Baicalein derivatives, preparation method thereof and application as pancreatic lipase inhibitors

Abstract

The present invention relates to the field of medicine, and particularly relates to a baicalein derivative, a preparation method thereof, and an application as a pancreatic lipase inhibitor. The baicalein derivative is a baicalein derivative having the structure of Formula I or a pharmaceutically acceptable salt thereof: #imgabs0# Formula I. The baicalein derivative provided by the present invention can potently inhibit the activity of hPL, and its IC 50 can reach 0.49 μM. The baicalein derivative provided by the present invention has the advantages of easily available raw materials, high safety, simple preparation process, high yield, etc. This type of derivative can also be used as a raw material drug and combined with any pharmaceutically acceptable oral excipient / formulation to prepare tablets, capsules, suspensions or oral liquids, and then used for the prevention and treatment of obesity and hyperlipidemia.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a class of baicalein derivatives, a preparation method thereof, and an application as pancreatic lipase inhibitors. Background Art

[0002] Obesity is a global health problem. Due to the high incidence and mortality rates of obesity, it is considered to be the fastest-growing and largest public health problem in both developed and developing countries. Research shows that obesity is caused by a long-term imbalance between energy absorption and energy consumption in the human body, and it has also been found that obesity is an important inducer of various metabolic diseases such as hypertension, hyperlipidemia, arteriosclerosis, diabetes, and coronary heart disease.

[0003] Among all the research targets for the prevention and treatment of obesity, human pancreatic lipase is widely regarded as the most promising therapeutic target for obesity. Human pancreatic lipase (hPL) is the key enzyme responsible for hydrolyzing total triglycerides. It is secreted by the human pancreas and released into the gastrointestinal system, where it acts synergistically with bile salts secreted by the liver to break down fats into fatty acids and glycerol. A large number of studies have shown that inhibiting hPL activity can reduce the digestion and absorption of dietary fat by the digestive organs, thereby significantly improving the symptoms of metabolic diseases such as obesity and hyperlipidemia.

[0004] Currently, the commonly used anti-obesity drug orlistat in clinical practice is a potent covalent inhibitor of PL. It was approved as an anti-obesity drug by the US Food and Drug Administration in 1999. Although orlistat shows excellent pancreatic lipase inhibitory effects and has a good effect on clinical obesity treatment, being able to prevent the absorption of about 30% of dietary fat in the human body, orlistat has non-negligible gastrointestinal adverse reactions, such as fecal incontinence, gastrointestinal flatulence, abdominal cramps, diarrhea, and oily spotting. Therefore, it is particularly important to develop potent and safe novel human pancreatic lipase inhibitors and apply them to the prevention and treatment of metabolic diseases such as obesity.

[0005] Baicalein (abbreviated as BC), the main active ingredient of the traditional Chinese medicine Scutellaria baicalensis, has various physiological activities and pharmacological effects such as antibacterial, antiviral, anti-inflammatory, antioxidant, scavenging oxygen free radicals, anti-cancer, anti-tumor, anticoagulant, anti-thrombosis formation, and protecting the liver, cardiovascular and cerebrovascular systems, and neurons. Its chemical name is 5,6,7-trihydroxyflavone, with a CAS registration number of 352000-07-8, and its structural formula is:

[0006] .

[0007] The research team found in previous studies that baicalein has the effect of inhibiting hPL (IC 50= 2.19 µM), but the natural compound has poor water solubility and poor drug-likeness.

[0008] Therefore, the inventors used this compound as a lead compound for structural optimization, designed and synthesized a series of novel baicalein derivatives, and investigated the activities, water solubility, and safety of these compounds in inhibiting hPL. Summary of the Invention

[0009] The present invention provides a class of novel baicalein derivatives and finds that they can be used as inhibitors of hPL to block the absorption of lipid substances, achieving the effects of weight loss and lipid reduction.

[0010] To achieve the above object, the present invention provides a novel baicalein derivative having the structure of Formula I or a pharmaceutically acceptable salt thereof:

[0011]

[0012] Formula I,

[0013] Preferably, R is any one of hydrogen, amino, pyrrolidine, piperidine, cyclohexylimine, acetamide, benzamide, dimethylamine, aniline, p-fluoroaniline, p-chloroaniline, p-bromoaniline, fluorine, fluoromethyl, chlorine, or bromine.

[0014] Preferably, for the baicalein derivative or a pharmaceutically acceptable salt thereof provided by the present invention, the structure is selected from any one of the following structures:

[0015]

[0016]

[0017]

[0018]

[0019]

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027] 。

[0028] In the technical solution of the present invention, the pharmaceutically acceptable salts include sodium salts, potassium salts, calcium salts or magnesium salts.

[0029] In addition, the present invention provides the use of the above-mentioned baicalein derivatives or their pharmaceutically acceptable salts in the preparation of drugs for treating hyperlipidemia and obesity.

[0030] The baicalein derivatives or their pharmaceutically acceptable salts exert a weight loss and lipid-lowering effect by strongly inhibiting human pancreatic lipase, and human pancreatic lipase is one of its action targets.

[0031] In addition, the present invention provides a preparation method of the above-mentioned baicalein derivatives, and the method is selected from any one of the following methods (see Figure 1 ):

[0032] 。

[0033] In the synthesis method 1, the preparation method of compounds 1-12 includes the following steps:

[0034] Nitro-substituted cinnamic acid reacts with oxalyl chloride to obtain intermediate a;

[0035] Intermediate a reacts with 3,4,5-trimethoxyphenol to obtain intermediate b;

[0036] Intermediate b reacts with iodine to obtain compound S1;

[0037] Compound S1 reacts with sodium metabisulfite to obtain compound S2;

[0038] Compound S2 is demethylated to obtain compound 1;

[0039] Or, first perform an amino substitution reaction on compound S2, and then demethylate to obtain compounds 2-12.

[0040] Preferably, the preparation method of compounds 1-12 includes the following steps:

[0041] Dissolve nitro-substituted cinnamic acid in DCM. Under ice bath conditions, slowly dropwise add oxalyl chloride. The molar ratio of nitro cinnamic acid to oxalyl chloride is 1:(1.1 - 2). After the reaction is complete, rotary evaporate to dryness to obtain intermediate a;

[0042] Dissolve intermediate a and 3,4,5-trimethoxyphenol with a molar ratio of (1 - 1.5):1 in toluene to make it dissolve. Stir at reflux temperature for 30 - 40 minutes; after cooling, add BF3•Et2O and continue reflux reaction. The molar ratio of BF3•Et2O to 3,4,5-trimethoxyphenol is (1 - 3):1 to obtain intermediate b;

[0043] Dissolve intermediate b in DMSO, add iodine. The molar ratio of intermediate b to iodine is 1:(0.1 - 0.5). Heat and react at 120 - 150 °C for 1 - 5 h to obtain compound S1;

[0044] Dissolve compound S1 in an ethanol aqueous solution, add sodium metabisulfite and reflux react. The molar ratio of compound S1 to sodium metabisulfite is 1:(2 - 5). After the reaction is complete, obtain compound S2;

[0045] Dissolve compound S2 in an appropriate amount of DCM. Under low temperature conditions below -10 °C, dropwise add BBr3. The molar ratio of compound S2 to BBr3 is 1:5 - 15. After the reaction is complete, perform recrystallization to obtain compound 1;

[0046] Or, dissolve compound S2, NaH, and halogenated hydrocarbon with a molar ratio of 1:(2 - 5):(2 - 5) in a solvent and react under anhydrous and anaerobic conditions for 1 - 24 h. After the reaction is complete, obtain compound S3;

[0047] Add the compound to the HI / CH3COOH solution, heat to 110 - 130 °C and react for 3 - 12 h. Add sodium thiosulfate to remove the excess iodine, and perform recrystallization to obtain compounds 2 - 12.

[0048] For the synthesis method 2, the preparation method of the general formula compound K (the same as general formula I) includes the following steps:

[0049] React 3,4,5-trimethoxyphenol, potassium carbonate, and acetic anhydride to obtain intermediate c;

[0050] React intermediate c with BF3•Et2O to obtain intermediate d;

[0051] React intermediate d with sodium hydroxide solution and p-fluorobenzaldehyde to obtain intermediate e;

[0052] Heat and react intermediate e with iodine to obtain intermediate J;

[0053] Compound J is recrystallized after reacting with BBr3 to obtain a general formula compound K.

[0054] Preferably, the preparation method of the general formula compound K (the same as the general formula I) comprises the following steps:

[0055] Dissolve 3,4,5-trimethoxyphenol, potassium carbonate, and acetic anhydride with a molar ratio of 1:(1.5 - 2):(1.5 - 2) in THF, and react to obtain intermediate c;

[0056] Dissolve intermediate c in chloroform, add BF3•Et2O and reflux for reaction. The molar ratio of BF3•Et2O to intermediate c is (2 - 5):1 to obtain intermediate d;

[0057] Dissolve intermediate d in methanol, add sodium hydroxide solution and p-fluorobenzaldehyde under ice bath conditions. The molar ratio of intermediate 5 to p-fluorobenzaldehyde is 1:(1 - 1.2), and the molar ratio of intermediate d to sodium hydroxide is 1:(2 - 10). After the reaction is complete, add water to terminate, adjust the pH to 5 - 6, and filter by suction to obtain intermediate e;

[0058] Dissolve intermediate e in dimethyl sulfoxide, add iodine. The molar ratio of intermediate e to iodine is 1:(2 - 10), and heat and react at a temperature of 120 - 140 °C for 1 - 12 h to obtain intermediate J;

[0059] Under anhydrous and anaerobic conditions, dissolve compound J in DCM, and dropwise add BBr3 at a temperature of -15 °C. The molar ratio of compound J to BBr3 is 1:(6 - 10). After the reaction is complete, recrystallize to obtain the general formula compound K.

[0060] Preferably, the purity of the baicalein derivative is 90% - 100%, and for example, it can be 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.

[0061] In the technical solution of the present invention, when the baicalein derivative is applied, when its concentration range is above 90%, it can exert a safe and effective effect.

[0062] The present invention also provides a pharmaceutical composition, comprising a baicalein derivative, its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

[0063] The pharmaceutical composition includes any one of tablets, capsules, suspensions, granules, powders, emulsions, dripping pills, or oral liquids.

[0064] The pharmaceutically acceptable excipients include any one or a combination of two or more of carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, solubilizers, solubilizing agents, osmotic pressure regulators, surfactants, coating materials, colorants, pH regulators, antioxidants, bacteriostatic agents or buffers.

[0065] After the baicalein derivative provided by the present invention is prepared into a drug, it can be administered by oral administration. Among them, oral administration can make the compound enter the gastrointestinal tract by swallowing.

[0066] The solution provided by the present invention has the following advantages:

[0067] 1. The baicalein derivative provided by the present invention can strongly inhibit the activity of hPL, and its IC 50 is between 0.49 and 17.92 μM.

[0068] Human pancreatic lipase is a key enzyme for lipid absorption in the gastrointestinal tract. Strong inhibition of hPL can effectively reduce the digestion and absorption of dietary lipids, thereby exerting its weight loss and lipid-lowering effects. The baicalein derivative can be used as a new inhibitor of hPL for the preparation of weight loss drugs. Especially 4'-pyrrolidine baicalein, 4'-piperidine baicalein, and 4'-amino baicalein, their IC 50 values are all lower than 1 μM, indicating that the drug exposure concentration of these components in the gastrointestinal tract after entering the body can efficiently inhibit hPL, thereby improving the digestion and absorption of lipids in the body and having a good weight loss effect.

[0069] 2. The baicalein derivative provided by the present invention has the advantages of easily available raw materials, high safety, simple extraction and preparation processes, high yield, etc., providing a new drug source for the prevention and treatment of obesity, and having good application prospects in the preparation of weight loss drugs. Description of the Drawings

[0070] Figure 1 is the synthetic route diagram of the baicalein derivative described in the present invention;

[0071] Figure 2 is the dose-dependent inhibition curve of 4'-amino baicalein on hPL;

[0072] Figure 3 is the dose-dependent inhibition curve of 4'-pyrrolidine baicalein on hPL;

[0073] Figure 4 is the dose-dependent inhibition curve of 4'-piperidine baicalein on hPL. Detailed Embodiments

[0074] The present invention will be described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several changes and improvements can still be made. These all belong to the protection scope of the present invention.

[0075] For the experimental methods without specific conditions noted in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications. The reagents and raw materials used in the present invention are all commercially available.

[0076] Abbreviations:

[0077] DCM is dichloromethane;

[0078] BF3·Et2O is boron trifluoride diethyl ether complex;

[0079] EA is ethyl acetate;

[0080] DMSO is dimethyl sulfoxide;

[0081] BBr3 is boron tribromide;

[0082] NaH is sodium hydride.

[0083] The present invention will be further described below in conjunction with embodiments:

[0084] Example 1. Synthetic route of baicalein derivatives

[0085] 1. Preparation method of compound 1 (4'-aminobaicalein):

[0086] The reaction process is as follows:

[0087] .

[0088] The specific steps are as follows:

[0089] (1) Place nitro-substituted cinnamic acid (6.7 g, 34 mmol) in a 500 ml eggplant-shaped flask, add 100 ml of DCM to dissolve it, then slowly dropwise add oxalyl chloride (6.6 g, 51 mmol) under ice bath conditions. After the addition is complete, remove the ice bath and react at room temperature for 3 h. After detecting the completion of the reaction by thin layer chromatography (TLC), rotary evaporate to obtain a yellowish-white solid intermediate a.

[0090] (2)Dissolve the above intermediate a and 3,4,5-trimethoxyphenol (6 g, 33 mmol) in toluene (100 ml), add BF3·Et2O (20 ml), and stir at reflux temperature for 5 h. Monitor the reaction by TLC. After the reaction is completed, slowly add the reaction solution to an ice-water mixture and stir for 30 min. Extract with EA three times to obtain the organic phase. Then wash the organic phase twice with saturated NaCl solution, dry over anhydrous Na2SO4, filter under reduced pressure, and rotary evaporate to obtain intermediate b.

[0091] (3)Place the obtained intermediate b (5.6 mmol) in a 200-ml single-necked flask, dissolve it in 15 ml of DMSO, add iodine (142 mg, 0.56 mmol), and heat to 130 ° °C and react for 3 h. After detecting the reaction by TLC and turning off the heating device, allow the reaction solution to cool to room temperature, then add 300 ml of water. A large amount of solid precipitates. After the solid precipitates, add an aqueous solution of sodium thiosulfate to remove the excess iodine. Stir at room temperature for 0.5 h and then filter by suction. Wash the filter cake with water, and then dry it and perform silica gel column chromatography to obtain compound S1.

[0092] (4)Place compound S1 (2 g, 5.6 mmol) in a 100-ml single-necked eggplant-shaped flask, add 50 ml of an ethanol-water solution, add sodium metabisulfite and reflux for 2 h. Monitor the reaction by TLC, add concentrated hydrochloric acid (4 ml) with a concentration of 12.1 mol / L and continue to react for 1 h. After the reaction is completed, add water to terminate the reaction, adjust the pH to 8-9 with ammonia water, extract with DCM three times to obtain the organic phase. Then wash the organic phase twice with saturated NaCl solution, dry over anhydrous Na2SO4, filter under reduced pressure, and rotary evaporate to obtain compound S2.

[0093] (5)Place compound S2 (200 mg, 0.6 mmol) in a three-necked flask (100 ml), add 40 ml of anhydrous DCM to dissolve it under anhydrous and anaerobic conditions, and then slowly drip a solution of BBr3 (4.8 mmol) in DCM (5 ml) under a low-temperature ice bath. After the constant-rate dripping is completed, transfer the reaction device to room temperature and stir for 12 h. Monitor by TLC. After the reaction is complete, add water and stir to precipitate a solid. Filter by suction using a Buchner funnel. Wash the filter cake twice with water, place it in an oven to dry, and then recrystallize with ethanol to obtain compound 1.

[0094] 1 1H NMR (600 MHz, DMSO- d6 ) δ 12.95 (s, 1H), 7.73 (d, J= 8.7 Hz, 2H), 6.66 - 6.65 (m, 2H), 6.58 (s, 1H), 6.53 (s, 1H), 6.02 (s, 2H). MS (ESI): m / z = 286.07[M + H] + .

[0095] 2. Preparation of Compound 2 (4'-Pyrrolidinylbaicalein):

[0096] The reaction process is as follows:

[0097] .

[0098] The specific steps are as follows:

[0099] Take the compound S2 obtained in the preparation process of Example 1. Put compound S2 (1 g, 3 mmol) into a 100 - ml single - necked eggplant - shaped flask, add 20 ml of DMF to dissolve it, then add NaH (360 mg, 9 mmol) and stir for 20 min. Under ice - bath conditions, add 1,4 - dibromobutane (1 ml, 9 mmol) dropwise. After the dropwise addition, transfer it to room temperature and react for 6 - 10 h. Monitor the reaction by TLC. After the reaction is completed, add water to terminate the reaction. Extract with DCM three times to obtain the organic phase. Then wash the organic phase twice with saturated NaCl solution, dry it with anhydrous Na2SO4, filter under reduced pressure, and rotary - evaporate to obtain compound S3.

[0100] Take the above - mentioned compound S3 (500 mg, 1.47 mmol) and put it into a single - necked flask (100 ml). Add a solution of 45% HI / CH3COOH (2:1) (10 ml). Heat the reaction to 110 °C and reflux for 18 h. Monitor by TLC. After the reaction is complete, cool the resulting mixture to room temperature and carefully pour it into crushed ice. Then add 20% sodium thiosulfate (5 mL). Stir for 30 minutes, filter to collect the precipitate, and then recrystallize with ethanol to obtain compound 2.

[0101] 1 H NMR (600 MHz, DMSO -d6 ) δ 12.97 (s, 1H), 10.34 (s, 1H), 8.65 (s, 1H),7.86 (d, J = 8.7 Hz, 2H), 6.64 (d, J = 4.3 Hz, 2H), 6.62 (s, 1H), 6.54 (s, 1H),3.33 (d, J= 6.1 Hz, 4H), 1.99 - 1.96 (m, 4H). MS (ESI): m / z = 340.11 [M + H] + .

[0102] 3. Preparation of Compound 3 (4'-piperidyl baicalein):

[0103] For the preparation of Compound 3, refer to the preparation method of Compound 2, except that 1,4-dibromobutane was replaced with 1,5-dibromopentane (9 mmol).

[0104] 1 H NMR (600 MHz, DMSO -d6 ) δ 7.89 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 6.72 (s, 1H), 6.57 (s, 1H), 3.39 (t, J = 5.0 Hz, 4H), 1.61 (s, 6H). MS(ESI): m / z = 354.13 [M + H] + .

[0105] The structural formula of the obtained Compound 3 is as follows:

[0106] .

[0107] 4. Preparation of Compound 4 (4'-cyclohexylimine baicalein):

[0108] For the preparation of Compound 4, refer to the preparation method of Compound 2, except that 1,4-dibromobutane was replaced with 1,6-dibromohexane (9 mmol).

[0109] 1 H NMR (600 MHz, DMSO -d6 ) δ 8.29 (s, 1H), 7.85 - 7.79 (m, 2H), 7.50 (s, 1H), 6.77 - 6.71 (m, 2H), 6.59 (d, J = 4.4 Hz, 2H), 3.36 - 3.28 (m, 4H), 1.67 - 1.55 (m, 8H). MS (ESI): m / z = 368.15 [M + H] + .

[0110] The structural formula of the obtained compound 4 is as follows:

[0111] .

[0112] 5. Preparation of compound 5 (4'-acetamido baicalein):

[0113] The reaction process is as follows:

[0114] .

[0115] The specific steps are as follows:

[0116] Place the above compound S2 (300 mg, 0.92 mmol) in a 100 ml single-necked eggplant-shaped flask, add 5 ml of DMF to dissolve it, then add triethylamine (278 mg, 2.76 mmol), stir for 5 min, add acetyl chloride (100 μl, 1.38 mmol) dropwise under ice bath conditions. After the addition is complete, transfer it to room temperature and react for 10 - 24 h. Monitor the reaction by TLC. After the reaction is completed, add water to terminate the reaction, filter by suction, dry, and obtain compound S4.

[0117] Place the above compound S4 (200 mg, 0.54 mmol) in a single-necked flask (100 ml), add a 45% HI / CH3COOH solution (6 ml), heat the reaction to 110 °C and reflux for 18 h. Monitor by TLC. After the reaction is complete, cool the obtained mixture to room temperature and carefully pour it into crushed ice, then add 20% sodium thiosulfate (5 mL) by mass percentage, stir for 30 minutes, filter by suction to collect the precipitate, and then recrystallize with ethanol to obtain compound 5.

[0118] 1 H NMR (600 MHz, DMSO -d6 ) δ 9.02 (s, 1H), 7.68 - 7.62 (m, 2H), 7.48 - 7.42(m, 2H), 7.08 (s, 1H), 7.03 (t, J = 0.9 Hz, 1H), 6.19 (t, J = 0.9 Hz, 1H), 4.52(t, J = 0.9 Hz, 2H). MS (ESI): m / z = 326.10 [M + H] + .

[0119] 6. Preparation of compound 6 (4'-butyramido baicalein):

[0120] Preparation of Compound 6: Referring to the preparation method of Compound 5, except that acetyl chloride was replaced with butyryl chloride (1.5 mmol).

[0121] 1 H NMR (600 MHz, DMSO -d6 ) δ 8.40 (s, 1H), 7.68 - 7.62 (m, 2H), 7.47 - 7.41(m, 2H), 7.08 (s, 1H), 7.03 (t, J = 0.9 Hz, 1H), 6.19 (t, J = 0.9 Hz, 1H), 4.52(t, J = 0.9 Hz, 2H), 2.25 (d, J = 12.4 Hz, 2H), 1.66 (qt, J = 7.5, 6.2 Hz, 2H),0.97 (t, J = 7.6 Hz, 3H).MS (ESI): m / z = 354.13 [M + H] + 。

[0122] The structural formula of the obtained Compound 6 is as follows:

[0123] 。

[0124] 7. Preparation of Compound 7 (4'-benzamido baicalein):

[0125] Preparation of Compound 7: Referring to the preparation method of Compound 5, except that acetyl chloride was replaced with benzoyl chloride (1.5 mmol).

[0126] 1 H NMR (600 MHz, DMSO -d6 ) δ 8.73 (s, 1H), 7.95 (dt, J = 8.0, 0.9 Hz, 2H),7.63 - 7.57 (m, 2H), 7.54 - 7.40 (m, 5H), 7.08 (s, 1H), 7.03 (t, J = 0.9 Hz, 1H),6.19 (t, J = 0.9 Hz, 1H), 4.52 (t, J = 0.9 Hz, 2H).MS (ESI): m / z= 388.11 [M + H] + .

[0127] The structural formula of the obtained compound 7 is as follows:

[0128] .

[0129] 8. Preparation of compound 8 (4'-dimethylaminoscutellarin):

[0130] Dissolve the compound S2 obtained in Example 1 in acetone, and then successively add methyl iodide (CH3I) and potassium carbonate (K2CO3). Among them, the molar ratio of compound S2, methyl iodide, and potassium carbonate is 1:4:4, and react for 6 - 24 h. The intermediate S5 is obtained by silica gel column chromatography separation and purification.

[0131] Under anhydrous and anaerobic conditions, dissolve the intermediate S5 in a solvent (DCM), and dropwise add BBr3 at -15 °C. The molar ratio of compound S5 to BBr3 is 1:9. After the reaction is complete, recrystallize to obtain compound 8.

[0132] 1 H NMR (600 MHz, DMSO -d6 ) δ 7.53 - 7.47 (m, 2H), 7.08 (s, 1H), 7.03 (t, J J = 0.9 Hz, 1H), 6.87–6.81 (m, 2H), 6.19 (t, J J = 0.9 Hz, 1H), 4.52 (t, J J = 0.9 Hz,2H), 2.92 (s, 6H). MS (ESI): m / z m / z = 312.12 [M + H] + .

[0133] The final structural formula of the obtained compound 8 is as follows:

[0134] .

[0135] 9. Preparation of compound 9 (4'-methylaminoscutellarin):

[0136] For the preparation of the compound, refer to the preparation method of compound 8, the difference is the amount of methyl iodide added. The molar ratio of compound S2, methyl iodide, and potassium carbonate is 1:2:2.

[0137] 1 H NMR (600 MHz, DMSO- d6 ) δ 7.81 (d,J = 8.5 Hz, 2H), 6.87 (s, 1H), 6.71(d, J = 8.6 Hz, 2H), 6.67 (s, 1H), 3.91 (s, 3H). MS (ESI): m / z = 300.08[M + H] + .

[0138] The structural formula of the obtained compound 8 is finally as follows:

[0139] .

[0140] 10. Preparation of compound 10 (4'-ethylamine baicalein):

[0141] For the preparation of compound 10, refer to the preparation method of compound 8, except that methyl iodide is replaced by ethyl iodide. The molar ratio of compound S2, ethyl iodide, and potassium carbonate is 1:2:2.

[0142] 1 H NMR (600 MHz, DMSO- d6 ) δ 7.56 - 7.50 (m, 2H), 7.08 (s, 1H), 7.03 (t, J =0.9 Hz, 1H), 6.74 - 6.68 (m, 2H), 6.19 (t, J = 0.9 Hz, 1H), 4.52 (t, J = 0.9 Hz,2H), 3.28 (dd, J = 4.2, 3.5 Hz, 1H), 3.22 (qd, J = 6.1, 3.7 Hz, 2H), 1.25 (t, J =6.1 Hz, 3H). MS (ESI): m / z = 312.08[M + H] + .

[0143] The structural formula of the obtained compound 10 is finally as follows:

[0144] .

[0145] 11. Preparation of compound 11 (4'-diethylamine baicalein):

[0146] For the preparation of compound 11, refer to the preparation method of compound 8, except that methyl iodide is replaced by ethyl iodide. The molar ratio of compound S2, ethyl iodide, and potassium carbonate is 1:4:4.

[0147] 1 H NMR (600 MHz, DMSO- d6 ) δ 7.54 - 7.48 (m, 2H), 7.03 (t, J J = 0.9 Hz, 1H), 6.77 - 6.72 (m, 2H), 6.19 (t, J J = 0.9 Hz, 1H), 4.52 (t, J J = 0.9 Hz, 2H), 3.27 (q, J J = 7.0 Hz, 4H), 1.19 (t, J J = 7.0 Hz, 6H). MS (ESI): m / z m / z = 340.15[M + H] + .

[0148] The structural formula of the obtained compound 11 is finally as follows:

[0149] .

[0150] 12. Preparation of Compound 12 (4'-N,N-dibromopropylamine baicalein):

[0151] For the preparation of Compound 12, refer to the preparation method of Compound 2, except that the amount of 1,4-dibromobutane added is 6 mmol.

[0152] 1 H NMR (600 MHz, DMSO- d6 ) δ 7.54 - 7.48 (m, 2H), 7.03 (t, J J = 0.9 Hz, 1H), 6.80 - 6.74 (m, 2H), 6.19 (t, J J = 0.9 Hz, 1H), 4.52 (t, J J = 0.9 Hz, 2H), 3.43 (t, J J = 4.9 Hz, 4H), 3.38 (t, J J = 5.4 Hz, 4H), 2.09 - 2.01 (m, 4H). MS (ESI): m / z m / z = 527.00[M + H] + .

[0153] The structural formula of the obtained compound 12 is finally as follows:

[0154] 。

[0155] 13. Preparation of Compound 13 (4'-Anilinoscutellarein):

[0156] The reaction process is as follows:

[0157] 。

[0158] The specific steps are as follows:

[0159] Place 3,4,5-trimethoxyphenol (3 g, 16.3 mmol) and K2CO3 (3.4 g, 24.5 mmol) in a 200 ml eggplant-shaped flask, add 20 ml of anhydrous THF to dissolve them, then add acetic anhydride (2.5 g, 24.5 mmol). After adding the materials, stir at room temperature for 2 h. Monitor the reaction by TLC. After the reaction is completed, add water and stir at room temperature for 1 h. After no solid precipitates, extract three times with DCM. The obtained organic phase is washed twice with saturated NaCl solution, dried over anhydrous Na2SO4, filtered under reduced pressure, and evaporated to dryness to obtain intermediate c.

[0160] Place intermediate c (3.6 g, 16.1 mmol) in a 200 ml single-necked eggplant-shaped flask, add 15 ml of CHCl3 to dissolve it, add BF3-Et2O (5 ml), and reflux at heating for 5 h. Monitor the reaction by TLC. After the reaction is completed, transfer it to room temperature to cool it. After complete cooling, add cold water until no white smoke is generated. After no solid precipitates, extract three times with DCM to obtain the organic phase. Then wash the organic phase twice with saturated NaCl solution, dry over anhydrous Na2SO4, filter under reduced pressure, and evaporate to dryness to obtain intermediate d.

[0161] Place intermediate d (2 g, 8.9 mmol) in a 200 ml three-necked flask, add 250 ml of MeOH to dissolve it. Subsequently, slowly add 10 ml of 10% aqueous NaOH solution dropwise under ice bath conditions. After adding, add p-bromobenzaldehyde (9.1 mmol), transfer it to room temperature and react for 12 h. Monitor the reaction by TLC. After the reaction is completed, add 500 ml of water, adjust the pH to 5 - 6 with 2 mol / L hydrochloric acid (HCl), stir at room temperature for 1 h, filter by suction, and wash the filter cake with water and then dry it to obtain intermediate e.

[0162] The preparation of compound J1 was carried out with reference to the preparation of compound S1 in compound 1 above. Subsequently, compound J1 (500 mg, 1.3 mmol) was placed in a 100 ml eggplant-shaped single-necked flask, and then Pd(dba)3 (238 mg, 0.26 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (187 mg, 0.3 mmol), cesium carbonate (Ce2CO3) (847 mg, 2.6 mmol), aniline (156 mg, 1.6 mmol) were added in sequence. Finally, 20 ml of anhydrous DMF was added to dissolve all of them. It was heated to 105 ° C and reacted for 12 h. After the reaction was completed as detected by TLC, it was transferred to room temperature. The reaction solution was cooled, extracted with EA, and purified by silica gel column to obtain compound J2.

[0163] Under anhydrous and anaerobic conditions, compound J2 was dissolved in a solvent (DCM), and BBr3 was added dropwise at a temperature of -15 ° C. The molar ratio of compound J2 to BBr3 was 1:9. After the reaction was completed, recrystallization was carried out to obtain compound 13.

[0164] 1 H NMR (600 MHz, DMSO -d6 ) δ 7.62 - 7.56 (m, 2H), 7.22 - 7.14 (m, 2H), 7.10 - 7.01 (m, 4H), 6.95 - 6.89 (m, 2H), 6.83 (tt, J = 6.9, 1.1 Hz, 1H), 6.19 (t, J = 0.9Hz, 1H), 4.52 (t, J = 0.9 Hz, 2H). MS (ESI): m / z = 360.12 [M + H] + .

[0165] 14. Preparation of compound 14 (4'-p-fluoroaniline baicalein):

[0166] For the preparation of compound 14, the preparation of compound 13 was referred to, except that aniline in the preparation process of compound J2 was replaced with p-fluoroaniline (9.1 mmol).

[0167] 1 H NMR (600 MHz, DMSO -d6 ) δ7.62 - 7.56 (m, 2H), 7.35 - 7.27 (m, 2H), 7.27 - 7.24 (m, 3H), 7.08 (s, 1H), 7.05 - 7.01 (m, 2H), 6.95 - 6.89 (m, 2H), 6.19 (t, J J = 0.9 Hz, 1H), 4.52 (t, J J = 0.9 Hz, 2H). MS (ESI): m / z m / z = 378.11 [M + H] + .

[0168] The structural formula of the obtained compound 14 is as follows:

[0169] .

[0170] 15. Preparation of compound 15 (4'-p-chloroaniline baicalein):

[0171] For the preparation of compound 15, refer to the preparation of compound 13, except that aniline in the preparation of compound J2 was replaced with p-chloroaniline (9.1 mmol).

[0172] 1 1H NMR (600 MHz, DMSO -d6 ) δ 7.62 - 7.56 (m, 1H), 7.14 - 7.09 (m, 1H), 7.09 - 7.01 (m, 2H), 6.95 - 6.89 (m, 1H), 6.21 - 6.17 (m, 1H), 4.52 (t, J J = 0.9 Hz, 1H). MS (ESI): m / z m / z = 395.07 [M + H] + .

[0173] The structural formula of the obtained compound 15 is as follows:

[0174] .

[0175] 16. Preparation of compound 16 (4'-p-bromoaniline baicalein):

[0176] For the preparation of compound 16, refer to the preparation of compound 13, except that aniline in the preparation of compound J2 was replaced with p-bromoaniline (9.1 mmol).

[0177] 1 1H NMR (600 MHz, DMSO -d6 )δ 7.62–7.56 (m, 2H), 7.42-7.36 (m, 2H), 7.08(s, 1H), 7.05-6.97 (m, 3H), 6.95-6.89 (m, 2H), 6.19 (t, J = 0.9 Hz, 1H), 5.81(s, 1H), 4.52 (t, J = 0.9 Hz, 2H). MS (ESI): m / z = 438.03 [M + H] + .

[0178] The structural formula of the obtained compound 16 is as follows:

[0179] .

[0180] 17. Preparation of compound 17 (4'-fluoroscutellarein):

[0181] For the preparation of compound 17, refer to the preparation of compound 13, except that p-bromobenzaldehyde in the preparation of intermediate e was replaced with p-fluorobenzaldehyde (9.1 mmol).

[0182] 1 H NMR (600 MHz, DMSO -d6 ) δ 12.61 (s, 1H), 8.14-8.11 (m, 2H), 7.40 (t, J = 8.8 Hz, 2H), 6.91 (s, 1H), 6.62 (s, 1H). MS (ESI): m / z = 289.05 [M + H] + .

[0183] The structural formula of the obtained compound 17 is as follows:

[0184] .

[0185] 18. Preparation of compound 18 (2',4'-difluoroscutellarein):

[0186] For the preparation of compound 18, refer to the preparation of compound 13, except that p-bromobenzaldehyde in the preparation of intermediate e was replaced with 2,4-difluorobenzaldehyde (9.1 mmol).

[0187] 1 H NMR (600 MHz, DMSO -d6 ) δ12.47 (s, 1H), 10.62 (s, 1H), 8.84 (s, 1H), 8.06 (td, J J = 8.8, 6.5 Hz, 1H), 7.53 (ddd, J J = 11.8, 9.2, 2.5 Hz, 1H), 7.33 (td, J J = 8.5, 2.5 Hz, 1H), 6.63 (s, 1H), 6.57 (d, J J = 0.8 Hz, 1H). MS (ESI): m / z m / z = 307.04 [M + H] + .

[0188] The structural formula of the obtained compound 18 is as follows:

[0189] 。

[0190] 19. Preparation of compound 19 (2'-fluoroscutellarein):

[0191] For the preparation of compound 19, refer to the preparation of compound 13, except that p-bromobenzaldehyde in the preparation of intermediate e was replaced with 2-fluorobenzaldehyde (9.1 mmol).

[0192] 1 1H NMR (600 MHz, DMSO -d6 ) δ 7.66 (ddd, J J = 9.1, 4.0, 1.6 Hz, 1H), 7.47 (dddd, J J = 8.6, 7.9, 4.0, 1.6 Hz, 1H), 7.28 (td, J J = 8.8, 1.4 Hz, 1H), 7.19 (ddd, J J = 10.2, 7.9, 1.4 Hz, 1H), 7.08 (s, 1H), 7.03 (t, J J = 0.9 Hz, 1H), 6.19 (t, J J = 0.9 Hz, 1H), 4.53 (t, J J = 0.9 Hz, 2H). MS (ESI): m / z m / z = 287.07 [M + H] + .

[0193] The structural formula of the obtained compound 19 is as follows:

[0194] 。

[0195] 20. Preparation of Compound 20 (3'-fluoroscutellarein):

[0196] For the preparation of Compound 20, refer to the preparation of Compound 13, except that p-bromobenzaldehyde in the preparation of intermediate e was replaced with 3-fluorobenzaldehyde (9.1 mmol).

[0197] 1 H NMR (600 MHz, DMSO -d6 ) δ 7.60 (ddd, J J = 7.9, 2.3, 1.3 Hz, 1H), 7.42(td, J J = 7.8, 5.0 Hz, 1H), 7.32 (dt, J J = 12.0, 2.2 Hz, 2H), 7.20 (dddd, J J = 10.1,8.1, 2.1, 1.2 Hz, 1H), 7.10 – 7.04 (m, 2H), 6.20 (t, J J = 0.9 Hz, 1H), 4.58 (t, J J = 0.9 Hz, 2H). MS (ESI): m / z m / z = 287.07 [M + H] + .

[0198] The structural formula of the obtained Compound 20 is as follows:

[0199] 。

[0200] 21. Preparation of Compound 21 (4'-trifluoromethylscutellarein):

[0201] For the preparation of Compound 21, refer to the preparation of Compound 13, except that p-bromobenzaldehyde in the preparation of intermediate e was replaced with 4-trifluoromethylbenzaldehyde (9.1 mmol).

[0202] 1 H NMR (600 MHz, DMSO -d6 ) δ 12.53 (s, 1H), 8.29 (d, J J = 8.1 Hz, 2H), 7.93(d, J= 8.1 Hz, 2H), 7.07 (s, 1H), 6.63 (s, 1H). MS (ESI): m / z = 339.04 [M + H] + .

[0203] The structural formula of the obtained compound 21 is as follows:

[0204] 。

[0205] 22. Preparation of compound 22 (4'-bromoscutellarein):

[0206] For the preparation of compound 22, refer to the preparation of compound 13, except that p-bromobenzaldehyde in the preparation of intermediate e is replaced by 3-fluorobenzaldehyde (9.1 mmol).

[0207] 1 H NMR (600 MHz, DMSO -d6 ) δ 12.59 (s, 1H), 10.64 (s, 1H), 8.84 (s, 1H), 8.05 - 7.99 (m, 2H), 7.80 - 7.75 (m, 2H), 6.96 (s, 1H), 6.63 (s, 1H). MS (ESI): m / z = 348.97 [M + H] + .

[0208] The structural formula of the obtained compound 22 is as follows:

[0209] 。

[0210] 23. Preparation of compound 23 (4'-chloroscutellarein):

[0211] For the preparation of compound 23, refer to the preparation of compound 13, except that p-bromobenzaldehyde in the preparation of intermediate e is replaced by p-chlorobenzaldehyde (9.1 mmol).

[0212] 1 H NMR (600 MHz, DMSO -d6 ) δ 12.60 (s, 1H), 10.60 (s, 1H), 8.83 (s, 1H), 8.10 - 8.08 (m, 2H), 7.65 - 7.63 (m, 2H), 6.97 (s, 1H), 6.63 (s, 1H). MS (ESI): m / z = 305.02 [M + H] + .

[0213] The structural formula of the obtained compound 23 is as follows:

[0214] 。

[0215] 24. Preparation of compound 24 (4'-cyano baicalein):

[0216] For the preparation of compound 24, refer to the preparation of compound 13, except that p-bromobenzaldehyde in the preparation of intermediate e was replaced with p-cyanobenzaldehyde (9.1 mmol).

[0217] 1 H NMR (600 MHz, DMSO -d6 ) δ 12.52 (s, 1H), 10.68 (s, 1H), 8.89 (s, 1H), 8.28 - 8.26 (m, 2H), 8.06 - 8.04 (m, 2H), 7.12 (s, 1H), 6.66 (s, 1H). MS (ESI): m / z = 296.05 [M + H] + .

[0218] The structural formula of the obtained compound 24 is as follows:

[0219] 。

[0220] 25. Preparation of compound 25 (3'-chloro-4'-fluoro baicalein):

[0221] For the preparation of compound 25, refer to the preparation of compound 13, except that p-bromobenzaldehyde in the preparation of intermediate e was replaced with 3-chloro-4-fluorobenzaldehyde (9.1 mmol).

[0222] 1 H NMR (600 MHz, DMSO -d6 ) δ 7.67 (dd, J = 3.6, 2.2 Hz, 1H), 7.47 (ddd, J =8.2, 4.0, 2.2 Hz, 1H), 7.15 (dd, J = 10.1, 8.2 Hz, 1H), 7.10–7.04 (m, 2H), 6.20(t, J= 0.9 Hz, 1H), 4.58 (t, J = 0.9 Hz, 2H). MS (ESI): m / z = 322.02 [M + H] + .

[0223] The structural formula of the obtained compound 25 is as follows:

[0224] 。

[0225] 26. Preparation of compound 26 (4'-fluoro-6'-chloro baicalein):

[0226] For the preparation of compound 26, refer to the preparation of compound 13, except that p-bromobenzaldehyde in the preparation process of intermediate e was replaced with 4-fluoro-6-chlorobenzaldehyde (9.1 mmol).

[0227] 1 H NMR (600 MHz, DMSO -d6 ) δ 7.57 (dd, J = 8.5, 4.9 Hz, 1H), 7.27 (dd, J =12.1, 2.2 Hz, 1H), 7.12 - 7.04 (m, 2H), 7.00 (t, J = 0.9 Hz, 1H), 6.20 (d, J =0.9 Hz, 1H), 4.58 (t, J = 0.9 Hz, 2H). MS (ESI): m / z = 322.02 [M + H] + .

[0228] The structural formula of the obtained compound 25 is as follows:

[0229] 。

[0230] Example 2. Inhibitory effect of baicalein derivatives on hPL

[0231] 1. Materials and methods

[0232] A series of baicalein derivatives were synthesized and prepared by the inventors;

[0233] Human pancreatic lipase (hPL) was recombinantly expressed by the inventors [1] , and the specific substrate (DDAO-ol) and its hydrolysis product (DDAO) were synthesized and prepared by the inventors [1] ;

[0234] Orlistat, an existing marketed pancreatic lipase inhibitor.

[0235] Baicalein, a natural human pancreatic lipase inhibitor.

[0236] Remaining control group: Structures similar to those of the present invention in 202210271409.1.

[0237] 2. Experimental method:

[0238] In this experiment, DDAO-ol was used as a specific near-infrared fluorescence probe for hPL to construct an in vitro high-throughput screening system for hPL inhibitors. 66 μL of Tris-HCl buffer, 10 μL of hPL solution (final concentration, 0.25 μg / mL), 20 μL of porcine bile salt (final concentration, 0.1 mg / mL), and 2 μL of inhibitor were mixed and pre-incubated at 37 ° °C for 3 minutes, and then DDAO-ol (final concentration, 20 μM) was added to start the initial reaction. Subsequently, the fluorescence signal of the hydrolysis product (DDAO) of DDAO-ol was measured using a multifunctional microplate reader under the detection conditions of an excitation wavelength of 600 nm and an emission wavelength of 660 nm. Three parallel experiments were performed to ensure the accuracy of the results. The data were reported as the mean and the standard deviation was indicated. The IC 50 value was calculated by nonlinear regression analysis using GraphPad Prism 8.0 software (GraphPad Software, Inc. in LaJolla, USA).

[0239] 3. Experimental results.

[0240] 1) The dose-dependent inhibition curves obtained using GraphPad Prism 8.0 software. Taking 4'-aminobaicalein, 4'-pyrrolidine baicalein, or 4'-piperidine baicalein as examples, their dose-dependent inhibition curves are shown respectively in Figures 2 to 4 ;

[0241] 2) The IC 50 value can be viewed in "Results" of GraphPad Prism 8.0 software, and the results in Table 1 are obtained:

[0242] Table 1: Inhibitory effects of baicalein and its derivatives on hPL activity

[0243]

[0244]

[0245]

[0246] From the data in Table 1, it can be seen that the IC 50 values of 26 synthesized baicalein derivatives are in the range of 0.49 μM to 17.92 μM, and the effects are significant. In particular, the IC 50 value of 4'-pyrrolidine baicalein can reach 0.49 μM, and the effect is very prominent.

[0247] Example 3. Baicalein derivatives can effectively reduce the level of triglycerides in the blood of rats after intragastric administration of olive oil

[0248] 1. Experimental animals: Fifty adult male SD rats (weighing 180 g - 200 g) were selected. After 3 days of adaptive feeding, they were randomly divided into 5 groups according to body weight, with 10 rats in each group.

[0249] 2. Experimental grouping: (1) Olive oil, (2) Pure water, (3) The combination of orlistat (10 mg / kg body weight) and olive oil, (4) The combination of 4'-pyrrolidine baicalein (10 mg / kg body weight) and olive oil, (5) The combination of 4'-amino baicalein (10 mg / kg body weight) and olive oil.

[0250] The olive oil dose for each animal was 5 mg / kg (body weight).

[0251] 3. Experimental detection index: Blood samples were collected at intervals of 0, 1, 2, and 4 h after administration of olive oil, and the triglyceride level was measured using a biochemical analyzer.

[0252] 4. Experimental results: See Table 2

[0253] Table 2: Effects of baicalein derivatives on the triglyceride level in the blood of rats after intragastric administration of olive oil (unit: mg / dL).

[0254] Group / Time (h) 0 1 2 4 Purified water 115±16.52 81.5±4.61 83.25±5.54 64.25±7.15 Olive oil 127±11.24 204.25±19.14 152±14.8 85±6.67 4’-Tetrahydropyrrole baicalein 106.25±9.03 171.5±26.28 106.25±14.60 95.5±20.54 4’-Aminobaicalein 120.32±15.32 180.4±18.44 129.9±21.23 101±13.24 4’-Piperidine baicalein 130.9±12.88 190.67±11.3 165.3±5.29 121.64±9.51 2’,4’-Difluoro baicalein 114.73±9.39 196.3±17.42 153.8±16.4 131.7±7.4 4’-Bromo baicalein 127.56±13.1 193.12±9.34 170.45±10.6 140.84±11.96 Orlistat 115.75±22.86 160±20.2 113.25±17.44 93.75±21.54

[0255] The experimental results showed that after 1 h, the triglyceride level in the olive oil group increased sharply to 204 mg / dL. It is worth noting that the 4'-pyrrolidine baicalein (10 mg / kg) group and the 4'-amino baicalein (10 mg / kg) group showed similar lipid-lowering effects in mice, the same as that of the commercially available anti-PL inhibitor (orlistat, 10 mg / kg).

[0256] The experimental results indicate that both 4'-pyrrolidine baicalein and 4'-amino baicalein have lipid-lowering effects.

[0257] Example 4. Acute toxicity study

[0258] 1. Experimental animals: Fifteen adult male SD rats (weighing 180 g - 200 g) were selected. The animals were fed adaptively for 3 days and randomly divided into 3 groups according to body weight, with 5 rats in each group.

[0259] 2. Experimental grouping: (1) Control group: 0.5% sodium carboxymethylcellulose; (2) 4'-pyrrolidine tetrahydroxyflavone (250 mg / kg); (3) 4'-aminotetrahydroxyflavone (250 mg / kg).

[0260] 3. Experimental detection indexes: After administration, the mice were monitored every hour within the first 6 hours, and then any signs of toxicity in the mice were monitored every day for 14 days. The body weight was measured every day, and the observations on any toxic symptoms or mortality were recorded within 14 days.

[0261] 4. Experimental results: During the entire toxicity test period (2 weeks), no toxic symptoms or deaths were observed in 10 mice. No significant difference in body weight was observed between the experimental group and the control group (receiving saline). In addition, the potential effects of 4'-pyrrolidine tetrahydroxyflavone and 4'-aminotetrahydroxyflavone on the important organs of mice were also studied. The results showed that after 14 days of repeated treatment of mice with 250 mg / kg of 4'-pyrrolidine tetrahydroxyflavone and 4'-aminotetrahydroxyflavone respectively every day, no obvious damage was observed in the heart, liver, spleen, lung, kidney, brain and gastrointestinal tissues compared with the control group.

[0262] This indicates that 4'-pyrrolidine tetrahydroxyflavone and 4'-aminotetrahydroxyflavone have good safety.

[0263] Example 5. Oral tablets and their preparation method

[0264] 1. Composition of oral tablets:

[0265] The active ingredient is: 4'-pyrrolidine tetrahydroxyflavone or 4'-aminotetrahydroxyflavone or a combination of 4'-pyrrolidine tetrahydroxyflavone and 4'-aminotetrahydroxyflavone (with equal amounts of the two in combination) provided in Example 1, and the total weight of the active ingredient is 10 g;

[0266] The weight of the remaining excipients is: 20 g of chitosan, 5 g of croscarmellose sodium, 62 g of microcrystalline cellulose, 1 g of magnesium stearate, and 2 g of silicon dioxide.

[0267] 2. Preparation method of oral tablets, including the following steps:

[0268] (1) Weigh each component according to the ratio, including 4'-pyrrolidine tetrahydroxyflavone, 4'-aminotetrahydroxyflavone tablets, the composition of 4'-pyrrolidine tetrahydroxyflavone and 4'-aminotetrahydroxyflavone, chitosan, croscarmellose sodium, microcrystalline cellulose, magnesium stearate and silicon dioxide, and pass through a 40-mesh sieve respectively.

[0269] (2) Mix silica and water evenly according to a mass ratio of 1:2, sieve through a 40-mesh sieve, add it to 4'-tetrahydropyrrole baicalein or 4'-amino baicalein tablets or a composition of 4'-tetrahydropyrrole baicalein and 4'-amino baicalein, mix evenly, granulate by wet method, then dry at a temperature of 60 °C, control the moisture content to ≤2.5%, and sieve through a 20-mesh sieve to obtain granules;

[0270] (3) Mix the granules with chitosan, croscarmellose sodium, microcrystalline cellulose, and magnesium stearate evenly and then press into tablets to obtain tablets.

[0271] Alternatively, the tablets can be coated. For example, a commercially available coating powder, or hydroxypropyl methylcellulose, polyethylene glycol, magnesium stearate, and pigment are mixed with a solvent (such as water or ethanol, etc.) to prepare a coating solution for coating the tablets.

[0272] It should be noted that the prior art part in the protection scope of the present invention is not limited to the embodiments given in this application document. All prior arts that do not conflict with the solution of the present invention, including but not limited to prior patent documents, prior published publications, prior public uses, etc., can be included in the protection scope of the present invention.

[0273] In addition, the combination methods of the technical features in this case are not limited to the combination methods recorded in the claims of this case or the combination methods recorded in the specific embodiments. All the technical features recorded in this case can be freely combined or combined in any way, unless contradictions occur between them.

[0274] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the above specific embodiments. Those skilled in the art can make various changes or modifications within the scope of the claims, which do not affect the essence of the present invention. Without conflict, the embodiments of this application and the features in the embodiments can be combined with each other arbitrarily.

[0275] Reference [1] HU Q, Z-H T, H-N W, et al. Rational design, and development of a novel and highly specific near-infrared fluorogenic substrate for sensing and imaging of human pancreatic lipase in living systems [J]. Sensors and Actuators: B Chemical, 2021, 341: 130033.

Claims

1. A baicalein derivative having a structure of formula 2 or a pharmaceutically acceptable salt thereof, characterized in that: The structure of Formula 2 is as follows: 。 2. A pharmaceutical composition for weight loss and lipid reduction, characterized in that: The pharmaceutical composition contains the baicalein derivative or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

3. The drug composition for reducing weight and lowering blood lipids according to claim 2, characterized in that: The pharmaceutically acceptable excipient is selected from any one of starch, dextrin, lactose, microcrystalline cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and magnesium stearate, or a mixture of several of them.

4. The drug composition for reducing weight and lowering blood lipids according to claim 2, characterized in that: The pharmaceutical composition is in the form of tablets, capsules, suspensions, granules, powders, emulsions, pills or oral liquids.

5. Use of the baicalein derivative or a pharmaceutically acceptable salt thereof according to claim 1 in preparing a medicament for treating hyperlipidemia and obesity.

6. The use according to claim 5, characterized in that: The baicalein derivative or its pharmaceutically acceptable salt exerts the weight-loss and lipid-lowering effects by inhibiting human pancreatic lipase, and human pancreatic lipase is one of its action targets.

7. A method for preparing the baicalein derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the method is selected from any one of the following methods, wherein R is 4'-tetrahydropyrrole: 。 8. The preparation method according to claim 7, characterized in that: In the synthesis method 1, the preparation method of the compound according to claim 1 comprises the following steps: Nitro-substituted cinnamic acid and oxalyl chloride react to obtain intermediate a; Intermediate a and 3,4,5-trimethoxyphenol react to obtain intermediate b; Intermediate b reacts with iodine to obtain compound S1; Compound S1 reacts with sodium pyrosulfite to obtain compound S2; The compound S2 is first subjected to an amine substitution reaction, and then demethylated to obtain the compound of claim 1.

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