Idebenone derivative as well as preparation method and application thereof

Abstract

The invention provides an idebenone derivative and a preparation method and application thereof, the idebenone derivative has an uronic acid structure, the water solubility of idebenone can be improved, the first-pass effect of idebenone is reduced, and more and more effective medicine schemes are provided for treating mitochondrial dysfunction and neurodegenerative diseases. Meanwhile, the idebenone derivative has better stability in air and lighter color, the use and storage conditions of idebenone can be reduced, and the application scene of idebenone in the fields of cosmetics and the like is greatly widened; moreover, the preparation method of the idebenone derivative is simple, conditions are mild, and the idebenone derivative has a good application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to an idebenone derivative and a preparation method and application thereof. Background Art

[0002] Idebenone, as an effective antioxidant, is widely used in medical and cosmetic fields.

[0003] In terms of molecular structure, idebenone is a 1,4-benzoquinone ring substituted with a hydroxydecyl group. The benzoquinone ring can receive two electrons to generate a stable hydroquinone with antioxidant effects, which makes idebenone have excellent activity in scavenging oxygen free radicals. However, due to this, its properties are relatively unstable and it is easy to undergo oxidation reactions and become ineffective. On the other hand, the presence of hydroxyl-containing long carbon side groups makes idebenone significantly lipophilic, which is conducive to its entry into the mitochondrial membrane, so that it can better penetrate the blood-brain barrier and play its role. Idebenone has the function of an electron carrier in the mitochondrial electron transport chain. It can bypass mitochondrial enzyme complex I (NADH dehydrogenase) and transfer electrons directly to mitochondrial enzyme complex III (coenzyme Q-cytochrome C reductase) through mitochondrial enzyme complex II (succinate dehydrogenase), so that mitochondria can restore the production of a certain amount of adenosine triphosphate (ATP) when the function of mitochondrial enzyme complex I is impaired.

[0004] Due to its special mechanism of action, idebenone has been used to treat mitochondrial dysfunction and neurodegenerative diseases. To date, almost all clinical trials using idebenone to treat these diseases have been conducted in the form of oral medication. After oral administration, idebenone can be rapidly absorbed through the gastrointestinal tract, but due to the first-pass effect in the liver and intestinal mucosa, most of the poorly water-soluble idebenone is metabolized and consumed, and only less than 1% of the administered dose can enter the systemic circulation. Therefore, although idebenone can penetrate the blood-brain barrier well, its low oral bioavailability may make it difficult for the drug to reach therapeutic concentration levels in the brain even after high doses.

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

[0006] In summary, due to the problems of insufficient stability, poor water solubility and dark color of idebenone, its application scope and effect are limited. Summary of the invention

[0007] In view of the deficiencies in the prior art, the present invention aims to provide an idebenone derivative and a preparation method and application thereof.

[0008] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

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

[0010]

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

[0012] In the present invention, the uronic acid refers to a compound and its derivatives formed when the primary hydroxyl group in a reducing sugar is oxidized 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 of monouronic acid, disuronic acid, oligouronic acid or polyuronic acid, or a combination of at least two of them.

[0014] In the present invention, when the uronic acid is a disaccharide uronic acid, an oligosaccharide uronic acid or a polysaccharide uronic acid, since the uronic acid contains two or more carboxyl groups, multiple carboxyl groups may be attached to the uronic acid during the reaction. Group.

[0015] Preferably, the uronic acid is one or a combination of at least two of glucuronic acid, galacturonic acid, mannuronic acid, iduronic acid, guluronic acid, chondroitin, pectin 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 the present 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 the idebenone derivative as described in the first aspect, the preparation method comprising the following steps:

[0020] Idebenone reacts with uronic acid to obtain the idebenone derivative.

[0021] Preferably, the molar ratio of idebenone to the uronic acid carboxylic acid group in uronic acid is 1.0:(1.0-1.3), such as 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 activating agent.

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

[0024] Preferably, the molar ratio of idebenone to activator is 1.0:(1.3-1.8), 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, chloroform or dioxane.

[0028] Preferably, before the reaction, idebenone and uronic acid are dissolved in a solvent at -5°C to 5°C (eg, -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 20-40°C, for example 20°C, 23°C, 25°C, 28°C, 30°C, 33°C, 35°C, 38°C or 40°C.

[0031] In the present invention, the extent of the reaction can be detected by 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 h, for example 12 h, 15 h, 18 h, 20 h, 22 h or 24 h.

[0033] Preferably, the reaction is carried out under the protection of 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 of sodium bicarbonate, potassium bicarbonate or calcium bicarbonate, or a combination of at least two of them.

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

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

[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 comprises the following steps:

[0041] S1: dissolving idebenone and uronic acid in a solvent at -5°C to 5°C to obtain a reactant solution;

[0042] S2: adding an activator and a catalyst to the reactant solution, and stirring and mixing under the protection of a protective gas to react to obtain a mixed product;

[0043] S3: adding a quencher to the mixed product, extracting with an extractant three times, combining the organic liquid layers, and drying with a desiccant to obtain a crude product;

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

[0045] In another aspect, the present invention provides use of the idebenone derivatives described above in cosmetics.

[0046] In another aspect, the present invention provides use of the idebenone derivatives described above in the preparation of drugs for treating mitochondrial dysfunction or neurodegenerative diseases.

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

[0048] The idebenone derivatives of the present invention have a uronic acid structure, which can greatly improve the water solubility of idebenone, reduce the first-pass effect of idebenone, and provide more and more effective drug solutions for the treatment of mitochondrial dysfunction and neurodegenerative diseases. At the same time, the inventors unexpectedly found that the idebenone derivatives have better stability in the air and lighter color, which can reduce the use and storage conditions of idebenone, greatly broadening the application scenarios of idebenone in the field of transdermal absorption such as cosmetics. On the other hand, the preparation method of the idebenone derivatives is simple, the conditions are mild, and it has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1It is a graph showing the overall antioxidant capacity test results of Examples 1 to 8 and related substances. DETAILED DESCRIPTION

[0050] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0051] Example 1

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

[0053] S1: In a 50 mL reaction bottle, 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 at 0°C, and stir to obtain a uniform and clear reactant 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 was introduced. The temperature was raised to 30° C. under a continuous argon atmosphere, and the mixture was stirred and mixed to react. The reaction progress was monitored by thin layer chromatography. The reaction was terminated after the reaction was continued for 16 h to obtain a mixed product.

[0055] S3: Sodium bicarbonate (1.000 g) was added to the mixed product to quench the reaction, and the reaction mixture was extracted three times with dichloromethane, using 5 mL each time, the organic liquid layers were combined, and anhydrous sodium sulfate (2.000 g) was added to dry the organic liquid layers to obtain a crude product;

[0056] S4: The obtained 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 obtained idebenone derivative has the following hydrogen NMR spectrum: 1 HNMR (400MHz, CDCl 3 ): 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 a preparation method thereof. The preparation method of the idebenone derivative is basically the same as that of Example 1, except that glucuronic acid is replaced by galacturonic acid; the specific structural formula is as follows:

[0061]

[0062] The obtained idebenone derivative has the following hydrogen NMR spectrum: 1 HNMR (400MHz, CDCl 3 ): 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 a preparation method thereof. The preparation method of the idebenone derivative is as follows:

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

[0066] S2: Add N,N'-dicyclohexylcarbodiimide (1.857 g, 9.0 mmol) and 4-dimethylaminopyridine (0.078 g) to the reactant solution, and introduce argon gas. Heat to 30°C under a continuous argon atmosphere and stir to mix for reaction. Monitor the reaction progress by thin layer chromatography. After the reaction is continued for 18 hours, the reaction is terminated to obtain a mixed product.

[0067] S3: Potassium bicarbonate (1.000 g) was added to the mixed product to quench the reaction, and the reaction mixture was extracted three times with dichloromethane, using 5 mL each time, the organic liquid layers were combined, and anhydrous sodium sulfate (2.000 g) was added to dry the organic liquid layers to obtain a crude product;

[0068] S4: The obtained 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 obtained idebenone derivative has the following hydrogen NMR spectrum:1 HNMR (400MHz, CDCl 3 ): 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 a preparation method thereof. The preparation method of the idebenone derivative is as follows:

[0073] S1: In a 50 mL reaction bottle, gradually dissolve idebenone (1.692 g, 5.0 mmol) and hyaluronic acid (2.463 g, containing 6.5 mmol of carboxylic acid group) in 15 mL of dichloromethane at 0°C, and stir to obtain a uniform and clear reactant 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 was introduced. The temperature was raised to 30° C. under a continuous argon atmosphere, and the mixture was stirred and mixed to react. The reaction progress was monitored by thin layer chromatography. The reaction was terminated after the reaction was continued for 16 h to obtain a mixed product.

[0075] S3: Sodium bicarbonate (1.000 g) was added to the mixed product to quench the reaction, and the reaction mixture was extracted three times with dichloromethane, using 5 mL each time, the organic liquid layers were combined, and anhydrous sodium sulfate (2.000 g) was added to dry the organic liquid layers to obtain a crude product;

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

[0077]

[0078] The obtained idebenone derivative has the following hydrogen NMR spectrum: 1 HNMR (400MHz, CDCl 3): 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 a preparation method thereof. The preparation method of the idebenone derivative is as follows:

[0081] S1: In a 50 mL reaction bottle, gradually dissolve idebenone (1.692 g, 5.0 mmol) and alginic acid (0.969 g, containing 5.5 mmol of carboxylic acid group) in 15 mL of dichloromethane at 0°C, and stir to obtain a uniform and clear reactant 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 was introduced. The temperature was raised to 30° C. under a continuous argon atmosphere, and the mixture was stirred and mixed to react. The reaction progress was monitored by thin layer chromatography. The reaction was terminated after the reaction was continued for 16 h to obtain a mixed product.

[0083] S3: Sodium bicarbonate (1.000 g) was added to the mixed product to quench the reaction, and the reaction mixture was extracted three times with dichloromethane, using 5 mL each time, the organic liquid layers were combined, and anhydrous sodium sulfate (2.000 g) was added to dry the organic liquid layers to obtain a crude product;

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

[0085]

[0086] The obtained idebenone derivative has the following hydrogen NMR spectrum: 1 HNMR (400MHz, CDCl 3 ): 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 a preparation method thereof. The preparation method of the idebenone derivative is as follows:

[0089] S1: In a 50 mL reaction bottle, 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 at -5°C, and stir to obtain a uniform and clear reactant solution;

[0090] S2: Add N,N'-carbonyldiimidazole (1.246 g, 6.5 mmol) and 4-dimethylaminopyridine (0.078 g) to the reactant solution, and introduce argon gas. Heat to 20°C under continuous argon atmosphere and stir to mix for reaction. Monitor the reaction progress by thin layer chromatography. After the reaction is continued for 24 hours, the reaction is terminated to obtain a mixed product.

[0091] S3: Calcium bicarbonate (1.000 g) was added to the mixed product to quench the reaction, and the reaction mixture was extracted three times with dichloromethane, using 5 mL each time, the organic liquid layers were combined, and anhydrous calcium chloride (2.000 g) was added to dry the organic liquid layers to obtain a crude product;

[0092] S4: The obtained 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 obtained idebenone derivative has the following hydrogen NMR spectrum: 1 HNMR (400MHz, CDCl 3 ): 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 a preparation method thereof. The preparation method of the idebenone derivative is as follows:

[0097] S1: In a 50 mL reaction bottle, 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 at 5°C, and stir to obtain a uniform and clear reactant solution;

[0098] S2: Add N,N'-carbonyldiimidazole (1.246 g, 6.5 mmol) and 4-dimethylaminopyridine (0.078 g) to the reactant solution, and introduce argon gas. Heat to 40°C under continuous argon atmosphere and stir to mix for reaction. Monitor the reaction progress by thin layer chromatography. After the reaction is continued for 12 hours, the reaction is terminated to obtain a mixed product.

[0099] S3: Sodium bicarbonate (1.000 g) was added to the mixed product to quench the reaction, and the mixture obtained by the reaction was extracted three times with dichloromethane, using 5 mL each time, the organic liquid layers were combined, and anhydrous magnesium sulfate (2.000 g) was added to dry the organic liquid layers to obtain a crude product;

[0100] S4: The obtained 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 H 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 a preparation method thereof. The preparation method of the idebenone derivative is as follows:

[0104] S1: In a 50 mL reaction bottle, 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 at 15°C, and stir to obtain a uniform and clear reactant solution;

[0105] S2: Add N,N'-carbonyldiimidazole (1.246 g, 6.5 mmol) and 4-dimethylaminopyridine (0.078 g) to the reactant solution, and introduce argon gas. Heat to 50°C under a continuous argon atmosphere and stir to mix for reaction. Continue the reaction for 6 hours and then terminate the reaction to obtain a mixed product.

[0106] S3: Sodium bicarbonate (1.000 g) was added to the mixed product to quench the reaction, and the mixture obtained by the reaction was extracted three times with dichloromethane, using 5 mL each time, the organic liquid layers were combined, and anhydrous magnesium sulfate (2.000 g) was added to dry the organic liquid layers to obtain a 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 H NMR spectrum of the obtained idebenone derivative was consistent with that of Example 6.

[0109] Comparative Example 1

[0110] In a 50 mL reaction bottle, 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 while maintaining 0°C, stir and mix to obtain a uniform and clear reactant solution, then maintain room temperature and dry under vacuum to remove dichloromethane to obtain a mixture of idebenone and glucuronic acid.

[0111] Comparative Example 2

[0112] The glucuronic acid in Example 1 was replaced by gluconic acid, and the preparation method remained unchanged to obtain a derivative of idebenone modified by gluconic acid.

[0113] The specific structural formula is as follows:

[0114]

[0115] The obtained idebenone derivative has the following hydrogen NMR spectrum: 1 HNMR (400MHz, CDCl 3 ): 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] The glucuronic acid in Example 1 was replaced by 1-adamantanedecarboxylic acid, and the preparation method remained unchanged to obtain a derivative of idebenone modified by 1-adamantanedecarboxylic acid.

[0118] The specific structural formula is as follows:

[0119]

[0120] The obtained idebenone derivative has the following hydrogen NMR spectrum: 1 HNMR (400MHz, CDCl 3): 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] With reference to the 2020 edition of the Chinese Pharmacopoeia, accurately weigh 1.00 g of the solid dispersion powder of the test sample, place it in a certain volume of pure water at 25°C±2°C, shake it vigorously for 30 seconds every 5 minutes, and observe the dissolution within 30 minutes. If there are no visible solute particles, it is considered to be completely dissolved.

[0123] In the water solubility test, the amount of pure water is assumed to be m:

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

[0125] When 1mL≤m<10mL, it is judged to be easily soluble;

[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 very slightly soluble;

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

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

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

[0133]

[0134]

[0135] Oxidation stability test:

[0136] This test evaluates the stability of the sample based on its overall antioxidant capacity under certain storage conditions.

[0137] Preparation of samples to be tested:

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

[0139] Working solution preparation:

[0140] Take 6 mg of ABTS (2,2-azino-di(3-ethyl-benzothiazole-6-sulfonic acid) diammonium salt) and fully dissolve it in 1.6 mL of distilled water to obtain ABTS stock solution; add 2 mg of potassium persulfate (K 2 S 2 O 8 ) was fully dissolved in 3.0 mL of distilled water to obtain K 2 S 2 O 8 Stock solution: Take 1mL ABTS stock solution and 1mL K 2 S 2 O 8 The stock solutions were mixed and placed in a dark box for 12 h to obtain the ABTS working solution.

[0141] Antioxidant test:

[0142] Monitored by UV-visible spectrophotometer, the prepared ABTS working solution was diluted with distilled water until its absorbance at 734 nm was 0.7, recorded as A 0 Then, the antioxidant sample to be tested was added to the diluted working solution to form a uniform mixed solution with a concentration of 10 nM. After being kept at 25°C for 30 min, the absorbance at 734 nm was measured using a UV-visible spectrophotometer and recorded as A. s According to the Lambert-Beer law, the antioxidant capacity ratio (ABTS) of the test sample was calculated using the following formula: + %):

[0143] ABTS + % = (A 0 -A s ) / A 0 ×100%.

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

[0145] It can be seen from Examples 1 to 7 and Example 8 that the idebenone derivatives prepared by the method provided by the present invention have a higher yield, while the yield of the idebenone derivatives prepared using conditions outside the scope of the present invention is lower.

[0146] It can be seen from Examples 1 to 8 and the idebenone control group that the idebenone derivatives with a uronic acid structure provided by the present invention have much higher water solubility than idebenone, which is beneficial to reduce the first-pass effect of the drug and provide more and more effective drug solutions for the treatment of mitochondrial dysfunction and neurodegenerative diseases.

[0147] It can be seen from Examples 1 to 8 and Comparative Example 1 that the reason why the idebenone derivatives provided by the present invention have excellent water solubility is the result of the preparation reaction process, rather than being achieved by simple mixing.

[0148] It can be seen from Examples 1 to 8 and the idebenone control group that the idebenone derivatives with a uronic acid structure provided by the present invention have better overall antioxidant capacity than idebenone both initially and after 45 days of storage, indicating that the idebenone derivatives provided by the present invention have better stability and can reduce the use and storage conditions of idebenone.

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

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

[0151] It can be seen from Examples 1 to 8 and Comparative Example 2 that, although the introduction of the 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 at the initial stage and after 45 days of storage.

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

[0153] It can be seen from Examples 1 to 8 and the idebenone control group that the idebenone derivatives provided by the present invention are lighter in 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 the present invention illustrates the idebenone derivatives and their preparation methods and applications through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned process steps to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials selected by the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. An idebenone derivative, characterized in that: The idebenone derivative has the following structure: Wherein, R is a uronic acid residue, and n is an integer greater than or equal to 1.

2. The idebenone derivative according to claim 1, characterized in that The uronic acid is one of monouronic acid, disuronic acid, oligouronic acid or polyuronic acid, or a combination of at least two of them.

3. The idebenone derivative according to claim 1 or 2, characterized in that The uronic acid is one or a combination of at least two of glucuronic acid, galacturonic acid, mannuronic acid, iduronic acid, guluronic acid, chondroitin, pectin acid, hyaluronic acid or alginic acid; Preferably, the uronic acid is hyaluronic acid or alginic acid; More preferably, the uronic acid is alginic acid.

4. The idebenone derivative according to any one of claims 1 to 3, characterized in that The uronic acid is alginic acid.

5. The method for preparing an idebenone derivative according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: Idebenone reacts with uronic acid to obtain the idebenone derivative.

6. The preparation method according to claim 5, characterized in that: The molar ratio of idebenone to the uronic acid carboxylic acid group in uronic acid is 1.0:(1.0-1.3); Preferably, the reaction is carried out in the presence of an activator; Preferably, the activation reagent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and / or N,N'-dicyclohexylcarbodiimide; Preferably, the molar ratio of idebenone to activator is 1.0:(1.3-1.8); Preferably, the reaction is carried out in the presence of a catalyst; Preferably, the catalyst is one or a combination of at least two of 4-dimethylaminopyridine, 4-piperidinylpyridine or N,N'-carbonyldiimidazole; Preferably, the reaction is carried out in a solvent selected from one or a combination of at least two of dichloromethane, chloroform or dioxane.

7. The preparation method according to claim 5 or 6, characterized in that: Before the reaction, idebenone and uronic acid are dissolved in a solvent at -5°C to 5°C; Preferably, the reaction is carried out under stirring; Preferably, the reaction temperature is 20-40°C; Preferably, the reaction time is 12 to 24 hours; Preferably, the reaction is carried out under the protection of a protective gas; Preferably, the protective gas is selected from one or a combination of at least two of helium, neon, argon or nitrogen; Preferably, after the reaction is completed, a quencher is added to the reaction solution to quench the reaction; Preferably, the quencher is one or a combination of at least two of sodium bicarbonate, potassium bicarbonate or calcium bicarbonate; Preferably, after the reaction is quenched, the reaction solution is extracted with an extractant, the organic liquid layers are combined, and dried with a desiccant to obtain a crude product, and the crude product is purified to obtain a purified idebenone derivative; Preferably, the extractant is selected from one or a combination of dichloromethane or chloroform; Preferably, the desiccant is one or a combination of at least two of anhydrous magnesium sulfate, anhydrous sodium sulfate or anhydrous calcium chloride.

8. The preparation method according to any one of claims 5 to 7, characterized in that: The preparation method of the idebenone derivative specifically comprises the following steps: S1: dissolving idebenone and uronic acid in a solvent at -5°C to 5°C to obtain a reactant solution; S2: adding an activator and a catalyst to the reactant solution, and stirring and mixing under the protection of a protective gas to react to obtain a mixed product; S3: adding a quencher to the mixed product, extracting with an extractant three times, combining the organic liquid layers, and drying with a desiccant to obtain a crude product; S4: purifying the crude product to obtain the idebenone derivative.

9. Use of the idebenone derivative according to any one of claims 1 to 4 in cosmetics.

10. Use of the idebenone derivative according to any one of claims 1 to 4 in the preparation of a medicament for treating mitochondrial dysfunction or neurodegenerative diseases.

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