Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
  • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/34—Alcohols
  • A61K8/347—Phenols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9755—Gymnosperms [Coniferophyta]
  • A61K8/9767—Pinaceae [Pine family], e.g. pine or cedar
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9783—Angiosperms [Magnoliophyta]
  • A61K8/9789—Magnoliopsida [dicotyledons]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/18—Antioxidants, e.g. antiradicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations

Definitions

• 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.
• ROS Reactive oxygen species
• 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.
• 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.
• 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.
• the invention also aims to provide a method for obtaining such polyphenol derivatives from polyphenols of plant extracts.
• the invention aims to take advantage of the properties of these flavonoid polyphenolic compositions in cosmetology, dietetics and therapeutics.
• polyphenol derivative compositions of the invention are characterized in that said polyphenols contain monomers, oligomers or polymers of units corresponding to formula (I):
• 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.
• core A phloroglucinol type nucleus
• core B catechol type nucleus
• 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 )
• 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),
• (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).
• 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.
• AGI unsaturated
• 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.
• 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.
• 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).
• 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.
• 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.
• 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, 3)
• 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.
• 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.
• 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.
• an alkylating agent in particular an anhydride or an acid chloride
• 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).
• an aprotic solvent anhydrous acetone, for example
• a mineral base potassium carbonate, etc.
• the alkylation reaction is stopped, after cooling, by adding a dilute acid (hydrochloric acid, for example) until an acidic pH is obtained.
• a dilute acid hydroochloric acid, for example
• 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.
• 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.
• 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.
• a solvent capable of creating an azeotrope with the water in order to allow its elimination, as and when it is formed.
• 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.
• 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.
• 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).
• a basic catalysis agent for example, triethylamine or pyridine
• acylating agents 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.
• a basic aqueous phase Na 3 PO 4 , K 3 PO 4
• organic solution CHCl 3 , CH 2 Cl 2
• reaction is preferably carried out at room temperature over a period of about 7 to 8 hours.
• 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.
• acidulated water HCl, qs acidic pH
• 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.
• compositions of the invention are therefore particularly suitable for the preparation of cosmetic preparations.
• compositions are associated with suitable vehicles for external use.
• 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.
• 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.
• 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.
• 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.
• compositions are advantageously in a form suitable for administration, especially orally, topically or parenterally.
• compositions are more particularly in the form of solutions, tablets, capsules, or syrups.
• compositions are in the form of creams, ointments, gels, lotions or patches.
• parenteral administration the compositions are in the form of a sterile or sterilizable injectable solution.
• FIGS. 1 to 11 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
• 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
• 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
• 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,
• 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.
• C18 reverse phase
• 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.
• 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.
• 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 infrared spectrum recorded in ATR mode with Fourier transform 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 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.
• 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:

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