Synthesis and biological evaluation of substituted benzo[h]cinnolinones and 3H-benzo[6,7]cyclohepta[1,2-c]pyridazinones: higher homologues of the antihypertensive and antithrombotic 5H-indeno[1,2-c]pyridazinones.
Several substituted benzo[h]cinnolinones 3 and 3H-benzo[6,7]cyclohepta[1,2-c]pyridazinones 4, which were designed as less rigid congeners of 5H-indeno[1,2-c]pyridazinones 2, were synthesized and tested as antihypertensive, inotropic, antithrombotic, antiinflammatory, and antiulcer agents. While the seven-membered ring derivatives displayed only antithrombotic properties, which were comparable to that of acetylsalicylic acid, most of the benzo[h]cinnolinones exhibited significant antihypertensive, inotropic, and antithrombotic properties. In this respect, the 8-amino (3b) and 8-acetylamino (3c) together with the 4,4a-dehydro analogue of 3c (11) were found to possess the most potent and long-lasting antihypertensive activity. In particular, the dextro isomer of 3c was more active than the racemic form, with lower tachycardiac effects. Unlike the lower homologues 2, none of the compounds showed significant antiinflammatory or antiulcer activity.
Cignarella
G
G
Istituto Chimico Farmaceutico e Tossicologico, Universitá di Milano, Italy.
Barlocco
D
D
Pinna
G A
GA
Loriga
M
M
Curzu
M M
MM
Tofanetti
O
O
Germini
M
M
Cazzulani
P
P
Cavalletti
E
E
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D016275:Atrial Function; D001794:Blood Pressure / Q000187:drug effects*; D003508:Cycloheptanes / Q000138:chemical synthesis* / Q000494:pharmacology; D005342:Fibrinolysis; D005343:Fibrinolytic Agents / Q000138:chemical synthesis*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D003508:Cycloheptanes; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D011724:Pyridazines