MXPA06013555A - Azasugar derivatives, heparanase inhibitors, method for preparing same, compositions containing same, use thereof - Google Patents

Abstract

The invention concerns heparanase inhibiting compounds of general formula (I) wherein R represents a hydrogen atom, an hydroxyl radical, a -OSO3- radical, a -O-(C1-C5)alkyl radical or an -O- aralkyl radical;Z represents a COO-radical or a hydroxyl radical;X represents -OH or a saccharide unit of formula A, Y represents H, C1-C5alkyl or a saccharide unit of formula D;in free form or in the form of pharmaceutically acceptable salts formed with a base or an acid as well as in the form of solvates or hydrates. The derivatives of the invention are useful as medicines.

Description

DERIVATIVES OF SUGAR. HEPARANASE INHIBITORS. YOUR PREPARATION PROCESS. THE COMPOSITIONS THAT CONTAIN THEM AND THEIR UTILIZATION.

The subject of the invention is sugar derivatives, heparanase inhibitors, their preparation, the compositions containing them and their application in therapy. Heparanases are enzymes of the endoglucuronidases type that have as substrate the polysaccharides of the family heparin / heparan sulfate (HS). Type I and II heparanases are known (McKenzie et al., Biochem. Biophys., Res. Commun., (2000), Vol.276, p.1170-1177). These hydrolyse specifically the ß-1? 4 type bonds between a saccharide unit of the D-glucuronic acid type and a saccharide unit of the D-glucosamine type and release HS fragments of approximately 10 to 20 saccharide units (Pikas, DS et al. , J. Biol. Chem., (1998), Vol.273, p.18770-18777). Heparanases in the same way degrade the polysaccharide chains of proteoglycans containing heparan sulfates (HSPG, proteoglycans of the heparan sulfate type) (Vlodavsky and Friedmann, J. Clin. Invest., (2001), Vol. 108. p.341-347). HSPGs are constituted by a central protein to which HS linear chains are covalently linked (Kjellen et al., Annu Rev. Biochem., (1991), Vol.60, p.443-475). HSPGs are ubiquitous macromolecules. Like HS, HSPG are present on the surface of numerous cell types and in the extracellular matrix (ECM, extracellular matrix, from the English Extracellular Matrix) (Kjellen ef al., (1991), ibid., Bernfield et al., Annu., Rev. Biochem., (1999), Vol.68 , p.729-777; David ef al., FASEB J., (1993), Vol.7, p.1023-1030; Lozzo ef al., Annu., Rev. Biochem., (1998), Vol.67. p.609-652). The NDE, a major component of the connective tissues of vertebrates and invertebrates, occupies the extracellular environment. This involves the organs and surrounds the endothelium, mainly the capillary endothelia (Wight et al., Arteriosclerosis, (1989), Vol.9, p.1-20), thus playing a role of maintenance and protective barrier of the organs and endothelia (McKenzie ef al., Biochem. J; 2003; Vol.373; p.423-435). The ECM is also a key modulator, involved in different cellular mechanisms, mainly cell differentiation and repair (Folkman ef al., Adv. Exp. Med. Biol., (1992), Vol.313, p.355-364) . Heparanase inhibitor compounds have been described in the prior art. For example, the international patent application WO 02/0600374 describes benz-1,3-azole derivatives, the international patent application WO 03/074516 refers to phthalimido carboxylic acid derivatives and benzoxazole, the international patent application WO 04 / 013132 describes derivatives of furantiazoles or also the international patent application WO 04/046123 describes benzoxazole, benzothiazole and benzimidazole derivatives. The synthesis of derivatives of short chain azaazúcares (2 residues) in which the nitrogen atom replaces the atom of oxygen in position 5 has been described in Takahashi et al, Chem. Lett., (1994), Vol.11, p.2119; Takahashi ef al, Tetrahedron, (2001), Vol.57. p.6915-6926,). However, its activities have not been identified in vivo. The azaazúcares derivatives with only one residue, of the following formula: they have already been described (US patent 6,583,158, Ichikawa et al., J. Amer. Chem. Soc, (1998), Vol.120, p.3007). There is constantly a need to find and develop products that exhibit good in vitro and in vivo activity. It has now been found, surprisingly, that the synthetic azazucar derivatives show good activity as heparanase inhibitors. The present invention therefore relates to new derivatives of azaazucar, inhibitors of heparanases. These new compounds exhibit a good heparanase inhibitory activity. The object of the invention relates to the compounds that respond to the general formula (I): (i) wherein: R represents a hydrogen atom, a hydroxyl radical, a radical -OSO3, a radical -O-alkyloid-Cs) or a radical -O-aralkyl; Z represents a radical "COO" or a hydroxyl radical X represents a hydroxyl radical or a saccharide unit of formula A: wherein: - Ri represents an oxygen atom, which allows A to join the sugar unit or another saccharide unit, R2 represents a radical - NH2, a radical NHCOalkyl (C? -C5), a radical --NHCOaryl, a radical -NHSO 3) a hydroxyl radical, a radical -O-alkylic acid-Cs), an -O-aralkyl radical or a radical -OSO 3, -R 3 represents a hydroxyl radical, a radical -OSO 3, a radical -O-alkyl (C? -C5) or a radical -O-aralkyl, -R4 represents a hydroxyl radical, a radical -OSO3, a radical -O-alkylofCi-Cs), an -O-aralkyl radical or a saccharide unit of formula B: (B) wherein: - R6 represents an oxygen atom, which allows B to bind to another saccharide unit of formula A, - R and R8 have the same definition as R3 as defined above, - R9 represents a hydroxyl radical, a radical -OSO3, a radical -O-alkyloid-Cs), a radical -O-aralkyl or a saccharide unit of the formula A as defined above, - R5 has the same definition as R3 as is defined above; Y represents a hydrogen atom, a radical alkyloid -Cs) or a saccharide unit of formula D - Rio, R? 2 and? 3 have respectively the same definitions as R5, R3 and R2 as defined above, - Rn represents: - an alkylene radical (C? -C3) that allows D to be incorporated into the unit sugar or - an oxygen atom that allows D to be incorporated into another saccharide unit, - R? represents a radical -O-alkyloid-Cs) or a radical -O-E in which E represents a radical of the following formula: wherein: - R15 represents a radical -O-alkyl (d-C5), an -O-aralkyl radical or a saccharide unit of formula D in which Rn represents an oxygen atom, - R 16 and R? they have the same definition as R3 as defined above, with the proviso, however, that when X and R each represent a hydroxyl radical, Y does not represent a hydrogen atom, and it is understood that the number of saccharide units contained in the formula (I) compound is comprised between 1 and 10 0, in free form or in the form of salts formed with a base or an acid acceptable from a pharmacological viewpoint as well as in the form of solvates or hydrates. According to one of its preferred aspects, the invention relates to the compounds of general formula (I): (I) wherein: R represents a hydroxyl radical; Z represents a radical COO "or a radical l hydroxyl X represents a hydroxyl radical or a radical extraction unit of formula A: wherein: - R represents an oxygen atom, - R2 represents a radical --N HCOC H3, a radical --NH SO3 or a radical --OSO3"- R3 represents a hydroxyl radical or a radical --O-alkyl (d- C5 ), - R represents a hydroxyl radical, an -O-aralkyl radical or a saccharide unit of formula B: wherein: - R6 represents an oxygen atom, - R7 represents a radical --OSO3, - R8 represents a hydroxyl radical, a radical -O-alkyl (d-C5) or a radical -O-aralkyl, - R9 represents a radical -OSO3, a radical -O-aralkyl, a radical -O-alkyl (d-C5) or a saccharide unit of formula A as defined above, - R5 represents a radical -OSO3, Y represents a hydrogen atom or a saccharide unit of formula wherein: - R10 has the same definition as R5 as defined above, - R12 represents a hydroxyl radical or a radical --OSO3, - R13 represents a radical --NHSO3, - Rn represents a methylene radical attached to the azaazucar unit or an oxygen atom bonded to E, -R14 a radical -OCH3 or a radical of formula -OE in which E represents a radical of the formula: in which - R15 represents a unit D in which Rn represents an oxygen atom which makes it possible to join E to D, - R16 represents a radical --OSO3, - R17 represents a hydroxyl radical, it being understood that the number of saccharide units contained in the compound of formula (I) is between 2 and 10, in free form or in the form of salts with a base or an acid acceptable from a pharmaceutical point of view as well as in the form of solvates or hydrates. Particularly preferred compounds are the compounds of formula 1 wherein Y is a hydrogen atom. The invention encompasses the azaazucar derivatives in their acid form or in the form of any one of their pharmaceutically acceptable salts. In the acid form, the functions -COO 'and -SO3 are respectively in the form -COOH and -SO3H.

According to one of its particularly preferred aspects, the present invention relates to the following compounds: • (sodium 2,4-di-O-sodium sulfonate-aL-idopyranosyluronate) - (1-4) - (2-acetamido-2) -deoxy-6-O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (2-O-sodium sulfonate-aL-idopyranosyluronate sodium) - (1-4) - (2-acetamido-2-deoxy) -6-O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (5- (hydroxy) -4-oxypiperidine-3-carboxylate sodium (3S, 4R, 5R)) (compound No. 20) • (Sodium 2,4-di-O-sodium sulfonate-DL-idopyranosyluronate) - (1-4) - (2-N-sodium sulfonate-2-deoxy-6-O-sodium sulfonate-aD-glucopyranosyl) - ( 1-4) - (sodium 2-O-sodium sulfonate-al-idopyranosyluronate) - (1-4) - (2-N-sodium sulfonate-2-deoxy-6-O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (5- (hydroxy) -4-oxypiperidine-3-carboxylic acid sodium (3S, 4R, 5R)) (Compound No. 27) • (3-O-methyl-2,4-di-carboxylate) Sodium sodium sulfonate-al-idopyranosyluronate) - (1-4) - (3-O-methyl-2,6-di-O-sodium sulfonate-DD-glucopyranosyl) - (1-4) - (3- O-methyl-2-O-sodium sulfonate-a- Sodium L-idopyranosyluronate) - (1-4) - (3-O-methyl-2,6-di-O-sodium s ulfonate-aDg I ucop rancros il) - (1-4) - (5- ( sodium hydroxy) -4-oxypiperid i-3-carboxylate (3S, 4R, 5R)) (compound n ° 47) • (sodium 2,4-di-O-sodium sulfonate-aL-idopyranosyluronate) - (1 -4) - (2,6-di-O-sodium s-ulfonate-aDg I ucopyranes il) - (1-4) - (2-O-sodium sulfonate-aL-idopyranosyluronate sodium) - (1-4) - (2,6-di-O-sodium s ulfonate-aDg I ucop i ranos il) - (1-4) - (5- (h id roxi) -4-oxip i pe rid i n -3-carboxylate sodium (3S, 4R, 5R)) (compound No. 69) • (4-O-propyl-2-O-sodium sulfonate-al-idopyranosyluronate sodium) - (1-4) - (2,6-di- O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (2- O-sodium sulfonate-al-idopyranosyluronate sodium) - (1-4) - (2,6-di-O-sodium-sulphonate- aDg I ucop iran osi I) - (1-4) - (5- (hydroxy) -4-oxi pipe rid in -3-carboxylate sodium (3S, 4R, 5R)) (compound no. 74). • (sodium 2,4-di-O-sodium sulfonate-al-idopyranosyluronate) - (1-4) - (2-acetamido-2-deoxy-6-O-sodium sulfonate-aD-gl ucop irán os il) - (1-4) - (2-O-sodium sodium sulfonate-al-idopyranosyluronate) - (1-4) - (2-acetamido-2-deoxy-6-O-sodium sulfonate-aD-glucopyranosyl) - ( 1-4) - (3- (idroxy) -5-hydroxymethyl-4-oxypiperidine (3R, 4R, 5R)) (compound no. 123). • (4-O-phenylpropyl-2-O-sodium sulfonate-al-idopyranosyluronate sodium) - (1-4) - (2-a-cetamido-2-deoxy-6-I hate you ulfonato-aDg I ucop i ranos i I) - (1-4) - (2-O-sodium sulfonate-aL-idopyranosyluronate sodium) - (1-4) - (2-acetamido-2-deoxy-6-O-sodium sulfonate-aD- glucopyranosyl) - (1-4) - (5- (hydroxy) -4-oxypiperidin-3- sodium carboxylate (3S, 4R, 5R)) (compound No. 1 24). In the context of the present invention: an (d-C5) alkyl radical represents an aliphatic radical, which may comprise from 1 to 5 carbon atoms, linear or branched saturated. As examples, there may be mentioned the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl radicals, ..., an -O-aralkyl radical represents an alkyl group as defined above but substituted with an aromatic radical which it may contain substituents. Examples are p-methoxybenzyl, phenylmethyl, phenylethyl, phenylpropyl, ..., an alkylene radical (d-C3) represents a bivalent alkyl group comprising from 1 to 3 carbon atoms. "Pharmaceutically acceptable salt" is understood to mean the azaazúcares derivatives of the invention, an azaazucar derivative in which one or more of the functions -COO or / and -SO3 are ionically bound to an acceptable cation from a pharmacological point of view. Preferred salts according to the invention are those in which the cation is selected from the alkali metal cations and more preferably even those in which the cation is Na + or K +. In its principle, the process for the preparation of the compounds according to the invention uses mono-, di- or oligosaccharide-based syntones prepared as previously published in the literature and are chosen taking into account mainly the orthogonality of the protective groups. Reference will be made mainly to EP 300099, EP 529715, EP 621282 and EP 649854 as well as to C. van Boeckel, M. Petitou, Angew. Chem. Int. Ed. Engl., (1993), Vol.32, p.1671-1690. These synthons are coupled to one another so that a fully protected equivalent of a compound according to the invention is produced. This protected equivalent is transformed into a compound according to the invention using processes well known to the person skilled in the art. The compounds of the invention which also contain an azaa-sugar moiety (or substituted piperidine), their synthesis requires the preparation of a precursor of this moiety containing protective groups compatible with the subsequent couplings to mono, di, or oligosaccharides. The precursors of the azaazúcares are prepared according to the processes described in the bibliography. Reference will be made in particular to the work "Iminosugars as Glycosidase Inhibitors", AE Stütz, Wiley-VCH, 1999. When the syntons necessary for the construction of the chain are available, we proceed to the coupling of these synths with each other. In the aforementioned coupling reactions, a "donor" synthon, activated on its anomeric carbon, reacts with an "acceptor" synthon, which has at least one free hydroxyl. The present invention relates to a process for the preparation of the compounds of formula (I) characterized in that: in a first step, a completely protected equivalent of the desired compound (I) is prepared; in a second stage, negatively charged groups (carboxylates, sulfonates) as well as the free hydroxyls are introduced and / or unmasked. The synthesis of the precursor is carried out according to the reactions known to the person skilled in the art, using in particular the osidic synthesis methods (G .J. Boons, Tetrahedron, (1996), Vol .52. P.1095-1 121; WO98 / 03554 and WO99 / 36443) according to which a glycosidic binding donor oligosaccharide is coupled to a glycosidic binding acceptor oligosaccharide to yield another oligosaccharide whose size is equal to the sum of the sizes of the two reactive species. This sequence is repeated until the desired formula (I) compound is obtained. The structure of the desired final compound determines the nature of the chemical entities used in the different stages of the synthesis, so as to control the stereochemistry and the regioselectivity, according to the rules known to the person skilled in the art. The compounds of the invention they are obtained from their completely protected polysaccharide precursors using, in general, the following sequence of reactions: - Liberation and substitution of the functions that must be transformed into N- and / or O-sulfonate groups. - Release of the other functions and optional joining of the fragments together, for example, by a reductive amination reaction. The release of carboxylic acid functions can be carried out at different stages of this process. The compounds of the invention can be prepared using different strategies known to the expert in the osidic and organic synthesis technique. The process described above is the preferred process of the invention. However, the compounds of formula (I) can be prepared by other known methods of sugar chemistry described, for example, in "Monosaccharides, Their chemistry and their roles in natural producís", P.M. Collins and R.J. Ferrier, J. Wiley & sons, 1995 and in G.J. Boons, Tetrahedron, (1996), Vol.52. p.1095-1121. The protecting groups used in the preparation process of the compounds (I) are those commonly used in sugar chemistry, for example, in Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, John Wiley & Sons, New York, 1999. Protective groups are advantageously chosen, for example, from the groups acetyl, halogenomethyl, benzoyl, levulinyl, benzyl, substituted benzyl, optionally substituted trityl, carbamate, tetrahydropyranyl, allyl, pentenyl, fer-butyldimethylsilyl (tBDMS ) or trimethylsilylethyl. The activating groups are those classically used in the sugar chemistry according to, for example, G.J. Boons, Tetrahedron, (1996), Vol.52, p.1095-1121. These activating groups are chosen, for example, from imidates, thioglycosides, pentenylglycosides, xanthates, phosphites or halides. The process described above allows obtaining the compounds of the invention in the form of salts. To obtain the corresponding acids, the compounds of the invention in the form of salts are contacted with a cation exchange resin in acid form. The compounds of the invention in the form of acids can be neutralized by a base to obtain the desired salt. For the preparation of the salts of the compounds of formula (I), any mineral or organic base, which yields with the compounds of formula (I), the salts acceptable from a pharmaceutical viewpoint can be used. The sodium, potassium, calcium or magnesium hydroxide is preferably used as the base. The sodium and calcium salts of the compounds of formula (I) are the preferred salts. The compounds according to the invention are the subject of biochemical and pharmacological studies. The following non-limiting tests illustrate the present invention. The following terms are defined: PET: polyethylene terephthalate, Am: acetoxymethyl, DM MS: Eagle's medium modified by Dulbecco, EDTA: ethylenediaminetetraacetic acid, Tris: tris (hydroxymethyl) aminomethane, AT: Antithrombin III, nkat: nanokatal = unit of enzymatic measurement (provided by the manufacturer), which represents the amount of substrate catalyzed per unit of time. 1 . Evaluation of the activity of the heparanase inhibitors in an enzymatic system (determination of the Cl sn of the compounds according to the invention). The activity of heparanase is evidenced by its ability to deg radar the fondaparinux. The concentration of fondaparinux is determined thanks to its anti-factor Xa activity. A. Material and methods Heparanase is produced by Sanofi-Synthelabo (Labége, France). The reagents of the factor Xa dosages are marketed by Ch romogenix (Montpellier, France). Increasing concentrations of a compound according to the invention are mixed, inhibitor of hepase (variable dilutions: from 1 nM to 10 μM) at a fixed concentration of heparanase (for each batch, preliminary experiments allow to determine the sufficient enzymatic activity for each batch). the 0.45μg / ml degrowth of fondaparinux added). After 5 minutes at 37 ° C the mixture is placed in the presence of fondaparinux and left at 37 ° C for 1 hour. The reaction is stopped by heating at 95 ° C for 5 minutes. The concentration of residual fondaparin ux is measured finally by the addition of factor Xa and its specific chromogenic substrate (Ref. S2222). The different mixtures are made according to the process indicated below: Reaction mixture 50 μl of sodium acetate buffer (0.2 M, pH 4.2) are mixed with 50 μl of fondaparinux (0.45 μg / ml) and 59 μl of a heparanase solution. Incubate 1 hour at 37 ° C, then 5 minutes at 95 ° C. 100 μl of the reaction mixture is then mixed with 50 μl of 50 mM Tris buffer, 175 mM NaCI 75 mM EDTA, pH 14. It is then passed from pH 4.2 to pH 7. The anti-factor Xa activity of fondaparinux it is measured in the following way: Determination of the anti-factor Xa activity of fondaparinux 100 μl of the solution obtained in step a) is mixed with 100 μl of AT (0.5 μ / ml). It is kept for 2 minutes at 37 ° C and then 100 μl factor Xa (7nkat / ml) is added. It is kept for 2 minutes at 37 ° C and then 100 μl of chromogenic substrate (Ref .: S2222) (1 mM) is added. It is kept for 2 minutes at 37 ° C and then 100 μl of acetic acid (50%) is added. The reading of the optical density is carried out at 405 nm. A percentage of inhibition is determined in relation to the control without inhibitor. A curve of the percentages of inhibition allows an IC50 to be calculated. B. Results The compounds according to the present invention have Cl50 comprised between 10 nM and 10 μM. For example, compound n ° 27 has an Cl50 of 11 ± 4 nM (mean ± SD, performed in two tests) 2. Effect of heparanase inhibitors on the invasion of HT1080 tumor cells The in vitro effect of the compounds of formula (I) was tested, inhibitors of heparanases, in the invasion of HT1080 tumor cells. A. Material and methods: a) Cell culture: The cells from human fibrosarcomas, HT1080 (ATCC CCL-121) are cultured in a DMEM medium (Ref: GIBCO 11960-044) containing 5% Fetal Calf Serum, glutamine (2 mM) (Ref .: GIBCO 25030-024), sodium pyruvate (1 mM) (Ref .: GIBCO 11360-039) and non-essential amino acids (1X) (Ref .: GIBCO 11140-035), in bottles cultures covered by collagen (Becton Dickinson 75 cm2; Ref.354523), up to 50 to 80% confluence. b) Cell invasion assay Determinations of the invasion of HT1080 are carried out with the Becton Dickinson Falcon HTS Fluoroblok Multiwell Insert System in 24-well plates (Ref .: 351158). These de-ermination chambers provide the cells with conditions that allow their invasive properties to be evaluated in vitro. The kit consists of a plate associated with the culíivo inserts that contains a perforated PET membrane with 8 micrometer pores in which a uniform layer of Malrigel Maírix (Becíon Dickinson; Ref.354230) was deposited.

The maírigel is a soluble basal membrane exluded from the EHS (Engelbrefh-Holm-Swarm), which, due to its composition, forms when it solidifies, a structure equivalent to a basement membrane.

The Matrigel layer occludes the pores of the membrane, blocking in this way the migration of non-invasive cells through the membrane. By the conlrario, the invasive cells (irrespective of whether they are processed or not) they will be able to detach themselves and invade the Mairigel layer before migrating to the membrane.

The quantification of cell migration is carried out by means of Calcein AM labeling (Molecular Probes C-31 00). The emitted fluorescent signal is measured by a Perkin Elmer Wallac VICTOR 3 lecimer and can be correlated directly with the number of cells that have invaded M aírigel gel. Comparing them with the controls carried out in the same experiment that the products studied (response in the presence of 0% and 5% of fetal serum), it is possible to determine a percentage of inhibition of the cellular invasion in the presence of the productions. B. Results A series of independent demineralizations (ranging from 2 to 4) have shown that at a concentration between 1 nM and 10 μM, the compounds according to the invention inhibit on average cell invasion with a percentage comprised in 8 and For example, a series of independent determinations has allowed us to show that 1 0 μM of the compound n ° 20 in hiben on average the cellular invasion with a percentage equal to 40.3 ± 8.3% (mean ± standard deviation). In addition, compound No. 20 has an effect depending on the dose in the cell invasion. In fact: - at a concentration of 0.3 μM, compound no. 20 inhibits cellular invasion 26 + 3%, at a concentration of 1 μM, compound no. 20 inhibits cell invasion 53 + 11%. These results show an increase in the inhibition of cell invasion as a function of the dose of compound No. 20. The compounds of formula (I) according to the present invention therefore have a good affinity for heparanases and present an inhibitory effect of heparanases. It has been shown in animals and in humans that the increase in heparanase secretion and cancer progression are correlated (Goldschmit et al., PNAS, (2002), Vol.99 (15), p.10031-10036). For example, a high level of heparanase has been detected in the serum of animals that have metastatic tumors (VIodavsky ef al., Isr. J. Med. Sci., (1988), Vol.24 (9-10), p.464-470) or also in the urine of patients affected by cancer who have developed numerous metastases (VIodavsky ef al., Curr. Biol., (1997), Vol.7 (1). P.43-51). Tumor biopsies have revealed the same correlation (VIodavsky et al., Isr. J. Med. Sci., (1988), Vol.24 (9-10), p.464-470). There is, therefore, a correlation between the increase in heparanase secretion and the metasylar potential of tumor cells (VIodavsky et al., Invasion Matastasis, (1 994), Vol.14, p.290-302, Nature Medicine, (1 999), Vol.5, pp. 793-802). The heparanasas, secreted by the tumor cells, degrade the HSPG and HS, main components of the ECM. The ECM perforated in this way allows the lumoral and melastatic cells to circulate and also allows the invasion of the newly formed blood vessels (angiogenesis) (Suza n ne A. Eccles, Nat. Med., (1 999), Vol. 5 (7), p.793-809). Angiogenesis is a process of generating new capillary vessels from pre-existing vessels or by mobilization and differentiation of cells from the bone marrow. Thus, an uncontrolled proliferation of endoleal cells and a mobilization of angiosblasts from the bone marrow in the processes of neovascularization of the tumors are observed at the same time. Thus, heparanases represent relevant targets for therapies that seek to inhibit the processes of cancer cell invasion and metastatization on the one hand, and angiogenesis on the other hand. Cancer (or carcinoma) is understood to be any malignant cell growth of the epithelium, present in the skin, but also, and especially, in the wall of the organs, as well as the appearance of metastatic lumoral cells such as melanomas, mesothelioma, lymphoma, leukemia. , fibrosarcoma, rhabdomyosarcoma, masliocioma, but also the carcinomas that They affect a tissue such as the colon, rectum, prostate, lungs, breasts, pancreas, intestine, kidneys, ovaries, uterus, cervix, gallbladder, liver and stomach. Carcinomas infiltrate adjacent tissues and spread (metastasize) to other distant organs, for example, liver, lungs, brain or bones. A compound exhibiting an inhibitory activity of heparanases such as the compounds of the invention may therefore be useful for the treatment of such cancers (Fang J ef al., Proc. Nati. Acad. Sci. USA, (2000 ), Vol.97 (8), pp. 3884-3889, Kondraganti et al., Cancer Res., (2000), Vol.60 (24), pp. 6851-6855), and mainly colorectal cancer, of the prostate, lung, breast, pancreas, kidney, gallbladder and ovaries. The p75 receptors, receptor of the molecules of the neurotrophin family (NT), have been identified as a representative marker of the metasylation phenomenon in the brain. It has also been shown that NT secretion involves an increase in the secretion of heparanases (Marchetíi D. et al, J. Cell, Biochem., (2004), Vol.91 (1), p 206-20). Thus, a compound that exhibited an inhibitory activity of the heparan cells as the compounds of the invention may, therefore, be useful for reducing melasisation at the level of the central nervous system by inhibiting the action of the P75 receptor acyivation (Marchetli D. et al., Pathol, Oncol., Res., (2003), Vol.9 (3)., pp. 147-158 and Epub, (2003), Review, Walch ET. ef al., Int. J. Cancer, ( 1999), Vol.82 (1), pp. 112-120, Menler DG. Ef al., Invasión Metastasis, (1994-95), Vol.14 (1-6), p. 372-384; Marcheiti D. ef al., Int. J. Cancer, (1993), Vol.55 (4). p.692-699). The activity of heparanases in the HSPG of the ECM also seems to be correlated with the sequence of inflammatory and immune reactions (VIodavsky et al., Invasion metastasis, (1994), Vol.4, pp. 290-302, Goldschmif et al. ., Med. Sci., (2002), V _L99 (15), p.10031-10036). The inhibition of platelets, granulocytes, lymphocytes B and T, macrophages and masiocytes with the ECM, is associated with the degradation of HS by heparanases (VIodavsky et al., Invasión Metástasis, (1992), Vol.12, p. 112-127). Thus, a compound like the compounds of the invention, which had an inhibitory activity on heparanases, can therefore be useful for the eradication of inflammatory diseases, mainly chronic inflammatory diseases such as rheumatoid arthritis or IBD (inflammatory disease). Small Inflammatory Bowel Disease), which comprise two forms of chronic inflammatory diseases of the intestine: UC (ulcerative colitis) and Crohn's disease (CD) or autoimmune diseases. Other studies allow us to think that heparanases may play a role in the development of cardiovascular diseases (Journal of Pharmacological Sciences, (2004), 94, No. Supplement 1, pp. 160P, prinl., And Meeing Info .: 77lh Annual Meeling of íhe Japanese Pharmacological Society, Osaka, Japan, March 08-10, 2004. Japanese Pharmacological Society, and Miller, Heather Ann, Diss. Abstr. Int., (1984), B 2003, 64 (5); Demir et al., Clin. Appl. Thromb. Hemost., (2001), Vol.7 (2), p. 131-140), such as resennosis after angioplasty, diseases associated with vascular complications of diabetes such as diabetic retinopathies, arteriosclerosis (Atherosclerosis, (1999), Vol.145, p.97-106, J. Clin. ., (1997), Vol.100, p.867-874) or also thromboembolic diseases and arthrosis of the arteries. Thus, a compound, inhibitor of heparanases, according to the invention can present a preferential therapy in these palologies. For example, heparanases are known to be involved in certain cases of renal insufficiency in which renal filtering and resorption functions may be altered (FASEB J, (2004), Vol.18, pp. 252-263). Thus, a compound, heparanase inhibitor, according to the invention can present a preferred therapy in said pathologies. The HSMs of the ECM also seem to play a role as main regulators of cell growth and activation, by modulating growth facords, in particular, FGF (Fibroblast growth growth factors). . For example, the activity of heparanases involves the release of growth factors such as FGFs, which mainly stimulate angiogenesis and promote tissue progression (Bashkin et al., Biochemistry, (1989), Vol.28, p.1737-1743 ). Thus, heparanasas represent relevant targets for the eradication of diseases in which they are implicated.

FGF. In general, FGF are implied in an important way by means of exocrine, paracrine or juxitacrine secretions in the deregulation phenomena of the stimulation of the growth of cancer cells. In addition, FGF initiate the fumoral angiogenesis that plays a preponderant role at the same time on the growth of the tumor and also on the phenomena of metastasis. Angiogenesis is a process of generation of new capillary vessels from preexisting vessels or by mobilization and differentiation of cells of the bone marrow. Thus, an unalloyed proliferation of endoleal cells and a mobilization of angioblasts from the bone marrow in the processes of neovascu larization of the tumors is observed. It has been shown in vitro and in vivo that several growth factors stimulate endoihelial proliferation, mainly FGF-1 or a-FG F and FGF-2 or b-FGF. The a-FG F and b-FG F play, for example, an important role in the growth and the maintenance of the cells of the próslala (Dolí JA et al., Prostate, (2001), Vol.305. .49-293 Several papers show the presence of a-FGF and b-FGF and their FG FR receptors simulinely in human breast tissue lines (principally M CF7) and in tumor biopsies Glioma cells produce in vitro and in vivo a-FG F and b-FGF and have in their surface different FGF receptors.

More recently, the positive role of pro angiogenic agents and mainly of FGF in leukemias and lymphomas has been documented (Thomas DA et al., Acta Haematol, (2001), Vol.207, p.106-190). There is a correlation between the process of angiogenesis of the bone marrow and the "exframedullary diseases" in the CM L (chronic myelomonocytic leukemia, from English chroníc myelomonocyíic leukemia,). The proliferation and migration of vascular smooth muscle cells contributes to the minute hypertrophy of the arteries and thus plays a preponderant role in the arteriosclerosis and in the restenosis after angioplasty and endorealectomy. In vivo studies show, after carolide injury due to "balloon damage", a local production of a-FGF and b-FG F. Vascular systems due to diabeles are characterized by an allegation of vascular reactivity and blood flow, hyperpermeability, an exacerbated proliferative response, and an increase in matrix protein deposits. More precisely, a-FG F and b-FGF are present in the pre-retinal membranes of patients suffering from diabetic retinopathies, in the membranes of the underlying capillaries and in the viral humor of patients suffering from proliferative retinopathies. Rheumatoid arthritis (RA) is a chronic disease with an unknown etiology. When affectala to numerous organs, the most severe form of RA is a synovial inflammation of the ariculations progressive that ends in destruction. Angiogenesis seems to have an important impact on the progression of this pathology. Thus, a-FGF and b-FGF have been detected in the synovial tissue and in the arylic fluid of patients suffering from RA, indicating that this growth factor originates in the initiation and / or progression of this paiology. In the models of AIA (adjuvant-induced model of arylhrysis) in the rayo, it has been shown that overexpression of b-FGF increased the severity of the disease while an antibody neutralized ani b- FGF blocks the progression of RA (Yamashita ef al., J.lmmunol., (2002), Vol.57, p. 168-450, Manabe et al., Rheumatol, (1999), Vol.20, p.38 -714). Angiogenesis and inflammation are also important phenomena involved in the processes involved in osteoarthritis that leads to a destruction of the joint associated with pain. Angiogenesis may also play a role in chondrocyte hyperplasia and ossification thus contributing to joint modifications (Bonnel CS et al Rheumafology. (1) 7-162005). IBD (inflammatory bowel disease) comprises two forms of chronic inflammatory diseases of the infeslino: UC (ulcerative colitis) and Crohn's disease (CD). IBDs are characterized by an immune dysfunction that arises in an inappropriate production of inflammatory cyclin that induce the establishment of a local micro-vascular system. This angiogenesis of inflammatory origin results in an inlesinal ischemia induced by vasoconstriction. Circulating and local sources of b-FG F have been determined in patients afflicted with these pathologies (Kanazawa et al., American Journal of Gastroenterology, (2001), Vol. 28, pp. 96-822, Thorn ef al., Scandinavian Journal of Gastroenterology, (2000), Vol.12, pp. 35-408). A compound that exhibits an inhibitory activity of heparanases such as the compounds of the invention may, therefore, be useful for the eradication of diseases associated with "a posilive regulation of FG F and / or its receptors. Thanks to its low toxicity and its pharmacological and biological properties, the compounds of the present invention will find its application in the treatment of any carcinoma that has an important degree of vasculature (lung, breast, prostate, esophagus) or indus meiásíasis (colon, stomach, melanoma) or that are sensitive to a-FG F or b-FGF in an autocrine or ulimal form in the paliologies of lipo lymphomas and leukemias. These compounds represented a preferential therapy either alone or in association with a chemo-therapy or an adaptive radio-therapy or in association with an irradiation with anti-angiogenic compounds. The compounds according to the invention also find their application in the treatment of cardiovascular diseases such as alellosclerosis, reslenosis after angioplasty, in the treatment of diseases associated with the complications that appear after the placement of endovascular prostheses and / or aorio-coronary bridges or diabetic vascular complications such as diabetic retinopathies. The compounds according to the invention also have their application in the inflammation of chronic inflammatory diseases such as rheumatoid arthritis or IBD. The products according to the invention also find their application in the treatment of macular degeneration. A major feature of the loss of vision in the adult is neovascularization and consecutive hemorrhages that cause important functional features at eye level and that arise in early blindness. Recently, the study of the mechanisms involved in the phenomena of ocular neovascularization has allowed us to demonstrate the implication of proangiogenic facilli in these pathologies. The compounds of the invention can also be used in combination with one or several anti-cancer treatments, such as surgical treatments, radiotherapy or in combination with compounds that block angiogenesis. For example, the compounds of the invention may be used alone or in association with another active ingredient such as cisplaine, cyclophosphamide, meioirexine, 5-fluorouracil, pacliaxel, doceiaxel, vincrysin, vinblasyin, vinorelbine, doxorubicin, tamoxifen, toremifene, acetyl of megestrol, anasyrozole, goserelin, capeciiabine, and raloxifene, or molecules that have an anliangiogenic acfivity; for the treatment of cancer. According to another of its aspects, the present invention has for its object a pharmaceutical composition which contains, as active principle, a compound of formula (I) in free form or in the form of salts formed with an acceptable base or acid. from a pharmaceutical point of view, according to the invention, optionally in association with one or several inert and appropriate excipients. Said excipients are chosen according to the desired dosage form and administration: oral, sublingual, subcutaneous, intramuscular, intravenous, irradermic, transmucosal, local or recessive. In each dosage unit, the active ingredient is present in the doses adapted to the daily doses intended in order to obtain the desired prophylactic or therapeutic effect. Each dosage unit can contain 0, 1 to 1000 mg of active ingredient, preferably 0.5 to 50 mg. The pharmaceutical compositions of the invention can be used for oral, sublingual, subcutaneous, inramuscular, iniravenous, inratracheal, isopic, inanal, transdermal, rectal, intraocular or vaginal administration. The administration forms may be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal seals ("patch"), injectable or suppository pens. For the local administration, ointments, creams, lotions, eye drops, gels, spray or aceile. Said uniform forms are dosed to allow a daily administration of from 1 to 100 mg of aclive principle per kg of body weight, according to the used dosage form. To prepare tablets, a pharmaceutically acceptable vehicle, which may be composed of diluents, such as laclosa, microcrystalline cellulose or starch, and formulation adjuvants such as agglomerates, (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), is added to the principle, whether micronized or not, for example. .), dispersion agents such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenalo or rheumathasone sodium stearate. Moisturizing or falsifying agents such as sodium lauryl sulphide can also be added. The execution techniques can be direct compression, dry g ranulation, wet granulation or hot melt. The tablets may be denuded, coated as dragees, for example with sucrose, or coated with various polymers or other suitable materials. They can be designed to allow rapid, delayed or prolonged release of the polymeric principle thanks to polymeric mallets or specific polymers used in the coating. To prepare capsules, the active ingredient is mixed with dry pharmaceutical vehicles (simple mixture, dry or wet granulation, or hot melt), liquid or semi-solid. The capsules can be duos or blades, film or not, in order to have a fast, prolonged or releded aclivity (for example for an enllic form). A composition in the form of syrup or elixir or for administration in the form of drops may contain the active principle conjunctly with a sweetener, preferably calorie, melilparaben or propylparaben as anisopic, a flavoring agent and a colorant. The dispersible powders and greases in water can contain the active principle blended with dispersing agents or moisturizing agents, or dispersing agents such as polyvinylpyrrolidone, likewise with sweeteners or taste-regulating agents. For partial administration, suppositories prepared with binders that melt at the rectal temperature, for example cocoa butter or polyethylene glycols, are used. For parenteral administration, aqueous suspensions, isolone saline solutions or injectable sterile solutions are used which contain dispersing agents and / or mixtures which can be compared from a pharmacological viewpoint, for example, propylene glycol or butylene glycol. The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives, or with a polymer matrix or with a cyclodextrin (ransdermic patches, prolonged release forms). The compositions for local administration according to the invention comprise a medium comparable to the skin. May occur mainly in the form of aqueous, alcoholic or hydroalcoholic solutions, gels, water-in-oil or water-in-water emulsions which have the appearance of a cream or a gel, microemulsions, aerosols, or else in the form of vesicular dispersions which they contain ionic and / or non-ionic lipids. These galenic forms are prepared according to the usual methods of the fields considered. The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives, either with a polymer matrix or with a cyclodextrin (transdermal patches, prolonged release forms). The local compositions according to the invention comprise a medium compatible with the skin. They can be present mainly in the form of aqueous, alcoholic or hydroalcoholic solutions, gels, water-in-oil or oil-in-water emulsions which have the appearance of a cream or a gel, microemulsions, aerosols, or else in the form of dispersions. vesicles containing ionic and / or nonionic lipids. These galenic forms are prepared according to the usual methods of the fields considered. The following examples, given by way of nonlimiting, illustrate the preparation of the compounds according to the present invention. Abbreviations used in the text that appears next: Ac = aceylic All = alilo Bn = benzyl Me = melyl Ph = phenyl PM B = (4-meloxy) benzyl PM BBr = (3-bromo-4-meioxy) benzyl Z = benzyloxycarbonyl CCM = thin layer chromatography The examples given below illustrate the preparation of compounds according to the invention, without limiting it. In order to deal with the preparation of these different examples, the preparation of compounds (PREPARATION) useful for obtaining compounds of the invention or for hearing preparations is described below. For the preparations and examples that appear below, the following experimental methods are used: Method 1 Oxidation of primary alcohols in acid and transformation into benzyl ester TEMPO® (0.02 molar equivalents) and a saturated aqueous solution of hydrogen are a. sodium bicarbonate (4 L / mol) to a solution of the compound to be oxidized (1 molar uivalent) in tetrahydrofuran (TH F) (3.5 L / mol). After cooling to 0 ° C, Bromodan (2 molar equivalents) was a to gola duranfe 20 min. After 3h of magnetic stirring the reaction mixture is concentrated and the residue is dried by repelled evaporation of dimethylformamide (DM F) (4.95 L / mol). The compound is written in this way it is used as such in the next stage. A solution of the preceding compound in dimethylformamide (13.1 L / mol) is prepared at room temperature (1-15h) with benzyl bromide (10 molar equivalents), and potassium hydrogencarbonate (5 molar equivalents). The reaction mixture is concentrated, the residue is dissolved in ethyl acetate (35 L / mol), washed with water, dried (sodium sulfate), and concentrated. Column chromatography provides the expected benzyl ester. Method 2 Coupling to the imidates catalyzed by tert-butyldimethylsilyl triflate A solution of ferd-butyldimethylsilyl triflate in dichloromelane (0.1M, 0.15 moles per mole of imidale) is a, under argon, at -20 C, to a solution of the imidate and the glycosyl acceptor in a dichloromelan / diethyl ether mixture (1: 2, 22.5-45 L / mol) in the presence of 4 Á molecular sieve. After 10-45 minutes (CCM), solid sodium hydrogencarbonate is a. The solution is filtered, washed with water, dried and evaporated to dryness. Method 3 Saponification method of the esters. To a solution of the compound to be saponified in ureahydrofuran (160 L / mol), successively, at -5 ° C, hydrogen peroxide (H2O2) at 30% (7.16 L / mol ester), and an aqueous solution 0.7 are a successively. N of lithium hydroxide (2.3 moles per mole of ester). After 1 h of stirring at -5 ° C, the reaction medium is set at 4 ° C at 0 ° C, and agifa aemperaíura ambienle hasla the disappearance of esérres. The reaction product is optionally purified on the LH-20 column. Method 4 Sulfonation Triethylamine / sulfur dioxide complex (5 moles by hydroxyl operation) is a to a solution in dimellformamide (90 L / mol) of the sulfalar compound. After 1 to 22 hours at 55 ° C, at 0 ° C methanol or an aqueous solution of sodium hydrogencarbonate is a, and after 0.5-24 h of stirring at room temperature, the reaction medium is stirred. purifies medium column LH-20, or two columns Sephadex® G-25 (successively eluted with an aqueous solution of 0.2 M sodium chloride, and water). The fractions containing the product are concentrated in vacuo to yield the desired composition. Method 5 Hydrogenolysis of benzyl ethers and / or benzyl esters A solution of the compound in a mixture of glacial acetic acid / water / ferricorbenol under a nitrogen-containing atmosphere is allowed to stir for 6-1 6h (CC M). hydrogen peroxide (3-1 5 bars) in the presence of palladium on carbon (equivalent to 0.7-3 times the mass of the compound) at 5 or 10%. After filtering, the solution was deposited in the upper part of a column of Sephadex® G-25 eluted with 0.2 M sodium chloride. Concentrate the fractions that contain the production and desalination using the same column eluted with water. The final compound is forced after lyophilization. Useful preparations for the preparation of the compounds according to the invention are described hereinafter. Preparation 1: Synthesis of 5- (benzyloxy) -4-hydroxypiperidine-1,3-dicarboxylic acid dibenzyl ester (3S.4R.5R) (n ° 6) Step 1.a: Preparation of 1-benzyl-3- (benzyloxy) -5- (hydroxymethyl) piperidin-4-ol (3R.4R.5R) (n ° 2) The synisis of compound 1 is described in T.M. Jespersen and M. Bols, Tetrahedron (1994) 50 (47), 13449-13460 and in US Patent 5,844,102. The synthesis of compound 2 is described in the text WO98 / 50359. To a solution of compound 1 (10.8 g, 42.8 mmol) in methanol (590 mL) are added successively sodium cyanoborohydride (5.38 g, 2 molar equivalents), and acetic acid (7.4 mL, 3 g). molar equivalents) at -10 ° C and a solution of benzylamine (5.1 mL, 1.1 equivalents) in meianol (100 mL). After returning to At room temperature, the reaction mixture is brought to 50 ° C for 2 h. After returning to ambient temperature, a 2% sodium hydrogencarbonate solution (85 mL) is added. The methanol is concentrated in vacuo, the residue is diluted with dichloromethane and the organic phase is washed with water, with an aqueous solution of sodium chloride, dried (Na2SO), and concentrated in vacuo. The test is applied directly in the next step without purification. Step 1.b: Preparation of f4- (acetyloxy) -1-benzyl-5- (benzyloxy) piperidin-3-ip methyl acetate (3R.4R.5R) (n ° 3) To a solution of the crude compound 2 ( 10.8 g) obtained in step 1.a in dichloromean (345 mL), are added successively at 0 ° C, under argon, yiellylamine (13.5 mL, 2.25 molar equivalents), 4- (dimethylamino) pyridine. (DMAP) (7.84 g, 1.5 equivalents), and acyl anhydride (61 mL, 15 molar equivalents). The temperature is maintained at 0 ° C for 10 min, and the reaction medium is placed at ambient temperature for 16 h. The reaction mixture is concentrated in vacuo, and the residue is purified on silica gel to provide compound 3 (7.65 g, 43%, 2 steps). 1 H NMR (CDCl 3) d 7.36-7.18 (m, 10H, Ar), 4.60-4.42 (dd, 2H, OCH2Ph), 2.02, 1.99 (2s, 6H, 2CH3CO). Step 1.c: Preparation of 4- (acetyloxy) -3- (acetyloxymethyl) -5- (benzyloxy) piperidine-1-benzyl carboxylate (3R.4R, 5R) (n ° 4) To a solution of compound 3 ( 2.31 g, 5.6 mmole) is obtained in step 1.b in tetrahydrofuran (28 mL), and, under argon, at -10 ° C, benzyloxycarbonyl chloride (2.4 mL, 3 g) is added. molar equivalents), and the reaction medium is left with stirring at room temperature for 18 h. The reaction mixture is concentrated in vacuo and the residue is purified on silica gel (1: 9 diethyl ether - diisopropylether) to yield compound 4 (2.14 g, 84%). Mass spectrum (ESI) m / z 478.3 [(M + Na) +]. Step 1.d: Preparation of 3- (benzyloxy) -4-hydroxy-5- (hydroxymethyl) piperidin-1-benzylcarboxylate (3R.4R.5R) (n ° 5) To a solution of compound 4 ( 1.9 g, 4.2 mmol) obtained in elapa 1.c, in dioxane (25 mL), a solution of 0.84 M lithium hydroxide monohydrate (25 mL, 5 mL) is added at 0 ° C. molar equivalents). The reaction medium is maintained at 0 ° C for 5 min., And it is placed at room temperature for 30 min. After neulization with hydrochloric acid (HCl: 3 N), the reaction medium is diluted with dichloromethane, washed with water, dried (Na 2 SO 4), filtered and concentrated. The residue is purified on silica gel (3: 1 acetone ethyl cyclohexane), to yield compound 5 (1.59 g, 90%). Mass Species (ESI) m / z 394.4 [(M + Na) +]. Step 1.e: Preparation of dibenzyl 5- (benzyloxy) -4-hydroxypiperidine-1,3-dicarboxylate (3S, 4R, 5R) (n ° 6) Compound 5 (3.18 g, 8.6 mmoles) obtained in step 1.d, was brought according to METHOD 1 to yield compound 6 (2.92 g, 71%). Mass spectrum (ESI) m / z 476.5 [(M + Na) +]. Preparation 2: Synthesis of (Benzyl 2,4-di-O-acetyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-azido-3-O-benzyl-2-deoxy- a, ß-D-glucopyranose trichloroacetimidate) (n ° 11) 11 Step 2.a: Preparation of (Benzyl 2-O-acetyl-3-O-benzyl-L-idopyranosyluronate) - (1-4) - (1,6-anhydro-2-azido-3-O-benz ! -2-deoxy-ß-D-glucopyranose) (n ° 8) Compound 7 in 2'-O-acetylated form (18.0 g, 31.48 mmol), prepared in the same way as the 2'-O-benzoyl compound described in Y. Ichikawa et al., Tetrahedron Lett. (1986) 27 (5) 611-614, was used according to METHOD 1 to yield, after purification on silica gel (3: 7 ethyl acetyl-cyclohexane), compound 8 (16.4 g, 77%) . Mass spectrum (ESI) m / z 698.3 [(M + Na) +]. Step 2.b: Preparation of (Benzyl 2,4-di-O-acetyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (1,6-di-O-acetyl-2-azido -3-O-benzyl-2-deoxy-a.β-D-glucopyranose) (n ° 9) To a solution of compound 8 (3.74 g, 5.54 mmole) obtained in step 2.a, in Acidic anhydride (52 mL, 100 molar equivalents), urea-fluoroacetic acid (TFA) (4.7 mL, 11 molar equivalents) is added at 0 ° C. After returning to ambient temperature, the reaction mixture is stirred for 16 h, concentrated, coevaporated with loluene, and purified on silica gel (4: 1 ethyloluene-acetone), to provide the 9 (4, 33 g, 95%). Mass Spec (ESI) m / z 842.2 [(M + Na) +]. Step 2.c: Preparation of (Benzyl 2,4-di-O-acetyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-azido-3-O -benzyl-2-deoxy-a, β-D-glucopyranose) (n ° 10) To a solution of compound 9 (4.3 g, 5.24 mmol) obtained in step 2.b, in diethyl ether (210 mL), benzylamine (BnNH2) (22 mL, 38 molar equivalents) is added at 0 ° C. After 4.5 h of stirring at room temperature, the medium is acidified with 1N HCl, extracted with ethyl acetate, dried (Na 2 SO 4), concentrated and purified on silica gel (35:65 ethyl acetate-cyclohexane. ) to yield 10 (3.4 g, 83%). Mass spectrum (ESI) m / z 800.2 [(M + Na) *]. Step 2.d: Preparation of (Benzyl 2,4-di-O-acetyl-3-O-benzyl-aL -idopyranosyluronate) - (1-4) - (6-O-acetyl-2-azydo-3 -O-benzyl-2-deoxy-a.β-D -glucopyranose trichloroacetimidate) (n ° 11) To a solution of compound 10 (3.38 g, 4.35 mmol) obtained in step 2.c, in dichloromethane (82 mL), cesium carbonate (Cs2CO3) (2.26 g, 1.6 molar equivalent), and trichloroacetonitrile (CCI3CN) (1.74 mL, 5.0 molar equivalent) are added under argon. After 1.5 h of stirring, the reaction mixture was Fillra and concentrate. The residue is purified on silica gel (3: 7 ethyl-cyclohexane acelate) to provide 11 (2.96 g, 74%). 1 H NMR (CDCl 3) d 6.43 (d, H-1 to Glc '), 5.64 (d, H-1 ß Glc1), 5.17 (d, IdoUA ").

Preparation 3: If n thesis of (3-O-benzyl-2,4-d? -O-sod? Or sulfonate-aL-idopyrano-s-iluronate sodium) - (1-4) - (2-acetamido) -3-O-benzyl-2-deoxy-6-O-sulphonate-aDg Icopyranos i I) - (1-4) - (3-O-benzyl-2-O-sc • gave its Ifone sodium alkylsulphonate) - (1-4) - (2-acetamido-3-O-benzyl-2-deoxy-6-O-sodium sulfonate-aD-glucopyranos Üb 1-4; - (5- (l enci I oxy) -4-oxi pi pe rid i n-1 -carboxi lato Step 3.a: Preparation of (benzyl 2,4-di-O-acetyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-azido-3-O-benzyl) -2-deoxy-aD-glucopyranosyl) - (1-4) - (benzyl 2-O-acetyl-3-O-benzyl-aL -idopyranosyluronate) - (1-4) - (1,6-anhydro-2-) azido-3-O-benzyl-2-deoxy-β-D-glucopyranose) (n ° 12) Compound 11 (455 mg, 0.50 mmol) obtained in step 2.d and the compound 8 (675 mg, 1 mmol) obtained in step 2.a are treated according to method 2 to provide, after purification, compound 12 (385 mg, 54%). Mass Spec (ESI) m / z 1.457.6 [(M + Na) +]. Step 3.b: Preparation of (benzyl 2,4-di-O-acetyl-3-O-benzyl-aL -dopyranosyluronate) - (1-4) - (6-O-acetyl-2-azido-3- O-benzyl-2-deoxy-aD-glucopyranosyl) - (1-4) - (benzyl 2-O-acetyl-3-O-benzyl-L-idopyranosyluronate) - (1-4) - (1,6 -di-O-acetyl-2-azido-3-O-benzyl-2-deoxy-a.β-D-glucopyranose) (n ° 13) Compound 12 (365 mg, 0.254 mmole) obtained in step 3. a, is treated as for the synthesis of compound 9 (step 2.b) to yield, after purification on silica gel (1: 1 Et 2 O -diopropyl ether), 13 (376 mg, 97%). Mass spectrum (ESI) m / z 1.560.7 [(M + Na) +]. Step 3.c: Preparation of (benzyl 2,4-di-O-acetyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-azido-3-O -benzyl-2-deoxy-aD-glucopyranosyl) - (1-4) - (benzyl 2-Oa cetyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2 -azido-3-O-benzyl-2-deoxy-a, β-D-glucopyranose) (n ° 14) Compound 13 (364 mg, 0.237 mmol) obtained in step 3.b is treated as for the synthesis of compound 10 (elapa 2.c) to yield, after purification on silica gel (7: 3). diisopropyl), compound 14 (310 mg, 87%). Mass spectrum (ESI) m / z 1.518.8 [(M + Na) +]. Step 3.d: Preparation of (benzyl 2,4-di-O-acetyl-3-O-benzyl-aLi dop iran osiluronate) - (1-4) - (6-O-acetyl-2-azido-3- O -be nc il-2-deoxy-aD-glucopyranosyl) - (1-4) - (benzyl 2-O-acetyl-3-O-benzyl-aL-idopyranosyluronate) - (1-4) - (6-O -acetyl-2-azido-3-O-benzyl-2-deoxy-a, ß-D-glucopyranose trichloroacetimidate) (n ° 15) Compound 14 (279 mg, 0.187 mmole) available in elapa 3.c, is prepared as for the synthesis of compound 11 (step 2.d), to provide, after purification on silica gel (1: 1 Et 2 O - diisopropyl ether), 15 (230 mg, 75%). Mass spectrum (ESI) m / z 1660.6 [(M + Na) +]. Step 3.e: Preparation of (benzyl 2,4-di-O-acetyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-azydo-3-O -benzyl-2-deoxy-aD -glucopyranosyl) - (1-4) - (benzyl 2-O-acetyl-3-O-benzyl-aL -dopyranosyluronate) - (1-4) - (6-O-acetyl) L-2-azido-3-O-benzyl-2-deoxy-aD-gl ucop i ranks i I) - (1-4) - (5- (benzyloxy) -4-oxy piper id i n- 1,3-dibenzyl dicarboxylate (3S.4R.5R)) (n ° 16) Compounds 15 (217 mg, 0.122 mmol) obtained in step 3.d, and 6 (126 mg, 0.264 mmol) obtained in step 1 .e, were brought according to METHOD 2 to provide, after purification, compound 16 (168 mg, 66%).

Mass Species (ESI) m / z 1,976.0 [(M + Na) +]. Step 3.f: Preparation of (benzyl 2,4-di-O-acetyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-acetamido-3-O -benzyl-2-deoxy-aD-lucopyranosyl) - (1-4) - (benzyl 2-O-acetyl-3-O-benzyl-aL-idopyranosyluronate) - (1-4) - (6-O-acetyl- 2-acetamido-3-O-benzyl-2-deoxy-aD-glucopyranosyl) - (1-4) - (5- (benzyloxy) -4-oxo-piperidin-1,3-dicarboxylic acid dibenzyl ester (3S, 4R, 5R)) ( n ° 17) Compound 16 (138.5 mg, 70.9 μmol) obtained in step 3.e, is dissolved in pyridine (1.16 mL), and iodolelic acid (1.14 mL, 225 equivalents) is added. molars) at 0 ° C. The reaction medium is stirred for 14 h at ambient temperature, concentrated and purified on silica gel (3: 2 cyclohexane-ethyl acetate) to yield compound 17 (118 mg, 84%). Mass spectrum (ESI) m / z 2.007.7 [(M + Na) +]. Step 3.g: Preparation of (3-O-benzyl-α-idopyranosyluronic acid) - (1-4) - (2 -acetamido -3-OI-benzyl-2-deoxy-aD-glucopyranosyl) - 1 • 4) - (3-O-benzyl-L-butyranosyl-uronic acid) - (1-4) - (2-acetamyl-3-O-benzyl-2-d-oxoxy-aD-lucopiranes I-1-4-4) - ( 5- (benzyloxy) -4-oxypiperidin-3-carboxylic acid-1-benzylcarboxylate (3S.4R.5R)) (n ° 18) Compound 17 (101 mg, 50.9 μmol) obtained in the country 3. f, is evaporated according to METHOD 3, the reaction medium is acidified with 6N hydrochloric acid (pH 1), and extracted with dichloromethane. The organic phase is washed with 5% sodium sulphite (Na 2 SO 3), and with water. After drying, filter and concentrate, the rest is applied in gross in the next stage. Mass spectrum (ESI) m / z 1 .505.6 [(M + H) +]. Step 3.h: Preparation of (3-O-benzyl-2,4-di-O-sodium sulfonate-a-ido-phenyls, sodium iluronate) - (1-4) - (2-acetamido-3-O-benzyl) -2-deoxy-ß-O-sodium ss-phonate-aDg I ucopiranos i I) - (1 -4) - (3-O-benzyl-2-O-sodium sulfonate-aL-idopyranosyluronate sodium) - (1 -4) - (2-acetamido-3-O-benzyl-2-deoxy-6-O-sodium sulfonate-aDg I ucopiranos i I) - (1 -4) - (5- (benzyloxy) -4- oxipiperid i n-1 -carboxylate of sodium benzyl-3-carboxylate (3S, 4R, 5R)) (n ° 19) The crude compound 18 obtained in step 3.g, is treated according to M ETHOD 4, for provide compound 19 (50 mg, 54% (2 steps)). Mass Spectrum (ESI) m / z 2.014 [(M-3Na + 3H) "] Preparation 4: Synthesis of sodium (3-O-benzyl-2,4-di-O-sodium sulfonate-aL-idopyranosyluronate) - (1 -4) - (3-O-benzyl-2-deoxy-2-N-sodium sulfonate-6-O-sodium s ulfonate-aDg I ucopiranos i I) - (1-4) - (3- O-benzyl-2-O-sodium sulfonate-al-idopyranosyluronate sodium) - (1 -4) - (3-O-benzyl-2-deoxy-2-N-sodium sulfonate-6-O-sodium sulfonate-aD -glucopyranosyl) - (1-4) - (5- (benzyloxy) -4-oxypiperidin-1-benzyl-3-carboxylic acid carboxylate (3S, 4R. 5R)) (No. 26) 16 to) 24 C) 26 sodium salt Step 4. a: Prep arac tion of (acid 3-O-benzyl-α-idopyranos iluronic) - (1-4) - (2-azide o-3-O-benzyl-2-d esoxi-aD-glucopyri-ranosyl) - (1-4) - (3-0-benzyl laL- • idopi-ranosiluronic acid) - (1-4) - (2-azi-do-3-O-benzyl-2-d) ? esoxi -aDg lucoi pyranosyl) - (1-4) - (5- (benzyloxy) -4-oxypiperidi n-1-carboxylate of sodium benzyl-3-carboxylate (3S.4R.5R)) (n ° 24) Compound 16 (175 mg, 89.6 μmol) obtained in step 3.e, was prepared according to METHOD 3, and the reaction medium is acidified with 6N hydrochloric acid (pH 2). The mixture is purified on a Sephadex0 LH-20 column (1: 1 dichloromethane-ethanol), to yield compound 24 (100 mg, 76%). Mass Spec (ESI) m / z 1474.1 [(M + H) +]. Step 4.b: Preparation of (3-O-benzyl-α-L-p-ypiranosyluronic acid) - (1-4) - (2-amino-3-O-benzyl-2-deoxy-aD-glucopyranosyl) - (1- 4) - (3-O-benzyl-α-idopyranosyluronic acid) - (1-4) - (2-amino-3-O-benzyl-2-deoxy-aD-glucopyranosyl) - (1-4) - (5) benzyl-3-carboxylic acid (benzyloxy) -4-oxypiperidine-1-carboxylate (3S.4R.5R)) (n ° 25) To a solution of compound 24 (35 mg) obtained in step 4.a, in a 1: 1 mixture meianol-felrahydrofuran (1 mL), a 10% Pd / C / ethylenediamine complex prepared according to the method described in H. Sajiki et al., J. Org. Chem. (1998), Vol.63, p. 7990-7992) (107 mg). The medium is placed under H2 pressure (3 bar) at room temperature for 16 h. After filtering and concentrating, the reaction product is reacted again under the same conditions, purified on silica gel (ethyl acetate-pyridine-acetic acid-water, 6: 2: 0.6: 1) to yield the compound 25 (12 mg, 44%). Mass spectrum (ESI) m / z 1421.4 [(M + H) +]. Step 4.c: Preparation of sodium (3-O-benzyl-2,4-di-O-sodium sulfonate-α-idopyranosyluronate) - (1-4) - (3-O-benzyl-2-deoxy-2) -N-Sodium Sulfonate-6-O-Sodium Sulfonate-aDg Icopyrins il) - (1-4) - (3-O-benzyl-2-O-sodium sulfonate-aL-idopyranosyluronate sodium) - (1-4) - (3-O-benzyl-2-deoxy-2-N-sc • sulfone to-6-O-sodium sulfonate -aD -qi ucopyranosyl il) -d -4) - (5- (benzyloxy) -4-oxypipyridin-1-carboxyl-ato-benzyl-3-carboxylate sodium (3S, 4R, 5R)) ín ° 26) The compound 25 (8.5 mg, 5.98 μmol) obtained in the stage 4. b, is treated according to method 4, to provide compound 26 (7 mg, 56%). Mass Spec (ESI) m / z 2.133.8 [(M-H) ']. Preparation 5: Synthesis of (Benzyl 2-O-acetyl-4-O-levulinoyl-3-O-methi-aL-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- (3- Bromo-4-methoxy) -benzyl-3-O-methyl-a, β-D-glucopyranose tri-chloroacetimide) (n ° 40) 28 29 30 31 38 39 40 Step 5.a: Preparation of 1,6-anhydro-4-O- (tetrahydropyran-2-yl) -2-O- (4-methoxy) benzyl-β-D-glucopyranose (No. 29) To a solution of compound 28 (41 g, 180 mmol) (prepared according to H. Paulsen and W. Síenzel, Chem. Ber. (1978) 111, 2348-57) in para-methoxybenzyl alcohol (25 mL, 1.1 equivalents molars) is added, at 40 ° C, sodium (1.37 g, 0.33 molar equivalents). The reaction mixture is brought to 110 ° C for 20 min, methanol (20 mL) is added at 0 ° C, and agitation is maintained 16 h at room temperature. After concentrating, a purification on silica gel (3: 7 elophyl ether diisopropyl ether) yields 29 (20.1 g, 31%). Mass spectrum (ESI) m / z 384.2 [(M + Na) +]. Step 5.b: Preparation of 116-anhydro-4-O- (tetrahydropyran-2-yl) -2-O- (4-methoxy) benzyl-3-O-methyl-β-D-glucopyranose (# 30) To a solution of compound 29 (13.1 g, 35.8 mmol) obtained in step 5.a, in dimethylformamide (107 mL) are added successively, at 0 ° C and under argon, methylene iodide (2). , 67 mL) and sodium hydride (2.68 g). After returning to ambient temperature, the reaction mixture is stirred for 16 h, melanol is added at 0 ° C, the medium is extracted with ethyl acetate, dried (Na 2 SO 4), filtered and concentrated to yield 30 which is directly applied. in the next day. Mass spectrum (ESI) m / z 403.3 [(M + Na) +]. Step 5.c: Preparation of 1,6-anhydro-2-O- (4-methoxy) benzyl-3-O-methyl-β-D-glucopyranose (# 31) To a solution in methanol (143 mL) of the composite 30, obtained in step 5.b, a 0.25 M methanolic solution is added of camphorsulfonic acid (CSA) (1 mole equivalent). After 30 min of magnetic stirring, the medium is diluted with dichloromethane, washed with water, with a 2% aqueous solution of sodium hydrogencarbonate, with water, dried (Na 2 SO 4), filtered and concentrated. Purification on silica gel (3: 7 ethyl acetate-cyclohexane) yields compound 31 (9.0 g, 85%). Mass spectrum (ESI) m / z 319.1 [(M + Na) +]. Step 5.d: Preparation of ethyl 2-O-acetyl-4,6-O-isopropylidene-3-O-methyl-1-thio-a.β-L-idopyranoside (No. 33) To a solution of the crude compound 32 ( 1.99 g, 7.1 mmol) (prepared according to P. Duchaussoy er al., Carbohydr. Res. (1999), 317, 63-84) in dichloromelane (37 mL) are added successively, at 0 ° C, under argon, triethylamine (2.2 mL), DMAP (173 mg), and acetic anhydride (1.34 mL). The temperature is maintained at 0 ° C for 10 minutes, and the reaction medium is set at room temperature for 16 hours. The reaction mixture is concentrated in vacuo, and the residue is purified on silica (1: 1 Et2O-cyclohexane) to give compound 33 (2.1 g, 92%). Mass spectrum (ESI) m / z 343.3 [(M + Na) +]. Step 5.e: Preparation of (2-O-acetyl-4,6-O-isopropylidene-3-O-methyl-a-L- -idopyranosyl) - (1-4; | - (1,6-anhydro-2- O- (4- metoo xi) benzyl-3-O-methyl-P-D-glucopyranose) (n 34a) V (2-O- -acetyl-4,6-O-isopropyl-3-O-methyl- ß- L -idopi ranosil) - (1 -4) - (1, 6- an hydro-2-O- (4-methoxy) benzyl-3-O-methyl-β-D-glucopyranose) (n ° 34ß) To a mixture under argon of compound 33 (1.86 g, 5.79 mmoles) obtained in step 5.d, and of compound 31 (1.46 g, 4.94 mmoles) obtained in step 5.c, in the presence of 4 Á molecular sieve (2.89 g) in toluene (50 mL) is added, at -20 ° C, a solution of? / - iodosuccinimide (1.38 g), and of trifluoromethanesulfonic acid (63, 5 μL) in a 1: 1 mixture of dichloromethane-dioxane (16.5 mL). After 45 min of agitation, solid sodium hydrogencarbonate is added to the reaction medium, and after filtration the mixture is diluted with dichloromethane, washed with an aqueous solution of sodium thiosulphonate (Na2S2O3) at 10%, and an aqueous solution of sodium chloride saíurada. After drying and concentrating, the resin is applied directly in the next step. Mass Species (ESI) m / z 577.4 [(M + Na) +]. Step 5.f: Preparation of (2-O-acetyl-3-O-methyl-α-idopyranosyl) - (1-4) - (1,6-anhydro-2-O- (4-methoxy) benzyl-3 -O-methyl-β-D-glucopyranose) (No. 35a), and (2-O-acetyl-3-O-methyl-β-L-idopyranosyl) - (1-4) - (1,6-anhydrous) -2-O- (4-methoxy) benzyl-3-O-methyl-β-D-glucopyranose) (n ° 35β) To a solution of the mixed compound 34D and 34D obtained in step 5.e, in dichloro-1 , 2-ethane (12 mL), 70% acrylic acid (55 mL) is added. The mixture is heated at 60 ° C for 50 min, concentrated in vacuo and the residue purified on silica gel (3: 2 loluene-acetone) to yield the 35D compound (1.56 g, 61%, two layers). ), and the compound 35D (0.36 g, 14%, two eiapas). Mass Spec (ESI) m / z 537.5 [(M + Na) +]. Step 5.g: Preparation of (Benzyl 2-O-acetyl-3-O-methyl-a-L- idopyranosyluronate) - (1-4) - (1,6-anhydro-2-O- (3-bromo-4-methoxy) benzyl-3-O-methyl-β-D-glucopyranose) (n ° 36) The compound 35 D (0.975 g, 1.89 mmol) obtained in step 5f, is treated according to METHOD 1 to yield, after purification on silica gel (1: 1 acid-cyclohexane acrylate), compound 36 (1.09 g, 83%). 1 H NMR (CDCl 3) D 7.54-6.86 (m, 8H, Ar). Step 5.h: Preparation of (Benzyl 2-O-acetyl-4-O-levulinoyl-3-O-methyl-aL-idopyranosMuronate) - (1-4) - (1,6-anhydro-2-O- ( 3-bromo-4-methoxy) benzyl-3-O-methyl-β-D-glucopyranose) (n ° 37) To a solution under argon of compound 36 (1.09 g, 1.56 mmole) available in the bottle 5.g, in dioxane (35 mL) are added successively DMAP (43 mg, 0.2 molar equivalent), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (0.675 g, 2 molar equivalent), and levulinic acid (0.361 mL, 2 mole equivalents), and after 16 h of agitation, the reaction medium is washed successively with a solution of hydrosulphide of polasium (KHSO4) 10%, with water, with 2% sodium hydrogencarbonate, then the solution is dried (Na2SO4), filtered and concentrated to yield a residue which is purified on silica gel (ethyl acetate-dichloromene 2: 3) which yields the compound 37 (1.07 g, 86%) . Mass Species (ESI) m / z 819.4 [(M + Na) +]. Step 5.i: Preparation of (Benzyl 2-O-acetyl-4-O-levulinoyl-3-O-methyl-α-idopyranosyluronate) - (1-4) - (1,6-di-O-acetyl-2) -OR- (3- bromo-4-methoxy) benzyl-3-O-methyl-a, β-D-glucopyranose) (n ° 38) Compound 37 (1.07 g, 1.34 mmol) obtained in step 5.h, It was used as for the syn- thesis of compound 9 (step 2.b), to yield, after purification on silica gel (ethyl acetate-dichloromethane 2: 3), compound 38 (1.04 g, 87%). Mass spectrum (ESI) m / z 921.4 [(M + Na) +]. Step 5.: Preparation of (Benzyl 2-O-acetyl-4-O-levulinoyl-3-O-methyl-aL-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- ( 3-bromo-4-methoxy) benzyl-3-O-methyl-a.β-D-glucopyranose) (n ° 39) The compound 38 (1.04 g, 1.16 mmol) obtained in the step . i, was brought as for the synthesis of compound 10 (elapa 2.c), to provide, after purification on silica gel (ethyl acetate-dichloromethane 1: 1), the compound 39 (740 mg, 74%). Mass Species (ESI) m / z 877.3 [(M + Na) +]. Step 5.k: Preparation of (Benzyl 2-O-acetyl-4-O-levulinoyl-3-O-methyl-aL -dopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- (3-bromo-4-methoxy) benzyl-3-O-methyl-α, β-D-glucopyranose trichloroacetimidate) (No. 40) The compound 39 (740 mg, 860 μmol) obtained in step 5.j, was It appeared as for the syn- thesis of compound 11 to yield, after purification on silica gel (ethyl acetate-dichloromethane 3: 7), compound 40 (714 mg, 83%). 1 H NMR (CDCl 3) d 6.39 (d, H-1a Glc1), 5.76 (d, H-1β Glc1). PREPARATION 6: Synthesis of (3-O-m ethyl -2,4-di-O-sodium sulfonate-a-L- sodium idopyranosyluronate) - (1 -4) - (3-O-methyl-2,6-di-O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (3-O-methyl-2-O-sodium sodium sulfonate-al-idopyranosyluronate) - (1-4) - (3-O-methyl-2,6-di-O-sodium sulfonate-aD-gl ucopi ranosi I) - (1-4) - (5- ( benzyloxy) -4-oxypiperidin-1-benzyl-3-carboxylic acid carboxylate (3S, 4R, 5R)) (compound n ° 46) 43 44 0u Hn, J - OUHH CCOOOOHH e) 46 sodium salt Step 6.a: Preparation of (benzyl 2-O-acetyl-4-O-levulinoyl-3-O-methyl-aL-idopyranosyluron ato) - (1-4) - (6-O-acetyl-2-O- (3-b rom Q-4-methoxy) benzyl-3-O-methyl-aD-glucopyranosyl) - (1-4) - (5- (benzyloxy) -4- Q dibenzyl oxypiperidin-1,3-dicarboxylate (3S.4R.5R)) (n ° 41) A mixture of compound 40 (94 mg, 0.094 mmol, 1.0 molar equivalent) obtained in step 5.k, and of compound 6 (111 mg, 0.234 mmol, 2.5 molar equivalents) obtained in step 1.e, was brought according to METHOD 2 to yield, after purification on Sephadex0 column LH-20, and on silica gel (dichloromethane) - ethyl acetyl 9: 1), compound 41 (62 mg, 50%).

Mass Spec (ESI) m / z 1.336.5 [(M + Na) +]. Step 6.b: Preparation of (benzyl 2-O-acetyl-3-O-methyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- (3-bromo-4- m ethoxy) benz I -3-O-methyl-aDg I upipiranos i I - (1-4) - (5- (benzyloxy) -4-oxypiperdin-1,3-dicarboxylate dibenzyl (3S, 4R.5R)) (n ° 42) To a solution of compound 41 (60 mg, 45.7 μmol) obtained in step 6.a, in a mixture 1: 2 toluene / ethanol (9 mL) is added acetate of hydrazine (21 mg, 10 molar equivalents). After 3h of magnetic stirring, the mixture is concentrated in vacuo and the remainder is diluted with dichloromethane, washed with a 2% sodium hydrogencarbonate solution, with water, and the organic phase is dried (Na2SO4), filtered and concentrate The residue is purified on silica gel (ethyl acetate-cyclohexane 3: 2) to yield compound 42 (48 mg, 88%). Mass spectrum (ESI) m / z 1.238.5 [(M + Na) +]. Step 6.c: Preparation of (benzyl 2-O-acetyl-4-O-levulinoyl-3-O-methyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- ( 3-bromo-4-methoxy) benzyl-3-O-methyl-aD-gl ucopi ranosyl) - (1-4) - (benzyl 2-O- acetyl-3-O-methyl-aL-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- (3-bromo-4-methoxy) benzyl-3-O-methyl-aD-glucopyranosyl ) - (1-4) - (5- (benzyloxy) -4-oxypiperidine-1,3-dicarboxylic acid dibenzyl ester (3S, 4R, 5R)) (n ° 43) A mixture of compound 40 (197.7 mg, 197, 7 μmol, 1.14 molar equivalents) obtained in step 5.k, and of compound 42 (210.5 mg, 173.2 μmol, 1.0 molequiv.) Obtained in step 6.b, was brought according to the Method 2 to yield, after purification on a Sephadex0 LH-20 column, and on silica gel (toluene-acetone 1: 1), compound 43 (176 mg, 50%). Mass spectrum (ESI) m / z 2.075.0 [(M + Na) +]. Step 6.d: Preparation of (Benzyl 2-O-acetyl-4-O-levulinoyl-3-Om ethyl-aL-ido pyran osylidenate) - (1-4) - (6-O-acetyl-3) -O-methyl-aD -gl ucop ira nosil) - (1-4) - (benzyl 2-O-acetyl-3-O-methyl-aL-idopyranosyluronate) - (1-4) - (6-O-acetyl) -3-O-methyl-aD-glucopyranosyl) - (1-4) - (5- (benzyloxy) -4-oxypiperidine-1,3-dicarboxylic acid dibenzyl ester (3S, 4R, 5R)) (No. 44) A a solution of compound 43 (69 mg, 33.6 μmol) obtained in step 6.c, in aceionitrile (3 mL), is added, at 0 ° C and under an argon atmosphere, zirconium tetrachloride (ZrCl4) (39 mg, 5 molar equivalents). After 45 min of stirring at ambient temperature, the mixture is concentrated in vacuo, and the remainder is diluted with ethyl acetate, washed with water and after drying, filtering and concentrating, the residue is purified on silica gel (3). : 7 acetone-toluene) to yield compound 44 (52 mg, 89%).

Mass spectrum (ESI) m / z 1.676.7 [(M + Na) +]. Step ß.e: Preparation of (3-O-methyl-aL-id opyranosyluride or co) - (1-4) - (3-Om ethyl -aDg luco piran os il) - (1-4) - (acid 3-O-meti la-idopiranos ilu ron ico) - (1-4) - (3-O-methyl-aD-l ucopi ranosi I) - (1-4) - (5- (benzyloxy) -4- Oxypiperidine-1-benzyl-3-carboxylic acid carboxylate (3S.4R, 5R)) (n ° 45) Compound 44 (18 mg, 11 μmol) obtained in step 6.d, is treated according to METHOD 3 for yield, after purification, compound 45 (5.8 mg, 47%) which may be partially purified in the carboxylic acid groups. Mass spectrum (ESI) m / z 1.118.4 [(M + H) +]. Step 6.f: Preparation of sodium (3-O-methyl-2,4-di-O-sodium sulfonate-α-idopyranosyluronate) - (1-4) - (3-O-methyl-2,6-di-O -sodiumsulphonate-aDg I ucopiranos i I) - (1-4) - (3-O-methyl-2-O-sodium sulfonate-aL-idopyranosyluronate of hatred) - (1-4) - (3- O -meti 1-2.6 -di -O-sodium-a-bis-a-d-Icopi-ranosi I) - (1-4) - (5- (benzyloxy) -4-oxypiperidin-1-benzyl-3-carboxylate sodium carboxylate (3S, 4R, 5R)) (n ° 46) Compound 45 (7 mg, 6.26 μmol) obtained in elapa 6.e, is prepared according to METHOD 4 to yield, after purification, compound 46 ( 10 mg, 77%) which may be partially spherified in the carboxylic acid groups. Mass Spec (ESI) m / z 1897.0 [(M + Na-H) +]. Preparation 7: Synthesis of (Benzyl 2-O-acetyl-4-O-levulinoyl-3-O-benzyl-a-L- idopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- (4-methoxy) benzyl-3-O-benzyl-a.β-D-glucopyranose trichloroacetimidate) (n ° 57) 48 49 50 51 52 53 54 55 56 57 Step 7.a: Preparation of 1,6-anhydro-4-O- (tetrahydropyran-2-yl) -2-O- (4-methoxy) benzyl-3-O-benzyl-β-D-glucopyranose (n °) 48) To a solution of 29 (19.96 g, 54.5 mmol) obtained in step 5.a, in DMF (300 mL) is added, at 0 ° C, benzyl bromide (5.1 mL), and sodium hydride (4.6 g). At the end of the addition, the mixture is placed at ambient temperature for 16 h, methanol (18 mL) is added at 0 ° C, and after 1 h of stirring at room temperature, the medium is diluted with ethyl acetate (600 mL) , washed with water (300 mL), dried (Na2SO), filtered and concentrated. The resin is purified by means of flash chromalography (5:95 ethyl acetate - ether diisopropyl), to provide 48 (20.6 g, 83%). Mass Spec (ESI) m / z 479.3 [(M + Na) +]. Step 7.b: Preparation of 1,6-anhydro-2-O- (4-methoxy) benzyl-3-O-benzyl-β-D-glucopyranose (n ° 49) Compound 48 (20.6 g, , 2 mmole) obtained in the stage 7. a, it was brought as for the synisis of compound 31 (step 5.c), to yield, after purification on silica (3: 7 ethyl acetate-cyclohexane), 49 (14.4 g, 86%). Mass Species (ESI) m / z 395.4 [(M + Na) +]. Step 7.c: Preparation of (2-O-acetyl-4,6-O-isopropylidene-3-O-benzyl-a.β, L-idopyranosyl) - (1-4) - (1,6-anhydro- 2-O- (4-methoxy) benzyl-3-O-benzyl-β-D-glucopyranose) (n ° 51) The compound 50 (prepared according to the method described by C.

Tabeur et al. for the 2-O-benzoyl derivative, Carbohydr.Res. (1996), 281, 253-276) (16.91 g, 42.6 mmoles) and the compose 49 (14.44 g, 38.8 mmoles) obtained in elapa 7.b, are reacted as for the synthesis of 34 (step 5 e), to yield, after purification on silica (15:85 ethyl acetate - diisopropyl ether) compound 51 (17.05 g, 62% (56% alpha-L)). Mass spectrum (ESI) m / z 729.3 [(M + Na) +]. Step 7.d: Preparation of (2-O-acetyl-3-O-benzyl-α-idopyranosyl) - (1-4) - (1,6-anhydro-2-O- (4-methoxy) benzyl-3 -O-benzyl-B-D-glucopyranose) (n ° 52) Compound 51 (12.38, 17.51 mmol) obtained in step 5.c, is treated as for the synthesis of 35 (step 5.f ) for provide, after purification on silica (4: 1 toluene-acetone), 52 (10.85 g, 93%). Mass spectrum (ESI) m / z 689.3 [(M + Na) +]. Step 7.e: Preparation of (Benzyl 2-O-acetyl-3-O-benzyl-aL-id opiranos iluronate) - (1-4) - (1,6-anhydro-2-O- (4- m ethoxy) benz I-3-O-benzyl-β-D-glucopyranose) (n ° 53) Compound 52 (10.85 g, 16.27 mmol) obtained in step 7.d is treated according to the METHOD 1 to yield, after purification on silica gel (3: 7 acetone-cyclohexane), 53 (8.44 g, 61%). Mass spectrum (ESI) m / z 793.3 [(M + Na) +]. Step 7.f: Preparation of (Benzyl 2-O-acetyl-3-O-benzyl-4-O-levulinoyl-β-L-idopyranosyluronate) - (1-4) - (1,6-anhydro-2-O - (4-methoxy) benzyl-3-O-benzyl-β-D-glucopyranose) (n ° 54) Compound 53 (3.2 g, 3.77 mmol) obtained in step 7.e, is treated as for the synthesis of 37 (step 5.h), to provide 54 (3.17 g, 89%) after purification on silica (acetone-uencene 1: 4). Mass Species (ESI) m / z 891.3 [(M + Na) +]. Step 7.g: Preparation of (Benzyl 2-O-acetyl-4-O-levulinoyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (1,6-di-O-acetyl) -2-O- (4-methoxy) benzyl-3-O-benzyl-a, β-D-glucopyranose) (n ° 55) Compound 54 (1.45 g, 1.53 mmol) obtained in the bottle 7. f, it will be as for the synosphesis of 9 but at 0 ° C it lasts 1 h to yield, after purification on silica (lolueno - acelona 85:15), 55 (1.25 g, 78%). Mass Species (ESI) m / z 993.3 [(M + Na) +]. Step 7.h: Synthesis of (Benzyl 2-O-acetyl-4-O-levulinoyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- ( 4-methoxy) benzyl-3-O-benzyl-a, β-D-glucopyranose) (n ° 56) Compound 55 obtained in step 7.g, is as for the syn- losis of 10 (step 2.c) , to yield, after purification on silica (diethyl ether-dichloromethane 25:75), 56 (429 mg, 56%). Mass spectrum (ESI) m / z 951.3 [(M + Na) +]. Step 7. i: Preparation of (Benzyl 2-O-acetyl-4-O-levulinoyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- ( 4-methoxy) benzyl-3-O-benzyl-a, β-D-glucopyranose trichloroacetimidate) (n ° 57) Compound 56 (429 mg, 426 μmol) obtained in efapa 7.h, is treated as for synthesis of 11 (step 2.d) to provide, after purification on silica (elilocephalus-cyclohexane 1: 1), derivative 57 (396 mg, 80%). H NMR (CDCl 3) D 6.45 (d, H-1D), 5.89 (d, H-1D). Preparation 8: Preparation of (Benzyl 2-O-acetyl-4-O-allyl-3-O-benzyl-aL -dopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- (4 -methoxy) benzyl-3-O-benzyl-a.β-D-glucopyranose trichloroacetimidate) (No. 62) 60 61 62 Step 8.a: Preparation of (Benzyl 2-O-acetyl-4-O-allyloxycarbonyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (1,6-anhydro-2-) O- (4-methoxy) benzyl-3-O-benzyl-β-D-glucopyranose) (n ° 58) To a solution of 53 (0.800 g, 0.9414 mmol) obtained in step 7.e, in THF (9.4 mL) are added, at 0 ° C and under argon atmosphere, pyridine (759 μL, 9.41 mmol), DMAP (115 mg, 0.94 mmol), and allyl chloroformate (995 μL, 9.41 mmol) in THF solution (2.35 mL). Stirring is maintained overnight, the reaction mixture is diluted with ethyl acetate, washed with 10% KHSO, with 2% sodium hydrogencarbonate, with water, dried (Na2SO), filtered and concentrated. The residue is purified by flash chromatography (1: 9 acetone-toluene) to give 58 (0.809 g, 92%). Mass spectrum (ESI) m / z 877.3 [(M + Na) +]. Step 8.b: Preparation of (Benzyl 2-O-acetyl-4-O-allyl-3-O-benzyl-α-idopyranosoluronate) - (1-4) - (1,6-anhydro-2-O) - (4-methoxy) benzyl-3-O-benzyl-β-D-glucopyranose) (n ° 59) To a solution in THF (6 mL) of compound 58 (0.805 g, 0.862 mmol) in step 8. a, palladium diacetate (3.9 mg, 0.017 mmol) and triphenylphosphine (22.6 mg, 0.086 mmol) are successively added under an argon atmosphere. The temperature of the The mixture is brought to 90 ° C for 15 min, the medium is concentrated in vacuo and purified on silica (15:85 acetylene-íoluene) to yield 59 (0.587 g, 66%). Mass Spec (ESI) m / z 833.4 [(M + Na) +]. Step 8.c: Preparation of (Benzyl 2-O-acetyl-4-O-allyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (1,6-di-O-acetyl-2-O - (4-methoxy) benzyl-3-O-benzyl-a.β-D-glucopyranose) (n ° 60) Compound 59 (0.587 g, 0.660 mmole) available in step 8.b, is ready as for synthesis of compound 55 (step 7.g), to provide, after purification on silica (9: 1 acetone-toluene), 60 (0.37 g, 57%) Mass spectrum (ESI) m / z 936.4 [(M + Na) +]. Step 8.d: Preparation of (Benzyl 2-O-acetyl-4-O-allyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- ( 4-methoxy) benzyl-3-O-benzyl-a, β-D-glucopyranose) (n ° 61) The compound 60 obtained in step 8.c, is prepared as for the synthesis of 10 (step 2.c) , to yield, after purification on silica (cyclohexane-ethyl acetate 2: 3), 61 (240 mg, 70%). Mass spectrum (ESI) m / z 893.4 [(M + Na) +]. Step 8.e: Preparation of (Benzyl 2-O-acetyl-4-O-allyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- ( 4-methoxy) benzyl-3-O-benzyl-a.β-D-glucopyranose trichloroacetimidate) (n ° 62) Compound 61 (234 mg, 246 μmol) obtained in the step 8. d, it is treated as for the synthesis of 11 (step 2.d), to provide, after purification on silica (86:14 acetone - toluene), derivative 62 (249 mg, 93%). 1 H NMR (CDCl 3) d 6.40 (d, H-1a), 5.81 (d, H-1β). The synthesis of PREPARATIONS 9 and 10 can be schematized as follows: d) h) fOfic OAc COOBn r- ° A 'fMc COOBn OAc OH OAc OH OAc OAc OH 66 71 e) 72 68 sodium salt 73 sodium salt Preparation 9: Synthesis of I (sodium 3-O-benzulfonate-aL-idopyranosyluronate) - (1-4) - (3-O-benzyl-2,6-di-O- sodium sulfonate-aD-glucopyranosyl) - (1-4) - (3-O-benzyl-2-O-sodium sulfonate-aL-idopyranosyluronate sodium) - (1-4) - (3-O-benzyl-2.6- di-O-sodium sulfonate-a-D-gl ucopi ranosi I) - (1-4) - (5- (benzyl oxy) -4-oxypiperidine-1-carboxylate sodium benzyl-3-carboxylate (3S. 4R.5R)) (n ° 68) Step 9.a: Preparation of (benzyl 2-O-acetyl-4-O-levulinoyl-3-O-benzyl-aL-idopi ranosi I uronate) - (1-4) - (6-O-acetyl-2-O - (- 4-methoxy) benzyl-3-O-benzyl-aD-glucopyranosyl) - (1-4) - (5- (benzyloxy) -4-oxypiperidine- 1,3-dibenzyl dicarboxylate (3S.4R, 5R)) (n ° 63) Compound 57 (396 mg, 0.34 mmol) obtained in step 7. i, and compound 6 (405 mg, 0.85 mmol) obtained in step 1.e, are treated according to METHOD 2 to yield, after purification, 63 (369 mg, 73%). 1 H NMR (CDCl 3) ü 5.29 (d, H-1 Glc "), 5.13 (d, H-1 IdoUA 1"). Step 9.b: Preparation of (benzyl 2-O-acetyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- (4-methoxy) benzyl- 3-O-benzyl-α-D-Icopyridyl) - (1-4) - (5- (benzyloxy) -4-oxypipe dibenzyl-1,3-dicarboxylate dicarboxylate (3S, 4R, 5R)) (n 64) Compound 63 (372 mg, 0.254 mmol) obtained in the stage 9. a, treated as for the synthesis of 42 (step 6.b), to provide, after purification on silica (ethyl acetate-cyclohexane 2: 3), compound 64 (301 mg, 87%). 1 H NMR (CDCl 3) D 5.29 (d, H-1 Glc "), 5.10 (d, H-1 IdoUA 1"), 3.97 (dd, H-4 IdoUA1") Step 9.c: Preparation of (benzyl 2-O-acetyl-4-O-levulinoyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-O- (4-methoxy) benzyl-3-O-benzyl-aDg I ucopi ranosi l) - (1-4) - (benzyl 2-O- acetyl-3-O-benzyl lal-idopi ranosi I uronate) - (1 -4) - (6-O-aceti I-2-O- (4-methoxy) benzyl-3-O-benzyl-aD-glucopyranosyl) - (1-4) - (5- (benzyloxy) -4-oxypiperidine-1,3-dicarboxylic acid dibenzyl ester (3S, 4R. 5R)) (n ° 65) Compounds 57 (124 mg, 0.108 mmol) obtained in step 7. i, and 64 (150 mg, 0.110 mmol) obtained in elapa 9.b, are treated according to METHOD 2 to yield, after purification, 65 (90 mg, 35%). 1 H NMR (CDCl 3) d 5.28 (d, H-1 Glc "), 5.16 (d, H-1 IdoUA1"), 5.13 (d, H-1 ldoUAv), 4.74 (d, H-1 Glc? V). Step 9.d: Preparation of (benzyl 2-O-acetyl-4-O-levulinoyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-3-O-benzyl) α-D-glucopyranosyl) - (1-4) - (benzyl 2-O-acetyl-3-O-benzyl L-idopi ranosyluronate) - (1-4) - (6-O-acetyl-3-O- benz I -dg I ucopyros il) - (1-4) - (5- (benzyloxy) -4-oxy piperidin -1, Dibenzyl 3-dicarboxylate (3S, 4R.5R)) (n ° 66) Compound 65 (45 mg, 0.19 mmol) obtained in step 9 c, is treated as for the synthesis of 44 (step 6. d), to provide, after purification on silica (ethyl acetate-cyclohexane 3: 2), compound 66 (34 mg, 91%). Mass spectrum (ESI) m / z 1,982.0 [(M + Na) +]. Step 9.e: Preparation of (3-O-benzyl-α-idopyranosyluronic acid) - (1-4) - (3-O-benzyl-α-d-lucopyranosyl) - (1-4) - (3-O- acid) benzyl-aL-idopi ranosi I u ron ico) - (1-4) - (3-O-benzyl-aD-gl ucopi ranosi I) - (1-4) - (5- (benzyloxy) -4-oxypiperidine -1 -carboxi lato of benzyl-3-carboxylic acid (3S.4R.5R)) (n ° 67) Compound 66 (25 mg, 12.8 μmol) obtained in step 9.d, is treated according to METHOD 3. The mixture of The reaction is acidified by 6N hydrochloric acid (pH 2), and deposited on an LH-20 column (100 mL) equilibrated with a 9: 1 DMF / water mixture. The fractions containing the product are concentrated and purified on silica (dichloromethane-methanol 7: 3) to give 67 (10.4 mg, 59% >) which may be partially purified in the carboxylic acid groups. Mass Species (ESI) m / z 1422.7 [(M + H) +]. Step 9.f: Preparation of (3-O-benzyl-2,4-di-O-sodium sulfonate-aL-idopi ranosi sodium urea) - (1-4) - (3-O-benzyl-2.6 -di-O-sodium-ulfonate-aDg I ucopiranos i I) - (1-4) - (3-O-benzyl-2-O-sodium-sulphonate-aL-idopyranosyluronate sodium) - (1-4) - (3-O-benzyl-2,6-di-O-sodium s-phonate-aDg I ucopyrins il) - (1-4) - (5- (benzyloxy) -4-oxypiperidine-1-carboxylate benzyl-3 sodium carboxylate (3S, 4R.5R)) (n ° 68) Compound 67 (10.4 mg, 9 μmoles) available in step 9.e, is treated according to METHOD 4 to provide 68 which is directly applied. on the next map. PREPARATION 10: Synthesis of sodium (4-O-allyl-3-O-benzyl-2-O-sodium sulfonate-aL-idopyranosyluronate) - (1-4) - (3-O-benzyl-2,6- di-O-sodium s ulfonate-aDg I ucop ira nos il) - (1-4) - (3-O-benzyl-2-O-sodium sulfonate-aL-idopyranosyluronate sodium) - (1-4) - (3-O-benzyl-2.6- di -O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (5- (benzyloxy) -4-oxypiperidine-1-carboxylic acid sodium benzyl-3-carboxylate (3S, 4R.5R)) (n ° 73) bl cap 10 .g: Preparation of (benzyl 2-O-acetyl-4-O-allyl-3-O-benzyl-a-L-idopyranosyluronate) - (1-4) - (6- O-acetyl -2- O- (4-methoxy) benzyl-3-O-benzyl-A-g Ipipiranosi I) - (1-4) - (benzyl 2-O-acetyl-3-O-benzyl) la- L- dopyranos iluronate) - (1-4) - (6-O-acetyl-2- O- (4-methoxy) benzyl-3-O-benzyl-a-D-ql ucopyranosyl l) - ( 1-4) - (5- (benzyloxy) -4-oxypiperidin-1,3-dibenzyl-3-dicarboxylate (3S, 4R.5R)) (n ° 70) Compound 62 (244 mg, 0.223 mmol) obtained in The phase 8. e and compound 64 (138 mg, 0.101 mmol) available in step 9.b were brought according to METHOD 2 to yield, after purification, 70 (100 mg, 43%). 1 H NMR (CDCl 3) d 5.28 (d, H-1 Glc "), 5.25 (d, H-1 ldoUAv), 5.16 (d, H-1 IdoUA1"), 4.72 (d, H-1 Glc? V). Step 1Q.h: Preparation of (benzyl 2-O-acetyl-4-O-allyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-3-O-benzyl) α-D-glucopyranosyl) - (1-4) - (benzyl 2-O-acetyl-3-O-benzyl-lal-idopiranos iluronate) - (1-4) - (6-O-aceti I -3-O -benzyl-aDg Iuclo-pyranosyl) - (1-4) - (5- (benzyloxy) -4-oxypiperidine-1,3-dicarboxylic acid dibenzyl ester (3S.4R.5R)) (n ° 71) Compound 70 (92 mg, 40.0 μmol) obtained in step 10. g, was brought as for the synisis of compound 44 (step 6d), to provide, after purification on silica (aceilone-ololone 17:83 ), compound 71 (44 mg, 59%).

Mass spectrum (ESI.) M / z 1.924.0 [(M + Na) +]. Step 10. i: Preparation of (4-O-allyl-3-O-benzyl-α-idopyranosyluronic acid) - (1-4) - (3-O-benzyl-Dd-glucopyranosyl) - (1-4) - (3-O-benzyl-α-L-idopyranosyluronic acid) - (1-4) - (3-O-benzyl-aD-glucopyranosyl) - (1-4) - (5- (benzyloxy) -4-oxypiperidin-1- benzyl-3-carboxylic acid carboxylate (3S.4R.5R)) (n ° 72) Compound 71 (41 mg, 21.6 μmol) obtained in step 10.h, is treated according to method 3. The mixture of reaction is deposited on a column of LH-20 (210 mL) equilibrated with a 1: 1 dichloromelan-ethanol mixture. The fractions containing the prodrug are concentrated and purified on silica to provide 72 (30.3 mg, 96%) which may be partially esterified in the carboxylic acid groups. Mass spectrum (ESI) m / z 1462.4 [(M + H) +]. Step 10. i: Preparation of sodium (4-O-allyl-3-O-benzyl-2-O-sodium sulfonate-α-idopyranosyluronate) - (1-4) - (3-O-benzyl-2,6-di) -O-sodium bisulphonate-aD-gl ucopi ranosi I) - (1-4) - (3-O-benzyl I -2-O-sodium sulfonate-aL-idopyranosyluronate sodium) - (1-4) - ( 3-O-benzyl-2,6-di-O-sodium ss-p-Icpipyranos i I) - (1 -4) - (5- (benzyloxy) -4-oxypiperid i-1-carboxylate benci lo-3-ca sodium rboxi lato (3S.4R.5R)) (n ° 73) Compound 72 (10.0 mg, 6.44 μmol) obtained in step 10. i, is treated according to the method 4 to provide 73 that is applied directly in the next stage. Preparation 11: Synthesis of methyl (2-N-sodium sulfonate-2,4-dideoxy-4-formyl-3,6-di-O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (sodium 2-O-sodium sulfonate- al-idopi ranosi I u ro born) - (1 -4) - (2-N-sodium sulfonate-2-deoxy-6-O-sodium sulfonate-aD-glucopyranoside) (No. 89) 87 sodium salt 88 sodium salt 89 sodium salt Step 1 1.a: Preparation of 1, 6: 2,3-di-anhydro-4-deoxy-4- (prop-1-en-1-yl) -β-D-mannopyranose (n ° 76) To a solution of the epoxide 75 (1, 2 g, 7, 14 mmol) (prepared according to AG Kelly and JS Roberts, J. Chem. Soc, Chem. Comm? n., (1980), Vol.288) in ethanol (56.5 mL), is added, under argon, rhodium trichloride monohydrate ( 202 mg, 0.15 molar equivalents). After stirring for 1h25 at 75 ° C, the reaction medium is poured into 250 mL of ice water and after 5 min of stirring the product is extracted with diethyl ether, dried (Na2SO) and concentrated. The residue is purified on silica (diisopropyl ether-cyclohexane 45:55) and the fractions containing compound 76 are partially concentrated (76 is volatile). 1 H NMR (CDCl 3) d 3.42 (dd, H-2), 3.00 (dd, H-3), 2.64 (dd, H-4). Step 11. b: Preparation of 1,6-anhydro-2-azido-2,4-dideoxy-4- (prop-1-en-1-yl) -β-D-glucopyranose (n ° 77) Compound 76 obtained in step 11.a is dissolved in a dimethylformamide-water mixture (40 mL, 4: 1), sodium nitride (7.0 g) is added, and the mixture is brought to reflux for 10, 5h. The reaction medium is extracted with ethyl acetate, washed with water and with a saturated aqueous sodium chloride solution, dried (Na2SO), concentrated and purified on silica gel to yield compound 77 (674 mg, 48%). 1 H NMR (CDCl 3) D 5.8-5.6 (m, 2H, CH = CH). Step 11.c: Preparation of 1,3,6-tri-O-acetyl-2-azido-2,4-dideoxy-4- (prop-1-en-1-yl) -aB-D-glucopyranose (No. 78) Compound 77 (3.5 g, 16.57 mmol) reachable in step 11.b is treated as for the synthesis of compound 9 (step 2.b) for yield, after purification, the compound 78 (5.88 g, 100%). Mass Spec (ESI) m / z 378 [(M + Na) +]. Step 11. d: Preparation of 3.6-di-O-acetyl-2-azido-2,4-dideoxy-4- (prop-1-en-1-yl) -a, BD-glucopyranose (n ° 79) to a solution of compound 78 (5.88 g, 16.5 mmol) obtained in step 11.c, in letter hydro-furane (140 mL) is added ellanolamine (4.0 mL, 4 molar equivalents), at 0 ° C. After 16h at + 4 ° C, the medium is diluted with ethyl acetate, acidified (1N HCl), washed with water, dried (Na2SO), and concentrated to yield, after purification, compound 79 ( 4.66 g, 90%). Mass spectrum (ESI) m / z 336 [(M + Na) +]. Step 11. e: Preparation of 3,6-di-O-acetyl-2-azido-2,4-dideoxy-4- (prop-1-en-1-yl) -a.β-D-glucopyranose trichloroacetimidate ( No. 80) To a solution of compound 79 (4.66 g, 14.9 mmol) obtained in step 11.d, in dichloromethane (285 mL) is added, under argon, potassium carbonate (K2CO3) (3, 34 g, 1.6 molar equivalents), and CCI3CN (7.6 mL, 5 molar equivalents). After 17h of magnetic stirring, the reaction mixture is filtered, concentrated and purified on silica to yield compound 80 (5.65 g, 83%). 1 H NMR (CDCl 3) d 8.77 (s, NH (isomer a)), 5.70 (dd, H-3), 2.64 (d, H-1β). Step 11.f: Preparation of methyl (3,6-di-O-acetyl-2-azido-2,4-dideoxy-4- (prop-1-en-1-yl) -aD-lucopyranosyl) - (1-4) ) - (methyl 2-O-acetyl-3-O-benzyl-idopi-ranosyluronate) - (1-4) - (6-O-acetyl-3-O- benz l-2-benzyloxycarbon Mam i no-2-deoxy-a-D-gl ucopi ranósido) (n ° 82) Compound 80 (5.65 g, 12.3 mmol) obtained in step 11. e, and compound 81 (prepared according to JC Jacquinet et al., Carbohydr. Res. 130 (1984), 221-241) (11.54 g, 1.2 molar equivalents) are reacted according to METHOD 2 to yield, After purification, compound 82 (9.39 g, 71%). Mass spectrum (ESI) m / z 1.077.5 [(M + H) +]. Step 11. g: Preparation of methyl (3,6-di-O-acetyl-2-azido-214-dideoxy-4- (1,2-dihydroxypropyl) -aD-lucopyranosyl) - (1-4) - (methyl) 2-O-acetyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-3-O-benzyl-2-benzyloxycarbonylamino-2-deoxy-aD-glucopyranoside) (n ° 83) To a solution of compound 82 (513 mg, 0.476 mmol) obtained in step 11.f, in a 1: 1 tetrahydrofuran-dichloromethane mixture (8 mL) are added N-methylmorpholine N-oxide monohydrocarbon (NMO) (1.11 g, 20 molar equivalents) and tetrahydroxide osmium (OsO) 4% in water (8.35 mL, 1 molar equivalent). After 3 days of ambient temperature agitation, a 1: 1 dichloromethane-water mixture is added, as well as a 37.5% solution of sodium hydrogen sulfide (NaHSO 3), and the stirring is maintained an additional 30 minutes. The reaction mixture is ex-chlorinated with dichloromethane, purified on silica and the fraction conferring the production of paraffin is reacted again under the above conditions until complete disappearance. After purification, it is finally obliged compound 83 (293 mg, 66%). Mass spectrum (ESI) m / z 1111.4 [(M + H) +]. Step 11.h: Preparation of methyl (3,6-di-O-acetyl-2-azido-2,4-dideoxy-4- (5-methyl-2-phenyl) 1-1, 3-dioxolan -4- il) -alpha -glucopyranosyl) - (1-4) - (methyl 2-O-acetyl-3 O -benzyl-aL-idopyranosyl uro-nato) - (1-4) - (6-O-acetyl-3-) O-benzyl-2-b < enciloxicarbonilam ino-2-deoxy-aD-glucopyranoside) (n ° 84) To a solution of compound 83 (518 mg, 0.466 mmol) obtained in step 11.g, in acetonitrile add, under argon, CSA (21.6 mg, 0.2 molequiv), and benzylidene dimethylacetal (160 μL, 2.3 molar equivalents). After stirring for 1 h 30, the medium is neutralized with rheidylamine, concentrated to dryness and purified on silica to yield compound 84 (454 mg, 74%). Mass spectrum (ESI) m / z 1.199.5 [(M + H) +]. Step 11. i: Preparation of methyl (2-azido-2,4-dideoxy-4- (5-methyl-2-phenyl-1,3-dioxolan-4-yl) -aD-glucopyranosyl) - (1-4) ) - (3-O-benzyl-L-pyridine) (1-4) - (3-O-benzyl-2-benzyloxycarbonylamino-2-deoxy-aD-glucopyranoside) (n ° 85) Compound 84 (215 mg, 0.18 mmol) in ether 11. h, is evaporated according to method 3. After 16 h of magnetic agitation at room temperature, the medium is diluted with methanol (12.5 mL), and an aqueous 4N sodium hydroxide solution (11.5 mL) is added at 0 ° C. The mixture is stirred 4h at 0 ° C, acidified (pH 5) with 6N hydrochloric acid, extracted with dichloromethane, washed with Na2SO35%, and finally with saturated sodium chloride. After Drying and concentrating, the residue is purified on silica to yield the compound 85 (157 mg, 86%). Mass spectrum (ESI) m / z 1017.3 [(M + H) +]. Step 11.I: Preparation of methyl (2-azido-2,4-dideoxy-4- (5-methyl-2-phenyl-1,3-d-oxolan-4-yl) -3,6-di- • O- -sodium sulfonate -a- D- q <lucose> pyranosyl) - (1-4) - (sodium 3- O -benzyl-2-O-sodium sulfonate -A- L-id lopiranus iluronate) - (1-4) - (3-O-benzyl-2-b-enzyloxycarbonyl) 2- -deoxy-6- -O-sodium sulfonate-a;- D -gluco P-ranoside) (n ° 86) Compound 85 (160 mg, 0.157 mmol) obtained in step 11. i, was used according to METHOD 4 to provide compound 86 (215 mg, 95%). Mass Spec (ESI) m / z 689.1 [(M + H-3Na) 2"] Step 11. k: Preparation of methyl (2-amino-2,4-dideoxy-4- (1, 2- dihydroxypropyl) -3.6-di-O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (sodium 2-O-sodium sulfonate-α-idopyranosyluronate) - (1-4) - (2-amino-2- deoxy-6-O-sodium sulfonate-aD-glucopyranoside) (n ° 87) Compound 86 (210 mg, 0.145 mmol) obtained in step 11 j was brought in according to step 5 without acidic acid to yield compound 87 (108 mg, 73%) If necessary, the reaction is repeated several times until the disappearance of the benzylic protons by NMR Mass Spectrum (ESI) m / z 996.1 [(M + H - Na) " ] Step 11.1: Preparation of methyl (2-N-sodium sulfonate-2,4-dideoxy-4- (1,2-dihydroxypropyl) -3,6-di-O-sodium sulfonate-aD-gl -copi-ranosyl) - (1-4) - (sodium 2-O-sodium sulfonate-aL- idopyranosyluronate) - (1-4) - (2-N-sodium sulfonate-2-deoxy-6-O-sodium sulfonate-aD-glucopyranoside) (n ° 88) To a solution of compound 87 (106 mg, 0, 104 mmoles) obtained in step 1 1. k, in water (7 mL), pyridine complex is added at 0 ° C. SO 3 (662 mg, 4.16 mmol) maintaining the pH at 9.3 with 1 N soda. The temperature is raised again to room temperature, the reaction medium is stirred for 16 h while maintaining the pH at 9.3 and purified in a column of Sephadex G-25 gel equilibrated with a 0.2 M sodium chloride solution. After collecting the fractions containing the product and concentrating, the residue is purified with the same SephadexD G-25 column eluted with water, to yield Compound 88 (16 mg, 91%). Mass spectrum (ESI) / z 1 .199.8 [(M + H - Na) "] Step 1 1. m Preparation of methyl (2-N-sod? Or sulfonate-2,4-dideoxy-4-) formyl-3.6-di-O-sodium s-ulfonate-aDg I ucop i ranosi I) - (1 - 4) - (sodium 2-O-sodium sulfo nato-aL-id opi ranos i I uro nato) - (1 - 4) - (2-N-sodium sulfonate-2-deoxy-6-O-sodium sulfonate-aD-glucopyranoside) (n ° 89) Sodium periodate (22.1 mg, 1.1 molar equivalents) is added to a Solution of compound 88 (1 15 mg, 94 μmol) obtained in step 1 1.1, in water (1.9 mL) After 1 h of magnetic stirring, the reaction medium is purified on a column of Sephadex gel. G-15 equilibrated with water to yield compound 89 (107 mg, 96%) Preparation 12: Synthesis of (2-acetamido-3,4-di-O-benzyl-2-deoxy-6-O-sodium sulfonate-aDg I ucopi ranosi I) - (1-4) - (5- (benzyloxy) -4- Oxypyridine N-1-carboxylate of sodium benzyl-3-carboxylate (3S, 4R, 5R)) (No. 97) /? - &? oC (NHICa3 93 94 95 sodium 96 97 Step 12.a: Preparation of (6-O-acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-aD-glucopyranosyl) - (1-4) - (5- ( benzyloxy) -4-oxypiperidine-1,3-dicarboxylic acid dibenzyl ester (3S, 4R, 5R)) (n ° 94) Compound 93 (prepared according to R. Verduyn et al., Red. Trav. Chim. Pays-Bas, 109 (1990), 12, 591) (361 mg, 0.631 mmol) and compound 6 (200 mg, 0.421 mmol) obtained in step 1.e, were brought according to method 2 to provide, after purification, the compound 94 (224 mg, 60%). Mass Spectrum (ESI) m / z 885.4 [(M + H) +]. Step 12. b: Preparation of (6-O-acetyl-2-acetamido-3,4-di-O-benzyl-2-deoxy-aDg I ucopi ranosi I) - (1-4) - (5- (benzyl oxy) ) -4-Oxypiperidine-1,3-dicarboxylic acid dibenzyl ester (3S.4R.5R)) (# 95) Compound 94 (56.3 mg, 63.6 μmol) available in step 12.a, is treated as for the synthesis of 17 (stage 3.f), to yield the compound 95 (54.5 mg, 95%). Mass spectrum (ESI) m / z 901.2 [(M + H) +]. Step 12.c: Preparation of (2-Acetamido-3,4-di-O-benzyl-2-deoxy-aD-gluco-iranosyl) - (1-4) - (5- (benzyloxy) -4-oxy-iperidin-1- Benzyl-3-carboxylic acid carboxylate (3S.4R.5R)) (n ° 96) Compound 95 (101 mg, 50.9 μmol) obtained in the elapa 12. b, it is treated according to METHOD 3. The rest is applied in the rough in the next stage. Step 12.d: Preparation of (2-acetamido-3,4-di-O-benzyl-2-deoxy-6-O-sodium s-ulfonate-aDg I ucopiranos i I) - (1-4) - (5- (benzyloxy i) -4-ox ip di-di-1-benzylcarboxylic acid o-3 -carboxylate sodium (3S.4R.5R)) (n ° 97) The crude compound 96 obtained in the step 12. c, was brought according to METHOD 4, to provide the compound 97 (35 mg, 88% (2 eiapas)), which can be partially variegated in the carboxylic acid function. Mass Species (ESI) m / z 847.2 [(M-H) ']. Preparation 13: Synthesis of 3- (benzyloxy) -5-r (benzyloxy) methyl-1-4-h id roxypiperid i-1-benzyl carboxylate (3R.4R.5R) (n ° 100) 99 100 Step 13.a Preparation of 8- (benzyloxy) -2-phenyltetrahydro-4H- ri.31dioxinor5,4-c1pyridin-6 (5H) -benzylcarboxylate (4aR.R8aR) (n ° 99) To a solution of compound 5 (250 mg, 0.67 mmol) in acetoniiryl (13.4 mL ) add camphorsulfonic acid (31 mg, 0.2 molequiv) and benzaldehyde dimethylacetal (0.23 mL, 2.3 molequiv). After 1 h of magnetic stir at ambient temperature, the reaction medium is neurallized with Iriethylamine, concentrated, and purified on silica gel (15:85 ethyl acetate-cyclohexane) to give compound 99 (281 mg, 91% ). Mass Species (ESI) m / z 482.2 [(M + Na) +]. Step 13. b: Preparation of benzyl 3- (benzyloxy) -5-r (benzyloxy) methyl-1-4-hydroxypiperidine-1-carboxylate (3R.4R.5R) (n ° 100) To a solution of compound 99 ( 141 mg, 0.31 mmol) obtained in step 13.a in dichloromethane (1.2 mL), are added successively, at 0 ° C, under argon, triethylsilane (0.20 mL, 4 molar equivalent), trifluoroacetic acid (0.09 mL, 4 molar equivalents), and trifluoroacetic anhydride (3 μL, 0.07 molar equivalents). The temperature is maintained at 0 ° C for 5 min, and the reaction medium is placed at ambient temperature for 3.5 h. the reaction mixture is neutralized with an aqueous solution of sodium hydrogencarbonate, with water, and the organic phase is dried (Na2SO), filtered and concentrated in vacuo. The residue is purified on silica gel to yield compound 100 (76 mg, 54%). Mass Spec (ESI) m / z 462.3 [(M + H) +]. Preparation 14: 102 Synthesis of (3-O-benzyl-2,4-di-O-sodium sulfonate-aL-idopyranes ilurone to sodium) - (1-4) - (2-acetamid o-3-O-benzyl-2) -deoxy-6-O -sodium its Ifonato-a-D-glucopyranosyl l) - (1 -4) - (3-O-benzyl-2-O-sodium sulfon ato-L-idopyranos sodium urauronate) - ( 1-4) - (2-acetamido-3-O-benzyl-2-d-p-oxy-6-O-! Sodium sulfonate-aD-glucopyranosyl) - (1-4) - (3- (benzyloxy) -5- Benzyl f (benzyloxy) metin-4-oxypiperidin-1-carboxylate (3R, 4R, 5R)) (No. 104) Step 14.a: Preparation of (benzyl 2,4-di-O-acetyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-azido-3-O -benzyl-2-deoxy-aDg lucopiranos i I) - (1-4) - (benzyl 2-0 -aceti I -3-O-benzyl- L-idopi ranosi I u ron ato) - (1-4 ) - (6-O-acetyl-2-azido-3-O-benzyl I-2-deoxy-aDg lucopyrin il) - (3- (benzyloxy) -5-r (benzyloxy) methyl] -4-oxypiperidine Benzyl-1-carboxylate (3R, 4R, 5R)) (No. 101) Compounds 15 (123 mg, 0.075 mmol) and 100 (69 mg, 0.149 mmol) are treated according to METHOD 2 to provide, after purification, compound 101 (117 mg, 80%). D / D ratio 55/45. Mass spectrum (ESI) m / z 1.962 [(M + Na) +]. Step 14. b: Preparation of (benzyl 2,4-di-O-acetyl-3-O-benzyl-α-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-acetamido-3-O -benzyl-2-deoxy-aD-glucopyranosyl) - (1-4) - (benzyl 2-O-acetyl-3-O-benzyl-aL-idopyranosyluronate) - (1-4) - (6-O-acetyl- 2-acetamido-3-O-benzyl-2-deoxy-aD-lucopyranosyl) - (1-4) - (3- (benzyloxy) -5-r (benzyloxy) -methin-4-oxo-piperidine-1-carboxylic acid benzyl ester ( 3R, 4R, 5R)) (n ° 102) Compound 101 (117 mg, 60 μmol) is dissolved in pyridine (1 mL) and thioacetic acid (1 mL, 225 molar equivalents) is added at 0 ° C. The reaction medium is stirred 17 h at room temperature, concentrated and purified on silica gel (4:96 ethanol-toluene), to yield compound 102 (50 mg, 42%). Mass spectrum (ESI) m / z 1.971.9 [(M + H) +].

Step 14. c Preparation of 3-O-benzyl-α-L-idopyranosyluronic acid- (1-4) - (2-acetamido • 3-O-benzyl-2-deoxy-α-D-glucopyranosyl) - (1 - 4) -acid 3-O-benzyl-lal-idopi ranosyluronyl) - (1-4) - (2-acetamido-3-O-benzyl-2-d-esoxi- aD-glucopyranosyl) - (1-4) - (3-Benzyloxy) -5-benzylkyloxy) methyl-4-oxypiperidin-1-benzylcarboxylate (3R.4R.5R)) (# 103) Compound 102 (50 mg, 25 μmol) is treated according to METHOD 3 to yield the derivative 103. Mass spectrum (ESI) m / z 1,581.7 [(M + H) +]. Stage 14 .d • Preparation of sodium (3-0-benzyl-2,4-di- O-sodium sulfonate-al-idopyranosyluronate) - (1-4) - (2 -acetamide-3-O) -benzyl-2-deoxy-6-o-sodium-ul-p-a-I-p-p-p-phenyl) - (1-4) - (3-O-benzyl-2- O-sodium sulfonate-al-idopyranosyl sodium luronate) - ( 1-4) - (2-Aceta-my-3-O-benzyl-2-deoxy-6-O-sulfonate-aD-glucopyranosyl) - (1-4) - (3-) (benzyloxy) -5- T (benzyloxy) methy «I -4-oxypi iperidine-1-benzyl boxylidene (3R. 4R, 5R)) in? 104) Compound 103 is treated according to METHOD 4 , to provide compound 104 (43 mg, 80% (2 steps)). Mass Spectrum (ESI) m / z 2.134.3 [(M-Na) "]. Preparation 15: Synthesis of (benzyl 2-O-acetyl-3-O-benzyl-4-O-phenylpropyl-aL-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-azido-3-O-benzyl-2-deoxy-a.β-D-glucopyranose trichloroacetimidate) (No. 114) 105 106 107 C) 109 108 110 g-h) 111 112 j) 114 113 Step 15.a: Preparation of (4,6-O-isopropylidene-3-O-benzyl-2-O- (4-methoxy) benzyl-idopi ranosi I) - (1-4) - (1, 6-anhydro-2-azido-3-O-benzyl-2-deoxy-β-D-glucopyranose) (No. 106) To a solution of compound 105 (63.2 g, 111 mmol) (prepared according to CAA van Boeckel et al., J. Carbohydrate Chemistry (1985) 4 (3), 293-321) in DMF (445 mL) is added, at 0 ° C and under argon, NaH (6.93 g, 1.3 molar equivalent) and para-methoxybenzyl chloride (24 mL, 1.6 molar equivalent). After 2 h of magnetic agitation, meianol (9 mL) is added, the reaction medium is concentrated in vacuo, the reaction mixture is concentrated in dilute with ethyl acephalous, wash with water, dry (Na2SO4), filter and concentrate. The residue obtained is purified on silica (ethyl acetate-cyclohexane 15:85) to give 106. Mass spectrum (ESI) m / z 707.3 [(M + NH4) +]. Step 15. b: Preparation of (3-O-benzyl-2-O- (4-methoxy) benzyl-α-idopyranosyl) - (1-4) - (1,6-anhydro-2-azido-3-O -benzyl-2-deoxy-β-D-glucopyranose) (n ° 107) The compound 106 obtained in the preceding step is placed in the presence of 80% acetic acid in water. After 15 h of magnetic stirringThe reaction mixture is cooled with ice, diluted (dichloromethane) and neutralized with sodium hydrogencarbonate. The organic phase is dried (Na2SO), filtered and concentrated. The obtained residue is purified on silica (acétalo of ethyl-cyclohexane 3: 7) to provide 107 (63.2 g, 88%, 2 stages). Mass spectrum (ESI) m / z 672.3 [(M + Na) +]. Step 15.c: Preparation of (3-O-benzyl-6-O-tert-butyldimethylsilyl-2-O- (4-methoxy) benz la-idopi ranosi I) - (1-4) - (1 , 6-anhydro-2-azido-3-O-benzyl-2-deoxy-β-D-glucopyranose) (# 108) Compound 107 (64.2 g) is dissolved in dichloromethane (200 mL). At 0 ° C and under argon, triethylamine (30.3 mL, 2.2 molar equivalents), 4-dimethylaminopyridine (1.21 g, 0.1 molar equivalent), and rerc-butyldimethylsilyl chloride (17, 04 g, 1.1 molar equivalents). After 4 h of magnetic stirring, 10% re-buildyl dimethylsilyl chloride is added again and after one hour, the reaction medium dilute with dichloromethane, wash with water, dry (Na2SO), filter and concentrate. The residue obtained is purified on silica (15:85 ethylocyclohexane acelaide) to give 108. Mass Spec (ESI) m / z 786.3 [(M + Na) +]. Step 15. d: Preparation of (3-O-benzyl-6-O-tert-butyldimethylsilyl-2-O- (4-methoxy) benzyl-4-Of eny I propylaL-idopiranos il) - (1-4 ) - (1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-β-D-glucopyranose) (No. 109) To a solution of compound 108 in dimethylformamide (485 mL) is added, at 0 ° C and under argon, phenylpropyl bromide (74 mL, 5 molar equivalents) and NaH (7 g, 1.5 molar equivalent). After 5.5 h of magnetic stirring, mefanol (50 mL) is added, the reaction medium is concentrated in vacuo, the reaction product is diluted with ethyl acetate, washed with water, dried (Na 2 SO 4), it is filtered and concentrated. The remaining acid is purified on silica (ethyl acéfalo-cyclohexane 15:85) to provide 109 (49.3 g, 58%, 2 steps). Mass spectrum (ESI) m / z 904.3 [(M + Na) +]. Step 15.ef: Preparation of (2-O-acetyl-3-O-benzyl-6-O-tert-butyldimethylsilyl-4-O-phenylpropi la L-idopi ranosyl) - (1-4) - (1,6- anhydro-2-azido-3-O-benzyl-2-deoxy-β-D-glucopyranose) (No. 110) To a solution of 109 (49.3 g, 55.9 mmol) in dichloromethane (2.2 L) is added water (112 mL) and, at 0 ° C, DDQ (19.03 g, 1.5 molar equivalent) ). After 3 h of stirring at 0 ° C, a solution of sodium hydrogencarbonate is added. The organic phase is dried (Na2SO), filtered and concentrated. The rest obienido Dissolve in pyridine (335 mL), and add acetic anhydride (28 mL) and 4-dimethylaminopyridine (682 mg). After 16 h of magnetic stirring, the reaction mixture is concentrated in vacuo and the obfeated residue is purified on silica (ethyl acetate-cyclohexane 15:85) to yield 110 (34.4 g, 77%, 2 layers). Mass Spec (ESI) m / z 826.4 [(M + Na) +]. Step 15.gh: Preparation of (benzyl 2-O-acetyl-3-O-benzyl-4-Of in i I propi la-idopi ranosi I uronate) - (1-4) - (1.6-anh id ro-2 -zido-3-O-benzyl-2-deoxy-β-D-glucopyranose) (No. 111) To a solution of 110 (25.17 g, 31.3 mmol) in aceine (1.46 L) is added, at 0 ° C, a 3.5 M aqueous solution of sulfuric acid (45 mL) which contains chromic anhydride (10 g). After 3 h of magnetic stirring at 0 ° C, the reaction medium is diluted with dichloromethane, washed with water, dried, filtered and concentrated to give a reaction product which is applied directly in the following step. The remaining residue is dissolved in dimethylformamide (230 mL) and polasium hydrogen carbonate (16.7 g, 5 mole equivalents) and benzyl bromide (39.8 mL, 10 molar equivalents) are added. The reaction mixture is stirred 16 h at ambient temperature, diluted with ethyl acetate, washed with water, dried, filtered, concentrated and purified on silica gel (ethyl cephalo-toluene 1: 4) to yield compound 111 (22.6 g, 91%, 2 steps). Mass Spec (ESI) m / z 811.3 [(M + NH4) +].

Step 15. i: Preparation of (benzyl 2-O-acetyl-3-O-benzyl-4-Of in ilpropi la L-idopi ranosi I uonate) - (1-4) - (1,6-di-O- aceti l-2-azido-3-O-benzyl-2-deoxy-a, β-D-glucopyranose) (n ° 112) To a solution of compound 111 (1.11 g, 1.39 mmol) in acetic anhydride (13.2 mL, 100 molar equivalents), urea fluoride (TFA) (1.14 mL, 11 molar equivalents) was added at 0 ° C. After returning to ambient temperature, the reaction mixture is stirred for 3.5 hours, concentrated, coevaporated with toluene, and purified on silica gel (85:15 loluene-acetyl ether) to give the compound 112 ( 1.15 g, 93%). Mass Spec (ESI) m / z 918.3 [(M + Na) +]. Step 15.: Preparation of (benzyl 2-O-acetyl-3-O-benzyl-4-O-phenylpropyl-L-idopyranosyluronate) - (1-4) - (6-O-acetyl-2-azido-3 -O-benzyl-2-deoxy-a, β-D-glucopyranose) (No. 113) To a solution of the compound 112 (1.13 g, 1.26 mmol) in diethyl ether (51 mL), benzylamine (BnNH2) (5.25 mL, 38 molar equivalents) is added at 0 ° C. After 5h15 stirring at room temperature, the medium is acidified with 1N HCl, extracted with diethyl ether, dried (Na2SO4), concentrated and purified on silica gel (35:65 ethyl acetate-cyclohexane) to yield 113 (0.97 g, 90%). Mass Spec (ESI) m / z 854.3 [(M + H) +]. Step 15.k: Preparation of (benzyl 2-O-acetyl-3-O-benzyl-4-O-pheni I propi la-idopi ranosi I uronate) - (1-4) - (6-O-acetyl-2 -azido-3-O-benzyl-2-deoxy-a, β-D-glucopyranose trichloroacetimidate) (No. 114) To a solution of compound 113 (0.95 g, 1.12 mmol) in dichloromene (21.2 mL), cesium carbonate (Cs2CO3) (0.583 g, 1.6 molar equivalent) is added under argon, and trichloroacetonitrile (CCI3CN) (0.56 mL, 5.0 molar equivalent). After 35 min of stirring, the reaction mixture is filtered and concentrated. The residue is purified on silica gel (25:75 ethyl acetate-cyclohexane) to yield 114 (995 mg, 90%). Mass spectrum (ESI) m / z 1021.5 [(M + Na) +]. Preparation 16: Synthesis of (benzyl 3-O-benzyl-4-O-phenylpropyl-2-O-sodium sulfonate-α-idopyranosyluronate) - (1-4) - (2-acetamido-3-O-benzyl) 2-deoxy-6-O-sodium sulphonate-aDg I ucopiranos i I) - (1-4) - (benzyl 3-O-benzyl-2-O-sodium sulfonate-aL-idopiranos iluronate) - ( 1 -4) - (2-acetamido-3-O-benzyl-2-deoxy-6-O-sodium sulfonate-aDg I ucopyra nos i I) - (1-4) - (5- (benzyloxy) -4 -oxi piperidin -1.3- 118 122 sodium salt Step 16.a: Preparation of (b < sncil 2-O-acetyl-3-O-benzyl-4-O-phenylpropyl-α-idopyranosyl uronate) - (1-4) - (6- O -acetyl-2-azido-3-O-benzyl-2-deoxy-aD-glucopyranosi D-1- • 4) - (benzyl 2-O -acetyl-3-O-benzyl-L- -idopi ranosi I uronate) - (1-4) - (1,6-an ihydro-2-azido-3-O-benzyl-2-deoxy-β-D-glucopyranose) (No. 115) Compound 114 (990 mg, 0.99 mmole) and compound 8 (1.15 g, 1.7 mmole) are treated according to method 2 to yield, after purification, compound 115 (623 mg, 42%). Mass Spec (ESI) m / z 1.533.8 [(M + Na) +]. Step 16.b: Preparation of (benzyl 2-O-acetyl-3-O-benzyl-4-O-phen i I propyla-idopiranos I-uronate) - (1-4) - (6-O-acetyl) l-2-azi-do-3-O-benzyl-2-deoxy-aD-glucopyranosyl) - (1-4) - (benzyl 2-Oa cetyl-3-O-benzyl L-idopi ranosi I uronate) - (1 -4) - (1,6-di-O-aceti I -2-azido-3-O ° benzyl-2-deoxy-a.β-D-glucopyranose) (n ° 116) Compound 115 (590 mg, 0.39 mmol) was used as for the syn- thesis of compound 112 to yield, after purification on silica gel (7: 3 cyclohexane-ethyl acetate), 116 (609 mg, 97%) . Mass spectrum (ESI) m / z 1636.2 [(M + Na) +]. Step 16. c: Preparation of (benzyl 2-O-acetyl-3-O-benzyl-4-O-phenylpropyl lal-idopi ranosi luronate) - (1-4) - (6-O-acetyl-2-azido -3-O-benzyl-2-deoxy-aD-glucopyranosyl) - (1-4) - (benzyl 2-O-acetyl-3-O-benzyl-idopyranos iluronate) - (1-4) - (6 -O-acetyl-2-azido-3-O-benzyl-2-deoxy-a, β-D-glucopyranose) (n ° 117) Compound 116 (592 mg, 0.367 mmole) is treated as for the synthesis of the compound 113 to yield, after purification on silica gel (65:35 cyclohexane-ethyl acetate), compound 117 (530 mg, 92%). Mass spectrum (ESI) m / z 1593.9 [(M + Na) +]. Step 16.d: Preparation of (benzyl 2-O-acetyl-3-O-benzyl-4-Ofyl-propyl-aLi-do-p-nosylidene) - (1-4) - (6-O-acetyl-2-azi) do-3-O-benzyl-2-deoxy-aD-glucopyranosyl) - (1-4) - (benzyl 2-O-acetyl-3-O-benzyl-idopiranos I-uronate) - (1 - 4) - (6-O-aceti I -2-azido-3-O-benzyl-2-deoxy-a.β-D-glucopyranose trichloroacetimidate) (No. 118) The compound 117 (511 mg, 0.325 mmol) was It appeared as for the syn- losis of compound 114 to yield, after purification on silica gel (7: 3 cyclohexane-ethyl ether), 118 (495 mg, 89%). Elemental analysis calculated for C85H9oCI3N7O25: C, 59.49; H, 5.29; N, 5.71. Found: C, 59.49; H, 5.50; N, 5.48. Step 16. e: Preparation of (benzyl 2-O-acetyl-3-O-benzyl-4-O- Pheni I propyl-L-idopi ranosi I uronate) - (1-4) - (6-O-aceti I -2-azido-3-O-benzyl-2-deoxy-aDg I ucopyranes il) - (1 -4) - (benzyl 2-O-acetyl-3-O-benzy lal-idopi ranosi I ucña to) - (1-4) - (6-O -aceti I -2-azido-3-O-benzyl) -2-deoxy-aD-glucopyranosyl) - (1-4) - (5- (benzyloxy) -4-oxypiperidine-1,3-dicarboxylic acid dibenzyl ester (3S, 4R.5R)) (No. 119) Compounds 118 (479 mg, 0.279 mmol) and 6 (255 mg, 0.536 mmol) were prepared according to METHOD 2 to yield, after purification, compound 119 (375 mg, 66%). Elemenlal analysis calculated for C1nH1? N7O30: C, 59.49; H, 5.29; N, 5.71. Found: C, 59.49; H, 5.50; N, 5.48. Step 16. f: Preparation of (benzyl 2-O-acetyl-3-O-benzyl-4-O-fe nylpropyl-a-L-idopiyranosyluronate) - (1-4) - (6-O-acetyl-2 -acetamido- 3- O-benzyl-2-deoxy--aD-lucopyranosi D-1 -4) - (benzyl 2-O-acetyl-3-O-benzyl-a-L -idopyranosyluronate) - (1-4) ) - (6- O -acetyl-2-acetamido-3-O-benzyl-2-deoxy-a-D-giucopyranosyl) - (1-4) - (5- (benzyloxy) -4-oxypiperidine n- 1 , Dibenzyl 3-dicarboxylate (3S.4R, 5R)) (n ° 120) Compound 119 (180 mg, 88.7 μmoles) is dissolved in pyridine (1.4 mL) and thioacetic acid (1.4 mL, 225 molar equivalents) is added at 0 ° C. The reaction medium was stirred for 17 h at ambient temperature, concentrated and purified on silica gel (4: 1 -oluene-aceilone) to yield compound 120 (153 mg, 84%). Mass Spec (ESI) m / z 2.084.8 [(M + Na) +]. Step 16.g: Preparation of (benzyl 3-O-benzyl-4-O-phenylpropyl-α-L-idopyranosyluronate) - (1-4) - (2-acetamido-3-O-benzyl-2-deoxy-a- D-glucopyranosyl) - (1-4) - (benzyl 3-O-benzyl-ido-phenyl-silicate) - (1-4) - (2-acetamido-3-O-benzyl-2-deoxy-aD) -gl ucopi ranosil) - (1-4) - (5- (benzyloxy) -4-oxypiperidine-1,3-dicarboxylic acid dibenzyl ester (3S, 4R, 5R)) (n ° 121) Compound 120 (190 mg, 93.6 μmoles) is treated according to Method 3. The obtained polyol is dissolved in dimellylformamide (4.4 mL), and polasium hydrogencarbonate (85 mg, 10 molar equivalents) as well as benzyl bromide (202 μL, 20 molar equivalents) are added at 0 ° C. The reaction mixture was stirred at ambient temperature for 16 h, and purified on an LH-20 column. A purification on silica gel (acetyl cyclohexane 2: 3) yields 121 (1 08 mg, 62% (2 elaps)). Mass Spec (ESI) m / z 1 .884.2 [(M + Na) +]. Step 16. h: Preparation of (benzyl 3-O-benzyl-4-O-phenylpropyl-2-O-sodium sulfonate-α-idopyranosyluronate) - (1-4) - (2-acetamido-3-O-benzyl) 2-deoxy-6-O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (benzyl 3-O-benzyl-2-O-sodium its Ifonato-aL-id opi ranos iluro nato) - (1 - 4) - (2-Acetamido-3-O-benzyl-2-deoxy-6-O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (5- (benzyloxy) -4-oxypiperidin-1,3 dibenzyl dicarboxylate (3S, 4R, 5R)) (n ° 122) Compound 121 (41 mg, 21.6 pmol) was brought according to METHOD 4 to yield compound 122 (49 mg, 99%). Mass Spectrum (ESI) m / z 2.301, 0 [(M - H) "] The examples below illustrate the preparation of compounds of the invention, without limiting it. The mass spectra and R.M.N. confirm the structures of the compounds compiled. Example 1: Synthesis of sodium (2,4-di-O-sodium sulfonate-D1-idopyranosyluronate) - (1-4) - (2-acetamido-2-deoxy-6-O-sodium sulfonate -aD-glucopyranosyl) - ( 1-4) - (2-O-sodium sulfonate - sodium α-idopyranosyluronate) - (1-4) - (2-acetamido-2-deoxy-6-O-sodium sulfonate-aD -glucopyranosyl I) - ( 1-4) - (5- (hydroxy) -4-oxy-piperidine-3-carboxylic acid sodium (3S, 4R, 5R)) (compound No. 20) " Sodium salt Compound 19 of PREPARATION 3 (50 mg, 24.02 μmol) is prepared according to method 5 to yield compound 20 (26 mg, 72%). 1 H NMR (D 2 O) d 5.23 (d, H-1 Glc "), 5.13 (d, H-1 IodoUA" '), 5.10 (d, H-1 ldoUAv), 5.09 (d, H-1 Glc! v), 3.62, 3.04, 2.64, 2.47 (4m, 4H, H-2, H-2 ', H-6, H-6' pip '). Example 2: Synthesis of sodium 2-acetamido-2-deoxy-6-O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (5- (hydroxy) -4-oxypiperidine-3-carboxylate (3S. 4R.5R)) (compound n ° 21) (sodium salt) 21 Compound 97 of PREPARATION 12 was brought according to method 5 to yield compound 21. 1 H NMR (D 2 O) d 5,21 (d, H-1 Glc "), 3.40, 3.40, 3.40, 3.10 (4m, 4H, H-2, H-2 \ H-6, H-6"pip1). Example 3: Synthesis of sodium (2,4-di-O-sodium sulfonate-α-idopyranosyluronate) - (1-4) - (2-acetamido-2-deoxy-6-O-sodium sulfonate-aDg Icopyrin nos il) - (1-4) - (5- (hydroxy) -4-oxypiperidine-3-ca sodium rboxylate (3S.4R, 5R)) (compound n ° 22) (sodium salt) 22 In the same manner, compound 22 was prepared. 1H NMR (D 2 O) d 5,19 (d, H-1 Glc "), 5,15 (d, H-1 IdoUA 1"), 3.27, 3.23 , 3.09, 2.89 (4m, 4H, H-2, H-2 \ H-6, H-6 'pip1). Example 4: Synthesis of (2-acetamido-2-deoxy-6-O-sodium sulfonate-a-D-glucopyranosyl) - (1-4) - (2-O-sodium sulfonate-a-L-idopyrano- Sodium siluronate) - (1-4) - (2-acetamido-2-deoxy-6-O-sodium s-apht-aDg I ucopyranes il) - (1-4) - (5- (hydroxy) -4- sodium oxipiperidi n-3-carboxylate (3S, 4R, 5R)) (Compound No. 23) (sodium salt) 2. 3 In the same manner compound 23 was prepared. 1 H NMR (D 2 O) d 5,26 (d, H-1 Glc "), 5,14 (d, H-1 IodoUA '"), 5.09 (d, H -1 Glc? V). Example 5: Synthesis of sodium (2,4-di-O-sodium sulfonate-D-idopyranosyluronate) - (1-4) - (2-N-sodium sulfonate-2-deoxy-6-O-sodium sulphonate) aDg I upipiranos i I) - (1-4) - (2-I hate sodium sulfonate-aL-idopyrano-sodium siluronate) - (1-4) - (2-N-sodium sulfonate-2-deoxy-6-) O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (5- (hydroxy) -4-oxy-piperidine-3-carboxylate sodium (3S, 4R, 5R)) (compound n ° 27) (sodium salt) 27 Compound 26 of PREPARATION 4 (7.0 mg, 3.28 μmol) is treated according to method 5 to yield compound 27 (2.9 mg, 55%). 1H-NMR (D2O) d 5.53 (d, H-1 Glc "), 5.44 (d, H-1 Glc? V), 5.23 (d, H-1 IodoUA" 1), 5.21 (d, H-1 ldoUAv), 3.09, 3.07, 2.58, 2.44 (4m, 4H, H-2, H-2 \ H-6, H-6 'pip1). Example 6: Synthesis of sodium (3-O-methyl-2, 4-di-O-sodium sulfonate-α-idopyranosyluronate) - (1-4) - (3-O-methyl-2,6-di-O- sodium sulfonate-aD-glucopyranosyl) - (1-4) - (3-O-methyl-2-O-sodium sulfonate-aL-idopyranosyluronate sodium) - (1-4) - (3-O-methyl-2, 6-di-O-sodium s-ulfonate-aDg I upipiranos i I) - (1-4) - (5- (hydroxy) -4-oxypiperidine-3-carboxylate sodium (3S, 4R, 5R)) (compound No. 47) (sodium salt) 47 Compound 46 of PREPARATION 6 was brought according to method 5 to yield, after purification, compound 47 (5 mg, 57%). Mass spectrum (ESI) m / z 1650.9 [(M-Na + H) *]. Example 7: Synthesis of (2,4-di-O-sodium sulfonate-a-L-idopyranosyluronate of so dio) - (1-4) - (2,6-di-O-sodium-sulfonate-Dd-glucopyranosyl) - (1-4) -11-O-sodium-sulfonate-aLi-dopyranosyluronate sodium) - (1- 4) - (2,6-di-O-sodium-sulfonate-α-D-glucopyranosyl) - (1-4) - (5- (hydroxy) -4-oxypiperi din-3-carboxylate sodium (3S, 4R, 5R)) (compound n ° 69) bear. rOSOj coo NH OSOj "OSOJ" OSOJ "OSOJ" 69 sodium salt The brute compound 68 of PREPARATION 9, is scored according to METHOD 5 to yield 69 (3.8 mg, 25%, two eiapas). 1 H NMR (D 2 O) d 5.62 (d, H-1 Glc?), 5.52 (d, H-1 Glc "), 5.21 (d, H-1 ldoUAv), 4.99 (d, H-1 IdoUA1"). Example 8: Synthesis of (4-O-propyl-2-O-sodium sulfonate-α-idopiranos sodium uranium) - (1-4) - (2,6-di-O-sodium sulfonate-a - Dg 1 ucopyranes il) - (1-4) - (sodium 2-O-sodium sulfonate-α-idopyranosyluronate) - (1-4) - (2,6-di-O-sodium sulfonate-a- D -glucopyranosyl) - (1-4) - (5- (hydroxy) -4-oxypiperidine-3-carboxylate sodium (3S, 4R, 5R)) (Compound No. 74) 74 sodium salt The crude compound 73 of PREPARATION 10 was brought according to METHOD 5 to yield 74 (6.0 mg, 62%, two steps). 1H-NMR (D2O) d 5.68 (d, H-1 Glc? V), 5.55 (d, H-1 Glc "), 5.21 (d, H-1 ldoUAv), 5.18 (d , H-1 IdoUA1"). Example 9: S intis sis of methyl (2,4-di-O-sodium its [fon at o - a - L -idopyranosyluronate sodium) - (1-4) - (2 -acetamid o-2- Deoxy-6-O-sodi or sulfonate-α-D-glucopyranosyl D-1,4-) - (5-hydroxy-4-oxo-1-yl-1-yl-3-carboxylate sodium (3S, 4R, 5R)) - (1-4) - (2- N-sodi or sulfonate-2,4-dideoxy-4-methyl-3,6-di-O-sodium-sulfonate-a-D-ql-ucopyranosyl) - (1- 4) - (sodium 2-O-sodium sulfonate-a-L-idopyranosyluronate) - (1-4) - (2-N-sodium sulfonate-2-deoxy-6-O-sodium sulfonate-aD-glucopyranoside) (compound n ° 90) 90 Sodium salt To a solution of compound 89 (24 mg, 26.9 μmol) of PREPARATION 11, and of compound 22 (61 mg, 1.9 molar equivalent) of EXAMPLE 3 in phosphate buffer (pH 7) is added , at 0 ° C, sodium cyanoborohydride (4.4 mg, 2.4 molquiv). After stirring for 8 h at 0 ° C, the reaction medium is placed at ambient temperature for 16 h and successively purified on a column of Sephadex G-25 gel eluted with 0.2 M sodium chloride followed by the same Sephadex0 G-25 column eluted with water to yield the compound 90 (17 mg, 31%). Mass Spec (ESI) m / z 2.029.3 [(M + H-Na) "] Example 10: Synthesis of methyl (2,4-di-O-sodium sulfonate-aL-idopyranosyluronate sodium) - (1-4) ) - (2-acetamido-2-deoxy-6-O-sodium sulfonate-aD-gl ucopi ranosi I) - (1-4) - (5-hydroxy-4-oxypiperidin-1-yl-3-carboxylate) sodium (3S. 4R, 5R)) - (1-4) - (2-N-sodium sulfonate-2,4-dideoxy-4-methyl-6-O-sodium sulfonate-aD-lucopyranosyl) - (1-4) - (sodium 2-O-sodium sulfonate-α-idopyranosyluronate) - (1-4) - (2-N-sodium sulfonate-2-deoxy-6-O-sodium sulfonate-aD-glucopyranoside) (compound n "91) 91 sodium salt In the same manner compound 91 was prepared. Mass Spectrum (ESI) m / z 1.927.1 [(M + H -Na) ']. Example 11: Synthesis of Methyl (5-h? C -oxo-1-ox? P? Per? D? N-1? -3-carboxylate> sodium (3S, 4R, 5R)) - (1 -4) - (2-N-sodium-sulfonate-2,4-dideoxy-4-methyl-3,6-di-O-sul-sulfonate-a-glucopyranosyl) - (1-4) - ( sodium 2- O-sodium its ylphonate- aL-id opi ranosi I uronate) - (1-4) - (2-N-sodium lysulfonate-2-deoxy-6-O-sodium s ulfonate-aDg I ucopi ranos id o) (compound n ° 92) 92 sodium salt In the same manner compound 92 was prepared. Mass spectrum (ESI) m / z 1321.1 [(M + H-Na) "] Example 12: Preparation of (2-acetamido-2-deoxy) -6-O-sodium sulfonate-aDg I ucopyranes il) - (1-4) - (5-h id roxy-4-oxypi peridin-1-methyl-3-carboxylate sodium (3S.4R, 5R)) (compound n ° 98) OSOj "coo HMe NHAc 98 sodium salt Compound 97 of PREPARATION 12 (20 mg, 21.3 μmoles), was brought according to METHOD 5 in a 3: 1: 1 mixture meianol-acetic acid-water under hydrogen stream to yield compound 98 (6.0 mg, 57%). Mass Spec (ESI) m / z 456.8 [(M-H) "] Example 13: Synthesis of sodium (2,4-di-O-sodium sulfonate-α-idopyranosyluronate) - (1-4) - (2-acetamido- • 2-deoxy-6-O-sodium sulfonate-a- -D-glucopyranosyl) - (1-4W2-O -sodium sulfonate-α-L-idopyranosyluron sodium) - (1 - 4) - (2- acetamido-2-deoxy- -6- O- sodium, ulphonate-a-D-g Icopyridans i I) - (1-4) - (5- (hydroxy) -3-hydroxymethyl-4-oxypiperidine- (3R14R, 5R)) (compound n ° 123) Sodium salt Compound 104 (41 mg, 19 μmol) is treated according to METHOD 5, to yield compound 123 (10.7 mg, 38%). 1H NMR (D2O) d 5.28 (d, H-1 Glc "), 5.20 (d, H-1 IdoUA1"), 5.17 (d, H-1 ldoUAv), 5.15 (d, H-1 Glc? V), 3.21, 3.19, 2.68, 2.59 (4m, 4H, H-2, H-2 ', H-6, H-6"pip1) Example 14 : Synthesis of sodium (4-O-pheny1propyl-2-O-sodium sulfonate-a1-idopyranosyluronate) - (1-4) - (2-acetamido-2-deoxy-6-O-sodium s ulfonate-aDg) Ipipepiras i I) - (1-4) - (2-O-sodium sodium sulfonate-aL-idopyranosyluronate) - (1-4) - (2-acetamido-2-deoxy-6-O-sodium sulphonate) α-d-glycopipenes il) - (1-4) - (5- (hydroxy) -4-oxypiperidine-3-carboxylate sodium (3S, 4R, 5R)) (compound no. 124) 124 Sodium salt Compound 122 was brought according to the 5th method to yield the compound 124. 1 H-NMR (D 2 O) d 5,28 (d, H-1 Glc "), 5,21 (d, H-1 ldoUA), 5,16 (d, H-1 IdoUA" 1), 5, 16 (d, H-1 Glc? V), 3.23, 3.20, 2.93, 2.75 (4m, 4H, H-2, H-2 \ H-6, H-6 'pip1) .

Claims (10)

1. Compounds of general formula (I): (I) wherein: R represents a hydrogen atom, a hydroxyl radical, a radical -OSO3, a radical -O-alkyl (C? -C5) or a radical -O-aralkyl; Z represents a radical "COO" or a hydroxyl radical X represents a hydroxyl radical or a saccharide unit of formula A: (A) in which: - R represents an oxygen atom, which allows A to be attached to the azaazucar unit or another saccharide unit, R2 represents a radical -NH2, a radical NHCOalkylid-Cs), a radical -NHCOaryl, a radical -NHSO3, a hydroxyl radical, an -O-alkyloxyCi-Cs radical), an -O-aralkyl radical or a radical -OSO3, -R3 represents a hydroxyl radical, a radical -OSO3, an radical -O-alkylCi-Cs) or an O-aralkyl radical, -R4 represents a hydroxyl radical, a radical -OSO3, a radical -O-alkyl-Cs), a radical -O-aralkyl or a saccharide unit of formula B: wherein: - R6 represents an oxygen atom, which allows B to join another saccharide unit of formula A: - R7 and R8 have the same definition as R3 as defined above, - R9 represents a hydroxyl group, a radical -OSO3, a radical -O-alkyloCi-Cs), a radical -O-aralkyl or a saccharide unit of formula A lal as defined above, -R5 has the same definition as R3al as defined above; Y represents a hydrogen atom, an alkyl radical -CS) or a saccharide unit of formula D in which: - Rio, R? 2 and R13 have in particular the same definitions as R5, R3 and R2 as defined earlier. - Rn represent it: - an alkylene radical ^^ Cs) which allows D to be incorporated into the sugar unit or - an oxygen atom which allows D to be incorporated into another saccharide unit, - R14 represents a radical -O-alkyl (C? - C5) or a radical of formula -OE in which E represents a radical of the formula: (AND) wherein: - R15 represents a radical -O-alkylCi-Cs), an -O-aralkyl radical or a saccharide unit of formula D in which Rn represents an oxygen atom, - R16 and R17 have the same definition as R3 as defined above, with the proviso, however, that when X and R each represent a hydroxyl radical, Y does not represent a hydrogen atom, and it being understood that the number of saccharide units contained in the compound of formula ( I) is comprised between 1 and 10, in free form or in the form of salts formed with an acceptable base or acid from a pharmaceutical viewing point as well as in form solvalos or hidraíos.

2. Compounds according to claim 1 of general formula (I): (I) wherein: R represents a hydrogen atom, a hydroxyl radical, a radical -OSO3, a radical -O-alkyloxyCi-Cs) or a radical -O-aralkyl; Z represents a radical "COO" or a hydroxyl radical X represents a hydroxyl radical or a saccharide unit of formula A: (A) in which: - Ri represents an oxygen atom, - R2 represents a radical --NHCOCH3, a radical --NHSO3 or a radical --OSO3, - R3 represents a hydroxyl radical or a radical --O-alkyl (C? - C5), - R represents a hydroxyl radical, an -O-aralkyl radical or a saccharide unit of formula B: (B) wherein: - R6 represents an oxygen atom, - R7 represents a radical --OSO3", - R8 represents a hydroxyl radical, an -O-C5-alkyl radical - or an -O-aralkyl radical, - R9 represents a radical -OSO3, a radical -O-aralkyl, a radical -O-alkyloxyCTCs) or a saccharide unit of formula A as defined above, - R5 represents a radical -OSO3; Y represents a hydrogen atom or a saccharide unit of Formula D: wherein: - R10 has the same definition as R5 as defined above, - R12 represents a hydroxyl radical or a radical --OSO3, - Ri3 represents a radical --NHSO3, - Rn represents a methylene radical attached to the azaazucar unit or an oxygen atom bonded to E, -R14 a radical -OCH3 or a radical of formula -OE in which E represents a radical of the formula: (AND) wherein: - R15 represents a unit D in which Rn represents an oxygen atom that makes it possible to join E to D, - R16 represents a radical --OSO3, - R17 represents a hydroxyl radical, it being understood that the number of saccharide units contained in the compound of general formula (I) is comprised between 2 and 10, in free form or in the form of salts with a pharmaceutically acceptable base or acid as well as in the form of solvates or hydrates.

3. Compounds of the general formula (I) according to any one of claims 1 or 2, wherein Y is a hydrogen atom and Z a COO radical. "

4. Compounds according to any one of claims 1 to 3, chosen from: • (2,4-di-O-sodium sulfonafo-aL-idopyranosyluronal sodium) - (1 -4) - (2-acetamido-2-deoxy-6-O-sodium sulfonate-aD-glucopyranosyl) - (1 - 4) - (sodium 2-O-sodium sulfonate-α-idopyranosyluronate) - (1-4) - (2-α-methido-2-deoxy-6-O-sodium sulfonate-α-D-glucopyranosyl) - (1 -4) - (5- (hydroxy) -4-oxypiperidine-3-carboxylate sodium (3S, 4R, 5R)), • (2,4-di-O-sodium sulfonate-aL-idopranosyluronate sodium) - ( 1-4) - (2-N-sodium sulfonate-2-deoxy-6-O-sodium sulfonate-aD- glucopyranosyl) - (1-4) - (sodium 2-O-sodium sulfonate-al-idopyranosyluronate) - (1-4) - (2-N-sodium-sulfonate-2-deoxy-6-O-sodium-sulfonate-a) -glucopyranosyl) - (1-4) - (5- (hydroxy) -4-oxypiperidine-3-carboxylic acid sodium (3S, 4R, 5R)), • (3-O-methyl-2,4-di-O) sodium sodium sulfonate-al-idopyranosyluronate) - (1-4) - (3-O-methyl-2,6-di-O-sodium sulfonate-aD-glucopyranosyl) - (1-4) - (3-O -methyl-2-O-sodium sulfonate-al-idopyranosyluronate sodium) - (1 -4) - (3-O-methyl-2,6-di-O-sodium s-ulfonate-aDg I ucop i ranos il) - (1-4) - (5- (hydroxy) -4-oxi pipe rid in -3-carboxylate sodium (3S, 4R, 5R)), • (2,4-di-O-sodium sulfonate-α-idopyranosyluronate sodium) - (1 -4) - (2,6-di-O-sodium its Ifonato-aDg lucopi ranosi l) - (1 -4) - (2-O-sodium sulfonate-aL-idopyranosyluronal sodium) - (1 -4) - (2,6-di-O-sodium its Ifonalo-aDg I ucopi ranosi l) - (1 -4) - (5- (h id roxi) -4-oxipipe rid in-3-carboxilaío sodium (3S, 4R, 5R)), • (4-O-propyl-2-O-sodium sulfonation-al-idopyranosyluronal sodium) - (1-4) - (2,6-di) -O-Sulfonalo-aD-glucopyranosyl) - (1-4) - (2-O-sodium sulphonated-al-idopyranosyluronal sodium) - (1-4) - (2,6-di-O-sodium sulfonation- aD-glucopyranosyl) - (1-4) - (5- (hydroxy) -4-oxypiperidine-3-carboxylate sodium (3S, 4R, 5R)). • (2,4-di-O-sodium sulfonalo-aL-idopyranosyluronal sodium) - (1 -4) - (2-acetamido-2-deoxy-6-O-sodium sulfonate-aD-glucopyranosyl) - (1 - 4) - (2-O-sodium sulfonate-al-idopyranosyluronate sodium) - (1 -4) - (2-acelamido-2-deoxy-6-O-sodium sulfonate-aD- glucopyranosyl) - (1-4) - (3- (hydroxy) -5-hydroxymethyl-4-oxypiperidine- (3R, 4R, 5R)) • (4-O-phenylpropyl-2-O-sodium sulfonate-al-idop i ranosilu róñalo of sodium) - (1-4) - (2-acelamido-2-deoxy-6-O-sodium sulfonato-aD-glucopyranosyl) - (1-4) - (2-O-sodium sulfonato-aL- idopi ranosilu sodium ato rum) - (1-4) - (2-acetamido-2-deoxy-6-O-sodium sulfonaio-aD-glucopyranosyl) - (1-4) - (5- (hydroxy) -4- sodium oxypiperidine-3-carboxylane (3S, 4R, 5R))

5. Pharmaceutical compositions which contain, as an active principle, a compound of general formula (I) according to any one of claims 1 to 4, optionally in association with one or several inert and appropriate excipiens.

6. Pharmaceutical composition according to claim 5, useful in the irradiation of diseases in which heparanases are implicated.

7. Pharmaceutical composition according to claim 5, useful in the treatment of carcinomas that have a degree of vascularization such as carcinoma of the lung, breast, prostate and esophagus, cancers that induce meiasis such as colon cancer and cancer. slogan, melanomas, gliomas, lymphomas or leukemias.

8. Pharmaceutical composition according to claim 5, in the case of cardiovascular diseases such as aerosol, post-angioplasty resenhosis, diseases associated with complications that appear after the placement of a prosthesis. endovascular and / or aorio-coronary or other vascular ingestions of cardiac hyperlofia or vascular complications of diabetes such as diabetic retinopathies.

9. Pharmaceutical composition according to claim 5, useful in the irradiation of chronic inflammatory diseases such as rheumatoid arthritis or I BD.

10. Pharmaceutical composition according to claim 5, useful in the traumatization of macular degeneration.