Design, Synthesis and Discovery of 1-(2-(6-Chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides as Highly Potent Factor Xa Inhibitors

Abstract

Serine protease factor Xa (fXa), positioned at the juncture of the intrinsic and the extrinsic pathways, plays a pivotal role in the blood coagulation cascade.1) Selective inhibition of fXa without affecting the existing thrombin levels may cause less impairment of primary hemostasis and thus should be a safer anticoagulant therapy than direct inhibition of thrombin. Clinical findings have confirmed the potential of fXa inhibition for producing excellent antithrombotic efficacy with minimal bleeding risk when compared to direct thrombin inhibitors. [2][3][4][5][6] Our previous communications have reported a series of 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as potent and selective fXa inhibitors with good oral bioavailability and half-life. [7][8][9] This class of fXa inhibitors, as represented by compounds 1-4, possesses a substituent either at the 6-position (chloro) or at the 3-position (methylsulfonyl, aminosulfonyl, aminocarbonyl, fluoro or cyano) on the P1 naphthalene moiety. The individual fXa affinity enhancing effect of the 6-chloro and the 3-methylsulfonyl substituents prompted us to wonder if the two substituents could be synergetic to each other for further fXa binding potency improvement. To answer this question, we designed compounds 5 and 6 that bear a tri-b-substituted 6-chloro-3-methylsulfonyl naphthalene moiety as the fXa S1 binding element.Ethyl 1-(6-chloro-3-(methylsulfonyl)naphthalen-2-yl)-3-methyl-1H-pyrazole-5-carboxylate 7 was the key building block needed for the synthesis of compounds 5 and 6, and the tri-b-substituted naphthalene 8 would be the precursor for its preparation, as analyzed in Chart 1. The amino group would lead to the pyrazole via condensation of the corresponding hydrazine, and the iodo group would serve as a handle to install the methylsulfonyl substituent through a copper-mediated C-S cross coupling with sodium methanesulfinate.10) 6-Chloro-3-iodo-2-naphthylamine 8 could be synthesized from methyl 3-amino-2-naphthoate 9 via iodode-diazoniation followed by Curtius rearrangement. Based upon Levy's precedent work, 11) compounds 9-11 could be prepared from the Diels-Alder product 12 of 4-chloro-oquinodimethane (13) and maleic anhydride. To produce the o-quinodimethane in situ, Levy forced the cheletropic elimination of sulfur dioxide from 1,3-dihydrobenzo[c]thiophene-S,S-dioxide using strong heat at 230°C. In direct contrast, the 1,4-dihydro-2,3-benzoxathiin-3-oxide (also known as sulfinate or sultine) undergoes the sulfur dioxide cheletropic elimination smoothly around 80°C.12-17) Hoey and Dittmer 13) have developed a convenient one-step synthesis of 1,4-dihydro-2,3-benzoxathiin-3-oxide in high yield from a,aЈ-dihalo-o-xylene and sodium hydroxymethanesulfinate (rongalite). Townsend and co-workers 12) have elegantly applied this methodology in the preparation of tetra-b-substituted naphthalenes. We thus chose sulfinate 15 over sulfone 14 as the precursor for 4-chloro-o-quinodimethane 13.The synthesis of ethyl 1-(6-chloro-3-(methylsulfonyl)-naphthalen-2-yl)-3-methyl-1H-p...