative is also reported.