114870-03-0

Basic information

• Product Name: Fondaparinux sodium
• Synonyms: decasodium (2R,3S,4S,5R,6R)-3-[(2R,3R,4R,6R)-5-[(2R,3R,4S,5S,6S)-6-carboxylato-5-[(2R,3R,4R,5S,6R)-4,5-dihydroxy-3-(sulfonatoamino)-6-(sulfonatooxymethyl)oxan-2-yl]oxy-3,4-dihydroxy-oxan-2-yl]oxy-3-(sulfonatoamino)-4-sulfonatooxy-6-(sulfonatooxymethyl)oxan-2-yl]oxy-4-hydroxy-6-[(2R,3S,4R,5R,6S)-4-hydroxy-6-methoxy-5-(sulfonatoamino)-2-(sulfonatooxymethyl)oxan-3-yl]oxy-5-sulfonatooxy-oxane-2-carboxylate; decasodium (2R,3S,4S,5R,6R)-3-({(2R,3R,4R,5R,6R)-5-{[(2R,3R,4R,5S,6S)-6-carboxylato-5-({(2R,3R,4R,5S,6R)-4,5-dihydroxy-3-(sulfonatoamino)-6-[(sulfonatooxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-3,4-dihydroxytetrahydro-2H-pyran-2-yl]oxy}-3-(sulfonatoamino)-4-(sulfonatooxy)-6-[(sulfonatooxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-4-hydroxy-6-({(2R,3S,4R,5R,6S)-4-hydroxy-6-methoxy-5-(sulfonatoamino)-2-[(sulfonatooxy)methyl]tetrahydro-2H-pyran-3-yl}oxy)-5-(sulfonatooxy)tetrahydro-2H-pyran-2-carboxylate (non-preferred name)
• CAS NO: 114870-03-0
• Molecular Formula: C₃₁H₄₃N₃O₄₉S₈*10Na
• Molecular Weight: 1728.0815
• Mol File: 114870-03-0.mol
• Article Data: 1

Chemical Properties

• Storage Temp.: 2-8°C
• Solubility: Water
• CAS DataBase Reference: Fondaparinux sodium(CAS DataBase Reference)
• NIST Chemistry Reference: Fondaparinux sodium(114870-03-0)
• EPA Substance Registry System: Fondaparinux sodium(114870-03-0)

Safety Data

• Hazardous Substances Data: 114870-03-0(Hazardous Substances Data)

Usage

Description

Fondaparinux sodium was first introduced in the US for prophylaxis of deep vein thrombosis which may lead to pulmonary embolism following major orthopaedic surgery. Fondaparinux is the first of a new class of antithrombic agents distinct from low molecular weight heparin (LMWH) and heparin. This entirely synthetic molecule is a copy of the heparin pentasaccharide sequence, the shortest fragment able to catalyze antithrombin lllmediated inhibition of factor Xa thereby inhibiting thrombin generation without antithrombin action. Fondaparinux does not display significant effects on coagulation tests (such as activated partial thromboplastin time and prothrombin time), does not bind to platelet factor 4 or promote heparin-induced thrombocytopenia. In phase III studies, fondaparinux significantly reduced the incidence of thromboembolism following orthopedic surgery, with an overall risk reduction of 50% in comparison to the LMWH, enoxaparin. Following subcutaneous administration, fondaparinux has a nearly complete bioavailability, a rapid onset of action, a prolonged half-life (17.2 h) enabling once daily dosing and is not metabolized preceeding renal excretion. The drug appears to be generally safe, with haemoragic complications either comparable to or higher than those for LMWH.

Chemical Properties

White Powder (after lyophilisation)

Originator

Sanofi-Synthelabo (France)

Uses

Different sources of media describe the Uses of 114870-03-0 differently. You can refer to the following data:
1. Fondaparinux sodium has been used to test its neutralizing effect towards enterovirus D68-947 infection. It may be used in ultraviolet photodissociation (UVPD) measurements.
2. Synthetic pentasaccharide corresponding to the anti-thrombin binding site of heparin. Anti-thrombotic.

Definition

ChEBI: An organic sodium salt, being the decasodium salt of fondaparinux.

Brand name

Arixtra (GlaxoSmithKline).

Biochem/physiol Actions

Fondaparinux sodium is an antithrombotic anticoagulant, a Factor Xa inhibitor. Fondaparinux sodium is chemically related to low molecular weight heparins. Its pentasaccharide structure corresponds to the antithrombin III (ATIII) binding site of heparin. Fondaparinux sodium binding at this site potentiates the natural inhibitory effect of ATIII against factor Xa by a factor of approximately 300, which results in inhibition of thrombin generation.

Clinical Use

Prophylaxis of deep vein thrombosis Treatment of deep vein thrombosis, pulmonary embolism, unstable angina and after a myocardial infarction

Synthesis

Starting from Dglucose, D-cellobiose, and D-glucosamine, the production process for the synthesis of the pentasaccharide involves about 55 steps. The synthesis was accomplished by preparing a fully-protected pentasaccharide, and then converting it into the final product. The choice of protecting groups was dictated by two factors: the need to introduce sulfate substituents (O- as well as N-linked), carboxylate groups and hydroxyl groups, in the proper positions on the target molecule, and the constraints of current methods for oligosaccharide synthesis, particularly the use of 2-azido glucose derivatives to achieve stereoselective introduction of α-D-linked glucosamine units. All the monosaccharide synthons were obtained from glucose or from glucosamine, and the synthesis is outlined in the scheme. Trisaccharide 108 and disaccharide 109 are the two key building blocks in the synthesis. Coupling 108 and 109 was carried out at -20°C in DCE. Fully protected pentasaccharide 110 was then converted into the target compound 10 using traditional methods: saponification, O-sulfation, cleavage of benzyl ethers with simultaneous reduction of azido into amino functions and finally N-sulfation. Preparation of trisaccharide building block 108 started from 1,6-anhydrocellobiose (111). Selective protection at 4’,6’ position was achieved through benzylidenation to provide crude 112 which was converted into epoxide 113 by treatment with sodium methoxide and benzylation. Compound 113 was isolated after filtration on silica gel and crystallization (m.p. 184-5°C). Trans-diaxial opening of the epoxide yielded the 2-azido derivative (66%) which was acetylated to give 114 (99%). The benzylidene was cleaved (92%) and the diol was then converted into 115 by successive tritylation, levulinoylation, detritylation, oxidation, methylation and hydrazinolysis (60% over the 6 steps). Imidate 116 was prepared in the usual way from its hydroxyl precursor and coupled with 115 to give O-linked trisaccharide 117 in 78% yield. Compound 117 was acetolysed (91%), the anomeric acetate was cleaved by benzylamine in ether (100%) and imidate 108 was obtained by reaction with potassium carbonate and trichloroacetonitrile at room temperature (α, β- mixture with α as the predominant isomer, 76%). The preparation of the other building block 109 is described as following. Selective 6-acetylation of 118 by N - acetylimidazole in DCE gave 119 in 60% yield. Treatment of 119 with 120 using DCE/pyridinium perchlorate and followed dechloroacetylation using hydrazinedithiocarbonate afforded the crystalline disaccharide 109.

Drug interactions

Potentially hazardous interactions with other drugs Increased risk of bleeding in combination with any other drugs that affect coagulation.

Metabolism

Although not fully evaluated, there is no evidence of fondaparinux metabolism and in particular no evidence for the formation of active metabolites. Fondaparinux is excreted to 64-77% by the kidney as unchanged compound.

Relevant articles and documents

Synthesis of methyl glycoside derivatives of tri- and penta-saccharides related to the antithrombin III-binding sequence of heparin, employing cellobiose as a key starting-material.

Two key synthons for the title pentasaccharide derivative, methyl O-(methyl 2-O-benzoyl-3-O-benzyl-alpha-L-idopyranosyluronate)-(1----4)-6-O-acetyl- 2-azido - 3-O- benzyl-2-deoxy-beta-D-glucopyranoside and O-(methyl 2,3-di-O-benzyl-4-O- chloroacetyl-beta-D-glucopyranosyluronate)-(1----4)-3,6-di-O-acetyl-2-az ido-2- deoxy-alpha-D- glucopyranosyl bromide, were prepared from a common starting material, cellobiose. They were coupled to give a tetrasaccharide derivative that underwent O-dechloroacetylation to the corresponding glycosyl acceptor. Its condensation with the known 6-O-acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-alpha-D-glucopyranosyl bromide afforded a 77% yield of suitably protected pentasaccharide, methyl O-(6-O- acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-alpha-D-glucopyranosyl)-(1----4)- O- (methyl 2,3- di-O-benzyl-beta-D-glucopyranosyluronate)-(1----4)-O-(3,6-di-O-acetyl-2- azido-2 - deoxy-alpha-D-glucopyranosyl)-(1----4)-O-(methyl 2-O-benzoyl-3-O-benzyl-alpha-L- idopyranosyluronate)- (1----4)-6-O-acetyl-2-azido-3-O-benzyl-2-deoxy-beta-D-glucopyranoside. Sequential deprotection and sulfation gave the decasodium salt of methyl O-(2- deoxy-2-sulfamido-6-O-sulfo-alpha-D-glucopyranosyl)-(1----4)-O-(be ta-D- glucopyranosyl-uronic acid)-(1----4)-O-(2-deoxy-2-sulfamido-3,6-di-O-sulfo-alpha-D-gluco pyranosyl)- (1----4)-O-(2-O-sulfo-alpha-L-idopyranosyluronic acid)-(1----4)-2-deoxy-2- sulfamido-6-O- sulfo-beta-D-glucopyranoside (3). In a similar way, the trisaccharide derivative, the hexasodium salt of methyl O-(2-deoxy-2-sulfamido-6-O-sulfo-alpha-D- glucopyranosyl)- (1----4)-O-(beta-D-glucopyranosyluronic acid)-(1----4)-2-deoxy-2-sulfamido-3,6- di-O- sulfo-alpha-D-glucopyranoside (4) was synthesized from methyl O-(6-O-acetyl-2- azido- 3,4-di-O-benzyl-2-deoxy-alpha-D-glucopyranosyl)-(1----4)-O-(methyl 2,3-di-O- benzyl-beta- D-glucopyranosyluronate)-3,6-di-O-acetyl-2-azido-2-deoxy-alpha-D- glucopyranoside. The pentasaccharide 3 binds strongly to antithrombin III with an association constant almost equivalent to that of high-affinity heparin, but the trisaccharide 4 appears not to bind.