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

Abstract

Factor Xa (FXa), a trypsin-like serine protease, occupies the central position that links the intrinsic and extrinsic mechanisms in the blood coagulation cascade. FXa is known to activate prothrombin to thrombin. Thrombin has several procoagulant functions, including the activation of platelets, feedback activation of other coagulation factors, and conversion of fibrinogen to insoluble fibrin clots.6-10) Comparison of hirudin 11-15) (a thrombin inhibitor) and tick anticoagulant peptide [16][17][18][19][20][21][22] (a FXa inhibitor) suggests that inhibition of FXa may result in less risk of bleeding, leading to a more favorable safety/efficacy ratio. [23][24][25][26] Direct inhibition of FXa has therefore emerged as an attractive strategy for the discovery of novel antithrombotic agents. [27][28][29][30][31][32][33] In a previous paper, 4) we reported the synthesis and evaluation of compounds in a series of spiro [5H-oxazolo[3,2-a] (Table 1).These differences will affect the overall conformation of the compound, and differences in conformation between N,N-spiro acetal and N,O-spiro acetal might affect FXa inhibitory activity. In addition, differences in basicity between N,N-spiro acetal and N,O-spiro acetal might work on FXa inhibitory activity. ChemistryFirst, the keto-ester 5, an acyclic precursor, was prepared as shown in Chart 1.Ethyl glycinate 1 was converted by ring opening glycidyl methyl ether 2 to the corresponding amino-alcohol. The amino-alcohol was treated with benzyl chloroformate in THF-H 2 O in the presence of sodium carbonate with an Nprotected amino-alcohol 3 obtained in good yield. In the next step, the amino-alcohol 3 was oxidized to the keto-ester 5 by the 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl benzoate 4-NaClO oxidation method. was allowed to react with keto-ester 5 in toluene, the key intermediate 7 containing a N,N-spiro acetal structure on the Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd.; 722 Jimba-aza-Uenohara, Gotemba, Shizuoka 412-8524, Japan. Received June 10, 2006; accepted September 2, 2006; published online September 5, 2006 We have already reported unique compounds containing a N,O-spiro acetal structure as an orally active factor Xa (FXa) inhibitor. This time, we described a N,N-spiro acetal structure as an analogue of the N,O-spiro acetal structure for an orally active FXa inhibitor. The synthesis of these analogues could be achieved in a similar fashion to the N,O-spiro acetal synthesis. Consequently, FXa inhibitory activity was increased and more active compounds could be found (M58163: IC 50 ‫16.0؍‬ nM, M58169: IC 50 ‫85.0؍‬ nM). Additionally, the absolute configuration could be determined by X-ray crystallography analysis (M58169: (R)-config.).

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

“…These activities were almost equivalent compared with N,N-acetal compounds 11 and 12, 5) and were superior to N,O-acetal compound 13.…”

“…These compounds also had approximately equivalent activity compared to corresponding N,N-acetal compounds 14 and 15, 5) and had slightly higher activity than corresponding N,O-acetal compound 16. 4) In addition, compound 7c and 10c, in which a substituent was changed to a proton from the methoxymethyl or the hydroxymethyl moiety as a side chain, had high activities (IC 50 ; 7c: 1.5 nM, 10c: 3.0 nM).…”

“…4) In addition, compound 7c and 10c, in which a substituent was changed to a proton from the methoxymethyl or the hydroxymethyl moiety as a side chain, had high activities (IC 50 ; 7c: 1.5 nM, 10c: 3.0 nM). Although corresponding N,O-or N,N-acetal compounds 17-19 tended to reduce their activity, 5) compounds 7c and 10c could maintain high activity. Based on these results, we have thought that the features of N,S-and N,SO 2 -spiro acetal scaffolds were as below.…”

“…4,5) The other key tricyclic compounds 6b and 6c were obtained with the amino-thiol 4 and the other keto-ester 5b 4) or the aldehyde-ester 5c 2) instead of the keto-ester 5a. To synthesize compound 6b, which has the acetoxymethyl moiety as a side chain, reaction for amide formation was carried out by adding p-toluene sulfonic acid, and toluene following the first N,S-sipro acetal formation step.…”

“…In previous papers, 4,5) we reported that spiro[5H-oxazolo [3,2- With change of the central atom from oxygen to nitrogen, the inhibitory activity of FXa tended to increase. This improvement of activity might be based on the slight difference in the conformation between the N,O-and the N,N-spiro acetal structures.…”