FR2937642A1 - C-GLYCOSIDE ANALOGUES OF ALPHA-GALACTOSYLCERAMIDES HAVING IMMUNOSTIMULATORY AND IMMUNOREGULATORY ACTIVITIES - Google Patents

Abstract

C-glycosidic analogs of alpha-galactosylceramides having immunostimulatory and immunoregulatory activities of the general formula:

Description

C-glycosidic analogs of alpha-galactosylceramides with immunostimulatory and immunoregulatory activities

The subject of the invention is C-glycosidic analogs of alpha-galactosylceramides having immunostimulatory and immunoregulatory activities as well as pharmaceutical compositions containing these analogs, in particular for the treatment of autoimmune diseases, cancers and for use as an adjuvant in vaccines. Alpha-galactosylceramide, called KRN 7000, is known for its immunostimulatory and anti-cancer activities. This molecule however comprises an anomeric C-O bond sensitive to hydrolysis which gives it a short duration of action. In order to obtain more stable molecules in vivo, C-glycosidic analogues of KRN 7000 were prepared and tested for their activities (Chen et al (2004), Toba et al (2005), Yang et al (2004). ), Franck et al (2006)).

The C-glycosidic analogs of alpha-galactosylceramides are of great therapeutic interest and there is therefore an important need for this class of molecules. The present invention relates to novel C-glycosidic analogs of alphagalactosylceramides having an ester, thionoester or ether function in place of the amide function. Surprisingly, these C-glycosidic analogs of alphagalactosylceramides have immunoregulatory and immunostimulatory properties demonstrated ex vivo and in vivo. In addition, these molecules can be synthesized in an inexpensive method allowing access to many analogues carrying different structural modifications.

The subject of the invention is compounds of general formula (I): embedded image in which OH (I) RI represents a hydrogen atom or a group chosen from -CO-R ', -CS- R 'and -CH 2 -R'; R2 represents a group selected from -CO-R ", -CS-R" and -CH2-R "; R 'and R" independently represent a group selected from linear or branched compounds comprising 5 to 30 carbon atoms, and preferably 20 to 26 carbon atoms, R3 represents a group chosen from linear or branched alkyl radicals comprising 4 to 15 carbon atoms, these compounds preferably correspond to the general formula ( II): wherein R 2 and R 3 are as defined above In an advantageous embodiment, the invention relates to compounds of general formula (III): ## STR5 ## m is an integer from 4 to 29 and preferably from 19 to 25, n is an integer from 3 to 14. preferably, m is 21, 22, 23, 24 or 25 and n is 3, 4, 5, 9, 11, 12, 13 or 14. Particularly advantageously, the invention relates to a compound of formula ( The invention relates to the above compounds for use as a medicament.

The subject of the invention is also these compounds for the treatment of autoimmune diseases, cancers or infectious diseases. The invention also relates to these compounds for use as an adjuvant in a vaccine. The invention thus relates to pharmaceutical compositions comprising a compound according to one of the preceding claims and a suitable pharmaceutical vehicle. The invention also relates to a process for preparing a compound of formula (I)

Wherein R1 represents a hydrogen atom or a group selected from -CO-R ', -CS-R' and -CH2-R '; R2 represents a hydrogen atom; group chosen from -CO-R ", -CS-R" and -CH2-R ", R 'and R" independently represent a group chosen from linear or branched alkyl radicals comprising 5 to 30 carbon atoms, and preferably 20 to 30 carbon atoms; to 26 carbon atoms, R3 represents a group selected from linear or branched alkyl radicals comprising 4 to 15 carbon atoms, comprising a step of reacting a compound of formula (V)

R5O OR4 wherein R4 represents a protecting group selected from TBDPS, TBDMS and TIPS, R5 represents a protecting group selected from PMB, benzyl and TBDMS; with a compound of formula (VI)

OR6 (VI) wherein R6 represents an optionally substituted benzyl group; to obtain a compound of formula (VII) (VII) and then obtaining the compound of general formula (I) from this compound (VII). TBDPS is tert-butyldiphenylsilyl, TIPS is triisopropylsilyl, TBDMS is tert-butyldimethylsilyl, and PMB is paramethoxybenzyl. (V) The radical R 6 represents a benzyl optionally substituted with an alkoxy group comprising 1 to 6 carbon atoms. Preferably R6 is a protecting group selected from benzyl and PMB (paramethoxybenzyl). Obtaining compounds of general formula (I) from compounds of formula (VII) is carried out according to conventional techniques well known to those skilled in the art. The compound of general formula (VII) constitutes the pivotal compound from which a wide variety of compounds of formula (I) can be obtained very easily. The invention therefore also relates to a compound of general formula (VII) as described above.

The invention thus relates to compounds for the treatment of autoimmune diseases, infectious diseases and cancers. The invention also relates to methods of therapeutic treatment of autoimmune diseases, infectious diseases and cancers comprising administering an effective amount of a compound of the invention to an individual. The invention finally relates to the use of the compounds according to the invention for the manufacture of medicaments for the treatment of autoimmune diseases, infectious diseases and cancers. Autoimmune diseases are diseases caused by the hyperactivity of the immune system against tissues or substances that are normally present in the body. Preferably, the invention relates to compounds for the therapeutic treatment of autoimmune diseases such as type I diabetes, encephalomyelitis, rheumatism and inflammations, allergies, asthma, contact sensitivity and inflammation. atherosclerosis. In another embodiment, the present invention provides compounds for the treatment of cancers. By cancer is meant all neoplastic malignant formations, regardless of the histological nature. There are two major categories of malignancies: carcinomas of epithelial origin and sarcomas of conjunctive origin. Malignant tumors are composed of atypical, invasive or disseminating cells, generally characterized by an autonomous capacity of growth, an imprecise delimitation, a capacity of invasion of the neighboring tissues and vessels and a tendency to disseminate by the production of metastases. These include cancers of the breast, prostate, lungs, esophagus, skin, bladder, stomach, liver, uterus, colon and rectum.

The invention also relates to compounds for the treatment of infectious diseases and in particular for infectious diseases of Mycobacterium tuberculosis, Streptococcus pneumoniae, Plasmodium spp., Trypanosoma cruzi, Cryptococcus neoformans, the hepatitis B virus, the diabetogenic encephalomyocardia and respiratory syncytium virus. The compounds according to the present invention have immunoregulatory and / or immunostimulatory properties. Thus, the compounds according to the present invention can be used as an adjuvant in vaccines. In vaccination, adjuvants are classically defined as substances capable of potentiating or modulating the immune response against one or more coadministered antigens. The invention relates to pharmaceutical compositions comprising a compound as defined above and a suitable pharmaceutical carrier. These compositions can be formulated for administration to mammals, including humans. The dosage varies according to the treatment and the condition in question. These compositions are made so that they can be administered by the digestive or parenteral route. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active ingredient can be administered in unit dosage forms, in admixture with pharmaceutical carriers. classics, animals or humans. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, subcutaneous forms of administration intramuscular, intravenous, intranasal or intraocular and forms of rectal administration. When preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient. A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

A syrup or elixir preparation may contain the active ingredient together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable colorant. Water-dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, as well as with taste correctors or sweeteners. The compounds according to the invention can be used in therapy alone, or in combination with at least one other active agent. The present invention therefore also relates to a product comprising a compound according to the invention and another active agent as a combination product for simultaneous, separate or spread over time use in therapy, and in particular in the treatment of cancers. Another subject of the invention is a vaccine composition comprising a compound according to the invention and at least one antigen. The antigen is typically selected from inactivated infectious agents, live attenuated agents and infectious agent subunits or inactivated toxins. The vaccines are usually inoculated by injection, but they can be ingested orally or by nasal spray. The compounds according to the invention can be prepared according to the different methods of preparation described below and in the examples. The C-glycosidic analogs are synthesized according to the general method described below. A solution of 1 Mg of magnesium trimethylsilylacetylide in THF is prepared by slow addition of methylmagnesium bromide (5 eq., 3 mMUL in THF) on trimethylsilylacetylene (5 eq.) At -20 ° C. After returning to ambient temperature, the reaction medium is stirred vigorously for 1 h 30. The solution of magnesium alkynide (5 eq) is then added at 78 ° C. using a cannula on the derivative of DErythrose A (1 eq.) In solution in THF (C = 0.4 mol / l). L). After rapid return to 0 ° C, the reaction medium is then stirred in a cold room for 12h. After treatment, the desired product is purified to give 1 (75-87%) as a yellow oil. To compound 1 (1 eq.) Dissolved in a suitable solvent (C = 0.35 mol / L) is added dropwise at 0 ° C a solution of the chosen protective reagent (RC1, 1.07 eq.) And a base ( 1.1 eq.) In the same solvent (C = 4 mol / L). DMAP (0.09 eq.) Is added and the reaction mixture is stirred for 3h. After treatment, the desired product 2 is isolated. To a solution of the base (1.7 eq., C = 0.5 mol / L) in a suitable solvent was slowly added at 0 ° C a solution of the alcohol 2 dissolved in the same solvent (C = 0.2 mol / L) . Tetra-n-butylammonium iodide (0.11 eq.) And imidazole (0.11 eq.) Are rapidly added, and then a solution of the chosen protective reagent (R'Br, 1.07 eq.) In the same solvent (1.5 eq., C = 0.5 mol / L) is slowly added. The reaction medium is stirred at ambient temperature for 4 hours. After treatment, the desired product B is isolated. Compound Pivot C Alkyne B, epoxyaldehyde (S. Guillarme, K. Plé and A. Haudrechy, J. Org Chem., 2006, 71, 3, 1015 and A. Banchet, S. Guillarme, A. Haudrechy , Synlett, 2007, 9, 1467) and lithium bromide are coevaporated three times with toluene and then dried under vacuum. Lithium alkynide is prepared by adding n-butyl lithium (0.9 eq.) At -78 ° C to a solution of alkyne B (C = 0.5 mol / L) in a suitable solvent. The reaction medium is stirred for 1 h 30, allowing the temperature to rise to 0 ° C. In parallel, the zinc dichloride (1.9 eq.) Is melted under vacuum and dissolved in the same solvent (C = 0.9 mol / L) at 0 ° C.

After 20 min, the lithium alkynide is slowly added to the zinc dichloride solution. The reaction medium is concentrated in vacuo (C0.9.9 mol / L) and stirred for 1 h at 0 ° C. Then a solution of the epoxyaldehyde (0.29 eq.) In the same solvent (C = 0.2 mol / L) is slowly added. The reaction medium is concentrated in vacuo (C0.9.9 mol / L) and stirred for 4 h at 0-5 ° C. Finally lithium bromide (1 eq.) Is added and the reaction mixture is stirred for 12h at room temperature. After treatment, the product C is isolated. D: R 3 = CH 2 CH 2 R "The compound C (1 eq.), Coevaporated several times with toluene, in solution in a suitable solvent (C = 0.1 mol / l), is then slowly added at 0 ° C. to a solution of a base (2.3 eq.) in the same solvent (C = 0.2 mon) Then the selected protective reagent (R1Br or R1C1, 2.5 eq.) is slowly added The reaction medium is stirred at room temperature for 3h. the desired product 3 is isolated.

Compound 3 (1 eq.) Is dissolved in a suitable solvent (C = 0.06 mol / L). The deprotecting reagent is then added and the reaction mixture is optionally heated. After treatment, the desired product 4 is isolated. To a solution of oxalyl chloride (1.5 eq C = 0.14 mon) in a suitable solvent at -78 ° C is added a solution of dimethylsulfoxide (3 eq.) In the same solvent (C = 1.4 mol / L) . The reaction mixture is stirred for 15 min after addition of a solution of 4 (1 eq.) In the same solvent (C = 0.1 mol / L). The temperature is kept at -78 ° C for 1 hour. Then the chosen base (5 eq.) Is slowly added. The temperature is slowly raised to room temperature in about 1.5 hours. After another 1:30 at room temperature and then treatment, the crude reaction product is co-evaporated three times with toluene and used for the Wittig reaction step without any additional purification. To a solution of appropriate Wittig salt (4 eq., R "-CH 2 -PPh 3 + X-, C = 0.1 mol / L) in a suitable solvent at -40 ° C is slowly added n-butyllithium (3.9 eq. The dark red solution is stirred for 1 hour, allowing the temperature to rise to 0 ° C. The aldehyde (from Swern oxidation) dissolved in the same solvent (C = 0.15). mol / L) is added dropwise The orange solution is stirred for 1h at room temperature After treatment, the desired product is isolated R 'R'O R'O RI O ~ O \ `,, BnO' ## STR5 ## To a solution of compound 5 (C = 2.2 mol / L) in a suitable solvent was added tosylhydrazine (100 eq. ) and the reaction medium is stirred vigorously under reflux A solution of sodium acetate (200 eq, C = 4.4 mol / L) is added over 6 hours After treatment, the desired product D is isolated HO (I) RIO R'O BnO 1 / i / OBn BnO 6 (R '= H, Z = C (Me) 2) 7 ( R '= R2, Z = C (Me) 2) 8 (R' = R2, Z = H, H) To the saturated compound D (1 eq.) Is added the deprotecting reagent (1.5 eq.) Dissolved in a solvent appropriate (C = 0.1 mol / L). After stirring for 40 min at room temperature and then treatment, the desired product 6 is isolated. To a solution of alcohol 6 (1 eq., C = 0.03 mol) in a suitable solvent is added the selected carboxylic acid (4 eq.), DMAP (4 eq.) And EDCI ( 5.2 eq.). The reaction mixture is then heated to 26-28 ° C. After stirring for 18 h, then treatment, the desired product 7 is isolated. To a solution of 7 (1 eq., C = 0.02 mol) in a suitable solvent is added at 0 ° C 12N hydrochloric acid (0.45 eq.). After stirring for 5 days and then treatment, the desired product 8 is isolated. To a solution of the diol 8 (C = 0.08 mol / L) in a suitable solvent is added palladium (II) dihydroxide 20% on charcoal (0.46 eq.) And the flask is placed under an atmosphere of hydrogen. After vigorous stirring for 6 h 30, the reaction medium is filtered, washed with CH 2 Cl 2, and then with a 4: 1 MeOH / H 2 O mixture (10 mL). The filtrate is passed through an HPLC filter and then evaporated. The white solid obtained is purified using the CPC technique, with a separation mixture of nheptane / CH 2 Cl 2 / acetonitrile / MeOH / H 2 O 10: 5: 5: 5: 1 (mobile phase = organic phase / stationary phase = aqueous phase, ascending mode: injection = 8 mg in 5 mL, flow rate = 6 mL / min, rotation = 1300 / min, AP = 35 bar and VM = 63 mL). Two compounds are isolated, one corresponding to the expected ester (I) in the form of a white solid, Rf = 0.26 (90/10 CH2Cl2 / MeOH). 10 15 Figures

FIG. 1: Determination of the Interaction Between the [C-KRN] Ligand According to the Invention and the TNK Cells FIG. 2: Comparison of the Activity with the Control Ligands FIG. 3: [IFNy] / [IL4] Ratio indicating that the ligand [C-KRN] promotes a Th2 response Figure 4: In vivo activation of TNK cells with the ligand [C-KRN]

Examples

Example 1: Compound Synthesis [C-KRN]

An active compound called [C-KRN] has been synthesized and tested in the context of the present invention. This compound is represented below: ## STR2 ## This compound was synthesized according to the detailed process described below: ## STR1 ## A solution of 1 mol / L of trimethylsilylacetylide Magnesium in THF is prepared by slowly adding methylmagnesium bromide (5 eq, 3 mol / L in THF) to trimethylsilylacetylene (5 eq.) at -20 ° C. After cooling to room temperature, the reaction medium The magnesium alkynide solution (5 eq.) is then added vigorously for 1 hr., at a temperature of 78 ° C. using a cannula on the D-Erythrose A derivative (1 eq.) in solution. in THF (C = 0.4 mol / L) After rapid return to 0 ° C., the reaction medium is then stirred in a cold room for 12 h After treatment, the desired product is purified to give 1 (75 to 87%) in the form of a yellow oil to compound 1 (1 eq.) dissolved in CH2Cl2 (C = 0.35 mon) is added to the drop in drop at 0 ° C a solution of TBDMSC1 (1.07 eq.) and Et3N (1.1 eq.) in CH2Cl2 (C = 4 mol / L). DMAP (0.09 eq.) Is added and the reaction mixture is stirred for 3h. After treatment, the desired product 2 is isolated (80%). To a solution of NaH (1.7 eq., C = 0.5 mon) in THF / DMF (4/1) was slowly added at 0 ° C a solution of dissolved alcohol 2 of THF / DMF (4/1). (C = 0.2 mol / L). Tetra-n-butylammonium iodide (0.11 eq.) And imidazole (0.11 eq.) Are rapidly added, followed by a solution of PMBBr (1.07 eq.) In THF / DMF (4/1). (1.5 eq., C = 0.5 my) is slowly added. The reaction medium is stirred at ambient temperature for 4 hours. After treatment, the desired product B is isolated (80%). Compound Pivot C Alkyne B, epoxyaldehyde (S. Guillarme, K. Plé and A. Haudrechy, J. Org Chem., 2006, 71, 3, 1015 and A. Banchet, S. Guillarme, A. Haudrechy , Synlett, 2007, 9, 1467) and lithium bromide are coevaporated three times with toluene and then dried under vacuum. Lithium alkynide is prepared by adding n-butyl lithium (0.9 eq.) At -78 ° C to a solution of alkyne B (C = 0.5 mol / L) in diethyl ether. The reaction medium is stirred for 1 h 30, allowing the temperature to rise to 0 ° C. In parallel, zinc dichloride (1.9 eq) was melted under vacuum and dissolved in diethyl ether (C = 0.9 mon) at 0 ° C. After 20 min, the lithium alkynide is slowly added to the zinc dichloride solution. The reaction medium is concentrated under vacuum (C 0.9 mon) and stirred for 1 h at 0 ° C. Then a solution of epoxyaldehyde (0.29 eq) in diethyl ether (C = 0.2 mon) is slowly added. The reaction medium is concentrated under vacuum (C 0.9 mol / L) and stirred for 4 h at 0-5 ° C. Finally lithium bromide (1 eq.) Is added and the reaction mixture is stirred for 12h at room temperature. After treatment, the desired product C is isolated (60-65%).

PMBO PMBO BnO BnO BnO 'Y "" OBn BnO' Y "" OBn BnO BnO 3 (R = TBDMS) 4 (R = H) Compound C (1 eq.), Coevaporated several times with toluene, in solution in anhydrous DMF (C = 0.1 mol / L) is then slowly added at 0 ° C. to a solution of NaH (2.3 eq.) in anhydrous DMF (C = 0.2 mol / L). Then BnBr (2.5 eq.) Is slowly added.

The reaction medium is stirred at ambient temperature for 3 hours. After treatment, the desired product 3 is isolated (83-86%).

Compound 3 (1 eq.) Is dissolved in 99% methanol (C = 0.06 μm). Ammonium fluoride (15 eq) is then added and the reaction mixture is optionally heated. After treatment, the desired product 4 is isolated (92-95%).

To a solution of oxalyl chloride in CH 2 Cl 2 (1.5 eq C = 0.14 μm) at -78 ° C is added a solution of dimethylsulfoxide (3 eq) in CH 2 Cl 2 (C = 1.4 μm). The reaction mixture is stirred for 15 min after addition of a solution of alcohol 4 (1 eq.) In CH 2 Cl 2 (C = 0.1 mon). The temperature is kept at -78 ° C for 1 hour. Then Et3N (5 eq.) Was slowly added. The temperature is slowly raised to room temperature in about 1.5 hours. After another 1:30 at room temperature, and then treatment, the crude reaction product is coevaporated three times with toluene and used for the Wittig reaction step without any additional purification.

To a solution of H- (CH2) 13PPh3 + CE in THF (4 eq., C = 0.1 mol / L) at -40 ° C is slowly added n-butyllithium (3.9 eq.) In solution in the hexane. The dark red solution is stirred for 1 hour, allowing the temperature to rise to 0 ° C. The aldehyde (from the Swern oxidation) dissolved in THF (C = 0.15 μm) is added dropwise. The orange solution is stirred for 1h at room temperature. After treatment, the desired product is isolated (70-79%).

To a solution of compound 5 (C = 2.2 μm) in DME was added tosylhydrazine (100 eq) and the reaction mixture was stirred vigorously under reflux. A solution of sodium acetate (200 eq., C = 4.4 mol / L) is added over 6 hours. After treatment, the desired product D is isolated (77-79%). D: R 3 = CH 2 CH 2 R "HO OH OH HO (I) To the saturated compound D (1 eq.) Is added DDQ (1.5 eq.) Dissolved in CH 2 Cl 2 / H 2 O 18: 1 (C = 0.1 mol). stirring for 40 min at room temperature, then treatment, the desired product 6 is isolated (77-82%).

To a solution of alcohol 6 in CH 2 Cl 2 (1 eq., C = 0.03 mol) is added CH 3 (CH 2) 14 COOH (4 eq), DMAP (4 eq) and EDCI (5.2 eq. ). The reaction mixture is then heated to 26-28 ° C. After stirring for 18 h and then treatment, the desired product 7 is isolated (77-82%). To a solution of 7 in methanol HPLC (1 eq., C = 0.02 mol / L) is added at 0 ° C 12N hydrochloric acid (0.45 eq.). After stirring for 5 days and then treatment, the desired product 8 is isolated (78-81%). To a solution of diol 8 (C = 0.08 mol) in CH 2 Cl 2 / MeOH 1: 1 is added 20% palladium (II) dihydroxide on charcoal (0.46 eq) and the flask is placed under a hydrogen atmosphere. After vigorous stirring for 6 h 30, the reaction medium is filtered off, washed with dichloromethane and then with a 4: 1 mixture of MeOH / H 2 O (10 mL). The filtrate is passed through an HPLC filter and then evaporated. The white solid obtained is purified using the CPC technique, with a separation mixture of nheptane / CH 2 Cl 2 / acetonitrile / MeOH / H 2 O 10: 5: 5: 5: 1 (mobile phase = organic phase / stationary phase = aqueous phase, ascending mode: injection = 8 mg in 5 mL, flow rate 20 = 6 mL / min, rotation = 1300 / min, P = 35 bar and VM = 63 mL). Two compounds are isolated, one corresponding to the expected ester (I) in the form of a white solid, Rf = 0.26 (90/10 CH2Cl2 / MeOH). The spectroscopic data are collated below: 1: 1H NMR (ppm, CDCl 3) δ: 4.58 (dd, 1H, J = 5.8, 6.0 Hz), 4.3 (ddd, 1H, J = 4.3, 5.3, 6.4 Hz) , 4.24 (q, 1H, J = 6.4, 12Hz), 3.99 (dd, 1H, J = 4.3, 6.0Hz), 3.91 (dd, 1H, J = 5.3, 12Hz), 1.47 (s, 3H), 1.36 (s, 3H), 0.17 (s, 9H). 13 C NMR (ppm, CDCl3) δ: 108.9, 103.7, 91.7, 79.1, 77.4, 62, 60.5, 27.4, 25.3, 0. MS (HR) (ESI) m / z calcd for C12H22O4Si (M + Na): CH3 (CH 2) 14 HO OO BnO O / 4q O ~ Z BnO_ Y OBn BnO

6 (R '= H, Z = C (Me) 2)

7 (R '= (CH 2) 14 -CH 3, Z = C (Me) 2) 8 (R' = (CH 2) 14-CH, Z = H, H) 281.128, found: 281.09. Microanalysis: calculated C = 55.78% and H = 8.58%, found C = 55.67% and H = 8.39%. 2: IR (film, v, cm -1): 3418, 2957, 2858, 2174, 1472, 1381, 1251, 1217, 1082, 843, 779.1H NMR (ppm, CDCl3) δ: 4.61 (dd, 1H, J); = 6.0, 6.3 Hz), 4.31 (dd, 1H, J = 6.0, 12.4 Hz), 4.25- 4.30 (m, 1H), 4.25 (d, 1H, J = 6.3 Hz), 3.94 (dd, 1H, J = 7.6, 11 Hz), 3.86 (dd, 1H, J = 3.5, 11 Hz), 3.11 (s, 3H), 1.41 (s, 3H), 0.95 (s, 9H), 0.43 (s, 9H), 0.32 ( s, 6H). 13 C NMR (ppm, CDCl 3) δ: 108.9, 104.1, 90.4, 79.9, 76.9, 62, 61.4, 27.7, 25.9, 25.4, 18.4, 0. MS (HR) (ESI) m / z calcd for C18H36O4Si2 (M + Na) ): 395.214, found: 395.317. Microanalysis: calculated C = 58.02% and H = 9.74%, found C = 58.11% and H = 10.05%.

B: [α] 19D = + 43.7 ° (C = 0.0125g / mL, CHCl3). IR (film, v, cm 1): 3284, 2986, 2954, 2933, 2883, 2856, 2114, 1613, 1586, 1515, 1464, 1381, 1372, 1303, 1251, 1173, 1079, 1037, 837, 778. 1H NMR (ppm, CDCl3) δ: 4.72 (d, 1H, J = 11.2Hz), 4.42 (d, 1H, J = 11.2Hz), 4.10-4.35 (m, 3H, J = 1.9, 4.6, 5.9Hz). , 3.92 (dd, 1H, J = 4.7, 9.5 Hz), 3.67 (dd, 1H, J = 5.8, 9.5 Hz), 2.55 (d, 1H, J = 1.9 Hz), 1.47 (s, 3H), 1.35 ( s, 3H), 0.82 (s, 9H), O (s, 6H). 13C NMR (ppm, CDCl3) δ: 158.9, 129.5, 128.6, 113.3, 108.4, 80.0, 77.1, 74.9, 69.6, 66.8, 61.1, 54.7, 26.7, 25.4, 24.5, 17.7, 0. MS (HR) (ESI) m / z calcd for C23H36O5Si (M + Na): 443.232, found 443.218. Microanalysis: calculated C = 65.68% and H = 8.63%, found C = 65.77% and H = 8.40%. C: [α] 19 D = + 68.7 ° (C = 0.011 g / mL, CHCl 3) IR (film, v, cm -1): 3484, 3063, 3030, 2929, 2358, 1721, 1612, 1586, 1514 , 1497, 1454, 1371, 1077, 836, 735, 697. UV (e in Lmol-1cm): e1 = 1129 (CHCl3, C = 0.002 mull, X = 244 nm, Abs = 2.277), e2 = 1486 (CHCl 3, C = 0.002 mol / L, X = 268 nm, Abs = 2.972). 1H NMR (ppm, CDCl3) δ: 7.32-7.50 (m, 15H), 7.30 (d, 2H, J = 8Hz), 6.82 (d, 2H, J = 8Hz), 5.02 (d, 1H, J = 5Hz) , 4.8-4.88 (dd, 2H, J = 12, 68 Hz), 4.80-4.83 and 4.92-4.96 (dd, 2H, J = 12, 170 Hz), 4.70-4.75 and 5.00-5.05 (dd, 2H, J). = 12, 128 Hz), 4.43 (d, 1H, J = 4Hz), 4.27-4.30 (m, 2H, J = 4.6Hz), 4.20 (dd, 1H, J = 5.9Hz), 4.08 ( ddd, 1H, J = 6.7, 11 Hz), 4.05 (dd, 2H, J = 7.1 Hz), 4.00 (2dd, 2H, J = 6.8 Hz), 3.84 (s, 3H), 3.77 (dd, 2H, J = 4.5, 11Hz), 3.70 (dd, 2H, J = 9, 11Hz), 3.56 (dd, 2H, J = 5.11Hz), 1.52 (s, 3H), 1.40 ( s, 3H), 1.33 (s, 3H), 0.91 (s, 9H), 0.08 (s, 6H). 13C NMR (ppm, CDCl3) δ: 159.4, 138.2-138.7, 130.0, 129.3, 127.5-128.6, 113.9, 108.9, 85.2, 82.6, 80.5, 78.0, 75.9, 74.9, 74.6, 74.1, 73.7, 73.1, 70.2, 67.6 , 62.4, 61.9, 55.3, 27.6, 25.9, 25.2, 18.4. MS (HR) (ESI) m / z calcd for C 50 H 64 O 10 Si (M + Na): 875.426, found: 875.4. Microanalysis: calculated C = 70.39% and H = 7.56%, found C = 70.16% and H = 7.88%. 3: IR (film, v, cm -1): 3418, 2931, 2361, 2341, 1732, 1615, 1587, 1516, 1455, 1110, 836. UV (e in Lmol-cm): and = 1717 (FIG. CHCl 3, C = 0.00146 mol, a = 245 nm, Abs = 2.507) e2 = 1962 (CHCl3, C = 0.00146 mol / L, a = 264 nm, Abs = 2.865). 1 H NMR (ppm, CDCl 3) δ: 4.72 (d, 1H, J = 11.2 Hz), 4.42 (d, 1H, J = 11.2 Hz), 4.10-4.35 (m, 3H, J = 1.9, 4.6, 5.9 Hz). ), 3.92 (dd, 1H, J = 4.7, 9.5 Hz), 3.67 (dd, 1H, J = 5.8, 9.5 Hz), 2.55 (d, 1H, J = 1.9 Hz), 1.47 (s, 3H), 1.35 (s, 3H), 0.82 (s, 9H), O (s, 6H). 13C NMR (ppm, CDCl3) δ: 158.9, 129.5, 128.6, 113.3, 108.4, 80.0, 77.1, 74.9, 69.6, 66.8, 61.1, 54.7, 26.7, 25.4, 24.5, 17.7, 0. MS (HR) (ESI) m / z calcd for C57H70O10Si (M + Na): 965.473, found 965.400. Microanalysis: calculated C = 72.74% and H = 7.49%, found C = 72.46% and H = 7.84%. 4: UV (e in Lmol-cm): and = 1544 (CHCl 3, C = 0.00169 mol, a, = 247 nm, Abs = 2.609) e 2 = 1841 (CHCl 3, C = 0.00146 mol), a. = 264 nm, Abs = 3.111). 1H NMR (ppm, CDCl3) δ: 4.72 (d, 1H, J = 11.2Hz), 4.42 (d, 1H, J = 11.2Hz), 4.10-4.35 (m, 3H, J = 1.9, 4.6, 5.9Hz). , 3.92 (dd, 1H, J = 4.7, 9.5 Hz), 3.67 (dd, 1H, J = 5.8, 9.5 Hz), 2.55 (d, 1H, J = 1.9 Hz), 1.47 (s, 3H), 1.35 ( s, 3H), 0.82 (s, 9H), O (s, 6H). 13C NMR (ppm, CDCl3) δ: 158.9, 129.5, 128.6, 113.3, 108.4, 80.0, 77.1, 74.9, 69.6, 66.8, 61.1, 54.7, 26.7, 25.4, 24.5, 17.7, 0. MS (HR) (ESI) m / z calcd for C57H70O10Si (M + Na): 851.386, found: 851.357. Microanalysis: calculated C = 73.89% and H = 6.81%, found C = 73.87% and H = 6.91%. D: 1H NMR (ppm, CDCl3) δ: 4.72 (d, 1H, J = 11.2 Hz), 4.42 (d, 1H, J = 11.2 Hz), 4.10-4.35 (m, 3H, J = 1.9, 4.6, 5.9; Hz), 3.92 (dd, 1H, J = 4.7, 9.5 Hz), 3.67 (dd, 1H, J = 5.8, 9.5 Hz), 2.55 (d, 1H, J = 1.9 Hz), 1.47 (s, 3H), 1.35 (s, 3H), 0.82 (s, 9H), 0 (s, 6H). 13C NMR (ppm, CDCl3) δ: 158.9, 129.5, 128.6, 113.3, 108.4, 80.0, 77.1, 74.9, 69.6, 66.8, 61.1, 54.7, 26.7, 25.4, 24.5, 17.7, 0. MS (HR) (ESI) m / z calcd for C64H86O9 (M + Na): 1021.626, found 1021.630. Microanalysis: calculated C = 76.98% and H = 8.69%, found C = 76.94% and H = 8.62%. 6: 1H NMR (ppm, CDCl3) δ: 4.72 (d, 1H, J = 11.2 Hz), 4.42 (d, 1H, J = 11.2 Hz), 4.10-4.35 (m, 3H, J = 1.9, 4.6, 5.9; Hz), 3.92 (dd, 1H, J = 4.7, 9.5 Hz), 3.67 (dd, 1H, J = 5.8, 9.5 Hz), 2.55 (d, 1H, J = 1.9 Hz), 1.47 (s, 3H), 1.35 (s, 3H), 0.82 (s, 9H), 0 (s, 6H). 13C NMR (ppm, CDCl3) δ: 158.9, 129.5, 128.6, 113.3, 108.4, 80.0, 77.1, 74.9, 69.6, 66.8, 61.1, 54.7, 26.7, 25.4, 24.5, 17.7, 0. MS (HR) (ESI) m / z calcd for C 56 H 78 O 8 (M + Na): 901.569, found: 901.500. Microanalysis: calculated C = 76.50% and H = 8.94%, found C = 76.92% and H = 9.03%. 7: mp 70-72 ° C. 1H NMR (ppm, CDCl3) δ: 4.72 (d, 1H, J = 11.2Hz), 4.42 (d, 1H, J = 11.2Hz), 4.10-4.35 (m, 3H, J = 1.9, 4.6, 5.9Hz). , 3.92 (dd, 1H, J = 4.7, 9.5 Hz), 3.67 (dd, 1H, J = 5.8, 9.5 Hz), 2.55 (d, 1H, J = 1.9 Hz), 1.47 (s, 3H), 1.35 ( s, 3H), 0.82 (s, 9H), O (s, 6H). 13C NMR (ppm, CDCl3) δ: 158.9, 129.5, 128.6, 113.3, 108.4, 80.0, 77.1, 74.9, 69.6, 66.8, 61.1, 54.7, 26.7, 25.4, 24.5, 17.7, 0. MS (HR) (ESI) m / z calcd for C82H12809 (M + Na): 1279.955, found 1279.954. Microanalysis: calculated C = 78.30% and H = 10.26%, found C = 77.90% and H = 10.26%. 8: mp 40-41 ° C. 1H NMR (ppm, CDCl3) δ: 4.72 (d, 1H, J = 11.2Hz), 4.42 (d, 1H, J = 11.2Hz), 4.10-4.35 (m, 3H, J = 1.9, 4.6, 5.9Hz). , 3.92 (dd, 1H, J = 4.7, 9.5 Hz), 3.67 (dd, 1H, J = 5.8, 9.5 Hz), 2.55 (d, 1H, J = 1.9 Hz), 1.47 (s, 3H), 1.35 ( s, 3H), 0.82 (s, 9H), O (s, 6H). 13C NMR (ppm, CDCl3) δ: 158.9, 129.5, 128.6, 113.3, 108.4, 80.0, 77.1, 74.9, 69.6, 66.8, 61.1, 54.7, 26.7, 25.4, 24.5, 17.7, 0. MS (HR) (ESI) m / z calcd for C79H12409 (M + Na): 1239.924, found 1239.886. Microanalysis (% calculated with water molecule M = 1235.858 g / mol): C = 76.78% and H = 10.28%, found C = 76.91% and H = 10.17%. (I): 1 H NMR (ppm, CDCl 3) δ: 4.72 (d, 1H, J = 11.2 Hz), 4.42 (d, 1H, J = 11.2 Hz), 4.10-4.35 (m, 3H, J = 1.9, 4.6 , 5.9 Hz), 3.92 (dd, 1H, J = 4.7, 9.5 Hz), 3.67 (dd, 1H, J = 5.8, 9.5 Hz), 2.55 (d, 1H, J = 1.9 Hz), 1.47 (s, 3H). ), 1.35 (s, 3H), 0.82 (s, 9H), 0 (s, 6H). 13C NMR (ppm, CDCl3) δ: 158.9, 129.5, 128.6, 113.3, 108.4, 80.0, 77.1, 74.9, 69.6, 66.8, 61.1, 54.7, 26.7, 25.4, 24.5, 17.7, 0. MS (HR) (ESI) m / z calcd for C 51 H 1000 O (M + Na): 879.736, found 879.50.

Example 2 Synthesis of Other Compounds

Other preferred compounds of general formula III having potential biological activity will be synthesized.

H3C ~ (CH2) mn and m are defined in the tables below: HO ("OH 25 HO n 22 24 Biological Activity 4 XX Autoimmune Diseases 12 XX Cancers 13 XX Cancers n 21 22 23 24 25 Biological Activity 3 X Auto-immune diseases 4 XX Autoimmune diseases X Auto-immune diseases 9 XX Cancers 11 XX Cancers 12 XXX Cancers 13 XXX Cancers 14 XX Cancers These molecules can be tested according to the protocols described below. esterified ligand to activate ex vivo TNK cells

a) Experimental Protocol The ligand is dissolved in DMSO to obtain a sample of concentration 2 mg / ml.

The splenocytes of the BALB / c naive mice are cultured in the presence of increasing amounts of the ligand (from 0.02 to 20 g / ml). The internal controls are carried out with two synthetic ligands: KRN 7000 (marketed by Alexis Biochemicals) and a-Gal (C12) Cer (marketed by Avanti Polar Lipids), whose effectiveness in inducing a specific cellular response of TNK cells is already recognized (Figure 1). Scheme 1: Control Ligands: C11H23HN C13H27 HO5-Gal (C12) Cer C25H51

HN O HO O C14H29

HO KRN 7000 HO Cell proliferation is measured after three days of culture by incorporation of tritiated thymidine (a measure of the radioactivity incorporated by the cells during activation). The quantities of cytokines (IL-4 and IFN-γ) are determined by the ELISA test in the harvested samples after 30 hours of culture.

In order to determine whether ligand recognition is restricted to the CDld molecule, the cultures were performed in the absence or in the presence of blocking anti-CD1d antibodies. They then make it impossible for the CDR1 molecule to be presented to the invariant TCR of the TNK lymphocyte. b) Ex vivo tests

The results obtained show us that our esterified ligand is capable of inducing the proliferation of splenocytes as well as the secretion of IL-4 and IFN-γ. These responses are dose-dependent and specific for TNK cells since they are completely inhibited in the presence of anti-CDld blocking antibodies (FIG. 1).

However, compared to internal controls, [C-KRN] ligand gives weaker responses, both for cell proliferation and for cytokine secretion. But, given the average purity of the ligand, these results are very encouraging (Figure 2). It should also be noted that the concentration ranges are different for the internal controls and the ligand [C-KRN]. Calculation of the [IFN-y] / [IL-4] ratio makes it possible to determine whether the ligand favors Th1 (inflammatory) or Th2 (immunoregulatory) type responses. A significant decrease in the [IFN-y] / [IL-4] ratio is observed with the esterified ligand, as with the α-Gal (C12) Cer ligand, translating an imbalance of the cytokine balance towards a Th2-type response (secretion IL-4 greater than the secretion of IFN-γ) (Figure 3). This result is surprising and leads us to think that the nature of the branching between phytosphingosine and acyl chains could have a significant influence on the production of certain cytokines. This implication can then either improve or compromise the interactions between the ligand and the CD 1 d or between the Ga1Cer / CDld complex and the TNK lymphocyte receptor.

Thus our esterified ligand has potential in the treatment of autoimmune pathologies where Th2 responses must be favored in order to counteract Th1 responses.

Example 4: Ability of the esterified ligand to activate TNK cells in vivo

a) Experimental protocol

The ligand (KRN 7000 or [C-KRN]) is injected intraperitoneally into naive BALB / c mice (2 mice per ligand). Serum cytokine levels (IL-4 and IFN-γ) were detected at different times after injection. b) Results obtained

The esterified ligand is capable of activating the TNK lymphocytes in vivo. Indeed, 6 hours after injection of the [C-KRN] ligand, the [IFN-y] / [IL-4] ratio reflects a Th2 response. This remains, however, not very marked but durable because it is also observed that the secretion of IFN-γ seems to be later than with KRN 7000. The strong secretion of IFN-γ is obtained 24h 5 after the injection of [C -KRN] (against 6h for the KRN 7000). Thus, our esterified ligand induces a weak Th2 response but relatively prolonged in time (Figure 4). Note: The low ratio [IFN-y] / [IL-4] may be due to the average purity of our sample. It may also be noted that the impurities present do not appear to be cytotoxic.

The information provided by the immunological tests on our esterified ligand is very encouraging. Against all odds, this analogue seems to induce, in vitro and in vivo, a Th2 response favorable to the treatment of autoimmune inflammatory diseases. 22 REFERENCES

Banchet A., S. Guillarme, A. Haudrechy, Synlett, 2007, 9, 1467 Chen et al., Organic Letters, 2004, Vol. 6, No. 22, p. 4077-4080.

Franck and Tsuji, Accounts of Chemical Research, 2006, Vol.39, No. 10, p. 692-701. Guillarme S., K. Plé and A. Haudrechy, J. Org. Chem., 2006, 71, 3, 1015. Toba et al., Tetrahedron Letters, 2005, Vol. 46, p. 5043-5047. Yang et al., Angewandte Chemie, Int. Ed., 2004, Vol. 43, p. 3818-3822.

Claims (10)

REVENDICATIONS1. Compound of general formula (I): ## STR2 ## wherein R 1 represents a hydrogen atom or a group selected from -CO-R ', -CS-R' and -CH 2 -R '; a group chosen from -CO-R ", -CS-R" and -CH2-R "; R 'and R" independently represent a group chosen from linear or branched alkyl radicals comprising 5 to 30 carbon atoms, and preferably 20 to 26 carbon atoms, R3 represents a group chosen from linear or branched alkyl radicals comprising 4 to 15 carbon atoms. 2. Compound according to claim 1 of general formula (II): wherein R 2 and R 3 are as defined in claim 1. 3. Compound according to claim 2 of general formula (III): H3C ~ (CH2) m wherein m is an integer between 4 and 29 and preferably between 19 and 25, n is an integer between 3 and 14. 4. A compound according to claim 3 wherein m is 21, 22, 23, 24 or 25, n is 3, 4, 5, 9, 11, 12, 13 or 14. 5. Compound of formula (IV): (CH2) 24CH3 HO ("OH OH HO (IV) 6. Compound according to one of the preceding claims for use as a medicament. 7. Compound according to one of the preceding claims for the treatment of autoimmune diseases, cancers or infectious diseases. HO (OH OH (III) 10 20 8. Compound according to one of the preceding claims for use as an adjuvant in a vaccine. 9. A pharmaceutical composition comprising a compound according to one of the preceding claims and a suitable pharmaceutical carrier. 10. A process for the preparation of a compound of formula (I) wherein R1 represents a hydrogen atom or a group chosen from -CO-R ', -CS-R' and -CH 2 -R ', R 2 represents a group selected from -CO-R ", -CS-R" and -CH 2 -R ", R' and R" independently represent a group selected from linear or branched alkyl radicals comprising 5 to 30 carbon atoms, and preferably 20 to 26 carbon atoms, R3 represents a group selected from linear or branched alkyl radicals comprising 4 to 15 carbon atoms, comprising a step of reacting a compound of formula ( Wherein R4 is a protecting group selected from TBDPS, TBDMS and TIPS, R5 is a protecting group selected from PMB, Bn and TBDMS; formula (VI) wherein OR6 (VI) wherein R6 is a protecting group selected from benzyl and PMB to give a compound of formula (VII) 26 (VII) obtaining the compound of general formula (I) from this compound (VII).