Non-alcoholic steatohepatitis treatment drugs

Abstract

To provide safe and effective treatments for non-alcoholic steatohepatitis (NASH). [Solution] A pharmaceutical agent for the treatment, prevention and / or diagnosis of NASH, comprising the following structural formula: [C6] A pharmaceutical product comprising 5-[5-methyl-2-(4-trifluoromethylphenyl)-thiazole-4-yl]-3H-[1,2,3]triazole-4-carbonitrile or a pharmaceutically acceptable salt thereof, represented by JPEG2026084701000008.jpg4078.

Description

[Technical Field]

[0001] This invention relates to a therapeutic agent for non-alcoholic steatohepatitis. [Background technology]

[0002] Non-alcoholic fatty liver disease (NAFLD) is a liver disease primarily characterized by fatty liver, excluding causes such as alcoholic liver disease, viral liver disease, and drug-induced liver injury. NAFLD is estimated to affect 25% of the adult population worldwide (Non-Patent Literature 1), and among these, progressive non-alcoholic steatohepatitis (NASH) is a serious medical and public health burden due to its high mortality rate from liver-related and cardiovascular events, progressing from hepatic metabolic failure and cirrhosis to end-stage liver disease requiring liver transplantation and even hepatocellular carcinoma (Non-Patent Literature 2).

[0003] The 2020 NAFLD / NASH Treatment Guidelines of the Japanese Society of Gastroenterology and the Japanese Society of Hepatology state that differential diagnosis of NASH from simple fatty liver disease (NAFL), which does not progress from fatty liver, is necessary when treating NASH (Non-Patent Literature 3, Non-Patent Literature 4). Pathological diagnosis by liver biopsy is considered essential for this differential diagnosis, and it has been reported that 59% of patients who undergo liver biopsy are diagnosed with NASH. The prevalence of NASH is estimated to be approximately 1.5% to 6.45% (Non-Patent Literature 1).

[0004] NASH is characterized by inflammation accompanied by hepatocyte damage due to intrahepatic fat. Representative diagnostic criteria for NASH involve scoring steatosis, lobular inflammation, and ballooning of hepatocytes in liver biopsy specimens, with the sum of these scores used to determine the NAFLD Activity Score (NAS). Furthermore, since fibrosis is almost always present in the liver of NASH patients, the liver is further classified according to the stage of fibrosis. The stage of hepatic fibrosis is strongly correlated with both overall mortality and liver-related mortality, making it crucial to assess the degree of hepatic fibrosis (Non-patent Literature 3-5).

[0005] Many NASH patients have co-occurring conditions such as type 2 diabetes, obesity, hypertension, and dyslipidemia (Non-Patent Literature 1), which increase their cardiovascular risk, and these complications are also associated with the progression of liver-related conditions (Non-Patent Literature 6).

[0006] Despite its significant impact on healthcare economics, NASH still lacks approved medications for its treatment, representing a very large unmet medical need.

[0007] On the other hand, Patent Document 1 describes the following structural formula as an example of a compound that enhances citric acid cycle activity and improves hyperglycemia: [ka] A 5-[5-methyl-2-(4-trifluoromethylphenyl)-thiazole-4-yl]-3H-[1,2,3]triazole-4-carbonitrile represented by is disclosed. Furthermore, Non-Patent Literature 7 states that the above compound (referred to as "OPC-163493" in the document) is a novel mitochondrial uncoupling agent targeting the liver, and that it showed potent antidiabetic effects in multiple diabetic animal models, regardless of whether they were type 2 or type 1 diabetes. It also lowered blood pressure in spontaneously stroke-prone hypertensive rats (SHRSP), delayed the onset of stroke, and extended lifespan. It also showed improvement in renal dysfunction, such as albuminuria, in SHRSP. Experimental results showed that these beneficial effects on blood vessels were exerted by OPC-163493 improving the bioavailability of nitric oxide in the vascular endothelium. Furthermore, OPC-163493 is known to be highly safe (Non-Patent Literature 8). [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] WO 2015 / 008872 A1 [Non-patent literature]

[0009] [Non-Patent Document 1] Younossi, ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016, 64, 73-84. [Non-Patent Document 2] Younossi, ZM, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 2016, 64, 1577-1586. [Non-Patent Document 3] Tokushige, K., et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease / nonalcoholic steatohepatitis 2020. J Gastroenterol 2021, 56, 951-963. [Non-Patent Document 4] Tokushige, K., et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease / nonalcoholic steatohepatitis 2020. Hepatol Res 2021, 51, 1013-1025. [Non-Patent Document 5] Kleiner, DE, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005, 41, 1313-1321. [Non-Patent Document 6] Pais, R., et al. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol 2013, 59, 550-6. [Non-Patent Document 7] Kanemoto, N., et al. Antidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler. Nat Commun 2019, 10, 2172. [Non-Patent Document 8] Inoue, Y., et al. Preclinical safety profile of a liver-localized mitochondrial uncoupler: OPC-163493. EXCLI J 2022, 21, 213-235

Summary of the Invention

Problems to be Solved by the Invention

[0010] An object of the present invention is to provide a safe and effective therapeutic agent for NASH.

Means for Solving the Problems

[0011] As a result of intensive studies to solve the above problems, the present inventors have found that the following structural formula:

Chemical Formula

[0012] OPC-163493 or its pharmaceutically acceptable salts in this invention exhibit hepatoprotective effects, fatty liver improvement effects, NASH pathology improvement effects, anti-fibrotic effects, and hepatomegaly inhibitory effects, even at doses lower than those that show antidiabetic effects. Through these effects, the compound can exert a more potent NASH therapeutic effect than conventional drugs. Therefore, according to this invention, a safe and effective therapeutic agent for NASH can be provided. [Brief explanation of the drawing]

[0013] [Figure 1] Figure 1 shows the concentration of alanine aminotransferase (ALT) in the blood after administration of each test compound. [Figure 2] Figure 2 shows the NAS (NAFLD activity score) after administration of each test compound. [Figure 3] Figure 3a shows fat deposition after administration of each test compound, and Figure 3b shows balloon-like swelling after administration of each test compound. [Figure 4] Figure 4 shows the area of ​​fibrosis after administration of each test compound. [Figure 5] Figure 5a shows the liver weight after administration of each test compound, and Figure 5b shows the liver weight / body weight ratio (LW / BW) after administration of each test compound. [Modes for carrying out the invention]

[0014] In this specification, "non-alcoholic steatohepatitis (NASH)" is defined as a condition characterized by fat accumulation in more than 5% of hepatocytes, accompanied by hepatocyte damage (balloon-like degeneration of hepatocytes) and inflammation. In a classification published by the NASH Clinical Research Network in 2005, a NAFLD activity score (NAS) was proposed, which uses a scoring system based on the degree of steatosis (0-3), the degree of parenchymal inflammation (0-2), and the frequency of balloon-like hepatocyte appearance (0-2). A total score of 2 or less is considered non-NASH, 3-4 points is borderline, and 5 points or more is considered NASH (Non-Patent Literature 5). In particular, NASH that can be treated, prevented, and / or diagnosed by the pharmacological effects of OPC-163493 or its pharmaceutically acceptable salts (hepatoprotective effect, fatty liver improvement effect, improvement of NASH pathology effect, anti-fibrotic effect, and hepatomegaly inhibitory effect) and which is difficult to treat with other compounds. Such NASH can be identified, for example, by confirming that a subject who has or is suspected of having NASH does not respond to administration of other NASH development compounds (e.g., obeticholic acid), but does respond to administration of OPC-163493 or its pharmaceutically acceptable salts.

[0015] In this specification, “to treat” or “to treat” means to address a disease condition in a subject (patient), including suppressing (e.g., inhibiting or delaying progression), alleviating, improving, or curing the disease condition. In this specification, “prevent” or “prevention” means substantially preventing or delaying the onset (onset or manifestation) of a disease condition, and this includes reducing the risk of onset. In this specification, "to diagnose" means to determine (judge) the disease state of a subject (patient), which includes determining whether or not the subject has a disease, determining the degree or progression of the disease state, determining the effectiveness of treatment for the disease, and determining whether or not there is a risk of the disease recurring after treatment.

[0016] In this specification, “subject” refers to a human or non-human mammal (e.g., monkey, chimpanzee, baboon, dog, cat, pig, cow, sheep, goat, mouse, rat, guinea pig, etc.).

[0017] "OPC-163493 or its pharmaceutically acceptable salts" as used herein can be synthesized, for example, by the procedure described in WO 2015 / 008872 A1.

[0018] OPC-163493 contains three tautomers in the triazole moiety. The above structural formula shows one tautomer of OPC-163493, but OPC-163493 is not limited to this and also includes the other two tautomers.

[0019] Since OPC-163493 has a basic group, it can readily form pharmaceutically acceptable salts with commonly pharmaceutically acceptable acids. Examples of such "acids" include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.) and organic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid, etc.). Furthermore, since OPC-163493 has an acidic group, it can be easily reacted with pharmaceutically acceptable basic compounds to form pharmaceutically acceptable salts. Examples of such "basic compounds" include inorganic bases (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.) and organic bases (e.g., methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, etc.) and ammonium salts. Furthermore, OPC-163493 may form salts with amino acids such as lysine, arginine, aspartic acid, and glutamic acid.

[0020] OPC-163493 and its pharmaceutically acceptable salts also include their various solvates (e.g., hydrates, ethanolates, etc.) and crystal polymorphs.

[0021] OPC-163493 and its pharmaceutically acceptable salts may be co-crystals or co-crystal salts. Here, co-crystals or co-crystal salts mean crystalline substances composed of two or more unique solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, etc.). Co-crystals and co-crystal salts can be produced by applying known co-crystallization methods.

[0022] In addition, OPC-163493 also includes isotope-labeled compounds that are identical to OPC-163493 except that one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into OPC-163493 include, respectively 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 36 Cl and other hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine isotopes. Specific isotope-labeled OPC-163493 containing the above isotopes and / or other isotopes of other atoms, such as 3 H and 14 C and other radioactive isotopes incorporated compounds are useful in drug tissue distribution assays and / or substrate tissue distribution assays. Tritiation (i.e., 3 H), and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to ease of preparation and detectability. Furthermore, deuterium (i.e., 2Substitution with heavier isotopes such as H) is expected to bring about certain therapeutic benefits, such as improved metabolic stability, increased in vivo half-life, or reduced dose requirements. The isotope-labeled compound of OPC-163493 can be prepared in the production method of OPC-163493 by substituting the non-isotope labeling reagent with a readily available isotope labeling reagent.

[0023] The following describes pharmaceutical compositions containing OPC-163493 or a pharmaceutically acceptable salt thereof (hereinafter referred to as "this compound" unless otherwise specified) as an active ingredient.

[0024] The above-mentioned pharmaceutical composition is a formulation of the compound in the form of a conventional pharmaceutical composition, and is prepared using carriers, diluents and / or excipients such as commonly used fillers, bulking agents, binders, humectants, disintegrants, surfactants, lubricants, etc. (collectively referred to herein as "pharmaceutically acceptable carriers").

[0025] Such pharmaceutical compositions can be selected from various forms depending on the therapeutic purpose, and typical examples include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions, etc.).

[0026] A wide range of known carriers can be used when forming tablets, such as excipients including lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders including water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; and dried starch, sodium alginate, agar powder, laminaran powder, and sodium bicarbonate. Examples of additives include disintegrants such as ammonium, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, and lactose; disintegration inhibitors such as sucrose, stearic acid, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as refined talc, stearate, boric acid powder, and polyethylene glycol.

[0027] Furthermore, the tablets may be coated with a conventional coating material as needed, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double-coated or multi-layered tablets.

[0028] A wide range of known carriers can be used when forming the product into pill form. Examples include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol; and disintegrants such as laminaran and agar.

[0029] A wide range of known carriers can be used when forming the suppository, such as polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

[0030] When prepared as an injectable preparation, the liquid, emulsion, and suspension preparations are preferably sterilized and isotonic with blood. A wide range of known diluents can be used when forming these liquid, emulsion, and suspension preparations, including, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbetane fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and conventional solubilizers, buffers, analgesics, and, if necessary, colorants, preservatives, fragrances, flavorings, sweeteners, and / or other pharmaceuticals may also be included.

[0031] The amount of this compound contained in the pharmaceutical composition is not particularly limited and can be appropriately selected from a wide range, but it is generally preferable to contain this compound in an amount of about 1 to 70% by weight in the pharmaceutical composition.

[0032] There are no particular restrictions on the method of administration of the above-mentioned pharmaceutical composition, and it may be administered in a manner appropriate to the various formulations and / or the age, sex, disease state, and other conditions of the subject (especially humans). For example, tablets, pills, liquids, suspensions, emulsions, granules, and capsules are administered orally. In the case of injections, they may be administered intravenously alone or mixed with conventional infusion fluids such as glucose and amino acids, or, if necessary, alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. In the case of suppositories, they are administered rectally.

[0033] The dosage of the above pharmaceutical composition may be appropriately selected according to the method of use and / or the age, sex, severity of the disease, and other conditions of the subject (especially human). Typically, it is administered at a dose of approximately 0.001 to 100 mg per kg of body weight per day, preferably 0.001 to 50 mg, in one to several divided doses.

[0034] The above dosages vary depending on various conditions; therefore, a lower dosage may be sufficient in some cases, while a dosage exceeding the above range may be necessary in others.

[0035] As shown in the examples described later, this compound has excellent hepatoprotective effects, fatty liver improvement effects, NASH pathology improvement effects, anti-fibrotic effects, and hepatomegaly inhibitory effects. Here, the "hepatoprotective effect" mentioned above includes the effect of lowering the concentration of ALT in the blood. The "effect of improving NASH pathology" mentioned above includes the effect of reducing NAS. The "fatty liver improvement effect" mentioned above includes the effect of reducing fat deposition. The "anti-fibrotic effect" mentioned above includes the effect of suppressing the expansion of the fibrotic area. The "hepatomegaly inhibitory effect" mentioned above includes the effect of reducing liver weight. Furthermore, this compound exhibits these effects at doses lower than those at which antidiabetic effects are observed. Through these effects, this compound may exert a more potent NASH therapeutic effect than conventional drugs. For example, the dose of this compound (OPC) required to produce an effect equivalent to that achieved with a given dose of obeticholic acid (OCA), which has been proven to improve NASH, is significantly smaller than the dose of OCA. Furthermore, this compound is also excellent in terms of safety (Non-Patent Document 7). Therefore, this compound can be applied to safe and effective therapeutic drugs for NASH, among other applications.

[0036] Therefore, as one embodiment, the present invention provides a pharmaceutical agent for the treatment, prevention and / or diagnosis of NASH, comprising the compound as an active ingredient.

[0037] The present invention also provides, in one embodiment, a hepatoprotective agent containing the compound as an active ingredient.

[0038] The present invention also provides, in one embodiment, a fatty liver treatment agent containing the compound as an active ingredient.

[0039] In one embodiment, the present invention also provides an agent for improving the condition of NASH, which contains the compound as an active ingredient.

[0040] The present invention also provides, in one embodiment, an anti-fibrotic agent comprising the compound as an active ingredient.

[0041] The present invention also provides, in one embodiment, a hepatomegaly inhibitor containing the compound as an active ingredient.

[0042] Furthermore, as one embodiment of the present invention, the present invention provides a pharmaceutical composition for the treatment, prevention, and / or diagnosis of NASH, comprising the compound as an active ingredient and a pharmaceutically acceptable carrier or excipient.

[0043] The present invention also provides, in one embodiment, the compound for use in the treatment, prevention and / or diagnosis of NASH.

[0044] The present invention also provides, in one embodiment, the use of the compound in the manufacture of a pharmaceutical or pharmaceutical composition for the treatment, prevention and / or diagnosis of NASH.

[0045] The present invention also provides, in one embodiment, a method for treating, preventing and / or diagnosing NASH, comprising administering an effective amount of the compound to a subject.

[0046] All patent and non-patent document disclosures cited herein are incorporated herein by reference as a whole. [Examples]

[0047] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0048] Example 1 (Test compound) The compound OPC-163493 (OPC) was synthesized according to the procedure described in WO 2015 / 008872 A1. The control compound, obeticholic acid (6-ethylchenodeoxycholic acid, OCA), was purchased from Fujifilm Wako Pure Chemical Industries, Ltd. Each test compound was prepared in a 5% gum arabic solution to a concentration of 10 mL / kg according to the respective dosage.

[0049] (STAM mouse, a NASH model animal) The STAM model mouse used to evaluate the test compound is an animal model that exhibits disease progression similar to human NASH, with a background of late type 2 diabetes, and the disease progresses from fatty liver, NASH, fibrosis, cirrhosis, and liver cancer. It has the following characteristics: (i) balloon-like degenerated cells, which are characteristic pathological findings of human NASH; (ii) burned-out NASH phenomenon, in which lipid droplets decrease as fibrosis progresses; (iii) fibrosis progresses from around the central vein; and (iv) a slight elevation of ALT, a liver damage marker. The efficacy of the test substance can be evaluated using NAS and the degree of fibrosis, which are clinical evaluation items for NASH (Fujii, M., et al. A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma. Med Mol Morphol 2013, 46, 141-52.). The number of drug efficacy evaluation tests using STAM mice has exceeded 600, and the results have been published in papers and at academic conferences. Of the test substances evaluated by SMC Laboratories, Inc., more than 15 have progressed to the clinical stage (as of May 2021, SMC Laboratories website: https: / / www.smccro-lab.com / jp / cell / ).

[0050] (Test method) Two-day-old C57BL / 6J male mice were subcutaneously administered 200 μg / body of streptozotocin. At four weeks of age, their diet was changed from a normal diet to a high-fat diet (57% fat, HFD32; CLEA Nippon Co., Ltd.) to create NASH-inducing STAM mice. At six weeks of age, the mice were divided into groups based on body weight. The groups consisted of six groups: 8 normal mice (not administered streptozotocin), 8 NASH-inducing STAM mice given a vehicle (5% gum arabic solution), 8 STAM mice given low-dose OPC (OPC-L; 0.6 mg / kg·day), 8 STAM mice given medium-dose OPC (OPC-M; 2 mg / kg·day), 8 STAM mice given high-dose OPC (OPC-H; 6 mg / kg·day), and 8 STAM mice given OCA (20 mg / kg·day). The test compounds were administered orally twice daily for 21 days, from 6 weeks to 9 weeks of age. The doses per dose were 0.3 mg / kg for low-dose OPC, 1 mg / kg for medium-dose OPC, 3 mg / kg for high-dose OPC, and 10 mg / kg for OCA. During the administration period, body weight was measured before the first dose each day and this was reflected in the daily dose. No dropouts were observed during the health monitoring period, and necropsy was performed on all subjects the day after the final dose. Necropsy was performed by collecting blood by cardiac puncture under isoflurane anesthesia, followed by exsanguination. The collected whole blood was transferred to a heparin (Novoheparin; Mochida Pharmaceutical Co., Ltd.) treated polypropylene tube, centrifuged at 4°C at 1000g for 15 minutes, and plasma was obtained. The plasma was stored at -80°C until ALT measurement. After exsanguination, the liver was collected, washed with chilled saline, and weighed. Two pieces of liver tissue were excised from the left lateral lobe for pathological specimen preparation. Plasma ALT was measured using FUJI DRI-CHEM 7000 (Fujifilm). The excised liver tissue was fixed in Bouin's solution for 24 hours, then embedded in paraffin to form blocks, from which section slides were prepared. Slides stained with HE (Lilly-Meyer hematoxylin; Mutoh Chemical Co., Ltd., Eosin; Fujifilm Wako Pure Chemical Corporation) and Sirius Red (Picrosirius Red; Fujifilm Wako Pure Chemical Corporation) were blinded, and HE-stained slides were used for NAS determination, while Sirius Red-stained slides were used for fibrosis area measurement. NAS (Nonalcoholic Fat Saturation Score) was determined by evaluating and scoring three parameters—fat deposition, intralobular inflammation, and ballooning hepatocytes—according to Kleiner's criteria (Kleiner, DE, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005, 41, 1313-21.), and the NAS was calculated as the sum of these scores. Fibrosis area was measured by capturing bright-field images of Sirius Red stained sections at 200x magnification using a digital camera (DFC295; Leica), and quantifying the positive area in 5 fields per section using ImageJ software (National Institutes of Health).

[0051] (result) As shown in Figure 1, the STAM mouse group administered with Vehicle showed a significant increase in ALT compared to normal mice, while the OPC-administered group showed a significant decrease in ALT (hepatoprotective effect). As shown in Figure 2, the STAM mouse group administered with Vehicle showed a 4.8 increase in NAS compared to normal mice, but the OPC-administered group showed a decrease in NAS at a low dose comparable to that of the OCA-administered group (improvement of NASH pathology). As shown in Figure 3a, in the OPC administration group, fat deposition was significantly suppressed to the same extent as in the OCA administration group, even at low doses (fatty liver improvement effect). Furthermore, as shown in Figure 3b, a tendency toward a decrease in balloon-like swelling was observed in the OPC administration group, similar to the OCA administration group. As shown in Figure 4, the STAM mouse group administered with Vehicle showed a 0.84% ​​increase in fibrotic area compared to normal mice, but the OPC-administered group showed a significant inhibitory effect on fibrosis, similar to that of the OCA-administered group, even at low doses (anti-fibrotic effect). Furthermore, as shown in Figures 5a and 5b, while the STAM mouse group administered Vehicle showed significant liver enlargement compared to normal mice, the OPC-administered group showed a significant decrease in liver weight to a similar degree as the OCA-administered group (inhibitory effect on liver enlargement).

[0052] Based on the results above, OPC demonstrated an effect equivalent to that of OCA 20 mg / kg·day, which has been shown to improve NASH in a human clinical trial (Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment (REGENERATE), ClinicalTrials.gov:NCT02548351), at a dose of 0.6 mg / kg·day (minimum effective dose, MED) (OCA / OPC dose ratio: 33 times). This result demonstrates the potent therapeutic effect of OPC on NASH, and its therapeutic effect in human clinical trials can be expected. Furthermore, based on the above results and the fact that the MED for OPC in the diabetes model shown in Non-Patent Literature 6 was 2 mg / kg·day, it was concluded that OPC is also superior as a NASH treatment drug from a pharmacodynamic standpoint (the diabetes MED / NASH MED dose ratio was 3.3 times).

[0053] Therefore, the present invention makes it possible to provide OPC-163493 as a safe and effective treatment for NASH, a disease for which treatment satisfaction is still low, there are no effective treatments, and it is a significant medical and public health burden.

Claims

1. A medical device for the treatment, prevention, and / or diagnosis of non-alcoholic steatohepatitis (NASH), with the following structural formula: 【Chemistry 1】 A pharmaceutical product comprising 5-[5-methyl-2-(4-trifluoromethylphenyl)-thiazole-4-yl]-3H-[1,2,3]triazole-4-carbonitrile or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition for the treatment, prevention, and / or diagnosis of non-alcoholic steatohepatitis (NASH), comprising the following structural formula: 【Chemistry 2】 A pharmaceutical composition comprising 5-[5-methyl-2-(4-trifluoromethylphenyl)-thiazole-4-yl]-3H-[1,2,3]triazole-4-carbonitrile or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

3. The following structural formula is used for the treatment, prevention and / or diagnosis of non-alcoholic steatohepatitis (NASH): 【Transformation 3】 5-[5-methyl-2-(4-trifluoromethylphenyl)-thiazole-4-yl]-3H-[1,2,3]triazole-4-carbonitrile or a pharmaceutically acceptable salt thereof, represented as .

4. In the manufacture of pharmaceuticals or pharmaceutical compositions for the treatment, prevention, and / or diagnosis of non-alcoholic steatohepatitis (NASH), the following structural formula: 【Chemistry 4】 Use of 5-[5-methyl-2-(4-trifluoromethylphenyl)-thiazole-4-yl]-3H-[1,2,3]triazole-4-carbonitrile or a pharmaceutically acceptable salt thereof.

5. A method for treating, preventing and / or diagnosing non-alcoholic steatohepatitis (NASH) in a subject, wherein an effective amount of the following structural formula is: 【Transformation 5】 A method comprising administering to a subject 5-[5-methyl-2-(4-trifluoromethylphenyl)-thiazole-4-yl]-3H-[1,2,3]triazole-4-carbonitrile or a pharmaceutically acceptable salt thereof.

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