Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as a Factor Xa Inhibitor. II. Substituent Effect on Biological Activities.

Abstract

Factor Xa (FXa) is a serine protease which plays a critical role in the coagulation cascade, serving as the point of convergence of intrinsic and extrinsic pathways.3-7) It represents an attractive target for anticoagulant drug development. [8][9][10][11][12][13][14] Most nonpeptide FXa inhibitors reported in the literature are dibasic compounds. Nagahara et al. 15,16) have reported the synthesis and evaluation of a series of bis(amidino)-derivatives, and through investigation, DX-9065a (1) [17][18][19][20][21] was found to be a selective FXa inhibitor. Further, YM-60828 (2), [22][23][24][25][26][27] which is closely related to 1 in terms of structure, was found to have a more potent inhibitory effect on FXa.On the other hand, as described in the preceding paper, 1) we have synthesized M55113 (3) as a potent inhibitor of FXa (IC 50 ϭ0.06 mM) with high selectivity for FXa over trypsin and thrombin. Compared with the structure of compound 3, the features of compound 1 and compound 2 include a functional acid group in the linker part of the molecule. According to the Xray structure of the complex of compound 1 in des- GlaFXa,28) it is clear that the nitrogen atom of Gln-192 forms a weak hydrogen bond with the acid function of compound 1.In order to obtain a compound which has powerful inhibitory activity on FXa, it is necessary to introduce a functional group into the position at which compound 3 and Gln-192 of FXa protein are expected to form a hydrogen bond.In this paper, we wish to report the continuing search for potent compounds that have a substituent at the piperazine and piperidine rings of compound 3. Thus, the structure-activity relationships of compound 3 derivatives were examined. ChemistryA key intermediate 7 was prepared from glycine ethyl ester hydrochloride, as illustrated in Chart 1. The compound 5, obtained by the reaction of glycine ethyl ester hydrochloride (4) with bromoacetaldehyde diethyl acetal in the presence of cesium carbonate (Cs 2 CO 3 ) 29,30) and sodium iodide, was treated with 6-chloro-2-naphthalenesulfonyl chloride under basic conditions, and the resulting sulfonamide 6 was hydrolyzed with aqueous trifluoroacetic acid (TFA) to give the formyl compound 7.Synthetic routes of compounds 12 and 17 are shown in Chart 2. Compound 9 was prepared by protection of the primary amino group with di-tert-butyl dicarbonate (Boc 2 O) and subsequent debenzylation of a secondary amino group with H 2 over Pd/C. Condensation of 9 with 4-chloropyridine 1-oxide under basic conditions gave the 4-piperidinopyridine 1-oxide derivative 10. Hydrogenolysis of 10 over Raney Ni 31) in methanol (MeOH), followed by treatment with HClMeOH, yielded compound 11. The final compound 12 was obtained smoothly by reductive condensation of 11 with the intermediate 7. 32)Reaction conditions in the preparation of compound 17 from compound 13 33) were not much different from the conversion of 8 to 12.Synthesis of 4-substituted piperidine derivatives containing another functional group (compound 18-20) in place of the hydroxyl...

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 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 organic layer was washed with brine and was dried with anhydrous Na 2 […”

“…The reaction mixture was stirred at room temperature for 2 h and then saturated NaHCO 3 aqueous solution was added to the reaction mixture at 0°C. The mixture was extracted with CH 2 Cl 2 and the organic layer was washed with brine and dried with anhydrous Na 2 -1-(phenylmethyl)-spiro[imidazo[1,2-a]pyrazine-2(3H ),4piperidin]-5(1H)-one (13) To a solution of compound 6 (5.26 g) and compound 12 4) (10.3 g) in toluene (200 ml), was added p-toluenesulfonic acid monohydrate (44.2 mg). The reaction mixture was stirred at room temperature for 1 h then was refluxed for 2 h. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel flash column chromatography (eluant: AcOEt-AcOEt/MeOHϭ98/2) to afford compound 13 (7. …”

“…The reaction mixture was stirred at room temperature for 1 h and then saturated NaHCO 3 aqueous solution was added to the reaction mixture at 0°C. The mixture was extracted with CH 2 Cl 2 and the organic layer was washed with brine and dried with anhydrous Na 2 To the solution of compound 25 (50.0 g) in 1,2-dichloroethane (500 ml) was added 1,8-bis(dimethylamino)naphthalene (4.92 g). Then a-chloroethyl chloroformate (31.0 ml) was dropwised into the above solution at 0°C.…”

“…Compound 16 2) was treated with benzyl chloroformate in CH 2 Cl 2 in the presence of Et 3 N to obtaine the N-protected compound 17. Then the diethylacetal portion of compound 17 was removed to obtain the desired aldehyde-ester 18, which was reacted with diamine 6 in toluene to obtain the non-side-chain key intermediate 19.…”

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

“…[21][22][23][24] Direct inhibition to FXa has therefore emerged as an attractive strategy for the discovery of novel antithrombotic agents. [25][26][27][28][29][30][31] In preceding papers, 1,2) we reported the synthesis and evaluation of compounds in a series of 1-arylsulfonyl-3-piperazinone derivatives, of which M55113 (1) In more recent investigations, fixation of the conformation of testing compounds is believed to affect the strength of interaction between such compounds and the target enzyme. Accordingly, in the next stage of investigation our interest was focused on the synthesis of compounds containing a rigid structure in the central part of the compound (2, 3), and on comparison of the inhibitory activities of the compounds thus synthesized for FXa with those of previously reported compounds.…”