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 relationships 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-alkylation. A transamination procedure for synthesizing derivatives with different 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 relaxing activity in vitro, and the active compounds were evaluated in vivo in guinea pigs as bronchodilator agents in comparison to theophylline. Among the compounds studied, the most interesting properties were displayed by the 4-amino-1-ethyl-6-methyl derivative (21). The toxicological evaluation of this derivative is also reported.
Campillo
N
N
Instituto de Química Médica CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
García
C
C
Goya
P
P
Alkorta
I
I
Páez
J A
JA
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D007928:Lethal Dose 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D009126:Muscle Relaxation; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023382:Toxicity Tests, Acute; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D001993:Bronchodilator Agents; C108915:PF 904; D011719:Pyrazines; D013829:Thiadiazines