Novel antiasthmatic agents with dual activities of thromboxane A2 synthetase inhibition and bronchodilation. 1. 2-[2-(1-Imidazolyl)alkyl]-1(2H)-phthalazinones.
A number of 4-substituted 2-[omega-(1-imidazolyl)alkyl]-1(2H)-phthalazinones were synthesized in order to develop agents possessing both thromboxane A2 synthetase inhibitory and bronchodilatory activities. The pharmacological evaluation of these compounds disclosed that they have both activities to various extents. Both activities were slightly dependent on the length of the 2-substituents and largely affected by the nature of the 4-substituents. Compounds bearing phenyl and thienyl groups exhibited relatively high and well-rounded activities. Among these compounds, 12j and 15f were found to be the most effective agents having well-rounded activities in vitro and in vivo. Introduction of a carboxyl group reduced both activities contrary to our expectation. 4-(3-Pyridyl)phthalazinone 18b was of particular interest because of unexpectedly high in vivo activities in spite of an absence of significant in vitro activities.
Yamaguchi
M
M
Fuji-gotemba Research Laboratories, Chugai Pharmaceutical Company, Ltd., Shizuoka, Japan.
Kamei
K
K
Koga
T
T
Akima
M
M
Kuroki
T
T
Ohi
N
N
D000818:Animals; D001993:Bronchodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001993:Bronchodilator Agents; D007093:Imidazoles; D010793:Phthalazines; C084854:2-(2-(1-imidazolyl)ethyl)-4-(3-pyridyl)-1(2H)-phthalazinone; D013930:Thromboxane-A Synthase