Derivative of rice bran extract as well as preparation method and application of derivative

Abstract

The invention discloses a derivative of a rice bran extract as well as a preparation method and application of the derivative. A C-3 benzoate prodrug system is constructed, the transmembrane absorption efficiency is remarkably improved by optimizing the oil-water partition coefficient, fixed-point slow release of active ingredients is achieved through inflammatory tissue esterase, and high bioavailability and low irritation are both considered. Meanwhile, C-25 fluorine atoms are introduced to serve as biological electron isosteres, and target affinity is enhanced by means of the unique electronic effect and polar hydrophobicity of the C-25 fluorine atoms; spatial conformation is locked through side chain saturation, so that the compound shows anti-inflammatory and tissue repair activity which is obviously superior to that of natural cycloartanol under the same dosage.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chemical industry, in particular to a derivative of rice bran extract and a preparation method thereof. BACKGROUND

[0002] As one of the main food crops in the world, rice is often regarded as a by-product in the processing process, but it actually contains rich natural active ingredients, and oryzanol is one of the most valuable ones. As the outer layer of rice, rice bran plays an important role in protecting the endosperm, and thus it is rich in various plant nutrients. High-purity oryzanol can be separated from rice bran oil through refining and extraction process, and this extraction source also gives oryzanol the properties of natural and safety, which lays a foundation for its subsequent application in many fields.

[0003] As a valuable plant nutrient derived from rice bran oil, oryzanol has been highly praised in the fields of functional food (health food) and daily chemical cosmetics for a long time. Modern phytochemical research has confirmed that oryzanol is actually an ester complex formed by ferulic acid and various triterpene alcohols, among which, cycloartanol and its structural analogues are the key "aglycone" components that constitute the core biological activity of oryzanol. In the field of oral health food, cycloartanol is widely used to regulate lipid metabolism, improve autonomic nervous dysfunction and relieve menopausal syndrome due to its unique 9,19-cyclopropane skeleton, and it is a highly respected "sub-health" intervention material. In the field of cosmetics and dermatology, it is often added to barrier repair creams or sensitive skin care lotions as a mild soothing and repairing factor because its spatial conformation is highly consistent with the sterol components in human sebum film, and it is used to relieve skin redness and dryness.

[0004] Although cycloartanol is safe and widely used, its potency shows obvious limitations in dealing with complex or severe inflammatory reactions, and there is a "efficacy ceiling" that is difficult to break through. In oral application scenarios, when the body encounters systemic inflammatory storms induced by high-fat diet, alcohol or chemical toxins (such as acute liver injury, metabolic inflammation), the anti-inflammatory activity of natural cycloartanol is too mild to quickly cut off the cascade reaction of key inflammatory factors like clinical drugs, and it cannot effectively inhibit tissue necrosis. In the field of external skin care, it often lags behind and is weak in soothing when facing physical damage (such as strong ultraviolet burns) or severe contact dermatitis. This "mildness in excess and insufficient strength" makes it difficult for it to be used as a core efficacy material to guide the development of emergency repair or high-potency anti-inflammatory products, but only as an auxiliary additive in functional food and cosmetics.

[0005] In addition to the insufficient activity intensity, the low bioavailability is a common problem that limits the potential of cycloartane in food and cosmetics. First, the absorption barrier of "not going in": the free hydroxyl group in the cycloartane molecule makes its polarity too large, and the oil-water partition coefficient (LogP) is not ideal. When taken orally, this limits its transmembrane transport efficiency in the gastrointestinal mucosa; when used externally, it makes it difficult to penetrate the dense stratum corneum of the skin, resulting in most of the active ingredients remaining on the surface and failing to reach the dermis or target organs in the body. Second, the metabolic short board of "not staying": the side chain end (especially the tertiary carbon region at C-25) is a sensitive recognition site for oxidative metabolic enzymes (such as cytochrome P450) in the body. Whether in liver metabolism or in the local enzyme environment of the skin, this site is prone to oxidation and metabolism such as hydroxylation, causing the molecule to rapidly polarize and be excreted out of the body. The synergistic restriction of "poor absorption" and "fast metabolism" forces existing products to use extremely high addition amounts to maintain weak effects, greatly increasing costs and limiting the application of high-end formulations. SUMMARY

[0006] To solve or partially solve the problems in the related art, the first aspect of the present application provides a derivative of rice bran extract, which has a chemical structure shown in formula (I), or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof I.

[0007] The second aspect of the present application provides a preparation method of the derivative of rice bran extract, comprising the following steps: Step (1): dissolve cycloartane in an alkaline organic solvent, and drop benzoylating reagent in the presence of a catalyst to react; after the reaction is completed, the intermediate is obtained by post-treatment; Step (2): dissolve the intermediate obtained in step (1), fluorination reagent and photocatalyst in a mixed solvent, and perform photochemical reaction under the atmosphere of inert gas and ultraviolet light irradiation; after the reaction is completed, the solvent is removed to obtain a crude product, and the target product is obtained by separation and purification.

[0008] Further, in step (1): the alkaline organic solvent is anhydrous pyridine; the benzoylating reagent is benzoyl chloride; the catalyst is 4-dimethylaminopyridine (DMAP); wherein the molar ratio of cycloartane to benzoylating reagent is 1:1.0-1.5; the molar ratio of cycloartane to catalyst is 1:0.01-0.1.

[0009] Further, in step (1), the temperature for dropping the benzoylating reagent is controlled between -5°C and 5°C; the reaction temperature after dropping is controlled between 20°C and 30°C, the reaction time is 2-6h, and the post-treatment includes: quenching the reaction solution in ice water, precipitating, extracting with ethyl acetate, washing the organic phase with acid solution, alkaline solution and brine in sequence, drying and concentrating, and optionally recrystallizing with ethanol / acetone mixed solvent.

[0010] Further, in step (2), the fluorinating reagent is N-fluorobenzenesulfonimide (NFSI), and the photocatalyst is tetrabutylammonium decatungstate (TBADT); wherein the molar ratio of the intermediate to the fluorinating reagent is 1:1.2-2.0, and the molar ratio of the intermediate to the photocatalyst is 1:0.01-0.05.

[0011] Further, in step (2), the mixed solvent is a mixture of acetonitrile and dichloromethane, and the volume ratio of the two is 1:1-4:1; the wavelength of the ultraviolet light source is 360nm-375nm, and the power of the light source is 30W-60W.

[0012] Further, in step (2), the photochemical reaction time is 10-24h; the separation and purification are performed by using a Prep-HPLC, a C18 chromatographic column, and a mixed system of acetonitrile and water as the mobile phase, and a gradient elution program covering the range of acetonitrile:water volume ratio 90:10-100:0.

[0013] Further, in step (1), the molar ratio of cyclopropanospirostanol to benzoyl chloride is 1:1.2, and the molar ratio to 4-dimethylaminopyridine is 1:0.05; the dropping temperature is 0°C, and the reaction time is 3-4h; in step (2), the molar ratio of the intermediate to N-fluorobenzenesulfonimide is 1:1.5, and the molar ratio to tetrabutylammonium decatungstate is 1:0.02; the volume ratio of acetonitrile to dichloromethane is 2:1; the wavelength of the ultraviolet light source is 365nm, the power is 40W, and the reaction time is 12-18h.

[0014] The third aspect of the present application provides the use of the derivative, and the derivative is used for preparing health food and cosmetics.

[0015] The beneficial technical effects of the present application are as follows: To address the challenge of high polarity and difficulty in penetrating biological barriers inherent in natural alcohol compounds, this invention constructs a C-3 benzoic acid ester prodrug system. The introduction of a hydrophobic benzoyl group optimizes the oil-water partition coefficient (LogP) of the molecule, enabling it to not only efficiently fuse with and penetrate the stratum corneum of the skin or the gastrointestinal mucosa, but also to utilize esterases highly expressed in inflamed tissues for site-directed hydrolysis and sustained release of the active ingredient. This mechanism improves bioavailability while avoiding the irritation that may be caused by high local concentrations of free hydroxyl groups.

[0016] This invention introduces a fluorine atom at position C-25 as a "bioisosteric" form of hydrogen or hydroxyl, which not only enhances the dipole interaction between the molecule and the hydrophobic pocket of the target protein through its strong electron-withdrawing effect and unique "polar hydrophobicity," but also restricts the free swing of the spatial conformation through side chain saturation. This more rigid and better-matched "locked conformation" allows the compounds of this invention to exhibit significantly superior endogenous anti-inflammatory efficacy and tissue repair activity compared to natural cycloarpineol at the same dosage. Attached Figure Description

[0017] Figure 1 This is HE staining image 200 of the model group of Experimental Example 2 in this application of the present invention; Figure 2 HE staining image 400 of the model group of Experimental Example 2 in this application; Figure 3 HE staining image 200 of a low-dose group of a derivative of Experimental Example 2 in this application of the present invention; Figure 4 HE staining image 400 of a low-dose group of a derivative of Experimental Example 2 in this application; Figure 5 HE staining image 200 of a high-dose group of a derivative of Experimental Example 2 in this application of the present invention; Figure 6 HE staining image 400 of a high-dose group of a derivative of Experimental Example 2 in this application; Figure 7 HE staining image 200 of the original drug group in Experimental Example 2 of this application; Figure 8 HE staining image 400 of the original drug group in Experimental Example 2 of this application; Figure 9 This is HE staining image 200 of the normal control group of Experimental Example 2 in this application of the present invention; Figure 10 This is HE staining image 400 of the normal control group of Experimental Example 2 in this application. Detailed Implementation

[0018] The alternative embodiments of this application will now be described in more detail with reference to the accompanying drawings. While alternative embodiments of this application are shown in the drawings, it should be understood that this application can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to make this application more thorough and complete, and to fully convey the scope of this application to those skilled in the art.

[0019] The terminology used in this application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The singular forms “a,” “the,” and “the” used in this application and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise. It should also be understood that the term “and / or” as used herein refers to and includes any or all possible combinations of one or more of the associated listed items.

[0020] The contents of this application will be described in detail below with reference to the accompanying drawings, as follows: This invention application provides a derivative of rice bran extract, said derivative having the chemical structure shown in formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, or stereoisomer thereof. To address the challenge of poor transdermal absorption and low bioavailability of natural cycloarbutin due to the high polarity of the free hydroxyl group at the C-3 position, this invention constructs a highly efficient "prodrug system" by introducing a large hydrophobic benzoyl group. This modification fundamentally alters the oil-water partition coefficient (LogP) of the molecule, significantly enhancing the affinity of the molecule for ceramides and free fatty acids in the stratum corneum of the skin using the "like dissolves like" principle, thereby greatly improving physical permeability and transmembrane transport efficiency. Simultaneously, the benzoic acid ester bond at the C-3 position acts as a prodrug structure in vivo, effectively preventing glucuronidation metabolism of the free hydroxyl group before absorption, and allowing for slow hydrolysis by endogenous esterases after entering the deep epidermis or joint cavities. This "slow-release mechanism" avoids potential stimulation caused by sudden changes in local drug concentration, significantly improving the bioavailability and safety of the drug.

[0021] Introducing a fluorine atom at the end of the molecular side chain not only plays a crucial role in metabolic blocking but also significantly enhances the affinity for the target site by utilizing fluorine's unique electronic effects and van der Waals radius (1.47 Å, similar to hydrogen and hydroxyl groups). As an excellent "bioisostere," the fluorine atom at the C-25 position endows the side chain end with special "polar hydrophobicity," enabling it to significantly enhance binding stability when embedded in the hydrophobic pocket of anti-inflammatory receptors or enzymes through dipole-dipole or electrostatic interactions generated by the strong dipole moment of the CF bond. Furthermore, the introduction of the fluorine atom, combined with the saturation of the double bond, effectively alters the spatial flexibility of the side chain, making it exhibit a "conformation-locked" state that is more conducive to receptor binding compared to the free swinging state of natural products, thereby significantly improving the anti-inflammatory efficacy per molecule at the microscopic level.

[0022] In one embodiment of this invention, a method for preparing a derivative of the rice bran extract is provided, comprising the following steps: Step (1): Dissolve cycloarpine alcohol in an alkaline organic solvent, and add benzoylation reagent dropwise in the presence of a catalyst to carry out the reaction; after the reaction is completed, the intermediate is obtained by post-treatment; Step (2): Dissolve the intermediate, fluorinating agent and photocatalyst obtained in step (1) in a mixed solvent and carry out a photochemical reaction under an inert gas atmosphere and ultraviolet light irradiation; after the reaction is completed, remove the solvent to obtain the crude product, and then separate and purify to obtain the target product.

[0023] This embodiment employs a synthesis strategy of "protection-guided first, then precise modification". Step (1) utilizes esterification to block the C-3 hydroxyl group, eliminating the interference of the hydroxyl group on subsequent free radical reactions. Furthermore, the strong electron-withdrawing inductive effect of the benzoyl group reduces the electron cloud density in the A and B ring regions, thereby pushing the electrophilic photocatalyst to the far-end side chain of the molecule through the "polar mismatch" principle, improving regioselectivity. Step (2) utilizes the hydrogen atom transfer (HAT) photocatalytic mechanism to activate the inert CH bond under mild conditions. The photocatalyst abstracts hydrogen atoms from specific sites on the side chain to generate carbon free radicals, which are then captured by the fluorinating reagent, completing the conversion from the CH bond to the CF bond. This avoids the harsh conditions and low selectivity of traditional fluorination reactions.

[0024] In one embodiment of this invention application, in step (1): the alkaline organic solvent is anhydrous pyridine; the benzoylating agent is benzoyl chloride; the catalyst is 4-dimethylaminopyridine (DMAP); wherein the molar ratio of cycloargentol to benzoylating agent is 1:1.0 to 1.5; and the molar ratio of cycloargentol to catalyst is 1:0.01 to 0.1.

[0025] Anhydrous pyridine acts as both a solvent and an acid-binding agent, neutralizing the hydrogen chloride (HCl) byproduct generated in the reaction and driving the reaction forward. DMAP, as a strong nucleophilic catalyst, forms a highly active N-acylpyridinium salt intermediate with benzoyl chloride. This intermediate is far more electrophilic than benzoyl chloride itself, significantly reducing the activation energy for the acylation of sterically hindered triterpenoid 3-OH, thus greatly shortening the reaction time and increasing the conversion rate. The reagent ratio is designed to ensure complete substrate conversion (with a slight excess of benzoyl chloride) while avoiding excessive reagent that would increase post-processing difficulties; DMAP requires only a small amount of catalyst to maintain efficient cycling.

[0026] In one embodiment of this invention, in step (1): the temperature during the addition of the benzoylating reagent is controlled between -5°C and 5°C; the reaction temperature after the addition is completed is controlled between 20°C and 30°C, and the reaction time is 2 to 6 hours. The post-treatment includes: quenching the reaction solution in ice water to precipitate the precipitate, extracting it with ethyl acetate, washing the organic phase sequentially with acidic solution, alkaline solution and brine, drying and concentrating it, and optionally recrystallizing it using a mixed solvent of ethanol / acetone.

[0027] The low-temperature dropwise addition is to effectively control the intense exothermic reaction in the initial stage of acylation, preventing local overheating that could lead to side reactions (such as elimination reactions) or reagent decomposition. The subsequent increase to room temperature provides sufficient kinetic energy to complete the conversion. The post-processing utilizes the solubility difference between the product and impurities: acid washing removes residual pyridine and DMAP (converting them to water-soluble salts), and alkali washing removes excess benzoic acid (a hydrolysis product). The recrystallization step utilizes the crystallization properties of the intermediate in ethanol / acetone to further remove trace impurities, obtaining a high-purity intermediate. This is crucial for the subsequent photochemical reaction, as trace impurities can quench free radicals or poison the photocatalyst.

[0028] In one embodiment of this invention application, in step (2): the fluorinating agent is N-fluorobisbenzenesulfonylimide (NFSI); the photocatalyst is tetrabutylammonium decatungstate (TBADT); wherein the molar ratio of the intermediate to the fluorinating agent is 1:1.2 to 2.0; and the molar ratio of the intermediate to the photocatalyst is 1:0.01 to 0.05.

[0029] TBADT (decatungstate) is a polyoxometalate with an extremely strong hydrogen abstraction ability (HAT) in its excited state (W*) and a large size. It tends to attack CH bonds, which have high electron cloud density and low steric hindrance. Due to the electron-withdrawing effect and steric hindrance of the benzoyl group at C-3, TBADT preferentially attacks the C-25 position (electron-rich, sterically hindrance tertiary carbon) at the end of the side chain, generating a stable tertiary carbon radical. NFSI, as a mild and efficient electrophilic fluorinating agent, can rapidly capture these carbon radicals, completing the fluorine atom transfer. The molar ratio is set to compensate for the unavoidable chain termination loss in the radical reaction, ensuring the efficient execution of the main reaction.

[0030] In one embodiment of this invention application, in step (2): the mixed solvent is a mixture of acetonitrile and dichloromethane, with a volume ratio of 1:1 to 4:1; the wavelength of the ultraviolet light source is 360nm to 375nm, and the power of the light source is 30W to 60W.

[0031] The mixed solvent system resolves the conflict between solubility and polarity: dichloromethane (DCM) provides excellent solubility for strongly lipophilic triterpenoid substrates, while acetonitrile (MeCN) is an ideal medium for photochemical reactions, stabilizing polar intermediates and promoting electron transfer. The light source parameters are precisely matched to the photophysical properties of the catalyst: TBADT exhibits the strongest ligand-metal charge transfer (LMCT) absorption band near 365 nm, and ultraviolet light in this band most efficiently excites the catalyst to generate high-energy radical species. The power range is designed to provide sufficient photon flux to maintain the reaction rate while avoiding excessive energy that could lead to product decomposition or solvent evaporation.

[0032] In one embodiment of this invention application, in step (2): the photochemical reaction time is 10 to 24 hours; the separation and purification are performed using preparative high performance liquid chromatography (Prep-HPLC), using a C18 column, with the mobile phase being a mixture of acetonitrile and water, and the gradient elution program covering the range of acetonitrile:water volume ratio from 90:10 to 100:0.

[0033] Reaction time control is crucial for free radical reactions; too short a time leads to incomplete conversion, while too long a time may result in the formation of polyfluorinated byproducts (such as difluorinated derivatives). Prep-HPLC separation is a solution to the challenge of minimal polarity differences between fluorinated products and starting materials. Because the introduction of a single fluorine atom has a negligible impact on the overall molecule's polarity, conventional column chromatography struggles to separate them. C18 reversed-phase chromatography utilizes the "polar hydrophobicity" of fluorine atoms and the retention time differences resulting from side-chain conformational changes, combined with gradient elution of a high proportion of organic phase, to efficiently achieve baseline separation of the target monofluorinated product from the starting material and isomer byproducts.

[0034] In one embodiment of this invention, in step (1), the molar ratio of cycloarpineol to benzoyl chloride is 1:1.2, and the molar ratio of cycloarpineol to 4-dimethylaminopyridine is 1:0.05; the dropping temperature is 0°C, and the reaction time is 3-4 h; in step (2), the molar ratio of the intermediate to N-fluorobis(benzenesulfonyl)imide is 1:1.5, and the molar ratio of the intermediate to tetrabutylammonium decatungstate is 1:0.02; the volume ratio of acetonitrile to dichloromethane is 2:1; the wavelength of the ultraviolet light source is 365 nm, the power is 40 W, and the reaction time is 12-18 h.

[0035] The specific parameters in this set represent the optimal process window, optimized through experiments. Under these conditions, the first-step reaction exhibits the highest acylation efficiency and the fewest byproducts. In the second-step reaction, a 2:1 solvent ratio achieves the optimal balance between substrate solubility and radical lifetime. The combination of 1.5 equivalents of NFSI and 0.02 equivalents of photocatalyst, along with 40W / 365nm illumination, results in peak regioselectivity for C-25 fluorination, while minimizing overfluorination side reactions and substrate degradation, thus achieving the highest overall yield.

[0036] In one embodiment of this invention application, the application of the derivative is provided, characterized in that the derivative is used in the preparation of health foods and cosmetics.

[0037] The fluorine atom at position C-25 of this derivative significantly enhances the CF bond energy, blocking easily oxidized double bonds and easily metabolized sites, thus significantly improving chemical stability (storage stability) and metabolic stability (long-lasting effect). The benzoyl group at position C-3 regulates the lipophilicity (LogP) of the molecule, promoting transmembrane absorption (transdermal / intestinal) and exerting a prodrug sustained-release effect in vivo through enzymatic hydrolysis. This structural modification allows it to deeply penetrate and repair the skin barrier when used as a cosmetic ingredient, and to maintain a longer-lasting blood drug concentration when used as a health food, thereby exerting anti-inflammatory and regulatory effects superior to those of natural products.

[0038] For clarity, the following examples will be used to provide a detailed description.

[0039] Example 1

[0040] Step 1: Benzoylation Reaction In a reaction flask equipped with a drying tube and a magnetic stirrer, cycloartenol (4.28 g, 10 mmol) was dissolved in anhydrous pyridine (20 mL). Benzoyl chloride (1.41 g, 10 mmol, i.e., 1.0 equivalent) was slowly added dropwise under -5°C ice-salt bath cooling, followed by a catalytic amount of 4-dimethylaminopyridine (DMAP, 12 mg, 0.01 mmol). After the addition was complete, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 h. TLC monitoring showed that the starting material was substantially converted. The reaction mixture was quenched in crushed ice water, precipitating a solid. The mixture was extracted with ethyl acetate, followed by routine acid washing, alkali washing, water washing, and drying and concentration to obtain the cycloartenol benzoate intermediate. Yield: 88%.

[0041] Step 2: Photocatalytic Selective CH Bond Fluorination. The cycloarpine benzoate (532 mg, 1 mmol) prepared in the previous step was placed in a quartz photochemical reaction tube. The fluorinating reagent N-fluorobis(benzenesulfonyl)imide (NFSI, 378 mg, 1.2 mmol, i.e., 1.2 equivalents) and the photocatalyst tetrabutylammonium decatungstate (TBADT, 33 mg, 0.01 mmol, i.e., 0.01 equivalents) were added. The solid was dissolved in a deoxygenated acetonitrile / dichloromethane (volume ratio 1:1, 10 mL total). High-purity nitrogen gas was bubbled into the reaction system for 15 minutes. The reaction tube was sealed, and the reaction was carried out at room temperature with magnetic stirring for 10 hours under UV LED light (wavelength 360 nm, power 30 W). After the reaction was completed, the solvent was evaporated under reduced pressure. The crude product was separated by preparative high-performance liquid chromatography (Prep-HPLC) (C18 column, acetonitrile:water gradient elution), the fraction was collected and lyophilized to obtain the target product. Results: A white solid powder was obtained, with an overall yield (based on the second step) of 18.5%.

[0042] Example 2

[0043] This embodiment uses optimized process parameters, corresponding to the best implementation method described in claim 7.

[0044] Step 1: Benzoylation Reaction In a reaction flask equipped with a drying tube and a magnetic stirrer, cycloartenol (4.28 g, 10 mmol) was dissolved in anhydrous pyridine (20 mL). Benzoyl chloride (1.69 g, 12 mmol, i.e., 1.2 equivalents) was slowly added dropwise under ice bath cooling at 0°C, followed by a catalytic amount of 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol, i.e., 0.05 equivalents). After the addition was complete, the ice bath was removed, and the reaction mixture was stirred at room temperature for 3.5 h. TLC monitoring showed complete disappearance of the starting material. Post-treatment was the same as in Example 1, involving drying with anhydrous sodium sulfate and concentration under reduced pressure, with recrystallization by ethanol / acetone if necessary. Cycloartenol benzoate intermediate was obtained. Yield: 96%.

[0045] Step 2: Photocatalytic Selective CH Bond Fluorination. The cycloarpine benzoate (532 mg, 1 mmol) prepared in the previous step was placed in a quartz photochemical reaction tube. The fluorinating reagent N-fluorobis(benzenesulfonyl)imide (NFSI, 473 mg, 1.5 mmol, i.e., 1.5 equivalents) and the photocatalyst tetrabutylammonium decatungstate (TBADT, 66 mg, 0.02 mmol, i.e., 0.02 equivalents) were added. The solid was dissolved in a deoxygenated acetonitrile / dichloromethane (2:1 volume ratio, 10 mL total) mixed solvent. High-purity nitrogen gas was bubbled into the reaction system for 15 minutes. The reaction tube was sealed, and the reaction was carried out at room temperature with magnetic stirring for 15 hours under UV LED light (wavelength 365 nm, power 40 W). After the reaction, the solvent was removed by vacuum distillation. The crude product was separated by preparative high-performance liquid chromatography (Prep-HPLC), and the fraction was collected and lyophilized. Results: The target product was obtained as a white solid powder, with an overall yield (based on the second step) of 26.8%.

[0046] 1H NMR (300 MHz, DMSO-d6) δ 8.05–7.96 (m, 2H, Ar-H), 7.70–7.62 (m,1H, Ar-H), 7.58–7.49 (m, 2H, Ar-H), 4.72–4.60 (m, 1H, H-3), 2.05–1.85 (m,2H), 1.78–1.50 (m, 6H), 1.36 (d , 6H, H-26, H-27), 1.45–1.10 (m, 12H, overlapping skeletal signals), 0.98 (s, 3H, Me), 0.92 (d,3H, H-21), 0.90 (s,3H,Me), 0.88 (s,3H,Me), 0.83 (s, 3H, Me), 0.60 (d,1H, H-19a), 0.38 (d,1H,H-19b). 13C NMR (75 MHz, DMSO-d6) δ(ppm):165.6 (C=O), 133.4, 130.1, 129.6,128.9 (Ar-C), 94.8 (d, C-25), 80.7 (C-3), 52.3, 49.0, 48.1, 47.2, 45.4, 44.0(d, C-24), 39.4, 36.2, 35.9, 35.0, 32.9, 32.2, 30.0, 29.8 (d, C-26, C-27),28.2, 26.8, 26.2, 25.8, 23.7, 21.5, 21.2, 19.5, 18.5, 18.2, 15.4. Example 3

[0047] Step 1: Benzoylation Reaction In a reaction flask equipped with a drying tube and a magnetic stirrer, cycloartenol (4.28 g, 10 mmol) was dissolved in anhydrous pyridine (20 mL). Benzoyl chloride (2.11 g, 15 mmol, i.e., 1.5 equivalents) was slowly added dropwise under cooling at 5°C, followed by a catalytic amount of 4-dimethylaminopyridine (DMAP, 122 mg, 1.0 mmol, i.e., 0.1 equivalents). After the addition was complete, the reaction mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC until complete. Post-processing was performed as described above to obtain the cycloartenol benzoate intermediate. Yield: 95% (slight loss due to excessive reagent washing during post-processing).

[0048] Step 2: Photocatalytic Selective CH Bond Fluorination. The cycloarpine benzoate (532 mg, 1 mmol) prepared in the previous step was placed in a quartz photochemical reaction tube. The fluorinating reagent N-fluorobis(benzenesulfonyl)imide (NFSI, 630 mg, 2.0 mmol, i.e., 2.0 equivalent) and the photocatalyst tetrabutylammonium decatungstate (TBADT, 165 mg, 0.05 mmol, i.e., 0.05 equivalent) were added. The solid was dissolved in a deoxygenated acetonitrile / dichloromethane (4:1 volume ratio, 10 mL total) mixed solvent. High-purity nitrogen gas was bubbled into the reaction system for 15 minutes. The reaction tube was sealed, and the reaction was carried out under UV LED light (wavelength 375 nm, power 60 W) with magnetic stirring at room temperature for 24 h. After the reaction, the solvent was removed by vacuum distillation. The crude product was separated by preparative high-performance liquid chromatography (Prep-HPLC), and the fraction was collected and lyophilized. Results: The target product was obtained as a white solid powder, with an overall yield (based on the second step) of 23.5%.

[0049] Experimental Example 1 1. Experimental Materials and Instruments Test sample: Control group (Group A): Cyclocarbanol (raw material, purity >98%).

[0050] Experimental Group (Group B): Fluorinated cycloarpine benzoate derivative (the compound obtained in Example 2 of this invention, with a purity >98%).

[0051] Experimental animals: male SD rats (Sprague-Dawley), weighing 220±20g, SPF grade.

[0052] Solvent / Carrier: 0.5% sodium carboxymethyl cellulose (CMC-Na) aqueous solution (containing 0.1% Tween-80 suspension aid).

[0053] Instrument: Agilent 1290-6460 LC-MS / MS (Liquid Chromatography-Tandem Mass Spectrometry).

[0054] 2. Specific experimental steps Step 1: Animal grouping and drug administration 1. Twelve healthy SD rats were selected and randomly divided into two groups of six each (N=6).

[0055] 2. Fasting treatment: Fast for 12 hours before the experiment, but drink water freely to eliminate the interference of food on drug absorption.

[0056] 3. Preparation of reagents: Grind the reference standard and the test sample separately, suspend them in 0.5% CMC-Na solution, prepare a suspension with a concentration of 5 mg / mL, and sonicate for 30 minutes to ensure uniformity.

[0057] 4. Oral administration (PO): Both groups of rats were administered the drug via a single oral gavage at a dose of 20 mg / kg.

[0058] Step 2: Blood Sample Collection 1. Blood collection time points: Blood was collected before administration (0 h) and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 h after administration.

[0059] 2. Blood collection method: Blood was collected from the orbital venous plexus (approximately 0.2 mL / time) and collected in a heparin lithium anticoagulant tube.

[0060] 3. Plasma separation: The blood sample was centrifuged at 4000 rpm for 10 minutes at 4°C, and the supernatant plasma was separated and stored in a -80°C refrigerator for testing.

[0061] Step 3: Sample preparation and analysis (LC-MS / MS) 1. Protein precipitation: Take 50 μL of plasma, add 150 μL of acetonitrile solution containing internal standard (such as dexamethasone), vortex for 3 minutes to precipitate proteins.

[0062] 2. Centrifugation sampling: Centrifuge at 12000 rpm for 10 minutes, and take the supernatant for LC-MS / MS analysis.

[0063] 3. Detection conditions: Electrospray ionization (ESI) source, positive ion mode, multiple reaction monitoring (MRM) scan.

[0064] Step 4: Data Processing The main pharmacokinetic parameters were calculated using WinNonlin 8.3 software and a non-compartmental analysis (NCA) model.

[0065] Experimental results 4. Experimental Conclusions As can be seen from the table above, the blood drug concentration in the control group increased slowly and had a low peak value (ng / mL) after administration, and then decreased rapidly, indicating poor absorption and rapid metabolism.

[0066] In contrast, the experimental group exhibited a steep absorption phase, rapidly reaching a high peak plasma concentration (ng / mL). More importantly, during the elimination phase, the curve in the experimental group showed a significantly gentler slope, indicating that the drug clearance rate was significantly slower than that in the control group.

[0067] Overall evaluation: 1. Improved absorption: The peak concentration and area under the curve (AUC) of the experimental group were 4.0-fold and 6.2-fold higher than those of the control group, respectively. This confirms that the benzoylation modification at the C-3 position significantly improves the lipophilicity of the molecule, making it easier to penetrate the gastrointestinal mucosal barrier and enter the bloodstream.

[0068] 2. Metabolic stability: The elimination half-life of the experimental group was extended from 2.4 h to 7.8 h. This strongly demonstrates that the introduction of a fluorine atom at C-25 successfully blocked the oxidative attack of metabolic enzymes and significantly improved the metabolic stability of the compound.

[0069] Conclusion: The derivative obtained in Example 2 of the present invention has excellent oral bioavailability and good pharmacokinetic properties, overcoming the poor drug-likeness of natural cycloarpineol, and has great potential to be developed into a long-acting oral anti-inflammatory drug or a highly effective functional food ingredient.

[0070] Experimental Example 2 I. Experimental Grouping and Treatment The experiment was conducted with 5 groups of mice (n=10 per group): Normal control group: normal saline by gavage + normal saline by intraperitoneal injection; Model group: Liver inflammation was induced by gavage with normal saline and intraperitoneal injection of LPS (10 mg / kg); Original drug group: Cyclocarpine (50 mg / kg) administered by gavage + LPS administered intraperitoneally; Low-dose derivative group: Cyclocarpine derivative (25 mg / kg) administered by gavage + LPS intraperitoneal injection; High-dose derivative group: Cyclocarpine derivative (50 mg / kg) was administered by gavage + LPS was administered intraperitoneally.

[0071] The drug administration cycle was 7 days. Modeling was performed 1 hour after the last administration, and liver tissue was collected 24 hours after modeling for HE staining.

[0072] II. Experimental Results 1. Normal control group Under low magnification, the liver lobule structure is intact and clear, and the hepatic cords are arranged neatly radially around the central vein. The hepatocytes are uniform in size and regular in shape. Under high magnification, the hepatocytes have abundant, pale red cytoplasm, and the nuclei are bluish-purple, centrally located, and have clearly defined nucleoli. There is no dilation of the hepatic sinusoids, no inflammatory cell infiltration within the lobules or portal areas, and no hepatocyte degeneration or necrosis (see [link to article]). Figures 9-10 ).

[0073] 2. Model Group Under low magnification, the liver lobule structure was severely damaged, with disordered and broken hepatic cords, and significant dilation and congestion of the central vein and hepatic sinusoids. Under high magnification, numerous hepatocytes showed hydropic degeneration (loose and clear cytoplasm) and punctate necrosis (some hepatocyte nuclei were pyknosis, fragmented, and dissolved). Numerous inflammatory cells (mainly neutrophils and macrophages) were diffusely distributed in the portal areas and lobules, indicating severe liver tissue damage (see [link to article]). Figures 1-2 ).

[0074] 3. Original drug group Under low magnification, the structure of the liver lobules was partially restored, and the arrangement of the hepatic cords was more regular than in the model group, but local structural disorder was still visible. Under high magnification, the degree of hydropic degeneration of hepatocytes was reduced, the number of punctate necrotic foci decreased, and the area of ​​inflammatory cell infiltration was reduced, but a small number of inflammatory cells were still aggregated in the portal areas, and the hepatic sinusoids were slightly dilated (see...). Figures 7-8 ).

[0075] 4. Low-dose derivative group Under low magnification, the hepatic lobule structure was basically intact, with only slight disorganization of the hepatic cords around the central vein; under high magnification, the area of ​​hepatocyte degeneration was further reduced, necrotic foci were rare, inflammatory cell infiltration was mainly limited to the portal area, and hepatic sinusoidal dilation was not obvious (see...). Figures 3-4 ).

[0076] 5. High-dose derivative group Under low magnification, the hepatic lobule structure was nearly normal, the hepatic cords were arranged radially and neatly, the central vein was not dilated, and the morphology of the hepatic sinusoids was normal. Under high magnification, the hepatocytes were regular in morphology, with homogeneous cytoplasm, and no obvious degeneration or necrosis. Only occasional scattered inflammatory cells were seen in the portal areas, and the liver tissue damage was basically repaired (see...). Figures 5-6 ).

[0077] Results and conclusions: Cyclocarpine derivatives can significantly reduce LPS-induced inflammatory damage to mouse liver tissue, and the improvement effect is dose-dependent. At the same dose, the anti-inflammatory and hepatoprotective effects of the derivatives are superior to those of the original drug, cyclocarpine.

[0078] The embodiments of this invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical application, or improvement of the technology in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A derivative of rice bran extract, characterized in that, The derivative has the chemical structure shown in formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, or stereoisomer thereof. I。 2. A method for preparing a derivative of the rice bran extract, characterized in that, Includes the following steps: Step (1): Dissolve cycloarpine alcohol in an alkaline organic solvent, and add benzoylation reagent dropwise in the presence of a catalyst to carry out the reaction; after the reaction is completed, the intermediate is obtained by post-treatment; Step (2): Dissolve the intermediate, fluorinating agent and photocatalyst obtained in step (1) in a mixed solvent and carry out a photochemical reaction under an inert gas atmosphere and ultraviolet light irradiation; after the reaction is completed, remove the solvent to obtain the crude product, and then separate and purify to obtain the target product.

3. The preparation method according to claim 2, characterized in that, In step (1): the alkaline organic solvent is anhydrous pyridine; the benzoylating agent is benzoyl chloride; the catalyst is 4-dimethylaminopyridine (DMAP); wherein the molar ratio of cycloargentol to benzoylating agent is 1:1.0 to 1.5; and the molar ratio of cycloargentol to catalyst is 1:0.01 to 0.

1.

4. The preparation method according to claim 2, characterized in that, In step (1): the temperature during the addition of the benzoylating reagent is controlled between -5°C and 5°C; the reaction temperature after the addition is completed is controlled between 20°C and 30°C, and the reaction time is 2 to 6 hours. The post-treatment includes: quenching the reaction solution in ice water to precipitate the precipitate, extracting it with ethyl acetate, washing the organic phase sequentially with acidic solution, alkaline solution and brine, drying and concentrating it, and optionally recrystallizing it with a mixed solvent of ethanol / acetone.

5. The preparation method according to claim 2, characterized in that, In step (2): the fluorinating agent is N-fluorobisbenzenesulfonamide (NFSI); the photocatalyst is tetrabutylammonium decatungstate (TBADT); wherein the molar ratio of the intermediate to the fluorinating agent is 1:1.2 to 2.0; and the molar ratio of the intermediate to the photocatalyst is 1:0.01 to 0.

05.

6. The preparation method according to claim 2, characterized in that, In step (2): the mixed solvent is a mixture of acetonitrile and dichloromethane, with a volume ratio of 1:1 to 4:1; the wavelength of the ultraviolet light source is 360nm to 375nm, and the power of the light source is 30W to 60W.

7. The preparation method according to claim 2, characterized in that, In step (2): the photochemical reaction time is 10 to 24 hours; the separation and purification are performed using preparative high performance liquid chromatography (Prep-HPLC) with a C18 column, the mobile phase is a mixture of acetonitrile and water, and the gradient elution program covers the range of acetonitrile:water volume ratio from 90:10 to 100:

0.

8. The preparation method according to any one of claims 3 to 7, characterized in that: In step (1), the molar ratio of cycloarpineol to benzoyl chloride is 1:1.2, and the molar ratio of cycloarpineol to 4-dimethylaminopyridine is 1:0.05; the dropping temperature is 0°C, and the reaction time is 3-4 h; in step (2), the molar ratio of the intermediate to N-fluorobis(benzenesulfonyl)imide is 1:1.5, and the molar ratio of the intermediate to tetrabutylammonium decatungstate is 1:0.02; the volume ratio of acetonitrile to dichloromethane is 2:1; the wavelength of the ultraviolet light source is 365 nm, the power is 40 W, and the reaction time is 12-18 h.

9. The application of the derivative according to claim 1, characterized in that, The derivatives are used to prepare health foods and cosmetics.

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