Flavonoid polyphenol derivative formulations and using them for controlling pathologies and living body ageing

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a polyphenol derivative formulation and is used in cosmetics, nutrition science and therapy. The polyphenol derivative formulation possessing antioxidant and antiradical activity and having an effect on carbonyl stress. A method for preparing the formulation. The cosmetic formulation possessing antioxidant and antiradical activity and having an effect on carbonyl stress. Using the formulation in nutrition science. The formulation to be used as a therapeutic agent possessing antioxidant and antiradical activity and having an effect on carbonyl stress. The pharmaceutical formulation possessing antioxidant and antiradical activity and having an effect on carbonyl stress.

EFFECT: formulation has an effect on carbonyl stress.

23 cl, 11 dwg, 5 ex

 

The invention relates to compositions derived flavonoid polyphenols for the prevention and combating of numerous pathologies and aging of tissues and living organisms. It relates also to a process for the preparation of these compositions and to their use, in particular in cosmetics, nutrition and therapy.

More than half a century ago, there was developed the hypothesis that the aging of the human body is the result of the accumulation of multiple injuries caused to the tissues radical containing compounds or compounds with reactivity to chemical oxidation.

By the mid 50-ies after several works with rubber chemist Herman found that preventingthe formation of free radicals, have the most reliable tool to combat degradation and cracking of rubber.By analogy, he suggests that the aging of tissues in humans (for example, the appearance of skin wrinkles), apparently due to abnormal formation within cells is very reactive chemical compounds, in particular, free radicals, and reactions initiated by these compounds.

Reactive forms of oxygen (EOR) are formed at the mitochondrial level by uncontrolled transfer of electron(s) to oxygen (EOR: superoxide anion radical, hydrogen peroxide, pen is dinitrite, free radicals,...).

These reactive forms of oxygen (EOR) spread in other cell compartments or in the cytoplasm, depending on their water/jirorastvorimogo and cause serious damage.

In the context outlined in the last decade, studies have been conducted active substances for use in the fight against aging, thanks to their ability to interrupt an oxidizing chain reaction, i.e. to prevent oxidative stress. Indeed, any substance capable of interacting with EOR and reduce their damaging effect in the long term, can have a positive effect on health status and for the same reasons, slows down aging as the cause of the development of the main pathologies. We are talking about the trap free radicals (the ability to immediately give a single electron) and/or antioxidants (simultaneous transfer of twoelectrons), such as vitamins (E and C) and polyphenols.

However, the destruction of which are associated with aging or accompany basic pathology, are not, apparently, the only consequence of poor control of the flow of electrons caused by "leakage" of electrons in the process of mitochondrial metabolismand in the intracellular EOR in these phenomena, it is obvious, also participate in other sources of potential ruin is lnyh effects such as "reaction Mierda" and carbonyl stress.

When carbonyl stress, carbonyl (aldehyde group of glucose exerts its electrophilic properties with respect to nucleophilic residues of proteins (amino, tilenum,...); here is the starting point of carbonyl stress, which increases with education agents transfer.

The resultingchemicals or products of glycosylation are the end products ofglycosylation: the products AGE (Advanced Glycated End-Products), in which glucose or its fragments are associated with amino acid residues in a reversible way.

The reaction Mierda going on at the same time, increase at the same time reducing ability of sugars and their derivatives. The resulting dicarbonyl compounds acquire stronger ability to oxidation than their predecessors, and easily give up their electrons, such as oxygen. Since originally generated superoxide anion effects from EOR are the same as in the case of intracellular stress. Thus, carbonyl stress has a second type of stress is oxidative.

In contrast to the mechanisms mentioned above occurring with EOR mitochondrial origin, this new oxidative stress occurs outside of cells, i.e. in the extracellular what atrice. It affects amino acids or residues of the proteins in this matrix, particularly collagen and elastin. This oxidative stress is particularly strong due to the fact that the enzyme systems protectionare not as efficient as the systems in the cage, and lead to increased effects of alkylation products which are added to the products of glycosylation and glycoamylase resulting from carbonyl stress.

Thus, carbonyl stress, accompanied by extracellular oxidative stress plays at least as important a role as intracellular oxidative stress in the development of aging and the appearance of tissue damage inherent in the basic pathological processes.

The study by the inventors of the phenomena leading to the aging of tissues, forced to explore a wider range of biochemical mechanisms involved in these phenomena, which led to the development of new concepts for the identification of new biological targets, which can additionally be affected to more effectively combat them.

The research of the inventors has led to the need to modify the structure of polyphenols with antioxidant properties and property of trapping free radicals, such as polyphenols, which are included in rastitel the data extracts in order, further, to give them properties capture carbonylic stress factors.

Thus, the objective of the invention is to provide new compositions derived polyphenols consisting of super active polyphenols, which are able to act simultaneously with great efficiency on many biological targets (oxidative and carbonyl stress) and are stable.

The objective of the invention is also to propose a method allowing to obtain the derivatives of polyphenols polyphenols from plant extracts.

According to another aspect of the invention is intended for use properties of the proposed compositions polyphenol flavonoid type in cosmetics, nutrition and therapy.

Compositions derived polyphenols according to the invention are distinguished by the fact that these polyphenols contain monomers, oligomers or polymers consisting of units corresponding to the formula (I):

These units are characterized by the simultaneous presence of rings phloroglucinol type (ring A) and ring Katholieke type (ring In), connected with each other by communication with three carbons, such as C.

Most often in these units the ring And poses with additional oxygen, heterotic the om by education connection of one of its oxygens with carbon bfragment (in the case of the flavonoid skeleton) of the formula (II):

All three carbon fragment can be sp2 hybridized (double bond betweenbandcand a carbonyl group in position (a), as in the case of quercetin formula (III):

or contain one double bond betweenandandcand carbonyl group in positionbas in the case of Canicola formula (IV):

or only one carbonandmay be sp3-hybridized, or all three carbon can be sp3-hybridized, as in the case of catechin formula (V):

In this case, carbonandfragment With the most often serves as a place of connection with rings And other units to form oligomers or polymers.

These derivatives superantivirus in relation to their nucleophilic activity by alkylation of at least one phenolic group of each unit and stabilized by esterification of all other remaining free groups with a mixture of fatty acids, mainly unsaturated fatty acids (AGI).

As a rule, specific substitution on derivatives included in compositions according to the invention, allows to model their activity and make them capable of specifically inhibiting the OS is ESD mechanisms, involved in many pathologies and aging processes mentioned above.

Mainly, the number ofOalkyl groups in the molecule is not equal to the number of hydroxyl groups per average onunit, and is preferably 1 or 2 groups, more specifically 1 group.

Alkyl or alkyl groups are, in particular, methyl, ISO-propyl or tert-butylene group.

Effective stabilization is achieved by formation of esters AG between hydroxyl groups (alcoholic and phenolic), the remaining free after alkylation (2-3, preferably, 3 groups), and fatty acids derived from vegetable oils characterized by a particularly high content of fatty acids, mainly unsaturated (AGI). Oils chosen for their beneficial effect on health. Mainly in the obtained active substances contained unsaturated fatty acids in ratios identical to the proportions of these acids in the oils from which they are extracted.

These esters preferably include a mixture of acyl radicals R of fatty acids of olive oil (Olea europeaor grapeseed oil (Vitis vinifera).

More specifically, these radicals are the radicals R of saturated fatty acids (AGS = stearic acid; 7-8%), mononine imennyh fatty acids (AGMI = oleic acid; 55-75%) and polyunsaturated essential fatty acids (AGPI; 15-18%): DIMENSIONI (linoleic acid) and tridenosenh (linolenic acid) groups of ω-6 and ω-3, located in the derivatives according to the invention in proportions identical to the proportions of these acids in the oils, which have a most beneficial effect on health, according to epidemiological data services.

Spent stabilizing allows, in addition, to protect super active flavonoid polyphenols from certain premature degradation (oxidation in air or light) and at the same time to give them a lipophilic character in order to enhance their ability to resorbtive and interaction.

Mostly this stabilization is temporary and its effectiveness should not continue to occur, if derivatives are when you need to recover all of its antioxidant activity. Therefore, stabilization must be reversible under the action of biological systems that affect the stabilizing group, in particular enzymes, such as lipase, esterase or protease.

More specifically the invention relates to compositions, characterized in that the above-mentioned derivatives consist of units corresponding to the formula (VI):

where

- R1indicates water is gender or place of attachment of the same units on the radical R 7,

- R2denotes hydrogen or O-acyl radical of a fatty acid of vegetable oil, denoted by the radical R, described above,

- R3denotes hydrogen, a carbonyl group, or the place of attachment of the radical R5or R6the other one,

- R4denotes an alkyl radical or an acyl radical of a fatty acid of vegetable oil, denoted by the radical R, described above,

- R5denotes hydrogen or place of attachment of the other units by the radical R3directly or through a carbon group (methylene, metallinou,...)

- R6denotes hydrogen or place of attachment of the other units by the radical R3directly or through a carbon group (methylene, metallinou,...),

- R7denotes an alkyl radical or an acyl radical of a fatty acid of vegetable oil, denoted by the radical R, described above, or the place of attachment of the same units on the radical R1,

and diastereoisomers and regioisomers of these units.

As an example, derivatives of dimers of catechin (B3) and epicatechin trimer (C2), formula (VII) and (VIII):

In accordance with a preferred variant of the invention described above derivatives correspond alkilirovanny, and then the stable is derived from plant extracts. Therefore, they have patterns of polyphenols, which are found in these plant extracts in the form of a mixture.

These extracts are, in particular, herbal extracts of grape, green tea or tea made from fermented leaves, raw and roasted cocoa beans, or pine.

The grape extracts obtained from grape seeds or grape Marc.

In accordance with the invention, compositions derived polyphenols, described above, is produced by interaction of the respective polyphenolic compositions:

- in the first stage, with an alkylating agent under conditions leading to the substitution of hydrogen of at least 1 phenolic Oh-group on the monomer unit constituting each molecule, preferably, 1-2 groups, alkyl group, and

- in the second stage, with allermuir agent, in particular with the anhydride or acid chloride of the acid, under conditions leading to the substitution of hydrogen in the groups HE left free after alkylation with a mixture of acyl radicals-COR, released by acylation agent, and R have the values specified above.

In the alkylation reaction using reagents produced in the sale, such as halides (iodides, bromides,etc.) or a complex of sulfuresters, based half chemical equivalent. They slowly introduced into a solution of polyphenol is xtracta in an aprotic solvent (for example, anhydrous acetone) in the presence of inorganic base (potassium carbonate,...) at boiling under reflux and under stirring in an inert atmosphere (ideally, nitrogen, argon).

The alkylation reaction is stopped after cooling by adding dilute acid (such as hcl) to obtain an acidic pH. The stirring is continued for approximately 45 minutes. Reaction medium was concentrated under vacuum (the solvent is evaporated). The aqueous layer was extracted with an equal volume of immiscible solvent (such as ethyl acetate, dichloromethane,...), which itself is washed two equivalent volumes of distilled water (until neutral). The obtained organic layer is dried over anhydrous sodium sulfate, then filtered and evaporated under reduced pressure to allocate in the form of alkyl residue of polyphenols.

Allerease agent derived from plant oils in accordance with the following procedure:

the saponification of the glycerides of vegetable oil with subsequent acidification,

activation by dehydration when allermuir agent is an acid anhydride, or by chlorination when using the acid chloride of the acid, but is suitable for use and other derivatives, creating the same activating effect (depending on the task: per the etherification, enzymatic acylation).

The saponification reaction is carried out in a water layer in the presence of an alkaline agent such as potassium hydroxide, is used in at least stoichiometric amount, preferably at the boiling point under reflux. Then the solution brought to acidic pH by the addition of inorganic acid, and extracted with an organic solvent for separation of a mixture of free acid formed during the reaction.

The reaction of dehydration is carried out under reflux in the presence of a solvent, capable of forming azeotropic mixture with water, which removes at least her education.

Use, for example, toluene, removing the water by means of system type “Dean Stark.

The chlorination reaction is carried out in the presence of a solvent capable of dissolving the free fatty acids. The reaction catalyze a Lewis base and are slow addition of the chlorination agent and at a controlled temperature of about 0°C. When the addition is complete, stirring is continued at room temperature then the reaction medium was concentrated by evaporation under vacuum and the resulting acid chlorides purified by distillation.

Mainly:

as solvent for the reaction of chlorination is used, for example, dichloromethane or chloroform, with the services is provided he was not stabilized with alcohol,

the chlorination agent is, for example, thionyl chloride or oxalicacid,

the catalyst may be dimethylformamide,

cleaning acylchlorides carry out distillation at high vacuum in the "ball of the furnace" (Kugelrohr).

The acylation reaction is often carried out in the presence of a solvent capable of solubilisate, at least partially, alkylated polyphenolic compounds obtained by the above-described alkylation.

Suitable solvents are selected from halogen derivatives, such as dichloromethane, chloroform or 1,2-dichloroethane, or astrozone, such as pyridine, hexane or even, depending on the alkyl compounds, subject to dissolution.

Alkylated polyphenolic derivatives, dissolved in the selected reaction solvent, which mainly add a catalytic agent having a basic character (for example, triethylamine or pyridine), guide for mixing in an inert atmosphere (argon, nitrogen).

As acylation agents take four equivalents of anhydride or acid chloride of AG obtained above. These agents are added dropwise, dissolved in the reaction solvent, if these agents is not only the pyridine. When pyridine is both solvent is ό catalyst, then perform the addition in the reverse order. Then a solution of polyphenol derivative is added dropwise to allerigies that get in advance.

You can use the embodiment, which is added with vigorous stirring the alkaline aqueous phase (Na3PO4, K2PO4) to the organic solution (CHCl3CH2Cl2) alkyl polyphenolic derivatives and agents alkylation, implementing, therefore, the conditions of Schotten's-Bauman.

Regardless of the adopted methodology the reaction is carried out preferably at room temperature over a time of approximately 7 to 8 hours.

The obtained esterified derivatives cleanse by adding acidified water (HCl until acidic pH), then carry out several washing of the organic layer distilled water. After drying over sodium sulfate the solution is filtered, evaporated to dryness and receive alkylated and stable active flavonoid substance.

Received active compounds with dual activity according to the invention to detect reactive oxygen species (EOR) regardless of their intracellular or extracellular origin and, at the same time, dicarbonyl compounds (antiglycation and anti-AGE), are of great is of interest as the most complete and most effective means today to fight against aging skin.

Compositions according to the invention is particularly interesting to obtain cosmetic products.

In these preparations, the composition is combined with the appropriate media, suitable for outdoor use. The advantage of them thatfat-soluble nature of these compositions is conducive to their introduction in conventional herbal form, widely used in cosmetics.

Thus, the invention relates to cosmetic compositions, characterized in that they contain one or more compositions of derivatives of flavonoid polyphenols described above, together with inert carriers suitable for topical application, in an amount effective for anti-aging of the skin.

These songs are presented in a form suitable for topical application means, such as a cream, ointment, emulsion, gel, liposomes, lotion.

Composition containing 0.5-5% of active substance, preferably 2-3%.

The invention relates also to a method of preventing aging of the skin, characterized in that applied to the skin or taken internally one or more cosmetic compositions described above.

According to another aspect of great interest, the compositions according to the invention can be used in nutrition. In particular, due to its radical scavenging activity and ability to catch ebonyline connection compositions provide the best food preservation. In addition, compositions, typically, represent a factor of enrichment with vitamins. Therefore, they can be added to drinks such as fruit juices, soft drinks, dairy products and processed products, such as butter.

The composition can also be used as such in liquid form or in pellet or similar form, in the form of a gel or paste, and put, for example, confectionery products, such as fruit pasta, candy, chewing gum.

Properties of the compositions according to the invention can be successfully detected using the compositions in the quality of medicines.

Thus, the invention relates also to pharmaceutical compositions characterized in that they contain a therapeutically effective amount of at least one composition described above together with a pharmaceutically acceptable carrier.

Mostly, these compositions are in a form suitable, in particular, for oral, topical or parenteral administration.

So, more specifically, for the oral route of administration of the composition are in the form of solutions, tablets, gelatin capsules, or syrups.

For the topical route of administration of the composition are in the form of creams, ointments, gels, Los is ons or patches.

For parenteral routes of administration of the composition are in the form of a sterile or sterilizable solutions for injection.

Other characteristics and advantages of the invention are disclosed as an illustration, in the examples described below, which gives a reference to Fig.1-11, which show, respectively:

- Figure 1: chromatogram CLHP-ESI-MS (TIC)Omethylated catechins,

- Figure 2: range of IR-FT, recorded by ATR method, alkyl (methylated) flavonolignan polyphenols from grape seed,

- Figure 3: NMR spectrum of 2D HMBC1H13C (500 MHz) flavonolignan polyphenols from grape seed, alkyl-dimethylsulfate,

- Figure 4: range of IR-FT, recorded by ATR method, the fatty acids obtained after saponification of olive oil virgin,

- Figure 5: gasthe chromatogram, detektiruya mass spectrometry (GC-DSQ2) methyl esters derived from acid chlorides AG olive oil,

- 6: range of IR-FT dichlorides AG olive oil (ATR method),

- 7: spectrum of the proton NMR at 500 MHz (CDCl3) dichlorides AG olive oil,

- Fig: range of IR-FT flavonolignan polyphenols from grape seed, alkyl and stable AG olive oil,

- Figure 9: part of the NMR spectrum1H (500 MHz, CDCl3in weak fields flavonolignan polyphenols from grape costache is, alkyl and stable AG olive oil, and integral curves

- Figure 10: part of the NMR spectrum1H (500 MHz, CDCl3in strong fields flavonolignan polyphenols from grape seed, alkyl and stable AG olive oil, and integral curves

- 11: an NMR spectrum of 2D HMBC1H13C (500 MHz, CDCl3) flavonolignan of grape seed polyphenols, alkyl and stable AG olive oil.

Example 1: phaseOalkylation of catechin

In a two-neck flask, equipped with a fridge, dissolve 50 mg (0,172 mmol) catechin in 5 ml of anhydrous acetone. Under stirring in argon atmosphere in the presence of 23.8 mg (0,172 mmol, 2 chemical EQ.) potassium carbonate (K2CO3) gain of 8.3 ál (0,086 mmol = 2 chemical EQ.) dimethylsulfate (LCA). The reaction is carried out under reflux for 27 hours.

The reaction medium is filtered on ritterband glass No. 4 for removal To2CO3evaporate the acetone. The residue is treated with 20 ml of ethyl acetate. The organic layer after washing 2 times with 20 ml water, drying over sodium sulfate, filtration and evaporation to dryness, gives the rest mass of 48 mg (crude yield = of 91.6%, including monomethylamine derivative, molecular weight = 304).

The resulting mixture was analyzed by vysokoeffektivnikh chromatography on "obetovannoi" column (C18) in combination with detection of mass spectrometry at atmospheric pressure and ionization in electrospray (CLHP-ESI-MS), presented in figure 1. There are streams of ions, of which the most intensive flow of ions have mass ions characteristic ofmonomethylarsonic catechins ([M+H]+=305), retention time (TR) = 15,79; 15,95; 17,75 and 17,84 minutes, and least intense flows of ions have mass ([M+H]+=319), retention time (TR) = 21,66; 23,66; 24,67; to 26.02 and 27,34 minutes, corresponding demetilirovanny derived catechin.

Example 2: phaseOalkylation of flavonoid polyphenols

31,18 g ("108 mmol"expressed in "catechin" links) extract polyphenols from grape seeds are dissolved in 120 ml aprotic solvent (anhydrous anhydride) in the presence of 6 chemical equivalents of potassium carbonate (44,64 g = 646 mmol). In one litre three-neck flask, equipped with a refrigerator, the resulting suspension is heated under reflux with stirring in an argon atmosphere.

Using a dropping funnelis added dropwise within 15 minutes 7.65 ml donor metrov (dimethylsulfate, 81,5 mmol; each mol DMS releases 2 moles "metrov" = 2×81,5 = 163 equivalent, i.e. a 1.5 chemical equivalents/mass used polyphenolic extract) orISO-cuts (2-iodopropane).

When calculating chemical equivalents based on the fact that "most" average 4 phenolic hydroxyl group capable of alkylaromatic n flavonones unit. Thus, consider that each portion of the extract weight 290 g corresponds to 1 pray catechin, which has 4 phenolic groups, of which one, even two groups, must be converted(s) in group(s) methyl(o) orISO-propyl(s) ether(s). Therefore, the chemical equivalent of the alkylating agent is the fourth part of the number of moles of "catechin", which is used in the extract.

After heatingunder reflux for eight hours in an argon atmosphere, the reaction medium is cooled. After introduction of the solution tenfold diluted hydrochloric acid, to achieve an acidic pH (540 ml), stirring is continued for an additional 45 minutes. Reaction medium was concentrated under vacuum (evaporation of acetone). The residual aqueous layer was extracted with an equal volume of ethyl acetate and washed twice with 400 ml of distilled water (until neutral wash water). This organic phase is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain the residue alkyl polyphenols (to 20.88 g; crude yield = 63,9%).

In the preferred case, when each molecule of the original extract is subjected to only one methylation on flavonols unit ("catechin"), get a mixture of different possible Regio and stereoisomers, such as monomers and dimers of the following formulas (IX)to(XXVI):

As in the previous example, alkylated (methylated) structure of these flavonolignan connections by analyzing the different spectra of these compounds are:

- The presence of a simple methyl ester of phenolreflected on the IR spectrum (Figure 2), in particular, the appearance of absorption bands in the range between 2974 and 2836 cm-1characteristic of C-H bonds inmethyl group (elongation)and of absorption bands in the range between 1064 and 1035 cm-1characteristic of C-O bonds in the ether groups (C-O).

- NMR spectrum of 2D HMBC shows the correlation betweenaromatic hydrocarbons associated with oxygen, (148-160 ppm), and protons simple methyl esters at a resonance between 3,7-of 3.94 ppm This area in an enlarged scale included in the total spectrum, presented in Figure 3.

Example 3: Getting alleluya agents.

Stage No. 1:saponification of olive oil

To 50,46 g of olive oil virgin (57 mmol, = "171 EQ."), placed in a flask equipped with fridge, add 16,08 g of potassium hydroxide (285 mmol, 1,67 equiv.) dissolved in 2.5 ml of ethanol and 50 ml of water. The reaction is carried out under reflux for 5 hours. Then the reaction mixture is additionally stirred for 14 hours at room temperature.

After diluting the obtained solution 300 ml of water are added tenfold diluted hydrochloric acid (3.7%; and the weight/volume), to establish the acidic pH of the aqueous layer (about 250 ml). The contents of the flask, which includes on the surface of the pasty "insoluble" the product is transferred to a separating funneland extracted with 700 ml of hexane. The organic layer is separated, then washed 2 times with 300 ml of distilled water (to a neutral pH of this water layer).

The organic layer is dried over sodium sulfate, filtered on ritterband glass No. 4, then evaporated to obtain a residue weight of 42.9 g (crude yield = 88,8%).

The infrared spectrum recorded by the methodATR with Fourier transformation (Figure 4)shows the band characteristic of the free organic acids, at 1709 cm-1and at the same time, the disappearance of the bands esters of the original oil.

Stage No. 2:Activation of fatty acids obtained after saponification of olive oil through the formation of acid chlorides:

In the flask, cooled with ice bath in an atmosphere of argon stirred solution of 41.5 g of free fatty acids (147,1 mmol)obtained in stage 1 in 232 ml of chloroform (stabilized Amelina). Using a dropping funnel was added dropwise to 13.8 ml oxalicacid (162 mm = 1.1 EQ.) within 30 minutes. Inject 1 ml of dimethylformamide (DMF) and continue stirring on an ice bath for 5 minutes. After concentration under onigen is m the pressure of the reaction mixture (chloroform and excess oxalylamino) get them 44.3 g of oily residue, slightly colored in yellow (crude yield = 100%).

By distillation in a ball furnace (kugelrhor) with a substantial vacuum (2 mm Hg) disappears staining obtained residue (colorless liquid), simultaneously collect fractions, warded off when the temperature 178-195°C.

For analysis of the composition of the mixture of anhydrides of fatty acids several microlitres distillate is treated with methanol. The entire volume injected into the gas chromatograph, equipped with a column type of “FAME” (Fatty Acid Methyl Ester) and a linear detector mass(DSQ-II). On the chromatogram presented in Figure 5, the peak with retention time of 17.8 min corresponds to stearate (M+.= 298), the peak with retention time 18,07 min corresponds to oleate (M+.= 296), the peak with retention time 18,08 min corresponds to linoleate (M+.= 294) and the peak with retention time 19,38 min corresponds linolenate (M+.= 292). The relative intensity of the peaks of these components is well indicated by their respective ratios.

IR spectra FT (6) and the NMR of the proton (Fig.7) are in full compliance with the education exclusively these acid chlorides:

The band at 1798 cm-1characteristic of acylchlorides.

The protons alpha-carbonyl group (t,J=7.5 Hz) chemical shift, equal to 2.9 ppm, characteristic for the conversion of the carboxyl groups in chlorine is midride acid.

Example 4: the Acylation extract alkyl flavonoids grape seed

21,93 g (72 mmol = 288 chemical EQ.) extract of grape seed flavonoids, alkyl (methylated) according to example 2, is placed in an atmosphere of argon and partially dissolved in 270 ml of chloroform (stabilized Amelina). To the reaction medium is added to the agent of the main character, triethylamine (40,56 ml = 29,45 g (d=0,726) = 291,5 mmol = 1 chemical EQ.) and the "solution" is subjected to ultrasonic treatment for 5 minutes. Under stirring with a magnetic stirrer at room temperature is added dropwise via the dropping funnel over 20 minutes 87,55 g alleluya agents obtained in example No. 3 (anhydrides AG olive oil = 288 mmol = 1 chemical equiv.) diluted with 60 ml of chloroform. The evolution of gas takes place in the fall of every drop.

Reactions are still for seven hours with stirring at room temperature, then put the mixture into a separating funnel and washed with 190 ml of tenfold diluted hydrochloric acid, 90 ml of a 10% (weight/volume) solution of NaHCO3in the water and finally with distilled water until neutral (three times in 90 ml). The organic phase is dried over sodium sulfate, filtered, then evaporated to dryness under reduced pressure. Get the balance weight 67,27 g alkyl is stabilized active flavonoids grape seed (= 49,68 mmol; crude yield = 69%, average molecular weight = 1354).

To identify the received active substances, all products have been most subjected to spectral analyses:

The infrared spectrum with the Fourier transform, obtained by the method of ATR(),shows the appearance of an intense band at 1764 cm-1characteristic of carboxy phenol esters,accompanied by the disappearance of the broad band with center at 3350 cm-1that corresponded to the free hydroxyl phenols.

- Range of the proton NMR (500 MHz, CDCl3) presents its integral curves in two parts. In weak fields (Fig. 9) range allows you to "calculate" the proportion of aromatic protons = 5,5 (area of 7.95-5,90 ppm) relative to the olefinic protons: the array center to 5.35 ppm calibrated for 8 protons (in accordance, on average, four-olefins in catechin unit). In strong fields (Fig. 10) can be observed singlet signals metaxylem aromatic ethers (4,05-to 3.58 ppm) and an array of signals characteristic of the methylene protons alpha to the carboxy aromatic esters with center at δ=2,49 ppm

- An NMR spectrum, the two-dimensionalheterocyclic,1N13With the greatest breadth of the spectrum at 500 MHz (Fig. 11), in inverse mode (HMBC), clearly shows the correlation, which is located in full compliance with a variety of structures flavonolignan polyphenols alkyl (simple methyl esters with aromatic oxygen cycle) and esterified (esters of fatty acids, mainly unsaturated, in the form of a statistical mixture obtained from the olive oil used to obtain the acylation agents, phenols and alicyclic alcohols).

In preferred cases, when each molecule of the original extract is subjected to only one methylation on flavonols unit ("catechin") and when all residual phenolic groups and flavonolignan alcohol group etilirovany a mixture of AG olive oil, get a mixture of different possible Regio - and stereoisomeric monomers and dimers represented by the following formula (XXVII)to(XXXI):

Example 5: Cosmetic composition

Recipe And

PHASEThe INITIAL SUBSTANCE%
101Water80,8000
102EDTA ternatively0,0500
103Glycerin5,0000
104Carbomer0,3500
201 Clearinghouse wheat0,7500
202Clearinghouse barley1,7500
203Cetearyl alcohol2,5000
204The composition according to the invention0,05-1
205Butyrospermum Parkii2,5000
206Tocopherylacetate0,5000
207Grape seed oil (Vitis Vinifera)3,0000
208Cetyl alcohol1,0000
209Cetilistat potassium1,0000
301Preservatives0,6000
401Fragrant substance0,2000
501Sodium hydroxide Dorn 6,00

Recipe

PHASEThe INITIAL SUBSTANCE%
101Water79,40000
102EDTA ternatively0,05000
103Citric acid to a final pH of 5.50,15000
201Xanthographa resin0,30000
202Butyleneglycol5,00000
301Cetearate-201,50000
302Literallayout2,00000
303The composition according to the invention0,05-1
304Oil Butyrospermum Parkii1,00000
305 Exellent4,00000
306Dimethicone3,00000
307Squalene2,00000
308Tocopherylacetate0,50000
401Preservatives0,60000
501Fragrant substance0,50000

1. Composition derived polyphenols with antioxidant and antiradical activity and has the effect on carbonyl stress, characterized in that the said derivatives of polyphenols originate from monomers, oligomers or polymers consisting of units corresponding to the formula (I):

moreover, these units are characterized by the simultaneous presence of rings phloroglucinol type (ring A) and ring Katholieke type (ring b), connected to each other by a fragment with 3 carbon atoms, such as,
and in the specified units of the ring And polyphenols may be associated with additional oxygen-containing heterocycle by the formation of ties one of his at the MOU oxygen with carbon b fragment, as in the case of the flavonoid skeleton of the formula (II):

either of these units all 3 carbon fragment From these polyphenols can be sp2-hybridized (double bond between b and C and carbonyl group in position (a), as in the case of quercetin formula (III):

or a double bond formed between a and C and the carbonyl group is in position b, as in the case of Canicola formula (IV):

or only one carbon and sp3-hybridized, or all 3 of the carbon is sp3-hybridized, as in the case of catechin formula (V):

moreover, the carbon and the outline can serve as a connection point with rings And other units with the formation of oligomers or polymers,
these derivatives superantivirus against nucleophilic activity by alkylation of one or two phenolic groups to each unit and stabilized by esterification of all of the remaining hydroxyl groups (phenolic and alcohol) mixtures of fatty acids, mainly unsaturated (UFA).

2. The composition according to claim 1, characterized in that the alkyl group or alkyl groups are methyl, isopropyl or tert-utilname.

3. The composition according to claim 1, characterized in that the said esters are esters of W the situations acids of vegetable oils.

4. The composition according to claim 3, characterized in that the above esters include the radicals R, the corresponding saturated fatty acids such as stearic acid, monounsaturated fatty acids, such as oleic acid, and essential polyunsaturated acids, such as linoleic and linolenic acid.

5. The composition according to claim 3, characterized in that the vegetable oil selected from olive oil or grape seed oil.

6. The composition according to claim 1, characterized in that the mentioned derivatives consist of units corresponding to formula (VI):

in which
R1denotes hydrogen or place of attachment of the same units on the radical R7,
R2denotes hydrogen or O-acyl radical of a fatty acid of vegetable oil, denoted by the radical R, described above,
R3denotes hydrogen, a carbonyl group, or the place of attachment of the radical R5or R6other units,
R4denotes an alkyl radical or an acyl radical of a fatty acid of vegetable oil, denoted by the radical R, described above,
R5denotes hydrogen or place of attachment of the other units by the radical R3directly or through a carbon group (methylene, metallinou),
R6denotes hydrogen or place connec what of the other units by the radical R 3directly or through a carbon group (methylene, metallinou),
R7denotes an alkyl radical or an acyl radical of a fatty acid of vegetable oil, denoted by the radical R, described in item 8, or the place of attachment of the same units on the radical R1,
and diastereoisomers and regioisomers of these units.

7. The composition according to claim 6, characterized in that the said derivatives are derivatives of dimers of catechin (EOI) and epicatechin trimer (C2), formula (VII) and (VIII):

8. The composition according to claim 1, characterized in that these derivatives correspond to the stable and alkilirovanny derived plant extracts.

9. The composition according to claim 8, characterized in that these plant extracts are extracts of grape, green tea or tea made from fermented leaves, raw and roasted cocoa beans, or pine.

10. The composition according to claim 9, characterized in that the said grape extracts obtained from grape seeds or grape Marc.

11. The method of obtaining the composition according to one of claims 1 to 10, characterized in that it includes the interaction of the composition of polyphenols, educated units described in 1:
in the first stage, with an alkylating agent under conditions leading to the substitution of hydrogen of at least 1 HE-GRU the dust of phenol on Monomeric unit, component of each molecule, preferably 1-2 groups, alkyl group, and
in the second stage, with allermuir agent, in particular with the anhydride or acid chloride of the acid, under conditions leading to the substitution of hydrogen in the groups HE left free after alkylation with a mixture of acyl radicals-COR, released by acylation agent, and R has the values listed in item 8.

12. The method according to claim 11, characterized in that allerease agent derived from plant oils in accordance with the following procedure:
saponification of the glycerides of vegetable oil with subsequent acidification,
activation by dehydration when allermuir agent is an acid anhydride, or by chlorination when using the acid chloride of the acid.

13. Cosmetic composition with antioxidant and antiradical activity and has the effect on carbonyl stress, characterized in that it contains one or more compositions derived polyphenols, according to one of claims 1 to 10, together with inert carriers suitable for topical application, in an amount effective for anti-aging of the skin.

14. The composition according to item 13, characterized in that it has a form suitable for administration by topical, such as cream, ointment, emulsion, gels, liposomes, lotion.

15. The composition according to the .13 or 14, characterized in that it contains 0.5-5% of active substance, preferably 2-3%.

16. The use of a composition according to one of claims 1 to 10 in dietetics.

17. The application of clause 16, wherein the specified composition is added to beverages, such as fruit juices, soft drinks, dairy products and processed products, such as oil, in liquid form or in pellet or similar form, in the form of gels or pastes, introduced, for example, confectionery products, such as pastes, candies, chewing gum.

18. Composition according to one of claims 1 to 10 for use as a drug with antioxidant and antiradical activity and has the effect on carbonyl stress.

19. Pharmaceutical composition having antioxidant and antiradical activity and has the effect on carbonyl stress, characterized in that it contains a therapeutically effective amount of at least one composition according to one of claims 1 to 10 together with a pharmaceutically acceptable carrier.

20. The composition according to p or 19, characterized in that it has a form suitable, in particular, for the introduction of oral, topical or parenteral.

21. The composition according to claim 20, characterized in that it has a form suitable for administration by mouth, such as RA is creative, tablet, gelatin capsule or syrup.

22. The composition according to claim 20, characterized in that it has a form suitable for topical application means, such as a cream, ointment, gels, lotions or patches.

23. The composition according to claim 20, characterized in that it has a form suitable for administration by parenteral, such as sterile or sterilizable injection.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cosmetology and represents an oil-in-water emulsion sun-protection cosmetic composition containing: (A) 1 to 7.5 wt % of octyl methoxycinnamate; (B) 1 to 4 wt % of tret-butyl methoxydibenzoyl methane and/or 2-hydroxy-4-methoxybenzophenone; (C) 0.5 to 3 wt % of a polyoxyethylene/polyoxyalkylene alkyl ester block copolymer; (D) 10 wt % or more of a nonpolar oil relative to the total amount of the oil component; wherein an average emulsion particle diameter makes not more than 700 nm.

EFFECT: invention provides developing the stable sun-protection composition having improved ultraviolet blocking capability and good usability.

4 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to cosmetology, particularly a composition enriched with silver nanoparticles and a method of producing said composition. The composition is intended to replace water as the basic component for producing cosmetic products (shampoos, Balsams, masks, intimate hygiene agents, creams etc). The composition contains a dry 65% whey protein concentrate, a micellar solution of silver nanoparticles in form of an aqueous solution having concentration of 500 mg/l in amount of 0.01-0.5% and additionally water. The method of producing said composition involves heating water to temperature of 50-55°C, adding the whey protein concentrate to the heated water in portions, recirculating the obtained mixture for 15 minutes using a cam-driven pump, adding the micellar solution of silver nanoparticles to the stirred mixture and cooling the obtained mixture to 30°C.

EFFECT: invention enables to obtain cosmetic material which protects skin from inflammatory processes and ageing, controls and maintains the skin water-oil balance.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to cosmetology, particularly to hair colouring products. The present invention represents a keratin fibre lightener characterised by the fact that it contains in a cosmetic carrier: 4-acetyl-1-methylpyridinium-n-toluene sulphonate, at least one toxicologically sage additional lightening activator and/or a pharmacologically acceptable salt thereof, and hydrogen peroxide.

EFFECT: using the hair lightener according to the invention enables providing the improved blonding ability and reduced hair damage.

13 cl, 2 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: present inventions relate to protein engineering, plant molecular biology and pest control, as well as a hybrid insecticide protein and use thereof. Described is a hybrid insecticide protein which includes from the N-end to the C-end an N-end portion of Cry3A protein which is fused with the C-end portion of Cry1Ab protein, wherein the position of the crossover of the Cry3A protein and the Cry1Ab protein is located in a conservative block 2, in a conservative block 3 or in a conservative block 4 and has anti-western corn rootworm activity. Also disclosed are nucleic acid molecules which code the novel proteins, methods of producing proteins, methods for use thereof, as well as transgenic plants and seeds thereof which contain such proteins.

EFFECT: inventions enable to obtain cheap means of controlling Diabrotica worms.

39 cl, 8 dwg, 9 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to two-component hair dye, which includes first component, containing alkaline agent, second component, containing hydrogen peroxide, as well as non-aerosol vessel-foaming agent, intended for supply of liquid mixture of first component and second component in form of foam. Said liquid mixture contain anionic SAS, selected from components (A1)-(A3) or components (A4) and (A5), where component (A1) is represented by anionic SAS of carboxylate class, component (A2) is represented by anionic SAS of sulfonate class, component (A3) is represented by anionic SAS of phosphate class, component (A4) is represented by ionic SAS, and component (A5) is represented by alkanolamide of fatty acid. Also claimed invention relates to method of hair dyeing.

EFFECT: invention has good discoloration and dyeing capacities.

22 cl, 4 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: invention refers to production of oral hygiene products. The presented oral care composition contains amorphous quartz having the particle size characterised by the fact that D90 makes less than 50 mcm, and one or more active substance is an antibacterial agent, and specified in a group consisting of cationic antibacterial agents specified in a group consisting of chlorhexidine, cetylpyridinium chloride, bisguanides, benzalkonium chloride, benzethonium chloride; metal salts specified in a group consisting of bivalent stanum salts, zinc salts, copper salts; and combinations thereof.

EFFECT: using amorphous quartz having good compatibility with the above antibacterial properties as a part of the product, particularly a tooth paste, provides storage-stable and high availability of the antibacterial product alongside with the effective and safe cleansing and polishing of the dental tissue.

8 cl, 2 ex, 30 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to preparing a mouthwash containing water, a moisturiser in the amount of 5 wt % to 15 wt % and 0.01 wt % - 5 wt % of a compound presented by the structure (III), wherein R1 and R2 are independently specified in hydrogen atoms, C2-6 -alkenyl group and C1-6 - alkyl group; and the compound (III) is dissolved in ethanol.

EFFECT: invention involves a method for reducing bacterial population on the substrate by substrate contact with the composition containing the compound of the structure (IV), wherein R1 and R2 are independently specified in the substituted or unsubstituted methyl group, substituted or unsubstituted ethyl group and substituted or unsubstituted butyl group.

11 cl, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to capsule suspensions prepared by coacervation, and to methods for reducing leakage of the capsule content in such suspensions during storage. Substance of the method for reducing leakage of the capsule content consists in storage of the capsules prepared by coacervation, in the capsule suspension containing min. 20 wt %, a moisturiser, which is at least a moisturiser specified in sorbitol, glycerol, polyethylene glycol, propylene glycol, xylitol, erythritol or betaine. What is also presented is the above capsule suspension containing at least one capsule prepared by coacervation and at least 20 wt % of the above moisturiser.

EFFECT: using the above moisturiser in the amount of min 20 wt % provides reducing the leakage rate of the capsule content.

21 cl, 4 tbl, 2 ex, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a method for preparing a soft tissue filler composition, involving the stages as follows: preparing a HA (hyaluronic acid) ingredient cross-linked with at least one cross-linking agent specified in a group of 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis(2.3-epoxypropoxy)butane, 1,4-bisglycidyl dioxybutane. 1,2-bis(2,3-epoxypropoxy)ethylene and 1-(2,3-epoxypropyl)-2,3 epoxycyclohexane; reducing pH of the above HA ingredient to more than approximately 7.2; and adding the solution containing lidocaine to the above HA ingredient having reduced pH as specified above to prepare the above soft tissue filler composition.

EFFECT: invention provides better stability and cohesion.

12 cl, 5 ex, 3 tbl, 9 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to oral hygiene and personal hygiene compositions, and more specifically to compositions comprising a film immersed into a carrier, wherein the film contains a relatively high concentration of a zinc compound. According to the invention, the oral hygiene composition comprises the film immersed into the carrier wherein the zinc compound is found in the amount from approximately 35 wt % to approximately 60 wt %.

EFFECT: increase in the solid content in the film enhances the active compound delivery per a unit area that is important to achieve the highest delivery efficiency.

23 cl, 2 dwg, 14 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to an antioxidant preparation containing 5-aminosalicylic acid, quercetic and 5% alcoholic extract of propolis as an active agent, and Lutrol F127, Cremophore RH-40 and glycerol as a base in certain proportions.

EFFECT: preparation has the pronounced antioxidant action and is recommended for the correction of the free-radical oxidation processes.

1 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to pharmacology, neurology and cell engineering. What is described is using Napelline as a cerebroprotective agent. The mode of action of the agent is activation of cerebral neural stem cells.

EFFECT: invention achieves extending the range of high-effective cereroprotective agents.

3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely preparing an agent of hindu lotus seed extract (Nelumbo nucifera) possessing immunotropic and antioxidant activity. The agent possessing immunotropic and antioxidant activity prepared by extraction of hindu lotus seed extract (Nelumbo nucifera) in 50% ethanol in a Soxhlet extraction apparatus in the specific proportions.

EFFECT: agent possesses manifested immunotropic and antioxidant activity.

6 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and may be used for prevention of acute postoperative pancreatitis. For this purpose, the underlying background therapy is combined with intravenous bolus administration of dalargin 0.002 g and the antioxidant thioctic acid depending on a risk level of the complication measured in terms of the area of intervention in abdominal operations. A high risk level requires thioctic acid to be administered in a dose of 600 mg intravenously drop-by-drop 1 hour before the operation and on the following day, and thioctic acid in a dose of 300 mg on the third day intravenously drop-by-drop. In a moderate risk level thioctic acid is administered intravenously drop-by-drop in a dose of 600 mg 1 hour before the operation and in a dose of 300 mg on the following day. And in a low risk level, thioctic acid is administered intravenously drop-by-drop in a dose of 300 mg 1 hour before the operation.

EFFECT: method enables the more effective prevention of acute postoperative pancreatitis ensured by the combined use of drugs with antisecretory and antioxidant activity.

2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and represents application of calix[6]arene of formula (1A) or (1B) for treatment of skin contamination with uranium, plutonium or americium.

EFFECT: invention ensures stability of calix[6]arenes with actinides in static mode.

5 cl, 4 ex, 11 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to otolaryngology. Dissection of adhesion between lateral and medial wall of nasal cavity is performed by heated distal end of semiconductor laser lightguide in contact way in continuous mode. Power of laser radiation is 8.5 W. Time of exposure from 5 to 15 seconds. 1% solution of emoxipin is introduced into zone of coagulation necrosis in form of injection. Lighting of necrosis zones is carried out by means of laser physiotherapeutic apparatus "LA-2". Course of treatment constitutes 5-7 days.

EFFECT: method ensures recovery of nasal respiration, prevents possibility of recurrence development.

1 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to otorhinolaryngology. A heated distal flat end of a light guide of ATKUS-15 semi-conductor laser is used to excise a cicatrical diaphragm in a contact continuous mode. Laser radiating power is 8.5-9 Wt. An exposure length is 30 to 60 seconds. That is followed by introducing 1% emoxipin 1 ml into a formed coagulation necrosis. The necrotic areas are exposed to LA-2 physiotherapeutic laser apparatus. The therapeutic course makes 7 days.

EFFECT: method provides the nasal breathing recovery, prevents any possible recurrences.

1 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a cardioprotective and antioxidant drug. The cardioprotective and antioxidant drug prepared by the three-staged extraction of ground tick trefoil (Hedysarum alpinum) herb in aqueous-alcoholic solutions to be randomly agitated at room temperature in a blacked-out place under certain circumstances; then the fractions are poured out and dried in a thermostat.

EFFECT: drug prepared by the above method possesses no side action and shows manifested cardioprotective and antioxidant action.

2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel chemically stable antioxidant compound which contains a lipophilic cationic moiety linked by a linking moiety to an antioxidant molecule and an anionic component for said cationic moiety, where the antioxidant compound is a mitoquinone, selected from: 10-(6'-ubiquinone)propyltriphenylphosphonium, 10-(6'-ubiquinonyl)pentyltriphenylphosphonium, 10-(6'-ubiquinonyl)decyltriphenylphosphonium, and 10-(6'-ubiquinonyl)pentadecyltriphenylphosphonium, having general formula I: or quinol form thereof, where R1, R2 and R3 denote CH3, the C atom in (C)n is saturated and n equals 3, 5, 10 or 15, and Z denotes an anionic component which is selected from a group consisting of methanesulphonate and ethanesulphonate. The invention also relates to a pharmaceutical composition for reducing oxidative stress in a cell, containing said compound and optionally containing β-cyclodextrin, a method of reducing oxidative stress in a cell and a method of producing an antioxidant compound.

EFFECT: improved properties of compounds.

25 cl, 31 dwg, 13 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound - 5-hydroxy-6-methyl-1-(thietanyl-3)pyrimidine-2,4(1H,3H)-dione of formula , which inhibits generation of active forms of oxygen and has antioxidant activity.

EFFECT: improved properties of compounds.

2 cl, 1 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cosmetology and represents an oil-in-water emulsion sun-protection cosmetic composition containing: (A) 1 to 7.5 wt % of octyl methoxycinnamate; (B) 1 to 4 wt % of tret-butyl methoxydibenzoyl methane and/or 2-hydroxy-4-methoxybenzophenone; (C) 0.5 to 3 wt % of a polyoxyethylene/polyoxyalkylene alkyl ester block copolymer; (D) 10 wt % or more of a nonpolar oil relative to the total amount of the oil component; wherein an average emulsion particle diameter makes not more than 700 nm.

EFFECT: invention provides developing the stable sun-protection composition having improved ultraviolet blocking capability and good usability.

4 ex, 4 tbl

Up!