Idrabiotaparinux
抗血栓治療中の出血率を低下させるためのイドラビオタパリナックスの使用
(biotinylated idraparinux, SSR-126517, SSR-126517E)
Idrabiotaparinux has an attached biotin moiety at the non-reducing end unit, which allows its neutralisation with avidin, an egg-derived protein with low antigenicity. This compound is currently investigated in clinical trials for prevention of recurrent VTE in patients with acute pulmonary embolism. The future of idrabiotaparinux depends also on the safety and efficacy of avidin.
Symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism (PE) – treatment and secondary prevention of recurrent venous thromboembolism (VTE).
Idrabiotaparinux (biotinylated idraparinux, SSR-126517, SSR-126517E) is a long-acting selective pentasaccharide indirect factor Xa coagulation inhibitor, administered by once weekly subcutaneous (SC) injection at a dose of 3mg in patients without severe renal insufficiency and, after an initial dose of 3mg, at 1.8mg in those with renal insufficiency.
Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible.
These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux.
Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.
Idrabiotaparinux is intended as a substitute for current long-term oral anticoagulation (e.g. with warfarin) and has no known food or drug interactions, no need for overlapping with other anticoagulants or for laboratory blood monitoring.
Idrabiotaparinux has superseded the development and marketing of the non-biotinylated idraparinux. Idrabiotaparinux is also in phase III clinical trials for the prevention of stroke in patients with atrial fibrillation (AF).
Idrabiotaparinux will be the first once a week anticoagulant for the treatment of patients with VTE. It is intended to provide a predictable response with fixed dosing, no interactions with food, no requirement for overlapping with other therapy and no routine laboratory monitoring.
Developer Sanofi-aventis.
Standard treatment of venous thromboembolism,including deep vein thrombosis and pulmonary
embolism, is started with a rapidly acting parenteral anticoagulant such as heparin or low-molecular-weight
heparin for at least 5 days and is overlapped with a Vitamin K antagonist such as warfarin.
Warfarin is then continued for at least 3 months. Although eff ective, this drug has important limitations. Lifestyle changes are necessary because of interactions with food, alcohol,and other drugs, and the unpredictable anticoagulant eff ect of warfarin necessitates frequent coagulation monitoring and dose adjustments to optimise the balance between effi cacy and safety. Warfarin reduces the risk of recurrent venous thromboembolism by up to 90%, but there is a catch-up eff ect if warfarin is stopped in patients with unprovoked venous thromboembolism. This eff ect means that, by 2 years,the risk of recurrence in patients treated for 3 months is akin to that in patients treated for 12 months.
Consequently, some experts recommend life-long warfarin therapy for patients with unprovoked venousthromboembolism. The complexity of such treatment has prompted the development of new oral and parenteral anticoagulants that are more convenient to administer than is warfarin Idraparinux is a synthetic pentasaccharide that accel erates antithrombin-dependent inhibition of factor Xa and has a half-life of about 80 h. When compared with conventional anticoagulation therapy,
idraparinux given once-weekly by subcutaneous injection was non-inferior for treatment of deep vein thrombosis,but was inferior for treatment of pulmonary embolism. In patients with venous thromboembolism who received a 6 month course of anticoagulant treatment, idraparinux was better than was placebo for prevention of recurrent venous thromboembolism.6However, when compared with warfarin for stroke prevention in patients with atrial fi brillation, there was an excess of major bleeding with idraparinux (including intracranial haemorrhage).7Prompted by these safety concerns, idrabiotaparinux was developed as a replacement for idraparinux.
Idrabiotaparinux (International Non-proprietary Name), or SSR126517 (laboratory code), is developed by sanofi-aventis as the first long-acting anticoagulant administered once-weekly by subcutaneous route, with the unique property to be almost instantly and specifically neutralizable by intravenous administration of avidin. It is developed as an alternative to vitamin K antagonists (VKA). Idrabiotaparinux 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.
Idraparinux
In the EQUINOX trial, which enrolled 757 patients with DVT treated for 6 months with equimolar doses of either idrabiotaparinux or idraparinux, the administration of idrabiotaparinux was demonstrated to provide bioequipotent results to idraparinux in terms of pharmacokinetics and pharmacodynamics, in patients with symptomatic deep venous thrombosis (Journal of Thrombosis and Haemostasis, 2010, Vol. 9, p. 92-99). The results of this bioequipotency trial indicated that idrabiotaparinux could be a suitable treatment for patients with deep venous thrombosis. However, the apparent failure of idraparinux in patients with pulmonary embolism indicated the need for a formal evaluation of idrabiotaparinux in this patient group (N. Eng. J. Med., 2007, Vol. 357, p. 1094-104).
IDRABIOTAPARINUX
It has now been demonstrated, in a phase III study involving 3202 patients with pulmonary embolism, that idrabiotaparinux is a safe and effective drug in the treatment of pulmonary embolism in patients with or without deep venous thrombosis and in the secondary prevention of venous thromboembolic events in said patients. The invention therefore relates to idrabiotaparinux for use in the treatment of pulmonary embolism in patients with or without deep venous thrombosis and the secondary prevention of venous thromboembolic events in said patients, wherein the efficacy and safety of said uses are clinically proven by a phase III clinical trial. According to the instant invention, the terms below have the following meanings:
“idrabiotaparinux” designates the sodium salt of this compound, as defined above, or any other pharmaceutically acceptable salt thereof;
-a “phase III clinical trial” refers to an international, multicenter, randomized, double-blind, double-dummy, parallel group study involving a large patients group (3202 patients in the instant invention), aiming at being the definitive assessment of how effective and safe the drug is, in comparison with current standard treatment; – “deep venous thrombosis” refers to a blood clot in a deep vein of the lower limbs;
new polysaccharides of the invention, are comparable to the oligosaccharides of the prior art antithrombotic activity. But they also have the advantage of being quickly neutralized by a specific antidote in an emergency. This specific antidote avidin (The Merck Index, Twelfth Edition, 1996, MN 920, pages 151-152) or streptavidin, two tetrameric protein with respective masses equal to approximately 66 000 and 60 000 Da, which have a very high affinity for biotin. In general, the invention relates to synthetic polysaccharides antithrombotic activity has at least one covalent bond with biotin or a biotin derivative. As a derivative of biotin include the biotin derivatives listed in the catalog Pierce 1999-2000 pages 62-81, for example 6-biotinamido hexanoate,
you,
or 2-biotinamido éthanethiole
Patent application WO 02/24754 describes synthetic polysaccharides which have a covalent bond with biotin (hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-pentanoic acid) or with a biotin derivative. Such polysaccharides have an antithrombotic activity which means that they can be used as anticoagulants, and also have the advantage of being able to be rapidly neutralized with a specific antidote, in an emergency situation. This specific antidote is avidin (The Merck Index, Twelfth edition, 1996, M.N. 920, pages 151-152) or streptavidin, two tetrameric proteins of respective weights equal to approximately 66 000 and 60 000 Da, which have a very strong affinity for biotin.
Patent application WO 02/24754 describes in particular the following compound, known as idrabiotaparinux:
In the mammalian body, idrabiotaparinux is partly metabolized at the level of the amide bond adjacent to the biotin group, thus producing a pentasaccharide compound bearing an amine chain —NH—CO—(CH2)5—NH2 on the first glucosamine unit, as described in patent application WO 2010/023374.
It may be desirable, in particular in the context of clinical developments of molecules of pharmaceutical interest, to limit or even prevent the metabolization of compounds of this type.
Novel polysaccharides with structures analogous to some of those described in patent application WO 02/24754 have now been identified, which polysaccharides have antithrombotic properties and a neutralization capacity, for example via avidin, which are comparable to those described in that patent application, but which also have improved metabolic stability.
Generally, the invention therefore relates to synthetic polysaccharides with antithrombotic activity having at least one covalent bond with biotin or a biotin derivative, characterized in that said covalent bond is resistant to metabolic cleavage and comprises a linkage X chosen from —O—, —N(R)—, —N(R)—CO— and —N(R′)—CO—N(R″)—, in which R is an alkyl group and R′ and R″, which may be identical or different, are, independently of one another, hydrogen atoms or alkyl groups.
For the purposes of the present invention, and unless otherwise mentioned in the text, the term “alkyl” is intended to mean a linear or branched, saturated aliphatic group comprising from 1 to 6 carbon atoms, and advantageously a methyl group.
Biotin, or hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-pentanoic acid, is the compound having the following formula:
By way of biotin derivatives, mention may be made of those indicated in the Pierce catalog 1999-2000, pages 62 to 81, or in patent application WO 02/24754.
Idrabiotaparinux sodium;
Molecular Formula:C53H88N4O51S8.9NaCAS
Registry Number:405159-59-3
nonasodium methyl (2-deoxy-3 ,4-di-O-methyl-2-{6 – [5 - (2-oxohexahydro-1H-thieno [3,4-d] imidazol-4-yl) pentanamido] hexanamido} -6-O-sulfo-α-D-glucopyranosyl) – (1 → 4) – (2,3-di-O-methyl-β-D-glucopyranosyluronate) – (1 → 4) – (2,3,6 -tri-O-sulfo-α-D-glucopyranoside) – (1 → 4) – (2,3-di-O-methyl-α-L-idopyranosyluronate) – (1 → 4) -2,3,6 – tri-O-sulfo-α-D-glucopyranoside
抗血栓治療中の出血率を低下させるためのイドラビオタパリナックスの使用
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SYNTHESIS
WO2002024754A1
FIGURE 9
Synthesis of the pentasaccharide 39
39
PREPARATION 34
Methyl (6-O-acetyl-2-azido-2-deoxy-3) 4-di-0-methyl-O-glucopyranosyl) – (1 → 4) – (benzyl 2,3-di-O-methyl- β-D-glucopyranosyluronate) – (1 – → 4) – (3,6-di-O-acetyl-2-0-benzyl–D-glucopyranosyl) – (1 -> 4) – (benzyl 2,3 -di-O-methyl-a-idopyranosyl-uronate) – (1 → 4) -2,3,6-tri-0-benzyLa-D-glucopyranoside (39)
Compound 6-0-acetyl-2 was dissolved -azido-2-deoxy-3 ,4-di-0-methyl-, β-D-glucopyranose trichloroacetimidate 38 (265 mg, 0.631 mmol) (obtained by J. Basten, and Chem. Lett Bioorg. Med. al.. (1992), 2 (9), 901)
and
compound 32 (584 mg, 0.420 mmol) (obtained by P. Westerduin and Med. Bioorg Chem. al., 1994, 2, 1267) in a dichloromethane / diethyl ether 1/2 (v / v) (28.5 mL).
After addition of 4 Å molecular sieves powder, the mixture is cooled to -20 ° C. and a 0.1 M solution of trimethylsilyl trifluoromethanesulfonate in dichloromethane (94.6 uL). After 10 minutes, again added the imidate (53.8 mg) and a 0.1 M solution of trimethylsilyl trifluoromethanesulfonate in dichloromethane (19.2 uL). After 10 minutes, the mixture was neutralized by addition of solid sodium hydrogen carbonate. After filtration and concentration, the residue was purified by column chromatography on silica gel (toluene / ethyl acetate 3/1 (v / v)) to give 499 mg of compound 39. [Α] = +66 (c = 1, 07, dichloromethane).
FIGURE 10 -Summary of the pentasaccharide 44 (Method I)
COMPOUND 39
COMPD 40
COMPD 44
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US20120232262
In scheme 1, the starting, intermediate and final compounds are the following:
compound (I): N-succinimidyl N-biotinyl-6-aminocaproate,
compound (II): N-biotinyl-6-aminocaproic acid,
compound (II′): N-biotinyl-6-aminocaproate carboxylate,
compound (III): biotin,
compound (III′): cyanomethyl biotinate.
EXAMPLE 1 Preparation of the Compound (I)
The reactions are monitored by LC with the following conditions: Symmetry C18 150×4.6 mm 5μ column (Waters); eluent A: 0.01 M KH2PO4 buffer adjusted to pH=3; eluent B: acetonitrile; flow rate 1 ml/min; gradient: t=0 min A/B 85/15, t=9 min A/B 65/35, t=10 min A/B 85/15, t=15 min A/B 85/15. This method makes it possible to visualize the biotin (compound (III), tR=4.5 min), the intermediate activated ester (III′) (tR=8.4 min), the N-biotinyl-6-aminocaproic acid (compound (II), tR=5.5 to 5.6 min), the intermediate mixed anhydride (II′) (tR=11.2 min) and the N-succinimidyl N-biotinyl-6-aminocaproate (compound (I), tR=7.9 to 8.2 min).
1.1: Preparation of the Compound (II)
7.5 kg of biotin (III), triethylamine (15 l, 2 V, 3.5 eq), NMP (15 l, 2 V) and, finally, chloroacetonitrile (3.5 kg, 0.47 OU, 1.5 eq) are charged to a reactor. The medium is heated to 60° C. After this temperature has been maintained for 2 h, an LC analysis shows that all the biotin has been converted into compound (III′) (<2%). The medium is cooled to 50° C. and then transferred into another reactor, containing aminocaproic acid (9.05 kg, 1.206 OU, 2.2 eq). Rinsing is carried out with NMP (0.1 V). The medium is heated to 100° C. and maintained at this temperature for 2 h. An LC analysis shows that less than 2% of activated biotin (III′) remains. The medium is cooled to 60° C. Acetonitrile (60 l, 8 V) preheated to 55° C. is run in. The mixture is stirred for 30 minutes at 60° C., and then cooled to 20° C. Stirring is carried out for 1 h. The suspension is filtered, then rinsing is carried out with 3 times acetonitrile (5 V) and then with THF (5 V). Drying is carried out under vacuum at a maximum of 60° C. until there is no change in weight. 12.0 kg of the compound (II) are thus obtained, with a yield of 109% and an organic purity, measured by LC, of 98.6%.
10.0 kg of the compound (II) are recharged to a reactor. Hydrochloric acid (90 l, 9 V of water+10 l, 1 V of 36% HCl) is then added. The suspension is stirred at 20° C. for 30 min. The suspension is filtered and rinsing is carried out 3 times with water (4 V, 40 l), then twice with THF (3.5 V). Drying is carried out under vacuum at a maximum of 45° C. until there is no change in weight. 6.1 kg of the compound (II) are thus obtained, with a yield of 66%.
1.2: Preparation of the Compound (I)
In a reactor, 3 kg of the compound (II) are suspended in DMF (25 l, 8.3 V) and the temperature is brought to −5° C. Triethylamine (1.02 kg, 0.34 OU, 1.2 eq) is then added. After stirring for 15 minutes, ethyl chloroformate (1.1 kg, 0.365 OU, 1.2 eq) is added gently (over the course of at least 1 h). Rinsing is carried out with DMF (0.9 l, 0.3 V). The medium is stirred at −5° C. for at least 2 h. The suspension becomes finer and yellow. An LC analysis shows that all the compound (II) (<3%) has reacted.
N-Hydroxysuccinimide (1.04 kg, 0.386 OU, 1.2 eq) in solution in DMF (3 l, 1 V) is then introduced in 1 step (over the course of at least 20 min). Rinsing is carried out with DMF (1.5 l, 0.5 V). The medium is stirred for 1 h 30 at −5° C. An LC analysis shows that the presence of residual compound (II) is less than 3%. The temperature is brought to 22° C., the suspension is taken up in DCM (12 V, 36 l) and the resulting organic phase is washed with water (15 l, 5 V). The organic phase is drawn off and the aqueous phase is extracted twice with DCM (30 l, 3 V). The organic phases are mixed and are washed with water (1.5 l, 0.5 V). The organic phase is concentrated to 6 V, i.e. 181. Heating is carried out at 40° C. and MTBE (6.25 V, 19 l) is added over the course of a minimum of 1 h. The mixture is maintained at 40° C. for 1 h, and then MTBE (8.75 V, 26 l) is added over the course of a minimum of 2 h. The mixture is maintained at 40° C. for at least 30 minutes, and then cooled to 20° C. over the course of a minimum of 2 h, and maintained at this temperature for 30 minutes. The suspension is filtered by suction and the cake is washed with acetone (5 V, 15 l) and then twice more with acetone (2 V, 6 l). The resulting product is filtered by suction and dried in an oven under vacuum at a maximum of 40° C. until there is no change in weight.
3 kg of the compound (I) are thus obtained in the form of a cream powder, with a yield of 80% and an organic purity, measured by LC, of 96.0%. Except for the compound (II), the presence of which is not problematic for a subsequent coupling reaction with a polysaccharide since it will be inert during this coupling, the purity of the compound (I) is 98%.
The biotinylated polysaccharides, the preparation of which is described above, are for example such as those described in patent applications WO 02/24754 and WO 2006/030104. They may in particular be the biotinylated pentasaccharide known under the International Nonproprietary Name “idrabiotaparinux” and described in patent application WO 02/24754, or the biotinylated hexadecasaccharides described in examples 1 and 2 of patent application WO 2006/030104.
In order to prepare these biotinylated polysaccharides, the compound (I) is coupled, respectively, with the pentasaccharide 44 described in patent application WO 02/24754
pentasaccharide 44: methyl (2-amino-2-deoxy-3,4-di-O-methyl-6-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2,3-di-O-methyl-β-D-glucopyranosyluronic acid)-(1→4)-(2,3,6-tri-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2,3-di-O-methyl-α-L-idopyranosyluronic acid)-(1→4)-2,3,6-tri-O-sulfonato-α-D-glucopyranoside
EXAMPLE 2
Preparation of a biotinylated polysaccharide, idrabiotaparinux
A solution of 1.22 kg of the crude pentasaccharide 44 (containing salts), as described in patent application WO 02/24754, is prepared in 8.51 of water (7 V). 0.5 kg (1.6 eq) of the compound (I), 0.12 kg (2.0 eq) of NaHCO3 and 0.37 kg of NaCl are added thereto. The solution is in the form of a white suspension. 3.7 l of acetone are added thereto and the reaction medium is stirred at approximately 25° C. for at least 22 h. This suspension is then slowly run into a mixture of ethanol (120 l) and MTBE (60 l) cooled beforehand to approximately 4° C., which makes it possible to precipitate the biotinylated pentasaccharide. The resulting suspension is then filtered and rinsed successively with absolute ethanol and acetone. The precipitate is oven-dried under a vacuum until there is no change in weight. 1.60 kg of crude idrabiotaparinux (containing salts) are thus obtained in the form of a cream powder, with an organic purity of 99%, and with a yield of 109% with respect to the pentasaccharide 44 and a chemical yield of 70% over the last 3 stages.
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WO2010023374A1
Compound of Preparation Example 1:
Methyl (2 – [N-(6-aminohexanoyl)]-2-deoxy-3 ,4-di-O-methyl-6-O-sulfonato-UD-glucopyranosyl) – (1 → 4) – (acid 2, 3 -di-O-methyl-β-D-glucopyranosyluronic) – (1-rf) – (2,3,6-tri-O-sulphonate-D-glucopyranosyl) – (1 → 4) – (2,3 – di-O-methyl-alpha-L-idopyranosyluronique) – (1 → 4) -2,3,6-tri-Osulfonato-D-glucopyranoside, sodium salt
Compound 1
1) Preparation of 6 – (benzyloxycarbonylamino) hexanoate succinimidyl
To a solution of 6 – (benzyloxycarbonyl amino) hexanoic acid (1.00 g, 3.77 mmol) in dimethylformamide (20 mL) was added triethylamine (0.63 mL, 4.52 mmol) and stirring the mixture at room temperature under argon for 30 minutes. The solution was cooled to 0 ° C and added dropwise ethyl chloroformate (0.43 mL, 4.52 mmol). After two hours at room temperature, N-hydroxysuccinimide (0.52 g, 4.52 mmol) and stirring the mixture overnight at room temperature. Evaporated to dryness before the residue in water to which is added with ethyl acetate. The phases were separated and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated to dryness before purification on a column of silica gel with pentane mixture of ethyl acetate / (75/25 v / v) as eluent. Once the fractions evaporated to give 1.13 g 6 – (benzyloxycarbonylamino) succinimidyl hexanoate as an oil. TLC: R f = 0.22 on silica gel plate with a mixture of n-heptane/ethyl acetate (30/70 v / v) as eluent.
2) Preparation of compound the
Grafting the amine is carried out on the chain 44 pentasaccharide, or methyl (2 – amino-2-deoxy-3 ,4-di-0-methyl-6-0-sulfonato-α-D-glucopyranosyl) – (1 → 4) – (2,3 – di-0-methyl-β-D-glucopyranosyluronic) – (1 -> 4) – (2,3,6-tri-0-sulphonato-α-D-gluco-pyranosyl) – (1 → 4) – (2,3-di-O-methyl-α-L-idopyranosyl-uronic acid) – (1 → 4) – 2,3,6-tri-O-sulfo-α-nato- D-glucopyranoside, sodium salt, the preparation of which is described in patent application WO 02/24754:
44
To a solution of 6 – (benzyloxycarbonylamino) succinimidyl hexanoate (783 mg, 2.16 mmol) in N, N-dimethylformamide (10 mL) was added the pentasaccharide 44 (505 mg, 0.29 mmol). After stirring for 24 hours in an inert atmosphere and at room temperature, the solvent was evaporated under reduced pressure and the residue (40 mL) before washing the solution with chloroform (2 x 30 mL) dissolved in water. The chloroform phase is washed with water (10 mL) and aqueous phases were combined and evaporated to dryness under reduced pressure. The solid residue was triturated with 2-propanol (10 mL) and the suspension centrifuged for 5 minutes at 2500 rpm. The alcoholic phase is removed and replaced with 2-propanol (10 mL) and centrifugation was repeated. After having extracted the solvent, the crude product was dried under vacuum.
-2-deoxy-3 ,4-di-0-methyl-6-0-sulfonato-α-D [N-(benzyloxycarbonyl-6-aminohexanoyl)] – thus obtained 399 mg of the compound “, or methyl (2 -glucopyranosyl) – (1 → 4) - (the acid 2 3-di-0-methyl-β-D-glucopyranosyluronic) – (1 → 4) – (2,3,6-tri-0-sulfonato-α- D-glucopyranosyl) – (1 – »4) – (2,3-di-0-methyl-α-L-idopyranosyluronique) – (1 – → 4) -2,3,6 – tri-O-sulphonate- α-D-glucopyranoside, wherein Pg is benzyloxycarbonyl:
January 1 compound
Proton NMR at 200 MHz in deuterated water: The structure of the expected product is confirmed that the spectrum is identical to that performed on a product synthesized according to Example 5 of WO 02/24754 without the signals due to the biotin portion atoms but with signals of 7.4 to 7.5 ppm due to the benzyloxy group.
3) Preparation of compound 1
The product ‘s obtained at the end of the previous step (399 mg) is dissolved in deuterated water (10 mL). The solution of palladium on charcoal are treated with 10% (25 mg) and the solution was allowed to stir 20 hours in the presence of hydrogen at atmospheric pressure. Mixed with water (15 mL) was diluted, the catalyst was filtered and the solution was washed with chloroform (2 x 15 mL) before evaporating to dryness under reduced pressure. An aliquot (98 mg to 320 mg) of this product was purified on a column of Sephadex G-25 (2.5 x 50 cm) with water as eluent to give 25 mg of compound 1.
HPLC: Tr = 15.4 min column X-Terra RP-18 15W x 4.6 mm, 5μ particles of Waters in SA. With detection at 211 nm UV lamp.Eluent 1: water containing 0.02 M ammonium acetate and 0.05 M di-n-butylamine, adjusted to pH 7 with acetic acid. 2 Eluant: acetonitrile / water (90/10 v / v) containing 0.05 M di-n-butylamine and 0.08M acetic acid. The proportions of eluents are programmed so that the eluent composition is 10% 2 0 min. , 20% at 25 min. , 50% at 40 min. , 50% at 43 min. and 5% to 50 minutes. Proton NMR at 600 MHz in deuterated water: The structure of the expected product is confirmed that the spectrum is identical to that performed on a product synthesized according to Example 5 of WO 02/24754 without the signals due to the biotin portion atoms.
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IDRABIOTAPARINUX
REFERENCES
JOURNAL OF THROMBOSIS AND HAEMOSTASIS vol. 9, 2010, pages 92 – 99
BULLER HARRY R ET AL: “Idraparinux versus standard therapy for venous thromboembolic disease“, NEW ENGLAND JOURNAL OF MEDICINE, vol. 357, no. 11, September 2007 (2007-09) , pages 1094-1104,
EQUINOX INVESTIGATORS: “Efficacy and safety of once weekly subcutaneous idrabiotaparinux in the treatment of patients with symptomatic deep venous thrombosis.“, JOURNAL OF THROMBOSIS AND HAEMOSTASIS : JTH JAN 2011 LNKD- DOI:10.1111/J.1538-7836.2010.04100.X PUBMED:20946157, vol. 9, no. 1, January 2011 (2011-01), pages 92-99,
N. ENG. J. MED. vol. 357, 2007, pages 1094 – 104
PRANDONI P ET AL: “Idraparinux: review of its clinical efficacy and safety for prevention and treatment of thromboembolic disorders“, EXPERT OPINION ON INVESTIGATIONAL DRUGS, ASHLEY PUBLICATIONS LTD., LONDON, GB, vol. 17, no. 5, 1 May 2008 (2008-05-01), pages 773-777,
SAVI P ET AL: “Reversible biotinylated oligosaccharides: A new approach for a better management of anticoagulant therapy“, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, BLACKWELL PUBLISHING, OXFORD, GB, vol. 6, no. 10, 1 January 2008 (2008-01-01), pages 1697-1706,
Emerging anticoagulants.Kennedy B, Gargoum FS, Kennedy L, Khan F, Curran DR, O’Connor TM.Curr Med Chem. 2012;19(20):3388-416. Review.
1
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ANONYMOUS: “Bioequipotency Study of SSR126517E and Idraparinux in Patients With Deep Venous Thrombosis of the Lower Limbs (EQUINOX)” INTERNET CITATION, [Online] 10 April 2008 (2008-04-10), pages 1-4, XP002503606 Retrieved from the Internet: URL:http://www.clinicaltrials.gov/ct2/show/NCT00311090?term=equinox&rank=1> [retrieved on 2008-11-11]
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BULLER HARRY ROGER ET AL: “Idrabiotaparinux, a Biotinylated Long-Acting Anticoagulant, in the Treatment of Deep Venous Thrombosis (EQUINOX Study): Safety, Efficacy, and Reversibility by Avidin” BLOOD, vol. 112, no. 11, November 2008 (2008-11), page 18, XP009118800 & 50TH ANNUAL MEETING OF THE AMERICAN- SOCIETY-OF-HEMATOLOGY; SAN FRANCISCO, CA, USA; DECEMBER 06 -09, 2008 ISSN: 0006-4971
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HIRSH J ET AL: “Beyond unfractionated heparin and warfarin: Current and future advances” CIRCULATION, LIPPINCOTT WILLIAMS & WILKINS, US, vol. 116, no. 5, 1 July 2007 (2007-07-01), pages 552-560, XP002503605 ISSN: 0009-7322
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PRANDONI P ET AL: “Idraparinux: review of its clinical efficacy and safety for prevention and treatment of thromboembolic disorders” EXPERT OPINION ON INVESTIGATIONAL DRUGS, ASHLEY PUBLICATIONS LTD., LONDON, GB, vol. 17, no. 5, 1 May 2008 (2008-05-01), pages 773-777, XP008098574 ISSN: 1354-3784
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*
SAVI P ET AL: “Reversible biotinylated oligosaccharides: A new approach for a better management of anticoagulant therapy” JOURNAL OF THROMBOSIS AND HAEMOSTASIS, BLACKWELL PUBLISHING, OXFORD, GB, vol. 6, no. 10, 19 July 2008 (2008-07-19), pages 1697-1706, XP002503607 ISSN: 1538-7933
PATENTS
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Polysaccharides with antithrombotic activity comprising at least a covalent bond with biotin or a biotin derivative
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Heparins including at least one covalent bond with biotin or a biotin derivative, method for preparing same and use thereof
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Method for preparing n-succinimidyl n-biotinyl-6-aminocaproate
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Use of idrabiotaparinux for decreasing the incidence of bleedings during an antithrombotic treatment
EP2233143A1 *
Mar 24, 2009
Sep 29, 2010
Sanofi-Aventis
Use of idrabiotaparinux for decreasing the incidence of bleedings during an antithrombotic treatment
Filed under: Phase3 drugs, Uncategorized Tagged: Idrabiotaparinux