Raboisson Pierre, Baurand Anthony, Cazenave Jean-Pierre, Gachet Christian, Schultz Dominique, Spiess Bernard, Bourguignon Jean-Jacques
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081 du CNRS, Université Louis Pasteur, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch Cedex, France.
J Org Chem. 2002 Nov 15;67(23):8063-71. doi: 10.1021/jo026268l.
In our effort to identify potent purinergic P2Y(1) receptor antagonists as potent platelet aggregation inhibitors with enhanced metabolic stability, we developed an efficient route for the large-scale preparation of 2'-deoxy-C-nucleosides of pyrazolo[1,5-a]-1,3,5-triazine. The key strategic elements of this novel synthetic approach involved the following: (i) the use of a novel activating group, the N-methyl-N-phenylamino group, which was easily generated in high yield by treatment of the pyrazolo[1,5-a]-1,3,5-triazin-4-one (5) with phosphorus oxychloride and dimethylaniline under high pressure, (ii) a regio- and stereospecific palladium-mediated coupling reaction of the readily available unprotected glycal 1,4-anhydro-2-deoxy-D-erythro-pent-1-enitol (4b) and the 8-iodo derivative (16), and (iii) the stereoselective reduction of the ketone group of the furanosyl ring followed by the subsequent displacement of the N-methyl-N-phenylamino group upon treatment with methylamine. The beta configuration at the anomeric C-1' position of the glycal moieties was perfectly retained throughout this conversion. This procedure afforded 8-(2'-deoxy-beta-D-ribofuranosyl)-2-methyl-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (21) and 8-(2'-deoxy-beta-D-xylofuranosyl)-2-methyl-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (24) with an overall yield of 50% and 39%, respectively. Finally, the conversion of nucleosides 21 and 24 to the pyrazolotriazine C-nucleotides 3',5'-bisphosphate 2 and 3',5'-cyclophosphate 26 is also described herein and represents the first reported nucleotide derivatives within the pyrazolo[1,5-a]-1,3,5-triazine series. Preliminary biological testing has shown that compound 2 strongly inhibits ADP-induced human platelet aggregation and shape change and possesses significant efficacies 30 min after injection in rat, highlighting a strong P2Y(1)-receptor antagonist activity in vitro combined with a prolonged duration of action in vivo.
为了寻找强效的嘌呤能P2Y(1)受体拮抗剂作为具有更高代谢稳定性的强效血小板聚集抑制剂，我们开发了一种高效路线，用于大规模制备吡唑并[1,5 - a]-1,3,5 - 三嗪的2'-脱氧 - C - 核苷。这种新颖合成方法的关键策略要素包括：(i) 使用一种新型活化基团，即N - 甲基 - N - 苯基氨基，通过在高压下用三氯氧磷和二甲基苯胺处理吡唑并[1,5 - a]-1,3,5 - 三嗪 - 4 - 酮(5)可轻松高产率地生成；(ii) 对易于获得的未保护糖基1,4 - 脱水 - 2 - 脱氧 - D - 赤藓糖 - 1 - 戊烯醇(4b)和8 - 碘衍生物(16)进行区域和立体特异性钯介导的偶联反应；(iii) 对呋喃糖环的酮基进行立体选择性还原，随后在用甲胺处理时N - 甲基 - N - 苯基氨基被取代。在整个转化过程中，糖基部分异头C - 1'位的β构型完美保留。该方法分别以50%和39%的总收率得到8 - (2'-脱氧 - β - D - 核糖呋喃糖基)-2 - 甲基 - 4 - (N - 甲基氨基)吡唑并[1,5 - a]-1,3,5 - 三嗪(21)和8 - (2'-脱氧 - β - D - 木糖呋喃糖基)-2 - 甲基 - 4 - (N - 甲基氨基)吡唑并[1,5 - a]-1,3,5 - 三嗪(24)。最后，本文还描述了核苷21和24转化为吡唑并三嗪C - 核苷酸3',5'-双磷酸酯2和3',5'-环磷酸酯26的过程，这是吡唑并[1,5 - a]-1,3,5 - 三嗪系列中首次报道的核苷酸衍生物。初步生物学测试表明，化合物2强烈抑制ADP诱导的人血小板聚集和形态变化，并且在大鼠注射后30分钟具有显著疗效，突出了其在体外具有强大的P2Y(1)受体拮抗剂活性以及在体内具有延长的作用持续时间。
