WO2004035048A1

WO2004035048A1 - Hepatic fibrosis inhibitor

Info

Publication number: WO2004035048A1
Application number: PCT/JP2003/013304
Authority: WO
Inventors: Hitoshi Togashi; Sumio Kawata
Original assignee: Mitsubishi Pharma Corporation
Priority date: 2002-10-18
Filing date: 2003-10-17
Publication date: 2004-04-29
Also published as: AU2003301398A1; JP2006096664A

Abstract

A drug with which hepatic fibrosis in chronic hepatopathy such as viral hepatitis or alcoholic hepatopathy can be inhibited. The hepatic fibrosis inhibitor contains as an active ingredient a pyrazolone derivative represented by the following formula (I): (I) (wherein R1 represents hydrogen, aryl, etc. and R2 represents hydrogen, aryloxy, etc., provided that R1 and R2 in cooperation may represent C3-5 hydroxyalkyl; and R3 represents hydrogen, C1-5 alkyl, phenyl, etc.), a physiologically acceptable salt of the derivative, or a hydrate or solvate of either.

Description

Specification

Liver fibrosis inhibitor Technical field

The present invention relates to a liver fibrosis inhibitor comprising a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. Background art

Liver fibrosis is a common response to necrosis and damage of hepatocytes, and is caused by numerous factors. Hepatic fibrosis can be caused, for example, by processes that inhibit liver homeostasis (especially inflammation or toxic damage, alterations in hepatic blood flow), or by infections of the liver (virus, bacterial, fungal, or parasitic infections). It is known. In addition, various storage abnormalities due to congenital metabolic abnormalities are often associated with fibrosis, including lipid abnormalities (Gaucher disease), glycogenosis, α-antitrypsin deficiency, and iron overload syndrome due to storage of exogenous substances. (Hemochromatosis) and copper storage disease (Wilson's disease), accumulation of toxic metabolites (tyrosinemia, fructoseemia, galactosemia), and peroxisome abnormalities (Zellweger syndrome). In addition, many chemicals and drugs (eg, alcohol, methotrexate, etc.) also cause liver fibrosis. In addition, impaired liver circulation (eg, chronic heart failure, Pad-Chiari syndrome, venous obstruction, portal vein thrombosis) and chronic obstruction of the biliary outflow tract can also cause liver fibrosis. Liver fibrosis is common in some chronic liver diseases. For example, liver fibrosis plays an important role in the progression from viral hepatitis to cirrhosis. In particular, there is an urgent need to develop hepatic fibrosis suppression therapy for interferon ineffective patients. During the process of liver fibrosis, extracellular matrix (collagen, laminin, proteodalican) increases. Hepatic stellate cells are the major producers of extracellular matrix in the liver, and their function is regulated by cytokines and growth factors produced by Kupffer cells and p-macrophages. Platelet-derived growth factor (PDGF) is important in this process It plays a role and is involved in the activation and proliferation of hepatic stellate cells (HSCs), eventually leading to liver fibrosis. Therefore, if a drug that suppresses the proliferation of hepatic stellate cells by PDGF is developed, it is possible to suppress liver fibrosis and suppress the development of chronic human liver injury.

On the other hand, the following formula (I):

(Wherein, R ¹ represents a hydrogen atom, aryl, alkyl having 1 to 5 carbons or alkoxycarbonylalkyl having 3 to 6 carbons, and R ² represents a hydrogen atom, aryloxy, aryl mercapto, carbon number Represents 1 to 5 alkyl or 1 to 3 hydroxyalkyl, or R ¹ and R ² together represent an alkylene having 3 to 5 carbon atoms, R ³ is a hydrogen atom, and has 1 to 5 carbon atoms. Alkyl, cycloalkyl having 5 to 7 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, benzyl, naphthyl or phenyl, or alkoxy having 1 to 5 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, total carbon number of 2 Alkoxycarbonyl having 5 to 5 carbon atoms, alkylmercapto having 1 to 3 carbon atoms, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluoromethyl, carboxyl, Represents a phenyl substituted with the same or different 1 to 3 substituents selected from the group consisting of ano, hydroxyl, nitro, amino, and acetoamide.) Applications include normalization of brain function (see Japanese Patent Publication No. Hei 5-3-1325), inhibitory action on lipid peroxide production (see Japanese Patent Publication No. Hei 5-325128), and anti-ulcer effect (particularly Japanese Unexamined Patent Publication No. Hei 3 (1995) -215254, and the effect of suppressing blood glucose elevation (see Japanese Unexamined Patent Publication No. Hei 3 (1995) -26) are known.

In addition, among the compounds of the above formula (I), a preparation containing 3-methyl-1-phenyl-12-pyrazolin-15-one as an active ingredient has been a cerebral protective agent (general) since June 2001. The name is “Edaravone” and the product name is “Radicut”: manufactured and sold by Mitsubishi Pell Pharma Co., Ltd. This "edaravone" has been reported to have high reactivity to active oxygen (Kawai, H., et al., J. Pharaacol. Exp. Ther., 281 (2), 921, 1997; Wu, TW. Et al., Life Sci, 67 (19), 2387, 2000). As described above, edaravone is a free radical scavenger that functions to prevent cell damage by eliminating various free radicals including active oxygen. Nevertheless, there have been no reports on whether edaravone is effective in suppressing liver fibrosis. Disclosure of the invention

An object of the present invention is to provide a drug capable of suppressing liver fibrosis in chronic liver injury such as viral hepatitis or alcoholic liver injury.

The present inventors have solved the above-mentioned problem by administering a pyrazolone derivative represented by the formula (I) to hepatic stellate cells known to be involved in the progression of hepatic fibrosis, The effect on the proliferation of stellate cells was examined. As a result, they found that the administration of the pyrazolone derivative suppressed the growth of hepatic stellate cells, and completed the present invention.

That is, according to the present invention, the following formula (I):

(Wherein, R ¹ represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms; R ² represents a hydrogen atom, an aryloxy group, an aryl group) R ³ represents a mercapto group, an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 3 carbon atoms; or R ¹ and R ² together represent an alkylene group having 3 to 5 carbon atoms; Are a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, and benzyl. , A naphthyl group, a phenyl group, or an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, and an alkoxyl group having 2 to 5 carbon atoms. Carbonyl group, alkylmercapto group having 1 to 3 carbon atoms, alkylamino group having 1 to 4 carbon atoms, dialkylamino group having 2 to 8 carbon atoms, halogen atom, trifluoromethyl group, propyloxyl group, cyano group, hydroxyl group , A nitro group, an amino group and an acetoamide group, each representing a fluorine group substituted with 1 to 3 identical or different substituents. )

And a hepatic fibrosis inhibitor comprising, as an active ingredient, a pyrazolone derivative represented by or a physiologically acceptable salt thereof, or a hydrate or solvate thereof. According to a preferred embodiment of the present invention, the pyrazolone derivative represented by the formula (I) is 3-methyl-11-phenyl-2-birazolin-5-one or a physiologically acceptable salt thereof, or a hydrate or solvent thereof. It is Japanese.

According to a preferred embodiment of the present invention, there is provided a liver fibrosis inhibitor used for the treatment and / or prevention of chronic liver injury.

According to a preferred embodiment of the present invention, the chronic liver injury is viral hepatitis or alcoholic liver injury.

According to a preferred embodiment of the present invention, there is provided a liver fibrosis inhibitor which suppresses liver fibrosis by suppressing the proliferation of hepatic stellate cells.

According to still another aspect of the present invention, a pharmaceutically effective amount of the pyrazolone derivative represented by the above formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof, includes a human. A method for suppressing hepatic fibrosis, comprising a step of administering to a mammal.

According to still another aspect of the present invention, a pyrazolone derivative represented by the above formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof, for producing a liver fibrosis inhibitor. Use of an object is provided. BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the measurement of L1-900 cell proliferation when various concentrations of edaravone were added. BEST MODE FOR CARRYING OUT THE INVENTION

The hepatic fibrosis inhibitor according to the present invention comprises a bilazopine derivative represented by the formula (I) defined herein or a physiologically acceptable salt thereof, or a hydrate or solvate thereof. including.

The compound represented by the formula (I) used in the present invention can also have a structure represented by the following formula (I ′) or (1 ″) due to tautomerism. For convenience, one of the tautomers is shown, but the existence of the following tautomers is obvious to those skilled in the art: The active ingredient of the medicament of the present invention is represented by the following formula (1 ′) Alternatively, a compound represented by (1 ") or a physiologically acceptable salt thereof, or a hydrate or solvate thereof may be used.

(Ι ') (I ")

In the formula (I), the aryl group in the definition of R ¹ may be either a monocyclic or polycyclic aryl group. For example, a phenyl group, a naphthyl group or another such as a methyl group, a butyl group or another such an alkyl group, a methoxy group or a butoxy group, or another such alkoxy group, a chlorine atom or another such halogen atom, or a hydroxyl group or other such substituent. -Rule group and the like. The same applies to the aryl moiety in other substituents having an aryl moiety (such as an aryloxy group).

R \ R ² and alkyl groups of 1 to 5 carbon atoms in the definition of R ³ are straight chain, it may be either branched. Examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and the like. Other substituents having an alkyl moiety (alkoxycarbonylalkyl groups) The same applies to the alkyl moiety in

The total alkoxycarbonylalkyl group having a carbon number of 3 to 6 in the definition of R ^1, main butoxycarbonyl methyl group, ethoxycarbonylmethyl group, propoxy force Lupo Nirumechiru group, main butoxycarbonyl E methyl group, main butoxycarbonyl-propyl group and the like No.

Examples of the aryloxy group in the definition of R ² include a p-methylphenoxy group, a ρ-methoxyphenoxy group, and —chlorochlorooxy group, p-hydroxyphenoxy group, and the like. Examples include a mercapto group, a p-methylphenylmercapto group, a p-methoxyphenylmercapto group, a p-chloromethylphenylmercapto group, and a p-hydroxyphenylmercapto group.

Examples of the hydroxyalkyl group having 1 to 3 carbon atoms in the definitions of R ² and R ³ include a hydroxymethyl group, a 2-hydroxyethyl group, and a 3-hydroxypropyl group. Examples of the cycloalkyl group having 5 to 7 carbon atoms in the definition of R ³ include a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

In the definition of R ^3, the alkoxy group having 1 to 5 carbon atoms in the substituent of the phenyl group, main butoxy group, an ethoxy group, a propoxy group, isopropoxy group, butoxy sheet group, Penchiruokishi group and the like, total carbon Examples of the alkoxycarbonyl group having a number of from 2 to 5 include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxy S-carboxy group, and the like, and an alkylmercapto group having 1 to 3 carbon atoms includes , A methylmercapto group, an ethylmercapto group, a propylmercapto group, and the like. Examples of the alkylamino group having 1 to 4 carbon atoms include a methylamino group, an ethylamino group, a propylamino group, a butylamino group, and the like. Examples of the dialkylamino group having 2 to 8 carbon atoms include a dimethylamino group, a getylamino group, and a dipropylamino group. Examples include a mino group and a dibutylamino group.

As the compound (I) preferably used as an active ingredient of the liver fibrosis inhibitor of the present invention, for example, the following compounds can be mentioned.

3-Methinolay 1-Fuenolay 2-Pyrazolin-5-one;

3-methyl-1- (2-methylphenyl) -1-pyrazolin-1-one; 3-Methylenol 1- (3-methylpheninole) 1-2-pyrazolin-1 5-one; 3-methyl-1- (4-methylphenyl) 1-2-pyrazolin-1 5-one; 3-methylen 1- (3,4-dimethinoleffe 1- 2-Vilazoline-5-one; 1- (4-ethylphenyl) 1-3-methyl-2-pyrazolin-15-one; 3-Methyl-1- (4-propylphenyl) 1-2-pyrazolin-1 5-one 1- (4-butynolephenyl) 1-3-methyl-12-pyrazolin-15-one; 1- (3-trifluoromethylphenyl) -13-methyl_2-pyrazolin_5-one;

1- (4-trifluoromethylphenyl) -1-methyl-2-pyrazolin-15-one;

1- (2-Methoxyphenyl) -1-3-Methyl-2-pyrazolin-1-5-one; 1- (3-Methoxyphenyl) -3- 3-Methyl-1-birazolin-1-5-one; 1- (4-Methoxyphenyl) ) — 3-Methyl-2-pyrazolin-1-one; 1- (3,4-Dimethoxyphenyl) -1-3-methyl-2-pyrazolin-1-one;

1- (4-ethoxyphenyl) 1 3-Methynole 2-pyrazolin-5-one; 3-Methyl-11 (4-propoxyphenyl) 1-2-pyrazolin-1 5-one; 1-1 (4-butoxyphenyl) 1-Methyl-2-pyrazolin-1-5-one; 1- (2-chlorophen-2-7) 1-3-Methylenol 2-pyrazolin-1-5-one; 1- (3-chlorophenyl) -1-3-methyl-1 2-Pyrazolin 5-one; 1-(4-1-mouth) 2- 3-pyrazoline 1-5-pyrazoline-5-one; 1-1 (3,4-Jik mouth) Methyl-2-pyrazolin-5-one; 1- (4-bromopheninole) 1-3-methyl-12-pyrazolin-5-one; 1-1 (4-fluorophenyl) -13-methyl-12-pyrazolin-1-5-one 1- (3-chloro-1-4-methinolepheninole) 1-3-methyl-2-pyrazolin-1-5 N;

1- (3-methylmercaptophenyl) -3-methyl-2-pyrazolin-1-5-one; 1- (4-Methylmercaptofur) -1-3-Methyl-1-pyrazolin-1-one;

4- (3-methyl-5-oxo-1-pyrazolin-1-yl) benzoic acid; 1- (4-ethoxycarboyphenyl) -1-methyl-2-pyrazolin-1-one;

1- (4-12-Trophenyl) 1-3-Methinole 2-pyrazolin-1 5-one; 3-Echinole 1-1 1-Feninole-1 2-pyrazolin-1 5-one;

1-phenyl-1-3-propyl-1-birazolin-5-one;

1,3-diphenyl-2-pyrazolin-1-5-one;

3-Fueneru 11- (p-tolyl) 1-2-Pyrazolin-1 5-one;

1-1- (4-methoxyphenyl) -1-3-phenyl-2-pyrazolin-1-5-one; 1- (4-chlorophen-2-ole) 1-3-phenyl-2-5-pyrazolin-5-one; 3 , 4—Dimethinole 1- 1-Fen 2-u 2-pyrazolin-5-one;

4-isobutynole 1 3-methinole 1-feninole 2-pyrazolin-5-one; 4- (2-hydroxyxethyl) 1-3-methyl-1-phenyl-2-pyrazolin-1-one;

3-Methyl 4-phenoxy 1-phenyl 2-birazolin-5-one; 3-methinole 4-phenyl / lecapto 1-1-fu 7 7 2-pyrazolin-5-on;

3,3,, 4,5,6,7-hexahydr-2-ene-2H-indazole-1 3-one;

3- (Ethoxycarbonylmethyl) 11-phenyl / 2-pyrazoline-15-one;

1-Feninole 2-Pyrazolin-5-one;

3-methyl-2-birazolin-5-one;

1,3-dimethyl-1-pyrazolin-15-one;

1-ethyl-3-methyl-2-birazolin-5-one;

1-butyl-3-methyl-1-birazolin-5-one; 1- (2-Hydroxyethyl) 1-3-methyl-2-pyrazolin-5-one; 1-hexyl hex ^ / le 3-methyl-1-pyrazolin-5-one;

1-benzyl-3-methyl-2-pyrazolin-5-one;

1- (α-naphthyl) — 3-methyl-2-pyrazolin-1-5-one;

1-methyl-3-phenylenol 2-birazolin-1-one;

3-Methyl-1- (4-methylphenyl) 1-2-pyrazolin-15-one; 1- (4-butylphenyl) — 3-methyl-2-pyrazolin_5-one; 1- (4-Methoxyphenyl) -3 Methyl-1-birazolin-5-one; 1- (4-butoxyphenyl) 1-3-methyl-12-pyrazolin-15-one; 1- (4-chlorophenyl) -1-3-methyl-12-pyrazolin-1 5 1- (4-Hydroxyphenyl) 1-3-methyl-2-pyrazolin-1 5-one; 1- (3,4-Dihydroxyphenyl) 1-3-methyl-2-pyrazolin-1 5-one;

1- (2-Hydroxyphenyl) 1-3-Methylenol 2-Pyrazolin-1-5-one 1- (3-Hydroxyphenyl) _3-Methyl-1-pyrazolin-15-one 1- (4-Hydroxyphenyl) 1-3 —Methyl-1-pyrazolin-5-one 1- (3,4-hydroxyphenyl) —3-methyl-2-pyrazolin-15-one;

1- (4-hydroxyphenyl) -1-3-phenyl-2-pyrazolin-1 5-one; 1- (4-hydroxymethylphenyl) 1-3-methyl-2-pyrazolin-1 5-one;

1- (4-aminophenyl) 1-methyl-2-pyrazolin-5-one; 1- (4-methylaminophenyl) -3-methyl-2-pyrazolin-5-one; 1- (4-dimethylaminophenyl) -3-methyl-2-pyrazolin-5-one; 1- (4-butylaminophenyl) -3-methyl-2-pyrazolin_5-one; 1- (4-dimethylaminophenyl) 1-3-Methyl-2-pyrazolin-5-one;

I (acetoamidophenyl) 1-methyl-2-pyrazolin-15-one; and And

1- (4-Cyanophenyl) -13-methyl-2-pyrazolin-15-one The active ingredient of the liver fibrosis inhibitor of the present invention includes, in addition to the free form compound represented by the formula (I), Acceptable salts may be used. Physiologically acceptable salts include salts with mineral acids such as hydrochloric acid, sulfuric acid, hydrogen bromide, and phosphoric acid; methanesulfonic acid, ρ-toluenesulfonic acid, benzenesulfonic acid, acetic acid, glycolic acid, glucuronic acid. Salts with organic acids such as acids, maleic acid, fumanoleic acid, oxalic acid, asconoleic acid, cunic acid, salicylic acid, nicotinic acid, tartaric acid; salts with alkali metals such as sodium and potassium; magnesium and calcium Salts with alkaline earth metals; ammonium, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-11-propanol, ethanolamine, N-methyl Examples thereof include salts with amines such as glutamine and L-glutamine. Further, a salt with an amino acid such as glycine may be used.

As an active ingredient of the liver fibrosis inhibitor of the present invention, a hydrate of the compound represented by the above formula (I) or a physiologically acceptable salt thereof, or a compound represented by the above formula (I) Or a solvate of a physiologically acceptable salt thereof. The type of the organic solvent forming the solvate is not particularly limited, and examples thereof include methanol, ethanol, ether, dioxane, and tetrahydrofuran. Further, the compound represented by the above formula (I) may have one or more asymmetric carbons depending on the type of the substituent, and may have a stereoisomer such as an optical isomer or a diastereomer. . As the active ingredient of the hepatic fibrosis inhibitor of the present invention, pure stereoisomers, arbitrary mixtures of stereoisomers, racemates and the like may be used.

The compounds represented by the formula (I) are all known compounds, and can be easily synthesized by those skilled in the art by the method described in Japanese Patent Publication No. 5-31523.

The dosage of the hepatic fibrosis inhibitor of the present invention is not particularly limited, but it is generally 0.1% per day in the case of oral administration generally as the weight of the compound represented by the formula (I) as an active ingredient. ~ 1000 mg / kg body weight, preferably 0.5 to 50 mg / kg body weight per day, and 0.01 to 100 mg / kg body weight per day for parenteral administration, preferably 0.1 to 10 mg. /kg Weight. The above dose is preferably administered once a day or divided into two or three times a day, and may be appropriately increased or decreased depending on age, disease state and symptoms.

As the hepatic fibrosis inhibitor of the present invention, the compound represented by the above formula (I), a physiologically acceptable salt thereof, or a hydrate or solvate thereof may be administered as it is. However, in general, it is preferable to prepare and administer a pharmaceutical composition containing the above-mentioned substance as an active ingredient and a pharmacologically and pharmaceutically acceptable additive. Pharmaceutically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coatings, pigments, diluents, bases, dissolving agents Alternatively, a solubilizing agent, a tonicity agent, a pH adjusting agent, a stabilizer, a propellant, an adhesive, and the like can be used.

Pharmaceutical compositions suitable for oral administration include, as excipients, excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; disintegration agents such as carboxymethylcellulose, starch, or carboxymethylcellulose calcium. Binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl ^^ pyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; hydroxypropylmethylcellulose, Coating agents such as sucrose, polyethylene dalicol or titanium oxide; bases such as vaseline, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, and hard fat can be used.

Pharmaceutical compositions suitable for injection or infusion include solubilizing agents or solubilizing agents which can constitute aqueous or ready-to-use injections such as distilled water for injection, physiological saline, and propylene glycol; glucose, sodium chloride , D-mannitol, glycerin and the like; additives such as inorganic acids, organic acids, pH regulators such as inorganic bases and organic bases, and the like.

The form of the liver fibrosis inhibitor of the present invention is not particularly limited, and can take various forms available to those skilled in the art. As a drug suitable for oral administration, for example, tablets, powders, granules, hard gelatin capsules, suppositories, or lozenges can be prepared using solid pharmaceutical additives. Syrup, syrup, Soft gelatin capsules and the like can be prepared. In addition, injections, drops, inhalants, suppositories, transdermal absorbents, transmucosal absorbents, and the like can be prepared as pharmaceuticals suitable for parenteral administration. It should be noted that a brain protectant (drip) containing the compound of the above formula (I) as an active ingredient is already used in clinical practice (generic name: edaravone, trade name: Radicut: manufactured by Mitsubishi Pharma Corporation) The above-mentioned commercial preparations can be used as they are in the hepatic fibrosis inhibitor of the present invention.

The liver fibrosis inhibitor of the present invention is effective for suppressing liver fibrosis in chronic liver disorders such as viral hepatitis or alcoholic liver disorders. That is, the hepatic fibrosis inhibitor of the present invention acts as a prophylactic agent for preventing hepatic fibrosis and a therapeutic agent for inhibiting the progression of Z or hepatic fibrosis (more preferably, a hepatic fibrosis is restored to a normal state). And a therapeutic agent for recovery).

In the present specification, “liver damage” is interpreted in the broadest sense and includes all of liver damage due to tissue / cell damage, rupture of the liver, inflammation, liver function deterioration, liver failure and the like. Specific liver diseases that cause liver damage include, for example, liver abscess, liver cancer, alcoholic liver injury, cirrhosis, amoebic liver abscess, autoimmune hepatitis, biliary obstruction, chronic active hepatitis, chronic persistent hepatitis, Coccidioidosis, haemomatosis, viral hepatitis (hepatitis A, B, C, D, E), hepatocellular carcinoma, primary biliary cirrhosis, suppurative liver abscess, rye Syndrome, sclerosing cholangitis, Wilson's disease and the like. The term “hepatic disorder” referred to in the present invention is preferably a liver disorder accompanied by liver fibrosis. Preferred specific examples of such a liver disorder include viral hepatitis (hepatitis A, B, and C). , Hepatitis D, E) or alcoholic liver injury.

The administration route of the liver fibrosis inhibitor of the present invention is not particularly limited, and it can be administered orally or parenterally. The administration route of parenteral administration is not particularly limited, and it can be injected intravenously, intramuscularly, intradermally, or subcutaneously.

Further, the liver fibrosis inhibitor of the present invention can be administered prophylactically prior to the onset of liver fibrosis. In addition, a liver fibrosis inhibitor of the present invention may be administered to a patient who has developed liver fibrosis for the purpose of preventing the worsening of symptoms or reducing the symptoms. Examples that can be administered

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples. Synthesis example: Synthesis of 3-methyl-1-phenyl-2-pyrazolin-15-one (hereinafter referred to as edaravone)

13.0 g of ethyl acetate acetate and 10.8 g of phenylhydrazine were added to 5 ml of ethanol, and the mixture was stirred under reflux for 3 hours. After allowing the reaction mixture to cool, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the title compound (11.3 g) as colorless crystals. Yield 67%

Melting point 1 27.5 to 18.5 ° C Example 1:

(Method)

A subculture of human cultured hepatic stellate cells (LI-90; purchased from the Human Science Foundation, catalog No .; J CRB 0 160) was used for the experiment.

(1) PDGF-BB (Platelet derived growth factor-BB, Austrial Biologicals, Catalog No .; GF-0 70-3) at various concentrations (50 ng / m1, 100 ng / ml, 200 ng) / m 1), and then kneaded with LI-90. The proliferation of LI-90 was evaluated using WST-1 ATSSE (using Takara Shuzo WST 1 cell proliferation kit). In the WST-1 assay, an increase in absorbance corresponds to an increase in cell number.

(2) The activation of LI-90 was examined by the expression of α-SMA (a-smooth muscle actin). _α -SMA expression was measured by Western blotting using an antibody purchased from Dako.

(3) Superoxide in cells' Mn—TB AP that eliminates hydrogen peroxide (Manganese (III) tetrakis (4-carboxyphenyl) porphyrin _N Cayman Chemical Co., Catalog No. 758 50) (100 nM, l / zM, 10 μΜ) was added simultaneously with PDGF-BB to grow LI-90 Was examined.

(4) Edaravone (100 ηΜ, 1 μΜ, Ι Ο μΜ) was added simultaneously with PDGF-BB, and the proliferation of LI-190 was examined.

(Result)

24 hours after the addition of PDGF-BB, proliferation of LI-190 was observed, and the degree of the growth was dependent on the amount of PDGF-BB. At the same time, a-SMA expression was enhanced by PDG F-BB.

Table 1 below shows the results of measuring cell proliferation of LI-90 when various concentrations of Mn_TBAP or edaravone were added. Fig. 1 also shows the results when edaravone was added. table 1

Experimental group Measured absorbance (nm)

Control opening 0.15 6 ± 0.008

PDGF-BB 0.2 3 ± 0. 024

Μη-ΤΒΑΡ (ΙΟΟηΜ) + PDGF-BB 0.1 4 1 ± 0.0 1 3

Mn-TBAP (1 μM) + PDGF-BB 0.126 ± 0.021

Μη-ΤΒΑΡ (10 u Μ) + PDGF— ΒΒ 0.07 5 ± 0.01 1 1

Edaravone (100nM) + PDGF-ΒΒ 0.22 7 ± 0.027

Edaravone (1 ZM) + PDGF-BB 0.185 ± 0.014

Edaravone (10 "M) + PDGF-BB 0.137 ± 0.017 Mn-TBAP of reactive oxygen species scavenger (superoxide 'hydrogen peroxide) is PDGF-BB (200 ng / m1) In addition, Mn-TB AP was inhibited by PDGF-BB (200 ng / m 1). —Suppressed the expression of SMA. However, when the concentration of Mn-TBAP was increased to 1 μΜ or 10 μΜ, LI-90 did not proliferate, but rather decreased the number of cells. This is thought to be due to the cytotoxicity of Mn-TB AP.

The NAD PH oxidase inhibitor DP I (10 μΜ) significantly suppressed PDGF-ΒΒ induced LI-190 cell proliferation (ρ <0.001).

In addition, edaravone inhibited the proliferation of LI_90 by PDGF-II in a concentration-dependent manner. Unlike Μη-TBAΡ, cytotoxicity with increasing edaravone concentration was not observed up to 10 μΜ.

(Books)

卩 00-; 68 activates and promotes the proliferation of hepatic stellate cells. In this process, ROS (Reactive Oxygen Species) derived from NAD キシ oxidase plays a role as a signal transmitter. It is thought that it plays. NA DPH oxidase produces superoxide, which is converted into hydrogen peroxide, hydric xyl radicals, and other organic ion radicals inside cells. Both Mn-TBAP and edaravone, which eliminate intracellular ROS, inhibited PDGF-BB-induced LI-190 proliferation in a concentration-dependent manner. Mn-TBAP showed cytotoxicity with increasing concentrations, whereas edaravone was not cytotoxic with increasing concentrations and was effective at a wide range of concentrations. Industrial potential

The agent of the present invention is useful for suppressing liver fibrosis in chronic liver injury such as viral hepatitis or alcoholic liver injury. In particular, the medicament of the present invention can suppress the proliferation of hepatic stellate cells without exhibiting cytotoxicity, and thus is clinically useful as a medicament for treating and / or preventing chronic hepatic injury with few side effects.

All the contents described in the specification of Japanese Patent Application No. 2002-304301, which is the application on which the priority claimed in the present application is based, are incorporated herein by reference as part of the disclosure of this specification. And

Claims

The scope of the claims

(Wherein, R ¹ represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5 carbon atoms or an alkoxycarboyl alkyl group having 3 to 6 carbon atoms; R ² represents a hydrogen atom, an aryloxy group, an aryl group) Represents a reel mercapto group, an alkyl group having 1 to 5 carbon atoms, or a hydroxyalkyl group having 1 to 3 carbon atoms; or represents an alkylene group having 3 to 5 carbon atoms; ³ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, a benzyl group, a naphthyl group, a phenyl group, or C1-C5 alkyl group, C1-C5 alkoxy group, C1-C3 hydroxyalkyl group, C2-C5 alkoxycarbonyl group, C1-C3 alkyl Mercapto group, alkylamino group with 1 to 4 carbon atoms, total carbon number 2 8 substituted with 1 to 3 identical or different substituents selected from the group consisting of a dialkylamino group, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetoamide group. Represents a phenyl group.)

A liver fibrosis inhibitor comprising, as an active ingredient, a pyrazolone derivative represented by or a physiologically acceptable salt thereof, or a hydrate or solvate thereof.

2. The liver fibrillation inhibitor according to claim 1, wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-12-pyrazolin-15-one.

3. The hepatic fibrosis inhibitor according to claim 1 or 2, which is used for the treatment and / or prevention of chronic liver injury.

4. The hepatic fibrosis inhibitor according to any one of claims 1 to 3, wherein the chronic liver injury is viral hepatitis or alcoholic liver injury.

5. The hepatic fibrosis inhibitor according to any one of claims 1 to 4, which suppresses hepatic fibrosis by suppressing the proliferation of hepatic stellate cells.

6. The following formula (I):

(Wherein, R ¹ represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms; R ² represents a hydrogen atom, an aryloxy group, an aryl group) R represents a mercapto group, an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 3 carbon atoms; or R ¹ and R ² together represent an alkylene group having 3 to 5 carbon atoms; ³ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, a benzyl group, a naphthyl group, a phenyl group, or a carbon atom having 1 to 5 carbon atoms. 5 alkyl groups, 1 to 5 carbon atoms alkoxy group, 1 to 3 carbon atoms hydroxyalkyl group, 2 to 5 carbon atoms alkoxycarbonyl group, 1 to 3 carbon alkylmercapto group, carbon Alkylamino group of number 1 to 4, total carbon number 2 Substituted with the same or different 1 to 3 substituents selected from the group consisting of dialkylamino group, halogen atom, trifluoromethyl group, carboxyl group, cyano group, hydroxyl group, nitro group, amino group and acetoamide group Represents a phenyl group.)

And administering a pharmaceutically effective amount of a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof, to a mammal including a human.

7. The method for suppressing liver fibrosis according to claim 6, wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-11-phenyl-2-pyrazolin-5-one.

8. The method for suppressing liver fibrosis according to claim 6 or 7, which is performed for treatment and / or prevention of chronic liver injury.

9. The chronic liver injury is viral hepatitis or alcoholic liver injury. 9. The method for suppressing liver fibrosis according to any one of claims to 8.

10. The method for suppressing hepatic fibrosis according to any one of 1 to 9, wherein hepatic fibrosis is suppressed by suppressing the proliferation of hepatic stellate cells.

1 1. The following formula (I) for producing a liver fibrosis inhibitor:

(Wherein, R ¹ represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms; R ² represents a hydrogen atom, an aryloxy group, an aryl group) Represents a mercapto group, an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 3 carbon atoms; or! ^ And! ^, Together represents an alkylene group having 3 to 5 carbon atoms; R ³ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, a benzyl group, a naphthyl group, a phenyl group, or a carbon atom; Alkyl group having 1 to 5 carbon atoms, alkoxy group having 1 to 5 carbon atoms, hydroxyalkyl group having 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, alkyl mercapto having 1 to 3 carbon atoms Group, alkylamino group with 1-4 carbon atoms, total carbon number 2- 8 substituted with 1 to 3 identical or different substituents selected from the group consisting of dialkylamino group, halogen atom, trifluoromethyl group, carboxyl group, cyano group, hydroxyl group, nitro group, amino group and acetoamide group Represents a phenyl group.)

Use of a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof.

12. The use according to claim 11, wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-11-phenyl-2-pyrazolin-15-one.

13. The use according to claim 11 or 12, wherein the hepatic fibrosis inhibitor is used for the treatment and / or prevention of chronic liver injury.

1 4. The claim wherein the chronic liver injury is viral hepatitis or alcoholic liver injury. 11. Use according to any of 1 to 13.

15. The use according to any one of claims 11 to 14, wherein the hepatic fibrosis inhibitor suppresses hepatic fibrosis by suppressing the proliferation of hepatic stellate cells.