A tricyclic matrine derivative, preparation method and application thereof, and pharmaceutical composition

Abstract

The present application relates to the technical field of biological medicine, in particular to a kind of tricyclic sophoridine compound and its preparation method and application, pharmaceutical composition.The tricyclic sophoridine compound provided in the present application has good potential in preventing and / or treating diseases with lipid metabolic disorder syndrome such as fatty liver disease, diabetes, obesity, etc., and the tricyclic sophoridine compound has low toxicity and high safety.As shown in the test results of examples, the tricyclic sophoridine compound provided in the present application can significantly reduce the body weight of MASLD model mice induced by high-fat feed, improve liver function, glucose-lipid metabolic disorder, insulin resistance index and liver steatosis and other pathological abnormalities, and no toxic side effects are observed for 6 weeks of 100mg / kg dose gavage, and acute toxicity test also shows that it has very high safety.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a tricyclic matrine compound, its preparation method and application, and pharmaceutical compositions. Background Technology

[0002] Obesity, metabolic dysfunction-associated fatty liver disease (MASLD), and diabetes, among other disorders of glucose and lipid metabolism, have become a major public health challenge posing serious threats to health. These diseases do not exist in isolation but constitute a tightly intertwined and mutually reinforcing "metabolic disorder syndrome." Their core pathophysiological mechanisms, such as insulin resistance, chronic inflammation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, adipose tissue dysfunction, and gut microbiota dysbiosis, exhibit high overlap and interaction. Patients often suffer from multiple metabolic diseases simultaneously or sequentially, forming a complex "multi-disease coexistence" state, significantly increasing the risk of cardiovascular and cerebrovascular events, liver and kidney failure, and even the severity of diseases caused by sudden infectious diseases.

[0003] These diseases are complex and difficult to treat, with a significant gap in new drug development. Taking MASLD as an example, its natural course is complex and dynamically evolving, encompassing a gradual progression from metabolic dysfunction-associated fatty liver (MAFL) to MASH, liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Currently, investigational drugs targeting MASLD / MASH commonly act on metabolism, fibrosis, and inflammation. Among these, research targeting metabolism is the most popular, involving targets including THR-β, FXR, GLP-1R, PPAR, and FGF21. The first new MASH drug, the THR-β agonist Resmetirom (MGL-3196), has been marketed; however, its overall efficacy and safety require further data verification. The PPARα / γ dual agonist Saroglitazar has not received a significant market response for the treatment of MAFLD and MASH, and its safety remains to be investigated. Therefore, there is an urgent need to explore and develop a highly effective and safe drug for treating fatty liver diseases such as MASLD / MASH and their common comorbidities such as obesity and diabetes. Summary of the Invention

[0004] Therefore, the purpose of this invention is to provide a tricyclic matrine butamine compound, its preparation method and application, and a pharmaceutical composition thereof. The tricyclic matrine butamine compound provided by this invention has a good therapeutic effect on metabolic dysfunction-associated fatty liver disease (MASLD).

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a tricyclic matrine compound having the structure shown in Formula I: Formula I; R includes unsubstituted or substituted aryl groups.

[0006] Preferably, the substituents in the substituted aryl group include at least one selected from halogen, cyano, alkyl, alkoxy, haloalkyl, and haloalkoxy. The number of carbon atoms in the alkyl, alkoxy, haloalkyl, and haloalkoxy groups is independently 1 to 6.

[0007] Preferably, the substituents include bromine, chlorine, cyano, methyl, ethyl, n-propyl, tert-butyl, methoxy, trifluoromethyl, or trifluoromethoxy. The aryl group includes phenyl or naphthyl.

[0008] This invention also provides a method for preparing the tricyclic matrine butylamine compound described in the above technical solution, comprising the following steps: Compound 5, R-sulfonyl chloride, the first organic amine, and the first organic solvent were mixed and subjected to a sulfonation reaction to obtain compound 6; The compound 6, hydrazine hydrate, and a second organic solvent were mixed and subjected to a hydrazinolysis reaction to obtain the tricyclic matrine compound. Among them, the structural formula of compound 5 is The structural formula of compound 6 is .

[0009] Preferably, the preparation method of compound 5 includes the following steps: Matrine was subjected to an amide hydrolysis reaction under alkaline conditions to obtain compound 1; Compound 1 was mixed with ditert-butyl dicarbonate, a second organic amine and a third organic solvent, and a substitution reaction was carried out to obtain compound 2. Compound 2, the reducing agent, and the fourth organic solvent were mixed and a reduction reaction was carried out to obtain compound 3. Compound 3, phthalimide, triphenylphosphine, diethyl azodicarbonate and the fifth organic solvent were mixed and subjected to photoelectrophoresis to obtain compound 4. Compound 4 was subjected to a deprotection reaction to obtain compound 5; The structural formulas of matrine and compounds 1-4 are as follows: .

[0010] Preferably, the first organic amine comprises at least one of triethylamine and N,N-diisopropylethylamine; The first organic solvent includes chlorinated hydrocarbons; The second organic solvent includes at least one of alcohol solvents and amide solvents.

[0011] Preferably, the second organic amine comprises at least one of triethylamine and N,N-diisopropylethylamine; The third organic solvent includes at least one of chlorinated hydrocarbons and furan solvents; The reducing agent includes at least one of lithium aluminum hydride and sodium borohydride; The fourth organic solvent includes ether solvents; The fifth organic solvent may include at least one of furan solvents and amide solvents; The deprotection reaction is carried out under conditions of trifluoroacetic acid and a sixth organic solvent, which includes at least one of chlorinated and furan solvents.

[0012] This invention also provides the use of the tricyclic matrine compounds described in the above-mentioned technical solutions in the preparation of medicaments for the prevention and / or treatment of diseases accompanied by glucose and lipid metabolism disorders.

[0013] Preferably, the disease accompanied by glucose and lipid metabolism disorder syndrome includes at least one of metabolic dysfunction-related fatty liver disease, diabetes, and obesity.

[0014] The present invention also provides a pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises the tricyclic matrine compound described in the above-described technical solution.

[0015] The tricyclic matrine compounds provided by this invention have great potential in the prevention and / or treatment of diseases accompanied by fatty liver disease, diabetes, obesity, and other disorders of glucose and lipid metabolism. Furthermore, these compounds exhibit low toxicity and high safety. As shown in the test results of the examples, the tricyclic matrine compounds provided by this invention can significantly reduce the body weight of MASLD model mice induced by a high-fat diet, improve liver function, glucose and lipid metabolism disorders, insulin resistance indicators, and pathological abnormalities such as hepatic steatosis. Moreover, no toxic side effects were observed after a 6-week course of 100 mg / kg / day via gavage, and acute toxicity experiments also demonstrated its extremely high safety.

[0016] The method for preparing tricyclic matrine butylamine compounds provided by this invention has the advantages of high yield, simple preparation method, simple operation, low production cost, and suitability for industrial production. Attached Figure Description

[0017] Figure 1 Synthetic route diagram for tricyclic matrine butamine compounds; Figure 2 This is a diagram of the animal experimental dosing regimen for compound I-1 in test example 2; Figure 3 The final body weight of the mice in test example 2 after 10 weeks of drug administration is shown in the figure. Figure 4 This is a graph showing the average weekly food intake per mouse in Test Example 2 during the 10-week drug administration period; Figure 5 The graph shows the body fat percentage of the mice in Test Example 2 after 10 weeks of drug administration; Figure 6 The image shows the liver weight of the mice in test example 2 10 weeks after drug administration; Figure 7 The liver index of the mice in test example 2 after 10 weeks of drug administration is shown in the graph. Figure 8 This is a graph showing the fasting blood glucose levels of mice in Test Example 2 10 weeks after administration. Figure 9 This is a graph showing the non-fasting blood glucose levels of mice in Test Example 2 10 weeks after drug administration; Figure 10 This is a graph showing the serum insulin levels of mice in Test Example 2 10 weeks after drug administration; Figure 11 This is a graph showing the insulin resistance index of mice in Test Example 2 after 10 weeks of drug administration. Figure 12 The graph shows the serum triglyceride levels in mice in Test Example 2 10 weeks after administration. Figure 13 This is a graph showing the total cholesterol levels in the serum of mice in Test Example 2 10 weeks after drug administration; Figure 14 The graph shows the serum alanine aminotransferase (ALT) levels in mice in Test Example 2 after 10 weeks of drug administration. Figure 15 The image shows the serum aspartate aminotransferase (AST) levels in mice in Test Example 2 10 weeks after administration. Figure 16 The images show the gross, H&E, and Oil Red staining results of the mouse liver tissue in Test Example 2. Figure 17 The image shows the NAS score of the liver tissue pathology of mice in test case 2; Figure 18 A graph showing the triglyceride content in the liver of mice in test example 2; Figure 19 A graph showing the total cholesterol content in the liver of mice in test example 2; Figure 20 Figure 1 shows the initial and final body weights of mice in the acute toxicity test in Example 3. Figure 21 A graph showing serum alanine aminotransferase (ALT) levels in mice tested in Example 3 for acute toxicity. Figure 22 The graph shows the serum aspartate aminotransferase (AST) levels in mice tested in Example 3 for acute toxicity. Figure 23The graph shows the alkaline phosphatase levels in the serum of mice tested in Example 3 for acute toxicity. Figure 24 A graph showing the total bilirubin levels in the serum of mice tested in Example 3 for acute toxicity. Figure 25 A graph showing serum urea levels in mice tested in Example 3 for acute toxicity. Figure 26 A graph showing serum creatinine levels in mice tested in Example 3 of the acute toxicity experiment; Figure 27 The image shows the liver and kidney of mice tested for acute toxicity of compound I-1 in Example 3, with H&E staining and pathological images. Detailed Implementation

[0018] This invention provides a tricyclic matrine compound having the structure shown in Formula I: Formula I; R includes unsubstituted or substituted aryl groups.

[0019] In this invention, the substituents in the substituted aryl group may include at least one selected from halogen, cyano, alkyl, alkoxy, haloalkyl, and haloalkoxy; the halogen may include fluorine, chlorine, bromine, or iodine, specifically bromine or chlorine. In this invention, the number of carbon atoms in the alkyl, alkoxy, haloalkyl, and haloalkoxy groups may independently be 1 to 6, or 1 to 4, specifically 1, 2, 3, 4, 5, or 6. In this invention, the halogen in the haloalkyl and haloalkoxy groups may independently be fluorine, chlorine, bromine, or iodine, specifically fluorine. In this invention, the number of substituents in the substituted aryl group may be 1 to 3, specifically 1, 2, or 3. In this invention, the substituents may specifically include bromine, chlorine, cyano, methyl, ethyl, n-propyl, tert-butyl, methoxy, trifluoromethyl, or trifluoromethoxy. In this invention, the aryl group may include phenyl or naphthyl.

[0020] In this invention, R may include p-methylphenyl, p-trifluoromethoxyphenyl, p-trifluoromethylphenyl, p-bromophenyl, p-methoxyphenyl, phenyl, m-trifluoromethylphenyl, o-methylphenyl, m-methylphenyl, p-ethylphenyl, p-propylphenyl, p-tert-butylphenyl, 2,4,6-trimethylphenyl, 2,5-dimethylphenyl, 3,5-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dichlorophenyl, p-chlorophenyl, m-bromophenyl, m-chlorophenyl, m-trifluoromethoxyphenyl, p-cyanophenyl, m-cyanophenyl, or naphthyl.

[0021] In this invention, the tricyclic matrine compound may have any of the following structures:

[0022]

[0023] .

[0024] This invention also provides a method for preparing the tricyclic matrine butylamine compounds described in the above technical solution (reaction route see...). Figure 1 ), including the following steps: Compound 5, R-sulfonyl chloride, the first organic amine, and the first organic solvent were mixed and subjected to a sulfonation reaction to obtain compound 6; The compound 6, hydrazine hydrate, and a second organic solvent were mixed and subjected to a hydrazinolysis reaction to obtain the tricyclic matrine compound. Among them, the structural formula of compound 5 is The structural formula of compound 6 is .

[0025] Unless otherwise specified, the materials and equipment used in this invention are all commercially available products in the field.

[0026] In this invention, compound 5, R-sulfonyl chloride, a first organic amine, and a first organic solvent are mixed and subjected to a sulfonation reaction to obtain compound 6; the definition of R in R-sulfonyl chloride is the same as the definition of R in Formula I.

[0027] In this invention, the molar ratio of compound 5 and R-sulfonyl chloride can be 1:1.25~1.35, or 1:1.28~1.32, or specifically 1:1.3.

[0028] In this invention, the R-sulfonyl chloride may include p-methylbenzenesulfonyl chloride, p-trifluoromethoxybenzenesulfonyl chloride, p-trifluoromethylbenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, benzenesulfonyl chloride, m-trifluoromethylbenzenesulfonyl chloride, o-methylbenzenesulfonyl chloride, m-methylbenzenesulfonyl chloride, p-ethylbenzenesulfonyl chloride, p-propylbenzenesulfonyl chloride, p-tert-butylbenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2,5-dimethylbenzenesulfonyl chloride, 3,5-dimethylbenzenesulfonyl chloride, 3,4-dimethylbenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, m-bromobenzenesulfonyl chloride, m-chlorobenzenesulfonyl chloride, m-trifluoromethoxybenzenesulfonyl chloride, p-cyanobenzenesulfonyl chloride, m-cyanobenzenesulfonyl chloride, or naphthalenesulfonyl chloride.

[0029] In this invention, the molar ratio of compound 5 to the first organic amine can be 1:2 to 5, or 1:2.5 to 3.5, specifically 1:3. In this invention, the first organic amine can include at least one of triethylamine and N,N-diisopropylethylamine.

[0030] In this invention, the first organic solvent may include chlorinated hydrocarbons, specifically dichloromethane; the second organic solvent may be an anhydrous second organic solvent. In this invention, the ratio of compound 5 to the second organic solvent may be 1 mol: 9~9.5 L, or 1 mol: 9.2~9.4 L.

[0031] In this invention, the temperature of the sulfonation reaction can be 20~30℃, or 22~28℃; the time of the sulfonation reaction can be 6~10h, or 7~9h, specifically 8h.

[0032] After completing the sulfonation reaction, the present invention may further include: concentrating the sulfonation reaction solution obtained from the sulfonation reaction and then purifying it by column chromatography to obtain compound 6. In the present invention, the column chromatography purification can be Flash column purification; the eluent used in the column chromatography purification can be dichloromethane and methanol, and the volume ratio of dichloromethane to methanol can be 99:1.

[0033] After obtaining compound 6, the present invention mixes compound 6, hydrazine hydrate, and a second organic solvent to carry out a hydrazinolysis reaction to obtain the tricyclic matrine compound (Formula I).

[0034] In this invention, the molar ratio of compound 6 to hydrazine hydrate can be 1:40~60, or 1:45~55, and specifically 1:48.

[0035] In this invention, the second organic solvent may include at least one of alcohol solvents and amide solvents, specifically including at least one of ethanol, methanol, and N,N-dimethylformamide; the second organic solvent may be an anhydrous second organic solvent. In this invention, the ratio of intermediate 6 to the second organic solvent may be 1 mol: 13.5~14 L, or 1 mol: 13.5~13.7 L.

[0036] In this invention, the temperature of the hydrazine hydrolysis reaction can be 70~90℃, or 75~85℃, specifically 80℃; the time of the hydrazine hydrolysis reaction can be 6~10h, or 7~9h, specifically 8h.

[0037] After completing the hydrazine hydrolysis reaction, the present invention may further include: extracting the hydrazine hydrolysis reaction solution obtained from the hydrazine hydrolysis reaction, and sequentially washing, drying, concentrating, and purifying the obtained organic phase by column chromatography to obtain tricyclic matrine butamine compounds. In the present invention, the extraction may be performed using ethyl acetate and water, and the number of extractions may be 2-4 times, specifically 3 times. In the present invention, the washing may be performed using saturated brine, and the number of washings may be 2-4 times, specifically 3 times. In the present invention, the drying may be performed using a desiccant, which may include anhydrous sodium sulfate and / or anhydrous magnesium sulfate. In the present invention, the column chromatography purification may be performed using a Flash column; the eluent used in the column chromatography purification may be dichloromethane and methanol, and the volume ratio of dichloromethane to methanol may be 94:6.

[0038] In this invention, the preparation method of compound 5 (reaction route see...) Figure 1 This may include the following steps: Matrine was subjected to an amide hydrolysis reaction under alkaline conditions to obtain compound 1; Compound 1 was mixed with ditert-butyl dicarbonate, a second organic amine and a third organic solvent, and a substitution reaction was carried out to obtain compound 2. Compound 2, the reducing agent, and the fourth organic solvent were mixed and a reduction reaction was carried out to obtain compound 3. Compound 3, phthalimide, triphenylphosphine, diethyl azodicarbonate and the fifth organic solvent were mixed and subjected to photoelectrophoresis to obtain compound 4. Compound 4 was subjected to a deprotection reaction to obtain compound 5; The structural formulas of matrine and compounds 1-4 are as follows: .

[0039] In this invention, matrine is subjected to an amide hydrolysis reaction under alkaline conditions to obtain compound 1.

[0040] In this invention, the amide hydrolysis reaction may include: mixing matrine, an alkaline reagent and water to carry out the amide hydrolysis reaction.

[0041] In this invention, the molar ratio of matrine to alkaline reagent can be 1:50~60, or 1:53~57, specifically 1:50, 1:51, 1:52, 1:53, 1:54, 1:55, 1:56, 1:57, 1:58, 1:59 or 1:60.

[0042] In this invention, the alkaline reagent may include alkali metal hydroxides, specifically sodium hydroxide and / or potassium hydroxide.

[0043] In this invention, the mixing can be achieved by dissolving an alkaline reagent in water to obtain an alkaline reagent aqueous solution, and then mixing matrine with the alkaline reagent aqueous solution. In this invention, the mass concentration of the alkaline reagent aqueous solution can be 30-50%, or 35-45%, and further 35-40%.

[0044] In this invention, the temperature of the amide hydrolysis reaction can be 90~120℃, or 95~115℃, or even 100~110℃; the time of the amide hydrolysis reaction can be 8~20h, or 10~18h, or even 15~16h.

[0045] After completing the amide hydrolysis reaction, the present invention may further include: cooling the hydrolysis reaction solution obtained from the amide hydrolysis reaction to precipitate a paste, adding concentrated hydrochloric acid to adjust the pH value to 1, removing the solvent by vacuum distillation to obtain a reddish-brown paste; dissolving in methanol, filtering, adding thionyl chloride to the obtained filtrate and stirring at room temperature, removing the solvent by vacuum distillation, dissolving in anhydrous ethanol to remove impurities, filtering, and drying the obtained solid to constant weight to obtain compound 1.

[0046] After obtaining compound 1, the present invention mixes compound 1, ditert-butyl dicarbonate, a second organic amine and a third organic solvent to carry out a substitution reaction to obtain compound 2.

[0047] In this invention, the molar ratio of compound 1 and ditert-butyl dicarbonate can be 1:1.4~1.6, or 1:1.45~1.55, and specifically 1:1.5.

[0048] In this invention, the molar ratio of compound 1 to the second organic amine can be 1:2 to 5, or 1:2.5 to 4, or even 1:3 to 3.5. In this invention, the second organic amine can include at least one of triethylamine and N,N-diisopropylethylamine (DIPEA).

[0049] In this invention, the third organic solvent may include at least one of chlorinated hydrocarbons and furan solvents, specifically at least one of dichloromethane and tetrahydrofuran. In this invention, the ratio of compound 1 to the third organic solvent may be 1 mol: 3-4 L, or 3.1-3.3 L, or even 1 mol: 3.15-3.2 L.

[0050] In this invention, the temperature of the substitution reaction can be 20~30℃, or 22~28℃; the time of the substitution reaction can be 10~14h, or 11~13h, or even 12h.

[0051] After completing the substitution reaction, the present invention may further include: extracting the substitution reaction solution obtained from the substitution reaction, and sequentially washing, drying, and concentrating the obtained organic phase to obtain compound 2. In the present invention, the extraction may be performed using a saturated ammonium chloride aqueous solution, and the number of extractions may be 2 to 4, specifically 3. In the present invention, the washing may be performed using saturated brine, and the number of washings may be 2 to 4, specifically 3. In the present invention, the drying may be performed using a desiccant, which may include anhydrous sodium sulfate and / or anhydrous magnesium sulfate.

[0052] After obtaining compound 2, the present invention mixes compound 2, a reducing agent and a fourth organic solvent to carry out a reduction reaction to obtain compound 3.

[0053] In this invention, the reducing agent may include at least one of lithium aluminum hydride and sodium borohydride. In this invention, the molar ratio of compound 2 to the reducing agent may be 1:1.05~1.2, or 1:1.08~1.12, specifically 1:1.1.

[0054] In this invention, the fourth organic solvent may include an ether solvent, specifically tetrahydrofuran and / or diethyl ether; the fourth organic solvent may be an anhydrous fourth organic solvent. In this invention, the ratio of compound 2 to the fourth organic solvent may be 1 mol: 6.5~7 L, or 1 mol: 6.5~6.7 L.

[0055] In this invention, the temperature of the reduction reaction can be -20 to -10°C, or -18 to -12°C, or even -15°C; the time of the reduction reaction can be 0.5 to 2 hours, or 0.8 to 1.2 hours, or even 1 hour.

[0056] After the reduction reaction is completed, the present invention may further include: quenching, drying, filtering, and concentrating the reduction reaction solution obtained from the reduction reaction sequentially to obtain compound 3. In the present invention, the quenching may be performed using ethyl acetate. In the present invention, the drying may be performed using a desiccant, which may include anhydrous sodium sulfate and / or anhydrous magnesium sulfate. In the present invention, the filtration may be performed using diatomaceous earth filtration.

[0057] After obtaining compound 3, the present invention mixes compound 3, phthalimide, triphenylphosphine, diethyl azodicarbonate and a fifth organic solvent, and performs a photoelectrophoresis reaction to obtain compound 4.

[0058] In this invention, the molar ratio of compound 3 and phthalimide can be 1:1.8~2.2, or 1:1.9~2.1, or specifically 1:2.

[0059] In this invention, the molar ratio of compound 3 to triphenylphosphine can be 1:1.8~2.2, or 1:1.9~2.1, or specifically 1:2.

[0060] In this invention, the molar ratio of compound 3 and diethyl azodicarbonate can be 1:1.8~2.2, or 1:1.9~2.1, or specifically 1:2.

[0061] In this invention, the fifth organic solvent may include at least one of furan solvents and amide solvents, specifically including at least one of tetrahydrofuran and N,N-dimethylformamide; the fifth organic solvent may be an anhydrous organic solvent. In this invention, the ratio of compound 3 to the fifth organic solvent may be 1 mol: 6~7 L, or 1 mol: 6.5~6.8 L, or even 1 mol: 6.6~6.7 L.

[0062] In this invention, the temperature of the photoelongation reaction can be 70~90℃, or 75~85℃, specifically 80℃; the time of the photoelongation reaction can be 6~10h, or 7~9h, specifically 8h; the photoelongation reaction can be carried out under a protective atmosphere, which may include nitrogen, argon or helium.

[0063] After completing the photoelongation reaction, the present invention may further include: concentrating the photoelongation reaction solution obtained from the photoelongation reaction and then purifying it by column chromatography to obtain compound 4. In the present invention, the column chromatography purification can be Flash column purification; the eluent used in the column chromatography purification can be dichloromethane and methanol, and the volume ratio of dichloromethane to methanol can be 98:2.

[0064] After obtaining compound 4, the present invention performs a deprotection reaction on compound 4 to obtain compound 5.

[0065] In this invention, the deprotection reaction can be carried out by mixing compound 4, trifluoroacetic acid and the sixth organic solvent to perform a deprotection reaction of Boc.

[0066] In this invention, the molar ratio of compound 4 to trifluoroacetic acid can be 1:15~30, or 1:20~25, and specifically 1:23.

[0067] In this invention, the sixth organic solvent may include at least one of chlorinated hydrocarbons and furan solvents, specifically including at least one of dichloromethane and tetrahydrofuran; the sixth organic solvent may be an anhydrous sixth organic solvent. In this invention, the ratio of compound 4 to the sixth organic solvent may be 1 mol: 8.5~9 L, or 1 mol: 8.8~8.9 L.

[0068] In this invention, the temperature of the deprotection reaction can be -5~5℃, or -2~2℃, or even 0℃; the time of the deprotection reaction can be 3~6h, or 4~5h.

[0069] After completing the deprotection reaction, the present invention may further include: neutralizing the deprotected reaction solution obtained from the deprotection reaction, separating the phases, and sequentially drying, concentrating, and purifying the obtained organic phase by column chromatography to obtain compound 5. In the present invention, the neutralization may be achieved by adjusting the pH to 8 using a saturated sodium carbonate solution. In the present invention, the drying may be achieved using a desiccant, which may include anhydrous magnesium sulfate and / or anhydrous sodium sulfate. In the present invention, the column chromatography purification may be achieved using a Flash column; the eluent used in the column chromatography purification may be dichloromethane and methanol, and the volume ratio of dichloromethane to methanol may be 97:3.

[0070] This invention also provides the application of the tricyclic matrine butamine compounds described in the above-mentioned technical solutions in the preparation of medicaments for the prevention and / or treatment of diseases accompanied by glucose and lipid metabolism disorders. In this invention, the diseases accompanied by glucose and lipid metabolism disorders may include at least one of metabolic dysfunction-related fatty liver disease, diabetes, and obesity. The tricyclic matrine butamine compounds provided by this invention can significantly reduce the body weight of MASLD model mice induced by a high-fat diet, improve liver function, glucose and lipid metabolism disorders, insulin resistance indicators, and pathological abnormalities such as hepatic steatosis. They have great potential in the prevention and / or treatment of diseases accompanied by glucose and lipid metabolism disorders such as fatty liver disease, diabetes, and obesity, and exhibit high safety, showing promising application prospects in anti-MASLD.

[0071] The present invention also provides a pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises the tricyclic matrine compound described in the above-described technical solution.

[0072] The present invention does not have any particular limitation on the pharmaceutically acceptable excipients, and any pharmaceutically acceptable excipients well known to those skilled in the art can be used.

[0073] In this invention, the mass content of the active component in the pharmaceutical composition can be 0.5-99%, or 5-50%, specifically 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%.

[0074] The present invention does not impose any particular limitation on the dosage form of the pharmaceutical composition; any pharmaceutical dosage form well known to those skilled in the art may be used.

[0075] To further illustrate the present invention, the following detailed descriptions of the tricyclic matrine butamine compounds, their preparation methods, applications, and pharmaceutical compositions provided by the present invention are provided in conjunction with the embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0076] Example 1 I-1; (1) 4.832 mmol of matrine was dissolved in 20 mL of 35 wt% sodium hydroxide aqueous solution, heated under reflux for 16 h, and after cooling, a large amount of paste was precipitated. 36 wt% concentrated hydrochloric acid was slowly added dropwise to the paste to adjust the pH to 1. The solvent was removed by vacuum distillation to obtain a reddish-brown paste. 60 mL of methanol was added to the paste to completely dissolve the organic matter, and the filtrate was collected by filtration. 3 mL of thionyl chloride was added to the filtrate, and the mixture was stirred at room temperature for 8 h. The solvent was removed by vacuum distillation, and soluble impurities were dissolved in 70 mL of anhydrous ethanol. The mixture was filtered, and the resulting solid fraction was dried to constant weight to obtain compound 1 (white solid, 1.07 g, yield 70%).

[0077] (2) Compound 1 (1 g, 3.156 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and 4.734 mmol of ditert-butyl dicarbonate and 9.468 mmol of triethylamine were added sequentially. The reaction was carried out at room temperature with stirring for 12 h. The reaction was monitored by TLC until it was complete. The reaction system was extracted three times with saturated ammonium chloride solution. The organic phases were combined and washed three times with saturated brine. The organic phases were dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to constant weight to obtain compound 2 (yellow oil, 1.16 g, yield 97%).

[0078] (3) Compound 2 (1.16 g, 3.048 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, cooled to -15 °C, and 3.353 mmol of lithium aluminum hydride was slowly added. The reaction was carried out at -15 °C with stirring for 1 h. The reaction was monitored by TLC until it was complete. The reaction system was quenched with ethyl acetate, dried with anhydrous magnesium sulfate, filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to constant weight to obtain compound 3 (colorless oil, 1.05 g, yield 98%).

[0079] (4) Under argon protection, compound 3 (1.05 g, 2.979 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and 5.958 mmol of triphenylphosphine and 5.958 mmol of phthalimide were added sequentially. The mixture was cooled to 0 °C, and 5.958 mmol of diethyl azodicarbonate was slowly added. The mixture was reacted at 80 °C with stirring for 8 h. The reaction was monitored by TLC until it was complete. The reaction system was concentrated, and the crude product was purified by Flash column chromatography (eluted for 20 min with a mixture of dichloromethane and methanol at a volume ratio of 98:2) to obtain compound 4 (yellow oil, 1.09 g, yield 76%).

[0080] (5) Compound 4 (1.09 g, 2.263 mmol) was dissolved in 20 mL of anhydrous dichloromethane, then cooled to 0 °C and 4 mL of trifluoroacetic acid was added dropwise. The deprotection reaction was carried out for 4 h under ice-water bath (0 °C). The reaction was monitored by TLC. The pH was adjusted to 8 by adding saturated sodium carbonate solution. The organic phase was collected by separation and dried with anhydrous magnesium sulfate. After filtration, the obtained organic phase was concentrated and purified by Flash column (eluted with a mixture of dichloromethane and methanol at a volume ratio of 97:3 for 40 min) to obtain compound 5 (pale yellow, 0.82 g, yield 95%).

[0081] (6) Compound 5 (0.82 g, 2.149 mmol) was dissolved in 20 mL of anhydrous dichloromethane, and 6.447 mmol of triethylamine (the molar ratio of compound 5 to triethylamine was 1:3) and 2.794 mmol of p-toluenesulfonyl chloride (the molar ratio of compound 5 to p-toluenesulfonyl chloride was 1:1.3) were added sequentially. The substitution reaction was carried out by stirring at room temperature for 8 h. The reaction was monitored by TLC until it was complete. The reaction system was concentrated, and the crude product was purified by Flash column (eluting with a mixture of dichloromethane and methanol at a volume ratio of 99:1 for 15 min) to obtain compound 6 (yellow oil, 0.79 g, yield 69%).

[0082] (7) Compound 6 (0.79 g, 1.475 mmol) was dissolved in 20 mL of anhydrous ethanol, 5 mL of hydrazine hydrate was added, and the mixture was heated under reflux for 8 h. The reaction was monitored by TLC until it was complete. The reaction system was extracted three times with ethyl acetate / water, the organic phases were combined, the organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by Flash column (eluting with a mixture of dichloromethane and methanol at a volume ratio of 94:6 for 30 min) to obtain tricyclic matrine compound I-1 (yellow solid, 0.39 g, yield 65%).

[0083] Compound I-1: 1H NMR (400 MHz, DMSO-) d 6) δ 7.68 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 3.47 - 3.32 (m, 4H), 3.16 (s, 4H), 2.80 (d, J = 63.8 Hz, 1H), 2.58 - 2.53 (m, 2H), 2.38 (s, 3H), 1.92 (s, 1H), 1.86 - 1.56 (m, 7H), 1.40 - 1.20 (m, 9H). 13 C NMR (101 MHz, DMSO-) d 6) δ 142.8, 136.9, 129.5(2), 127.2(2), 62.3,56.7, 56.1, 48.6, 46.8, 35.9, 33.9, 30.9, 30.6, 27.8, 27.6, 22.0, 21.0, 20.4, 20.3, 18.6. HRMS: calcd for C 22 H 35 N3O2S [M+H] + : 406.25227, found: 406.25119.

[0084] Example 2 I-2; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with p-trifluoromethoxybenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-2 (yellow solid, yield 65%).

[0085] Compound I-2: 1 H NMR (400 MHz, DMSO-) d 6) δ 7.95 (d, J = 8.3 Hz, 2H), 7.57 (d, J =8.3 Hz, 2H), 3.44-3.30 (m, 2H), 3.15 (t, J= 11.2 Hz, 1H), 2.61-2.30 (m, 4H), 2.05-1.73 (m, 3H), 1.69-1.60 (m, 5H), 1.45 (d, J = 12.5 Hz, 2H), 1.36-1.18 (m, 10H), 1.15-0.97 (m, 1H). 13 C NMR (101 MHz, DMSO-) d 6) δ 150.7, 139.0, 129.8(2),121.0(2), 119.9 (q, J CF = 319.2 Hz), 61.7, 60.6, 56.2, 55.8, 55.7, 54.9, 44.8, 33.0, 32.8, 31.9, 28.4, 27.6, 22.5, 20.3, 19.9. HRMS: calcd for C 22 H 32 F3N3O3S [M+H] + : 476.21892, found: 476.21732.

[0086] Example 3 I-3; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with p-trifluoromethylbenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-3 (light yellow solid, yield 73%).

[0087] Compound I-3: 1 H NMR (400 MHz, DMSO-) d 6): δ 8.03 (d, J = 8.3 Hz, 2H), 7.95 (d, J =8.3 Hz, 2H), 3.16 (s, 7H), 2.48 - 2.31 (m, 4H), 1.87 (s, 2H), 1.66 - 1.56 (m, 4H), 1.45 (d, J = 11.3 Hz, 1H), 1.29 (s, 3H), 1.28 - 1.11 (m, 7H); 13 C NMR (101 MHz, DMSO-d 6): δ 144.0, 132.1(q, J CF = 32.3 Hz), 128.1(2), 126.0 (2) (q, J CF = 4.0 Hz), 123.6 (q, J CF = 273.7 Hz), 61.8, 56.6, 55.9, 55.8, 48.6, 45.2, 41.1, 33.2, 32.5,32.3, 28.3, 27.5, 22.6, 20.3, 20.0; HRMS: calcd for C 22 H 32 F3N3O2S [M+H] + :460.22401, found: 460.22241.

[0088] Example 4 I-4; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with p-bromobenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-4 (white solid, yield 61%).

[0089] Compound I-4: 1 H NMR (400 MHz, DMSO-) d 6) δ7.81 (d, J = 8.3 Hz, 2H), 7.74 (d, J =8.2 Hz, 2H), 4.79 (s, 3H), 3.48-3.32 (m, 2H), 3.16-3.06 (m, 1H), 2.62 (t, J =7.4 Hz, 2H), 2.44 (d, J = 11.3 Hz, 1H), 1.87 (dd, J = 17.1, 5.6 Hz, 2H), 1.79-1.54 (m, 6H), 1.51-0.82 (m, 14H). 13 C NMR (101 MHz, DMSO-) d6) δ 138.9, 132.0,129.3, 126.3, 61.9, 56.3, 55.9, 55.8, 45.6, 39.4, 38.7, 33.2, 31.7, 28.7,28.1, 27.5, 22.0, 20.3, 20.1. HRMS: calcd for C 40 H 48 N₂O₂SBr [M+H] + : 470.14713, found: 470.14612.

[0090] Example 5 I-5; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with p-methoxybenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-5 (white solid, yield 64%).

[0091] Compound I-5: 1 H NMR (400 MHz, DMSO-) d 6) δ 7.72 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H), 3.38 (d, J = 12.6 Hz, 5H), 3.10 (dd, J = 12.3, 10.7Hz, 1H), 2.62 - 2.55 (m, 1H), 1.93 (t, J = 3.1 Hz, 1H), 1.85 (dt, J = 10.3, 5.2 Hz, 1H), 1.80 - 1.63 (m, 5H), 1.59 (d, J = 4.6 Hz, 1H), 1.52 - 1.44 (m, 1H), 1.44 - 1.33(m, 3H), 1.33 - 1.08 (m, 9H). 13 C NMR (101 MHz, DMSO-) d6) δ162.2, 131.4, 129.6,129.3, 114.1, 62.3, 56.6, 56.0, 55.7, 54.9, 46.5, 40.9, 38.6, 33.7, 32.1,30.7, 29.0, 27.8, 27.6, 22.0, 20.3, 20.2. HRMS: calcd for C 22 H 35 N3O3S [M+H] + :422.24718, found: 422.24601.

[0092] Example 6 I-6; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with benzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-6 (white solid, yield 59%).

[0093] Compound I-6: 1 H NMR (400 MHz, DMSO-) d 6) δ7.80 (d, J = 7.1 Hz, 2H), 7.67 - 7.56 (m, 3H), 3.48 - 3.37 (m, 2H), 3.27 (s, 2H), 3.17 (dd, J = 12.5, 10.5 Hz, 1H), 2.55 (d, J = 11.3 Hz, 1H), 2.45 (t, J = 6.9 Hz, 2H), 1.92 (d, J = 3.2 Hz, 1H), 1.86(s, 1H), 1.69 (tt, J = 12.0, 9.7, 3.7 Hz, 5H), 1.58 (dd, J = 24.4, 4.9 Hz, 1H), 1.50 - 1.43 (m, 1H), 1.42 - 1.33 (m, 2H), 1.33 - 1.25 (m, 5H), 1.18 (d, J = 44.8 Hz, 4H). 13 C NMR (101 MHz, DMSO-)d 6) δ 13 C NMR (101 MHz, DMSO-) d 6): δ 140.04, 132.42,128.91 (2), 127.07 (2), 62.19, 56.71, 56.01, 55.99, 46.29, 41.06, 38.74,33.68, 32.34, 31.09, 27.99, 27.56, 22.27, 20.32, 20.18. HRMS: calcd forC 21 H 33 N3O2S [M+H] + : 392.23662, found: 392.23538.

[0094] Example 7 I-7; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with m-trifluoromethylbenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-7 (yellow solid, yield 56%).

[0095] Compound I-7: 1 H NMR (400 MHz, DMSO-) d 6): δ 8.14 (d, J = 7.9 Hz, 1H), 8.03 (d, J =6.9 Hz, 2H), 7.84 (t, J = 8.0 Hz, 1H), 3.55 (s, 5H), 3.38 (dd, J = 12.8, 7.6 Hz, 1H), 3.14 (dd, J = 12.7, 9.3 Hz, 1H), 2.40 - 2.21 (m, 2H), 1.91 - 1.79 (m, 2H), 1.70 - 1.53 (m, 6H), 1.43 (d, J = 13.0 Hz, 1H), 1.37 - 1.27 (m, 5H), 1.27 - 1.15 (m, 5H). 13 C NMR (101 MHz, DMSO-)d 6): δ 141.2, 131.4, 130.4, 129.4 (q, J CF = 33.3 Hz), 129.1 (q, J CF = 4.0 Hz), 123.6 (q, J CF = 273.7 Hz), 124.5 (q, J CF = 4.0 Hz), 61.5,56.0, 55.8, 55.6, 44.0, 40.7, 38.7, 33.7, 32.5, 31.6, 28.7, 27.5, 22.6, 20.3,19.8. HRMS: calcd for C 22 H 32 F3N3O2S [M+H] + : 460.22401, found: 460.22289.

[0096] Example 8 I-8; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with o-methylbenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-8 (white solid, yield 71%).

[0097] Compound I-8: 1 H NMR (400 MHz, DMSO-) d 6) δ 7.91 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.39 (d, J = 7.8 Hz, 2H), 3.68 - 3.58 (m, 2H), 3.40 (t, J = 12.2 Hz, 1H), 2.70 (t, J = 11.0 Hz, 2H), 2.42 - 2.39 (m, 1H), 2.15 - 2.06 (m, 4H), 1.93 - 1.71 (m, 5H), 1.57 - 1.45 (m, 6H), 1.40- 1.21 (m, 6H), 0.97 - 0.53 (m, 4H). 13 C NMR (101MHz, DMSO-) d 6) δ 140.8, 137.0, 132.5, 132.3, 128.1, 126.2, 63.3, 59.9, 56.5,56.4, 56.1, 48.3, 41.4, 36.0, 32.9, 28.1, 27.5, 27.5, 23.7, 20.5, 20.1, 19.4. HRMS:C 22 H 35 N3O2S [M+H] + : 406.25227, found: 406.25112.

[0098] Example 9 I-9; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with m-methylbenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-9 (white solid, yield 68%).

[0099] Compound I-9: 1 H NMR (400 MHz, DMSO-) d 6) δ7.60 (d, J = 10.0 Hz, 2H), 7.47 (d, J = 5.1 Hz, 2H), 3.49-3.36 (m, 2H), 3.16 (t, J = 11.4 Hz, 1H), 2.55-2.47 (m,3H), 2.40 (s, 3H), 2.07-1.74 (m, 3H), 1.71-1.46 (m,7H), 1.44-0.92 (m, 12H). 13 C NMR (101 MHz, DMSO-) d 6) δ 140.0, 138.6, 133.1, 128.8, 127.3, 124.3, 62.2, 56.6,56.1, 56.0, 46.1, 40.3, 38.7, 33.6, 31.4, 30.6, 28.1, 27.6, 22.2, 20.9, 20.3,20.2. HRMS:C 22 H35 N3O2S [M+H] + : 406.25227, found: 406.25153.

[0100] Example 10 I-10; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with p-ethylbenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-10 (white solid, yield 58%).

[0101] Compound I-10: 1 H NMR (400 MHz, DMSO-) d 6) δ 7.74 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 3.65-3.48 (m, 2H), 3.28 (t, J = 11.8 Hz, 1H), 2.73-2.55 (m,6H), 2.33-1.96 (m, 5H), 1.87-1.75 (m,6H), 1.56-1.42 (m, 4H), 1.36-1.23 (m,9H). 13 C NMR (101 MHz, DMSO-) d 6) δ 149.0, 138.3, 128.1, 127.6, 63.4, 58.2, 56.9(2), 48.0, 41.8, 39.6, 35.0, 33.4, 30.8, 28.9, 28.2, 28.0, 23.0, 21.2, 20.9,15.4. HRMS: calcd for C 23 H 37 N3O2S [M+H] + : 420.26792, found: 420.26691.

[0102] Example 11 I-11; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with p-propylbenzenesulfonyl chloride. Step (7) yields tricyclic matrine butylamine compound I-11 (white solid, yield 61%).

[0103] Compound I-11:1 H NMR (400 MHz, DMSO-) d 6) δ 7.70 (d, J = 7.8 Hz, 2H), 7.39 (d, J = 7.9 Hz, 2H), 3.82 (s, 2H), 3.48-3.35 (m, 2H), 3.20-3.11 (m, 1H), 2.63 (t, J = 7.6 Hz, 2H), 2.47 (d, J = 6.1 Hz, 2H), 1.94-1.78 (m, 2H), 1.75-1.54 (m, 8H), 1.51-1.09 (m, 13H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ 147.1,137.3, 128.7(2), 127.2(2), 62.2, 56.5, 56.0(2), 46.2, 38.7, 36.9, 33.6, 31.1(2), 31.0, 28.0, 27.6, 23.8, 22.1, 20.3, 20.2, 13.5. HRMS: calcd for C 24 H 39 N3O2S[M+H] + : 434.28357, found: 434.28256.

[0104] Example 12 I-12; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with p-tert-butylbenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-12 (white solid, yield 67%).

[0105] Compound I-12: 1 H NMR (400 MHz, DMSO-) d 6) δ7.73 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 7.3 Hz, 2H), 4.05 (s, 4H), 3.52-3.35 (m, 2H), 3.17 (t, J= 11.4 Hz, 1H), 1.93(t, J = 20.5 Hz, 2H), 1.76-1.59 (m, 6H), 1.48 (d, J = 11.1 Hz, 3H), 1.34-1.07 (m,19H). 13 C NMR (101 MHz, DMSO-) d 6) δ 155.3, 137.3, 127.1(2), 125.6(2), 62.1, 56.5,56.0(2), 46.0, 40.5, 38.8, 34.8, 33.7, 31.4, 31.2, 30.8(3), 28.0, 27.6, 22.3,20.3, 20.1. HRMS: calcd for C 25 H 41 N3O2S [M+H] + : 448.29922, found: 448.29764.

[0106] Example 13 I-13; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with 2,4,6-trimethylbenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-13 (white solid, yield 71%).

[0107] Compound I-13: 1 H NMR (400 MHz, DMSO-) d 6) δ7.02 (d, J = 21.8 Hz, 2H), 3.66-3.49 (m, 2H), 3.31 (t, J = 12.2 Hz, 1H), 2.69 (t, J = 12.7 Hz, 2H), 2.53 (s, 7H), 2.33-1.92 (m, 7H), 1.83 (dq, J = 19.9, 12.1, 9.5 Hz, 4H), 1.65-1.13 (m, 10H), 1.06-0.57 (m, 4H). 13 C NMR (101 MHz, DMSO-) d6) δ 141.7, 138.4(2), 136.7, 131.8(2), 63.2, 58.3, 56.5, 56.4, 54.9, 47.7, 39.6, 38.3, 35.6, 29.4, 27.7, 27.5,27.3, 23.4, 22.1, 20.5, 20.4, 20.2. HRMS: calcd for C 24 H 39 N3O2S [M+H] + :434.28357, found: 434.28242.

[0108] Example 14 I-14; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with 2,5-dimethylbenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-14 (white solid, yield 57%).

[0109] Compound I-14: 1 H NMR (400 MHz, DMSO-) d 6) δ7.72 (s, 1H), 7.43-7.15 (m, 2H), 4.46 (s, 3H), 3.69-3.51 (m, 2H), 3.37 (t, J = 12.2 Hz, 1H), 2.69 (t, J = 11.6 Hz, 2H), 2.46 (s, 3H), 2.32 (d, J = 14.3 Hz, 3H), 2.26 (d, J = 6.8 Hz, 1H), 2.09 (dd, J = 19.0, 6.4 Hz, 2H), 1.92-1.75 (m, 4H), 1.51 (dq, J = 22.7, 13.8, 9.3 Hz, 5H), 1.37-1.25 (m, 4H), 1.13-0.50 (m, 4H). 13 C NMR (101 MHz, DMSO-) d6) δ 140.4, 135.7,133.9, 133.0, 132.3, 128.4, 63.2, 58.8, 56.5, 56.4, 54.9, 48.2, 38.8, 35.8,29.1, 28.2, 27.5, 27.5, 23.3, 20.5, 20.4, 20.2, 19.0. HRMS: calcd forC 23 H 37 N3O2S [M+H] + : 420.26792, found: 420.26687.

[0110] Example 15 I-15; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with 3,5-dimethylbenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-15 (white solid, yield 64%).

[0111] Compound I-15: 1 H NMR (400 MHz, DMSO-) d 6) δ 7.42 (s, 2H), 7.27 (s, 1H), 3.49-3.34 (m, 2H), 3.14 (t, J = 11.3 Hz, 1H), 2.63-2.49 (m, 3H), 2.49-2.39 (m,1H), 2.35 (s, 6H), 1.91-1.85 (m, 2H), 1.74-1.66 (m, 5H), 1.63-1.03 (m, 14H). 13 C NMR (101 MHz, DMSO-) d 6) δ 139.9, 138.3(2), 133.6, 124.6(2), 62.1, 56.4,56.1, 56.0, 54.9, 45.7, 38.7, 33.4, 31.6, 29.2, 28.2, 27.6, 22.2, 20.8, 20.3, 20.1, 18.6. HRMS: calcd for C 23 H 37 N3O2S [M+H] + : 420.26792, found: 420.26696.

[0112] Example 16 I-16; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with 3,4-dimethylbenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-16 (white solid, yield 69%).

[0113] Compound I-16: 1 H NMR (400 MHz, DMSO-) d 6) δ 7.42 (s, 2H), 7.27 (s, 1H), 3.47(q, J = 6.6 Hz, 1H), 3.36 (dd, J = 12.5, 6.5 Hz, 1H), 3.14 (t, J = 11.3 Hz, 1H), 2.56 (t, J = 7.2 Hz, 2H), 2.49-2.39 (m, 1H), 2.35 (s, 7H), 1.89 (d, J = 10.9 Hz, 2H), 1.76-1.55 (m, 6H), 1.51-1.01 (m, 13H). 13 C NMR (101 MHz, DMSO-) d 6) δ 139.9,138.4, 138.3, 133.7, 124.6, 123.1, 62.1, 56.4, 56.1, 56.0, 54.9, 45.7, 39.8,38.7, 33.4, 31.6, 29.6, 28.2, 27.6, 22.2, 20.8, 20.3, 20.1. HRMS: calcd forC 23 H 37 N3O2S [M+H] + :420.26792, found: 420.26674.

[0114] Example 17 I-17; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with 3,5-dichlorobenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-17 (yellow solid, yield 60%).

[0115] Compound I-17: 1H NMR (400 MHz, DMSO-) d 6) δ7.93 (s, 1H), 7.86 (s, 2H), 3.56(q, J = 6.4 Hz, 1H), 3.39-3.34(m, 1H), 3.11 (dd, J = 12.9, 9.0 Hz, 1H), 2.42 (dd, J = 29.9, 11.1 Hz, 2H), 2.00-1.72 (m, 5H), 1.70-1.41 (m, 8H), 1.39-1.23 (m, 11H). 13 C NMR (101 MHz, DMSO-) d 6) δ 168.6, 143.0, 134.5, 131.8, 125.9(2), 61.2,55.8, 55.7, 55.5, 54.9, 43.2, 34.8, 32.0, 30.7, 28.9, 27.4, 22.5, 20.5, 20.3,19.7. HRMS: calcd for C 21 H 31 Cl2N3O2S [M+H] + : 460.15857, found: 460.15747.

[0116] Example 18 I-18; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with p-chlorobenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-18 (yellow solid, yield 64%).

[0117] Compound I-18: 1 H NMR (400 MHz, DMSO-) d 6) δ7.83 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 3.51-3.38 (m, 5H), 3.20-3.10 (m, 1H), 2.54 (d, J = 15.2 Hz, 2H),1.96-1.82 (m, 2H), 1.76-1.66 (m, 5H), 1.62-1.52 (m, 1H), 1.48 (d,J = 9.3 Hz,1H), 1.42-0.80 (m, 11H). 13 C NMR (101 MHz, DMSO-) d 6) δ 138.8, 137.3, 129.1(2),129.0(2), 61.9, 56.5, 55.9(2), 45.6, 40.7, 38.7, 33.3, 31.8, 31.5, 28.1,27.5, 22.2, 20.3, 20.1. HRMS: calcd for C 21 H 32 ClN3O2S [M+H] + : 426.19765, found: 426.19651.

[0118] Example 19 I-19; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with m-bromobenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-19 (yellow solid, yield 65%).

[0119] Compound I-19: 1 H NMR (400 MHz, DMSO-) d 6) δ 7.98 (s, 1H), 7.84 (t, J = 9.3 Hz, 2H), 7.54 (t, J = 7.9 Hz, 1H), 3.52 (q, J = 6.5 Hz, 1H), 3.36 (dd, J = 12.7, 7.5Hz, 1H), 3.12 (d, J = 36.5 Hz, 5H), 2.47 (d, J = 6.9 Hz, 2H), 1.86 (s, 2H), 1.72-1.53 ​​(m, 6H), 1.44 (d, J = 12.8 Hz, 1H), 1.37-1.17 (m, 10H). 13 C NMR (101 MHz, DMSO- d6) δ 142.0, 135.1, 130.9, 129.6, 126.3, 121.7, 61.6, 56.1, 55.8, 55.7,48.6, 44.3, 41.2, 33.4, 32.7, 32.6, 28.6, 27.5, 22.6, 20.3, 19.9. HRMS:C 21 H 32 BrN3O2S [M+H] + : 470.14713, found: 470.14586.

[0120] Example 20 I-20; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with m-chlorobenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-20 (yellow solid, yield 61%).

[0121] Compound I-20: 1 H NMR (400 MHz, DMSO-) d 6) δ 7.87 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 3.54-3.49 (m, 1H), 3.40-3.34 (m, 1H), 3.12-3.07 (m, 1H), 2.64 (t, J = 7.5 Hz, 2H), 2.49 (s, 1H), 2.42(d, J = 11.0 Hz, 1H), 1.86 (s, 2H), 1.71-1.42 (m,6H), 1.50-1.42 (m,3H), 1.35-1.16 (m,10H). 13 C NMR (101 MHz, DMSO-) d 6) δ 141.6, 133.5, 132.3, 130.8, 126.9,126.1, 61.5, 55.9, 55.8, 55.7, 44.2, 38.6, 33.3, 32.6, 28.7, 28.6, 27.5,22.2, 22.1, 20.3, 19.9. HRMS: calcd for C21 H 32 ClN3O2S [M+H] + : 426.19767, found: 426.19653.

[0122] Example 21 I-21; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with m-trifluoromethoxybenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-21 (yellow solid, yield 66%).

[0123] Compound I-21: 1 H NMR (400 MHz, DMSO-) d 6) δ 7.87 (d, J = 7.8 Hz, 1H), 7.79-7.66 (m, 3H), 3.54 (q, J = 6.6 Hz, 1H), 3.40 (dd, J = 12.5, 7.2 Hz, 1H), 3.43-3.38 (m, 1H), 2.49 (d, J = 14.5 Hz, 2H), 2.42 (d, J = 12.1 Hz, 2H), 1.88 (dd, J =12.0, 5.6 Hz, 2H), 1.78 -1.53 ​​(m, 8H), 1.39-1.12 (m, 11H). 13 C NMR (101 MHz, DMSO- d 6) δ148.04 (q, J CF = 2.0 Hz), 142.3, 131.3, 126.3, 125.0, 120.0 (q, J CF =258.6Hz), 119.6, 61.8, 56.5, 55.9, 55.8, 45.0, 41.2, 38.8, 33.0, 32.7, 32.6,28.4, 27.5, 22.5, 20.3, 19.9. HRMS: calcd for C 22 H 32 F3N3O3S [M+H] + : 476.21892, found: 476.21691.

[0124] Example 22 I-22; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with p-cyanobenzenesulfonyl chloride. Step (7) yields tricyclic matrine butylamine compound I-22 (white solid, yield 72%).

[0125] Compound I-22: 1 H NMR (400 MHz, DMSO-) d 6) δ8.08 (d, J = 8.1 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 5.45 (s, 2H), 3.50 (q, J = 6.6 Hz, 1H), 3.39 (dd, J = 12.8, 6.9Hz, 1H), 3.21-3.10 (m, 1H), 2.56 (t, J = 7.3 Hz, 2H), 2.41 (dd, J = 29.6, 11.0Hz, 2H), 1.86 (s, 2H), 1.69-1.51 (m, 6H), 1.47-1.19 (m, 11H). 13 C NMR (101 MHz, DMSO- d 6) δ 144.0, 133.0(2), 127.9(2), 117.8, 114.7, 61.7, 56.4, 55.8, 55.7,45.1, 39.8, 38.8, 33.0, 32.5, 29.7, 28.3, 27.5, 22.3, 20.3, 19.9. HRMS: calcdfor C 22 H 33 N4O2S [M+H] + : 417.23187, found: 417.23058.

[0126] Example 23 I-23; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with m-cyanobenzenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-23 (white solid, yield 69%).

[0127] Compound I-23: 1 H NMR (400 MHz, DMSO-) d 6) δ8.32 (d, J = 1.8 Hz, 1H), 8.13 (dd, J = 7.9, 1.7 Hz, 2H), 7.80 (t, J = 7.9 Hz, 1H), 3.51 (q, J = 6.4 Hz, 1H), 3.37(dd, J = 12.7, 7.6 Hz, 1H), 3.06 (dd, J = 12.7, 9.2 Hz, 1H), 2.73 (t, J = 7.5 Hz, 2H), 2.39 (dd, J = 39.3, 10.8 Hz, 2H), 1.92-1.80 (m, 2H), 1.76-1.46 (m, 8H), 1.46-1.09 (m, 11H). 13 C NMR (101 MHz, DMSO-) d 6) δ 140.8, 136.0, 131.9, 131.1,130.2, 117.8, 111.9, 61.3, 55.7, 55.6, 55.6, 43.8, 38.9, 38.6, 33.7, 32.3,28.6, 27.5, 27.4, 22.0, 20.3, 19.8. HRMS: calcd for C 22 H 33 N4O2S [M+H] + :417.23187, found: 417.23057.

[0128] Example 24 I-24; Prepared according to the method of Example 1, the only difference from Example 1 is that p-methylbenzenesulfonyl chloride in step (6) is replaced with naphthalenesulfonyl chloride. Step (7) yields tricyclic matrine compound I-24 (white solid, yield 72%).

[0129] Compound I-24: 1 H NMR (400 MHz, DMSO-) d 6) δ8.43 (d, J= 8.0 Hz, 1H), 8.25 (dd, J = 14.8, 7.6 Hz, 2H), 8.08 (d, J = 8.1 Hz, 1H), 7.74-7.62 (m,3H), 3.76-3.62 (m,2H), 3.45 (t, J = 12.0 Hz, 1H), 2.56 (d, J = 11.0 Hz, 1H), 2.32-1.81 (m, 5H),1.76 (t, J = 10.9 Hz, 3H), 1.64-1.22 (m, 11H), 1.12-0.46 (m, 5H). 13 C NMR (101MHz, DMSO-) d 6) δ 137.3, 137.2, 133.8, 128.9, 128.6, 127.9, 127.8, 126.8,124.5, 124.5, 62.8, 60.4, 58.3, 56.2, 47.5, 35.1, 32.2, 30.1, 29.4, 27.8,27.5, 23.1, 22.4, 20.3, 20.1. HRMS: calcd for C 25 H 35 N3O2S [M+H] + : 442.25226, found: 442.25112.

[0130] Comparative Example 1 II-1; Compound I-6 was prepared according to steps (1) to (7) of Example 6.

[0131] (8) Compound I-6 (0.40 g, 1.024 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and 5.120 mmol of anhydrous potassium carbonate and 10.24 mmol of iodomethane were added. The mixture was heated under reflux for 8 h. The reaction was monitored by TLC until it was complete. The reaction system was concentrated and purified by Flash column (eluting with a mixture of dichloromethane and methanol at a volume ratio of 94:6 for 15 min) to obtain compound II-1 (yellow solid, yield 87%).

[0132] Compound II-1: 1 H NMR (400 MHz, DMSO-) d 6 ): δ7.86-7.80 (m, 2H), 7.71-7.65 (m,1H), 7.61 (dd, J = 8.3, 6.6 Hz, 2H), 3.40 (dd, J = 12.4, 6.1 Hz, 2H), 3.23-3.07(m, 3H), 3.03 (s, 9H), 2.58-2.52 (m, 1H), 2.45 (dd, J = 11.5, 3.4 Hz, 1H), 1.95-1.84 (m, 2H), 1.84-1.54 (m, 8H), 1.47 (d, J = 11.8 Hz, 1H), 1.38-1.20 (m,8H). 13 C NMR (101 MHz, DMSO-) d 6 ): δ 139.3, 132.7, 129.0, 127.6, 127.3, 125.5, 65.2,62.0, 56.4, 55.9, 54.9, 52.2, 46.3, 38.6, 33.5, 30.8, 28.6, 27.7, 27.5, 26.6,22.2, 21.7, 20.3, 20.1. HRMS: calcd for C 24 H 40 N3O2SI [MI] + : 434.2836, found:434.2816.

[0133] Comparative Example 2 II-2; The compound was prepared according to the method of Comparative Example 1, except that benzenesulfonyl chloride in step (6) was replaced with p-methylbenzenesulfonyl chloride, and compound II-2 was obtained in step (8).

[0134] Compound II-2: 1 H NMR (400 MHz, DMSO-) d 6 ): δ 7.73 (dd, J = 20.2, 8.2 Hz, 2H), 7.45 (dd, J = 24.3, 8.0 Hz, 2H), 3.67-3.51 (m, 1H), 3.44-3.36 (m,1H), 3.29-3.12(m, 3H), 3.03 (d,J = 2.7 Hz, 10H), 2.56 (d, J = 11.0 Hz, 1H), 2.42 (d, J = 10.1Hz, 3H), 2.34-2.06 (m, 1H), 2.04-1.75 (m, 3H), 1.72-1.60 (m, 6H), 1.59-1.40 (m, 3H), 1.40-1.01 (m, 6H). 13 C NMR (101 MHz, DMSO-) d 6 ): δ 143.5, 136.6, 130.0,129.5, 127.4, 127.2, 65.1, 62.4, 62.1, 56.1, 54.9, 54.5, 52.2, 46.8, 37.0,33.7, 32.9, 30.3, 27.9, 24.9, 24.5, 22.1, 21.0, 20.2, 18.5. HRMS: calcd forC 25 H 42 N3O2SI [MI] + : 448.2992, found: 448.2975.

[0135] Comparative Example 3 II-3; The compound was prepared according to the method of Comparative Example 1, except that benzenesulfonyl chloride in step (6) was replaced with p-ethylbenzenesulfonyl chloride, and compound II-3 was obtained in step (8).

[0136] Compound II-3: 1 H NMR (400 MHz, DMSO-) d 6 ): δ 7.75 (dd, J = 21.5, 8.0 Hz, 2H), 7.47 (dd, J = 25.7, 8.0 Hz, 2H), 3.67-3.33 (m, 3H), 3.31-3.13 (m, 3H), 3.10 (s,10H), 2.77-2.64 (m, 2H), 2.33-1.95 (m, 1H), 1.93-1.50 (m, 11H), 1.50-1.33 (m,2H), 1.33-1.08 (m, 8H). 13C NMR (101 MHz, DMSO-) d 6 ): δ 137.0, 136.4, 128.8, 128.3,127.5, 127.3, 65.2, 62.0, 56.2, 55.9, 55.0, 52.2, 46.8, 46.2, 37.1, 33.4,30.8, 28.0, 27.5, 24.8, 22.2, 21.5, 21.3, 20.1, 18.4, 15.2. HRMS: calcd forC 26 H 44 N3O2SI [MI] + : 462.3149, found: 462.3130.

[0137] Test Example 1 In vitro lipid-lowering activity test To evaluate the ameliorative effect of the compounds on hepatocyte steatosis, this experiment employed a free fatty acid (FFA)-induced lipid accumulation model in AML12 cells. Normal mouse hepatocytes (CL-0602, Wuhan Pronosai) were seeded in 96-well plates and cultured in dedicated DMEM / F12 medium (CM-0602, Wuhan Pronosai). When the cells reached approximately 50% confluence, control, model (0.1 mM FFA, oleic acid to palmitic acid molar ratio 2:1), positive control (2 μM Triacsin C, Sigma-Aldrich, USA), and groups treated with different concentrations of the test compounds were established and treated for 24 h. After treatment, the cells were lysed, and intracellular triglyceride (TG) levels were measured at 550 nm using a TG assay kit (E1013, Beijing Pulilai) and a microplate reader (PerkinElmer, USA), following the kit instructions. The test results are shown in Table 1.

[0138] Table 1. Triglyceride-lowering activity test results of compounds I-1~I-24 and II-1~II-3

[0139] Note: "-" in Table 1 indicates that no test was conducted.

[0140] As shown in Table 1, compounds I-1, I-2, I-3 and I-4 all exhibited an inhibition rate of over 45% against triglycerides at a concentration of 10 μM.

[0141] Test Example 2 The therapeutic effect of compound I-1 (denoted as 7d) on a high-fat diet-induced MASLD mouse model Male C57BL / 6J mice (20 - 22 g) were purchased from Beijing Sparf Bioscience Co., Ltd. The mice were housed in a specific pathogen - free (SPF) animal facility and were formally experimented after one - week of adaptive feeding. All animal experiments were conducted in accordance with the "Guide for the Care and Use of Laboratory Animals" issued by the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences (Laboratory Animal Use License No.: SYXK (Beijing) 2022 - 0023) and followed the ARRIVE Guidelines 2.0.

[0142] After one - week of adaptation, the mice were randomly divided into two groups and fed with a low - fat diet (LFD; 10 kcal% fat, D12450J, Research Diets, USA) or a high - fat diet (HFD; 60 kcal% fat, D12492, Research Diets, USA) for 6 weeks to induce an obesity model. Subsequently, the mice fed with the high - fat diet were randomly divided into four groups (6 mice per group), and the grouping and treatments were as follows: LFD group: Fed with a low - fat diet and intragastrically administered with a control solvent daily for 10 weeks; HFD group: Fed with a high - fat diet and intragastrically administered with a control solvent daily for 10 weeks; Compound I - 1 - L group: Fed with a high - fat diet and intragastrically administered with 50 mg / kg of Compound I - 1 daily for 10 weeks; Compound I - 1 - H group: Fed with a high - fat diet and intragastrically administered with 100 mg / kg of Compound I - 1 daily for 10 weeks; BBR group: Fed with a high - fat diet and intragastrically administered with 100 mg / kg of the positive drug berberine (BBR) daily for 10 weeks as the control group.

[0143] During the drug administration period, the body weight and food intake of the mice were monitored and recorded weekly.

[0144] Body composition and sample collection: One day before the end of the experiment, the body fat content of the mice was measured using a nuclear magnetic resonance body composition analyzer (QMR06 - 090H, Niumai, China). At the end of the experiment, the mice were fasted for 12 h without water deprivation, and the fasting blood glucose was measured by collecting blood from the tail vein using a blood glucose meter (ACCU - CHEK Performa, Roche, Switzerland). Subsequently, blood samples were collected by orbital blood sampling, centrifuged to separate serum after standing at room temperature, and stored at - 80 °C for later use. After blood collection, the mice were sacrificed, and the liver and epididymal white adipose tissue were quickly separated and weighed. The liver weight was recorded and the liver index (liver weight / body weight) was calculated. Part of the liver tissue was fixed in 4% paraformaldehyde for pathological analysis; the remaining liver tissue was snap - frozen in liquid nitrogen and stored at - 80 °C for subsequent biochemical index detection.

[0145] Serum and liver biochemical markers were detected: Serum insulin concentration was measured using a mouse insulin ELISA kit (80-INSMSU-E01, Alpco, USA). The insulin resistance index (HOMA2-IR) was calculated using the open-source software HOMA2 Calculator (https: / / www.dtu.ox.ac.uk / homacalculator). Serum alanine aminotransferase (ALT, C009-2-1), aspartate aminotransferase (AST, C010-2-1), triglycerides (TG, A110-1-1), and total cholesterol (CHO, A111-1-1) were measured using commercial kits from Nanjing Jiancheng Bioengineering Institute, following the manufacturer's instructions. Frozen liver tissue was collected, liver homogenate was prepared, and the TG and CHO levels in the liver tissue were measured using the same kits.

[0146] Liver histopathological evaluation: Liver tissue fixed in 4% paraformaldehyde was embedded in paraffin, sectioned, and stained with hematoxylin and eosin (H&E); another portion of liver tissue was frozen sectioned and stained with Oil Red O (ORO). The stained sections were observed and photographed under a microscope. The severity of hepatic steatosis, intralobular inflammation, and hepatocellular ballooning degeneration was graded according to the Nonalcoholic Fatty Liver Disease Activity Scale (NAS).

[0147] Statistical analysis: All experimental data are expressed as mean ± standard deviation (Mean ± SD). One-way ANOVA was performed using GraphPadPrism 9.0 software to determine the significance of differences between groups. #P < 0.05 and ##P < 0.01 indicate a difference compared to the LFD group; P<0.05, P<0.01 indicates a comparison with the HFD model group.

[0148] Effects of compound I-1 on body weight, food intake, and body composition in HFD-induced obese mice: Figure 2 This is a diagram of the dosing regimen for the animal experiment in Example 2. Figure 3 This is a graph showing the final body weight of mice 10 weeks after drug administration. Figure 4 This graph shows the average weekly food intake per mouse during the 10-week drug administration period. Figure 5 This image shows the body fat percentage of mice 10 weeks after drug administration. Figure 6 Image showing liver weight in mice 10 weeks after drug administration. Figure 7 This is a graph showing the liver index of mice 10 weeks after drug administration. Figure 2As shown, after successfully establishing the HFD-induced obesity model, following 10 weeks of drug intervention, compared with the HFD model group, a dose of compound I-1 at 100 mg / kg (compound I-1-H group) significantly reduced the final body weight of mice. Figure 3 ), but had no significant effect on average food intake ( Figure 4 Meanwhile, the body fat percentage of mice in the compound I-1-H group ( Figure 5 The liver weight of mice in the compound I-1-H group was also significantly reduced. Figure 6 ) and liver index (liver weight / body weight) Figure 7 The levels were also lower than those in the HFD model group. The trends of these indicators were similar to those in the positive control group (BBR), indicating that compound I-1 can effectively inhibit HFD-induced increases in body weight and body fat, and reduce liver enlargement.

[0149] The effect of compound I-1 on improving glucose metabolism disorder induced by HFD in obese mice: Figure 8 This is a graph showing the fasting blood glucose levels in mice 10 weeks after drug administration. Figure 9 This is a graph showing the non-fasting blood glucose levels in mice 10 weeks after drug administration. Figure 10 This is a graph showing serum insulin levels in mice 10 weeks after drug administration. Figure 11 This is a graph showing the insulin resistance index of mice after 10 weeks of drug administration. Compared with the LFD group, the HFD model group mice showed significant abnormalities in glucose metabolism. Compared with the HFD group, both doses of compound I-1 significantly reduced fasting blood glucose in mice. Figure 8 ), non-fasting blood glucose ( Figure 9 ) and fasting serum insulin levels ( Figure 10 Correspondingly, insulin resistance status, as assessed by the HOMA2-IR index, was also significantly improved in the compound I-1 administration group. Figure 11 The above results indicate that compound I-1 can effectively alleviate HFD-induced hyperglycemia and insulin resistance.

[0150] Effects of compound I-1 on blood lipids and liver damage markers in HFD-induced obese mice: Serum biochemical marker results are as follows Figures 12-15 As shown, where, Figure 12 The image shows serum triglyceride levels in mice 10 weeks after drug administration. Figure 13 This is a graph showing the total cholesterol levels in the serum of mice 10 weeks after drug administration. Figure 14 The image shows the serum alanine aminotransferase (ALT) levels in mice 10 weeks after drug administration. Figure 15 The image shows serum aspartate aminotransferase (AST) levels in mice 10 weeks after drug administration. Serum biochemical markers showed that, compared to the HFD group, administration of compound I-1 significantly reduced serum triglycerides (TG). Figure 12 ) and total cholesterol (CHO, Figure 13 The level of ALT in the HFD group mice was comparable to that of the positive control drug BBR. Regarding liver injury markers, serum ALT in the HFD group mice... Figure 14 ) and AST ( Figure 15 The levels of ALT were significantly elevated. Intervention with compound I-1 could significantly reverse the increase in ALT, and its effect on reducing AST also showed a certain decreasing trend.

[0151] Effects of compound I-1 on hepatic steatosis and histopathology in HFD-induced obese mice: Figure 16 Images show the gross, H&E, and Oil Red staining results of mouse liver tissue. Figure 17 This is a graph showing the NAS score results of mouse liver tissue pathology. Figure 18 This is a graph showing the triglyceride content in mouse liver. Figure 19 This is a graph showing the total cholesterol content in mouse livers. H&E staining and Oil Red O staining show ( Figure 16 In the HFD group, mice exhibited significant lipid accumulation in the liver (strongly positive Oil Red O staining), hepatocyte steatosis, ballooning degeneration, and inflammatory cell infiltration. Treatment with compound I-1 significantly improved these pathological changes. Quantitative scoring was performed using the NAS system. Figure 17 Further investigation confirmed that mice in the compound I-1 administration group had significantly lower scores for steatosis, intralobular inflammation, and ballooning degeneration compared to the HFD group. Consistent with pathological observations, liver biochemical markers showed that compound I-1 significantly reduced HFD-induced liver TG (triglycerides). Figure 18 ) and CHO ( Figure 19 ) levels rise.

[0152] In summary, in the HFD-induced MASLD mouse model constructed in this test case, compound I-1 effectively reduced mouse body weight and body fat percentage, improved glucose and lipid metabolism disorders and insulin resistance, and significantly alleviated hepatic steatosis, inflammation, and hepatocyte damage. Its overall efficacy is comparable to or better than that of the positive control drug berberine. These results indicate that compound I-1 has good potential for in vivo treatment of metabolic-associated fatty liver disease (MASLD).

[0153] Test Example 3 Acute toxicity test of compound I-1 in mice SPF-grade Kunming mice (18-20 g) were purchased from Spiford (Beijing) Biotechnology Co., Ltd. After purchase, the mice were housed in an SPF-grade animal facility under specialized care. Formal experiments began after a 3-day acclimatization period. Results are presented as mean ± standard deviation (Mean ± SD) or as representative plots. Differences were determined using GraphPad Prism 9.0 software via one-way ANOVA or t-tests. P<0.05, P<0.01 vs. Control group.

[0154] Mice were randomly divided into groups of six (half male and half female) based on body weight. After a 6-hour fast, they were administered the drug either by gavage (ig) or intraperitoneal injection (ip). The experimental groups and treatments are as follows: Control (ig) group: mice were given a single oral gavage of the control solvent; Compound I-1 (500 mg / kg, ig): Mice were given a single oral gavage of 500 mg / kg of compound I-1; Control (ip) group: Mice were injected intraperitoneally with the control solvent once; Compound I-1 (50 mg / kg, ip): Mice were given a single intraperitoneal injection of 50 mg / kg of compound I-1.

[0155] The solvent for preparing the above drugs was 10% DMSO + 30% PEG300 + 5% Tween-80 + 55% sterile water by volume. The same solvent was used for the control group via gavage and intraperitoneal injection.

[0156] The general health status and mortality rate of mice were monitored daily for 7 consecutive days after drug administration, and mouse body weight was recorded before administration and on days 1, 3, 5, and 7 after administration. Mice were sacrificed on day 7, and blood samples were collected. Serum was separated by centrifugation at 2500×g for 10 min. Serum levels of liver function indicators (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL)) and kidney function indicators (blood urea nitrogen (UREA) and creatinine (CRE)) were measured using a Hitachi 7100 fully automated biochemical analyzer (Hitachi, Japan). Simultaneously, liver and kidney tissues were subjected to H&E pathological staining to evaluate potential tissue toxicity.

[0157] Figure 20 The images show the initial and final body weights of mice in the acute toxicity experiment of Example 3. After 7 days of observation, no mouse deaths occurred in any of the treatment groups (500 mg / kg by gavage and 50 mg / kg by intraperitoneal injection). Compared with their respective control groups, the body weight of mice in the compound I-1 treatment groups did not change significantly during the observation period. Figure 20 This indicates that compound I-1 had no significant effect on the general condition and growth and development of mice at the tested dose.

[0158] Serum biochemical index test results as follows Figures 21-27 As shown, where, Figure 21 This is a graph showing serum alanine aminotransferase (ALT) levels in mice during an acute toxicity experiment. Figure 22 This is a graph showing the serum aspartate aminotransferase (AST) levels in mice during an acute toxicity experiment. Figure 23This is a graph showing the alkaline phosphatase levels in the serum of mice during an acute toxicity experiment. Figure 24 This is a graph showing the total bilirubin levels in the serum of mice in an acute toxicity experiment. Figure 25 This is a graph showing the serum urea levels in mice during an acute toxicity experiment. Figure 26 This is a graph showing serum creatinine levels in mice during an acute toxicity experiment. Figure 27 The images show the H&E staining pathological images of the liver and kidney of mice in the acute toxicity experiment of compound I-1. Compared with the control group, there were no significant changes in liver function indicators (ALT, AST, ALP, TBIL) and kidney function indicators (UREA, CRE) in the compound I-1 administration group. No obvious structural changes, such as degeneration, necrosis, or inflammatory infiltration, were observed in the liver and kidney tissues of the mice in the compound I-1 administration group, which was consistent with the trend of changes in serum biochemical indicators.

[0159] In summary, in the acute toxicity evaluation of this test case, compound I-1, whether administered by gavage (500 mg / kg) or intraperitoneal injection (50 mg / kg), did not cause death or weight loss in mice, nor did it lead to a significant increase in serum liver and kidney function markers or histopathological damage to major organs (liver and kidneys). These results indicate that compound I-1 has a favorable safety profile at the tested dose, providing important safety evidence for its subsequent pharmacodynamic studies and potential clinical applications.

[0160] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A tricyclic matrine butamine compound, characterized in that, It has the structure shown in Equation I: Equation I; R includes unsubstituted or substituted aryl groups.

2. The tricyclic matrine butamine compound according to claim 1, characterized in that, The substituents in the substituted aryl group include at least one selected from halogen, cyano, alkyl, alkoxy, haloalkyl, and haloalkoxy. The number of carbon atoms in the alkyl, alkoxy, haloalkyl, and haloalkoxy groups is independently 1 to 6.

3. The tricyclic matrine butamine compound according to claim 2, characterized in that, The substituents include bromine, chlorine, cyano, methyl, ethyl, n-propyl, tert-butyl, methoxy, trifluoromethyl, or trifluoromethoxy. The aryl group includes phenyl or naphthyl.

4. A method for preparing the tricyclic matrine butylamine compound according to any one of claims 1 to 3, characterized in that, Includes the following steps: Compound 5, R-sulfonyl chloride, the first organic amine, and the first organic solvent were mixed and subjected to a sulfonation reaction to obtain compound 6; The compound 6, hydrazine hydrate, and a second organic solvent were mixed and subjected to a hydrazinolysis reaction to obtain the tricyclic matrine compound. Among them, the structural formula of compound 5 is The structural formula of compound 6 is .

5. The preparation method according to claim 4, characterized in that, The preparation method of compound 5 includes the following steps: Matrine was subjected to an amide hydrolysis reaction under alkaline conditions to obtain compound 1; Compound 1 was mixed with ditert-butyl dicarbonate, a second organic amine and a third organic solvent, and a substitution reaction was carried out to obtain compound 2. Compound 2, the reducing agent, and the fourth organic solvent were mixed and a reduction reaction was carried out to obtain compound 3. Compound 3, phthalimide, triphenylphosphine, diethyl azodicarbonate and the fifth organic solvent were mixed and subjected to photoelectrophoresis to obtain compound 4. Compound 4 was subjected to a deprotection reaction to obtain compound 5; The structural formulas of matrine and compounds 1-4 are as follows: 。 6. The preparation method according to claim 4, characterized in that, The first organic amine includes at least one of triethylamine and N,N-diisopropylethylamine; The first organic solvent includes chlorinated hydrocarbons; The second organic solvent includes at least one of alcohol solvents and amide solvents.

7. The preparation method according to claim 5, characterized in that, The second organic amine includes at least one of triethylamine and N,N-diisopropylethylamine; The third organic solvent includes at least one of chlorinated hydrocarbons and furan solvents; The reducing agent includes at least one of lithium aluminum hydride and sodium borohydride; The fourth organic solvent includes ether solvents; The fifth organic solvent may include at least one of furan solvents and amide solvents; The deprotection reaction is carried out under conditions of trifluoroacetic acid and a sixth organic solvent, which includes at least one of chlorinated and furan solvents.

8. The use of the tricyclic matrine compound according to any one of claims 1 to 3 in the preparation of a medicament for the prevention and / or treatment of diseases accompanied by glucose and lipid metabolism disorders.

9. The application according to claim 8, characterized in that, The diseases associated with glucose and lipid metabolism disorder syndrome include at least one of metabolic dysfunction-related fatty liver disease, diabetes, and obesity.

10. A pharmaceutical composition, characterized in that, It includes an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient includes the tricyclic matrine compound as described in any one of claims 1 to 3.

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