CN113413380B

CN113413380B - Application of mPGES-2 inhibitor in preparation of medicine for treating and/or preventing nonalcoholic fatty liver disease

Info

Publication number: CN113413380B
Application number: CN202110912860.2A
Authority: CN
Inventors: 孙莹; 陈京硕; 钟丹丹; 张红星
Original assignee: Xuzhou Medical University
Current assignee: Xuzhou Medical University
Priority date: 2021-08-10
Filing date: 2021-08-10
Publication date: 2022-03-08
Anticipated expiration: 2041-08-10
Also published as: CN113413380A

Abstract

The invention discloses an application of an mPGES-2 inhibitor in preparing a medicament for treating and/or preventing non-alcoholic fatty liver disease, in particular to an application of a compound shown as a formula (I) or a pharmaceutically acceptable derivative thereof in preparing a medicament for preventing and/or treating non-alcoholic fatty liver disease;

experiments prove that the compound can be used for improving and treating the non-alcoholic fatty liver disease, has obvious effects on improving and treating the non-alcoholic fatty liver disease, can be prepared into a medicament by an acceptable carrier, and is used for preventing and treating the non-alcoholic fatty liver disease.

Description

Application of mPGES-2 inhibitor in preparation of medicine for treating and/or preventing nonalcoholic fatty liver disease

Technical Field

The invention relates to application of an mPGES-2 inhibitor SZ0232, in particular to application of the mPGES-2 inhibitor SZ0232 in preparing a medicament for treating and/or preventing nonalcoholic fatty liver diseases, and belongs to the technical field of medicines.

Background

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease caused by the pathological accumulation of lipids (mainly triglycerides) in liver cells, a progressively developing liver disease. NAFLD is very easily induced by factors such as overnutrition, obesity, metabolic syndrome, type 2 diabetes and the like. With the improvement of living standard of people, NAFLD has become the first chronic liver disease in China at present and seriously harms human health. However, there is no known drug for NAFLD internationally, and patients cannot obtain direct effective treatment in early stage (mainly manifested by simple hepatic cell steatosis or lipid deposition), and further develop to nonalcoholic steatohepatitis, hepatic fibrosis, liver cirrhosis, liver cancer and the like, and finally endanger life. Therefore, the research and development of the medicine for effectively intervening the non-alcoholic fatty liver disease in the early stage of the onset of the non-alcoholic fatty liver disease has good clinical significance.

mPGES-2 is a specific bifunctional enzyme whose function is affected by glutathione (gshi) and heme (heme). It normally binds to GSH and heme in vivo to form a complex, binding PGH to₂Metabolizing to malondialdehyde and separating from heme to produce PGE₂. Previous studies in this group found that mPGES-2 knockout significantly improved insulin sensitivity in insulin resistant mice, which is likely due to improvement in nonalcoholic fatty liver disease symptoms. At present, the function of mPGES-2 in the treatment of the non-alcoholic fatty liver disease is not reported at home and abroad, so that the mPGES-2 inhibitor SZ0232 is used for improving and/or treating the non-alcoholic fatty liver disease, a new way is opened for the treatment of the non-alcoholic fatty liver disease, and the mPGES-2 inhibitor has very important significance for improving the life quality of patients with the non-alcoholic fatty liver disease.

Disclosure of Invention

The invention mainly aims to provide application of a compound mPGES-2 inhibitor SZ0232 shown in a formula (I) in preparing a medicament for treating and/or preventing nonalcoholic fatty liver diseases so as to make up for the defects of the existing treatment method.

It is another object of the present invention to provide a medicament for treating and/or preventing non-alcoholic fatty liver disease.

In order to achieve the purpose, the technical scheme adopted by the invention comprises the following steps:

the embodiment of the invention provides an application of a compound shown as a formula (I) or a pharmaceutically acceptable derivative thereof in preparing a medicament for preventing and/or treating non-alcoholic fatty liver diseases;

wherein the pharmaceutically acceptable derivative is selected from at least one of a pharmaceutically acceptable salt, polymorph, co-crystal, radiolabeled form, and combinations thereof.

In the present invention, the chemical name of the compound represented by the formula (I) is N, N' - ((4- ((4- (2-oxopyrrolidin-1-yl) phenyl) sulfonamido) -1, 2-phenylene) bis (oxy)) bis (ethane-2, 1-diyl)) bisamide.

Experiments prove that the compound can be used for improving and treating the non-alcoholic fatty liver disease, and has remarkable effects on improving and treating the non-alcoholic fatty liver disease.

The embodiment of the invention also provides a medicament for treating and/or preventing the nonalcoholic fatty liver disease, which comprises a compound shown in the formula (I) or a pharmaceutically acceptable derivative thereof;

Further, the medicament also comprises a pharmaceutically acceptable carrier and/or excipient.

Compared with the prior art, the invention has the beneficial effects that:

the compound SZ0232 shown in the formula (I) can be used for improving and treating the non-alcoholic fatty liver disease, can obviously prove that the compound SZ0232 has obvious effect on improving and treating the non-alcoholic fatty liver disease, can be prepared into a medicament through an acceptable carrier, and is used for preventing and treating the non-alcoholic fatty liver disease.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments described in the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.

FIG. 1 is a graph showing the results of the morphological effect of compound SZ0232 on liver tissue in db/db mice in an exemplary embodiment of the invention;

FIG. 2 is a graph showing the effect of compound SZ0232 on liver lipid accumulation in db/db mice in an exemplary embodiment of the invention;

FIG. 3 is a graph showing the effect of compound SZ0232 on liver serum triglyceride levels in db/db mice in an exemplary embodiment of the invention;

FIG. 4 is a graph showing the effect of compound SZ0232 on hepatic triglycerides in db/db mice in an exemplary embodiment of the invention;

FIG. 5 is a graph showing the effect of compound SZ0232 on the level of hepatic malondialdehyde in db/db mice in an exemplary embodiment of the invention;

FIGS. 6 and 7 are graphs showing the effect of compound SZ0232 on liver ACOT4 levels in db/db mice in an exemplary embodiment of the invention.

Detailed Description

In view of the defects in the prior art, the inventor of the present invention provides a technical scheme of the present invention through long-term research and a large amount of practice, and mainly provides a pharmaceutical use of an mPGES-2 inhibitor SZ0232 for treating and/or preventing nonalcoholic fatty liver diseases. The technical solution, its implementation and principles, etc. will be further explained as follows.

One aspect of the embodiments of the present invention provides a use of a compound represented by formula (I) or a pharmaceutically acceptable derivative thereof for the preparation of a medicament for the prevention and/or treatment of non-alcoholic fatty liver disease;

Further, the compound represented by the formula (I) has a chemical structure of SZ0232 and a chemical name of N, N' - ((4- ((4- (2-oxopyrrolidin-1-yl) phenyl) sulfonamide) -1, 2-phenylene) bis (oxy)) bis (ethane-2, 1-diyl)) bisamide.

The term "pharmaceutically acceptable salts" as used herein is intended to refer to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in SM Berge et al, in j.pharmaceutical Sciences, 1977, 66, 1-19, the contents of which are incorporated by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentylpropionates, gluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, laurates, laurylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, embonates, pectinates, persulfates, 3-phenylpropionates, phosphates, pivaloates, propionates, stearates, succinates, salts, Sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, pentanoates, and the like.

Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C1-4 alkyl) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include suitable non-toxic ammonium salts formed using such salts as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates, quaternary ammonium salts and amine cations.

As used herein, "pharmaceutically acceptable salt" refers to a form of the disclosed compound in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; for example, alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which 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 an organic solvent, or a mixture of the two; generally, a nonaqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used.

The term "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound that, when administered to a subject, provides (directly or indirectly) a compound of formula (I) or a metabolite or residue having antibacterial activity.

Salts of the compounds of formula (I) are preferably pharmaceutically acceptable, but non-pharmaceutically acceptable salts should also fall within the scope of the invention as such are useful intermediates in the preparation of pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts include, but are not limited to, pharmaceutically acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids, or pharmaceutically acceptable organic acids thereof such as hydrochloric, propionic, butyric, tartaric, maleic, hydroxy, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, toluenesulfonic, benzenesulfonic, salicylic, p-amino, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

Corresponding base salts include, but are not limited to, those formed with pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium, for example, salts formed with triethylamine, alkoxyamines such as those formed with ethanolamine, and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine. Pharmaceutically acceptable salts and their formation and general information are well known to those skilled in the art, as described in general textbooks such as "salts for handbook pharmacy" PHStahl, CGWermuth, 1 st edition, 2002, willi-VCH.

The compounds of the present disclosure provided herein also include all polymorphs and pseudopolymorphs of the compounds of formula (I). "polymorphs" are known in the art (see, e.g., J.thermal anal.Cal.64: 37-60(2001)) and are believed to be where the compound of formula (I) is capable of different crystalline phases. The crystalline phases may have different molecular arrangements ("packing polymorphism") and/or conformations ("conformational polymorphism") in the lattice. For example, in two different polymorphs of a compound of formula (I), each polymorph may have the molecules arranged in a different basic crystal system-triclinic, monoclinic, orthorhombic, tetragonal, trigonal, hexagonal or cubic. The term "anhydrate" as used herein is any crystalline form of the compound of formula (I) in which the water molecules are the non-convergent part of the crystal. The anhydrate of the compound of formula (I) can be prepared, for example, by crystallization from a substantially water-free solvent. In one embodiment, the compound of formula (I) is an anhydrate, i.e., as a free base, in which the crystal lattice is substantially free of water molecules and any water molecules present are present as "surface water" (e.g., loosely bound to the surface of the crystal), as those skilled in the art are distinguishable and distinguishable from the water molecules (e.g., hydrates) that are an integral part of the crystal by, for example, thermogravimetric analysis (TGA) and/or Differential Scanning Calorimetry (DSC). In one embodiment, the anhydrate of the compound of formula (I) has less than about 0.2 moles of water, in another embodiment less than about 0.15 moles of water, in another embodiment about 0.12 moles of water, in another embodiment less than about 0.1 moles of water, in another embodiment less than about 0.085 moles of water, in another embodiment less than about 0.075 moles of water, in another embodiment less than about 0.06 moles of water, in another embodiment less than about 0.057 moles of water, in another embodiment less than about 0.05 moles of water, in another embodiment less than about 0.025 moles of water, in another embodiment less than about 0.02 moles of water, in another embodiment less than about 0.01 moles of water, in another embodiment less than about 0.005 moles of water, in another embodiment less than about 0.03 moles of water, and in another embodiment less than about 0.001 moles of water, the presence of surface water is taken into account in each embodiment and each of the embodiments described is based on every 1 mole of compound of formula (I).

The compounds of the present disclosure provided herein also include all co-crystals of the compounds of formula (I). "eutectic" is known in the art and is considered to be a structurally homogeneous crystalline material comprising two or more neutral building blocks in a well-defined stoichiometric amount, e.g., a compound of formula (I) and a coform material. Pharmaceutical 4 (3): 317-322(2007). As used herein, "co-crystal" includes all polymorphs of the co-crystal, i.e., all different crystalline phases of the co-crystal. The main difference between solvates and co-crystals is the physical state of the isolated pure substance. For example, for a two-component system, if one component is a liquid at a temperature of about 25 ℃, crystals containing both components are designated as solvates, and if both components are solids at that temperature, crystals containing both components are designated as co-crystals. Sekhon "Pharmaceutical Co-crystals-AReview," ars. pharm.50 (3): 99-117(2009). In addition, co-crystals and salts may be considered "extrema" on the scale of possible multicomponent structures. Salts are formed by ionization, e.g., by an acid-base reaction or proton donation occurring between the active pharmaceutical ingredient and an acidic or basic substance. Conversely, when the active pharmaceutical ingredient lacks ionizable sites capable of salt formation, the co-crystal may form, for example, hydrogen bonds, π - π or van der Waals interactions between the components through non-ionization. Structural differences between co-crystals, salts and hydrates are exemplified in Crystal Growth & Design9 (6): 2950-2967(2009) are incorporated by reference herein in figures 1 and 2. The preparation of the co-crystals is known in the art, for example as described in the above-cited references and U.S. patent nos. 7452555B2 and 7935817B 2.

In one embodiment, the crystals of the compound having formula (I) comprise hydrochloric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, succinic acid, fumaric acid, citric acid, oxalic acid, benzoic acid, or any mixture thereof. In another embodiment, the crystals of the compound having formula (I) comprise hydrochloric acid, benzenesulfonic acid, toluenesulfonic acid, L-tartaric acid, fumaric acid, or any mixture thereof. In another embodiment, the co-crystal has a compound of formula (I) and hydrochloric acid. In another embodiment, the co-crystal has a compound of formula (I) and benzenesulfonic acid. In another embodiment, the co-crystal has a compound of formula (I) and toluenesulfonic acid. In another embodiment, the co-crystal has a compound of formula (I) and L-tartaric acid. In another embodiment, the co-crystal has a compound of formula (I) and fumaric acid. In another embodiment, the co-crystal contains about 1 equivalent of the compound of formula (I) and about 0.5 equivalent of fumaric acid, for example, from about 0.3 to about 0.7 equivalent of fumaric acid in one embodiment, from about 0.4 to about 0.6 equivalent of fumaric acid in another embodiment, from about 0.44 to about 0.56 equivalent of fumaric acid in another embodiment or from about 0.47 to about 0.53 equivalent of fumaric acid in another embodiment. In another embodiment, the co-crystal comprises 1 equivalent of the compound of formula (I) and 0.5 equivalent of fumaric acid. Analytical techniques such as infrared spectroscopy, single crystal X-ray diffraction (XRD), powder X-ray diffraction (PXRD), melting point determination, DSC, Differential Thermal Analysis (DTA), TGA, solid state nmr (ssnmr), and X-ray photoelectron spectroscopy (XPS) can be used to elucidate the structure of the co-crystal. In certain embodiments, XRD, SSNMR and/or XPS are used to determine whether a co-crystal or salt thereof is present. In certain embodiments, when a sufficiently large single crystal cannot be grown, then SSNMR or XPS is used to determine if a co-crystal or salt thereof is present.

Further, the drug is capable of improving at least liver tissue morphology of non-alcoholic fatty liver disease.

Further, the drug is capable of at least reducing hepatic lipid accumulation in non-alcoholic fatty liver disease.

Further, the drug is capable of at least reducing liver lipid peroxidation in non-alcoholic fatty liver disease.

Further, the medicine can up-regulate the liver ACOT4 level of non-alcoholic fatty liver mice, and relieve the symptoms of non-alcoholic fatty liver by increasing the liver ACOT4 level.

Further, the medicament is capable of at least alleviating the symptoms of nonalcoholic fatty liver disease.

Further, the non-alcoholic fatty liver disease is non-alcoholic fatty liver disease induced by type 2 diabetes.

Yet another aspect of the embodiments of the present invention provides a medicament for treating and/or preventing non-alcoholic fatty liver disease, comprising a compound represented by formula (I) or a pharmaceutically acceptable derivative thereof;

Further, the medicament also comprises a pharmaceutically acceptable carrier and/or excipient. The carrier and/or excipient may be any pharmaceutically acceptable carrier and excipient known to those skilled in the art to be suitable for such use. The term "pharmaceutically acceptable carrier" as used herein has a meaning well known to those skilled in the art and can include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, the like, and combinations thereof.

Furthermore, the dosage form of the medicine comprises injection, oral liquid, capsules, tablets or granules.

Further, the drug of the present invention may be in any form suitable for administration to a patient, for example, the mode of administration of the drug includes subcutaneous administration, oral administration, intramuscular administration, intraperitoneal administration, or the like, but is not limited thereto.

The optimum dose and frequency of administration will depend on the particular condition being treated and its severity; the age, sex, size and weight, diet and general physical condition of the particular patient; other medications that the patient may take; the route of administration; preparing a formula; as well as various other factors known to physicians and others skilled in the art.

By the technical scheme, the compound SZ0232 shown in the formula (I) can be used for improving and treating the non-alcoholic fatty liver disease, and can obviously prove that the compound SZ0232 has obvious effects on improving and treating the non-alcoholic fatty liver disease, and can be prepared into a medicament by an acceptable carrier for preventing and treating the non-alcoholic fatty liver disease.

In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention are described in further detail below with reference to the accompanying drawings and several preferred embodiments, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

The materials, reagents and the like used in the following examples are commercially available, unless otherwise specified, for example:

experimental animals: the db/db mice used in this example were purchased from Jiangsu Jiejiaokang Biotech Co.

Histology H & E staining: liver tissues were fixed with 10% formalin for 24H, paraffin embedded, cut into 5 micron sections for H & E staining and evaluated by microscopic observation.

Liver oil red O staining: liver tissues were fixed with 10% formalin for 24h, sugar-precipitated in 20%, 30% sucrose solution gradient, OCT gel-embedded, cut into 5 micron sections for Oil Red O staining, and evaluated by microscopic observation.

Serum TG detection: blood is collected from the orbit of the mouse, the mouse is stood for 20min at room temperature, centrifuged for 15min at 3000rpm, and upper serum is carefully sucked up and stored at-80 ℃ for later use. The TG kit is purchased from Nanjing to build a bioengineering institute.

Detection of liver TG: taking out the liver tissue block from-80 ℃, putting the liver tissue block into liquid nitrogen, weighing, quickly putting the liver tissue block into a homogenizing tube containing 1mL of precooled PBS, and homogenizing for 15s by using an automatic homogenizer; transfer the homogenate into a 10mL glass tube, 2: 1, 4mL of chloroform/methanol solution, and sealing the cover; vortex mixer vortex vigorously to mix well, when mixing begins timing, vortex for 30 s. Centrifuging at 2000rpm for 30min at 4 deg.C for phase separation; transferring the upper aqueous phase to a new tube, and extracting the upper aqueous phase again; the lower organic phase was removed and transferred to another 10mL glass tube. Blow-drying the organic phase with nitrogen in a fume hood, adding 500. mu.L of 3% Triton X-100(v/v) solution, repeatedly blowing, and shaking at 55 deg.C on a constant temperature shaking table until the lipid is dissolved. The content of TG in lipid was determined by conventional methods.

Liver MDA detection: MDA kit (MO 63103) was purchased from Sigma, USA.

Liver ACOT4 test: and detecting the expression condition of the ACOT4 protein in the liver by adopting a protein immunoblotting method. ACOT4 and β -actin antibodies were purchased from Sigma, USA.

And (3) data analysis: the experimental data were statistically analyzed using the SPSS 16.0 software, with t-test for two comparisons and one-way ANOVA for multiple comparisons, expressed as Mean ± standard error (Mean ± SEM), and considered statistically different when P < 0.05.

Example 1

To investigate the effect of SZ0232 shown in formula (I) on nonalcoholic fatty liver mice, the inventors of the present invention administered 0.5mg/kg of SZ0232 and a normal saline control treatment to every other day intraperitoneal injection to db/db mice of 8 weeks of age, respectively. After 10 weeks of treatment, liver tissues were taken for H & E staining to observe pathological changes in the liver (see fig. 1), oil red staining to observe lipid accumulation in the liver (see fig. 2), serum and intrahepatic TG levels, effects of drugs on triglyceride levels in db/db mice (see fig. 3 and 4), effects of drugs on MDA levels of liver peroxidation products in mice (see fig. 5), effects of drugs on expression of ACOT4 levels in mouse livers, and the small molecule compound (SZ0232) was shown to reduce symptoms of nonalcoholic steatohepatitis by reducing lipid peroxidation in the liver and up-regulating ACOT4 levels in the liver of db/db mice (see fig. 6 and 7).

In conclusion, the experiments prove that the mPGES-2 inhibitor SZ0232 has the effect of improving and treating the non-alcoholic fatty liver, can be prepared into a medicament through an acceptable carrier and is used for preventing and treating the non-alcoholic fatty liver.

Furthermore, the medicament prepared from the mPGES-2 inhibitor SZ0232 provided by the invention not only reduces lipid accumulation, but also reduces lipid peroxidation, and has the advantages of less administration times and small dosage.

While the invention has been described with reference to illustrative embodiments, it will be understood by those skilled in the art that various other changes, omissions and/or additions may be made and substantial equivalents may be substituted for elements thereof without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims

1. Use of a compound of formula (I) in the manufacture of a medicament for the treatment of non-alcoholic fatty liver disease;

2. use according to claim 1, characterized in that: the non-alcoholic fatty liver disease is induced by type 2 diabetes.