| Abstract
| - In our effort to identify potent purinergic P2Y1 receptor antagonists as potent platelet aggregationinhibitors with enhanced metabolic stability, we developed an efficient route for the large-scalepreparation of 2‘-deoxy-C-nucleosides of pyrazolo[1,5-a]-1,3,5-triazine. The key strategic elementsof this novel synthetic approach involved the following: (i) the use of a novel activating group, theN-methyl-N-phenylamino group, which was easily generated in high yield by treatment of thepyrazolo[1,5-a]-1,3,5-triazin-4-one (5) with phosphorus oxychloride and dimethylaniline under highpressure, (ii) a regio- and stereospecific palladium-mediated coupling reaction of the readily availableunprotected 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 thesubsequent displacement of the N-methyl-N-phenylamino group upon treatment with methylamine.The β configuration at the anomeric C-1‘ position of the glycal moieties was perfectly retainedthroughout this conversion. This procedure afforded 8-(2‘-deoxy-β-d-ribofuranosyl)-2-methyl-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (21) and 8-(2‘-deoxy-β-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-nucleotides3‘,5‘-bisphosphate 2 and 3‘,5‘-cyclophosphate 26 is also described herein and represents the firstreported nucleotide derivatives within the pyrazolo[1,5-a]-1,3,5-triazine series. Preliminary biologicaltesting has shown that compound 2 strongly inhibits ADP-induced human platelet aggregationand shape change and possesses significant efficacies 30 min after injection in rat, highlighting astrong P2Y1-receptor antagonist activity in vitro combined with a prolonged duration of action invivo.
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