Benzopyrone analogue as well as preparation method and application thereof

Abstract

The invention discloses a benzopyrone analogue as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The benzopyrone analogue has a structural formula as shown in a formula B in the specification. The invention also discloses a preparation method and application of the benzopyrone analogue. The invention provides a benzopyrone analogue with a new structure, and the benzopyrone analogue is named as ZDZ-553. The benzopyrone analogue can obviously reduce the content of triglyceride and cholesterol in the liver, also can obviously inhibit the inflammatory reaction of the liver of an NASH mouse, and can obviously reduce the mRNA level of inflammatory factors IL-6, IL-1beta and TNF-alpha in the liver. Therefore, the benzopyrone analogue disclosed by the invention can be used for preparing the medicine for resisting the non-alcoholic steatohepatitis.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a benzopyranone analog, its preparation method, and its application. Background Technology

[0002] Benzopyranones are organic compounds formed by the fusion of a benzene ring and a pyranone ring. They are widely found in natural products, such as flavonoids and chromogens. Their basic skeleton is C9H6O2, formed by the fusion of a benzene ring (A ring) and a pyranone ring (C ring) through two adjacent carbon atoms. Different substituents (such as hydroxyl, methyl, methoxy, aryl, and ester groups) can be introduced at positions 3, 4, 5, 6, 7, and 8 of the pyranone ring, resulting in a variety of analogs. Modern research indicates that analogs with the benzopyranone structure may possess various biological activities, including anti-inflammatory, antioxidant, antibacterial, antiviral, and antitumor effects. They also exhibit good antimetabolite activity and have therapeutic effects on diabetes, lowering blood lipids, and lowering uric acid, demonstrating promising pharmaceutical prospects and development value.

[0003] The general structural formula of benzopyranone is shown in Formula A: .

[0004] Nonalcoholic steatohepatitis (NASH) is a type of fatty liver disease unrelated to excessive alcohol consumption and is a severe form of nonalcoholic fatty liver disease (NAFLD). This disease is closely related to metabolic disorders such as obesity, insulin resistance, type 2 diabetes, and hyperlipidemia, and can progress to liver fibrosis and cirrhosis, even leading to liver failure or liver cancer. Currently, there are no specific drugs for treating NASH in China. Internationally, only the United States has the first drug approved for NASH treatment—Resmetirom—which was launched in April 2025.

[0005] Therefore, it is necessary to investigate whether benzopyranone analogues can be used to prepare drugs for the treatment of non-alcoholic steatohepatitis (NAH), in order to obtain a new drug that can alleviate the progression of NHA. Summary of the Invention

[0006] One of the objectives of this invention is to provide a benzopyranone analog.

[0007] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: a benzopyranone analog, the structural formula of which is shown in Formula B: .

[0008] The above structural formula is named ZDZ-553.

[0009] The beneficial effects of the benzopyranone analogues of the present invention are: This invention provides a novel benzopyranone analogue, named ZDZ-553. This benzopyranone analogue significantly reduces hepatic triglyceride and cholesterol levels, significantly inhibits hepatic inflammatory responses in NASH mice, and significantly reduces the mRNA levels of hepatic inflammatory factors IL-6, IL-1β, and TNF-α. Therefore, the benzopyranone analogue of this invention can be used to prepare drugs for treating non-alcoholic steatohepatitis.

[0010] The second objective of this invention is to provide a first method for preparing the above-mentioned benzopyranone analogue.

[0011] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: A method for preparing a benzopyranone analogue, comprising the following steps: Step 1: Preparation of ethyl 3,5-bis(trifluoromethyl)benzoyl ester With a molar ratio of 1:(0.2-0.4):(0.3-0.5), potassium monoethyl malonate, 3,5-bis(trifluoromethyl)benzoic acid, and N,N-dicarbonylimidazolium were weighed separately. First, potassium monoethyl malonate and 3,5-bis(trifluoromethyl)benzoic acid were mixed evenly, and then the intermediate ethyl 3,5-bis(trifluoromethyl)benzoyl was synthesized under the activation of N,N-dicarbonylimidazolium. Step 2: Preparation of benzopyranone analogs With a molar ratio of 1:(0.9-1.2), the intermediate 3,5-bis(trifluoromethyl)benzoyl ethyl acetate prepared in step 1 was reacted with 5-methoxybenzene-1,3-diol under N-dimethylaminopyridine catalysis at high temperature to obtain compound ZDZ-55 as shown in formula B.

[0012] The reaction route for the first method of preparing benzopyranone analogs of the present invention is as follows: , In this context, arrow Ⅰ represents MgCl2, N(C2H5)3, CDI, and THF; arrow Ⅱ represents DMAP.

[0013] The second objective of this invention is to provide a second method for preparing the above-mentioned benzopyranone analogues.

[0014] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: A method for preparing a benzopyranone analogue, comprising the following steps: Step 1: Preparation of ethyl 3,5-bis(trifluoromethyl)benzoyl ester With a molar ratio of 1:(0.2-0.4):(0.3-0.5), potassium monoethyl malonate, 3,5-bis(trifluoromethyl)benzoic acid, and N,N-dicarbonylimidazolium were weighed separately. First, potassium monoethyl malonate and 3,5-bis(trifluoromethyl)benzoic acid were mixed evenly, and then the intermediate ethyl 3,5-bis(trifluoromethyl)benzoyl was synthesized under the activation of N,N-dicarbonylimidazolium. Step 2: Preparation of benzopyranone analogs Step 2.1: At a molar ratio of 1:(0.4-0.6), the intermediate 3,5-bis(trifluoromethyl)benzoyl ethyl acetate prepared in step 1 is reacted with phloroglucinol at high temperature under the catalysis of 0.1-0.2 equivalents of N-dimethylaminopyridine to obtain the intermediate 2-(3,5-bistrifluoromethylphenyl)-5,7-dihydroxy-4H-carboline-4-one; Step 2.2: At a molar ratio of 1:(1.5-2.5), the intermediate 2-(3,5-bis(trifluoromethylphenyl)-5,7-dihydroxy-4H-carboline-4-one) and bromomethyl methyl ether were reacted at room temperature under the catalysis of excess N-dimethylaminopyridine to obtain the intermediate 2-(3,5-bis(trifluoromethylphenyl)-5-hydroxy-7-(methoxymethoxy)-4H-carboline-4-one; Step 2.3: At a molar ratio of 1:(2-5), the intermediate 2-(3,5-bistrifluoromethylphenyl)-5-hydroxy-7-(methoxymethoxy)-4H-carboline-4-one was reacted with iodomethane under the catalysis of sodium hydroxide to obtain the intermediate 2-(3,5-bistrifluoromethylphenyl)-5-methoxy-7-(methoxymethoxy)-4H-carboline-4-one; Step 2.4: The intermediate 2-(3,5-bis(trifluoromethylphenyl)-5-methoxy-7-(methoxymethoxy)-4H-carboline-4-one was reacted in excess concentrated hydrochloric acid to obtain compound ZDZ-553 as shown in Formula B.

[0015] The reaction route for the second method of preparing benzopyranone analogs of the present invention is as follows: In this context, arrow Ⅰ represents MgCl2, N(C2H5)3, CDI, and THF; arrow Ⅱ represents DMAP; arrow Ⅲ represents MOM-Br and THF; arrow Ⅳ represents Me-I and DMSO; and arrow Ⅴ represents HCl.

[0016] The beneficial effects of the method for preparing benzopyranone analogs of the present invention are: This invention provides two preparation methods with different reaction routes. The methods are simple, have high yields, low costs, broad market prospects, and are suitable for large-scale promotion and application.

[0017] Based on the above technical solution, the present invention can be further improved as follows.

[0018] Furthermore, in step 2.1, the temperature of the high-temperature reaction is 180℃-200℃, and the time is 2h-3h.

[0019] The further beneficial effect of using the above parameters is that the reaction effect is better.

[0020] Furthermore, in step 2.2, the reaction time at room temperature is 1-2 hours.

[0021] The further beneficial effect of using the above parameters is that the reaction effect is better.

[0022] Furthermore, in step 2.3, the reaction temperature is 70℃-80℃ and the time is 12h-24h.

[0023] The further beneficial effect of using the above parameters is that the reaction effect is better.

[0024] Furthermore, in step 2.4, the reaction time is 1h-1.5h.

[0025] The further beneficial effect of using the above parameters is that the reaction effect is better.

[0026] A third objective of this invention is to provide applications of the aforementioned benzopyranone analogues.

[0027] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: the application of the above-mentioned benzopyranone analog and the benzopyranone analog prepared by the above-mentioned method in the preparation of drugs for anti-non-alcoholic steatohepatitis.

[0028] The beneficial effects of using the benzopyranone analogues of the present invention are: The benzopyranone analogues of this invention can significantly reduce liver triglyceride and cholesterol levels, and also significantly inhibit liver inflammation in NASH mice, significantly reducing the mRNA levels of liver inflammatory factors IL-6, IL-1β, and TNF-α. Therefore, the benzopyranone analogues of this invention can be used to prepare drugs for treating non-alcoholic steatohepatitis (NASH), opening up new application areas for benzopyranone analogues and new drugs for treating NASH, possessing significant pharmaceutical value and broad social significance. Attached Figure Description

[0029] Figure 1 In Examples 1 and 2 of the present invention, the benzopyranone analog ZDZ-553 1 H NMR spectrum.

[0030] Figure 2 In Examples 1 and 2 of the present invention, the benzopyranone analog ZDZ-553 13 C NMR spectrum.

[0031] Figure 3 In Examples 1 and 2 of the present invention, the benzopyranone analog ZDZ-553 19 F NMR spectrum.

[0032] Figure 4 The HRMS of benzopyranone analog ZDZ-553 in Examples 1 and 2 of the present invention.

[0033] Figure 5 The HPLC purity of benzopyranone analog ZDZ-553 in Examples 1 and 2 of the present invention is shown.

[0034] Figure 6 This is a graph showing the mRNA expression level of the liver inflammatory factor IL-6 in an experimental example of the present invention.

[0035] Figure 7 This is a graph showing the mRNA expression level of the liver inflammatory factor IL-1B in an experimental example of the present invention.

[0036] Figure 8 This is a graph showing the mRNA expression level of the liver inflammatory factor ITNF-α in an experimental example of the present invention. Detailed Implementation

[0037] The present invention will be described in detail below with reference to the accompanying drawings, but the scope of protection of the present invention is not limited thereto.

[0038] Example 1 The method for preparing the benzopyranone analog in this embodiment includes the following steps: Step 1: Preparation of ethyl 3,5-bis(trifluoromethyl)benzoyl ester 100 mmol of potassium monoethyl malonate, 100 mmol of magnesium chloride (catalyst), 20 mmol of 3,5-bis(trifluoromethyl)benzoic acid, and 30 mmol of N,N'-carbonyldiimidazole were suspended in 300 mL of anhydrous tetrahydrofuran and stirred at room temperature for 3 h. The reaction endpoint was determined by TLC. After the reaction was completed, 200 mL of 1N dilute hydrochloric acid was added to quench the reaction, and the mixture was extracted twice with 200 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain a pale yellow oily liquid, ethyl 3,5-bis(trifluoromethyl)benzoyl.

[0039] Step 2: Preparation of benzopyranone analogs 10 mmol of ethyl 3,5-bis(trifluoromethyl)benzoyl ester, 9 mmol of 5-methoxybenzene-1,3-diol, and 4 mmol of 4-dimethylaminopyridine (DMAP) prepared in step 1 were heated to 180 °C under nitrogen protection and reacted for 2 h. After the reaction was completed, 100 mL of tetrahydrofuran was added to dissolve the product. The crude product was purified by silica gel chromatography column chromatography with a mixture of dichloromethane and acetone in a volume ratio of 30:1 as the eluent to obtain the product, named ZDZ-553.

[0040] The reaction routes involved are shown below:

[0041] In this context, arrow Ⅰ represents MgCl2, N(C2H5)3, CDI, and THF; arrow Ⅱ represents DMAP.

[0042] Example 2 Step 1: Preparation of ethyl 3,5-bis(trifluoromethyl)benzoyl ester Same as Example 1.

[0043] Step 2: Preparation of benzopyranone analogs Step 2.1: Mix 10 mmol of ethyl 3,5-bis(trifluoromethyl)benzoyl ester, 18 mmol of phloroglucinol, and 4 mmol of 4-dimethylaminopyridine (DMAP) thoroughly, heat to 180 °C under nitrogen protection, and react for 2.5 h. After the reaction is complete, add 100 mL of tetrahydrofuran to dissolve the crude product. Purify the crude product by silica gel column chromatography with a mixture of dichloromethane and acetone in a volume ratio of 30:1 as the eluent to obtain white crystals of 2-(3,5-bistrifluoromethylphenyl)-5,7-dihydroxy-4H-carboline-4-one.

[0044] Step 2.2: Dissolve 10 mmol of the intermediate 2-(3,5-bis(trifluoromethylphenyl)-5,7-dihydroxy-4H-carboline-4-one in 200 mL of anhydrous tetrahydrofuran. Add 30 mmol of N,N-diisopropylethylamine and 15 mmol of bromomethyl methyl ether. Stir at room temperature for 1.5 h, and detect the reaction endpoint by TLC. After the reaction is complete, quench the reaction with 500 mL of 1N dilute hydrochloric acid, filter and dry to obtain a white solid 2-(3,5-bis(trifluoromethylphenyl)-5-hydroxy-7-(methoxymethoxy)-4H-carboline-4-one.

[0045] Step 2.3: 10 mmol of the intermediate 2-(3,5-bis(trifluoromethylphenyl)-5-hydroxy-7-(methoxymethoxy)-4H-carboline-4-one was dissolved in 30 mL of dimethyl sulfoxide, followed by the addition of 9 mmol of sodium hydroxide and 20 mmol of iodomethane. The reaction was carried out at 70 °C for 18 h, and the reaction endpoint was detected by TLC. After the reaction was completed, 100 mL of 1N dilute hydrochloric acid was added to quench the reaction, and 200 mL of ethyl acetate was added for extraction twice. The organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography with a 50:1 mixture of dichloromethane and acetone as the eluent to obtain white crystals of 2-(3,5-bis(trifluoromethylphenyl)-5-methoxy-7-(methoxymethoxy)-4H-carboline-4-one.

[0046] Step 2.4: Dissolve 10 mmol of 2-(3,5-bis(trifluoromethylphenyl)-5-methoxy-7-(methoxymethoxy)-4H-carboline-4-one in 100 mL of methanol, add 30 mL of concentrated hydrochloric acid, and react at room temperature for 1.2 h. After the reaction is complete, filter to obtain the product, named ZDZ-553.

[0047] The reaction routes involved are shown below: In this context, arrow Ⅰ represents MgCl2, N(C2H5)3, CDI, and THF; arrow Ⅱ represents DMAP; arrow Ⅲ represents MOM-Br and THF; arrow Ⅳ represents Me-I and DMSO; and arrow Ⅴ represents HCl.

[0048] The configurations and NMR characteristics of the products obtained in Examples 1 and 2 are as follows: like Figure 1 As shown, 1 H NMR (400 MHz, DMSO- d 6) δ 10.51 (s, 1H), 8.14 (s, 1H), 8.10 (s, 2H), 6.57 (d, J = 2.4 Hz, 1H), 6.23 (d, J = 2.4 Hz, 1H), 6.09 (s, 1H), 3.81 (s, 3H).

[0049] like Figure 2 As shown, 13 C NMR (151 MHz, DMSO- d 6) δ 163.62, 159.96, 157.10, 156.97,152.56, 142.15, 129.80 (q, J= 32.8 Hz), 129.16 (d, J = 4.3 Hz), 123.87 (q, J = 272.8 Hz), 122.16 – 121.84 (m), 112.77, 101.83, 98.56, 93.73, 56.24.

[0050] like Figure 3 As shown, 19 FNMR (565 MHz, Chloroform- d ) δ -61.13 (-CF3 × 2).

[0051] like Figure 4 As shown, HRMS (ESI): Precision Quality in C 18 H 10 F6O4 [M+H] + The calculated value is 405.0556; the actual detected signal value is 405.0590.

[0052] like Figure 5 As shown, the purity is 99.31%.

[0053] Example 3 The method for preparing the benzopyranone analog in this embodiment includes the following steps: Step 1: Preparation of ethyl 3,5-bis(trifluoromethyl)benzoyl ester 100 mmol of potassium monoethyl malonate, 100 mmol of magnesium chloride (catalyst), 30 mmol of 3,5-bis(trifluoromethyl)benzoic acid, and 40 mmol of N,N'-carbonyldiimidazole were suspended in 300 mL of anhydrous tetrahydrofuran and stirred at room temperature for 2–5 hours. The reaction endpoint was determined by TLC. After the reaction was completed, 200 mL of 1N dilute hydrochloric acid was added to quench the reaction, and the mixture was extracted twice with 200 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain a pale yellow oily liquid, ethyl 3,5-bis(trifluoromethyl)benzoyl.

[0054] Step 2: Preparation of benzopyranone analogs 10 mmol of ethyl 3,5-bis(trifluoromethyl)benzoyl ester, 9 mmol of 5-methoxybenzene-1,3-diol, and 5 mmol of 4-dimethylaminopyridine (DMAP) prepared in step 1 were heated to 180 °C under nitrogen protection and reacted for 2 h. After the reaction was completed, 100 mL of tetrahydrofuran was added to dissolve the product. The crude product was purified by silica gel chromatography column chromatography with a mixture of dichloromethane and acetone in a volume ratio of 30:1 as the eluent to obtain product ZDZ-553.

[0055] The reaction route involved is the same as in Example 1.

[0056] Example 4 The method for preparing the benzopyranone analog in this embodiment includes the following steps: Step 1: Preparation of ethyl 3,5-bis(trifluoromethyl)benzoyl ester 100 mmol of potassium monoethyl malonate, 100 mmol of magnesium chloride (catalyst), 40 mmol of 3,5-bis(trifluoromethyl)benzoic acid, and 50 mmol of N,N'-carbonyldiimidazole were suspended in 300 mL of anhydrous tetrahydrofuran and stirred at room temperature for 3 h. The reaction endpoint was determined by TLC. After the reaction was completed, 200 mL of 1N dilute hydrochloric acid was added to quench the reaction, and the mixture was extracted twice with 200 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain a pale yellow oily liquid, ethyl 3,5-bis(trifluoromethyl)benzoyl.

[0057] Step 2: Preparation of benzopyranone analogs 10 mmol of ethyl 3,5-bis(trifluoromethyl)benzoyl ester, 9 mmol of 5-methoxybenzene-1,3-diol, and 6 mmol of 4-dimethylaminopyridine (DMAP) prepared in step 1 were heated to 180 °C under nitrogen protection and reacted for 3 h. After the reaction was completed, 100 mL of tetrahydrofuran was added to dissolve the product. The crude product was purified by silica gel chromatography with a mixture of dichloromethane and acetone in a volume ratio of 30:1 as the eluent to obtain product ZDZ-553.

[0058] The reaction route involved is the same as in Example 1.

[0059] Example 5 Step 1: Preparation of ethyl 3,5-bis(trifluoromethyl)benzoyl ester Same as Example 3.

[0060] Step 2: Preparation of benzopyranone analogs Step 2.1: Mix 10 mmol of ethyl 3,5-bis(trifluoromethyl)benzoyl ester, 18 mmol of phloroglucinol, and 4 mmol of 4-dimethylaminopyridine (DMAP) thoroughly, heat to 200 °C under nitrogen protection, and react for 2 h. After the reaction is complete, add 100 mL of tetrahydrofuran to dissolve the crude product. Purify the crude product using a silica gel column with a mixture of dichloromethane and acetone in a volume ratio of 30:1 as the eluent to obtain white crystals of 2-(3,5-bistrifluoromethylphenyl)-5,7-dihydroxy-4H-carboline-4-one.

[0061] Step 2.2: Dissolve 10 mmol of the intermediate 2-(3,5-bis(trifluoromethylphenyl)-5,7-dihydroxy-4H-carboline-4-one in 200 mL of anhydrous tetrahydrofuran. Add 30 mmol of N,N-diisopropylethylamine and 20 mmol of bromomethyl methyl ether. Stir at room temperature for 1 h, and detect the reaction endpoint by TLC. After the reaction is complete, quench the reaction with 500 mL of 1N dilute hydrochloric acid, filter and dry to obtain a white solid 2-(3,5-bis(trifluoromethylphenyl)-5-hydroxy-7-(methoxymethoxy)-4H-carboline-4-one.

[0062] Step 2.3: 10 mmol of the intermediate 2-(3,5-bis(trifluoromethylphenyl)-5-hydroxy-7-(methoxymethoxy)-4H-carboline-4-one was dissolved in 30 mL of dimethyl sulfoxide, followed by the addition of 9 mmol of sodium hydroxide and 20 mmol of iodomethane. The reaction was carried out at 80 °C for 12 h, and the reaction endpoint was detected by TLC. After the reaction was completed, 100 mL of 1N dilute hydrochloric acid was added to quench the reaction, and 200 mL of ethyl acetate was added for extraction twice. The organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography with a 50:1 mixture of dichloromethane and acetone as the eluent to obtain white crystals of 2-(3,5-bis(trifluoromethylphenyl)-5-methoxy-7-(methoxymethoxy)-4H-carboline-4-one.

[0063] Step 2.4: Dissolve 10 mmol of 2-(3,5-bis(trifluoromethylphenyl)-5-methoxy-7-(methoxymethoxy)-4H-carboline-4-one in 100 mL of methanol, add 30 mL of concentrated hydrochloric acid, and react at room temperature for 1 h. After the reaction is complete, filter to obtain product ZDZ-553.

[0064] The reaction route involved is the same as in Example 2.

[0065] Example 6 Step 1: Preparation of ethyl 3,5-bis(trifluoromethyl)benzoyl ester Same as Example 4.

[0066] Step 2: Preparation of benzopyranone analogs Step 2.1: Mix 10 mmol of ethyl 3,5-bis(trifluoromethyl)benzoyl ester, 18 mmol of phloroglucinol, and 4 mmol of 4-dimethylaminopyridine (DMAP) thoroughly, heat to 190 °C under nitrogen protection, and react for 3 h. After the reaction is complete, add 100 mL of tetrahydrofuran to dissolve the crude product. Purify the crude product using a silica gel column with a mixture of dichloromethane and acetone in a volume ratio of 30:1 as the eluent to obtain white crystals of 2-(3,5-bistrifluoromethylphenyl)-5,7-dihydroxy-4H-carboline-4-one.

[0067] Step 2.2: Dissolve 10 mmol of the intermediate 2-(3,5-bis(trifluoromethylphenyl)-5,7-dihydroxy-4H-carboline-4-one in 200 mL of anhydrous tetrahydrofuran. Add 30 mmol of N,N-diisopropylethylamine and 25 mmol of bromomethyl methyl ether. Stir at room temperature for 2 h, and detect the reaction endpoint by TLC. After the reaction is complete, quench the reaction with 500 mL of 1N dilute hydrochloric acid, filter and dry to obtain a white solid 2-(3,5-bis(trifluoromethylphenyl)-5-hydroxy-7-(methoxymethoxy)-4H-carboline-4-one.

[0068] Step 2.3: 10 mmol of the intermediate 2-(3,5-bis(trifluoromethylphenyl)-5-hydroxy-7-(methoxymethoxy)-4H-carboline-4-one was dissolved in 30 mL of dimethyl sulfoxide, followed by the addition of 9 mmol of sodium hydroxide and 20 mmol of iodomethane. The reaction was carried out at 75 °C for 18 h, and the reaction endpoint was detected by TLC. After the reaction was completed, 100 mL of 1N dilute hydrochloric acid was added to quench the reaction, and 200 mL of ethyl acetate was added for extraction twice. The organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography with a mixture of dichloromethane and acetone in a volume ratio of 50:1 to obtain white crystals of 2-(3,5-bis(trifluoromethylphenyl)-5-methoxy-7-(methoxymethoxy)-4H-carboline-4-one.

[0069] Step 2.4: Dissolve 10 mmol of 2-(3,5-bis(trifluoromethylphenyl)-5-methoxy-7-(methoxymethoxy)-4H-carboline-4-one in 100 mL of methanol, add 30 mL of concentrated hydrochloric acid, and react at room temperature for 1.5 h. After the reaction is complete, filter to obtain product ZDZ-553.

[0070] The reaction route involved is the same as in Example 2.

[0071] Experimental Example This experimental case was set up to study the therapeutic effect of compound ZDZ-553 prepared in Example 1 against non-alcoholic steatohepatitis (NASH).

[0072] Control group mice were fed a maintenance diet, while model group and drug-treated group mice were fed a choline-deficient high-fat diet with 60% fat content for 12 weeks. During weeks 8-12, compound ZDZ-553 prepared in Example 1 was administered to mice by gavage at doses of 30 mg / kg and 60 mg / kg, respectively, designated as the drug-treated group. Simultaneously, the control and model groups received an equal volume of physiological saline. The results are shown in Table 1.

[0073] Table 1. Effects of compound ZDZ-553 on liver fat and cholesterol content in mice.

[0074] Therefore, the compound ZDZ-553 prepared in Example 1 has a certain reversal effect on the mouse NASH model. The 30 mg / kg administration group reduced liver triglycerides by 28% and cholesterol levels by 36%; the 60 mg / kg administration group reduced liver triglycerides by 55% and cholesterol levels by 51%. Furthermore, compound ZDZ-553 can significantly inhibit the inflammatory response in the liver of NASH mice, significantly reducing the mRNA expression levels of liver inflammatory factors IL-6, IL-1β, and TNF-α. This is an important pathway by which the compound exerts its anti-inflammatory activity, treating NASH by inhibiting the expression of key inflammatory factors in the NASH inflammatory response process. The results are as follows... Figures 6-8 As shown.

[0075] Therefore, the benzopyranone analogues of the present invention can be used to prepare drugs for treating non-alcoholic steatohepatitis, which not only opens up new application areas for benzopyranone analogues, but also opens up new drugs for treating non-alcoholic steatohepatitis, and has positive pharmaceutical value and broad social significance.

[0076] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A benzopyranone analogue, characterized in that, Its structural formula is shown in formula B: .

2. The method for preparing the benzopyranone analogue according to claim 1, characterized in that, Includes the following steps: Step 1: Preparation of ethyl 3,5-bis(trifluoromethyl)benzoyl ester With a molar ratio of 1:(0.2-0.4):(0.3-0.5), potassium monoethyl malonate, 3,5-bis(trifluoromethyl)benzoic acid, and N,N-dicarbonylimidazolium were weighed separately. First, potassium monoethyl malonate and 3,5-bis(trifluoromethyl)benzoic acid were mixed evenly, and then the intermediate ethyl 3,5-bis(trifluoromethyl)benzoyl was synthesized under the activation of N,N-dicarbonylimidazolium. Step 2: Preparation of benzopyranone analogs With a molar ratio of 1:(0.9-1.2), the intermediate 3,5-bis(trifluoromethyl)benzoyl ethyl acetate prepared in step 1 was reacted with 5-methoxybenzene-1,3-diol under N-dimethylaminopyridine catalysis at high temperature to obtain compound ZDZ-55 as shown in formula B.

3. The method for preparing the benzopyranone analogue according to claim 1, characterized in that, Includes the following steps: Step 1: Preparation of ethyl 3,5-bis(trifluoromethyl)benzoyl ester With a molar ratio of 1:(0.2-0.4):(0.3-0.5), potassium monoethyl malonate, 3,5-bis(trifluoromethyl)benzoic acid, and N,N-dicarbonylimidazolium were weighed separately. First, potassium monoethyl malonate and 3,5-bis(trifluoromethyl)benzoic acid were mixed evenly, and then the intermediate ethyl 3,5-bis(trifluoromethyl)benzoyl was synthesized under the activation of N,N-dicarbonylimidazolium. Step 2: Preparation of benzopyranone analogs Step 2.1: At a molar ratio of 1:(0.4-0.6), the intermediate 3,5-bis(trifluoromethyl)benzoyl ethyl acetate prepared in step 1 is reacted with phloroglucinol at high temperature under the catalysis of 0.1-0.2 equivalents of N-dimethylaminopyridine to obtain the intermediate 2-(3,5-bistrifluoromethylphenyl)-5,7-dihydroxy-4H-carboline-4-one; Step 2.2: At a molar ratio of 1:(1.5-2.5), the intermediate 2-(3,5-bis(trifluoromethylphenyl)-5,7-dihydroxy-4H-carboline-4-one) and bromomethyl methyl ether were reacted at room temperature under the catalysis of excess N-dimethylaminopyridine to obtain the intermediate 2-(3,5-bis(trifluoromethylphenyl)-5-hydroxy-7-(methoxymethoxy)-4H-carboline-4-one; Step 2.3: At a molar ratio of 1:(2-5), the intermediate 2-(3,5-bistrifluoromethylphenyl)-5-hydroxy-7-(methoxymethoxy)-4H-carboline-4-one was reacted with iodomethane under the catalysis of sodium hydroxide to obtain the intermediate 2-(3,5-bistrifluoromethylphenyl)-5-methoxy-7-(methoxymethoxy)-4H-carboline-4-one; Step 2.4: The intermediate 2-(3,5-bis(trifluoromethylphenyl)-5-methoxy-7-(methoxymethoxy)-4H-carboline-4-one was reacted in excess concentrated hydrochloric acid to obtain compound ZDZ-553 as shown in Formula B.

4. The method for preparing benzopyranone analogs according to claim 3, characterized in that, In step 2.1, the high-temperature reaction is carried out at a temperature of 180℃-200℃ for 2h-3h.

5. The method for preparing benzopyranone analogs according to claim 3, characterized in that, In step 2.2, the reaction time at room temperature is 1-2 hours.

6. The method for preparing benzopyranone analogs according to claim 3, characterized in that, In step 2.3, the reaction temperature is 70℃-80℃ and the time is 12h-24h.

7. The method for preparing benzopyranone analogs according to claim 3, characterized in that, In step 2.4, the reaction time is 1h-1.5h.

8. The use of the benzopyranone analogue according to claim 1, or the benzopyranone analogue according to any one of claims 2-7, in the preparation of a drug for treating non-alcoholic steatohepatitis.

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