A general approach toward the synthesis of C-nucleoside pyrazolo[1,5-a]-1,3,5-triazines and their 3',5'-bisphosphate C-nucleotide analogues as the first reported in vivo stable P2Y(1)-receptor antagonists.
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.
Raboisson
Pierre
P
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. pierreraboisson@aol.com
Baurand
Anthony
A
Cazenave
Jean-Pierre
JP
Gachet
Christian
C
Schultz
Dominique
D
Spiess
Bernard
B
Bourguignon
Jean-Jacques
JJ
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D006801:Humans; D009705:Nucleosides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D009711:Nucleotides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D010712:Phosphatidic Acids; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D058472:Receptors, Purinergic P2Y1; D014227:Triazines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology
D009705:Nucleosides; D009711:Nucleotides; C546382:P2RY1 protein, human; C546384:P2ry1 protein, rat; D010712:Phosphatidic Acids; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D014227:Triazines; C021632:bisphosphatidic acid; D000244:Adenosine Diphosphate