Johnson R A, Gorman R R, Wnuk R J, Crittenden N J, Aiken J W
Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
J Med Chem. 1993 Oct 15;36(21):3202-6. doi: 10.1021/jm00073a023.
The synthesis of 2,8-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (Tröger's base) from p-toluidine and of two Tröger's base analogs from other anilines by reaction with hexamethylenetetramine in trifluoroacetic acid is described. 2,3,6,7-Tetrahydro-9-methyl-2,6-di-p-tolyl-1H,5H-pyrimido[5,6,1-ij] quinazoline is formed as a secondary product in the reaction of p-toluidine and hexamethylenetetramine. One of the Tröger's base analogs, 2,8-bis(3'-pyridylmethyl)-6H,12H-5,11-methanodibenzo[b,f][1,5]d iazocine (5), is an effective inhibitor of the enzyme, thromboxane A2 (TxA2) synthase, with an ED50 of 30 ng/mL in a specified in vitro assay. Three analogs having substituents on the bridging methylene group of the bicyclic nucleus of the Tröger's base structure were prepared, but all were considerably less active than the aforementioned compound in the inhibition assay. The structures of these inhibitors of TxA2 synthase fall outside the classical structure-activity relationship that has been established for this class of enzyme inhibitors.
描述了由对甲苯胺合成2,8-二甲基-6H,12H-5,11-亚甲基二苯并[b,f][1,5]二氮杂环辛烷（特罗格碱）以及由其他苯胺与六亚甲基四胺在三氟乙酸中反应合成两种特罗格碱类似物的过程。在对甲苯胺与六亚甲基四胺的反应中，会生成副产物2,3,6,7-四氢-9-甲基-2,6-二对甲苯基-1H,5H-嘧啶并[5,6,1-ij]喹唑啉。特罗格碱类似物之一，2,8-双(3'-吡啶基甲基)-6H,12H-5,11-亚甲基二苯并[b,f][1,5]二氮杂环辛烷（5），在特定的体外测定中是血栓素A2（TxA2）合酶的有效抑制剂，半数有效浓度（ED50）为30 ng/mL。制备了三种在特罗格碱结构双环核的桥连亚甲基上有取代基的类似物，但在抑制测定中，它们的活性都比上述化合物低得多。这些TxA2合酶抑制剂的结构不符合已为此类酶抑制剂建立的经典构效关系。
