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

• Published in: Journal of organic chemistry Vol. 67; no. 23; pp. 8063 - 8071
• Main Authors: Raboisson, P, Baurand, A, Cazenave, JP, Gachet, C, Schultz, D, Spiess, B, Bourguignon, JJ
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 15.11.2002
• Subjects: Adenosine Diphosphate - pharmacology; Animals; Blood Platelets - drug effects; Chemistry; Chemistry, Organic; Humans; Nucleosides - administration & dosage; Nucleosides - chemical synthesis; Nucleosides - pharmacology; Nucleotides - administration & dosage; Nucleotides - chemical synthesis; Nucleotides - pharmacology; Phosphatidic Acids; Physical Sciences; Platelet Activation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - pharmacology; Purinergic P2 Receptor Antagonists; Rats; Receptors, Purinergic P2Y1; Science & Technology; Triazines - administration & dosage; Triazines - chemical synthesis; Triazines - pharmacology; REAGENT; INHIBITION; PLATELET-AGGREGATION; COUPLING REACTIONS; FURANOID GLYCALS; ADENOSINE; MICE; THROMBOEMBOLISM; P2Y RECEPTOR; 2'-DEOXYPSEUDOURIDINE
• ISSN: 0022-3263
• 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.