CN118206492A - A type of 2,4-dinitrophenoxy compound and its preparation method - Google Patents

Abstract

The present invention discloses a class of 2,4-dinitrophenoxy compounds and a preparation method thereof, and belongs to the field of pharmaceutical chemistry. The present invention provides a class of 2,4-dinitrophenoxy compounds or pharmaceutically acceptable salts thereof having a structure as shown in formula (I), the compound or pharmaceutically acceptable salt thereof has better pharmacokinetic properties than HU6, and can be used as a mitochondrial uncoupler, and has therapeutic prospects for obesity, non-alcoholic fatty liver disease, hepatic steatosis or diabetes.

Description

A type of 2,4-dinitrophenoxy compound and its preparation method

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a class of 2,4-dinitrophenoxy compounds and a preparation method thereof.

Background technique

In recent years, obesity and type 2 diabetes have become prevalent metabolic diseases worldwide. In the field of seeking treatments for obesity and the research field of the mechanism of obesity-induced diabetes development, mitochondria have become an increasingly popular focus. As a key subcellular organelle that utilizes fuel at the cellular level and provides the necessary energy for life activities in the body, mitochondria's functional level affects the overall metabolic balance. The close correlation between mitochondrial function and obesity and type 2 diabetes suggests that the regulation of energy metabolism and energy balance in the body directly affects the occurrence and development of the above-mentioned metabolic syndrome. From the perspective of bioenergetics, current studies believe that the occurrence and development of obesity and type 2 diabetes are related to the body's energy supply exceeding energy demand. Reducing the coupling efficiency of mitochondrial oxidative phosphorylation can increase energy demand at the cellular level to alleviate the metabolic pressure caused by excess energy supply. Therefore, the mitochondrial uncoupling mechanism is of great significance in the pathogenesis and treatment of obesity and diabetes. Targeting the mechanism of mitochondrial proton leakage is the most direct strategy to reduce mitochondrial coupling efficiency.

Mitochondrial uncouplers are cytotoxic at high concentrations due to a drop in ATP concentrations and depolarization and permeabilization of plasma and lysosomal membranes. However, this effect is concentration-dependent, and at nontoxic doses, mitochondrial uncoupling can protect cells from death. Therefore, the development of mitochondrial-specific and safer uncouplers suitable for human use may lead to powerful and differentiated approaches to treat these diseases. Recent studies using a controlled-release oral formulation of DNP (CRMP (controlled-release mitochondrial protonophore)) are an important attempt to achieve an enhanced therapeutic index.

The most famous chemical uncoupler in history, 2,4-dinitrophenol (DNP), has been proven to increase energy consumption in both humans and animals. However, it has obvious side effects, and high doses can cause increased sweating, rashes, cataracts, and death. The main reason for its withdrawal from the market is that its therapeutic window is too narrow (the minimum lethal dose is only twice the dose that significantly increases the basal metabolic rate).

Recently, Rivus has developed DNP prodrug HU6 as a controlled metabolic promoter that activates mitochondrial uncoupling, thereby promoting the natural process of cellular thermogenesis, thereby reducing fat and addressing obesity and complications caused by obesity.

The inventors discovered a class of 2,4-dinitrophenoxy compounds in the process of studying mitochondrial uncouplers. These compounds have more excellent pharmacokinetic properties than HU6. It is expected that these inhibitors will have good therapeutic effects and have good development prospects.

Summary of the invention

The invention designs and synthesizes a class of 2,4-dinitrophenoxy compounds, and finds that the structural compound has significant mitochondrial decoupling activity.

The present invention provides a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof:

in:

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are independently selected from H or D, and at least one of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ is D;

X is NO ₂ , and Y is H; or, X is H, and Y is NO ₂ .

In one embodiment of the present invention, preferably, at least one of R ₁ , R ₂ and R ₃ is D. More preferably, at least one of R ₁ and R ₂ is D.

In one embodiment of the present invention, the above compound is specifically selected from:

In one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt, the inorganic salt includes hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, salicylate.

The present invention also provides a pharmaceutical composition, comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent.

The present invention also provides the use of the above 2,4-dinitrophenoxy compounds or pharmaceutically acceptable salts thereof as mitochondrial uncoupling agents.

The present invention also provides the use of the above-mentioned 2,4-dinitrophenoxy compounds or pharmaceutically acceptable salts thereof in preparing drugs for treating obesity, non-alcoholic fatty liver disease, liver steatosis or diabetes.

Beneficial effects:

The 2,4-dinitrophenoxy compounds provided by the present invention have more excellent pharmacokinetic properties than HU6, and can be used as mitochondrial uncouplers, and have therapeutic prospects for obesity, non-alcoholic fatty liver disease, liver steatosis or diabetes.

Detailed ways

The technical solution of the present invention will be described in detail below in conjunction with embodiments.

In the present invention, D is an isotope of H.

The present invention also provides a pharmaceutical composition comprising the compound of the general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into solid preparations for oral administration, including, but not limited to capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, the compounds of the general formula (I) of the present invention are mixed as active ingredients with at least one conventional inert excipient (or carrier), for example, with sodium citrate or dicalcium phosphate. Or mixed with the following ingredients: (1) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (2) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic, etc.; (3) humectants, such as glycerol, etc.; (4) disintegrators, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, etc.; (5) solubilizers, such as paraffin, etc.; (6) absorption accelerators, such as quaternary ammonium compounds, etc.; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate, etc.; (8) adsorbents, such as kaolin, etc.; (9) lubricants, such as talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc., or mixtures thereof. Capsules, tablets and pills may also contain buffers.

The solid dosage forms such as tablets, pills, capsules, pills and granules can be coated or microencapsulated with coating and shell materials such as enteric coatings and other materials known in the art. They can contain opacifiers, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient can also be formed into microcapsules with one or more of the above-mentioned excipients.

The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, etc. In addition to the compound of formula (I) or its pharmaceutically acceptable salt as an active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water and other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil, etc. or mixtures of these substances, etc. In addition to these inert diluents, the liquid dosage form of the present invention may also include conventional adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices, etc.

The suspending agent includes, for example, ethoxylated stearyl alcohol, polyoxyethylene sorbitol, and sorbitan, microcrystalline cellulose, agar, etc. or a mixture of these substances.

The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, excipients include water, ethanol, polyols and suitable mixtures thereof.

The compound of the present invention or its pharmaceutically acceptable salt can be configured into dosage forms for topical administration, including ointments, powders, suppositories, drops, sprays and inhalants, etc. The compound of the present invention of general formula (I) or its pharmaceutically acceptable salt as an active ingredient is mixed with a physiologically acceptable carrier and optional preservatives, buffers, and propellants that may be required under sterile conditions.

The pharmaceutical composition of the present invention comprises a compound of the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient, and diluent. When preparing the pharmaceutical composition, the compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is usually mixed with a pharmaceutically acceptable carrier, excipient, or diluent. The content of the compound of the general formula (I) or a pharmaceutically acceptable salt thereof can be 0.01-1000 mg, for example 0.05-800 mg, 0.1-500 mg, 0.01-300 mg, 0.01-200 mg, 0.05-150 mg, 0.05-50 mg, etc.

The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually based on conventional conditions.

Example 1: 5-((2,4-dinitrophenoxy)methyl-d ₂ )-1-methyl-2-nitro-1H-imidazole (Compound 1)

Preparation of (1-methyl-2-nitro-1H-imidazol-5-yl)methane-d ₂ -ol (Intermediate 2)

1-Methyl-2-nitro-1H-imidazole-5-carboxylic acid ethyl ester intermediate 1 (1 g, 5.0 mmol) was dissolved in anhydrous THF (15 mL), and lithium aluminum deuteride (210 mg, 5.0 mmol) was slowly added under ice bath. After the addition, the mixture was reacted at 0°C for 3 hours. After the reaction was completed, water was slowly added to quench the mixture, and ethyl acetate (50 mL x 2) was used for extraction. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 2 (0.54 g, yield: 67.5%, light yellow solid).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.12 (s, 1H), 5.40 (s, 1H), 3.93 (s, 3H).

Preparation of 5-((2,4-dinitrophenoxy)methyl-d ₂ )-1-methyl-2-nitro-1H-imidazole (Compound 1) (1-methyl-2-nitro-1H-imidazole-5-yl)methane-d 2 -ol intermediate 2 (200 mg, 1.25 mmol) was dissolved in DMF (5 mL), potassium carbonate (345 mg, 2.5 mmol) and 2,4-dinitrofluorobenzene (232 mg, 1.25 mmol) were added, and the mixture was reacted at 60°C overnight. After the reaction was completed, the mixture was diluted with ethyl acetate (50 mL), washed with water (100 mL x 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain compound 1 (76 mg, yield: 18.6%, light yellow solid).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (d, J = 2.4 Hz, 1H), 8.58 (dd, J = 9.6, 2.4 Hz, 1H), 7.82 (d, J = 9.6 Hz, 1H), 7.40 (s, 1H), 3.95 (s, 3H).

MS-ESI(m/z):326.12[M+1] ⁺ .

Example 2: 5-((2,4-dinitrophenoxy)methyl-d)-1-methyl-2-nitro-1H-imidazole (Compound 2)

Preparation of (1-methyl-2-nitro-1H-imidazol-5-yl)methane-d-ol (Intermediate 3)

Dissolve 1-methyl-2-nitro-1H-imidazole-5-carboxylic acid ethyl ester intermediate 1 (1g, 5.0mmol) in anhydrous methanol (10mL), slowly add sodium borodeuteride (210mg, 5.0mmol) under ice bath, react at room temperature for 10 minutes after addition, quench with water after reaction, extract with ethyl acetate (50mL x 2), combine organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain intermediate 3 (0.67g, yield: 84.8%, light yellow solid). ^1H NMR (400MHz, DMSO- _d6 ) δ7.12 (s, 1H), 5.56 (d, J = 5.3Hz, 1H), 4.55 (d, J = 5.3Hz, 1H), 3.93 (s, 3H).

Preparation of 5-((2,4-dinitrophenoxy)methyl-d)-1-methyl-2-nitro-1H-imidazole (Compound 2)

The synthesis method was based on the preparation of compound 1, and the product was purified by preparative HPLC to obtain compound 2 (45 mg, yield: 13.2%, light yellow solid).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (d, J=2.4 Hz, 1H), 8.58 (dd, J=9.6, 2.4 Hz, 1H), 7.82 (d, J=9.6 Hz, 1H), 7.40 (s, 1H), 5.66 (s, 1H), 3.95 (s, 3H).

MS-ESI(m/z):325.08[M+1] ⁺ .

Example 3: 5-((2,4-dinitrophenoxy)methyl)-1-(methyl-d ₃ )-2-nitro-1H-imidazole (Compound 3)

Preparation of ethyl 2-nitro-1H-imidazole-5-carboxylate (Intermediate 5)

Dissolve 2-amino-1H-imidazole-5-carboxylic acid ethyl ester intermediate 4 (1.55 g, 10 mmol) in acetic acid (20 mL), add saturated sodium nitrite aqueous solution (10 mL, 100 mmol) dropwise, and stir at room temperature for 4 hours. After the reaction is completed, add water (50 mL), extract with ethyl acetate (100 mL x 2), combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain intermediate 5 (1.12 g, yield: 60.5%, brown solid). ¹ H NMR (CDCl ₃ , 400 MHz) δ7.73 (s, 1H), 4.35 (q, J＝7.1 Hz, 2H), 1.34 (t, J＝7.1 Hz, 3H)

Preparation of ethyl 1-(methyl-d ₃ )-2-nitro-1H-imidazole-5-carboxylate (Intermediate 6)

Dissolve 2-nitro-1H-imidazole-5-carboxylic acid ethyl ester intermediate 5 (1g, 5.4mmol) in DMF (10mL), add 60% sodium hydrogen hydride (259mg, 6.5mmol) in batches under ice bath, react at room temperature for 1 hour, then add deuterated iodomethane (1.17g, 8.1mmol) dropwise under ice bath, stir at room temperature overnight. After the reaction is completed, add water (50mL), extract with ethyl acetate (50mL x 3), combine the organic phases, wash with water, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify with column chromatography to obtain intermediate 6 (0.3g, yield: 27.5%, light brown solid). ¹ H NMR (CDCl ₃ , 400MHz) δ7.70 (s, 1H), 4.39 (q, J＝7.1Hz, 2H), 1.39 (t, J＝7.1Hz, 3H).

Preparation of (1-(methyl-d ₃ )-2-nitro-1H-imidazol-5-yl)methanol (Intermediate 7)

The synthesis method refers to the preparation of intermediate 2, wherein lithium aluminum tetrahydride replaces lithium aluminum deuteride, and the product is a light yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.12 (s, 1H), 5.40 (t, J=5.3 Hz, 1H), 4.55 (d, J=5.3 Hz, 2H).

5-((2,4-dinitrophenoxy)methyl)-1-(methyl-d ₃ )-2-nitro-1H-imidazole (Compound 3)

The synthesis method was based on the preparation of compound 1, and the product was purified by preparative HPLC to obtain compound 3 (71 mg, yield: 32.4%, light yellow solid).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (d, J=2.4 Hz, 1H), 8.58 (dd, J=9.6, 2.4 Hz, 1H), 7.82 (d, J=9.6 Hz, 1H), 7.40 (s, 1H), 5.66 (s, 2H).

MS-ESI(m/z):327.14[M+1] ⁺ .

Examples 4-6 were obtained by similar operations to those of Example 1 (see Table 1).

Table 1: Structure and data of Examples 4 to 6

Example 7

Pharmacokinetic study of HU6 and compounds 1-6

Materials and methods: Male C57BL/6 mice aged 5 to 7 weeks weighing 18 to 20 g were obtained from Beijing Weitong Lihua Co., Ltd. For 7 days before the study and during the study, animals were isolated in polycarbonate cages with 3 animals per cage in an environmentally monitored, well-ventilated room maintained at a temperature of (22±3°C) and a relative humidity of 40% to 80% in a laminar flow chamber. Fluorescent lighting provided approximately 12 hours of illumination per day. The litter was corn cobs and was changed once a week. An identification number was assigned to each animal. Mice had ad libitum access to irradiated sterilized dry pelleted food (Shanghai Slake Laboratory Animal Co., Ltd.) and sterile drinking water throughout the study.

Animals were randomly assigned (n=4) to groups based on body weight using a computer generated randomization program. The following doses were administered by oral gavage in saline containing 7.1% DMSO: vehicle alone (saline containing 7.1% DMSO), 100 mg/kg HU6, or Compounds 1-6.

Plasma was collected by orbital puncture into 0.5 ml heparin-coated centrifuge tubes after 0, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 20 h, and 24 h.

The samples were centrifuged at 4000 rcf for 5 minutes in a benchtop centrifuge. The clear supernatant was transferred to a fresh tube and stored at 80°C for PK analysis.

Table 2: Pharmacokinetic data of HU6 and compounds 1-6 (analyte DNP or 6-D-DNP)

Results (see Table 2): PK analysis showed that HU6 and compounds 1-6 were hydrolyzed into DNP residues, and only a small amount of HU6 and compounds 1-6 were detected in plasma. Compared with HU6, the maximum plasma concentration (Cmax) of DNP residues in animals administered with compounds 1, 2, and 5 was greatly reduced, and Tmax was delayed. At the same time, significantly higher total exposure to DNP residues was measured in animals receiving compounds 1, 2, and 5. In summary, due to the reduction in Cmax, compounds 1, 2, and 5 are safer drugs than HU6. Compounds 3, 4, and 6 showed pharmacokinetics comparable to HU6 in animals.

The structural formulas of DNP and 6-D-DNP are:

Example 8

Plasma concentrations of ALT, AST, and ALP liver enzymes after administration of HU6, compound 1, compound 2, and compound 4 to mice with induced fatty liver disease

Male C57BL/6 mice were obtained from Beijing Weitong Lihua Co., Ltd. For 7 days before the study and during the study, animals were isolated in polycarbonate cages with 3 animals per cage in an environmentally monitored, well-ventilated room maintained at a temperature of (22±3°C) and a relative humidity of 40% to 80% in a laminar flow chamber. Fluorescent lighting provided approximately 12 hours of illumination per day. In the first week, mice had free access to irradiated sterilized dry pelleted food (Shanghai Slake Laboratory Animal Co., Ltd.) and sterile drinking water.

After acclimatization, the diet was changed to a methionine/choline deficient diet (MCD) to induce non-alcoholic fatty liver disease (NAFLD) in the animals throughout the study. After four weeks of feeding with MCD, the animals were divided into four groups (n=8) and administered 0 mpk, or 100 mpk of HU6, compound 1 or compound 2 in saline containing 7.1% DMSO by oral gavage. Blood was collected in tubes without anticoagulants, and serum samples were processed by immediate centrifugation at 6000 g for 15 minutes at 4°C, and then transferred to new test tubes. Three liver enzymes in the samples were analyzed using a TOSHIBA TBA 40FR automatic biochemical analyzer: ALT, AST and ALP.

Table 3: Plasma concentrations of ALT, AST and ALP liver enzymes in mice after administration of HU6 and compounds 1, 2 and 4

Compound ALT(U/L) AST(U/L) ALP(U/L) PBS 563 459 176 Hu6 170 258 143 Compound 1 67 113 128 Compound 2 74 109 137 Compound 4 124 169 127

Results (see Table 3): ALT and AST levels were significantly increased in mice treated with MCD. These levels were significantly reduced with the addition of HU6, compound 1, and compounds 2 and 4. Compounds 1, 2, and 4 showed a greater degree of reduction.

Example 9

Oral glucose tolerance test after administration of HU6, compound 1, and compound 2 to mice with induced fatty liver disease

Mice were treated as described in Example 8. After five weeks of treatment with HU6, Compound 1, Compound 2, and Compound 4, all study animals were subjected to an oral glucose tolerance test (OGTT). Baseline (time 0) glucose levels were measured after a 16-hour fast. Blood glucose levels were measured at 30 minutes, 60 minutes, and 120 minutes after oral administration of 2 g/kg of glucose using the Accu Chek Performa System.

Table 4: Oral glucose tolerance test after administration of HU6 and compounds 1-2, 4

Compound Blood glucose 120 minutes after loading (mmol/l) PBS 5.1 Hu6 3.8 Compound 1 2.9 Compound 2 3.3 Compound 4 3.1

Results (see Table 4): In all three treatment groups, blood glucose levels were significantly lower 120 minutes after the glucose test. Among them, the blood glucose levels of the Compound 1, Compound 1, 2 and 4 treatment groups were lower.

For compounds of the general formula (I), the linking groups and substituent groups have an important influence on the pharmacokinetic properties of the compounds. Although the present invention is illustrated by the specific examples above, it should not be construed as being limited thereto; rather, the present invention encompasses the general aspects disclosed above. Various modifications and embodiments may be made without departing from the spirit and scope of the present invention.

Claims (10)

1. A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: in: R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are independently selected from H or D, and at least one of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ is D; X is NO ₂ , and Y is H; or, X is H, and Y is NO ₂ . 2 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein at least one of R ₁ , R ₂ and R ₃ is D. 3 . 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that the pharmaceutically acceptable salt is an inorganic salt or an organic salt, the inorganic salt comprising hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, and salicylate. 5. A pharmaceutical composition, characterized in that it is a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. 6. The pharmaceutical composition according to claim 5, characterized in that it contains an acceptable carrier, excipient or diluent. 7. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use as a mitochondrial uncoupling agent. 8. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating obesity and diabetes. 9. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hepatic fatty degeneration. 10. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-alcoholic fatty liver disease.