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

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

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Ⅺ_6,Ⅺ_7,Ⅺ_9对Cox B6有一定的抑制作用。

Naturally occurring nuclcosidcs of pyrrolo [2,3-d] pyrimidine, tubercidin, sangivamycin and toyocamycin were known as antibiotics 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 duc 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-subtituted 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 thc key intermediate (Ⅸ). After hydrogenation, amination of compound Ⅸ gave the final free hydroxy products. All the cmopounds were tested in vitro against HSV-1 and Cox B6. Only three of them (Ⅸ_6, Ⅸ_7, Ⅸ_9) showed certain activities against Cox B6.