Nitroxyl polyphenol derivatives, method for preparing the same, and use thereof

Abstract

The object of the present invention is a nitroxyl polyphenol derivative of formula (i), wherein Q is a group derived from polyphenol; L is an ester linking group containing 1 to 3 carbon atoms; A is a 5- or 6-membered heterocyclic group containing one nitrogen atom in the form of a nitroxyl radical (NO·), and both carbon atoms adjacent to the nitroxyl radical are independently substituted with one or two C1-C3 alkyl groups; n is an integer from 1 to 5. The object of the present invention is also a method for preparing the derivative defined above, and its use as an antioxidant, in particular as an anti-aging agent. Q-(L-A) n (i)

Description

Technical Field

[0001] The object of the present invention is nitroxyl polyphenol derivatives, a method for preparing the same, and their use as antioxidants, particularly as anti-aging agents, in beauty, pharmacy and medicine.

Background Art

[0002] Cellular senescence is a major cellular process that occurs in adult organisms and is also necessary for normal organ formation (embryonic development). Cellular senescence is associated with all medical conditions defined as age-related diseases (e.g., type 2 diabetes, atherosclerosis, neurodegenerative diseases) and is accompanied by an increase in inflammation in tissues and organs. With the progress of civilization, exposure to compounds that accelerate aging has increased. Furthermore, methods used for therapeutic purposes (radiotherapy and chemotherapy) further accelerate the senescence of normal cells as a side effect. Senescence is associated with excessive exposure to ultraviolet light (photoaging of the skin). An increase in the number of senescent cells is observed after transplantation. Preventing or reducing the effects of cellular senescence may help maintain the health and good performance of the body for a longer period and may contribute to preventing and / or eliminating the effects of age-specific diseases and the undesirable effects of treatments.

[0003] Currently, there is an ongoing need for novel compounds with potential anti-aging activity, and polyphenols are a very promising class of compounds. However, the use of these compounds is associated with many limitations, such as limited bioavailability and the need for high concentrations to ensure an effective action.

[0004] In connection with the above, it is reasonable to search for novel derivatives based on polyphenols, the use of which would not have the aforementioned drawbacks. The prior art describes derivatives of resveratrol and curcumin containing amino acids (e.g., phenylalanine, threonine, leucine, or proline) added as a result of an esterification reaction (J.R. Manjunatha, B.K. Bettadaiah, P.S. Negi, and P.S. Srinivas, Food Chemistry, Vol. 139, No. 1 - 4, 15.08.2013, pp. 332 - 338, and A. Mattarei, M. Azzolini, M. La Spina, M. Zoratti, C. Paradisi, L. Biasutto, Scientific Reports, 5, 14.10.20215, pp. 1 - 11). However, information regarding the antioxidant / anti - aging activity of the aforementioned derivatives is not found in the cited publications.

[0005] EP2189155A1 simply discloses generally that a composition showing anti - aging activity against human skin may contain polyphenols as antioxidants.

Summary of the Invention

Problems to be Solved by the Invention

[0006] Therefore, an object of the present invention was to design and synthesize polyphenol derivatives showing antioxidant activity, particularly anti - aging activity, and to solve the problem that bioavailability is low and it is necessary to use high - concentration compounds.

Means for Solving the Problems

[0007] The subject of the present invention is a nitroxyl polyphenol derivative of the following formula: Q-(L - A) n In the formula, Q is a group derived from polyphenol; L is an ester - linking group containing 1 to 3 carbon atoms; A is a 5- or 6-membered heterocyclic group containing one nitrogen atom in the form of a nitroxyl radical (NO·), and both carbon atoms adjacent to the nitroxyl radical are independently substituted with one or two C1-C3 alkyl groups; n is an integer from 1 to 5.

[0008] Preferably, Q is a derivative of curcumin, quercetin, genistein or daidzein, and L is an ester linking group of the formula -OC(O)-(CH2) x -, where x is an integer from 0 to 2. More preferably, Q is a derivative of curcumin, and L is an ester linking group of the formula -OC(O)-(CH2) x -, where x is an integer from 0 to 2.

[0009] Also preferably, Q is a derivative of resveratrol. Preferably, L in the nitroxyl derivative of resveratrol is an ester linking group of the formula -(CH2) x -C(O)O- or -OC(O)-(CH2) x -, where x is an integer from 0 to 2. More preferably, L is an ester linking group of the formula -(CH2) x -C(O)O-, where x is an integer from 0 to 2.

[0010] Preferably, A is a piperidine-1-oxyl group in which both carbon atoms adjacent to the nitroxyl radical are independently substituted with two C1-C3 alkyl groups. More preferably, A is a 2,2,6,6-tetramethylpiperidine-1-oxyl group.

[0011] Preferably, n is 1 or 2. Preferably, the aforementioned nitroxyl polyphenol derivative is a derivative of the following formula.

[0012]

Chemical formula

[0013] Preferably, the aforementioned nitroxyl polyphenol derivative is a derivative of the following formula.

[0014]

Chemical formula

[0015] Preferably, the aforementioned nitroxyl polyphenol derivative is a derivative of the following formula.

[0016]

Chemical formula

[0017] An object of the present invention is a method for preparing a nitroxyl polyphenol derivative of the following formula: Q-(L-A) n wherein Q is a group derived from a polyphenol; L is an ester linking group of the formula -OC(O)-(CH2) x -, wherein x is an integer from 0 to 2; A is a 5- or 6-membered heterocyclic group containing one nitrogen atom in the form of a nitroxyl radical (NO·), and both carbon atoms adjacent to the nitroxyl radical are independently substituted with one or two C1-C3 alkyl groups; n is an integer from 1 to 5; the method includes reacting a polyphenol with a 5- or 6-membered heterocyclic compound containing one nitrogen atom in the form of a nitroxyl radical (NO·), and both carbon atoms adjacent to the nitroxyl radical are independently substituted with one or two C1-C3 alkyl groups, and one of the other carbon atoms is substituted with a carboxyl group of the general formula -(CH2) x -C(O)OH, wherein x is an integer from 0 to 2; the reaction is carried out in an organic solvent at a temperature in the range of -10 to 30 °C in the presence of a deprotonating agent for the hydroxy group and an activating agent for the carboxyl group.

[0018] Preferably, the reaction is carried out for 48 to 72 hours. Preferably, both carbon atoms adjacent to the nitroxyl radical are independently substituted with two C1-C3 alkyl groups, and one of the other carbon atoms is of the general formula -(CH2) x - substituted with a carboxy group of -C(O)OH, where x is an integer from 0 to 2, a piperidine-1-oxyl compound, more preferably a 4-carboxy-2,2,6,6-tetramethylpiperidine-1-oxyl compound, in which both carbon atoms adjacent to the nitroxyl radical are independently substituted with one or two C1-C3 alkyl groups, and one of the other carbon atoms is of the general formula -(CH2) x - substituted with a carboxy group of -C(O)OH, where x is an integer from 0 to 2, and is used as a 5- or 6-membered heterocyclic compound containing one nitrogen atom in the form of a nitroxyl radical (NO·).

[0019] Preferably, 4-dimethylaminopyridine is used as a deprotonating agent for the hydroxy group. Preferably, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,N'-dicyclohexylcarbodiimide, more preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, is used as an activating agent for the carboxy group.

[0020] Preferably, an aprotic polar solvent, more preferably dichloromethane, is used as the organic solvent. Preferably, a keto group-containing polyphenol such as curcumin, quercetin, genistein or daidzein, more preferably curcumin, is used as the polyphenol.

[0021] Preferably, when a keto group-containing polyphenol is used, the reaction is carried out at a temperature in the range from -10°C to a temperature lower than room temperature, more preferably in the range from -10°C to 0°C. Preferably, resveratrol is used as the polyphenol.

[0022] Preferably, when resveratrol is used, the reaction is carried out at a temperature in the range from room temperature to 30 °C. The object of the present invention is also a method for preparing a nitroxyl polyphenol derivative of the following formula: Q-(L-A) n wherein, Q is a derivative of resveratrol; L is an ester linking group of the formula -(CH2) x -C(O)O-, wherein x is an integer from 0 to 2; A is a 5- or 6-membered heterocyclic group containing one nitrogen atom in the form of a nitroxyl radical (NO·), and both carbon atoms adjacent to the nitroxyl radical are independently substituted with one or two C1-C3 alkyl groups; n is an integer of 1 or 2; the method comprising a) reacting a benzaldehyde derivative substituted with at least one hydroxy group with a silylating agent to protect at least one hydroxy group, the reaction being carried out at a temperature in the range from 0 °C to room temperature in an organic solvent in the presence of an activator for the silylating agent; b) reacting the protected benzaldehyde derivative prepared in step a) with an alkyltriphenylphosphonium halide to convert the aldehyde group to an alkene group, the reaction being carried out at a temperature in the range from -78 °C to room temperature in an organic solvent in the presence of a strong base; c) subjecting the alkene group in the derivative prepared in step b) to a coupling reaction with a halogenated benzene derivative substituted with at least one ester group of the formula -(CH2) x -C(O)OR, wherein R is a C1-C3 alkyl group and x is an integer from 0 to 2; the reaction being carried out at a temperature in the range from room temperature to 190 °C in an optional organic solvent in the presence of a catalyst, a phosphonium ligand and a base; d) Reacting the derivative prepared in step c) with a reducing agent to reduce at least one ester group to at least one alcohol group, wherein the reaction is carried out at a temperature in the range of -78 °C to room temperature in an organic solvent; e) Reacting the derivative prepared in step d) with an oxidizing agent to oxidize at least one alcohol group to at least one aldehyde group, wherein the reaction is carried out at a temperature in the range of 0 °C to room temperature in an organic solvent; f) Reacting the derivative prepared in step e) with an oxidizing agent to oxidize at least one aldehyde group to at least one acidic group, wherein the reaction is carried out at a temperature in the range of 0 °C to room temperature in an organic solvent or a mixture of organic solvents; g) Reacting the derivative prepared in step f) with a 5- or 6-membered heterocyclic compound containing one nitrogen atom in the form of a nitroxyl radical (NO·) to prepare a nitroxyl polyphenol derivative containing at least one protected hydroxy group, wherein both carbon atoms adjacent to the nitroxyl radical are independently substituted with one or two C1-C3 alkyl groups, and one of the other carbon atoms is substituted with a hydroxy group, and the reaction is carried out at a temperature in the range of room temperature to 30 °C in an organic solvent in the presence of a deprotonating agent for the hydroxy group and an activating agent for the carboxy group; h) Reacting the nitroxyl polyphenol derivative containing at least one protected hydroxy group prepared in step g) with a reagent functioning as a source of fluoride ions to deprotect at least one hydroxy group, wherein the reaction is carried out at a temperature in the range of 0 °C to room temperature in an organic solvent. The method comprises the steps above.

[0023] Preferably, in step a), hydroxy or dihydroxybenzaldehyde is used as a benzaldehyde derivative. Preferably, in step a), an alkylsilyl halide, more preferably tert-butyldimethylsilyl chloride, is used as the silylating agent.

[0024] Preferably, in step a), imidazole, a mixture of triethylamine and 4-dimethylaminopyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene, or a mixture of 18-crown-6 ether and potassium hydride, more preferably imidazole, is used as the activator for the silylating agent.

[0025] Preferably, the reaction in step a) is carried out for 4 to 24 hours. Preferably, in step b), methyltriphenylphosphonium bromide is used as the alkyltriphenylphosphonium halide.

[0026] Preferably, the reaction in step b) is carried out for 4 to 24 hours. Preferably, in step b), n-butyllithium, lithium diisopropylamide, potassium tert-butoxide, or potassium bis(trimethylsilyl)amide, more preferably n-butyllithium, is used as the strong base.

[0027] Preferably, in step c), ethyl 4-iodobenzoate or dimethyl 5-bromoisophthalate is used as the halogenated benzene derivative substituted with at least one ester group of the formula -(CH2) x -C(O)OR, where R is a C1-C3 alkyl group and x is an integer from 0 to 2.

[0028] Preferably, in step c), a palladium(0) or (II) complex, more preferably palladium acetate, is used as the catalyst. Preferably, in step c), tri(o-tolyl)phosphine is used as the phosphonium ligand.

[0029] Preferably, in step c), triethylamine is used as the base. Preferably, in step c), the organic solvent is the base used. Preferably, the reaction in step c) is carried out at a temperature in the range of 50 to 90 °C.

[0030] Preferably, the reaction in step c) is carried out for 20 to 40 hours. Preferably, in step d), diisobutylaluminum hydride or lithium aluminum hydride, more preferably diisobutylaluminum hydride, is used as the reducing agent.

[0031] Preferably, the reaction in step d) is carried out at a temperature in the range of -78 °C to -50 °C. Preferably, the reaction in step d) is carried out for 1 to 24 hours.

[0032] Preferably, in step e), pyridinium dichromate, pyridinium chlorochromate, oxalyl chloride, triethylamine in dichloromethane, tetrapropylammonium perruthenate, or 4-methylmorpholine 4-oxide in tetrahydrofuran, more preferably pyridinium dichromate, is used as the oxidizing agent.

[0033] Preferably, the reaction in step e) is carried out for 2 to 18 hours. Preferably, the reaction in step e) is carried out at a temperature in the range from 10 °C to room temperature. Preferably, in step f), an NaClO2 and NaH2PO4·H2O solution is used as the oxidizing agent.

[0034] Preferably, in step f), tert-butanol, tetrahydrofuran or 2-methylbut-2-ene or a mixture thereof is used as the organic solvent. Preferably, the reaction in step f) is carried out for 2 to 8 hours.

[0035] Preferably, the reaction in step f) is carried out at a temperature in the range of 0 to 3 °C. Preferably, in step g), a hydroxypiperidine-1-oxyl compound in which both carbon atoms adjacent to the nitroxyl radical are independently substituted with two C1-C3 alkyl groups, more preferably a 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl compound, is a 5- or 6-membered heterocyclic compound containing one nitrogen atom in the form of a nitroxyl radical (NO·), in which both carbon atoms adjacent to the nitroxyl radical are independently substituted with one or two C1-C3 alkyl groups, and one of the other carbon atoms is substituted with a hydroxy group.

[0036] Preferably, in step g), 4-dimethylaminopyridine is used as a deprotonating agent for the hydroxy group. Preferably, in step g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,N'-dicyclohexylcarbodiimide, more preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, is used as an activator for the carboxy group.

[0037] Preferably, the reaction in step g) is carried out for 16 to 52 hours. Preferably, in step h), tetra-n-butylammonium fluoride is used as a reagent serving as a source of fluoride ions.

[0038] Preferably, the reaction in step h) is carried out for 1 to 5 hours. Preferably, in steps a) to e), g) and h), an aprotic solvent, more preferably dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile, or ether, is used as the organic solvent.

[0039] The subject of the present invention is also the use of the aforementioned nitroxyl polyphenol derivatives as antioxidants, preferably as anti-aging agents. The derivatives of the present invention are a combination of two compounds, namely a polyphenol and a nitroxyl radical-containing compound. It has been shown that both polyphenols alone and nitroxyl radical-containing compounds alone have a certain degree of antioxidant activity. However, the resulting derivatives have much better activity than the components used as their structural units. The derivatives of the present invention delay the aging of cells caused by oxidants that increase the level of reactive oxygen species due to their antioxidant activity. These exhibit biological activity effects on a number of molecular targets within cells. The antioxidant properties of the derivatives of the present invention can be modified by changing the number of parent molecules or substituted / free hydroxy groups. For example, by leaving at least one free OH group in the resveratrol derivative, a compound that is active over a wide pH range can be obtained, because the nitroxyl radical exhibits its effect at acidic pH, while the free OH group of resveratrol exhibits its effect at alkaline pH. Furthermore, the presence of a keto moiety (>C=O to =C-OH) that can be converted to an enol moiety affects the antioxidant properties of derivatives of curcumin, quercetin, genistein, and daidzein. Therefore, it is not important to leave free OH groups in these derivatives. Furthermore, the type of nitroxyl radical-containing group incorporated is also very important for the antioxidant properties. A heterocyclic group having a substituent on the carbon atom adjacent to the nitrogen atom in the form of a nitroxyl radical has been shown to be most preferred because it enhances the stability of the radical within the cell and prevents conversion to hydroxylamine.

[0040] The research results regarding the antioxidant / anti-aging properties of the derivatives of the present invention on the induction of aging of human skin fibroblasts are shown in FIGS. 1 to 6.

Brief Description of the Drawings

[0041]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

DETAILED DESCRIPTION OF THE INVENTION

[0042] The abbreviations and terms used in this specification, drawings and claims have the meanings commonly understood by those skilled in the technical field to which the present invention pertains. However, for clarity, the following terms and abbreviations should be understood as follows.

[0043] The term "a 5- or 6-membered heterocyclic group (heterocyclic compound) containing one nitrogen atom in the form of a nitroxyl radical (NO·)" means a saturated, unsaturated or aromatic 5- or 6-membered heterocyclic group containing one nitrogen atom in the form of a nitroxyl radical, such as a piperidine-1-oxyl group, a pyridine-1-oxyl group, a pyrrolidine-1-oxyl group, a pyrroline-1-oxyl group and a pyrrole-1-oxyl group, etc.

[0044] The term "group derived from a polyphenol" means a polyphenol molecule in which one to all of the hydroxy groups can be substituted with a 5- or 6-membered heterocyclic group as defined above containing one nitrogen atom in the form of a nitroxyl radical, such as resveratrol, curcumin, quercetin, genistein, and daidzein, etc.

[0045] The term "ester linking group containing 1 to 3 carbon atoms" means a group of the formula -(CH2) x -C(O)O- or -OC(O)-(CH2) x - where x is an integer from 0 to 2, that is, groups such as -(CH2)2-C(O)O-, -CH2-C(O)O-, -C(O)O-, -OC(O)-(CH2)2-, -OC(O)-CH2- or -OC(O)-. The type of ester linking group depends on the method for preparing the nitroxyl polyphenol derivative.

[0046] The term "C1-C3 alkyl group" means a methyl, ethyl or propyl group. The term "both carbon atoms adjacent to the nitroxyl radical are independently substituted with one or two C1-C3 alkyl groups" means that each of the two carbon atoms adjacent to the nitroxyl radical may be substituted with a different or the same number of C1-C3 alkyl groups, where the groups may be the same or different. Preferably, both carbon atoms are substituted with two C1-C3 alkyl groups.

[0047] Room temperature (rt) means a temperature in the range of 18 to 25 °C. THF: Tetrahydrofuran CH2Cl2: Dichloromethane 4-carboxy-TEMPO: 4-carboxy-2,2,6,6-tetramethylpiperidine-1-oxyl compound 4-hydroxy-TEMPO: 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl compound TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl compound EDCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide DMAP: 4-Dimethylaminopyridine Pd(OAc)2: Palladium(II) acetate DCC: N,N'-Dicyclohexylcarbodiimide TBSCl: tert-Butyldimethylsilyl chloride CH3PPh3Br: Methyltriphenylphosphonium bromide Et3N: Triethylamine ToP: Tri(o-tolyl)phosphine DIBALH: Diisobutylaluminum hydride TBAF: Tetra-n-butylammonium fluoride PDC: Pyridinium dichromate t-BuOH: tert-Butanol nBuLi: n-Butyllithium EtOAc: Ethyl acetate Et2O: Diethyl ether MeOH: Methanol CHCl3: Chloroform The present invention is illustrated by the following non-limiting examples. Unless otherwise specified, known reaction methods, commercially available apparatuses, and reagents generally used in the technical field to which the present invention pertains were used in the following examples.

[0048] Example 1: Synthesis of nitroxyl polyphenol derivatives in which all hydroxy groups are substituted with nitroxyl radical-containing groups.

[0049]

Chemical formula

[0050] In a round-bottom flask under an argon atmosphere, curcumin (78.5 mg, 0.21 mmol), 4-carboxy-TEMPO (158.4 mg, 0.79 mmol), EDCI (86.1 mg, 0.55 mmol) as an activator for the carboxy group, and DMAP (30.3 mg, 0.25 mmol) as a deprotonating agent for the hydroxy group were dissolved in 35 mL of dichloromethane and stirred at -4 °C for 48 hours. Also, the reaction was carried out using DCC instead of EDCI as an activator for the carboxy group. After 2 days, the product was purified by column chromatography using CH2Cl2:MeOH (20:1) as the eluent and silica gel as the stationary phase. In the subsequent step, the product was purified by preparative chromatography using CHCl3:MeOH (25:2) as the eluent. The obtained product was eluted from the silica gel using methanol to obtain compound H5 in the form of an orange solid (72.5 mg, 46%).

[0051] The synthesis of the resveratrol derivative was carried out in the same manner. In a round-bottom flask under an argon atmosphere, resveratrol (100 mg, 0.44 mmol), 4-carboxy-TEMPO (562.4 mg, 2.6 mmol), EDCI (238.1 mg, 1.53 mmol) as an activator for the carboxy group, and DMAP (26.8 mg, 0.22 mmol) as a deprotonating agent for the hydroxy group were dissolved in 35 mL of dichloromethane and stirred at room temperature for 48 hours. Subsequently, the product was purified using the method described above.

[0052] The aforementioned reaction is carried out at a temperature in the range of -10°C to 30°C. However, the experiments conducted have shown that in the case of polyphenols containing a keto group (-C(O)-) (curcumin, quercetin, genistein, and daidzein), it is preferable to carry out the reaction at a temperature below room temperature (i.e., a temperature from -10°C to below room temperature (about 17°C)), and more preferably at a temperature in the range of -10°C to 0°C. On the other hand, in the case of polyphenols without a keto group (resveratrol), the aforementioned wider temperature range (i.e., -10°C to 30°C) can be used without problems, and considering the more rapid progress of the reaction, the preferred range is from room temperature to 30°C. The difference in the temperature used is due to the keto-enol equilibrium. The keto-enol equilibrium shifts to the enol form at room temperature, which may lead to the esterification of the enol group and the substitution of the nitroxyl radical at this position. As a result, a mixture of different products may be obtained. Therefore, in the case of polyphenols containing a keto group, it is important to use a lower temperature at which the keto-enol equilibrium does not shift to the enol form.

[0053] Regarding the reaction time, when it is extended to 72 hours, the yield of the reaction increases. In the aforementioned synthesis, a 4-carboxy-2,2,6,6-tetramethylpiperidine-1-oxyl compound was used as a heterocyclic compound containing one nitrogen atom in the form of a nitroxyl radical. However, other compounds containing a nitroxyl radical that are derivatives of piperidine, pyridine, pyrrolidine, pyrroline, and pyrrole, in which both carbon atoms adjacent to the nitrogen atom in the form of a nitroxyl radical are independently substituted with one or two (the same or different) methyl, ethyl, or propyl groups, and one of the other carbon atoms is substituted with a carboxy group of the formula -C(O)OH, -CH2C(O)OH, or -(CH2)2C(O)OH, can also be used under the same conditions.

[0054] In the aforementioned reaction, any polar aprotic solvent can be used. When the above method is used with slight modifications within the knowledge of those skilled in the art, any polyphenol derivative in which all hydroxy groups are replaced with nitroxyl radical-containing groups can be obtained. As described above, when selecting reaction parameters, attention should be paid to whether there is a keto group in the polyphenol.

[0055] Example 2: Synthesis of nitroxyl resveratrol derivatives containing at least one free hydroxy group. a) Synthesis of nitroxyl resveratrol derivatives containing two free hydroxy groups:

[0056]

Chemical formula

[0057] Step a): Imidazole (5.923 g, 86.88 mmol) as an activator for the silylating agent was added to a stirred suspension of dichloromethane (40 mL) containing 3,5-dihydroxybenzaldehyde (1.2 g, 14.48 mmol). After 15 minutes, the solution became clear, which was cooled to 0 °C, and TBSCl (5.019 g, 33.30 mmol) was added as the silylating agent. The reaction mixture was returned to room temperature and stirred for 14 hours. Subsequently, the mixture was poured into 200 mL of cold water and extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine, dehydrated over anhydrous MgSO4, and the solvent was evaporated. The product was purified by column chromatography on silica gel using an EtOAc:hexane (1:10) system as the eluent. Compound 2 in the form of a white solid was obtained (5.033 g, 95%).

[0058] In the aforementioned reaction, the silylating agent is added at about 0 °C. However, the subsequent reaction is carried out at a temperature higher than 0 °C but below room temperature. In this reaction, TBSCl was used as the silylating agent. However, other alkylsilyl halides commonly used for protecting hydroxy groups can also be used in this reaction.

[0059] Furthermore, imidazole, which is used as an activator for the silylating agent, can be replaced with other reagents such as a mixture of triethylamine and 4-dimethylaminopyridine, a mixture of triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene, or a mixture of 18-crown-6 ether and potassium hydride. Additionally, other organic aprotic solvents such as dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran, or toluene can also be used as the solvent.

[0060] The reaction is carried out for 4 to 24 hours while monitoring the progress of the reaction using thin-layer chromatography (TLC). The reaction time specified in the examples corresponds to the point at which no significant change occurred on the TLC plate in the system thereafter.

[0061] Step b): Strong base (n-BuLi, 1.6 M in THF, 10.306 mL, 16.5 mmol) was added dropwise at -78 °C to a suspension of anhydrous THF (18 mL) containing CH3PPh3Br (5.890 g, 16.5 mmol). After 20 minutes, a solution of aldehyde 2 (5.033 g, 13.75 mmol) in anhydrous THF (9.5 mL) was added using a cannula. The reaction mixture was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction was quenched by adding 30 mL of brine. This was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with water, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by column chromatography on silica gel using an Et2O:hexane (1:100) system as the eluent. Compound 3 was obtained in the form of a colorless oil (4.611 g, 92%).

[0062] The reagents in the aforementioned reaction are added at a temperature of approximately -78 °C. However, the subsequent reaction can be carried out at temperatures in the range from -78 °C to room temperature. In the aforementioned reaction, any alkyltriphenylphosphonium halide commonly used in the reaction for converting an aldehyde group to an alkene group can be used. Further, instead of n-BuLi, other strong bases such as lithium diisopropylamide, potassium tert-butoxide, or potassium bis(trimethylsilyl)amide can also be used. Further, toluene and dichloromethane are also suitable as solvents.

[0063] If analysis using TLC chromatography reveals that the reaction is not yet complete, the stirring of the reaction mixture at room temperature is extended to 24 hours. Step c): In a dry vial containing a magnetic stir bar, under an argon atmosphere, compound 3 (1 g, 2.73 mmol), ethyl 4-iodobenzoate (0.73 g, 2.60 mmol), Pd(OAc)₂ catalyst (0.031 g, 0.14 mmol), and tri(o-tolyl)phosphine (ToP) ligand (0.063 g, 0.21 mmol) were placed in anhydrous triethylamine (4.5 mL). The mixture was stirred in a sealed vial at 60 °C for 2 hours, followed by 24 hours at 80 °C. After cooling, the mixture was diluted by adding CH₂Cl₂ and poured into water. The aqueous layer was extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO₄, and the solvent was evaporated. The product was purified by silica gel column chromatography using an Et₂O:hexane (1:9) system as the eluent. Compound 4 in the form of a white solid was obtained (0.97 g, 71%).

[0064] In the above reaction, the formula -(CH₂) x-C(O)OR (wherein R is a C1-C3 alkyl group and x is an integer from 0 to 2), the type of the halogenated benzene derivative substituted with at least one ester group depends on the number of OH groups substituted with nitroxyl radical-containing groups in the final polyphenol derivative and the type of the linking group that links the nitroxyl radical-containing group to the polyphenol molecule. When the final derivative contains one nitroxyl radical-containing group, the benzene derivative is a derivative containing one ester group; when the final derivative contains two nitroxyl radical-containing groups, the benzene derivative is a derivative containing two ester groups (Example 2a below). Further, the ester group may be a -C(O)OR, -CH2C(O)OR or -(CH2)2-C(O)OR group, wherein R is methyl, ethyl or propyl. Generally, the reaction conditions are the same regardless of the type of the halogenated benzene derivative used.

[0065] In the above reaction, other palladium(0) or (II) complexes can be used as the catalyst, and other phosphonium ligands commonly used in the coupling reaction between an alkene group and a benzene derivative can be used as the ligand.

[0066] In the reaction, triethylamine is used as the base. In this case, triethylamine is also the solvent. However, the reaction can also be carried out in other organic aprotic solvents such as dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile, or ether.

[0067] In the above reaction, a temperature in the range of preferably 50°C to 90°C, that is, an initial temperature of 60°C and subsequently 80°C was used. However, according to the generally available chemical knowledge, the palladium-catalyzed coupling reaction can be carried out at a temperature in the range of room temperature to 190°C.

[0068] Step d): A solution of compound 4 (2 g, 4.0 mmol) in anhydrous CH2Cl2 (60 mL) was cooled to -78 °C, and DIBALH (1 M in CH2Cl2, 12 mL, 12.0 mmol) was added dropwise as a reducing agent. The mixture was stirred at this temperature for 2.5 h. The reaction was quenched by adding potassium sodium tartrate solution (1 M, 3 mL), HCl (1 M, 3 mL), and water (12 mL). The mixture was left for 2 h (until it reached room temperature). Subsequently, the mixture was poured into 30 mL of water and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 60 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an EtOAc:hexane (1:4) system as the eluent. Compound 5 in the form of a white solid was obtained (1.62 g, 86%).

[0069] In the above reaction, similar results can be obtained when lithium aluminum hydride is used as the reducing agent. Furthermore, the reaction can also be carried out in other aprotic solvents such as dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile, or ether.

[0070] The reaction is carried out for 1 - 24 h while monitoring the progress of the reaction using thin layer chromatography (TLC). The reaction time specified in the examples corresponds to the point at which no significant change occurs on the TLC plate in the system thereafter.

[0071] The above-mentioned reaction is preferably carried out at a temperature selected from the range of -78 °C to -50 °C because the reaction between DIBALH and compound 4 proceeds rapidly and there is no need to use a higher temperature. However, according to generally available chemical knowledge, the reduction reaction from an ester group to an alcohol group can be carried out at a temperature in the range of -78 °C to room temperature. Considering the high reactivity of the reducing agent, it is a necessary condition to add the reducing agent at the reduction temperature.

[0072] Step e): Compound 5 (1.62 g, 3.4 mmol) was dissolved in CH2Cl2 (18 mL), and pyridinium dichromate (PDC) (3.20 g, 8.5 mmol) as an oxidizing agent was added in two portions. The reaction was carried out at room temperature for 6 hours. Subsequently, this was filtered through a celite layer, and the filtrate was concentrated using an evaporator. The product was purified by silica gel column chromatography using an EtOAc:hexane (5:95) system as an eluent. Compound 6 in the form of a white solid was obtained (1.484 g, 92%).

[0073] In the above reaction, pyridinium dichromate (PDC) was used as an oxidizing agent. However, in this reaction, other oxidizing agents generally used to oxidize an alcohol group to an aldehyde group, such as pyridinium chlorochromate, oxalyl chloride, triethylamine in dichloromethane, tetrapropylammonium perruthenate in tetrahydrofuran, or 4-methylmorpholine 4-oxide, etc., can be used. Further, as the solvent, other aprotic solvents known in the art, such as dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile, or ether, etc., can be used.

[0074] The reaction can also be carried out at a temperature close to 0 °C. However, this extends the reaction time to about 18 hours. Therefore, the reaction is preferably carried out at a temperature in the range of 10 °C to room temperature.

[0075] Step f): Compound 6 (1.484 g, 3.17 mmol) was dissolved in a mixture of t-BuOH (30 mL) and THF (9 mL) at room temperature. Subsequently, the solution was cooled to 0 °C and 2-methylbut-2-ene (5.19 mL, 49.26 mmol) was added. After 20 minutes, an aqueous solution of NaH2PO4·H2O (3.782 g, 9.57 mmol) and NaClO2 (80%, 0.863 g, 7.66 mmol) as the oxidizing agent in H2O (16 mL) was added dropwise. The reaction mixture was stirred at 0 - 3 °C for 5 hours and quenched by adding solid Na2SO3 (1.23 g, 9.75 mmol). The aqueous layer was extracted with EtOAc (4 × 100 mL), dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an EtOAc:hexane (1:1) system as the eluent. Compound 7 in the form of a white solid was obtained (0.967 g, 63%).

[0076] The reagents in the above reaction are added at a temperature of about 0 °C. However, the subsequent reaction can also be carried out at room temperature, but preferably in the range of 0 °C - 3 °C. Step g): Compound 7 (0.967 g, 1.99 mmol) was dissolved in CH2Cl2 (35 mL), and subsequently, EDCI (0.770 g, 4.97 mmol) as an activator for the carboxy group, DMAP (0.243 g, 1.99 mmol) as a deprotonating agent for the hydroxy group, and 4-hydroxy-TEMPO (0.515 g, 2.99 mmol) were added. The reaction was carried out at room temperature for 16 hours and quenched by adding 20 mL of 10% sodium carbonate solution. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with H2O, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using a MeOH:CH2Cl2 (5:95) system as the eluent. Compound 8 in the form of a brown solid was obtained (1.096 g, 86%).

[0077] DDC can also be used as an activator for the carboxy group. In the aforementioned synthesis, the 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl compound was used as a heterocyclic compound containing one nitrogen atom in the form of a nitroxyl radical. However, other compounds containing a nitroxyl radical, which are derivatives of piperidine, pyridine, pyrrolidine, pyrroline, and pyrrole, in which both carbon atoms adjacent to the nitrogen atom in the form of a nitroxyl radical are independently substituted with one or two (identical or different) methyl, ethyl, or propyl groups, and one of the other carbon atoms is substituted with a hydroxy group, can also be used under the same conditions.

[0078] The reaction can also be carried out in other organic aprotic solvents such as dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile, or ether.

[0079] In this reaction, similar results can also be obtained when using a slightly higher temperature, i.e., a temperature up to 30°C. Step h): Compound 8 (1.096 g, 1.71 mmol) was dissolved in anhydrous THF (50 mL), cooled to 0°C, and subsequently TBAF (1 M in THF, 4.27 mL, 4.27 mmol) was added as a source of fluoride ions. The reaction mixture was warmed to room temperature, stirred for 2 hours, and quenched by adding 20 mL of brine. This was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with H2O, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using a MeOH:CH2Cl2 (1:9) system as the eluent. A brown solid was obtained, which was subsequently recrystallized from Et2O. Compound H3 in the form of a beige solid was obtained (0.549 g, 78%).

[0080] The reaction can also be carried out in other organic aprotic solvents such as dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile, or ether.

[0081] In the above reaction, when adding the reagent, it is preferable to use a temperature in the range of 0 to 5 °C. Subsequently, the mixture is left to stand until it reaches room temperature and stirred at this temperature for an appropriate time. b) Synthesis of nitroxyl resveratrol derivatives containing one free hydroxy group:

[0082]

Chemical formula

[0083] Step a): Imidazole (3.35 g, 49.14 mmol), as an activator for the silylating agent, was added to a stirred suspension of 4-hydroxybenzaldehyde (1.2 g, 16.38 mmol) in dichloromethane (40 mL) and cooled to 0 °C. TBSCl (2.96 g, 19.66 mmol) was added. The mixture was returned to room temperature and stirred for 5 hours. Subsequently, it was poured into 200 mL of cold water and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine, dehydrated over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an EtOAc:hexane (1:10) system as the eluent. Compound 2 in the form of a white solid was obtained (3.560 g, 92%).

[0084] Step b): n-BuLi (1.6 M in THF, 11.31 mL, 18.10 mmol) was added dropwise to a suspension of anhydrous THF (19 mL) containing CH3PPh3Br (6.461 g, 16.5 mmol) at -78 °C. After 20 minutes, a solution of anhydrous THF (10 mL) containing aldehyde 2 (3.560 g, 15.08 mmol) was added via cannula. The mixture was allowed to warm to room temperature over 1 h and stirred at this temperature for an additional 4 h. The reaction was quenched by the addition of 30 mL of brine. This was extracted with CH2Cl2 (3 × 40 mL). The combined organic layers were washed with water, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an Et2O:hexanes (1:100) system as eluent. Compound 3 was obtained in the form of a colorless oil (3.142 g, 89%).

[0085] Step c): In a dry vial, under an argon atmosphere, compound 3 (2.0 g, 8.545 mmol), dimethyl 5-bromoisophthalate (2.123 g, 7.768 mmol), Pd(OAc)2 (0.096 g, 0.427 mmol), and tri(o-tolyl)phosphine (0.196 g, 0.644 mmol) were placed in anhydrous triethylamine (15 mL). The mixture was stirred in a sealed vial at 60 °C for 2 h, then at 80 °C for 38 h. After cooling, the mixture was diluted with CH2Cl2 and poured into water. The aqueous layer was extracted with dichloromethane (3 × 40 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an Et2O:hexanes (1:9) system as eluent. Compound 4 was obtained as a white solid (2.220 g, 67%).

[0086] Step d): A solution of compound 4 (2.22 g, 5.21 mmol) in anhydrous CH2Cl2 (78 mL) was cooled to -78 °C, DIBALH (1 M in CH2Cl2, 26.05 mL, 26.05 mmol) was added dropwise, and the mixture was stirred at this temperature for 2.5 h. The reaction was quenched by adding sodium potassium tartrate solution (1 M, 6 mL), HCl (1 M, 6 mL), and water (24 mL), and after returning to room temperature, the mixture was stirred for 2 h. Subsequently, the mixture was poured into 50 mL of water and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an EtOAc:hexane (1:1) system as the eluent. Compound 5 in the form of a white solid was obtained (1.72 g, 89%).

[0087] Step e): Compound 5 (1.72 g, 4.6 mmol) was dissolved in CH2Cl2 (24 mL), and PDC (8.66 g, 23 mmol) was added in two portions. The reaction was carried out at room temperature for 16 h. Subsequently, the mixture was filtered through a Celite layer, and the filtrate was concentrated using an evaporator. The product was purified by silica gel column chromatography using an EtOAc:hexane (1:4) system as the eluent. Compound 6 in the form of a white solid was obtained (1.395 g, 82%).

[0088] Step f): Compound 6 (1.395 g, 3.81 mmol) was dissolved in a mixture of t-BuOH (40 mL) and THF (12 mL) at room temperature. Subsequently, the solution was cooled to 0 °C and 2-methylbut-2-ene (6.24 mL, 59.21 mmol) was added. After 20 minutes, an aqueous solution of NaH2PO4·H2O (9.03 g, 22.86 mmol) and NaClO2 (80%, 2.06 g, 18.30 mol) in H2O (38 mL) was added dropwise. The reaction mixture was stirred at 0 - 3 °C for 5 hours and quenched by adding solid Na2SO3 (2.94 g, 23.29 mmol). The aqueous layer was extracted with EtOAc (8 × 60 mL), dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using MeOH:CH2Cl2 (1:1 - 3:2) containing 0.1% AcCOOH as the eluent. Compound 7 in the form of a white solid was obtained (0.896 g, 59%).

[0089] Step g): Compound 7 (0.896 g, 2.25 mmol) was dissolved in CH2Cl2 (39 mL), and subsequently, EDCI (1.44 g, 9.29 mmol), DMAP (0.824 g, 6.75 mola), and 4-hydroxy-TEMPO (1.35 g, 7.87 mol) were added. The reaction was carried out at room temperature for 52 hours and quenched by adding 20 mL of 10% sodium carbonate solution. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with H2O, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using EtOAc:hexane (1:4) as the eluent. Compound 8 in the form of an orange solid was obtained (1.176 g, 74%).

[0090] Step h): Compound 8 (1.76 g, 1.83 mmol) was dissolved in anhydrous THF (52 mL), cooled to 0 °C, and subsequently TBAF (1 M in THF, 2.75 mL, 2.75 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 2 hours, and quenched by adding 20 mL of brine. The mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with H2O, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an EtOAc:hexane (2:3) system as the eluent. An orange solid was obtained, which was subsequently recrystallized from Et2O. Compound H2 was obtained in the form of a beige solid (0.783 g, 80%).

[0091] Example 3: Antioxidant / Anti-aging Property Test In a cell-based test, three strains of human skin fibroblasts obtained from healthy volunteers were used to investigate the effect of biological variation on the efficacy of the test compound. The cells were subcultured and seeded in 6- or 12-well plates (cell density: 5,000 cells per 1 cm 2 area). The cells were placed in an incubator under optimal conditions for growth (37 °C, 5% CO2) for 24 hours. After the required time had elapsed, hydrogen peroxide (concentration: 200 μM, experimentally determined to be optimal for inducing fibroblast aging) and test compounds H3 and H5; or the test compound alone were added to the cells to determine the cytotoxicity of the compound. Compound H3 is a resveratrol derivative having one nitroxyl group, and compound H5 is a nitroxyl curcumin derivative. Subsequently, depending on the type of experiment to be performed, the cells were placed in the incubator for 24 hours, 48 hours, 72 hours, or 7 days. Subsequently, the number of cells in the culture was counted, and the percentage of proliferating cells (%) or the percentage of SA-β-gal-positive cells (%) was determined.

[0092] Figure 1 shows the cell numbers in culture after treatment with substances H3 and H5. The horizontal lines in the chart indicate the treatment points, and the results are normalized to this number. As can be seen from the data obtained, neither of the two compounds prepared has cytotoxicity against human skin fibroblasts at concentrations up to 5 μM (experimentally determined value; the active concentrations of the test compounds are shown in the figure).

[0093] The next step was to determine cell proliferation based on the bromodeoxyuridine (BrdU) incorporation assay. BrdU, a synthetic nucleoside (thymidine) analogue, is incorporated into DNA molecules during the S phase of cell division. As a result of immunocytochemically staining cell nuclei with BrdU (Figure 2), information on the percentage of cultured cells that have undergone division is obtained. The test confirmed that neither compound H3 nor H5 has any cytotoxicity (the percentage of BrdU-positive cells (%) was the same as the control).

[0094] Subsequently, the activity of senescence-associated β-galactosidase (SA-β-gal) was tested. An increase in SA-β-gal activity is observed in cells that have undergone cellular senescence (one of the markers of senescence). Figure 3 shows the results demonstrating that the percentage of cells (%) with increased SA-β-gal activity after treatment with H3 and H5 was the same as that of the untreated control.

[0095] The next step was to investigate whether the prepared compound protects cells from aging induced by oxidative stress. For this purpose, 200 μM hydrogen peroxide was used (the concentration was determined experimentally). Different concentrations of H3 and H5 were added to cell cultures in which accelerated aging was induced. The results show that the compound protects cells from the effects of oxidative stress (the number of cells is increased compared to the culture with only hydrogen peroxide added, Figure 4). The compound showed a protective effect, and the percentage of dividing cells was 10 times higher compared to the cells treated with H2O2 alone (40% vs. 4%, Figure 5). When H3 and H5 were added to the cells treated with hydrogen peroxide, as shown in Figure 6, the number of cells with increased SA-β-gal activity decreased from 90% (H2O2) to 60% (H2O2 + H3 or H5). It is also worth emphasizing that the obtained compound H3 was shown to have much better activity than the components (resveratrol (RSV) and TEMPO) that make it up.

[0096] Based on the above results, it can be speculated that derivatives of other polyphenols such as quercetin, genistein, and daidzein exhibit antioxidant / anti-aging properties similar to those of the obtained derivatives because similar main groups responsible for antioxidant / anti-aging properties are present in the molecule after substituting their hydroxyl groups with nitroxyl radical-containing groups as described above.

Claims

1. Nitroxyl polyphenol derivatives of the formula: Q-(L-A) ｎ wherein Q is a group derived from a polyphenol, such as curcumin, quercetin, genistein, or daidzein; L is an ester linking group of formula -OC(O)-(CH 2 ) x -, where x is an integer from 0 to 2; or Q is a group derived from a polyphenol, resveratrol, and L is an ester linking group of formula -(CH 2 ) x -C(O)O-, where x is an integer from 0 to 2; A is a 5- or 6-membered heterocyclic group containing one nitrogen atom in the form of a nitroxyl radical (NO.), and both carbon atoms adjacent to the nitroxyl radical are substituted with one or two C １ ~C ３ are substituted independently with alkyl groups; n is an integer from 1 to 5.

2. Q is a group derived from a polyphenol, curcumin, and L is a group of the formula -OC(O)-(CH ２ ) ｘ 2. The nitroxyl polyphenol derivative according to claim 1, wherein x is an ester linking group of the formula: -, wherein x is an integer of 0 to 2.

3. A nitroxyl polyphenol derivative according to claim 1 or 2, wherein A is a piperidine-1-oxyl group in which both carbon atoms adjacent to the nitroxyl radical are independently substituted with two C 1 -C 3 alkyl groups, and preferably a 2,2,6,6-tetramethylpiperidine-1-oxyl group.

4. 3. The nitroxyl polyphenol derivative according to claim 1, wherein n is 1 or 2.

5. The following formula: 【Chemical 1】 【Chemistry 2】 and 【Chemistry 3】 The nitroxyl polyphenol derivative according to claim 1 or 2, which is a derivative selected from the group consisting of:

6. Nitroxyl polyphenol derivatives of the formula: Q-(L-A) ｎ wherein Q is a group derived from a polyphenol, such as curcumin, quercetin, genistein, or daidzein; L is a group of the formula -OC(O)-(CH ２ ) ｘ - an ester linking group, where x is an integer from 0 to 2; A is a 5- or 6-membered heterocyclic group containing one nitrogen atom in the form of a nitroxyl radical (NO.), and both carbon atoms adjacent to the nitroxyl radical are substituted with one or two C １ ~C ３ are substituted independently with alkyl groups; n is an integer from 1 to 5.

1. A method for preparing Curcumin, quercetin, genistein or daidzein and a 5- or 6-membered heterocyclic compound containing one nitrogen atom in the form of a nitroxyl radical (NO.), wherein both carbon atoms adjacent to the nitroxyl radical are 1 or 2 C １ ~C ３ and one of the other carbon atoms is independently substituted with an alkyl group of the general formula -(CH ２ ) ｘ substituted with a carboxy group of the formula —C(O)OH, where x is an integer from 0 to 2; The method is characterized in that the reaction is carried out in an organic solvent at a temperature ranging from −10° C. to below room temperature in the presence of a deprotonating agent for the hydroxy group and an activating agent for the carboxy group.

7. Piperidine-1-oxyl compounds (where both carbon atoms adjacent to the nitroxyl radical have two C １ ~C ３ and one of the other carbon atoms is independently substituted with an alkyl group of the general formula -(CH ２ ) ｘ -C(O)OH, where x is an integer from 0 to 2), preferably 4-carboxy-2,2,6,6-tetramethylpiperidine-1-oxyl compounds, and 5- or 6-membered heterocyclic compounds containing one nitrogen atom in the form of a nitroxyl radical (NO.), where both carbon atoms adjacent to the nitroxyl radical are substituted with one or two C １ ~C ３ and one of the other carbon atoms is independently substituted with an alkyl group of the general formula -(CH ２ ) ｘ 7. The method according to claim 6, characterized in that the compound is used as a compound substituted with a carboxy group of the formula -C(O)OH, where x is an integer from 0 to 2.

8. 8. The method according to claim 6 or 7, characterized in that 4-dimethylaminopyridine is used as a deprotonating agent for the hydroxy group.

9. 8. The method according to claim 6 or 7, characterized in that 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,N'-dicyclohexylcarbodiimide, preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, is used as activating agent for the carboxy group.

10. 8. The method according to claim 6 or 7, characterized in that an aprotic polar solvent, preferably dichloromethane, is used as the organic solvent.

11. 8. The process according to claim 6 or 7, characterized in that the reaction is carried out at a temperature ranging from -10°C to 0°C.

12. Nitroxyl polyphenol derivatives of the formula: Q-(L-A) ｎ (In the formula, Q is a group derived from a polyphenol, resveratrol; L is a group of the formula -(CH ２ ) ｘ an ester linking group of —C(O)O—, where x is an integer from 0 to 2; A is a 5- or 6-membered heterocyclic group containing one nitrogen atom in the form of a nitroxyl radical (NO.), and both carbon atoms adjacent to the nitroxyl radical are substituted with one or two C １ ~C ３ are substituted independently with alkyl groups; n is an integer of 1 or 2.

1. A method for preparing a) reacting a benzaldehyde derivative substituted with at least one hydroxy group with a silylating agent to protect the at least one hydroxy group, the reaction being carried out in an organic solvent at a temperature ranging from 0° C. to room temperature in the presence of an activating agent for the silylating agent; b) reacting the protected benzaldehyde derivative prepared in step a) with an alkyltriphenylphosphonium halide to convert the aldehyde group to an alkene group, wherein the reaction is carried out in an organic solvent at a temperature ranging from −78° C. to room temperature in the presence of a strong base; c) converting the alkene group in the derivative prepared in step b) to a compound of the formula -(CH ２ ) ｘ coupling reaction with a halogenated benzene derivative substituted with at least one ester group of the formula —C(O)OR, wherein R is C １ ~C ３ alkyl group, and x is an integer from 0 to 2; said reaction being carried out in the presence of a catalyst, a phosphonium ligand, and a base, optionally in an organic solvent, at a temperature ranging from room temperature to 190°C; d) reacting the derivative prepared in step c) with a reducing agent to reduce at least one ester group to at least one alcohol group, wherein the reaction is carried out in an organic solvent at a temperature ranging from −78° C. to room temperature; e) reacting the derivative prepared in step d) with an oxidizing agent to oxidize at least one alcohol group to at least one aldehyde group, wherein the reaction is carried out in an organic solvent at a temperature ranging from 0° C. to room temperature; f) reacting the derivative prepared in step e) with an oxidizing agent to oxidize at least one aldehyde group to at least one acidic group, wherein the reaction is carried out in an organic solvent or a mixture of organic solvents at a temperature ranging from 0° C. to room temperature; g) reacting the derivative prepared in step f) with a 5- or 6-membered heterocyclic compound containing one nitrogen atom in the form of a nitroxyl radical (NO.) to prepare a nitroxyl polyphenol derivative containing at least one protected hydroxy group, wherein both carbon atoms adjacent to the nitroxyl radical are one or two C １ ~C ３ each independently substituted with an alkyl group and one of the other carbon atoms is substituted with a hydroxy group, and the reaction is carried out in an organic solvent at a temperature ranging from room temperature to 30° C. in the presence of a deprotonating agent for the hydroxy group and an activating agent for the carboxy group; h) reacting the nitroxyl polyphenol derivative containing at least one protected hydroxy group prepared in step g) with a reagent that functions as a source of fluoride ions to deprotect the at least one hydroxy group, wherein the reaction is carried out in an organic solvent at a temperature ranging from 0° C. to room temperature; A method comprising:

13. 13. The method according to claim 12, characterized in that in step a) hydroxy- or dihydroxybenzaldehyde is used as benzaldehyde derivative and / or an alkylsilyl halide, preferably tert-butyldimethylsilyl chloride, is used as silylating agent and / or imidazole, a mixture of triethylamine with 4-dimethylaminopyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene, or a mixture of 18-crown-6 ether with potassium hydride, preferably imidazole alone, is used as activating agent for the silylating agent.

14. 14. The method according to claim 12 or 13, characterized in that in step b) methyltriphenylphosphonium bromide is used as alkyltriphenylphosphonium halide and / or n-butyllithium, lithium diisopropylamide, potassium tert-butoxide or potassium bis(trimethylsilyl)amide, preferably n-butyllithium, is used as strong base.

15. In the step c), 4-iodobenzoic acid ethyl ester or dimethyl 5-bromoisophthalate is reacted with the compound of the formula -(CH ２ ) ｘ It is used as a halogenated benzene derivative substituted with at least one ester group of the formula —C(O)OR, where R is C １ ~C ３ 14. The process according to claim 12 or 13, characterized in that x is an alkyl group and x is an integer from 0 to 2, and / or a palladium(0) or (II) complex, preferably palladium acetate, is used as catalyst, and / or tri(o-tolyl)phosphine is used as phosphonium ligand, and / or triethylamine is used as base.

16. 14. The method according to claim 12 or 13, characterized in that the base used is the organic solvent in step c).

17. 14. The method according to claim 12 or 13, characterized in that the reaction in step c) is carried out at a temperature in the range of 50 to 90°C.

18. 14. A method according to claim 12 or 13, characterized in that diisobutylaluminum hydride or lithium aluminium hydride, preferably diisobutylaluminum hydride, is used as reducing agent in step d).

19. 14. The method according to claim 12 or 13, characterized in that the reaction in step d) is carried out at a temperature ranging from -78°C to -50°C.

20. 14. The method according to claim 12 or 13, characterized in that pyridinium dichromate, pyridinium chlorochromate, oxalyl chloride, triethylamine in dichloromethane, tetrapropylammonium perruthenate, or 4-methylmorpholine 4-oxide in tetrahydrofuran, preferably pyridinium dichromate, is used as oxidizing agent in step e).

21. 14. The method according to claim 12 or 13, characterized in that the reaction in step e) is carried out at a temperature ranging from 10° C. to room temperature.

22. In step f), NaClO ２ and NaH ２ P.O. ４ ・H ２ 14. The method according to claim 12 or 13, characterized in that an O solution is used as the oxidizing agent and / or tert-butanol, tetrahydrofuran or 2-methylbut-2-ene or a mixture thereof is used as the organic solvent.

23. 14. The method according to claim 12 or 13, characterized in that the reaction in step f) is carried out at a temperature in the range of 0 to 3°C.

24. In step g), both carbon atoms adjacent to the nitroxyl radical have two C １ ~C ３ Hydroxypiperidine-1-oxyl compounds, preferably 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl compounds, each independently substituted with an alkyl group, are preferably 5- or 6-membered heterocyclic compounds containing one nitrogen atom in the form of a nitroxyl radical (NO.) (both carbon atoms adjacent to the nitroxyl radical have one or two C １ ~C ３ 14. The method according to claim 12 or 13, characterized in that 4-dimethylaminopyridine is used as a deprotonating agent for the hydroxy groups (each of which is independently substituted by an alkyl group and one of the other carbon atoms is substituted by a hydroxy group), and / or 4-dimethylaminopyridine is used as a deprotonating agent for the hydroxy groups, and / or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,N'-dicyclohexylcarbodiimide, preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, is used as an activating agent for the carboxy groups.

25. 14. The method according to claim 12 or 13, characterized in that tetra-n-butylamine fluoride is used as the reagent serving as the source of fluoride ions in step h).

26. 14. The method according to claim 12 or 13, characterized in that in steps a) to e) and g) and h), an aprotic solvent, preferably dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile or an ether, is used as the organic solvent.

27. An antioxidant comprising the nitroxyl polyphenol derivative according to any one of claims 1 to 5.

28. 28. The antioxidant according to claim 27, characterized in that the antioxidant is used as an anti-aging agent.

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