Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
  • C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
  • C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
  • C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

• the present invention relates to a therapeutic agent for liver disease useful for treating various liver diseases.
• liver is an important organ that controls the metabolism in the body, and it is estimated that 40,000 deaths from liver disease occur annually in Japan. Liver disease is acutely or chronically impaired by various factors such as alcohol, nutritional deficiency, viral infection, and chemical toxins, resulting in hepatic necrosis, fatty liver, impaired bile secretion, and cirrhosis. At present, there is no drug widely used in the treatment and prevention of these diseases that shows remarkable efficacy by oral administration.
• An object of the present invention is to provide a therapeutic agent for liver disease that has an excellent therapeutic effect on liver disease, is stable, can be administered orally as well as parenterally, and is safe.
• the present inventors conducted extensive research to develop a therapeutic agent for liver disease with excellent efficacy and practicality, and found that oral administration of stable beraprost significantly reduced the decline in liver function Alternatively, they have found that the present invention provides an improvement effect, and have completed the present invention.
• the present invention provides a therapeutic agent for liver disease comprising beraprost or a pharmacologically acceptable salt thereof as an active ingredient.
• the therapeutic agent for liver disease of the present invention has an excellent therapeutic effect on various liver diseases, is a safe drug, and is chemically stable and can be administered orally.
• the compound name of beraprost which is a compound used as a therapeutic agent for liver disease of the present invention, is ( ⁇ ) — (lR *, 2R *, 3aS *, 8bS *) 1, 2, 3, 3 a, 8 b—Tetrahydro 2—Hydroxy 11-([E) — (3 S ⁇ ) -1-3-Hydroxy-4-methyl-1-octen-6-ynyl] — 1 H—Sic-Mouth penta [b] benzofuran 1 5— Petite acid, represented by the following structural formula Compound.
• Beraprost is a PG I 2 derivative having a skeleton obtained by converting the structure of the exoenol moiety, which is a characteristic structure of PG I 2 , to an inter-m-phenylene type, as disclosed in JP-A-58-32277 and JP-A- 57-144276 and JP-A-58-124778.
• it is not known to have such a therapeutic effect on veraplastic liver disease.
• Beraprost which is an active ingredient of the therapeutic agent for liver disease of the present invention, includes not only racemic but also d-form and one-body.
• This beraprost can be produced, for example, by the method described in the aforementioned Japanese Patent Publication No. 58-124778.
• beraprost salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts, primary, secondary and tertiary amine salts.
• all pharmaceutically acceptable salts such as basic amino acid salts are included.
• the therapeutic agent for liver disease of the present invention is used for acute or chronic liver disease such as fatty liver, alcoholic hepatitis, toxic liver injury, depressed liver, bile secretion disorder, congestive liver disorder, and ischemic disease.
• liver disorders, liver failure plays It is effective for hepatitis and liver cirrhosis, and is effective for other liver disorders such as liver dysfunction after surgery, viral liver damage, liver function improvement such as liver cancer, protection of transplanted organs during liver transplantation, liver function after transplantation It is also an effective drug for improvement.
• the dose of the compound will vary depending on the type and degree of the disease to be treated, but may be used in the treatment of acute or chronic liver diseases such as fatty liver, alcoholic hepatitis, toxic liver damage, bile secretion disorder and cirrhosis.
• the therapeutic agent for liver disease of the present invention may use beraprost or a salt thereof as it is.
• Power It can also be orally administered in the form of a solid containing the following additives.
• additives include excipients such as starches, lactose, sucrose, glucose, mannitol, calcium carbonate, calcium sulfate, and the like: binders, such as starches, dextrin, gum arabic, tragacanth, methylcellulose, gelatin, and gelatin. Polyvinylpyrrolidone, polyvinyl alcohol, etc .: Disintegrants such as starch, polyvinylpyrrolidone, crystalline cellulose, etc., Lubricants such as magnesium stearate, talc, etc .: coloring agents, fragrances and the like.
• excipients such as starches, lactose, sucrose, glucose, mannitol, calcium carbonate, calcium sulfate, and the like: binders, such as starches, dextrin, gum arabic, tragacanth, methylcellulose, gelatin, and gelatin.
• Polyvinylpyrrolidone, polyvinyl alcohol, etc . Disintegrants such
• Specific dosage forms include conventionally used dosage forms such as tablets, dragees, powders, granules, troches, capsules, pills, and syrups.
• liver disease of the present invention may also be administered parenterally in the form of a sterile solution and may contain other solutes, for example, enough sodium chloride or glucose to make the solution isotonic. Since the therapeutic agent for liver disease of the present invention has chemical structural stability, there is no difficulty in formulation, and a wide range of administration methods such as the above-mentioned oral formulation, various injections, suppositories and the like can be applied.
• test compound Verabrost sodium salt was used as the substance.
• the test compound was administered in advance to rats that had been fasted for 24 hours, and 1 hour later, 12.5% carbon tetrachloride oil was injected at 2 ml / kg, and when the test compound was administered orally, the test compound was administered intraperitoneally.
• GOT glutamate-loxaxacetate transaminase
• Table 5 shows the LD5 [] values for the administration route and gender.
• the pathological findings were as follows: male to male rats and major findings common to each administration route: mild to moderate congestion of the lung, mild to moderate hemorrhage in the glandular stomach, and catarrh of the small intestine in the fatal cases. .
• Tablets of the present invention were prepared according to the formulation shown in Table 6 below,
• the therapeutic agent for liver disease of the present invention has therapeutic and preventive effects on various liver diseases, is a safe drug, and is a chemically stable drug. It can be used effectively for prevention.

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• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Gastroenterology & Hepatology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Steroid Compounds (AREA)
• Furan Compounds (AREA)

Priority Applications (4)

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Publications (1)

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• 1992
  • 1992-10-23 CA CA002099667A patent/CA2099667C/en not_active Expired - Fee Related
  • 1992-10-23 JP JP50761193A patent/JP3173008B2/ja not_active Expired - Fee Related
  • 1992-10-23 EP EP92921831A patent/EP0565730B1/en not_active Expired - Lifetime
  • 1992-10-23 WO PCT/JP1992/001382 patent/WO1993007876A1/ja not_active Ceased
  • 1992-10-23 US US08/078,298 patent/US5475026A/en not_active Expired - Lifetime
  • 1992-10-23 DE DE69228235T patent/DE69228235T2/de not_active Expired - Fee Related

Patent Citations (2)

Non-Patent Citations (1)

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