KR100420616B1 - Novel terephthalamide derivatives - Google Patents

Abstract

The present invention relates to a novel terephthalic acid amide derivative having excellent antiviral action against hepatitis B virus, and more particularly, to a terephthalic acid amide derivative comprising a substituted phenylpiperazine group represented by the following Chemical Formula 1, a pharmaceutically acceptable compound thereof A salt and a method for preparing the same.

[Formula 1]

In the above formula, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group or a lower acyl group, a trifluoromethyl group, an amino group or a nitro group.

Description

Novel terephthalamide derivatives

The present invention relates to a novel terephthalic acid amide derivative having excellent antiviral action against hepatitis B virus, and more particularly, to a terephthalic acid amide derivative comprising a substituted phenylpiperazine group represented by the following Chemical Formula 1, a pharmaceutically acceptable compound thereof A salt and a method for preparing the same.

[Formula 1]

In the above formula, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group or a lower acyl group, a trifluoromethyl group, an amino group or a nitro group.

Hepatitis B virus (HBV) is a major pathogen of hepatitis with an infection of about 300 million people around the world. It is well known to be involved in the transition. Much research has been conducted on HBV due to its association with liver disease and molecular biological characteristics of the virus. However, only preventive vaccines for hepatitis B have been developed so far, and no obvious treatment has been developed. Some of the Nucleosides compounds, which have been developed primarily for the treatment of Acquired immune deficiency syndrome (AIDS) for some time, have been reported to be effective as HBV inhibitors [J. Org. Chem., 1992, Vol. 57, 2217], these nucleic acid compounds are known to be limited in the development of a desirable hepatitis B therapeutic agent due to the high cost of treatment and inherent side effects and toxicity of the nucleic acid compounds.

Therefore, in recent years, studies on non-nucleic acid-based compounds have been actively conducted, and quinolone-based compounds [European Patent Publication Nos. 563732, 563734], Iridoid-based Compounds [Korean Patent Publication No. 94-1886], and Chioketen Compounds International Patent Publication No. 96-33711 and Previpoline compound [Japanese Patent Publication No. 92-169527] have been filed for a patent application. However, there is no clear development result so far.

The present inventors have conducted continuous research to solve side effects and toxicity problems and to develop non-nucleic acid compounds having an excellent hepatitis B treatment effect. As a result, the compounds of the present invention are non-nucleosides having a unique structure of terephthalamide. The present invention was completed by confirming that HBV proliferation inhibitory effect is strong as a compound.

Accordingly, an object of the present invention is to provide a novel terephthalate amide derivative, a pharmaceutically acceptable salt thereof, and a method for preparing the same, which have a strong HBV growth inhibitory effect.

The present invention is characterized by a terephthalic acid amide derivative having a substituted phenylpiperazine group represented by the following formula (1) and a pharmaceutically acceptable salt thereof.

Formula 1

In the above formula, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group or a lower acyl group, a trifluoromethyl group, an amino group or a nitro group.

Referring to the present invention in more detail as follows.

In the terephthalic acid amide derivative represented by Chemical Formula 1 according to the present invention, R ¹ is preferably a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 3 carbon atoms or a lower alkoxy group, and particularly preferably R ¹ is In the case of a hydrogen atom, a fluorine atom, a methyl group, a methoxy or an ethoxy group.

Representative examples of the terephthalic acid amide derivative represented by Formula 1 according to the present invention are as follows:

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4-phenylpiperazin,

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (2-methylphenyl) piperazine,

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (2-methoxyphenyl) piperazine,

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (2-ethoxyphenyl) piperazine,

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (2-fluorophenyl) piperazine,

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (2-chlorophenyl) piperazine,

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (4-fluorophenyl) piperazine,

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (4-chlorophenyl) piperazine,

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (4-methoxyphenyl) piperazine,

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (4-nitrophenyl) piperazine,

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (4-aminophenyl) piperazine,

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (4-acetylphenyl) piperazine,

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- [3- (trifluoromethyl) phenyl] piperazine .

In addition, the terephthalic acid amide derivative represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable acid addition salt according to a conventional method in the art. Examples may be salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, citric acid, maleic acid, methanesulfonic acid and the like.

In addition, the present invention includes a method for preparing a terephthalic acid amide derivative represented by Chemical Formula 1, and a process of preparing the terephthalic acid amide derivative represented by Chemical Formula 1 according to the present invention may be represented by the following Scheme 1.

Scheme 1

In the above scheme, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group or a lower acyl group, a trifluoromethyl group, an amino group or a nitro group.

The preparation process of the terephthalic acid amide derivative according to the present invention will be described in more detail with reference to Scheme 1 as follows.

First, the compound represented by Chemical Formula 3 is reacted with an acid chloride such as pivaloyl chloride to generate a highly reactive acid anhydride, and then reacted with a pyridylpiperazine derivative represented by Chemical Formula 2 to be represented by Chemical Formula 4 Obtain benzoic acid methyl ester. In general, the reaction is carried out for 2 to 3 hours at 15 ℃ to 25 ℃ in the presence of a tertiary organic base.

Hydrolysis of the obtained compound represented by formula (4) yields a benzoic acid derivative represented by formula (5). In this case, a mixed solvent in which water is added to lower alcohols such as methanol, ethanol and isopropanol is used as the solvent. This hydrolysis reaction is carried out at 20 ~ 25 ℃ for 2 to 3 hours.

The benzoic acid derivative represented by Chemical Formula 5 is reacted with an acid chloride to produce an acid anhydride, followed by reaction with Chemical Formula 6 to obtain a terephthalic acid amide derivative represented by Chemical Formula 1 as an object of the present invention. At this time, a nonpolar solvent such as methylene chloride, chloroform is used as the solvent. In general, the reaction is carried out at 20 to 25 ℃ for 2 to 3 hours.

In addition, among the compounds represented by the formula (1), a compound in which R ¹ is an amino group is obtained by hydrogen reduction reaction of a compound in which R ¹ is a nitro group. In general, this reaction proceeds by pressurization using hydrophobic water in the presence of an active metal catalyst such as Ranickel in a solvent such as methanol, ethanol, ethyl acetate and the like.

The compounds represented by Formula 3 and Formula 6 used in the production method of the present invention as described above can be easily purchased as commercial products.

In addition, a method for synthesizing the compound represented by Chemical Formula 2 is a known substance introduced in various literatures, and is known from 2-chloro-3-nitropyridine, a commercially available reagent (J. Med. Chem., 1994, Vol .37, 999-1014) can be easily manufactured and used.

Such a present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

Preparation Example 1 1- [3- (isopropylamino) -2-pyridyl] piperazine (Formula 2)

Step (1): Preparation of 1- (3-nitro-2-pyridyl) piperazine

Anhydrous piperazine (135 g) was dissolved in methylene chloride (800 mL), then 2-chloro-3-nitropyridine (40 g) was slowly added at 10 ° C to 15 ° C and reacted at 10 ° C to 15 ° C for 2 hours. . After completion of the reaction, the methylene chloride solution was washed twice with water (800 mL) and the layers were separated and the organic layer was concentrated under reduced pressure. The resulting precipitate was washed with water and a small amount of ethanol and dried in vacuo to give 45.2 g (yield 86%) of the title compound.

m.p. : 79 to 82 ° C

Step (2): Preparation of 1- (3-nitro-2-pyridyl) -4-[(1,1-dimethylethoxy) carbonyl] piperazine

1- (3-nitro-2-pyridyl) piperazine (20.8 g) obtained in step (1) was dissolved in methylene chloride (250 mL), cooled and triethylamine (23 mL) at 0 ° C to 5 ° C. And di-t-butyl dicarbonate (24.3 g) were added sequentially and reacted for 2 hours. After completion of the reaction, the methylene chloride solution was washed with water (250 mL) and separated and the organic layer was concentrated under reduced pressure. Methanol and water were added to the residue, and the precipitated solid was filtered, washed with water and methanol and dried to obtain 27.4 g (yield 89%) of the title compound.

m.p. : 75 to 76 ° C

Step (3): Preparation of 1- (3-amino-2-pyridyl) -4-[(1,1-dimethylethoxy) carbonyl] piperazine

The 1- (3-nitro-2-pyridyl) -4-[(1,1-dimethylethoxy) carbonyl] piperazine (8.5 g) obtained in step (2) was added to methanol (80 g) in a pressurized reaction vessel. ㎖), and about 1 g of Ranickel (50% slurry aqueous solution) was added thereto, followed by filling with Susosu, followed by hydrogen reduction at 50 to 60 psi for 6 hours. After completion of the reaction, diatomaceous earth (celite) was laid and filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was treated with hexane and ether to crystallize, filtered, washed and dried to yield 7.14 g (yield 93%) of the title compound.

m.p. : 158-159 ℃

Step (4): Preparation of 1- [3-isopropylamino) -2-pyridyl] -4-[(1,1-dimethylethoxy) carbonyl] piperazine

To methanol (60 mL) was added 1- (3-amino-2-pyridyl) -4-[(1,1-dimethylethoxy) carbonyl] piperazine (5.0 g) obtained in step (3), Acetone (7 mL), glacial acetic acid (6 mL), and sodium cyanoborohydride (4.8 g) were added sequentially at 10 ° C., followed by reaction at room temperature for 8 hours. Aqueous solution of 3N-sodium hydroxide was added to neutralize, and excess water was gradually added to precipitate crystals. After stirring for 1 hour, the mixture was filtered, washed with water and methanol and dried to obtain 5.18 g (yield 90%) of the title compound.

m.p. : 85 ~ 86 ℃

Step (5): Preparation of 1- [3- (isopropylamino) -2-pyridyl] piperazine (Formula 2)

1- [3- (isopropylamino) -2-pyridyl] -4-[(1,1-dimethylethoxy) carbonyl] piperazine (3) obtained in step (4) in 3N-hydrochloric acid (40 ml). 4.5 g) was added thereto and reacted at 25 ° C to 30 ° C for 2 hours. After completion of the reaction, 3N-sodium hydroxide aqueous solution was added dropwise to adjust the pH to 9.0 and extracted with chloroform (120 mL). The layer separated chloroform layer was washed with water, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain 3.0 g (yield 96%) of the title compound as a pale yellow liquid.

Example 1 Preparation of 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester (Formula 4)

Monomethyl terephthalate (Formula 3, 2.8 g) was added to methylene chloride (80 ml), and triethylamine (2.3 ml) was added thereto to dissolve. Cooling was followed by addition of pivaloyl chloride (2.1 mL) at 5 ° C. and stirring at 20 ° C. for 2 hours. 1- [3- (isopropylamino) -2-pyridyl] piperazine (Formula 2, 3 g) and triethylamine (2.3 mL) obtained in Step (5) of Preparation Example 1 were added sequentially, followed by 2 at 30 ° C. The reaction was carried out for a time. The reaction solution was washed twice with water and aqueous sodium bicarbonate solution, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The concentrated residue was treated with ether, and the precipitated solid was filtered, washed with ether and hexane and dried to yield 4.22 g (yield 81%) of the title compound.

m.p. : 116-118 degreeC

Example 2: 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid (Formula 5)

In methanol (60 mL), 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid methyl ester obtained in Example 1 (Formula 4, 3.82 g) ) Was added and 1N aqueous sodium hydroxide solution (20 ml) was added slowly to hydrolyze at 20 ° C-25 ° C for 3 hours. When acidified by the slow addition of water (80 mL) and 2N hydrochloric acid, crystalline powder precipitates. Filtration, washing with water and methanol and drying gave 3.39 g (yield 92%) of the title compound.

m.p. : 215-217 ℃

Example 3: 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4-pentyl piperazine (Compound No. 1)

To methylene chloride (30 mL) was added 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid (0.5 g) obtained in Example 2, followed by Ethylamine (0.23 mL) was added and dissolved. After cooling, pivaloyl chloride (0.2 ml) was added at 0 ° C to 5 ° C, and gradually heated, and reacted at 20 ° C to 25 ° C for 2 hours. Triethylamine (0.24 mL) and 1-phenylpiperazine (0.21 g) were added sequentially and reacted at 25 ° C for 3 hours. The reaction solution was washed twice with an aqueous sodium carbonate solution and water, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The concentrated residue was recrystallized with ethanol and ether, and the precipitated crystals were filtered, washed with ether and dried to obtain 0.58 g (yield 83%) of the title compound.

m.p. : 188 ~ 190 ℃

Example 4: 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (2-methoxyphenyl) piperazine (Compound No. 2)

The target compound was obtained by the same production method as in Example 3.

Yield: 84%

m.p. : 139 ~ 141 ℃

Example 5: 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (4-fluorophenyl) piperazine (Compound No. 3)

The target compound was obtained by the same production method as in Example 3.

Yield: 85%

m.p. : 110 ~ 112 ℃

Example 6: 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (4-methoxyphenyl) piperazine (Compound No. 4)

The target compound was obtained by the same production method as in Example 3.

Yield: 82%

m.p. : 146 ~ 148 ℃

Example 7: 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (4-nitrophenyl) piperazine ( Compound number 5)

The target compound was obtained by the same production method as in Example 3.

Yield: 79%

m.p. : 182 ~ 184 ℃

Example 8: 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- [3- (trifluoromethyl) Phenyl] piperazine (Compound No. 6)

The target compound was obtained by the same production method as in Example 3.

Yield: 81%

m.p. : 144-146 ℃

Example 9 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (2-methylphenyl) piperazine (Compound Number 7)

To methylene chloride (30 mL) was added 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid (0.4 g) obtained in Example 2, followed by Ethylamine (0.17 mL) was added and dissolved. After cooling, pivaloyl chloride (0.16 mL) was added at 0 ° C to 5 ° C, and gradually heated, and reacted at 20 ° C to 25 ° C for 2 hours. Triethylamine (0.32 mL) was further added, and 1- (2-methylphenyl) piperazine hydrochloride (0.21 g) was added, followed by reaction at 25 ° C for 3 hours. The reaction solution was washed twice with 0.1 N aqueous sodium hydroxide solution and water, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The concentrated residue was added to ethanol and ether to precipitate a uniform crystal. The mixture was stirred for 1 hour, filtered, washed with ether and dried to obtain 0.43 g (yield 76%) of the title compound.

m.p. : 137 ~ 140 ℃

Example 10 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (2-ethoxyphenyl) piperazine (Compound No. 8)

The target compound was obtained by the same preparation method as in Example 9.

Yield: 78%

m.p. : 147 ~ 149 ℃

Example 11 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (2-fluorophenyl) piperazine (Compound No. 9)

The target compound was obtained by the same preparation method as in Example 9.

Yield: 74%

m.p. : 134-136 degreeC

Example 12 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (2-chlorophenyl) piperazine ( Compound number 10)

The target compound was obtained by the same preparation method as in Example 9.

Yield: 81%

m.p. : 156-157 ℃

Example 13: 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (4-chlorophenyl) piperazine ( Compound no.11)

To methylene chloride (35 ml) was added 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid (0.4 g) obtained in Example 2, followed by Ethylamine (0.17 mL) was added and dissolved. After cooling, pivaloyl chloride (0.16 mL) was added at 0 ° C to 5 ° C, and gradually heated, and reacted at 20 ° C to 25 ° C for 2 hours. Triethylamine (0.48 mL) was further added, and 1- (4-chlorophenyl) piperazine dihydrochloride (0.27 g) was added, followed by reaction at 25 ° C. for 3 hours. The reaction solution was washed twice with 0.1 N aqueous sodium hydroxide solution and water, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. Ether was added to the concentrated residue, and the mixture was filtered through a crystal, and recrystallized with ethyl acetate and ether to obtain 0.43 g (yield 72%) of the title compound.

m.p. : 141-143 ℃

Example 14 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (4-aminophenyl) piperazine ( Compound number 12)

1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] 4- (4-nitrophenyl) piperazine ( Formula 5, 0.4 g) was dissolved in methanol (20 ml) and ethyl acetate (4 ml) in a pressurized reaction vessel, and about 0.2 g of Ranickel (50% slurry aqueous solution) was added. The hydrogen reduction reaction was carried out for a time. After completion of the reaction, diatomaceous earth (celite) was laid and filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was treated with methanol and ether to crystallize, filtered, washed with ether and dried to yield 0.35 g (yield 91%) of the title compound.

m.p. : 163-165 ℃

Example 15 1- [4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoyl] -4- (4-acetylphenyl) piperazine ( Compound number 13)

1- (4-acetylphenyl) piperazine from 4- [1- [3- (isopropylamino) -2-pyridyl] piperazin-4-yl-carbonyl] benzoic acid obtained in Example 2 above Synthesis by the method of Example 3 and recrystallized with ethyl acetate and ether to prepare the target compound.

Yield: 70%

m.p. : 200 ~ 202 ℃

Experimental Example 1 In vivo Inhibitory Activity Test of Hepatitis B Virus Polymerase

Recently, the present inventors have filed a patent application by expressing and separating the recombinant polymerase protein of hepatitis B virus in E. coli and measuring the enzyme activity thereof (Korean Patent Application Nos. 94-3918 and 96-33998). The inventors have established a method for measuring reverse transcriptase activity of hepatitis B virus polymerase in vivo using this enzyme. The basic principle is the same as the enzyme-immunological method (ELISA), and the reaction is performed by incorporating biotin- and DIG-modified nucleotides into the substrate, and then using the anti-DIG antibody attached to the polymerized substrate. Recognition method was used.

20 μl of hepatitis B virus polymerase, 20 μl of reaction mixture and 20 μl of sample were mixed and reacted at 14 ° C. to 30 ° C. for 18 to 24 hours, and compared with the result of control experiment without sample. Reverse transcriptase inhibitory activity was confirmed.

The inhibitory activity results of each sample are shown in Table 1 below.

Experimental Example 2: Hepatitis B virus DNA polymerase inhibition test secreted from hepatitis B virus producing cell line

Hepatitis B virus producing and secreting a cell line (HepG 2.2.15), the inhibitor candidate was treated with 1 nM at a final concentration of 10 μM and incubated for 1 week, the culture medium was taken separately, and then concentrated 5 μL of virus particles Take Polymerase buffer solution containing 10 μM dGTP, dCTP and dATP (50 mM Tris-Cl, pH 7.4, 30 mM NH ₄ Cl, 20 mM MgCl ₂ , 0.55 Nonidet P-40, 0.3% 2-mercaptoethanol) and 1 μCi, respectively. Α- ³² P-dTTP (3000 Ci / mmol) was mixed and reacted at 37 ° C. for 120 minutes. After the reaction, the mixture was treated with 1% SDS and 0.2 mg / mL proteinase K, and then extracted twice with saturated phenol to remove the protein. Radioactivity was measured using DEAE-cellulose (DE-81) paper or electrophoresed on a 0.8% agarose gel after passing the reaction solution through a Sephadex G-50 column. Based on the measured amount of radioactivity, the degree of activity inhibition of HBV DNA polymerase was calculated. Inhibitory activity of each sample is shown in Table 1 below.

TABLE 1

According to the experimental results of Table 1, in the case of compound No. 2 and compound No. 8 of the present invention, the enzyme inhibitory activity in vivo is relatively weaker than that of compound No. 9, but all the inhibitory activity in the cell line is strong. As a result, the terephthalic acid amide derivative according to the present invention is considered to have another inhibitory mechanism in addition to the reverse transcription inhibitory action of hepatitis B virus polymerase.

In addition, even in the measurement results according to the known method, the terephthalic acid amide derivative according to the present invention did not show cytotoxicity (Cytotoxicity) up to 200 μM.

Therefore, since the S.I. (Selectivity Index) indicating the drug-to-toxic ratio is 1,000 or more, it was found that the terephthalic acid amide derivative of the present invention has excellent action selectivity.

The terephthalic acid amide derivative according to the present invention is effective in the treatment and prevention of hepatitis B because of its excellent antiviral action against hepatitis B virus and of no cytotoxicity.

Claims (4)

A terephthalic acid amide derivative comprising a substituted phenylpiperazine group represented by the following formula (1) and a pharmaceutically acceptable salt thereof: [Formula 1] In the above formula, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group or a lower acyl group, a trifluoromethyl group, an amino group or a nitro group. The compound according to claim 1, wherein R ¹ is a hydrogen atom, a fluorine atom, a methyl group, a methoxy group or an ethoxy group. 1) preparing a compound represented by the following Chemical Formula 4 by reacting the compound represented by the following Chemical Formula 2 with the compound represented by the following Chemical Formula 3; 2) hydrolyzing the benzoic acid methyl ester represented by Chemical Formula 4 to prepare a compound represented by the following Chemical Formula 5; And 3) a process of reacting a compound represented by Formula 5 with an acid chloride to produce an acid anhydride, and then reacting it with a compound represented by Formula 6 Method for producing a terephthalic acid amide derivative represented by the following formula (1) characterized in that consisting of: [Formula 2] [Formula 3] [Formula 4] [Formula 5] [Formula 6] [Formula 1] In the above formulas, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group or a lower acyl group, a trifluoromethyl group, an amino group or a nitro group. A prophylactic and therapeutic agent for hepatitis B characterized by containing a terephthalic acid amide derivative represented by the following Chemical Formula 1 and a pharmaceutically acceptable salt thereof: [Formula 1] In Formula 1, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group or a lower acyl group, a trifluoromethyl group, an amino group or a nitro group.