476468-38-9Relevant academic research and scientific papers
Cyclic nucleotide phosphodiesterase type 4 inhibitors: Evaluation of pyrazolo[1,5-a]-1,3,5-triazine ring system as an adenine bioisostere
Raboisson, Pierre,Schultz, Dominique,Muller, Christian,Reimund, Jean-Marie,Pinna, Guillaume,Mathieu, Romain,Bernard, Philippe,Do, Quoc-Tuan,DesJarlais, Renee L.,Justiano, Helene,Lugnier, Claire,Bourguignon, Jean-Jacques
, p. 816 - 829 (2008/09/20)
A series of 8-substituted pyrazolo[1,5-a]-1,3,5-triazines were considered as a bioisosteric replacement for the 9-substituted adenine derivatives resulting in the discovery of 8-(2-methoxybenzyl)-4-(N-methylamino)-2-n-propylpyrazolo[1,5-a]-1,3,5-triazine (14d) and 2-trifluoromethyl-8-(2-methoxybenzyl)-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (14e) as a new structural class of potent phosphodiesterase type 4 inhibitors (IC50 = 13 nM and 11 nM, respectively) with high isoenzyme selectivity. An original tandem of reactions involving a palladium-mediated cross-coupling reaction (PMCCR) of the readily available 8-iodo-2-methyl-4-(N-methyl-N-phenylamino)pyrazolo[1,5-a]-1,3,5-triazine (11a) and arylboronic acids or alkynes followed by the displacement of the N-methyl-N-phenylamino group constitute the key steps in a novel synthetic approach developed herein. The treatment of 11a-c with n-BuLi and selected aldehydes represents an interesting alternative to the PMCCR for the synthesis of benzylic derivatives 14a-i. Preliminary biological testing has shown that compounds 14d and 14e strongly inhibit LPS-induced TNFα release from human mononuclear cells from healthy subjects. These two compounds were selected for further biological evaluation.
Novel substituted pyrazolo[1,5 a]-1,3,5-triazine derivatives and their analogues, pharmaceutical compositions containing same, use thereof as medicine and methods for preparing same
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Page/Page column 17, (2008/06/13)
The invention concerns novel substituted pyrazolo[1,5 A]-1,3,5-triazine derivatives and some of their structural analogues, and their therapeutic uses, more particularly for preventing and treating pathologies involving central and/or peripheral neuronal degeneration. The invention also concerns methods for preparing same and novel synthesis intermediates. The compounds of the invention correspond more particularly to general formulae (Ia) and (Ib).
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.
Raboisson, Pierre,Baurand, Anthony,Cazenave, Jean-Pierre,Gachet, Christian,Schultz, Dominique,Spiess, Bernard,Bourguignon, Jean-Jacques
, p. 8063 - 8071 (2007/10/03)
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.
Efficient synthesis of 8-substituted pyrazolo[1,5-a]-1,3,5-triazines by regioselective acylation
Raboisson, Pierre,Schultz, Dominique,Lugnier, Claire,Bourguignon, Jean-Jacques
, p. 9501 - 9503 (2007/10/03)
An efficient two-step synthesis of 8-acylated pyrazolo[1,5-a]-1,3,5-triazines has been accomplished. The key strategic elements of this novel synthetic approach involve the use of the N-methyl-N-phenylamino activating group, which was easily obtained in high yield by treatment of the pyrazolotriazin-4-one with phosphorus oxychloride and dimethylaniline through high pressure reaction coupled with a regioselective acylation at position 8 followed by the subsequent displacement of the N-methyl-N-phenylamino group upon treatment with various amines.
