Pharmaceutical composition

Abstract

This pharmaceutical composition contains a compound represented by formula (1) or a pharmaceutically-acceptable salt thereof, said compound or salt being used so as to be orally administered to a human in an amount of 50-1200 mg per day in terms of a free form of the compound.

Description

Pharmaceutical composition

[0001] The present disclosure relates to a pharmaceutical composition.

[0002] Non-alcoholic fatty liver disease (NAFLD), which is one of the fatty liver diseases, is a liver disease caused by the accumulation of excessive lipids in the liver due to metabolic syndrome such as obesity, diabetes, dyslipidemia, hypertension, etc. In a specific population of NAFLD, it progresses to non-alcoholic steatohepatitis (NASH), and liver fibrosis is formed by inflammation, hepatocyte death, etc. Subsequently, it may cause liver cirrhosis and ultimately lead to liver cancer and cardiovascular diseases (Non-Patent Document 1).

[0003] As a therapeutic agent for NAFLD and NASH, Patent Document 1 discloses a compound represented by the following formula (1): or a pharmaceutically acceptable salt thereof. Further, Patent Document 2 discloses that the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof has a hypoglycemic effect on rats.

[0004] Recently, a change in the name of fatty liver disease has been announced. Specifically, fatty liver disease is collectively referred to as "steatotic liver disease" (SLD), and conventional NAFLD and NASH are referred to as "metabolic dysfunction associated steatotic liver disease" (MASLD / metabolic dysfunction-related fatty liver disease) and "metabolic dysfunction associated steatohepatitis" (MASH / metabolic dysfunction-related steatohepatitis), respectively.

[0005] International Publication No. 2022 / 039178 International Publication No. 2013 / 187533

[0006] Hepatology. 2018 Jan;67(1):328-357 Journal of the Pet Nutrition Society, 2013 16(1):18-24

[0007] When determining the dosage of an active ingredient contained in a pharmaceutical product to be administered to humans, the dosage (mg / m ２ ) per body surface area (m ２Human Equivalent Dose (HED), which is calculated so that the body surface area (BMO) remains constant between test animals and humans, is often used as a reference. Conversion based on body surface area is widely used because the correlation between physiological parameters such as blood flow and cell number and body surface area is better than the correlation between those parameters and body weight across animal species. However, since there have been reports that the correlation between the surface area of ​​the digestive tract and body surface area is poor across animal species (Non-Patent Literature 2), it was unclear whether conversion based on body surface area could be applied when determining the dosage of pharmaceuticals that act in the lumen of the digestive tract, such as the compound represented by formula (1) described in Patent Literature 1 or its pharmaceutically acceptable salt. Furthermore, since the compound represented by formula (1) or its pharmaceutically acceptable salt is a digestive enzyme inhibitor, it was considered difficult to predict its effects across animal species.

[0008] This disclosure relates to dosages of compounds represented by formula (1) above or pharmaceutically acceptable salts thereof that exhibit superior efficacy and safety.

[0009] In view of the above problems, the present inventors have diligently devised a method different from the conventional conversion method based on body surface area, and have found that safety and efficacy can be achieved by orally administering the compound represented by formula (1) or a pharmaceutically acceptable salt thereof to humans at an amount of 50 to 1200 mg per day, converted to the free form of the compound.

[0010] This disclosure includes the following embodiments: [1] Formula (1): [1] A pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable salt thereof, wherein the compound or the salt is used to be orally administered to a human being in an amount of 50 to 1200 mg per day, converted to the free form of the compound. [2] The pharmaceutical composition according to [1], wherein the compound or the salt is used to be orally administered to a human being in an amount of 150 to 600 mg per day, converted to the free form of the compound. [3] The pharmaceutical composition according to [1] or [2], wherein the pharmaceutically acceptable salt is a hydrochloride salt. [4] The pharmaceutical composition according to any one of [1] to [3] for use in the treatment of MASH or MASLD. [5] The pharmaceutical composition according to any one of [1] to [3] for use in the treatment of obesity. [6] The pharmaceutical composition according to any one of [1] to [3] for use in promoting the secretion of glucagon-like peptide-1. [7] The pharmaceutical composition according to any one of [1] to [3] for use in inhibiting the breakdown of ingested proteins in the gastrointestinal tract. [8] A pharmaceutical composition according to any one of [1] to [3] for use in promoting the secretion of fibroblast growth factor 21.

[0011] [A1] A method comprising orally administering to a human patient in need of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, in an amount of 50 to 1200 mg per day, converted to the free form of the compound. [A2] The method according to [A1], wherein the compound or the salt is orally administered in an amount of 150 to 600 mg per day, converted to the free form of the compound. [A3] The method according to [A1] or [A2], wherein the pharmaceutically acceptable salt is a hydrochloride salt. [A4] The method according to any one of [A1] to [A3] for treating MASH or MASLD. [A5] The method according to any one of [A1] to [A3] for treating obesity. [A6] The method according to any one of [A1] to [A3] for promoting the secretion of glucagon-like peptide-1. [A7] The method according to any one of [A1] to [A3] for inhibiting the breakdown of ingested proteins in the gastrointestinal tract. [A8] The method according to any one of [A1] to [A3] for promoting the secretion of fibroblast growth factor 21.

[0012] [B1] The compound represented by formula (1) or a pharmaceutically acceptable salt thereof, administered orally to a human in an amount of 50 to 1200 mg per day, converted to the free form of the compound represented by formula (1). [B2] The compound described in [B1] or a pharmaceutically acceptable salt thereof, administered orally to a human in an amount of 150 to 600 mg per day, converted to the free form of the compound represented by formula (1). [B3] The compound described in [B1] or [B2] or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride salt. [B4] The compound described in any of [B1] to [B3] or a pharmaceutically acceptable salt thereof, for use in the treatment of MASH or MASLD. [B5] The compound described in any of [B1] to [B3] or a pharmaceutically acceptable salt thereof, for use in the treatment of obesity. [B6] The compound described in any of [B1] to [B3] or a pharmaceutically acceptable salt thereof, for use in promoting the secretion of glucagon-like peptide-1. [B7] A compound described in any of [B1] to [B3] or a pharmaceutically acceptable salt thereof, for use in inhibiting the breakdown of ingested proteins in the gastrointestinal tract. [B8] A compound described in any of [B1] to [B3] or a pharmaceutically acceptable salt thereof, for use in promoting the secretion of fibroblast growth factor 21.

[0013] [C1] The use of a compound represented by formula (1) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition, wherein the pharmaceutical composition is used so that the compound or the salt is administered orally to a human being in an amount of 50 to 1200 mg per day, converted to the free form of the compound. [C2] The use according to [C1], wherein the pharmaceutical composition is used so that the compound or the salt is administered orally to a human being in an amount of 150 to 600 mg per day, converted to the free form of the compound. [C3] The use according to [C1] or [C2], wherein the pharmaceutically acceptable salt is a hydrochloride salt. [C4] The use according to any one of [C1] to [C3], wherein the pharmaceutical composition is used for the treatment of MASH or MASLD. [C5] The use according to any one of [C1] to [C3], wherein the pharmaceutical composition is used for the treatment of obesity. [C6] The use according to any one of [C1] to [C3], wherein the pharmaceutical composition is used to promote the secretion of glucagon-like peptide-1. [C7] The use according to any one of [C1] to [C3], wherein the pharmaceutical composition is used to inhibit the breakdown of ingested proteins in the gastrointestinal tract. [C8] The use according to any one of [C1] to [C3], wherein the pharmaceutical composition is used to promote the secretion of fibroblast growth factor 21.

[0014] It is possible to provide a dosage of the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof that exhibits excellent efficacy and safety.

[0015] This shows the plasma FGF-21 concentration in normal mice. This shows the plasma FGF-21 concentration in MASH-pathological mice. This shows the plasma FGF-21 concentration in obese and diabetic monkeys. This shows the plasma hydroxyproline concentration in humans. This shows the total plasma GLP-1 concentration in humans (single dose). This shows the total plasma GLP-1 concentration in humans (repeated dose).

[0016] The embodiments of this disclosure will be described in detail below, but this disclosure is not limited to these embodiments, and various modifications are possible without departing from its essence.

[0017] <Definition> In this specification, "includes" means that in addition to the elements explicitly stated to be included, other elements may also be included.

[0018] <Pharmaceutical Composition> One embodiment of the present disclosure relates to a pharmaceutical composition comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound or the salt is used to be orally administered to a human being in an amount of 50 to 1200 mg per day, calculated in terms of the free form of the compound.

[0019] [Active ingredient] The pharmaceutical composition according to this embodiment contains, as an active ingredient, a compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof.

[0020] The pharmaceutically acceptable salts of the active ingredient in this embodiment are not particularly limited as long as they are usable as pharmaceuticals, but examples include inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, and phosphate, and organic salts such as fumarate, maleate, malate, tartrate, citrate, succinate, methanesulfonate, p-toluenesulfonate, lactate, acetate, and palmitate. The pharmaceutically acceptable salt is preferably a hydrochloride salt.

[0021] The active ingredient in this embodiment may form a solvate, such as a hydrate. In this specification, a solvate is defined as a compound represented by the above formula or a pharmaceutically acceptable salt thereof.

[0022] If stereoisomers (e.g., enantiomers, diastereomers) exist for the active ingredient in this embodiment, the individual stereoisomers and mixtures thereof (e.g., racemates) shall be included in the compound represented by the above formula or a pharmaceutically acceptable salt thereof.

[0023] The active ingredients in this embodiment can be synthesized by referring to known methods (for example, the methods described in International Publication No. 2011 / 071048, International Publication No. 2015 / 137407, or International Publication No. 2015 / 137408).

[0024] [Other Components] The pharmaceutical composition according to this embodiment may further contain other components, to the extent that they do not impair the technical effects of the disclosure. Other components vary depending on the dosage form, etc., but examples include acidic substances, excipients, lubricants, binders, disintegrants, fluidizers (e.g., silicon dioxide), surfactants, suspending agents, emulsifiers, preservatives, colorants, fragrances, sweeteners, flavoring agents, and viscosity modifiers. One or more known components can be used as the above other components as appropriate.

[0025] [Dosage Forms] The pharmaceutical compositions according to this embodiment can be administered orally or parenterally. Examples of available dosage forms are given below, but the available dosage forms in this disclosure are not limited to these. Examples of oral dosage forms include tablets, pills, granules, powders, capsules, syrups, emulsions, lozenges, oral solutions, and suspensions. Examples of parenteral dosage forms include injections, infusions, drips, eye drops, enemas, nasal drops, ear drops, ointments, gels, lotions, patches (including tapes or poultices), topical solutions, and suppositories. Oral administration is preferred, preferably in the form of tablets, pills, granules, powders, or capsules, and more preferably tablets.

[0026] [Applications] The pharmaceutical composition according to this embodiment can inhibit specific digestive enzymes in the lumen of the digestive tract. As a result, the pharmaceutical composition according to this embodiment can treat various conditions (e.g., diseases) that involve the amount and residence time of nutrients digestible by the digestive enzymes in the digestive tract. Furthermore, the pharmaceutical composition according to this embodiment can treat various conditions (e.g., diseases) that involve various hormones whose secretion levels may be affected by the digestive enzymes.

[0027] Examples of such nutrients include proteins. Therefore, the specific digestive enzymes mentioned above include one or more known proteolytic enzymes, more specifically, at least one of trypsin or enteropeptidase, and preferably trypsin and enteropeptidase.

[0028] The pharmaceutical composition according to this embodiment can be used, for example, to treat fatty liver disease by inhibiting the specific digestive enzymes described above by the compound represented by formula (1) or a pharmaceutically acceptable salt thereof. Here, "treatment" of fatty liver disease includes preventing the onset of fatty liver disease, suppressing the progression of fatty liver disease, alleviating the symptoms of fatty liver disease, and curing fatty liver disease.

[0029] Specific examples of fatty liver disease include metabolic dysfunction-associated steatohepatitis (MASH) and metabolic dysfunction-associated fatty liver disease (MASLD). MASH may also be expressed as non-alcoholic steatohepatitis (NASH). MASLD may also be expressed as non-alcoholic fatty liver disease (NAFLD).

[0030] Furthermore, the pharmaceutical composition according to this embodiment can be used to treat obesity. Here, "treatment" of obesity includes suppressing weight gain, reducing weight, and so on.

[0031] The pharmaceutical composition according to this embodiment can be used to promote the secretion of glucagon-like peptide-1 (GLP-1).

[0032] Glucagon-like peptide-1 is known to be a hormone secreted from L cells in the small intestine that promotes insulin secretion from pancreatic β cells. By promoting the secretion of glucagon-like peptide-1, the pharmaceutical composition according to this embodiment can be used to treat fatty liver disease and obesity.

[0033] The pharmaceutical composition according to this embodiment can be used to inhibit the breakdown of ingested proteins in the gastrointestinal tract. By inhibiting protein breakdown in the gastrointestinal tract, the pharmaceutical composition according to this embodiment suppresses the digestion and absorption of proteins, and it is thought that the retention of undigested proteins (including partially digested peptides, etc.) in the gastrointestinal tract affects the secretion behavior of gastrointestinal hormones, thereby exhibiting effects such as appetite suppression. As a result, the pharmaceutical composition according to this embodiment can be used in the treatment of fatty liver disease and obesity.

[0034] The pharmaceutical composition according to this embodiment can be used to promote the secretion of fibroblast growth factor 21 (FGF-21). Fibroblast growth factor 21 is known to be involved in the regulation of glucose metabolism and to suppress blood glucose elevation independently of insulin by promoting glucose uptake in adipocytes. By promoting the secretion of fibroblast growth factor 21, the pharmaceutical composition according to this embodiment can be used to treat fatty liver disease and obesity.

[0035] [Dosage Setting by Gelatin Loading] When setting dosages for human administration, it has been common practice to refer to dosages for non-human animal species, such as body weight conversion or body surface area conversion. While these methods are considered applicable to drugs that are absorbed relatively well from the gastrointestinal tract and distributed throughout the body, it is not necessarily clear whether they are applicable to drugs that are not absorbed well in the gastrointestinal tract and act within the lumen. Furthermore, in cases of dosage setting using body weight conversion or body surface area conversion, it is difficult to extrapolate the pharmacological effects expressed in diseased animals from the pharmacological effects expressed in normal animals, and it is also difficult to extrapolate the pharmacological effects expressed by long-term administration in certain animal species from the pharmacological effects expressed by short-term administration in different animal species. On the other hand, if a drug targets a specific digestive enzyme, it is thought to have almost the same effect regardless of the animal species. In addition, the inhibitory effect on digestive enzymes is a primary reaction, and there is no need to consider the accumulation of the drug, so it is thought that there is no difference between short-term and long-term administration. Based on the above considerations, finding a correlation between the inhibitory effect on digestive enzymes and indicators of drug efficacy may be useful in determining dosages across different animal species.

[0036] The compound represented by formula (1) above, or a pharmaceutically acceptable salt thereof, inhibits specific digestive enzymes in the lumen of the digestive tract. Therefore, the dose of the pharmaceutical composition according to this embodiment for humans can be determined based on the degree of said inhibitory effect. That is, when determining the dose of the pharmaceutical composition according to this embodiment for humans, it can be determined, for example, based on the degree of said inhibitory effect in humans, or it can be determined based on the degree of said inhibitory effect in animal species other than humans. Examples of animal species other than humans include, but are not limited to, monkeys, rabbits, guinea pigs, cattle, pigs, sheep, horses, dogs, rats, or mice.

[0037] To evaluate the degree of the above inhibitory effect, plasma hydroxyproline concentration can be used. For example, when gelatin, a type of protein, is administered, the hydroxyproline produced by its breakdown is absorbed into the bloodstream from the small intestine. The absorbed hydroxyproline can be used as the plasma hydroxyproline concentration, and the degree of its increase or decrease can be used as an indicator. Gelatin is a protein that makes up collagen protein, which has a characteristic amino acid sequence of glycine (Gly)-proline (Pro)-hydroxyproline (Hyp) at a high frequency. This characteristic amino acid sequence has little difference in sequence homology between animal species and is highly conserved, so the amount of hydroxyproline produced by hydrolyzing gelatin can be used as an indicator that reflects the degree of inhibition of the enzyme.

[0038] In this case, for example, the absolute amount of hydroxyproline in plasma may be compared, or the amount of plasma hydroxyproline under arbitrary conditions may be compared relatively to the amount of plasma hydroxyproline under certain conditions. More specifically, when evaluating the degree of the inhibitory effect of any compound, the area under the plasma concentration-time curve (AUC) calculated from the plasma concentration profile of hydroxyproline when the compound is not administered is set to 100%, and the change in the area under the plasma concentration-time curve when the compound is administered is expressed as a percentage and can be used as the hydroxyproline elevation suppression rate (%). The formula for calculation is as follows: Hydroxyproline elevation suppression rate (%) = 100 - [(AUC under compound administration conditions / AUC under non-compound administration conditions) × 100]

[0039] The hydroxyproline elevation suppression rate (%) can be set as a threshold value of any value, as long as it produces the desired effect depending on the application of the compound. Examples of values ​​that are not particularly limited include 15% or more, 30% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, or 80% or more. For example, when the hydroxyproline elevation suppression rate (%) is used to evaluate the pharmaceutical composition according to this embodiment, the threshold can be set individually and specifically depending on whether it is used for the treatment of fatty liver disease and / or for the treatment of obesity. In this case, for example, the threshold may be 40% or more, or 40% or more, 45% or more, 50% or more, 55% or more, or 60% or more.

[0040] When the pharmaceutical composition according to this embodiment is used to treat at least one of the conditions (e.g., diseases) described in the [Uses] section above, if the rate of suppression of plasma hydroxyproline elevation is above an arbitrary threshold, at least one of the following changes will be observed: improvement of liver fibrosis, weight loss, decrease in hemoglobin A1c (HbA1c), increased secretion of fibroblast growth factor 21 (FGF-21), or increased secretion of glucagon-like peptide-1 (GLP-1). Therefore, by administering the pharmaceutical composition according to this embodiment at a dose that shows a rate of suppression of plasma hydroxyproline elevation above an arbitrary threshold, it can be applied to at least one of the conditions (e.g., diseases) described in the [Uses] section above.

[0041] Further, if the plasma hydroxyproline elevation inhibitory rate in a single administration of the pharmaceutical composition according to the present embodiment is equal to or higher than an arbitrary threshold value, it is presumed that the plasma hydroxyproline elevation inhibitory rate will reach the arbitrary threshold value even when the composition is administered continuously or discontinuously multiple times. Therefore, by using the plasma hydroxyproline elevation inhibitory rate as an index, it is possible to estimate the transition of an index that changes secondarily due to long-term administration based on an index that changes due to a single administration.

[0042] Further, as will be described in detail in the examples below, the pharmaceutical composition according to the present embodiment can be used for the treatment of either fatty liver disease and / or obesity when administered at a dose showing a plasma hydroxyproline elevation inhibitory rate of at least 40% or more. Therefore, according to one embodiment, it is preferable to set the administration dose of the pharmaceutical composition described in the present disclosure to a dose at which the plasma hydroxyproline elevation inhibitory rate is 40% or more, more preferably 45% or more, and even more preferably 50% or more.

[0043] [Daily Dose in Humans] The pharmaceutical composition according to the present embodiment is used such that the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof is orally administered to humans in an amount of 50 to 1200 mg, 50 to 800 mg, 100 to 600 mg, 150 to 600 mg, or 200 to 600 mg per day, preferably 150 to 600 mg, and particularly preferably 200 to 600 mg, in terms of the free form of the compound. By adopting such a dosage regimen, both safety and efficacy can be achieved. Here, the "free form" means a state in which the compound does not form a salt.

[0044] [Number of administrations per day] For the pharmaceutical composition according to the present embodiment, as the number of administrations per day, the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof can be administered to humans once, twice, three times, four times, or five times a day. Among these, it is preferable to administer once, twice, three times, or four times a day, and more preferably once, twice, or three times a day.

[0045] Also, when administering multiple times a day, the dose per administration is preferably the amount obtained by dividing the dose per day by the number of administrations per day.

[0046] Among these, for the pharmaceutical composition according to the present embodiment, the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof is preferably administered once, twice, or three times a day in an amount of 50 mg or more per administration, more preferably once, twice, or three times a day in an amount of 50 to 1200 mg per administration, even more preferably once, twice, or three times a day in an amount of 50 to 800 mg per administration, even more preferably once, twice, or three times a day in an amount of 100 to 800 mg per administration, particularly preferably once, twice, or three times a day in an amount of 100 to 600 mg per administration, even more preferably once, twice, or three times a day in an amount of 150 to 600 mg per administration, and most preferably once, twice, or three times a day in an amount of 200 to 600 mg per administration.

[0047] Furthermore, it is preferable to administer 50 mg or more per dose once, twice, or three times a day; more preferably 50 to 1200 mg per dose once, twice, or three times a day; even more preferably 50 to 800 mg per dose once, twice, or three times a day; even more preferably 100 to 800 mg per dose once, twice, or three times a day; particularly preferably 100 to 600 mg per dose once, twice, or three times a day; even more preferably 150 to 600 mg per dose once, twice, or three times a day; and most preferably 200 to 600 mg per dose once, twice, or three times a day.

[0048] [Timing of Administration] The pharmaceutical composition according to this embodiment allows the compound represented by formula (1) above or a pharmaceutically acceptable salt thereof to be administered to a human at any time. Any time can be before a meal, immediately before a meal, during a meal, immediately after a meal, after a meal, or between meals. Here, "before a meal" refers to any time approximately 30 minutes before a meal, "immediately before a meal" refers to any time less than approximately 30 minutes before a meal, "immediately after a meal" refers to any time less than approximately 30 minutes after a meal, "after a meal" refers to any time approximately 30 minutes after a meal, and "between meals" refers to any time between meals, other than the other administration timings mentioned above.

[0049] For example, when administering the compound represented by formula (1) above or a pharmaceutically acceptable salt thereof after meals, if administered 1 to 3 times a day, it should be after breakfast, lunch, and / or dinner. If administered 1 or 2 times a day, it should be after breakfast and / or dinner.

[0050] [Administration Period] There are no particular limitations on the administration period of the pharmaceutical composition according to this embodiment. For example, it can be administered until the symptoms described in the above [Uses] of a human are improved or cured. The compound represented by formula (1) or a pharmaceutically acceptable salt thereof is preferably administered continuously for two days or more, more preferably for seven days or more, and even more preferably for ten days or more. Among these, it is preferable to administer the compound represented by formula (1) or a pharmaceutically acceptable salt thereof for at least four weeks, and more preferably for at least eight weeks.

[0051] The present disclosure will be described in more detail below using examples and comparative examples, but the technical scope of the present disclosure is not limited thereto. Hereinafter, a formulation containing the hydrochloride salt of the compound represented by formula (1) above (hereinafter referred to as "compound (1)") will be referred to as the test formulation.

[0052] [Reference Example 1] (Gelatin Loading Test) The test formulation was orally administered to normal animals, and gelatin (Sigma-Aldrich Japan) was orally administered 30 minutes later. Blood was collected under anesthesia before and at time points after gelatin administration. The collected blood was stored on ice, centrifuged, and then frozen as plasma samples. The plasma hydroxyproline (Hyp) concentration of the obtained samples was measured by LC / MS / MS. The test results are shown in Table 1. Note that the AUC for monkeys, dogs, and rats was calculated from the concentration 0 to 8 hours after administration of the test formulation, and the AUC for mice was calculated from the concentration 0 to 4 hours after administration of the test formulation.

[0053] The following describes the test methods used to obtain the data set for the examples. Note that the test methods described below are examples only and are not limited thereto. Any other test methods that a person skilled in the art can employ may be used as appropriate to obtain the necessary data set.

[0054] (Test Method 1) Male C57BL / 6JRj mice were fed either Gubra Amylin NASH diet (GAN diet) or a normal diet for 38 weeks prior to the start of treatment. C57BL / 6JRj mice underwent liver biopsy for histological confirmation of liver pathology (steatosis score > 2 and fibrosis stage > 1). C57BL / 6JRj mice fed the GAN diet (GAN-fed mice) were randomly assigned according to quantitative liver fibrosis staining. Next, the assigned GAN-fed mice were treated with Vehicle (0.5 w / v% methylcellulose 400 solution, administered orally once daily), the high-QD group of the compound represented by formula (1) (30 mg / kg, administered orally once daily), the low-BID group of the compound represented by formula (1) (15 mg / kg, administered orally twice daily), and the high-BID group of the compound represented by formula (1) (30 mg / kg, administered orally twice daily). In addition, C57BL / 6JRj mice fed a normal diet were treated with Vehicle (0.5 w / v% methylcellulose 400 solution, administered orally once daily). Comparisons before and after administration were performed using liver biopsy, histopathological NAFLD activity score, and fibrotic stage. The final quantitative endpoints included metabolic parameters, plasma / liver biochemistry, and liver histological morphological measurements.

[0055] (Test Method 2) Six-week-old C57BL / 6J Jms Slc male mice were given a Standard Diet (SD) or FFD for 20 weeks. After confirming weight gain, elevated Alanine Aminotransferase (ALT) levels, and insulin resistance, the mice were divided into groups based on three parameters: weight, ALT level, and fasting blood glucose level. Vehicle (0.5 w / v% methylcellulose 400 solution) and the compound shown in formula (1) (10 mg / kg once daily, 30 mg / kg once daily, 30 mg / kg twice daily) were administered orally for 18 weeks. ALT was measured by tail vein blood sampling at weeks 2, 4, 6, 8, 12, and 18 of administration. Saturated and fasting blood glucose levels were measured at week 15 of administration. Blood insulin was also measured from fasting plasma. Autopsy was performed at 18 weeks after administration, and body weight, liver weight, hematological tests, blood biochemical tests, liver triglyceride (TG) and total cholesterol (TCHO) levels were measured, liver hydroxyproline levels were measured, and the percentage of Sirius Red-positive area and hepatic crown-like structure (hCLS) were measured from liver pathological specimens.

[0056] (Test Method 3) Twelve-week-old Zucker fatty (ZF) rats were repeatedly administered the compound shown in formula (1) once daily for 14 days at doses of 3, 10, and 30 mg / kg. The effect of the compound shown in formula (1) on HbA1c reduction was evaluated using the difference in HbA1c concentration (Delta HbA1c) before and after administration as an indicator. Body weight change and cumulative food intake during the repeated administration period were also determined.

[0057] (Test Method 4) To investigate the effect of repeated oral administration of the compound represented by formula (1) on the reduction of HbA1c levels in Zucker Diabetic Fatty (ZDF) rats, and the effect of the pharmaceutical composition according to this embodiment on insulin deficiency accompanied by disease progression, a study was conducted in which the compound represented by formula (1) was administered orally once daily for 14 days at doses of 3, 10, and 30 mg / kg. The difference in HbA1c levels (Delta HbA1c) between day 0 (grouping day) and day 15 was determined.

[0058] (Evaluation) Table 2 shows the rate of suppression of Hyp increase in the above (gelatin loading test), the changes in improvement of liver fibrosis, weight loss, decrease in HbA1c and increase in GLP-1 in the above (test method 1) to (test method 4), and the results of the increase in FGF-21 in the test shown in [Reference Example 2] below. In Table 2, "○" indicates that a significant change was observed, "×" indicates that no significant change was observed, and "-" indicates that it was not measured.

[0059]

[0060] Tables 1 and 2 show that when the suppression rate of plasma hydroxyproline elevation was 40% or higher, significant changes were observed in liver fibrosis improvement, weight loss, HbA1c reduction, FGF-21 elevation, and GLP-1 elevation, and this trend was common across multiple animal species.

[0061] [Reference Example 2] The concentration of FGF-21 in the blood after continuous administration of compound (1) was evaluated using normal mice, MASH-pathogenic mice, and obese / diabetic monkeys. In MASH-pathogenic mice, administration of compound (1) was started after feeding a high-fat, high-cholesterol, and high-fructose experimental diet for 22 weeks, and measurements were taken daily from the start of administration until the fourth day. In obese / diabetic monkeys, administration of compound (1) was started after feeding a high-fat experimental diet for approximately 11 months, and measurements were taken at the start of administration, one week, two weeks, and four weeks after the start of administration. Compared to normal mice, the increase in FGF-21 concentration after administration of compound (1) (30 g / kg, twice daily) was significant in MASH-pathogenic mice, and an increase in FGF-21 concentration was also confirmed in MASH-pathogenic monkeys with an administration of 10 mg / kg, twice daily. The results are shown in Figures 1-3.

[0062] [Example 1] (Investigation Method) Healthy Japanese adult males were divided into cohorts 1-1 to 1-8, and each cohort was randomly assigned to either the investigational drug group (6 participants) or the placebo group (2 participants). On Day 1, the investigational drug or placebo was administered orally as a single dose under fasting conditions.

[0063] (Safety) Adverse events, clinical laboratory values ​​(hematological tests, blood biochemical tests, urinalysis (including renal impairment markers)), vital signs, body weight, skeletal muscle index, physical findings, standard 12-lead electrocardiogram, and fecal occult blood were investigated. In cohorts 1-1 to 1-8, no serious adverse events, severe adverse events, adverse events leading to discontinuation of administration, or adverse events leading to discontinuation of the trial after completion of administration occurred.

[0064] [Example 2] (Clinical Trial Method) Healthy Japanese adult males were divided into cohorts 2-1 to 2-3, and six subjects were assigned to the investigational drug group. In each cohort, the six subjects were randomly assigned in groups of three to either Group A (Phase 1: Investigational drug administered immediately before breakfast, Phase 2: Investigational drug administered after breakfast) or Group B (Phase 1: Investigational drug administered after breakfast, Phase 2: Investigational drug administered immediately before breakfast).

[0065] (Safety) Adverse events, clinical laboratory values ​​(hematological tests, blood biochemical tests, urinalysis (including renal impairment markers)), vital signs, body weight, skeletal muscle index, physical findings, standard 12-lead electrocardiogram, and fecal occult blood were investigated. In cohorts 2-1 to 2-3, no serious adverse events, severe adverse events, adverse events leading to discontinuation of administration, or adverse events leading to discontinuation of the trial after completion of administration occurred.

[0066] (Plasma Hydroxyproline Concentration) In both Group A and Group B described above, initially, without administering the test product, only an oral loading of 10 g of gelatin was performed 15 minutes after the start of breakfast, and the plasma hydroxyproline concentration at that time was used as the baseline. In Group A, the test product was administered orally as a single dose immediately before breakfast on Day 1 (5 minutes before the start of breakfast) and after breakfast on Day 6 (30 minutes after the start of breakfast), and the plasma hydroxyproline concentration was measured when 10 g of gelatin was orally loaded 15 minutes after the start of breakfast on Day 1 and Day 6. In Group B, the test product was administered orally as a single dose after breakfast on Day 1 (30 minutes after the start of breakfast) and immediately before breakfast on Day 6 (5 minutes before the start of breakfast), and the plasma hydroxyproline concentration was measured when 10 g of gelatin was orally loaded 15 minutes after the start of breakfast on Day 1 and Day 6.

[0067] Administering the test drug immediately before breakfast (before gelatin loading) suppressed the increase in plasma hydroxyproline concentration caused by gelatin loading in a dose-dependent manner. AUC of plasma hydroxyproline concentration ０－８ The inhibition rates of plasma hydroxyproline elevation were 41.1% for 50 mg of the test formulation, 58.2% for 200 mg, and 67.8% for 600 mg. The results are shown in Figure 4.

[0068] [Example 3] (Investigation Method) Healthy Japanese adult males were divided into cohorts 3-1 to 3-3, and each cohort was randomly assigned to either the investigational drug group (6 participants) or the placebo group (2 participants). On Day 1, the investigational drug or placebo was administered orally as a single dose 5 minutes before the start of breakfast. After a 2-day drug-free period, the investigational drug or placebo was administered orally three times a day, 5 minutes before the start of breakfast, lunch, and dinner on Days 4 to 10.

[0069] (Safety) Adverse events, clinical laboratory values ​​(hematological tests, blood biochemical tests, urinalysis (including renal impairment markers)), vital signs, body weight, skeletal muscle index, physical findings, standard 12-lead electrocardiogram, and fecal occult blood were investigated. In cohorts 3-1 to 3-3, no serious adverse events, severe adverse events, adverse events leading to discontinuation of administration, or adverse events leading to discontinuation of the trial after completion of administration occurred.

[0070] (Total plasma GLP-1 concentration) The changes in total plasma GLP-1 concentration after a single dose (Days 1-2) and after repeated doses (Days 10-11) were examined. The total plasma GLP-1 concentration before the single dose was similar in the test drug group and the placebo group, and increased after meals in both groups. On Days 1-2, the 200 mg test drug group tended to maintain a higher total plasma GLP-1 concentration. On Days 10-11, the increase in total plasma GLP-1 concentration after lunch and dinner was generally greater in the test drug group, and this high level tended to be maintained thereafter. The results are shown in Figures 5 and 6.

Claims

1. The following formula (1): A pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable salt thereof, wherein the compound or salt is used to be orally administered to a human being in an amount of 50 to 1200 mg per day, calculated as the free form of the compound.

2. The pharmaceutical composition according to claim 1, wherein the compound or the salt is used to administer orally to a human being in an amount of 150 to 600 mg per day, calculated as the free form of the compound.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

4. The pharmaceutical composition according to claim 1 or 2, for use in the treatment of MASH or MASLD.

5. The pharmaceutical composition according to claim 1 or 2, for use in the treatment of obesity.

6. The pharmaceutical composition according to claim 1 or 2, for use in promoting the secretion of glucagon-like peptide-1.

7. The pharmaceutical composition according to claim 1 or 2, for use in inhibiting the breakdown of ingested proteins in the gastrointestinal tract.

8. The pharmaceutical composition according to claim 1 or 2, for use in promoting the secretion of fibroblast growth factor 21.

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