Abstract
A significant improvement on the synthesis of the PAR-1 antagonist RWJ-58259 is described, which involves a base-related two-fold yield increase in the indazole N-alkylation, and an easier purification and a nine-fold yield increase in the urea formation, by using triphosgene/propylene oxide as urea coupling traceless reagents.
Highlights
In addition to the key role of thrombin in blood coagulation processes, this serine protease mediates multiple cellular responses, such as platelet aggregation and cell proliferation in fibroblasts, neurons, and endothelial, smooth muscle, and tumor cells.[1]
N-Alkylation of the indazole derivative 1 The alkylation of indazole 1 to the 1-(2,6-dichlorobenzyl) derivative 2 has been described in 33% yield using one equiv of 2,6-dichlorobenzyl bromide and KOH as base.2a,6 When we first attempted to reproduce this alkylation, compound 2 was obtained in a similar low yield (34%) and the TLC and HPLC (Novapak C18) analyses of the crude reaction mixture showed the presence of a peak (30%) with the same Rf and tR of the starting material 1
Trying to increase the yield of 2, we repeated the reaction using a 30% excess of 2,6-dichlorobenzyl bromide, but, contrary to what we expected, the yield of 2 decreased and we could only isolate the bromide of the product of dialkylation 3, which coeluted with the starting indazole 1 on TLC and on the HPLC Novapak C18 column
Summary
In addition to the key role of thrombin in blood coagulation processes, this serine protease mediates multiple cellular responses, such as platelet aggregation and cell proliferation in fibroblasts, neurons, and endothelial, smooth muscle, and tumor cells.[1]. PAR-1 is the principal thrombin-activated receptor involved in platelet aggregation and in endothelial and tumor cell proliferation. It has been proposed that a PAR-1 antagonist could have potential for treating thrombosis, atherosclerosis, inflammation and cancer metastasis, without altering thrombin’s role in hemostasis.[1] The first potent and in vivo effective PAR-1 antagonists were SFLLRN-based peptidomimetics, which provided the first in vivo proof-of-concept of the therapeutic potential of PAR-1 antagonists.1a,2 Among these, the indazole-derived urea RWJ-58259 (Scheme 1, 7) reached advanced preclinical studies in different animal models[3,4] and, in spite of its low oral bioavailability,[3] it is considered an standard reference in pharmacological studies on PAR-1 receptors.[4,5]. We undertook and describe the optimization of these two steps
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