WO2003002586A1

WO2003002586A1 - [4-(4-cyanobenzoyl)phenyl]glycofuranoside derivatives, use of said derivatives as a medicament, production method thereof and pharmaceutical compositions containing same

Info

Publication number: WO2003002586A1
Application number: PCT/FR2002/002145
Authority: WO
Inventors: Luc Lebreton; Christiane Legendre; Soth Samreth
Original assignee: Laboratoires Fournier Sa
Priority date: 2001-06-21
Filing date: 2002-06-20
Publication date: 2003-01-09
Also published as: FR2826368A1; FR2826368B1

Abstract

The invention relates to novel [4-(4-cyanobenzoyl)phenyl] glycofuranoside derivatives having formula (I), wherein R represents a glycofuranosyl group. Said compounds have an anti-atheromatous activity.

Description

Γ4- (4-CYANOBENZOYL PHENYL1GLYCOFURANOSIDE DERIVATIVES, USE AS MEDICAMENT, PROCESS FOR OBTAINING SAME AND COMPOSITIONS

PHARMACEUTICALS CONTAINING THEM.

The present invention relates to new derivatives of [4- (4-cyanobenzoyl) phenyl] glycofuranoside, their use as a medicament and the pharmaceutical compositions containing them.

In particular, the compounds according to the invention are particularly advantageous for their anti-atheromatous activity.

Patent EP 051 023 describes certain benzoylphenyloside derivatives as being antithrombotic agents, in particular for treating or preventing venous thrombosis. Only compounds of pyranoside structure are described.

According to the present invention, it has been demonstrated that certain specific benzoylphenylglycofuranoside derivatives also exhibit anti-atheromatous activity and are therefore very advantageous in particular for the prevention or regression of arterial atheromatous plaques.

The invention relates to [4- (4-cyanobenzoyl) phenyl] glycofuranoside derivatives of formula (I):

in which -R represents a glycofuranosyl group of formula

and is chosen from:

• α-D-xylofuranosyl

• β-D-xylofuranosyl

• α-D-riboruranosyle • β-D-ribofuranosyle • α-D-arabinofuranosyle

• β-D-arabinofuranosyle

• -D-lyxofuranosyle

• β-D-lyxofuranosyle • α-L-xylofuranosyle

• β-L-xylofuranosyl

• α-L-arabinofuranosyle

• β-L-arabinofuranosyle as well as their esters resulting from the esterification of at least one -OH function of the glycofuranosyl group into -OC (O) R _! , Ri representing an (CC ₃ ) alkyl or cyclopropyl group, their solvates and hydrates.

By alkyl is meant a monovalent, hydrocarbon, saturated, linear or branched radical.

By (Cι-C ₃ ) alkyl means an alkyl radical comprising from 1 to 3 carbon atoms.

According to a particular aspect, the present invention relates to the compounds of formula (I) in which R represents a glycofuranosyl group chosen from:

• α-D-xylofuranosyl

• β-D-xylofuranosyl • β-D-ribofuranosyl

• α-D-arabinofuranosyle

• β-D-arabinofuranosyle

• α-D-lyxofuranosyle

• β-D-lyxofuranosyle • α-L-xylofuranosyle

• β-L-xylofuranosyl

• α-L-arabinofuranosyle and their esters resulting from the esterification of at least one -OH function of the glycofuranosyl group in -OC (O) Rι, Ri representing a group (Q- C ₃ ) alkyl or cyclopropyl, their solvates and hydrates. The compounds [4- (4-cyanobenzoyl) phenyl] α-D-arabinofuranoside and [4- (4- cyanobenzoyl) phenyl] β-D-xylofuranoside, as well as their esters resulting from the esterification of at least one function - OH of the glycofuranosyl group at -OC (O) R ₁₅ Ri representing a (C ₁ -C ₃ ) alkyl or cyclopropyl group, their solvates and hydrates are currently preferred.

Among the "esters" of the compounds according to the invention, more particularly preferred are the compounds of formula (I) in which all the -OH functions of the glycofuranosyl group are esterified to -OC (O) Rι, Ri representing a group (C ₁ -C ₃ ) alkyl or cyclopropyl, preferably methyl.

The compounds of formula (I) according to the invention can be prepared according to the process comprising:

(1) the reaction of 4-hydroxy-4'-cyanobenzophenone (HT) with a peracetylated pentose of furanose structure, corresponding to formula (F):

(IV) in which Ac represents an acetyl group chosen from the group consisting of 1,2,3,5-tetra-O-acetyl-D-xylofuranose, 1,2,3,5-tetra-O-acetyl- L-xylofuranose, 1,2,3,5-tetra-O-acetyl-L-arabinofuranose, 1,2,3,5-tetra-O-acetyl-D-arabinofuranose, 1,2,3,5-tetra- O-acetyl-D-lyxofuranose and 1,2,3,5-tetra-O-acetyl-D-ribofuranose, in the form of mixture 0 (/ β or in the appropriate α or β form, to obtain, optionally after purification, the corresponding furanoside compound of formula (H):

in which R 'represents the furanosyl group R as defined for (I) in which all the -OH functions are protected in function -OAc; and

(2) the deacetylation reaction of the furanoside compound of formula (II), thus obtained, to obtain the compound of formula (I). When the compound (H) is prepared in the form of an α β mixture, the pure α and β compounds are separated and purified, for example by chromatography on silica gel.

The esters of the compounds of formula (I) can be obtained by a conventional esterification reaction of the compounds of formula (I) with a C ₂ -C ₄ alkanoic or cycloalkanoic acid.

Advantageously, the reaction (DT) + (TV) of step (1) is carried out in an organic solvent (in particular dichloromethane), in the presence of a Lewis acid, such as for example tetrachloride. tin, at a temperature between 25 ° C and the boiling point of the solvent, for 10 to 30 hours.

In step (2) the deacetylation (or saponification) reaction is advantageously carried out, by action on the compound of formula (H) of ammonia in solution in an anhydrous alcohol, in particular methanol.

As a variant, the reaction (HT) + (TV) → (H) of step (1) can be replaced by the following step (1 '):

(1 ') the reaction of 4-hydroxy-4'-cyanobenzoρhenone (TTT) with a trichloroacetimidate of furanoside structure, of formula (V):

(V) in which Ac represents an acetyl group chosen from the group consisting of 2,3,5-tri-O-acetyl-D-xylofuranosyl trichloroacetimidate, 2,3,5-tri-O-acetyl- trichloroacetimidate L-xylofuranosyl, 2,3,5-tri-O-acetyl-L-arabinofuranosyl trichloroacetimidate, 2,3,5-tri-O-acetyl-D-arabinofuranosyl trichloroacetimidate, 2,3,5-tri-O-acetyl-D-lyxofuranosyl trichloroacetimidate,

1- 2,3,5-tri-O-acetyl-D-ribofuranosyl trichloroacetimidate, in the form of an α / β mixture or in the appropriate α or β form, to obtain, optionally after purification, the corresponding furanoside compound of formula ( H).

Advantageously, the reaction (TTT) + (V) - »(H) is carried out in an anhydrous solvent in the presence of a Lewis acid such as boron trifluoride.

The reactions (IH) + (TV) → (II) and (JE) + (V) → (H apply to the preparation of all the compounds of formula (H) according to the invention.

For the synthesis of the compounds of formula (I) in which R represents an α-D-lyxofuranosyl, β-D-lyxofuranosyl, β-D-ribofuranosyl or α-D-ribofuranosyl group, the compounds of formula (H) may be prepared , according to another alternative, by coupling 4-hydroxy-4'-cyanobenzophenone (TTT) with: a) either the compound of formula (VI):

in which Ac represents an acetyl group and Ph a phenyl group and chosen from 5-O-acetyl-2,3-O-phenylboranediyl-α-D-lyxofuranosyl bromide, 5-O-acetyl-2,3 bromide -O-phenylboranediyl-β-D- lyxofuranosyl, 5-O-acetyl-2,3-O-phenylboranediyl-α-D-ribofuranosyl bromide and 5-O-acetyl-2,3-O-phenylboranediyl bromide -β-D- ribofuranosyl; b) or the compound (VU):

in which Ac represents an acetyl group and Ph a phenyl group and chosen from 1,5-di-O-acetyl-2,3-O-phenylboranediyl-α-D-lyxofuranose, 1,5-di-O-acetyl -2,3-O-phenylboranediyl-β-D-lyxofuranose, 1,5-di-O-acetyl-2,3-O- phenylboranediyl-α-D-ribofuranose and 1,5-di-O-acetyl -2,3-O-phenylboranediyl- β-D-ribofuranose; under the same conditions as the (H) + (HT) reaction.

The compound (VI) is obtained by bromination of the corresponding compound (VU), by the action of hydrobromic acid. For the synthesis of compounds (VI) and (VH), reference may in particular be made to W. V. DAHLHOFF et al, Z. Naturforsch, 45b, p. 547-551 (1990).

The compounds (HT), (IV) and (V) are obtained from the corresponding sugars according to techniques well known to those skilled in the art.

The anti-atheromatous activity of the compounds according to the invention was evaluated as a function of their ability to lower the serum cholesterol level in mice subjected to a fatty diet.

It has indeed been shown in several publications a close correlation between a lipid overload and a marked increase in the atheromatous risk (Lancet 1996, 348 pages 1339-1342; Lancet 1990, 335 pages 1233-1235). This correlation makes it possible to implement a faster test than direct tests on the atheroma plate, said tests requiring a long treatment of animals and a heavy histological study of the walls of the aortic arch.

The test used consists in administering a single dose of the compound to female mice of the C57BL / 6J strain. The protocol is as follows: the first day (D0), the mice are fasted from 9 am to 5 pm, a blood sample being taken at 2 pm. At 5 p.m., a set amount of food (fatty diet comprising 1.25% cholesterol and 0.5% cholic acid) is distributed. On the second day (Jl), at 9 am, the food remains are weighed and the mice fasted from 9 am to 2 pm. At 2 p.m., a blood sample is taken. For the groups of treated mice, the compound is administered by tubing, suspended in a solution of gummy water, at 3%, the second day (D1) at 9 am. Control groups receive only gummy water.

The compounds were tested at a dose of 10 mg / kg. Total serum cholesterol is measured. The compounds according to the invention have percentages of inhibition of the increase in cholesterolemia compared to the control group of between 15 and 50%. Furthermore, it may be noted that the analysis of the cholesterol content of the different classes of serum lipoproteins shows a favorable effect of the products on the HDL-cholesterol / total cholesterol ratio.

These results show that the compounds according to the invention exhibit anti-atheromatous activity. A subject of the invention is therefore the compounds of formula (I), their esters, solvates and hydrates for their use as a medicament.

The compounds of formula (I) or one of their esters, solvates or hydrates, can be, in particular, used for the preparation of a medicament, intended for the treatment or the prevention of atheroma plaque.

The compounds of formula (I), or one of their esters, solvates or hydrates may also be used for the preparation of a medicament intended to treat, in particular in humans, cholesterol overloads and / or to correct a lipid profile failed.

The compounds of formula (I) according to the invention may also be useful as active principle of medicaments useful for preventing or treating metabolic syndrome, dyslipidemias, hypertriglyceridemias, too high LDL or too low HDL levels, type 2 diabetes, obesity or overweight.

The present invention therefore also relates to pharmaceutical compositions containing a compound of formula (I) or one of its esters, solvates or hydrates. These pharmaceutical compositions generally contain suitable excipients. Said excipients are chosen according to the form pharmaceutical and the desired mode of administration, in particular oral or injectable. These pharmaceutical compositions are prepared according to conventional methods well known to those skilled in the art.

They may also be prescribed with the aim of restoring degraded lipid parameters, treating metabolic syndrome or combating obesity.

In order to obtain the desired therapeutic or prophylactic effect, the daily dosage will be approximately 25 to 500 mg of at least one compound according to the invention, administered in one or more doses during the day.

By way of example, the compounds according to the invention can be formulated in the form of capsules or tablets which can be administered orally. In the case of a formulation in the form of a capsule, the active principle will be finely ground beforehand and mixed with excipients known to those skilled in the art, such as, for example, lactose, pregelatinized starch, magnesium stearate. The mixture will preferably be produced so as to obtain a unit dose of between 10 and 500 mg of active principle.

In the formulations of a medicament intended for the prevention or the treatment of the pathologies previously mentioned, it may be advantageous to associate a compound according to the invention with a known active principle so as to obtain a greater or faster medical benefit. By way of example of such active principles, there may be mentioned: a) lipid-lowering or cholesterol-lowering agents such as for example HMG-CoA reductase inhibitors (in particular simvastatin, lovastatin, atorvastatin, fluvastatin) α such as for example the compounds of the class of fibrates (in particular fenofibrate, bezafibrate, gemfibrozil) or the inhibitors of intestinal absorption of cholesterol (for example ezetimibe); b) the active principles intended to fight against diabetes such as, for example, the PPAR γ activators of the glitazone class (in particular rosiglitazone, troglitazone, pioglitazone), biguanides (in particular metformin), sulfonylureas (for example tolbutamide, gliclazide), α-glucosidase inhibitors (especially acarbose or miglitol); c) active ingredients intended to combat obesity, for example compounds of the fenfluramine type. The invention also relates to pharmaceutical compositions containing as active principle a compound of formula (I) as well as a second active principle chosen from the compounds mentioned above and, in general, excipients usually used by those skilled in the art to make the dosage formulations. In the examples which follow, the expression "preparation" designates the examples describing the synthesis of intermediate compounds and, by "example" those describing the synthesis of compounds of formula (I) or (H) according to the invention. The purpose of these examples is to illustrate the invention and cannot in any way limit its scope. The melting points are measured on the Koffler bench and the spectral values of Nuclear Magnetic Resonance are characterized by the chemical displacement calculated with respect to the TMS, by the number of protons associated with the signal and by the shape of the signal (s for singlet, d for doublet, t for triplet, m for multiplet). The working frequency and the solvent used are indicated for each compound. In these examples, the abbreviation DMSO denotes dimethylsulfoxide.

PREPARATION 1 l-O-Methyl-2,3,5-tri-O-acetyl-D-arabinofuranose, compound 2.1

1.25 ml of thionyl chloride are added dropwise to a suspension of 25.39 g of D-arabinofuranose in 250 ml of methanol. The reaction mixture is stirred for 12 hours at room temperature and then 3.5 ml of pyridine are added. After partial evaporation of the solvents, 125 ml of pyridine are added and the reaction mixture is cooled in ice. 125 ml of acetic anhydride are then added and the reaction mixture is stirred for 24 hours. The reaction mixture is then hydrolyzed by addition of a water / ice mixture and then acidified with an aqueous solution of IN hydrochloric acid until a pH = 3 is obtained. The reaction mixture is extracted with ethyl acetate and the organic phase is washed successively with an aqueous solution of IN hydrochloric acid, an aqueous solution saturated with sodium carbonate and then with water. Then, the solvents are evaporated under reduced pressure. According to an analogous procedure, the following compounds are prepared:

- l-O-methyl-2,3,5-tri-O-acetyl-D-xylofuranose, compound 2.2,

- l-O-methyl-2,3,5-tri-O-acetyl-L-xylofuranose, compound 2.3,

- l-O-methyl-2,3,5-tri-O-acetyl-L-arabinofuranose, compound 2.4,

- 1-O-methyl-2,3,5-tri-O-acetyl-D-ribofuranose, compound 2.5.

PREPARATION 2

1,2,3,5-Tetra-O-acetyl-D-arabinofuranose, compound 1.1

1.21 ml of sulfuric acid and then 16.15 ml of acetic anhydride are added to 33.00 g of compound 2.1 dissolved in 300 ml of dichloromethane. The reaction mixture is stirred at room temperature for 5 hours then 14 ml of triethylamine are added until a pH = 7.8 is obtained. The solvents are evaporated under reduced pressure and the oil obtained is purified by chromatography on a column of silica gel, eluting with a toluene / acetone mixture, 95/5, v / v. According to an analogous procedure, the following compounds are prepared:

- 1,2,3,5-tetra-O-acetyl-D-xylofuranose, compound 1.2,

- 1,2,3,5-tetra-O-acetyl-L-xylofuranose, compound 1.3,

- 1,2,3,5-tetra-O-acetyl-L-arabinofuranose, compound 1.4,

- 1,2,3,5-tetra-O-acetyl-D-ribofuranose, compound 1.5.

PREPARATION 3

2,3,5-tri-O-acetyl-L-arabinofuranosyl trichloroacetimidate, compound V.l a) 2,3,5-tri-O-acetyl-L-arabinofuranose

At 0 ° C., 0.5 ml of hydrobromic acid at 30% in acetic acid is added to 200 mg of compound 1.4 dissolved in 10 ml of dichloromethane. The reaction mixture is stirred for 45 minutes at room temperature then the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a toluene / ethyl acetate mixture 75/25, v / v. b) At 0 ° C., 180 μl of acetonitrile trichloride and then a drop of 1,8-diazabicyclo [5.4.0] undec-7-ene are added to 80 mg of the compound obtained in a) dissolved in 2 ml of dichloromethane . The reaction mixture is stirred at 0 ° C for 30 minutes then the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel, eluting with a toluene / ethyl acetate mixture, 8/2, v / v.

EXAMPLE 1

[4- (4-Cyanobenzoyl) phenyl] 2β ^ -tri-O-acé yl-αrD-arabinofiιranoside, compound π.l [4- (4-Cyanobenzoyl) phenyI] 2 ^ -MO-acelyl-β-D-arabinofuranoside , compound B 2 (EXAMPLE 2) At 0 ° C., under a nitrogen atmosphere, 23 ml of tin tetrachloride are added dropwise to a suspension of 34.30 g of compound 1.1 and 21.85 g of 4-hydroxy-4'-cyanobenzophenone. At the end of the addition, the stirring of the reaction mixture is maintained for 15 minutes at 0 ° C. and then for 5 hours 30 minutes at room temperature. The reaction mixture is then taken up in ethyl acetate and then washed successively 2 times with an aqueous solution of IN hydrochloric acid, with water, 2 times with an aqueous solution of IN sodium hydroxide and then with water. until a pH = 7 is obtained. The organic phase is dried over magnesium sulphate and the solvents are evaporated under reduced pressure. The oil obtained is purified by chromatography on a column of silica gel, eluting with a toluene / ethyl acetate mixture, 9/1, v / v. The compounds Il.l and II.2 are thus separated.

Compound II.1: 1 H NMR (250 MHz, CDC1 ₃ ): 7.74-8.04 (m, 8H); 6.11 (s, 1H), 5.27 (d, 1H, J = 1.5 Hz); 5.10 (dd, 1H, J = 4.6 Hz); 4.29-4.40 (m, 2H); 4.20 (dd, 1H, J = 6.2 Hz and J = 13 Hz); 2.04-2.12 (2s, 9H). Compound II.2: 1H NMR (250 MHz, CDC1 ₃ ): 7.74-8.04 (m, 8H); 6.09 (d, 1H, J = 4.6 Hz), 5.47 (dd, 1H, J = 5.5 Hz); 5.33 (d, 1H, J = 7.1 Hz); 4.29-4.40 (m, 2H); 4.03 (m, 1H); 2.04-2.12 (2s, 9H).

According to an analogous procedure, the compounds (H) presented in TABLE 1 below are prepared.

TABLE 1

EXAMPLE 8

[4- (4-Cyanobenzoyl) phenyl] 2 ^ -tri-O-aœryl-α-L-arabmofuranoside, compound π.8

47.8 mg of 4-hydroxy-4'-cyanobenzophenone are added to a solution of 90 mg of compound V1 in 1.5 ml of dichloromethane, in the presence of 3A molecular sieve. The reaction mixture is then cooled to 0 ° C. and 5.3 μl of boron trifluoride etherate are added. The reaction mixture is stirred at 0 ° C for 3 hours 30 minutes. After adding triethylamine until a pH = 7 is obtained, ethyl acetate is added. After filtration, the reaction mixture is washed 3 times with an aqueous solution of sodium hydroxide IN, 1 time with an aqueous solution of hydrochloric acid IN, with water until a pH = 7 is obtained and then with an aqueous solution saturated with sodium chloride. The organic phase is dried over magnesium sulfate and the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel, eluting with a toluene / acetone mixture,

97/3, v / v.

[α] ²² _D = -71 ° (c = 0.51, DMSO).

EXAMPLE 9

[4- (4-Cyanobenzoyl) phenyl] α-D-arabinofuranoside

8.6 g of [4- (4-cyanobenzoyl) phenyl] 2,3,5-tri-O-acetyl-α-D- arabinofuranoside (compound II.1) are dissolved in 200 ml of an ammonia solution 2M in methanol then the reaction mixture is stirred for 4 hours at room temperature. After evaporation of the solvents under reduced pressure, toluene is added and the mixture is again evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a dichloromethane / methanol mixture, 96/4, v / v. The solid obtained is dried at 100 ° C; Mp 154 ° C; [α] _D ^27.6 = + 116 ° (c = 0.25, CH ₃ OH).

The compounds presented in TABLE 2 below are prepared according to a procedure analogous to that of EXAMPLE 9.

TABLE 2

EXAMPLE 17 [4- (4-CyanobenzoyI) phenyl] β-D-lyxofuranoside

A suspension of 4.00 g of phenylboronic acid in 50 ml of toluene is heated at 80 ° C for 2 hours until the solution becomes clear. The solvents are then evaporated under reduced pressure to give a white solid, triphenylboroxine. 3.66 g of β-D-lyxopyranose are added to a suspension of 2.53 g of this white solid in toluene. The reaction mixture is stirred at reflux until the solution becomes homogeneous. The solvent is evaporated and the residue is dissolved in 30 ml of pyridine. 4.6 ml of acetic anhydride are then added and the reaction mixture is stirred under argon for 2 hours at room temperature. The solvents are evaporated under reduced pressure. By evaporation of the solvent under reduced pressure, 1,5-O-diacetyl-2,3-O-phenylboranediyl-α-D-lyxofuranose (compound VII.1) is obtained. 20 ml of a 30% hydrobromic acid solution in acetic acid are added and the reaction mixture is stirred for 48 hours. The solvents are evaporated under reduced pressure and then by azeotropic entrainment with toluene to give 8.8 g of a solid. 2.32 g of this solid, 1.58 g of silver oxide and 1.52 g of 4-cyano-4'-hydroxybenzophenone in 30 ml of acetonitrile are stirred under argon, at room temperature for 12 hours. After filtration and concentration, the solution is treated by adding 10 ml of a 2M solution of ammonia in methanol. The solvents are evaporated under reduced pressure and the residue is purified by chromatography on silica gel, eluting with a mixture of a 2M solution of ammonia in methanol / dichloromethane, 5/95, v / v. [α] _D ²⁶ = - 154 ° (c = 0.4, DMSO)

EXAMPLE 18

[4- (4-Cyanobenzoyl) phenyl] 2,3,5-tri-O-acetyl-β-D-Iyxofuranoside, compound

II.9 0.15 ml of acetic anhydride is added to 147 mg of the compound of EXAMPLE 17 in 5 ml of pyridine. The reaction mixture is stirred under argon for 12 hours and 50 ml of ethyl acetate are added. After 3 washes with an aqueous 0.1N hydrochloric acid solution, the organic phase is dried over magnesium sulfate and the solvents are evaporated under reduced pressure. The oil obtained is purified by chromatography on a column of silica gel, eluting with an ethyl acetate / hexane mixture, 30/70, v / v. [α] _D ²⁶ = - 114 ° (c = 0.7, DMSO)

EXAMPLE 19 [4- (4-Cyanobenzoyl) phenyl] α-D-Iyxofuranoside

3.6 ml of a 1M solution of tin tetrachloride in dichloromethane are added, at room temperature, under an argon atmosphere, to a solution of 0.96 g of 1,5-O-2,3-diacetyl -O-phenylboranediyle-α-D-lyxofuranofuranose (compound VII.l prepared in. EXAMPLE 17) and 0.67 g of 4-cyano-4'-hydroxybenzophenone in 20 ml of anhydrous dichloromethane. The reaction mixture is stirred at reflux for 3 hours and an additional 3 ml of a 1M solution of tin tetrachloride in dichloromethane are added and the stirring is maintained for 2 hours at reflux and for 48 hours at room temperature. A saturated aqueous ammonium chloride solution is then added, the reaction mixture is extracted with ethyl acetate then washed with brine and dried over magnesium sulfate. Solvents are evaporated under reduced pressure and the oil obtained is stirred at room temperature in 10 ml of a solution of 2 M ammonia in methanol for 48 hours. The solvents are evaporated under reduced pressure and the residue obtained is purified by chromatography on a column of silica gel, eluting with a mixture of a solution of 2 M ammonia in methanol / dichloromethane, 1 to 5/99 to 95, v / v. The product is then stirred in 10 ml of ethylene glycol at room temperature for 12 hours. Ethyl acetate is added and the organic phase is extracted with water, 3 times with an aqueous solution of 1M sodium hydroxide, with water and then with salt water. The organic phase is dried over magnesium sulfate, filtered and the solvents are evaporated under reduced pressure. The product obtained is purified by chromatography on a column of silica gel as above.

[] _D ²⁶ = + 135 ° (c = 0.32, DMSO)

Claims

Compounds of formula (I)

in which -R represents a glycofuranosyl group of formula

and is chosen from:

• α-D-xylofuranosyl

• β-D-xylofuranosyl

• α-D-ribofuranosyl

• β-D-ribofuranosyl

• α-D-arabinofuranosyl

• β-D-arabinofuranosyl

• α-D-lyxofuranosyl

• β-D-lyxofuranosyl

• α-L-xylofuranosyl

• β-L-xylofuranosyl

• α-L-arabinofuranosyl

• β-L-arabinofuranosyl as well as their esters resulting from the esterification of at least one -OH function of the glycofuranosyl group into -OC(O)R _l5 Ri representing a (-C)alkyl or cyclopropyl group, their solvates and hydrates .

2 - Compounds according to claim 1, characterized in that R represents a glycofuranosyl group chosen from: • α-D-xylofuranosyl

• β-D-xylofuranosyl

• β-D-ribofuranosyl

• α-D-arabinofuranosyl

• β-D-arabinofuranosyl

• α-D-lyxofuranosyl

• β-D-lyxofuranosyl

• α-L-xylofuranosyl

• β-L-xylofuranosyl

• α-L-arabinofuranosyl.

3 - [4-(4-Cyanobenzoyl)phenyl] α-D-arabinofuranoside according to claim 1, as well as its esters resulting from the esterification of at least one -OH function of the glycofuranosyl group to -OC(O)R _l5 Ri representing a (Cι-C ₃ ) alkyl or cyclopropyl group, their solvates and hydrates.

4 - [4-(4-Cyanobenzoyl)phenyl] β-D-xylofuranoside according to claim 1, as well as its esters resulting from the esterification of at least one -OH function of the glycofuranosyl group to -OC(O)R _l5 Ri representing a (Ci-C ₃ ) alkyl or cyclopropyl group, their solvates and hydrates.

5 - Compounds according to claim 1 of formula (H):

in which R' represents the furanosyl group R as defined for (I) in claim 1, in which all the -OH functions are protected by the -OAc function.

6 - Compound according to any one of claims 1 to 5 for its use as a medicine. 7 - Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament intended for the treatment or prevention of atherosclerotic plaque. ι

8 - Use of a compound according to any one of claims 1 to 5 for the preparation of a medication intended for the treatment or prevention of metabolic syndrome, dyslipidemia, hypertriglyceridemia, levels of LDL that are too high or too low of HDL, type 2 diabetes or obesity.

9 - Use of a compound according to any one of claims 1 to 5, in combination with another active principle chosen from: a) hypolipidemic or hypocholesterolemic agents such as for example HMG-CoA reductase inhibitors, PPAR α activators or inhibitors of intestinal cholesterol absorption; b) active ingredients intended to combat diabetes such as for example PPAR γ activators of the glitazone class, biguanides, sulfonylureas, α-glucosidase inhibitors; c) active ingredients intended to combat obesity, for the preparation of a medicinal product intended for the treatment or prevention of the risk of atherosclerosis, metabolic syndrome, dyslipidemia, hypertriglyceridemia, levels of LDL that are too high or too low HDL, type 2 diabetes or obesity.

10 - Pharmaceutical compositions containing as active principle a compound according to any one of claims 1 to 5, in association with a pharmaceutically acceptable excipient.

11 - Pharmaceutical compositions containing as active principle a compound according to any one of claims 1 to 5, in association with a second active principle chosen from: a) hypolipidemic or hypocholesterolemic agents, such as for example HMG-CoA inhibitors reductase, PPAR α activators or inhibitors of intestinal cholesterol absorption; b) active ingredients intended to combat diabetes, such as for example PPAR γ activators of the glitazone class, biguanides, sulfonylureas, α-glucosidase inhibitors; c) active ingredients intended to combat obesity. 12 - Process for obtaining a compound according to any one of claims 1 to 5, characterized in that it comprises the following steps: (1) reaction of 4-hydroxy-4'-cyanobenzophenone (HT) with a peracetylated pentose of furanose structure, corresponding to the formula (TV):

(IV) in which Ac represents an acetyl group chosen from the group consisting of 1,2,3,5-tetra-O-acetyl-D-xylofuranose, 1,2,3,5-tetra-O-acetyl- L-xylofuranose, 1,2,3,5-tetra-O-acetyl-L-arabinofuranose, 1,2,3,5-tetra-O-acetyl-D-arabinofuranose, 1,2,3,5-tetra- O-acetyl-D-lyxofuranose and 1,2,3,5-tetra-O-acetyl-D-ribofuranose, in the form of an α/β mixture or in the appropriate α or β form, to obtain, optionally after purification, the corresponding furanosidic compound of formula (H):

in which R' represents the furanosyl group R as defined for (I) in claim 1, in which all the -OH functions are protected by the -OAc function; And

(2) the deacetylation reaction of the furanosidic compound of formula (H), thus obtained, to obtain the compound of formula (I) and (3) optionally the esterification of the compound of formula (I) thus obtained. 13 - Process for obtaining a compound according to any one of claims 1 to 5, characterized in that it comprises the following steps:

(1') reaction of 4-hydroxy-4'-cyanobenzophenone (TTT) with a trichloroacetimidate of furanoside structure, of formula (V):

(V) in which Ac represents an acetyl group chosen from the group consisting of 2,3,5-tri-O-acetyl-D-xylofuranosyl trichloroacetimidate, 2,3,5-tri-O-acetyl-trichloroacetimidate, L- xylofuranosyl, 2,3,5-tri-O-acetyl-L-arabinofuranosyl trichloroacetimidate, 2,3,5-tri-O-acetyl-D-arabinofuranosyl trichloroacetimidate, 2,3,5-tri-trichloroacetimidate 2,3,5-tri-O-acetyl-D-ribofuranosyl O-acetyl-D-lyxofuranosyl, 1-trichloroacetimidate, in the form of an α/β mixture or in the appropriate α or β form, to obtain, optionally after purification , the corresponding furanosidic compound of formula (H),

(2) deacetylation reaction of the furanosidic compound of formula (H), thus obtained, to obtain the compound of formula (I);

(3) optionally the esterification of the compound of formula (I) thus obtained.