Stillings M R, Freeman S, Myers P L, Readhead M J, Welbourn A P, Rance M J, Atkinson D C
J Med Chem. 1985 Feb;28(2):225-33. doi: 10.1021/jm00380a013.
During an investigation of the antiinflammatory properties of a number of tetracyclic derivatives of 6,8-dichlorodibenz[b,f]oxepin-10(11H)-one, the ring-expanded 1,3-dichloro-5H-dibenz[b,g]-1,4-oxazocine (9) was prepared and found to be considerable pharmacological interest. It was subsequently found that the corresponding ring-opened amino acid 66, a close analogue of the antiinflammatory agent fenclofenac, also possessed significant antiinflammatory activity, superior both to the dibenzoxazocine and to fenclofenac. These findings prompted extensive synthetic programs in both areas, and a number of derivatives in the amino acid series showed potencies considerably in excess of the standard compound. These phenylacetic acids, however, were significantly more ulcerogenic than fenclofenac whereas the corresponding dibenzoxazocines showed few signs of ulcerogenicity at doses up to 1 g/kg.
在对6,8-二氯二苯并[b,f]氧杂环庚三烯-10(11H)-酮的多种四环衍生物的抗炎特性进行研究期间，制备了扩环的1,3-二氯-5H-二苯并[b,g]-1,4-恶唑嗪（9），并发现其具有相当大的药理学意义。随后发现，相应的开环氨基酸66，即抗炎药芬氯酸的紧密类似物，也具有显著的抗炎活性，优于二苯并恶唑嗪和芬氯酸。这些发现促使在这两个领域开展了广泛的合成研究，氨基酸系列中的一些衍生物显示出的效力大大超过标准化合物。然而，这些苯乙酸比芬氯酸的致溃疡性明显更强，而相应的二苯并恶唑嗪在剂量高达1 g/kg时几乎没有致溃疡迹象。
