WO2003002585A1

WO2003002585A1 - [4-(4-cyanobenzoyl)phenyl]glycopyranoside derivatives, use of same as a medicament, production method thereof and compositions

Info

Publication number: WO2003002585A1
Application number: PCT/FR2002/002144
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: FR2826367A1; FR2826367B1

Abstract

The invention relates to novel [4-(4-cyanobenzoyl)phenyl]glycopyranoside derivatives having formula (I), wherein X represents a hydrogen atom or a methyl group and R represents a glycopyranosyl group. Said compounds have an anti-atheromatous activity.

Description

[4- (4-CYANOBENZOYL) PHENYL] GLYCOPYRANOSIDE DERIVATIVES, USE AS DRUGS, PROCESS FOR OBTAINING SAME AND COMPOSITIONS

The present invention relates to new derivatives of [4- (4- cyanobenzoyl) phenyl] glycopyranoside, 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.

Certain documents of the prior art, and in particular EP 051 023 and J. Med. 10 Chem. 1993, 36, 898-903, describe certain benzoylphenylglycopyranoside derivatives as being antithrombotic agents, in particular for treating or preventing venous thrombosis.

More recently, benzophenone derivatives comprising an α-D-xylopyranosyl or 5-thio-α-D-xylopyranosyl group, exhibiting activity of interest for the prevention or regression of arterial atheromatous plaques, were disclosed in the patent application. publication published under number WO 99/67261. These compounds exhibit rapid metabolism, greater than 95%. To improve the bioavailability of therapeutically active molecules, it is preferable that these molecules have a lower metabolic rate. Also, the problem which the present invention proposes to solve is to obtain new compounds exhibiting anti-atheromatous activity, with lower metabolic rates than the compounds of the prior art.

According to the present invention, it has been shown that certain particular benzoylphenylglycopyranoside derivatives exhibit lower metabolic rates, with greater anti-atheromatous activity than the compounds of the prior art.

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

in which :

- X represents a hydrogen atom or a methyl group,

- R represents a glycopyranosyl group chosen from: • -D-xylopyranosyl

• α-D-ribopyranosyle

• β-D-ribopyranosyle

• α-D-arabinopyranosyle

• β-D-arabinopyranosyle • α-D-lyxopyranosyle

• β-D-lyxopyranosyle

• α-L-xylopyranosyle

• β-L-xylopyranosyle

• α-L-arabinopyranosyle • β-L-arabinopyranosyle

• α-D-glucopyranosyle

• α-D-galactopyranosyle

• α-D-mannopyranosyle

• β-D-mannopyranosyl as well as their esters resulting from the esterification of at least one -OH function of the glycopyranosyl group into -OC (O) R _1; R _\ representing a (C ₁ -C ₃ ) alkyl or cyclopropyl group, their solvates and hydrates.

By alkyl is meant a monovalent, hydrocarbon, saturated, linear or branched radical. By (CrC ₃ ) alkyl is meant an alkyl radical comprising from 1 to 3 carbon atoms. The compounds of formula (I) correspond to the following formulas given as a function of the glycopyranosyl group R: (1) α-D-xylopyranosyl

(2) α-D-ribopyranosyle

(3) β-D-ribopyranosyl

(4) α-D-arabinopyranosyle

(5) β-D-arabinopyranosyle

(6) α-D-lyxopyranosyle

(7) β-D-lyxopyranosyl

(8) α-L-xylopyranosyl

(9) β-L-xylopyranosyl

(10) α-L-arabinopyranosyle

(11) β-L-arabinopyranosyle

(12) α-D-glucopyranosyl

(13) α-D-galactopyranosyle

(14) α-D-mannopyranosyle

(15) β-D-mannopyranosyl

with X as defined for (I).

According to a particular aspect, the present invention relates to the compounds of formula (la):

in which R is as defined for (I), as well as their esters resulting from the esterification of at least one -OH function of the glycopyranosyl group in -OC (O) Ri, \ representing a (CrC ₃ ) alkyl group or cyclopropyl, their solvates and hydrates. A particular aspect of the invention also relates to the compounds of formula (I) and (la) in which:

- R represents a glycopyranosyl group chosen from:

• α-D-xylopyranosyle • α-D-ribopyranosyle

• β-D-ribopyranosyle

• α-D-arabinopyranosyle

• β-D-arabinopyranosyle

• α-D-lyxopyranosyle • α-L-xylopyranosyle

• β-L-xylopyranosyle

• α-L-arabinopyranosyle

• α-D-glucopyranosyle

• α-D-galactopyranosyle • α-D-mannopyranosyle

• β-D-mannopyranosyl as well as their esters resulting from the esterification of at least one -OH function of the glycopyranosyl group into -OC (O) R _1; R _\ representing a (- C ₃ ) alkyl or cyclopropyl group, their solvates and hydrates. The compounds chosen from:

- [4- (4-cyanobenzoyl) -2,6-dimethylphenyl] α-D-xylopyranoside,

- [4- (4-cyanobenzoyl) -2,6-dimethylphenyl] α-D-lyxopyranoside,

- [4- (4-cyanobenzoyl) -2,6-dimethylphenyl] β-L-xylopyranoside,

- [4- (4-cyanobenzoyl) -2-methylphenyl] α-D-xylopyranoside, as well as their esters resulting from the esterification of at least one function

-OH of the glycopyranosyl group in -OC (O) R _1; Rj representing a (- C ₃ ) alkyl or cyclopropyl group, their solvates and hydrates, are particularly preferred compounds.

By “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 group glycopyranosyle are esterified in -OC (O) Rι, Ri representing a group (Cι- C ₃ ) alkyl or cyclopropyl, in particular a methyl group.

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

(1) the reaction of the 4-hydroxy-4'-cyanobenzophenone derivative of formula

(m):

where X is as defined for (I), with a pentose or peracetylated hexose of pyranose structure, corresponding to formula (IV):

where Z is H or -CH ₂ OAc, with Ac representing an acetyl group and chosen from the group consisting of 1,2,3,4-tetra-O-acetyl-D-xylopyranose, 1,2,3,4 - tetra-O-acetyl-L-xylopyranose, 1,2,3,4,6-penta-O-acetyl-D-glucopyranose,

1,2,3,4,6-penta-O-acetyl-D-galactopyranose, 1,2,3,4,6-penta-O-acetyl-D-mannopyranose, 1,2,3,4-tetra- O-acetyl-L-arabinopyranose, 1,2,3,4-tetra-O-acetyI-D-arabinopyranose, 1,2,3,4-tetra-O-acetyl-D-lyxopyranose and 1,2,3, 4-tetra-O-acetyl-D-ribopyranose, in the form of an α / β mixture or in the appropriate α or β form, to obtain, optionally after purification, the corresponding osidic compound of formula (II):

in which X is as defined for (I) and R ′ represents the pyranosyl group R as defined for (I) in which all the -OH functions are protected in function -OAc; and

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

When the compound (IL) 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 (III) + (IV) 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 (IH) + (IV) → (II) of step (1) can be replaced by the following step (1 '):

(1 ′) the reaction of the compound (JE) with a halopentose or peracetylated halohexose of pyranose structure, corresponding to the formula (V):

where Y is a chlorine, bromine or iodine atom, bromine being preferred, and Z is H or -CH ₂ OAc, and chosen from the group consisting of 2,3,4-tri-O-acetyl halides 2,3,4,6-D-xylopyranosyl, 2,3,4-tri-O-acetyl-L-xylopyranosyl, 2,3,4,6-tetra- O-acetyl-D-glucopyranosyl, 2,3,4,6-tetra -O-acetyl-D-galactopyranosyl, 2,3,4,6-tetra-O-acetyl-D-mannopyranosyl, 2,3,4-tri-O-acetyl-L-arabinopyranosyl, 2,3, 4,4-tri-O-acetyl-D-arabinopyranosyl, 2,3,4-tri-O-acetyl-D-lyxopyranosyl, 2,3,4-tri-O-acetyl-D-ribopyranosyl, in the form of a mixture α / β or in the appropriate α or β form, with the 4- (4-hydroxybenzoyl) benzonitrile derivative of formula (III):

where X is as defined for (I), to obtain, after purification, the corresponding osidic compound of formula (ET).

Advantageously, the reaction (V) + (IH) - »(H) is carried out in an anhydrous solvent such as dichloromethane, 1,2-dichloroethane or acetonitrile, in the presence of a coupling agent such as silver trifluoromethanesulfonate (triflate) or silver oxide at a temperature of the order of -10 ° to + 10 ° C for 5 to 40 hours. Sodium hydride can also be used as coupling agent, for example in hexamethylphosphoramide. Advantageously, the operation is carried out under an inert and dry atmosphere, for example under a nitrogen or argon atmosphere and in the presence of a humidity sensor, such as a molecular sieve.

The reactions (IV) + (El) → (E) and (V) + (TU) → (D) apply to the preparation of all of the compounds of formula (H) according to the invention.

The compounds (IV) and (V) are prepared according to techniques well known to those skilled in the art, from the corresponding sugars. For the compounds (I) in which two hydroxy groups of the pyranosyl group are situated on the same side of the plane, it is possible, according to another alternative, to use instead of the compound (V), a corresponding boronate (VI) in which the said functions hydroxy of the pyranosyl group are linked to a boron derivative to form a boronate. For the synthesis of this boronate, reference may in particular be made to Chem. Sci., 1990, 45 (4), 547-51.

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 strain C57BL / 6I. 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 determined quantity 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. The anti-atheromatous effect of the compounds according to the invention was also evaluated by means of a test on mice deficient in Apolipoprotein E (Apo E), subjected to a normal diet. Following this test, the injured area at the aortic sinus was measured after 14 weeks of daily treatment. The following table indicates the results obtained after treatment with the compounds of Examples 15 and 25, with respect to an untreated control group:

These results confirm the favorable effect of the compounds according to the invention for preventing or combating atheroma.

Metabolism studies on hepatic microsomes have been carried out for the compounds according to the invention. The [4- (4-cyanobenzoyl) phenyl] α-D-xylopyranoside (compound A) described in Example 4 of WO 99/67261 was used for comparison. Solutions of compounds (I) and of compound A at 100 μM are prepared in DMSO. The test compounds are incubated at a final concentration of 1 μM (using the 100 μM solutions to obtain 1% final (v / v) of DMSO in the samples), in the presence of human hepatic microsomes (commercial preparation purchased from the company Tébu, France), at a concentration of 1 mg of protein per ml of sample, for times t = 0 or 60 minutes at 37 ° C., in an agitating water bath. The final volume is adjusted with a solution containing 0.1 N of Tris-HCl (tris (hydroxymethyl) aminomethane hydrochloride), 5 M of magnesium chloride, buffered to pH = 7.4. The reaction is initiated by addition of a regenerative system (containing 100 mM glucose-6-phosphate, 20 mM of β NADP (Nicotinamide Adenine Dinucleotide Phosphate) and 20 UT / ml of glucose-6-phosphate dehydrogenase) and stopped by immersing the tubes in ice and adding 50 μl of trifiuoroacetic acid to 1 ml of microsomal sample. The samples are prepared according to TABLE A below.

TABLE A

(*): volume to obtain a final protein concentration of 1 mg / ml per sample. 100 μl of a solution of an internal standard (4- (4-nitrobenzoyl) -phenyl 1,5- dithio-β-D-xylopyranoside) at 20 μg / ml in a water / methanol mixture, 80/20, v / v, are added to each tube. After centrifugation, the supernatant is analyzed by HPLC. The results, presented in TABLE B below, are expressed as a percentage of variation of the compound to be tested between the times t = 0 (tO) and t = 60 minutes (t60), that is to say of variation between tO and t60 of the ratio R defined by:

Peak height of the test compound

R =

Peak height of internal standard TABLE B

The compound of EXAMPLE 15 ([4- (4-cyanobenzoyl) -2,6-dimethylphenyl] α-D-xylopyranoside) according to the invention, as well as all the compounds tested according to the invention have a much higher metabolic rate lower than compound A of the prior art.

The above results show that the compounds according to the invention exhibit on the one hand an anti-atheromatous activity and on the other hand a low rate of metabolization.

The compounds of formula (I) or one of their esters, solvates or hydrates, may be used for the preparation of a medicament, intended for the treatment or 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 metabohque 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, solvents 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.

The products according to the invention are advantageously prescribed vis-à-vis the atheroma plaque, and in particular for the prevention or treatment of atheromatous risk.

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 ingredient will be finely ground beforehand and mixed with excipients known to those skilled in the art, such as for example lactose, pregelatinized starch, stearate. magnesium. 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, mention may be made of: a) lipid-lowering or cholesterol-lowering agents such as, for example, HMG-CoA reductase inhibitors (in particular simvastatin,

. lovastatin, atorvastatin, fluvastatin), PPAR α activators such as for example the compounds of the fibrate class (in particular fenofibrate, bezafibrate, gemfibrozil) or the inhibitors of intestinal absorption of cholesterol (for example ezetimibe); b) the active ingredients intended for combating diabetes, such as, for example, the PPAR γ activators of the glitazone class (in particular the rosiglitazone, troglitazone, pioglitazone), biguanides (in particular metformin), sulfonylureas (for example tolbutamide, gliclazide), α-glucosidase inhibitors (in particular 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, "preparation" designates the examples describing the synthesis of intermediate compounds and "example" those describing the synthesis of compounds of formulas (I) or (III) according to the invention. These examples are intended to illustrate the invention, and should in no 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, q for quadruplet, 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

2,6-Dimethyl-4-hydroxy-4'-cyanobenzophenone, compound III.1 a) 4-cyanobenzoic acid chloride

A mixture of 29.8 g of 95% phosphorus pentachloride and 20 g of 4-cyanobenzoic acid is heated to 70 ° C. and stirred at this temperature for

4 hours. After returning to room temperature and adding toluene, the mixture is evaporated under reduced pressure. The operation is repeated 4 times. The solid obtained is dried under reduced pressure. b) 2,6-Dimethyl-4-methoxy-4'-cyanobeπzophenone

To 23.82 g of aluminum trichloride and 20.57 g of 3,5-dimethylanisole in 200 ml of dichloromethane at 0 ° C., 22.75 g of 4-cyanobenzoic acid chloride are added. The reaction mixture is stirred at room temperature for 20 hours then is poured onto an ice / IN hydrochloric acid mixture. The organic phase is washed three times with a solution of IN hydrochloric acid, then with a saturated solution of sodium hydrogencarbonate then with water, until a pH = 7 is obtained. After drying over magnesium sulphate , the solvents are evaporated off under reduced pressure and the residue obtained is purified by chromatography on silica gel, eluting with a methylcyclohexane / ethyl acetate mixture, 9/1, v / v.

1H NMR (300MHz, CDC1 ₃ ); 7.85-7.69 (m, 4H); 7.37-7.26 (m, 1H); 6.85- 6.72 (m, 2H); 3.87 (s, 3H); 2.43 (s, 3H); c) 2,6-Dimethyl-4-hydroxy-4'-cyanobenzophenone, compound III.l. 20.91 g of 2,6-dimethyl-4-methoxy-4'-cyanobenzophenone dissolved in

80.3 ml of dichloromethane, under an inert atmosphere, at -30 ° C., 22.36 ml of boron tribromide are added dropwise. The reaction mixture is stirred at -30 ° C for 2 hours. After returning to ambient temperature, 150 ml of water and 75 ml of ethanol are added. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water until pH = 6, then with a saturated aqueous solution of sodium chloride and are dried over magnesium sulfate. The solvents are evaporated under reduced pressure then the residue obtained is purified by chromatography on silica gel, eluting with a toluene / ethyl acetate mixture, 95/5, v / v (yield = 36%). F = 154 ° C

1H NMR (300MHz, CDC1 ₃ ): 7.90-7.74 (m, 4H); 6.57 (s, 2H); 5.01 (s, 1H); 2.35 (s, 6H)

According to the same procedure, the following compound is synthesized: 2-methyl-4-hydroxy-4'-cyanobenzophenone, compound III.2. using methylanisole instead of 3,5-dimethylanisole 1H NMR (300MHz, CDC1 ₃ ); 7.74-7.34 (m, 4H); 7.26-7.24 (m, 1H); 6.79-6.67 (m, 2H); 5.46 (s, 1H); 2.43 (s, 3H); PREPARATION 2

Tetra-O-acetyl-β-L-xylopyranose, compound IV.l Tetra-O-acetyl-α-L-xylopyranose, compound IV.2

To 15 g of L-xylose in 40 ml of pyridine, 40 ml of acetic anhydride are added dropwise at 0 ° C. The reaction mixture is stirred under an inert atmosphere, at room temperature, for 6 hours. After evaporation of the solvents under reduced pressure, toluene is added and the mixture is again evaporated under reduced pressure. The oil obtained is taken up in ethyl acetate and then washed successively with an aqueous solution of IN hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and then with water until pH = 7 and with a saturated aqueous solution of sodium chloride. The organic phase is then dried over magnesium sulfate and the solvents evaporated under reduced pressure. The residue obtained is crystallized from diethyl ether. Tetra-O-acetyl-β-L-xylopyranose (compound IV.l) is isolated in the form of crystals. The residual oil obtained is purified by chromatography on silica gel, eluting with a toluene / ethyl acetate mixture, 85/15, v / v and tetra-O-acetyl-α-L-xylopyranose (compound TV .. 2) is isolated.

Compound IV.l: F = 126 ° C Compound rV.2: F = 86 ° C PREPARATION 3 2,3,4-tri-O-acetyl-α-L-xylopyranosyl bromide, compound Vl 20 ml of a solution of hydrobromic acid at 33% in acetic acid, are added at 0 ° C to a solution of 7g of tetra-O-acetyl-α-L-xylopyranose (compound TV.2) in 40 ml of dichloromethane stabilized at 1 amylene. The reaction mixture is stirred at 0 ° C for 1 hour 30 minutes and then is poured onto ice. After extraction with cold dichloromethane, the organic phase is washed successively with ice water, a saturated aqueous solution in sodium hydrogencarbonate then with water until pH = 7. After drying over magnesium sulphate, the solvents are evaporated under reduced pressure.

According to the same procedure, the following compounds are synthesized: 2,3,4-tri-O-acetyl-α-L-arabinopyranosyl bromide, compound V.2 2,3,4,6-tetra-O- bromide acetyl-D-mannopyranosyl, compound V.3

Mp 53-54 ° C; [α] _D ²⁰ = + 128 ° (c = 1.8, CHC1 ₃ ).

EXAMPLE 1

[4- (4-Cyanobenzoyl) -2,6-dimethylphenyl] 2 _y 3,4-tri-O-acetyl-α-D-xyIopvranoside, compound m

In 10 ml of dichloromethane, 1 g of tetra-O-acetyl-D-xylopyranose and 1.02 g of 2,6-dimethyl-4-hydroxy-4'-cyanobenzophenone (compound III.1) are dissolved and then 0.92 ml of tin tetrachloride are added at 0 ° C., under an inert atmosphere. After returning to room temperature, the reaction mixture is stirred for 2 hours and then poured into IN hydrochloric acid. After addition of ethyl acetate, the organic phase is washed successively with a 1N sodium hydroxide solution, with water until pH = 7, then with a saturated aqueous solution of sodium chloride. The organic phase is then 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 / ethyl acetate mixture, 9/1, v / v; [α] _D ²⁸ = + 120 ° (c = 0.8, DMSO).

The compounds presented in TABLE 1 below are prepared according to a procedure analogous to that of EXAMPLE 1. The derivatives (II) in α and β form are generally obtained and separated by chromatography on a column of silica gel eluting with a toluene / ethyl acetate mixture, varying from 9/1 to 8/2, v / v.

TABLE 1

EXAMPLE 9

[4- (4-Cyanobenzoyl) -2,6-dimethylphenyl] 23,4-M ^ -acefyl-β-L-xyIopyranoside, compound I 9

To a solution of 1.68 g of 2,3,4-tri-O-acetyl-α-L-xylopyranosyl bromide (compound Vl) and 1.25 g of 2,6-dimethyl-4-hydroxy-4 ' - cyanobenzophenone (compound III.l) in 25 ml of acetonitrile, 1.15 g of silver oxide II are added at room temperature. The reaction mixture is stirred at room temperature and protected from light for 24 hours then is filtered through celite and rinsed with ethyl acetate. The filtrate is washed with an aqueous solution of IN sodium hydroxide and then is filtered through celite. The filtrate is washed successively with an aqueous solution of sodium hydroxide IN, three times, an aqueous solution of hydrochloric acid IN then with water until pH = 6-7, then with a saturated aqueous solution of chloride sodium. The organic phase is then 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, 95/5, v / v then with a dichloromethane / methanol mixture, 99.5 / 0.5, v / v; Mp 83 ° C; [α] _D ²⁶ = -4 ° (c = 0.4, DMSO).

EXAMPLE 10 [4- (4-Cyanobenzoyl) -2,6-dimemylphenyl] 2,4-ω-O-acelyl-o L-arabmopyranoside

The compound of EXAMPLE 10 is prepared according to a procedure analogous to that of EXAMPLE 9. [α] _D ²⁵ ′ ⁶ = + 59 ° (c = 0.25, DMSO) using bromide of 2, 3 , 4-trio-O-acetyl-α-L-arabinopyranosyle.

EXAMPLE 11

[4- (4-Cyanobenzoyl) -2,6-dimethylphenyl] 2,3,4-tri-O-acetyl-α-D arabinopyranoside To a solution of 320 mg of 2,6-dimethyl-4-hydroxy-4 ' - cyanobenzophenone (compound III.l) and 295 mg of 2,3,4-tri-O-acetyl-α-D-arabinopyranosyl bromide in 10 ml of acetonitrile, 245 mg of silver oxide I are added. The reaction mixture is stirred at room temperature and protected from light for 2 days then is filtered on silica, rinsing with ethyl acetate. The solvents are evaporated under reduced pressure and the residue is purified by chromatography on silica gel, eluting with an ethyl acetate / hexane mixture, 3/10, v / v; [α] _D ²⁶ = - 51 ° (c = 0.48, DMSO). EXAMPLE 12 [4- (4-Cyanobenzoyl) -2,6-dimefoylphen ^

A mixture of 3.5 g of 2,6-dimethyl-4-hydroxy-4 '-cyanobenzophenone (compound III.l) and 540 mg of a suspension of 60% sodium hydride in oil in 30 ml of hexamethylphosphoramide is stirred at room temperature for 4 hours, then 2.86 g of 2,3,4,6-tetra-O-acetyl-D-mannopyranosyl bromide (compound V.3) in 10 ml of hexamethylphosphoramide are added. The reaction mixture is stirred at room temperature for 12 hours then is poured onto a water / ice mixture. After extraction with diethyl ether, the organic phase is washed with an aqueous solution of IN sodium hydroxide and then dried over magnesium sulfate. The solvents are evaporated under reduced pressure and the residue obtained is purified by chromatography on silica gel, eluting with a toluene / ethyl acetate mixture, 8/1, v / v; Mp 93 ° C;

[α] _D ²² = - 56 ° (c = 0.3, DMSO).

EXAMPLE 13 [4- (4-anobenzoyl) -2,6-dimeftylphen ^ lg of 2,6-dimethyl-4-hydroxy-4'-cyanobenzophenone (compound III.l) and 2.34 g of bromide of 2.3 , 4,6-tetra-O-acetyl-D-mannopyranosyl (compound V.3) are dissolved in 30 ml of anhydrous dichloromethane, in the presence of 4A molecular sieve and under a nitrogen atmosphere. This solution is cooled to -20 ° C and 3.07 g of silver triflate are added, protected from light. After 1 hour of stirring at −20 ° C., the temperature of the reaction mixture is allowed to return to ambient temperature and stirring is continued for 12 hours. The reaction mixture is filtered through celite. After adding dichloromethane, the filtrate is washed successively with an aqueous solution of IN hydrochloric acid, with water, with an aqueous solution of sodium hydroxide IN and then with water. 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 / ethyl acetate mixture, 8/1, v / v; Mp 86 ° C; [α] _D ²⁷ = + 52 ° (c = 0.8, DMSO). EXAMPLE 14

[4- (4-Cyanobenzoyl) -2,6-dimethylphenyl] α-D-ribopyranoside

A 95.9 mg of 2,6-dimethyl-4-hydroxy-4'-cyanobenzophenone (compound III.l) dissolved in 3 ml of tetrahydrofuran, 20 mg of a 60% sodium hydride suspension in the oil is added. After adding 120 mg of 3-O-acetyl-2,4-O-phenylboranediyl-α-D-ribopyranosyl bromide, compound VU (prepared according to Chem. Sci., 1990, 45 (4), 547-51), the reaction mixture is stirred at reflux under an inert atmosphere for 23 hours. 60 mg of compound VI.l are added again and the reaction mixture is stirred at reflux for an additional 24 hours. The reaction mixture is filtered through celite and the solvents are evaporated under reduced pressure. 10 ml of a solution of 2M ammonia in methanol is added and the mixture is stirred at room temperature for 12 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 2M ammonia mixture in methanol / dichloromethane, 2/98, v / v; [α] _D ²⁴ = + 91 ° (c = 0.3, DMSO).

EXAMPLE 15 [4- (4-Cyanobenzoyl) -2,6-dimethylphenyl] α-D-xylopyranoside

370 mg of [4- (4-cyanobenzoyl) -2,6-dimethylphenyl] 2,3,4-tri-O-acetyl-α-D- xylopyranoside (compound II.1) are added to 8 ml of a solution of 2M ammonia in methanol then the reaction mixture is stirred for 6 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, 95/5, v / v. The solid obtained is dried under reduced pressure; Mp 202 ° C; [α] _D ²⁸ = + 124 ° (c = 0.44, DMSO). The compounds presented in TABLE 2 below are prepared according to a procedure analogous to that of EXAMPLE 15.

TABLE 2

Claims

1. Compounds of formula (I):

in which :

- X represents a hydrogen atom or a methyl group,

- R represents a glycopyranosyl group chosen from:

• α-D-xylopyranosyle • α-D-ribopyranosyle

• β-D-ribopyranosyle

• α-D-arabinopyranosyle

• β-D-arabinopyranosyle

• α-D-lyxopyranosyle • β-D-lyxopyranosyle

• α-L-xylopyranosyle

• β-L-xylopyranosyle

• α-L-arabinopyranosyle

• β-L-arabinopyranosyle • α-D-glucopyranosyle

• α-D-galactopyranosyle

• α-D-mannopyranosyle

Β-D-mannopyranosyl as well as their esters resulting from the esterification of at least one -OH function of the glycopyranosyl group in -OC (O) Rι, Ri representing a (- C ₃ ) alkyl or cyclopropyl group, their solvates and hydrates. a) Compounds according to claim 1 of formula (la)

in which R is as defined for (I), as well as their esters resulting from the esterification of at least one -OH function of the glycopyranosyl group in

-OC (O) Rι, Ri representing a group (Cι-C ₃ ) alkyl or cyclopropyl, their solvates and hydrates. b) Compounds according to claim 1 or 2, characterized in that R represents a glycopyranosyl group chosen from: • α-D-xylopyranosyl

• α-D-ribopyranosyle

• β-D-ribopyranosyle

• α-D-arabinopyranosyle

• β-D-arabinopyranosyle • α-D-lyxopyranosyle

• α-L-xylopyranosyle

• β-L-xylopyranosyle

• α-L-arabinopyranosyle

• α-D-glucopyranosyle • α-D-galactopyranosyle

• α-D-mannopyranosyle

• β-D-mannopyranosyle. c) Compound according to claim 1 chosen from:

- [4- (4-cyanobenzoyl) -2,6-dimethylphenyl] α-D-xylopyranoside, - [4- (4-cyanobenzoyl) -2,6-dimethylphenyl] α-D-lyxopyranoside,

- [4- (4-cyanobenzoyl) -2,6-dimethylphenyl] β-L-xylopyranoside,

- [4- (4-cyanobenzoyl) -2-methylphenyl] α-D-xylopyranoside, as well as their esters resulting from the esterification of at least one -OH function of the glycopyranosyl group in -OC (O) R ₁ , Ri representing a (d-C ₃ ) alkyl or cyclopropyl group, their solvates and hydrates.

5. Compounds according to claim 1 of formula (E):

in which X is as defined for (I) and R 'represents the pyranosyl group R as defined for (I) in claim 1 in which all the -OH functions are protected in function -OAc.

6. Compound according to any one of claims 1 to 5 for its use as a medicament.

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 atheroma plaque.

8. 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 metabolic syndrome, dyslipidemias, hypertriglyceridemias, too high LDL levels or too low HDL, type 2 diabetes or obesity.

9. Use of a compound according to any one of claims 1 to 5, in association with another active principle chosen from: a) lipid-lowering or cholesterol-lowering agents such as, for example, HMG-CoA reductase inhibitors, PPAR α activators or inhibitors of intestinal cholesterol absorption; b) the active principles intended to fight against diabetes such as for example the PPAR γ activators of the class of glitazones, biguanides, sulfonylureas, α-glucosidase inhibitors; c) the active ingredients intended for combating obesity, for the preparation of a medicament intended for the treatment or prevention of atheromatous risk, metabolic syndrome, dyslipidemias, hypertriglyceridemia, too high LDL 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) lipid-lowering or cholesterol-lowering agents, such as for example HMG-CoA reductase inhibitors , PPAR α activators or inhibitors of intestinal absorption of cholesterol; b) the active principles intended for combating diabetes, such as for example the PPAR γ activators of the class of glitazones, biguanides, sulfonylureas, α-glucosidase inhibitors; c) active ingredients intended to combat obesity.

12. Method for obtaining a compound according to any one of claims 1 to 5, characterized in that it comprises the following steps:

(1) reaction of the 4-hydroxy-4'-cyanobenzophenone derivative of formula (ET):

where X is as defined for (I) in claim 1, with a peracetylated pentose or hexose of pyranose structure, corresponding to the formula (TV):

1,2,3,4,6-penta-O-acetyl-D-galactopyranose, 1,2,3,4,6-penta-O-acetyl-D-mannopyranose, 1,2,3,4-tetra- O-acetyl-L-arabinopyranose, 1,2,3,4-tetra-O-acetyl- D-arabinopyranose, 1,2,3,4-tetra-O-acetyl-D-lyxopyranose and 1,2,3, 4-tetra-O-acetyl-D-ribopyranose, in the form of an α β mixture or in the appropriate α or β form, to obtain, optionally after purification, the corresponding osidic compound of formula (E):

in which X is as defined for (I) and R 'represents the pyranosyl group R as defined for (I) in claim 1 in which all the -OH functions are protected in function -OAc; and

(2) the deacetylation reaction of the osidic compound of formula (E), thus obtained, to obtain the compound of formula (I).

(3) optionally the esterification of the osidic compound of formula (T) thus obtained

13. Method for obtaining a compound according to any one of claims 1 to 5, characterized in that it comprises the following steps:

(1 ') reaction of the 4-hydroxy-4'-cyanobenzophenone derivative of formula (IE):

where X is as defined for (I) in claim 1, with a peropetylated halopentose or halohexose of pyranose structure, corresponding to the formula (V):

where Y is a chlorine, bromine or iodine atom, bromine being preferred, and Z is H or -CH ₂ OAc, and chosen from the group consisting of 2,3,4-tri-O-acetyl halides D-xylopyranosyl, 2,3,4-tri-O-acetyl-L-xylopyranosyl, 2,3,4,6-tetxa- O-acetyl-D-glucopyranosyl, 2,3,4,6-tetra -O-acetyl-D-galactopyranosyl, 2,3,4,6-tetra-O-acetyl-D-mannopyranosyl, 2,3,4-tri-O-acetyl-L-arabinopyranosyl, 2,3, 4,4-tri-O-acetyl-D-arabinopyranosyl, 2,3,4-tri-O-acetyl-D-lyxopyranosyl, 2,3,4-tri-O-acetyl-D-ribopyranosyl, in the form of a mixture α / β or in the appropriate α or β form, to obtain, after purification, the corresponding osidic compound of formula (E):

in which X is as defined for (I) in claim 1 and R 'represents the pyranosyl group R as defined for (I) in claim 1 in which all the -OH functions are protected in function -OAc; and

(2) the deacetylation reaction of the osidic compound of formula (E), thus obtained, to obtain the compound of formula (I),

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