Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors III. Effect of Ring Opening of Piperazinone Moiety on Inhibition

Abstract

Recently, direct inhibition of factor Xa (FXa), which links the intrinsic and extrinsic mechanisms in the blood coagulation cascade, [3][4][5][6][7] has emerged as an attractive strategy for the discovery of novel antithrombotic agents. [8][9][10][11] In previous papers, 1,2) we reported the synthesis and biological activity of new compounds in a series of 1-arylsulfonyl-3-piperazinone derivatives, and through this investigation M55113 (1) (IC 50 : 0.06 mM) and M55551 (2) (IC 50 : 0.006 mM) were confirmed to be somewhat favorable as FXa inhibitors.In order to investigate the role played a piperazine moiety in these compounds, we focused on comparison of the activity of compounds which have an ethylenediamine structure in place of the piperazine ring of M55113 and M55551. The present paper concerns the synthesis of such compounds together with their inhibition of FXa. ChemistrySynthesis of ethylenediamine derivative 9 corresponding to M55113 and M55551 was achieved as shown in Chart 1. Compound 6, prepared by the reaction of N-tert-butoxycarbonyl-1,2-diaminoethane hydrochloride (4) with 6-chloro-2-naphthalenesulfonyl chloride (5) under basic conditions, was deprotected with trifluoroacetic acid (TFA) to yield compound 7. The condensation of 7 with 1-(4-pyridinyl)-4-piperidinecarboxaldehyde (8) prepared by Swern oxidation 12) of the corresponding methanol yielded the desired ethylenediamine derivative 9 in the presence of reducing agent. 13) The route of synthesis of compound 13, which contains an amide group on the ethylenediamine moiety of compound 9, is shown in Chart 2. Compound 11, prepared by the reaction Discovery Research Center, Mochida Pharmaceutical Co., Ltd.; 722 Jimba-aza-uenohara, Gotemba, Shizuoka 412-8524, Japan. Received November 5, 2003; accepted February 2, 2004 Compounds containing an ethylenediamine structure in place of the piperazine ring of M55113 (1) and M55551 (2) were synthesized to investigate the effects of a piperazine moiety and evaluated for activity as factor Xa (FXa) inhibitors. Most such compounds, however, exhibited lower activity (1/10-1/100) than that of M55113 and M55551 as FXa inhibitors.

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

“…180 Installing substituents on the piperidine of P4 generally maintained or improved the potency as shown in 135 (fXa IC 50 181 On the other hand, replacing the ketopiperazine scaffold with more the flexible ethylenediamine linker led to significantly lower potency, as illustrated by 143 (fXa IC 50 5 800 nM) and 144 (fXa IC 50 5 3,270 nM). 182 In a separate report, a series of ethylenediamine-based fXa inhibitors was also disclosed. 183 The sulfonamides 145 (fXa IC 50 5 1,090 nM) and 146 (fXa IC 50 410,000 nM) showed little to no fXa inhibitory activity (Fig.…”

Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors V. A Series of New Derivatives Containing a Spiro[imidazo[1,2-a]pyrazine-2(3H),4'-piperidin]-5(1H)-one Scaffold

“…The mixture was stirred at 150-160°C in a sealed tube for 4 h then it was concentrated in vacuo. The resulting residue was purified by amino-silica gel column chromatography (Fuji Silysia Chemical Ltd., Chromatorex NH 3 (4.32 g). The reaction mixture was refluxed for 5 h. Then paraformaldehyde was added to the reaction mixture and it was refluxed for another 10 h. Then 10% HCl-MeOH (5 ml) was added to the mixture and it was refluxed for 1 h. After cooling, the reaction mixture was alkalinized with saturated NaHCO 3 aqueous solution and was extracted with CH 2 Cl 2 .…”

“…The mixture was extracted with CH 2 Cl 2 and the organic layer was washed with brine and dried with anhydrous Na 2 SO 4 . The solvent was removed under reduced pressure and the resulting residue was purified by amino-silica gel column chromatography (Fuji Silysia Chemical Ltd., Chromatorex NH 3 (2.62 g) was added to the reaction mixture. The reaction mixture was refluxed for 10 h. Then paraformaldehyde (0.13 g) was added to the reaction mixture and was refluxed for another 2 h. After cooling, 10% HCl-MeOH (10 ml) was added to the mixture and the reaction mixture was stirred at room temperature for 30 min.…”