KR20080045536A - Pharmaceutical composition having a hepatitis treatment and prevention or hepatoprotective effect comprising a pyridine compound - Google Patents

Abstract

The present invention is to provide a pharmaceutical composition comprising a pyridine compound having hepatitis treatment and prophylactic or hepatoprotective efficacy.

Description

A pharmaceutical compositions containing pyridine derivatives as an effective ingredient for the prevention and treatment of hepatitis or the liver protection}

The present invention provides a pharmaceutical composition comprising a pyridine compound having therapeutic and prophylactic or hepatoprotective efficacy for hepatitis.

The liver is located between the digestive system and the circulatory system of the human body and plays an important role in protecting the whole body from toxic substances from outside and in metabolizing ex vivo substances. Since the extracellular substance that enters the living body once passes through the liver, the liver is at higher risk of being exposed to many toxic substances besides nutrients and is more likely to be damaged than other organs.

The liver is an organ with excellent regenerative capacity and is fully recovered from minor damage. However, sustained damage caused by excessive intake of alcohol, abuse of chemicals, viral hepatitis, and biliary secretion can lead to a loss of function as well as complete destruction of liver tissue and inability to return to normal. Eventually, hepatic fibrosis develops into lethal cirrhosis. In addition, liver disease is a pain or subjective symptoms do not appear in the early stages, because it is found only in the late stages can not be treated in a timely manner, resulting in a high mortality disease.

Despite the seriousness of liver disease, there is no effective liver disease treatment yet. In the case of liver disease caused by hepatitis virus, antiviral drugs are used, but the side effects are serious. Recently, there is no effective treatment method for liver disease caused by toxic substances that are increasing due to alcohol and environmental pollution. . Thus, there was an urgent need for drug development to treat and prevent liver damage while maintaining the structure and function of liver tissue, but there has been a limitation in developing a liver disease treatment agent because no experimental method has been developed. In other words, it is true that drugs called hepatoprotectants were not supported by accurate experiments.

However, recently, animal models have been developed and contribute greatly to the development of therapeutic agents for liver disease. To develop therapeutic agents for liver disease caused by toxic substances, carbon tetrachloride-derived animal models are used. Acute hepatitis models derived from galactosamine (hereinafter abbreviated as D-Gal) and lipopolysaccharide (hereinafter referred to as LPS) are used.

In particular, the D-Gal / LPS-induced liver injury model is an animal model suitable for developing liver disease treatment and prevention agents because hepatic injury is induced by an immune response in which most liver diseases actually progress (Hepatology, 1999, 30, 151-159). In acute hepatitis model induced by D-Gal / LPS, D-Gal inhibits RNA and protein synthesis in hepatocytes, maximizing liver toxicity by LPS, and LPS is a cytokine of kupffer cells, which are macrophages of liver. , Nitric oxide (NO), promotes the secretion and synthesis of free radicals. In this case, it is known that tumor necrosis factor alpha (TNF-α) induced by excessively produced nitric oxide (NO) plays a major role in causing sepsis or acute hepatitis, and in fact, TNF-α is in vivo and tested. in vitro (in vitro) leads to hepatocyte apoptosis results have been reported (Am J Physiol Regulatory Integrative comp Physiol , 2000, 278, R1196-R1201). Thus, acute liver injury induced by D-Gal / LPS is called alanine aminotransferase (hereinafter ALT) and GPT indices, aspartate aminotransferase (AST) and GOT. This is an indicator of the increase in the amount of. Thus, the effect on liver damage can be demonstrated by measuring changes in these indicators.

Recently, many animal drugs have been developed to protect the liver function and to prevent hepatitis or to treat hepatitis (Bioorg. Med. Chem., 1997, 7 2193-2198; Eur). J. Pharmacol., 1999, 368, 245-250).

On the other hand, the present inventors studied to determine the effectiveness of the pyridine compound as a therapeutic agent for inflammation and immune disease, and as a result, the synthesis of a pyridine compound of a novel structure and the compound of the inflammatory cytokines (Ttok, alpha-1, etc.) It has already been disclosed through the Korean Patent Application No. 2006-32449 having a production inhibitory activity and effective as a therapeutic agent for inflammatory and immune diseases.

The present invention has completed the present invention by confirming that the pyridine compound disclosed through the above patent shows a clear therapeutic effect in the acute hepatitis model as a new result obtained by repeated studies of the present inventors.

It is an object of the present invention to provide a pharmaceutical composition for treating and preventing or protecting hepatitis, in which a pyridine compound showing a prophylactic and therapeutic effect against liver disease caused by hepatitis virus and liver disease caused by toxic substances is included as an active ingredient.

The present invention is characterized by a pharmaceutical composition for the treatment and prophylaxis or protection of hepatitis containing a pyridine compound or a pharmaceutically acceptable salt thereof.

In Chemical Formula 1,

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are independently hydrogen, halo, cyano, nitro, acyl, hydroxy, amino, C ₁ -C ₆ lower alkyl, C ₂ -C ₆ lower alkenyl, C ₁ -C ₆ lower alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₁₀ alkylamino, C ₄ -C ₉ cycloalkylamino, C ₄ -C ₉ heterocycloalkylamino, arylamino, acylamino, acyl oxy, C ₁ ~C ₆ alkyl sulfinyl, C ₁ ~C ₆ alkylsulfonyl, C ₁ ~C ₆ alkyl-sulfonylamino, aryl sulfinyl, arylsulfonyl, arylsulfonyl, amino, aryl, heteroaryl, C ₁ -C ₁₀ aralkyl, C ₁ -C ₁₀ heteroaralkyl, aryloxy and heteroaryloxy, or each of these may combine with a substituent adjacent to each other to form a ring; X is oxygen or sulfur; Y is oxygen or NR _6, wherein R ₆ is selected from hydrogen, C ₁ -C ₆ loweralkyl, acyl, aryl, heteroaryl, C ₁ -C ₁₀ aralkyl and C ₁ -C ₁₀ heteroaralkyl, or _May combine with a neighboring substituent R ₅ to form a ring; The aryl is selected from phenyl, naphthyl and fused phenyl; The hetero aryl may be a pentagonal or hexagonal heterocyclic ring containing 1 to 3 hetero atoms selected from oxygen, nitrogen, and sulfur, or may be a fused heterocyclic ring, wherein the aryl and hetero Aryl may be substituted with 1 to 4 substituents selected from halo, hydroxy, C ₁ -C ₆ lower alkyl, C ₁ -C ₆ lower alkoxy, and amino.

In the pyridine compound represented by Formula 1, preferably _, R _1, R _2, R _3, R _4, and R ₅ are independently hydrogen, halo, hydroxy, C ₁ -C ₆ lower alkyl. , C ₁ -C ₆ lower alkoxy, aryloxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₁₀ aralkylamino, arylamino, acylamino, aryl, heteroaryl, and C ₁ -C ₁₀ heteroaral May be selected from the group of the substituents, or may form a ring with a substituent adjacent to each other; X is oxygen or sulfur; Y is oxygen or NR _6, wherein R ₆ is selected from hydrogen, C ₁ -C ₆ loweralkyl, aryl, heteroaryl, C ₁ -C ₁₀ aralkyl, and C ₁ -C ₁₀ heteroaralkyl; Said aryl is phenyl; The heteroaryl is selected from furan, thiophene, pyridine, piperidine, piperazine, morpholine, pyrrolidine, and benzodioxol; The aryl and heteroaryl may be aryl or 1, which may be substituted with 1 to 4 substituents selected from halo, hydroxy, C _{1 to} C ₆ lower alkyl, C _{1 to} C ₆ lower alkoxy, and amino. It is the case of the pyridine compound shown.

In addition, the pyridine compound represented by Formula 1 may be used together with an acid such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, citric acid, fumaric acid, lactic acid, maleic acid, succinic acid and tartaric acid. It is also possible to form acceptable salts thereof. In addition, the pyridine compound represented by Formula 1 may form a pharmaceutically acceptable salt by reacting with alkali metal ions or ammonium ions such as sodium or potassium. Therefore, the novel compounds according to the present invention also include pharmaceutically acceptable salts of the pyridine compounds represented by the formula (1).

In addition, the pyridine compound of the present invention is a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient in addition to the active material, such as tablets, capsules, troches, solutions, suspensions, etc. It may be formulated into a formulation for oral administration or parenteral administration. In the case of oral administration, it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc., and in the case of parenteral administration, it may be prepared in the form of injections for intraperitoneal, subcutaneous, muscle, and transdermal.

In addition, the dosage of the active substance according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally based on an adult patient having a weight of 70 kg. In the range of 0.01 to 1000 mg / day, and may be dividedly administered once a day to several times at regular intervals according to the judgment of a doctor or pharmacist.

The present invention as described above will confirm the cell adhesion factor production inhibition and cell adhesion inhibitory effect of the pyridine compound represented by Formula 1 according to the following examples, but the method of preparing the compound represented by Formula 1 and its Specific examples of the formulation method may refer to the method disclosed in Korean Patent Application No. 2006-32449.

Example 1 D-Gal / TNF-α Induced Acute Liver Injury Model Test

1) Measurement of AST and ALT for drugs in D-GalN / LPS-induced hepatitis model

Experimental rats weighing 200 g (Sprague-Dawley (SD) rats, charls liver japan co.) Were adapted to the laboratory environment and were fed with sufficient feed and water. The experimental group was divided into normal group, carboxymethyl cellulose (CMC) administration group and drug administration group. The drug concentration of the experimental group was orally administered at a dose of 100 mg / kg 1 hour, followed by D-Gal (600 mg / kg) and LPS (100 μg / kg) in turn intraperitoneally. As a control group, the saline-administered group received only the same amount of saline. 24 hours after the administration, blood was collected, and livers were removed for tissue staining, and a part of the left side of the liver was taken in 10% formalin. Blood was centrifuged at 3000 rpm and serum was collected and stored at minus 20 ° C. The amount of ALT and AST enzymes was measured using an ARKRAY FACTORY (Japan) kit to measure blood GOT and GPT. Analyzer, SPOTCHEMTM SP4410, Arkray, Japan). The results are shown in Table 1 below.

Test group GOT (IU / l) GPT (IU / l)  Control (Voice Control) 132.5 ± 24.5 41.43 ± 6.11  GalN / LPS-intoxicated 5432.3 ± 3068.9 3124.7 ± 1977.8 2-ethyl-8- (4-fluoro-phenyl) -6-methyl-2H- [2,7] naphthyridin-1-one 30 mg / kg 2105.2 ± 3008.9 889.3 ± 1309.2 100 mg / kg 2036.9 ± 1467.1 880.3 ± 741.5  DDB (positive control), 30 mg / kg 4795.6 ± 1115.2 4814.5 ± 640.6

2-ethyl-8- (4-fluoro-phenyl) -6-methyl-2H- [2,7] naphthyridin-1-one, a compound of the present invention, is a GOT and GPT in hepatitis rats induced with GalN / LPS. It lowered the level by more than 50% and showed more than twice the effect of DDB (Biphenyldimethyl dicarboxylate), which is the drug used in the actual clinical practice.

As described above, according to the present invention, since the pyridine compound represented by Chemical Formula 1 is excellent in the therapeutic effect in the acute hepatitis model induced by D-Gal / LPS, it is effective as an agent for treating and preventing hepatitis or liver protection.

Claims (2)

Pharmaceutical composition for the treatment and prevention of hepatitis or liver protection, characterized in that it contains a pyridine compound or a pharmaceutically acceptable salt thereof. [Formula 1]

In Chemical Formula 1, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are independently hydrogen, halo, cyano, nitro, acyl, hydroxy, amino, C ₁ -C ₆ lower alkyl, C ₂ -C ₆ lower alkenyl, C ₁ -C ₆ lower alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₁₀ alkylamino, C ₄ -C ₉ cycloalkylamino, C ₄ -C ₉ heterocycloalkylamino, arylamino, acylamino, acyl oxy, C ₁ ~C ₆ alkyl sulfinyl, C ₁ ~C ₆ alkylsulfonyl, C ₁ ~C ₆ alkyl-sulfonylamino, aryl sulfinyl, arylsulfonyl, arylsulfonyl, amino, aryl, heteroaryl, C ₁ -C ₁₀ aralkyl, C ₁ -C ₁₀ heteroaralkyl, aryloxy and heteroaryloxy, or each of these may combine with a substituent adjacent to each other to form a ring; X is oxygen or sulfur; Y is oxygen or NR _6, wherein R ₆ is selected from hydrogen, C ₁ -C ₆ loweralkyl, acyl, aryl, heteroaryl, C ₁ -C ₁₀ aralkyl and C ₁ -C ₁₀ heteroaralkyl, or _May combine with a neighboring substituent R ₅ to form a ring; The aryl is selected from phenyl, naphthyl and fused phenyl; The hetero aryl may be a pentagonal or hexagonal heterocyclic ring containing 1 to 3 hetero atoms selected from oxygen, nitrogen, and sulfur, or may be a fused heterocyclic ring, wherein the aryl and hetero Aryl may be substituted with 1 to 4 substituents selected from halo, hydroxy, C ₁ -C ₆ lower alkyl, C ₁ -C ₆ lower alkoxy, and amino. The method of claim 1, R _1, R _2, R _3, R ₄ and R ₅ are independently hydrogen, halo, hydroxy, C ₁ -C ₆ lower alkyl, C ₁ -C ₆ lower alkoxy, aryloxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₁₀ aralkylamino, arylamino, acylamino, aryl, heteroaryl, and C ₁ -C ₁₀ heteroaralkyl, or may form a ring with a substituent adjacent to each other; X is oxygen or sulfur; Y is oxygen or NR _6, wherein R ₆ is selected from hydrogen, C ₁ -C ₆ loweralkyl, aryl, heteroaryl, C ₁ -C ₁₀ aralkyl, and C ₁ -C ₁₀ heteroaralkyl; Said aryl is phenyl; The heteroaryl is selected from furan, thiophene, pyridine, piperidine, piperazine, morpholine, pyrrolidine, and benzodioxol; Said aryl and heteroaryl are aryl or substituted heteroaryl in which 1 to 4 substituents are selected from halo, hydroxy, C ₁ -C ₆ lower alkyl, C ₁ -C ₆ lower alkoxy, and amino. Pharmaceutical composition.