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CN-121987630-A - Application of hydroxynisone in preparing medicine for treating or preventing chronic hepatitis B with hepatic fibrosis

CN121987630ACN 121987630 ACN121987630 ACN 121987630ACN-121987630-A

Abstract

The invention provides application of a compound shown in a formula (I), solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof in preparing a medicament for treating or preventing chronic hepatitis B with liver fibrosis, and clinical researches prove that the compound can effectively reverse liver fibrosis, and has better effect in treating fibrosis in a tandem region, obvious fibrosis, progressive liver fibrosis or cirrhosis.

Inventors

  • LUO YING
  • MA SONGJIANG

Assignees

  • 北京康蒂尼药业股份有限公司

Dates

Publication Date
20260508
Application Date
20210514

Claims (10)

  1. 1. The application of a compound shown in a formula (I), a solvate, a hydrate, a prodrug or a pharmaceutically acceptable salt thereof in preparing a medicament for treating or preventing chronic hepatitis B with liver fibrosis, (I) , The chronic hepatitis b with liver fibrosis subjects ALT (alanine aminotransferase) < 8-fold ULN (upper standard limit), whereas subjects with 3ULN < ALT <8ULN and TBiL > 2-fold ULN are excluded.
  2. 2. The use according to claim 1, wherein the chronic hepatitis b is accompanied by liver fibrosis as a significant liver fibrosis, progressive stage liver fibrosis or cirrhosis; preferably, the liver cirrhosis is compensatory liver cirrhosis.
  3. 3. The use according to any one of claims 1-2, wherein the significant liver fibrosis is characterized by one, two or more of the following: (1) The significant liver fibrosis is characterized by an Ishak scoring system, which refers to liver fibrosis with Ishak score of 3 or more or 4 or more, for example, ishak score of about 3-6; (2) The significant liver fibrosis is characterized by a Scheuer scoring system, which means that the Scheuer score is about 2 or more or 3 liver fibrosis, for example, the Scheuer score is about 2-4; (3) The significant liver fibrosis is characterized by a METAVIR scoring system, meaning liver fibrosis having a METAVIR score of about ≡2 or ≡3, e.g., METAVIR scores of about 2-4; (4) The significant liver fibrosis is characterized by a Knodell scoring system, meaning liver fibrosis with a Knodell score of about ≡2 or ≡3, e.g., a Knodell score of about 2-4, and/or (5) The significant liver fibrosis is characterized by liver hardness measurements, meaning liver fibrosis with LSM of about 5.8 kilopascals or more, for example, LSM of about 5.8-12.4 kPa.
  4. 4. The use according to any one of claims 1-3, wherein the progressive liver fibrosis may be characterized by one, two or more of the following: (1) The progressive liver fibrosis is characterized by an Ishak scoring system, for example, liver fibrosis with an Ishak score of ∈4 or ∈5, for example, an Ishak score of about 4-6; (2) The progressive liver fibrosis is characterized by a Scheuer scoring system, which means that the Scheuer score is about 3 or more liver fibrosis, or about 3-4; (3) The progressive liver fibrosis is characterized by a METAVIR scoring system, meaning that the METAVIR score is about 3 or more or about 3-4 liver fibrosis; (4) The progressive liver fibrosis is characterized by a Knodell scoring system, which means that the Knodell score is about greater than or equal to 2 or greater than or equal to 3 liver fibrosis, or about 2-4 or 2-3 liver fibrosis, and/or (5) The progressive stage liver fibrosis is characterized by liver hardness measurements, with bilirubin being normal, ALT <5 ULN, LSM being about≥9.0 kPa or≥10.0 kPa liver fibrosis, or with bilirubin being normal and ALT being normal, LSM being about≥6.0 kPa liver fibrosis.
  5. 5. The use according to any one of claims 1-4, wherein the cirrhosis is characterized by one, two or more of the following: (1) The liver cirrhosis is characterized by an Ishak scoring system, namely liver cirrhosis with Ishak score of more than or equal to 5 or about 5-6; (2) The cirrhosis is characterized by a Scheuer scoring system, namely cirrhosis with a Scheuer score of approximately equal to or greater than 4; (3) The liver cirrhosis is characterized by a METAVIR scoring system, namely the liver cirrhosis with the METAVIR score of more than or equal to 4; (4) The liver cirrhosis is characterized by a Knodell scoring system, which means liver cirrhosis with a Knodell score of about ≡4, and/or (5) The cirrhosis is characterized by liver hardness measurements, meaning cirrhosis with LSM of about 12.0 kPa or about 13.0 kPa.
  6. 6. The use according to any one of claims 1 to 5, wherein chronic hepatitis b with liver fibrosis does not progress to liver cancer.
  7. 7. The use according to any one of claims 1 to 6, wherein the compound of formula (I) is used in an amount of 50 to 500 mg/day, for example 80 to 450 mg/day, 100 to 400 mg/day, 120 to 360 mg/day, 180 mg/day, 270 mg/day, 360 mg/day; Preferably, the drug is administered from 1 to 5 times per day, for example 3 times per day.
  8. 8. The use according to any one of claims 1 to 7, wherein the pharmaceutically acceptable salts comprise salts of the compound of formula (I) with organic acids selected from propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid and citric acid or acidic amino acids selected from aspartic acid and glutamic acid, with inorganic bases, including sodium, potassium, calcium, aluminium salts and ammonium salts, or with organic bases, including methylamine, ethylamine and ethanolamine salts, or with basic amino acids selected from lysine, arginine and ornithine, with inorganic acids selected from hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid, or with organic acids selected from formic acid, acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid.
  9. 9. The use according to any one of claims 1 to 8, wherein the medicament further comprises one or more pharmaceutically acceptable carriers or excipients.
  10. 10. The use according to any one of claims 1 to 9, wherein the pharmaceutical dosage form is a capsule.

Description

Application of hydroxynisone in preparing medicine for treating or preventing chronic hepatitis B with hepatic fibrosis The application relates to a patent application number 202110531848.7 submitted to China national intellectual property agency at 5-14 days of 2021, and the application of the name of the application in preparing medicines for treating or preventing chronic hepatitis B with hepatic fibrosis. Technical Field The invention belongs to the field of medicines, and in particular relates to application of hydroxy-nylon in preparing medicines for treating or preventing chronic hepatitis B with liver fibrosis. Background Liver fibrosis is a common pathological basis in the progress of chronic liver diseases, various chronic injuries cause degeneration and necrosis of liver cells, fibrous connective tissue is abnormally proliferated and excessively deposited to wrap regenerated liver cells, so that 'artificial lobules' are formed to destroy the original tissue structure of the liver, and finally the liver is nodular and hard, and liver functions are damaged and even completely disappear, so that cirrhosis is formed. Liver fibrosis is histologically reversible, and reversal of cirrhosis is difficult, but there is still a small fraction reversible. Various chronic diseases can cause liver fibrosis, such as chronic viral hepatitis, chronic alcoholism, cholestasis, congenital enzyme-deficient metabolic disorder, long-term exposure to toxins and drugs, etc. Liver fibrosis and cirrhosis are one of the main causes affecting the quality of life of patients with liver diseases and medical expenses. The market demand for liver-protecting medicaments has increased year by year. Liver fibrosis is a key pathological process in the progression of chronic hepatitis b to cirrhosis. Reversing or delaying the natural progress of liver fibrosis, obviously reducing the occurrence of liver cirrhosis and liver cancer and reducing the death of patients. At present, no specific and effective anti-hepatic fibrosis therapeutic drug exists clinically, and the liver injury and inflammation are relieved mainly by treating the basic diseases causing the liver injury, and the hepatic fibrosis is prevented and treated. Liver fibrosis treatment includes both liver fibrosis etiology treatment and anti-liver fibrosis treatment. For chronic viral hepatitis B liver fibrosis, the continuous damage to the liver can be relieved by inhibiting and removing HBV, and the repair of fibrotic liver tissues can be promoted to a certain extent. However, for patients with hepatitis B liver fibrosis/cirrhosis, the problem of liver fibrosis cannot be completely solved by pure antiviral treatment. The annual incidence rate of the liver cirrhosis in the decompensation period is 3% -5%, the survival rate of the liver cirrhosis in the decompensation period for 5 years is only 14% -35%, and the annual incidence rate of the hepatocellular carcinoma of the liver cirrhosis patient is 3% -6%. Therefore, there is an urgent need for effective anti-hepatic fibrosis drugs, particularly for the treatment or prevention of chronic viral hepatitis b progressive stage hepatic fibrosis or compensatory stage cirrhosis, and there is a new report that patients and doctors are urgently required to find safe and effective therapeutic drugs. Disclosure of Invention The invention provides application of a compound shown in a formula (I) (i.e. hydroxynisone), solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof in preparing a medicament for treating and/or preventing chronic hepatitis B with liver fibrosis, 。 The invention also provides a compound shown in the formula (I), a solvate, a hydrate, a prodrug or a pharmaceutically acceptable salt thereof, which is used for treating and/or preventing chronic hepatitis B with liver fibrosis. The present invention also provides a method for treating and/or preventing chronic hepatitis b complicated with liver fibrosis, comprising the step of administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I), a solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof. According to some embodiments of the invention, the chronic hepatitis b liver fibrosis may be a header area fibrosis, a significant liver fibrosis, a progressive stage liver fibrosis, or cirrhosis. According to some embodiments of the invention, the liver cirrhosis may be compensatory or decompensated liver cirrhosis. According to some embodiments of the invention, the catchment area fibrosis may be characterized by an Ishak scoring system, for example, liver fibrosis with an Ishak score of ∈1. For example, ishak score. Gtoreq.1, ishak score. Gtoreq.2, or Ishak score of about 1-3, about 1-2, about 2-3 liver fibrosis, etc. According to some embodiments of the invention, the catchment area fibrosis may be characterized by a Scheuer scoring system, for example, may refer to liver fibros