Arbutin analogue, preparation method thereof and application of arbutin analogue in preparation of medicine for treating chronic colitis

Abstract

The invention discloses an arbutin analogue, a preparation method thereof and application of the arbutin analogue in preparation of a medicine for treating chronic colitis, and belongs to the technical field of medicines. The arbutin analogue is structurally characterized in that a galactosyl group is connected with a polysubstituted benzene ring through a flexible connecting chain-(CH) n-O-to form a novel structure which is remarkably different from a known compound arbutin. The arbutin analogue is prepared through chemical synthesis, and a pharmaceutical composition containing the arbutin analogue is provided. Pharmacological experiments prove that the representative compounds hydroquinone monogalactoside and 3, 4-dihydroxyphenol galactoside show disease treatment activity obviously superior to that of arbutin in a DSS-induced mouse chronic colitis model, the disease activity index can be effectively improved, and colon tissue damage can be relieved. Therefore, the compound provided by the invention can be used for preparing medicines for preventing and / or treating chronic colitis. Formula (1)

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a bearberry glycoside analogue, a preparation method thereof and application thereof in preparing a medicine for treating colonic diseases. BACKGROUND

[0002] Chronic colitis refers to inflammatory lesions of the colon caused by various causes, and clinically mainly includes chronic colitis, ulcerative colitis (UC), granulomatous colitis and Crohn's disease (CD), etc. Chronic colitis is formed due to infection of various pathogens, diet and other environmental factors, combined with genetic background and immune dysfunction of the body, etc.

[0003] At present, the treatment of chronic colitis in the clinic still lacks efficient and specific drugs, and a comprehensive treatment plan is often used, and common drugs include salicylic acid drugs such as sulfasalazine (SASP). Although these drugs can control the inflammatory response and relieve clinical symptoms to a certain extent, there are still problems such as limited efficacy, easy recurrence and more adverse reactions, so it is of important clinical significance to develop new efficient and safe anti-colitis drugs.

[0004] In recent years, natural products have attracted widespread attention in the treatment of inflammatory bowel disease due to their multi-target and low toxicity characteristics. Arbutin, as a natural glycoside compound extracted from various plants, early researches were mostly focused on its whitening, antioxidant and other effects. The latest research found that arbutin showed significant anti-inflammatory and immunoregulatory activity, and showed good therapeutic potential in experimental colitis models. Its mechanism of action may involve inhibition of the activation of inflammatory signaling pathways such as nuclear factor-kappa B (NF-κB), reduction of pro-inflammatory cytokine levels such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and regulation of intestinal mucosal barrier function. The natural source characteristics and good safety of arbutin provide a good prospect for its application in the field of chronic colitis treatment, and it is expected to become an effective supplement or alternative to traditional anti-colitis drugs.

[0005] Inflammatory bowel disease (IBD), such as chronic colitis and ulcerative colitis (UC), is a chronic intestinal inflammatory disease with complex etiology and easy recurrence. Current clinical treatment mainly relies on aminosalicylic acid drugs, glucocorticoids and immunosuppressants. However, these drugs have the following limitations: (1) long-term use is prone to drug resistance, leading to decreased efficacy; (2) glucocorticoids and other systemic administration methods have significant side effects and poor patient tolerance; (3) lack of lesion targeting, and high risk of adverse reactions due to systemic exposure. Arbutin, as a known hydroquinone glucoside compound, is widely used in the field of cosmetics due to its whitening and antioxidant activity. However, the glucoside bond in arbutin is easily hydrolyzed by alpha-glucosidase in the human upper digestive tract, leading to the premature release of active molecules hydroquinone and absorption into the blood. This not only makes it difficult to achieve effective concentration at the site of colonic lesions, but also may cause systemic toxicity. Therefore, arbutin itself is not suitable for the treatment of colonic diseases. SUMMARY

[0006] In view of the above status in the prior art, the purpose of the present application is to provide an arbutin analogue, a preparation method thereof and an application thereof in the preparation of a drug for treating chronic colitis. The present application provides a novel glycosylated phenolic compound that can target the release of the colon site, is highly efficient and has low toxicity, overcoming the deficiencies of arbutin and other prior art compounds in the treatment of colitis. The present application also provides a preparation method of the arbutin analogue and an application thereof in the preparation of a drug for preventing and / or treating chronic colitis.

[0007] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows: The present application provides an arbutin analogue, which is a compound having the following formula (I), or a pharmaceutically acceptable salt or solvate thereof: , Formula (I) In the formula: R1, R2, R3, R4, R5 are each independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; n is 0 or an integer from 1 to 10; the hydroxyl group in the sugar moiety is optionally protected by a protecting group, or is optionally substituted; R6 is a four-carbon sugar, a five-carbon sugar, a six-carbon sugar or a substituted monosaccharide derivative thereof; the four-carbon sugar is erythrose or threose, the five-carbon sugar is ribose, deoxyribose, arabinose, lyxose or xylose, and the six-carbon sugar is glucose, mannose, altrose, gulose, sorbose, talose, allose, galactose or idose.

[0008] Further, the core structure of the compounds of formula (I) is characterized by a glycosyl unit being connected to a polyhydroxylated benzene ring unit via a flexible alkyl chain linker (-(CH2) n ) and an ether bond (-O-).

[0009] Further, the glycosyl unit is a monosaccharide or polysaccharide residue; preferably, the monosaccharide residue is selected from glucose, galactose, mannose, fucose, N-acetylglucosamine or N-acetylgalactosamine. In case of a polysaccharide residue, the galactose residue is linked to the polyhydroxylated benzene ring, and the other saccharides are linked to the galactose. More preferably, the glycosyl group is a β-D-galactopyranosyl group.

[0010] Further, one or more of the hydroxyl groups (-OH) of the glycosyl unit can be optionally protected by a protecting group, such as acetyl (-Ac), benzoyl (-Bz) or benzyl (-Bn), or substituted by other substituents, such as C1-C6 alkyl.

[0011] The benzene ring unit comprises five substitution sites (R 5 ). These substituents can be the same or different, and are independently selected from the group consisting of: hydrogen; halogen: fluorine, chlorine, bromine; oxygen-containing groups: hydroxyl, C1-C6 alkoxy (e.g. methoxy, ethoxy), C1-C6 acyloxy; nitrogen-containing groups: amino, nitro, cyano, C1-C6 alkylamino; hydrocarbon groups: C1-C6 alkyl (e.g. methyl, ethyl, isopropyl), C3-C6 cycloalkyl (e.g. cyclopropyl); halogenated hydrocarbon groups: C1-C6 haloalkyl, such as trifluoromethyl.

[0012] In a preferred embodiment, at least one of R 5 is a hydroxyl group.

[0013] The present application provides a method for preparing the arbutin analog, comprising the steps of: subjecting an activated form of a galactose derivative (e.g. acetyl galactose trichloroimidate) to a glycosylation reaction with hydroquinone, a hydroquinone mono-protected derivative, 3,4-dihydroxyphenol and a phenol having a protected hydroxyl group, in the presence of a catalyst, and optionally followed by a deprotection reaction to obtain the arbutin analog.

[0014] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the arbutin analog, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0015] Furthermore, the pharmaceutical composition is formulated as a colon-targeted formulation, such as a pH-dependent coated tablet, a colonic enzyme-degrading capsule, or a time-release formulation, to further enhance drug accumulation in the colon.

[0016] Furthermore, the pharmaceutically acceptable carrier is an alkaline substance, and the carrier includes alkaline excipients or alkaline solvents. The alkaline excipients are one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, sodium caprylate, sodium isooctanoate, sodium citrate, and sodium tartrate. The alkaline solvents are one or more of sodium bicarbonate solution or injection, sodium citrate solution or injection, sodium lactate solution or injection, compound sodium lactate glucose solution or injection, sodium hydroxybutyrate solution or injection, monosodium glutamate solution or injection, and potassium glutamate solution or injection.

[0017] Furthermore, the alkaline excipient is sodium bicarbonate, potassium bicarbonate, or sodium hydroxide, and the alkaline solvent is a sodium bicarbonate solution or an injection solution.

[0018] The present invention also provides the use of the arbutin analogues, or pharmaceutically acceptable salts or solvates thereof, or the pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of chronic colitis.

[0019] Furthermore, the colonic disease is ulcerative colitis.

[0020] Compared with existing technologies (especially arbutin), the technical solution provided by this invention has the following significant beneficial effects: 1. Structural Innovation and New Applications: This invention is the first to design and synthesize glycosylated arbutin analogs (especially hydroquinone monogalactoside and 3,4-dihydroxyphenol galactoside) with galactose as the core feature. This key structural change (replacing the glucose group of arbutin with a galactose group) demonstrates the novel medicinal value and outstanding advantages of this class of compounds in the treatment of chronic colitis, opening up new applications for known structural units.

[0021] 2. Superior in vivo efficacy: As demonstrated by the pharmacological experiments in the detailed embodiments section, in a mouse model of ulcerative colitis induced by dextran sulfate sodium (DSS), the arbutin analogue of the present invention, at the same dose, exhibited significantly better therapeutic effects than positive control drugs (such as mesalazine) and arbutin. Specifically, it can more effectively inhibit the increase of the disease activity index (DAI), significantly improve colonic shortening, and histopathological examination shows more complete repair of colonic mucosal epithelial damage and a significant reduction in inflammatory cell infiltration.

[0022] 3. Improved safety potential: the galactoside bond is more stable to the upper digestive tract enzyme system of human body than the glucoside bond, and can be specifically hydrolyzed by the colon flora. This property indicates that the compound of the present application has the potential for colon-targeted release, thereby reducing the absorption and exposure of active molecules in the whole body, and obtaining better safety than arbutin and traditional drugs.

[0023] 4. Feasible synthetic path: the preparation method route is simple, the reaction conditions are mild, the raw materials are easy to obtain, the post-treatment is simple, the total yield is good, and it is suitable for large-scale production, and has good industrialization and application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 is the weight change result of each group of mice during administration; Figure 2 is the colon length (cm) result of each group of mice at the end of administration, *P<0.05 compared with the model group; Figure 3 is the treatment effect result of arbutin analogues D3, D6, arbutin and mesalazine on chronic colitis induced by DSS in mice; Figure 4 is the inhibition effect diagram of arbutin analogue D3 on inflammatory factors. DETAILED DESCRIPTION

[0025] The technical solutions of the present application will be further described in detail below in combination with specific examples and drawings, but the protection scope of the present application is not limited thereto.

[0026] Example 1: Synthesis of compound D3 The synthesis route of compound D3 (pyrocatechol monogalactoside) is as follows: , 1. Synthesis of compound D1 Compound peracetyl galactose (1 g, 2.6 mmol) and p-benzyloxyphenol (610 mg, 3.1 mmol) were placed in a 50 mL round-bottom flask, dissolved in 10 mL dichloromethane, protected by nitrogen, and then trifluoroboron ether (5 mL, 3.9 mmol) was added under ice bath, stirred for 6 h, and the reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to 7.0, dichloromethane and water were extracted, the organic phase was retained, saturated brine was washed, anhydrous magnesium sulfate was dried, and 950.8 mg of white foamy solid was obtained, which was compound D1, with a yield of 69%. mp: 143-145 ℃; 1 H NMR (400 MHz, Chloroform- d ) δ7.42~7.29 (m, 5H), 6.96~6.91 (m, 2H), 6.90~6.84 (m, 2H), 5.55~5.40 (m, 2H), 5.07 (dd, J = 10.5, 3.4 Hz, 1H), 5.01 (s, 2H), 4.91 (d, J = 8.0 Hz, 1H), 4.22 (dd, J = 11.3, 6.9 Hz, 1H), 4.14 (dd, J = 11.3, 6.4 Hz, 1H), 3.99 (t, J = 6.7 Hz, 1H), 2.17 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H); 13 C NMR (101 MHz, DMSO- d 6) δ 170.86, 170.15, 170.12, 152.35, 152.21, 136.48, 128.55, 128.38, 128.23, 118.79, 116.54, 98.99, 71.37, 70.29, 70.12, 70.11, 67.96, 61.70, 20.80, 20.70, 20.65. HRMS (ESI) calcd for C 27 H 30 O 11 Na + [M+Na] + : 553.168 6;found: 553.169 0.

[0027] 2、Synthesis of compound D3 Compound D1 (1 g, 1.9 mmol) was added to a 50 mL round bottom flask, dissolved in 10 mL of methanol, and sodium methoxide methanol solution (1 mL, 5 mol / L) was added and stirred for 2 h. The reaction was monitored by TLC until the starting material completely reacted. Cation exchange resin was added, the pH was adjusted to 7.0, the resin was removed by filtration, and concentrated under reduced pressure to obtain white solid compound D2.

[0028] White solid D2 was added to a 50 mL round bottom flask, methanol (10 mL) and palladium-carbon (50 mg) were added, and hydrogen was replaced three times. The reaction was stopped after 2 h of reaction and the reaction was monitored until the starting material disappeared. Silica gel was filtered and concentrated under reduced pressure to obtain 289.4 mg of white solid, which was compound D3, with a yield of 56%. mp: 140~141 ℃; 1H NMR (400 MHz, Deuterium Oxide) δ 6.96 ~ 6.85 (m, 2H), 6.71 (dq, J = 8.2, 3.5 Hz, 2H), 4.76 (dd, J = 7.1, 2.3 Hz, 1H), 3.83 (d, J = 2.8 Hz, 1H), 3.66 ~ 3.57 (m, 5H); 13 C NMR (101 MHz, DMSO- d 6) δ 152.68, 151.00, 118.27, 116.00, 102.92, 75.90, 73.84, 70.92, 68.67, 60.94, 40.70, 40.66, 40.50, 40.45, 40.29, 40.24, 40.03, 39.82, 39.61, 39.40. HRMS (ESI) calcd for C 12 H 16 O7Na + [M+Na] + : 295.079 4;found: 295.080 0。

[0029] Example 2: Synthesis of compound D6 The synthesis route of compound D6 (3,4-dihydroxyphenyl galactoside) is as follows: , 1. Synthesis of compound D4 Compound peracetyl galactose (1 g, 2.6 mmol) and 3,4-dibenzoyl phenol (940 mg, 3.1 mmol) were placed in a 50 mL round-bottom flask, dissolved in 10 mL dichloromethane, protected by nitrogen, and then trifluoroboron ether (5 mL, 3.9 mmol) was added under ice bath, stirred for 6 h, and the reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to 7.0, dichloromethane and water were extracted, the organic phase was retained, washed with saturated brine, dried over anhydrous magnesium sulfate, and 872 mg of white foamy solid was obtained, which was compound D4, with a yield of 53%. mp: 173 ~ 175 ℃ 1 H NMR (400 MHz, Methanol-d4) δ7.43 – 7.25 (m, 10H), 6.90 (d, J = 8.9 Hz, 1H), 6.70 (d, J= 2.8 Hz, 1H), 6.53(dd, J = 8.8, 2.8 Hz, 1H), 5.81 – 5.72 (m, 1H), δ 5.28 – 5.15 (m, 3H), 5.14(dt, J = 3.4, 1.1 Hz, 4H). 4.23 – 4.03 (m, 3H), 2.15 – 1.92 (m, 12H). 13 C NMR(101 MHz, Methanol-d4) δ 170.82, 170.11, 170.08, 152.62, 150.11, 143.86,136.96, 136.49, 128.53, 128.50, 128.48, 128.34, 128.26, 128.23, 128.19,128.18, 115.98, 112.34, 103.73, 98.72, 71.34, 71.17, 71.03, 70.97, 70.07,67.92, 61.66, 20.77, 20.66, 20.61.HRMS(ESI)calcd for C 34 H 36 NaO 12 + [M+Na] + :659.209 9.; found: 659.209 2.

[0030] 2. Synthesis of compound D6 Compound D4 (1 g, 1.6 mmol) was added to a 50 mL round-bottom flask, dissolved in 10 mL of methanol, and then a sodium methoxide methanol solution (1 mL, 5 mol / L) was added. The mixture was stirred for 2 h, and the reaction was monitored by TLC until the starting material was completely reacted. A cation exchange resin was added, the pH was adjusted to 7.0, the resin was removed by filtration, and the mixture was concentrated under reduced pressure to obtain a white solid, D5. The white solid D5 was added to a 50 mL round-bottom flask, along with 10 mL of methanol and 50 mg of palladium on carbon. The mixture was purged with hydrogen three times, and the reaction was allowed to proceed for 3 h. The reaction was monitored until the starting material disappeared. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain 157.3 mg of a white solid, compound D6, with a yield of 34.76%. mp: 168–169 °C 1 H NMR (400 MHz, Deuterium Oxide) δ 6.96~6.85 (m, 2H), 6.71 (dq, J =8.2,3.5 Hz, 2H), 4.76 (dd,J =7.1, 2.3 Hz, 1H), 3.83 (d, J =2.8 Hz, 1H), 3.66~3.57 (m, 5H); 13 C NMR (101 MHz, DMSO- d 6) δ 152.68, 151.00, 118.27, 116.00, 102.92,75.90, 73.84, 70.92, 68.67, 60.94, 40.70, 40.66, 40.50, 40.45, 40.29, 40.24,40.03, 39.82, 39.61, 39.40. HRMS(ESI)calcd for C 12 H 16 O7Na + [M+Na] + : 295.079 4; found: 295.080 0.

[0031] Example 3: Animal Experiment In animal experiment 1, 60 mice were randomly divided into 6 groups (n=10): a blank control group, a model group, a mesalazine group, an arbutin group, a D3 compound group, and a D6 compound group. Except for the blank control group, which drank plain water, all other groups freely ingested a 2.0 g / L sodium dextran sulfate (DSS) aqueous solution. Each intervention group was administered the corresponding compound daily via gavage (50 mg / kg), while the blank control group and the model group received an equal volume of pure water via gavage. From the start of the experiment, mouse weight was measured every two days, and the animals were sacrificed on day 15. During the experiment, daily changes in mouse weight were recorded, and the length of the mouse colon was measured after the experiment.

[0032] like Figure 1 As shown, during the 15-day observation period, the D3 and D6 components provided by this invention exhibited a significant advantage in maintaining the body weight of model mice. The body weight of the model group mice continued to decrease, with a cumulative decrease of 3.15 g, indicating successful model establishment. While the positive control drugs mesalazine and arbutin showed some alleviating effects, their body weight still showed a significant downward trend. In contrast, the D6 group experienced a weight loss of only 0.5 g, and the D3 group a decrease of 0.87 g. The weight change curves of both groups were highly similar to those of the normal control group, maintaining body weight at near-normal levels throughout the experiment. These results clearly demonstrate that the D3 and D6 components provided by this invention have a significant effect in inhibiting body weight loss induced by the model, with the D6 group showing the best performance, highlighting its superior role in body weight protection.

[0033] This inventionFigure 2 The colon length measurement results of mice in each group at the end of administration are shown. Figure 2 As shown, compared with the normal control group (6.10 cm), the colon length of the model group (4.21 cm) was significantly shortened, indicating that the modeling was successful. In the treatment group, the colon length of the positive control drug mesalazine group was 4.70 cm, while the colon lengths of the D3 and D6 groups provided by the present application were 5.14 cm and 5.87 cm, respectively, which were significantly improved compared with the model group (P < 0.05 compared with the model group), and also had a significantly improved effect compared with the mesalazine group and the arbutin group.

[0034] Notably, the colon length recovery effect of the D6 group was the most prominent, which was 1.66 cm longer than that of the model group, and numerically exceeded the traditional drug mesalazine group; the D3 group also showed a clear improvement effect, and the colon length was increased by 0.93 cm compared with the model group. This result further confirmed from the morphological level that the D3 and D6 components of the present application, especially D6, had a significant advantage in relieving colon tissue damage and promoting structural recovery, and exhibited excellent technical effects and application potential.

[0035] As shown in the figure, Figure 3 By comparing the pathological section results of the colon tissues of mice in each group, the D3 and D6 components of the present application exhibited a significant advantage in repairing the colon mucosa damage caused by chronic colitis induced by DSS. The colon mucosa structure of the model group was severely damaged, accompanied by a large number of inflammatory cell infiltration, while the positive control drugs mesalazine and arbutin could only partially improve this pathological change. In contrast, the treatment effect of the D6 group was the most prominent, and the integrity of the colon mucosa structure and the crypt morphology were significantly recovered, the inflammatory infiltration was effectively inhibited, and the tissue morphology was closest to the normal control group; the D3 group also showed a clear repair effect. This result confirmed from the histopathology level that the D3 and D6 components of the present application, especially D6, had a significant technical advantage over traditional drugs in reducing colonic inflammation and promoting tissue repair.

[0036] The present application further studied the inhibitory activity of compound D3 on the release of inflammatory factors IL-6, TNF-ɑ and NO by LPS-induced mouse mononuclear macrophages RAW264.7. The experimental results showed that LPS significantly promoted the release of inflammatory factors IL-6, TNF-ɑ and NO, while D3 significantly inhibited the release of these inflammatory factors, and showed a good dose-effect relationship ( Figure 4 ). As shown in the figure, Figure 4As shown, the present application further evaluates the inhibitory effect of compound D3 on the release of key inflammatory factors (TNF-α, IL-6 and NO) of mouse mononuclear macrophage RAW264.7 induced by lipopolysaccharide (LPS) at the cellular level. The results clearly show that D3 has direct and strong anti-inflammatory activity in the in vitro model, and the good dose-effect relationship provides a solid mechanism for the excellent therapeutic effect of D3 in vivo (D6) Figures 1-3 ) and in vivo (D3

[0037] Based on the structural homology of D3 and D6 and the previous overall pharmacodynamic evaluation (D6 shows better or equivalent effect than D3 in improving body weight, colon length and histopathology), it can be known that D6 should also have the same or better activity of inhibiting the release of inflammatory factors at the cellular level, and the effect is also dose-dependent. The present application links the clear molecular mechanism of D3 with the excellent overall efficacy of D6, and further proves the comprehensive advantages and great potential of the compounds (D3 and D6) of the present application from two aspects of "in vitro mechanism" and "in vivo efficacy".

[0038] The above examples are only used to illustrate the technical solutions of the present application, but not to limit it; although the present application has been described in detail with reference to the foregoing examples, for those skilled in the art, the technical solutions recorded in the foregoing examples can be modified, or some technical features can be replaced by equivalent; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions claimed by the present application.

Claims

1. An arbutin analogue, characterized in that: It is a compound having the following formula (I), or a pharmaceutically acceptable salt or solvate thereof: ， Formula (I), In the formula: R1, R2, R3, R4, and R5 are each independently selected from: hydrogen, halogen, hydroxyl, amino, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl. n is 0 or an integer from 1 to 10; The hydroxyl groups in the glycosyl moiety are optionally protected by protecting groups or optionally substituted; R6 is a tetracarbon sugar, pentose sugar, hexose sugar, or a monosaccharide derivative thereof; the tetracarbon sugar is erythrose or threose, the pentose sugar is ribose, deoxyribose, arabinose, lysose, or xylose, and the hexose sugar is glucose, mannose, arbutin, gulose, sorbose, taloose, allose, galactose, or idole.

2. The arbutin analogue according to claim 1, characterized in that: The R6 is selected from hydrogen, glucose, galactose, or their substituted monosaccharide derivatives.

3. The arbutin analogue according to claim 1, characterized in that, R1, R2, R3, R4, and R5 are each independently selected from: hydrogen, fluorine, chlorine, hydroxyl, methyl, trifluoromethyl, or methoxy; n is 1, 2, or 3.

4. The arbutin analogue according to claim 1, characterized in that, The arbutin analogue is specifically one of the following structural formulas: 。 5. The method for preparing the arbutin analogue according to any one of claims 1-4, characterized in that, The preparation method includes the following steps: in the presence of a catalyst, an activated form of galactose derivative is subjected to a glycosylation reaction with hydroquinone, a hydroquinone monoprotected derivative, or 3,4-dihydroxyphenol and phenol with a protected hydroxyl group, followed by a deprotection reaction to obtain the arbutin analogue.

6. A pharmaceutical composition comprising a therapeutically effective amount of an arbutin analogue, or a stereoisomer, tautomer, nitride, solvate, pharmaceutically acceptable salt or prodrug as described in any one of claims 1-4, and one or more pharmaceutically acceptable carriers or excipients.

7. The pharmaceutical composition according to claim 6, characterized in that: The pharmaceutically acceptable carrier is an alkaline substance, and the carrier includes alkaline excipients or alkaline solvents. The alkaline excipients are one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, sodium caprylate, sodium isooctanoate, sodium citrate, and sodium tartrate. The alkaline solvents are one or more of sodium bicarbonate solution or injection, sodium citrate solution or injection, sodium lactate solution or injection, compound sodium lactate glucose solution or injection, sodium hydroxybutyrate solution or injection, monosodium glutamate solution or injection, and potassium glutamate solution or injection.

8. The pharmaceutical composition according to claim 7, characterized in that: The alkaline excipient is sodium bicarbonate, potassium bicarbonate, or sodium hydroxide, and the alkaline solvent is a sodium bicarbonate solution or an injection solution.

9. The use of the arbutin analogue according to any one of claims 1-4 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for the prevention or treatment of chronic colitis.

10. The application according to claim 9, characterized in that, The chronic colitis mentioned includes inflammatory bowel disease and Crohn's disease.

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