Use of compounds for the preparation of a medicament for the treatment and / or prevention of fatty liver disease and related disorders

Abstract

The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a kind of compound in the preparation of treating and / or preventing fatty liver disease and related diseases, more particularly to a kind of small molecule compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate in the preparation of treating and / or preventing fatty liver disease and related diseases.The compound of the present application can significantly inhibit lipid accumulation in hepatocytes, and no obvious toxic side effects are found, and the safety is high;can effectively inhibit HFD diet-induced weight gain, lipid accumulation, liver steatosis, and can reduce the content of triglyceride and total cholesterol in liver and serum, reduce the level of ALT and AST in plasma, has the effect of inhibiting liver damage and protecting liver function, and the effect is good.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a use of a compound in the preparation of a medicament for treating and / or preventing fatty liver disease and related diseases, and more particularly to a use of a small molecule compound or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof in the preparation of a medicament for treating and / or preventing fatty liver disease and related diseases. BACKGROUND

[0002] Nonalcoholic fatty liver disease (NAFLD) refers to excessive deposition of lipids in the liver of patients without a history of alcoholism or other secondary causes of liver fatty degeneration, and is the main indication for liver transplantation in developed and developing countries, including liver fatty degeneration (NAFL, which is the non-progressive stage of NAFLD) and nonalcoholic steatohepatitis (NASH, which is the progressive stage of NAFLD). NASH is a key link in the deterioration of NAFLD, and 25% of NAFL patients can progress to NASH, accompanied by hepatocyte fatty degeneration, ballooning, inflammation and fibrosis, and 35%-50% of NASH patients can progress to liver cancer. In addition, NAFLD is closely related to metabolic diseases such as insulin resistance, hypertension, dyslipidemia and obesity, and thus the occurrence of the disease can also promote the gradual development of various metabolic syndromes such as diabetes. It is estimated that the global prevalence of NAFLD is about 25%, and the number of NAFLD patients in China has increased sharply from 18% to nearly 30% in 10 years, and it is estimated that the number of patients in China will exceed 300 million by 2030.

[0003] Regarding the high incidence and related incidence of NASH, it is currently believed that there is an unmet medical need to determine a therapy that can slow down, stop or reverse the progression of NASH and NAFLD. Although several drugs are being used for treatment, none of the drugs has been approved by the U.S. Food and Drug Administration. Therefore, it is still necessary to further discover a safer and more effective drug for treating NAFLD. SUMMARY

[0004] In view of the deficiencies of the prior art, the present application provides a use of a compound in the preparation of a medicament for treating and / or preventing fatty liver disease and related diseases, and the inventors have found that the compound can significantly inhibit lipid accumulation in hepatocytes, and no obvious toxic side effects are observed, and oral administration of the compound of the present application can effectively relieve nonalcoholic fatty liver disease, and is safe and effective.

[0005] Therefore, the present application provides a use of a compound represented by formula (I) or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof in the preparation of a medicament for treating and / or preventing fatty liver and related diseases,

[0006]

[0007] wherein:

[0008] dashed lines represent no or single bonds;

[0009] W1is selected from CR7, N;

[0010] W2is selected from C or N;

[0011] W3is selected from C or N;

[0012] X is selected from C or N;

[0013] n is selected from 0, 1, 2;

[0014] L is selected from -C(O)NH(CH2) Z1 -, -C(O)(CH2) Z2 -, -(CH2) Z3 - ;

[0015] Z1is selected from 0, 1, 2, 3;

[0016] Z2is selected from 0, 1, 2, 3;

[0017] Z3is selected from 0, 1, 2, 3;

[0018] R1, R2, R3are each independently selected from H, F, Cl, Br, I, alkyl, haloalkyl;

[0019] or,

[0020] R1is H, R2and R3form a 5- or 6-membered heterocyclic ring,

[0021] R4is selected from H, alkyl, benzyl, said alkyl, benzyl being optionally substituted with aryl, alkyl;

[0022] R5is selected from H, alkyl;

[0023] R6is selected from H, aryl;

[0024] R7is selected from H, aryl, said aryl being optionally substituted with alkyl;

[0025] Optionally, the medicament further comprises one or more pharmaceutically acceptable carriers or excipients.

[0026] In some embodiments, W1is selected from N.

[0027] In some embodiments, W2is selected from C.

[0028] In some embodiments, W3is selected from N.

[0029] In some embodiments, X is selected from N.

[0030] In some embodiments, n is selected from 1, 2.

[0031] In some embodiments, L is selected from -C(O)(CH2) Z2 Z3- .

[0032] In some embodiments, Z1 is selected from 1.

[0033] In some embodiments, Z2 is selected from 0, 2.

[0034] In some embodiments, Z3 is selected from 1.

[0035] In some embodiments, R1, R2, R3 are each independently selected from H, F, Cl, Br, I, C1-C6 haloalkyl;

[0036] Preferably, R1, R2, R3 are each independently selected from H, F, trifluoromethyl;

[0037] More preferably, any one of R1, R2, R3 is selected from H, F, trifluoromethyl, and the remaining two are H.

[0038] In some embodiments, R1 is H, and R2 and R3 form a 5- or 6-membered heterocycle comprising one or two heteroatoms, said heteroatoms being O and / or N;

[0039] Preferably, said heteroatoms are O;

[0040] More preferably, said heterocycle is a 5-membered heterocycle comprising two O.

[0041] In some embodiments, R4 is selected from H, C1-C6 alkyl, benzyl, said C1-C6 alkyl, benzyl being optionally substituted with phenyl, C1-C6 alkyl;

[0042] Preferably, R4 is selected from H, methyl, benzyl, said methyl, benzyl being optionally substituted with phenyl, methyl;

[0043] More preferably, R4 is selected from benzyl, said benzyl being optionally substituted with methyl.

[0044] In some embodiments, R5 is selected from H, C1-C6 alkyl;

[0045] Preferably, R5 is selected from H, methyl.

[0046] In some embodiments, R6 is selected from H, phenyl;

[0047] Preferably, R6 is selected from phenyl. ​

[0048] In some embodiments, R7 is selected from H, phenyl, said phenyl being optionally substituted with C1-C6 alkyl;

[0049] Preferably, R7 is selected from phenyl, said phenyl being optionally substituted with methyl.

[0050] In some embodiments, W1 is selected from N; W2 is selected from C; W3 is selected from N;

[0051] L is selected from -C(O)(CH2) Z2 -, -(CH2) Z3- ;

[0052] X is selected from N;

[0053] R1, R2, R3 are each independently selected from H, F, Cl, Br, I, C1-C6 haloalkyl;

[0054] Preferably, R1, R2, R3 are each independently selected from H, F, trifluoromethyl;

[0055] More preferably, any one of R1, R2, R3 is selected from H, F, trifluoromethyl, and the remaining two are H.

[0056] In some embodiments, W1 is selected from CR7; W2 is selected from N; W3 is selected from C;

[0057] L is selected from -C(O)NH(CH2) Z1- ;

[0058] X is selected from C;

[0059] R1 is H, R2 and R3 form a 5- or 6-membered heterocycle;

[0060] Preferably, R2 and R3 form a 5- or 6-membered heterocycle comprising one or two heteroatoms, said heteroatoms being O and / or N;

[0061] More preferably, said heteroatoms are O;

[0062] Further preferably, said heterocycle is a 5-membered heterocycle comprising two O.

[0063] In some embodiments, the compound is selected from the following structural formulae:

[0064]

[0065] In some embodiments, the fatty liver disease is non-alcoholic fatty liver disease.

[0066] In some embodiments, the fatty liver disease is simple steatosis.

[0067] In some embodiments, the fatty liver disease is non-alcoholic steatohepatitis.

[0068] In some embodiments, the fatty liver disease is liver fibrosis.

[0069] In some embodiments, the fatty liver disease is liver cirrhosis.

[0070] In some embodiments, the fatty liver disease is liver cancer.

[0071] In some embodiments, the fatty liver disease is diet-induced non-alcoholic fatty liver disease.

[0072] In some embodiments, the fatty liver disease is high-fat high-cholesterol diet-induced non-alcoholic fatty liver disease.

[0073] In some embodiments, the fatty liver-related disease is diabetes.

[0074] In some embodiments, the fatty liver-related disease is obesity.

[0075] In some embodiments, the fatty liver-related disease is hyperlipidemia.

[0076] In some embodiments, the fatty liver-related disease is insulin resistance.

[0077] Definitions of Terms

[0078] The following terms and phrases, as used herein, are intended to have the following meanings, unless otherwise specified. In addition, unless otherwise indicated, the groups and substituents of the present application have the ordinary meaning known in the art of organic chemistry.

[0079] Substituents of the compounds of the present application are disclosed according to group type or range. It is specifically intended that the present application include each and every independent combination of the members of these group types and ranges. For example, the term "C1-C6alkyl" specifically includes methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl, independently disclosed.

[0080] The term "C1-C6alkyl" means an alkyl group having from 1 to 6 carbon atoms, preferably "C1-C4alkyl", more preferably "C1-C3alkyl", most preferably "C1-C2alkyl". Examples of "C1-C6alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, i-propyl), butyl (e.g., n-butyl, i-butyl, t-butyl), pentyl (e.g., n-pentyl, i-pentyl, neopentyl), and the like. Examples of "C1-C4alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, i-propyl), butyl (e.g., n-butyl, i-butyl, t-butyl), and the like. Examples of "C1-C3alkyl" include methyl, ethyl, propyl (e.g., n-propyl, i-propyl), and the like. Examples of "C1-C2alkyl" include methyl, ethyl.

[0081] The term "C1-C6haloalkyl" means a group in which one or more (e.g., 2, 3, or 4) hydrogen atoms of any of the above C1-C6alkyl groups are replaced with a halogen, preferably fluorine. Examples include monofluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, and the like, preferably trifluoromethyl.

[0082] The term "heterocyclyl" means a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered (preferably 5-10 membered, 6-10 membered, or 9-10 membered) saturated or unsaturated monocyclic, bicyclic, or polycyclic carbocyclic group in which one or more carbon atoms are replaced with a heteroatom such as nitrogen, oxygen, and sulfur.

[0083] The term "aryl" means a group in which all of the carbon atoms in each carbon ring have p-orbitals that form a conjugated pi system, preferably "C6-C10aryl", such as phenyl or naphthyl.

[0084] The term "benzyl" means

[0085] In the present application, the phrase "each independently selected from" as used throughout the description herein can mean that the specific options expressed between the same or different symbols in different groups are independent of each other, or that the specific options expressed between the same or different symbols in the same group are independent of each other, unless explicitly indicated otherwise.

[0086] In the present application, "substituted" or "substitution" means that any one hydrogen on the specified atom or group is replaced with a selection of the specified group, provided that the normal valency of the specified atom is not exceeded.

[0087] In the present application, "optionally" means that the selection can be made, or not.

[0088] In the present application, illustratively, the dashed line in formula (I) represents no or a single bond, represents a dashed line to indicate the absence or a single bond, i.e., no more than the normal valency for the indicated atom, depending on the valency of W1and W2.

[0089] The term "pharmaceutically acceptable salt" refers to a salt of a compound provided herein, which is formed from the reaction of a basic functional group present in the compound with a suitable inorganic or organic acid (acid addition salt), and includes, but is not limited to, hydrohalides, such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, and the like; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, and the like; lower alkylsulfonic acid salts, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, and the like; arylsulfonic acid salts, such as benzenesulfonates, p-toluenesulfonates, and the like; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, tartarates, oxalates, maleates, and the like; amino acid salts, such as glycine, t-butylamine, arginine, ornithine, glutamic acid, aspartic acid, and the like; or a salt of an acidic functional group present in a compound provided herein with a suitable inorganic or organic base (base addition salt), and includes, but is not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, and the like; alkaline earth metal salts, such as calcium salts, magnesium salts, and the like; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, and the like; inorganic base salts, such as ammonium salts; organic base salts, such as tertiary octylamine salts, dibenzylamine salts, morpholine salts, glucamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, tetramethylamine salts, tris(hydroxymethyl)aminomethane salts, and the like.

[0090] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.

[0091] The term "solvate" refers to a pharmaceutically acceptable solvate of a compound of the present application formed from the association of one or more solvent molecules with a compound of the present application, non-limiting examples of solvent molecules include water, ethanol, acetonitrile, isopropanol, DMSO, ethyl acetate.

[0092] The term "stereoisomer" refers to a molecule having the same molecular formula but differing in the arrangement of atoms in space, which is a phenomenon in organic chemistry.

[0093] The term "prodrug" means a derivative of a compound of the application that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound. Prodrugs are often active drugs themselves, but they typically have little or no activity until they are converted to the active form in vivo. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, ed., 5th ed.).

[0094] The term "carrier" refers to a system that can change the way a drug enters the body and its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ. The drug carrier release and targeting system can reduce drug degradation and loss, reduce side effects, and improve bioavailability. As a carrier, the high molecular surfactant has a unique amphiphilic structure, can self-assemble, and form various forms of aggregates, such as micelles, microemulsions, gels, liquid crystals, vesicles, etc. These aggregates have the ability to encapsulate drug molecules and good membrane permeability, and can be used as excellent drug carriers.

[0095] The term "excipient" refers to an additional substance in a pharmaceutical preparation other than the main drug, which can also be called an auxiliary material. Auxiliary materials include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human blood albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, a partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin, and the like.

[0096] The term "treatment" generally means obtaining a desired pharmacological and / or physiologic effect. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or can be therapeutic in terms of a partial or complete stabilization or cure for a disease and / or adverse effect attributable to the disease. As used herein, "treatment" covers any treatment of a patient at risk of developing a disease or symptom thereof, and includes: (a) preventing the disease or symptom from occurring in a patient that can be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, i.e., arresting its development; or (c) relieving the disease symptom, i.e., causing the disease or symptom to regress.

[0097] The term "subject" includes both human and non-human animals. Exemplary human subjects include humans afflicted with a disease (e.g., a disease described herein) (referred to as patients) or normal individuals. The term "non-human animals" in the present application includes all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles) and mammals (e.g., non-human primates, domestic animals such as sheep, dogs, cats, cows, pigs, etc.).

[0098] The term "effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A "therapeutically effective amount" of a compound of the present application can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. A therapeutically effective amount also encompasses an amount of a compound that has therapeutic benefits in combination with any toxic or detrimental side effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Since a prophylactic dose is used in subjects prior to or at the early stages of disease, the prophylactically effective amount can be less than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of the drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with the cancer.

[0099] Advantages over the prior art:

[0100] 1. The compounds of the present application, such as G435-0611, V008-4072, V012-3807, V012-5871, V019-1315, can significantly inhibit lipid accumulation in hepatocytes, and no obvious toxic side effects are observed, and the safety is high.

[0101] 2. Oral administration of the compounds of the present application, such as V012-3807, can effectively inhibit HFD diet-induced body weight gain, lipid accumulation, liver steatosis, and can reduce the content of triglyceride and total cholesterol in liver and serum, and reduce the levels of ALT and AST in plasma, has the effect of inhibiting liver damage and protecting liver function, and has good treatment effect. BRIEF DESCRIPTION OF DRAWINGS

[0102] The accompanying drawings are included to provide a further understanding of the technical scheme of the present application, and constitute a part of the specification, and are used together with the embodiments of the present application to explain the technical scheme of the present application, and do not constitute a limitation on the technical scheme of the present application.

[0103] Figure 1 The cell bodipy staining and the quantitative result graph;

[0104] Figure 2Figure of the results of the body weight and liver weight of the HFD-fed mice;

[0105] Figure 3 Figure of the results of the liver TG and blood biochemical tests of the HFD-fed mice;

[0106] Figure 4 Figure of the results of the H&E and oil red O staining of the mouse liver. DETAILED DESCRIPTION

[0107] The above technical features of the present application and the technical features described in detail below (such as the embodiments) can be combined with each other to form new or preferred technical solutions, but the present application is not limited to only these embodiments, and neither are these embodiments limiting the present application in any way.

[0108] The experimental methods in the following examples are all conventional methods unless otherwise specified. The preparations involved in the following examples are all ordinary commercially available products unless otherwise specified, and can be purchased on the market.

[0109] Activity test example

[0110] 1. Experimental animals and feeding

[0111] Experimental animals: 8-10 week old, 22.0-26.0 g male C57BL / 6 mice were selected as experimental objects.

[0112] Feeding environment: SPF level experimental animal center, SPF level mouse feed was purchased from Nantong Turophy Feedstuff Technology Co., Ltd.

[0113] Feeding conditions: room temperature between 22-24℃, humidity between 40-70%, light and dark alternating lighting time for 12h, free water and food intake.

[0114] 2. Experimental cells and schemes

[0115] Experimental cells: Huh-7 hepatocytes were selected as experimental objects. Huh-7 hepatocytes were purchased from the National Identification Cell Culture Collection Center.

[0116] Culture of Huh-7 hepatocytes: HUH7 cell line was cultured in a full-automatic new biochemical incubator (model: ZXSD-B1160), purchased from Shanghai Zhi Cheng, with a culture condition of 37℃, 5% CO2.

[0117] Experimental steps:

[0118] (1) Plate cells: select Huh-7 hepatocytes, plate in a 24-well plate, with a density of 100,000 cells per well.

[0119] (2) Drug pretreatment: After the cells were plated and adhered for 12 h, 20 μΜ of the compound of the present application was added to the culture medium to pretreat the cells, and the numbers were as shown in Table 1.

[0120] Table 1

[0121] Number CAS Number Source of Purchase G435-0611 1111320-25-2 chemdiv - shanghai chempartner V008-4072 1048600-09-4 chemdiv - shanghai chempartner V012-3807 1047504-12-0 chemdiv - shanghai chempartner V012-5871 1047434-70-7 chemdiv - shanghai chempartner V019-1315 1047551-52-9 chemdiv - shanghai chempartner V012-6761 1047382-40-0 chemdiv - shanghai chempartner

[0122] (3) Palmitic acid (PA) / oleic acid (OA) induced lipid droplet accumulation: After 8 h of drug pretreatment, palmitic acid and oleic acid were added to the culture medium to induce the cells to produce lipid droplets, with the PA concentration being 0.5 mM PA, the OA concentration being 1.0 mM OA, and the concentration of the compound of the present application being 20 μΜ.

[0123] (4) Staining: After 18 h of induction, the cell waste liquid was discarded, and the cells were washed twice with PBS, fixed with 4% paraformaldehyde at room temperature for 45 min, discarded, washed twice with PBS, and stained with BODIPY for 10 min, discarded, and washed twice with PBS.

[0124] (5) High-content cell imaging system was used for detection.

[0125] (6) Data were analyzed and plotted.

[0126] 3. Pathological detection

[0127] The main operation procedures for preparing paraffin specimen sections are as follows: trimming the liver → processing the embedding frame → rinsing with running water → dehydration → transparency → embedding → sectioning → spreading the sections → drying or baking for standby use.

[0128] The main steps of hematoxylin-eosin (H&E) staining and oil red O staining used in the examples of the present application are described as follows:

[0129] The main steps of hematoxylin-eosin (H&E) staining are as follows: deparaffinizing the paraffin specimen sections to water → staining the cell nucleus with hematoxylin → staining the cytoplasm with eosin → dehydrating and mounting → microscopic examination, image acquisition and analysis.

[0130] The main steps of oil red O (Oil red O) staining are as follows: after the sections are dried, enter 50% ethanol for washing → oil red O ethanol staining solution → 50% ethanol differentiation, tap water termination of differentiation → hematoxylin restain the nucleus, tap water return blue, glycerol gelatin mounting.

[0131] 4. Molecular biology detection

[0132] The ADVIA 2400 automatic biochemical analyzer (Siemens, Tarrytown, NY) was used to prepare animal serum according to the manufacturer's instructions for analysis of triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

[0133] Liver tissue homogenate was centrifuged for analysis of liver triglyceride content using commercially available kits (TG: 290-63701, TC: 294-65801; Wako; Tokyo, Japan) according to the manufacturer's instructions.

[0134] The application will be further described in detail below with reference to examples:

[0135] Example 1: Effect of treatment with compounds of the application on fat accumulation in hepatocytes

[0136] The hepatocytes were divided into different compound treatment groups, control solution groups, BSA groups. After the cells adhered for 12 h, 20 μM different compounds were added to the culture medium in the different compound treatment groups, and the compounds were pretreated for 8 h, and then 0.5 mM PA and 1.0 mM OA were added to the culture medium, and the treatment was performed for 18 h; the PA / OA treatment alone was used as the control solution group; no PA / OA treatment was used as the BSA group; after the treatment, BODIPY staining was performed, and imaging was performed on a high-content imaging system, wherein the experimental treatment method for the effect of the compounds on fat accumulation in hepatocytes is shown in Table 2, and the results are shown in Figure 1

[0137] Table 2: Effect of compound treatment on fat accumulation in hepatocytes

[0138]

[0139] Figure 1 The BODIPY staining imaging and intensity contrast images of hepatocytes after treatment with different compounds are shown in Figures 1 to 5. It can be seen from Figure 1 compared with the PA / OA (PO) group, the relative fluorescence intensity of the fat droplets of G435-0611, V008-4072, V012-3807, V012-5871 and V019-1315 was significantly reduced, and the number of cells was basically unchanged. It was shown that the compounds of the application could significantly inhibit the lipid accumulation in hepatocytes, and no obvious toxic side effects were observed.

[0140] Example 2: Effect of compound V012-3807 on HFD diet-induced non-alcoholic fatty liver disease

[0141] ​C57 wild type mice 32, divided into 4 groups, 8 in each group, respectively given normal diet (Normal chow, NC, ingredients: protein 19.2%, carbohydrate 67.3%, fat 4.3%; percentage of heat: protein 20%, carbohydrate 70%, fat 10%; total heat mass ratio: 3.85kcal / g) and high-fat diet (high-fat diet; HFD, ingredients: protein 18.3%, carbohydrate 20.8%, fat 60.9%; total heat mass ratio 5.2kcal / g) feeding, recorded as NC group and HFD group. After 12 weeks of feeding, one group of NC-fed mice was given 60mg / kg V012-3807 oral gavage treatment, and the other group was given solvent treatment. Similarly, one group of HFD-fed mice was given 60mg / kg V012-3807 oral gavage treatment, and the other group was given solvent treatment. The administration frequency was once a day, and the administration was continued for 12 weeks, during which NC or HFD feeding was continued.

[0142] After 24 weeks, the mice were taken for material, and the body weight and liver weight of the mice were determined; the HFD-fed mice were subjected to corresponding molecular biology detection; the liver tissue was subjected to pathological detection, and the results are shown in Figures 2-4

[0143] From the results of Figure 2 It can be seen that oral administration of V012-3807 can significantly reduce the increase in body weight and liver weight of HFD-fed mice, indicating that V012-3807 has an inhibitory effect on individual fat accumulation and obesity.

[0144] From the results of Figure 3 It can be seen that oral administration of V012-3807 can significantly reduce the content of triglyceride and total cholesterol in the liver and serum of HFD-fed mice, and reduce the levels of ALT and AST in plasma, indicating that V012-3807 has the effect of inhibiting liver lipid accumulation, inhibiting liver damage and protecting liver function.

[0145] From the results of Figure 4 It can be seen that oral administration of V012-3807 significantly improves the fatty degeneration of the liver of HFD-fed mice and significantly reduces lipid deposition, indicating that V012-3807 has a good effect on treating non-alcoholic fatty liver disease.

[0146] Finally, it should be emphasized that the above only describes the preferred embodiments of the present application and is not intended to limit the present application. For those skilled in the art, the present application can have various changes and modifications, and any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.​

Claims

1. The use of a compound or a pharmaceutically acceptable salt in the preparation of a medicament for the treatment and / or prevention of fatty liver disease, characterized in that, The compound has the following structural formula: 。 2. The use according to claim 1, characterized in that, The drug also includes one or more pharmaceutically acceptable carriers or excipients.

3. The use according to claim 1, characterized in that, The fatty liver disease mentioned refers to non-alcoholic fatty liver disease, simple steatosis, and non-alcoholic steatohepatitis.

4. The use according to claim 3, characterized in that, The fatty liver disease mentioned refers to diet-induced non-alcoholic fatty liver disease or non-alcoholic fatty liver disease induced by a high-fat, high-cholesterol diet.

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