Discovery of R-142086 as a Factor Xa (FXa) Inhibitor: Syntheses and Structure-Activity Relationships of Cinnamyl Derivatives

Abstract

Warfarin is widely used as a sole oral anticoagulant for the treatment and prevention of thromboembolic diseases. However, many reports have mentioned the defects of warfarin. It requires periodic monitoring because of its narrow therapeutic window and, in addition, warfarin interacts with many different foods and drugs. [4][5][6] Therefore, new anticoagulants based on novel mechanisms need to be developed. Recently, blood coagulation factor Xa (FXa) has attracted considerable attention as a novel anticoagulation target.FXa acts at the convergence point of the intrinsic pathway and the extrinsic pathway in a blood coagulation cascade. 7)FXa converts prothrombin into thrombin and leads to fibrin clot formation. It is thought that the inhibition of FXa effectively diminishes the thrombin generation and, as a result, leads to the inhibition of clot formation. Indeed, many FXa inhibitors have been synthesized and their anticoagulant activities reported. 8,9) In these reports, FXa inhibitors exhibit less bleeding risk than warfarin and thrombin inhibitors. We have also conducted research to discover orally-active novel FXa inhibitors. [10][11][12][13] Previously, we found that the series of cinnamyl derivatives represented by 1 and 2 produced potent in vitro FXa inhibitory activities and high selectivity. Moreover, these compounds also exhibited potent ex vivo anticoagulant activities in hamsters after oral administration.However, regarding the chemical structure, these compounds are highly hydrophilic with two amidino groups. It seems that enhancement of these compounds' lipophilicity may improve the plasma concentration after oral administration and the resulting oral anticoagulant activity. Similarly, conversion of these compounds into their prodrug forms may be promising for high oral activity. Herein, we describe our synthetic efforts and further evaluations to discover R-142086 with ex vivo anticoagulant activity in dogs.Chemistry Cinnamyl derivatives with various imidoyl group on the piperidine ring were synthesized as shown in Chart 1. Piperidine 3 13) was reacted with iminoethers 14,15) under basic conditions, followed by acid hydrolysis to give corresponding bisamidine derivatives 4a-g. Other cinnamyl derivatives with a five-membered cyclic imidoyl group (6a, 6b) were synthesized by the same methods as compound 4d. Monoamidine derivatives were synthesized as shown in Chart 2. A t-butoxycarbonyl (Boc) group of compound 7 13) was converted to a methyl group (8a) by treatment with formaldehyde solution and formic acid. Compound 7 was also deprotected under an acidic condition to give piperidine 9. This compound was then subjected to a usual condition to give acetamide 8b. Piperidine 9 was converted to corresponding N-alkyl or N-aryl compounds (8c-k) by reductive amination with aldehydes or ketones (method A), or treatment with alkyl-or arylbromide under a basic condition (method B), or Pd-catalyzed amination with arylbromide and phosphine 10 (method C).16) Reduction of the nitro group of compounds 8a-k afforde...

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

“…and negative results in the Ames assay. 134 Group 2. Isoxazoline, isoxazole, and pyrazole scaffolds Using 22 as a template along with structure-based design, a series of bisamidine butanoates was prepared, as exemplified by 54 (fXa K i 5 34 nM) (Fig.…”

Photoinduced C–H monofluoroalkenylation with gem-difluoroalkenes through hydrogen atom transfer under batch and flow conditions

“…Organic compounds that contain monofluoroalkene motifs are ubiquitous in bioactive molecules (Scheme 1). 1 Furthermore, rapidly accessing diverse multisubstituted monofluoroalkenes is highly desirable in drug discovery. 2 As readily available synthons, gem -difluoroalkenes have proved to be ideal substrates to obtain diverse multisubstituted monofluoroalkenes.…”

Palladium-Catalyzed Stereoconvergent Formylation of (E/Z)-β-Bromo-β-fluorostyrenes: Straightforward Access to (Z)-α-Fluorocinnamic Aldehydes and (Z)-β-Fluorocinnamic Alcohols

“…The 2-fluoropropenol motif is also the key structure of several biologically active compounds and is used as a building block . Introduction of a fluorine atom in the cinnamic alcohol part of the Factor Xa inhibitor leads to the most active compound, which furthermore responds negatively to the Ames test, unlike the nonfluorinated analogue . ( Z )-α-Fluorocinnamic aldehydes and ( Z )-β-fluorocinnamic alcohols themselves are found in several patents either as intermediate or final products .…”