Ranifibranol for use in the treatment of visceral vasodilation in patients with hepatic symptoms

Abstract

The present invention relates to the use of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof for the treatment of visceral vasodilation in patients with hepatic symptoms.

Description

【Technical Field】 【0001】 The present invention relates to a method for treating splanchnic vasodilation in patients with liver symptoms, and relates to a method comprising administering ranifibranor or its deuterated form or a pharmaceutical salt thereof to a patient. 【Background Art】 【0002】 Liver symptoms such as cirrhosis, acute liver failure (ALF), or acute-on-chronic liver failure (ACLF) are end-stage diseases caused by multiple different acute and chronic injuries, both hepatic and extrahepatic. These injuries mainly reduce liver function, but can also lead to systemic complications and multiple organ failure. Generally, one of the reasons for extrahepatic complications and organ failure is a change in systemic hemodynamics. The characteristics of this change include splanchnic vasodilation (which forms porto-systemic collateral pathways), and other systemic hemodynamic changes (which lead to a decrease in total peripheral resistance and systemic hypotension). Furthermore, when liver disease leads to portal hypertension, increased venous pressure causes congestive splenomegaly and an enlarged spleen can be observed. Ultimately, systemic hypotension is not only a cause of renal dysfunction (one of the causes of ascites), but also a cause of increased cardiac output and hepatic encephalopathy. In conclusion, splanchnic vasodilation causes hyperdynamic circulation, which contributes to the persistence and worsening of liver failure. Therefore, when treating advanced liver disease, it is important to be able to suppress splanchnic vasodilation in addition to hepatic resistance. From a clinical perspective, the hyperdynamic syndrome mainly caused by splanchnic vasodilation is considered to be a prerequisite for the progression of multiple organ failure. 【0003】 Treatments for visceral vasodilation are known in the art and are not limited to, but include, liver transplantation, dialysis, insertion of a transjugular intrahepatic portosystemic shunt (TIPS) (for lowering intra-portal blood pressure), hemodialysis, hepatic dialysis, intravenous albumin administration, visceral vasoconstrictors (e.g., vasopressin, midodrine, somatostatin, ornipressin, terlipressin), albumin-conjugated membrane dialysis (e.g., molecular adsorbents recirculation system (MARS)), pentoxifylline, acetylcysteine, and misoprostol. Currently, treatment is limited to palliative care, merely delaying the liver transplant that will ultimately be needed. The only effective treatment for hepatic symptoms is transplantation. However, the use of such transplants is limited due to donor shortages, high costs, and the need for lifelong immunosuppression. Therefore, there is a clear need for alternative therapies to visceral vasodilation, especially in patients with hepatic symptoms. 【0004】 Ranifibranol {4-[1-(1,3-benzothiazole-6-ylsulfonyl)-5-chloroindole-2-yl]butanoic acid; CAS number: 927961-18-0} is a pan-PPAR agonist currently in clinical development for the treatment of patients with non-alcoholic steatohepatitis (NASH). U.S. Patent No. 11,504,380 discloses a method for preventing progression in patients with cirrhosis at risk of progression from the compensated to decompensated stage, comprising administering ranifibranol to the patient. 【0005】 It is known that ranifibranol can exert vasoconstrictive effects in the visceral region of patients with hepatic symptoms. In particular, it has been shown that administration of ranifibranol improves mesenteric blood flow, mesenteric wall thickness, and spleen weight in patients with hepatic symptoms, and further suppresses mesenteric vasodilation, which in turn suppresses visceral vasodilation. [Overview of the Initiative] [Means for solving the problem] 【0006】 This disclosure relates to ranifibranol, its deuterated derivative, or its pharmaceutically acceptable salt, or to a pharmaceutical composition comprising ranifibranol, its deuterated derivative, or its pharmaceutically acceptable salt, for use in the treatment of visceral vasodilation in patients with hepatic symptoms. In some embodiments, the hepatic symptoms are cirrhosis, acute hepatic failure, acute exacerbation of chronic hepatic failure, hepatopulmonary syndrome, hepatorenal syndrome, and hepatic encephalopathy. In some embodiments, the hepatic symptoms are cirrhosis, preferably decompensated cirrhosis. 【0007】 This disclosure also relates to a method for treating visceral vasodilation in patients with hepatic symptoms. In particular, this disclosure relates to a method for treating visceral vasodilation in patients with hepatic symptoms, comprising administering to the patient ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawing] 【0008】 [Figure 1] Figure 1 shows the evaluation of spleen weight in animals that underwent partial portal vein ligation (PPVL) with or without administration of ranifibranol at doses of 10 mg / kg and 30 mg / kg. [Figure 2] Figure 2 shows the evaluation of mesenteric vessel wall thickness in animals that underwent partial portal vein ligation (PPVL) with or without administration of ranifibranol at doses of 10 mg / kg and 30 mg / kg (quantification and imaging of mesenteric vessels by microcomputed tomography (μCT)). [Figure 3] Figure 3 shows the evaluation of superior mesenteric artery flow in animals that underwent partial portal vein ligation (PPVL) with or without administration of ranifibranol at doses of 10 mg / kg and 30 mg / kg. [Figure 4]Figure 4 shows the evaluation of vascular structure using immunohistochemical staining for CD34 expression in capillaries in animals that underwent partial portal vein ligation (PPVL) with or without administration of ranifibranol at doses of 10 mg / kg and 30 mg / kg. [Modes for carrying out the invention] 【0009】 In this specification, articles including "a" and "an" are understood to mean that there is one or more objects being claimed or described. 【0010】 In this specification, the term "about xx" includes the value "xx". 【0011】 In this specification, the term "xx~yy" includes the endpoints "xx" and "yy". 【0012】 In this specification, the terms “prevent,” “prevention,” “prophylaxis,” “preventive treatment,” or “prophylactic treatment” include treatments that lead to the prevention of disease, and treatments that reduce or delay the onset of disease or the risk of developing disease. 【0013】 In this specification, the terms “treatment” or “curative treatment” are defined as treatments that lead to a cure, or treatments that alleviate, improve and / or eliminate, reduce and / or stabilize the symptoms of a disease or pain caused by a disease. According to the present invention, the terms “for use in the treatment of visceral vasodilation in a patient” or “for use in a curative treatment of visceral vasodilation in a patient” mean that the product used acts directly on the visceral vascular structure, in particular to improve mesenteric blood flow, mesenteric wall thickness and spleen weight, and to reduce mesenteric vasodilation. 【0014】 In this specification, the term "visceral vasodilation" means dilation of the blood vessels that supply blood to the intestinal tract, which occurs, for example, through relaxation of the smooth muscle cells that make up the blood vessels. Visceral vasodilation includes venous visceral vasodilation and / or arterial visceral vasodilation. 【0015】 The embodiments described herein can be combined. 【0016】 This disclosure relates to ranifibranol, its deuterated derivatives, or its pharmaceutically acceptable salts for use in the treatment of visceral vasodilation in patients with hepatic symptoms. 【0017】 Ranifibranol {4-[1-(1,3-benzothiazole-6-ylsulfonyl)-5-chloroindole-2-yl]butanoic acid; CAS number: 927961-18-0} is a pan-PPAR agonist. Ranifibranol is described in Example 117 of International Publication No. 2007 / 026097, where it is obtained as a pale yellow powder with a melting point of 74-80°C and has the following structure. [ka] 【0018】 In some embodiments, ranifibranol is in crystalline form. Examples of crystalline forms of ranifibranol are described in International Publication Nos. 2023 / 194339, 2023 / 016319, 2022 / 122014, 2022 / 261410, or 2022 / 258060, all of which are incorporated herein by reference. 【0019】 In some embodiments, ranifibranol may be its deuterated form. In some embodiments, the deuterated form of ranifibranol may be a compound of formula (I). [ka] And, As described in French Patent Application Publication No. 3084254, at least one of the groups R1 to R7 is a deuterium (D) atom, and the other groups R1 to R7 are hydrogen (H) atoms. In some embodiments, at least group R1 is D. In some embodiments, at least one of the groups R2 to R7 is D, particularly at least one of groups R2 and R3 and / or at least one of groups R4 and R5 and / or at least one of groups R6 and R7 is D. In a preferred embodiment, each of R2, R3, R4, R5, R6 and R7 is D. 【0020】 In some embodiments, the deuterated form of ranifibranor is 4-(1-(2-deuterio-1,3-benzothiazol-6-yl)sulfonyl)-5-chloro-1H-indol-2-yl)butanoic acid. In another embodiment, the deuterated form of ranifibranor is 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloro-indol-2-yl]-2,2,3,3,4,4-hexadeuteriobutanoic acid. 【0021】 In some embodiments, ranifibranor or its deuterated form is in the form of one of the pharmaceutically acceptable salts or solvates. The term "solvate" is used herein to describe a molecular complex comprising ranifibranor or its deuterated form and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water. The pharmaceutically acceptable salts of ranifibranor or its deuterated form include its base addition salts. The base addition salts can be prepared from inorganic bases and organic bases. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, magnesium hydroxide and calcium hydroxide. Examples of organic bases include amines, amino alcohols, basic amino acids such as lysine or arginine, and quaternary ammonium compounds such as betaine or choline. 【0022】 The inventors have found that ranifibranor, its deuterated form, or a pharmaceutically acceptable salt thereof is particularly useful for the treatment of visceral vasodilation in patients with liver symptoms. In fact, ranifibranor was tested in a mouse model that did not develop liver impairment or liver symptoms, particularly cirrhosis. The mice in this model had a partially ligated portal vein. Partial ligation of the portal vein causes vasoconstriction (increased portal vein pressure) without inducing cirrhosis. And the organ circulation deteriorates due to vasoconstriction. Therefore, this model reproduces the conditions that can occur in patients with liver symptoms, such as hepatic or extrahepatic inducing events. In the mice administered ranifibranor, the mesenteric blood flow, mesenteric wall thickness, and spleen weight were improved, and mesenteric vasodilation was suppressed. The mouse model used is known to reflect visceral vasodilation, hyperdynamic circulation, and prehepatic portal hypertension with portosystemic shunt without causing liver dysfunction. The data obtained indicate that ranifibranor acts directly on the visceral vascular structure and this action is not due to improvement of liver function. Therefore, in patients with liver symptoms, ranifibranor, its deuterated form, or its pharmaceutical salt can exert a therapeutic effect, particularly a vasoconstrictive effect on the visceral vascular structure. 【0023】 In one embodiment, the patient is a human. In another embodiment, the patient is a non-human animal such as a dog, cat, horse, cow, pig, sheep, goat, primate, etc. 【0024】 In some embodiments, the liver symptoms are cirrhosis, acute liver failure, acute exacerbation of chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome, and hepatic encephalopathy. In some embodiments, the liver symptoms are cirrhosis. In some embodiments, the cirrhosis is decompensated cirrhosis. 【0025】 In this specification, the term “acute hepatic failure (ALF)” is defined as a syndrome characterized by a rapid decline in liver function in patients without a history of liver disease, featuring jaundice, coagulation disorders (INR > 1.5), and hepatic encephalopathy. Acute hepatic failure is a condition in which non-apoptotic cell death forms are thought to play a significant role in disease progression and onset, and therefore may be a promising therapeutic target. The causes of ALF are diverse, including drug toxicity, drug overdose, acetaminophen overdose, autoimmune hepatitis, viral hepatitis, and Wilson's disease. 【0026】 In this specification, the term “acute exacerbation of chronic liver failure (ACLF)” refers to a distinct clinical concept encompassing a rapid deterioration of liver function in patients with cirrhosis (often decompensated cirrhosis), a condition that typically develops in association with triggering events and results in one or more organ failure and a high short-term mortality rate. The main contributing factor is thought to be the inability to control inflammation. Characteristic findings of ACLF include its rapid progression, the need for multi-organ support, and high short- and medium-term mortality rates of 50–90%. 【0027】 In this specification, the term "cirrhosis" includes cirrhosis due to alcohol use disorders such as early-stage alcohol dependence, chronic alcohol dependence, or late-stage alcohol dependence; cirrhosis due to viral chronic hepatitis; cirrhosis due to non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) and / or metabolic-related fatty liver disease (MAFLD) and / or metabolic-related steatohepatitis (MASH); cirrhosis due to primary biliary cirrhosis and / or primary sclerosing cholangitis; and drug-induced cirrhosis. In some embodiments, cirrhosis is either compensated or decompensated. In some embodiments, decompensated cirrhosis includes decompensated cirrhosis due to alcohol use disorders such as early-stage alcohol dependence, chronic alcohol dependence, or late-stage alcohol dependence; decompensated cirrhosis due to viral chronic hepatitis; decompensated cirrhosis due to non-alcoholic fatty liver disease (NAFLD), and / or non-alcoholic steatohepatitis (NASH), and / or metabolic-related fatty liver disease (MAFLD), and / or metabolic-related steatohepatitis (MASH); decompensated cirrhosis due to primary biliary cirrhosis, and / or primary sclerosing cholangitis; and even drug-induced decompensated cirrhosis. 【0028】 In this specification, the term “hepatorenal syndrome (HRS)” means a condition characterized by impaired renal function in patients with liver disease (e.g., cirrhosis, alcoholic hepatitis, or fulminant hepatic failure). Generally, HRS develops when there is acute liver damage (e.g., infection, gastrointestinal bleeding, and / or excessive use of diuretics). A characteristic feature of HRS is congestion or occlusion of intrahepatic capillaries, leading to portal hypertension. 【0029】 In this specification, the term "hepatitis" refers to hepatitis A, hepatitis B, or hepatitis C. 【0030】 In some embodiments, patients with hepatic symptoms are already receiving treatment for those symptoms. In some embodiments, existing treatments include antidiabetic drugs, non-selective beta-blockers, statins, antibiotics, vasoconstrictors, lactulose therapy, or rifaximin. 【0031】 Another aspect of the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically effective amount of ranifibranol, its deuterated derivative, or its pharmaceutically acceptable salt for use in the treatment of visceral vasodilation in patients with hepatic symptoms. Advantageously, the pharmaceutical composition of the present disclosure comprises, as an active ingredient, a pharmaceutically effective amount of ranifibranol, its deuterated derivative, or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure relates to a pharmaceutical composition comprising, as an active ingredient, a pharmaceutically effective amount of ranifibranol, its deuterated derivative, or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients. In some embodiments, ranifibranol (or its deuterated derivative, or its pharmaceutically acceptable salt) is formulated into a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. Advantageously, the pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of ranifibranol, its deuterated derivative, or its pharmaceutically acceptable salt, is administered to patients who have developed or are suspected of developing visceral vasodilation. 【0032】 In embodiments comprising administering a therapeutically effective amount of ranifibranol, its deuterated derivative, or its pharmaceutically effective salt to a patient in need of treatment, “therapeutically effective,” “therapeutically effective amount,” or “pharmaceutically effective” means the amount of ranifibranol, its deuterated derivative, or its pharmaceutically effective salt, or pharmaceutical composition required to suppress or reverse the condition (for example, to treat visceral vasodilation in a patient with hepatic symptoms). The therapeutically effective amount is specifically determined according to factors such as the toxicity and potency of the drug. These factors vary with other factors such as efficacy, relative bioavailability, patient weight, severity of adverse side effects, and preferred dosage form. Toxicity may be determined using methods well known in the art. Potency may be determined using similar indicators. Therefore, a pharmaceutically effective amount is the amount that a clinician considers to be toxicologically safe and effective. 【0033】 Depending on the mode of administration, the dosage may be adjusted as appropriate to ensure that ranifibranol (or its deuterated form) reaches the desired concentration, either locally or systemically. If the patient's response to the dosage is insufficient, a higher dose (or an effective higher dose via another, more localized route of administration) may be used, as long as the patient's tolerance allows. Ranifibranol or its pharmaceutically acceptable salt may also be administered multiple times a day to ensure that an appropriate concentration is reached in the body. An appropriate concentration can be determined, for example, by measuring the peak and sustained plasma concentrations of the drug in the patient. In this specification, "dose" and "dosage" are used interchangeably. 【0034】 In some embodiments, ranifibranol, its deuterated derivative, or its pharmaceutically acceptable salt is administered in doses of approximately 5 mg to approximately 1,200 mg. Advantageously, ranifibranol, its deuterated derivative, or its pharmaceutically acceptable salt may be administered in doses of at least approximately 5 mg, at least approximately 10 mg, at least approximately 15 mg, at least approximately 20 mg, at least approximately 25 mg, at least approximately 30 mg, at least approximately 35 mg, at least approximately 40 mg, at least approximately 45 mg, at least approximately 50 mg, at least approximately 55 mg, at least approximately 60 mg, at least approximately 65 mg, at least approximately 70 mg, at least approximately 75 mg, at least approximately 80 mg, at least approximately 85 mg, at least approximately 90 mg, at least approximately 95 mg, at least approximately 100 mg, at least approximately 150 mg. It is administered in doses of at least approximately 200 mg, at least approximately 250 mg, at least approximately 300 mg, at least approximately 350 mg, at least approximately 400 mg, at least approximately 450 mg, at least approximately 500 mg, at least approximately 550 mg, at least approximately 600 mg, at least approximately 650 mg, at least approximately 700 mg, at least approximately 750 mg, at least approximately 800 mg, at least approximately 850 mg, at least approximately 900 mg, at least approximately 950 mg, at least approximately 1,000 mg, at least approximately 1,050 mg, at least approximately 1,100 mg, at least approximately 1,150 mg, or at least approximately 1,200 mg. Ranifibranol (or its deuterated derivative) may be administered once daily (QD), twice daily (BID), three times daily (TID), or four times daily (QID), but the daily dose shall not exceed the maximum dose described herein, i.e., about 1,200 mg. In some embodiments, ranifibranol (or its deuterated derivative, or its pharmaceutically acceptable salt) is administered to subjects with food. In some embodiments, ranifibranol (or its deuterated derivative, or its pharmaceutically acceptable salt) is administered to subjects in a fasted state.In some embodiments, ranifibranol, its deuterated derivative, or its pharmaceutically acceptable salt is administered at a daily dose of approximately 5 mg to 1,200 mg. Advantageously, ranifibranol, its deuterated form, or its pharmaceutically acceptable salts are administered in doses of at least approximately 5 mg per day, at least approximately 10 mg per day, at least approximately 15 mg per day, at least approximately 20 mg per day, at least approximately 25 mg per day, at least approximately 30 mg per day, at least approximately 35 mg per day, at least approximately 40 mg per day, at least approximately 45 mg per day, at least approximately 50 mg per day, at least approximately 55 mg per day, at least approximately 60 mg per day, at least approximately 65 mg per day, at least approximately 70 mg per day, at least approximately 75 mg per day, at least approximately 80 mg per day, at least approximately 85 mg per day, at least approximately 90 mg per day, at least approximately 95 mg per day, at least approximately 100 mg per day, at least approximately 150 mg per day. It is administered in doses of at least approximately 200 mg per day, at least approximately 250 mg per day, at least approximately 300 mg per day, at least approximately 350 mg per day, at least approximately 400 mg per day, at least approximately 450 mg per day, at least approximately 500 mg per day, at least approximately 550 mg per day, at least approximately 600 mg per day, at least approximately 650 mg per day, at least approximately 700 mg per day, at least approximately 750 mg per day, at least approximately 800 mg per day, at least approximately 850 mg per day, at least approximately 900 mg per day, at least approximately 950 mg per day, at least approximately 1,000 mg per day, at least approximately 1,050 mg per day, at least approximately 1,100 mg per day, at least approximately 1,150 mg per day, or at least approximately 1,200 mg per day. 【0035】 In some embodiments, the prepared composition is used in vivo. Depending on the predetermined in vivo administration method, the composition used may be in solid, semi-solid, or liquid dosage form, but is not limited to these forms. In some embodiments, the pharmaceutical composition is in solid dosage form. Specific examples of solid dosage forms include tablets, capsules, stick packs, pouches, lozenges, powders, pills, or granules. Preferred solid dosage forms include tablets, capsules, or stick packs, with tablets being particularly preferred. Advantageously, the composition is administered in a unit dose form suitable for administering a precise dose in a single dose. The composition may also contain one or more pharmaceutically acceptable excipients, depending on the desired form. The selection of excipients depends largely on factors such as the dosage form, the effect of the excipients on solubility and stability, and the properties of the formulation. The pharmaceutical compositions of the present invention can be prepared by conventional methods, such as those described in Remington's Pharmaceutical Sciences, 19th edition (Mack Publishing Company, 1995), which is incorporated herein by reference. 【0036】 In some embodiments, the pharmaceutical composition comprises 5 mg to 1,200 mg of ranifibranol, its deuterated form, or a pharmaceutically acceptable salt thereof. Specifically, the pharmaceutical composition comprises at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, and at least Each contains 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1,000 mg, at least 1,050 mg, at least 1,100 mg, at least 1,150 mg, or 1,200 mg of ranifibranol, its deuterated form, or a pharmaceutically acceptable salt thereof. Specifically, the pharmaceutical composition contains 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,050 mg, 1,100 mg, 1,150 mg, or 1,200 mg of ranifibranol, its deuterated form, or a pharmaceutically acceptable salt thereof. 【0037】 In any of the embodiments described above, ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof may exist in crystalline form, either on its own or in a pharmaceutical composition. 【0038】 During in vivo treatment, administration may be via oral, parenteral, intramuscular, intranasal, sublingual, intratracheal, inhalation, ophthalmic, vaginal, or rectal route. Those skilled in the art will understand that the route of administration will differ depending on the disease being treated. Advantageously, ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, is administered orally, parenterally, or topically to the patient. In some embodiments, a pharmaceutical composition containing ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof is administered orally. 【0039】 In some embodiments, a pharmaceutical composition comprising ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof may further include a second active ingredient such as empagliflozin, phasocostat, resmethylome, efluxifermin, berapectin, ocaliba, vasopressin, midodrine, somatostatin, ornipressin, terlipressin, pentoxifylline, acetylcysteine, misoprostol, antidiabetic agents, nonselective beta-blockers, statins, antibacterial agents, vasoconstrictors, lactulose therapy, rifaximin, or any of the components suitable for effectively treating such diseases. 【0040】 Another aspect of the present disclosure relates to a method for treating visceral vasodilation in patients with hepatic symptoms, comprising administering to the patient an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof. 【0041】 According to this disclosure, ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, is particularly effective in treating liver symptoms such as cirrhosis, acute liver failure, acute exacerbation of chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome, and hepatic encephalopathy. Advantageously, ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, is particularly effective in treating visceral vasodilation. 【0042】 In some embodiments, the present disclosure relates to a method for treating visceral vasodilation in patients having hepatic symptoms selected from cirrhosis, acute hepatic failure, acute exacerbation of chronic hepatic failure, hepatopulmonary syndrome, hepatorenal syndrome, and hepatic encephalopathy, and the method comprises administering to the patient a pharmaceutical composition comprising an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients as defined above. 【0043】 In some embodiments, the present disclosure relates to a method for treating visceral vasodilation in patients with hepatic symptoms of cirrhosis, particularly decompensated cirrhosis, comprising administering to a patient a pharmaceutical composition comprising an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients as defined above. 【0044】 For therapeutic procedures, the dosage, method of administration, and form of administration defined above are applicable. 【0045】 Another aspect of this disclosure relates to a method for treating visceral vasodilation in patients with hepatic symptoms, comprising administering to a patient ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof. Embodiments disclosed relating to the above method also apply to this aspect of this disclosure. 【0046】 In some embodiments, the present disclosure relates to a method for treating visceral vasodilation in patients with hepatic symptoms, comprising administering to a patient a pharmaceutical composition comprising an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients as defined above. 【0047】 In some embodiments, the present disclosure relates to a method for treating visceral vasodilation in patients with acute hepatic failure, comprising administering to the patient a pharmaceutical composition comprising an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients as defined above. 【0048】 In some embodiments, the Disclosure relates to a method for treating visceral vasodilation in patients with acute exacerbations of chronic hepatic failure, comprising administering to the patient a pharmaceutical composition comprising an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients as defined above. Embodiments disclosed relating to the above method also apply to this aspect of the Disclosure. 【0049】 In some embodiments, the Disclosure relates to a method for treating visceral vasodilation in patients with hepatopulmonary syndrome, comprising administering to a patient a pharmaceutical composition comprising an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients as defined above. Embodiments disclosed relating to the above method also apply to this aspect of the Disclosure. 【0050】 In some embodiments, the Disclosure relates to a method for treating visceral vasodilation in patients with hepatorenal syndrome, comprising administering to a patient a pharmaceutical composition comprising an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients as defined above. Embodiments disclosed relating to the above method also apply to this aspect of the Disclosure. 【0051】 In some embodiments, the Disclosure relates to a method for treating visceral vasodilation in patients with hepatic encephalopathy, comprising administering to a patient a pharmaceutical composition comprising an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients as defined above. Embodiments disclosed relating to the above method also apply to this aspect of the Disclosure. 【0052】 In some embodiments, the Disclosure relates to a method for treating visceral vasodilation in patients with cirrhosis, comprising administering to a patient a pharmaceutical composition comprising an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients as defined above. In some embodiments, the cause of cirrhosis may be alcohol use disorder such as early, chronic, or late-stage alcoholism; viral chronic hepatitis; non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH); primary biliary cirrhosis and / or primary sclerosing cholangitis; or even drugs. In some embodiments, the cirrhosis may be compensated or decompensated. Embodiments disclosed with respect to the above method also apply to this aspect of the Disclosure. 【0053】 Another aspect of this disclosure relates to the use of ranifibranol as defined above, its deuterated derivative, or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for the treatment of hepatic symptoms, particularly cirrhosis, acute hepatic failure, acute exacerbation of chronic hepatic failure, hepatopulmonary syndrome, hepatorenal syndrome, or hepatic encephalopathy. 【0054】 Another aspect of this disclosure relates to the use of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as defined above, in the manufacture of a pharmaceutical product for the treatment of cirrhosis, particularly decompensated cirrhosis. Embodiments disclosed with respect to the above method also apply to this aspect of this disclosure. 【0055】 Another aspect of this disclosure relates to the use of an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as defined above, in the manufacture of a pharmaceutical product for the treatment of hepatic symptoms, particularly cirrhosis, acute hepatic failure, acute exacerbation of chronic hepatic failure, hepatopulmonary syndrome, hepatorenal syndrome, or hepatic encephalopathy. Another aspect of this disclosure relates to the use of an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as defined above, in the manufacture of a pharmaceutical product for the treatment of cirrhosis, particularly decompensated cirrhosis. Embodiments disclosed with respect to the above methods also apply to this aspect of this disclosure. 【0056】 Another aspect of this disclosure relates to the use of a pharmaceutical composition comprising an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients as defined above, in the manufacture of a pharmaceutical for the treatment of hepatic symptoms, particularly cirrhosis, acute hepatic failure, acute exacerbation of chronic hepatic failure, hepatopulmonary syndrome, hepatorenal syndrome, or hepatic encephalopathy. Another aspect of this disclosure relates to the use of a pharmaceutical composition comprising an effective amount of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients as defined above, in the manufacture of a pharmaceutical for the treatment of cirrhosis, particularly decompensated cirrhosis. Embodiments disclosed with respect to the above methods also apply to this aspect of this disclosure. 【0057】 Aspects of this disclosure will be further described by reference to the following non-limiting embodiments. 【0058】 1. A method for treating visceral vasodilation in a patient with hepatic symptoms, comprising administering to the patient a pharmaceutical composition containing ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof. 【0059】 2. A method for treating visceral vasodilation in patients with the liver symptoms described in item 1, where the liver symptoms are cirrhosis, acute liver failure, acute exacerbation of chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome, or hepatic encephalopathy. 【0060】 3. Treatment methods for visceral vasodilation in patients with the liver symptoms described in item 2, where the above liver symptoms are due to cirrhosis, particularly decompensated cirrhosis. 【0061】 4. A method for treating visceral vasodilation in patients with hepatic symptoms described in any of items 1 to 3, wherein the patient's mesenteric blood flow, mesenteric wall thickness, and / or spleen weight are improved by administering ranifibranol, its deuterated derivative, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof. 【0062】 5. A method for treating visceral vasodilation in patients with hepatic symptoms described in any of items 1 to 4, administered at a daily dose of approximately 5 mg to 1,200 mg of ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof. 【0063】 6. The above pharmaceutical composition is in solid dosage form, and is a method for treating visceral vasodilation in patients having the liver symptoms described in any of items 1 to 5. 【0064】 7. A method for treating visceral vasodilation in patients with hepatic symptoms as described in any of items 1 to 6, wherein the solid dosage form is a tablet, capsule, or stick pack. 【0065】 8. A method for treating visceral vasodilation in patients with hepatic symptoms as described in any of items 1 to 7, comprising the above pharmaceutical composition 5 mg to 1,200 mg of ranifibranol, its deuterated form, or a pharmaceutically acceptable salt thereof. 【0066】 9. The above pharmaceutical composition contains at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, and a small amount. A method for treating visceral vasodilation in patients with hepatic symptoms as described in any of items 1 to 8, comprising at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1,000 mg, at least 1,050 mg, at least 1,100 mg, at least 1,150 mg, or 1,200 mg of ranifibranol, its deuterated form, or a pharmaceutically acceptable salt thereof. 【0067】 10. A method for treating visceral vasodilation in a patient with decompensated cirrhosis of the liver, comprising administering to the patient ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof. 【0068】 11. A method for treating visceral vasodilation in a patient with decompensated cirrhosis of the liver as described in item 10, comprising administering ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, thereby improving the patient's mesenteric blood flow, mesenteric wall thickness, and / or spleen weight. 【0069】 12. A method for treating visceral vasodilation in patients with decompensated cirrhosis as described in any of items 10 to 11, in which ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof is administered at a daily dose of approximately 5 mg to approximately 1,200 mg. 【0070】 13. The above pharmaceutical composition is in solid dosage form, and is a method for treating visceral vasodilation in patients with decompensated cirrhosis of the liver as described in any of items 10 to 12. 【0071】 14. A method for treating visceral vasodilation in a patient with decompensated cirrhosis of the liver, as described in any of items 10 to 13, wherein the solid dosage form is a tablet, capsule, or stick pack. 【0072】 15. The above pharmaceutical composition comprises 5 mg to 1,200 mg of ranifibranol, its deuterated form, or a pharmaceutically acceptable salt thereof, and is a method for treating visceral vasodilation in patients with decompensated cirrhosis of the liver as described in any of items 10 to 14. 【0073】 16. The above pharmaceutical composition contains at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, and at least A method for treating visceral vasodilation in patients with decompensated cirrhosis of the liver as described in any of items 10 to 15, comprising 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1,000 mg, at least 1,050 mg, at least 1,100 mg, at least 1,150 mg, or 1,200 mg of ranifibranol, its deuterated form, or a pharmaceutically acceptable salt thereof. 【0074】 The present invention will be explained by the following examples. [Examples] 【0075】 Materials and methods Experiments were conducted using Swiss mice (7-10 mice per group). Portal hypertension was induced using a partial portal vein ligation (PPVL) model. The midline abdomen was incised, and the portal vein was isolated from the surrounding tissue. The portal vein and a 27-gauge blunt needle placed along it were ligated with ligature suture (Silk Cut 5-0). The needle was then removed to induce controlled portal vein stenosis. One week after ligation, the mice were administered ranifibranol (10 mg / kg or 30 mg / kg) or Vehicle daily for 7 days in a therapeutic environment. The effect of ranifibranol on angiogenesis was evaluated by hemodynamic analysis of the liver and systemic tissue, serum, and histological analysis of the liver and mesentery. Vascular corrosion casting is a technique that allows for the capture of the three-dimensional structure of the vascular bed. In short, vascular corrosion templates were obtained by inserting a 26-gauge catheter into the ileocolic vein after euthanasia and then perfusing with Batson No. 17 solution. Soft tissue was dissolved overnight in a 25% potassium hydroxide solution. Vascular corrosion templates of the mesenteric venous vascular structure were analyzed using μCT. 【0076】 result Hemodynamic parameters Compared to the control group, mice treated with PPVL showed a significantly increased portal pressure (control group: 4.34 mmHg → PPVL mouse group: 10.85 mmHg). Superior mesenteric artery flow also increased significantly in PPVL-treated mice, but as shown in Figure 3, it decreased after administration of 30 mg / kg of ranifibranol (a 51.7% decrease). 【0077】 Spleen weight Compared to the control group, mice treated with PPVL showed a significant increase in spleen weight due to the presence of portal hypertension (control group: 0.38% of body weight → PPVL mouse group: 0.63% of body weight). As shown in Figure 1, spleen weight decreased by 23.7% (0.57% of body weight at 10 mg / kg) and 56.1% (0.49% of body weight at 30 mg / kg) depending on the dose of ranifibranol, indicating an improvement in the mesenteric vascular structure. 【0078】 Vascular corrosion casting method Vascular structure evaluation using μCT confirmed that, compared to the control group of mice, mice treated with PPVL showed dilation of the mesenteric venous vascular structure and increased mesenteric vascular wall thickness (control group: 20.31 μM → PPVL mouse group: 37.53 μM). As shown in Figure 2, mesenteric vascular wall thickness decreased with ranifibranol 10 mg / kg (28.95 μM, a 49.8% decrease) and ranifibranol 30 mg / kg (28.53 μM, a 52.3% decrease). Dilation of the mesenteric venous vascular structure also decreased (data not shown). 【0079】 Angiogenesis and vasodilation Vascular structure evaluation using immunohistochemical staining for CD34 revealed an increase in the number of blood vessels in the mesenteric region of PPVL animals. This reflects angiogenesis in the mesenteric region due to increased mesenteric blood flow and portal pressure. This reinforces data showing an increase in mesenteric venous vessels observed by vascular corrosion casting. As observed by vascular corrosion casting, ranifibranol treatment significantly reduced CD34 staining in a dose-dependent manner (a decrease of 69.5% and 135.8% with 10 mg / kg and 30 mg / kg of ranifibranol, respectively), indicating a direct suppression of angiogenesis and vasodilation (Figure 4).

Claims

[Claim 1] Ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof for use in the treatment of visceral vasodilation in patients with hepatic symptoms. [Claim 2] Ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the liver symptoms are cirrhosis, acute liver failure, acute exacerbation of chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome, or hepatic encephalopathy. [Claim 3] Ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 2, wherein the liver symptoms are cirrhosis, particularly decompensated cirrhosis. [Claim 4] Ranifibranol, its deuterated derivative, or its pharmaceutically acceptable salt for use according to any one of claims 1 to 2, wherein ranifibranol, its deuterated derivative, or its pharmaceutically acceptable salt is administered at a daily dose of approximately 5 mg to approximately 1,200 mg. [Claim 5] The deuterated form of the aforementioned ranifibranol is formula (I): 【Chemistry 1】 (wherein the group R １ ~R ７ At least one of them is a deuterium (D) atom, and the other group R １ ~R ７ Ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 2, wherein the compound is a hydrogen (H) atom. [Claim 6] A pharmaceutical composition comprising a pharmaceutically effective amount of ranifibranol, its deuterated form, or a pharmaceutically acceptable salt thereof, for use in the treatment of visceral vasodilation in patients with hepatic symptoms. [Claim 7] The pharmaceutical composition for use according to claim 6, wherein the pharmaceutical composition is in solid dosage form, semi-solid dosage form, or liquid dosage form, and preferably in solid dosage form. [Claim 8] The pharmaceutical composition for use according to any one of claims 6 to 7, wherein the solid dosage form is a tablet, capsule, stick pack, pouch, lozenge, powder, pill, or granule, and preferably a tablet, capsule, or stick pack. [Claim 9] The pharmaceutical composition for use according to any one of claims 6 to 7, comprising 5 mg to 1,200 mg of ranifibranol, its deuterated form, or a pharmaceutically acceptable salt thereof. [Claim 10] The pharmaceutical composition is administered in amounts of at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, and at least A pharmaceutical composition for use according to claim 9, comprising 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1,000 mg, at least 1,050 mg, at least 1,100 mg, at least 1,150 mg, or 1,200 mg of ranifibranol, its deuterated form, or a pharmaceutically acceptable salt thereof. [Claim 11] The pharmaceutical composition for use according to any one of claims 6 to 7, wherein the pharmaceutical composition is administered orally, parenterally, or topically. [Claim 12] A method for treating visceral vasodilation in a patient with hepatic symptoms, comprising administering to the patient ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing ranifibranol, its deuterated derivative, or a pharmaceutically acceptable salt thereof. [Claim 13] The method according to claim 12, wherein the liver symptoms are cirrhosis, acute liver failure, acute exacerbation of chronic liver failure, hepatopulmonary syndrome, hepatorenal syndrome, or hepatic encephalopathy. [Claim 14] The method according to claim 13, wherein the liver symptoms are cirrhosis, particularly decompensated cirrhosis. [Claim 15] The method according to any one of claims 12 to 14, wherein ranifibranol, its deuterated form, or a pharmaceutically acceptable salt thereof is administered at a daily dose of approximately 5 mg to approximately 1,200 mg. [Claim 16] The method according to any one of claims 12 to 14, wherein the pharmaceutical composition is in solid dosage form. [Claim 17] The method according to claim 16, wherein the solid dosage form is a tablet, a capsule, or a stick pack.

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