A class of dictamni acid derivatives, pharmaceutical compositions and their use in treating fatty liver

Abstract

The application belongs to the technical field of medicine, and specifically discloses a kind of dictamni acid derivative and a preparation method, a pharmaceutical composition and purposes thereof, specifically, the application relates to a dictamni acid derivative shown in formula (I) or a pharmaceutically acceptable salt thereof, a preparation method of the dictamni acid derivative, a composition containing one or more compounds, and purposes of the compounds in preparing medicines for preventing and / or treating fatty liver related diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a kind of dictamni acid derivatives isolated from Dictamni Cortex and the use thereof in treating fatty liver. BACKGROUND

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

[0003] Dictamni Cortex is the dried root bark of Dictamnus dasycarpus Turcz. of the Rutaceae family. It has the effects of expelling wind and detoxifying, clearing heat and drying dampness, and is traditionally used to treat various diseases such as eczema, wind rash, rheumatic arthralgia, scabies, damp-heat sores, yellowish watery discharge, jaundice and red urine. Modern medical research has shown that Dictamni Cortex has various pharmacological effects such as antibacterial, anti-inflammatory, antitumor and liver protection (Liu Lei et al., Chinese Patent Medicine, 2016.38(12):9.). Dictamni Cortex contains various characteristic components such as terpenes, alkaloids, jujubone, obacunone and coumarin. The degradation of limonin components is a unique active component in Dictamni Cortex. The inventors have discovered a series of dictamni acid components from Dictamni Cortex, which can effectively inhibit the accumulation of oleic acid in liver cells, and have good application prospects in the development of fatty liver treatment drugs. SUMMARY

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

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

[0006] To solve the technical problems of the present application, the present application provides the following technical solutions:

[0007] The first aspect of the technical scheme of the present application is to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0008]

[0009] wherein:

[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 alkenylacyl, n is independently selected from 0-3, is independently selected from or

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

[0012]

[0013] Further, the C 1-3 alkyl in R1 in formula (I) is preferably selected from methyl, ethyl, propyl, isopropyl. The C 1-4 alkoxyacyl in R2 is preferably selected from linear alkoxyacyl, branched alkoxyacyl; the C 1-4 alkenylacyl is selected from linear alkenylacyl or branched alkenylacyl. Further, the linear alkoxyacyl of R2 is selected from methoxyacyl, ethoxyacyl, propionyl or butoxyacyl; the branched alkoxyacyl is selected from isopropoxyacyl; the linear alkenylacyl is selected from propenylacyl, 2-butenylacyl, 3-butenylacyl; the branched alkenylacyl is selected from isopropenylacyl.

[0014] Further, the compound is selected from:

[0015]

[0016] The pharmaceutically acceptable salt is selected from the group consisting of a salt formed by a compound and an organic base, an inorganic base. The organic base includes meglumine, tris-hydroxymethyl aminomethane and N-methyl-glucamine, methylamine, ethylamine, diethylamine, triethylamine, propylamine, butylamine, octylamine, hexanediamine, ethylenediamine, propylenediamine, butylenediamine, benzylamine, phenethylamine, o-xylylamine, p-xylylamine, and the inorganic base includes 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, potassium carbonate.

[0017] The second aspect of the technical scheme is to provide a preparation method of the compound or the pharmaceutically acceptable salt thereof, and the preparation method is as follows: the cortex dictamni medicinal material is crushed, extracted with distilled water and / or ethanol, and then separated by column chromatography after being extracted with an organic solvent to obtain the compound.

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

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

[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 silica gel, diol, cyano and amino fillers; the reverse phase fillers include macroporous resin, microporous resin, C18, C8 and phenyl fillers; and the gel fillers include HW type gel and Sephadex type gel.

[0021] The third aspect of the present application provides a pharmaceutical composition comprising the effective amount of one or more compounds or pharmaceutically acceptable salts thereof according to the first aspect of the present application and a pharmaceutically acceptable carrier or excipient. The dosage form of the pharmaceutical composition includes tablets, capsules, pills, granules, powders, drop pills, oral solutions or suspensions. The pharmaceutical composition can be prepared into ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems. In order to prepare tablets of the compounds of the present application, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate and the like; the wetting agents can be water, ethanol, isopropyl alcohol and the like; the binders can be starch paste, dextrin, sugar syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, low-substituted hydroxypropyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol and the like; the disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate and the like; the lubricants and glidants can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like. The tablets can be further prepared 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 prepare the administration units into capsules, the effective ingredients, the compounds of the present application, can be mixed with diluents and glidants, and the mixture can be directly placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants and glidants used for preparing tablets of the compounds of the present application can also be used for preparing capsules of the compounds of the present application. In addition, if necessary, colorants, preservatives, flavors, taste correctors or other additives can also be added to the pharmaceutical preparations. In order to achieve the purpose of medication and enhance the therapeutic effect, the drugs or pharmaceutical compositions of the present application can be administered by any known administration method.

[0022] The fourth aspect of the present application provides the use of the compounds or pharmaceutically acceptable salts thereof according to the first aspect of the present application and the pharmaceutical compositions according to the third aspect of the present application in the preparation of a medicament 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 present application provides the use of Compound 2 and Compound 6 or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing Compound 2 or Compound 6 in the preparation of a medicament 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 salt described above is the same as the pharmaceutically acceptable salt described in the first aspect of the present patent. The pharmaceutical composition comprises one or more compounds or pharmaceutically acceptable salts thereof in an effective dose of Compound 2 and Compound 6 and a pharmaceutically acceptable carrier or excipient. The dosage form of the pharmaceutical composition includes tablets, capsules, pills, granules, powders, dripping pills, oral liquids or suspensions. The pharmaceutical composition can be prepared into ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0026] Beneficial technical effects:

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

[0028] The following examples and pharmacological activity experiments are used to further illustrate the present application, but this does not mean any limitation to the present application.

[0029] Example 1 Preparation of white bark magnolia tree acid derivatives in white bark magnolia tree

[0030] Baixianpi medicinal material (50 kg) was pulverized and extracted with distilled water by reflux extraction for 3 times, 2 h each time. Then it was extracted with 95% ethanol for 3 times, 2 h each time. The extract was combined and concentrated, and then extracted with ethyl acetate for 3 times. The ethyl acetate fraction (1.01 kg) was separated by silica gel (60-100 mesh) column and eluted with chloroform-methanol (100:1-1:1) gradient, 100:1, 50:1, 20:1, 10:1, 5:1, 2:1, 1:1, to obtain 7 fractions (Fr.G-1-7). Fr.G-4 (320 g) was separated by C18 column and eluted with methanol-water (10%-90%) gradient, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, to obtain 9 fractions (Fr.B2-1-9). Fr.B2-3 was selected and purified by preparative high performance liquid chromatography, with the following conditions: (1) column: YMC-Pack ODS-A (250 x 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 compounds 1 and 2.

[0031] The aqueous phase fraction (10 kg) was separated by macroporous resin column and eluted with ethanol-water (0-95%) gradient, 0%, 30%, 50%, 95%, to obtain 4 fractions (Fr.D1-4). Then D2 was separated by silica gel (60-100 mesh) column and eluted with dichloro-methanol (100:1-1:1), 100:1, 50:1, 20:1, 10:1, 5:1, 2:1, 1:1, to obtain 7 fractions (Fr.H1-7). Fr.H1 was selected and purified by preparative high performance liquid chromatography, with the following conditions: (1) column: Capcell Pak MG-IIC 18 (250 x 10 mm, 5 μm); (2) mobile phase: water / methanol (35 / 65) solution; (3) flow rate: 3.0 mL / min; (5) detection wavelength: 220 nm, to obtain compound 3. Fr.H6 was selected and purified by preparative high performance liquid chromatography, with the following conditions: (1) column: Capcell Pak MG-IIC 18 (250 x 10 mm, 5 μm); (2) mobile phase: water / methanol (50 / 50) solution; (3) flow rate: 3.0 mL / min; (5) detection wavelength: 205 nm, to obtain fraction Fr.F4. Fraction Fr.F4 was selected and subjected to chiral separation, with the following conditions: (1) column: CHIRALPAK IG (250 x 4.6 mm, 5 μm); (2) mobile phase: n-hexane / isopropanol (82 / 18) solution; (3) flow rate: 0.4 mL / min; (5) detection wavelength: 205 nm, to obtain compounds 4 and 5.

[0032] The structure of the compound was determined by UV, IR, NMR, MS and CD, etc.

[0033] The above compound spectrum information and nuclear magnetic signal attribution 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 1393 cm -1 ; 1 H NMR (CDC13, 600 MHz) δ H : 4.32 (1H, dd, J = 10.8, 2.8 Hz, H-2), 1.65 (1H, td, J = 11.5, 2.9 Hz, H-3a), 1.59 (1H, m, H-3b), 1.95 (1H, dddq, J = 13.0, 9.6, 6.2, 2.8 Hz, H-4), 1.08 (1H, d, J = 6.4 Hz, H-5), 2.09 (1H, m, H-8), 2.62 (1H, dd, J = 17.4, 8.4 Hz, H-9α), 2.37 (1H, dd, J = 17.4, 11.7 Hz, H-9β), 1.36 (1H, s, H-11), 1.53 (1H, s, J = 10.8, 2.8 Hz, H-12); 13 C NMR (CDC13, 101 MHz); 13 C NMR (CDC13, 126 MHz) 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), 51.4 (C-8), 34.7 (C-9), 176.3 (C-10), 21.7 (C-11), 29.4 (C-12); (+)-HRESIMS m / z 253.1042 [M+Na] + (calcd for C 11 H 18 O5Na + , 253.1046).

[0037] Compound 2

[0038]

[0039] colorless oil; 1 H NMR (CDC13, 400 MHz) δ: 4.24 (1H, ddd, J = 10.6, 5.0, 3.1 Hz, H-2), 1.47-1.62 (2H, m, H-3), 1.95 (1H, dpd, J = 16.2, 6.4, 3.2 Hz, H-4), 1.06 (3H, d, J = 6.4 Hz, H-5), 2.07 (1H, ddd, J = 11.4, 9.6, 8.1 Hz, H-8), 2.61 (1H, dd, J = 17.4, 8.1 Hz, H-9a), 2.36 (1H, dd, J = 17.4, 11.4 Hz, H-9b), 1.53 (3H, s, H-11), 1.36 (3H, s, H-12), 2.74 (1H, d, J = 5.0 Hz, 2-OH), 3.81 (3H, s, 1-OCH3); 13 C NMR (CDC13, 101 MHz) 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 (log ε) 209.5 (4.25) nm; ECD (MeOH) λ max (Δ ε) 217 (-5.6) nm; IR v max 3501, 2976, 1761 and 1724 cm -1 . 1 H NMR (CDC13, 700 MHz) δ H5.14 (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-9a), 2.35 (1H, dd, J = 17.4, 11.6 Hz, H-9b), 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 C NMR (CDC13, 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 H 24 O6H + ,313.1646).

[0043] Compound 4, 5

[0044]

[0045] Colorless oil; UV (MeOH) λ max (log ε) 203 (3,56) nm; IR v max 2979, 2937, 1743, 1418, 1394 cm -1 ; 1 H NMR (CDC13, 700 MHz) δ H2.64 (1H, dd, J = 17.2, 7.8 Hz, 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 = 6.2 Hz, H-5); 13 C NMR (CDC13, 176 MHz) 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);; (+)-HRESIMS m / z 201.1126 [M+H] + (calcd for C 10 H 16 O4H + , 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 Influence of the compounds on the proliferation of HepG2 cells

[0048] HepG2 cells were inoculated in 96-well cell culture plates, and after 24 h of culture, different concentrations of the test compounds were added, and a solvent control group was set up, and 3 parallel holes were set up for each drug concentration. After 24 h of drug action on the cells, the culture solution was discarded, 100 μl of MTT (0.5 mg / ml) solution was added to each hole, and incubation was continued for 4 h, the MTT solution was discarded, 150 μl of DMSO was added to each hole, and the mixture was shaken in a shaker, and the absorbance value was measured at 570 nm wavelength in an enzyme-labeled instrument. Cell survival rate (%) = (average OD value of drug-treated cells / average OD value of solvent control cells) x 100%.

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

[0050] Effect Example 2 Protective effect of the compounds on oleic acid-induced lipid deposition in hepatocytes

[0051] HepG2 cells were inoculated in 96-well cell culture plates at a density of 8 x 10 4The cells were inoculated in 96-well cell culture plates at 1 x 104 / ml, and after 24 h of culture, the sample to be tested and sodium oleate (240 μM) were added, and a fenofibrate positive drug control group (20 μM), a test substance group (10 μM), a solvent control group and a model group were set up, with 5 parallel holes for each drug concentration, and the cells were further treated for 24 h. The culture solution was discarded, 100 μL of PBS was added to each hole, and after 30 s, it was poured out, and the operation was repeated three times. Then 100 μL of 4% paraformaldehyde was added to each hole to fix the cells, and the cells were allowed to stand for 40 min. The paraformaldehyde was poured out, 100 μL of PBS was added to each hole, and after 30 s, it was poured out, and the operation was repeated three times. 100 μL of oil red stain was added to each hole, and the cells were stained in the dark for 1 h. The stain was removed, 100 μL of PBS was added to each hole, and after 30 s, it was poured out, and the operation was repeated three times, 50 μL of isopropyl alcohol was added to each hole, and the cells were shaken on a shaker for 10 min, and the OD value was measured at 532 nm on an enzyme-labeled instrument, and the inhibition rate (%) was calculated = (model group OD average - drug group OD average) / (model group OD average) x 100%.

[0052] Table 1 Protective effect of compounds 1-3 on oleic acid-induced lipid deposition in hepatocytes

[0053]

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

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

[0056]

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

Claims

1. A leuconic acid derivative or a pharmaceutically acceptable salt thereof, wherein, The chlorogenic acid derivatives mentioned above are selected from: 。 2. The crocin derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The pharmaceutically acceptable salts are selected from salts formed by the reaction of the dictamnus acid derivatives with inorganic or organic bases.

3. A method for preparing the dictamnus acid derivative of claim 1 or 2, comprising extracting the dictamnus root bark with water and / or ethanol to obtain an extract, and purifying the extract by extraction and column chromatography to obtain the dictamnus acid derivative.

4. A pharmaceutical composition, wherein, The pharmaceutical composition comprises the crocin derivative of claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

5. The pharmaceutical composition according to claim 4, wherein, The dosage forms of the pharmaceutical composition include tablets, capsules, pills, granules, powders, drop pills, oral liquids, or suspensions.

6. Use of the crocin derivative of claim 1 or 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 4 or 5, in the preparation of a medicament for the prevention, relief, and / or treatment of fatty liver.

7. The use according to claim 6, wherein, The fatty liver is either non-alcoholic fatty liver or alcoholic fatty liver.

8. Use of compound 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing compound 2, in the preparation of a medicament for the prevention, relief, and / or treatment of fatty liver. 。 9. The use according to claim 8, wherein, The fatty liver is either non-alcoholic fatty liver or alcoholic fatty liver.

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