Studies on the synthesis of condensed heterocyclic isoquinolone derivatives. I. Studies on the synthesis and pharmacology of thiazino, oxazino and pyrimido isoquinolones.
作者:KAZUO KUBO、NORIKI ITO、YASUO ISOMURA、ISAO SOZU、HIROSHIGE HOMMA、MASUO MURAKAMI
DOI:10.1248/cpb.27.2372
日期:——
5-Oxo-1, 2, 3, 5-tetrahydro-5H-imidazo [1, 2-b] isoquinoline (IIa) and related compounds were synthesized from homophthalic acid and an aliphatic 1, 2- or 1, 3-diamine. In addition, homophthalic acids or o-carboxyphenylmalonic acid diesters were allowed to react with an aliphatic 1, 2- or 1, 3-aminoalcohol or aminothiol with heating in the presence of p-toluenesulfonic acid, yielding a series of oxazolo- or oxazino-isoquinolones (VI) or thiazolo- or thiazino-isoquinolones (IV). Oxidation of IV gave the corresponding sulfoxides (VII) and sulfones (VIII). Treatment of o-cyanomethylbenzenesulfonyl chloride with an N-alkyl 1, 2- or 1, 3-diamine gave N-alkyl-imidazo- or pyrimido-benzothiazine-5, 5-dioxide (XI). The compounds thus prepared were evaluated for their anti-inflammatory effect in rats, using the carrageenin paw edema method, and some of the condensed heterocyclic isoquinolone derivatives were found to exhibit strong anti-inflammatory activity. These compounds were also examined for analgesic activity in terms of the inhibition of acetic acid induced writhing. Compound VIIIk showed stronger anti-inflammatory activity than phenylbutazone, as well as analgesic activity comparable to that of aminopyrine, and had very low toxicity.
5-氧代-1,2,3,5-四氢-5H-咪唑并[1,2-b]异喹啉(IIa)及相关化合物由均苯二甲酸和脂肪族 1,2-或 1,3-二胺合成。此外,均苯二甲酸或邻羧基苯丙二酸二酯与脂肪族 1、2- 或 1、3-氨基醇或氨基硫醇在对甲苯磺酸存在下加热反应,可生成一系列噁唑或噁唑-异喹啉酮(VI)或噻唑或噻嗪-异喹啉酮(IV)。IV 氧化后得到相应的硫醚(VII)和砜(VIII)。用 N-烷基 1,2-或 1,3-二胺处理邻氰甲基苯磺酰氯,可得到 N-烷基咪唑或嘧啶基苯并噻嗪-5,5-二氧化物(XI)。采用角叉菜胶爪水肿法对由此制备的化合物进行了大鼠抗炎效果评估,发现其中一些缩合杂环异喹啉酮衍生物具有很强的抗炎活性。这些化合物还通过抑制醋酸引起的蠕动来检测其镇痛活性。化合物 VIIIk 显示出比苯基丁氮酮更强的抗炎活性,以及与氨基比林相当的镇痛活性,而且毒性很低。