CA2780627A1 - Novel mannopyranoside derivatives with anticancer activity - Google Patents

Abstract

The present invention relates to compounds derived from mannopyranoside and to their use as medicaments, in particular for the treatment of cancerous diseases, as well as to their method of preparation and to pharmaceutical compositions comprising such compounds. Also part of the invention are medical devices treated at the surface with compounds derived from mannopyranoside according to the invention.

Description

NOVEL MANNOPYRANOSIDE DERIVATIVES WITH ACTIVITY
CANCER
The present invention relates to compounds derived from mannopyranoside, has a method of synthesis by green chemistry of such compounds, and their use in title of medicines, especially for the treatment of cancerous diseases, as well as of the pharmaceutical compositions comprising such compounds. Also do from the invention of implantable medical devices surface-treated with compounds derived from mannopyranoside according to the invention.
Many pathologies have been described in the state of the art as having a component or a stage related to the phenomenon of angiogenesis. We can mention others of very numerous cancers, diabetic retinopathies, atherosclerosis, osteoarthritis, polyarthritis rheumatoid, psoriasis, as well as inflammatory pathologies or those linked to a delayed healing.
Angiogenesis is a mechanism of neovascularization that starts at from a pre-existing capillary network. The budding of small vessels, the capillaries, from pre-existing ones, intervenes for the better during development embryonic and implantation of the placenta, when it comes to healing an injury, or to overcome the obstruction a ship; but also for the worse in cancers (growth of tumors and development of metastases), rheumatoid arthritis, certain diseases ophthalmological such as diabetic retinopathy or age-related macular degeneration.
For all of these processes, the general pattern remains the same. Cell activation endothelial leads to degradation of the basement membrane and the extracellular matrix surrounding. The migration oriented is followed by a proliferative phase. The cells are different then in a structure capillary type to form a vascular network necessary for tissue development.
However, angiogenesis is not controlled by a single factor, but by inductor balance and inhibitors produced by normal or tumor cells. Among these factors, polypeptides such as fibroblast-2 growth factor ("Fibroblast Growth Factor-2 ":
FGF-2) and the "vascular endothelial growth factor (Vascular Endothelial Growth Factor ": VEGF) have emerged as key regulators of angiogenesis.
Many molecules have been studied for their inhibitory effect or activator of angiogenesis.

2 Regarding the inhibition of angiogenesis, a conceptual revolution recent in cancer treatment consists of targeting the vascular network that irrigates a tumor. It is now well established that the development of intra or peritumoral is a key event for both tumor growth and dissemination metastatic by the bloodstream. In December 2005, the English scientific journal Nature, which devoted his number at angiogenesis, counted more than 300 inhibitors, of which 80 in progress clinical trials.
But the first drugs tested - angiostatin, endostatin, interferons, inhibitors matrix metalloproteinases, etc. - were disappointing. Among more molecules recent, we can quote bevacizumab. Injected to the patient, it neutralizes a type of VEGF
circulating in capillaries or diffuse in the tumor, VEGF-A. His first indication was in 2004 for the metastatic colorectal cancer, in combination with chemotherapy. It is today in clinical trials against metastatic kidney cancer, lung cancer and breast. VEGF-A
has the disadvantage of increasing the risk of high blood pressure and bleeding. We can also mention sunitinib and sorafenib which have the advantage of to authorize a formulation in the form of tablets to be taken orally and which lead to results encouraging therapeutics. They also have the disadvantage to generate some effects side effects such as hypertension, fatigue or skin problems.
In addition, the molecules currently used for their properties inhibitors angiogenesis have high toxicities often prohibitive for the continuation of treatments, this toxicity limits the duration and effectiveness of the medications current.
There is therefore a constant and extremely important need for compounds inhibitors angiogenesis having a very low toxicity and a better affinity with receivers, in the purpose of proposing new cancer treatments with a excellent anti-activity tumor.
It is therefore in order to remedy all of these disadvantages and to provide of the compounds with very low angiogenesis inhibition activity toxicity combined with excellent activity, these compounds being particularly useful for preparation of anticancer drugs, that the inventors have developed what makes the object of this invention.
The inventors have indeed discovered that certain derivatives of mannopyranoside show excellent anticancer activity and very low toxicity, these compounds that can be

3 used for the preparation of pharmaceutical compositions for Treatment of cancerous diseases.
The subject of the present invention is therefore a compound derived from mannopyranoside or his pharmaceutically acceptable salts, corresponding to one of the following formulas > Formula (1) B
BB

B
BA

B
B

boy Wut in which :
A is a silica nanoparticle or a selected metallic nanoparticle from column elements (IB), (IIB), (IIIB), (IVB), (VB), (VIB), (VIIB) or (VIIIB) the classification of Mendeleyev, and B is a group carrying a mannopyranoside function, also called polar head, corresponding to the following structure:
R
O
ON / N \ N
HO
HO
O

OO

S
in which m is an integer between 0 and 10, and preferably m = 3, 4, 5 or 6, the groups B being linked to the nanoparticle A via the sulfur atom, and the number of B groups bound to the nanoparticle A being between 100 and 1000, and preference between 400 and 600,

4 - Formula (II):
HO
HO
R
O
HO OO
OH
HO

Y
in which Y represents one of the following groupings O /
n OO
OX or OH
H HO
ho OR2 with:
on, n 'and n "being integers between 1 and 12, and preferably between 1 and 6, and where "is 0 when X represents an oxygen atom, - Formula (III):
Z
HO-- ~ O
OH
HO

in which Z represents one of the following groupings OH ~ / IP IP
-CH2-B or -X-HP or -X ~, X ~ OH or -XR
OH OH OH OH

in which :

WO 2011/05824

5 PCT / FR2010 / 000749 the radicals R 1 and R '1, which are identical or different, represent a radical selected from -O-P03H2, -N3, -CH2-PO3H2, -CH2-COOH, -SO3H2, -OPHO2H, -CH2-B (OH) 2, -X-PHO2H, X'-PO2H-X-PO3H2, and preferably -CH2-COOH and -N3, the radical R2 represents a linear or branched C1-C12 alkyl chain, and preferably in C1-C4; a linear or branched C1-C12 alkyl chain, and preferably C1-C4, carrier at least one -OH, -NH2, -SH, -000H, -N3, -NO2 group; a cycle hydrocarbon, saturated or unsaturated C3-C6; a C3-C10 hydrocarbon ring, saturated or unsaturated, carrier at least one -OH, -NH2, -SH, -000H, -N3, -NO2, C1-C4 alkyl group;
a saturated or unsaturated heterocycle having at least one heteroatom selected from the atoms oxygen, nitrogen or sulfur; a radical - (CH2-CH2-O) yH, wherein is comprised between 1 and 12, and preferably between 1 and 6, and the groups X and X ', which are identical or different, are chosen from: N, O, S, a chain C1-C4 alkyl, the X and X 'groups being preferably atoms oxygen.
Among the C1-C4 alkyl chains mentioned for R2, it is possible in particular quote radicals methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl and n-hexyl, the methyl radical being the most preferred.

Of the saturated hydrocarbon rings mentioned for R2, it is possible to particular quote the cyclopropane, cyclobutane, cyclopentane and cyclohexane.
Unsaturated hydrocarbon rings and saturated heterocycles mentioned for R2, mention may in particular be made of the phenyl, oxadiazole and triazole rings, oxazole, isoxazole, imidazole, thiadiazole, pyrrole, tetrazole, furan, thiophene, pyrazole, pyrazoline, pyrazolidine, thiazole, isothiazole, pyridine, pyrimidine, piperidine, pyran, pyrazine, pyridazine, indole, indazole, benzoxazole, naphthalene, quinoline, quinoxaline, quinazoline, anthracene and acridine cycles phenyls being the most preferred.
According to an advantageous embodiment, when the compound of the invention is a compound of formula (1), the nanoparticle A is chosen from nanoparticles of gold, iron and cobalt, and more particularly gold nanoparticles. Nanoparticles A
can have a diameter between 2 and 10 nm, and preferably between 4 and 8 nm.
Due to the presence of multipolar heads (groups B), the compounds of Formula 1) have a better affinity for receptors, and therefore anti-aging properties angiogenic improved compared to known compounds of the prior art.

6 According to another advantageous embodiment, when the compound of the invention is a compound of formula (II) in which not Y = HO n .. X

ho then n = 1, n '= 2 and n "= 0, and X represents an oxygen atom.
The compounds according to the invention can be used as a principle active for the manufacture of medicinal products, in particular for the prevention and / or disease treatment dependent on an inhibition of angiogenesis, among which one can all particularly to mention cancerous diseases, diabetic blindness, degeneration macular, polyarthritis rheumatoid and psoriasis.
Another subject of the invention is a pharmaceutical composition comprising, at title of active ingredient, at least one compound according to the invention as defined above.
above, and at least one a pharmaceutically acceptable excipient, said composition possibly also to be used for prevention and / or treatment of diseases dependent on inhibition of angiogenesis, such as those mentioned above.
The form of the drug or pharmaceutical composition may be a solution, a suspension, an emulsion, tablets, capsules, suppositories, and will depend on the way chosen.
Thus, within the meaning of the present invention, the medicament or the composition pharmaceutical may be administered by any suitable route, for example by see oral, local, systemic, intravenous, intramuscular or mucosal, or using a patch.
Depending on the route of administration of the drug or composition invention, the person skilled in the art will choose one or more excipients pharmaceutically suitable. Examples include, but are not limited to limiting suitable excipients for oral administration: talc, lactose, starch and its derivatives, cellulose and its derivatives, polyethylene glycols, polymers acrylic acid, the gelatin, magnesium stearate, animal fats, vegetable or synthetic, derived from paraffin, glycols, stabilizers, preservatives, antioxidants, the agents

7 wetting agents, anti-caking agents, dispersants, emulsifiers, modifying agents of the taste, penetrants, solubilizers, etc.
When it is intended for the treatment of cancerous diseases, the composition pharmaceutical may further comprise one or more active ingredients antitumor among which may be mentioned antimitotics, inducers of the differentiation, antibodies, etc.
More particularly, these active ingredients may be doxorubicin, etoposide, fluorouracil, melphalan, cyclophosphamide, beomycin, vinblastine, mitomycin, lomustine (UNFC), taxotere, taxol, metotrexate and cisplatinum.
The compounds of the invention can be prepared according to well known from those skilled in the art, these syntheses having already been described in the documents following:
BG Davis et al., J. Org. Chem., 1998, 63, 9614-9615, - ME Evans et al., Carb. Res., 1977, 54, 105-54, PAM Van der Klein et al., Carb. Res., 1992, 224, 193-200, - HH Baer et al., Carb. Res., 1990, 200, 377-389, - C. Grondal, Synlett, 2003, 10, 1568-1569, EA Hauser et al., Experiments in Colloid Chemistry, McGraw Hill, 1940, p.18, J. Turkevich et al., Discuss. Faraday. Soc., 1951, 11, 55-75, J. Kimling et al., J. Phys. Chem. B, 2006, 110, 15700-15707, Boronate Formation: R. Soundararajan et al., J. Org. Chem., 1990, 55, 2274-2275, - Formation of borates:
J. Meulenhoff et al., Allg. Chem., 1925, 373, SD Ross et al., J. Org. Chem., 1965, 30, 2852, - CJ Salomon et al., Tetrahedron Lett., 1995, 36, 6759-6760, Pyrophosphonate Formation: AM Michelson, Biochem. Acta., 1964, 91, 1-- Synthesis of hydrogenophosphonates:
Clavel et al., Tetrahedron Letters, 2004, 45 (40), 7465-7467, Z. Ge et al., Journal of Applied Polymer Science, 2007, 104 (2), 1138-1142, - K. Jarowicki et al., Journal of the Chemical Society-Perkin Transactions, 2001, (18), 2109-2135, F. Onyemauwa et al., Organic Letters, 2006, 8, 5255-5258.

8 The compounds of the invention may also be prepared according to a process ecological, also called green chemistry process. This process presents the advantage of not require solvent, or additional purification step by chromatography, while allowing to obtain high yields. Indeed, the processes described in the prior art very often require protection / deprotection steps which are reagent users and expensive and polluting solvents. Thus, the inventors have developed a process allowing to overcome these disadvantages, said method comprising at least the steps following:
(i) a halogenation step between a compound of formula (I '), (II') or (III ') carrier of minus a primary alcohol function, by reaction with a mixture dihalogen / phosphine or N-halosuccinimide / phosphine, said compounds (I '), (II') or (III ') corresponding to the formulas above :
- Formula (I '):

B ' B 'B' B ' BA

B ' B ' B ' where A has the same meaning as above, and B 'is a grouping corresponding to the following structure OH
O
O

HO 0 - / ,, NOT
HO
O

OO

M S-in which my the same meaning as before,

9 the groups B 'being linked to the nanoparticle A via the sulfur atom, and the number of groups B 'linked to the nanoparticle A being between 100 and 1000, and preferably between 400 and 600, - Formula (II ') HO
HO OH
OH
O
HO OO
OH
HO

Y
in which Y, n, n 'and n "have the same meaning as before, - Formula (III '):
OH
~ _, OH
HO

the radical R2 and the groups X and X 'being as defined previously, (ii) a nucleophilic substitution step of the halogenated compounds obtained during of the stage (i) by reaction with a nucleophilic reagent bearing an R radical, and / or R ' 1, the latter being preferably a lithien, the nucleophilic reagent being particularly selectable among LiO-P03H2, NaN3, LiCH2-PO3H2, LiCH2-COOH, LiSO3H2, LiOPHO2H, LiCH2-B (OH) 2, LiX-PHO2H, LiX'-PO2H-X-P03H2, to obtain the compounds of formula (I), (II) or (III) of the invention.
In steps (i) and (ii), the reagents are preferably used in proportions stoichiometric.
According to an advantageous embodiment, the phosphine used during the step (He is chosen from a trialkylphosphine whose alkyl chain is C1-C6, the triphenylphosphine Pcp3 or 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, and even more preferred step (i) is carried out with a 12 / Pcp3 mixture, in the presence of imidazole. Reagents used during the stage (i) are preferably previously ground and then heated in a bath oil at a temperature may vary from 60 to 100 C, with stirring, for a period of time between 15 and 30 minutes.

At the end of step (i), the reaction mixture is dissolved in a solvent such as methanol, concentrated and then filtered through silica gel.
Step (ii) can, for its part, advantageously be carried out by mixing the compound halogen obtained in step (i) with a nucleophilic reagent carrying a radical RI and / or R'1.
The reagents used during step (ii) are preferably preferably crushed, then heated in an oil bath at a temperature ranging from 60 to 100 C, under stirring during a duration between 15 and 30 minutes. At the end of step (ii), the mixture reaction is purified, preferably by flash filtration on silica gel.
An example of synthesis according to the green chemistry method is shown schematically in Figure 5 annexed, the method implemented comprising a step of iodizing the a-D-mannopyranoside, the iodo-α-D-mannopyranoside obtained being then reacted in proportions stoichiometric with sodium azide (NaN3), the latter allowing functionalization of mannopyranoside in position 6.
Finally, a last object according to the invention relates to a medical device implantable in the human body, said device being surface-treated by at least one compound derived from mannopyranoside according to the invention. Among the devices mentioned above, we can mention the prostheses, and more particularly vascular stents, urethral Bile. The need for such devices exist because, currently, many medical devices do not allow that limited implantation in the human body due to angiogenesis excessive.
In addition to the foregoing, the invention also includes other provisions which will be apparent from the following description, which refers to examples of preparation of compounds according to the invention, as well as highlighting examples anti-activity tumor of the compounds of the invention relative to other compounds representative of the state of art not forming part of the invention, as well as in FIGS.
annexed, following FIG. 1 represents the synthesis scheme of compounds la at 5a, FIG. 2 represents the synthesis scheme of compounds 6a to 9a, 3 represents the synthesis scheme of the compounds 10a to 13a (functionalization mannopyranoside in position 6 with a carboxy group), FIG. 4 represents the synthesis scheme of compounds 14a to 16a (functionalization mannopyranoside in position 6 with an azido group), FIG. 5 represents the synthesis scheme of a compound of formula (11) according to the invention, FIG. 6 represents the synthesis scheme of a compound of formula (III) according to the invention, FIG. 7 represents the synthesis scheme of a compound of formula (III) according to the invention, - Figure 8 summarizes the synthesis of a pyrophosphonate derivative (compounds lg to 6g) having the formula (111) of the invention.
- Figure 9 summarizes the synthesis of a pyrophosphate derivative (compounds 1h to 6h) responding to the formula (I11) of the invention, FIG. 10 represents the synthesis scheme of a compound corresponding to the formula (I1) of the invention, 11 represents the synthesis scheme of a compound corresponding to the formula (111) of the invention (compounds li to 7i), FIGS. 12a and 12b are histograms representing the neo-angiogenic in of different compounds of the invention (Nicosia model), 13 is a histogram showing the cytotoxic effect of various composed of the invention, 14 is a graph showing the survival rate of mice in number function of treatment days, for different compounds of the invention, FIG. 15 is a graph showing tumor growth as a function of number of days of treatment, for different compounds of the invention, and - Figure 16 represents photographs of the vascularization of embryos of chickens during of a classical test for the study of in vivo angiogenesis performed on the membrane chorioallantoic (CAM).
It should be understood, however, that these examples are given only purely illustrative of the invention, of which they do not constitute in any way a any limitation.

EXAMPLE 1 Preparation of a Compound of Formula (I) 1) SYNTHESIS OF 2-BROMOETHYL-2,3,4,6-TETRA-O-ACETYL-α-D
MANNOPYRANOSIS (Compound la) 8 g of acetyl-2,3,4,6-tetra-OaD-mannopyranose (20.5 mmol, 1 eq.) Dissolved in 70 mL
of dichloromethane are reacted with 4.34 mL of 2-bromoethanol (61.5 mmol, 2 eq.) and 15.5 mL of BF3-Et2O (123 mmol, 5 eq). After stirring for 8 hours at room temperature ambient, the reaction mixture is diluted in CH 2 Cl 2, washed with water, a solution saturated NaHCO3, then again with water. The aqueous phase is then dried on Na2SO4, filtered and evaporated. The product is purified by column chromatography silica gel (ethyl acetate (AcOEt) / petroleum ether (EP) 5/5 v / v). We get 2-bromoethyl-2,3,4,6 tetra-O-acetyl-α-D-mannopyranoside as a white powder (8.5 g, 91%).
Rf: 0.86 (AcOEt / EP 5/5 v / v).
MS (ESI + / MeOH): m / z 477.01, 478.95 [M + Na] +.
1 H NMR (400.13 MHz, CDCl 3) δ (ppm): 2.00, 2.05, 2.11, 2.16 (4s, 12H, Hb);
3.52 (t, 2H, J8 - j = 6.0 Hz, Hg); 3.93 (m, 2H, H7); 4.13 (m, 2H, H5 and H6a); 4.27 (dd, 1H, J6b-5 = 5.8 Hz, J6b-6a = 12.6 Hz, H6b); 4.88 (d, 1H, J1-2 = 1.6 Hz, H,); 5.27 (dd, 1H, J2_1 = 2.0 Hz, J2-3 = 3.2 Hz, H2); 5.29 (t, 1H, J4-5 = J4 -3 = 1.6 Hz, H4); 5.35 (dd, 1H, J3_2 = 3.6 Hz, J3_4 = 10.0 Hz, H3).
13 C NMR (100.62 MHz, CDCl3) δ (ppm): 20.67, 20.70, 20.75, 20.87 (4 Cb);
29.60 (C8);
62.41 (C6); 66.00 (C4); 68.48 (C7); 68.93 (C5); 69.02 (C3); 69.42 (C2);
97.75 (CI); 169.76, 169.86, 170.03, 170.62 (4 Q.
2) SYNTHESIS OF 2'-AZIDOETHYL-2,3,4,6-TETRA-O-ACETYL-α-D
MANNOPYRANOSIS (Compound 2a) 5.7 g of 2-bromoethyl-2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside (compound 1) (12.6 mmol, 1 eq.) and 1.64 g of sodium azide (25.16 mmol, 2 eq) are dissolved in 50 mL of dimethylformamide (DMF). After stirring for 4 hours at a temperature of 65 ° C., The mixture The reaction is diluted in 50 ml of AcOEt and extracted with NaCl solution.
saturated, then washed with distilled water to remove the DMF. The organic phase is then dried on Na2SO4, filtered and concentrated to give a white solid, 2'-azidoethyl-2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside (5.25 g, 96%).
Rf: 0.86 (AcOEt / EP 5/5 v / v).
MS (ESI + / MeOH) m / z: 440.112 [M + Na] +.

1 H NMR (400.13 MHz, CDCl3) δ (ppm): 2.00.2.05, 2.11, 2.16 (4s, 12H, Hb);
3.47 (m, 2H, H8); 3.67 (m, 1H, Hia); 3.87 (m, 1H, H7b); 4.05 (ddd, 1H, J5-6a = 2.4 Hz, J5-6b = 5.2 Hz, J5-4 = 9.7 Hz, H5); 4.13 (dd, 1H, J6a-5 = 2.6 Hz, J6a-6b = 12.2 Hz, H6a); 4.29 (dd, JH, J6b-5 = 5.2 Hz, J6b-6a = 12.4 Hz, H6b); 4.87 (d, 1H, J1-2 = 1.6 Hz, H,); 5.30 (t, 1H, J4-3 =
J4-5 = 10.0 Hz, H4); 5.28 (dd, 1H, J2-, = 2.0 Hz, J2_3 = 3.2 Hz, H2); 5.36 (dd, 1H, J3-2 = 3.2 Hz, J3-4 = 10.0 Hz, H3).
13 C NMR (100.62 MHz, CDCl 3) δ (ppm): 20.63, 20.68, 20.71, 20.84 (4C, CO;
50.32 (C8); 62.42 (C6); 65.96 (C4); 67.02 (C7); 68.82 (C5 and C3); 69.36 (C2);
97.71 (CI); 169.73, 169.78, 169.98, 170.59 (4C, Ca).
3) SYNTHESIS OF 2'-AZIDOETHYL-α-MANNOPYRANOSIS (Compound 3a) 6.8 g of 2'-azidoethyl-2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside (16.3 mmol, 1 eq.) And 880 mg of sodium methanolate (16.3 mmol, 1 eq.) Are dissolved in 60 mL of methanol.
After stirring for 30 minutes at room temperature, the solution is neutralized with balls of Amberlyst IRC-50-H + resins, filtered and concentrated. The oil obtained is then purified by silica gel column chromatography with an elution gradient (CH2Cl2 / MeOH 9/1 v / v to 6/4 v / v CH 2 Cl 2 / MeOH) to give white crystals (2.44 g, 65%).
Rf: 0.4 (CH2Cl2 / MeOH 8/2 v / v).
MS (ESI + / MeOH) m / z: 272.11 [M + Na] +; 288.02 [M + K] +; 521.19 [2M + Na] +.
1 H NMR (400.13 MHz, CD3OD) δ (ppm): 3.41 (t, 2H, J8-7 = 5.0 Hz, C8); 3.60 (m, 3H, H30H5 and H7a); 3.71 (m, 2H, H4 and H6a); 3.85 (m, 2H, H2 and H6b); 3.92 (m, 1 H, H7b); 4.81 (d, 1H, J1_2 = 1.2 Hz, HI).
1H NMR (100.62MHz, CD3OD) δ (ppm): 51.76 (C8); 62.94 (C6); 67.74 (C7);
72.08 (C2); 72.49 (C4); 68.54, 74.93 (C3 and C5); 101.82 (C,).
4) SYNTHESIS OF 2'-AZIDOETHYL-2,3-O-ISOPROPYLIDENE-aD-MANNOPYRANOSIS (Compound 4a) Formation of di-O-isopropylidene 9.5 g of 2'-azidoethyl-α-D-mannopyranose (compound 3a) (38.10 mmol, 1 eq) are set .suspension in 40 mL of acetone, 23.5 mL of 2,2-dimethoxypropane (190 mmol, eq.) are then added, followed by 362 mg of para-toluenesulfonic acid (APTS) (1.9 mmol, 0.05 eq.) Are also added. The mixture is left under magnetic stirring at ambient temperature for 4 hours. The reaction is monitored by TLC (EtOAc / 6/4 petroleum ether) which then indicates that there is no more starting material (Rf = 0), some traces of monoisopropylidene (Rf =

0.5) are observed, the product mainly present being the diisopropylidene (Rf = 0.8).
The APTS is then neutralized with 5% NaHCO3 solution, and the solution is then concentrated to remove all traces of acetone. The di-O-isopropylidene obtained is extracted with ether of petroleum, then dried over Na2SO4, filtered and concentrated. The product obtained in the form of a Yellow oil is pure enough to be put right back into reaction. The sentence aqueous containing the mono-isopropylidene is then lyophilized.
Selective opening 7.5 g of 2'-azidoethyl-2,3,4,6-di-O-isopropylidene-α-D-mannopyranose (22.9 mmol, 1 eq.) are dissolved in 60 mL of acetic acid / water 80/20 v / v. After 2 hours stirring at a temperature of 35 ° C., the starting material (2-azidoethyl-α-D
mannopyranose) reappears. The solvents are then evaporated and then co-evaporated with toluene.
oil obtained is purified by gel column chromatography.
silica (AcOEt / EP 6/4 v / v) to give a slightly yellow oil (5.65 g, 85%).
Characterization of diisopropylidene:
Rf: 0.63 (AcOEt / EP 5/5 v / v).
MS (ESI + / MeOH) m / z: 352.20 [M + Na] +; 368.02 [M + K] +.
1 H NMR (400.13 MHz, acetone-d6) δ (ppm): 1.31, 1.32 (2s, 6H, Hb and Hd);
1.47, 1.48 (2s, 6H, H, and He); 3.50 (t, 2H, J = 4.8 Hz, H8); 3.53 (m, 1H, H5); 3.72 (m, 3H, H6a, H4 and Hia), 3.82 (dd, 1H, J6b-5 = 5.8 Hz, J6b-6a = 10.6 Hz, H6b); 3.93 (qt, 1H, J = 5.2 Hz, H7b); 4.03 (dd, 1H, J3-2 = 5.6 Hz, J3_4 = 8.0 Hz, H3); 4.18 (d, 1H, J2-3 = J2-1 = 5.6 Hz, H2);
5.09 (s, 1H, H 1).
13 C NMR (100.62 MHz, acetone-d 6) δ (ppm): 20.11, 29.38 (Cb and Cd); 27,45, 30.50 (This And this) ; 52.18 (C8); 63.48, 63.53 (C5 and C6); 68.17 (C7); 74.47 (C4);
76.78 (C3); 77.83 (C2) 99.68 (CI); 109.76 (Ca).
Characterization of monoisopropylidene:
Rf: 0.26 (AcOEt / EP 6/4 v / v).
MS (ESI + / MeOH) m / z: 312.12 [M + Na] +; 328.15 [M + K] +, (ESI- / MeOH) m / z: 324.12 [M + Cl] -.
1H NMR (400.13 MHz, acetone-d6 + D20) δ (ppm): 1.27, 1.41 (2s, 6H, Hb and H) ; 3.45 (t, 2H, J = 5.0 Hz, H8); 3.52 (m, 2H, H4 and H5); 3.62 (dd, 1H, J6a-5 =
5.2 Hz, J6a-6b = 1 1.6 Hz, H6a);
3.67 (m, 1H, H7a); 3.80 (m, 1H, H6b); 3.93 (m, 1H, H7b); 4.02 (m, 1H, H3); 4.09 (d, 1H, J2-3 =
J2-i = 5.6 Hz, H2); 5.03 (s, 1H, H1).

13 C NMR (100.62 MHz, acetone-d 6 + D 2 O) (ppm): 2.34, 29.11 (Cb and Q); 51.95 (C8); 62.97 (C6); 67.74 (C7); 70.41, 72.62 (C4 and C5); 77.30 (C2); 80.42 (C3); 98.60 (THIS) ; 110.60 (Ca).
5) SYNTHESIS OF 2'-AZIDOETHYL-2,3-O-ISOPROPYLIDENE-4,6-0-(CYCLOSULFATE) -aD-MANNOPYRANOSE (Compound 5a) Formation of sulphite:
100 mg of 2'-azidoethyl-2,3-O-isopropylidene-α-D-mannopyranose (compound 4a) (0,345 mmol, 1 eq.) and 169 L of triethylamine (0.001 mmol, 3 eq.) are dissolved in 2 mL of CH2Cl2.
The balloon is placed in an ice bath and 27 L of thionyl chloride (0.38 mmol, 1.1 eq.) are added slowly. A white precipitate of triethylammonium chloride appears quickly and the reaction mixture gradually becomes yellow, then brown. After 5 minutes stirring at a temperature of 0 C, there is no longer any starting material, the desired sulphite is obtained in the form of 2 diastereoisomers (Rf = 0.53 and 0.62 (AcOEt / EP 5/5)).
The mixture is filtered, the organic phase is washed with distilled water, a solution hydrochloric acid (HCI) to iN, then again with water. The organic phase is then dried over Na2SO4, filtered and concentrated to give a solid brown directly handed reaction.
Sulphate formation:
Raw sulphite (0.345 mmol, 1 eq.) Is dissolved in 2 mL of a mixture (1/1 v / v). 81 mg of sodium metaperiodate (0.38 mmol, 1.1 eq.), 0.5 mL of water and a grain of ruthenium chloride (1.38 × 10 -3 mmol, 0.004 eq.) are added successively.
The reaction is exothermic, a precipitate of Na103 is formed very rapidly. After 1 hour stirring at room temperature, the sulfite was consumed, the reaction mixture is filtered and diluted in 20 mL of CH2Cl2. The organic phase is washed with a solution of 5% NaHCO 3, some water distilled, then dried, filtered and concentrated. The brown solid obtained is dissolved in a minimum CH 2 Cl 2 and filtered through silica. The silica is rinsed several times with CH2Cl2. We then obtain a white solid (80 mg, 66%).
Rf: 0.58 (AcOEt / EP 5/5 v / v).
MS (ESI + / MeOH) m / z: 374.13 [M + Na] +, (ESI + / MeOH) m / z: 386.08 [M + Cl] -.
1 H NMR (400.13 MHz, acetone-d6) δ (ppm): 1.37, 1.52 (2s, 6H, Cb and Q); 3.55 (m, 2H, H8); 3.80 (m, 1H, Hia); 4.29 (m, 1H, H7b); 4.26 (td, 1H, J5.4 = JS_ba =

10.7 Hz, J5-6b = 5.5 Hz, H5) 4.36 (d, 1H, J2, = J2.3 = 6.0 Hz, H2); 4.43 (dd, 1H, J3.2 = 5.6 Hz, J3.4 =
8.0 Hz, H3); 4.6 (dd, 111, J4-3 = 7.6 Hz, J4-5 = 10.8 Hz, H4); 4.63 (t, 1H, J6a-5 = J6a-6b = 10.8 Hz, H6a); 4.84 (dd, 1H, J6b-5 5.6 Hz, J6b-6a = 10.4 Hz, H6b); 5.28 (s, 1H, H1).
13 C NMR (100.62 MHz, acetone-d6) δ (ppm): 27.16, 29.13 (Cb and C); 52.06 (C8) 60.35 (C5); 68.75 (C7); 74.34 (C6); 74.95 (C3); 77.88 (C2); 86.65 (C4);
99.70 (C1); 112.07 (It).
The syntheses of compounds la to 5a described above are summarized in Figure 1 attached.
6) SYNTHESIS OF PENT-1-EN-5-YLHEXA (ETHYLENEGLYCOL) (Compound 6a) 25 g of hexa (ethylene glycol) (88.5 mmol, 4.12 eq) are dissolved in a solution of 50% NaOH. After stirring for 30 minutes at a temperature of 100 ° C., 2.58 mL
of 5-bromopent-1-ene (21.85 mmol, 1 eq) are added. We keep the mixture under stirring at a temperature of 100 C for 15 minutes. The mixture is then diluted in CH2C12 and the product is extracted with petroleum ether. Water is added to the phase CH2CI2 which is re-extracted several times with petroleum ether. The organic phases are collected, washed with a minimum of water, dried over Na2SO4, filtered and concentrated. oil yellow obtained is purified on a column of silica gel (AcOEt / EP 9/1 v / v then AcOEt / MeOH 9/1 v / v) to give a yellow liquid oil (3.19 g, 99%).
Rf: 0.14 (AcOEt / EP 5/5 v / v).
MS (ESI + / MeOH) m / z: 373.27 [M + Na] +; 389.20 [M + K] +.
1 H NMR (400.13 MHz, CDCl3) δ (ppm): 1.68 (m, 2H, H14); 2.09 (m, 2H, H15);
3.46 (t, 2H, J13-14 = 6.6 Hz, H13); 3.56-3.73 (m, 24H, H1-12); 4.99 (m, 2H, H17);
5.81 (m, 2H, H16).
13 C NMR (100.62 MHz, CDCl3) δ (ppm): 28.66 (C14); 30.12 (C15); 61.51, 61.58, 69,98, 70.11, 70.21, 70.35, 70.47, 70.58, 72.46 and 72.58 (13C, C1-13); 114.59 (C17) ; 138.18 (C16).
7) SYNTHESIS OF (1-THIOACETYLPENT-5-YL) HEXA (ETHYLENE GLYCOL) (Compound 7a) 3.1 g of pent-1-en-5-ylhexa (ethylene glycol) (8.85 mmol, 1 eq.), 3.1 ml of acid thioacetic (44.3 mmol, 5 eq.) and a spatula of azobisisobutyronitrile (A.IBN) (100 mg) are dissolved in 12 mL of freshly distilled tetrahydrofuran on sodium.
After 1 hour stirring at reflux (90-100 ° C.), the mixture is diluted in AcOEt then washed with a solution saturated NaHCO3. The organic phase is dried over Na 2 SO 4, filtered and concentrated for give a yellow liquid oil which is purified on a column of silica gel (AcOEt / EP 9/1 v / v then AcOEt / MeOH 9/1 v / v). A yellow liquid oil (2.68 g, 71%) is obtained.
Rf: 0.27 (AcOEt / MeOH 9/1 v / v).
MS (ESI + / MeOH) m / z: 449.26 [M + Na] +, (ESI + / MeOH) m / z: 461.17 [M + C] -.
1 H NMR (400.13 MHz, CDCl3) δ (ppm): 1.40 (m, 2H, H15); 1.58 (m, 4H, H14 and H16) 1.83 (s, 1H, OH); 2.32 (s, 3H, H19); 2.86 (t, 2H, J 17 16 = 7.2 Hz, H 17);
3.44 (t, 2H, J13? 14 = 6.6 Hz, H13); 3.56-3.73 (m, 24H, H1-12) =
13 C NMR (100.62 MHz, CDCl3) δ (ppm): 25.25 (C15); 28.90 (C17); 28.99, 29.24 (C14 and C16); 30.52 (C19); 61.55, 69.96, 70.17, 70.42, 70.98 and 72.43 (13C, C1_13);
195.84 (C18) -8) SYNTHESIS OF (1-THIOMETHOXYTRITYLPENT-5-YL) HEXA (ETHYLENE GLYCOL) (Compound 8a) Deprotection of acetate:
2.6 g of (1-thioacetylpent-5-yl) hexa (ethylene glycol) (60.9 mmol, 1 eq.) Are reacted with 3 mL concentrated HCl in 65 mL of absolute ethanol. After 20 hours stirring at a temperature of 60 C, the mixture is neutralized with ammonia, then concentrated. The solution obtained is then diluted in AcOEt, the organic phase is washed with water, dried on Na2SO4, filtered and concentrated. The brown-black oil obtained is enough pure to be handed directly in reaction.
Protection with trityl The deprotected thiol is brought into contact with 2.8 g of methoxytrityl chloride (91.3 mmol, 1.5 eq.) In 60 mL of anhydrous THF. After 24 hours of agitation at temperature ambient, the The solution is concentrated and purified by gel column chromatography.
silica (AcOEt / MeOH 9/1 v / v) to give a yellow oil (3.65 g, 91%).
Rf: 0.4 (AcOEt / MeOH 7/3 v / v).
MS (ESI + / MeOH): 679.34 [M + Na] +.
1 H NMR (400.13 MHz, acetone-d 6) δ (ppm): 1.31 (m, 2H, H 15); 1.40 (m, 4H, H14 and H16); 2.17 (t, 2H, J 17-18 = 7.4 Hz, H 17); 2.87 (s, 1H, OH); 3.35 (t, 2H, J13-14 = 6.4 Hz, H13); 3,47-3.63 (m, 24H, H1.12); 3.79 (s, 3H, H21); 6.86-7.42 (m, 14H, rHA).

13 C NMR (100.62 MHz, acetone-d6) δ (ppm): 27.37, 30.16 (3C, C, 4, C, 5 and C16), 33.54 (C17); 56.50 (C21); 62.94, 62.94, 67.64, 71.82, 72.19 and 72.33 (13C, C1-13) ; 74.48 (C18); 1 14.86, 128.32, 129.61, 131.26 and 132.54 (14C, CHAT); 138.81, 147.37 (3C, C19);
160.12 (C20) -9) SYNTHESIS OF O- (1-THIOMETHOXYTRITYLPENT-5-YL) -O-PROPARGYLHEXA (ETHYLENE GLYCOL) (Compound 9a) 100 mg of (1-thiomethoxytritylpent-5-yl) hexa (ethylene glycol) (0.152 mmol,]
eq.) are dissolved in 3 mL of freshly distilled THF. 7.3 mg of sodium hydride (0.183 mmol, 1.2 eq.) then 16 L of 2-bromopropyne (0.213 mmol, 1.4 eq.) are added to mixture to a temperature of 0 C. After stirring for 18 hours at room temperature, the mixture is concentrated then purified on silica gel column (AcOEt / EP 8/2 v / v). The O-(] -thiomethoxytritylpent-5-yl) -O-propargylhexa (ethylene glycol) is obtained under the form of a whitish oil (103 mg, 97%).
Rf: 0.34 (AcOEt).
MS (ESI + / MeOH) m / z: 717.39 [M + Na] +.
1 H NMR (400.13 MHz, CDCl3) δ (ppm): 1.28 (m, 2H, H15); 1.42 (m, 4H, H14 and H16);
2.14 (t, 2H, J 17.16 = 7.4 Hz, H 17); 2.43 (t, 1H, J = 2.4 Hz, H2 '); 3.36 (t, 2H, J, 3-14 = 6.8 Hz, H, 3) 3.52-3.71 (m, 24H, H1_12); 3.79 (s, 3H, H21); 4.20 (d, 2H, J = 2.4 Hz, H1 ') ; 6.79-7.40 (m, 14H, HA,).
1H NMR (100.62MHz, CDCl3) δ (ppm): 25.59 (C, 5); 28.46, 29.19 (C 14 and C 16);
31.96 (C17); 55.20 (C21); 58.39 (C1,); 65.85 (C2 '); 69.10, 70.05, 70.40, 70.56 and 71.17 (13C, C1-13) 74.51 (C, 8); 113.03, 126.44, 127.77, 129.47 and 130.73 (14C, CHAT); 137.12, 145.32 (3C, C19);
157.94 (C20) -The syntheses of compounds 6a to 9a described above are shown in FIG.
Figure 2 attached.

CLICK CHEMISTRY OF COMPOUNDS 5a AND 9a - FUNCTIONALIZATION
MANNOPYRANOSIDE IN POSITION 6 BY A CARBOXY GROUP (cf.
Figure 3:
10) SYNTHESIS OF {1- [2,3-0-ISOPROPYLIDENE-4,6-O-CYCLOSULFATE-a-D-mannopyranosyl] ETHYL-IH-1,2,3-triazol-4-yl} methylcarbamate [O- (1-THIOMETHOXYTRITYLPENT-5-YL) -O-HEXA (ETHYLENE GLYCOL)] (Compound 10a) 40 mg of 2'-azidoethyl-2,3-O-isopropylidene-4,6-O-cyclosulfate-aD-mannopyranose (0.11 mmol, 1 eq.) And 88 mg of O- (1-thiomethoxytritylpent-5-yl) -O-propargylhexa (ethylene glycol) (0.13 mmol, 1.1 eq.) are dissolved in 4 mL of a mixed CH2Cl2 / H2O (1/1 v / v). 7 mg of CuSO4, 5H2O (0.03 mmol, 0.25 eq.) And 11.3 mg ascorbate sodium (0.06 mmol, 0.5 eq) are added. After 24 hours of agitation at room temperature, the The reaction mixture is diluted in CH 2 Cl 2 and washed with water. The organic phase is then dried, filtered, concentrated and purified by chromatography on silica gel column with a gradient of eluent (CH 2 Cl 2 / MeOH 99/1 v / v to 98/2 v / v) to give a colorless oil (80 mg, 64%).
Rf: 0.4 (CH2Cl2 / MeOH 9/1 v / v).
MS (ESI + / MeOH) m / z: 1068.62 [M + Na] +, (ESI + / MeOH) m / z: 1080.77 [M + Cl] -.
1H NMR (400.13 MHz, CD3OD) δ (ppm): 1.36 (m, 6H, H25, H26 and H27); 1.34 1.49 (2s, 6H, Hb and Hc); 2.14 (t, 2H, J28_27 = 7.2 Hz, H28); 3.38 (t, 2H, J24-25 = 6.4 Hz, H24); 3.44-3.66 (m, 25H, H5 and H12-23); 3.78 (s, 3H, H32); 3.97 (m, 1H, H7a); 4.15 (m, JH, H7b); 4.27 (m, 3H, H2, H3 and H6a); 4.50 (m, 2H, H6b and H4); 4.64 (m, 4H, H8 and H1), 5.12 (s, 1H, H1) ; 6.81-7.39 (m, 14H, HAr); 8.07 (s, 1H, H9).
13 C NMR (100.62 MHz, CD3OD) δ (ppm): 26.34, 28.20 (Cb and C18; 26.71 (C26);
29.62 (C27); 30.23 (C25); 33.03 (C28); 51.19 (C8); 55.79 (C32); 59.79 (C5);
65.14 (C11); 67.42 (C7) 70.95, 71.19, 71.49, 71.58, 72.03 (13C, C12-24); 73.53 (C6); 74.46, 77.23 (C2 and C3); 85.66 (C4);
98.96 (C1); 108.26, 111.66 (C29 and Ca); 114, 11, 127, 66, 128, 86, 130, 73 and 132.02 (14C, CHAT);
126.04 (C9); 138.40, 146.86 (4Civ, C30 and C10); 159.71 (C31).

11) SYNTHESIS OF 1- [6-CYANO-6-DEOXY-4-O-SODIUMSULFATE-2,3-0-Isopropylidene-D-mannopyranosyl] ETHYL-IH-1,2,3-triazol-4-YL} methyl- [O- (1-THIOMETHOXYTRITYLPENT-5-YL) -O-HEXA (ETHYLENEGLYCOL)] (Compound 11a) 160 mg of {1- [2,3-O-isopropylidene-4,6-O-cyclosulfate) -α-D
mannopyranosyl] ethyl-LH
1,2,3-triazol-4-yl} methylcarbamate [O- (1-thiométhoxytritylpent-5-yl) -O
hexa (ethylene glycol)] (0.15 mmol, 1 eq.) and 15 mg of sodium cyanide (0.31 mmol, 2 eq.) are dissolved in 1.5 mL of DMF. After stirring for 4 hours at room temperature, the reaction mixture is diluted in 10 mL of a 5% NaHCO3 solution (to avoid a possible risk of acid release HCN) and washed with CH2Cl2. The product is extracted with water and then the phase aqueous is lyophilized. The yellow powder obtained is purified by column chromatography silica gel (CH 2 Cl 2 / MeOH 9/1 v / v) to give a colorless oil (106 mg, 65%).
Rf: 0.24 (CH 2 Cl 2 / MeOH 9/1 v / v).
MS (ESI + / MeOH) m / z: 1117.77 [M + Na] +, (ESI + / MeOH) m / z: 1071.63 [M-Na] -.
1H NMR (400.13 MHz, CD3OD) δ (ppm): 1.31 and 1.50 (2s, 6H, Hb and Hc); 1.38 (m, 6H, H26, H27 and H28); 2.15 (t, 2H, J29-28 = 7.2 Hz, H29); 2.70 (dd, 1H, J6a-5 =
8.8 Hz, J6a-6b = 17.2 Hz, H6a); 3.02 (dd, 1H, J6b-5 = 3.0 Hz, J6b-6a = 17.0 Hz, H6b); 3.38 (t, 2H, J25-26 = 6.4 Hz, H25); 3,48-3.66 (m, 26H, H4.5 and H13-24); 3.78 (s, 3H, H33); 3.93 (m, 1H, H8a); 4.10 (d, 1H, J2-3 = J2_1 = 4.8 Hz, H2); 4.19 (m, 2H, H8b and H3); 4.65 (m, 4H, H9 and H12); 5.00 (s, 1H, H1); 6.82-7.39 (m, 14H, HAr); 8.04 (s, 1H, H10).
13 C NMR (100.62 MHz, CD3OD) δ (ppm): 21.83 (C6); 26.60, 28.05 (Cb and CJ;
26.69 (C27); 29.62 (C28); 30.17 (C26); 33.04 (C29); 51.17 (C9); 55.81 (C33);
64.87 (C12); 66.66, 76.70 (C4 and C5); 67.02 (C8); 70.47, 70.99, 71.20, 71.26, 71.35 and 72.02 (13C, C13-25); 77.54 (C2);
77.92 (C3); 98.52 (C1); 110.98 (C30 and Ca); 118.96 (C7); 114.12, 127.67, 128.87, 130.72 and 132.01 (14C, CHAr); 125.87 (C10); 138.38, 146.00 and 146.84 (4C1, C31 and C11); 159.71 (C32).

12) SYNTHESIS OF {1- [ACID (6,7-DIDESOXY-4-O-SODIUMSULFATE-2,3-0-Isopropylidene-D-MANNO-HEPTOPYRANOSYL) uronic] Ethyl IH-1,2,3 Triazol-4-yl} methylcarbamate [O- (1-pent-5-yl) -O-hexa (ethylene glycol)]
(Compound 12a) 200 mg of {1- [6-cyano-6-deoxy-4-O-sodium sulphate-2,3-O-isopropylidene-a]
mannopyranosyl] ethyl-1H-1,2,3-triazol-4-yl} methyl- [O- (1-thiométhoxytritylpent-5-yl) -O
hexa (ethylene glycol)] (0.18 mmol, 1 eq.) and 60 mg of sodium hydroxide (NaOH) (1.46 mmol, 8 eq.) Are dissolved in 1.5 mL of a 30% aqueous solution of hydrogen peroxide. The solution is stirred at room temperature. At 12 hours and 24 hours of reaction, 60 mg of NaOH and 1.5 mL
H2O2 are added to the reaction medium. After 48 hours, the solution is neutralized with Amberlyst H + resins, before being filtered and lyophilized. The product obtained is then purified by silica gel column chromatography with an elution gradient (CH2Cl2 / MeOH 9/1 v / v to 5/4 v / v NH4OH / iPrOH) to give a yellow oil (80 mg, 52%).
Rf: O (CH2Cl2 / MeOH 8/2 v / v).
MS (ESI + / MeOH) m / z: 864.34 [M + Na] +.
1 H NMR (400.13 MHz, D 2 O) (ppm): 1.35 and 1.52 (2s, 6H, Hb and Hc); 1.44 (m, 2H, H27); 1.60 (m, 2H, H26); 1.73 (m, 2H, H28); 2.29 (dd, 1H, J6a-5 = 10.6 Hz, J6a-6b = 15.0Hz, H6a) 2.80 (dd, 1H, J6b-5 = 2.0 Hz, J6b-6a = 15.2 Hz, H6b); 2.89 (t, 2H, J29-28 =
8.0 Hz, H29); 3.53 (t, 2H, J25-26 = 6.6 Hz, H25); 3.50-3.69 (m, 26H, H5 and H13-24); 3.88 (m, 1H, H8a);
4.17 (m, 2H, H8b and H4); 4.19 (d, 1H, J2-3 = J2-1 = 5.6 Hz, H2); 4.30 (m, 1H, H3); 4.68 (m, 4H, H9 and H12); 4.95 (s, 1H, H1); 8.12 (s, 1H, H10).
1 H NMR (100.62 MHz, D 2 O) (ppm): 23.80 (C 28); 24.24 (C27); 25.45 and 26.80 (Cb and CJ; 28.06 (C26); 38.92 (C6); 49.99 (C9); 50.89 (C29); 62.95 (C12); 65.47 (C8); 66.41 (C5) 66.54, 68.69, 69.07, 69.40, 69.53 and 70.70 (13C, C13-25); 75.21 (C2); 76,00 (C3); 78.30 (C4) 95.99 (C1); 110.39 (Ca); 125.55 (C10); 143.85 (Ci,); 177.75 (C7) -

13) SYNTHESIS OF {1- [ACID (6,7-DIDESOXY-α-MANNO) HEPTOPYRANOSYL) uronic] ETHYL-IH-1,2,3-triazol-4-yl} methylcarbamate [O- (1-PENT-5-YL) -O-HEXA (ETHYLENE GLYCOL) (Compound 13a) 60 mg of {1- [6,7-dideoxy-4-O-sodiumsulfate-2,3-O-isopropylidene-manno heptopyranosyl) uronic] ethyl-1H-1,2,3-triazol-4-yl} methyl- [O- (1-pent-5-yl)]
O-hexa (ethylene glycol)] (0.07 mmol, 1 eq) are dissolved in 2 mL of a mixture MeOH / THF (1/1 v / v), then reacted with Amberlyst 15-H + resins for 36 hours.
Resins are filtered and the solution is neutralized with a solution of NaHCO3 5%. Solvents organics are evaporated and the remaining water is freeze-dried. The mixture is taken up in methanol and the Insoluble NaHCO3 is filtered. The oil obtained is pure enough to be delivered directly reaction (40 mg, 80%).
Rf: 0.18 (AcOEt / MeOH 5/5 v / v).
MS (ESI + / MeOH) m / z: 765.86 [M-3H + 3Na] +.
1 H NMR (400.13 MHz, CD3OD) δ (ppm): 1.49 (m, 2H, H27); 1.61 (m, 2H, H26);
1.80 (m, 2H, H28); 2.41 (dd, 1H, J6a-5 = 10.2 Hz, J6a-6b = 16.2 Hz, H6a); 2.84 (m, 3H, H29 and H6b); 3.49 (t, 2H, J25-26 = 6.4 Hz, H25); 3.40-3.79 (m, 28H, H2-5 and 1113-24); 3.92 (m, IR H8a); 4.22 (m, JH, H8b); 4.71 (d, 1H, J1-2 = 1.2 Hz, H,); 4.87 (m, 2H, H9); 4.92 (m, 2H, H12) ; 8.65 (s, 1H, H10).
1H NMR (100.62MHz, D2 O) δ (ppm): 23.79 (C28); 24.23 (C27); 28.06 (C26);
36.51 (C6); 50.67 (C9); 50.90 (C29); 62.55 (C12); 65.29 (C8); 67.88, 69.08, 69.54 and 70.70 (13C, C13-25); 52.32, 69.36, 69.82, 70.16 (4C, C2-5); 99.48 (C,); 109.39 (C11);
146.74 (C10); 175.27 (C7) -CLICK CHEMISTRY OF COMPOUNDS 5a AND 9a - FUNCTIONALIZATION
MANNOPYRANOSIDE IN POSITION 6 BY AN AZIDO GROUP (cf Figure 4)

14) SYNTHESIS OF {1- (6-AZIDO-6-DEOXY-2,3-O-ISOPROPYLIDENE-4-O) SODIUMSULFATE-aD-mannopyranosyl) ETHYL-IH-1,2,3-triazol-4-YL} METHYL- [O- (1-THIOPENT-5-YL) -O-HEXA (ETHYLENE GLYCOL) 1 (Compound 14a) 530 mg of {1 - [2,3-O-isopropylidene-4,6-O- (cyclosulfate) -α-D
mannopyranosyl] ethyl 1H-1,2,3-triazol-4-yl} methyl- [O- (1-thiomethoxytritylpent-5-yl) -O-hexa (ethylene glycol)] (0.51 mmol, 1 eq.) and 65 mg of sodium azide (1.00 mmol, 2 eq.) are reacted in 10 mL of DMF. The same protocol as for 2'-azidoethyl-2,3,4,6-tetra-O-acetyl-aD-mannopyranose (Compound 2a) is then followed (Example 1). We then obtain a yellow oil (350 mg, 62%).
Rf: 0.15 (8.5 / 1.5 v / v CH2Cl2 / MeOH).

15) SYNTHESIS OF {1- (6-AZIDO-6-DEOXY-2,3-aD) Mannopyranosyl) ETHYL-IH-1,2,3-triazol-4-yl} methylcarbamate [O- (1-THIOPENT-5-YL) -O-HEXA (ETHYLENE GLYCOL)] (Compound 15a) 200 mg of {1- (6-azido-6-deoxy-2,3-O-isopropylidene-4-O-sodium sulphate-α-D
mannopyranosyl) ethyl-1H-1,2,3-triazol-4-yl} methyl- [O- (1-thiopent-5-yl) -O-hexa (ethylene glycol)] (0.18 mmol, 1 eq) are reacted with 50 mg of ammonium nitrate (CAN) (0.09 mmol, 0.5 eq) in 4 mL of a CH3CN / H20 mixture (95/5 v / v). After 4 stirring hours at 60 ° C., the reaction mixture is diluted in CH 2 Cl 2, washed several times to water, and the lyophilized aqueous phase. The yellow oil obtained is purified by chromatography on column of silica gel with a gradient of eluent (CH 2 Cl 2 / MeOH 90/10 v / v to CH2Cl2 / MeOH
80/20 v / v) to give {1- (6-azido-6-deoxy-4-O-sodium sulphate-α-D
mannopyranosyl) ethyl 1H-1,2,3-triazol-4-yl} methyl- [O- (1-thiopent-5-yl) -O-hexa (ethylene glycol)] sub form of a colorless oil (100 mg, 72%).
This compound is then reacted with Amberlyst H + resins in 6 mL
a MeOH / THF (1/1 v / v) for 24 hours. The same protocol as for {1-[Acid (6,7-dideoxy-α-D-manno-heptopyranosyl) uronic] ethyl-1H-1,2,3-tri azo-4-yl } Methyl- [O- (1-pent-5-yl) -O-hexa (ethylene glycol) (compound 13a) is then followed (Example 1). We then gets a yellow oil (150 mg, 53%).
Rf: 0.25 (CH 2 Cl 2 / MeOH 9/1 v / v).
1 H NMR (400.13 MHz, CD 3 OD) δ (ppm): 1.47 (m, 2H, H 2 O); 1.60 (m, 2H, H25);
1.71 (m, 2H, H27); 2.70 (t, 2H, J28-27 = 7.2 Hz, H28); 3.48 (t, 2H, J24-25 = 6.2 Hz, H24); 3.19-3.78 (m, 30H, H2-6 and H12-23); 3.88 (m, 1H, H7a); 4.13 (m, 1H, H7b); 4.63 (m, 4H, H8 and H11); 4.72 (s, 1H, H1); 8.03 (s, 1H, H9).
13 C NMR (100.62 MHz, CD3OD) δ (ppm): 26.13 (C26); 30.07 (C27); 30.36 (C25) ; 39.66 (C28); 51.34 (C8); 62.85 (C6); 65.05 (C11); 66.79 (C7); 68.38, 70.81, 71.24, 71.59, 71.93, 72.15, 72.51 and 75.01 (17C, C2-5 and Cie-24); 101.70 (Cl); 132.57 (C9); 161.04 (C1o).
SYNTHESIS OF THE COMPOUND OF FORMULA (I), IN WHICH WAS A
GOLD NANOPARTICLE:
Two solutions, one containing 60 mg of tetrachloroauric acid (HAuC14) (0.18 mmol, 1 eq.) And 250 mL of water, and the other containing 150 mg of sodium citrate (0.5 mmol, 2.78 eq.) dissolved in 10 mL of water are heated in parallel to a temperature of 60 C
during 10 minutes. The hot sodium citrate solution is then added to the solution of HAuCI4, then the mixture is brought to a temperature of 120 C for 2.5 hours. The solution passes gradually from gray to red-burgundy, which indicates that gold nanoparticles have formed. Once the solution has returned to room temperature, 50 mg of solubilized glycoconjugate in 1 mL of MeOH are added and stirred at room temperature.
ambient for 48 hours. The gold nanoparticles are then precipitated by adding a Saturated NaCl solution.
After a night at rest, the supernatant is removed and the gold nanoparticles are centrifuged for 30 minutes at a speed of 14,000 rpm. They are then washed several times to the water, then with methanol and dried in the open air.
Size of gold nanoparticles A: 6-7 nm, Size of the compounds of formula (1): 7-8 nm.
EXAMPLE 2 PREPARATION OF A COMPOUND OF FORMULA (II) 1) SYNTHESIS OF 2,3,4,6-TETRA-O-ACETYL-α-MANNOPYRANOSIDE
3,6,8-DIOXAOCTYLE (Compound lb) OAc OAc Co Reagents:
ac0 he ' -2 "
0 4 s OH - TEG: MW = 150.17 I
H3CyO3 '0 ~~ - BF3Et20: MW = 141.93 MW: 480.46 To a solution containing 25.7 g (0.07 mol-1 eq) of penta-mannose acetate and 26 mL (0.21 mol - 3 eq) of triethylene glycol in 150 mL of dichloromethane anhydrous cooled to at a temperature of 0 ° C., 60 ml (0.56 mol-8) are added under an argon atmosphere.
eq.) of BF3Et2O
drip. The reaction mixture is then allowed to come back to ambient temperature. The mixture is kept stirring overnight, and the reaction is followed by CCM
(Et2O / MeOH 90/10 v / v). Once the reaction is complete, the reaction mixture is washed successively with 2 times 100 ml of a saturated aqueous solution of NaHCO 3, with 2 times 100 mL of distilled water and finally with 100 mL of brine solution. The sentence organic is dried over Na 2 SO 4, filtered and evaporated under reduced pressure. The gross reaction is then purified by column chromatography on silica gel with eluent (EP / Et20 60/40 v / v).

Physical appearance: Yellow oil.
Yield: 79%.
Rf: 0.43 (Et2O / MeOH 90/10 v / v).

MS: (ESI + / MeOH) m / z: 503.1 [M + Na] +, (ESI + / MeOH) m / z: 479.3 [MH] -.

1 H NMR (400.13 MHz, CDCl3) δ (ppm): 2.05, 2.09, 2.12, 2.13 (4s, 12H, H2);
3,55-3.68 (m, 12H, HI, H2 ', HY, H4', H5>, H0; 4.05-4.11 (m, 1H, H6a); 4.17-4.24;
(m, 2H, H5 and H6b);
5.18 (d, 1H, 3HCl-H 2 = 1.8 Hz, HI); 5.20 (dd, 1H, 3HH-HI = 1.9 Hz, 3H2-H3 =
3.2 Hz, H2); 5.25 (t, 1H, 3HH4-H3 = 3H4-H5 = 9.9 Hz, H4); 5.36 (dd, 1H, 3HH3-H2 = 3.3 HZ, 3HH3-H4 = 10.1 HZ, H3).
13 C NMR (100.62 MHz, CDCl 3) δ (ppm): 20.5 (2 C), 20.6, 20.7 (4 C, C 2); 61.03 (IC, C6 '); 62.5 (Cl, C6); 66.0 (Cl, C4); 66.53 (1C, Cl); 68.1 (1C, C5); 68.8 (1C, C3); 69.94 (2C, C3 and C4 '); 70.1 (1C, C2); 70.44 (1C, C2 '); 72.60 (1C, C5 '); 91.8 (1C, THIS) ; 169.8, 170.1, 170.2 and 170.9 (4C, Cl-).
2) SYNTHESIS OF BI (2,3,4,6-TETRA-O-ACETYL-α-MANNOPYRANOSIDE) 3,6,8-DIOXAOCTYLE (Compound 2b) AcO OAc Co OAc OAc 4 6 OAc Reagents -O Man (OAc) 5: MW = 390.34 Aco 5 II BF3Et20: MW = 141.93 Co O3'l0 2 'J

Ac = CH CO C34H50022 3 MW: 810.75 To a solution containing 13.4 g (27.9 mmol - 1 eq) of the compound Ib and 10 g (27.9 mmol 1 eq.) Of penta-acetate aD-mannose in 120 mL of anhydrous dichloromethane cooled to a at 0 ° C., 35.5 ml (0.28 mol - 10 ml) are added under an argon atmosphere.
eq.) of BF3Et2O
drip. The reaction mixture is then allowed to come back to ambient temperature. The mixture is kept stirring overnight, and the reaction is followed by CCM
(Et2O / MeOH 90/10 v / v). Once the reaction is complete, the reaction mixture is washed successively with 2 times 80 ml of a saturated aqueous solution of NaHCO 3, with 2 times 80 mL
distilled water and finally with 80 mL of a brine solution. The sentence organic is dried on Na 2 SO 4, filtered and evaporated under reduced pressure. The raw reaction is subsequently purified by chromatography on a column of silica gel with eluent (EP / Et20 60/40 v / v).
Physical appearance: White foam.

Yield: 87%.
Rf 0.61 (Et20).
MS: (ESI + / MeOH) m / z: 833.4 [M + Na] +; 811.2 [M + H] +, (ESI- / MeOH) m / z: 809.3 [M-Hf; 845.4 [M + C1] -.

1 H NMR (400.13 MHz, CDCl3) δ (ppm): 1.98, 2.00, 2.11, 2.13 (4s, 24H, H2õ);
3,42-3.46 (m, 6H, H3, H5, H6b); 3.51 (dd, 2H, 3H6a-H5 = 7.1 Hz, 2H6a-H6b = 2.0 Hz, H6a); 3.53 (dd, 2H, 3 H4-H3 = 8.5 Hz, 3 H4-H5 = 2.7 Hz, H4); 3.58 (s, 4H, H3 '); 3.60 (t, 4H, 3HH2'-H1 '= 3.4 Hz, H2');
3.63 (dd, 2H, 3H2-H3 = 9.2 Hz, 3H2-H1 = 1.8 Hz, H2); 3.67 (t, 4H, 3HCl-H2) = 3.3 Hz, H1,); 5.40 (dd, 2H, 3HCl-H2 = 1.5 Hz, H1).
13 C NMR (100.62 MHz, CDCl 3) δ (ppm): 20.6, 20.7, 20.75, 20.9 (8C, C 2);
62.26 (2C, C6); 66.53 (2C, C1 '); 69.94 (2C, C3 '); 70.44 (2C, C2); 70.46 (2C, C4);
73.34 (2C, C2); 74,80 (2C, C3); 76.66 (2C, C5); 103.79 (2C, Cl).
3) SYNTHESIS OF 3,6,8-DIOXAOCTYL BI (aD-MANNOPYRANOSIDE) (Compound 3b) HO OH
HO

OH OH

HO 5 t 1 Reagents O ~ b HO 2 McONa: MW = 54.02 03 Amberlyst Resins 15-H`
2 ' MW: 474.45 2.20 g (4 mmol - 0.3 eq) of MeONa are added to a solution of 100 mL of methanol containing 11 g (13 mmol - 1 eq) of compound 2b. The reaction is followed by CCM
(iPrOH / NH4OH 60/40 v / v). After 30 minutes, the reaction medium is neutralized with Amberlyst 15-H + acid resins. Then, the resins are filtered, rinsed with methanol. The crude obtained after concentration is purified by column chromatography silica gel with an elution gradient (iPrOH / NE14OH 80/20 v / v to iPrOH / NH4OH 60/40 v / v).
Physical appearance: Light beige foam.
Yield: 97%.
Rf: 0.35 (iPrOH / NH4OH 60/40 v / v).
MS (ESI + / MeOH) m / z: 497.3 [M + Na] +; 475.4 [M + H] +, (ESI- / MeOH) m / z: 473.3 [MH] -.

1 H NMR (400.13 MHz, MeOD) δ (ppm): 3.41-3.46 (m, 6H, H3, H5, H6b); 3.53 (dd, 2H, 3H6a-H5 = 7.5HZ, 2H6a-H6b = 2.1Hz, H6a); 3.54 (dd, 2H, 3H4-H3 = 8.5HZ, 3HH4-H5 = 3.1 Hz, H4), 3.57 (m, 4H, H3 '); 3.60 (t, 4H, 3H2'-H1 '= 3.3 Hz, H2 =); 3.64 (dd, 2H, 3JH2-H3 = 8.7 Hz, 3H2-H1 =
1.5 Hz, H2); 3.66 (t, 4H, 3HCl-H '= 3.3 Hz, H 1,); 5.38 (dd, 2H, 3HCl-H2 =
1.9 Hz, H1).
13 C NMR (100.62 MHz, MeOD) δ (ppm): 63.08 (2C, C6); 66.64 (2C, Cl); 70.11 (2C, C3 '); 70.44 (2C, C2 '); 70.51 (2C, C4); 73.35 (2C, C2); 75.20 (2C, C3);
76.83 (2C, C5); 104.19 (2C, C,).
4) SYNTHESIS OF BI (6-DEOXY-6-IODO-α-MANNOPYRANOSIDE) 3,6,8-DIOXAOCTYLE (Compound 4b) HO
HO
OH Reagents:

0 -b I2: MW = 253.81 HO 5 Imidazole MW = 68.08 HO 3 2 PPh3: MW = 262.29 OO
O 3 ' 2 ' C 1 aH32N6012 MW: 524.48 0.4 g (1.58 mmol - 1.5 eq) of iodine, 0.5 g (1.05 mmol - 1 eq) of compound 3b, 0.42 g (1.58 mmol - 1.5 eq.) of triphenylphosphine (PPh3) and 145 mg (2.1 mmol - 2 eq.) Imidazole crushed together in a small flask with a glass rod. The reaction mixture is heated at a temperature of 100 C with stirring for 10 minutes. The iodination reaction is followed by TLC (90/10 v / v CH 2 Cl 2 / MeOH). The mixture is then cooled to temperature ambient and solubilized in methanol. The raw reaction is then concentrated under reduced pressure, and purified by silica gel column chromatography (CH2Cl2 / MeOH
90/10 v / v).

5) SYNTHESIS OF BI (6-DESOXY-6-AZIDO-α-MANNOPYRANOSIDE) DIOXAOCTYLE (Compound 5b) HO

4 6 Reagents HO 5 NaN3: MW = 65.01 ~
HO
3 2 ^^ O
O
O

MW: 524.48 140 mg of compound 4b (0.14 mmol, 1 eq.) And 38 mg of sodium azide (0.57 mmol, 4 eq.) are mixed and ground in a mortar for 5 minutes, the mixture is then immersed in a bath of oil at a temperature of 80 C. After 20 minutes of manual stirring, the mixed The reaction is directly purified by gel column chromatography.
silica (CH2Cl2 / MeOH 9/1 v / v) to give a yellow oil (53 mg, 70%).
The synthesis scheme of the compound of formula (II) is shown in FIG.
attached.
EXAMPLE 3 PREPARATION OF A COMPOUND OF FORMULA (III) 1) SYNTHESIS OF 6-MONOMETHOXYTRITYL-α-MANNOPYRANOSIDE
METHYL (Composed on) g of methyl α-D-mannopyranoside (51.5 mmol, 1 eq) and 1.9 g of DMAP (15.45 mmol, 0.3 eq.) are dissolved in 80 mL of pyridine. 24 g of chloride monomethoxytrityl (77.25 mmol, 1.5 eq.) Are added to the mixture by fraction. The reaction is completed after 1.5 hours, the reaction medium is then diluted in AcOEt and washed successively with a 2N solution of HCI, 5% NaHCO3 solution and water. The sentence organic is dried on Na2SO4, filtered and concentrated. The product is then purified by gel flash chromatography of silica with an elution gradient (CH 2 Cl 2 to CH 2 Cl 2 / MeOH 95/5 v / v) to give a slightly yellow powder (21.6 g, 90%).
Rf: 0.43 (CH 2 Cl 2 / MeOH 95/5 v / v).
MS (ESI + / MeOH) m / z: 489.45 [M + Na] +; 955.67 [2M + Na] +, (ESI + / MeOH) m / z: 465.28 [MH] -.

1 H NMR (400.13 MHz, CDCl 3) δ (ppm): 1.65-3.00 (3m, 3H, -OH); 3.30 (s, 3H, -OCH 3) 3.32 (m, 1H, H6a); 3.37 (m, 1H, H6b); 3.55-3.80 (m, 4H, H2, H3, H4 and H5);
3.72 (s, 3H, H13) 4.65 (d, 1H, J 1-2 = 1.4 Hz, H 1); 6.70-7.40 (m, 14H, H9, 10.11).
13 C NMR (100.62 MHz, CDCl 3) δ (ppm): 54.90 (-OCH 3); 55.21 (C13); 64.98 (C6) 69.91, 69.99, 70.23 and 71.6 (C2, C3, C4 and C5); 87.15 (C7); 100.64 (C1); 1 13.38, 127.19, 127.85, 128.42, 130.42 (14C, C9, 10.11); 135.32, 144.17, 144.26 (C8); 158.72 (C] 2) -2) SYNTHESIS OF 2,3,4-TRI-O-BENZYL-6-MONOMETHOXYTRITYL-aD-METHYL MANNOPYRANOSIDE (Compound 2e) g of methyl 6-monomethoxytrityl-α-D-mannopyranoside (10.72 mmol, 1 eq.) are dissolved in 19 mL of benzyl bromide (160.8 mol, 15 eq.). 15 g of KOH (268 mmol, 20 eq.) are then added and the mixture is heated to a temperature of 80 C.
After 1 hour of reaction, the reaction medium is diluted in CH2Cl2, and then the phase organic is washed with water distilled, dried over Na2SO4, filtered and concentrated. The product is then purified by chromatography on silica gel with an elution gradient (EP up to EP / Et20 5/5 v / v) for give an off-white foam (7.1 g, 90%).
Rf: 0.62 (EP / Et 2 O 6/4 v / v).
MS (ESI + / MeOH) m / z: 759.45 [M + Na] +.
1 H NMR (400.13 MHz, CDCl3) δ (ppm): 3.19 (dd, 1H, J6a-5 = 5.2 Hz, J6b-6a =
9.8 Hz, H6a); 3.28 (s, 3H, -OCH3); 3.43 (dd, 1H, H6b-5 = 1.7 Hz, J6b-6a = 9.8 Hz, H6b); 3.64 (s, 3H, H13);
3.69 (m, 1H, H5); 3.73 (dd, 1H, J2-1 = 1.8 Hz, J2-3 = 3.1 Hz, H2); 3.79 (dd, IR J3-2 = 3.2 Hz, J3-4 = 9.3 Hz, H3); 3.95 (t, 1H, J4-3 = J4-5 = 9.6 Hz, H4); 4.42-4.69 (m, 4H, Ha) ; 4.74 (s, 1H, H1) 6.66-7.49 (m, 29H, H9.10, 11, c, d, e) =
13 C NMR (100.62 MHz, CDCl3) δ (ppm): 55.00 (-OCH3); 55.22 (C13); 63.85 (C6) 71.91 (C5); 75.32 (C4); 75.59 (C2); 80.37 (C3); 72.43, 72.86 and 75.20 (Ca) ; 86.01 (C7); 98.87 (C1); 113.18, 128.61, 127.45-127.90, 128.21-128.74, 130.64 (29C, C9.1o, 11, c, d, e); 135.92, 138.48, 138.76, 138.81, 144.72 and 144.90 (6C, Cb and C8); 158.52 (C12) -3) SYNTHESIS OF 2,3,4-TRI-O-BENZYL-α-MANNOPYRANOSIDE
METHYL (Compound 3e) 7.12 g of 2,3,4-tri-O-benzyl-6-monomethoxytrityl-α-D-mannopyranoside methyl (9.66 mmol, 1 eq.) Are dissolved in 80 mL of 95/5 v / v CH 3 CN / H 2 O mixture.
530 mg of (0.97 mmol, 0.1 eq) are then added and the mixture is heated to a temperature of 60 C

during 30 minutes. The reaction medium is then diluted with CH 2 Cl 2, then the phase The organic material is washed with distilled water, dried over Na 2 SO 4, filtered and concentrated. The product is then purified by flash chromatography on silica gel with a elution gradient (EP / Et20 3/7 v / v) to give a colorless oil (4.26 g, 95%).
Rf: 0.5 (Et20 / EP 4/6 v / v).
MS (ESI + / MeOH) m / z: 487.12 [M + Na] +; 951.34 [2M + Na] +.
1 H NMR (400.13 MHz, CDCl3) δ (ppm): 1.88 (s, 1H, -OH); 3.25 (s, 3H, -OCH3);
3.57 (m, 1H, H5); 3.73 (m, 3H, H6a and H2); 3.80 (dd, 1H, J6a-5 = 3.0 Hz, J6a-6b =
11.8 Hz, H6b); 3.85 (dd, 1H, J3-2 = 3.0 Hz, J3.4 = 9.4 Hz, H3); 3.92 (t, 1H, J4-3 = J4-5 = 9.6 Hz, H4); 4.61 (m, 2H, Ha) 4.65 (m, 3H, H, and Ha); 4.73 (d, 2H, J = 12.4 Hz, Ha); 4.89 (d, 2H, J = 10.8 Hz, Ha); 7.21 to 7.305 (m, 15H, Hc, d, e) =
1H NMR (100.62 MHz, CDCl3) δ (ppm): 54.73 (-OCH3); 62.37 (C6); 71.99 (C5) 74.64 (C2); 74.83 (C4); 72.17, 72.90, 75.16 (3Ca); 80.17 (C3); 99.29 (CI) ; 127.54 to 128.35 (Cc, d, e); 138.21, 138.37, 138.42 (Cb).
4) SYNTHESIS OF .. 2,3,4-TRI-O-BENZYL-6-DEOXY-6-OXY-aD-METHYL MANNOPYRANOSIDE (Compound 4e) 500 mg of methyl 2,3,4-tri-O-benzyl-α-D-mannopyranoside (1.1 mmol, 1 eq.) are dissolved in 12 mL of CH2Cl2 before adding 2.5 g of 4A molecular sieve and 464 mg of pyridinium chlorochromate (2.15 mmol, 2 eq). After 1 hour of agitation at temperature ambient, the reaction medium is filtered on celite then on activated charcoal, before being purified by chromatography on silica (AcOEt / EP 3/7 v / v) to give an oil transparent (250 mg, 50%).
Rf 0.2 (AcOEt / EP 5/5 v / v).
MS (ESI + / MeOH) m / z: 485.46 [M + Na] +.
1 H NMR (400.13 MHz, CDCl3) δ (ppm): 3.31 (s, 3H, -OCH3); 3.70 (t, 1H, J2-, = J2-3 =
2.8 Hz, H2); 3.88 (dd, 1H, J3-2 = 3.0 Hz, J3-4 = 7.8 Hz, H3); 3.98 (t, 1H, J4-5 = J4-3 = 8.2 Hz, H4) 4.01 (m, 111, H5); 4.54-4.76 (m, 6H, Ha); 4.78 (d, 1H, J, -2 = 2.8 Hz, HI);
7.19-7.29 (m, 15H, Hc, d, e); 9.66 (s, 1H, H6).
13 C NMR (100.62 MHz, CDCl3) δ (ppm): 55.51 (-OCH3); 72.27, 72.91 and 74.66 (3Ca);
74.17 (C2); 74.36 (C4); 76.00 (C5); 79.15 (C3); 99.42 (CI); 127.61 to 128.41 (Ccd, e); 137.73, 138.02 (3Cb); 197.86 (C6).

5) SYNTHESIS OF 2,3,4-TRI-O-BENZYL-6-DEOXY-6-ALLYL-α-D
METHYL MANNOPYRANOSIDE (Compound 5e) 693 mg of methyltriphosphonium bromide (1.95 mmol, 1.2 eq.) Are dissolved in 12 mL of anhydrous THF before adding under an argon atmosphere at a temperature of -5 C, 2 mL
BuLi (4.88 mmol, 3 eq.). Stirring is maintained for 30 minutes at a temperature of -C. The solution becomes yellow then 751 mg of 2,3,4-tri-O-benzyl-6-deoxy-6-oxy-a-D-methyl mannopyranoside (1.63 mmol, 1 eq.) previously dissolved in 8 mL
from THF
anhydrous are added to the solution at a temperature of -78 C. After 2 hours stirring at this temperature and 16 hours of stirring at room temperature, the medium reaction is diluted Et 2 O then washed with NH 4 Cl solution. The organic phase is then dried on Na2SO4, filtered, concentrated and purified on a silica column (AcOEt / EP 2/8 v / v) to give a beige oil (300 mg, 60%).
Rf: 0.55 (AcOEt / EP 3/7 v / v).
MS (ESI + / MeOH) m / z: 484.45 [M + Na] +.
1H NMR (400.13 MHz, CD3OD) δ (ppm): 3.27 (s, 3H, -OCH3); 3.71 (t, 1H, J4-3 =
J4-5 =
9.4 Hz, H4); 3.75 (dd, 1H, J2-1 = 1.8 Hz, J2-3 = 3.0 Hz, H2); 3.84 (dd, 1H, J3_2 = 3.2 Hz, J3-4 = 9.2 Hz, H3); 3.98 (m, 1H, H5); 4.57-4.81 (m, 6H, Ha); 4.68 (d, 1H, J1_2 = 1.6 Hz, H1); 5.24, 5.27 (2m, 1H, Hia); 5.40, 5.45 (2m, 1H, H7b); 5.99 (m, 1H, H6); 4.73 (d, 2H, J = 12.4 Hz, Ha); 7,21-7.35 (m, 15H, Hc, d, e).
13 C NMR (100.62 MHz, CD3OD) δ (ppm): 54.70 (-OCH3), 72.40, 72.80 and 75.11 (3Ca);
72.83 (C5); 74.80 (C2); 78.73 (C4); 79.82 (C3); 99.12 (C1); 118.12 (C7);
127.49-128.31 (Cc, d, e) ; 135.49 (C6); 138.31, 138.48, 138.59 (Cb).
6) SYNTHESIS OF 6-DEOXY-6-ACID (2,3,4-TRI-O-BENZYL-α-D) METHYL) BORONIC MANNOPYRANOSIDE (Compound 6e) 100 mg of methyl 2,3,4-tri-O-benzyl-6-deoxy-6-allyl-aD-mannopyranoside (0.22 mmol, 1 eq.) are dissolved in 2 mL of pentane before adding under argon to a temperature of -78 C, 36 .tL of boron tribromide (0.22 mmol, 1 eq.) And 34 gL of triethylsilane (0.22 mmol, 1 eq.). Stirring is maintained for 3 hours at this temperature, then for 15 minutes to ambient temperature. 17 mg of sodium hydroxide (0.44 mmol, 2 eq.) Are then added between reaction, which is then stirred for 30 minutes. The solution is diluted in AcOEt and then washed with water. The organic phase is dried over Na 2 SO 4, filtered, concentrated and then purified on silica column (AcOEt / EP 2/8 v / v) to give a white oil (100 mg, 91%).
Rf: 0.34 (AcOEt / EP 5/5 v / v).
MS (ESI + / MeOH) m / z: 529.87 [M + Na] +.
1H NMR (400.13 MHz, CD3OD) δ (ppm): 3.33 (dd, 1H, J6a-5 = 7.6 Hz, J6a-6b =
10.0 Hz, H6a); 3.38 (s, 3H, H-OCH3); 3.52 (m, 1H, H5); 5.57 (dd, 1H, J6b-5 = 2.4 Hz, J6b-6a = 10.0 Hz, H6b) 3.78 (t, 1H, J4-3 = J4-5 = 9.2 Hz, H4); 3.80 (m, 1H, H2); 4.61-5.01 (m, 6H, Ha); 4.76 (d, 1H, J1-2 =
1.6 Hz, H1); 7.26-7.41 (m, 15H, Hc, d, e) =
13 C NMR (100.62 MHz, CD3OD) δ (ppm): 7.04 (C6); 55.02 (C-OCH 3); 71.41 (C5) 72.07, 72.70 and 75.37 (3Ca); 74.58 (C2); 78.58 (C4); 79.90 (C3); 99.03 (C1); 127.60 to 128.43 (Cc, d, e); 138.17, 138.22 and 138.26 (3Cb).
7) SYNTHESIS OF 6-DEOXY-6-ACID (α-MANNOPYRANOSIDE OF
METHYL) BORONIC (Compound 7e) 100 mg of boronate (0.42 mmol, 1 eq) are dissolved with resins Amberlyst 15-H + in 4 mL of a MeOH / THF mixture (1/1 v / v) according to the same protocol as for the {1-[(6,7-Dideoxy-α-D-manno-heptopyranosyl) uronic] ethyl-1H-1,2,3-triazole 4-yl} methyl-[O- (1-pent-5-yl) -O-hexa (ethylene glycol)] (compound 13a) (Example 1). We obtain an oil whitish (0.40 mg, 85%).
Rf: 0.52 (IPrOH / NH4Cl 5/5 v / v).
MS (ESI + / MeOH) m / z: 259.37 [M + Na] +.
1 H NMR (400.13 MHz, D20) δ (ppm): 1.57 (m, 1H, Hia); 1.88 (m, 1H, H7b);
2.68 (m, 1H, H6a); 2.78 (m, 1H, H6b); 3.25 (s, 3H, H-OCH3); 3.36 (t, 1H, J4-5 =
J4-3 = 9.6 Hz, H4); 3.45 (td, 1H, J5-6a = J5-4 = 9.4 Hz, Js-6b = 2.7 Hz, H5); 3.57 (dd, 1H, J3-4 = 9.4 Hz, J3-2 = 3.5 Hz, H3); 3.79 (dd, 1H, J2-3 = 3.4 Hz, J2-1 = 1.7 Hz, H2); 4.57 (s, 1H, H1).
13 C NMR (100.62 MHz, D 20) δ (ppm): 32.90 (C, 7); 37.72 (C6); 55.16 (C-OCH3);
70.26 (C2); 70.58 (C4); 70.88 (C3); 71.04 (C5); 101.23 (C1).
The synthetic scheme of the compound of formula (III) (compound 7e) is presented at the figure 6 annexed.

EXAMPLE 4 PREPARATION OF A COMPOUND OF FORMULA (III) 1) SYNTHESIS OF 2,3,4-TRI-O-ACETYL-6-MONOMETHOXYTRITYL-aD-METHYL MANNOPYRANOSIDE (Compound lf) H34O I i OAc Reagents:
, 0 Co MeOTrCI: MW = 308.81 AcO Ac20: MW = 102.09 2 '- DMAP: MW = 122.17 Hic o OMe -C33H36O1o M. 592.63 6 g (30.86 mmol - 1 eq) of methyl α-D-mannopyranoside and 1.13 g (9.26 mmol) - 0.3 eq.) of DMAP are dissolved in 60 mL of pyridine. 14.2 g (46.30 mmol - 1.5 eq.) of chloride monomethoxytrityl are added to the mixture by fraction. The reaction of 1.5 hard tritylation hours, and is followed by TLC (CH 2 Cl 2 / MeOH 95/5 v / v). 13.15 mL (137.97 mmol -4.5 eq.) acetic anhydride are then added to the reaction medium. The acetylation is followed by CCM
(Et20 / EP 7/3 v / v). After 3 hours of reaction, the pyridinium salts are filtered and mixing The reaction is diluted in 250 ml of AcOEt. The organic phase is washed successively with a solution of 2N HCl (up to pH = 1), a solution of 5% NaHCO3, and distilled water, then dried over Na2SO4, filtered and concentrated. The product is then purified by chromatography on silica gel with an elution gradient (Et20 / EP 3/7 v / v up to Et20 / EP
5/5 v / v) to give a white foam.
Physical appearance: White foam.
Yield: 90%.
Rf: 0.62 (Et20 / EP 7/3 v / v).
MS: (ESI + / MeOH) m / z: 615.2 [M + Na] +.
1 H NMR (400.13 MHz, CDCl 3) δ (ppm): 1.61, 1.81 and 2.02 (3s, 9H, H 2 '); 3.07 (m, 2H, H6a and H6b); 3.32 (s, 3H, -OCH3); 3.62 (s, 3H, H4 '); 3.76 (m, 1H, H5);
4.62 (d, 1H, 3HCl-H2 = 1.7 Hz, H1); 5.09-5.17 (m, 3H, H2, H3 and H4); 6.67-7.22 (m, 14H, 14HPh).

13 C NMR (100.62 MHz, CDCl 3) δ (ppm): 21.0, 21.1 and 21.3 (3C, C 2); 55.4 (l VS, -OCH3); 55.6 (1 C, C4 '); 62.9 (1 C, C6); 67.1 (1 C, C4); 69.8 (1 C, C3);
70.2 (1 C, C2); 70.5 (1 C, C5); 86.8 (Cl, C3 '); 98.7 (Cl, Cl) 113.5, 127.3, 128.2, 128.3, 128.9 and 130.8 (14C, CHph) 135.9, 144.7 and 144.8 (3C, ClvPh); 155.0 (1C, ClvPh-OCH3); 169.8, 170.4 and 170.6 (3C, Cy).
2) SYNTHESIS OF 2,3,4-TRI-O-ACETYL-α-MANNOPYRANOSIDE
METHYL (Compound 2f) OH
6 OAc AcO 2 ACO 3 1 Reagent:
2 ' H3C 110 - OMe - CAN: MW = 548.23 MW: 320.29 9.16 g (15.45 mmol - 1 eq) of 2,3,4-tri-O-acetyl-6-monomethoxytrityl-aD-Methyl mannopyranoside is dissolved in 150 mL of CH3CN / H20 (95/5 v / v).
847 mg (1.55 mmol - 0.1 eq.) Of CAN is added, then the mixture is heated at a temperature The reaction is monitored by TLC (Et 2 O / EP 7/3 v / v) and lasts 1 hour. The reaction medium is then diluted with CH2Cl2. The organic phase is then washed twice with water distilled, then dried over Na2SO4, filtered and concentrated. The product is then purified by flash chromatography on silica gel with an elution gradient (CH2Cl2 until CH2Cl2 / MeOH 96/4 v / v) to give a white powder.
Physical appearance: White powder.
Yield: 90%.
Rf: 0.67 (CH2Cl2 / MeOH 95 / 5v / v).
MS: (ESI + / MeOH) m / z: 321.4 [M + H] +; 343.1 [M + Na] +; 663.5 [2M + Na] +, (ESI- / MeOH) m / z: 639.2 [2M-H] -.

1 H NMR (400.13 MHz, CDCl 3) δ (ppm): 1.75, 1.83 and 1.90 (3s, 9H, H 2 '); 2.48 (s, 1H, OH) ; 3.18 (s, 3H, -OCH 3); 3.41 (dd, 1H, 3H6a-H5 = 4.5Hz, 2H6a-H6b = -12.6 Hz, H6a); 3.48 (dd, 1H, 3H6b-H5 = 2.0HZ, 2H6b-H6a = -12.5Hz, H6b); 3.54 (ddd, 1H, 3H5-H6a =
4.5 Hz, 3JH5-H6b = 2.3 Hz, 3H5-H4 = 9.9 Hz, H5); 4.50 (d, 1H, 3H1-H2 = 1.6 Hz, H1); 5.00 (t, 1 H, 3HH4-H3 = 3H4-H5 = 10.0 Hz, H4); 5.01 (dd, 1H, 3H2-H1 = 1.8 Hz, 3H2-H3 = 3.5 Hz, H3); 5.13 (dd, 1H, 3JH3-H2 = 3,4 Hz, 3JH3-H4 = 10.2 Hz, H3).
13 C NMR (100.62 MHz, CDCl 3) δ (ppm): 20.9, 21.0 and 21.1 (3C, C 2 =); 55.5 (1C, -OCH3); 61.6 (1 C, C6); 66.7 (] C, C4); 69.3 (1 C, C3); 69.2 (] C, C2);
70.9 (1 C, C5); 98.1 (1 C, C1); 170.2, 170.4 and 171.0 (3C, C1 ').
3) SYNTHESIS OF 6-O-HYDROGENOPHOSPHONATE-aD-METHYL MANNOPYRANOSIDE (Compound 4f) II
HO 'HQ

QH Reagents:
O

H (PO) (OPh) 2: MW = 234.19 1 - Et3N: MW = 101.19 MeONa: MW = 54.02 QMe - Amberlyst 15-H 'resins MW: 258.16 0.5 g (1.56 mmol - 1 eq) of methyl 2,3,4-tri-O-acetyl-α-D-mannopyranoside (Compound 3f) are dissolved in 10 mL of distilled pyridine. 2.1 mL (10.92 mmol - 7 eq.) From Diphenyl phosphite are added dropwise to the mixture at room temperature.
room. After 30 minutes of stirring, 4 mL of Et 3 N / H 2 O (1/1 v / v) are added to reaction medium, then the mixture is stirred for 30 minutes additional. The reaction is followed by TLC (iPrOH / NH 4 OH 95/5 v / v). The reaction mixture is then concentrated and then diluted in 50 mL of CH2Cl2. The organic phase is washed three times with a saturated solution of NaHCO3, washed with distilled water, then dried over Na2SO4, filtered and concentrated. During this step, all of the starting sugar is consumed. 28 mg (0.46 mmol 0.3 eq.) From MeONa are added to the reaction medium and then diluted again in 10 ml of MeOH
Anhydrous. The The reaction is monitored by TLC (iPrOH / NH4OH 9/1 v / v) and lasts 30 minutes. The reaction medium is then neutralized with Amberlyst 15-H + acid resins. Resins are then filtered, then rinsed with McOH. The crude obtained after concentration is purified by chromatography on silica gel column with an elution gradient (iPrOH up to iPrOH / NH4OH 9/1 v / v).

Physical appearance: Light beige powder.
Yield: 93%.
Rf: 0.24 (iPrOH / NH4OH 9/1 v / v).
MS (ESI + / MeOH) m / z: 259.2 [M + H] +; 281.1 [M + Na] +; 539.2 [2M + Na] +, (ESI- / MeOH) m / z: 257.4 [MH] -.

1H NMR (400.13 MHz, CD3OD) δ (ppm): 3.23-3.26 (m, 1H, H6a); 3.32 (s, 3H, -OCH 3) 3.32-3.36 (m, 1H, H5); 3.45 (t, 1H, 3H4-H3 = 3HH4-H5 = 9.4 Hz, H4); 3.5 (dd, 1H, 3JH6b-H5 = 2.2 Hz, 2H6b-H6a = -10.9 Hz, H6b); 3.65 (dd, 1H, 3HH 3 -H 2 = 3.4 Hz, 3HH 3 -H 4 = 9.5 Hz, H3); 3.82 (dd, 1H, 3HH-H2 = 1.7HZ, 3H2-H3 = 3.4Hz, H2); 6.10 (d, 1H, 3HCl-H2 = 1.5 Hz, H1).
13 C NMR (100.62 MHz, CD3OD) δ (ppm): 6.3 (C, C6); 55.0 (1C, -OCH3); 69.8 (IC, C2); 70.1 (1C, C3); 70.6 (1C, C4); 71.5 (1C, C5, 101.1 (1C, C1).
31 P NMR (162 MHz, CD 3 OD) δ (ppm): 9.23 (s, H (PO) OH).

The synthetic scheme of the compound of formula (III) (compound 4f) is presented in the figure 7 annexed.
EXAMPLE 5 Preparation of a Derivative Formula Derivative (III) 1) SYNTHESIS OF 2,3-O-ISOPROPYLIDENE-4,6-0- (CYCLOSULFATE) -aD-METHYL MANNOPYRANOSIDE (Compound 1g) 3.79 g of methyl 2,3-O-isopropylidene-α-D-mannopyranoside (16.18 mmol, 1 eq.), 6.75 mL of triethylamine (48.54 mmol, 3 eq.) And 1.3 mL of thionyl chloride (17.80 mmol, 1.1 eq.) are reacted in 75 mL of CH2Cl2 according to the same protocol as for 2'-azidoethyl 2,3-O-isopropylidene-4,6-0- (cyclosulfate) -uD-mannopyranose (Compound 5a) (Example 1) The crude sulphite (16.18 mmol, 1 eq.), 3.8 g of sodium metaperiodate (17.80 mmol, 1.1 eq.), 20 mL
water and 14 mg of ruthenium chloride (0.06 mmol, 0.004 eq.) are then reacted in 60 mL of a CH2Cl2 / CH3CN solution (1/1 v / v) according to the same protocol.
Rf: 0.48 (AcOEt / EP 3/7 v / v).
MS (ESI + / MeOH) m / z: 297.65 [M + H] +; 319.23 [M + Na] +.

2) SYNTHESIS OF 6,7-DIDEOXY-DIMETHOXYPHOSPHINYL-2,3-0-METHYL ISOPROPYLIDENE-4-SODIUMSULFATE-α-MANNOPYRANOSIDE
(Compound 2g) In a bicol, 3.5 g of dimethylmethylphosphonate (28.37 mmol, 2 eq.), 3 drops of 1,1-diphenylethylene (colored indicator) and 10 mL of DMPU (40.53 mmol, 4 eq.) are dissolved in 20 mL of anhydrous THF under an argon atmosphere. The bicol is immersed in a bath at a temperature of -80 C for 5 minutes. An excess of BuLi is then added drip until a persistent red color is obtained. 6 g of cyclosulfate (20.27 mmol, 1 eq.) previously dissolved in 40 mL of anhydrous THF are added dropwise.
The solution becomes yellow after adding a few drops. The bath is then maintained at a temperature of -70 / -80 C for 3 hours, then for 14 hours at room temperature. The mixture is then diluted in CH2Cl2, and the product is washed out with water.
The aqueous phase is washed with CH2Cl2 before being lyophilized. The brown oil obtained is purified by chromatography on silica gel (CH 2 Cl 2 / MeOH 9/1 v / v) to give an oil yellow (1.84 g, 20%).
Rf: 0.28 (CH 2 Cl 2 / MeOH 9/1 v / v).
MS (ESI + / MeOH) m / z: 465.15 [M + Na] +
(ESI- / MeOH) m / z: 419.18 [M-Na] -.
1 H NMR (400.13 MHz, CD3OD) δ (ppm): 1.33, 1.51 (2s, 6H, H10); 1.89 and 2.17 (2m, 4H, H6 and H7); 3.35 (s, 3H, -OCH3); 3.62 (m, 1H, H5); 3.74 and 3.77 (2s, 6H, Hg); 4.10 (d, 1H, J2-1 = J2_3 = 5.2 Hz, H2); 4.23 (m, 2H, H3 and H4); 4.83 (s, 1H, H1).
1H NMR (100.62MHz, CD3OD) δ (ppm): 21.00 and 25.28 (C6 and C7); 26.30 and 27,90 (C1o); 53.09 and 53.16 (C8); 55.43 (-OCH3); 68.60 (C5); 76.79 (C2); 77.93 and 78.56 (C3 and C4) 99.54 (Ci); 110.41 (C9).
31 P NMR (81.02 MHz, CD3OD) δ (ppm): 36.31.
3) SYNTHESIS OF 6,7-DIDEOXY-PHOSPHINYL-α-MANNOPYRANOSIDE
METHYL (Compound 3g) 1.8 g of 6,7-dideoxy-dimethoxyphosphinyl-2,3-O-isopropylidene-4-sodium sulphate D-methyl mannopyranoside (4.07 mmol, 1 eq.) are first reacted in 15 mL of a mixture CH 3 CN / H 2 O (8/2 v / v) according to the protocol described for 2'-azidoethyl-2,3-O-isopropylidene-α-D-mannopyranose (compound 4a) (Example 1). 1.1 g of the product obtained, a yellow oil (3.67 mmol, 1 eq.), are reacted with 2.9 mL of pyridine (36.77 mmol, 10 eq.) And 2.42 mL of trimethylsilane bromide (18.33 mmol, 5 eq) in 12 mL of dichloromethane under argon atmosphere. After stirring for 8 hours at room temperature, the mixture is concentrated and 10 mL of 0.1N sodium hydroxide are then added. The agitation is kept for 30 minutes. The traces of pyridine are removed by three extractions with Et20, then the phase aqueous solution is acidified with a solution of HCI at IN before extraction three times at the Et20. The organic phases are collected, dried over Na2SO4, filtered and concentrated to give a colorless oil (708 mg, 71%).
Rf: 0.18 (CH 2 Cl 2 / MeOH 8/2 v / v).
MS (ESI + / MeOH) m / z: 295.12 [M + Na] +.
1 H NMR (400.13 MHz, CD3OD) δ (ppm) 1.94 and 2.17 (2m, 4H, H6 and H7); 3.36 (s, 3H, -OCH3); 7.20 (m, 1H, H5); 3.87 (m, 2H, H2 and H3); 4.32 (t, 1H, J4.3 =
J4.5 = 9.2 Hz, H4); 4.64 (s, 1H, H1).
13 C NMR (100.62 MHz, CD3OD) δ (ppm): 20.93 and 25.03 (C6 and C7); 55.52 (-OCH 3) 70.33 (H5); 71.58 and 71.85 (C2 and C3); 78.48 (C4); 102.23 (C1).
31 P NMR (81.02, CD3OD) δ (ppm): 36.66.
4) SYNTHESIS OF 6,7-DIDEOXY-PHOSPHINYL-2,3,4-O-ACETYL-α-D
METHYL MANNOPYRANOSIDE (Compound 4g) 1.1 g of methyl 6,7-dideoxy-phosphinyl-α-D-mannopyranoside (2.74 mmol, 1 eq.) and 2 ml of acetic anhydride (10.9 mmol, 4 eq) are reacted in 20 ml of pyridine. After 1 stirring time at room temperature, the solution is diluted in CH2CI2, then washed with a solution of HCI at IN and water. The organic phase is dried on Na2SO4, filtered and concentrated to give a brown oil (850 mg, 64%).
Rf: 0.15 (CH 2 Cl 2 / MeOH 8/2 v / v).
MS (ESI + / MeOH) m / z: 421.87 [M + Na] +.
1H NMR (400.13 MHz, CD3OD) δ (ppm): 1.90 and 2.21 (2m, 4H, H6 and H7); 2.01 and 2.11 (2s, 6H, Hb); 3.41 (s, 3H, -OCH3); 3.62 (m, 1H, H5); 4.41 (t, 1H, J4_3 =
J4_5 = 9.8 Hz, H4); 4.67 (s, 1H, HI); 5.12 (m, 1H, H2); 5.26 (dd, 1H, J3_2 = 3.4 Hz, J3_4 = 9.8 Hz, H3).
13 C NMR (100.62 MHz, CD3OD) δ (ppm): 19.62 and 25.18 (C6 and C7); 20.73 and 20.85 (Cb); 55.66 (-OCH3); 70.63, 71.56, 72.87 (H2, C3 and C5); 75.73 (C4); 99.68 (This) ; 171,75, 172.26 (Ca).

31 P NMR (81.02, CD3OD) δ (ppm) 36.31.
5) SYNTHESIS OF 6,7-DIDEOXY-PYROPHOSPHINYL-2,3,4-O-ACETYL-α-D
METHYL MANNOPYRANOSIDE (Compound 5g) 700 mg of methyl 6,7-dideoxy-phosphinyl-2,3,4-O-acetyl-α-D-mannopyranoside (0.15 mmol, 1 eq.) Are dissolved in 8 mL of methanol before adding dibutylamine (0.15 mmol, 1 eq.). The mixture is left stirring at room temperature during 30 minutes. The The solvent is then evaporated and then coevaporated with anhydrous pyridine to eliminate all traces of water. The phosphonic monosalt of dibutylamine obtained is dissolved in 7 mL of Anhydrous THF, then diphenyl chlorophosphate (0.15 mmol, 1 eq.) and dibutylamine (4.39 mmol, 3 eq.) are successively added. The mixture is stirred with ambient temperature under argon atmosphere for 2 hours.
In the same way, the monosel of dibutylamine orthophosphate is prepared:
acid orthophosphoric acid (4.39 mmol, 3 eq.) is dissolved in 8 mL of methanol, then of the dibutylamine (4.39 mmol, 3 eq.) is then added. After 20 minutes stirring at temperature the traces of pyridine are removed by coevaporation at room temperature.
anhydrous pyridine. The orthophosphate dibutylammonium monosel (4.39 mmol, 3 eq.) is dissolved in 8 mL of anhydrous pyridine, then the activated phosphonic anhydride is added slowly. The solution is kept stirring at room temperature under an argon atmosphere for 15 hours.
The solvents are then evaporated, the oil obtained is purified by gel chromatography silica (IPrOH / NH4Cl, 9/1 v / v) to give a clear oil (470 mg, 50%).
Rf: 0.12 (CH 2 Cl 2 / MeOH 8/2 v / v).
MS (ESI + / MeOH) m / z: 421.87 [M + Na] +.
1H NMR (400.13 MHz, CD3OD) δ (ppm): 1.74 and 2.00 (2m, 4H, H6 and H7); 2.02 and 2.10 (2s, 6H, Hb); 3.40 (s, 3H, -OCH 3); 3.58 (m, 1H, H5); 4.43 (t, 1H, J4-3 =
J4-5 = 9.8 Hz, H4); 4.69 (s, 1H, H1); 5.13 (m, 1H, H2); 5.28 (dd, 1H, J3-2 = 3.4 Hz, J3-4 = 9.8 Hz, H3).
13 C NMR (100.62 MHz, CD3OD) δ (ppm): 19.56 and 25.01 (C6 and C7); 20.73 and 20.85 (Cb); 55.69 (-OCH3); 70.63, 71.58, 72.87 (H2, C3 and C5); 75.71 (C4); 99.65 (C1); 171,75, 172.26 (Ca).
31 P NMR (81.02, CD3OD) δ (ppm): -9.9 and 8.4.

6) SYNTHESIS OF 6,7-DIDEOXY-PYROPHOSPHINYL-α-MANNOPYRANOSIDE
OF METHYL (Compound 6g) 470 mg of methyl 6,7-dideoxy-phosphinyl-α-D-mannopyranoside (0.89 mmol, 1 eq.) are deprotected according to the protocol described for 2'-azidoethyl-aD-mannopyranose (compound 3a) (Example 1) in 8 mL of methanol and in the presence of 190 mg of methanolate sodium (3.55 mmol, 4 eq.), to give a white oil (297 mg, 80%).
Rf: 0.20 (IPrOH / NH4Cl 5/5 v / v).
MS (ESI + / MeOH) m / z: 441.57 [M + Na] +.
1 H NMR (400.13 MHz, D 2 O) δ (ppm): 1.97 (m, 1H, H7a); 2.36 (m, 1H, H7b); 2.99 (M, 1H, H6a); 3.13 (m, 1H, H6b); 3.37 (s, 3H, -OCH3); 3.78 (m, 1H, H5); 3,89-3.96 (m, 2H, H2 and H3); 4.45 (t, 1H, J4-5 = J4-3 = 9.4 Hz, H4); 4.70 (s, 1H, H 1).
13 C NMR (100.62 MHz, D 2 O) (ppm): 26.81 (C, 7); 47.60 (C6); 55.43 (-OCH3);
69.16 (C5); 69.94 (C3); 70.44 (C2); 79.03 (C4); 100.99 (CI).
31 P NMR (81.02, CD3OD) δ (ppm): -9.8 and 8.5.
The synthetic scheme of the pyrophosphonate derivative of formula (III) (compound 6g) is shown in Figure 8 attached.
EXAMPLE 6 PREPARATION OF A DERIVATIVE PYROPHOSPHATE OF FORMULA (III) The compounds 1h, 2h and 3h are prepared according to the procedure described below.
above (cf.
synthesis of compounds 1, 2 and 3 of Example 3).
1) Synthesis of Ethyl (6-Deoxy-6-Phosphate-2,3,4-Tri-O-benzyl) D-MANNOPYRANOSIDE OF METHYL (Compound 4h) 100 mg of sugar (0.22 mmol, 1 eq.) And 750 mg of diethyldiethylphosphoramidite (0.22 mmol, 1 eq.) are dissolved in 2 mL of THF before adding under an atmosphere of argon 290 L of ] H-Tetrazole drop by drop. After 4 hours of stirring at room temperature ambient, 600 mg of acid meta-chloroperbenzoic acid (mCPBA) (3.47 mmol, 1.6 eq.) previously dissolved in 6 mL of CH 2 Cl 2 are added to the mixture at a temperature of -78 C. Stirring is maintained at this temperature for 10 minutes, then at room temperature for 10 minutes.
minutes. The mixture The reaction is diluted with AcOEt and washed with NaHCO3 solution.
saturated. The sentence The organic product is dried over Na 2 SO 4, filtered, concentrated and then purified on silica column (AcOEt / EP 2/8 v / v) to give a transparent oil.
Rf: 0.45 (CH 2 Cl 2 / MeOH 9/1 v / v).

MS (ESI + / MeOH) m / z: 623.13 [M + Na] +.
1H NMR (400.13 MHz, CDCl3) δ (ppm): 1.21 (t, 6H, J8-7 = 7.1 Hz, H8); 2.80 (m, 1H, H6a); 2.93 (m, 1H, H6b); 3.29 (s, 3H, -OCH3); 3.78 (td, 1H, J5-4 = J5-6a = 9.3 Hz, J5-6b = 2.6 Hz, H5); 4.03 (m, 4H, H7); 4.53 (s, 1H, H1); 4.55-4.64 (m, 6H, Ha); 5.00 (t, 1H, J4-5 = J4-3 = 9.9 Hz, H4); 5.07 (dd, 1H, J2-3 = 3.3 Hz, J2-1 = 1.7 Hz, H2); 5.15 (dd, 1H, J3-2 =
3.4 Hz, J3-4 = 10.0 Hz, H3); 7.17-7.31 (m, 15H, H, d, e).
13 C NMR (100.62 MHz, CDCl3) δ (ppm): 16.42 and 16.58 (C8); 32.63 (C6); 55.76 (-OCH3); 64.03 and 64.10 (H7); 69.31 (C3 and C4); 69.97 (C2); 70.58 (C5);
98.84 (CI); 72.33, 73.01 and 75.34 (Ca); 127.64-128.56 (Cc, d, e); 138.30, 138.41 and 138.55 (Cb).
31 P NMR (81.02 CDCl3) δ (ppm): 28.0.
2) SYNTHESIS OF 6-DEOXY-6-PHOSPHATE-2,3,4-TRI-O-BENZYL-α-D
METHYL MANNOPYRANOSIDE (Compound 5h) Compound 5h is prepared according to the procedure described above (cf.
Example 5 synthesis of 6,7-dideoxy-phosphinyl-2,3,4-O-acetyl-α-D-mannopyranoside methyl).
Rf: 0.23 (CH 2 Cl 2 / MeOH 9/1 v / v).
MS (ESI + / MeOH) m / z: 567.34 [M + Na] +.
1H NMR (400.13 MHz, CDCl3) δ (ppm): 2.96 (m, 1H, H6a); 3.23 (m, 1H, H6b);
3.28 (s, 3H, -OCH3); 3.65 (td, 1H, J5-4 = J5-6a = 9.3 Hz, Js-6b = 2.6 Hz, H5); 4.51 (s, 1H, HI); 4.54 to 4.64 (m, 6H, Ha); 5.04 (t, 1H, J4-5 = J4-3 = 9.9 Hz, H4); 5.04 (dd, 1H, J2-3 =
3.3 Hz, J2-1 = 1.7 Hz, H2) 5.17 (dd, 1H, J3-2 = 3.4 Hz, J3-4 = 10.0 Hz, H3); 7.18-7.32 (m, 15H, Hc, d, e) =
13 C NMR (100.62 MHz, CDCl3) δ (ppm): 32.61 (C6); 55.78 (-OCH3); 69.33 (C3 and C4);
69.89 (C2); 70.56 (C5); 98.84 (C,); 72.36, 73.05 and 75.34 (Ca); 127,64-128.53 (Ce, d, e); 138.33, 138.48 and 138.65 (Cb).
31 P NMR (81.02 CDCl 3) δ (MPm): 22.5.
3) SYNTHESIS OF 6-DEOXY-6-PYROPHOSPHATE-2,3,4-TRI-O-BENZYL-α-D
METHYL MANNOPYRANOSIDE (Compound 6h) 100 mg of 6-deoxy-6-phosphate-2,3,4-tri-O-benzyl-α-D-mannopyranoside methyl (0.52 mmol, 1 eq.) Are dissolved in 3 mL of anhydrous THF, followed by 85 L of pyridine (1.03 mmol, 2 eq.) And 52 μL of POCI3 (0.57 mmol, 1.1 eq.) Are added at a temperature 0 C under argon atmosphere. Stirring is maintained at a temperature of 0 C for 4 hours, a few mL of saturated NaHCO3 solution are added to a temperature of 0 C, and the mixture is stirred for a further 15 minutes. The reaction medium is then lyophilized, then purified on a silica column (CH 2 Cl 2 / MeOH 9/1 v / v) to give an oil whitish (35 mg, 30%).
Rf: 0.12 (CH 2 Cl 2 / MeOH 8/2 v / v).
MS (ESI + / MeOH) m / z: 647.78 [M + Na] +.
1H NMR (400.13 MHz, CDCl3) δ (ppm): 2.96 (m, 1H, H6a); 3.23 (m, 1H, H6b);
3.28 (s, 3H, -OCH3); 3.65 (td, 1H, J5-4 = J5-6a = 9.3 Hz, J5-6b = 2.6 Hz, H5); 4.51 (s, 1H, H1); 4.54 to 4.64 (m, 6H, Ha); 5.04 (t, 1H, J4-5 = J4-3 = 9.9 Hz, H4); 5.04 (dd, 1H, J2-3 =
3.3 Hz, J2-1 = 1.7 Hz, H2) 5.17 (dd, 1H, J3-2 = 3.4 Hz, J3-4 = 10.0 Hz, H3); 7.18-7.32 (m, 15H, Hc, d, e) =
13 C NMR (100.62 MHz, CDCl3) δ (ppm): 32.61 (C6); 55.78 (-OCH3); 69.33 (C3 and C4);
69.89 (C2); 70.56 (C5); 98.84 (C1); 72.36, 73.05 and 75.34 (Ca); 127,64-128.53 (Cc, d, e); 138.33, 138.48 and 138.65 (Cb).
31 P NMR (81.02 CDCl3) δ (ppm): -6.78 and 7.34.
4) SYNTHESIS OF 6-DEOXY-6-PYROPHOSPHATE-α-MANNOPYRANOSIDE
OF METHYL (Compound 7h) Compound 7h is prepared according to the procedure described above (cf.
Example 5 synthesis of 6,7-dideoxy-pyrophosphinyl-2,3,4-O-acetyl-α-D-mannopyranoside methyl).
Rf: 0.12 (IPrOH / NH4Cl 7/3 v / v).
MS (ESI + / MeOH) m / z: 377.91 [M + Na] +.
1 H NMR (400.13 MHz, CD3OD) δ (ppm): 3.44 (s, 3H, H-ocH3); 3.64 (m, 1H, H5);
3.67 (t, 1H, J4-3 = J4-5 = 10.0 Hz, H4); 3.77 (m, 1H, H6a); 3.80 (d, 1H, J2-1 =
J2-3 = 5.6 Hz, H2); 3.91 (d, 1H, J1-2 = 1.6 Hz, H1); 3.96 (dd, 1H, J6b-5 = 1.8 Hz, J6b-6a = 9.8 Hz, H6b); 3.97 (dd, 1H, J3-2 =
1.6 Hz, J3-4 = 3.2 Hz, H3).
13 C NMR (100.62 MHz, CD 3 OD) δ (ppm): 58.59 (CO, 64.42 (C 4), 67.57 (C 3);
68.19 (C2); 70.19 (C5); 98.51 (C1).
31 P NMR (81.02 CDCl3) δ (ppm): -6.53 and 8.62.
The synthesis scheme of the pyrophosphate derivative of formula (III) is presented in Figure 9 attached.

EXAMPLE 7 PREPARATION OF A COMPOUND OF FORMULA (II) 1) SYNTHESIS OF 6-DESOXY-6-AZIDO-D-MANNOPYRANOSYL- (1,6) -6-DESOXY-METHYL 6-AZIDO-D-MANNOPYRANOSYL- (1,4) -D-MANNOPYRANOSIDE
To 2.35 g of methyl mono-2,3-isopropylidene-mannopyranoside (0.01 mol, 1 g.
eq.) dissolved in 40 ml of anhydrous THF are added 12 g of trichloroacetimidate (0.03 mole, 3 eq.).
The solution is then cooled to a temperature of 0 C, before 30 mL
(0.28 moles) BF3Et2O are added dropwise under an argon atmosphere. The mixture reaction is then kept at room temperature and left stirring throughout a night. Once the reaction is complete, the reaction mixture is washed successively with 2 times 80 mL of saturated aqueous solution of NaHCO 3 and then with 2 times 80 ml of distilled water. The organic phase is dried with Na 2 SO 4, filtered and evaporated under reduced pressure. The residue obtained is chromatographed on silica gel using a mixture of CH2Cl2 / MeOH as eluent. The product obtained is a white powder (5 g, 80% yield).
Rf: 0.5 (CH2Cl2 / MeOH: 8/2 v / v).
MS (ESI + / MeOH) m / z: 661.7 [M + Na] +; 661.7 [M + H] +.
3.3 g of trisaccharide (5 mmol, 1 eq.) And 2.1 ml of triethylamine (15 mmol, 3 eq.) are dissolved in 25 mL of CH2Cl2. The balloon is placed in an ice bath and 3.5 mL of chloride thionyl (5.5 mmol, 1.1 eq) are slowly added. A white precipitate of chloride of triethylammonium appears rapidly and the reaction mixture becomes gradually yellow.
After stirring for 5 minutes at a temperature of 0 ° C., the starting product has gone, sulphite desired is obtained. The mixture is filtered, the organic phase is washed with distilled water, a solution of HCI to IN, then again water. It is then dried on Na2SO4, filtered and concentrated to give a brown solid directly reacted.
Sulphate formation:
The crude sulphite (5 mmol, 1 eq.,) Is dissolved in 20 ml of a mixture CH2C12 / CH3CN (1/1 v / v). 1.17 g of sodium metaperiodate (5.5 mmol, 1.1 eq.), 5 mL of water and three grain of ruthenium chloride are added successively. The reaction is exothermic, a precipitate of Na103 is formed very quickly. After 1 hour stirring at room temperature ambient, sulphite has been When the reaction mixture is consumed, it is filtered and diluted in 200 ml of CH 2 Cl 2. The organic phase is washed with a solution of 5% NaHCO3, distilled water and then dried, filtered and concentrated.

The solid obtained is dissolved in a minimum of CH 2 Cl 2 and filtered through silica.
The silica is rinsed several times with CH2CI2. A white solid is obtained (2.8 g, 70%).
Formation of di-azido protected:
823 mg of cyclic sulfate (0.15 mmol, 1 eq.) And 200 mg of sodium azide (0.31 mmol, 2 eq.) are dissolved in 10 mL of DMF. After 4 hours of stirring at room temperature ambient, the reaction mixture is diluted in 50 mL of 5% NaHCO3 and taken up with 100 mL
of CH2C12, washed with water, dried over Na 2 SO 4, and then evaporated. The powder obtained is dissolved in 10 mL of methanol, then treated with 2 mL of Amberlite H + resin. After evaporation of solvent, 800 mg of yellow powder are isolated and chromatographed on silica gel with a gradient of elution (CH2Cl2 to CH2Cl2 / MeOH 6/4 v / v) to give a white powder (yield 80%).
Rf: 0.67 (CH2Cl2 / MeOH 6/4 v / v).
MS (ESI + / MeOH) m / z: 688.7 [M + H] +; 710.7 [M + Na] +.
(ESI- / MeOH) m / z: 687.7 [MH] -.
The synthetic scheme of the compound of formula (I1) exemplified is presented at Figure 10 attached.
EXAMPLE 8 PREPARATION OF A COMPOUND OF FORMULA (III) 1) SYNTHESIS OF METHYL 6-DEOXY-6-IODO-α-MANNOPYRONOSIDE
(Compound li) A solution of 25 mL of anhydrous THF containing 4.90 g (19.3 mmol, 1.5 eq.) Of diiode is added, dropwise, under nitrogen, to a solution of anhydrous THF at reflux containing 100 mL of THF
anhydrous containing 2.5 g (12.8 mmol-1 eq) of methyl α D-mannopyranoside, 5 g (19.3 mmol - 1.5 eq.) of Pcp3 and 1.75 g (25.7 mmol - 2 eq) of imidazole. After 3 hours of reaction to reflux, the mixture is cooled to room temperature, the imidazole salts are filtered and after concentration of the filtrate, the crude The reaction is directly purified by gel column chromatography.
silica (CH 2 Cl 2 / MeOH 9/1 v / v). The product is then recrystallized from Et 2 O to give crystals white (85%).
Rf: 0.25 (CH 2 Cl 2 / MeOH 9/1 v / v).
M.p .: 118-120C.
MS (ESI + / CH3CN-H2O-CF3CO3H) m / z: 305.0 [M + H] +, 327.0 [M + Na] +, 609.0 [2M + H] +, (ESI- / CH3CN- H2O-CF3CO3H) m / z: 339.2 [M + Cl] +.
1H NMR (400.13 MHz, CDCl3) δ (ppm): 3.26 (dd, 1H, J6a-5 = 7.0 Hz, ha-6b = 10.9.
Hz, H6a); 3.32 (s, 3H, -OCH3); 3.32-3.36 (m, 1H, H5); 3.45 (t, 1H, J4-3 = J4-5 = 9.4 Hz, H4); 3.5 (dd, 1H, J6b-5 = 2.2 Hz, J6b-6a = 10.9 Hz, H6b); 3.65 (dd, IR J3-2 = 3.4 Hz, J3-4 = 9.5 Hz, H3);
3.82 (dd, 1H, J 1-2 = 1.7 Hz, J2-3 = 3.4 Hz, H2); 6.10 (d, 1H, J1-2 = 1.5 Hz, H1).
13 C NMR (100.62 MHz, CDCl3) δ (ppm): 6.31 (C6); 55.08 (-OCH3); 69.86 (C2);
70.14 (C3);
70.66 (C4); 71.59 (C5); 101, 10 (C1).
[?] D: + 67.5 (c = 1.00 g / 100 mL, MeOH).
2) SYNTHESIS OF 6-DESOXY-6-IODO-2,3,4-TRI-O-BENZYL-α-D
METHYL MANNOPYRANOSIDE (Compound 2i) 4.37 g of methyl 6-deoxy-6-iodo-D-mannopyranoside (14.34 mmol, 1 eq.) are dissolved in 100 mL of anhydrous DMF before adding 8.5 mL of benzyl bromide (71,72 mmol, 5 eq.). 1.7 g of NaH (71.72 mmol, 5 eq.) are then added in small portions time. After 4 hours of reaction, 5 mL of MeOH are added and the mixture is diluted in ether And, O before washing with water. The The organic phase is washed several times with water, dried and concentrated.
Purification by chromatography on a silica column (AcOEt / EP 4/6 v / v) makes it possible to obtain the produced in the form of a yellow oil (3.57 g, 44%).
Rf: 0.42 (EP / AcOEt 8/2 v / v).
MS (ESI ESI + / CH3CN-H2O-CF3CO3H) m / z: 543.1 [M-OCH3] +, 592.2 [M + NH4] +, 597.1 [M + Na] +.
1 H NMR (400.13 MHz, CDCl3) δ (ppm): 3.31-3.43 (m, 1H, H6a); 3.38 (s, 3H, -OCH3); 3,47-3.59 (m, 2H, H5 and H6b); 3.76-3.80 (m, 2H, H2 and H4); 3.90 (dd, 1H, J3-2 =
2.9 Hz, J3-4 = 9.2 Hz, H3); 4.61 (s, 2H, Ha); 4.74 (d, 2H, J = 12.2 Hz, Na); 4.76 (d, 1H, J1, = 1.5 Hz, H1) ; 4.84 (d, 2H, J = 11.0 Hz, Ha);
7.28-7.41 (m, 15H, 15Hc, d, e).
1H NMR (100.62MHz, CDCl3) δ (ppm): 7.01 (C6); 55.05 (-OCH3); 71.48 (C5);
72.09, 72.73 (2 Ca); 74.56 (C2); 75.44 (Ca); 78.52 (C4); 79.87 (C3); 99.05 (C1);
127.66, 127.82, 128.06, 128.33, 128.40 (15C, C ,, d, e); 138.11 (Cb); 138.24 (2Cb).
[aID: + 28.0 (c = 1.00 g / 100 mL, CHCl3).
3) SYNTHESIS OF (3R, 4R, 5S, 6R) -3,4,5-TRIS (BENZYLOXY) -TETRAHYDRO-6-METHOXYPYR-2-ENE (Compound 3i) 1 g of methyl 6-deoxy-6-iodo-2,3,4-tri-O-benzyl-α-mannopyranoside (1.74 mmol, 1 eq.) and 2.6 mL of DBU (17.4 mmol, 10 eq.) are reacted under argon in 20 ml.
mL of DMF. After 3 hours and a half of reaction at 80 C, the solution is cooled to room temperature ambient, diluted in AcOEt and washed with saturated NaHCO3 solution. The organic phase is then washed with water, dried, concentrated and purified by chromatography on a silica column (AcOEt / EP 2/8 v / v) to give a brown oil (430 mg, 56%).
Rf: 0.34 (AcOEt / EP 5/5 v / v).

MS (ESI + / MeOH): m / z 469.34 [M + Na] +.
1 H NMR (400.13 MHz, CDCl3) δ (ppm): 3.62 (s, 3H, -OCH3); 3.99 (dd, 1H, J2, = 2.6 Hz, J2-3 =
8.2 Hz, H2); 4.02 (m, 2H, H4 and 1Ha); 4.17 (d, 2H, J = 10.2 Hz, Ha); 4,34-4.62 (m, 4H, Ha), 4.94 (dd, 1H, J3.2 = 1.2 Hz, J3_4 = 5.1 Hz, H3); 4.73 (d, 1H, J1-2 = 2.2 Hz, H,); 4.82, 4.90 (2m, 2H, H6); 7.18-7.32 (m, 15H, Hc, d, e) =
13 C NMR (100.62 MHz, CDCl 3) δ (ppm): 55.52 (-OCH 3); 72.27, 72.91 and 74.66 (3Ca); 74,34 (C3); 76.08 (C2); 79.18 (C4); 82.34 (CO; 99.43 (C 1); 127.59-129.11 (Cc, d, e); 137.73, 138.02, 140.12 (3Cb and C5) -4) SYNTHESIS OF (3R, 4R, 5S, 6R) -3,4,5-TRIS (BENZYLOXY) -TETRAHYDRO-6-METHOXYPYRAN-2-ONE (Compound 4i) 1.13 g of (3R, 4R, 5S, 6R) -3,4,5-tris (benzyloxy) -tetrahydro-6-methoxypyr-2-ene (2.53 mmol, 1 eq.) are dissolved in 500 mL of tBuOH before adding 1.3 g of K2CO3 (8.36 mmol, 3.3 eq.) dissolved previously in 100 mL of water. 0.12 g of K1vInO4 (0.76 mmol, 0.3 eq) in solution in 100 mL of water and 406 mg of Na104 (1.90 mmol, 0.75 eq.) In solution in 100 ml of water are then added. After lh stirred at room temperature, the solution is extracted with CH 2 Cl 2, the organic phase is dried, concentrated and purified on a silica column (AcOEt / EP 5/5 v / v). The product is obtained in the form of a pale yellow oil (1.07 g, 94%).
Rf: 0.55 (AcOEt / EP 6/4 v / v).
MS (ESI + / MeOH): m / z 471.18 [M + Na] +.
1 H NMR (400.13 MHz, CDCl 3) δ (ppm): 3.54 (s, 3H, -OCH 3); 3.73 (dd, 1 H, J2_1 = 2.7 Hz, J2_3 =
8, 1 Hz, H2); 4.01 (m, 2H, H4 and 1Ha); 4.15 (d, 2H, J = 10.4 Hz, Ha); 4.96 (dd, 1H, J3_2 = 1.0 Hz, J3_4 = 5.0 Hz, H3); 4.76 (d, 1H, J1-2 = 2.6 Hz, HI); 7.20-7.29 (m, 15H, Hed, e).
13 C NMR (100.62 MHz, CDCl 3) δ (ppm): 55.51 (-OCH 3); 72.27, 72.91 and 74.66 (3Ca); 74.17 (C5); 74.36 (C3); 76.00 (C2); 79.15 (C4); 99.42 (CI); 127.61 to 128.41 (Ce, d, e); 137.73, 138.02 (3Cb).
5) SYNTHESIS OF (3R, 4R, 5S, 6R) -3,4,5-TRIS (BENZYLOXY) -TETRAHYDRO-6-METHOXYPYRAN-2-OL (Compound 5i) 1.07 g of (3R, 4R, 5S, 6R) -3,4,5-tri (benzyloxy) -tetrahydro-6-methoxypyran-2-one (2.39 mmol, 1 eq.) are reacted with 1,80 mg of NaBH4 (4,78 mmol, 2 eq.) in 25 ml of MeOH. After 16 hours stirred at room temperature, 2 mL of water are added and the solution is then concentrated. A
silica gel column chromatography (AcOEt / EP 5/5 v / v) makes it possible to get the product in form a yellow oil (1 g, 94%).
Rf 0.55 (AcOEt / EP 5/5 v / v).
MS (ESI + / MeOH) m / z 473.67 [M + Na] +

1 H NMR (400.13 MHz, CDCl3) δ (ppm): 3.49 (s, 3H, -OCH3); 3.60 (dd, 1H, J2_1 = 1.2 Hz, J2_3 =
6.8 Hz, H2); 3.82 (m, 2H, H4 and 1Ha); 4.00 (d, 1H, J = 10.4 Hz, 1Ha); 4.10 (dd, 1H, J3_2 = 1.0 Hz, J3-4 =
5.0 Hz, H3); 4.31 (t, 1H, J5.4 = J5.6 = 6.2 Hz, H5); 4.38-4.78 (m, 4H, Ha);
4.77 (d, 1H, J1.2 = 2.6 Hz, H1);
7.18-7.31 (m, 15H, Hc, d, e).
13 C NMR (100.62 MHz, CDCl 3) δ (ppm): 57.40 (-OCH 3); 73.60, 74.23, 74.86 (3Ca); 76.65 (C3) 78.61 (C2); 79.12 (C4); 100.56 (C1); 127.97-128.64 (Ced, e); 137.14, 137.89 (3Cb).
6) SYNTHESIS OF (3R, 4R, 5S, 6R) -3,4,5-TRIS (BENZYLOXY) -TETRAHYDRO-6-OXYDIISOPROPYLPHOSHONYLMETHOXYPYRANE (Compound 6i) 640 mg of (3R, 4R, 5S, 6R) -3,4,5-tri (benzyloxy) -tetrahydro-6-methoxypyran-2-ol (1.43 mmol, 1 eq.) are dissolved in 6.4 mL of DMF to form a very viscous solution.
14 mg of Lil (0.10 mmol, 0.07 eq.) And 241 mg of tBuOK (2.14 mmol, 1.5 eq.) Are then added.
solution becomes liquid. Under argon, 482 mg of phosphonate (1.86 mmol, 1.3 eq.) previously dissolved in 3.2 mL of DMF are added to the mixture drop by drop. The reaction is left 10 minutes under agitation at temperature ambient temperature and then heated for 3 hours at 60 C. After cooling, the mixture is diluted in AcOEt and washed with a saturated NaCl solution. The organic phase is dried over Na2SO4, filtered, concentrated and purified on a silica column (AcOEt / EP 8/2 v / v) to give a colorless oil (698 mg, 78%).
Rf: 0.45 (AcOEt / EP 8/2 v / v).
MS (ESI + / MeOH): m / z 651.90 [M + Na] +.
1 H NMR (400.13 MHz, CDCl3) δ (ppm): 1.35 (d, 8H, J8 -7 = 6.0 Hz, H8); 3.22 (s, 2H, H6); 3.55 (s, 3H, -OCH3); 3.66 (dd, 1H, J2, = 1.2 Hz, J2.3 = 6.4, Hz, H2); 3.89 (m, 2H, H4 and] Ha); 4.06 (d, 2H, J =
10.4 Hz, Ha); 4.16 (dd, 1H, J3.2 = 1.2 Hz, J3.4 = 6.0 Hz, H3); 4.37 (t, 1H, J5.4 = J5.6 = 6.2 Hz, H5); 4,44-4.84 (m, 6H, Ha, H, and H7); 7.26-7.36 (m, 15H, Hc, from).
13 C NMR (100.62 MHz, CDCl 3) δ (ppm): 17.99 (C 6); 23.78, 23.83, 23.97, 24.01 (C8); 56.94 (-OCH3); 69.47, 71.95 and 72.67 (3Ca); 72.10 and 72.17 (C7); 73.12 (C5); 75.27 (C3); 75.92 (C2); 77.17 (C4) ; 102.86 (CI); 127.53-128.46 (C 1, d, e); 137.23, 138.35 (3Cb).
7) SYNTHESIS OF (3R, 4R, 5S, 6R) -3,4,5-TRIS (BENZYLOXY) -TETRAHYDRO-6-OXYPHOSHONYLMETHOXYPYRANE (Compound 7i) 700 mg of (3R, 4R, 5S, 6R) -3,4,5-tris (benzyloxy) -tetrahydro-6-oxydiisopropylphosphonyl-methoxypyran (1.12 mmol, 1 eq.) are reacted in 20 mL of CH2Cl2 with 900 L of pyridine (11.2 mmol, 10 eq.) and 813 L of TMSBr (5.59 mmol, 5 eq.). After 16 hours stirring at temperature ambient, the mixture is diluted in AcOEt and then washed with water. The sentence organic is dried and concentrated. The resulting transparent oil is pure enough to be delivered directly in reaction. The protected phosphonate dissolved in 30 mL of a 1/1 v / v MeOH / THF mixture, degassed previously under argon, is reacted with Pd / C under an atmosphere of H2. After 18 hours of reaction, the solution is filtered and concentrated. The product is obtained in the form of a white oil (43% on both stages) Rf: 0.15 (Isopropanol, 5/5 v / v NH4OH).
MS (ESI + / MeOH): m / z 277.64 [M + Na] +.
1 H NMR (400.13 MHz, D 20) δ (ppm): 3.25 (s, 3H, -OCH 3); 3.48 (m, 2H, H4 and H5) ; 3.60 (m, 2H, H3 and H6a); 3.76 (m, 1H, H6b); 3.77 (dd, 1H, J2_1 = 1.8 Hz, J2-3 = 3.4 Hz, H2); 4.61 (d, 1H, JI -2 = 2.0 Hz, HI).
13 C NMR (100.62 MHz, D 20) δ (ppm): 54.61 (-OCH 3); 60.86 (C6); 66.67 (C4);
69.82 (C2) 70.44 (C3); 72.45 (C5); 100.76 (C,).
BIOLOGICAL RESULTS:

A- On rat aorta rings The biological effects of the compounds of the invention on angiogenesis have been tested according to a technique well known to those skilled in the art: the ring technique of rat aorta (Nicosia et al., M. Am. J. Pathol., 1994 Nov; 145 (5): 1023-9). This approach is fast and consists of placing a rat aortic ring a millimeter thick in a culture system in three dimensions formed from a type 1 collagen network.
aortes are obtained in Sprague-Dawley rats and cultured for 9 to 11 days in the presence or no compounds to test. Angiogenesis is then assessed by evaluating the number, the size and the organization of vascular buds progressing in the lattice of collagen.
The histograms of Figures 12a and 12b represent the neoangiogenic effect in vitro (Nicosia model) of different compounds of the invention - Control: untreated aorta, Compound 111 (compound 4f): aorta treated with a compound of formula (III) in which Z
is -X-HP (O) OH, X is an oxygen atom and R2 is a methyl group (synthesized according to example 4), Compound II: aorta treated with a compound of formula (11) in which not YHOX

not' X is an oxygen atom, n = 1, n '= 2 and n "= 0, and RI = R'1 _ -N3, Compound 111 (compound 7e): aorta treated with a compound of formula (III) in which Z
is -CH2-B (OH) 2 and R2 is a methyl group (synthesized according to the example 3), Compound I: aorta treated with a compound of formula (1) in which A is a gold nanoparticle, Ri = -COOH and m = 5, and - Reference: aorta treated with sunitinib: the Sutent (marketed by Pfizer) answering the formula (CH3 p Name /

NH

H
O
NOT
H
B- On endothelial cells Human dermal endothelial cells (15,000 / well) are treated with different compounds within the definition of the invention for 48 hours.
At the end of this treatment, the number of cells is estimated thanks to the activity succinates dehydrogenases (MTT assay, Mosmann TJ, Immunol Methods, 1983 Dec. 16;
65 (1-2): 55-63). The results show that the treatment of cells with the compounds of the invention to three different doses (10 "2 mol.L- ', 10-4 mol.L-' and 10-6 mol.L-1) has no effect cytotoxic endothelial cells.
The histogram of Figure 13 represents the cytotoxic effect of different compounds - Control: untreated cells, Compound III (compound 4f): cells treated with a compound of formula (111) in which Z is -X-HP (O) OH, X is an oxygen atom and R2 is a methyl group (synthesized according to Example 4), Compound II: cells treated with a compound of formula (11) in which not Y = HO n .. X
ho X is an oxygen atom, n = 1, n '= 2, n "= 0, and R 1 = R' 1 -N 3, - Compound 1: cells treated with a compound of formula (1) in which A
is a gold nanoparticle, RI -COOH and m = 5, and Compound III (compound 7e): cells treated with a compound of formula (I11) in which Z is -CH2-B (OH) 2 and R2 is a methyl group (synthesized according to the Example 3).

C-On mice with B16 melanoma A melanoma is induced on a mouse by subcutaneous injection of cells tumor (B16 cells). The tumor develops within 10 days in sub-position cutaneous (ventral side thigh). The size of the tumor is measured with calipers and its estimated volume according to formula V = L x 1 x 1, where L represents the length and 1 represents the width. Different compounds of the invention were administered to mice that received melanoma cells syngeneic agents (B 16) at a dose of 300 mg / kg.
The different compounds tested are as follows - Control: untreated mice, M6P: mice treated with mannose-6-phosphate (M6P), Compound III (compound 4f): mice treated with a compound of formula (III) in which Z
is -X-HP (O) OH, X is an oxygen atom and R2 is a methyl group (synthesized according to Example 4), Compound III (compound 7e): mice treated with a compound of formula (III) in which Z is -CH2-B (OH) 2 and R2 is a methyl group (synthesized according to the Example 3), Compound II: cells treated with a compound of formula (I1) in which O

not YHOX

hio X is an oxygen atom, n = 1, n '= 2, n "= 0, and R2 = R'2 = -N3, Compound I: cells treated with a compound of formula (1) in which A is a gold nanoparticle, RI = -COOH and m = 3.
The survival rate of the mice according to the number of days of treatment is represent on the graph of Figure 14 attached.
The evolution of tumor growth as a function of the number of days of treatment is represented on the graph of the appended FIG.
We observed a strong (65%) inhibition of tumor growth in the group of the mouse treated with the compound 7f of formula (111) of the invention, a 40% inhibition in the group of mice treated with the compound 4e of formula (I1I) of the invention, and inhibition of 30% in the group of mice treated with the compound of formula (1) of the invention. In parallel, no mortality was observed in the mice group treated with the compound 7f of formula (III) of the invention after 18 days of treatment, in comparison to the untreated mouse (40% mortality).
D- Angiogenic Activity on Chorioallantoic Membrane (CAM) In the photographs of the annexed Figure 16, we can observe the results obtained during of a classical test for the study of in vivo angiogenesis performed on the membrane chorioallantoic (CAM) chicken embryo.
The different compounds tested are as follows - Control: untreated mice, - Reference: mice treated with Sutent, M6P: mice treated with mannose-6-phosphate (M6P), Compound I: cells treated with a compound of formula (1) in which A
is a gold nanoparticle, RI = -N3 and m = 5, Compound IIa cells treated with a compound of formula (II) in which not YHOX
not"

O
not' X is an oxygen atom, n = 1, n '= 2, n "= 0, and R 1 = R' 1 -N 3, Compound IIb: cells treated with a compound of formula (II) (composed of example 7) in which O
Y = i0 0 HO

R, = R ', = -N3, and R2 is a methyl group, Compound III (compound 4f): mice treated with a compound of formula (III) in which Z
is -X-HP (O) OH, X is an oxygen atom and R2 is a methyl group (synthesized according to Example 4), Compound 111 (compound 7e): mice treated with a compound of formula (III) in which Z is -CH2-B (OH) 2 and R2 is a methyl group (synthesized according to the Example 3).
The compounds of the invention exhibit a strong inhibitory effect, as well as effects considerably lower than those of the reference. The composed of The invention also has an anti-angiogenic activity greater than that of the M6P.

Claims (15)

1. Compound derived from mannopyranoside or its pharmaceutically acceptable salts acceptable characterized in that it corresponds to one of the following formulas:

~ Formula (I) in which :
~ A is a silica nanoparticle or a selected metallic nanoparticle from column elements (IB), (IIB), (IIIB), (IVB), (VB), (VIB), (VIIB) or (VIIIB) the classification of Mendeleyev, and ~ B is a group carrying a mannopyranoside function corresponding to the following structure:

in which m is an integer between 0 and 10, and preferably m = 3, 4, 5 or 6, the groups B being linked to the nanoparticle A via the sulfur atom, and the number of B groups bound to the nanoparticle A being between 100 and 1000, and preference between 400 and 600, ~ Formula (II):

in which Y represents one of the following groupings with:
.smallcircle. n, n 'and n "being integers between 1 and 12, and preferably between 1 and 6, and .smallcircle. n "being 0 when X represents an oxygen atom, ~ Formula (III):

in which Z represents one of the following groupings or -X-R1 in which the radicals R1 and R'1, which are identical or different, represent radicals selected from -O-PO3H2, -N3, -CH2-PO3H2, -CH2-COOH, -SO3H2, -OPHO2H, -CH2-B (OH) 2, -X-PHO2H, X'-PO2H-X-PO3H2, and preferably -CH2-COOH and -N3, the radical R2 represents a linear or branched C1-C12 alkyl chain, and preferably in C1-C4; a linear or branched C1-C12 alkyl chain, and preferably C1-C4, carrier at least one -OH, -NH2, -SH, -COOH, -N3, -NO2 group; a cycle hydrocarbon, saturated or unsaturated C3-C6; a C3-C10 hydrocarbon ring, saturated or unsaturated, carrier at least one -OH, -NH2, -SH, -COOH, -N3, -NO2, C1-C4 alkyl group;
a saturated or unsaturated heterocycle having at least one heteroatom selected from the atoms oxygen, nitrogen or sulfur; a radical - (CH2-CH2-O) yH, wherein is comprised between 1 and 12, and preferably between 1 and 6, and the groups X and X ', which are identical or different, are chosen from: N, O, S, a chain C1-C4 alkyl, the X and X 'groups being preferably atoms oxygen. 2. Compound according to claim 1, characterized in that R2 represents a C1-C4 alkyl chain chosen from methyl, ethyl and n-propyl radicals, isopropyl, n butyl, tert-butyl, isobutyl and n-hexyl, and preferably the radical methyl. 3. Compound according to claim 1, characterized in that R2 represents a saturated hydrocarbon ring selected from cyclopropane, cyclobutane, cyclopentane and the cyclohexane. 4. Compound according to claim 1, characterized in that R2 represents a unsaturated hydrocarbon ring or a saturated heterocycle selected from rings phenyl, oxadiazole, triazole, oxazole, isoxazole, imidazole, thiadiazole, pyrrole, tetrazole, furan, thiophene, pyrazole, pyrazoline, pyrazolidine, thiazole, isothiazole, pyridine, pyrimidine, piperidine, pyran, pyrazine, pyridazine, indole, indazole, benzoxazole, naphthalene, quinoline, quinoxaline, quinazoline, anthracene and acridine, and preferably phenyl rings. 5. Compound according to one of claims 1 to 4, characterized in that the nanoparticles A of the compound of formula (1) are chosen from nanoparticles of gold, iron and of cobalt. 6. Compound according to one of claims 1 to 5, characterized in that the A nanoparticles have a diameter of between 2 and 10 nm, and preferably between 4 and 8 nm. 7. Process for the preparation of a compound derived from mannopyranoside according to one Claims 1 to 6, characterized in that it comprises at least the steps following:
(i) a halogenation step between a compound of formula (I '), (II') or (III ') carrier of minus a primary alcohol function, by reaction with a mixture dihalogen / phosphine or N-halosuccinimide / phosphine, said compounds (I '), (II') or (III ') answering formulas following wherein A is as defined in claims 1 to 6, and B 'is a grouping corresponding to the following structure:

in which m is as defined in claims 1 to 6, the groups B 'being linked to the nanoparticle A via the sulfur atom, and the number of groups B 'linked to the nanoparticle A being between 100 and 1000, and preferably between 400 and 600, in which Y, n, n 'and n "are as defined in claims 1 to 6, radical R2 and the groups X and X 'being as defined in claims 1 at 6, (ii) a nucleophilic substitution step of the halogenated compounds obtained during of step (i) by reaction with a nucleophilic reagent carrying an R1 and / or R'1 radical, to get the compounds of formula (I), (II) or (III) as defined according to Claims 1 to 6. 8. Process according to claim 7, characterized in that step (i) is conducted with a diiodine / triphenylphosphine mixture, in the presence of imidazole. 9. Compound derived from mannopyranoside according to one of claims 1 to 6, for use as a medicine. The compound of claim 9 for use as a medicament for the prevention and / or treatment of dependent diseases of an inhibition angiogenesis. 11. A compound according to claim 10 for use as a drug for the treatment of cancerous diseases, blindness diabetic, macular degeneration, rheumatoid arthritis and psoriasis. 12. A compound according to claim 11 for use as a drug for the treatment of cancerous diseases. 13. Pharmaceutical composition characterized in that it comprises, as a active principle, at least one compound derived from mannopyranoside as defined according to one of Claims 1 to 6, and at least one pharmaceutically acceptable excipient. 14. Pharmaceutical composition according to claim 13, characterized in that that it comprises one or more antitumor active ingredients chosen from doxorubicin, etoposide, fluorouracil, melphalan, cyclophosphamide, Beomycin, vinblastine, mitomycin, lomustine (UNFC), taxotere, taxol, metotrexate and cisplatinum. 15. Implantable medical device characterized in that it is treated in area by at least one compound derived from mannopyranoside as defined according to one of of the Claims 1 to 6, said device being selectable from prostheses, and more particularly vascular, urethral and biliary stents.