抗病毒药物4-取代吡咯[2,3-d]嘧啶开环核苷衍生物的合成

天然吡咯2,3-d]嘧啶核苷及其5-位取代衍生物为既有抗肿瘤活性又有抗病毒作用的抗生素,然毒性过高,未能成为药物。为降低此类化合物的毒性,并考察其构效关系,以4-氯-吡咯2,3-d]嘧啶为原料,用钠盐直接甙化法与2-氯甲基-1,3-双苄基-丙三醇缩合,得关键中间体Ⅸ,经氨化、氢解,合成了一系列4-取代吡咯2,3-d]嘧啶开环核苷衍生物。所得新化合物均经抗病毒活性筛选(HSV-1,Cox B6),只有化合物Ⅺ₆,Ⅺ₇,Ⅺ₉对Cox B6有一定的抑制作用。

SYNTHESIS OF ANTIVIRAL AGENTS ACYCLIC NUCLEO-SIDES OF 4-SUBSTITUTED PYRROLO [2,3-d] PYRIMIDINE

Naturally occurring nucleosides of pyrrolo 2,3-d] pyrimidine, tubercidin, sangivamycin and toyocamycin were known as antibodies not only for their potent antitumor activity but also for their significant antiviral effects. However, none of them was developed to be a useful drug due to their high toxicity. In order to reduce the toxicity of this kind of compounds and reveal the relationship between structure and biological activity, a series of acyclic analogues of tubercidin with varied 4-substituted amino groups were synthesized. 4-chlor-pyrrolo (2,3-d) pyrimidin was used as starting material which reacted with 1,3-dibenzyloxy-glycerol-2-chloro-methylether by direct sodium salt glycosylation procedure provided the key intermediate (IX). After hydrogenation, amination of compound IX gave the final free hydroxy products. All the compounds were tested in vitro against HSV-1 and Cox B6. Only three of them (XI6, XI7, XI9) showed certain activities against Cox B6.