New bronchodilators. II. 3H-imidazo[4,5-c]quinolin-4(5H)-ones.
A series of novel 3-substituted imidazo[4,5-c]quinolin-4(5H)-ones (2a-w) was prepared by the reaction of imidazo[4,5-c]quinolin-4(5H)-ones (6) with several electrophiles under basic conditions. The bronchodilatory activity of these compounds was evaluated on the basis of their protective effects against antigen-induced contraction (the Schultz-Dale reaction) of guinea-pig trachea (in vitro) and antigen inhalation-induced bronchospasm in passively sensitized guinea-pigs (in vivo). Although correlations between in vitro and in vivo activities were not clear, short alkyl chains such as the methyl and ethyl groups at the 3-position were important for potent activity, especially in vivo. Substituents at the 5-position were more tolerant of the activity than those at the 3-position. 5-Ethyl-3-methyl-3H-imidazo[4,5-c]quinolin-4(5H)-one (21) exhibits the most potent bronchodilatory activity among our tested compounds and is at least 5-fold more active than theophylline in vivo.
Suzuki
F
F
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Kuroda
T
T
Hayashi
H
H
Nakasato
Y
Y
Manabe
H
H
Ohmori
K
K
Kitamura
S
S
D000818:Animals; D001986:Bronchial Spasm / Q000517:prevention & control; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D006168:Guinea Pigs; D007093:Imidazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011804:Quinolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013806:Theophylline / Q000008:administration & dosage / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
D001993:Bronchodilator Agents; D007093:Imidazoles; D011804:Quinolines; D013806:Theophylline