An idebenone derivative, its preparation method and application

Abstract

This invention provides an idebenone derivative, its preparation method, and its applications. The idebenone derivative has a uronic acid structure, which improves the water solubility of idebenone and reduces its first-pass effect, providing more and more effective drug options for treating mitochondrial dysfunction and neurodegenerative diseases. Simultaneously, the idebenone derivative exhibits better stability in air and a lighter color, reducing the requirements for its use and storage, and significantly expanding its application scenarios in cosmetics and other fields. Furthermore, the preparation method of this idebenone derivative is simple and mild, showing promising application prospects.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to an idebenone derivative, its preparation method, and its application. Background Technology

[0002] Idebenone is a powerful antioxidant widely used in the medical and cosmetic fields.

[0003] Structurally, idebenone is a 1,4-benzoquinone ring with a hydroxydecyl substitution. This benzoquinone ring accepts two electrons, forming a stable hydroquinone with antioxidant properties, thus giving idebenone excellent activity in scavenging oxygen free radicals. However, this also makes it relatively unstable and prone to oxidation, leading to its degradation. On the other hand, the presence of a long hydroxyl side group gives idebenone significant lipophilicity, facilitating its entry into the mitochondrial membrane and better penetration of the blood-brain barrier to exert its effects. Idebenone functions as an electron carrier in the mitochondrial electron transport chain. It can bypass mitochondrial enzyme complex I (NADH dehydrogenase) and directly transfer electrons through mitochondrial enzyme complex II (succinate dehydrogenase) to mitochondrial enzyme complex III (coenzyme Q-cytochrome C reductase), thereby enabling mitochondria to restore a certain amount of adenosine triphosphate (ATP) production even when mitochondrial enzyme complex I is impaired.

[0004] Given its unique mechanism of action, idebenone has been used to treat mitochondrial dysfunction and neurodegenerative diseases. To date, almost all clinical trials involving idebenone for these diseases have been conducted orally. Following oral administration, idebenone is rapidly absorbed from the gastrointestinal tract; however, due to the first-pass effect in the liver and intestinal mucosa, most of the poorly water-soluble idebenone is metabolized and consumed, with less than 1% of the administered dose entering systemic circulation. Therefore, although idebenone can cross the blood-brain barrier relatively well, its low oral bioavailability may prevent the drug from reaching therapeutic concentrations in the brain, even after high doses.

[0005] In the field of cosmetic applications, because idebenone is usually an orange-yellow crystalline powder, its color is difficult for consumers to accept sensoryly, and it can also easily stain the user's clothes yellow.

[0006] In summary, the limited application range and effectiveness of idebenone are due to its insufficient stability, poor water solubility, and dark color. Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide an idebenone derivative, its preparation method, and its application.

[0008] To achieve this objective, the present invention adopts the following technical solution:

[0009] On one hand, the present invention provides an idebenone derivative having the following structure:

[0010]

[0011] Where R is a uronic acid residue and n is an integer greater than or equal to 1, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 18, 20, etc.

[0012] In this invention, the uronic acid refers to a compound and its derivatives formed by oxidizing the primary hydroxyl group in a reducing sugar to a carboxyl group; the uronic acid contains both an aldehyde group and a carboxyl group, or the tautomer of the uronic acid contains both an aldehyde group and a carboxyl group.

[0013] Preferably, the uronic acid is one or a combination of at least two of monouronic acid, disaccharide uronic acid, oligouronic acid, or polyuronic acid.

[0014] In this invention, when the uronic acid is a disaccharidic acid, oligouronic acid, or polyuronic acid, because the uronic acid contains two or more carboxyl groups, multiple carboxyl groups may be attached to the uronic acid during the reaction process. Group.

[0015] Preferably, the uronic acid is one or a combination of at least two of the following: glucuronic acid, galacturonic acid, mannulic acid, iduronic acid, guluronic acid, chondroitin, pectic acid, hyaluronic acid, or alginic acid.

[0016] Preferably, the uronic acid is hyaluronic acid or alginic acid.

[0017] More preferably, the uronic acid is alginic acid.

[0018] In this invention, the conformation of the uronic acid is not limited. For example, the glucuronic acid can be L-glucuronic acid or D-glucuronic acid.

[0019] In a second aspect, the present invention provides a method for preparing an idebenone derivative as described in the first aspect, the method comprising the following steps:

[0020] Idebenone and uronic acid are reacted to obtain the idebenone derivative.

[0021] Preferably, the molar ratio of the uronic acid carboxyl group in the idebenone and uronic acid is 1.0:(1.0 to 1.3), for example, 1.0:1.0, 1.0:1.1, 1.0:1.2 or 1.0:1.3.

[0022] Preferably, the reaction is carried out in the presence of an activator.

[0023] Preferably, the activating agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and / or N,N'-dicyclohexylcarbodiimide.

[0024] Preferably, the molar ratio of idebenone to activator is 1.0:(1.3 to 1.8), for example 1.0:1.3, 1.0:1.4, 1.0:1.5, 1.0:1.6, 1.0:1.7 or 1.0:1.8.

[0025] Preferably, the reaction is carried out in the presence of a catalyst.

[0026] Preferably, the catalyst is one or a combination of at least two of 4-dimethylaminopyridine, 4-piperidinylpyridine, or N,N'-carbonyldiimidazole.

[0027] Preferably, the reaction is carried out in a solvent selected from one or a combination of at least two of dichloromethane, trichloromethane, or dioxane.

[0028] Preferably, before the reaction, idebenone and uronic acid are dissolved in a solvent at -5°C to 5°C (e.g., -5°C, -3°C, 0°C, 2°C, 4°C or 5°C).

[0029] Preferably, the reaction is carried out under stirring.

[0030] Preferably, the reaction temperature is 20 to 40°C, for example 20°C, 23°C, 25°C, 28°C, 30°C, 33°C, 35°C, 38°C or 40°C.

[0031] In this invention, the extent of the reaction can be detected using conventional monitoring methods in the art, including but not limited to high performance liquid chromatography, thin-layer chromatography, and liquid chromatography-mass spectrometry.

[0032] Preferably, the reaction time is 12 to 24 hours, for example, 12 hours, 15 hours, 18 hours, 20 hours, 22 hours or 24 hours.

[0033] Preferably, the reaction is carried out under the protection of a protective gas.

[0034] Preferably, the protective gas is selected from one or a combination of at least two of helium, neon, argon, or nitrogen.

[0035] Preferably, after the reaction is completed, a quencher is added to the reaction solution to quench the reaction.

[0036] Preferably, the quencher is one or a combination of at least two of sodium bicarbonate, potassium bicarbonate, or calcium bicarbonate.

[0037] Preferably, after the quenching reaction, the reaction solution is extracted with an extractant, the organic liquid layers are combined, and dried with a drying agent to obtain a crude product. The crude product is then purified to obtain a purified idebenone derivative.

[0038] Preferably, the extractant is selected from one or a combination of two of dichloromethane or trichloromethane.

[0039] Preferably, the desiccant is one or a combination of at least two of anhydrous magnesium sulfate, anhydrous sodium sulfate, or anhydrous calcium chloride.

[0040] As a preferred technical solution, the preparation method of the idebenone derivative specifically includes the following steps:

[0041] S1: Dissolve idebenone and uronic acid in a solvent at -5℃ to 5℃ to obtain a reaction solution;

[0042] S2: Add activator and catalyst to the reactant solution, and stir and mix under protective gas to carry out the reaction, and obtain a mixed product;

[0043] S3: Add a quencher to the mixture and extract three times with an extractant. Combine the organic liquid layers and dry with a drying agent to obtain the crude product.

[0044] S4: Purify the crude product to obtain the idebenone derivative.

[0045] On the other hand, the present invention provides the use of the idebenone derivatives described above in cosmetics.

[0046] On the other hand, the present invention provides the use of the idebenone derivatives described above in the preparation of medicaments for treating mitochondrial dysfunction or neurodegenerative diseases.

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] The idebenone derivative of this invention has a uronic acid structure, which can significantly improve the water solubility of idebenone and reduce its first-pass effect, providing more and more effective drug options for the treatment of mitochondrial dysfunction and neurodegenerative diseases. Simultaneously, the inventors unexpectedly discovered that the idebenone derivative has better stability in air and a lighter color, which can reduce the usage and storage conditions of idebenone and greatly broaden its application scenarios in cosmetics and other transdermal absorption fields. Furthermore, the preparation method of this idebenone derivative is simple and mild, showing promising application prospects. Attached Figure Description

[0049] Figure 1The graph shows the overall antioxidant capacity test results of Examples 1-8 and related substances. Detailed Implementation

[0050] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0051] Example 1

[0052] This embodiment provides an idebenone derivative and its preparation method. The preparation method of the idebenone derivative is as follows:

[0053] S1: In a 50 mL reaction flask, at 0 °C, gradually dissolve idebenone (1.692 g, 5.0 mmol) and glucuronic acid (0.971 g, containing 5.0 mmol of carboxylic acid group) in 10 mL of dichloromethane, and stir to obtain a homogeneous and clear reaction solution.

[0054] S2: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.246 g, 6.5 mmol) and 4-dimethylaminopyridine (0.078 g) were added to the reactant solution, and argon gas was introduced. The mixture was stirred and mixed under a continuous argon atmosphere at 30 °C. The reaction process was monitored by thin-layer chromatography. The reaction was stopped after 16 h to obtain the mixed product.

[0055] S3: Add sodium bicarbonate (1.000g) to the mixture to quench the reaction, and extract the mixture three times with dichloromethane, using 5mL each time. Combine the organic liquid layers, and add anhydrous sodium sulfate (2.000g) to dry the organic liquid layer to obtain the crude product.

[0056] S4: The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: dichloromethane: ethyl acetate = 20:9:1) to obtain the idebenone derivative (1.775 g, yield 69%); the specific structural formula is as follows:

[0057]

[0058] The 1H NMR spectrum of the obtained idebenone derivative: 1 HNMR (400MHz, CDCl3): δ5.67(s,1H),4.78-4.32(m,8H),3.78(s,6H),3.59(d,2H),1.85(s,3H),1.56(d,2H),1.34-0.89(m,16H).

[0059] Example 2

[0060] This embodiment provides an idebenone derivative and its preparation method. The preparation method of the idebenone derivative is basically the same as that in Example 1, except that glucuronic acid is replaced with galacturonic acid; the specific structural formula is as follows:

[0061]

[0062] The 1H NMR spectrum of the obtained idebenone derivative: 1 HNMR (400MHz, CDCl3): δ5.72(s,1H),4.83-4.39(m,8H),3.78(s,6H),3.58(d,2H),1.85(s,3H),1.56(d,2H),1.34-0.89(m,16H).

[0063] Example 3

[0064] This embodiment provides an idebenone derivative and its preparation method. The preparation method of the idebenone derivative is as follows:

[0065] S1: In a 50 mL reaction flask, at 0 °C, gradually dissolve idebenone (1.692 g, 5.0 mmol) and mannulic acid (0.971 g, containing 5.0 mmol of carboxylic acid group) in 10 mL of dichloromethane, and stir to obtain a homogeneous and clear reaction solution.

[0066] S2: N,N'-dicyclohexylcarbodiimide (1.857 g, 9.0 mmol) and 4-dimethylaminopyridine (0.078 g) were added to the reactant solution, and argon gas was introduced. The mixture was stirred and mixed under a continuous argon atmosphere to 30 °C. The reaction process was monitored by thin-layer chromatography. The reaction was stopped after 18 h to obtain a mixed product.

[0067] S3: Add potassium bicarbonate (1.000g) to the mixture to quench the reaction, and extract the mixture three times with dichloromethane, using 5mL each time. Combine the organic liquid layers, and add anhydrous sodium sulfate (2.000g) to dry the organic liquid layer to obtain the crude product.

[0068] S4: The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: dichloromethane: ethyl acetate = 20:9:1) to obtain the idebenone derivative (1.852 g, yield 72%); the specific structural formula is as follows:

[0069]

[0070] The 1H NMR spectrum of the obtained idebenone derivative: 1HNMR (400MHz, CDCl3): δ5.69(s,1H),4.90-4.32(m,8H),3.79(s,6H),3.59(d,2H),1.86(s,3H),1.56(d,2H),1.34-0.89(m,16H).

[0071] Example 4

[0072] This embodiment provides an idebenone derivative and its preparation method. The preparation method of the idebenone derivative is as follows:

[0073] S1: In a 50 mL reaction flask, at 0 °C, gradually dissolve idebenone (1.692 g, 5.0 mmol) and hyaluronic acid (2.463 g, containing 6.5 mmol of carboxylic acid groups) in 15 mL of dichloromethane, and stir to obtain a homogeneous and clear reaction solution.

[0074] S2: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.246 g, 6.5 mmol) and 4-dimethylaminopyridine (0.078 g) were added to the reactant solution, and argon gas was introduced. The mixture was stirred and mixed under a continuous argon atmosphere at 30 °C. The reaction process was monitored by thin-layer chromatography. The reaction was stopped after 16 h to obtain the mixed product.

[0075] S3: Add sodium bicarbonate (1.000g) to the mixture to quench the reaction, and extract the mixture three times with dichloromethane, using 5mL each time. Combine the organic liquid layers, and add anhydrous sodium sulfate (2.000g) to dry the organic liquid layer to obtain the crude product.

[0076] S4: The crude product was separated and purified by gel permeation chromatography (mobile phase: tetrahydrofuran) to obtain the idebenone derivative (1.818 g, yield 52%); the specific structural formula is as follows:

[0077]

[0078] The 1H NMR spectrum of the obtained idebenone derivative: 1 HNMR (400MHz, CDCl3): δ8.19(s,1H),6.11(d,1H),5.45(d,1H),4.80-4.50(m,4H),4.20-4.07(m,5H),3 .96(s,1H),3.79(s,6H),3.73-3.50(m,6H),2.02(s,3H),1.86(s,3H),1.60(d,2H),1.38-0.95(m,16H).

[0079] Example 5

[0080] This embodiment provides an idebenone derivative and its preparation method. The preparation method of the idebenone derivative is as follows:

[0081] S1: In a 50 mL reaction flask, at 0 °C, gradually dissolve idebenone (1.692 g, 5.0 mmol) and alginic acid (0.969 g, containing 5.5 mmol of carboxylic acid groups) in 15 mL of dichloromethane, and stir to obtain a homogeneous and clear reaction solution.

[0082] S2: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.438 g, 7.5 mmol) and 4-dimethylaminopyridine (0.092 g) were added to the reactant solution, and argon gas was introduced. The mixture was stirred and mixed under a continuous argon atmosphere at 30 °C. The reaction process was monitored by thin-layer chromatography. The reaction was stopped after 16 h to obtain a mixed product.

[0083] S3: Add sodium bicarbonate (1.000g) to the mixture to quench the reaction, and extract the mixture three times with dichloromethane, using 5mL each time. Combine the organic liquid layers, and add anhydrous sodium sulfate (2.000g) to dry the organic liquid layer to obtain the crude product.

[0084] S4: The crude product was separated and purified by gel permeation chromatography (mobile phase: tetrahydrofuran) to obtain the idebenone derivative (1.121 g, yield 64%); the specific structural formula is as follows:

[0085]

[0086] The 1H NMR spectrum of the obtained idebenone derivative: 1 HNMR (400MHz, CDCl3): δ5.62(d,1H),4.60(s,1H),4.82-4.71(m,2H),4.09 -3.78(m,9H),3.59(d,2H),1.85(s,3H),1.56(d,2H),1.34-0.89(m,16H).

[0087] Example 6

[0088] This embodiment provides an idebenone derivative and its preparation method. The preparation method of the idebenone derivative is as follows:

[0089] S1: In a 50 mL reaction flask, at -5 °C, gradually dissolve idebenone (1.692 g, 5.0 mmol) and iduronic acid (0.971 g, containing 5.0 mmol of carboxylic acid group) in 10 mL of dichloromethane, and stir to obtain a homogeneous and clear reaction solution.

[0090] S2: N,N'-carbonyldiimidazole (1.246 g, 6.5 mmol) and 4-dimethylaminopyridine (0.078 g) were added to the reactant solution, and argon gas was introduced. The mixture was stirred and mixed under a continuous argon atmosphere to 20 °C. The reaction process was monitored by thin-layer chromatography. The reaction was stopped after 24 h to obtain the mixed product.

[0091] S3: Add calcium bicarbonate (1.000 g) to the mixture to quench the reaction, and extract the mixture three times with dichloromethane, using 5 mL each time. Combine the organic liquid layers, and add anhydrous calcium chloride (2.000 g) to dry the organic liquid layer to obtain the crude product.

[0092] S4: The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: dichloromethane: ethyl acetate = 20:9:1) to obtain the idebenone derivative (1.209 g, yield 47%); the specific structural formula is as follows:

[0093]

[0094] The 1H NMR spectrum of the obtained idebenone derivative: 1 HNMR (400MHz, CDCl3): δ5.62(s,1H),4.77-4.38(m,8H),3.76(s,6H),3.59(d,2H),1.85(s,3H),1.60(d,2H),1.42-0.97(m,16H).

[0095] Example 7

[0096] This embodiment provides an idebenone derivative and its preparation method. The preparation method of the idebenone derivative is as follows:

[0097] S1: In a 50 mL reaction flask, at 5 °C, gradually dissolve idebenone (1.692 g, 5.0 mmol) and iduronic acid (0.971 g, containing 5.0 mmol of carboxylic acid group) in 10 mL of dichloromethane, and stir to obtain a homogeneous and clear reaction solution.

[0098] S2: N,N'-carbonyldiimidazole (1.246 g, 6.5 mmol) and 4-dimethylaminopyridine (0.078 g) were added to the reactant solution, and argon gas was introduced. The mixture was stirred and mixed under a continuous argon atmosphere to 40 °C. The reaction process was monitored by thin-layer chromatography. The reaction was stopped after 12 h to obtain the mixed product.

[0099] S3: Add sodium bicarbonate (1.000g) to the mixture to quench the reaction, and extract the mixture three times with dichloromethane, using 5mL each time. Combine the organic liquid layers, and add anhydrous magnesium sulfate (2.000g) to dry the organic liquid layer to obtain the crude product.

[0100] S4: The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: dichloromethane: ethyl acetate = 20:9:1) to obtain the idebenone derivative (1.312 g, yield 51%).

[0101] The 1H NMR spectrum of the obtained idebenone derivative was consistent with that of Example 6.

[0102] Example 8

[0103] This embodiment provides an idebenone derivative and its preparation method. The preparation method of the idebenone derivative is as follows:

[0104] S1: In a 50 mL reaction flask, while maintaining the temperature at 15 °C, gradually dissolve idebenone (1.692 g, 5.0 mmol) and iduronic acid (1.942 g, containing 10.0 mmol of carboxylic acid group) in 10 mL of dichloromethane, and stir to obtain a homogeneous and clear reaction solution.

[0105] S2: N,N'-carbonyldiimidazole (1.246 g, 6.5 mmol) and 4-dimethylaminopyridine (0.078 g) were added to the reactant solution, and argon gas was introduced. The mixture was stirred and mixed under a continuous argon atmosphere until the temperature was raised to 50 °C. The reaction was carried out for 6 hours and the mixed product was obtained.

[0106] S3: Add sodium bicarbonate (1.000g) to the mixture to quench the reaction, and extract the mixture three times with dichloromethane, using 5mL each time. Combine the organic liquid layers, and add anhydrous magnesium sulfate (2.000g) to dry the organic liquid layer to obtain the crude product.

[0107] S4: The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: dichloromethane: ethyl acetate = 20:9:1) to obtain the idebenone derivative (0.309 g, yield 12%).

[0108] The 1H NMR spectrum of the obtained idebenone derivative was consistent with that of Example 6.

[0109] Comparative Example 1

[0110] In a 50 mL reaction flask, idebenone (1.692 g, 5.0 mmol) and glucuronic acid (0.971 g, containing 5.0 mmol of carboxylic acid groups) were gradually dissolved in 10 mL of dichloromethane while maintaining 0 °C. The mixture was stirred to obtain a homogeneous and clear reaction solution. The solution was then dried under vacuum at room temperature to remove the dichloromethane, yielding a mixture of idebenone and glucuronic acid.

[0111] Comparative Example 2

[0112] By replacing glucuronic acid in Example 1 with gluconic acid, while keeping the preparation method unchanged, a derivative of idebenone modified with gluconic acid was obtained.

[0113] The specific structural formula is as follows:

[0114]

[0115] The 1H NMR spectrum of the obtained idebenone derivative: 1 HNMR (400MHz, CDCl3): δ5.16 (s, 1H), 4.69-4.20 (m, 5H), 3.99 ~ 3.35 (m, 13H), 1.84 (s, 3H), 1.60 (d, 2H), 1.42-0.97 (m, 16H).

[0116] Comparative Example 3

[0117] By replacing glucuronic acid in Example 1 with 1-adamantanecarboxylic acid and keeping the preparation method unchanged, a derivative of idebenone modified with 1-adamantanecarboxylic acid was obtained.

[0118] The specific structural formula is as follows:

[0119]

[0120] The 1H NMR spectrum of the obtained idebenone derivative: 1 HNMR (400MHz, CDCl3): δ3.76 (s, 6H), 3.57 (d, 2H), 2.21~1.64 (m, 20H), 1.42-0.97 (m, 16H).

[0121] Water solubility test:

[0122] According to the 2020 edition of the Chinese Pharmacopoeia, accurately weigh 1.00g of the solid dispersion powder of the test sample, place it in a certain volume of pure water at 25℃±2℃, shake vigorously for 30s every 5min, and observe the dissolution within 30min. If no solute particles are visible to the naked eye, it is considered to be completely dissolved.

[0123] In the water solubility test, let the amount of pure water be m:

[0124] When m < 1 mL, it is judged to be extremely soluble;

[0125] It is considered easily soluble when 1mL≤m<10mL;

[0126] When 10mL ≤ m < 30mL, it is considered dissolved;

[0127] When 30mL≤m<100mL, it is judged to be slightly soluble;

[0128] When 100mL≤m<1000mL, it is judged as slightly soluble;

[0129] When 1000mL≤m<10000mL, it is judged to be extremely slightly soluble;

[0130] When m ≥ 10000 mL, it is judged as almost insoluble or insoluble.

[0131] The water solubility test results of Examples 1-10 and related substances are shown in Table 1.

[0132] Table 1. Water solubility test results of Examples 1-10

[0133]

[0134]

[0135] Oxidative stability test:

[0136] This test assesses the stability of the sample by evaluating its overall antioxidant capacity under certain storage conditions.

[0137] Sample preparation:

[0138] The samples prepared in Examples 1-8 and Comparative Example 1, as well as idebenone, were placed in a constant temperature and humidity chamber with a relative humidity of 75% and a temperature of 40°C for 45 days.

[0139] Preparation of working solution:

[0140] Dissolve 6 mg of ABTS (2,2-azino-bis(3-ethyl-benzothiazole-6-sulfonic acid) diammonium salt) in 1.6 mL of distilled water to obtain ABTS stock solution; dissolve 2 mg of potassium persulfate (K2S2O8) in 3.0 mL of distilled water to obtain K2S2O8 stock solution; mix 1 mL of ABTS stock solution and 1 mL of K2S2O8 stock solution and let stand in a dark chamber for 12 h to obtain ABTS working solution.

[0141] Antioxidant test:

[0142] The prepared ABTS working solution was diluted with distilled water to a concentration of 0.7 at 734 nm using a UV-Vis spectrophotometer, denoted as A0. The antioxidant sample to be tested was then added to the diluted working solution to form a homogeneous mixture with a concentration of 10 nM. After incubation at 25 °C for 30 min, the absorbance at 734 nm was measured using a UV-Vis spectrophotometer and denoted as A0. s According to Beer-Lambert Law, the antioxidant capacity ratio (ABTS) of the test sample is calculated using the following formula. + %):

[0143] ABTS + % = (A0 - A s ) / A0×100%.

[0144] The overall antioxidant capacity test results of Examples 1-10 and related substances are as follows: Figure 1 As shown.

[0145] As can be seen from Examples 1-7 and Example 8, the idebenone derivative prepared by the method provided by the present invention has a high yield, while the yield of the idebenone derivative prepared using conditions outside the scope of the present invention is low.

[0146] As can be seen from Examples 1-8 and the idebenone control group, the idebenone derivative with a uronic acid structure provided by the present invention has a much higher water solubility than idebenone, which is beneficial to reducing the first-pass effect of the drug and providing more and more effective drug options for the treatment of mitochondrial dysfunction and neurodegenerative diseases.

[0147] As can be seen from Examples 1-8 and Comparative Example 1, the excellent water solubility of the idebenone derivatives provided by the present invention is a result of the preparation reaction process described above, rather than something that can be achieved simply by mixing.

[0148] As can be seen from Examples 1-8 and the idebenone control group, the idebenone derivative with a uronic acid structure provided by the present invention has better overall antioxidant capacity than idebenone after initial and 45-day storage, indicating that the idebenone derivative provided by the present invention has better stability and can reduce the usage and storage conditions of idebenone.

[0149] As can be seen from Example 5 and other examples, the idebenone derivative with an alginate structure provided by the present invention has better overall antioxidant capacity than other examples after 45 days of storage, indicating that the idebenone derivative with an alginate structure has better stability.

[0150] As can be seen from Examples 1-8 and Comparative Example 1, the reason why the idebenone derivatives provided by the present invention have better stability is the result of the preparation reaction process described above, rather than being achieved by simple mixing.

[0151] As can be seen from Examples 1-8 and Comparative Example 2, although the introduction of a sugar acid structure in Comparative Example 2 can improve the water solubility of idebenone, the idebenone derivative provided by the present invention has better overall antioxidant capacity both initially and after 45 days of storage.

[0152] As can be seen from Examples 1-8 and Comparative Example 3, although the introduction of (cyclic) fatty acid structures in Comparative Example 3 can improve the antioxidant capacity of adidiquinone, its water solubility is still poor, making it difficult to apply in practice.

[0153] As can be seen from Examples 1-8 and the idebenone control group, the idebenone derivatives provided by the present invention have a lighter color, especially when the uronic acid is hyaluronic acid or alginic acid, the color is light yellow, which is more easily accepted by cosmetic consumers, thereby broadening its application field.

[0154] The applicant declares that this invention illustrates the idebenone derivative, its preparation method, and its application through the above embodiments. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily rely on the above process steps to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials used in this invention, additions of auxiliary components, and selection of specific methods all fall within the protection and disclosure scope of this invention.

Claims

1. An idebenone derivative, characterized in that, The idebenone derivative has the following structure: Where R is a uronic acid residue and n is an integer from 1 to 20; The uronic acid is alginic acid; The preparation method of the idebenone derivative includes the following steps: Idebenone and uronic acid are reacted to obtain the idebenone derivative; The reaction is carried out in the presence of an activator; The activator is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and / or N,N'-dicyclohexylcarbodiimide; The reaction is carried out in the presence of a catalyst; The catalyst is one or a combination of at least two of 4-dimethylaminopyridine, 4-piperidinylpyridine, or N,N'-carbonyldiimidazole.

2. The method for preparing the idebenone derivative according to claim 1, characterized in that, The preparation method includes the following steps: Idebenone and uronic acid are reacted to obtain the idebenone derivative.

3. The preparation method according to claim 2, characterized in that, The molar ratio of idebenone and uronic acid carboxylic acid groups is 1.0:(1.0~1.3).

4. The preparation method according to claim 2, characterized in that, The reaction is carried out in the presence of an activator.

5. The preparation method according to claim 4, characterized in that, The activator is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and / or N,N'-dicyclohexylcarbodiimide.

6. The preparation method according to claim 4, characterized in that, The molar ratio of idebenone to activator is 1.0:(1.3~1.8).

7. The preparation method according to claim 2, characterized in that, The reaction is carried out in the presence of a catalyst.

8. The preparation method according to claim 7, characterized in that, The catalyst is one or a combination of at least two of 4-dimethylaminopyridine, 4-piperidinylpyridine, or N,N'-carbonyldiimidazole.

9. The preparation method according to claim 2, characterized in that, The reaction is carried out in a solvent selected from one or a combination of at least two of dichloromethane, trichloromethane, or dioxane.

10. The preparation method according to claim 2, characterized in that, Before the reaction, idebenone and uronic acid are dissolved in a solvent at -5℃ to 5℃.

11. The preparation method according to claim 2, characterized in that, The reaction was carried out under stirring.

12. The preparation method according to claim 2, characterized in that, The reaction temperature is 20~40℃.

13. The preparation method according to claim 2, characterized in that, The reaction time is 12-24 h.

14. The preparation method according to claim 2, characterized in that, The reaction is carried out under the protection of a protective gas.

15. The preparation method according to claim 14, characterized in that, The protective gas is selected from one or a combination of at least two of helium, neon, argon, or nitrogen.

16. The preparation method according to claim 2, characterized in that, After the reaction is completed, a quencher is added to the reaction solution to quench the reaction.

17. The preparation method according to claim 16, characterized in that, The quenching agent is one or a combination of at least two of sodium bicarbonate, potassium bicarbonate, or calcium bicarbonate.

18. The preparation method according to claim 16, characterized in that, After quenching the reaction, the reaction solution was extracted with an extractant, the organic liquid layers were combined, and dried with a drying agent to obtain a crude product. The crude product was then purified to obtain a purified idebenone derivative.

19. The preparation method according to claim 18, characterized in that, The extractant is selected from one or a combination of two of dichloromethane or trichloromethane.

20. The preparation method according to claim 18, characterized in that, The desiccant is one or a combination of at least two of anhydrous magnesium sulfate, anhydrous sodium sulfate, or anhydrous calcium chloride.

21. The preparation method according to any one of claims 2-20, characterized in that, The preparation method of the idebenone derivative specifically includes the following steps: S1: Dissolve idebenone and uronic acid in a solvent at -5℃ to 5℃ to obtain a reaction solution; S2: Add activator and catalyst to the reactant solution, and stir and mix under protective gas to carry out the reaction, and obtain a mixed product; S3: Add a quencher to the mixture and extract three times with an extractant. Combine the organic liquid layers and dry with a drying agent to obtain the crude product. S4: Purify the crude product to obtain the idebenone derivative.

22. The application of the idebenone derivative according to claim 1 in cosmetics.

23. The use of the idebenone derivative according to claim 1 in the preparation of a medicament for treating mitochondrial dysfunction or neurodegenerative diseases.

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