EP2219641A1

EP2219641A1 - Compositions containing flavanoid polyphenol derivatives, and applications thereof in controlling diseases and ageing of living organisms

Info

Publication number: EP2219641A1
Application number: EP08850951A
Authority: EP
Inventors: Joseph Vercauteren
Original assignee: Caudalie
Current assignee: Caudalie
Priority date: 2007-11-15
Filing date: 2008-11-17
Publication date: 2010-08-25
Also published as: CN101909618A; FR2923718B1; RU2010123791A; FR2923718A1; US20100266523A1; RU2499596C2; CA2705838A1; JP2011503171A; JP2014141519A; WO2009063439A1

Abstract

The invention relates to compositions of polyphenol derivatives, characterised in that said polyphenols contain monomers, oligomers or polymers of units of the formula (I), wherein said units are characterised by the simultaneous presence of a phloroglucinol-type core (core A) and of a catechol-type core (core B) bonded together by a segment of 3 carbons such as C, said derivatives being over-activated in terms of nucleophilic power by the alkylation of at least one phenol function of each constituent monomer unit, and stabilised by the esterification of all the others with mixtures of fatty acids in proportions representing those of vegetable oils mainly consisting of AGI. These compositions can particularly be used in cosmetics, nutrition and therapy.

Description

Compositions of flavonoid polyphenolic derivatives and their applications for combating the pathologies and aging of living organisms

The subject of the invention is polyphenolic flavonoid derivative compositions for preventing and controlling most pathologies and the aging of tissues and living organisms. It also relates to a process for preparing these compositions and their applications, in particular in the cosmetic, dietary and therapeutic fields.

For more than half a century, the hypothesis has developed that the aging of the human organism results from the accumulation of multiple tissue damage by radical species or oxidative chemical reactivities.

In the mid-1950s, after much work on rubber, the chemist Harman found that preventing the formation of free radicals was the surest way to combat its degradation and cracking. By analogy, he suggests that the aging of tissues in humans (appearance of wrinkles on the skin, for example) is due to the "abnormal" formation within cells, highly reactive chemical species, and in particular, free radicals and the reactions they trigger.

Reactive oxygen species (ROS) are formed at the mitochondrial level by uncontrolled "transfer" of electron (s) to oxygen (EOR: superoxide anion, peroxides, peroxynitrites, free radicals, ...). These EORs then spread to other cellular compartments or cytoplasm, depending on their hydro / liposolubility, where they create considerable damage.

In this context, the search for active substances to fight against aging has, in recent decades, been based on their ability to break chain oxidation reactions, that is to say to prevent oxidative stress. Indeed, any substance capable of interacting with the EORs, diminishes their deleterious effects and, in the long term, will have a positive impact on health and, for the same reasons, will slow down aging as the development of the main pathologies. These are scavengers of free radicals (ability to deliver a single electron at a time) and / or antioxidants (transfer of two electrons at the same time) such as vitamins (E and C) and polyphenols.

However, the damage that causes the aging of the body or that accompany the main pathologies, would not only be the result of poor control of the flow of electrons due to "leakage" of mitochondrial metabolism and intracellular EOR, but would imply also other sources of potential deleterious effects involving the "Maillard reaction" and carbonyl stress.

In carbonyl stress, the carbonyl (aldehyde) function of glucose exerts its electrophilic properties with respect to the nucleophilic residues of proteins (amines, thiols, ...): this is the starting point of carbonyl stress which is amplified by propagator training. The created chemical species, or glycation products, are considered as end products: they are AGEs for "Advanced Glycated End-Products", in which glucose or its fragments are irreversibly bound to the amino acid residues.

The Maillard reactions that occur at the same time increase the reducing capacity of sugars and their derivatives. The dicarbonyl compounds that form, acquire a much stronger oxidability than their precursors and easily transfer their electrons to oxygen, for example. From the initially formed superoxide anion, the same sequence of EOR as in the case of intracellular stress is produced. Thus, the carbonyl stress is doubled of a second type of oxidative stress.

Unlike the previously mentioned mechanisms for EORs of mitochondrial origin, this new oxidative stress occurs outside the cells, within the extracellular matrix. It therefore relates to the amino acids or the residues of the proteins of this matrix, and in particular, the collagen and elastin fibers. This oxidative stress, which is particularly important because the enzymatic protection systems are not as effective as those located in the cell, leads to an increase in the alkylation phenomena which add to the glycation and glycoxidation products resulting from the stress. carbonyl.

Thus, carbonyl stress, coupled with extracellular oxidative stress, is at least as important as intracellular oxidative stress in the development of aging and the establishment of tissue alterations accompanying the main pathologies. The study by the inventors of the phenomena leading to the aging of the tissues thus led them to a more extensive consideration of the biochemical mechanisms that are responsible for them and to come up with new concepts making it possible to define new biological targets of complementary actions for them. fight more effectively.

Their research then led to modify the structure of polyphenols with antioxidant properties and trapping free radicals, such as those constituting plant extracts, to give them greater ability to trap carbonyl stressors.

It is therefore an object of the invention to provide novel compositions of polyphenol derivatives constituting overactivated polyphenols which are both capable of acting with great efficiency on a larger number of biological targets and are stabilized.

The invention also aims to provide a method for obtaining such polyphenol derivatives from polyphenols of plant extracts.

According to yet another aspect, the invention aims to take advantage of the properties of these flavonoid polyphenolic compositions in cosmetology, dietetics and therapeutics.

The polyphenol derivative compositions of the invention are characterized in that said polyphenols contain monomers, oligomers or polymers of units corresponding to formula (I):

(D

These units are characterized by the simultaneous presence of a phloroglucinol type nucleus (core A) and a catechol type nucleus (core B), linked together by a 3-carbon bond such as C.

In the most frequent case, in these units, ring A is joined to an additional oxygenated heterocycle by formation of a bond of one of its oxygens with carbon B of segment C (case of the flavonoid skeleton) of formula (II )

flavonoid

(II)

The 3 carbons of segment C can be sp2 hybrids (double bond between b and c and carbonyl in a), as is the case with quercetin of formula (III),

quercetin

(III) or have a double bond between a and c and carbonyl in b, as in cyanidol of formula (IV),

(IV) or its carbon a. can be sp3 hybrid alone, or finally be all 3 sp3 hybrids, as in the case of catechin of formula (V).

catechin

(V)

Carbon a. Segment C most often serves as a point of attachment with the nuclei A of the other units to form the oligomers or polymers.

Said derivatives are overactivated, with regard to their nucleophilic power, by alkylation of at least one phenolic function of each unit and stabilized by esterification with mixtures of fatty acids, mainly unsaturated (AGI), of all the others remaining free.

In general, the specific substitutions of the derivatives of the compositions of the invention lead to a modulation of their activity and render them capable of simultaneously and specifically inhibiting the main mechanisms involved in the major pathologies and aging mentioned above. Advantageously, the number of -O-alkyl groups per molecule does not equal the number of hydroxyls present on average per unit and, preferably, it is 1 or 2, more especially equal to 1.

The alkyl group (s) are more particularly methyl, isopropyl or tert-butyl groups.

The effective stabilization is obtained by formation of AG esters between the hydroxyl functions (alcoholic and phenolic), remaining free after alkylation (from 2 to 3, preferably 3), and fatty acids derived from vegetable oils characterized by their particular richness in predominantly unsaturated fatty acids (AGI). The oils are chosen for their favorable impact on health. Advantageously, the assets obtained then contain proportions of unsaturated fatty acids identical to those of the oils from which they come.

Said esters preferably comprise mixtures of acyl radicals R of the fatty acids of olive oil (Olea europea) or of grape seed oil (Vitis vinifera).

These are especially R radicals of saturated fatty acids (AGS = stearic acid, 7-8%), monounsaturated fatty acids (MUFA = oleic acid, 55-75%) and essential polyunsaturated fatty acids. (PUFA, 15-18%): diunsaturated (linoleic) and triunsaturated (linolenic) of the C 6 -6 and C 3 -3 series, present in the derivatives of the invention in proportions identical to those of the oils which exert maximum health benefit, according to data from epidemiology.

This stabilization also makes it possible to protect the overactivated flavonoid polyphenols from destruction. certain premature (oxidation in air or light), while giving them a lipophilic character in order to increase their chances of being resorbed and to act.

Advantageously, this stabilization is, however, temporary, and is no longer effective when the derivatives are placed in a situation to act, in order to restore all their antioxidant power. It must therefore be reversible by simple action of the biological systems to which the stabilizing groups are then exposed, and in particular, enzymes such as lipases, esterases or proteases.

More specifically, the invention relates to compositions characterized in that said unit derivatives correspond to formula (VI)

(VI) in which

- R ¹ is a hydrogen or the R ⁷ junction point of the same unit

R ² is a hydrogen, or an O-acyl radical of a fatty acid of a vegetable oil, represented by R as defined above.

- R ³ is a hydrogen, a carbonyl or the junction at R ⁵ or R of another unit,

R ⁴ is an alkyl radical, or an acyl radical of a fatty acid of a vegetable oil, represented by R as defined above R is a hydrogen or the R junction point of another unit, directly, or through a carbonaceous entity (methylene, methylmethyne, ...)

R ⁶ is a hydrogen or the R ³ junction point of another unit, directly, or through a carbonaceous entity (methylene, methylmethyne, ...),

- R ⁷ is an alkyl radical, or an acyl radical of a fatty acid of a vegetable oil, represented by R as defined above, or the junction point at R ¹ of the same unit, and the diastereoisomers and the regioisomers of these motifs.

By way of example, the derivatives of catechin dimer (B3) and epicatechin trimer (C2) of formulas (VII) and (VIII) can be given:

derivative of the B3 dimer derived from the C2 terner

(VI I) (VI I I)

According to a preferred embodiment of the invention, the derivatives defined above correspond to alkylated and then stabilized derivatives of plant extracts. They therefore present the structures of the polyphenols present as a mixture in these plant extracts. These include plant extracts of vine, green or fermented tea, fresh beans or roasted cocoa or pine.

Grape extracts are obtained from seeds or grape marc.

In accordance with the invention, the polyphenol derivative compositions defined above are obtained by reacting the corresponding polyphenol compositions in a first step with an alkylating agent under conditions permitting substitution of the hydrogen of at least 1 phenolic OH group per monomeric unit constituting each molecule, preferably 1 to 2, with an alkyl group, and in a second step, with an acylating agent, in particular an anhydride or an acid chloride, in conditions for substituting the hydrogen -OH groups, still free after alkylation, with a mixture of -COR acyl radicals released by the acylating agent, R being as defined above.

The alkylation reaction uses commercially available reagents, such as halides (idodides, bromides, ...), or sulfuric esters with one and a half chemical equivalent). They are added slowly to a solution of the polyphenol extract in an aprotic solvent (anhydrous acetone, for example), and in the presence of a mineral base (potassium carbonate, etc.), brought to reflux, with stirring and atmosphere. inert (nitrogen, argon, ideally).

The alkylation reaction is stopped, after cooling, by adding a dilute acid (hydrochloric acid, for example) until an acidic pH is obtained. The agitation is continued for an additional 45 min, approx. The reaction medium is concentrated under vacuum (evaporation of the solvent). The aqueous phase is extracted with an equal volume of immiscible solvent (such as ethyl acetate, dichloromethane, etc.), which is itself washed with two equivalent volumes of distilled water.

(until neutrality). This organic phase is dried over anhydrous sodium sulphate, then filtered and evaporated under reduced pressure to give up the residue of the alkylated polyphenols.

The acylating agent is prepared from a vegetable oil by a process comprising: saponification of glycerides from a vegetable oil, followed by acidification, dehydration activation in the case where the acylating agent is an acid anhydride, or by chlorination, in the case where it is an acid chloride, but other derivatives conferring the same activation effect can be used (transesterification, enzymatic acylation, according to case).

The saponification reaction is carried out in the aqueous phase in the presence of an alkaline agent such as potassium hydroxide in an amount at least stoichiometric, preferably at reflux temperature. The solution is then brought to acidic pH by the addition of mineral acid, and then extracted with an organic solvent to isolate the mixture of free acids formed during the reaction.

The dehydration reaction is carried out under reflux, in the presence of a solvent capable of creating an azeotrope with the water, in order to allow its elimination, as and when it is formed. For example, toluene is used and the water is trapped by a "Dean Stark" type system.

The chlorination reaction is conducted in the presence of a solvent capable of dissolving the free fatty acids. It is catalyzed by a Lewis base and carried out by slow addition of the chlorinating agent, at a controlled temperature, close to 0 ^° C. When the addition is complete, the stirring is prolonged at ambient temperature, then the medium The reaction is concentrated by evaporation in vacuo, and the chlorides are purified by distillation. Advantageously, the solvent used is chlorination, dichloromethane or chloroform, for example, provided that it is not stabilized with an alcohol, the chlorinating agent is, for example, thionyl chloride or dichloromethane. The oxalyl catalyst may be dimethylformamide, the purification of the acyl chlorides takes place by distillation under high vacuum in a "ball furnace" (Kugelrohr).

The acylation reaction is most often carried out in the presence of a solvent allowing even partial solubilization of the alkylated polyphenol compounds resulting from the alkylation reaction described above.

Suitable solvents are chosen from halogenated derivatives such as dichloromethane, chloroform or 1,2-dichloroethane, or nitrogen derivatives such as pyridine, or even hexane, depending on the alkyl compounds to be dissolved.

The alkylated polyphenol derivatives, dissolved in the chosen reaction solvent and advantageously added with a basic catalysis agent (for example, triethylamine or pyridine) are placed under stirring and inert atmosphere (argon, nitrogen).

Four equivalents of anhydrides or AG chlorides as prepared above are used as acylating agents. They are added dropwise in solution in the reaction solvent, if it is not pyridine alone. In the case where the pyridine is both the solvent and the basic catalyst, a "reverse" addition is carried out. It is the solution of the polyphenol derivatives which is added dropwise to the preformed acylpyridiniums.

An alternative that can be applied consists in adding, with vigorous stirring, a basic aqueous phase (Na ₃ PO ₄ , K ₃ PO ₄ ) to the organic solution (CHCl ₃ , CH ₂ Cl ₂ ) of the alkylated polyphenol derivatives and acylation agents, thereby producing the conditions of Schotten-Baumann.

Whatever the procedure adopted, the reaction is preferably carried out at room temperature over a period of about 7 to 8 hours.

The esterified derivatives thus formed are purified by addition of acidulated water (HCl, qs acidic pH) and then by several washes of the organic phase with distilled water. After drying over sodium sulfate, the solution is filtered and then evaporated to dryness to deliver the alkylated and stabilized flavonoid actives.

The dual-potential active ingredients of the invention, capable of trapping both EORs, whatever their intra- or extracellular origin, and dicarbonyl compounds (anti-glycation and anti-AGEs), are of great interest as the most complete and most effective means of fight against skin aging.

The compositions of the invention are therefore particularly suitable for the preparation of cosmetic preparations.

In these preparations, the compositions are associated with suitable vehicles for external use. Advantageously, their liposoluble character promotes their incorporation into the galenic forms usually used in cosmetics.

The invention therefore relates to cosmetic compositions characterized in that they contain an amount effective to combat aging of the skin, of one or more compositions of derivatives of flavonoid polyphenols as defined above in combination with inert vehicles suitable for external use.

These compositions are in a form suitable for topical administration such as cream, ointment, emulsion, gel, liposomes, lotion.

They contain from 0.5 to 5% of active product, preferably from 2 to 3%.

The invention also relates to a method for preventing aging of the skin, characterized by the application to the skin or ingestion of one or more cosmetic compositions as defined above.

According to another aspect of great interest, the compositions of the invention can be used in dietetics. Thanks in particular to their anti-free radical and compounding properties carbonylated, they ensure a better preservation of food. In addition, they generally constitute a contribution of vitamin factor. They are therefore added with advantage to drinks, for example fruit juices, tonic drinks, dairy products and derivatives such as butter.

They can also be used as such in liquid form, or in granules or the like, gels or in the form of a paste, for example incorporated into confectioneries such as fruit pastes, sweets, chewing pastes.

The properties of the compositions of the invention are also advantageously used for use as medicaments.

The invention thus relates to pharmaceutical compositions, characterized in that they contain a therapeutically effective amount of at least one composition as defined above, in association with a pharmaceutically acceptable vehicle.

These compositions are advantageously in a form suitable for administration, especially orally, topically or parenterally.

Thus, for oral administration, the compositions are more particularly in the form of solutions, tablets, capsules, or syrups.

For topical administration, the compositions are in the form of creams, ointments, gels, lotions or patches. For parenteral administration, the compositions are in the form of a sterile or sterilizable injectable solution.

Other features and advantages of the invention are given, by way of illustration, in the examples which follow, in which reference is made to FIGS. 1 to 11, which represent, respectively:

FIG. 1: the chromatogram of CLHP-ESI-MS (TIC) of O-methylated catechins,

FIG. 2: the ATR-mode IR-FT spectrum of alkylated grape seed flavanic polyphenols

(Methylated) - Figure 3: the ¹ H- ¹³ C (500 MHz) HMBC 2D NMR spectrum of dimethylsulfate-alkylated grape seed flavanolic polyphenols,

FIG. 4: the IR-FT spectrum of the fatty acids resulting from the saponification of a "virgin" olive oil, in ATR mode,

FIG. 5: the gas chromatogram, detected by mass spectrometry (GC-DSQ2) of the methyl esters prepared from the olive AG chlorides; FIG. 6: the IR-FT spectrum of the AG chlorides; olive

(in ATR mode), FIG. 7: the proton NMR spectrum at 500 MHz (CDCl ₃ ) of the olive AG chlorides,

Figure 8: the IRFT spectrum of flavanol polyphenols grape seed alkylated and stabilized with olive oil AG,

Figure 9: the low field part of the spectrum of

¹ H NMR (500 MHz, CDCl ₃₎ flavanol polyphenols of grape seed alkylated and stabilized by olive oil AG and integration curves,

FIG. 10: the strong-field portion of the ¹ H NMR spectrum (500 MHz, CDCl ₃ ) of the grafted flavanic polyphenols alkylated and stabilized with olive oil AGs and integration curves,

11: the ¹ H- ¹³ C HMBC 2D NMR spectrum (500 MHz, CDCl3) of grafted flavan polyphenols alkylated and stabilized with olive oil AGs.

Example 1 Step O-Alkylation of Catechin

50 mg (0, 172 mmol) of catechin are dissolved in 5 mL of anhydrous acetone in a bicolain topped with a refrigerant. Under stirring and argon atmosphere, in the presence of 23.8 mg

(0.172 mmol, 2 eq chemical) of potassium carbonate (K 2 CO 3), 8.3 μL (0.086 mmol = 2 eq) of dimethylsulphate (DMS) are added. The reaction is refluxed for 27 hours.

The reaction medium is filtered on No. 4 frit to remove K2CO3 and the acetone is evaporated. The residue is taken up in 20 ml of ethyl acetate. The organic phase, washed with 2 times 20 ml of water, dried over sodium sulphate, filtered and evaporated to dryness, leaves a residue of 48 mg (crude yield = 91.6%, on the basis of monomethylated derivatives, pm = 304).

The mixture obtained is analyzed by "reverse phase" (C18) high performance liquid chromatography with detection by atmospheric pressure mass spectrometry and electrospray ionization (HPLC-ESI-MS), presented in FIG. of ions, the most intense, with characteristic mass of monomethylated catechins ([M + H] = 305), at retention times (TR) = 15.79; 15.95; 17.75 and 17.84 minutes, and minority, mass ([M + H] ⁺ = 319), at RT 21.66; 23.66; 24.67; 26.02 and 27.34 minutes, corresponding to various dimethylated catechins.

Example 2 Step d / O-alkylation of flavonoid polyphenols

31.18 g ("108 mmol", expressed in "catechinic" units) of polyphenolic extract of grape seeds, are placed in solution in 120 ml of aprotic solvent (anhydrous acetone), in the presence of 6 chemical equivalents of potassium (44.64 g = 646 mmol). The resulting suspension is refluxed, with stirring under an argon atmosphere, in a 1 liter tricols flask equipped with a refrigerant.

Using a dropping funnel, 7.65 ml of the methyl donor (dimethyl sulfate, 81.5 mmol) are added dropwise over a period of 15 minutes, each mole of DMS liberating 2 moles of methyl "= 2x81.5 = 163 equivalents, ie = 1.5 chemical equivalents / mass of polyphenol extract used), or iso-propyl (2-iodopropane).

The calculation of the chemical equivalents is done by counting a "maximum" average of 4 phenolic hydroxyl residues which can be alkylated by "flavanolic unit". Thus, it is considered that each slice of 290 g of extract corresponds to 1 mole of catechin, which has four phenolic functions of which only one or even two must be converted into methyl ether (s). ), or iso-propyl (s). The chemical equivalent of the alkylation reagent is therefore equal to one quarter of the number of moles of "catechin" present in the extract used.

After refluxing for eight hours under an argon atmosphere, the reaction is cooled. After addition of a hydrochloric acid solution at the tenth, until an acidic pH (540 ml) is obtained, stirring is continued for another 45 minutes. The reaction medium is concentrated under vacuum (evaporation of acetone). The residual aqueous phase is extracted with an equal volume of ethyl acetate, which is washed twice with 400 ml of distilled water (until neutrality of the wash water). This organic phase is then dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give up the residue of the alkylated polyphenols.

(20.88 g, crude yield = 63.9%).

In the preferred case, in which each molecule of the initial extract undergoes a single methylation per flavanolic unit ("catechin"), a mixture of the different possible regio- and stereoisomers, such as the monomers and dimers figured below, is obtained. below, in formulas IX to XXVI:

As for the previous example, the (methylated) alkyl structures of these flavonoid compounds are deduced from the analysis of their different spectra:

The presence of phenolic methyl ethers results in IR (FIG. 2), in particular by the appearance of absorption bands between 2974 and 2836 cm ^-1 characteristic of the methyl CHs (elongation) and, between 1064 and 1035 cm. ^"1 , those characteristics of the functions (CO) ethers. The 2D NMR spectrum HMBC shows correlations between oxygenated aromatic carbons (from 148 to 160 ppm) and the protons of methyl ethers, resonating from 3.7 to 3.94 ppm. An expansion of this zone is inserted in the overall spectrum shown in FIG.

Example 3 Preparation of acylating agents

Step 1: saponification of olive oil:

50.46 g of "virgin" olive oil (57 mmol, = "171 eq") placed in a flask equipped with a condenser, are added 16.08 g of potassium hydroxide (285 mmol, 1 g). , 67 eq), dissolved in 2.5 mL of ethanol and 50 mL of water. The reaction is refluxed for 5 hours. It is stirred for a further 14 hours at room temperature. After the resulting solution is diluted with 300 ml of water, hydrochloric acid is added one tenth (3.7%, w / v) until an acidic pH of the aqueous phase (about 250 ml) is obtained. The contents of the flask, which contains an "insoluble" pasty on the surface, is then transferred to a separating funnel and extracted with 700 mL of hexane. The organic phase is separated and then washed with 2 times 300 ml of distilled water (obtaining a neutral pH of this aqueous phase). The organic phase is dried over sodium sulphate, filtered on frit No. 4 and then evaporated to give a residue of 42.9 g (crude yield = 88.8%).

The infrared spectrum recorded in ATR mode with Fourier transform (FIG. 4) shows a characteristic band of free organic acids at 1709 cm ^-1 , together with the disappearance of the ester bands of the starting oil.

Step 2: Activation of the fatty acids resulting from the saponification of olive oil by formation of chlorides:

The solution of 41.5 g of free fatty acids (147.1 mmol) from stage 1 in 232 ml of chloroform (stabilized on amylene) is stirred under an argon atmosphere in a flask. cooled by an ice bath. 13.8 ml of oxalyl chloride (162 mM = 1.1 eq) are added dropwise through a dropping funnel over a period of 30 minutes. 1 ml of dimethylformamide (DMF) is introduced and the stirring is continued on an ice bath for 5 minutes. Concentration under reduced pressure of the reaction mixture (chloroform and excess oxalyl chloride) then gives 44.3 g of oily residue, slightly colored yellow (crude yield = 100%).

By distillation in a furnace (kugelrhor) under high vacuum (2 mm Hg), this residue is removed from its color (colorless liquid), collecting the fractions which distill from 178 to 195 ° C.

In order to analyze the composition of the mixture of fatty acid chlorides obtained, a few microliters of distillate are exposed to methanol. The totum is then injected onto a gas chromatograph equipped with a FAME (Fatty Acid Methyl Ester) type column and a mass detector. online (DSQ-II). In the chromatogram presented in FIG. 5, the peak at 17.8 min corresponds to stearate (M + '= 298), that at 18.07 min to the oleate (M + - = 296), that at 18.08 min to a linoleate (M + - = 294 ) and that at 19.38 min with linolenate (M + - = 292). Their relative intensities are a good indication of their respective proportions.

The IR-FT (Fig. 6) and proton NMR spectra (Fig. 7) are in perfect agreement with the exclusive formation of these chlorides: A band at 1798 cm ^-1 , characteristic of acyl chlorides.

The alpha protons of the carbonyl (t, J = 7.5 Hz) show a chemical shift at 2.9 ppm, characteristic of the conversion of carboxyls to acid chlorides.

Example 4 Acylation of the Alkylated Grape Seed Flavonoid Extract

21.93 g (72 mmol = 288 eq. Chemicals) of flavonoid extract of alkylated grape pips (methylated), according to Example No. 2, are partially dissolved in 270 ml of chloroform (stabilized with amylene), and placed under an argon atmosphere. They are supplemented with the basic agent, triethylamine (40.56 mL = 29.45 g (d = 0.726) = 291.5 mmol = 1 chemical eq.), And the "solution" is sonicated for 5 minutes. . With magnetic stirring and at room temperature, with the aid of a dropping funnel, over a period of 20 minutes, 87.55 g of acylating agents as prepared in example no. 3 (olive oil AG chlorides = 288 mmol = 1 chemical eq.) Diluted in 60 mL of chloroform. Gaseous release occurs at each drop of water. The reaction is left stirring for another seven hours at room temperature, before being placed in a separating funnel and washed with 190 ml of hydrochloric acid at the tenth, 90 ml of a solution of NaHCO ₃ at 10% (w / v). ) in water, and finally, with distilled water until neutral (three times 90 mL). The organic phase is dried over sodium sulphate, filtered and then evaporated to dryness under reduced pressure. It abandons a residue of 67.27 g of alkylated and stabilized grape seed flavonoid actives (= 49.68 mmol, crude yield = 69%, average pm = 1354).

In order to obtain means of identification of these assets, the totum is then subjected to the maximum of spectral measurements: - The infrared spectrum by Fourier transform acquired in ATR () mode, shows the appearance of an intense band at 1764 cm ^-1 , characteristic of the carboxy esters of phenolic esters, concomitant with the disappearance of the wide band centered on 3350 cm ^-1 , which corresponded to the free phenolic hydroxyls.

The proton NMR spectrum (500 MHz, CDCl ₃ ) is presented with its integral curves, in two parts. With weak fields (Fig. 9), it allows to "count" the proportion of aromatic protons = 5.5 (region of 7.95 to 5, 90 ppm), compared to olefinic protons: massive centered on 5.35 ppm calibrated to 8 protons (consistent with an average of four olefins per catechism unit). In strong fields (Fig. 10), it allows to observe the singlet signals of methoxyls of aromatic ethers (from 4.05 to 3.58 ppm) and the bulk of the signals characteristic of methylenic protons in alpha of ester carboxyls. aromatics, centered on δ = 2.49 ppm. The ¹ H- ¹³ C long-range heteronuclear ^2- dimensional NMR spectrum at 500 MHz (Fig. 11), obtained in reverse (HMBC) mode, clearly shows the correlations that are in perfect agreement with the diverse structures of alkylated flavanolic polyphenols. (Methyl ethers of aromatic oxygens) and esterified (predominantly unsaturated fatty acid esters, in statistical mixture as resulting from the olive oil used to prepare the acylating agents, phenols and alicyclic alcohols).

In the preferred case, where each molecule of the initial extract has undergone only one methylation per flavanolic unit ("catechin"), and where the residual phenolic functions and the flavanolic alcohol are all acylated by the AG mixture. of olive oil, we obtain a mixture of the different regio- and stereoisomers possible of monomers and dimers figured below, in the formulas XXVII to XXXI:

Example 5 Cosmetic Formulations - FORMULA A

FORM B

Claims

Compositions of polyphenol derivatives, characterized in that they are polyphenol derivatives containing monomers, oligomers or polymers of units corresponding to formula (I):

(D these units being characterized by the simultaneous presence of a phloroglucinol type nucleus (core A) and a catechol type nucleus (core B), connected to each other by a segment with 3 carbons such as C, said derivatives being overactivated, with regard to their nucleophilic power, by alkylation of at least one phenolic function of each unit and stabilized by esterification with mixtures of predominantly unsaturated fatty acids (AGI) of all the other hydroxyl functions (phenolic and alcoholic).

2. Compositions according to claim 1, characterized in that in said units the nucleus A of the polyphenols is attached to an additional oxygenated heterocycle by forming a bond of one of its oxygen with the carbon b of the segment C, as in the case of the flavonoid skeleton of formula (II)

flavonoid: n)

3. Compositions according to claim 1, characterized in that in said units the 3 carbons of the C segment of said polyphenols are hybrid sp2 (double bond between b and c and carbonyl in a) as for quercetin of formula (III)

quercetin

:or)

or a double bond is formed between a and c and carbonyl in b, as for cyanidol of formula (IV),

(IV) or carbon _^ a is only sp3 hybrid, or all three are sp3 hybrids, as in the case of catechin of formula (V)

catechin

(V) carbon a. segment C can then serve as a point of attachment with the nuclei A of the other units to form the oligomers or polymers.

4. Compositions according to any one of claims 1 to 3, characterized in that the number of -O-alkyl groups per unit does not equal the number of hydroxyls present on average per unit.

5. Compositions according to claim 4, characterized in that the number of hydroxyls present on average per unit is equal to 1 or 2.

6. Compositions according to any one of claims 1 to 5, characterized in that the alkyl group (s) are methyl, isopropyl or tert-butyl groups.

7. Compositions according to any one of claims 1 to 6, characterized in that said esters are fatty acid esters of vegetable oils.

8. Compositions according to claim 7, characterized in that these esters comprise the radicals R corresponding to saturated fatty acids, such as stearic acid, monounsaturated fatty acids, such as oleic acid, and essential polyunsaturated fatty acids, such as linoleic and linolenic acids.

9. Compositions according to claim 7 or 8, characterized in that the vegetable oils are chosen from olive oil or grape seed.

10. Compositions according to any one of claims 1,2, 4 to 5, characterized in that said unitary derivatives correspond to the formula (VI)

(VI) in which

- R ¹ is a hydrogen or the R ⁷ junction point of the same unit - R ² is a hydrogen, or an O-acyl radical of an unsaturated fatty acid of a vegetable oil,

R ³ is a hydrogen, a carbonyl or the R ⁵ or R junction of another unit,

R ⁴ is an alkyl radical, or an acyl radical of an unsaturated fatty acid of a vegetable oil, represented by R as defined above,

- R ⁵ is a hydrogen or the R ³ junction point of another unit, directly, or through a carbonaceous entity (methylene, methylmethyne, ...), - R is hydrogen or the R junction point from another unit, directly, or through a carbon entity (methylene, methylmethyne, ...),

R ⁷ is an alkyl radical, or an acyl radical of a fatty acid of a vegetable oil, represented by R as defined in claim 8, or the joining point in R ¹ of the same unit, and diastereoisomers and regioisomers of these motifs.

11. Compositions according to claim 10, characterized in that said derivatives are derivatives of catechin dimer (B3) and epicatechin trimer (C2), of formulas (VII) and (VIII):

derivative of the B3 dimer derived from the C2 terner

(VI I) (VI I I)

12. Compositions according to any one of claims 1 to 11, characterized in that said derivatives correspond to stabilized and alkylated derivatives of plant extracts.

13. Compositions according to claim 12, characterized in that said plant extracts are extracts of vine, green tea or fermented, fresh beans or roasted cocoa or pine.

14. Compositions according to claim 13, characterized in that said grape extracts are obtained from seeds or grapes.

Process for the preparation of compositions according to any one of Claims 1 to 14, characterized in that it comprises the reaction of the polyphenol compositions formed from units as defined in any one of Claims 1 to 3, in a first step, with an alkylating agent under conditions which make it possible to substitute the hydrogen of at least 1 phenolic OH group per constituent monomeric unit of each molecule, preferably from 1 to 2, with an alkyl group, and

in a second step, with an acylating agent, in particular an anhydride or an acid chloride, under conditions making it possible to substitute hydrogen for -OH groups, still free after alkylation, with a mixture of acyl radicals; COR released by the acylating agent, R being as defined in the claim

16. The method of claim 15, characterized in that the acylating agent is obtained from a vegetable oil according to a process comprising:

the saponification of the glycerides of a vegetable oil, followed by acidification, an activation by dehydration in the case where the acylating agent is an acid anhydride, or by chlorination, in the case where an acid chloride

17. Cosmetic compositions, characterized in that they contain an effective amount for combating aging of the skin, of one or more polyphenol derivative compositions according to any one of claims 1 to 14, in combination with vehicles inert suitable for external use.

18. Compositions according to claim 17, characterized in that they are in a form suitable for a topical administration such as cream, ointment, emulsion, gel, liposomes, lotion.

19. Compositions according to claim 17 or 18, characterized in that they contain from 0.5 to 5% of active product, preferably from 2 to 3%.

20. Application of the compositions according to any one of claims 1 to 14, in dietetics.

21. Application according to claim 20, characterized in that said compositions are added to beverages, for example fruit juices, tonic drinks, dairy products and derivatives such as butter, in liquid form, or in granules or the like, gels or in the form of dough, for example incorporated in confectionery such as fruit pastes, sweets, chewables.

22. Compositions according to any one of claims 1 to 14 for use as medicaments.

23. Pharmaceutical compositions, characterized in that they contain a therapeutically effective amount of at least one composition according to any one of claims 1 to 14, in association with a pharmaceutically acceptable vehicle.

24. Compositions according to claim 22 or 23, characterized in that they are in a form suitable for oral, topical or parenteral administration.

25. Compositions according to claim 24, characterized in that they are in a form for a oral administration, such as solution, tablet, fGTPelplnullee nonu sQiπrτno-pn.

26. Compositions according to claim 24, characterized in that it is in a form for topical administration, such as cream, ointment, gels, lotions or patch.

27. Compositions according to claim 24, characterized in that it is in a form for parenteral administration, such as a sterile injectable or sterilizable solution.