Dictamnic acid derivatives, pharmaceutical composition and application of dictamnic acid derivatives in treatment of fatty liver

Abstract

The invention belongs to the technical field of medicines, particularly discloses a dictamnoic acid derivative as well as a preparation method, a pharmaceutical composition and application thereof, and particularly relates to a dictamnoic acid derivative shown in a formula (I) or pharmaceutically acceptable salt thereof and a preparation method thereof, a composition containing one or more compounds, a pharmaceutical composition containing one or more compounds, and a pharmaceutical composition containing one or more compounds. The invention also discloses application of the compounds in preparation of medicines for preventing and / or treating fatty liver related diseases. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medicine, and in particular relates to a class of difficile acid derivatives separated from difficile cortex and use thereof in treating fatty liver. Background Art

[0002] Fatty liver disease (FLD), also known as fatty liver for short, is a chronic progressive disease caused by excessive fat accumulation in liver cells due to multiple factors, including simple fatty liver and its evolved fatty hepatitis, liver fibrosis, cirrhosis and liver cancer. With the development of society and changes in lifestyle, fatty liver has become one of the most common diseases in the world. The incidence in the Chinese population has reached 15%-20%, and it is increasing year by year. However, there is still no effective drug approved for the treatment of fatty liver. Only some guidelines recommend pioglitazone, an insulin sensitizer, and vitamin E, an antioxidant, for the treatment of non-alcoholic fatty liver disease (NAFLD). Statins and fibrates, lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, ursodeoxycholic acid, probiotics and synbiotics are currently potential beneficial drugs for the treatment of NASH, but the results of clinical trials are not sufficient to obtain approval from regulatory authorities. Therefore, the discovery of drugs against fatty liver has always been an important topic in the field of drug research and discovery (Zhang Shanshan and Wang Laiyou, World Chinese Journal of Digestion, 2019.27(2):7.).

[0003] Dictamnus dasycarpus Turcz. is the dried root bark of Dictamnus dasycarpus Turcz. of the Rutaceae family. It is bitter and cold in nature. It has the effects of dispelling wind and detoxifying, clearing heat and drying dampness. It is traditionally used to treat eczema, rubella, rheumatic arthralgia, scabies, sores, damp-heat sores, yellow water dripping, jaundice and red urine. Modern medical research shows that Dictamnus dasycarpus has multiple pharmacological effects such as antibacterial, anti-inflammatory, anti-tumor and liver protection (Liu Lei et al., Chinese Patent Medicine, 2016.38(12):9.). Dictamnus dasycarpus contains multiple characteristic components such as terpenes, alkaloids, quercetin, flavonoids, coumarins, etc. Among them, degraded limonin components are the unique active ingredients in Dictamnus dasycarpus. The inventors have discovered a series of dacric acid components from Dictamnus dasycarpus, which can effectively inhibit the accumulation of oleic acid in hepatocytes and have good application prospects in developing fatty liver treatment drugs. Summary of the invention

[0004] The technical problem solved by the present invention is to provide a class of dandruff acid derivatives, and a preparation method and a pharmaceutical composition thereof and use thereof in preparing a drug for preventing, alleviating or treating fatty liver.

[0005] The inventors have found that the five daunoic acid components in the Dictamni cortex can significantly inhibit the accumulation of oleic acid-induced fat in liver cells, and thus have the effect of resisting fatty liver. The daunoic acid components have a five-membered lactone ring skeleton and a fatty acid side chain. Pharmacological experiments have shown that daunoic acid derivatives 1, 2, 3, 4, and 5 can effectively inhibit oleic acid-induced HepG2 cell lipid deposition at a dose of 10 μM. Under the action of 240 μM sodium oleate, the inhibitory activity of compounds 1, 2, and 3 is much higher than the activity of the positive control drug fenofibrate in this experiment at a dose of 20 μM. Under the action of 180 μM sodium oleate, the inhibitory activity of compounds 4 and 5 is much higher than the activity of the positive control drug fenofibrate in this experiment at a dose of 10 μM.

[0006] In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:

[0007] The first aspect of the technical solution of the present invention is to provide a leucic acid derivative or a pharmaceutically acceptable salt thereof represented by formula (I),

[0008]

[0009] in:

[0010] In formula (I), R1 is independently selected from H or C 1-3 Alkyl, R2 is independently selected from H, OH, C 1-4 Alkoxyacyl or C 1-4 Alkenyloxy, n is independently selected from 0-3, Independently selected or

[0011] Furthermore, the general formula I does not include compound 2 and compound 6.

[0012]

[0013] Furthermore, C in R1 in formula (I) 1-3 The alkyl group is preferably selected from methyl, ethyl, propyl and isopropyl. 1-4 The alkoxyacyl group is preferably selected from a straight chain alkoxyacyl group and a branched chain alkoxyacyl group; 1-4 The alkeneoxy group is selected from a straight chain alkeneoxy group or a branched chain alkeneoxy group. Furthermore, the straight chain alkoxy group of R2 is selected from a methoxy group, an ethoxy group, a propionyl group or a butoxy group; the branched chain alkoxy group is selected from an isopropoxy group; the straight chain alkeneoxy group is selected from a propenoxy group, a 2-butenoxy group, a 3-butenoxy group; the branched chain alkeneoxy group is selected from an isopropenoxy group.

[0014] Further, the compound is selected from:

[0015]

[0016] The pharmaceutically acceptable salt is selected from the salts formed by the compound and organic bases and inorganic bases. The organic bases include meglumine, trishydroxymethylaminomethane and N-methyl-glucamine, methylamine, ethylamine, diethylamine, triethylamine, propylamine, butylamine, octylamine, hexylenediamine, ethylenediamine, propylenediamine, butylenediamine, benzylamine, phenylethylamine, o-phenylenediamine, and p-phenylenediamine, and the inorganic bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, copper hydroxide, iron hydroxide, ammonium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

[0017] The second aspect of the technical solution of the present invention is to provide a method for preparing the compound or a pharmaceutically acceptable salt thereof described in the first aspect, wherein the preparation method is as follows: the Dictamni cortex is crushed, extracted with distilled water and / or ethanol, the extract is extracted with an organic solvent, and then separated by column chromatography to obtain the compound.

[0018] The extraction solvent includes water, ethanol and ethanol aqueous solution of any concentration.

[0019] The extraction solvent is an organic solvent that is immiscible with water or a mixed solvent in any proportion. The organic solvent includes but is not limited to n-butanol, ethyl acetate, chloroform, dichloromethane, ether, petroleum ether, cyclohexane, and n-hexane. The mixed solvent includes but is not limited to a mixture of two or more organic solvents in any proportion as well as a mixture of two or more organic solvents in any proportion as well as a mixture of the above solvents with methanol, ethanol, acetone, and the like.

[0020] The column chromatography includes normal pressure column chromatography, medium pressure column chromatography and high performance liquid column chromatography. The fillers used include normal phase fillers, reverse phase fillers and gel fillers. The normal phase fillers include fillers such as silica gel, diol, cyano, amino, etc.; reverse phase fillers include fillers such as macroporous resin, microporous resin, C18, C8, phenyl, etc.; gel fillers include HW type gel and Sephadex type gel.

[0021] The third aspect of the technical solution of the present invention provides a pharmaceutical composition, which includes an effective dose of one or more compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or excipient as described in the first aspect of the present invention. The dosage form of the pharmaceutical composition includes tablets, capsules, pills, granules, powders, drop pills, oral liquids or suspensions. The pharmaceutical composition can be made into a common preparation, or a sustained-release preparation, a controlled-release preparation, a targeted preparation and various microparticle delivery systems. In order to prepare the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, adhesives, wetting agents, disintegrants, lubricants, and glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia paste, gelatin paste, sodium methyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl thiocarbamide, polyethylene glycol, etc.; the disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl thiocarbamide, cross-linked sodium methyl cellulose, sodium methyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid esters, sodium dodecyl sulfate, etc.; the lubricant and glidant can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc. The tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets. In order to make the dosing unit into a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The diluents, adhesives, wetting agents, disintegrants, and glidants used to prepare the tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention. In addition, if necessary, colorants, preservatives, spices, flavoring agents or other additives can also be added to the pharmaceutical preparation. In order to achieve the purpose of medication and enhance the therapeutic effect, the medicine or pharmaceutical composition of the present invention can be administered by any known method of administration.

[0022] The fourth aspect of the technical solution of the present invention is to provide the use of the compound or pharmaceutically acceptable salt thereof described in the first aspect of the present invention and the pharmaceutical composition described in the third aspect in the preparation of a method for preventing, alleviating and / or treating fatty liver. The fatty liver includes alcoholic fatty liver and non-alcoholic fatty liver.

[0023] The fifth aspect of the technical solution of the present invention is to provide the use of Compound 2 and Compound 6 or their pharmaceutically acceptable salts or a pharmaceutical composition containing Compound 2 or Compound 6 in the preparation of a drug for preventing, alleviating and / or treating fatty liver. The fatty liver includes alcoholic fatty liver and non-alcoholic fatty liver.

[0024]

[0025] The pharmaceutically acceptable salts are the same as the pharmaceutically acceptable salts described in the first aspect of the present invention. The pharmaceutical composition comprises effective doses of one or more compounds of compound 2 and compound 6 or their pharmaceutically acceptable salts and a pharmaceutically acceptable carrier or excipient. The dosage form of the pharmaceutical composition comprises tablets, capsules, pills, granules, powders, drop pills, oral liquids or suspensions. The pharmaceutical composition can be made into a common preparation, or a sustained-release preparation, a controlled-release preparation, a targeted preparation and various microparticle delivery systems.

[0026] Beneficial technical effects:

[0027] The daunoic acid derivatives in the Dauci Dictamni of the present invention have significant effects on preventing and treating fatty liver. Pharmacological experiments have shown that compounds 1, 2, 3, 4, and 5 can effectively inhibit oleic acid-induced lipid deposition in HepG2 cells at a dose of 10 μM. Under the action of 240 μM sodium oleate, the inhibitory activity of compounds 1, 2, and 3 is much higher than the activity of the positive control drug fenofibrate in this experiment at a dose of 20 μM. Under the action of 180 μM sodium oleate, the inhibitory activity of compounds 4 and 5 is much higher than the activity of the positive control drug fenofibrate in this experiment at a dose of 10 μM, and has the potential to be further developed into drugs for preventing and treating fatty liver. DETAILED DESCRIPTION

[0028] The following examples and pharmacological activity experiments are used to further illustrate the present invention, but they do not mean any limitation of the present invention.

[0029] Example 1 Preparation of Dictamni Acid Derivatives from Dictamni Cortex

[0030] The medicinal material of Dictamni (50 kg) was crushed and extracted with distilled water for 3 times under reflux, each time for 2 hours. Then it was extracted with 95% ethanol for 3 times, each time for 2 hours. After the extracts were combined and concentrated, they were extracted with ethyl acetate for 3 times. The ethyl acetate part (1.01 kg) was passed through a silica gel (60-100 mesh) column and gradient eluted with chloroform-methanol (100:1-1:1), and the elution ratio was 100:1, 50:1, 20:1, 10:1, 5:1, 2:1, 1:1, and a total of 7 fractions (Fr.G-1-7) were obtained. Fr.G-4 (320 g) was passed through a C18 column and gradient eluted with methanol-water (10%-90%), and the elution ratio was 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and a total of 9 fractions (Fr.B2-1-9) were obtained. Fr.B2-3 were selected for preparative HPLC purification. The liquid phase conditions were as follows: (1) chromatographic column: YMC-Pack ODS-A (250×20 mm, 5 μm); (2) mobile phase: water / methanol (55 / 45) solution; (3) flow rate: 7.0 mL / min; (5) detection wavelength: 205 nm to obtain the above-mentioned compounds 1 and 2.

[0031] The aqueous phase (10 kg) was passed through a macroporous resin column and eluted with ethanol-water (0-95%) gradient at a ratio of 0%, 30%, 50%, and 95%, to obtain four components (Fr.D1-4). D2 was then separated with silica gel (60-100 mesh) and eluted with dichloromethanol (100:1-1:1) at a ratio of 100:1, 50:1, 20:1, 10:1, 5:1, 2:1, and 1:1, to obtain seven components (Fr.H1-7). Fr.H1 was selected for preparative HPLC purification, and the liquid phase conditions were as follows: (1) Chromatographic column: Capcell Pak MG-IIC 18 (250×10mm, 5μm); (2) mobile phase: water / methanol (35 / 65) solution; (3) flow rate: 3.0mL / min; (5) detection wavelength: 220nm, to obtain the above compound 3. Fr.H6 was selected for preparative HPLC purification, and the liquid phase conditions were as follows: (1) chromatographic column: Capcell Pak MG-IIC 18 (250×10mm,5μm); (2) mobile phase: water / methanol (50 / 50) solution; (3) flow rate: 3.0mL / min; (5) detection wavelength: 205nm, component Fr.F4 was obtained. Component Fr.F4 was selected for chiral separation, and the liquid phase conditions were: (1) chromatographic column: CHIRALPAK IG (250×4.6mm,5μm); (2) mobile phase: n-hexane / isopropanol (82 / 18) solution; (3) flow rate: 0.4mL / min; (5) detection wavelength: 205nm, and the above compounds 4 and 5 were obtained.

[0032] The structures of the compounds were confirmed by UV, IR, NMR, MS and CD spectroscopic methods.

[0033] The spectral information and NMR signal attribution of the above compounds are as follows:

[0034] Compound 1

[0035]

[0036] Colorless oil; 66.3(c 0.08,MeOH); UV(MeOH)λ max (logε)206(3.05)nm; ECD(MeOH)λ max (Δε):210(-1.7)nm; IR ν max 2978, 2934, 2877, 1742, 1422 and 1393cm -1 ; 1 H NMR (CDCl3, 600MHz)δ H :4.32(1H,dd,J=10.8,2.8Hz,H-2),1.65(1H,td,J=11.5,2.9Hz,H-3a),1.59 (1H,m,H-3b),1.95(1H,dddq,J=13.0,9.6,6.2,2.8Hz,H-4),1.08(1H,d,J=6. 4Hz,H-5),2.09(1H,m,H-8),2.62(1H,dd,J=17.4,8.4Hz,H-9α),2.37(1H,dd, J=17.4,11.7Hz,H-9β),1.36(1H,s,H-11),1.53(1H,s,J=10.8,2.8Hz,H-12); 13 C NMR (CDCl3, 101 MHz); 13 C NMR (CDCl3, 126MHz)δ C :178.3(C-1),67.6(C-2),39.5(C-3),30.3(C-4),17.6(C-5),87.9(C-7),5 1.4(C-8),34.7(C-9),176.3(C-10),21.7(C-11),29.4(C-12); (+)-HRESIMS m / z253.1042[M+Na] + (calcd for C 11 H 18 O5Na + ,253.1046).

[0037] Compound 2

[0038]

[0039] Colorless oil; 1 H NMR (CDCl3, 400MHz) δ: 4.24 (1H, ddd, J = 10.6, 5.0, 3.1Hz, H-2), 1.47-1.62 (2H, m, H-3), 1 .95(1H,dpd,J=16.2,6.4,3.2Hz,H-4),1.06(3H,d,J=6.4Hz,H-5),2.07(1H,ddd,J=11.4, 9.6,8.1Hz,H-8),2.61(1H,dd,J=17.4,8.1Hz,H-9a),2.36(1H,dd,J=17.4,11.4Hz,H-9b) ,1.53(3H,s,H-11),1.36(3H,s,H-12),2.74(1H,d,J=5.0Hz,2-OH),3.81(3H,s,1-OCH3); 13 C NMR (CDCl3, 101MHz)δ C :175.8(C-1),67.6(C-2),39.7(C-3),30.3(C-4),17.7(C-5),87.1(C-7),51.5(C -8),34.5(C-9),175.0(C-10),21.7(C-11),29.4(C-12),52.9(-OCH3); (+)-ESIMS m / z 267.1[M+Na] + .

[0040] Compound 3

[0041]

[0042] Colorless oil; 31.0(c 0.20,MeOH); UV(MeOH)λ max (logε)209.5(4.25)nm; ECD(MeOH)λ max (Δε)217(-5.6)nm; IRν max 3501, 2976, 1761 and 1724cm -1 . 1 H NMR (CDCl3, 700MHz)δ H: 5.14 (1H, dd, J = 11.3, 2.5 Hz, H-2), 1.92 (1H, overlapped, H-3a), 1.61 (1H, ddd, J = 13.7, 10.7, 2.6 Hz, H-3b), 1.72 (1H, dqt, J = 13.5, 6.7, 3.4 Hz, H-4), 1.02 (1H, d, J = 6.5 Hz, H-5), 2.07 (1H, ddd, 11.5, 9.5, 8.2 Hz, H-8), 2.65 (1H, dd, J = 17.4, 8.2 Hz, H-9α), 2.35 (1H, dd, J = 17.4, 11.6 Hz, H-9β), 1.33 (1H, s, H-11), 1.51 (1H, s, H-12), 7.06 (1H, dq, J = 15.6, 6.9 Hz, H-14), 5.93 (1H, d, J = 15.5 Hz, H-15), 1.92 (1H, overlapped, H-16), 3.75 (1H, s, 1-OCH3); 13 13C NMR (CDCl3, 176 MHz) δ C : 170.8 (C-1), 69.3 (C-2), 36.9 (C-3), 30.6 (C-4), 17.9 (C-5), 86.8 (C-7), 51.3 (C-8), 34.5 (C-9), 174.7 (C-10), 29.4 (C-11), 21.6 (C-12), 165.8 (C-13), 146.9 (C-14), 121.5 (C-15), 18.2 (C-16), 52.6 (-OCH3); (+)-HRESIMS m / z 313.1641 [M + H] + (calcd for C 16 19 24 H + 12O6H, 313.1646).

[0043] Compounds 4, 5

[0044]

[0045] Colorless oil; UV (MeOH) λ max (log ε) 203 (3.56) nm; IR ν max 2979, 2937, 1743, 1418, 1394 cm -1 ; 1 1H NMR (CDCl3, 700 MHz) δ H:2.64(1H,dd,J=17.2,7.8Hz,H-9a),2.42(2H,m,H-9b,3a),2.22(1H,m,H-3b),2.16(1H,m ,H-8),2.11(1H,m,H-4),1.54(3H,s,H-12),1.36(3H,s,H-11),1.10(3H,d,J=6.2Hz,H-5); 13 C NMR (CDCl3, 176MHz)δ C :177.3(C-2),174.7(C-10),86.9(C-7),50.8(C-8),40.3(C-3),34.6(C-9),31.2(C-4),29.3(C-12),21.5(C-11),19.3(C-5); IMS(+)-HRES m / z 201.1126[M+H] + (calcd for C 10 H 16 4H + ,201.1121).Compound 4:ECD(MeOH)λ max (Δε)214(-0.2)nm.Compound 5:ECD(MeOH)λ max (Δε)213(0.6)nm.

[0046] Pharmacological experiments

[0047] Effect Example 1 Effect of Compounds on HepG2 Cell Proliferation

[0048] HepG2 cells were inoculated in a 96-well cell culture plate. After 24 hours of culture, different concentrations of the test compound were added. A solvent control group was set up at the same time. Three parallel wells were set up for each drug concentration. After 24 hours of drug action on the cells, the culture medium was discarded, 100 μl of MTT (0.5 mg / ml) solution was added to each well, and the culture was continued for 4 hours. The MTT solution was discarded, 150 μl of DMSO was added to each well, and the mixture was shaken on an oscillator. The absorbance value was measured at a wavelength of 570 nm on an ELISA reader. Cell survival rate (%) = (mean OD value of drug-treated cells / mean OD value of solvent-controlled cells) × 100%.

[0049] Compounds 1, 2, 3, 4, and 5 had no cytotoxic activity against HepG2 cells at a concentration of 10 μM.

[0050] Effect Example 2: Protective Effect of Compounds on Oleic Acid-Induced Lipid Deposition in Hepatocytes

[0051] HepG2 cells were collected at 8×10 4 / ml were inoculated in a 96-well cell culture plate. After culturing for 24 hours, the test sample and sodium oleate (240μM) were added. At the same time, a fenofibrate positive drug control group (20μM), a test substance group (10μM), a solvent control group and a model group were set up. Five parallel wells were set up for each drug concentration, and the cells were continued to act for 24 hours. The culture medium was discarded, and 100μL PBS was added to each well. After 30s, it was poured out and repeated three times. Then 100μL 4% paraformaldehyde was added to each well to fix the cells and allowed to stand for 40min. Pour out the paraformaldehyde, add 100μL PBS to each well, pour it out after 30s, and repeat three times. 100μL of oil red dye was added to each well and placed in the dark to avoid light for staining for 1h. The dye was removed, 100 μL PBS was added to each well, and the mixture was poured out after 30 seconds. This process was repeated three times. 50 μL isopropanol was added to each well, and the mixture was placed on an oscillator for 10 minutes. The OD value was measured at 532 nm using a microplate reader, and the inhibition rate (%) was calculated as (mean OD value of the model group - mean OD value of the drug-treated group) / (mean OD value of the model group) × 100%.

[0052] Table 1 Protective effects of compounds 1 to 3 on lipid deposition in hepatocytes induced by oleic acid

[0053]

[0054] *** P<0.001 compared with blank control group; # P<0.05, ## P<0.01 compared with the model group.

[0055] Table 2 Protective effects of compounds 4-5 on lipid deposition in hepatocytes induced by oleic acid

[0056]

[0057] * P<0.05 compared with blank control group; # P<0.05, ## P<0.01, ### P<0.001 compared with the model group.

Claims

1. A dacrylic acid derivative represented by formula (I) or a pharmaceutically acceptable salt thereof, in: R1 is independently selected from H or C 1-3 Alkyl, R2 is independently selected from H, OH, C 1-4 Alkoxyacyl or C 1-4 Alkenyloxy, n is independently selected from 0-3, Independently selected or Furthermore, the general formula I does not include compound 2 and compound 6.

2. The divaricate acid derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The C 1-3 Alkyl is selected from methyl, ethyl, propyl, isopropyl; C 1-4 The alkoxyacyl group is selected from a linear alkoxyacyl group and a branched alkoxyacyl group; 1-4 The alkeneoxyacyl group is selected from a linear alkeneoxyacyl group or a branched alkeneoxyacyl group.

3. The dizzynic acid derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that: The compound is selected from:

4. The dizzynic acid derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The pharmaceutically acceptable salt is selected from the salt formed by the reaction of the compound with an inorganic base or an organic base.

5. The method for preparing the divaricate acid derivative according to any one of claims 1 to 4, characterized in that: The preparation method is as follows: the Dictamni Cortex medicinal materials are extracted with water and / or ethanol, the extract is extracted and separated and purified by column chromatography to obtain the compound.

6. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

7. The pharmaceutical composition according to claim 6, characterized in that The dosage form of the pharmaceutical composition includes tablets, capsules, pills, granules, powders, dripping pills, oral liquids or suspensions.

8. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claims 6 to 7 in the preparation of a drug for preventing, alleviating and / or treating fatty liver.

9. The method according to claim 8, characterized in that The fatty liver includes non-alcoholic fatty liver or alcoholic fatty liver.

10. Use of Compound 2 and Compound 6 or their pharmaceutically acceptable salts or a pharmaceutical composition containing Compound 2 or Compound 6 in the preparation of a drug for preventing, alleviating and / or treating fatty liver, 11. The method according to claim 10, characterized in that The fatty liver includes non-alcoholic fatty liver or alcoholic fatty liver.

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