Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitor.

Abstract

Regarding the prevention of blood coagulation, most research in the past decade has been focused on thrombin inhibition.1,2) More recently, inhibition of factor Xa (FXa), which is directly responsible for prothrombin activation, has emerged as an attractive target.FXa, which converts prothrombin to thrombin, holds a central position in the coagulation cascade.3) One molecule of FXa generates over 100 molecules of thrombin. Therefore, inhibition of FXa may be more effective than inhibition of thrombin for the prevention of blood coagulation. 4,5) In addition, a recent study by Harker et al. 6) in a balloon model of thrombosis showed that FXa inhibitors might have less bleeding risk than thrombin inhibitors. 7)Most of the nonpeptide FXa inhibitors reported in the literature are dibasic compounds. Nagahara et al. 8,9) have reported synthesis and evaluation of a series of bis(amidino)-derivatives, and through investigation compound DX-9065a (1) [10][11][12][13][14] was found to be a selective FXa inhibitor. Further, a compound YM-60828 (2) [15][16][17][18][19][20] which is closely related to 1 in terms of structure was found to have a more potent inhibitory effect on FXa.A characteristic common to compounds 1 and 2 is having two amidino groups in their molecules, and is considered the presence of more than one such strongly basic group is seen as an unfavorable element for adequate oral absorption and the good pharmacokinetics necessary for oral antithrombotic agents.Based on these considerations, a compound (3) recently reported by ZENECA Co. 21) is of great interest in the following points:i) The pK a value of 4-(piperidino)pyridine is about 12 and is nearly equal to that of amidinonaphthalene.ii) The basicity of two nitrogen atoms in the piperazine ring is reduced by the adjacent acyl and sulfonyl groups.iii) Due to a resonance structure of 4-dialkylaminopyridines, a 4-(piperidino)pyridine moiety in compound 3 is thought to have a plane structure as well as the naphthalene moiety in compounds 1 and 2.To analyze the role of the carbonyl group in compound 3, the following compounds were synthesized and the inhibitory activity of FXa in vitro was evaluated in our laboratory.In compound 4 the carbonyl group is removed and in compounds 5 and 6 the carbonyl group is replaced by a methylene group. In the present paper we wish to report the process of the above investigation. Chemistry Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., 722, Jimba-aza-Uenohara, Gotemba, Shizuoka 412-8524, Japan. Received January 25, 2001; accepted June 11, 2001 Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), which is a key enzyme in coagulation cascade responsible for the generation of thrombin by limited proteolysis of its zymogen, prothrombin. We have investigated 1-arylsulfonyl-3-piperazinone derivatives, containi...

Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors VI. A Series of New Derivatives Containing N,S- and N,SO2-Spiro Acetal Scaffolds

“…The supernatant was decanted and The remaining Et 2 O was removed under reduced pressure to afford the compound 4 (0.89 g, 86% yield) as a colorless amorphous solid. 1 …”

“…The precipitate was collected by filtration to afford deprotected compound (2.7 g, 86% yield) as a pale yellow amorphous solid. 1 …”

“…The solvent was removed under reduced pressure and the resulting residue was purified by silica gel flash column chromatography (eluant: CH 2 Cl 2 -CH 2 Cl 2 / MeOHϭ97/3-95/5) to afford the deprotected compound (176 mg, 95% yield) as a colorless amorphous solid. 1 […”

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

“…The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluents: CH 2 Cl 2 : MeOHϭ19 : 1) to give compound 15 (2.5 g, 68%) as brown powder, mp 84-87°C. 1 -H of piperidine). 5 mmol) were dissolved in ClCH 2 CH 2 Cl (670 ml) and benzyl chloroformate (32.1 ml, 224.7 mmol) was added dropwise to the solution with the reaction temperature maintained at 0°C.…”

“…[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.…”