Synthesis and pharmacological evaluation of 6-(7-theophylline)-3(2H)-pyridazinone.

Since the introduction of theophylline (1) as the first PDE-inhibitor used in the treatment of asthma, there has been intense activity in this area of therapy to design drugs with improved potency and efficacy. Derivatives of theophylline and other purine analogs were prepared and tested as PDE-inhibitors and cardiac stimulants, some of them being several times more active than theophylline. A variety of 4,5-dihydro-6-phenyl-3(2H)-pyridazinone derivatives are PDE-inhibitors like CI-914 (2) which produced a cardiotonic effect accompanied by only slight decreases in blood pressure and moderate increases in heart rate. In a recent report some 6-phenyl-3(2H)-pyridazinones showed a bronchospasmolytic effect more marked than that of xanthines. In this paper we report the synthesis and pharmacological profile of 6-(7-theophylline)-3(2H)-pyridazinone; the synthesis is shown in Scheme 1.