Suzuki F, Kuroda T, Hayashi H, Nakasato Y, Manabe H, Ohmori K, Kitamura S
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Chem Pharm Bull (Tokyo). 1992 Dec;40(12):3245-52. doi: 10.1248/cpb.40.3245.
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.
通过咪唑并[4,5-c]喹啉-4(5H)-酮(6)与几种亲电试剂在碱性条件下反应，制备了一系列新型的3-取代咪唑并[4,5-c]喹啉-4(5H)-酮(2a-w)。基于这些化合物对豚鼠气管抗原诱导收缩（舒尔茨-戴尔反应，体外）和被动致敏豚鼠抗原吸入诱导支气管痉挛（体内）的保护作用，对其支气管扩张活性进行了评估。虽然体外和体内活性之间的相关性不明确，但3-位的短烷基链如甲基和乙基对强效活性很重要，尤其是在体内。5-位的取代基比3-位的取代基对活性的耐受性更强。在我们测试的化合物中，5-乙基-3-甲基-3H-咪唑并[4,5-c]喹啉-4(5H)-酮(21)表现出最有效的支气管扩张活性，并且在体内活性至少比茶碱高5倍。
