|MOL. MASS||1727.17683 g/mol|
Idraparinux selectively blocks coagulation factor Xa.
- Idrabiotaparinux, developed by sanofi-aventis, is the biotinylated pentasaccharide corresponding to the structure depicted below. The pentasaccharide structure of idrabiotaparinux is the same as idraparinux, another antithrombotic agent developed by sanofi-aventis (see structure below). However in idrabiotaparinux, the presence of a biotin hook covalently linked to the first saccharidic unit enables the compound to be neutralized by avidin or streptavidin, as described in the international patent application WO 02/24754 .
- In the EQUINOX trial, which enrolled patients with DVT treated for 6 months with equimolar doses of either idrabiotaparinux or idraparinux, idrabiotaparinux, with the same anti-activated factor X pharmacological activity (hereafter “anti-Xa activity”) as idraparinux, was shown to have a similar efficacy, but, surprisingly, a better safety with less observed bleedings, in particular major bleedings.
- Therefore, the subject-matter of the invention is the use of idrabiotaparinux for the manufacture of a medicament useful for the treatment and secondary prevention of thrombotic pathologies, wherein the use of idrabiotaparinux involves a decrease in the incidence of bleedings during said treatment.
- In other words, the invention relates to the use of idrabiotaparinux as an antithrombotic treatment, wherein said use minimizes the risk of bleedings during the antithrombotic treatment. Indeed, idrabiotaparinux enables to increase the benefit-risk ratio during the antithrombotic treatment.
- Example 3
- Methyl O-4-O-(4-nitrophenyl)-6-O-acetyl-2,3-O-di-phenylmethyl-α-D-glucopyranosyl-(1→4)-O-(methyl 3-O-methyl-2-O-acetyl-α-L-idopyranosyluronate)-(1→4)-O-2,3,6-tri-O-acetyl-α-D-glucopyranoside (100 mg, 0.09 mmol), obtained by the known imidate coupling of the trichloroacetimidate of O-4-O-(4-nitrophenyl)-6-O-acetyl-2,3-O-di-phenylmethyl-α-D-glucopyranoside and methyl O-(methyl 3-O-methyl-2-O-acetyl-α-L-idopyranosyluronate)-(1→4)-O- 2,3,6-tri-O-acetyl-α-D-glucopyranoside, was dissolved in tetrahydrofuran (9 ml) and cooled to -5 °C. At this temperature a 30% aq. solution of hydrogen peroxide (4.5 ml) was added to the reaction mixture, and after 10 min a 1.25 M lithium hydroxide solution (4.7 ml) was added. The mixture was stirred for 1 h at -5 °C, after which time the temperature was raised to 0 °C and the mixture was stirred overnight. The reaction mixture was acidified with 6N hydrogen chloride at 0 °C to pH 1.5, after which the saponified compound was extracted with ethyl acetate. The organic layers were pooled, dried over magnesium sulfate, and evaporated to give 63 mg (84%) of methyl O-4-O-(4-nitrophenyl)-2,3-O-di-phenylmethy1-α-D-glucopyranosyl-(1→4)-O-3-O-methyl-α-L-idopyranuronosyl-(1→4)-O-α-D-glucopyranoside, which was dissolved in methanol (8 ml). 10% Pd on charcoal (63 mg) was added and the mixture hydrogenolyzed overnight. After filtration and evaporation 27 mg (50%) of methyl O-4-O-(4-aminophenyl)-α-D-glucopyranosyl-(1→4)-O-3-O-methyl-α-L-idopyranuronosyl-(1→4)-O-α-D-glucopyranoside were obtained.
13 mg of methyl O-4-O-(4-aminophenyl)-O-α-D-glucopyranosyl-(1→4)-O-3-O-methyl-α-L-idopyranuronosyl-(1→4)-O-α-D-glucopyranoside were dissolved in 2 ml of dry N,N-dimethylformamide, and under an atmosphere of nitrogen 148 mg of triethylamine sulfurtrioxide complex were added. The mixture was stirred overnight at 50 °C, after which an aq. solution of sodium hydrogen carbonate was added under ice cooling. The mixture was stirred for 1 h at room temperature, concentrated to a small volume and desalted on a Sephadex G-10 column with water. The crude product obtained was purified by HPLC using a Mono-Q anion exchange column to give 11 mg (37%) of methyl O-4-O-(4-sulfoaminophenyl)-2,3,6-tri-O-sulfo-α-D-glucopyranosyl-(1→4)-O-3-O-methyl-2-O-sulfo-α-L-idopyranuronosyl-(1→4)-O-2,3,6-tri-O-sulfo-α-D-glucopyranoside nonakis sodium salt. [α]D²⁰ = +52.2° (c=0.67; water). Anomeric protons chemical shifts: 5.5; 5.17; and 5.15 ppm.
- US 20120041189 A1,
- EXAMPLE 1Preparation of the Compound of Formula (I) in Crystalline Form (Scheme 1)1.1: Preparation of the Compound of Formula (I′)The compound of formula (I″) is obtained, for example, according to the teaching of patent EP 0 529 715 B1 or of the articles “Bioorg. Med. Chem.” (1994, Vol. 2, No. 11, pp. 1267-1280), “Bioorg. Med. Chem. Letters” (1992, Vol. 2, No. 9, pp. 905-910) or “Magnetic Resonance in Chemistry” (2001, Vol. 39, pp. 288-293). The compound of formula (I″) (5 g, 3.06 mmol) is dissolved in acetonitrile (10 mL). Deionized water (12.2 mL) and aqueous 30% sodium hydroxide solution (4.1 g) are then added. The mixture is heated to 40° C. and maintained at this temperature for 5 hours. The reaction medium is then cooled to 20° C. and acidified to pH 6.25 with aqueous 1N hydrochloric acid solution (about 17.7 g) before extraction with MTBE of certain impurities, the saponified product remaining in the aqueous phase. The residual acetonitrile, contained in the aqueous phase, is then removed by concentration, followed by diluting with deionized water (125 mL). The saponified product is finally precipitated at pH 1.5 by adding aqueous 1N hydrochloric acid solution (about 17.6 g) at 20° C. The suspension is maintained for 4 hours at 20° C. before filtration. The wet solid is finally dried in a vacuum oven at 30° C. to give 2.93 g (93.6%) of compound of formula (I).NMR (anomeric protons of the saccharide units D, E, F, G, H): 5.79, 5.14, 5.55, 5.92, 4.94 ppm.1.2 Preparation of the Crude Compound of Formula (I)The compound of formula (I′) obtained after the preceding step is dissolved in tetrahydrofuran (18 mL). Palladium-on-charcoal (0.3 g) is added. The reaction medium is hydrogenated at 0.3 bar of hydrogen (relative pressure) for 4 hours. After filtering and evaporating, 2.12 g (99%) of the crude compound of formula (I) are obtained.1.3: Preparation of the Compound of Formula (I) in Crystalline Form Using an Isopropanol/MTBE MixtureThe crude hydrogenated product obtained after the preceding step is dissolved in isopropanol (13 mL) at 65° C., and then crystallized at room temperature. The suspension is then cooled to 40° C., followed by addition of MTBE (13 mL), and is then cooled slowly to 10° C. After maintenance at 10° C. for 2 hours, the crystalline hydrogenated product is filtered off, washed and dried. 1.66 g of the compound of formula (I) in crystalline form are thus obtained, in the form of a cream-white powder. The reaction yield for the production of the compound of formula (I) in crystalline form, from the compound of formula (I′), is 92.5%. When expressed relative to the starting compound (I″), the reaction yield for the production of the compound of formula (I) in crystalline form is 86.6%.NMR (anomeric protons of the saccharide units D, E, F, G, H) of the compound of formula (I) in crystalline form: 5.77, 5.11, 5.51, 5.84, 5.01 ppm.1.4: Preparation of the Compound of Formula (I) in Crystalline Form Using IsopropanolThe crude hydrogenated product obtained after step 1.2 is dissolved in isopropanol (5 volumes) at 75° C. The medium is then cooled slowly until crystals appear, according to the known standard techniques for crystallization. The process is performed, for example, by a first step of cooling at 65° C. for 1 hour, and than a second step of cooling to a final temperature of 25° C. over 4 hours or of 5° C. over 6 hours, and finally maintenance at this final temperature for 30 minutes. The suspension is then filtered and rinsed with isopropanol (2×0.1 V) and compound (I) is isolated in the form of white crystals, which appear under a microscope in the form of needles. The 1H NMR analysis of these crystals is identical to that described after step 1.3 above.EXAMPLE 4Preparation of Idraparinux from the Compound of Formula (I) in Crystalline Form (Scheme 2)The preparation of idraparinux (II) from the compound of formula (I) is summarized in Scheme 2.The compound of formula (I) in crystalline form, as obtained according to Example 1.3, is dissolved in N,N’-dimethylformamide (6.6 mL) and then heated to 30.degree. C. Under an inert atmosphere, 3.8 g of pyridine-sulfur trioxide complex are added slowly, followed by maintenance at 30.degree. C. for 4 hours. The reaction medium is then poured into aqueous 23.8% sodium hydrogen carbonate solution (16.3 g) maintained at a maximum of 25.degree. C., to obtain the compound of formula (II). The reaction medium is kept stirring for hours. The solution of sulfated product is then poured onto an MTBE/isopropanol/ethanol mixture (171 mL/70 mL/70 mL). Precipitation of the product is observed, and, after filtering off, washing and drying the cake, 4.99 g (96.8%) of compound of formula (II) are obtained, and are then purified by anion-exchange chromatography according to the usual techniques.
NMR (anomeric protons of the saccharide units D, E, F, G, H) of the compound of formula (II): 5.48, 4.68, 5.44, 5.08, 5.18 ppm.It thus appears that the process according to the invention makes it possible to obtain idraparinux (compound of formula (II)) in a chemical yield of about 84% (precisely 83.8% according to the protocols described above) starting from the compound of formula (I”), i.e. a gain in yield of about 30% relative to the process described in patent EP 0 529 715 B1.IDRAPARINUX
- Bousser MG, Bouthier J, Büller HR, et al. (January 2008). “Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial”. Lancet 371 (9609): 315–21. doi:10.1016/S0140-6736(08)60168-3.PMID 18294998.
- Buller HR, Cohen AT, Davidson B, et al. (September 2007). “Idraparinux versus standard therapy for venous thromboembolic disease”. N. Engl. J. Med. 357 (11): 1094–104. doi:10.1056/NEJMoa064247. PMID 17855670.
- Bioorg Med Chem1994,2,(11):1267
- Drugs Fut2002,27,(7):639
- EP 0454220, JP 1992225994, US 5378829, US 5382570, US 5529985, US 5773605
- EP 0529715
- Bioorg Med Chem Lett. 2009 Jul 15;19(14):3875-9. doi: 10.1016/j.bmcl.2009.03.155. Epub 2009 Apr 5.
- Chemistry – A European Journal, 2012 , vol. 18, 34 p. 10643 – 10652
- Magnetic Resonance in Chemistry, 2001 , vol. 39, 5 p. 288 – 293
- Tetrahedron, 2013 , vol. 69, 15 p. 3149 – 3158…….. MP 210-15 DEG CENT
- I. Capila, R.J. Linhardt Angew. Chem., Int. Ed., 41 (2002), p. 390
- I. Capila, R.J. Linhardt
- L. Roden D.A. Lane, U. Lindahl (Eds.), Chemical and Biological Properties, Clinical Applications, CRC Press, Boca Raton, FL (1989), p. 1
- L. Roden
- (a) C.A.A. van Boeckel, M. Petitou Angew. Chem., Int. Ed. Engl., 32 (1993), p. 1671
- (b) M. Petitou, C.A.A. van Boeckel Angew. Chem., Int. Ed., 43 (2004), p. 3118
- (a) C.A.A. van Boeckel, M. Petitou
- M. Petitou, B. Casu, U. Lindahl Biochimie, 85 (2003), p. 83Article |
- M. Petitou, B. Casu, U. Lindahl
- (a) M. Petitou, P. Duchaussoy, I. Lederman, J. Choay, J.C. Jacquinet, P. Sinay, G. Torri Carbohydr. Res., 167 (1987), p. 67Article |
- (b) P.-A. Driguez, I. Lederman, J.-M. Strassel, J.-M. Herbert, M. Petitou J. Org. Chem., 64 (1999), p. 9512
- (c) J. Choay, M. Petitou, J.C. Lormeau, P. Sinay, B. Casu, G. GattiBiochem. Biophys. Res. Commun., 116 (1983), p. 492Article |
- (d) P. Sinay, J.C. Jacquinet, M. Petitou, P. Duchaussoy, I. Lederman, J. Choay, G. Torri Carbohydr. Res., 132 (1984), p. C5
- (a) M. Petitou, P. Duchaussoy, I. Lederman, J. Choay, J.C. Jacquinet, P. Sinay, G. Torri
- (a) P. Westerduin, C.A.A. van Boeckel, J.E.M. Basten, M.A. Broekhoven, H. Lucas, A. Rood, H. van der Heijden, R.G.M. van Amsterdam, T.G. van Dinther, D.G. Meuleman, A. Visser, G.M.T. Vogel, J.B.L. Damm, G.T. Overklift
- Bioorg. Med. Chem., 2 (1994), p. 1267Article | PDF (1579 K)
- (b) J.M. Herbert, J.P. Herault, A. Bernat, R.G.M. van Amsterdam, J.C. Lormeau, M. Petitou, C. van Boeckel, P. Hoffmann, D.G. Meuleman Blood, 91 (1998), p. 4197
- (a) P. Prandoni, D. Tormene, M. Perlati, B. Brandolin, L. SpieziaExpert Opin. Investig. Drugs, 17 (2008), p. 773
- (b) A.S. Go, D.E. Singer Lancet, 371 (2008), p. 278Article|
- (a) P. Prandoni, D. Tormene, M. Perlati, B. Brandolin, L. Spiezia
- I.M. Pinilla, M.B. Martinez, J.A. Galbis Carbohydr. Res., 338 (2003), p. 549Article |
- I.M. Pinilla, M.B. Martinez, J.A. Galbis
- S.D. Debenham, E.J. Toone Tetrahedron: Asymmetry, 11 (2000), p. 385Article |
- S.D. Debenham, E.J. Toone
- A. Meijer, U. Ellervik J. Org. Chem., 69 (2004), p. 6249 and references therein
- A. Meijer, U. Ellervik
- P. Duchaussoy, G. Jaurand, P.-A. Driguez, I. Lederman, F. Gourvenec, J.-M. Strassel, P. Sizun, M. Petitou, J.-M. HerbertCarbohydr. Res., 317 (1999), p. 63Article |
- P. Duchaussoy, G. Jaurand, P.-A. Driguez, I. Lederman, F. Gourvenec, J.-M. Strassel, P. Sizun, M. Petitou, J.-M. Herbert
- J. Lee, X.-A. Lu, S.S. Kulkarni, Y. Wen, S.-C. Hung J. Am. Chem. Soc., 126 (2004), p. 476
- J. Lee, X.-A. Lu, S.S. Kulkarni, Y. Wen, S.-C. Hung
- L.A.G.M. van den Broek, D.J. Vermaas, B.M. Heskamp, C.A.A. van Boeckel Recl. Trav. Chim. Pays-Bas., 112 (1993), p. 82
- R.R. Schmidt, J. Michel Angew. Chem., Int. Ed. Engl., 19 (1980), p. 731
- L.A.G.M. van den Broek, D.J. Vermaas, B.M. Heskamp, C.A.A. van Boeckel
- (a) F. Lin, W. Peng, W. Xu, X. Han, B. Yu Carbohydr. Res., 339 (2004), p. 1219
- Article | PDF (270 K)
- (b) P.L. Anelli, C. Biffi, F. Montanari, S. Quici J. Org. Chem., 52 (1987), p. 2559
- (c) P.L. Anelli, S. Banfi, F. Montanari, S. Quici J. Org. Chem., 54 (1989), p. 2970
- (a) F. Lin, W. Peng, W. Xu, X. Han, B. Yu
- (a) P. Bourhis, F. Machetto, P. Duchaussoy, J.-P. Herault, J.-M. Mallet, J.-M. Herbert, M. Petitou, P. Sinay
- For other examples of 4,6-locked idose glycosyl donors, see: Bioorg. Med. Chem. Lett., 7 (1997), p. 2843
- Article | PDF (244 K)
- (d) J. Tatai, P. Fugedi Org. Lett., 9 (2007), p. 4647
|WO2002024754A1||Sep 20, 2001||Mar 28, 2002||Akzo Nobel Nv||Polysaccharides with antithrombotic activity comprising at least a covalent bond with biotin or a biotin derivative|
|WO2006030104A1 *||Sep 7, 2005||Mar 23, 2006||Sanofi Aventis||Biotinylated hexadecasaccharides, preparation and use thereof|
|WO2007042469A2 *||Oct 6, 2006||Apr 19, 2007||Organon Nv||Anticoagulant antithrombotic dual inhibitors comprising a biotin label|
|EP0230023A2 *||Dec 19, 1986||Jul 29, 1987||Marion Merrell Dow Inc.||Pharmaceutical compositions for the enhancement of wound healing|
|EP0300099A1 *||Jul 20, 1987||Jan 25, 1989||Akzo N.V.||New pentasaccharides|
|EP0301618A2 *||Jul 4, 1988||Feb 1, 1989||Akzo N.V.||New pentasaccharides|
|EP0454220A1 *||Apr 16, 1991||Oct 30, 1991||Akzo Nobel N.V.||Carbohydrate derivatives comprising a trisaccharide unit|
|GB1110939A *||Title not available|
|US3017407 *||Aug 18, 1958||Jan 16, 1962||Riker Laboratories Inc||Process for producing polysulfuric acid esters of polysaccharides|