A fluorine-containing long-chain compound, a self-assembled structure thereof, a preparation method thereof, and use thereof

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a fluorinated long-chain compound, its self-assembly structure, its preparation method, and its uses. The structural formula of the fluorinated long-chain compound of this invention is shown in Formula I. It can undergo self-assembly, achieving a sustained-release effect of flurbiprofen and 4-octylitaconic acid (or analogs of both), thereby enhancing anti-inflammatory and analgesic efficacy and reducing the adverse reactions of both, showing great application potential.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a fluorine-containing long-chain compound, its self-assembly structure, its preparation method, and its uses. Background Technology

[0002] Pain is a significant public health issue. According to the International Association for the Study of Pain, one in five people worldwide experiences chronic pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used clinical medications for antipyretics, anti-inflammation, and analgesia (Barkin 2015), widely used to treat and relieve various types of mild to moderate pain. The United States consumes approximately 30 billion doses of NSAIDs annually (Macedo et al. 2021).

[0003] Flurbiprofen is a derivative of benzyl alkyl acid and is currently the most potent propionic acid nonsteroidal anti-inflammatory drug (NSAID) known for its analgesic effect. It alleviates inflammation and pain by inhibiting cyclooxygenase and reducing prostaglandin production. Studies have shown that flurbiprofen can also exert its anti-inflammatory effect by inhibiting the expression of inducible nitric oxide synthase in RAW264.7 macrophages (Hinz et al. 2001). However, due to the presence of its free carboxylic acid group (-COOH), flurbiprofen may cause gastrointestinal adverse reactions. Therefore, it is often designed as a prodrug to mask this group. Many ester prodrugs have been synthesized, and researchers have attempted to use a "mutual prodrug" approach, combining two pharmacologically active substances to provide synergistic effects and reduce the adverse reactions of flurbiprofen (Ashraf et al. 2016).

[0004] Despite increased research on flurbiprofen prodrugs, some inherent challenges remain. For example, once released from the injection site, the prodrug typically transforms rapidly into its active form, limiting its potential for prolonged release. To address these issues, "self-assembled prodrugs" can achieve maximum drug loading efficiency and controlled, prolonged release kinetics. The design approach for self-assembled prodrugs typically involves covalently modifying a known prodrug with an additional biocompatible moiety (e.g., a natural fatty acid), transforming the prodrug into a self-deliverable carrier. This approach can increase the delivery amount of the parent drug and may undergo slower degradation (Cheetham et al. 2017). Although several self-assembled prodrugs for nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported, most of the covalently modified biocompatible moieties are pharmacologically inactive molecules. Therefore, developing self-assembled nanomedicine delivery systems combining two pharmacologically active substances has significant innovative and practical value.

[0005] 4-Octylitaconic acid is a derivative of the small molecule metabolite itaconic acid, which can be hydrolyzed into itaconic acid in macrophages. Itaconic acid is an important regulator of immunity and inflammation. In macrophages, itaconic acid and its derivatives have been shown to inhibit the tricarboxylic acid cycle enzyme succinate dehydrogenase, preventing the production of reactive oxygen species in complex I (Shi et al. 2022). Furthermore, studies have shown that 4-octylitaconic acid can exert an anti-inflammatory effect by targeting glyceraldehyde-3-phosphate dehydrogenase, blocking glycolysis, and reducing the release of inflammatory factors (Liao et al. 2019). However, its significant cellular permeability means that 4-octylitaconic acid may enter normal cells and interfere with metabolism.

[0006] Both flurbiprofen and 4-octylitaconic acid exert anti-inflammatory effects by acting on macrophages. Therefore, co-designing them as a self-assembling prodrug could enhance anti-inflammatory and analgesic effects while reducing adverse reactions, representing a promising drug development strategy. However, current research on the covalent modification and linking of flurbiprofen and 4-octylitaconic acid is lacking. Designing the linking molecular chains to construct a prodrug capable of self-assembly and smoothly releasing the active drug within the macrophage environment remains a pressing problem in this field. Summary of the Invention

[0007] In view of the problems existing in the prior art, the present invention provides a class of fluorinated long-chain compounds that can have anti-inflammatory and analgesic effects, and further provides a method for preparing the compound, its self-assembly structure and uses.

[0008] The compound represented by Formula I, or its salt, or its crystal form, or its stereoisomer, has the following structural formula:

[0009]

[0010] in,

[0011] X1 is selected from oxygen, carbonyl, substituted or unsubstituted methylene; wherein the substituent is selected from methyl;

[0012] X2 is selected from oxygen or carbonyl;

[0013] X3 is selected from oxygen, substituted or unsubstituted methylene groups; wherein the substituents are selected from =CH2;

[0014] X4 is selected from substituted or unsubstituted methylene groups; wherein the substituents are selected from methyl or =CH2;

[0015] X5 is selected from oxygen, carbonyl, substituted or unsubstituted methylene; wherein the substituent is selected from =CH2;

[0016] X6 is selected from oxygen or carbonyl groups;

[0017] X7 is absent, or is selected from oxygen, substituted or unsubstituted methylene; wherein the substituent is selected from methyl or =CH2;

[0018] X8 is absent, or is selected from oxygen, substituted or unsubstituted methylene groups; wherein the substituents are selected from =CH2;

[0019] X9 is either absent or selected from carbonyl groups;

[0020] X 10 The form is either absent or selected from oxygen, substituted or unsubstituted methylene groups; wherein the substituents are selected from =CH2;

[0021] X 11 It is either absent or selected from substituted or unsubstituted methylene groups; wherein the substituents are selected from =CH2;

[0022] X 12 It is either non-existent or selected from the carbonyl group;

[0023] X 13 It is either non-existent, or selected from oxygen;

[0024] R is selected from H or C1~C 12 alkyl.

[0025] Preferably, the compound has the structural formula shown in Formula II:

[0026]

[0027] in,

[0028] R1 is selected from methyl or H,

[0029] R2 is connected to other parts of the molecule via a single or double bond; when R2 is connected to other parts of the molecule via a single bond, R2 is selected from H; when R... 10 When R2 is connected to other parts of the molecule via a double bond, it is selected from =CH2;

[0030] R3 is connected to other parts of the molecule via a single or double bond; when R3 is connected to other parts of the molecule via a single bond, R3 is selected from H; when R... 11 When R3 is connected to other parts of the molecule via a double bond, it is selected from =CH2;

[0031] R is selected from H or C1~C 12 alkyl.

[0032] Preferably, the compound has the following structural formula:

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041] Preferably, the compound has the structural formula shown in Formula III:

[0042]

[0043] in,

[0044] R4 is selected from H or methyl.

[0045] R5 is connected to other parts of the molecule via a single or double bond; when R5 is connected to other parts of the molecule via a single bond, R5 is selected from H; when R5 is connected to other parts of the molecule via a double bond, R5 is selected from =CH2.

[0046] R6 is connected to other parts of the molecule via a single or double bond; when R6 is connected to other parts of the molecule via a single bond, R6 is selected from H; when R6 is connected to other parts of the molecule via a double bond, R6 is selected from =CH2.

[0047] R is selected from C1 to C2. 12 alkyl.

[0048] Preferably, the compound has the following structural formula:

[0049]

[0050] Preferably, the compound has the structural formula shown in Formula IV:

[0051]

[0052] in,

[0053] R7 is connected to other parts of the molecule via a single or double bond; when R7 is connected to other parts of the molecule via a single bond, R7 is selected from H; when R7 is connected to other parts of the molecule via a double bond, R7 is selected from =CH2.

[0054] R8 is connected to other parts of the molecule via a single or double bond; when R8 is connected to other parts of the molecule via a single bond, R8 is selected from H; when R8 is connected to other parts of the molecule via a double bond, R8 is selected from =CH2.

[0055] R is selected from C1 to C2. 12 alkyl.

[0056] Preferably, the compound has the following structural formula:

[0057]

[0058] This invention also provides a method for preparing the above-mentioned compound, or its salt, or its crystal form, or its stereoisomer, comprising the following steps:

[0059]

[0060] Step 1: Flurbiprofen is reacted with a chlorinating agent to obtain compound I-53-1;

[0061] Step 2: Compound I-53-1, triacetaldehyde, and iodide reagent are reacted to obtain compound I-53-2;

[0062] Step 3: React compound I-53-2 and compound F to obtain the compound shown in formula II.

[0063] Preferably, in step 1, the chlorinating agent is selected from at least one of oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, or triphosgene;

[0064] And / or, the reaction may or may not use a solvent; when the reaction uses a solvent, the solvent is selected from at least one of dichloromethane, petroleum ether, n-hexane, tetrahydrofuran, toluene, or benzene.

[0065] And / or, the reaction is carried out in the presence of a catalyst selected from at least one of N,N-dimethylformamide, N,N-dimethylaniline and pyridine, triethylamine or N-methylpyrrolidone;

[0066] And / or, the reaction temperature range is -20℃ to 80℃.

[0067] Preferably, in step 2, the iodizing agent is selected from at least one of sodium iodide or elemental iodine;

[0068] And / or, the solvent for the reaction is selected from at least one of dichloromethane or acetonitrile;

[0069] And / or, the reaction is carried out in the presence of a catalyst selected from at least one of AlCl3 or zinc chloride;

[0070] And / or, the reaction temperature range is 0℃~40℃.

[0071] Preferably, in step 3, the solvent for the reaction is selected from at least one of acetonitrile, ethyl acetate, dichloromethane, acetone, tetrahydrofuran, toluene, 1,4-dioxane, diethyl ether, n-hexane, cyclohexane, or N,N-dimethylformamide.

[0072] And / or, the reaction is carried out in the presence of a catalyst selected from at least one of DBU, sodium carbonate, potassium carbonate, cesium carbonate, or triethylamine;

[0073] And / or, the reaction temperature range is 0℃~40℃.

[0074] This invention also provides a method for preparing the above-mentioned compound, or its salt, or its crystal form, or its stereoisomer, comprising the following steps:

[0075]

[0076] Step a: Flurbiprofen is reacted with compound C to obtain compound D;

[0077] Step b involves reacting compound D and compound E to obtain the compound shown in formula III.

[0078] Preferably, in step 4, the solvent for the reaction is selected from at least one of acetonitrile, ethyl acetate, dichloromethane, acetone, tetrahydrofuran, toluene, 1,4-dioxane, diethyl ether, n-hexane, cyclohexane, or N,N-dimethylformamide.

[0079] And / or, the reaction is carried out under the action of a base, wherein the base is selected from tetrabutylammonium bisulfate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, or triethylamine.

[0080] And / or, the reaction temperature is in the range of 0℃ to 40℃.

[0081] Preferably, in step 5, the solvent for the reaction is selected from at least one of acetonitrile, ethyl acetate, dichloromethane, chloroform, acetone, tetrahydrofuran, toluene, 1,4-dioxane, diethyl ether, n-hexane, cyclohexane, N,N-dimethylformamide, N,N-dimethylacetamide, or DMSO.

[0082] And / or, the reaction is carried out under the action of a base, wherein the base is selected from at least one of DBU, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, potassium bicarbonate or sodium bicarbonate;

[0083] And / or, the reaction is carried out in the presence of a catalyst selected from at least one of sodium iodide or potassium iodide;

[0084] And / or, the reaction temperature is in the range of 0℃ to 80℃.

[0085] The present invention also provides a self-assembled structure formed by self-assembly of the above-mentioned compound, or its salt, or its crystal form, or its stereoisomer.

[0086] The present invention also provides the use of the above-described compound, or its salt, or its crystal form, or its stereoisomer, or the above-described self-assembled structure, in the preparation of anti-inflammatory and / or analgesic medicaments.

[0087] The present invention also provides a medicament for anti-inflammatory and / or analgesic purposes, which is made by adding pharmaceutically acceptable excipients or auxiliary ingredients to the above-mentioned compound, or its salt, or its crystal form, or its stereoisomer, or its self-assembled structure as the active ingredient.

[0088] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0089] "Substitution" refers to the replacement of a hydrogen atom in a molecule with another different atom or molecule. "Substitution" can mean being replaced by one group or by at least two groups.

[0090] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a -C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C1-C4 alkyl" refers to alkyl groups containing 1 to 4 carbon atoms.

[0091] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as C1-C6 alkoxy groups.

[0092] "Alkylene" refers to a divalent functional group formed by a saturated hydrocarbon chain with a specified number of member atoms, such as "—CH2—" or "—CH2—CH2—".

[0093] The hydrogen atoms in the compounds of this invention can be various isotopes of hydrogen, such as protium (¹H), deuterium (²H), or tritium (¹H). 3 H).

[0094] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0095] The terms "salt" and "pharmaceutical salt" refer to acidic and / or basic salts formed by the above-described compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-described compounds or their stereoisomers with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0096] This invention covalently modifies and links flurbiprofen and 4-octylitaconic acid to construct a class of long-chain compounds capable of self-assembly, achieving sustained-release effects of flurbiprofen and 4-octylitaconic acid (or their analogues), thereby enhancing anti-inflammatory and analgesic efficacy and reducing adverse reactions. Therefore, this invention has excellent application prospects.

[0097] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0098] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0099] Figure 1 This is an in vitro degradation assay of compound I-53 in rat plasma.

[0100] Figure 2 The analgesic efficacy of the compounds of this invention in a chronic inflammatory pain model. Detailed Implementation

[0101] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0102] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR determination was performed using a Bruker Avance III 400 NMR spectrometer, with deuterated dimethyl sulfoxide (d6-DMSO) or deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0103] LCMS determination was performed using an Agilent LCMS1260-6110 (ESI) column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm). Column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: gradient from 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] over 3 min, held at this condition for 1 min, then gradient to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] over 0.05 min, and held at this condition for 0.7 min.

[0104] 1) Medicinal materials and reagents

[0105] The silica gel plates used for thin-layer chromatography are HSGF254 silica gel plates from Yantai Xinnuo Chemical Co., Ltd., with a thickness of 1mm.

[0106] Thin-layer chromatography (TLC) was performed using products from Yantai Jiangyou Silica Gel Development Co., Ltd., with a specification of 0.2±0.03 mm.

[0107] Column chromatography typically uses 100-200 mesh or 200-300 mesh silica gel from Rushan Taiyang Desiccant Co., Ltd. (Weihai, Shandong) as the carrier.

[0108] 2) Main instruments

[0109] Sartorius BSA124S electronic balance (Sartorius Scientific Instruments Beijing Co., Ltd.);

[0110] 98-2 Magnetic Stirrer (Shanghai Sile Instruments Co., Ltd.);

[0111] MS-H-PRO + Numerical control heating type magnetic stirrer (Dalong Xingchuang Experimental Instruments Beijing Co., Ltd.);

[0112] ZF-I Three-Purpose Ultraviolet Analyzer (Shanghai Anting Electronic Instrument Factory);

[0113] R-201 rotary evaporator (Shanghai Shenshun Biotechnology Co., Ltd.);

[0114] W201D constant temperature water bath (Shanghai Shenshun Biotechnology Co., Ltd.);

[0115] SHB-III circulating water vacuum pump (Zhengzhou Huicheng Science & Technology Co., Ltd.);

[0116] DLSB-5 / 20℃ Low Temperature Cooling Circulation Pump (Gongyi Yuhua Instrument Co., Ltd.);

[0117] 2XZ-2 rotary vane vacuum pump (Linhai Yonghao Vacuum Equipment Co., Ltd.);

[0118] Example 1: Preparation of Compound I-9

[0119]

[0120] Step 1: At room temperature, dissolve flurbiprofen 1-1 (1.00 g, 4.1 mmol) in dry dichloromethane (50 mL), cool to 0 °C in an ice-water bath, and slowly add oxalyl chloride (1.04 g, 8.2 mmol) and catalytic amount of dry DMF (0.1 mL) to the reaction system in sequence. After the addition is complete, allow the mixture to rise naturally to room temperature and stir for 10 h. Take a sample, evaporate to dryness, and perform a rough chromatogram. The starting material is basically completely converted. Concentrate under reduced pressure to obtain crude product FI-1. The crude product is used directly in the next step of the reaction without purification. 1 H NMR (400MHz, CDCl3) δ7.60-7.50(m,2H),7.41(dt,J=21.8,7.6Hz,4H),7.23-7.05(m,2H),3.79(q,J=7.2Hz,1H),1.57(d,J=7.2Hz,3H).

[0121] Step 2: NaI (741 mg, 8.2 mmol) and metaldehyde 1-2 (1.83 g, 13.8 mmol) were dissolved in dry dichloromethane (50 mL) at 0°C in an ice-water bath. The crude product FI-1 obtained in the previous step, AlCl3 (16.5 mg, 0.1 mmol), and I2 (7.3 mg, 0.3 mmol) were added sequentially to the reaction system, and the mixture was stirred at room temperature for 12 h. Water (50 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Column purification yielded 1.4 g of product FI-2, with a yield of 86%. 1H NMR (400MHz, CDCl3) δ7.59-7.50(m,2H),7.49-7.30(m,4H),7.26(s,1H),7.20-7.01(m,2H),6.55 (dd,J=12.6,6.0Hz,1H),3.78(q,J=7.3Hz,1H),1.77(dd,J=15.0,5.8Hz,2H),1.64-1.48(m,4H).

[0122]

[0123] Step 3: Place lactic acid 1-14 (3.7 mL, 51 mmol) and acetic acid 1-15 (15 mL) in a 50 mL flask, and slowly add acetyl chloride (11 mL) at 0 °C. The mixture is then allowed to react at room temperature for 24 h. The product is concentrated under reduced pressure to obtain 8 g of crude product 1-16. The crude sample shows 55% acetic acid remaining. The remaining acetic acid is removed using an azeotropic reaction with toluene, leaving 35% acetic acid remaining in the crude sample.

[0124] Step 4: Dissolve acid 1-16 (4.0 g, 30 mmol) and tert-butanol 1-17 (4.9 g, 66 mmol) in dichloromethane (90 mL), add 4-dimethylaminopyridine (1.1 g), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.5 g) in three portions at 0 °C. React at room temperature for 3 h, extract with dichloromethane (3 × 20 mL), combine the organic phases, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and purify by column chromatography to obtain 930 mg of product 1-18, yield 16%.

[0125] Step 5: Dissolve precursor compound 1-18 (930 mg, 4.9 mmol) in methanol (2 mL), dissolve potassium carbonate (2 g) in water (7 mL) and methanol (4 mL), add 4-dimethylaminopyridine (1.1 g), add the potassium carbonate solution dropwise to the reaction mixture at 0 °C, react at room temperature for 3 h, extract with dichloromethane (3 × 10 mL), combine the organic phases, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure to obtain 300 mg of crude product 1-19, yield 42%.

[0126] Step 6: Dissolve 490 mg of carboxylic acid compound 1-10 and 300 mg of alcohol 1-19 in dichloromethane (10 mL), add 4-dimethylaminopyridine (126 mg, 1.0 mmol) and N,N-diisopropylethylamine (582 mg, 6.15 mmol), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (589 mg, 3.0 mmol) at 0 °C. React at room temperature for 8 h, evaporate to dryness and concentrate the reaction solution, and purify by column chromatography to obtain 285 mg of product 1-20, yield 48%.

[0127] Step 7: Dissolve 285 mg of precursor compound 1-20 in dichloromethane (2 mL), add trifluoroacetic acid (0.3 mL), react at room temperature for 8 h, concentrate the reaction solution under reduced pressure, and purify by column chromatography to obtain 150 mg of product 1-21, yield 62%. 1 H NMR (400MHz, CDCl3) δ6.45 (s, 1H), 5.81 (s, 1H), 5.25 (q, J = 7.1Hz, 1H), 3.51-3.26 (m, 2H), 1.36-1.14 (m, 15H), 0.88 (t, J = 6.6Hz, 3H).

[0128]

[0129] Step 8: At room temperature, the precursor compound FI-2 (200 mg, 0.5 mmol), carboxylic acid compound 1-21 (150 mg, 0.5 mmol), and DBU (97 μL) were dissolved in dry acetonitrile (5 mL) and stirred at room temperature for 12 h. TLC monitoring showed that approximately 20% of the precursor compound remained. A 10% sodium thiosulfate aqueous solution was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 122 mg of a pale yellow oily product I-9, with a yield of 42%. 1 H NMR (400MHz, CDCl3) δ7.53 (d, J = 7.7Hz, 2H), 7.50-7.31 (m, 4H), 7.18-7.05 (m, 2H), 6.97-6.82 (m, 1H), 6.46-6.28 (m, 1H), 5.82-5.68 (m, 1H), 5 .20-4.87(m,1H),4.18-3.99(m,2H),3.75(q,J=7.2Hz,1H),3.49-3.21 (m,2H),1.72-1.39(m,11H),1.36-1.22(m,10H),0.87(t,J=6.6Hz,3H).

[0130] Example 2 Preparation of compound I-22

[0131]

[0132] Step 1: Dissolve 433 mg of carboxylic acid compounds 1-9 and 262 mg of alcohol 1-19 in dichloromethane (8 mL), add 4-dimethylaminopyridine (110 mg, 0.9 mmol) and N,N-diisopropylethylamine (508 mg, 5.37 mmol), add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (514 mg, 2.68 mmol) at 0 °C, react at room temperature for 8 h, concentrate the reaction solution by rotary evaporation, and purify by column chromatography to obtain 282 mg of product 1-23, yield 49%.

[0133] Step 2: Dissolve 282 mg of precursor compound 1-25 in dichloromethane (2 mL), add trifluoroacetic acid (0.3 mL), react at room temperature for 8 h, concentrate the reaction solution under reduced pressure, and purify by column chromatography to obtain 160 mg of product 1-26, yield 67%. 1 H NMR (400MHz, CDCl3) δ6.36 (s, 1H), 5.78 (s, 1H), 5.16 (q, J = 7.1Hz, 1H), 3.50-3.33 (m, 2H), 1.41-1.20 (m, 15H), 0.87 (t, J = 6.6Hz, 3H).

[0134]

[0135] Step 3: At room temperature, the precursor compound FI-2 (200 mg, 0.51 mmol), carboxylic acid compound 1-26 (160 mg, 0.51 mmol), and DBU (97 μL) were dissolved in dry acetonitrile (5 mL), and stirred at room temperature for 12 h. TLC monitoring showed that approximately 20% of the precursor compound remained. A 10% sodium thiosulfate aqueous solution was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 137 mg of a pale yellow oily product I-22, with a yield of 46%. 1 H NMR (400MHz, CDCl3) δ7.53 (d, J = 7.7Hz, 2H), 7.49-7.31 (m, 4H) 7.18-7.02 (m, 2H) ),6.95-6.82(m,1H),6.42-6.22(m,1H),5.82-5.61(m,1H),5.16-4.89(m,1H), 4.13(p,J=6.7Hz,2H),3.82-3.66(m,1H),3.52-3.21(m,2H),1.64(q,J=7.2Hz, 1H),1.58(s,3H),1.56-1.38(m,6H),1.38-1.17(m,12H)0.87(t,J=6.6Hz,3H).

[0136] Example 3 Preparation of compound I-35

[0137]

[0138] Step 1: At room temperature, itaconic anhydride 1-5 (2.24 g, 20 mmol) was added to n-octanol 1-7 (2.69 g, 20.7 mmol), and the mixture was stirred at 100 °C for 5 h. A sample was taken and evaporated to dryness. A coarse spectral analysis was performed. After the reaction was complete, the product 1-10 was purified by slurrying with n-hexane to obtain 3.0 g of product 1-10, with a yield of 62%. (The ratio of products with double bonds on both sides was approximately 12:1).

[0139] Step 2: Dissolve 2.0 g of carboxylic acid compound 1-11 and 1.0 g of alcohol 1-10 in dichloromethane (40 mL), add 4-dimethylaminopyridine (503 mg, 4.1 mmol) and N,N-diisopropylethylamine (3.2 g, 24.7 mmol), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.37 g, 12.4 mmol) at 0 °C. React at room temperature for 8 h, concentrate the reaction solution by rotary evaporation, and purify by column chromatography to obtain 1.52 g of product 1-12, yield 52%.

[0140] Step 3: Dissolve 1.52g of precursor compound 1-12 in dichloromethane (7mL), add trifluoroacetic acid (7mL), react at room temperature for 8h, concentrate the reaction solution by rotary evaporation to obtain 1.50g of product, which is directly used in the next step (the ratio of products with double bonds on both sides is approximately 12:1). 1 H NMR (400MHz, CDCl3) δ6.48(s,1H),5.87(s,1H),4.79(s,2H),4.12(t,J=6.8Hz,2H ),3.43(s,2H),1.62(t,J=7.0Hz,2H),1.35-1.24(m,10H),0.87(t,J=6.7Hz,3H).

[0141]

[0142] Step 4: At room temperature, the precursor compound FI-2 (200 mg), carboxylic acid compound 1-13 (151 mg), and DBU (97 μL) were dissolved in dry acetonitrile (5 mL), and stirred at room temperature for 12 h. TLC monitoring showed that approximately 20% of the precursor compound remained. A 10% sodium thiosulfate aqueous solution was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 40 mg of a pale yellow oily product I-35, with a yield of 14%. 1H NMR (400MHz, CDCl3) δ7.54 (d, J=6.4Hz, 2H), 7.40 (dq, J=22.0, 7.4Hz, 4H), 7.17-7.0 4(m,2H),7.00-6.86(m,1H),6.44(s,0.5H),6.38(s,0.5H),5.81(s,0.5H),5.76(s,0 .5H),4.82-4.51(m,2H),4.08(q,J=7.3Hz,2H),3.75(dd,J=7.1,2.5Hz,1H),3.35(d ,J=16.7Hz,2H),1.68-1.40(m,8H),1.39-1.16(m,10H),0.87(dt,J=7.1,3.4Hz,3H).

[0143] Example 4: Preparation of Compound I-48

[0144]

[0145] Step 1: Dissolve 300 mg of carboxylic acid compounds 1-9 and 160 mg of alcohol 1-22 in dichloromethane (6 mL), add 4-dimethylaminopyridine (75 mg, 0.6 mmol) and N,N-diisopropylethylamine (480 mg, 3.57 mmol), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (356 mg, 1.79 mmol) at 0 °C. React at room temperature for 8 h, evaporate to dryness and concentrate the reaction solution, and purify by column chromatography to obtain 300 mg of product 1-23, yield 70%.

[0146] Step 2: Dissolve 395 mg of precursor compound 1-23 in dichloromethane (2 mL), add trifluoroacetic acid (0.4 mL), react at room temperature for 7 h, concentrate the reaction solution under reduced pressure, and purify by column chromatography to obtain 150 mg of product 1-24, yield 62%. 1 H NMR (400MHz, CDCl3) δ6.36 (s, 1H), 5.87-5.74 (m, 1H), 4.51 (s, 2H), 4.15 (t, J = 6.7Hz ,2H),3.44(s,2H),1.65(p,J=6.6Hz,2H),1.39-1.18(m,10H),0.87(t,J=6.7Hz,3H).

[0147]

[0148] Step 3: At room temperature, the precursor compound FI-2 (265 mg, 0.67 mmol), carboxylic acid compound 1-21 (200 mg, 0.67 mmol), and DBU (129 μL) were dissolved in dry acetonitrile (5 mL) and stirred at room temperature for 12 h. TLC monitoring showed that approximately 20% of the precursor compound remained. A 10% sodium thiosulfate aqueous solution was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 168 mg of a pale yellow oily product I-48, with a yield of 45%. 1 H NMR (400MHz, CDCl3) δ7.54 (d, J=7.2Hz, 2H), 7.41 (dt, J=22.1, 6.8Hz, 4H), 7.18-7.0 2(m,2H),6.99-6.85(m,1H),6.37(s,0.5H),6.33(s,0.5H),5.78(s,0.5H),5.73(s,0 .5H),4.74-4.44(m,2H),4.14(dt,J=9.2,6.7Hz,2H),3.74(dd,J=7.3,3.8Hz,1H),3 .42(d,J=21.8Hz,2H),1.75-1.41(m,8H),1.40-1.16(m,10H),0.87(t,J=6.5Hz,3H).

[0149] Example 5 Preparation of compound I-53

[0150]

[0151] At room temperature, FI-2 (1.40 g, 3.52 mmol), I-24 (854.00 mg, 3.52 mmol), and DBU (693.00 mg, 4.55 mmol) were dissolved in dry acetonitrile (30 mL) and stirred at room temperature for 12 h. After the reaction was complete as monitored by TLC, 10% sodium thiosulfate aqueous solution (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (dichloromethane / petroleum ether (v / v) = 10–50%), and monitored by TLC (dichloromethane / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.2–0.3 was collected to give the pale yellow oily compound I-53 (846.0 mg, yield 46.9%).

[0152] 1H NMR (400MHz, CDCl3) δ7.58-7.50(m,2H),7.47-7.33(m,4H),7.17-7.05(m, 2H),6.98-6.91(m,1H),6.29(d,J=51.6Hz,1H),5.75(d,J=27.6Hz,1H),4.0 6(dt,J=18.3,6.8Hz,2H),3.79-3.70(m,1H),3.39-3.17(m,2H),1.65-1.5 0(m,7H),1.47(d,J=5.4Hz,1H),1.35-1.20(m,10H),0.88(t,J=6.6Hz,3H).

[0153] Example 6 Preparation of compound I-53-1

[0154]

[0155] Step 1: At room temperature, the precursor compound FI-2 (300 mg, 0.75 mmol), itaconic acid monomethyl ester 1-3 (72 mg, 0.75 mmol), and DBU (147 μL, 0.98 mmol) were dissolved in anhydrous acetonitrile (3 mL), and stirred at room temperature for 12 h. TLC monitoring showed that approximately 20% of the precursor compound remained. A 10% sodium thiosulfate aqueous solution was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 140 mg of a pale yellow oily product I-53-1, with a yield of 47%. 1 H NMR (400MHz, CDCl3) δ7.53 (d, J = 8.3Hz, 2H), 7.50-7.31 (m, 4H), 7.18-7.03 (m, 2H), 7.02-6.87 (m, 1H), 6.36 (s, 0.5H),6.24(s,0.5H),5.79(s,0.5H),5.72(s,0.5H),3.82-3.58(m,4H),3.44-3.14(m,2H),1.58-1.46(m,6H).

[0156] Example 7 Preparation of compound I-53-2

[0157]

[0158] Step 1: At room temperature, the precursor compound FI-2 (200 mg, 0.5 mmol), itaconic acid monobutyl ester 1-4 (93 mg, 0.5 mmol), and DBU (98 μL, 0.65 mmol) were dissolved in anhydrous acetonitrile (3 mL), and stirred at room temperature for 12 h. TLC monitoring showed that approximately 25% of the precursor compound remained. A 10% sodium thiosulfate aqueous solution was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 116 mg of a pale yellow oily product I-53-2, with a yield of 51%. 1 H NMR (400MHz, CDCl3) δ7.53 (d, J = 7.1Hz, 2H), 7.48-7.32 (m, 4H), 7.18-7.05 (m, 2H), 7.00-6.89 (m, 1H), 6.36 (s, 0.5H), 6.23 (s, 0.5H), 5.78 (s, 0.5H) ),5.71(s,0.5H),4.07(dt,J=17.9,6.7Hz,2H),3.81-3.67(m,1H),3.42- 3.10(m,2H),1.68-1.44(m,8H),1.44-1.23(m,2H),0.91(q,J=7.6Hz,3H).

[0159] Example 8 Preparation of compound I-53-3

[0160]

[0161] Step 1: At room temperature, itaconic anhydride 1-5 (1.12 g) was added to dodecanol 1-35 (2.0 g), and the mixture was stirred at 80 °C for 1 h. A sample was taken for rotary evaporation and rough spectral analysis. After the reaction was complete, the product 1-36 was purified by slurrying with n-hexane to obtain 2.0 g of product 1-36, with a yield of 77%. 1 H NMR (400MHz, CDCl3) δ6.45(s,1H),5.82(s,1H),4.09(t,J=6.7Hz,2H),3.33(s,2H),1.62(p,J=6.8Hz,2H),1.40-1.18(m,18H),0.88(t,J=6.7Hz,3H).

[0162]

[0163] Step 2: At room temperature, the precursor compound FI-2 (200 mg), carboxylic acid compound 1-36 (185 mg), and DBU (97 μL) were dissolved in dry acetonitrile (5 mL), and stirred at room temperature for 12 h. TLC monitoring showed that approximately 30% of the precursor compound remained. A 10% sodium thiosulfate aqueous solution was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 117 mg of a pale yellow oily product I-53-43 (42% yield). 1 HNMR (400MHz, CDCl3) δ7.58-7.50(m,2H),7.48-7.32(m,4H),7.17-7.03(m,2H),6.94(q,J=5.8Hz,1H),6.35(s,0.5H),6.23(s,0.5H),5.78(s, 0.5H),5.71(s,0.5H),4.14-3.96(m,2H),3.82-3.67(m,1H),3.41-3.1 5(m,2H),1.68-1.39(m,9H),1.38-1.16(m,17H),0.88(t,J=6.6Hz,3H).

[0164] Example 9 Preparation of compound I-55

[0165]

[0166] Step 1: At room temperature, itaconic anhydride 1-5 (2 g, 17.8 mmol) and p-methoxybenzyl alcohol 1-6 (2.5 g, 17.8 mmol) were dissolved in n-hexane (10 mL) and toluene (10 mL), and stirred at room temperature for 16 h. A sample was taken and evaporated to dryness, and a coarse spectral analysis was performed. After the reaction was complete, the reaction mixture was evaporated to dryness, and purified by slurrying with n-hexane to obtain 3.0 g of product A1, with a yield of 67% (the ratio of products with double bonds on both sides was approximately 10:1). 1 H NMR (400MHz, CDCl3) δ7.28(d,J=8.4Hz,2H),6.88(d,J=8.5Hz,2H),6.46(s,1H),5.82(s,1H),5.09(s,2H),3.80(d,J=1.4Hz,3H),3.36(s,2H).

[0167] Step 2: Dissolve 3g of carboxylic acid compound A1 and 1.66g of octanol 1-7 in dichloromethane (50mL), add 4-dimethylaminopyridine (776mg, 6.35mmol) and N,N-diisopropylethylamine (6.6mL, 38.1mmol), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.65g, 19mmol) at 0℃. React at room temperature for 8h, concentrate the reaction solution by rotary evaporation, and purify by column chromatography to obtain 1.0g of product 1-8, yield 22%. (The ratio of products with double bonds on both sides is approximately 8:1).

[0168] Step 3: Dissolve 1.0 g of precursor compounds 1-8 in dichloromethane (30 mL), add trifluoroacetic acid (0.64 mL), react at room temperature for 8 h, concentrate the reaction solution by rotary evaporation, and purify by column chromatography to obtain 200 mg of product 1-9, yield 29%. (The ratio of products with double bonds on both sides is approximately 10:1). 1 H NMR (400MHz, CDCl3) δ6.34(s,1H),5.73(s,1H),4.16(t,J=6.8Hz,2H),3.38(s,2H),1.66(t,J=7.0Hz,2H),1.40-1.21(m,10H),0.88(t,J=6.6Hz,3H).

[0169]

[0170] Step 4: At room temperature, the precursor compound FI-2 (164 mg, 0.41 mmol), carboxylic acid compound 1-9 (100 mg, 0.41 mmol), and DBU (80 μL, 0.53 mmol) were dissolved in anhydrous acetonitrile (3 mL), and stirred at room temperature for 12 h. TLC monitoring showed that approximately 30% of the precursor compound remained. A 10% sodium thiosulfate aqueous solution was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 101 mg of a pale yellow oily product I-55, with a yield of 48%. 1 H NMR (400MHz, CDCl3) δ7.54(d,J=7.7Hz,2H),7.40(dq,J=20.7,7.5Hz,4H),7.19-7.14(m,2H),6.95-6.82(m,1H),6.34(s,0.5H),6.28(s,0.5H),5 .72(s,0.5H),5.62(s,0.5H),4.13(dt,J=17.9,6.8Hz,2H),3.75(t,J=7 .3Hz,1H),3.42-3.18(m,2H),1.75-1.15(m,18H),0.88(t,J=6.6Hz,3H).

[0171] Example 9 Preparation of compound I-55-1

[0172]

[0173] Step 1: Dissolve 1.5 g of carboxylic acid compound A1 and 470 g of n-butanol 1-38 in dichloromethane (50 mL), add 388 mg of 4-dimethylaminopyridine and 1.8 g of N,N-diisopropylethylamine, and add 1.83 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0 °C. React at room temperature for 8 h, concentrate the reaction solution by rotary evaporation, and purify by column chromatography to obtain 1.2 g of product 1-39, with a yield of 59%. (The ratio of products with double bonds on both sides is approximately 8:1).

[0174] Step 2: Dissolve 1.45 g of precursor compound 1-39 in dichloromethane (30 mL), add trifluoroacetic acid (0.64 mL), react at room temperature for 8 h, concentrate the reaction solution by rotary evaporation, and purify by column chromatography to obtain 600 mg of product 1-40, with a yield of 60%. (The ratio of products with double bonds on both sides is approximately 15:1). 1 H NMR (400MHz, CDCl3) δ6.43-6.30(m,1H),5.80-5.69(m,1H),4.18(t,J=6.6Hz,2H),3 .39(d,J=1.2Hz,2H),1.71-1.55(m,2H),1.51-1.27(m,2H),,0.94(t,J=7.3Hz,3H).

[0175]

[0176] Step 3: At room temperature, the precursor compound FI-2 (180 mg, 0.46 mmol), carboxylic acid compound 1-40 (85 mg, 0.46 mmol), and DBU (87 μL) were dissolved in dry acetonitrile (5 mL) and stirred at room temperature for 12 h. TLC monitoring showed that approximately 20% of the precursor compound remained. A 10% sodium thiosulfate aqueous solution was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 110 mg of a pale yellow oily product I-55-1, with a yield of 57%. 1H NMR (400MHz, CDCl3) δ7.59-7.49(m,2H),7.50-7.31(m,4H),7.17-7.04(m,2H),6.93-6.83(m,1H),6.34(s,0.5H),6.28(s,0.5H),5.71(s,0. 5H),5.61(s,0.5H),4.14(dt,J=17.3,6.6Hz,2H),3.74(dd,J=7.2,2.6Hz,1H),3.42-3.17(m,2H),1.71-1.31(m,10H),0.87(t,J=6.7Hz,3H).

[0177] Example 10 Preparation of compound I-55-2

[0178]

[0179] Step 1: Dissolve 3.5 g of carboxylic acid compound A1 and 2.76 g of dodecanol 1-35 in dichloromethane (50 mL), add 4-dimethylaminopyridine (904 mg) and N,N-diisopropylethylamine (4.2 g), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.26 g) at 0 °C. React at room temperature for 8 h, concentrate the reaction solution by rotary evaporation, and purify by column chromatography to obtain 2.78 g of product 1-36, with a yield of 45%. (The ratio of products with double bonds on both sides is approximately 8:1).

[0180] Step 2: Dissolve 1.0 g of precursor compound 1-36 in dichloromethane (30 mL), add trifluoroacetic acid (0.64 mL), react at room temperature for 8 h, evaporate to dryness and concentrate the reaction solution, and purify by column chromatography to obtain 650 mg of product 1-37, yield 65%. 1 H NMR (400MHz, CDCl3) δ6.36(s,1H),5.74(s,1H),4.17(t,J=6.8Hz,2H),3.39(s,2H),1.78-1.55(m,2H),1.26(d,J=7.6Hz,18H),0.86(t,J=6.7Hz,3H).

[0181]

[0182] Step 3: At room temperature, the precursor compound FI-2 (200 mg, 0.51 mmol), carboxylic acid compound 1-37 (160 mg, 0.51 mmol), and DBU (97 μL) were dissolved in dry acetonitrile (5 mL) and stirred at room temperature for 12 h. TLC monitoring showed that approximately 20% of the precursor compound remained. A 10% sodium thiosulfate aqueous solution was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 128 mg of a pale yellow oily product I-55-2, with a yield of 47%. 1 H NMR (400MHz, CDCl3) δ7.57-7.50(m,2H),7.47-7.33(m,4H),7.16-7.05(m, 2H),6.93-6.83(m,1H),6.34(s,0.5H),6.28(s,0.5H),5.71(s,0.5H),5.61 (s,0.5H),4.20-4.04(m,2H),3.79-3.67(m,1H),3.36-3.20(m,2H),1.71- 1.58(m,2H),1.57-1.39(m,7H),1.38-1.18(m,19H),0.88(t,J=6.8Hz,3H).

[0183] Example 11 Preparation of compound I-58

[0184]

[0185] Step 1: Dissolve the starting alcohol (2.32 g) in dichloromethane (60 mL), add imidazole (3.27 g), and add tert-butyldimethylchlorosilane (6.0 g) at 0 °C. React at room temperature for 3 h, add water and extract with dichloromethane (3 × 20 mL). Combine the organic phases, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure and purify by column chromatography to obtain 3.82 g of product 1-31, yield 83%.

[0186] Step 2: Dissolve the precursor compound (3g) in tetrahydrofuran (7mL) and water (7mL), add lithium hydroxide (620mg), and react at 50℃ for 8h. After the reaction is complete, adjust the pH to 2 with 1M hydrochloric acid, extract with ethyl acetate, combine the organic phases, dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure to obtain 2.0g of crude product 1-32, yield 70%.

[0187] Step 3: Dissolve 2.0 g of carboxylic acid compound 1-32 and 1.18 g of alcohol 1-7 in dichloromethane (8 mL), add 4-dimethylaminopyridine (553 mg) and N,N-diisopropylethylamine (2.58 g), add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.6 g) at 0 °C, react at room temperature for 6 h, extract with water using dichloromethane (3 × 20 mL), combine the organic phases, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and purify by column chromatography to obtain 1.2 g of product 1-33, yield 40%.

[0188] Step 4: 1.2 g of precursor compound 1-33 dissolved in tetrahydrofuran (36 mL) was added to a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (3.6 mL) at 0 °C and reacted for 1 h. After the reaction was complete, water was added. The mixture was extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were dried over anhydrous Na₂SO₄. The mixture was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 500 mg of product 1-34, with a yield of 65%. 1 H NMR (400MHz, CDCl3) δ6.25 (s, 1H), 5.82 (s, 1H), 4.33 (d, J = 6.3Hz, 2H), 4.17 (t ,J=6.7Hz,2H),1.74-1.56(m,2H),1.44-1.17(m,10H),0.88(t,J=6.7Hz,3H).

[0189]

[0190] Step 5: Dissolve 222 mg of carboxylic acid compound 1-1 and 200 mg of alcohol 1-34 in dichloromethane (3 mL), add 4-dimethylaminopyridine (56 mg) and N,N-diisopropylethylamine (337 μL), add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143 mg) at 0 °C, react at room temperature for 5 h, concentrate the reaction solution by rotary evaporation, and purify by column chromatography to obtain 217 mg of product I-58, yield 56%. 1 H NMR (400MHz, CDCl3) δ7.59-7.50(m,2H),7.48-7.32(m,4H),7.20-7.08(m,2H),6.30(s,1H),5.67(s,1H),4.93-4. 75(m,2H),4.17-4.08(m,2H),3.80(q,J=7.1Hz,1H),1.70-1.51(m,3H),1.36-1.19(m,12H),0.87(t,J=6.7Hz,3H).

[0191] Example 12 Preparation of compound I-58-1

[0192]

[0193] Step 1: Dissolve 183 mg of carboxylic acid compound 1-1 and 120 mg of alcohol 1-41 in dichloromethane (5 mL), add 4-dimethylaminopyridine (45 mg) and N,N-diisopropylethylamine (213 mg), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (215 mg) at 0 °C. React at room temperature for 8 h. According to TLC monitoring, about 40% of the precursor compound remains. Quench the reaction with water, extract with ethyl acetate (3 × 10 mL), combine the organic phases, dry with anhydrous Na2SO4, concentrate under reduced pressure to obtain crude product, and purify the crude product by column to obtain 35 mg of pale yellow oily product I-58-1, with a yield of 12%. 1 H NMR (400MHz, CDCl3) δ7.53(d,J=8.0Hz,2H),7.40(ddd,J=14.6,13.3,7.3Hz,4H),7.14(t,J=10.0Hz,2H),6.30(s,1H),5.68 (s,1H),4.84(s,2H),4.15(t,J=6.1Hz,2H),3.80(q,J=7.1Hz,1H),1.68-1.52(m,6H),1.42-1.31(m,3H),1.00-0.89(m,3H).

[0194] Example 12 Preparation of compound I-58-2

[0195]

[0196] Step 1: Dissolve 512 mg of carboxylic acid compound 1-1 and 567 mg of alcohol 1-42 in dichloromethane (10 mL), add 4-dimethylaminopyridine (128 mg) and N,N-diisopropylethylamine (597 mg), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (600 mg) at 0 °C. React at room temperature for 8 h. According to TLC monitoring, about 40% of the precursor compound remains. Quench the reaction with water, extract with ethyl acetate (3 × 10 mL), combine the organic phases, dry with anhydrous Na2SO4, concentrate under reduced pressure to obtain crude product, and purify the crude product by column to obtain 160 mg of pale yellow oily product I-58-2, with a yield of 15%. 1H NMR (400MHz, CDCl3) δ7.53(d,J=7.8Hz,2H),7.39(ddd,J=14.6,13.4,7.3Hz,4H),7.14(t,J=10.0Hz,2H),6.30(s,1H),5.67(s,1 H), 4.84 (s, 2H), 4.13 (t, J = 6.0Hz, 2H), 3.80 (q, J = 7.2Hz, 1H), 1.69-1.51 (m, 7H), 1.27 (d, J = 17.0Hz, 16H), 0.88 (t, J = 6.7Hz, 3H).

[0197] The technical solution of the present invention will be further explained through experiments below.

[0198] Experimental Example 1: Self-assembly of compounds

[0199] I. Experimental Methods

[0200] The appearance and solubility of compound I-53 were observed.

[0201] Add 1 mL of distilled water to a vial containing 1 mmol of compound I-53, shake well at room temperature to obtain a milky white solution. Measure the particle size of each compound using a Brookhaven particle size potentiometer.

[0202] II. Experimental Results

[0203] As shown in Table 1, the compounds of the present invention form nano-sized particles through self-assembly.

[0204] Table 1. Particle size values ​​of the compounds of the present invention

[0205]

[0206]

[0207] Sustained-release effect of compound in mouse plasma in in vitro, Example 2

[0208] I. Experimental Methods

[0209] Experimental animals: Male C57BL / 6J mice aged 8-10 weeks were selected for the experiment. The mice were housed in sawdust bedding cages at 25±1 degrees Celsius, humidity of 40%-60%, with 12 hours of light / 12 hours of darkness, with no more than 5 mice per cage, and free access to water and food.

[0210] 1. Expose rats to 5% isoflurane for 2-3 minutes until complete anesthesia. Fix them to a rat board and continue to maintain anesthesia with 2% isoflurane. Collect approximately 1 mL of arterial blood from each rat, anticoagulate with heparin, centrifuge at 3500 rpm for 10 minutes, and collect the supernatant for later use.

[0211] 2. Take three 1 mL plasma samples from each group and place them in a 37℃ water bath for about 15 to 30 minutes. Add 100 μL of compound I-53 (50 mg / mL) and the control drug flurbiprofen axetil (Fa) to each group to make the plasma concentration 100 μg / mL.

[0212] 3. For group Fa, 50 μL of sample was taken at 0, 20, 30, 40, 60 and 120 s respectively, and 150 μL of acetonitrile was added to precipitate the protein. After centrifugation at 20,000 rpm for 10 min, the supernatant was collected, and the original drug and metabolite flurbiprofen (F) were measured by high performance liquid chromatography (HPLC).

[0213] For group I-53, 50 μL of sample was taken at 0, 5, 10, 20, 40, 60 and 120 min, 150 μL of acetonitrile was added to precipitate the protein, and the supernatant was collected after centrifugation at 20,000 rpm for 10 min and measured by HPLC.

[0214] II. Experimental Results

[0215] like Figure 1 As shown, Fa can be completely metabolized and released into F within 2 minutes; while I-53 requires at least 2 hours to metabolize and release most of the F. The results indicate that I-53 achieves sustained release.

[0216] Example 3: Analgesic efficacy of compound in a chronic inflammatory pain model

[0217] I. Experimental Methods

[0218] Experimental animals: Male C57BL / 6J mice aged 8-10 weeks were selected for the experiment. The mice were housed in sawdust bedding cages at 25±1 degrees Celsius, humidity of 40%-60%, with 12 hours of light / 12 hours of darkness, with no more than 5 mice per cage, and free access to water and food.

[0219] Experimental plan:

[0220] 1. A chronic inflammatory pain model (CFA model) was established by subcutaneous injection of 20 μL of Freund's complete adjuvant (CFA) into the left paw of mice;

[0221] 2. Behavioral experiments:

[0222] The analgesic effects of the compound of this invention (administered in equimolar mass with Fa), the control drug Fa, and the 4-OI mixture in a CFA model were evaluated using a von Frey assay. Mice were placed in a perforated plastic compartment for pain behavior (20×20×14cm) with a wire mesh bottom (0.5×0.5cm). Acclimation began 3 days prior to testing. On the day of testing, the mechanical withdrawal threshold was assessed using an electronic von Frey assay. Stimulation was applied to the palmar portion of the mouse's left hind paw with the tip perpendicular to the paw, with progressive pressure. A rapid withdrawal or retraction was considered a positive response, and the pressure value elicited was recorded. Measurements were repeated three times, and the average value was taken.

[0223] II. Experimental Results

[0224] like Figure 2 As shown, in the CFA model, both the compounds of this invention and the mixed drug group of Fa and 4-OI can relieve inflammatory pain. Furthermore, the compounds of this invention have better and longer-lasting effects compared to the mixed drug group, with compounds I-53, I-58, I-55-1, I-55-2, and I-53-3 exhibiting particularly good efficacy.

[0225] As can be seen from the above embodiments and experimental examples, the compounds of the present invention can undergo self-assembly, achieving a sustained-release effect of flurbiprofen and 4-octylitaconic acid (or analogs of the two), thereby enhancing the anti-inflammatory and analgesic efficacy and reducing the adverse reactions of both, and have good application prospects.

Claims

1. The compound represented by Formula III, characterized in that, The compound shown in Formula III has the following structural formula: Formula III in, R4 is selected from methyl. R5 is connected to other parts of the molecule via a single or double bond; when R5 is connected to other parts of the molecule via a single bond, R6 is connected to other parts of the molecule via a double bond, R5 is selected from H, and R6 is selected from =CH2; when R5 is connected to other parts of the molecule via a double bond, R6 is connected to other parts of the molecule via a single bond, R5 is selected from =CH2, and R6 is selected from H. R is selected from C1~C12 alkyl groups.

2. The compound according to claim 1, characterized in that: The compound has the following structural formula: 。 3. The self-assembled structure formed by the compound of claim 1 or 2 through self-assembly.

4. Use of the compound of claim 1 or 2 or the self-assembled structure of claim 3 in the preparation of anti-inflammatory and / or analgesic medicaments.

5. A drug for anti-inflammatory and / or analgesic purposes, characterized in that: It is made by adding pharmaceutically acceptable excipients or auxiliary ingredients to the compound of claim 1 or 2 or the self-assembled structure of claim 3 as the active ingredient.

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