JP5061352B2 - Liver disease therapeutic agent and liver function improving agent - Google Patents

Description

  The present invention relates to a liver disease therapeutic agent and a liver function improving agent, for example.

  The liver has various functions such as detoxification, nutrient synthesis, decomposition, storage, and bile secretion, and is an important organ for maintaining the homeostasis of living organisms. Depending on the factors, acute or chronic liver dysfunction may occur. This induces liver diseases such as viral hepatitis, drug-induced liver injury, and alcoholic liver injury.

  Viral hepatitis, which is a typical liver disease, is hepatitis induced by viral infection. Representative examples of viral hepatitis include hepatitis C and hepatitis B, and these hepatitis are known to lead to the development of cirrhosis and liver cancer when symptoms worsen.

  The number of carriers of hepatitis C virus (HCV) in Japan is estimated to be 1.5 million (see Non-Patent Document 1). Among hepatitis C virus carriers, 70 to 80% of carriers are transferred to chronic hepatitis C and become chronic hepatitis C patients. About 30% of chronic hepatitis C patients become patients with type C cirrhosis within 10 to 30 years, and about 80% of patients with type C cirrhosis develop liver cancer within 5 to 10 years. Thus, since the incidence of liver cancer in patients with chronic hepatitis C is extremely high, treatment of chronic hepatitis C is extremely important.

Conventionally, interferon and ribavirin are typically used as components for the treatment of viral hepatitis. Specifically, interferon is administered to a patient alone or in combination with interferon and ribavirin. Thereby, since hepatitis virus is removed from the body, viral hepatitis may be treated (see Patent Document 1).
JP-A-6-234657 Treatment guide for chronic hepatitis, edited by Japanese Society of Hepatology, Bunkodo, p21-p23

  However, since the treatment method disclosed in Patent Document 1 involves serious side effects such as fever, thrombocytopenia, leukopenia, hair loss, headache, tinnitus, depression, etc., the physical burden on the patient is large. In addition, since interferon is a protein and cannot be administered orally, it has to rely on injection administration, and there is a problem in terms of convenience and safety. In addition, treatment costs may be difficult due to high treatment costs.

  Moreover, depending on the genotype of the hepatitis virus and the timing of administration of the therapeutic component, there were not a few cases where the therapeutic effect was not achieved. Specifically, even when interferon and ribavirin were administered in combination, the maximum rate at which hepatitis virus can be removed from the body was about 50%.

  Due to these problems, when the treatment method disclosed in Patent Document 1 becomes inappropriate, liver protection therapy may be performed to suppress progression to liver cirrhosis or liver cancer. In this liver protection therapy, strong minophagen C or ursodeoxycholic acid is used as a liver function improving agent. As a result, liver function can be improved. This can be confirmed by the fact that liver function index substance values such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are kept at a low value.

However, since strong minophagen C is administered by injection, there is a problem in terms of convenience and safety. In addition, when administered for a long period of time, the injection site hardens, and it may be difficult to continue the administration.
Ursodeoxycholic acid can be administered orally, but is not effective for all patients, and may not be effective for some chronic hepatitis C patients.

  Furthermore, other liver diseases have the same problems as those described above for viral hepatitis.

  Accordingly, an object of the present invention is to provide a liver disease therapeutic agent that has few side effects, can be administered orally, is highly versatile, and is inexpensive.

  The inventors of the present invention are that rifamycin antibiotics can improve liver function in liver diseases such as viral hepatitis and, as a result, suppress progression from hepatitis to cirrhosis and prevent the development of liver cancer. As a result, the present invention has been completed.

  Incidentally, rifamycin antibiotics are rifamycin, which is an antibiotic produced by Streptomyces meditelaneei, and its derivatives, and have been used as a component of anti-tuberculosis drugs for many years. Yes.

  By the way, in recent years, an angiogenesis inhibitory action of rifamycin antibiotics was discovered, and based on this finding, it was shown that the progression of liver cancer can be suppressed by rifamycin antibiotics (Japanese Patent Application Laid-Open No. 2004-75665). reference). However, the purpose of administration of rifamycin antibiotics was not to prevent the development of cancer cells in liver tissue induced by this liver disease by treating the liver disease. Therefore, patients who are the targets of administration of rifamycin antibiotics are limited to those patients who are already likely to have cancer cells in liver tissue.

  In addition, rifamycin antibiotics have been conventionally administered as antibacterial agents to tuberculosis patients and leprosy patients, and have not been used for patients who do not develop these diseases.

In addition, when rifamycin antibiotics are used for the treatment of tuberculosis, their liver toxicity has been a concern. In particular, it has been reported that serious side effects sometimes appear when used in combination with other anti-tuberculosis drugs. Therefore, conventionally, rifamycin antibiotics have not been used as a liver disease therapeutic agent or a liver function improving agent. In a model of animal drug-induced hepatitis caused by carbon tetrachloride (CCl ₄ ), which is the only toxic substance, it has been reported that administration of rifampicin reduces liver cell damage and lowers liver function indicator substance values. (Huang, R., Okuno, H., Takasu, M., Shiozaki, Y., and Inoue, K. 334, 1995. Takeda, K., Watanabe, J., Inoue, K., and Kanamura, S. Rifampicin suppre . Ses hepatic CYP2E1 expression and minimizes DNA injury caused by carbon tetrachloride in perivenular hepatocytes of mice Alcohol Clin Exp Res, 24: 87S-92S, 2000.). However, drug-induced hepatitis due to carbon tetrachloride is induced by cell injury due to toxicity of chemical substances, and the pathogenesis mechanism is completely different from that of hepatitis C, which is thought to involve an immune reaction. The present invention shows that rifampicin is effective for the treatment of hepatitis C in humans, which is thought to be deeply involved in a kind of immune response, and hepatitis with ConA in mice or galactosamine in rats. It ’s groundbreaking.

  Specifically, the present invention provides the following.

  (1) A therapeutic agent for liver diseases comprising rifamycin B or a rifamycin B derivative or a pharmacologically acceptable salt thereof as an active ingredient.

  Here, the “derivative of rifamycin B” refers to a compound synthesized directly from rifamycin B or through a plurality of intermediates, and specifically includes rifamycin SV, rifampicin, rifabutin, rifapentine and the like. .

  The “pharmacologically acceptable salt” refers to a salt that has not lost its therapeutic effect on liver diseases. Specifically, an acid addition salt such as hydrochloride and a base addition salt such as sodium salt are included. Can be mentioned.

  “Liver disease” is a general term for chronic or acute diseases caused by endogenous or exogenous causes in liver tissue. Specific examples of intrinsic or exogenous causes include obesity, viral infection, alcohol Ingestion, immune system abnormalities, bile retention in the liver associated with abnormalities in the bile duct, and the like.

  “Active ingredient” refers to an ingredient showing a therapeutic effect on liver diseases. In addition, the therapeutic agent for liver disease may contain components other than the active ingredient as long as the therapeutic effect on liver disease is not lost.

［式中Ｒ^１は水素又はＣ_１−３アルキルカルボニル基を示し、Ｒ^２は水素、Ｃ_１−３アルキルカルボニル基、ヒドロキシカルボニルメチレン基又は置換基を有していてもよいアミノカルボニルメチレン基を示し、Ｒ^３は水素、ホルミル基、Ｃ_１−１０アルコキシイミノ基又は置換基を有していてもよいピペラジニルイミノ基、２，４−ジニトロアニリノイミノ基を示す。］(2) The therapeutic agent for liver disease according to (1), wherein the rifamycin B or the rifamycin B derivative is a rifamycin antibiotic represented by the general formula (I), or a pharmacologically acceptable salt thereof. .

[Wherein R ¹ represents hydrogen or a C _1-3 alkylcarbonyl group, and R ² represents hydrogen, a C _1-3 alkylcarbonyl group, a hydroxycarbonylmethylene group or an aminocarbonylmethylene group which may have a substituent. R ³ represents hydrogen, a formyl group, a C _1-10 alkoxyimino group or an optionally substituted piperazinylimino group or a 2,4-dinitroanilininoimino group. ]

Here, the “C _1-3 alkylcarbonyl group” refers to a group in which a linear or branched alkyl group having 1 to 3 carbon atoms is bonded to the carbonyl carbon of the carbonyl group.

  “Hydroxycarbonylmethylene group” refers to a hydroxycarbonyl group, which is a group in which a hydroxyl group is bonded to the carbonyl carbon of a carbonyl group, substituted with one of the methyl group hydrogen atoms.

The “aminocarbonylmethylene group which may have a substituent” is a group represented by the general formula (III). Here, R ⁶ and R ⁷ each represent hydrogen or a linear or branched alkyl group having 1 to 3 carbon atoms.

The “C _1-10 alkoxyimino group” refers to a group in which a linear or branched alkyl group having 1 to 10 carbon atoms is bonded to an oxygen atom of an oxime group.

The “optionally substituted piperazinyl imino group” is a group represented by the general formula (IV). Here, R ^{8 to} R ¹⁵ each represent hydrogen, a linear or branched alkyl group having 1 to 3 carbon atoms, and R ¹⁶ represents hydrogen, a linear chain having 1 to 6 carbon atoms or A branched alkyl group, a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms, and a benzyl group are shown.

  The “2,4-dinitroanilinoimino group” is a group in which a hydrogen atom bonded to a nitrogen atom of an imino group is substituted by a group obtained by removing one hydrogen atom from the amino group of 2,4-dinitroaniline. Point to.

［式中Ｒ^４は水素又はＣ_１−３アルキルカルボニル基を示し、Ｒ^５は水素、Ｃ_１−６アルキル基を示す。］(3) The therapeutic agent for liver disease according to claim 1, wherein the rifamycin B or the rifamycin B derivative is a rifamycin antibiotic represented by the general formula (II) or a pharmacologically acceptable salt thereof. .

[Wherein R ⁴ represents hydrogen or a C _1-3 alkylcarbonyl group, and R ⁵ represents hydrogen or a C _1-6 alkyl group. ]

Here, the “C _1-6 alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms.

  (4) The therapeutic agent for liver disease according to (2), wherein the rifamycin antibiotic is selected from the group consisting of rifampicin, rifamycin-SV, 3-formylrifamycin, rifapentine, and rifamycin B.

  (5) The therapeutic agent for liver disease according to (3), wherein the rifamycin antibiotic is rifabutin.

  (6) Used for the treatment of liver disease selected from the group consisting of steatohepatitis, viral hepatitis, cirrhosis, primary biliary cirrhosis, alcoholic liver disease, autoimmune hepatitis, primary sclerosing cholangitis (1 ) To (5) The liver disease therapeutic agent according to any one of the above.

  According to the therapeutic agent for liver disease described in (6), liver function is improved, so that liver disease can be treated. Thus, it is possible to prevent the development of liver cancer by preventing the development of cancer cells in liver tissue as a result of the progression of liver disease.

  Here, “viral hepatitis” refers to hepatitis caused by the hepatitis virus, and examples thereof include hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E.

  (7) A liver function improving agent comprising rifamycin B or a rifamycin B derivative or a pharmacologically acceptable salt thereof as an active ingredient.

  Here, the “pharmacologically acceptable salt” refers to a salt that has not lost the action of improving liver function, and specifically, an acid addition salt such as hydrochloride and a base addition salt such as sodium salt. Is mentioned.

  “Active ingredient” refers to an ingredient that exhibits an effect of improving liver function. Moreover, the liver function improving agent may contain components other than the active ingredient as long as the improvement effect of liver function is not lost.

According to the liver disease therapeutic agent of the present invention, the following effects can be obtained.
Because it uses rifamycin antibiotics as an active ingredient, it can treat liver diseases. This can also prevent liver cancer that can develop as a result of progression of liver disease.
Since rifamycin antibiotics can treat liver diseases with a small dose compared to the dose as a conventional antibacterial agent, the possibility of occurrence of side effects can be reduced.

According to the liver function improving agent of the present invention, the following effects can be obtained.
Because rifamycin antibiotic is used as an active ingredient, liver function can be improved. Thereby, for example, liver disease can be treated, and liver cancer that can develop as a result of progression of liver disease can also be prevented.
Since rifamycin antibiotics can improve liver function with a small dose compared to the dose as a conventional antibacterial agent, the possibility of occurrence of side effects can be reduced.

Furthermore, according to the liver disease therapeutic agent or liver function improving agent of the present invention, the following effects can be obtained.
Rifamycin antibiotics can be administered orally because they are easily absorbed from the digestive tract and are not easily affected by digestive enzymes.
Rifamycin antibiotics are highly versatile, for example, so that viral hepatitis can be treated even in patients who are not effective for treatment with interferon or ursodeoxycholic acid.
In addition, since rifamycin antibiotics are inexpensive, a therapeutic agent for liver disease or a liver function improving agent can be provided at a low cost, so that the economic burden on the patient can be reduced.

It is a figure which shows a time-dependent change of the liver function of a patient after the chemical | medical agent administration of the Example of this invention.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, embodiments of the present invention will be described.
The present invention relates to a therapeutic agent for liver disease and an agent for improving liver function, which comprise rifamycin antibiotics and / or pharmacologically acceptable derivatives of rifamycin antibiotics as active ingredients.

<Composition>
The therapeutic agent for liver disease and the liver function improving agent of the present invention contain rifamycin antibiotics as active ingredients.

[Active ingredients]
(Rifamycin antibiotics)
The rifamycin antibiotic is not particularly limited as long as it is a compound that can be used as a liver disease therapeutic agent or a liver function improving agent. That is, the rifamycin antibiotic is a compound represented by general formula (I) or general formula (II). Here, in the general formula (I), R ¹ represents hydrogen and a C _1-3 alkylcarbonyl group, and R ² has hydrogen, a C _1-3 alkylcarbonyl group, a hydroxycarbonylmethylene group, and a substituent. And R ³ represents hydrogen, formyl group, C _1-10 alkoxyimino group, or piperazinylimino group which may have a substituent. In the general formula (II), R ⁴ represents hydrogen and a C _1-3 alkylcarbonyl group, and R ⁵ represents hydrogen and a C _1-6 alkyl group.

The “aminocarbonylmethylene group optionally having substituent (s)” for R ² is a group represented by the general formula (III). Here, R ⁶ and R ⁷ each represent hydrogen and a C _1-3 alkyl group.

The “piperazinylimino group optionally having substituent (s)” for R ³ is a group represented by the general formula (IV). Here, R ^{8 to} R ¹⁵ each represent hydrogen and a C _1-3 alkyl group, and R ¹⁶ represents hydrogen, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a benzyl group, and 2,4-dinitro. Represents a phenyl group;

Here, the “C _1-6 alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, or a 1-propyl group. 2-propyl group, 2-methyl-1-propyl group, 2-methyl-2-propyl group, 1-butyl group, 2-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, 2 -Methyl-1-butyl group, 3-methyl-1-butyl group, 2-methyl-2-butyl group, 3-methyl-2-butyl group, 2,2-dimethyl-1-propyl group, 1-hexyl Group, 2-hexyl group, 3-hexyl group, 2-methyl-1-pentyl group, 3-methyl-1-pentyl group, 4-methyl-1-pentyl group, 2-methyl-2-pentyl group, 3-methyl-2-pentyl group, 4-methyl-2-pentyl group, 2-methyl-3-pentyl group 3-methyl-3-pentyl group, 2,3-dimethyl-1-butyl group, 3,3-dimethyl-1-butyl group, 2,2-dimethyl-1-butyl group, 2-ethyl-1-butyl Group, 3,3-dimethyl-2-butyl group, 2,3-dimethyl-2-butyl group and the like.

The “C _1-3 alkyl group” refers to a C _1-6 alkyl group having 1 to 3 carbon atoms.

The “C _1-10 alkoxyimino group” is a group in which a C _1-10 alkyl group _{indicating a} linear or branched alkyl group having 1 to 10 carbon atoms is bonded to an oxygen atom of the oxime group Specifically, methoxyimino group, ethoxyimino group, 1-propyloxyimino group, 2-propyloxyimino group, 2-methyl-1-propyloxyimino group, 2-methyl-2-propyloxyimino group Group, 1-butyloxyimino group, 2-butyloxyimino group, 1-pentyloxyimino group, 2-pentyloxyimino group, 3-pentyloxyimino group, 2-methyl-1-butyloxyimino group, 3- Methyl-1-butyloxyimino group, 2-methyl-2-butyloxyimino group, 3-methyl-2-butyloxyimino group, 2,2-dimethyl-1-propoxy Oxyimino group, 1-hexyloxyimino group, 2-hexyloxyimino group, 3-hexyloxyimino group, 1-octyloxyimino group, 2-octyloxyimino group, 3-octyloxyimino group, 1- Nonyloxyimino group, 2-nonyloxyimino group, 3-nonyloxy group, 1-decyloxy group, 2-decyloxy group, 3-decyloxy group, 2-methyl-1-pentyloxyimino group, 3-methyl-1-pentyl Oxyimino group, 4-methyl-1-pentyloxyimino group, 2-methyl-2-pentyloxyimino group, 3-methyl-2-pentyloxyimino group, 4-methyl-2-pentyloxyimino group, 2- Methyl-3-pentyloxyimino group, 3-methyl-3-pentyloxyimino group, 2,3-dimethyl-1-butylo Xiimino group, 3,3-dimethyl-1-butyloxyimino group, 2,2-dimethyl-1-butyloxyimino group, 2-ethyl-1-butyloxyimino group, 3,3-dimethyl-2-butyloxy Examples include an imino group and a 2,3-dimethyl-2-butyloxyimino group.

The “C _3-8 cycloalkyl group” refers to a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Groups.

“C _1-3 alkylcarbonyl group” refers to a C _1-3 alkyl group bonded to the carbonyl carbon of the carbonyl group, such as methylcarbonyl group, ethylcarbonyl group, 1-propylcarbonyl group, 2-propyl. A carbonyl group is mentioned.

In the rifamycin antibiotic represented by the general formula (I), R ¹ is preferably hydrogen or a methylcarbonyl group, more preferably a methylcarbonyl group, and R ² is preferably hydrogen or a hydroxycarbonylmethylene group. ³ includes hydrogen, formyl group, octanoxyimino group, 4-methylpiperazinylimino group, 4-cyclopentylpiperazinylimino group, 4-benzylpiperazinylimino group, 2,6-dimethyl-4- A benzylpiperazinylimino group and a 2,4-dinitroanilininoimino group are preferable, and hydrogen, formyl group, 4-methylpiperazinylimino group, and 4-cyclopentylpiperazinylimino group are more preferable.

In the rifamycin antibiotic represented by the general formula (II), R ⁴ is preferably hydrogen or a methylcarbonyl group, more preferably a methylcarbonyl group, and R ⁵ is preferably a 2-methylpropyl group.

In addition, in the rifamycin antibiotics represented by the general formula (I), rifampicin (R ¹ = methylcarbonyl group, R ² = hydrogen, R ³ = 4-methylpiperazinylimino group), rifamycin-SV (R ¹ = methylcarbonyl group, R ² = hydrogen, R ³ = hydrogen), 3-formylrifamycin (R ¹ = methylcarbonyl group, R ² = hydrogen, R ³ = formyl group), rifapentine (R ¹ = methylcarbonyl) Group, R ² = hydrogen, R ³ = 4-cyclopentylpiperazinylimino group), rifamycin B (R ¹ = methylcarbonyl group, R ² = hydroxycarbonylmethylene group, R ³ = hydrogen) is more preferred, II) The rifamycin antibiotic represented by rifabutin (R ⁴ = methylcarbonyl group, R ⁵ = 2-methylprote) More preferred is a pill group).

(Pharmacologically acceptable derivatives of rifamycin antibiotics)
A pharmacologically acceptable derivative of a rifamycin antibiotic is preferable in that it can increase the solubility in a solvent (for example, water) and improve the absorption efficiency into the body. Although it does not specifically limit as a pharmacologically acceptable derivative, The salt generally used in pharmaceutical formulation and the hydrate of these salts may be sufficient. Here, examples of the pharmacologically acceptable salt include acid addition salts and base addition salts.

  The acid addition salt is not particularly limited. For example, hydrochloride, acetate, sulfate, nitrate, oxalate, maleic acid, tartrate, citrate, carbonate, succinate, benzoic acid, acetate , Hydrobromide, hydrogen iodide, phosphate, fumarate, gluconate, p-toluenesulfonate, methanesulfonate, ethanesulfonate.

  Base addition salts include, but are not limited to, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, organic amine salts such as ethanolamine salts, triethylamine salts, and methylamine salts. And ammonium salts.

[Additive]
The liver disease therapeutic agent or liver function improving agent of the present invention may be administered alone, but is preferably administered in the form of a pharmaceutical composition further containing a pharmacologically and pharmaceutically acceptable additive. . Examples of pharmacologically and pharmaceutically acceptable additives include excipients, disintegrating agents, disintegrating aids, emulsifiers, suspending agents, dispersing agents, binders, lubricants, coating agents, dyes, and dilutions. Agents, base materials, solubilizers, solubilizers, tonicity agents, pH adjusters, stabilizers, propellants, and adhesives.

  Examples of excipients include glucose, lactose, D-mannitol, starch, and crystalline cellulose. Examples of disintegrants and disintegration aids include carboxymethylcellulose, starch, and carboxymethylcellulose potassium, and emulsifiers and suspending agents. Examples of the dispersant include polyoxyl stearate, sucrose fatty acid ester, and sodium lauryl sulfate. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, and the like. , Magnesium stearate, aluminum silicate, talc, etc., coating agents include hydroxypropyl methylcellulose, sucrose, polyethylene glycol, titanium oxide, etc. Flow paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, hard fat and the like.

  In addition, the additive used in the preparation for injection or infusion is not particularly limited, but examples of the solubilizer or solubilizer include distilled water for injection, physiological saline, propylene glycol, and the like. , Inorganic acid, organic acid, inorganic base, organic base and the like.

<Manufacturing method>
(Method for producing rifamycin antibiotics)
Rifamycin B, which is an example of the rifamycin antibiotic according to the present invention, is a kind of antibiotic produced by Streptomyces meditelanenai and is known from the culture solution of Streptomyces meditelanei. (See Japanese Patent Publication No. 37-1697, page 2, right column, line 8 to page 4, right column, line 32).
Rifampicin, rifapentine, rifabutin, rifamycin SV and derivatives thereof can be synthesized from this rifamycin B by a known method (Japanese Examined Patent Publication No. Sho 62-41671, page 2, left column, line 30 to right column; Japanese Patent Publication No. 62-41672, page 2, left column 34 to right column 31, Japanese Patent Publication No. Sho 62-41673, page 2, left column 32 to right column 29, Japanese Patent Laid-Open No. 1-149790, page 3, lower right column Line 12 to page 7, upper right column 7 line, page 8 lower left column 4 line to page 10, lower left column 14 line; Japanese Patent Laid-Open No. 2-304090, 9th line 9th to 21st line 20; Japanese Patent Laid-Open No. 2-56487 Gazette, page 13 upper left row 18 to page 18 upper left row 9 line, page 19 upper right row 15 to page 28 upper left row 13; JP-A-3-16984, page 17 lower right row 18 to page 22 Lower left three lines, page 23 Lower line 10 to 33, lower left line 20; JP-A-4-159283, paragraphs 0038-0070, 0081-0107; JP-A-4-230688, paragraphs 0065-0103, 0118-0147; JP-A-4 No. 247088, paragraphs 0076-0120, 0136-0139; U.S. Pat. No. 4,002,752). The rifamycin antibiotics include “rifampicin” (manufactured by Alexis) as rifampicin, “rifaphtin tablet (trade name)” (manufactured by Sanofi-Aventis) as rifapentine, and “rifabutin” (USP) as rifabutin. “Rifamycin SV sodium salt” (manufactured by MP Biomedicals) and the like are commercially available as rifamycin SV, and these products may be used.

<Diseases to be administered>
The therapeutic agent for liver disease or the liver function improving agent of the present invention includes steatohepatitis (for example, nonalcoholic steatohepatitis), viral hepatitis, cirrhosis, primary biliary cirrhosis, alcoholic liver disease, autoimmune hepatitis, It can be used for primary sclerosing cholangitis, liver cancer and the like. Here, examples of viral hepatitis include hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E.

  The present invention also provides the following liver disease treatment method and liver function improvement method.

  A therapeutic agent for liver disease comprising rifamycin B or a derivative of rifamycin B or a pharmacologically acceptable salt thereof as an active ingredient is administered to a subject suffering from liver disease (for example, human or non-human animal). A method of treating liver disease including procedures.

  A method for improving liver function, comprising administering a therapeutic agent for liver disease comprising rifamycin B or a rifamycin B derivative or a pharmacologically acceptable salt thereof as an active ingredient to a subject (eg, a human or non-human animal) .

[Administration method and dosage form]
Among the therapeutic agents for liver diseases or liver function improving agents according to the present invention, rifampicin, rifapentine and rifabutin are already used in a very large number of patients such as tuberculosis patients, and their usage and side effects are well known. Therefore, the therapeutic method or liver function improving agent of the present invention can select an administration method and administration form that can suppress side effects based on experience.

  The liver disease therapeutic agent according to the present invention can be used in combination with various existing components used for the treatment of liver diseases. Specifically, it can be used in combination with at least one component selected from the group of therapeutic agents for liver diseases such as strong neominophagen C, ursodeoxycholic acid, propage germanium, glutathione, malotilate, and glycyrronic acid. Further, selected from the group consisting of various interferons such as interferon alpha (Interferon-α), interferon alpha-2a (Interferon-α-2a), interferon alpha-2b (Interferon-α-2b), interferon beta (Interferon-β), etc. Can be used in combination with at least one or more components. Furthermore, it can be used in combination with at least one component selected from the group of antiviral agents such as lamivudine and ribavirin.

  The therapeutic agent for liver disease or the liver function improving agent of the present invention can be administered either orally or parenterally (for example, intravenous injection, intramuscular injection, subcutaneous injection). The mode of administration can be appropriately selected according to the medical condition of the patient receiving the administration, but oral administration is preferable from the viewpoint of convenience and safety.

In the case of oral administration, rifamycin antibiotics can be administered in the form of solid or liquid preparations, specifically tablets, granules, capsules, powders, troches, solutions, suspensions, emulsions and the like.
In the case of parenteral administration, the rifamycin antibiotic can be administered in a form dissolved in an appropriate solvent.

[Dose]
The dose of the therapeutic agent for liver disease or the liver function improving agent of the present invention can be appropriately set depending on the target disease, administration method and the like. When rifampicin is administered orally, the dosage is about 10-900 mg / day, preferably about 50-450 mg / day. When rifabutin is orally administered, the dose is about 10 to 600 mg / day, preferably about 20 to 300 mg / day. When rifapentine is administered orally, the dose is about 50 to 1800 mg / week, preferably about 50 to 1200 mg / week.

[Dose period]
The therapeutic agent for liver disease or liver function improving agent of the present invention is preferably administered continuously for at least one month or more, more preferably for one year or more continuously, depending on the symptoms of the patient to whom it is administered.

<Example 1> Effect of treatment to improve liver function in chronic hepatitis C patients by small dose administration of rifampicin Six patients with chronic hepatitis C (an example of liver disease) were treated with rifampin (Rifadin (registered trademark)) (Daiichi Pharmaceutical Co., Ltd.). Manufactured daily) was orally administered 150 mg (1 capsule) daily, and blood of each patient was collected periodically. The alanine aminotransferase (ALT) value and aspartate aminotransferase (AST) value in the collected blood were measured.

Here, the patient selected as the subject in this example was in the following state.
First, it was estimated from biopsy and platelet count that 5 out of 6 patients were C-type cirrhosis patients with liver fibrosis equivalent to F3-F4.
Secondly, all patients were chronic hepatitis C patients with hepatitis C virus type Ib, which is considered difficult to treat with interferon. Four patients were treated with interferon, but one of them had no therapeutic effect. In 4 patients, treatment was stopped due to strong side effects.
Third, all these patients were treated with ursodeoxycholic acid administration, but no therapeutic effect was seen.

  FIG. 1 is a graph showing changes over time in the average values of ALT values and AST values of six patients with chronic hepatitis C. Since ALT and AST values indicate the concentration of aminotransferase that is effluxed from damaged liver cells, higher values indicate that more liver cells are damaged and liver function is reduced. I suggest that.

The ALT value was measured by the following method.
First, serum is separated from the collected blood, and this serum is periodically measured by the lactate dehydrogenase-conjugated UV method (“Hitachi Automatic Analyzer 7350”, manufactured by Hitachi High-Technologies Corporation) in accordance with JSCC. The value was calculated.

The AST value was measured by the following method.
First, serum is separated from the collected blood, and this serum is periodically measured by a malate dehydrogenase conjugate UV method (“Hitachi Automatic Analyzer 7350”, manufactured by Hitachi High-Technologies Corporation) in accordance with JSCC. The AST value was calculated.

  As shown in FIG. 1, the ALT value and the AST value were remarkably decreased after about 1 month after the start of administration compared to before the administration of the drug, and then remained low until 6 months. In addition, the ALT value and the AST value are normal values of 11 to 40 IU / L, and often show high values exceeding the upper limit of normal values in patients with viral chronic hepatitis. In chronic hepatitis, it is generally judged that the symptoms of hepatitis are improved when the ALT value and the AST value decrease. Therefore, from this result, it was found that the liver function was improved and the symptoms of viral hepatitis were improved by drug administration.

  It was also found that this drug can sufficiently improve the symptoms of viral hepatitis even by oral administration. Rifampicin was able to effectively improve the symptoms of hepatitis even in patients with chronic hepatitis C who have hepatitis C virus of type Ib.

  Known side effects of rifampicin administration include liver disorders, gastrointestinal disorders, blood disorders, rashes, and fever. However, these 6 side effects were not found in 6 patients who were administered rifampicin in this example. Further, even after the end of the evaluation period of this example, rifampicin was administered to these patients for several years, but no side effects occurred, and the state of low ALT and AST values was maintained over a long period of time. There was no onset.

  From the above results, it became clear that rifampicin has an action as a liver function improving agent in chronic hepatitis C.

  Moreover, even if the dose of rifampicin as a liver disease therapeutic agent and liver function improving agent is significantly smaller than the dose as a tuberculosis therapeutic agent (for example, about 450 mg once a day), It was found that the liver function was improved.

<Example 2> Liver protection effect by administration of rifampicin (1)
The liver protective effect of rifampicin was evaluated by a mouse viral hepatitis model induced by concanavalin A (ConA). That is, “GK-001” (manufactured by Lupin Limited) as a rifampicin preparation at doses of 50 mg / kg · day, 100 mg / kg · day, and 200 mg / kg · day to 8 mice in each group for 4 days. Orally administered continuously. One hour after the administration on the fourth day, 0.2 mg of ConA dissolved in phosphate physiological saline (PBS) was administered from the tail vein. The same operation was performed on mice in a group administered with 200 mg / kg GK-001 only once and mice in a group not administered with GK-001. 24 hours after the administration of ConA, the mice were anesthetized and arterial blood was collected. Blood ALT values, AST values, and blood lactate dehydrogenase (LDH) values were measured.

  The LDH value was measured and calculated by separating serum from the collected blood, and using this serum by the paranitrophenyl phosphate substrate method (“Automatic Analyzer 7170”, manufactured by Hitachi, Ltd.) in accordance with JSCC.

The results are shown in Table 1.

From Table 1, it can be seen that in the group administered with rifampicin, the ALT value, the AST value, and the LDH value significantly decreased as the dosage increased. From this result, it was shown that rifampicin suppresses the decrease in liver function induced by ConA.

<Example 3> Liver protection effect by administration of rifampicin (2)
The liver protective effect of rifampicin was evaluated by a rat viral hepatitis model induced by galactosamine (Gal). That is, as a rifampicin preparation, “GK-001” (manufactured by Lupine Limited) was administered to 8 rats in each group at a dose of 50 mg / kg · day, 100 mg / kg · day, and 200 mg / kg · day. Oral administration was continued for consecutive days. One hour after the administration on the fourth day, 350 mg / kg of Gal dissolved in physiological saline was intraperitoneally administered. The same operation was performed on rats in a group administered with 200 mg / kg GK-001 only once and rats in a group not administered with GK-001. 24 hours after the administration of Gal, the rats were anesthetized and arterial blood was collected. Blood ALT, AST, and LDH values were measured. The results are shown in Table 2.

From Table 2, it can be seen that in the group to which rifampicin was administered, the ALT value, the AST value, and the LDH value significantly decreased as the dosage increased. From this result, it was shown that rifampicin suppresses the decrease in liver function induced by Gal.

Claims (4)

Rifamycin antibiotics or pharmacologically acceptable salts thereof as active ingredients; in steatohepatitis, viral hepatitis, and alcoholic liver disease, obesity, viral infection, and liver cell damage associated with alcohol consumption A therapeutic agent for liver disease used to improve the symptoms of hepatitis ,
The therapeutic agent for liver disease, wherein the rifamycin antibiotic is a rifamycin antibiotic represented by general formula (I) or general formula (II), or a pharmacologically acceptable salt thereof.

[Wherein R ¹ represents hydrogen or a C _1-3 alkylcarbonyl group, and R ² represents hydrogen, a C _1-3 alkylcarbonyl group, a hydroxycarbonylmethylene group or an aminocarbonylmethylene group which may have a substituent. R ³ represents hydrogen, a formyl group, a C _1-10 alkoxyimino group or an optionally substituted piperazinylimino group or a 2,4-dinitroanilininoimino group. ]

[Wherein R ⁴ represents hydrogen or a C _1-3 alkylcarbonyl group, and R ⁵ represents hydrogen or a C _1-6 alkyl group. ] Rifamycin antibiotic or a pharmacologically acceptable salt thereof as an active ingredient improves liver cell damage associated with obesity, viral infection, and alcohol intake, cirrhosis by improving the symptoms of hepatitis, and A therapeutic agent for liver disease used to prevent progression of liver cancer ,
The therapeutic agent for liver disease, wherein the rifamycin antibiotic is a rifamycin antibiotic represented by general formula (I) or general formula (II), or a pharmacologically acceptable salt thereof.

[Wherein R ¹ represents hydrogen or a C _1-3 alkylcarbonyl group, and R ² represents hydrogen, a C _1-3 alkylcarbonyl group, a hydroxycarbonylmethylene group or an aminocarbonylmethylene group which may have a substituent. R ³ represents hydrogen, a formyl group, a C _1-10 alkoxyimino group or an optionally substituted piperazinylimino group or a 2,4-dinitroanilininoimino group. ]

[Wherein R ⁴ represents hydrogen or a C _1-3 alkylcarbonyl group, and R ⁵ represents hydrogen or a C _1-6 alkyl group. ] The liver disease therapeutic agent according to claim 1 or 2, wherein the rifamycin antibiotic is selected from the group consisting of rifampicin, rifamycin-SV, 3-formylrifamycin, rifapentine, and rifamycin B. The liver disease therapeutic agent according to claim 1 or 2 , wherein the rifamycin antibiotic is rifabutin.

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